Asymmetric synthesis of 4,4-disubstituted 2-cyclopentenones from optically active 1-chlorovinyl p-tolyl sulfoxides and cyanomethyllithium with formation of a quaternary chiral center

Article abstract of DOI:10.1016/S0040-4039(01)02034-2

Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which were synthesized from unsymmetrical ketones and (R)-(-)-chloromethyl p-tolyl sulfoxide in three steps, with cyanomethyllithium gave optically active 2-amino-1-cyano-5,5-disubstituted-1,3-cyclopentadienes with very high asymmetric induction from the sulfoxide chiral center. The products were converted to the enantiomerically pure 4,4-disubstituted 2-cyclopentenones by heating with phosphoric acid in acetic acid.

Full text of DOI:10.1016/S0040-4039(01)02034-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9241–9244
Asymmetric synthesis of 4,4-disubstituted 2-cyclopentenones from
optically active 1-chlorovinyl p-tolyl sulfoxides and
cyanomethyllithium with formation of a quaternary chiral center
Tsuyoshi Satoh,* Masaaki Yoshida and Hiroyuki Ota
Department of Chemistry, Faculty of Sciences, Science University of Tokyo, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 20 September 2001; accepted 26 October 2001
Abstract—Treatment of optically active 1-chlorovinyl p-tolyl sulfoxides having two different substituents at the 2-position, which
were synthesized from unsymmetrical ketones and (R)-(−)-chloromethyl p-tolyl sulfoxide in three steps, with cyanomethyllithium
gave optically active 2-amino-1-cyano-5,5-disubstituted-1,3-cyclopentadienes with very high asymmetric induction from the
sulfoxide chiral center. The products were converted to the enantiomerically pure 4,4-disubstituted 2-cyclopentenones by heating
with phosphoric acid in acetic acid. © 2001 Elsevier Science Ltd. All rights reserved.
The cyclopentenone ring system is one of the most
abundantly distributed carbon skeletal structure in nat-
ural and unnatural organic compounds. Accordingly,
novel strategies for the synthesis of cyclopentenones
continued to receive considerable attention in the field
of synthetic organic chemistry.1 Two famous recent
methods for construction of cyclopentenones are the
Nazarov cyclization2 and Pauson–Khand reaction.3
Recently, the Pauson–Khand reaction has been devel-
oped to a synthesis of optically active cyclopentenones
by using, for example, brucine N-oxide as a chiral
source.4 On the other hand, construction of the quater-
nary carbon center has been a formidable work. Espe-
cially, the asymmetric synthesis of the quaternary
carbon center is a quite interesting challenge in syn-
thetic organic chemistry.5
Recently, we reported a novel method for synthesis of
4,4-disubstituted 2-cyclopentenones
chlorovinyl p-tolyl sulfoxide 3 (synthesized from ketone
and chloromethyl p-tolyl sulfoxide 2) and
5
from 1-
1
cyanomethyllithium via the enaminonitrile 4 (Scheme
1).6a As shown in Scheme 1, it is expected that if an
unsymmetrical ketone (1; R1 and R2 are different sub-
stituents) and chiral sulfoxide 2 were used in this reac-
tion, optically active 4 and 5 could be synthesized.
Based on this expectation, we investigated the asym-
metric synthesis of 4,4-disubstituted 2-cyclopentenones
O
O
TolSCH2Cl
R1
R1
R2
STol
Cl
LiCH2CN
2
O
R2
1
3
CN
H+
O
R1
R1
NH2
*
*
R2
R2
heating
4
5
Scheme 1.
Keywords: sulfoxides; optically active sulfoxides; 4,4-disubstituted 2-cyclopentenones; asymmetric synthesis; quaternary chiral center.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02034-2

9242
T. Satoh et al. / Tetrahedron Letters 42 (2001) 9241–9244
5 starting from optically active (R)-(−)-chloromethyl
p-tolyl sulfoxide (R)-27 with unsymmetrical ketones,
and quite interesting results were obtained.
optical purity was 98.8%. One recrystallization of the
product from AcOEt–hexane gave us the optically pure
(−)-10 (mp 114–116°C, [h]2D1 −428.5 (c 0.4 acetone)).
The same treatment of Z-vinylsulfoxide
9 with
First of all, a synthesis of optically pure 1-chlorovinyl
p-tolyl sulfoxides (8 and/or 9) was investigated (Scheme
2). According to the previous paper,6 (R)-(−)-2 was
treated with LDA at −78°C followed by acetophenone
to give the adduct 6 in 99% yield as a mixture of two
diastereomers. The adduct 6 was acetylated with acetic
anhydride and pyridine in the presence of DMAP to
afford the acetate 7 in 96% yield. The acetate 7 was a
mixture of two inseparable diastereomers. The mixture
was treated with dimsylsodium in DMSO at room
temperature to afford the desired optically pure 1-
chlorovinyl p-tolyl sulfoxides 8 and 9 in 90% yield. The
1-chlorovinyl p-tolyl sulfoxides were separable on silica
gel flash column chromatography and the ratio of 8 and
9 was found to be 4:1. 8: [h]2D1 +280.5 (c 0.4 acetone). 9:
[h]2D7 −9.3 (c 0.2 acetone). The geometry of the two
cyanomethyllithium gave (+)-10 in 96% yield with very
high ee value (94.4% ee). Obviously, E- and Z-vinylsul-
foxides gave the enantiomers of the enaminonitrile,
respectively, in very high ee value.
To ascertain the absolute configuration of the product
10, (−)-10 was heated with phosphoric acid in 1,4-diox-
ane to give (−)-11 (oil, [h]2D7 −119.0 (c 0.4 toluene)) in
low yield (see Table 1, entry 1). Comparing the sign of
the specific rotation of the product with that of the
reported optically active 11,9 the absolute configuration
of the enone was unambiguously determined to be S.
As shown in Scheme 4, (S)-(−)-10 is derived from the
adduct of the vinyl sulfoxide 8 with acetonitrile, the
cyanomethyllithium must be selectively introduced
from the re face of the vinyl sulfoxide. The observed
high selectivity is most conveniently explained by
assuming the formation of a chelate with the lithium
ion between the oxygen of the sulfoxide and the chlo-
rine, where the cyanomethyl anion approach takes
place from the less-hindered re face. This is the first
example for the asymmetric synthesis by conjugate
addition to a,b-unsaturated sulfoxide having a halogen
atom on the a-position.10
1
isomers could be easily determined by H NMR.6b
The main product, E-vinylsulfoxide 8, was treated with
5 equiv. of cyanomethyllithium at −78°C to room tem-
perature for 2 h (Scheme 3). The desired enaminonitrile
10 was obtained in 93% yield, which showed a minus
sign for the specific rotation. The optical purity was
determined by using HPLC with a chiral stationary
column,8 and we were somewhat surprised that the
O
O
OR
LDA
CH3SOCH2Na
S
S
CH3
Tol
Tol
ClCH2
Ph
PhCOCH3
DMSO
90%
:
:
Cl
(R)-(-)-2
6 R=H
7 R=COCH3
O
O
S
S
CH3
Ph
Ph
Tol
Tol
+
:
:
Cl
Cl
CH3
9
8
Scheme 2.
O
CN
H+
heating
CH3
Ph
5 eq.
LiCH2CN
S
CH3
Ph
O
Ph
NH2
Tol
:
THF -78 °C - r. t.
93%, 98.8% ee
Cl
CH3
(S)-(-)-10
(S)-(-)-11
8
[α]D21 -428.5 (c 0.40 acetone;
[α]D27 -119.0 (c 0.40 toluene;
100% ee)
100% ee)
O
CN
Ph
5 eq.
H+
LiCH2CN
Ph
O
S
CH3
Ph
NH2
Tol
heating
:
Cl
CH3
96%, 94.4% ee
CH3
(R)-(+)-10
[α]D31 +418.8 (c 0.40 acetone;
(R)-(+)-11
[α]D32 +115.1 (c 0.30 toluene;
94.4% ee)
9
98.1% ee)
Scheme 3.

T. Satoh et al. / Tetrahedron Letters 42 (2001) 9241–9244
9243
Table 1. Hydrolysis and decyanation of (S)-(−)-10 with acids under reflux conditions
CN
CH3
CH3
Ph
O
O
Acid
(S)-(-)-10
Ph
(S)-(-)-11
reflux
12
Entry
Acid
Solvent
Time (h)
Yield (%)
(S)-(−)-11
12
1
2
3
4
H3PO4
H3PO4
AcOH, H3PO4
5% H2SO4
H3PO4
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
AcOH
29
77
77
77
16
44
59
33
78
65
39
8
6
42
Trace
Trace
50
5
6a
H3PO4
AcOH
86
a To a solution of (S)-(−)-10 (29 mg, 0.15 mmol) in 10 ml of acetic acid was added phosphoric acid (85%, 4 ml) and water (0.6 ml). The reaction
mixture was stirred and heated under reflux for 44 h. The reaction mixture was neutralized with 5% aq. NaOH followed by satd aq. NH4Cl and
the whole was extracted with AcOEt–hexane. The organic layer was dried over MgSO4 and the solvent was evaporated to give an oil, which was
purified by silica gel column chromatography to afford 22 mg (86%) of (S)-(−)-11.
CH3
S(O)Tol
Li
si
Ph
Ph
CH3
LiCH2CN
Ph
H3C
re
S
O
Cl
CH3
Li
Cl
NH2
CH2CN
CN
(S)-(-)-10
CH2CN
Scheme 4.
Next, we have to establish better conditions for the
hydrolysis and decyanation of (S)-(−)-10 to obtain the
enone 11 in good yield. The results of the investigation
are shown in Table 1. Entry 1 has been mentioned
above. Heating 10 with acid rapidly gave hydrolyzed
cyanoenone 12; however, decyanation was quite slow.
We finally found that phosphoric acid in acetic acid is
the conditions of choice. As shown in entry 6, heating
(S)-(−)-10 in acetic acid with phosphoric acid for 44 h
gave the desired enone in 86% yield. These conditions
seem to be somewhat severe; however, the reaction was
rather clean and the mass balance was good.
To investigate the generality of these reactions, we
further studied this method starting from 2-hexanone
(Scheme 5). The vinyl sulfoxides E-13 and Z-14 were
synthesized from 2-hexanone in a similar way as
described for the synthesis of 8 and 9. In the deacetyla-
tion step, in this case, the ratio of 13 and 14 was almost
1:1. The vinyl sulfoxide 13 was treated with
O
CN
CH3
H+
O
5 eq.
LiCH2CN
S
CH3
n-C4H9
NH2
Tol
:
:
n-C4H9
THF -78 °C - r. t.
Cl
heating
83%
CH3
n-C4H9
97%, 99.2% ee
(S)-(-)-16
[α]D32 -43.1 (c 0.40 toluene)
(R)-(-)-15
13
14
[α]D29 -176.5 (c 0.40 acetone)
O
S
CN
LiCH2CN
H+
n-C4H9
O
5 eq.
CH3
n-C4H9
NH2
Tol
heating
83%
n-C4H9
Cl
CH3
95%, 99.5% ee
CH3
(R)-(+)-16
(S)-(+)-15
[α]D28 +172.7 (c 0.40 acetone)
[α]D30 +41.6 (c 0.35 toluene)
Scheme 5.

9244
T. Satoh et al. / Tetrahedron Letters 42 (2001) 9241–9244
cyanomethyllithium in the same way as described above
to obtain the desired enaminonitrile (−)-15 in 97% yield
with better ee (99.2% ee) than the case of (S)-(−)-10.
Booker-Milburn, K. I.; Sharpe, A. J. Chem. Soc., Perkin
Trans. 1 1998, 983.
2. (a) Blumenkopf, T. A.; Overman, L. E. Chem. Rev. 1986,
86, 857; (b) Habermas, K. L.; Denmark, S. E.; Jones, T.
K. Org. React. 1994, 45, 1.
3. (a) Pauson, P. L. Tetrahedron 1985, 41, 5855; (b) Schore,
N. E. Org. React. 1991, 40, 1; (c) Brummond, K. M.;
Kent, J. L. Tetrahedron 2000, 56, 3263; (d) Perez-Serrano,
L.; Blanco-Urgoiti, J.; Casarrubios, L.; Dominguez, G.;
Perez-Castells, J. J. Org. Chem. 2000, 65, 3513 and
references cited therein.
4. (a) Geis, O.; Schmalz, H.-G. Angew. Chem., Int. Ed.
1998, 37, 911; (b) Kerr, W. J.; Lindsay, D. M.; Rankin,
E. M.; Scott, J. S.; Watson, S. P. Tetrahedron Lett. 2000,
41, 3229; (c) Hiroi, K.; Watanabe, T. Tetrahedron Lett.
2000, 41, 3935.
The enaminonitrile (−)-15 was heated in the solution of
phosphoric acid in acetic acid to give the enone (−)-16
in 83% yield. Comparing the sign of specific rotation of
the enone (−)-16 with that of the reported optically
active 16,9 the absolute configuration of the enone was
determined to be S. The result from the vinyl sulfoxide
14 is shown in Scheme 5. Again, the asymmetric induc-
tion is explained by the chelated model shown in
Scheme 4.
It is worth noting that the asymmetric induction men-
tioned in this paper is one of the highest in the asym-
metric synthesis using chiral sulfoxide. Investigation of
the scope and limitation of this asymmetric synthesis
and applications to synthesis of natural products are
underway in this laboratory.
5. (a) Martin, S. F. Tetrahedron 1980, 36, 419; (b) Fuji, K.
Chem. Rev. 1993, 93, 2037; (c) Corey, E. J.; Guzman-
Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
6. (a) Satoh, T.; Ota, H. Tetrahedron 2000, 56, 5113; (b)
Satoh, T.; Takano, K.; Ota, H.; Someya, H.; Matsuda,
K.; Koyama, M. Tetrahedron 1998, 54, 5557.
7. Satoh, T.; Sato, T.; Ohara, T.; Ueda, Y.; Yamakawa, K.
Acknowledgements
J. Org. Chem. 1989, 54, 3130.
8. HPLC analysis of racemic 10 using a chiral column
(Daisel CHIRALCEL OD, 10% 2-isopropanol in hexane)
showed clear base-line separation of both enantiomers.
9. Riviere, P.; Mauvais, A.; Winterfeldt, E. Tetrahedron:
Asymmetry 1994, 5, 1831. The authors of this paper
reported the value of specific rotation of (S)-(−)-11, −72.5
and (S)-(−)-16, −30.6. These values are much smaller
than our values. The authors did not mention the ee of
these enones in their paper.
This work was supported by a Grant-in-Aid for Scien-
tific Research No. 11640545 from the Ministry of Edu-
cation, Science, Sports, and Culture, Japan, which is
gratefully acknowledged.
References
10. Some recent reviews for the sulfoxide-mediated asymmet-
ric synthesis: (a) Walker, A. J. Tetrahedron: Asymmetry
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1717; (c) Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.;
Giannetto, P. Tetrahedron: Asymmetry 1997, 8, 1339; (d)
Iwata, C. Yakugaku Zasshi 1999, 119, 126.
1. Some recent reviews and a monograph for construction
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