Asymmetric synthesis of substituted prolines by 1,3-dipolar cycloadditions of azomethine ylides from chiral 6-isopropyl-5-phenylmorpholin-2-ones

Article abstract of DOI:10.1002/1099-0690(200108)2001:16<3133::AID-EJOC3133>3.0.CO;2-O

Chiral saturated alanine- and glycine-derived 6-isopropyl-5-phenylmorpholin-2-ones 11 and 12 have been prepared and employed for the generation of carboxy-stabilized ylides in asymmetric 1,3-dipolar cycloaddition reactions under thermal conditions, with electron-deficient dipolarophiles bearing double and triple bonds. The cycloadducts are obtained with high stereocontrol and mainly with endo selectivity, and can be used for the synthesis of highly substituted enantiomerically pure prolines.

Full text of DOI:10.1002/1099-0690(200108)2001:16<3133::AID-EJOC3133>3.0.CO;2-O

FULL PAPER
Asymmetric Synthesis of Substituted Prolines by 1,3-Dipolar Cycloadditions of
Azomethine Ylides from Chiral 6-Isopropyl-5-phenylmorpholin-2-ones
[a]
[b]
[a]
[a]
´
Rafael Chinchilla, Larry R. Falvello, Nuria Galindo, and Carmen Najera*
Keywords: Prolines / Asymmetric synthesis / Morpholin-2-ones / Azomethine ylides / 1,3-Dipolar cycloadditions
Chiral saturated alanine- and glycine-derived 6-isopropyl-5- ing double and triple bonds. The cycloadducts are obtained
phenylmorpholin-2-ones 11 and 12 have been prepared and
with high stereocontrol and mainly with endo selectivity, and
employed for the generation of carboxy-stabilized ylides in can be used for the synthesis of highly substituted enantio-
asymmetric 1,3-dipolar cycloaddition reactions under ther- merically pure prolines.
mal conditions, with electron-deficient dipolarophiles bear-
Introduction
been used in the cycloaddition with N-methylmaleimide,
but achieving almost no facial selectivity when R ϭ Me.[9]
However, total stereoselectivity was obtained with ylides 2
by double asymmetric induction when R ϭ (ϩ)- or (Ϫ)-
menthyl or (Ϫ)-8-phenylmenthyl.[10] Related ylide 3 has
been used in a cycloaddition reaction with vinylene carbon-
ate for the chiral synthesis of both enantiomers of 1,4-dide-
oxy-1,4-iminolyxitol and 1,4-dideoxy-1,4-iminoribitol.[11]
Oppolzer’s camphor sultam derived azomethine ylides 4[12]
have also been employed as dipoles, whereas the cyclic spe-
cies 5 reacted with Oppolzer’s chiral acryloyl sultam as part
of an asymmetric synthesis of the antitumor antibiotic (Ϫ)-
quinocarcin.[13] Seebach’s imidazolidinone-derived ylide
6[14] and Williams’ oxazin-2-one-derived ylides 7[15] have
been used in 1,3-dipolar cycloaddition reactions with high
stereocontrol. Ylides 7 are generated as mixtures of the cor-
responding (E)- and (Z)-azomethine ylides, affording the
corresponding mixtures of diastereomers after 1,3-dipolar
cycloaddition reactions, although with high endo selectiv-
ity.[15a] Ylides 7 can be obtained mainly as the (E) isomer
when sterically demanding R1 groups are present,[15a] a fact
which has been used in the asymmetric synthesis of the
antimitotic arrest agent (ϩ)-spirotryprostatin B, the natural
The proline structure is present in many compounds with
interesting biological features. Examples are drugs such as
captopril and enalapril, which are employed clinically due
to their anti-hypertensive properties.[1] In addition, the
trans-4-hydroxy--proline (-Hyp) is present in plants bon-
ded to small lateral chains of polysaccharides to form glyco-
proteins.[2] In animals, proline residues of protocollagen are
hydroxylated to hydroxyproline, thus stabilizing the triple
helix of protocollagen.[2] -Hyp is also formed in a number
of secondary metabolites, which act as antibiotics such as
the echinocandins.[3] Moreover, the kainoids form an im-
portant family of proline derivatives that exhibit potent ne-
uroexcitatory activity in the mammalian central nervous
system.[4] Proline and derivatives have also been used as
chiral ligand or synthetic precursors.[5]
The most direct strategy for the synthesis of func-
tionalized proline derivatives is the 1,3-dipolar cycloaddi-
tion reaction between an in situ generated carboxy-stabil-
ized azomethine ylide and a dipolarophile.[6] The asymmet-
ric version of this reaction allows the synthesis of enantio-
merically enriched prolines with the simultaneous creation
of up to four stereochemically defined centers.[7] Different
strategies have been developed for achieving this asymmet-
ric 1,3-dipolar cycloaddition reaction with α-imino ester de-
rived dipoles, the use of chiral azomethine ylides being one
of the most successfully employed.[7] Examples of these
chiral azomethine ylides have been reported from β-lactam
imines 1, which afforded the corresponding metalodipoles
by reaction with DBU as base and AgOAc.[8] Ylides 2 have
(Ϫ) enantiomer being obtained by using ent-7 [R1
ϭ
CH2C(Me)2OMe].[15b]
However, the most widely used chiral carboxy-stabilizing
azomethine ylides have been Harwood’s saturated oxazin-2-
one derivatives 8 or ent-8,[16] specially those prepared from
(R)-phenylglycinol (R1 ϭ Ph). These species reacted with
dipolarophiles bearing two electron-withdrawing groups at
C-3 with high de and endo selectivity. The addition of
MgBr2·Et2O improved the cycloaddition yields, and other
dipolarophiles with a single electron-withdrawing group
could be used affording mainly the endo adducts.[16f] The
reaction has also been performed with aldehydes[16d,16o] and
imines[16m] as dipolarophiles affording, after hydrolysis, syn-
β-hydroxy α-amino acids and syn-β-amino α-amino acids,
respectively. Moreover, intramolecular dipolar cycloaddi-
tion reactions to double[16e] and triple[16g] bonds have also
been carried out using these derivatives.
[a]
Department of Organic Chemistry, Faculty of Sciences,
University of Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: (internat.) ϩ 34-96/590-3549
E-mail: cnajera@ua.es
[b]
´
´
Departamento de Quımica Inorganica de Ciencias de los
´
Materiales de Aragon, Facultad de Ciencia, Universidad de
Zaragoza Ϫ CSIC
50009 Zaragoza, Spain
Eur. J. Org. Chem. 2001, 3133Ϫ3140
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
1434Ϫ193X/01/0816Ϫ3133 $ 17.50ϩ.50/0
3133

´
R. Chinchilla, L. R. Falvello, N. Galindo, C. Najera
FULL PAPER
hydrogenation of the imine moiety took place opposite to
the bulky isopropyl group. Reaction of these derivatives
with different electron-deficient olefins or acetylenes in the
presence of an excess of paraformaldehyde in toluene at 80
°C, afforded the corresponding cycloadducts produced by a
1,3-dipolar cycloaddition reaction between the in situ gen-
erated azomethine ylides 13 or 15 and the dipolarophiles
(Scheme 1 and Table 1). When alanine-derived dipole 13
was allowed to react with symmetrically substituted elec-
tron-poor olefins such as dimethyl maleate, a high 91:9
endo/exo diastereoselectivity was detected in the crude
1
product by H NMR (Table 1, Entry 1). The major isomer
14a was isolated by column chromatography, and its config-
uration determined by NOESY experiments, which showed
correlations between the isopropyl and methyl groups of the
oxazin-2-one skeleton and between the former methyl
group and the hydrogen atoms at the α-position relative to
the carbonyl group. When N-methylmaleimide was used as
dipolarophile a lower endo/exo ratio was observed (Table 1,
Entry 2), the configuration of the endo major isomer 14b
being unequivocally determined by X-ray analysis[21] (Fig-
ure 1). This observed endo/exo ratio is higher than for the
reported examples when using a related dipole 8 (R1 ϭ 2-
Naph, R2 ϭ Me, R3 ϭ H), which afforded a low value (36%
endo and 26% exo).[16i] In addition, the use of N-ethylmalei-
mide as dipolarophile lowered even more the endo/exo ratio
(Table 1, Entry 3). From the results in Table 1 we could de-
duce that the degree of asymmetric induction using these
ylides is fairly high. This can also be observed in the reac-
tion of acetylenes such as diethyl acetylenedicarboxylate
with alanine-derived 1,3-dipole 13, which gave almost ex-
clusively cycloadduct 14d in 75% isolated yield after attack
of the dipolarophile to the less hindered side of the 1,3-
dipole (Table 1, Entry 4). The reported reaction of a com-
parable alanine-derived dipole such as 8 (R1 ϭ 2-naphthyl,
Recently, we have prepared chiral alanine and glycine im-
ine derivatives with 3,5-dihydro-2H-1,4-oxazin-2-one struc-
ture 9 and 10, which have been used as templates for the
asymmetric synthesis of α-methyl α-amino acids after al-
kylation,[17] and for the preparation of useful chiral didehy-
dro amino acid derivatives after condensation reaction with
aldehydes.[18] In this context, we were interested to investig-
ate the possible use of the corresponding reduced tetrahy-
dro-1,4-oxazin-2-ones as starting materials for the prepara-
tion of chiral carboxy-stabilized ylides with oxazin-2-one
structure. Moreover, the presence of a bulky isopropyl
group at C-6 could influence the enantioselective bias of the
cycloaddition reaction. We report therefore the use of the
saturated oxazin-2-ones 11 and 12, prepared by catalytic
hydrogenation of 9 and 10, respectively, for the generation
of chiral azomethine ylides and reactivity of these as 1,3-
dipoles suitable for the asymmetric synthesis of highly sub-
stituted prolines.[19]
Results and Discussion
Starting 3,5-dihydro-2H-1,4-oxazin-2-ones 9[17c] and
10[18c] were prepared as previously described. Catalytic hy-
drogenation[20] of these derivatives under normal pressure
in the presence of palladium on carbon allowed the isola-
tion of the corresponding saturated cis-oxazinones 11 and
12 in 99 and 70% yield, respectively. No other diastereomers
were detected (1H NMR) and the relative stereochemistry
was determined by NOE experiments, confirming that the Scheme 1
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Asymmetric Synthesis of Substituted Prolines
FULL PAPER
Table 1. 1,3-Dipolar cycloaddition reaction of dipoles 13 and 15 and different dipolarophiles
[a] From the crude reaction mixture (GC and 1H NMR 300 MHz). Ϫ [b] Isolated pure isomer after column chromatography and crystalliza-
[c]
[d]
tion. Ϫ 99:1 dr. Ϫ 96:4 dr.
R2 ϭ Me, R3 ϭ H) with dimethyl acetylenedicarboxylate, methyl substituent on dipole 13 might also play a role in
even in the presence of a Lewis acid such as MgBr2·OEt2 driving the regioselectivity. Moreover, the previous reaction
and under sonication, afforded only 4% of the correspond- of an alanine-derived dipole 8 (R1 ϭ 2-Naph, R2 ϭ Me,
ing cycloadduct.[16i]
R3 ϭ H) with methyl acetylenecarboxylate under thermal
When the reaction was performed with unsymmetrically conditions afforded only a Michael adduct of the tetrahy-
substituted dipolarophiles such as ethyl acetylenecarb- dro-1,4-oxazin-2-one to the triple bond, the cycloadduct be-
oxylate, only the regioisomer 14e was detected (Table 1, ing obtained under Lewis acid catalysis but also with op-
Entry 5). This regioselectivity agrees with the expected posite regiochemistry compared to 14e.[16i]
values of the coefficients of the frontier orbitals in stabilized
The use of the in situ generated glycine-derived dipole 15
azomethine ylides and dipolarophiles,[7b,7f] however being afforded a similar endo/exo ratio in the reaction with di-
opposite to a reported result employing methyl acetylene- methyl maleate than when using dipole 13 in shorter reac-
carboxylate and dipole 8 (R1 ϭ Ph, R2 ϭ R3 ϭ H).[16c] The tion times (Table 1, Entry 6). This obtained endo/exo ratio
Eur. J. Org. Chem. 2001, 3133Ϫ3140
3135

´
R. Chinchilla, L. R. Falvello, N. Galindo, C. Najera
FULL PAPER
pyl groups in pseudo-axial and pseudo-equatorial positions,
respectively, than occupying pseudo-equatorial and pseudo-
axial positions (Figure 2). Although these two conforma-
tions would exist as an equilibrium, any of them shows an
axial substituent to the approaching dipolarophile thus
blocking one of the faces of the dipole. The most stable
conformation was employed for further calculations. As a
comparison, a PM3 calculation was performed on dipole 7
(R1 ϭ H), which also bears two substituents at C-5 and C-
6, also giving a higher stability for the conformer showing
a pseudo-axial phenyl group at C-5, although in this case
the difference of energies between both conformers was
lower than 1 kcal/mol.
Figure 1. X-ray structure of endo adduct 14b
The next step consisted in searching transition structures
from the reaction between the dipole 13 and N-methylmale-
imide using the PM3 semi-empirical method;[24] endo and
exo transition structures were located showing that the pro-
cess is concerted but asynchronous (Figure 3), and a heat
of formation favoring the endo approach by 0.7 kcal/mol.
We also performed calculations using the hybrid
HartreeϪFock (HF)/DFT methods implemented in the
GAUSSIAN 98 suite of programs[25] searching endo and
exo transition structures from a similar reaction but using
a dipole deprived of the phenyl and isopropyl groups due
to computational limitations. Thus, the combination of the
three-parameter Becke exchange functional with the
LeeϪYangϪParr nonlocal correlation functional known as
is higher than the reported when using a similar glycine-
derived dipole 8 (R1 ϭ Ph, R2 ϭ R3 ϭ H), which afforded
a 77:23 endo/exo ratio,[16c] although lower than the reported
using dipole 7 (R1 ϭ H), which afforded only the endo dia-
stereomer.[15a] However, when N-methylmaleimide was em-
ployed, a lower endo/exo ratio was achieved (Entry 7) com-
pared to the result obtained using dipole 13 (Entry 2), a
similar value than the reported when related dipole 8 (R1 ϭ
Ph, R2 ϭ R3 ϭ H) was used (68:32 endo/exo isolated ra-
tio).[16c]
A theoretical study was carried out in order to obtain
insight into the observed preferred endo selectivity of this
dipolar cycloaddition reaction. Computational studies on
the asymmetric induction in 1,3-dipolar cycloadditions of
related oxazin-2-ones 8 have been reported recently em-
ploying semi-empirical (PM3 and AM1) and ab initio
methods (HF/3-21G), but only for the intramolecular ver-
sion.[22] In our case, semi-empirical calculations were per-
formed on the dipole 13 using the PM3 Hamiltonian[23] as
implemented in MOPAC in CS Chem3D,[24] showing a con-
formation 2.4 kcal more stable with the phenyl and isopro-
Figure 3. The endo and exo transition structures of the reaction
between dipole 13 and N-methylmaleimide (PM3 Hamiltonian, dis-
Figure 2. The two possible low energy conformations (PM3 Hamil-
tonian) of the dipole 13
˚
tances are expressed in A)
3136
Eur. J. Org. Chem. 2001, 3133Ϫ3140

Asymmetric Synthesis of Substituted Prolines
FULL PAPER
B3LYP[26] was applied with the basis set 6-31G(d); endo and
exo transition structures were located showing a degree of
asynchronicity similar than the calculated at the semi-em-
pirical level, and a difference in energies of 1.2 kcal/mol
favoring the endo transition state (Figure 4). All transition
structures were characterized by frequency calculations as
first-order saddle points showing only one imaginary fre-
quency corresponding to the new created CϪC bonds. The
obtained electronic energies at B3LYP/6-31G(d) were cor-
rected for zero-point energies, which were scaled by a factor
of 0.96.[27]
Conclusions
We conclude that chiral 2,3,5,6-tetrahydro-6-isopropyl-5-
phenyl-1,4-oxazin-2-ones derived from glycine and alanine,
which have been prepared by catalytic hydrogenation of the
corresponding 3,5-dihydro-2H-1,4-oxazin-2-ones, are useful
systems for the generation of chiral carboxy-stabilized yl-
ides after reaction with formaldehyde. These ylides can be
used for the thermally-induced 1,3-dipolar cycloaddition re-
action to electron-deficient olefins and acetylenes giving the
corresponding cycloadducts mainly with endo selectivity, as
has been observed with other oxazin-2-one-derived systems.
The diastereoselectivity of the reaction proves high, and a
superior reactivity towards acetylenic compounds com-
pared to related oxazin-2-one-derived ylides has been ob-
served. The isolated cycloadducts can be employed for the
preparation of highly substituted enantiomerically pure
proline derivatives.
Experimental Section
General: Melting points were determined with a Reichert Thermo-
var hot plate apparatus and are uncorrected. Ϫ IR spectra were
recorded with a Nicolet 510 P-FT and only the structurally import-
ant peaks are listed. Ϫ NMR spectra were measured with a Bruker
AC-300 and DRX-500 using CDCl3 as solvent and TMS as in-
ternal standard, unless otherwise stated. Ϫ Optical rotations were
measured with a Jasco DIP-1000 polarimeter. Ϫ Low-resolution
electron-impact (EI) mass spectra were obtained at 70 eV with a
Shimadzu QP-5000. Ϫ HRMS (EI) were recorded with a Finnigan
MAT 95S. Microanalyses were performed by the Microanalysis
Service of the University of Alicante. Ϫ X-ray data were collected
using Mo-Kα radiation (graphite crystal monochromator, λ ϭ
˚
0.71073 A). Ϫ Analytical TLC was performed with Schleicher &
Schuell F1400/LS silica gel plates and the spots were visualized
with UV light at 254 nm. Ϫ Flash chromatography was carried out
with Merck silica gel 60 (0.040Ϫ0.063 nm).
Figure 4. The endo and exo transition structures of the reaction
between the model dipole and N-methylmaleimide (B3LYP/6-
˚
31G(d), distances are expressed in A)
Synthesis of Saturated Oxazinones 11 and 12: A solution of oxazi-
none 9 or 10 (1 mmol) and Pd/C (80 mg) in EtOAc (6 mL) was
stirred under hydrogen (1 atm) for 1.5 and 4 h, respectively. The
suspension was filtered through Celite and the solvent removed in
vacuo (15 Torr) to afford 11 in 99% yield and, after column chro-
matography (silica gel), 12 in 70% yield.
The isolated cycloadducts 14 and 16 can be used for the
preparation of highly functionalized prolines. Thus, transes-
terification reaction of adduct 14b with methanol followed
by hydrogenolysis at 3.5 bar in the presence of a catalytic
amount of Pearlman’s catalyst and trifluoroacetic acid in a
mixture of methanol and water, afforded the corresponding
α-amino acid methyl ester. Hydrolysis and further treatment
with propylene oxide in methanol allowed the isolation of
proline derivative 17 in 60% overall yield (Scheme 2).
(3S,5S,6R)-6-Isopropyl-3-methyl-5-phenylmorpholin-2-one
(11):
White solid. Ϫ M.p. 135Ϫ136 °C from n-hexane/ethyl acetate. Ϫ
[α]2D5 ϭ ϩ76.7 (c ϭ 1.0, CH2Cl2). Ϫ TLC: Rf ϭ 0.35 (n-hexane/
1
ethyl acetate, 1:1). Ϫ IR (KBr): ν˜ ϭ 3311, 1728 cmϪ1. Ϫ H NMR
(300 MHz): δ ϭ 0.75, 1.11, 1.42 (3 d, J ϭ 6.7 Hz, 9 H, 3 ϫ CH3),
1.87 [m, 2 H, CH(CH3)2, NH], 3.66 (q, J ϭ 6.7 Hz, 1 H, CHCϭ
O), 4.23 (d, J ϭ 3.4 Hz, 1 H, CHPh), 4.41 (dd, J ϭ 9.8, 3.4 Hz, 1
H, CHO), 7.36 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 18.3,
19.0, 19.2 (3 ϫ CH3), 29.9 [CH(CH3)2], 49.0, 56.5 (CHPh, CHCϭ
O), 88.7 (CHO), 128.0, 128.6, 128.9, 137.2 (ArC), 171.7 (CϭO). Ϫ
MS (EI): m/z (%) ϭ 233 (2) [Mϩ], 146 (15), 133 (81), 132 (100),
131 (41), 91 (40), 65 (16), 44 (30), 43 (15), 41 (19). Ϫ HRMS calcd.
for C14H19NO2: 233.1416; found 233.1418.
(5R,6S)-6-Isopropyl-5-phenylmorpholin-2-one (12): White solid. Ϫ
M.p. 104Ϫ105 °C from n-hexane/ethyl acetate. Ϫ [α]2D5 ϭ Ϫ102.0
(c ϭ 1.0, CH2Cl2). Ϫ TLC: Rf ϭ 0.41 (n-hexane/ethyl acetate, 1:2).
Scheme 2
Eur. J. Org. Chem. 2001, 3133Ϫ3140
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R. Chinchilla, L. R. Falvello, N. Galindo, C. Najera
FULL PAPER
1
Ϫ IR (KBr): ν˜ ϭ 3312, 1723 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ CHCH2), 3.36 (d, J ϭ 13.4 Hz, CHCHH), 3.44 (d, J ϭ 7.9 Hz, 1
0.80, 1.08 (2 d, J ϭ 6.7 Hz, 6 H, 2 ϫ CH3), 1.75 [m, 1 H, H, CHCN), 3.56 (m, 3 H, CHCHH, CH3CH2), 3.98 (d, J ϭ 4.3 Hz,
CH(CH3)2], 3.67, 3.76 (2 d, J ϭ 17.7 Hz, 2 H, CH2), 4.31 (m, 2 H, 1 H, CHPh), 4.16 (m, 1 H, CHO), 7.21, 7.34 (2 m, 5 H, ArH). Ϫ
CHPh, CHO), 7.34 (m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 13C NMR (75 MHz): δ ϭ 12.2, 17.8, 21.3, 25.4 (4 ϫ CH3), 28.3
19.0, 19.1 (2 ϫ CH3), 29.4 [CH(CH3)2], 45.4 (CH2), 57.3 (CHPh), [CH(CH3)2], 34.1 (CH2CH3), 43.6 (CHCH2), 53.6 (CHCH2), 56.5
86.8 (CHO), 128.1, 128.9, 138.1 (ArC), 169.9 (CϭO). Ϫ MS (EI): (CHCN), 63.2 (CHPh), 68.8 (CN), 86.6 (CHO), 127.9, 128.4, 29.0,
m/z (%) ϭ 219 (2) [Mϩ], 119 (63), 118 (100), 91 (29), 41 (15). Ϫ 136.6 (ArC), 169.2, 175.5, 178.0 (3 ϫ CϭO). Ϫ MS (EI): m/z (%) ϭ
HRMS calcd. for C13H17NO2: 219.1259; found 219.1256.
355 (1) [Mϩ Ϫ Me], 181 (20), 147 (12), 146 (100), 104 (18), 91 (42),
66 (11), 55 (21), 44 (10), 43 (17), 41 (20), 40 (14). Ϫ HRMS calcd.
for C20H23N2O4: 355.1658; found 355.1660.
Thermal Cycloadditions. ؊ General Procedure: A suspension of pa-
raformaldehyde (10 mmol, 300 mg) and the corresponding di-
polarophile (5 mmol) in sodium-dried toluene (30 mL) was heated
at 80 °C and a solution of oxazinone 11 or 12 (1 mmol) in toluene
Diethyl (3R,4S,8aS)-3-Isopropyl-8a-methyl-1-oxo-4-phenyl-3,4,6,8a-
tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-7,8-dicarboxylate
(14d):
(10 mL) was added dropwise. The reaction mixture was stirred at 80 White solid. Ϫ M.p. 117Ϫ118 °C from n-hexane/ethyl acetate. Ϫ
°C until completion (GC), cooled at room temperature and filtered
through a plug of silica gel (EtOAc). The solvents were removed in
[α]2D5 ϭ ϩ106.6 (c ϭ 1.45, CH2Cl2). Ϫ TLC: Rf ϭ 0.71 (n-hexane/
ethyl acetate, 1:1). Ϫ IR (KBr): ν˜ ϭ 1737 cmϪ1. Ϫ 1H NMR
vacuo (15 Torr). Column chromatography eluting with mixtures of (300 MHz): δ ϭ 0.63, 1.10 [2 d, J ϭ 6.7 Hz, 6 H, (CH3)2CH], 1.25,
n-hexane and ethyl acetate gave cycloadducts in yields and diaster-
eoselectivities shown in Table 1. Physical and analytical data follow.
1.36 (2 t, J ϭ 7.3 Hz, 6 H, 2 ϫ CH3CH2), 1.70 (s, 3 H, CH3CN),
2.03 [m, 1 H, (CH3)2CH], 3.72 (d, J ϭ 16.5 Hz, 1 H, CHHN), 4.17,
4.32 (2 m, 7 H, 2 ϫ CH2O, CHHN, CHPh, CHO), 7.35 (m, 5 H,
ArH). Ϫ 13C NMR (75 MHz): δ ϭ 13.9, 14.0, 18.6, 21.0, 26.2 (5
ϫ CH3), 28.2 [CH(CH3)2], 58.9 (CH2N), 61.4, 61.8 (2 ϫ CH2O),
63.4 (CHPh), 75.4 (CN), 85.9 (CHO), 128.2, 128.3, 128.9, 130.3,
137.3, 146.5 (CϭC, ArC), 162.1, 164.4, 168.7 (3 ϫ CϭO). Ϫ MS
(EI): m/z (%) ϭ 370 (5) [Mϩ Ϫ OEt], 226 (19), 147 (11), 146 (100),
131 (89), 91 (32), 43 (15), 41 (11). Ϫ C23H29NO6 (415.5): calcd. C
66.5, H 7.0, N 3.4; found C 66.3, H 7.0, N 3.4.
Dimethyl (3S,4S,7S,8R,8aS)-3-Isopropyl-8a-methyl-1-oxo-4-phenyl-
hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine-7,8-dicarboxylate
(14a):
Colourless oil. Ϫ [α]2D5 ϭ ϩ111.7 (c ϭ 2.0; CH2Cl2). Ϫ TLC: Rf ϭ
0.64 (n-hexane/ethyl acetate, 1:1). Ϫ IR (film): ν ϭ 1736 cmϪ1. Ϫ
˜
1H NMR (300 MHz): δ ϭ 0.41, 1.05 [2 d, J ϭ 6.4 Hz, 6 H,
(CH3)2CH], 1.41 (s, 3 H, CH3CN), 2.20 [m, 1 H, (CH3)2CH], 3.34
(m, 1 H, CHHN), 3.37 (d, J ϭ 6.3 Hz, 1 H, CHCN), 3.44 (dd, J ϭ
11.3, 6.3 Hz, 1 H, CHCH2), 3.52 (dd, J ϭ 14.0, 6.7 Hz, 1 H,
CHHN), 3.67, 3.70 (2 s, 6 H, 2 ϫ OCH3), 4.34 (d, J ϭ 3.7 Hz, 1 Ethyl (3R,4S,8aS)-3-Isopropyl-8a-methyl-1-oxo-4-phenyl-3,4,6,8a-
H, CHPh), 4.44 (dd, J ϭ 9.8, 3.7 Hz, 1 H, CHO), 7.30, 7.43 (2m, tetrahydro-1H-pyrrolo[2,1-c][1,4]oxazine-7-carboxylate (14e): White
5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 19.4, 20.4, 28.4 [CH3CN, solid. Ϫ M.p. 92Ϫ93 °C from n-hexane/ethyl acetate. Ϫ [α]2D5
ϭ
(CH3)2CH], 30.9 [(CH3)2CH], 43.5 (CHCH2), 52.2, 52.4 (CHCN, ϩ31.9 (c ϭ 1.2, CH2Cl2). Ϫ TLC: Rf ϭ 0.67 (n-hexane/ethyl acet-
OCH3), 56.1 (CH2N), 57.6 (OCH3), 62.4 (CHPh), 67.2 (CN), 85.8
(CHO), 127.8, 128.6, 128.8, 137.8 (ArC), 170.6, 172.7, 173.5 (3 ϫ δ ϭ 0.69, 1.08 [2 d, J ϭ 6.4 Hz, 6 H, (CH3)2CH], 1.31 (t, J ϭ
CϭO). Ϫ MS (EI): m/z (%) ϭ 389 (5) [Mϩ], 344 (45), 230 (54), 200
7.0 Hz, 3 H, CH3CH2), 1.52 (s, 3 H, CH3CN), 3.74 (dd, J ϭ 18.3,
(70), 146 (100), 131 (91), 91 (61), 59 (27), 55 (29), 43 (26), 41 (37). 1.8 Hz, 1 H, CHHN), 3.99 (d, J ϭ 2.4 Hz, 1 H, CHPh), 4.21Ϫ4.36
ate, 1:1). Ϫ IR (KBr): ν ϭ 1738 cmϪ1. Ϫ 1H NMR (300 MHz):
˜
Ϫ HRMS calcd. for C21H27NO6: 389.1838; found 389.1836.
(m, 4 H, CH2O, CHO, CHHN), 6.84 (s, 1 H, CHϭC), 7.27Ϫ7.42
(m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 14.0, 19.1, 19.2, 27.5
(4 ϫ CH3), 29.2 [CH(CH3)2], 60.9, 61.1 (2 ϫ CH2), 64.5 (CHPh),
71.1 (CN), 84.4 (CHO), 127.9, 128.7, 129.0, 137.3, 137.4, 140.0
(CϭC, ArC), 162.8 (CH2OCϭO), 170.1 (CHOCϭO). Ϫ MS (EI):
m/z (%) ϭ 298 (3) [Mϩ Ϫ OEt], 170 (24), 154 (29), 146 (76), 132
(11), 131 (100), 91 (38), 43 (14), 41 (16). Ϫ HRMS calcd. for
C18H20NO3: 298.1443; found 298.1427.
(4S,6aS,9bS,3R,9aR)-3-Isopropyl-8,9b-dimethyl-4-phenylhexa-
hydropyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7,9(8H)-trione
(14b): White solid. Ϫ M.p. 210Ϫ211 °C from n-hexane/ethyl acet-
ate. Ϫ [α]2D5 ϭ ϩ44.0 (c ϭ 1.0, CH2Cl2). Ϫ TLC: Rf ϭ 0.37 (n-
hexane/ethyl acetate, 1:1). Ϫ IR (KBr): ν˜ ϭ 1732, 1704 cmϪ1. Ϫ
1H NMR (300 MHz): δ ϭ 0.76, 1.09 [2 d, J ϭ 6.8 Hz, 6 H,
(CH3)2CH], 1.58 (s, 3 H, CH3CN), 1.75 [m, 1 H, (CH3)2CH], 2.99
(s, 3 H, NCH3), 3.28 (m, 1 H, CHCH2), 3.35 (dd, J ϭ 13.6, 1.8 Hz, Dimethyl (3S,4R,7R,8S,8aR)-3-Isopropyl-1-oxo-4-phenylhexahydro-
1 H, CHHN), 3.47 (d, J ϭ 7.9, 1 H, CHCN), 3.54 (dd, J ϭ 13.6,
1H-pyrrolo[2,1-c][1,4]oxazin-7,8-dicarboxylate (16a): White solid. Ϫ
9.4 Hz, 1 H, CHHN), 3.89 (d, J ϭ 4.2 Hz, 1 H, CHPh), 4.16 (t, M.p. 188Ϫ190 °C from n-hexane/ethyl acetate. Ϫ [α]2D5 ϭ ϩ44.4
J ϭ 4.2 Hz, 1 H, CHO), 7.21, 7.35 (2 m, 5 H, ArC). Ϫ 13C NMR (c ϭ 1.0, CH2Cl2). Ϫ TLC: Rf ϭ 0.58 (n-hexane/ethyl acetate, 1:1).
(75 MHz): δ ϭ 17.8, 21.1, 25.2, 25.5 (4 ϫ CH3), 28.3 [CH(CH3)2], Ϫ IR (KBr): ν ϭ 1737, 1729 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ
1
˜
43.5 (CHCH2), 53.4 (CH2N), 56.3 (CHCN), 63.2 (CHPh), 68.8 0.75, 1.10 [2 d, J ϭ 6.9 Hz, 6 H, (CH3)2CH], 1.87 [m, 1 H,
(CN), 86.7 (CHO), 128.1, 128.5, 129.0, 136.3 (ArC), 169.1, 175.8, CH(CH3)2], 3.09 (t, J ϭ 9.3 Hz, 1 H, CHCH2), 3.29 (m, 2 H, CH2),
178.3 (3 ϫ CϭO). Ϫ MS (EI): m/z (%) ϭ 341 (0.43) [Mϩ Ϫ Me], 3.67, 3.71 (2 s, 6 H, 2 ϫ CH3O), 3.73 (m, 1 H, CHCHCH2), 4.17
146 (100), 131 (76), 104 (20), 91 (45), 55 (27), 43 (23), 41 (29). Ϫ (d, J ϭ 6.4 Hz, 1 H, NCHCO), 4.41 (d, J ϭ 3.7 Hz, 1 H, CHPh),
C20H24N2O4 (356.4): calcd. C 67.4, H 6.8, N 7.9; found C 67.0, H 4.44 (t, J ϭ 4.4 Hz,1 H, CHO), 7.33 (m, 5 H, ArH). Ϫ 13C NMR
6.8, N 7.6.
(75 MHz): δ ϭ 17.9, 20.7 [(CH3)2CH], 28.4 [CH(CH3)2], 44.7, 49.5
(2 ϫ CHCO2CH3), 52.2, 52.4 (2 ϫ CH3O), 54.6 (CH2), 61.9, 63.6
(CHPh, NCHCOO), 87.6 (CHO), 127.9, 128.4, 128.6, 136.7 (ArC),
170.2, 170.5, 172.2 (3 ϫ CϭO). Ϫ MS (EI): m/z (%) ϭ 375 (5)
[Mϩ], 330 (12), 316 (19), 275 (21), 217 (15), 216 (100), 186 (20),
154 (14), 146 (66), 131 (77), 91 (40), 59 (17), 43 (16), 41 (23). Ϫ
HRMS calcd. for C14H25NO6: 375.1682; found 375.1674.
(3R,4S,6aS,9aR,9bS)-8-Ethyl-3-isopropyl-9b-methyl-4-phenylhexa-
hydropyrrolo[3Ј,4Ј:3,4]pyrrolo[2,1-c][1,4]oxazine-1,7,9(8H)-trione
(14c): White solid. Ϫ M.p. 161Ϫ162 °C from n-hexane/ethyl acet-
ate. Ϫ [α]2D5 ϭ ϩ46.9 (c ϭ 1.0, CH2Cl2). Ϫ TLC: Rf ϭ 0.37 (n-
hexane/ethyl acetate, 1:1). Ϫ IR (KBr): ν ϭ 1748, 1702 cmϪ1. Ϫ
˜
1H NMR (300 MHz): δ ϭ 0.76, 1.08 [2 d, J ϭ 6.7 Hz, 6 H,
(CH3)2CH], 1.21, (t, J ϭ 7.3 Hz, 3 H, CH3CH2), 1.60 (s, 3 H, (3R,4R,6aR,9aS,9bR)-3-Isopropyl-8-methyl-4-phenylhexahydro-1H-
CH3CN), 1.71 [m, 1 H, (CH3)2CH], 3.25 (t, J ϭ 7.9 Hz, 1 H, pyrrolo[2,1-c][1,4]oxazine-1,7,9(8H)-trione (16b): White solid. Ϫ
3138
Eur. J. Org. Chem. 2001, 3133Ϫ3140

Asymmetric Synthesis of Substituted Prolines
FULL PAPER
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M.p. 242Ϫ243 °C from n-hexane/dichloromethane. Ϫ [α]2D5 ϭ ϩ1.60
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Greenwich, 1993, vol. 3, p. 161Ϫ204. Ϫ [7c] H. Waldmann, Syn-
1
Ϫ IR (KBr): ν ϭ 1741, 1693 cmϪ1. Ϫ H NMR (300 MHz): δ ϭ
˜
[7d]
lett 1995, 133Ϫ141. Ϫ
1995, 6, 2475Ϫ2486. Ϫ
R. Grigg, Tetrahedron: Asymmetry
0.70, 1.20 [2 d, J ϭ 6.4 Hz, 6 H, (CH3)2CH], 1.85 [m, 1 H,
CH(CH3)2], 2.22 (t, J ϭ 9.0 Hz, 1 H, CHHN), 3.02 (s, 4 H, CH3N,
CHCH2), 3.16 (d, J ϭ 6.7 Hz, 1 H, CHCOO), 3.25 (d, J ϭ 9.0 Hz,
1 H, CHHN), 3.54 (t, J ϭ 6.7 Hz, 1 H, NCHCHCON), 4.08 (d,
J ϭ 3.7 Hz, 1 H, CHPh), 4.37 (dd, J ϭ 10.4, 3.7 Hz, 1 H, CHO),
7.19, 7.39 (2 m, 5 H, ArH). Ϫ 13C NMR (75 MHz): δ ϭ 17.7,
19.6 [(CH3)2CH], 25.9 (CH3N), 29.6 [CH(CH3)2], 41.7, 44.3 (2 ϫ
CHCON), 51.4 (CH2), 59.7 (CHPh, NCHCOO), 89.6 (CHO),
128.7, 128.8, 129.3, 129.8 (ArC), 165.3 (OCϭO), 175.5, 178.0 (2 ϫ
NCϭO). Ϫ MS (EI): m/z (%) ϭ 342 (3) [Mϩ], 242 (58), 241 (29),
146 (100), 131 (99), 91 (46), 65 (20), 41 (27). Ϫ C19H22N2O4 (375.4):
calcd. C 66.6, H 6.5, N 8.2; found C 66.0, H 6.5, N 7.8.
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Synthesis of (1S,3aS,6aR)-1,5-Dimethyl-4,6-dioxohexahydro-1H-
pyrrolo[3,4-c]pyrrole-1-carboxylic Acid (17): A solution of 14b
(0.6 mmol) in HCl (g)/MeOH (10 mL) was stirred overnight and
the solvent removed in vacuo (15 Torr). The residue was dissolved
in MeOH (8 mL), H2O (0.8 mL), and TFA (160 µL), and Pd(OH)2
on carbon (160 mg) was added. The reaction vessel was charged
with H2, and the mixture was hydrogenated at 3.5 bar for 36 h. The
mixture was then purged with nitrogen and filtered (Celite) to re-
move the catalyst. The filtrate was concentrated (15 Torr), and the
resulting residue was dissolved in 6  HCl (5 mL) and heated under
reflux for 4 h. Water was added, and the mixture was extracted
with EtOAc. The aqueous layer was concentrated (15 Torr), and
the solid residue was dissolved in MeOH (3 mL). Propylene oxide
(1 mL) was added, and the mixture was again heated under reflux
for 30 min. The solvent was evaporated and the residue was washed
with a mixture of Et2O/MeOH and filtered, affording 17 in 60%
yield as a white solid. Ϫ M.p. 202Ϫ206 °C. Ϫ [α]2D5 ϭ ϩ67.1 (c ϭ
1.0, 2  HCl). Ϫ 1H NMR (500 MHz, D2O): δ ϭ 1.66 (s, 3 H,
CH3CN), 2.95 (s, 3 H, CH3N), 3.56 (d, J ϭ 8.9 Hz, 1 H, CHCN),
3.74 (dd, J ϭ 12.7, 8.9 Hz, 1 H, CHHN), 3.80 (m, 1 H, CHHN),
3.89 (dt, J ϭ 8.9, 2.4 Hz, 1 H, CHCH2).
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J.-F. Peyronel, S. Grisoni, B. Carboni, T. Courgeon, R. Carrie,
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R. Chinchilla, L. R. Falvello, N. Galindo, C. Najera
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3140
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