Enantioselective synthesis of (-)-sclerophytin A by a stereoconvergent epoxide hydrolysis

Article abstract of DOI:10.1021/ja108185z

The cytotoxic natural product (-)-sclerophytin A was constructed in 13 steps from geranial. Highlights from the synthesis are a stereoselective Oshima-Utimoto reaction, a Shibata-Baba indium-promoted radical cyclization, and a novel stereoconvergent epoxide hydrolysis.

Full text of DOI:10.1021/ja108185z

Published on Web 10/28/2010
Enantioselective Synthesis of (-)-Sclerophytin A by a Stereoconvergent
Epoxide Hydrolysis
Bin Wang, Armando P. Ramirez, Justin J. Slade, and James P. Morken*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
Received September 21, 2010; E-mail: morken@bc.edu
Scheme 2
Abstract: The cytotoxic natural product (-)-sclerophytin A was
constructed in 13 steps from geranial. Highlights from the
synthesis are a stereoselective Oshima-Utimoto reaction, a
Shibata-Baba indium-promoted radical cyclization, and a novel
stereoconvergent epoxide hydrolysis.
The oxygenated cembrane diterpenes are a large class of natural
products comprising cladiellins, briarellins, asbestinins, and sar-
codictyins. Their intricate chemical structures have captivated many
in the synthetic chemistry community, with recent successes in the
crafting of polyanthellin A,1 asbestinins,2 briarellins E and F,3
vigulariol,4 and astrogorgin5 being highly notable recent achieve-
ments.6 In addition to intriguing structures, these compounds also
tend to possess potent biological activity. Among the cladiellins,
it occurs without interference from the adjacent alkenes, was
proposed to convert 4 to cyclic acetal 3, stereoselectively. Notably,
appropriately functionalized substrate 4 is readily available in a
single step from geranial.
sclerophytin A (Scheme 1) is a particularly striking compound; it
was isolated from the marine soft coral Sclerophytum capitalis and
found to exhibit remarkable potency against mouse leukemia cells
(cytotoxic at 1 ng/mL versus L1210 cell line), yet its original
structural formulation was incorrect.7,8 Total syntheses by the
Paquette and Overman groups established the correct formulation
of sclerophytin A to be that depicted in Scheme 1.9 As a means to
examine the utility of the stereoselective Oshima-Utimoto reac-
tion10 in chemical synthesis, we’ve been attracted to the target
sclerophytin A and its structural relatives.11 Herein, we describe a
short enantioselective route to ketone 1 (Scheme 1), a key in-
termediate in a prior synthesis of vigulariol,4b and show that 1 can
be readily converted to sclerophytin A by a three-step sequence
involving a novel stereoconvergent epoxide hydrolysis.
To begin the synthesis, allylic alcohol (E)-4 was prepared in
92% yield and 98% enantiomeric excess by Brown methallylation12
of geranial and was then subjected to the Oshima-Utimoto reaction.
This sequence delivered 3 as a mixture of epimers in 62% yield
(Scheme 2). Subsequent Jones oxidation of the Oshima-Utimoto
product 3 to the derived lactone revealed >20:1 anti/syn (C4:C5)
stereoselection from the Oshima-Utimoto reaction.13 After R-io-
dination to give 5, we examined the tin-free radical reactions
pioneered by Shibata and Baba for reductive radical-mediated
transformation.14 Thus, treatment of 5 with InCl3 and NaBH4
delivered the reductive radical cyclization product in 56% yield.
The intermediate lactone was subsequently reduced with DIBAL-H
affording lactol 6 in 85% yield. Of note, the radical ring closure
proceeded with excellent stereoselectivity (>10:1; relative config-
uration established by X-ray analysis, see Scheme 2), presumably
a consequence of reaction through transition structure TS-1. Also
of note is that the In-promoted radical reaction proceeded in similar
efficiency as the optimized tin-based reaction (Ph3SnH/AIBN).
Conversion of 6 to ketone 1 was accomplished in four straight-
forward synthesis steps (Scheme 3). First the alcohol was acylated
and then displaced with cyanide under the aegis of scandium triflate
(f 7). Addition of butenylmagnesium bromide, followed by
aqueous workup, delivered ketone 8 (same as 2, Scheme 1) which
was converted to ketone 1 by ring-closing metathesis.15
Scheme 1
Conversion of ketone 1 to sclerophytin A requires trans
dioxygenation of the trisubstituted alkene. It was considered that
this might be accomplished by hydrolytic ring-opening of an
intermediate epoxide. As depicted in Scheme 4, peracid epoxidation
occurs regioselectively but without stereocontrol and, therefore,
provides a mixture of both r-9 and ꢀ-9. While epoxidation of the
tertiary alcohol 10 (derived from 1 by addition of MeMgBr) could
In terms of retrosynthetic analysis (Scheme 1), we considered
that ketone 1 might arise by ring-closing olefin metathesis of triene
2 and that 2 might be obtained from intermediate 3 by a 6-exo-trig
radical cyclization of an appropriately modified derivative. The
Oshima-Utimoto reaction of the allylic alcohol embedded in 4, if
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C O M M U N I C A T I O N S
Scheme 3
Scheme 5
be accomplished stereoselectively as ascertained by Clark,4b
spontaneous cyclization to vigulariol could not be avoided (efforts
to protect alcohol 10 were futile). Examination of the X-ray structure
of epoxy ketone r-9 (see Scheme 4), however, inspired a solution.
The structural feature of consequence is a near linear alignment
(160°) of the carbonyl oxygen, C6 of the epoxide (eunicellin
numbering), and the epoxide oxygen. While the carbonyl oxygen
and C6 are separated by 3.68 Å in r-9, it was reasoned that
proximity would be increased, perhaps facilitating intramolecular
oxirane rupture, upon conversion of the carbonyl to the tetrahedral
hydrate. This reactivity would be unique to stereoisomer r-9 and
would lead to oxygenation of the alkene in a manner that is
stereochemically appropriate to the target.
isolated in 88% yield as a single product stereoisomer. Finally,
subjection of 11 to MeMgCl delivered sclerophytin A in excellent yield
and in agreement with characterization data.7,9f
In conclusion, we have described an enantioselective synthesis
of (-)-sclerophytin A that occurs in 13 steps from geranial. The
versatility of radical reactions and the Oshima-Utimoto reaction
suggests that the synthesis strategy described herein may be
transferable to a number of other eunicellin-derived natural products,
and these will be reported in due course.
Acknowledgment. We thank Dr. Bo Li (Boston College) for
X-ray structures. We thank the NIGMS (GM-59417) and the NSF
(DBI-0619576; BC Mass Spectrometry Center) for support.
Scheme 4
Supporting Information Available: Characterization and proce-
dures. This material is available free of charge via the Internet at http://
pubs.acs.org.
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