Use of odorless thiols: Formal asymmetric Michael addition of hydrogen sulfide to α-substituted α,β-unsaturated carbonyl compounds

Article abstract of DOI:10.1021/ol016406d

(formula presented) The Michael addition to α-substituted α,β-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded diastereoselectively. The Michael adducts were converted to β-mercapto esters and amides via a Wagner-

Full text of DOI:10.1021/ol016406d

ORGANIC
LETTERS
2001
Vol. 3, No. 20
3121-3124
Use of Odorless Thiols: Formal
Asymmetric Michael Addition of
Hydrogen Sulfide to r-Substituted
r,â-Unsaturated Carbonyl Compounds
Kiyoharu Nishide, Shin-ichi Ohsugi, Hiroaki Shiraki, Hirokazu Tamakita, and
Manabu Node*
Department of Pharmaceutical Manufacturing Chemistry,
Kyoto Pharmaceutical UniVersity, Misasagi, Yamashina, Kyoto 607-8414, Japan
node@mb.kyoto-phu.ac.jp
Received July 9, 2001
ABSTRACT
The Michael addition to r-substituted r,â-unsaturated esters and amides using complex A containing a chiral odorless thiol proceeded
diastereoselectively. The Michael adducts were converted to â-mercapto esters and amides via a Wagner−Meerwein rearrangement with boron
trifluoride etherate and a thiol exchange reaction using odorless 1-dodecanethiol. This conversion constitutes a formal asymmetric Michael
addition of hydrogen sulfide to r,â-unsaturated carbonyl compounds using odorless thiols instead of the toxic hydrogen sulfide.
The Michael addition of a thiol to R,â-unsaturated carbonyl
compounds is a fundamental reaction in organic chemistry.1
From the standpoint of asymmetric synthesis, this reaction
essentially consists of an asymmetric 1,4-addition and an
asymmetric protonation. Excellent diastereoselective2 and
enantioselective3 Michael additions of thiols to R,â-unsatur-
ated carbonyl compounds have been extensively studied.
However, the enantioselective protonation of enolates and
enols has only recently been recognized as a promising
method for the construction of a tertiary carbon center in
asymmetric synthesis.4 Therefore, much effort has been
focused on the enantioselective protonation of the enolates
derived from the parent carbonyl compounds.4 Only a few
studies have been reported on the reaction of the enolates
generated by 1,4-addition of a thiolate anion to R,â-
unsaturated carbonyl compounds.3g,h,5 Thiophosphonates of
1,1′-binaphthol as chiral equivalents of hydrogen sulfide were
used in radical additions to strained alkenes but with low
diastereoselectivity.6a Recently, Palomo et al. reported an
(1) Schmalz, H.-G. ComprehensiVe Organic Synthesis; Pergamon
Press: Oxford, 1991; Vol. 4, Chapter 1.5, pp 199-236.
(2) (a) Wu, M.-J.; Wu, C.-C.; Tseng, T.-C.; Pridgen, L. N. J. Org. Chem.
1994, 59, 7188-7189. (b) Tomioka, K.; Muraoka, A.; Kanai, M. J. Org.
Chem. 1995, 60, 6188-6190.
(3) (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417-
430. (b) Yamashita, H.; Mukaiyama, T. Chem. Lett. 1985, 363-366. (c)
Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Matsumoto, K. J. Org.
Chem. 1988, 53, 1157-1161. (d) Nishimura, K.; Ono, M.; Nagaoka, Y.;
Tomioka, K. J. Am. Chem. Soc. 1997, 119, 12974-12975. (e) Tomioka,
K.; Okuda, M.; Nishimura, K.; Manabe, S.; Kanai, M.; Nagaoka, Y.; Koga,
K. Tetrahedron Lett. 1998, 39, 2141-2144. (f) Kanemasa, S.; Oderaotoshi,
Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675-8676. (g) Emori, E.;
Arai, T.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1998, 120, 4043-
4044. (h) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem.,
Int. Ed. 2001, 40, 440-442.
(4) (a) Fehr, C. Angew. Chem., Int. Ed. Engl. 1996, 35, 2566-2587. (b)
Eames, J.; Weerasooriya, N. Tetrahedron: Asymmetry 2001, 12, 1-24. Also
see the references therein.
(5) (a) Pracejus, H.; Wilcke, F.-W.; Hanemann, K. J. Prakt. Chem. 1977,
319, 219-229. (b) Kobayashi, N.; Iwai, K. J. Am. Chem. Soc. 1978, 100,
7071-7072. (c) Kumar, A.; Salunkhe, R. V.; Rane, R. A.; Dike, S. Y. J.
Chem. Soc., Chem. Commun. 1991, 485-486. (d) Miyata, O.; Shinada, T.;
Ninomiya, I.; Naito, T. Tetrahedron 1997, 53, 2421-2438.
10.1021/ol016406d CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/31/2001

excellent asymmetric synthesis of â-mercapto carboxylic acid
derivatives by intramolecular sulfur transfer reaction.6b
However, there is no precedent for the highly asymmetric
Michael addition of hydrogen sulfide to R-substituted R,â-
unsaturated carbonyl compounds based on asymmetric pro-
tonation. We report herein the highly diastereoselective
Michael addition of a chiral odorless thiol to R-substituted
R,â-unsaturated carbonyl compounds and specific degrada-
tion of the Michael adduct using Lewis acid and an odorless
thiol. This constitutes a formal asymmetric Michael addition
of hydrogen sulfide under odorless conditions.
Recently, we developed a tandem Michael additions
Meerwein-Ponndorf-Verley reduction7 for the asymmetric
transformation of R,â-unsaturated ketones to secondary
alcohols using the chiral aluminum complex A generated
from Me2AlCl and (-)-10-mercaptoisoborneol,8,9 as shown
in Scheme 1. On the basis of the above reaction, we planned
aluminum enolate containing the chiral reagent, it is highly
likely that the intramolecular protonation from the hydro-
sulfonium ion in B occurs diastereoselectively to give the
sulfide 2 via the complex C. Therefore, removal of the chiral
reagent moiety from the sulfide to the â-mercapto derivative
3 would serve as a novel method for an asymmetric Michael
addition of hydrogen sulfide to R-substituted R,â-unsaturated
carbonyl compounds.
In previous tandem reactions (Scheme 1), it is known that
the Michael addition of a chiral thiol to the â-carbon of a
â-substituted R,â-unsaturated ketone proceeds with no
selectivity. Thus, an R-substituted R,â-unsaturated carbonyl
compound without a substituent at the â-carbon would be
suitable as the substrate for our strategy. Results of the
asymmetric protonation in the Michael addition of a chiral
thiol to R-substituted acrylic acid derivatives are summarized
in Table 1. The reaction of benzyl methacrylate (1a) with
Scheme 1. A Novel Asymmetric Reduction of
R,â-Unsaturated Ketones via Tandem Michael Addition-MPV
Reduction
Table 1. Asymmetric Michael Addition of Chiral Thiol to
R-Substituted Acrylic Acid Derivatives
substrate
Me2AlCl time
yield de
entry
R
Y
(equiv) (h) product (%) (%)
1
2
3
4
5
6
7
8
9
1a Me OBn
1a
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.2
1.2
1.2
1.2
1
12
2
2
2
2
2
1
2
1
1
1
2
2a
2a
2b
2c
2d
2e
2d
2g
2g
2h
2i
90 96a
67 92a
82 90b
90 93c
86 85a
92 94a
90 96c
40 90c
89 47c
100 75c
92 78c
100 80c
100 85c
1b Et OBn
1c Bn OBn
1d Me OMe
1e Bn OMe
1f Bn OEt
1g Ph OMe
1g
to examine the diastereoselective protonation of the 1,4-
adduct B in the Michael addition of complex A to R-sub-
stituted R,â-unsaturated carbonyl compounds 1 (Scheme 2).
Since the 1,4-adduct B forms the ten-membered ring
10 1h Me NHPh
11 1i Me NH(4-Br)Ph
12 1j Me NH(4-Cl)Ph
13 1k Me NH(4-F)Ph
2j
2k
a Determined by integrated intensity on NMR spectrum with shift reagent
Eu(fod)3. b Determined by ratio of isolated two diastereomers. c Determined
by integrated intensity on NMR spectrum (without shift reagent).
Scheme 2. A Strategy for the Synthesis of Optically Active
â-Mercapto Carbonyl Compounds 3 via Asymmetric Michael
Addition of A to 1
the chiral aluminum complex A (1.5 equiv) generated from
(-)-10-mercaptoisoborneol (98% ee) and Me2AlCl was
carried out in dichloromethane at room temperature. After
(6) (a) Fabbri, D.; Delogu, G.; De Lucchi, O. Tetrahedron: Asymmetry
1993, 4, 1591-1596. (b) Palomo, C.; Oiarbide, M.; Dias, F.; Ortiz, A.;
Linden, A. J. Am. Chem. Soc. 2001, 123, 5602-5603. See also the following
reference: (c) de March, P.; Figueredo, M.; Font, J.; Gonza´lez, L.; Salgado,
A. Tetrahedron: Asymmetry 1996, 7, 2603-2606.
(7) (a) Nishide, K.; Shigeta, Y.; Obata, K.; Node, M. J. Am. Chem. Soc.
1996, 118, 13103-13104. (b) Node, M.; Nishide, K.; Shigeta, Y.; Shiraki,
H.; Obata, K. J. Am. Chem. Soc. 2000, 122, 1927-1936.
(8) Eliel, E. L.; Frazee, W. J. J. Org. Chem. 1979, 44, 3598-3599.
(9) (-)-10-Mercaptoisoborneol has almost no odor compared to other
malodorous thiols. The syntheses and utility of other new odorless thiols
and sulfides will be published elsewhere.
3122
Org. Lett., Vol. 3, No. 20, 2001

1 h, the reaction gave both the highest yield and diastereo-
meric excess of all the adducts10 (entry 1). Prolonging the
reaction time resulted in a lowering of both the yield and de
of the product due to side reactions of debenzylation and
enolization in the Michael adduct (entry 2). The R-substit-
uents (Me, Et, Bn) on the benzyl esters did not affect the
yields and de values of the products which were generally
excellent (entries 1, 3, and 4). The diastereoselectivity in
the reaction of methyl methacrylate (1d) (entry 5) was lower
than that of benzyl methacrylate (1a) (entry 1), presumably
because the substituents at the R-position and the alkoxy
moiety in the ester group were less bulky. Methyl and ethyl
R-benzyl methacrylates (1e,f) (entries 6 and 7) both gave
good results. Therefore, bulkiness of either the R-substituent
or the alkoxy moiety of the ester is required to give
satisfactory results. The R-phenyl-substituted ester (1g) gave
high diastereoselectivity in 1 h but afforded a low yield of
the product (entry 8). When the reaction was prolonged, the
yields increased but the de values decreased presumably due
to the easy epimerization of the weakly acidic benzylic
methine (entry 9).
deduced that the protonation would occur from the inside
of the 10-membered ring, as illustrated in Scheme 3.
We next tried to convert the Michael adducts 2 into the
â-mercapto esters and amides 3. The chiral thiol reagent was
specifically designed to contain an isoborneol skeleton,
making it easy to remove under relatively mild conditions.
Thus, the Michael adduct 2a was subjected to boron
trifluoride etherate followed by the addition of ethanedithiol
to give the â-mercapto ester 3a, along with the dithioacetal
4 (Scheme 4). To avoid the stench of ethanedithiol, the
Scheme 4. Synthesis of â-Mercapto Ester 3a from Michael
Adduct 2a
Next, we examined the reactivity of the R-substituted R,â-
unsaturated amides in the Michael addition. The reaction of
the N-alkyl methacrylamides gave low diastereoselectivity
(∼60% de), while the reaction of anilide 1h showed relatively
high diastereoselectivity (75% de) (entry 10), indicating that
the donating ability of the lone pair of electrons on the
nitrogen atom might be related to the degree of diastereo-
selectivity in the adduct. Therefore, we attempted to improve
the diastereoselectivity by using amides containing haloge-
nated anilines 1i-k. As a result of the weak donating ability
of the nitrogen lone pair, the Michael addition reaction of
these halogenated anilides showed a higher de than the
reaction of 1h (entries 11-13). On the other hand, the
reaction of methacrylamides containing a secondary amine
(NR2) did not occur under the same conditions. In the case
of the enolate of the above amides, significant allylic strain
is generated on the nitrogen substituents and may retard the
1,4-addition of the thiol.
odorless 1-dodecanethiol9 was used in the thiol exchange of
D. The results of the major diastereomers of the esters 2a,
2c, and 2f, which were obtained by chromatographic separa-
tion, are listed in entries 1-3 of Table 2. Removal of the
Table 2. Removal of Isoborneol Moiety from Michael Adduct
2
substrateb
Dod-SH time
yield
The configuration of the resulting esters and amides was
determined to be R by chemical conversion to known
compounds.11 We initially thought that the protonation of
the E-enolate intermediate B-1 could occur from the outside
of the 10-membered ring7 as shown in Scheme 2. However,
MOPAC PM3 calculations of the sulfonium enolates B
revealed that the Z-enolate (B-2) is more stable than the
E-enolate (B-1), as shown in Scheme 3. Therefore, we
entry
R
Y
(equiv)
(h) product (%)c
1
2
3
4
5
6
2a Me OBn
2c Bn OBn
2f Bn OEt
2h Me NHPh
2i Me NH(4-Br)Ph
2j Me NH(4-Cl)Ph
30
30
30
10
10
10
2
2
2
3
2.5
3.5
3a
3c
3f
3h
3i
86d
89d
80d
74d,f
77e,f
91d,f
3j
a 1-Dodecanethiol. b Substrates 2a, 2c, and 2f are the major diastereomers
in the reaction of Table 1, obtained by chromatographic separation (Kusano
silica gel packed column Si-10 or 40). Substrates 2h, 2i, and 2j were
obtained by amidation of acid 5 in Scheme 5. c Ee of all products was
detected as >98%. d Daicel Chiralcel OJ. e Shiseido Ceramospher Chiral
RU-1. f Ee. was determined by its acetate.
Scheme 3. PM3 Calculations of the Intermediates B
chiral reagent moiety proceeded smoothly at room temper-
ature in good yields. The configuration at the R-carbon was
completely retained under the acidic conditions.
Since we could not isolate the major diastereomers of the
amides 2 by chromatographic separation, we tried synthesiz-
Org. Lett., Vol. 3, No. 20, 2001
3123

ing â-mercapto amides utilizing the major diastereomer of
the ester 2a. Namely, the optically pure amides 2h-j
were synthesized from the benzyl ester 2a (100% de) by
debenzylation using Me2AlCl in odorless 1-dodecyl methyl
sulfide,9 followed by amidation of the carboxylic acid 5 with
the aniline derivatives (Scheme 5). The â-mercapto amides
a formal asymmetric Michael addition of hydrogen sulfide
to R-substituted R,â-unsaturated carbonyl compounds. The
above synthetic method using odorless thiols instead of toxic
malodorous hydrogen sulfide should be of great interest to
green chemistry.
Acknowledgment. We are grateful for a Grant-in-Aid
(No. 13470474) from the Ministry of Education, Science,
Sports and Culture of Japan for partial financial support of
this research.
Scheme 5. An Alternative Synthetic Method for Optically
Pure Amides 2h-j
Supporting Information Available: Typical experimen-
tal procedure and spectroscopic data for 2a, 2h, 3a, 3h, and
6 and an ORTEP drawing of the intermediate for the
synthesis of the captopril derivative 6. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL016406D
(10) The diastereomeric excess of protonation depended on the dryness
of the (-)-10-mercaptoisoborneol which was used after drying overnight
over phosphorous pentoxide under high vacuum.
(11) For example, the R-configuration at the R-position of the ester 2f
was determined by comparison of the sign of the specific rotation of (R)-
ethyl 2-methyl-3-phenylpropionate obtained by reductive desulfurization
of 2f with Raney nickel with that in the literature: (a) Levene, P. A.; Marker,
R. E. J. Biol. Chem. 1935, 110, 299-309. (b) Cohen, S. G.; Milovanovic,
A. J. Am. Chem. Soc. 1968, 90, 3495-3502. (c) Jacques, J.; Gros, C.;
Bourcier, S. Stereochemistry: Fundamentals and Methods; Georg Thieme
Publishers: Stuttgart, 1977; Vol. 4, p 84, entry l. An X-ray crystallographic
analysis of (2S)-N-{3-[(1R,2S,4S)-2-hydroxybornane-10-sulfenyl]-2-meth-
ylpropanoyl}-L-proline benzyl ester, an intermediate for the synthesis of
the captopril derivative 6, showed the S-configuration at the R-position of
the amide carbonyl, in which the enantiomer (+)-A was used (see
Supporting Information).
3h-j with higher optical purity (>98% ee) were prepared
from 2h-j by degradation of the chiral reagent moiety
(entries 4-6 in Table 2). This method was applied to the
asymmetric synthesis of the captopril derivative 612 (overall
yield 74% from 2a in three steps).
In conclusion, we have found a highly diastereoselective
Michael addition of a thiol to R-substituted R,â-unsaturated
esters. Subsequent cleavage of the chiral auxiliary from the
Michael adduct via a Wagner-Meerwein rearrangement and
a thiol exchange of the vinyl thioether intermediates furnished
(12) Captopril is used in clinics as an orally active antihypertensive agent
having a unique inhibitory action on the angiotensin-converting enzyme.
Its derivative 6 was prepared from ent-5 which was obtained in this Michael
addition of (+)-A derived from (-)-10-camphorsulfonic acid.
3124
Org. Lett., Vol. 3, No. 20, 2001