Advances in Lewis acid controlled carbon-carbon bond-forming reactions enable a concise and convergent total synthesis of bullatacin

Article abstract of DOI:10.1021/ol061847o

(Chemical Equation Presented) Lewis acids control regioselectivity in the alkylation of epi-chlorohydrin and the stereochemistry of an alkyne addition to set the C24/C23 anti relationship. These advances facilitate an efficient total synthesis of bullatac

Full text of DOI:10.1021/ol061847o

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4379-4382
Advances in Lewis Acid Controlled
Carbon Carbon Bond-Forming
−
Reactions Enable a Concise and
Convergent Total Synthesis of
Bullatacin
Hongda Zhao, Jeffrey S. T. Gorman, and Brian L. Pagenkopf*
The Department of Chemistry, The UniVersity of Western Ontario,
London, ON N6A 5B7, Canada, and The Department of Chemistry,
UniVersity of Texas, Austin, Texas 78712
bpagenko@uwo.ca
Received July 26, 2006
ABSTRACT
Lewis acids control regioselectivity in the alkylation of epi-chlorohydrin and the stereochemistry of an alkyne addition to set the C24/C23 anti
relationship. These advances facilitate an efficient total synthesis of bullatacin in 13.3% overall yield from commercial starting materials.
Bullatacin is an archetypal member of the family of annona-
ceous acetogenin natural products that have been extensively
studied for both the synthetic challenges their structures elicit
and the potent and selective cytotoxicity these compounds
display.1 The bis(THF) region with its flanking hydroxyl
groups is found in various stereochemical arrangements in
related natural products, and the ubiquitous butenolide
portion occurs in natural products of even greater number
and variety.2
We imagined a straightforward, scaleable approach involving
three key retrosynthetic disconnections. The first is intro-
duction of the butenolide in as complete a state as pos-
sible to enhance synthetic convergence. The second is
addition of a hydrocarbon chain critical to our analogue
project. This segment will serve as a spacer that will allow
correlation of activity on the distance between the THF
region and the butenolide moiety.4 Finally, introduction of
the left-hand aliphatic chain to a desymmetrized 2,5-bis(THF)
completes the strategy. In practice, however, two of these
tasks proved to be overtly inefficient: establishing the
C(23)-C(24) anti stereochemistry by addition of the left-
Bullatacin has been synthesized previously,3 but we found
that for purposes of analogue preparation more operationally
simple, cost-effective, and modular pathways were desired.
(1) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J. Nat. Prod. 1999, 62,
504-540.
(2) (a) Bermejo, A.; Figade`re, B.; Zafra-Polo M. C.; Barrachina, I.;
Estornell E.: Cortes D. Nat. Prod. Rep. 2005, 22, 269-303. (b) Zafra-
Polo M. C.; Figade`re, B.; Gallardo, T.; Tormo, J. R.; Cortes, D. Phytochem-
istry 1998, 48, 1087-1117.
(3) (a) Tinsley, J. M.; Mertz, E.; Chong, P. Y.; Rarig, R.-A. F.; Roush,
W. R. Org. Lett. 2005, 7, 4245-4248. (b) Avedissian, H.; Sinha, S. C.;
Yazbak, A.; Sinha, A.; Neogi, P.; Sinha, S. C.; Keinan, E. J. Org. Chem.
2000, 65, 6035-6051. (c) Sinha, S. C.; Sinha, B. A.; Yazbak. A.; Keinan
E. Tetrahedron Lett. 1995, 36, 9257-9260. (d) Naito, H.; Kawahara, E.;
Maruta, K.; Maeda, M.; Sasaki, S. J. Org. Chem. 1995, 60, 4419-4427.
(e) Hoye, T. R.; Tan, L. S. Tetrahedron Lett. 1995, 36, 1981-1984.
Figure 1. Bullatacin
10.1021/ol061847o CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/15/2006

Scheme 1. Retrosynthetic Analysis
Scheme 2. Preparation of the Desymmetrized Bis(THF) Core
Segment
hand aliphatic chain to a C(23) aldehyde and preparation of
the butenolide. In this communication we address both of
these issues and reveal new Lewis acid controlled reactions
that achieve excellent stereocontrol in (1) the addition of
aliphatic terminal acetylides to tetrahydrofuran-2-carbalde-
hydes and (2) complete regiocontrol in the alkylation of epi-
chlorohydrin.
7, oxidation of the secondary alcohol to the ketone, and
stereoselective hydride reduction using L-selectride followed
by Mitsunobu inversion, for a transformation that in principle
should only require two steps.11 We successfully employed
this sequence during our initial investigations, but clearly a
less laborious approach was desired.
In this regard, we report herein a practical and general
alternative for this transformation that relies on our observa-
tion that aliphatic titanium acetylide 8 reacts with bis(THF)
7 to give 9 with high 10:1 anti selectivity and in good 85%
isolated yield (96% based on either recovered starting
material, Scheme 3). The stereochemistry was assigned by
NMR analysis of esters of each diastereomer.12
The right-hand side of bullatacin requires syn stereochem-
istry from addition to aldehyde 10, which was prepared in
78% yield from 9 by protecting group adjustments and Swern
oxidation. Recently, syn alkylation of a related mono-THF
aldehyde substrate by the Carreira zinc acetylide method was
reported.13 We were able to successfully reproduce those
results with a model mono-THF substrate. However, ap-
plication of the same conditions with bis(THF) aldehyde 10
failed, and others have commented on the difficulties
This synthesis of bullatacin began by double allylation of
the easily prepared C2-symmetric bis-epoxide 2 to give the
known diol 3 (Scheme 2).5 The desymmetrization of 3 was
accomplished by mono-acylation to give acetate 4 in
quantitative yield.6 The THF rings were constructed stepwise
with complete stereocontrol using the cobalt-catalyzed
aerobic oxidative cyclization reported by Mukaiyama.7-9
With one alcohol of 6 protected as its TBS ether, Swern
oxidation gave aldehyde 7.
With the bis(THF) core 7 at hand, the stage was set for
introduction of either side chain. Additions of aliphatic
carbanions to bis(THF)-2-carbaldehydes (i.e., 7, Scheme 2)
are known to give poor stereoselectivity under standard
chelation-controlled conditions. We are unaware of reagents
for the selective addition of aliphatic organometallic reagents
to bis(THF)-2-carbaldehydes such as 7 that give preferentially
anti stereochemistry as required for the left-hand side.10
Others have pioneered a solution to this problem (not shown)
that involves an unselective Grignard addition to aldehyde
(10) (a) Emde, U.; Koert, U. Eur. J. Org. Chem. 2000, 1889-1904. (b)
Shunya, T.; Kenji, F.; Nobuo, S.; Tadashi, N. Heterocycles 2000, 53, 1361-
1370.
(11) Harmange, J.-C.; Figade`re, B.; Cave´, A. Tetrahedron Lett. 1992,
33, 5749-5752.
(4) For a lead reference, see: Abe, M.; Murai, M.; Ichimaru, N.;
Kenmochi, A.; Yoshida, T.; Kubo, A.; Kimura, Y.; Moroda, A.; Makabe,
H.; Nishioka, T.; Miyoshi, H. Biochemistry 2005, 44, 14898-14906.
(5) Robbins, M. A.; Devine, P. N.; Oh, T. Org. Synth. 1999, 76 101-
109.
(6) Maezaki, N.; Kojima, N.; Sakamoto, A.; Tominaga, H.; Iwata, C.;
Tanaka, T.; Monden, M.; Damdensuren, B.; Nakamori, S. Chem. Eur. J.
2003, 9, 389-399. ref 2.
(7) Hanessian, S.; Roy, R. Can. J. Chem. 1985, 63, 163-72.
(8) Inoki, S.; Mukaiyama, T. Chem. Lett. 1990, 67-70.
(9) Alternatively, preparing both THF rings concurrently in the same
pot using identical oxidation conditions was significantly less efficient in
our experience. Wang, Z.-M.; Tian, S.-K.; Shi, M. Tetrahedron Lett. 1999,
40, 977-980.
(12) (a) Ramirez, E. A.; Hoye, T. R. In Studies in Natural Products
Chemistry; Atta-ur-Rahman, Ed.; Elsevier: New York, 1995; Vol 17,
Structure and Chemistry (Part D), pp 251-282. (b) Gale, J. B.; Yu, J.-G.;
Hu, X. E.; Khare, A.; Ho, D. K.; Cassady, J. M. Tetrahedron Lett. 1993,
34, 5847-5850. Amoroux, R.; Chastrette, F.; Chastrette, M. J. Heterocycl.
Chem. 1981, 18, 565. Mulholland, R. L., Jr.; Chamberlain, A. R. J. Org.
Chem. 1988, 53, 1082. A detailed discussion of all stereochemical
assignments and comparisons to literature examples will be provided
elsewhere.
(13) (a) Kojima, N.; Maezaki, N.; Tominaga, H.; Asai, M.; Yanai, M.;
Tanaka, T. Chem. Eur. J. 2003, 9, 4980-4990. (b) Maezaki, N.; Tominaga,
H.; Kojima, N.; Yanai, M.; Urabe, D.; Tanaka, T. Chem. Commun. 2004,
406-407. (c) Frantz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc.
1999, 121, 11245-11246.
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Org. Lett., Vol. 8, No. 19, 2006

Scheme 3. Modular Synthesis Based on the Bis(THF) 7
sometimes encountered with the alkyne addition.14 After
alkylation of epi-chlorohydrin with the lithium enolate of
White’s lactone 15 to afford halohydrin 1819 in 86% isolated
yield (Scheme 4, lower route). Closure of the halohydrin to
the epoxide with NaH and elimination of the sulfoxide gave
13 in 99% ee and 63% yield overall from 15. This
modification is an important advance because it allows the
most efficient synthesis to date of this useful butenolide
epoxide.
fruitless screening of stoichiometry and solvents, we found
that with gentle heating the reaction ensued at 50 °C and
the addition product 12 was obtained in 75% yield (syn:anti
) 4:1).15 Although the selectivity is lower for the bis(THF)
substrate than for mono-THF systems, this approach is more
efficient than Grignard addition, oxidation, and L-selectride
reduction described above. Furthermore, results underscore
the important reactivity differences between bis(THF)s and
mono-THF 2-carbaldehydes.
Introducing the butenolide essentially intact (as 13) by
alkylation of 12 is a transparent strategy to enhance
convergence of the synthetic stream (Scheme 3). However,
this direct approach is seldom employed, and we were also
reluctant to engage this route because an efficient synthesis
of 13 is lacking. One difficulty arises from the poor
regioselectivity in the alkylation of epi-chlorohydrin with 15,
which leads to the formation of epoxides 16 and 17 and
ultimately to 13 as a mixture of diastereomers (Scheme 4,
upper route).16 This problem has prompted others to devise
creative alternatives for accessing the same butenolide
architecture, but none appear as concise and convergent as
that detailed below.17
Scheme 4. Regioselective Alkylation of epi-Chlorohydrin
Mediated by Et3B
Advances in epoxide functionalization often arise from the
judicious pairing of nucleophile and Lewis acid.18 In this
regard, we report herein a novel Et3B-promoted regioselective
Addition of the lithium acetylide of 12 (Scheme 3) with
epoxide 13 cleanly afforded alcohol 14 in 65% isolated yield
(95% yield based on either recovered starting material).20
The natural product was ultimately revealed by reduction of
(14) For a literature summary and discussion, see Kirkham, J. E. D.;
Courtney, T. D. L.; Lee V.; Baldwin, J. E. Tetrahedron 2005, 61, 7219-
7232.
(15) Recently, addition of a propargylic alkyne to a bis(THF) has been
reported: Tominaga, H.; Maezaki, N.; Yanai, M.; Kojima, N.; Urabe, D.;
Ueki, R.; Tanaka, T. Eur. J. Org. Chem. 2006, 1422-1429.
(16) A related reverse alkylation strategy has been reported that
circumvents epi-chlorohydrin, but translactonization then becomes prob-
lematic. (a) Hoye, T. R.; Hanson, P. R.; Hasenwinkel, L. E.; Ramirez, E.
A.; Zhuang, Z. Tetrahedron Lett. 1994, 35, 8525-8528. (b) Hoye, T. R.;
Hanson, P. R.; Hasenwinkel, L. E.; Ramirez, E. A.; Zhuang, Z. Tetrahedron
Lett. 1994, 35, 8529-8532.
(17) (a) Evans, P. A.; Murthy, V. S. Tetrahedron Lett. 1998, 39, 9627-
9628. (b) Trost, B. M.; Calkins, T. L. Tetrahedron Lett. 1995, 36, 6021-
6024. (c) Schaus, S. E.; Braˆnalt, J.; Jacobsen, E. N. J. Org. Chem. 1998,
63, 4876-4877 (d) Marshall, J. A.; Hinkle, K. W. J. Org. Chem. 1997, 62,
5989-5995.
(18) Zhao, H.; Pagenkopf, B. L. Chem. Commun. 2003, 2592-2593.
(19) The structure of 18 was confirmed by single-crystal X-ray analysis.
Org. Lett., Vol. 8, No. 19, 2006
4381

both alkynes with diimide followed by oxidative cleavage
of the two benzyl ethers with DDQ (90% overall).21
In summary, a total synthesis of bullatacin from bis-
epoxide 2 has been accomplished in 13.3% overall yield,
which constitutes the most efficient synthesis of bullatacin
to date by an order of magnitude. One streamlining feature
that facilitated the synthesis is the stereoselective titanium
acetylide addition to bis(THF) aldehyde 7. The second is a
short route to butenolide 13 made possible by a new Et3B-
mediated regioselective alkylation of epi-chlorohydrin. These
tactics are being successfully applied to the synthesis of other
annonaceous acetogenins and analogues, and these results
will be reported in due course.
Johnson, NSERC, and the University of Western Ontario
for financial assistance.
Supporting Information Available: General experimen-
tal procedures, characterization of all new compounds, and
stereochemical analysis and X-ray structure data for 18 in
CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL061847O
(20) (a) Jiang, S.; Liu, Z.-H.; Sheng, G.; Zeng, B.-B.; Cheng, X.-G.;
Wu, Y. L.; Yao, Z. J. J. Org. Chem. 2002, 67, 3404-3408. (b) Yamaguchi,
M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(21) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett. 1982,
23, 885-888. (b) Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5,
3009-3011.
Acknowledgment. We thank the donors of the American
Chemical Society Petroleum Research fund, Johnson and
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