Stereogenic evolution of clasto-lactacystin β-lactone from L-serine

Article abstract of DOI:10.1002/ejoc.200600835

Reported herein is a novel synthesis of clasto-lactacystin β-lactone. The γ-lactam core was selectively prepared by an intramolecular C-H insertion to establish the stereocenter, C(6). The ensuing construction of the quaternary C(5) and carbinol C(9) cent

Full text of DOI:10.1002/ejoc.200600835

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200600835
Stereogenic Evolution of clasto-Lactacystin β-Lactone from -Serine
L
Cheol H. Yoon,[a] David L. Flanigan,[a] Kyung S. Yoo,[a] and Kyung W. Jung*[a]
Keywords: Stereoselctive C–H insertion / Rhodium catalysis / γ-Lactam / Aldol reaction / Lactacystin β-lactone
Reported herein is a novel synthesis of clasto-lactacystin β-
lactone. The γ-lactam core was selectively prepared by an
intramolecular C–H insertion to establish the stereocenter,
C(6). The ensuing construction of the quaternary C(5) and
carbinol C(9) centers was facilitated by aldol with excellent
stereoselection. All these new stereochemistries were in-
duced by the inherent chirality of
chiral auxiliaries or reagents.
L-serine without employing
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Recently, a synthetic proteasome inhibitor was approved In these previous syntheses, the C(5) quaternary center was
to treat multiple myeloma, thus validating this new drug established using aldol or acylation at an early stage, then
mechanism.[1] With such growing interest, substantial ef- the formation of γ-lactam was carried out later presumably
forts have been made toward drug discovery utilizing pro- because the quaternary center was considered to be the
teasome inhibition. Lactacystin (1) and its analog, clasto- most difficult to construct. This strategy required the use
lactacystin β-lactone (2) are known to induce apoptosis of chiral auxiliaries or reagents, and consequently the pro-
(programmed cell death) in human monoblast cells by spe- cedures were relatively cumbersome and costly.
cific inhibition of the 20S proteasome, which overcomes the
Bcl-2 protective function (Figure 1).[2] A structural conge-
ner of lactacystin, salinosporamide A (3), isolated from ma-
rine sediment, is also a highly selective proteasome inhibi-
tor.[3]
In order to overcome these shortcomings, we embarked
on an efficient synthesis by starting with an inexpensive chi-
ral commodity, -serine. Another noteworthy salient feature
was to change the order of key structural and functional
manipulations compared to the other known syntheses,
where we diastereoselectively introduced the C(5) quater-
nary center at a relatively late stage. Herein we report a
novel synthesis of 2 employing a stereoseletive aldol proto-
col, resulting in the simultaneous installation of the C(5)
and C(9) centers (Scheme 1). The γ-lactam core can be ef-
ficiently derived from -serine by stereoselective C–H inser-
tion into the diazoamide 7.[5]
Reduction of O-tert-butyl serine methyl ester (9), pre-
pared from -serine (8) in two steps by known procedures,[6]
afforded amino alcohol 10 in a high yield (Scheme 2). The
amino alcohol was subjected to N,O-acetonide formation,
followed by bromoacetylation to yield 11. Displacement of
the bromide 11 with the phenylsulfonyl group, and subse-
quent diazo transfer using pABSA produced the diazo com-
pound 12. This entire series of reactions can be performed
on large scales and requires no significant purification ef-
forts. Intramolecular C–H insertion of diazo compound 12
yielded the desired trans-γ-lactam 13 in 85% yield with ex-
Figure 1. Representative examples of natural 20S-Proteasome in-
hibitors.
A number of synthetic routes have been explored to sup- clusive regio- and stereoselectivities. The configuration of
ply lactacystin and its β-lactone analog for clinical trials.[4] the two newly generated stereocenters at C(6) and C(7) of
the γ-lactam 13 was unambiguously elucidated and dis-
cussed in our previous report.[5b]
[a] Loker Hydrocarbon Research Institute and Department of
Chemistry, University of Southern California,
Desulfonylation of the γ-lactam 13 was realized with
Na(Hg) in a high yield (Scheme 3). After the acetonide
group was cleaved under acidic conditions with Dowex
resin, the resulting hydroxy group was subsequently oxid-
Los Angeles, California 90089-1661, USA
Fax: +1-213-821-4096
E-mail: kwjung@usc.edu
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2007, 37–39
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
37

C. H. Yoon, D. L. Flanigan, K. S. Yoo, K. W. Jung
SHORT COMMUNICATION
Scheme 1. Retrosynthetic analysis of 2.
Scheme 2. Synthesis of γ-lactam 13 by C–H insertion.
Scheme 3. Stereoselective aldol reaction.
ized to give the corresponding carboxylic acid, which was
then subjected to esterification to afford the methyl ester in the equatorial position, accounting for the observed ex-
16. Exposure of 16 to Me3O·BF4 in dichloromethane pro- cellent stereoselectivity at the C(9) (Figure 2).[8] Addition-
duced the imino ether 17, where O-methylation was ob- ally, the β-face of 17 would be blocked by the bulky O-tert-
served exclusively without any concomitant N-methylation. butyl substituent, thus we expected the aldol reaction of 17
The resultant imino ether compound turned out to be a to yield the desired product 18 selectively through 17a. The
suitable aldol precursor rather than the corresponding structure of 18 was confirmed as the desired product by the
amide because steric congestion was diminished at the C(5) synthesis of the known final compound 2 derived from 18
center and the acidity of the C(5) proton was enhanced.[7] (vide infra).
Enolization of 17 with LDA followed by the addition of
isobutyraldehyde at –78 °C afforded the aldol product 18 as diate 21 for the selective methylation in 6 steps (Scheme 4).
a single isomer. The secondary hydroxy moiety in 18 was protected with an
The aldol product 18 was converted into the key interme-
The aldol was anticipated to take place via closed chair- acetyl group. Treatment of the resultant acetate with Dowex
like transition states, where the isopropyl group would lie resin followed by BF3·OEt2 afforded the hydroxy amide
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Eur. J. Org. Chem. 2007, 37–39

Stereogenic Evolution of clasto-Lactacystin β-Lactone from -Serine
SHORT COMMUNICATION
selective aldol reaction to form the highly congested quater-
nary center. An outstanding aspect of the synthesis is that
the formation of all four stereocenters was controlled by
the inherent chirality of -serine without employing chiral
auxiliaries or chiral inducing reagents throughout. In fact,
three stereochemistry generating steps (12 to 13, 17 to 18,
and 21 to 22) are perfectly selective to culminate in one
desired isomer. Therefore, we believe that this synthesis is
expeditious and convenient to offer an inexpensive and
pragmatic approach towards a large scale preparation of
clasto-lactacystin β-lactone (2).
Figure 2. Proposed transition states for the aldol reaction of 17.
compound 19. Selective protection of the amide was con-
ducted in a three consecutive step conversion; O-THP pro-
tection, N-Boc protection and hydrolysis of THP group.
The lactam 21 underwent methylation stereoselectively to
furnish the compound 22 as a single isomer in 88% yield.[4c]
Supporting Information (see also the footnote on the first page of
this article): Full experimental details and spectroscopic infor-
mation (1H and 13C NMR) are provided for all compounds.
Acknowledgments
We acknowledge generous financial support from the National In-
stitute of General Medical Sciences of the National Institutes of
Health (RO1 GM 62767).
[1] a) J. Adams, Drug Discovery Today 2003, 8, 307–315; b) J. Ad-
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P. R. Jensen, W. Fenical, Angew. Chem. Int. Ed. 2003, 42, 355–
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[4] Reviews on lactacystin total syntheses, see: a) T. Nagamitsu, T.
Sunazuka, H. Tanaka, S. Omura, P. A. Sprengeler, A. B. Smith,
J. Am. Chem. Soc. 1996, 118, 3584–3590; b) E. J. Corey, W.-
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2513–2528. For recent total syntheses, see; d) T. J. Donohoe,
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2004, 43, 2293–2296; e) H. Ooi, N. Ishibashi, Y. Iwabuchi, J.
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Scheme 4. Stereoselective C(7) methylation.
The total synthesis of clasto-lactacystin β-lactone (2) was
completed from 22 by following the reported procedures
(Scheme 5).[4a] Thus, deprotection of the N-Boc group with
TFA, simultaneous hydrolysis of methyl ester and acetate
under basic conditions, and lactone formation with BOPCl
afforded clasto-lactacystin β-lactone (2) successfully.
[5] a) C. H. Yoon, M. J. Zaworotko, B. Mouton, K. W. Jung, Org.
Lett. 2001, 3, 3539–3542; b) C. H. Yoon, D. L. Flanigan, B.-D.
Chong, K. W. Jung, J. Org. Chem. 2002, 67, 6582–6584; c)
D. L. Flanigan, C. H. Yoon, K. W. Jung, Tetrahedron Lett.
2005, 46, 143–146.
[6] J. G. Adamson, M. A. Blaskovich, H. Groenevelt, G. A. Lajoie,
J. Org. Chem. 1991, 56, 3447–3449.
[7] Aldol reactions of lactam 16, and their analogs (N-protected
with tBoc, Cbz, benzyl, etc.) afforded β-elimination products
predominantly. These results and additional aldols with other
sustrates will be reported in a separate full account.
[8] C. H. Heathcock, C. T. Buse, W. A. Kleschick, M. C. Pirrung,
J. E. Sohn, J. Lampe, J. Org. Chem. 1980, 45, 1066–1081.
Received: September 25, 2006
Scheme 5. Synthesis of clasto-lactacystin β-lactine (2).
In summary, this novel synthesis of clasto-lactacystin β-
lactone (2) involves two key steps, γ-lactam formation by
RhII-catalyzed intramolecular C–H activation and stereo-
Published Online: November 13, 2006
Eur. J. Org. Chem. 2007, 37–39
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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