Synthesis of the C14-C25 Subunit of Bafilomycin A1

Article abstract of DOI:10.1021/jo035068m

The enantioselective synthesis of the C14-C25 subunit of bafilomycin A ₁, was realized in a convergent route. The sequence involves two dynamic kinetic resolution steps of 2-alkyl 1,3-diketones that use optically active ruthenium complexes, an

Full text of DOI:10.1021/jo035068m

Syn th esis of th e C14-C25 Su bu n it of Ba filom ycin A1
Florence Eustache, Peter I. Dalko, and J anine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received J uly 23, 2003
The enantioselective synthesis of the C14-C25 subunit of bafilomycin A1 was realized in a
convergent route. The sequence involves two dynamic kinetic resolution steps of 2-alkyl 1,3-diketones
that use optically active ruthenium complexes, an anti-selective reduction of a â-hydroxyketone to
control the C23 stereogenic center, and an aldol-type reaction under Evans’ conditions, which sets
the C17 and C18 stereogenic centers.
SCHEME 1. Molecu la r Str u ctu r es of th e
P lecom a cr olid e An tibiotics
In tr od u ction
The bafilolides, including bafilomycins1 and leucani-
cidins,2 are members of the plecomacrolide family of
macrolide antibiotics that includes concanamycins,3 hy-
grolidins,4 formamicin, and the recently discovered mi-
cromonospolides5 (Scheme 1).6 Bafilomycin A1 was iso-
lated from the fermentation broth of Streptomyces griseus
in 19837 and has since shown interesting biological
activities. This compound is a potent and specific inhibi-
tor of vacuolar H+-ATPases (V-ATPases) in vitro and in
vivo.8 Given that V-ATPases are known to participate in
(1) Review: Gagliardi, S.; Rees, M. Farina, C. Curr. Med. Chem.
1999, 6, 1197.
(2) (a) Isogai, A.; Sakuda, S.; Matsumoto, S.; Ogura, M.; Furihata,
K.; Seto H.; Suzuki, A. Agric. Biol. Chem. 1984, 48. 1379. (b) Sakuda,
S.; Isogai, A.; Matsumoto, S.; Ogura, M.; Furihata, K.; Seto H.; Suzuki,
A. Agric. Biol. Chem. 1987, 51, 2841.
(3) (a) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3857 and 3861. (b) Kinashi,
H.; Sakaguchi, K.; Higashijima, T.; Miyazawa, T. J . Antibiot. 1982,
35, 1618. (c) Kinashi, H.; Someno, K.; Sakaguchi, K. J . Antibiot. 1984,
37, 1333. (d) Westley, J . W.; Liu, C.-M.; Sello, L. H.; Evans, R. H.;
Troupe, N.; Blount, J . F.; Chiu, A. M.; Todaro, L. J .; Miller, P. A. J .
Antibiot. 1984, 37, 1738. (e) Woo, J .-T.; Shinohara, C.; Sakai, K.;
Hasumi, K.; Endo, A. J . Antibiot. 1992, 45, 1108. (f) Ishii, T.; Hida, T.;
Iinuma, S.; Muroi, M.; Nozaki, Y. J . Antibiot. 1995, 48, 12. For
synthesis see, for example: (g) Makino, K.; Nakajima, N.; Hashimoto,
S.-i.; Yonemitsu, O. Tetrahedron Lett. 1996, 37, 9077. (h) Toshima, K.;
J yojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.; Matsumura, S.
J . Org. Chem. 2001, 66, 1708.
(4) (a) Seto, H.; Akao, H.; Furihata K.; Otake. N. Tetrahedron Lett.
1982, 23, 2667. (b) H. Seto, I. Tajima, H. Akao, K. Furihata and N.
Otake. J . Antibiot. 1984, 37, 610.
(5) (a) Ohta, E.; Ohta, S.; Kubota, N. K.; Suzuki, M.; Ogawa, T.;
Yamasaki, A.; Ikegami, S. Tetrahedron Lett. 2001, 42, 4179. (b) Ohta,
E.; Kubota, N. K.; Ohta, S.; Suzuki, M.; Ogawa, T.; Yamasaki, A.;
Ikegami, S. Tetrahedron 2001, 57, 8463.
(6) For related compounds, see: (a) Goets, M. A.; McCormick, P. A.;
Monaghan, R. L.; Ostlind, D. A.; Hensens, O. D.; Liesch J . M.; Albers-
Schonberg, G. J . Antibiot. 1985, 38, 161. (b) Wilton, J . H.; Hokanson
G. C.; French. J . C. J . Antibiot. 1985, 38, 1449. (c) Meyer, M.; Keller-
Schierlein, W.; Drautz, H.; Blank W.; Zahner. H. Helv. Chim. Acta
1985, 68, 83.
(7) Isolation: (a) Werner, G.; Hagenmaeir, H.; Drautz, H.; Baum-
gartner, A.; Za¨hner, H. J . Antibiot. 1984, 37, 110. (b) Werner, G.;
Hagenmaier, H.; Albert, K.; Kohlshorn, H.; Drautz, H. Tetrahedron
Lett. 1983, 24, 5193.
(8) (a) Sundquist, K. T.; Marks, S. C. J . Bone Miner. Res. 1994, 9,
1575. (b) Gagliardi, S.; Gatti, P. A.; Belfiore, P.; Zochetti, A.; Clarke,
G. D.; Farina, C. J . Med. Chem. 1998, 41, 1883.
bone resorption, inhibitors of such enzymes may poten-
tially be used for the treatment of osteoporosis.8a,9
Furthermore, this compound displays broad antibacterial
and antifungal activity.10
10.1021/jo035068m CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/20/2003
9994
J . Org. Chem. 2003, 68, 9994-10002

C14-C25 Subunit of Bafilomycin A1
SCHEME 2. Dyn a m ic Kin etic Resolu tion of
1,3-Dik eton es
The stereochemistry of bafilomycin A1 was initially
assigned on the basis of molecular modeling and NMR
data11 and was later confirmed by X-ray analysis.12 The
conformation of the molecule in solution has been shown
to be indistinguishable from its solid-state conformation.12b
Bafilomycin A1 is a 16-membered macrolide with 12
stereogenic centers, two diene units, and an acid- and
base-sensitive six-membered hemiketal that participates
in a hydrogen-bond network with the C17 hydroxyl group
and the carbonyl of the 16-membered lactone, all of which
is necessary for biological activity.
In view of the interesting chemical structure and
biological properties, considerable effort has been devoted
to the development of efficient total syntheses of ba-
filomycins.13-17 To date, four total syntheses of bafilomy-
cin A113-16 and one synthesis of bafilomycin V1 have been
reported.17 Furthermore, several partial syntheses of
bafilomycin A1 and of its analogues have also been
published.18-21
Somewhat surprisingly, in all of the total syntheses
the assembly of the backbone of the molecule followed
an identical strategy, as the coupling of the two major
fragments C1-C11 and C12-C25 were achieved by Stille
reaction and the macrolactonization was realized under
Yamaguchi’s conditions. However, the differences in the
total syntheses were the methods to control the stereo-
genic centers, which were based either on asymmetric
aldolization,13 crotylborations,15 allenylzincations,17 or the
use of chiral pools.14,16
Previously we described that the dynamic kinetic
resolution of 2-alkyl 1,3-diketones by enantioselective
monoreduction, using (R,R)-I and (S,S)-I chiral ruthe-
nium catalysts affords â-hydroxyketones in high regio-,
diastereo-, and enantioselectivity22 (Scheme 2). As an
extension of this work, we wish to report that this
dynamic kinetic reduction approach can be used to
prepare the C14-C25 fragment of bafilomycin A1 in a
highly convergent and enantioselective manner.
The disconnection of bafilomycin A1 into fragments A
and B follows the classical strategy used in published
syntheses of this molecule. The preparation of fragment
A, which corresponds to the C14-C25 subunit of bafilo-
mycin, is illustrated in Scheme 3. This approach includes
four key steps: an anionic coupling of a dithiane frag-
ment with an alkyl halide to establish the C19-C20
bond; the enantioselective monoreduction of the 2-alkyl
1,3-diketones 3 and 4 to control the stereogenic centers
at C15, C16 and C21, C22, respectively; a stereoselective
reduction of a â-hydroxyketone to set the C23 center; and
an aldol-type Evans coupling to control the C17 and C18
stereogenic centers (Scheme 3).
(9) (a) Woo, J .-T.; Ohba, Y.; Tagami, K.; Sumitani, K.; Yamaguchi,
K.; Tsuji, T. Biol. Pharm. Bull. 1996, 19, 297. (b) Gagliardi, S.; Nadler,
G.; Consolandi, E.; Parini, C.; Morvan, M.; Legave, M. N.; Belfiore, P.;
Zocchetti, A.; Clarke, G. D.; J ames, I.; Nambi, P.; Gowen, M.; Farina,
C. J . Med. Chem. 1998, 41, 1568.
(10) Bowman, E. J .; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
Resu lts a n d Discu ssion
(11) Corey, E. J .; Ponder, J . W. Tetrahedron Lett. 1984, 25, 4325.
(12) (a) 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. (b) Baker, G. H.; Brown, P. J .; Dorgan, R. J . J .; Everett, J .
R. J . Chem. Soc., Perkin Trans. 2 1989, 1073 and references therein.
(13) (a) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(b) Calter, M. A. Ph.D. Thesis, Harvard University, 1993.
(14) (a) Toshima, K.; J yojima, T.; Yamaguchi, H.; Murase, H.;
Yoshida, T.; Matsumura, S.; Nakata, M. Tetrahedron Lett. 1996, 37,
1069. (b) Toshima, K.; Yamaguchi, H.; J yojioma, T.; Noguchi, Y.;
Nakata, M.; Matsumura, S. Tetrahedron Lett. 1996, 37, 1073. (c)
Toshima, K.; J yojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.;
Murase, H.; Nakata, M.; Matsumura, S. J . Org. Chem. 1997, 62, 3271.
(15) (a) 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. (b) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M.
D.; Roush, W. R. Angew. Chem., Int. Ed. 1999, 38, 1652.
(16) (a) Hanessian, S.; Tehim, A.; Meng, Q.; Grandberg, K. Tetra-
hedron Lett. 1996, 37, 9001. (b) Hanessian, S.; Ma, J .; Wang, W. J .
Am. Chem. Soc. 2001, 123, 10200.
Diketones 3 and 4 were prepared in two steps from
2-(benzyloxy)acetic acid 1. After treatment of 1 with
benzotriazole23 in the presence of DCC (THF, rt), the
acylbenzotriazole 2 was isolated in 96% yield. The
addition of the lithium enolates of propiophenone and of
2-methyl 1,3-diketone, generated both with LDA at room
temperature in THF, to 2 led to the desired diketones 3
(72% yield) and 4 (72% yield), respectively. Diketones 3
and 4 were reduced under asymmetric transfer hydro-
genation conditions. When compound 3 was reduced by
complex (R,R)-I (1 mol %), Et3N (2 equiv), and HCO2H
(5 equiv) in CH2Cl2 at room temperature for 16 h, a
mixture of two separable â-hydroxyketones 5 and 5′22
were obtained in a ratio of 68/3224 in 89% yield. The major
isomer 5 was formed in an enantiomeric excess of 93%.25
The relative configuration at C2 and C3, which corre-
sponds to the C15 and C16 stereogenic centers in bafilo-
(17) (a) Marshall, J . A.; Adams, N. D. Org. Lett. 2000, 2, 2897. (b)
Marshall, J . A.; Adams, N. D. J . Org. Chem. 2002, 67, 733.
(18) Granberg, K. L.; Edvinsson, K. M.; Nilsson, K. Tetrahedron Lett.
1999, 40, 755.
(19) Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett. 1995,
36, 175.
(20) Gatti, P. A.; Gagliardi, S.; Cerri, A.; Visconti, M.; Farina, C. J .
Org. Chem. 1996, 61, 7185.
(21) Poupon, J .-C.; Demont, E.; Prunet, J .; Fe´re´zou, J .-P. J . Org.
Chem. 2003, 68, 4700.
(23) (a) Katritzky, A. R.; Chang, H. X.; Yang, B. Synthesis 1995,
503. (b) Katritzky, A. R.; Rogovoy, B. V. Chem. Eur. J . 2003, 9, 4586.
(24) The diastereoselectivity was determined by 1H NMR analysis.
(25) The enantiomeric purity was determined by chiral HPLC:
Chiracel OD-H column; eluent, hexane/2 propanol 98/2.
(22) Eustache, F.; Cossy, J . Dalko, P. I. Org. Lett. 2002, 4, 1263.
J . Org. Chem, Vol. 68, No. 26, 2003 9995

Eustache et al.
SCHEME 3. Retr osyn th etic An a lysis of
Ba filom ycin A1
SCHEME 4a
a
Reagents and conditions: (a) DCC, benzotriazole, rt (96%); (b)
LDA, THF (72%); (c) LDA, THF, (72%); (d) (R,R)-I, HCO2H, Et3N,
CH2Cl2, (dr ) 68/32, 89%); (e) (1) E, SnCl2, (TMSO)2 then AcOH,
THF, H2O (78%); (f) LiOH, THF, H2O (78%); (g) (S,S)-I, Et3N,
HCO2H, CH2Cl2 (dr ) 72/28, 92%).
mycin A1, was determined by 1H NMR. The value of
coupling constants between the protons at C2 and C3 was
J ) 5.9 Hz, which is representative of a syn stereochem-
istry. Furthermore, the transformation of 5 to the known
hydroxyacid 7 confirmed the relative syn stereochemistry
of the substituents and established the absolute config-
uration of the stereogenic centers by comparison of their
[R]D. The conversion of 5 to 7 was realized in two steps
by using a Baeyer-Villiger oxidation26 [(TMSO)2; SnCl4;
(()-1,2-(tosylaminocyclohexane, CH2Cl2, rt, then THF/
AcOH/H2O] followed by saponification of ester 6 [LiOH‚
H2O; THF/H2O]. The acid 7 was isolated in 78% yield and
configuration and the 2S and 3S absolute configuration
was determined by comparison of the [R]20 of 8 [+15.0,
D
(c 2.30, CH2Cl2)] with the [R]20D reported in the literature
for the same compound [+11.9, (c 2.30, CH2Cl2)]28 (Scheme
4). The two optically active â-hydroxy ketones 5 and 8
were then transformed into, respectively, the C19-C14
and C20-C25 subunits of bafilomycin A1.
For the preparation of the C14-C19 subunit and
particularly to control the stereogenic centers at C17 and
C18, the addition of the (Z)-boron enolate 12 derived from
Evans’ chiral propionyl benzyl-oxazolidinone29 to alde-
hyde 11 was planned. It was anticipated that the reaction
would proceed with anti-Felkin selectivity with R-sub-
stituted aldehydes producing syn,anti-aldols.30 Thus,
aldehyde 11 was prepared from the previously synthe-
sized â-hydroxyester 6 in a three-step sequence (Scheme
5). After protection of the hydroxyl group in 6 as a tert-
its [R]20 [-11.0 (c 2.5, CHCl3)] was compared with the
D
[R]20 of the known (2S,3S)-â-hydroxyacid [+12.9 (c 3.7,
D
CHCl3)].27 The comparison of the [R]20 allowed us to
D
attribute the 2R and 3R absolute configuration for the
stereogenic centers in compound 5. In parallel, diketone
4 was reduced with the (S,S)-I ruthenium complex
(1 mol %) in the presence of a mixture of HCO2H/Et3N
in CH2Cl2. The reaction afforded a mixture of two
diastereomers 8 and 8′ in a ratio of 72/2824 in 92% yield.22
The enantiomeric excess of 94% for the major isomer 8
was determined by chiral HPLC.25 The syn relative
(28) Evans, D. A.; Kozlowski, M. C.; Murry, J . A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J . J . Am. Chem. Soc. 1999,
121, 669.
(29) (a) Evans, D. A.; Bartroli, J .; Shih, T. L. J . Am. Chem. Soc.
1981, 103, 2127. (b) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 83.
(30) Cowden, C. J .; Paterson, I. In Organic Reactions; Paquette L.
A., Ed.; Wiley: New York, 1997; p 1.
(26) Yoshikaura, N.; Yamado, Y. M. A.; Das, J .; Sasai, H.; Shibasaki,
M. J . Am. Chem. Soc. 1999, 121, 4168.
(27) (a) Ghosh, A. K.; Kim, J .-H. Tetrahedron Lett. 2001, 42, 1227.
(b) Ghosh, A. K.; Fidanze, S.; Onishi, M.; Hussain, K. A. Tetrahedron
Lett. 1997, 7171.
9996 J . Org. Chem., Vol. 68, No. 26, 2003

C14-C25 Subunit of Bafilomycin A1
SCHEME 5a
3.9 Hz, J H16-H17 ) 3.9 Hz, and J H17 -H18 ) 7.3 Hz) showed
a cis-relationship between the substituents at C15-C16
and C16-C17 and a trans-relationship between the
substituents at C17-C18. Consequently, the anti-Felkin
type aldolization was confirmed, producing a syn,anti,-
syn-stereotetrad. Having obtained the desired absolute
configurations for the stereogenic centers in amide 14,
the hydroxy group at C17 was protected as a tert-
butyldimethylsilyl ether with TBDMSOTf (2,6-lutidine,
CH2Cl2, -30 °C, 97% yield), and the resulting amide 15
was reduced with DIBAL-H to produce aldehyde 16 in
89% yield. Different conditions were tested to convert
aldehyde 16 to thioketal 17. When BF3‚OEt2 was used
in the presence of propane-1,3-dithiol, degradation of the
substrate was observed. On the contrary, the use of TiCl4
in CH2Cl2 at -78 °C afforded the desired product 17 in
98% yield (Scheme 5).
The synthesis of iodide 23 corresponding to the C20-
C25 subunit of bafilomycin was realized from â-hydroxy-
ketone 8. To set the required syn,anti-stereotriad of
the fragment, â-hydroxyketone
8 was reduced by
Me4NBH(OAc)3 in acetic acid.32 Under these conditions,
an inseparable mixture of 1,3-diols 19 (anti,syn) and 19′
(syn,syn) was obtained in a ratio of 90/10 in 76% yield.
To separate the two isomers and also to establish the
relative stereochemistry of the hydroxyl groups at C21
and C23, the mixture of 1,3-diols was transformed to the
corresponding acetonides 20 and 20′ using 2,2-dimeth-
oxypropane in the presence of CSA in acetone (dr ) 90/
10, 74%). The 13C NMR analysis of the major isomer 20
confirmed the anti-relationship between the two hydroxy
groups.33 As the ketal protecting group in 20 revealed
unsuitable for further transformations, compounds 19
and 19′ were treated with tert-butyldimethylsilyl tri-
fluoromethanesulfonate (TBDMSOTf) in the presence of
2,6-lutidine to afford after purification the corresponding
bis-tert-butyldimethylsilyl ether 21. After cleavage of the
benzyl ether (H2, Pd/C, K2CO3, AcOEt), alcohol 22 was
obtained in 71% yield and transformed to iodide 23 in
95% yield under Garegg’s conditions34 (Scheme 6).
The coupling of subunit C14-C19 to fragment C20-
C25 was realized under Hanessian’s conditions.16b The
generation of the dithiane anion from 17 with tert-
butyllithium in HMPA proceeded at -78 °C, and after
addition of iodide 23, the coupling product 24 was isolated
in a nonoptimized 28% yield (Scheme 7).
a
Reagents and conditions: (a) TBDMSOTf, 2,6-lutidine, (quant);
(b) DIBAL-H, toluene, -78 °C; (quant); (c) Swern (90%); (d) (80%);
(e) (MeO)MeNH‚HCl, Me3Al; (97%); (f) HF‚Pyr THF, (77%); (g)
TBDMSCl, 2,6-lutidine, (97%); (h) DIBAL-H, THF (89%); (i)
HS(CH2)3SH, TiCl4, (98%).
butyldimethylsilyl ether, the ester group in 9 was then
reduced by DIBAL-H (toluene, -78 °C) in quantitative
yield, and the resulting alcohol 10 was oxidized to the
corresponding aldehyde 11 in 90% yield with a Swern
reaction [(COCl)2, DMSO, Et3N, CH2Cl2, -78 °C]. When
aldehyde 11 was added to the oxazolidine boron enolate
12, the aldol product 13 was obtained in 80% yield as a
single diastereomer (Scheme 5).
The stereochemical confirmation of the aldol 13 was
ascertained through lactone 18, via amide 14. This latter
compound was obtained in 97% yield from oxazolidine
13 by treatment with the aluminum amide of the
N,O-dimethyl hydroxylamine [Me(MeO)NH‚HCl, AlMe3,
CH2Cl2),31 which after deprotection of the hydroxy groups
at C15 (HF/pyridine) cyclized to lactone 18 in 77% yield.
Con clu sion
In summary, the synthesis of the C14-C25 fragment
of bafilomycin A1 was realized in 11 steps in a sequence
involving two enantioselective transfer-hydrogenation
steps induced by chiral Ru-complexes. These reactions
set the C15, C16, C21, and C22 stereogenic centers in a
dynamic kinetic resolution. The synthesis also involves
an anti-selective reduction of a â-hydroxyketone to
control the C23 stereogenic center and an aldol-type
reaction under Evans’ conditions, which sets the C17 and
(32) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(33) Rychnovsky, S. D.; Rogers, B. N.; Richardson, R. I. Acc. Chem.
The value of the coupling constants in 18, (J H15-H16
)
Res. 1998, 31, 9.
(31) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J . J . Am.
Chem. Soc. 1998, 120, 5921.
(34) Garegg, P.; Samuelson, B. J . Chem. Soc., Perkin Trans. 1 1980,
2866.
J . Org. Chem, Vol. 68, No. 26, 2003 9997

Eustache et al.
SCHEME 6a
matography was performed on precoated silica gel (60 F254).
Melting points are uncorrected. Mass spectra were obtained
by GC/MS with electron impact ionization at 70 eV. Only
selected ions are reported. Optical rotations were measured
1
on a Perkin-Elmer 343 polarimeter. H and 13C spectra were
recorded at 300 and 75 MHz, respectively. Spectra were
recorded in CDCl3, and chemical shifts (δ) are expressed in
ppm relative to residual CHCl3 at δ ) 7.27 ppm for 1H and to
1
CDCl3 at δ ) 77.1 ppm for 13C. H NMR J values are given in
Hz. IR spectrum were recorded as neat films (NaCl cell) and
KBr pellets for solids.
(()-1-(1H-Ben zotr iazol-1-yl)-2-ben zyloxyeth an -1-on e (2).
To a solution of benzyloxyacetic acid 1 (2.49 g, 15.0 mmol,
1 equiv) in THF (60 mL) at 0 °C were added 1H-1,2,3-benzo-
triazole (1.78 g, 15.0 mmol, 1 equiv) and a solution of DCC
(1.79 g, 15.0 mmol, 1 equiv) in THF (10 mL). After 12 h at
room temperature, the solution was filtered through Celite,
and the filtrate washed with an aqueous solution of HCl
(2 N). The organic phase was dried over MgSO4, filtered,
evaporated, and purified by flash chromatography on silica gel
(petroleum ether/AcOEt 4/1) to give 2 as a white solid (3.84 g,
96%). Rf ) 0.44 (petroleum ether/EtOAc 4/1). Mp: 67 °C. IR
(film): 1750, 1485, 1450, 1400 cm-1. 1H NMR: δ 8.17 (dt, 1H,
J ) 7.0 and 1.0 Hz), 8.00 (dt, 1H, J ) 8.5 and 1.0 Hz), 7.56
(ddd, 1H, J ) 8.3, 7.2 and 1.1 Hz), 7.42 (ddd, 1H, J ) 8.3, 5.9
and 1.3 Hz), 7.40-7.24 (m, 5H), 5.14 (s, 2H), 4.76 (m, 2H). 13
C
NMR: δ 168.5, 145.4, 136.6, 130.4, 130.3, 128.2, 127.8, 126.0,
119.8, 113.6, 73.4, 68.3. MS (EI, 70 eV) m/z (rel intensity): 238
([MH - N2]+., 16), 180 (13), 162 (10), 146 (42), 118 (29), 91
(100), 65 (12). Anal. Calcd for C15H13N3O2: C, 67.40; H, 4.90;
N, 15.72. Found: C, 67.65; H, 5.19; N, 15.64.
(()-4-Ben zyloxy-2-m eth yl-1-ph en ylbu tan e-1,3-dion e (3).
To
a solution of lithium diisopropylamide (32.9 mmol,
1.1 equiv) in THF (220 mL) at -78 °C was added dropwise a
solution of propiophenone (4.29 mL, 32.9 mmol, 1.1 equiv) in
THF (150 mL). After 1 h at -78 °C, a solution of acylbenzo-
triazole 2 (7.98 g, 29.9 mmol, 1 equiv) in THF (100 mL) was
added. After 15 min at -78 °C and 1.5 h at room temperature,
the reaction mixture was quenched with H2O and extracted
with ether (3 times). The organic phases were dried over
MgSO4, evaporated, and purified by flash chromatography on
silica gel (petroleum ether/EtOAc 9/1) to give 3 as a white solid
(6.08 g, 72%). Rf ) 0.25 (petroleum ether/EtOAc 9/1). Mp: <50
a
Reagents and conditions: (a) Me4NBH(OAc)3, AcOH (dr ) 90/
10, 76%); (b) 2,2-DMP, CSA, acetone (74%); (c) TBDMSOTf, 2,6-
lutidine (90%); (d) H2,Pd/C (10%) K2CO3, AcOEt (71%); (e) I2,
imidazole, PPh3, toluene (95%).
SCHEME 7a
°C. IR (CHBr3): 1725, 1670, 1595, 1450 cm-1 1H NMR: δ
.
7.99-7.93 (m, 2H), 7.63-7.56 (m, 1H), 7.50-7.42 (m, 2H),
7.26-7.16 (m, 3H), 7.11-7.05 (m, 2H), 4.80 (q, 1H, J ) 7.0
Hz), 4.41 (s, 2H), 4.10 (s, 2H), 1.39 (d, 3H, J ) 7.0 Hz).
13C NMR: δ 205.9, 197.7, 136.7, 135.7, 133.3, 128.7, 128.6,
128.5, 128.0, 127.7, 73.9, 73.5, 51.4, 12.6. MS (EI, 70 eV) m/z
(rel intensity): 283 (MH+•, 0.1), 176 (53), 148 (7), 105 (100),
91 (80), 77 (28), 51 (6). HRMS (CI+, CH4): calcd for C18H19O3
(MH+•) 283.1334, found 283.1332.
(()-1-Ben zyloxy-3,5-d im eth ylh exa n e-2,4-d ion e (4). To
a solution of lithium diisopropylamide (6.18 mmol, 1.1 equiv)
in THF (41 mL) at -78 °C was added dropwise a solution of
2-methylpentan-3-one (0.763 mL, 6.18 mmol, 1.1 equiv) in THF
(28 mL). After 1 h at -78 °C, a solution of acylbenzotriazole 2
(1.5 g, 5.62 mmol, 1.0 equiv) in THF (19 mL) was added. After
15 min at -78 °C and 1.5 h at room temperature, the reaction
mixture was quenched with H2O and extracted with ether
(3 times). The organic phases were dried over MgSO4, evapo-
rated, and purified by flash chromatography on silica gel
(petroleum ether/EtOAc 9/1) to give 4 as a colorless liquid
a
Reagents and conditions: (a) t-BuLi, HMPA, THF (28%).
C18 stereogenic centers. With subunit C14-C25 in hand,
progress toward the total synthesis of bafilomycin A1
continues and will be reported in due course.
Exp er im en ta l Section
Gen er a l P r oced u r es. Unless otherwise specified, materi-
als were purchased from commercial suppliers and used
without further purification. THF and diethyl ether were
distilled from sodium/benzophenone immediately before use.
CH2Cl2, DMF, DMSO, Et3N, and diisopropylamine were dis-
tilled from CaH2 under argon. Moisture-sensitive reactions
were conducted in oven- or flame-dried glassware under an
argon atmosphere. Flash chromatography was carried out on
Kieselgel 60 (230-400 mesh), and analytical thin-layer chro-
(1.00 g, 72%). Rf
) 0.27 (petroleum ether/EtOAc 9/1).
1H NMR: δ 7.39-7.26 (m, 5H), 4.55 (d, 1H, J ) 12.2 Hz), 4.51
(d, 1H, J ) 12.2 Hz), 4.09 (q, 1H, J ) 7.2 Hz), 4.05 (dapp, 2H,
J ) 1.5 Hz), 2.78 (qq, 1H, J ) 6.9 and 6.9 Hz), 1.27 (d, 3H,
J ) 7.2 Hz), 1.09 (d, 3H, J ) 6.9 Hz), 1.08 (d, 3H, J ) 6.9 Hz).
13C NMR: δ 211.1, 205.5, 136.8, 128.5, 128.0, 127.9, 74.1, 73.5,
54.5, 40.3, 18.3, 18.3, 12.2. MS (EI, 70 eV) m/z (rel intensity):
177 ([M - (CH3)2CHCdO]+•, 0.37), 142 (29), 91 (100), 71 (37),
9998 J . Org. Chem., Vol. 68, No. 26, 2003

C14-C25 Subunit of Bafilomycin A1
65 (6). HRMS (CI+, CH4): calcd for C15H21O3 (MH+•) 249.1491,
found 249.1495.
251 (MH+•, 86), 233 (44), 143 (100), 119 (23), 101 (50). Anal.
Calcd for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.84;
H, 8.92.
Gen er a l P r oced u r e for th e Mon or ed u ction of Dik e-
t on es 3 a n d 4. The ruthenium complex (R,R)-I or (S,S)-I
(1 mol %) was added to a mixture of diketone (1 equiv) in a
CH2Cl2 solution which was degassed three times. After 16 h
at room temperature, the reaction mixture was washed with
water (3 times), and the aqueous phases were extracted with
CH2Cl2 (3 times). The organic phases were combined, dried
over MgSO4, and evaporated, and the residue was purified by
flash chromatography on silica gel.
(-)-P h en yl (2R,3R)-4-Ben zyloxy-3-h yd r oxy-2-m eth yl-
bu ta n oa te (6). To a mixture of molecular sieves 4 Å (1 g) and
racemic trans-N,N′-bis(p-toluenesulfonyl)cyclohexan-1,2-di-
amine (0.223 g, 0.532 mmol, 0.8 equiv) at 0 °C were added
successively SnCl4 (5.32 mL, 1 M in CH2Cl2, 5.32 mmol, 0.8
equiv) and bis(trimethylsilylperoxide) (53.2 mL, 1 M in
CH2Cl2, 53.2 mmol, 8 equiv). After 10 min at 0 °C, a solution
of â-hydroxyketone 5 (1.89 g, 6.65 mmol, 1 equiv) in CH2Cl2
(35 mL) was added. After 12 h at room temperature, the
reaction was cooled to 0 °C and quenched with a saturated
aqueous NaHCO3 solution (23.6 mL) followed by the addition
of sodium thiosulfate (7.83 g). After 3 h at room temperature,
the reaction mixture was filtered through Celite, and the
filtrate was washed with an aqueous HCl (1 N) solution,
followed by brine. The organic phases were dried over
Na2SO4 and evaporated. The residue was dissolved in a
mixture of THF/H2O (37 mL/10 mL) and acetic acid (2.8 mL).
After stirring for 18 h at room temperature, the reaction
mixture was washed with a saturated aqueous NaHCO3
solution (2 times), the aqueous phases were washed with ether
(2 times). The organic phases were gathered and washed with
a HCl (1 N) aqueous solution and then with brine, and finally
they were evaporated. The residue was purified by flash
chromatography on silica gel (petroleum ether/EtOAc 2/1) to
give 6 as a pale yellow oil (1.55 g, 78%). Rf ) 0.26 (petroleum
(-)-(2R,3R)-4-Ben zyloxy-3-h yd r oxy-2-m eth yl-1-p h en yl-
bu ta n -1-on e35 (5) a n d (-)-(2S,3R)-4-ben zyloxy-3-h yd r oxy-
2-m eth yl-1-p h en ylbu ta n -1-on e (5′). Diketone 3 (0.2 g, 0.893
mmol, 1 equiv), (R,R)-I (0.236 mL, 0.03 M in CH2Cl2, 7.09 µmol,
0.01 equiv), Et3N (0.199 mL, 1.42 mmol, 2 equiv), HCO2H
(0.136 mL, 3.55 mmol, 5 equiv). Purification by flash chro-
matography (CH2Cl2/diethyl ether 96/4). (-)-5: Rf ) 0.42
(CH2Cl2/diethyl ether: 96/4). ee ) 93%.36 [R]20D ) -30.0 (c 1.1,
CH2Cl2). IR (film): 3420, 1670, 1595, 1575, 1445, 1360, 1210
cm-1. 1H NMR: δ 8.01-7.93 (m, 2H), 7.64-7.56 (m, 1H), 7.52-
7.44 (m, 2H), 7.35-7.24 (m, 5H), 4.51 (s, 2H), 4.23 (m, 1H),
3.74 (qd, 1H, J ) 7.2 and 5.5 Hz), 3.57 (dd, 1H, J ) 9.6 and
5.1 Hz), 3.50 (dd, 1H, J ) 9.6 and 5.9 Hz), 2.91 (d, 1H, J ) 4.4
Hz, OH), 1.29 (d, 3H, J ) 7.2 Hz). 13C NMR: δ 204.4, 137.8,
136.2, 133.3, 128.7, 128.5, 128.4, 128.2, 127.7, 73.4, 71.6, 71.1,
42.6, 12.8. MS (CI+, CH4) m/z (rel intensity): 285 (MH+•, 33),
267 (20), 177 (70), 168 (22), 163 (25), 159 (23), 136 (37), 135
(100), 105 (48). Anal. Calcd for C18H20O3: C, 76.03; H, 7.09.
Found: C, 76.05; H, 7.09. (-)-5′: Rf ) 0.43 (CH2Cl2/diethyl
ether/EtOAc 4/1). [R]20 ) -24.8 (c 1.0, CH2Cl2). IR (film):
D
3440, 1745, 1590, 1490, 1450, 1190, 1160 cm-1
.
1H NMR: δ
ether: 96/4). ee ) nd. [R]20 ) -36.0 (c 1, CH2Cl2). IR (film):
D
7.45-7.19 (m, 8H), 7.10-6.95 (m, 2H), 4.60 (sapp, 2H), 4.22
(m, 1H), 3.68-3.56 (m, 2H), 2.95 (dq, 1H, J ) 7.0 and 5.5 Hz),
2.84 (bd, 1H, J ) 4.8 Hz, OH), 1.39 (d, 3H, J ) 7.0 Hz).
13C NMR: δ 173.5, 150.5, 137.7, 129.3, 128.4, 127.8, 125.8,
121.4, 73.5, 71.2, 70.9, 42.3, 12.0. MS (EI, 70 eV) m/z (rel
intensity): 207 ([M - PhO]+•, 4), 184 (6), 121 (2), 107 (2), 95
(2), 94 (8), 92 (9), 91 (100), 85 (4), 77 (2), 65 (5). Anal. Calcd
for C18H20O4: C, 71.98; H, 6.71. Found: C, 71.84; H, 6.83.
3420, 1670, 1595, 1575, 1445, 1360, 1210 cm-1 1H NMR: δ
8.01-7.93 (m, 2H), 7.63-7.56 (m, 1H), 7.52-7.44 (m, 2H),
7.36-7.22 (m, 5H), 4.54 (d, 1H, J ) 11.9 Hz), 4.49 (d, 1H, J )
11.9 Hz), 4.10 (qd, 1H, J ) 6.5 and 6.5 Hz), 3.83 (qd, 1H, J )
7.3 and 6.1 Hz), 3.62 (dd, 1H, J ) 9.6 and 5.5 Hz), 3.57 (dd,
1H, J ) 9.6 and 5.0 Hz), 3.27 (d, 1H, J ) 6.6 Hz, OH), 1.25
(d, 3H, J ) 7.3 Hz); 13C NMR: δ 205.1, 137.8, 136.7, 133.3,
128.6, 128.5, 128.4, 127.7, 73.5, 73.0, 72.1, 42.1, 14.9. HRMS
(CI+, CH4): calcd for C18H21O3 (MH+•) 285.1491, found 285.1487.
(-)-(4S,5S)-6-Ben zyloxy-2,4-d im eth ylh exa n -5-h yd r oxy-
3-on e (8) and (+)-(4R,5S)-6-ben zyloxy-2,4-dim eth ylh exan -
5-h yd r oxy-3-on e (8′). Diketone 4 (0.2 g, 0.806 mmol, 1 equiv),
(S,S)-I (0.269 mL, 0.03 M in CH2Cl2, 8.06 µmol, 0.01 equiv),
Et3N (0.226 mL, 1.61 mmol, 2 equiv), HCO2H (0.155 mL, 4.03
(-)-(2R,3R)-4-Ben zyloxy-3-h yd r oxy-2-m et h ylb u t a n o-
ic Acid (7). To a solution of â-hydroxyester 6 (0.05 g, 0.167
mmol, 1 equiv) in THF (1 mL) was added a solution of LiOH‚
H2O (35 mg, 0.833 mmol, 5 equiv) in H2O (0.5 mL). After 15
min at room temperature, the reaction was diluted with H2O
and Et2O, and the reaction mixture was extracted with Et2O
(3 times). The aqueous phase was acidified with a 2 N HCl
aqueous solution until pH ) 3 and extracted with CH2Cl2
(5 times). The organic phases were dried over MgSO4, filtered,
and evaporated, and the residue was purified by flash chro-
matography on silica gel (CH2Cl2/MeOH 9/1) to produce 7 as
a colorless oil (29 mg, 78%). Rf ) 0.31 (CH2Cl2/MeOH 9/1).
[R]20D ) -11.0 (c 2.5, CHCl3). IR (film): 3400, 1710, 1450, 1210,
mmol,
5 equiv). Purification by flash chromatography
(CH2Cl2/diethyl ether 96/4). (-)-8: Rf ) 0.21 (petroleum ether/
diethyl ether: 6/4). ee ) 94%.37 [R]20D ) -15.0 (c 2.3, CH2Cl2).
IR (film): 3440, 1705 cm-1 1H NMR δ: 7.40-7.25 (m, 5H),
.
4.53 (sapp, 2H), 4.08-4.00 (m, 1H), 3.48 (dd, 1H, J ) 9.6 and
4.8 Hz), 3.42 (dd, 1H, J ) 9.6 and 6.2 Hz), 2.97 (qd, 1H, J )
7.0 and 5.6 Hz), 2.76 (qq, 1H, J ) 6.7 and 6.7 Hz), 2.74
(bs, 1H, OH), 1.15 (d, 3H, J ) 7.0 Hz), 2.09 (d, 3H, J )
6.7 Hz), 1.07 (d, 3H, J ) 6.7 Hz). 13C NMR: δ 218.4, 137.8,
128.4, 127.8, 127.7, 73.4, 71.6, 70.8, 46.0, 40.3, 18.1, 17.9, 12.0.
MS (CI+, CH4) m/z (rel intensity): 251 (MH+•, 86), 233 (44),
143 (100), 119 (23), 101 (50). Anal. Calcd for C15H22O3: C,
71.97; H, 8.86. Found: C, 71.83; H, 9.05. HRMS (CI+, CH4):
calcd for C15H23O3 (MH+•) 251.1647, found 251.1643. (+)-8′:
Rf ) 0.25 (petroleum ether/diethyl ether 6/4). ee ) 85%.37
1095 cm-1 1H NMR: δ 7.41-7.28 (m, 5H), 4.56 (sapp, 2H),
.
4.19-4.09 (m, 1H), 3.60-3.50 (m, 2H), 2.72 (dq, 1H, J ) 7.0
and 5.5 Hz), 1.23 (d, 3H, J ) 7.0 Hz). 13C NMR: δ 179.9, 137.6,
128.5, 127.9, 127.7, 73.5, 71.4, 70.6, 41.8, 11.6. MS (EI, 70 eV)
m/z (rel intensity): 224 (M+•, 0.7), 178 (2), 107 (18), 103 (11),
91 (100), 85 (25), 65 (9). HRMS (CI+, CH4): calcd for C12H17O4
(MH+•) 225.1127, found 225.1126.
(-)-P h en yl (2R,3R)-4-Ben zyloxy-3-(ter t-bu tyld im eth -
ylsiloxy)-2-m eth ylbu tyr a te (9). To a solution of â-hydroxy
ester 6 (0.8 g, 2.67 mmol, 1 equiv) in CH2Cl2 (36 mL) at
-78 °C were added TBDMSOTf (0.919 mL, 4.34 mmol,
1.5 equiv) and 2,6-lutidine (0.930 mL, 8.68 mmol, 3 equiv).
After 1 h at -78 °C, the reaction was quenched with a
saturated aqueous NH4Cl solution and extracted with CHCl3
(3 times). The organic phases were dried over MgSO4 and
evaporated, and the residue was purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 9/1 to give 9 as a
colorless oil (1.1 g, 100%). Rf ) 0.53 (petroleum ether/EtOAc
9/1). [R]20D ) -3.7 (c 0.75, CH2Cl2). IR (film): 1760, 1590, 1490,
[R]20 ) +20.0 (c 1.0, CH2Cl2). IR (film): 3440, 1705 cm-1
.
D
1H NMR: δ 7.40-7.27 (m, 5H), 4.57 (d, 1H, J ) 11.8 Hz), 4.52
(d, 1H, J ) 11.8 Hz), 3.89 (m, 1H), 3.51 (dapp, 2H, J ) 5.1 Hz),
3.08 (bs, 1H, OH), 3.02 (qd, 1H, J ) 7.0 Hz), 2.74 (qq, 1H, J )
7.2 and 7.2 Hz), 1.10 (d, 6H, J ) 7.2 Hz), 1.07 (d, 3H, J ) 7.0
Hz). 13C NMR: δ 219.1, 137.8, 128.4, 127.8, 127.4, 73.5, 72.9,
72.2, 45.8, 41.0, 17.8, 14.1. MS (CI+, CH4) m/z (rel intensity):
(35) Reetz, M. T.; Kesseler, K.; J ung, A. Tetrahedron 1984, 40, 4327.
(36) Column: Daicel CHIRALCEL OD-H. Eluent: n-hexane/2-
propanol 98/2. Flow rate: 1 mL/min-1. λ ) 220 nm.
(37) Column: Daicel CHIRALCEL OJ -H. Eluent: n-hexane/2-
propanol 98/2. Flow rate: 1 mL/min-1. λ ) 220 nm.
1455, 1380, 1360, 1250, 1190 cm-1 1H NMR: δ 7.43-7.31
.
(m, 8H), 7.11-7.04 (m, 2H), 4.63 (d, 1H, J ) 12.1 Hz), 4.56
J . Org. Chem, Vol. 68, No. 26, 2003 9999

Eustache et al.
(d, 1H, J ) 12.1 Hz), 4.47-4.38 (dt, 1H, J ) 6.6 and 5.0 Hz),
3.59 (dd, 1H, J ) 9.8 and 5.5 Hz), 3.53 (dd, 1H, J ) 9.8 and
6.6 Hz), 3.00 (qd, 1H, J ) 7.2 and 5.0 Hz), 1.35 (d, 3H, J )
7.2 Hz), 0.94 (s, 9H), 0.14 (s, 3H), 0.13 (s, 3H). 13C NMR: δ
173.3, 150.8, 138.0, 129.3, 128.4, 127.8, 127.7, 125.5, 121.5,
73.4, 72.7, 71.7, 43.5, 25.8, 18.1, 11.4, -4.2, -4.9. MS (CI+,
CH4) m/z (rel intensity): 415 (MH+•, 24), 339 (23), 357 (24),
321 (100), 231 (19). Anal. Calcd for C24H34O4Si: C, 69.53;
H, 8.26. Found: C, 69.42; H, 8.40.
organic phases were washed with
a
saturated aqueous
NaHCO3 solution and then with brine. The resulting solution
was dried over MgSO4, filtered, and evaporated, and the
residue was purified by flash chromatography on silica
gel (petroleum ether/AcOEt 4/1) to give 13 as a colorless oil
(0.305 g, 80%). Rf ) 0.33 (petroleum ether/EtOAc 4/1).
[R]20 ) +34.9 (c 0.8, CH2Cl2). IR (film): 3500, 1170, 1700,
D
1390, 1250, 1210, 1100 cm-1. 1H NMR: δ 7.39-7.18 (m, 10H),
4.74-4.62 (m, 1H), 4.54 (d, 1H, J ) 12.1 Hz), 4.49 (d, 1H, J )
12.1 Hz), 4.30-4.20 (m, 1H), 4.15 (dapp, 2H, J ) 4.8 Hz), 3.63-
3.45 (m, 2H), 3.32 (dd, 1H, J ) 13.4 and 3.1 Hz), 2.77 (dd, 1H,
J ) 13.4 and 9.7 Hz), 1.95-1.81 (m, 1H), 1.24 (d, 3H, J ) 7.0
Hz), 1.10 (m, 1H), 0.88 (s, 9H), 0.85 (3H), 0.11 (s, 3H), 0.07
(s, 3H). 13C NMR: δ 176.7, 153.1, 138.3, 135.3, 129.4, 128.9,
128.3, 2C), 127.5, 127.4, 127.3, 73.2, 73.0, 72.7, 72.2, 66.1, 55.5,
40.3, 38.4, 37.7, 28.8, 18.1, 10.9, 9.0, -4.4, -5.1. MS (CI+, CH4)
m/z (rel intensity): 556 (MH+•, 100), 540 (18), 498 (17), 234
(+)-(2S,3R)-4-Ben zyloxy-3-(ter t-bu tyld im eth ylsiloxy)-
2-m eth ylbu ta n -1-ol (10). To a solution of ester 9 (0.422 g,
1.02 mmol, 1 equiv) in toluene (16 mL) at -78 °C was added
dropwise a solution of DIBAL-H in hexane (3.06 mL, 1 M in
hexane, 3.06 mmol, 3 equiv). After 1 h at -78 °C, the reaction
was quenched by addition of a saturated aqueous sodium and
potassium tartrate solution. The aqueous phase was extracted
with ether (3 times), the organic phases were dried over MgSO4
and evaporated, and the residue was purified by flash chro-
matography on silica gel (petroleum ether/EtOAc 4/1) to give
alcohol 10 as a colorless oil (0.330 g, 100%). Rf ) 0.28
(38), 215 (18), 178 (15). HRMS (CI+, CH4): calcd for C31H46
NO6Si (MH+•) 556.3098, found 556.3094.
-
(+)-(2S,3R,4S,5R)-6-Ben zyloxy-5-(ter t-bu tyld im eth ylsi-
loxy)-3-h yd r oxy-2,4-d im eth yl-N-m eth oxy-N-m eth ylh ex-
a n a m id e (14). To a suspension of N,O-dimethylhydroxyl-
amine chlorhydrate (0.185 g, 1.89 mmol, 3 equiv) in CH2Cl2
(2.4 mL) at -15 °C was added a solution of AlMe3 (0.946 mL,
2 M in toluene, 1.89 mmol, 3 equiv) at room temperature. After
30 min, the reaction media was cooled to -15 °C, and a
solution of amide 13 (0.35 g, 0.631 mmol, 1 equiv) in CH2Cl2
(5.7 mL) was added. After 24 h at -15 °C, the reaction was
quenched with a saturated aqueous potassium sodium tartrate
solution and extracted with CH2Cl2 (4 times). The organic
phases were dried over MgSO4, filtered, and evaporated, and
the residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc 1/1) to produce amide 14 as a colorless
oil (0.269 g, 97%). Rf ) 0.33 (petroleum ether/EtOAc 1/1).
[R]20D ) +8.7 (c 1.0, CH2Cl2). IR (film): 3440, 1640, 1460, 1250,
(petroleum ether/EtOAc 9/1). [R]20 ) +9.0 (c 1.0, CH2Cl2). IR
D
(film): 3320, 1610, 1590, 1470, 1250 cm-1. H NMR: δ 7.38-
1
7.27 (m, 5H), 4.56 (d, 1H, J ) 11.9 Hz), 4.51 (d, 1H, J ) 11.9
Hz), 3.97 (tdapp, 1H, J ) 5.4 and 3.8 Hz), 3.60 (d, 2H, J ) 6.2
Hz), 3.50 (d, 2H, J ) 5.4 Hz), 2.48 (bs, 1H, OH), 2.05-1.89
(m, 1H), 0.89 (s, 9H), 0.88 (d, 3H, J ) 6.6 Hz), 0.08 (s, 3H),
0.06 (s, 3H). 13C NMR: δ 138.1, 128.4, 127.6, 73.4, 72.3, 65.5,
39.2, 25.8, 18.1, 11.7, -4.3, -5.0. MS (EI, 70 eV) m/z (rel
intensity): 325 (MH+•, 0.01), 203 (13), 175 (14), 145 (6), 21
(100), 73 (10). Anal. Calcd for C18H32O3Si: C, 66.62; H, 9.94.
Found: C, 66.64; H, 9.90.
(2R,3R)-4-Ben zyloxy-3-(ter t-b u t yld im et h ylsiloxy)-2-
m eth ylbu ta n a l (11). To a solution of oxalyl chloride (0.475
mL, 5.53 mmol, 2.2 equiv) in CH2Cl2 (37 mL) at -78 °C was
added DMSO (0.504 mL, 7.03 mmol, 2,8 equiv). After 30 min,
a solution of alcohol 10 (0.814 g, 2.51 mmol, 1 equiv) in
CH2Cl2 (10 mL) was added. The reaction mixture was stirred
for 20 min at -78 °C, at which time Et3N (1.66 mL, 11.8 mmol,
4.7 equiv) was added. After 15 min at -78 °C, 15 min at 0 °C,
the reaction mixture was quenched with a saturated aqueous
NaCl solution and extracted with petroleum ether (3 times).
The organic phases were dried over MgSO4 filtered, and
evaporated, and the residue was purified by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc 9/1) to give
aldehyde 11 as a colorless oil (0.750 g, 90%), which was
immediately used in the following reaction. Rf ) 0.35 (petro-
1
1100, 1060 cm-1. H NMR: δ 7.37-7.22 (m, 5H), 4.57 (d, 1H,
J ) 12.1 Hz), 4.46 (d, 1H, J ) 12.1 Hz), 4.43 (ddd, 1H, J )
6.2, 6.2 and 1.6 Hz), 4.09 (d, 1H, J ) 1.6 Hz, OH), 3.74 (ddd,
1H, J ) 9.7, 2.2 and 1.6 Hz), 3.70 (s, 3H), 3.43 (d, 2H, J ) 6.2
Hz), 3.21 (s, 3H), 3.09-2.95 (m, 1H), 1.78 (dqd, 1H, J ) 9.7,
7.0 and 1.6 Hz), 1.15 (d, 3H, J ) 7.0 Hz), 0.86 (s, 9H), 0.78 (d,
3H, J ) 7.0 Hz), 0.09 (s, 3H), 0.05 (s, 3H). 13C NMR: δ 138.5,
128.2, 127.6, 127.4, 72.9, 71.9, 69.6, 61.7, 37.6, 35.7, 25.9, 18.2,
9.4, 9.2, -4.3, -5.0. MS (EI, 70 eV) m/z (rel intensity): 424
([M - Me]+•, 0.11), 382 (11), 300 (28), 274 (18), 173 (6), 117
(21), 91 (100), 75 (10). Anal. Calcd for C23H41NO5Si: C, 62.83;
H, 9.40; N, 3.19. Found: C, 62.43; H, 9.44; N, 3.04.
leum ether/EtOAc 9/1). IR (film): 3460, 1740, 1690, 1480 cm-1
.
1H NMR: δ 9.75 (d, 1H, J ) 1.0 Hz), 7.40-7.28 (m, 5H), 4.55
(d, 1H, J ) 11.9 Hz), 4.50 (d, 1H, J ) 11.9 Hz), 4.33 (ddd, 1H,
J ) 6.5, 5.2 and 3.8 Hz), 3.50 (dd, 1H, J ) 9.6 and 5.2 Hz),
3.42 (dd, 1H, J ) 9.6 and 6.5 Hz), 2.61 (qdd, 1H, J ) 7.0, 3.8
and 1.0 Hz), 1.07 (d, 3H, J ) 7.0 Hz), 0.86 (s, 9H), 0.06
(s, 3H), 0.05 (s, 3H). 13C NMR: δ 204.3, 137.9, 128.4, 127.7,
127.6, 73.4, 71.8, 70.5, 50.0, 25.7, 18.0, 7.6, -4.3, -5.0. MS
(EI, 70 eV) m/z (rel intensity): 321 ([M - H]+•, 0.35), 215 (11),
199 (8), 173 (8), 117 (14), 91 (100), 73 (10). HRMS (CI+, NH3):
calcd for C18H34O3NSi [M + NH4]+• 340.2308, found 340.2310.
(+)-(2S,3R,4S,5R)-6-Ben zyloxy-3,5-bis(ter t-bu tyldim eth -
y lsilox y)-2,4-d im e t h yl-N -m e t h oxy -N -m e t h y lh e x a n a -
m id e (15). To a solution of amide 14 (0.271 g, 0.617 mmol,
1 equiv) in CH2Cl2 (8 mL) at -78 °C were added TBDMSOTf
(0.426 mL, 1.85 mmol, 3 equiv) and 2,6-lutidine (0.430 mL,
3.70 mmol, 6 equiv). After 3 h at -40 °C, the reaction was
quenched with a saturated aqueous NH4Cl solution and
extracted with CH2Cl2 (3 times). The organic phases were dried
over MgSO4, filtered, evaporated, and purified by silica gel
chromatography (petroleum ether/EtOAc 9/1) to produce 15
as a colorless oil (0.33 mg, 97%). Rf ) 0.25 (petroleum ether/
(+)-(4S)-3-[(2S,3R,4S,5R)-6-Ben zyloxy-5-(ter t-b u t yld i-
m eth ylsiloxy)-3-h yd r oxy-2,4-d im eth yl-h exa n oyl]-4-ben -
zyloxa lid in -2-on e (13). To a solution of propionyl (5S)-5-
benzyl oxazolidinone29 (0.160 g, 0.688 mmol, 1 equiv) in CH2Cl2
(1.5 mL) at 0 °C were added dropwise Bu2BOTf (0.206 mL,
0.812 mmol, 1.18 equiv) and Et3N (0.125 mL, 0.908 mmol, 1.32
equiv) After 20 min, the reaction mixture was cooled to
-78 °C, and aldehyde 9 (0.246 g, 0.764 mmol, 1.1 equiv) in
CH2Cl2 (0.3 mL) was added dropwise. After 1 h at -78 °C and
2 h at 0 °C, a buffered phosphate solution (pH ) 7, 0.756 mL)
was added followed by the addition of MeOH (2.27 mL) and a
mixture of 30% H2O2/MeOH 2/1. After 1 h at 0 °C, the reaction
mixture was concentrated under vacuum, and ether was added
followed by a saturated aqueous Na2S2O4 solution. The aque-
ous solution was extracted with ether (4 times), and the
EtOAc 9/1). [R]20 ) -8.2 (c 1.55, CH2Cl2). IR (film): 1660,
D
1470, 1460, 1260, 1060 cm-1. H NMR: δ 7.36-7.22 (m, 5H),
1
4.56 (d, 1H, J ) 11.9 Hz), 4.49 (d, 1H, J ) 11.9 Hz), 4.05 (dd,
1H, J ) 6.6 and 4.4 Hz), 3.69-3.61 (m, 1H), 3.66 (s, 3H), 3.53-
3.46 (m, 2H), 3.14 (s, 3H), 3.09-2.96 (m, 1H), 1.91 (qdd, 1H,
J ) 7.2, 7.2 and 4.4 Hz), 1.12 (d, 3H, J ) 7.0 Hz), 0.97 (d, 3H,
J ) 7.2 Hz), 0.90 (s, 9H), 0.88 (s, 9H), 0.07 (s, 3H), 0.05 (s,
3H), 0.04 (s, 3H), 0.01 (s, 3H). 13C NMR: δ 173.7, 138.6, 128.1,
127.7, 127.5, 73.7, 73.5, 73.2, 72.8, 61.1, 42.7, 38.1, 26.1, 26.0,
18.4, 18.3, 14.1, 12.0, -3.8, -4.1, -4.4, -4.5. MS (EI, 70 eV)
m/z (rel intensity): 538 ([M - Me]+•, 2), 496 (99), 300 (39),
260 (20), 204 (8), 149 (12), 117 (14), 91 (100), 73 (24). HRMS
(CI+, CH4): calcd for C29H56NO5Si2 (MH+•) 554.3697, found
10000 J . Org. Chem., Vol. 68, No. 26, 2003

C14-C25 Subunit of Bafilomycin A1
554.3705. Anal. Calcd for C29H55NO5Si2: C, 62.88; H, 10.01;
N, 2.53. Found: C, 62.88; H, 10.07; N, 2.39.
2.58 (qd, 1H, J ) 7.3 and 7.3 Hz), 2.40 (qdd, 1H, J ) 7.2, 4.0
and 3.9 Hz), 1.39 (d, 3H, J ) 7.3 Hz), 0.99 (d, 3H, J ) 7.2 Hz).
13C NMR: δ 173.1, 137.0, 128.6, 128.1, 127.9, 78.6, 73.9, 73.1,
68.6, 41.3, 34.2, 15.4, 6.7. MS (CI+, CH4) m/z (rel intensity):
265 (MH+•, 100), 247 (8), 185 (12), 157 (27), 139 (19), 125 (23),
(+)-(2S,3R,4S,5R)-6-Ben zyloxy-3,5-bis(ter t-bu tyldim eth -
ylsiloxy)-2,4-d im eth ylh exa n a l (16). To a solution of amide
15 (0.232 g, 0.419 mmol, 1 equiv) in THF (3.3 mL) at -78 °C
was added a solution of DIBAL-H (0.503 mL, 1 M in hexane,
1.01 mmol, 2.4 equiv) dropwise. After 2 h at -78 °C, acetone
was added to the reaction mixture, and 15 min after this
addition, the reaction was poured on an aqueous solution of
tartaric acid (0.5 M in H2O, 28 mL) and cyclohexane (28 mL)
and stirred for 1 h at room temperature. The aqueous phase
was extracted with ether (5 times), the organic phases were
dried over MgSO4, filtered, and evaporated, and the residue
was purified by flash chromatography on silica gel to produce
aldehyde 16 as a colorless oil (0.184 g, 89%). Rf ) 0.61
119 (16). HRMS (CI+, CH4): calcd for C15H21O4 (MH+•
265.1440, found 265.1437.
)
1-Ben zyloxy-3,5-d im et h yl-h exa n e-2,4-d iols (19) a n d
(19′). To a solution of â-hydroxyketones 8 and 8′ (0.639 g, 2.56
mmol, 1 equiv) in acetic acid (8.5 mL) at 0 °C was added
dropwise a solution of Me4NBH(OAc)3 (2.03 g, 7.68 mmol, 3
equiv) in AcOH (17 mL). After 12 h at room temperature,
CH2Cl2 (32 mL) was added to the reaction mixture, and then
a saturated aqueous NaHCO3 solution (32 mL) was slowly
added. After 45 min at room temperature, the aqueous phase
was extracted with CH2Cl2 (3 times), then the organic phases
were dried over MgSO4, filtered, and evaporated, and the
residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc 2/1) to produce an inseparable mixture
of two diastereomers 19 and 19′ as (0.49 g, dr ) 90/10, 76%).
Rf ) 0.24 (petroleum ether/EtOAc 2/1). IR (film): 3490, 1450,
(petroleum ether/EtOAc 9/1). [R]20 ) +21.5 (c 0.8, CH2Cl2).
D
IR (film): 1725, 1470, 1460, 1250, 1100, 1030 cm-1. H NMR:
1
δ 9.66 (s, 1H), 7.39-7.24 (m, 5H), 4.55 (d, 1H, J ) 12.1 Hz),
4.47 (d, 1H, J ) 12.1 Hz), 4.34 (dd, 1H, J ) 6.9 and 2.1 Hz),
4.01 (dd, 1H, J ) 5.5 and 3.6 Hz), 3.46 (dd, 1H, J ) 9.6 and
5.5 Hz), 3.38 (dd, 1H, J ) 9.6 and 5.5 Hz), 2.48 (qd, 1H, J )
7.0 and 2.1 Hz), 1.91 (qdd, 1H, J ) 6.9, 6.9 and 3.6 Hz), 1.13
(d, 3H, J ) 7.0 Hz), 0.89 (s, 9H), 0.88 (d, 3H, J ) 6.9 Hz), 0.86
(s, 9H), 0.09 (s, 3H), 0.08 (s, 3H), 0.05 (s, 3H), -0.02 (s, 3H).
13C NMR: δ 205.3, 138.2, 128.3, 127.6, 127.5, 73.5, 73.1, 72.0,
71.7, 49.8, 42.2, 26.0, 25.9, 18.4, 18.3, 10.6, -3.6, -4.0, -4.1,
1090 cm-1 1H NMR: δ 7.41-7.28 (m, 5H), 4.61 (d, 1H, J )
.
11.8 Hz), 4.55 (d, 1H, J ) 11.8 Hz), 4.24-4.15 (m, 1H), 3.57
(dd, 1H, J ) 9.5 and 8.1 Hz), 3.50 (dd, 1H, J ) 9.5 and 3.8
Hz), 3.30 (tapp, 1H, J ) 6.1 Hz), 2.99 (bs, 1H, OH), 2.89 (bs,
1H, OH), 2.00-1.75 (m, 2H), 0.95 (d, 3H, J ) 6.6 Hz), 0.94 (d,
3H, J ) 7.4 Hz), 0.92 (d, 3H, J ) 6.6 Hz). 13C NMR: δ 138.0,
128.5, 127.8, 127.7, 80.2, 73.5, 72.5, 71.5, 36.4, 30.8, 19.7, 16.7,
-4.4. MS (CI+, CH4) m/z (rel intensity): 512 ([M + NH4]+•
,
13), 437 (20), 353 (98), 305 (100), 265 (30), 255 (28), 215 (39),
185 (24). HRMS (CI+, CH4): calcd for C27H54NO4Si2 [M +
NH4]+• 512.3591, found 512.3585.
11.9. MS (EI, 70 eV) m/z (rel intensity): 161 ([M - PhCH2]+•
2), 131 (13), 107 (17), 101 (7), 91 (100), 73 (21).
,
(-)-(4S,5R,6R)-4-Ben zyloxym et h yl-6-isop r op yl-2,2,5-
tr im eth yl-1,3-d ioxa n e (20). Into the diastereomeric mixture
of 19 and 19′ (0.3 g, 1.19 mmol, 1 equiv) in acetone (4.2 mL)
were added 2,2-dimethoxypropane (1.46 mL, 11.9 mmol, 10
equiv) and CSA (5 mol %). After 5 h at room temperature, the
reaction mixture was concentrated under vacuum, and the
residue was purified by flash chromatography on silica gel
(petroleum ether/CH2CL2 8/2). Ketal 20 was obtained as a
white solid (0.231 g, 67%). Rf ) 0.43 (petroleum ether/CH2Cl2
8/2). [R]20D ) -21.0 (c 1.0, CH2Cl2). Mp: 54 °C. IR (film): 1450,
(+)-(2S,3R,4S,5R)-5-Ben zyloxy-2,4-bis(ter t-bu tyldim eth -
ylsiloxy)-1,3-d im eth ylp en tyl]-1,3-d ith ia n e (17). To a solu-
tion of aldehyde 16 (0.182 g, 0.368 mmol, 1 equiv) in CH2Cl2
(14 mL) at -78 °C was added 1,3-propanedithiol (0.186 mL,
1.84 mmol, 5 equiv) followed by a dropwise addition of TiCl4
(80 µL, 0.74 mmol, 2 equiv). After 30 min at -78 °C, the
reaction was quenched with a saturated aqueous NaHCO3
solution and warmed to room temperature. The aqueous phase
was extracted with CH2Cl2 (5 times), the organic phases were
dried over MgSO4, filtered, and evaporated, and the residue
was purified by flash chromatography on silica gel (petroleum
ether, AcOEt 95/5) to give thioketal 17 as a white oil (0.211 g,
1
1375, 1220, 1100, 1025 cm-1. H NMR: δ 7.38-7.33 (m, 5H),
4.64 (d, 1H, J ) 11.9 Hz), 4.50 (d, 1H, J ) 11.9 Hz), 4.07 (ddd,
1H, J ) 7.0, 5.8 and 4.6 Hz), 3.51 (dd, 1H, J ) 9.7 and 7.0
Hz), 3.46 (dd, 1H, J ) 9.7 and 5.8 Hz), 3.06 (dd, 1H, J ) 7.3
and 5.1 Hz), 1.86 (m, 1H), 1.73 (m, 1H), 1.37 (s, 3H), 1.35 (s,
3H), 0.95 (d, 3H, J ) 6.8 Hz), 0.93 (d, 3H, J ) 6.8 Hz), 0.85 (d,
3H, J ) 6.9 Hz). 13C NMR: δ 138.4, 128.3, 127.7, 127.5, 100.4,
79.1, 73.3, 69.9, 68.4, 35.2, 31.6, 25.4, 23.5, 18.7, 17.5, 12.5.
MS (EI, 70 eV) m/z (rel intensity): 292 (MH+•, 0.02), 277 (7),
171 (8), 162 (8), 118 (12), 107 (19), 91 (100), 69 (12), 59 (12).
Anal. Calcd for C18H28O3: C, 73.93; H, 9.65. Found: C, 73.92;
H, 9.74.
(-)-(4S,5R,6S)-4-Ben zyloxym et h yl-6-isop r op yl-2,2,5-
tr im eth yl-1,3-d ioxa n e (20′). 1H NMR: δ 7.15-7.30 (m, 5H),
4.58 (d, 1H, J ) 12.1 Hz), 4.43 (d, 1H, J ) 12.1 Hz), 4.05 (ddd,
1H, J ) 6.3, 6.3 and 2.6 Hz), 3.44 (dd, 1H, J ) 9.6 and 6.6
Hz), 3.37 (dd, 1H, J ) 9.7 and 5.8 Hz), 3.26 (dd, 1H, J ) 9.6
and 5.9 Hz), 1.50-1.65 (m, 2H), 1.35 (d, 3H, J ) 4.5 Hz), 1.20
(s, 6H), 0.89 (d, 3H, J ) 6.6 Hz), 0.72 (d, 3H, J ) 6.6 Hz). 13C
NMR: δ 128.2, 127.7, 127.5, 78.9, 73.3, 72.3, 71.0, 30.8, 29.8,
29.0, 19.6, 19.5 (2C), 17.3.
(2S,3R,4R)-1-Ben zyloxy-2,4-b is(ter t-b u t yld im et h ylsi-
loxy)-3,5-d im eth ylh exa n e (21). To a solution of diols 19 and
19′ (0.118 g, 0.468 mmol, 1 equiv) in CH2Cl2 (6 mL) at -78 °C
were added TBDMSOTf (0.323 mL, 1.40 mmol, 3 equiv) and
2,6-lutidine (0.326 mL, 2.81 mmol, 6 equiv). After 1 h at
-78 °C and 2 h at -35 °C, the reaction was quenched with a
saturated aqueous NH4Cl solution. The aqueous phase was
extracted with CH2Cl2 (4 times). The organic phases were dried
over MgSO4, filtered, and evaporated, and the residue was
purified by flash chromatography on silica gel (petroleum
ether/EtOAc 9/1) to give 21 as a colorless oil (0.202 g, 90%).
98%). Rf ) 0.50 (petroleum ether/EtOAc 95/5). [R]20 ) +1.4
D
(c 2.5, CH2Cl2). IR (film): 1460, 1250, 1085, 1030 cm-1
.
1H
NMR: δ 7.39-7.24 (m, 5H), 4.56 (d, 1H, J ) 12.1 Hz), 4.46 (d,
1H, J ) 12.1 Hz), 4.20 (dd, 1H, J ) 6.6 and 2.2 Hz), 4.02-
3.94 (m, 1H), 3.98 (d, 1H, J ) 9.2 Hz), 3.48 (dd, 1H, J ) 10.0
and 5.9 Hz), 3.41 (dd, 1H, J ) 10.0 and 4.4 Hz), 2.92-2.68 (m,
4H), 2.14-2.02 (m, 1H), 1.99-1.77 (m, 3H), 1.05 (d, 3H, J )
6.6 Hz), 0.91 (s, 9H), 0.88 (s, 9H), 0.85 (d, 3H, J ) 7.3 Hz),
0.14 (s, 6H), 0.10 (s, 3H), 0.05 (s, 3H). 13C NMR: δ 138.4, 128.2,
127.6, 127.4, 73.9, 73.1, 72.8, 72.2, 52.3, 41.8, 40.1, 30.3, 30.2,
26.2, 26.1, 26.0, 18.6, 18.4, 11.7, 11.2, -3.5, -3.6, -4.3. MS
(CI+, CH4) m/z (rel intensity): 585 (MH+•, 12), 569 (37), 527
(48), 487 (9), 435 (100), 437 (13). HRMS (CI+, CH4): calcd for
C
30H57O3S2Si2 (MH+•) 585.3288, found 585.3272.
(-)-(3S,4R,5S,6R)-6-Ben zyloxym et h yl-4-h yd r oxy-3,5-
d im eth yltetr a h yd r op yr a n -2-on e (18). To a solution of 14
(0.06 g, 0.14 mmol, 1 equiv) in THF (2.4 mL) at 0 °C was added
a solution of HF‚pyr complex (0.70 mL). After 5 min at room
temperature, the reaction mixture was diluted with Et2O and
H2O, and Na2CO3 (solid) was added in small portions until
pH ) 7-8 was obtained. The aqueous phase was extracted
with Et2O (5 times), and the organic phases were dried over
MgSO4, filtered, evaporated, and purified by flash chromatog-
raphy on silica gel to produce 18 as a colorless oil (0.028 g,
77%). Rf ) 0.30 (petroleum ether/EtOAc 1/1). [R]20 ) -59.5
D
(c 1.15, CH2Cl2). IR (film): 1720, 1450, 1370, 1360, 1210, 1100,
1050 cm-1 1H NMR: δ 7.42-7.28 (m, 5H), 4.62 (d, 1H, J )
.
11.9 Hz), 4.57 (d, 1H, J ) 11.9 Hz), 4.48 (ddd, 1H, J ) 5.6, 4.9
and 3.9 Hz), 3.82-3.70 (m, 1H), 3.71 (dd, 1H, J ) 10.1 and
4.9 Hz), 3.63 (dd, 1H, J ) 10.1 and 5.6 Hz), 2.66 (bd, 1H, OH),
J . Org. Chem, Vol. 68, No. 26, 2003 10001

Eustache et al.
Rf ) 0.90 (petroleum ether/EtOAc 9/1). [R]20 ) 0.0 (c 1.05,
1H, J ) 6.7, 6.7 and 3.5 Hz), 0.94 (d, 3H, J ) 6.7 Hz), 0.93 (s,
9H), 0.92 (s, 9H), 0.92 (d, 3H, J ) 7.0 Hz), 0.89 (d, 3H, J ) 6.7
Hz), 0.13 (s, 3H), 0.11 (s, 3H), 0.09 (s, 3H), 0.08 (s, 3H). 13C
NMR: δ 78.4, 71.6, 42.9, 31.3, 26.1, 25.9, 21.4, 18.4, 18.2, 17.3,
15.4, 12.2, -3.3, -3.8, -4.2. MS (CI+, CH4) m/z (rel inten-
sity): 501 (MH+•, 15), 485 (14), 443 (15), 369 (53), 303 (15),
285 (18), 241 (90), 237 (100), 187 (49), 109 (22). HRMS (CI+,
CH4): calcd for C20H46O2ISi2 (MH+•) 501.2081, found 501.2083.
D
CH2Cl2). IR (film): 1465, 1255, 1050 cm-1. H NMR: δ 7.36-
1
7.25 (m, 5H), 4.54 (d, 1H, J ) 11.8 Hz), 4.48 (d, 1H, J ) 11.8
Hz), 3.99-3.92 (m, 1H), 3.50 (dd, 1H, J ) 6.2 and 2.9 Hz),
3.45 - 3.42 (m, 2H), 1.87-1.72 (m, 2H), 0.91 (s, 9H), 0.90-
0.86 (6H), 0.87 (s, 9H), 0.85 (d, 3H, J ) 7.0 Hz), 0.08 (s, 3H),
0.07 (s, 3H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR: δ 138.5, 128.2,
127.6, 127.4, 78.4, 74.6, 73.1, 72.8, 41.2, 30.7, 26.2, 25.7, 25.6,
21.5, 18.5, 18.4, 16.7, 11.6, -3.6, -3.4, -4.0, -4.4. MS (CI+,
CH4) m/z (rel intensity): 481 (MH+•, 23), 465 (21), 423 (34),
373 (42), 357 (36), 349 (46), 315 (74), 257 (21), 241 (54), 217
(-)-2-(1S,2R,3S,4R)-5-Ben zyloxy-2,4-b is[(ter t-b u t yld i-
m et h ylsiloxy)-1,3-d im et h ylp en t yl]-2-(2R,3S,4R)-2,4-b is-
[(ter t-b u t yld im et h ylsiloxy)-3,5-d im et h ylh exyl]-1,3-d i-
th ia n e (24). To a solution of thioketal 17 (0.062 g, 0.106 mmol,
1 equiv) in THF (0.5 mL) at -78 °C were added HMPA
(74 mL, 0.43 mmol, 4.02 equiv) and t-BuLi (1.7 M in pentane)
until the yellow color became persistent, at which time an
extra addition of t-BuLi (75 mL, 1.7 M in pentane, 0.13 mmol,
1,2 equiv) was made. After 1 h at -78 °C, a solution of iodide
23 (0.07 g, 0.14 mmol, 1.33 equiv) in THF (0.3 mL) was added.
The reaction was quenched 1 h later at -78 °C with a
saturated aqueous NH4Cl solution and extracted with EtOAc
(3 times). The organic phases were dried over MgSO4, filtered,
and evaporated, and the residue was purified by flash chro-
matography on silica gel (petroleum ether/EtOAc 95/5) and
then on TLC plates (same eluant) to give 24 as a colorless oil
(44), 187 (100). HRMS (CI+, CH4): calcd for C27H53O3Si2 (MH+•
481.3533, found 481.3527.
)
(+)-(2S,3R,4R)-2,4-Bis(ter t-b u t yld im et h ylsiloxy)-3,5-
d im eth ylh exa n -l-ol (22). A solution of 21 (0.230 g, 0.479
mmol, 1 equiv), K2CO3 (0.05 g), Pd/C 10% (0.05 g, 4.8.0 µmol,
0.1 equiv) was stirred under 1 atm of hydrogen at room
temperature. After 2 h, the reaction was filtered through
Celite, and the filtrate was evaporated. The residue was
purified by flash chromatography on silica gel (petroleum
ether/EtOAc 95/5) to give alcohol 22 as a colorless oil (0.133
g, 71%). Rf ) 0.45 (petroleum ether/EtOAc 95/5). [R]20D ) +2.7
(c 1.55, CH2Cl2). IR (film): 3450, 1460, 1390, 1360, 1255, 1040
cm-1. 1H NMR: δ 3.73-3.65 (m, 1H), 3.67-3.55 (m, 2H), 3.41
(dd, 1H, J ) 4.6 and 4.6 Hz), 2.04 (dd, 1H, J ) 7.9 and 4.6 Hz,
OH), 1.94 (qdd, 1H, J ) 7.3, 7.3 and 4.6 Hz), 1.81 (dqd, 1H,
J ) 6.9, 6.9 and 4.6 Hz), 0.95 (d, 3H, J ) 7.0 Hz), 0.93 (s, 9H),
0.92 (3H), 0.91 (s, 9H), 0.89 (d, 3H, J ) 6.6 Hz), 0.1 (s, 6H),
0.09 (s, 3H), 0.07 (s, 3H). 13C NMR: δ 79.4, 74.6, 65.3, 40.2,
31.7, 26.1, 25.9, 21.0, 18.4, 18.2, 18.1, 14.5, -3.6, -4.2, -4.3,
-4.4. MS (CI+, CH4) m/z (rel intensity): 391 (MH+•, 53), 333
(41), 259 (100), 243 (43), 175 (19), 127 (14). HRMS (CI+, CH4):
calcd for C20H47O3Si2 (MH+•) 391.3070, found 391.3065.
(-)-(2S,3R,4R)-2,4-Bis(ter t-bu tyldim eth ylsiloxy)-1-iodo-
3,5-d im eth ylh exa n e (23). To a solution of 22 (0.067 g, 0.17
mmol, 1 equiv), imidazole (0.023 g, 0.34 mmol, 2 equiv), and
PPh3 (0.091 g, 0.34 mmol, 2 equiv) in toluene (0.7 mL) at 0 °C
was added. After 1.5 h, I2 (0.088 g, 0.34 mmol, 2 equiv), Et2O,
and H2O were added to the reaction mixture at 0 °C. The
aqueous phase was extracted with Et2O (3 times). The organic
phases were dried over MgSO4, filtered, and evaporated, and
the residue was purified by flash chromatography on silica gel
(petroleum ether/EtOAc 92/2) to give iodide 23 as a yellow oil
(0.082 g, 95%). Rf ) 0.74 (petroleum ether/EtOAc 98/2).
(0.028 g, 28%). Rf ) 0.24 (petroleum ether). [R]20 ) -1.5
D
(c 0.75, CH2Cl2). IR (film): 1470, 1460, 1390, 1360, 1255, 1070
cm-1 1H NMR: δ 7.35-7.25 (m, 5H), 4.56 (d, 1H, J ) 11.9
.
Hz), 4.45 (d, 1H, J ) 11.9 Hz), 4.32 (dapp, 1H, J ) 7.5 Hz),
4.16-4.11 (m, 1H), 3.79-3.55 (m, 4H), 2.95-2.38 (m, 5H), 2.12
(dd, 1H, J ) 15.9 and 7.5 Hz), 2.06-1.70 (m, 4H), 1.49 (d, 1H,
J ) 15.9 Hz), 1.31-1.24 (m, 1H), 1.06 (d, 3H, J ) 6.6 Hz),
1.02 (d, 3H, J ) 6.6 Hz), 0.97-0.88 (m, 45H), 0.26-0.04
(m, 24H). 13C NMR: δ 139.0, 128.6, 128.2, 127.8, 79.2, 74.7,
73.8, 73.6, 71.9, 70.5, 59.5, 48.7, 44.7, 43.1, 39.9, 30.4, 27.3,
26.6, 26.6, 26.6, 26.5, 26.4, 25.8, 24.3, 22.6, 19.1, 18.9, 18.6,
17.2, 13.0, 12.4, 8.2, -1.4, -2.7, -2.8, -3.3, -3.6, -3.9, -3.9,
-4.0. MS (CI+, CH4) m/z: 957 (MH+•, 4), 941 (9), 825 (19), 693
(12), 437 (68), 305 (57), 187 (100), 185 (16). HRMS (CI+, CH4):
calcd for C50H101O5S2Si4 (MH+•) 957.6168, found 957.6143.
Ack n ow led gm en t. We thanks Rhodia for financial
support, and F.E. thanks the CNRS and Rhodia for a
grant.
[R]20D ) -9.5 (c 1.5, CHCl3). IR (film): 1465, 1250, 1050 cm-1
1H NMR: δ 3.43-3.23 (m, 4H), 2.03-1.90 (m, 1H), 1.76 (qqd,
.
J O035068M
10002 J . Org. Chem., Vol. 68, No. 26, 2003