Alkynyliodonium salts in organic synthesis. Application to the total synthesis of (-)-Agelastatin A and (-)-Agelastatin B

Article abstract of DOI:10.1021/ja027121e

The asymmetric total syntheses of (-)-agelastatin A and (-)-agelastatin B were accomplished in 14 steps each from (R)-epichlorohydrin. The pivotal transformation in both sequences was a sulfinate-promoted cyclization of an alkynyliodonium salt to furnish

Full text of DOI:10.1021/ja027121e

Published on Web 07/12/2002
Alkynyliodonium Salts in Organic Synthesis. Application to the Total
Synthesis of (-)-Agelastatin A and (-)-Agelastatin B
Ken S. Feldman* and Joe C. Saunders
Department of Chemistry, The PennsylVania State UniVersity, UniVersity Park, PennsylVania 16802
Received May 31, 2002
Scheme 1
Alkynyliodonium salts have demonstrated utility in the synthesis
of functionalized five-membered heterocyclic and carbocyclic
systems by virtue of their ability to initiate a reaction sequence
proceeding through both nucleophile/electrophile capture chemistry
and carbene chemistry to fashion three, and even four, new bonds
in a single operation.1 Whereas these two-carbon reagents can be
conveniently prepared by treatment of alkynylstannanes with PhI-
(CN)OTf (Stang’s reagent)2a among other procedures,2 the inherent
thermal instability of the more functionally elaborate iodonium salts
cautioned against their use in complex molecule synthesis. Ongoing
in-house efforts to expand the scope of alkynyliodonium salt
chemistry have led to successful protocols for exploiting these
conjunctive reagents in increasingly more challenging contexts.3
The culmination of one such study, the total synthesis of the
functionally and stereochemically rich marine alkaloid (-)-agel-
astatin A (1),4 is described below. This potent antileukemic principle
Scheme 2
isolated from the sponge Agelas dendromorpha features a central
cyclopentane ring bearing four nitrogen-substituted stereogenic
centers and a sensitive bromopyrrole unit. Facile generation of the
pivotal cyclopentane core endowed with suitable functionality for
further elaboration of the nitrogen appendages relies on the
cyclopentene-forming sequence that initiates with alkynyliodonium
salt 4 and proceeds through a putative alkylidenecarbene intermedi-
ate to deliver the bicyclic oxazolidinone template 3 (Scheme 1).
The concave/convex framework of 3 should enforce the desired
stereochemical outcome upon amine addition to C(8). The choice
of amide protecting group in 2 is an area of some concern, given
the difficulties encountered during its attempted removal in an
earlier agelastatin A effort.5a
The synthesis of 4 commences with chiral epoxyalkyne 5, which
is readily available through BF3‚THF-mediated6 addition of LiCt
CTMS to chiral epichlorohydrin.7,8 Opening the epoxide with azide
at the least hindered carbon followed standard procedures,9 and
application of Vilarrasa’s oxazolidinone synthesis10 to the inter-
mediate hydroxyazide delivered 6 in good yield. Conversion of the
alkynylsilane to the requisite stannane 7 set the stage for the key
transformation in the synthesis route. Exposure of alkynylstannane
7 to Stang’s reagent at -42 °C, followed by concentration in vacuo
at -42 °C, dissolution of the crude alkynyliodonium salt in DME
(-42 f 0 °C), and rapid cannulation of this chilled solution into
a refluxing suspension of TolSO2Na (1 equiv) in DME, led to the
isolation of two characterizable products, Scheme 2. The desired
cyclopentene 3 was formed in modest yield as a single stereoisomer
via 1,5 C-H insertion of the presumed intermediate alkylidenecar-
bene of 8 into the otherwise unactivated secondary C-H bond of
the oxazolidinone unit. The sulfonylalkyne 9, which plausibly arises
from a 1,2-shift within carbene 8, proved to be the major product.
No further information is available at present which addresses the
question of S versus C migration in this step, but earlier work by
Ochiai et al. on a related alkylidenecarbene indicated that the sulfone
and not the alkyl group migrated.11 No product(s) resulting from
alkylidenecarbene insertion into the lone pair of the oxazolidinone’s
oxygen (i.e., 10) was observed despite earlier precedent that
suggested this possibility.12
The synthesis continued with the conjugate addition of o-
nitrobenzylamine to the unsaturated sulfone moiety within 3 to
furnish the secondary amine as the anticipated (vide supra) single
diastereomer (Scheme 3). Acylation of this secondary amine with
* To whom correspondence should be addressed. E-mail: ksf@chem.psu.edu.
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9060
J. AM. CHEM. SOC. 2002, 124, 9060-9061
10.1021/ja027121e CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
by the Universita` di Trento group, and by comparison of the 13C
NMR spectrum and optical rotation with published data.
Scheme 3
Acknowledgment. We thank the National Institutes of Health
(GM37681) for financial support and Dr. M. D’Ambrosio for a
sample of agelastatin A.
Supporting Information Available: Characterization data ([R]20
,
D
1H and 13C NMR, IR, LRMS, HRMS, or elemental analysis) and copies
1
of H and 13C NMR spectra for 1-3, 6, 7, 9, and 11-14 (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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the parent pyrrole 2-carboxylic acid chloride furnished amide 2 and
presaged bromine addition in the final step of the synthesis. In this
way, complications that might arise from carrying a more func-
tionalized pyrrole unit through several steps of the route can be
avoided. Facile oxazolidinone hydrolysis without interference from
the urea unit led to alcohol 11 in excellent yield. In the second
complex transformation of the plan, treatment of alcohol 11 under
standard Swern oxidation conditions afforded a single product,
tricycle 12, in good yield. This multistep sequence presumably
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mination of the pyrrole moiety at C(13), eq 1.13 Careful titration
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A (1) essentially free of other brominated products in good yield.
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1
confirmed by comparison of H NMR and TLC data with that of
an authentic sample of the naturally occurring material provided
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