Synthesis of (+)-CP-263,114

Full text of DOI:10.1021/ja001958x

7424
J. Am. Chem. Soc. 2000, 122, 7424-7425
The synthesis commenced (Scheme 2) with Pd(0)-catalyzed
Synthesis of (+)-CP-263,114
cross-coupling between 3 and vinyl stannane 4,6 affording diene
5 in 80% yield. Compound 5 was converted to rac-6 by a two-
step procedure involving Cu(I)-mediated conjugate addition of a
PMB-protected hydroxymethyl group followed by C-acylation of
a subsequently generated lithium enolate using Mander’s reagent
(NCCO2Me).7 Exposure of rac-6 to Corey’s oxazaborolidine
reduction catalyst8 and catecholborane initiated an efficient kinetic
resolution that directly generated (+)-6 from rac-6 in 90% ee
and 31% yield (theoretical yield is 50%).9
Chuo Chen, Mark E. Layton, Scott M. Sheehan, and
Matthew D. Shair*
Department of Chemistry and Chemical Biology
HarVard UniVersity, Cambridge, Massachusetts 02138
ReceiVed June 2, 2000
The crucial fragment coupling/tandem cyclization was con-
ducted by conversion of enantiomerically pure 710 to Grignard
reagent 8 followed by exposure to (+)-6. This stereospecific
reaction directly afforded compound 9 in 53% yield. In a single
transformation (Scheme 3), cyclopentanone (+)-6 was alkylated
with vinyl Grignard 8, affording a bromomagnesium alkoxide that
underwent anion-accelerated oxy-Cope rearrangement11 followed
by spontaneous transannular Dieckmann-like cyclization to deliver
9. Compound 9 was transformed to â-ketoester 10 by deproto-
nation under thermodynamic control followed by C-acylation with
NCCO2Me.
CP-263,114 (phomoidride B, 1) and CP-225,917 (phomoidride
A, 2) are closely related fungal metabolites that were isolated as
a consequence of their ability to inhibit squalene synthase and
Ras farnesyltransferase (Scheme 1).1 Both molecules present a
dense array of diverse, highly oxygenated and sensitive func-
tionality mounted upon an unusual bicyclo[4.3.1]deca-1(9)-ene
ring system. These compounds have inspired many laboratories
to develop approaches to the CP core ring system,2 including
studies by Danishefsky3 and co-workers that raised the question
of a possible new naturally occurring family member, and by
Nicolaou4 and co-workers that resulted in the first syntheses of
(+)-1 and (-)-2. We recently reported a fragment coupling/
tandem cyclization reaction comprising a chelation-controlled
alkylation, an anion accelerated oxy-Cope rearrangement, and a
transannular cyclization that resulted in direct synthesis of the
core structures of 1 and 2 from readily accessible starting
materials.5 This contribution describes a synthesis of (+)-1 using
a substantially more complex version of the same fragment
coupling/tandem cyclization reaction.
To prepare for installation of the quaternary center at C14,
compound 10 was converted to enolcarbonate 11 by a five-step
procedure that included removal of the PMB group, two-step
oxidation to the carboxylic acid, protection of the acid as a MOM
ester, and generation of the enol carbonate. Exposure of enol
carbonate 11 to TMSOTf and (MeO)3CH initiated a multistep
and multitask one-pot reaction that led directly to compound 14.
During this transformation, the quaternary center at C14 was
installed, the pseudoester cage ring system was assembled, and a
free acid at C14 was liberated for eventual homologation.
One plausible mechanism for the direct conversion of 11f14
is displayed in Scheme 4 and begins with TMSOTf-promoted
ionization of the enol carbonate to liberate silylketene acetal 12
and a carbomethoxenium ion fragment. Recombination of 12 and
the acyl cation at C14 affords intermediate 13,12 poised for
TMSOTf-catalyzed ionization of the C7 MOM group and cy-
clization to form the pseudoester cage ring system as shown.
Following acyl-transfer and cyclization, TMSOTf catalyzes
deprotection of the MOM ester at C14 to generate acid 14.
One carbon homologation of the acid of 14 was greatly
complicated by the surprising sensitivity of the γ-lactone func-
tionality. A two-step sequence comprising diazoketone formation4
and photolytic Wolff rearrangement accomplished the homolo-
gation in modest yield.13 Following homologation, the â-ketoester
was triflated using KNiPr2 and Tf2O to afford 15 in 55% yield.
Attempts to carbonylate the enoltriflate of 15 using CO and
catalysts derived from Pd complexed to phosphine ligands were
unsuccessful due to the extreme steric hindrance surrounding the
triflate. Following extensive experimentation, it was discovered
Scheme 1
(1) (a) Dabrah, T. T.; Harwood: H. L.; Huang, L. G.; Jankovich, N. D.;
Kaneko, T.; Li, J.-C.; Lindsey, S.; Moshier, P. M.; Subashi, T. A.; Therrien,
M.; Watts, P. C. J. Antibiot. 1997, 50, 1-7. (b) Dabrah, T. T.; Kaneko, T.;
Massefski, W., Jr.; Whipple, E. B. J. Am. Chem. Soc. 1997, 119, 1594-
1598.
(2) (a) Nicolaou, K. C.; Harter, M. W.; Boulton, L.; Jandeleit, B. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1194-1196. (b) Nicolaou, K. C.; Postema,
M. H. D.; Miller, N. D.; Yang, G. Angew. Chem., Int. Ed. Engl. 1997, 36,
2821-2823. (c) Davies, H. M. L.; Calvo, R.; Ahmed, G. Tetrahedron Lett.
1997, 38, 1737-1740. (d) Sgarbi, P. W. M.; Clive, D. L. Chem. Commun.
1997, 2158-2160. (e) Armstrong, A.; Critchley, T. J.; Mortlock, A. A. Synlett
1998, 552-553. (f) Kwon, O.; Su, D.-S.; Meng, D.; Deng, W.; D’Amico, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1877-1880. (g) Kwon,
O.; Su, D.-S.; Meng, D.; Deng, W.; D’Amico, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 1998, 37, 1880-1882. (h) Waizumi, N.; Itoh, T.; Fukuyama,
T. Tetrahedron Lett. 1998, 39, 6015-6018. (i) Bio, M. M.; Leighton, J. L. J.
Am. Chem. Soc. 1999, 121, 890-891. (j) Nicolaou, K. C.; Baran, P. S.; Jautelat,
R.; He, Y.; Fong, K. C.; Choi, H.-S.; Yoon, W. H.; Zhong, Y.-L. Angew.
Chem., Int. Ed. 1999, 38, 549-552. (k) Clive, D. L. J.; Sun, S.; He, X.; Zhang,
J.; Gagliardini, V. Tetrahedron Lett. 1999, 40, 4605-4609. (l) Yoshimitsu,
T.; Yanagiya, M.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 5215-5218. (m)
Sulikowski, G. A.; Agnelli, F.; Corbett, M. A. J. Org. Chem. 2000, 65, 337-
342. For recent reviews, see: (n) Hepworth, D. Chem. Ind. (London) 2000,
2, 59. (o) Starr, J. T.; Carreira, E. M. Angew. Chem., Int. Ed. 2000, 39, 1415-
1421.
(6) The synthesis of vinyl stannane 4 is described in the Supporting
Information.
(7) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(8) For a comprehensive review of the CBS catalyst, see: Corey, E. J. and
Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-2012.
(9) For examples of kinetic resolution using the oxazaborolidine-catalyzed
reduction, see: (a) Kurosu, M.; Kishi, Y. J. Org. Chem. 1998, 63, 6100-
6101. (b) Schmalz, H.; Jope, H. Tetrahedron 1998, 54, 3457-3464. (c)
Bringmann, G.; Hinrichs, J.; Kraus, J.; Wuzik, A.; Schulz, T. J. Org. Chem.
2000, 65, 2517-2527.
(3) Meng, D.; Qiang, T.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl.
1999, 38, 3197-3201.
(10) Compound 7 was synthesized in eight steps from R-glyceraldehyde
acetonide. For details see the Supporting Information.
(11) Evans, D. A.; Golob, A. M. J. Am. Chem. Soc. 1975, 97, 4765-4766.
(12) (MeO)3CH is not required for this reaction, but it was discovered that
the C6 ketal resisted hydrolysis in the presence of (MeO)3CH; most likely it
is modulating the acidity of the reaction.
(13) The modest yield of the Arndt-Eistert homologation is more indicative
of the extreme sensitivity of derivatives of 14 rather than the inefficiency of
the reactions.
(4) (a) Nicolaou, K. C.; Baran, P. S.; Zhong, Y.-L.; Choi, H. S.; Yoon, W.
H.; He, Y.; Fong, K. C. Angew. Chem., Int. Ed. 1999, 38, 1669-1675. (b)
Nicolaou, K. C.; Baran, P. S.; Zhong, Y. L.; Fong, K. C.; He, Y.; Yoon, W.
H.; Choi, H. S. Angew. Chem., Int. Ed. 1999, 38, 1676-1678. (c) Nicolaou,
K. C.; Jung, J.-K.; Yoon, W. H.; He, Y.; Zhong, Y.-L.; Baran, P. S. Angew.
Chem., Int. Ed. 2000, 39, 1829-1832.
(5) Chen, C.; Layton, M. E.; Shair, M. D. J. Am. Chem. Soc. 1998, 120,
10784-10785.
10.1021/ja001958x CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/18/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 30, 2000 7425
Scheme 2a
a Reagents: (a) (E,E)-Me3SnCHdCH(CH)Me (4), Pd2(dba)3, PPh3, DMF, 65 °C, 80%. (b) Li2(PMBOCH2)Cu(thiophene)CN, TMSCl, THF, -78 °C.
n
(c) BuLi, Et2O, -78 f 0 °C, NCCO2Me, -78 f 0 °C, 62% over two steps. (d) (+)-Me-CBS, catecholborane, CH2Cl2, 23 °C, 90%, ee, 31%. (e)
tBuLi, Et2O, -78 °C, then MgBr2 -78 f 23 °C, THF, then add (+)-6 in toluene, -78 f 23 °C, dilute to 0.01 M, 53%. (f) KHMDS, THF, then
NCCO2Me, -78 f 0 °C, 51%. (g) BCl3, -78 f -30 °C. (h) Dess-Martin periodinane, pyridine, H2O-CH2Cl2, 23 °C. (i) NaClO2, NaH2PO4, 2-methyl-
2-butene, MeOH-H2O, 23 °C. (j) MOMCl, Et3N, CH2Cl2, 23 °C. (k) KHMDS, THF, then NCCO2Me, -78 f 50 °C. (l) TMSOTf, HC(OMe)3, CH2Cl2,
-78 f 0 °C, 83-92% over six steps. (m) MsCl, Et3N, THF, 0 °C, then CH2N2 -50 °C. (n) hν, tBuOH-Et2O, 23 °C, 12% over two steps. (o) KNiPr2,
Et2O, then Tf2O, -78 f 0 °C, 55%. (p) Pd(OAc)2, P(OMe)3, CO (500 psi), Et3N, THF-MeCN, 23 °C, 70%. (q) HCO2H, 23 °C, 79%.
Scheme 4
that the crucial carbonylation could be accomplished by exposure
of 15 to a catalyst derived from Pd(OAc)2 and P(OMe)3, affording
anhydride ortho ester 16 in 70% yield.14
Global deprotection of 16 was accomplished upon treatment
with neat HCO2H to directly afford CP-263,114 (phomoidride
B, 1) in 79% yield. A synthetic sample of 1 was identical to
authentic samples of the natural product as judged by 1H NMR,15
IR, HRMS, HPLC, and TLC analyses. The optical rotation
measured for synthetic 1 was [R]D +14° (c ) 0.0033, CH2Cl2)
while natural 1 is reported to have [R]D -11° (c ) 0.48, CH2-
Cl2).1a This assignment of the absolute configuration of 1 is in
agreement with the recent assignment made by Nicolaou and co-
workers.4c
Scheme 3
cyclization (6 + 8 f 9)16 and a Lewis acid-catalyzed O f C
acyl transfer reaction (11 f 14). In addition, the discovery of a
Pd(0)-P(OMe)3 complex that catalyzes the carbonylation of a
highly hindered enol triflate where many other Pd catalysts fail
may lead to future applications of Pd(0)-P(OMe)3-catalyzed
reactions involving hindered substrates.17
Acknowledgment. We gratefully acknowledge financial support from
the following sources: NIH (GM59403-01A1), Bristol-Myers Squibb,
Camille and Henry Dreyfus Foundation, Alfred P. Sloan Foundation,
Merck & Co., Pharmacia & Upjohn, and SmithKline Beecham. M.E.L.
acknowledges an NSF predoctoral fellowship. We are also grateful to
Dr. T. Kaneko of Pfizer Central Research for generous samples of 1 and
2 and to Mr. Jason Chen, Mr. Ryan Spoering, and Mr. Carl Morales for
their contributions.
During the course of our synthesis of (+)-1, two new
Supporting Information Available: Details of experimental proce-
transformations were developed that may have applications
dures and analytical data are included (PDF). This material is available
beyond their use in this synthesis; a fragment coupling/tandem
free of charge via the Internet at http://pubs.acs.org.
(14) For the use of P(OMe)3 in a Pd-catalyzed carbonylation, see: Kayaki,
Y.; Noguchi, Y.; Iwasa, S.; Ikariya, T.; Noyori, R. Chem. Commun. 1999,
1235-1236.
JA001958X
(16) Sheehan, S. M.; Lalic, G.; Chen, J. Shair, M. D. Angew. Chem., Int.
(15) Although synthetic (+)-1 was purified to a single HPLC peak and 1H
NMR analysis unequivocally proved its identitiy, it always contained a small
amount of a proton-bearing compound unassociated with (+)-1.
Ed. 2000. In Press.
(17) Griffiths, C.; Leadbeater, N. E. Tetrahedron Lett. 2000, 41, 2487-
2490.