Enantioselective C-C bond cleavage creating chiral quaternary carbon centers

Article abstract of DOI:10.1021/ol061359g

A chiral all-carbon benzylic quaternary carbon center is created by the asymmetric intramolecular addition/ring-opening reaction of a boryl-substituted cyclobutanone, which involves enantioselective β-carbon elimination from a symmetrical rhodium cyclobutanolate. The asymmetric reaction was successfully applied to a synthesis of sesquiterpene, (-)-α-herbertenol.

Full text of DOI:10.1021/ol061359g

ORGANIC
LETTERS
2006
Vol. 8, No. 15
3379-3381
Enantioselective C−C Bond Cleavage
Creating Chiral Quaternary Carbon
Centers
Takanori Matsuda, Masanori Shigeno, Masaomi Makino, and Masahiro Murakami*
Department of Synthetic Chemistry & Biological Chemistry, Kyoto UniVersity, Katsura,
Kyoto 615-8510, Japan
murakami@sbchem.kyoto-u.ac.jp
Received June 3, 2006
ABSTRACT
A chiral all-carbon benzylic quaternary carbon center is created by the asymmetric intramolecular addition/ring-opening reaction of a boryl-
substituted cyclobutanone, which involves enantioselective -carbon elimination from a symmetrical rhodium cyclobutanolate. The asymmetric
â
reaction was successfully applied to a synthesis of sesquiterpene, (−)-r-herbertenol.
Chiral all-carbon quaternary centers are often contained in
natural products and pharmaceuticals, yet the synthesis of
such centers with control of asymmetry remains a significant
challenge for synthetic chemists.1 A few methods can be
envisaged for the asymmetric construction of chiral quater-
nary centers (Scheme 1). A direct method to achieve this
transformation is by the stereoselective introduction of a
carbon-carbon bond onto an unsymmetrically gem-disub-
stituted sp2 carbon of an olefin (A) or onto a tertiary sp3
carbon with resident chirality (B). In these carbon-carbon
bond-forming methods, the stereochemical information is
installed at a highly sterically congested carbon. The de-
symmetrization of a preinstalled symmetrically substituted
quaternary carbon center would also provide convenient
access to chiral quaternary centers. This alternative pathway
(C) dispenses with the need to form a carbon-carbon bond
with control of asymmetry in the midst of significant steric
congestion.
Scheme 1
We previously reported the rhodium-catalyzed intermo-
lecular reaction of arylboronic acids with cyclobutanones,
which produces arylated ketones through a 1,2-addition to
the carbonyl group and subsequent ring-opening of the
resulting rhodium cyclobutanolates by â-carbon elimination.2
We envisioned that selective cleavage of one of the two
prochiral carbon-carbon single bonds of a symmetrical
cyclobutane skeleton would open an avenue for the asym-
(1) Reviews on asymmetric construction of quaternary carbon centers:
(a) Fuji, K. Chem. ReV. 1993, 93, 2037. (b) Corey, E. J.; Guzman-Perez,
A. Angew. Chem., Int. Ed. 1998, 37, 388. (c) Christoffers, J.; Mann, A.
Angew. Chem., Int. Ed. 2001, 40, 4591. (d) Denissova, I.; Barriault, L.
Tetrahedron 2003, 59, 10105. (e) Christopher, J. D.; Overman, L. E. Proc.
Nat. Acad. Sci. U.S.A. 2004, 101, 5363. (f) Christoffers, J., Baro, A., Eds.
Quaternary Stereocenters; Wiley-VCH: Weinheim, 2005.
(2) (a) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6, 1257.
(b) Matsuda, T.; Makino, M.; Murakami, M. Bull. Chem. Soc. Jpn. 2005,
78, 1528. (c) Matsuda, T.; Makino, M.; Murakami, M. Angew. Chem., Int.
Ed. 2005, 44, 4608.
10.1021/ol061359g CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/20/2006

metric synthesis of chiral quaternary carbon centers via
pathway C in Scheme 1.3 In this paper, we report the
rhodium-catalyzed asymmetric synthesis of 1-indanones
having benzylic quaternary carbon centers4 and the applica-
tion of this method to a synthesis of a naturally occurring
sesquiterpene, (-)-R-herbertenol.
Scheme 3. Rhodium-Catalyzed Addition/Ring-Opening of 3a
To achieve the desymmetrization reaction, we prepared
cyclobutanone 3a having a 2-borylphenyl group at the
3-position (Scheme 2). An o-bromostyrene derivative was
Scheme 2. Synthesis of Boryl-Substituted Cyclobutanone 3aa
Our attention was then focused on an asymmetric version
of the ring-opening reaction. Various chiral phosphine ligands
were examined, and good enantioselectivities were observed
with chiral biaryl diphosphine ligands. Representative results
are listed in Table 1. The (S)-SEGPHOS ligand induced the
best enantioselectivity of 95% ee for the reaction of 3a (entry
1). The use of diphosphine ligands possessing a wider bite
angle than SEGPHOS resulted in a decrease in enantiose-
lectivity (entries 2 and 3).8 The same trend was observed
among the three chiral ligands in the reaction of 3b, and
product 4b was obtained in 79% ee with SEGPHOS (entries
4-6). Cyclobutanone 3c, having a bulky isopropyl group at
the 3-position, also yielded 4c in 94% ee although the
reaction required higher catalyst loading and longer reaction
time (entry 7).
The synthetic potential of the intramolecular addition/ring-
opening reaction was demonstrated by application in the
asymmetric synthesis of a sesquiterpene, (-)-R-herbertenol
(13),10 which exhibits a range of biological properties
including antifungal activity.11 In a manner similar to that
for the synthesis of 3a from 1 (Scheme 2), aryl ketone 7,
prepared from 2-bromo-5-methylbenzaldehyde (6), was
transformed to the symmetrical cyclobutanone 8, armed with
an arylboronic acid moiety (Scheme 4). The rhodium-
prepared by methylenation of 2-bromophenyl ethyl ketone
(1) with the Petasis reagent. Subsequent [2 + 2] cycload-
dition with dichloroketene followed by dechlorination with
zinc afforded cyclobutanone 2. After the carbonyl group was
protected as a cyclic ketal, the o-bromo group was trans-
formed into a boronic acid functionality. Deprotection of the
ketal group, followed by treatment with pinacol furnished
3a, equipped with a symmetrically substituted quaternary
center and two prochiral carbon-carbon single bonds which
were potentially amenable to enantioselective cleavage.
When boryl-substituted cyclobutanone 3a was heated in
1,4-dioxane-H2O (20:1) in the presence of a rhodium(I)
catalyst (10 mol % of Rh, Rh/DPPB5 ) 1:1) at 100 °C for
6 h, an intramolecular addition/ring-opening reaction oc-
curred to afford 3-ethyl-3-methyl-1-indanone (4a) in 87%
yield (Scheme 3). Mechanistically, the reaction proceeds via
(i) transmetalation of the boryl group of 3a with rhodium-
(I), (ii) intramolecular addition of the arylrhodium species
to the carbonyl group, forming a symmetrical bicyclo[2.1.1]-
hexane skeleton, (iii) ring-opening of the cyclobutanolate
moiety by â-carbon elimination,6 and (iv) protonolysis7 to
furnish a methyl group. Thus, the original symmetrically
substituted quaternary carbon center at the benzylic position
of 3a was desymmetrized in 4a.
(6) For recent examples of synthetic application of â-carbon elimination
with transition metal cyclobutanolates, see: (a) Pd: Nishimura, T.; Uemura,
S. Synlett 2004, 201. (b) Ni: Murakami, M.; Ashida, S.; Matsuda, T. J.
Am. Chem. Soc. 2005, 127, 6932.
(7) Deuterium labeling experiments revealed that 1,4- and 1,3-Rh shifts
occurred prior to protonolysis. See the Supporting Information for further
details.
(8) Dihedral angles (θ) of free phosphines: SEGPHOS 67.2°; MeO-
BIPHEP 72.3°; BINAP 86.2°. Jeulin, S.; Duprat de Paule, S.; Ratovelo-
manana-Vidal, V.; Geneˆt, J.-P.; Champion, N.; Dellis, P. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5799.
(9) 4a (R ) Et): Hill, R. K.; Newkome, G. R. Tetrahedron 1969, 25,
1249.
(3) For analogous reaction creating a chiral center by â-carbon elimination
from Pd(II) cyclobutanolate, see: Matsumura, S.; Maeda, Y.; Nishimura,
T.; Uemura, S. J. Am. Chem. Soc. 2003, 125, 8862.
(4) For recent examples of asymmetric synthesis of 3,3-disubstituted
1-indanones, see: (a) Shintani, R.; Hayashi, T. Org. Lett. 2005, 7, 2071.
(b) Fillion, E.; Wilsily, A. J. Am. Chem. Soc. 2006, 128, 2774.
(5) DPPB ) 1,4-bis(diphenylphosphino)butane.
(10) For asymmetric total synthesis of 13: (a) Abad, A.; Agullo´, C.;
Cun˜at, A. C.; Perni, R. H. J. Org. Chem. 1999, 64, 1741. (b) Kita, Y.;
Futamura, J.; Ohba, Y.; Sawama, Y.; Ganesh, J. K.; Fujioka, H. J. Org.
Chem. 2003, 68, 5917. ent-13: (c) Srikrishna, A.; Babu, N. C.; Rao, M. S.
Tetrahedron Lett. 2004, 60, 2125 and references therein.
(11) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Perkin Trans.
1 1986, 701.
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Org. Lett., Vol. 8, No. 15, 2006

Scheme 4. Synthesis of (-)-R-Herbertenol (13)a
Table 1. Asymmetric Synthesis of Indanones 4a
entry
3
R
L*
4
% yieldb % eec,d
1
2
3
4
5
6
7e
3a Et
3a Et
3a Et
3b Ph
3b Ph
3b Ph
(S)-SEGPHOS
(R)-MeO-BIPHEP 4a
(S)-BINAP
(S)-SEGPHOS
(R)-MeO-BIPHEP 4b
(S)-BINAP
4a
96
98
93
93
97
97
81
95 (S)
75 (R)
69 (S)
79
60
36
4a
4b
4b
4c
3c i-Pr (S)-SEGPHOS
94
a The reaction was carried out with 3, [RhCl(CH2dCH2)2]2 (3.5 mol %,
7 mol % Rh), chiral phosphine (7 mol %), and K3PO4 (0.5 equiv) in
dioxane-H2O (20:1) at 100 °C for 4-5 h. b Isolated yield by preparative
TLC. c For 4a and 4c, the enantiomeric excess (ee) was determined by chiral
GC analysis. For 4b, the enantiomeric excess (ee) was determined by chiral
HPLC analysis. d The absolute configuration in parentheses was determined
by comparing optical rotation with reported value.9 e 7 mol % of
[RhCl(CH2dCH2)2]2 and 14 mol % of (S)-SEGPHOS for 12 h.
catalyzed asymmetric addition/ring-opening reaction of 8
using SEGPHOS afforded indanone 9 in 93.7% ee (84%
chemical yield). Subsequent Baeyer-Villiger oxidation with
m-CPBA caused migration of the aryl group to afford lactone
10, whose ester linkage was then cleaved with NaOH. Both
hydroxy and carboxy groups were methylated with Me2SO4.
Finally, the benzyloxy group was transformed to a bromo
group affording 12. The bromo ester 12 was transformed to
R-herbertenol 13 according to the procedure reported by
Mukherjee12 in order to determine the absolute configuration
of the quaternary center. Measurement of the optical rotation
of 13 established that the absolute stereochemistry was that
of the natural enantiomer.
carbon center. The utility of the desymmetrization process
was demonstrated by application to a synthesis of (-)-R-
herbertenol.
Acknowledgment. We thank Takasago International
Corp. for its generous gift of (S)-SEGPHOS. T.M. acknowl-
edges a support by Eisai Award in Synthetic Organic
Chemistry, Japan.
In summary, we have developed a method for the
enantioselective cleavage of a carbon-carbon single bond
by â-carbon elimination to create a chiral benzylic quaternary
Supporting Information Available: Experimental pro-
cedures and NMR spectral data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Paul, T.; Pal. A.; Gupta, P. D.; Mukherjee, D. Tetrahedron Lett.
2003, 44, 737.
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