A concise total synthesis of salinosporamide A

Article abstract of DOI:10.1039/b607109k

A concise and straightforward 14-step total synthesis of (±)-salinosporamide A, based on a diastereoselective acid-catalysed intramolecular cyclisation of 6 to the pyrrolidinone 7, and a regioselective reduction of the malonate derivative 8b to the aldehy

Full text of DOI:10.1039/b607109k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A concise total synthesis of salinosporamide A
Nicholas P. Mulholland,a Gerald Pattenden*a and Iain A. S. Waltersb
Received 19th May 2006, Accepted 12th June 2006
First published as an Advance Article on the web 29th June 2006
DOI: 10.1039/b607109k
A concise and straightforward 14-step total synthesis of
( )-salinosporamide A, based on a diastereoselective acid-
catalysed intramolecular cyclisation of 6 to the pyrrolidinone
7, and a regioselective reduction of the malonate derivative 8b
to the aldehyde 9, is described.
on: i) a stereocontrolled acid catalysed intramolecular cyclisation
of the substituted amide 6 leading to the pyrrolidinone 7, ii) a
regioselective reduction of the malonate derivative 8b producing
the key aldehyde intermediate 9, and iii) installation of the
cyclohexenyl side chain, from 9. Although no biosynthesis studies
have been published, our synthetic approach has features in
common with the most likely origin of the pyrrolidinone ring in
salinosporamide A in vivo, i.e. an intramolecular aldolisation from
a substituted b-keto amide intermediate derived from a b-keto acid
and an a-amino acid.10,11
Salinosporamide A (1) is a potent proteasome 20S inhibitor
recently isolated from a marine bacterium of the new genus
Salinospora, by Fenical et al.1 The metabolite is unique, but is
related to the b-lactone pyrrolidinone-based terrestrial natural
product omuralide (also know as clasto-lactacystin b-lactone) 2,2
which is formed by lactonisation of the more familiar proteasome
20S inhibitor lactacystin 3.3 Salinosporamide A is reported to
be approximately thirty five times more effective at proteosome
inhibition than omuralide. The special proteasome inhibitory
properties of the natural pyrrolidinones 1, 2 and 3 have heightened
interest in their potential in therapy for various types of cancer,
also Alzheimer’s disease, arthritis and asthma. It is not surprising
therefore that these compounds have been attractive targets for
total synthesis.4
Thus, protection of the a-substituted b-keto ester 412 as its
dioxolan 5a, followed by hydrolysis to the corresponding car-
boxylic acid 5b and treatment with dimethyl 2-aminomalonate
first gave the substituted amide 6. W◦hen a solution of 6 in 4 : 1
acetic acid–water13 was heated at 65 C for 4 days, it underwent
deprotection of the dioxolan and in situ intramolecular cyclisation
leading to a single diastereomer of the ( )-pyrrol◦idinone 7,
which was obtained as colourless crystals, mp 82–83 C. X-Ray
crystallographic analysis showed that the pyrrolidinone had the
expected anti arrangement between the C3–C4 alkyl chains shown
in structure 7.14 Treatment of the tertiary alcohol 7 with excess
TMSOTf in CH2Cl2 containing 2,6-lutidine at −78 ◦C to 0 ◦C,
followed by 1 M HCl, gave the corresponding TMS ether 8a
in 91% yield.15 The nitrogen centre in the pyrrolidinone 8a was
next protected as its PMB derivative 8b which, to our satisfaction,
underwent regioselective reduction using Super-hydride in CH2Cl2
at −78 ◦C producing the aldehyde 9 in 78% yield.16
The stage was now set to carry out the difficult operation of
attaching the 2-cyclohexenyl side-chain to the aldehyde group
in 9, at the same time installing the correct stereochemistry for
the newly introduced stereogenic centres. Fortunately, an elegant
solution to this problem had already been worked out by Corey
et al.,5 and this protocol was also followed by Danishefsky et al.,
in their synthesis of salinosporamide A. Thus, the aldehyde 9,
◦
was treated with 2-cyclohexenylzinc bromide in THF at −78 C,
The first total synthesis of salinosporamide A (1) was described
by Corey et al.,5 using a route starting from S-threonine. A year
later Corey et al.6 published a modified route to salinosporamide
A from S-threonine and, simultaneously, Danishefsky et al.7
presented an alternative synthesis of the natural product starting
from a known chiral pool pyroglutamate derivative.8 In earlier
investigations we described a synthetic route to (+)-lactacystin 3,
which was based on a novel radical cyclisation of an a-ethynyl
substituted serine as the key step.9 We now present a concise and
straightforward 14-step total synthesis of ( )-salinosporamide
A, which is outlined in Scheme 1. Our synthesis of 1 hinges
according to the protocol of Corey et al., and we were delighted to
find that the addition was essentially diastereoselective producing
the adduct 10 in 87% yield.17 Sequential deprotection of the TMS
and benzyl ether groups in 10, followed by the PMB group,
then gave the triol ester 11, which is the same intermediate in
the synthesis of salinosporamide A presented by Corey et al.,5
Hydrolysis of the methyl ester in 11, followed by treatment of
the resulting b-hydroxy acid, in situ, with BOP–Cl to give the
corresponding b-lactone, and then chlorination with Ph3PCl2
finally gave ( )-salinosporamide A (1), as a colourless solid, mp
169–172 ◦C. The synthetic salinosporamide A showed 1H and 13
C
NMR spectroscopic data and mass spectrometric data which were
identical to those presented for the natural product.
We have therefore developed a conceptually straightforward
synthetic route to ( )-salinosporamide A (1), which uses 14 steps
aSchool of Chemistry, University of Nottingham, Nottingham, NG7 2RD,
England, UK. E-mail: GP@nottingham.ac.uk; Tel: +44 (0)115 951 3530
bAstraZeneca R & D Charnwood, Medicinal Chemistry, Bakewell Road,
Loughborough, LE11 5RH, England, UK
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Scheme 1 Reagents and conditions: (i) ethylene glycol, p-TSA, PhH, 110 ◦C, 14 h; (ii) 2 M NaOH, EtOH, 70 ◦C, 3 h; (iii) dimethyl aminomalonate.HCl,
HOBt, EDC.HCl, CH2Cl2, NMM, 0 ◦C to RT (82% over 3 steps); (iv) 4 : 1 AcOH–H2O, 65 ◦C, 4 days (71%); (v) excess TMSOTf, 2,6-lutidine, CH2Cl2,
−78 ◦C to 0 ◦C, then 1 M HCl (91%); (vi) PMB–Br, NaH, DMF, 0 ◦C to RT, 14 h (82%); (vii) Super-hydride (1.0 M in THF), CH2Cl2, −78 ◦C, 3 h (78%);
(viii) 2-cyclohexenylzinc bromide, THF, −78 ◦C (87%); (ix) BCl3.DMS, CH2Cl2, 24 h, 0 ◦C to RT; (x) 48% HF in H2O–MeCN (1 : 9), RT, 22 h; (xi) CAN,
MeCN, H2O (3 : 1), 0 ◦C, 1 h (87% over 3 steps); (xii) [MeTeAlMe2]2, PhMe, RT, 24 h; (xiii) BOP–Cl, CH2Cl2, pyridine, RT, 3 h; (xiv) PPh3Cl2, MeCN,
pyridine, RT, 4 h (45% over 3 steps).
from the substituted b-ketoester 4. The key features of the synthetic
route are the diastereoselective acid-catalysed cyclisation of 6 to
7, and the facile regioselective reduction of the malonate 8b to
the aldehyde 9, using Super-hydride at −78 ◦C. There are a range
of options available to develop the route into an enantioselective
synthesis of (+)-salinosporamide A, and some of those options
are now being pursued.
A. Kawai, Y. Kohno, O. Hara and T. Shioiri, J. Am. Chem. Soc., 1989,
111, 1524–1525; (c) Y. Hamada, O. Hara, A. Kawai, Y. Kohno and T.
Shioiri, Tetrahedron, 1991, 47, 8635–8652.
9 C. J. Brennan, G. Pattenden and G. Rescourio, Tetrahedron Lett., 2003,
44, 8757–8760.
10 For some studies on the biosynthesis of lactacystin 3, see: A. Nakagawa,
¯
S. Takahashi, K. Uchida, K. Matsuzaki, S. Omura, A. Nakamura,
N. Kurihara, T. Nakamatsu, Y. Miyake, K. Take and M. Kainosho,
Tetrahedron Lett., 1994, 35, 5009–5012.
We thank AstraZeneca for financial support (studentship to
N. P. M.). We also thank Dr A. J. Blake of this School for the
crystal structure determination of 7.
11 Some studies of the biosynthesis of salinosporamide A have been
made by L. L. Beer and B. S. Moore; unpublished work, personal
correspondence with B. S. Moore, Scripps Institution of Oceanography,
UCSD, CA.
12 cf.M. Lee and D. H. Kim, Bioorg. Med. Chem., 2002, 10, 913–922.
13 For a related acid catalysed reaction of diketene with substituted
aminomalonates see; G. Simig, G. Doleschall, G. Hornya´k, J. Fetter,
K. Lempert, J. Nyitrai, P. Huszthy, T. Gizur and M. Kajta´r-Peredy,
Tetrahedron, 1985, 41, 479–484.
Notes and references
1 R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A. Kauffman, P. R.
Jensen and W. Fenical, Angew. Chem., Int. Ed., 2003, 42, 355–357.
2 Reviewed in: (a) E. J. Corey and W.-D. Z. Li, Chem. Pharm. Bull., 1999,
47, 1–10; (b) E. J. Corey, G. A. Reichard and R. Kania, Tetrahedron
Lett., 1993, 34, 6977–6980; (c) E. J. Corey and G. A. Reichard, J. Am.
Chem. Soc., 1992, 114, 10677–10678; (d) G. Fenteany, R. F. Standaert,
G. A. Reichard, E. J. Corey and S. L. Schreiber, Proc. Natl. Acad. Sci.
U. S. A., 1994, 91, 3358–3362.
14 Crystal data for 7: C18H23NO7, M = 365.37, monoclinic, a = 14.292(6),
◦
3
˚
˚
b = 11.057(4), c = 11.287(5) A, b = 92.090(7) , U = 1782.5(13) A ,
T = 150(2) K, space group P21/c, Z = 4, l(Mo–Ka) = 0.105 mm−1
,
15038 reflections measured, 4068 unique (Rint = 0.124). Final R1 [3308
F ≥ 4r(F)] = 0.0421, wR2 (all data) = 0.123. CCDC reference number
608046. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b607109k.
15 A small amount (<10%) of the corresponding O-TMS epimer was
produced concurrently, resulting from a retro-aldolisation process. The
epimer was cleanly removed by chromatography.
3 (a) S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi,
H. Tanaka and Y. Sasaki, J. Antibiot., 1991, 44, 113–116; (b) S. Omura,
K. Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya, S. Fujita and A.
Nakagawa, J. Antibiot., 1991, 44, 117–118.
16 The regioselective reduction of 8b, leading to 9, can be rationalised
on steric grounds, with the bulky O-TMS group inhibiting hydride
delivery to the adjacent syn-orientated CO2Me group. It is also possible
that the same O-TMS group exercises an inductive effect and activates
the corresponding anti-orientated CO2Me in 8b to reduction, as a
consequence of their antiplanar relationship.
4 For a review see:J. S. Panek, C. E. Masse, A. J. Morgan and J. Adams,
Eur. J. Org. Chem., 2000, 2513–2528, and references therein; see also
(a) T. J. Donohoe, H. O. Sintim, L. Sisangia, K. W. Ace, P. M. Guyo, A.
Cowley and J. D. Harling, Chem.–Eur. J., 2005, 11, 4227–4238; (b) T. J.
Donohoe, H. O. Sintim, L. Sisangia and J. D. Harling, Angew. Chem.,
Int. Ed., 2004, 43, 2293–2269; (c) H. Ooi, N. Ishibashi, Y. Iwabuchi,
J. Ishihara and S. Hatekeyama, J. Org. Chem., 2004, 69, 7765–7768;
(d) J. J. Wardrop and E. G. Bowen, Chem. Commun., 2005, 5106–5108;
(e) C. J. Hayes, A. E. Sherlock and M. D. Selby, Org. Biomol. Chem.,
2006, 4, 193–195; (f) N. Fukuda, K. Sasaki, T. V. R. S. Sastry, M. Kanai
and M. Shibasaki, J. Org. Chem., 2006, 71, 1220–1225.
5 L. R. Reddy, P. Saravanan and E. J. Corey, J. Am. Chem. Soc., 2004,
126, 6230–6231.
6 (a) L. R. Reddy, J.-F. Fournier, B. V. S. Reddy and E. J. Corey, Org.
Lett., 2005, 7, 2699–2701; (b) L. R. Reddy, J.-F. Fournier, B. V. S. Reddy
and E. J. Corey, J. Am. Chem. Soc., 2005, 127, 8974–8976.
7 A. Endo and S. J. Danishefsky, J. Am. Chem. Soc., 2005, 127, 8298–
8299.
17 Data for compound 10: colourless solid, mp 157–160 ◦C; mmax
(CHCl3)/cm−1 3564, 2953, 1755, 1721, 1688, 1514; dH (360 MHz,
CDCl3) 7.34–7.26 (5H, m, C6H5), 7.23 (2H, d, J 8.7, ArH), 6.80 (2H,
=
d, J 8.7, ArH), 6.05 (1H, app. d, J 10.2, CH2CH ), 5.63 (1H, app. d,
=
J 10.2, CH2CH CH), 4.80 (1H, d, J 15.3, OCHHPMB), 4.52 (2H, s,
OCH2Ph), 4.42 (1H, d, J 15.3 OCHHPMB), 4.20 (1H, dd, J 3.3, 7.9,
CH(OH)), 3.89 − 3.80 (2H, m, CH2OBn), 3.79 (3H, s, CO2Me), 3.62
=
(3H, s, ArOMe), 3.03 (1H, dd, J 3.8, 9.4, C( O)CH), 2.26 (1H, br s,
=
CH2CH CHCH), 2.04 (2H, br s, CH2), 1.91–1.89 (2H, m, CH2), 1.76
(3H, s, CCH3), 1.59–1.51 (2H, m, CH2), 0.16 (9H, s, TMS); dC (90 MHz,
CDCl3) 177.7 (s), 169.5 (s), 157.8 (s), 138.7 (s), 134.7 (d), 130.6 (s), 128.2
(d), 127.7 (d), 127.3 (d), 127.1 (d), 123.8 (d), 113.2 (d), 86.2 (s), 82.4
(s), 76.8 (d), 72.9 (t), 68.8 (t), 55.2 (q), 51.7 (q), 48.3 (d), 47.7 (t), 38.2
(d), 29.4 (t), 26.1 (t), 25.0 (t), 20.8 (q), 20.5 (t), 2.7 (q); m/z (ES) Found
632.3041 (M + H+, C34H47NO7SiNa requires 632.3014).
8 cf. (a) J. K. Thottathil, J. L. Moniot, R. H. Mueller, M. K. T. Wong
and T. P. Kissick, J. Org. Chem., 1986, 51, 3140–3143; (b) Y. Hamada,
2846 | Org. Biomol. Chem., 2006, 4, 2845–2846
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The Royal Society of Chemistry 2006
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