Studies for the enantiocontrolled preparation of substituted tetrahydropyrans: Applications for the synthesis of leucascandrolide A macrolactone

Article abstract of DOI:10.1016/j.tet.2011.05.020

Strategies for the stereocontrolled preparations of 2,6-cis- and 2,6-trans-substituted tetrahydropyrans have been devised. These studies have explored methodology for asymmetric induction in S_E′ reactions using chiral 1,3,2-diazaborolidine controllers. Reactions with aldehydes at -78°C yield nonracemic 1,5-diols for chemoselective internal backside displacements. This concept is developed as a flexible and reliable strategy in studies toward leucascandrolide A macrolactone 2 via the sequential applications of S_E′ reactions leading to the C₁-C₉ aldehyde 14, and the bis-tetrahydropyran 59, respectively.

Full text of DOI:10.1016/j.tet.2011.05.020

Tetrahedron 67 (2011) 5083e5097
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Studies for the enantiocontrolled preparation of substituted tetrahydropyrans:
applications for the synthesis of leucascandrolide A macrolactone
*
David R. Williams , Scott V. Plummer, Samarjit Patnaik
Department of Chemistry, Indiana University, 800 E. Kirkwood Ave., Bloomington, IN 47405, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Strategies for the stereocontrolled preparations of 2,6-cis- and 2,6-trans-substituted tetrahydropyrans
0
Received 11 March 2011
Received in revised form 20 April 2011
Accepted 6 May 2011
have been devised. These studies have explored methodology for asymmetric induction in SE reactions
using chiral 1,3,2-diazaborolidine controllers. Reactions with aldehydes at ꢀ78 ꢁC yield nonracemic
1,5-diols for chemoselective internal backside displacements. This concept is developed as a flexible and
reliable strategy in studies toward leucascandrolide A macrolactone 2 via the sequential applications of
Available online 14 May 2011
0
SE reactions leading to the C1eC9 aldehyde 14, and the bis-tetrahydropyran 59, respectively.
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Nonracemic 1,5-diols
Tetrahydropyran synthesis
Asymmetric induction
0
SE reactions
Boron-auxiliary
1. Introduction
Calcareous sponges possess skeletons composed exclusively of
calcium carbonate spicules, and are relatively rare species com-
pared to marine sponges of other classes. The calcareous genera,
Leucetta and Clathrina have been systematically examined and have
been shown to yield metabolites that characteristically embody the
2-aminoimidazole motif.1 In 1996, Pietra and co-workers reported
the isolation of the first bioactive macrocyclic metabolites from
Leucascandra caveolata, a calcareous sponge found along the
northeastern coast of New Caledonia.2,3 Two novel macrolides,
leucascandrolide A (1) and B were identified. The structure of 1 was
elucidated by extensive spectroscopic studies and Mosher ester
analysis, which revealed a pattern of 1,3-oxygenations in an 18-
membered macrolactone. Two trisubstituted tetrahydropyran
rings were incorporated within the features of the macrocycle via
bridging ethers at C3/C7 and C11/C15. An unusual ester side chain
containing two Z-alkenes, a central 2,4-disubstituted-1,3-oxazole
and a terminal methyl carbamate was attached at the C5 hydroxyl
of the macrolide 2.
In addition, strong inhibition of Candida albicans, a pathogenic
yeast infecting immune-compromised individuals, was also ob-
served. Subsequently, it was found that the macrolactone 2 was
essential for cytotoxicity, whereas the oxazole-containing ester side
chain of 1 contributed significantly to the antifungal properties of
the natural product. Recent cell-based studies to investigate the
mechanism of action have unambiguously established cytochrome
bc1 complex as the principal cellular target of leucascandrolide A.4
Samples of sponge harvested from other locations failed to yield
traces of either leucascandrolide A or B, which has led to sugges-
tions that these metabolites may originate from sources of oppor-
tunistic microbial colonization of extensively dead portions of the
sampled sponge. As a result, numerous efforts have recorded suc-
cessful pathways toward the synthesis of the racemic and optically
active natural product and its macrolactone 2.5 In this
report, we provide a full account of our previous study for an
The biological profile of leucascandrolide A displayed potent
cytotoxicity based on in vitro assays with KB tumor and P338
murine leukemia cell lines (IC50 0.05 and 0.25 mg/mL, respectively).
* Corresponding author. Tel.: þ1 812 855 6629; fax: þ1 812 855 8300; e-mail
address: williamd@indiana.edu (D.R. Williams).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.020

5084
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
enantiocontrolled synthesis of leucascandrolide A macrolactone 2
as a thematic investigation of synthetic methodology for the con-
struction of tetrahydropyran-containing natural metabolites.6a,b
Tetrahydropyrans (THP) are common structural features among
marine natural products of polyketide origin. The presence of two
distinct tetrahydropyranyl rings in 2 attracted our interest in de-
veloping a general strategy, which could offer sufficient flexibility
to meet the requirements for stereoselective formation of the 2,6-
cis-substituted THP (spanning the C3eC7 region of 2) as well as the
2,6-trans-substitution of the second THP system (C11eC15 region).
This objective would appear to be aligned with the obvious ad-
vantages for a convergent synthesis. However, our implementation
of a thematic approach must also meet the crucial demands of
enantioselectivity in the formation of two independent, but teth-
ered, THP ring systems.
Unfortunately, the alternative cyclization from 9 yields substantial
amounts of diene 10 upon mesylation or tosylation of this activated
homoallylic alcohol. Further attempts for desilylation (TBAF) of the
sulfonates of 9 resulted only in elimination. Overall, these results
outlined some key parameters and potential pitfalls for stereo-
controlled dehydrations of 1,5-diol derivatives.
2. The retrosynthetic plan
Basedontheseexperiences, wedeviseda retrosyntheticapproach
to leucascandrolide A macrolactone 2 as illustrated in Scheme 1. The
18-membered lactone 2 evolves from the bis-tetrahydropyranyl
precursor 11 by nucleophilic addition of the E-alkenyl side chain to
the C17 aldehyde 11. Subsequent oxidations at C1 and C5 include
a stereocontrolled hydride reduction to establish the C5 b-hydroxy
These considerations led us to evaluate our previous efforts for
the intramolecular dehydration of 1,5-diols affording the ring clo-
sure of THP systems via CeO nucleophilic backside displacement.
Clearly, some level of chemoselectivity can be anticipated for such
reactions as the ring closure of the triol resulting from mild hy-
drolysis of 3 occurs by the addition of sodium methoxide at 22 ꢁC to
give the expected THP 4 (80%).7
substituent. Each THP ring system is sequentially formed by intra-
molecular displacements from chiral 1,5-diol intermediates 12 and
15. This idea focused our attention on the formation of the C9eC10
bond of 12 and the stereoselective introduction of C9 chirality as the
key convergent step of the plan. To0address this issue, we envisioned
the use of the aldehyde 14 in an SE reaction which would unite two
nonracemic components in the formation of the homoallylic alcohol
13. In similar fashion, asymmetric induction in the SE0 process would
offer a convenient preparation of the starting, nonracemic 1,5-diol
derivative 15.
OBn
OH
O
HO
1) cat. TsOH
MeOH
OR
O
OTs
O
BnO
2) then add
NaOMe
4
(R = H)
3
OH
(80%)
5
5
HO
OH
3
TsCl (1.2 eq)
7
Ph3CO
2
CH2Cl2, Et3N (5:1 v/v)
O
O
HO
OH
H
H
H
H
9
H
4
9
1
+
BnO
OR
H
(R = CPh3)
cat. DMAP
°C, 16 h
O
HO
H3CO
H3C
H3CO
H3C
O
H
O
H
O
11
H
O
6
O
5
H
(84%)
Ph3CO
12
18
[ratio 4:6; 3:2]
15
15
17
17
H
H
11
2
The robust reaction also proceeds uniformly for diastereomers
of 3 yielding, in each case, the anticipated THP isomer. Competing
formation of four-membered and seven-membered cyclic ethers is
not observed. However, the treatment of the analogous triol (5)
with tosyl chloride (1.1 equiv) and triethylamine in CH2Cl2 con-
taining small amounts of 4-dimethylaminopyridine (DMAP) over
16 h provided substantial amounts of the tetrahydrofuranyl
byproduct 6 in addition to the THP 4 (R¼CPh3). This evidence in-
dicates that strongly nucleophilic conditions favor the execution of
the desired internal backside displacement. On the other hand, we
have also examined the generality of alkoxide-mediated displace-
ments for the formation of 2,6-cis- and trans-substituted THP
ethers in the course of our studies of phorboxazole A.8
O
H
O
H
H
H
H
H
H
9
9
OR
OR
OR
OR
H3CO
H3C
HO
H3C
10
OH
11
H
H
OTs
OR
12
13
OTs
OR
O
OH
H
H
H
H
1) MsCl
Et3N; CH2Cl2
O
N
OR
O
RO
15
OPiv
O
OPiv
PMBO
H
H
O
2) cat. TsOH
MeOH
14
N
THPO
OH
3) NaH
(72%)
Scheme 1. Retrosynthetic analysis for macrolide 2 (R¼protecting unit).
PMBO
8
7
(Piv = pivalate)
1) TsCl
Et3N; CH2Cl2
O
N
O
3. Results and discussion
OPiv
OPiv
N
PMBO
PMBO
2) TBAF
THF
Our proposed study relies upon an effective SE0 methodology for
asymmetric induction in key CeC bond constructions, and we
chose to examine the Corey ‘Stein’ protocol9 for boron-mediated
allylations based upon our prior studies to extend the scope of
this reaction.10 These efforts have notably led to total syntheses of
hennoxazole A,11 amphidinolide K,12 and phorboxazole A.13 To ap-
ply this approach toward the synthesis of C1eC9 aldehyde 14, we
first prepared the allylic stannane 16 (Scheme 2), commencing with
OH
OTBS
OH
10
9
(Piv = pivalate)
In this study, 1,5-diol derivative 7 is treated with meth-
anesulfonyl chloride followed by deprotection with mild acid (cat.
TsOH, MeOH), and subsequent addition of NaH provides the facile
alkoxide-induced displacement to afford only the cis-THP 8.

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5085
the alkylation of 2-lithio-1,3-dithiane with (R)-epichlorohydrin.14
Ph
Ts
Ph
Ph
Ts
N
Bu3Sn
Effectively, this reaction proceeds with net inversion via initial
opening of the oxirane and subsequent internal displacement of
chloride to give 19 (86%). Copper-catalyzed addition of the Grignard
reagent prepared from 2-bromo-3-trimethylsilylpropene15 to ep-
oxide 19 was followed by protection of the resulting alcohol as the
tert-butyldimethylsilyl (TBS) ether 20b. Chemoselective conversion
of the allylic silane 20 to its corresponding bromide in the presence
of the dithiane moiety was accomplished using freshly recrystal-
lized N-bromosuccinimide (NBS) at ꢀ78 ꢁC by incorporating an-
hydrous DMF as a solvent, and this material was directly utilized for
reaction with tributylstan0nylcuprate to yield 16 in 77% overall
yield.16 Our asymmetric SE reaction is effected following the mild
and quantitative transmetallation of 16 with (4S,5S)-2-bromo-1,3-
bis[(4-methylphenyl)sulfonyl]-4,5-diphenyl-1,3,2-diazaborolidine
(21)17 in CH2Cl2 at 22 ꢁC. Whereas the analogous transposition from
allylic silane 20 does not proceed, the in situ generation of allyl-
borane 22 is followed by condensation with aldehyde 23 at ꢀ78 ꢁC.
The activated complexation in 24 leads to a favored Zimmer-
maneTraxler transition state, which affords high diastereofacial
selectivity in the production of the (S)-homoallylic alcohol 25 [dr
11:1]. Furthermore, our studies using the enantiomer of 16 showed
that the observed asymmetric induction was solely attributed
to the C2-symmetric auxiliary and was not affected by the chirality
of the homoallylic TBS silyl ether.
N
B
B
Br
Ph
N
N
Ts
21
Ts
CH2Cl2, rt, 10 h; then
O
OTBS
S
H
OTBS
S
H
OPMB
S
H
16
23
S
–78 °C, 1.5 h, 100%, 11:1 dr
22 (Ts = SO2C4H4CH3)
Tol
Ph
O
O
S
OH
N
B
R
Ph
H
H
N
δ–
OTBS
OPMB
O
S
O
δ+
PMBO
O
S
H
Tol
S
H
25
S
H2C
S
24 R =
TBSO
H
OTs
3
1) TsCl, Et3N
DMAP, CH2Cl2,
72 h, 100%
1) NaH, PhH
90 °C, 40 h
73%
7
O
OH
OR
H
O
H
2) HF•pyr., CH3CN
16 h, 87%
2) MeI (excess)
CaCO3
10% aq. CH3CN
96%
H
OR
S
H
S
14 (R = PMB)
26 (R = PMB)
Scheme 3. Synthesis of 2,6-cis-THP 14.
For this transformation, we chose to examine asymmetric in-
duction in the SE0 reaction of the stannane 27 with the incorporation
of the nonracemic (R,R)-1,3,2-diazaborolidine auxiliary ent-21. Sev-
eral attempts explored pathways for the preparation of this stannane
precursor. For example, protection of commerciallyavailable methyl-
(S)-(þ)-3-hydroxy-2-methylpropionate (28) as its benzyl ether was
followed by the cerium chloride-mediated addition of (trimethylsi-
lylmethyl)-magnesium chloride to directly yield allylic silane 29
(Scheme 4).18 Dissolving metal reduction with calcium in liquid
ammoniaeTHF led to the preparation of iodide 30 as well as its cor-
responding bromide, which were to be utilized in a copper-catalyzed
Grignardreactionwiththenonracemicepoxide34(showninScheme
5). Unfortunately, iodide 30, aswellastheanalogous bromide, proved
unstable and rapidly decomposed on standing at room temperature.
An alternative route (Scheme 5) was devised from propionate 28 by
adapting the reports of White and co-workers to provide 2(S)-2,3-
dimethyl-3-buten-1-ol.19 In this manner, formation of the tosylate
32 and exchangewith LiBr in DMFafforded gram quantities of 2(S)-1-
bromo-2,3-dimethyl-3-butene (33), which led to a well-behaved
Grignard reagent for copper(I)-catalyzed addition to optically pure
34.20 Protectionof thesecondaryhydroxylof35, oxidativecleavageof
the terminal alkene, and kinetic deprotonation of methyl ketone 36
led to excellent yields of the enol triflate 37 by quenching the in-
termediate potassium enolate with Comins reagent.21 In 1999
Busacca and co-workers reported the nickel(O)-catalyzed cross-
coupling of cyclic and acyclic enol triflates with simple Grignard re-
agents,22 and the application of this approach led to reactions with
commercially available (trimethylsilylmethyl)magnesium chloride
in the presence of Ni(acac)2 yielding the allylic silane 38. Final con-
version of 38 to the corresponding stannane 27 proceeded smoothly
as described previously in the case of silane 20 via the formation of
the bromide, which was used without purification to afford the
TMS
O
1)
BrMg
nBuLi, THF, –78 °C
H
H
S
S
CuI, THF, –50 to –10 °C
75%
2) TBSCl, imid., DMF
O
S
H
then
Cl
S
R
–78 °C to rt, 86%
19
17 (R = H)
18 (R = Li)
97%
TMS
Bu3Sn
1) NBS, 3:2 DMF/CH2Cl2
O
, –78 °C, 5 h
OR
OTBS
2) Bu3SnLi, CuBr•DMS
THF, –78 to –40 °C
77% for two steps
S
H
S
H
S
S
20a (R = H)
20b (R = TBS)
16
Scheme 2. Formation of allylic stannane 16.
The quantitative formation of 25, contaminated with small
amounts of its diastereomer (dr 11:1), directly led to tosylation
and mild cleavage of the TBS silyl ether under buffered conditions
to minimize elimination side reactions. Subsequent treatment of
26 with sodium hydride in benzene produced an effective cycli-
zation to the tetrahydropyran via internal displacement with in-
version. Chromatographic purification was followed by mild
hydrolysis of the dithiane acetal to yield the desired 2,6-cis-THP 14
(Scheme 3).
The convergent operation of our retrosynthetic plan was
designed to link aldehyde 14 with the C10eC17 component 27,
providing a stereoselective formation of the C9 homoallylic alcohol
13 (of Scheme 1).
NH
1)
BnO
CCl
3
1) Ca°, NH3
THF
92%
cat. TfOH, CH2Cl2
95%
O
H C
3
TMS
H C
3
TMS
H C
3
OCH
3
2) PPh3
imid., I2
67%
2) CeCl3 (5.0 eq)
BnO
I
HO
MgCl (5.0 eq)
TMSCH2
28
30
29
THF, –78 °C to rt;
then SiO2, CH2Cl2, 75%
Scheme 4. Preparation of optically active silane 30.

5086
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
C
10eC17 component 27 (R¼SnBu3). Although we had also devised
clarity. While our reaction attempts using the lithium enolate
(LiHMDS, THF, ꢀ78 ꢁC, then 14) or the boron enolate (c-hex2BCl;
Et3N; 0 ꢁC; then ꢀ78 ꢁC, then 14) were marred by poor stereo-
selection, the Mukaiyama aldol reaction of the corresponding tri-
methylsilyl enol ether 39 with aldehyde 14 proved to be highly
diastereoselective (dr 91:9) in favor of the unwanted C9 stereo-
chemistry of 40. This reaction is anticipated to occur via an open
transition state, and the results can be rationalized on the basis of
the Evans polar model, which has been advanced to predict the
preferential formation of 1,3-anti-products in condensations of silyl
a related route to 27 with notably fewer steps, Scheme 5 was pre-
ferred for multigram-scale reactions with minimal requirements for
chromatographic separations.
O
O
1) BrPh3PCH3,nBuLi
THF, 0 °C to rt, 84%
1) TBDPSCl, imid., DMF
100%
MeO
OH
H3C
OTBDPS
2) TBAF, THF, 1.5 h
3) TsCl, DMAP, pyr.
61% for 2 steps
4) LiBr, DMF
2) (MeO)NHMe•HCl
CH3
28
CH3
iPrMgCl, THF, –10 °C
31
3) MeLi, Et2O, 0 °C
2 h, 91% for 2 steps
enol ethers with b
-alkoxyaldehydes.24
40 °C, 6 h
61% for 2 steps
X
Mg°, THF, reflux
then
1) TBSCl, imid., DMF
96%
H3C
X
OTBS
2) O3, CH2Cl2-MeOH
(1:1); then DMS
–78 °C to rt, 98%
CH3
O
34
H
32 (X = OTs)
33 (X = Br)
OTBS
RO
CuBr•DMS, THF
H
3) KHMDS, THF, –78 °C
–78 °C to rt, 80%
35 (R = H; X = CH2)
36 (R = TBS; X = O)
then
Cl
N
NTf2
THF, –78 °C, 87%
1)
TMS
Ni(acac)2, Et2O
rt, 15 h, 75%
MgCl
H3C
H3C
R
OTf
2) NBS, 3:2 DMF/CH2Cl2
A model study was designed to advance our understanding of
the SE0 reactions derived by incorporation of the chiral auxiliary of
nonracemic 1,3,2-diazaborolidines as summarized in Table 1.25 In
each case, transmetallations of the starting stannane (CH2Cl2;
22 ꢁC) with (S,S)-bromoborane 21 or its corresponding (R,R)-iso-
mer ent-21 were followed by reactions with nonracemic stan-
nanes 41 and ent-41 at ꢀ78 ꢁC. Diastereomeric alcohols were
analyzed by NMR spectroscopy and chiral HPLC, and major
products were purified and characterized by NMR analysis of their
corresponding Mosher esters.26 While a clear trend shows that the
inclusion of the boron controller dictates the stereochemistry of
the major adduct, it is also evident that mismatched stereo-
genicity at the allylic carbon of the starting stannane can be det-
rimental. Since the initial transmetallations of 41 with 21 and with
ent-21 lead to the formation of diastereomeric allylborane re-
agents, we concluded that substitutions at the allylic site lead to
non-reinforcing, destabilizing interactions in the preferred, closed
O
OTBS
OTBS
TBSO
TBSO
, –78 °C, 5 h
H
H
37
38 (R = TMS)
27 (R = SnBu3)
3) Bu3SnLi, CuBr•DMS
THF, –78 to –40 °C
89% for two steps
Scheme 5. Preparation of nonracemic allylic stannane 27.
Since stereocontrolled introduction of asymmetry at C9 was
a critical aspect of our retrosynthetic hypothesis, we conducted
a number of preliminary experiments to evaluate the role of allylic
chirality in the starting stannane 27 as well as the features of
-asymmetry of the aldehyde component 14. Indeed, SE reactions
of 27 with aldehyde 14 are catalyzed with BF3 etherate in CH2Cl2 at
ꢀ78 ꢁC, and result in the desired adduct, albeit as a mixture of C9
diastereomers. Subsequent studies showed that the major isomer
was of the undesired (9S)-configuration.23 An examination of the
aldol union between methyl ketone 36 and 14 provided additional
0
b
Table 1
0
SE reactions of aldehyde 14 using nonracemic 1,3,2-diazaborolidines
Entry
Stannanea
Boron-auxiliary
Major productb
Yield [dr]c,d
X
Y
SnBu3
100%
42a/42b [dr 91:9]
1
ent-21 (R,R)
O
Ph2ttBuSiO
CH3
H
H
Ph2ttBuSiO
CH3
41
OPMB
2
3
41
21 (S,S)
42b X¼H; Y¼OH
98%
42a/42b [dr 33:67]
SnBu3
97%
X
Y
ent-21 (R,R)
43a/43b [dr 69:31]
Ph2ttBuSiO
CH3
ent-41
O
H
H
Ph2ttBuSiO
CH3
OPMB
4
ent-41
21 (S,S)
43b X¼H; Y¼OH
93%
43a/43b [dr 12:88]
a
The tineboron exchange was conducted at 22 ꢁC in CH2Cl2 and condensations with 14 were carried out at ꢀ78 ꢁC in CH2Cl2.
Major products were isolated by careful chromatography or HPLC and fully characterized using the Mosher ester analysis.26
Yields are based on isolation of the diastereomeric mixture following a short path flash silica gel chromatography.
Ratios were calculated from 1H NMR (400 MHz) data in C6D6 via integration of alkenyl hydrogen signals.
b
c
d

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5087
O
O
O
O
transition state arrangement, whereas the alternative allylic di-
astereomer could be incorporated as a harmless, or perhaps
0
reinforcing, influence. In addition, the SE reactions of stannane 41
O
O
H
H
H
H
PPTs, CH2Cl2
AcOH/THF/H2O (3:1:1)
78%, 5:1 dr
using 21 (S,S) and ent-21 (R,R) with achiral aldehydes gave similar
trends to those in Table 1, suggesting that stereogenicity at the
H3CO
H3C
OPMB
H3CO
H3C
OPMB
78%, 3:1 dr
12
12
b
-carbon of aldehyde 14 was not vital in determining the stereo-
47
48
17
17
selectivity of these reactions.
OTBS
OH
TBSO
HO
H
H
The application of these results to our leucascandrolide studies
utilized (R,R)-bromoborane ent-21 for exchange with stannane 27
(from Scheme 5) in CH2Cl2 (10 h, 22 ꢁC) as shown in Scheme 6.
Addition of 14 at ꢀ78 ꢁC provided a facile condensation yielding the
desired (R)-alcohol 45 as the major adduct (dr 8.5:1). The ar-
rangement depicted in 44 displays the favorable features of the
OH
5
OH
O
O
O
H
DIBAL-H
H
O
H
H
H
H
H
OPMB
CH2Cl2, 0 °C
H3CO
H3C
OPMB
H3CO
H
H
O
OPMB
H3CO
H
AliBu2
O
0
boron-mediated SE closed transition state and indicates the rein-
15
O
OH
O
17
O
49 [dr 3:1]
forcing properties of the allylic stereochemistry, which projects the
small hydrogen substituent HA into the region of the sulfonyl ox-
ygen. The sterically demanding chain (R1) is disposed away from
the developing transition state while minimizing the outcome for
A(1,3) interactions by placing methyl into the plane of the vinyl
hydrogen (HB). Flash chromatographic separation of the di-
astereomers afforded the pure C9 homoallylic alcohol in 88% yield,
and O-methylation using Meerwein’s salt was followed by oxida-
tive cleavage of the terminal alkenes to provide the diketone 47. The
presence of pH 7 phosphate buffer in the NaIO4 cleavage was es-
sential to avoid epimerization of the C12 stereochemistry.
H
H
H
50
Scheme 7. Formation of cyclic ketal 49.
The loss of stereochemical integrity led us to abandon the acetal
approach and seek opportunities for direct reductions of diketone
47. Surprisingly, the exposure of 47 to L-Selectride at ꢀ78 ꢁC
resulted in chemoselective reduction of only the C5 carbonyl
(Scheme 8). Equatorial hydride delivery provided the axial alcohol,
which was then protected as its tert-butyldiphenylsilyl ether 51.
However, the stereocontrolled reduction of the acyclic ketone 51
presented a challenge since preliminary reactions with common
hydride reagents gave nearly 1:1 mixtures of diastereomeric alco-
hols. For this reason, we chose to explore reagent-based control
using chiral hydrides. In fact, timely results in our laboratories had
registered the noteworthy reductions of 52 and 53 to their re-
spective alcohols 54 and 55 using nonracemic amino alcohols in
combination with LiAlH4.11,28
Ts
(R)
(R)
Ph
Ph
O
N
H
O
B
Br
R
1
12
Tol
S
H C
SnBu
17
N
3
3
O
ent-21
N
Ts
H
B
Ph
13
B
H
CH2Cl2, –78 °C
N
CH
3
OTBS
S
TBSO
O
H
Ph
H
A
O
R
2
Tol
27
14
O
44
R1 = the aldehyde component
R2 = the C13—C17 segment of
H
O
H
H
OPMB
27
stannane
O
5
O
1) OsO4 (2.5 wt% in tBuOH)
NMO, acetone-H2O (2:1)
16h
O
H
H
H
H
H
H
9
1
RO
9
OPMB
H CO
OPMB
3
11
H C
3
H C
3
2) NaIO4, THF-pH 7 buffer
(1:1), 16 h, 80% for 2 steps
O
17
OTBS
OTBS
TBSO
TBSO
Me3OBF4; CH2Cl2
proton sponge
4 Å molecular sieves
45 (R = H) (95%, 8.5:1 dr)
47
46 (R = CH3) (96%)
0
Scheme 6. The convergent SE reaction of nonracemic stannane 27 and 14.
Formation of 55, in the course of our studies of hennoxazole A,
was a particularly interesting and unprecedented example because
the Terashima reagent29 was devised for the selective reduction of
alkynyl and alkenyl ketones. In the event, the reduction of acyclic
ketone 51 (Scheme 8) via the chiral aluminum hydride prepared
from (ꢀ)-N-methylephedrine (1.0 equiv) and N-ethylaniline
(2.0 equiv) resulted in the formation of the desired anti-Felkin
product 56 with >95% diastereoselectivity. Furthermore, the use of
the (þ)-N-methylephedrine ligand under identical conditions gave
the Felkin product 57 with equally impressive selectivity and yield.
Our strategy for construction of the 2,6-trans-THP was designed
to effect stereocontrol via an internal backside displacement. Thus,
the tosylation of 56 with p-toluenesulfonic anhydride proceeded
quantitatively, whereas p-toluenesulfonyl chloride led to in-
effective, slow conversions indicative of a sterically hindered al-
cohol (Scheme 9). Removal of the TBS ethers was readily
accomplished using commercial HFepyridine, which was buffered
by additional quantities of pyridine.30 The resulting diol was
For transformation of 47 into the 2,6-trans THP 50 of leu-
cascandrolide A, we sought to employ an internally directed re-
duction of the bicyclic acetal 49 (Scheme 7) to establish the
desired C11 stereochemistry via diisobutylaluminum hydride
according to the original reports of Kotsuki and Yamamoto.27 Ex-
posure of 47 to tetrabutylammonium fluoride (TBAF) in aqueous
THF led to rapid elimination of methanol and formation of the
C9eC10 conjugated enone. The addition of various buffers with
aqueous TBAF prevented the elimination, but failed to cleave the
C15 silyl ether. In these attempts, we observed evidence of epi-
merization of the C12 stereochemistry. Finally, we were able to
achieve desilylation of 47 using aqueous acetic acid in THF at
22 ꢁC, which resulted in diol 48 (78%) along with small quantities
of its C12 diastereomer. These keto alcohols were separated by
careful column chromatography, and diol 48 was dehydrated to
afford bicyclic acetal 49 using catalytic pyridinium tosylate (PPTs)
in CH2Cl2 (0.01 M). Unfortunately, proton NMR data showed that
49 was a 3:1 mixture of C12 epimers.

5088
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
O
5
OTBDPS
transmetallation with dimethylzinc as adapted from the reports by
Wipf and co-workers.31 We had anticipated characteristics of
-chelation control in the addition of the alkenylzinc species to
5
b
O
O
1) L-Selectride®, THF,
–78 °C, 1.5 h, 84%
2) TBDPSCl, imid.,
DMF, 40 h, 73%
H
H
H
H
H
a Lewis acid-coordinated aldehyde 60. However, this did not ma-
terialize, and a mixture of C17 diastereomers [dr 1:1] was imme-
diately oxidized to give the enone 61 (75%). Since the Terashima
reagent offered significant precedence for the asymmetric re-
duction of enone systems, we were surprised to observe conjugate
hydride reduction as the major reaction pathway in the application
to enone 61. On the other hand, the CoreyeBakshieShibata (CBS)
borohydride reduction32 gave an 89% yield of a 5:1 mixture of
separable C17 diastereomers, in favor of the desired R-alcohol 63.
The minor product was recycled via the oxidationeCBS reduction
sequence and acetylation to 64 was followed by oxidative depro-
tection of the primary OPMB ether. A two-step oxidation afforded
carboxylic acid 65 (56% overall yield), and methanolysis produced
a crude seco-acid, which was directly subjected to the Yonemitsu-
modified Yamaguchi protocol30 to give the macrolactone 66 (63%
for two steps). Fluoride deprotection at C5 then yielded the leu-
cascandrolide A macrolactone 2, which was identical in all respects
with physical and spectroscopic data provided by Leighton and co-
workers5a as utilized in their esterification to afford synthetic leu-
cascandrolide A (1).
OPMB
OPMB
MeO
H3C
MeO
H3C
11
11
O
O
47
51
OTBS
OTBS
TBSO
TBSO
H
(–)-N-Me-ephedrine (2.0 eq)
N-ethylaniline (4.0 eq)
LAH (2.0 eq), Et2O, –78 °C
OTBDPS
(+)-N-Me-ephedrine (2.0 eq)
N-ethylaniline (4.0 eq)
LAH (2.0 eq), Et2O, –78 °C
92%, >95:5 dr
95%, >95:5 dr
O
H
H
OTBDPS
OPMB
MeO
H3C
11
OH
O
H
H
57
OPMB
MeO
H3C
OTBS
11
TBSO
H
OH
56
OTBS
TBSO
H
Scheme 8. The stereocontrolled formation of nonracemic 1,5-diol derivatives.
OTBDPS
OTBDPS
4. Conclusions
O
H
O
H
In summary, a convergent, enantiocontrolled synthesis of leu-
cascandrolide A macrolactone 2 has been achieved and establishes
a route for the formal total synthesis of leucascandrolide A. A
general strategy has been developed for asymmetric induction in
1) Ts2O, pyr., CH2Cl2
100%
NaH, PhH, 60 °C
16 h, 73%
H
H
H
OPMB
OPMB
MeO
H C
3
MeO
H C
3
11
11
2) HF•pyr, pyr, THF
84%
OH
OTs
56
58
0
15
15
SE reactions with aldehydes using chiral 1,3,2-diazaborolidine
OTBS
OH
TBSO
HO
H
auxiliaries, which were incorporated by quantitative exchange
with allylstannanes. The role of pre-existing chirality at the allylic
site of the starting stannane led to reinforcing and non-reinforcing
OTBDPS
OTBDPS
5
1)
CH2Cl2, Cp2Zr(H)Cl
then Me2Zn, –78 °C
0
O
O
H H
9
steric interactions in closed transition states of the SE reaction.
H
H
H
1
OPMB
X
OPMB
Stereodefined 1,5-diol derivatives were prepared as precursors for
internal backside displacements to yield 2,6-cis- and 2,6-trans-
substituted THP ring systems. These efforts have uncovered un-
then aldehyde 60
MeO
H C
MeO
H C
3
11
O
–78 to 0 °C, 1 h
3
O
H
O
2) DMP, NaHCO3
CH2Cl2
(75% for 2 steps)
H
17
H
precedented stereoselectivity in the reductions of acyclic b-alkoxy
61
Dess—Martin
periodinane
NaHCO3, CH2Cl2
(95%)
59 X = H, OH
60 X = O
ketones using the chirally modified Terashima hydride reagent.
Finally, our studies have demonstrated an effective and reliable
strategy, which is generally applicable for the stereocontrolled
synthesis of substituted tetrahydropyranyl ring systems encoun-
tered in marine macrolide natural products.
OTBDPS
1) DDQ, CH2Cl2, pH 7 buffer
(100%)
2) DMP, NaHCO3
CH2Cl2
Ph
H
5
Ph
O
O
N
B
CH
H
H
H
62
9
1
3
OPMB
MeO
H C
3
3) NaClO2, NaH2PO4
2-methyl-2-butene
aq. tBuOH, 0 °C
OR
BH3•THF, THF, –10 °C
89%, 5:1 d.r.
O
H
17
5. Experimental
56% for 2 steps
Ac2O
63 R = H
5.1. General procedures
pry, DMAP
CH2Cl2
64 R = Ac
(97%)
Infrared (FT-IR) spectra were recorded on a Mattson Galaxy
4020-IR instrument or Nicolet Avatar 360 FT-IR spectrometer and
are reported in wavenumbers (cmꢀ1). Proton nuclear magnetic
resonance (1H NMR) spectra were recorded on Varian XL-300,
Varian VXR-400, or Varian Inova 500 instruments. 1H NMR chem-
1) K2CO3, MeOH, 16 h
OTBDPS
OR
Cl
O
2)
5
5
Cl
O
O
Cl
Cl
H
H
H
O
H
9
H
1
1
9
OH
O
H
MeO
H C
3
MeO
3
Et3N, DMAP, PhH
63% for 2 steps
O
11
O
OAc
H C
ical shifts are reported in parts per million on the d scale, using the
O
H
17
H
17
reference of the appropriate signal for residual solvent hydrogens.
Carbon magnetic resonance (13C NMR) spectra were recorded on
Varian VXR-400 or Varian Inova 500 instruments. 13C NMR shifts
are reported in parts per million using CDCl3 as an internal standard
(77.0 ppm). Optical rotations were measured on a PerkineElmer
241 polarimeter at 589 nm (sodium D line) using a 10 cm path
length and a 1 mL volume. Concentration (c) is reported as g/
100 mL and temperature is reported in ꢁC. Mass spectra were
obtained on a Kratos MS80 RFAQQ instrument.
21
H
TBAF
THF
(67%)
66 R = TBDPS
R = H
65
2
Scheme 9. Completion of the synthesis of 2.
directly utilized for ring closure with NaH in benzene at 60 ꢁC to
give 59 (73%), and subsequent oxidation yielded aldehyde 60 (95%).
Within reach of our final objective, we planned the nucleophilic
attachment of the C18eC22 alkenyl chain and macrolactonization. To
this end, hydrozirconation of 4-methyl-1-pentyne was followed by
Diethyl ether (Et2O) and tetrahydrofuran (THF) were freshly
distilled from sodium benzophenone ketyl. Methylene chloride

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5089
(CH2Cl2), dimethylformamide (DMF), pyridine (pyr), propylene
oxide, acetonitrile (CH3CN), triethylamine (Et3N), benzene, di-
methyl sulfide (DMS), acetic anhydride, iodomethane, and N-eth-
ylaniline were distilled from calcium hydride prior to use.
Bulk solvents, ethyl acetate (EtOAc), and hexanes (hex) for flash
chromatography were distilled prior to use. Column chromatog-
raphy was conducted using silica gel 60 (230e400 mesh) from E.M.
Science. Analytical thin-layer chromatography (TLC) was per-
formed on glass-backed silica gel plates precoated (0.25 mm thick)
with 60 (F254) from E.M. Scientific. Spots were visualized under UV
light and/or staining with ethanolic p-anisaldehyde or ceric am-
monium molybdate.
Chemicals were purchased from Aldrich Chemical Company and
Acros, and were used without further purification unless noted. All
alkyllithium reagents were periodically titrated, using menthol as
a standard and 2,2-bipyridine as an indicator. Anhydrous reactions
were performed in flame-dried glassware under an inert
atmosphere.
(12), 105 (16), 101 (10), 93 (16), 75 (32), 73 (100); HRMS m/e calcd
for C13H26OS2Si (Mþ) 290.1194, found 290.1207.
5.1.3. 2-[(S)-(tert-Butyldimethylsilanyloxy)-4-(trimethylsila-
nylmethyl)pent-4-enyl]-[1,3]dithiane (20b). To a solution of alcohol
20a (3.13 g, 10.8 mmol) in DMF (54.0 mL) was added imidazole
(1.47 g, 21.6 mmol) and tert-butyldimethylsilyl chloride (1.95 g,
12.9 mmol). The colorless solution was stirred for 18 h, and then
diluted with 30% Et2O/hexanes (100 mL). The solution was washed
with saturated aq NH4Cl (100 mL) and saturated aq NaCl (100 mL).
The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(150 g SiO2, 1% EtOAc/hexanes) to yield 4.22 g (97%) of allylsilane
20b as a thick colorless oil: [
a
]
D24þ17 (c 2.9, CHCl3); Rf¼0.70 in 20%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 4.62 (s, 1H), 4.57 (s,
1H), 4.13e4.07 (m, 2H), 2.92e2.74 (m, 4H), 2.22 (A of ABX,
JAB¼13.6 Hz, JAX¼4.9 Hz, 1H), 2.15e1.83 (m, 3H), 2.05 (B of ABX,
JAB¼13.7 Hz, JBX¼8.0 Hz, 1H), 1.73 (ddd, J¼13.6, 8.7, 4.4 Hz, 1H), 1.55
(A of AB, JAB¼13.4 Hz, 1H), 1.47 ( B of AB, JAB¼13.4 Hz, 1H), 0.90 (s,
9H), 0.11 (s, 3H), 0.08 (s, 3H), 0.02 (s, 9H); 13C NMR (101 MHz,
5.1.1. (R)-2-[1,3]Dithian-2-ylmethyloxirane (19). To a cold (ꢀ78 ꢁC)
solution of 1,3-dithiane (13.9 g, 116 mmol) in THF (150 mL) was
added n-BuLi (51.0 mL of a 2.5 M solution in THF, 127 mmol). The
yellow solution was stirred for 20 min at ꢀ78 ꢁC, and then
warmed to ꢀ20 ꢁC over 2.5 h. The reaction mixture was again
cooled to ꢀ78 ꢁC, and (R)-epichlorohydrin (12.7 mL, 162 mmol)
was added dropwise. The yellow solution was stirred for 1 h at
ꢀ78 ꢁC, and then warmed to ambient temperature overnight. After
quenching the reaction mixture with saturated aq NaHCO3, the
solution was diluted with Et2O (250 mL). The solution was washed
with saturated aq NaHCO3 (250 mL) and saturated aq NaCl
(250 mL). The organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. The crude residue was purified by flash chro-
matography (500 g SiO2, 5e10% EtOAc/hexanes) to yield 17.5 g
CDCl3) d 143.5, 110.4, 67.5, 46.8, 44.1, 42.4, 30.5, 29.9, 26.9, 26.1, 25.9,
18.0, ꢀ1.4, ꢀ4.3, ꢀ4.6; IR (neat) 3084, 2945, 2899, 2846, 1640, 1475,
1416, 1244, 1073, 842 cmꢀ1; MS (DCI/CH4) 404 (3), 347 (30), 275
(26), 219 (28), 191 (60), 165 (12), 147 (32), 121 (15), 93 (16), 75 (20),
73 (100); HRMS m/e calcd for C19H40OS2Si2 (Mþ) 404.2059, found
404.2073.
5.1.4. Tributyl-((S)-5-[1,3]dithian-2-yl-4-(tert-butyldimethylsilany-
loxy)-2-methylenepentyl)stannane (16). To a cold (ꢀ78 ꢁC) solution
of allylsilane 20b (5.00 g, 12.4 mmol) in 60% DMF/CH2Cl2 (62 mL)
was added propylene oxide (8.64 mL, 124 mmol) and N-bromo-
succinimide (6.62 g, 37.2 mmol). The cloudy reaction mixture was
stirred for 5 h at ꢀ78 ꢁC, and then cannulated into a vigorously
stirring 0 ꢁC mixture of Et2O (100 mL) and saturated aq NaHSO3
(100 mL). The layers were separated, and the organic layer was
washed with water (100 mL) and saturated aq NaCl (100 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The crude allyl bromide was used without further purifica-
tion for the next step: Rf¼0.50 in 5% EtOAc/hexanes.
(86%) of epoxide 19: [
a
]
24þ4.6 (c 1.5, CHCl3); Rf¼0.20 in 5% EtOAc/
D
hexanes; 1H NMR (400 MHz, CDCl3)
d
4.26 (t, J¼7.0 Hz, 1H),
3.18e3.14 (m, 1H), 2.97e2.81 (m, 5H), 2.55 (dd, J¼5.0, 2.7 Hz, 1H),
2.17e2.09 (m, 1H), 1.96 (t, J¼6.6 Hz, 2H), 1.94e1.83 (m, 1H); 13C
NMR (101 MHz, CDCl3)
d 49.6, 47.4, 44.7, 38.6, 30.4, 30.2, 25.6; IR
(neat) 3038, 2991, 2899, 2820, 1482, 1416, 1277, 1258, 1178, 974,
921, 836 cmꢀ1; MS (DCI, CH4) 176 (67), 146 (18), 120 (18), 117 (6),
85 (27), 74 (38), 73 (12), 71 (34); HRMS m/e calcd for C7H12OS2
(Mþ) 176.0330, found 176.0331.
To a cold (0 ꢁC) solution of tributyltin hydride (6.98 mL,
25.9 mmol) in THF (36 mL) was added LDA (25.9 mL of a freshly
prepared 1.0 M solution in THF, 25.9 mmol). The yellow solution
was stirred at 0 ꢁC for 30 min, and then transferred via cannula to
a cold (ꢀ78 ꢁC) suspension of copper(I) bromide dimethyl sulfide
(4.90 g, 23.5 mmol) in THF (72 mL). The brown reaction mixture
was stirred for 2 h at ꢀ78 ꢁC, and then the allyl bromide was
added as a solution in THF (18 mL). The purple solution was
warmed to ꢀ40 ꢁC over 45 min, and then quenched with satu-
rated aq NH4Cl. The biphasic mixture was diluted with Et2O
(150 mL), filtered through a plug of Celite, and then washed with
saturated aq NH4Cl (100 mL) and saturated aq NaCl (100 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(250 g of Et3N-deactivated SiO2, 100% hexanes) to provide 5.94 g
(77% yield for the two steps) of allylstannane 16 as a colorless oil:
5.1.2. (S)-1-[1,3]Dithian-2-yl-4-(trimethylsilanylmethyl)pent-4-en-
2-ol (20a). A solution of 2-bromoallylsilane (17.3 g, 89.3 mmol) in
THF (60 mL) was added dropwise to a stirred suspension of mag-
nesium turnings (6.49 g, 268 mmol) in THF (40 mL) at such a rate as
to maintain a gentle reflux during the course of the addition
(30 min). The light gray solution of the Grignard reagent was added
dropwise to a ꢀ50 ꢁC solution of epoxide 19 (10.5 g, 59.6 mmol) and
copper (I) iodide (1.70 g, 8.93 mmol) in THF (120 mL). The orange
solution was warmed to ꢀ10 ꢁC, and stirred for 2 h. The reaction
mixture was quenched with saturated aq NH4Cl and warmed to
room temperature. The solution was diluted with Et2O (250 mL),
and washed with saturated aq NH4Cl (250 mL) and saturated aq
NaCl (250 mL). The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (500 g SiO2, 10% EtOAc/hexanes) to yield 13.0 g
[
a
]
24 þ10 (c 1.2, CHCl3); Rf¼0.60 in 5% EtOAc/hexanes; 1H NMR
D
(400 MHz, CDCl3)
d 4.56 (s, 1H), 4.47, s(1H), 4.15e4.08 (m, 2H),
2.92e2.74 (m, 4H), 2.19 (dd, J¼13.3, 5.1 Hz, 1H), 2.15e2.07 (m, 1H),
2.03e1.84 (m, 3H)1.79 (A of AB, JAB¼11.4 Hz, 1H), 1.70 (B of AB,
JAB¼11.4 Hz, 1H), 1.73 (ddd, J¼13.8, 8.9, 4.7 Hz, 1H), 1.51e1.44 (m,
6H), 1.34e1.25 (m, 6H), 0.91e0.84 (m, 24), 0.12 (s, 3H), 0.09 (s,
(75%) of alcohol 20a as a pale yellow oil: [
a
]
24þ21 (c 1.9, CHCl3);
D
Rf¼0.24 in 20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 4.69 (d,
J¼4.0 Hz, 2H), 4.31 (dd, J¼8.6, 5.8 Hz, 1H), 4.08e4.01 (m, 1H),
2.97e2.81 (m, 4H), 2.16e1.83 (m, 6H), 1.56 ( A of AB, JAB¼13.7 Hz,
1H), 1.53 (B of AB, JAB¼13.7 Hz, 1H), 0.03 (s, 9H); 13C NMR (101 MHz,
9H); 13C NMR (101 MHz, CDCl3)
d 146.0, 107.9, 67.7, 46.8, 44.1,
42.4, 30.5, 29.8, 29.1, 27.4, 26.1, 25.9, 19.2, 18.0, 13.7, 9.4, ꢀ4.3,
CHCl3)
d 144.3, 111.0, 65.6, 46.8, 44.5, 42.7, 30.7, 30.3, 26.9, 26.2,
ꢀ4.6; IR (neat) 3066, 2918, 2854, 1625, 1473, 1424, 1360, 1247,
ꢀ1.1; IR (neat) 3440, 3077, 2945, 2892, 1633, 1422, 1251, 1152, 1060,
1084, 942, 839 cmꢀ1
; HRMS m/e calcd for C28H58OS2SiSn
855 cmꢀ1; MS (DCI/CH4) 290 (1), 162 (13), 161 (12), 141 (20), 134
620.2720, found 620.2716.

5090
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5.1.5. (S)-5-[(S)-2-(tert-Butyldimethylsilanyloxy)-3-[1,3]dithian-2-
ylpropyl]-1-(4-methoxybenzyloxy)hex-5-en-3-ol (25). A flame-dried
Schlenk flask was charged with (S,S)-1,2-bis-para-toluenesulfonyl-
1,2-diphenylethane (2.00 g, 3.85 mmol), diluted with CH2Cl2
(25 mL), and cooled to 0 ꢁC. Fresh BBr3 (3.85 mL of 1.0 M solution in
CH2Cl2, 3.85 mmol) was added dropwise and the reaction was
warmed to ambient temperature. The orange reaction mixture was
stirred for 1 h, and then the CH2Cl2 and HBr were removed under
reduced pressure (0.1 mmHg). The reaction was diluted again with
CH2Cl2 (25 mL) and, after 10 min, concentrated under high vacuum.
The resulting white solid was diluted with CH2Cl2 (23 mL) and
cooled to 0 ꢁC. A solution of stannane 16 (2.66 g, 4.28 mmol) in
CH2Cl2 (5 mL) was added and the yellow solution was stirred for
16 h at ambient temperature.
273 (4), 241 (2), 227 (14), 223 (2), 121 (100); HRMS m/e calcd for
C
30H43O6S3Si (MþꢀC4H9) 623.1991, found 623.1974.
5.1.7. Toluene-4-sulfonic acid (1S,5S)-6-[1,3]dithian-2-yl-5-hydroxy-
1-[2-(4-methoxybenzyloxy)ethyl]-3-methylene-hexyl ester (26). To
a solution of the tosylate from 25 (1.37 g, 2.01 mmol) in CH3CN was
added hydrogen fluorideepyridine (60e70%, 6.3 mL). After stirring
at room temperature for 16 h, the acidic reaction mixture was
neutralized with saturated aq NaHCO3. The solution was diluted
with Et2O (150 mL), and washed carefully with saturated aq
NaHCO3 (150 mL). The organic layer was dried (MgSO4), filtered,
and concentrated in vacuo. The crude residue was purified by flash
chromatography (60 g SiO2, 30e40% EtOAc/hexanes) to yield 0.99 g
(87%) of alcohol 26 as a colorless oil: [
a
]
D22þ12 (c 1.1, CHCl3); Rf¼0.30
The reaction mixture was cooled to ꢀ78 ꢁC, and a solution of
aldehyde 23 (0.55 g, 2.85 mmol) in CH2Cl2 (4 mL) was added
over 5 min. After 1.5 h the reaction was quenched with satu-
rated aq NaHCO3 and warmed to ambient temperature. The
solution was diluted with CH2Cl2 (100 mL) and washed with
saturated aq NaHCO3 (100 mL). The organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. The resulting
residue was suspended in Et2O and filtered through a fritted
glass funnel. The remaining white solid (recovered bis-
sulfonamide) can be recrystallized from CHCl3 and reused. The
clear ethereal solution was concentrated in vacuo. The crude
residue was purified by flash chromatography (75 g SiO2, 20%
EtOAc/hexanes) to yield 1.54 g (quant., 11:1 dr) of homoallylic
in 40% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.78 (d,
J¼8.2 Hz, 2H), 7.30 (d, J¼8.2 Hz, 2H), 7.21 (d, J¼8.6 Hz, 2H), 6.88 (d,
J¼8.6 Hz, 2H), 4.91 (s, 1H), 4.89 (s, 1H), 4.91e4.86 (m, 1H),
4.00e3.96 (m, 1H), 4.32e4.22 (m, 3H)3.81 (s, 3H), 3.45e3.29 (m,
2H), 2.95e2.80 (m, 4H), 2.43 (s, 3H), 2.38 (d, J¼6.3 Hz, 2H),
2.17e2.09 (m, 3H), 2.03 (dd, J¼14.2, 8.7 Hz, 1H), 1.95e1.80 (m, 5H);
13C NMR (101 MHz, CDCl3)
d 159.1, 144.6, 140.6, 134.2, 130.2, 129.7,
129.2, 127.9, 117.2, 113.8, 79.4, 72.6, 65.8, 65.4, 55.3, 44.1, 42.4, 41.4,
34.4, 30.3, 30.0, 21.6, 10.4; IR (neat) 3453, 3064, 2932, 1647, 1614,
1515, 1343, 1258, 1178, 1093, 921, 809 cmꢀ1; HRMS (FAB, NBA, Naþ)
m/e calcd for C28H39O6S3 (MþþH) 567.1909, found 567.1920.
5.1.8. (2S,6R)-2-[1,3]Dithian-2-ylmethyl-6-[2-(4-methoxybenzyloxy)
ethyl]-4-methylenetetrahydropyran. To a solution of tosylate 26
(0.99 g, 1.75 mmol) in benzene (58 mL) was added NaH (280 mg of
a 60% dispersion in mineral oil, 7.00 mmol). The reaction mixture
was heated to 90 ꢁC, and stirred for 40 h. The suspension was then
cooled to ambient temperature, and diluted with Et2O (100 mL) and
saturated aq NaCl (100 mL). The layers were separated, and the
resulting aqueous layer was extracted with Et2O (100 mL). The
combined organic layers were dried (MgSO4), filtered, and con-
centrated in vacuo. The crude residue was purified by flash chro-
matography (50 g SiO2, 10e30% Et2O/hexanes) to yield 504 mg
alcohol 25 as a colorless oil: [
a
]
22þ16 (c 1.2, CHCl3); Rf¼0.40 in
D
40% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.26e7.24 (m,
2H), 6.90e6.86 (m, 2H), 4.89 (s, 2H), 4.45 (s, 2H), 4.15e4.08 (m,
2H), 3.98e3.91 (m, 1H), 3.80 (s, 3H), 3.72e3.59 (m, 2H),
2.91e2.74 (m, 5H), 2.29 (dd, J¼13.8, 5.4 Hz, 1H), 2.21e2.15 (m,
2H), 2.14e2.07 (m, 2H), 1.93e1.71 (m, 5H), 0.89 (s, 9H), 0.11 (s,
3H), 0.07 (s, 3H); 13C NMR (101 MHz, CDCl3)
d 159.2, 142.8,
130.1, 129.3, 115.4, 113.8, 72.9, 68.9, 68.5, 67.3, 55.2, 44.4, 44.4,
44.0, 42.3, 36.2, 30.5, 29.9, 26.0, 25.9, 18.0, ꢀ4.3, ꢀ4.6; IR (neat)
3459, 3066, 2948, 2849, 1615, 1502, 1473, 1419, 1247, 1094, 1040,
942, 843 cmꢀ1; MS (DCI/CH4) 526 (0.4), 395 (20), 275 (38), 274
(31), 273 (100), 254 (8), 241 (9); HRMS m/e calcd for
C27H46O4S2Si (Mþ) 526.1607, found 526.2607.
(73%) of 2,6-cis-pyran as a light yellow oil: [
a
]
D22ꢀ15 (c 0.79, CHCl3);
Rf¼0.52 in 40% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.27 (d,
J¼8.6 Hz, 2H), 6.88 (d, J¼8.6 Hz, 2H), 4.72e4.71 (m, 2H), 4.46 (A of
AB, JAB¼11.4 Hz, 1H), 4.43 (B of AB, JAB¼11.4 Hz, 1H), 4.23 (dd, J¼9.9,
4.7 Hz, 1H), 3.80 (s, 3H), 3.61e3.54 (m, 3H), 3.47e3.41 (m, 1H),
2.92e2.72 (m, 4H), 2.19 (d, J¼13.6 Hz, 2H), 2.12e2.04 (m, 1H),
5.1.6. Toluene-4-sulfonic acid (1S,5S)-5-(tert-butyldimethylsilany-
loxy)-6-[1,3]dithian-2-yl-1-[2-(4-methoxybenzyloxy)-ethyl]-3-
methylenehexyl ester. To a solution of alcohol 25 (0.99 g, 1.89 mmol)
in CH2Cl2 (19 mL) at ambient temperature was added Et3N (1.32 mL,
9.45 mmol), 4-(dimethylamino)pyridine (0.25 g, 2.08 mmol), and
para-toluenesulfonyl chloride (0.90 g, 4.72 mmol). The brown re-
action mixture was stirred for 72 h, and then diluted with Et2O
(50 mL). The solution was washed with saturated aq NH4Cl (50 mL)
and saturated aq NaHCO3 (50 mL). The organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (50 g SiO2, 5e10% EtOAc/hexanes)
2.01e1.74 (m, 7H); 13C NMR (101 MHz, CDCl3)
d 159.1, 144.2, 130.7,
129.3, 113.8, 108.9, 75.3, 74.2, 72.8, 66.6, 55.3, 43.6, 41.8, 40.7, 40.7,
36.4, 30.3, 29.9, 26.0; IR (neat) 3064, 2939, 2892, 2853, 1647, 1614,
1515, 1416, 1251, 1086, 1027, 816 cmꢀ1; MS (DCI/CH4) 394 (2), 274
(15), 273 (67), 141 (70), 122 (22), 121 (100), 97 (28), 93 (24), 77 (10);
HRMS m/e calcd for C21H30O3S2 (Mþ) 394.1636, found 394.1625.
5 .1. 9 . { ( 2 S , 6 R ) - 6 - [ 2 - ( 4 - M e t h o x y b e n z yl o x y ) e t hyl ] - 4 -
methylenetetrahydropyran-2-yl}-acetaldehyde (14). To a solution of
the dithianyl THP derived from 26 (500 mg, 1.27 mmol) in 10%
aqueous CH3CN (127 mL) was added iodomethane (30.7 mL,
493 mmol) and calcium carbonate (2.29 g, 22.9 mmol). The sus-
pension was stirred overnight at ambient temperature, and then
diluted with Et2O (200 mL) and saturated aq NaCl (200 mL). The
layers were separated, and the resulting organic layer was dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (25 g SiO2, 15% EtOAc/hexanes) to
22
to yield 1.32 g (quant.) of the tosylate of 25 as a light yellow oil: [a D
]
þ15 (c 1.8, CHCl3); Rf¼0.39 in 20% EtOAc/hexanes; 1H NMR
(400 MHz, CDCl3)
d
7.76 (d, J¼8.1 Hz, 2H), 7.27 (d, J¼8.1 Hz, 2H), 7.19
(d, J¼8.6 Hz, 2H), 6.85 (d, J¼8.6 Hz, 2H), 4.90e4.83 (m, 1H), 4.80 (s,
1H), 4.78 (s, 1H), 4.28 (A of AB, JAB¼11.4 Hz, 1H), 4.24 (B of AB,
JAB¼11.4 Hz, 1H), 4.09e3.99 (m, 2H), 3.79 (s, 3H), 3.44e3.28 (m, 2H),
2.90e2.80 (m, 2H), 2.78 (dd, J¼7.6, 3.7 Hz, 2H), 2.40 (s, 3H), 2.39 (A of
ABX, JAB¼14.3, JAX¼5.7 Hz, 1H), 2.29 (B of ABX, JAB¼14.3 Hz,
JBX¼7.4 Hz, 1H), 2.14e1.74 (m, 7H), 1.71e1.64 (m, 1H), 0.86 (s, 9H),
yield 372 mg (96%) of aldehyde 14 as a clear, colorless oil: [
a
]
D22ꢀ15
0.09 (s, 3H), 0.03 (s, 3H); 13C NMR (101 MHz, CDCl3)
d
159.2, 144.4,
(c 1.0, CHCl3); Rf¼0.41 in 40% EtOAc/hexanes; 1H NMR (400 MHz,
140.6, 134.6, 130.5, 129.7, 129.1, 127.9, 127.8, 117.0, 113.8, 79.6, 72.5,
67.2, 65.5, 55.3, 44.2, 43.9, 42.4, 41.8, 34.3, 30.5, 30.0, 26.1, 25.9, 21.6,
18.0, ꢀ4.3, ꢀ4.6; IR (neat) 3071, 2938, 2859, 1615, 1517, 1438, 1360,
1261, 1193, 1183, 1094, 1020, 907, 824 cmꢀ1; MS (DCI/CH4) 623 (1),
CDCl3)
d
9.72 (t, J¼2.0 Hz, 1H); 7.26e7.24 (m, 2H), 6.89e6.87 (m,
2H), 4.75 (s, 2H), 4.43 (A of AB, JAB¼11.6 Hz, 1H), 4.40 (B of AB,
JAB¼11.6 Hz, 1H), 3.82e3.75 (m, 1H), 3.80 (s, 3H), 3.57e3.46 (m, 3H),
2.59 (d of A of ABX, JAB¼16.2 Hz, JAX¼8.4 Hz, J¼2.8 Hz, 1H), 2.48 (d

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5091
of B of ABX, JAB¼16.2 Hz, JBX¼4.5 Hz, J¼2.0 Hz, 1H), 2.27e2.19 (m,
2H), 2.02e1.96 (m, 2H), 1.80e1.74 (m, 2H); 13C NMR (101 MHz,
3072, 2954, 2930, 2857, 1643, 1467, 1258, 1082, 829 cmꢀ1; HRMS m/
e calcd for C16H34O2Si (Mþ) 286.2328, found 286.2338.
CDCl3) d 201.2, 159.1, 143.5, 130.6, 129.3, 113.7, 109.4, 77.2, 75.6, 73.5,
72.6, 66.0, 55.3, 49.6, 40.4, 36.3; IR (neat) 3070, 2932, 2860, 2721,
1719, 1660, 1607, 1515, 1363, 1244, 1093, 1033 cmꢀ1; MS (DCI/CH4)
304 (3), 193 (2), 176 (16), 138 (16), 137 (83), 122 (27), 121 (100) 118
(48); HRMS m/e calcd for C18H24O4 (Mþ) 304.1675, found 304.1678.
5.1.12. (3S,6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-2,3-dimethyl-
oct-1-ene. To a solution of alcohol 35 (1.59 g, 5.55 mmol) in DMF
(28 mL) were added imidazole (0.76 g, 11.1 mmol) and tert-butyl-
dimethylsilyl chloride (1.00 g, 6.66 mmol). The reaction mixture
was stirred for 16 h at ambient temperature. The solution was di-
luted with 30% Et2O/hexanes (50 mL) and saturated aq NH4Cl
(50 mL). The layers were separated, and the organic layer was
washed with saturated aq NaCl (50 mL). The organic solution was
dried (MgSO4), filtered, and concentrated in vacuo. The crude res-
idue was purified by flash chromatography (75 g SiO2, 2% EtOAc/
hexanes) to yield 2.13 g (96%) of the silyl ether of 35 (R¼TBS) as
5.1.10. (R)-4-Bromo-2,3-dimethylbut-1-ene (33). To a cold (0 ꢁC)
solution containing 2(S)-2,3-dimethyl-3-buten-1-ol (3.12 g,
28.3 mmol) in pyridine (140 mL) were added 4-(dimethylamino)
pyridine (0.35 g, 2.83 mmol) and para-toluenesulfonyl chloride
(10.8 g, 56.6 mmol). The mixture was then warmed to ambient
temperature and stirred for 16 h. The reaction mixture was diluted
with Et2O (250 mL) and 5% aq HCl (250 mL). The layers were sep-
arated, and the aqueous layer was extracted with Et2O (250 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified via filtration
through a plug of silica gel to provide the corresponding tosylate.
This material was taken on to the next step without further
purification.
a clear, colorless oil: [
a
]
D
22 þ10.3 (c 1.15, CHCl3); Rf¼0.75 in 20%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 4.68e4.67 (m, 2H),
3.80e3.76 (m, 1H), 3.70e3.60 (m, 2H), 2.12e2.05 (m, 1H), 1.66e1.61
(m, 2H), 1.64 (s, 3H), 1.40e1.32 (m, 4H), 0.99 (d, J¼6.7 Hz, 3H), 0.89
(s, 9H), 0.88 (s, 9H), 0.04 (s,12H); 13C NMR (101 MHz, CDCl3)
d 150.0,
109.4, 69.4, 60.1, 41.2, 40.0, 35.1, 30.2, 25.9, 25.9, 19.8, 18.9, 18.3, 18.1,
ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat) 3061, 2948, 2849, 1645, 1468, 1389, 1261,
1094, 839 cmꢀ1; MS (DCI/CH4) 401 (1), 343 (41), 219 (13), 189 (33),
149 (24),133 (13),109 (100), 95 (63), 81 (72), 75 (33), 73 (67); HRMS
m/e calcd for C22H49O2Si2 (MHþ) 401.3271, found 401.3254.
To a solution of the tosylate in DMF (140 mL) was added lithium
bromide (7.27 g, 83.7 mmol). The suspension was heated to 40 ꢁC,
and stirred for 16 h. The reaction mixture was cooled to ambient
temperature, and diluted with pentane (250 mL). The organic so-
lution was washed with saturated aq NaCl (3ꢂ250 mL), dried
(MgSO4), filtrated, and concentrated in vacuo at 0 ꢁC. The crude
residue was purified by flash chromatography (150 g SiO2, 100%
pentane) to yield 2.79 g (61% for two steps) of homoallyl bromide
5.1.13. (3S,6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-3-methyl-oc-
tan-2-one (36). The silyl ether of 35 was dissolved in 1:1 MeOH/
CH2Cl2 (54 mL), and the colorless solution was cooled to ꢀ78 ꢁC. A
stream of ozone was introduced until the color of the solution was
light blue. The reaction mixture was purged with Ar for 10 min at
ꢀ78 ꢁC, and then quenched by the addition of Me2S (4 mL). The
solution was warmed to ambient temperature and stirred for an
additional 16 h. At this time the mixture was concentrated in vacuo
and the crude residue purified by flash chromatography (75 g SiO2,
2e4% EtOAc/hexanes) to give 2.09 g (98%) of methyl ketone 36 as
33 as a clear, colorless oil: [
a
]
D22þ7.4 (c 1.9, CHCl3); Rf¼0.61 in 100%
pentane; 1H NMR (400 MHz, CDCl3)
d 4.85 (s, 1H), 4.79 (s, 1H), 3.44
(A of ABX, JAB¼9.9 Hz, JAX¼6.3 Hz, 1H), 3.34 (B of ABX, JAB¼9.9 Hz,
JBX¼7.3 Hz, 1H), 2.54 (sextet, J¼6.9 Hz, 1H), 1.73 (s, 3H), 1.17 (d,
J¼6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 146.6, 111.7, 43.1, 38.1,
19.7, 18.2; IR (neat) 3066, 2972, 2918, 1645, 1606, 1463, 1438, 1370,
1222, 1104 cmꢀ1; MS (DEI) 163 (38), 142 (28), 120 (21), 118 (22), 113
(44), 83 (43), 81 (100), 80 (22), 69 (41); HRMS m/e calcd for C6H12Br
(MHþ)163.1022, found 162.9949.
a clear, colorless oil: [
a]
D
22 þ15.7 (c 1.50, CHCl3); Rf¼0.57 in 20%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 3.82e3.77 (m, 1H),
3.64 (t, J¼6.6 Hz, 2H), 2.51e2.42 (m, 1H), 2.12 (s, 3H), 1.70e1.56 (m,
3H), 1.47e1.33 (m, 3H), 1.07 (d, J¼7.0 Hz, 3H), 0.88 (s, 9H), 0.88 (s,
9H), 0.04 (s, 3H), 0.03 (s, 3H), 0.03 (s, 6H); 13C NMR (101 MHz,
5.1.11. (3S,6S)-1-(tert-Butyldimethylsilanyloxy)-6,7-dimethyloct-7-
en-3-ol (35). Preparation of the Grignard reagent: to a 25 mL two-
neck round bottom flask fitted with a reflux condenser was added
Mg turnings (0.50 g, 20.4 mmol). The flask was flame-dried, and
then cooled to ambient temperature. The turnings were combined
with THF (4 mL), and then a solution of homoallyl bromide 33
(0.50 g, 3.07 mmol) in THF (3þ1 mL) was added dropwise. The light
green solution was refluxed for 10 min, and then was allowed to
cool to ambient temperature.
CDCl3) d 212.6, 69.1, 59.8, 47.2, 40.0, 34.7, 28.3, 27.9, 25.9, 25.9, 18.2,
18.1, 16.1, ꢀ4.5, ꢀ4.6, ꢀ5.3; IR (neat) 2965, 2860, 1719, 1469, 1356,
1244, 1093, 842 cmꢀ1; MS (DCI/CH4) 403 (1), 345 (71), 271 (20), 245
(41), 214 (24), 213 (82), 197 (27), 185 (19), 171 (24), 159 (55), 147
(78), 140 (13), 139 (83), 129 (38), 121 (62), 113 (22), 95 (40), 89 (80),
73 (100); HRMS m/e calcd for C21H47O3Si2 (MHþ) 403.3064, found
403.3084.
The solution of Grignard reagent was added dropwise to a cold
(ꢀ78 ꢁC) solution of epoxide 3420 (0.42 g, 2.04 mmol) and copper(I)
iodide (78 mg, 0.41 mmol) in a mixture of THF/DMS (9 mL; 20:1 by
volume). The mixture was stirred for 1 h at ꢀ78 ꢁC, and then
quenched carefully with the addition of saturated aq NH4Cl. The
biphasic mixture was warmed to ambient temperature and diluted
with Et2O (50 mL). The organic solution was washed with saturated
aq NH4Cl (50 mL) and saturated aq NaCl (50 mL). The combined
aqueous layers were extracted with Et2O (50 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(25 g SiO2, 5% EtOAc/hexanes) to yield 0.41 g (70%) of alcohol 35 as
5.1.14. Trifluoromethanesulfonic acid (2S,5S)-5,7-bis-(tert-butyl-di-
methylsilanyloxy)-2-methyl-1-methyleneheptyl ester (37). To a cold
(ꢀ78 ꢁC) solution of potassium bis(trimethylsilyl)amide (1.56 mL of
a 0.5 M solution in toluene, 0.78 mmol) in THF (7.8 mL) was added
a solution of methyl ketone 36 (300 mg, 0.75 mmol) in THF (1.8 mL)
over 45 min. After the addition was complete, the solution was
allowed to stir for an additional 30 min. At this time a solution of
Comins reagent21 (0.35 g, 0.89 mmol) in THF (500
mL) was added
dropwise, and the reaction mixture stirred for 4 h at ꢀ78 ꢁC. The
solution was quenched with saturated aq NH4Cl, warmed to am-
bient temperature, and diluted with Et2O (25 mL). The extracts
were washed with saturated aq NH4Cl (25 mL), dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude residue was purified by
flash chromatography (25 g SiO2, 2% Et2O/hexanes) to give 0.35 g
a clear, colorless oil: [
a
]
D
22 ꢀ13.3 (c 0.24, CHCl3); Rf¼0.23 in 10%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 4.67 (br s, 2H), 3.87 (m,
1H), 3.83e3.74 (m, 2H), 3.49 (br s, 1H), 2.12 (m, 1H), 1.64 (s, 3H),
1.64e1.61 (m, 2H), 1.49e1.30 (m, 4H), 1.00 (d, J¼6.8 Hz, 3H), 0.89 (s,
(87%) of enol triflate 37 as a clear, colorless, oil: [
a
]
22þ10.5 (c 1.71,
D
CHCl3); Rf¼0.60 in 10% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
9H), 0.07 (s, 6H); 13C NMR (101 MHz, CDCl3)
d
150.0, 109.5, 72.6,
d
5.10 (d, J¼3.9 Hz, 1H), 4.91 (d, J¼3.9 Hz, 1H), 3.83e3.81 (m, 1H),
63.0, 41.3, 38.2, 35.5, 30.8, 25.8, 19.7, 18.8, 18.1, ꢀ5.6; IR (neat) 3452,
3.65 (t, J¼6.5 Hz, 2H), 2.41e2.36 (m, 1H), 1.71e1.41 (m, 6H), 1.14 (d,

5092
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
J¼6.8 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H), 0.04 (m, 12H); 13C NMR
35.2, 31.1, 30.6, 29.1, 27.5, 27.4, 25.9, 19.7, 18.3, 18.1, 17.7, 13.7, 9.9,
9.5, ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat) 3081, 2958, 2849, 1620, 1458, 1360,
1266, 1099, 843 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for
C30H65O2Si2Sn (MþꢀC4H9) 633.3545, found 633.3668.
(101 MHz, CDCl3)
d 160.8, 102.4, 69.0, 59.8, 40.0, 38.5, 34.0, 29.0,
25.9, 25.8, 18.2, 18.0, 17.7, ꢀ4.5, ꢀ4.6, ꢀ5.4; IR (neat) 2953, 2928,
2854, 1665, 1478, 1424, 1256, 1207, 1143, 1089, 932, 829 cmꢀ1
.
5.1.15. (3S,6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-3-methyl-2-
(trimethylsilanylmethyl)-oct-1-ene (38). To a cold (0 ꢁC) solution of
enol triflate 37 (0.29 g, 0.53 mmol) in THF (5.3 mL) were added
Ni(acac)2 (27 mg, 0.11 mmol) and (trimethylsilylmethyl)magne-
sium chloride (1.60 mL of a 1.0 M solution in Et2O, 1.60 mmol). The
reaction mixture was warmed to ambient temperature and stirred
for 16 h. The solution was quenched with pH 7 phosphate buffer
(15 mL), and diluted with Et2O (15 mL). The layers were separated,
and the organic layer was dried (MgSO4), filtered, and concentrated
in vacuo. The crude residue was purified by flash chromatography
(10 g SiO2, 1e2% EtOAc/hexanes) to yield 0.19 g (75%) of allylsilane
38 as a clear, colorless oil; Rf¼0.76 in 10% EtOAc/hexanes; 1H NMR
5.1.17. (R)-4-[(1S,4S)-4,6-Bis-(tert-butyldimethylsilanyloxy)-1-
methylhexyl]-1-{2S,6R}-6-[2-(4-methoxybenzyloxy)ethyl]-4-
methylenetetrahydropyran-2-yl}-pent-4-en-2-ol (45). A flame-dried
Schlenk flask was charged with (R,R)-1,2-bis-para-toluenesulfonyl-
1,2-diphenylethane (590 mg, 1.13 mmol), diluted with CH2Cl2
(7.8 mL), and cooled to 0 ꢁC. Fresh BBr3 (1.13 mL of 1.0 M solution in
CH2Cl2, 1.13 mmol) was added dropwise and the solution was
warmed to ambient temperature. The orange reaction mixture was
stirred for 1 h, and then the CH2Cl2 and HBr were removed under
reduced pressure (0.1 mmHg). The reaction was diluted again with
CH2Cl2 (7.8 mL) and, after 10 min, concentrated under high vacuum.
The resulting white solid was diluted with CH2Cl2 (7.3 mL) and
cooled to 0 ꢁC. A solution of stannane 27 (873 mg, 1.27 mmol) in
CH2Cl2 (1.0 mL) was added and the resulting yellow solution was
stirred for 16 h at ambient temperature.
(400 MHz, CDCl3) d 4.59 (s, 1H), 4.54 (s, 1H), 3.81e3.76 (m, 1H), 3.65
(app dt, J¼6.6,1.4 Hz, 2H),1.93e1.84 (m, 1H),1.69e1.60 (m, 2H),1.50
(s, 2H), 1.47e1.38 (m, 3H), 1.38e1.26 (m, 1H), 0.99 (d, J¼6.9 Hz, 3H),
0.89 (s, 9H), 0.88 (s, 9H), 0.04 (s, 12H), 0.01 (s, 9H); 13C NMR
The solution was cooled to ꢀ78 ꢁC, and a solution of aldehyde 14
(257 mg, 0.84 mmol) in CH2Cl2 (1 mL) was added over 5 min. After
1.5 h the reaction was quenched with saturated aq NaHCO3 and
warmed to ambient temperature. The mixture was diluted with
CH2Cl2 (25 mL) and washed with saturated aq NaHCO3 (25 mL). The
organic layer was dried (MgSO4), filtered, and concentrated in
vacuo, and the resulting residue was suspended in Et2O and filtered
through a fritted glass funnel. The remaining white solid (recovered
bis-sulfonamide) can be recrystallized from CHCl3 and reused. The
clear ethereal solution was concentrated in vacuo. The crude resi-
due was purified by flash chromatography (50 g SiO2, 7.5% EtOAc/
hexanes) to yield 522 mg (88%) of alcohol 45, as well as 51 mg (9%)
of the minor diastereomer. Characterization data for the major
(101 MHz, CDCl3)
d 152.4, 105.5, 69.5, 60.1, 40.9, 40.0, 35.2, 30.9,
26.0, 25.9, 25.6,19.7,18.3,18.1, ꢀ1.2, ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat) 3077,
2945, 2853, 1633, 1475, 1251, 1073, 855 cmꢀ1; MS (DCI/CH4) 473 (2),
415 (32), 340 (14), 329 (19), 209 (24),197 (18),191 (14),155 (35),148
(27), 115 (33), 95 (51), 89 (45), 74 (61), 73 (100); HRMS m/e calcd for
C25H57O2Si3 (MHþ) 473.3666, found 473.3684.
5.1.16. (3S,6S)-6,8-Bis-(tert-butyldimethylsilanyloxy)-3-methyl-2-
(tributylstannylmethyl)oct-1-ene (27). To a cold (ꢀ78 ꢁC) solution of
allylsilane 38 (833 mg, 1.76 mmol) in 60% DMF/CH2Cl2 (8.8 mL)
were added propylene oxide (1.23 mL, 17.6 mmol) and N-bromo-
succinimide (1.25 g, 7.04 mmol). The cloudy reaction mixture was
stirred for 1 h at ꢀ78 ꢁC, and then warmed to ꢀ10 ꢁC over 2.5 h. The
reaction mixture was cooled back down to ꢀ78 ꢁC and quenched
with saturated aq NaHSO3. After warming to ambient temperature,
the light yellow solution was diluted with Et2O (25 mL). The organic
solution was washed with water (25 mL) and saturated aq NaCl
(25 mL), dried (MgSO4), filtered, and concentrated in vacuo. This
allyl bromide was identified and used without further purification
for the next step: Rf¼0.74 in 10% EtOAc/hexanes; 1H NMR
product 45 was as follows: [
a
]
D22þ7.9 (c 2.1, CHCl3); Rf¼0.36 in 20%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d
7.25 (d, J¼8.6 Hz, 2H),
6.87 (d, J¼8.6 Hz, 2H), 4.84 (s, 1H), 4.81 (s, 1H), 4.71 (s, 2H), 4.44 (A
of AB, JAB¼11.6 Hz, 1H), 4.42 (B of AB, JAB¼11.6 Hz, 1H), 4.02e4.00
(m, 1), 3.80 (s, 3H), 3.80e3.75 (m, 1H), 3.71 (s, 1H), 3.65 (t, J¼6.7 Hz,
2H), 3.55e3.52 (m, 4H), 2.28e1.29 (m, 17H), 1.01 (d, J¼7.0 Hz, 3H),
0.89 (s, 9H), 0.88 (s, 9H), 0.04 (s, 12H); 13C NMR (101 MHz, CDCl3)
d
159.1, 151.3, 143.8, 130.4, 129.3, 113.7, 110.1, 109.0, 79.4, 76.0, 72.7,
(400 MHz, CDCl3)
d
5.21 (s, 1H), 4.98 (s, 1H), 3.98 (m, 2H), 3.82e3.78
70.1, 69.4, 66.4, 60.0, 55.2, 42.5, 42.2, 41.0, 40.5, 40.1, 40.0, 36.2, 35.0,
31.0, 25.9, 25.9, 19.9, 18.3, 18.1, ꢀ4.3, ꢀ4.6, ꢀ5.3; IR (neat) 3498,
3071, 2943, 2869, 1655, 1620, 1512, 1468, 1360, 1261, 1114, 1045,
839 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for C40H72O6Si2Na
(MþþNa) 727.4766, found 727.4749.
(m,1H), 3.65 (t, J¼6.4 Hz, 2H), 2.38e2.30 (m,1H),1.69e1.38 (m, 5H),
1.31e1.19 (m, 1H), 1.08 (d, J¼6.4 Hz, 3H), 0.89 (s, 9H), 0.88 (s, 9H),
0.07 (s, 3H), 0.04 (m, 9H).
To a cold (0 ꢁC) solution of tributyltin hydride (1.00 mL,
3.70 mmol) in THF (5 mL) was added LDA (3.70 mL of a freshly
prepared 1.0 M solution in THF, 3.70 mmol). The yellow solution
was stirred at 0 ꢁC for 30 min, and then transferred via cannula to
a cold (ꢀ78 ꢁC) suspension of copper(I) bromide dimethyl sulfide
(0.70 g, 3.34 mmol) in THF (10 mL). The brown reaction mixture
was stirred for 2 h at ꢀ78 ꢁC, and then the allyl bromide, prepared
as above, was added as a solution in THF (2.5 mL). The purple so-
lution was warmed to ꢀ40 ꢁC over 45 min, and then quenched with
saturated aq NH4Cl. The biphasic mixture was diluted with Et2O
(50 mL), filtered through a plug of Celite, and then washed with
saturated aq NH4Cl (50 mL) and saturated aq NaCl (50 mL). The
crude residue was purified by flash chromatography (60 g of Et3N-
deactivated SiO2, 100% pentane) to give 1.08 g (89% for two steps) of
5.1.18. (2S,6R)-2-[(2R,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)-
2-methoxy-5-methyl-4-methylenedecyl]-6-[2-(4-methoxybenzyloxy)
ethyl]-4-methylenetetrahydropyran (46). To a solution of alcohol 45
(156 mg, 221 mmol) in CH2Cl2 (7 mL) at ambient temperature were
ꢀ
added proton sponge (403 mg, 1.88 mmol), crushed 4 A molecular
sieves (402 mg), and trimethyloxonium tetrafluoroborate (229 mg,
1.55 mmol). The reaction mixture was stirred for 16 h, and then
filtered through a pad of Celite to remove the solids. The filtrate was
diluted with Et2O (50 mL), and washed with 1 M aq HCl (2ꢂ25 mL).
The organic layer was dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(10 g SiO2, 7.5% EtOAc/hexanes) to yield 152 mg (96%) of methyl
allylstannane 27 as a clear, colorless oil: [
a
]
22þ10.6 (c 1.11, CHCl3);
ether 46 as a clear, colorless oil: [
a]
D22þ6.1 (c 1.1, CHCl3); Rf¼0.36 in
D
Rf¼0.75 in 10% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d
4.50 (s,
20% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.26e7.24 (m, 2H),
1H), 4.47(s, 1H), 3.81e3.75 (m, 1H), 3.65 (dt, J¼6.7, 1.2 Hz, 2H),
1.90e1.82 (s, 1H), 1.77 (A of AB, JAB¼11.9 Hz, 1H), 1.74 (B of AB,
JAB¼11.9 Hz, 1H), 1.70e1.58 (m, 2H), 1.52e1.25 (m, 16H), 1.00 (d,
J¼6.9 Hz, 3H), 0.90e0.82 (m, 15H), 0.89 (s, 9H), 0.88 (s, 9H), 0.04 (s,
6.88e6.86 (m, 2H), 4.81 (s, 2H), 4.71e4.70 (m, 2H), 4.43 (A of AB,
JAB¼11.5, 1H), 4.41 (B of AB, JAB¼11.5 Hz, 1H), 3.80 (s, 3H), 3.80e3.75
(m, 1H), 3.65 (t, J¼6.8 Hz, 2H), 3.56 (t, J¼6.7 Hz, 2H), 3.51e3.36 (m,
3H), 3.31 (s, 3H), 2.30e1.35 (m, 17H), 1.00 (d, J¼6.7 Hz, 3H), 0.89 (s,
12H); 13C NMR (101 MHz, CDCl3)
d
154.6, 103.5, 69.5, 60.1, 40.9, 40.1,
9H), 0.88 (s, 9H), 0.04 (s, 12H); 13C NMR (101 MHz, CDCl3)
d 159.1,

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5093
151.2, 144.7, 130.6, 129.2, 113.7, 110.0, 108.5, 76.8, 75.5 (2), 72.6, 69.4,
66.6, 60.0, 56.4, 55.2, 40.9, 40.8, 40.3, 40.1, 39.7, 39.0, 36.5, 35.0,
30.9, 25.9 (2), 19.9, 18.3, 18.1, ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat) 3070, 2952,
2833, 1647, 1607, 1502, 1462, 1244, 1106, 1027 cmꢀ1; HRMS (MALDI)
m/e calcd for C41H74O6Si2Na (MþþNa) 741.4922, found 741.3160.
69.1, 68.8, 68.3, 66.6, 64.6, 59.8, 57.0, 55.2, 47.2, 45.7, 40.0, 38.8, 36.6,
34.8, 30.3, 28.0, 25.9, 25.9, 18.2, 18.1, 15.9, ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat)
3435, 2943, 2849, 1710, 1507, 1458, 1365, 1261, 1099 cmꢀ1; HRMS
(FAB, NBA, Naþ) m/e calcd for C39H72O8Si2 (MþþNa) 747.4663,
found 747.4672.
5.1.19. (2R,6S)-2-[(2S,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)-
2-methoxy-5-methyl-4-oxodecyl]-6-[2-(4-methoxybenzyloxy)ethyl]-
tetrahydropyran-4-one (47). To a solution of olefin 46 (339 mg,
5.1.21. (2S,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)
-1-{(2R,4R,6S)-4-tert-butyldiphenylsilanyloxy}-6-[2-(4-
methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-2-methoxy-5-
methyldecan-4-one (51). To a solution of the alcohol prepared
above from 47 (300 mg, 0.41 mmol) in DMF (2 mL) were added
imidazole (141 mg, 2.07 mmol) and tert-butyldiphenylsilyl chloride
(0.29 mL, 1.24 mmol). The reaction mixture was stirred for 48 h,
and then diluted with 30% Et2O/hexanes (15 mL) and saturated aq
NH4Cl (15 mL). The layers were separated, and the aqueous layer
was extracted with 30% Et2O/hexanes (15 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(25 g SiO2, 7.5% EtOAc/hexanes) to yield 290 mg (73%) of silyl ether
471
methylmorpholine N-oxide (138 mg, 1.18 mmol) and osmium te-
troxide (500 L of a 2.5 wt % solution in tert-BuOH, 38 mol). The
mmol) in 33% aq acetone (3.2 mL) were added 4-
m
m
reaction mixture was stirred for 16 h at ambient temperature, and
then quenched with sodium bisulfite (1 g). The solution was diluted
with EtOAc (15 mL) and saturated aq NaCl (15 mL). The layers were
separated, and the aqueous phase was extracted with EtOAc
(2ꢂ15 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude tetrol was taken into
the next reaction without purification.
To a solution of crude tetrol in 1:1 THF/pH 7 phosphate buffer
(2.4 mL) was added sodium periodate (302 mg, 1.41 mmol). The
cloudy reaction mixture was stirred for 16 h at ambient tempera-
ture, and then diluted with Et2O (15 mL) and saturated aq NaCl
(15 mL). The layers were separated, and the aqueous layer was
extracted with Et2O (15 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The crude res-
idue was purified by flash chromatography (20 g SiO2, 25% EtOAc)
to yield 274 mg (80% overall) of diketone 47 as a clear, colorless oil:
51 as a clear, colorless oil: [
a
]
D
22þ5.2 (c 0.8, CHCl3); Rf¼0.64 in 50%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.65e7.62 (m, 4H),
7.44e7.33 (m, 6H), 7.26 (d, J¼8.6 Hz, 2H), 6.87 (d, J¼8.6 Hz, 2H), 4.44
(s, 2H), 4.21 (m, 1H), 4.09e4.05 (m, 2H), 3.85e3.75 (m, 2H), 3.80 (s,
3H), 3.64 (t, J¼6.7 Hz, 2H), 3.56 (t, J¼6.7 Hz, 2H), 3.27 (s, 3H), 2.75 (A
of ABX, JAB¼16.2 Hz, JAX¼7.7 Hz, 1H), 2.51 (B of ABX, JAB¼16.2 Hz,
JBX¼5.0 Hz, 1H), 2.49 (m, 1H), 1.79e1.54 (m, 8H), 1.49e1.33 (m, 3H),
1.29e1.23 (m, 3H), 1.08 (s, 9H), 1.07 (d, J¼7.0 Hz, 3H), 0.88 (s, 9H),
0.88 (m, 9H), 0.04 (s, 6H), 0.03 (s, 6H); 13C NMR (101 MHz, CDCl3)
[
a
]
22þ3.1 (c 2.0, CHCl3); Rf¼0.41 in 40% EtOAc/hexanes; 1H NMR
d 213.0, 159.0, 135.7, 134.2, 130.8, 129.6, 129.1, 127.6, 113.7, 74.4, 72.6,
D
(400 MHz, CDCl3)
d
7.23 (d, J¼8.6 Hz, 2H), 6.87 (d, J¼8.6 Hz, 2H),
69.3, 69.1, 68.6, 67.0, 66.2, 59.8, 57.0, 55.2, 47.1, 45.8, 40.3, 40.1, 39.0,
38.9, 36.4, 34.9, 28.0, 27.0, 25.9, 25.9,19.3,18.2,18.1,16.0, ꢀ4.4, ꢀ4.6,
ꢀ5.3; IR (neat) 3066, 3046, 2943, 2854, 1704, 1606, 1512, 1458, 1419,
1360, 1237, 1104, 1035, 843 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd
for C55H90O8Si3Na (MþþNa) 985.5841, found 985.5839.
4.42 (s, 2H), 3.88e3.82 (m, 1H), 3.80 (s, 3H), 3.80e3.70 (m, 3H), 3.63
(t, J¼6.6 Hz, 2H), 3.65e3.52 (m, 2H), 3.27 (s, 3H), 2.77 (A of ABX,
JAB¼16.6 Hz, JAX¼7.0 Hz, 1H), 2.50 (B of ABX, JAB¼16.6 Hz,
JBX¼5.4 Hz, 1H), 2.47e2.35 (m, 3H), 2.29e2.20 (m, 2H), 1.96e1.87
(m, 2H), 1.84e1.76 (m, 1H), 1.69e1.55 (m, 4H), 1.43e1.32 (m, 3H),
1.06 (d, J¼6.9 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.03 (s, 12H); 13C
5.1.22. (2R,4S,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)-1-
{(2R, 4R, 6S)-4-(tert-butyldiphenylsilanyloxy)-6-[2-(4-
methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-2-methoxy-5
-methyldecan-4-ol (56). Preparation of the Terashima reagent:
a flame-dried, two-neck round bottom flask equipped with a reflux
condenser was charged with lithium aluminum hydride (104 mg,
2.74 mmol). After diluting with Et2O (3 mL), a solution of (ꢀ)-N-
methylephedrine (491 mg, 2.74 mmol) in Et2O (8 mL) was added
slowly over 15 min. The suspension was heated to reflux and stirred
for 1 h. N-Ethylaniline (690 mL, 5.48 mmol) was then added
dropwise, and the suspension refluxed an additional hour. The
finely dispersed, light gray reagent was cooled to ambient tem-
perature, and was directly used as a suspension in ether.
NMR (101 MHz, CDCl3) d 212.6, 206.9, 159.1, 130.3, 129.2, 113.8, 74.0,
73.9, 73.6, 72.7, 69.1, 65.9, 59.8, 57.0, 55.2, 47.7 (2), 47.2, 45.3, 40.2,
40.0, 36.5, 34.7, 27.9, 25.9, 25.8, 18.2, 18.0, 15.9, ꢀ4.4, ꢀ4.6, ꢀ5.3; IR
(neat) 2958, 2929, 2879, 1712, 1620, 1508, 1462, 1370, 1244, 1086,
1020, 829 cmꢀ1; HRMS (MALDI) m/e calcd for C39H70O8Si2Na
(MþþNa) 745.4507, found 745.3170.
5.1.20. (2S,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)-1-
{(2S,4R,6S)-4-hydroxy-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahy-
dropyran-2-yl}-2-methoxy-5-methyldecan-4-one. To a cold (ꢀ78 ꢁC)
solution of diketone 47 (355 mg, 491
m
mol) in THF (24 mL) was
added L-SelectrideÒ (589
mL of a 1.0 M solution in THF, 589 mmol).
The reaction mixture was stirred at ꢀ78 ꢁC for 1.5 h. The solution
was quenched with MeOH (1 mL), stirred for 15 min, and then
warmed to ambient temperature. The solution was diluted with
Et2O (50 mL) and saturated aq NaHCO3 (50 mL). The layers were
separated, and the aqueous layer was extracted with Et2O (50 mL).
The combined organic layers were dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
chromatography (25 g SiO2, 50% EtOAc/hexanes) to yield 300 mg
To a cold (ꢀ78 ꢁC) solution of ketone 51 (256 mg, 0.27 mmol) in
Et2O (2.66 mL) was added freshly prepared Terashima reagent
(2.12 mL of a finely dispersed suspension in Et2O, est. 0.53 mmol).
The reaction mixture was stirred for 2 h at ꢀ78 ꢁC, quenched with
saturated aq NaHCO3, and warmed to room temperature. The
mixture was diluted with Et2O (15 mL) and saturated aq NaHCO3
(15 mL). The layers were separated, and the aqueous layer was
extracted with Et2O (15 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. The crude res-
idue was purified by flash chromatography (25 g SiO2, 15% EtOAc/
hexanes) to yield 244 mg (95%) of alcohol 56 as a clear, colorless oil:
22
(84%) of the C5 hydroxyeC11 ketone as a clear, colorless oil: [a]
D
þ6.5 (c 2.1, CHCl3); Rf¼0.29 in 50% in EtOAc/hexanes; 1H NMR
(400 MHz, CDCl3)
d
7.25 (d, J¼7.6 Hz, 2H), 6.86 (d, J¼7.6 Hz, 2H),
4.44 (A of AB, JAB¼11.6 Hz, 1H), 4.41 (B of AB, JAB¼11.6 Hz, 1H), 4.22
(m, 1H), 3.92e3.82 (m, 4H), 3.79 (s, 3H), 3.63 (t, J¼6.4 Hz, 2H), 3.56
(t, J¼6.7 Hz, 2H), 3.28 (s, 3H), 2.73 (A of ABX, JAB¼16.2 Hz,
JAX¼8.0 Hz, 1H), 2.52 (B of ABX, JAB¼16.2 Hz, JBX¼4.5 Hz, 1H),
2.49e2.44 (m, 1H), 1.82e1.61 (m, 8H), 1.50e1.34 (m, 6H), 1.05 (d,
J¼7.0 Hz, 3H), 0.88 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H), 0.03 (s, 6H); 13C
[a
]
D
22þ4.1 (c 0.78, CHCl3); Rf¼0.43 in 30% EtOAc/hexanes; 1H NMR
(400 MHz, CDCl3)
d 7.65e7.62 (m, 4H), 7.45e7.33 (m, 6H), 7.26 (d,
J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H), 4.43 (s, 2H), 4.20 (m, 1H),
4.08e3.97 (m, 2H), 3.79 (s, 3H), 3.79e3.74 (m, 1H), 3.71e3.62 (m,
3H), 3.57e3.53 (m, 3H), 3.31 (s, 3H), 1.81e1.13 (m, 14H), 1.08 (s, 9H),
0.89 (m, 21H), 0.05 (s, 3H), 0.04 (s, 3H), 0.04 (s, 6H); 13C NMR
NMR (101 MHz, CDCl3)
d
213.0, 159.0, 130.6, 129.2, 113.7, 74.4, 72.6,
(101 MHz, CDCl3) d 159.1, 135.7, 134.1, 130.6, 129.7, 129.1, 127.6, 113.7,

5094
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
79.8, 74.9, 72.7, 69.7, 69.3, 68.5, 66.9, 66.1, 60.0, 56.0, 55.3, 40.2, 39.7,
39.4, 39.1, 39.0, 38.0, 36.3, 35.5, 28.3, 27.0, 25.9 (2), 19.3, 18.3, 18.1,
14.1, ꢀ4.3, ꢀ4.6, ꢀ5.3; IR (neat) 3484, 3071, 2933, 2849, 1625, 1586,
1517, 1468, 1419, 1350, 1261, 1084, 1045, 843 cmꢀ1; HRMS (FAB,
NBA, Naþ) m/e calcd for C55H92O8Si3Na (MþþNa) 987.5998, found
987.6254.
3H), 2.41 (s, 3H), 1.99e1.92 (m, 1H), 1.81e1.71 (m, 3H), 1.67e1.51 (m,
6H), 1.41e1.32 (m, 2H), 1.30e1.18 (m, 5H), 1.09 (s, 9H), 0.90 (s, 9H),
0.87 (s, 9H), 0.84 (d, J¼7.0 Hz, 3H), 0.05 (s, 6H), 0.03 (s, 3H), 0.02 (s,
3H); 13C NMR (101 MHz, CDCl3)
d 159.0, 144.2, 135.7, 134.8, 134.2,
134.1, 130.7, 129.7, 129.6, 129.1, 127.7, 127.6, 127.6, 113.7, 84.9, 74.5,
72.6, 69.4, 69.3, 68.6, 67.0, 66.1, 59.9, 56.0, 55.2, 40.0, 39.7, 38.9,
36.4, 36.3, 35.5, 35.4, 27.8, 27.0, 25.9, 25.9, 21.6, 19.3, 18.3, 18.0, 13.9,
ꢀ4.4, ꢀ4.6, ꢀ5.3; IR (neat) 3071, 2933, 2854,1615,11,517,1468,1419,
1360, 1247, 1178, 1119, 1045, 902, 834 cmꢀ1; HRMS (FAB, NBA, Naþ)
m/e calcd for C62H98O10SSi3Na (MþþNa) 1141.6087, found
1141.6092.
A small sample of 56 was characterized by conversion to its
(S)-Mosher ester derivative upon reaction with (S)-(þ)-
-trifluoromethylphenylacetyl chloride (Aldrich) in CDCl3 con-
taining Et3N and a crystal of 4-dimethylaminopyridine: 1H NMR
(400 MHz, CDCl3)
a-methoxy-
a
d
7.66e7.30 (m, 15H), 7.24 (d, J¼8.7 Hz, 2H), 6.86
(d, J¼8.7 Hz, 2H), 5.19e5.14 (m, 1H), 4.42 (s, 2H), 4.20 (m, 1H),
4.12e4.01 (m, 2H), 3.79 (s, 3H), 3.76e3.69 (m, 1H), 3.64 (t, J¼6.7,
6.7 Hz, 2H), 3.56e3.50 (m, 2H), 3.48 (s, 3H), 3.19e3.11 (m, 1H), 3.15
(s, 3H), 1.91 (ddd, J¼14.2, 8.4, 5.8 Hz, 1H), 1.83e1.10 (m, 16H), 1.07 (s,
9H), 0.91e0.83 (m, 3H), 0.88 (s, 9H), 0.87 (S, 9H), 0.04 (s, 9H), 0.02
(s, 3H).
5.1.25. Toluene-4-sulfonic acid (1S,2S,5S)-1-((S)-3-{(2R,4R,6S)-4-
(tert-butyldiphenylsilanyloxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahy
dropyran-2-yl}-2-methoxypropyl)-5,7-dihydroxy-2-methylheptyl
ester (58). Preparation of pyridinium hydrofluoride stock solution:
to a nalgene container was added 2.0 g of pyridinium hydrofluoride
(Aldrich), 4 mL of pyridine, and 16 mL of THF.
In similar fashion, a sample of 56 was converted into its
(R)-Mosher ester via reaction with (R)-(ꢀ)-
fluoromethylphenylacetyl chloride (Aldrich) and was characterized
as follows: 1H NMR (400 MHz, CDCl3)
7.68e7.30 (m, 15H), 7.24 (d,
J¼8.6 Hz, 2H), 6.85 (d, J¼8.7 Hz, 2H), 5.23e5.17 (m, 1H), 4.41 (s, 2H),
4.20 (s, 1H), 4.12e4.01 (m, 2H), 3.79 (s, 3H), 3.71e3.60 (m, 3H),
3.56e3.49 (m, 2H), 3.55 (s, 3H), 3.32e3.23 (m, 1H), 3.20 (s, 3H),
2.03e1.91 (m, 1H), 1.83e1.14 (m, 16H), 1.07 (s, 9H), 0.91e0.84 (m,
3H), 0.89 (s, 9H), 0.86 (s, 9H), 0.04 (s, 6H), 0.02 (s, 3H), 0.00 (s, 3H).
a
-methoxy-
a
-tri-
A solution of the tosylate (prepared from 56) in THF (1.2 mL) was
placed in a small plastic reaction vessel, and HF$pyr stock solution
(6 mL) was added dropwise followed by stirring the reaction mix-
ture for 16 h at ambient temperature. The acidic solution was
neutralized to pH 7 with saturated aq NaHCO3 (10 mL), and then
diluted with Et2O (15 mL). The layers were separated, and the
aqueous layer extracted with Et2O (15 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated in vacuo. The
crude residue was purified by flash chromatography (10 g SiO2,
80e90% EtOAc/hexanes) to yield 89 mg (84%) of diol 58 as a thick
d
5.1.23. (2R,4R,5S,8S)-8,10-Bis-(tert-butyldimethylsilanyloxy)-1-{(2R,
4R,6S)-4-(tert-butyldiphenylsilanyloxy)-6-[2-(4-methoxybenzyloxy)
ethyl]-tetrahydropyran-2-yl}-2-methoxy-5-methyldecan-4-ol
(57). The Terashima reagent was prepared as described in the
preparation of 56 except for the use of (þ)-N-methylephedrine.
colorless oil: [
a
]
D
22ꢀ6.9 (c 0.45, CHCl3); Rf¼0.22 in 80% EtOAc/hex-
anes; 1H NMR (400 MHz, CDCl3)
d
7.79 (d, J¼8.2 Hz, 2H), 7.65e7.62
(m, 4H), 7.43e7.24 (m, 10H), 6.86 (d, J¼8.9 Hz, 2H), 4.73 (ddd, J¼6.1,
6.1, 3.1 Hz, 1H), 4.42 (s, 2H), 4.22e4.18 (m, 1H), 4.07e3.97 (m, 2H),
3.84e3.68 (m, 3H), 3.80 (s, 3H), 3.53e3.50 (m, 2H), 3.35e3.32 (m,
1H), 3.20 (s, 3H), 2.58 (s, 1H, eOH), 2.41 (s, 3H), 1.95e1.12 (m, 17H),
1.08 (s, 9H), 0.85 (d, J¼6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3)
Reaction with the ketone 51 (18 mg; 18.7 mmol) was carried out
using the same conditions as indicated for 56. Formation of a new
diastereomer was observed (>95:5 ratio), and upon work up, the
crude residue was purified by flash chromatography (10 g SiO2, 15%
EtOAc/hexanes) to yield 16.6 mg (92%) of alcohol 57 as a clear,
colorless oil: Rf¼0.35 in 30% EtOAc/hexanes; 1H NMR (400 MHz,
d
159.1, 144.4, 135.7, 134.8, 134.2, 130.7, 129.7, 129.1, 127.7, 127.6,
113.8, 84.7, 74.6, 72.5, 71.8, 69.4, 68.4, 67.0, 66.1, 61.9, 55.9, 55.3,
39.4, 39.0, 38.9, 38.2, 36.3, 35.7, 35.5, 35.0, 27.8, 27.0, 21.6, 19.3, 14.2;
IR (neat) 3400, 3061, 2948, 2864, 1615, 1522, 1473, 1429, 1350, 1242,
1163, 1104, 1035, 902, 804 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd
for C50H70O10SSiNa (MþþNa) 913.4357, found 913.4388.
CDCl3)
d
7.67e7.60 (m, 4H), 7.46e7.32 (m, 6H), 7.26 (d, J¼8.6 Hz,
2H), 6.86 (d, J¼8.6 Hz, 2H), 4.44 (s, 2H), 4.20 (m, 1H), 4.10e3.97 (m,
2H), 3.80 (s, 3H), 3.81e3.76 (m, 1H), 3.70e3.60 (m, 4H), 3.59e3.51
(m, 2H), 3.32 (s, 3H), 3.23 (d, J¼3.4 Hz, 1H), 1.90 (ddd, J¼14.1, 8.7,
5.3 Hz, 1H), 1.81e1.10 (m, 16H), 1.08 (s, 9H), 0.89 (s, 18H), 0.86 (d,
6.8 Hz, 3H), 0.05 (s, 6H), 0.04 (s, 6H); IR (neat) 3481, 3070, 2933,
2848, 1625, 1585, 1516, 1464 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd
for C55H92O8Si3Na (MþþNa) 987.5998, found 987.6098.
5.1.26. 2-[(2S,5S,6R)-6-((R)-3-{(2R,4R,6S)-4-(tert-Butyldiphenylsila-
nyloxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-2-
methoxypropyl)-5-methyltetrahydropyran-2-yl]-ethanol
(59). To
a solution of diol 58 (89 mg, 0.10 mmol) in benzene (10 mL) at
ambient temperature was added NaH (20 mg of a 60% dispersion in
mineral oil, 0.50 mmol). The suspension was heated to 60 ꢁC, with
stirring for 16 h. The cream-colored reaction mixture was cooled to
room temperature and quenched with saturated aq NH4Cl. The
quenched reaction mixture was diluted with Et2O (15 mL) and
saturated aq NH4Cl (15 mL). The layers were separated and the
aqueous phase was extracted with Et2O (15 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography
(7.5 g SiO2, 50% EtOAc) to yield 51 mg (71%) of alcohol 59 as a clear,
5.1.24. Toluene-4-sulfonic acid (1S,2S,5S)-5,7-bis-(tert-butyldimethy
lsilanyloxy)-1-((S)-3-{(2R,4R,6S)-4-(tert-butyldiphenylsilanyloxy)-6-
[2-(4-methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-2-
methoxypropyl)-2-methylheptyl ester. To a cold (0 ꢁC) solution of
alcohol 56 (120 mg, 0.24 mmol) in CH2Cl2 (1.24 mL) were added
pyridine (80.0 mL, 0.99 mmol) and p-toluenesulfonic anhydride
(81.0 mg, 0.25 mmol). The light brown reaction mixture was
allowed to warm to ambient temperature and stirred for 30 min.
The solution was diluted with Et2O (15 mL) and saturated aq NH4Cl
(15 mL). The layers were separated, and the aqueous layer extracted
with Et2O (15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (7.5 g SiO2, 15% EtOAc) to yield
colorless oil: [
a
]
D
22þ9.8 (c 0.95, CHCl3); Rf¼0.51 in 80% EtOAc/hex-
anes; 1H NMR (400 MHz, CDCl3)
d 7.65e7.62 (m, 4H), 7.45e7.40 (m,
2H), 7.38e7.34 (m, 4H), 7.26 (d, J¼8.2 Hz, 2H), 6.86 (d, J¼8.2 Hz, 2H),
4.43 (s, 2H), 4.22e4.18 (m, 1H), 4.10e4.00 (m, 2H), 3.93e3.85 (m,
1H), 3.80 (s, 3H), 3.78e3.70 (m, 2H), 3.68e3.64 (m, 1H), 3.61e3.52
(m, 3H), 3.31 (s, 3H), 2.97e2.94 (m, 1H, eOH), 2.01e1.90 (m, 2H),
1.82e1.18 (m, 15H), 1.08 (s, 9H), 1.01 (d, J¼6.4 Hz, 3H); 13C NMR
140 mg (100%) of the tosylate of 56 as a thick, colorless oil: [
a
]D22ꢀ1.2
(c 0.97, CHCl3); Rf¼0.30 in 20% EtOAc/hexanes; 1H NMR (400 MHz,
CDCl3)
d
7.78 (d, J¼8.2 Hz, 2H), 7.66e7.63 (m, 4H), 7.43e7.33 (m,
6H), 7.30e7.24 (m, 4H), 6.86 (d, J¼8.9 Hz, 2H), 4.70e4.67 (m, 1H),
4.42 (s, 2H), 4.22e4.19 (m, 1H), 4.07e4.02 (m, 2H), 3.80 (s, 3H),
3.69e3.61 (m, 3H), 3.55e3.51 (m, 2H), 3.33e3.30 (m, 1H), 3.22 (s,
(101 MHz, CDCl3) d 159.0, 135.7, 134.2, 134.1, 130.7, 129.6, 129.1,
127.6, 113.7, 74.5, 73.0, 72.5, 70.1, 69.2, 68.6, 66.9, 66.2, 61.1, 56.3,
55.2, 39.4, 39.4, 38.9, 37.0, 36.3, 35.7, 33.2, 27.8, 27.0, 26.0, 19.3, 18.5;

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5095
IR (neat) 3439, 3056, 3046, 2933, 2864, 1610, 1507, 1463, 1424,1360,
1247, 1109, 1050, 824 cmꢀ1; HRMS (FAB, NBA, NAþ) m/e calcd for
C43H62O7SiNa (MþþNa) 741.4163, found 741.4147.
3.57 (t, J¼6.7 Hz, 2H), 3.59e3.48 (m, 2H), 3.29 (s, 3H), 2.89 (A of
ABX, JAB¼15.6 Hz, JAX¼6.4 Hz, 1H), 2.76 (B of ABX, JAB¼15.6 Hz,
JBX¼7.0 Hz, 1H), 2.08 (dd, J¼7.3, 7.3 Hz, 2H), 1.79e1.23 (m, 16H), 1.08
(s, 9H), 0.96 (d, J¼6.1 Hz, 3H), 0.92 (d, J¼6.7 Hz, 6H); 13C NMR
5.1.27. [(2S,5S,6R)-((R)-3-{(2R,4R,6S)-4-(tert-Butyldiphenylsilany-
loxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-2-
methoxypropyl)-5-methyltetrahydropyran-2-yl]acetaldehyde
(101 MHz, CDCl3) d 198.3, 159.0, 146.6, 135.7, 134.2, 131.7, 130.8,
129.6, 129.1, 127.6, 113.6, 74.2, 73.1, 72.6, 69.2, 68.5, 67.7, 67.1, 66.3,
57.0, 55.2, 43.3, 41.7, 40.2, 39.4, 39.0, 38.3, 36.4, 33.9, 27.9, 27.6, 26.6,
22.4, 19.3, 18.3; IR (neat) 3071, 3041, 2963, 2849, 1704, 1669, 1620,
1512,1458,1355,1242,1104,1030, 814 cmꢀ1; HRMS (FAB, NBA, Naþ)
m/e calcd for C49H70O7SiNa (MþþNa) 821.4789, found 821.4793.
(60). To a solution of alcohol 59 (51 mg, 71 mmol) in CH2Cl2 (1.0 mL)
was added sodium bicarbonate (30 mg, 0.36 mmol) followed by the
DesseMartin periodinane (45 mg, 0.11 mmol). After allowing the
solution to stir for 1 h at ambient temperature, the reaction mixture
was quenched with saturated aq Na2S2O3 (0.5 mL). The mixture
was then diluted with Et2O (15 mL) and saturated aq NH4Cl (15 mL).
The layers were separated, and the aqueous phase was extracted
with Et2O (15 mL). The combined organic layers were dried
(MgSO4), filtered, and concentrated in vacuo. The crude residue was
purified by flash chromatography (7.5 g SiO2, 30% EtOAc/hexanes)
5.1.29. (E)-(R)-1-[(2S,5S,6R)-6-((R)-3-{(2R,4R,6S)-4-(tert-Butyldiphe
nylsilanyloxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahydropyran-2-
yl}-2-methoxypropyl)-5-methyltetrahydropyran-2-yl]-6-methylhept-
3-en-2-ol (63). To a ꢀ10 ꢁC solution of (S) CBS-oxazaborolidine 62
(62
mL of a 1.0 M solution in toluene, 62
mmol) in THF (200
mL) was
added BH3$THF (31
m
L of a 1.0 M solution in THF, 31 mmol). The
to yield 49 mg (95%) of aldehyde 60 as a thick clear oil: [
a
]
D22þ15 (c
mixture was stirred for 10 min at ꢀ10 ꢁC, and then a solution of
0.85, CHCl3); Rf¼0.44 in 50% EtOAc/hexanes; 1H NMR (400 MHz,
enone 61 (24.8 mg, 31.0 mmol) in THF (400 mL) was added dropwise.
CDCl3)
d
9.79 (s, 1H), 7.66e7.63 (m, 4H), 7.43e7.33 (m, 6H), 7.26 (d,
The colorless reaction mixture was stirred for 10 min at ꢀ10 ꢁC, and
J¼8.5 Hz, 2H), 6.86 (d, J¼8.5 Hz, 2H), 4.44 (s, 2H), 4.40e4.34 (m,1H),
4.20 (br s, 1H), 4.10e4.05 (m, 2H), 3.80 (s, 3H), 3.59e3.46 (m, 4H),
3.28 (s, 3H), 2.85 (d of A of ABX, JAB¼16.0 Hz, JAX¼9.0 Hz, J¼3.0 Hz,
1H), 2.40 (d of AB of ABX, JAB¼16.0 Hz, JBX¼4.9 Hz, J¼1.5 Hz, 1H),
1.77e1.23 (m, 15H), 1.08 (s, 9H), 0.96 (d, J¼6.1 Hz, 3H); 13C NMR
then quenched with water (200 mL). The biphasic mixture was
stirred for 10 min while warming to room temperature, and then
was diluted with Et2O (10 mL) and saturated aq NaCl (10 mL). The
layers were separated, and the aqueous layer was extracted with
Et2O (10 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. The crude residue was purified
by flash chromatography (4 g SiO2, 30% EtOAc/hexanes) to yield
22.1 mg (89%) of allyl alcohol 63 as the major component of a 5:1
mixture of diastereomers. Purification by flash chromatography
(4 g SiO2, 20% EtOAc/hexanes, using two columns in sequence)
allowed for the separation into two fractions; 16 mg (65%) of pure
major diastereomer 63 and 6.1 mg (24%) of a mixture of C17 di-
astereomers, which were recycled via oxidation. Characterization
(101 MHz, CDCl3)
d 201.6, 159.0, 135.7, 134.2, 130.8, 129.6, 129.1,
127.6, 113.7, 74.1, 72.8, 72.6, 69.2, 68.5, 67.0, 66.7, 66.3, 56.7, 55.2,
46.4, 39.9, 39.4, 39.0, 38.2, 36.4, 33.8, 27.8, 27.0, 26.4, 19.3, 18.3; IR
(neat) 3066, 2933, 2854, 2731, 1719, 1615, 1512, 1438, 1237, 1104,
1045, 824 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for C43H60O7SiNa
(MþþNa) 739.4006, found 739.4003.
5.1.28. (E)-1-[(2S,5S,6R)-6-((S)-3-{(2R,4R,6S)-4-(tert-Butyldiphenylsi
lanyloxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahydropyran-2-yl}-
2-methoxypropyl)-5-methyltetrahydropyran-2-yl]-6-methylhept-3-
data for the major diastereomer 63 is as follows: [
a
]
24þ11 (c 0.97,
D
CHCl3); Rf¼0.50 in 50% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
en-2-one (61). To
0.47 mol) in CH2Cl2 (700
Schwartz’s reagent (Cp2ZrHCl; Aldrich) (121 mg, 470
a
solution of 4-methyl-1-pentyne (55.3
L) at ambient temperature was added
mol). The
m
L,
d 7.65e7.62 (m, 4H), 7.44e7.33 (m, 6H), 7.26e7.24 (m, 2H),
m
m
6.87e6.84 (m, 2H), 5.65 (ddd, J¼15.6, 7.0, 7.0 Hz, 1H), 5.49 (dd,
J¼15.6, 6.4 Hz, 1H), 4.43 (s, 2H), 4.38e4.30 (m, 1H), 4.20 (m, 1H),
4.10e3.98 (m, 3H), 3.80 (s, 3H), 3.64e3.54 (m, 4H), 3.32 (s, 3H), 2.94
(d, J¼4.3 Hz, 1H), 1.95e1.84 (m, 4H), 1.80e1.20 (m, 16H), 1.08 (s, 9H),
1.00 (d, J¼6.4 Hz, 3H), 0.87 (d, J¼6.7 Hz, 3H), 0.86 (d, J¼6.7 Hz, 3H);
m
yellow reaction mixture was stirred for 10 min, and then cooled to
ꢀ78 ꢁC. Dimethylzinc (235
mL of a 2.0 M solution in CH2Cl2,
470 mmol) was added dropwise, and the solution stirred for 15 min
at ꢀ78 ꢁC. A solution of aldehyde 60 (38.6 mg, 47.0
mmol) in CH2Cl2
13C NMR (101 MHz, CDCl3)
d 159.0, 135.7, 134.2, 134.2, 130.7, 129.6,
(300þ200
m
L) was added dropwise, and the reaction mixture
129.5, 129.1, 127.6, 113.7, 74.8, 73.2, 72.5, 69.2, 69.0, 68.6, 67.4, 66.9,
66.3, 56.6, 55.3, 41.6, 40.4, 39.5, 39.4, 39.0, 37.3, 36.3, 33.5, 28.2,
27.6, 27.0, 26.2, 22.4, 22.2, 19.3, 18.5; IR (neat) 3435, 3061, 2938,
warmed to 0 ꢁC. After stirring for 1 h at 0 ꢁC, the reaction mixture
was quenched carefully with saturated aq NH4Cl and warmed to
room temperature. The suspension was diluted with Et2O (25 mL),
and filtered through a pad of Celite. The filtrate was washed with
saturated aq NH4Cl (25 mL), dried (MgSO4), filtered, and concen-
trated in vacuo. The crude allylic alcohol was filtered through a pad
of silica gel (30% EtOAc), and taken on to the next step without
purification.
2854, 1748, 1606, 1517, 1458, 1424, 1252, 1109, 1035, 824 cmꢀ1
;
HRMS (FAB, NBA, Naþ) m/e calcd for C49H72O7Si (MþþNa) 823.4945,
found 823.4977.
5.1.30. Acetic acid (R)-(E)-1-[(2S,5S,6R)-6-((R)-3-{(2R,4R,6S)-4-(tert-but
yldiphenylsilanyloxy)-6-[2-(4-methoxybenzyloxy)ethyl]-tetrahydo-
pyran-2-yl}-2-methoxypropyl]-5-methyltetrahydropyran-2-
ylmethyl)-5-methylhex-2-enyl ester (64). To a solution of alcohol 63
To a solution of the crude allyl alcohol in CH2Cl2 (500
22 ꢁC were added sodium bicarbonate (18.0 mg, 0.22 mmol) and
DesseMartin periodinane (27.3 mg, 64.4 mol). The mixture was
mL) at
m
(16.0 mg, 20.0
mmol) in CH2Cl2 (200
m
L) were added pyridine
stirred at ambient temperature for 1 h, and then saturated aq
Na2S2O3 was added dropwise. After stirring for 10 min, the solution
was diluted with Et2O (15 mL) and saturated aq NH4Cl (15 mL). The
layers were separated, and the aqueous layer was extracted with
Et2O (15 mL). The combined organic layers were dried (MgSO4),
filtered, and concentrated in vacuo. The crude residue was purified
by flash chromatography (4 g SiO2, 20% EtOAc) to provide enone 61
(6.5 L, 80 mol), acetic anhydride (4.0
m
m
m
L, 40 mol), and a catalytic
m
amount of 4-(dimethylamino)pyridine (two crystals). The reaction
mixture was stirred for 16 h at ambient temperature, and then di-
luted with Et2O (10 mL) and saturated aq NH4Cl (10 mL). The layers
were separated, and the aqueous layer was extracted with Et2O
(10 mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated in vacuo. The crude residue was purified by flash
chromatography (2.5 g SiO2, 20% EtOAc) to yield 16.3 mg (97%) of
(75%) as a clear, colorless oil: [
a]
D22þ9.1 (c 1.0, CHCl3); Rf¼0.57 in 50%
EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d
7.66e7.63 (m, 4H),
acetate 64 as a clear, colorless oil: [
a
]
D22þ32 (c 0.93, CHCl3); Rf¼0.50
7.43e7.33 (m, 6H), 7.26 (d, J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz, 2H), 6.82
(dt, J¼15.9, 7.3 Hz, 1H), 6.11 (d, J¼15.9 Hz, 1H), 4.43 (s, 2H),
4.37e4.30 (m, 1H), 4.20 (br s, 1H), 4.10e4.02 (m, 2H), 3.80 (s, 3H),
in 40% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
d 7.66e7.62
(m, 4H), 7.43e7.33 (m, 6H), 7.26 (d, J¼8.6 Hz, 2H), 6.86 (d, J¼8.6 Hz,
2H), 5.70 (ddd, J¼14.6, 7.3, 7.3 Hz, 1H), 5.43e5.31 (m, 2H), 4.42

5096
D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
(s, 2H), 4.19 (m, 1H), 4.11e4.04 (m, 2H), 3.89e3.83 (m, 1H), 3.80
(s, 3H), 3.64e3.56 (m, 3H), 3.51e3.47 (m, 1H), 3.38 (s, 3H), 2.02
(s, 3H), 2.08e1.97 (m, 1H), 1.93e1.86 (m, 2H), 1.82e1.22 (m, 17H),
1.08 (s, 9H), 0.94 (d, J¼5.8 Hz, 3H), 0.86 (d, J¼6.7 Hz, 6H); 13C NMR
21.3, 19.2, 18.3; IR (neat) 3071, 2943, 2859, 2717, 1724, 1620, 1463,
1438, 1355, 1227, 1099, 1025, 819 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e
calcd for C43H64O7SiNa (MþþNa) 743.4319, found 743.4336.
(101 MHz, CDCl3)
d
170.1, 159.0, 135.7, 135.7, 134.3, 134.2, 132.7,
5.1.33. [(2R,4S,6R)-6-{(S)-3-[(2R,3R,6S)-6-((R)-(E)-2-Acetoxy-6-
methyhept-3-enyl)-3-methoxytetrahydropyran-2-yl]-2-
methylpropyl}-4-(tert-butyldiphenylsilanyloxy)-tetrahydropyran-2-yl]
acetic acid (65). To a cold (0 ꢁC) solution of aldehyde (prepared
130.9, 129.7, 129.6, 129.1, 127.6, 113.7, 73.8, 72.6, 71.9, 71.6, 69.2, 68.1,
67.3, 67.3, 66.4, 56.5, 55.3, 41.5, 39.6, 39.4, 39.0, 38.6, 36.8, 36.5,
34.6, 28.1, 28.1, 27.0, 26.9, 22.2, 22.2, 21.4, 19.3, 18.4; IR (neat) 3076,
2943, 2854, 1724, 1620, 1507, 1473, 1424, 1360, 1232, 1114, 1035,
819 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for C51H74O8SiNa
(MþþNa) 865.5051, found 865.5089.
above) (15.6 mg, 21.6
(400 L; 1:1 by volume) was added 2-methyl-2-butene (79
135 L of a pre-mixed oxidant solution (prepared by dissolving
35.2 mg sodium chlorite and 41.4 mg sodium dihydrogen phos-
phate in 270 L of water). The reaction mixture was stirred for
mmol) in a mixture of CH3CN tert-butanol
m
mL) and
m
5.1.31. Acetic acid (R)-(E)-1-((2S,5S,6R)-6-{(R)-3-[(2R,4R,6S)-4-(tert-but
yldiphenylsilanyloxy)-6-(2-hydroxyethyl)tetrahydropyran-2-yl]-2-
methoxypropyl}-5-methyltetrahydropyran-2-ylmethyl)-5-methylhex-
m
30 min at 0 ꢁC, and then diluted with Et2O (10 mL). The organic
solution was washed with water (15 mL), saturated aq Na2S2O3
(10 mL), and saturated aq NaCl (10 mL). The combined aqueous
layers were extracted with Et2O (2ꢂ15 mL). The combined organic
layers were dried (Na2SO4), filtered, and concentrated in vacuo. The
crude residue was purified by flash chromatography (2.5 g SiO2,
40% EtOAc) to yield 8.9 mg (56%) of carboxylic acid 65 as a clear,
2-enyl ester. To a solution of the PMB ether 64 (18.5 mg, 21.9
CH2Cl2 (1.8 mL), pH 7 phosphate buffer (450 L), and tert-butanol
(45 L) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(14.9 mg, 65.8 mol). The reaction mixture was stirred for 1.5 h at
mmol) in
m
m
m
ambient temperature, and then diluted with Et2O (15 mL). The or-
ganic solution was washed with water (2ꢂ10 mL) and saturated aq
NaHCO3 (15 mL). The combined aqueous layers were extracted with
Et2O (15 mL). The combined organic layers were dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude residue was purified by
flash chromatography (2.5 g SiO2, 30% EtOAc) to yield 16.1 mg (100%)
of primary C1-alcohol from 64 as a clear, colorless oil: [a]D22þ32 (c 0.79,
CHCl3); Rf¼0.41 in 50% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
colorless oil: [
a]
D
22þ39 (c 0.45, CHCl3); Rf¼0.43 in 50% EtOAc/hex-
anes; 1H NMR (400 MHz, CDCl3)
d 7.64e7.62 (m, 4H), 7.45e7.35 (m,
6H), 5.73 (ddd, J¼14.3, 7.3, 7.3 Hz, 1H), 5.45e5.35 (m, 2H),
4.34e4.30 (m, 1H), 4.19 (m, 1H), 4.02e3.97 (m, 2H), 3.66e3.61 (m,
1H), 3.46e3.42 (m, 1H), 3.37 (s, 3H), 2.44e2.33 (m, 2H), 2.21e2.15
(m, 1H), 2.10 (s, 3H), 1.90 (t, J¼7.0 Hz, 2H), 1.87e1.25 (m, 15H), 1.08
(s, 9H), 0.89 (d, J¼5.8 Hz, 3H), 0.86 (d, J¼6.4 Hz, 6H); 13C NMR
d
7.65e7.63 (m, 4H), 7.44e7.34 (m, 6H), 5.70 (ddd, J¼15.3, 7.3, 7.3 Hz,
(101 MHz, CDCl3) d 172.4, 171.8, 135.7, 134.0, 133.9, 132.8, 129.8,
1H), 5.41 (dd, J¼15.3, 7.0 Hz, 1H), 5.34e5.29 (m, 1H), 4.20 (m, 1H),
4.16e4.11 (m, 1H), 4.08e4.04 (m, 1H), 3.98e3.92 (m, 1H), 3.86e3.76
(m,1H), 3.74e3.62 (m, 2H), 3.50e3.43 (m,1H), 3.39 (s, 3H), 3.27e3.22
(m,1H), 2.11e1.99 (m,1H), 2.03 (s, 3H),1.90 (t, J¼7.0 Hz, 2H),1.84e1.74
(m, 2H),1.72e1.22 (m,15H),1.08 (s, 9H), 0.92 (d, J¼6.1 Hz, 3H), 0.86 (d,
129.7, 129.5, 127.7, 127.6, 73.7, 71.9, 71.2, 69.4, 69.1, 67.9, 65.9, 56.3,
41.5, 41.3, 40.3, 39.4, 39.1, 38.3, 35.6, 35.4, 28.7, 28.0, 27.4, 22.3, 22.2,
21.5, 19.2, 18.3; IR (neat) 3366 (br), 3081, 2953, 1738, 1635, 1453,
1433, 1374, 1227, 1124, 1040 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd
for C43H64O8SiNa (MþþNa) 759.4269, found 759.4268.
J¼6.7 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d 170.2, 135.7, 134.2, 132.8,
129.6,127.6, 73.8, 71.7, 71.5, 70.5, 68.9, 67.9, 66.3, 59.5, 56.4, 41.5, 39.3,
39.0, 39.0, 38.4, 37.9, 35.9, 35.2, 28.4, 28.1, 27.1, 27.0, 22.2, 22.2, 21.3,
19.3, 18.2; IR (neat) 3430, 3066, 2933, 2864, 1748, 1620, 1463, 1424,
1384,1252,1119,1040, 819 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for
C43H66O7SiNa (MþþNa) 745.4476, found 745.4499.
5.1.34. (1R,3R,5R,7S,9R,13R,15S,18S)-7-(tert-Butyldiphenylsilany-
loxy)-3-methoxy-18-methyl-13-((E)-4-methylpent-1-enyl)-
12,19,20-trioxatricyclo[13.3.1.10,0]eicosan-11-one (66). To a solution
of carboxylic acid 65 (8.9 mg, 12.1 mmol) in MeOH (1.2 mL) was
added potassium carbonate (109 mg, 0.79 mmol). The suspension
was stirred for 16 h at ambient temperature, and then diluted with
pH 4 buffer (10 mL). The aqueous solution was extracted with EtOAc
(3ꢂ10 mL). The combined organic layers were dried (Na2SO4), fil-
tered, and concentrated in vacuo. The seco-acid (C17 hydroxy of 65)
was carried onto the next step without additional purification.
To a solution of the seco-acid in benzene (120 mL) were added
triethylamine (0.10 mL, 0.75 mmol), 2,4,6-trichlorobenzoyl chlo-
5.1.32. Acetic acid (R)-(E)-1-((2S,5S,6R)-6-{(R)-3-[(2R,4S,6R)-4-(tert-
butyldiphenylsilanyloxy)-6-(2-oxoethyl)tetrahydropyran-2-yl]-2-met
hoxypropyl}-5-methyltetrahydropyran-2-ylmethyl)-5-methylhex-2-
enyl ester. To a solution of alcohol, prepared from 64 as described
above, (15.8 mg, 21.9
bicarbonate (9.2 mg, 0.11 mmol) and DesseMartin periodinane
(13.9 mg, 32.8 mol). The mixture was stirred for 1.5 h at ambient
mmol) in CH2Cl2 (300 mL) were added sodium
m
ride (79 mL, 0.51 mmol), and 4-(dimethylamino)pyridine (15 mg,
temperature, and then quenched with saturated aq Na2S2O3. After
stirring for an additional 10 min, the mixture was then diluted with
Et2O (15 mL) and saturated aq NH4Cl (15 mL). The layers were
separated and the aqueous layer extracted with Et2O (15 mL). The
combined organic layers were dried (MgSO4), filtered, and con-
centrated in vacuo. The crude residue was purified by flash chro-
matography (3.5 g SiO2, 20% EtOAc) to yield 15.6 mg (99%) of the
0.12 mmol). The reaction mixture was stirred for 1 h at ambient
temperature, and then more DMAP (15 mg, 0.12 mmol) was added.
The solution was then stirred for 20 h, and subsequently quenched
with aqueous 0.1 M NaHSO4 (100 mL). The aqueous solution was
extracted with CH2Cl2 (2ꢂ100 mL). The combined organic layers
were dried (MgSO4), filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography (2.5 g SiO2, 15%
EtOAc) to yield 5.2 mg (63% for two steps) of macrolactone 66 as
corresponding aldehyde as a clear, colorless oil: [
a
]
22þ34 (c 0.71,
D
CHCl3); Rf¼0.67 in 50% EtOAc/hexanes; 1H NMR (400 MHz, CDCl3)
a colorless film: [
a
]
D
22þ44 (c 0.26, CHCl3); Rf¼0.59 in 50% EtOAc/
d
9.79 (t, J¼2.4 Hz, 1H), 7.66e7.63 (m, 4H), 7.45e7.35 (m, 6H), 5.69
hexanes; 1H NMR (400 MHz, CDCl3)
d 7.65e7.63 (m, 4H), 7.46e7.35
(ddd, J¼14.7, 7.0, 7.0 Hz, 1H), 5.40 (dd, J¼14.7, 7.0 Hz, 1H), 5.37e5.31
(m, 1H), 4.49e4.43 (m, 1H), 4.21e4.13 (m, 2H), 3.90e3.85 (m, 1H),
3.64e3.61 (m, 1H), 3.48e3.44 (m, 1H), 3.37 (s, 3H), 2.46 (d of A of
ABX, JAB¼16.0 Hz, JAX¼8.8 Hz, J¼3.0 Hz, 1H), 2.34 (d of B of ABX,
JAB¼16 Hz, JBX¼4.3 Hz, J¼2.1 Hz,1H), 2.05e1.98 (m,1H), 2.02 (s, 3H),
1.78e1.25 (m, 15H), 1.09 (s, 9H), 0.93 (d, J¼6.1 Hz, 3H), 0.86 (d,
(m, 6H), 5.72 (ddd, J¼15.0, 7.07.0 Hz, 1H), 5.41 (dd, J¼15.0, 6.7 Hz,
1H), 5.38e5.32 (m, 1H), 4.36e4.26 (m, 2H), 3.95e3.90 (m, 3H), 3.67
(t, J¼10.4 Hz, 1H), 3.54 (t, J¼10.4 Hz, 1H), 3.34 (s, 3H), 2.52e2.44 (m,
2H), 2.28e2.22 (m, 1H), 2.00e1.24 (m, 15H), 1.19 (d, J¼7.0 Hz, 3H),
1.11 (s, 9H), 1.10e1.00 (m, 2H), 0.86 (d, J¼6.7 Hz, 6H); 13C NMR
(101 MHz, CDCl3)
d 169.9, 135.6, 135.6, 134.0, 132.1, 130.2, 129.9,
J¼6.4 Hz, 6H); 13C NMR (101 MHz, CDCl3)
d
202.2, 170.1, 135.7, 134.0,
129.8, 127.7, 73.6, 73.5, 70.7, 69.5, 69.4, 66.3, 63.2, 57.3, 43.2, 43.1,
41.6, 39.0, 38.6, 38.6, 35.6, 30.9, 28.1, 27.2, 27.0, 24.1, 22.3, 19.4, 18.2;
IR (neat) 3066, 2948, 2849, 1738, 1655, 1556, 1468, 1419, 1261, 1109,
132.6, 129.7, 127.6, 73.7, 71.9, 71.5, 68.4, 67.6, 67.4, 66.0, 56.5, 49.6,
41.5, 39.1, 39.1, 38.7, 38.6, 36.7, 34.7, 28.2, 28.1, 27.0, 26.9, 22.2, 22.2,

D.R. Williams et al. / Tetrahedron 67 (2011) 5083e5097
5097
1060, 1045, 834 cmꢀ1; HRMS (FAB, NBA, Naþ) m/e calcd for
C41H60O6SiNa (MþþNa) 699.4057, found 699.4085.
6. (a) Williams, D. R.; Plummer, S. V.; Patnaik, S. Angew. Chem., Int. Ed. 2003, 42,
3934; (b) For a second-generation synthesis: Williams, D. R.; Plummer, S. V.;
Patnaik, S. Org. Lett. 2003, 5, 5035.
7. (a) Williams, D. R.; Moore, J. L.; Yamada, M. J. Org. Chem. 1986, 51, 3916;
(b) Moore, J. L. Total Synthesis of Pseudomonic Acid C. Ph.D. Thesis, Indiana
University, Bloomington, Indiana, 1988.
8. Williams, D. R.; Clark, M. P.; Berliner, M. A. Tetrahedron Lett. 1999, 40, 2287.
9. Corey, E. J.; Yu, C.-M.; Kim, S. S. J. Am. Chem. Soc. 1989, 111, 5495.
10. Williams, D. R.; Brooks, D. A.; Meyer, K. G.; Clark, M. P. Tetrahedron Lett. 1998, 39,
7251.
11. Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc. 1999, 121, 4924.
12. Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123, 765.
13. Williams, D. R.; Kiryanov, A. A.; Emde, U.; Clark, M. P.; Berliner, M. A.; Reeves, J.
T. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12058.
5.1.35. Leucascandrolide A macrolactone (2). To a solution of the
silyl ether 66 (10.4 mg, 15.2
mmol) in THF (250 mL) was added TBAF
(200 L of a 1.0 M solution in THF). The light brown solution was
m
stirred for 16 h at ambient temperature, and then diluted with EtOAc
(15 mL) and saturated aq NaCl (15 mL). The layers were separated,
and the aqueous layer extracted with EtOAc (15 mL). The combined
organic layers were dried (MgSO4), filtered, and concentrated in
vacuo. The crude residue was purified by flash chromatography (1 g
SiO2, 60% EtOAc/hexanes) to give 4.4 mg (67%) of the Leucascan-
14. The preparation of epoxide 19 utilized (R)-epichlorohydrin (97% ee, Aldrich) by
adapting the earlier reports of Seebach, co-workers. Seebach, D.; Willert, I.;
D20
drolide A macrolactone 2, which was characterized as follows: [
a
]
€
Beck, A. K.; Grobel, B.-T. Helv. Chim. Acta 1978, 61, 2510.
þ23 (c 0.22, EtOH), lit.2
[a]D
20þ24 (c 0.05, EtOH); Rf¼0.17 in 60%
15. (a) Nishiyama, H.; Yokoyama, H.; Narimatsu, S.; Itoh, K. Tetrahedron Lett. 1982,
23, 1267; (b) Trost, B. M.; Grese, T. A.; Chan, D. M. T. J. Am. Chem. Soc. 1991, 113,
7350.
EtOAc/hexanes; 1H NMR (500 MHz, C5D5N)
d 6.38 (s, 1H, eOH),
5.82e5.74 (m, 2H), 5.56 (dd, J¼15.9, 6.9 Hz, 1H), 4.65 (app t,
J¼11.4 Hz, 1H), 4.43 (m, 1H), 4.19 (t, J¼11.4 Hz,1H), 4.07 (d, J¼11.6 Hz,
1H), 3.94 (t, J¼10.7 Hz, 1H), 3.76 (t, J¼10.9 Hz, 1H), 3.39 (s, 3H), 2.69
(ABq, J¼13.0, 3.7 Hz, 1H), 2.54e2.47 (m, 2H), 2.15e2.10 (m, 1H),
1.96e1.83 (m, 5H), 1.76e1.61 (m, 3H), 1.55e1.48 (m, 2H), 1.44e1.18
(5H), 1.09 (d, J¼7.0 Hz, 3H), 1.10e1.02 (m, 1H), 0.80 (d, J¼6.6 Hz, 3H),
16. Piers, E.; Chong, J. M.; Gustafson, K.; Anderson, R. J. Can. J. Chem. 1984, 62, 1.
17. For information regarding the preparation of 21: Williams, D. R.; Kammler, D.
C.; (4R,5R)-2-Bromo-1,3-bis[(4-methylphenyl)sulfonyl]-4,5-diphenyl-1,3,2-dia-
zaborolidine. e-EROS Encyclopedia of Reagents for Organic Synthesis [Online];
John Wiley & Sons, Ltd., Posted October 15, 2002. http://onlinelibrary.wiley.
com/o/eros/articles/rn00115/frame.html.
18. For an example procedure: Bunnelle, W. H.; Narayanan, B. A. Org. Synth. 1990,
69, 89.
0.79 (d, J¼6.6 Hz, 3H); 13C NMR (101 MHz, C5D5N)
d 170.3, 131.9,
19. White, J. D.; Reddy, G. N.; Spessard, G. O. J. Am. Chem. Soc. 1988, 110, 1624.
20. The chiral oxirane building block 34 was conveniently produced via the known
reduction of d-malic acid (i). See: Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan,
A. Can. J. Chem. 1984, 62, 2146; Selective conversion of (R)-1,2,4-butanetriol to
the primary tert-butyldimethylsilyl ether ii utilized the published dibutyl-
stannanediyl acetal method. See: Leigh, D.; Martin, R. P.; Smart, J. P.; Truscello,
A. M. J. Chem. Soc., Chem. Commun. 1994, 1373 Monotosylation and treatment
with NaH provided 34 in excellent overall yield.
131.6, 73.9 (2C), 70.9, 69.9, 69.7, 63.8, 63.2, 56.7, 44.0, 43.4, 41.8, 40.0,
39.7, 39.5, 35.9, 31.4, 28.3, 27.4, 24.3, 22.3 (2C), 18.5; IR (neat) 3420,
2963, 2869, 1738, 1460, 1389, 1281, 1188, 1153, 1084, 1060 cmꢀ1; MS
(DEI) 438 (6), 329 (21), 208 (11), 165 (15), 159 (40), 142 (24), 121 (10),
111 (30), 95 (64), 93 (45), 87 (29), 81 (60), 79 (56), 71 (33); HRMS m/e
calcd for C25H42O6 (Mþ) 438.2961, found 438.2961. The comparisons
of our data with those reported by Leighton and co-workers5a for 2
confirms these materials as identical.
1) BH3 DMS, (MeO)3B
THF, 100%
O
HO
OH
HO
O
O
2) Bu2SnO, MeOH
Sn
Bu Bu
OH
O
80
C
i
then TBSŠCl
CHCl3, 100%
Acknowledgements
1) TsCl, Et3N, DMAP
CH2Cl2, Š10
82%
C
The authors gratefully acknowledge the National Institutes of
Health (GM042897) for the generous support of our work.
OTBS
OTBS
HO
O
H
2) NaH, DMF, 1 h
97%
OH
ii
34
.
References and notes
21. Comins, D.; Dehghani, A. Tetrahedron Lett. 1992, 33, 6299.
22. Busacca, C. A.; Eriksson, M. C.; Fiaschi, R. Tetrahedron Lett. 1999, 40, 3101
Contrary to the results reported in this paper, we found Ni(acac)2 to be an
efficient catalyst for the conversion of the enol triflate to allylsilane 38.
23. For a review of SE0 reactions of allylic stannanes with achiral and nonracemic
1. For leading references: (a) Alvi, K. A.; Peters, B. M.; Hunter, L. M.; Crews, P.
Tetrahedron 1993, 49, 329; (b) Crews, P.; Clark, D. P.; Tenney, K. J. Nat. Prod. 2003,
66, 177; (c) Ciminiello, P.; Fattorusso, E.; Mangoni, A.; Di Blasio, B.; Pavone, V.
Tetrahedron 1990, 46, 4387; (d) Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron
1989, 45, 2193; (e) Akee, R. K.; Carroll, T. R.; Yoshida, W. Y.; Scheuer, P. J. J. Org.
Chem. 1990, 55, 1944.
0
aldehydes: Williams, D. R.; Nag, P. P. Reactions of SE substitution for organo-
stannanes in organic synthesis In Tin Chemistry e Fundamentals, Frontiers and
Applications; Davies, A. G., Gielen, M., Pannell, K. H., Tiekink, E. R. T., Eds.; Wiley:
Chichester, England, 2008; pp 515e560.
2. D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Pietra, F. Helv. Chim. Acta 1996, 79, 51.
ꢁ
3. D’Ambrosio, M.; Tato, M.; Pocsfalvi, G.; Debitus, C.; Pietra, F. Helv. Chim. Acta
24. Evans, D. A.; Dart, M. J.; Duffy, J. L.; Yang, M. G. J. Am. Chem. Soc. 1996, 118, 4322.
25. The model studies of Table 1 have previously been published as part of an
extensive investigation of this SE0 methodology: Williams, D. R.; Meyer, K. G.;
Shamim, K.; Patnaik, S. Can. J. Chem. 2004, 82, 120.
1999, 82, 347.
4. Ulanovskaya, O. A.; Janjic, J.; Suzuki, M.; Sabharwal, S. S.; Schumacker, P. T.;
Kron, S. J.; Kozmin, S. A. Nat. Chem. Biol. 2008, 4, 418.
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I.; Tudge, M. Angew. Chem., Int. Ed. 2003, 42, 343; Paterson, I.; Tudge, M. Tet-
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2002, 41, 4098; Fettes, A.; Carreira, E. M. J. Org. Chem., 68, 9274. (e) Wang, Y.;
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T. Chem. Commun. 2002, 2066; (g) Kopecky, D. J.; Rychnovsky, S. D. J. Am. Chem.
Soc. 2001, 123, 8420; (h) Su, Q.; Panek, J. S. Angew. Chem., Int. Ed. 2005, 44, 1223;
(i) Jung, H. H.; Sieders, J. R.; Floreancig, P. E. Angew. Chem., Int. Ed. 2007, 46,
26. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95, 512; (b) Ohtani, I.;
Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092.
27. (a) Kotsuki, H. Synlett 1991, 97; (b) Ishihara, K.; Mori, A.; Yamamoto, H. Tetra-
hedron 1990, 46, 4595.
28. Williams, D. R.; Lowder, P. D.; Gu, Y.-G. Tetrahedron Lett. 2001, 41, 9397.
29. (a) Terashima, S.; Tanno, N.; Koga, K. J. Chem. Soc., Chem. Commun. 1980, 1026;
(b) Terashima, S.; Tanno, N.; Koga, K. Chem. Lett. 1980, 981; (c) Tanno, N.;
Terashima, S. Chem. Pharm. Bull. 1983, 31, 837.
30. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434.
31. (a) Wipf, P.; Xu, W. Tetrahedron Lett. 1994, 35, 5197; (b) Wipf, P.; Ribe, S. J. Org.
Chem. 1998, 63, 6454.
ꢂ
8464; (j) Ferrie, L.; Reymond, S.; Capdevielle, P.; Cossy, J. Org. Lett. 2007, 9, 2461;
(k) Evans, P. A.; Andrews, W. J. Angew. Chem., Int. Ed. 2008, 47, 5426; (l) Yadav, J.
S.; Pattanayak, M. R.; Das, P. P.; Mohapatra, D. K. Org. Lett. 2011, 13, 1710.
32. For a review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.