Stereoselective synthesis of 3,4-disubstituted pyroglutamates by ring transformation of 5-ylidene-1,3-dioxan-4-ones with N-(diphenylmethylene)-glycinate

Article abstract of DOI:10.1016/S0957-4166(00)00403-1

N-(Diphenylmethylene)-glycinate gives stereoselective conjugate addition to readily available (E) and (Z)-5-ylidene-1,3-dioxan-4-ones. Hydrolytic cleavage of the imine functionality of the resulting Michael-adducts causes ring transformation to new, optically active 3,4-disubstituted pyroglutamates. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00403-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 4365–4375
Stereoselective synthesis of 3,4-disubstituted pyroglutamates
by ring transformation of 5-ylidene-1,3-dioxan-4-ones with
N-(diphenylmethylene)-glycinate
Akbar Ali,a,b Viqar Uddin Ahmad,b Burkhard Ziemera and Ju¨rgen Liebschera,*
aInstitut fu¨r Chemie, Humboldt-Universita¨t Berlin, Hessische Straße 1–2, D-10115 Berlin, Germany
bHEJ Research Institute of Chemistry, University of Karachi, Karachi 75270, Pakistan
Received 25 September 2000; accepted 6 October 2000
Abstract
N-(Diphenylmethylene)-glycinate gives stereoselective conjugate addition to readily available (E) and
(Z)-5-ylidene-1,3-dioxan-4-ones. Hydrolytic cleavage of the imine functionality of the resulting Michael-
adducts causes ring transformation to new, optically active 3,4-disubstituted pyroglutamates. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
Pyroglutamates are biologically important compounds, natural as well as synthetic members
of this family exhibiting important pharmacological properties.1,2 They are of further interest as
conformationally constrained glutamate analogues.3 Several syntheses of this class of com-
pounds are known, among them the reactions of a,b-unsaturated esters as CꢀCꢀC building
blocks with protected a-amino acid derivatives as CꢀN units. Imines derived from a-amino
esters turned out to be very useful in such syntheses.4–9 Since the starting Michael-addition of
the aminocarboxylate is stereoselective,4–10 this approach is particularly useful for the asymmet-
ric synthesis of pyroglutamates.6,7,9 Chiral information to be exploited can be located in a
substituent attached to the Michael-system7,9 or in the imine of amino esters with chiral
ketones.6,7,10
We report here the stereoselective synthesis of new 3,4-disubstituted pyroglutamates 4 and 5
applying 5-ylidene-1,3-dioxan-4-ones 1 as chiral Michael-systems. These dioxanones are readily
available in (E) and (Z)-configuration from (R)-3-hydroxybutyrate, a monomer of naturally
occurring poly-(R)-3-hydroxybutyrate (PHB), by acetalisation with pivalaldehyde and aldol
reaction.11,12 The dioxanones 1 were already applied in the synthesis of enantiopure 4-substituted
* Corresponding author. Tel: (+49) 30-2093-9039; fax: (+49) 30-2093-8907; e-mail: liebscher@chemie.hu-berlin.de
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00403-1

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A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
3-(1-hydroxyethyl) pyrrolidine-2-ones using nitromethane as the CꢀN building block.13 Michael-
addition and subsequent reduction of the nitro to the amino group caused ring transformation
by nucleophilic attack at the carbonyl carbon atom, opening the ring and splitting off
pivalaldehyde.
2. Results and discussion
Reaction of ethyl N-(diphenylmethylene)-glycinate with (E) and (Z)-5-ylidene-1,3-dioxan-4-
ones (E)-1 and (Z)-1 in the presence of DBU and LiBr gave the corresponding Michael-adducts
2 and 3 in high yields (Scheme 1; Table 1). Although three new stereogenic centres were created
Scheme 1.
Table 1
Michael-adducts 2, 3 and pyroglutamates 4 and 5
Entry
R
Configuration of
reactant 1
Adducts 2+3
dr 2:3
Pyroglutamates 4 or 5
(% yield)a
(% yield)b
1
2
3
4
5
6
7
8
CH3
CH3
C2H5
C2H5
(CH2)2Ph
(CH2)2Ph
Ph
E
Z
E
Z
E
Z
E
E
2a/3a (82)
2a/3a (80)
2b/3b (78)
2b/3b (76)
2c/3c (85)
2c/3c (82)
2d/3d (76)
No reactionc
75:25
35:65
80:20
30:70
90:10
20:80
95:05
–
4a (98)
5a (97)
4b (97)
5b (98)
4c (98)
5c (97)
4d (96)
–
Cyclohexyl
a Major isomer could be obtained in analytically pure form by flash chromatography.
b Obtained from pure adducts 2 or 3, respectively.
c Starting material was completely recovered.

A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
4367
(dr 65:35 to 95:05), only two products could be detected in all the cases. The preferred mode of
attack at 1 occurred from the bottom side, i.e. re for (E)-1 and si for (Z)-1 while the protonation
always took place from the si-face (an overall anti addition to the exocyclic double bond).12
Thus, diastereomer 2 is the major product starting from (E)-1 and diastereomer 3 is the major
product derived from (Z)-1. This anti-selective Michael-addition is assumed to proceed through
a chelation-controlled transition state (Fig. 1).10 The observed diastereoselectivities were lower in
the reactions of (Z)-1 compared with the corresponding (E) isomer. It is worth mentioning that
cyclohexyl-substituted 5-ylidene-1,3-dioxan-4-one (E)-1 (R=cyclohexyl) did not react at all
under the conditions, being successful in all of the other cases. It is likely that the CꢀC double
bond is sterically too congested by the secondary cyclohexyl substituent to allow a Michael-
addition to occur. However, the generally high degree of substitution at the double bond of
reactants 1 seems to be advantageous for the Michael-addition since less crowded Michael-
systems can alternatively undergo 1,3-diploar cycloaddition of the azomethine-ylide derived
from a-amino acids to the CꢀC double bond.10
Figure 1. Chelation-controlled transition state model for the Michael-addition of N-(diphenylmethylene)-glycinate to
(E)-5-ylidene-1,3-dioxan-4-one (E)-1
The major isomers 2 or 3 derived from (E)-1 and (Z)-1, respectively, can easily be obtained
in a diastereomerically pure state by simple flash chromatography or by crystallisation. They
were further submitted to hydrolytic cleavage of the azomethine structure in order to deprotect
the amino group. The resulting a-amino esters could not be observed, but cyclised in almost
quantitative yields to 4 or 5 by the nucleophilic attack of the amino group at the carbonyl
carbon atom at position 4, opening the 1,3-dioxan-4-one ring and destruction of the acetal
moiety by releasing pivalaldehyde (Scheme 2). The structures of products 2–5 were elucidated on
the basis of X-ray crystal analysis of compounds 2a (Fig. 2) and 3d (Fig. 3). The absolute
configurations of the pyroglutamates 4 and 5 can be concluded from their precursors 2 and 3,
1
respectively, and were confirmed by NMR experiments. The coupling constants in the H NMR
spectra of 4 and 5 were not useful for assignment of the relative configuration of substituents at
positions 2, 3 and 4 (see Section 3). Thus 2D-NOESY correlations were applied to confirm the
configuration in 4 and 5 (Fig. 4).
In summary, a straightforward access to new optically active pyroglutamates 4 and 5 from
5-ylidene-1,3-dioxanones 1 and ethyl N-(diphenylmethylene)-glycinate was developed as a
two-step procedure by Michael-addition and hydrolytic cleavage of the azomethine. This
method allows the stereoselective synthesis of either isomer by using either (E)-1 or (Z)-1 as
reactant. Pyroglutamates 4 and 5 are promising candidates for reductive transformation into
protein kinase C modulators.14

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A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
Scheme 2.
Figure 2. X-Ray crystal analysis of compound 2a
3. Experimental
1H NMR and 13C NMR spectra were recorded at 300 and 75.5 MHz, respectively, on a
1
Bruker AC-300 in CDCl3 with TMS as internal standard. 2D NMR experiments include H–1H
COSY, HMQC, NOESY and HMBC. Optical rotations were determined with a Perkin Elmer
polarimeter 241 (c=1, CHCl3, d=1 mm). For preparative column chromatography silica
(0.04–0.063 mm, Merck) was used. Starting glycinate and all other compounds used were
purchased from Aldrich, Fluka or Merck. The ylidenedioxanones 1a–1e were synthesised
following or adapting literature procedures.11–13

A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
4369
Figure 3. X-Ray crystal analysis of compound 3c
Figure 4. Most significant cross peaks from the NOESY spectra of 4a and 5a
3.1. General procedure for the Michael-addition of ethyl N-(diphenylmethylene)-glycinate to
chiral ylidenedioxanones (E)-1 or (Z)-1
To a suspension of LiBr (0.105 g, 1.2 mmol) in dry THF (5 ml) was added a solution of imine
(0.30 g, 1.1 mmol) in dry THF (5 ml) under argon atmosphere and stirring. After 15 min the
solution was cooled to −78°C. A solution of 5-ylidenedioxanone [(E)-1 for the synthesis of 2 and
(Z)-1 for the synthesis of 3] (1 mmol) in dry THF (5 ml) was added dropwise over 20 min. DBU
(0.17 g, 1.1 mmol) was then added slowly. After stirring overnight, the reaction mixture was
allowed to warm to 0°C and was quenched with saturated aqueous NH4Cl solution (10 ml). The
organic phase was extracted with Et2O (3×30 ml); combined organic extracts were dried
(MgSO4) and evaporated under reduced pressure to yield a pale yellow residue, which was
purified by flash chromatography (silica gel, hexane–Et2O, 4:1).

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3.1.1. Ethyl (2R,3R)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]butanoate 2a
Yield: 82%; mixture of 2a and 3a; dr 80:20; major isomer 2a: Rf=0.44 (hexane–Et2O, 4:1);
colourless crystals, mp 112–113°C; [h]2D0=+185.2 (c=1, CHCl3); H NMR (CDCl3) l 0.86 [s,
1
9H, C(CH3)3], 0.89 (d, J=7.1 Hz, 3H, CH3CH), 1.08 (t, J=7.1 Hz, 3H, OCH2CH3), 1.42 (d,
J=6.0 Hz, 3H, CH3CHO), 2.45 (ddq, J=1.5, 10.2, 7.1 Hz, 1H, CH3CH), 2.70 (dd, J=1.5, 9.8
Hz, 1H, CHCꢁO), 3.75 (dq, J=9.8, 6.0 Hz, 1H, CHO), 3.95 (q, J=7.1 Hz, 2H, OCH2), 4.41 (d,
J=10.2 Hz, 1H, CHN), 4.78 (s, 1H, OCHO), 7.11–7.14 (m, 2H, ArH), 7.23–7.40 (m, 6H, ArH),
7.58–7.63 (m, 2H, ArH); 13C NMR (CDCl3) l 13.06 (CH3CH), 14.05 (OCH2CH3), 20.20
(CH3CHO), 23.88 [C(CH3)3], 35.12 [C(CH3)3], 37.60 (CH3CH), 48.15 (CHCꢁO), 60.58 (OCH2),
68.15 (CHN), 74.23 (CHO), 107.78 (OCHO), 128.0, 128.03 (×2), 128.22 (×2), 128.59, 128.75
(×3), 130.50 (CH, Ar), 136.04, 139.32 (C, Ar), 169.32 (CꢁN), 172.03, 172.05 (CꢁO). Anal. calcd
for C28H35NO5: C, 72.23; H, 7.58; N, 3.01. Found: C, 72.20; H, 7.70; N, 2.99.
3.1.1.1. Crystal structure determination of compound 2a15. A single crystal of 2a with the
dimensions 1.12×1.07×1.00 mm was measured on a STOE Stadi4 diffractometer using Mo Ka
,
radiation (u=0.71073 A). Crystal data: C28H35NO5, M=465.57, orthorhombic space group
3
,
,
P212121, a=9.2522 (7), b=13.9982 (17), c=20.165 (5) A, i=90°, V=2611.6 (7) A , Z=4,
Dc=1.184 g cm−3, F (000)=1000, v (Mo Ka)=0.081 mm−1. At 180 (2) K in the range of
1.77<q<25.25°, 2889 reflections were measured, 2690 were unique (R(int)=0.0038). The final
residuals were wR2(all)=0.0797 and R1(obs)=0.0317. The maximum and minimum peaks in the
−3
,
final difference map were 0.140 and −0.120 e A , respectively.
3.1.2. Ethyl (2S,3S)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]butanoate 3a
Yield: 80%; colourless oil, mixture of 2a and 3a; dr 30:70; major isomer 3a: Rf=0.48
1
(hexane–Et2O, 4:1); [h]2D0=−134.2 (c=1, CHCl3); H NMR (CDCl3) l 0.58 [s, 9H, C(CH3)3],
1.05 (t, J=7.1 Hz, 3H, OCH2CH3), 1.16 (d, J=7.1 Hz, 3H, CH3CH), 1.30 (d, J=6.0 Hz,
CH3CHO), 2.29 (dd, J=1.1, 9.8 Hz, 1H, CHCꢁO), 2.58 (m, 1H, CH3CH), 3.93 (q, J=7.1 Hz,
2H, OCH2), 4.20 (d, J=9.04 Hz, 1H, CHN), 4.44 (dq, J=9.8, 6.0 Hz, 1H, CHO), 4.60 (s, 1H,
OCHO), 7.10–7.13 (m, 2H, ArH), 7.21–7.39 (m, 6H, ArH), 7.55–7.58 (m, 2H, ArH); 13C NMR
(CDCl3) l 14.01 (OCH2CH3), 14.12 (CH3CH), 20.17 (CH3CHO), 23.50 [C(CH3)3], 34.39
[C(CH3)3], 37.31 (CH3CH), 52.66 (CHCꢁO), 60.72 (OCH2), 68.03 (CHN), 74.95 (CHO), 106.74
(OCHO), 127.49 (×2), 128.10 (×2), 128.35 (×2), 128.61, 128.94 (×2), 130.68 (CH, Ar), 135.87,
139.24 (C, Ar), 170.64 (CꢁN), 171.95, 172.27 (CꢁO). Anal. calcd for C28H35NO5: C, 72.23; H,
7.58; N, 3.01. Found: C, 72.12; H, 7.61; N, 2.92.
3.1.3. Ethyl (2R,3R)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]pentanoate 2b
Yield: 78%; mixture of 2b and 3b; dr 80:20; major isomer 2b: Rf=0.48 (hexane–Et2O, 4:1);
colourless crystals, mp 75–76°C; [h]2D0=+134 (c=1, CHCl3); H NMR (CDCl3) l 0.83 [s, 9H,
1
C(CH3)3], 0.88 (t, J=7.1 Hz, 3H, OCH2CH3), 1.15 (t, J=7.1 Hz, 3H, CH3CH2), 1.17 (d, J=6.0
Hz, 3H, CH3CHO), 1.62–1.72 (m, 2H, CH3CH2), 2.31 (ddt, J=2.2, 10.2, 7.1 Hz, 1H, CHCH2),
2.42 (dd, J=2.2, 9.8 Hz, 1H, CHCꢁO), 3.93 (dq, J=9.8, 6.0 Hz, 1H, CHO), 4.05 (q, J=7.1 Hz,
2H, OCH2), 4.23 (d, J=6.8 Hz, 1H, CHN), 4.75 (s, 1H, OCHO), 7.05–7.09 (m, 2H, ArH),
7.20–7.38 (m, 6H, ArH), 7.54–7.58 (m, 2H, ArH); 13C NMR (CDCl3) l 12.35 (CH3CH2), 14.08

A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
4371
(OCH2CH3), 20.38 (CH3CHO), 23.57 (CH3CH2), 23.91 [C(CH3)3], 35.05 [C(CH3)3], 44.01
(CHCH2), 48.49 (CHCꢁO), 61.08 (OCH2), 66.59 (CHN), 73.46 (CHO), 107.18 (OCHO), 127.76
(×2), 128.05 (×2), 128.53 (×2), 128.81, 128.95 (×2), 130.42 (CH, Ar), 136.20, 139.44 (C, Ar),
169.30 (CꢁN), 171.0, 171.90 (CꢁO). Anal. calcd for C29H37NO5: C, 72.62; H, 7.78; N, 2.92.
Found: C, 72.54; H, 7.61; N, 2.90.
3.1.4. Ethyl (2S,3S)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]pentanoate 3b
Yield: 80%; mixture of 2b and 3b; dr 75:25; major isomer 3b: Rf=0.51 (hexane–Et2O, 4:1);
colourless oil; [h]2D0=−72.4 (c=1, CHCl3); H NMR (CDCl3) l 0.57 [s, 9H, C(CH3)3], 0.86 (t,
1
J=7.1 Hz, 3H, OCH2CH3), 1.05 (t, J=7.1 Hz, 3H, CH3CH2), 1.29 (d, J=6.4 Hz, 3H,
CH3CHO), 1.40 and 1.72 (each m, 2×H, CH3CH2), 2.30 (ddt, J=1.0, 8.6, 7.1 Hz, 1H, CHCH2),
2.39 (dd, J=1.0, 9.8 Hz, 1H, CHCꢁO), 3.94 (q, J=7.1 Hz, 2H, OCH2), 4.27 (d, J=8.6 Hz, 1H,
CHN), 4.45 (dq, J=9.8, 6.4 Hz, 1H, CHO), 4.62 (s, 1H, OCHO), 7.12–7.15 (m, 2H, ArH), 7.24
(m, 1H, ArH), 7.30–7.44 (m, 4H, ArH), 7.49–7.57 (m, 2H, ArH), 7.73 (m, 1H, ArH); 13C NMR
(CDCl3) l 12.09 (CH3CH2), 13.98 (OCH2CH3), 19.73 (CH3CHO), 23.50 [C(CH3)3], 25.26
(CH3CH2), 34.34 [C(CH3)3], 44.13 (CHCH2), 48.24 (CHCꢁO), 60.76 (OCH2), 67.13 (CHN),
74.97 (CHO), 106.67 (OCHO), 127.54, 128.07, 128.28 (×2), 128.55, 129.02 (×2), 130.05, 130.62,
132.40 (CH, Ar), 135.91, 139.42 (C, Ar), 170.73 (CꢁN), 172.08, 172.38 (CꢁO). Anal. calcd for
C29H37NO5: C, 72.62; H, 7.78; N, 2.92. Found: C, 72.42; H, 7.74; N, 2.89.
3.1.5. Ethyl (2R,3R)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]-5-phenylpentanoate 2c
Yield: 85%; mixture of 2c and 3c; dr 90:10; major isomer 2c: Rf=0.52 (hexane–Et2O, 4:1);
1
colourless oil; [h]2D0=+82.2 (c=1, CHCl3); H NMR (CDCl3) l 0.81 [s, 9H, C(CH3)3], 1.11 (d,
J=6.0 Hz, 3H, CH3CHO), 1.13 (t, J=7.1 Hz, 3H, OCH2CH3), 1.97 and 2.19 (each m, 2×H,
CH2CH2Ph), 2.36 (m, 1H, CHCH2), 2.48 (dd, J=3.0, 9.8 Hz, 1H, CHCꢁO), 2.50–2.70 (m, 2H,
CH2CH2Ph), 3.91 (dq, J=9.8, 6.0 Hz, 1H, CHO), 4.02 (q, J=7.1 Hz, 2H, OCH2), 4.21 (d,
J=5.3 Hz, 1H, CHN), 4.70 (s, 1H, OCHO), 7.02–7.09 (m, 5H, ArH), 7.14–7.38 (m, 8H, ArH),
7.53–7.57 (m, 2H, ArH); 13C NMR (CDCl3) l 14.10 (OCH2CH3), 20.30 (CH3CHO), 23.94
[C(CH3)3], 32.14 (CH2CH2Ph), 33.72 (CH2CH2Ph), 35.08 [C(CH3)3], 41.81 (CHCH2), 48.89
(CHCꢁO), 61.16 (OCH2), 66.46 (CHN), 73.47 (CHO), 107.22 (OCHO), 125.91, 127.74 (×2),
128.09 (×2), 128.38 (×2), 128.49 (×2), 128.60 (×2), 128.87, 129.03 (×2), 130.52 (CH, Ar), 136.17,
139.36, 141.69 (C, Ar), 169.07 (CꢁN), 171.17, 171.79 (CꢁO). Anal. calcd for C35H41NO5: C,
75.65; H, 7.44; N, 2.52. Found: C, 75.47; H, 7.50; N, 2.57.
3.1.6. Ethyl (2S,3S)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]-5-phenylpentanoate 3c
Yield: 86%; mixture of 2c and 3c; dr 20:80; major isomer 3c: Rf=0.50 (hexane–Et2O, 4:1);
colourless crystals, mp 104–105°C; [h]2D0=−97.8 (c=1, CHCl3); H NMR (CDCl3) l 0.60 [s, 9H,
1
C(CH3)3], 1.05 (t, J=7.1 Hz, 3H, OCH2CH3), 1.23 (d, J=6.0 Hz, 3H, CH3CHO), 1.73 and 2.13
(each m, 2×H, CH2CH2Ph), 2.41–2.51 (m, 3×H, CHCH2, CHCꢁO and CH2CH2Ph), 2.69 (m,
1H, CH2CH2Ph), 3.93 (q, J=7.1 Hz, 2H, OCH2), 4.28 (d, J=7.9 Hz, 1H, CHN), 4.41 (dq,
J=9.8, 6.0 Hz, 1H, CHO), 4.65 (s, 1H, OCHO), 7.05–7.38 (m, 13H, ArH), 7.52–7.56 (m, 2H,
ArH); 13C NMR (CDCl3) l 14.01 (OCH2CH3), 19.78 (CH3CHO), 23.56 [C(CH3)3], 33.57
(CH2CH2Ph), 34.11 (CH2CH2Ph), 34.41 [C(CH3)3], 41.58 (CHCH2), 48.95 (CHCꢁO), 60.91

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A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
(OCH2), 67.08 (CHN), 74.78 (CHO), 106.71 (OCHO), 125.88, 127.51 (×2), 128.09 (×2), 128.30
(×2), 128.33 (×2), 128.36 (×2), 128.61, 129.06 (×2), 130.65 (CH, Ar), 135.93, 139.37, 141.40 (C,
Ar), 170.50 (CꢁN), 171.92, 172.57 (CꢁO). Anal. calcd for C35H41NO5: C, 75.65; H, 7.44; N, 2.52.
Found: C, 75.36; H, 7.29; N, 2.52.
3.1.6.1. Crystal structure determination of compound 3c15. A single crystal of 2a with the
dimensions 0.80×0.56×0.48 mm was measured on a STOE Ipds diffractometer using Mo Ka
,
radiation (u=0.71073 A). Crystal data: C35H41NO5, M=555.69, monoclinic space group P21,
3
,
,
a=9.459 (3), b=17.438 (4), c=9.625 (4) A, i=100.1°, V=1563.6 (9) A , Z=2, Dc=1.180 g
cm−3, F (000)=596, v (Mo Ka)=0.078 mm−1. At 180 (2) K in the range of 2.15<q<25.94°, 5722
reflections were measured, 3132 were unique (R(int)=0.0214). The final residuals were wR2(all)
=
0.1017, and R1(obs)=0.0377. The maximum and minimum peaks in the final difference map were
−3
,
0.284 and −0.253 e A , respectively.
3.1.7. Ethyl (2R,3S)-3-[(2R,5R,6R)-2-(t-butyl)-6-methyl-4-oxo-1,3-dioxan-5-yl]-2-
[(diphenylmethylene)-amino]-3-phenylpropanoate 2d
Yield: 76%; mixture of 2d and 3d; dr 95:05; major isomer 2d: Rf=0.46 (hexane–Et2O, 4:1);
1
colourless crystals, mp 53–55°C; [h]2D0=+115.0 (c=1, CHCl3); H NMR (CDCl3) l 0.61 (t,
J=7.1 Hz, 3H, OCH2CH3), 0.71 [s, 9H, C(CH3)3], 1.46 (d, J=6.0 Hz, 3H, CH3CHO), 3.11 (dd,
J=3.0, 9.4 Hz, 1H, CHCꢁO), 3.51–3.58 (m, 3H, OCH2 and CHPh), 3.69 (dq, J=9.4, 6.0 Hz,
1H, CHO), 3.98 (s, 1H, OCHO), 5.08 (d, J=10.9 Hz, 1H, CHN), 7.16–7.41 (m, 13H, ArH),
7.63–7.71 (m, 2H, ArH); 13C NMR (CDCl3) l 13.50 (OCH2CH3), 19.95 (CH3CHO), 23.72
[C(CH3)3], 34.73 [C(CH3)3], 48.56 (CHPh), 50.94 (CHCꢁO), 60.09 (OCH2), 66.89 (CHN), 73.68
(CHO), 107.22 (OCHO), 127.77, 128.04 (×2), 128.10 (×2), 128.18 (×2), 128.49 (×2), 128.62,
128.80 (×2), 129.89 (×2), 130.54 (CH, Ar), 136.26, 137.07, 139.48 (C, Ar), 169.64 (CꢁN), 171.47,
172.68 (CꢁO). Anal. calcd for C33H37NO5: C, 75.12; H, 7.07; N, 2.65. Found: C, 75.03; H, 7.24;
N, 2.58.
3.2. General procedure for the transformation of Michael-adducts 2 and 3 to pyroglutamates
4 or 5
The solution of Michael-adducts 2 or 3 (1 mmol) in a mixture of MeOH, H2O, dioxane and
AcOH (4:1:5:0.1) (20 ml) was refluxed for 20 h. After cooling to room temperature the solvents
were removed under reduced pressure and the residue was mixed with saturated aqueous
NaHCO3 solution (5 ml). The mixture was extracted with CH2Cl2 (3×30 ml); combined organic
extracts were dried (MgSO4) and evaporated to give colourless oil. Products were purified by
flash chromatography (silica gel, 5% MeOH–CH2Cl2).
3.2.1. (−)-Ethyl (2R,3R,4R)-4-[(1R)-1-hydroxyethyl]-3-methyl-5-oxo-2-pyrrolidinecarboxylate
4a
Yield: 98%; colourless oil; Rf=0.40 (5% MeOH–CH2Cl2); [h]2D0=−82.9 (c=1, CHCl3); H
1
NMR (CDCl3) l 1.06 (d, J=7.1 Hz, 3H, CH3CH), 1.23 (d, J=6.4 Hz, 3H, CH3CHO), 1.24 (t,
J=7.1 Hz, CH2CH3), 2.03 (dd, J=7.5, 9.0 Hz, 1H, CHCꢁO), 2.48 (m, 1H, CHCH3), 3.81 (dq,
J=7.5, 6.4 Hz, 1H, CHO), 4.10 (d, J=9.4 Hz, 1H, CHN), 4.17 (q, J=7.1 Hz, 2H, OCH2), 5.23
(br s, 1H, OH), 6.50 (br s, 1H, NHCꢁO); 13C NMR (CDCl3) l 14.26 (OCH2CH3), 15.71
(CH3CH), 21.30 (CH3CHO), 35.31 (CHCH3), 52.43 (CHCꢁO), 58.73 (CHN), 61.50 (OCH2),

A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
4373
68.70 (CHO), 171.09 (OCꢁO), 180.14 (NCꢁO). Anal. calcd for C10H17NO4: C, 55.80; H, 7.96; N,
6.51. Found: C, 55.78; H, 7.99; N, 6.48.
3.2.2. (+)-Ethyl (2S,3S,4R)-4-[(1R)-1-hydroxyethyl]-3-methyl-5-oxo-2-pyrrolidinecarboxylate
5a
Yield: 97%; colourless oil; Rf=0.42 (5% MeOH–CH2Cl2); [h]2D0=+19.1 (c=1, CHCl3); H
1
NMR (CDCl3) l 1.20 (d, J=6.4 Hz, 3H, CH3CH), 1.24 (t, J=7.1 Hz, 3H, CH3CH2O), 1.30 (d,
J=6.4 Hz, CH3CHO), 1.96 (dd, J=6.0, 8.3 Hz, 1H, CHCꢁO), 2.16 (m, 1H, CHCH3), 3.71 (d,
J=5.3 Hz, 1H, CHN), 4.56 (dq, J=8.3, 6.4 Hz, 1H, CHO), 4.16 (q, J=7.1 Hz, 2H, OCH2), 4.56
(br s, 1H, OH), 6.67 (br s, 1H, NHCꢁO); 13C NMR (CDCl3) l 14.12 (OCH2CH3), 19.94
(CH3CH), 20.89 (CH3CHO), 37.04 (CHCH3), 54.36 (CHCꢁO), 61.07 (CHN), 61.82 (OCH2),
68.95 (CHO), 171.35 (OCꢁO), 178.72 (NCꢁO). Anal. calcd for C10H17NO4: C, 55.80; H, 7.96; N,
6.51. Found: C, 55.74; H, 8.02; N, 6.45.
3.2.3. (−)-Ethyl (2R,3R,4R)-3-ethyl-4-[(1R)-1-hydroxyethyl]-5-oxo-2-pyrrolidinecarboxylate 4b
1
Yield: 97%; colourless oil; Rf=0.40 (5% MeOH–CH2Cl2); [h]2D0=−81.4 (c=1, CHCl3); H
NMR (CDCl3) l 0.92 (t, J=7.1 Hz, 3H, CH3CH2), 1.23 (t, J=7.1 Hz, 3H, OCH2CH3), 1.26 (d,
J=6.0 Hz, 3H, CH3CHO), 1.28 and 1.55 (each m, 2×H, CH2), 2.14 (dd, J=6.4, 8.3 Hz, 1H,
CHCꢁO), 2.33 (m, 1H, CHCH2), 3.82–3.85 (m, 2H, CHO and OH), 4.16 (q, J=7.1 Hz, 2H,
OCH2), 4.22 (d, J=9.0 Hz, 1H, CHN), 6.80 (br s, 1H, NHCꢁO); 13C NMR (CDCl3) l 11.92
(CH3CH2), 14.15 (OCH2CH3), 21.38 (CH3CHO), 22.99 (CH3CH2), 43.0 (CHCH2), 50.99
(CHCꢁO), 58.16 (CHN), 61.45 (OCH2), 68.47 (CHO), 171.21, 171.92 (OCꢁO), 179.79 (NCꢁO).
Anal. calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.52; H, 8.42; N, 6.05.
3.2.4. (+)-Ethyl (2S,3S,4R)-3-ethyl-4-[(1R)-1-hydroxyethyl]-5-oxo-2-pyrrolidinecarboxylate 5b
1
Yield: 98%; colourless oil; Rf=0.43 (5% MeOH–CH2Cl2); [h]2D0=+18.7 (c=1.75, CHCl3); H
NMR (CDCl3) l 0.94 (d, J=7.5 Hz, 3H, CH3CH2), 1.22 (d, J=7.1 Hz, 3H, OCH2CH3), 1.23
(d, J=6.0 Hz, 3H, CH3CHO), 1.54–1.69 (m, 2H, CH2), 2.03 (dd, J=5.3, 7.1 Hz, 1H, CHCꢁO),
2.22 (m, 1H, CHCH2), 2.95 (br s, 1H, OH), 3.78 (dq, J=7.1, 6.0 Hz, 1H, CHO), 3.79 (d, J=4.1
Hz, 1H, CHN), 4.15 (q, J=7.1 Hz, 2H, OCH2), 7.05 (br s, 1H, NHCꢁO); 13C NMR (CDCl3)
l 10.73 (CH3CH2), 14.07 (OCH2CH3), 20.71 (CH3CHO), 27.95 (CH3CH2), 42.88 (CHCH2),
52.29 (CHCꢁO), 59.38 (CHN), 61.53 (OCH2), 69.27 (CHO), 171.43, 172.56 (OCꢁO), 178.76
(NCꢁO). Anal. calcd for C11H19NO4: C, 57.63; H, 8.35; N, 6.11. Found: C, 57.65; H, 8.38; N,
6.02.
3.2.5. (−)-Ethyl (2R,3R,4R)-4-[(1R)-1-hydroxyethyl]-5-oxo-3-phenethyl-2-pyrrolidine-
carboxylate 4c
Yield: 98%; colourless oil; Rf=0.47 (5% MeOH–CH2Cl2); [h]2D0=−71.6 (c=1, CHCl3); H
1
NMR (CDCl3) l 0.1.20 (d, J=6.4 Hz, 3H, CH3CHO), 1.23 (d, J=7.1 Hz, 3H, OCH2CH3), 1.56
and 1.88 (each m, 2×H, CH2CH2Ph), 2.18 (dd, J=6.4, 9.0 Hz, 1H, CHCꢁO), 2.41 (m, 1H,
CHCH2), 2.55 and 2.73 (each m, 2×H, CH2CH2Ph), 3.67 (br s, 1H, OH), 3.78 (t, J=6.4 Hz, 1H,
CHO), 4.17 (q, J=7.1 Hz, 2H, OCH2), 4.25 (d, J=7.9 Hz, 1H, CHN), 6.79 (br s, 1H, NHCꢁO),
7.06–7.15 (m, 3H, ArH), 7.19–7.24 (m, 2H, ArH); 13C NMR (CDCl3) l 14.15 (OCH2CH3), 21.23
(CH3CHO), 31.77 (CH2CH2Ph), 33.37 (CH2CH2Ph), 40.52 (CHCH2), 50.82 (CHCꢁO), 58.11
(CHN), 61.45 (OCH2), 68.40 (CHO), 126.21, 128.21 (×2), 128.56 (×2) (CH, Ar), 140.94 (C, Ar),

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A. Ali et al. / Tetrahedron: Asymmetry 11 (2000) 4365–4375
171.18 (OCꢁO), 179.76 (NCꢁO). Anal. calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59. Found:
C, 66.67; H, 7.64; N, 4.52.
3.2.6. (+)-Ethyl (2S,3S,4R)-4-[(1R)-1-hydroxyethyl]-5-oxo-3-phenethyl-2-pyrrolidine-
carboxylate 5c
Yield: 98%; colourless oil; Rf=0.50 (5% MeOH–CH2Cl2); [h]2D0=+17.3 (c=1, CHCl3); H
1
NMR (CDCl3) l 0.1.22 (d, J=7.1 Hz, 3H, OCH2CH3), 1.24 (d, J=6.4 Hz, 3H, CH3CHO),
1.83–1.95 (m, 2H, CH2CH2Ph), 2.05 (dd, J=4.5, 6.0 Hz, 1H, CHCꢁO), 2.38 (m, 1H, CHCH2),
2.57 and 2.75 (each m, 2×H, CH2CH2Ph), 3.77 (dq, J=6.4, 6.0 Hz, 1H, CHO), 3.86 (d, J=3.4
Hz, 1H, CHN), 4.16 (q, J=7.1 Hz, 2H, OCH2), 4.23 (br s, 1H, OH), 7.10–7.15 (m, 3H, ArH),
7.19–7.25 (m, 2H, ArH), 6.79 (br s, 1H, NHCꢁO); 13C NMR (CDCl3) l 14.10 (OCH2CH3),
20.73 (CH3CHO), 32.89 (CH2CH2Ph), 37.66 (CH2CH2Ph), 41.61 (CHCH2), 53.29 (CHCꢁO),
60.19 (CHN), 61.99 (OCH2), 69.45 (CHO), 126.18, 128.30 (×2), 128.53 (×2) (CH, Ar), 140.98 (C,
Ar), 172.69 (OCꢁO), 178.38 (NCꢁO). Anal. calcd for C17H23NO4: C, 66.86; H, 7.59; N, 4.59.
Found: C, 66.78; H, 7.60; N, 4.60.
3.2.7. (−)-Ethyl (2R,3S,4R)-4-[(1R)-1-hydroxyethyl]-5-oxo-3-phenyl-2-pyrrolidinecarboxylate
4d
1
Yield: 96%; colourless oil; Rf=0.58 (5% MeOH–CH2Cl2); [h]2D0=−85.6 (c=1, CHCl3); H
NMR (CDCl3) l 0.95 (d, J=5.6 Hz, 3H, CH3CHO), 1.23 (d, J=7.1 Hz, 3H, OCH2CH3), 2.62
(t, J=8.3 Hz, 1H, CHCꢁO), 3.63 (dq, J=8.3, 5.6 Hz, 1H, CHO), 3.68 (dd, J=6.2, 8.3 Hz, 1H,
CHPh), 4.12 (d, J=6.2 Hz, 1H, CHN), 4.19 (q, J=7.1 Hz, 2H, OCH2), 4.60 (br s, 1H, OH),
6.58 (br s, 1H, NHCꢁO), 7.21–7.26 (m, 5H, ArH); 13C NMR (CDCl3) l 14.13 (OCH2CH3),
20.88 (CH3CHO), 47.07 (CHPh), 50.01 (CHCꢁO), 61.66 (CHN), 62.02 (OCH2), 65.56 (CHO),
127.79 (×2), 127.91, 128.89 (×2) (CH, Ar), 138.51 (C, Ar), 171.07 (OCꢁO), 180.14 (NCꢁO). Anal.
calcd for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C, 64.82; H, 6.99; N, 4.96.
Acknowledgements
Financial support from the Deutscher Akademischer Austauschdienst (DAAD) and the
Fonds der Chemischen Industrie is gratefully acknowledged.
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.
.