Asymmetric synthesis of α-amino carbonyls (aldehydes, ketones and acids) using lithium (R)-N-benzyl-N-α-methylbenzylamide

Article abstract of DOI:10.1055/s-2001-17449

The diastereoselective conjugate addition of lithium (R)-N-benzyl-N-α-methylbenzylamide to α,β-unsaturated esters and subsequent enolate hydroxylation, followed by reduction and oxidative cleavage provides a facile route to N,N-protected α-amino aldehydes and ketones. Further manipulation furnishes α-amino acids in high enantiomeric excess.

Full text of DOI:10.1055/s-2001-17449

LETTER
1599
Asymmetric Synthesis of -Amino Carbonyls (Aldehydes, Ketones and Acids)
using Lithium (R)-N-benzyl-N- -methylbenzylamide
Asymmetric
S
t
ynthesi
e
s
of -Ami
p
no Carbonyl
h
s
en G. Davies,*a Simon W. Epstein,a Osamu Ichihara,b Andrew D. Smitha
a
The Dyson Perrins Laboratory, University of Oxford, South Parks Road, Oxford, OX1 3QY, UK
Fax +44(0)1865275633; E-mail: steve.davies@chemistry.ox.ac.uk
b
Evotec OAI, 151 Milton Park, Abingdon, Oxon, OX14 4SD, UK
Received 9 August 2001
Ph
Ph
Abstract: The diastereoselective conjugate addition of lithium (R)-
N-benzyl-N- -methylbenzylamide to , -unsaturated esters and
subsequent enolate hydroxylation, followed by reduction and oxi-
dative cleavage provides a facile route to N,N-protected -amino al-
dehydes and ketones. Further manipulation furnishes -amino acids
in high enantiomeric excess.
NH2
Ph
N
Ph
N
Li
t
OH
CO2 Bu
t
R
CO2 Bu
R
R
O
OH
Figure
Key words: -amino acids, conjugate addition, lithium amides,
asymmetric synthesis -amino aldehyde -amino acid
We have previously demonstrated that anti- -hydroxy- -
amino acids can be prepared by conjugate addition of a
homochiral lithium amide with concomitant diastereose-
lective enolate oxidation with (–)-(camphorsulfonyl)ox-
aziridine.10 Application of this methodology upon
addition of lithium (R)-N-benzyl-N- -methylbenzylamide
to tert-butyl crotonate 1, tert-butyl cinnamate 2 and tert-
butyl 5-methyl-hex-2-enoate 3 gave the anti- -hydroxy-
-amino esters 4–611 with high diastereoselectivity (crude
diastereomeric excess > 90% by 1H NMR analysis) and as
single diastereoisomers in excellent yield after purifica-
tion. -Amino esters 4–6 were subsequently reduced with
LiAlH4 to afford amino diols 7–912 in uniformly excellent
yield. H5IO6 mediated oxidation of amino diols 7–9 fur-
nished the aldehydes 10–1213 in excellent yield, with no
observable epimerisation (Scheme 1).
-Amino carbonyl compounds have been widely used as
chiral synthons for natural product synthesis.1 As a result
of their synthetic utility, many efficient and versatile
asymmetric syntheses of -amino acids and derivatives
have been investigated to allow for the incorporation of
novel structural motifs not found within the chiral pool
into these building blocks.2 The most common route to the
synthesis of -amino aldehydes and ketones is that de-
rived from their parent proteinogenic -amino acids, typ-
ically via reduction to the amino alcohol and subsequent
oxidation3 or by application of Weinreb amide methodol-
ogy.4 The asymmetric synthesis of -amino aldehydes and
ketones has similarly been investigated, with these reac-
tive functionalities having been prepared by nucleophilic
additions to both protected imines5 and pseudoephedrine Having clearly demonstrated the utility of this methodol-
N-Boc- -amino acid amides,6 as well as asymmetric alky- ogy for the asymmetric synthesis of -amino aldehydes,
lation of imines.7 We have previously shown that the dia- extension to the preparation of -amino ketones was in-
stereoselective conjugate addition of lithium amides de- vestigated. Thus, conjugate addition of lithium (R)-N-
rived from -methylbenzylamine to , -unsaturated es-
ters provides an efficient route for the asymmetric
synthesis of homochiral -amino acid derivatives.8 We re-
benzyl-N- -methylbenzylamide to ethyl 1-cyclopentene-
1-carboxylate 13 and subsequent enolate oxidation gave
-hydroxyl- -amino ester 14 with high diastereoselectiv-
port herein that lithium (R)-N-benzyl-N- -methylbenzyla- ity (crude diastereomeric excess > 90% by 1H NMR anal-
mide can be utilized for the asymmetric synthesis of N,N- ysis) and as a single diastereoisomer in 62% yield after
protected -amino aldehydes, N,N-protected -amino ke- purification. LiAlH4 reduction to the amino diol 15 and
tones and -amino acids from -amino acid derivatives. subsequent oxidative cleavage furnished ketone 16, al-
While the Arndt–Eistert procedure provides a widely used though with slight (6%) epimerisation upon oxidation in
route for the homologation of -amino acids to -amino this case (Scheme 2).
acids,9 the selective degradation of homochiral -hydroxy
Having demonstrated the preparation of -amino alde-
-amino esters is equally applicable as a route towards -
hydes and ketones, manipulation of -amino aldehydes
amino carbonyl derivatives (Figure).
10–12 to their -amino acid hydrochloride salts was suc-
cessfully accomplished in a two step procedure. Thus, so-
dium chlorite oxidation of aldehydes 10–12 gave the N-
benzyl-N- -methylbenzyl protected -amino acid deriva-
tives 17–1914 in 54–64% yield. Subsequent Pd-catalyzed
hydride transfer deprotection and treatment with aqueous
HCl gave (R)-alanine hydrochloride 20 and (R)-leucine
hydrochloride 2115 in > 98% enantiomeric excess and (R)-
Synlett 2001, No. 10, 28 09 2001. Article Identifier:
1437-2096,E;2001,0,10,1599,1601,ftx,en;D18301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1600
S. G. Davies et al.
LETTER
Ph
O
Ph
O
Ph
(i)
Ph
N
Ph
N
Ph
N
(i)
t
t
H
OH
CO2 Bu
CO2 Bu
R
R
R
R
OH
1, R = Me
2, R = iBu
4, R = Me, 89%
5, R = iBu, 91%
6, R = Ph, 90%
10, R = Me
11, R = iBu
12, R = Ph
17, R = Me, 54%
18, R = iBu, 64%
19, R = Ph, 64%
3, R = Ph
(ii)
(ii),(iii)
Ph
N
Ph
N
NH2 HCl
(iii)
Ph
Ph
OH
R
H
R
OH
R
O
OH
O
20, R = Me, 92%, >98% e.e.
21, R = iBu, 93%, >98% e.e.
22, R = Ph, 91%, 94% e.e.
10, R = Me, 95%
11, R = iBu, 90%
12, R = Ph, 95%
7, R = Me, 95%
8, R = iBu, 98%
9, R = Ph, 96%
Scheme 3 Reagents and Conditions: (i). NaClO2, cyclohexene, Me-
OH, 0 °C; (ii). 4.4% HCO2H, MeOH, Pd-C, 40 °C, 2 h; (iii). HCl(aq)
Scheme 1 Reagents and Conditions: (i). lithium (R)-N-benzyl-N- -
methylbenzylamide (1.6 equiv), THF, –78 °C, 2 h then (–)-(camphor-
sulfonyl) oxaziridine, THF, –78 °C to r.t.; (ii). LiAlH4, THF, –78 °C
to r.t.; (iii). H5IO6, DCM–H2O (1:1), 0 °C, 30 min.
reoselective conjugate addition of lithium (R)-N-benzyl-
N- -methylbenzylamide and concommitant enolate hy-
droxylation, reduction and oxidative cleavage. The exten-
sion of this protocol to the preparation of novel -amino
carbonyl derivatives is currently being investigated within
our laboratory.
phenylglycine hydrochloride 22 in 94% enantiomeric ex-
cess. The enantiomeric excesses of 20–22 were unambig-
uously determined in each case by 1H NMR spectroscopic
analysis of the corresponding Mosher’s amide derivatives
of the derived methyl esters and comparison to authentic
racemic samples (Scheme 3).
Acknowledgement
In conclusion, this methodology represents a novel asym-
metric synthesis of -amino aldehydes, -amino ketones
The authors wish to acknowledge the support of the EPSRC and
Oxford Asymmetry International plc for providing a CASE award
and -amino acids via the application of the highly diaste- (S. W. E) and to New College, Oxford for a Junior Research Fel-
lowship (A. D. S).
Ph
References and Notes
Ph
N
(i)
(1) For representative examples, see (a) Golebiowski, A.;
Jacobsson, U.; Jurczak, J. Tetrahedron 1987, 43, 3063.
(b) Rittle, K. E.; Homnick, C. F.; Ponticello, G. S.; Evans, B.
E. J. Org. Chem. 1982, 47, 3016. (c) Hanson, G. J.;
Lindberg, T. J. Org. Chem. 1985, 50, 5399. (d) Garner, P.;
Park, J. M. J. Org. Chem. 1988, 53, 2979.
(2) For instance, see: (a) Myers, A. G.; Gleason, J. L.; Yoon, T.
J. Am. Chem. Soc. 1995, 117, 8488. (b) Bull, S. D.; Davies,
S. G.; Epstein, S. W.; Ouzman, J. V. A. Chem. Commun.
1998, 659. (c) Schöllkopf, U.; Groth, U. Angew. Chem., Int.
Ed. Engl. 1981, 20, 977.
CO2Et
OH
CO2Et
14, 62%
13
(ii)
Ph
Ph
N
(iii)
Ph
N
Ph
(3) Reetz, M. T. Chem. Rev. 1999, 99, 1121.
OH
(4) (a) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22,
3815. (b) Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.
(c) Hocart, S. J.; Nekola, M. V.; Coy, D. H. J. Med. Chem.
1988, 31, 1820.
(5) Alexakis, A.; Lensen, N.; Tranchier, J.-P.; Mangeney, P.;
Feneau-Dupont, J.; Declercq, J. P. Synthesis 1995, 1038.
(6) Meyers, A. G.; Yoon, T. Tetrahedron Lett. 1995, 36, 9429.
(7) Wenglowsky, S.; Hegedus, L. S. J. Am. Chem. Soc. 1998,
120, 12468.
O
OH
16, 85%, 88% d.e.
15, 92%
Scheme 2 Reagents and Conditions: (i). lithium (R)-N-benzyl-N- -
methylbenzylamide (1.6 equiv), THF, –78 °C, 2 h then (–)-(camphor-
sulfonyl) oxaziridine, THF, –78 °C to r.t.; (ii). LiAlH4, THF, –78 °C
to r.t.; (iii). H5IO6, DCM–H2O (1:1), 0 °C, 30 min.
Synlett 2001, No. 10, 1599–1601 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of -Amino Carbonyls
1601
(8) (a) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry
1991, 2, 183. (b) Davies, S. G.; Fenwick, D. R. J. Chem.
Soc., Chem. Commun. 1995, 1109.
(9) For examples, see: (a) Plucinska, K.; Liberek, B.
Tetrahedron 1987, 43, 3509. (b) Grieco, P. A.; Hon, Y. S.;
Pedrez-Medrano, A. J. Am. Chem. Soc. 1988, 110, 1630.
(10) Bunnage, M. E.; Chernega, A. N.; Davies, S. G.; Goodwin,
C. J. J. Chem. Soc., Perkin Trans. 1 1994, 2373.
(Pho-,m-,p-), 72.0 (C(2)H), 64.5 (C(1)H2), 58.1 (C(a)H), 54.9
(C(3)H), 51.7 (NCH2)37.9 (C(4)H2), 25.2 (C(5)H), 23.3,
22.9 (C(5)(CH3)2), 16.3 (C( )Me); HRMS (CI+) C22H32NO2
requires 342.2433; found 342.2436.
(13) Experimental procedure for the synthesis of 11; H5IO6 (267
mg, 1.2 mmol) in H2O (2 mL) was added to a stirred solution
of the diol 8 (363 mg, 1.1 equiv) in DCM (2 mL) at 0 °C.
After 30 min the mixture was extracted with Et2O (2 20
mL) and the organic extracts washed with saturated sodium
bicarbonate (20 mL) and brine (20 mL) to afford 11 (295 mg,
90%) as a colorless oil; [ ]D22+1.3 (c 0.63, CHCl3);
(11) All new compounds were fully characterized; experimental
procedure for the synthesis of 5; n-butyllithium (2.5 M, 6.2
mL, 15.5 mmol) was added dropwise to a stirred solution of
(R)-N-benzyl-N- -methylbenzylamine (3.4 g, 16.0 mmol) in
THF (20 mL) at –78 °C under Ar. After 30 min, a solution of
(E)-tert-butyl 5-methyl-hex-2-enoate 2 (1.84 g, 10.0 mmol)
in THF (20 mL) was added via cannula. After 2 h, (–)-
(camphorsulfonyl)oxaziridine (7.3 g, 32 mmol) was added at
–78 °C and warmed to r.t. After 2 h, the reaction was cooled
to –78 °C and quenched by the addition of saturated aq
NH4Cl (5 mL) and warmed to r.t. After concentration in
vacuo, the residue was extracted with Et2O, washed
sequentially with 10% aq citric acid solution (20 mL),
saturated aq bicarbonate solution (10 mL) and brine (20
mL), dried (MgSO4) and concentrated in vacuo. Purification
by column chromatography on silica gel (hexane–Et2O, 10:1
to 5:1) gave 5 (2.54 g, 91%) as a colorless oil; [ ]D22 –18.9
(c 1.0, CHCl3); max(film)/cm–1 1722 (C=O); H (500 MHz,
CDCl3) 7.48–7.22 (10 H, m, Ph), 4.35 (1 H, d, JA,B 15.6,
NCHA), 3.99 (1 H, d, J2,3 1.4, C(2)H), 3.95 (1 H, q, J 7.0,
C( )H), 3.66 (1 H, d, JB,A 15.6, NCHB), 3.26 (1 H, m,
C(3)H), 2.89 (1 H, br d, J 1.9, OH), 1.94, (1 H, m, C(5)H),
1.59 (2 H, m, C(4)H2), 1.45 (9 H, s, (CH3)3C)), 1.29 (3 H, d,
J 7.0, C( )Me), 0.90 (3 H, d, J 6.8, C(5)CH3), 0.68 (3 H, d, J
6.5, C(5)CH3); C (50 MHz, CDCl3) 174.9 (C=O), 144.1,
143.5 (Phipso), 128.4, 128.2, 127.9, 127.2, 126.5 (Pho-,m-,p-),
82.5 (C(CH3), 71.1 (C(2)H), 59.4 (C(a)H), 57.0 (C(3)H),
51.0 (NCH2), 36.9 (C(4)H2), 28.0 (C(CH3)3), 24.1 (C(5)H),
23.6, 22.1 (C(5)(CH3)2), 20.4 (C( )Me); HRMS (CI+)
C26H38NO3 requires 412.2852; found 412.2856.
max(film)/cm–1 1723 (C=O); H (500 MHz, CDCl3) 9.42 (1
H, s, CHO), 7.51–7.27 (10 H, m, Ph), 4.16 (1 H, q, J 6.8,
C( )H), 4.00 (1 H, d, JA,B 14.7, NCHA), 3.96 (1 H, d, JB,A
14.7, NCHB), 3.41 (1 H, t, J 6.4, C(2)HCHO), 1.82 (1 H, app
sept, J 6.6, C(4)H), 1.77 (1 H, m, C(3)H2), 1.51 (3 H, d, J 6.9,
C( )Me), 1.50 (1 H, obscured, C(3)HA), 0.95 (3 H, d, J 6.8,
C(4)CH3), 0.93 (3 H, d, J 6.8, C(4)CH3); C (125 MHz,
CDCl3) 203.9 (C=O), 144.2, 141.3, (Phipso), 128.9, 128.8,
128.3, 127.8, 127.5 (Pho-,m-,p-), 64.2 (C(a)H), 58.9 (C(2)H),
51.1 (NCH2), 36.1 C(3)H2), 25.7 (C(4)H) 23.3, 23.2
(C(4)(CH3)2), 18.7 (C( )Me); HRMS (CI+) C21H28NO
requires 310.2171, found 310.2177.
(14) Experimental procedure for the synthesis of 18; cyclohexene
(1.0 mL) followed by NaClO2 (95 mg, 1.05 mmol) was
added to a stirred solution of the aldehyde 11 (295 mg, 0.96
mmol) in MeOH (5 mL) at 0 °C. After 30 min, the mixture
was extracted with Et2O (2 20 mL) and the organic
extracts washed with saturated sodium bicarbonate (20 mL)
and brine (20 mL) before concentration in vacuo to afford 18
(198 mg, 64%) as a colorless oil; [ ]D25+28.9 (c 1.0, CHCl3);
max(film)/cm–1 1704 (C=O); H (500 MHz)7.56–7.30 (10 H,
m, Ph), 4.17 (1 H, q, J 6.8, C( )H), 4.05 (1 H, d, JA,B 15.1,
NCHA), 3.99 (1 H, d, JB,A 15.1, NCHB), 3.50 (1 H, dd, J2,3A
7.6, J2,3B 6.9, C(3)H), 2.00 (1 H, app sept, J 6.7, (C(4)H),
1.76 (1 H, m, C(4)H), 1.58 (2 H, m, C(3)H2), 1.41 (3 H, d, J
6.8, C( )Me), 0.92 (3 H, d, J 6.7, C(4)CH3), 0.88 (3 H, d, J
6.7, C(4)CH3); C (62.5 MHz, CDCl3) 178.3 (C=O), 143.3,
140.6, (Phipso), 129.4, 129.1, 129.0, 128.6, 128.2, 128.0,
127.6 (Pho-,m-,p-), 59.9, 59.3 (C(a)H, C(2)H), 52.1
(12) Experimental procedure for the synthesis of 8; LiAlH4 (1 M
in THF, 5.4 mL, 5.4 mmol) was added dropwise to a stirred
solution of 5 (2.23 g, 5.4 mmol) in THF (10 mL) at –78 °C
under N2 and allowed to warm to r.t. After 24 h, 2 M
NaOH(aq)was added cautiously at 0 °C and the mixture
heated at reflux for 30 min before being cooled, filtered
through celite (eluent Et2O), dried and concentrated in
vacuo. Purification by column chromatography (Et2O) gave
8 (1.81 g, 98%) as a colorless oil; [ ]D25 –21.0 (c 1.0,
CHCl3); max(film)/cm–1 3401 (OH); H (500 MHz,
(NCH2)39.4 (C(3)H2), 26.0 (C(4)H), 22.8 (C(4)(CH3)2),
18.7 (C( )Me); HRMS (CI+) C21H28NO2 requires 326.2120;
found 326.2123.
(15) Experimental procedure for the synthesis of 21; Pd-C (77
mg, 10 mol%) was added to a stirred solution of 18 (77 mg,
0.24 mmol) in 4.4% formic acid in MeOH (10 mL) and
heated at 40 °C for 2 h. Upon cooling, the suspension was
filtered through celite®, acidified (1 mL, 10 M HCl) and
concentrated in vacuo to afford 21 (37 mg, 93%) as a white
solid; [ ]D25 –3.2 (c 0.5, H2O); Lit.16(ent)[ ]D20+2.8 (c 0.61,
H2O); H (500 MHz, D2O) 3.97 (1 H, m, CH2CHCO2H), 1.75
(1 H, app. quintet, J 5.9, (CH3)2CHCH2), 1.64 (2 H, m,
CHCH2CH), 0.87 (3 H, d, J 6.2, (CH3)2CH), 0.85 (3 H, d, J
6.2, (CH3)2CH); the ee was determined to be > 98% through
derivatization of the methyl ester as its Mosher’s amide.
(16) Oppolzer, W.; Moretti, R. Tetrahedron 1988, 17, 5541.
CDCl3)7.47–7.26 (10 H, m, Ph), 4.06 (1 H, d, JA,B 14.6,
NCHA), 3.97 (1 H, q, J 6.9, C( )H), 3.80 (1 H, d, JB,A 14.6,
NCHB), 3.57 (1 H, m, C(2)H), 3.41 (2 H, m, C(1)H2), 2.90 (1
H, m, C(3)H), 2.75 (2 H, br s, CH(OH)CH2OH), 1.90 (1 H,
m, (C(5)H), 1.59 (1 H, m (C(4)HA), 1.39 (3 H, d, J 6.9,
C( )Me), 1.36 (1 H, obscured, (C(4)HB), 1.02 (3 H, d, J 6.6,
C(5)CH3), 0.87 (3 H, d, J 6.5, C(5)CH3); C (125 MHz,
CDCl3)144.0, 141.7 (Phipso), 128.5, 127.9, 127.2, 126.9
Synlett 2001, No. 10, 1599–1601 ISSN 0936-5214 © Thieme Stuttgart · New York