Efficient asymmetric syntheses of β-lactams bearing a cyclopropane or an epoxide moiety and their application to the syntheses of novel isoserines and taxoids

Full text of DOI:10.1021/jo971908j

224
J . Org. Chem. 1998, 63, 224-225
Sch em e 1a
Efficien t Asym m etr ic Syn th eses of â-La cta m s
Bea r in g a Cyclop r op a n e or a n Ep oxid e
Moiety a n d Th eir Ap p lica tion to th e
Syn th eses of Novel Isoser in es a n d Ta xoid s
Iwao Ojima* and Songnian Lin
Department of Chemistry, State University of New York at
Stony Brook, Stony Brook, New York 11794-3400
Received October 16, 1997
In the course of our study on the exploration of the
â-lactam synthon method (â-LSM),1-6 we became interested
in the design and synthesis of novel isoserines bearing a
cyclopropane or an epoxide moiety in the molecule. Because
of their unique steric and electronic nature, these novel
isoserines may serve as new and useful building blocks for
peptides, peptidomimetics, protease inhibitors, and taxoid
antitumor agents. We describe here highly efficient asym-
metric syntheses of â-lactams bearing a cyclopropane or an
epoxide moiety at the C-4 position and their application to
the syntheses of novel methanoisoserine, oxaisoserines, and
taxoids bearing these unique isoserines at the C-13 position.
(3R,4S)-1-PMP-3-TIPSO-4-(2-methyl-1-propenyl) â-lactam
1 (PMP ) p-methoxyphenyl, TIPSO ) triisopropylsiloxy) and
(3R,4S)-1-t-Boc-3-TIPSO-4-(2-methyl-1-propenyl) â-lactam 2
(t-Boc ) tert-butoxycarbonyl) with high enantiomeric purity
(>96% ee) were prepared in excellent yields through a highly
efficient chiral ester enolate-imine cyclocondensation reac-
tion previously reported from these laboratories.7-10
a
Key: (i) HF/Py; (ii) Et2Zn (5 equiv), CH2I2 (10 equiv), ClCH2CH2Cl,
rt, 2 h; (iii) TIPSCl, NEt3, DMAP; (iv) CAN; (v) (t-Boc)2O, NEt3, DMAP;
(vi) NEt3, DMAP, MeOH.
Sch em e 2
hydroxyl group as the TIPS ether proceeded smoothly to give
â-lactam 5 in quantitative yield by reacting 4 with TIPSCl
(2 equiv) in the presence of Et3N and (dimethylamino)pyri-
dine (DMAP) at 35 °C. Treatment of â-lactam 5 with ceric
ammonium nitrate (CAN), removing N-PMP, followed by
protection with N-t-Boc gave N-t-Boc â-lactam 6 in 92% yield
(Scheme 1). Ring opening of 4-cyclopropyl â-lactam 6 with
methanol in the presence of NEt3 (2 equiv) and DMAP (0.5
equiv) followed by deprotection of TIPS using HF/pyridine
gave N-t-Boc-methanonorstatine methyl ester (7) in 92%
yield for two steps (Scheme 1).
Attempted cyclopropanation of â-lactam 1 through a
11
modified Simmons-Smith reaction using Et2Zn and CH2I2
resulted in the recovery of the starting material. This may
well be due to the bulkiness of the TIPS group at the C-3
position of â-lactam 1. Accordingly, the TIPS group was
removed using HF/pyridine to give 3-OH â-lactam 3 in high
yield. Reaction of â-lactam 3 with Et2Zn (5 equiv) and CH2I2
(10 equiv) in 1,2-dichloroethane12 at room temperature
afforded 4-((S)-2,2-dimethylcyclopropyl) â-lactam 4 as the
sole product in 93% yield (Scheme 1). Protection of the C-3
Reaction of â-lactam 2 with m-chloroperoxybenzoic acid
(m-CPBA) (3 equiv) in CH2Cl2 at room temperature resulted
in the formation of a 1:1 mixture of â-lactams, 8-R and 8-S,
in 90% yield; i.e., no diastereoselection took place. In
contrast, the reaction of 3-OH â-lactam 9 with m-CPBA (1.5
equiv) in CH2Cl2 at room temperature afforded 4-((R)-2-
methyl-1,2-epoxypropyl) â-lactam 10 as the sole product in
92% yield (Scheme 2). N-t-Boc-oxanorstatine methyl ester
(11) was obtained in 96% yield through ring opening of
4-epoxy â-lactam 10 with methanol in the presence of NEt3
(2 equiv) and DMAP (0.5 equiv) (Scheme 2).
The single-crystal X-ray structures of â-lactam 4 (Scheme
1) and a derivative of â-lactam 10, 3-[(4-nitrobenzoyl)oxy]
â-lactam 12 are shown in Figure 1. The extremely high
diastereoselectivity observed in these cyclopropanation and
epoxidation reactions can be explained by taking into
account the highly organized transition-state structures13
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(8) Ojima, I.; Slater, J . C.; Michaud, E.; Kuduk, S. D.; Bounaud, P.-Y.;
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1997, 40, 267-278 and references therein.
(10) Ojima, I.; Kuduk, S. D.; Pera, P.; Veith, J . M.; Bernacki, R. J . J .
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(11) Furukawa, J .; Kawabata, N.; Nishimura, J . Tetrahedron 1968, 24,
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S0022-3263(97)01908-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/01/1998

Communications
J . Org. Chem., Vol. 63, No. 2, 1998 225
Sch em e 3a
a
Key: (i) 13a and 13b, LiHMDS, THF, -40 °C, 30 min, 84-91%;
(iii) HF/Py, 0 °C f rt, 24 h, 88-96%.
Sch em e 4a
F igu r e 1. Chem 3D representation of the X-ray structues of
â-lactams 4 (a ) and 12 (b).
F igu r e 2. Proposed transition state structures for the formation
of â-lactams 4 (a ) and 10 (b).
a
Key: (i) 13b, LiHMDS, THF, -40 °C, 30 min, 81-88%; (ii) HF/
Py, 0 °C f rt, 24 h, 66-78%.
illustrated in Figure 2. The constrained â-lactam skeleton
maximizes the directing effect of C-3 hydroxyl group to
achieve the exclusive formation of cyclopropane 4 or epoxide
10.
is 2.48 for 14b, which is the best ratio ever reported. It is
very intriguing that 15-R is highly active (IC50 ) 0.44-0.68
nM; 1 order of magnitude more potent than paclitaxel), while
15-S is 1-2 orders of magnitude less active (IC50 ) 6.50-
21.7 nM) against human cancer cell lines A121 (ovarian),
A549 (nonsmall lung), HT-29 (colon) and MCF-7 (breast).
In summary, the asymmetric syntheses of â-lactams
bearing a cyclopropane or an epoxide moiety has been
achieved with complete stereochemical control. These â-lac-
tams were further converted to the novel norstatine ana-
logues and taxoids, which showed extremely potent cyto-
toxicity. The strong directing effect of the C-3 hydroxy group
of â-lactams in both cyclopropanation and epoxidation is
particularly noteworthy. Further studies on the scope and
limitation of this methodology for preparation of a variety
of â-lactams bearing a cyclopropane or an epoxide moiety
as synthetic intermediates as well as the structure-activity
relationships (SAR) of the new taxoids bearing these unique
isoserine residues are actively underway.
As a part of our continuing SAR study of paclitaxel and
docetaxel analogues,7-10 we synthesized novel taxoids bear-
ing the methanonorstatine residue at the C-13 position using
baccatins and the coupling protocol developed in these
laboratories.5,7-10,14-19 The coupling of 7-TES-baccatin
(13a )14,20 or 7-TES-10-(cyclopropanecarbonyl)-10-deacetyl-
baccatin (13b)8 with â-lactam 6 was carried out under the
standard conditions using LiHMDS in THF at -40 °C,
followed by deprotection with HF/pyridine, to afford the
corresponding new taxoid 14a or 14b in good to excellent
yield (Scheme 3). In a similar manner, taxoids, 15-R and
15-S, bearing the oxanorstatine residue at the C-13 position,
were synthesized through coupling of â-lactams 8-R and 8-S
with baccatin 13b in good yields (Scheme 4).
The anti-tumor activity of these novel taxoids was evalu-
ated in vitro.21 Taxoids 14a and 14b exhibited extremely
high potency against a drug-resistant human breast cancer
cell line LCC6-MDR (IC50 ) 2.77 nM for 14a , 2.95 nM for
14b, while paclitaxel has a IC50 value of 346 nM), and the
activity ratio for (drug resistant cells)/(drug sensitive cells)
Ack n ow led gm en t. This research was supported by a
grant from the National Institutes of Health (NIGMS).
Generous support from Indena, SpA, Italy, is also gratefully
acknowledged. We would also like to thank Professor
Stephen A. Koch and Ms. Hua-Fen Hsu for X-ray crystal-
lography. The authors acknowledge the university NMR
facility at Stony Brook, which was supported by a grant
from National Science Foundation (CHE 9413510). The
authors would like to thank Dr. Ralph J . Bernacki and
Paula Pera, Department of Experimental Therapeutics,
Grace Cancer Drug Center, Roswell Park Cancer Institute,
for cytotoxicity assay of new taxoids.
(14) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.-M.;
Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
(15) Ojima, I.; Sun, C. M.; Zucco, M.; Park, Y. H.; Duclos, O.; Kuduk, S.
D. Tetrahedron Lett. 1993, 34, 4149-4152.
(16) Ojima, I.; Zucco, M.; Duclos, O.; Kuduk, S. D.; Sun, C.-M.; Park, Y.
H. Bioorg. Med. Chem. Lett. 1993, 3, 2479-2482.
(17) Ojima, I.; Kuduk, S. D.; Slater, J . C.; Gimi, R. H.; Sun, C. M.
Tetrahedron 1996, 52, 209-224.
(18) Holton, R. A.; Biediger, R. J .; Boatman, P. D. In Taxol: Science and
Applications; Suffness, M., Ed.; CRC Press: New York, 1995; pp 97-121.
(19) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Clowers, J . S.;
Harriman, G. C. B.; Hepperle, M.; Park, H. In Taxol®: Science and
Applications; Suffness, M., Ed.; CRC Press: New York, 1995; pp 317-375.
(20) Denis, J .-N.; Greene, A. E.; Gue´nard, D.; Gue´ritte-Voegelein, F.;
Mangatal, L.; Potier, P. J . Am. Chem. Soc. 1988, 110, 5917-5919.
(21) The cytotoxicity assays of 14 and 15 were carried out by Dr. Ralph
J . Bernacki and Paula Pera, Department of Experimental Therapeutics,
Grace Cancer Drug Center, Roswell Park Cancer Institute. Detailed
biological data will be published elsewhere.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures for the asymmetric syntheses of â-lactams 1-6, 8-10, and
12 as well as taxoids 14 and 15; characterization data for new
compounds 3-12, 14, and 15; X-ray data for 4 and 12 (38 pages).
J O971908J