Synthesis of cryptophycin 52 using the shi epoxidation

Article abstract of DOI:10.1021/ol025933+

Matrix presented A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion. Several epoxidation results for cryptophycin substrates are disclosed followed by a discussion of t

Full text of DOI:10.1021/ol025933+

ORGANIC
LETTERS
2
002
Vol. 4, No. 10
813-1815
Synthesis of Cryptophycin 52 Using the
Shi Epoxidation
1
†
,†
†
‡
David W. Hoard, Eric D. Moher,* Michael J. Martinelli, and Bryan H. Norman
Chemical Process Research and DeVelopment and DiscoVery Chemistry Research
DiVisions, Lilly Research Laboratories, Eli Lilly and Company,
Indianapolis, Indiana 46285
moher_eric_d@lilly.com
Received March 26, 2002
ABSTRACT
A synthesis of cryptophycin 52 is reported using a Shi epoxidation strategy to install the epoxide moiety in a diastereoselective fashion.
Several epoxidation results for cryptophycin substrates are disclosed followed by a discussion of the details relating to the preparation of
cryptophycin 52 in two synthetic steps from one of the intermediate epoxides.
1
The cryptophycins, exemplified by cryptophycin 1 (1), are
aimed at discovering and developing cryptophycin analogues
possessing refined biological properties. From this effort has
emerged cryptophycin 52 (2), which has undergone ad-
cytotoxic macrocyclic depsipeptides isolated from blue-green
algae (Nostoc sp. strains ATCC 537189 and GSV 224 ).
Cryptophycin 1 (1) has been shown by Moore and coworkers
to be a potent tumor selective cytotoxin in vivo. Note-
worthy is the broad spectrum of antitumor activity exhibited
by 1 across a variety of tumors implanted in mice. Particu-
larly compelling is the observation that 1 significantly
reduced the mean tumor burden from a Taxol-resistant
2
3
5
vanced clinical evaluation for the treatment of solid tumors.
Several research groups have adopted programs aimed at
addressing the synthetic challenges associated with this
structurally intriguing class of molecules. The first reports
on the total synthesis of cryptophycins appeared in 1994 from
3
,4
6
7
7
the research groups of Kitigawa, Moore, and Tius. These
were soon followed by numerous approaches comprised of
3
mammary adenocarcinoma tumor implanted in mice.
8
both formal and total syntheses. A strategical theme common
to the majority of syntheses of epoxide-containing crypto-
(2) 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.
(
3) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R. E.; Corbett,
T. H.; Valeriote, F. A.; Demchik, L. J. Am. Chem. Soc. 1994, 116, 4729.
4) Golakoti, T.; Ogino, J.; Heltzel, C. E.; Husebo, T. L.; Jensen, C. M.;
(
Larsen, L. K.; Patterson, G. M. L.; Moore, R. E.; Mooberry, S. L.; Corbett,
As a result of these findings, we engaged in a collaboration
with the University of Hawaii and Wayne State University
T. H.; Valeriote, F. A. J. Am. Chem. Soc. 1995, 117, 12030.
(
5) (a) Moore, R. E.; Tius, M. A.; Barrow, R. A.; Liang, J.; Corbett, T.
H.; Valeriote, F. A.; Hemscheidt, T. K. PCT Int. Appl. WO 9640184 A1
9961219, 1996. (b) Wagner, M. M.; Paul, D. C.; Shih, C.; Jordan, M. A.;
1
†
Chemical Process Research and Development.
Wilson, L.; Williams, D. C. Cancer Chemother. Pharmacol. 1999, 43, 115
and references therein.
‡
Discovery Chemistry Research.
(
1) For recent reviews, see: (a) Shih, C.; Al-Awar, R. S.; Fray, A. H.;
(6) Kobayashi, M.; Kurosu, M.; Wang, W.; Kitigawa, I. Chem. Pharm.
Bull. (Japan) 1994, 42, 2394.
(7) Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore, R. E.;
Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479.
(8) For example, see: Eggen, M.; Nair, S. K.; Georg, G. I. Org. Lett.
2001, 3, 1813 and references therein.
Martinelli, M. J.; Moher, E. D.; Norman, B. H.; Patel, V. F.; Shultz, R. M.;
Toth, J. E.; Varie, D. L.; Corbett, T. H.; Moore, R. E. In Anticancer
Agents: Frontiers in Cancer Chemotherapy; Ojima, I., Vite, G. D., Altman,
K., Eds.; Washington, DC, 2001; Vol. 796, pp 171-189. (b) Eggen, M.-J.;
Georg, G. I. Med. Res. ReV. 2002, 22, 85.
1
0.1021/ol025933+ CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/25/2002

1
0
phycins (e.g., 1) has been the introduction of the epoxide
pharmacophore in a single late-stage operation through the
use of m-CPBA or dimethyl dioxirane. The reported epoxi-
dations proceed with a diastereoselectivity of 2-3:1 neces-
sitating a chromatographic separation of the desired (major)
â-isomer. As part of our initial efforts to generate supplies
of 2 and synthetic intermediates to fuel clinical development
and SAR, respectively, we adopted the Moore-Tius syn-
dioxirane source. While a promising hit, olefin 3 appeared
to be a very poor substrate for the Shi epoxidation due to
steric as well as solubility factors. A maximum conversion
of only 17% was obtained under “forcing” conditions using
3 equiv of ketone 5 and 6 equiv of Oxone. Moreover, a mixed
solvent system employing methylene chloride in addition to
the prescribed acetonitrile or dimethoxymethane and water
was necessary to help solubilize the substrate.
thesis of 2.5 The final synthetic sequence (Scheme 1)
a,7
7,9
Scheme 1
Having experienced very limited success in achieving a
late-stage epoxidation with reasonable diastereocontrol, we
turned our attention toward earlier intermediates in the
synthesis, which may be more amenable to optimization of
the Shi procedure. From careful inspection of the synthetic
intermediates available from the Moore-Tius route, we
identified styrenyl intermediate precursors to 3 that are the
most compatible with an early epoxidation approach (Scheme
2
). These substrates were subjected to an epoxidation screen
culminates in an epoxidation of styrene 3 employing m-
CPBA to produce a 2:1 mixture of epoxides 2 and 4 from
which 2 is isolated in 51% yield by reversed-phase HPLC.
Herein, we report on an approach aimed at generating the
epoxide of 2 in a more efficient manner to facilitate our
support for continuing biological evaluation.
Scheme 2
We began by screening general methods for the direct
epoxidation of styrene 3 looking for enhanced diastereo-
selection relative to m-CPBA. Evident from the results
depicted in Table 1, the only method giving any enhancement
Table 1. Reagent Screen for the Epoxidation of 3
entry
reagent
time
temp
2:4a
1
2
3
411
511
6
m-CPBA
24 h
24 h
24 h
23 h
20 h
4 h
rt
rt
rt
rt
rt
0 °C
rt
1.9:1
VO(acac)2- t-BuOOH
Mo(CO)6- t-BuOOH
J acobsen (S,S)
1.9:1b
1.9:1b
1:1.9b
1.9:1b
1.9:1
J acobsen (R,R)
dimethyl dioxirane
monoperoxyphthalic
acid-Mg salt
Ni(acac)2-RCHO-O2
MeReO3-H2O2
7
24 h
1.1:1
812
913
0
24 h
24 h
1 h
rt
rt
0 °C
c
1.7:1
1.5:1
1
1
1
1
1
1
1
CF3CO3H
using the Shi method as well as m-CPBA (Table 2).16 The
Shi epoxidation method offered the greatest level of dia-
1
CH3CO3H
14 h
6 h
24 h
8 h
5 h
4 h
rt
rt
1.7:1
c
c
c
214
TolSO2imidazole-H2O2
t-BuOOH-Ti(O-i-Pr)4
(EtO)2POCl-H2O2
PhCN-H2O2
3
415
5
610
-10 °C
(9) Fray, A. H. Tetrahedron: Asymmetry 1998, 9, 2777.
rt
rt
rt
(
10) Tu, Y.; Wang, Z.-X.; Shi, Y. J. Am. Chem. Soc. 1996, 118, 9806.
c
(11) Jacobsen Asymmetric Epoxidation (JAE): Jacobsen, E. N.; Zhang,
Shi method
3.5:1b
W.; Muci, A. R.; Ecker, J. R.; Deng, L. J. Am. Chem. Soc. 1991, 113,
7
1
5
063.
a
b
Ratio determined by HPLC; see ref 22. Very low conversion to
(12) Yamada, T.; Takai, T.; Rhode, O.; Mukaiyama, T. Chem. Lett. 1991,
c
epoxides. Styrene epoxidation products were not detected.
.
(13) Adam, W.; Mitchell, C. Angew. Chem., Int. Ed. Engl. 1996, 35,
33.
(14) Kluge, R.; Schulz, M.; Liebsch, S. Tetrahedron 1996, 52, 2957.
15) Kende, A. S.; Delair, P.; Blass, B. E. Tetrahedron Lett. 1994, 35,
to the magnitude of diastereoselection was that of Shi (entry
(
16), which utilizes fructose-derived ketone 5 as a chiral
8123.
1814
Org. Lett., Vol. 4, No. 10, 2002

1
8,19
2
. In the event, addition of crude 13 to a mixture of 10,
2
0
Table 2. Shi10 vs m-CPBA Epoxidation Results (â:R Epoxide
DCC, and DMAP furnished, after silica gel chromatogra-
phy, fully protected amino ester 14 in 71% overall yield
1
8
21
Ratios) for Styryl Substrates
from styrene 8. For the final stage of the synthesis, we
envisioned cleavage of the Fmoc protecting group to reveal
a free amine which, upon exposure to 2-hydroxypyridine as
substrate
m-CPBAa,b
Shia,c
1
1
8
7
1:1, >95% conversion
1.5:1, >95% conversion
2:1, >95% conversion
5:1, >95% conversion
5:1, >95% conversion
9.5:1, 70-85% conversion
d
9
reported by Fray, would smoothly afford macrocycle 2.
Toward that end, treatment of a DMF solution of 14 with 5
equiv of piperidine rapidly (<55 min) provided the expected
seco-amine, which was not isolated but instead was observed
to slowly convert to 2 in situ over 16 h giving cryptophycin
a
Ratio determined by HPLC; see Supporting Information. b Methylene
c
chloride, 1-2 equiv of 99% m-CPBA, room temperature. Oxone (10
equiv), 5 (4 equiv), NaHCO3 (aq), Na2EDTA, Bu4NOH, CH3CN. d Buffered
with aqueous sodium bicarbonate.
21
5
2 (2) in 79% isolated yield after chromatography. Further
purification of 2 to homogeneity, removing residual undesired
R-epoxide 4, could be readily accomplished through prepara-
tive reversed-phase HPLC in a manner analogous to that
stereoselection observed to date for the epoxidation of the
cryptophycin intermediates, while the m-CPBA cases gave
levels of diastereoselection generally inferior to those
exhibited by 3. While modest, the selectivity generally
observed across these substrates warranted further investiga-
tion into a synthetic route incorporating an early epoxidation
strategy with the Shi epoxidation as a key step. All else being
equal, late-stage intermediate 7 would be the preferred
substrate for epoxidation since manipulations of the sensitive
epoxide functionality would be minimized. However, the
conversion to epoxide products was inferior to that of
substrates 8 and 11 leaving behind significant levels of
styrene starting material, which complicated the final puri-
fication of 2. Indeed, obtaining high conversions for these
substrates is a general challenge, the results of Table 2
reflecting the employment of 4 equiv of 5 and 10 equiv of
Oxone for the epoxidations.
2
2
outlined in earlier reports.
In conclusion, a synthesis of cryptophycin 52 (2) has been
demonstrated based on the Shi epoxidation, which provides
an efficient alternative method for installing the cryptophycin
epoxide moiety. The route circumvents the commonly
employed last-step epoxidation, which exhibits poor diaste-
reoselectivity. An overall yield of 56% from styrene 8 was
realized for this route as compared with 34% experienced
5
a,7
for the Moore-Tius route using m-CPBA as the epoxi-
dizing agent.
Acknowledgment. We thank Mr. David Robbins and Mr.
Joseph Turpin for analytical support.
Supporting Information Available: Detailed experi-
mental procedures and characterization for 13, 14, and 2.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Further optimization was thus focused on styrene 8.
Gratifyingly, employing careful pH control17 not only
allowed for ketone 5 and Oxone levels to be reduced to 2
and 4 equiv, respectively, without compromising conversion,
OL025933+
but a slight gain in diastereoselection to 6.5:1 â:R was
realized (Scheme 3). With alcohol 1318 in hand, the stage
(16) These intermediates carry Fmoc nitrogen protection instead of the
Boc protection used in the reported5 route. It was necessary to switch
from Boc to Fmoc since the benzylic epoxide was not compatible with the
acidic conditions necessary to remove the Boc group at a later point in the
synthesis.
a,7
was set for elaboration of the cryptophycin skeleton through
esterification with an appropriately functionalized amino acid
unit followed by deprotection and macrocyclization to furnish
(
17) Wang, Z.-X.; Yong, T.; Frohn, M.; Shi, Y. J. Org. Chem. 1997,
2, 2328.
18) All isolated new compounds displayed H NMR and mass spectral
data consistent with their assigned structure.
19) Fmoc-protected amine 10 was prepared from 95a in two steps: (a)
HCl, EtOAc, 91%; (b) Fmoc-Cl, Na2CO3, dioxane, water, 93%.
20) Premixing of all the components with DCC addition last, which is
6
1
(
(
Scheme 3
(
the typical protocol for DCC-mediated esterifications, led to the production
of acylated tetrahydrofuran i as a byproduct (20%) contaminating 14.
(
21) Yield of â-epoxide, corrected for 10% R-epoxide present as a
contaminant.
(22) (a) Patel, V. F.; Andis, S. L.; Kennedy, J. H.; Ray, J. E.; Schultz,
R. M. J. Med. Chem. 1999, 42, 2588. (b) Also see ref 5a.
Org. Lett., Vol. 4, No. 10, 2002
1815