Concise epoxide-based synthesis of the C14-C25 bafilomycin A1 polypropionate chain

Article abstract of DOI:10.1016/j.tetlet.2012.02.067

An efficient nonaldol convergent synthesis of the C14-C25 polyketide fragment of bafilomycin A₁ was completed in 16% overall yield and 8 steps in its longest linear sequence. This synthesis highlights the formation of the key fragments using a

Full text of DOI:10.1016/j.tetlet.2012.02.067

Tetrahedron Letters 53 (2012) 2199–2201
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise epoxide-based synthesis of the C14–C25 bafilomycin A1
polypropionate chain
⇑
Elizabeth M. Valentín, Marlenne Mulero, José A. Prieto
Department of Chemistry, University of Puerto Rico, Río Piedras Campus, PO Box 23346, San Juan, PR 00931-3346, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient nonaldol convergent synthesis of the C14–C25 polyketide fragment of bafilomycin A1 was
completed in 16% overall yield and 8 steps in its longest linear sequence. This synthesis highlights the
formation of the key fragments using a three-step sequence of epoxide cleavage, alkyne reduction, and
epoxidation developed in our laboratory; starting from suitably protected enantiomeric epoxides of
trans-2,3-epoxybutanol. This chemistry represents a quick asymmetric and diastereoselective construc-
tion of the polyketide chain of bafilomycin A1, in which every stereogenic center was constructed using
solely epoxide chemistry.
Received 3 February 2012
Revised 9 February 2012
Accepted 14 February 2012
Available online 21 February 2012
Keywords:
Bafilomycin A1
Enantiomeric epoxides
Epoxide cleavage
Polypropionates
Dithiane coupling
Ó 2012 Elsevier Ltd. All rights reserved.
The bafilomycins (1) belong to a group of molecules in the family
of the plecomacrolides. The hygrolidins, the concanamycins, and
formamicin have been included in this group. Bafilomycin A1 (1a)
was isolated in 1983 by Wagner from a broth of Streptomyces griseus
(Fig. 1).1 Its relative stereochemistry was determined by Corey and
Ponder in 1984 using extensive NMR analysis, and confirmed in
1987 using X-ray crystallography.2–4 More recently, several previ-
ously unknown bafilomycins (F–J) were isolated from a marine
strain of Streptomyces.5 Common structural features of the bafil-
omycins include the 16-membered macrolide with a tetraene core,
a long polyketide chain with a cyclic hemiacetal, a C14 methoxy, and
a C23 isopropyl group. Bafilomycin A1 exhibits potent antifungal
and antibacterial activities. It is also the first known inhibitor of Vac-
uolar H+-ATPase (V-ATPase), providing treatments for bone resorp-
tion diseases such as osteoporosis and osteoarthritis, in addition to
showing potential as an anticancer treatment for eight different hu-
man cancer cell lines.6–11 These singular biological activities, along
with the challenging structural features presented make bafilomy-
cin A1 a well studied target for synthetic efforts.
of fragments. Those who studied different methodologies have
found creative ways to bring about the stereoselective synthesis
of the C13–C25 portion of the molecule. For instance, Patterson ap-
plied a series of stereocontrolled aldol additions to a-methylene-b-
alkoxy aldehydes, followed by hydroxyl-directed hydrogenation of
the methylene moiety.22 Marshall used enantioenriched allenyl-
zinc reagents, starting from nonracemic propargylic mesylates,
which undergo SE20 additions to aldehydes to yield anti-homoprop-
argylic alcohols to synthesize the C15–C25 fragment.23 More
MeO
OR1
OR3
14 O OH O
19
23
1
HO
O
R2
1a bafilomycin A1, R1 = H, R2 = OMe, R3 = H
O
1b bafilomycin B1, R1 = H, R2=OMe, R3 =
O
H
N
O
S
The presence of the C19 carbonyl offers the opportunity to ap-
ply convergent methods to synthesize this polypropionate chain.12
To date, there have been five total syntheses of bafilomycin A1,13–20
and several reports on the synthesis of the important C13–C25
polypropionate segment.21–24 The total syntheses of bafilomycin
A1 have focused mainly on facial differentiation for aldolic coupling
HO
1c bafilomycin F, R1 = H, R2=OMe, R3 =
O
O
OH
NH
O
O
1d bafilomycin G, R1 = H, R2 = OMe, R3 = Me
1e bafilomycin H, R1 = Me, R2 = OMe, R3 = Me
1f bafilomycin J, R1 = H, R2 = OMe, R3 = Me
⇑
Corresponding author. Tel.: +1 787 759 6880; fax: +1 787 759 6885.
E-mail address: jose.prieto2@upr.edu (J.A. Prieto).
Figure 1. Structures of the bafilomycin family.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.067

2200
E. M. Valentín et al. / Tetrahedron Letters 53 (2012) 2199–2201
recently, Cossy used a dynamic kinetic resolution of nonchiral ke-
tones with an optically active ruthenium complex.24
BnO
HO
HO
BrMg
BnO
BnBr, NaH
An alternative approach for the synthesis of polypropionates is
the regioselective cleavage of an oxirane ring. Epoxides can be pre-
pared enantioselectively with several well-known methodologies,
like the Sharpless asymmetric epoxidation.25 They can be cleaved
with a number of organometallic reagents, including boranes,
alanes, Grignard reagents, and cuprates.26 The ring opening of
unactivated epoxides can be considered an SN2 process; therefore,
epoxides will predictably be cleaved at the least hindered carbon
(in the absence of coordinating groups) when treated with a nucle-
ophile. The ease of access and the predictability of their cleavage
reaction are what have interested us in developing a methodology
for the synthesis of polypropionates based on the regioselective
cleavage of disubstituted epoxides.27–35 Our methodology consists
of three reiterative steps: the cleavage of a disubstituted epoxide
with an alkynyl alane reagent, reduction of the alkyne, and stereo-
selective epoxidation of the newly formed alkenol (Scheme 1). This
provides a new epoxide to which the three-step process is re-
peated, allowing the preparation of a number of stereochemical
possibilities. One of the advantages of this methodology is that
the only enantiomeric step is the first epoxidation, given that the
absolute configuration of the first hydroxy is given by this step,
while the relative configuration between the hydroxy and the adja-
cent methyl group is given by the epoxide geometry. Because of
this, several polypropionate permutations can be constructed
without the need for any aldolic steps. For this approach to be suc-
cessful, we have studied the stereoselective epoxidation of homo-
allylic alcohols,27,30,35 and the regioselective cleavage of these
epoxides.31–33 This methodology has led to the successful linear
synthesis of the all anti fragments of streptovaricin U and other
polypropionate modules.34 Aimed at extending our methodology
to more varied polypropionate targets and to expand it from linear
to convergent, herein we present an epoxide-based approach for
the enantioselective synthesis of the C14–C25 polypropionate frag-
ment of bafilomycin A1.
Our approach is based on the use of both enantiomers of trans-
2,3-epoxybutanol 2.25 The (+) enantiomer was used for the con-
struction of the C21–C22 stereocenters, while the (ꢀ) enantiomer
was used in the C15–C16 centers. Alkyl iodide 9, corresponding
to the C20–C25 segment (Scheme 2), was previously synthesized
both by Hanessian in his total synthesis of bafilomycin A1,18 and
by Cossy in her C14–C25 synthesis, both using different methodol-
ogies.24 Our approach began by the protection of epoxide (+)-2 as
the benzyl ether 3, which proceeded in 93%. Cleavage with cis-1-
propenylmagnesium bromide catalyzed with 5% CuI, yielded 82%
of homoallylic alcohol 4. Epoxidation of 4 using our microwave as-
sisted VO(acac)2/TBHP conditions yielded 60% of syn,anti,cis epoxy
alcohol 5 as the only observed epoxide, in complete agreement
with previous results using different protecting groups.30 For the
introduction of the terminal isopropyl and the C23 hydroxy, epox-
ide 5 was cleanly cleaved using Me3Al, producing 80% of 1,3-diol 6,
which was subsequently protected as the bis-TBS ether 7. Hydrog-
5% CuI
THF/ether
-78 ºC
KI, THF
93%
O
O
4
(+)-2
3
82%
VO(acac)2
TBHP
BnO
BnO
HO
Me3Al
toluene, mw
60%
O
toluene
0 ºC
HO OH
5
6
80%
TBSOTf
DIEA
BnO
HO
H2, Pd/C
MeOH/
EtOAc
98%
DCM
93%
TBSO OTBS
TBSO OTBS
7
8
I2, PPh3
imidazole
20
25
I
toluene
91%
TBSO OTBS
9
Scheme 2. Synthesis of alkyl iodide 9.
enolysis of 7 required a polar 4:1 methanol: ethyl acetate solvent
mixture, to produce 98% of the desired alcohol 8. Finally, this alco-
hol was converted into the alkyl iodide 9 in 91% using Garegg’s
conditions.37 The synthesis of 9 was carried out in 7 steps and
30% overall yield, starting from known enantiomeric epoxide (+)-
2. We believe this represents an improvement over previous
published procedures for this fragment, as it more than doubles
previously published yields while rivaling, or even reducing the
number of synthetic steps in other syntheses.18,24
Racemic epoxide 13, the precursor for the C14–C18 stereotetrad
(Scheme 3), was previously prepared stereoselectively by us start-
ing from ethyl 2,3-epoxybutyrate by an iteration of our methodol-
ogy.27,36 The anti epoxide relationship was obtained via an
iodolactonization/methanolysis and the OTIPS group arose from
HO
TIPSO
10
Et2Al
TIPSCl, TEA
DMAP, DCM
93%
toluene
O
O
61%
(-)-2
TIPSO
TIPSO
HO
Na, NH3,
t-BuOH, -78 ºC
64%
HO
11
12
1,3-dithiane
TIPSO
MMPP, EtOH
18
t-BuLi, HMPA
15
76% combined yield, dr = 1:1
THF, -78 ºC
70%
O
35% isolated yield of 13
HO
13
TIPSO
TIPSO
MeO
19
14
S
S
S
O
O
S
HO HO
14
PPTS, DCM
65%
RO
RO
RO
cleavage
(1)
reduction
(2)
15
O
OH
OH
syn
1) t-BuLi, HMPA
THF, -78 ºC
trans
TIPSO
19
25
14
RO
RO
OR
O
O
OR
repeat
S S
epoxidation
(3)
2)
I
O
O
steps 1 - 3
TBSO OTBS
R = TBS
OH
cis
OH OH
anti
(1.3 equiv)
16
Scheme 1. Reiterative epoxide-based methodology for polypropionate synthesis.
Scheme 3. Synthesis of dithiane 5 and polypropionate fragment 16.

E. M. Valentín et al. / Tetrahedron Letters 53 (2012) 2199–2201
2201
an ester reduction/alcohol protection sequence. This route pro-
vided stereoselective access to the required syn,anti,trans epoxy
alcohol, but lacked chiral alternatives. We therefore applied the
enantiomeric (but non diastereoselective) route presented in
Scheme 3. The TIPS-protected epoxide 10 was prepared in 93%
yield from the known epoxide (ꢀ)-2. This was followed by epoxide
cleavage with diethypropynyl aluminum, obtaining homopropar-
gylic alcohol 11 in 61%. Sodium/ammonia reduction of 11 yielded
homoallylic alcohol 12 in 64%. At this point, several stereoselective
methods for the epoxidation of 12 generated a mixture of epoxides,
mostly favoring the syn,syn diastereomer of 13.27,30 We therefore
used the nonstereoselective MMPP epoxidation, obtaining 76% of
a 50:50 mixture of 13 and its syn diastereomer. Although this
alternate method gives a lower yield of the desired epoxide, this
reaction can be made in multigram quantities, and the mixture
of epoxides is easily separated by flash chromatography. Once
epoxide 13 was procured, we selected 1,3-dithiane as the coupling
agent because of known successes and the reliability and
versatility of dithianes.38 Cleavage of 13 using 1,3-dithiane gener-
ated 70% of diol 14. Protection of the diol as an acetonide provided
the C15-C18 syn,anti,syn stereotetrad 15 in 65%.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References and notes
1. Werner, G.; Hagenmaier, H.; Albert, K.; Kohlshorn, H. Tetrahedron Lett. 1983, 24,
5193–5196.
2. Corey, E. J.; Ponder, J. W. Tetrahedron Lett. 1984, 25, 4325–4328.
3. Baker, G. H.; Brown, P. J.; Dorgan, R. J. J.; Everett, J. R.; Ley, S. V.; Slawin, A. M. Z.;
Williams, D. E. Tetrahedron Lett. 1987, 28, 19–22.
4. Baker, G. H.; Brown, P. J.; Dorgan, R. J. J.; Everett, J. R. J. Chem. Soc., Perkin Trans. 2
1989, 175, 1073–1079.
5. Carr, G.; Williams, D. E.; Díaz-Marrero, A. R.; Patrick, B. O.; Bottriell, H.; Balgi, A.
D.; Donohue, E.; Roberge, M.; Andersen, R. J. J. Nat. Prod. 2010, 73, 422–427.
6. Bowman, E. J.; Siebers, A.; Altendorf, K. Proc. Natl. Acad. Sci. U.S.A. 1988, 85,
7972–7976.
7. Ohta, T.; Arakawa, H.; Futagami, F.; Fushida, S.; Kitagawa, H.; Kayahara, M.;
Nagakawa, T.; Miwa, K.; Kurashima, K.; Numata, M.; Kitamura, Y.; Terada, T.;
Ohkuma, S. J. Pathol. 1998, 185, 324–330.
8. Lim, J.-H.; Park, J.-W.; Kim, M.-S.; Park, S.-K.; Johnson, R. S.; Chun, Y.-S. Mol.
Pharmacol. 2006, 70, 1856–1865.
9. Perez-Sayans, M.; Somoza-Martín, J. M.; Barros-Angueira, F.; Gándara Rey, J.
M.; Garcia-Garcia, A. Cancer Treat. Rev. 2009, 35, 707–713.
10. Wu, Y. C.; Wu, W. K. K.; Li, Y.; Yu, L.; Li, Z. J.; Wong, C. C. M.; Li, H. T.; Sung, J. J.
Y.; Cho, C. H. Biochem. Biophys. Res. Commun. 2009, 382, 451–456.
11. Fais, S. J. Intern. Med. 2010, 267, 515–525.
12. Toshima, K. Curr. Org. Chem. 2004, 8, 185–210.
With reliable methods to synthesize fragments 9 and 15 now
available, the last step in our synthesis was the coupling of these
fragments. After unsuccessful attempts using several published
conditions,39 we found that the most effective way to obtain the
desired product was to first deprotonate dithiane 15 with t-BuLi,
followed by the addition of HMPA, and finally adding alkyl iodide
9. This resulted in 53% of the coupling product 16.
13. Evans, D. A.; Calter, M. A. Tetrahedron Lett. 1993, 34, 6871–6874.
14. Toshima, K.; Jyojima, T.; Yamaguchi, H.; Murase, H.; Yoshida, T.; Matsumura, S.;
Nakata, M. Tetrahedron Lett. 1996, 37, 1069–1072.
15. Toshima, K.; Yamaguchi, H.; Jyojima, T.; Noguchi, Y.; Nakata, M. Tetrahedron
Lett. 1996, 37, 1073–1076.
16. Toshima, K.; Jyojima, T.; Yamaguchi, H.; Noguchi, Y.; Yoshida, T.; Murase, H.;
Nakata, M.; Matsumura, S. J. Org. Chem. 1997, 62, 3271–3284.
17. Scheidt, K. A.; Tasaka, A.; Bannister, T. D.; Wendt, M. D.; Roush, W. R. Angew.
Chem., Int. Ed. 1999, 38, 1652–1655.
We have successfully completed the enantioselective synthesis
of the C14–C25 bafilomycin A1 polypropionate chain in 16% overall
yield and 8 steps in its longest linear sequence, starting from
known enantiomeric epoxides (ꢀ)-2 and (+)-2. Fragments 9 and
15 were synthesized using our epoxide cleavage methodology,
thus proving its effectiveness in the synthesis of polypropionate
chains. All stereocenters were generated from the epoxide precur-
sors. Completion of the synthesis, along with further studies using
this methodology for the elaboration of other polypropionate tar-
gets, is currently underway.
18. Hanessian, S.; Ma, J.; Wang, W.; Gai, Y. J. Am. Chem. Soc. 2001, 123, 10200–
10206.
19. Scheidt, K. A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G.
J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981–6990.
20. Kleinbeck, F.; Carreira, E. Angew. Chem., Int. Ed. 2009, 48, 578–581.
21. Roush, W. R.; Bannister, T. D. Tetrahedron Lett. 1992, 21, 3587–3590.
22. Paterson, I.; Bower, S.; McLeod, M. D. Tetrahedron Lett. 1995, 36, 175–178.
23. Marshall, J. A.; Adams, N. D. Org. Lett. 2000, 2, 2897–2900.
24. Eustache, F.; Dalko, P. I.; Cossy, J. J. Org. Chem. 2003, 68, 9994–10002.
25. Gao, Y.; Klunder, J. M.; Hanson, R. M.; Masamune, H.; Ko, S. Y.; Sharpless, K. B. J.
Am. Chem. Soc. 1987, 109, 5765–5780.
26. Gorzynski Smith, J. Synthesis 1984, 629–655.
27. Tirado, R.; Prieto, J. A. J. Org. Chem. 1993, 58, 5666–5673.
28. Arbelo, D. O.; Prieto, J. A. Tetrahedron Lett. 2002, 43, 4111–4114.
29. Arbelo, D. O.; Castro-Rosario, L.; Prieto, J. A. Synth. Commun. 2003, 33, 3211–
3223.
Acknowledgments
30. Torres, G.; Torres, W.; Prieto, J. A. Tetrahedron 2004, 60, 10245–10251.
31. Tirado, R.; Torres, G.; Torres, W.; Prieto, J. A. Tetrahedron Lett. 2005, 46, 797–
801.
We gratefully acknowledge the generous financial support from
NIH-RISE (2R25GM061151-09) and NIH-SCORE (2S06GM-08102-
29) Programs. We also thank Dr. Abimael Rodríguez’s laboratory
for their help with the HRMS(ESI) analysis of 16.
32. Rodríguez, D.; Mulero, M.; Prieto, J. A. J. Org. Chem. 2006, 71, 5826–5829.
33. Dávila, W.; Torres, W.; Prieto, J. A. Tetrahedron 2007, 63, 8218–8226.
34. Torres, W.; Rodríguez, R. R.; Prieto, J. A. J. Org. Chem. 2009, 74, 2447–2451.
35. Rodríguez-Berríos, R. R.; Torres, G.; Prieto, J. A. Tetrahedron 2011, 67, 830–836.
36. Mulero, M. Ph.D. Thesis, University of Puerto Rico, Rio Piedras, 2006.
37. Garegg, P. J.; Samuelsson, B. J. Chem. Soc. Chem. Commun. 1979, 978–980.
38. Smith, A. B.; Adams, C. M. Acc. Chem. Res. 2004, 37, 365–377.
39. (a) Ide, M.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2491–2499; (b) Ide, M.;
Tsunashima, K.; Nakata, M. Bull. Chem. Soc. Jpn. 1999, 72, 2501–2507; (c) Smith,
A. B.; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.; Moser, W. H.
Tetrahedron 2003, 125, 14435–14445.
Supplementary data
Supplementary data (experimental procedures and NMR spec-
tra for all new compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.02.067.