Anti-selective direct catalytic asymmetric aldol reaction of thiolactams

Article abstract of DOI:10.1021/ol301200q

An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Br?nsted base cooperative catalyst comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.

Full text of DOI:10.1021/ol301200q

ORGANIC
LETTERS
2012
Vol. 14, No. 12
3108–3111
Anti-Selective Direct Catalytic
Asymmetric Aldol Reaction
of Thiolactams
Devarajulu Sureshkumar,† Yuji Kawato,†,‡ Mitsutaka Iwata,† Naoya Kumagai,*,† and
Masakatsu Shibasaki*,†
Institute of Microbial Chemistry, Tokyo, 3-14-23 Kamiosaki, Shinagawa-ku,
Tokyo 141-0021, Japan, and Graduate School of Pharmaceutical Sciences,
The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-0033, Tokyo, Japan
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Received May 2, 2012
ABSTRACT
An anti-selective direct catalytic asymmetric aldol reaction of thiolactam is described. A soft Lewis acid/hard Brønsted base cooperative catalyst
comprised of mesitylcopper/(R,R)-Ph-BPE exhibited high catalytic performance to produce an anti-aldol product with high stereoselectivity. The
highly chemoselective nature of the present catalysis allows for the use of enolizable aldehydes as aldol acceptors. The diverse transformations
of the thiolactam moiety highlight the synthetic utility of the present anti-aldol protocol.
Direct catalytic asymmetric aldol reactions have gained
increasing popularity as the scope of the reaction has sub-
stantially expanded over the past decade.1,2 The direct aldol
methodology emerged as an atom-economical variant of the
well-known catalytic asymmetric aldol reaction,3 allowing
for direct access to enantioenriched β-hydroxy carbonyl
entities from unmodified aldol donors and acceptors.
Elimination of the demanding preactivation/preformation
process of active enolates in a separate operation is an
obvious practical advantage. The scope of aldol donors
amenable to in situ chemoselective enolization/aldol addi-
tion, however, was initially limited to mostly ketones and
aldehydes.1ꢀ3 Studies to enhance the synthetic utility of
this methodology led to the implementation of other aldol
donors in the carboxylic oxidation state that are generally
reluctant to generate active enolates catalytically.4,5 We
have particularly focused on the soft Lewis basic character
of the thiocarbonyl functionality to enable chemoselective
activation via soft Lewis acid/hard Brønsted base
† Institute of Microbial Chemistry.
‡ The University of Tokyo.
(4) There are numerous examples of direct aldol reactions using aldol
donors bearing electron-withdrawing R-substituents that are readily
enolized under mild basic conditions.
(1) For reviews of direct catalytic asymmetric aldol reactions, see:
(a) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002, 1595. (b) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580.
(c) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Berlin, 2004.
(d) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107,
5471. (e) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600.
(2) For selected early examples of direct catalytic asymmetric
aldol reactions, see: (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai,
H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871.
(b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168. (c) List, B.; Lerner, R. A.; Barbas,
C. F., III. J. Am. Chem. Soc. 2000, 122, 2395. (d) Trost, B. M.; Ito, H.
J. Am. Chem. Soc. 2000, 122, 12003. (e) Mahrwald, R.; Ziemer, B.
Tetrahedron Lett. 2002, 43, 4459.
(5) For direct catalytic asymmetric aldol (-type) reactions using
aldol donors in the carboxylic acid oxidation state without electron-
withdrawing R-substituents: Alkylnitriles: (a) Suto, Y.; Tsuji, R.; Kanai,
M.; Shibasaki, M. Org. Lett. 2005, 7, 3757. Activated amides: (b) Saito,
S.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 8704. β,γ-Unsaturated
ester: (c) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 10842. 5H-Oxazol-4-ones: (d) Misaki, T.; Takimoto, G.;
Sugimura, T. J. Am. Chem. Soc. 2010, 132, 6286. R-Hydroxyacylpyr-
roles: (h) Trost, B. M.; Seganish, W. M.; Chung, C. K.; Amans, D.
Chem.;Eur. J. 2012, 18, 2948. (f) R-Phosphonoester via [1,2] phospho-
nate-phosphate rearrangement: Corbett, M. T.; Uraguchi, D.; Ooi, T.;
Johnson, J. S. Angew. Chem., Int. Ed. 2012, 51, 4685. (g) Direct catalytic
asymmetric aldol reaction of thiazolidinethiones where the use of a
stoichiometric amount of silylating reagent was essential: Evans, D. A.;
Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125, 8706.
(3) Recent general review of asymmetric aldol reactions: Geary,
L. M.; Hultin, G. P. Tetrahedron: Asymmetry 2009, 20, 131. See also
ref 1c.
r
10.1021/ol301200q
Published on Web 06/05/2012
2012 American Chemical Society

Table 1. Direct Catalytic Asymmetric Aldol Reaction Using the
First and Second Generation Catalysta
Scheme 1. Anti-Selective Direct Catalytic Asymmetric Aldol
Reaction of Thiolactams
cooperative catalysis.6,7 Herein, we report the direct catalytic
asymmetric aldol reaction of thiolactam 2, which preferen-
tially affords anti-aldol products with high enantioselectivity
(Scheme 1). Diverse functional group transformations of
thiolactam highlight the synthetic utility of the product 3.
We recently documented a syn-selective direct catalytic
asymmetric aldol reaction of thioamides promoted by a
chiral soft Lewis acid/hard Brønsted base/hard Lewis base
cooperative catalyst (e.g., the reaction of isobutyraldehyde
(1a) and N,N-diallylthiopropanamide (4a), Table 1,
entry 3).7b,8,9 The first-generation catalyst in this reaction
required tedious catalyst preparation; a [Cu(CH3CN)4]-
PF6/(R,R)-Ph-BPE complex as a soft Lewis acid and a Li
aryloxide as a Brønsted base need to be freshly prepared
separately. We later disclosed the simplified catalytic
system comprising mesitylcopper/(R,R)-Ph-BPE (second-
generation catalyst), which allowed for a simple operation
and comparable catalytic efficiency in the reaction using
N,N-diallylthioacetamide (4b) (entries 1,2).10,11 In our
continuing studies of the direct aldol methodology in this
line, we observed an unexpectedly drastic decrease in
stereoselectivity when the second-generation catalyst was
applied to a direct aldol reaction of N,N-diallylthioprop-
a 1a:4 = 1:1.2. b Determined by 1H NMR analysis. c Determined by
HPLC analysis. d 2 mol % of 6 and 1.5 mol % of 7 were used. e 1 mol %
of 6 was used. f The opposite enantiomer was obtained in excess.
anamide (4a) (Table 1, entry 4). This striking result was
likely due to the particularly high catalytic efficiency of the
second-generation catalyst specifically for 4a; the reaction
proceeded remarkably faster than when using thioacet-
amide 4b, and the initially formed product syn-5 under-
went a rapid retro-aldol/aldol reaction to give virtually
racemic syn-5 under otherwise identical conditions. The
diastereoselectivity was also decreased, and anti-5 was
obtained with moderate enantioselectivity.12 Indeed, when
the reaction was run with a reduced catalyst loading
(0.5 mol %) and quenched over a shorter period, the
retro-aldol reaction was not prominent and syn-5 was
obtained with high stereoselectivity (entry 5). The absolute
configuration of the syn- and anti-5 suggested that both
products were produced via the Z-enolate of 4a, and
prochiral-face selection of aldehyde 1a was opposite
(Figure 1a).1c The retro-aldol reaction of anti-5 was much
slower than that of syn-5, and a higher fraction of anti-5
was produced by extending the reaction time. This finding
led us to isolate anti-5 as a thermodynamic product with
high enantioselectivity, but none of the attempts suc-
ceeded, presumably due to inadequate stereocontrol via a
disfavored cyclic transition state for anti-5 (Figure 1a).13
Todevelop a complementaryanti-selectiveprotocol for the
(6) For recent reviews on cooperative catalysis, see: Lewis acid/
Brønsted base: (a) Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102,
2187. (b) Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011, 50,
4760. Lewis acid/Lewis base: (c) Kanai, M.; Kato, N.; Ichikawa, E.;
Shibasaki, M. Synlett 2005, 1491. (d) Paull, D. H.; Abraham, C. J.; Scerba,
M. T.; Alden-Danforth, E.; Lectka, T. Acc. Chem. Res. 2008, 41, 655.
Lewis acid/Brønsted acid and Lewis acid/Lewis acid: (e) Yamamoto, H.;
Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924. (f) Yamamoto, H.;
Futatsugi, K. In Acid Catalysis in Modern Organic Synthesis; Yamamoto,
H., Ishihara, K., Eds.; Wiley-VCH: Weinheim, 2008.
(7) (a) Suzuki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2009, 48, 5026. (b) Iwata, M.; Yazaki, R.; Suzuki, Y.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 18244. (c) Iwata,
M.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Tetrahedron: Asymmetry
2010, 21, 1688. (d) Iwata, M.; Yazaki, R.; Chen, I.-H.; Sureshkumar, D.;
Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2011, 133, 5554.
(8) For application of thioamides as pronucleophiles under stoichio-
metric conditions, see: (a) Tamaru, Y.; Harada, T.; Nishi, S.; Mizutani,
M.; Hioki, T.; Yoshida, Z. J. Am. Chem. Soc. 1980, 102, 7806.
(b) Tamaru, Y.; Hioki, T.; Yoshida, Z. Tetrahedron Lett. 1984, 25,
5793. (c) Goasdoue, C.; Goasdoue, N.; Gaudemar, M. Tetrahedron Lett.
1983, 24, 4001. (d) Goasdoue, C.; Goasdoue, N.; Gaudemar, M.
Tetrahedron Lett. 1984, 25, 537. (e) Goasdoue, C.; Gaudemar, M.
Tetrahedron Lett. 1985, 26, 1015.
(9) Use of thioamide as a pronucleophile in asymmetric aldol reac-
tion under stoichiometric conditions, see: Iwasawa, N.; Yura, T.;
Mukaiyama, T. Tetrahedron 1989, 45, 1197.
(12) The absolute configuration of anti-5 was determined after con-
verting to the reported compound. Details are summarized in the
Supporting Information.
(10) Kawato, Y.; Iwata, M.; Yazaki, R.; Kumagai, N.; Shibasaki, M.
Tetrahedron 2011, 67, 6539.
(11) For synthesis, characterization, and application of mesitylcop-
per, see: (a) Tsuda, T.; Yazawa, T.; Watanabe, K.; Fujii, T.; Saegusa, T.
J. Org. Chem. 1981, 46, 192. (b) Tsuda, T. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L., Ed.; Wiley: New York, 1995; p 3271.
(c) Eriksson, H.; Hakansson, M. Organometallics 1997, 16, 4243.
(13) The possibility of the production of anti-5 through the E-enolate
of thioamide 4a cannot be ruled out. Although the formation of the
Z-enolate is generally favored for thioamides, the production of the anti-
product was observed at higher temperature and this result was ascribed
to the reaction through the E-enolate in ref 8a. However, at ꢀ70 °C, the
formation of the E-enolate is unlikely and we assume that anti-5 was
obtained through the transition state described in Figure 1.
Org. Lett., Vol. 14, No. 12, 2012
3109

Scheme 2. Substrate Generalitya
Figure 1. (a) Rapid aldol/retro-aldol reaction of acyclic thio-
amide 4 and syn-5 through Z-enolate. anti-5 was obtained likely
through a disfavored cyclic transition state with moderate
enantioselectivity. (b) Expected anti-aldol product from thio-
lactam 2 through E-enolate.
Table 2. Anti-Selective Direct Catalytic Asymmetric Aldol
Reaction of Thiolactamsa
thiolactam 2
entry
R
product x y time(h) yieldb(%) anti/synb ee (%)a
1
2
3
4
5
6
allyl
Bn
Ph
PMP
PMP
PMP
2a
2b
2c
2d
2d
2d
3aa 3 3
3ab 3 3
3ac 3 3
3ad 3 3
3ad 3 0
3ad 1 1
48
14
24
24
24
48
80
88
76
94
71
58
>20/1
>20/1
>20/1
>20/1
>20/1
>20/1
82
82
95
94
95
95
a 1a: 0.24 mmol, 2: 0.2 mmol. bDetermined by 1H NMR analysis.
cIsolated yield of anti-diastereomer. dDetermined by HPLC analysis.
e5 mol % of catalyst were used. f10 mol % of catalyst were used. gIsolated
yield of anti and syn products.
a 1a: 0.24 mmol. 2: 0.2 mmol. b Determined by 1H NMR analysis.
c Determined by HPLC analysis. PMP = p-methoxyphenyl.
directaldol reactionofthioamides, we turnedour attention
toward thiolactam as an aldol donor because; (1) it
exclusively generates an E-enolate and the anti-product
can be obtained via a favored cyclic transition state, and
(2) various functional group transformations of the aldol
product are anticipated (Figure 1b). Initial attempts using
isobutyraldehyde (1a) and N-allylthiobutyrolactam (2a)
with 3 mol % of the second-generation catalyst and a
phenolic additive 6 afforded the desired anti-aldol product
3aa predominantly in 82% ee (Table 2, entry 1). Although
the N-Bn (2b) derivative produced a similar outcome
(entry 2), the introduction of an aromatic substituent on
the nitrogen led to a remarkable increase in enantioselec-
tivity (entry 3). For the synthetic utility of the aldol
product, thiolactam 2d bearing an N-p-methoxyphenyl
(PMP) group amenable to oxidative removal is more
Scheme 3. Reaction with Six-Membered Thiolactams 2e and 2f
favorable, and product 3ad was obtained in high stereo-
selectivity (entry 4).14 Phenol 6 is particularly beneficial for
3110
Org. Lett., Vol. 14, No. 12, 2012

Scheme 4. Transformation of the Aldol Product
enhancing the catalytic efficiency, likely due to acceleration
of the proton-transfer process (entry 4 vs 5).15,16 High
stereoselectivity was maintained with a 1 mol % catalyst
loading, albeit with only a moderate yield (entry 6).
The reaction with benzaldehyde (1o) exhibited a marginal
anti preference with moderate enantioselectivity (entry 15).
The retro-aldol pathway was not prominent,17 and this lower
stereoselectivity likely resulted from a less compatible transi-
tion state for aromatic aldehydes. The reaction with six-
membered thiolactams 2e and 2f produced the aldol products
with only a slight preference for anti diastereoselectivity, and
the N-aryl substituent had no obvious beneficial effect on
enantioselectivity (Scheme 3).18
The present anti-selective direct aldol reaction is applic-
able to a wide range of aldehydes (Scheme 2). In addition
to R-branched aldehydes (entries 1,2), the reaction with
R-nonbranched aldehydes proceeded exclusively from the
E-enolate derived from thiolactam 2d to afford the desired
anti-aldol products with high stereoselectivity (entries
3ꢀ9). A 1-g scale reaction using octanal (1f) and 2d was
performed with no detrimental effects. Ester, ether, pyridine,
and imide functionalities were tolerated (entries 10ꢀ14),
whereas BOM-protected aldehyde 1k gave 3kd in moderate
yield and lower stereoselectivity (entry 11). Although the
Lewis basic pyridyl group in aldehyde 1m may coordinate to
Cuþ, resulting in deteriorated catalytic efficiency, product
3md was obtained with 5 mol % of the catalyst in reasonable
yield with high enantioselectivity (entry 13). A much lower
stereoselectivity was observed with aromatic aldehydes.
Thiolactam in the aldol product can be transformed into
various synthetically useful functionalities as shown in
Scheme 4.19,20
In summary, we developed an anti-selective direct cata-
lytic asymmetric aldol reaction of thiolactams. N-(p-
Methoxyphenyl)thiobutyrolactam 2d was a particularly
suitable substrate to afford anti-aldol products with high
enantioselectivity. The aldol product was transformed into
various enantiomerically enriched pyrrolidino compounds
and acyclic amino alcohols. Application of the present
anti-aldol protocol to the enantioselective synthesis of
biologically significant compounds is ongoing.
(14) The absolute and relative configuration of 3ad was confirmed by
X-ray crystallographic analysis. See Supporting Information for details.
(15) 2,2,5,7,8-Pentamethylchromanol (6) is particularly effective in
the direct aldol reaction. The reaction using p-methoxyphenol under
otherwise identical conditions affords the inferior result: 70% yield of
3ad, anti/syn = 20/1, 94% ee (anti).
Acknowledgment. This work was supported by KAKEN-
HI (Nos. 20229001 and 23590038). We thank Mr. Akinobu
Matsuzawa at The University of Tokyo for X-ray crystal-
lographic analysis of 3ad, 3cd, 3hd, and 3od. D.S. thanks JSPS
for a postdoctral fellowship. Y.K. thanks JSPS for a predoctral
fellowship. Dr. H. Sato at RIGAKU corporation is gratefully
acknowledged for technical support in X-ray crystallographic
analysis.
(16) All the components of the catalyst are commercially available
and used as received.
(17) The constant enantioselectivity was observed from the reaction
samples quenched at different reaction times (4ꢀ24 h). In contrast, the
aldol reaction of benzaldehyde (1o) and thioacetamide 4b with the first-
generation catalyst gave a different enantioselectivity and a retro-aldol
reaction was highly anticipated (ref 7c).
(18) The use of DMF instead of THF as solvent gave better stereo-
selectivity in the reaction with thiolactam 2f (THF: 70% yield of 3af,
anti/syn = 1.3/1, 81% ee (anti), 65% ee (syn)).
(19) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197 and references cited
therein.
Supporting Information Available. Characterization of
new compounds and experimental procedures. This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(20) The details of transformation are described in Supporting
Information.
(21) Murai, T.; Mutoh, Y. Chem. Lett. 2012, 41, 2 and references
cited therein.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
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