Diastereoselective Pt catalyzed cycloisomerization of polyenes to polycycles

Article abstract of DOI:10.1021/ja500656k

Application of a tridentate NHC containing pincer ligand to Pt catalyzed cascade cyclization reactions has allowed for the catalytic, diastereoselective cycloisomerization of biogenic alkene terminated substrates to the their polycyclic counterparts.

Full text of DOI:10.1021/ja500656k

Communication
pubs.acs.org/JACS
Diastereoselective Pt Catalyzed Cycloisomerization of Polyenes to
Polycycles
Michael J. Geier and Michel R. Gagne*
́
Caudill Laboratories, Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
27599-3290, United States
S
* Supporting Information
protodemetalation. Our catalyst design features centered on the
ABSTRACT: Application of a tridentate NHC containing
pincer ligand to Pt catalyzed cascade cyclization reactions
has allowed for the catalytic, diastereoselective cyclo-
isomerization of biogenic alkene terminated substrates to
the their polycyclic counterparts.
hypothesis that the electrophilic activation of a coordinated
alkene would be principally controlled by its trans ligand, while
its two cis ligands would primarily impact the facility with which
it could be oxidized at the Pt-alkyl stage. This led us to seek a
pincer ligand with a poorly donating trans ligand and strongly
donating cis ligands. Limbach et al. have recently reported the
hydrovinylation13 and hydroamination14 of ethylene mediated
by a series of Pt catalysts engendering these target features, two
cis NHC ligands and a trans pyridine.
he construction of complex polycyclic hydrocarbon
T
frameworks from simple polyene substrates by cyclaze
enzymes (e.g., eq 1) has long been the envy of synthetic
chemists.1 The remarkably selective fashion in which products
are formed has attracted a variety of biomimetic approaches.2
Of note are recent reports in which cyclization is initiated by
organocatalysts,3 M+,4 H+,5 and X+ reagents.6
We initiated our studies by examining the ability of complex
1 to induce cyclization of 2. Remarkably, after only 3 h at room
temperature, complete conversion to the cyclization/proto-
nolysis product 3 was observed. Surprisingly, the cyclization
proceeded in the absence of added base and provided none of
the previously observed Brønsted acid catalyzed monocycliza-
tion product 4,15 which reports on the buildup of acid; i.e., H+
is rapidly consumed in situ.
The formation of polycycles via cascade cyclization reactions
has long benefitted from the installation of nucleophilic
terminating groups, which enhance the efficiency of the
cyclization.1,2 By contrast, the cyclization of strictly hydro-
carbon containing substrates must overcome the lack of H-
bond assistance in the terminating alkene, often leading to slow
reactions and incomplete cyclization. While aryl terminating
groups have been well tolerated as a result of cation−π
stability,4a,e,5a,b,6a,b few examples of strictly polyene containing
substrates are known.4d,7
We have previously reported the synthesis of polycyclic Pt-
alkyl compounds from simple and complex polyenes using
Pt(triphos)2+ as the cyclization initiator (eq 2).8,9 The
triphosphino pincer ligand renders the resulting Pt-alkyl
compounds remarkably stable, but susceptible to Pt−C bond
functionalization with strongly oxidizing agents (e.g., F+ or
Cu2+).10 We also considered the feasibility of an alternative
oxidant, H+, which oxidatively protonates the metal as the first
elementary step in the protodemetalation of a PtII−C bond.11
By following a Pt(II) initiated electrophilic cascade cyclization
with an oxidative protonolysis scheme, we sought a cyclization/
protonation approach to sterol-like polycyclic compounds.
Despite the desirability of such an atom economical cyclo-
isomerization procedure, this goal required a solution to the
high stability of Pt-alkyl cations to acid.12
Our working mechanism has the reaction being initiated by
selective coordination of the Pt electrophile to the least
substituted alkene,16 and subsequent ionic cyclization to B with
liberation of H+ from the phenol terminating group (Scheme
1). Protodemetalation of B generates 3 and regenerates the Pt
catalyst. The lack of 4 indicates that H+ never builds up and it
reacts more quickly with B than it does with 2.
Intrigued by the efficiency with which 1 induces cyclization
in phenol terminating substrate 2, we explored its applicability
with the significantly more challenging alkene terminating
groups.8b Remarkably, 1 proved effective at initiating the
diastereoselective cyclization of a variety of polyene substrates.
Bi-, tri-, and tetracyclization reactions all proceeded in the
presence of 10% 1. Additionally tolerated were terminating
To facilitate such a scheme, we required a catalyst that was
not only sufficiently electrophilic to initiate the cation olefin
cyclization but also electron rich enough to undergo rapid
Received: January 21, 2014
Published: February 11, 2014
© 2014 American Chemical Society
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Scheme 1. Polyene Cycloisomerization Mechanism
Table 1. Polyene Cycloisomerization
reactions to generate tertiary carbenium ions via 5-exo, 6-endo,
and 6-exo cyclization geometries.
Reaction times varied, from 5 h for 9 to up to 2 days for the
slower bicyclization reactions (e.g., 5). While the bicyclizations
of 5 and 7 do not proceed to completion after 48 h, addition of
20 mol % Ph2NH as a proton shuttle allows for full
consumption of starting material (e.g., 5) and shorter reaction
times (e.g., 7, <24 h). Thus a positive role for a proton shuttle
is noted, at least for some problematic cascade reactions.
In addition to the 2→3 transformation and the faster
protonolysis of B than 2, the cyclization of 9→10 also reports
on a low steady-state concentration of H+, as 10 is prone to
conversion to 23 under acidic conditions (Scheme 2).17 In this
Scheme 2. Conversion of Kinetic Product 10 to
Thermodynamic Product 23
case, formation of 10 uncontaminated with 23 again suggests
that Pt-alkyl protodemetalation occurs quickly, in this situation
faster than alkene isomerization. As Yamamoto has previously
observed using a Brønsted−Lewis acid (BLA) catalyst, the aryl
ether substrate 11 cyclizes to rearranged 12.18
a
b
Products formed as a single diastereomer. Conditions: 1 (0.015
c
mmol), substrate (0.15 mmol), solvent (1 mL). Ph2NH (0.030
Cyclization of 15 also proceeded rapidly to a mixture of two
products, the desired tricyclization product with 5-contiguous
stereocenters and an unknown bicyclic product. Compound 16
terminates the C-ring with a 3° cation-generating 6-exo
cyclization followed by elimination (23% yield, Table 1). In a
rare example of premature termination in Pt-initiated cascade
cyclizations, an unidentified bicyclic product is competitively
generated (46% yield, see Supporting Information (SI)).
For 19 to terminate in a 3° carbocation requires a C-ring 5-
exo cyclization, the carbenium ion from which is particularly
prone to Wagner−Meerwein rearrangements.7a,8b In this way
the thermodynamically more stable tetrasubstituted alkene
product 20 forms from a combination of hydride/methyl shift
and subsequent elimination (39%). A compound consistent
with 24 is formed as a minor product (10%; see SI), likely the
result of a single hydride shift that instead eliminates to give the
trisubstituted alkene (Scheme 3).
mmol).
Scheme 3. Competing Wagner−Meerwein Rearrangement of
a Polycyclic Cation Intermediate Derived From 19
terminates the D-ring in a 5-exo manner to generate an exocylic
tertiary cation akin to the protosterol cation observed in the
conversion of 2,3-oxidosqualene to lanosterol (Scheme 4).
From this exocyclic cation, a methyl and a hydride shift
generates a tertiary cation at C13, with elimination to C14
creating the unsaturation at the C/D ring junction.19 In
contrast, from the protosterol cation, a series of two hydride
Finally, cyclization of 21 provided the tetracycle 22 in 44%
yield, forming five stereocenters and providing the 6−6−6−5
sterol framework in a single step. Initial cyclization again
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NMR experiments and Dr. Mee-Kyung Chung for assistance
with HRMS.
Scheme 4. Terminating Events in Cyclization of 2,3-
Oxidosqualene and 21
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures as well as spectroscopic data are
available in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
mgagne@unc.edu
■
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
The NIH (GM-60578) is thanked for their generous support.
M.J.G. thanks NSERC of Canada for a Postgraduate Scholar-
ship. The authors thank Laura L. Adduci for assistance with
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