Total synthesis of (-)-belactosin C and derivatives via double diastereoselective tandem mukaiyama aldol lactonizations

Article abstract of DOI:10.1021/ol070275k

Equation presented The enantioselective synthesis of (-)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama aldol-lactonizaton (TMAL) process. One approach involved a distal double diastereoselective TMAL rea

Full text of DOI:10.1021/ol070275k

ORGANIC
LETTERS
2007
Vol. 9, No. 8
1537-1540
Total Synthesis of (−)-Belactosin C and
Derivatives via Double
Diastereoselective Tandem Mukaiyama
Aldol Lactonizations
Sung Wook Cho and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
romo@mail.chem.tamu.edu
Received February 2, 2007
ABSTRACT
The enantioselective synthesis of (
aldol-lactonizaton (TMAL) process. One approach involved a distal double diastereoselective TMAL reaction with a dipeptide glyoxamide,
whereas a second approach involved amide coupling of a dipeptide with a -lactone carboxylic acid, obtained via the TMAL process employing
a chiral silyl ketene acetal. Notable improvements in diastereoselectivity were achieved in a proximal double diastereoselective TMAL process.
−)-belactosin C and derivatives was accomplished in a concise manner employing the tandem, Mukaiyama
â
The recently isolated bacterial metabolites, belactosins A-C
from a fermentation broth of Streptomyces sp. UCK14,
uniquely contain a â-lactone dipeptide motif and exhibit
anticancer activities1 subsequently attributed to regulation
of the ubiquitin-proteasome pathway through inhibition of
the 20S proteasome (Figure 1).2 Belactosins A and C possess
the greatest inhibitory activity toward the chymotrypsin
activity of the rabbit 20S proteasome (IC50 ) 0.21 µM),
whereas belactosin B which lacks the â-lactone moiety shows
greatly reduced activity (>10 µM). In addition, degradation
studies of belactosin A suggested that the â-lactone moiety
was indeed responsible for the observed antiproliferative
activity.2 A benzyl ester derivative, KF33955, which is
presumably more cell permeable, exhibited increased growth
inhibitory activity than belactosins A and C (IC50 ) 0.46
µM vs 51 and 200 µM, respectively) toward HeLa S3 cells.
A recent X-ray study of N-CBz-O-Bn homobelactosin C
bound to the yeast 20S proteasome showed that the N-
terminal γ-threonine residue in the catalytic pocket of the
proteasome is acylated by the â-lactone moiety and that the
orientation of binding differs from another â-lactone-
containing proteasome inhibitor, omuralide.3
As part of a program to develop concise and diastereo-
selective routes to â-lactones, we developed the tandem
Mukaiyama aldol-lactonization (TMAL) process which al-
lows access to both cis- and trans-â-lactones depending on
the Lewis acid employed (Figure 2).4 We and others5 have
(1) (a) Mizukami, T.; Asai, A.; Yamashita, Y.; Katahira, R.; Hasegawa,
A.; Ochiai, K.; Akinaga, S. U.S. Patent 5 663 298, 1997; Chem. Abstr.
1997, 126, 79. (b) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.;
Mizukami, T. J. Antibiot. 2000, 53, 81. (c) Yamaguchi, H.; Asai, A.;
Mizukami, T.; Yamashita, Y.; Akinaga, S.; Ikeda, S.-i.; Kanda, Y. EP Patent
1 166 781 A1, 2000; Chem. Abstr. 2000, 133, 751.
(2) Asai, A.; Tsujita, T.; Sharma, S. V.; Yamashita, Y.; Akinaga, S.;
Funakoshi, M.; Kobayashi, H.; Mizukami, T.; Asahi-machi, M.-S. Biochem.
Pharmacol. 2004, 67, 227.
(3) Groll, M.; Larionov, O. V.; Huber, R.; De Meijere, A. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 4576.
10.1021/ol070275k CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/23/2007

involving a late-stage lactonization step. We were attracted
to the possibility of direct construction of belactosin and
derivatives via the TMAL process using a chiral silyl ketene
acetal and the required glyoxamide dipeptide (strategy A,
Figure 3). This would enable rapid SAR studies of these
Figure 1. Structures of belactosins A-C and a more potent
derivative, KF33955.
Figure 3. Strategies toward belactosin C employing double
diastereoselective TMAL processes.
used this method to prepare various â-lactones including
natural products such as (-)-panclicin D,4a,c tetrahydrolip-
statin/orlistat,5a,6 (-)-grandinolide,7 and okinonellin B,8 the
latter two targets being accessed via â-lactone intermediates
obtained by the TMAL process.
enzyme inhibitors toward the proteasome and possibly other
cellular proteins. However, although this reaction would
constitute a double diastereoselective process, a high degree
of diastereoselectivity was not assured given the distance
between stereogenic centers. Therefore, an alternative strat-
egy would employ chiral glyoxamides11 bearing cleavable
chiral auxiliaries expected to impart higher diastereoselec-
tivity via double diastereodifferentiation due to the greater
proximity of the resident stereogenic centers (strategy B,
Figure 3). The resulting â-lactone carboxylic acid 3 and
simpler â-lactone acids could then be coupled to the protected
orn-ala dipeptide and other peptides for structure-activity
studies. Herein, we disclose our synthesis of belactosin C
and derivatives employing these two synthetic strategies.
The synthesis of the required chiral silyl ketene acetal 2a
commenced with the known hydrodeamination12 of L-
isoleucine (4) with hydroxylamine-O-sulfonic acid followed
by conversion to the thioester 6a via the acid chloride
(Scheme 1).13 Conversion to the silyl ketene acetal (E/Z, ∼9:
Figure 2. Tandem Mukaiyama aldol-lactonization (TMAL) process
leading to cis- and trans-â-lactones.
To date, three total syntheses of the belactosins and
analogues have been reported9 along with several studies
regarding fragment syntheses.10 In general, these syntheses
require multiple steps to construct the key â-lactone nucleus
(4) (a) Yang, H. W.; Romo, D. J. Org. Chem., 1997, 62, 4. (b) Yang, H.
W.; Zhao, C.; Romo, D. Tetrahedron 1997, 53, 16471. (c) Wang, Y.; Zhao,
C.; Romo, D. Org. Lett. 1999, 1, 1197.
Scheme 1. Synthesis of the Ketene Acetal 2
(5) (a) Dollinger, L. M.; Howell, A. R. J. Org. Chem. 1996, 61, 7248.
(b) Yin, J.; Yang, X. B.; Chen, Z. X.; Zhang, Y. H. Chin. Chem. Lett.
2005, 16, 1448.
(6) Ma, G.; Zancanella, M.; Oyola, Y.; Richardson, R. D.; Smith, J. W.;
Romo, D. Org. Lett. 2006, 8, 4497.
(7) Zemribo, R.; Champ, M. S.; Romo, D. Synlett 1996, 278.
(8) Schmitz, W. D.; Messerschmidt, B.; Romo, D. J. Org. Chem. 1998,
63, 2058.
(9) (a) Armstrong, A.; Scutt, J. N. Chem. Commun. 2004, 5, 510. (b)
Arionov, O. V.; de Meijere, A. Org. Lett. 2004, 6, 2153. (c) Kumaraswamy,
G.; Padmaja, M.; Markondaiah, B.; Jena, N.; Sridhar, B.; Kiran, M. U. J.
Org. Chem. 2006, 71, 337.
(10) (a) Begis, G.; Sheppard, T. D.; Cladingboel, D. E.; Motherwell, W.
B.; Tocher, D. A. Synthesis 2005, 19, 3186. (b) Larionov, O. V.;
Kozhushkov, S. I.; Brandl, M.; de Meijere, A. MendeleeV Commun. 2003,
5, 199. (c) Jain, R. P.; Vederas, J. C. Org. Lett. 2003, 5, 4669. (d) Armstrong,
A.; Scutt, J. Org. Lett. 2003, 5, 2331. (e) Brandl, M.; Kozhushkov, S.;
Loscha, K.; Kokoreva, O.; Yufit, D.; Howard, J.; de Meijere, A. Synlett
2000, 1741.
1) was accomplished using procedures described previously.4
An identical route was employed to prepare the achiral silyl
ketene acetal 2b.
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Org. Lett., Vol. 9, No. 8, 2007

The glyoxamide substrate 1 was prepared in two steps
from the known protected dipeptide, O-Bn-orn-N-Cbz-ala 7
(Scheme 2).9b Acylation with acryloyl chloride provided
Table 1. Double Diastereoselective TMAL Reaction with
Aldehyde 1 and Chiral Ketene Acetal 2a: Synthesis of
Belactosin C
Scheme 2. Synthesis of the Glyoxamide Dipeptide 1 and
TMAL Reaction with Achiral Ketene Acetal 2b
amide 8 which was converted via ozonolysis to a mixture
of the desired glyoxamide 1 and its corresponding hydrate
following purification by flash column chromatography.
Stirring the mixture with 4 Å molecular sieves enabled
dehydration to deliver the desired glyoxamide 1 suitable for
the subsequent TMAL process.
With chiral and achiral ketene acetals 2a/b and glyoxamide
dipeptide 1 in hand, we first set out to study the inherent
diastereoselectivity, if any, imparted by the dipeptide on the
configuration of the â-lactone generated. On the basis of
previous studies of the ZnCl2-mediated TMAL process, we
expected exclusive formation of trans-â-lactone. Indeed,
treatment of aldehyde 1 with ketene acetal 2b under standard
TMAL conditions gave exclusively trans-â-lactones 9a/9b
albeit in low yield. On the basis of 13C NMR, the ratio of
diastereomers 9a/9b was ∼1:1. As expected, the stereogenic
centers of the dipeptide are too distal to have any impact on
the diastereoselectivity.
dipeptides. Although several chiral glyoxylates are known,11
we elected to study a variant of the known tartrate-derived
auxiliaries that would be more readily synthesized and
deprotected by hydrogenolysis, a requirement for the some-
what labile â-lactone moiety that would be generated.14 The
synthesis commenced with known diol 11, available in four
steps from (-)-L-dimethyl tartrate.15 Monomethylation of diol
11 proceeded efficiently, and subsequent acylation with
acryloyl chloride gave acrylate 13. Oxidative cleavage of
the double bond in acrylate 13 provided chiral glyoxylate
14 (Scheme 3).
Scheme 3. Synthesis of Chiral Glyoxamide 14
However, when chiral ketene acetal 2a was employed, this
led to the formation of four diastereomers including cis-â-
lactones with a slight preference for trans-diastereomers
(Table 1). In this case, the stereogenic center of the ketene
acetal clearly does impact the diastereoselectivity but not in
a favorable manner. After careful purification, the cis-(10a/
10b) and trans-(10c/10d) diastereomers could be separated;
however, the two trans-diastereomers were inseparable.
We next studied the TMAL reactions of glyoxylate esters
including those bearing a chiral auxiliary, which could be
readily deprotected and then coupled to a number of
Application of the TMAL process to chiral glyoxylate 14
delivered an equimolar mixture of cis- and trans-â-lactones
(11) For a review describing the use of chiral glyoxals in synthesis, see:
Whitesell, J. Chem. ReV. 1992, 92, 953.
(12) Doldouras, G. A.; Kollonitsch, J. J. Am. Chem. Soc. 1978, 100,
341.
(14) â-Lactone benzyl esters were previously utilized by Yamaguchi and
co-workers in this context. See ref 1c.
(13) For the synthesis of a related phenylthio ketene acetal, see ref 9b.
(15) Prasad, K. R.; Chandrakumar, A. Synthesis 2006, 2159.
Org. Lett., Vol. 9, No. 8, 2007
1539

Scheme 4. TMAL Reaction with Chiral Glyoxamide 13
Scheme 5. Coupling of â-Lactone Acid 16 and Dipeptide 7:
Synthesis of (-)-Belactosin C
in 73% yield; however, greater selectivity for one trans-
diastereomer was obtained (15a/15b ) 1:5, Scheme 4).
Furthermore, the purification was greatly simplified by the
presence of the chiral auxiliary enabling separation of the
trans-diastereomers by simple column chromatography.
To determine if this was the matched or mismatched series
with a desire to improve the diastereoselectivity for the
required trans-diastereomer, the enantiomeric glyoxylate ester
ent-14 was prepared (not shown)16 and utilized in the TMAL
reaction. However, this proved to be the mismatched case
as the diastereoselectivity of 15a/15b decreased to 1.5:1
(Scheme 4).
Cleavage of the chiral auxiliary by hydrogenolysis of ester
15a gave â-lactone acid (-)-3, which could be correlated to
the same compound reported by Kumaraswamy et al. ([R]D
-3.1; lit. ([R]D -3.0).9c Subsequent coupling with protected
dipeptide 7 generated protected belactosin C 10c, and
deprotection by the method of Armstrong9a gave belactosin
C in diastereomerically pure form; spectral data correlated
well with those previously reported (Scheme 5).1a
glyoxylate. This strategy is unique in that the pharmacophoric
â-lactone moiety of these proteasome inhibitors is con-
structed in a single step via the TMAL process leading to
concise approaches to these novel proteasome inhibitors.
Further biological evaluation of these and other belactosin
derivatives including diastereomers and structural derivatives
is underway and will be reported in due course.17
Acknowledgment. We thank the NSF (CHE-0416260)
for support of these investigations. The NSF (CHE-0077917)
also provided funds for purchase of NMR instrumentation.
We thank Prof. John A. Porco (Boston University) for
initially bringing these natural products to our attention.
Supporting Information Available: Selected experi-
1
mental procedures and characterization data (including H
and 13C NMR spectra) for 2a, 6a, 8, 9, 12, 13, 15a, and
15b. This material is available free of charge via the Internet
at http://pubs.acs.org.
In summary, the TMAL process enabled a concise
synthesis of (-)-belactosin C and derivatives employing
double diastereoselective processes with chiral ketene acetals
and a dipeptide glyoxamide or a novel tartrate-derived chiral
OL070275K
(17) Another synthesis of belactosin C appeared while this manuscript
was under review. See: Kumaraswamy, G.; Markondaiah, B. Tetrahedron
Lett. 2007, 48, 1707.
(16) See Supporting Information for details.
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Org. Lett., Vol. 9, No. 8, 2007