New entry to convertible isocyanides for the Ugi reaction and its application to the stereocontrolled formal total synthesis of the proteasome inhibitor omuralide

Article abstract of DOI:10.1021/ol701446y

The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids culminated in the formal total synthesis of the proteasome inhibitor omuralide featuring a stereocontrolled Ugi reaction. Indole-isocyanide was name

Full text of DOI:10.1021/ol701446y

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3631-3634
New Entry to Convertible Isocyanides
for the Ugi Reaction and Its Application
to the Stereocontrolled Formal Total
Synthesis of the Proteasome Inhibitor
Omuralide§
Cynthia B. Gilley, Matthew J. Buller, and Yoshihisa Kobayashi*
Department of Chemistry and Biochemistry, UniVersity of California, San Diego,
9500 Gilman DriVe, Mail Code 0343, La Jolla, California 92093-0343
ykoba@chem.ucsd.edu
Received June 21, 2007
ABSTRACT
The development of a new convertible isocyanide, indole-isocyanide, for ready access to pyroglutamic acids culminated in the formal total
synthesis of the proteasome inhibitor omuralide featuring a stereocontrolled Ugi reaction. Indole-isocyanide was named after the facilitation
of hydrolysis of the resulting 2-(2,2-dimethoxyethyl)anilide via an N-acylindole intermediate obtained by the Ugi multicomponent condensation
reaction followed by the indole formation.
Omuralide (1), derived from the natural product lactacystin
(2),1 has been shown to be a selective inhibitor of the 20S
proteasome found in mammalian and bacterial cells.2 A great
deal of attention has been devoted recently to proteasome
inhibition as a novel therapeutic target in human cancer due
to the distinctly different mechanism of action from known
chemotherapeutics.3 In 2003, FDA approval of Velcade for
the treatment of multiple myeloma validated proteasome
inhibition as a novel cancer therapy.4 A structurally related
and more potent proteasome inhibitor, salinosporamide A
(3), was reported by Fenical recently.5
The combination of the unique biological profile and the
structural complexity of omuralide (1)6 and salinosporamide
A (3)7 has led to intense research efforts by synthetic
chemists. Both molecules share a fused γ-lactam-â-lactone
core structure which could easily be obtained from a
§ In memory of Dr. Kenji Koga.
(4) Richardson, P. G. Clin. AdV. Hemato. Oncol. 2003, 1, 596-600.
(5) (a) 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. For
congeners of salinosporamide A, see: (b) Williams, P. G.; Buchanan, G.
O.; Feling, R. H.; Kauffman, C. A.; Jensen, P. R.; Fenical, W. J. Org. Chem.
2005, 70, 6196-6203. (c) Stadler, M.; Bitzer, J.; Mayer-Bartschmid, A.;
Mueller, H.; Benet-Buchholz, J.; Gantner, F.; Tichy, H. V.; Reinemer, P.;
Bacon, K. B. J. Nat. Prod. 2007, 70, 246-252. (d) Reed, K. A.; Manam,
R. R.; Mitchell, S. S.; Xu, J.; Teisan, S.; Chao, T. H.; Deyanat-Yazdi, G.;
Neuteboom, S. T. C.; Lam, K. S.; Potts, B. C. M. J. Nat. Prod. 2007, 70,
269-276.
(1) (a) Omura, S.; Fujimoto, T.; Otoguru, 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.
(2) Corey, E. J.; Reichard, G. A.; Kania, R. Tetrahedron Lett. 1993, 34,
6977-6980.
(3) (a) Fenteany, G. A.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.;
Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3358-3362. (b)
Fenteany, G. A.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J.;
Schreiber, S. L. Science 1995, 268, 726-731.
10.1021/ol701446y CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/02/2007

Scheme 1. Overall Strategy toward the Synthesis of
Omuralide (1)
pyroglutamic acid derivative. We envisioned utilizing the
Ugi multicomponent condensation reaction to form the
γ-lactam ring of omuralide (1) from a densely functionalized
γ-ketoacid (Scheme 1). The challenging aspects to this
strategy are the stereoselective construction of the R-carbon
(C4 in the carbon numbering of omuralide) and selective
cleavage of the sterically more hindered C-terminal exo-
amide (C9 vs C1) of the Ugi product. Although numerous
reports of the Ugi reaction of levulinic acid (4) to prepare
pyroglutamic acid amides have been published,8 the inherent
challenges described above have prohibited its general utility
in natural product synthesis.
Armstrong developed 1-cyclohexenyl isocyanide to allow
the facile hydrolysis of the C-terminal amide via azlactone
under mild acidic conditions.9b This process is effective for
most Ugi products, except the pyroglutamic acid amide and
the related lactam amides which cannot form the activated
intermediate. Ugi’s convertible isocyanide,10 activated via
N-acyloxazolidinone, was ineffective for the hydrolysis due
to steric hindrance surrounding the resultant amide. There-
fore, design modification of the convertible isocyanide was
required for efficient access to pyroglutamic acids employing
the Ugi reaction.
We report 1-isocyano-2-(2,2-dimethoxyethyl)benzene (5)
as a convertible isocyanide which readily affords pyro-
glutamic acids via the Ugi reaction (Scheme 2).11,12 The initial
Scheme 2. Synthesis of 2-Methylpyroglutamic Acid by Ugi
Reaction with Convertible Isocyanide 5
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118, 3584-3590. (f) Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.;
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S. Chem. Commun. 1998, 1929-1930. (h) Corey, E. J.; Li, W.-D.;
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L.; Harling, J. D. Angew. Chem., Int. Ed. 2004, 43, 2293-2296. (q) Ooi,
H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.; Hatakeyama, S. J. Org. Chem.
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K. W.; Guyo, P. M.; Cowley, A.; Harling, J. D. Chem.-Eur. J. 2005, 11,
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Ugi product, anilide 6, derived from levulinic acid (4), is
readily converted to the corresponding carboxylic acid 8 via
N-acylindole 7 under mild conditions. This privileged ability
of the 2-(2,2-dimethoxyethyl)anilide 6, originally reported
by Fukuyama,13 has proven to be effective even with the
(8) (a) Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1997, 38, 359-
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Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725-2728. (d) Tye, H.;
Whittaker, M. Org. Biomol. Chem. 2004, 2, 813-815. For total synthesis
employing the Ugi reaction as a key step, see: (e) Jossang, A.; Melhaoui,
A.; Bodo, B. Heterocycles 1996, 43, 755-766. (f) Bauer, S. M.; Armstrong,
R. W. J. Am. Chem. Soc. 1999, 121, 6355-6366. (g) Beck, B.; Hess, S.;
Do¨mling, A. Bioorg. Med. Chem. Lett. 2000, 10, 1701-1705. (h) Marcac-
cini, S.; Pepino, R.; Torroba, T.; Miguel, D.; Garcia-Valverde, M.
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Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124,
6552-6554. For recent reviews on multicomponent condensation reactions,
see: (j) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-
1634. (k) Do¨mling, A. Chem. ReV. 2006, 106, 17-89.
(7) For salinosporamide A total syntheses, see: (a) Reddy, L. R.;
Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126, 6230-6231. (b)
Reddy, L. R.; Fournier, J. F.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2005,
7, 2699-2701. (c) Reddy, L. R.; Fournier, J. F.; Reddy, B. V. S.; Corey,
E. J. J. Am. Chem. Soc. 2005, 127, 8974-8976. (d) Endo, A.; Danishefsky,
S. J. J. Am. Chem. Soc. 2005, 127, 8298-8299. (e) Mullholand, N. P.;
Pattenden, G.; Walters, I. A. S. Org. Biomol. Chem. 2006, 4, 2845-2846.
(f) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007, 9, 2143-2146. (g)
Ling, T.; Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts, B. C.
M. Org. Lett. 2007, 9, 2289-2292.
3632
Org. Lett., Vol. 9, No. 18, 2007

Scheme 3. Formal Total Synthesis of Omuralide (1) Featuring Stereoselective Ugi Reaction with Convertible Isocyanide 5
hindered amide. To our knowledge, this is the first demon-
stration of the isocyanide in the Ugi reaction. The subsequent
selective hydrolysis of the sterically more hindered exo-amide
proves the concept as a convertible isocyanide. With the
methodology to efficiently access pyroglutamic acid deriva-
tives, we intended to show the utility of the isocyanide 5 in
the synthesis of omuralide (1) as a platform to investigate
the general applicability in natural product synthesis.
After preliminary studies,14 it was realized that γ-ketoacid
13 would be a key precursor of a stereocontrolled Ugi
reaction to reach Corey’s intermediate 176h,15 for the formal
total synthesis of omuralide (1) (Scheme 3). We then
embarked on the investigation of an efficient enantioselective
synthesis of chiral ketoacid 13. Because of the mild condi-
tions of the Evans anti-selective aldol reaction of acyl-
oxazolidinone 9,16 we believed it possible to use R-(hy-
droxymethyl)cinnamaldehyde 1017 directly in the aldol
reaction without protection of the primary alcohol in advance.
By modifying the original reaction conditions to include an
extra equivalent of TMSCl and Et3N to protect the free
alcohol in situ, as well as including an additional equivalent
of MgCl2, the aldol reaction proceeded smoothly to afford
the resulting 1,3-diol adduct in 78% yield as a 10:1
diastereomixture. The diol was protected as the acetonide
to give 11 isolated as a single diastereomer. It was unam-
biguously assigned as the required anti-aldol product by
X-ray crystallography,18 which is consistent with the litera-
ture.16 Lithium peroxide mediated hydrolysis of the chiral
auxiliary and benzyl protection of the resultant carboxylic
acid gave 12 in 91% yield. Ozonolysis of the exo-olefin
followed by hydrogenolysis of the benzyl ester provided the
Ugi precursor ketoacid 13, which was then subjected to the
Ugi reaction with the isocyanide 5 without purification. It
should be noted that ketoacid 13 exists as a single diaste-
reomer of a hemiketal at C4 (13a). The 13C NMR chemical
shift of C4 clearly indicated the hemiketal carbon instead of
an intact carbonyl group (Figure 1).19
(9) For convertible isocyanides, see: (a) Do¨mling, A.; Ugi, I. Angew.
Chem., Int. Ed. 2000, 39, 3168-3210. See pp 3183-3184 and refs therein.
(b) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996, 118, 2574-
2583. (c) Rikimaru, K.; Yanagisawa, A.; Kan, T.; Fukuyama, T. Synlett
2004, 41-44. (d) Rikimaru, K.; Mori, K.; Kan, T.; Fukuyama, T. Chem.
Commun. 2005, 394-396. (e) Pirrung, M. C.; Ghorai, S. J. Am. Chem.
Soc. 2006, 128, 11772-11773.
(10) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999, 55, 7411-7420.
(11) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Abstracts of Papers,
Presented at the 232th National Meeting of American Chemical Society,
San Francisco, CA, United States, September 10-14, 2006; ORGN-739.
(12) Preparation of isocyanide 5 and the application to synthesis of
quinoline is reported. Kobayashi, K.; Yoneda, K.; Mizumoto, T.; Umakoshi,
H.; Morikawa, O.; Konishi, H. Tetrahedron Lett. 2003, 44, 4733-4736.
Our execution of the preparative synthesis (10 g scale) of isocyanide 5 is
reported in the Supporting Information.
Much to our delight, the Ugi reaction of ketoacid 13 with
isocyanide 5 and p-methoxybenzylamine in 2,2,2-trifluoro-
ethanol furnished γ-lactam 14 in 78% yield as a single
diastereomer. The relative stereochemistry of the resulting
stereocenter C4 of the Ugi product 14 was unambiguously
assigned by X-ray crystallography.20 At this time we believe
the diastereoselectivity arises due to the preference of small
(17) Compound 10 was prepared in one step starting from the known
allyl alcohol (Doi, T.; Hirabayashi, K.; Kokubo, M.; Komagata, T.;
Yamamoto, K.; Takahashi, T. J. Org. Chem. 1996, 61, 8360-8361). For
experimental procedures, see Supporting Information. The synthesis of 10
by DIBALH reduction of (Z)-2-cyano-3-phenyl-2-propen-1-ol is previously
reported without spectroscopic data: Campi, E. M.; Dyall, K.; Fallon, G.;
Jackson, W. R.; Perlmutter, P.; Smallridge, A. J. Synthesis 1990, 855-
856.
(13) (a) Arai, E.; Tokuyama, H.; Linsell, M. S.; Fukuyama, T. Tetra-
hedron Lett. 1998, 39, 71-74. (b) Greene, T. W.; Wuts, P. G. M. Greene’s
ProtectiVe Groups in Organic Synthesis, 4th ed.; John Wiley & Sons: New
York, 1999; p 640.
(14) Kobayashi, Y.; Gilley, C. B.; Ozboya, K.; Ju, L. Abstracts of Papers,
Presented at the 229th National Meeting of American Chemical Society,
San Diego, CA, United States, March 13-17, 2005; ORGN-566.
(15) The compound 17 was obtained by Corey (ref 6h) in 10 steps from
the known compound in 30% overall yield (89% per step) and by us in 14
steps from 10 in 14% overall yield (87% per step).
(18) CCDC 634646 contains the supplementary crystallographic data of
11. The data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, UK; fax: +44(1223)336033 or
deposit@ccdc.cam.ac.uk.
(19) Mondon, A.; Menz, H.; Zander, J. Chem. Ber. 1963, 96, 826-839.
(20) CCDC 634644 contains the supplementary crystallographic data of
14.
(16) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am.
Chem. Soc. 2002, 124, 392-393.
Org. Lett., Vol. 9, No. 18, 2007
3633

secondary alcohol, and NaOMe-mediated removal of the
pivaloate. The conversion of 17 to omuralide (1) was reported
by Corey.6h
In this paper, we introduced the isocyanide 5 as a
convertible isocyanide. To our knowledge, this is the first
demonstration of the isocyanide in the Ugi reaction. The
resulting anilide is amenable to facile hydrolysis to yield a
free pyroglutamic acid via N-acylindole. The feasibility and
applicability of this methodology were proven by its use in
the stereocontrolled formal total synthesis of omuralide (1).
This Ugi strategy with the isocyanide for the synthesis of
pyroglutamic acids would be applicable to the synthesis of
a structurally related natural product, salinosporamide A (3),
as well as others containing a pyroglutamic acid moiety. We
propose to name this convertible isocyanide as indole-
isocyanide after the facilitation of hydrolysis of the resulting
anilide via N-acylindole intermediate.23
Figure 1. Observed structure of γ-ketoacid 13.
nucleophiles to approach the carbonyl group of 1,3-dioxan-
4-ones exclusively from the axial direction.21
To circumvent certain undesired side reactions,22 we
decided to selectively remove the acetonide protecting group
before forming the indole. The treatment of the Ugi product
14 with catalytic CSA in MeOH furnished the corresponding
diol without formation of N-acylindole. The resulting diol
was protected as a diacetate, which was stable under the acid-
catalyzed indole formation conditions that afforded the
desired N-acylindole 15. Direct conversion to the methyl ester
diol 16 occurred in 87% yield by stirring in a 10:1 MeOH/
Et3N mixture overnight at room temperature. The following
sequence led to the completion of the formal total synthesis
of omuralide: selective pivaloate formation of the primary
alcohol of 16, subsequent TBS protection of the remaining
Acknowledgment. The authors greatly acknowledge the
University of California, a GAANN fellowship (C.B.G.), and
a Kaplan fellowship (M.J.B.) for financial support of this
research. The authors also thank Professor Arnold Rheingold
(UCSD) for X-ray crystallography, Dr. Yongxuan Su (UCSD)
for Mass Spectroscopy, and UCSD undergraduate students,
Lei Ju, Kerem Ozboya, and Man Ting Loo, for their
preliminary results.
(21) Jochims, J. C.; Kobayashi, Y.; Skrzelewski, E. Tetrahedron Lett.
1974, 7, 571-574.
Supporting Information Available: Characterization
data for all new compounds and CIF files of X-ray crystal-
lographic analysis of both compounds 11 and 14. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Despite numerous attempts to form the N-acylindole from Ugi
product anilide 14, we were unsuccessful because the reaction was always
complicated by acetonide deprotection and undesired N,O-acetal formation
with both primary and secondary alcohols which was unexpectedly facile
from this substrate (0.3 equiv of CSA, benzene, rt, 63% of the mixture of
N-acylindole A, and bicyclic N,O-acetal B and C as shown below).
OL701446Y
(23) Although the structure of the isocyanide 5 does not contain an indole
itself before Ugi reaction, we believe the name appropriately describes the
function and character as a convertible isocyanide. Moreover, we are
currently developing a series of convertible isocyanides which could
systematically be named by using this format indicating the activation
method for the hydrolysis of the resulting amide derived from isocyanide
in Ugi/Passerini multicomponent condensation reactions. Gilley, C. B.;
Kobayashi, Y., unpublished results.
3634
Org. Lett., Vol. 9, No. 18, 2007