Cyclotrimerization approach to unnatural structural modifications of pancratistatin and other amaryllidaceae constituents - Synthesis and biological evaluation

Article abstract of DOI:10.1139/V06-078

The phenanthridone core of pancratistatin lacking all aromatic oxygenation was prepared by cyclotrimerization of acetylene-containing scaffolds 30 and 41, reflecting the natural and the C-1 epi configuration, respectively, of the amino inositol moiety. Th

Full text of DOI:10.1139/V06-078

1313
Cyclotrimerization approach to unnatural
structural modifications of pancratistatin and
other amaryllidaceae constituents — Synthesis
and biological evaluation1
Tomas Hudlicky, Michael Moser, Scott C. Banfield, Uwe Rinner,
Jean-Charles Chapuis, and George R. Pettit
Abstract: The phenanthridone core of pancratistatin lacking all aromatic oxygenation was prepared by
cyclotrimerization of acetylene-containing scaffolds 30 and 41, reflecting the natural and the C-1 epi configuration, re-
spectively, of the amino inositol moiety. The cobalt-catalyzed formation of the aromatic core led to bisTMS derivatives
39 and 48, as well as bisacetyl derivative 51. The effectiveness of cyclotrimerization of the natural or trans series was
compared with that of the cis series. In addition, the yields of cyclotrimerization were compared for propargylic amines
and propargylic amides. Eleven derivatives, including the fully hydroxylated phenantridone 39, were tested against
seven cancer cell lines. Three of the compounds displayed activities only an order of magnitude less than those of 7-
deoxypancratistatin. Full experimental and spectral details are provided for all key compounds and future projections
for the preparation of unnatural analogs of Amaryllidaceae constituents are advanced, along with some new insight into
the minimum pharmacophore of pancratistatin.
Key words: cyclotrimerization, alkaloids, cobalt catalyst.
Résumé : Faisant appel à une cyclotrimérisation des dérivés acétyléniques 30 et 41 qui reflètent respectivement les
configurations naturelle et C-1-épi, on a préparé la phénanthridone, le squelette fondamental de la pancratistatine ne
comportant pas d’oxygène aromatique. La formation catalysée par le cobalt du noyau fondamental à conduit aux déri-
vés bisTMS 39 et 48 ainsi qu’au dérivé bisacétylé 51. On a comparé l’efficacité de la cyclotrimérisation de la série na-
ture ou trans avec celle de la série cis. De plus, on a comparé les rendements des cyclotrimérisations avec des amines
et des amides propargyliques. Onze dérivés, y compris la phénantridone totalement hydroxylé (39) ont été évalués
contre sept souches de cancer. Trois de ces composés présentent des activités qui ne sont qu’un ordre de grandeur infé-
rieures à celle de la 7-désoxypancratistatine. On rapporte l’ensemble des détails expérimentaux et spectraux relatifs à
tous les intermédiaires clés. Les projections relatives à la préparation d’analogues non naturels des constituants de
l’Amaryllidaceae sont avancées et l’on possède déjà de nombreuses pistes nouvelles concernant la nature du pharmaco-
phore minimal de la pancratistatine.
Mots clés : cyclotrimérisation, alcaloïdes, catalyseur de cobalt.
[Traduit par la Rédaction] Hudlicky et al. 1337
Introduction
and significant effort has been devoted to the investigation
of the mode of action (6), active pharmacophore (7), and
more bioavailable agents (8). To date many truncated ver-
sions of the key constituents have been prepared (9) and
evaluated for activities against several cancer cell lines.
From the results of these evaluations, several generalizations
Pancratistatin (1) and its congeners (Fig. 1) have been at
the forefront of activities in both synthetic and medicinal
communities (1). All four naturally occurring constituents
have been synthesized by many creative approaches (2–5),
Received 7 November 2005. Accepted 4 March 2006. Published on the NRC Research Press Web site at http://canjchem.nrc.ca on
1 August 2006.
Dedicated to Dr. Alfred Bader in recognition of his service to the organic chemistry community.
T. Hudlicky,2 M. Moser, and S. Banfield. Department of Chemistry and Centre for Biotechnology, Brock University,
500 Glenridge Avenue, St. Catharines, ON L2S 3A1, Canada.
U. Rinner. Institut für Organische Chemie, Universität Wien, Währinger Strasse 38, 1090 Wien, Austria.
G.R. Pettit. Department of Chemistry and Biochemistry and the Cancer Research Institute, Arizona State University, Tempe,
Arizona 85287, USA.
1This article is part of a Special Issue dedicated to Dr. Alfred Bader.
2Corresponding author (e-mail: thudlicky@brocku.ca).
Can. J. Chem. 84: 1313–1337 (2006)
doi:10.1139/V06-078
© 2006 NRC Canada

1314
Can. J. Chem. Vol. 84, 2006
Fig. 1. Amaryllidaceae constituents (1–4) and some recently syn-
thesized unnatural mimics (5–7).
for eventual attachment to the amino inositol unit, we have
chosen the cyclotrimerization approach portrayed in Fig. 2,
which is based on acetylene- and nitrile-containing scaffolds
and their cobalt-catalyzed trimerization to aromatic (15) and
heteroaromatic (16) variants of the pancratistatin type. This
unique transformation was discovered in 1864 by Berthelot
(17), who prepared benzene by passing acetylene over hot
copper. We note that Berthelot’s paper, published in 1866, is
usually cited as the event of original discovery (17b, 17c).
This is not the correct citation and for historical interest we
include the original description of his 1864 experiment here:
Il est un cas de condensation de l’acetylene naissant très-
remarquable et qui mérite un examen particulier, bien que la
démonstration en soit plutôt vraisemblable que rigoureuse-
ment établie: c’est la condensation de l’acétylène en ben-
zine. Entre la formule de l’acétylène, C4H2, et celle de la
benzine C12H6, c’est-à-dire entre les poids de ces deux corps
ramenés à l’état gazeux et au même volume, il existe une re-
lation très-simple; la deuxième formule est triple de la pre-
mière :
H
O
H
O
HO
OH
OH
OH
OH
2
1
3
10 10b
O
O
O
O
6
NH
NH
7
OH
O
OH
O
Pancratistatin (1)
Narciclasine (2)
OH
OH
O
H
H
O
H
O
O
O
O
O
OH
OH
NH
NH
O
O
7-Deoxypancratistatin (3)
Lycoricidine (4)
3 C4H2 = C12H6.
H
H
O
O
Or cette relation n’existe pas seulement entre les formulas
des deux corps; mais on peut admettre que, dans certaines
circonstances que nous allons signaler, l’acétylène naissant
se transforme réellement en benzine. Voici ces circonstances.
Nous avons vu précédemment (p. 286) qu’en faisant pas-
ser un courant de vapeur de formène trichloré (chloroforme),
C2HCl3, sur du cuivre chauffé au rouge, le chlore est absorbé
et l’acétylène prend naissance. Répétons cette expérience
avec le formène tribromé (bromoforme), C2HBr3, nous ob-
tiendrons de la benzine. Nous sommes donc autorisés à pen-
ser que 3 molécules d’acétylène naissant peuvent se
condenser en une seule molécule de benzine : la benzine se-
rait alors du triacétylène.
OH
OH
HO
OH
OH
4
O
O
O
NH
N
H
X
O
O
5
L
actone narciclasine mimic, 7 β-Carboline-1-one
X = OH mimic
6 Lactone lycoricidine mimic,
X = H
have emerged with regard to the structural elements essen-
tial to activity. First, the hydroxyphenanthridone moiety is
thought to be essential to high activity of pancratistatin and
narciclasine; its deletion, as in 7-deoxypancratistatin and
lycoricidine, leads to a significant drop in activity (10). Sec-
ond, the amino inositol motif is also essential, save for small
changes at C-1 and C-2; deletion of the hydroxyls at these
positions or altering substitution patterns at C-1 does not al-
together eliminate activity (7, 11). Various unnatural deriva-
tives with specific deletions in the hydroxylated ring have
been tested. A recent article established that the minimum
requirement for activity is the 2,3,4-triol pattern found in all
active constituents (11). Third, deletion of some of the aro-
matic oxygenation lowers activity significantly (12). Fourth,
recently synthesized lactone mimics 5 and 6, in both config-
urations at C-4, were found inactive, suggesting that the
phenanthridone unit is essential for retention of activity (13).
Finally, an indole mimic of pancratistatin (7) recently pre-
pared in our laboratory possessed borderline activity against
one cell line (Table 1) (14).
This is an example of condensation of the nascent acety-
lene that is very remarkable and deserves a close examina-
tion, even though the demonstration is rather plausible then
rigorously established: it is the condensation of the acetylene
into benzene. There is a very simple relationship between
the formula of acetylene, C4H2, and the formula of benzene,
C12H6, specifically between the weight of equal volumes of
those two bodies in the gas state: the second formula is triple
of the first:
3 C4H2 = C12H6.
Now such relation does not just exist between the formu-
las of the two bodies; but we can admit that under certain
particular circumstances that we may point to, nascent acety-
lene is actually transformed to benzene. We have already
seen (p.286) that by passing
a stream of gaseous
trichlorinated formene (chloroform), C2HCl3, over red-hot
copper, chlorine is absorbed and acetylene is generated. By
repeating this experience with tribrominated formene
(bromofrom), C2HBr3, we would obtain some benzene. This
leads us to think that three molecules of nascent acetylene
could combine to form a single molecule of benzene. Thus
benzene would be a triacetylene.
The reaction enjoyed moderate attention and, indeed, ex-
hibited moderate yields in most of the documented examples
in the literature, including recent applications (18). An ex-
These observations, as well as the bioavailability studies,
indicate that the greatest opportunity for structural alter-
ations exists in modifications of the aromatic core of the nat-
ural product. To prepare a large number of derivatives, a
diversity-oriented synthesis strategy (DOS) is the most effi-
cient way to generate libraries of compounds for testing.
Rather than synthesize uniquely functionalized aryl residues
© 2006 NRC Canada

Hudlicky et al.
Table 1. Evaluation of the activities of aromatic deoxygenated TMS derivatives of 7-deoxypancratistatin.
1315
OH
Murine P388 lumphocytic leukemia and human cancer cell results (GI50 values in µg/mL)
HO
OH
OH
Murine P388
O
O
1
2
3
4
5
6
7
0.039
0.028
0.032
Breast
0.017
CNS
0.048
0.062
0.016
NCI-H460 KM20L2
lymphocytic
leukemia
Pancreas
BXPC-3
Lung
Colon
Prostate
DU-145
NH
1
OH
O
Entry
Compound
MCF-7
SF-268
OH
HO
OH
OH
O
O
0.44
0.0012
18.3
0.29
0.22
0.021
>10
3.6
NH
3
O
OH
OH
OH
O
O
0.026
>10
4.9
0.019
0.021
0.032
0.011
NH
2
OH
O
OH
HO
OH
OH
>10
4.4
NH
N
H
7
O
OH
NH
HO
OH
OH
MeO
4.3
3.3
> 10
3.8
2.8
> 10
4.7
2.6
52
O
OTBS
BzO
O
O
TMS
TMS
> 10
> 10
3.6
> 10
2.2
> 10
3.1
> 10
13.1
NTs
31
OTBS
HO
O
O
TMS
TMS
NTs
32
ception to such critique is found in the classic application of
cyclotrimerization to the total synthesis of estrone by Funk
and Vollhardt in 1977 (19), shown in Fig. 3. Despite the at-
tention this synthesis received, only once more was this
technique featured in a total synthesis effort — an approach
to morphine also disclosed by Vollhardt and co-workers (20)
(Fig. 3). In the estrone synthesis, the initial cyclization fur-
nished a low yield of 13 in addition to the intermediate
benzocyclobutane, which, under the conditions of the reac-
tion, underwent [4+2] cyclization to 13 in a total yield of
71%. In the approach to morphine, benzofuran 15 yielded
the tetracyclic morphine skeleton as a single diastereomer
with C-5, C-9, and C-13 correctly set, indicating the poten-
tial for adjustment to the total synthesis of morphine itself,
once appropriate substitution parameters for the incipient
quaternary center at C-13 were designed. The emphasis on
multicomponent reactions and cascade processes, so preva-
lent in the last decade or so (21, 22), seemed in sharp con-
trast to the apparent underutilization of cyclotrimerization
techniques that satisfy both of these criteria. We reasoned
that the modest yields reported in most of the applications
could be addressed though appropriate reaction engineering
and optimization of conditions. The benefits that would be
harvested in the area of structure and activity relationships
(SAR) for the analogs of the pancratistatin group of com-
pounds seemed to outweigh the uncertainty and expectations
of moderate yields in the construction of aromatic nuclei of
the analogs.
In this manuscript we report the successful synthesis of
several pancratistatin analogs by a high-yielding cyclotri-
© 2006 NRC Canada

1316
Can. J. Chem. Vol. 84, 2006
Table 1 (concluded).
Murine P388 lumphocytic leukemia and human cancer cell results (GI50 values in µg/mL)
Murine P388
lymphocytic
leukemia
Pancreas
BXPC-3
Breast
CNS
Lung
Colon
Prostate
DU-145
Entry
Compound
MCF-7 SF-268 NCI-H460 KM20L2
OH
HO
O
O
TMS
TMS
8
NTs
3.0
1.7
1.5
1.7
1.6
1.6
1.7
1.7
1.6
1.4
1.6
1.8
33
OH
HO
OH
OH
TMS
TMS
9
3.3
3.9
1.7
NTs
34
OH
HO
O
O
TMS
TMS
10
NTs
43
Note: Compounds 36, 37, 38, 39, 44, and 48 are marginally inactive to completely inactive in the p388 leukemia cell lines.
merization protocol from fully functionalized scaffolds of
type 9 (23). The biological evaluation of the analogs, also
reported herein, provided some surprising results and cast
some uncertainty on the previously held views regarding
some of the structural features deemed essential for biologi-
cal function.
of the steric issues associated with multiply silylated sites or
perhaps random desilylation processes similar to those ob-
served when Rainier used an iron-based catalyst (24). Only
the cobalt-coordinated tetracycle 20 was isolated in low
yield from the reactions of bisacetylene 19 (Scheme 1). The
final cycloaddition of bis(trimethylsilyl)acetylene (BTMSA)
did not lead to the fully silylated arene 21, presumably be-
cause of steric crowding.
When Ni(COD)2 was employed as a catalyst, the cyclo-
trimerization of 22 gave an interesting dimeric product (23)
in 47% yield. The use of a zirconium catalyst (25) did not
lead to dimeric 23 and gave other products.3
Results and discussion
The original intent of our study was the investigation of a
de novo approach to pancratistatin (1) from scaffold 9 in
which the acetylene partners would provide a triply silylated
arene that could be converted to the fully oxygenated core of
pancratistatin. Portrayed in Scheme 1 are the results of this
particular approach, which met with abject failure because
Adjustments in the strategic plan led to the construction of
simpler scaffolds unencumbered by TMS groups and
cyclotrimerization attempts to attain a 7-deoxypancratistatin
3 The exposure of propargylic amide 22 to a zirconium-based catalyst led to some unusal results. The propargylic amide was lost and
tosylamide 18 was recovered, in addition to an unusual structure, tentatively identified as cyclic allene A, which may result in an ene reac-
tion between the propargyl group and the hydrogen at 10b.
A [(1R,2S,6R)-4,4-Dimethyl-12-methylene-14-(4-methylphenylsulfonyl)-11-trimethylsilyl-3,5-dioxa-14-azatricyclo-[7.5.0.02,6]tetradeca-7,9,10-
trien-13-one]: [α]28D +79.0 (c 0.95, CHCl3). Rf 0.81 (hexanes – ethyl acetate, 4:1). IR (CHCl3, cm–1) ν: 3683, 3020, 2962, 2932, 2401, 2167,
1
1736, 1660, 1598, 1509, 1374, 1308, 1278, 1251, 1216, 1189, 1176, 1091, 1063, 950, 908, 847, 757, 669, 582. H NMR (300 MHz, CDCl3,
50 °C, ppm) δ: 8.00 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 6.11 (s, 1H), 5.80 (dd, J = 9.9, 3.1 Hz, 1H), 5.64 (d, J = 10.2 Hz, 1H),
4.71 (t, J = 5.0 Hz, 1H), 4.63 (d, J = 4.8 Hz, 1H), 4.40 (m, 1 H), 2.43 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 0.14 (s, 9H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 145.6, 142.7, 135.5, 129.8, 128.9, 128.0, 125.1, 121.5, 110.7, 104.0, 77.5, 74.4, 69.8, 62.9, 41.0, 28.1, 27.0, 22.0, 0.0. MS
(EI) m/z (relative intensity): 456 (M+ – CH3, 30), 415 (10), 414 (30), 413 (23), 259 (11), 258 (30), 242 (7), 230 (10), 220 (5), 215 (5), 161
(6), 156 (8), 155 (29), 149 (11), 140 (5), 139 (13), 129 (6), 108 (5), 107 (7), 106 (12), 105 (9), 99 (6), 98 (11). HRMS (EI) calcd. for
C23H26O5NSSi-CH3: 456.1301; found: 456.1289.
© 2006 NRC Canada

Hudlicky et al.
1317
Fig. 2. Cyclotrimerization approach to aromatic core variants of
pancratistatin.
intermediate sulfate anion 25a as shown in Fig. 4. Further
study is required to optimize the production of either 26 or
27, the latter containing the structural features of narcicla-
sine.
OR
OR
RO
OR
OR
RO
OR
OR
Y
Y
The TMS group was removed with tetrabutylammonium
triphenyldifluorosilicate (TBAT) in 84% yield from acety-
lene 26 to avoid previously encountered problems with steric
bulk at the incipient C-10 of the aromatic nucleus. Following
the protection of the C-2 alcohol as a TBS ether (89%),
tosylamide 29 was alkylated with propargyl bromide to yield
the required compound 30 in 79% yield. As mentioned above,
the prospects for high yields in the cyclotrimerization were
not promising based on the rather modest yields reported
throughout the literature. Yet, after optimization, acetylene
derivative 30 was converted to tetracyclic tosylamide 31 in
83% yield (slow addition over 36 h of a mixture of 30, cata-
lyst, and BTMSA to a heated solution of BTMSA, which
was recovered by distillation upon completion of the reac-
tion). Tosylamide 31 was converted to fully deprotected
tetraol 34 (as shown in Scheme 3) to provide compounds
lacking the phenanthridone carbonyl group for biological
evaluation. Oxidation of 31 to the state of phenanthridone
proved somewhat arduous, proceeding in 15% yield to 35
with NaIO4–RuCl3. Oxidation studies on bisbenzoate 37 led
to the same results under these conditions. With the reaction
buffered by solid Na2CO3, the oxidation occurred more
slowly to give 38 in 33% yield. This material was subjected
to reductive detosylation with sodium naphthalide, during
which a partial loss of the benzoate groups occurred as a re-
sult of the basic conditions. The crude material was treated
first under stronger basic conditions CH3ONa in MeOH)
then under acidic conditions (Dowex 50WX8-100 in MeOH)
to provide the 7-deoxypancratistatin nucleus having TMS
groups in place of the aromatic oxygenation. The prepara-
tion of this key compound in 14 steps and 0.3% overall yield
starting from aziridine 10 signified the successful validation
of the cyclotrimerization strategy as an approach to com-
pounds with variations in the aromatic core.
Y
X
X
Y
Y
Y
X
X
X
X
H
N
Ts
N
X
Y
X
Y
O
Z
8
9
Br
OH
OH
O
O
sN
T
Nu-
11
10
E+
R = Ac, TBS, C(Me)2
X = C, N
Y = H, TMS, O-, COCH3
Z = H2, O
substitution pattern instead. These efforts were divided into
three distinct areas: (i) synthesis of building blocks exhibit-
ing the stereochemistry of the “natural” or trans series, with
respect to stereochemical configuration at C-1 and C-2;
(ii) synthesis of the corresponding “unnatural” or cis series;
and (iii) comparison of the overall efficiency of these two
approaches with one that would employ propargyl amides
vs. propargyl amines. Upon attaining the nucleus of Amaryl-
lidaceae constituents, all of these approaches would be eval-
uated and the best one chosen for the eventual production of
analogs.
Cyclotrimerization of scaffolds in the trans or natural
series
The intermediate reflecting the natural amino inositol con-
figuration was synthesized as shown in Scheme 2 (23).
Vinylaziridine 10 (26) was reacted with the aluminum com-
plex prepared from lithium (trimethylsilyl)acetylene to pro-
vide 18 in 69% yield. After column chromatography, the
product of this reaction was treated with 2,2-dimethoxy-
propane (DMP) and acetone to reprotect the diol liberated in
the portion of the mixture by the action of AlCl3. The
reprotected compound was used without further purification.
The tosylaziridine 18 was first converted to the cis-diol 24
by the action of OsO4 and N-methylmorpholine-N-oxide
(NMO) (44% yield, 76% conversion), and the cyclic sulfate
25 was then generated in 82% yield by treatment with
SO2Cl2 and NEt3. Cyclic sulfates, whose reactivity resem-
bles that of epoxides (27), are easily opened with weak
nucleophiles such as ammonium benzoate. Such opening
generates the required trans relationship at C-1/C-2 of pan-
cratistatin, as has been previously demonstrated (27b). Treat-
ment of 25 with ammonium benzoate generated,
surprisingly, a mixture of the desired 26, as a minor product
accompanied by the elimination product 27, displaying the
substitution parameters of narciclasine or lycoricidine. In-
vestigation of this reaction revealed that 27 does not origi-
nate in 26 nor is it derived from 25 by syn elimination.
Careful experimentation revealed that the likely source of 27
is the intramolecular elimination of proton at C-10b by the
Cyclotrimerization of scaffolds in the cis or unnatural
series
The unnatural or cis series intermediate was synthesized
as shown in Scheme 4. The purpose of this approach was
twofold. First, it would avoid the lack of selectivity in the
cyclic sulfate opening encountered with 25, leaving this re-
action for the latter part of the synthesis. Second, it would
provide the analogs with unnatural C-1 configuration for
biological testing. The bisbenzoate 41 was subjected to
cyclotrimerization under the optimized conditions applied to
compound 30 in the trans series and provided tetracycle 42
in 87% yield (as shown in Scheme 5).
Deprotection of the benzoate and generation of the cyclic
sulfate was accomplished in high yield and trans-benzoate
alcohol 36 was generated in essentially quantitative yield.
Upon exposure of 44 to ammonium benzoate in dimethyl-
formamide (DMF) in this series, the elimination to the
narciclasine/lycoricidine manifold was not observed. A pos-
sible explanation may lie in the relative acidities of pro-
pargylic vs. benzylic protons at C-10b in 25 vs. 44,
respectively. Fully deprotected analogs 34 (lacking the phen-
anthridone carbonyl) and 39 (containing the amide) were ob-
© 2006 NRC Canada

1318
Can. J. Chem. Vol. 84, 2006
Fig. 3. Applications of cyclotrimerization strategy in total synthesis (Vollhardt’s estrone and morphine).
O
O
TMS
CoCp(CO)2
71%
TMS
TMS
+
H
H
M
T
S
12
13
O
H
H
Estrone (14)
HO
MeO
MeO
MeO
O
CoCp(C2H4)2
O
O
13
9
TMS
X
X
NMe
5
TMS
HO
CoCp
TMS
TMS
15 X = NMeAc
16
Morphine (17)
Scheme 1. Cyclotrimerization approach to fully silylated aromatic core. Reagents and conditions: (i) DMP, p-TSA, acetone, rt, then
PhINTs, Cu(acac)2, H3CCN, 0 °C to rt, then n-Bu3SnH, AIBN, THF, reflux, 25% over three steps; (ii) BuLi, TMS–acetylene, AlCl3,
toluene, 0 °C to rt, then DMP, p-TSA, acetone, rt, 69% over two steps; (iii) BuLi, TMS – propargyl bromide, (n-Bu)4NI, THF, rt, 46%
(66% by conversion); (iv) CpCo(CO)2, BTMSA, 140 °C; (v) BuLi, propiolic acid anhydride, THF, 0 °C to rt, 46%; (vi) Ni(COD)2,
PPh3, toluene, BTMSA, rt, 47%.
Br
OH
O
O
O
O
i
ii
OH
TsN
HTs
N
18
TMS
11
10
iii
v
O
O
O
O
O
O
MS
T
iv
O
NTs
TMS
NTs
TMS
NTs
TMS
CoCp
O
20
19
22
TMS
vi
O
O
O
O
TMS
TMS
TMS
TMS
TMS
O
Ts
N
O
NTs
NTs
O
O
21
23
TMS
© 2006 NRC Canada

Hudlicky et al.
1319
Scheme 2. Scaffold for cyclotrimerization in the trans or natural series. Reagents and conditions: (i) BuLi, TMS–acetylene, AlCl3, to-
luene, 0 °C to rt; (ii) DMP, acetone, rt, 69% over two steps; (iii) OsO4, NMO, CH2Cl2, rt, 44% (76% by conversion); (iv) SO2Cl2,
NEt3, CH2Cl2, 0 °C to rt, 82%; (v) H5C6COONH4, DMF, 70 °C, then H2O, H2SO4, THF, rt; (vi) TBAT, H3CCN, rt, 84%; (vii) TBSCl,
imidazole, DMF, rt, 89%; (viii) NaHMDS, propargyl bromide, (nBu)4NI, THF, –0 °C to rt, 79%.
O
O
S
OH
O
2
O
O
H
1
O
O
O
O
O
O
O
O
i, ii
iii
iv
10b
TsN
BzO
H
TMS
NHTs
TMS
NHTs
TMS
NHTs
10
18
24
25
v
OTBS
OR
OH
OH
BzO
BzO
O
O
O
O
O
O
O
O
viii
vi
+
NTs trans
series
NHTs
TMS
NHTs
26 (33%)
TMS
NHTs
30
28, R = H
29, R = TBS
27 (60%)
vii
Synthesis of the bisacetyl derivative of 7-
deoxypancratistatin
Fig. 4. Generation of enyne 25.
O
O
As a prelude to a de novo synthesis of one of the Amaryl-
lidaceae constituents, we decided to prepare the bisacetyl
derivative 51 shown in Scheme 7. Both arylsilanes and
acetophenones should respond to Tamao oxidation (28) or
Baeyer–Villiger oxidation (29), respectively, as means of
generating the required oxygenation of the aromatic nucleus.
Having noticed the experimental difficulties experienced by
Vollhardt and Funk (19) in establishing the phenolic unit in
estrone from a TMS group, we thought the bis(acetyl)arene
would provide an alternative way to accomplish this task. To
this end, the cyclotrimerization of bisacetylene 41 (cis se-
ries) was performed with hex-3-yne-2,5-diol protected as a
bisTBS ether 49. Tetracycle 50 was obtained as a mixture of
diastereomers in 31% yield. The mixture was treated with
tetrabutylammonium fluoride (TBAF) and oxidized to the
bisacylated tetracycle 51 in 51% yield over two steps. In fu-
ture endeavors, the oxidation of this compound to acetyl
catechols will be pursued as the means of establishing the
C-8/C-9 oxygenation of pancratistatin-type constituents.
S
H+
O
O
26
O
O
O
25
+
O
-PhCO2
27
H
MS
T
HTs
N
25a
tained in a manner similar to that employed in the trans
series. Overall, the cis series synthesis of phenanthridone 48
proved to be three times higher yielding because of higher
selectivity in the cyclic sulfate opening. The eventual syn-
thesis of C-1 epimeric analogs would originate in the cis-
diol 24.
Cyclotrimerization of propargyl amides
To avoid the modest yields of benzylic oxidation in the
tetracycles 31 and 37, we chose to investigate the cyclo-
trimerization protocol on propargylic amides, which could
be easily generated by acylation of tosylamide 18. Initially,
the enyne 45, obtained by acylation of 18 with propiolic acid
anhydride, was chosen for this purpose (as shown in
Scheme 6). Cyclotrimerization of this material furnished
metal complex 46 in 11% yield and with apparent isomeri-
zation of the olefin to the configuration representing 2-
deoxylycoricidine. When 47 was synthesized from 40 in
35% yield over two steps (cis series) and subjected to the
same optimized conditions for cyclotrimerization, the
tetracyclic phenanthridone 48 was obtained in 5% yield. It
remains unclear whether these low yields are a function of
unfavorable rotamer population of the imides such as 45 or
47 or whether the additional basic oxygen interferes with the
catalytic cycle by complexation with the catalyst. Apparently
these issues did not prevent the aforementioned cyclo-
trimerization of amide 22 to the dimeric phenanthridone 23
obtained in 47% yield (Scheme 1).
Biological evaluation
Several of the compounds in both the trans or natural and
the C-1 epimeric series were evaluated in the cancer cell line
series listed in Table 1. The activity profiles of pancratista-
tin, 7-deoxypancratistatin, and narciclasine (Table 1, entries
1, 2, and 3, respectively) are shown for comparison, along
with two unnatural analogs previously synthesized in our
laboratory (Table 1, entries 4 and 5). Some rather surprising
and unexpected results were obtained. While the fully pro-
tected core of 7-deoxypancratistatin (Table 1, entry 6) is es-
sentially inactive, the partially deprotected intermediates
(Table 1, entries 7 and 8), as well as the fully deprotected
tetraol (Table 1, entry 9) are quite active, having activities
only 10-fold less than those of 7-deoxypancratistatin. This is
surprising for several reasons: First, it has been widely held
that the phenathridone amide carbonyl is essential for activ-
ity, since Chapleur and co-workers (13) demonstrated that
© 2006 NRC Canada

1320
Can. J. Chem. Vol. 84, 2006
Scheme 3. Cyclotrimerization of the trans scaffold. Reagents and conditions: (i) CpCo(CO)2, BTMSA, xylene, 140 °C, 83%;
(ii) NaOMe, MeOH, rt, 99%; (iii) TBAF, THF, rt, 85%; (iv) Dowex 50WX8-100, MeOH, 70 °C, 79%; (v) NaIO4, RuCl3, CH3CN–
CCl4–H2O, rt, 15%; (vi) TBAF, THF, rt, 84%; (vii) BzCl, pyridine, rt, 86%; (viii) NaIO4, RuCl3, Na2CO3, CH3CN–CCl4–H2O, rt, 33%;
(ix) Na-naphthalide, THF, –65 °C, then NaOMe, MeOH, rt, 32%; (x) Dowex 50WX8-100, MeOH, 70 °C, 94%.
OTBS
OTBS
OR
BzO
BzO
HO
O
O
O
O
O
O
TMS
TMS
TMS
TMS
i
ii
NTs
NTs
NTs
30
31
32, R = TBS
33, R = H
iii
vi
v
iv
OH
OTBS
NTs
OH
BzO
BzO
HO
OH
O
O
O
O
TMS
TMS
TMS
TMS
TMS
TMS
OH
34
NTs
NTs
OH
36
35
O
vii
OBz
OBz
NTs
BzO
BzO
HO
OH
OH
O
O
O
O
TMS
TMS
TMS
TMS
TMS
TMS
ix, x
viii
NTs
NH
37
38
39
O
O
Scheme 4. Scaffold for cyclotrimerization in the cis or unnatural series. Reagents and conditions: (i) BzCl, pyridine, 0 °C to rt, 80%;
(ii) TBAT, H3CCN, rt, 76%; (iii) NaHMDS, propargyl bromide, (nBu)4NI, THF, –70 °C to rt, 94%.
OH
OBz
OBz
HO
BzO
BzO
O
O
O
O
O
O
i
ii, iii
TMS
NHTs
TMS
NHTs
NTs cis
series
41
24
40
the lactone analogs 5 and 6 are inactive. Second, these com-
pounds represent the first examples of pancratistatin analogs
that retain activity despite the absence of all aromatic oxy-
genation, in addition to lacking the amide moiety. Third, and
very surprising, these derivatives have shown greater activ-
ity than the fully deprotected bisTMS derivative 39 (Table 1,
entry 16) in which the phenanthridone amide is present. This
difference in activity may also be ascribed to the fact that a
tosyl group is a common pharmacophore and several trun-
cated derivatives of pancratistatin containing tosyl groups
were shown to be more active than those lacking it (9c). As
it has been assumed that the phenolic hydroxyl and the am-
ide may be required as a donor–acceptor pair for hydrogen
bonding, our results indicate that these requirements may be
offset by other structural features. The only other active
compound was the C-1 epimeric diol (Table 1, entry 10),
where activity supports the observation that changes at C-1
of the pharmacophore do not drastically alter biological
profiles. The fact that four of the intermediates displayed
profiles only an order of magnitude lower that those of
7-deoxypancratistatin is promising and will guide us in fur-
ther design of unnatural analogs with variable functionality
in the aromatic core.
Summary and conclusion
The successful synthesis of several analogs of pancra-
tistatin was achieved by the cobalt-catalyzed cyclotrimeri-
zation of acetylenic scaffolds with BTMSA and protected
2,5-hex-3-yne. Both configurations at the C-1 hydroxylated
aminoinositol unit were examined, with the unnatural, or cis
series, being clearly a higher-yielding and more efficient
process. The cyclotrimerizations of bisacetylenes with N-
propargylic substituents were also much higher yielding than
the corresponding processes that employed the propargylic
amides. The attainment of bisacetyl derivative 51 bodes well
for eventual installation of the methylenedioxy unit via the
Baeyer–Villiger reaction in a de novo synthesis of 7-
© 2006 NRC Canada

Hudlicky et al.
1321
Scheme 5. Cyclotrimerization of the cis scaffold. Reagents and conditions: (i) CpCo(CO)2, BTMSA, xylene, 140 °C, 87%; (ii) 1%
NaOH, MeOH, rt, 99%; (iii) SO2Cl2, NEt3, CH2Cl2, 0 °C to rt, 70%; (iv) H5C6COONH4, DMF, 70 °C, 99%; (v) BzCl, pyridine, rt,
86%; (vi) NaIO4, RuCl3, Na2CO3, CH3CN–CCl4–H2O, rt, 33%; (vii) Na-naphthalide, THF, –65 °C, then NaOMe, MeOH, rt, 32%; (viii)
Dowex 50WX8-100, MeOH, 70 °C, 94%; (ix) NaOMe, MeOH, rt, 99%; (x) Dowex 50WX8-100, MeOH, 70 °C, 79%.
OBz
OBz
OH
BzO
BzO
HO
O
O
O
O
O
O
MS
MS
MS
MS
T
T
T
i
ii
NTs
OBz
NTs
OH
NTs
iii
T
41
42
43
O
O
S
O
O
BzO
BzO
OH
OH
O
O
O
O
10b
MS
MS
MS
MS
MS
MS
T
T
T
T
T
v
iv
Ts
N
Ts
N
Ts
N
T
37
36
44
ix, x
vi
B
O
H
O
H
O
z
BzO
HO
OH
OH
HO
OH
OH
O
O
TMS
TMS
TMS
TMS
TMS
TMS
vii, viii
NTs
NH
NTs
38
39
34
O
O
deoxypancratistatin. Based on the surprising and promising
results of biological activity, it now seems prudent to pro-
ceed further with the preparation of diversely functionalized
analogs of Amaryllidaceae constituents.
formed by the analytical division at Brock University, St.
Catharines, Ontario.
N-[(1R,2R,5R,6S)-2-(2-Trimethylsilylethynyl)-5,6-
(isopropylidenedioxy)cyclohex-3-en-1-yl]-4-methyl-
benzenesulfonamide (18)
Experimental section
O
CH3
All nonaqueous reactions were conducted in an argon at-
mosphere using standard Schlenk techniques for the exclu-
sion of moisture and air. Methylene chloride was distilled
from calcium hydride; THF and toluene were dried over po-
tassium/benzophenone. Analytical thin-layer chromatogra-
phy was performed on Silicycle 60 Å 250 µm TLC plates
with F-254 indicator. Flash column chromatography was
performed using silica gel 60 (230–400 mesh). Melting
points were recorded on a Hoover Unimelt apparatus and are
uncorrected. IR spectra were obtained on a PerkinElmer One
FT-IR spectrometer. Optical rotation was measured on a
CH3
O
H3C
HTs
N
Si
H
C
3
H3C
C21H29NO4SSi
419.61 g/mol
To a solution of of (trimethylsilyl)acetylene (2.75 g,
28.00 mmol) in 40 mL toluene was added BuLi (1.6 mol/L,
17.50 mL, 28.00 mmol) at 0 °C. During the addition, a
heavy white precipitate formed. The reaction mixture was
stirred at 0 °C for 10 min before AlCl3 (1.24 g, 9.33 mmol)
was added. After stirring for a further 10 min, aziridine 10
(1.00 g, 3.11 mmol), dissolved in 5 mL toluene, was added
dropwise. Additional AlCl3 (622 mg, 4.67 mmol) was added
and the suspension was allowed to warm to room tempera-
ture over 18 h. The reaction was quenched by addition of
1 mol/L HCl (100 mL) and diluted with ethyl acetate
(50 mL). The layers were separated and the aqueous layer
was extracted with ethyl acetate (3 × 50 mL). The combined
organic layers were washed with brine (40 mL), dried over
1
PerkinElmer 341 polarimeter at a wavelength of 589 nm. H
and 13C NMR spectra were recorded on a 300 MHz Brucker
spectrometer. All chemical shifts are referenced to TMS or
residual undeuterated solvent (CHCl3). The data for the pro-
ton spectra are reported as follows: chemical shift (multiplic-
ity, singlet (s), doublet (d), triplet (t), quartet (q), and
multiplet (m), coupling constants (Hz), integration). Carbon
spectra were recorded with complete proton decoupling and
the chemical shifts are reported in ppm (δ) relative to solvent
resonance as internal standard. Combustion analysis were
performed by Chemisar Laboratories Inc., Guelph, Ontario.
Mass spectra and high-resolution mass spectra were per-
© 2006 NRC Canada

1322
Can. J. Chem. Vol. 84, 2006
Scheme 6. Propargyl amide series. Reagents and conditions:
(i) DMP, p-TSA, acetone, rt, then PhINTs, Cu(acac)2, H3CCN,
0 °C to rt, then n-Bu3SnH, AIBN, THF, reflux, 25% over three
steps; (ii) BuLi, TMS–acetylene, AlCl3, toluene, 0 °C to rt, then
DMP, p-TSA, acetone, rt, 69% over two steps; (iii) BuLi,
propiolic acid anhydride, THF, 0 °C to rt, 46%; (iv) TBAT,
H3CCN, rt, 61%; (v) CpCo(CO)2, BTMSA, xylene, 140 °C,
11%; (vi) CpCo(CO)2, BTMSA, xylene, 140 °C, 5%.
MgSO4, and the solvent was removed under reduced pres-
sure. Flash column chromatography of the residue (hexanes –
ethyl acetate, 2:1 to 1:2) afforded the title compound and the
corresponding free diol. The diol was dissolved in 40 mL of
acetone and protected by addition of 2,2-dimethoxypropane
(486 mg, 4.67 mmol) and p-TSA (0.2 g). After 15 min the
solution was diluted with ethyl acetate (200 mL), washed
with satd. aq. NaHCO3 (3 × 40 mL) and brine (40 mL). The
organic phase was dried over MgSO4 and the solvent was re-
moved under reduced pressure affording 900 mg of pure
acetonide 18 (2.14 mmol, 69%); mp 168 °C. [α]21 +30.2 (c
0.20, CH2Cl2). Rf 0.48 (hexanes – ethyl acetateD, 2:1). IR
(CHCl3, cm–1) ν: 3269, 3020, 2401, 2176, 1600, 1427, 1375,
1330, 1251, 1216, 1159, 1094, 1075, 972, 928, 846, 759,
669. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.83 (d, J =
8.0 Hz, 2H), 7.26 (d, J = 7.5 Hz, 2H), 5.83 (m, 2H), 4.63 (d,
J = 8.0 Hz, 1H), 4.50 (m, 1H), 4.05 (dd, J = 8.5, 6.1 Hz,
1H), 3.60 (q, J = 8.3 Hz, 1H), 3.14 (d, J = 8.4 Hz, 1H), 2.41
(s, 3H), 1.34 (s, 3H), 1.26 (s, 3H), 0.14 (s, 9H). 13C NMR
(75 MHz, CDCl3, ppm) δ: 143.2, 138.9, 130.4, 129.4, 127.5,
124.6, 110.1, 103.5, 87.9, 76.5, 71.8, 56.8, 34.6, 27.9, 25.9,
21.6, 0.0. MS (EI) m/z (relative intensity): 420 (MH+, 0.6),
419 (M+, 1.6), 255 (12), 254 (76), 253 (17), 207 (20), 191
(11), 190 (20), 175 (26), 171 (10), 155 (28), 149 (16), 147
(11), 139 (43), 124 (17), 123 (10), 121 (16), 117 (7), 107
(10), 105 (10), 100 (10), 99 (82), 98 (57), 97 (11), 92 (15),
91 (100), 89 (10), 85 (10), 84 (13), 83 (15), 77 (12), 75 (24),
73 (64), 65 (16), 59 (11), 58 (14), 57 (10), 45 (14), 44 (18),
43 (56), 41 (11). HRMS (EI) calcd. for C21H29O4NSSi:
419.1587; found: 419.1582. Anal. calcd. for C21H29O4NSSi:
C 60.11, H 6.97; found: C 60.33, H 7.07.
Br
H
O
O
O
i
OH
TsN
11
10
ii
O
O
O
iii, iv
O
HTs
N
18
TMS
NTs
45
O
O
O
O
O
MS
T
v
NTs
NTs
TMS
45
46
O
O
COCoCp
BzO
OBz
OBz
(3aS,4R,5R,7aR)-2,2-Dimethyl-4-[4-methylphenyl(3-
trimethylsilyl-2-propynyl)sulfonamido]-5-(2-trimetylsilyl-
1-ethynyl)-3a,4,5,7a-tetrahydro-1,3-benzodioxole (19)
BzO
O
O
O
O
TMS
vi
Ts
N
Ts
N
MS
T
CH3
47
48
H3C
CH3
O
O
O
O
Si
CH3
CH3
Scheme 7. Bisketone approach. Reagents and conditions:
(i) CpCo(CO)2, xylene, 140 °C, 31%; (ii) TBAF, THF, rt, 72%;
(iii) IBX, DMSO, rt, 71%.
O
N
S
O
B
O
B
O z
Si
z
H
C
3
H3C
BzO
+
BzO
O
O
O
O
CH3
CH3
TBSO
OTBS
i
C27H39NO4SSi2
529.84 g/mol
NTs
NTs
TBSO
OTBS
To a solution of of tosylamide 18 (200 mg, 0.48 mmol) in
3 mL THF was added BuLi (1.6 mol/L, 0.30 mL,
0.48 mmol) at 0 °C under argon. The solution was stirred for
5 min and trimethylsilyl propargyl bromide (0.37 mL,
2.38 mmol) and a catalytic amount of N(n-Bu)4I were
added. The reaction mixture was allowed to stir for 1 h at
0 °C and then it was warmed to room temperature and
stirred for 16 h. The reaction was quenched by the addition
of satd. aq. NH4Cl (20 mL) and extracted with ethyl acetate
(4 × 20 mL). The combined organic phases were washed
with brine (10 mL), dried over MgSO4, and the solvent was
49
41
50
ii, iii
OBz
NTs
BzO
O
O
O
O
51
© 2006 NRC Canada

Hudlicky et al.
1323
removed under reduced pressure. Flash column chromatog-
raphy of the residue (hexanes – ethyl acetate, 7:1 to 2:1) af-
forded sulfonamide 19 (115 mg, 0.22 mmol, 46%) and
starting material 18 (40 mg, 20%). Rf 0.63 (hexanes – ethyl
acetate, 5:1). IR (CHCl3, cm–1) ν: 2959, 2926, 2180, 1599,
1497, 1381, 1347, 1249, 1216, 1159, 1095 1068, 1016,
1000, 972, 920, 843, 814, 760, 734, 699, 666, 642, 596, 568,
(relative intensity): 471 (MH+, 0.1), 456 (9), 306 (19), 258
(7), 248 (16), 242 (7), 224 (7), 207 (7), 191 (24), 190 (72),
176 (8), 175 (35), 161 (7), 159 (7), 157 (7), 156 (10), 155
(90), 151 (6), 149 (9), 147 (9), 139 (15), 131 (7), 124 (11),
123 (8), 121 (7), 119 (5), 117 (6), 115 (6), 112 (8), 109 (5),
108 (6), 107 (5), 105 (7), 100 (7), 99 (7), 98 (9), 97 (10), 92
(13), 91 (100), 90 (5), 89 (9), 85 (7), 84 (7), 83 (12), 79 (5),
77 (8), 75 (19), 74 (10), 73 (77), 71 (6), 70 (7), 69 (9), 65
(13), 64 (10), 63 (5), 60 (6), 59 (12), 58 (8), 57 (9), 56 (5),
55 (8), 53 (30), 51 (5), 45 (14), 44 (17), 43 (49), 42 (6), 41
(10). HRMS (EI) calcd. for C21H29O4NSSi: 471.1536;
found: 471.1527.
1
544, 482. H NMR (300 MHz, CDCl3, ppm) δ: 8.01 (d, J =
8.3 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 5.91 (m, 2H), 4.62
(m, 2H), 4.17 (m, 1H), 4.10 (d, J = 7.3 Hz, 2H), 3.77 (d, J =
10.5 Hz, 1H), 2.42 (s, 3H), 1.53 (s, 3H), 1.34 (s, 3H), 0.18
(s, 9H), 0.08 (s, 9H). 13C NMR (75 MHz, CDCl3, ppm) δ:
143.0, 138.0, 132.8, 129.1, 128.5, 123.3, 109.8, 104.2,
100.6, 90.5, 88.0, 77.3, 74.0, 72.7, 61.3, 33.2, 28.0, 25.8,
21.6, 0.0, –0.4. MS (EI) m/z (relative intensity): 529 (M+,
0.2), 514 (M+ – CH3, 4.1), 366 (12), 365 (27), 364 (100),
347 (12), 215 (16), 209 (28), 207 (15), 168 (11), 155 (10),
149 (17), 139 (66), 111 (15), 97 (11), 91 (47), 84 (10), 83
(33), 75 (16), 73 (86), 71 (12), 59 (16), 53 (13), 43 (32).
HRMS (EI) calcd. for C27H39O4NSSi: 529.2138; found:
529.2144.
N-[(1R,2R,5R,6S)-2-Trimethylsilylethynyl-5,6-
(isopropylidenedioxy)cyclohex-3-en-1-yl]-N-(4-
methylphenylsulfonyl)-(3aS,3bR,9bR,10R,11aS)-2,2-
dimethyl-5-oxo-9-trimethylsilyl-3a,3b,4,5,9b,11a-
hexahydro[1,3]dioxolo[4,5-c]phenanthridine-10-en-7-
carboxamide (23)
CH3
N-[(1R,2R,5R,6S)-2-(2-Trimethylsilylethynyl)-5,6-
(isopropylidenedioxy)cyclohex-3-en-1-yl]-N-propioloyl-4-
methylbenzenesulfonamide (22
O
TMS
CH3
CH3
CH3
H3C
O
O
S
N
O
O
CH3
O
O
N
H3C
CH3
O
O
Si
S
CH3
O
O
O
H
C
3
CH3
O
TMS
N
S
C48H58N2O10S2Si2
943.28 g/mol
O
O
CH3
C24H29NO5SSi
471.64 g/mol
To a solution of of bis(cyclooctadiene)nickel(0) (15 mg,
0.06 mmol) and triphenylphosphine (57 mg, 0.22 mmol) in
5
mL toluene was added bisacetylene 22 (86 mg,
To a solution of of acetonide 18 (250 mg, 0.60 mmol) in
5 mL THF was added BuLi (1.6 mol/L, 0.41 mL,
0.66 mmol) at 0 °C under argon. Propiolic acid anhydride
(87 mg, 0.72 mmol) was added and the solution was allowed
to warm to room temperature overnight. The reaction was
quenched by the addition of satd. aq. NH4Cl (20 mL) and
extracted with ethyl acetate (4 × 20 mL). The combined or-
ganic phases were washed with brine (10 mL), dried over
MgSO4, and the solvent was removed under reduced pres-
sure. Flash column chromatography of the residue (hexanes –
ethyl acetate, 3:1) afforded the tosylamide 22 (128 mg,
0.18 mmol), immediately followed by of (trimethyl-
silyl)acetylene (27 mg, 0.27 mmol, 39 µL) at room tempera-
ture under argon. The solution was stirred overnight,
quenched by the addition of satd. aq. NH4Cl (20 mL) and
extracted with ethyl acetate (4 × 20 mL). The combined or-
ganic phases were washed with brine (10 mL), dried over
MgSO4, and the solvent was removed under reduced pres-
sure. Flash column chromatography of the residue (hexanes –
ethyl acetate, 5:1) afforded the cyclotrimerized dimer 23
(40 mg, 0.04 mmol, 47%) as a slightly yellow oil. [α]28
D
+53.6 (c 0.74, CHCl3). Rf 0.64 (hexanes – ethyl acetate, 4:1).
IR (CHCl3, cm–1) ν: 3430, 3020, 2172, 1686, 1677, 1598,
1374, 1253, 1216, 1171, 1076, 845, 756. 1H NMR
(300 MHz, CDCl3, 50 °C, ppm) δ: 8.30 (d, J = 8.2 Hz, 2H),
7.71 (d, J = 7.9 Hz, 1H), 7.49 (m, 2H), 7.31 (d, J = 8.1 Hz,
2H), 7.16 (m, 2H), 7.08 (d, J = 7.9 Hz, 1H), 5.16 (m, 4H),
5.55 (m, 1H), 4.76 (m, 3H), 4.58 (m, 1H), 4.42 (m, 1H),
4.20 (d, J = 10.8 Hz, 1H), 3.63 (t, J = 10.5 Hz, 1H), 2.45 (s,
3H), 2.43 (s, 3H), 1.38 (m, 12H), 0.49 (s, 9H), 0.16 (s, 9H).
MS (EI) m/z (relative intensity): 943 (M+, 0.1), 927 (0.1),
456 (9), 256 (7), 255 (8), 254 (47), 253 (12), 231 (5), 229
(15), 207 (19), 206 (6), 191 (12), 190 (27), 189 (6), 176 (7),
0.27 mmol, 46%) as a slightly yellow foam. [α]21 +29.2
D
(c 0.25, CH2Cl2). Rf 0.71 (hexanes – ethyl acetate, 3:1). IR
(CHCl3, cm–1) ν: 3297, 3021, 2988, 2961, 2177, 2110, 1932,
1795, 1739, 1675, 1597, 1494, 1457, 1366, 1307, 1250,
1
1216, 845, 756. H NMR (300 MHz, CDCl3, ppm) δ: 8.03
(d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.98 (m, 2H),
5.11 (m, 1H), 4.74 (m, 2H), 4.25 (d, J = 10.8 Hz, 1H), 3.23
(s, 1H), 2.43 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H), 0.02 (s, 9H).
13C NMR (75 MHz, CDCl3, ppm) δ: 153.7, 145.2, 136.0,
132.6, 130.1, 129.2, 123.3, 110.6, 103.4, 89.6, 82.7, 75.5,
73.7, 72.8, 65.8, 34.0, 27.9, 25.8, 21.9, –0.2. MS (EI) m/z
© 2006 NRC Canada

1324
Can. J. Chem. Vol. 84, 2006
175 (18), 161 (6), 156 (6), 155 (32), 151 (5), 149 (20), 147
(8), 145 (5), 140 (6), 139 (39), 135 (6), 133 (5), 131 (10),
129 (6), 123 (6), 121 (10), 119 (9), 117 (8), 116 (6), 115 (5),
109 (5), 108 (6), 107 (7), 105 (7), 100 (8), 99 (45), 98 (36),
97 (12), 95 (7), 93 (7), 92 (13), 91 (86), 90 (6), 89 (9), 86
(5), 85 (10), 84 (16), 83 (12), 82 (5), 81 (8), 79 (6), 77 (10),
75 (24), 74 (12), 73 (100), 71 (15), 70 (13), 69 (19), 67 (7),
65 (17), 64 (6). HRMS (EI) calcd. for C48H58O10N2S2Si2-
CH3: 927.2837; found: 927.2824.
42 (6), 41 (8). HRMS (EI) calcd. for C21H31O6NSSi-CH3:
438.1407; found: 438.1400. Anal. calcd. for C21H31O6NSSi:
C 55.60, H 6.89; found: C 55.20, H 7.02.
(3aS,4R,5R,5aS,8aS,8bS)-N-(7,7-Dimethyl-2,2-dioxo-4-
trimethylsilanylethynyl hexahydro-1,3,6,8-tetraoxa-2␭6-
thia-as-indacen-5-yl)-4-methylbenzenesulfonamide (25)
To a solution of diol 24 (150 mg, 0.33 mmol) in 5 mL dry
O
O
(3aS,4R,5R,6S,7S,7aS)-6,7-Dihydroxy-2,2-dimethyl-4-(4-
methylphenylsulfonamido)-5-(2-trimethylsilyl-1-
ethynyl)perhydro-1,3-benzodioxole (24)
S
O
O
O
O
CH3
CH3
OH
HO
O
H3C
CH3
Si
H3C CH3
21H29NO8S2Si
515.67 g/mol
NHTs
CH3
O
C
H3C
Si
NHTs
H3C CH3
C21H31NO6SSi
453.63 g/mol
CH2Cl2 was added triethylamine (0.37 mL, 2.65 mmol) at
0 °C. The solution was stirred for 10 min and SO2Cl2
(0.99 mL, 1.0 mol/L solution, 0.99 mmol) was added
dropwise. After the addition, the solution was allowed to
warm to room temperature and was stirred for 3 h. Further
addition of triethylamine (0.37 mL, 2.65 mmol) and SO2Cl2
(0.99 mL, 1.0 mol/L solution, 0.99 mmol) led to total con-
sumption of the starting material (2 h). The reaction mixture
was diluted with CH2Cl2 (30 mL) and extracted with water
(2 × 10 mL). The organic phase was dried over Na2SO4, fil-
tered, and the solvent was removed under reduced pressure.
Purification by flash column chromatography (hexanes –
ethyl acetate, 2:1) afforded cyclic sulfate 25 (140 mg,
0.27 mmol, 82%); mp 169 °C. [α]26 –51.5 (c 1.40, CHCl3).
Rf 0.89 (hexanes – ethyl acetate, 3:D7). IR (CHCl3, cm–1) ν:
3684, 3617, 3374, 3020, 2964, 2928, 2401, 2182, 1721,
1599, 1520, 1496, 1404, 1334, 1307, 1291, 1252, 1216,
1160, 1093, 1013, 985, 924, 848, 813, 759, 669, 548, 505,
To a solution of of (trimethylsilyl)acetylene 18 (1.55 g,
3.68 mmol) in 40 mL CH2Cl2 was added N-methyl-
morpholine-N-oxide (5.18 mg, 4.42 mmol) and six small
crystals of OsO4. The reaction mixture was stirred for 3 h at
room temperature. The reaction was quenched by the addi-
tion of satd. aq. NaHSO3 (50 mL), the organic and the aque-
ous phases were separated, and the aqueous phase was
extracted with ethyl acetate (3 × 50 mL). The combined or-
ganic phases were washed with brine (20 mL), dried over
Na2SO4, and the solvent was removed under reduced pres-
sure. Flash column chromatography of the residue (hexanes –
ethyl acetate, 1:1) afforded diol 24 (768 mg, 1.69 mmol,
46%) as white crystals (mp 87 °C) and the starting material
(488 mg, 1.16 mmol, 32%). [α]21 +32.5 (c 0.45, CHCl3). Rf
D
0.37 (hexanes – ethyl acetate, 1:1). IR (CHCl3, cm–1) ν:
3684, 3577, 3359, 3020, 2991, 2962, 2903, 2401, 2178,
1731, 1599, 1519, 1423, 1383, 1375, 1334, 1306, 1250, 1216,
1160, 1093, 1066, 929, 848, 814, 771, 669, 627, 598, 557,
1
475, 462, 454. H NMR (300 MHz, CDCl3, ppm) δ: 7.81 (d,
J = 8.2 Hz, 2H), 7.28 (d, J = 8.3 Hz, 2H), 5.03 (m, 3 H),
4.48 (m, 1H), 4.14 (m, 1H), 3.52 (m, 1H), 3.04 (m, 1H),
2.43 (s, 3H), 1.38 (s, 3H), 1.19 (s, 3H), 0.21 (s, 9H). 13C
NMR (75 MHz, CDCl3, ppm) δ: 143.6, 138.3, 129.5, 127.5,
110.6, 98.1, 93.3, 82.4, 80.7, 77.3, 73.4, 54.4, 36.0, 27.4,
25.2, 21.7, –0.2. MS (EI) m/z (relative intensity): 500 (M+ –
CH3, 15), 391 (16), 309 (7), 244 (5), 243 (35), 242 (100),
238 (6), 234 (5), 233 (5), 231 (6), 229 (9), 228 (8), 225 (8),
222 (6), 207 (5), 206 (6), 205 (8), 204 (18), 191 (6), 190 (7),
180 (6), 178 (6), 177 (8), 176 (8), 175 (6), 171 (6), 169 (5),
167 (9), 165 (12), 164 (8), 163 (13), 162 (7), 161 (9), 160
(5), 159 (5), 156 (7), 155 (34), 153 (7), 152 (6), 151 (10),
150 (9), 149 (41), 147 (6), 140 (6), 139 (16), 138 (5), 137
(11), 135 (10), 133 (7), 129 (7), 127 (6), 126 (8), 125 (8),
124 (9), 123 (11), 122 (5), 121 (7), 119 (9), 115 (5), 113 (8),
112 (9), 111 (15), 110 (7), 109 (12), 108 (7), 107 (7), 105
(7), 102 (6), 100 (7), 99 (10), 98 (10), 97 (21), 96 (9), 95
(15), 93 (5), 92 (9), 91 (42), 89 (6), 85 (21), 84 (13), 83
(23), 82 (10), 81 (16), 80 (7), 79 (7), 77 (6), 76 (8), 75 (11),
73 (26), 72 (6), 71 (48), 70 (23), 69 (45), 68 (9), 67 (12), 65
1
512, 460. H NMR (300 MHz, CDCl3, ppm) δ: 7.79 (d, J =
8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 5.80 (d, J = 9.4 Hz,
1H), 4.11 (m, 3H), 4.01 (d, J = 5.8, 1H), 3.89 (m, 1H), 3.26
(s, 2H), 2.80 (t, J = 5.5 Hz, 1H), 2.42 (s, 3H), 1.41 (s, 3H),
1.25 (s, 3H), 0.13 (s, 9H). 13C NMR (75 MHz, CDCl3, ppm)
δ: 143.5, 138.4, 129.8, 127.2, 109.5, 102.5, 89.6, 78.1, 77.4,
72.5, 69.9, 54.9, 36.9, 27.9, 25.9, 21.7, 0.0. MS (EI) m/z
(relative intensity): 438 (M+ – CH3, 28), 380 (7), 366 (11),
351 (7), 322 (15), 282 (6), 254 (12), 242 (6), 226 (13), 225
(24), 224 (8), 222 (9), 212 (6), 211 (9), 194 (7), 193 (6), 180
(7), 178 (8), 172 (5), 171 (8), 157 (6), 156 (6), 155 (60), 154
(5), 153 (7), 152 (6), 151 (6), 150 (6), 149 (16), 141 (7), 140
(11), 139 (27), 129 (8), 128 (5), 125 (12), 124 (8), 123 (6),
109 (5), 108 (7), 107 (7), 101 (14), 100 (16), 99 (15), 98
(14), 97 (7), 92 (14), 91 (100), 90 (5), 89 (6), 86 (5), 85
(11), 84 (14), 83 (8), 77 (8), 75 (29), 74 (10), 73 (84), 72
(5), 71 (8), 70 (33), 69 (9), 65 (15), 64 (6), 63 (5), 61 (7), 60
(6), 59 (29), 58 (9), 55 (10), 53 (8), 45 (14), 44 (9), 43 (57),
© 2006 NRC Canada

Hudlicky et al.
1325
(9), 64 (6), 59 (8), 58 (13), 57 (48), 56 (18), 55 (40), 54 (6),
53 (9), 51 (5), 45 (5), 43 (65), 42 (8), 41 (29). HRMS (EI)
calcd. for C21H29O8NS2Si-CH3: 500.0869; found: 500.0846.
Anal. calcd. for C21H29O8NS2Si: C 48.91, H 5.67; found: C
49.32, H 5.86.
(9), 51 (19), 50 (12), 47(6), 45 (11), 44 (27), 43 (94), 42
(15), 41 (38). HRMS (EI) calcd. for C28H35O7NSSi-CH3:
542.1669; found: 542.1660.
(3aS,4R,7S,7aR)-7-Hydroxy-2,2-dimethyl-4-(4-
methylphenylsulfonamido)-5-(2-trimethylsilyl-1-ethynyl)-
3a,4,7,7a-tetrahydro-1,3-benzodioxole (27)
To a solution of cyclic sulfate 25 (462 mg, 0.90 mmol) in
5 mL dry DMF was added ammonium benzoate (312 mg,
(3aS,4S,5R,6R,7R,7aS)-4-Hydroxy-2,2-dimethyl-7-(4-
methylphenylsulfonamido)-5-phenylcarbonyloxy-6-(2-
trimethylsilyl-1-ethynyl)perhydro-1,3-benzodioxole (26)
To a solution of cyclic sulfate 25 (462 mg, 0.90 mmol) in
5 mL dry DMF was added ammonium benzoate (312 mg,
OH
O
CH3
OH
CH3
O
O
O
CH3
H3C
Si
NHTs
O
CH3
H3C CH3
O
H3C
C21H29NO5SSi
435.61 g/mol
HTs
N
Si
H3C CH3
C28H35NO7SSi
557.73 g/mol
2.24 mmol). The reaction mixture was heated to 70 °C for
2 h, then cooled to 40 °C and the excess DMF was removed
under reduced pressure. The residue was suspended in
25 mL THF and 3 drops of H2O and H2SO4 were added. The
resulting mixture was stirred for 1.5 h, quenched with satd.
aq. NaHCO3 (25 mL), and diluted with CH2Cl2. The aque-
ous phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried over Na2SO4 and evap-
orated at reduced pressure. Column chromatography (hex-
anes – ethyl acetate, 2:1) afforded allyl alcohol 27 (234 mg,
2.24 mmol). The reaction mixture was heated to 70 °C for
2 h, then cooled to 40 °C and the DMF was removed under
reduced pressure. The residue was suspended in 25 mL THF
before 3 drops of H2O and H2SO4 were added. The resulting
mixture was stirred for 1.5 h and then quenched with satd.
aq. NaHCO3 (25 mL) and diluted with CH2Cl2. The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The
combined organic phases were dried over Na2SO4 and evap-
orated at reduced pressure. Column chromatography (hexanes –
ethyl acetate, 2:1) afforded benzoate 26 (167 mg,
0.30 mmol, 33%); mp 105 °C. [α]22 –38.4 (c 0.98, CHCl3).
Rf 0.19 (hexanes – ethyl acetate, 2:D1). IR (CHCl3, cm–1) ν:
3275, 2924, 2853, 2323, 2177, 1702, 1601, 1452, 1383,
1332, 1275, 1249, 1219, 1159, 1119, 1093, 1069, 1027, 845,
0.54 mmol, 60%); mp 131 °C. [α]22 –42.7 (c 0.30, CHCl3).
D
Rf 0.33 (hexanes –ethyl acetate, 2:1). IR (CHCl3, cm–1) ν:
3318, 3020, 2928, 2401, 2149, 1726, 1600, 1424, 1384,
1332, 1251, 1216, 1158, 1094, 1060, 926, 865, 846, 814,
1
771, 669, 603, 550, 515. H NMR (300 MHz, CDCl3, ppm)
δ: 7.80 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.37 (d,
J = 5.2 Hz, 1H), 5.76 (d, J = 9.5 Hz, 1H), 4.51 (m, 1H), 4.38
(m, 1H), 4.32 (m, 1H), 3.96 (dd, J = 3.2, 9.4 Hz, 1H), 3.16
(s, 1H), 2.42 (s, 3H), 1.33 (s, 3H), 1.28 (s, 3H), 0.22 (s, 9H).
1
814, 761, 712, 664, 568, 550. H NMR (300 MHz, CDCl3,
ppm) δ: 8.07 (d, J = 7.2 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H),
7.58 (m, 1H), 7.45 (m, 2H), 7.28 (d, J = 7.2 Hz, 2H), 5.75
(d, J = 7.1 Hz, 1H), 5.31 (dd, J = 4.2, 7.7 Hz, 1H), 4.30 (m,
1H), 4.23 (m, 1H), 4.08 (m, 2H), 3.26 (m, 1H), 3.16 (s, 1H),
2.41 (s, 3H), 1.50 (s, 3H), 1.24 (s, 3H), 0.10 (s, 9H). 13C
NMR (75 MHz, CDCl3, ppm) δ: 166.7, 143.7, 138.1, 133.7,
130.3, 129.9, 128.7, 127.6, 110.0, 101.1, 90.5, 78.5, 77.5,
72.2, 70.5, 66.6, 54.3, 36.2, 28.2, 26.0, 21.8, 0.0. MS (EI)
m/z (relative intensity): 542 (M+ – CH3, 2.1), 366 (10), 351
(8), 276 (16), 264 (6), 263 (27), 225 (8), 224 (8), 212 (5),
180 (5), 179 (6), 169 (6), 155 (22), 151 (6), 150 (8), 149 (8),
141 (8), 140 (8), 139 (14), 137 (7), 135 (6), 133 (7), 132 (7),
127 (12), 126 (8), 125 (13), 124 (8), 123 (13), 122 (37), 121
(9), 120 (7), 113 (11), 112 (12), 111 (23), 110 (7), 109 (14),
108 (30), 107 (7), 106 (9), 105 (58), 104 (12), 101 (6), 100
(8), 99 (19), 98 (18), 97 (38), 96 (10), 95 (17), 94 (7), 93
(10), 92 (13), 91 (60), 89 (5), 87 (5), 86 (7), 85 (61), 84
(21), 83 (53), 82 (13), 81 (19), 80 (11), 79 (9), 78 (9), 77
(32), 75 (8), 74 (6), 73 (15), 72 (7), 71 (65), 70 (34), 69
(53), 68 (11), 67 (15), 65 (16), 64 (7), 63 (6), 60 (7), 59
(12), 58 (11), 57 (100), 56 (22), 55 (57), 54 (7), 53 (11), 52
13C NMR (75 MHz, CDCl , ppm) : 143.3, 137.8, 137.3,
δ
3
129.6, 127.4, 125.0, 109.0, 102.3, 98.0, 77.6, 77.6, 66.2,
53.9, 26.4, 24.5, 21.7, –0.2. MS (EI) m/z (relative intensity):
420 (M+ – CH3, 6), 349 (9), 337 (7), 336 (15), 335 (61), 212
(16), 206 (6), 205 (7), 204 (8), 192 (6), 190 (6), 181 (8), 180
(43), 178 (12), 177 (9), 176 (11), 175 (6), 165 (5), 155 (14),
150 (6), 149 (18), 139 (15), 120 (13), 107 (8), 105 (6), 104
(6), 101 (6), 100 (7), 97 (13), 96 (6), 95 (5), 92 (12), 91
(75), 90 (5), 85 (16), 84 (7), 83 (9), 81 (5), 77 (8), 75 (25),
74 (12), 73 (100), 71 (13), 70 (6), 69 (12), 65 (13), 60 (6),
59 (13), 58 (7), 57 (12), 55 (11), 45 (11), 44 (6), 43 (44), 42
(8), 41 (13). HRMS (EI) calcd. for C21H29O5NSSi:
435.1536; found: 435.1534. Anal. calcd. for C21H29O5NSSi:
C 57.90, H 6.71; found: C 57.45, H 7.00.
(3aS,4S,5R,6R,7R,7aS)-4-Hydroxy-2,2-dimethyl-7-(4-
methylphenylsulfonamido)-5-phenylcarbonyloxy-6-(1-
ethynyl)perhydro-1,3-benzodioxole (28)
To a solution of TMS-protected acetylene 26 (436 mg,
0.78 mmol) in 15 mL dry acetonitrile was added TBAT
(633 mg, 1.17 mmol). The reaction mixture was stirred at
© 2006 NRC Canada

1326
Can. J. Chem. Vol. 84, 2006
9:1) afforded TBS-protected alcohol 29 (319 mg,
OH
0.53 mmol, 89%) as white crystals; mp 83 °C. [α]19 –36.9
D
O
O
O
(c 1.20, CHCl3). Rf 0.33 (hexanes – ethyl acetate, 5:1). IR
(CHCl3, cm–1) ν: 3309, 3066, 2988, 2955, 2931, 2896, 2859,
2254, 1720, 1601, 1586, 1495, 1472, 1463, 1452, 1383,
1373, 1328, 1272, 1221, 1160, 1112, 1094, 1081, 1054,
1027, 1005, 987, 909, 840, 814, 781, 734, 664, 650, 579,
CH3
CH3
O
NHTs
1
564, 549, 514, 466. H NMR (300 MHz, CDCl3, ppm) δ:
C25H27NO7S
485.55 g/mol
8.08 (d, J = 8.2 Hz, 2H), 7.86 (d, J = 8.2 Hz, 2H), 7.58 (m,
1H), 7.46 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 5.29 (d, J =
7.5 Hz, 1H), 5.23 (m, 1H), 4.32 (m, 1H), 4.10 (m, 1H), 4.08
(m, 2H), 3.09 (m, 1H), 2.38 (s, 3H), 1.83 (d, J = 2.3 Hz,
1H), 1.52 (s, 3H), 1.26 (s, 3H), 0.86 (s, 9H), 0.15 (s, 3H),
0.13 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ: 165.8,
143.1, 139.2, 133.5, 130.1, 129.9, 129.3, 128.6, 127.7,
109.6, 80.1, 78.5, 77.7, 73.8, 72.7, 67.4, 55.0, 33.3, 28.1,
26.2, 25.8, 21.7, 18.1, –4.8, –4.9. MS (EI) m/z (relative in-
tensity): 584 (M+ – CH3, 3.7), 420 (9), 378 (5), 377 (18),
363 (6), 362 (20), 288 (5), 207 (7), 206 (7), 192 (6), 191
(32), 181 (5), 180 (15), 179 (89), 155 (12), 139 (5), 129 (5),
106 (9), 105 (100), 91 (34), 85 (5), 77 (20), 75 (14), 73 (32),
59 (6), 57 (9), 43 (13), 41 (7). HRMS (EI) calcd. for
C31H41O7NSSi-CH3: 584.2138; found: 584.2150. Anal. calcd.
for C31H41O7NSSi: C 62.08, H 6.89; found: C 61.86, H 6.64.
room temperature for 4 h, quenched with satd. aq. NH4Cl
(25 mL), and extracted with ethyl acetate (3 × 20 mL). The
combined organic phases were dried over Na2SO4, filtered,
and evaporated at reduced pressure. Column chromatogra-
phy (hexanes – ethyl acetate, 1:1) afforded alcohol 28
(318 mg, 0.65 mmol, 84%) as white crystals; mp 103 °C.
[α]19 –23.4 (c 0.85, CHCl3). Rf 0.41 (hexanes – ethyl ace-
tate, D1:1). IR (CHCl3, m–1) ν: 440, 3288, 3155, 2988, 2254,
1726, 1697, 1600, 1453, 1375, 1331, 1279, 1247, 1222,
1163, 1119, 1095, 1069, 908, 815, 734, 651, 545.1H NMR
(300 MHz, CDCl3, ppm) δ: 8.06 (d, J = 7.5 Hz, 2H), 7.84 (d,
J = 8.2 Hz, 2 H), 7.58 (m, 1H), 7.44 (m, 2H), 7.28 (d, J =
8.1 Hz, 2H), 5.59 (d, J = 8.0 Hz, 1H), 5.31 (dd, J = 3.6,
6.8 Hz, 1H), 4.33 (m, 1H), 4.23 (m, 1H), 4.08 (m, 2H), 3.19
(m, 1H), 3.03 (s, 1H), 2.38 (s, 3H), 2.02 (d, J = 2.7 Hz, 1H),
1.51 (s, 3H), 1.24 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm)
δ: 166.7, 143.6, 138.2, 133.7, 130.2, 129.7, 129.5, 128.7,
127.6, 109.9, 79.6, 78.5, 77.4, 73.2, 72.4, 69.4, 54.3, 34.6,
28.0, 26.1, 21.7. MS (EI) m/z (relative intensity): 470 (M+ –
CH3, 3.2), 377 (6), 362 (5), 263 (7), 225 (8), 179 (16), 155
(17), 150 (7), 139 (9), 134 (8), 132 (5), 123 (5), 122 (24),
108 (8), 106 (13), 105 (100), 92 (8), 91 (48), 85 (6), 80 (6),
78 (7), 77 (34), 75 (8), 73 (11), 71 (5), 70 (11), 69 (7), 65
(11), 59 (7), 58 (5), 57 (8), 55 (8), 53 (5), 51 (13), 50 (7), 45
(7), 44 (13), 43 (25), 41 (11). HRMS (EI) calcd. for
C25H27O7NS-CH3: 470.1273; found: 470.1283. Anal. calcd.
for C25H27O7NS: C 61.84, H 5.60; found: C 61.45, H 5.36.
(3aS,4S,5R,6R,7R,7aS)-2,2-Dimethyl-7-(4-
methylphenyl(2-propynyl)sulfonamido)-4-(tert-
butyldimethylsilyloxy)-5-phenylcarbonyloxy-6-(1-
ethynyl)perhydro-1,3-benzodioxole (30)
OTBS
O
O
CH3
O
CH3
O
Ts
N
(3aS,4S,5R,6R,7R,7aS)-2,2-Dimethyl-7-(4-methylphenyl-
sulfonamido)-4-(tert-butyldimethylsilyloxy)-5-phenyl-
carbonyloxy-6-(1-ethynyl)perhydro-1,3-benzodioxole (29)
C34H43NO7SSi
637.86 g/mol
OTBS
To a solution of tosylamide 29 (411 mg, 0.69 mmol) in
11 mL of dry THF was added NaHMDS (0.82 mL,
0.82 mmol) at –70 °C. The reaction mixture was stirred for
0.5 h, while warming up to 0 °C. TMS – propargyl bromide
(408 mg, 3.43 mmol) and (n-Bu)4NI (252 mg, 0.69 mmol)
were added. The reaction mixture was stirred at room tem-
perature for 6 h, quenched with satd. aq. NH4Cl (30 mL),
extracted with ethyl acetate (3 × 30 mL), dried over Na2SO4,
and the solvent was evaporated at reduced pressure. Column
chromatography (hexanes – ethyl acetate, 9:1) afforded
imide 30 (345 mg, 0.54 mmol, 79%) as colourless foam.
[α]19 –37.5 (c 0.24, CHCl3). Rf 0.54 (hexanes – ethyl ace-
tate, D3:1). IR (CHCl3, cm–1) ν: 3309, 3068, 2987, 2956,
2931, 2896, 2859, 2255, 2125, 1722, 1601, 1586, 1495, 1472,
1463, 1453, 1384, 1373, 1351, 1331, 1308, 1269, 1221,
1159, 1095, 1027, 1006, 990, 961, 910, 865, 840, 815, 781,
734, 712, 666, 650, 599, 583, 546, 467. 1H NMR (300 MHz,
O
O
CH3
O
CH3
O
NHTs
C31H41NO7SSi
599.81 g/mol
To a solution of alcohol 28 (290 mg, 0.60 mmol) in 4 mL
dry DMF were added imidazole (204 mg, 2.99 mmol) and
TBSCl (451 mg,2.99 mmol). The reaction mixture was
stirred at room temperature for 18 h, quenched with water
(20 mL) and, after stirring for an additional 10 min, ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic
phases were dried over Na2SO4 and evaporated at reduced
pressure. Column chromatography (hexanes – ethyl acetate,
© 2006 NRC Canada

Hudlicky et al.
1327
CDCl3, ppm) δ: 8.18 (d, J = 8.1 Hz, 2H), 8.00 (d, J = 8.2 Hz,
2H), 7.59 (m, 1H), 7.47 (m, 2H), 7.28 (d, J = 8.1 Hz, 2H),
5.35 (m, 1H), 4.84 (m, 2H), 4.42 (m, 1H), 4.15 (m, 3H),
3.64 (m, 1H), 2.42 (s, 3H), 2.22 (m, 1H), 2.00 (d, J =
2.2 Hz, 1H), 1.64 (s, 3H), 1.36 (s, 3H), 0.94 (s, 9H), 0.25 (s,
3H), 0.18 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ:
165.9, 143.5, 137.8, 133.4, 130.2, 129.9, 129.4, 128.6,
128.5, 109.7, 80.5, 78.7, 78.5, 74.9, 74.7, 73.9, 73.0, 66.6,
58.7, 30.9, 28.2, 26.3, 25.8, 25.8, 21.7, 18.1, –4.8, –5.0. MS
(EI) m/z (relative intensity): 622 (M+ – CH3, 2.6), 522 (7),
401 (6), 400 (19), 245 (7), 222 (9), 192 (7), 191 (35), 181
(6), 180 (15), 179 (94), 167 (7), 155 (18), 150 (7), 149 (23),
139 (15), 137 (8), 135 (6), 129 (8), 122 (5), 113 (6), 111 (6),
109 (5), 106 (9), 105 (100), 97 (10), 95 (8), 92 (9), 91 (48),
85 (14), 84 (6), 83 (14), 81 (10), 77 (19), 75 (13), 73 (41),
71 (18), 70 (12), 69 (23), 67 (6), 66 (6), 65 (7), 59 (6), 57
(34), 56 (12), 55 (22), 53 (5), 43 (27), 41 (21). HRMS (EI)
calcd. for C34H43O7NSSi-CH3: 622.2295; found: 622.2284.
Anal. calcd. for C34H43O7NSSi: C 64.02, H 6.79; found: C
63.82, H 6.94.
76.1, 71.6, 68.5, 57.0, 48.5, 35.8, 28.2, 26.1, 25.7, 21.3,
18.0, 1.8, 1.8, –4.9, –5.2. MS (EI) m/z (relative intensity):
750 (M+ – C(CH3)3, 15), 692 (6), 653 (6), 652 (11), 596 (8),
595 (16), 594 (12), 572 (5), 571 (10), 570 (19), 562 (8), 496
(7), 495 (5), 472 (6), 471 (6), 430 (6), 415 (6), 414 (12), 179
(22), 167 (7), 155 (8), 151 (5), 150 (5), 149 (29), 139 (7),
137 (6), 135 (6), 129 (5), 127 (5), 125 (10), 123 (9), 121 (6),
113 (8), 112 (8), 111 (18), 110 (7), 109 (13), 106 (6), 105
(55), 99 (9), 98 (12), 97 (34), 96 (11), 95 (20), 91 (14), 88
(6), 87 (5), 86 (37), 85 (32), 84 (65), 83 (35), 82 (13), 81
(20), 77 (10), 75 (10), 74 (5), 73 (41), 72 (6), 71 (51), 70
(29), 69 (54), 68 (10), 67 (16), 60 (7), 59 (7), 58 (8), 57
(96), 56 (37), 55 (80), 54 (7), 53 (7), 51 (6), 49 (12), 47
(14), 45 (9), 44 (7), 43 (100), 42 (17), 41 (73). HRMS (EI)
calcd. for C42H61O7NSSi3-C(CH3)3: 750.2772; found: 750.2772.
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-11-(tert-butyldimethylsilyloxy)-
7,8-di(trimethylsilyl)-3a,3b,4,5,9b,10,11,11a-
octahydro[1,3]dioxolo[4,5-c]phenanthridin-10-ol (32)
OTBS
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-10-phenylcarbonyloxy-11-(tert-
butyldimethylsilyloxy)-7,8-di(trimethylsilyl)-
3a,3b,4,5,9b,10,11,11a-octahydro[1,3]dioxolo[4,5-
c]phenanthridine (31)
HO
O
CH3
TMS
CH3
O
Ts
N
MS
T
OTBS
C
35H57NO6SSi3
704.15 g/mol
BzO
O
CH3
TMS
CH3
O
To a solution of benzoate 31 (110 mg, 0.13 mmol) in
1 mL THF was added 0.5 mL of a 2.25 mol/L solution of
freshly prepared sodium methoxide in methanol. The reac-
tion was stirred for 10 min, quenched with NH4Cl (3 mL),
and diluted with ethyl ether (10 mL). The organic phase was
separated and washed with NaHCO3 (3 mL) and satd. NaCl
solution (3 mL). After drying over MgSO4 and filtration, the
solvent was removed under vacuum and the residue was pu-
rified by column chromatography (hexanes – ethyl acetate,
3:1). The product 32 was isolated as crystalline foam in 99%
yield (88 mg, 0.12 mmol); mp 97 °C. [α]22 +14.2 (c 0.60,
CH2Cl2). Rf 0.40 (hexanes – ethyl acDetate, 3:1). IR
(CH2Cl2, cm–1) ν: 3516, 2986, 2954, 2931, 2898, 2859,
2253, 1912, 1738, 1599, 1553, 1495, 1471, 1463, 1455,
1407, 1383, 1371, 1361, 1346, 1308, 1250, 1220, 1161,
1122, 1091, 1007, 977, 948, 910, 858, 839, 811, 780, 756,
Ts
N
MS
T
C
42H61NO7SSi3
808.26 g/mol
To a solution of CpCo(CO)2 (5 µL) in BTMSA (12 mL)
were added dropwise with a syringe pump bisacetylene 30
(324 mg, 0.51 mmol) and CpCo(CO)2 (5 µL) dissolved in
xylene (2 mL) and BTMSA (8 mL) at 140 °C over 30 h.
During this slow addition, extra catalyst was added directly
into the reaction mixture in aliquots: 5 µL after 5 h and 3 µL
after 20 and 29 h. The reaction mixture was heated under ar-
gon for further 12 h. BTMSA and xylene were removed un-
der high vacuum and the residue was purified by column
chromatography (hexanes
– ethyl acetate, 9:1). The
1
cyclotrimerized product 31 was isolated as crystalline foam
734, 700, 675, 656, 628, 605, 577, 559, 540, 513, 472. H
in 83% yield (341 mg, 0.42 mmol); mp 97 °C. [α]22 +17.6
NMR (300 MHz, CDCl3, ppm) δ: 7.36 (d, J = 8.1 Hz, 2H),
7.24 (s, 1H), 7.15 (s, 1H), 6.86 (d, J = 7.8 Hz, 2H), 5.07 (m,
1H), 4.65 (dd, J1 = 75.0 Hz, J2 = 17.1 Hz, 2H), 4.26 (m,
3H), 4.04 (m, 1H), 2.82 (d, J = 12.9 Hz, 1H), 2.34 (m, 1H),
2.24 (s, 3H), 1.57 (s, 3H), 1.41 (s, 3H), 0.92 (s, 9H), 0.33 (s,
9H), 0.28 (s, 9H), 0.16 (s, 3H), 0.13 (s, 3H). 13C NMR
(75 MHz, CDCl3, ppm) δ: 144.7, 143.7, 142.3, 137.8, 134.0,
133.2, 133.0, 132.2, 128.6, 127.4, 109.4, 79.1, 75.3, 73.5,
69.2, 58.5, 51.4, 36.3, 28.5, 26.1, 25.6, 21.4, 17.9, 1.8, 1.8, –
5.0, –5.1. MS (EI) m/z (relative intensity): 689 (M+ – CH3,
5), 688 (7), 648 (10), 647 (18), 646 (32), 588 (7), 550 (11),
549 (22), 548 (50), 491 (9), 490 (14), 476 (5), 460 (9), 459
D
(c 0.65, CHCl3). Rf 0.60 (hexanes – ethyl acetate, 3:1). IR
(CHCl3, cm–1) ν: 2956, 2930, 2857, 1724, 1601, 1511, 1452,
1348, 1267, 1251, 1219, 1160, 1109, 957, 839, 757, 712,
1
670, 627, 560, 536, 515. H NMR (300 MHz, CDCl3, ppm)
δ: 8.15 (d, J = 7.6 Hz, 2H), 7.73 (m, 1H), 7.58 (m, 2H), 7.38
(m, 4H), 6.63 (d, J = 7.9 Hz, 2H), 5.96 (s, 1H), 4.85 (m,
2H), 4.49 (m, 4H), 3.12 (d, J = 11.9 Hz, 1H), 2.21 (s, 3H),
1.91 (s, 3H), 1.59 (s, 3H), 1.05 (s, 9H), 0.45 (s, 9H), 0.35
(m, 12H), 0.33 (s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ:
165.6, 145.9, 143.6, 141.9, 137.1, 134.5, 133.2, 132.7,
130.7, 130.1, 129.6, 128.5, 128.4, 127.5, 109.1, 79.4, 77.3,
© 2006 NRC Canada

1328
Can. J. Chem. Vol. 84, 2006
(14), 458 (33), 457 (34), 433 (8), 432 (9), 430 (10), 428 (6),
414 (7), 385 (5), 316 (6), 315 (7), 304 (6), 303 (7), 302 (5),
276 (8), 275 (15), 274 (24), 258 (5), 243 (5), 202 (8), 159
(14), 149 (10), 139 (9), 131 (10), 129 (11), 124 (9), 123 (6),
121 (6), 119 (7), 117 (8), 115 (6), 105 (10), 101 (7), 100 (7),
98 (5), 97 (6), 92 (8), 91 (21), 88 (9), 86 (45), 85 (10), 84
(69), 82 (6), 81 (11), 77 (9), 75 (35), 74 (13), 73 (100), 71
(6), 70 (5), 69 (10), 59 (11), 58 (6), 57 (11), 56 (8), 55 (10),
51 (6), 49 (9), 47 (18), 45 (9), 43 (24), 41 (15). HRMS (EI)
calcd. for C35H57O6NSSi3-CH3: 688.2980; found: 688.3006.
Anal. calcd. for C35H57O6NSSi3: C 59.70, H 8.16; found: C
59.36, H 7.83.
(100), 42 (15), 41 (60). HRMS (EI) calcd. for
C29H43O6NSSi2: 589.2350; found: 589.2322. Anal. calcd. for
C29H43O6NSSi2: C 59.05, H 7.35; found: C 58.72, H 6.92.
(1S,2S,3S,4S,4aR,10bR)-5-(4-Methylphenylsulfonyl)-8,9-
di(trimethylsilyl)-1,2,3,4,4a,5,6,10b-octahydro-1,2,3,4-
phenanthridinetetraol (34)
OH
HO
OH
TMS
OH
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-7,8-di(trimethylsilyl)-
3a,3b,4,5,9b,10,11,11a-octahydro[1,3]dioxolo[4,5-
c]phenanthridin-10,11-diol (33)
Ts
N
MS
T
C
26H39NO6SSi2
549.83 g/mol
OH
HO
O
To a solution of acetonide 33 (27 mg, 0.05 mmol) in
MeOH (0.5 mL) was added 1 drop of water and a spatula tip
of strong acidic Dowex 50WX8-100 ion exchange resin. The
reaction was heated for 4 h at 70 °C, dried by addition of
MgSO4, and filtered. The solvent was removed under vac-
uum and the residue was diluted in CHCl3 and filtered again.
After removal of the solvent, the deprotected tetraol 34 was
isolated as an oily solid in 79% yield (20 mg, 0.04 mmol).
[α]22 +23.9 (c 0.61, CH2Cl2). Rf 0.44 (hexanes – ethyl ace-
tate, D1:2). IR (CH2Cl2, cm–1) ν: 3410, 2954, 2926, 2902,
2253, 1793, 1646, 1599, 1494, 1450, 1409, 1331, 1307,
1289, 1265, 1249, 1186, 1153, 1122, 1089, 1063, 1020, 970,
909, 856, 840, 811, 735, 673, 650, 629, 582, 565, 539, 481.
1H NMR (300 MHz, CDCl3, ppm) δ: 7.42 (s, 1H), 7.25 (d, J
= 6.0 Hz, 2H), 7.14 (s, 1H), 6.85 (d, J = 8.1 Hz, 2H), 4.69
(d, J = 16.2 Hz, 1H), 4.49 (s, 1H), 4.36 (m, 3H), 4.27 (d, J =
10.5 Hz, 1H), 4.03 (m, 1H), 3.57 (brs, 4H) 2.91 (d, J =
11.7 Hz, 1H), 2.21 (s, 3H), 0.32 (s, 9H), 0.28 (s, 9H). 13C
NMR (75 MHz, CDCl3, ppm) δ: 145.5, 143.0, 143.0, 134.7,
134.3, 133.9, 132.2, 131.3, 128.9, 127.6, 74.9, 70.8, 70.4,
69.6, 55.3, 47.9, 38.9, 21.4, 1.9, 1.9. MS (EI) m/z (relative
intensity): 534 (M+ – CH3, 5), 467 (5), 466 (11), 460 (8),
459 (15), 458 (36), 457 (5), 450 (6), 430 (6), 396 (6), 395
(12), 394 (35), 387 (8), 386 (26), 342 (6), 324 (6), 323 (5),
322 (13), 316 (5), 304 (7), 303 (7), 302 (8), 288 (6), 287 (5),
286 (6), 276 (6), 275 (10), 274 (21), 273 (5), 272 (7), 258
(6), 257 (5), 256 (8), 252 (6), 244 (6), 242 (6), 234 (9), 232
(6), 231 (8), 230 (8), 229 (8), 228 (11), 216 (6), 215 (17),
214 (52), 213 (21), 212 (5), 206 (9), 205 (7), 204 (12), 203
(8), 202 (15), 200 (6), 193 (10), 191 (5), 190 (7), 189 (6),
188 (9), 187 (14), 186 (15), 185 (7), 184 (5), 181 (6), 171
(5), 167 (6), 162 (6), 159 (6), 158 (7), 157 (8), 156 (11), 155
(8), 149 (19), 143 (6), 141 (6), 140 (10), 139 (15), 138 (6),
137 (37), 136 (16), 135 (8), 134 (6), 133 (8), 132 (5), 131
(12), 130 (10), 129 (13), 128 (8), 127 (7), 126 (7), 124 (15),
122 (5), 116 (6), 115 (7), 113 (7), 112 (5), 111 (10), 110 (9),
109 (10), 108 (8), 107 (10), 105 (7), 99 (11), 98 (31), 97
(18), 96 (8), 95 (13), 93 (10), 92 (22), 91 (52), 90 (5), 83
(8), 81 (22), 80 (8), 79 (8), 78 (5), 77 (13), 76 (5), 75 (27),
74 (13), 73 (100), 71 (31), 69 (22), 68 (8), 67 (12), 65 (14),
64 (9), 63 (6), 60 (11), 59 (5), 57 (56), 56 (15), 55 (38), 54
CH3
TMS
CH3
O
Ts
N
MS
T
C29H43NO6SSi2
589.89 g/mol
To a solution of TBS-protected alcohol 32 (49 mg,
0.07 mmol) in 0.1 mL THF was added 84 µL of a 1.0 mol/L
solution of TBAF in THF. The reaction was stirred for
10 min at room temperature, quenched with NH4Cl (3 mL)
and diluted with ethyl ether (5 mL). The organic phase was
separated and extracted three times with ethyl ether (3 mL).
After drying over MgSO4 and filtration, the solvent was re-
moved under vacuum and the residue was purified by col-
umn chromatography (pentane –ethyl ether, 3:1). The
deprotected diol 33 was isolated as crystalline foam in 85%
yield (35 mg, 0.06 mmol); mp 91 °C. [α]22 +33.7 (c 0.39,
CH2Cl2). Rf 0.57 (hexanes – ethyl acDetate, 1:2). IR
(CH2Cl2, cm–1) ν: 3469, 2987, 2956, 2931, 2253, 1771,
1725, 1634, 1599, 1495, 1453, 1384, 1376, 1342, 1307,
1250, 1221, 1159, 1121, 1091, 1058, 974, 911, 872, 856,
1
840, 811, 790, 734, 675, 650, 626, 578, 561, 542. H NMR
(300 MHz, CDCl3, ppm) δ: 7.45 (d, J = 8.4 Hz, 2H), 7.36 (s,
1H), 7.19 (s, 1H), 6.95 (d, J = 8.4 Hz, 2H), 4.88 (dd, J1 =
8.7 Hz, J2 = 6.0 Hz, 1H), 4.45 (m, 3H), 4.28 (t, J = 5.4 Hz,
1H), 4.18 (m, 1H), 4.07 (dd, J1 = 12.0 Hz, J2 = 8.7 Hz, 1H),
2.88 (dd, J1 = 12.0 Hz, J2 = 2.4 Hz, 1H), 2.58 (d, J = 2.7 Hz,
1H), 2.27 (s, 3H), 2.21 (d, J = 4.8 Hz, 1H), 1.58 (s, 3H),
1.37 (s, 3H), 0.32 (s, 9H), 0.30 (s, 9H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 145.4, 143.8, 142.5, 137.3, 134.5, 132.9,
132.6, 131.8, 128.9, 127.6, 109.9, 78.3, 76.2, 72.5, 71.4,
57.3, 49.2, 38.4, 28.1, 25.7, 21.5, 1.9, 1.9. MS (EI) m/z (rel-
ative intensity): 574 (M+ – CH3, 0.1), 458 (5), 155 (5), 149
(15), 111 (11), 109 (6), 105 (7), 99 (6), 98 (19), 97 (37), 96
(9), 95 (10), 91 (9), 87 (18), 86 (6), 85 (29), 84 (23), 83
(38), 82 (10), 81 (15), 77 (5), 75 (14), 73 (19), 72 (5), 71
(50), 70 (45), 69 (87), 68 (13), 67 (11), 60 (8), 59 (9), 58
(11), 57 (82), 56 (45), 55 (72), 54 (6), 53 (5), 44 (5), 43
© 2006 NRC Canada

Hudlicky et al.
1329
(6), 53 (7), 45 (23), 43 (43), 41 (28). HRMS (EI) calcd. for
C26H39O6NSSi2: 549.2037; found: 549.2031.
(3aS,3bR,9bR,10R,11S,11aS)-11-Hydroxy-2,2-dimethyl-4-
(4-methylphenylsulfonyl)-10-phenylcarbonyloxy-7,8-
di(trimethylsilyl)-3a,3b,4,5,9b,10,11,11a-
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-5-oxo-10-phenylcarbonyloxy-11-
(tert-butyldimethylsilyloxy)-7,8-di(trimethylsilyl)-
3a,3b,4,5,9b,10,11,11a-octahydro[1,3]dioxolo[4,5-
c]phenanthridine (35)
octahydro[1,3]dioxolo[4,5-c]phenanthridine (36)
OH
BzO
O
CH3
OTBS
TMS
CH3
O
BzO
O
Ts
N
CH3
MS
T
MS
MS
H
3
T
T
C
O
C36H47NO7SSi2
694.00 g/mol
Ts
N
O
To a solution of cyclic sulfate 44 (344 mg, 0.53 mmol) in
dry DMF (8 mL) was added ammonium benzoate (184 mg,
1.32 mmol). The reaction mixture was heated to 70 °C for
2 h, then cooled to 40 °C, and the DMF was removed under
reduced pressure. The residue was suspended in THF (8 mL)
before 1 drop each of H2O and H2SO4 were added. The re-
sulting mixture was stirred for 1.5 h and then quenched with
satd. aq. NaHCO3 (30 mL) and diluted with CH2Cl2. The
aqueous phase was extracted with CH2Cl2 (3 × 30 mL). The
combined organic phases were dried over Na2SO4, filtered,
and evaporated at reduced pressure. Benzoate 36 (410 mg,
0.59 mmol, 99%) was obtained as foamy white crystals and
used without further purification; mp 91 °C. [α]27 +63.7 (c
1.00, CH2Cl2). Rf 0.38 (hexanes – ethyl acetateD, 2:1). IR
(CH2Cl2, cm–1) ν: 3019, 2954, 2401, 1719, 1602, 1494,
1452, 1384, 1346, 1318, 1269, 1250, 1216, 1159, 1115,
1091, 1070, 955, 876, 841, 810, 757, 714, 669, 627, 564,
456. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.92 (d, J =
8.1 Hz, 2H), 7.59 (t, J = 7.5 Hz, 1H), 7.43 (t, J = 7.5 Hz,
2H), 7.32 (d, J = 7.2 Hz, 2 H), 7.18 (d, J = 7.8 Hz, 2 H),
6.59 (d, J = 8.1 Hz, 2 H), 5.87 (m, 1 H), 4.66 (m, 2H), 4.35
(m, 4H), 3.04 (m, 2H), 2.10 (s, 3H), 1.71 (s, 3H), 1.40 (s,
3H), 0.28 (s, 9H), 0.12 (s, 9H). 13C NMR (75 MHz, CDCl3,
ppm) δ: 166.8, 146.0, 143.9, 142.2, 137.2, 134.8, 133.7,
132.8, 132.4, 130.8, 129.9, 128.8, 128.7, 127.7, 109.8, 78.3,
76.9, 73.0, 71.0, 56.7, 47.6, 37.0, 29.9, 28.1, 25.9, 21.6, 1.9,
1.8. MS (EI) m/z (relative intensity): 693 (2), 484 (8), 472
(9), 471 (23), 317 (12), 316 (37), 285 (5), 169 (20), 155 (6),
149 (8), 147 (6), 139 (5), 123 (8), 122 (44), 121 (5), 119
(14), 111 (6), 106 (7), 105 (74), 97 (10), 95 (7), 91 (22), 88
(11), 86 (63), 85 (12), 84 (100), 83 (11), 82 (9), 81 (10), 78
(6), 77 (44), 75 (9), 74 (10), 73 (56), 71 (12), 70 (7), 69
(26), 67 (7), 65 (6), 60 (6), 59 (8), 57 (21), 56 (7), 55 (19),
52 (5), 51 (25), 50 (13), 49 (21), 47 (25), 45 (12), 44 (8), 43
(34), 42 (6), 41 (18). HRMS (EI) calcd. for C36H47O7NSSi2:
693.9979; found: 693.2603. Anal. calcd. for C36H47O7NSSi2:
C 62.30, H 6.83; found: C 62.18, H 6.70.
C42H59NO8SSi3
822.24 g/mol
To a suspension of tosylamide 31 (20 mg, 0.02 mmol) in
CH3CN–CCl4–H2O (2:2:3, 0.5 mL) were added NaIO4
(22 mg, 0.10 mmol) and a catalytic amount of RuCl3·H2O.
After 3 h, NaIO4 (15 mg) and another catalytic amount of
RuCl3·H2O were added. The reaction mixture was stirred at
room temperature overnight. After another addition of
NaIO4 (15 mg) and another catalytic amount of RuCl3·H2O
the next day, the starting material was fully converted. The
heterogeneous reaction was diluted with CH2Cl2 (25 mL)
and extracted with water. The organic phase was dried with
Na2SO4, filtered, and purified by flash chromatography (hex-
anes – ethyl acetate, 2:1). The oxidized product 35 was iso-
lated as colorless oil in 15% yield (3 mg, 0.003 mmol).
[α]22 –97.8 (c 0.09, CH2Cl2). Rf 0.63 (hexanes – ethyl ace-
tate, D3:1). IR (CHCl3, cm–1) ν: 3055, 2986, 2957, 2930,
2857, 2305, 1721, 1697, 1600, 1581, 1509, 1452, 1422,
1363, 1265, 1221, 1175, 1148, 1108, 1068, 939, 895, 880,
840, 739, 705, 656, 636, 603, 544, 516, 476. 1H NMR
(300 MHz, CDCl3, ppm) δ: 8.38 (m, 3H), 7.64 (m, 3H), 7.44
(m, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.24 (m, 2H), 5.93 (s,
1H), 5.74 (m, 1H), 4.57 (m, 1H), 4.44 (s, 1H), 4.34 (m, 1H),
3.94 (m, 1H), 2.45 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 0.99
(s, 9H), 0.32 (s, 3H), 0.25 (m, 21H). MS (EI) m/z (relative
intensity): 764 (M+ – C(CH3)3, 4), 610 (7), 445 (5), 432 (6),
431 (11), 430 (25), 422 (5), 421 (12), 358 (6), 356 (9), 332
(10), 331 (28), 307 (9), 302 (7), 217 (5), 215 (7), 189 (8),
181 (6), 180 (11), 179 (43), 169 (6), 167 (10), 165 (5), 155
(8), 151 (7), 150 (8), 141 (9), 140 (7), 139 (11), 137 (8), 135
(10), 129 (8), 127 (8), 126 (6), 125 (11), 124 (11), 123 (16),
122 (9), 121 (20), 119 (24), 117 (9), 113 (9), 112 (10), 111
(21), 110 (8), 109 (16), 107 (7), 106 (10), 105 (100), 100
(7), 99 (13), 98 (16), 97 (38), 96 (13), 95 (25), 93 (8), 92
(11), 91 (35), 89 (6), 88 (98), 87 (12), 86 (37), 85 (55), 84
(44), 83 (46), 82 (36), 81 (32), 80 (6), 79 (9), 78 (5), 77
(27), 76 (6), 75 (14), 74 (10), 73 (73), 72 (11), 71 (65), 70
(44), 69 (71), 68 (14), 67 (20), 65 (10). HRMS (EI) calcd.
for C42H59O8NSSi3-C(CH3)3: 764.2565; found: 764.2597.
HRMS (EI) calcd. for C42H59O8NSSi3-CH3: 806.3034;
found: 806.3073.
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-methyl-
phenylsulfonyl)-10,11-di(phenylcarbonyloxy)-7,8-di(tri-
methylsilyl)-3a,3b,4,5,9b,10,11,11a-
octahydro[1,3]dioxolo[4,5-c]phenanthridine (37)
To a solution of of alcohol 36 (142 mg, 0.21 mmol) in
pyridine (1 mL) was added benzoyl chloride (35 µL,
© 2006 NRC Canada

1330
Can. J. Chem. Vol. 84, 2006
OBz
Na2CO3 (60 mg) and NaIO4 (340 mg, 1.59 mmol) in H2O
(3 mL). A catalytic amount of RuCl3·H2O (1 mg) was added
and the reaction was stirred at room temperature. After 3 h,
the same amount of NaIO4 buffered with Na2CO3 and an-
other catalytic amount of RuCl3·H2O were added. The reac-
tion mixture was stirred at room temperature overnight.
After another addition of the same amount of oxidant the
next day and one additional hour, the starting material was
fully converted. The heterogeneous reaction was diluted
with CH2Cl2 (25 mL) and washed with water and brine. The
organic phase was dried with Na2SO4, filtered, and purified
by flash chromatography (hexanes – ethyl acetate, 3:1). The
oxidized product 38 was isolated as colorless oil in 33%
yield (48 mg, 0.059 mmol); mp 105 °C. [α]23D –72.5 (c 0.65,
CH2Cl2). Rf 0.74 (hexanes – ethyl acetate, 2:1). IR
(CH2Cl2, cm–1) ν: 3057, 2956, 2927, 2856, 2306, 1968,
1729, 1698, 1600, 1582, 1494, 1452, 1365, 1315, 1266,
1221, 1176, 1093, 1070, 1027, 955, 857, 843, 740, 710, 666,
BzO
O
O
CH3
CH3
TMS
Ts
N
MS
T
C
43H51NO8SSi2
798.10 g/mol
0.31 mmol) at 0 °C. The ice bath was removed and the reac-
tion mixture was stirred for 4 h at room temperature. The re-
action was quenched with 5 drops of MeOH, diluted with
ethyl acetate (50 mL), and washed with 1.0 mol/L HCl (2 ×
20 mL) and brine (20 mL). The organic phase was dried
over Na2SO4, filtered, and the solvent was removed under
reduced pressure. Flash column chromatography of the resi-
due (hexanes – ethyl acetate, 5:1) afforded dibenzoate 37
(140 mg, 0.18 mmol, 86%) as foamy white crystals; mp
107 °C. [α]25 –12.7 (c 1.39, CH2Cl2). Rf 0.62 (hexanes –
ethyl acetate,D2:1). IR (CHCl3, cm–1) ν: 3020, 2954, 1726,
1602, 1585, 1493, 1452, 1407, 1384, 1373, 1349, 1316,
1249, 1218, 1170, 1159, 1093, 1070, 1027, 983, 954, 858,
1
637, 608, 587, 545. H NMR (300 MHz, CDCl3, ppm) δ:
8.35 (s, 1H), 8.34 (d, J = 6.9 Hz, 2H), 8.11 (d, J = 6.9 Hz,
2H), 7.62 (m, 3H), 7.48 (m, 4H), 7.34 (d, J = 8.4 Hz, 2H),
7.25 (m, 2H), 6.17 (t, J = 3.3 Hz, 1H), 5.82 (t, J = 3.6 Hz,
1H), 5.70 (dd, J1 = 5.7 Hz, J2 = 8.4 Hz, 1H), 4.69 (dd, J1 =
8.7 Hz, J2 = 12.6 Hz, 1H), 4.52 (m, 1H), 3.94 (dd, J1 =
3.3 Hz, J2 = 12.6 Hz, 1H), 2.45 (s, 3H), 1.47 (s, 3H), 1.40 (s,
3H), 0.25 (s, 9H), 0.19 (s, 9H). 13C NMR (75 MHz, CDCl3,
ppm) δ: 166.9, 165.1, 164.6, 154.8, 146.0, 144.1, 138.5,
135.6, 133.8, 133.3, 131.6, 130.0, 129.6, 129.1, 129.0,
128.9, 128.7, 128.2, 127.3, 109.9, 74.6, 73.5, 68.8, 68.5,
63.0, 40.1, 28.3, 26.1, 21.7, 1.6, 1.3 (two signals missing).
MS (EI) m/z (relative intensity): 796 (M+ – CH3, 0.4), 477
(6), 356 (5), 355 (6), 331 (6), 179 (6), 122 (5), 106 (8), 105
(100), 97 (7), 91 (13), 85 (6), 83 (8), 81 (7), 77 (19), 73
(19), 71 (8), 69 (14), 67 (5). HRMS (EI) calcd. for
C43H49O9NSSi2-CH3: 796.2432; found: 796.2444.
1
841, 811, 711, 670, 627, 578, 562, 550, 532, 514, 462. H
NMR (300 MHz, CDCl3, ppm) δ: 8.10 (m, 4H), 7.59 (m,
2H), 7.48 (m, 4H), 7.25 (m, 4H), 6.45 (d, J = 8.1 Hz, 2H),
6.21 (s, 1H), 5.74 (t, J = 2.4 Hz, 1H), 4.77 (d, J = 16.5 Hz,
1H), 4.71 (dd, J1 = 5.4 Hz, J2 = 10.2 Hz, 1H), 4.50 (m, 2H),
4.34 (d, J = 16.2 Hz, 1H), 3.04 (d, J = 11.7 Hz, 1H), 2.05 (s,
3H), 1.84 (s, 3H), 1.47 (s, 3H), 0.31 (s, 9H), 0.20 (s, 9H).
13C NMR (75 MHz, CDCl3, ppm) δ: 165.1, 164.3, 146.3,
144.0, 141.9, 136.6, 134.6, 133.6, 133.4, 132.6, 131.9,
130.3, 130.1, 129.8, 129.7, 128.8, 128.5, 128.4, 128.4,
128.3, 127.4, 109.8, 76.3, 70.0, 68.3, 56.1, 47.4, 38.0, 27.9,
25.9, 21.3, 1.7, 1.6. MS (EI) m/z (relative intensity): 798
(M+, 4), 797 (6), 642 (6), 476 (7), 340 (7), 179 (5), 149 (5),
123 (6), 122 (31), 106 (8), 105 (100), 97 (8), 95 (5), 91 (10),
84 (6), 83 (9), 77 (37), 74 (6), 73 (23), 71 (10), 70 (5), 69
(10), 67 (6). HRMS (EI) calcd. for C43H51O8NSSi2:
797.2874; found: 797.2863. Anal. calcd. for C43H51O8NSSi2:
C 64.71, H 6.44; found: C 64.71, H 6.50.
(1R,2S,3S,4S,4aR,10bR)-1,2,3,4-Tetrahydroxy-8,9-
di(trimethylsilyl)-1,2,3,4,4a,5,6,10b-octahydro-6-
phenanthridinone (39)
OH
O
H
O
H
(3aS,3bR,9bR,10R,11S,11aS)-2,2-Dimethyl-4-(4-methyl-
phenylsulfonyl)-5-oxo-10,11-di(phenylcarbonyloxy)-7,8-
di(trimethylsilyl)-3a,3b,4,5,9b,10,11,11a-
octahydro[1,3]dioxolo[4,5-c]phenanthridine (38)
To a suspension of tosylamide 37 (141 mg, 0.18 mmol) in
CH3CN–CCl4–H2O (4:4:3, 11 mL) was added a solution of
MS
MS
T
T
OH
H
N
O
C19H31NO5Si2
409.62 g/mol
OBz
BzO
O
CH3
To a solution of of tosylate 38 (39 mg, 0.05 mmol) in
THF (0.5 mL) under argon was added a 0.4 mol/L solution
of sodium naphthalide (at –65 °C) until the green colour per-
sisted. The reaction was quenched with satd. aq. NH4Cl and
extracted with CH2Cl2 (6 × 10 mL). The combined organic
phases were dried over MgSO4, filtered, and the organic sol-
vent was removed under reduced pressure. The residue was
dissolved in MeOH. After addition of a 2.25 mol/L solution
MS
MS
H
3
T
T
C
O
Ts
N
O
C
43H49NO9SSi2
812.09 g/mol
© 2006 NRC Canada

Hudlicky et al.
1331
1
of sodium methoxide (64 µL), the reaction mixture was
stirred for 20 min. The solution was quenched with satd. aq.
NH4Cl and extracted with CH2Cl2 (6 × 10 mL). The com-
bined organic phases were dried over MgSO4, filtered, and
the organic solvent was removed under vacuum. Flash col-
umn chromatography of the residue (pentane – diethyl ether,
1:2) afforded a diol (7 mg, 0.02 mmol, 32%). The diol
(6 mg, 0.01 mmol) was dissolved in MeOH and heated to re-
flux for 4 h after addition of a spatula tip of Dowex 50WX8-
100. The ion exchange resin was removed by filtration and
the solvent was removed under reduced pressure. Flash col-
umn chromatography of the residue (CHCl3–MeOH, 6:1) af-
forded tetraol 39 (5 mg, 0.01 mmol, 25% over three steps);
814, 792, 734, 711, 686, 662, 650, 575, 548, 512, 466. H
NMR (300 MHz, CDCl3, ppm) δ: 7.95 (m, 4H), 7.79 (d, J =
8.1 Hz, 2H), 7.56 (m, 2H), 7.42 (m, 4H), 7.28 (d, J =
8.4 Hz, 2H), 5.86 (dd, J1 = 2.7 Hz, J2 = 4.2 Hz, 1H), 5.68
(dd, J1 = 2.7 Hz, J2 = 8.1 Hz, 1H), 5.04 (d, J = 7.5, 1H),
4.38 (m, 2H), 3.87 (m, 1H), 3.23 (t, J = 7.8 Hz, 1H), 2.42 (s,
3H), 1.51 (s, 3H), 1.31 (s, 3H), 0.06 (s, 9H). 13C NMR
(75 MHz, CDCl3, ppm) δ: 165.3, 165.3, 143.6, 138.8, 133.9,
133.7, 130.1, 130.1, 129.8, 129.7, 129.6, 128.9, 128.8,
127.6, 110.6, 101.6, 90.5, 78.1, 75.1, 71.8, 69.7, 57.4, 36.4,
28.1, 26.3, 21.9, 0.0. MS (EI) m/z (relative intensity): 646
(M+ – CH3, 3), 282 (6), 214 (11), 155 (7), 122 (9), 106 (10),
105 (100), 91 (15), 77 (21), 73 (8), 69 (9), 57 (6), 55 (6), 43
(11), 41 (6). HRMS (EI) calcd. for C35H39O8NSSi:
661.2166; found: 661.2158. Anal. calcd. for C35H39O8NSSi:
C 63.52, H 5.94; found: C 63.97, H 5.95.
mp 213 °C. [α]23 +60.5 (c 0.15, MeOH). Rf 0.38 (CHCl3–
D
MeOH, 6:1). IR (CHCl3, cm–1) ν: 3385, 2953, 2926, 1705,
1652, 1600, 1586, 1447, 1410, 1375, 1318, 1250, 1217,
1155, 1128, 1093, 1055, 955, 857, 838, 757, 667, 630, 572,
1
549. H NMR (300 MHz, CD3OD, ppm) δ: 8.31 (s, 1H),
(3aS,4S,5S,6R,7R,7aS)-6-(1-Ethynyl)-2,2-dimethyl-7-[4-
methylphenyl(propynyl)sulfonamido]-4,5-
di(phenylcarbonyloxy)perhydro-1,3-benzodioxole (41)
7.79 (s, 1H), 4.87 (s, 5H), 4.61 (m, 1H), 4.22 (t, J = 3.3 Hz,
1H), 4.05 (m, 1H), 3.95 (m, 2H), 3.33 (m, 1H), 0.41 (s, 9H),
0.40 (s, 9H). 13C NMR (75 MHz, CDCl3, ppm) δ: 168.3,
153.0, 145.3, 139.0, 134.9, 132.7, 129.1, 75.1, 72.1, 72.0,
70.2, 51.6, 41.1, 2.0, 1.9. MS (ESI) m/z (relative intensity):
454 ([M + formate]–, 72), 444 ([M + Cl]–, 100), 408 ([M –
H]–, 2), 394 (7), 311 (5), 265 (8), 171 (17), 111 (7), 89 (12).
HRMS (ESI) calcd. for C42H61O7NSSi3 + Cl–: 444.1429;
found: 444.1429.
OBz
BzO
O
CH3
H
C
3
O
Ts
N
(3aS,4S,5S,6R,7R,7aS)-2,2-Dimethyl-7-(4-methyl-
phenylsulfonamido)-4,5-di(phenylcarbonyloxy)-6-(2-
trimethylsilyl-1-ethynyl)perhydro-1,3-benzodioxole (40)
C35H33NO8S
627.70 g/mol
OBz
To a solution of TMS-protected acetylene 40 (976 mg,
1.48 mmol) in dry acetonitrile (35 mL) was added TBAT
(1.19 g, 2.21 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, quenched with satd. aq. NH4Cl
(50 mL), and extracted with ethyl acetate (3 × 50 mL). The
combined organic phases were dried over Na2SO4 and evap-
orated at reduced pressure. Column chromatography (hex-
anes – ethyl acetate, 4:1 to 2:1) afforded unprotected
acetylene (664 mg, 1.13 mmol, 76%) as white crystals. To
these crystals (418 mg,0.71 mmol) dissolved in THF (2 mL)
was added NaHMDS (1.0 mol/L, 0.85 mL, 0.85 mmol) at
–70 °C under argon. The reaction mixture was allowed to
warm up to 0 °C over a period of 20 min and was further
stirred for 10 min at this temperature. Propargyl bromide
(422 mg, 3.54 mmol) and (nBu)4NI (262 mg, 0.71 mmol)
were added and the solution was allowed to warm to room
temperature overnight. The reaction was quenched by addi-
tion of satd. aq. NH4Cl (40 mL) and extracted with ethyl ac-
etate (4 × 40 mL). The combined organic phases were
washed with brine (20 mL), dried over MgSO4, and the sol-
vent was removed under reduced pressure. Flash column
chromatography of the residue (hexanes – ethyl acetate, 3:2)
afforded tosylamide 41 (419 mg, 0.67 mmol, 94%; 71% over
BzO
O
CH3
CH3
O
H3C
Si
NHTs
H3C CH3
C35H39NO8SSi
661.84 g/mol
To a solution of of diol 24 (721 mg, 1.59 mmol) in
pyridine (5 mL) was added benzoyl chloride (0.44 mL,
3.82 mmol) at 0 °C. The ice bath was removed and the reac-
tion mixture was stirred for 1.5 h at room temperature. The
reaction was quenched with 10 drops of MeOH, diluted with
ethyl acetate (150 mL), and washed with 1.0 mol/L HCl (3 ×
20 mL), water (20 mL), and brine (20 mL). The organic
phase was dried over Na2SO4 and the solvent was removed
under reduced pressure. Flash column chromatography of
the residue (hexanes – ethyl acetate, 6:1 to 3:1) afforded
dibenzoate 40 (840 mg, 1.27 mmol, 80%) as white crystals;
mp 149 °C. [α]23 –99.9 (c 4.50, CH2Cl2). Rf 0.71 (hexanes
D
– ethyl acetate, 2:1). IR (CDCl3, cm–1) ν: 3673, 3264, 3066,
3034, 2988, 2961, 2938, 2901, 2255, 2183, 1966, 1911,
1728, 1601, 1585, 1493, 1452, 1384, 1374, 1329, 1316,
1274, 1248, 1222, 1162, 1094, 1070, 1026, 1003, 910, 848,
two steps) as crystalline foam ; mp 86 °C. [α]23 –99.0
D
(c 1.40, CH2Cl2). Rf 0.29 (hexanes – ethyl acetate, 3:1). IR
(CH2Cl2, cm–1) ν: 3300, 3064, 2988, 2939, 2593, 2126,
1918, 1732, 1602, 1586, 1494, 1452, 1386, 1374, 1352,
© 2006 NRC Canada

1332
Can. J. Chem. Vol. 84, 2006
1328, 1274, 1247, 1222, 1157, 1097, 1071, 1037, 1003, 921,
894, 854, 817, 736, 710, 667, 578, 564, 545, 526, 460. H
J2 = 9.0 Hz, 1H), 4.59 (dd, J1 = 16.5 Hz, J2 = 60.0 Hz, 2H),
4.03 (dd, J1 = 8.4 Hz, J2 = 12.6 Hz, 1H), 3.28 (dd, J1 =
8.7 Hz, J2 = 12.6 Hz, 1H), 2.31 (s, 3H), 1.56 (s, 3H), 1.37 (s,
3H), 0.39 (s, 9H), 0.12 (s, 9H). 13C NMR (75 MHz, CDCl3,
ppm) δ: 165.4, 165.3, 146.2, 144.3, 142.7, 137.4, 133.6,
133.3, 133.1, 132.6, 132.5, 131.4, 129.7, 129.7, 129.3,
129.1, 129.0, 128.3, 128.1, 127.5, 110.7, 76.9, 73.7, 69.7,
69.5, 58.1, 48.0, 39.4, 27.5, 25.1, 21.4, 1.8, 1.6. MS (EI) m/z
(relative intensity): 430 (2), 256 (5), 230 (11), 167 (5), 149
(19), 137 (11), 136 (6), 129 (15), 123 (9), 122 (5), 121 (7),
113 (6), 112 (10), 111 (7), 109 (8), 197 (6), 105 (19), 98 (7),
97 (12), 96 (6), 95 (15), 93 (9), 91 (8), 87 (5), 85 (12), 84
(13), 83 (19), 82 (10), 81 (41), 79 (7), 77 (10), 73 (23), 71
(26), 70 (21), 69 (100), 68 (16), 67 (15), 61 (6), 60 (19), 58
(6), 57 (49), 56 (31), 55 (46), 54 (6), 53 (8), 45 (12), 44
(12), 43 (59), 42 (15), 41 (67). HRMS (EI) calcd. for
C43H51O8NSSi2: 797.2874; found: 797.2885.
1
NMR (300 MHz, CDCl3, ppm) δ: 8.04 (d, J = 7.5 Hz, 2H),
7.92 (m, 4H), 7.52 (m, 1H), 7.43 (m, 3H), 7.30 (m, 4H),
5.95 (m, 1H), 5.70 (dd, J1 = 2.1 Hz, J2 = 9.6 Hz, 1H), 4.99
(dd, J1 = 5.7 Hz, J2 = 8.7 Hz, 1H), 4.40 (m, 1H), 4.22 (m,
3H), 4.00 (m, 1H), 2.38 (s, 3H), 2.22 (s, 1H), 2.05 (d, J =
1.5 Hz, 1H), 1.65 (s, 3H), 1.36 (s, 3H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 165.0, 164.8, 143.6, 137.2, 133.5, 133.1,
129.8, 129.7, 129.3, 129.0, 128.5, 128.3, 128.0, 110.6, 79.9,
78.1, 75.0, 75.0, 74.2, 73.3, 71.3, 68.5, 62.6, 36.5, 36.4,
33.2, 28.0, 26.0, 21.5. MS (EI) m/z (relative intensity): 612
(M+ – CH3, 1), 472 (11), 414 (5), 355 (7), 246 (5), 232 (5),
214 (8), 190 (16), 189 (97), 173 (7), 171 (6), 170 (7), 155
(7), 149 (14), 139 (8), 137 (11), 136 (5), 129 (5), 123 (7),
122 (9), 121 (9), 119 (5), 106 (11), 105 (100), 97 (7), 95 (8),
92 (9), 91 (24), 85 (7), 83 (9), 82 (6), 81 (26), 78 (6), 77
(21), 73 (11), 71 (12), 70 (6), 69 (61), 68 (8), 67 (7), 65 (7),
60 (10), 59 (5), 57 (23), 56 (9), 55 (19), 45 (8), 43 (32), 41
(24), 40 (9), 39 (10). HRMS (EI) calcd. for C35H33O8NS-
CH3: 612.1692; found: 612.1682.
(3aS,3bR,9bR,10S,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-7,8-di(trimethylsilyl)-
3a,3b,4,5,9b,10,11,11a-octahydro[1,3]dioxolo[4,5-
c]phenanthridine-10,11-diol (43)
(3aS,3bR,9bR,10S,11S,11aS)-2,2-Dimethyl-4-(4-
methylphenylsulfonyl)-10,11-di(phenylcarbonyloxy)-7,8-
di(trimethylsilyl)-3a,3b,4,5,9b,10,11,11a-
OH
octahydro[1,3]dioxolo[4,5-c]phenanthridine (42)
HO
O
CH3
TMS
CH3
O
OBz
BzO
O
Ts
N
CH3
MS
T
TMS
CH3
C29H43NO6SSi2
589.89 g/mol
O
Ts
N
MS
T
Protected diol 42 (100 mg, 0.13 mmol) was dissolved in a
1% sodium hydroxide solution in methanol (2 mL) and
stirred for 1 h at room temperature. The reaction was
quenched with NH4Cl and extracted with CH2Cl2. The or-
ganic solvents were dried over Na2SO4 and removed under
high vacuum. The residue was purified by column chroma-
tography (hexanes – ethyl acetate, 3:1 to 1:1). The diol 43
was isolated as foamy crystals in 99% yield (73 mg,
0.12 mmol); mp 121 °C. [α]25 +35.5 (c 1.50, CH2Cl2). Rf
0.18 (hexanes – ethyl acetate,D2:1). IR (CH2Cl2, cm–1) ν:
3406, 3055, 2954, 2927, 2871, 1727, 1599, 1495, 1455,
1376, 1347, 1266, 1250, 1213, 1160, 1124, 1091, 1072,
1042, 1002, 972, 931, 877, 858, 840, 740, 704, 672, 656,
602, 563, 546, 519, 486, 479, 467, 463, 455. 1H NMR
(300 MHz, CDCl3, ppm) δ: 7.65 (s, 1H), 7.43 (d, J = 8.1 Hz,
2H), 7.21 (s, 1H), 6.98 (d, J = 8.1 Hz, 2H), 4.74 (t, J =
7.8 Hz, 1H), 4.56 (d, J = 16.2 Hz, 1H), 4.35 (m, 3H), 3.91
(m, 1H), 3.75 (m, 1H), 3.11 (s, 1H), 2.87 (s, 1H), 2.67 (dd,
J1 = 8.1 Hz, J2 = 12.3 Hz, 1H), 2.29 (s, 3H), 1.54 (s, 3H),
1.33 (s, 3H), 0.33 (s, 9H), 0.32 (s, 9H). 13C NMR (75 MHz,
CDCl3, ppm) δ: 145.6, 143.9, 142.5, 137.4, 133.9, 133.8,
132.3, 132.1, 128.9, 127.4, 110.3, 77.1, 75.8, 70.3, 68.8,
57.0, 47.6, 41.0, 27.7, 25.0, 21.5, 1.9, 1.9. MS (EI) m/z (rel-
ative intensity): 574 (M+ – CH3, 13), 471 (12), 459 (10), 458
(22), 435 (23), 434 (65), 432 (11), 429 (13), 428 (29), 342
(11), 335 (17), 322 (20), 285 (21), 274 (12), 185 (10), 169
C
43H51NO8SSi2
798.10 g/mol
To a solution of CpCo(CO)2 (5 µL) in BTMSA (12 mL)
bisacetylene 41 (370 mg, 0.59 mmol), CpCo(CO)2 (5 µL)
dissolved in xylene (2 mL), and BTMSA (8 mL) were added
dropwise with a syringe pump at 140 °C over 30 h. During
this slow addition, extra catalyst was added directly into the
reaction mixture in aliquots: 3 µL after 5 h, 5 µL after 20 h,
and 3 µL after 29 h. The reaction mixture was heated under
argon for further 12 h. BTMSA and xylene were removed
under high vacuum and the residue was purified by column
chromatography (hexanes
– ethyl acetate, 9:1). The
cyclotrimerized product 42 was isolated as crystalline foam
in 87% yield (407 mg, 0.51 mmol); mp 131 °C. [α]23D +43.1
(c 0.75, CH2Cl2). Rf 0.37 (hexanes – ethyl acetate, 3:1). IR
(CDCl3, cm–1) ν: 3065, 3034, 2986, 2954, 2901, 2255, 1911,
1729, 1602, 1586, 1493, 1452, 1384, 1374, 1348, 1316,
1272, 1251, 1218, 1178, 1162, 1120, 1093, 1069, 1027,
1002, 971, 910, 874, 856, 839, 812, 784, 734, 670, 649, 628,
1
564, 519. H NMR (300 MHz, CDCl3, ppm) δ: 7.89 (d, J =
7.5 Hz, 2H), 7.85 (d, J = 8.7 Hz, 2H), 7.52 (m, 4H), 7.34
(m, 4H), 7.26 (m, 2H), 7.04 (d, J = 8.1 Hz, 2H), 6.19 (dd,
J1 = 5.4 Hz, J2 = 8.4 Hz, 1H), 5.70 (dd, J1 = 5.1 Hz, J2 =
9.3 Hz, 1H), 4.98 (t, J = 7.5 Hz, 1H), 4.76 (dd, J1 = 7.2 Hz,
© 2006 NRC Canada

Hudlicky et al.
1333
(79), 155 (30), 150 (15), 149 (19), 147 (27), 139 (15), 133
(10), 131 (13), 129 (17), 125 (14), 124 (14), 123 (14), 119
(45), 111 (21), 109 (21), 105 (15), 97 (38), 96 (17), 95 (28),
92 (12), 91 (65), 85 (23), 84 (14), 83 (32), 82 (17), 81 (31),
79 (14), 77 (14), 73 (51), 71 (33), 70 (21), 69 (75), 68 (14),
67 (22), 65 (15), 59 (12), 57 (55), 56 (19), 55 (61), 53 (11),
45 (15), 44 (15), 43 (100), 42 (15), 41 (54). HRMS (EI)
calcd. for C29H43O6NSSi2-CH3: 574.2115; found: 574.2099.
Anal. calcd. for C29H43O6NSSi2: C 59.05, H 7.35; found: C
58.77, H 7.37.
(3aS,4R,5R,7aR)-5-(1-Ethynyl)-2,2-dimethyl-4-[4-
methylphenyl(propioloyl)sulfonamido]-3a,4,5,7a-
tetrahydro-1,3-benzodioxolone (45)
O
CH3
CH3
O
O
N
S
O
O
(3aS,3bR,6aS,6bR,12bR,12cS)-5,5-Dimethyl-7-(4-methyl-
phenylsulfonyl)-10,11-di(trimethylsilyl)-3a,3b,6a,6b,
7,8,12b,12c-octahydro-1,3,4,6-tetraoxa-2-thia-7-aza-
dicyclopenta[a,c]phenanthrene-2,2-dioxide (44)
H
C
3
C21H21NO5S
399 46 g/mol
To a solution of acetonide 18 (250 mg, 0.60 mmol) in
THF (5 mL) was added BuLi (1.6 mol/L, 0.41 mL,
0.66 mmol) at 0 °C under argon. Propiolic acid anhydride
(87 mg, 0.72 mmol) was added and the solution was allowed
to warm to room temperature overnight. The reaction was
quenched by addition of satd. aq. NH4Cl (20 mL) and the
aqueous phase extracted with ethyl acetate (4 × 20 mL). The
combined organic phases were washed with brine (10 mL),
dried over MgSO4, and the solvent was removed under re-
duced pressure. Flash column chromatography of the residue
(hexanes – ethyl acetate, 3:1) afforded a bisacetylene (128 mg,
0.27 mmol, 46%) as a slightly yellow foam. To a solution of
this bisacetylene (150 mg, 0.32 mmol) in acetonitrile (5 mL)
was added TBAT (340 mg, 0.63 mmol). The reaction mix-
ture was stirred at room temperature for 30 h, then diluted
with 30 mL ethyl acetate, and washed with satd. aq. NH4Cl
(3 × 10 mL) and with brine (10 mL). The organic phase was
dried over MgSO4 and the solvent was removed under re-
duced pressure. Flash column chromatography of the residue
(hexanes – ethyl acetate, 3:1) afforded the bisacetylene 45
(77 mg, 0.19 mmol, 61%) as a colorless oil. [α]21 +30.3 (c
0.25, CH2Cl2). Rf 0.40 (hexanes – ethyl acetateD, 3:1). IR
(CHCl3, cm–1) ν: 3298, 3021, 2989, 2937, 2876, 2591, 2403,
2109, 1917, 1732, 1674, 1597, 1511, 1495, 1485, 1456, 1429,
1399, 1366, 1309, 1270, 1246, 1216, 1189, 1172, 1141,
1120, 1085, 1067, 1027, 1019, 998, 971, 946, 923, 897, 865,
To a solution of diol 43 (494 mg, 0.84 mmol) in dry
CH2Cl2 (20 mL) was added triethylamine (5 mL) at 0 °C.
The solution was stirred for 10 min and SO2Cl2 (1.0 mol/L
solution, 15 mL) were added dropwise via syringe pump
over a period of 2 h. Additional NEt3 (5 mL) and SO2Cl2
(15 mL) were added over a period of 2 h for full conversion
(TLC). The reaction mixture was diluted with CH2Cl2
(30 mL), quenched with satd. aq. NH4Cl (50 mL), and ex-
tracted with CH2Cl2 (3 × 50 mL). The organic phase was
dried over Na2SO4, filtered, and the solvent was removed
under reduced pressure. Purification by flash column chro-
matography (hexanes – ethyl acetate, 5:1) afforded cyclic
sulfate 44 (383 mg, 0.59 mmol, 70%); mp 110 °C. [α]26
1
830, 813, 757. H NMR (300 MHz, CDCl3, ppm) δ: 7.97 (d,
D
+24.6 (c 0.40, CH2Cl2). Rf 0.66 (hexanes – ethyl acetate,
2:1). IR (CHCl3, cm–1) ν: 3462, 3021, 2963, 2870, 1732,
1597, 1456, 1385, 1355, 1308, 1249, 1213, 1182, 1162,
1127, 1090, 1056, 995, 919, 883, 840, 795, 756, 669, 627,
562. 1H NMR (300 MHz, CDCl3, ppm) δ: 7.42 (m, 3H), 7.28
(s, 1H), 7.00 (d, J = 8.1 Hz, 2H), 5.35 (dd, J1 = 7.2 Hz, J2 =
9.6 Hz, 1H), 5.04 (t, J = 7.2 Hz, 1H), 4.75 (m, 2H), 4.63 (d,
J = 16.2 Hz, 1H), 4.27 (d, J = 16.2 Hz, 1H), 3.69 (dd, J1 =
8.1 Hz, J2 = 12.3 Hz, 1H), 2.99 (t, J = 10.8 Hz, 1H), 2.30 (s,
3H), 1.57 (s, 3H), 1.34 (s, 3H), 0.34 (s, 9H), 0.33 (s, 9H).
13C NMR (75 MHz, CDCl3, ppm) δ: 145.0, 144.0, 141.3,
135.1, 131.7, 130.8, 129.6, 128.8, 127.3, 125.6, 109.8, 80.9,
78.0, 75.1, 73.0, 54.3, 45.2, 36.5, 25.5, 22.9, 19.7, 0.0, 0.0.
MS (EI) m/z (relative intensity): 636 (M+ – CH3, 1), 88 (11),
86 (65), 84 (100), 73 (6), 69 (6), 49 (21), 47 (27), 43 (6).
HRMS (EI) calcd. for C29H41O8NS2Si2-CH3: 636.1577;
found: 636.1556. Anal. calcd. for C29H41O8NS2Si2: C 53.43,
H 6.34; found: C 53.52, H 6.47.
J = 8.0 Hz, 2H), 7.40 (d, J = 9.5 Hz, 2H), 5.98 (m, 2H), 5.07
(m, 1H), 4.70 (m, 2H), 4.21 (d, J = 10.4 Hz, 1H), 3.24 (s,
1H), 2.39 (s, 3H), 2.16 (s, 1H), 1.48 (s, 3H), 1.38 (s, 3H).
13C NMR (75 MHz, CDCl3, ppm) δ: 153.6, 145.4, 136.0,
132.6, 129.7, 129.2, 123.6, 110.6, 83.0, 81.5, 75.2, 73.4,
72.9, 72.7, 65.4, 32.9, 27.8, 25.8, 21.9. MS (EI) m/z (relative
intensity): 384 (MH+ – CH3, 8), 306 (18), 248 (11), 228 (7),
224 (10), 204 (12), 170 (9), 156 (8), 155 (77), 152 (9), 139
(11), 135 (20), 119 (22), 118 (46), 107 (5). HRMS (EI)
calcd. for C21H21O5NS-CH3: 384.0906; found: 384.0898.
Carbonyl-␩1-cyclopentadienyl-␩6-(3aS,3bR,11aR)-2,2-
dimethyl-4-(4-methylphenylsulfonyl)-7,8-di(trimethyl-
silyl)-3a,3b,4,5,11,11a-hexahydro[1,3]dioxolo[4,5-c]-
phenanthridin-5-onylcobalt (46)
A solution of bisacetylene 45 (165 mg, 0.43 mmol) and
CpCo(CO)2 (10 µL) in BTMSA (10 mL) and xylene
(10 mL) was added with a syringe pump to a refluxing solu-
© 2006 NRC Canada

1334
Can. J. Chem. Vol. 84, 2006
OBz
O
O
CH3
CH3
BzO
O
CH3
TMS
H
C
3
O
O
N
MS
O
T
S
Ts
N
O
O
Co
O
C
H
C
3
C35H31NO9S
641.69 g/mol
C35H44CoNO6SSi2
721.91 g/mol
0.43 mmol) at –70 °C under argon. The reaction mixture
was allowed to warm to 0 °C over a period of 20 min and
was further stirred for 10 min at this temperature. Propiolic
acid anhydride (130 mg, 1.07 mmol) was added and the so-
lution was allowed to warm to room temperature overnight.
The reaction was quenched by addition of satd. aq. NH4Cl
(20 mL) and the aqueous phase extracted with ethyl acetate
(4 × 20 mL). The combined organic phases were washed
with brine (10 mL), dried over MgSO4, and the solvent was
removed under reduced pressure. Flash column chromatog-
raphy of the residue (hexanes – ethyl acetate, 3:2) afforded
an unseparable 3:2 rotamer mixture of tosylamide 47
(128 mg, 0.27 mmol, 46%) as oily white crystals; mp
121 °C. [α]23 –124.6 (c 1.05, CH2Cl2). Rf 0.62 (hexanes –
ethyl acetate,D2:1). IR (CH2Cl2, cm–1) ν: 3292, 3055, 2987,
2831, 2686, 2522, 2411, 2306, 2113, 1731, 1677, 1602,
1551, 1422, 1363, 1266, 1189, 1173, 1116, 1095, 1071,
tion of CpCo(CO)2 (10 µL) in BTMSA (25 mL) over a pe-
riod of 35 h. After the addition was completed, the reaction
mixture was refluxed for an additional 6 h. The solvent was
removed under reduced pressure (0.1 mbar, 1 bar =
100 kPa). The reddish brown residue was purified by flash
column chromatography (pentane to ether – pentane, 1:1)
and afforded the cobalt complex 46 (33 mg, 0.05 mmol,
11%) as a yellow oil. [α]26 +27.6 (c 0.23, CHCl3). Rf 0.53
(hexanes –ethyl acetate, 3D:1). IR (CHCl3, cm–1) ν: 3261,
3019, 2958, 2934, 2873, 2401, 1693, 1599, 1521, 1496,
1456, 1383, 1375, 1328, 1287, 1272, 1251, 1216, 1158,
1
1096, 1071, 969, 928, 857, 841, 812, 757, 669. H NMR
(300 MHz, CDCl3, ppm) δ: 8.00 (s, 1H), 7.51 (s, 1H), 7.36
(d, J = 8.2 Hz, 2H), 6.96 (d, J = 8.1 Hz, 2H), 6.01 (d, J =
7.7 Hz, 1H), 5.91 (m, 1H), 5.71 (d, J = 9.8 Hz, 1H), 4.57
(m, 1H), 4.18 (m, 3H), 4.00 (m, 1H), 3.61 (m, 1H), 2.18 (s,
3H), 1.58 (m, 2H), 1.33 (s, 3H), 1.18 (s, 3H), 0.23 (s, 9H),
0.21 (s, 9H). 13C NMR (75 MHz, CDCl3, ppm) δ: 169.5,
152.6, 144.8, 141.7, 141.0, 140.0, 136.3, 136.1, 135.7,
129.5, 129.1, 128.8, 126.9, 124.3, 109.9, 79.5, 79.3, 72.7,
65.9, 60.4, 41.8, 30.5, 28.7, 28.2, 26.2, 25.9, 21.6, 1.9, 1.8.
MS (FAB) m/z (relative intensity): 744 (M+ + Na, 0.1). MS
(EI) m/z (relative intensity): 656 (M+ – Cp, 4.8), 614 (5),
613 (11), 505 (7), 501 (8), 500 (20), 460 (9), 459 (21), 458
(8), 420 (6), 419 (14), 418 (38), 358 (6), 357 (13), 356 (7),
343 (6), 341 (7), 340 (7), 329 (5), 325 (8), 294 (7), 288 (6),
279 (5), 255 (8), 254 (37), 253 (23), 228 (6), 205 (6), 171
(6), 155 (18), 149 (17), 141 (5), 140 (7), 139 (33), 124 (8),
100 (11), 99 (65), 98 (52), 97 (6), 95 (8), 92 (11), 91 (58),
85 (7), 83 (9), 81 (5), 77 (6), 75 (18), 74 (11), 73 (100), 71
(13), 69 (13), 67 (5), 65 (10). HRMS (EI) calcd. for
C35H44O6NSSi2Co-CO: 693.1811; found: 693.1807.
1
1055, 1027, 896, 853, 740, 705, 618, 574, 546. H NMR
(300 MHz, CDCl3, ppm) δ: 8.15 (m, 3H), 8.02 (m, 1H), 7.97
(m, 2H), 7.58 (m, 1H), 7.49 (m, 3H), 7.40 (m, 4H), 6.06 (m,
1H), 5.72 (dd, J1 = 2.1 Hz, J2 = 10.2 Hz, 1H), 5.35/4.96 (m,
1H), 4.96 (m, 1H), 4.46 (m, 2H), 3.30/3.18 (m, 1H),
2.45/2.43 (s, 3H), 2.19/2.14 (m, 1H), 1.74/1.64 (s, 3H), 1.42
(s, 3H). 13C NMR (75 MHz, CDCl3, ppm) δ: 165.3,
165.1/164.9, 153.2, 145.4/145.2, 136.7, 133.7, 133.3/133.2,
130.9/130.0, 129.9, 129.9, 129.6, 129.4/129.3, 129.2/129.0,
128.7, 128.4/128.3, 111.2/111.0, 83.6/83.2, 79.4/79.0,
75.9/75.4, 75.2/75.1, 74.4/74.1, 74.0/73.2, 71.2/71.1,
68.3/68.1, 62.8, 33.8/31.5, 27.9/27.8, 26.2/26.0, 21.7. MS
(EI) m/z (relative intensity): 626 (M+ – CH3, 1), 122 (9), 119
(5), 105 (47), 91 (8), 88 (19), 86 (100), 84 (100), 77 (14), 64
(16), 53 (15), 51 (11), 49 (31), 48 (6), 47 (37), 44 (7), 43
(17). HRMS (EI) calcd. for C35H31O9NS-CH3: 626.1485;
found: 626.1495.
(3aS,4S,5S,6R,7R,7aS)-6-(1-Ethynyl)-2,2-dimethyl-7-[4-
methylphenyl(propioloyl)sulfonamido]-4,5-di(phenyl-
carbonyloxy)perhydro-1,3-benzodioxole (47)
(3aS,3bR,9bR,10S,11S,11aS)-2,2-Dimethyl-4-(4-methyl-
phenylsulfonyl)-5-oxo-10,11-di(phenylcarbonyloxy)-7,8-
di(trimethylsilyl)-3a,3b,4,5,9b,10,11,11a-
To a solution of TMS-protected acetylene 40 (976 mg,
1.48 mmol) in dry acetonitrile (35 mL) was added TBAT
(1.19 g, 2.21 mmol). The reaction mixture was stirred at
room temperature for 1.5 h, quenched with satd. aq. NH4Cl
(50 mL), and extracted with ethyl acetate (3 × 50 mL). The
combined organic phases were dried over Na2SO4 and evap-
orated under reduced pressure. Column chromatography
(hexanes – ethyl acetate, 4:1 to 2:1) afforded unprotected
acetylene (664 mg, 1.13 mmol, 76%) as white crystals. To a
solution of this material (210 mg, 0.36 mmol) in THF
(6 mL) was added NaHMDS (1.0 mol/L, 0.43 mL,
octahydro[1,3]dioxolo[4,5-c]phenanthridine (48)
To a solution of CpCo(CO)2 (2 µL) in BTMSA (6 mL),
bisacetylene 47 (105 mg, 0.16 mmol) and CpCo(CO)2
(2 µL) dissolved in xylene (1 mL) and BTMSA (4 mL) were
added dropwise with a syringe pump at 140 °C over 30 h.
During this slow addition, extra catalyst was added directly
into the reaction mixture in aliquots: 2 µL after 5 h and after
20 h, and 1 µL after 29 h. After 5 h and after 20 h, addi-
tional CpCo(CO)2 (2 µL) was added, and after 29 h, addi-
tional CpCo(CO)2 (1 µL) was added. The reaction mixture
was heated under argon for a further 12 h. BTMSA and
© 2006 NRC Canada

Hudlicky et al.
1335
OBz
catalyst was added directly into the reaction mixture in
aliquots: 5 µL after 5, 17, 29, and 41 h. The reaction mixture
was heated under argon for a further 12 h. Xylene was re-
moved at high vacuum and the residue was purified by col-
umn chromatography (hexanes – ethyl acetate, 9:1 to 6:1).
All four diastereoisomers of the cyclotrimerized product 50
were isolated as crystalline foam in 31% overall yield
(52 mg, 0.05 mmol). MS (EI) m/z (relative intensity): 954
(M+ – CH3, 0.1), 912 (10), 526 (12), 253 (12), 179 (12), 147
(11), 106 (12), 105 (100), 91 (16), 77 (17), 75 (27), 73 (33).
The mixture of diastereoisomers was dissolved in THF
(0.5 mL), treated with TBAF (1.0 mol/L solution in THF,
0.55 mL) and stirred for 2 h. The reaction mixture was
quenched with satd. NH4Cl solution and extracted three
times with diethyl ether. The combined organic phases were
dried over MgSO4, filtered, and evaporated to dryness. Col-
umn chromatography (hexanes – ethyl acetate, 1:2) gave a
mixture of four diastereomeric diols (29 mg, 0.04 mmol,
72%), used immediately in the next step. IR (CDCl3, cm–1)
ν: 3417, 3019, 2978, 2929, 2857, 1727, 1601, 1452, 1384,
1375, 1347, 1316, 1276, 1216, 1160, 1092, 1070, 1027, 758,
713, 668.
BzO
O
O
CH3
H
MS
MS
T
T
C
3
Ts
N
O
C
43H49NO9SSi2
812.09 g/mol
xylene were removed at high vacuum and the residue was
purified by column chromatography (hexanes – ethyl ace-
tate, 9:1). The cyclotrimerized product 48 was isolated as a
colourless oil in 5% yield (7 mg, 0.01 mmol). [α]22 –20.9
D
(c 0.25, CH2Cl2). Rf 0.32 (hexanes – ethyl acetate, 4:1). IR
(CH2Cl2, cm–1) ν: 3061, 2987, 2957, 2928, 2856, 1728,
1704, 1601, 1584, 1494, 1452, 1405, 1366, 1316, 1266,
1219, 1189, 1175, 1094, 1027, 1003, 963, 841, 816, 739,
712, 672, 660, 638, 602, 572, 545, 512. 1H NMR (300 MHz,
CDCl3, ppm) δ: 8.44 (s, 1H), 8.30 (d, J = 8.4 Hz, 2H), 8.13
(s, 1H), 8.07 (m, 2H), 7.99 (m, 2H), 7.64 (m, 1H), 7.52 (m,
3H), 7.39 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 6.44 (s, 1H),
5.85 (dd, J1 = 7.2 Hz, J2 = 10.8 Hz, 1H), 5.25 (dd, J1 =
2.4 Hz, J2 = 7.2 Hz, 1H), 4.98 (t, J = 7.2 Hz, 1H), 3.90 (t, J =
11.1 Hz, 1H), 3.76 (d, J = 12.0 Hz, 1H), 2.45 (s, 3H), 1.49
(s, 3H), 1.32 (s, 3H), 0.44 (s, 9H), 0.39 (s, 9H). 13C NMR
(75 MHz, CDCl3, ppm) δ: 166.4, 165.5, 165.5, 155.6, 146.7,
144.2, 138.4, 137.9, 136.7, 133.8, 133.4, 131.1, 129.9, 129.8,
129.3, 129.2, 129.0, 128.8, 128.8, 128.4, 126.8, 110.4, 75.4,
73.5, 72.0, 70.5, 66.1, 46.1, 27.6, 25.5, 21.7, 1.7, 1.6. MS
(EI) m/z (relative intensity): 796 (M+ – CH3, 1), 525 (6), 477
(5), 179 (5), 149 (7), 129 (8), 106 (9), 105 (100), 98 (7), 97
(13), 96 (6), 95 (8), 91 (13), 85 (10), 84 (9), 83 (17), 82 (8),
81 (13), 77 (16), 73 (25), 71 (17), 70 (10), 69 (30), 68 (6),
67 (8). HRMS (EI) calcd. for C43H49O9NSSi2-CH3:
796.2432; found: 796.2399. Anal. calcd. for C43H49O9NSSi2:
C 63.60, H 6.08; found: C 63.46, H 6.00.
To the diastereomeric diols (17 mg, 0.02 mmol) dissolved
in DMSO (1 mL) was added o-iodoxybenzoic acid (IBX,
(75 mg, 0.28 mmol). The reaction mixture was stirred for 1
day, diluted with diethyl ether, and washed four times with
water. The ether phase was dried over MgSO4, filtered, and
evaporated to dryness. The pure product 51 was obtained by
column chromatography (ethyl ether – pentane, 2:1) as a
white crystalline single diastereomer in 71% yield (12 mg,
0.02 mmol); mp 119 °C. [α]23 +38.6 (c 0.06, CH2Cl2). Rf
0.48 (hexanes – ethyl acetateD, 1:1). IR (CDCl3, cm–1) ν:
3020, 2926, 2855, 1759, 1727, 1602, 1510, 1452, 1316,
1273, 1216, 1162, 1092, 1068, 1027, 933, 814, 758, 710,
1
667, 548. H NMR (600 MHz, CDCl3, ppm) δ: 7.89 (2m,
4H), 7.62 (d, J = 8.3 Hz, 2H), 7.58 (m, 1H), 7.52 (m, 1H),
7.52 (s, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 (t, J = 7.9 Hz,
2H), 7.15 (d, J = 8.1 Hz, 2H), 7.08 (s, 1H), 6.12 (dd, J1 =
4.8 Hz, J2 = 8.6 Hz, 1H), 5.74 (dd, J1 = 4.7 Hz, J2 = 7.9 Hz,
1H), 5.03 (dd, J1 = 6.8 Hz, J2 = 8.8 Hz, 1H), 4.73 (t, J =
7.4 Hz, 1H), 4.62 (d, J = 16.8 Hz, 1H), 4.53 (d, J = 16.7 Hz,
1H), 4.00 (dd, J1 = 8.9 Hz, J2 = 12.6 Hz, 1H), 3.43 (dd, J1 =
8.9 Hz, J2 = 12.6 Hz, 1H), 2.41 (s, 3 H), 2.35 (s, 3H), 2.20
(s, 3H), 1.54 (s, 3H), 1.36 (s, 3H). 13C NMR (150 MHz,
CDCl3, ppm) δ: 201.7, 200.0, 165.4, 165.3, 143.8, 139.3,
138.6, 137.7, 137.4, 136.4, 133.8, 133.5, 129.8, 129.8,
129.4, 128.6, 128.4, 127.5, 126.2, 125.1, 110.8, 96.1, 76.2,
74.1, 70.1, 69.8, 59.4, 48.5, 39.6, 30.3, 29.2, 27.8, 27.7,
25.4, 21.5. MS (EI) m/z (relative intensity): 737 (M+, 0.1),
133 (14), 105 (6), 89 (41), 87 (18), 73 (11), 59 (12), 45
(100). HRMS (EI) calcd. for C41H39O10NS: 737.2295;
found: 737.2306.
(3aS,3bR,9bR,10S,11S,11aS)-7,8-Diacetyl-2,2-dimethyl-4-
(4-methylphenylsulfonyl)-10,11-di(phenylcarbonyloxy)-
3a,3b,4,5,9b,10,11,11a-octahydro[1,3]dioxolo[4,5-
c]phenanthridine (51)
Acknowledgements
To a solution of 2,5-di(tert-butyldimethylsilyloxy)-3-
hexyne (1.00 g) in CpCo(CO)2 (5 µL), bisacetylene 41
(108 mg, 0.17 mmol) and CpCo(CO)2 (5 µL) dissolved in
xylene (5 mL) were added dropwise with a syringe pump at
140 °C over 30 h. During and after this slow addition, extra
The authors wish to thank Professor Peter Vollhardt (Uni-
versity of California, Berkeley) for helpful discussions and
advice related to cyclotrimerization. The following agencies
are gratefully appreciated for financial support of this work:
Natural Sciences and Engineering Research Council of Can-
© 2006 NRC Canada

1336
Can. J. Chem. Vol. 84, 2006
5. For total syntheses of lycoricidine, see: (a) S. Ohta and S.
Kimoto. Chem. Pharm. Bull. 24, 2977 (1976); (b) H. Paulsen
and M. Stubbe. Tetrahedron Lett. 23, 3171 (1982); (c) H.
Paulsen and M. Stubbe. Liebigs Ann. Chem. 535 (1983);
(d) N. Chida, M. Ohtsuka, and S. Ogawa. Tetrahedron Lett.
32, 4525 (1991); (e) T. Hudlicky and H.F. Olivo. J. Am.
Chem. Soc. 114, 9694 (1992); ( f ) N. Chida, M. Ohtsuka,
and S. Ogawa. J. Org. Chem. 58, 4441 (1993); (g) S.F. Martin
and H.H. Tso. Heterocycles, 35, 85 (1993); (h) T. Hudlicky,
H.F. Olivo, and B. McKibben. J. Am. Chem. Soc. 116, 5108
(1994); (i) for ent-lycoricidine, see: G.E. Keck and T.T.
Wager. J. Org. Chem. 61, 8366 (1996); ( j) G.E. Keck, T.T.
Wager, and J.F.D. Rodriquez. J. Am. Chem. Soc. 121, 5176
(1999); (k) S. Elango and T.H. Yan. Tetrahedron, 58, 7335
(2002); (l) A. McLachlan, N. Kekre, J. McNulty, and S.
Pandey. Apoptosis, 10, 619 (2005); (m) N. Kekre, C. Griffin,
J. McNulty, and S. Pandey. Cancer Chemother. Pharmacol.
56, 29 (2005).
ada (NSERC), Canada Foundation for Innovation (CFI), On-
tario Innovation Trust (OIT), Brock University, TDC Re-
search Foundation, Inc. (fellowship to Michael Moser), and
TDC Research, Inc. Professor George R. Pettit is pleased to
acknowledge the financial assistance from Grant No. R01
CA90441-01-05 awarded by the Division of Cancer Treat-
ment and Diagnosis, National Cancer Institute, DHHS, and
the Arizona Biomedical Research Commission.
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