Catalytic enantioselective amination of silyl enol ethers using chiral dirhodium(II) carboxylates: Asymmetric formal synthesis of (-)-metazocine

Article abstract of DOI:10.1021/ol702019b

(Chemical Equation Presented) Dirhodium(II) tetrakis[N- tetrafluorophthaloyl-(S)-tert-leucinate], Rh₂(S-TFPTTL)₄, is an exceptionally efficient catalyst for enantioselective aminations of silyl enol ethers derived from acyclic ketone

Full text of DOI:10.1021/ol702019b

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4559-4562
Catalytic Enantioselective Amination of
Silyl Enol Ethers Using Chiral
Dirhodium(II) Carboxylates: Asymmetric
Formal Synthesis of (−
)-Metazocine†
Masahiro Anada, Masahiko Tanaka, Takuya Washio, Minoru Yamawaki,
Takumi Abe, and Shunichi Hashimoto*
Faculty of Pharmaceutical Sciences, Hokkaido UniVersity, Sapporo 060-0812, Japan
hsmt@pharm.hokudai.ac.jp
Received August 17, 2007
ABSTRACT
Dirhodium(II) tetrakis[N-tetrafluorophthaloyl-(S)-tert-leucinate], Rh2(S-TFPTTL)4, is an exceptionally efficient catalyst for enantioselective aminations
of silyl enol ethers derived from acyclic ketones or -enones with [N-(2-nitrophenylsulfonyl)imino]phenyliodinane (NsN IPh), providing
N-(2-nitrophenylsulfonyl)- -amino ketones in high yields and with enantioselectivities of up to 95% ee. The effectiveness of the present catalytic
r
,
â
d
r
protocol has been demonstrated by an asymmetric formal synthesis of (−)-metazocine.
The catalytic asymmetric amination of ketone-derived enol
ethers is one of the most powerful methods for the prepara-
tion of enantioenriched R-amino ketones, which are versatile
building blocks for the synthesis of biologically active
compounds such as syn- and anti-R-amino alcohols.1 Re-
cent advances2-6 in this field include Sharpless asym-
metric aminohydroxylation of silyl enol ethers,2 Cu(II)- and
Ag(I)-catalyzed electrophilic amination of silyl enol ethers
with azodicarboxylate derivatives,3,4 and Ag(I)-catalyzed
regio- and enantioselective N-nitroso aldol reaction of tin-
(IV) enolates.5 In this context, the aziridination of silyl enol
ethers followed by ring opening of aziridine intermediates
provides an attractive and practical entry to R-amino ketone
derivatives.7 While high levels of enantiocontrol in aziridi-
nations of alkenes have already been achieved using a variety
of different chiral transition-metal catalysts,8 the goal for
those of enol derivatives remains elusive.9 To our knowledge,
† This paper is dedicated to the the memory of the late Dr. Yoshihiko
Ito, Professor Emeritus of Kyoto University.
(6) (a) Recently, Jørgensen and co-workers reported L-proline-catalyzed
direct asymmetric R-aminations of alkyl methyl ketones with azodicar-
boxylates, which led to a mixture of the expected 3-hydrazino ketones (up
to 99% ee) and 1-hydrazino regioisomers (76:24∼91:9 regioselectivity):
Kumaragurubaran, N.; Juhl, K.; Zhuang, W.; Bøgevig, A.; Jørgensen, K.
A. J. Am. Chem. Soc. 2002, 124, 6254-6255. See also: (b) Thomassigny,
C.; Prim, D.; Greck, C. Tetrahedron Lett. 2006, 47, 1117-1119.
(7) (a) Lociuro, S.; Pellacani, L.; Tardella, P. A. Tetrahedron Lett. 1983,
24, 593-596. (b) Cipollone, A.; Loreto, M. A.; Pellacani, L.; Tardella, P.
A. J. Org. Chem. 1987, 52, 2584-2586. (c) Evans, D. A.; Faul, M. M.;
Bilodeau, M. T. J. Am. Chem. Soc. 1994, 116, 2742-2753. (d) Du Bois,
J.; Hong, J.; Carreira, E. M.; Day, M. W. J. Am. Chem. Soc. 1996, 118,
915-916. (e) Du Bois, J.; Tomooka, C. S.; Hong, J.; Carreira, E. M. Acc.
Chem. Res. 1997, 30, 364-372.
(1) For recent reviews on enantioselective amination of carbonyl
compounds, see: (a) Duthaler, R. O. Angew. Chem., Int. Ed. 2003, 42,
975-978. (b) Greck, C.; Drouillat, B.; Thomassigny, C. Eur. J. Org. Chem.
2004, 1377-1385. (c) Erdik, E. Tetrahedron 2004, 60, 8747-8782. (d)
Janey, J. M. Angew. Chem., Int. Ed. 2005, 44, 4292-4300. (e) Guillena,
G.; Ramo´n, D. J. Tetrahedron: Asymmetry 2006, 17, 1465-1492.
(2) Phukan, P.; Sudalai, A. Tetrahedron: Asymmetry 1998, 9, 1001-
1005.
(3) Evans, D. A.; Johnson, D. S. Org. Lett. 1999, 1, 595-598.
(4) Yamashita, Y.; Ishitani, H.; Kobayashi, S. Can. J. Chem. 2000, 78,
666-672.
(5) Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360-
5361.
10.1021/ol702019b CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/26/2007

only two examples have been reported. Adam and co-workers
were the first to demonstrate asymmetric induction (up to
52% ee) in the reaction of enol acetates or silyl enol ethers
and [(p-tolylsulfonyl)imino]phenyliodinane (TsNdIPh, 2a)
using 5.5-6 mol % of copper(I)-bis(oxazoline) or copper-
(I)-diimine complexes as chiral catalysts.10 Thereafter, Che
and co-workers explored the amination of silyl enol ethers
with TsNdIPh in the presence of 12.5 mol % of chiral
ruthenium(II)-salen catalyst, in which high enantioselectivity
(97% ee) was achieved only with 1-trimethylsiloxy-1-
cyclohexene, albeit in poor substrate conversion (23%).11
We recently reported that the enantioselective ben-
zylic C-H amination of aromatic hydrocarbons with
[N-(4-nitrophenylsulfonyl)imino]phenyliodinan (pNsNdIPh,
2b) catalyzed by chiral dirhodium(II) carboxylates pro-
vides sulfonamides in up to 84% ee.12 In this process,
trifluoroacetic acid (TFA), gave R-amino ketone 4b in 94%
yield (Table 1, entry 1). The enantioselectivity of this reaction
Table 1. Rh(II)-Catalyzed Enantioselective Amination of Silyl
Enol Ether 3a with 2a
temp
(°C)
time
(h)
yieldb
(%)
eec
(%)
entry
2
Rh(II)
product
1
2
3
4
5e
6
7
8g
9g
2b
2c
2d
2a
2c
2c
2c
2c
2c
1a
1a
1a
1a
1a
1b
1c
1b
1a
0
0
0
0
0
1
0.5
2
4b
4c
4d
4a
4c
4c
4c
4c
4c
94
94
95
55
NRf
93
82
94
93
57
86
60d
77
6
24
0.5
6
5
18
0
0
86
67
95
88
-40
-40
a All reactions were performed on a 0.2 mmol scale (0.1 M) with 1.05
equiv of 2. b Yield of isolated products. c Determined by HPLC. d The
preferred absolute stereochemistry was not determined. e Z/E ) 1:>99 of
3a was used. f No reaction. g 3 mol % of the catalyst was used.
Rh2(S-TCPTTL)4 (1a), characterized by the substitution of
chlorine atoms for four hydrogen atoms on the phthalimido
group in the parent dirhodium(II) complex, Rh2(S-PTTL)4
(1c), proved to be the catalyst of choice in terms of product
yield and enantioselectivity as well as catalytic activity.13
Herein, we report the first successful example of catalytic
enantioselective amination of silyl enol ethers derived from
acyclic ketones or enones with sulfonyliminoiodinanes, in
which the fluorinated complex Rh2(S-TFPTTL)4 (1b) has
emerged as the catalyst of choice for achieving enantiose-
lectivities as high as 95% ee.
At the outset, we explored the amination of silyl enol ether
3a (Z/E ) 96:4) derived from phenylacetone with 1.05
equiv of pNsNdIPh (2b) in the presence of 2 mol % of
Rh2(S-TCPTTL)4 (1a). The reaction proceeded smoothly in
CH2Cl2 at 0 °C and, after treatment with 90% aqueous
was determined to be 57% ee by HPLC analysis (Daicel
Chiralpak AD-H). The preferred absolute stereochemistry of
4b [[R]24 -103.1 (c 0.89, CHCl3) for 57% ee] was estab-
D
lished as R by chemical correlation.14 A survey of nitrene
precursors revealed that [(2-nitrophenylsulfonyl)imino]-
phenyliodinane (NsNdIPh, 2c) was greatly superior in terms
of reaction rate and enantioselectivity (86% ee, entry 2).15
Although the use of [(2,4-dinitrophenylsulfonyl)imino]-
phenyliodinane (DNsNdIPh, 2d) resulted in levels of product
yield and asymmetric induction similar to those found with
2b (entry 3), the use of TsNdIPh (2a), the most commonly
used nitrene precursor in this field, markedly diminished the
product yield (entry 4).16 Interestingly, the amination of (E)-
isomer of 3a (Z/E ) 1:>99) with 2c did not work even
after 24 h (entry 5). We then evaluated the performance of
[Rh2(S-TFPTTL)4] (1b)17 and [Rh2(S-PTTL)4] (1c).18,19 While
[Rh2(S-TFPTTL)4] exhibited essentially the same rate and
(8) For reviews on transition-metal-catalyzed enantioselective aziridi-
nation of alkenes with (arylsulfonylimino)phenyliodinanes and arylsulfonyl
azides, see: (a) Jacobsen, E. N. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999;
Vol. 2, Chapter 17, pp 607-618. (b) Mu¨ller, P.; Fruit, C. Chem. ReV. 2003,
103, 2905-2919. (c) Katsuki, T. Chem. Lett. 2005, 34, 1304-1309.
(9) For enantioselective amination of silyl enol ethers using stoichiometric
amounts of chiral nitridomanganese complexes, see: (a) Minakata, S.; Ando,
T.; Nishimura, M.; Ryu, I.; Komatsu, M. Angew. Chem., Int. Ed. 1998, 37,
3392-3394. (b) Svenstrup, N.; Bøgevig, A.; Hazell, R. G.; Jørgensen, K.
A. J. Chem. Soc., Perkin Trans 1 1999, 1559-1565.
(10) Adam, W.; Roschmann, K. J.; Saha-Mo¨ller, C. R. Eur. J. Org. Chem.
2000, 557-561.
(11) Liang, J.-L.; Yu, X.-Q.; Che, C.-M. Chem. Commun. 2002, 124-
125.
(12) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto,
S. Tetrahedron Lett. 2002, 43, 9561-9564.
(13) Recently, Reddy and Davies reported enantioselective benzylic C-H
amination using dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-(1-ada-
mantyl)glycinate], Rh2(S-TCPTAD)4, as a catalyst; see: Reddy, R. P.;
Davies, H. M. L. Org. Lett. 2006, 8, 5013-5016.
(14) For the determination of absolute stereochemistry, see the Supporting
Information.
(15) A survey of solvents revealed that CH2Cl2 was the optimal solvent
for this transformation. While toluene and benzotrifluoride exhibited nearly
the same yields and enantioselectivities as CH2Cl2, reaction times to
complete the reaction in these solvents were extended (toluene, 9 h, 92%
yield, 86% ee; PhCF3, 6 h, 95% yield, 85% ee).
(16) (a) Mu¨ller, P.; Baud, C.; Jacquier, Y. Can. J. Chem. 1998, 76, 738-
750. (b) Mu¨ller, P.; Baud, C.; Jacquier, Y. Tetrahedron 1996, 52, 1543-
1548. (c) Na¨geli, I.; Baud, C.; Bernardinelli, G.; Jacquier, Y.; Moran, M.;
Mu¨ller, P. HelV. Chim. Acta 1997, 80, 1087-1105.
(17) Tsutsui, H.; Yamaguchi, Y.; Kitagaki, S.; Nakamura, S.; Anada,
M.; Hashimoto, S. Tetrahedron: Asymmetry 2003, 14, 817-821.
(18) Minami, K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada, M.;
Hashimoto, S. AdV. Synth. Catal. 2005, 347, 1483-1487 and references
cited therein.
4560
Org. Lett., Vol. 9, No. 22, 2007

enantioselectivity as those found with Rh2(S-TCPTTL)4
(entry 6), Rh2(S-PTTL)4 was less effective in terms of both
reactivity and enantioselectivity (entry 7). An examination
of the temperature profile demonstrated that optimal enan-
tiocontrol was achieved with Rh2(S-TFPTTL)4 at -40 °C,
affording R-amino ketone 4c in 94% yield with 95% ee,
although 3 mol % of the catalyst was necessary to achieve
full conversion within reasonable reaction times (entry 8).
In contrast, catalysis with Rh2(S-TCPTTL)4 under the same
conditions required significantly longer reaction times to
reach completion and resulted in 88% ee (entry 9).
was consistently observed with either electron-withdrawing
or electron-donating groups present at the para position on
the benzene ring (90% and 95% ee, respectively), whereas
no reaction proceeded with 3n bearing a more sterically
demanding ethyl group.
Having identified the effectiveness of the combination of
Rh2(S-TFPTTL)4 as the catalyst and 2c as the nitrene
precursor, the applicability of this catalytic system to a range
of silyl enol ethers was then investigated (Table 2). The size
During the course of the above studies, we found that
dirhodium(II) carboxylates are effective catalysts for 1,4-
hydrosilylation of R,â-enones.21,22 This observation led us
to explore the feasibility of using Rh2(S-TFPTTL)4 to mediate
one-pot sequential 1,4-hydrosilylation/enantioselective ami-
nation of R,â-enones.23 Upon completion of the 1,4-hydro-
silylation reaction of benzalacetone (5a) with triethylsilane
in the presence of 3 mol % of Rh2(S-TFPTTL)4 (performed
in CH2Cl2 under reflux for 3 h), the reaction mixture (Z/E
ratio of 3f ) 85:15) was treated with 2c (1.05 equiv) at -40
°C for 8 h in the same reaction vessel. After the usual
workup, the desired R-amino ketone 4g was obtained in 82%
overall yield with 94% ee, very comparable to that obtained
in the amination of 3f (eq 2 vs Table 2, entry 6). While the
mechanistic profile of the dirhodium(II) carboxylate-
catalyzed 1,4-hydrosilylation is not clear at present,22 this
result strongly suggested that the integrity of the ligands on
the dirhodium framework was not compromised during the
1,4-hydrosilylation process.
Table 2. Enantioselective Amination Reaction of Silyl Enol
Ethers Catalyzed by 1b
silyl enol ether
SiR′3
product
Z/E time
yielda eeb
(%) (%)
entry
R
ratio
(h)
1
2
3
4
5
6
7
8
9
3a Ph
Et3Si
96:4
96:4
5
4
6
6
4
8
9
8
3
4c
4c
4c
4e
4f
94 95
94 93
94 95
95 84c
91 78c
3b Ph
Me3Si
3c Ph
t-BuMe2Si 96:4
3d 4-ClC6H4
3e 4-MeOC6H4
3f PhCH2
3g 4-ClC6H4CH2
Et3Si
Et3Si
Et3Si
Et3Si
96:4
96:4
>99:1
86:14
87:13
88:12
95:5
4g 94 95
4h 80 90c
3h 4-MeOC6H4CH2 Et3Si
4i
4j
82 90
81 47c
3i CH3(CH2)3
Et3Si
Et3Si
10 3j c-C6H11CH2
24 4k 89 56c
a Yield of isolated products. b Determined by HPLC. c The preferred
absolute stereochemistry was not determined.
of the trialkylsilyl group had little impact on product yield
and enantioselectivity (entries 1-3). However, switching the
R substituent from a phenyl group to p-chloro- or p-meth-
oxyphenyl groups diminished enantioselectivity (84% and
78% ee, entries 4 and 5). While the amination of benzyl-
substituted silyl enol ethers 3f-h gave the respective
R-amino ketones 4g-i in high yield with high levels of
enantioselectivity (90-95% ee, entries 6-8),20 use of silyl
enol ethers 3i,j derived from 2-heptanone and 4-cyclohexyl-
2-butanone resulted in only modest enantioselection (47%
and 56% ee, entries 9 and 10). The amination of silyl enol
ether 3k derived from propiophenone provided R-amino
ketone 4l in 97% yield with 93% ee, in which the preferred
absolute stereochemistry of 4l was opposite to that of 4c
(eq 1).14 In this system (R ) Me), high enantioselectivity
The N-2-nitrophenylsulfonyl group is synthetically advan-
tageous since the alkylation of N-monosubstituted Ns-amides
and deprotection proceed under mild conditions.24 To
demonstrate the utility of the present catalytic protocol, we
thus explored a novel, catalytic approach to (-)-metazocine
(21) Anada, M.; Tanaka, M.; Suzuki, K.; Nambu, H.; Hashimoto, S.
Chem. Pharm. Bull. 2006, 54, 1622-1623.
(22) For a seminal work on Rh(II)-catalyzed hydrosilylation reactions
of 1-alkynes and 1-alkenes, see: (a) Doyle, M. P.; High, K. G.; Nesloney,
C. L.; Clayton, T. W., Jr.; Lin, J. Organometallics 1991, 10, 1225-1226.
(b) Doyle, M. P.; Devora, G. A.; Nefedov, A. O.; High, K. G. Organome-
tallics 1992, 11, 549-555.
(23) For a recent review on single-pot catalysis of fundamentally different
transformations, see: Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed.
2004, 43, 3754-3760.
(24) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373-6374. For a review on the nitrophenylsulfonamide chemistry,
see: (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353-359.
(19) For a practical synthesis of Rh2(S-PTTL)4, see: Tsutsui, H.; Abe,
T.; Nakamura, S.; Anada, M.; Hashimoto, S. Chem. Pharm. Bull. 2005,
53, 1366-1368.
(20) No reaction was observed when the (E)-isomer of 3f (Z/E ) 1:>99)
was used.
Org. Lett., Vol. 9, No. 22, 2007
4561

without racemization. Ring-closing metathesis (RCM) of 8
in the presence of 10 mol % of the second-generation Grubbs
catalyst (9)30 proceeded smoothly in toluene under reflux to
give the tetrasubstituted alkene 10 in 84% yield.31 Removal
of the Ns group under standard Fukuyama conditions24 and
subsequent reductive alkylation produced tetrahydropyridine
Scheme 1. Asymmetric Formal Synthesis of (-)-Metazocine
12 [[R]22 +6.4 (c 0.98, ether)] in 77% yield. This product
D
exhibited spectroscopic data identical to the intermediate in
Meyers’ asymmetric synthesis of (+)-metazocine, except for
the sign of optical rotation [lit.,26a [R]D25 -6.8 (c 1.5, ether)
for (S)-12]. Thus, Grewe cyclization32 of 12 with HBr as
reported by Meyers and co-workers26a completed the catalytic
asymmetric synthesis of (-)-metazocine (6), which is a much
more potent analgesic than the (+)-enantiomer.33
In summary, we have demonstrated that Rh2(S-TFPTTL)4
is an exceptionally effective catalyst for enantioselective
aminations of silyl enol ethers derived from acyclic ketones
with NsNdIPh. Furthermore, we have developed a novel,
one-pot sequential 1,4-hydrosilylation/amination procedure
for the enantioselective synthesis of N-(2-nitrophenylsulfo-
nyl)-R-amino ketones from R,â-enones. The effectiveness
of the present catalytic protocol has been demonstrated by
an asymmetric formal synthesis of (-)-metazocine. Further
studies on the scope of the reaction as well as mechanistic
and stereochemical studies are currently in progress.
(6), a benzomorphan analgesic (Scheme 1).25-28 The one-
pot 1,4-hydrosilylation/enantioselective amination of 4-meth-
oxybenzalacetone (5b) led to the formation of R-amino
Acknowledgment. This research was supported in part
by a Grant-in-Aid for Scientific Research on Priority Areas
“Advanced Molecular Transformations of Carbon Resources”
from the Ministry of Education, Culture, Sports, Science and
Technology, Japan, and also by Grant-in-Aid from Innovation
Plaza Hokkaido in Japan Science and Technology Agency.
We thank S. Oka, M. Kiuchi, and T. Hirose of the Center
for Instrumental Analysis at Hokkaido University for techni-
cal assistance in MS and elemental analysis.
ketone 4i in 83% yield with 90% ee [mp 127-128 °C; [R]24
D
-72.5 (c 1.14, CHCl3) for 90% ee]. Fortunately, we found
that trituration of 4i (90% ee) in methanol gave crystals of
75% ee (32%, mp 129-132 °C), while the mother liquor
contained 4i with >99% ee [66%, mp 125-126 °C, [R]24
D
-81.9 (c 0.89, CHCl3)]. N-Alkylation of 4i (>99% ee) with
3-methyl-3-buten-1-ol under Mitsunobu conditions24,29 gave
the N,N-disubstituted R-amino ketone 7 in 71% yield, which,
upon Wittig methylenation, furnished diene 8 in 61% yield
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(25) Palmer, D. C.; Strauss, M. J. Chem. ReV. 1977, 77, 1-36.
(26) For chiral auxiliary-based asymmetric syntheses of (+)-6, see: (a)
Meyers, A. I.; Dickman, D. A.; Bailey, T. R. J. Am. Chem. Soc. 1985, 107,
7974-7978. (b) Ge´nisson, Y.; Marazano, C.; Das, B. C. J. Org. Chem.
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(27) For catalytic asymmetric synthesis of an intermediate for (-)-6,
see: (a) Kitamura, M.; Hsiao, Y.; Noyori, R. Tetrahedron Lett. 1987, 28,
4829-4832. (b) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta,
T.; Takaya, H.; Noyori, R. J. Org. Chem. 1994, 59, 297-310.
(28) For the first catalytic asymmetric synthesis of (-)-6, see: Trost, B.
M.; Tang, W. J. Am. Chem. Soc. 2003, 125, 8744-8745.
OL702019B
(29) For examples of N-alkylation under Mitsunobu conditions, see: (a)
Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris, G. D.,
Jr.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709-5712. (b) Tsunoda,
T.; Otsuka, J.; Yamamiya, Y.; Itoˆ, S. Chem. Lett. 1994, 23, 539-542.
(30) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(31) For recent examples of RCM to form tetrasubstituted alkenes, see:
Stewart, I. C.; Ung, T.; Pletnev, A. A.; Berlin, J. M.; Grubbs, R. H.; Schrodi,
Y. Org. Lett. 2007, 9, 1589-1592 and references cited therein.
(32) Grewe, R.; Mondon, A. Chem. Ber. 1948, 81, 279-286.
(33) May, E. L.; Eddy, N. B. J. Org. Chem. 1959, 24, 1435-1437.
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Org. Lett., Vol. 9, No. 22, 2007