Total synthesis of cryptophycin analogues via a scaffold approach

Article abstract of DOI:10.1021/ol0609356

Allylation of in situ generated β,γ-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins. Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols is possible, which affords novel analogues of these potent antimitotic agents.

Full text of DOI:10.1021/ol0609356

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2993-2996
Total Synthesis of Cryptophycin
Analogues via a Scaffold Approach
J. Adam McCubbin, Matthew L. Maddess, and Mark Lautens*
DaVenport Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George St., Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received April 18, 2006
ABSTRACT
Allylation of in situ generated
â,γ-unsaturated aldehydes affords rapid access to vinyl halide analogues of fragment A of the cryptophycins.
Three scaffolds are prepared in gram quantities by a ring-closing metathesis approach. Derivatization via a variety of cross-coupling protocols
is possible, which affords novel analogues of these potent antimitotic agents.
Antimitotic agents1 display remarkable structural variety and
are arguably the most useful class of pharmaceuticals for
the chemotherapeutic treatment of a variety of cancers.2
Within this group of molecules, the cryptophycin depsipep-
tides3 (Figure 1) are among the most potent thus far
described, operating at picomolar concentrations, and 40- to
400-fold more active than paclitaxel4 or vinblastine5 in
several tumor cell lines.6 Of additional import is a reduced
susceptibility to Pgp (P-glycoprotein)7 mediated multiple
drug resistance (MDR) relative to other anticancer agents.8
The low abundance of the cryptophycins combined with
extraordinary clinical potential9 and their modular nature has
made them an ideal target for total synthesis.10
Allylation of â,γ-unsaturated aldehydes generated by the
treatment of 2-vinyloxiranes (e.g., 8 and 9, Figure 2) with a
Lewis acid11 affords the basic core structure of fragment A
[(S)-6 or (S)-7] of the cryptophycins. In particular, we were
interested in substrates that contained functionality that could
(6) Wagner, M. M.; Paul, D. C.; Shih, C.; Jordan, M. A.; Wilson, L.;
Williams, D. C. Cancer Chemother. Pharmacol. 1998, 115.
(7) (a) Gottesman, M. M.; Pastan, I. Biochemistry 1993, 32, 385. (b)
Shen, D. W.; Fojo, A.; Chin, J. E.; Roninson, I. B.; Richert, N.; Pastan, I.;
Gottesman, M. M. Science 1986, 232, 643. (c) Gros, P.; Ben Neriah, Y.;
Croop, J. M.; Housanman, D. E. Nature 1986, 323, 718.
(1) For a review on antimitotic agents, see: Li, Q.; Sham, H. L.;
Rosenberg, S. Ann. Rep. Med. Chem. 1999, 34, 139.
(2) (a) Jordan, M. A.; Wilson, L. Curr. Opin. Cell Biol. 1998, 10, 123.
(b) Giannakakou, P.; Sackett, D.; Fojo, T. J. Natl. Cancer Inst. 2000, 92,
182.
(3) For reviews, see: (a) Tius, M. A. In Handbook of EnVironmental
Chemistry; Gribble, G. W., Ed.; Springer: Berlin, 2003; p 265.; (b) Hong,
J.; Zhang, L. In Frontiers of Biotechnology and Pharmaceuticals; Zhao,
K., Reiner J., Chen, S.-H., Eds.; Science Press New York Ltd.: New York,
2002; p 193. (c) Li, T.; Shih, C. In Frontiers of Biotechnology and
Pharmaceuticals; Zhao, K., Reiner, J., Chen, S.-H., Eds.; Science Press
New York Ltd.: New York, 2002; p 172. (d) Tius, M. A. Tetrahedron
2002, 58, 4343. (e) Eggen, M.-J.; Georg, G. I. Med. Res. ReV. 2002, 22,
85. (f) Shih, C.; Teicher, B. A. Curr. Pharm. Des. 2001, 7, 1259.
(4) Nicolaou, K. C.; Dai, W.-M.; Guy, R. K. Angew. Chem., Int. Ed.
Engl. 1994, 33, 15.
(8) Smith, C. D.; Zhang, X.; Mooberry, S. L.; Patterson, G. M. L.; R.
Moore, E. Cancer Res. 1994, 54, 3779.
(9) (a) Liang, J.; Moore, R. E.; Moher, E. D.; Munroe, J. E.; Al-awar,
R. S.; Hay, D. A.; Varie, D. L.; Zhang, T. Y.; Aikins, J. A.; Martinelli, M.
J.; Shih, C.; Ray, J. E.; Gibson, L. L.; Vasudevan, V. Polin, L.; White, K.;
Kushner, J.; Simpson, C.; Pugh, S.; Corbett, T. H. InVest. New Drugs 2005,
23, 213. (b) Drew, L.; Fine, R. L.; Do, T. N.; Douglas, G. P.; Petrylak, D.
P. Clin. Cancer Res. 2002, 8, 3922.
(10) For recent total syntheses, see: (a) Danner, P.; Bauer, M.; Phukan,
P.; Maier, M. E. Eur. J. Org. Chem. 2005, 11, 317. (b) Tripathy, N. K.;
Georg, G. I. Tetrahedron Lett. 2004, 45, 5309. (c) Ghosh, A. K.; Bischoff,
A. Eur. J. Org. Chem. 2004, 10, 2131. (d) Vidya, R.; Eggen, M.-J.; Nair,
S. K.; Georg, G. I.; Himes, R. H. J. Org. Chem. 2003, 68, 9687. (e) Ghosh,
A. K.; Swanson, L. J. Org. Chem. 2003, 68, 9823.
(5) (a) Mitchison T., Kirschner, M. W. Nature 1984, 312, 237. (b)
Kirschner, M. W.; Mitchison, T. Nature 1986, 324, 621. (c) Avila, J. FASEB
J. 1990, 4, 3284.
10.1021/ol0609356 CCC: $33.50
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been widely employed for this purpose, and from the list of
available alternatives we selected Amano lipase AK on the
basis of its commercial availability and success in similar
systems.17
With some optimization,18 we were pleased to find that
after 4 days at room temperature, the fully resolved alcohol
(S)-619 and the optically enriched acetate (R)-1220 were
recovered (Scheme 1).21
Scheme 1
Figure 1. Various cryptophycin structures.
be readily derivatized (e.g., scaffolds 4 or 5) via a variety of
metal cross-coupling reactions.12 Functionalization would
allow for the synthesis of a wide variety of analogues that
have not previously been prepared. As evidenced by the
structural diversity of other antimitotic agents that are
accommodated by the active site of â-tubulin,13 it may be
possible to discover new pharmacologically active com-
pounds based on substitution on this olefin.
The resolution of the vinylic iodide (7) under the same
conditions gave both the resolved alcohol (S)-722 and acetate
(R)-13 in near perfect ee (E ) 478). The enantiomerically
enriched acetate was hydrolyzed to (R)-7 without a significant
loss of optical purity. With suitable substrates now in hand
((S)-6, (S)-7, and (R)-7) we began construction of the
macrocylic cryptophycin scaffolds.
Purification of the free acid coupling partner (10, Figure
2) was both ineffective and difficult; moreover we were
concerned about its stability to storage. Consequently, we
investigated a one-pot procedure for the synthesis of 17 from
the allyl-protected depsipetide (11, Scheme 2).23 Palladium-
catalyzed deallylation of 11, followed by esterification with
(S)-6 under Yamaguchi conditions afforded the macrocyclic
precursor (17) in excellent yield. Esterification of (S)-7 and
(R)-7 under identical conditions afforded 18 and epi-18
respectively in comparable yields. The macrocycle (4) was
Figure 2. Retrosynthetic analysis of the cryptophycin scaffolds.
Based on our recent study14 concerning the selective
terminal homologation of bishomoallylic alcohols and a
precedent established by Georg,10(b) our strategy involves
ring-closing metathesis (RCM) as the final step for scaffold
formation, following esterification of the depsipeptide frag-
ment 11 with the appropriate bishomoallylic alcohol (6 or
7, Figure 2).
(16) For reviews, see: (a) Roberts, S. M. In PreparatiVe Biotransfor-
mations; Wiley: Chichester, 1992-1997. (b) Faber, K. In Biotransforma-
tions in Organic Chemistry, 3rd ed.; Springer: Weinheim, 1997. (c) Wong,
C.-H.; Whitesides, G. M. In Enzymes in Synthetic Organic Chemistry;
Elsevier Science: New York, 1994.
(17) (a) Taber, D. F.; Jiang, Q. J. Org. Chem. 2001, 66, 1876. (b) Suh,
Y. G.; Min, K.-H.; Lee, Y.-S.; Seo, S.-Y.; Kim, S.-H.; Park, H.-J.
Tetrahedron Lett. 2002, 43, 3825. (c) Zhu, B.; Panek, J. S. Eur. J. Org.
Chem. 2001, 1701. (d) Zhu, B.; Panek, J. S. Tetrahedron Lett. 2000, 12,
1863.
(18) We first subjected the corresponding homoallylic homopropargylic
alcohol to the resolution conditions of Taber (3 mass equiv AK, 60 °C,
neat vinyl acetate) and observed that regardless of conversion, both the
acetate and unreacted alcohol were racemic.
The depsipeptide portion (11) was prepared by known
literature procedures or slight modifications thereof.15 To
prepare enantiomerically pure vinyl halide bishomoallylic
alcohols (6 and 7), we decided to employ enzymatic
resolution16 of racemic bishomoallylic alcohols to gain ready
access to both antipodes of the desired products. Lipases have
(19) Stereochemistry was confirmed by comparison of HPLC traces of
this alcohol and of the identical substrate prepared previously. See ref 11a
(20) Currently, this acetate is not of sufficient optical purity to be useful
in the preparation of cryptophycin analogues. We are investigating solutions
to this problem.
(21) Calculated according to: Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.;
Shi, C. J. J. Am. Chem. Soc. 1982, 104, 7294.
(11) (a) Lautens, M.; Maddess, M. L.; Sauer, E. L.; Ouellet, S. G. Org.
Lett. 2002, 4, 83. (b) Lautens, M.; Ouellet, S. G.; Raeppel, S. Angew. Chem.,
Int. Ed. 2000, 39, 4079.
(12) Tsuji, J. In Palladium Reagents and Catalysis: New PerspectiVes
for the 21st Century; Wiley: Chichester, U.K., 2004.
(13) Mitra, A.; Sept, D. Biochemistry 2004, 43, 13955.
(14) Lautens, M.; Maddess, M. L. Org. Lett. 2004, 6, 1883.
(15) See Supporting Information for details.
(22) Absolute stereochemistry was proven by X-ray analysis of 22.
(23) For details on the synthesis of 11, see Supporting Information.
2994
Org. Lett., Vol. 8, No. 14, 2006

quantities of the three macrocylic scaffolds (4, 5, and epi-5)
in hand, we initiated preliminary investigations directed
toward derivatization of the vinylic halides, Table 1.
Sonogashira25 coupling of 4 with phenyl acetylene gave
the cross-coupled product 20a in good yield. The vinyl iodide
substrates (5 and epi-5) were notably more reactive, affording
21a and epi-21a, respectively, in improved yield under milder
reaction conditions. We have also demonstrated examples
of Suzuki-Miyaura26 reactions on all three scaffolds (4, 5,
and epi-5) with phenylboronic acid and CsF that afforded
analogues 20b, 21b, and epi-21b, respectively, in high yield.
We were surprised to find that in the case of 5, when the
base is changed to K2CO3, no coupling product was observed,
but rather the intramolecular Heck product 22 was isolated
in good yield. Similarly, attempted Stille coupling of 4 with
tributylphenyltin gave the isomeric product 23. For the
former product (22) a crystal structure has been obtained
that confirms both the structure and relative stereochemistry
about the macrocycle (Figure 3).27
Scheme 2
smoothly formed under treatment with Grubbs’ second
generation catalyst (14) in CH2Cl2 (0.014 M) at room
temperature (Scheme 2). Attempted ring-closure of epi-18
under the same conditions was very sluggish and required
more forcing conditions. Moreover, along with the formation
of the desired product (epi-5) a second macrocylic compound
was isolated that appears to be the terminal olefin 19.24
Fortunately, use of the less active catalyst (15) suppressed
the pathway leading to 19 and provided the desired macro-
cycle (epi-5) in good yield. The latter method was used for
the preparation of the third cryptophycin scaffold (5), which
proceeded without incident and in good yield. With gram
Table 1. Cryptophycin Scaffold Coupling Reactions
Figure 3. Crystal structure of 22.
Finally, we have initiated investigations aimed at the
installation of the epoxide moiety upon the trisubstituted
(24) This product was a single disasteromer, suggesting it was not formed
by RCM with the internal olefin, followed by ROM/RCM to form the
macrocycle.
(25) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(26) (a) Suzuki, A. J. Organomet. Chem. 2002, 653, 83. (b) Miyaura,
N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(27) Colorless needles, dimensions 0.30 × 0.16 × 0.15 mm3, ortho-
rhombic, P 21 21 21, a ) 10.4580(3), b ) 17.8240(5), c ) 21.1220(7) Å,
R ) 90°, â ) 90°, γ ) 90°, V ) 3937.2(2) Å3, F ) 1.248 g cm-3, T )
150(2) K, θmax ) 27.49°, Nonius Kappa-CCD diffractometer using graphite-
monochromated Mo KR radiation (λ ) 0.71073 Å). Of 28907 reflections
collected, 8968 were independent (Rint ) 0.0665). The data frames were
integrated and scaled using the Denzo-SMN package (Otwinowski, Z.;
Minor, W. Methods Enzymol. 1997, 276, 307-326.). Solution and refine-
ment with SHELXTL V6.12 (G. M. Sheldrick, SHELXTL-Windows NT.
V6.12, Bruker Analytical X-ray Systems Inc., Madison, WI, 2001), non-
hydrogen atoms were refined with anisotropic parameters, hydrogen atoms
were refined on calculated positions using a riding model, goodness of fit
1.038, R1 ) 0.0479, wR2 ) 0.0953, residual electron density 0.217 to
-0.289 e Å-3. CCDC-288364 (22) contains the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
4/5 conditionsa
R1
R2
config (*) product (yield, %)
4
4
4
a
b
c
H
H
CCPh
Ph
(S)
(S)
20a (69)
20b (77)
23 (84)
5
5
5
a
b
d
a
b
CCPh
Ph
H
H
(S)
(S)
21a (98)
21b (80)
22 (85)
epi-5
epi-5
CCPh
Ph
H
H
(R)
(R)
epi-21a (97)
epi-21b (87)
a (a) Phenylacetylene, Pd(PPh3)4, CuI, dioxane, 80 °C; (b) PhB(OH)2,
Pd(PPh3)4, CsF, dioxane, 80 °C; (c) PhB(OH)2, Pd(PPh3)4, K2CO3, dioxane,
80 °C; (d) PhSnBu3, Pd(PPh3)4, dioxane, 80 °C.
Org. Lett., Vol. 8, No. 14, 2006
2995

olefins. For example, treatment of 20a (Scheme 3) under
from the rearrangement/allylation of 2-vinyloxiranes are
efficiently converted to derivatizable des-epoxy cryptophycin
analogues. Three scaffolds have been constructed in two steps
from enzymatically resolved bishomoallylic alcohols, and we
have demonstrated that the vinyl halide they contain is
convertible to a variety of C-C bonds via cross-coupling
protocols. On the basis of these findings, we are currently
studying the selective introduction of the epoxide moiety and
building a library of compounds for biological testing.
Scheme 3
Acknowledgment. We thank Merck Frosst Canada and
NSERC (Canada) for an Industrial Research Chair and the
University of Toronto for financial support of this work. We
also thank Dr. Alan Lough for X-ray structure determination.
M.M. thanks NSERC (Canada) for financial support in the
form of a postgraduate fellowship.
Jacobsen’s conditions28 afforded the epoxides 24 and 25 in
moderate yield and with good diastereoselectivity.29 Further
screening of epoxidation conditions is currently underway.
In summary, we have demonstrated that products arising
Supporting Information Available: Crystallographic
data in CIF format, full experimental details, and character-
1
ization, including H and 13C NMR spectroscopic data for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(28) Brandes, B. D.; Jacobsen, E. N. J. Org. Chem. 1994, 59, 4378.
(29) The configurations at the epoxide functionalities for 24maj and
24min have not yet been established.
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