Total synthesis of bafilomycin A1

Article abstract of DOI:10.1021/jo970314d

The highly stereoselective total synthesis of the macrolide antibiotic, bafilomycin A₁ (1), the first specific potent inhibitor of vacuolar H⁺-ATPase, has been achieved by a convergent route involving the synthesis and coupling of its 16-membered tetraenic lactone and β-hydroxyl hemiacetal side-chain subunits. The C1-C17 16-membered lactone aldehyde 2 was synthesized through the coupling of the C5-C11 vinyl iodide 4 and the C12-C17 vinylstannane 5, followed by construction of the C1-C4 diene and macrolactonization. The aldol coupling of 2 and the C18-C25 ethyl ketone 3 followed by desilylation provided 1, which was identical with natural bafilomycin A₁. The key synthetic segments 3-5 were effectively synthesized from the readily available chiral materials, D-glucose, ethyl (S)-lactate, and methyl (S)-3-hydroxy-2-methylpropionate, respectively.

Full text of DOI:10.1021/jo970314d

J . Org. Chem. 1997, 62, 3271-3284
3271
Tota l Syn th esis of Ba filom ycin A1
Kazunobu Toshima,* Takaaki J yojima, Hiroyuki Yamaguchi, Yasunobu Noguchi,
Takehito Yoshida, Hidekazu Murase, Masaya Nakata, and Shuichi Matsumura
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223, J apan
Received February 19, 1997X
The highly stereoselective total synthesis of the macrolide antibiotic, bafilomycin A1 (1), the first
specific potent inhibitor of vacuolar H+-ATPase, has been achieved by a convergent route involving
the synthesis and coupling of its 16-membered tetraenic lactone and â-hydroxyl hemiacetal side-
chain subunits. The C1-C17 16-membered lactone aldehyde 2 was synthesized through the
coupling of the C5-C11 vinyl iodide 4 and the C12-C17 vinylstannane 5, followed by construction
of the C1-C4 diene and macrolactonization. The aldol coupling of 2 and the C18-C25 ethyl ketone
3 followed by desilylation provided 1, which was identical with natural bafilomycin A1. The key
synthetic segments 3-5 were effectively synthesized from the readily available chiral materials,
D-glucose, ethyl (S)-lactate, and methyl (S)-3-hydroxy-2-methylpropionate, respectively.
In tr od u ction
the impressive biological features of 1, great effort has
been devoted to the chemical synthesis of 1. In this
context, an efficient aldol method for the assembly of 1
was recently reported by Evans and Calter,9 and elegant
syntheses of the C13-C25 segments of 1 have been
independently disclosed by Roush’s10 and Paterson’s11
groups. Hanessian et al. also reported the chemical
transformation of bafilomycin A1 to isobafilomycin A1
possessing an 18-membered lactone.12 In this paper, we
describe the full account of our recent total synthesis of
the architecturally and biologically attractive natural
product, bafilomycin A1 (1).13
Bafilomycin A1 (1) was first isolated in 1983 by Werner
and Hagenmaier1a from a culture of Streptomyces griseus
sp. sulphuru as a new type of antibiotic that exhibited
activity against Gram-positive bacterial and fungi.1
Furthermore, bafilomycin A1 (1) was later found to show
immunosuppressive activity2 and proved to be the first
specific potent inhibitor of vacuolar H+-ATPase attracting
particular interest.3 The absolute configuration of 1 was
originally proposed by Corey4 on the basis of NMR data
and computer molecular modeling and then established
by X-ray crystallographic analysis.5 Structurally, bafilo-
mycin A1 (1) is constructed from a 16-membered tetraenic
lactone ring and a â-hydroxyl hemiacetal side chain. The
intramolecular hemiacetal ring and the macrolactone
ring are linked by a C3 spacer and a hydrogen-bonding
system. Bafilomycin A1 (1) belongs to a family of
polyketide macrolide antibiotics, and the other macrolide
antibiotics such as elaiophylin,6 the concanamycins,7 and
the hygrolidins8 are closely related to the bafilomycins
(Figure 1). Among them, however, the bafilomycins and
concanamycins have a novel diene system containing a
methyl enol ether. Because of the unique structural and
Syn th etic P la n
The retrosynthetic analysis of bafilomycin A1 (1) is
shown in Figure 2 along with our synthetic plan. The
target molecule 1 would be obtained by deprotection of
an aldol A followed by spontaneous intramolecular hemi-
acetalization. The aldol coupling14 of a 16-membered
lactone aldehyde B and a ethyl ketone C would give a
key intermediate A. The lactone skeleton was further
partitioned into three fragments, D, E, and F , through
disconnection of the C4-C5, C11-C12, and acyl oxygen
bonds. In the synthetic direction, each of these analog’s
bond constructions is based on powerful synthetic reac-
tions. For example, the synthesis of dienes through the
Pd(0)-catalyzed coupling of vinyl iodides and vinylstan-
nanes (Stille cross coupling)15 is reported to work well
X Abstract published in Advance ACS Abstracts, April 15, 1997.
(1) (a) Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H.;
Drautz, H. Tetrahedron Lett. 1983, 24, 5193. (b) Werner, G.; Hagen-
maier, H.; Drautz, H.; Baumgartner, A.; Za¨hner, H. J . Antibiot. 1984,
37, 110. (c) Meyer, M.; Keller-Schierlein, W.; Drautz, H.; Blank, W.;
Za¨hner, H. Helv. Chim. Acta 1985, 68, 83. (d) 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. (e) Deeg, M.; Hagenmaier, H.;
Kretschmer, A. J . Antibiot. 1987, 40, 320. (f) Baker, G. H.; Brown, P.
J .; Dorgan, R. J . J .; Everett, J . R. J . Chem. Soc., Perkin Trans. 2 1989,
1073.
(9) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(10) (a) Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33,
3587. (b) Roush, W. R.; Bannister, T. D.; Wendt, M. D. Tetrahedron
Lett. 1993, 34, 8387.
(2) Heinle, S.; Stuenkel, K.; Zaehner, H.; Drautz, H.; Drautz, H,;
Bessler, W. G. Arzneim. Forsch. 1988, 38, 1130; Chem. Abstr. 109,
142203m.
(3) Bowman, E. J .; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
(4) Corey, E. J .; Ponder, J . W. Tetrahedron Lett. 1984, 25, 4325.
(5) Baker, G. H.; Brown, P. J .; Dorgan, R. J . J .; Everett, J . R.; Ley,
S. V.; Slawin, A. M. Z.; William, D. J . Tetrahedron Lett. 1987, 28, 5565.
(6) (a) Arcamone, F. M.; Bertazzoli, C.; Ghione, M.; Scotti, T. Gion.
Microbiol. 1959, 7, 207. (b) Arai, M. J . Antibiot. Ser. A 1960, 13, 46
and 51.
(7) (a) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3857 and 3861. (b) Kinashi,
H.; Someno, K.; Sakaguchi, K. J . Antibiot. 1984, 37, 1333.
(8) (a) Seto, H.; Akao, H.; Furihata, K.; Otake, N. Tetrahedron Lett.
1982, 23, 2667. (b) Seto, H.; Tajima, I.; Akao, H.; Furihata, K.; Otake,
N. J . Antibiot. 1984, 37, 610.
(11) Paterson, I.; Bower, S.; Mcleod, M. D. Tetrahedron Lett. 1995,
36, 175.
(12) Hanessian, S.; Meng, Q.; Oliver, E. Tetrahedron Lett. 1994, 35,
5393.
(13) For our preliminary communications of this work, see: (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 yojima, T.; Noguchi, Y.; Nakata, M.;
Matsumura, S. Tetrahedron Lett. 1996, 37, 1073.
(14) For some reviews on the stereoselective aldol reaction, see: (a)
Evans, D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(b) Mukaiyama, T. Org. React. 1882, 28, 203. (c) Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1984; Vol. 3, p 111. (d) Braun, M. Angew. Chem., Int. Ed. Engl.
1987, 26, 24. (e) Hoffmann, R. W. Angew. Chem., Int. Ed. Engl. 1987,
26, 489.
(15) Stille, J . K.; Groh, B. L. J . Am. Chem. Soc. 1987, 109, 813.
S0022-3263(97)00314-9 CCC: $14.00 © 1997 American Chemical Society

3272 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
F igu r e 1. Molecular structures of bafilomycin A1 (1) and structurally related macrolide antibiotics.
F igu r e 2. Retrosynthetic analysis of bafilomycin A1 (2).
with highly functionalized coupling partners. The syn-
thesis of dienes by the Wittig reaction also has a high
potential. Furthermore, the highly evolved methods for
macrolactonization are currently available.16 The highly
stereoselective syntheses of an appropriately protected
16-membered lactone aldehyde 2, which makes use of the
fragments 4, 5, and D, and a suitably protected ethyl
ketone 39 and aldol coupling of 2 and 3 leading to the
total synthesis of 1 are described in the following discus-
sion.
(S)-lactate, was first converted into the diacetate 7 using
acetic anhydride and 4-(dimethylamino)pyridine (4-
DMAP) in quantitative yield. This temporary protection
of the hydroxyl groups was necessary for clear ozonolysis
of the olefin. Ozonolysis of 7 in MeOH-CH2Cl2 at -78
°C, followed by in situ reduction of the resultant aldehyde
8 using sodium borohydride and deacetylation of 9
employing sodium methoxide, afforded the triol 10 in 94%
overall yield from 7. Regioselective p-methoxybenzylide-
nation of the 1,3-diol in 10 using p-methoxybenzaldehyde
dimethyl acetal and DL-10-camphorsulfonic acid (CSA)
in N,N-dimethylformamide (DMF) at 25 °C proceeded
smoothly to give the alcohol 11 in 94% yield. Oxidation
of 11 employing pyridinium chlorochromate (PCC) and
powdered molecular sieves 3A (MS 3A) in CH2Cl2 and
the subsequent Wittig reaction of the resultant ketone
12 with methylenetriphenylphosphorane in benzene af-
forded 13 in 95% overall yield. At this stage, we found
that the hydroboration of 13 using dicyclohexylborane in
THF at 25 °C for 1 h proceeded with complete stereose-
lectivity to give only the desired alcohol 14 in 88% yield
after the subsequent oxidative workup. The remarkable
high stereoselectivity of this reaction might be explained
as follows. 1H-NMR studies of 13 including NOE experi-
ments indicated that it existed in a chair conformation,
Resu lts a n d Discu ssion
Syn th esis of th e C5-C11 Segm en t 4. The synthesis
of the vinyl iodide 4 corresponding to the C5-C11
segment of bafilomycin A1 (1) is summarized in Scheme
1. The starting material 6,17 readily prepared from ethyl
(16) For references on macrolactonization in macrolide synthesis,
see: (a) Paterson, I.; Mansuri, M. M. Tetrahedron 1985, 41, 3569. (b)
Boeckman, R. K.; Goldstein, S. W. In The Total Synthesis of Natural
Products; Aspimon, J ., Ed.; Wiley: New York, 1988; Vol. 7, p 1. (c)
Tatsuta, K. In Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer-Verlag: Berlin, Heidelberg, 1990;
p 1.
(17) Mulzer, J .; Schulze, T.; Strecker, A.; Denzer, W. J . Org. Chem.
1988, 53, 4098.

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3273
Sch em e 1a
a
Reagents and conditions: (a) Ac2O, 4-DMAP, EtOAc, rt, 1 h, 100%; (b) O3, MeOH-CH2Cl2, -78 °C, 2 h then Me2S; (c) NaBH4, MeOH-
CH2Cl2, rt, 0.5 h; (d) NaOMe, MeOH, rt, 3 h, 94% from 7; (e) (MeO)2CHC6H4OMe, CSA, DMF, rt, 1.5 h, 94%; (f) PCC, MS 3A, CH2Cl2, rt,
1.5 h, 100%; (g) Ph3PdCH2, C6H6, rt, 1 h, 95%; (h) BH3‚Me2S, C6H10, THF, rt, 1 h then NaOH-H2O, H2O2, 88%; (i) TsCl, Py, rt, 1.5 h,
100%; (j) HCtCLi, DMSO, rt, 1.5 h, 66%; (k) 80% AcOH-H2O, 40 °C, 13 h, 84%; (l) Cp2ZrCl2, Me3Al, I2, (ClCH2)2, rt, 13 h, 82%; (m) PvCl,
Et3N, CH2Cl2, rt, 14 h, 97%; (n) DEIPSOTf, 2,6-lutidine, CH2Cl2, rt, 4 h, 100%.
the corresponding triethylsilyl, tert-butyldimethylsilyl,
and p-methoxylbenzyl ethers, this silyl ether had suf-
ficient stability in subsequent reactions, while still of-
fering reasonable liability in the final deprotection step
using tetrabutylammonium fluoride (TBAF) and acetic
acid in THF.20 The trans configuration of the trisubsti-
tuted olefin of 4 was clearly confirmed by NOE experi-
ments. Thus, NOE between the vinyl hydrogen and the
methylene hydrogens was observed while no NOE be-
tween the vinyl hydrogen and the methyl group at the
vinyl position was detected.
Syn th esis of th e C12-C17 Segm en t 5. Scheme 2
illustrates the synthesis of the vinylstannane 5 corre-
F igu r e 3.
sponding to the C12-C17 segment of bafilomycin A1 (1).
and the olefin and C3 hydrogen were located in the same
orientation as depicted in Figure 3. Approach of dicy-
clohexylborane to the olefin of 13 might be strongly
In this synthesis, the aldehyde 20,21 which could be easily
prepared from commercially available methyl (S)-3-
hydroxy-2-methylpropionate, was chosen as the starting
interrupted by the C4 methyl substituent. As a conse-
material. Treatment of 20 with in situ generated γ-meth-
quence, dicyclohexylborane reacts from the less hindered
side leading to the desired S configuration at the C2
oxyallylchromium reagent,10,22 which was prepared from
CrCl2 and CH2dCHCH(OMe)2 in the presence of trim-
position in 14. Tosylation of 14 using p-toluenesulfonyl
ethylsilyl iodide (TMS-I) in THF at -42 °C for 16 h,
chloride in pyridine yielded the tosylate 15, which was
afforded the C2,C3-syn-C3,C4-anti homoallylic alcohol
subjected to the reaction with 5 equiv of lithium acetylide
ethylenediamine complex in dimethyl sulfoxide (DMSO)
to give the acetylene 16 in 66% overall yield. After
deprotection of the p-methoxybenzylidene group in 16
(19) (a) Toshima, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett.
1986, 27, 4741. (b) Toshima, K.; Tatsuta, K.; Kinoshita, M. Bull. Chem.
Soc. J pn. 1988, 61, 2369. (c) Toshima, K.; Mukaiyama, S.; Kinoshita,
under mild acidic conditions, the resultant diol 17 was
treated with Cp2ZrCl2, Me3Al, and I2 in 1,2-dichloroet-
hane18 to cleanly afford only the trisubstituted trans vinyl
iodide 18 in 63% overall yield from 16. In contrast, it
was found that the vinyl iodination of the protected 16
gave only a poor yield of the corresponding vinyl iodide.
Selective protection of the primary alcohol in 18 with a
pivaloyl group, followed by silylation of the resultant 19
with the diethylisopropylsilyl (DEIPS) group19 using
diethylisopropylsilyl trifluoromethanesulfonate (DEIP-
SOTf) and 2,6-lutidine in CH2Cl2 furnished the suitably
protected vinyl iodide 4 in 97% overall yield. The DEIPS
group in 4 was a key protecting group for the total
synthesis of 1 because it was found that, in contrast to
M.; Tatsuta, K. Tetrahedron Lett. 1989, 30, 6413. (d) Toshima, K.;
Misawa, M.; Ohta, K.; Tatsuta, K.; Kinoshita, M. Tetrahedron Lett.
1989, 30, 6417. (e) Toshima, K.; Yanagawa, K.; Mukaiyama, S.;
Tatsuta, K. Tetrahedron Lett. 1990, 31, 6697. (f) Toshima, K.; Nozaki,
Y.; Mukaiyama, S.; Tamai, T.; Nakata, M.; Tatsuta, K.; Kinoshita, M.
J . Am. Chem. Soc. 1995, 117, 3717.
(20) For other applications of DEIPS protecting group to natural
product synthesis, see: (a) Evans, D. A.; Kaldor, S. W.; J ones, T. K.;
Clardy, J .; Stout, T. J . J . Am. Chem. Soc. 1990, 112, 7001. (b) Romo,
D.; J ohnson, D. D.; Plamondon, L.; Miwa, T.; Schreiber, S. L. J . Org.
Chem. 1992, 57, 5060. (c) Romo, D.; Meyer, S. D.; J ohnson, D. D.;
Schreiber, S. L. J . Am. Chem. Soc. 1993, 115, 7906. (d) Paterson, I.;
Tillyer, R. D.; Smaill, J . B. Tetrahedron Lett. 1993, 34, 7137. (e)
Oikawa, H.; Oikawa, M.; Ueno, T.; Ichihara, A. Tetrahedron Lett. 1994,
35, 4809. (f) Oikawa, M.; Ueno, T.; Oikawa, H.; Ichihara, A. J . Org.
Chem. 1995, 60, 5048. (g) Paterson, I.; McLeod, M. D. Tetrahedron
Lett. 1995, 36, 9065. The silylating reagents, DEIPS-Cl and DEIPS-
OTf, are now commercially available from Tokyo Kasei Kogyo Co., Ltd.
(21) Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetrahedron
Lett. 1986, 27, 6241.
(18) Rand, C. L.; Van Horn, D. E.; Moore, M. W.; Negishi, E. J . Org.
Chem. 1981, 46, 4096.
(22) Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
5263.

3274 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
Sch em e 2a
a
Reagents and conditions: (a) CrCl2, CH2dCHCH(OMe)2, TMS-I, THF, -42 °C, 16 h, 62%; (b) 1% HCl-MeOH, rt, 0.5 h, 100%; (c)
Me2C(OMe)2, CSA, CH2Cl2, rt, 16 h, 76%; (d) OsO4, NMO, acetone-H2O, rt, 16 h; (e) NaIO4, THF-H2O, rt, 0.5 h; (f) CrCl2, CHI3, THF,
rt, 14 h, 50% from 23; (g) n-Bu3SnCl, n-BuLi, THF, -78 °C, 1 h, 69%.
Sch em e 3a
a
Reagents and conditions: (a) MeMgI, Et2O, rt, 0.5 h, 94%; (b) PCC, MS 3A, CH2Cl2, rt, 0.5 h, 94%; (c) Ph3PdCH2, C6H6, rt, 0.5 h,
81%; (d) H2, Raney-Ni(W4), dioxane, rt, 24 h, 92%; (e) 50% AcOH-H2O, 80 °C, 2 h, 93%; (f) LAH, THF, 60 °C, 16 h, 77%; (g) Ph3P, DEAD,
MS 3A, C6H6, reflux, 7 h, 12%; (h) N,N-carbonyldiimidazole, CH2Cl2, rt, 2.5 h, 85%; (i) TBS-Cl, imidazole, DMF, 40 °C, 16 h, 87%; (j) 1
N NaOH, MeOH, rt, 16 h, 87%; (k) TsCl, Py, rt, 4 h; (l) NaOMe, MeOH-CHCl3, rt, 16 h, 71% from 36; (m) 2-ethyl-1,3-dithiane, n-BuLi,
THF, -20 °C, 1 h; (n) TBAF, THF, rt, 2.5 h, 97% from 38; (o) t-Bu2Si(OTf)2, DMF, rt, 2 h, 95%; (p) MeI, CaCO3, MeCN-H2O, rt, 6 h, 72%.
21 as a major diastereomer with 10:1.1:0.5 selectivity in
62% yield. The complete isolation of 21 from the other
isomers was impractical at this stage. Therefore, the
trityl group in the crude 21 was removed under acidic
conditions using 1% HCl-MeOH, and the resultant crude
diol 22 was then protected with an isopropylidene group
employing 2,2-dimethoxypropane and CSA in CH2Cl2; a
76% yield of the pure acetonide 23 was obtained after
chromatography. Dihydroxylation of 23 using a catalytic
amount of OsO4 and 4-methylmorpholine N-oxide (NMO)
in acetone-H2O followed by the sequential periodate-
oxidation of 24 and Takai’s reaction23 of the resultant
aldehyde 25 using CrCl2 and CHI3 in THF gave only the
trans vinyl iodide 26 in 50% overall yield from 23.
Finally, treatment of 26 with n-Bu3SnCl and n-BuLi in
THF at -78 °C for 1 h afforded the vinylstannane 5 in
69% yield.
Syn th esis of th e C18-C25 Segm en t 3. The syn-
thesis of the ethyl ketone 3 corresponding to the C18-
C25 segment of bafilomycin A1 (1) is depicted in Scheme
3. This synthesis began with the conversion of the sugar
derivative 27,19d which was obtained from D-glucose, into
31, which possessed an isopropyl group by a standard
manner. Thus, the Grignard reaction of 27 with MeMgI
in ether, followed by PCC oxidation of 28, the Wittig
reaction of 29 using methylenetriphenylphosphorane,
and hydrogenolysis of the olefin in 30 in the presence of
Raney-Ni (W4) in dioxane gave 31 in high (66%) overall
yield from 27. Hydrolysis of the 1,2-isopropylidene group
in 31 with 50% aqueous acetic acid gave the free sugar
32 in 93% yield, which was then treated with lithium
aluminum hydride (LAH) in THF to afford the triol 33
in 77% yield. The triol 33 was first subjected to the one-
pot epoxidation of the vicinal diol using triphenylphos-
phine and diethyl azodicarboxylate (DEAD) in refluxing
benzene.24 However, unfortunately, this reaction gave
the epoxide 37 in only miserable yield while the furan
ring was significantly produced. Therefore, stepwise
synthesis of the protected epoxide 38 from 33 was next
carried out. Selective protection of the 1,2-diol of 33 with
a carbonate using N,N ′-carbonyldiimidazole in CH2Cl2
followed by silylation of the resultant alcohol 34 with the
tert-butyldimethylsilyl (TBS) group provided 35 in 74%
overall yield. After removal of the carbonate group in
35 by hydrolysis under alkaline conditions, selective
tosylation of the primary alcohol 36 and the sequential
epoxidation of the resultant crude tosylate using sodium
methoxide gave the epoxide 38 in 62% overall yield from
35. The reaction of 38 with 5 equiv of 2-ethyl-2-lithio-
1,3-dithiane in THF at -20 °C for 1 h afforded the
dithioacetal 39, whose silyl group was removed by TBAF
in THF to give the diol 40 in 97% overall yield. Finally,
the diol 40 was protected with a di-tert-butylsilyl group,
and the dithioacetal group of 41 was then cleaved using
(23) Takai, K.; Nitta, K.; Utimoto, K. J . Am. Chem. Soc. 1986, 108,
7408.
(24) Achab, S.; Das, B. C. Synth. Commun. 1982, 12, 931 and
references cited therein.

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3275
Sch em e 4a
a
Reagents and conditions: (a) PdCl2(dppf), DMF, 50 °C, 15 h, 60%; (b) MeLi, Et2O, rt, 0.5 h, 79%; (c) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C, 20 min; (d) PhMe, 100 °C, 14 h, 98% from 43; (e) DIBAL, PhMe, -78 °C, 5 min, 97%; (f) MnO2, CH2Cl2, rt, 2 h, 100%; (g)
NaHMDS, THF, rt, 0.5 h, 89%; (h) PPTS, MeOH, rt, 0.5 h, 98%; (i) MTrCl, Et3N, 4-DMAP, CH2Cl2, rt, 5 h, 91%; (j) 1 N KOH, dioxane,
80 °C, 2 h, 64% for 55, 32% for 56; (k) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4-DMAP, PhMe (0.002 M for 55), 110 °C, 16 h, 42%; (l)
PPTS, MeOH, rt, 14 h, 80%; (m) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, 20 min, 74%; (n) NaHMDS, THF, rt, 12 h, 39%.
Ta ble 1. Th e Cr oss Cou p lin gs of 4 a n d 5 by P d -Ca ta lysts
MeI in the presence of CaCO3 to furnish the ethyl ketone
39 in 68% overall yield. The cyclic protection at the C5
4 + 5
8 42
DMF
50 °C, 15 h
and C7 positions in 3 was required for a high level of
aldol stereoselectivity as suggested by Evans9 and con-
firmed by Paterson.10
entry
Pd-catalyst (0.2 equiv)
yield (%)
Syn th esis of th e Ma cr ocyclic Ald eh yd e 2. With
the C5-C11, C12-C17, and C18-C25 segments of ba-
filomycin A1 (1) in hand, our attention next turned to the
construction of the macrocyclic lactone moiety of 1. The
synthesis of the 16-membered lactonic aldehyde 2 for the
aldol condensation with the ethyl ketone 3 is summarized
in Scheme 4. We first examined the cross-coupling
reactions between the vinyl iodide 4 corresponding to the
C5-C11 segment and the vinylstannane 5 corresponding
to the C12-C17 segment by the Stille method15 using
several Pd-catalysts, such as Pd(PPh3)4, PdCl2(PPh3)2,
PdCl2(MeCN)2, and PdCl2(dppf). From the results shown
in Table 1, the catalyst PdCl2(dppf) developed by Ha-
yashi25 was clearly found to be superior in this coupling
1
2
3
4
Pd(PPh3)4
trace
33
36
PdCl2(PPh3)2
PdCl2(MeCN)2
PdCl2(dppf)
60
reaction. Thus, the reaction of 1 equiv of 4 and 1 equiv
of 5 using a catalytic amount of PdCl2(dppf) in DMF at
50 °C for 15 h afforded the desired E,E-diene 42 in 60%
yield. The 1H NMR spectrum of 42, interestingly, showed
1
that it consisted of a ca. 3:1 inseparable mixture. The H
NMR spectra of 43-56 also showed similar phenomenon.
On the other hand, it was found that the 1H NMR spectra
(25) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158.

3276 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
Sch em e 5a
a
Reagents and conditions: (a) PhBCl2, i-Pr2NEt, CH2Cl2, -78 °C, 2.5 h, 58%; (b) TBAF, AcOH, THF, 60 °C, 12 h, 45%.
of the desilylation product of 42 and the conformationally
rigid lactone 57 indicated that they are single compounds.
Therefore, it is reasonable to assume that this insepa-
rable mixture should be due to the conformational
isomers. Deprotection of the pivaloyl group in 42 using
methyllithium followed by Swern oxidation of the result-
ant alcohol 43 gave the aldehyde 44. At this stage, we
first tried the Horner-Wadsworth-Emmons reaction of
44 and 47, the latter of which was obtained by the
coupling of the phosphonic aldehyde 4526 and the phos-
phonic ester 46,27 to construct the C1-C4 diene in one
step. However, this reaction in the presence of several
bases such as lithium bis(trimethylsilyl)amide (LiH-
MDS), sodium bis(trimethylsilyl)amide (NaHMDS), po-
tassium bis(trimethylsilyl)amide (KHMDS), and NaH
caused only â-elimination of 44 even at low temperature
(-78 °C), and the desired tetraene 52 was not obtained
at all. Therefore, stepwise construction of the diene,
which included the use of the base-free Wittig reagent
48 in the first step, was next carried out. The Wittig
reaction of 44 with 48 in toluene at 100 °C for 14 h
proceeded smoothly to afford only the trans isomer 49 in
98% overall yield from 43. In order to determine the
configuration of the newly formed olefin in 49, an NOE
experiment was conducted. Thus, irradiation of the C3
vinyl hydrogen caused no NOE enhancement of the C2
methyl group. This implied that the configuration of the
olefin was trans. Reduction of the ethyl ester in 49 using
diisobutylaluminum hydride (DIBAL) in toluene at -78
°C followed by oxidation of the resultant allyl alcohol 50
using MnO2 provided the R,â-unsaturated aldehyde 51
in 97% overall yield. In the allyl alcohol 50, the geometry
of the C2-C3 olefin was clearly confirmed by the pres-
ence of NOE enhancement of the methylene hydrogens
of the hydroxymethylene moiety by the irradiation of the
C3 vinyl hydrogen. The Horner-Wadsworth-Emmons
reaction of 51 with 5 equiv of the phosphonic ester 46
using NaHMDS in THF gave 52 in 89% yield as a
mixture of the cis- and trans-isomers. It was found that
NaHMDS was superior to the other previously mentioned
bases with respect to both the yield and the stereoselec-
tivity, and the desired cis-isomer of 52 was predominately
obtained (Z/E ) 2/1). Although these isomers could not
be separated at this stage, each isomer was isolated in a
pure form before the macrolactonization mentioned be-
low. The isopropylidene group in 52 was removed under
mild acidic conditions using pyridinium p-toluene-
sulfonate (PPTS) in MeOH, and the resultant diol 53 was
then selectively protected with a monomethoxytrityl
(MTr) group to afford the secondary alcohol 54 in 89%
overall yield. Hydrolysis of the methyl ester of 54 under
basic conditions yielded the hydroxyl carboxylic acid 55
and the isomer 56 in 64 and 32% yields, respectively. In
1
the H NMR spectra of 55 and 56, the chemical shifts of
the C3 vinyl hydrogens of 55 and 56 were quite different
and at 6.74 and 5.80 ppm, respectively, and the former
was very similar to that (6.67 ppm) of bafilomycin A1.
The cyclization of the seco-acid 55 in order to construct
the 16-membered lactone ring was best effected by the
Yamaguchi method28 using 2,4,6-trichlorobenzoyl chlo-
ride, triethylamine, and 4-DMAP at 110 °C under high
dilution conditions to give the macrocyclic lactone 57 in
42% yield. From the results shown in Table 2, it was
unfortunately found that other macrolactonizations by
Mukaiyama’s,29 Keck’s,30 and Palomo-Coll’s31 methods
gave 57 in only poor yields in this case. Furthermore,
we found that the macrolactonization of a mixture of 55
and 56 by the Yamaguchi method also gave 57 as the
sole lactone product in a similar yield. Finally, treatment
of 57 with PPTS in MeOH gave the alcohol 58 in 80%
yield, which was subjected to Swern oxidation to furnish
the 16-membered lactonic aldehyde 2 in 74% yield.
Tota l Syn th esis of 1. We then had in our hands both
the 16-membered lactonic aldehyde 2 and the ethyl
ketone 3 leading to the total synthesis. The stereoselec-
tive connection of these segments by several aldol reac-
tions was next tested as shown in Table 3. A similar type
of aldol reaction using an R-substituted lactonic aldehyde
and an R-unsubstituted â-siloxy ethyl ketone was previ-
ously studied and performed in our total synthesis of
elaiophylin19a,b and in Seebach’s elaiophylin aglycon
synthesis.32 The coupling of 2 and 59,33 which is an
acyclic analog of 3, by the method using n-Bu2BOTf and
(28) Inagawa, J .; Hirata, K.; Katsuki, H.; Yamaguchi, M. Bull.
Chem. Soc. J pn. 1979, 52, 1989.
(29) Mukaiyama, T.; Usui, M.; Saigo, K. Chem. Lett. 1976, 49.
(30) Boden, E. P.; Keck, G. E. J . Org. Chem. 1985, 50, 2394.
(31) Diago-Meseguer, J .; Palomo-Coll, A. L. Synthesis 1980, 547.
(32) (a) Seebach, D.; Chow, H.-F.; Lackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmenmann, J . J . Am. Chem. Soc. 1985, 107, 5292.
(b) Seebach, D.; Chow, H.-F.; Lackson, R. F. W.; Sutter, M. A.;
Thaisrivongs, S.; Zimmenmann, J . Liebigs Ann. Chem. 1986, 1281.
(26) Gallagher, G.; Welb, R. C. Synthesis 1974, 122.
(27) Grell, W.; Machleidt, H. Liebigs Ann. Chem. 1966, 699, 53.

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3277
Ta ble 2. Ma cr ola cton iza tion s of th e seco-Acid 55
Ta ble 3. Ald ol Cou p lin gs of 2 a n d 3 or 59
2 + 3 or 59 f C16,C17-anti-C17,C18-syn aldol G + C16,C17-syn-C17,C18-syn aldol H
yield (%)
entry
ethyl ketone (2 equiv)
reagents (2 equiv)
solvent
T (°C)
time (h)
G
H
1
2
3
4
59
3
3
n-Bu2BOTf, i-Pr2NEt
n-Bu2BOTf, i-Pr2NEt
PhBCl2, i-Pr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
25
25
-78
25
4
4
2.5
1
19
44
57
2
38
15
1
3
(-)-Ipc2BOTf, i-Pr2NEt
i-Pr2NEt,34 which were employed during the elaiophylin
syntheses, afforded the corresponding aldol product G
(C16,C17-anti-C17,C18-syn) and its diastereomer H
(C16,C17-syn-C17,C18-syn)35 in 19 and 38% yields,
respectively. On the other hand, the stereoselectivity was
dramatically changed in the aldol reaction of 2 and 3,
which possessed a cyclic protecting group, under similar
conditions, and the aldols 60 (G-type) and 61 (H-type)
were obtained in 44 and 15% yields, respectively (Scheme
5). Furthermore, the aldol reaction between 2 (1 equiv)
and 3 (2 equiv) was found to be best achieved by Evans’
THF at 60 °C for 12 h gave the synthetic 1 in 45% yield.
Thus, the obtained synthetic 1 was identical to the
authentic sample of natural bafilomycin A1 on the basis
of H-NMR, IR, [R]D, mp, mmp, and TLC behaviors in
several solvent systems.
1
Con clu sion s
The total synthesis of bafilomycin A1, the first specific
inhibitor of vacuolar H+-ATPase, has been completed
using three principle subunits, followed by macrolacton-
ization and aldol reaction. The described total synthesis
is characterized by high convergency and stereocontrol
at several stages. This synthetic strategy should find
wide application in the synthesis of the other structurally
related and biologically important macrolide antibiotics
such as the hygrolidins39 and the concanamycins19d,20g and
for the synthesis of designed bafilomycin A1 analogs with
potential applications in biology and medicine.
recently disclosed procedure9 using PhBCl2 and i-Pr2-
36
NEt in CH2Cl2 at -78 °C for 2.5 h to produce 60 in 58%
yield with >95:5 diastereoselectivity as the major aldol
product,37 while the chiral (-)-diisopinocamphenylboron
enolate38 of 3 was shown to be less effective in this case.
Finally, desilylation of 60 using TBAF and acetic acid in
(33) The ethyl ketone 57 was also prepared by a way similar to that
of 3.
(34) (a) Inoue, T.; Mukaiyama, T. Bull. Chem. Soc. J pn. 1980, 53,
174. (b) Masamune, S.; Choy, W.; Kerdesky, F. A. J .; Imperiali, B. J .
Am. Chem. Soc. 1981, 103, 1566. (c) Evans, D. A.; Nelson, J . V.; Vogel,
E.; Taber, T. R. J . Am. Chem. Soc. 1981, 103, 3099.
(35) The stereochemistry of the minor isomer was assigned by
analogy.
(36) Hamana, H.; Sasakura, K.; Sugasawa, T. Chem. Lett. 1984,
1729.
(37) These findings are in agreement with those of Evans; see ref
9.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. 1H-
NMR spectra were measured in CDCl3 using TMS as internal
standard unless otherwise noted. Silica gel TLC and column
chromatography were performed on Merck TLC 60F-254 (0.25
mm) and Merck Kieselgel 60 or Fuji-Davison BW-820MH,
(38) (a) Brown, H. C.; Singaram, B. J . Org. Chem. 1984, 49, 945.
(b) Meyers, A. I.; Yamamoto, Y. J . Am. Chem. Soc. 1986, 103, 4278.
(c) Paterson, I.; Lister, M. A.; McClure, C. K. Tetrahedron Lett. 1986,
27, 4787. (d) Paterson, I. McClure, Tetrahedron Lett. 1987, 28, 1229.
(39) (a) Makino, K.; Kimura, K.; Nakajima, N.; Hashimoto, S.;
Yonemitsu, O. Tetrahedron Lett. 1996, 37, 9073. (b) Makino, K.;
Nakajima, N.; Hashimoto, S.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 9077.

3278 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
respectively. Air- and/or moisture-sensitive reactions were
carried out under an atmosphere of argon with oven-dried
glassware. In general, organic solvents were purified and
dried by the appropriate procedure, and evaporation and
concentration were carried out under reduced pressure below
30 °C, unless otherwise noted.
stirred at 25 °C for 1.5 h, ether (95.0 mL) was added, and the
resultant mixture was then stirred. Purification of the mixture
by flash column chromatography (700 g of silica gel, ether)
gave 12 (9.15 g, 100%) as a pale yellow oil: Rf 0.17 (6:1
n-hexane-ethyl acetate); [R]31 +11.4° (c 0.27, CHCl3); 1H-
D
NMR δ 0.86 (3H, d, J ) 6.4 Hz), 2.08 (1H, dddq, J ) 11.1,
10.6, 6.4, 4.8 Hz), 2.28 (3H, s), 3.55 (1H, dd, J ) 11.1, 11.1
Hz), 3.82 (3H, s), 3.88 (1H, d, J ) 10.6 Hz), 4.18 (1H, dd, J )
11.1, 4.8 Hz), 5.49 (1H, s), 6.92 (2H, d, J ) 8.5 Hz), 7.44 (2H,
d, J ) 8.5 Hz); HRMS (EI) m/z 250.1191 (250.1205 calcd for
C14H18O4, M+). Anal. Calcd for C14H18O4: C, 67.18; H, 7.25.
Found: C, 67.18; H, 7.27.
Olefin 13. To a stirred solution of 12 (7.05 g, 28.2 mmol)
in dry benzene (106 mL) was added methylenetriphenylphos-
phorane (23.4 g, 84.4 mmol) under argon. After the reaction
mixture was stirred at 25 °C for 1 h, the reaction was quenched
Dia ceta te 7. To a stirred solution of 617 (11.1 g, 85.3 mmol)
in dry ethyl acetate (111 mL) at 0 °C were added 4-(dimethy-
lamino)pyridine (22.9 g, 188 mmol) and acetic anhydride (20.1
mL, 213 mmol). After the reaction mixture was stirred at 25
°C for 1 h, ethanol (5 mL) and water (130 mL) were added
slowly to the reaction mixture under ice-cooling and the
resultant mixture was then extracted with ethyl acetate (70
mL × 3). The extracts were washed with saturated aqueous
NaCl (130 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. Purification of the residue by flash column
chromatography (920 g of silica gel, 6:1 n-hexane-ethyl
acetate) gave 7 (18.2 g, 100%) as a pale yellow oil: Rf 0.50
(8:1 n-hexane-ethyl acetate); [R]32D -44.3° (c 0.87, CHCl3); 1H-
NMR δ 1.05 (3H, d, J ) 6.8 Hz), 1.20 (3H, d, J ) 6.4 Hz), 2.01
(3H, s), 2.07 (3H, s), 2.42 (1H, dq, J ) 6.8, 6.8 Hz), 4.95-5.10
(3H, m), 5.68 (1H, ddd, J ) 17.8, 9.8, 8.2 Hz); HRMS (EI) m/z
214.1219 (214.1205 calcd for C11H18O4, M+). Anal. Calcd for
C11H18O4: C, 61.66; H, 8.47. Found: C, 61.76; H, 8.58.
Tr iol 10. Ozone was bubbled into a solution of 7 (10.0 g,
46.6 mmol) in MeOH-CH2Cl2 (1:1, 100 mL) at -78 °C for 2 h.
Excess ozone was then removed by purging with argon, and
dimethyl sulfide (34.1 mL, 46.6 mmol) was added dropwise.
The reaction was warmed to 0 °C for 0.5 h, and NaBH4 (2.65
g, 70.0 mmol) was then added to the reaction mixture. After
the resultant mixture was stirred at 25 °C for 0.5 h, the
mixture was neutralized with solid CO2. Water (100 mL) was
then added to the mixture, and then the resultant mixture
was extracted with chloroform (40 mL × 3). The extracts were
washed with saturated aqueous NaCl (100 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. To an ice-cold
solution of the residue in dry MeOH (102 mL) was added 5 M
NaOMe/MeOH (23.7 mL, 117 mmol). After the reaction was
stirred at 25 °C for 3 h, the reaction was quenched with ion-
exchange resin IR-120B. The resultant mixture was filtered,
and the resin was washed with MeOH. The combined filtrate
and washings were concentrated in vacuo. Purification of the
residue by flash column chromatography (320 g of silica gel,
6:1 chloroform-methanol) gave 10 (5.20 g, 94% from 7) as a
colorless oil: Rf 0.31 (5:1 chloroform-methanol); [R]27D -7.86°
(c 1.73, CHCl3); 1H-NMR δ 0.89 (3H, d, J ) 6.8 Hz), 1.19 (3H,
d, J ) 6.4 Hz), 1.84 (1H, m), 2.94 (1H, br s), 3.30 (1H, br d, J
) 2.1 Hz), 3.45 (1H, br s), 3.58 (1H, br ddd, J ) 6.6, 3.9, 2.1
Hz), 3.65 (2H, br d, J ) 6.1 Hz), 3.91 (1H, br dq, J ) 6.4, 3.9
Hz); HRMS (EI) m/z 134.0964 (134.0943 calcd for C6H14O3,
M+). Anal. Calcd for C6H14O3: C, 53.71; H, 10.52. Found:
C, 53.53; H, 10.82.
Alcoh ol 11. To an ice-cold solution of 10 (5.20 g, 38.8 mmol)
in dry DMF (52.0 mL) were added p-methoxybenzaldehyde
dimethyl acetal (7.74 mL, 46.3 mmol) and DL-10-camphore-
sulfonic acid (0.899 g, 3.88 mmol) with stirring. After the
reaction mixture was stirred at 25 °C for 1.5 h, the reaction
was quenched with saturated aqueous NaHCO3 (50 mL) under
ice-cooling, and the resultant mixture was then extracted with
ether (20 mL × 3). The extracts were washed with saturated
aqueous NaCl (50 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. Purification of the residue by flash
column chromatography (500 g of silica gel, 10:1 toluene-ethyl
acetate) gave 11 (9.23 g, 94%) as a pale yellow oil: Rf 0.27
(10:1 chloroform-ethyl acetate); [R]30D -17.9° (c 1.38, CHCl3);
1H-NMR δ 0.81 (3H, d, J ) 6.8 Hz), 1.27 (3H, d, J ) 6.4 Hz),
1.92 (1H, m), 2.25 (1H, d, J ) 9.6 Hz), 3.50 (1H, dd, J ) 11.0,
11.0 Hz), 3.63 (1H, dd, J ) 10.1, 2.6 Hz), 3.81 (3H, s), 3.97
(1H, m), 4.09 (1H, dd, J ) 11.0, 4.6 Hz), 5.47 (1H, s), 6.90 (2H,
d, J ) 8.8 Hz), 7.42 (2H, d, J ) 8.8 Hz); HRMS (EI) m/z
253.1431 (253.1440 calcd for C14H21O4, M + H+). Anal. Calcd
for C14H20O4: C, 66.65; H, 7.99. Found: C, 66.38; H, 8.32.
Keton e 12. To an ice-cold solution of 11 (9.23 g, 36.6 mmol)
in dry CH2Cl2 (92.3 mL) were slowly added powdered molec-
ular sieves 3A (73.2 g) and pyridinium chlorochromate (15.3
g, 73.2 mmol) with stirring. After the reaction mixture was
with saturated aqueous NH4
Cl (100 mL), and the resultant
mixture was then extracted with ether (30 mL × 3). The
extracts were washed with saturated aqueous NaCl (100 mL),
dried over anhydrous Na2
SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(350 g of silica gel, 10:1 n-hexane-ethyl acetate) gave 13 (6.65
g, 95%) as a white solid: Rf 0.30 (10:1 n-hexane-ethyl acetate);
[R]30 -4.66° (c 0.30, CHCl3); mp 43.5-44.5 °C (n-hexane,
D
flakes); 1H-NMR δ 0.73 (3H, d, J ) 6.6 Hz), 1.82 (1H, dd, J )
1.2, 1.2 Hz), 2.05 (1H, dddq, J ) 11.1, 10.0, 6.6, 4.6 Hz), 3.54
(1H, dd, J ) 11.1, 11.1 Hz), 3.79 (3H, s), 3.86 (1H, d, J ) 10.0
Hz), 4.17 (1H, dd, J ) 11.1, 4.6 Hz), 4.95-5.05 (2H, m), 5.51
(1H, s), 6.87 (2H, d, J ) 8.4 Hz), 7.43 (2H, d, J ) 8.4 Hz).
Anal. Calcd for C15H20O3: C, 72.55; H, 8.12. Found: C, 72.37;
H, 8.31.
Alcoh ol 14. To a stirred solution of cyclohexene (23.8 mL,
233 mmol) in dry THF (88.0 mL) at 0 °C was added dropwise
10 M BH3‚SMe2 (11.7 mL, 117 mmol). After 0.5 h, dry THF
(29.0 mL) was further added to the reaction mixture, the
resultant mixture was then stirred at 0 °C for 3 h, and a
solution of 13 (5.83 g, 23.5 mmol) in dry THF (17.5 mL) was
added at 0° C. After the mixture was stirred at 25 °C for 1 h,
water (135 mL), 3 M aqueous NaOH (39.0 mL), and 30%
aqueous H2O2 (39.8 mL) were carefully added to the ice-cooled
reaction mixture. After 2 h at 50 °C, the mixture was cooled
to ambient temperature and extracted with ether (100 mL ×
3). The extracts were washed with saturated aqueous NaCl
(300 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. Purification of the residue by flash column chroma-
tography (625 g of silica gel, 5:2 n-hexane-acetone) gave 14
(5.50 g, 88%) as a white solid: Rf 0.13 (5:1 n-hexane-acetone);
[R]30 -4.27° (c 0.15, CHCl3); mp 78.5-79.5 °C (n-hexane,
D
needles); 1H-NMR δ 0.80 (3H, d, J ) 6.6 Hz), 1.20 (3H, d, J )
7.2 Hz), 1.99 (1H, m), 2.17 (1H, m), 2.39 (1H, dd, J ) 9.0, 2.4
Hz), 3.48 (1H, dd, J ) 11.1, 11.1 Hz), 3.51 (1H, dd, J ) 11.2,
2.0 Hz), 3.62 (1H, ddd, J ) 11.2, 9.0, 4.3 Hz), 3.81 (3H, s),
3.95 (1H, ddd, J ) 11.2, 2.0, 2.0 Hz), 4.13 (1H, dd, J ) 11.1,
4.8 Hz), 5.38 (1H, s), 6.88 (2H, d, J ) 8.4 Hz), 7.37 (2H, d, J
) 8.4 Hz); HRMS (EI) m/z 267.1620 (267.1596 calcd for
C15
H22O4, M+). Anal. Calcd for C15H22O4: C, 67.65; H, 8.33.
Found: C, 67.79; H, 8.63.
Tosyla te 15. To a stirred solution of 14 (0.507 g, 1.90
mmol) in dry pyridine (10.1 mL) at 0 °C was added p-
toluenesulfonyl chloride (1.09 g, 5.71 mmol). After the reaction
mixture was stirred at 25 °C for 1.5 h, the reaction was
quenched with water (10 mL) and the resultant mixture was
then extacted with ethyl acetate (5 mL × 3). The extracts were
washed with saturated aqueous NaCl (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (50 g of silica
gel, 4:1 n-hexane-acetone) gave 15 (0.800 g, 100%) as a white
solid: Rf 0.26 (3:1 n-hexane-ethyl acetate); [R]26 -3.28° (c
D
1
1.06, CHCl3); mp 67.0-67.5 °C (n-hexane, cubes); H-NMR δ
0.77 (3H, d, J ) 6.8 Hz), 1.08 (3H, d, J ) 7.0 Hz), 1.97 (1H,
m), 2.28 (1H, m), 2.43 (3H, s), 3.37 (1H, dd, J ) 10.1, 2.0 Hz),
3.40 (1H, dd, J ) 11.2, 11.2 Hz), 3.80 (3H, s), 3.92 (1H, dd, J
) 10.0, 7.6 Hz), 4.05 (1H, dd, J ) 11.2, 4.6 Hz), 4.28 (1H, dd,
J ) 10.0, 5.8 Hz), 5.34 (1H, s), 6.85 (2H, d, J ) 8.4 Hz), 7.29
(2H, d, J ) 8.4 Hz), 7.31 (2H, d, J ) 8.0 Hz), 7.79 (2H, d, J )
8.0 Hz); HRMS (EI) m/z 421.1660 (421.1685 calcd for C22H29O6S,

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3279
M + H+). Anal. Calcd for C22H28O6S: C, 62.84; H, 6.71.
Found: C, 62.58; H, 7.01.
J ) 13.2, 10.6 Hz), 2.20 (1H, d, J ) 5.7 Hz), 2.43 (1H, br dd,
J ) 13.2, 2.9 Hz), 3.23 (1H, ddd, J ) 7.7, 5.7, 5.7 Hz), 4.10
(1H, dd, J ) 11.0, 4.3 Hz), 4.27 (1H, dd, J ) 11.0, 5.0 Hz),
5.90 (1H, br s); HRMS (EI) m/z 382.0992 (382.1005 calcd for
C15H37O3I, M+).
Acetylen e 16. To a stirred solution of 15 (1.06 g, 2.52
mmol) in dry dimethyl sulfoxide (10.6 mL) was added lithium
acetylide ethylenediamine complex (90%, 1.29 g, 12.6 mmol).
After the reaction mixture was stirred at 25 °C for 1.5 h, the
reaction was quenched with saturated aqueous NH4Cl (10 mL)
under ice-cooling, and the resultant mixture was then ex-
tracted with ether (5 mL × 3). The extracts were washed with
saturated aqueous NaCl (10 mL), dried over anhydrous Na2-
SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (70 g of silica gel, 8:1
n-hexane-acetone) gave 16 (0.409 g, 66%) as a white solid:
C5-C11 Segm en t 4. To a stirred solution of 19 (0.443 g,
1.16 mmol) in dry CH2Cl2 (8.9 mL) at 0 °C were added dropwise
2,6-lutidine (0.351 mL, 3.02 mmol) and diethylisopropylsilyl
trifluoromethansulfonate (0.482 mL, 2.32 mmol). After the
reaction mixture was stirred at 25 °C for 4 h, the mixture was
poured into ice-cooled water (9 mL), and the resultant mixture
was then extracted with ether (7 mL × 3). The extracts were
washed with saturated aqueous NaCl (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (30 g of silica
gel, 15:1 n-hexane-acetone) gave 4 (0.591 g, 100%) as a
Rf 0.76 (5:1 chloroform-methanol); [R]30 -11.6° (c 0.38,
D
CHCl3); mp 79.5-80.5 °C (n-hexane, needles); 1H-NMR δ 0.88
(3H, d, J ) 6.8 Hz), 1.19 (3H, d, J ) 6.6 Hz), 1.97 (1H, t, J )
2.1 Hz), 1.98-2.25 (3H, m), 2.46 (1H, m), 3.38 (1H, dd, J )
10.0, 2.0 Hz), 3.47 (1H, dd, J ) 11.1, 11.1 Hz), 3.81 (3H, s),
4.09 (1H, dd, J ) 11.1, 4.6 Hz), 5.42 (1H, s), 6.88 (2H, d, J )
8.4 Hz), 7.39 (2H, d, J ) 8.4 Hz); HRMS (EI) m/z 275.1648
(275.1647 calcd for C17H23O3, M + H+). Anal. Calcd for
C17H22O3: C, 74.42; H, 8.08. Found: C, 74.12; H, 8.38.
Diol 17. 16 (0.380 g, 1.39 mmol) was dissolved in 80%
aqueous acetic acid (11.5 mL), and the resultant solution was
stirred at 40 °C for 13 h. The reaction mixture was then
concentrated in vacuo. Purification of the residue by flash
column chromatography (20 g of silica gel, 1:1 n-hexane-ethyl
acetate) gave 17 (0.182 g, 84%) as a white solid: Rf 0.16 (1:1
colorless oil: Rf 0.23 (25:1 n-hexane-ethyl acetate); [R]32
D
-0.06°, [R]32 -1.73° (c 1.20, CHCl3); 1H-NMR δ 0.64 (4H, q,
435
J ) 7.7 Hz), 0.86 (3H, d, J ) 7.0 Hz), 0.95-1.03 (16H, m),
1.21 (9H, s), 1.80 (3H, s), 1.8-1.93 (1H, m), 1.95-2.07 (1H,
m), 2.02 (1H, dd, J ) 13.0, 10.8 Hz), 2.42 (1H, br dd, J ) 13.0,
3.0 Hz), 3.51 (1H, dd, J ) 4.5, 4.5 Hz), 3.87 (1H, dd, J ) 11.0,
7.3 Hz), 4.25 (1H, dd, J ) 11.0, 4.9 Hz), 5.85 (1H, br s); HRMS
(EI) m/z 510.2001 (510.2026 calcd for C22H43O3SiI, M+).
Alcoh ol 21. To a stirred suspension of CrCl3 (5.60 g, 35.4
mmol) in dry THF (56.0 mL) at 0 °C was added slowly LiAlH4
(0.671 g, 17.7 mmol). After 20 min at 0 °C, CH2dCHCH(OMe)2
(1.40 mL, 11.8 mmol), 1 M TMS-I/n-hexane (10.1 mL, 11.8
mmol), and a solution of aldehyde 2021 (0.975 g, 2.95 mmol)
in dry THF (3.0 mL) were added to the reaction mixture at
-42 °C. After 16 h at -42 °C, the reaction was quenched with
1 M aqueous HCl (43.4 mL) under ice-cooling, and the
resultant mixture was then extracted with ether (30 mL × 3).
The extracts were washed with saturated aqueous NaCl (40
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(120 g of silica gel, 2:1 n-hexane-ethyl acetate) gave 21 and
its unseparable diastereomers (0.736 g, 62%, 10:1.1:0.5) as a
colorless oil: Rf 0.50 (3:1 n-hexane-ethyl acetate); 1H-NMR δ
1.14 (3H, d, J ) 7.0 Hz), 1.99 (1H, m), 2.55 (1H, d, J ) 2.3
Hz), 3.05 (1H, dd, J ) 9.0, 4.2 Hz), 3.22 (3H, s), 3.23 (1H, m),
3.33 (1H, dd, J ) 8.1, 6.2 Hz), 3.73 (1H, m), 5.08 (1H, dd, J )
17.1, 1.9 Hz), 5.28 (1H, dd, J ) 10.2, 1.9 Hz), 5.72 (1H, ddd, J
) 17.1, 10.2, 8.1 Hz), 7.20-7.35 (9H, m), 7.40-7.48 (6H, m).
Anal. Calcd for C27H30O3: C, 80.56; H, 7.51. Found: C, 80.48;
H, 7.75.
Diol 22. To an ice-cold solution of a mixture of 21 and its
diastereomers (1.10 g, 2.73 mmol) in dry MeOH (10.0 mL) was
added dropwise 10% HCl-MeOH (1.0 mL). After the reaction
mixture was stirred at 25 °C for 0.5 h, the reaction was
neutralized with Et3N under ice-cooling, and the resultant
mixture was then concentrated in vacuo. Purification of the
residue by flash column chromatography (200 g of silica gel,
1:2 n-hexane-ethyl acetate) gave 22 (0.438 g, 100%) as a
mixture of its diastereomers: Rf 0.22 (1:2 n-hexane-ethyl
acetate); 1H-NMR δ 1.01 (3H, d, J ) 7.0 Hz), 1.98 (1H, m),
2.46 (1H, br s), 2.50 (1H, br d, J ) 3.9 Hz), 3.30 (3H, s), 3.56
(1H, dd, J ) 7.9, 7.8 Hz), 3.60-3.78 (3H, m), 5.37 (1H, dd, J
) 17.0, 1.9 Hz), 5.42 (1H, dd, J ) 10.2, 1.9 Hz), 5.76 (1H, ddd,
J ) 17.0, 10.2, 7.9 Hz); HRMS (EI) m/z 161.1176 (161.1178
calcd for C8H17O3, M + H+).
n-hexane-ethyl acetate); [R]30 -14.6° (c 1.39, CHCl3); mp
D
38.0-39.0 °C (n-hexane, needles); 1H-NMR δ 0.99 (3H, d, J )
6.8 Hz), 1.09 (3H, d, J ) 6.8 Hz), 1.80-2.05 (2H, m), 2.00 (1H,
t, J ) 2.3 Hz), 2.27 (1H, ddd, J ) 16.6, 8.0, 2.3 Hz), 2.40 (1H,
ddd, J ) 16.6, 4.3, 2.3 Hz), 2.55 (1H, br t, J ) 4.2 Hz), 2.81
(1H, br d, J ) 5.6 Hz), 3.45 (1H, br ddd, J ) 6.4, 6.4, 5.6 Hz),
3.65 (1H, br ddd, J ) 10.3, 6.0, 4.2 Hz), 3.85 (1H, br ddd, J )
10.3, 4.2, 1.8 Hz); HRMS (EI) m/z 157.1239 (157.1229 calcd
for C9H17O2, M + H+). Anal. Calcd for C9H16O2: C, 69.19; H,
10.32. Found: C, 69.07; H, 10.58.
Vin yl Iod id e 18. To a stirred solution of Cp2ZrCl2 (0.587
g, 2.01 mmol) in dry 1,2-dichloroethane (17.6 mL) was added
dropwise 2 M Me3Al/n-hexane (3.01 mL, 6.02 mmol). After
0.5 h at 25 °C, a solution of 17 (0.157 g, 1.00 mmol) in dry
1,2-dichloroethane (1.57 mL) was added to the reaction
mixture. After 13 h, to the reaction mixture at -30 °C was
added slowly a solution of I2 (2.55 g, 10.0 mmol) in dry THF
(17.8 mL), and the resultant mixture was stirred at -30 °C
for 1.5 h. The reaction mixture was warmed to 0 °C, and ice-
cooled saturated aqueous K2CO3 (40 mL) was added. The
resultant mixture was extracted with ether (30 mL × 3). The
extracts were washed with saturated aqueous Na2S2O3 (30 mL
× 2) and saturated aqueous NaCl (30 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo. Purification of the
residue by flash column chromatography (30 g of silica gel,
3:1 n-hexane-acetone) gave 18 (0.244 g, 82%) as a colorless
oil: Rf 0.43 (10:1 chloroform-methanol); [R]31D -26.1° (c 1.42,
1
CHCl3); H-NMR δ 0.87 (3H, d, J ) 6.4 Hz), 0.94 (3H, d, J )
7.0 Hz), 1.73-1.95 (2H, m), 1.83 (3H, s), 2.09 (1H, dd, J )
13.6, 11.0 Hz), 2.45 (1H, br dd, J ) 13.6, 2.6 Hz), 2.64 (1H, br
s), 2.84 (1H, br s), 3.42 (1H, br dd, J ) 6.8, 4.4 Hz), 3.65 (1H,
br dd, J ) 10.4, 7.1 Hz), 3.82 (1H, br dd, J ) 10.4, 2.0 Hz),
5.90 (1H, br s); HRMS (EI) m/z 298.0460 (298.0430 calcd for
C10H19O2I, M+).
Aceton id e 23. To a stirred solution of a mixture of 22 and
its diastereomers (0.398 g, 2.48 mmol) in dry CH2Cl2 (8.0 mL)
at 0 °C were added 2,2-dimethoxypropane (1.20 mL, 9.94
mmol) and DL-10-camphoresulfonic acid (0.231 g, 0.990 mmol).
After the reaction mixture was stirred at 25 °C for 16 h, the
reaction was neutralized with Et3N under ice-cooling, and the
resultant mixture was then concentrated in vacuo. Purifica-
tion of the residue by flash column chromatography (50 g of
silica gel, 20:1 n-hexane-ethyl acetate) gave the pure 23 (0.378
g, 76%) as a colorless oil: Rf 0.20 (15:1 n-hexane-ethyl
P iva la te 19. To an ice-cold solution of 18 (1.13 g, 3.79
mmol) in dry CH2Cl2 (11.2 mL) were added dropwise triethy-
lamine (0.950 mL, 6.82 mmol) and pivaloyl chloride (0.560 mL,
4.54 mmol) with stirring. After the reaction mixture was
stirred at 25 °C for 14 h, the mixture was poured into ice-
cooled water (13 mL), and the resultant mixture was then
extracted with ether (10 mL × 3). The extracts were washed
with saturated aqueous NaCl (13 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (75 g of silica gel, 5:1
n-hexane-acetone) gave 19 (1.41 g, 97%) as a colorless oil: Rf
0.24 (8:1 n-hexane-acetone); [R]32D -17.5° (c 0.79, CHCl3); 1H-
NMR δ 0.88 (3H, d, J ) 6.8 Hz), 0.99 (3H, d, J ) 7.0 Hz), 1.22
(9H, s), 1.82 (3H, s), 1.84 (1H, m), 2.00 (1H, m), 2.07 (1H, dd,
acetate); [R]26 +14.5° (c 1.70, CHCl3); 1H-NMR δ 1.11 (3H, d,
D
J ) 7.0 Hz), 1.36 and 1.39 (each 3H, each s), 1.78 (1H, m),
3.29 (3H, s), 3.43 (1H, dd, J ) 8.4, 6.8 Hz), 3.61 (1H, dd, J )
11.9, 1.8 Hz), 3.81 (1H, dd, J ) 8.4, 2.2 Hz), 4.09 (1H, dd, J )
11.9, 2.8 Hz), 5.27 (1H, dd, J ) 17.0, 1.9 Hz), 5.29 (1H, dd, J

3280 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
) 9.8, 1.9 Hz), 5.68 (1H, ddd, J ) 17.0, 9.8, 6.8 Hz); HRMS
(EI) m/z 200.1393 (200.1412 calcd for C11H20O3, M+). Anal.
Calcd for C11H20O3: C, 65.97; H, 10.07. Found: C, 65.83; H,
10.32.
3H, dd, J ) 4.0, 1.0 Hz), 5.79 (2/3H, d, J ) 4.0 Hz), 5.86 (1/
3H, d, J ) 4.0 Hz). Anal. Calcd for C10H18O4: C, 59.39; H,
8.97. Found: C, 59.10; H, 9.21.
Keton e 29. To a stirred solution of 28 (2.75 g, 13.7 mmol)
in dry CH2Cl2 (27.5 mL) at 0 °C were added powdered
molecular sieves 3A (14.1 g) and pyridinium chlorochromate
(11.8 g, 54.8 mmol). After the reaction mixture was stirred
at 25 °C for 0.5 h, ether (42 mL) was added. The resultant
mixture was stirred and then purified by flash column chro-
matography (134 g of silica gel, ether) to give 29 (2.55 g, 94%)
Vin yl Iod id e 26. To a stirred solution of 23 (0.497 g, 2.48
mmol) in acetone-water (8:3, 27.5 mL) were added OsO4 (63.1
mg, 0.250 mmol) and 4-methylmorphorine N-oxide (1.46 g, 12.4
mmol). After 16 h at 25 °C, the reaction mixture was poured
into saturated aqueous Na2SO3 (30 mL), and the resultant
mixture was then extracted with ethyl acetate (15 mL × 3).
The extracts were washed with saturated aqueous NaCl (20
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
The residue (0.500 g) was dissolved in THF-water (3:1, 20
mL), and NaIO4 (0.913 g, 4.26 mmol) was added to the solution.
The reaction mixture was stirred at 25 °C for 0.5 h and then
poured into ice-cooled water. The resultant mixture was
extracted with ether (10 mL × 3). The extracts were washed
with saturated aqueous NaCl (20 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. A solution of the residue
(0.359 g) in dry THF (3.6 mL) was added to a suspension of
CrCl2 (1.20 g, 10.6 mmol) in dry THF (12.0 mL) under ice-
cooling. The reaction mixture was stirred at 0 °C for 20 min,
and CHI3 (1.4 g, 3.55 mmol) was then added. After 14 h at 25
°C, the reaction mixture was poured into a mixture of
saturated aqueous Na2S2O3 and saturated aqueous NaHCO3
(1:1, 20 mL), and the resultant mixture was extracted with
ether (15 mL × 3). The extracts were washed with saturated
aqueous NaCl (20 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. Purification of the residue by flash
column chromatography (60 g of silica gel, 15:1 n-hexane-
ethyl acetate) gave 26 (0.406 g, 50% from 23) as a colorless
oil: Rf 0.35 (10:1 n-hexane-ethyl acetate); [R]32D +13.6° (c 0.85,
CHCl3); 1H-NMR δ 1.08 (3H, d, J ) 7.0 Hz), 1.36 and 1.39
(each 3H, each s), 1.75 (1H, m), 3.30 (3H, s), 3.43 (1H, dd, J )
8.6, 6.1 Hz), 3.60 (1H, dd, J ) 11.9, 1.9 Hz), 3.81 (1H, dd, J )
8.6, 3.0 Hz), 4.08 (1H, dd, J ) 11.9, 2.6 Hz), 6.32 (1H, d, J )
14.4 Hz), 6.43 (1H, dd, J ) 14.4, 6.1 Hz); HRMS (EI) m/z
327.0435 (327.0453 calcd for C11H20O3I, M + H+).
as a colorless oil: Rf 0.41 (2:1 n-hexane-ethyl acetate); [R]33
D
1
-21.1° (c 0.94, CHCl3); H-NMR δ 1.13 (3H, d, J ) 7.1 Hz),
1.27 and 1.42 (each 3H, each s), 2.34 (3H, s), 2.93 (1H, dq, J
) 7.1, 1.6 Hz), 4.00 (1H, d, J ) 1.6 Hz), 4.32 (1H, d, J ) 4.0
Hz), 5.92 (1H, d, J ) 4.0 Hz). Anal. Calcd for C10H16O4: C,
59.99; H, 8.15. Found: C, 59.87; H, 8.26.
Olefin 30. To a stirred solution of 29 (2.50 g, 12.5 mmol)
in dry benzene (37.5 mL) was added methylenetriphenylphos-
phorane (13.9 g, 50.0 mmol). The reaction mixture was stirred
at 25 °C for 0.5 h and then concentrated in vacuo. Purification
of the residue by flash column chromatography (900 g of silica
gel, 10:1 n-hexane-ethyl acetate) gave 30 (2.02 g, 81%) as a
colorless oil: Rf 0.22 (10:1 n-hexane-ethyl acetate); [R]26
D
-1.60°, [R]26 -2.29° (c 0.43, CHCl3); 1H-NMR δ 1.09 (3H, d,
435
J ) 7.2 Hz), 1.35 and 1.55 (each 3H, each s), 1.80 (3H, br s),
2.26 (1H, ddq, J ) 7.2, 7.2, 2.8 Hz), 3.95 (1H, br d, J ) 7.2
Hz), 4.35 (1H, dd, J ) 4.1, 2.8 Hz), 4.88 (1H, br s), 5.03 (1H,
br s), 5.74 (1H, d, J ) 4.1 Hz). Anal. Calcd for C11H18O3: C,
66.64; H, 9.75. Found: C, 66.45; H, 9.89.
Aceton id e 31. To a solution of 30 (0.500 g, 2.52 mmol) in
dioxane (10.0 mL) was added a catalytic amount of Raney-Ni
(W4). After the reaction mixture was vigorously stirred at 25
°C for 24 h under H2, the mixture was filtered, and the catalyst
was washed with dioxane. The combined filtrate and washings
were concentrated in vacuo. Purification of the residue by
flash column chromatography (25 g of silica gel, 3:1 n-hexane-
acetone) gave 31 (0.468 g, 92%) as a colorless oil: Rf 0.20 (10:1
n-hexane-ethyl acetate); [R]30 +25.5° (c 1.86, CHCl3); 1H-
D
NMR δ 0.91 (3H, d, J ) 6.4 Hz), 1.00 (3H, d, J ) 6.4 Hz), 1.06
(3H, d, J ) 7.1 Hz), 1.31 and 1.53 (each 3H, each s), 1.99 (1H,
dseptet, J ) 8.6, 6.4 Hz), 2.27 (1H, ddq, J ) 7.1, 3.6, 0.9 Hz),
3.27 (1H, dd, J ) 8.6, 3.6 Hz), 4.29 (1H, dd, J ) 4.0, 0.9 Hz),
5.77 (1H, d, J ) 4.0 Hz). Anal. Calcd for C11H20O3: C, 65.97;
H, 10.06. Found: C, 66.23; H, 9.69.
F r ee Su ga r 32. A solution of 31 (4.68 g, 23.3 mmol) in 50%
aqueous acetic acid (47.0 mL) was stirred at 80 °C for 2 h and
then concentrated in vacuo. Purification of the residue by flash
column chromatography (230 g of silica gel, 3:2 n-hexane-
acetone) gave 32 (3.05 g, 93%) as a white solid: Rf 0.20 (3:2
n-hexane-acetone); mp 75.0-75.5 °C (n-hexane, needles); 1H-
NMR δ 0.94 (3H, d, J ) 7.0 Hz), 0.95 (3H, d, J ) 6.4 Hz), 1.12
(4/5 × 3H, d, J ) 6.4 Hz), 1.14 (1/5 × 3H, d, J ) 6.4 Hz), 1.65-
1.95 (2H, m), 2.70 (4/5H, br d, J ) 9.2 Hz), 2.83 (1/5H, br d, J
) 5.2 Hz), 3.30 (4/5H, dd, J ) 8.4, 6.0 Hz), 3.62 (1/5H, dd, J )
8.0, 5.9 Hz), 3.65 (4/5H, ddd, J ) 9.2, 9.2, 4.2 Hz), 3.78 (1/5H,
ddd, J ) 5.2, 5.2, 2.0 Hz), 4.09 (4/5H, br d, J ) 3.6 Hz), 4.14
(1/5H, br s), 5.10-5.25 (1H, m). Anal. Calcd for C8H16O3: C,
59.98; H, 10.07. Found: C, 60.01; H, 10.49.
Tr iol 33. To a stirred solution of 32 (3.05 g, 19.0 mmol) in
dry THF (47.0 mL) at 0 °C was added slowly LiAlH4 (1.44 g,
38.0 mmol). After the reaction mixture was stirred at 25 °C
for 16 h, water (2.3 mL), 10% aqueous NaOH (2.5 mL), and
water (6.8 mL) were carefully added under ice-cooling. The
resultant mixture was filtered, and the filter cake was washed
with CHCl3. The filtrate and washing were combined and then
concentrated in vacuo. Purification of the residue by flash
column chromatography (500 g of silica gel, 10:1 chloroform-
methanol) gave 33 (2.38 g, 77%) as a white solid: Rf 0.40 (10:1
chloroform-methanol); [R]30D -38.3° (c 0.70, CHCl3); mp 65.5-
66.0 °C (n-hexane, flakes); 1H-NMR δ 0.92-0.97 (9H, m), 1.75-
1.95 (2H, m), 1.95-2.15 (3H, br s), 3.36 (1H, dd, J ) 6.0, 6.0
Hz), 3.60 (1H, dd, J ) 11.0, 4.0 Hz), 3.71 (1H, dd, J ) 11.0,
8.0 Hz), 4.00 (1H, ddd, J ) 8.0, 4.0, 2.4 Hz). Anal. Calcd for
C8H18O3: C, 59.23; H, 11.18. Found: C, 59.18; H, 11.20.
Ca r bon a te 34. To a stirred solution of 33 (2.08 g, 12.8
mmol) in dry CH2Cl2 (62.4 mL) was added N,N ′-carbonyldi-
C12-C17 Segm en t 5. To a stirred solution of 26 (0.487 g,
1.49 mmol) in dry THF (15.0 mL) at -78 °C were added
dropwise 1.6 M n-BuLi/n-hexane (1.83 mL, 2.98 mmol) and
n-Bu3SnCl (0.970 mL, 3.58 mmol). After the reaction mixture
was stirred at -78 °C for 1 h, water (20 mL) was added, and
the resultant mixture was warmed to 25 °C and then extracted
with ether (10 mL × 3). The extracts were washed with
saturated aqueous NaCl (20 mL), dried over anhydrous Na2-
SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (37 g of silica gel, 20:1
n-hexane-ethyl acetate) gave 5 (0.504 g, 69%) as a colorless
oil: Rf 0.45 (10:1 n-hexane-ethyl acetate); [R]32D +16.4° (c 1.01,
1
CHCl3); H-NMR δ 0.85-0.93 (15H, m), 1.10 (3H, d, J ) 7.0
Hz), 1.24-1.38 (6H, m), 1.35 (3H, s), 1.37 (3H, s), 1.44-1.57
(6H, m), 1.77 (1H, m), 3.28 (3H, s), 3.40 (1H, ddd, J ) 9.0, 6.3,
1.2 Hz), 3.60 (1H, dd, J ) 11.6, 1.8 Hz), 3.82 (1H, dd, J ) 9.0,
2.2 Hz), 4.08 (1H, dd, J ) 11.6, 2.8 Hz), 5.79 (1H, dd, J ) 19.0,
6.3 Hz), 6.21 (1H, dd, J ) 19.0, 1.2 Hz); HRMS (EI) m/z
490.2427 (490.2469 calcd for C23H46O3Sn, M+).
Alcoh ol 28. To a stirred solution of 2719d (1.90 g, 10.2
mmol) in dry ether (19.0 mL) was added dropwise 4 M MeMgI/
ether (25.0 mL, 100 mmol) under ice-cooling. The reaction
mixture was stirred at 25 °C for 0.5 h, the reaction was
quenched with saturated aqueous NH4Cl (30 mL) under ice-
cooling, and the resultant mixture was then extracted with
ethyl acetate (20 mL × 3). The extracts were washed with
saturated aqueous NaCl (30 mL), dried over anhydrous Na2-
SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (100 g of silica gel, 1:1
toluene-ethyl acetate) gave 28 (1.92 g, 94%) as a colorless oil
and a mixture of C5 epimers: Rf 0.30 (2:1 n-hexane-ethyl
acetate); 1H-NMR δ 1.11 (1/3 × 3H, d, J ) 7.0 Hz), 1.13 (2/3 ×
3H, d, J ) 7.0 Hz), 1.16 (1/3 × 3H, d, J ) 6.4 Hz), 1.21 (2/3 ×
3H, d, J ) 6.4 Hz), 1.30 and 1.54 (each 1/3 × 3H, each s), 1.32
and 1.55 (each 2/3 × 3H, each s), 2.24 (1/3H, m), 2.36 (2/3H,
d, J ) 3.9 Hz), 2.53 (2/3H, m), 2.77 (1/3H, d, J ) 1.7 Hz), 3.48
(1/3H, dd, J ) 8.2, 4.2 Hz), 3.58 (2/3H, dd, J ) 5.9, 4.1 Hz),
3.90-4.10 (1H, m), 4.33 (2/3H, dd, J ) 4.0, 1.9 Hz), 4.35 (1/

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3281
imidazole (2.70 g, 16.6 mmol). After the reaction mixture was
stirred at 25 °C for 2.5 h, saturated aqueous NaCl (60 mL)
was added, and the resultant mixture was then extracted with
ethyl acetate (30 mL × 3). The extracts were concentrated in
vacuo. Purification of the residue by flash column chroma-
tography (150 g of silica gel, 1:1 n-hexane-ethyl acetate) gave
34 (2.45 g, 85%) as a white solid: Rf 0.66 (1:4 toluene-ethyl
mmol) was added to the solution under stirring. After the
reaction mixture was stirred at -20 °C for 2 h, the mixture
was cooled to -50 °C. To this solution was added dropwise a
solution of 38 (0.153 g, 0.930 mmol) in dry THF (0.46 mL).
The resultant solution was further stirred at -50 f -20 °C
for 2 h. The reaction mixture was poured into saturated
aqueous NH4Cl (10 mL) under ice-cooling, and the resultant
mixture was then extracted with ethyl acetate (5 mL × 3).
The extracts were washed with saturated aqueous NaCl (10
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(30 g of silica gel, 15:1 n-hexane-ethyl acetate) gave es-
sentially pure 39 (0.241 g) as a pale yellow oil. To a stirred
solution of 39 (0.241 g) in dry THF (2.41 mL) at 0 °C was added
dropwise 1 M TBAF/THF (0.889 mL, 0.889 mmol). After the
reaction mixture was stirred at 25 °C for 2.5 h, the reaction
was quenched with ice-cold water (3 mL), and the resultant
mixture was then extracted with ethyl acetate (3 mL × 3).
The extracts were washed with saturated aqueous NaCl (4
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(10 g of silica gel, 6:1 n-hexane-ethyl acetate) gave 40 (0.168
g, 97% from 38) as a colorless oil: Rf 0.19 (4:1 n-hexane-ethyl
acetate); [R]27 -40.0° (c 0.33, CHCl3); mp 46.0-46.5 °C (n-
D
hexane, flakes); 1H-NMR δ 0.84 (3H, d, J ) 6.4 Hz), 0.99 (3H,
d, J ) 6.4 Hz), 1.00 (3H, d, J ) 7.0 Hz), 1.74 (1H, d, J ) 4.6
Hz), 1.75-1.95 (2H, m), 3.34 (1H, ddd, J ) 9.9, 4.6, 2.4 Hz),
4.27 (1H, dd, J ) 10.4, 8.0 Hz), 4.61 (1H, dd, J ) 10.4, 8.0
Hz), 4.93 (1H, ddd, J ) 8.0, 8.0, 5.9 Hz). Anal. Calcd for
C9H16O4: C, 57.43; H, 8.57. Found: C, 57.17; H, 8.74.
Silyl Eth er 35. To a stirred solution of 34 (6.54 g, 34.7
mmol) in dry DMF (130 mL) at 0 °C were added imidazole
(8.51 g, 125 mol) and tert-butyldimethylsilyl chloride (15.7 g,
104 mmol). After the reaction mixture was stirred at 40 °C
for 16 h, ice-cold water (150 mL) was added, and the resultant
mixture was then extracted with ether (50 mL × 3). The
extracts were washed with saturated aqueous NaCl (100 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(500 g of silica gel, 4:1 n-hexane-ethyl acetate) gave 35 (9.32
g, 87%) as a colorless oil: Rf 0.73 (1:1 n-hexane-ethyl acetate);
[R]27D -53.3° (c 1.19, CHCl3); 1H-NMR δ 0.08 (6H, s), 0.89 (9H,
s), 0.98 (3H, d, J ) 6.4 Hz), 1.03 (3H, d, J ) 6.4 Hz), 1.04 (3H,
d, J ) 7.0 Hz), 1.93 (1H, dseptet, J ) 6.4, 4.4 Hz), 2.30 (1H,
m), 3.86 (2H, d, J ) 4.4 Hz), 4.30-4.36 (2H, m). Anal. Calcd
for C15H30O4Si: C, 59.56; H, 10.00. Found: C, 59.27; H, 10.19.
Diol 36. To a stirred solution of 35 (1.74 g, 5.64 mmol) in
MeOH (35.0 mL) at 0 °C was added dropwise 1 M aqueous
NaOH (11.9 mL, 11.9 mmol). After the reaction mixture was
stirred at 25 °C for 16 h, the reaction was neutralized with
ion-exchange resin CG-50 under ice-cooling. The resultant
mixture was filtered, and the resin was washed with MeOH.
The filtrate and washing were combined and then concentrated
in vacuo. Purification of the residue by flash column chroma-
tography (80 g of silica gel, 3:2 n-hexane-ethyl acetate) gave
36 (1.39 g, 87%) as a colorless oil: Rf 0.20 (1:1 n-hexane-ethyl
acetate); [R]27D -5.71° (c 1.05, CHCl3); 1H-NMR δ 0.10 (3H, s),
0.12 (3H, s), 0.92 (3H, d, J ) 6.6 Hz), 0.93 (9H, s), 0.94 (3H, d,
J ) 6.6 Hz), 0.99 (3H, d, J ) 7.1 Hz), 1.77 (1H, ddq, J ) 7.1,
2.1, 2.0 Hz), 1.93 (1H, dseptet, J ) 6.6, 6.6 Hz), 2.55 (2H, br
s), 3.43 (1H, dd, J ) 6.6, 2.1 Hz), 3.45 (1H, dd, J ) 10.4, 4.1
Hz), 3.64 (1H, dd, J ) 10.4, 8.0 Hz), 4.17 (1H, ddd, J ) 8.0,
4.1, 2.0 Hz). Anal. Calcd for C14H32O3Si: C, 60.82; H, 11.67.
Found: C, 60.59; H, 11.83.
acetate); [R]27 +42.0° (c 0.70, CHCl3); 1H-NMR δ 0.96 (6H, d,
D
J ) 6.4 Hz), 0.97 (3H, d, J ) 7.0 Hz), 1.04 (3H, t, J ) 7.4 Hz),
1.72-2.20 (7H, m), 2.50 (1H, dd, J ) 15.0, 9.2 Hz), 2.72-2.86
(2H, m), 2.88-3.08 (2H, m), 3.34 (1H, dd, J ) 12.0, 5.4 Hz),
3.41 (1H, d, J ) 5.2 Hz), 3.88 (1H, d, J ) 1.9 Hz), 4.27 (1H, br
d, J ) 9.6 Hz). Anal. Calcd for C14H28O2S2: C, 57.49; H, 9.65.
Found: C, 57.31; H, 9.88.
Cyclic Silyl Eth er 41. To a stirred solution of 40 (0.175
g, 0.575 mmol) in dry DMF (0.383 mL) at 0 °C was added
dropwise t-Bu2Si(OTf)2 (97%, 0.259 mL, 0.690 mmol). After
the reaction mixture was stirred at 25 °C for 2 h, the reaction
was quenched with ice-cold water (1 mL), and the resultant
mixture was then extracted with ethyl acetate (0.5 mL × 3).
The extracts were washed with saturated aqueous NaCl
(1 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. Purification of the residue by flash column chroma-
tography (12 g of silica gel, 15:1 n-hexane-ethyl acetate) gave
41 (0.245 g, 95%) as a white solid: Rf 0.75 (4:1 n-hexane-
ethyl acetate); [R]28 +59.0° (c 0.41, CHCl3); mp 74.0-75.0 °C
D
(hexane, flakes); 1H-NMR δ 0.88 (6H, d, J ) 6.4 Hz), 0.98 (3H,
d, J ) 6.8 Hz), 1.03 (18H, s), 1.07 (3H, t, J ) 7.2 Hz), 1.75
(1H, m), 1.88-2.20 (7H, m), 2.65-2.86 (4H, m), 3.61 (1H, dd,
J ) 8.0, 3.0 Hz), 4.39 (1H, ddd, J ) 8.0, 5.2, 1.7 Hz). Anal.
Calcd for C22H44O2SiS2: C, 61.05; H, 10.25. Found: C, 61.22;
H, 10.13.
Ep oxid e 38. To a stirred solution of 36 (2.54 g, 9.20 mmol)
in dry pyridine (50.9 mL) at 0 °C was added p-toluenesulfonyl
chloride (5.26 g, 27.6 mmol). The reaction mixture was stirred
at 25 °C for 4 h and then poured into ice-cold water (60 mL).
The resultant mixture was extracted with ethyl acetate (30
mL × 3). The extracts were washed with saturated aqueous
NaCl (100 mL), dried over anhydrous Na2SO4, and concen-
trated in vacuo. To a stirred solution of the residue (3.56 g)
in dry CHCl3 (35.6 mL) at 0 °C was added dropwise 5 M
NaOMe/MeOH (2.48 mL, 12.4 mmol). After the reaction
mixture was stirred at 25 °C for 16 h, the reaction was
neutralized with solid CO2, and the resultant mixture was
poured into ice-cold water (40 mL). The resultant mixture was
extracted with CHCl3 (20 mL × 3). The extracts were washed
with saturated aqueous NaCl (20 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (120 g of silica gel, 6:1
n-hexane-ethyl acetate) gave 38 (1.69 g, 71% from 36) as a
C18-C25 Segm en t 3. To a stirred solution of 41 (0.165 g,
0.381 mmol) in 80% aqueous MeCN (4.95 mL) were added
CaCO3
(0.382 g, 3.81 mmol) and MeI (0.712 mL, 11.4 mmol).
After the reaction mixture was stirred at 25 °C for 6 h, water
(10 mL) was added, and the resultant mixture was extracted
with ethyl acetate (7 mL × 3). The extracts were washed with
saturated aqueous NaCl (10 mL), dried over anhydrous Na2-
SO4
, and concentrated in vacuo. Purification of the residue
by flash column chromatography (13 g of silica gel, 40:1
n-hexane-ethyl acetate) gave 3 (0.0940 g, 72%) as a white
solid: Rf
0.63 (10:1 n-hexane-ethyl acetate); [R]30 +85.2° (c
D
0.89, CHCl3); mp 40.0-40.5 °C (hexane); IR (CHCl3) 1719 cm-1
1
(CdO); H-NMR δ 0.73 (3H, d, J ) 7.0 Hz), 0.86 (3H, d, J )
6.9 Hz), 0.97 (9H, s), 0.99 (9H, s), 1.01 (3H, d, J ) 7.0 Hz),
1.07 (3H, d, J ) 7.1 Hz), 1.73 (1H, dseptet, J ) 7.0, 2.1 Hz),
2.23 (1H, m), 2.38 (1H, dd, J ) 14.2, 3.4 Hz), 2.53 (1H, dq, J
) 10.8, 7.0 Hz), 2.56 (1H, dq, J ) 10.8, 7.0 Hz), 2.71 (1H, dd,
J ) 14.2, 10.1 Hz), 3.68 (1H, dd, J ) 9.6, 2.1 Hz), 4.62 (1H,
ddd, J ) 10.1, 5.9, 3.4 Hz). Anal. Calcd for C19H38O3Si: C,
66.37; H, 11.53. Found: C, 66.61; H, 11.18.
Cou p lin g 4 a n d 5. To a solution of 4 (1.01 g, 1.98 mmol)
and 5 (0.969 g, 1.98 mmol) in dry DMF (24.2 mL) was added
[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride
(PdCl2(dppf)) (0.290 g, 0.396 mmol). After the reaction mixture
was stirred at 50 °C for 15 h under argon, ice-cold water (25
mL) was added, and the resultant mixture was then extracted
with ether (15 mL × 3). The extracts were washed with
saturated aqueous NaCl (15 mL), dried over anhydrous Na2-
colorless oil: Rf 0.56 (4:1 n-hexane-ethyl acetate); [R]30
D
-8.97° (c 1.36, CHCl3); 1H-NMR δ 0.05 (6H, s), 0.87 (3H, d, J
) 6.4 Hz), 0.91 (9H, s), 0.92 (3H, d, J ) 6.4 Hz), 1.04 (3H, d,
J ) 6.8 Hz), 1.42 (1H, m), 1.83 (1H, m), 2.58 (1H, dd, J ) 4.6,
2.4 Hz), 2.79 (1H, dd, J ) 4.6, 4.0 Hz), 2.87 (1H, dd, J ) 6.9,
4.0, 2.4 Hz), 3.41 (1H, dd, J ) 5.2, 5.0 Hz). Anal. Calcd for
C14H30O2Si: C, 65.05; H, 11.70. Found: C, 64.81; H, 11.94.
Dith ioa ceta l 40. A solution of 2-ethyl-1,3-dithiane (0.437
g, 2.96 mmol) in dry THF (4.78 mL) was cooled to -40 °C under
argon. A solution of 1.69 M n-BuLi/hexane (1.75 mL, 2.96

3282 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (230 g of silica gel, 50:1
benzene-acetone) gave 42 (0.694 g, 60%) as a colorless oil: Rf
0.25 (80:1 chloroform-methanol); [R]30D +18.1° (c 1.32, CHCl3);
1H-NMR δ 0.64 (4H, q, J ) 7.8 Hz), 0.88 (3H, d, J ) 6.4 Hz),
0.95-1.05 (16H, m), 1.11 (3H, d, J ) 6.8 Hz), 1.21 (9H, s),
1.365 and 1.37 (3H, each s), 1.385 and 1.39 (3H, each s), 1.72-
1.93 (3H, m), 1.74 (3H, s), 2.03 (1H, m), 2.30 (1H, br d, J )
11.6 Hz), 3.28 (3H, s), 3.45-3.55 (2H, m), 3.60 (1H, dd, J )
11.9, 1.8 Hz), 3.83 (1H, dd, J ) 8.5, 2.3 Hz), 3.87 (1H, dd, J )
10.6, 7.7 Hz), 4.09 (1H, dd, J ) 11.9, 2.6 Hz), 4.28 (1H, dd, J
) 10.6, 4.6 Hz), 5.37 and 5.39 (1H, each dd, J ) 15.6, 7.6 Hz),
5.86 (1H, d, J ) 11.0 Hz), 6.45 (1H, dd, J ) 15.6, 11.0 Hz);
HRMS (EI) m/z 582.4320 (582.4316 calcd for C33H62O6Si, M+).
Anal. Calcd for C33H62O6Si: C, 67.99; H, 10.72. Found: C,
67.60; H, 11.02.
was stirred at 100 °C for 14 h, the reaction was quenched with
saturated aqueous NH4Cl (10 mL) at 25 °C and the resultant
mixture was extracted with ether (5 mL × 3). The extracts
were washed with saturated aqueous NaCl (10 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (45 g of silica
gel, 8:1 n-hexane-ethyl acetate) gave 49 (0.444 g, 98%) as a
colorless oil: Rf 0.35 (8:1 n-hexane-ethyl acetate); [R]24
D
1
+27.3° (c 0.80, CHCl3); H-NMR δ 0.64 (4H, q, J ) 7.8 Hz),
0.78 (3H, d, J ) 6.4 Hz), 0.95-1.05 (16H, m), 1.10 (3H, d, J )
6.8 Hz), 1.28 (3H, t, J ) 7.2 Hz), 1.365 and 1.37 (3H, each s),
1.385 and 1.39 (3H, each s), 1.70-1.90 (3H, m), 1.74 (3H, s),
1.85 (3H, d, J ) 1.6 Hz), 2.24 (1H, m), 2.70 (1H, m), 3.28 (3H,
s), 3.45-3.58 (2H, m), 3.59 (1H, dd, J ) 11.9, 1.6 Hz), 3.82
(1H, dd, J ) 8.6, 2.4 Hz), 4.08 (1H, dd, J ) 11.9, 2.6 Hz), 4.10-
4.24 (2H, m), 5.37 and 5.39 (1H, each dd, J ) 15.2, 7.2 Hz),
5.85 (1H, d, J ) 10.9 Hz), 6.44 (1H, dd, J ) 15.2, 10.9 Hz),
6.96 (1H, dd, J ) 10.0, 1.6 Hz); HRMS (EI) m/z 580.4153
(580.4160 calcd for C33H60O6Si, M+). Anal. Calcd for C33H60O6-
Si: C, 68.23; H, 10.41. Found: C, 68.11; H, 10.79.
Alcoh ol 43. To a stirred solution of 42 (0.602 g, 1.03 mmol)
in dry ether (18.1 mL) at 0 °C was added dropwise 1.06 M
MeLi/ether (2.46 mL, 2.58 mmol). After the reaction mixture
was stirred at 25 °C for 0.5 h, the reaction was quenched with
ice-cold water (20 mL), and the resultant mixture was then
extracted with ether (8 mL × 3). The extracts were washed
with saturated aqueous NaCl (20 mL), dried over anhydrous
Na2SO4, and concentrated in vacuo. Purification of the residue
by flash column chromatography (50 g of silica gel, 50:1
n-hexane-acetone) gave 43 (0.407 g, 79%) as a pale yellow
Allyl Alcoh ol 50. To a stirred solution of 49 (0.343 g, 0.578
mmol) in dry toluene (10.3 mL) at -78 °C was added dropwise
1.02 M diisobutylalminum hydride/toluene (1.26 mL, 1.27
mmol). After the reaction mixture was stirred at -78 °C for
5 min, the reaction was carefully quenched with methanol, and
the resultant mixture was then allowed to warm to 25 °C. A
solution of potassium sodium tartrate tetrahydrate (1.63 g,
5.78 mmol) in water (8.16 mL) was added to the mixture, and
the resultant mixture was then extracted with ether (5 mL ×
3). The extracts were washed with saturated aqueous NaCl
(10 mL), dried over anhydrous Na2SO4, and concentrated in
vacuo. Purification of the residue by flash column chroma-
tography (31 g of silica gel, 4:1 n-hexane-ethyl acetate) gave
oil: Rf 0.24 (5:1 n-hexane-acetone); [R]27 +14.7° (c 2.46,
D
CHCl3); 1H-NMR δ 0.63-0.75 (4H, m), 0.89 (3H, d, J ) 6.6
Hz), 0.97-1.07 (16H, m), 1.12 (3H, d, J ) 6.8 Hz), 1.365 and
1.37 (3H, each s), 1.385 and 1.39 (3H, each s), 1.73-2.00 (4H,
m), 1.76 (3H, s), 2.27 (1H, br dd, J ) 12.4, 3.0 Hz), 2.70 (1H,
t, J ) 5.9 Hz), 3.29 (3H, s), 3.45-3.78 (5H, m), 3.83 (1H, dd,
J ) 8.9, 2.3 Hz), 4.09 (1H, dd, J ) 11.8, 2.4 Hz), 5.38 and 5.41
(1H, each dd, J ) 15.2, 7.2 Hz), 5.87 (1H, d, J ) 10.8 Hz), 6.45
(1H, dd, J ) 15.2, 10.8 Hz); HRMS (EI) m/z 498.3744 (498.3741
calcd for C28H54O5Si, M+).
50 (0.301 g, 97%) as a colorless oil: Rf 0.23 (5:1 n-hexane-
1
ethyl acetate); [R]28 +17.9° (c 1.03, CHCl3); H-NMR δ 0.64
D
(4H, q, J ) 7.9 Hz), 0.78 (3H, d, J ) 6.4 Hz), 0.94-1.05 (16H,
m), 1.11 (3H, d, J ) 6.8 Hz), 1.365 and 1.37 (3H, each s), 1.385
and 1.39 (3H, each s), 1.69 (3H, d, J ) 1.4 Hz), 1.72-1.85 (3H,
m), 1.74 (3H, s), 2.30 (1H, m), 2.61 (1H, m), 3.28 (3H, s), 3.45-
3.55 (2H, m), 3.60 (1H, dd, J ) 11.8, 1.8 Hz), 3.83 (1H, dd, J
) 8.4, 2.4 Hz), 4.00 (2H, br d, J ) 5.5 Hz), 4.09 (1H, dd, J )
11.8, 2.6 Hz), 5.87 and 5.89 (1H, each dd, J ) 15.6, 7.6 Hz),
5.57 (1H, dd, J ) 9.6, 1.4 Hz), 5.85 (1H, d, J ) 11.0 Hz), 6.44
(1H, dd, J ) 15.6, 11.0 Hz); HRMS (EI) m/z 538.4040 (538.4054
calcd for C31H58O5Si, M+).
P h osp h on ic Ester 47. To a stirred solution of 46 (0.200
g, 0.833 mmol) in dry THF (1.0 mL) at -78 °C was added 1 M
NaN(TMS)2/THF (1.25 mL, 1.25 mmol). After the reaction
mixture was stirred at -78 °C for 0.5 h, a solution of 45 (0.243
g, 1.25 mmol) in dry THF (1.62 mL) was added to the reaction
mixture. The resultant mixture was further stirred at 25 °C
for 12 h, and the reaction was quenched with saturated
aqueous NH4Cl (5 mL) under ice-cooling. The resultant
mixture was extracted with ether (5 mL × 3). The extracts
were washed with saturated aqueous NaCl (7 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (25 g of silica
gel, 10:1 chloroform-methanol then 25 g of silica gel, 3:2
n-hexane-acetone) gave 47 (0.0910 g, 39%) and the trans
isomer (0.0769 g, 33%) as colorless oils. 47: Rf 0.51 (3:1
Ald eh yd e 51. To a solution of 50 (0.980 g, 1.82 mmol) in
dry CH2Cl2 (29.4 mL) was added MnO2 (4.74 g, 54.5 mmol).
After the reaction mixture was stirred at 25 °C for 2 h, the
mixture was filtered through Celite, and the filter cake was
washed with CH2Cl2. The filtrate and washings were com-
bined and concentrated in vacuo. Purification of the residue
by flash column chromatography (100 g of silica gel, 8:1
n-hexane-ethyl acetate) gave 51 (0.976 g, 100%) as a colorless
oil: Rf 0.47 (4:1 n-hexane-ethyl acetate); [R]27D +21.7° (c 0.90,
1
n-hexane-acetone); H-NMR δ 1.25-1.38 (9H, m), 3.27 (1H,
m), 3.72 (3H, s), 3.80 (3H, s), 4.05-4.20 (4H, m), 6.14 (1H, dd,
J ) 11.0, 6.2 Hz). Anal. Calcd for C11H21O6P: C, 47.14; H,
7.55. Found: C, 46.89; H, 7.29. Trans isomer of 47: Rf 0.49
(3:1 n-hexane-acetone); 1H-NMR δ 1.25-1.38 (9H, m), 3.64
(3H, s), 3.83 (3H, s), 3.94 (1H, m), 4.03-4.18 (4H, m), 5.10 (1H,
dd, J ) 11.0, 8.0 Hz). Anal. Calcd for C11H21O6P: C, 47.14;
H, 7.55. Found: C, 46.90; H, 7.27.
1
CHCl3); H-NMR δ 0.67 (4H, q, J ) 7.8 Hz), 0.75 (3H, d, J )
6.4 Hz), 0.95-1.15 (19H, m), 1.365 and 1.37 (3H, each s), 1.38
and 1.39 (3H, each s), 1.68-1.90 (3H, m), 1.74 (3H, s), 1.78
(3H, d, J ) 1.6 Hz), 2.22 (1H, m), 2.91 (1H, m), 3.28 (3H, s),
3.50 (1H, m), 3.57-3.65 (2H, m), 3.82 and 3.83 (1H, each dd,
J ) 8.4, 2.4 Hz), 4.09 (1H, dd, J ) 11.8, 2.6 Hz), 5.39 and 5.41
(1H, dd, J ) 15.4, 7.0 Hz), 5.85 (1H, d, J ) 10.8 Hz), 6.44 (1H,
dd, J ) 15.4, 10.8 Hz), 6.78 (1H, dd, J ) 10.0, 1.6 Hz), 9.42
(1H, s); HRMS (EI) m/z 537.3975 (537.3975 calcd for C31H57O5-
Si, M + H+).
Eth yl Ester 49. To a stirred solution of oxalyl chloride
(0.136 mL, 1.56 mmol) in dry CH2Cl2 (3.68 mL) at -78 °C was
added dropwise a solution of dimethyl sulfoxide (0.207 mL,
3.12 mmol) in dry CH2Cl2 (0.519 mL). After the reaction
mixture was stirred at -78 °C for 3 min, a solution of 43 (0.389
g, 0.780 mmol) in dry CH2Cl2 (2.34 mL) was added to the
reaction mixture. After the resultant mixture was stirred at
-78 °C for 20 min, triethylamine (0.654 mL, 4.68 mmol) was
added, and the resultant mixture was allowed to warm to 0
°C over 40 min with stirring. The reaction was quenched with
water (15 mL) and the resultant mixture was then extracted
with a mixture of benzene-ether (4:1, 10 mL × 3). The
extracts were washed with saturated aqueous NaCl (20 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo. To
a stirred solution of the crude oil (0.388 g) in dry toluene (11.6
mL) was added ethyl 2-(triphenylphosphoranylidene)pro-
pionate 48 (2.32 g, 7.02 mmol). After the reaction mixture
Meth yl Ester 52. To a solution of 46 (0.570 g, 2.37 mmol)
in dry THF (5.70 mL) at -78 °C was added dropwise 1.0 M
NaN(TMS)2/THF (2.28 mL, 2.28 mmol) with stirring. After
the reaction mixture was stirred at -78 °C for 0.5 h, a solution
of 51 (0.255 g, 0.475 mmol) in dry THF (2.50 mL) was added
to the reaction mixture at -78 °C. After the resultant mixture
was stirred at 25 °C for 0.5 h, the reaction was quenched with
saturated aqueous NH4Cl (10 mL) under ice-cooling, and the
resultant mixture was then extracted with ether (5 mL × 3).
The extracts were washed with saturated aqueous NaCl (10
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography

Total Synthesis of Bafilomycin A1
J . Org. Chem., Vol. 62, No. 10, 1997 3283
(30 g of silica gel, 6:1 n-hexane-ethyl acetate) gave 52 (0.589
g, 89%) as a colorless oil and a mixture of cis- and trans-
isomers (Z/E ) 2/1): Rf 0.45 (6:1 n-hexane-acetone); 1H-NMR
δ 0.57-0.70 (4H, m), 0.76 and 0.78 (3H, each d, J ) 6.4 Hz),
0.93-1.05 (16H, m), 1.11 (3H, d, J ) 6.8 Hz), 1.355 and 1.36
(3H, each s), 1.38 and 1.39 (3H, each s), 1.70-1.85 (3H, m),
1.73 (3H, s), 1.99 (3H, d, J ) 1.4 Hz), 2.20-2.37 (1H, m), 2.55-
2.78 (1H, m), 3.28 (3H, s), 3.43-3.55 (2H, m), 3.56 (1H, dd, J
) 11.9, 1.5 Hz), 3.63 (1/3 × 3H, s), 3.65 (2/3 × 3H, s), 3.76 (1/3
× 3H, s), 3.80 (2/3 × 3H, s), 3.82 (1H, dd, J ) 8.6, 2.3 Hz),
4.09 (1H, dd, J ) 11.9, 2.4 Hz), 5.37 and 5.39 (1H, each dd, J
) 15.4, 7.2 Hz), 5.48 (1/3H, d, J ) 9.9 Hz), 5.60 (1/3H, s), 5.85
(1H, d, J ) 10.8 Hz), 6.03 (2/3H, d, J ) 9.9 Hz), 6.44 (1H, dd,
J ) 15.4, 10.8 Hz), 6.61 (2/3H, s). Anal. Calcd for C31H62O7-
Si: C, 67.48; H, 10.03. Found: C, 67.48; H, 10.28.
(1H, m), 3.69 (3H, s), 3.75-3.83 (1H, m), 3.78 (3H, s), 5.44 (1H,
dd, J ) 15.4, 8.6 Hz), 5.82 (1H, d, J ) 10.8 Hz), 6.07 (1H, d, J
) 10.0 Hz), 6.22 and 6.24 (1H, each dd, J ) 15.4, 10.8 Hz),
6.74 (1H, s), 6.83 (2H, d, J ) 8.4 Hz), 7.15-7.35 (8H, m), 7.43
(4H, d, J ) 7.2 Hz); MS (ESI) m/z 858 (858 calcd for C51H76
-
NO8Si, M + NH4+). 56: Rf 0.27 (2:1 n-hexane-acetone); [R]28
D
+5.8° (c 1.19, CHCl3); 1H-NMR δ 0.63 (4H, q, J ) 7.9 Hz), 0.75
and 0.755 (3H, each d, J ) 6.4 Hz), 0.92-1.05 (16H, m), 1.16
(3H, d, J ) 6.8 Hz), 1.65-1.88 (3H, m), 1.69 (3H, s), 1.80 (3H,
s), 1.90-2.05 (1H, m), 2.25-2.43 (1H, m), 2.55-2.70 (1H, m),
3.03 (1H, dd, J ) 8.6, 4.2 Hz), 3.18-3.28 (1H, m), 3.20 (3H, s),
3.38 (1H, dd, J ) 8.5, 6.4 Hz), 3.42-3.48 (1H, m), 3.67 (3H, s),
3.76-3.82 (1H, m), 3.78 (3H, s), 5.44 (1H, dd, J ) 15.4, 8.6
Hz), 5.56 (1H, d, J ) 9.9 Hz), 5.80 (1H, s), 5.83 (1H, d, J )
10.8 Hz), 6.22 and 6.24 (1H, each dd, J ) 15.4, 10.8 Hz), 6.83
(2H, d, J ) 8.4 Hz), 7.15-7.35 (8H, m), 7.43 (4H, d, J ) 7.2
Hz); MS (ESI) m/z 858 (858 calcd for C51H76NO8Si, M + NH4+).
Diol 53. To a stirred solution of 52 (0.104 g, 0.166 mmol)
in dry MeOH (3.10 mL) at -20 °C was added pyridinium
p-toluenesulfonate (41.7 mg, 0.166 mmol). After the reaction
mixture was stirred at 25 °C for 0.5 h, the reaction was
quenched with saturated aqueous NaHCO3 (5 mL) under ice-
cooling, and the resultant mixture was then extracted with
ether (3 mL × 3). The extracts were washed with saturated
aqueous NaCl (4 mL), dried over anhydrous Na2SO4, and
concentrated in vacuo. Purification of the residue by flash
column chromatography (10 g of silica gel, 1:1 n-hexane-ethyl
acetate) gave 53 (0.0954 g, 98%) as a colorless oil: Rf 0.26 (1:1
La cton e 57. A solution of 55 (0.145 g, 0.172 mmol) in dry
THF (1.72 mL) were added triethylamine (0.0528 mL, 0.378
mmol) and 2,4,6-trichlorobenzoyl chloride (0.0537 mL, 0.344
mmol). After the reaction mixture was stirred at 25 °C for 2
h, the resultant triethylamine hydrochloride was then filtered
off, and the filtrate was diluted with dry toluene (86.0 mL)
under argon. This solution was then added slowly at 110 °C
to a solution of 4-(dimethylamino)pyridine (0.210 g, 1.72 mmol)
in dry toluene (2.87 mL). After the addition was complete,
the resultant mixture was further stirred at 110 °C for 15 h
and then diluted with water (100 mL) at 25 °C. The resultant
mixture was extracted with ether (30 mL × 3). The extracts
were washed with saturated aqueous NaCl (50 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (15 g of silica
gel, 10:1 n-hexane-ethyl acetate) gave 57 (0.0596 g, 42%) as
1
n-hexane-ethyl acetate); H-NMR δ 0.58-0.70 (4H, m), 0.74
and 0.76 (3H, each d, J ) 6.4 Hz), 0.92-1.06 (19H, m), 1.65-
1.85 (3H, m), 1.73 (3H, s), 1.98 (3H, s), 2.15-2.23 (2H, m),
2.23-2.38 (1H, m), 2.55-2.78 (1H, m), 3.27 (3H, s), 3.42-3.82
(5H, m), 3.63 (1/3 × 3H, s), 3.65 (2/3 × 3H, s), 3.76 (1/3 × 3H,
s), 3.80 (2/3 × 3H, s), 5.43 (1H, dd, J ) 15.2, 8.6 Hz), 5.46
(1/3H, d, J ) 9.8 Hz), 5.58 and 5.60 (1/3H, each s), 5.86 (1H,
d, J ) 10.8 Hz), 6.00 (2/3H, d, J ) 9.8 Hz), 6.52 (1H, dd, J )
15.2, 10.8 Hz), 6.59 and 6.61 (2/3H, each s). Anal. Calcd for
C32H58O7Si: C, 65.94; H, 10.03. Found: C, 65.70; H, 10.27.
Tr ityl Eth er 54. To an ice-cold solution of 53 (0.236 g,
0.404 mmol) in dry CH2Cl2 (7.10 mL) were added triethylamine
(0.169 mL, 1.21 mmol), 4-(dimethylamino)pyridine (2.47 mg,
0.0202 mmol) and (p-methoxyphenyl)diphenylmethyl chloride
(0.274 g, 0.889 mmol) with stirring. After the reaction mixture
was stirred at 25 °C for 5 h, the reaction was quenched with
water (10 mL), and the resultant mixture was extracted with
ether (3 mL × 3). The extracts were washed with saturated
aqueous NaCl (5 mL), dried over anhydrous Na2SO4, and con-
centrated in vacuo. Purification of the residue by flash column
chromatography (35 g of silica gel, 5:1 n-hexane-ethyl acetate)
gave 54 (0.313 g, 91%) as a colorless oil: Rf 0.69 (2:1 n-hexane-
acetone); 1H-NMR δ 0.57-0.69 (4H, m), 0.73 and 0.74 (3H,
each d, J ) 6.4 Hz), 0.93-1.06 (16H, m), 1.15 (3H, d, J ) 6.8
Hz), 1.67-1.80 (3H, m), 1.68 (3H, s), 1.98 (3H, s), 2.20-2.35
(1H, m), 2.50 (1/3H, d, J ) 2.4 Hz), 2.53 (2/3H, d, J ) 2.4 Hz),
2.55-2.78 (1H, m), 3.04 (1H, m), 3.17-3.53 (4H, m), 3.20 (3H,
s), 3.63 (1/3 × 3H, s), 3.65 (2/3 × 3H, s), 3.78 and 3.79 (6H,
each s), 5.44 (1H, dd, J ) 15.4, 8.4 Hz), 5.46 (1/3H, d, J ) 9.8
Hz), 5.59 (1/3H, s), 5.82 (1H, d, J ) 11.0 Hz), 6.01 (2/3H, d, J
) 9.8 Hz), 6.22 (1/3H, dd, J ) 15.4, 11.0 Hz), 6.25 (2/3H, dd,
J ) 15.4, 11.0 Hz), 6.60 and 6.61 (2/3H, each s), 6.83 (2H, d,
J ) 8.8 Hz), 7.15-7.37 (8H, m), 7.44 (4H, d, J ) 7.4 Hz); MS
(ESI) m/z 872 (872 calcd for C52H78NO8Si, M + NH4+).
a colorless oil: Rf 0.53 (3:1 n-hexane-ethyl acetate); [R]22
D
1
-178° (c 0.33, CHCl3); H-NMR δ 0.65-0.80 (4H, m), 0.95-
1.15 (22H, m), 1.53 (3H, s), 1.62-1.80 (2H, m), 1.92 (3H, d, J
) 1.4 Hz), 1.95-2.10 (1H, m), 2.33-2.48 (1H, m), 2.61 (1H,
dd, J ) 14.6, 9.6 Hz), 3.07 (1H, dd, J ) 9.9, 4.9 Hz), 3.17 (1H,
dd, J ) 9.9, 5.6 Hz), 3.22 (3H, s), 3.63 (1H, br s), 3.65 (3H, s),
3.79 (3H, s), 3.85 (1H, br d, J ) 3.9 Hz), 5.15 (1H, dd, J ) 8.3,
1.6 Hz), 5.40 (1H, dd, J ) 15.4, 4.0 Hz), 5.90 (1H, d, J ) 11.0
Hz), 5.94 (1H, d, J ) 10.0 Hz), 6.43 (1H, ddd, J ) 15.4, 11.0,
1.4 Hz), 6.69 (1H, s), 6.83 (2H, d, J ) 8.4 Hz), 7.17-7.38 (8H,
m), 7.47 (4H, d, J ) 8.2 Hz). Anal. Calcd for C51H70O7Si: C,
74.41; H, 8.57. Found: C, 74.16; H, 8.78.
Alcoh ol 58. To a stirred solution of 57 (83.4 mg, 0.101
mmol) in dry MeOH (2.50 mL) at 0 °C was added pyridinium
p-toluenesulfonate (22.5 mg, 0.101 mmol). After the reaction
mixture was stirred at 25 °C for 14 h and then poured into
ice-cold saturated aqueous NaHCO3 (3 mL), the resultant
mixture was extracted with ethyl acetate (1 mL × 3). The
extracts were washed with saturated aqueous NaCl (3 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(6 g of silica gel, 2:1 n-hexane-ethyl acetate) gave 58 (44.6
mg, 80%) as a colorless oil: Rf 0.23 (2:1 n-hexane-ethyl
acetate); [R]26 -192° (c 0.24, CHCl3); 1H-NMR δ 0.64-0.83
D
(4H, m), 0.90 (3H, d, J ) 6.8 Hz), 0.98-1.13 (19H, m), 1.68
(3H, s), 1.70-1.85 (2H, m), 1.94 (3H, s), 2.05-2.25 (1H, m),
2.40-2.55 (2H, m), 3.00 (1H, dd, J ) 8.6, 5.4 Hz), 3.29 (3H, s),
3.30-3.43 (1H, m), 3.47-3.60 (1H, m), 3.62 (1H, t, J ) 2.8
Hz), 3.67 (3H, s), 3.94 (1H, dd, J ) 5.7, 5.7 Hz), 5.12 (1H, dd,
J ) 4.4, 3.8 Hz), 5.39 (1H, dd, J ) 15.4, 6.2 Hz), 5.88 (1H, d,
J ) 9.2 Hz), 5.92 (1H, d, J ) 10.8 Hz), 6.47 (1H, dd, J ) 15.4,
10.8 Hz), 6.67 (1H, s); HRMS (EI) m/z 550.3698 (550.3690 calcd
for C31H54O6Si, M+).
seco-Acid 55. To an ice-cold solution of 54 (0.275 g, 0.321
mmol) in dioxane (8.25 mL) was added dropwise 1 M aqueous
KOH (3.21 mL, 3.21 mmol). After the reaction mixture was
stirred at 80 °C for 2 h, the reaction was neutralized with ion-
exchange resin CG-50, the resultant mixture was filtered, and
the resin was washed with dioxane. The combined filtrate and
washings were concentrated in vacuo. Purification of the
residue by flash column chromatography (50 g of silica gel,
1:2 n-hexane-ethyl acetate) gave 55 (0.167 g, 64%) and 56
(0.0832 g, 32%) as colorless oils. 55: Rf 0.35 (2:1 n-hexane-
acetone); [R]28D +20.5° (c 2.19, CHCl3); 1H-NMR δ 0.64 (4H, q,
J ) 7.9 Hz), 0.73 and 0.74 (3H, each d, J ) 6.4 Hz), 0.93-1.07
(16H, m), 1.15 (3H, d, J ) 6.8 Hz), 1.67-1.83 (3H, m), 1.69
(3H, s), 1.92-2.05 (1H, m), 2.00 (3H, s), 2.20-2.35 (1H, m),
2.65-2.80 (1H, m), 3.03 (1H, dd, J ) 8.6, 4.2 Hz), 3.15-3.27
(1H, m), 3.20 (3H, s), 3.38 (1H, dd, J ) 8.6, 6.4 Hz), 3.45-3.53
Ald eh yd e 2. To a stirred solution of oxalyl chloride (0.0127
mL, 0.146 mmol) in dry CH2Cl2 (0.342 mL) at -78 °C was
added dropwise a solution of dimethyl sulfoxide (0.0194 mL,
0.0729 mmol) in dry CH2Cl2 (0.0486 mL). After the reaction
mixture was stirred at -78 °C for 3 min, a solution of 58 (40.2
mg, 0.0729 mmol) in dry CH2Cl2 (0.241 mL) was added to the
reaction mixture. After the resultant mixture was stirred at
-78 °C for 20 min, triethylamine (0.0612 mL, 0.438 mmol)
was added, and the resultant mixture was allowed to warm
to 0 °C over 40 min with stirring. The reaction was quenched

3284 J . Org. Chem., Vol. 62, No. 10, 1997
Toshima et al.
with water (3 mL), and the resultant mixture was then
extracted with a mixture of benzene-ether (4:1, 2 mL × 3).
The extracts were washed with saturated aqueous NaCl (3
mL), dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(5 g of silica gel, 5:1 n-hexane-acetone) gave 2 (29.8 mg, 74%)
as a colorless oil: Rf 0.22 (8:1 n-hexane-acetone); [R]30D -180°
(c 1.20, CHCl3); 1H-NMR δ 0.67-0.80 (4H, m), 0.98-1.13 (13H,
m), 1.01 (3H, d, J ) 7.0 Hz), 1.05 (3H, d, J ) 7.0 Hz), 1.17
(3H, d, J ) 7.0 Hz), 1.68 (3H, s), 1.7-1.8 (2H, m), 1.93 (3H, d,
J ) 1.3 Hz), 2.40-2.55 (2H, m), 2.78 (1H, ddq, J ) 9.2, 7.0,
1.9 Hz), 3.31 (3H, s), 3.62 (1H, dd, J ) 2.4, 1.9 Hz), 3.65 (3H,
s), 3.87 (1H, dd, J ) 6.0, 5.6 Hz), 5.31 (1H, dd, J ) 5.6, 5.4
Hz), 5.36 (1H, dd, J ) 15.2, 6.0 Hz), 5.87 (1H, d, J ) 9.2 Hz),
5.92 (1H, d, J ) 11.0 Hz), 6.50 (1H, dd, J ) 15.2, 11.0 Hz),
6.62 (1H, s), 9.77 (1H, d, J ) 1.8 Hz); HRMS (EI) m/z 548.3510
(548.3533 calcd for C31H52O6Si, M+).
Hz), 5.83 (1H, d, J ) 9.6 Hz), 5.90 (1H, d, J ) 11.0 Hz), 6.45
(1H, dd, J ) 15.6, 11.0 Hz), 6.62 (1H, s); MS (ESI) m/z 908
(908 calcd for C50H94NO9Si2, M + NH4+).
Ba filom ycin A1 (1). To an ice-cold solution of 60 (22.4 mg,
0.0250 mmol) in dry THF (0.67 mL) were added acetic acid
(0.0072 mL, 0.125 mmol) and 1 M TBAF/THF (0.125 mL, 0.125
mmol) with stirring. After the reaction mixture was stirred
at 60 °C for 12 h, the mixture was poured into ice-cold
saturated aqueous NaHCO3 (2 mL), and the resultant mixture
was then extracted with ethyl acetate (1 mL × 3). The extracts
were washed with saturated aqueous NaCl (2 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification
of the residue by flash column chromatography (2 g of silica
gel, 3:2 n-hexane-ethyl acetate) gave 1 (7.0 mg, 45%) as a
white solid: Rf 0.37 (1:1 n-hexane-ethyl acetate); [R]30D -3.34°
(c 0.26, CH2Cl2) [[R]30 of natural bafilomycin A1: -3.07° (c
D
0.26, CH2Cl2)]; mp 97.0-98.0 °C [mp of natural bafilomycin
A1: 98.0-99.0 °C]; mixed mp 97.5-99.0 °C; IR (KBr) 3440,
2966, 2933, 2875, 2372, 2345, 1688, 1625, 1467, 1365, 1247,
1110, 966, 915, 758, 591 cm-1; 1H-NMR δ 0.77 (3H, d, J ) 6.7
Hz), 0.83 (3H, d, J ) 6.7 Hz), 0.90 (3H, d, J ) 6.8 Hz), 0.93
(3H, d, J ) 6.4 Hz), 0.94 (3H, d, J ) 6.4 Hz), 1.04 (3H, d, J )
7.2 Hz), 1.06 (3H, d, J ) 7.0 Hz), 1.16 (1H, ddd, J ) 11.9, 11.0,
2.0 Hz), 1.33 (1H, m), 1.45-1.70 (2H, br), 1.76 (1H, br q, J )
7.2 Hz), 1.89 (1H, m), 1.94 (3H, s), 1.95 (1H, m), 1.98 (3H, d,
J ) 1.0 Hz), 2.07-2.20 (2H, m), 2.30 (1H, dd, J ) 11.9, 4.6
Hz), 2.54 (1H, ddq, J ) 9.2, 7.0, 1.9 Hz), 3.25 (3H, s), 3.29
(1H, br), 3.49 (1H, dd, J ) 10.2, 2.2 Hz), 3.64 (3H, s), 3.68
(1H, ddd, J ) 11.0, 9.9, 4.6 Hz), 3.89 (1H, dd, J ) 9.2, 8.9 Hz),
4.14 (1H, ddd, J ) 11.0, 4.0, 2.0 Hz), 4.63 (1H, d, J ) 4.0 Hz),
4.96 (1H, dd, J ) 8.9, 1.2 Hz), 5.17 (1H, dd, J ) 15.2, 9.2 Hz),
5.51 (1H, d, J ) 2.0 Hz), 5.78 (1H, br d, J ) 9.2 Hz), 5.81 (1H,
d, J ) 10.6 Hz), 6.51 (1H, dd, J ) 15.2, 10.6 Hz), 6.67 (1H, s);
HRMS (EI) m/z 623.4161 (623.4159 calcd for C35H59O9, M +
H+). The 1H-NMR and IR spectra were identical with those
of the authentic sample of bafilomycin A1.
Ald ol 60. To a stirred solution of 3 (29.8 mg, 0.0872 mmol)
in dry CH2Cl2 (0.348 mL) at -78 °C were added dropwise
PhBCl2 (0.0113 mL, 0.0872 mmol) and i-Pr2NEt (0.0152 mL,
0.0872 mmol). After the reaction mixture was stirred at -78
°C for 0.5 h and at 0 °C for 0.5 h, a solution of 2 (24.0 mg,
0.0436 mmol) in dry CH2Cl2 (0.218 mL) was added to the
reaction mixture at -78 °C. The resultant mixture was
further stirred at -78 °C for 2.5 h, and the reaction was
quenched with pH 7 phosphate buffer (2 mL). The resultant
mixture was then extracted with ether (1 mL × 3). The
extracts were washed with saturated aqueous NaCl (2 mL),
dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification of the residue by flash column chromatography
(4 g of silica gel, 5:1 n-hexane-ethyl acetate and then 4 g of
silica gel, 10:1 chloroform-ethyl acetate) gave 60 (22.2 mg,
57%) and 61 (0.4 mg, 1%) as colorless oils. 60: Rf 0.16 (10:1
1
chloroform-ethyl acetate); [R]28 -42.7° (c 0.44, CHCl3); H-
D
NMR δ 0.68-0.80 (4H, m), 0.73 (3H, d, J ) 7.2 Hz), 0.85 (3H,
d, J ) 6.9 Hz), 0.91 (3H, d, J ) 7.0 Hz), 0.95-1.12 (22H, m),
0.95 (9H, s), 0.97 (9H, s), 1.16 (3H, d, J ) 7.2 Hz), 1.65-1.85
(3H, m), 1.66 (3H, s), 1.94 (3H, s), 1.98 (1H, m), 2.20 (1H, m),
2.4-2.55 (2H, m), 2.45 (1H, dd, J ) 15.4, 3.6 Hz), 2.80 (1H,
dd, J ) 15.4, 10.0 Hz), 2.83 (1H, ddq, J ) 9.2, 7.0, 2.2 Hz),
3.28 (3H, s), 3.60-3.70 (3H, m), 3.66 (3H, s), 3.81 (1H, ddd, J
) 9.8, 4.0, 2.4 Hz), 3.96 (1H, dd, J ) 6.0, 4.0 Hz), 4.66 (1H,
ddd, J ) 10.0, 5.9, 3.6 Hz), 5.29 (1H, dd, J ) 4.0, 2.6 Hz), 5.43
(1H, dd, J ) 15.6, 6.0 Hz), 5.90 (1H, d, J ) 9.2 Hz), 5.93 (1H,
d, J ) 11.2 Hz), 6.47 (1H, dd, J ) 15.6, 11.2 Hz), 6.68 (1H, s);
MS (ESI) m/z 908 (908 calcd for C50H94NO9Si2, M + NH4+).
61: Rf 0.22 (10:1 chloroform-ethyl acetate); 1H-NMR δ 0.66-
0.82 (4H, m), 0.78 (3H, d, J ) 7.2 Hz), 0.87 (3H, d, J ) 6.6
Hz), 0.95-1.10 (25H, m), 0.98 (9H, s), 1.00 (9H, s), 1.19 (3H,
d, J ) 6.9 Hz), 1.65-1.85 (3H, m), 1.66 (3H, s), 1.93 (3H, s),
1.95-2.08 (1H, m), 2.15-2.30 (1H, m), 2.35-2.58 (2H, m), 2.58
(1H, dd, J ) 14.4, 3.8 Hz), 2.74 (1H, dd, J ) 14.4, 10.2 Hz),
2.88 (1H, d, J ) 3.6 Hz), 3.29 (3H, s), 3.35-3.47 (1H, m), 3.58-
3.70 (2H, m), 3.64 (3H, s), 3.78 (1H, ddd, J ) 7.6, 3.9, 3.2 Hz),
3.88 (1H, dd, J ) 6.2, 5.2 Hz), 4.78 (1H, ddd, J ) 9.8, 6.0, 3.8
Hz), 4.98 (1H, dd, J ) 5.0, 3.9 Hz), 5.34 (1H, dd, J ) 15.6, 7.0
Ack n ow led gm en t. We are grateful to Emeritus
Prof. M. Kinoshita (Keio University) and Prof. K.
Tatsuta (Waseda University) for their stimulating and
helpful discussions. We also sincerely thank Prof. A.
Zeeck (Georg-August-Universita¨t Go¨ttingen), Profs. H.
Hagenmaier, H. Za¨hner, and H.-P. Fiedler (Eberhard-
Karls-Unibersita¨t Tu¨bingen), Prof. W. Keller-Schierlein
(Eidgeno¨ssischen Technischen Hochschule), Dr. R. J . J .
Dorgan (SmithKline Beecham), and Dr. H. H. Peter
(Ciba-Geigy Ltd.) for supplying authentic samples of
bafilomycin A1 and other bafilomycins. We are indebted
to Mr. K. Hokazono of Keio University for elemental
analyses and Ms. T. Miyara of Pharmaceutical Research
Center, Meiji Seika Kaisha, Ltd., for measurement of
MS(ESI). Financial support by The Naito Foundation
is gratefully acknowledged.
J O970314D