Enantiospecific total synthesis of the potent antitumor macrolides cryptophycins 1 and 8

Full text of DOI:10.1021/jo971645t

7098
J . Org. Chem. 1997, 62, 7098-7099
Given the profound activity of the cryptophycins, it is
not surprising that it has attracted considerable synthetic
interest.2,6 All efforts to date have focused on the
synthesis of 3, while subsequent epoxidation of this olefin
does not occur with good selectivity.2,6 We wish to report
here an enantiospecific synthesis of both cryptophycins
1 and 8 that allows for the exclusive generation of the
desired products.
We recognized from the outset that the stereospecific
introduction of the requisite epoxide/chlorohydrin could
best be accomplished from an appropriately functional-
ized precursor, so we chose diol 4 as a suitable target.
Further disconnection about the amide and ester linkages
led to our first retrosynthetic targets.
The requisite carbon backbone of the cryptophycins
was prepared from aldehyde 5 (Scheme 1).7,8 Reaction
of this aldehyde with 69 under standard Evans aldol
conditions afforded an excellent yield of a single crystal-
line product which was revealed to be the desired adduct
7.10,11 Following transamidation via the Weinreb proto-
col,12 addition of allylmagnesium bromide gave â,γ-
unsaturated ketone 8. The remaining stereocenter was
introduced with concomitant differentiation of the hy-
droxyl groups via intramolecular Tishchenko reaction
with acetaldehyde.13 The remaining alcohol was pro-
tected as the p-methoxybenzyl ether followed by conver-
sion of the acetate into TIPS ether 9. Oxidative cleavage
of the olefin was followed by Horner-Emmons olefination
and deprotection to afford the cryptophycin backbone 10.
The depsipeptoid portion of the cryptophycins was
prepared in a convergent fashion from the appropriately
protected building blocks. Condensation of 112 (Scheme
2) with amine 1214 was followed by desilylation and
oxidation to give acid 13.15 Esterification16 and debenz-
ylation gave the fully elaborated depsipeptoid 14, which
was coupled with 10 under Yamaguchi conditions.17 The
secoamide, which was revealed via exposure to acid, was
closed to the macrolide in excellent yield. Fluoride
En a n tiosp ecific Tota l Syn th esis of th e
P oten t An titu m or Ma cr olid es
Cr yp top h ycin s 1 a n d 8
Kevin M. Gardinier and J ames W. Leahy*
Department of Chemistry, University of California,
Berkeley, California 94720-1460
Received September 4, 1997X
In 1990, Schwartz and co-workers reported the isola-
tion of a novel depsipeptide from a Nostoc cyanobacte-
rium that was extremely active against filamentous fungi
and yeast of the genus Cryptococcus.1 Subsequently,
Moore and co-workers determined the structure of this
compound (cryptophycin 1, 1)2 and found that it was a
member of a family of macrolides that could be isolated
from Nostoc sp GSV 224,3 and that these compounds
exhibited extraordinary activity against a variety of
tumor cell lines.4 For example, 1 has an IC50 cytotoxicity
value of 20 pM against SKOV3 human ovarian carci-
noma.5 In addition to the natural cryptophycins, Moore
found that the synthetically derived cryptophycin 8 (2)
was more active in vivo than 1.5 Other modifications
about this epoxide portion (natural or synthetic) have led
to a significant loss of biological activity (e.g. cryptophycin
3 (3)).5
(6) (a) de Muys, J .-M.; Rej, R.; Nguyen, D.; Go, B.; Fortin, S.;
Lavalle´e, J .-F. Bioorg. Med. Chem. Lett. 1996, 6, 1111. (b) Salamonczyk,
G. M.; Han, K.; Guo, Z.-w.; Sih, C. J . J . Org. Chem. 1996, 61, 6893. (c)
Ali, S. M.; Georg, G. I. Tetrahedron Lett. 1997, 38, 1703.
(7) Prepared from (R)-ethyl mandelate via a two-step procedure (1.
Triisopropylsilyl (TIPS) chloride, imidazole (92%). 2. DIBAL, -78 °C
(94%)). The use of a TIPS protecting group was crucial, as the
corresponding TBS group was subject to migration in subsequent steps.
(8) All new compounds gave satisfactory 1H and 13C NMR data and
were within acceptable combustion analytical limits.
(9) Gage, J . R.; Evans, D. A. Org. Synth. 1989, 69, 83.
(10) Evans, D. A.; Kaldor, S. W.; J ones, T. K.; Clardy, J .; Stout, T.
J . J . Am. Chem. Soc. 1990, 112, 7001.
(11) This aldol reaction is apparently sensitive to the scale of the
reaction. While attempts to perform the transformation on large scale
has led to the formation of an undesired diastereomer (i), the desired
product could reliably and reproducibly be formed when less than 2 g
of 5 were used. It has previously been reported that aldol additions to
R-siloxy aldehydes gave rise to an undesired diastereomer.10
(1) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J . E.; Chartrain,
M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M. J .; Liesch, J . M.;
Yudin, K. J . Ind. Microbiol. 1990, 5, 113.
(2) See: Barrow, R. A.; Hemscheidt, T.; Liang, J .; Paik, S.; Moore,
R. E.; Tius, M. A. J . Am. Chem. Soc. 1995, 117, 2479 and references
cited within.
(3) See: Subbaraju, G. V.; Golakoti, T.; Patterson, G. M. L.; Moore,
R. E. J . Nat. Prod. 1997, 60, 302 and references cited within.
(4) Smith, C. D.; Zhang, X.; Mooberry, S. L.; Patterson, G. M. L.;
Moore, R. E. Cancer Res. 1994, 54, 3779.
(5) Golakoti, T.; Ogino, J .; Heltzel, C. E.; Husebo, T. L.; J ensen, C.
M.; Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.;
Corbett, T. H.; Valeriote, F. A. J . Am. Chem. Soc. 1995, 117, 12030.
(12) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
4171.
(13) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447.
(14) Prepared via reduction (BH3•THF (100%)) of the known amide
(Hioki, H.; Okuda, M.; Miyagi, W.; Ito, S. Tetrahedron Lett. 1993, 34,
6131).
(15) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936.
(16) Fredrick, D.; Bengt, F.; Leif, G.; Ulf, R. J . Chem. Soc., Perkin
Trans. 1 1993, 1, 11.
(17) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989.
S0022-3263(97)01645-9 CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 21, 1997 7099
Sch em e 1
Sch em e 2
deprotection then gave the desired cryptophycin diol 4
in 21% overall yield from 5.
be closed under the previously disclosed conditions5 to
give 1 which is identical in all respects to authentic
cryptophycin 1.
With our advanced target in hand, all that remained
was the stereospecific introduction of the epoxide func-
tionality. Sharpless has developed an excellent method
for the in situ conversion of vicinal diols into epoxides.18
In the case of the cryptophycins, however, the basic
transesterification required in the final step is incompat-
ible. We therefore sought an alternative that would allow
for the selective cleavage of the ester formed at the
homobenzylic position. In this regard, we chose 4-azido-
1,1,1-trimethoxybutane19 as our ortho ester since it would
allow for the stereospecific introduction of the chloride
and would give a 4-azidobutyrate ester in the process.20
Employing Sharpless’s conditions with this novel ortho
ester gave the anticipated 15. The azidobutyrate was
chosen because, under reductive conditions, the azide
could be transformed into the amine, causing it to
undergo intramolecular lactamization and thus depro-
tection. Indeed, selective reduction under Staudinger
conditions21 resulted in the cleavage of the butyrate and
gave exclusively cryptophycin 8 (2). The epoxide could
In summary, we have achieved a highly efficient and
enantiospecific total synthesis of cryptophycins 1 and 8.
The use of these methods for the preparation of novel
analogues as well as the elucidation of the mechanism
of biological activity are currently underway. Further-
more, we have generated a novel ortho ester to be used
in conjunction with known methodology to allow for the
stereospecific formation of epoxides in the presence of
other base sensitive functionality. Studies on other diol
systems will be reported in due course.
Ack n ow led gm en t. We thank the National Science
Foundation (CHE 95-02149) and the Research Corpora-
tion (1995 Cottrell Scholar Award to J .W.L.) for their
financial support of this work. We also thank Professor
R. E. Moore at the University of Hawaii for his generous
gift of authentic cryptophycin 1 for comparison pur-
poses.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
details for the synthesis of 1-15 (21 pages).
(18) Kolb, H. C.; Sharpless, K. B. Tetrahedron 1992, 48, 10515.
(19) Generated from 4-chlorobutyronitrile via formation of the ortho
ester followed by azide displacement (NaN3, 18-c-6 (99%)). See also
Ueno, H.; Maruyama, A.; Miyake, M.; Nakao, E.; Nakao, K.; Umezu,
K.; Nitta, I. J . Med. Chem. 1991, 34, 2468.
J O971645T
(20) See Shoichi, K.; Sakai, K.; Shiba, T. Bull. Chem. Soc. J pn. 1986,
59, 1296.
(21) Staudinger, H.; Meyer, J . Helv. Chim. Acta 1919, 2, 635.