Direct catalytic asymmetric mannich-type reaction of α-sulfanyl lactones

Article abstract of DOI:10.1021/ol4008734

Catalytic asymmetric Mannich-type reactions of α-sulfanyl lactones to aldimines were promoted by a chiral Ag complex/DBU binary catalyst. The reaction proceeded in a syn-selective manner in high enantioselectivity. Alkylative activation of the sulfide of the Mannich adduct allowed for the formation of trisubstituted aziridines.

Full text of DOI:10.1021/ol4008734

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Catalytic Asymmetric Mannich-
Type Reaction of r‑Sulfanyl Lactones
Sho Takechi,†,‡ Naoya Kumagai,*,† and Masakatsu Shibasaki*,†,§
Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki,
Shinagawa-ku, Tokyo 141-0021, Japan, Graduate School of Pharmaceutical Sciences,
The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and JST,
ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
nkumagai@bikaken.or.jp; mshibasa@bikaken.or.jp
Received March 29, 2013
ABSTRACT
Catalytic asymmetric Mannich-type reactions of R-sulfanyl lactones to aldimines were promoted by a chiral Ag complex/DBU binary catalyst. The
reaction proceeded in a syn-selective manner in high enantioselectivity. Alkylative activation of the sulfide of the Mannich adduct allowed for the
formation of trisubstituted aziridines.
Catalytic asymmetric Mannich reactions offer direct
access to the optically active β-amino carbonyl architec-
ture,1 which serves as a synthetically useful chiral building
block for biologically important nitrogen-containing com-
pounds.2 Among them, a direct type of reaction in which
the generation of active enolates and enantioselective
addition are integrated in one pot meets the increasing
demand for the development of environmentally benign
processes; preformation of active enolate species in sepa-
rate processes and coproduction of undesirable wastes
can be avoided.3 Although considerable effort has been
devoted to developing direct Mannich reactions during the
past decade, there is still room for improvement: readily
enolizable aldehydes or ketones have been selected as pri-
vileged pronucleophiles,3 while less acidic pronucleophiles
(4) Recent selected examples of asymmetric Mannich reactions of
active methylene compounds with aldimines in organocatalysis: (a)
Song, J.; Wang, Y.; Deng, L. J. Am. Chem. Soc. 2006, 128, 6048. (b)
Tillman, A. L.; Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. (c) Fini,
F.; Bernardi, L.; Herrera, R. P.; Pettersen, D.; Ricci, A.; Sgarzani, V.
Adv. Synth. Catal. 2006, 348, 2043. (d) Song, J.; Wang, Y.; Deng, L. Org.
Lett. 2007, 9, 603. (e) Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini,
F.; Fochi, M.; Pettersen, D.; Sgarzani, V.; Ricci, A. Chem.;Eur. J. 2007,
13, 8338. (f) Yamaoka, Y.; Miyabe, H.; Yasui, Y.; Takemoto, Y.
Synthesis 2007, 2571. (g) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem.
2007, 72, 9998. (h) Kang, Y. K.; Kim, D. Y. J. Org. Chem. 2009, 74, 5734.
(i) Takada, K.; Tanaka, S.; Nagasawa, K. Synlett 2009, 1643. (j)
† Institute of Microbial Chemistry (BIKAKEN), Tokyo.
‡ The University of Tokyo.
Sohtome, Y.; Tanaka, S.; Takada, K.; Yamaguchi, T.; Nagasawa, K.
§ JST, ACT-C.
(1) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard, A. J.;
ꢀ
ꢀ
Angew. Chem., Int. Ed. 2010, 49, 9254. (k) Probst, N.; Madarasz, A.;
ꢀ
Valkonen, A.; Papai, I.; Rissanen, K.; Neuvonen, A.; Pihko, P. M.
Feringa, B. L. Chem. Soc. Rev. 2010, 39, 1656.
Angew. Chem., Int. Ed. 2012, 51, 8495. Related examples in metal
catalysis: (l) Marig, M.; Kjaersgaard, A.; Juhl, K.; Gathergood, N.;
Jørgensen, K. A. Chem.;Eur. J. 2003, 10, 2359. (m) Sasamoto, N.;
Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am. Chem. Soc. 2006, 128,
14010. (n) Chen, Z.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2008, 130, 2170. (o) Hamashima, Y.; Sasamoto, N.;
Umebayashi, N.; Sodeoka, M. Chem.;Asian J. 2008, 3, 1443. (p) Nojiri,
A.; Kumagai, N.; Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 3779. (q)
Hatano, M.; Horibe, T.; Ishihara, K. Org. Lett. 2010, 12, 3502. (r)
Hatano, M.; Moriyama, K.; Maki, T.; Ishihara, K. Angew. Chem., Int.
Ed. 2010, 49, 3823. (s) Hatano, M.; Ishihara, K. Synthesis 2010, 3785. (t)
Rueping, M.; Bootwicha, T.; Sugiono, E. Synlett 2011, 323. (u)
Tsubogo, T.; Shimizu, S.; Kobayashi, S. Chem.;Asian. J. 2013, 8, 872.
(2) For general reviews on catalytic asymmetric Mannich-type reac-
tions: (a) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric
Catalysis, Supplement 1; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.;
Springer: Berlin, 2003; Chapter 29.5, p 143. (b) Friestad, G. K.; Mathies,
A. K. Tetrahedron 2007, 63, 2541. (c) Kobayashi, S.; Mori, Y.; Fossey,
J. S.; Salter, M. M. Chem. Rev. 2011, 111, 2626.
(3) For recent reviews of direct Mannich (-type) reactions, see: (a)
Marques, M. M. B. Angew. Chem., Int. Ed. 2006, 45, 348. (b) Ting, A.;
Schaus, S. E. Eur. J. Org. Chem. 2007, 5797. (c) Verkade, J. M. M.; van
Hemert, L. J. C.; Quaedflieg, P. J. L. M.; Rutjes, F. P. J. T. Chem. Soc.
ꢀ
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Rev. 2008, 37, 29. (d) Gomez Arrayas, R.; Carretero, J. C. Chem. Soc.
Rev. 2009, 38, 1940.
r
10.1021/ol4008734
XXXX American Chemical Society

in the carboxylic oxidation state have been largely ne-
glected because of their reluctance to form active enolates
through in situ deprotonation.4,5
of the sulfanyl group after the reaction,6 we envisaged
developing a direct catalytic asymmetric Mannich-type
reaction of aldimine 5 and R-sulfanyl lactones 1, which is
in the carboxylic acid oxidation state (Scheme 2).8 Analo-
gous manipulation of the Mannich product 6 would
produce enantiomerically enriched trisubstituted aziri-
dines 7. Although there are a few leading examples of the
enantioselective synthesis of trisubstituted aziridines by
coupling of imines and R-diazocarbonyl compounds,9À11
potentially explosive R-diazocarbonyl compounds are re-
quired and our protocol offers complementary access.
Scheme 1. Direct Catalytic Asymmetric Aldol Reaction of
R-Sulfanyl Lactones 1
Scheme 2. Direct Catalytic Asymmetric Mannich-Type
Reaction of R-Sulfanyl Lactones 1
Recently, wereported a direct catalytic asymmetricaldol
reaction of R-sulfanyl lactones 1 promoted by a soft Lewis
acid/hard Brønsted base cooperative catalytic system
comprised of AgPF6, a BIPHEP-type ligand (R)-2, and
DBU.6,7 SoftÀsoft interaction between Ag and the sulfa-
nyl moiety afforded in situ chemoselective activation of
R-sulfanyl lactones 1 to catalytically generate the corre-
sponding enolates by the synergistic action of the mild
Brønsted base (Scheme 1).6 Even in the presence of highly
enolizable R-nonbranched aliphatic aldehydes, preferen-
tial enolate formation of 1 proceeded to afford the corre-
sponding aldol products 3 with high stereoselectivity,
highlighting the potency of chemoselective activation
through softÀsoft interaction. The sulfanyl moiety of
the product 3 served as a latent leaving group upon
S-alkylation toproduce trisubstituted epoxide4, endorsing
the utility of the products as chiral building blocks.
Initial investigations of the AgPF6/(S)-2/DBU binary
catalyst system,6,12 which was prepared by mixing the
components in a 1:1:1 molar ratio, in Mannich-type reac-
tions were conducted with a five-membered R-sulfanyl
lactone 1a and various N-protected aldimines derived
from 4-fluorobenzaldehyde 5aÀc. At room temperature,
the reaction using Ts-protected aldimine 5a afforded
syn-adduct 6aa predominantly with excellent enantioselec-
tivity, albeit with modest reactivity (Table 1, entry 1).
The aldimine bearing N-diphenylphosphinoyl (P(O)Ph2)
group 5b exhibited worse reactivity, and the enantioselec-
tivity decreased significantly (entry 2).13 In contrast, the
reaction of N-Boc protected aldimine 5c reached comple-
tion under identical conditions, affording syn-adduct 6ac
in 89% ee (entry 3). 5c was much more soluble in toluene
than 5a and 5b, and the reaction could be performed at
À30 °C under homogeneous conditions, affording the
product 6ac in almost perfect stereoselectivity (entry 4).
On the basis of the robustness of the chemoselective
activation strategy of R-sulfanyl lactones 1 with the
cooperative catalytic system and productive replacement
(5) Direct catalytic asymmetric Mannich-type reactions using pro-
nucleophiles in the carboxylic oxidation states or ester surrogates: (a)
Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2005, 44, 4365. (b) Yazaki, R.; Nitabaru, T.; Kumagai, N.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 14477. (c) Suzuki, Y.;
Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2009,
48, 5026. (d) Morimoto, H.; Lu, G.; Aoyama, N.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 9588.
ꢀ
(9) Early examples of racemic systems: (a) Casarrubios, L.; Perez,
(6) Takechi, S.; Yasuda, S.; Kumagai, N.; Shibasaki, M. Angew.
Chem., Int. Ed. 2012, 51, 4218.
J. A.; Brookhart, M.; Templeton, J. L. J. Org. Chem. 1996, 61, 8358. (b)
Williams, A. L.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 1612.
(10) Enantioselective synthesis of trisubstituted aziridines via auxili-
ary approach: (a) Davis, F. A.; Liu, H.; Reddy, G. V. Tetrahedron Lett.
1996, 37, 5473. (b) Davis, F. A.; Liu, H.; Zhou, P.; Fang, T.; Reddy,
G. V.; Zhang, Y. J. Org. Chem. 1999, 64, 7559. (c) Davis, F. A.; Deng, J.;
Zhang, Y.; Haltiwanger, R. C. Tetrahedron 2002, 58, 7135. (d) Davis,
F. A.; Deng, J. Org. Lett. 2007, 9, 1707. (e) Hashimoto, T.; Nakatsu, H.;
Watanabe, S.; Maruoka, K. Org. Lett. 2010, 12, 1668.
(11) (a) Huang, L.; Wulff, W. D. J. Am. Chem. Soc. 2011, 133, 8892.
(b) Hashimoto, T.; Nakatsu, H.; Yamamoto, K.; Maruoka, K. J. Am.
Chem. Soc. 2011, 133, 9730.
(12) For a general review of enantioselective Ag catalysis: Naodovic,
M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132.
(7) 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.
(8) For the discussion on the sulfide functionality stabilizing a
carbanion through appreciable stereoelectronic effects, see: (a) Epiotis,
N. D.; Yates, R. L.; Bernardi, F.; Wolfe, S. J. Am. Chem. Soc. 1976, 98,
5435. (b) Lehn, J.-M.; Wipff, G. J. Am. Chem. Soc. 1976, 98, 7498. (c)
Schaumann, E. Top. Curr. Chem. 2007, 274, 1.
(13) For the utility of N-diphenylphosphinoyl imines: Weinreb,
S. M.; Orr, R. K. Synthesis 2005, 1205.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Direct Catalytic Asymmetric Mannich-Type Reaction
of R-Sulfanyl Lactones 1a and Aldimines 5aÀca
Table 2. Direct Catalytic Asymmetric Mannich-Type Reaction
of R-Sulfanyl Lactones 1 and Boc-Aldimines 5a
imine 5
1
imine 5
time
x
(h) product (%) syn/antic (%)
yieldb
eed
temp yieldb
product (°C)
(%) syn/antic
eed(syn)
entry
R =
n =
entry PG =
x
(%)
1
2
3
4
5
6
7
4-FC6H4
4-ClC6H4
5c
1
1
1
1
1
1
1
1
1
1
1
2
2
3
1a 3 48 6ac
1a 3 48 6ad
1a 3 48 6ae
1a 3 24 6af
1a 5 48 6ag
1a 5 48 6ah
1a 5 24 6ai
1a 5 24 6ai
1a 5 48 6aj
1a 3 48 6ak
1a 5 48 6al
1b 5 48 6bj
1b 5 50 6bm
1c 5 48 6cf
79
78
87
80
70
42
79
75
89
94
71
88
49
0
>20/1 99
>20/1 99
>20/1 99
14/1 96
7/1 97
1
2
3
Ts
5a
5
5
5
5
3
6aa
6ab
6ac
6ac
6ac
rt
67
18
74
85
89
>20/1
>20/1
12/1
99
63
89
99
99
5d
P(O)Ph2 5b
rt
4-NO2C6H4 5e
Ph 5f
Boc
5c
5c
5c
rt
4e,f Boc
5e
Boc
À30
>20/1
>20/1
4-MeC6H4 5g
4-MeOC6H4 5h
4-TfOC6H4 5i
À30
6/1 97
a AgPF6/(S)-2/DBU = 1:1:1. 1a: 0.2 mmol. 5: 0.24 mmol, 0.2 M.
>20/1 96
>20/1 >99
>20/1 94
6/1 97
b Determined by 1H NMR analysis with (CHCl2)2 as an internal
standard. c Determined by 1H NMR analysis. d Determined by chiral
stationary phase HPLC. e Run at 0.5 M. f Reaction time was 24 h.
8e 4-TfOC6H4 5i
9
3-pyridyl
5j
10 2-furyl
11 nC5H11
12 3-pyridyl
13f PhCH2CH2 5m
14 Ph 5f
5k
51
5j
>20/1 99
>20/1 82
>20/1 96
The catalyst loading could be reduced to 3 mol % with no
loss of stereoselectivity (entry 5).14 Irrespective of the
protecting group on the nitrogen, syn-(2R,3S)-adducts
were predominantly obtained,15 suggesting that the CÀC
bond formation between the Ag-enolate of 1a and imines 5
proceeded through a similar transition state irrespective of
the protecting group on the nitrogen.
À
À
a AgPF6/(S)-2/DBU = 1:1:1. 1: 0.2 mmol. 5: 0.24 mmol. b Isolated
yield. c Determined by 1H NMR analysis. d Ee of syn-adduct, determined
by chiral stationary phase HPLC. e 2.3 g of 5i were used. Yield and
stereoselectivity were determined after recrystallization. f 1.5 equiv of
imine 5m (0.3 mmol) were used.
The scope of the direct catalytic Mannich-type reaction
of 1 with Boc imines is summarized in Table 2.16 Although
syn-adducts were predominantly produced with uniformly
high enantioselectivity, the reactivity and diastereomeric
ratio were dependent on the electronic nature of the
substituents on the aromatic ring. Aromatic iminesbearing
electron-deficient substituents 5c,d,e produced Mannich
adducts in high diastereo- and enantioselectivity (entries 1À3).
As the electron density of the aromatic ring increased, the
diastereoselectivity decreased steadily (entries 4À6).
Prochiral-face selection of approaching imines was com-
promised with electron-rich imines, presumably because
the higher Lewis basicity of the imine nitrogen had a
negative effect. The particularly low yield in the reaction
of MeO-substituted imine 5h was ascribed to its intrinsic
low electrophilicity (entry 6). Replacing the 4-MeO group
with an electron-withdrawing 4-TfO group enhanced both
the reactivity and stereoselectivity (entry 7). The reaction
could be run on 2.3 g scale with no detrimental effect, and
facile recrystallization provided optically pure product 6ai
in 75% yield (entry 8). Imineshavinga heteroaromaticring
were applicable to the present catalysis (entries 9, 10).
A pyridyl group could potentially coordinate to Ag and
compromise the stereochemical outcome, but imine 5j was
served as an electron-deficient imine and afforded the
syn-adduct in high stereoselectivity (entry 9). The reaction
conditions were sufficiently mild to allow the reaction with
the nonbranched aliphatic imine 5l, which is susceptible to
tautomerization to the corresponding enamine (entry 11).
Whereas six-membered R-sulfanyl lactone 1b could be
applicable as a pronucleophile, less reactivity or lower
enantioselectivity was observed (entries 12, 13). The pres-
ent catalytic system failed to promote the reaction of
ε-lactone 1c, probably because of reluctant formation of
the enolate (entry 14).
Further manipulation of the Mannich adducts is out-
lined in Scheme 3. Oxidation of the sulfanyl group of 6af
with mCPBA followed by syn-elimination of the transient
sulfoxide under elevated temperature gave R,β-unsaturated
(17) General review on catalytic asymmetric aza-MoritaÀBaylisÀ
Hillman reaction: (a) Masson, G.; Housseman, C.; Zhu, J. Angew.
Chem., Int. Ed. 2007, 46, 4614. (b) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem.
2007, 2905.
(18) The aza-MoritaÀBaylisÀHillman reaction using R,β-unsatu-
rated ester nucleophile is largely limited: (a) Raheem, I. T.; Jacobsen,
E. N. Adv. Synth. Catal. 2005, 347, 1701. (b) Abermil, N.; Masson, G.;
Zhu, J. J. Am. Chem. Soc. 2008, 130, 12596. (c) Abermil, N.; Masson, G.;
Zhu, J. Adv. Synth. Catal. 2010, 352, 656. (d) Yukawa, T.; Seelig, B.; Xu,
Y.; Morimoto, H.; Matsunaga, S.; Berkessel, A.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 11988. For partially successful examples: (e) Shi,
M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507. (f) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521. (g) Kawahara, S.;
Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2003, 5, 3103. (h) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790.
(14) The reaction in the absence of either AgPF6 or DBU produced
no desired product, suggesting that cooperative catalysis of a soft Lewis
acid and hard Brønsted base is essential.
(15) See Supporting Information.
(16) The absolute configuration of 6af was determined by X-ray
crystallographic analysis.
(19) Azirine formation with Boc amide resulted in poor yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

treatment with Meerwein’s salt afforded an S-methylated
sulfonium intermediate, which was transformed into tri-
substituted aziridine 11af with DBU. Hydrogenolysis of the
aziridine 11af over Pd(OH)2 produced R,R-disubstituted
R-amino acid derivative 12af.
Scheme 3. Transformations of the Product
In summary, we have developed a catalytic asymmetric
Mannich-type reaction of R-sulfanyl lactones and aldi-
mines promoted by the soft Lewis acid/hard Brønsted base
cooperative catalyst AgPF6/(S)-2/DBU. Two contiguous
stereogenic centers were newly constructed in a pre-
ferential syn-configuration with high enantioselectivity.
The β-amino-R-methylthio scaffold embedded in the
adduct was utilized to give enantioenriched trisubstituted
aziridine, a pivotal intermediate for R,R-disubstituted
R-amino acid derivatives.
Acknowledgment. This work was financially supported
by KAKENHI (20229001 and 23590038) from JSPS and
JST, ACT-C. S.T. thanks JSPS for a predoctoral fellow-
ship. Mr. Akinobu Matsuzawa at the University of Tokyo
is gratefully acknowledged for technical assistance in
X-ray crystallographic analysis of syn-6af.
butyrolactone 8af, which is analogous to aza-MoritaÀ
BaylisÀHillman products from 2-furanone.17,18 This pro-
cedure could be applied to Mannich adduct 6al, derived
from aliphatic imine to afford corresponding product 8al
in 84% yield. Facile recrystallization provided enantio-
merically pure 6af, which was reduced by NaBH4, and
newly generated primary alcohols were protected by a
MOM group to give 9af. The protecting group on nitro-
gen was converted from Boc to Ts,19 and subsequent
Supporting Information Available. Experimental pro-
cedures and characterization of the products. This mate-
rial is available free of charge via the Internet at http://
pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX