Photoinduced electron transfer (PET) promoted oxidative activation of 1- (N-benzyl-N-methylglycyl)-(S)-prolinol: Development of novel strategies towards enantioselective syntheses of α-amino acids, their N-methyl derivatives and α-hydroxy acids employing

Article abstract of DOI:10.1002/(SICI)1099-0690(200002)2000:4<657::AID-EJOC657>3.0.CO;2-6

PET activation of 1-(N-benzyl-N-methylglycyl)-(S)-prolinol (1) in dry acetonitrile, utilizing 1,4-dicyanonaphthalene (DCN) as a light-harvesting electron-acceptor and methyl viologen (MV⁺⁺) as an electron-transfer mediator, leads to the formati

Full text of DOI:10.1002/(SICI)1099-0690(200002)2000:4<657::AID-EJOC657>3.0.CO;2-6

FULL PAPER
Photoinduced Electron Transfer (PET) Promoted Oxidative Activation of
1-(N-Benzyl-N-methylglycyl)-(S)-prolinol: Development of Novel Strategies
Towards Enantioselective Syntheses of ␣-Amino Acids, Their N-Methyl
Derivatives and ␣-Hydroxy Acids Employing (S)-Prolinol as a
Recyclable Chiral Auxiliary
Ganash Pandey,*[a] Parthasarathi Das,[a] and P. Yella Reddy[a]
Keywords: Photoinduced electron transfer (PET) / Enantioselective syntheses / α-Amino acids / α-Hydroxy acids / (S)-
Prolinol / Recyclable chiral auxiliary
PET activation of 1-(N-benzyl-N-methylglycyl)-(S)-prolinol
(1) in dry acetonitrile, utilizing 1,4-dicyanonaphthalene
(DCN) as a light-harvesting electron-acceptor and methyl
viologen (MV++) as an electron-transfer mediator, leads to
the formation of 3-[benzyl(methyl)amino]perhydropyrrolo-
[2,1-c][1,4]oxazin-4-one (3). When this photolysis is carried
out in aqueous acetonitrile, exclusively 3-hydroxy-
perhydropyrrolo[2,1-c][1,4]oxazin-4-one (4) is produced. The
formation of 3 can be rationalized in terms of intramolecular
cyclization of the in situ generated iminium cation
intermediate (2) by the OH moiety of (S)-prolinol, while 4 is
generated by hydrolysis of 2 followed by acetalization.
Nucleophilic alkylation of 3 and 4, using Grignard reagents
and allyltrimethylsilane/TiCl4, provides 12a؊d & 15 and 17a؊
c & 21, respectively, in a highly stereoselective manner.
Hydrolysis of the resultant amides (12, 15, 17, and 21)
provides α-amino acid derivatives (14) and α-hydroxy acids,
respectively, in optically active form, along with the
recovered (S)-prolinol chiral auxiliary in its recyclable form.
generated by PET processes from amineϪarene pairs, are
known to undergo Hϩ transfer from the α-CϪH bond to
the geminate ion radical within the solvent cage, resulting in
an amineϪarene adduct through coupling of the resultant
radical species.[12] However, we[13] as well as others[14] have
reported that PET reactions between a tert-amine and cer-
tain potent electron acceptors in polar solvents lead to a
sequential two-electron oxidation [electron-proton-electron
(E-P-E) sequence] of the amine, leading to iminium cation
intermediates. Based on these premises, we have developed
a photosystem utilizing 1,4-dicyanonaphthalene (DCN) as
a light-harvesting electron-acceptor and methyl viologen di-
cation (MVϩϩ) as an electron-transfer mediator, as shown
in Figure 1, for the in situ generation of iminium cation
intermediates from tert-amines for synthetic purposes.[6,7,13]
Since the orientation of deprotonation of an amine rad-
Introduction
The generation of radical ions, critical intermediates in
the development of a modern concept of organic reactiv-
ity,[1Ϫ2] by PET processes has acquired prominence in the
past decade[3Ϫ4] as photoexcitation readily induces well-de-
fined redox potential differences between interacting sub-
strates Ϫ a prerequisite for electron transfer. Significant
progress has been made in understanding the reactivity pro-
files of these high-energy odd-electron species,[5] which have
facilitated the application of PET reactions in driving ener-
getically uphill processes in chemical synthesis.[6Ϫ8] The
product formation from PET reactions is dependent,
among many other parameters, on the redox potentials of
the donorϪacceptor (DϪA) pairs and the solvent po-
larity[9Ϫ11] and therefore, a change in any one of these par-
ameters has a significant influence on the reaction dynamics ical cation, the precursor for the generation of an iminium
of the radical ions. For example, tert-amine radical cations, cation by the above route, depends upon the kinetic acidity,
Figure 1. A photosystem to effect sequential two-electron oxidation of amines
this being subject to the steric arrangement of the α-CϪH
[a]
bond of the amine,[15] the generation of iminium cations
Division of Organic Chemistry (Synthesis),
National Chemical Laboratory,
from unsymmetrically substituted tert-amines has been
Pune 411008, India
Fax: (internat.) ϩ 91-20/589-3153
shown to be highly regioselective.[16] The application of this
concept has also been demonstrated in the synthesis of cyc-
E-mail: pandey@ems.ncl.res.in
Eur. J. Org. Chem. 2000, 657Ϫ664
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0204Ϫ0657 $ 17.50ϩ.50/0
657

G. Pandey, P. Das, P. Y. Reddy
FULL PAPER
lic amino ethers by intramolecular trapping of in situ gener- ated[21] α-amino acids show that there is scope for further
ated iminium cations by a tethered hydroxy group. This has development in this area. In this context, we set out to ex-
proved to be an excellent route for the alkylation of cyclic plore the route shown in Scheme 2 using 3 as a new glycine-
amines at their α-positions.[16] As part of our ongoing re- derived template for the synthesis of α-amino acids and
search efforts in this area, we envisaged the synthesis of 3 their N-methyl derivatives. The synthesis of the predesigned
and 4 as predesigned substrates that would allow the prep- substrate 3 was envisaged as being possible by PET acti-
aration of α-amino acids and their N-methyl derivatives, vation of 1, easily available in 84% yield by amination of
and of α-hydroxy carboxylic acids, respectively, by PET ac- 10, which, in turn, could be obtained by reaction of (S)-
tivation of 1 as shown in Scheme 1.
proline ester 9 with chloroacetyl chloride using benzyl-
(methyl)amine in the presence K2CO3 as a base in aceto-
nitrile, followed by reduction of 11 with NaBH4 (Scheme 3).
Scheme 3. Synthesis of 1-(N-benzyl-N-methylglycyl)-(S)-prolinol
(1): i) ClCH2COCl, NaHCO3/H2O, 2 h; ii) PhCH2(Me)NH,
K2CO3/CH3CN, 6 h; iii) NaBH4, EtOH, 12 h
Scheme 1. PET activation of 1-(N-benzyl-N-methylglycyl)-(S)-pro-
linol (1): i) hν, DCN/MVϩϩ, CH3CN
The design of compounds 3 and 4 was conceived by con-
sidering their unique structural features: a reactive α-amino
ether and hemiacetal functionality, highly suitable for ster-
eoselective nucleophilic alkylation reactions; ease of hy-
drolysis of the resultant amides to procure the correspond-
ing α-amino acids, their N-methyl derivatives, and α-
hydroxy carboxylic acids, respectively, and the recovery of
the (S)-prolinol chiral auxiliary in its recyclable form.
(Scheme 2). We are pleased to disclose the findings of our
studies in this article.[17]
The PET cyclization of 1 involved irradiation of a mix-
ture of 1 (2.0 g, 7.69 mmol), DCN (0.32 g, 1.79 mmol), and
MVϩϩ (0.08 g, 0.311 mmol) in CH3CN using Pyrex-filtered
light (> 280 nm) emanating from a 450-W Hanovia me-
dium-pressure mercury lamp at ambient temperature, with-
out removing dissolved air present in the solution. The pro-
gress of the reaction was monitored by TLC as well as by
HPLC. After 8 h of irradiation, the concentration of 1 was
considerably diminished, and photolysis was discontinued.
Removal of the solvent under reduced pressure followed by
chromatographic purification of the crude mixture gave 3
(73% yield) as a diastereomeric mixture (dr ϭ 13.3:1) along
with a minor amount of 4 (3Ϫ5%). The diastereomeric ratio
of 3 was measured by HPLC analysis. DCN was recovered
quantitatively (ca. 97%), but our efforts to obtain pure dia-
stereomers were, however, unsuccessful.
The formation of 3 (de ϭ 93%) may be rationalized in
terms of regioselective in situ generation of iminium cation
2 by selective deprotonation of the acidic methylene group
of the glycine moiety, followed by further one-electron
transfer to the regenerated DCN according to the cycle
shown in Figure 1. The stereochemistry of 3 was deter-
mined by comparing the chemical shift values for the 3-H
signals, which appeared relatively upfield at δ ϭ 4.75 in the
major isomer, as opposed to δ ϭ 4.85 in the minor iso-
mer.[22] This assignment was further corroborated by the
absence of any NOE between 3-H and 8a-H. The preference
for the formation of the major diastereomer 3 (de ϭ 93%)
Scheme 2. Proposed setereoselective alkylations of substrates 3
and 4
Results and Discussion
Synthesis and Utilization of 3-[Benzyl(methyl)amino]-
perhydropyrrolo[2,1-c][1,4]oxazin-4-one (3)
Although there are some very good methodologies[18Ϫ20] in the cyclization of 2 may be explained by assuming back
for the synthesis of α-amino acids through the alkylation of side attack of the OH moiety of prolinol on the iminium
several glycine-derived chiral templates, the problems as- cation, leading to a preferred energy-minimized transition
sociated with cleavage of the auxiliary ring system and the state structure (A), with the amine functionality remaining
recovery of chiral information, as well as the difficulty in in an equatorial position (C) so as to produce the energeti-
extending these strategies to the synthesis of N-methyl- cally favourable trans-bicyclic system, as shown in Figure 2.
658
Eur. J. Org. Chem. 2000, 657Ϫ664

Electron Transfer (PET) Promoted Oxidative Activation of 1-(N-Benzyl-N-methylglycyl)-(S)-prolinol
FULL PAPER
Figure 2. Transition-state model to explain the stereoselectivity du-
ring the PET cyclisation of 1
Nucleophilic ring-opening of 3 (Scheme 4) was initially
carried out by the addition of a separately prepared Grig-
nard reagent[23] (4 equiv.) to a stirred solution of 3 in dry
diethyl ether at Ϫ50°C and stirring for a further 4 h at this
temperature. After allowing the reaction mixture to warm
to room temp., it was quenched by the addition of saturated
NH4Cl solution. Purification of the crude mixture by col-
umn chromatography gave the corresponding amides
12a؊d and 13a؊d in a combined yield of 70Ϫ75%. The
diastereomeric ratios of 12a؊d/13a؊d are indicated in
Scheme 4. These ratios were determined by comparing the
relative integrals of the N-methyl peaks in the 1H-NMR
spectra and were further confirmed by analyzing the prod-
ucts by HPLC. The products were also characterized by
Scheme 5. Hydrolysis of substrates 12 and 13
measured optical rotations with those of authentic samples
independently prepared from the commercially available α-
amino acids. Debenzylation, achieved by hydrogenation in
the presence of 10% Pd on charcoal, gave the corresponding
N-methyl α-amino acid esters. The free amino acids could
also be obtained from 14 by N-demethylation of the corre-
sponding debenzylated products according to known pro-
cedures.[24]
In order to explore an alternative approach to alkylation,
Lewis acid mediated allylation[25Ϫ26] of 3 was also carried
out. Addition of allyltrimethylsilane (2.8 mmol) followed by
TiCl4 (2.88 mmol) to a stirred solution of 3 (1.93 mmol) in
dry dichloromethane at Ϫ78°C gave 15 and 16 in a 9:1 ratio
in a combined yield of 90% (Scheme 6). Again, chromatog-
raphy did not permit separation of the diastereomers. The
absolute stereochemistry of the allylated product 15, was
determined by transforming it into the corresponding am-
ino acid ester 24, obtained by hydrolysis and subsequent
catalytic hydrogenation of the resulting hydrolysed product
23, and finally comparing its optical rotation value [α]D
with that of an authentic sample prepared independently
from commercially available (S)-norvaline.
1
their IR, H-NMR, 13C-NMR, and mass spectral data.
Scheme 4. Stereoselective alkylation of 3 using Grignard reagents:
i) RMgX ether, Ϫ50°C
Due to the close similarity of the Rf values of 12a؊d and
13a؊d, we did not succeed in isolating them in pure form
by column chromatography. Thus, the diastereomeric mix-
tures of 12a؊d and 13a؊d were hydrolyzed directly by heat-
ing in dry methanolic HCl for 12 h in a sealed tube. Stand-
ard workup of basification and purification gave the corre-
sponding α-amino acid esters in yields of 70Ϫ72%. (S)-Pro-
linol, the chiral auxiliary, was recovered in 96% yield
(Scheme 5).
Scheme 6. TiCl4-mediated allylation of 3: i) TiCl4, allyltrimethylsi-
lane, dichloromethane, Ϫ78 ° C, 4 h
Synthesis and Utilization of
3-Hydroxyperhydropyrrolo[2,1-c][1,4]oxazin-4-one (4)
Since determination of the enantiomeric excesses (ee val-
Enantiomerically pure α-hydroxy carboxylic acids are
ues) of the α-amino acid esters 14a؊d by HPLC using a synthetically as well as biologically important substrates.[27]
chiral column proved difficult, their optical purities and Therefore, syntheses of α-hydroxy carboxylic acids in op-
absolute configurations were assessed by comparing the tically pure form have attracted considerable interest. Gen-
Eur. J. Org. Chem. 2000, 657Ϫ664
659

G. Pandey, P. Das, P. Y. Reddy
FULL PAPER
erally, these compounds are prepared by diastereoselective silica gel (60Ϫ120 mesh), eluting with mixtures of petro-
reduction of chiral α-keto esters and amides.[28][29] Alterna- leum ether and ethyl acetate. The absolute stereochemistry
tive approaches involving asymmetric oxygenation of chiral at the new chiral centre of 17a؊c was established by com-
imide enolates, as reported by Evans et al.,[30] and alky- paring the optical rotation values [α]D of the corresponding
lation of the chiral N-(benzyloxyacetyl)-trans-2,5-bis(me- α-hydroxy carboxylic acids, obtained after catalytic hydro-
thoxymethoxymethyl)pyrrolidine have also been re- genation followed by hydrolysis, with the known values of
ported.[31]
the commercially available α-hydroxy acids. The catalytic
The possibility of producing 4 in good yield through PET hydrogenation, using 10% Pd/C as Exemplified in the Ex-
activation of 1 in aqueous CH3CN (Scheme 2) and the pres- perimental Section, of 17c gave 25. As an alternative strat-
ence of its hemiacetal functionality led us to envisage utiliz- egy,[33] we also alkylated 4 (R ϭ H) by adding allyltrimeth-
ation of this molecule for the enantioselective synthesis of ylsilane in the presence of TiCl4 in dry dichloromethane,
α-hydroxy carboxylic acids through nucleophilic alkylation which gave a separable 4:1 mixture of 19 and 20. The for-
followed by hydrolytic recovery of the (S)-prolinol chiral mation of 19 and 20 can be rationalized in terms of nucleo-
auxiliary. To this end, PET activation of 1 in CH3CN/H2O philic addition of allyltrimethylsilane to the oxocarbenium
(3:1), according to a similar photoirradiation protocol as species generated by TiCl4-mediated elimination of the hy-
described for the synthesis of 3, gave 4 in 92% yield. The droxyl moiety of 4. Therefore, in order to obtain a ring-
diastereomeric ratio of 4 (17:3) was ascertained by compar- opened intermediate identical to that obtained following a
1
ing the integrals of the 3-H signals in the H-NMR spec- Grignard reaction (Scheme 8), we decided to protect the
trum [δ ϭ 5.30 (major), 5.25 (minor)]. Our various efforts OH group of 4 as OTBDMS. Similar strategies have also
to obtain pure diastereomers were, however, unsuccessful. been reported by others[34] in the context of allylation reac-
Therefore, we decided to proceed to the next step using 4 tions of lactols. Allylation of 4 (R ϭ TBDMS) in a similar
directly as a diastereomeric mixture, with the hope that dia- manner as described above gave corresponding mixtures of
stereomers could be resolved after the alkylation step.
21 and 22 (9:1) along with minor amounts of 19؊20 (<
In order to transform 4 into a molecule from which the 8%). After TBDMS deprotection, the major diastereomer
corresponding α-hydroxy carboxylic acids could easily be 21 was isolated in pure form by careful column chromatog-
obtained, we considered nucleophilic alkylation of the cyc- raphy. The (S) configuration at the new chiral centre in 21
lic hemiacetal functionality by means of a Grignard reac- was ascertained by comparing the [α]D value of the 2-
tion. Cyclic acetals, particularly lactols, have frequently hydroxypentanoic acid, obtained by deprotection of the
been utilized in CϪC bond-forming reactions with Grig- TBDMS group from 21 and 22 to give separable 26 (major
nard reagents,[32] which offer a high degree of stereocontrol. diastereomer) followed by catalytic hydrogenation and hy-
We first alkylated 4 by treating a stirred solution in dry drolysis of the hydrogenated product 27, with that of the
THF at Ϫ40°C with 4 equiv. of a separately prepared Grig- authentic material.
nard reagent and allowing the mixture to warm to room
temp. over a period of 6 h. Standard workup and purifi-
cation gave the products 17a؊c and 18a؊c in a combined
yield of 50Ϫ60%. Details of the product yields, together
with their diastereomeric ratios (dr) as estimated by HPLC
1
(R ϭ Ph) or by H-NMR (R ϭ Me, allyl), are given in
Scheme 7.
Scheme 8. TiCl4-mediated allylation of 4: i) TiCl4, allyltrimethylsi-
lane, dichloromethane, Ϫ78°C, 4 h
Conclusion
We have developed a new glycine-derived chiral template,
based on the recyclable chiral (S)-prolinol chiral auxiliary,
Scheme 7. Stereoselective alkylation of 4 using Grignard reagents:
that allows the synthesis of α-amino acids, their N-methyl
i) RMgX, THF, Ϫ40°C, room temperature, 6 h
derivatives, and α-hydroxy acids with good optical purities.
Both enantiomers of chiral 2-hydroxypentanoic acid and
In each case, the major diastereomers could easily be iso- their related derivatives can be prepared from 4, simply by
lated in pure form by careful column chromatography on changing the nature of the alkylation reaction.
660
Eur. J. Org. Chem. 2000, 657Ϫ664

Electron Transfer (PET) Promoted Oxidative Activation of 1-(N-Benzyl-N-methylglycyl)-(S)-prolinol
FULL PAPER
1
cmϪ1. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.45Ϫ1.55 (m, 1 H),
1.80Ϫ2.10 (m, 3 H), 2.40 (s, 3 H), 3.15 (s, 2 H), 3.30Ϫ3.35 (m, 2
H), 3.60Ϫ3.70 (m, 4 H), 4.15Ϫ4.20 (m, 1 H), 7.25Ϫ7.30 (m, 5 H).
Experimental Section
Solvents and anhydrous liquid reagents were dried according to
established procedures. All reported yields refer to the isolated ma-
terial and were not optimized. Temperatures above and below am-
bient temperature refer to bath temperatures unless otherwise
stated. Ϫ The equipment used for photolysis consisted of a 450-
W Hanovia medium-pressure mercury lamp and a Pyrex-filtered
immersion well and reaction vessels. Ϫ Analytical TLC was per-
formed using precoated silica gel plates (0.25 mm). Ϫ Column
chromatography was performed on silica gel using standard chrom-
atographic techniques. Ϫ HPLC was performed on a reversed-
phase Nucleosil C18 column using water and acetonitrile as el-
uents. Ϫ Mass spectra (m/z, relative intensity) were recorded in
electronic impact mode at a voltage of 70 eV.
Ϫ
13C NMR (CDCl3, 50.32 MHz): δ ϭ 24.1, 27.5, 42.4, 47.2, 60.0,
60.7, 61.6, 65.8, 126.9, 127.0, 128.9, 138.0, 170.8. Ϫ MS; m/z (rel.
intensity): 262 [Mϩ] (3), 134 [PhCH2N(Me)CH2]ϩ (100), 120
[PhCH2NMe]ϩ (41), 91 [PhCH2]ϩ (79).
PET Activation of 1-(N-Benzyl-N-methylglycyl)-(S)-prolinol.
؊
Synthesis of 3-[Benzyl(methyl)amino]perhydropyrrolo[2,1-c][1,4]-
oxazin-4-one (3): A solution of 1 (2.0 g, 7.63 mmol), DCN (0.32 g,
1.79 mmol), and MVϩϩ (0.08 g, 0.311 mmol) in acetonitrile (1.8 L)
was irradiated using a 450-W Hanovia medium-pressure mercury
vapor lamp housed in a Pyrex-jacketed immersion well for 8 h.
During the course of the irradiation, the color of the solution
turned first to blue, then darkened, but ultimately turned to pale-
yellow. Progress of the reaction was monitored by TLC (acetone/
petroleum ether, 3:7) and HPLC. After 74% conversion of the start-
ing material, irradiation was discontinued. The solvent was re-
moved under reduced pressure and the residual crude photolysate
was purified by column chromatography eluting with acetone/
petroleum ether to give first DCN in 98% yield (0.31 g). Further
elution with the same solvent system gave 1.6 g (73%) of 3 as a
mixture of two diastereomers (de ϭ 93%). Ϫ IR (CHCl3): ν˜ ϭ 3010,
Synthesis of 1-(Chloroacetyl)-(S)-proline Methyl Ester (10): To a
stirred solution of Methyl (S)-prolinoate (10.0 g, 77.52 mmol) in
150 mL of ice-cold water was added NaHCO3 (13.02 g,
155.04 mmol). After dissolution of the NaHCO3, chloroacetyl
chloride (13.14 g, 116.28 mmol) was added dropwise over a period
of 15 min and stirring was continued for a further 1 h at 0°C. The
reaction mixture was then neutralized with 10% HCl solution and
extracted with chloroform. The combined organic extracts were
dried with anhydrous sodium sulfate and concentrated under re-
duced pressure to give 10 in 98% yield. Ϫ IR (neat): ν˜ ϭ 2950,
1640, 1450 cmϪ1. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.45Ϫ2.30
1
(m, 4 H), 2.40 (s, 3 H), 3.30 (dd, 1 H, J ϭ 10.8 Hz, J ϭ 5.8 Hz),
3.65Ϫ3.80 (m, 5 H), 4.15 (dd, 1 H, J ϭ 9.8 Hz, J ϭ 5.2 Hz), 4.75
(s, 1 H), 7.30Ϫ7.35 (m, 5 H); discernible signals for the other dia-
stereomer: δ ϭ 2.45 (s, 3 H), 4.85 (s, 1 H). Ϫ 13C NMR (CDCl3,
50.32 MHz): δ ϭ 22.8, 29.0, 37.2, 45.4, 57.0, 57.6 (57.2), 67.4, 91.2
(88.1), 127.2, 128.3, 129.2, 138.8, 165.9. Ϫ MS; m/z (rel. intensity):
260 [Mϩ] (not visible) 135 [PhCH2N(Me)CH3] (100), 120
[PhCH2NMe]ϩ (40), 91 [PhCH2]ϩ (57).
1
1735, 1645 cmϪ1. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 2.10Ϫ2.40
(m, 4 H), 3.60Ϫ3.70 (m, 2 H), 3.75 (s, 3 H), 4.10 (s, 2 H), 4.55Ϫ4.60
(m, 1 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 24.8, 29.2, 42.5,
47.7, 52.5, 59.3, 165.5, 172.1. Ϫ MS; m/z (rel. intensity): 205 [Mϩ]
(4), 146 (51), 70 (100).
Synthesis of 1-(N-Benzyl-N-methylglycyl)-(S)-proline Methyl Ester
(11): A solution of 10 (9.5 g, 46.19 mmol) in dry acetonitrile
(100 mL) was placed in a 250-mL two-necked round-bottomed
flask equipped with a magnetic stirring bar and fitted with an ar-
gon gas balloon. Anhydrous K2CO3 (7.65 g, 55.43 mmol) was then
added to the flask under stirring. After 10 min, benzyl(methyl)-
amine (6.70 g, 55.42 mmol) was added dropwise over a period of
10 min and stirring was continued at room temperature. The pro-
gress of the reaction was monitored by TLC. After completion
(6 h), the reaction mixture was filtered and concentrated under re-
duced pressure. The crude residue was purified by column chroma-
tography eluting with acetone/petroleum ether (1:4) to give 12.6 g
of 11 (94% yield) as a viscous liquid. Ϫ IR (CHCl3): ν˜ ϭ 3020,
1730, 1640, 1495 cmϪ1. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ
1.90Ϫ2.35 (m, 4 H), 2.40 (s, 3 H), 3.15 (dd, 2 H, J ϭ 9.8, 5.2 Hz),
3.55Ϫ3.65 (m, 4 H), 3.75 (s, 3 H), 4.55Ϫ4.65 (m, 1 H), 7.30Ϫ7.35
(m, 5 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 25.0, 28.9, 42.4,
46.8, 52.0, 58.78, 60.0, 61.7, 127.1, 128.2, 129.2, 138.5, 169.2, 172.7.
Ϫ MS; m/z (rel. intensity): 290 [Mϩ] (3), 134 [PhCH2N(Me)CH2]ϩ
(94), 120 [PhCH2NMe]ϩ (33), 91 [PhCH2]ϩ (100).
General Procedure for the Alkylation of 3 Using Grignard Reagents:
This is exemplified by the synthesis of 1-(N-benzyl-N-methylphe-
nylalanyl)-(S)-prolinol (12a and 13a). A 50-mL two-necked round-
bottomed flask, equipped with a magnetic stirring bar and an ar-
gon gas balloon, was charged with a solution of 3 (0.51 g,
1.96 mmol) in dry diethyl ether (20 mL) and then cooled to Ϫ50°C.
Benzylmagnesium bromide, freshly prepared from magnesium
(0.19 g, 7.84 mmol) and benzyl bromide (1.34 g, 7.84 mmol) in di-
ethyl ether (10 mL), was added slowly to the cooled, stirred solu-
tion, and stirring was continued for 4 h at Ϫ50°C. After allowing
the mixture to warm to room temperature and stirring for an ad-
ditional 2 h, the reaction was quenched by the addition of saturated
ammonium chloride solution. The aqueous layer was extracted
with diethyl ether, and the combined extracts were washed with
brine and dried with anhydrous sodium sulfate. Concentration un-
der reduced pressure followed by purification of the residue by col-
umn chromatography on silica eluting with acetone/petroleum
ether (1:4) gave 0.52 g of 12a and 13a (5.3:1) in a combined yield
of 76% as a viscous liquid. The diastereomeric ratio was deter-
mined by measuring the relative integrals of the N-methyl group
signals in the 1H-NMR spectrum and was further corroborated by
HPLC analysis using a C18 column and aqueous acetonitrile as
eluent. Ϫ IR (CHCl3): ν˜ ϭ 3450, 1638, 1460 cmϪ1. Ϫ 1H NMR
Synthesis of 1-(N-Benzyl-N-methylglycyl)-(S)-prolinol (1): An etha-
nolic solution (120 mL) of 11 (11.2 g, 38.62 mmol) was placed in a
250-mL round-bottomed flask equipped with a magnetic stirring
bar. Sodium tetrahydroborate (2.19 g, 57.93 mmol) was added por-
tionwise under stirring. On completion of the addition, the reaction
mixture was stirred at room temp. for 12 h. It was then concen- (CDCl3, 200 MHz): δ ϭ 1.40Ϫ2.10 (m, 4 H), 2.45 (s, 3 H, major),
trated and the residue was washed with saturated aqueous
NaHCO3 solution. The aqueous layer was extracted with ethyl
acetate and the combined extracts were washed with brine. The
combined organic phases were then concentrated under reduced
pressure and the crude residue was purified by column chromatog-
raphy eluting with acetone/petroleum ether (2:3) to give 8.45 g
(84%) of 1 as a viscous liquid. Ϫ IR (CHCl3): ν˜ ϭ 3400, 1634, 1495
2.42 (s, 3 H, minor), 2.60Ϫ2.75 (m, 1 H), 3.00 (dd, 1 H, J ϭ
12.8 Hz, J ϭ 5.8 Hz), 3.30Ϫ3.60 (m, 4 H), 3.70 (dd, 1 H, J ϭ
12.8 Hz, J ϭ 5.8 Hz), 3.80 (s, 2 H), 4.10Ϫ4.20 (m, 1 H), 7.30Ϫ7.35
(m, 10 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 24.4, 28.3, 32.8,
38.9 (38.7), 47.3, 58.4 (58.2), 61.3, 66.6, 66.9, 126.4, 127.2, 128.4,
128.5, 128.9, 129.5, 138.0, 139.4, 172.6. Ϫ MS; m/z (rel. intensity):
352 [Mϩ] (1), 261 [Mϩ Ϫ 91] (11), 224 [PhCH2N(Me)CHCH2Ph]ϩ
Eur. J. Org. Chem. 2000, 657Ϫ664
661

G. Pandey, P. Das, P. Y. Reddy
FULL PAPER
(96), 91 [PhCH2]ϩ (100). Ϫ Similar procedures were adopted with
other Grignard reagents, furnishing the products detailed below.
necked test tube. The tube was sealed and heated to 65°C for 12 h
in an oil bath. The sealed tube was then cooled to room tempera-
ture and opened by scissoring the tip. The methanolic HCl was
evaporated to dryness and the resulting viscous residue was basified
with saturated sodium bicarbonate solution (to pH ϭ 8). The aque-
ous layer was extracted with diethyl ether and the combined ex-
tracts were dried with anhydrous sodium sulfate. Concentration fol-
lowed by purification of the crude residue by chromatography on
a silica gel column eluting with ethyl acetate/petroleum ether (1:12)
gave methyl (S)-N-benzyl-N-methylphenylalaninoate (14a) (0.28 g,
1-(N-Benzyl-N-methylalanyl)-(S)-prolinol (12b & 13b): Yield 72%;
dr ϭ 3.6:1. Ϫ IR (CHCl3): ν˜ ϭ 3450, 1635, 1450 cmϪ1. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 1.25 (d, 3 H, J ϭ 6.2 Hz), 1.50Ϫ1.55 (m,
1 H), 1.60Ϫ2.10 (m, 4 H), 2.25 (s, 3 H, major), 2.30 (s, 3 H, minor),
3.30Ϫ3.35 (m, 1 H), 3.55Ϫ3.70 (m, 4 H), 4.05Ϫ4.15 (m, 1 H),
4.20Ϫ4.25 (m, 1 H), 7.30Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3,
50.32 MHz): δ ϭ 8.9 (9.8), 24.2, 27.5, 37.3 (37.7), 47.4, 57.4 (57.1),
59.7, 60.5 (60.1), 65.9, 126.7, 127.9, 128.6, 138.9, 173.5. Ϫ MS;
m/z (rel. intensity): 276 [Mϩ] (1), 192 (46), 148
[PhCH2N(Me)CHMe]ϩ (32), 91 [PhCH2]ϩ (100).
72%) as a clear liquid. Further elution with CHCl3/MeOH gave
25
(S)-prolinol (0.14 g, 96%) as a viscous liquid. 14a: [α]D(obsd)
ϭ
25
Ϫ51.2 (c ϭ 1, CHCl3); [α]D(authentic) ϭ Ϫ73.6 (c ϭ 1.4, CHCl3).
Ϫ IR (neat): ν˜ ϭ 3010, 1745, 1454 cmϪ1. Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 2.40 (s, 3 H), 3.10 (dd, 1 H, J ϭ 7.2 Hz, J ϭ
7.0 Hz), 3.25 (dd, 1 H, J ϭ 7.2 Hz, J ϭ 7.0 Hz), 3.65 (dd, 1 H, J ϭ
7.2 Hz, J ϭ 4.8 Hz), 3.70 (d, 1 H, J ϭ 14.6 Hz), 3.75 (s, 3 H), 3.87
(d, 1 H, J ϭ 14.6 Hz), 7.30Ϫ7.35 (m, 10 H). Ϫ 13C NMR (CDCl3,
50.32 MHz): δ ϭ 36.0, 38.0, 51.1, 59.0, 67.4, 126.4, 127.1, 128.3,
128.4, 128.8, 129.4, 138.6, 139.4, 173.6. Ϫ MS; m/z (rel. intensity):
1-(N-Benzyl-N-methylphenylglycyl)-(S)-prolinol (12c & 13c): Yield
1
70%; dr ϭ 2.8:1. Ϫ IR (CHCl3): ν˜ ϭ 3400, 1637, 1495 cmϪ1. Ϫ H
NMR (CDCl3, 200 MHz): δ ϭ 1.5Ϫ1.60 (m, 1 H), 1.65Ϫ2.00 (m,
4 H), 2.40 (s, 3 H), 3.30Ϫ3.35 (m, 1 H), 3.60Ϫ3.85 (m, 4 H),
4.20Ϫ4.30 (m, 1 H), 4.55 (s, 1 H), 7.30Ϫ7.35 (m, 10 H); discernible
signal for the other diastereomer: δ ϭ 2.35 (s, 3 H). Ϫ 13C NMR
(CDCl3, 50.32 MHz): δ ϭ 24.6, 28.1, 39.4, 47.6, 58.5, 61.7, 67.7,
69.8 (69.2), 127.2, 128.2, 128.4, 128.8, 129.1, 129.4, 129.6, 139.4,
283 [Mϩ] (2), 224 [PhCH2N(Me)CHCH2Ph]ϩ (42), 192 [Mϩ
Ϫ
benzyl] (53), 91 [PhCH2]ϩ (100). Ϫ Similar procedures were ad-
opted to obtain other amino acid esters. The physical data of the
respective products are as follows.
139.7, 173.4.
Ϫ MS; m/z (rel. intensity): 224 (75), 210
[PhCH2N(Me)CHPh]ϩ (82), 118 (18), 91 [PhCH2]ϩ (100).
1-(N-Benzyl-N-methylvalinyl)-(S)-prolinol (12d & 13d): Yield 68%;
dr ϭ 2.2:1. Ϫ IR (CHCl3): ν ϭ 3400, 1635, 1452 cmϪ1. Ϫ 1H NMR
˜
(S)-N-Benzyl-N-methylalanine Methyl Ester (14b): Yield 70%. Ϫ
(CDCl3, 200 MHz): δ ϭ 0.97 (d, 3 H, J ϭ 6.8 Hz), 1.12 (d, 3 H,
J ϭ 7.2 Hz), 1.55Ϫ1.60 (m, 1 H), 1.85Ϫ1.95 (m, 3 H), 2.25Ϫ2.30
(m, 1 H), 2.35 (s, 3 H), 3.17 (t, 1 H, J ϭ 9.2 Hz), 3.50Ϫ3.80 (m, 5
H), 3.97 (d, 1 H, J ϭ 5.8 Hz), 4.35Ϫ4.45 (m, 1 H), 7.30Ϫ7.35 (m,
5 H); discernible signals for the other diastereomer: δ ϭ 0.87 (d, 3
H, J ϭ 6.8 Hz), 2.30 (s, 3 H). Ϫ 13C NMR (CDCl3, 50.32 MHz):
δ ϭ 19.6, 19.9, 24.5, 28.2, 28.6 (27.8), 38.5 (38.2), 47.9, 57.8, 60.7,
67.3, 70.1, 126.7, 128.1, 129.2, 140.0, 173.8. Ϫ MS; m/z (rel. inten-
sity): 261 [Mϩ Ϫ iPr] (12), 176 [PhCH2N(Me)CHCHMe2]ϩ (100),
91 [PhCH2]ϩ (81).
25
25
[α]D(obsd) ϭ Ϫ59.3 (c ϭ 1, CHCl3); [α]D(authentic) ϭ Ϫ99.1 (c ϭ
1.2, CHCl3). Ϫ IR (neat): ν˜ ϭ 3000, 1740, 1456 cmϪ1. Ϫ H NM
1
R (CDCl3, 200 MHz): δ ϭ 1.37 (d, 3 H, J ϭ 7.3 Hz), 2.35 (s, 3 H),
3.50 (q, 1 H, J ϭ 7.3 Hz), 3.70 (d, 1 H, J ϭ 13.4 Hz), 3.75 (s, 3 H),
3.80 (d, 1 H, J ϭ 13.4 Hz), 7.25Ϫ7.35 (m, 5 H). Ϫ 13C NMR
(CDCl3, 50.32 MHz): δ ϭ 14.9, 37.8, 51.0, 58.3, 60.6, 126.0, 128.2,
128.7, 139.4, 173.6. Ϫ MS; m/z (rel. intensity): 207 [Mϩ] (2), 192
[Mϩ
Ϫ
methyl] (12), 176 [PhCH2N(Me)CHMe]ϩ (21), 91
[PhCH2]ϩ (100).
(S)-N-Benzyl-N-methylphenylglycine Methyl Ester (14c): Yield 70%.
Synthesis of 1-(N-Benzyl-N-methylallylglycyl)-(S)-prolinol (15 & 16):
A 50-mL two-necked round-bottomed flask, equipped with a mag-
netic stirring bar and an argon gas balloon, was charged with a
solution of 3 (0.50 g, 1.91 mmol) in dry CH2Cl2 (20 mL) and then
cooled to Ϫ78°C. Allyltrimethylsilane (0.33 g, 2.88 mmol) followed
by TiCl4 (0.54 g, 2.85 mmol) was then slowly added to the stirred
solution. After stirring for 4 h at Ϫ78°C, the reaction mixture was
allowed to warm to room temperature and then quenched by the
addition of saturated ammonium chloride solution. After bas-
ification with aqueous NaHCO3, the mixture was extracted with
CH2Cl2 and the combined extracts were washed with brine and dried
with anhydrous sodium sulfate. Concentration under reduced press-
ure followed by column chromatography of the residue on silica gel
eluting with acetone/petroleum ether (1:4) gave 0.52 g (90%) of 15
and 16 (9:1) as a clear liquid. Ϫ IR (CHCl3): ν˜ ϭ 3460, 1637, 1454
cmϪ1. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ 1.45Ϫ2.10 (m, 4 H),
2.30 (s, 3 H, major), 2.28 (s, 3 H, minor), 2.40Ϫ2.50 (m, 1 H),
2.65Ϫ2.75 (m, 1 H), 3.20Ϫ3.70 (m, 7 H), 4.20Ϫ4.30 (m, 1 H),
4.95Ϫ5.20 (m, 2 H), 5.65Ϫ5.75 (m, 1 H), 7.30Ϫ7.35 (m, 5 H). Ϫ
13C NMR (CDCl3, 50.32 MHz): δ ϭ 24.5, 28.2, 29.0 (29.8), 38.4
(38.6), 47.9, 58.0, 61.1, 64.9, 67.3, 117.2, 127.2, 128.4, 128.0, 135.1,
25
Ϫ [α]D(obsd)25 ϭ ϩ5.8 (c ϭ 1, CHCl3); [α]D(authentic) ϭ ϩ11.9 (c ϭ
1.2, CHCl3). Ϫ IR (neat): ν˜ ϭ 3020, 1745 cmϪ1. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 2.30 (s, 3 H), 3.57 (d, 1 H, J ϭ 13.8 Hz),
3.67 (d, 1 H, J ϭ 13.8 Hz), 3.75 (s, 3 H) 4.40 (s, 1 H), 7.25Ϫ7.45
(m, 10 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 39.0, 51.5, 58.6,
72.0, 127.0, 128.1, 128.2, 128.5, 128.8, 136.7, 139.0, 172.2. Ϫ MS;
m/z (rel. intensity): 224 (10), 210 [PhCH2N(Me)CHPh]ϩ (60), 91
[PhCH2]ϩ (100).
(S)-N-Benzyl-N-methylvaline Methyl Ester (14d): Yield 70%. Ϫ
[α]D(obsd)25 ϭ Ϫ26.1 (c ϭ 1.2, CHCl3); [α]D(authentic)25 ϭ Ϫ68.1 (c ϭ
1.3, CHCl3). Ϫ IR (neat): ν˜ ϭ 3010, 1745 cmϪ1. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 0.90 (d, 3 H, J ϭ 7.6 Hz), 1.12 (d, 3 H,
J ϭ 7.6 Hz), 2.15 (m, 1 H), 2.30 (s, 3 H), 2.92 (d, 1 H, J ϭ 15.2 Hz),
3.55 (d, 1 H, J ϭ 16.2 Hz), 3.75 (s, 3 H), 3.80 (d, 1 H, J ϭ 16.2 Hz),
7.30Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 19.5,
20.0, 27.5, 37.8, 50.5, 58.8, 73.1, 127.0, 128.3, 128.6, 139.7, 172.2.
Ϫ
MS; m/z (rel. intensity): 192 [Mϩ
Ϫ iPr] (15), 176
[PhCH2N(Me)CHCHMe2]ϩ (58), 91 [PhCH2]ϩ (100).
(S)-N-Benzyl-N-methylallylglycine Methyl Ester (23): Yield 76%. Ϫ
IR (neat): ν˜ ϭ 3020, 1745, 1640 cmϪ1. Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 2.30 (s, 3 H), 2.50Ϫ2.55 (m, 2 H), 3.45 (t, 1 H, J ϭ
6.6 Hz), 3.62 (d, 1 H, J ϭ 14.6 Hz), 3.75 (s, 3 H), 3.82 (d, 1 H, J ϭ
139.3, 172.0. Ϫ MS; m/z (rel. intensity): 302 [Mϩ] (4), 261 [Mϩ
allyl] (10), 174 [PhCH2N(Me)CHCHMe2]ϩ (100), 91 [PhCH2]ϩ (60).
Ϫ
General Method for the Hydrolysis of 12a؊d & 13a؊d and 15 & 14.6 Hz), 5.15Ϫ5.20 (m, 2 H), 5.85Ϫ5.90 (m, 1 H), 7.30Ϫ7.35 (m,
16: This is exemplified by the hydrolysis of 1-(N-benzyl-N-methyl-
phenylalanyl)-(S)-prolinol (12a & 13a). A mixture of compounds
5 H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 34.2, 38.0, 51.0, 58.6,
65.8, 117.0, 127.1, 128.3, 128.8, 135.0, 139.5, 172.5. Ϫ MS; m/z (rel.
12a and 13a (0.50 g, 1.42 mmol) was dissolved in 15 mL of dry 6  intensity): 233 [Mϩ] (1), 192 [Mϩ
Ϫ
allyl] (49), 174
methanolic HCl and the solution was transferred to a narrow-
662
[PhCH2N(Me)CHCH2CHϭCH2]ϩ (43), 91 [PhCH2]ϩ (100).
Eur. J. Org. Chem. 2000, 657Ϫ664

Electron Transfer (PET) Promoted Oxidative Activation of 1-(N-Benzyl-N-methylglycyl)-(S)-prolinol
FULL PAPER
Synthesis of (S)-N-Benzyl-N-methylnorvaline Methyl Ester (24): A
solution of 23 (0.23 g, 0.98 mmol) in ethanol (25 mL) was placed
in a 50-mL round-bottomed flask equipped with a magnetic stir-
ring bar. To the stirred solution, 10% palladium on activated char-
coal was added and the flask was saturated with hydrogen at atmos-
pheric pressure. After stirring for 12 h at room temperature, the
mixture was filtered through Celite, the filtrate was concentrated,
and the residue was purified by column chromatography on silica
Synthesis of (2S)-(2-Hydroxymethyl)-1-[(2R)-2-hydroxypentanoyl]p-
yrrolidine (25): A solution of 17c (0.36 g, 1.80 mmol) in ethanol
(15 mL) was placed in a 25-mL round-bottomed flask equipped
with a magnetic stirring bar. To the stirred solution, palladium on
activated charcoal (10% Pd) was added and the flask was saturated
with hydrogen at atmospheric pressure. After stirring for 12 h at
room temperature, the mixture was filtered through Celite, and the
filtrate was concentrated to yield 25 in 98% yield. Ϫ 1H NMR
eluting with ethyl acetate/petroleum ether (1:12) to give (S)-(Ϫ)-N- (CDCl3, 200 MHz): δ ϭ 0.90 (t, 3 H, J ϭ 6.6 Hz), 1.45Ϫ1.70 (m,
benzyl-N-methylnorvaline methyl ester 24 (0.20 g, 90%) as a vis-
4 H), 1.85Ϫ2.10 (m, 4 H), 3.30 (m, 1 H), 3.60Ϫ3.85 (m, 3 H),
4.10Ϫ4.30 (m, 2 H).
25
25
cous liquid. Ϫ [α]D(obsd) ϭ Ϫ62.2 (c ϭ 1, CHCl3); [α]D(authentic)
ϭ Ϫ76.4 (c ϭ 1.2, CHCl3). Ϫ IR (neat): ν˜ ϭ 3000, 1740 cmϪ1
1H NMR (CDCl3, 200 MHz): δ ϭ 0.90 (t, 3 H, J ϭ 6.2 Hz),
.
General Procedure for the Hydrolysis of 17a and 25: This is exem-
plified by the hydrolysis of (S)-2-(hydroxymethyl)-1-[(2R)-2-hydroxy-
2-phenylacetyl]pyrrolidine (17a). Amide 17a (0.42 g, 1.78 mmol) was
suspended in 1  H2SO4 (15 mL) and the mixture was heated at
60Ϫ80°C for 0.5Ϫ1 h to ensure complete hydrolysis. After cooling
to ambient temperature, the solution was neutralized by the addition
of saturated NaHCO3 solution. The resulting mixture was cooled,
acidified with conc. HCl, and extracted with ethyl acetate. The com-
bined extracts were dried with Na2SO4 and concentrated to give (R)-
Ϫ
1.40Ϫ1.50 (m, 2 H), 1.70Ϫ1.85 (m, 2 H), 2.30 (s, 3 H), 3.32 (t, 1
H, J ϭ 7.2 Hz), 3.57 (d, 1 H, J ϭ 16.2 Hz), 3.75 (s, 3 H), 3.82 (d,
1 H, J ϭ 16.2 Hz), 7.30Ϫ7.35 (m, 5 H). Ϫ 13C NMR (CDCl3,
50.32 MHz): δ ϭ 14.0, 19.7, 32.0, 37.9, 51.0, 58.8, 65.6, 127.1,
128.4, 128.9, 139.9, 173.4. Ϫ MS; m/z (rel. intensity): 235 [Mϩ] (2),
176 [PhCH2N(Me)CHCH2CH2CH3]ϩ (92), 91 [PhCH2]ϩ (100).
Synthesis of 3-Hydroxyperhydropyrrolo[2,1-c][1,4]oxazin-4-one
(4): A solution of 1 (2.0 g, 7.63 mmol), DCN (0.32 g, 1.79 mmol), mandelic acid (0.24 g, 88%). The purity of the product was checked
25
and MVϩϩ (0.080 g, 0.311 mmol) in 1.8 L acetonitrile/water (3:2)
was irradiated for 10 h using an identical setup as described above
for the synthesis of 3. After most of the starting material had been
consumed, irradiation was discontinued. The solvent was removed
under reduced pressure and purification of the crude photolysate
by column chromatography eluting with acetone/petroleum ether
gave 1.10 g (92%) of 4 (m.p. 154Ϫ156°C) as a mixture of two dia-
stereomers (dr ϭ 6.6:1). DCN was recovered in 98% yield. Ϫ IR
by 1H NMR and by optical rotation measurements; [α]D(obsd)
Ϫ150.4 (c ϭ 1.6, H2O); [α]D(lit) ϭ Ϫ155.0 (c ϭ 2.5, H2O).
ϭ
25
25
(2R)-2-Hydroxypentanoic Acid: Yield: 82%. Ϫ [α]D(obsd) ϭ ϩ3.1
25
(c ϭ 2.26, H2O); [α]D(lit) ϭ ϩ3.2 (c ϭ 2, H2O).[35]
Hydrolysis of (2S)-2-(Hydroxymethyl)-1-[(2R)-2-hydroxypropanoyl]-
pyrrolidine (17b): (S)-2-(Hydroxymethyl)-1-[(2R)-2-hydroxypro-
panoyl]pyrrolidine (17b) (0.35 g, 2.02 mmol) was hydrolyzed by re-
fluxing in dry methanol (12 mL) containing conc. H2SO4 (0.5 mL)
for 2 h to furnish (R)-methyl lactate (0.16 g) in 78% yield. Ϫ
(CHCl3): ν ϭ 3380, 1637 cmϪ1. Ϫ 1H NMR (CDCl3, 200 MHz):
˜
δ ϭ 1.35Ϫ1.60 (m, 1 H), 1.70Ϫ2.20 (m, 3 H), 3.45Ϫ4.00 (m, 5 H),
5.10 (br. s, 1 H), 5.25 (s, 1 H, minor), 5.30 (s, 1 H, major). Ϫ 13C
NMR (CDCl3, 50.32 MHz): δ ϭ 22.2, 28.5, 44.6, 57.6, 62.0, 88.8
(89.5), 166.3. Ϫ MS; m/z (rel. intensity): 157 [Mϩ] (2), 129 (18), 98
(25), 70 (100).
20
20
[α]D(obsd) ϭ ϩ7.18 (neat); [α]D(lit) ϭ ϩ7.46 (neat).[36]
Synthesis of 3-Allylperhydropyrrolo[2,1-c][1,4]oxazin-4-one (19): Ac-
cording to the same reaction procedure as described above for the
synthesis of 15 and 16, the synthesis of 3-allylperhydropyrrolo[2,1-
c][1,4]oxazin-4-one was carried out. Purification by column chro-
matography on silica eluting with ethyl acetate/petroleum ether
(2:3) gave diastereomerically pure 19 in 96% yield as a clear liquid.
Ϫ IR (neat): ν˜ ϭ 2945, 1635, 1340 cmϪ1. Ϫ 1H NMR (CDCl3,
200 MHz): δ ϭ 1.30Ϫ1.45 (m, 2 H), 1.75Ϫ2.00 (m, 2 H), 2.10Ϫ2.20
(m, 1 H), 2.50Ϫ2.60 (m, 1 H), 2.70Ϫ2.80 (m, 1 H), 3.30Ϫ3.75 (m,
3 H), 4.20Ϫ4.30 (m, 2 H), 5.10Ϫ5.25 (m, 2 H), 5.85Ϫ5.95 (m, 1
H). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 22.5, 29.0, 36.9, 45.0,
57.6, 68.0, 76.5, 117.5, 134.2, 168.2. Ϫ MS; m/z (rel. intensity): 196
[Mϩ Ϫ 1] (<1), 151 (15), 112 (100), 84 (50), 70 (46).
Alkylation of 4 Using Grignard Reagents: Reactions were carried
out according to the General Procedure as described for the alky-
lation of 3, to furnish the following products.
(2S)-2-(Hydroxymethyl)-1-[(2R)-2-hydroxy-2-phenyl-
acetyl]pyrrolidine (17a): Yield: 50%. Ϫ IR (CHCl3): ν˜ ϭ 3381, 1630,
1
1452 cmϪ1. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.40Ϫ1.60 (m, 1
H), 1.75Ϫ1.85 (m, 2 H), 1.90Ϫ2.10 (m, 1 H), 2.90 (dt, 1 H, J ϭ
9.6, 6.4 Hz), 3.50Ϫ3.65 (m, 3 H), 4.10Ϫ4.15 (m, 1 H), 4.65 (d, 1
H, J ϭ 5.4 Hz), 5.10 (d, 1 H, J ϭ 5.4 Hz), 7.30Ϫ7.35 (m, 5 H). Ϫ
13C NMR (CDCl3, 75.3 MHz): δ ϭ 24.2, 27.4, 47.0, 61.6, 65.5,
72.7, 128.5, 128.9, 138.8, 172.8. Ϫ MS; m/z (rel. intensity): 142 [Mϩ
Ϫ Ph] (13), 70 (100).
Protection of 4 as tert-Butyldimethylsilyl Ether: A 100-mL two-
necked round-bottomed flask equipped with a reflux condenser, a
magnetic stirring bar, and an argon gas balloon was charged with a
solution/suspension of 4 (1.2 g, 7.64 mmol) in dry dichloromethane
(60 mL). To the stirred solution, imidazole (0.78 g, 11.46 mmol)
was added. After complete dissolution of 4 and the imidazole,
TBDMSCl (1.44 g, 9.55 mmol) was added and the reaction mixture
was refluxed. The progress of the reaction was monitored by TLC.
After completion (4 h), the mixture was washed with water. The
organic layer was extracted with CH2Cl2 and the combined organic
layers were dried with anhydrous sodium sulfate. After concen-
tration under reduced pressure, the crude residue was purified by
(2S)-2-(Hydroxymethyl)-1-[(2R)-2-hydroxypropanoyl]pyrrolidine
(17b): Yield 60%. Ϫ IR (CHCl3): ν˜ ϭ 3376, 1635 cmϪ1. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 1.35 (d, 3 H, J ϭ 6.2 Hz), 1.45Ϫ2.15 (m,
4 H), 3.50Ϫ3.75 (m, 4 H), 4.10Ϫ4.15 (m, 1 H), 4.35 (q, 1 H, J ϭ
6.2 Hz). Ϫ 13C NMR (CDCl3, 50.32 MHz): δ ϭ 20.7, 24.4, 28.1,
47.1, 61.6, 65.7, 65.8, 175.3. Ϫ MS; m/z (rel. intensity): 142 [Mϩ Ϫ
Me] (13), 70 (100).
(2S)-1-[(2R)-2-Allyl-2-hydroxyacetyl]-2-(hydroxymethyl)-
pyrrolidine (17c): Yield 60%. Ϫ IR (CHCl3): ν˜ ϭ 3360, 1640 cmϪ1
.
Ϫ
1H NMR (CDCl3, 200 MHz): δ ϭ 1.40Ϫ2.00 (m, 4 H), column chromatography on silica gel eluting with ethyl acetate/
2.45Ϫ2.55 (m, 2 H), 3.30 (m, 1 H), 3.55Ϫ3.80 (m, 3 H), 4.15Ϫ4.25 petroleum ether (1:8) to afford TBDMS-protected 4 (1.86 g) in 96%
(m, 2 H), 4.95Ϫ5.10 (m, 2 H), 5.85Ϫ5.95 (m, 1 H). Ϫ 13C NMR yield (1.94 g, dr ϭ 85:15). Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ
(CDCl3, 50.32 MHz): δ ϭ 24.3, 28.4, 39.8, 47.3, 61.5, 65.9, 69.2, 0.45 (s, 6 H), 0.90 (s, 9 H), 1.40Ϫ2.10 (m, 4 H), 3.45Ϫ4.00 (m, 4
117.8, 132.4, 173.5. Ϫ MS; m/z (rel. intensity): 199 [Mϩ] (1), 84 H), 4.15 (dd, 1 H, J ϭ 12.2 Hz, J ϭ 5.8 Hz), 5.10 (s, 1 H, major),
(46), 70 (100).
5.15 (s, 1 H, minor).
Eur. J. Org. Chem. 2000, 657Ϫ664
663

G. Pandey, P. Das, P. Y. Reddy
FULL PAPER
[10]
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I. R. Gould, D. Ege, J. E. Moser, S. Farid, J. Am. Chem. Soc.
1990, 112, 4290.
Synthesis of (2S)-1-[(2S)-2-Allyl-2-hydroxyacetyl]-2-(hydroxymeth-
yl)pyrrolidine (26): According to the same procedure as described
above for the synthesis of 19, 21 and 22 were prepared. The crude
mixture of 21 and 22 thus obtained was subjected to TBDMS de-
protection by treating with tetrabutylammonium fluoride solution.
Purification of the deprotected product by column chromatography
on silica eluting with acetone/petroleum ether (2:3) gave dia-
stereomerically pure 26 in 92% yield. Ϫ IR (CHCl3): ν˜ ϭ 3382,
M. A. Kellett, D. G. Whitten, I. R. Gould, W. R. Bergmark, J.
Am. Chem. Soc. 1991, 113, 358.
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1
1668, 1638 cmϪ1. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.45Ϫ2.20
[16] [16a]
G. Pandey, G. Kumaraswamy, P. Y. Reddy, Tetrahedron
(m, 4 H), 2.30Ϫ2.60 (m, 2 H), 3.30Ϫ3.50 (m, 1 H), 3.55Ϫ3.85 (m,
3 H), 4.20 (dq, 1 H, J ϭ 7.2 Hz, J ϭ 4.8 Hz), 4.37 (dd, 1 H, J ϭ
9.6 Hz, J ϭ 5.2 Hz), 5.05Ϫ5.25 (m, 2 H), 5.85 (m, 1 H). Ϫ 13C
NMR (CDCl3, 75.3 MHz): δ ϭ 24.5, 27.5, 39.0, 47.3, 61.3, 66.0,
69.0, 118.0, 132.7, 174.0. Ϫ MS; m/z (rel. intensity): 199 [Mϩ] (3),
182 (31), 152 (15), 128 (14), 85 (53), 70 (100).
[16b]
1992, 48, 8295. Ϫ
G. Pandey, K. Sudha Rani, Tetrahedron
[16c]
Lett. 1988, 29, 4157. Ϫ
G. Pandey, K. Sudha Rani, U. T.
Bhalerao, Tetrahedron Lett. 1990, 31, 1199.
[17]
[17a]
For preliminary communications, see:
G. Pandey, P. Y.
Reddy, P. Das, Tetrahedron Lett. 1996, 37, 3175. Ϫ [17b] G. Pan-
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[18b]
Synthesis of (2S)-2-(Hydroxymethyl)-1-[(2S)-2-hydroxypentanoyl]p-
yrrolidine (27): According to the same hydrogenation procedure as
described above for the synthesis of 25, the allyl group of 26 was
reduced to furnish (2S)-2-(hydroxymethyl)-1-[(2S)-2-hydroxypenta-
noyl]pyrrolidine (27) in 94% yield. Ϫ IR (CHCl3): ν˜ ϭ 3400, 1666
cmϪ1. Ϫ 1H NMR (200 MHz): δ ϭ 0.95 (t, 3 H, J ϭ 6.6 Hz),
1.45Ϫ1.80 (m, 3 H), 1.80Ϫ2.25 (m, 5 H), 3.25 (ddd, 1 H, J ϭ 7.8,
5.2, 3.8 Hz), 3.55Ϫ3.75 (m, 3 H), 4.10Ϫ4.35 (m, 2 H). Ϫ MS; m/
z (rel. intensity): 202 [Mϩ ϩ 1] (1) 170 (86), 141 (33), 128 (21),
70 (100).
44, 5253. Ϫ
R. O. Duthaler, Tetrahedron 1994, 50, 1539.
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Synthesis of (2S)-2-Hydroxypentanoic Acid: (2S)-2-Hydroxypenta-
noic acid was synthesized in 80% yield from (2S)-2-(hydroxy-
methyl)-1-[(2S)-2-hydroxypentanoyl]pyrrolidine (27) according to
the same hydrolysis procedure as described for 17a. The purity of
the acid was verified by measuring its optical rotation; [α]D(obsd)25 ϭ
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25
Ϫ2.5 (c ϭ 1.8, H2O); [α]D(lit) ϭ Ϫ2.7 (c ϭ 2.2, H2O).[35]
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Acknowledgments
P. S. D. is thankful to the CSIR, New Delhi, for the award of a
Research Fellowship.
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Received July 12, 1999
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664
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