New synthetic route for the enantioselective total synthesis of salinosporamide A and biologically active analogues

Article abstract of DOI:10.1021/ol0508734

(Chemical Equation Presented) A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4 → 5.

Full text of DOI:10.1021/ol0508734

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2699-2701
New Synthetic Route for the
Enantioselective Total Synthesis of
Salinosporamide A and Biologically
Active Analogues
Leleti Rajender Reddy, Jean-Franc
E. J. Corey*
¸ois Fournier, B. V. Subba Reddy, and
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received April 20, 2005
ABSTRACT
A total synthesis of the salinosporamide analogue 3 is described that starts with the novel cyclization 4
f 5.
One of the most fascinating biologically active natural
products to have been isolated recently is the marine
microbial metabolite salinosporamide A (1) first described
by the Fenical group at the Scripps Oceanographic Institute.1
Salinosporamide A is structurally related to omuralide (2a)2
and lactacystin (2b),3 natural products from a terrestrial
Salinosporamide is a somewhat more potent inhibitor of the
proteasome than omuralide. Even more interesting is the
report that 1 is much more potent than 2a in terms of in
vitro cytotoxic activity against many tumor cell lines (IC50
values of 10 nM or less).1,4 In continuation of our program
on the study of proteasome inhibitors, we recently developed
the first total synthesis of salinosporamide5 by a route that
started with S-threonine, which was converted in a few highly
efficient steps to the keto acrylamide 4 (Scheme 1). A key
early step in this synthesis was the Baylis-Hillman cycliza-
(3) (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113-116. (b) Omura, S.;
Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa,
A. J. Antibiot. 1991, 44, 117-118.
(4) Bortezomib (Velcade), a peptidyl boronic acid which is a reversible
(0.6 nM Ki) proteasome inhibitor, is currently in use and approved for the
treatment of multiple myeloma. In addition, there are numerous ongoing
clinical trials on the use of this agent for treatment of other malignant
diseases. See: (a) Richardson, P. G.; Barlogie, B.; Berenson, J.; Singhal,
S.; Jagannath, S.; Irwin, D.; Rajkumar, S. V.; Srkalovic, G.; Alsina, M.;
Alexanian, R.; Siegel, D.; Orlowski, R. Z.; Kuter, D.; Limentani, S. A.;
Lee, S.; Hideshima, T.; Esseltine, D.-L.; Kauffman, M.; Adams, J.;
Schenkein, D. P.; Anderson, K. C. N. Engl. J. Med. 2003, 348, 2609-
2617. (b) Richardson, P. G.; Hideshima, T.; Anderson, K. C. Cancer Control
2003, 10, 361-369. (c) Steinberg, D. The Scientist 2003, 17 (S2), S18-
S22. (d) Adams, J. Proteasome Inhibitors in Cancer Therapy; Humana
Press: New York, 2004.
organism which are potent and useful covalent inhibitors of
proteasome function and consequent protein degradation.
(1) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C. A.;
Jensen, P. R.; Fenical, W. Angew. Chem., Int. Ed. 2003, 42, 355-357.
(2) (a) Reviewed in: Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull.
1999, 47, 1-10. (b) Corey, E. J.; Reichard, G. A.; Kania, R. Tetrahedron
Lett. 1993, 34, 6977-6980. (c) Corey, E. J.; Reichard, G. A. J. Am. Chem.
Soc. 1992, 114, 10677-10678. (d) Fenteany, G.; Standaert, R. F.; Reichard,
G. A.; Corey, E. J.; Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1994, 91,
3358-3362.
(5) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 6230-6231.
10.1021/ol0508734 CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/26/2005

Scheme 1
tion of 4 to the γ-lactam 5 with 9:1 diastereoselectivity and
After extractive isolation and flash chromatography on silica
gel, a single diastereomerically pure product, 5, was obtained
in 83% overall yield from 4. As indicated in Scheme 1, the
unsaturated γ-lactam 5 could be silylated to 6 (96% yield)
which underwent radical-mediated stereoselective cyclization
to the previously obtained bicyclic γ-lactam 7 (89%).5
Debenzylation of 7 and Dess-Martin periodinane oxidation
gave the aldehyde 8 which upon reaction with 2-propenyl-
magnesium chloride and trimethylsilyl chloride8 in THF at
-78 °C for 5 h was transformed into the corresponding
secondary alcohol TMS ether. Treatment of this product with
1 atm of H2 and Pd-C catalyst in ethanol produced pure 9
in good yield. The secondary hydroxyl group of 9 was
protected as the dimethyl-i-propylsilyl (DMIPS) ether and
the silicon bridge was excised5 to form the dihydroxy
γ-lactam 10 in 84% overall yield from 9. Cleavage of the
N-p-methoxybenzyl group in 10 by ceric ammonium nitrate
produced 11. The conversion of 11 to the required salino-
sporin-like target 3 was accomplished by a novel sequence
of three reactions, the first of which involved the cleavage
in good yield. We now report an unusual alternative
cyclization which is completely diastereoselective, less time-
consuming, and very efficient. The intermediate γ-lactam
5, which can readily be converted to salinosporamide A (1),
also serves to provide access to a variety of interesting
salinosporamide/omuralide analogues by the new route that
is outlined in Scheme 1.
The keto acrylamide 4 was allowed to react with the dark
brown Kulinkovich reagent (3.5 equiv)6,7 formed by reaction
of 4 equiv of Ti(i-PrO)4 with 7 equiv of cyclopentylmag-
nesium chloride in t-BuOMe at -40 °C for 30 min, and the
mixture was maintained at -40 °C for an additional 30 min
to effect cyclization. Iodine (5 equiv) was added to the
resulting reaction mixture containing the R-titanamethyl-γ-
lactam intermediate to generate, after 2 h at -40 °C and 2
h at 23 °C, the corresponding R-iodomethyl-γ-lactam which,
without isolation, was exposed to Et3N for 30 min at 23 °C.
(6) For reviews on the application of titanacyclopropane reagents, see
(a) Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597-2632. (b) Sato, F.;
Okamoto, S. AdV. Synth. Catal. 2001, 343, 759-784.
(7) For the closest precedent to this cyclization involving δ,ꢀ-enones,
see: (a) Kablaoui, N. M.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118,
3182-3191. (b) Mandal, S. K.; Amin, S. R.; Crowe, W. E. J. Am. Chem.
Soc. 2001, 123, 6457-6458. (c) Crowe, W. E.; Vu, A. T. J. Am. Chem.
Soc. 1996, 118, 1557-1558. (d) Quan, L. G.; Cha, J. K. Tetrahedron Lett.
2001, 42, 8567-8569.
(8) At -78 °C, the rate of reaction of 2-propenylmagnesium chloride
with Me3SiCl is slow relative to that with the aldehyde 8. The inclusion of
TMSCl in the reaction mixture allows rapid silylation of the alkoxide
intermediate formed by attack of the Grignard reagent on 8, thereby
preventing retroaldol cleavage of this adduct. See: Corey, E. J.; Li. W.;
Nagamitsu, T. Angew. Chem., Int. Ed. 1998, 37, 1676-1679.
2700
Org. Lett., Vol. 7, No. 13, 2005

of the methyl ester to generate the corresponding carboxylic
acid. This turned out to be an unusually difficult and
challenging step since none of the known general procedures
for the conversion of RCOOMe to RCOOH9 worked at all
due to the strong steric shielding of the COOMe carbonyl
in 11 and the propensity of 11 to undergo retroaldol cleavage
and other decomposition reactions. Cleavage of the methyl
ester function of 11 was accomplished cleanly using a new
reagent, Me2AlTeMe, that is generated by heating tellurium
powder (1.2 equiv) and trimethylaluminum (1 equiv) in
toluene at reflux for 6 h and cooling the product to ambient
temperature to give a 0.8 M solution of [Me2AlTeMe]2 in
toluene. Treatment of the dihydroxy ester 11 with a freshly
prepared solution of [Me2AlTeMe]2 (0.8 M in toluene) at
23 °C for 12 h under nitrogen followed by quenching of the
reaction mixture with 1 N hydrochloric acid and extractive
isolation with ethyl acetate afforded the dihydroxy acid
corresponding to 11 cleanly. CAUTION: Organotellurium
reagents should be used only in a well-ventilated hood;
treatment with 1 N hydrochloric acid (or bleach) effects their
destruction and deodorization. When the crude acid was
subjected to reaction with 4 equiv of Ph3PCl2 in dry 1:1
CH3CN-pyridine at 23 °C for 12 h, it was transformed
directly into the DMIPS ether of 3, which was obtained as
a colorless oil in 89% yield after extractive isolation with
ethyl acetate and flash chromatography on silica gel. This
very efficient operation combines side-chain chlorination
with a novel method of â-lactone formation in a single step.
Finally, desilylation afforded the target omuralide-salino-
sporamide hybrid 3 as a colorless solid in 92% yield after
extractive isolation (EtOAc) and flash chromatography on
silica gel.10
efficiently into â-methyl omuralide (13) via 12 using
reactions strictly analogous to those previously described for
the synthesis of salinosporamide A.5
Scheme 2
In our experience, the synthetic methodology shown in
Schemes 1 and 2 provide an efficient and practical pathway
for the synthesis of omuralide analogues, such as 13, and
also salinosporamide A (1) and its analogues, such as 3.
Acknowledgment. J.-F. Fournier is grateful to NSERC
of Canada for a postdoctoral fellowship. We thank Millen-
nium Pharmaceuticals, Inc. for a general research grant.
Supporting Information Available: Experimental pro-
cedures and spectral data for reaction products 3 and 5-13.
This material is available free of charge via the Internet at
http://pubs.acs.org.
As mentioned above, the synthetic route outlined in
Scheme 1 provides access to a host of interesting members
of the salinosporamide/omuralide series. We have previously
reported the conversion of intermediate 8 to salinosporamide
A.5 In addition, the γ-lactam 5 has been transformed
OL0508734
(10) Found for pure 3: Rf ) 0.45 (silica gel plate, EtOAc-hexane 1:1);
mp ) 144-145 °C; [R]D23 ) -22.5 (c 0.5, CHCl3); FTIR (film) νmax
:
;
(9) For reviews, see: (a) Greene, T. W.; Wuts, P. G. M. ProtectiVe
Groups in Organic Synthesis, 3rd ed.; John Wiley and Sons: New York,
1999. (b) Kocienski, P. J. Protecting Groups, 3rd ed.; Georg Thieme:
Stuttgart, New York, 2004. (c) Salomon, C. J.; Mata, E. G.; Mascaretti, O.
A. Tetrahedron 1993, 49, 3691-3734. (d) Nicolaou, K. C.; Estrada, A. A.;
Zak, M.; Lee, S. H.; Safina, B. S. Angew. Chem., Int. Ed. 2005, 44, 1378-
1382. (e) Olah, G. A.; Narang, S. C.; Salem, G. F.; Gupta, B. G. B. Synthesis
1981, 142-143. (f) Marchand, P. S. J. Chem. Soc., Chem. Commun. 1971,
667-668. (g) Bartlett, P. A.; Johnson, W. S. Tetrahedron Lett. 1970, 4459-
4462.
3222, 2960, 2944, 2867, 1833, 1710, 1254, 1090, 1059, 852, 825, 777 cm-1
1H NMR (CDCl3, 500 MHz) δ 6.43 (1H, s (br)), 3.97 (1H, m), 3. 84 (1H,
t, J ) 6.5 Hz), 3.77 (1H, m), 2.82 (1H, t, J ) 7.5 Hz), 2.27 (1H, m), 2.12
(1H, m), 1.93 (1H, m), 1.82 (3H, s), 1.12 (3H, d, J ) 7.0 Hz), 1.08 (3H,
d, J ) 7.0 Hz); 13C NMR (CDCl3, 125 mHz) δ 177.72, 167.47, 85.89,
79.04, 71.94, 44.92, 42.49, 31.53, 28.24, 19.92, 19.74, 18.76. HRMS (ESI)
calcd for C12H19ClNO4 [M + H]+: 276.1002; found: 276.1006. The
â-lactone 3 prepared by the route shown in Scheme 1 was identical with a
sample of 3 that had been synthesized in these laboratories by a different
route (submitted for publication).
Org. Lett., Vol. 7, No. 13, 2005
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