Studies on the synthesis of bafilomycin A1: Stereochemical aspects of the fragment assembly aldol reaction for construction of the C(13)-C(25) segment

Article abstract of DOI:10.1021/jo016413f

Highly stereoselective syntheses of aldols 8a-c corresponding to the C(13)-C(25) segment of bafilomycin A₁ were developed by routes involving fragment assembly aldol reactions of chiral aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium enolates of 7a,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group. Studies of the reactions of chiral aldehydes with Takai's (y-methoxyallyl)chromium reagent 40 are also described. The stereoselectivity of these reactions is also highly dependent on the protecting groups and stereochemistry of the chiral aldehyde substrates.

Full text of DOI:10.1021/jo016413f

J . Org. Chem. 2002, 67, 4275-4283
4275
Stu d ies on th e Syn th esis of Ba filom ycin A1: Ster eoch em ica l
Asp ects of th e F r a gm en t Assem bly Ald ol Rea ction for
Con str u ction of th e C(13)-C(25) Segm en t
William R. Roush,*,1 Thomas D. Bannister,2 Michael D. Wendt,2 J ill A. J ablonowski,2 and
Karl A. Scheidt3
Departments of Chemistry, Indiana University, Bloomington, Indiana 47405, and University of Michigan,
Ann Arbor, Michigan 48109
roush@umich.edu
Received December 28, 2001
Highly stereoselective syntheses of aldols 8a -c corresponding to the C(13)-C(25) segment of
bafilomycin A1 were developed by routes involving fragment assembly aldol reactions of chiral
aldehyde 6a and the chiral methyl ketones 7. A remote chelation effect plays a critical role in
determining the stereoselectivity of the key aldol coupling of 6a and the lithium enolate of 7b. The
protecting group for C(23)-OH of the chiral aldehyde fragment also influences the selectivity of
the lithium enolate aldol reaction. In contrast, the aldol reaction of 6a and the chlorotitanium
enolates of 7a ,c were much less sensitive to the nature of the C(15)-hydroxyl protecting group.
Studies of the reactions of chiral aldehydes with Takai’s (γ-methoxyallyl)chromium reagent 40 are
also described. The stereoselectivity of these reactions is also highly dependent on the protecting
groups and stereochemistry of the chiral aldehyde substrates.
Bafilomycin A1 (1),4 a member of the hygrolide family
of macrolide antibiotics,5 is a potent vacuolar H+-ATPase
inhibitor that displays broad antibacterial and antifungal
activity.6 The stereochemistry of bafilomycin A1, and of
the hydrolide family in general, was initially assigned
by Corey on the basis of a molecular modeling analysis
of published NMR data.5 The stereostructural assignment
of 1 was subsequently verified by X-ray crystallography.7,8
Other members of this family include the hygrolidins
(e.g., hygrolidin, 2), which are active against SV-40
transformed C-3H-2K cells,9,10 leucanicidin, which has
antifungal and insecticidal activity,11 L-681,110A1, an
inhibitor of Na+/K+-ATPase,12 and L-155,175, which has
antiparasitic activity.13 The concanamycins (e.g., concano-
mycin A, 3), are 18-membered lactone congeners which
also are potent vacuolar H+-ATPase inhibitors.14 The
newest member of this family is formamicin, 4, which
displays significant cytotoxicity against murine tumor cell
lines in vitro, particularly leukemia cells.15,16
(1) Address correspondence to this author at the Department of
Chemistry, University of Michigan, Ann Arbor, MI 48109-1055.
(2) Indiana University.
(3) University of Michigan.
(4) Werner, G.; Hagenmaier, H.; Drautz, H.; Baumgartner, A.;
Za¨hner, H. J . Antibiot. 1984, 37, 110.
(5) Corey, E. J .; Ponder, J . W. Tetrahedron Lett. 1984, 25, 4325.
(6) Bowman, E. J .; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci.
U.S.A. 1988, 85, 7972.
(7) 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.
(8) Baker, G. H.; Brown, P. J .; Dorgan, R. J . J .; Everett, J . R. J .
Chem. Soc., Perkin Trans. 2 1989, 1073 and references therein.
(9) Seto, H.; Tajima, I.; Akao, H.; Furihata, K.; Otake, N. J . Antibiot.
1984, 37, 610.
(10) Seto, H.; Akao, H.; Furihata, K.; Otake, N. Tetrahedron Lett.
1982, 23, 2667.
(11) Isogai, A.; Sakuda, S.; Matsumoto, S.; Ogura, M.; Furihata, K.;
Seto, H.; Suzuki, A. Agric. Biol. Chem. 1984, 48, 1379.
(12) Hensens, O. D.; Monaghan, R. L.; Huang, L. Y.; Albers-
Scho¨nberg, G. J . Am. Chem. Soc. 1983, 105, 3672.
(13) Goetz, M. A.; McCormick, P. A.; Monaghan, R. L.; Ostlind, D.
A.; Hensens, O. D.; Liesch, J . M.; Albers-Scho¨nberg, G. J . Antibiot.
1985, 38, 161.
The interesting biological activity of this group of
compounds has stimulated interest both in the semisyn-
thesis of analogues,17-19 as well as the chemical synthesis
(14) Kinashi, H.; Someno, K.; Sakaguchi, K.; Higashijima, T.;
Miyazawa, T. Tetrahedron Lett. 1981, 22, 3861.
10.1021/jo016413f CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/21/2002

4276 J . Org. Chem., Vol. 67, No. 12, 2002
Roush et al.
of the natural products themselves. Total syntheses of
bafilomycin A1 have been recorded by Evans,20 Tosh-
ima,21-23 Hanessian,24 and also our laboratory.25,26 Several
other studies on the synthesis of the bafilomycin have
been reported,27,28 including a very recent total synthesis
of bafilomycin V1 by Marshall and co-workers.29 A total
synthesis of hygrolidin has been accomplished by Yone-
mitsu,30,31 and total syntheses of concanamicin F (the
aglycone of concanamicin A) have been recorded by both
the Toshima and Paterson groups.32,33 We report here the
details of our synthesis of the C(13)-C(25) segment of 1
via a fragment assembly aldol sequence, preliminary
accounts of which have been reported previously.34,35
These studies strongly influenced the evolution of the
strategy for our ultimately successful bafilomycin total
synthesis.25,26
From the outset, our strategy for the synthesis of
bafilomycin A1 focused on the assembly of three key
fragments: stereotriad 5, corresponding to the C(5)-
C(11) segment of the natural product; aldehyde 6, the
C(21)-C(25) fragment; methyl ketone 7, the C(13)-C(20)
unit. We anticipated that the C(10)-C(14) diene unit
spanning fragments 5 and 7 could be introduced by a
Wittig- or Horner-type olefination sequence, or via a
Pd(0) mediated cross coupling reaction, and that a dia-
stereoselective aldol reaction would be used in the union
of the chiral methyl ketone (deriving from fragment 7)
with the chiral aldehyde 6. However, it was not obvious
at the outset what the preferred order of fragment
coupling would be, nor was it apparent what the stereo-
chemical control opportunities would be for the proposed
aldol coupling of fragments 6 and 7.
process have now been recorded in the synthesis of
natural (and unnatural) products.36 However, in 1989
when our studies on this problem were initated, relatively
little information was available that would allow us to
predict with confidence the outcome of the proposed aldol
coupling. Because both fragments 6 and 7 are chiral, we
expected that the stereochemical course of this reaction
would depend on the intrinsic diastereofacial preference
of each.37 While it was reasonable to expect that the
aldehyde fragment would favor production of the desired
C(21,22)-syn diastereomer 8 by application of the Felkin-
Anh paradigm,38-41 assuming that the reaction did not
proceed by way of a chelate-controlled pathway,42 less
certain was the diastereofacial selectivity preference of
the chiral methyl ketone fragment 7.43-48 Although a
considerable body of information existed concerning aldol
reactions of chiral ethyl ketone enolates, there were
indications that the diastereofacial selectivity of chiral
ethyl ketone enolates is dependent on the metal counter-
ion.49-52 Moreover, evidence also existed that aldol reac-
tions of methyl ketone enolates are often less diastereo-
facial selective than the corresponding ethyl ketone
enolates.36f Accordingly, we decided to address the ster-
eochemistry of the proposed aldol coupling as the first
step in the development of our strategy for the total
synthesis of bafilomycin A1.
The results of this study, preliminary accounts of which
were published in 1992 and 1993,34,35 served to define
the protecting groups that would be used for the R1 and
R2 positions of 6 and 7, as well as the preferred order of
The aldol reaction has been studied extensively during
the past decade, and numerous applications of this
(30) Makino, K.; Kimura, K.; Nakajima, N.; Hashimoto, S.; Yone-
mitsu, O. Tetrahedron Lett. 1996, 37, 9073.
(15) Igarashi, M.; Kinoshita, N.; Ikeda, T.; Nakagawa, E.; Hamada,
M.; Takeuchi, T. J . Antibiot. 1997, 50, 926.
(16) Igarashi, M.; Nakamura, H.; Naganawa, H.; Takeuchi, T. J .
Antibiot. 1997, 50, 932.
(17) Hanessian, S.; Tehim, A.; Meng, Q. C.; Grandberg, K. Tetra-
hedron Lett. 1996, 37, 9001.
(31) Makino, K.; Nakajima, N.; Hashimoto, S.; Yonemitsu, O.
Tetrahedron Lett. 1996, 37, 9077.
(32) J yojima, T.; Miyamoto, N.; Katohno, M.; Nakata, M.; Mat-
sumura, S.; Toshima, K. Tetrahedron Lett. 1998, 39, 6007.
(33) Paterson, I.; Doughty, V. A.; McLeod, M. D.; Trieselmann, T.
Angew. Chem., Int. 2000, 39, 1308.
(18) Gatti, P. A.; Gagliardi, S.; Cerri, A.; Visconti, M.; Farina, C. J .
Org. Chem. 1996, 61, 7185.
(19) Gagliardi, S.; Gatti, P. A.; Belfiore, P.; Zocchetti, A.; Clarke, G.
D.; Farina, C. J . Med. Chem. 1998, 41, 1883.
(20) Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871.
(21) Toshima, K.; J yojima, T.; Yamaguchi, H.; Murase, H.; Yoshida,
T.; Matsumura, S.; Nakata, M. Tetrahedron Lett. 1996, 37, 1069.
(22) Toshima, K.; Yamaguchi, H.; J yojima, T.; Noguchi, Y.; Nakata,
M.; Matsumura, S. Tetrahedron Lett. 1996, 37, 1073.
(23) Toshima, K.; J yojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida,
T.; Murase, H.; Nakata, M.; Matsumura, S. J . Org. Chem. 1997, 62,
3271.
(24) Hanessian, S.; Ma, J .; Wang, W.; Gai, Y. J . Am. Chem. Soc.
2001, 123, 10200.
(25) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.;
Roush, W. R. Angew. Chem., Int. Ed. 1999, 38, 1652.
(26) Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.;
Savall, B. M.; Fegley, G. J .; Roush, W. R. J . Am. Chem. Soc. 2002, in
press.
(34) Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 33, 3587.
(35) Roush, W. R.; Bannister, T. D.; Wendt, M. D. Tetrahedron Lett.
1993, 34, 8387.
(36) Reviews of the aldol reaction: (a) Cowden, C. J .; Paterson, I.
Org. React. 1997, 51, 1. (b) Franklin, A. S.; Paterson, I. Contemp. Org.
Synth. 1994, 1, 317. (c) Heathcock, C. H. In Comprehensive Organic
Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York, 1991;
Vol. 2, p 181. (d) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Heathcock, C. H., Ed.; Pergamon
Press: New York, 1991; Vol. 2, p 239. (e) Paterson, I. In Comprehensive
Organic Synthesis; Heathcock, C. H., Ed.; Pergamon Press: New York,
1991; Vol. 2, p 301. (f) Braun, M. Angew. Chem., Int. Ed. Engl. 1987,
26, 24. (g) Heathcock, C. H. Asymmetric Synth. 1984, 3, 111. (h) Evans,
D. A.; Nelson, J . V.; Taber, T. R. Top. Stereochem. 1982, 13, 1.
(37) Masamune, S.; Choy, W.; Petersen, J . S.; Sita, L. R. Angew.
Chem., Int. Ed. Engl. 1985, 24, 1.
(38) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199.
(39) Anh, N. T.; Eisenstein, O. Nouv. J . Chim. 1977, 1, 61.
(40) Lodge, E. P.; Heathcock, C. H. J . Am. Chem. Soc. 1987, 109,
3353.
(27) Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett. 1995,
36, 175.
(28) Marshall, J . A.; Adams, N. D. Org. Lett. 2000, 2, 2897.
(29) Marshall, J . A.; Adams, N. D. J . Org. Chem. 2002, 67, 733.
(41) Roush, W. R. J . Org. Chem. 1991, 56, 4151.
(42) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1984, 23, 556.

Bafilomycin A1
J . Org. Chem., Vol. 67, No. 12, 2002 4277
coupling of fragments 5-7 in the ultimately successful
total synthesis.25 Stereochemical studies of aldol reactions
of chiral methyl ketone20,53-58 and ethyl ketone metal
enolates58-60 subsequently published from several labo-
ratories, including our own,53-55,59 have now defined a
significant number of the stereochemical features of
fragment assembly aldol reactions that can be used for
predictive purposes in designing efficient syntheses of
complex target molecules.
of ethyl isobutyrylacetate.66 Fra´ter anti alkylation67 of the
lithium enolate of 14 with MeI followed by in situ
silylation of the alkoxide with TBS-OTf provide ester
15 in 70% yield with >95:5 diastereoselectivity. Reduc-
tion of the ester to the primary alcohol with DIBAL-H
and subsequent Swern oxidation68 of the alcohol afforded
aldehyde 6b in 83% overall yield.
Syn th esis of Ald eh yd e 6. Because the stereochem-
istry (and the stereoselectivity) of the fragment assembly
aldol coupling of 6 and 7 would depend on the diaste-
reofacial preferences of each component,37 it was neces-
sary that both fragments be synthesized with high
enantiomeric purity. After several inital routes were
rejected owing to poor diastereo- and/or enantioselectiv-
ity,61,62 our first workable synthesis of 6 was developed
on the basis of an Evans’ asymmetric aldol reaction of
chiral crotonate imide 10.63 Thus, asymmetric aldol
reaction of 10 with isobutyraldehyde provided syn aldol
11 in 91% yield as the only observed isomer. Reduction
of the borate ester regenerated from 11 with LiBH4
produced diol 12 in 85% yield. Tosylation of the primary
hydroxyl group under standard conditions followed by
reduction of the tosylate using LiAlH4 in Et2O and then
protection of the secondary alcohol as a p-methoxybenzyl
(PMB) ether64 gave 13 in 65% overall yield. Oxidative
cleavage65 of the vinyl group then completed the synthesis
of aldehyde 6a .
Ald ol Rea ction s of 6: In itia l Stu d ies. The aldol
reaction of 6a and isopropyl methyl ketone (16a ) was
(56) Evans, D. A.; Duffy, J . L.; Dart, M. J . Tetrahedron Lett. 1994,
35, 8537.
(57) Paterson, I.; Gibson, K. R.; Oballa, R. M. Tetrahedron Lett. 1996,
37, 8585.
(58) Evans, D. A.; Dart, M. J .; Duffy, J . L.; Yang, M. G. J . Am. Chem.
Soc. 1996, 118, 4322.
(59) Gustin, D. J .; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3447.
(60) Evans, D. A.; Yang, M. G.; Dart, M. J .; Duffy, J . L. Tetrahedron
Lett. 1996, 37, 1957.
(61) Bannister, T. D. Ph.D. Thesis, Indiana University, 1991.
(62) (a) One route to 6 based on the addition of diisopropylcuprate
to â-alkoxy aldehyde i was abandoned since the key carbonyl addition
step proceeded with only 4:1 diastereoselectivity (cf.: Still, W. C.;
Schneider, J . A. Tetrahedron Lett. 1980, 21, 1035). (b) A second route
based on the asymmetric (E)-crotylboration of isobutyraldehyde was
abandoned since the volatile homoallylic alcohol iii was obtained with
e90% ee (Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339. Brown, H. C.;
Bhat, K. S. J . Am. Chem. Soc. 1986, 108, 5919). (c) A third route to 6
involving the Sharpless asymmetric epoxidation of iv also was
abandoned as epoxy alcohol v was obtained with only 92% ee (Katsuki,
T.; Martin, V. S. Org. React. 1996, 48, 1). (d) A route involving the
Heathcock-Evans anti aldol reaction of isobutyraldehyde and the
L-valine-derived acyloxazolidinone was also discarded, as in our hands
the desired anti aldol (corresponding to 15) was obtained with only
4:1 diastereoselectivity and in moderate yield (cf.: Walker, M. A.;
Heathcock, C. H. J . Org. Chem. 1991, 56, 5747).
Ultimately, the preferred method for synthesis of 2,3-
anti aldehyde 6 originated from from â-hydroxy ester 14,
which is easily prepared by enantioselective reduction
(43) Seebach, D.; Chow, H. F.; J ackson, R. F. W.; Lawson, K.; Sutter,
M. A.; Thaisrivongs, S.; Zimmermann, J . J . Am. Chem. Soc. 1985, 107,
5292.
(44) Duplantier, A. J .; Nantz, M. H.; Roberts, J . C.; Short, R. P.;
Somfai, P.; Masamune, S. Tetrahedron Lett. 1989, 30, 7357.
(45) Paterson, I.; Goodman, J . M. Tetrahedron Lett. 1989, 30, 997.
(46) Paterson, I.; Goodman, J . M.; Lister, M. A.; Schumann, R. C.;
McClure, C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663.
(47) Trost, B. M.; Urabe, H. J . Org. Chem. 1990, 55, 3982.
(48) Evans, D. A.; Gage, J . R. Tetrahedron Lett. 1990, 31, 6129.
(49) McCarthy, P. A.; Kageyama, M. J . Org. Chem. 1987, 52, 4681.
(50) Evans, D. A.; Clark, J . S.; Metternich, R.; Novack, V. J .;
Sheppard, G. S. J . Am. Chem. Soc. 1990, 112, 866.
(63) Evans, D. A.; Sjogren, E. B.; Bartroli, J .; Dow, R. L. Tetrahedron
Lett. 1986, 27, 4957.
(64) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu,
O. Tetrahedron 1986, 42, 3021.
(65) VanRheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
(51) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J . Am.
Chem. Soc. 1991, 113, 1047.
(52) Martin, S. F.; Lee, W.-C. Tetrahedron Lett. 1993, 34, 2711.
(53) Gustin, D. J .; VanNieuwenhze, M. S.; Roush, W. R. Tetrahedron
Lett. 1995, 36, 3443.
(54) Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
(55) Roush, W. R.; Dilley, G. J . Tetrahedron Lett. 1999, 40, 4955.
(66) Geneˆt, J . P.; Ratovelomanana-Vidal, V.; Can˜o de Andrade, M.
C.; Pfister, X.; Guerreiro, P.; Lenoir, J . Y. Tetrahedron Lett. 1995, 36,
4801 and references therein.
(67) Fra´ter, G.; Mu¨ller, U.; Gu¨nther, W. Tetrahedron 1984, 40, 1269.
(68) Tidwell, T. T. Org. React. 1990, 39, 297.

4278 J . Org. Chem., Vol. 67, No. 12, 2002
Roush et al.
examined to assess the diastereofacial preference of the
chiral aldehyde. Treatment of the lithium enolate of 16a ,
generated by using LiN(TMS)2 in THF, with 6a for 1
min21 at -78 °C provided a 3:1 mixture of diastereomeric
aldols 17a , 18a in 94% yield. The stereochemistry of each
aldol was verified by treatment with 1.0 equiv of DDQ,
which effected oxidative cyclization to the corresponding
p-methoxybenzylidene acetals, the stereostructures of
nated over diastereomer 22 by a ratio of 10:1. Interest-
ingly, the stereoselectivity of the aldol coupling of 6a and
19 was dependent on the reaction conditions. When the
lithium enolate of 19 was treated with 6a for a longer
time (30 min) at -78 °C or at higher temperatures (-40
°C, 5 min), substantial amounts of the C(18)-epimer 23
(up to 50% of 23) and enone 24 (from the -40 °C
experiment only) were also obtained. These products
presumably arise by intramolecular abstraction of the
C(18)-H by the intermediate C(21) lithium alkoxide.
Moreover, if the lithium enolate aldol reaction was
performed in the presence of HMPA, selectivity dropped
to 1:1.2 with the undesired epimer 22 predominating. Use
of the sodium enolate and the dibutylboron enolate
generated from 19 each gave ca. 1:1 mixtures of the two
aldols. Attempts to improve the stereoselectivity of the
boron aldol reaction via triple asymmetric synthesis,44
by using the boron enolate generated from 6a and (-)-
Ipc2BOTf,46 were also unsuccessful, as this experiment
provided the unwanted aldol 22 as the major component
of a 2:1 mixture. No reaction was observed in attempts
to couple 19 and 6a using enol borane intermediate from
19 and the enantiomeric (+)-Ipc2BOTf.
1
which were easily confirmed by H NMR analysis (see
Supporting Information).69 The aldol reaction of 6a and
16a was less selective (1.4:1 in favor of 17a ) by using
the boron enolate generated by treatment of 16a with
Bu2BOTf and Et3N but improved to 4.2:1 by using the
chiral boron enolate prepared from 16a and (-)-Ipc2BOTf
according to Paterson’s protocol.46 The aldol reactions of
aldehyde 6b and the lithium and dibutylboron enolates
of pinacalone (16b) were also examined and were found
to be less selective than the corresponding reactions of
6a . Comparable results for the aldol reactions of 6a ,b
have been reported by Evans.58
These studies showed that the intrinsic diastereofacial
preference of 6a ,b favors the naturally occurring C(21)
bafilomycin stereochemistry, when the aldol reaction is
performed with a lithium enolate. Because the selectivity
of the aldol reactions was modestly better using 6a with
a PMB protecting group rather than 6b with a TBS ether,
we concentrated on 6a in the studies which follow.
The aldol reaction of 6a and the model chiral methyl
ketone 19 was next examined. Methyl ketone 19 was
synthesized from the readily available homoallylic alcohol
2070 by protection of the hydroxyl group as a TBS ether
and Wacker oxidation71 of the vinyl group.
The stereochemistry of the new hydroxyl groups in 21
and 22 was assigned by conversion of each compound to
the corresponding p-methoxybenzylidene acetals 25 and
26. In view of concerns raised by the isolation of the
C(18)-epimer 23, the C(18) stereochemistry of 21 was
assigned by conversion to the spiroketal 28, the stereo-
1
chemistry of which follows unambiguously from the H
NMR NOE and coupling constant (J ) data that are
shown. The stereochemical assignment of C(18) of 22 is
more involved and is summarized in the Supporting
Information.
The dependence of aldol stereoselectivity on reaction
conditions and especially on the nature of the metal
enolate was curious. (Subsequent studies from our labo-
ratory have established that the dependence of aldol
stereoselectivity on metal enolate is general for methyl
ketone aldol reactions.53-55,59) To determine if the product
distribution reflected kinetic or thermodynamic control,
we treated aldol 22, the minor product of the aldol
reaction of 6a and 19, with 1.1 equiv of LiN(TMS)2 in
THF at -78 °C for 15 min and also with Li(NTMS)2 in
THF-HMPA at -78 °C for 15 min, to regenerate the
lithium aldolate. Diastereomer 21 was not observed in
The lithium enolate of 19 underwent a highly diaste-
reoselective reaction with 6a under kinetically controlled
conditions (THF, -78 °C, 30 s before NH4Cl quench).
Under these conditions, the desired aldol 21 predomi-
(69) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 889.
(70) Roush, W. R.; Palkowitz, A. D.; Ando, K. J . Am. Chem. Soc.
1990, 112, 6348.
(71) Hegedus, L. S. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 4; p 551.

Bafilomycin A1
J . Org. Chem., Vol. 67, No. 12, 2002 4279
19 and TBS-protected chiral aldehyde 6b (which is less
diastereofacial selective than 6a in reactions with achiral
methyl ketone enolates; vide supra) is virtually nonselec-
tive.73
Syn th esis of Ch ir a l Meth yl Keton e 7. The excellent
stereoselectivity of the aldol reaction of 6a and the
lithium enolate of 19 encouraged us to proceed with the
synthesis of the originally targeted methyl ketone 7. We
elected to synthesize 7a with the C(15)-hydroxyl pro-
tected as a triethylsilyl (TES) ether, in anticipation that
this protecting group would be suitable for use in the total
synthesis. The synthesis of 7a began with ethyl â-hy-
droxy-R-methylbutyrate 32, which we prepared with 20:1
stereoselectivity via the Frater-Seebach alkylation of
ethyl (R)-â-hydroxybutyrate.67 Aldehyde 33 was prepared
from 32 by a four-step sequence involving DIBAL reduc-
tion of an intermediate 3,4-dimethoxybenzylidene ac-
etal.74,75 Treatment of aldehyde 33 with the diisopropyl
(S,S)-tartrate modified (E)-crotylboronate 3476 in toluene
at -78 °C in the presence of activated 4 Å molecular
sieves provided a single homoallylic alcohol (via a matched
double asymmetric transformation)70 with g98:2 selectiv-
ity by 1H NMR analysis. Protection of the C(17) hydroxyl
as a TBS ether then provided 35 in 85% yield for the two
steps. The stereochemistry of 35 was verified by the
accidental conversion of the derived aldehyde 36 to the
pyranose 37 upon exposure to wet MgSO4.
either case, indicating that the aldol reaction of 6a and
the lithium enolate of 19 is kinetically controlled under
the conditions specified above.
To gain additional insight into the factors that control
the stereoselectivity of the aldol reaction of 6a and 19,
we examined the aldol coupling of 19 with isobutyralde-
hyde and also the reaction of 6a and the enantiomeric
methyl ketone, ent-19. The reaction of the lithium enolate
of 19 and isobutyraldehyde provided a ca. 1.5:1 mixture
of aldols, while the reaction of 6a and ent-19 gave a 5:1
mixture favoring aldol 30. These results, in concert with
the data presented previously for the reaction of aldehyde
6a and methyl ketones 16 (3:1 ds favoring 17a ) and 19
(10:1 ds favoring 21), indicate that Masamune’s multi-
plicativity rule does not apply rigorously to these double
asymmetric fragment assembly aldol reactions.37 Al-
though the stereochemistry of aldol 29 was not assigned
rigorously, we have tentatively assigned the major dis-
tereomer as the 1,4-syn isomer depicted for 29 by
1
application of the H NMR analysis of the characteristic
ABX pattern for the methylene R-to the ketone carbon-
yl.72 This assignment indicates that the lithium enolate
of 19 exhibits a re-diastereofacial preference, which in
turn is consistent with the diminished selectivity ob-
served in the aldol reaction of ent-19 and 6a (5:1),
compared to the 10:1 selectivity for the reaction of 19 and
6a . We believe that the lithium enolate of 19 and 6a
represents the matched case, while the combination of
6a and ent-19 represents the mismatched pair in these
fragment assembly aldol reactions.37 Because the selec-
tivity of the reaction of 19 and isobutyraldehyde is very
modest, it appears that the stereochemical course of these
reactions is dominated by the diastereofacial preference
of the chiral aldehyde component. This conclusion is
reinforced by the observation that the aldol reaction of
(72) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; VanNieuwehnze,
M. S.; Gustin, D. J .; Dilley, G. D.; Lane, G. D.; Scheidt, K. A.; Smith,
W. J . J . Org. Chem. 2002, 67, 4284.

4280 J . Org. Chem., Vol. 67, No. 12, 2002
Roush et al.
We were now ready to introduce the C(14) and C(15)
stereocenters of the targeted methyl ketone 7a . Hoffmann
had developed an (E)-(γ-methoxyallyl)boronate reagent
that in principle could be used for the present purposes.77
However, in view of the difficulties associated with the
synthesis of Hoffmann’s (E)-(γ-methoxyally)lboronate, we
elected to explore use of Takai’s (γ-methoxyallyl)chro-
mium reagent which is generated in situ from acrolein
dimethyl acetal, TMS-I, and CrCl2.78 We were delighted
to find that subjecting aldehyde 36 to Takai’s reaction
conditions provided homoallylic alcohol 38 with ca. 7:1
selectivity; the isolated yield of 38 was 76%. Multiple
gram quantities (>10 g) of allyl methyl ether 38 were
synthesized by using this procedure. The stereochemistry
of 38 was assigned by conversion to the pyranose deriva-
tive 39, which exhibited J 14,15 ) 3.1 Hz and J 15,16 ) 11.4
chairlike transition states similar to 43 and 44 are
thought to be involved.81 It is known that substituted
allylchromium reagents equilibrate between (E) and (Z)
isomers at rates faster than carbonyl addition and that
the (E) isomer (cf. 40E) is more reactive than the (Z)-
isomer.81 Application of the Felkin-Anh model for nu-
cleophilic addition to R-methyl chiral aldehydes,38,39 or
our “gauche pentane” model of asymmetric induc-
tion,41,70,81 leads to the prediction that transition state
43 should be favored in reactions of the (methoxyallyl)-
chromium reagent 40E with chiral aldehydes 42. Takai,
however, favors a mechanism involving the intermediacy
of an internally chelated (Z)-(methoxyallyl)chromium
species, which would require that the major product 45
be produced through a boatlike transition state (not
shown).78,82
1
Hz in the H NMR spectrum. These data are unambigu-
ously consistent with the 14,15-anti-15,16-syn stereo-
chemical relationship in 38. Finally, the synthesis of 7a
was completed by protection of C(15)-OH as a TES ether,
DDQ oxidative deprotection of the DMPM ether,64 and
PCC oxidation of the resulting C(19)-OH.
Because there were no other examples of reactions of
chiral aldehydes with Takai’s reagent 40 at the time that
our synthesis of 7a was developed, we examined the
reactions of 40 with several other chiral aldehydes. After
our report of the conversion of 36 to 38, several additional
examples of the reactions of the (γ-alkoxyallyl)chromium
species have appeared.23,82,83 The additional results sum-
marized here indicate the reaction diastereoselectivity is
sensitive to the nature of the protecting groups and the
stereochemistry of the aldehyde substrate. Surprisingly,
the reaction of 40 with aldehyde 6a (with a â-p-meth-
oxybenzyl ether protecting group) gives a 60:40 mixture
of products in which the anti-Felkin isomer 46 predomi-
nates. However, when the â-alkoxy protecting group is
switched to a TBS ether, as in 47, the Felkin diastere-
omer 45 is the major component of a 62:38 mixture. On
the other hand, the reaction of the 2,3-syn aldehyde 48
with a â-alkoxy PMB ether protecting group provides the
Felkin isomer 45 as the major product (ds ) 72:28). The
most selective substrate of those examined is 49, which
gave a 9:1 mixture favoring the Felkin isomer 45.
The Takai methoxyallylation protocol is mechanisti-
cally related to the reactions of the Hiyama-Nozaki
crotylchromium reagent with aldehydes79,80 in which
(73) The diminished selectivity of the aldol reaction of 19 and the
TBS protected aldehyde 6b, compared to the reaction with the PMB-
protected 6a and 19, is consistent with our observations that the
stereoselectivities of methyl ketone fragement assembly aldol reactions
are highly dependent on the aldehyde â-protecting group and especially
that TBS-ether-protected â-alkoxy aldehydes are much less Felkin
selective in reactions with chiral methyl ketone lithium enolates than
are analogous â-alkoxy aldehydes bearing alkyl ether protecting groups
(see refs 53 and 55).
(74) Ishihara, K.; Mori, A.; Yamamoto, H. Tetrahedron 1990, 46,
4595.
(75) The more direct sequence involving conversion of 32 to the
corresponding dimethoxybenzyl (DMPM) ether via treatment with the
DMPM-imidate reagent followed by DIBAL reduction of the ester to
the aldehyde was less efficient and more difficult to perform on large
scale.
(76) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339.
(77) Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T.
Liebigs Ann. Chem. 1985, 2246.
(78) Takai, K.; Nitta, K.; Utimoto, K. Tetrahedron Lett. 1988, 29,
5263.
(80) Buse, C. T.; Heathcock, C. H. Tetrahedron Lett. 1978, 19, 1685.
(81) Roush, W. R. In Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: New York, 1991; Vol. 2, p 1.
(82) Fu¨rstner, A. Chem. Rev. 1999, 99, 991.
(79) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J . Am. Chem.
Soc. 1977, 99, 3179.
(83) Boeckman, R. K., J r.; Hudack, R. A., J r. J . Org. Chem. 1998,
63, 3524.

Bafilomycin A1
J . Org. Chem., Vol. 67, No. 12, 2002 4281
Surprisingly, however, changing the terminal TBDPS
ether protecting group to a pivaloate ester in 50, or by
changing the stereochemistry of the C(4)-methyl group
as in 51, gave substrates that exhibited very poor
selectivity in reactions with the (methoxyallyl)chromium
reagent 40. While the factors that govern the diastereo-
selectivity of these reactions are not readily apparent,
one can speculate that chelate pathways involving either
The lack of stereoselectivity in the aldol reaction of 6a
and 7a prompted us to examine several additional
substrates (52-55) in an attempt to uncover the factor-
(s) responsible for the aberrant behavior of methyl ketone
7a . The lithium enolates of 52-55 were generated by
treatment with LiN(TMS)2 in THF at -78 °C and allowed
to react with 6a for e1 min at -78 °C. These reactions
also proved to be only moderately selective (2-3:1) for
the 21(R) aldol stereoisomers 56-59. Aldol 59 (R ) H)
was unstable to chromatography, so in this case the
lithium aldolate was treated with TBS-OTf before reac-
tion workup, thereby permitting aldol 59 (R ) TBS) to
be isolated. Control experiments established that the
reaction of 53 and 6a is kinetically controlled, as regen-
eration of the lithium aldolate from the minor aldol
diastereomer (LiN(TMS)2, THF, -78 °C, 15 min) failed
to result in its equilibration with 57.
42
the Z-isomer of the reagent78 or the substrate may be
competitive in some of these cases. It is indeed fortuitous
that aldehyde 36 that we targeted for the bafilomycin
A1 synthesis is one of the more selective substrates for
the Cr(II)-mediated methoxyallylation reaction.
These results established that the C(17) alkoxy pro-
tecting group of the methyl ketone fragment has an
insignificant influence on the reaction diastereoselectiv-
ity, as ketones 52-54 with TBS, TES, and PMB protect-
ing groups at this position gave essentially identical
results in the aldol reactions with 6a . However, compari-
son of the results of reaction of 6a with 19 (10:1
selectivity) and 55 (3:1 selectivity), which have C(15)-
OBzl and C(15)-OTBDPS groups, respectively, indicates
that a C(15)-alkoxy group is needed to achieve good
diastereoselectivity in this aldol reaction. On the basis
of these data, we speculated that the aldol reaction of
6a and 19 proceeds by way of a chelated transition state
such as 60. Although remote chelation effects are rarely
observed,42,84,85 this hypothesis is consistent with the
observations that enolates deriving from 56-58 with
vinyl substituents, rather than C(15)-alkoxy groups, give
low selectivity in the aldol reactions with 6a . This
transition state model also explains the behavior of
methyl ketone 7a with a C(15)-triethylsilyl ether which
also should be precluded from participation in a chelated
Ald ol Rea ction s of 6a a n d 7a . The aldol reaction of
6a and 7a was performed by using the conditions that
gave the optimal 10:1 selectivity in the aldol reaction of
6a and 19. Thus, treatment of 7a with LiN(TMS)2 in THF
at -78 °C gave the lithium enolate, to which was added
a solution of aldehyde 6a in THF. The reaction was
quenched 30 s later by addition of aqueous NH4Cl. To
our considerable surprise, this reaction gave a 55:45
mixture of aldols 8a and 9a . The stereochemistry at C(21)
of both diastereomers was verified by DDQ oxidation to
the corresponding p-methoxybenzylidene acetals (see
Supporting Information).69
(84) Tomooka, K.; Okinaga, T.; Suzuki, K.; Tsuchihashi, G. Tetra-
hedron Lett. 1987, 28, 6335.
(85) Frenette, R.; Monette, M.; Bernstein, M. A.; Young, R. N.;
Verhoeven, T. R. J . Org. Chem. 1991, 56, 3083.

4282 J . Org. Chem., Vol. 67, No. 12, 2002
Roush et al.
transition state such as 61.86 Finally, this hypothesis is
also consistent with the results of the aldol reactions of
6a and the sodium enolate of 19, and also of the lithium
enolate of 19 in the presence of HMPA, since chelates
involving the C(15)-alkoxy group should be less likely
under these conditions.
consistent with the particpation of the C(15)-alkoxy group
in the chelated transition state 62. However, the results
of aldol reactions of methyl ketones 7a and 52-55, which
are incapable of participating in such highly organized,
chelated transition structures, indicate that several less
diastereoselective transition states must also be acces-
sible. It is conceivable that both chairlike (64, 65) and
boatlike (66, 67) transition states could be involved.
Several computational studies indicate that chairlike and
boatlike transition states in methyl ketone aldol reactions
are relatively close in energy.90,91 Moreover, some data
exist in the boron aldol area indicating that methyl
ketone aldol reactions that proceed by way of boatlike
transition states exhibit opposite enolate face selectivity
compared to the pathways involving chairlike transition
structures.36f,46 Therefore, both the chairlike and boatlike
transition structures must be considered in any transi-
tion state analysis.
It is well appreciated that lithium enolates are ag-
gregated in solution87,88 and that the dimeric forms are
believed to be the most reactive species.87 Accordingly,
it may well be that transition structure 60 is overly
simplified and that the C(15)-alkoxy substituent of 19 is
actually chelated to a second lithium cation in an
aggregate.89 Nevertheless, the hypothesis that chelation
involving the C(15)-alkoxy group is essential for high
stereoselection is easily tested experimentally: syntheti-
cally useful stereoselectivity should be restored if the
C(15)-alcohol protecting group of 7a is changed from a
triethylsilyl ether to a protecting group (cf. the MOM
ether protecting group of 7b) that can more easily
participate in a chelate. We were most pleased to find,
therefore, that the kinetically controlled aldol reaction
of aldehyde 6a and methyl ketone 7b provided 8b with
8:1 selectivity. The stereochemistry of the newly formed
hydroxyl center was assigned by conversion to the
p-methoxybenzylidene acetal 63.69
We expect that the diastereofacial selectivity of aldol
reactions that proceed via nonchelated chairlike transi-
tion states should favor the Felkin diastereomers (e.g.,
56-58 from 52-54), in view of Evans’ observation that
the aldol reactions of chiral ethyl ketone Z(O)-enolates
are highly diastereoselective by way of chairlike transi-
tion states analogous to 64.51,60 However, to account for
the modest selectivity of these fragment assembly methyl
ketone aldol reactions, we must invoke either the alter-
native chairlike transition state 65, in which the enolate
adds in an anti-Felkin sense to the chiral aldehyde or
the anti-Felkin boatlike transition structure 67. Further
analysis of 65 and 67 reveals that the enolate R-stereo-
center adopts a sterically disfavored rotamer with the “R”
group eclipsing the enolate double bond in 65, whereas
the enolate R-stereocenter adopts a more favorable rota-
mer with the medium-sized methyl group eclipsing the
enolate double bond in 67. On the assumption that the
chairlike and boatlike transition structures should be
comparable in energy (in the absence of overriding steric
effects),90 and because the foregoing analysis suggests
that 67 might have fewer destabilizing interactions than
65, we have invoked 67 to explain the significant produc-
tion of anti-Felkin diastereomers in the aldol reactions
of 7a and 52-55. Studies designed to probe this hypoth-
esis are in progress and will be reported in due course.
Tr a n sition Sta te An a lysis. The synthetically useful
stereoselectivity of the aldol reaction of 6a and 7b is
(87) Seebach, D. Angew. Chem., Int. Ed. Engl. 1988, 27, 1624.
(88) Williard, P. G.; Liu, Q. Y. J . Am. Chem. Soc. 1993, 115, 3380.
(89) For the disclosure of an aldol reaction of a lithium enolate in
the solid state: Wei, Y.; Bakthavatchalam, R. Tetrahedron Lett. 1991,
32, 1535.
(90) Li, Y.; Paddon-Row, M. N.; Houk, K. N. J . Org. Chem. 1990,
55, 481.
(86) For studies on the influence of protecting groups on chelate
controlled carbonyl additions: (a) Keck, G. E.; Castellino, S. J . Am.
Chem. Soc. 1986, 108, 3847. (b) Frye, S. V.; Eliel, E. L.; Cloux, R. J .
Am. Chem. Soc. 1987, 109, 1862. (c) Kahn, S. D.; Keck, G. E.; Hehre,
W. J . Tetrahedron Lett. 1987, 28, 279. (d) Keck, G. E.; Castellino, S.
Tetrahedron Lett. 1987, 28, 281. (e) Keck, G. E.; Castellino, S.; Wiley:
M. R. J . Org. Chem. 1986, 51, 5478. (f) Reetz, M. T.; Hu¨llmann, M.;
Seitz, T. Angew. Chem., Int. Ed. Engl. 1987, 26, 477.
(91) Bernardi, F.; Robb, M. A.; Suzzi-Valli, G.; Tagliavini, E.;
Trombini, C.; Umani-Ronchi, A. J . Org. Chem. 1991, 56, 6472.

Bafilomycin A1
J . Org. Chem., Vol. 67, No. 12, 2002 4283
Im p lica tion s for th e P r ojected Ba filom ycin A1
Tota l Syn th esis. Our goal at the outset of these studies
was to define the opportunities for use of the fragment
assembly aldol reaction for synthesis of the C(13)-C(25)
segment of bafilomycin A1. While the synthesis of 8b via
the aldol reaction of 6a and 7b satisfied this inital goal,
it was readily apparent that 8b would not be a viable
intermediate for the total synthesis. First, the C(15)-
MOM ether is too robust a protecting group for the
deprotection sequence planned for later in the synthesis.
However, given the sensitivity of aldol selectivity on the
C(23) and C(15) protecting groups in 6a and 7b, as well
as the senstivity of the Takai methoxyallylation reaction
to the nature of protecting groups on the aldehyde
substrate, we were unable to identify a workable revision
of the protecting group scheme that would be compatible
with use of the lithium enolate fragment assembly aldol
reaction as a key step in the projected total synthesis.
(Additional constraints on the nature of the C(15)-
hydroxyl protecting group became apparent as the total
synthesis progressed toward completion.25,26) Second,
even if a solution to the protecting group/reaction selec-
tivity problem had been achieved, it would have been
necessary to devise a strategy for protecting the C(19)
ketone to prevent intramolecular hemiketalization by the
C(15)-OH during the subsequent macrolactonization
reaction.
assembly aldol reaction at the very end of the synthesis,
after the macrocycle was assembled. In this scenerio,
C(15)-OH would be “protected” by the C(1)-acyl unit of
the natural product. It was not obvious, however, that a
C(15) acyloxy unit would be compatible with the condi-
tions of a lithium enolate aldol reaction. Because a
chlorotitanium enolate should be compatible with the
C(15)-acyloxy substituent of the methyl ketone, we
explored the aldol reaction of 6a with the titanium
enolate of methyl ketone 7c. To our considerable delight,
the aldol reactions of aldehyde 6a with the chlorotita-
nium enolates of both 7a ,c each provided the desired
Felkin diastereomers 8a ,c with g94:6 selectivity. Che-
lated transition states analogous to 62 seem unlikely
under these conditions, so the excellent diastereoselec-
tivity may be a consequence of the shorter Ti-O bond
lengths that maximize nonbonded interactions in the
boatlike transition state (i.e., analogous to 67),52 thereby
raising the energy of the competitive boatlike transition
state so that the vast majority of the reaction proceeds
via the chairlike transition structure analogous to 64.
Several studies addressing the latter issue were per-
formed using aldol 21 as a model system. However, we
found that the methyl hemiketal 68 was very sensitive
to elimination of methanol, leading to glycal 69. Glycal
69 was produced during the DDQ deprotection of 21, as
well as during the acid-catalyzed reaction of the hemi-
acetal with MeOH. Moreover, an NMR sample of 68
readily eliminated MeOH when allowed to stand in
CDCl3 overnight. Similar problems have been encoun-
tered by Marshall in his studies directed toward the
bafilomycin synthesis.28 In addition, spiroketalization of
68 occurred readily during the catalytic debenzylation
reaction (leading to 28). Although we found that hemiket-
al 70 was much more stable when the C(17)-OH was
deprotected, this also did not appear to be a synthetically
useful solution to the problem at hand.
Su m m a r y. We have developed highly stereoselective
syntheses of aldols 8a -c corresponding to the C(13)-
C(25) segment of bafilomycin A1. In the course of these
investigations we discovered that a remote chelation
effect plays a critical role in determining the stereose-
lectivity of the key coupling of aldehyde 6a and the
lithium enolate of 7b and also that the C(23) protecting
group of the chiral aldehyde fragment influences the
selectivity of the lithium enolate aldol reaction. In
contrast, the aldol reaction of 6a and the titanium
enolates of 7a ,c proved to be much less sensitive to the
nature of the C(15)-hydroxyl protecting group. The latter
results defined an important technology platform that
permitted us to initiate efforts to complete the total
synthesis of bafilomycin A1.25,26
Ack n ow led gm en t. Support provided the National
Institute of General Medical Sciences (Grant GM 38436)
is gratefully acknowledged. We also thank Dr. Akihiro
Tasaka for helping to optimize the synthesis of 38.
Su p p or tin g In for m a tion Ava ila ble: Complete experi-
mental details and stereochemical assignments of all aldol
products and products of the Takai γ-methoxyallylation reac-
tions of chiral aldehydes and selected 1H NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
On the basis of these results, we concluded that it
would be appropriate to perform the key fragment
J O016413F