The remarkable effect of cosolvent on a samarium(II)-mediated 4-exo-trig cyclization: Further synthetic studies on pestalotiopsin A

Article abstract of DOI:10.1021/jo026827o

A samarium(II)-mediated 4-exo-trig cyclization in which a remote stereocenter serves to control the facial selectivity of the cyclization is described. The apparent coordination of a tertbutyldimethylsilyl ether to the samarium center appears to give rise

Full text of DOI:10.1021/jo026827o

Th e Rem a r k a ble Effect of Cosolven t on a Sa m a r iu m (II)-Med ia ted
4-exo-tr ig Cycliza tion : F u r th er Syn th etic Stu d ies on
P esta lotiop sin A
David J . Edmonds, Kenneth W. Muir, and David J . Procter*
Department of Chemistry, The J oseph Black Building, University of Glasgow,
Glasgow, G12 8QQ Scotland, U.K.
davidp@chem.gla.ac.uk
Received December 10, 2002
A samarium(II)-mediated 4-exo-trig cyclization in which a remote stereocenter serves to control
the facial selectivity of the cyclization is described. The apparent coordination of a tert-
butyldimethylsilyl ether to the samarium center appears to give rise to the selectivity. The
remarkable effect of the cosolvent, 2,2,2-trifluoroethanol, on the cyclization of this substrate, is
also discussed. A stereoselective synthesis of the general class of γ,δ-unsaturated aldehyde
cyclization substrate is reported, and the utility of the cyclization is demonstrated in an approach
to the fully functionalized core of pestalotiopsin A.
SCHEME 1 a
In tr od u ction
Samarium(II) iodide continues to be used widely
throughout organic synthesis. This mild, single-electron
reductant has been used to mediate a broad range of
radical and anionic transformations.1 We have recently
developed a stereoselective approach to functionalized
cyclobutanols via the samarium(II)-mediated 4-exo-trig
cyclizations of γ,δ-unsaturated aldehydes.2,3 This cycliza-
tion proceeds under mild conditions and allows the
generation of up to three contiguous stereocenters with
excellent stereocontrol. We have recently applied this
cyclization in the first synthetic studies on the structur-
ally intriguing natural product, pestalotiopsin A 4 (Scheme
1).4,5 The pestalotiopsins are an interesting class of
caryophyllene-type sesquiterpenes, isolated from Pesta-
lotiopsis sp., an endophytic fungus of Taxus brevifolia.5
Pestalotiopsin A is of particular interest, possessing
a unique oxa-tricyclic structure.6 In our preliminary
approach, cyclization of aldehyde 1 proceeded in high
yield to give anti-cyclobutanol 2. Cyclobutanol 2 could
a
Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C,
79%.
(1) For reviews on the use of samarium(II) iodide in organic
synthesis, see: (a) Soderquist, J . A. Aldrichim. Acta 1991, 24, 15. (b)
Molander, G. A. Chem. Rev. 1992, 92, 29-68. (c) Molander, G. A. Org.
React. 1994, 46, 211. (d) Molander, G. A.; Harris, C. R. Chem. Rev.
1996, 96, 307. (e) Molander, G. A.; Harris, C. R. Tetrahedron 1998,
54, 3321. (f) Krief, A.; Laval, A.-M. Chem. Rev. 1999, 99, 745. (g) Steel,
P. G. J . Chem. Soc., Perkin Trans. 1 2001, 2727.
(2) (a) J ohnston, D.; McCusker, C. M.; Procter, D. J . Tetrahedron
Lett. 1999, 40, 4913. (b) J ohnston, D.; McCusker, C. F.; Muir, K.;
Procter, D. J . J . Chem. Soc., Perkin Trans. 1 2000, 681.
(3) Prior to our work, a single example of such a cyclization had
been described by Weinges: Weinges, K.; Schmidbauer, S. B.; Schick,
H. Chem. Ber. 1994, 127, 1305.
(4) J ohnston, D.; Francon, N.; Edmonds, D. J .; Procter, D. J . Org.
Lett. 2001, 3, 2001.
(5) (a) Pulici, M.; Sugawara, F.; Koshino, H.; Uzawa, J .; Yoshida,
S.; Lobkovsky, E.; Clardy, J . J . Org. Chem. 1996, 61, 2122. (b) Pulici,
M.; Sugawara, F.; Koshino, H.; Okada, G.; Esumi, Y.; Uzawa, J .;
Yoshida, S. Phytochemistry 1997, 46, 313.
F IGURE 1. Synthetic approach to pestalotiopsin A.
then be readily converted to bicyclic lactones, such as 3,
which are precursors of the core of the natural product.
In this paper, we will describe the incorporation of a
stereocontrol element into substrates such as 1 to control
the facial selectivity of the cyclization thus leading to
enantiomerically pure cyclobutanol products. Enantio-
merically pure aldehydes 5 (Figure 1) were selected as
ideal cyclization substrates. We envisaged the derivatized
hydroxyl substituent on the lactone ring would control
the facial selectivity of the 4-exo-trig cyclization, despite
its remote position relative to the reacting centers.
According to our synthetic strategy, Figure 1, the direct-
ing hydroxyl substituent will be incorporated into the
target compound, becoming the C7-OH of pestalotiopsin
(6) Kende has reported a synthetic intermediate having a related
structure in his approach to Punctaporin B. See ref 13a.
10.1021/jo026827o CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/13/2003
3190
J . Org. Chem. 2003, 68, 3190-3198

Synthetic Studies on Pestalotiopsin A
SCHEME 2 a
F IGURE 2. Possible origins of remote stereocontrol in the
samarium(II)-mediated 4-exo-trig cyclization.
A. Our studies have resulted in the first synthesis of the
fully functionalized core of pestalotiopsin A.
Resu lts a n d Discu ssion
We envisaged two possible roles for the derivatized
hydroxyl stereocontrol element in generic substrates 5.
First, if the lactone substituent is bulky and noncoordi-
nating (Figure 2), we envisaged a steric blocking effect,
forcing radical attack on the opposite face of the olefin.
Alternatively, with a coordinating group in this position,
the samarium(III) radical anion might be delivered to the
same face of the alkene (Figure 2) via a nine-membered
chelate.7 We expected the nature of stereocontrol in the
cyclization would depend markedly on the nature of the
“R” substituent in the substrates.
a
Reagents and conditions: (i) LDA, THF-HMPA (4:1), -78 to
-30 °C, 86%, dr 1:1; (ii) TBDMSCl, imidazole, DMF, rt, 92% for
9a and 84% for 9b; (iii) MsCl, NEt3, CH2Cl2, -5 °C, 89%, E-only;
(iv) MsCl, NEt3, CH2Cl2, -5 °C to rt, 37% of 10 and 46% of 11; (v)
MsCl, 2,6-lutidine, CH2Cl2, 40 °C, 80%, E only.
In the synthesis of aldehydes 5, it was crucial that the
double-bond could be formed stereoselectively. In previ-
ous studies, we have shown that the anti selectivity of
the 4-exo-trig cyclization is dependent upon the initial
double-bond stereochemistry.4 We chose to proceed via
the aldol reaction of readily available (S)-â-hydroxy-γ-
butyrolactone 78 with aldehyde 6,2a followed by a regio-
and stereocontrolled dehydration to introduce the olefin
moiety.
Reaction of lactone 7 with aldehyde 6 proceeded in
excellent yield, giving a 1:1 mixture of the aldol products
8a -syn and 8b-a n ti. The stereochemistry of 8b-a n ti was
confirmed by single-crystal X-ray analysis,9 and that of
8a -syn was inferred from literature observations.8 The
ring hydroxyl in both 8a -syn and 8b-a n ti could be
protected with complete selectivity to give the mono-
silylated aldols 9a and 9b. Dehydration of syn adduct
9a (MsCl, NEt3, -5 °C) proceeded smoothly and rapidly
to give the E-alkene 10 as the only product, and in
excellent yield (Scheme 2). The stereochemistry of the
double bond in 10 was confirmed by single-crystal X-ray
analysis.9 The reaction of 9b under similar conditions
SCHEME 3 a
a
Reagents and conditions: (i) SmI2, THF-MeOH (4:1), 0 °C,
25%.
proceeded very slowly to give a mixture of 10 and the
corresponding Z-alkene 11 in 83% overall yield. Pleas-
ingly, the use of 2,6-lutidine in place of triethylamine in
the dehydration of 9b resulted in the formation of the
E-alkene 10 as the only detectable product in high yield.
Thus, both 8a and 8b can be efficiently converted to the
E-alkene 10. Deprotection of 10 under standard condi-
tions (MeI, CaCO3, aq MeCN, 60 °C, 99%) gave cycliza-
tion substrate 12.
With an efficient route to the TBDMS-protected
substrate 12 in place, we began to investigate the
samarium(II)-mediated cyclization. On treatment with
SmI2 in THF-MeOH, 12 underwent rapid reaction to
give a complex mixture of products from which only
cyclobutanol 13 could be isolated in low yield (Scheme
3). The stereochemistry of 13 was determined by single-
crystal X-ray analysis.9 Further studies on the cyclization
in MeOH allowed us to identify the elimination product
14 as one byproduct. Cyclobutanol 14 is presumably
formed by the elimination of the tert-butyldimethylsilyl-
oxy substituent from the intermediate samarium(III)
enolate. The elimination of the OTBDMS moiety appears
(7) Large chelates are not uncommon in SmI2-mediated transforma-
tions. Eight-membered chelates in particular have been invoked to
rationalize stereoselectivity in a number of reactions; see: (a) Evans,
D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447. (b) Molander,
G. A.; Etter, J . B.; Harring, L. S.; Thorel, P.-J . J . Am. Chem. Soc. 1991,
113, 8036. (c) Molander, G. A.; McKie, J . A. J . Am. Chem. Soc. 1993,
115, 5821. (d) Keck, G. E.; Truong, A. P. Org. Lett. 2002, 4, 3131.
(8) Prestwich has shown that aldol reactions of the dianion derived
from this lactone proceed with approach of the aldehyde from the
opposite face to the ring alkoxide; see: Shieh, H.-M.; Prestwich, G. D.
J . Org. Chem. 1981, 46, 4319.
(9) See the Supporting Information for details of X-ray analyses of
compounds 8b, 10, 13, epi-13, and 15.
J . Org. Chem, Vol. 68, No. 8, 2003 3191

Edmonds et al.
SCHEME 4 a
SCHEME 5 a
a
Reagents and conditions: (i) SmI2, THF, CF3CH2OH-MeOH
(3:1), 0 °C, 80% (13, 52%; epi-13, 6%; 15, 22%).
to be responsible for the low mass recovery in this
reaction. Additional byproducts can be envisaged, arising
from the further reduction of 14.
a
Reagents and conditions: (i) HF (40% aq), pyridine, MeCN, 0
°C to rt, 97%; (ii) TBDPSCl, imidazole, DMF, rt, 54%; (iii) MeI,
CaCO3, MeCN-H2O 4:1, 60 °C, 83%.
We believe the stereochemistry of cyclobutanol 13
suggests a cyclization directed by coordination of the
incoming samarium(III)-radical anion to the tert-
butyldimethylsilyloxy group (Figure 2). This was unex-
pected, as it has been observed that TBDMS ethers
appear not to coordinate to samarium(III).10 In an at-
tempt to disrupt any possible chelation, the cyclization
was carried out in the presence of HMPA.11 However,
HMPA is well-known to dramatically increase the reduc-
tion potential of SmI2,12 thus changing the very nature
of the reagent system. No products could be isolated from
this reaction. Studies using MeOD gave complete deu-
terium incorporation R- to the lactone carbonyl in 13,
confirming that the reaction concludes by protonation of
an intermediate samarium(III) enolate. In the formation
of 13, this protonation appears to occur from the more
hindered face, possibly due to protonation by a methanol
molecule coordinated to a samarium(III) center.
To improve the cyclization process, we investigated the
use of a less activating, more acidic alcohol cosolvent,
capable of tempering the reduction potential of SmI2
while ensuring rapid protonation of the intermediate
samarium(III) enolate, thus preventing elimination. With
these properties in mind, we felt fluorous alcohols might
prove suitable alternative cosolvents for the cyclization.
Pleasingly, cyclization using 2,2,2-trifluoroethanol as
cosolvent gave cyclobutanol products, 13/epi-13 and 15,
now in an excellent overall yield of 80%, with only a trace
of elimination (Scheme 4). Thus, the judicial choice of
cosolvent clearly has a remarkable effect on the efficiency
of the transformation. The stereochemistry of epi-13 and
15 was determined by single-crystal X-ray analysis.9 The
stereochemistry of cyclobutanol 15 suggests it arises from
a cyclization where the controlling group blocks one face
of the olefin acceptor, forcing the radical to approach from
the opposite face (see Figure 2). The ratio of “directed”
to “blocked” products was 2.6:1 (Scheme 4).
SCHEME 6 a
a
i
Reagents and conditions: (i) MOMCl, Pr2NEt, CH2Cl2, 0 °C
to rt, 98%; (ii) MeI, CaCO3, MeCN-H2O 2:1, rt, 82%.
TBDPS ether 18 and the potentially more coordinating
MOM ether 20. We chose to access these substrates from
alkene 10. Removal of the TBDMS protecting group from
alkene 10 was best achieved using aqueous HF in
acetonitrile-pyridine, giving alcohol 16 in excellent yield.
Protection as the TBDPS ether 17 and cleavage of the
thioacetal protecting group gave substrate 18 in good
yield (Scheme 5).
The MOM cyclization substrate 20 was prepared in a
similar manner. Protection of alcohol 16 under standard
conditions proceeded efficiently to give MOM ether 19.
Removal of the thioacetal protecting group proved trouble-
some in this case. After investigation of a number of
alternative methods, our original procedure was modified.
Using lower temperatures and a prolonged reaction time,
a good yield of the desired aldehyde 20 was obtained
(Scheme 6).
Treatment of aldehyde 18 with SmI2 in THF-methanol
led to complex mixtures of products. This could not be
improved using our trifluoroethanol conditions. The
major product observable in the crude NMR, and the only
isolable product, was the cyclobutanol 14. Attempts to
cyclize the MOM ether 20 with SmI2, using either
methanol or trifluoroethanol as cosolvent similarly led
to complex product mixtures, which in this case also
contained acyclic aldehyde byproducts. The study of
substrates 18 and 20 therefore failed to provide further
insight into the cyclization process. The TBDMS cycliza-
tion substrate 12 provides the most efficient progress
toward pestalotiopsin A.
With an efficient route to cyclobutanols 13 and 15 in
hand, we continued our synthetic approach. Crucially,
13 and 15 are potential precursors to either enantiomer
of the pestalotiopsin core. This is desirable as the
absolute stereochemistry of the natural product is not
known. Our approach should allow synthetic studies to
be carried out in either enantiomeric series starting from
In an attempt to investigate the role of the derivatized
hydroxyl in the cyclization, we prepared the bulky
(10) For the role of an OTBDMS group in a samarium(II)-mediated
reduction, see: Keck, G. E.; Wager, C. A. Org. Lett. 2000, 2, 2307.
(11) HMPA is known to disrupt chelation in SmI2-mediated trans-
formations, leading to a loss of stereoselectivity. For an illustrative
example, see: Fukazawa, S.-I.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J .
Am. Chem. Soc. 1997, 119, 1482.
(12) Shabangi, M.; Flowers, R. A. Tetrahedron Lett. 1997, 38, 1137.
(b) Shabangi, M.; Sealy, J . M.; Fuchs, J . R.; Flowers, R. A. Tetrahedron
Lett. 1998, 39, 4429. (c) Enemaerke, R. J .; Hertz, T.; Skrydstrup, T.;
Daasbjerg, K. Chem. Eur. J . 2000, 6, 3747. (d) Miller, R. S.; Sealy, J .
M.; Shabangi, M.; Kuhlman, M. L.; Fuchs, J . R.; Flowers, R. A. J . Am.
Chem. Soc. 2000, 122, 7718.
3192 J . Org. Chem., Vol. 68, No. 8, 2003

Synthetic Studies on Pestalotiopsin A
SCHEME 7 a
This was confirmed by NOE studies on the diastereo-
meric mixture. Key NOE observations are shown in
Figure 3. The reduction to lactol 26 constitutes the first
synthesis of the fully functionalized core of pestalo-
tiopsin A.
Con clu sion s
In summary, we have developed an efficient stereose-
lective route to generic cyclization substrates 5 from (S)-
â-hydroxy-γ-butyrolactone, featuring an aldol reaction
and convergent, selective dehydration. The cyclization of
one such substrate proceeds efficiently in the presence
of 2,2,2-trifluoroethanol as cosolvent. We have shown that
the remote stereocontrol element in this substrate is
capable of modest control of facial selectivity in the
samarium(II)-mediated 4-exo-trig cyclization. The nature
of stereocontrol appears to involve the unexpected coor-
dination of an OTBDMS ether to a samarium center. We
have applied this methodology to the stereoselective
synthesis of the fully functionalized core of pestalotio-
psin A.
a
Reagents and conditions: (i) TPAP, NMO, CH2Cl2, rt, 95% for
21, 90% for 23; (ii) vinyl ytterbium triflate, THF, -78 °C, 68% for
22, 81% for 24.
SCHEME 8 a
Exp er im en ta l Section
a
Gen er a l Con sid er a tion s. THF was freshly distilled from
sodium-benzophenone ketyl radical under a nitrogen atmo-
sphere and CH2Cl2 from calcium hydride. DMF was distilled
under vacuum from calcium hydride and stored over 3 Å
sieves. Triethylamine and 2,6-lutidine were distilled from
calcium hydride and stored over KOH pellets. HMPA was
distilled and stored over 3 Å sieves. Reactions were carried
out using oven-dried glassware. NMR spectra were obtained
using a Fourier transform spectrometer, operating at 400 MHz
for 1H and 100 MHz for 13C spectra. NMR signals were
assigned using DEPT-135, HMQC, and COSY spectra. Proton
spectra are referenced to residual CHCl3 at 7.270 ppm, and
carbon spectra to CDCl3 at 77.4 ppm. IR spectra were recorded
using a Fourier transform spectrometer. Mass spectra and
microanalyses were recorded at the University of Glasgow.
Samarium(II) iodide was prepared by the method of Ima-
moto and Ono, with the modification that the samarium-
iodine-THF mixture was heated at 60 °C rather than at
reflux.14
Reagents and conditions: (i) TESCl, imidazole, DMF, rt, 81%;
(ii) DIBAL-H, CH2Cl2, -78 °C, 97%, dr 3.4:1 (major isomer shown).
F IGURE 3. Key NOE observations for lactol 26.
a single enantiomer of starting material. For example,
cyclobutanol 13 was oxidized to cyclobutanone 21, which
was then treated with vinylytterbium triflate, according
to our previously described addition/trans-lactonization
sequence,4,13 giving bicyclic lactone 22 in good yield
(Scheme 7).
Cr ysta l Str u ctu r e An a lyses of 8b, 10, 13, epi-13, a n d
15. All measurements were made at 100 K using a Nonius
KappaCCD diffractometer and Mo KR X-rays, λ ) 0.710 73 Å.
Except for 13, the expected absolute structures were confirmed
experimentally from the X-ray data. This was not possible for
13 because the crystals were of poor quality, displaying
twinning and high mosaicity. However, our proposed molecular
structure for 13 has been confirmed by two independent
analyses. Only the better of these two analyses is described
here.
(3S,4S)-3-[(1S)-3-([1,3]Dith ia n -2-yl)-1-h yd r oxy-3-m eth -
ylbu tyl]-4-h yd r oxy-4,5-d ih yd r ofu r a n -2(3H)-on e 8a a n d
(3S,4S)-3-[(1R)-3-([1,3]Dith ia n -2-yl)-1-h yd r oxy-3-m eth yl-
bu tyl]-4-h yd r oxy-4,5-d ih yd r ofu r a n -2(3H)-on e 8b. To a
stirred solution of diisopropylamine [3.16 mL, 22.5 mmol, 3.8
equiv (2.3 equiv with respect to lactone)] in dry THF (25 mL)
at -78 °C under argon was added n-butyllithium (10.7 mL,
2.10 M in hexanes, 22.5 mmol, 3.8 equiv) dropwise, and the
mixture was stirred for 50 min. To the resulting LDA solution
was added â-hydroxy-γ-butyrolactone 7 (1.00 g, 9.80 mmol,
1.65 equiv) in THF (1.5 mL) dropwise, via cannula at -78 °C.
After a further 90 min, a solution of aldehyde 6 (1.21 g, 5.92
mmol, 1 equiv) in dry THF (6 mL) and HMPA (7 mL) was
Cyclobutanol 15 was also subjected to oxidation and
the addition/trans-lactonization sequence. Oxidation gave
cyclobutanone 23, which reacted smoothly with vinyl-
ytterbium triflate to give bicyclic lactone 24 in excellent
yield (Scheme 7). Lactones 22 and 24 can be considered
as pseudoenantiomers, lactone 22 simply requiring in-
version of the stereochemistry at C-7 to allow access to
the opposite enantiomer of the target.
Continuing our approach, the pendant primary alcohol
of lactone 22 was protected as the triethylsilyl ether 25
before reduction of the lactone carbonyl. Treatment of the
lactone with DIBAL-H at -78 °C gave lactol 26, which
was initially isolated as a 3.4:1 mixture of diastereoiso-
mers (Scheme 8). This mixture was found to equilibrate
on standing in CDCl3 solution, and as such, no attempt
was made to separate the diastereoisomers.
We envisaged that the major product would arise from
hydride attack from the convex face of the bicyclic system.
(13) For a similar addition/trans-lactonization sequence on a cy-
clobutanone substrate, see: (a) Kende, A. S.; Kaldor, I.; Aslanian, R.
J . Am. Chem. Soc. 1988, 110, 6265. (b) Kende, A. S.; Kaldor, I.
Tetrahedron Lett. 1989, 30, 7329.
(14) Imamoto, T.; Ono, M. Chem. Lett. 1987, 501.
J . Org. Chem, Vol. 68, No. 8, 2003 3193

Edmonds et al.
added dropwise via cannula at -78 °C and the solution allowed
to warm to -30 °C over 3 h. After 1 h, the reaction was
quenched with 10 mL of aq satd NH4Cl and the aqueous layer
extracted with 60% EtOAc in petroleum ether (40-60 °C). The
combined organic layers were washed with aq satd NaHCO3
and dried over MgSO4. Concentration followed by column
chromatography (silica gel, 60% EtOAc in petroleum ether
(40-60 °C)) gave the aldols 8a /b (1.33 g mg, 4.33 mmol, 73%)
as a 1:1 mixture of diastereomers, along with aldehyde 6 (185
mg, 0.91 mmol, 15%). Overall yield of the adducts was 86%
based on recovered starting material. Repeated chromatogra-
phy allowed separation of the 8a -syn and 8b-a n ti as a
colorless oil and a colorless solid, respectively. The anti-aldol
8b crystallized from hexane/CHCl3 to give colorless needles
(mp 90-93 °C), from which an X-ray crystal structure was
obtained (see the Supporting Information): MS m/z (EI mode)
306.1 (8) [M]+, 199.1 (5), 160.0 (7), 119.0 (100), 82.9 (15); HRMS
calcd for C13H22O4S2 306.0960, found 306.0963. Anal. Calcd
for C13H22O4S2: C, 50.95; H, 7.24. Found: C, 50.86; H, 7.23.
8a : νmax (film)/cm-1 3434br,m (OH), 2960m, 2931m, 2900m
(C-H), 1751s (CdO), 1176m; [R]D ) +7.10 (c ) 1.24, CHCl3);
1H NMR δ 1.19 (3H, s, 3H from C(CH3)2), 1.23 (3H, s, 3H from
C(CH3)2), 1.79-1.88 (1H, m, 1H from CH2CH2S), 1.97 (2H, d,
J ) 5.2 Hz, CMe2CH2), 2.09-2.16 (1H, m, 1H from CH2CH2S),
2.52 (1H, t, J ) 6.3 Hz, CHC(O)O), 2.69 (1H, d, J ) 3.5 Hz,
OH), 2.88-2.93 (4H, m, 2 × CH2S), 3.46 (1H, d, J ) 4.3 Hz,
OH), 4.03 (1H, dd, J ) 6.3, 9.2 Hz, 1H from CH(OH)CH2O),
4.24 (1H, s, CHS2), 4.28 (1H, apparent quintet, J ) 5.4 Hz,
CMe2CH2CH(OH)), 4.48 (1H, dd, J ) 6.9, 9.2 Hz, 1H from CH-
(OH)CH2O), 4.77 (1H, apparent dq, J ) 3.1, 6.6 Hz, CH(OH)-
CH2O); 13C NMR δ 26.2 (CH2CH2S), 26.6 (CH3), 27.3 (CH3),
31.6 (CH2S), 31.7 (CH2S), 39.0 (CMe2), 45.8 (CMe2CH2), 55.5
(CHC(O)O), 60.3 (CHS2), 67.9 (CMe2CH2CH(OH)), 69.8 (CH-
(OH)CH2O), 72.8 (CH2O), 176.0 (CdO).
Si 420.1825, found 420.1827; νmax (film)/cm-1 3473m (OH),
2956s, 2929s, 2898m, 2857m (CH), 1771s (CdO), 1471m,
1256m; [R]D ) -8.51 (c ) 1.01, CHCl3); 1H NMR δ 0.10 (3H, s,
3H from Si(CH3)2), 0.15 (3H, s, 3H from Si(CH3)2), 0.90 (9H, s,
Si(CH3)3), 1.16 (3H, s, 3H from C(CH3)2), 1.21 (3H, s, 3H from
C(CH3)2), 1.70 (1H, dd, AB system, J ) 1.4, 15.2 Hz, 1H from
CMe2CH2), 1.78-1.85 (1H, m, 1H from CH2CH2S), 1.98 (1H,
dd, AB system, J ) 9.5, 15.2 Hz, 1H from CMe2CH2), 2.08-
2.14 (1H, m, 1H from CH2CH2S), 2.53 (1H, dd, J ) 3.3, 5.6
Hz, CHC(O)O), 2.86-2.92 (4H, m, 2 × CH2S), 3.06 (1H, d, J )
4.9 Hz, OH), 3.97 (1H, dd, J ) 5.2, 9.0 Hz, 1H from CH-
(OTBDMS)CH2O), 4.28 (1H, s, CHS2), 4.38-4.43 (2H, m, 1H
from CH(OTBDMS)CH2O and CH(OH)), 4.75 (1H, apparent
q, J ) 5.6 Hz, CH(OTBDMS)). 13C NMR δ -4.4 (Si(CH3)), -3.9
(Si(CH3)), 18.1 (SiC(CH3)3) 26.0 (SiC(CH3)3) 26.3 (CH2CH2S),
26.6 (CH3), 26.9 (CH3), 31.6 (CH2S), 31.7 (CH2S), 38.8 (CMe2),
45.6 (CMe2CH2), 56.9 (CHC(O)O), 60.2 (CHS2), 66.8 (CH(OH)),
68.8 (CH(OTBDMS)), 74.4 (CH2O), 176.8 (CdO).
(3S,4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-[(1R)-3-([1,3]-
dith ian -2-yl)-1-h ydr oxy-3-m eth ylbu tyl]-4,5-dih ydr ofu r an -
2(3H)-on e 9b. Similarly, a solution of the anti-aldol 8b (340
mg, 1.11 mmol), imidazole (378 mg, 5.55 mmol), and TBDMSCl
(502 mg 3.32 mmol) in dry DMF (1.0 mL) was stirred at room
temperature for 19 h to give, after column chromatography
(silica gel, 30% EtOAc/petroleum ether (40-60 °C)), the
monoprotected anti-aldol 9b (393 mg, 0.935 mmol, 84%) as a
waxy white solid (mp 67-68 °C): νmax (golden gate)/cm-1
3490br,w (OH), 2927m, 2856m, (CH), 1761 (CdO), 1462m,
1
1105m, 998s; [R]D ) -74.2 (c ) 1.00, CHCl3); H NMR δ 0.10
(3H, s, 3H from Si(CH3)2), 0.13 (3H, s, 3H from Si(CH3)2), 0.90
(9H, s, Si(CH3)3), 1.20 (6H, s, C(CH3)2), 1.70 (1H, dd, AB
system, J ) 1.5, 15.4 Hz, 1H from CMe2CH2), 1.79-1.85 (1H,
m, 1H from CH2CH2S), 2.07-2.12 (1H, m, 1H from CH2CH2S),
2.21 (1H, dd, AB system, J ) 9.9, 15.5 Hz, 1H from CMe2CH2),
2.46 (1H, dd, J ) 4.5, 5.7 Hz, CHC(O)O), 2.86-2.91 (4H, m, 2
× CH2S), 3.28 (1H, d, J ) 3.3 Hz, OH), 3.97 (1H, dd, J ) 5.3,
9.0 Hz, 1H from CH2O), 4.11-4.18 (1H, m, CH(OH)), 4.27 (1H,
s, CHS2), 4.41 (1H, dd, J ) 6.4, 9.0 Hz, 1H from CH2O), 4.55
(1H, apparent q, J ) 5.9 Hz, CH(OTBDMS)); 13C NMR δ -4.3
(Si(CH3)), -4.1 (Si(CH3)), 18.2 (SiC(CH3)3), 26.0 (SiC(CH3)3)
26.3 (CH2CH2S), 26.7 (CH3), 27.1 (CH3), 31.6 (CH2S), 31.7
(CH2S), 38.7 (CMe2), 45.7 (CMe2CH2), 56.3 (CHC(O)O), 60.2
(CHS2), 67.9 (CH(OH)), 71.6 (CH(OTBDMS)), 74.2 (CH2O),
176.3 (CdO).
8b: νmax (golden gate)/cm-1 3255m (OH), 2966m, 2898m
(CH), 1757s (CdO), 1168m, 1078m, 997m; [R]D ) -50.8 (c )
1
1.03, CHCl3); H NMR δ 1.18 (3H, s, 3H from C(CH3)2), 1.20
(3H, s, 3H from C(CH3)2), 1.64 (1H, dd, J ) 1.2, 15.4 Hz, AB
system, 1H from CMe2CH2), 1.74-1.86 (1H, m, 1H from CH2-
CH2S), 2.03-2.14 (2H, m, 1H from CH2CH2S and 1H, AB
system, from CMe2CH2), 2.59 (1H, t, J ) 5.6 Hz, CHC(O)O),
2.84-2.92 (4H, m, 2 × CH2S), 3.08 (1H, broad s, OH), 3.69
(1H, broad s, OH), 4.06 (1H, dd, J ) 5.5, 9.4 Hz, 1H from CH-
(OH)CH2O), 4.09-4.46 (2H, m, CHS2 and CMe2CH2CH(OH)),
4.49 (1H, dd, J ) 6.6, 9.4 Hz, 1H from CH(OH)CH2O), 4.77
(1H, apparent q, J ) 6.0 Hz, CH(OH)CH2O); 13C NMR δ 26.3
(CH2CH2S), 26.8 (CH3), 27.0 (CH3), 31.6 (CH2S), 31.7 (CH2S),
38.8 (CMe2), 45.2 (CMe2CH2), 55.4 (CHC(O)O), 60.4 (CHS2),
68.1 (CMe2CH2CH(OH)), 70.6 (CH(OH)CH2O), 73.5 (CH2O),
176.5 (CdO). X-ray analysis of 8b: C13H22O4S2, M ) 306.43,
space group P212121, a ) 8.3999(1) Å, b ) 12.2442(2) Å, c )
29.2148(4) Å, Z ) 8, Dc ) 1.355 Mg/m3 , θmax ) 32.6°. Intensity
measurements: Nmeas, ) 15664; unique reflections, Nunique, )
5864 [Rint ) 0.039]; least-squares observations including
Friedel pairs, Nref , ) 9906; no. of parameters, Np, ) 351, R(F)
) 0.050, wR(F2) ) 0.091, Flack parameter ) -0.06(4), |∆F| <
(4S)-(E)-4-(ter t-Bu tyldim eth ylsilyloxy)-3-[3-([1,3]dith ian -
2-yl)-3-m eth ylbu tylid en e]-4,5-d ih yd r ofu r a n -2-on e 10 a n d
(4S)-(Z)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-[3-([1,3]d ith ia n -
2-yl)-3-m et h ylb u t ylid en e]-4,5-d ih yd r ofu r a n -2-on e 11.
Meth od A: F r om 9a . To a stirred solution of 9a (185 mg,
0.440 mmol) in dry CH2Cl2 (4.4 mL) at -5 °C under argon were
added triethylamine (0.91 mL, 6.53 mmol, 15 equiv) and
methanesulfonyl chloride (0.17 mL, 2.20 mmol, 5 equiv). The
reaction mixture was maintained between -5 and -10 °C for
2.5 h. The reaction was quenched with 3 mL of aq satd
NaHCO3, and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried over Na2SO4. Con-
centration followed by column chromatography (silica gel, 40%
EtOAc in petroleum ether (40-60 °C)) gave the E-olefin 10
(158 mg, 0.392 mmol, 89%) as a white solid.
0.39 e‚Å-3
.
(3S,4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-[(1S)-3-([1,3]-
dith ian -2-yl)-1-h ydr oxy-3-m eth ylbu tyl]-4,5-dih ydr ofu r an -
2(3H)-on e 9a . To a stirred solution of the syn-aldol 8a (660
mg, 2.15 mmol) in dry DMF (1.6 mL) under argon were added
imidazole (733 mg, 10.8 mmol, 5 equiv) and TBDMSCl (974
mg, 6.46 mmol, 3 equiv), and the reaction mixture was stirred
for 2 h at room temperature. The reaction was quenched with
4 mL of aq satd NaHCO3, and the aqueous layer was extracted
into 50% EtOAc in petroleum ether (40-60 °C). The combined
organic layers were washed with water and dried over Na2-
SO4. Concentration followed by column chromatography (silica
gel, 30% EtOAc in petroleum ether (40-60 °C)) gave the
monoprotected syn-aldol 9a (831 mg, 1.98 mmol, 92%) as a
viscous oil: MS m/z (EI mode) 420.1 (5) [M]+, 363.0 (3), 313.1
(8), 160.0 (11), 119.1 (100), 75.0 (33); HRMS calcd for C19H36O4S2-
Meth od B: F r om 9b. To a stirred solution of 9b (40 mg,
0.0951 mmol) in dry CH2Cl2 (1 mL) at -10 °C under argon
were added triethylamine (0.20 mL, 1.93 mmol, 20 equiv) and
methanesulfonyl chloride (35 µL, 0.475 mmol, 5 equiv). The
reaction mixture was maintained between -15 and -5 °C for
42 h before warming to room temperature for 5 h. The reaction
was quenched with 2 mL of aq satd NaHCO3 and the aqueous
layer extracted with CH2Cl2. The combined organic layers were
dried over Na2SO4 and concentrated to give a crude mixture
of the E- and Z-olefins. 1H NMR showed E/Z ) 1:1.5. The
olefins were easily separated by column chromatography (silica
gel, 20% EtOAc in petroleum ether (40-60 °C)) to give the
3194 J . Org. Chem., Vol. 68, No. 8, 2003

Synthetic Studies on Pestalotiopsin A
E-olefin 10 (14.0 mg, 0.0347 mmol, 37%) and the Z-olefin 11
(17.7 mg, 0.0440 mmol, 46%) as a white solid (mp 62-63 °C).
995s; [R]D ) -125.2 (c ) 0.98, CHCl3); 1H NMR δ 0.12 (3H, s,
3H from Si(CH3)2), 0.17 (3H, s, 3H from Si(CH3)2), 0.91 (9H, s,
Si(CH3)3), 1.15 (3H, s, 3H from C(CH3)2), 1.17 (3H, s, 3H from
C(CH3)2), 2.51 (1H, ddd, J ) 1.0, 7.1, 15.2 Hz, 1H from
CMe2CH2), 2.58 (1H, dd, J ) 8.5, 15.2 Hz, 1H from CMe2CH2),
4.10 (1H, dd, J ) 3.1, 9.8 Hz, 1H from CH2O), 4.44 (1H, dd, J
) 6.3, 9.8 Hz, 1H from CH2O), 5.08-5.10 (1H, m, CH(OTB-
DMS)), 6.89 (1H, ddd, J ) 2.0, 7.1, 8.8 Hz, CHdC), 9.50 (1H,
s, CHO); 13C NMR δ -4.3 (Si(CH3)), -3.8 (Si(CH3)), 18.2
(SiC(CH3)3), 21.6 (CH3), 22.3 (CH3), 26.0 (SiC(CH3)3), 36.0 (CH2-
CHdC), 46.2 (CMe2), 67.2 (CH(OTBDMS)), 74.3 (CH2O), 131.3
(CHdC), 141.6 (CHdC), 169.9 (C(O)O), 204.6 (CHO).
Meth od C: F r om 9b. To a stirred solution of 9b (150 mg,
0.357 mmol) in dry CH2Cl2 (3.5 mL) at room temperature
under argon were added 2,6-lutidine (0.71 mL, 6.06 mmol, 17
equiv) and methanesulfonyl chloride (0.14 mL, 1.78 mmol, 5
equiv). The reaction mixture was then heated at 40 °C for 22
h. The reaction was quenched with 5 mL of aq satd NaHCO3
and the aqueous layer extracted with CH2Cl2. The combined
extracts were washed with 0.5 M CuSO4 and dried over
MgSO4. Concentration followed by column chromatography
(silica gel, 20% EtOAc/petroleum ether (40-60 °C)) gave
1
E-olefin 10 (115 mg, 0.286 mmol, 80%). H NMR of the crude
(3S,4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-[(1R,2R)-2-h y-
d r oxy-3,3-d im et h ylcyclob u t yl]-4,5-d ih yd r ofu r a n -2(3H)-
on e 13, (3R,4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-3-[(1R,2R)-
2-h yd r oxy-3,3-d im e t h ylcyclob u t yl)-4,5-d ih yd r ofu r a n -
2(3H)-one epi-13,and (3R,4S)-4-(tert-Butyldimethylsilyloxy)-
3-[(1S ,2S )-2-h y d r o x y -3,3-d i m e t h y lc y c lo b u t y l)-4,5-
d ih yd r ofu r a n -2(3H)-on e 15. To a solution of SmI2 (3.52 mL,
0.1 M in THF, 0.352 mmol, 2.2 equiv), CF3CH2OH (0.85 mL),
and MeOH (0.29 mL) at 0 °C under argon was added aldehyde
12 (50 mg, 0.160 mmol) in THF solution (1 mL), via cannula.
After 30 min, the reaction was quenched with aq satd NaCl
(5 mL) and water (15 mL). The aqueous layer was extracted
with 60% EtOAc in petroleum ether (40-60 °C), and the
combined organic layers were dried over MgSO4 and concen-
trated. Column chromatography (silica gel, 30% EtOAc in
petroleum ether (40-60 °C)) gave cyclobutanols 13 (26.1 mg,
0.0830 mmol, 52%), epi-13 (2.9 mg, 0.0092 mmol, 6%), and
15 (11.1 mg, 0.0353 mmol, 22%), all as white crystalline solids.
showed the E-olefin as the only detectable product.
The E-olefin 10 crystallized from petroleum ether (40-60
°C) to give colorless crystals (mp 109-112 °C) from which a
crystal structure was obtained (see the Supporting Informa-
tion): MS m/z (EI mode) 402.2 (3) [M]+, 345.0 (4), 283.1 (10),
161.0 (54), 119.0 (100), 75.0 (20); HRMS calcd for C19H34O3S2-
Si 402.1719, found 402.1720. Anal. Calcd for C19H34O3S2Si: C,
56.67; H, 8.51. Found: C, 56.51; H, 8.57.
10: νmax (golden gate)/cm-1 2929m, 2900m, 2856m (CH),
1741s (CdO), 1681m, 1209s, 1097s, 993s; [R]D ) -125.2 (c )
1
1.00, CHCl3); H NMR δ 0.12 (3H, s, 3H from Si(CH3)2), 0.18
(3H, s, 3H from Si(CH3)2), 0.90 (9H, s, Si(CH3)3), 1.16 (3H, s,
3H from C(CH3)2), 1.19 (3H, s, 3H from C(CH3)2), 1.78-1.83
(1H, m, 1H from CH2CH2S), 2.07-2.12 (1H, m, 1H from CH2-
CH2S), 2.43 (1H, ddd, J ) 1.2, 5.4, 15.4 Hz, 1H from CMe2CH2),
2.69 (1H, dd, J ) 9.9, 15.4 Hz, 1H from CMe2CH2), 2.84-2.92
(4H, m, 2 × CH2S), 4.02 (1H, s, CHS2), 4.12 (1H, dd, J ) 2.6,
9.8 Hz, 1H from CH2O), 4.41 (1H, dd, J ) 6.1, 9.8 Hz, 1H from
CH2O), 5.12-5.14 (1H, m, CH(OTBDMS)), 7.00 (1H, ddd, J )
1.8, 5.4, 9.8 Hz, CHdC); 13C NMR δ -4.2 (Si(CH3)), -3.7 (Si-
(CH3)), 18.3 (SiC(CH3)3), 25.8 (CH3), 25.9 (CH3), 26.0 (SiC-
(CH3)3), 26.3 (CH2CH2S), 31.6 (2 × CH2S), 39.4 (CMe2), 40.4
(CH2CHdC), 60.3 (CHS2), 67.2 (CH(OTBDMS)), 74.7 (CH2O),
131.0 (CHdC), 142.9 (CHdC), 170.4 (CdO). X-ray analysis of
13. Cyclobutanol 13 crystallized from CHCl3/petroleum
ether (40-60 °C) to give colorless needles (mp 127 °C), from
which an X-ray crystal structure was obtained (see the
Supporting Information): MS m/z (EI+ mode) 314.2 (4) [M]+,
257.1 (13), 243.1 (42), 201.1 (18), 173.1 (12), 117.0 (100), 73.1
(59), 59.0 (16); HRMS calcd for C16H30O4Si 314.1913, found
314.1913; νmax (golden gate)/cm-1 3436m (OH), 2952m, 2929m,
2858m (CH), 1739s (CdO), 1461m, 1419w, 1394w, 1361w,
1245w, 1110m, 1082s, 993s; [R]D ) -26.6 (c ) 1.47, CHCl3);
1H NMR δ 0.07 (3H, s, 3H from Si(CH3)2), 0.09 (3H, s, 3H from
Si(CH3)2), 0.85 (9H, s, Si(CH3)3), 1.13 (6H, s, C(CH3)2), 1.30
(1H, apparent t, J ) 10.0 Hz, 1H from CMe2CH2), 1.74 (1H,
apparent t, J ) 10.0 Hz, 1H from CMe2CH2), 2.12-2.21 (1H,
m, CH(OH)CH), 2.53 (1H, dd, J ) 5.9, 9.9 Hz, CHCdO), 2.62
(1H, d, J ) 3.4 Hz, OH), 3.80 (1H, dd, J ) 3.4, 7.6 Hz,
CH(OH)), 3.98 (1H, dd, J ) 5.4, 9.2 Hz, 1H from CH2O), 4.25
(1H, apparent q, J ) 5.8 Hz, CH(OTBDMS)), 4.41 (1H, dd, J
) 6.0, 9.2 Hz, 1H from CH2O); 13C NMR δ -4.5 (Si(CH3)), -4.2
(Si(CH3)), 18.2 (SiC(CH3)3), 21.2 (CH3), 26.0 (SiC(CH3)3), 28.9
(CH3), 33.0 (CMe2CH2), 39.6 (CMe2), 40.3 (CH(OH)CH), 53.1
(CHC(O)O), 73.1 (CH(OTBDMS)), 74.2 (CH2O), 78.0 (CH(OH)),
178.1 (CdO). X-ray analysis of 13: C16H30O4Si, M ) 314.49,
space group P21, a ) 6.4174(2) Å, b ) 25.1035(7) Å, c )
10:
C19H34O3S2Si, M ) 402.67, space group P212121, a )
6.3021(1) Å, b ) 11.8532(6) Å, c ) 28.975(2) Å, Z ) 4, Dc )
1.236 Mg/m3, θmax ) 27.6°. Nmeas ) 9003; Nunique, ) 2775 [Rint
) 0.067]; Nref ) 4525; Np, ) 233, R(F) ) 0.044, wR(F2) ) 0.090,
Flack parameter ) -0.05(7), |∆F| < 0.34 e‚Å-3
.
11: νmax (golden gate)/cm-1 2958m, 2925m, 2887m, 2852m
(CH), 1738s (CdO), 1674m, 1384m, 1105m, 991s; [R]D ) -51.4
1
(c ) 1.01, CHCl3); H NMR δ 0.11 (3H, s, 3H from Si(CH3)2),
0.15 (3H, s, 3H from Si(CH3)2), 0.93 (9H, s, Si(CH3)3), 1.15 (6H,
s, C(CH3)2), 1.81-1.87 (1H, m, 1H from CH2CH2S), 2.07-2.12
(1H, m, 1H from CH2CH2S), 2.82-2.93 (5H, m, 2 × CH2S and
1H from CMe2CH2), 3.02-3.07 (1H, m, 1H from CMe2CH2),
3.98 (1H, dd, J ) 5.2, 9.2 Hz, 1H from CH2O), 4.04 (1H, s,
CHS2), 4.40 (1H, dd, J ) 6.6, 9.0 Hz, 1H from CH2O), 4.87-
4.90 (1H, m, CH(OTBDMS)), 6.52-6.56 (1H, apparent t, J )
9.2, CH×C); 13C NMR δ -4.2 (Si(CH3)), -4.1 (Si(CH3)), 18.4
(SiC(CH3)3), 25.5 (CH3), 25.6 (CH3), 26.1 (SiC(CH3)3) 26.4 (CH2-
CH2S), 31.8 (2 × CH2S), 37.7 (CH2CHdC), 40.0 (CMe2), 60.9
(CHS2), 70.3 (CH(OTBDMS)), 73.2 (CH2O), 130.7 (CHdC),
143.7 (CHdC), 168.8 (CdO).
11.5090(3) Å, â ) 91.53(1)°, Z ) 4, Dc ) 1.127 Mg/m3 , θmax
)
27.6°. Nmeas ) 14055; Nunique ) 4142 [Rint ) 0.098]; Nref ) 7535;
Np ) 380, R(F) ) 0.12, wR(F2) ) 0.30, absolute structure not
determined, |∆F| < 1.3 e‚Å-3
.
epi-13. Cyclobutanol epi-13 crystallized from petroleum
ether (40-60 °C) to give colorless needles (mp 106-107 °C)
from which an X-ray crystal structure was obtained (see the
Supporting Information): νmax (golden gate)/cm-1 3479w (OH),
2950m, 2929m, 2856m (CH), 1741s (CdO), 1462m, 1385w,
1360w, 1323m, 1097m, 993s; [R]D ) -4.1 (c ) 1.00, CHCl3);
1H NMR δ 0.11 (3H, s, 3H from Si(CH3)2), 0.13 (3H, s, 3H from
Si(CH3)2), 0.91 (9H, s, Si(CH3)3), 1.09 (3H, s, 3H from C(CH3)2),
1.11 (3H, s, 3H from C(CH3)2), 1.36 (1H, apparent t, J ) 10.2
Hz, 1H from CMe2CH2), 1.78 (1H, apparent t, J ) 10.2 Hz,
1H from CMe2CH2), 1.87 (1H, d, J ) 6.9 Hz, OH), 2.39-2.47
(1H, m, CH(OH)CH), 2.64 (1H, apparent t, J ) 6.4 Hz, CHCd
O), 3.90 (1H, apparent t, J ) 6.9 Hz, CH(OH)), 4.04 (1H,
dd, J ) 3.4, 9.6 Hz, 1H from CH2O), 4.25 (1H, dd, J ) 4.7, 9.6
Hz, 1H from CH2O), 4.62 (1H, ddd, J ) 3.4, 4.7, 5.9 Hz,
(E)-4-[(4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-2-oxo-4,5-d i-
h ydr ofu r an -3-yliden e]-2,2-dim eth ylbu tan al 12. To a stirred
solution of 10 (150 mg, 0.373 mmol) in MeCN (2.2 mL) and
water (1.1 mL) at room temperature were added CaCO3 (112
mg, 1.12 mmol, 3 equiv) and MeI (0.70 mL, 11.2 mmol, 30
equiv). The solution was heated to 60 °C and stirred for 18 h.
After this time, the solution was cooled and passed through a
short plug column (silica gel) eluted with 40% EtOAc in
petroleum ether (40-60 °C). Concentration gave the aldehyde
12 (115 mg, 0.368 mmol, 99%) as a white solid (mp 92 °C),
which was used without further purification: MS m/z (FAB+
mode) 313.2 (84) [M + H]+, 283.2 (9), 255.1 (34), 181.1 (63),
139.1 (17), 117.2 (9), 73.8 (100), 60.0 (14); HRMS calcd for
C
16H29O4Si 313.1835, found 313.1837; νmax (golden gate)/cm-1
2929m, 2856m (C-H), 1745s, 1725s (CdO), 1685w, 1463m,
J . Org. Chem, Vol. 68, No. 8, 2003 3195

Edmonds et al.
CH(OTBDMS)); 13C NMR δ -4.4 (Si(CH3)), -4.3 (Si(CH3)), 18.4
(SiC(CH3)3), 21.0 (CH3), 26.1 (SiC(CH3)3), 28.4 (CH3), 32.4
(CMe2CH2), 37.2 (CH(OH)CH), 39.6 (CMe2), 47.9 (CHC(O)O),
71.1 (CH(OTBDMS)), 73.7 (CH2O), 77.0 (CH(OH)), 176.5 (Cd
O). X-ray analysis of epi-13: C16H30O4Si, M ) 314.49, space
group P21, a ) 6.5054(1) Å, b ) 10.3069(1) Å, c ) 27.6367(4)
Å, â ) 95.565(1)°, Z ) 4, Dc ) 1.133 Mg/m3 , θmax ) 30.0°.
Nmeas ) 18910; Nunique ) 5552 [Rint ) 0.031]; Nref ) 10290; Np
) 395, R(F) ) 0.048, wR(F2) ) 0.087, Flack parameter 0.01-
mmol, 54%) as a colorless oil: MS m/z (FAB+ mode) 527.1 [M
+ H]+, 526.1 [M]+, 469.1, 407.1, 352.1, 271.1, 199.1, 161.1,
119.2, 73.8; HRMS calcd for C29H39O3S2Si [M + H]+ 527.21102,
found 527.2108; νmax (golden gate)/cm-1 2929, 2856 (CH), 1759
(CdO), 1675, 1461, 1427, 1388, 1105, 995; [R]D ) -53.3, (c )
1
0.92, CHCl3); H NMR δ 0.96 (3H, s, 3H from C(CH3)2), 1.06
(9H, s, Si(CH3)3), 1.08 (3H, s, 3H from C(CH3)2), 1.73-1.78 (1H,
m, 1H from CH2CH2S), 2.03-2.07 (1H, m, 1H from CH2CH2S),
2.16 (1H, dd, J ) 4.7, 15.2 Hz, 1H from CMe2CH2), 2.32 (1H,
dd, J ) 10.7, 15.2 Hz, 1H from CMe2CH2), 2.68-2.91 (4H, m,
2 × CH2S), 3.82 (1H, s, CHS2), 3.99 (1H, dd, J ) 5.3, 10.5 Hz,
1H from CH2O), 4.23 (1H, dd, J ) 1.4, 10.5 Hz, 1H from CH2O),
5.10 (1H, apparent d, J ) 5.0 Hz, CH(OTBDPS)), 6.93 (1H,
dd, J ) 3.6, 10.8 Hz, CHdC), 7.37-7.49 (6H, m, 6H from ArH),
7.68-7.74 (4H, m, 4H from ArH); 13C NMR δ 19.7 (SiC(CH3)3),
25.6 (CH3), 25.7 (CH3), 26.3 (CH2CH2S), 27.2 (SiC(CH3)3), 31.6
(CH2(CH2S)2), 39.3 (CMe2), 41.1 (CH2CHdC), 60.0 (CHS2), 68.3
(CH(OTBDPS)), 74.5 (CH2O), 128.1 (ArCH), 128.4 (2C from
ArCH), 130.0 (ArCH), 130.6 (ArCH), 131.3 (CHdC), 132.9
(ArCSi), 133.5 (ArCSi), 135.2 (ArCH), 136.3 (2C from ArCH),
142.5 (CHdC), 170.7 (CdO).
(6), |∆F| < 0.34 e‚Å-3
.
15. Cyclobutanol 15 crystallized from petroleum ether (40-
60 °C) to give colorless needles (mp 105 °C) from which an
X-ray crystal structure was obtained (see the Supporting
Information): νmax (golden gate)/cm-1 3452br,w (OH), 2952m,
2929m, 2858m (CH), 1749s (CdO), 1462m, 1361w, 1245m,
1
1095m, 993s; [R]D ) -61.8 (c ) 1.05, CHCl3); H NMR δ 0.09
(6H, s, Si(CH3)2), 0.91 (9H, s, Si(CH3)3), 1.06-1.11 (1H, m, 1H
from CMe2CH2), 1.13 (3H, s, 3H from C(CH3)2), 1.15 (3H, s,
3H from C(CH3)2), 1.73 (1H, apparent t, J ) 9.0 Hz, 1H from
CMe2CH2), 2.40-2.46 (1H, m, CH(OH)CH), 2.50 (1H, dd, J )
4.7, 10.7 Hz, CHC(O)O), 3.24 (1H, broad s, OH), 3.82 (1H, d,
J ) 7.7 Hz, CH(OH)), 4.20 (1H, d, J ) 10.0 Hz, 1H from CH2O),
4.30 (1H, dd, J ) 3.2, 10.0 Hz, 1H from CH2O), 4.62 (1H, dd,
J ) 3.2, 4.7 Hz, CH(OTBDMS)); 13C NMR δ -4.8 (Si(CH3)),
-4.2 (Si(CH3)), 18.3 (SiC(CH3)3), 21.3 (CH3), 25.9 (SiC(CH3)3),
29.2 (CH3), 33.4 (CMe2CH2), 35.7 (CH(OH)CH), 39.2 (CMe2),
51.8 (CHC(O)O), 70.0 (CH(OTBDMS)), 76.0 (CH2O), 78.2 (CH-
(OH)), 179.1 (CdO). X-ray analysis of 15: C16H30O4Si, M )
314.49, space group P212121, a ) 6.3837(1) Å, b ) 14.1709(3)
Å, c ) 20.0712(5) Å, Z ) 4, Dc ) 1.150 Mg/m3 , θmax ) 27.5°.
Nmeas ) 28522; Nunique ) 2397 [Rint ) 0.075]; Nref ) 4150; Np )
198, R(F) ) 0.045, wR(F2) ) 0.085, Flack parameter -0.03-
(E)-4-[(4S)-4-(ter t-Bu tyld im eth ylsilyloxy)-2-oxo-4,5-d i-
h ydr ofu r an -3-yliden e]-2,2-dim eth ylbu tan al 18. To a stirred
solution of thioacetal 17 (60 mg, 0.114 mmol) in MeCN (2 mL)
and water (0.5 mL) at room temperature were added CaCO3
(34 mg, 0.342 mmol, 3 equiv) and MeI (0.21 mL, 3.42 mmol,
30 equiv). The solution was heated to 60 °C and stirred for 24
h. After this time, the solution was cooled and passed through
a plug column (silica gel) eluted with 30% EtOAc in petroleum
ether (40-60 °C). Concentration gave the aldehyde 18 (41.3
mg, 0.0946 mmol, 83%) as a white solid (mp 71-74 °C): MS
m/z (FAB+ mode) 437.2 (40) [M + H]+, 410.3 (25), 379.1 (33),
199.0 (35), 181.0 (45), 136.0 (42), 73.7 (100; HRMS calcd for
(10), |∆F| < 0.23 e‚Å-3
.
C
26H33O4Si 437.2148, found 437.2148; νmax (golden gate)/cm-1
(4S)-(E)-3-[3-([1,3]Dith ia n -2-yl)-3-m eth ylbu tylid en e]-4-
h yd r oxy-4,5-d ih yd r ofu r a n -2-on e 16. To a stirred solution
of the TBDMS ether 10 (150 mg, 0.373 mmol) in MeCN (13.0
mL) and pyridine (6.50 mL) at 0 °C was added HF (1.65 mL,
40% aq soln) dropwise, and the solution was allowed to warm
slowly to room temperature. After 43 h, the reaction was
quenched by the careful addition of aq satd NaHCO3 (ap-
proximately 40 mL) and the aqueous layer extracted with 70%
EtOAc in petroleum ether (40-60 °C). The organic extracts
were washed with 0.1 M CuSO4 solution, combined, and dried
over Na2SO4. Concentration gave the alcohol 16 (104 mg, 0.362
mmol, 97%) as a colorless oil: MS m/z (EI+ mode) 288.1 [M]+,
160.0, 119.0; HRMS calcd for C13H20O3S2 288.0854, found
288.0852; νmax (film)/cm-1 3421 (OH), 2964, 2931, 2900 (CH),
1745 (CdO), 1675; [R]D ) -53.3 (c ) 1.21, CHCl3); 1H NMR δ
1.22 (3H, s, 3H from C(CH3)2), 1.29 (3H, s, 3H from C(CH3)2),
1.73-1.84 (1H, m, 1H from CH2CH2S), 2.06-2.13 (1H, m, 1H
from CH2CH2S), 2.32 (1H, dd, J ) 5.3, 14.9 Hz, 1H from
CMe2CH2), 2.80 (1H, dd, J ) 10.8, 14.9 Hz, 1H from CMe2CH2),
2.81-2.94 (4H, m, 2 × CH2S), 3.57 (1H, broad s, OH), 3.95
(1H, s, CHS2), 4.31 (1H, dd, J ) 1.3, 10.2 Hz, 1H from CH2O),
4.38 (1H, dd, J ) 5.3, 10.2 Hz, 1H from CH2O), 5.05 (1H,
apparent d, J ) 4.2 Hz, CH(OH)), 6.97 (1H, ddd, J ) 1.3, 5.3,
10.8 Hz, CHdC); 13C NMR δ 25.9 (CH2CH2S), 26.1 (CH3), 26.2
(CH3), 31.3 (CH2S), 31.4 (CH2S), 39.6 (CMe2), 41.4 (CH2CHd
C), 59.3 (CHS2), 65.6 (CH(OH)), 74.1 (CH2O), 132.5 (CHdC),
141.4 (CHdC), 170.4 (CdO).
(4S)-(E)-4-(ter t-Bu tyldiph en ylsilyloxy)-3-[3-([1,3]dith ian -
2-yl)-3-m eth ylbu tylid en e]-4,5-d ih yd r ofu r a n -2-on e 17. To
a stirred solution of alcohol 16 (28 mg, 0.0971 mmol) in dry
DMF (0.1 mL) at room temperature under argon were added
TBDPSCl (75 µL, 0.291 mmol, 3 equiv) and imidazole (33 mg,
0.485 mmol, 5 equiv). The reaction mixture was then stirred
overnight before quenching with aq satd NaHCO3 (1 mL) and
water (1 mL). The aqueous layer was extracted with 50%
EtOAc in petroleum ether (40-60 °C), and the extracts were
combined and dried (Na2SO4). Concentration followed by
column chromatography (silica gel, 20% EtOAc in petroleum
ether (40-60 °C)) gave the TBDPS ether 17 (27.6 mg, 0.0524
2962w, 2859w (CH), 1752s (CdO), 1714m (CdO), 1681m,
1464m, 1425s, 1194s, 1105s, 991s; [R]D ) -67.7 (c ) 0.90,
CHCl3); 1H NMR δ 0.957 (3H, s, 3H from C(CH3)2), 0.964 (3H,
s, C(CH3)2), 1.06 (9H, s, Si(CH3)3), 2.14-2.25 (2H, m, CMe2CH2),
3.96 (1H, dd, J ) 5.5, 10.2 Hz, 1H from CH2O), 4.23 (1H, dd,
J ) 1.9, 10.2 Hz, 1H from CH2O), 5.38 (1H, apparent d, J )
5.4 Hz, CH(OTBDPS)), 6.80 (1H, ddd, J ) 1.6, 6.5, 8.9 Hz,
CHdC), 7.36-7.50 (6H, m, 6H from ArH), 7.66-7.74 (4H, m,
4H from ArH), 9.28 (1H, s, CHO); 13C NMR δ 19.7 (SiC(CH3)3),
21.4 (CH3), 21.9 (CH3), 27.1 (SiC(CH3)3), 36.5 (CH2CHdC), 46.1
(CMe2), 68.1 (CH(OTBDPS)), 74.2 (CH2O), 128.3 (4 × ArCH),
128.4 (2 × ArCH), 130.6 (ArCH), 130.7 (ArCH), 131.5 (CHd
C), 132.8 (ArCSi), 133.2 (ArCSi), 136.2 (4 × ArCH), 141.3 (CHd
C), 170.2 (C(O)O), 204.3 (CHO).
(4S)-(E)-3-[3-([1,3]Dith ia n -2-yl)-3-m eth ylbu tylid en e]-4-
m eth oxym eth oxy-4,5-d ih yd r ofu r a n -2-on e 19. To a stirred
solution of alcohol 16 (90 mg, 0.312 mmol) in dry CH2Cl2 (0.5
i
mL) and Pr2NEt (0.5 mL) under argon at 0 °C was added
MOMCl (140 µL, approximately 1.25 mmol, 4 equiv) and the
solution allowed to warm slowly to rt over 24 h. A further
approximately 4 equiv of MOMCl was then added and the
solution stirred for a further 17 h. The reaction was quenched
by the addition of water (5 mL). The aqueous layer was
extracted with 60% EtOAc in petroleum ether (40-60 °C), and
the combined extracts were washed with aq satd NaHCO3 and
dried (Na2SO4). Concentration gave the MOM ether 19 (102
mg, 0.307 mmol, 98%) as a pale yellow oil. This was used
without further purification: MS m/z (FAB+ mode) 333.1 [M
+ H]+, 332.1 [M+], 271.1 160.1, 119.2, 89.6, 77.7; HRMS calcd
for C15H24O4S2 332.1194, found 332.1193; υmax (film)/cm-1 2961,
2897 (CH), 1761 (CdO), 1678; [R]D -49.9 (c ) 1.61, CHCl3);
1H NMR δ 1.16 (3H, s, 3H from C(CH3)2), 1.20 (3H, s, 3H from
C(CH3)2), 1.74-1.85 (1H, m, 1H from CH2CH2S), 2.04-2.13
(1H, m, 1H from CH2CH2S), 2.47 (1H, dd, J ) 6.0, 15.0 Hz,
1H from CMe2CH2), 2.68 (1H, dd, J ) 9.7, 15.0 Hz, 1H from
CMe2CH2), 2.81-2.95 (4H, m, 2 × CH2S), 3.43 (3H, s, CH3O),
4.00 (1H, s, CHS2), 4.36 (1H, dd, J ) 2.3, 10.4 Hz, 1H from
CH2O), 4.41 (1H, dd, J ) 5.4, 10.4 Hz, 1H from CH2O), 4.70
3196 J . Org. Chem., Vol. 68, No. 8, 2003

Synthetic Studies on Pestalotiopsin A
(1H, AB system, d, J ) 7.1, 1H from CH2O2), 4.75 (1H, AB
system, d, J ) 7.1, 1H from CH2O2), 5.00-5.01 (1H, m,
EtOAc in petroleum ether (40-60 °C), and the combined
organic portions were dried over MgSO4 and concentrated.
Column chromatography of the residue (silica gel, 20% EtOAc
in petroleum ether (40-60 °C)) gave the bicyclic lactone 22
(30.7 mg, 0.090 mmol, 68%) as a colorless oil: MS m/z (FAB+
mode) 341.2 (42) [M + H]+, 283.1 (18), 165.1 (27), 117.1 (24),
CH(OMOM)), 7.09 (1H, ddd, J ) 1.7, 6.1, 9.7 Hz, CHdC); 13
C
NMR δ 26.0 (2 × CH3), 26.3 (CH2CH2S), 31.6 (2 × CH2S), 39.6
(CMe2), 40.5 (CH2CHdC), 56.6 (CH3O), 60.5 (CHS2), 71.6
(CH(OMOM)), 72.6 (CH2O), 96.1 (CH2O2), 128.9 (CHdC), 144.4
(CHdC), 170.2 (CdO).
73.7 (100); HRMS calcd for
C18H33O4Si 341.2148, found
341.2143; νmax (golden gate)/cm-1 3325w,br (OH), 2927m,
2856m (CH), 1751s (CdO), 1462m, 1247m, 1039m, 926m, 835s,
(E)-4-[(4S)-4-Meth oxym eth oxy-2-oxo-4,5-d ih yd r ofu r a n -
3-ylid en e]-2,2-d im eth ylbu ta n a l 20. To a solution of thioac-
etal 19 (102 mg, 0.307 mmol) in acetonitrile (1.2 mL) and water
(0.6 mL) at rt under argon were added CaCO3 (92 mg, 0.920
mmol, 3 equiv) and MeI (0.57 mL, 9.20 mmol, 30 equiv), and
the solution was stirred for 44 h. The solution was then passed
through a plug column (silica gel, 60% EtOAc in petroleum
ether (40-60 °C)). Concentration gave the aldehyde 20 (60.8
mg, 0.251 mmol, 82%) as a colorless oil: MS m/z (FAB+ mode)
243.2 [M + H]+, 181.1, 137.1, 136.1, 107.3, 77.7, 63.9, 52.1;
HRMS calcd for C12H19O5 243.1232, found 243.1230; νmax (film)/
cm-1 2960m (CH), 1755s, (CdO), 1720s (CdO), 1682m, 1468m,
1381w, 1207m, 1147s, 1009s, 916m; [R]D -56.9 (c ) 0.98,
CHCl3); 1H NMR δ 1.16 (3H, s, 3H from C(CH3)2), 1.18 (3H, s,
3H from C(CH3)2), 2.51 (1H, dd, J ) 7.1, 15.0 Hz, 1H from
CMe2CH2), 2.58 (1H, dd, J ) 8.7, 15.0 Hz, 1H from CMe2CH2),
3.43 (3H, s, CH3O), 4.37 (1H, dd, J ) 2.2, 10.4 Hz, 1H from
CH2O), 4.43 (1H, dd, J ) 5.6, 10.4 Hz, 1H from CH2O), 4.69
(1H, AB system, d, J ) 7.1, 1H from CH2O2), 4.73 (1H, AB
system, d, J ) 7.2, 1H from CH2O2), 4.95 (1H, apparent d, J
) 5.5 Hz, CH(OMOM)), 6.98 (1H, ddd, J ) 1.7, 7.2, 8.7 Hz,
CHdC), 9.41 (1H, s, CHO); 13C NMR δ 21.7 (CH3), 22.3 (CH3),
36.5 (CH2CHdC), 46.3 (CMe2), 56.3 (CH3O), 71.1 (CH(O-
MOM)), 72.4 (CH2O), 95.8 (CH2O2), 129.1 (CHdC), 143.0 (CHd
C), 169.7 (C(O)O), 204.5 (CHO).
(3S,4S)-4-(ter t-Bu t yld im et h ylsilyloxy)-3-[(1R)-3,3-d i-
m eth yl-2-oxocyclobu tyl]-4,5-d ih yd r ofu r a n -2(3H)-on e 21.
To a stirred solution of 13 (15 mg, 0.048 mmol) in dry CH2Cl2
(0.9 mL) under argon at room temperature was added 4 Å
molecular sieves followed by NMO (23 mg, 0.190 mmol, 4
equiv) and a catalytic quantity of TPAP (few crystals). The
solution was stirred for 2 h before passing the mixture through
a short plug column eluting with 20% EtOAc in petroleum
ether (40-60 °C). Concentration gave the cyclobutanone 21
(15 mg, 0.048 mmol, 100%) and as a white crystalline solid
(mp 67-69 °C): MS m/z (CI+ mode) 313.2 (27) [M + H]+, 83.0
(7), 57.1 (100); HRMS calcd for C16H29O4Si 313.1835, found
313.1836; νmax (golden gate)/cm-1 2960m, 2929m, 2857m (CH),
1772s, 1755s (CdO), 1460m, 1385w, 1361w, 1255m, 1169m,
1005s; [R]D ) -62.2 (c ) 0.77, CHCl3); 1H NMR δ 0.08 (3H, s,
3H from Si(CH3)2), 0.10 (3H, s, 3H from Si(CH3)2), 0.90 (9H, s,
SiC(CH3)3), 1.20 (3H, s, 3H from C(CH3)2), 1.29 (3H, s, 3H from
C(CH3)2), 2.04 (1H, apparent t, J ) 10.9 Hz, 1H from
CMe2CH2), 2.27 (1H, dd, J ) 8.9, 10.7 Hz, 1H from CMe2CH2),
2.69 (1H, dd, J ) 4.1, 7.2 Hz, CHC(O)O), 3.71 (1H, ddd, J )
4.1, 8.8, 11.1 Hz, CHC(O)CMe2), 3.91 (1H, dd, J ) 6.3, 8.9 Hz,
1H from CH2O), 4.46 (1H, dd, J ) 6.5, 8.9 Hz, 1H from CH2O),
4.57 (1H, apparent q, J ) 6.5 Hz, CH(OTBDMS)); 13C NMR δ
-4.5 (Si(CH3)), -4.2 (Si(CH3)), 18.2 (SiC(CH3)3), 21.4 (CH3),
24.4 (CH3), 26.0 (SiC(CH3)3), 29.8 (CMe2CH2), 47.6 (CHC(O)O),
51.7 (CHC(O)CMe2), 58.3 (CMe2), 72.3 (CH(OTBDMS)), 73.2
(CH2O), 175.4 (C(O)O), 214.9 (CMe2C(O)).
1
777s; [R]D ) +31.9 (c ) 1.13, CHCl3); H NMR δ 0.05 (3H, s,
3H from Si(CH3)2), 0.09 (3H, s, 3H from Si(CH3)2), 0.88 (9H, s,
SiC(CH3)3), 1.09 (3H, s, 3H from C(CH3)2), 1.13 (3H, s, 3H from
C(CH3)2), 1.56 (1H, dd, J ) 6.4, 12.1 Hz, 1H from CMe2CH2),
1.94 (1H, br s, OH), 2.06 (1H, dd, J ) 9.1, 12.1 Hz, 1H from
CMe2CH2), 2.83 (1H, dd, J ) 2.0, 5.4 Hz, CHC(O)O), 3.11 (1H,
ddd, J ) 2.0, 6.4, 8.8 Hz, CHCH2CMe2), 3.58 (1H, dd, J ) 5.6,
11.4 Hz, 1H from CH2O), 3.71 (1H, dd, J ) 3.6, 11.4 Hz, 1H
from CH2O), 3.96-4.00 (1H, m, CH(OTBDMS)), 5.22 (1H, dd,
J ) 1.4, 11.1 Hz, 1H from CHdCH2), 5.33 (1H, dd, J ) 1.4,
17.4 Hz, 1H from CHdCH2), 5.99 (1H, dd, J ) 11.1, 17.4 Hz,
CHdCH2); 13C NMR δ -4.3 (Si(CH3)), -4.0 (Si(CH3)), 18.4
(SiC(CH3)3), 23.3 (CH3), 26.3 (SiC(CH3)3), 26.7 (CH3), 35.1
(CMe2CH2CH), 38.2 (CMe2CH2), 42.9 (CMe2), 53.5 (CHC(O)O),
65.6 (CH2OH), 72.1 (CH(OTBDMS)), 92.3 (CMe2C), 116.5
(CHdCH2), 134.8 (CHdCH2), 179.2 (CdO).
(3R,4S)-4-(ter t-Bu t yld im et h ylsilyloxy)-3-[(1S)-3,3-d i-
m e t h yl-2-oxocyclob u t yl]-4,5-d ih yd r ofu r a n -2(3H )-on e
23. As for the preparation of 21, cyclobutanol 15 (56 mg, 0.178
mmol), NMO (83 mg, 0.712 mmol, 4 equiv), and a catalytic
quantity of TPAP (few crystals) were stirred with 4 Å molec-
ular sieves in dry CH2Cl2 (2.5 mL) to give, after column
chromatography (silica gel, 20% EtOAc in petroleum ether
(40-60 °C)), the cyclobutanone 23 (50 mg, 0.160 mmol, 90%)
as a white solid (mp 84-85 °C): MS m/z (FAB+ mode) 313.1
(100) [M + H]+, 255.0 (38), 119.0 (9), 73.7 (70); HRMS calcd
for C16H29O4Si 313.1835, found 313.1833; νmax (golden gate)/
cm-1 2954m, 2929m, 2858m (C-H), 1774s, 1755s (CdO),
1462m, 1363m, 1107m, 995s; [R]D ) -30.7 (c ) 0.62, CHCl3);
1H NMR δ 0.10 (3H, s, 3H from Si(CH3)2), 0.11 (3H, s, 3H from
Si(CH3)2), 0.91 (9H, s, SiC(CH3)3), 1.19 (3H, s, 3H from
C(CH3)2), 1.30 (3H, s, 3H from C(CH3)2), 1.90 (1H, apparent t,
J ) 9.7 Hz, 1H from CMe2CH2), 2.10 (1H, apparent t, J ) 10.7
Hz, 1H from CMe2CH2), 2.81 (1H, apparent t, J ) 6.1 Hz, CHC-
(O)O), 3.84 (1H, ddd, J ) 6.3, 9.3, 11.0 Hz, CHC(O)CMe2), 4.23
(1H, dd, J ) 2.6, 9.7 Hz, 1H from CH2O), 4.31 (1H, dd, J )
4.3, 9.7 Hz, 1H from CH2O), 4.57-4.60 (1H, m, CH(OTBDMS));
13C NMR δ -4.4 (Si(CH3)), -4.2 (Si(CH3)), 18.3 (SiC(CH3)3),
22.2 (CH3), 24.4 (CH3), 26.0 (SiC(CH3)3), 31.2 (CMe2CH2), 45.1
(CHC(O)O), 50.7 (CHC(O)CMe2), 57.8 (CMe2), 70.2 (CH-
(OTBDMS)), 74.5 (CH2O), 176.1 (C(O)O), 212.5 (CMe2C(O)).
(1R,4R,5S)-4-[(1S)-1-(ter t-Bu tyld im eth ylsilyloxy)-2-h y-
d r oxye t h yl]-7,7-d im e t h yl-1-vin yl-2-oxa b icyclo[3.2.0]-
h ep ta n -3-on e 24. To a stirred solution of Yb(OTf)3 (190 mg,
0.306 mmol, 3.8 equiv) in THF (7.7 mL) at -78 °C under argon
was added vinylmagnesium bromide (0.32 mL, 1.0 M in THF,
4.0 equiv) and the solution stirred for 15 min. After this time,
a portion of the resulting bright orange vinylytterbium triflate
solution (4.2 mL, ∼2.0 equiv) was added via syringe to a stirred
solution of cyclobutanone 23 (25 mg, 0.0800 mmol) in THF (0.5
mL) at -78 °C. This solution was stirred for 1 h at -78 °C,
before the reaction mixture was quenched by the addition of
aq satd NH4Cl (2.5 mL) and aq satd potassium sodium tartrate
(2.5 mL). The aqueous layer was extracted with 60% EtOAc
in petroleum ether (40-60 °C), and the combined organic
portions were dried over MgSO4 and concentrated. Column
chromatography of the residue (silica gel, 20% EtOAc in
petroleum ether (40-60 °C)) gave the bicyclic lactone 24 (22.1
mg, 0.0649 mmol, 81%) as a white crystalline solid (mp 75-
76 °C): MS m/z (FAB+ mode) 341.2 (72) [M + H]+, 323.2 (16),
283.1 (23), 245.1 (11), 175.1 (13), 117.2 (26), 107.3 (18), 73.7
(100), 69.7 (15); HRMS calcd for C18H33O4Si 341.2148, found
341.2147; νmax (golden gate)/cm-1 3176m (OH), 2929m, 2856m
(1S,4S,5R)-4-[(1S)-1-(ter t-Bu tyld im eth ylsilyloxy)-2-h y-
d r oxye t h yl]-7,7-d im e t h yl-1-vin yl-2-oxa b icyclo[3.2.0]-
h ep ta n -3-on e 22. To a stirred solution of Yb(OTf)3 (480 mg,
0.774 mmol, 5.9 equiv) in THF (19.5 mL) at -78 °C under
argon was added vinylmagnesium bromide (0.82 mL, 1.0 M
in THF, 6.2 equiv) and the solution stirred for 15 min. After
this time, a portion of the resulting bright orange vinylytter-
bium triflate solution (6.9 mL, ∼2 equiv) was added via syringe
to a stirred solution of cyclobutanone 21 (41 mg, 0.131 mmol)
in THF (0.8 mL) at -78 °C. This solution was stirred for 20
min before the reaction mixture was quenched by the addition
of aq satd NH4Cl (4.0 mL) and aq satd potassium sodium
tartrate (4.0 mL). The aqueous layer was extracted with 60%
J . Org. Chem, Vol. 68, No. 8, 2003 3197

Edmonds et al.
(CH), 1759s (CdO), 1464m, 1250m, 1190m, 1105m, 1043s,
835s; [R]D ) -59.5 (c ) 1.10, CHCl3); H NMR δ 0.09 (3H, s,
assigned using NOE studies conducted on the crude product
mixture (see Figure 3): MS m/z (FAB+ mode, sodium) 479.1
(13) [M + Na]+, 439.1 (10), 307.1 (11), 289.1 (42), 175.0 (30),
115.2 (51), 73.7 (100), 59.9 (24); HRMS calcd for C24H48O4Si2-
Na 479.2989, found 479.2986; νmax (golden gate)/cm-1 3409w
(OH), 2952m, 2931m, 2875w, 2856w (CH), 1462w, 1250w,
1
3H from Si(CH3)2), 0.10 (3H, s, 3H from Si(CH3)2), 0.89 (9H, s,
SiC(CH3)3), 1.06 (3H, s, 3H from C(CH3)2), 1.16 (3H, s, 3H from
C(CH3)2), 1.54 (1H, dd, J ) 6.9, 12.2 Hz, 1H from CMe2CH2),
1.95 (1H, br s, OH), 2.09 (1H, dd, J ) 9.1, 12.2 Hz, 1H from
CMe2CH2), 2.85 (1H, dd, J ) 1.2, 5.7 Hz, CHC(O)O), 2.98 (1H,
ddd, J ) 1.2, 6.9, 9.1 Hz, CHCH2CMe2), 3.41-3.50 (2H, m,
2H from CH2O), 4.02 (1H, apparent q, J ) 5.6 Hz, CH(OTB-
DMS)), 5.24 (1H, dd, J ) 1.3, 11.1 Hz, 1H from CHdCH2),
5.36 (1H, dd, J ) 1.3, 17.3 Hz, 1H from CHdCH2), 6.01 (1H,
1
1091s, 1003s, 833s, 775s; H NMR δ 0.04 (3H, s, 3H from Si-
(CH3)2 of major), 0.06 (3H, s, 3H from Si(CH3)2 of major), 0.08
(3H, s, 3H from Si(CH3)2 of minor), 0.09 (3H, s, 3H from Si-
(CH3)2 of minor), 0.56-0.64 (12H, m, 6H from Si(CH2CH3)3 of
major and 6H from Si(CH2CH3)3 of minor), 0.88 (18H, s, 9H
from SiC(CH3)3 of major and 9H from SiC(CH3)3 of minor),
0.93-0.98 (18H, m, 9H from Si(CH2CH3)3 of major and 9H
from Si(CH2CH3)3 of minor), 1.02 (3H, s, 3H from C(CH3) of
minor), 1.05 (3H, s, 3H from C(CH3) of minor), 1.07 (3H, s, 3H
from C(CH3) of major), 1.08 (3H, s, 3H from C(CH3) of major),
1.47 (1H, dd, J ) 4.9, 11.8 Hz, 1H from CMe2CH2 of minor),
1.78-1.93 (3H, m, 2H from CMe2CH2 of major and 1H from
CMe2CH2 of minor), 2.18-2.21 (1H, m, CHCH(OH) of major),
2.48 (1H, apparent q, J ) 5.7 Hz, CHCH(OH) of minor), 2.76-
2.82 (2H, m, CMe2CH2CH of major and minor), 3.04 (1H, d, J
) 5.3 Hz, OH of major), 3.34 (1H, d, J ) 6.6 Hz, OH of minor),
3.41-3.51 (3H, m, 2H from CH2(OTES) of major and 1H from
CH2(OTES) of minor), 3.61 (1H, dd, J ) 4.8, 9.8 Hz, 1H from
CH2(OTES) of minor), 3.65 (1H, apparent q, J ) 5.8 Hz,
CH(OTBDMS) of major), 3.87-3.90 (1H, m, CH(OTBDMS) of
minor), 5.05 (1H, dd, J ) 2.1, 10.8 Hz, 1H from CHdCH2 of
major), 5.12 (1H, dd, J ) 2.0, 10.8 Hz, 1H from CHdCH2 of
minor), 5.24 (1H, dd, J ) 2.1, 17.2 Hz, 1H from CHdCH2 of
major), 5.31 (1H, dd, J ) 2.0, 17.2 Hz, 1H from CHdCH2 of
minor), 5.45 (1H, dd, J ) 4.2, 5.2 Hz, CH(OH) of major), 5.63
(1H, dd, J ) 5.3, 6.4 Hz, CH(OH) of minor), 5.94 (1H, dd, J )
10.8, 17.2 Hz, CHdCH2 of major), 6.14 (1H, dd, J ) 10.8, 17.2
Hz, CHdCH2 of minor); 13C NMR δ -4.3 (Si(CH3) of major
and minor), -3.7 (Si(CH3) of major), -3.5 (Si(CH3) of minor),
4.6 (Si(CH2CH3)3 of minor), 4.7 (Si(CH2CH3)3 of major), 7.1 (Si-
(CH2CH3)3 of minor), 7.2 (Si(CH2CH3)3 of major), 18.4 (SiC(CH3)3
of minor), 18.5 (SiC(CH3)3 of major), 23.5 (CH3 of major), 24.3
(CH3 of minor), 26.2 (SiC(CH3)3 of minor), 26.4 (SiC(CH3)3 of
major), 27.3 (CH3 of minor), 27.5 (CH3 of major), 37.8 (CMe2-
CH2CH of major), 37.9 (CMe2CH2CH of minor), 38.9 (CMe2CH2
of major), 39.0 (CMe2CH2 of minor), 39.5 (CMe2 of major), 40.3
(CMe2 of minor), 57.9 (CHCH(OH) of minor), 59.5 (CHCH(OH)
of major), 66.8 (CH2(OTES) of major), 66.9 (CH2(OTES) of
minor), 72.5 (CH(OTBDMS) of major), 73.5 (CH(OTBDMS) of
minor), 91.4 (CMe2C of minor), 92.2 (CMe2C of major), 102.4
(CH(OH) of minor), 104.1 (CH(OH) of major), 113.7 (CHdCH2
of minor), 113.9 (CHdCH2 of major), 138.2 (CHdCH2 of major),
139.9 (CHdCH2 of minor).
dd,
J
) δ -4.4
11.1, 17.3 Hz, CHdCH2); 13C NMR
(Si(CH3)), -4.2 (Si(CH3)), 18.4 (SiC(CH3)3), 23.0 (CH3), 26.1
(SiC(CH3)3), 26.7 (CH3), 36.0 (CMe2CH2CH), 38.7 (CMe2CH2),
43.1 (CMe2), 53.5 (CHC(O)O), 64.5 (CH2OH), 72.0 (CH(OTB-
DMS)), 92.3 (CMe2C), 116.5 (CHdCH2), 134.8 (CHdCH2),
177.5 (CdO).
(1S,4S,5R)-4-[(1S)-1-(ter t-Bu tyld im eth ylsilyloxy)-2-(tr i-
et h ylsilyloxy)et h yl]-7,7-d im et h yl-1-vin yl-2-oxa b icyclo-
[3.2.0]h ep ta n -3-on e 25. To a stirred solution of 22 (20 mg,
0.0587 mmol) in DMF (0.1 mL) at rt was added imidazole (28
mg, 0.411 mmol,7 equiv) followed by triethylchlorosilane (49
µL, 0.294 mmol, 5 equiv). The solution was stirred for 2.5 h
before the addition of aq satd NaHCO3 (2 mL). The aqueous
mixture was extracted with 20% EtOAc in petroleum ether
(40-60 °C), dried over Na2SO4, and concentrated. Purification
of the residue by column chromatography (silica gel, 3% EtOAc
in petroleum ether (40-60 °C)) gave the TES ether 25 (20 mg,
0.0440 mmol, 75%) as a colorless oil, along with starting
material (2.6 mg, 0.0076 mmol, 13%): MS m/z (FAB+ mode)
455.2 (38) [M + H]+, 425.2 (25), 397.1 (43), 289.1 (37), 251.1
(14), 161.1 (20), 115.2 (57), 73.7 (100), 59.9 (26); HRMS calcd
for C24H47O4Si2 455.3013, found 455.3014; νmax (golden gate)/
cm-1 2954m, 2929m, 2877m (CH), 1770s (CdO), 1461w,
1252m, 1082s, 1005m; [R]D ) +15.0 (c ) 1.39, CHCl3); 1H NMR
δ -0.01 (3H, s, 3H from Si(CH3)2), 0.05 (3H, s, 3H from Si-
(CH3)2), 0.62 (6H, q, J ) 7.8 Hz, 6H from Si(CH2CH3)3), 0.83
(9H, s, SiC(CH3)3), 0.96 (9H, t, J ) 7.9 Hz, 9H from Si-
(CH2CH3)3), 1.09 (3H, s, 3H from C(CH3)2), 1.10 (3H, s, 3H from
C(CH3)2), 1.54 (1H, dd, J ) 5.8, 12.2 Hz, 1H from CMe2CH2),
2.06 (1H, dd, J ) 9.2, 12.2 Hz, 1H from CMe2CH2), 2.93 (1H,
apparent t, J ) 2.6 Hz, CHC(O)O), 3.05 (1H, ddd, J ) 2.6,
5.8, 9.2 Hz, CHCH2CMe2), 3.37 (1H, dd, J ) 8.6, 9.9 Hz, 1H
from CH2OTES), 3.58 (1H, dd, J ) 5.2, 9.9 Hz, 1H from CH2-
OTES), 4.17 (1H, ddd, J ) 2.6, 5.2, 8.6 Hz, CH(OTBDMS)),
5.20 (1H, dd, J ) 1.3, 11.0 Hz, 1H from CHdCH2), 5.31 (1H,
dd, J ) 1.3, 17.3 Hz, 1H from CHdCH2), 5.97 (1H, dd, J )
11.0, 17.3 Hz, CHdCH2); 13C NMR δ -4.6 (Si(CH3)), -4.0 (Si-
(CH3)), 4.7 (Si(CH2CH3)3), 7.1 (Si(CH2CH3)3), 18.4 (SiC(CH3)3),
23.8 (CH3), 26.3 (SiC(CH3)3), 27.0 (CH3), 33.3 (CMe2CH2CH),
38.3 (CMe2CH2), 43.0 (CMe2), 53.3 (CHC(O)O), 64.8 (CH2-
(OTES)), 72.4 (CH(OTBDMS)), 91.6 (CMe2C), 116.3 (CHdCH2),
135.0 (CHdCH2), 180.3 (CdO).
Ack n ow led gm en t. We thank the University of
Glasgow (university scholarship to D.J .E.) and the
Carnegie trust (summer studentship to D.J .E) for
financial support of this project. We also thank Mr. J .
Gall of the NMR Spectroscopy Laboratory at the Uni-
versity of Glasgow and Mr. J . Tweedie for technical
assistance.
(1S,3R,4S,5R)-4-[(1S)-1-(ter t-Bu tyld im eth ylsilyloxy)-2-
tr ieth ylsilyloxyeth yl]-7,7-d im eth yl-1-vin yl-2-oxa bicyclo-
[3.2.0]h ep ta n -3-ol 26. To a stirred solution of 25 (19 mg,
0.0418 mmol) in CH2Cl2 (0.4 mL) at -78 °C was added
DIBAL-H (33 µL, 1.5 M in toluene, 0.0501 mmol, 1.2 equiv).
The solution was stirred at -78 °C for 2 h before quenching
with potassium sodium tartrate (35 mg, 0.124 mmol, 3 equiv)
in water (2 mL). The aqueous layer was separated and
extracted with CH2Cl2, and the combined organic portion was
dried over MgSO4. Concentration gave the lactol 26 (18.5 mg,
0.0404 mmol, 97%) as a 3.4:1 mixture of diastereomers. This
mixture was found to equilibrate on standing in CDCl3
solution, and no attempt was made to separate the diastere-
omers. The stereochemistry of the two diastereomers was
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental procedures and characterization data for compound 14.
Full details of the crystal structure analyses and ORTEP
diagrams of compounds 8b, 10, 13, epi-13, and 15. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O026827O
3198 J . Org. Chem., Vol. 68, No. 8, 2003