Direct Catalytic Asymmetric Conjugate Addition of Saturated and Unsaturated Thioamides

Article abstract of DOI:10.1021/acs.orglett.5b01644

Direct catalytic asymmetric conjugate addition of thiolactams to α,β-unsaturated thioamides was efficiently promoted by a soft Lewis acid/hard Bronsted base cooperative catalyst in a highly stereocontrolled manner. Thioamide functionality was crucial to p

Full text of DOI:10.1021/acs.orglett.5b01644

Letter
pubs.acs.org/OrgLett
Direct Catalytic Asymmetric Conjugate Addition of Saturated and
Unsaturated Thioamides
Nilanjana Majumdar,† Akira Saito,† Liang Yin,† Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,‡
†Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
‡JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
S
* Supporting Information
ABSTRACT: Direct catalytic asymmetric conjugate addition
of thiolactams to α,β-unsaturated thioamides was efficiently
promoted by a soft Lewis acid/hard Brønsted base cooperative
catalyst in a highly stereocontrolled manner. Thioamide
functionality was crucial to promote both the efficient
enolization of thiolactam pronucleophiles and the subsequent
stereoselective conjugate addition to α,β-unsaturated thio-
amides. Differential manipulation of the two thioamide
functionalities of the product highlights the synthetic utility
of the present catalytic system.
Scheme 1. Direct Catalytic Asymmetric Conjugate Addition
of Carboxylic Acid Derivatives
onjugate addition is a fundamental and reliable bond-
forming process, and its enantioselective version has gained
C
popularity in the field of asymmetric catalysis.1 The substrate
combination of a carbon-based pronucleophile and an electron-
deficient olefin has been extensively studied to develop a number
of enantioselective C−C bond-forming reactions. Among them,
active methylene compounds bearing fairly acidic protons, e.g.,
malonates, β-ketoesters, and α-cyanoesters, etc., have frequently
been employed as pronucleophiles because of their inherently
facile enolization. Aldehydes and ketones constitute a growing
class of potential nucleophiles in the flourishing field of
organocatalysis.2 In contrast, carbonyl compounds in the
carboxylic acid oxidation state have been far less explored as
pronucleophiles,3 likely because they are less prone to
enolization and the activation mode through an enamine is not
applicable. Although the use of preformed enolate species as
active nucleophiles is a viable option to afford the desired
product, direct use of a pronucleophile is advantageous in terms
of atom economy and synthetic efficiency.4 For electrophiles, the
reactivity is generally proportional to the electron-withdrawing
ability of the substituents attached to olefins. Similarly, enals,
enones, and nitroolefins exhibit sufficient electrophilicity in
conjugate additions, whereas olefins conjugated with carboxylic
acid derivatives are poor electrophiles and have been largely
neglected as electrophilic partners.5,6 In this context, the
intermolecular conjugate addition of pronucleophiles and
electrophiles that are both in the less reactive carboxylic acid
oxidation state is clearly an undesirable substrate combination,
and a catalytic enantioselective version of the reaction has
remained virtually unexplored despite the synthetic utility of the
corresponding conjugate adducts (Scheme 1). Quite recently,
Kobayashi et al. reported an efficient catalytic system comprising
KHMDS and chiral macro crown ether for highly diastereo- and
enantioselective conjugate addition of simple amides.7 In our
previous studies on the potential utility of thioamides as
pronucleophiles for catalytic asymmetric conjugate addition,8−10
intermolecular reactions barely proceeded under typical enoliza-
tion conditions for thioamides, and only intramolecular variants
of the reaction with limited substrate scope were reported.11
Herein, we report a direct catalytic asymmetric intermolecular
conjugate addition of thiolactams to α,β-unsaturated thioamides
as a demonstration of conjugate addition of substrates that are
both in a carboxylic acid oxidation state. Differential manipu-
lation of two thioamide functionalities embedded in the
conjugate adduct validates the synthetic utility of the present
catalysis.
Although a soft Lewis acid/hard Brønsted base cooperative
catalytic system comprising [Cu(CH3CN)4]PF6, a bisphosphine
Received: June 5, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01644
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ligand, and a Li phenoxide has proven to be effective for catalytic
generation of a thioamide enolate,12 no trace of intermolecular
conjugate addition to electron-deficient olefins (e.g., enones,
unsaturated esters, nitroolefins) was observed. We reasoned that
simultaneous activation of the electrophilic reaction partner
could enable intermolecular conjugate addition to take place in
the asymmetric environment of the Cu catalyst. α,β-Unsaturated
thioamides emerged as viable electrophiles that could be used to
meet this demand; this class of compound is soft Lewis basic and
can be electrophilically activated by a soft Lewis acid together
with a saturated thioamide as a pronucleophile. We began our
study with α,β-unsaturated thioamide 1a and saturated
thiopropionamide 2a as an electrophile and a pronucleophile,
respectively. The cooperative catalytic system comprising
mesitylcopper,13 (R)-DTBM-Segphos, and 2,2,5,7,8-pentameth-
yl-6-chromanol (HOAr 4), in which the chirally decorated
CuOAr was expected to function as a catalyst, promoted the
desired reaction to afford the diastereomixture of 3aa with
promising enantioselectivity (Scheme 2a).14 Although this result
For facile deprotection, N-benzhydrylpyrrolidine-2-thione
(5a) was selected as a thiolactam pronucleophile, and direct
catalytic conjugate addition was attempted with α,β-unsaturated
thioamide 1a under conditions identical to those used with
thiopropionamide 2a (Table 1). Thiolactam 5a exhibited much
Table 1. Optimization of Reaction Conditions Using
a
Thiolactam 5a as a Pronucleophile
Scheme 2. Initial Observations
a
b
1a: 0.1 mmol, 5a: 0.2 mmol. Determined by 1H NMR analysis with
c
1,1,2,2-tetrachloroethane as internal standard. Determined by 1H
NMR analysis of the crude product. ee of the anti-adduct.
d
higher reactivity, and the reaction reached completion in
approximately 10 min, affording the anti-adduct 6aa preferen-
tially with >99% ee, albeit with low diastereoselectivity (entry 1).
The diasteremeric ratio was improved by lowering the reaction
temperature to −40 °C without significant loss in reactivity
(entry 2). Whereas the use of a less sterically demanding ligand
such as (R)-Binap gave 6aa with lower diastereoselectivity, (R)-
Biphep 7, bearing highly substituted aromatic groups, was
identified as a optimal ligand to afford the desired product in high
diastereo- and enantioselectivity (entries 3 and 4). Catalyst
loading could be reduced to 5 mol% with marginal loss in
diastereoselectivity (entry 5).
The substrate scope of the direct catalytic conjugate addition
of thiolactams 5 to α,β-unsaturated thioamides 1 is summarized
in Table 2. The reaction could be scaled up to 1.0 g of 1a without
any detrimental effect on stereoselectivity (entry 1). The reaction
of 1, bearing alkyl and alkoxy substituents at the o-, m-, and p-
positions on the aromatic β-substituent, gave the desired product
in high yield and stereoselectivity (entries 2−5). Ester
functionality was tolerated under the mild basic conditions of
the present catalytic system (entry 6). p-Cl-substituted substrate
was less reactive in the present catalytic system, and product 6ga
was obtained after 6 h of stirring at −30 °C with moderate
diastereoselectivity (entry 7). Unsaturated thioamides having
heteroaromatic rings that could potentially coordinate to the
Cu(I) catalyst were compatible, albeit with marginal loss in
diastereoselectivity (entries 8 and 9). β-Methyl-substituted
unsaturated thioamide exhibited much lower reactivity, and a
higher reaction temperature (−20 °C) was required for the
reaction to proceed, affording 6ja with lower diastereo- and
enantioselectivity (entry 10). Notably, only 1,4-conjugate
addition proceeded with the α,β,γ,δ-unsaturated thioamide 1k
to afford the desired product 6ka having a pendant 1-propenyl
group on a 1,5-dithiocarbonyl framework (entry 11). Un-
expectedly, the reaction using six-membered thiolactam 5b gave
syn-6ab predominantly with various biaryl-type chiral bi-
demonstrated that the simultaneous activation strategy was
effective for intermolecular conjugate addition of substrates in
the carboxylic acid oxidation state, 3aa readily underwent retro-
reaction under the catalytic conditions. Indeed, resubjecting
racemic MP-3aa to the catalytic conditions gave a mixture of
substrates 1a and 2a and nonracemic mixtures of 3aa (Scheme
2b).15 Due to the rapid retro-reaction, obtaining the product with
high diastereo- and enantioselectivity turned out to be elusive
despite extensive efforts. The retro-reaction was likely triggered
by enolization at the α-nonbranched thioamide moiety of the
product (deprotonation of Hp), which appeared to be difficult to
suppress under the catalytic conditions used to generate the
thioamide enolate of 2a (deprotonation of Hs) (Scheme 2c).
Hence, we directed our focus on the use of thiolactam 5 as a
pronucleophile (Scheme 2d). With this substrate combination,
the identification of reaction conditions that allowed for
preferential enolization of 5 in the presence of the acyclic α-
nonbranched thioamide fragment of product 6 (preferential
deprotonation of Hs over Hp) was crucial to obtaining the
conjugate adduct in a kinetically controlled manner.
B
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diastereoselectivity for 6-membered lactam 5b (Table 2, entry
12) could be explained by more prominent epimerization from
anti to syn isomer. Indeed, the isolated minor diastereomer anti-
6ab (94% ee) was resubjected to the catalytic conditions, and
61% of syn-6ab was obtained with >99% ee after 24 h (Scheme
3c).18
Table 2. Direct Catalytic Asymmetric Conjugate Addition of
Thiolactam 5 to α,β-Unsaturated Thioamide 1
a
Differentiation of the two thioamide functionalities of the
conjugate adduct is of prime importance for the synthetic utility
of the methodology (Scheme 4). The α-nonsubstituted N,N-
Scheme 4. Transformation of the Product
a
b
c
1: 0.1 mmol, 5: 0.2 mmol. Isolated yields. Determined by 1H NMR
d
e
f
analysis. ee of major diastereomers. 1.0 g of 1a was used. (R)-
DMM-Garphos 8 (structure is shown in Table 1) was used instead of
(R)-Biphep 7.
dimethylthioamide moiety was more reactive toward alkylating
agents, e.g., MeI, to give an iminium thioether intermediate with
the thiolactam moiety intact, which was sufficiently reactive with
Li-enolate prepared from ethyl acetate to give β-ketoester 9. The
electrophilic activation of the thiolactam could be attained by
using the stronger alkylating agent MeOTf.19 Cyclization
proceeded upon heating to 50 °C in the presence of Et3N to
furnish bicyclic compound 10 having an azabicyclo[4.3.0]
skeleton. A benzhydryl group on the nitrogen was readily
removed by hydrogenolysis.
In conclusion, we have developed a direct catalytic asymmetric
conjugate addition of thiolactams to α,β-unsaturated thiola-
mides. Simultaneous activation of both the pronucleophile and
the electrophile was key to promoting the stereoselective C−C
bond formation of substrates that had inherently low reactivity.
Differential transformation of the two thioamide functionalities
of the product allows for flexible elaboration of the optically
active product and highlights the synthetic utility of the catalytic
system.
sphosphine ligands including 7. Among the ligands tested, (R)-
DMM-Garphos 8 was optimal to produce syn-6ab with 82% ee
(entry 12).16
The reactions summarized in Table 2 generally produced the
corresponding products with high enantioselectivity, with the
exception of α,β-unsaturated thioamide bearing an alkyl
substituent at the β-position (entry 10). Some reactions
displayed time-dependent erosion of diastereoselectivity, and
this observation prompted us to examine the stability of the
product under the catalytic conditions. When anti-6aa was
subjected to the optimal catalytic conditions at −40 °C for 24 h,
the syn-diastereomer was observed (Scheme 3a). Together with
Scheme 3. Stability of the Product under the Catalytic
Conditions
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization of new com-
pounds. The Supporting Information is available free of charge
on the ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01644.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nkumagai@bikaken.or.jp.
the observation that no crossover product was detected when the
anti-6aa was resubjected to the catalytic conditions in the
presence of α,β-unsaturated thioamide 1b (Scheme 3b),
epimerization would be a major pathway to produce the more
thermodynamically stable syn-6aa in Scheme 3a.17 Prolonged
reaction times with 5-membered lactam 5a tended to give lower
diastereomeric ratios (higher mole fraction of syn-isomer), and
undesired epimerization was partly associated even under the
optimized conditions. Enolates of 5- and 6-membered lactam 5a
and 5b likely reacted with 1a via a similar transition state to give
the anti-adducts predominantly, and unexpected reversal in
*E-mail: mshibasa@bikaken.or.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported financially by JST, ACT-C, and JSPS
KAKENHI Grant No. 25713002. N.M. and L.Y. thank JSPS for
postdoctoral fellowships. Dr. Tomoyuki Kimura is gratefully
acknowledged for technical assistance with the X-ray crystallo-
graphic analysis of syn-6ab and 10.
C
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Letter
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