Total synthesis of the potent androgen receptor antagonist (-)-arabilin: A strategic, biomimetic [1,7]-hydrogen shift

Article abstract of DOI:10.1021/ja209459f

The first total synthesis of (-)-arabilin, a Streptomyces metabolite that inhibits hormone activation of the androgen receptor, has been completed. The key step, a [1,7]-hydrogen shift, establishes the enol ether-containing skipped-tetraene substructure. This nonenzymatic pericyclic reaction is considered to be biomimetic.

Full text of DOI:10.1021/ja209459f

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Total Synthesis of the Potent Androgen Receptor Antagonist
(À)-Arabilin: A Strategic, Biomimetic [1,7]-Hydrogen Shift
Hee Nam Lim and Kathlyn A. Parker*
Department of Chemistry, Stony Brook University, Stony Brook, New York 11794, United States
S Supporting Information
b
Scheme 1. Nonenzymatic 8π,6π Electrocyclization of
(E,Z,Z,Z)-Tetraene 4
ABSTRACT: The first total synthesis of (À)-arabilin, a
Streptomyces metabolite that inhibits hormone activation of
the androgen receptor, has been completed. The key step, a
[1,7]-hydrogen shift, establishes the enol ether-containing
skipped-tetraene substructure. This nonenzymatic pericyc-
lic reaction is considered to be biomimetic.
rabilin (1) is a natural product that was isolated by the Imoto
A
group from Streptomyces sp. MK756-CF1 during a screen for
androgen receptor (AR) antagonists.1 Arabilin competitively
blocks binding of dihydrotestosterone (DHT) to the AR with
an IC50 of 11 μM and inhibits DHT-induced expression of
prostate-specific antigen mRNA in LNCaP cells. New structural
classes of AR antagonists, especially those that retain activity
against hormone refractory prostate cancer, are important leads
for drug development.2
We were intrigued by the possibility that, in nature, the enol
ether-containing skipped-polyene system of arabilin is formed from
a conjugated tetraene system by another thermally allowed, non-
enzymatic rearrangement, in this case, a [1,7]-hydrogen shift.6 The
thermal [1,7]-hydrogen shift is well-known as a step in the series of
sigmatropic rearrangements that leads to the biosynthesis and biomimetic
chemical synthesis of vitamin D compounds. However, aside from its role
in the vitamin D system, it is unknown as a component of a rationally
designed total synthesis. Furthermore, in geometrically disposed
trienes, it is reversible, in some cases leading to mixtures of isomers.7
In principle, a thermal [1,7]-hydrogen shift is available to
conjugated (E,Z,Z,Z)-tetraene 4; however the 8π electrocycliza-
tion is facile in this system. Alternatively, arabilin, but not the
SNF compounds, could be formed from the E,E,Z,Z isomer 5.
The helical transition state required for an antarafacial [1,7]-
hydrogen shift8 is available to isomer 5 (Scheme 2), but that
required for the 8π electrocyclization is not.9 Therefore, we
considered tetraene 5 to be a potential biogenetic and synthetic
precursor of arabilin. It seemed likely that we could obtain
tetraene 5 from the palladium-catalyzed coupling of (E,E)-
iododiene 6 and known chiral vinylstannane 7.10
The structure of arabilin was determined by a combination of
spectroscopic techniques, including HMQC, HMBC, and NOE
NMR methods. Although the configuration at C-6 was not
determined, we initially assumed this to be (R) by analogy to
that of its congeners.
The structure of arabilin is as intriguing as its potential role
in mechanistic and pharmacological studies. It is a biogene-
tic relative of spectinabilin (2) [the fully conjugated (E,E,E,Z)-
tetraene]3 and SNF4435 C (3a),4 both of which were isolated
from the same organism.
Before investing in the preparation of the proposed biosyn-
thetic intermediate 5, we tested the facility of the [1,7]-hydrogen
The SNF compounds (3a and 3b) are presumably derived
biogenetically from the fully conjugated (E,Z,Z,Z)-tetraene 4 (or
possibly from the Z,Z,Z,E isomer) by a nonenzymatic, thermal
8π,6π tandem electrocyclization reaction (Scheme 1).5 Spectin-
abilin and the SNF compounds have the R configuration at C-6.
Received: October 12, 2011
Published: November 16, 2011
r
2011 American Chemical Society
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Scheme 2. Postulated Key Step for the Total Synthesis:
Tandem Coupling and [1,7]-Hydrogen Shift
Scheme 4. Synthesis of Iododiene 6
Scheme 5. Convergent Synthesis of (À)-Arabilin
a picture in which the [1,7]-hydrogen shift is accelerated by both a
substituent-enforced favorable conformation and an oxygen sub-
stituent on the developing double bond. Internally unsubstituted
2,4,6-(Z,Z,E)-trien-1-ols and their ethers are known as natural
products and synthetic intermediates.14 [1,7]-Hydrogen shifts have
not been reported for these systems, and there is presumably no
difficulty in isolating or storing them. On the other hand, attempts
to prepare 9-p-nitrophenyl-2,4,6-trimethyl-2,4,6-(Z,Z,E)-hexatrien-
1-ol led to the conclusion that this alcohol is unstable.5a
Scheme 3. Tandem Reaction in the Model System
Having established the anticipated [1,7]-hydrogen shift to be
an efficient process, we turned our attention to its application in
the total synthesis. At this point, we needed to select a coupling
strategy that would lead to the biomimetic intermediate 5. For the
approach outlined in Scheme 2, we needed (E,E)-iododiene 6.
The desired iododiene 6 was obtained by defunctionalization
of iodo ester 14, itself prepared by a StillÀGennari reaction
with iodo reagent 1315,16 (Scheme 4). This four-step scheme17
utilized one chromatographic separation (of 15 from small
amounts of its E,Z isomer) and afforded the desired iododiene
6 quite cleanly from the reduction of bromide 16.18
Coupling of iododiene 6 with stannane 7 under the conditions
that had proven successful in the model system gave arabilin (1)
directly in 73% yield (Scheme 5). The optical rotation of our
synthetic arabilin was À139.4° (c 0.33, CHCl3, 20À21 °C),
whereas the value reported for the natural product was À166.2°
(c 0.13, CHCl3, 25 °C). The calculated enantiomeric excess of
our synthetic material was 84%.19 The correlation confirms the
assignment of the C-6 asymmetric center in arabilin as R.
The first total synthesis of (À)-arabilin requires 15 steps in the
longest linear sequence and 19 steps total from commercially
available starting materials. It demonstrates the effective use of a
[1,7]-hydrogen shift as a key step in total synthesis and supports
the premise that this rearrangement is a nonenzymatic step in the
biosynthesis of this interesting natural product.
shift in a closely related model system. Thus, iodotriene 8
(prepared as described in the Supporting Information) and
vinylstannane 911 were exposed to the Pd(0)/CuTC catalytic
system12 at room temperature. Monitoring of the coupling re-
action by TLC revealed the formation of a yellow product after
approximately 2 h and its subsequent disappearance concurrent
with the formation of a new colorless product. Enol silyl ether 11,
the product of coupling followed by [1,7]-hydrogen migration,
was isolated in 51% yield. These results are consistent with the
formation of tetraene 10 and its in situ thermal conversion to
enol ether 11 (Scheme 3).
We believe that this report represents only the third account of
a [1,7]-hydrogen shift that provides an enol ether product.13
Furthermore, this reaction is clearly exothermic, suggesting in-
teresting extensions in methodology development.
An analysis of the rearrangement of intermediate 10 in the
context of the literature on related compounds is consistent with
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
characterization of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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’ AUTHOR INFORMATION
(18) Chakraborty, T. K.; Goswami, R. K.; Sreekanth, M. Tetrahedron
Lett. 2007, 48, 4075–4078.
(19) In this asymmetric synthesis, the enantiomeric excess of the
final product was similar to that obtained from the same iodopyrone
intermediate in our synthesis of SNF4435 C and D (see ref 10).
Corresponding Author
kparker@notes.cc.sunysb.edu
’ ACKNOWLEDGMENT
We are grateful to the National Institutes of Health (GM
74776) and to Stony Brook University for financial support of
this work. In addition, we thank the National Science Foundation
for a grant to Stony Brook University for the purchase of NMR
instrumentation (CHE-0131146).
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