Enantioselective synthesis of the C1-C11 fragment of bafilomycin A1 using non-wittig and desymmetrization strategies

Article abstract of DOI:10.1021/jo034018e

The synthesis of the C1-C11 fragment 33 of bafilomycin A₁ was achieved. Intermediate ketone 16 was prepared in six steps from 4-oxopimelate 13. Desymmetrization of this ketone using Koga's chiral base followed by TMSCl quench furnished silyl en

Full text of DOI:10.1021/jo034018e

En a n tioselective Syn th esis of th e C1-C11 F r a gm en t of
Ba filom ycin A1 Usin g Non -Wittig a n d Desym m etr iza tion Str a tegies
J ean-Christophe Poupon, Emmanuel Demont, J oe¨lle Prunet,* and J ean-Pierre Fe´re´zou*,†
Laboratoire de Synthe`se Organique associe´ au CNRS, UMR 7652, Ecole Polytechnique,
DCSO, 91128 Palaiseau, France
joelle.prunet@polytechnique.fr; ferezou@terra.com.br
Received J anuary 7, 2003
The synthesis of the C1-C11 fragment 33 of bafilomycin A1 was achieved. Intermediate ketone 16
was prepared in six steps from 4-oxopimelate 13. Desymmetrization of this ketone using Koga’s
chiral base followed by TMSCl quench furnished silyl enol ether 17 with excellent enantioselectivity.
Further elaboration led to C5-C11 aldehyde 24, which was coupled with sulfone 3 to give lactone
25 in very good yield. The subsequent reductive elimination created the E-trisubstituted C4-C5
olefin with a 13:1 selectivity. The E C2-C3 double bond was then installed by methanol elimination,
and compound 33 was obtained after a few functional group manipulations and a Negishi methyl
zirconation.
SCHEME 1
In tr od u ction
Bafilomycin A1 1 (Scheme 1) was first isolated from
the broth of Streptomyces griseus in 1984 by Werner et
al.1 It is a 16-membered plecomacrolide with potent
biological activities due to its unique specific inhibitory
effect on vacuolar-type proton translocating ATP-ases (V-
ATPases).2 Four total syntheses of bafilomycin A1 1 and
one synthesis of a seco-form of the molecule, bafilomycin
V2, which is a methanolysis product of bafilomycin C2,
have been reported so far.3 Significant partial contribu-
tions as well as three total syntheses of the related
concanamycin F have also been described.4 Moreover,
extensive chemical studies are devoted to the synthesis
of derivatives possessing improved specificity in inhibit-
ing the V-ATPases overexpressed in the bone-resorbing
osteoclasts, a major metabolic disorder associated with
osteoporosis.5
† Current address: Far-Manguinhos, Fundac¸a˜o Oswaldo Cruz,
Laborato´rio de S´ıntese Orgaˆnica, Rua Sizenando Nabuco 100, Man-
guinhos, CEP 21041-250 Rio de J aneiro/RJ , Brazil.
(1) Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H.; Drautz,
H. Tetrahedron Lett. 1983, 24, 5193. Werner, G.; Hagenmaier, H.;
Drautz, H.; Baumgartner, A.; Za¨hner, H. J . Antibiot. 1984, 37, 110.
For structure elucidation, see: Corey, E. J .; Ponder, J . W. Tetrahedron
Lett. 1984, 25, 4325. Baker, G. H.; Brown, P. J .; Dorgan, R. J . J .;
Everett J . R.; Ley, S. V.; Slawin, A. M. Z.; Williams, D. J . Tetrahedron
Lett. 1987, 28, 5565.
The retrosynthesis we envisaged for the synthesis of
bafilomycin A16 is shown in Scheme 1. The macrolactone
can be opened and then disconnected between C-11 and
C-12 via a Stille- or Suzuki-type coupling reaction. The
resulting C1-C11 fragment 2 would be synthesized from
(2) Bowman, E. M.; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
(4) Partial contributions: (a) Roush, W. R.; Bannister, T. D.
Tetrahedron Lett. 1992, 33, 3587. Roush, W. R.; Bannister, T. D.;
Wendt, M. D. Tetrahedron Lett. 1993, 34, 8387. (b) Paterson, I.; Bower,
S.; McLeod, M. D. Tetrahedron Lett. 1995, 36, 175. (c) Hanessian, S.;
Wang, W.; Gai, Y.; Olivier, E. J . Am. Chem. Soc. 1997, 119, 10034. (d)
Breit, B.; Zahn, S. K. Tetrahedron Lett. 1998, 39, 1901. (e) Marshall,
J . A.; Adams, N. D. Org. Lett. 2000, 2, 2897. Total syntheses of the
related concanamycin F: (a) Toshima, K.; J yojima, T.; Miyamoto, N.;
Katohno, M.; Nakata, M.; Matsumara, S. J . Org. Chem. 2001, 66, 1708.
(b) Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T. Angew.
Chem., Int. Ed. 2000, 39, 1308.
(5) Review: Gagliardi, S.; Rees, M.; Farina, C. Curr. Med. Chem.
1999, 6, 1197.
(6) Previous publications from this group: (a) Demont, E.; Lopez,
R.; Fe´re´zou, J .-P. Synlett 1998, 1223. (b) Poupon, J .-C.; Lopez, R.;
Prunet, J .; Fe´re´zou, J .-P. J . Org. Chem. 2002, 67, 2118.
(3) Total syntheses of bafilomycin A1: (a) Evans, D. A.; Calter, M.
A. Tetrahedron Lett. 1993, 34, 6871. (b) Toshima, K.; J yojima, T.;
Yamaguchi, H.; Murase, H.; Yoshida, T.; Matsumura, S.; Nakata, M.
Tetrahedron Lett. 1996, 37, 1069. Toshima, K.; Yamaguchi, H.; J yojima,
T.; Noguchi, Y.; Nakata, M.; Matsumura, S. Tetrahedron Lett. 1996,
37, 1073. Toshima, K.; J yojima, T.; Noguchi, Y.; Yoshida, T.; Murase,
M.; Nakata, M.; Matsumura, S. J . Org. Chem. 1997, 62, 3271. (c)
Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W.
R. Angew. Chem., Int. Ed. 1999, 38, 1652. Scheidt, K. A.; Bannister,
T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G. J .; Roush,
W. R. J . Am. Chem. Soc. 2002, 124, 6981. (d) Hanessian, S.; Ma, J .;
Wang, W. J . Am. Chem. Soc. 2001, 123, 10200. Total synthesis of
bafilomycin V2: (e) Marshall, J . A.; Adams, N. D. J . Org. Chem. 2002,
67, 733.
10.1021/jo034018e CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/16/2003
4700
J . Org. Chem. 2003, 68, 4700-4707

Synthesis of the C1-C11 Fragment of Bafilomycin A1
SCHEME 2a
SCHEME 3
a
Key: (a) (COOMe)2, Et2O, -40 °C; (b) PhSH, Et3N, CH2Cl2,
0 to 20°C; (c) HC(OMe)3, MeOH, PTSA, reflux; (d) m-CPBA,
CH2Cl2, 0 °C.
sulfone 3 and aldehyde 4 by a convergent J ulia-Lythgoe
strategy instead of the two consecutive Horner-Wad-
sworth-Emmons reactions which have been employed
in all the published syntheses (except for Hanessian, who
chose an aldol reaction to make the C2-C3 bond).
stereotriads. Other clever solutions have been developed
in the case of aldol reactions.16 However, most of these
approaches requires the prerequisite preparation of both
homochiral partners.
Other answers to this problem have been developed
through non-aldol-type strategies. These methods involve
hydroboration of allylic alcohols,17 1,3-reduction of â-hy-
droxylated ketones,18 iodocyclization/radical reduction,19
or alternative routes involving conjugate additions of
Resu lts a n d Discu ssion
P r ep a r a tion of Su lfon e 3. Crystalline sulfone 3 was
synthesized on a 10-g scale in four steps from methyl
oxalate and 1-bromopropene via the known unsaturated
keto ester 5 (Scheme 2).7 Conjugate addition of thiophenol
to 5 gave the corresponding sulfenyl derivative 6.8
Transformation of 6 into the corresponding ketal 7
followed by oxidation of the sulfenyl residue with m-
chloroperbenzoic acid led to the expected ketal 3 in 28%
overall yield.
Syn th esis of th e Ald eh yd e P a r tn er . The next task
to achieve for the construction of 2 was the elaboration
of acetylenic aldehyde 4 bearing the required anti-anti
stereotriad at C6-C8.
Among the four possible diastereoisomers, the con-
struction of the anti-anti type of stereotriads is one of
the most difficult to achieve, particularly in an enanti-
oselective manner.9 One of the main reasons for this
difficulty is that such a triad formally results from a
mismatched attack of a chiral enolate (or allyl analogue)10
onto a chiral aldehyde under prevailing reagent-con-
trolled conditions. To date, Brown’s allyl boranes11 or
Roush’s allyl boronates12 give an efficient access to these
triads. The latter author recently succeeded in developing
an excellent access to such triads in the case of allylation
of R-methyl â-hydroxy aldehydes with Z-crotyltrifluorosi-
lanes.13 Allenyltin reactions14 or silicon-mediated allyla-
tion condensations15 were also shown to give anti,anti-
20
cuprates to γ-hydroxyl R,â-unsaturated esters or even
γ-hydroxyl R,â-unsaturated sulfones.21
For the construction of optically active aldehyde 4, we
decided to develop a desymmetrization reaction of meso
dimethyl ketone 9 with a chiral base (Scheme 3).22 This
ketone has been previously used for the construction of
an acyclic intermediate during a synthesis of racemic
tyrandamycin A.23 Interestingly, the resulting enol ether
11 can be envisioned not only to be a convenient precur-
sor of bafilomycin intermediates but also of numerous
other synthetic targets due to the anticipated flexibility
of the enol ether function. A second point of importance
is that such a strategy would allow synthesis of both
anti,anti-triad enantiomers, independently of preexisting
chiral centers, as it is the case for several routes already
developed (see refs 17-21 and also ref 12). Further
transformations of 11 into 4 could be reasonably envis-
aged by ozonolysis of enol ether 11 to give hydroxy acid
12, which has then to be transformed into 4.
Con str u ction of th e In ter m ediate Cycloh exan on e.
Looking for an efficient route for the construction of 9,
we turned to a cyclization-alkylation approach from
4-oxopimelate 13 instead of the apparently more straight-
forward route starting from 2,6-dimethyphenol.24 One
(16) Evans, D. A.; Dow, R. L.; Shih, T. L.; Takacs, J . M.; Zalher, R.
J . Am. Chem. Soc. 1990, 112, 5290.
(7) (a) Rambaud, M.; Bakasse, M.; Duguay, G.; Villieras, J . Synthesis
1988, 564. (b) Schummer, A.; Yu, H.; Simon, H. Tetrahedron 1991,
43, 9019.
(8) Bakuzis, P.; Bakuzis, M. L. F. J . Org. Chem. 1981, 46, 235.
(9) Reviews: (a) Hoffmann, R. W. Angew. Chem., Int. Ed. 1987, 26,
489. More focused on such a triad: (b) Hoffmann, R. W.; Dahmann,
G.; Andersen, M. W. Synthesis 1994, 629.
(10) Reviews on allylation reactions: (a) Roush, W. R. In Compre-
hensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press: Oxford,
1990; Vol. 2, p 1. (b) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93,
2207.
(11) Brown, H. C.; Bhat, K. S.; Randad, R. S. J . Org. Chem. 1989,
54, 1570.
(17) Toshima, K.; J yojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida,
T.; Murase, H.; Nakata, M.; Matsumura, S. J . Org. Chem. 1997, 62,
3271.
(18) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc.
1992, 114, 9434.
(19) Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme,
D.; Renaud, J .; Robinson, G.; Lavalle´e, J .-F.; Slassi, A.; J ung, G.;
Rancourt, J .; Durkin, K.; Liotta, D. J . Org. Chem. 1994, 59, 1166.
(20) Hanessian, S.; Wang, W.; Gai, Y.; Olivier, E. J . Am. Chem. Soc.
1997, 119, 10034.
(21) Dom`ınguez, E.; Carretero, J . C. Tetrahedron 1994, 50, 7557.
(22) Reviews on asymmetric synthesis using chiral lithium
amides: (a) Cox, P. J .; Simpkins, N. S. Tetrahedron: Asymmetry 1991,
2, 1. (b) Koga, K. Pure Appl. Chem. 1994, 66, 1487. (c) O’Brien, P. J .
Chem. Soc., Perkin Trans. 1 1998, 1439.
(12) Roush, W. R.; Palkowitz, A. D.; Palmer, M. A. J . J . Org. Chem.
1987, 52, 316.
(13) Chemler, S. R.; Roush, W. R. J . Org. Chem. 1998, 63, 3800.
(14) Marshall, J . A.; Perkins, J . F.; Wolf, M. A. J . Org. Chem. 1995,
60, 5556.
(15) J ain, N. F.; Takenaka, N.; Panek, J . S. J . Am. Chem. Soc. 1996,
118, 12475.
(23) Boeckman, R. K.; Starrett, J . E.; Nickell, D. G.; Sum, P.-E. J .
Am. Chem. Soc. 1986, 108, 5549.
(24) (a) Taschner, M. J .; Aminbhavi, A. S. Tetrahedron Lett. 1989,
30, 1029. (b) Liotta, D.; Arbiser, J .; Short, J . W.; Saindane, M. J . Org.
Chem. 1983, 48, 2932.
J . Org. Chem, Vol. 68, No. 12, 2003 4701

Poupon et al.
SCHEME 4a
SCHEME 5
a
Key: (a) (i) (CH2OH)2, PTSA, PhH, reflux, (ii) NaH, THF,
reflux; (b) (i) NaH, THF, 0 °C; t-BuLi, -78 °C, HMPA; MeI, -78
to +25 °C; (ii) NaOH/EtOH, reflux; (c) (i) L-Selectride, THF, -78
°C, (ii) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C, (iii) PTSA, acetone,
reflux.
intermediate 16 using chiral base (R,R)-18 could be
advantage of the pimelate route is to exhibit more
flexibility in allowing formal preparation of the corre-
sponding syn,syn-triad from an alternative axial reduc-
tion of the intermediate 15 to give the corresponding
equatorial alcohol. The synthesis of ketone 16 (9, R )
TBS) is summarized in Scheme 4.
effected under two sets of conditions, as shown by Koga:
29
internal quench, where the ketone is added to a
mixture of base and trimethylchlorosilane,30 and external
quench, where the base is added to the ketone followed
by TMSCl. The presence of LiCl is crucial to obtain a good
ee in the case of the external quench. The base is thus
generated by treating the easily available hydrochloride
salt of 1831 with 2 equiv of butyllithium.32 As shown in
Scheme 5, ketone 16 smoothly afforded silyl enol ether
17 in 54% yield and 97% ee33 for the internal quench and
80% yield and 94% ee for the external quench.34 The
absolute stereochemistry of 17 was proved by correlating
a later intermediate in the synthesis to a known com-
pound. These results parallel those observed for 4-tert-
butylcyclohexenol ether 20 obtained by Koga and co-
workers from 4-tert-butylcyclohexanone 19,29 with lower
yields but better enantioselectivities.
Dieckmann cyclization of the dioxolane derivative of
13 afforded cyclohexenecarboxylic ester 14.25 Interest-
ingly, the yield of the reaction was improved from 49%
(literature) to 73% from 13 using two modifications: the
intermediate acetal was not purified and the Dieckmann
reaction was conducted in refluxing tetrahydrofuran
instead of diethyl ether. For the subsequent dimethyla-
tion reaction, we addressed a one-pot dianion approach26
which, in our hands, gave better results than the two-
step procedure described by Narang and Dutta.27 The
dianion approach required strong basic conditions (1
equiv of NaH, then t-BuLi/HMPA in THF at -78 °C), and
the reaction was clean on a 1-g scale. When carried out
on a 30-g scale, ca. 5% R-monomethylated product was
formed together with the expected R,γ-dimethyl deriva-
tive (obtained as 9:1 mixture of diastereoisomers). Direct
refluxing of the alkylation crude extract in a 10% NaOH
ethanolic solution resulted in a decarboxylation reaction
together with total equilibration of the diastereomeric
mixture of the dimethylated products to the more stable
1,3-cis isomer 15, which was easily separated from the
corresponding monomethylated adduct by flash chroma-
tography. The rest of the synthesis of 16, including
L-Selectride reduction of the carbonyl group affording the
expected axial hydroxyl group exclusively, was carried
out according to Boeckman.23 Interestingly, reduction of
the carbonyl group under NaBH4/CeCl3 conditions of
Luche gave the corresponding equatorial hydroxyl group
in a 91:9 ratio (76% yield).28
Molecular calculations (Macromodel) have confirmed
unique severe constraints occurring from the ring sub-
stituents and particularly from the bulky axial OTBS
group (Figure 1). Conformational analysis of 16 reveals
a close proximity between the methyl groups of the axial
(29) Sugasawa, K.; Shindo, M.; Noguchi, H.; Koga, K. Tetrahedron
Lett. 1996, 37, 7377.
(30) Corey, E. J .; Gross, A. W. Tetrahedron Lett. 1984, 25, 495.
(31) Overberger, C. G.; Marullo, N. P.; Hiskey, R. G. J . Am. Chem.
Soc. 1961, 83, 1374.
(32) (a) Majewski, M.; Irvine, N. M.; MacKinnon, J . Tetrahedron:
Asymmetry 1995, 6, 1837. The important role of lithium salts for these
reactions has been previously noticed: (b) Bunn, B. J .; Simpkins, N.
S. J . Org. Chem. 1993, 58, 533. (c) Bunn, B. J .; Simpkins, N. S.;
Splavold, Z.; Crimmin, M. J . J . Chem. Soc., Perkin Trans. 1 1993, 3113.
(d) Majewski, M.; Lazny, R. Tetrahedron Lett. 1994, 35, 3653. A similar
effect has been observed with zinc chloride: (d) Coggins, P.; Gaur, S.;
Simpkins, N. S. Tetrahedron Lett. 1995, 36, 1545.
(33) The enantioselectivity analysis (1H NMR and GLC) was carried
out by preparing the Mosher ester of the R-hydroxy ketone derived
from 17 according to ref 23 (step a) and: Dale, J . A.; Mosher, H. S. J .
Am. Chem. Soc. 1973, 95, 512 (step b).
Desym m etr iza tion of th e In ter m ed ia te Cycloh ex-
a n on e. Deprotonation of the symmetrical cyclohexanone
(25) Lukes, R. M.; Poos, G. I.; Sarett, L. H. J . Am. Chem. Soc. 1952,
74, 1401.
(26) Huckin, S. N.; Weiler, L. J . Am. Chem. Soc. 1974, 96, 1082.
For reviews, see: (a) Kaiser, E. M.; Petty, J . D.; Knutson, P. L. A.
Synthesis 1977, 509. (b) Thompson, C. M.; Green, D. L. C. Tetrahedron
1991, 47, 4223.
(27) (a) Narang, S. A.; Dutta, P. C. J . Chem Soc. 1960, 2842. See
also: (b) Haga, K.; Oohashi, M.; Kaneko, R. Bull. Chem. Soc. J pn. 1984,
57, 1586.
(34) In this case, the enantioselectivity analysis (1H NMR) was
carried out by preparing the Mosher ester of the later intermediate
hydroxy ester 21 (see Scheme 6).
(28) Gemal, A. L.; Luche, J . L. J . Am. Chem. Soc. 1981, 103, 5454.
4702 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of the C1-C11 Fragment of Bafilomycin A1
SCHEME 7
F IGURE 1.
SCHEME 6a
Cou p lin g of Su lfon e 3 a n d Ald eh yd e 24. Model
J ulia couplings of sulfone 3 with diverse aldehydes have
been reported.6a Yields range from 52% to 95% if sulfone
3 is used in excess. The optimized conditions (3 equiv of
3, 3 equiv of LDA) were applied to aldehyde 24, and to
our surprise, lactone 25, resulting from cyclization of the
alkoxy ester adduct, was obtained in only 11% yield
(Scheme 7). Significant amounts of alcohol 26 (resulting
from reduction of 24) and ester 27 (the transesterification
product of sulfone 3 with alcohol 26) were produced.39
The deprotonation of sulfone 3 is probably incomplete,
and the condensation of the anion of this secondary
sulfone, which is reversible, does not efficiently compete
with the reduction of aldehyde 24 by LDA. No epimer-
ization of aldehyde 24 was observed.
We screened several strong bases to try to improve
the yield of this coupling reaction, with unfortunate
results.40 Finally, we decided to test lithium diethyl
amide, which has been used by Evans et al.41 for the key
coupling in the total synthesis of cytovaricin because it
is more kinetically efficient than LDA. Addition of this
base to sulfone 3 resulted in a deep orange color, in
opposition to the pale yellow color observed with LDA,
and lactone 25 was obtained in 83% yield as a 1:1 mixture
of diastereomers (Scheme 8). In addition, 94% of the
excess sulfone (4 equiv) was recovered after flash chro-
matography. Reductive elimination was performed with
sodium amalgam in methanol and produced the trisub-
stituted C4-C5 double bond of 31 with a 13:1 selectivity
in favor of the E isomer.6a Elimination of methanol must
a
Key: (a) (i) O3, CH2Cl2/MeOH, -78 °C; NaBH4, -78 to +20
°C, (ii) CH2N2, Et2O; (b) (i) PivCl, Py, (ii) DIBAL-H, THF, -78 to
-20 °C, (iii) IBX, THF, DMSO; (c) (i) CH3C(O)C(N2)P(O)-
(OMe)2, K2CO3, MeOH, 0 to 20 °C, (ii) DIBAL-H, toluene, -78 °C;
(d) (i) BuLi, TMSCl; Et3N; 2 N HCl, (ii) IBX, THF, DMSO.
tert-butyldimethylsilyloxy substituent and the axial pro-
tons susceptible to be removed. These constraints may
be responsible for a better discrimination in the depro-
tonation reaction for 16 than for 19 where the bulky tert-
butyl group adopts an equatorial position.
F in a l Ela bor a tion of Ald eh yd e C5-C11. Ozonolysis
of silyl enol ether 17 followed by reductive workup
(NaBH4) and treatment with diazomethane gave ester
alcohol 21 in 75% yield (Scheme 6). The hydroxyl group
was then protected as a pivalate ester and the methyl
ester reduced with DIBAL-H in THF. This reduction is
totally chemoselective because the reducing agent is
deactivated by THF so it does not affect the more
hindered ester function.35 Oxidation with IBX36 then
furnished aldehyde 22. Homologation to the correspond-
ing acetylenic compound was effected with Ohira’s re-
agent,37 which is easier to make and to store than
Seyferth’s phosphonate,38 and the pivalate ester was
reduced with DIBAL-H in toluene in good yield. Alcohol
23 [[R]D -9.8 (c 2.2, CH2Cl2) (lit.3c -6.7 (c 2.39, CH2Cl2))]
is identical to the compound described by Roush,3c
therefore establishing that the desymmetrization oc-
curred as shown in Scheme 5. Silylation of the acetylenic
moiety followed by IBX oxidation of the primary alcohol
provided aldehyde 24 (4, PG ) TBS) in 79% yield for the
two steps. In summary, the C5-C11 fragment of bafilo-
mycin A1 was synthesized in 16 steps in 11% overall yield.
(39) For examples of aldehyde reduction by LDA, see: Leonard, J .;
Hussain, N. J . Chem. Soc., Perkin Trans. 1 1994, 49. Majewski, M.
Tetrahedron Lett. 1988, 29, 4057.
(40) t-Buli added to the ester function to give ketone 28 and lithium
tetramethylpiperidide deprotonated the ortho aromatic proton, and the
resulting anion cyclized to furnish 29. If the reaction was quenched
with trimethylsilyl chloride, intramolecular condensation of the anion
on the ester gave compound 30 as a side product.
(35) Grosselin, F.; Lubell, W. D. J . Org. Chem. 1998, 63, 7463.
(36) Frigerio, M.; Santagostino, M.; Sputore, S. J . Org. Chem. 1999,
64, 4537.
(37) Ohira, S. Synth. Commun. 1989, 19, 561-564. Mu¨ller, S.;
Liepold, B.; Roth, G. J .; Bestmann, H. J . Synlett 1996, 521.
(38) Brown, D. G.; Velthuisen, E. J .; Commerford, J . R.; Brisbois,
R. G.; Hoye, T. R. J . Org. Chem. 1996, 61, 2540.
(41) Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T.
J . J . Am. Chem. Soc. 1990, 112, 7001.
J . Org. Chem, Vol. 68, No. 12, 2003 4703

Poupon et al.
SCHEME 8a
in vacuo to give 6 as a yellow oil which was unstable over silica
gel and used in the next reaction without further purification.
A mixture of crude 6 (0.104 mol), trimethyl orthoformate
(15 mL, 0.14 mol, 1.3 equiv), and a catalytic amount of p-TSA
in 200 mL of dry MeOH was refluxed for 72 h and then cooled
to room temperature, quenched with saturated aqueous
NaHCO3, and partitioned between water and Et2O. The layers
were separated, and the aqueous layer was extracted three
times with Et2O. The combined organic layers were washed
five times with brine, dried over MgSO4, filtered, and concen-
trated in vacuo to give after flash chromatography on silica
gel (petroleum ether/AcOEt, 9:1-3:1) 8.64 g (30% for three
steps) of 7 as a yellow oil: IR (film) 2949, 1745, 1637, 1584,
1476, 1374, 1202, 1049 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.43-7.32 (m, 5H), 3.79 (s, 3H), 3.25, 3.21 (2s, 6H), 3.16 (m,
1H), 2.22 (dd, 1H, J ) 15.0, 5.7 Hz), 2.10 (dd, 1H, J ) 15.0,
7.0 Hz), 1.28 (d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3)
δ 169.4, 134.4, 133.3, 129.0, 127.6, 101.4, 52.6, 49.9, 49.8, 40.4,
38.8, 22.0; MS (CI, NH3) m/z 302 (M + NH4+), 285 (M + H+).
a
Key: (a) LiNEt2, THF, -78 to 0 °C; (b) Na/Hg, MeOH, -40
°C; (c) (i) CSA, benzene, reflux, (ii) CH2N2, Et2O.
Met h yl 4-Ben zen esu lfon yl-2,2-d im et h oxyp en t a n oa t e
(3). To a solution of 3.1 g (10.8 mmol) of 7 in 100 mL of
CH2Cl2 at 0 °C was added 5.8 g (23.7 mmol, 2.2 equiv) of
m-CPBA (80% in m-chlorobenzoic acid). The resulting mixture
was stirred at this temperature for 3 h and quenched with
saturated aqueous NaHCO3 and 37% aqueous NaHSO3. The
biphasic mixture was stirred for 1 h, the layers were separated,
and the aqueous phase was extracted three times with Et2O.
The combined organic phases were washed three times with
brine, dried over MgSO4, filtered, and concentrated in vacuo
to give after purification by flash chromatography on silica gel
(petroleum ether/AcOEt, 80:20) 3.2 g (94%) of sulfone 3 as a
white solid: mp 65-67 °C; IR (film) 2956, 1749, 1447, 1305,
1223, 1148, 1085, 1049, 1005 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.43-7.32 (m, 5H), 3.72 (s, 3H), 3.23, 3.20 (2s, 6H), 3.13 (m,
1H), 2.60 (dd, 1H, J ) 14.6, 1.5 Hz), 1.94 (dd, 1H, J ) 14.6,
10.0 Hz), 1.24 (d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz, CDCl3)
δ 168.9, 136.9, 133.9, 129.3, 129.2, 101.0, 55.8, 52.8, 50.6, 49.0,
33.3, 14.3; MS (CI, NH3) m/z 302 (M + NH4+ - MeOH). Anal.
Calcd for C14H20O6S: C, 53.15; H, 6.37. Found: C, 53.25; H,
6.34.
SCHEME 9a
a
Key: (a) (i) K2CO3, MeOH; (ii) Cp2ZrCl2, AlMe3, H2O, CH2Cl2;
I2, THF, -78 °C to 0 °C.
be conducted under rigorously anhydrous conditions to
prevent methyl ketal hydrolysis. After diazomethane
treatment, diene 32 was isolated as a single isomer in
50% yield from 25.42
The final steps are described in Scheme 9. Removal of
the trimethylsilyl group followed by Negishi’s methyl
zirconation43 in the presence of 2 equiv of water3e led to
the C1-C11 fragment 33 (2, PG ) TBS), which proved
to be identical to the compounds reported by Marshall3e
and Roush.3c
E t h yl 8-H yd r oxy-1,4-d ioxa sp ir o[4.5]d ec-7-en e-7-ca r -
boxyla te (14).25 A mixture of diethyl 4-oxopimelate 13 (31 g,
0.20 mol), distilled ethylene glycol (18 mL, 0.32 mol, 1.6 equiv),
and a catalytic amount of p-TSA (250 mg, 1.3 mmol, 0.007
equiv) in 400 mL of toluene was heated in a flask fitted with
a Dean-Stark apparatus with a reflux condenser. After 12 h,
the mixture was cooled to room temperature, and 20 mL of
saturated aqueous NaHCO3 was added. The toluene was
removed in vacuo and the residue treated with Et2O and H2O.
The layers were separated. The aqueous layer was extracted
twice with Et2O. The combined organic layers were washed
three times with brine, dried over MgSO4, filtered, and
concentrated in vacuo to afford the desired ketal as a yellow
oil that was used without purification in the next reaction.
Con clu sion
We have synthesized the C1-C11 portion of bafilomy-
cin A1 in 21 steps and 3.3% overall yield (85% average
yield per step). The key steps of this approach are a
desymmetrization of a substituted cyclohexanone with
Koga’s amide base to install the anti-anti stereotriad at
C6-C8 and a J ulia coupling leading to the C4-C5
trisubstituted double bond in a highly selective manner.
To a suspension of NaH (80% dispersion in mineral oil, 7.2
g, 0.24 mol, 1.2 equiv) in 500 mL of dry THF at 0 °C was added
via cannula a solution of the previous crude ketal in 300 mL
of dry THF. The resulting solution was refluxed for 5 h and
cooled to 0 °C, and glacial acetic acid (15 mL, 0.26 mol, 1.3
equiv) was added with rapid stirring. The resulting solution
was diluted with Et2O, washed three times with brine, dried
over MgSO4, filtered, and concentrated in vacuo to give after
distillation 33 g (73% for two steps) of product 14 as a colorless
oil: bp 120 °C/0.01 mmHg; IR (film) 2958, 2888, 1728, 1654,
1616, 1477, 1366, 1354, 1298, 1197, 1124 cm-1; 1H NMR (400
MHz, CDCl3) δ 4.20 (q, 2H, J ) 7.3 Hz), 4.02 (m, 4H), 2.50 (t,
2H, J ) 6.8 Hz), 2.48 (s, 2H), 1.84 (t, 2H, J ) 6.8 Hz), 1.28 (t,
3H, J ) 7.3 Hz); 13C NMR (100 MHz, CDCl3) δ 172.1, 171.1,
107.5, 95.4, 64.6, 60.4, 32.8, 30.4, 28.0, 14.3; MS (CI, NH3) m/z
229 (M + H+). Anal. Calcd for C11H16O5: C, 57.88; H, 7.06.
Found: C, 57.77; H, 7.18.
Exp er im en ta l Section
For general methods, see ref 6b.
Meth yl 2,2-Dim eth oxy-4-ph en ylsu lfan ylpen tan oate (7).
To a solution of 20 g (0.13 mol) of methyl 2-oxopent-3-enoate7
and thiophenol (11 mL, 0.10 mol, 0.8 equiv) in 150 mL of
CH2Cl2 at 0 °C was added 1 mL (7.2 mmol, 0.05 equiv) of Et3N.
After the cooling bath was removed, the solution was stirred
at room temperature for 2 h, diluted with Et2O, washed three
times with brine, dried over MgSO4, filtered, and concentrated
(42) The geometry of both double bonds was assigned by NOE
experiments performed on the primary alcohol obtained by DIBAL-H
reduction of a model compound of 33.
(43) Negishi, E.-I.; Okukado, N.; King, A. O.; Van Horn, D. E.;
Spiegel, B. I. J . Am. Chem. Soc. 1978, 100, 2252.
4704 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of the C1-C11 Fragment of Bafilomycin A1
(7R *,9S *)-7,9-Dim e t h yl-1,4-d ioxa sp ir o[4.5]d e ca n -8-
on e (15). To a suspension of NaH (80% dispersion in mineral
oil, 4.8 g, 0.16 mol, 1.1 equiv) in 500 mL of dry THF at 0 °C
was added via cannula under nitrogen a solution of 33 g (0.14
mol) of 14 in 500 mL of dry THF. After 10 min, the solution
was cooled to -78 °C, and t-BuLi (1.7 M solution in pentane,
112 mL, 0.19 mol, 1.3 equiv) was slowly added via cannula.
The resulting red mixture was stirred at -78 °C for 15 min,
and HMPA (65 mL, 0.37 mol, 2.6 equiv) was added slowly via
syringe. After the resulting mixture was stirred for 10 min,
MeI (45 mL, 0.72 mol, 5 equiv) was rapidly added. The color
faded immediately. After 5 min, the cold bath was removed
and the pale yellow solution was stirred at room temperature
for 5 h. Then 30 mL of 1 N aqueous HCl was added, followed
by 200 mL of brine and 500 mL of Et2O. The layers were
separated. The aqueous layer was extracted twice with Et2O.
The combined organic layers were washed five times with
brine, dried over MgSO4, filtered, and concentrated in vacuo
to afford the dimethylated keto ester which was used without
purification in the next reaction.
-78 °C for 1 h then warmed to 0 °C, stirred for 90 min,
Cl, and diluted
quenched with 50 mL of saturated aqueous NH4
with 300 mL of Et2O. The layers were separated. The aqueous
layer was extracted twice with Et2O. The combined organic
phases were washed five times with brine, dried over MgSO4,
filtered, and concentrated in vacuo to give the desired hydroxy
acid (2.9 g) as a yellow solid that was used in the next reaction
without further purification.
The preceding crude hydroxy acid (2.9 g) was dissolved in
50 mL of Et2O in an Erlenmeyer flask, and a freshly distilled
solution of diazomethane was added until no more nitrogen
evolved. Several drops of acetic acid were added until the
solution became colorless and the resulting mixture was
concentrated in vacuo. Then 20 mL of pentane was added to
remove the acetic acid by azeotropic distillation. Flash chro-
matography on silica gel (Et2O/petroleum ether, 5:95-40:60)
gave 2.2 g (75% for two steps) of 21 as a colorless oil: [R]D
+2.4 (c 2.0, CH2Cl2); IR (film) 3452, 2955, 2884, 2857, 1740,
1462, 1436, 1360, 1255, 1171, 1084, 1033 cm-1; 1H NMR (400
MHz, CDCl3) δ 3.68 (s, 3H), 3.62 (t, 2H, J ) 5.6 Hz), 3.53 (dd,
1H, J ) 4.9, 4.4 Hz), 2.53 (dd, 1H, J ) 14.6, 3.9 Hz), 2.43 (t,
1H, J ) 5.6 Hz), 2.22 (m, 1H), 2.10 (dd, 1H, J ) 14.6, 9.2 Hz),
1.84 (m, 1H), 1.00 (d, 3H, J ) 6.6 Hz), 0.96 (d, 3H, J ) 7.1
Hz), 0.92 (s, 9H), 0.12, 0.10 (2s, 6H); 13C NMR (100 MHz,
CDCl3) δ 173.9, 80.3, 65.9, 51.6, 38.1, 37.3, 35.2, 26.2, 18.4,
17.2, 16.0, -3.9; MS (CI, NH3) m/z 305 (M + H+). Anal. Calcd
for C15H32O4Si: C, 59.16, H, 10.59. Found: C, 58.87, H, 10.63.
A solution of the crude keto ester in 320 mL of 10% aqueous
KOH and 80 mL of EtOH was refluxed for 8 h. The solution
was cooled to room temperature, and 500 mL of Et2O was
added. The layers were separated, and the aqueous layer was
extracted twice with Et2O. The combined organic layers were
washed twice with brine, dried over MgSO4, filtered, and
concentrated in vacuo to give after flash chromatography on
silica gel (petroleum ether/AcOEt, 95:5-60:40) 19.5 g (72% for
two steps) of 15 as a pale yellow solid that was identical to
the ketone reported by Boeckman.23
To 104 mg of (R)-(+)-R-methoxy-R-(trifluoromethyl)pheny-
lacetic acid (0.44 mmol, 3 equiv) in 1 mL of CH2Cl2 was added
58 µL (0.66 mmol, 4.5 equiv) of oxalyl chloride and a drop of
DMF. After 2 h, the solvent was removed under the vacuum
of a pump, and 1 mL of CH2Cl2 was added. A solution of 21
(45 mg, 0.15 mmol, and Et3N (84 µL, 0.60 mmol, 4.0 equiv) in
500 µL of CH2Cl2 was added followed by a crystal of DMAP.
After 1 night, the solution was diluted with Et2O and then
washed with saturated aqueous NH4Cl. The aqueous layer was
extracted twice with Et2O. The combined organic phases were
washed twice with brine, dried over MgSO4, filtered, and
(3R,4S,5S)-4-(ter t-Bu tyld im eth ylsiloxy)-3,5-d im eth yl-
1-tr im eth ylsiloxycycloh exen e (17), Exter n al Qu en ch P r o-
ced u r e. To a solution of (R,R)-(+)-bis(R-methylbenzyl)amine
hydrochloride (4.6 g, 17 mmol, 1.5 equiv) in 55 mL of THF at
-78 °C was added 19.3 mL (1.7 M in hexane, 33 mmol, 2.8
equiv) of BuLi. After 15 min, the resulting mixture was
warmed to 0 °C for 15 min. The resulting solution was warmed
to room temperature for 30 min and then cooled to -78 °C.
To a solution of 16 (3.0 g, 12 mmol) in 90 mL of THF at -110
°C was added (via cannula on the side of the flask) the cold
solution of chiral amide. The resulting solution was stirred at
this temperature for 5 min and then treated dropwise with
freshly distilled TMSCl (5.9 mL, 47 mmol, 4.0 equiv). After
15 min at -110 °C, the solution was warmed to -78 °C for
another 15 min, and then freshly distilled Et3N (8.1 mL, 59
mmol, 5.0 equiv) was added. After 20 min, the solution was
removed from the cold bath and 200 mL of satured aqueous
NaHCO3 was added followed by 200 mL of Et2O. The mixture
was warmed to room temperature, and the layers were
separated. The aqueous phase was extracted twice with
petroleum ether. The combined organic layers were washed
twice with water and then with brine, dried over MgSO4,
filtered, and concentrated in vacuo to give crude material that
was purified (important) by a quick flash chromatography (5%
Et2O, 93% petroleum ether, 2% Et3N) to give 3.1 g (80%) of 17
as a pale yellow oil: [R]D -18.8 (c 2.9, CH2Cl2); IR (film) 2957,
2928, 2856, 1668, 1472, 1371, 1251, 1190, 1175, 1105, 1081,
1
concentrated in vacuo. The H NMR spectrum showed 94% ee
by integrating the peaks at 4.46 ppm (major diastereomer) and
at 4.05 ppm (minor diastereomer).
(2R,3S,4S)-3-(ter t-Bu tyld im eth ylsiloxy)-2,4-d im eth yl-
6-oxoh exyl 2,2-Dim eth ylp r op ion a te (22). To 1.8 g (5.9
mmol) of 21 in 20 mL of freshly distilled pyridine at 0 °C was
added 870 µL (7.1 mmol, 1.2 equiv) of pivaloyl chloride. After
1.5 h at room temperature, 200 mL of Et2O and 200 mL of 1
N aqueous KHSO4 were added. The organic phase was washed
with 100 mL of 1 N aqueous KHSO4. The combined aqueous
phases were extracted five times with 100 mL of Et2O. The
combined organic phases were washed twice with water and
once with brine, dried over MgSO4, filtered, and concentrated
in vacuo. Flash chromatography on silica gel (Et2O/petroleum
ether, 0:100-30:70) gave 2.0 g (87%) of the pivalate ester as a
colorless oil: [R]D +11.0 (c 2.0, CH2Cl2); IR (film) 2958, 1734,
1283, 1160, 1135 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.21 (dd,
1H, J ) 10.9, 5.1 Hz), 3.87 (dd, 1H, J ) 10.9, 6.9 Hz), 3.66 (s,
3H), 3.49 (t, 1H, J ) 5.3 Hz), 2.52 (dd, 1H, J ) 15.2, 3.7 Hz),
2.25-2.18 (m, 1H), 2.09 (dd, 1H, J ) 15.2, 9.9 Hz), 1.99-1.93
(m, 1H), 1.20 (s, 9H), 0.99, 0.96 (2d, 6H, J ) 6.8, 7.0 Hz), 0.90
(s, 9H), 0.06, 0.05 (2s, 6H); 13C NMR (100 MHz, CDCl3) δ 178.8,
173.7, 77.7, 66.5, 51.3, 38.8, 37.0, 36.9, 33.8, 27.2, 26.1, 18.3,
17.9, 14.6, -4.0, -4.1; MS (CI, NH3) m/z 406 (M + NH4+), 389
(M + H+). Anal. Calcd for C20H40O5Si: C, 61.81; H, 10.37.
Found: C, 61.94; H, 10.41.
1
1035 cm-1; H NMR (400 MHz, CDCl3) δ 4.45 (d, 1H, J ) 1.8
Hz), 3.60 (d, 1H, J ) 3.1 Hz), 2.37 (m, 1H), 1.95 (m, 1H), 1.83
(m, 2H), 0.97 (d, 3H, J ) 2.6 Hz), 0.95 (d, 3H, J ) 3.6 Hz),
0.91 (s, 9H), 0.18 (s, 9H), 0.06, 0.05 (2s, 6H); 13C NMR (100
MHz, CDCl3) δ 149.3, 107.4, 73.7, 36.6, 35.6, 33.8, 26.3, 19.1,
18.9, 18.6, 0.4, -3.3; MS (CI, NH3) m/z 329 (M + H+).
Meth yl (3R,4R,5S)-4-(ter t-Bu tyld im eth ylsiloxy)-6-h y-
d r oxy-3,5-d im eth ylh exa n oa te (21). A stream of O3/O2 was
passed through a solution of 17 (3.1 g, 9.4 mmol) and 2 mg of
Sudan red in 120 mL of CH2Cl2 and 30 mL of MeOH at -78
°C until the color of the solution turned from pink to pale
yellow. After the resulting solution was purged with oxygen
and then with argon, sodium borohydride (1.3 g, 38 mmol, 4.0
equiv) was added and the resulting suspension was stirred at
To a solution of 2.0 g (5.1 mmol, 1.0 equiv) of the previous
pivalate ester in 50 mL of THF at -78 °C was added 12 mL
(15 mmol, 1.3 M solution in hexane, 3.0 equiv) of DIBAL-H.
The solution was warmed slowly to -20 °C over 1 h and stirred
at this temperature until no more starting material remained.
Then 0.5 mL of MeOH was added and 10 min later 50 mL of
saturated aqueous Rochelle’s salt. The mixture was vigorously
stirred at room temperature for 1 h, and 100 mL of Et2O was
J . Org. Chem, Vol. 68, No. 12, 2003 4705

Poupon et al.
added. The aqueous mixture was extracted three times with
100 mL of Et2O. The aqueous phase was acidified with 12 N
aqueous HCl and extracted twice with 50 mL of Et2O. The last
two organic phases were washed twice with water and
combined with the other organic phases. The combined organic
phases were washed twice with water and once with brine,
dried over MgSO4, filtered, and concentrated in vacuo. An
aliquot of the crude alcohol was purified by flash chromatog-
raphy on silica gel (Et2O/petroleum ether, 5:95-40:60): [R]D
+15.1 (c 3.2, CH2Cl2); IR (film) 3448, 2959, 1734, 1159, 1036
cm-1; 1H NMR (400 MHz, CDCl3) δ 4.26 (dd, 1H, J ) 10.9, 4.4
Hz), 3.87 (dd, 1H, J ) 10.9, 7.0 Hz), 3.77-3.72 (m, 1H), 3.63-
3.57 (m, 1H), 3.50 (dd, 1H, J ) 6.5, 3.4 Hz), 2.08-2.01 (m,
1H), 1.89-1.84 (m, 1H), 1.73-1.67 (m, 1H), 1.55-1.47 (m, 1H),
1.20 (s, 9H), 0.99, 0.95 (2d, 6H, J ) 7.0 Hz and J ) 6.8 Hz),
0.91 (s, 9H), 0.09, 0.07 (2s, 6H); 13C NMR (100 MHz, CDCl3) δ
178.7, 78.5, 66.9, 60.7, 39.0, 36.7, 34.4, 33.6, 27.4, 26.2, 18.5,
17.4, 15.1, -3.6, -4.1; MS (CI, NH3) m/z 361 (M + H+). Anal.
Calcd for C19H40O4Si: C, 63.28; H, 11.18. Found: C, 62.87; H,
11.11.
with the other organic phases. The combined organic phases
were washed twice with water and once with brine, dried over
MgSO4, filtered, and concentrated in vacuo. Flash chromatog-
raphy on silica gel (Et2O/petroleum ether, 5:95-30:70) gave
0.99 g (70% for four steps) of 23 which is identical to the
product described by Roush:3c [R]D -9.8 (c 2.2, CH2Cl2) (lit.3c
[R]D -6.7 (c 2.4, CH2Cl2)).
(2R,3S,4S)-3-(ter t-Bu tyld im eth ylsiloxy)-2,4-d im eth yl-
7-tr im eth ylsilylh ep t-6-yn a l (24). To 1.3 g (4.8 mmol) of
alcohol 23 in 90 mL of THF at -78 °C was added 7.0 mL (12
mmol, 1.7 M in hexane, 2.5 equiv) of BuLi. After 15 min, the
solution was warmed to -20 °C for 20 min. To the solution
cooled to -78 °C was added 3.0 mL (24 mmol, 5.0 equiv) of
TMSCl, and the solution was warmed to -50 °C over 30 min.
The cold bath was removed, and 100 mL of 2 N aqueous HCl
was added. The mixture was vigorously stirred at 0 °C for 15
min, and then 200 mL of Et2O was added. The organic phase
was directly washed with saturated aqueous NaHCO3. The
acidic aqueous phase was extracted three times with 50 mL
of Et2O. The combined organic phases were washed with the
remaining basic solution, twice with water and once with brine,
dried over MgSO4, filtered, and concentrated in vacuo. Flash
chromatography on silica gel gave 1.4 g (88%) of the desired
silyl derivative as a colorless oil: [R]D -13.3 (c 3.2, CH2Cl2);
The previous crude alcohol was dissolved in 30 mL of THF,
and 2.8 g (10 mmol, ca. 2.0 equiv) of IBX predissolved in 25
mL of dry DMSO was added via cannula. After 1 h, 30 mL of
water was added. Ten minutes later, 60 mL of Et2O was added
and the white precipitate was filtered (rinse several times with
Et2O). The aqueous phase was extracted three times with 30
mL of Et2O. The combined organic phases were washed twice
with water and once with brine, dried over MgSO4, filtered,
and concentrated in vacuo to give aldehyde 22. An aliquot was
purified by flash chromatography on silica gel (Et2O/petroleum
1
IR (film) 3357, 2957, 2175, 1472, 1250, 1030 cm-1; H NMR
(400 MHz, CDCl3) δ 3.72-3.66 (m, 1H), 3.62-3.56 (m, 1H),
2.59 (brt, 1H, J ) 5.7 Hz), 2.30 (dd, 1H, J ) 17.0, 6.6 Hz),
2.19 (dd, 1H, J ) 17.0, 7.2 Hz), 1.99-1.84 (m, 2H), 1.06, 1.06
(2d, 6H, J ) 7.1, 7.1 Hz), 0.92 (s, 9H), 0.16 (s, 9H), 0.14, 0.14
(2s, 6H); 13C NMR (100 MHz, CDCl3) δ 106.1, 86.3, 79.8, 65.9,
38.0, 36.6, 26.2, 23.7, 18.4, 16.5, 16.0, 0.2, -4.0, -4.1; MS (CI,
NH3) m/z 343 (M + H+), 324, 271, 211. Anal. Calcd for
ether, 0:100-20:80): IR (film) 2959, 1729, 1157, 1039 cm-1
;
1H NMR (400 MHz, CDCl3) δ 9.79 (brs, 1H), 4.21 (dd, 1H, J )
10.9, 5.2 Hz), 3.88 (dd, 1H, J ) 10.9, 6.9 Hz), 3.50 (m, 1H),
2.59 (dd, 1H, J ) 16.3, 2.5 Hz), 2.35-2.31 (m, 1H), 2.26-2.21
(m, 1H), 1.99-1.93 (m, 1H), 1.20 (s, 9H), 1.01 (d, 3H, J ) 6.6
Hz), 0.95 (d, 3H, J ) 7.0 Hz), 0.90 (s, 9H), 0.07 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 202.0, 178.4, 78.3, 66.7, 47.0, 39.1,
37.7, 31.8, 27.4, 26.3, 18.6, 18.6, 14.5, -3.7, -3.9; MS (CI, NH3)
m/z 376 (M + NH4+), 359 (M + H+).
C
18H38O2Si2: C, 63.09; H, 11.18. Found: C, 63.46; H, 11.31.
The previous alcohol (410 mg, 1.2 mmol) was dissolved in 7
mL of THF, and 680 mg (2.4 mmol, 2.0 equiv) of IBX
predissolved in 6 mL of dry DMSO was added via cannula.
After 2 h, 7 mL of water was added. Then 10 min later, 20
mL of Et2O was added and the white precipitate was filtered
(rinsed several times with Et2O). The aqueous phase was
extracted three times with 10 mL of Et2O. The combined
organic phases were washed twice with water and once with
brine, dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography on silica gel gave 370 mg (90%) of 24
as a colorless oil: [R]D +22.8 (c 2.1, CH2Cl2); IR (film) 2957,
2173, 1726, 1463, 1250, 1033 cm-1; 1H NMR (400 MHz, CDCl3)
δ 9.22 (d, 1H, J ) 2.0 Hz), 3.99 (dd, 1H, J ) 6.2, 3.3 Hz), 2.57
(m, 1H), 2.27 (d, 2H, J ) 6.2 Hz), 1.95 (m, 1H), 1.15 (d, 3H, J
) 7.0 Hz), 0.96 (d, 3H), 0.90 (s, 9H), 0.16 (s, 9H), 0.13, 0.10
(2s, 6H); 13C NMR (100 MHz, CDCl3) δ 204.5, 105.5, 86.7, 76.7,
49.9, 37.5, 26.0, 23.8, 18.3, 15.8, 11.6, 0.22, -4.3; MS (CI, NH3)
m/z 358 (M + NH4+), 341 (M + H+).
(4RS,5RS,6(1R,2S,4S))-5-Ben zen esu lfon yl-6-[2-(ter t-bu -
t yld im et h ylsiloxy)-1,3-d im et h yl-6-t r im et h ylsilylh ex-5-
yn yl]-3,3-dim eth oxy-5-m eth yltetr ah ydr opyr an -2-on e (25).
To a solution of 395 µL (3.8 mmol, 4.9 equiv) of diethylamine
in 6.3 mL of THF at -78 °C was added 2.4 mL (3.8 mmol, 1.6
M in hexane, 4.9 equiv) of BuLi. After 5 min, the resulting
solution was warmed to -15 °C, and after 10 min, it was
warmed to 0 °C for 15 min. To a solution of 1.22 g (3.9 mmol,
5.0 equiv) of sulfone 3 (dried three times by azeotropic
distillation with toluene) in 28 mL of THF at -78 °C was added
the previous basic solution. After 10 min at -78 °C, the
resulting red-orange solution was warmed for 1 h at -55 °C
and then recooled to -78 °C. A solution of 260 mg (0.75 mmol)
of aldehyde 24 in 4 mL of THF was added dropwise to the
cold basic solution (rinse with 1 mL of THF). After 1.2 h at
-78 °C, the solution was warmed to 0 °C for 20 min and then
quenched with 30 mL of 2 N aqueous NaHSO4 and diluted
with 100 mL of Et2O. The aqueous phase was extracted three
times with 50 mL of Et2O. The combined organic phases were
washed once with water and twice with brine, dried over
MgSO4, filtered, and concentrated in vacuo. Flash chromatog-
(2R,3S,4S)-3-(ter t-Bu tyld im eth ylsiloxy)-2,4-d im eth yl-
h ep t-6-yn -1-ol (23). To the crude aldehyde 22 in 25 mL of
MeOH at 0 °C was added 2.1 g (15 mmol, ca. 3 equiv) of thinly
powdered anhydrous K2CO3. A solution of 1.5 g (7.7 mmol, ca.
1.5 equiv) of Ohira’s diazophosphonate in 25 mL of MeOH was
added (the solution quickly turned milky green). After 1.5 h
at 20 °C, 500 mL of Et2O was added followed by 50 mL of
water. The aqueous phase was extracted three times with 50
mL of Et2O. The combined organic phases were washed three
times with 50 mL of brine, dried over MgSO4, filtered, and
concentrated in vacuo. An aliquot was purified by flash
chromatography on silica gel (Et2O/petroleum ether, 0:100-
20:80): [R]D +4.6 (c 2.5, CH2Cl2); IR (film) 3313, 2958, 2118,
1731, 1156, 1033 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.23 (dd,
1H, J ) 10.9, 5.3 Hz), 3.87 (dd, 1H, J ) 10.9, 7.3 Hz), 3.58
(dd, 1H, J ) 4.9, 4.8 Hz), 2.33 (ddd, 1H, J ) 16.9, 4.7, 2.7 Hz),
2.13 (ddd, 1H, J ) 16.9, 8.3, 2.6 Hz), 2.04-1.95 (m, 1H), 1.96
(t, 1H, J ) 2.6 Hz), 1.92-1.85 (m, 1H), 1.21 (s, 9H), 1.07 (d, J
) 6.9 Hz, 3H), 0.99 (d, 3H, J ) 6.9 Hz), 0.91 (s, 9H), 0.09, 0.08
(2s, 6H); 13C NMR (100 MHz, CDCl3) δ 177.0, 83.7, 77.7, 69.4,
66.8, 39.0, 37.1, 36.9, 27.5, 26.3, 22.2, 18.6, 17.1, 15.4, -3.9;
MS (CI, NH3) m/z 355 (M + H+); exact mass calcd for C20H39O3-
Si 355.2670, found 355.2668.
To a solution of the previous crude alkyne in 50 mL of
toluene at -78 °C was added 12 mL (15 mmol, 1.3 M solution
in hexane, ca. 3 equiv) of DIBAL-H. After 2 h, 0.5 mL of MeOH
was added and 10 min later 50 mL of saturated aqueous
Rochelle’s salt. The mixture was vigorously stirred at room
temperature for 1 h. Then 100 mL of Et2O was added. The
aqueous mixture was extracted three times with 100 mL of
Et2O. The aqueous mixture was acidified with 12 N aqueous
HCl and extracted twice with 50 mL of Et2O. The last two
organic phases were washed twice with water and combined
4706 J . Org. Chem., Vol. 68, No. 12, 2003

Synthesis of the C1-C11 Fragment of Bafilomycin A1
raphy on silica gel (Et2O/petroleum ether, 0:100-40:60) gave
396 mg (83%) of 25 as a 1.2:1 mixture of diasteromers which
could be separated for analytical purposes by careful chroma-
tography and 920 mg of recovered sulfone 3 (94% of the excess).
Ma jor isom er : IR (film) 2955, 2173, 1762, 1447, 1306, 1148,
Met h yl (4S,5S,6R)-1-Iod o-5-ter t-b u t yld im et h ylsiloxy-
2,4,6,8-tetr am eth yl-10-m eth oxy-1,7,9-u n decatr ien oate (33).
To a solution of 32 (76 mg, 0.16 mmol) in 1.5 mL of MeOH
was added 500 mg (3.6 mmol, 22 equiv) of thinly powdered
anhydrous K2CO3. After 3 h, 15 mL of Et2O was added followed
by 1.5 mL of water. The aqueous layer was extracted with
Et2O. The combined organic layers were washed with water
and brine, dried over anhydrous MgSO4, filtered, and concen-
trated in vacuo to give the desired crude terminal alkyne,
which was carried on to the next step without further purifica-
tion. An aliquot was purified by flash chromatography on silica
gel (Et2O/petroleum ether, 0:100-5:95): [R]D +24.7 (c 0.75,
CH2Cl2); IR (thin film) 3312, 2930, 2115, 1720, 1436, 1250,
1
1072 cm-1; H NMR (400 MHz, CDCl3) δ 7.91-7.89 (m, 2H),
7.72-7.70 (m, 1H), 7.64-7.60 (m, 2H), 5.32 (s, 1H), 3.69-3.67
(m, 1H), 3.25 (s, 3H), 3.23 (s, 3H), 2.90-2.80 (m, 1H), 2.70 (d,
1H, J ) 14.0 Hz), 2.43 (dd, 1H, J ) 17.0, 4.9 Hz), 2.19 (dd,
1H, J ) 17.0, 9.0 Hz), 2.16-1.94 (m, 1H), 1.57 (d, 1H, J )
14.0 Hz), 1.55 (s, 3H), 1.25 (d, 3H, J ) 6.9 Hz), 1.20 (d, 3H, J
) 6.9 Hz), 0.92 (s, 9H), 0.15 (s, 9H), 0.13, 0.13 (2s, 6H); 13C
NMR (100 MHz, CDCl3) δ 165.0, 135.9, 134.6, 130.6, 129.4,
107.1, 94.7, 85.6, 78.3, 77.5, 64.5, 50.4, 49.8, 41.3, 38.2, 36.1,
26.4, 22.8, 18.5, 17.9, 17.7, 11.1, 0.3, -3.8, -4.3; MS (CI, NH3)
m/z 642 (M + NH4+), 625 (M + H+). Min or isom er : IR (film)
2960, 2173, 1773, 1447, 1307, 1147, 1075 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.71-7.68 (m, 1H), 7.61-
7.58 (m, 2H), 4.95 (d, 1H, J ) 1.3 Hz), 3.57 (brt, 1H, J ) 5.3
Hz), 3.30 (s, 3H), 3.22 (s, 3H), 2.89-2.81 (m, 1H), 2.68 (d, 1H,
J ) 15.0 Hz), 2.40 (dd, 1H, J ) 17.0, 5.3 Hz), 2.23 (dd, 1H, J
) 17.0, 8.3 Hz), 1.95 (d, 1H, J ) 15.0 Hz), 1.95-1.89 (m, 1H),
1.49 (s, 3H), 1.31 (d, 3H, J ) 6.9 Hz), 1.08 (d, 3H, J ) 6.9 Hz),
0.90 (s, 9H), 0.16 (s, 9H), 0.14, 0.14 (2s, 6H); 13C NMR (100
MHz, CDCl3) δ 164.8, 137.1, 134.4, 130.8, 129.3, 106.4, 95.3,
86.2, 80.6, 78.7, 63.7, 51.4, 49.1, 39.4, 36.9, 36.7, 26.3, 23.6,
23.4, 18.5, 16.7, 12.1, 0.3, -3.5, -4.0; MS (CI, NH3) m/z 642
(M + NH4+), 625 (M + H+).
Meth yl (6R,7R,8S)-7-(ter t-Bu tyldim eth ylsiloxy)-2-m eth -
oxy-4,6,8-tr im eth yl-11-tr im eth ylsilylu n d eca -2,4-d ien -10-
yn oa te (32). To freshly prepared and powdered 6% Na/Hg
amalgam (1.2 g, ca. 3.3 mmol, 10 equiv) and NaHCO3 (270
mg, 3.3 mmol, 10 equiv) in 3 mL of dry MeOH at -40 °C was
added sulfone 25 (204 mg, 0.33 mmol, 1.0 equiv) in 2.5 mL of
THF (rinse with 0.5 mL of THF). After 1.5 h, the solution was
acidified with 1 N aqueous HCl. After decantation and separa-
tion, the aqueous layer was extracted three times with Et2O.
The combined organic layers were washed three times with
brine, dried over anhydrous MgSO4, filtered, and concentrated
in vacuo to give crude product 31. To this unpurified product
31 (ca. 0.33 mmol) (dried three times by azeotropic distillation
with benzene) diluted in 4 mL of dry benzene was added
camphorsulfonic acid (7.5 mg, 0.033 mmol, 0.1 equiv). The
solution was heated to reflux for exactly 30 min. After the
solution was cooled to 0 °C, freshly distilled CH2N2 was added
until no more nitrogen evolved. The resulting mixture was
concentrated in vacuo. Flash chromatography on silica gel
(Et2O/petroleum ether, 5:95) gave 76 mg (50% for two steps)
of 32 as a colorless oil: [R]D +34.2 (c 1.6, CH2Cl2); IR (film)
2956, 2173, 1721, 1249, 1105, 1030 cm-1; 1H NMR (400 MHz,
CDCl3) δ 6.60 (s, 1H), 5.94 (brd, 1H, J ) 9.6 Hz), 3.79, 3.66
(2s, 6H), 3.59 (dd, 1H, J ) 5.9, 3.0 Hz), 2.76-2.69 (m, 1H),
2.28 (dd, 1H, J ) 16.9, 5.9 Hz), 2.17 (dd, 1H, J ) 16.9, 7.5
Hz), 1.98 (s, 3H), 1.81-1.75 (m, 1H), 0.99 (d, 3H, J ) 6.9 Hz),
0.91 (d, 3H, J ) 6.9 Hz), 0.90 (s, 9H), 0.15 (s, 9H), 0.10, 0.07
(2s, 6H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.8, 141.8,
130.2, 106.4, 103.2, 86.1, 78.6, 60.4, 52.1, 37.8, 35.8, 26.3, 23.9,
18.7, 18.6, 16.5, 14.9, 0.3, -3.7, -3.8; MS (CI, NH3) m/z 484
(M + NH4+), 467 (M + H+); exact mass calcd for C25H47O4Si2
467.3013, found 467.3016.
1
1105, 1031 cm-1; H NMR (400 MHz, CDCl3) δ 6.59 (s, 1H),
5.93 (d, 1H, J ) 9.6 Hz), 3.81, 3.66 (2s, 6H), 3.55 (dd, 1H, J )
6.0, 3.1 Hz), 2.74-2.68 (m, 1H), 2.30 (ddd, 1H, J ) 16.7, 5.1,
2.5 Hz), 2.17 (ddd, 1H, J ) 16.7, 8.0, 2.5 Hz), 1.99 (s, 3H),
1.97 (t, 1H, J ) 2.5 Hz), 1.80-1.77 (m, 1H), 1.00 (d, 3H, J )
7.0 Hz), 0.96 (d, 3H, J ) 6.9 Hz), 0.92 (s, 9H), 0.09, 0.07 (2s,
6H); 13C NMR (100 MHz, CDCl3) δ 165.6, 142.8, 141.5, 130.4,
103.1, 88.6, 78.7, 69.6, 60.4, 52.1, 37.6, 36.1, 26.3, 22.4, 18.6,
18.6, 16.5, 14.9, -3.7; MS (CI, NH3) m/z 412 (M + NH4+), 395
(M + H+); exact mass calcd for C22H39O4Si 395.2618, found
395.2614.
To a mixture of Cp2ZrCl2 (95 mg, 0.32 mmol, 2.0 equiv) in
1.5 mL of CH2Cl2 was added dropwise AlMe3 (490 µL, 0.97
mmol, 2 M solution in hexane, 6.0 equiv). The resulting
solution was stirred for 10 min and cooled to -25 °C, and H2O
(6 µL, 0.32 mmol, 2.0 equiv) was added. After 10 min, a
solution of the previous crude product (ca. 0.16 mmol) in 250
µL of CH2Cl2 (100 µL rinse) was added. The solution was
stirred for 18 h at -25 °C, and a solution of I2 (410 mg, 1.6
mmol, 10 equiv) in 1.5 mL of THF was added dropwise. After
30 min, the solution was allowed to warm to 0 °C, stirred for
10 min, and quenched by addition of 300 µL of saturated
aqueous K2CO3. The mixture was then stirred for 30 min, 800
mg of MgSO4 was added, and the mixture was filtered through
a pad of Celite which was rinsed with Et2O. The organic layer
was washed with saturated aqueous Na2S2O3 and brine, dried
over anhydrous MgSO4, filtered, and concentrated in vacuo.
Flash chromatography on silica gel (Et2O/petroleum ether,
0:100-5:95) gave 52 mg (60% for two steps) of 33 as a colorless
oil, which is identical to the product described by Marshall:3e
[R]D +32.9 (c 0.59, CHCl3) (lit.3e [R]D +34.9 (c 0.67, CHCl3));
1H NMR (400 MHz, CDCl3) δ 6.60 (s, 1H), 5.93 (d, 1H, J ) 9.7
Hz), 5.84 (s, 1H), 3.81 (s, 3H), 3.66 (s, 3H), 3.41 (dd, 1H, J )
4.8, 3.4 Hz), 2.72-2.67 (m, 1H), 2.40 (dd, 1H, J ) 13.4, 3.9
Hz), 1.98 (s, 3H), 1.95 (dd, 1H, J ) 13.4, 10.5 Hz), 1.82-1.73
(m, 1H), 1.79 (s, 3H), 0.98 (d, 3H, J ) 6.9 Hz), 0.92 (s, 9H),
0.75 (d, 3H, J ) 6.8 Hz), 0.05 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 165.5, 147.0, 142.8, 142.1, 130.2, 130.0, 79.9, 75.4,
60.4, 52.1, 43.3, 36.3, 36.1, 26.2, 23.7, 18.9, 18.5, 16.0, 14.9,
-3.6, -3.7.
Ack n ow led gm en t. J .-C.P. thanks the MENR for a
fellowship. Financial support was provided by the CNRS
(UMR 7652) and the Ecole Polytechnique. We gratefully
acknowledge Professor Roush for communicating the
data on compound 23 prior to publication.
J O034018E
J . Org. Chem, Vol. 68, No. 12, 2003 4707