Highly Stereoselective Reduction of β-Keto Amides: The First General and Efficient Approach to N-mono- and non-Substituted anti-α-Alkyl β-Hydroxy Amides

Article abstract of DOI:10.1055/s-2003-43354

The first general protocol for the anti-selective reduction of α-alkyl-β-keto amides is described. This simple and efficient methodology based on an open-chain Felkin-Anh model pathway, allows the isolation of N-mono- and non-substituted anti-α-substituted β-hydroxy amides in good yields and with high diastereo-selectivity.

Full text of DOI:10.1055/s-2003-43354

LETTER
73
Highly Stereoselective Reduction of b-Keto Amides: The First General and
Efficient Approach to N-mono- and non-Substituted anti-a-Alkyl b-Hydroxy
Amides
H
a
ighly Stereoselec
i
tive Re
u
duction of
b
s
-
Ket o Am
e
i des ppe Bartoli,*a Marcella Bosco,a Enrico Marcantoni,b Paolo Melchiorre,a Samuele Rinaldi,a Letizia Sambria
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, v.le Risorgimento 4, 40136 Bologna, Italy
b
Dipartimento Scienze Chimiche, Università di Camerino, via S.Agostino 1, 62032 Camerino, (MC), Italy
Fax +39(51)2093654; E-mail: giuseppe.bartoli@unibo.it
Received 26 September 2003
In fact, the anti-reduction with KBEt3H9 and HSiMe2Ph10
as reducing agents works well only in the case of N-disub-
stituted compounds. In addition, the latter method fails
when the group bound to the ketone moiety is an alkyl
Abstract: The first general protocol for the anti-selective reduction
of a-alkyl-b-keto amides is described. This simple and efficient
methodology based on an open-chain Felkin–Anh model pathway,
allows the isolation of N-mono- and non-substituted anti-a-substi-
tuted b-hydroxy amides in good yields and with high diastereo- chain.
selectivity.
Moreover, compounds anti-2 are not directly available
Key words: stereoselectivity, b-keto amides, reduction, anti-b-hy-
droxy amides, Felkin–Anh model
from an aldol approach: in fact, the addition of amide
enolates to aldehydes requires the use of tertiary amides.11
In this communication we report the first general and
highly selective method for the reduction of N-mono- and
non-substituted a-alkyl-b-keto amides 1 to the corre-
sponding anti-b-hydroxy derivatives 2.
Although seminal research has recognized the aldol
reaction1 as the more appropriate chemical tool for the ste-
reocontrolled construction of acyclic b-hydroxy carbonyl-
ic systems,2 an efficient alternative approach3 can be
offered by the stereoselective reduction of a-substituted
b-keto acid derivatives having adjacent stereogenic cen-
ters.
The anti-reduction of 1,3-dicarbonyl compounds of type
1 should require a pathway proceeding through an open-
chain mechanism12 (see Scheme 2) according to the
Felkin–Anh model.13,14
In the course of our program to develop new methodolo-
gies for the reductions of b-functionalized carbonyl com-
pounds with an asymmetric a-carbon in their racemic
form, we have found that the correct choice of hydride,
solvent and Lewis acid allows the highly selective prepa-
ration of syn- or anti-a-substituted b-hydroxy deriva-
tives.4 Accordingly, two strategies – chelation and non-
chelation – have been accomplished that enabled the
achievement of an opposite diastereoselectivity by choos-
ing the appropriate reducing system. These approaches
have been reported to be useful in the synthesis of various
natural products including b-lactam5 and b-lactone anti-
biotics.6
OH
O
O
O
[H]-
R3
R3
R1
N
H
R1
N
H
R2
anti-2
R2
1
R3= H, alkyl, aryl
Scheme 1
However, the accomplishment of such a protocol presents
some problems; for example, the CeCl3-mediated reduc-
tion, which has been proved to be very useful in the case
of b-keto phospine oxides and related systems,15 affords a
poor selectivity in the present case. Probably, the high
charge density on the oxygen of the amide group pro-
motes the formation of a cyclic complex even in the pres-
ence of a Lewis acid with a low tendency to undergo
chelation phenomena.
The stereoselective synthesis of a-substituted b-hydroxy
amides is a challenging problem for synthetic organic
chemists since these moieties repeatedly appear in the
framework of natural products.7 In this context the devel-
opment of an efficient protocol for the anti-selective re-
duction of b-keto amides of type 1 (see Scheme 1) to N-
mono- and non-substituted b-hydroxy amides (anti-2)8
appears particularly important because, at present, a gen-
eral and efficient approach to these compounds is still
lacking.
Thus, in order to avoid the formation of a metal chelate, it
is essential to drastically reduce the electron density on
the amide moiety. With this in mind, we planned to con-
vert the b-keto amide 1 into the corresponding silyl deriv-
ative 3 by deprotonation of the amide hydrogen with an
appropriate base and subsequent silylation of the oxygen.
According to the Felkin–Anh rules, the acyclic compound
3 should preferentially assume the most stable conforma-
SYNLETT 2004, No. 1, pp 0073–0076
0
5.
0
1.
2
0
0
4
Advanced online publication: 26.11.2003
DOI: 10.1055/s-2003-43354; Art ID: G25303ST.pdf
© Georg Thieme Verlag Stuttgart · New York

74
G. Bartoli et al.
LETTER
Table 1 Highly anti-Selective Reduction of N-mono- and non-
Substituted a-Alkyl-b-keto Amides 1
tion 3A. Thus, the in situ addition of a hydride ion source
should afford the O-silylated compound 4, which can be
ultimately converted into the desired anti-b-hydroxy
amide 2 in good yield and very high selectivity,
(Scheme 2).
i) (i-Pr)3SiCl
ii) NaH
OH
O
O
O
iii) K-selectride
iiii) 6 N HCl/MeOH
R1
NH
R3
R1
1a–k
NH
R3
R2
2a–k
The formation of the intermediate 3 requires the use of a
base able to selectively deprotonate the amide proton rath-
er than the active methine a-proton. Considering that the
a-proton of a b-keto amide is assumed to exhibit a low ki-
netic acidity,16 we thought to favor the formation of 3 by
using a large excess of a silylating agent (5 equiv com-
pared to b-keto amide) and a kinetic base (1.1 equiv) at
room temperature. Furthermore, the use of an encumbered
metal hydride having a counter cation with low O-chelat-
ing ability should ensure a highly selective anti-reduction.
R2
–78 °C to r.t.,
Et2O
Entry Hydroxy amide 2
Yield (%)a anti/synb
1
2
3
4
85
71
90
84
>99/1
OH
OH
OH
O
O
O
Ph
N
H
2a
98/2
Ph
NH2
SiR'3
O
O
2b
O
O
1) B–
>99/1
>99/1
R1
N
R3
2) R'3SiX
R1
NH
R3
Ph
R2
O
R2
Ph
N
H
1
3
R'3Si
R1
2c
O
O
R2
SiR'3
O
OMe
1) H-
OH
OH
O
O
NH
R3
2) NH4Cl
R2
Ph
N
H
4
N
H-
R3
H
HCl/MeOH
OH
R1
3A
2d
5
88
>99/1
O
Ph
N
H
R1
NH
R3
anti-2
R2
OMe
2e
Scheme 2
6
7
8
75
58
77
99/1
99/1
99/1
OH
O
C7H15
N
H
After examination of various reaction conditions, the use
of (i-Pr)3SiCl as the silylating agent,17 NaH as the base, K-
selectride as the reducing agent, and a coordinating sol-
vent such as Et2O, was the best choice. Another crucial
point is the addition sequence of the silylating agent and
NaH base. The optimum conditions, in fact, require the
addition of (i-Pr)3SiCl before NaH. Probably, this proce-
dure avoids the deprotonation of the methine a-proton, fa-
voring the selective formation of the intermediate 3.
Under these conditions, quenching of the reaction with an
NH4Cl aqueous solution affords the O-silyl derivative 4.
Its formation should be ascribed to an internal migration
from the oxygen of the amide function to the more basic
alkoxide moiety after the reduction process. We were able
to isolate this compound 4a in pure form in the reduction
of 1a (Figure 1).18 On the other hand, compound 4 can be
easily converted in the corresponding anti-b-hydroxy
amides 2 by simple acidic treatment (6 N HCl/MeOH),
without a preliminary purification.
2f
OH
OH
O
N
H
2g
2h
O
N
H
9
78
>99/1
OH
O
N
H
2i
10
11
51
56
99/1
99/1
OH
O
O
N
H
2j
(i-Pr)3Si
OH
O
O
N
H
Ph
4a
NH
2k
a Yields of pure isolated products after chromatographic purification.
b Determined by 1H NMR and 13C NMR.
Figure 1
Synlett 2004, No. 1, 73–76 © Thieme Stuttgart · New York

LETTER
Highly Stereoselective Reduction of b-Keto Amides
75
Vol. 2; Trost, B. M.; Fleming, I., Eds.; Pergamon Press:
The results are summarized in Table 1. The methodology
shows its effectiveness with a significant series of N-
mono- and non-substituted a-alkyl-b-keto amides 1.
Yields vary from good to high (up to 90%); diastereomer-
ic excesses are excellent in all cases.
Oxford, 1991, Chap. 1, 239. (c) Evans, D. A.; Nelson, J. V.;
Taber, T. R. Top. Stereochem. 1982, 13, 1. (d) Heathcock,
C. H. Science 1981, 214, 395.
(2) For recent direct catalytic asymmetric aldol reactions, see:
(a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) List, B.; Lerner, R. A.; Barbas, C. F. III
J. Am. Chem. Soc. 2000, 122, 2395. (c) Yoshikawa, N.;
Kumagai, N.; Matsunaga, S.; Moll, G.; Oshima, T.; Suzuki,
T.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 2466.
(d) Trost, B. M.; Ito, H. J. Am. Chem. Soc. 2000, 122, 12003.
(3) Greeves, N. In Comprehensive Organic Synthesis, Vol. 7;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991, 1.
(4) (a) a-Alkyl b-hydroxy sulfones:Bartoli, G.; Bosco, M.;
Cingolani, S.; Marcantoni, E.; Sambri, L. J. Org. Chem.
1998, 63, 3624. (b) a-Alkyl b-hydroxy esters: Marcantoni,
E.; Alessandrini, S.; Malavolta, M.; Bartoli, G.; Bellucci, M.
C.; Sambri, L.; Dalpozzo, R. J. Org. Chem. 1999, 64, 1986.
(c) a-Alkyl b-hydroxy ketones:Bartoli, G.; Bellucci, M. C.;
Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Sambri, L.
Chem.–Eur. J. 2000, 14, 2590. (d) a-Alkyl b-hydroxy
carbonitriles: Dalpozzo, R.; Bartoli, G.; Bosco, M.; De Nino,
A.; Procopio, A.; Sambri, L.; Tagarelli, A. Eur. J. Org.
Chem. 2001, 2971.
The best results in terms of both selectivity and reactivity
were achieved with aromatic b-keto amides (R1 = Ph,
entries 1–5). It is noteworthy that the reduction of a non-
substituted amide (entry 2) affords the corresponding
product 2b in good yield and high selectivity.
When R1 is an alkyl chain, the reduction is still very effi-
cient in term of stereoselectivity. In the presence of a short
alkyl chain (entries 7, 10 and 11) the decrease in chemical
yield is ascribed to a difficult isolation of the hydrophilic
products. Varying the alkyl group in the a-position, an in-
crease in yield with very high anti-selectivity was ob-
served (entries 8 and 9).
In conclusion, we have developed the first general meth-
odology for a highly anti-selective reduction of N-mono-
and non-substituted a-alkyl-b-keto amides.
The observed anti-selectivity is explained in terms of an
open-chain Felkin–Anh model pathway. The key role for
such stereochemical outcome is ascribed to the formation
of the intermediate 3, generated by selective abstraction of
the amide proton with NaH in the presence of (i-Pr)3SiCl
as the silylating agent.
(5) Wild, H.; Kant, J.; Walker, D. G.; Ojima, I.; Ternansky, R.
J.; Morin, J. M. Jr.; Georg, G. I.; Ravikumar, V. T. In The
Organic Chemistry of b-lactams; Georg, G. I., Ed.; VCH
Publishers: New York, 1993, ; and references therein.
(6) (a) Mead, K. T.; Park, M. Tetrahedron Lett. 1995, 36, 1205.
(b) Brown, H. C.; Kulkarni, S. V.; Racherla, U. S. J. Org.
Chem. 1994, 59, 365. (c) Hanessian, S.; Tehim, A.; Chen, P.
J. Org. Chem. 1993, 58, 7768.
(7) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(8) (a) For a synthesis of anti-N-mono- and non-substituted b-
hydroxy amides via 2-iminooxetane, see: Barbaro, G.;
Battaglia, A.; Giorgianni, P. J. Org. Chem. 1992, 57, 5128.
(b) For a recent asymmetric approach, see: Kitagawa, O.;
Momose, S.-i.; Yamada, Y.; Shiro, M.; Taguchi, T.
Tetrahedron Lett. 2001, 42, 4865.
(9) Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1985,
26, 4643.
(10) (a) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107,
8294. (b) Fujita, M.; Hiyama, T. J. Org. Chem. 1988, 53,
5405.
(11) For diastereoselective syntheses of N-disubstituted syn- or
anti-b-hydroxy amides, see: (a) Ganesan, K.; Brown, H. C.
J. Org. Chem. 1994, 59, 7346. (b) Denmark, S. E.; Griedel,
B. D.; Coe, D. M.; Schnute, M. E. J. Am Chem. Soc. 1994,
116, 7026. (c) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.;
Downey, C. W. J. Am Chem. Soc. 2002, 124, 392.
(d) Evans, D. A.; Downey, C. W.; Hubbs, J. D. J. Am Chem.
Soc. 2003, 125, 8706.
(12) The syn-reduction of b-keto amides is based on the
preliminary formation of a chelate complex intermediate;
see: (a) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni,
E.; Massaccesi, M.; Rinaldi, S.; Sambri, L. Tetrahedron Lett.
2001, 42, 8811. (b) Fujita, M.; Hiyama, T. J. Org. Chem.
1988, 53, 5415. (c) Taniguchi, M.; Fujii, H.; Oshima, K.;
Utimoto, K. Tetrahedron 1993, 49, 11169.
Typical Procedure
To a dry Et2O (10 mL) solution of b-keto amide 1 (1 mmol), (i-
Pr)3SiCl (5 equiv) was added at r.t., followed by NaH (1.1 equiv).
The resulting mixture was stirred for 15 min and then cooled at
–78 °C. K-selectride (2.5 equiv, 1 M THF solution) was added drop
wise. After being stirred for 3 h at –78 °C, the reaction mixture was
allowed to rise to r.t. Then the reaction was quenched with sat.
NH4Cl and extracted with EtOAc. After evaporation of the solvent
under reduced pressure, the crude residue was dissolved in MeOH
(5 mL/mmol) and conc. HCl (1 mL/mmol) and stirred at r.t. for 1 h
or until the disappearance of silylated product (checked by TLC).
After evaporation of MeOH, the mixture was poured into a separa-
tion funnel together with 10 mL H2O and extracted with EtOAc.
Chromatographic purification afforded the anti-a-substituted b-hy-
droxy amides 2.19
Acknowledgment
This work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica, Metodologie e Applicazioni’
supported by MIUR, Rome, and by the University of Bologna, in
the framework of ‘Progetto di Finanziamento Pluriennale, Ateneo
di Bologna’. The authors thank Mr. Franco Lupidi from University
of Camerino for elemental analysis measurements.
(13) (a) Chérest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett.
1968, 2199. (b) Anh, N. T.; Einsenstein, O. Nouv. J. Chem.
1977, 1, 61.
(14) (a) Bürgi, H. B.; Dunitz, J. D.; Shefter, E. J. J. Am. Chem.
Soc. 1973, 95, 5065. (b) Bürgi, H. B.; Dunitz, J. D.; Lehn, J.
M.; Wipff, G. Tetrahedron 1974, 30, 1563. (c) Bürgi, H. B.;
Lehn, J. M.; Wipff, G. J. Am Chem. Soc. 1974, 96, 1956.
References
(1) For some reviews, see: (a) Heathcock, C. H. In Asymmetric
Synthesis, Part B, Vol. 3; Morrison, J. D., Ed.; Academic
Press: New York, 1984, Chap. 2. (b) Kim, B. M.; Williams,
S. F.; Masamune, S. In Comprehensive Organic Synthesis,
Synlett 2004, No. 1, 73–76 © Thieme Stuttgart · New York

76
G. Bartoli et al.
LETTER
(15) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Sambri, L. Chem.–Eur. J. 1997, 3, 1941; for related systems,
see ref. 4.
(16) Evans, D. A.; Ennis, M. D.; Le, T. J. Am Chem. Soc. 1984,
106, 1154.
(CH3), 17.8 (CH3), 26.0 (CH3), 50.5 (CH), 77.4 (CH), 126.9
(CH), 127.5 (CH), 127.8 (CH), 142.7 (C), 175.1 (C).
(19) A typical case is reported: (R*,S*)-2-ethyl-3-hydroxy-N-
methylhexanamide (2h).20 The title compound was isolated
by column chromatography (CH2Cl2/EtOAc) as a white
solid (mp = 135–137 °C); yield 77%; anti/syn = 99/1. 1H
NMR (300 MHz, CDCl3): d = 0.85–0.95 (m, 6 H, 2 × CH3),
1.30–1.55 (m, 4 H), 1.55–1.70 (m, 1 H, CH2), 1.70–1.85 (m,
1 H, CH2), 1.95–2.05 (m, 1 H, CH), 2.80 (d, 3 H, CH3,
(17) The use of a less hindered silylating agent results in a
reduced anti-selectivity of the process. This is consistent
with a Felkin–Anh model in which the presence of a bulky
group on the oxygen of the intermediate 3 (Scheme 2)
promotes the selective approach of the hydride anion to the
b-carbonyl from the opposite side. For the importance of
using bulky silylated reagents to effectively prevent
chelation, see: Chen, X.; Hortelano, E. R.; Eliel, E. L. J. Am
Chem. Soc. 1990, 112, 6130.
(18) Compound 4a was isolated by chromatography (pentane/
Et2O) in 87% yield, anti/syn>99/1. 1H NMR (300 MHz,
CDCl3): d = 0.86 (d, 3 H, JHH = 7.2 Hz), 0.90–1.00 (m, 21
H), 2.45–2.50 (m, 1 H), 2.79 (d, 3 H, JHH = 4.8 Hz), 4.91 (d,
1 H, JHH = 7.8 Hz), 5.80 (br s, 1 H, NH), 7.20–7.35 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 12.3 (CH), 14.1 (CH3), 17.7
J
HH = 4.8 Hz), 3.00 (bs, 1 H, OH), 3.60–3.70 (m, 1 H, CH),
6.00 (br s, 1 H, NH). 13C NMR (75 MHz, CDCl3): d = 12.0
(CH3), 14.0 (CH3), 19.2 (CH2), 23.6 (CH2), 25.9 (CH3), 38.2
(CH2), 53.5 (CH), 71.9 (CH), 176.2 (C). Anal. Calcd for
C9H19NO2: H, 11.05; C, 62.39; N, 8.08. Found: H, 11.36; C,
62.18; H, 7.90.
(20) Descriptors R*, S* indicate that diastereomeric compounds
are obtained as racemates. We prefer this terminology to
avoid the ambiguities that could arise from syn–anti
descriptors.
Synlett 2004, No. 1, 73–76 © Thieme Stuttgart · New York