Simple enantiospecific syntheses of the C(2)-diastereomers of omuralide and 3-methylomuralide

Article abstract of DOI:10.1021/ol050874w

(Chemical Equation Presented) Syntheses of two novel omuralide derivatives are described.

Full text of DOI:10.1021/ol050874w

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2703-2705
Simple Enantiospecific Syntheses of the
C(2)-Diastereomers of Omuralide and
3-Methylomuralide
Leleti Rajender Reddy, P. Saravanan, Jean-Franc
¸ois Fournier,
B. V. Subba Reddy, and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
12 Oxford Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received April 20, 2005
ABSTRACT
Syntheses of two novel omuralide derivatives are described.
Omuralide (1) is a highly selective and potent covalent
inhibitor of the proteasome, the cylindrical multiprotein
assembly that degrades polyubiquitinated proteins.1,2 The
proteasome functions to remove damaged or misfolded
proteins and to play a major role in maintaining optimum
levels of individual proteins in cells and tissues. This role is
especially important for regulatory proteins such as those
involved in signaling, cell-cycle control, DNA repair,
transcription, and apoptosis.2 As a result of previous synthetic
work in these laboratories, we were able to develop a clear
structure-activity correlation for a considerable number of
omuralide analogues.1a One interesting finding was that
2-methylomuralide3,4 (2) retained most of the potency of 1.1a
This fact prompted us to develop a synthesis of 2-epi-
omuralide (3) for evaluation of its activity in proteasome
inhibition, especially because of the availability in our
laboratory of advanced intermediates for the synthesis,
specifically the ester-aldehyde 4 (see Scheme 1). This chiral
ester aldehyde can be prepared in quantity from methyl
4-methyl-2-pentenoate by the use of catalytic enantioselective
methodology.4
(1) (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.
(2) (a) Hershko, A. Le Prix Nobel; Nobel Foundation: Stockholm, 2005.
(b) http://nobelprize.org/chemistry/laureates/2004/public.html. (c) De Mar-
tino, G. N.; Slaughter, C. A. J. Biol. Chem. 1999, 274, 22123-22126. (d)
Glickman, M. H.; Liechanover, A. Physiol. ReV. 2001, 82, 373-428. (e)
Tansey, N. P. New Engl. J. Med. 2004, 351, 393-394. (f) Ehlers, M. D.
Nature Neurosci. 2003, 6, 231-242. (g) Adams, J. Proteasome Inhibitors
in Cancer Therapy; Humana Press: New York, 2004.
Reaction of 4 with 2 equiv of the E-tert-butyldimethylsilyl
enol ether of methyl propionate in THF (from LDA and
methyl propionate in THF at -78 °C) and 1.1 equiv of
powdered LiClO4 (moisture-containing, but not dry) in CH2-
Cl2 at -78 °C for 20 h gave as major product the syn aldol
adduct 5. Acid-catalyzed methanolysis of crude 5 with
refluxing methanolic HCl and concomitant lactamization
provided the pure γ-lactam benzoate 6 (63% overall from
4) after flash chromatography on silica gel. Saponification
of the benzoate-methyl ester 6 provided the dihydroxy acid
(3) Corey, E. J.; Li, W.-D. Z. Tetrahedron Lett. 1998, 39, 7475-7478.
(4) Saravanan, P.; Corey, E. J. J. Org. Chem. 2003, 68, 2760-2764.
10.1021/ol050874w CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/26/2005

Scheme 1
Scheme 2
reagent formed from DMSO and ClCOCOCl in CH2Cl2 to
the primary alcohol precursor and Et3N at -78 °C,4 addition
of pentane to the reaction product, filtration, and evaporation
in vacuo (95% yield). It was crucial to use a nonaqueous
workup since 4 rapidly undergoes retroaldol cleavage under
aqueous conditions. Pure 4 could be stored unchanged at
-78 °C for at least 1 day. The optimum catalyst for the
transformation 4 f 5 was found to be LiClO4 (not rigorously
dried and containing a small amount (>2%) of moisture).
One straightforward explanation for the observed syn aldol
diastereoselectivity is outlined in Scheme 2. In this sequence,
the formyl and COOMe carbonyl oxygens of 4 coordinate
with LiClO4 to form a chelated intermediate which then
couples with the enol silyl ether as shown in Scheme 2 to
generate the syn aldol adducts. This pathway to the syn
product 5 appears to be favored over alternative pre-
transition-state assemblies because it involves a minimum
of steric repulsion.
We have also taken advantage of the availability of an
advanced intermediate (10) for the synthesis of other
omuralide derivatives6 to prepare 3-methyl-2-epi-omuralide
(8), a hybrid of 3, and salinosporamide A (9) (Scheme 3),
for which we have described three different routes.6,7,8 The
keto acrylamide 106,7 was added to the Kulinkovich reagent9
(3.5 equiv) formed by treatment of 4 equiv of Ti(i-PrO)4
with 7 equiv of cyclopentylmagnesium chloride in t-BuOMe
at -40 °C for 30 min and then allowed to react at -40 °C
for another 1 h and at -20 °C for 20 h. The cyclized
titanium-containing intermediate thus formed (see below) was
then quenched with excess 1 N hydrochloric acid. Extractive
isolation afforded a single diastereomeric γ-lactam, 11, which
was isolated in 95% yield after flash chromatography on
silica gel.10,11 The TBS ether protecting group of 11 was
cleaved using 1:1 48% aq HF in acetonitrile to form the
7. Reaction of 7 with bis(2-oxo-3-oxazolidinyl)phosphinic
chloride (BOPCl) and Et3N in CH2Cl2 at 23 °C for 1 h gave,
after extractive isolation (EtOAc) and flash chromatography
on silica gel, the desired â-lactone 3, mp 170-172 °C.5 The
structure of 3 was confirmed by single-crystal X-ray dif-
fraction analysis (Figure 1).
Figure 1. ORTEP presentation of 3.
(6) Reddy, L. R.; Fournier, J.-F.; Subba Reddy, B. V.; Corey, E. J. J.
Am. Chem. Soc., published online June 2, 2005 http://dx.doi.org/10.1021/
ja052376o.
(7) Reddy, L. R.; Fournier, J.-F.; Subba Reddy, B. V.; Corey, E. J. Org.
Lett. 2005, 7, 2699-2702.
A key step in the synthesis of 3 that is outlined in Scheme
1 is the doubly diastereoselective Mukaiyama aldol coupling
4 f 5. The preparation of the very sensitive aldehyde 4 was
accomplished by addition of a -78 °C solution of the Swern
(8) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004,
126, 6230-6231.
(9) 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.
(10) 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.
(5) Physical data for 3: Rf 0.50 (neat EtOAc); [R]23 -70.1 (c 1.0,
D
MeCN); FTIR (film) νmax 3456, 2948, 1835, 1719, 1648, 1510, 1250, cm-1
;
1H NMR (CDCl3, 600 MHz) δ 7.0 (1H, br s, -NH), 4.86 (1H, s), 3.75
(1H, dd, J ) 13.2, 6.0 Hz), 3.58 (1H, d, J ) 7.2 Hz), 2.70 (1H, q, J ) 7.8
Hz), 1.78 (1H, m), 1.24 (3H, d, J ) 8.4 Hz), 0.99 (3H, d, J ) 6.9 Hz), 0.90
(3H, d, J ) 6.8 Hz).
2704
Org. Lett., Vol. 7, No. 13, 2005

Since the absolute configurations at carbons 4 and 5 have
been established unambiguously by previous work6,7 and
since the absolute configuration at carbon 2 is now also clear,
there is no doubt about the overall correctness of the
transformation 10 f 11. The trans relationship of the methyl
substituent at C(2) and the hydroxyl group at C(3) of 11
contrasts with previous work on the Ti-mediated cyclization
of δ,ꢀ-unsaturated ketones10 and is thus surprising. This
observed trans arrangement of substituents at C(2) and C(3)
indicates that the cyclization occurs not through a bicyclic
organotitanium intermediate such as 14, but via a monocyclic
structure such as 15. The formation of intermediate 15 may
Scheme 3
occur by a pathway such as the following: (1) transfer of
(RO)2Ti from the Kulinkovich complex with cyclopentene
to the acrylamide R,â-double bond of 10 and (2) radical
addition of that intermediate to a chelate of MgCl+ with the
COOMe and CH3CO carbonyl oxygens of the complex from
10 to effect cyclization to 15. Proteolysis of 15 obviously
leads to the observed product 11. Regardless of the mecha-
nistic pathway for the formation of 11 from 10, it seems
likely that Kulinkovich complex induced cyclizations have
even greater synthetic potential than previously realized.
In summary, the omuralide analogues 3 and 8 are now
available by efficient and practical stereocontrolled routes.
dihydroxy ester 12,12 further transformed into 13 by oxidative
cleavage of the N-p-methoxybenzyl protecting group.13
Saponification of methyl ester 13 followed by lactonization
of the resulting dihydroxy acid yielded 3-methyl-2-epi-
omuralide 8 as a colorless solid14 that was distinctly different
from a sample of 3-methylomuralide.7
The relative stereochemistry of the titanacyclopentene-
mediated cyclization 10 f 11 about carbons 3 and 4 follows
unambiguously from the formation of the â-lactone ring.
Acknowledgment. J.-F.F. is grateful to NSERC of
Canada for a postdoctoral fellowship.
Supporting Information Available: Complete data for
the X-ray crystal structure of 3 are given. This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) Characterization data for 11: Rf 0.40 (hexanes-EtOAc 50:50); mp
43-44 °C; [R]23D +10.4 (c 2.5, CHCl3); FTIR (film) νmax 3386, 2954, 2935,
1748, 1683, 1515, 1245, 1177, 1055, 835 cm-1 1H NMR (CDCl3, 400
;
OL050874W
MHz) δ 7.09 (2H, d, J ) 8.8 Hz), 6.81 (2H, d, J ) 8.8 Hz), 4.88 (1H, d,
J ) 15.5 Hz), 4.54 (1H, d, J ) 16 Hz), 4.13 (1H, d, J ) 0.8 Hz), 4.04 (1H,
s), 3.76 (3H, s), 3.49 (3H, s), 2.59 (1H, m), 2.41 (1H, q, J ) 7.6 Hz), 1.41
(3H, s), 1.17 (3H, d, J ) 7.6 Hz), 1.09 (3H, d, J ) 7.2 Hz), 0.94 (9H, s),
0.90 (3H, d, J ) 6.4 Hz), 0.17 (3H, s), -0.05 (3H, s); 13C NMR (CDCl3,
100 MHz) δ 176.62, 173.18, 158.31, 130.95, 127.58, 113.98, 80.77, 79.78,
77.58, 55.44, 52.47, 48.40, 47.28, 28.80, 26.62, 24.34, 20.05, 19.11, 16.01,
10.37, -1.51, -4.08; HRMS (ESI) m/z calcd for C26H44NO6Si [M + H+]
494. 2938, found 494.2932.
(13) Characterization data for 13: colorless solid; Rf ) 0.2 (EtOAc);
mp ∼180 °C dec; [R]23D -2.6 (c 1.5, MeOH); FTIR (film) νmax 3325, 2956,
2925, 1725, 1683, 1252, 1167, 1096, 1021, 835 cm-1; 1H NMR (CD3OD,
600 MHz) δ 5.49 (1H, s, NH), 3.80 (1H, d, J ) 4.8 Hz), 3.73 (3H, s), 2.35
(1H, q, J ) 7.8 Hz), 1.63 (1H, m), 1.49 (3H, s), 1.26 (3H, d, J ) 7.8 Hz),
0.94 (3H, d, J ) 7.2 Hz), 0.90 (3H, d, J ) 6.6 Hz); 13C NMR (CDCl3, 100
MHz) δ 181.41, 171.33, 80.48, 78.96, 74.60, 51.23, 50.97, 31.33, 20.28,
18.51, 16.98, 11.53; HRMS (ESI) m/z calcd for C12H22NO5 [M + H+]
260.1498, found 260.1495.
(12) Characterization data for 12: colorless solid; Rf 0.60 (EtOAc); mp
126-128 °C [R]23 +22.0 (c 0.3, CHCl3); FTIR (film) νmax 3392, 2952,
D
1
2912, 1752, 1673, 1515, 1246, 1177, 1036, 835 cm-1; H NMR (CDCl3,
(14) Characterization data for 8: Rf ) 0.53 (EtOAc); mp 145-147 °C;
600 MHz) δ 7.32 (2H, d, J ) 8.4 Hz), 6.85 (2H, d, J ) 9.0 Hz), 4.75 (2H,
d, J ) 6.6 Hz), 3.80 (3H, s), 3.70 (3H, s), 3.65 (1H, d, J ) 5.5 Hz), 2.63
(1H, q, J ) 7.2 Hz), 2.15 (1H, m), 1.32 (3H, s), 1.24 (3H, d, J ) 7.2 Hz),
0.92 (3H, d, J ) 7.2 Hz), 0.87 (3H, d, J ) 6.6 Hz); 13C NMR (CDCl3, 125
MHz) δ 177.36, 172.44, 158.62, 131.24, 128.87, 113.90, 80.33, 77.54, 55.45,
52.48, 48.85, 46.27, 30.40, 21.48, 18.86, 17.86, 10.15; HRMS (ESI) m/z
calcd for C20H30NO6 [M + H+] 380.2028, found 380.2024.
[R]23 -12.2 (c 0.6, CHCl3); FTIR (film) νmax 3355, 2966, 2927, 1825,
D
1704, 1345, 1048, 850 cm-1; 1H NMR (CDCl3, 500 MHz) δ 6.63 (1H, br),
3.75 (1H, d, J ) 7.0 Hz), 2.79 (1H, q, J ) 8.0 Hz), 1.92 (1H, m) 1.69 (3H,
s), 1.24 (3H, d, J ) 6.0 Hz), 1.12 (3H, d, J ) 7.5 Hz), 1.08 (1H, d, J ) 6.5
Hz); 13C NMR (CDCl3, 125 MHz) δ 179.03, 169.91, 87.00, 79.59, 71.51,
44.36, 31.48, 19.87, 18.69, 16.84, 13.09; HRMS (CSI) calcd for C11H21-
lN2O4 [M + NH4]+ 245.1501, found 245.1491.
Org. Lett., Vol. 7, No. 13, 2005
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