A concise synthesis of (-)-hispidospermidin guided by a postulated biogenesis [10]

Full text of DOI:10.1021/ja0026758

9556
J. Am. Chem. Soc. 2000, 122, 9556-9557
Scheme 1
A Concise Synthesis of (-)-Hispidospermidin Guided
by a Postulated Biogenesis
Junko Tamiya and Erik J. Sorensen*
Department of Chemistry and
The Skaggs Institute for Chemical Biology
The Scripps Research Institute, 10550 N. Torrey Pines Road
BCC-123, La Jolla, California 92037
ReceiVed July 20, 2000
In the course of a microbial screen for novel inhibitors of
phospholipase C (PLC), a key enzyme in the inositol phospholipid
signaling pathway,1 scientists from the Nippon Roche Research
Center elucidated the unique and complex structure of (-)-
hispidospermidin (4).2 This tetracyclic natural product, which
comprises seven contiguous stereocenters and a trimethylsper-
midine chain, exhibited moderately potent inhibitory activity
against PLC and instigated serious efforts in the area of organic
synthesis.3 In this communication, we describe a concise, enan-
tiospecific synthesis of 4 by a pathway guided by our hypothesis
about the origin of its structure in Nature.
Scheme 2
Our plan evolved from a perceived homology between the
structures of 4 and spirocyclic cation 3 (Scheme 1). The transient
cation 3 can be traced, via the well-known compound γ-bisabolene
(2),4 to farnesyl pyrophosphate (1),5 the fundamental building
block of sesquiterpene biogenesis.6 We noted that the constitution
of cation 3 is quite clearly expressed in the structure of 4 and
thus reasoned that this natural product might be a noVel
trimethylspermidine-containing sesquiterpene.7
We considered the known spirocyclic ketone 68 (Scheme 2) to
be an ideal building block because it encompasses a significant
portion of the architecture of 4. Our hope was that a nucleophilic
derivative of ketone 6 could be joined in a stereocontrolled fashion
with 8-phenylmenthyl pyruvate (7).9 A benefit accruing from the
selection of compounds 6 and 7 as key intermediates for our
synthesis is that both compounds can be created enantiospecifi-
cally from the abundant monoterpene (R)-(+)-pulegone (5).
By a straightforward condensation, ketone 6 could be converted
to trisylhydrazone 8 (Scheme 3). Despite its sterically congested
nature, the putative vinyl Grignard reagent, produced from 8 under
the conditions shown,10 added diastereoselectively to the keto
function of 7 to give hydroxy ester 9.11,12 After protection of the
tertiary hydroxyl of 9 in the form of a 2-(trimethylsilyl)-
ethoxymethyl (SEM) ether,13 a reduction of the 8-phenylmenthyl
ester to alcohol 10 was achieved with diisobutylaluminum hydride
(Dibal-H). A Swern oxidation14 of 10 gave rise to aldehyde 11.
With an enforced proximity of functional groups with comple-
mentary reactivity, compound 11 was considered well-suited for
a carbonyl ene cyclization.15 Somewhat unexpectedly, when 11
was dissolved in acetic acid and allowed to stand at room
temperature, it underwent a Prins cyclization with participation
by the tertiary ether oxygen and afforded a mixture of tetracyclic
alcohol epimers shown as 12.16 This intrinsically favorable
bicyclization completed the tetracyclic architecture of the natural
product and verified our stereochemical assignment of 9. While
cleavage of the SEM ether of 11 could conceivably precede the
Prins ring closure, we found that the SEM ether of compound 10
was impervious to acetic acid at room temperature. We propose
(1) Singer, W. D.; Brown, H. A.; Sternweis, P. C. Annu. ReV. Biochem.
1997, 66, 475.
(2) Ohtsuka, T.; Itezono, Y.; Nakayama, N.; Sakai, A.; Shimma, N.; Yokose,
K.; Seto, H. J. Antibiot. 1994, 47, 6.
(3) For total syntheses of hispidospermidin, see: (a) Frontier, A. J.;
Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 1997, 119, 6686. (b)
Overman, L. E.; Tomasi, A. L. J. Am. Chem. Soc. 1998, 120, 4039. (c) Frontier,
A. J.; Raghavan, S.; Danishefsky, S. J. J. Am. Chem. Soc. 2000, 122, 6151.
(4) Parker, W.; Roberts, J. S.; Ramage, R. Quart. ReV. 1967, 21, 331.
(5) Cyclization of trans,trans-farnesyl pyrophosphate (1) to γ-bisabolene
(2) presupposes an initial isomerization of 1 to nerolidyl pyrophosphate or
alternatively to cis,trans-farnesyl pyrophosphate. For discussions, see: (a)
Cane, D. E. Acc. Chem. Res. 1985, 18, 220. (b) Andersen, N. H.; Syrdal, D.
D. Tetrahedron Lett. 1972, 2455.
(6) Ruzicka, L.; Eschenmoser, A.; Heusser, H. Experientia 1953, 9, 362.
(7) The biosynthesis of (-)-hispidospermidin has not yet been described.
(8) We achieved a 5-step synthesis of ketone 6 from (R)-(+)-pulegone (5)
and isoprene by a modification of the 7-step sequence described by Marx
and Norman (see: J. Org. Chem. 1975, 40, 1602).
(11) For diastereoselective additions of Grignard reagents to the pyruvate
ester of (-)-8-phenylmenthol, see: (a) Whitesell, J. K.; Deyo, D.; Bhatta-
charya, A. J. Chem. Soc., Chem. Commun. 1983, 802. (b) Whitesell, J. K.;
Buchanan, C. M. J. Org. Chem. 1986, 51, 5443.
(12) We isolated a single tertiary alcohol diastereomer and tentatively
assigned its stereochemistry as shown in 9 by analogy to the stereochemical
outcomes reported by Whitesell et al. (see refs 11a,b).
(13) Lipshutz, B. H.; Pegram, J. J. Tetrahedron Lett. 1980, 21, 3343.
(14) Mancuso, A. J.; Huang, S.-L.; Swern, D. J. Org. Chem. 1978, 43,
2480.
(15) (a) Marshall, J. A.; Andersen, N. H.; Johnson, P. C. J. Org. Chem.
1970, 35, 186. (b) For a review of carbonyl ene and Prins reactions, see:
Snider, B. B. In ComprehensiVe Organic Syntheses: Additions to C-X
p-Bonds, Part 2; Trost, B. M., Fleming, I., Eds.; Pergamon: New York, 1991;
Vol. 2, Chapter 2.1, p 527.
(9) 8-Phenylmenthyl pyruvate (7) was prepared by the reaction of (-)-8-
phenylmenthol with pyruvic acid in the presence of p-toluenesulfonic acid in
refluxing benzene. For a convenient synthesis of 8-phenylmenthol from
pulegone, see: (a) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97,
6908. (b) Ort, O. Organic Syntheses; John Wiley & Sons: New York, 1993;
Collect. Vol. 8, p 522.
(16) We could not isolate the anticipated carbonyl ene product, although
it may be a transient intermediate in this process. This transformation even
occurs to some extent on silica gel. We do not yet know if the outcome of
this reaction is dependent on the identity of the protecting group in 11.
(10) (a) Chamberlin, A. R.; Stemke, J. E.; Bond, F. T. J. Org. Chem. 1978,
43, 147. (b) Chamberlin, A. R.; Bloom, S. H. Org. React. (N.Y.) 1991, 39, 1.
10.1021/ja0026758 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/16/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 39, 2000 9557
Scheme 3a
a Reagents and conditions: (a) 2,4,6-triisopropylbenzenesulfonyl hydrazide, HCl (1.2 equiv), CH3CN, room temperature, 75%. (b) n-BuLi (2.05
equiv), Et2O/THF, -78 to -20 °C; then MgBr2‚OEt2, -78 °C; then 7, -78 °C to room temperature, 55% from 8. (c) SEMCl, n-Bu4NI, i-Pr2NEt,
CH2Cl2, 50 °C, ca. 100%. (d) Dibal-H, toluene, -78 °C, 93%. (e) (COCl)2, DMSO, CH2Cl2, -78 °C; then i-Pr2NEt, -78 °C to room temperature, ca.
100%. (f) AcOH, room temperature, 2 d, 83% or AcOH, 80 °C, 3 h, 87%. (g) (COCl)2, DMSO, CH2Cl2, -78 °C; then i-Pr2NEt, -78 °C to room
temperature, ca. 100%. (h) HONH2‚HCl, NaOAc‚3H2O, EtOH, room temperature, ca. 100%. (i) LiAlH4, NiCl2, Et2O, room temperature, 97%. (j) Rh/C
(2 equiv), EtOAc, H2, 1100 psi, (70% yield of a 3:1 mixture of epimers favoring 4). Ar ) 2,4,6-triisopropylbenzene.
that the tertiary ether oxygen of 11 intercepts a transient tertiary
carbocation in the course of the conversion of 11 to 12.
Interestingly, heating a mixture of 11 and trimethylspermidine
in toluene followed by exposure of the crude imine to acetic acid
afforded an equimolar mixture of 15 and its equatorial side chain
diastereomer, ostensibly through an aza-Prins cyclization with
ether oxygen participation.
A Swern oxidation14 of the diastereomeric mixture of alcohols
afforded tetracyclic ketone 13, a substance that was advanced to
∆8,9-dehydrohispidospermidin (15) by a reductive amination with
trimethylspermidine.3c The high haptophilicity of amines17 and
close spatial relationship between the trimethylspermidine moiety
and the ring alkene in 15 were expected to favor the formation
of 4 under the conditions of a hydrogenation. After considerable
experimentation, we found that 4 could be obtained as the major
component of a 3:1 mixture of diastereomers via a high-pressure
hydrogenation of 15 in the presence of rhodium on carbon.18 We
also converted ketone 13 to the corresponding oxime and thence
to the known unsaturated primary amine 143b by reduction under
the conditions shown.19 In their instructive synthesis, Overman
and Tomasi showed that 14 could be converted to 4 in a
completely diastereoselective fashion.3b By this known three-step
sequence, we also transformed 14 to 4 and established the identity
of our sample of synthetic (-)-hispidospermidin by comparison
with an authentic sample.
Following a strategy guided by our biogenetic postulate, we
achieved a concise, enantiospecific synthesis of the novel PLC
inhibitor (-)-hispidospermidin (4) from known compounds 6 and
7. A facile, acid-induced bicyclization of compound 11 is a
noteworthy stage of this synthesis.
Acknowledgment. This paper is dedicated with respect and affection
to our mentor Professor Albert Eschenmoser on the occasion of his 75th
birthday. Financial support from The Skaggs Institute for Chemical
Biology at TSRI, a Graduate Research Fellowship to J.T. (Abbott
Laboratories), a grant from the Merck Research Laboratories, and a
Beckman Young Investigator Award to E.J.S. are gratefully appreciated.
We thank Prof. Larry Overman and Dr. Adam Tomasi for samples of
natural and synthetic (-)-hispidospermidin and helpful discussions.
Supporting Information Available: Characterization data and
experimental procedures for compounds 9, 10, 11, 12, 13, 14, 15, and 4
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(17) Thompson, H. W.; Wong, J. K. J. Org. Chem. 1985, 50, 4270.
(18) We could not resolve this 3:1 mixture of stereoisomers by SiO2
chromatography or HPLC.
(19) Ganem, B.; Osby, J. O. Chem. ReV. 1986, 86, 763.
JA0026758