Enantioselective synthesis of bicarbocyclic structures with an all-carbon quaternary stereocenter through sequential cross metathesis and intramolecular Rauhut-Currier reaction

Article abstract of DOI:10.1016/j.tetlet.2010.03.026

A new extension of the Birch-Cope sequence is described which allows the efficient enantioselective construction of highly functionalized, fused bicarbocyclic structures with an all-carbon quaternary stereocenter in two steps. The two-step sequence includes a cross metathesis between a terminal alkene and a polarized alkene followed by an intramolecular Rauhut-Currier reaction with a trialkylphosphine catalyst.

Full text of DOI:10.1016/j.tetlet.2010.03.026

Tetrahedron Letters 51 (2010) 2636–2638
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Tetrahedron Letters
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Enantioselective synthesis of bicarbocyclic structures with an all-carbon
quaternary stereocenter through sequential cross metathesis and
intramolecular Rauhut–Currier reaction
*
Yuan Qiao, Sanjeev Kumar, William P. Malachowski
Chemistry Department, Bryn Mawr College, Bryn Mawr, PA 19010, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new extension of the Birch–Cope sequence is described which allows the efficient enantioselective con-
struction of highly functionalized, fused bicarbocyclic structures with an all-carbon quaternary stereo-
center in two steps. The two-step sequence includes a cross metathesis between a terminal alkene and
a polarized alkene followed by an intramolecular Rauhut–Currier reaction with a trialkylphosphine
catalyst.
Received 29 January 2010
Revised 5 March 2010
Accepted 8 March 2010
Available online 12 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
The enantioselective synthesis of fused bicarbocyclic structures
containing all-carbon quaternary stereocenters is an important
activity in organic synthesis. Due to their intriguing complex
chemical architecture and their potential therapeutic applications,
these structures have attracted the attention of synthetic chemists
for many decades. Recent examples of bicarbocyclic structures
with all-carbon quaternary stereogenic centers that have fomented
synthetic activity include the cyanthiwigins,1–6 the guanacastap-
enes,7–10 and platensimycin.11–16 One of the most common tools
to enantioselectively generate these structures is the Hajos–Par-
rish–Eder–Sauer–Weichert reaction.17–19 In fact, the popularity of
this reaction in natural product synthesis is another indication of
the demand for bicarbocyclic architectures, which can serve as
key intermediates in complex molecule construction.
systems can be merged to form a new ring while retaining one con-
jugated system for subsequent functionalization. Application of the
intramolecular Rauhut–Currier reaction to the cross metathesis
product 3 should afford valuable intermediates 4 on the path to
a range of complex chemical architectures. Details of the successful
transformation of 2–4 are presented herein.
The Birch–Cope sequence product 2 was subjected to cross
metathesis in the presence of an alkene (3–20 equiv) and the
second generation Hoveyda-Grubbs (HG2, 2.5 mol %) catalyst.
With the interest of developing new tools to create enantiome-
rically pure bicarbocyclic structures with all-carbon quaternary
stereocenters in an angular position, we have extended our
Birch–Cope sequence (Scheme 1)20,21 to rapidly create several such
structures with the hydrindane skeleton. The procedure selectively
functionalizes the terminal alkene of the Birch–Cope sequence
product 2 with a Grubbs cross metathesis reaction22 and then per-
forms an intramolecular Rauhut–Currier reaction with trialkyl-
phosphine to afford 4 (Scheme 1). One-pot tandem reactions,
such as the Rauhut–Currier reaction, are important for the efficient
construction of complex chemical structures and therefore are an
active research area in the synthetic community.23–31 The intramo-
lecular Rauhut–Currier reaction32 has experienced a resurgence
based on groundbreaking studies by Krische,33 Murphy,34,35 and
Roush.36 Under the influence of catalytic phosphine, conjugated
* Corresponding author. Tel.: +1 610 526 5016; fax: +1 610 526 5086.
E-mail address: wmalacho@brynmawr.edu (W.P. Malachowski).
Scheme 1. Olefin cross metathesis and Rauhut–Currier reaction to bicarbocyclic
structures with an all-carbon quaternary stereocenter in an angular position.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.03.026

Y. Qiao et al. / Tetrahedron Letters 51 (2010) 2636–2638
2637
Table 1
Olefin cross metathesis and Rauhut–Currier reaction
EWG
Yield (%)
87
E/Z ratio
ꢀ8.5:1
Conditions
Yield (%)
a
–C(@O)CH3
PBu3(0.3 equiv), CH2Cl2, 0 °C to rt
81
b
c
E only
ꢀ9:1
86
PBu3(0.3 equiv), CH3CN, 0 °C to rt
91
d
e
f
–C(@O)OCH3
–C(@O)OH
–S(O)2Ph
82
86
41
ꢀ30:1
N.D.
N.D.
PMe3(0.4 equiv), t-BuOH/THF,
D
81
no rxn
no rxn
Initially, the Grubbs second generation (G2) catalyst was tested, but
the reaction proved more efficient with HG2. Previous reports37,38
have described similar reactivity differences in Grubbs catalysts
used for related cross metathesis examples. In all cases, an excess
of alkene was essential for maximizing the conversion of 2.39 As
has been previously reported,22 the cross metathesis was amenable
to a variety of alkenes (Table 1). Alkenes functionalized with a ke-
tone, 1,3-dioxolane, ester, acid, and sulfone were all successful,
although the sulfone was markedly less efficient. The cross metath-
esis reactions predominantly or exclusively formed the E alkene
isomer.
A variety of Rauhut–Currier conditions, which modified both
phosphine and solvent, were explored to determine the optimum
method for conversion of 3–4 (Table 1).33–36 Consistent with previ-
ously reported tendencies in the Rauhut–Currier reaction,32 the
relatively more electrophilic alkenes in 3a and 3c easily underwent
tandem conjugate addition/Michael addition and subsequent
phosphine elimination to afford the products 4a and 4c, respec-
tively, in high yield. The regioselectivity of the tandem reaction
in 3a and 3c is presumably based on both electronic and steric
principles. Although the ring alkene might initially be considered
the more electrophilic alkene with two carbonyl substituents, our
previous studies20,21 have shown that the C-2 amide prefers to
adopt a more orthogonal conformation with respect to the ring
pi system for steric reasons. Therefore, the C-2 amide is unlikely
to contribute to ring alkene electron deficiency. Furthermore, the
vicinal quaternary center of the ring alkene undoubtedly also con-
tributes to a regioselective reaction at the least hindered alkene
beta position. Finally, the product resulting from initial conjugate
addition to the ring enone system would not be capable of elimi-
nating phosphine after subsequent Michael addition and therefore
would not generate a thermodynamically stable product.
reaction.32 Interestingly, the sequential enoate, then enone order
of addition witnessed in 3d is extremely rare with only one other re-
ported example to the best of our knowledge.40 Failure to react in the
more typical enone, then enoate order is again probably due to the
steric hindrance of the ring enone and the inability of the product
to eliminate phosphine. Despite repeated attempts to apply the con-
ditions that were used with 3d, acid 3e and sulfone 3f were resistant
to any Rauhut–Currier annulation procedure. The products of the
Rauhut–Currier reaction were epimerizable at the C-2 stereocenter,
but they were not separable and simple computational studies sug-
gest that the cis isomer is more thermodynamically stable. Equili-
bration between the two epimers was accomplished with heating
in the presence of an acid (1:1 2 M H2SO4/THF).
Removal of the chiral auxiliary was accomplished in the stan-
dard manner previously reported41,21 to form the isoxazolinone 5
(Scheme 2). Removal of the chiral auxiliary and formation of the
isoxazolinone eliminated epimerization and allowed for easier
spectroscopic and chromatographic analysis of the product.
In conclusion, a new extension of the Birch–Cope sequence is
reported which allows the efficient enantioselective construction
of highly functionalized hydrindane skeletons containing an
all-carbon quaternary stereocenter in an angular position. The pro-
cedure couples cross metathesis and an intramolecular Rauhut–
Currier procedure to generate the fused bicarbocyclic structures
in two steps.
Acknowledgments
We thank the Petroleum Research Fund (PRF #43238-AC1)
administered by the American Chemical Society and Bryn Mawr
College for their generous financial support of this work. Financial
support (to Y.Q.) through the Irena Bronstein-Bonte Fellowship is
gratefully acknowledged.
The less electrophilic alkenes such as 3d, 3e, and 3f were more
problematic, as expected based on prior art. Nevertheless, 3d was
successfully transformed to 4d with the use of the more reactive
trimethylphosphine and a polar, protic solvent, t-BuOH. Solvent
effects have been previously recognized in the Rauhut–Currier
reaction with polar, protic solvents generally accelerating the
Supplementary data
Supplementary data (general experimental details, copies of 1H
and 13C NMR spectra, gas and liquid chromatographs and mass
spectra for compounds 3a–d, 4a, 4c, 4d and 5. COSY and HMQC
for 5) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2010.03.026.
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