Total synthesis of salinosporamide A

Article abstract of DOI:10.1021/ol8016066

(Chemical Equation Presented) The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction as key reactions.

Full text of DOI:10.1021/ol8016066

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4239-4242
Total Synthesis of Salinosporamide A
Takeo Fukuda,† Kouhei Sugiyama,† Shiho Arima,† Yoshihiro Harigaya,†
,†
Tohru Nagamitsu,* and Satoshi Omura*
,‡
¯
School of Pharmacy, Kitasato UniVersity, Kitasato Institute for Life Sciences, Kitasato
UniVersity, and The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641,
Japan
nagamitsut@pharm.kitasato-u.ac.jp; omura-s@kitasato.or.jp
Received July 16, 2008
ABSTRACT
The total synthesis of salinosporamide A has been achieved through enzymatic desymmetrization, diastereoselective aldol reaction, intramolecular
aldol reaction, and intermolecular Reformatsky-type reaction followed by 1,4-reduction as key reactions.
Salinosporamide A (1),1 a potent 20S proteasome inhibitor,
was discovered from marine actinomycete Salinospora
tropicana by Fenical and co-workers in 2003 (Figure 1). The
factor-like activity.3 The proteasome inhibitory activity of 1
is approximately 35 times greater than 2, thus suggesting it
as a strong candidate for development of new anticancer
drugs, and related compounds are currently under investiga-
tion in clinical trials for the treatment of cancer.1,4 The unique
biological profile of salinosporamide A (1) in combination
with its structural complexity has led to intensive research
efforts by synthetic chemists. To date, several total syntheses
of 1 have been reported,5 most of which employ Corey’s
approach5a in the later stage of the total synthesis where there
is stereoselective installation of the cyclohexene ring of 1.
We report herein the total synthesis of salinosporamide A
(1) via the stereoselective construction of a cyclohexene ring
by a new approach as a key reaction in an early stage of the
total synthesis.
Figure 1. Structures of salinosporamide A (1), lactacystin (2), and
omuralide (3).
ˆ
(3) (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
ꢀ-lactone-γ-lactam bicycle structure is very similar to
omuralide (2),2 which is a well-known potent 20S proteasome
inhibitor derived from lactacystin (3) first discovered by us
in 1991 as a result of microbial screening for nerve growth
ˆ
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.
(4) (a) Chauhan, D.; Catley, L.; Li, G.; Podar, K.; Hideshima, T.;
Velankar, M.; Mitsiades, C.; Mitsiades, N.; Yasui, H.; Letai, A.; Ovaa, H.;
Berkers, C.; Nicholson, B.; Chao, T.-H.; Neuteboom, S. T. C.; Richardson,
P.; Palladino, M. A.; Anderson, K. C. Cancer Cell 2005, 8, 407–419. (b)
Macherla, V. R.; Mitchell, S. S.; Manam, R. R.; Reed, K. A.; Chao, T.-H.;
Nicholson, B.; Deyanat-Yazdi, G.; Mai, B.; Jensen, P. R.; Fenical, W.;
Neuteboom, S. T. C.; Lam, K. S.; Palladino, M. A.; Potts, B. C. M. J. Med.
† School of Pharmacy.
‡ Kitasato Institute for Life Sciences.
(1) 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.
(2) Corey, E. J.; Li, W.-D. Z. Chem. Pharm. Bull. 1999, 47, 1–10.
Chem. 200548, 3684–3687
.
10.1021/ol8016066 CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

The retrosynthetic analysis of 1 is shown in Scheme 1.
Stereoselective construction of the C2-side chain would be
achieved by intermolecular Reformatsky-type reaction of
Scheme 2
Scheme 1
R-chloro-γ-lactam 5 with benzyloxyacetaldehyde followed
by dehydration and 1,4-reduction. Synthesis of the γ-lactam
5, which exhibits C3-stereochemistry, could be accomplished
by intramolecular chelation-controlled aldol reaction of
N-acyloxazolidinone 6, which itself would be delivered from
ketone 7 via conversion of cyclohexanone into cyclohexene
and subsequent transcarbamation. Diastereoselective aldol
reaction of 8 with cyclohexanone was expected to afford
ketone 7 with the construction of C5 and C6 stereogenic
centers. The stereochemistry at C4 in intermediate 8 was to
be controlled by enzymatic desymmetrization of the diol.
The total synthesis was commenced with Wittig olefination
of the readily accessible aldehyde 10,6 which was converted
to diol 11 by hydrolysis as shown in Scheme 2. Desymme-
trization of the diol 11 with Lipase from Pseudomonas sp.
in i-Pr2O-vinyl acetate furnished the optically active acetate,
and the remaining primary hydroxyl group was then im-
mediately protected as a TBDPS ether to provide 9 (97%
ee).7 Removal of the acetyl group of 9 and protection of the
alcohol afforded the MEM ether 12. Deprotection of the
TBDPS group of 12 followed by intramolecular cyclic
carbamation with NaH and N-PMB protection afforded 13.
The carbamate 13 was subjected to osmium-catalyzed
dihydroxylation followed by oxidative cleavage of the
corresponding diol with NaIO4 to give aldehyde 8.
With the requisite aldehyde 8 in hand, aldol reaction of 8
with cyclohexanone was attempted in order to install both
of the desired C5 and C6 stereogenic centers. The chelation-
controlled aldol reaction smoothly proceeded, after quenching
with BzCl, and the corresponding benzoate 148 was furnished
in 79% isolated yield (dr ) 20:19). Attachment of the
cyclohexene ring with 2-cyclohexenylzinc chloride (Corey’s
(5) Total synthesis: (a) Reddy, L. R.; Saravanan, P.; Corey, E. 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) Endo, A.;
Danishefsky, S. J. J. Am. Chem. Soc. 2005, 127, 8298. (d) Ling, T.;
Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts, B. C. M. Org.
Lett. 2007, 9, 2289–2292. (e) Takahashi, K.; Midori, M.; Kawano, K.;
Ishihara, J.; Hatakeyama, S. Angew. Chem., Int. Ed. 2008, 47, 6244–6246.
Racemic synthesis: (f) Mulholland, N. P.; Pattenden, G.; Walters, I. A. S.
Org. Biomol. Chem 2006, 4, 2845–2846. (g) Ma, G.; Nguyen, H.; Romo,
D. Org. Lett. 2007, 9, 2143–2146. Formal synthesis: (h) Caubert, V.; Masse,
J.; Retailleau, P.; Langlois, N. Tetrahedron Lett. 2007, 48, 381–384. (i)
Margalef, I. V.; Rupnicki, L.; Lam, H. W. Tetrahedron 2008, 64, 7896–
7901. For a recent review, see: (j) Shibasaki, M.; Kanai, M.; Fukuda, N.
Chem. Asian J. 2007, 2, 20–38.
(7) For determination of the ee and absolute configuration, see the
Supporting Information.
(8) Stereochemistries of C5 and C6 were confirmed by NOE experiment
of an acetonide compound derived from diol 15; also see the Supporting
Information.
(9) The aldol reaction would proceed via a chelation-controlled six-
membered transition state as shown in Scheme 2. The re face of the formyl
group is considered to be sufficiently screened by the PMB group to favor
highly selective formation of the desired aldol product; see: Corey, E. J.;
Li, W.; Nagamitsu, T. Angew. Chem., Int. Ed. 1998, 37, 1676–1679.
(6) Ooi, H.; Ishibashi, N.; Iwabuchi, Y.; Ishihara, J.; Hatakeyama, S. J.
Org. Chem. 2004, 69, 7765–7768.
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Org. Lett., Vol. 10, No. 19, 2008

procedure) or other 2-cyclohexenylmetal reagents produced
1,2-addition of methylmagnesium bromide, followed by
Dess-Martin oxidation and N-PMB deprotection gave
ketone 19.
Construction of the γ-lactam and C3 stereogenic center
was established by N-acylation of 19 followed by intramo-
lecular aldol reaction using LHMDS (2.4 equiv) and chlo-
roacetyl chloride in one pot, in which the desired γ-lactam
5 was obtained as a single isomer.12
7 but with low stereoselectivity.10
We next turned to elaboration of the cyclohexene from
cyclohexenone (Scheme 3). However, the conversion of
Scheme 3
Next, we directed our efforts toward the installation of
the C2 side chain using 5 or the dechlorinated γ-lactam,
derived from 5 by reduction (Scheme 4).13 After extensive
Scheme 4
cyclohexanone to cyclohexene proved quite challenging.
Shapiro reaction, reduction of the enol triflate using pal-
ladium chemistry, and reduction-dehydration procedures
were all ultimately unsuccessful. After further investigation,
the problem was solved by elimination of the cyclic sulfate
derived from the diol.11 The benzoate 14 was subjected to
Luche reduction followed by solvolysis to afford the anti-
1,3-diol 15 stereoselectively. Reaction of 15 with thionyl
chloride gave the corresponding cyclic sulfite, which was
oxidized with NaIO4 and a catalytic amount of RuCl3 to
produce the cyclic sulfate 16. Exposure of 16 to DBU at
100 °C followed by treatment of the resulting O-sulfonic
acid with TsOH·H2O gave the desired cyclohexene 17 in high
overall yield from the benzoate 14 (82% in six steps).
Treatment of 17 with NaH triggered intramolecular tran-
scarbamation, and the corresponding primary alcohol was
converted to aldehyde 18 by Swern oxidation. Subsequent
investigation, only the aldehyde proved to be effective in
intermolecular coupling. SmI2-mediated intermolecular Re-
formatsky-type reaction of 5 with benzyloxy acetaldehyde
afforded 20. In this stage, attempts at deoxygenation reactions
(10) Cyclohexene ring construction of 8 with 2-cyclohexenylzinc
chloride (Corey’s procedure) gave the maximum yield and stereoselectivity
(17; 40% yield, 17: other stereoisomers ) 1:1.1).
(11) Winkler, J. D.; Rouse, M. B.; Greaney, M. F.; Harrison, S. J.; Jeon,
Y. T. J. Am. Chem. Soc. 2002, 124, 9726–9728.
Org. Lett., Vol. 10, No. 19, 2008
4241

were unsuccessful. Therefore, the ꢀ-hydroxy-γ-lactam 20
was converted to the R,ꢀ-unsaturated lactam 21 by mesy-
lation-elimination followed by alkaline hydrolysis. Subse-
quent screening of reductants for the stereoselective 1,4-
reduction of 21 led to the use of LiEt3BH to afford 4 (dr )
4.2:1). Deprotection of the MEM ether, TES protection of
the primary and secondary alcohols, and selective deprotec-
tion of the primary TES ether with HF·pyridine afforded 22.
A tandem approach involving oxidation of the primary
alcohol, Birch reduction to deprotect the benzyl group,
chelation-controlled aldol reaction as a key reaction in an
early stage of the total synthesis. This strategy differs from
those of other previously reported total syntheses. Other key
features of our total synthesis include enzymatic desymme-
trization, intramolecular aldol reaction, and intermolecular
Reformatsky-type reaction followed by 1,4-reduction. Further
improvements to the total synthesis and development of
salinosporamide A analogues are currently in progress in our
laboratory.
5a
ꢀ-lactonization with BOPCl, and chlorination with Ph3PCl2
Acknowledgment. We thank Ms. N. Sato (Kitasato
University) for kindly measuring NMR spectra. T.N. ac-
knowledges a Kitasato University research grant for young
researchers.
gave the desired ꢀ-lactone 23. Finally, deprotection of the
TES ether afforded salinosporamide A (1). Synthetic sali-
nosporamide A (1) was identical to reported spectra in all
1
1
respects (mp, [R]D, H and 13C NMR, IR, FAB-MS).
In summary, we have achieved the total synthesis of
salinosporamide A (1). The best feature of our synthetic route
is the stereoselective construction of the cyclohexene ring
with control of the C5 and C6 stereogenic centers through a
Note Added after ASAP Publication. In Scheme 4, the
structure of compound 23 was corrected on September 10,
2008.
Supporting Information Available: Characterization data
and experimental procedures. This material is available free
of charge via the Internet at http://pubs.acs.org.
(12) C3 stereochemistry was confirmed by NOE experiment of 5; also
see the Supporting Information.
(13) See the Supporting Information.
OL8016066
4242
Org. Lett., Vol. 10, No. 19, 2008