Biology-oriented synthesis of stereochemically diverse natural-product- derived compound collections by iterative allylations on a solid support

Article abstract of DOI:10.1002/chem.200601698

A strategy aiming at the introduction of stereocenters into polymer-bound natural-product-derived and -inspired compound collections is presented. Treatment of immobilized aldehydes with Brown's pinene-derived allylboranes results in the stereoselective f

Full text of DOI:10.1002/chem.200601698

FULL PAPER
DOI: 10.1002/chem.200601698
Biology-Oriented Synthesis of Stereochemically Diverse Natural-Product-
Derived Compound Collections by Iterative Allylations on a Solid Support
Jayant D. Umarye,[a, b] Torben Leßmann,[a, b] Ana B. García,[a, b] Victor Mamane,[a, c]
Stefan Sommer,[a] and Herbert Waldmann*[a]
Abstract: A strategy aiming at the in-
troduction of stereocenters into poly-
three allylations on a solid support give
access to 1,3-polyols with different rel-
ative configurations. Esterification with
acryloyl chloride and final ring-closing
metathesis yields a,b-unsaturated d-lac-
tones with multiply oxygenated side
chains, a substructure found in a group
of natural products with a broad range
of biological activity. The flexibility of
the approach is exemplified by the par-
allel synthesis of all eight diastereo-
mers of cryptocarya diacetate on a
solid support. The individual isomers
are obtained in overall yields of 40–
60% over 10 steps and with 63–85%
diastereoselectivity for the major
isomer.
mer-bound
natural-product-derived
and -inspired compound collections is
presented. Treatment of immobilized
aldehydes with Brownꢀs pinene-derived
allylboranes results in the stereoselec-
tive formation of homoallylic alcohols
with up to 89% ee (ee=enantiomeric
excess). Subsequent iterative ozonoly-
sis–allylation sequences with up to
Keywords: 1,3-polyols · asymmetric
synthesis · natural products · solid-
phase synthesis
Introduction
pound collections with a high degree of substituent variation
on a given scaffold. More recently, this concept was extend-
ed leading to molecule architectures with high skeletal di-
versity[2] for diversity-oriented synthesis (DOS)[3] and biol-
ogy-oriented synthesis (BIOS),[4] and of natural-product-de-
rived and -inspired compound collections.[2,4] BIOS refers to
natural products as evolutionary selected starting points for
compound-collection synthesis. Due to their biosynthetic
origin and their manifold interactions with sterically defined
protein structures, natural products exhibit a broad stereo-
chemical complexity. Particularly, multiple stereocenters are
present in many target molecules, which require steroselec-
tive methods for their synthesis. The fact that altering the
stereochemistry of a given molecule can drastically change
its overall shape, and consequently its biological profile, can
be taken as an incentive for diversification. Beyond substitu-
ent and skeleton variation, we hypothesized that a systemat-
ic reconfiguration of individual stereocenters of a given mol-
ecule might be of additional benefit. We felt that the synthe-
sis and biological evaluation of all diastereomeric isomers,
that is, a stereocomplementary synthesis, might further en-
lighten the potency of a molecule in biological assays.
The use of small molecules for the study of biological phe-
nomena lies at the heart of medicinal chemistry and chemi-
cal biology research.[1] To investigate the response of biolog-
ical systems to variations of the chemical structure of a
probe, synthesis strategies for rapid and efficient variation
and diversification of the target compound are in high
demand. Combinatorial chemistry may give access to com-
[a] Dr. J. D. Umarye, Dr. T. Leßmann, Dr. A. B. García, Dr. V. Mamane,
Dr. S. Sommer, Prof. Dr. H. Waldmann
Max-Planck-Institut für Molekulare Physiologie
Abteilung Chemische Biologie, Otto-Hahn-Strasse 11
44227 Dortmund (Germany) and
Universität, Dortmund, Fachbereich 3
Chemische Biologie, Otto-Hahn-Straße 6
44227 Dortmund (Germany)
Fax : (+49)231-133-2499
E-mail: Herbert.Waldmann@mpi-dortmund.mpg.de
[b] Dr. J. D. Umarye, Dr. T. Leßmann, Dr. A. B. García
These authors contributed equally to this work.
[c] Dr. V. Mamane
Current address: Synth›se OrganomØtallique et RØactivitØ, UMR
CNRS-UHP 7565
FacultØ des Sciences et Techniques
UniversitØ Henri PoincarØ Nancy 1
BP 239 Bd des Aiguillettes
However, only in relatively few cases have compound col-
lections been synthesized in which a set of stereochemical
descriptors of a given scaffold was systematically varied to
explore the full stereochemical “descriptor space” of a mol-
ecule. In such synthetic endeavors, powerful enantiocomple-
54506 Vandoeuvre-les-Nancy (France)
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mentary transformations are indispensable which give access
to stereoisomer libraries (for example, all diastereomers) of
a given (natural) product and analogues thereof. Notably,
Tietze et al. introduced stereoselective combinatorial syn-
thesis employing enantiocomplementary chiral catalysts for
the solution-phase synthesis of twelve stereoisomers of em-
etine[5] and Curran and co-workers prepared a sixteen-mem-
bered stereoisomer library of the pinesaw fly sex phero-
mone[6] as well as an eight-membered collection of Passiflor-
icin in solution employing fluorous tagging en route as key
technology.[7] Schreiber and co-workers synthesized a 4320-
membered library of dihydropyrancarboxamides in both en-
antiomeric forms.[8]
For the synthesis of natural-product-inspired and -derived
compound collections[4] solid-phase organic synthesis is a
viable technology. Immobilization of the substrate on a
polymeric carrier enables efficient and straightforward re-
moval of all surplus reagents required in the multistep se-
quences typical for the synthesis of such compound collec-
tions and thereby facilitates purification of the desired com-
pounds.
exist which also have biological activity, such as kurzilactone
(3), which is cytotoxic to KB cells.[17] Many of these small
molecules feature a carbon chain functionalized with at least
one 1,3-diol unit.
In a preliminary communication,[18] we reported our work
on stereocomplementary enantioselective reagent-controlled
carbonyl allylation on the solid phase[19] employing chiral al-
lylboranes[20] and applications to the synthesis of the natural
product cryptocarya diacetate and all its stereoisomers.
Herein, we give a full record on the synthesis of stereo-
chemically diverse 1,3-polyol collections on the solid phase
and their use in the synthesis of different natural products
and analogues thereof. The development of the allylation
method as such on solid support is described in full in an ac-
companying article.[21]
Retrosynthetic Analysis
We planned to synthesize the target structures, such as 4, by
means of a ring-closing metathesis (RCM) reaction of the
open acrylate 5 (Scheme 1). This approach is known from
Thus, we[4,9] and others[10] have used this approach for the
synthesis of different natural-product-derived and -inspired
compound collections in >10 steps on the polymeric carrier.
However, in general, to date only very few enantioselective
synthetic methods have been developed for solid-phase syn-
thesis in general.[11]
For instance, the generation of polyketide-type linear,
functionalized carbon chains on a solid support was accom-
plished by Paterson et al.[12] and our group[13] by using an
aldol-based strategy and by Paneket al. with chiral allylsi-
lanes,[14] but applications of these transformations to the ste-
reocomplementary synthesis of compound collections are
still unknown.
In the context of employing natural-product-inspired com-
pound collections in chemical biology, we became interested
in the synthesis and biological evaluation of natural-prod-
uct-derived molecules which contain an a,b-unsaturated d-
lactone moiety. Such molecules can, for instance, act as Mi-
chael acceptors for nucleophilic protein side chains and dis-
play a broad range of biological properties. Fostriecin 1 is a
Scheme 1. Retrosynthetic analysis of the target dehydrolactones.
different solution-phase approaches towards this class of
molecules.[22] Iterative cycles of allylation, protection, and
ozonolysis should deliver the molecular skeleton, such as 6,
with the correct and predictable stereochemical pattern. The
appropriate starting point of such a sequence would be an
immobilized aldehyde 7. Along with the availability of the
d- and l-enantiomers of Ipc2BAll, the stereochemical space
around the syn/anti-1,3-polyol-based a-pyrone natural prod-
ucts can be explored rapidly once the sequence is establish-
ed on solid support.
Two different linker concepts were considered for applica-
tion in this approach. The acid- and oxidant-labile Wang
linker should be orthogonal to the silyl protecting groups on
the hydroxyl groups of the growing carbon chain. Com-
pounds can be released from the resin and further modified
before final deprotection. Alternatively, attachment to the
resin by means of a silicon-based linker would allow global
deprotection and concomitant release of the final target
compounds from the resin in a single step, delivering the de-
sired molecules after only one purification step.
potent inhibitor of protein phosphatase 2 A,[15] pironetin 2 is
an inhibitor of tubulin assembly.[16] Apart from these rather
complex structures, structurally simpler natural products
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Biology-Oriented Synthesis
FULL PAPER
Establishment of the RCM sequence on the solid support:
In a recent report, we have shown that the asymmetric al-
Alternatively, we made use of a phenyldialkylsilyl
system.[25] Commercial bromopolystyrene resin 12 was lithi-
ated, quenched with diisopropyldichlorosilane and coupled
to the alcohol (Scheme 2B). Ozonolysis of the terminal
double bond led to the desired aldehyde 13 with a loading
of 0.5 mmolgÀ1.[24]
A
hydes, giving rise to homoallylic alcohols that can be con-
verted into compound collections.[21] This methodology
turned out to be applicable also to an iterative approach, re-
sulting in the synthesis of 1,3-syn diols and polyols on sub-
strates that were linked to the polymeric carrier via an ester
bond. This allowed quickrelease of the substrates and
straightforward analysis of the resulting methyl esters; how-
ever, the sensitivity of the a,b-unsaturated d-lactone moiety
towards nucleophiles demanded different modes of substrate
immobilization (Scheme 2). We chose the well-established
Wang-linker 8 as an acid-labile and oxidatively cleavable at-
tachment system. Commercial, enantiomerically pure b-hy-
droxyesters 9 were attached by activation of the linker as a
trichloroaetimidate (Scheme 2A) and subsequent nucleo-
philic substitution by the respective alcohol 9.[23] The immo-
bilized esters were converted to aldehydes 10[9f] by means of
The immobilized aldehydes were treated with the estab-
lished allylation conditions (3 equiv of the chiral allyl boron
reagent, À788C to room temperature, 16 h) and were con-
verted to the corresponding homoallylic alcohols 11 or 14,
as indicated by the disappearance of the carbonyl band at
ꢀ1732 cmÀ1 in the FTIR spectrum. Thereby, the stage was
set for further steps towards the desired a,b-unsaturated d-
lactones. Esterification of the homoallylic alcohols was ach-
ieved with acryloyl chloride in the presence of an amine
base and DMAP (DMAP=4-dimetylaminopyridine) in di-
chloromethane and could be monitored by the appearance
of a carbonyl band at 1732 cmÀ1 in the FTIR spectrum.
Although ring-closing metathesis on these kind of sub-
strates was reported with the use of Grubbs first-generation
a
reduction–oxidation sequence with loadings of
0.7 mmolgÀ1 in the case of primary alcohols and 0.4 to
0.5 mmolgÀ1 in the case of secondary alcohols.[24]
catalyst in solution,[22a,b,d] in some cases Ti
(OiPr)4 is used as
G
an additive[22c] or the more reactive Grubbs second-genera-
tion or Hoveyda–Grubbs cata-
lysts are employed.[7] In the
case of our immobilized sub-
strates, the use of the Grubbs
first-generation catalyst 17
alone was not sufficient to ach-
ieve full conversion of the sub-
strate. Addition of one equiva-
lent of Ti(OiPr)4 led to the de-
G
sired lactone 15 (Scheme 2) in
9% yield (based on the alde-
hyde loading of the resin).
However, the reaction could
be carried out without additive
when catalysts 18 or 19 were
used. As a standard protocol,
the catalyst was added in two
portions of 20 mol% each over
a period of 24 h in refluxing di-
chloromethane. Release of the
compounds was achieved by
subjecting the resins to pyri-
dine-buffered HF (15) or
DDQ
(DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone)
(16).[13b] In the case of lactone
15, an enantiomeric ratio of
94.5:5.5 (89% ee) could be de-
termined by GC analysis on a
chiral Lipodex E column.
Having found conditions for
the RCM, we were able to
generate a first set of small
molecules bearing the a,b-un-
saturated d-lactone moiety
Scheme 2. Establishment of the allylation/RCM sequence on a solid support. A) synthesis on Wang resin.
B) synthesis on a diisopropylsilyl resin. a) Resin 8 (1.2 mmolgÀ1), trichloroacetonitrile, DBU, CH2Cl2, then 9,
BF3·OEt2, cyclohexane/CH2Cl2; b) DIBAL-H, THF, À788C to RT, 16 h, c) IBX, DMSO/THF, RT, 16 h; d) i) d-
Ipc2BAll (3 equiv), THF, À788C; ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1:1, 08C, 2 h; e) nBuLi (6 equiv),
toluene, 608C, 15 h; f) iPr2SiCl2 (2 equiv), THF, 08C to RT, 2 h; g) DMAP (0.5 equiv), 2,6-lutidine (5 equiv), 4-
pentene-1-ol (3 equiv), CH2Cl2, RT, 15 h; h) O3, CH2Cl2, À788C then PPh3 (5 equiv), À788C to RT, 12 h;
i) acryloyl chloride (5 equiv), NEt3 (5 equiv), cat. DMAP, CH2Cl2, 08C to RT, 16 h; j) 17 (2”20 mol%), Ti-
A
THF, RT, 8 h; m) 18 (2”20 mol%), CH2Cl2, reflux, 24 h; n) DDQ (10 equiv), CH2Cl2, pH 7 buffer, 08C to RT,
16 h. DIBAL-H=diisobutylaluminium hydride; IBX=o-iodoxybenzoic acid.
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3307

H. Waldmann et al.
(Table 1). Interestingly, for aldehydes bearing an a-stereo-
center, the anti-directed allylation gave rise to higher selec-
tivity than the syn-directed transformation (entry 2
versus 3). As expected, the sequence worked equally well
for crotylated compounds (entry 6 and 7).
After the RCM reaction, the resin usually had turned
brown to blackbecause of the adsorption of ruthenium par-
ticles. After cleavage, the ruthenium content of the product
was still high (indicated by the brown color of the crude
product), but careful flash chromatography or preparative
HPLC served to remove the ruthenium.
Synthesis of euscapholide and all stereoisomers of cryptocar-
ya diacetate: With these results in hand, we approached the
synthesis of natural products and their stereoisomers. Eusca-
pholide (20) (Scheme 3) is a small pyrone natural product
which was isolated from the leaves of Euscaphis japonica.[26]
Compound 20 is the enantiomer of the lactone substructure
of tarchonathuslactone 21.[27] The synthesis of ent-20 fol-
lowed the route described above and delivered the desired
product in 44% overall yield from 10d and with a syn/anti
ratio of 92:8 (determined by integration of the methyl group
Scheme 3. Synthesis of ent-euscaphlide on
(10 equiv), CH2Cl2, pH 7 buffer, 08C to RT, 16 h.
a
solid support. a) DDQ
The absolute configuration of ent-20 was deduced from
the comparison of the specific rotation [a]2D0 =À100 (c=1.37
in MeOH) measured for synthetic ent-20 with the reported
value for the isolated natural product euscapholide (20)
([a]3D0 =+115.5 (c=1.52 in MeOH).[26]
1
signals in the H NMR spectrum).
Table 1. Asymmetric allylation and crotylation of immobilized aldehydes according to Scheme 2.
Entry
Aldehyde
Reagent
Alcohol
Lactone
Yield [%][a]
30
dr[b]
1
d-Ipc2BAll
–
2
3
d-Ipc2BAll
l-Ipc2BAll
28
18
90:10
80:20
4
5
l-Ipc2BAll
l-Ipc2BAll
34
37
90:10
80:20
6
7
l-Ipc2B(E-)Crot
l-Ipc2B(E-)Crot
38
48
95:5
95:5
1
[a] Isolated yield. [b] Determined by integration of the signals recorded for the methyl groups in the H NMR spectrum.
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Biology-Oriented Synthesis
FULL PAPER
This synthesis describes also the assembly of the stero-
were acylated with acryloyl chloride and then treated to the
RCM protocol by using catalyst 18. The immobilized lac-
tones 32–35 were released from the solid support in two dif-
ferent ways.
chemically demanding alcohol of tarchonanthuslactone 21[27]
and further confirms that the allylation on solid support pro-
G
ceeds with the same sense of induction as in solution-phase
synthesis.
Acidic conditions (TFA/dichloromethane 1:2, 20 min) did
not only lead to release from the solid support, but also to
partial deprotection. When immobilized compound 32 was
treated in this way, the resulting diol could be isolated by fil-
tration through a short silica column. It was acetylated to
give a diastereomeric mixture of products, from which the
major all-syn isomer 23 was isolated by careful flash chro-
matography in 11% overall yield after a total of 11 steps.
Comparison of the specific rotation of 23 ([a]2D0 =47.2 (c=
0.5 in CHCl3)) with literature data for the synthetic material
([a]2D9 =45.4 (c=0.33 in CHCl3),[28b] [a]2D0 =47.5 (c=0.6 in
CHCl3)[28c] and the isolated natural product [a]2D5 =55.8 (c=
1.06 in CHCl3)[28a] confirmed the absolute configuration.
Accordingly, the three non-natural stereoisomers of cryp-
tocarya diacetate 37, 39, and 41 were obtained following
identical cleavage and acetylating conditions.
In a different approach, the compounds could be released
by oxidative treatment of the resin with DDQ. In these
cases, the TBS (TBS=tert-butyldimethylsilyl) protecting
groups were not affected by the cleavage procedure, and
monoprotected compounds 36, 38, 40, and 42 could be iso-
lated in high overall yields (40–60% after a total of 10
steps).
The successful synthesis of ent-20 on solid support demon-
strated the applicability of the allylation and RCM sequence
to the synthesis of natural products and prompted us to
carry out the iterative allylation and ozonolysis sequence for
the generation of a natural-product-derived compound col-
lection. Cryptocarya diacetate 23[28] (Scheme 4), a natural
product isolated from the African tree Cryptocarya latifolia,
was chosen as the target. It embodies an a,b-unsaturated d-
lactone moiety and two additional acetoxy groups, all in rel-
ative syn configuration. Moreover, we strived to synthesize
all stereoisomers of the polyol frameworkpresent in the nat-
ural product by using the appropriate combinations of the
chiral allyl boranes.
Towards this end, aldehyde ent-10d (Scheme 4), obtained
by the same sequence as delineated above, underwent allyla-
tion with l- and d-Ipc2BAll and afforded diols 24 (syn/anti
1
ratio of 90:10, determined by H NMR spectroscopic analy-
sis after release from the polymeric carrier) and 25 (syn/anti
ratio of 20:80). The immobilized homoallylic alcohols were
protected as TBS ethers and subsequently transformed to al-
dehydes 26 and 27 by careful ozonolysis for six minutes. A
second allylation was performed with both of the enantio-
mers of Ipc2BAll and yielded triols 28, 29, 30, and 31, which
Scheme 4. Stereocomplementary synthesis of all (4’S)-isomers of cryptocarya diacetate. a) i) l-Ipc2BAll (3 equiv), THF, À788C; ii) pH 7 buffer, H2O2
30%, DMF/MeOH 1:1, 08C, 2 h; b) i) d-Ipc2BAll (3 equiv), THF, À788C; ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1:1, 08C, 2 h; c) TBSCl, imidazole,
cat. DMAP, CH2Cl2, RT, 16 h; d) O3, CH2Cl2, À788C, then PPh3, À788C to RT; e) acryloyl chloride, DIPEA, cat. DMAP, CH2Cl2, 08C to RT, 16 h;
f) Grubbs second-generation catalyst (2”20 mol%) (18), CH2Cl2, reflux, 24 h; g) i) trifluoroacetic acid/CH2Cl2 1:2, 20 min, RT; (ii Ac2O, NEt3, cat.
DMAP, CH2Cl2, 08C to RT, 3 h; h) DDQ (10 equiv), CH2Cl2, pH 7 buffer, 08C to RT, 16 h; DIPEA=diisopropyl ethyl amine.
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H. Waldmann et al.
In all cases, flash chromatography provided the major
isomer of the acylated compounds in pure form with yields
ranging from 10 to 20%, and with generally more than 90%
purity in the case of the TBS-protected compounds.
Starting from aldehyde 10d, the enantiomeric series of
compounds was synthesized in an analogous way to that de-
scribed above. Following this route, we could enlarge our
compound collection with four diastereomers of 23 and
TBS-protected analogues (Figure 1).[29] Further, the released
whereas the other isomers showed lower stereoisomer
ratios.
In summary, starting from two resin-bound enantiomeric
aldehydes 10d and ent-10d, we could rapidly access all iso-
mers of cryptocarya diacetate 23 in high overall yields.
Finally, this route could be further extended to obtain
compound 49 (Scheme 5) which represents a selectively pro-
tected version of a stereoisomeric analogue of the natural
product cryptocarya triacetate 50.[28a,b,30] The synthesis of
compound 49 required a total
of 14 consecutive steps on the
polymeric carrier including
three stereoselective carbonyl
allylation reactions. It was ob-
tained in stereoisomerically
pure form in an overall yield
of 1.6 mg (2%) after chroma-
tographic purification. The de-
crease in yield might be attrib-
uted to partial release of the
substrate during the repeated
Figure 1. (4’R)-isomers of cryptocarya diacetate (see Table 2 for yields and diastereomeric ratios).
A
ozonolysis reactions.
TBS-protected analogues could be transformed in solution-
phase synthesis to their corresponding diol lactones 50, 51,
52, and 53 by treating them with PPTS (PPTS=pyridinium
p-toluene sulfonic acid) in refluxing aqueous MeOH in 50 to
90% yield.
1H NMR spectroscopic analysis of the crude monoprotect-
ed products allowed the determination of the diastereomer
ratio. The isomer distributions of all reaction products are
summarized in Table 2. The first allylation of 10d with d-
Table 2. Results of the synthesis of stereoisomers.
Entry
Compound
(config.)
Yield
[%][a]
Ratio syn/syn-36:syn/anti-38:
anti/syn-40:anti/anti-42[b]
ACHTREUNG
1
2
3
4
5
6
7
8
36 (4’S,2’S,6R)
38 (4’S,2’S,6S)
40 (4’S,2’R,6R)
42 (4’S,2’R,6S)
40
50
57
60
42
67
50
42
ꢁ80:ꢂ5:13:2
18:67:1:14
13:2:77:8
Scheme 5. Synthesis of a diastereomeric analogue of cyrptocarya triace-
tate on a solid support. a) acryloyl chloride, NEt3, cat. DMAP, CH2Cl2,
08C to RT, 16 h; b) 19 (2”20 mol%), CH2Cl2, reflux, 24 h; c) DDQ
(10 equiv), CH2Cl2, pH 7 buffer, 08C to RT, 16 h.
2:13:5:80
ent-36 (4’R,2’R,6S)
ent-38 (4’R,2’R,6R)
ent-40 (4’R,2’S,6S)
ent-42 (4’R,2’S,6R)
ꢁ85:ꢂ=5:7:3
27:63:6:9
13:2:63:22
2:13:10:75
Synthesis of natural products isolated from Ravensara ani-
sata and their stereoisomers: The potential of this method
can be further demonstrated by the rapid synthesis of sever-
al natural products and their steroisomers from a single im-
mobilized precursor. (6S)-5,6-Dihydro-6-[(2R)-2-hydroxy-6-
phenylhexyl]-2H-pyran-2-one 51 was isolated by Hostett-
mann and co-workers from the tree Ravensara crassifolia.[31]
[a] Isolated overall yield based on the loading of aldehyde 16. [b] Deter-
mined by integration of the signals of the protons at C-6, C-4’, and C-2’
in the 500 MHz H NMR spectrum.
1
Ipc2BAll gave a 90:10 ratio of syn/anti selectivity, whereas
the allylation of 10d with l-Ipc2BAll gave an 80:20 ratio of
anti/syn isomers. Thus, the 1,3-syn stereochemical pattern is
the matched case and the 1,3-anti isomer is the mismatched
case. A similar trend was also observed for the second al-
A
final products. As a result, all-syn-hydroxyl-derived com-
pounds 36 and ent-36 showed good diastereomeric purity
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Biology-Oriented Synthesis
FULL PAPER
It exhibits antifungal activity against the phytopathogenic
fungus Cladosporium cucumarinum in a bioautographic
TLC assay. The closely related natural products 52 and 53
were isolated from leaves and barkextract from Ravensara
anisata.[32]
The synthesis of these natural products and their ana-
logues was conducted on both Wang and silyl linker. It start-
ed with the solution-phase synthesis of the homoallylic alco-
hols (R)- and (S)-55 (Scheme 6), which were synthesized in
suitable (entry 2). However, application of the Nokami
crotyl transfer agent (S)-56 delivered the desired product in
a straightforward way in high selectivity (entry 3).
Synthesis on Wang resin: The allylic alcohol (S)-55 (obtained
by allylation with l-Ipc2BAll, Table 3, entry 1) was immobi-
lized on Wang imidate to afford resin 57 (Scheme 7). The
resin-bound allylic alcohol 57 was converted to the corre-
sponding aldehyde by ozonolysis, leading to an aldehyde
loading of 0.5 mmolgÀ1.[23] Sub-
sequent allylation resulted in
the homoallylic alcohol 58,
which was acylated with
acryloyl chloride and under-
went RCM by using catalyst 18
to yield the resin-bound lac-
tone. Subsequent release of the
substrate by using TFA
Scheme 6. Asymmetric allylation of aldehyde 61.
(TFA=trifluoroacetic acid) af-
forded unsaturated d-lactone
[33]
solution by applying l-Ipc2BAll, a Keckallylation,
or the
ent-51 in 31% overall yield with high diastereoselectivity
(syn/anti ratio 91:9). The absolute configuration of synthetic
ent-51 was determined by comparison of the specific rota-
tion measured for ent-51 ([a]2D0 =+66 (c=1.0 in CHCl3))
with literature data for synthetic 51 ([a]D =À66 (c=2 in
CHCl3).[31a]
Nokami crotyl-transfer method[34] (Table 3). In our hands,
the use of a Ti-BINOL (BINOL=1,1’-bi-2-naphthol) cata-
lyst furnished variable results with respect to yield and se-
lectivity, but after some experimentation, reaction condi-
tions recently reported by Kurosu et al.[33b] turned out to be
Furthermore, the resin-
bound allylic alcohol 58 was
Table 3. Asymmetric allylation of aldehyde 61.
protected as a TBS ether after
the first allylation. Another
ozonolysis/allylation cycle with
l-Ipc2BAll delivered alcohol
59, which was further trans-
formed and finally released
with TFA or DDQ to yield un-
saturated d-lactones 60 and 61,
respectively. The diol lactone
Entry Reagent
Product Conditions Yield [%][a] er
(R/S)[b]
AHCTREUNG
1
2
l-IpcBAll
Bu3Sn(allyl), 5 mol% Ti(OiPr)4, 10 mol%, (S)-BINOL,
55a
55a
À1008C, 6 h
À158C, 38 h
73
67
3:97
98:2
A
G
toluene, MS 4 Š
3
(S)-56
55b
RT, 18 h
70
<1:99[c]
[a] Isolated yield. [b] Determined by HPLC on a Daicel ChirapakAD column, flow 0.5 mLmin À1, hexane/iso-
propanol 97:3. [c] Determined by HPLC as above, hexane/isopropanol 98:2.
Scheme 7. Iterative allylations in the synthesis of natural-product-derived compounds on a solid support. a) O3, CH2Cl2, À788C, then PPh3, À788C to RT;
b) i) l-Ipc2BAll (3 equiv), THF, À788C; ii) pH 7 buffer, H2O2 30%, DMF/MeOH 1:1, 08C, 2 h; c) acryloyl chloride, DIPEA, cat. DMAP, CH2Cl2, 08C to
RT, 16 h; d) 25 (2”20 mol%), CH2Cl2, reflux, 24 h; e) TFA/CH2Cl2, RT, 15 min; f) TBSCl, imidazole, cat. DMAP, CH2Cl2, RT, 16 h; g) DDQ, CH2Cl2,
pH 7 buffer, 08C to RT, 16 h; h) TBSOTf, 2,6-lutidine, CH2Cl2, 08C to RT, 10 h.
Chem. Eur. J. 2007, 13, 3305 – 3319
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3311

H. Waldmann et al.
chromatographic purification on silica with an overall yield
of 4% after 11 linear steps on the solid support.
Similarly, starting from (R)-57 and applying the iterative
allylation sequence with d-Ipc2BAll (Scheme 8), the TBS-
protected derivative 64 was obtained as a single diastereo-
1
mer (as judged by H NMR spectroscopy) in 10% overall
yield.
Synthesis on a silyl linker: As shown above, attachment of
the substrates via the Wang linker is a successful strategy.
However, while cleavage with DDQ gave rise to the desired
products in a protected form, release of the substrates with
TFA led only to partial deprotection. In order to have sub-
strate release and removal of all protecting groups in one
step, we developed this synthesis also on a silyl linker.
Lithiated PS resin[23] was quenched with dichlorodiethylsi-
lane (Scheme 9) and subsequently loaded with (5S,2E)-5-hy-
droxy-9-phenyl-non-2-ene (55b) to give rise to resin 65
(loading ꢀ0.6 mmolgÀ1, determined by HPLC analysis after
release of a sample). Application of the allylation sequence
gave rise to immobilized diol 66, which could be released in
63% overall yield. GCMS analysis of the corresponding ace-
tonide 67 indicated a syn/anti ratio of 19:1. Further al-
A
Scheme 8. Extension of the methodology to three syn-selective allylations
on solid support.
and application of catalyst 19 resulted in the immobilized
lactone, which could be released and simultaneously depro-
tected with pyridine-buffered hydrogen fluoride (408C,
18 h). After flash chromatography, the final compound 60
was obtained in 5% overall yield, based on the original
loading of 65. Separation of the diastereomers by analytical
HPLC analysis (Nucleodur C18 ISIS column) resulted in a
distribution of 85:9:3:2.
61 was obtained in 6% overall yield. It is the deacetylated
analogue[32c] of the natural products 52 and 53.
Finally, a third ozonolysis and allylation on the immobi-
lized material furnished triol 62, which could be converted
into the corresponding lactone 63 as a single product after
Scheme 9. Synthesis of natural-product-derived compounds on a diethylsilylpolystyrene resin. a) i) Et2SiCl2 (6 equiv), THF, 08C to RT, 2 h; ii) (5S,2E)-5-
hydroxy-9-phenyl-non-2-ene (3 equiv), 2,6-lutidine (3 equiv), DMAP (0.5 equiv), CH2Cl2, RT, 16 h; b) HF/pyridine, pyridine, THF, RT, 8 h; c) 2,2-di-
methoxypropane, cat. (+)-CSA; d) 19 (2”20 mol%), CH2Cl2, reflux, 24 h; e) HF/pyridine, pyridine, THF, 408C, 16 h. CSA=camphorsulfonic acid.
3312
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Chem. Eur. J. 2007, 13, 3305 – 3319

Biology-Oriented Synthesis
FULL PAPER
Accordingly, the diastereomeric compound 69 could be
obtained in 3% yield by analogy. The different structures of
the compounds could best be detected by means of
13C NMR spectroscopy, in which the carbon-bearing hydrox-
yl groups of the syn, anti-isomer 69 displayed a shift of d=
74.7, 73.0, and 68.1 ppm, while the corresponding carbon
atoms in the all-syn-compound 60 appeared at d=76.3, 72.9,
and 69.7 ppm.
to DBU (DBU=1,8-diazabicyclo[5.4.0]undec-7-ene) in di-
A
chloromethane at room temperature delivered smoothly the
desired bicyclic compounds 72 and ent-71 in high yields (en-
tries 3 and 4).
Interestingly, only compounds with a relative syn configu-
ration could be cyclized, while the corresponding anti com-
pounds did not react under any of these conditions.
Structurally diverse lactones: As the developed synthetic
strategy provides a,b-unsaturated d-lactones with high dia-
stereoselectivity, it was appealing to exploit their stereo-
chemical integrity for further diversification. Intramolecular
acid-catalyzed ring closure[30] should yield functionalized bi-
cyclic compounds (Scheme 10). Such bicyclic compounds
can be found as substructures of natural products like cryp-
tocaryolone.[28a]
Conclusion
We have shown that enantioselective allylation of polymer-
bound aldehydes is an efficient solid-phase synthesis method
for the stereocomplementary synthesis of collections of mul-
tiply functionalized carbon chains. This methodology should
enable the synthesis of various natural productlike struc-
tures, as we have demonstrated for selected examples of the
family of a,b-unsaturated d-lactones. The synthesis of all of
the diastereomers of cryptocarya diacetate demonstrates the
complementarity and selectivity of the single reaction steps,
whereas the synthesis of the ravensara lactones further ex-
emplifies the flexibility of this route.
Scheme 10. Synthesis of bicyclic derivatives. a) TsOH (0.12 equiv); ben-
zene, RT, 16 h; b) DBU, CH2Cl2, RT, 6 h.
We believe that such stereocomplementary syntheses ben-
eficially extend the more established solid-phase methodolo-
gies of introducing diversity into compound collections. No-
tably, we expect this concept to add favorably to our current
efforts in biology-oriented synthesis (BIOS), in which bio-
logically prevalidated and often stereochemically demanding
natural products are taken as starting points for the synthe-
sis of compound collections. In such endeavors, control over
the stereochemical course of a reaction is an indispensable
tool in order to specifically investigate the biological poten-
cy of each single stereoisomer.
Thus, exposure of unsaturated lactone 16 f to PTSA
(PTSA=para-toluenesulfonic acid) resulted in formation of
the saturated bicyclic lactone 70 in 66% yield (Table 4,
entry 1). Similarly, the exposure of unsaturated lactone ent-
46 (obtained from resin 35) to PTSA led to the formation of
(1R,5S,7R)-3-oxo-7-[(R)-2-hydroxypropyl]-2,6-dioxabicyclo-
A
the substrate ent-46 was not complete, and the resulting
yield was only moderate (38%). Gratifyingly, we found a
more efficient procedure. Exposure of compounds 43 and 46
Experimental Section
Table 4. Cyclization of a,b-unsaturated d-lactones according to
Scheme 10.
General: Unless otherwise noted, chemicals were obtained from Aldrich,
Acros, or Fluka and were used without further purification. Regular hy-
droxymethylpolystyrene (0.98 mmolgÀ1, 1% DVB, 100–200 mesh) and
Wang resin (1.10 mmolgÀ1, 1% DVB, 100–200 mesh) were purchased
Entry
Reactant
Method
a
Product
Yield [%]
66
from Novabiochem, Bromopolystyrene resin (2.68 mmolgÀ1
, 100–200
mesh) was purchased from Rapp Polymers. All solvents were distilled by
standard procedures. All reactions were performed under argon with
freshly distilled and dried solvents. Analytical chromatography was per-
1
formed by using Mercksilica gel 60 F
aluminum sheets. Flash chroma-
254
tography was performed by using Acros silica gel(0.035–0.07 mm). 1H
and 13C NMR spectrascopic data were recorded on a Bruker DRX 500 or
Varian Mercury VX 400 spectrometer at RT. NMR spectra were calibrat-
ed to the solvent signals of CDCl3 (d=7.26 and 77.00 ppm) and the next
abbreviations are used to indicate signal multiplicities: s (singlet), d (dou-
blet), t (triplet), q (quartet), quint (quintet), sext (sextet), sept (septet),
br (broad), ap (apparent). GCMS (EI) analysis was performed on a Hew-
lett–Packard 6890 series gas chromatograph connected to a Hewlett–
Packard 5973 series mass spectrometer; column: H&W 19091s-102 HP-
5mS, capillary: 25.0”201m”0.33mmm nominal. Chiral GC analysis was
performed on an Agilent Technologies 6890N; column Lipodex-E (25 m,
0.025 mm). LCMS was performed on a Hewlett–Packard 1100 series con-
nected to a Finnigan LCQ ESI-spectrometer. Preparative HPLC was per-
formed on a Hewlett–Packard Agilent Series 1100 System equipped with
a Nucleodur C18 gravity 5 mm column of Macherey&Nagel. High resolu-
2
3
4
a
b
b
38
80
75
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3313

H. Waldmann et al.
tion mass spectra (HRMS) were measured on a Jeol SX 102 A spectrom-
eter. IR spectra were measured on a Bruker Vector 22 spectrometer with
an A527 diffuse reflectance head from Spectra Tech. UV spectra were
measured on a Varian Cary 100 Bio spectrometer. The optical rotation
was determined with a Schmidt+Haensch Polartronic HH8 polarimeter.
(5 mg, 0.075 mmol), and imidazole (0.51 g, 7.5 mmol), the resin was
shaken for 24 h. The resin was filtered and washed with DMF, THF/H2O,
THF, and CH2Cl2 and was then dried in vacuo for 5 h (until the disap-
pearance of the bands at 3504 and 3062 cmÀ1 was detected by FTIR spec-
troscopy).
Representative experimental procedures for the attachment of substrate
to the polymeric support, ozonolysis, allylation, crotylation, TBDMS pro-
tection, acylation with acryloyl chloride and ring-closing metathesis
(RCM), and different substrate release procedures from the solid support
are given below.
General procedure for the introduction of the acrylate on solid support:
The resin-bound secondary alcohol (0.5 g) was swollen in CH2Cl2 (5 mL)
and the mixture was cooled to 08C. Diisopropylethyl amine (0.75 mL,
4.3 mmol), DMAP (10 mg, 0.08 mmol), and acryloyl chloride (0.36 mL,
4 mmol) were added to the cold mixture and it was shaken for 24 h at
RT. The resin was filtered and washed successively with THF, THF/H2O,
THF, and CH2Cl2 and was then dried in vacuo for 5 h (The reaction was
monitored by FTIR spectroscopy which showed the disappearance of
bands at approximately 3500 cmÀ1 and the appearance of a broad peakat
1725 to 1730 cmÀ1).
General procedure for the loading on bromopolystyrene resin: Bromo-
polystyrene resin (2.68 mmolgÀ1) was dried by azeotropic distillation with
toluene prior to use. It was swollen in toluene (5 mLgÀ1 resin) and nBuLi
(3 equiv, 2.5m in hexane) was added. After gentle stirring at 608C for 3 h,
additional nBuLi (3 equiv) was added, and the mixture was stirred at
608C for 15 h. The resulting blackresin was filtered and washed with tol-
uene and THF. THF was added (1.5 mLgÀ1 resin) and the mixture was
cooled to 08C. The appropriate dichlorosilane (4 equiv) was slowly
added, and the mixture was stirred for 2 h and subsequently filtered and
washed with THF and CH2Cl2. The resulting immobilized silylchloride
was swollen in CH2Cl2 and DMAP (0.5 equiv), 2,6-lutidine (2 equiv), and
alcohol (2 equiv) were added. The mixture was shaken for 16 h. The resin
was filtered and washed with CH2Cl2, dimethylformamide, CH2Cl2, and
MeOH and was then dried in vacuo.
General procedure for RCM on the solid support: The resin-bound acryl-
ic acid ester (0.25 g, ꢀ0.5 mmolgÀ1 loading) was suspended in CH2Cl2
(10 mL) and the mixture was degassed with argon. To the degassed mix-
ture, the RCM catalyst (0.02 mmol) was added, the mixture was warmed
to 408C and stirred for 12 h. A second portion of catalyst was added
(0.02 mmol) and the mixture was stirred at reflux for another 12 h. The
mixture was allowed to reach RT, and was then filtered. The filtrate was
washed successively with CH2Cl2, THF, and CH2Cl2 and was then dried
in vacuo.
General procedure for the ozonolysis on solid support: The resin was
swollen for 15 min in CH2Cl2 and cooled to À788C. Ozone was bubbled
through until the color turned deep green or blue and for an additional
8–10 min. When the polymeric support was the Wang resin, ozone was
bubbled through for only 2–3 min after observation of the blue color (ca.
6 min in total). Argon was then bubbled through the mixture to remove
excess ozone, PPh3 (5 equiv) was added and the mixture was shaken
from À788C to RT overnight. The resin was then filtered and washed
with CH2Cl2 and MeOH and dried in vacuo.
General procedure for release from the solid support by using TFA: The
resin (430 mg, loading 0.4 mmolgÀ1) was swollen in CH2Cl2 and was sub-
sequently treated with TFA/CH2Cl2 1:2 (20 mLgÀ1 resin, 8.6 mL) solution
for 5 min at RT. The resin was filtered and washed with CH2Cl2. The fil-
trate was co-evaporated with toluene and the brown residue was purified
by silica-gel column chromatography to yield the product.
General procedure for release from the solid support by using DDQ:
The resin (250 mg, loading 0.4 mmolgÀ1) was swollen in a mixture of
CH2Cl2 (10 mL) and pH 7 phosphate buffer (0.5 mL) and recrystallized
DDQ (180 mg, 0.8 mmol) was added at 08C. The mixture was shaken for
10 h while allowing the temperature to rise to RT. The resin was then fil-
tered off and washed with CH2Cl2. The filtrate was washed with a satu-
rated solution of NaHCO3 (3”15 mL) and brine and was then dried over
Na2SO4. After removal of solvent under reduced pressure, the required
lactone was obtained in 80–90% purity. The lactones were further puri-
fied by silica-gel column chromatography.
General procedure for the asymmetric allylation on solid support: The
supported aldehydes were dried by azeotropic distillation with toluene
(2–3 times) and high vacuum for at least 3 h. The resin was suspended in
THF (10–15 mLgÀ1 resin) and the allylborane (1m in Et2O solution,
4 equiv) was added at À788C. The resulting mixture was shaken over-
night allowing the temperature to warm up slowly to 08C. After quench-
ing the reaction with MeOH (4 mLgÀ1 resin), the resin was filtered and
washed consecutively with pH 7 buffer, H2O, THF, Et2O, CH2Cl2, and
MeOH. The resin was suspended in a mixture of DMF/MeOH 1:1
(12 mLgÀ1 resin each) and at 08C H2O2 (30%, 2.5 mLgÀ1 resin) and pH 7
buffer (2.5 mLgÀ1 resin) were added. The resulting mixture was shaken
for 2 h at RT (when the resin was hydroxymethylpolystyrene) or at 08C
(when the Wang resin was used). The resin was filtered and washed with
H2O, THF, CH2Cl2, and MeOH and was then dried in vacuo.
General procedure for the release from the dialkylsilylpolystyrene resins:
The resin was swollen in THF (5 mLgÀ1 resin) in a 15 mL Falcon tube
equipped with a magnetic stirring bar and a septum. Pyridine (75 mLgÀ1
resin) and HF/pyridine (100 mLgÀ1 resin) were added, and the suspension
was stirred for 16 h at 408C. Excess reagent was quenched with trimethyl-
silylmethanol (2 mLgÀ1 resin). Filtration through a pad of silica afforded
the crude product, which was further purified by flash chromatography
or preparative HPLC.
Asymmetric crotylation on solid support: trans-Butene (excess, 0.5 mL)
was added to a solution of tBuOK (1m in THF, 5 equiv, 1.5 mmol) at
À788C. A solution of nBuLi (2.5m in hexane, 6 equiv, 1.8 mmol) was
added dropwise and the mixture was stirred at À788C for 5 min then at
À458C for 40 min. The resulting solution was cooled to À788C, a solution
of (À)-MeOBIpc2 (7 equiv, 2.1 mmol, 665 mg) in Et2O (1.5 mL) was
added dropwise over 15 min and the stirring was maintained for 45 min.
BF3·Et2O (7.5 equiv, 2.25 mmol, 284 mL) was added dropwise and after
5 min to the aldehyde resin (ꢀ400 mg, 0.3 mmol), which had beforehand
been swollen in THF (10 mL) and cooled at À788C. The mixture was stir-
red overnight with the temperature rising slowly to 08C. After quenching
by the addition of MeOH (0.5 mL), the resin was washed consecutively
(R)-6-(3-Hydroxypropyl)-5,6-dihydro-2H-pyran-2-one (15): After release
from the resin, the compound was purified by preparative HPLC (lin.
gradient 10 to 95% acetonitrile + 0.1% TFA in H2O + 0.1% TFA).
Yield: 11.7 mg (from 589 mg diisopropylsilylpolystyrene resin), 12%;
Rf =0.18 (silica gel, CH2Cl2/MeOH 95:5); [a]2D0 =À102 (c=0.2 in CHCl3);
1H NMR (400 MHz, CDCl3): d=6.91–6.86 (m, 1H), 6.03 (ddd, 3J=9.7,
4J=2.1, 1.5 Hz, 1H), 4.51–4.44 (m, 1H), 3.72–3.69 (m, 2H), 2.38–2.34 (m,
2H), 1.91–1.66 ppm (m, 4H); 13C NMR (100 MHz, CDCl3): d=164.4
(CO), 145.0 (CH), 121.4 (CH), 77.8 (CH), 62.8 (CH2), 31.2 (CH2), 29.5
(CH2), 28.0 ppm (CH2); MS (FAB): m/z: 157.1 [M+H]+; HRMS (FAB):
m/z: calcd for C8H13O3: 157.0865 [M+H]+; found: 157.0880.
with pH 7 buffer, H2O, THF, Et2O, dichloromethane, and MeOH. DMF
G
(3 mL), MeOH (3 mL), pH 7 buffer (1 mL), and H2O2 (30%, 1 mL) were
added to the resin at 08C. The mixture was then shaken at 08C for 2 h
and filtered. The resin was washed with H2O, THF, Et2O, CH2Cl2, and
MeOH and was then dried overnight in vacuo.
(S)-6-(2-Hydroxyethyl)-5,6-dihydro-2H-pyran-2-one (16a): Yield: 4 mg
(from 120 mg resin), 30%; Rf =0.4 (silica gel, ethyl acetate/petroleum
1
ether 1:1); H NMR (400 MHz, CDCl3): d=6.90 (td, J=9.7, 3.9 Hz, 1H),
6.06 (td, J=9.7, 1.9 Hz, 1H), 4.62–4.55 (m, 3H), 2.42–2.39 (m, 2H), 2.25–
2.12 ppm (m, 2H); 13C NMR (100 MHz, CDCl3): d=163.39 (CO), 144.51
(CH), 121.57 (CH), 73.86 (CH), 63.60 (CH2), 33.51 (CH2), 29.37 ppm
(CH2); LCMS: m/z: 124 [MÀH2O]+.
General procedure for the protection of secondary alcohols with a tert-
butyldimethylsilyl group on solid support: The resin-bound secondary al-
cohol (1 g) was swollen in a mixture of CH2Cl2 (10 mL) and DMF
(10 mL) at RT. After addition of TBSCl (1.13 g, 7.5 mmol), DMAP
3314
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Chem. Eur. J. 2007, 13, 3305 – 3319

Biology-Oriented Synthesis
FULL PAPER
(S)-6-[(R)-1-Hydroxypropan-2-yl]-5,6-dihydro-2H-pyran-2-one
(16b):
residue was filtered through silica gel (CH2Cl2/MeOH 9:1) to yield a mix-
ture of the free diol and the monoprotected compound as a byproduct.
The diol was acetylated with Ac2O (0.05 mL), Et3N (0.07 mL), and a cat-
alytic amount of DMAP in CH2Cl2 (1 mL). The mixture was stirred for
3 h from 08C to RT, after which time 1 mL of a saturated solution of
NaHCO3 was added. The aqueous layer was extracted with CH2Cl2 (3”
10 mL). The combined organic extracts were dried over Na2SO4. The sol-
vent was removed under reduced pressure and the crude product was pu-
rified by silica-gel chromatography (CH2Cl2 to CH2Cl2/EtOAc 2:1) to
yield cryptocarya diacetate 30 with other minor isomers. After a second
chromatography (petroleum ether/ethyl acetate 1:1) 4 mg (11%) of pure
cryptocarya diacetate 30 were obtained.
Yield: 10 mg (from 300 mg resin), 28%; Rf =0.2 (silica gel, ethyl acetate/
petroleum ether 1:1); [a]2D5 =À120.6 (c=0.95 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=6.92–6.90 (m, 1H), 6.01 (d, J=9.4 Hz, 1H), 4.45–
4.43 (m, 1H), 3.74–3.70 (m, 2H), 2.40–2.39 (m, 2H), 2.06–2.03 (m, 1H),
1.00 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.30
(C), 145.43 (CH), 121.19 (CH), 79.87 (CH), 64.23 (CH2), 39.54 (CH),
26.87 (CH2), 12.68 ppm (CH3); LCMS: m/z: 157 [M+H]+.
(R)-6-[(R)-1-Hydroxypropan-2-yl]-5,6-dihydro-2H-pyran-2-one
(16c):
Yield: 4 mg (from 200 mg resin), 18%; Rf =0.2 (silica gel, ethyl acetate/
petroleum ether 1:1); 1H NMR (500 MHz, CDCl3): d=6.94 (ddd, J=9.5,
6.4, 2.1 Hz, 1H), 6.06 (ddd, J=9.5, 2.9, 0.9 Hz, 1H), 4.53 (td, J=12.6,
3.72 Hz, 1H), 4.45 (dd, J=10.9, 7.4 Hz, 1H), 4.39 (dd, J=10.9, 5.8 Hz,
1H), 2.56–2.47 (m, 1H), 2.36–2.30 (m, 2H), 1.13 ppm (d, J=7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=163.77 (C), 144.95 (CH), 121.48 (CH),
77.00 (CH), 68.43 (CH2), 36.20 (CH), 26.66 (CH2), 11.01 ppm (CH3);
LCMS: m/z: 157 [M+H]+.
The other diastereomers of cryptocarya diacetate were obtained follow-
ing the same protocol.
General procedure for the synthesis of TBS-protected cryptocarya ana-
logues: Release from the resin was achieved with DDQ as described
above. The lactones were further purified by silica-gel column chroma-
tography (ethyl acetate/petroleum ether 2:3) to yield the major diastereo-
isomer as an enriched diastereomer (>90% purity).
(R)-6-[(S)-1-Hydroxypropan-2-yl]-5,6-dihydro-2H-pyran-2-one
(16d):
Yield: 10 mg (from 300 mg resin), 34%; Rf =0.2 (silica gel, ethyl acetate/
petroleum ether 1:1); [a]2D5 =+60.3 (c=0.9 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=6.93–6.89 (m, 1H), 6.02 (td, J=9.9, 1.7 Hz, 1H),
4.47–4.41 (m, 1H), 3.76 (dd, J=10.9, 4.6 Hz, 1H), 3.71 (dd, J=10.9,
5.6 Hz, 1H), 2.39 (t, J=6.4 Hz, 2H), 2.10–2.03 (m, 1H), 1.00 ppm (d, J=
6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=164.34 (C), 145.46 (CH),
121.18 (CH), 79.89 (CH), 64.25 (CH2), 39.54 (CH), 26.88 (CH2),
12.69 ppm (CH3); LCMS: m/z: 157 [M+H]+; HRMS (FAB): m/z: calcd
for C8H13O3: 157.0865 [M+H]+; found: 157.0847.
General procedure for the removal of a TBS group in solution to yield
diol lactone analogues of cryptocarya diacetate: A catalytic amount of
PPTS (3 mg, 0.01 mmol) was added to a stirred solution of the TBS-pro-
tected lactone (0.17 mmol) in MeOH (3 mL) and water (20mL). The reac-
tion mixture was stirred at reflux for 16 h. The mixture was cooled and
neutralized with saturated NaHCO3 solution. The solution was evaporat-
ed and the residue underwent column chromatography on silica gel
(ethyl acetate) to furnish the diol lactone in high yield (80–90%). Follow-
ing this protocol, the four diastereomeric diol analogues 43, 44, 45, and
46 of cryptocarya were obtained.
(R)-6-[(R)-2-Hydroxypropyl]-5,6-dihydro-2H-pyran-2-one (16e): Yield:
6 mg (from 225 mg resin), 37%; Rf =0.2 (silica gel, ethyl acetate/petrole-
um ether 1:1); [a]2D5 =+59.6 (c=0.6 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=6.93–6.86 (m, 1H), 6.03 (d, J=9.9 Hz, 1H), 4.74–4.67 (m,
1H), 4.20–4.12 (m, 1H), 2.39–2.36 (m, 2H), 2.20 (brs, 1H), 1.90 (dd ap-
pears as t, J=9.8 Hz, 1H), 1.68 (dd appears as t, J=9.8 Hz, 1H),
1.25 ppm (d, J=6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.39
(C), 145.30 (CH), 121.33 (CH), 75.05 (CH), 63.57 (CH), 43.79 (CH2),
29.85 (CH2), 24.15 ppm (CH3); LRMS: m/z: 157.1 [M+H]+.
Cryptocarya diacetate 23: Yield: 10 mg (from 430 mg resin), 27%; [a]D20
=
+47.2 (c=0.5 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.86 (ddd, J=
9.8, 5.9, 2.5 Hz, 1H), 6.02 (ddd, J=9.8, 2.7, 1.0 Hz, 1H), 5.10 (dddd, J=
8.4, 7.0, 6.0, 3.7 Hz, 1H), 4.98 (ap sext, J=6.0 Hz, 1H), 4.49 (ddt, J=
10.4, 6.6, 3.9 Hz, 1H), 2.45 (dddd, J=18.2, 5.9, 3.9, 1.0 Hz, 1H), 2.31
(ddt, J=18.4, 11.5, 2.6 Hz, 1H), 2.16 (ddd, J=14.8, 8.6, 6.6 Hz, 1H), 2.07
(s, 3H), 2.04 (s, 3H), 2.01 (ddd, J=14.4, 7.4, 7.4 Hz, 1H), 1.94 (ddd, J=
14.7, 6.5, 3.7 Hz, 1H), 1.79 (dt, J=14.3, 5.8 Hz, 1H), 1.26 ppm (d, J=
6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.6 (CO), 170.5 (CO),
163.8 (CO), 144.7, 121.4, 74.9, 67.8, 67.7, 66.6, 40.5 (CH2), 39.2 (CH2),
29.2 (CH2), 21.1, 20.1 ppm; IR (KBr): n˜ =2925, 2857, 1731 (CO), 1373,
1241, 1038, 956, 815 cmÀ1; MS (ESI): m/z: 302 [M+NH4]+; HRMS (FAB,
m-NBA=m-nitrobenzoic acid): calcd for C14H21O6: 285.1338 [M+H]+;
found: 285.1367.
(5R,6R)-6-[(R)-1-Hydroxypropan-2-yl]-5-methyl-5,6-dihydro-2H-pyran-2-
one (16 f): Yield: 8 mg (from 200 mg resin), 38%; Rf =0.2 (silica gel,
ethyl acetate/petroleum ether 1:1); 1H NMR (400 MHz, CDCl3): d=6.68
(dd, J=9.6, 1.7 Hz, 1H), 5.95 (dd, J=9.6, 2.5 Hz, 1H), 4.35 (d, J=
10.9 Hz, 1H), 3.80–3.67 (m, 1H), 3.66–3.63 (m, 1H), 2.70–2.65 (m, 1H),
2.04–2.01 (m, 1H), 1.17 (d, J=7.2 Hz, 3H), 1.02 ppm (d, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=164.70 (C), 152.67 (CH), 119.95 (CH),
82.96 (CH), 64.24 (CH2), 36.13 (CH), 30.54 (CH), 15.68 (CH3), 9.67 ppm
(CH3); LCMS m/z: 171 [M+H]+.
(2R,4R)-1-[(S)-6-Oxo-3,6-dihydro-2H-pyran-2-yl]pentane-2,4-diyl diace-
A
tate (ent-23): Yield: 3.7 mg (from 250 mg resin), 11%; [a]2D0 =À44 (c=
0.46 in CHCl3); HRMS (FAB): m/z: calcd for C14H21O6: 285.1338
[M+H]+; found: 285.1315.
(16g): Yield: 6 mg (from 225 mg resin), 48%; Rf =0.2 (silica gel, ethyl
acetate/petroleum ether 4:1); [a]2D5 =À52.6 (c=0.53 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=6.67 (dd, J=9.7, 2.5 Hz, 1H), 5.96 (dd, J=9.7,
2.3 Hz, 1H), 4.37 (dd appears as a t, J=8.4 Hz, 1H), 4.23 (brs, 1H),
2.49–2.44 (m, 1H), 1.82–1.70 (m, 2H), 1.24 (d, J=6.2 Hz, 3H), 1.14 ppm
(d, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.19 (CO), 151.80
(CH), 119.99 (CH), 80.52 (CH), 63.40 (CH), 41.91 (CH2), 33.61 (CH),
24.03 (CH3), 16.36 ppm (CH3); LCMS: m/z: 171 [M+H]+; HRMS
(FAB): calcd for C9H15O3: 171.1021 [M+H]+; found: 171.0996.
(S)-6-[(2R,4R)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (ent-36): Yield: 11.4 mg (from 250 mg resin), 42%;
Rf =0.25 (silica gel, ethyl acetate/petroleum ether 2:3); [a]2D0 =À33.6 (c=
1.14 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.88 (ddd, J=9.7, 5.2,
3.1 Hz, 1H), 6.03 (td, J=9.7, 1.4 Hz, 1H), 4.54 (m, 1H), 4.22 (sep, J=
3.5 Hz, 1H), 3.99–3.94 (m, 1H), 2.37–2.32 (m, 2H), 2.08 (ddd, J=14.0,
8.9, 4.2 Hz, 1H), 1.74 (1/2ABq, J=2.6, 1H), 1.70 (1/2ABq, J=2.6, 1H),
1.58 (td, J=14.0, 8.8 Hz, 1H), 1.18 (d, J=6.2 Hz, 3H), 0.89 (s, 9H), 0.13
(s, 3H), 0.11 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=164.06 (C),
144.88 (CH), 121.44 (CH), 74.81 (CH), 68.81 (CH), 66.53 (CH), 44.31
(CH2), 42.99 (CH2), 30.05 (CH2), 25.74 (CH3), 23.81 (CH3), 17.80 (C),
À4.2 (CH3), À4.7 ppm (CH3); LCMS: m/z: 315 [M+H]+; HRMS (FAB):
m/z: calcd for C16H31O4Si: 315.1992 [M+H]+; found: 315.1970.
ent-Euscapholide (ent-20): Yield: 14.2 mg (from 450 mg resin), 44%; Rf =
0.2 (silica gel, ethyl acetate/petroleum ether 1:1); [a]2D5 =À100.5 (c=1.37
in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.91–6.86 (m, 1H), 6.01 (td,
J=12.5, 1.6 Hz, 1H), 4.67–4.60 (m, 1H), 4.12–4.04 (m, 1H), 2.42–2.38 (m,
2H), 2.01 (td, J=14.4, 8.0 Hz, 1H), 1.75 (ddd, J=14.4, 5.2, 4.1 Hz, 1H),
1.25 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=163.99
(C), 145.21 (CH), 121.21 (CH), 76.80 (CH), 65.21 (CH), 43.54 (CH2),
29.46 (CH2), 23.71 ppm (CH3); HRMS (FAB): m/z: calcd for C8H13O3:
157.0865 [M+H]+; found 157.0888.
(R)-6-[(2S,4S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (36): Yield: 15 mg (from 420 mg resin), 38%; [a]D20
=
+29.65 (c=1.4 in CHCl3); IR (KBr): n˜ =3355 (br, OH), 2925, 2880, 1720
(CO), 1459, 1260, 1070, 809 cmÀ1; MS (ESI): m/z: 315 [M+H]+, 332
[M+NH4]+; HRMS (FAB): m/z: calcd for C16H31O4Si: 315.1992 [M+H]+;
found: 315.2016.
General procedure for the synthesis of cryptocarya diacetate stereoiso-
mers: Resin 32 (430 mg, 0.13 mmol) was swollen in TFA/CH2Cl2 1:2
(20 mLgÀ1 resin, 8.6 mL) for 20 min at RT. The resin was filtered and
washed with CH2Cl2. The filtrate was co-evaporated with toluene. The
Chem. Eur. J. 2007, 13, 3305 – 3319
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3315

H. Waldmann et al.
A
(100), 332 [M+NH4]+; HRMS (FAB): m/z: calcd for C16H31O4Si:
315.1992 [M+H]+; found: 315.2022.
tate (37): Characterized from the isomer mixture. Yield: 31 mg (from
2.0 g resin), 18%; dr: 88:12; [a]2D0 =À20.5 (c=0.75 in CHCl3) (lit.[28c]
[a]2D0 =À35.6 (c=0.75 in CHCl3)); 1H NMR (400 MHz, CDCl3): d=6.85
(m, 1H), 6.01 (dd, J=10.0, 2.0 Hz, 1H), 5.17 (m, 1H), 4.96 (ap sext, J=
6.1 Hz, 1H), 4.48 (ddd, J=9.0, 6.2, 3.3 Hz, 1H), 2.34 (m, 2H), 2.10–1.99
(m, 2H), 2.05 (s, 3H), 2.04 (s, 3H), 1.88 (m, 1H), 1.77 (m, 1H), 1.26 ppm
(d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=170.5 (CO), 170.3
(CO), 163.6 (CO), 144.4, 121.5, 74.5, 67.9, 67.6, 40.4 (CH2), 39.6 (CH2),
29.6 (CH2), 21.3, 21.1, 20.1 ppm; IR (KBr): n˜ =2924, 2853, 1736 (CO),
1374, 1243, 1022, 816 cmÀ1; MS (ESI): m/z: 302 [M+NH4]+; HRMS
(FAB): m/z: calcd for C14H21O6: 285.1338 [M+H]+; found: 285.1327.
A
tate (41): Yield: 8 mg (from 300 mg resin), 20%; [a]2D0 =À41.5 (c=1.02 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=6.86 (ddd, J=9.6, 6.0, 2.5 Hz,
1H), 6.01 (ddd, J=9.8, 2.8, 1.0 Hz, 1H), 5.15 (ap sept, J=4.2 Hz, 1H),
4.99–4.87 (m, 1H), 4.47 (ddd, J=18.2, 6.4, 3.9 Hz, 1H), 2.50 (dddd, J=
19.2, 6.1, 3.9, 1.0 Hz, 1H), 2.31 (ddt, J=18.4, 11.7, 2.5 Hz, 1H), 2.15 (ddd,
J=14.6, 8.4, 6.2 Hz, 1H), 2.05 (s, 3H), 2.03 (m, 1H), 2.02 (s, 3H), 1.93–
1.83 (m, 2H), 1.23 ppm (d, J=6.2 Hz, 3H); 13C NMR/APT (100 MHz,
CDCl3): d=170.8 (CO), 170.6 (CO), 163.8 (CO), 144.7, 121.4, 74.9, 66.7,
66.6, 40.8 (CH2), 39.9 (CH2), 29.2 (CH2), 21.2, 21.0, 20.4 ppm; IR (KBr):
n˜ =2927, 2860, 1732 (CO), 1429, 1374, 1245, 1024, 956, 814 cmÀ1; MS
(ESI): m/z: 302 [M+NH4]+; HRMS (FAB, m-NBA): m/z: calcd for
C14H21O6: 285.1338 [M+H]+; found: 285.1355.
A
tate (ent-37): Yield: 4.8 mg (from 250 mg resin), 14%; [a]2D0 =+25.6 (c=
0.6 in CHCl3); HRMS (FAB): m/z: calcd for C14H21O6: 285.1338 [M+H]+
; found: 285.1322.
A
(R)-6-[(2R,4R)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (ent-38): Yield: 18 mg (from 250 mg resin), 67%;
Rf =0.26 (silica gel, ethyl acetate/petroleum ether 2:3); [a]2D0 =+3.8 (c=
1.79 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.88–6.86 (m, 1H), 6.03
(td, J=9.9, 1.9 Hz, 1H), 4.6–4.5 (m, 1H), 4.23–4.16 (m, 1H), 3.98–3.91
(m, 1H), 2.33–2.30 (m, 2H), 1.99 (ddd, J=14.2, 9.3, 3.3 Hz, 1H), 1.73
(ddd, J=14.2, 8.8, 2.9 Hz, 1H), 1.66–1.59 (series of d, 2H), 1.18 (d, J=
6.2 Hz, 3H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=164.13 (C), 145.19 (CH), 121.37 (CH), 74.57
(CH), 66.60 (CH), 65.15 (CH), 46.74 (CH2), 42.85 (CH2), 30.02 (CH2),
25.79 (CH3), 24.28 (CH3), 17.89 (C), À4.40 (CH3), À4.60 ppm (CH3);
LCMS: m/z: 315 [M+H]+; HRMS (FAB): m/z: calcd for C16H31O4Si:
315.1992 [M+H]+; found: 315.1973.
tate (ent-41): Yield: 5 mg (from 300 mg resin), 12%; [a]2D0 =+30 (c=0.62
in CHCl3); HRMS (FAB): m/z: calcd for C14H21O6: 285.1338 [M+H]+;
found: 285.1329.
(R)-6-[(2S,4R)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (ent-42): Yield: 11.5 mg (from 250 mg resin), 42%;
Rf =0.25 (silica gel, ethyl acetate/petroleum ether 40:60); [a]2D0 =+45 (c=
1.15 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.89–6.84 (m, 1H), 6.01
(td, J=9.9, 1.7 Hz, 1H), 4.51–5.45 (m, 1H), 4.33 (m, 1H), 4.08–4.00 (m,
1H), 2.37–2.34 (m, 2H), 2.08 (ddd, J=11.5, 7.5, 3.5 Hz, 1H), 1.91 (ddd,
J=12.0, 7.0, 3.6 Hz, 1H), 1.67 (d, J=3.6 Hz, 1H), 1.52 (d, J=2.5 Hz,
1H), 1.17 (d, J=6.2 Hz, 3H), 0.88 (s, 9H), 0.11 (s, 3H), 0.08 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=163.99 (C), 144.82 (CH), 121.44
(CH), 74.93 (CH), 67.40 (CH), 64.35 (CH), 42.95 (CH2), 41.33 (CH2),
29.96 (CH2), 25.73 (CH3), 24.02 (CH3), 17.82 (C), À4.68 (CH3),
À4.83 ppm (CH3); LCMS: m/z: 315 [M+H]+; HRMS (FAB): m/z: calcd
for C16H31O4Si: 315.1992 [M+H]+; found: 315.2027.
(S)-6-[(2S,4S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (38): Yield: 15 mg (from 420 mg resin), 38%; [a]D20
+4.3 (c=0.84 in CHCl3); IR (KBr): n˜ =3468 (br, OH), 2929, 2857, 1717
(CO), 1462, 1385, 1252, 1058, 825 cmÀ1; MS (ESI): m/z (%): 315 [M+1]+
(100), 332 [M+NH4]+; HRMS (FAB): m/z: calcd for C16H31O4Si:
315.1992 [M+H]+; found: 315.1974.
(S)-6-[(2R,4S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (42): Yield: 19 mg (from 318 mg resin), 60%; [a]D20
=
À37.98 (c=1.04 in CHCl3); IR (KBr): n˜3441 (br, OH), 2956, 2840, 1722
(CO), 1462, 1379, 1254, 1063, 836 cmÀ1; MS (ESI): m/z (%): 315 [M+H]+
(100), 332 [M+NH4]+; HRMS (FAB): m/z: calcd for C16H31O4Si:
315.1992 [M+H]+; found: 315.1963.
A
tate (39): Yield: 7 mg (from 350 mg resin), 23%; [a]2D0 =+43.5 (c=0.80 in
CHCl3); 1H NMR (400 MHz, CDCl3): d=6.85 (ddd, J=9.6, 5.1, 3.2 Hz,
1H), 6.02 (ddd, J=9.8, 2.3, 1.4 Hz, 1H), 5.17 (ddd, J=13.5, 8.0, 4.1 Hz,
1H), 4.94 (ap sept, J=3.5 Hz, 1H), 4.48 (m, 1H), 2.34 (m, 2H), 2.08–1.99
(m, 2H), 2.03 (s, 3H), 2.02 (s, 3H), 1.90 (m, 1H), 1.78 (ddd, J=14.4, 6.6,
3.5 Hz, 1H), 1.24 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=170.7 (C), 170.4 (C), 163.7 (C), 144.5, 121.6, 74.7, 67.3, 66.7, 40.9
(CH2), 40.2 (CH2), 29.7 (CH2), 21.2, 21.0, 20.4 ppm; IR (KBr): n˜ =2935,
(S)-6-[(2R,4R)-2,4-Dihydroxypentyl]-5,6-dihydro-2H-pyran-2-one
(43):
Yield: 30 mg (from 54 mg of ent-36), 87%; Rf =0.2 (silica gel, ethyl ace-
tate); [a]2D5 =À88.1 (c=1.13 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
6.90–6.86 (m, 1H), 5.98 (d, J=9.9 Hz, 1H), 4.68–4.60 (m, 1H), 4.13–4.02
(m, 2H), 2.43–2.36 (m, 2H), 2.01 (td, J=14.4, 7.4 Hz, 1H), 1.78–1.72 (m,
1H), 1.58–1.55 (m, 2H), 1.19 ppm (d, J=6.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=164.27 (C), 145.47 (CH), 121.05 (CH), 76.17
(CH), 69.37 (CH), 68.79 (CH), 44.46 (CH2), 42.31 (CH2), 29.32 (CH2),
24.18 ppm (CH3); LCMS: m/z: 200.9 (M)+; HRMS (FAB): m/z: calcd for
C10H17O4: 201.1127 [M+H]+; found: 201.1106.
2853, 1736 (CO), 1375, 1246, 1023, 822 cmÀ1
; MS (ESI): m/z: 302
[M+NH4]+; HRMS (FAB): m/z: calcd for C14H20O6: 284.1260 [M+H]+;
found: 285.1350.
A
tate (ent-39): Yield: 3 mg (from 250 mg resin), 10%; [a]2D0 =À32 (c=0.17
in CHCl3); HRMS (FAB): m/z: calcd for C14H21O6: 285.1338 [M+H]+;
found: 285.1316.
(R)-6-[(2R,4R)-2,4-Dihydroxypentyl]-5,6-dihydro-2H-pyran-2-one (44):
Yield: 20 mg (from 47 mg of ent-38), 67%; Rf =0.2 (silica gel, ethyl ace-
tate); [a]2D5 =+41 (c=0.98 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
6.88 (ddd, J=9.7, 5.6, 2.9 Hz, 1H), 6.01–5.97 (m, 1H), 4.76–4.69 (m, 1H),
4.24–4.18 (m, 1H), 4.10–4.03 (m, 1H), 2.37–2.32 (m, 2H), 1.85 (ddd, J=
14.4, 9.6, 2.8 Hz, 1H), 1.68 (ddd, J=14.4, 9.9, 2.8 Hz, 1H), 1.58–1.52 (m,
2H), 1.19 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
164.59 (C), 145.54 (CH), 121.19 (CH), 76.69 (CH), 68.83 (CH), 67.78
(CH), 44.97 (CH2), 43.02 (CH2), 29.87 (CH2), 24.30 ppm (CH3); LCMS:
m/z: 200.9 [M]+; HRMS (FAB): m/z: calcd for C10H17O4: 201.1127
[M+H]+; found: 201.1147.
(S)-6-[(2S,4R)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (ent-40): Yield: 13.5 mg (from 250 mg resin), 50%;
Rf =0.26 (silica gel, ethyl acetate/petroleum ether 4:6); [a]2D0 =À2.3 (c=
1.2 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.91–6.85 (m, 1H), 6.01
(td, J=9.7, 1.9 Hz, 1H), 4.54 (dd, J=8.2, 4.8 Hz, 1H), 4.33 (m, 1H), 4.12
(m, 1H), 2.35–2.32 (m, 2H), 1.91 (ddd, J=7.4, 3.8, 1.7 Hz, 1H), 1.74
(ddd, J=14.6, 10.1, 4.4 Hz, 1H), 1.55 (1/2ABq, J=2.7, 1H), 1.52 (1/
2ABq, J=2.7, 1H), 1.16 (d, J=6.1 Hz, 3H), 0.87 (s, 9H), 0.14 (s, 3H),
0.08 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=163.94 (C), 145.17
(CH), 121.39 (CH), 74.27 (CH), 66.32 (CH), 64.66 (CH), 44.40 (CH2),
41.49 (CH2), 29.70 (CH2), 25.79 (CH3), 23.93 (CH3), 17.82 (C), À4.47
(CH3), À4.96 ppm (CH3); LCMS: m/z: 315 [M+H]+; HRMS (FAB): m/z:
calcd for C16H31O4Si: 315.1992 [M+H]+; found: 315.1985.
(S)-6-[(2S,4R)-2,4-Dihydroxypentyl]-5,6-dihydro-2H-pyran-2-one
(45):
Yield: 15.5 mg (from 27 mg of ent-40), 90%; Rf =0.2 (silica gel, ethyl ace-
tate); [a]2D5 =À68.8 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3): d=
6.92–6.87 (m, 1H), 6.02–5.98 (m, 1H), 4.79–4.72 (m, 1H), 4.34–4.28 (m,
1H), 4.17–4.10 (m, 1H), 2.40–2.36 (m, 2H), 1.85 (ddd, J=14.4, 9.3,
2.7 Hz, 1H), 1.75 (ddd, J=14.4, 9.9, 2.9 Hz, 1H), 1.62–1.57 (m, 2H),
1.23 ppm (d, J=6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.73
(C), 145.66 (CH), 121.20 (CH), 75.08 (CH), 65.29 (CH), 64.32 (CH),
44.74 (CH2), 42.34 (CH2), 29.90 (CH2), 23.55 ppm (CH3); LCMS: m/z:
(R)-6-[(2R,4S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxypentyl]-5,6-dihy-
dro-2H-pyran-2-one (40): Yield: 20 mg (from 362 mg resin), 57%; [a]D20
+6.84 (c=1.17 in CHCl3); IR (KBr): n˜ =3450 (br, OH), 2959, 1720
(CO), 1471, 1382, 1253, 1059, 836 cmÀ1; MS (ESI): m/z (%): 315 [M+H]+
3316
www.chemeurj.org
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2007, 13, 3305 – 3319

Biology-Oriented Synthesis
FULL PAPER
3
200.9 [M]+; HRMS (FAB): m/z: calcd for C10H17O4: 201.1127 [M+H]+;
3.90–3.85 (m, 1H), 2.62 (t, J=7.6 Hz, 2H), 2.43–2.41 (m, 2H), 2.02 (ddd,
2J=15.0, 3J=7.5, 7.5 Hz, 1H), 1.77 (ddd, 2J=14.4, 3J=5.4, 3.9 Hz, 1H),
1.67–1.31 ppm (m, 8H); 13C NMR (125 MHz, CDCl3): d=164.1 (C),
145.3 (CH), 142.4 (CH), 128.4 (CH), 128.3 (CH), 125.7 (CH), 121.2
(CH), 76.3 (CH), 72.9 (CH), 69.8 (CH), 42.8 (CH2), 42.3 (CH2), 38.1
(CH2), 35.8 (CH2), 31.3 (CH2), 29.4 (CH2), 24.9 ppm (CH2); LCMS: m/z:
319.1 [M+H]+; HRMS (FAB): m/z: calcd for C19H27O4: 319.1909
[M+H]+; found: 319.1935.
found: 201.1088.
(R)-6-[(2S,4R)-2,4-Dihydroxypentyl]-5,6-dihydro-2H-pyran-2-one
(46):
Yield: 15 mg of 46 (from 50 mg of ent-42), 50% (8 mg, 25% of 73 was
also obtained as a minor product); Rf =0.2 (silica gel, ethyl acetate);
[a]2D5 =+73.6 (c=1.2 in CHCl3); 1H NMR (400 MHz, CDCl3): d=6.92–
6.87 (m, 1H), 6.02–5.99 (m, 1H), 4.71–4.64 (m, 1H), 4.22–4.13 (m, 2H),
2.44–2.40 (m, 2H), 2.08 (ddd, J=16.2, 8.8, 7.4 Hz, 1H), 1.77 (ddd, J=
16.2, 5.6, 3.7 Hz, 1H), 1.66–1.57 (m, 2H), 1.23 ppm (d, J=6.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=164.25 (C), 145.47 (CH), 121.11 (CH),
76.68 (CH), 66.20 (CH), 65.11 (CH), 44.30 (CH2), 41.84 (CH2), 29.36
(CH2), 23.51 ppm (CH3); LCMS: m/z: 200.9 [M]+; HRMS (FAB): m/z:
calcd for C10H17O4: 201.1127 [M+H]+; found: 201.1103.
(R)-6-[(2S,4S)-2-(tert-Butyldimethylsilyloxy)-4-hydroxy-8-phenyloctyl]-
5,6-dihydro-2H-pyran-2-one (61): Yield: 10 mg (from 720 mg resin),
9.3%; Rf =0.2 (silica gel, ethyl acetate/petroleum ether 1:1); [a]2D0 =+23.2
(c=0.96 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.28–7.25 (m, 2H),
7.18–7.16 (m, 3H), 6.87 (ddd, J=9.6, 5.2, 3.6 Hz, 1H), 6.03 (ddd, J=9.6,
2.4, 1.2 Hz, 1H), 4.58–4.51 (m, 1H), 4.26–4.20 (m, 1H), 3.80–3.74 (m,
1H), 2.62 (t, J=7.6 Hz, 2H), 2.37–2.30 (m, 2H), 2.07 (ddd, J=8.8, 8.8,
4.4 Hz, 1H), 1.82–1.45 (m, 9H), 0.89 (s, 9H), 0.13 (s, 3H), 0.11 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=164.06 (C), 144.85 (CH), 142.63
(C), 128.40 (CH), 128.38 (CH), 128.23 (CH), 128.21 (CH), 125.60 (CH),
121.47 (CH), 74.84 (CH), 70.27 (CH), 68.87 (CH), 42.98 (CH2), 42.65
(CH2), 37.77 (CH2), 35.88 (CH2), 31.51 (CH2), 30.04 (CH2), 25.77 (CH3 ”
3), 25.07 (CH2), 17.81 (C), À4.23 (CH3), À4.63 ppm (CH3); LCMS: m/z:
432 [M]+; HRMS (FAB): m/z: calcd for C25H41O4Si: 433.2774 [M+H]+;
found: 433.2769.
(R)-6-[(2R,4S,6R)-2,4-Bis(tert-butyldimethylsilyloxy)-6-hydroxyheptyl]-
5,6-dihydro-2H-pyran-2-one (49): Yield: 1.6 mg (from 450 mg resin), 2%;
Rf =0.08 (petroleum ether/ethyl acetate 4:1+0.1% MeOH); [a]2D0 =+
10.5 (c=0.19 in CHCl3); 1H NMR (500 MHz, CDCl3): d=6.87 (ddd, 3J=
9.5, 4.9, 3.6 Hz, 1H), 6.02 (ddd, 3J=9.9, 4J=1.9, 1.9 Hz, 1H) 4.64–4.55
(m, 1H), 4.17–4.07 (m, 2H), 4.01–3.93 (m, 1H), 2.37–2.32 (m, 2H), 2.06
(ddd, 2J=14.4, 3J=8.3, 4.2 Hz, 1H), 1.90 (ddd, 2J=13.6, 3J=7.0, 5.3 Hz,
1H), 1.81–1.57 (m, 4H), 1.18 (d, 3J=6.1 Hz, 3H), 0.90 (s, 9H), 0.88 (s,
9H), 0.12 (s, 3H), 0.09 (s, 3H), 0.07 (s, 3H), 0.65 ppm (s, 3H); 13C NMR
(125 MHz, CDCl3): d=144.4 (CO), 121.2 (CH), 74.4 (CH), 68.8 (CH),
66.0 (CH), 64.5 (CH), 42.9 (CH2), 42.8 (CH2), 42.1 (CH2), 30.1 (CH2),
25.9 (CH3), 24.1 (C), À4.4 ppm (C); LCMS: m/z: 473.1 [M+H]+; MS
(FAB): m/z: 473.5 [M+H]+; HRMS (FAB): m/z: calcd for C24H49O5Si2:
473.3119 [M+H]+; found: 473.3141.
(R)-6-[(2S,4S,6S)-2,4,6-Trihydroxy-10-phenyldecyl]-5,6-dihydro-2H-
pyran-2-one (63): Yield: 4.5 mg (from 700 mg resin), 4.3%; Rf =0.2 (silica
gel, ethyl acetate
+
2% MeOH); [a]2D0 =+25.6 (c=0.44 in CHCl3);
1H NMR (400 MHz, CD3COCD3): d=7.25–7.21 (m, 2H), 7.18–7.12 (m,
3H), 7.01–6.97 (m, 1H), 5.89 (dd, J=9.9, 2.3 Hz, 1H), 4.65–4.60 (m, 1H),
4.14–4.07 (m, 2H), 3.86–3.81 (m, 1H), 2.59 (t, J=7.6 Hz, 2H), 2.55–2.49
(m, 1H), 2.39–2.30 (m, 1H), 2.06–2.04 (m, 2H), 1.90–1.78 (m, 2H), 1.70–
1.45 ppm (m, 8H); 13C NMR (100 MHz, CD3COCD3): d=164.32 (C),
146.71 (CH), 143.54 (C), 129.17 (CH), 129.16 (CH), 129.03 (CH), 126.38
(CH), 121.51 (CH), 76.28 (CH), 72.11 (CH), 68.43 (CH), 44.56 (CH2),
43.34 (CH2), 38.80 (CH2), 36.50 (CH2), 31.75 (CH2), 25.10 ppm (CH2);
LCMS: m/z: 363 [M+H]+; HRMS (FAB): m/z: calcd for C21H31O5:
363.2171 [M+H]+; found: 363.2166.
A
13.11 mmol) and PPTS (217 mg, 1.14 mmol) were added to a stirred solu-
tion of 5-phenylpentanal (1.85 g, 11.42 mmol) in CH2Cl2 (11 mL, 08C).
After stirring at RT for 20 h, solid NaHCO3 (450 mg, 5.36 mmol) was
added and the turbid mixture was stirred for an additional 2 h. Filtration
from the precipitate and flash chromatography of the concentrated fil-
trate (petroleum ether/ethyl acetate 95:5+0.1% MeOH) afforded 1.75 g
(8.01 mmol, 70%) of a colorless oil. Rf =0.19 (petroleum ether/ethyl ace-
tate 9:1+0.1% MeOH); [a]2D0 =À1.0 (c=1.02 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.30–7.25 (m, 2H), 7.19–7.38 (m, 3H), 5.56 (dtq,
2J=15.2, 3J=6.3, 4J=1.2 Hz, 1H), 5.43 (dddq, 2J=15.2, 3J=7.8, 6.3, 4J=
(S)-6-[(2S,4R,6R)-2,4-Bis(tert-butyldimethylsilyloxy)-6-hydroxy-10-phe-
nyldecyl]-5,6-dihydro-2H-pyran-2-one (64): Yield: 12.2 mg (from 700 mg
resin), 10.5%; Rf =0.2 (silica gel, ethyl acetate/petroleum ether 1:4);
[a]2D0 =À34.4 (c=1.22 in CHCl3); 1H NMR (500 MHz, CDCl3): d=7.28–
7.18 (m, 2H), 7.18–7.16 (m, 3H), 6.91–6.88 (m, 1H), 6.01 (dd, J=9.7,
1.7 Hz, 1H), 4.72–4.69 (m, 1H), 4.10–4.07 (m, 2H), 3.68–3.66 (m, 1H),
2.61 (t, J=7.7 Hz, 2H), 2.40–2.37 (m, 1H), 2.28 (t 1/2ABq, J=18.7,
4.5 Hz, 1H), 2.11 (ddd, J=14.7, 8.7, 3.0 Hz, 1H), 1.91–1.85 (m, 1H),
1.71–1.56 (m, 6H), 1.52–1.46 (m, 2H), 1.42–1.38 (m, 2H), 0.89 (s, 9H),
0.88 (s, 9H), 0.11 (s, 3H), 0.09 (s, 3H), 0.05 ppm (brs, 6H); 13C NMR
(125 MHz, CDCl3): d=164.67 (C), 145.36 (CH), 142.88 (C), 128.38 (CH),
128.18 (CH), 125.50 (CH), 121.20 (CH), 74.16 (CH), 69.03 (CH), 68.93
(CH), 66.45 (CH), 45.01 (CH2), 43.92 (CH2), 41.10 (CH2), 38.16 (CH2),
36.00 (CH2), 31.62 (CH2), 30.26 (CH2), 25.82 (CH3 ”6), 25.47 (CH2),
17.98 (C), 17.88 (C), À4.05 (CH3), À4.27 (CH3), À4.53 (CH3), À4.54 ppm
(CH3); LCMS: m/z: 590 [M]+; HRMS (FAB): m/z: calcd for C33H59O5Si2:
591.3901 [M+H]+; found: 591.3944.
1.4 Hz, 1H), 3.61–3.55 (m, 1H,), 2.62 (t, J=7.7 Hz, 2H), 2.22 (dddt, 2J=
3
13.9, 3J=6.3, 4.0, 4J=1.3 Hz, 1H), 2.05 (dddt, 2J=14.0, 3J=7.8, 7.8, 4J=
0.9 Hz, 1H), 1.70 (brd, 3J=6.4 Hz, 1H), 1.68–1.35 ppm (m, 6H);
13C NMR (125 MHz, CDCl3): d=142.62 (C), 129.01 (CH), 128.4 (CH.),
128.2 (d, CH), 127.1 (d, CH), 125.6 (d, CH.), 70.8 (d, CH), 40.7 (CH2),
36.6 (CH2), 35.9 (CH2), 31.5 (CH2), 25.4 (CH2), 18.1 ppm (CH3); HRMS
(FAB): m/z: calcd for C15H23O: 219.1749 [M+H]+; found: 219.1739.
Determination of the loading of 55b on diethylsilylpolystyrene resin: A
sample of the resin was treated with HF/pyridine as described and the re-
sulting solution in THF was compared to a calibration curve taken from
different concentrations of 55b in THF on a Daicel ChirapakAD
column, eluent: n-hexane/isopropanol 98:2, flow 0.5 mLminÀ1
.
(R)-6-[(S)-2-Hydroxy-6-phenylhexyl]-5,6-dihydro-2H-pyran-2-one (ent-
51): Yield: 11 mg (from 300 mg resin), 31%; Rf =0.2 (silica gel, ethyl ace-
tate/petroleum ether 1:1); [a]2D5 =+66 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.29–7.25 (m, 2H), 7.19–7.15 (m, 3H), 6.90–6.86
(m, 1H), 6.02 (brd, J=9.9 Hz, 1H), 4.65–4.62 (m, 1H), 3.91–3.80 (m,
1H), 2.62 (t, J=7.6 Hz, 2H), 2.40–2.38 (m, 2H), 1.98–1.93 (m, 2H), 1.79–
1.75 (m, 1H), 1.67–1.62 (m, 2H), 1.50–1.47 (m, 3H), 1.40–1.36 ppm (m,
1H); 13C NMR (100 MHz, CDCl3): d=163.92 (C), 145.12 (CH), 142.39
(C), 128.35 (CH), 128.26 (CH), 125.67 (CH), 121.26 (CH), 76.90 (CH),
69.02 (CH), 41.91 (CH2), 37.47 (CH2), 35.82 (CH2), 31.31 (CH2), 29.46
(CH2), 25.01 ppm (CH2); LCMS: m/z: 275 [M+H]+.
(4R,6S)-4-Allyl-2,2-dimethyl-6-(4-phenylbutyl)-1,3-dioxane (67): Resin 66
(270 mg, 0.16 mmol) was treated with HF/pyridine and subsequent
column chromatography yielded 24.2 mg (0.10 mmol, 63%) of the free
diol as a colorless oil. This diol (22.8 mg, 0.09 mmol) was dissolved in 2,2-
dimethoxypropane (2 mL). (+)-Camphorsulfonic acid was added (1.8 mg,
0.007 mmol) and the mixture was stirred for 3.5 h at RT. The reaction
mixture was diluted with ethyl acetate (5 mL) and washed with a saturat-
ed aqueous NaHCO3 solution and brine. The organic phase was dried
over magnesium sulfate, concentrated, and then underwent column chro-
matography (silica gel, petroleum ether/ethyl acetate 99:1) to yield
12.0 mg (0.04 mmol, 46%) of a colorless oil. Rf =0.27 (petroleum ether/
ethyl acetate 95:5); [a]D20 =+4.3 (c=1.40 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=7.29–7.26 (m, 2H), 7.19–7.17 (m, 3H), 5.85–5.77 (m, 1H),
5.11–5.04 (m, 2H), 3.89–3.83 (m, 1H), 3.81–3.76 (m, 1H), 2.61 (t, 3J=
(R)-6-[(2S,4S)-2,4-Dihydroxy-8-phenyloctyl]-5,6-dihydro-2H-pyran-2-one
(60): Yield: 2.2 mg (from 270 mg Wang resin), 6.3%; 8.9 mg (from
900 mg diethylsilylpolystyrene resin, loading 0.6 mmolgÀ1), 5%; Rf =0.2
(silica gel, ethyl acetate); [a]2D0 =+55.6 (c=0.27 in CHCl3) (lit.[32b,c]
[a]2D5 =+62.1 (c=1.0 in CHCl3)); 1H NMR (500 MHz, CDCl3): d=7.29–
3
7.26 (m, 2H), 7.18–7.16 (m, 3H), 6.89 (ddd, J=9.4, 4.7, 3.9 Hz, 1H), 6.02
4
2
3
2
(ddd, 3J=9.6, J=1.6, 1.6 Hz, 1H) 4.70–4.64 (m, 1H), 4.15–4.10 (m, 1H),
7.6 Hz, 2H), 2.31 (ddd, J=13.9, J=6.3, 6.3 Hz, 1H), 2.15 (ddd, J=13.8,
Chem. Eur. J. 2007, 13, 3305 – 3319
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3317

H. Waldmann et al.
3J=7.0, 6.9 Hz, 1H), 1.65–1.52 (m, 4H), 1.49 (ddd, 2J=12.8, 3J=2.4,
2.4 Hz, 1H), 1.43 (s, 3H), 1.41–1.34 (m, 2H), 1.40 (s, 3H), 1.12 ppm (ddd,
2J=12.2, 3J=12.0, 12.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=142.7
(C), 134.3 (CH), 128.4 (CH), 128.2 (CH), 125.6 (CH), 117.0 (CH2), 98.4
(C), 68.9 (CH), 68.7 (CH), 40.9 (CH2), 36.5 (CH2), 36.3 (CH2), 35.9
(CH2), 31.5 (CH2), 30.3 (CH3), 24.7 (CH2), 19.8 ppm (CH3); MS (FAB):
m/z: 289.3 [M+H]+; HRMS (FAB): m/z: calcd for C19H29O2: 289.2168
[M+H]+; found: 289.2139.
C
G
(R)-6-[(2R,4R)-2,4-Dihydroxy-8-phenyloctyl]-5,6-dihydro-2H-pyran-2-
one (69): Yield: 5.3 mg (from 875 mg of diethylsilylpolystyrene resin),
3%; Rf =0.25 (silica gel, ethyl acetate + 0.1% MeOH); [a]2D0 =+33.9
(c=0.59 in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.29–7.25 (m, 2H),
3
3
7.20–7.16 (m, 3H), 6.89 (ddd, J=9.7, 5.4, 3.1 Hz, 1H), 6.02 (ddd, J=9.8,
4J=2.3, 1.2 Hz, 1H) 4.78–4.71 (m, 1H), 4.26–4.20 (m, 1H), 3.92–3.87 (m,
3
2
3
1H), 2.62 (t, J=7.7 Hz, 2H), 2.38–2.33 (m, 2H), 1.86 (ddd, J=14.4, J=
9.6, 2.5 Hz, 1H), 1.71 (ddd, 2J=14.4, 3J=10.1, 3.0 Hz, 1H), 1.69–
1.33 ppm (m, 8H); 13C NMR (100.71 MHz, CDCl3): d=164.4 (CO), 145.3
(CH), 142.4 (C), 128.4, 128.3, 125.7 (3”CH), 121.3 (CH), 74.7 (CH), 73.0
(CH), 68.1 (CH), 43.2 (CH2), 43.0 (CH2), 38.2 (CH2), 35.8 (CH2), 31.3
(CH2), 29.9 (CH2), 24.9 ppm (CH2); LCMS: m/z: 319.1 [M+H]+; MS
(FAB): m/z: 319.3 [M+H]+; HRMS (FAB): m/z: calcd for C19H27O4:
319.1909 [M+H]+; found: 319.1898.
Acknowledgements
This research was supported by the Zentrum für Angewandte Chemische
Genetik, the Alexander-von-Humboldt Stiftung (Postdoctoral fellowship
to J.D.U), the Max-Planck-Gesellschaft, the Deutsche Forschungsgemein-
schaft, the Fonds der Chemischen Industrie, and the European Union
(Postdoctoral fellowship to A.B.G.).
(1S,5S,8R,9R)-8,9-Dimethyl-2,6-dioxabicyclo[3.3.1]nonan-3-one (70): The
N
alcohol 23 f (6 mg, 0.03 mmol) was dissolved in anhydrous benzene
(1.5 mL) and treated with pTsOH (2 mg). The mixture was stirred over-
night at RT and was worked up with solid NaHCO3. Filtration, washing
with EtOAc, and removal of the solvent in vacuo afforded a crude prod-
uct which was purified by silica-gel chromatography (ethyl acetate/petro-
leum ether 1:10) to yield 70 (4 mg, 66%). Rf =0.5 (silica gel, ethyl ace-
tate/petroleum ether 1:4); [a]2D0 =À2.3 (c=0.42 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=4.32 (brs, 1H), 4.03 (brs, 1H), 3.85 (d 1/2ABq,
J=13.1, 3.5 Hz, 1H), 3.50 (1/2ABq, J=13.1 Hz, 1H), 2.80 (d 1/2ABq, J=
19.5, 4.8 Hz, 1H), 2.04–2.01 (brd, J=19.5 Hz, 1H), 2.36–2.29 (m, 1H),
2.15–2.08 (m, 1H), 1.17 (d, J=7.2 Hz, 3H), 1.03 ppm (d, J=7.2 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=169.49 (C), 82.26 (CH), 70.59 (CH),
60.82 (CH2), 34.19 (CH), 32.15 (CH2), 27.72 (CH), 15.52 (CH3),
14.09 ppm (CH3); HRMS (FAB): m/z: calcd for C9H15O3: 171.1021
[M+H]+; found: 171.0999.
[1] a) D. P. Walsh, Y. T. Chang, Chem. Rev. 2006, 106, 2476–2530;
b) D. R. Spring, Chem. Soc. Rev. 2005, 34, 472–482; c) A. R. Bus-
kirk, D. Liu, Chem. Biol. 2005, 12, 151–161; d) M. Arkin, Curr.
Opin. Chem. Biol. 2005, 9, 317–324.
[2] For reviews see, for example: a) A. Reayi, P. Arya, Curr. Opin.
Chem. Biol. 2005, 9, 240–247; b) Z. Gan, P. T. Reddy, S. Quevillon,
S. Couve-Bonnaire, P. Arya, Angew. Chem. 2005, 117, 1390–1392;
Angew. Chem. Int. Ed. 2005, 44, 1366–1368; c) R. Breinbauer, I.
Vetter, H. Waldmann, Angew. Chem. 2002, 114, 3002–3015; Angew.
Chem. Int. Ed. 2002, 41, 2879–2890; d) M. A. Koch, H. Waldmann,
Drug Discovery Today 2005, 10, 471–483; e) A. Ganesan, Curr.
Opin. Biotechnol. 2004, 15, 584–590.
A
N
[3] a) S. Shang, D. S. Tan, Curr. Opin. Chem. Biol. 2005, 9, 248–258;
b) M. D. Burke, S. L. Schreiber, Angew. Chem. 2004, 116, 48–60;
Angew. Chem. Int. Ed. 2004, 43, 46–58.
[4] A. Nçren-Müller, I Reis CorrÞa Jr., H. Prinz, C. Rosenbaum, K.
Saxena, H. Schwalbe, D. Vestweber, G. Cagna, S. Schunk, O.
Schwarz, H. Schiewe, H. Waldmann, Proc. Natl. Acad. Sci. USA
2006, 103, 10606–10611.
[5] L. F. Tietze, N. Rackelmann, G. Sekar, Angew. Chem. 2003, 115,
4386–4389; Angew . Chem. Int. Ed. 2003, 42, 4254–4257.
[6] S. Dandapani, M. Jeske, D. P. Curran, Proc. Natl. Acad. Sci. USA
2004, 101, 12008–12012.
(ent-71): DBU (2–5 mL) was added to a stirred solution of diol lactone 46
(8 mg, 0.04 mmol) in CH2Cl2 (3 mL) and the reaction mixture was stirred
at RT for 6 h. The solvent was evaporated and the residue underwent
column chromatography on silica gel (ethyl acetate) to furnish bicyclic
lactone ent-71 (6 mg, 75%). Rf =0.25 (silica gel, ethyl acetate); [a]D25
=
1
À35.8 (c=0.77 in CHCl3); H NMR (400 MHz, CDCl3): d=4.91–4.88 (m,
1H), 4.38–4.36 (m, 1H), 4.13–4.08 (m, 1H), 4.07–4.01 (m, 1H), 2.89 (brd,
J=19.1 Hz, 1H), 2.77 (dd, J=19.1, 5.2 Hz, 1H), 2.04–1.90 (m, 3H), 1.72–
1.61 (m, 3H), 1.20 ppm (d, J=6.2 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d=169.50 (C), 72.90 (CH), 65.94 (CH), 64.42 (CH), 63.54 (CH), 43.52
(CH2), 36.65 (CH2), 36.29 (CH2), 29.67 (CH2), 23.60 ppm (CH3); LCMS:
m/z: 200.9 [M]+; HRMS (FAB): calcd for C10H17O4: 201.1127 [M+H]+;
found: 201.1103.
[7] D. P. Curran, G. Moura-Letts, M. Pohlman, Angew. Chem. 2006, 118,
2483–2486; Angew. Chem. Int. Ed. 2006, 45, 2423–2426.
[8] R. A. Stavenger, S. L. Schreiber, Angew. Chem. 2001, 113, 3525–
3529; Angew. Chem. Int. Ed. 2001, 40, 3417–3421.
A
N
(71): A mixture of resin 35 (319 mg, 0.10 mmol) in TFA/CH2Cl2 1:2
(20 mLgÀ1 resin, 6.4 mL) was shaken for 15 min at RT. The resin was fil-
tered off and washed with CH2Cl2. The filtrate was co-evaporated with
toluene. The residue was filtrated through silica gel (CH2Cl2/MeOH 9:1)
to obtain the diol ent-46, which was dissolved in anhydrous benzene
(1.5 mL) and treated with pTsOH (0.12 equiv, 0.012 mmol, 2 mg). The
mixture was stirred overnight at RT and was then worked up by addition
of solid NaHCO3. Filtration, washing with ethyl acetate, and removal of
the solvent in vacuo afforded a crude product which was purified by
silica-gel chromatography (CH2Cl2/MeOH 0–5%) to yield 71 (7.5 mg,
38%). [a]2D0 =+26.35 (c=0.63 in CHCl3); IR (KBr): n˜ =3437, 2926, 2860,
1731 (CO), 1353, 1070, 986 cmÀ1; MS (EI): m/z: 141 [MÀC3H7O]+, 156
[MÀC2H5O]+, 167 [MÀCH4O]+; HRMS (FAB): m/z: calcd for C10H17O4:
201.1049 [M+H]+; found: 201.1114.
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Received: November 28, 2006
Published online: February 20, 2007
Chem. Eur. J. 2007, 13, 3305 – 3319
ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3319