Direct catalytic asymmetric intramolecular conjugate addition of thioamide to α,β-unsaturated esters

Article abstract of DOI:10.1002/chem.201102332

Proton transfer allows efficient access to optically active five- and six-membered ring systems bearing ester and thioamide functionalities in an anti fashion; these ring systems are amenable to differential functional group manipulation. Direct catalytic, asymmetric, intramolecular conjugate addition of thioamide to α,β-unsaturated esters is described. In situ generated Cu thioamide enolate, by catalytic deprotonation, underwent the conjugate addition/protonation, to achieve the complete transformation (see scheme).

Full text of DOI:10.1002/chem.201102332

DOI: 10.1002/chem.201102332
Direct Catalytic Asymmetric Intramolecular Conjugate Addition of
Thioamide to a,b-Unsaturated Esters
Yuta Suzuki,[a, b] Ryo Yazaki,[a, b] Naoya Kumagai,*[a] and Masakatsu Shibasaki*[a]
Catalytic asymmetric conjugate addition of carbon pronu-
cleophiles to electron-deficient olefin is one of the most reli-
phenylphospholano)ethane) exhibits high performance in
terms of catalytic efficiency and stereoselectivity. In this
context, we attempted to apply the cooperative catalyst to a
catalytic asymmetric intermolecular 1,4-type conjugate addi-
tion of thioamides to electron-deficient olefins. Despite sev-
eral trials, however, the reaction was unsuccessful,[11] pre-
sumably due to a different transition-state structure from
1,2-type addition, which would be unfavorable in the asym-
À
able and well-developed enantioselective C C bond-forming
reactions.[1] In situ generation of carbon nucleophiles offers
an efficient entry to this process, allowing for the construc-
tion of stereogenic carbon with perfect atom economy.[2]
Historically, active methylene compounds are widely used as
pronucleophiles due to their high enolization aptitude,[1] fol-
lowed by the successful application of aldehydes and ke-
tones as pronucleophiles by metal-based catalysis[3] and en-
amine catalysis.[4] Catalytic generation of active enolates
from carbonyl-type pronucleophiles in the carboxylic acid
oxidation state is a formidable task and thus their use in this
catalytic process is largely limited.[5] Our recent investiga-
tions of soft Lewis acid/hard Brønsted base cooperative cat-
alysis[6] revealed that thioamides are viable pronucleophiles,
because they are in the carboxylic acid oxidation state, al-
lowing for further manipulation of the product; specific
soft–soft interaction of thioamides and soft Lewis acids
allows for facile deprotonation with the aid of mild base to
generate thioamide enolates in a catalytic manner.[7–9] As
part of our continuing effort to pursue the utility of thioa-
mides as pronucleophiles, herein we report the direct cata-
lytic asymmetric intramolecular conjugate addition of thioa-
mide to a,b-unsaturated ester, providing enantiomerically
enriched five- and six-membered carbocycles bearing ester
and thioamide functions in an anti fashion.
metric environment provided by the [CuACHTUNGTRNEUNG(CH3CN)4]PF6/Ph-
BPE/LiOAr catalyst. To compensate for the entropic factor
for an intermolecular reaction, we turned our attention to
intramolecular conjugate addition of the thioamide function-
ality to an a,b-unsaturated ester.
An initial trial was conducted with substrate 1a; N,N-di-
benzylthiopropionamide and ethyl acrylate were tethered by
benzene, which was then exposed to 10 mol% of the [Cu-
ACHUTNGRENUN(G CH3CN)4]PF6/ACHTUTGNERNN(UGN S,S)-Ph-BPE/Li(OC6H4-p-OMe) catalyst in
THF at 08C; and the desired product anti-2a was obtained
in >99% yield and >20:1 anti selectivity, albeit with moder-
ate enantioselectivity (60% ee; Table 1, entry 1).[12] Nonpo-
lar (toluene) and aprotic polar (DMF) solvents were tested
and the reaction in DMF afforded the highest enantioselec-
tivity (entries 1–3). The reaction proceeded smoothly even
at À408C and enantioselectivity increased to 79% ee
(entry 4). The ligand (S)-Xyl-P-Phos (Xyl-P-Phos=2,2’,6,6’-
tetramethoxy-4,4’-bis(di(3,5-xylyl)phosphino)-3,3’-bipyridine)
outperformed (S,S)-Ph-BPE exhibiting higher enantioselec-
tivity with a marginal decrease in chemical yield (entry 5),
We have previously reported that [CuACTHNUTRGNEUNG
(CH3CN)4]+XÀ/
chiral bisphosphine ligand/LiOAr served as an effective soft
Lewis acid/hard Brønsted base cooperative catalyst for acti-
vating soft Lewis basic pronucleophiles.[10] For the 1,2-type
addition of in situ generated thioamide enolates, such as
aldol and Mannich-type reactions, a catalyst composed of
which was recovered by the use of [CuACHTNGUTERNNU(G CH3CN)4]SbF6 as a
cationic soft Lewis acid (entry 6). Intriguingly, the intramo-
lecular conjugate addition of 1a was catalyzed solely by
10 mol% of Li(OC6H4-p-OMe) in DMF with diastereos-
witching, affording the syn product 2a in >99% yield and
1:9.1 syn selectivity (entry 7), whereas no reaction proceed-
ed with 10 mol% of Li(OC6H4-p-OMe) in THF, even at
room temperature (entry 8). This observation suggested that
DMF significantly enhanced the Brønsted basicity of
Li(OC6H4-p-OMe) to induce enolization of the thioamide
and that the Li cation of Li thioamide enolate would be in
near proximity to the ester at the transition state to give
syn-2a preferentially. With the Cu–bisphosphine complex,
the intermediate is likely a Cu thioamide enolate with a
large bisphosphine ligand and conjugate addition in an anti-
fashion would be favorable.
[CuACHTUNGTRENNUNG(CH3CN)4]PF6/Ph-BPE/LiOAr (Ph-BPE=1,2-bis(2,5-di-
[a] Y. Suzuki, R. Yazaki, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki
Shinagawa-ku, Tokyo 141-0021 (Japan)
Fax : (+81)3-3441-7589
E-mail: mshibasa@bikaken.or.jp
nkumagai@bikaken.or.jp
[b] Y. Suzuki, R. Yazaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
With a suitable catalyst in hand, we next examined the
substrate scope of the intramolecular conjugate addition
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102332.
11998
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COMMUNICATION
Table 1. Initial screening.
Table 2. Direct catalytic asymmetric intramolecular conjugate addition of
thioamide to a,b-unsaturated ester.
Substrate
Product
t
Yield[a] anti/ ee[c]
XÀ
Ligand
Solvent
T
t
Yield[a] anti/
ee[b]
[%]
[h] [%]
syn[b] [%]
[8C] [h] [%]
syn[a]
À
1
2
3
4
5
6
PF6À
PF6À
PF6À
PF6À
PF6
U
THF
0
0
0
16 >99
16 >99
16 >99
>20:1
>20:1
>20:1
>20:1
20:1
60
61
69
79
86
86
–
1
2
1a
1b
2a 20 90
20:1 86
toluene
DMF
DMF
À40 16
À40 20
À40 20
91
72
90
2b 96 50
2c 72 87
20:1 83
4.4:1 87
À
SbF6 (S)-Xyl-P-Phos DMF
>20:1
7[c]
8[c]
–
–
DMF
THF
À40
8
>99
0
1:9.1
–
3
1c
RT 20
–
4
5
6
1d
1e
1 f
2d 20 66
2e 72 86
15:1 84
7.7:1 78
10:1 81
2 f 20
4
[a] Determined from 1H NMR spectroscopy of the crude mixture.
7
8
1g
1h
2g 20 64
2h 20 28
2.6:1 64
20:1 96
[b] Enantiomeric excess of anti isomer. [c] The reaction without [Cu-
ACHTUNGTRENNUNG
(CH3CN)4]+XÀ and chiral phosphine ligand.
(Table 2). Steric and electronic factors of a benzene-type
tether, as well as the tethering pattern, impacted the reactiv-
ity and stereoselectivity (entries 1–9). Substrates bearing
tolyl or naphthyl tether 1b and 1c afforded the correspond-
ing product with comparable enantioselectivity as in the re-
action of 1a, whereas 1b exhibited low reactivity, and only
moderate anti selectivity was observed with 1c (entries 2
and 3). The position of the chloro substituent on the ben-
zene tether led to remarkable difference in the diastereose-
lectivity (entries 4 and 5). Introduction of an electron-donat-
ing methoxy substituent considerably retarded the reaction
(entry 6). The reaction of substrates with a different tether-
ing pattern to the benzene ring, 1g and 1h, exhibited lower
reactivity than 1a, albeit with high anti- and enantioselectiv-
ity of 2h (entries 7 and 8). The reaction with a substrate
bearing oxa-tether 1i for the construction of the functional-
ized benzofuran derivative proceeded smoothly, but the ste-
reoselectivity was significantly decreased (entry 9). Alkyl-
tethered substrate 1j was applicable and the desired product
2j was obtained in high yield with moderate anti- and enan-
tioselectivity (entry 10).
9
1i
1j
2i 20 90
2j 96 99
4.4:1 28
3.1:1 65
10
1
[a] Isolated yield. [b] Determined from H NMR spectroscopy of crude mix-
ture. [c] Enantiomeric excess of anti isomer.
mediate ester enolate 4 (Scheme 1a). We assumed that in-
termediate 4 functions as a soft Lewis acid/hard Brønsted
base cooperative catalyst to directly generate thioamide
enolate
3
upon proton exchange with substrate
1
(Scheme 1b). With the mesitylcopper/(S)-Xyl-P-Phos cata-
lytic system, initial entry to Cu thioamide enolate 3 is ach-
ieved with the liberation of mesitylene, and the subsequent
catalytic cycle would be driven by 4.[14] Based on this as-
sumption, the mesitylcopper/(S)-Xyl-P-Phos catalyst was
evaluated with several substrates (Table 3). For substrate 1a,
a catalyst prepared from mesitylcopper (10 mol%) and (S)-
Xyl-P-Phos (7.5 mol%) promoted the conjugate addition
with comparable yield and stereoselectivity, confirming that
Cu ester enolate 4 functioned as a soft Lewis acid/hard
Brønsted base cooperative catalyst (entry 1).[15] Higher cata-
In the catalytic system of [CuACHTNUGTRENNUNG
Phos/Li(OC6H4-p-OMe),
Li(OC6H4-p-OMe)} and {Cu(OC6H4-p-OMe)/(S)-Xyl-P-
Phos+LiSbF6} are likely to be in equilibrium based on pre-
vious studies.[10c,13] Both Li(OC6H4-p-OMe) and Cu(OC6H4-
p-OMe)/(S)-Xyl-P-Phos would be operative as an actual
Brønsted base for the deprotonation of thioamide to gener-
ate Cu thioamide enolate 3 and protonation of the inter-
lytic performance over the [CuACTHNUTRGNE(UNG CH3CN)4]SbF6/(S)-Xyl-P-
Phos/Li(OC6H4-p-OMe) catalytic system was observed with
less reactive substrates, likely due to direct proton transfer
between intermediate 4 and substrate 1 (entries 2–6). The
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www.chemeurj.org
11999

M. Shibasaki, N. Kumagai et al.
Xyl-P-Phos/Li(OC6H4-p-OMe) catalyst (entry 5). For 1b and
1d, the decrease in diastereoselectivity was detected and
any attempts to enhance the diastereoselectivity resulted in
failure (entries 2 and 3).
Different manipulations of the thioamide and ester func-
tionality of the product are advantageous from a synthetic
point of view. The thioamide functionality of 2a was chemo-
selectively converted to thioester 5 or amide 6 by treatment
with MeOTf followed by TFA/H2O[16] or TFAA,[17] respec-
tively (Scheme 2). Reduction with LiAlH4 provided N-pro-
tected amino alcohol 7 in 90% yield.
Scheme 2. Transformation of the product.
In summary, we have developed a direct catalytic asym-
metric intramolecular conjugate addition of thioamide to
a,b-unsaturated esters. Catalytic generation of a thioamide
enolate with a soft Lewis acid/hard Brønsted base coopera-
tive catalyst was key to the efficient catalysis. A mesitylcop-
per/(S)-Xyl-P-Phos catalyst exhibited high catalytic perfor-
mance, in which the reaction intermediate functioned as cat-
alyst. Further investigation of the application of the present
Scheme 1. Proposed catalytic cycle for: a) [CuACHTUNGTRNEUNG(CH3CN)4]SbF6/(S)-Xyl-P-
Phos/Li(OC6H4-p-OMe) catalyst, and b) mesitylcopper/(S)-Xyl-P-Phos
catalyst.
Table 3. Direct catalytic asymmetric intramolecular conjugate addition
promoted by mesitylcopper/(S)-Xyl-P-Phos catalyst.
À
catalytic system to C C bond-forming reactions using other
soft Lewis basic pronucleophiles is ongoing.
x
Substrate Product t[d]
Yield[a,d] anti/
[%]
ee[c,d]
[%]
Acknowledgements
[h]
syn[b,d]
This work was financially supported by KAKENHI from JSPS (No.:
20229001 and 23590038). Y.S. and R.Y. thank JSPS for Predoctral Fellow-
ships. N.K. thanks the Sumitomo Foundation for financial support.
1
2
3
4
5
6
7.5 1a
7.5 1b
7.5 1d
7.5 1e
10 1 f
10 1h
2a
2b
2d
2e
2 f
2h
20 (20) 99 (90)
20 (96) 80 (50)
20 (20) 99 (66)
20 (72) 99 (86)
92 (20) 92 (4)
20 (20) 87 (28)
14:1 (20:1) 83 (86)
13:1 (20:1) 85 (83)
4.6:1 (15:1) 81 (84)
8:1 (7.7:1) 78 (78)
14:1 (10:1) 86 (81)
20:1 (20:1) 93 (96)
Keywords: atom economy · conjugate addition · cooperative
catalysis · proton transfer · thioamides
[a] Isolated yield. [b] Determined from 1H NMR spectroscopy of crude
mixture. [c] Enantiomeric excess of anti isomer. [d] Result in parentheses
is obtained from [Cu
catalyst (Table 2).
ACHTUNGTRENNUNG(CH3CN)4]SbF6/(S)-Xyl-P-Phos/Li(OC6H4-p-OMe)
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Cooperative Catalysis
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À
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Please note: Minor changes have been made to this manuscript since its
publication in Chemistry—A European Journal Early View. The Editor.
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