Professional Documents
Culture Documents
Thap
Thap
Natural Products
5996 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim DOI: 10.1002/anie.200353140 Angew. Chem. Int. Ed. 2003, 42, 5996 –6000
Angewandte
Chemie
collectively termed “thapsigargins”.[1] The members of this Despite the prevalence of the thapsigargins in the fields of
family of sesquiterpene lactones have a highly oxygenated molecular biology and oncology (a scan of the past 10 years'
tricyclic framework containing seven or eight stereogenic literature reveals almost 5000 hits for the keyword “thapsi-
centers and are functionalized with a range of different acyl gargin”), the synthetic community has been slow to reflect its
groups derived from acetic, butyric, angelic, and octanoic significance. To date, no total or partial synthesis of any
acids. The trilobolide subfamily (2–4) lack the acyloxy member of this family has been reported. Using degrada-
substituent at C2 and it is the first total synthesis of these tion,[1] Christensen and co-workers have carried out a number
of modifications on the periphery of the natural substance to
investigate some of the important structure–activity relation-
ships. However, no modification of the core has been possible
using this strategy. A flexible synthetic route to the thapsi-
gargins would allow the preparation of simplified analogues
and permit the investigation of detailed structure–activity
relationships, which would not be otherwise possible.
Our general approach to the thapsigargins is outlined in
Scheme 1. To allow access to all 16 natural compounds in the
series and a number of potential analogues, our plan leads to
the common intermediate A (PG = tert-butyldiphenylsilyl
(TBDPS)) as the point of late-stage divergent functionaliza-
tion of the cyclopentane ring prior to sequential introduction
of the various ester functionalities required. We envisaged the
installation of the two quarternary centers at C7 and C11 by a
three thapsigargins that we report herein. stereoselective cis-dihydroxylation of butenolide B. Assembly
Interest in the thapsigargins arose after they were of this lactone should be possible from the a-hydroxy ketone
recognized to be potent histamine liberators[2] and selective C, which we planned to generate by an enol ether metathesis/
and irreversible inhibitors of the ubiquitous sarco-endoplas- oxidation sequence from diene D. Cyclopentane E (PG =
mic reticulum Ca2+ ATP dependent pumps (SERCAs) up to tetrahydropyranyl (THP)), has already served as an inter-
subnanomolar concentrations.[3] When applied to intact cells, mediate in a synthesis of two other guaianolides: cladantho-
thapsigargin (1) is able to penetrate the cell where it binds to lide and estafiatin.[9]
and locks the SERCA into a conformation that has a poor The synthesis begins with the stereoselective epoxidation
affinity for Ca2+ and ATP.[4] Trilobolide (2) (KD = 1.0 nm) of commercially available (S)-(+)-carvone with basic hydro-
binds only 2.5 times less tightly to SERCA than 1 (KD = gen peroxide (Scheme 2).[10] Opening of the resulting oxirane
0.4 nm).[5] Thapsigargins demonstrate a remarkable specificity with lithium chloride in the presence of trifluoroacetic acid
for the SERCA isozymes, and have hence become powerful (TFA)[11] led exclusively to chlorohydrin 5, which was
tools to manipulate and study intracellular Ca2+-dependent protected to yield a diastereomeric mixture of the THP
signalling pathways.[6] Thapsigargin (1) has also been shown to ethers 6. Treatment of 6 with sodium methoxide effected a
restore apoptotic function in cancer cell lines.[7] This has regio- and stereoselective Favorskii rearrangement to give
recently led to the development of a potential treatment for methyl ester 7 as the sole product. At this point, the
prostate cancer using a prodrug conjugate of 1 that is cleaved protecting group was exchanged to the more robust TBDPS
and activated by prostate-specific antigen.[8] group (7!8). It should be noted that the Favorskii rearrange-
Scheme 1. The synthesis plan. PG = protecting group, MOM = methoxymethyl, TES = triethylsilyl.
Angew. Chem. Int. Ed. 2003, 42, 5996 –6000 www.angewandte.org 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5997
Communications
mixture could be separated by column chromatography to
give the C10 epimeric alcohols 12 a and 12 b.
Continuing the synthesis, alcohol 12 a was oxidized with
tetra-n-propylammonium perruthenate (TPAP)[13] and N-
morpholine-N-oxide (NMO) (Scheme 4) and the resulting
aldehyde was treated with the lithium anion of ethyl vinyl
5998 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2003, 42, 5996 –6000
Angewandte
Chemie
Angew. Chem. Int. Ed. 2003, 42, 5996 –6000 www.angewandte.org 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5999
Communications
[6] M, Treiman, C. Caspersen, S. B. Christensen, Trends Pharma-
col. Sci. 1998, 19, 131 – 135, and references therein.
[7] Y. Furuya, P. Lundmo, A. D. Short, D. L. Gill, J. T. Isaacs, Cancer
Res. 1994, 54, 6167 – 6175.
[8] S. R. Denmeade, C. M. Jakobsen, S. Janssen, S. R. Khan, E. S.
Garrett, H. Lilja, S. B. Christensen, J. T. Isaacs, J. Natl. Cancer
Inst. 2003, 95, 990 – 1000.
[9] E. Lee, J. W. Lim, C. H. Yoon, Y. Sung, Y. K. Kim, J. Am. Chem.
Soc. 1997, 119, 8391 – 8392.
[10] K. C. Nicolaou, J. Y. Xu, S. Kim, J. Pfefferkorn, T. Ohshima, D.
Vourloumis, S. Hosokawa, J. Am. Chem. Soc. 1998, 120, 8661 – 8673.
[11] J. S. Bajwa, R. C. Anderson, Tetrahedron Lett. 1991, 32, 3021 – 3024.
[12] The configuration of C10 and all subsequently formed stereo-
centers was unambiguously proven by X-ray analysis of 24 and
26 (vide infra).
[13] S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis
1994, 7, 639 – 666.
[14] M. Scholl, S. Ding, C. W. Lee, R. H. Grubbs, Org. Lett. 1999, 1,
953 – 956.
[15] Slow addition of catalyst was required to obtain high yield at low
catalyst loading. For examples of enol ether metathesis reactions
with Grubbs' Ru catalysts see: J. D. Rainier, J. M. Cox, S. P.
Allwein, Tetrahedron Lett. 2001, 42, 179 – 181; A. Okada, T.
Ohshima, M. Shibasaki, Tetrahedron Lett. 2001, 42, 8023 – 8027;
V. K. Aggarwal, A. M. Daly, Chem. Commun. 2002, 21, 2490 – 2491.
[16] Force field calculations suggest that the OTES group blocks the
convex face. Using AD mix a, 16 could be obtained as a single
diastereomer (matched case).
[17] An inconsequential side product resulting from protecting group
migration under the reaction conditions was also observed. As
its deprotection also gave tetraol 21, the separation from 20 was
not necessary.
Scheme 7. Completion of the synthesis of trilobolide, nortrilobolide, [18] E. P. Balskus, University of Cambridge, unpublished results.
and thapsivillosin F. Reagents and conditions: a) 1. NaBH4, MeOH, [19] B. Hartmann, A. M. Kanazawa, J. P. Depres, A. E. Greene,
0 8C, 86 %, d.r. = 4:1, 2. angelic acid, Et3N, 2,4,6-trichlorobenzoyl chlo- Tetrahedron Lett. 1991, 32, 5077 – 5080.
ride, toluene, 80 8C, 76 %; b) TBAF, THF, RT, quant; c) 1. isopropenyl
acetate, PS-TsOH, CH2Cl2, RT, 68 %, 2. HCl (aq), MeOH, 40 8C; d) (S)-
2-methylbutyric anhydride, DMAP, CH2Cl2, RT, 78 % over two steps;
e) butyric anhydride, DMAP, CH2Cl2, RT, 72 % over two steps; f) sene-
cioic anhydride, DMAP, CH2Cl2, RT, 73 % over two steps. TBAF = tetra-
butylammonium fluoride.
.
Keywords: asymmetric synthesis · natural products ·
terpenoids · total synthesis
6000 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org Angew. Chem. Int. Ed. 2003, 42, 5996 –6000