Spirodiepoxides in total synthesis: Epoxomicin

Article abstract of DOI:10.1021/ja044563c

The first use of the spirodiepoxide functional group in total synthesis, a study culminating in an efficient synthesis of the potent proteasome inhibitor epoxomicin, is described. Spirodiepoxides derived from allenes by oxidation are shown to give syn dis

Full text of DOI:10.1021/ja044563c

Published on Web 11/04/2004
Spirodiepoxides in Total Synthesis: Epoxomicin
Sreenivas Katukojvala, Kristin N. Barlett, Stephen D. Lotesta, and Lawrence J. Williams*
Department of Chemistry and Chemical Biology, Rutgers, The State UniVersity of New Jersey,
Piscataway, New Jersey 08854
Received September 8, 2004; E-mail: ljw@rutchem.rutgers.edu
Scheme 1
Substrate-directed and reagent-controlled asymmetric alkene
epoxidation and subsequent nucleophilic epoxide opening are
among the most widely used strategies for introducing molecular
complexity in target-oriented synthesis.1 Yet the analogous oxida-
tion/nucleophilic opening of the intrinsically stereogenic allene
remains unexplored in synthesis.2 The oxidation products, spiro-
diepoxides (e.g., 3), can in principle serve as synthetically useful
three-carbon units of bond formation and stereochemistry and
provide direct access to highly functionalized and highly enan-
tioenriched ketones and ketone derivatives. Here we present an
efficient route to the potent and selective proteasome inhibitor
epoxomicin3 (1) and thus establish the first use of the spirodiepoxide
functional group in total synthesis.
Scheme 2 a
Proteasome targeting has emerged as a new modality for the
potential treatment of diseases ranging from malaria to cancer.4
The importance of understanding and controlling proteasome
function led us to design new approaches to epoxomicin (1).5 In
the most concise approach, the functionality and stereochemical
arrangement of simplified structure 2, present in 1, would be
orchestrated simultaneously (Scheme 1), and modifications in the
peripheral highlighted portions of 2 would not encumber the
synthetic route. Spirodiepoxides of type 3 could serve as precursors
to such target systems. In the presence of a suitable nucleophile
such species should undergo regioselective SN2 reactions. Enan-
tiomerically pure spirodiepoxide would be derived from oxidation
of optically pure, and appropriately protected, allene (e.g., 5), which
would arise in turn from aldehyde, alkyne, and organometallic
precursors. The highlighted substituents of these precursors cor-
respond to those indicated in 2. Oxidation of 5, first at the less
hindered face of the more substituted π-bond, would give rise to 3
as the major isomer. This approach would require identification of
a hydroxyl protecting group for 5 and a nitrogen nucleophile suitable
for spirodiepoxide opening.
The pioneering work of Crandall stands as the only reported
systematic analysis of spirodiepoxides.6 Thus, simple allenes may
be oxidized to spirodiepoxides, which rearrange in the presence of
acid. A number of nucleophiles have been successfully added to
spirodiepoxides, and consistent with SN2 substitution, the ratio of
products corresponds to the ratio of oxidation products.
a Reagents and conditions: (i) DMDO, acetone, -40 to 23 °C, 2 h; then
nucleophile (see Supporting Information); (ii) DMDO, acetone, -50 to 23
°C, 2 h; (iii) Bu4NN3, CHCl3, -30 °C, 2 h; 30%. Major isomers shown.
SES ) SO2CH2CH2Si(CH3)3.
N-alkylated product 16 predominated, albeit in modest yield (30%),
when benzamide was first treated with n-BuLi. Benzenesulfonamide
in the presence of base8 gave adduct 17 (75%), but under neutral
conditions no product was observed. In hopes of inducing N-
alkylation of an amide precursor, we prepared N-acyl sulfonamide
18 by using our thio acid/azide amidation.9 Under a variety of
conditions (DIEA, K2CO3, LiHMDS, NaHMDS, or KHMDS), no
reaction with the spirodiepoxide took place. In the absence of base,
however, an unstable adduct formed and then decomposed upon
treatment with fluoride. While sodium azide added slowly to
spirodiepoxides derived from 6, tetrabutylammonium azide added
rapidly even at low temperature to give 19 in 73% yield.
When the spirodiepoxide derived from allenyl mesylate 20 was
exposed to tetrabutylammonium azide, epoxide 22 was formed in
30% yield. Azide appears to preferentially open the spirodiepoxide
rather than displace the neopentyl-like mesylate (see 21). The
nascent vicinal alkoxide displaces the mesylate to form a new
epoxide, which resists subsequent azide opening. Azide 22 and the
amine derived by reduction proved unstable and therefore were not
To initiate our studies, a series of O-protected hydroxy allenes
(6-13) was prepared and oxidized with dimethyldioxirane (DMDO),
as shown in Scheme 2. Functional group compatibility and
1
approximate ratios of oxidation products were determined by H
NMR analysis of the crude spirodiepoxides.7 While benzoate 13
led to ortho ester 14, silyl and alkyl ether protection is compatible
with the spirodiepoxide functionality and gave the corresponding
spirodiepoxides in ratios of approximately 2:1.
To proceed toward 1, suitable nitrogen nucleophiles were
identified by exposure to spirodiepoxides derived from allene 6.7
Addition of benzamide under neutral conditions led to O-alkylation/
cyclization and gave oxazolines 15 in 44% yield, whereas the
9
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10.1021/ja044563c CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
selectivity. Importantly, this transformation is achieved in the
absence of other stereodirecting functionalities. This report also
establishes that chiral spirodiepoxides can be prepared and ma-
nipulated on gram scale.13 Coupled with the two-step assembly of
all the carbon atoms of the targeted substructure, this method is a
highly efficient, flexible, and modular synthesis of highly func-
tionalized ketones and their derivatives. In addition to disclosing
the selective reaction of a spirodiepoxide in the presence of a
mesylate and several new and diverse reactions of spirodiepoxides
(e.g. formation of ortho ester 14, oxazoline 15, and azido epoxide
22), we have completed the synthesis of epoxomicin in an overall
yield of 26% from 23 (20% including all steps). This route should
also provide new epoxomicin analogues with improved activity and
selectivity. Issues such as the scope of compatible functional groups
and nucleophiles, control of regioselective nucleophilic addition,
stereoselective oxidation of the allene precursors, and elucidation
and exploitation of the mechanisms of spirodiepoxide opening are
under investigation.
a Reagents and conditions: (i) (-)-N-methylephedrine, Zn(OTf)2, Et3N,
toluene, rt, 2 h, TBSOCH2CCH then 23 14 h, 93%, >95% ee; (ii) a. MsCl,
Et3N, DCM, -65 to 23 °C, 2 h; b. MeMgBr, CuBr, LiBr, THF/tert-butyl
ether, -65 to 23 °C, 2 h, 91%; (iii) a. DMDO, -40 to 23 °C, 1.5 h; b.
Bu4NN3, CHCl3, -20 to 23 °C, 1 h, 73% (3:1 dr); c. 10% Pd/C, H2,
(Boc)2O‚K2CO3, EtOAc, rt, 12 h, 91%; d. TFA, 0 °C, 13 min; (iv) a. 26,
HCl‚Ile-OMe, DCC, HOBT, Et3N, DMF, 0 to 23 °C, 12 h, 93%; b. 25%
TFA-DCM, 10 to 23 °C, 40 min; c. TEA, Ac2O, DMAP, DCM, 0 to 23
°C, 3 h, 95%; d. 5% NaOH, MeOH-H2O, rt, 2 h, 99%; e. 27, DCC, HOBT,
DCM-DMF, rt, 3 h, 92%; f. 10% Pd/C, H2, MeOH, rt, 2 h, 100%; (v) 25,
DIEA, DCC, HOBT, DCM-DMF, rt, 4 h, 86%; (vi) a. TBAF, THF, 0 to
23 °C, 1 h, 89%; b. MsCl, DIEA, DCM, -40 to 23 °C, 1 h; c. K2CO3,
THF-H2O, rt, 3 h, 93%; d. TFA, 0 to 23 °C, 20 min, 88%.
Acknowledgment. Financial support by Merck & Co., Johnson
& Johnson (Discovery Award), donors of the American Chemical
Society Petroleum Research Fund, Graduate Assistance in Areas
of National Need (fellowship to S.D.L.), and Rutgers, The State
University of New Jersey is gratefully acknowledged. We thank
Prof. Spencer Knapp for stimulating discussions and critical reading
of the manuscript.
Supporting Information Available: Synthetic methods and char-
acterization data. This material is available free of charge via the Internet
at http://pubs.acs.org.
advanced. Amines related to 19, however, were stable to manipula-
tion leading to 1, as described below.
The optimized synthesis of epoxomicin is presented in Scheme
3. Isovaleraldehyde was subjected to asymmetric alkynylation10 to
form 24 (93% yield, >95% ee). The alcohol was converted to the
mesylate and subsequently transformed into allene 6 upon copper-
mediated11 SN2′ displacement (91%). As described above, treatment
of 6 with DMDO12 followed by exposure to azide smoothly
produced 19 (>95% er) in 73% yield (3:1 ratio of separable
diastereomers). In situ reduction/protection (91%) and then treat-
ment with acid converted the major azido alcohol to the stable crude
amine salt (25) ready for peptide coupling. DCC-promoted coupling
of 26 with methyl isoleucinate (93%), Boc removal and acetylation
(95%), saponification (99%), coupling to threonine 277 (see inset),
and then hydrogenolysis gave 28 (92%, two steps), which smoothly
coupled with 25 to furnish 29 (86%, 19 f 29). Exposure of 29 to
fluoride cleaved the silyl ether-protecting group (89%). The resultant
primary alcohol was converted to the mesylate and cyclized to give
the epoxide (93%), and then the tert-butyl ether was removed (88%)
to produce 1.
References
(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004-2021. Rao, A. S. In ComprehensiVe Organic Synthesis; Trost,
B. M., Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 357-
387. Hickey, M.; Goeddel, D.; Crane, Z.; Shi, Y. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5794-5798.
(2) For recent related allene oxidations with synthesis applications, see:
Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem. Soc. 2003,
125, 12694-12695. Fleming, S. A.; Carroll, S. M.; Sean, M.; Hirschi, J.;
Liu, R.; Pace, J. L.; Redd, J. T. Tetrahedron Lett. 2004, 45, 3341-3343.
(3) Hanada, H.; Sugawara, K.; Kaneta, K.; Toda, S.; Nishiyama, Y.; Tomita,
K.; Yamamoto, H.; Konishi, M.; Oki, T. J. Antibiot. 1992, 45, 1746-
1752. Meng, L.; Mohan, R.; Kwok, B. H. B.; Elofsson, M.; Sin, N.; Crews,
C. M. Proc. Natl. Acad. Sci. U.S.A., 1999, 96, 10403-10408.
(4) For proteasome structure, biology and applications lead references, see:
Kloetzel, P. M. Nat. ReV. Mol. Cell. Biol. 2001, 2, 179-188.
(5) Sin, N.; Kim, K. B.; Elofsson, M.; Meng, L.; Auth, H.; Kwok, B. H. B.;
Crews, C. M. Bioorg. Med. Chem. Lett. 1999, 9, 2283-2288.
(6) Crandall, J. K.; Machleder, W. H. Tetrahedron Lett. 1966, 7, 6037-6041.
Crandall, J. K.; Batal, D. J. Tetrahedron Lett. 1988, 29, 4791-4794.
Crandall, J. K.; Reix, T. Tetrahedron Lett. 1994, 35, 2513-2516. Crandall,
J. K.; Rambo, E. Tetrahedron Lett. 1994, 35, 1489-1492. Crandall, J.
K.; Machleder, W. H. J. Am. Chem. Soc. 1968, 90, 7292-7296. Crandall,
J. K.; Machleder, W. H.; Thomas, M. J. J. Am. Chem. Soc. 1968, 90,
7346-7347. Crandall, J. K.; Batal, D. J.; Lin, F.; Reix, T.; Nadol, G. S.;
Ng, R. A. Tetrahedron 1992, 48, 1427-1448. Crandall, J. K.; Rambo, E.
Tetrahedron 2002, 58, 7027-7036. Crandall, J. K.; Conover, W. W.;
Komin, J. B.; Machleder, W. H. J. Org. Chem. 1974, 39, 1723-1729.
Crandall, J. K.; Batal, D. J. J. Org. Chem. 1988, 53, 1338-1340. Crandall,
J. K.; Rambo, E. J. Org. Chem. 1990, 55, 5929-5930. Crandall, J. K.;
Batal, D. J.; Sebesta, D. P.; Lin, F. J. Org. Chem. 1991, 56, 1153-1166.
(7) See also: Supporting Information.
Spectral data for synthetic 1 proved identical to published data
25
for natural 1, including [R]D -64.0 (c 0.47, MeOH), lit3a -66.1
(c 0.50, MeOH), and confirms the stereochemical assignments in
Scheme 3. Chemical correlation secured the syn stereochemistry
of the major isomers of 15-17, 19, and 22 as shown in Scheme 2.
Nucleophilic opening of a spirodiepoxide effectively establishes
specific stereochemical communication across a carbonyl. As
depicted in eq 1, oxidation/nucleophilic opening installs three
(8) Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787-4790.
(9) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am.
Chem. Soc. 2003, 125, 7754-7755.
(10) Frantz, D.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806-1807.
(11) Elsevier, C. J.; Stehouwer, P. M.; Westmijze, H.; Vermeer, P. J. Org.
Chem. 1983, 48, 1103-1105. Elsevier, C. J.; Vermeer, P. J. Org. Chem.
1984, 49, 1649-1650.
(12) Murray, R. W.; Jeyaraman, R. J. Org. Chem. 1985, 50, 2847-2853.
(13) See also: Rameshkumar, C.; Xiong, H.; Tracey, M. R.; Berry, C. R.;
Yao, L. J.; Hsung, R. P. J. Org. Chem. 2002, 67, 1339-1345.
functional groups, nucleophile, ketone, and alcohol, with syn
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