Intramolecular Organocatalytic [3+2] Dipolar Cycloaddition: Stereospecific Cycloaddition and the Total Synthesis of (±)-Hirsutene

Article abstract of DOI:10.1002/anie.200352218

A testing ground for cyclopentannulation strategies: the triquinane natural product hirsutene is obtained through the intramolecular organocatalytic [3+2] cycloaddition of the 1,7-enyne (E)-1. The cycloaddition is stereospecific: reaction of the correspon

Full text of DOI:10.1002/anie.200352218

Angewandte
Chemie
Natural Product Synthesis
Intramolecular Organocatalytic [3+2] Dipolar
Cycloaddition: Stereospecific Cycloaddition and
the Total Synthesis of (Æ )-Hirsutene**
Jian-Cheng Wang and Michael J. Krische*
Nucleophilic catalysis represents an important subset of
organocatalytic transformations.[1,5] As part of a program
À
devoted to the design of phosphane-catalyzed C C bond-
Figure 1. Representative linear triquinanes.
forming reactions,[2] we recently reported the first intra-
molecular phosphane-catalyzed [3+2] cycloaddition of 2-
butynoates with electron-deficient alkenes.[2a] A challenge
inherent to the intramolecular cycloaddition resides in
suppression of competitive internal redox isomerization,
that is, phosphane-catalyzed conversion of the 2-alkynoates
to the corresponding 2,4-dienoates.[3] Indeed, whereas diqui-
nane formation proceeds smoothly, presumably owing to the
enhanced rate of five-membered-ring formation, competitive
isomerization circumvents hydrindane formation. Notably,
unlike the parent intermolecular cycloaddition discovered in
1995,[4,5] which generally provides cycloadducts as mixtures of
regio- and diastereomers, the intramolecular process affords
cycloadducts in isomerically pure form.[2a] In this account, the
first application of this intramolecular organocatalytic cyclo-
addition methodology in natural product synthesis is
reported, as demonstrated by the synthesis of the linear
triquinane hirsutene. These studies highlight the utility of this
cycloaddition methodology vis-à-vis diastereoselective con-
struction of quaternary centers and establish the intramolec-
ular cycloaddition as a stereospecific process.
Since the first structural elucidation of a polyquinane
natural product in 1966 (hirsutic acid-C, Figure 1),[6] over 250
polyquinane natural products have been isolated.[7] Over 80 of
these natural products belong to the structural subset known
as linear triquinanes, which are isolated from plants, microbes,
and marine organisms.[7b] The discovery of structurally novel
linear triquinanes continues unabated. For example, chlori-
nated linear triquinanes such as chloriolin C have been
isolated from fungal cultures taken from a Jaspis marine
sponge.[8] Efforts toward the synthesis of linear triquinane
natural products are fueled, in part, by their biological
activity. Hirustic acid-C and coriolin exhibit antibiotic and
antitumor activity, respectively.[9] Owing to their novel
structure, the linear triquinanes have also captured the
interest of synthetic chemists as a testing ground for new
cyclopentannulation strategies. In this latter capacity, hisu-
tene, a metabolite of the basidiomycete Coriolus consors and
presumed biogenetic precursor to coriolin and hirsutic acid-
C,[10] has been the focus of considerable attention.[7] Here we
present a concise and stereocontrolled approach to (Æ )-
hirsutene based on phosphane-catalyzed intramolecular
[3+2] cycloaddition methodology developed in our lab.
Retrosynthetically, hirsutene is envisioned to derive from
cycloadduct 6 by means of aldol cyclization–methylenation
(Scheme 1). The diquinane 6, which contains three of the four
stereogenic centers in hirsutene, will be obtained directly
through phosphane-catalyzed [3+2] dipolar cycloaddition of
the 1,7-enyne 5. The cycloaddition of 5 serves as a means of
exploring the utility of the intramolecular cycloaddition
methodology vis-à-vis stereoselective formation of quater-
nary carbon centers. Moreover, by examining the cyclo-
addition of both (E)- and (Z)-5, information regarding the
stereospecificity of the intramolecular cycloaddition may be
obtained. Finally, cycloaddition substrate 5 will be obtained
from dimethylhexenol 1 through sequential introduction of
enone and ynoate moieties.
The synthesis of cycloaddition substrate 5 begins with
tosylation of 3,3-dimethyl-hex-5-en-1-ol (1, Scheme 2).[11]
Displacement of the tosylate was attempted with an assort-
ment of acetylides under a range of conditions, but it could
only be achieved with lithium acetylide ethylenediamine
complex in DMSO. Under these conditions the resulting 1,7-
enyne 2 is produced in 68% yield.[12] Treatment of 1,7-enyne 2
with methyllithium followed by methyl chloroformate pro-
vides the corresponding ynoate 3 in 81% yield. Selective
ozonolytic cleavage of the terminal alkene residue in the
presence of the ynoate occurs smoothly to provide aldehyde 4
in 85% yield. Finally, olefination of 4 using 3-diethylphos-
phono-2-butanone[13] occurs in 60% yield to afford cyclo-
addition addition substrate 5 as a 5.5:1 ratio of E/Z isomers.
The acquisition of mono(enone)–mono(ynoate) 5 sets the
stage for phosphane-catalyzed cycloaddition. Gratifyingly,
exposure of (E)-5 to our previously defined conditions[2a] for
intramolecular phosphane-catalyzed [3+2] dipolar cycloaddi-
tion results in the formation of cycloadduct 6 in 88% yield.
[*] Prof. M. J. Krische, J.-C. Wang
Universityof Texas at Austin
Department of Chemistryand Biochemistry
1 UniversityStation–A5300
Austin, TX 78712-1167 (USA)
Fax: (+1)512-471-8696
E-mail: mkrische@mail.utexas.edu
[**] Acknowledgment is made to the Robert A. Welch Foundation (F-
1466), the NSF-CAREER program (CHE0090441), the Herman
Frasch Foundation (535-HF02), the NIH (RO1 GM65149-01),
donors of The Petroleum Research Fund administered bythe ACS
(34974-G1), the Research Corporation Cottrell Scholar Award
(CS0927), the Alfred P. Sloan Foundation, the Camille and Henry
Dreyfus Foundation, and Eli Lilly for support of this research.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 5855 –5857
DOI: 10.1002/anie.200352218
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5855

Communications
Scheme 1. Retrosynthetic analysis of hirsutene based on a phosphane-catalyzed [3+2] dipolar cycloaddition.
provide diol 7 as a mixture of diastereomers. Swern mod-
ification of the Moffatt oxidation provides an intermediate
keto-aldehyde in 78% yield, which upon exposure to base
affords the aldol cyclodehydration product 8 in 95% yield as a
single stereoisomer. Enone 8 is identical in all respects to the
previously reported material, which has been converted to
hirsutene in two manipulations.[14] As such, the synthesis of 8
represents a formal total synthesis of (Æ )-hirsutene. Whereas
the previously reported material is prepared in 18 steps from
2,2’-dimethylpentenal, the present route allows access to
enone 8 in 12steps from the very same precursor (Scheme 4).
Scheme 2. Preparation of cycloaddition substrate 5. Conditions:
ꢀ
a) TsCl, Pyr, 08C, 76%; b) LiC CH, DMSO, 58C, 68%; c) CH3Li, THF,
À788C, then ClCO2CH3, À308C, 81%; d) O3, CH2Cl2, À788C, then
PPh3, 85%; e) 3-diethylphosphono-2-butanone, NaH, THF, 358C, 60%,
5.5:1 E/Z ratio. DMSO=dimethyl sulfoxide, Pyr=pyridine, Ts=tolue-
nesulfonyl.
Moreover, 6 is obtained as a single stereoisomer with
placement of the methyl residue on the concave face of the
diquinane ring system, that is, formation of the quaternary
center occurs readily and with a stereochemistry consistent
with the structural features of hirsutene. To probe the
stereospecificity of the cycloaddition, (Z)-5 was exposed to
identical conditions. Formation of the epimeric diquinane epi-
6 is observed, without any detectable formation of the
cycloadduct derived from (Z)-5. These results firmly establish
the intramolecular phosphane-catalyzed [3+2] dipolar cyclo-
addition as a stereospecific process. This result is significant in
view of the fact that evidence for both stepwise and concerted
mechanisms exists for related intermolecular cycloaddi-
tions.[4e,5] A model accounting for the stereospecific cyclo-
addition of (E)- and (Z)-5 is given below (Scheme 3).
Scheme 4. Conversion of cycloadduct 6 to (Æ)-hirsutene. Conditions:
a) H2, Pd/C, CH3OH, 258C, 93%; b) LiAlH4, Et2O, 258C, 92%;
c) (COCl)2, DMSO, CH2Cl2, À788C, then TEA, 78%; d) KOH, Bu4NOH
(aq), THF/Et2O (1:1), reflux, 95%. TEA=triethylamine.
In summation, intramolecular phosphane-catalyzed [3+2]
dipolar cycloaddition enables a concise approach to the linear
triquinane hirsutene, whereby three contiguous stereogenic
centers, including a quaternary center, are created in a single
manipulation with control of relative stereochemistry. In
addition to demonstrating the applicability of this method-
ology vis-à-vis triquinane synthesis, these studies also reveal
that the intramolecular cycloaddition is stereospecific. Future
studies will be devoted to the design of related phosphane-
catalyzed transformations including enantioselective variants
of the methodology reported herein.
Elaboration of cycloadduct 6 to hirsutene is achieved in
six manipulations. Hydrogenation of 6 followed by LiAlH4
reduction occurs in yields of 93% and 92%, respectively, to
Received: June 24, 2003 [Z52218]
Keywords: cycloaddition · natural products ·
.
organocatalysis · phosphanes
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