Asymmetric Michael addition of malonate anions to prochiral acceptors catalyzed by L-proline rubidium salt

Article abstract of DOI:10.1021/jo960216c

L-Proline rubidium salt catalyzes the asymmetric Michael addition of malonate anions to prochiral enones and enals. This method can be applied to a wide range of substrates to give adducts with a predictable absolute configuration: (S)-adducts from (E)-enones/enals and (R)-adducts from cyclic (Z)-enones. Both the secondary amine moiety and the carboxylate moiety are critical for the catalytic activity and asymmetric induction. Varying the countercation also affects the reaction course. High enantiomeric excesses were attained when di(tert-butyl) malonate was added to (E)-enones in the presence of CsF. The stereochemistry of the Michael reaction indicates that asymmetric induction takes place via enantioface discrimination involving the acceptor α-carbon atom rather than the β-carbon atom.

Full text of DOI:10.1021/jo960216c

3520
J . Org. Chem. 1996, 61, 3520-3530
Asym m etr ic Mich a el Ad d ition of Ma lon a te An ion s to P r och ir a l
Accep tor s Ca ta lyzed by L-P r olin e Ru bid iu m Sa lt
Masahiko Yamaguchi,* Tai Shiraishi, and Masahiro Hirama
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba, Sendai 980-77, J apan
Received February 1, 1996X
L-Proline rubidium salt catalyzes the asymmetric Michael addition of malonate anions to prochiral
enones and enals. This method can be applied to a wide range of substrates to give adducts with
a predictable absolute configuration: (S)-adducts from (E)-enones/enals and (R)-adducts from cyclic
(Z)-enones. Both the secondary amine moiety and the carboxylate moiety are critical for the catalytic
activity and asymmetric induction. Varying the countercation also affects the reaction course. High
enantiomeric excesses were attained when di(tert-butyl) malonate was added to (E)-enones in the
presence of CsF. The stereochemistry of the Michael reaction indicates that asymmetric induction
takes place via enantioface discrimination involving the acceptor R-carbon atom rather than the
â-carbon atom.
The Michael addition reactions of enolates are some
of the most fundamental C-C bond-forming reactions.
Therefore, their catalytic asymmetric versions have been
studied extensively.1 The asymmetric reactions can be
categorized into two groups: (i) enantioselective addition
of prochiral enolates (donors) to acceptors; and (ii) enan-
tioselective addition of enolates (donors) to prochiral
acceptors (Figure 1). The former reactions discriminate
the enantiofaces of the donors, and asymmetric centers
are formed on the donors. Considerable progress has
been made for this group of reactions, and oxyindancar-
boxylates, phenylacetates, cyanoacetates, etc. have been
added to activated olefins to achieve more than 90% ee.2
Chiral environments constructed by crown ethers or
phosphines can effectively differentiate the donor enan-
tiofaces. However, this method inherently limits the
substrates that can be used. Acrylates, acroleins, and
vinyl ketones are typical acceptors. In contrast to
prochiral donor reactions, prochiral acceptor reactions
proceed via enantioface differentiation of Michael accep-
tors to generate chiral centers on the acceptors. This
method has the potential to produce various chiral
centers by simply changing the acceptors, although it has
met with less success than the former method. The
reported optical yields have been generally moderate at
best,3 and their applicability is quite limited. Very often,
previous reports have described only one or two combina-
tions of substrates, and acceptable results were obtained
usually with chalcone and related compounds. Reactions
with aliphatic acyclic enones, for example, have been
rare.
F igu r e 1. Asymmetric Michael addition reactions.
enals catalyzed by L-proline rubidium salt (Scheme 1),
which was the first catalytic asymmetric version of this
reaction.4 This method can be applied to a wide range
of substrates to give adducts with predictable absolute
configurations and enantiomeric excesses of close to 80%.
After our preliminary report, Sasai and Shibasaki re-
ported the lanthanide-catalyzed asymmetric addition of
malonates to cyclic (Z)-enones and chalcone, which gave
very high stereoselectivities (>90% ee).5 Taguchi used
pyrrolidylalkyl ammonium hydroxide derived from L-
We previously described the asymmetric Michael ad-
dition of a simple malonate anion to prochiral enones and
X Abstract published in Advance ACS Abstracts, May 1, 1996.
(1) A review: Perlmutter, P. Conjugate Addition Reactions in
Organic Synthesis; Pergamon Press: Oxford. 1992.
(3) See the following for the recent examples.; also see references
cited therein: Takasu, M.; Wakabayashi, H.; Furuta, K.; Yamamoto,
H. Tetrahedron Lett. 1988, 29, 6943. Sera, A.; Takagi, K.; Katayama,
H.; Yamada, H.; Matsumoto, K. J . Org. Chem. 1988, 53, 1157. Iwasawa,
N.; Yura, T.; Mukaiyama, T. Tetrahedron 1989, 45, 1197. Loupy, A.;
Sansoulet, J .; Zaparucha, A.; Merienne, C. Tetrahedron Lett. 1989, 30,
333. Botteghi, C.; Paganelli, S.; Schionato, A.; Boga, C.; Fava, A. J .
Mol. Catal. 1991, 66, 7. Hayashi, Y.; Otaka, K.; Saito, N.; Narasaka,
K. Bull. Chem. Soc. J pn. 1991, 64, 2122. Hirai, Y.; Terada, T.; Katoh,
H.; Sonohara, S.; Momose, T. Heterocycles 1991, 32, 7. Aoki, S.; Sasaki,
S.; Koga, K. Heterocycles 1992, 33, 493.
(4) Yamaguchi, M.; Shiraishi, T.; Hirama, M. Angew. Chem., Int.
Ed. Engl. 1993, 32, 1176.
(5) Sasai, H.; Arai, T.; Shibasaki, M. J . Am. Chem. Soc. 1994, 116,
1571. Sasai, H.; Arai, T.; Satow, Y. Houk, K. N.; Shibasaki, M. J . Am.
Chem. Soc. 1995, 117, 6194.
(2) For recent examples, see: Desimoni, G.; Quadrelli, P.; Righetti,
P. P. Tetrahedron 1990, 46, 2927. Brunner, H.; Zintl, H. Monatsh.
Chem. 1991, 122, 841. Dehmlow, E. W.; Knufinke, V. Liebigs Ann.
Chem. 1992, 283. Sawamura, H.; Hamashima, H.; Ito, Y. J . Am. Chem.
Soc. 1992, 114, 8295; Tetrahedron 1994, 50, 4439. Crosby J .; Stoddart,
J . F.; Sun, X.; Venner, M. R. W. Synthesis 1993, 141. Bonadies, F.;
Lattanzi, A.; Orelli, L. R.; Pesci, S.; Scettri, A. Tetrahedron Lett. 1993,
34, 7649. Riant, O.; Kagan, H. B.; Ricard, L. Tetrahedron 1994, 50,
4543. Kumamoto, T.; Aoki, S.; Nakajima, M.; Koga, K. Tetrahedron:
Asymmetry 1994, 5, 1431. Brunet, E.; Poveda, A. M. Rabasco, D.; Oreja,
E.; Font, L. M.; Batra, M. S.; Rodr´ıguez-Ubis, J . C. Tetrahedron:
Asymmetry 1994, 5, 935. To¨ke, L.; Fenichel, L.; Albert, M. Tetrahedron
Lett. 1995, 36, 5951.
S0022-3263(96)00216-2 CCC: $12.00 © 1996 American Chemical Society

Catalytic Asymmetric Michael Addition of Malonate
J . Org. Chem., Vol. 61, No. 10, 1996 3521
Ta ble 1. Use of Meta l L-P r olin a te in th e Asym m etr ic
Mich a el Ad d ition
Sch em e 1
proline and obtained optically active adducts from cyclic
(Z)-enones and 4-phenyl-3-propen-2-one.6 These are still
exceptional enolate addition reactions which can be
applied to several prochiral acceptors.7 Apparently,
further study is required to develop effective methods,
particularly for (E)-enones. We describe here recent
advances in the asymmetric malonate addition catalyzed
by L-proline salts.
We began work on the asymmetric reaction using a
novel catalyst system. Our initial idea was to use
combination of a lithium salt and an amine.8 While no
reaction took place by treating 2-cyclohexenone (1) and
dimethyl malonate (2) with triethylamine (10 mol %) at
room temperature, the addition of lithium perchlorate
(100 mol %) dramatically promoted the reaction to give
the racemic adduct (()-3 in 79% yield after 1.5 h (Scheme
2). However, we were disappointed to find that asym-
metric induction did not occur when optically active
amines such as (S)-1-phenylethylamine, (S)-nicotine, (-)-
sparteine, (-)-strychnine, L-prolinol, (-)-brucine, etc.,
were used in place of triethylamine.
M
mol %
time, h
yield, %a
ee, %b
config
Li
100
100
5
5
5
10
10
5
200
20
20
20
48
72
48
48
48
30
48
31
96
58
58
58
23
15
72
72
91
64
78
73
8
28
17
29
51
59
53
26
56
31
22
12
1
S
Sc
R
R
R
Rc
Sd
R
S
Na
K
Rb
Cs
Mg1/2
Ca1/2
Sr1/2
Ba1/2
41
39
48
S
S
S
a
b
Isolated yields are shown. Enantiomeric excesses were de-
termined by optical rotations. c Reaction in THF. 18-Crown-6 (10
d
mol %) was added.
in methanol, but the products were again racemic.10
After various trials, we observed an appreciable asym-
metric induction when 1 and 2 were reacted in chloroform
to give (S)-3 in 47% ee (Scheme 2). The absolute
configuration was determined by converting to a known
keto ester (S)-4.11 However, the catalytic activity was
very low, and the yield was only 13% after 112 h, even
when using 100 mol % of the salt. Addition of a small
amount (30 mol %) of water promoted the reaction, but
it was not enough to be useful with other less-reactive
acceptors.
Sch em e 2
Other L-proline metal salts were examined for higher
catalytic activity using the reaction of 2-cycloheptenone
(5) and diisopropyl malonate (6) (Table 1). Sodium and
potassium L-prolinate were more effective than the
lithium salt. Rubidium and cesium salts enhanced the
stereoselectivity. Interestingly, the absolute configura-
tion of the adduct 7 differed between the lithium reaction
and the rubidium reaction. Alkaline earth metal salts
showed somewhat similar trends. A small amount of
water promotes the rubidium salt reaction, since addition
of MS 4 Å completely inhibited the reaction.
L-Proline tetraalkylammonium salts were also used as
catalysts (Table 2). When the number of carbons in (n-
CnH2n+1)4N increased, the absolute configuration of the
adduct 7 changed from (R) to (S). Asymmetric inductions
of BnNMe3 salt, (1-phenylethyl)trimethylammonium salts,
and 1-(hydroxymethyl)-5-azoniaspiro[4.4]nonane salts
We next tested an amino acid lithium salt, which
possesses an amine group and lithium cation.9 L-Proline
lithium salt was prepared from the amino acid and
lithium hydroxide in methanol. The salt efficiently
promoted the Michael addition of 2 to enones and enals
(9) Use of proline in the asymmetric Michael addition reactions of
thiolate anion: Woodward, R. B.; Logusch, E.; Nambiar, K. P.; Sakan,
K.; Ward, D. E.; Au-Yeung, B.-W.; Balaram, P.; Browne, L. J .; Card,
P. J .; Chen, C. H.; Cheˆnevert, R. B.; Fliri, A.; Frobel, K.; Gais, H.-J .;
Garratt, D. G.; Hayakawa, K.; Heggie, W.; Hesson, D. P.; Hoppe, D.;
Hoppe, I.; Hyatt, J . A.; Ikeda, D.; J acobi, P. A.; Kim, K. S.; Kobuke,
Y.; Kojima, K.; Krowicki, K.; Lee, V. J .; Leutert, T.; Malchenko, S.;
Martens, J .; Matthews, R. S.; Ong, B. S.; Press, J . B.; Rajan Babu, T.
V.; Rousseau, G.; Sauter, H. M.; Suzuki, M.; Tatsuta, K.; Tolbert, L.
M.; Truesdale, E. A.; Uchida, I.; Ueda, Y.; Uyehara, T.; Vasella, A. T.;
Vladuchick,W. C.; Wade, P. A.; Williams, R. M.; Wong, H. N.-C. J . Am.
Chem. Soc. 1981, 103, 3210. Use of proline in the intramolecular
Michael addition: Kozikowski, A. P.; Mugrage, B. B. J . Org. Chem.
1989, 54, 2274.
(6) Kawara, A.; Taguchi, T. Tetrahedron Lett. 1994, 35, 8805.
(7) Silyl thioketene acetals were added to cyclic (Z)-enones and
chalcones. As high as 90% ee was attained in the reaction of 2-cyclo-
pentenone. Kobayashi, S.; Suda, S.; Yamada, M.; Mukaiyama, T. Chem.
Lett. 1994, 97.
(8) Combinatory use of amine and LiX in the Horner-Wadsworth-
Emmons reaction was reported: Blanchette, M. A.; Choy, W.; Davis,
J . T.; Essenfeld, A. P.; Masamune, S.; Roush, W. R.; Sakai, T.
Tetrahedron Lett. 1984, 25, 2183. Rathke, M. W.; Nowak, M. J . Org.
Chem. 1985, 50, 2624.
(10) Yamaguchi, M.; Yokota, N.; Minami, T. J . Chem. Soc., Chem.
Commun. 1991, 1088.
(11) Posner, G. H.; Weitzberg, M.; Hamill, T. G.; Asirvatham, E.;
Cun-Heng, H.; Clardy, J . Tetrahedron 1986, 42, 2919.

3522 J . Org. Chem., Vol. 61, No. 10, 1996
Yamaguchi et al.
Ta ble 2. Use of Tetr a a lk yla m m on iu m L-P r olin a te in th e
Asym m etr ic Mich a el Ad d ition
Ta ble 3. Effect of Ester Gr ou p on Asym m etr ic In d u ction
R
time, h
yield, %a
ee, %b
Me
Et
PhCH2
i-Pr
t-Bu
15
24
17
59
63
88
87
99
88
39
40
43
39
53
65
a
b
Isolated yields are shown. Enantiomeric excesses were de-
NR4
yield, %a
ee, %b
config
termined by 400 or 600 MHz 1H-NMR of ketals synthesized from
the adducts and (2R,3R)-2,3-butanediol.
Me4N
BnNMe3
33
34
51
43
33
41
39
23
22
17
R
R
R
R
R
organic solvents as well as in water are generally in the
(R)-PhCHMeNMe3
(S)-PhCHMeNMe3
(R)-1-(hydroxymethyl)-
5-azoniaspiro[4.4]nonane
(S)-1-(hydroxymethyl)-
5-azoniaspiro[4.4]nonane
Et4N
(n-Pr)4N
(n-Bu)4N
(n-C6H13)4N
(n-C10H21)4N
order of Li+ > Na+ > K+ > Rb+ > Cs+ and Mg2+ > Ca2+
> Sr2+ > Ba2+ 15
Solvation of tetraalkylammonium salt
.
other than tetramethyl derivative is believed to be
negligible.16 Thus, the cation effect shown in Tables 1
and 2 may be related to the effective size of the cation in
the solvent: L-Proline salts with large cations show (S)-
selectivity, and small cations show (R)-selectivity. Ad-
dition of 18-crown-6 to the L-proline rubidium salt
reaction altered the product configuration to give (S)-7
(Table 1). This inversion may be due to the strong
coordination of the polydentated ligand to the rubidium
cation, which increases the effective cation size. The
oxygenated ligand must be polydentated, since reactions
in THF gave results similar to those in chloroform (Table
1).
33
17
R
41
26
41
44
8
10
38
44
41
40
10
10
28
S
S
S
S
S
S
S
R
R
41
(n-C12H25)4N
BnNMe3
Et4N
(n-Bu)4N
45
48c
66c
69c
a
b
Isolated yields are shown. Enantiomeric excesses were de-
termined by optical rotations. c Reaction was carried out with (E)-
3-penten-2-one (8).
The ester group of malonate also affected asymmetric
induction (Table 3). Higher optical yields were attained
with diisopropyl ester 6 than with dimethyl ester 2. Use
of di(tert-butyl) ester further enhanced the selectivity,
although the yield decreased.
were intermediate between those of Et4N salt and Me4N
salt. The chirality of the ammonium salts does not affect
the stereochemical outcome. Apparently, the size of the
ammonium cation governs stereoselectivity, and its shape
is unimportant. Virtually the same relationship between
the cation structure and the product configuration was
obtained with (E)-3-penten-2-one (8) (Table 2), where
larger ammonium salts predominantly gave adduct (R)-
9. Ammonium cations may be associated with the
substrates and prolinate in the transition state. The
aggregation of malonate anion and tetraalkylammonium
salt has been reported in nonpolar aprotic solvents.12
Inversion of the absolute configuration by simply chang-
ing the size of the cation implies the involvement of more
than two competitive reaction pathways.13
Ta ble 4. Asym m etr ic Mich a el Ad d ition of Diisop r op yl
Ma lon a te to En on e a n d En a l
enone/enal
time, h yield, %a ee, % config
(E)-CH3CHdCHCOCH3
(E)-CH3CHdCHCOn-C3H7
(E)-n-C5H11CHdCHCOCH3
(E)-PhCHdCHCOCH3
2-cycloheptenone
2-cyclohexenone
(E)-n-C3H7CHdCHCHO
(E)-CH3CHdCHCHO
21
46
7 d
9 d
59
46
17
3
71
73b
62
79b
91
87
58
63
76
74
77
53
59
49
41
35
S
S
By analogy to the ammonium cation reactions, metal
cations may also play a role in the transition state.
Sodiomalonate alkylation in THF, DME, or DMF has
been reported to proceed via solvated ion pairs.14 How-
ever, the stereochemistry of the L-proline metal salt
reactions and the tetraalkylammonium salt reactions at
first appeared to differ. In the case of metal cations, salts
with a larger crystal radii gave (R)-7 (Table 1), while
larger tetraalkylammonium salts gave (S)-7 (Table 2).
This discrepancy may be explained if one considers
solvation. The numbers of coordinating solvents in
S
R
R
S
a
b
Isolated yields are shown. 20 mol % of rubidium L-prolinate
was used.
With use of the resulting optimized conditions, 6 was
added to several enones and enals in the presence of
L-proline rubidium salt (Table 4). The catalyst (5 mol
%) gave satisfactory results for relatively reactive sub-
strates. The applicability of this method to a wide range
(12) Reetz, M. T.; Hu¨tte, S.; Goddard, R. J . Am. Chem. Soc. 1993,
115, 9339.
(13) See for example: Inoue, Y.; Yamasaki, N.; Yokoyama, T.; Tai,
A. J . Org. Chem. 1992, 57, 1332. Hatanaka, Y.; Hiyama, T. J . Am.
Chem. Soc. 1990, 112, 7793.
(14) J ackman, L. M.; Lange, B. C. Tetrahedron 1977, 33, 2737.
Barlow, G. H.; Zaugg, H. E. J . Org. Chem. 1972, 37, 2246. Zaugg, H.
E.; Ratajczyk, J . F.; Leonard, J . E.; Schaefer, A. D. J . Org. Chem. 1972,
37, 2249.
(15) Hinton, J . F.; Amis, E. S. Chem. Rev. 1971, 71, 627.
(16) For examples: Bhattacharyya, D. N.; Lee, C. L.; Smid, J .;
Szwaec, M. J . Phys. Chem. 1956, 69, 608. Krumgalz, J . Chem. Soc.,
Faraday Trans. 1 1980, 76, 1887; 1982, 78, 437.

Catalytic Asymmetric Michael Addition of Malonate
J . Org. Chem., Vol. 61, No. 10, 1996 3523
Sch em e 3
Sch em e 4
induction comparable to that of the L-prolinate (Scheme
4). Rubidium N-benzyl-L-prolinate and triethylamine did
not catalyze the reaction, indicating the need for the
secondary amine moiety. Since L-proline, L-prolinol, and
pyrrolidine were not effective, the carboxylate moiety is
also critical. Recently, optically active pyrrolidylalky-
lammonium hydroxide was used for asymmetric mal-
onate addition.6 Thus, the carboxylate moiety can be
replaced with a tetraalkylammonium group. However,
the absolute configurations were opposite those in the
carboxylate reactions. Steric congestion around the
secondary amino group inhibited the Michael addition,
as indicated by the inertness of rubidium L-piperidin-
ecarboxylate, 2-methyl-L-prolinate, N-methyl-L-leucinate,
N-methyl-L-alaninate, and N-benzyl-L-leucinate. Ru-
bidium L-homoprolinate, L-thiazoline-4-carboxylate, and
2-methyl-L-thiazoline-4-carboxylate were also not effec-
tive catalysts.
Reaction of 1 and tert-butyl acetoacetate (16) in the
presence of L-proline rubidium salt gave (R)-adduct 17,
the absolute configuration of which was determined by
converting to a known (S)-diketone 1821 (Scheme 5).
Although the enantiomeric excess was not high, the
stereochemistry in the acetoacetate addition is the same
as that in the malonate addition. (R)-17 was decarboxy-
lated by a two-step procedure. When (R)-17 was heated
in 6 M HCl, a novel rearrangement took place to give
optically active (1S,5R)-2-oxabicyclo[3.3.1]nonan-3-one
[(1S,5R)-19]. This transformation involves decarboxy-
lation, intramolecular aldol reaction, fragmentation, and
addition of a carboxyl group to olefin.22 In fact, heating
(S)-18 in 6 M HCl gave (1S,5R)-19 in 51% yield.
of unhindered acceptors including aliphatic acyclic enone,
aromatic acyclic enone, cyclic enone, and enal is notable,
when compared to previous methods.3 However, multiple
substitution on the enone double bond inhibited the
reaction. Treatment with â,â-disubstituted enones or
R,â-disubstituted enones gave low yields of the product
under these reaction conditions.
The absolute configurations were determined by chemi-
cal correlations to known compounds using a decarboxy-
lation reaction (Scheme 3). (S)-9, (S)-11, and (S)-12 were
correlated to (S)-10.17 Similarly, (S)-13 was converted
to (S)-14.18 A ring-expansion reaction19 was used to
relate (R)-7 and (R)-15 to (R)-4.11 These studies revealed
that the acyclic (E)-enones and (E)-enals gave (S)-
adducts, while cyclic (Z)-enones gave (R)-adducts, when
L-proline rubidium salt was used (Table 4). These
asymmetric inductions are under kinetic control, since
the treatment of (R)-7 (58% ee) with D-proline rubidium
salt did not change the optical purity. (Z)-4-Phenyl-3-
buten-2-one was prepared by photoisomerization of the
(E)-isomer, and was subjected to the asymmetric reaction.
However, double-bond isomerization was more rapid than
C-C bond formation, and the above observations were
not confirmed for the acyclic (Z)-enone.20
Sch em e 5
The effect of the catalyst structure was examined.
Rubidium L-azetidinecarboxylate showed asymmetric
(17) Enders, D.; Papadopoulos, K. Tetrahedron Lett. 1983, 24, 4967.
(18) Tomioka, K.; Yasuda, K.; Koga, K. Tetrahedron Lett. 1986, 27,
4611.
(19) de Boer, T. J .; Backer, H. J . Organic Syntheses; Wiley: New
York, 1963; Collect. Vol. 4, p 225.
(20) Amine-catalyzed isomerization of (Z)-unsaturated carbonyl
compounds is known. See for example: Southwick, P. L.; Shozda, R.
J . J . Am. Chem. Soc. 1959, 81, 3298. Rappoport, Z.; Degani, C.; Patai,
S. J . Chem. Soc. 1963, 4513.
(21) Yamamoto, K.; Iijima, M.; Ogimura, Y. Tetrahedron Lett. 1982,
23, 3711.

3524 J . Org. Chem., Vol. 61, No. 10, 1996
Yamaguchi et al.
Ta ble 5. Asym m etr ic Mich a el Ad d ition of Di(ter t-bu tyl)
Sch em e 6
Ma lon a te to En on e
enone
time, h yield, %a ee, % config
(E)-CH3CHdCHCOCH3
(E)-n-C5H11CHdCHCOCH3
(E)-Ph(CH2)2CHdCHCOCH3
(E)-PhCHdCHCOCH3
(E)-CH3CHdCHCOC2H5
2-cyclohexenone
2-cycloheptenone
(E)-2-cyclododecenone
(E)-2-cyclopentadecenone
48
96
96
96
96
48
48
96
96
65
88
86
60
76
76
65
74
81
82
S
S
92b
73
52
84
84
R
R
75
45b
54b,c
S
a
b
Isolated yields are shown. Three equivalents of the malonate
were used. c) Isolated as dimethyl ester.
Sch em e 7
We previously reported the asymmetric nitroalkane
addition to enones using a catalyst.23 The asymmetric
induction mode was the same as in the malonate reac-
tion: (R)-Adducts were obtained from cyclic (Z)-enones,
and (S)-adducts were obtained from acyclic (E)-enones.
Examples are shown in Scheme 6. Essentially the same
mechanism may be involved in the malonate, acetoac-
etate, and nitroalkane reactions.
To attain higher asymmetric induction in the malonate
reaction, the use of di(tert-butyl) malonate (20) was
reexamined. To our delight, addition of CsF improved
the chemical yield without affecting the stereoselectivity
(Table 5). Enantiomeric excesses close to 90% were
attained with aliphatic (E)-enones. At present, this is
the best method for conducting the asymmetric malonate
addition to (E)-enones. Optical yields of adducts were
slightly decreased with cyclic (Z)-enones. The absolute
configurations were the same as in the diisopropyl
malonate reaction. CsF probably enolizes the malonate,
although CsF itself does not promote conjugate addition.
The tert-butyl ester 20 reacted with macrocyclic (E)-
enones to give adducts in more than 80% ee (Table 5).
The absolute configuration of adduct 22 derived from (E)-
2-pentadecenone (21)24 was determined by converting it
to optically active muscone (24) (Scheme 7).24,25 The
Michael adduct without isolation was thermally decar-
boxylated to give keto acid 23, which was transformed
to (S)-24 by decarboxylation under radical conditions.26
To synthesize the active ester in the second decarboxy-
lation reaction, the acid anhydride method using carbo-
diimide was more effective than the acid chloride method
using oxallyl chloride. A considerable amount of enol
lactone was formed in the latter method.
Figure 2 shows how we defined re- and si-enantiofaces
of enones, where the first priority is given to the Cd
group. This definition is relatively insensitive to changes
in the substituents compared with the conventional re/
si-face definition, and is useful for mechanistic discus-
(22) Related reactions were reported using ethylene glycol and
BF3‚OEt2: Suemune, H.; Oda, K.; Sakai, K. Tetrahedron Lett. 1987,
28, 3373.
F igu r e 2. re-Face and si-face definition of enantiofaces.
(23) Yamaguchi, M.; Shiraishi, T.; Igarashi, Y.; Hirama, M. Tetra-
hedron Lett. 1994, 35, 8233.
(24) Tanaka, K.; Ushio, H.; Kawabata, Y.; Suzuki, H. J . Chem. Soc.,
Perkin Trans. 1 1991, 1445.
(25) Branca, Q.; Fischli, A. Helv. Chim. Acta 1977, 60, 925.
(26) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
1985, 41, 3901.

Catalytic Asymmetric Michael Addition of Malonate
J . Org. Chem., Vol. 61, No. 10, 1996 3525
Oppolzer reported the addition of organocopper to chiral
enoates derived from (-)-8-phenylmenthol to give re(R)-
attack adducts for both (E)-enoate and (Z)-enoate. The
chiral auxiliary attached to the acceptors differentiated
their R-enantiofaces.29
The other asymmetric induction mode involves recog-
nition of the substituent arrangement at the â-carbon
atom (â-enantioface discriminating mechanism in Figure
4), and explicit examples are relatively rare.30 Kretchmer
reported the Grignard conjugate addition to 2-cyclohex-
enone (2) and (E)-3-penten-2-one (8) in the presence of
(-)-sparteine. Both acceptors gave re(â)-attack products
in low optical yields.31 It may be reasonable to assume
that the chiral catalyst in this reaction is located in the
vicinity of the â-carbon atom in the transition state, and
controls the stereochemical approach of the nucleophilic
donor carbon atom to the acceptor â-carbon atom. How-
ever, this asymmetric induction mechanism in principle
requires appropriate combinations of donor and acceptor
and should therefore be sensitive to the structure of the
substrates. The preferred use of chalcones in many
catalytic asymmetric Michael additions in the literature1-3
suggests the involvement of this mechanism. Phenyl
group and hydrogen atom differ both sterically and
electronically and are relatively easy to discriminate.32
The wide applicability of the present Michael addition
catalyzed by L-proline salts may be due to the involve-
ment of the R-enantioface discriminating mechanism,
which recognizes the arrangement of the carbonyl group
and the hydrogen atom. This reaction should be less
sensitive to the structure of donors and acceptors.
The transition state in the present reaction involves a
quaternary complex of donor, acceptor, L-prolinate, and
countercation. Although our understanding of the de-
tailed structure is premature, we propose that it includes
the formation of an iminium salt between the catalyst
and the acceptor.33 Nakanishi reported the formation of
L-proline iminium salts from enals.34 Unsaturated imi-
nium salt is more reactive than the corresponding enone
toward the malonate addition.35 When iminium salt,
prepared from (E)-4-phenyl-3-buten-2-one and pyrroli-
dine,36 was treated with dimethyl malonate in the pres-
ence of triethylamine (10 mol %), the starting material
was consumed at room temperature over several hours
to give the 1,4-adduct in 16% yield after aqueous workup.
F igu r e 3. si(R)-Attack in the L-proline rubidium salt-catalyzed
Michael addition.
sions. Since enones possess two prochiral centers, the
R-carbon and â-carbon, an enantioface can be described
as, for example, re(R), si(â), si(R)/si(â), or re(R)/si(â).
All of the donors that have been examined thus far in
the present asymmetric addition attack (E)-enones at the
si(R)/si(â)-face and (Z)-enones at the si(R)/re(â)-face, using
L-proline rubidium salt (Figure 3). Both cases involve
si(R)-attack. Similar observations were made for L-
proline tetraalkylammonium salts; si(R)-attack for
BnMe3N salt and re(R)-attack for (n-Bu)4N salt (Table
2). The involvement of separate mechanisms for cyclic
enones and acyclic enones is unlikely, since their behav-
iors are similar in many respects, such as the reaction
rate, the effect of the catalyst structure, the extent of the
asymmetric induction, etc. Most likely, the reaction takes
place via s-trans-conformation of the acceptors.27 Thus,
in these Michael additions, the arrangement of the
substituents at the acceptor R-carbon is recognized (R-
enantioface discriminating mechanism) rather than the
â-substituents, although the â-carbon is the C-C bond-
forming center (Figure 4). In the transition state, L-
prolinate should be located in the vicinity of the R-carbon,
which generates chiral environments for effective asym-
metric induction. Interactions between the carbonyl
group and the catalyst are conceivable. Addition of
1-nitrobutane to 1 and 8 gave the si(R)-attack products
as approximately 1:1 mixtures of diastereomers with
regard to the γ-carbon atom (Scheme 6).23 This is
consistent with the above view in that the chiral catalyst
affects the stereochemistry at the â-carbon atom, but not
at the remote γ-carbon atom.
(28) Oppolzer, W.; Lo¨her, H. J . Helv. Chim. Acta, 1981, 64, 2808;
Oppolzer, W.; Poli, G. Tetrahedron Lett. 1986, 27, 4717. For other
example: Takaki, K.; Maeda, T.; Ishikawa, M. J . Org. Chem. 1989,
54, 58. Pyne, S. G.; Griffith, R.; Edwards, M. Tetrahedron Lett. 1988,
29, 2089. Corey, E. J .; Hannon, F. J .; Boaz, N. W. Tetrahedron 1989,
45, 545.
(29) Such stereochemical outcome was also found in addition reac-
tions of chiral cuprate reagents: Leyendecker, F.; J esser, F.; Ruhland,
B. Tetrahedron Lett. 1981, 3601. Andersson, S.; J agner, S.; Nilsson,
M.; Urso, F. J . Organomet. Chem. 1986, 301, 257. Dieter, R. K.; Tokles,
M. J . Am. Chem. Soc. 1987, 109, 2040.
(30) The Sasai-Shibasaki Michael addition showed re(â)-attack to
2-cycloalkenone and chalcone.5 Discussion, however, is not simple here,
since chalcones are unusual substrates in the asymmetric Michael
addition as shown by many examples.
F igu r e 4. Asymmetric induction mechanisms in Michael
addition reactions.
(31) Kretchmer, R. A. J . Org. Chem. 1972, 37, 2744.
(32) Importance of π-π attractive interaction between the catalyst
and chalcone was indicated in the Michael addition reaction: Loupy,
A.; Zaparucha, A. Tetrahedron Lett. 1993, 34, 473.
(33) Example of iminium salt used in the asymmetric synthresis:
Takano, S.; Iwata, H.; Ogasawara, K. Heterocycles 1978, 9, 845.
(34) Sheves, M.; Nakanishi, K. J . Am. Chem. Soc. 1983, 105, 4033.
(35) Conjugate addition reactions to unsaturated iminium salts:
Pandit, U. K.; Cabre´, F. R. M.; Gase, R. A.; de Nie-Sarink, M. J . J .
Chem. Soc., Chem. Commun. 1974, 627. de Nie-Sarink, M. J .; Pandit,
U. K. Tetrahedron Lett. 1979, 2449.
A similar relationship between the acceptor olefin
stereochemistry and enantioface selection can be found
in the literature. Typical examples are the conjugate
addition reactions to chiral enoates.28 For example,
(27) Some conjugate addition reactions rigorously require s-cis
configuration of acceptors and are not applicable to cyclic enones. Hooz,
J .; Layton, R. B. J . Am. Chem. Soc. 1971, 93, 7320. Sinclair, J . A.;
Molander, G. A.; Brown, H. C. J . Am. Chem. Soc. 1977, 99, 954.
(36) Compare: Leonard, N. J .; Paukstelis, J . V. J . Org. Chem. 1963,
28, 3021.

3526 J . Org. Chem., Vol. 61, No. 10, 1996
Yamaguchi et al.
Sch em e 8
wide range of acceptors and gives adducts with a predict-
able absolute configuration. Especially high asymmetric
inductions were attained with (E)-enones. This reaction
is noteworthy because of the use of a simple and readily
available catalyst in a highly stereoselective reaction. The
stability of the catalyst with respect to oxygen and
moisture is another advantage of this method. It should
also be noted that the present Michael reactions involve
a new asymmetric carbonyl activation mechanism which
may find use in other enantioselective reactions.
1,2-Adduct was not detected. The low yield was due to
polymerization of the iminium salt. In contrast, es-
sentially no reaction took place with the enone itself
under these conditions. The following observations are
also consistent with a mechanism involving iminium
salt: (i) the requirement of an unhindered secondary
amine moiety in the catalyst; (ii) the requirement of a
small amount of water for promotion of the reaction; and
(iii) the lack of asymmetric induction in the malonate
addition to ethyl 2-cyano-2-octenoate, which cannot form
iminium salt. However, other noncovalent bond interac-
tions cannot be excluded at present.
Exp er im en ta l Section
1H-NMR and 13C-NMR spectra were obtained on a Varian
Gemini 200 (200 MHz), a Varian XL-200 (200 MHz), a J EOL
GX-400 (400 MHz), or a Brucker AM-600 (600 MHz). Chemi-
cal shift values are given in parts per million (ppm) relative
to internal Me4Si. In some cases, CHCl3 (δ 7.24 for 1H-NMR
1
and δ 77.0 for 13C-NMR) or D2O (δ 4.80 for H-NMR) was also
used for the internal standard. IR spectra were recorded on
a J ASCO FT/IR-7000. MS spectra were taken with a HITA-
CHI M-52 or a J EOL HX-110. Optical rotations were obtained
with a J ASCO DIP-370 polarimeter. Elemental analysis was
conducted with a YANACO CHN Corder MT-5. Chloroform
was purified by passing it through a basic alumina column
just prior to use. Methanol was distilled from magnesium
metal and stored over molecular sieves 3 Å. L-Proline,
D-proline, L-prolinol, and L-piperidinecarboxylic acid were
purchased from Aldrich, Fluka, or Wako and used as received.
N-Benzyl-L-proline,40 2-methyl-L-proline,41 N-benzyl-L-leu-
cine,42 N-methyl-L-alanine,42 L-homoproline,43 L-thiazoline-4-
carboxylic acid,44 and 2-methyl-L-thiazoline-4-carboxylic acid44
were prepared according to the literature. Teraalkylammo-
nium halides were purchased from Aldrich or Wako. (R)- and
(S)-(1-phenylethyl)trimethylammonium iodide were prepared
according to the literature.45
Finally, the present Michael addition reaction was
compared with the Hajos-Wiechert reaction, which is the
intramolecular asymmetric aldol reaction catalyzed by
L-proline.37 An enamine nucleophile intermediate has
been suggested in the latter reaction.38 There are
similarities in the catalyst structure-activity relation-
ship, although the former uses amino acid salts and the
latter uses amino acids. L-Proline and L-azetidine-2-
carboxylic acid derivatives are effective catalysts in both
reactions, while N-alkyl-L-proline and (()-piperidinecar-
boxylic acid derivatives are ineffective. These observa-
tions appear to indicate the involvement of similar
reaction intermediates. However, there are several dif-
ferences. The Hajos-Wiechert reaction showed a nega-
tive nonlinear effect, which supports the notion that two
molecules of the catalyst are involved in the transition
state.39 In contrast, the effect was not observed in the
Michael addition of 6 to 5. The transition-state structure
probably contains one molecule of the prolinate. The
effect of the countercation also differs between the aldol
reaction and the Michael reaction. The absolute config-
uration of the adducts gradually changed depending on
the size of cations in L-proline salts in the Michael
addition (Tables 1 and 2). In contrast, this only had a
small effect in the aldol reaction. L-Proline rubidium salt
and lithium salt promoted the aldol reaction equally well
to give the enones with the same absolute configuration
(Scheme 8). The stereochemistry is the same as that in
the reaction promoted by L-proline itself. Prolinate anion
appears to be the crucial species in the aldol reaction.
Use of L-proline BnNMe3 salt, (n-Bu)4N salt, or Et4N salt
gave aldol products with very low enantiomeric excesses,
although the reactions were much faster. Further stud-
ies are required to understand the precise role of this
useful amino acid in these catalytic asymmetric reactions.
In summary, L-proline rubidium salt promotes the
catalytic asymmetric Michael addition of malonate anions
to enones and enals. This reaction can be applied to a
Am in o Acid Sa lts. Amino acid salts were prepared by
adding 1 equiv of alkali metal hydroxide or tetraalkylammo-
nium hydroxide to the amino acid in methanol at 0 °C and
stirring at 25 °C for 1-3 h. After the solvent was evaporated,
the salts were dried at 25 °C in vacuo. The amino acid salts
thus obtained were used without further purification. Metha-
nol solutions of tetraalkylammonium hydroxides which were
not commercially available were prepared from tetraalkylam-
monium halides and 2 equiv of Ag2O at room temperature.46
Alkaline earth metal salts were prepared by treating the amino
acid with equimolar amounts of metal methoxides in methanol.
L-P r olin e Lith iu m Sa lt. Mp: >250 °C. [R]25D: -101 (c
1.0, MeOH). Anal. Calcd for C5H8NO2Li: C, 49.61; H, 6.66;
N, 11.57. Found: C, 50.02; H, 6.62; N, 11.52.
L-P r olin e Sod iu m Sa lt. Mp: 234-237 °C. [R]22D: -90 (c
1.0, MeOH).
L-P r olin e P ota ssiu m Sa lt. Mp: >250 °C. [R]24D: -81 (c
1.0, MeOH).
L-P r olin e Ru bid iu m Sa lt. Mp: >250 °C. [R]23 :-61 (c
D
1.0, MeOH). 1H-NMR (D2O): δ 1.60-1.78 (3H, m), 2.00-2.14
(1H, m), 2.62-2.80 (1H, m), 2.92-3.06 (1H, m), 3.45 (1H, dd,
J ) 8.0, 6.0 Hz). Anal. Calcd for C5H8NO2Rb‚1/2H2O: C, 28.79;
H, 4.35; N, 6.71. Found: C, 28.90; H, 4.58; N, 6.44.
(40) Goldstein, S. W.; Overman, L. E.; Rabinowitz, M. H. J . Org.
Chem. 1992, 57, 1179.
(41) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am. Chem.
Soc. 1983, 105, 5390.
(42) Quitt, P.; Hellerbach, J .; Vogler, K. Helv. Chim. Acta 1963, 46,
327.
(43) Cassal, J .-M.; Fu¨rst, A.; Meier, W. Helv. Chim. Acta 1976, 59,
1917.
(44) Howard-Lock, H. E.; Lock, C. J . L.; Martins, M. L.; Smalley, P.
S.; Bell, R. A. Can. J . Chem. 1986, 64, 1215. Nagasawa, H. T.; Goon,
D. J . W.; Muldoon, W. P.; Zera, R. T. J . Med. Chem. 1984, 27, 591.
(45) Cope, A. C.; Ciganek, E.; Fleckenstein, L. J .; Meisinger, M. A.
P. J . Am. Chem. Soc. 1960, 82, 4651. Lillis, V.; Mckenna, J .; Mckenna,
J . M.; Smith, M. J .; Taylor, P. S.; Williams, I. H. J . Chem. Soc., Perkin
Trans. 2 1980, 83.
(37) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. 1971, 83, 492.
Hajos, Z. G.; Parrish, D. R. J . Org. Chem. 1974, 39, 1615
(38) Agami, C. Bull. Soc. Chim. Fr. 1988, 499.
(39) Puchot, C.; Samuel, O.; Dun˜ach, E.; Zhao, S.; Agami, C.; Kagan,
H. B. J . Am. Chem. Soc. 1986, 108, 2353. Guillaneux, D.; Zhao, S.-H.;
Samuel, O.; Rainford, D.; Kagan, H. B. J . Am. Chem. Soc. 1994, 116,
9430 and references therein.
(46) Cundiff, R. H.; Markunas, P. C. Anal. Chem. 1956, 28, 792.
Cluett, M. L. Anal. Chem. 1959, 31, 610.

Catalytic Asymmetric Michael Addition of Malonate
J . Org. Chem., Vol. 61, No. 10, 1996 3527
L-P r olin e Cesiu m Sa lt. Mp: >250 °C. [R]26D: -50 (c 1.0,
MeOH). Anal. Calcd for C5H8NO2Cs‚H2O: C, 22.66; H, 3.80;
N, 5.28. Found: C, 22.74; H, 3.55; N, 5.17.
L-P r olin e Ma gn esiu m Sa lt. Mp: >250 °C. [R]25D: -54
(c 1.0, MeOH).
from ethanol/ether (3:1) gave the salt (1.01 g, 19%). Mp: >250
°C. [R]24D: -20 (c 1.0, MeOH). Anal. Calcd for C9H18NOBr:
C, 45.78; H, 7.68; N, 5.93. Found: C, 45.12; H, 7.66; N, 5.86.
Th e Mich a el Ad d it ion R ea ct ion of Diisop r op yl
Ma lon a te (6) to En on e a n d En a l. Diisop r op yl (R)-(+)-
(3-Oxocycloh ep tyl)m a lon a te [(R)-(+)-7]. Under an argon
atmosphere, a mixture of diisopropyl malonate (6, 1.30 mL,
6.72 mmol), 2-cycloheptenone (5, 0.50 mL, 4.48 mmol), and
L-proline rubidium salt (46 mg, 0.22 mmol) in chloroform (5
mL) was stirred for 59 h at 25 °C. The reaction was quenched
by adding 2 M HCl, and organic materials were extracted twice
with ethyl acetate. Combined extracts were washed with
brine, dried over Na2SO4, filtered, concentrated, and flash
chromatographed over silica gel, giving (R)-(+)-7 (1.21 g, 91%).
L-P r olin e Ca lciu m Sa lt. Mp: 152-162 °C dec. [R]23
:
D
-42 (c 1.0, MeOH). Anal. Calcd for C10H16N2O4Ca: C, 44.76;
H, 6.01; N, 10.44. Found: C, 45.01; H, 6.30; N, 10.41.
L-P r olin e Str on tiu m Sa lt. Mp: 190-205 °C dec. [R]25
:
D
-39 (c 1.0, MeOH). Anal. Calcd for C10H16N2O4Sr‚1/2H2O: C,
36.97; H, 5.27; N, 8.62. Found: C, 37.31; H, 5.07; N, 8.65.
L-P r olin e Ba r iu m Sa lt. Mp: 167-177 °C dec. [R]23D: -48
(c 1.0, MeOH). Anal. Calcd for C10H16N2O4Ba‚H2O: C, 32.06;
H, 4.57; N, 7.48. Found: C, 32.08; H, 4.40; N, 7.57.
L-Azetid in eca r boxylic Acid Ru bid iu m Sa lt. Mp: >250
°C. [R]26D: -78 (c 1.1, H2O). 11H-NMR (D2O): δ 1.15-2.32
(1H, m), 2.49-2.68 (1H, m), 3.41 (2H, t, J ) 7.8 Hz), 4.10 (1H,
dd, J ) 9.3, 6.8 Hz). IR (KBr): 3406, 1591 cm-1. Anal. Calcd
for C4H6NO2Rb‚1/2H2O: C, 24.69; H, 3.63; N, 7.20. Found: C,
24.85; H, 3.63; N, 6.94.
[R]23
:
+22 (c 1.0, CHCl3, 59% ee). 1H-NMR (200 MHz,
D
CDCl3): δ 1.24 (12H, d, J ) 6.2 Hz), 1.3-1.7 (3H, m), 1.7-2.1
(3H, m), 2.3-2.7 (5H, m), 3.23 (1H, d, J ) 7.1 Hz), 5.058 (1H,
septet, J ) 6.2 Hz), 5.062 (1H, septet, J ) 6.2 Hz). 13C-NMR
(50 MHz, CDCl3): δ 21.5, 21.6, 24.4, 28.8, 34.1, 35.5, 43.5, 47.2,
57.8, 69.0, 167.6, 212.6. IR (neat): 1729 cm-1. Anal. Calcd
for C16H26O5: C; 64.41, H; 8.78. Found: C; 64.39, H; 8.77. The
enantiomeric excess was determined as follows: A mixture of
(R)-(+)-7 (44 mg, 0.15 mmol), (2R,3R)-2,3-butanediol (0.2 mL,
0.23 mmol), and a catalytic amount of p-toluenesulfonic acid
in dry benzene (2 mL) was stirred for 24 h at rt (or at reflux
for 1 h). The reaction was quenched by adding saturated
aqueous NaHCO3, and the organic materials were extracted
twice with ethyl acetate. The combined extracts were washed
with water, dried over Na2SO4, filtered, concentrated, and flash
chromatographed over silica gel, giving ketal (50 mg, 92%).
The enantiomeric excess was determined by 1H-NMR (400
MHz, CDCl3) and observing the resonance signals at δ 3.22
(d, J ) 7.5 Hz) and δ 3.26 (d, J ) 7.8 Hz). Essentially the
same results were obtained by ketalization reaction with
(2S,3S)-2,3-butanediol.
N-Ben zyl-L-p r olin e Ru bid iu m Sa lt. Mp: 196-199 °C.
[R]27
: -60 (c 1.0, MeOH). Anal. Calcd for C12H14NO2-
D
Rb‚H2O: C, 46.84; H, 5.57; N, 4.55. Found: C, 47.40; H, 5.09;
N, 4.61.
2-Meth yl-L-pr olin e Ru bidiu m Salt. Mp: >250 °C. [R]22
:
D
-52 (c 1.0, MeOH). 11H-NMR (D2O): δ 1.31 (3H, s), 1.60-
1.90 (3H, m), 2.02-2.18 (1H, m), 2.78-3.06 (2H, m). IR
(KBr): 3398, 1580 cm-1. Anal. Calcd for C6H10NO2Rb‚H2O:
C, 31.11; H, 5.22; N, 6.05. Found: C, 31.71; H, 4.99; N, 6.08.
L-P ip er id in eca r boxylic Acid Ru bid iu m Sa lt. Mp: >250
°C. [R]24D: -5.8 (c 1.1, H2O). 11H-NMR (D2O): δ 1.30-1.68
(4H, m), 1.71-1.84 (1H, m), 1.86-2.00 (1H, m), 2.55-2.71 (1H,
m), 3.00-3.22 (2H, m). Anal. Calcd for C6H10NO2Rb‚1/2H2O:
C, 32.37; H, 4.53; N, 6.29. Found: C, 32.92; H, 4.91; N, 6.12.
N-Ben zyl-L-leu cin e Ru bidiu m Salt. Mp: >250 °C. [R]23
:
D
-2.4 (c 1.0, H2O). 11H-NMR (D2O): δ 0.83 (3H, d, J ) 6.8
Hz), 0.87 (3H, d, J ) 6.6 Hz), 1.35-1.62 (3H, m), 3.12 (1H, t,
J ) 6.5 Hz), 3.56 (1H, d, J ) 12.5 Hz), 3.76 (1H, d, J ) 12.4
Diisopr opyl (S)-(+)-(1-Meth yl-3-oxobu tyl)m alon ate [(S)-
(+)-9]. (E)-3-Penten-2-one (8) (Aldrich) was used after distil-
lation, which contained 17% of 4-methyl-3-penten-2-one. [R]26
:
D
+13 (c 1.0, CHCl3, 76% ee). 1H-NMR (200 MHz, CDCl3): δ
1.02 (3H, d, J ) 6.8 Hz), 1.25 (12H, d, J ) 6.3 Hz), 2.14 (3H,
s), 2.3-2.5 (1H, m), 2.6-2.9 (2H, m), 3.27 (1H, d, J ) 6.6 Hz),
5.05 (2H, septet, J ) 6.3 Hz). 13C-NMR (50 MHz, CDCl3): δ
17.5, 21.4, 21.5, 28.6, 30.1, 47.5, 56.4, 68.6, 167.9, 206.9. IR
Hz), 7.30-7.45 (5H, m). IR (KBr): 3298, 1575 cm-1
. Anal.
Calcd for C13H18NO2Rb‚H2O: C, 48.22; H, 6.23; N, 4.33.
Found: C, 48.58; H, 5.77; N, 4.33.
N-Meth yl-L-a la n in e Ru bid iu m Sa lt. Mp: 196-197 °C
dec. [R]27D: +1.1 (c 1.0, MeOH). 11H-NMR (D2O): δ 1.19 (3H,
d, J ) 7.0 Hz), 2.26 (3H, s), 3.02 (1H, q, J ) 7.0 Hz). IR
(neat): 1725 cm-1
. Anal. Calcd for C14H24O5: C; 61.74, H;
(KBr): 3404, 1589 cm-1
.
Anal. Calcd for C4H8NO2Rb‚H2O:
8.88. Found: C; 61.68, H; 8.76. The enantiomeric excess was
determined by 1H-NMR (600 MHz, CDCl3) of the ketal with
(2R,3R)-2,3-butanediol by observing at δ 3.37 (d, J ) 6.4 Hz)
and δ 3.52 (d, J ) 5.6 Hz). Treatment with (2S,3S)-2,3-
butanediol gave essentially the same results.
C, 23.37; H, 4.90; N, 6.81. Found: C, 23.57; H, 4.40; N, 6.90.
L-Hom op r olin e Ru bid iu m Sa lt. Mp: >250 °C. [R]23
:
D
-5.7 (c 1.0, MeOH). 11H-NMR (D2O): δ 1.22-1.44 (1H, m),
1.64-2.00 (3H, m), 2.27 (1H, dd, J ) 14.2, 7.4 Hz), 2.40 (1H,
dd, J ) 14.2, 7.0 Hz), 2.70-2.98 (2H, m), 3.28 (1H, quintet, J
) 7.2 Hz). IR (KBr): 3406, 1576, 1396 cm-1. Anal. Calcd for
C6H10NO2Rb‚1/2H2O: C, 32.37; H, 4.98; N, 6.29. Found: C,
32.24; H, 4.71; N, 6.21.
Diisopr opyl (S)-(+)-(1-Meth yl-3-oxoh exyl)m alon ate [(S)-
(+)-12]. [R]22D: +11 (c 1.0, CHCl3, 74% ee). 1H-NMR (200
MHz, CDCl3): δ 0.91 (3H, t, J ) 7.2 Hz), 1.02 (3H, d, J ) 6.7
Hz), 1.24 (12H, d, J ) 6.3 Hz), 1.60 (2H, q, J ) 7.2 Hz), 2.3-
2.5 (3H, m), 2.6-2.8 (2H, m), 3.28 (1H, d, J ) 6.6 Hz), 5.05
(2H, septet, J ) 6.3 Hz). 13C-NMR (50 MHz, CDCl3): δ 13.5,
17.1, 17.5, 21.46, 21.54, 28.7, 44.9, 46.7, 56.5, 68.6, 168.0, 209.3.
IR (neat): 1729 cm-1. Anal. Calcd for C16H28O5: C; 63.98, H;
9.39. Found: C; 63.68, H; 9.40. The enantiomeric excess was
L-Th ia zolin e-4-ca r boxylic Acid Ru bid iu m Sa lt. Mp:
232-235 °C dec. [R]23
:
-127 (c 1.50, H2O). 11H-NMR
D
(D2O): δ 2.75 (1H, dd, J ) 10.4, 8.8 Hz), 3.24 (1H, dd, J )
10.3, 7.2 Hz), 3.57 (1H, dd, J ) 8.6, 7.2 Hz), 3.95 (1H, d, J )
9.5 Hz), 4.32 (1H, d, J ) 9.5 Hz). IR (KBr): 3480, 1584 cm-1
.
1
determined by H-NMR (600 MHz, CDCl3) and observing the
Anal. Calcd for C4H8NO2SRb‚H2O: C, 20.39; H, 3.42; N, 5.94.
absorptions of the ketal with (2R,3R)-2,3-butanediol at δ 3.37
(d, J ) 6.3 Hz) and δ 3.54 (d, J ) 5.2 Hz).
Found: C, 20.70; H, 3.11; N, 5.74.
2-Meth yl-L-th iazolin e-4-car boxylic Acid Ru bidiu m Salt.
Obtained as 2:1 mixture of diastereomers. Mp: 164-168 °C
dec. [R]24D: -119 (c 1.2, H2O). 11H-NMR (D2O): δ 1.40 (1H,
d, J ) 6.6 Hz), 1.54 (2H, d, J ) 6.2 Hz), 2.82-3.00 (1H, m),
3.25-3.40 (1H, m), 3.62 (0.6H, dd, J ) 7.3, 7.1 Hz), 3.89 (0.3H,
t, J ) 7.1 Hz), 4.49 (0.6H, q, J ) 6.4 Hz), 4.82 (0.3H, q, J )
Diisop r op yl
(+)-(1-P en t yl-3-oxob u t yl)m a lon a t e.
[R]24 +8.0 (c 1.0, CHCl3, 77% ee). 1H-NMR (200 MHz,
:
D
CDCl3): δ 0.87 (3H, t, J ) 6.4 Hz), 1.24 (6H, d, J ) 6.3 Hz),
1.25 (6H, d, J ) 6.3 Hz), 1.2-1.5 (8H, m), 2.14 (3H, s), 2.4-
2.8 (3H, m), 3.46 (1H, d, J ) 5.4 Hz), 5.04 (2H, septet, 6.3 Hz).
13C-NMR (50 MHz, CDCl3): δ 13.8, 21.4, 22.3, 26.4, 30.0, 31.6,
31.9, 33.2, 45.2, 54.2, 68.5, 168.0, 168.2, 207.1. IR (neat): 1727
cm-1. Anal. Calcd for C18H32O5: C; 65.82, H; 9.82. Found:
C; 65.53, H; 9.67. The enantiomeric excess was determined
6.0 Hz). IR (KBr): 3366, 1586 cm-1
.
Anal. Calcd for
C5H8NO2SRb‚H2O: C, 24.05; H, 4.04; N, 5.61. Found: C,
23.26; H, 3.61; N, 4.89.
(S)-(-)-1-(H yd r oxym et h yl)-5-a zon ia sp ir o[4.4]n on a n e
Br om id e. Under an argon atmosphere, a mixture of L-prolinol
(2.27 g, 22.5 mmol), 1,4-dibromobutane (2.7 mL, 22.6 mmol),
and NaHCO3 (3.78 g, 45 mmol) in methanol (25 mL) was
heated at reflux for 3 days. After the mixture was cooled to
room temperature, the solvents were removed in vacuo, and
the residue was crystallized by adding ether. Recrystallization
1
by H-NMR (600 MHz, CDCl3) of the ketal with (2R,3R)-2,3-
butanediol by observing at δ 3.70 (d, J ) 5.0 Hz) and δ 3.81
(d, J ) 4.3 Hz).
Diisopr opyl (S)-(+)-(1-P h en yl-3-oxobu tyl)m alon ate [(S)-
(+)-13]. [R]24D: +11 (c 1.0, CHCl3, 53% ee). 1H-NMR (200
MHz, CDCl3): δ 0.96 (3H, d, J ) 6.3 Hz), 1.04 (3H, d, J ) 6.3

3528 J . Org. Chem., Vol. 61, No. 10, 1996
Yamaguchi et al.
Hz), 1.23 (3H, d, J ) 6.3 Hz), 1.24 (3H, d, J ) 6.3 Hz), 2.01
(3H, s), 2.8-3.1 (2H, m), 3.63 (1H, d, J ) 10.1 Hz), 3.94 (1H,
ddd, J ) 10.1, 8.4, 5.4 Hz), 4.77 (1H, septet, J ) 6.3 Hz), 5.05
(1H, septet, J ) 6.3 Hz), 7.2-7.3 (5H, m). 13C-NMR (50 MHz,
CDCl3): δ 21.2, 21.4, 21.5, 30.1, 40.3, 47.6, 57.6, 68.6, 69.1,
127.0, 128.17, 128.24, 140.4, 167.0, 167.6, 205.8. IR (neat):
1725, 758, 700 cm-1. Anal. Calcd for C19H26O5: C; 68.24, H;
7.84. Found: C; 68.52, H; 7.78. The enantiomeric excess was
determined by 1H-NMR (600 MHz, CDCl3) of the ketal with
(2R,3R)-2,3-butanediol by observing at δ 1.13 (s) and δ 1.19
(s).
Synthesized from (R)-(+)-15 (49% ee). [R]27D: +4.4 (c 0.82,
CHCl3). Lit.11 (S)-isomer. [R]20D: -10.0 (c 1.50, CHCl3, 95%
ee). 1H-NMR (200 MHz, CDCl3): δ 1.36-1.50 (1H, m), 1.60-
1.82 (1H, m), 1.88-2.52 (9H, m), 3.69 (3H, s). IR (neat): 1738,
1715 cm-1
.
Met h yl (S)-(+)-3-Met h yl-5-oxoh exa n oa t e [(S)-(+)-10].
Synthesized from (S)-(+)-9 (76% ee). [R]25
: +1.8 (c 30, ether).
D
Lit.17 (R)-isomer. [R]22D: -2.7° (c 30.7, ether). 1H-NMR (200
MHz, CDCl3): δ 0.98 (3H, d, J ) 6.4 Hz), 2.13 (3H, s), 2.20-
2.60 (5H, m), 3.67 (3H, s). 13C-NMR (50 MHz, CDCl3): δ 19.9,
26.2, 30.2, 40.6, 49.8, 51.3, 172.8, 207.5.
Diisop r op yl (R)-(+)-(3-Oxocycloh exyl)m a lon a te [(R)-
(+)-15]. [R]24D: +2.3 (c 1.0, CHCl3, 49% ee). 1H-NMR (200
MHz, CDCl3): δ 1.25 (12H, d, J ) 6.3 Hz), 1.4-2.7 (9H, m),
3.23 (1H, d, J ) 7.5 Hz), 5.06 (1H, septet, J ) 6.3 Hz), 5.07
(1H, septet, J ) 6.3 Hz). 13C-NMR (50 MHz, CDCl3): δ 21.25,
21.34, 24.3, 28.4, 37.6, 40.7, 44.8, 56.8, 68.7, 167.0, 167.1, 209.2.
IR (neat): 1725 cm-1. Anal. Calcd for C15H24O5: C; 63.36, H;
8.51. Found: C; 63.27, H; 8.48. The enantiomeric excess was
determined by 1H-NMR (600 MHz, DMSO-d6) of the ketal with
(2R,3R)-2,3-butanediol by observing at δ 3.19 (d, J ) 8.9 Hz)
and δ 3.21 (d, J ) 8.6 Hz).
Meth yl (S)-(-)-5-Oxo-3-p h en ylh exa n oa te [(S)-(-)-14].
Synthesized from (S)-(+)-13 (53% ee). [R]23D: -13 (c 1.0, C6H6).
Lit.18 (S)-isomer. [R]20D: -20.7 (C6H6, 93% ee). 1H-NMR (200
MHz, CDCl3): δ 2.06 (3H, s), 2.59 (1H, dd, J ) 15.4, 7.6 Hz),
2.70 (1H, dd, J ) 15.4, 7.5 Hz), 2.78-2.88 (2H, m), 3.58 (3H,
s), 3.68 (1H, quintet, J ) 7.4 Hz), 7.15-7.35 (5H, m). 13C-
NMR (50 MHz, CDCl3): δ 30.3, 37.2, 40.5, 49.3, 51.5, 126.8,
127.1, 128.6, 143.0, 172.1, 206.7.
(1S,5R)-(+)-1-Met h yl-2-oxa b icyclo[3.3.1]n on a n -3-on e
[(+)-19]. Treatment of (R)-(+)-17 (26% ee) with 6 M HCl gave
(+)-19 in 39% yield instead of diketone 18. Refluxing (S)-(+)-
18 in 6 M HCl also gave (+)-19 in 51% yield. [R]26D: +5 (c
0.8, CHCl3). 1H-NMR (400 MHz, CDCl3): δ 1.37 (3H, s), 1.38-
1.49 (1H, m), 1.50-1.60 (2H, m), 1.60-1.72 (3H, m), 1.82 (1H,
dq, J ) 13.8, 2.5 Hz), 1.92 (1H, brd, J ) 12.8 Hz), 2.3-2.4
(1H, m), 2.42 (1H, d, J ) 18.0 Hz), 2.65 (1H, ddd, J ) 18.0,
7.0, 0.8 Hz). 13C-NMR (50 MHz, CDCl3): δ 17.3, 26.6, 28.9,
30.3, 35.1, 36.4, 37.2, 80.7, 172.4. IR (neat): 1721 cm-1. MS
(EI): m/e 154 (M, 83), 139 (M - CH3, 10), 111 (M - C3H7, 84),
110 (M - CO2, 20), 97 (M - C3H5O, 100). HRMS: Calcd for
C9H14O2 154.0994; found 154.0987.
Diisop r op yl
(+)-(1-P r op yl-3-oxop r op yl)m a lon a t e.
[R]24 +4.6 (c 1.0, CHCl3, 41% ee). 1H-NMR (200 MHz,
:
D
CDCl3): δ 0.91 (3H, t, J ) 7.0 Hz), 1.24 (6H, d, J ) 6.3 Hz),
1.25 (6H, d, J ) 6.3 Hz), 1.3-1.5 (4H, m), 2.48 (1H, ddd, J )
18.5, 8.2, 2.0 Hz), 2.6-2.8 (2H, m), 3.44 (1H, d, J ) 5.9 Hz),
5.05 (2H, septet, J ) 6.3 Hz), 9.76 (1H, dd, J ) 2.0, 1.3 Hz).
13C-NMR (50 MHz, CDCl3): δ 13.6, 19.6, 21.16, 21.22, 31.8,
34.3, 45.6, 54.5, 68.5, 167.5, 167.8, 200.7. IR (neat): 1727 cm-1
.
Anal. Calcd for C15H26O5: C; 62.91, H; 9.15. Found: C; 62.41,
H; 8.92. The enantiomeric excess was determined by 1H-NMR
(600 MHz, CD3CN) of the ketal with (2R,3R)-2,3-butanediol
by observing at δ 3.46 (d, J ) 6.7 Hz) and δ 3.49 (d, J ) 6.6
Hz).
(S)-(+)-3-(2-Oxop r opyl)cycloh exa n on e [(S)-(+)-18]. Un-
der an argon atmosphere, a mixture of (R)-(+)-17 (351 mg, 1.38
mmol) and trifluoroacetic acid (1 mL) was stirred at room
temperature for 1 h. Volatile materials were removed by
repeated addition and evaporation of benzene. Benzene (5 mL)
was then added to the residue, and the mixture was heated
at reflux for 1 h. Removal of the solvent and flash chroma-
Diisop r op yl (S)-(+)-(1-Meth yl-3-oxop r op yl)m a lon a te
[(S)-(+)-11]. [R]22D: +5.6 (c 1.0, CHCl3, 35% ee). 1H-NMR
(200 MHz, CDCl3): δ 1.07 (3H, d, J ) 6.8 Hz), 1.25 (12H, d, J
) 6.3 Hz), 2.41 (1H, ddd, J ) 17.2, 8.6, 2.2 Hz), 2.70 (1H, dd,
J ) 17.2, 4.3 Hz), 2.7-3.0 (1H, m), 3.28 (1H, d, J ) 7.1 Hz),
5.059 (1H, septet, J ) 6.3 Hz), 5.065 (1H, septet, J ) 6.3 Hz),
9.75 (1H, dd, J ) 2.2, 1.1 Hz). 13C-NMR (50 MHz, CDCl3): δ
17.9, 21.6, 27.7, 48.1, 56.8, 68.9, 167.8, 200.8. IR (neat): 1727
cm-1. Anal. Calcd for C13H22O5: C; 60.45, H; 8.58. Found:
C; 60.40, H; 8.72. The enantiomeric excess was determined
tography on silica gel gave (S)-(+)-18 (191 mg, 90%). [R]22
:
D
+3.9 (c 3.1, C6H6, 26% ee). Lit.21 [R]25D: +14.6 (C6H6). 1H-
NMR (200 MHz, CDCl3): δ 2.14 (3H, s), 1.2-2.6 (11H, m). 13C-
NMR (50 MHz, CDCl3): δ 24.7, 30.2, 30.7, 34.1, 41.0, 47.3,
49.5, 206.7, 210.4. IR (neat): 1711 cm-1. Optical purity was
determined by 13C-NMR (50 MHz, CDCl3) of bisketal with
(2R,3R)-2,3-butanediol by observing at δ 23.4/23.8, 31.5/32.1,
and 36.4/37.4.
1
by H-NMR (600 MHz, CDCl3) of the ketal with (2R,3R)-2,3-
butanediol by observing at δ 3.30 (d, J ) 7.2 Hz) and δ 3.32
(d, J ) 7.2 Hz).
Rin g En la r gem en t of (R)-(+)-4 to Meth yl (R)-(+)-3-
Oxocycloh ep ta n ea ceta te by Dia zom eth a n e.19 A solution
of KOH (0.5 g) in H2O-MeOH (1:1, 1.5 mL) was slowly added
to a methanol (3 mL) solution of (R)-(+)-4 (49% ee, 130 mg,
0.77 mmol) and N-methyl-N-nitroso-p-toluenesulfonamide (199
mg, 0.93 mmol) at 0 °C. The mixture was stirred for 15 min
at the temperature and was acidified by adding 1 M HCl.
Organic materials were extracted with chloroform, dried over
Na2SO4, and concentrated in vacuo. The resulted carboxylic
acid was treated with diazomethane in ether at 0 °C, giving
an isomeric mixture of methyl 3-oxo- and 4-oxocyclohepta-
neacetate (99 mg, 70%). Methyl (R)-(+)-3-Oxocycloheptaneac-
etate (16% yield) was obtained by repeated flash chromatog-
raphy on silica gel. [R]24D: +21 (c 1.27, CHCl3). 1H-NMR, 13C-
NMR, IR, and the sign of the optical rotation coincided with
the compound synthesized by decarboxylation of (R)-(+)-7.
Or ga n om eta l Ad d ition to Diisop r op yl (S)-(+)-(1-Meth -
yl-3-oxop r op yl)m a lon a te [(S)-(+)-11] F ollow ed by Oxid a -
tion . Under an argon atmosphere, (S)-(+)-11 (35% ee, 174
mg, 0.67 mmol) in THF (3 mL) was added at -40 °C to
n-propylmagnesium bromide in THF (2 mL), prepared from
magnesium (100 mg, 4.11 mmol) and n-propyl bromide (0.4
mL). After stirring for 30 min at the temperature the mixture
was warmed to 0 °C. The reaction was quenched by adding 1
M HCl, and the organic materials were extracted twice with
ethyl acetate. The combined extracts were washed with water
and brine, dried over Na2SO4, filtered, concentrated, and flash
chromatographed over silica gel giving a diastereomeric
mixture of diisopropyl (1-methyl-3-hydroxyhexyl)malonate (99
ter t-Bu tyl (R)-(+)-3-Oxo-2-(3-oxocycloh exyl)bu ta n oa te
[(R)-(+)-17]. Reaction of tert-butyl acetoacetate (16) and 1
in the presence of 10 mol % of L-proline rubidium salt gave
(R)-(+)-17 in 77% yield as a 1:1 mixture of diastereomers.
[R]22D: +3 (c 1.1, CHCl3, 26% ee, mixture of diastereomers).
1H-NMR (200 MHz, CDCl3): δ 1.2-2.6 (9H, m), 1.47 (4.5H,
s), 1.48 (4.5H, s), 2.21 (1.5H, s), 2.23 (1.5H, s), 3.27 (0.5H, d,
J ) 8.8 Hz), 3.28 (0.5H, d, J ) 8.8 Hz). 13C-NMR (50 MHz,
CDCl3): δ 25.0, 28.3, 28.9, 29.5, 29.8, 38.1, 41.5, 41.6, 45.4,
45.9, 66.2, 66.6, 82.9, 167.6, 167.8, 202.2, 202.3, 210.0, 210.1.
IR (neat): 1715 cm-1. MS (EI): m/e 254 (M, 0.6), 198 (M -
C4H8, 100), 181 (M - C4H9O, 38). HRMS: Calcd for C14H22O4
254.1518; found 254.1519. The enantiomeric excess was
determined by converting to (S)-(+)-18.
Decar boxylation an d Ester ification P r ocedu r es. Meth -
yl (R)-(+)-3-Oxocycloh ep ta n ea ceta te. (R)-(+)-7 (54% ee,
500 mg, 1.67 mmol) in 6 M HCl (10 mL) was refluxed for 9 h.
On cooling, organic materials were extracted with chloroform,
dried over Na2SO4, and concentrated. The residue was dis-
solved in methanol (2 mL), and an excess diazomethane in
ether was added at 0 °C. After removing the solvents in vacuo,
the product (264 mg, 86%) was obtained by flash chromatog-
raphy on silica gel. [R]25D: +32 (c 1.9, CHCl3). 1H-NMR (200
MHz, CDCl3): δ 1.20-1.74 (3H, m), 1.78-2.04 (3H, m), 2.16-
2.40 (3H, m), 2.42-2.65 (4H, m), 3.68 (3H, s). 13C-NMR (50
MHz, CDCl3): δ 23.9, 28.1, 32.4, 36.2, 41.1, 43.5, 49.1, 51.2,
172.1, 212.6. IR (neat): 1738, 1702 cm-1
Meth yl (R)-(+)-3-Oxocycloh exa n ea ceta te [(R)-(+)-4].
.

Catalytic Asymmetric Michael Addition of Malonate
J . Org. Chem., Vol. 61, No. 10, 1996 3529
mg, 49%). The hydroxy ester (99 mg, 0.33 mmol) was oxidized
according to the Swern’s method (ClCOCOCl, DMSO, Et3N,
CH2Cl2, -60 °C), giving (S)-(+)-12 (81 mg, 82%). [R]22D: +5.6
(c 1.0, CHCl3). 1H-NMR, IR, and the sign of the optical rotation
coincided with (S)-(+)-12 obtained by the Michael addition.
Similarly, reaction of (S)-(+)-11 and methyllithium at -78
°C followed by PDC oxidation gave (S)-(+)-9. [R]23D: +4.8 (c
0.79, CHCl3).
m). 13C-NMR (50 MHz, CDCl3): δ 27.8, 27.9, 30.1, 33.2, 33.3,
34.1, 45.4, 55.6, 81.5, 81.6, 125.7, 128.2, 128.3, 141.7, 167.9,
168.1, 207.3. IR (neat): 1723 cm-1
. MS (EI): m/e 390 (M,
0.7), 334 (M - C4H8, 16), 278 (M - C8H16, 58), 261 (M -
C8H17O, 33), 242 (M - C8H20O2, 24), 234 (M - C9H16O2, 100).
HRMS: Calcd for C23H34O5 390.2412; found 390.2406. The
enantiomeric excess was determined by converting to methyl
ester (TFA and diazomethane) followed by ketalization with
(2R,3R)-2,3-butanediol. 1H-NMR (200 MHz, CDCl3) peaks at
δ 3.86 (d, J ) 4.8 Hz) and 3.96 (d, J ) 4.6 Hz) were compared.
Th e Mich a el Ad d it ion R ea ct ion of Di(ter t-b u t yl)
Ma lon a te (20) to En on es a n d En a ls. Di(ter t-bu tyl) (R)-
(+)-(3-Oxocycloh exyl)m a lon a te. Under an argon atmo-
sphere, a mixture of di(tert-butyl) malonate (20, 0.88 mL, 4.5
mmol), 1 (0.25 mL, 2.5 mmol), L-proline rubidium salt (100
mg, 0.50 mmol), and CsF (70 mg, 0.50 mmol) in CHCl3 (2 mL)
was stirred vigorously at rt for 35 h. The reaction was
quenched by adding 2 M HCl, and organic materials were
extracted twice with ethyl acetate. The combined extracts
were washed with brine, dried over Na2SO4, filtered, concen-
trated, and flash chromatographed over silica gel, giving the
(R)-(+)-adduct (658 mg, 84%). Mp: 37-38 °C. [R]26D: +4.2
(CHCl3, c 1.02, 65% ee). 1H-NMR (200 MHz, CDCl3): δ 1.18-
1.82 (2H, m), 1.47 (18H, s), 1.92-2.58 (7H, m), 3.10 (1H, d, J
) 7.7 Hz). 13C-NMR (50 MHz, CDCl3): δ 24.3, 27.5, 28.4, 37.5,
40.7, 44.7, 58.3, 81.3, 166.7, 209.3. IR (neat): 1725 cm-1. MS
(EI): m/e 256 (M, 31), 241 (M - CH3, 22), 200 (M - C4H8, 100).
HRMS: Calcd for C17H28O5 312.1937; found 312.1937. Anal.
Calcd for C17H28O5: C; 65.36, H; 9.03. Found: C; 65.06, H;
8.87. The enantiomeric excess was determined by converting
to dimethyl ester (trifluoroacetic acid (TFA) and diazomethane
at rt) followed by ketalization with (2R,3R)-2,3-butanediol
under toluene reflux in the presence of a catalytic amount of
p-toluenesulfonic acid. The crude product was analyzed to
avoid kinetic resolution during the ketalization procedures.
13C-NMR (50 MHz, CDCl3) peaks at δ 41.4/40.4 and 23.1/22.8
were compared. An authentic sample was prepared by ket-
alization of the racemic adduct, and these chemical shifts were
confirmed to be those of the diastereomers. The absolute
configuration was determined by decarboxylation in 6 M HCl
Di(ter t-b u t yl)
(+)-(1-P h en yl-3-oxob u t yl)m a lon a t e.
Mp: 92-94°C (hexane). [R]22D: +18 (CHCl3, c 1.1, 60% ee).
1H-NMR (200 MHz, CDCl3): δ 1.19 (9H, s), 1.46 (9H, s), 2.00
(3H, s), 2.84 (1H, dd, J ) 16.2, 9.3 Hz), 2.95 (1H, dd, J ) 16.2,
4.7 Hz), 3.50 (1H, d, J ) 10.2 Hz), 3.85 (1H, ddd, J ) 10.2,
9.3, 4.7 Hz), 7.10-7.28 (5H, m). 13C-NMR (50 MHz, CDCl3):
δ 27.4, 27.8, 30.2, 40.5, 48.0, 59.0, 81.3, 81.9, 126.9, 128.2,
128.3, 140.6, 166.8, 167.5, 206.2. IR (neat): 1744, 1715 cm-1
.
MS (EI): m/e 362 (M, 1), 306 (M - C4H8, 21), 289 (M - C4H9,
3), 250 (M - C8H16, 100). HRMS: Calcd for C21H30O5 362.2094;
found 3962.2089. The enantiomeric excess was determined
by converting to methyl ester (TFA and diazomethane) fol-
lowed by ketalization with (2R,3R)-2,3-butanediol. 1H-NMR
(200 MHz, CDCl3) peaks at δ 1.22 (s)/1.24 (s) and 3.85 (d, J )
9.7 Hz)/3.89 (d, J ) 9.3 Hz) were compared. The absolute
configuration was determined by decarboxylation in 6 M HCl
and esterification with diazomethane giving (S)-(+)-14. [R]22
-12 (C6H6, c 0.5).
:
D
Di(ter t-b u t yl) (+)-(1-Met h yl-3-oxop en t yl)m a lon a t e.
Mp: 44-45 °C (hexane). [R]23D: +14 (CHCl3, c 1.3, 76% ee).
1H-NMR (200 MHz, CDCl3): δ 1.01 (3H, d, J ) 6.6 Hz), 1.05
(3H, t, J ) 7.3 Hz), 1.46 (18H, s), 2.26-2.54 (3H, m), 2.58-
2.80 (2H, m), 3.12 (1H, d, J ) 6.8 Hz). 13C-NMR (50 MHz,
CDCl3): δ 7.6, 17.5, 27.8, 28.7, 36.2, 46.5, 58.1, 81.3, 167.8,
210.0. IR (neat): 1723 cm-1. Anal. Calcd for C17H30O5: C;
65.94, H; 9.62. Found: C; 65.17, H; 9.62. The enantiomeric
excess was determined by converting to methyl ester (TFA and
diazomethane) followed by ketalization with (2R,3R)-2,3-
butanediol. 1H-NMR (600 MHz, C6D6) peaks at δ 3.75 (d, J )
6.3 Hz) and δ 3.91 (d, J ) 5.5 Hz) were compared.
and esterification with diazomethane giving (S)-(+)-4. [R]22
+12 (CHCl3, c 2.9).
:
D
Di(ter t-b u t yl)
(R)-(+)-(3-Oxocycloh ep t yl)m a lon a t e.
Di(ter t-bu tyl) (S)-(+)-(1′-Meth yl-3-oxobu tyl)m a lon a te.
3-Penten-2-one (Aldrich) was used after distillation, which
contained 17% of 4-methyl-3-penten-2-one. Mp: 60-61 °C
(hexane). [R]30D: +15 (CHCl3, c 2.0, 88% ee). 1H-NMR (200
MHz, CDCl3): δ 1.01 (3H, d, J ) 7.0 Hz), 1.46 (18H, s), 2.14
(3H, s), 2.36 (1H, dd, J ) 17.6, 9.9 Hz), 2.60-2.80 (2H, m),
3.13 (1H, d, J ) 6.9 Hz). 13C-NMR (50 MHz, CDCl3): δ 17.5,
27.8, 28.7, 30.1, 47.8, 58.2, 81.4, 167.9, 207.3. IR (neat): 1721
cm-1. MS (EI): m/e 300 (M, 0.08), 244 (M - C4H8, 21), 188
(M - C8H16, 100). HRMS: Calcd for C16H28O5 300.1937; found
300.1920. Anal. Calcd for C16H28O5: C; 63.98, H; 9.39.
Found: C; 63.93, H; 9.50. The enantiomeric excess was
determined by converting to methyl ester (TFA and diaz-
omethane) followed by ketalization with (2R,3R)-2,3-butane-
diol. 1H-NMR (600 MHz, C6D6) peaks at δ 3.89 (d, J ) 5.5
Hz) and δ 3.74 (d, J ) 6.1 Hz) were compared. The absolute
configuration was determined by decarboxylation in 6 M HCl
[R]23 +29 (CHCl3, c 1.02, 76% ee). 1H-NMR (200 MHz,
:
D
CDCl3): δ 1.20-1.70 (2H, m), 1.46 (18H, s), 1.74-2.04 (4H,
m), 2.32-2.68 (5H, m), 3.10 (1H, d, J ) 6.7 Hz). 13C-NMR (50
MHz, CDCl3): δ 24.3, 27.7, 28.7, 34.0, 35.3, 43.4, 47.1, 59.1,
81.6, 167.3, 167.4, 212.7. IR (neat): 1729 cm-1. Anal. Calcd
for C18H30O5: C; 66.23, H; 9.26. Found: C; 66.93, H; 9.56. The
enantiomeric excess was determined by converting to methyl
ester (TFA and diazomethane) followed by ketalization with
(2R,3R)-2,3-butanediol. 1H-NMR (600 MHz, CDCl3) peaks at
δ 3.36 (d, J ) 7.4 Hz) and δ 3.38 (d, J ) 7.9 Hz) were compared.
The absolute configuration was determined by decarboxylation
in 6 M HCl and esterification with diazomethane giving methyl
(R)-(+)-3-oxocycloheptaneacetate. [R]18D: +49 (CHCl3, c 1.12).
Di(t-bu ytl) (+)-(3-Oxocyclod od ecyl)m a lon a te. (E)-2-
Cyclododecenone was synthesized from cyclododecanone via
silyl enol ether by using Tsuji method.47 Mp: 96.5-97.5 °C
(hexane). [R]21D: +4 (CHCl3, c 0.6, 81% ee). 1H-NMR (200
MHz, CDCl3): δ 1.20-1.72 (15H, m), 1.45 (9H, s), 1.47 (9H,
s), 1.74-1.92 (1H, m), 2.36 (1H, ddd, J ) 15.2, 6.8, 1.8 Hz),
2.52-2.82 (4H, m), 3.32 (1H, d, J ) 7.4 Hz). 13C-NMR (50
MHz, CDCl3): δ 22.6, 22.8, 23.1, 24.7, 25.1, 25.2, 25.5, 28.5,
33.3, 41.1, 44.3, 56.9, 82.0, 82.1, 168.4, 168.7, 211.6 (one peak
overlapped). IR (KBr): 1738, 1705 cm-1. MS (EI): m/z 396
(M, 3), 340 (M - C4H8, 10), 284 (M - C8H16, 100). HRMS:
Calcd for C23H40O5 396.2876; found 396.2878. The enantio-
meric excess was determined by converting to methyl ester
(TFA and diazomethane) followed by ketalization with (2R,3R)-
2,3-butanediol. 1H-NMR (600 MHz, CDCl3) peaks at δ 4.17
(d, J ) 3.5 Hz) and 4.30 (d, J ) 3.5 Hz) were compared.
Dim eth yl (S)-(+)-(3-Oxocyclopen tadecyl)m alon ate [(S)-
(+)-22]. Reaction of di(tert-butyl) malonate (20, 0.84 mL, 3.75
mmol) and (E)-2-cyclopentadecenone24 (21, 277 mg, 1.25 mmol)
and esterification with diazomethane giving (S)-(+)-10. [R]22
+1.5 (c 5.5, ether).
:
D
Di(ter t-bu tyl) (+)-(1-P en tyl-3-oxobu tyl)m a lon a te. [R]D
+7.5 (CHCl3, c 1.0, 88% ee). 1H-NMR (200 MHz, CDCl3): δ
0.87 (3H, t, J ) 6.5 Hz), 1.16-1.40 (8H, m), 1.46 (18H, s), 2.15
(3H, s), 2.47 (1H, dd, J ) 15.7, 6.6 Hz), 2.52-2.68 (1H, m),
2.73 (1H, dd, J ) 15.7, 3.4 Hz), 3.33 (1H, d, J ) 5.4 Hz). 13C-
NMR (50 MHz, CDCl3): δ 13.8, 22.3, 26.4, 27.8, 30.1, 31.7,
32.0, 32.2, 45.4, 55.7, 81.2, 81.3, 167.9, 168.2, 207.4. IR
(neat): 1725 cm-1
. Anal. Calcd for C20H36O5: C; 67.38, H;
10.18. Found: C; 67.26, H; 10.20. The enantiomeric excess
was determined by converting to methyl ester (TFA and
diazomethane) followed by ketalization with (2R,3R)-2,3-
butanediol. 1H-NMR (600 MHz, CDCl3) peaks at δ 3.81 (d, J
) 4.3 Hz) and δ 3.91 (d, J ) 5.0 Hz) were compared.
Di(ter t-bu tyl) (+)-(1-P h en yleth yl-3-oxobu tyl)m a lon a te.
[R]D +1.6 (CHCl3, c 1.0, 86% ee). 1H-NMR (200 MHz, CDCl3):
δ 1.45 (9H, s), 1.47 (9H, s), 1.62-1.81 (2H, m), 2.12 (3H, s),
2.42-2.86 (5H, m), 3.41 (1H, d, J ) 5.4 Hz), 7.10-7.33 (5H,
(47) Minami, I.; Takahashi, K.; Shimizu, I.; Kimura, T.; Tsuji, J .
Tetrahedron 1986, 42, 2971.

3530 J . Org. Chem., Vol. 61, No. 10, 1996
Yamaguchi et al.
gave crude product (985 mg). A part of the adduct (351 mg)
was treated with TFA and diazomethane. Flash chromatog-
raphy on silica gel gave dimethyl ester (S)-(+)-22 (86 mg,
corresponding to 54% yield from 21). [R]21D: +17 (CHCl3, c
1.0, 82% ee). 1H-NMR (200 MHz, CDCl3): δ 1.10-1.78 (22H,
m), 2.24-2.78 (5H, m), 3.51 (1H, d, J ) 6.2 Hz), 3.67 (3H, s),
3.68 (3H, s). 13C-NMR (50 MHz, CDCl3): δ 23.5, 25.9, 26.3,
26.7, 27.0 (3 carbons), 27.3, 27.6, 28.1, 32.4, 33.9, 42.5, 44.9,
52.7, 52.8, 55.4, 169.5, 169.7, 210.5. IR (neat): 1738 cm-1. MS
(EI): m/z 354 (M, 60), 323 (M - CH3O, 26), 263 (M - C3H7O3,
21), 223 (M - C5H7O4, 100). HRMS: Calcd for C20H34O5
354.2406; found 354.2404. The enantiomeric excess was
determined by ketalization with (2R,3R)-2,3-butanediol. 1H-
NMR (600 MHz, C6D6) peaks at δ 3.32 (s) and 3.33 (s) were
compared.
-11.7 (MeOH, c 0.8, (R)-muscone). 1H-NMR and IR spectra
coincided with the reported data.25 13C-NMR (CDCl3, 50 MHz)
δ 21.6, 23.5, 25.5, 26.6, 26.7, 27.0, 27.0, 27.1, 27.2, 27.6, 28.0,
29.5, 36.0, 42.5, 50.9, 212.5.
1-(4-P h en yl-3-bu ten -2-ylid en e)p yr r olid in e P er ch lor a te
(25).36 Triethylamine (80 µL, 0.58 mmol) was added to a
solution of pyrrolidine perchlorate (1.00 g, 5.83 mmol) and
4-phenyl-3-buten-2-one (1.63 g, 11.2 mmol) in ethanol (5 mL).
After stirring for 40 min, the precipitate was filtered and
washed with ethanol, giving 25 (1.12 g, 68%). 1H-NMR (200
MHz, CD3CN-CDCl3): δ 2.17-2.28 (4H, m), 2.64 (3H, s), 3.94-
4.18 (4H, m), 7.13 (1H, d, J ) 15.6 Hz), 7.25-7.62 (3H, m),
7.68-7.81 (2H, m), 7.89 (1H, d, J ) 15.6 Hz). IR (neat): 1626
cm-1. Anal. Calcd for C14H18NO4Cl. C; 56.10, H; 6.05; N, 4.67.
Found. C; 55.84, H; 6.04; N, 4.66.
Th e Ha jos-Wiech er t Rea ction w ith L-P r olin e Ru -
bid iu m Sa lt. Under an argon atmosphere, a mixture of
2-methyl-2-(3-oxobutyl)-1,3-cyclopentanedione (100 mg, 0.55
mmol) and L-proline rubidium salt (11 mg, 0.055 mmol) in
CHCl3 was stirred at rt for 54 h. The reaction was quenched
by adding 2 M HCl, and organic materials were extracted five
times with CH2Cl2. The combined extracts were dried over
Na2SO4 and concentrated in vacuo. Flash chromatography on
silica gel gave (+)-(3aS,7aS)-3a,4,7,7a-tetrahydro-3a-hydroxy-
7a-methyl-1,5(6H)-indandione (45 mg, 45%). [R]22D: +28 (c
0.90, CHCl3). Under an argon atmosphere a mixture of the
aldol (45 mg, 0.25 mmol) and a catalytic amount of p-
toluenesulfonic acid in benzene (10 mL) was heated at reflux
for 2 h. After the mixture was cooled to rt, saturated aqueous
NaHCO3 was added, and organic materials were extracted four
times with CH2Cl2. After the resulting mixture was dried over
Na2SO4, the solvents were removed in vacuo, and flash
chromatography on silica gel gave (7aS)-(+)-7,7a-dihydro-7a-
methyl-1,5(6H)-indandione, (39 mg, 95%). [R]22D: +158 (c 1.1,
benzene). It corresponds to 43% ee. Lit.37 [R]25D: +369 (c 1.0,
benzene).
(S)-(+)-Mu scon e, (S)-(+)-24. To a crude product obtained
from 21 (447 mg, 2.0 mmol) and 20 (1.0 mL, 4.5 mmol) was
added trifluoroacetic acid (1 mL). After standing for 1 h at
room temperature the solvent was evaporated in vacuo.
A
trace amount of trifluoroacetic acid was removed azeotropically
with benzene. Then, toluene (3 mL) was added, and the
mixture was stirred at reflux for 10 h. After the solvent was
removed, (S)-(+)-(3-oxocyclopentadecyl)acetic acid (S)-(+)-23
(389 mg, 69%) was obtained by flash chromatography on silica
gel. Mp: 86.5-88.0 °C (hexane). [R]22D: +12 (CHCl3, c 1.9).
1H-NMR (200 MHz, CDCl3): δ 1.20-1.45 (20H, m), 1.45-1.75
(2H, m), 2.29-2.52 (7H, m), 10.7 (1H, br). 13C-NMR (50 MHz,
CDCl3): δ 23.5, 25.4, 26.4, 26.6, 27.0 (two carbons overlapped),
27.1, 27.2, 27.5, 28.1, 31.1, 33.7, 39.8, 42.7, 47.1, 179.3, 211.6.
IR (KBr): 3600-2400, 1700 cm-1
. Under a nitrogen atmo-
sphere, a mixture of (S)-(+)-23 (148 mg, 0.52 mmol), 1-hydroxy-
2-mercaptopyridine (75 mg, 0.59 mmol), dicyclohexylcarbodi-
imide (186 mg, 0.90 mmol), 4-(N,N-dimethylamino)pyridine
(111 mg, 0.90 mmol), and benzene (4 mL) was stirred at reflux
for 0.25 h. A benzene (1 mL) solution of Bu3SnH (0.54 mL,
2.0 mmol) and a catalytic amount of AIBN were then added
at the temperature. Stirring was continued for 0.5 h at reflux,
when CCl4 (10 mL) was added. After another 1 h of heating,
the solvents were removed in vacuo. Iodine (2.0 g, 7.9 mmol),
CH2Cl2 (5 mL), and saturated aqueous KF (1 mL) were added,
and the mixture was stirred vigorously at rt overnight.
Insoluble materials were removed by filtration through celite.
Organic materials were extracted twice with CH2Cl2, washed
with aqueous NaHSO3 and brine, dried over Na2SO4, and
concentrated. Flash chromatography on silica gel gave (S)-
(+)-24 (65 mg, 52%). [R]22D: +9.4 (MeOH, c 1.12). Lit.24 [R]D
Ack n ow led gm en t. We thank Professor T. Minami,
Mr. K. Yokota, and Mr. M. Okuma (Kyushu Institute
of Technology) for encouragement and assistance at the
early stage of the present work. This work was sup-
ported by a grant from the Ministry of Education,
Science and Culture, J apan (No. 06225203).
J O960216C