Short and efficient synthesis of cryptophycin unit A

Article abstract of DOI:10.1021/ol063032l

(Chemical Equation Presented) Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality, while all further stereogenic centers are introduced under substrate control. The key

Full text of DOI:10.1021/ol063032l

ORGANIC
LETTERS
2007
Vol. 9, No. 5
817-819
Short and Efficient Synthesis of
Cryptophycin Unit A
Stefan Eissler,† Markus Nahrwold,† Beate Neumann,‡ Hans-Georg Stammler,‡ and
Norbert Sewald*,†
Department of Chemistry, Organic and Bioorganic Chemistry and Inorganic
Chemistry, Bielefeld UniVersity, UniVersita¨tsstrasse 25, 33615 Bielefeld, Germany
norbert.sewald@uni-bielefeld.de
Received December 15, 2006
ABSTRACT
Two short synthetic approaches toward cryptophycin unit A comprise a catalytic asymmetric dihydroxylation as the sole source of chirality,
while all further stereogenic centers are introduced under substrate control. The key step of the first route is a vinylogous Mukaiyama aldol
addition, which introduces the
r,â-unsaturated ester moiety with defined configuration at the δ-carbon atom. Likewise, allylation with
allyltributylstannane diastereoselectively gives the homoallylic alcohol that can be converted by a metathesis reaction to a unit A precursor.
Cryptophycins are a class of 16-membered macrocyclic
depsipeptides. The first representative, cryptophycin-1, was
isolated more than 15 years ago by Schwartz et al. at Merck
from the cyanophyte Nostoc sp. ATCC 537891 and later by
Moore et al. from Nostoc sp. GSV 224, who made a first
proposal regarding the stereochemistry in 1994.2 At the same
time, Kobayashi et al. reported on the isolation of the close
analogue arenastatin A (later renamed cryptophycin-24) from
the marine sponge Dysidea arenaria, providing the absolute
configuration and a first total synthesis.3
and analogues have been published since then, providing
detailed insight into the structure-activity relationship of
cryptophycins.4
Retrosynthetic disconnection at the depsipeptide ester and
amide bonds of cryptophycin-1 leads to four building blocks
corresponding to units A-D (Figure 1): unit A is a
structurally unique δ-hydroxy acid with four stereogenic
Cryptophycin-1 and related cryptophycins display tumor-
selective cytotoxicity even against multidrug-resistant cell
lines. Many syntheses of naturally occurring cryptophycins
† Organic and Bioorganic Chemistry.
‡ Inorganic Chemistry.
(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. Biotechnol. 1990, 5, 113.
(2) Golakoti, T.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.; Corbett,
T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. Soc. 1994, 116, 4729.
(3) (a) Kobayashi, M.; Kurosu, M.; Ohyabu, N.; Wang, W.; Fujii, S.;
Kitagawa, I. Chem. Pharm. Bull. 1994, 42, 2196. (b) Kobayashi, M.; Aoki,
S.; Ohyabu, N.; Kurosu, M.; Wang, W.; Kitagawa, I. Tetrahedron Lett.
1994, 35, 7969.
Figure 1. Retrosynthetic disconnection of cryptophycin-1 leading
to the four building block units A, B, C, and D.
10.1021/ol063032l CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/07/2007

centers; unit B is a D-tyrosine-derived R-amino acid; unit C
is a â-alanine derivative, and unit D is L-leucic acid. Usually,
the individual building blocks are synthesized as protected
precursors which are sequentially coupled to give an acyclic
depsipeptide and then cyclized. Ring closure can be effected
by either macrolactamization or ring-closing metathesis
(RCM) as pioneered by Georg and Tripathy in 2004.5 The
RCM strategy tolerates the highly sensitive benzylic epoxide
function. However, the epoxide is usually introduced at the
end of the synthesis. In most recent syntheses, the config-
uration of the future epoxide is preformed as a syn-diol,
which is later converted into the epoxide according to
Sharpless’ protocol,6 which was adapted for base-sensitive
substrates by Moher7 and co-workers and introduced into
cryptophycin synthesis by Leahy and Gardinier in 1997.8
Moher and co-workers were the first to establish the
stereochemistry of the syn-diol by an asymmetric dihydrox-
ylation (AD), though at the seco-cryptophycin stage after
introduction of all other stereogenic centers.7 We recently
reported on a stereodivergent 13-step synthesis of a unit A
precursor relying on an asymmetric dihydroxylation as the
sole source of chirality and subsequent diastereoselective
reactions.9
Scheme 1. Unit A Precursor Synthesis
The unit A synthesis discussed in the following obeys the
same principle but features a different set of disconnections.
The key step is the conversion of intermediate 6 to unit A
precursor 8 (Scheme 1). A similar approach was followed
by Sih and co-workers to a simpler unit A precursor with
only two stereogenic centers, but introduction of the R,â-
unsaturated ester moiety by a Reformatsky-type reaction with
tert-butyl 4-bromocrotonate and a Pb/Zn couple proceeded
without satisfactory regio- and diastereoselectivity.10 In
contrast to the Reformatsky reaction, vinylogous Mukaiyama
aldol additions with silylketene acetals11 proceed with
regioselective attack of the γ-carbon atom, a method recently
applied by Kalesse and co-workers to the total synthesis of
ratjadone.12
Our synthesis starts with (E)-4-phenylbut-3-enoic acid 1,
which was converted to methyl ester 2 by treatment with
cesium carbonate and methyl iodide in 97% yield. Methyl
ester 2 could also be obtained from phenylacetaldehyde by
a modified Knoevenagel condensation in 58% yield.13 The
previously described asymmetric dihydroxylation of 2 under
concomitant lactonization14 gave â-hydroxylactone 3 in 78%
yield after purification by crystallization and chromatography
of the residue. R-Methylation of the dianion derived from 3
with LDA/methyl iodide occurred without any O-methylation
1
and with complete diastereoselectivity according to the H
NMR spectrum of the crude product. After purification by
chromatography, lactone 4 was obtained in 87% yield. Georg
and co-workers used a Fra´ter alkylation to introduce the
δ-methyl substituent in a unit A synthesis before,15 though
with an acyclic substrate. In the case of lactone 4, however,
R-methylation occurs diastereoselectively in the absence of
the â-hydroxyl substituent as well, as was demonstrated in
the unit A synthesis of Ghosh and Swanson.16 Both protection
of the diol as acetonide and esterification to methyl ester 5
were effected by treatment with 2,2-dimethoxypropane,
methanol, and Amberlyst-15 at room temperature in 88%
yield.17 Selective reduction of methyl ester 5 with diisobut-
ylaluminum hydride gave aldehyde 6 in virtually quantitative
yield. Aldehyde 6 was used without prior purification, though
flash chromatography was possible without epimerization.
The magnesium bromide diethyl etherate mediated vinyl-
ogous Mukaiyama aldol addition of (E,Z)-(1-tert-butoxybuta-
1,3-dienyloxy)trimethylsilane 718 to aldehyde 6 gave unit A
precursor 89 in 42% yield and 95% de. The relative
configuration of 8 was proven by X-ray crystal structure
analysis (Figure 2). Because the enantioselectivity of the
asymmetric dihydroxylation14,17 is known, there is no doubt
regarding the absolute configuration of 8 as well.
(4) Recent reviews on cryptophycins: (a) Eissler, S.; Stoncius, A.;
Nahrwold, M.; Sewald, N. Synthesis 2006, 3747. (b) Eggen, M.; Georg, G.
I. Med. Res. ReV. 2002, 22, 85. (c) Tius, M. A. Tetrahedron 2002, 58, 4343.
(5) Tripathy, N. K.; Georg, G. I. Tetrahedron Lett. 2004, 45, 5309.
(6) Chang, H. T.; Sharpless, K. B. J. Org. Chem. 1996, 61, 6456.
(7) Liang, J.; Moher, E. D.; Moore, R. E.; Hoard, D. W. J. Org. Chem.
2000, 65, 3143.
(8) Gardinier, K. M.; Leahy, J. W. J. Org. Chem. 1997, 62, 7098.
(9) Mast, C. A.; Eissler, S.; Stoncius, A.; Stammler, H.-G.; Neumann,
B.; Sewald, N. Chem. Eur. J. 2005, 11, 4667.
The aldol addition step gave only a moderate yield and
was inconvenient insofar as the synthesis of silyl keteneacetal
(10) Salamonczyk, G. M.; Han, K.; Guo, Z.; Sih, C. J. J. Org. Chem.
1996, 61, 6893.
(11) Casiraghi, G.; Zanardi, F.; Appendino, G.; Rassu, G. Chem. ReV.
2000, 100, 1929.
(14) Wang, Z.-M.; Zhang, X.-L.; Sharpless, K. B. Tetrahedron Lett. 1992,
33, 6407.
(12) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.; Kalesse, M.
Angew. Chem. 2000, 112, 4535; Angew. Chem., Int. Ed. 2000, 39, 4364.
(13) Ragoussis, N.; Ragoussis, V. J. Chem. Soc., Perkin Trans. I 1998,
3529.
(15) Eggen, M.; Mossman, C. J.; Buck, S. B.; Nair, S. K.; Bhat, L.; Ali,
S. M.; Reiff, A.; Boge, T. C.; Georg, G. I. J. Org. Chem. 2000, 65, 7792.
(16) Ghosh, A. K.; Swanson, L. J. Org. Chem. 2003, 68, 9823.
(17) Harcken, C.; Bru¨ckner, R. Synlett 2001, 718.
818
Org. Lett., Vol. 9, No. 5, 2007

Scheme 2. Metathesis Approach from Aldehyde 6
and 32% yield over six and seven steps, respectively. Though
the synthesis outlined in Scheme 1 is the shortest one of a
unit A precursor with four stereogenic centers so far, the
overall yield is limited by the moderate efficiency of the
Mukaiyama aldol addition step. In contrast, the almost
equally short allylation/metathesis approach outlined in
Scheme 2 is one of the most efficient syntheses. Nevertheless,
an RCM approach starting from intermediate 9 (45% overall
yield) seems even more promising.
Figure 2. X-ray structure of unit A precursor 8 after crystallization
from n-hexane.
7 requires the addition of hexamethylphosphoric triamide.18
Alternatively, we investigated the allylation of aldehyde 6
with allyltributylstannane, which gave homoallylic alcohol
9 in 76% yield and 98% de (Scheme 2). Although 9 is a
potential unit A precursor for RCM,5 we used a metathesis
reaction with tert-butylacrylate and Grubbs’ second-genera-
tion catalyst to prepare unit A precursor 8 in 71% yield,
which confirmed the anticipated diastereoselectivity of the
allylation step.
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft and Fonds der Chemischen Industrie for
financial support.
Supporting Information Available: Synthetic procedures
and full spectroscopic data for compounds 2-6, 8, and 9
and the complete crystal data for 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
In summary, two syntheses of cryptophycin unit A
precursor 8 were developed, providing the compound in 24%
(18) Paterson, I.; Price, L. G. Tetrahedron Lett. 1981, 22, 2833.
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