Highly enantioselective proton-initiated polycyclization of polyenes

Article abstract of DOI:10.1021/ja305851h

This report describes the synthesis of a range of chiral polycyclic molecules (tricyclic to pentacyclic) from achiral polyene precursors by enantioselective proton-initiated polycyclization promoted by the 1:1 complex of o,o′-dichloro-BINOL and SbCl₅. Excellent yields (ca. 90% per ring formed) and enantioselectivety (20:1 to 50:1) were obtained. The process is practical as well as efficient, because the chiral ligand is both readily prepared from R,R- or S,S-BINOL and easily recovered from the reaction mixture by extraction.

Full text of DOI:10.1021/ja305851h

Communication
pubs.acs.org/JACS
Highly Enantioselective Proton-Initiated Polycyclization of Polyenes
Karavadhi Surendra and E. J. Corey*
Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States
S
* Supporting Information
chiral proton source that might both selectively activate the
ABSTRACT: This report describes the synthesis of a
terminal C−C double bond of a polyene and control the
range of chiral polycyclic molecules (tricyclic to
pentacyclic) from achiral polyene precursors by enantio-
selective proton-initiated polycyclization promoted by the
1:1 complex of o,o′-dichloro-BINOL and SbCl5. Excellent
yields (ca. 90% per ring formed) and enantioselectivety
(20:1 to 50:1) were obtained. The process is practical as
well as efficient, because the chiral ligand is both readily
prepared from R,R- or S,S-BINOL and easily recovered
from the reaction mixture by extraction.
absolute configuration of the product. We were aware of the
findings of Yamamoto’s group that complexes of the BINOL
monoether type with SnCl4 can initiate cation−olefin
cyclization with modest enantioselectivity.6
Our approach was guided by the conjecture that the
enantioselectivity and terminal CC selectivity of cation−
polyolefin cyclization might be improved by the use of a bulkier
and stronger Lewis acid than SnCl4. It was also surmised that
there might be additional benefit in increasing the acidity of the
BINOL derivative. Thus, we arrived at o,o′-dichloro-BINOL7 as
ligand and SbCl5 as the Lewis acid 5. We were very gratified to
find that the 1:1 complex of these simple components was
indeed a much stronger and more enantioselective polycycliza-
tion catalyst than those previously studied. The reactions
reported herein with the new catalyst occurred rapidly at −78
°C and provided the polycyclic product with remarkable
enantioselectivity, generally in the range 20−50:1. A typical
example of such cyclization is shown in Scheme 3.
he unmatched synthetic power of the enzymatic
T
conversion of (S)-2,3-oxidosqualene (1) to polycyclic
triterpenoids, as exemplified by the one-step biosynthesis of
lanosterol (2) shown in Scheme 1, has provided inspiration and
Scheme 1. Biosynthesis of Lanosterol
Scheme 3. Synthesis of Chiral Tetracycle
challenge to synthetic chemistry.1,2 Although the synthesis of
many polycyclic terpenoids, for instance, the pentacyclic
triterpenoid lupeol,3 has been greatly facilitated by the
application of cation−olefin polycyclization, the area clearly
requires further development to achieve its full potential.4
We recently reported that indium(III) iodide or bromide can
selectively activate C−C triple bonds and initiate cation−olefin
polycyclization, as exemplified by the one-step process 3 → 4
shown in Scheme 2.5 In this transformation In(III) functions as
a proton equivalent, and the initiating propargylic stereocenter
controls the absolute configuration of the product, which is
formed with complete diastereoselectivity. As a result of this
research we were encouraged to search for a strongly acidic,
The results for the R,R-5-catalyzed cyclization of an
additional eight substrates are summarized in Table 1 for four
cases of bicyclization and Table 2 for four tricyclization
reactions. Absolute stereochemistry was established by X-ray
crystallographic analysis of the tetracyclic reaction product, mp
110−112 °C, which was formed diastereoselectively in 84%
yield.8 The absolute configurations for the other products
shown in Tables 1 and 2 (all from R,R-5) were assigned by
analogy. In addition, the optical rotation of the product in
Table 1, entry 1, was close to that reported for a 4-
methylphenyl analogue of 6.6
Scheme 2. In(III)-Catalyzed Enantioselective Cationic
Polycyclization
Received: June 19, 2012
Published: July 10, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
crude cyclization product by extraction with aqueous sodium
hydroxide, and recovered (>95%) simply by acidification and
extraction. Thus, the use of o,o′-dichloro-BINOL, which is
readily made from BINOL,7 is practical even at 100 mol %.
The SbCl5 complex 5 is far superior as an enantioselective
proton donor in the type of cyclization described herein to the
corresponding complexes with In(III), Al(III), or Ti(IV) in
terms of reaction rate and enantioselectivity. It was also
ascertained that o,o′-dimethyl-BINOL and o,o′-diphenyl-BINOL
were unsatisfactory as catalysts, leading to much diminished
enantioselectivities.
Table 1. (R)-BINOL-SbCl5 (0.5 equiv)-Catalyzed
Polycyclization in CH2Cl2 at −78 °C
Figure 1. Pre-transition-state assembly for the cationic cyclization
initiated by proton transfer from catalyst 5.
a
b
Isolated yields of products fully characterized by NMR and MS. ee
determined by HPLC analysis using a Chiralcel OD-H column.
c
Cyclization occurred both para and ortho to Br.
The SbCl5 complex 5 may be of value for other proton-
accelerated reactions in which stereocenters are created from
achiral starting materials, and studies along these lines are in
progress. The absolute stereochemical course of the cyclizations
described herein can be explained rationally in terms of a
concerted protonation and cyclization process9 in which the
terminal CC is protonated π-face-selectively by 5 with a π−π
intraction between the developing cation and one of the
naphthyl subunits of 5 (see Figure 1).
Table 2. (R)-BINOL-SbCl5 (1.0 equiv)-Catalyzed
Polycyclization in CH2Cl2 at −78 °C
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for all
reactions and products, including H and 13C NMR spectra
1
and a CIF file. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
corey@chemistry.harvard.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
b
We are grateful to Pfizer Inc. for a postdoctoral fellowship to K.
S. and to Dr. S.-L. Zheng from Harvard University and Dr. Y.-S.
Chen at ChemMatCARS, APS, for the X-ray crystallographic
analysis.
Isolated yields of products fully characterized by NMR and MS. ee
determined by HPLC analysis using a Chiralcel OD-H column.
c
Cyclization occurred both para and ortho to OR.
The various substrates for these cyclization studies were
obtained starting with geraniol or farnesol acetate by the type of
copper-catalyzed cross-coupling shown in Scheme 3 for the
synthesis of the cyclization precursor 6. Cyclizations were
carried out at −78 °C in CH2Cl2 with reaction times in the
range of 4−6 h, using thin-layer chromatographic analysis to
follow the progress of the reaction. From 50 to 100 mol % of
catalyst was used. The ligand for 5 was easily removed from the
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■
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Journal of the American Chemical Society
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