Experimental and theoretical study of the 1,3-dipolar cycloaddition between D-glyceraldehyde nitrones and acrylates. Diastereoselective approach to 4-hydroxy pyroglutamic acid derivatives

TETRAHEDRON:

ASYMMETRY

Pergamon

Tetrahedron: Asymmetry 13 (2002) 173–190

Experimental and theoretical study of the 1,3-dipolar

cycloaddition between -glyceraldehyde nitrones and acrylates.

D

Diastereoselective approach to 4-hydroxy pyroglutamic acid

derivatives

Pedro Merino,^a,* Juan A. Mates,^aJulia Revuelta,^aTomas Tejero,^aUgo Chiacchio,^b

Giovanni Romeo,^c,* Daniela Iannazzo^cand Roberto Romeo^c

^aDepartamento de Qu´ımica Orga´nica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Aragon, Spain

^bDipartimento di Scienze Chimiche, Universita` di Catania, Viale Andrea Doria 6, Catania 95125, Italy

^cDipartimento Farmaco-Chimico, Universita` di Messina, Via SS. Annunziata, Messina 98168, Italy

Received 21 January 2002; accepted 20 February 2002

Abstract—The 1,3-dipolar cycloaddition reactions of ﬁve

D-glyceraldehyde nitrones with alkyl acrylates and Oppolzer’s sultam

acrylamide have been studied in detail, the study including double chiral induction experiments. A complete theoretical study of

the reaction has also been carried out using density functional methods (B3LYP/6-31G*) in which both ortho and meta channels

leading to 3,5- and 3,4-disubstituted isoxazolidines, respectively, were considered. The adducts obtained from the cycloaddition

reactions have been further used for the stereoselective synthesis of protected 4-hydroxy pyroglutamic acids, particularly the

reserved.

1. Introduction

homochiral form. Among them, Nozoe et al.⁸described

the oxidation of the enolate derived from -pyroglu-

L

Enantiomerically pure functionalized derivatives of

pyroglutamic acid have stirred up great interest among

synthetic chemists since they can be used both for the

construction of peptide-based drugs¹and as building

blocks in asymmetric synthesis.²Pyroglutamic acid

derivatives can also be considered as conformationally

constrained glutamate analogues of biological interest.³

In spite of the growing interest in highly functionalized

pyrrolidines related to pyroglutamic acid,⁴the synthesis

of 4-hydroxy-pyroglutamic acids 1 has received little

attention.

tamic acid; however, this procedure has been reported

to give low chemical yields due to side reactions.⁹While

preparing this work, Zhang et al.¹⁰reported the oxida-

tion of trans-4-hydroxy- -proline to give 1a in excellent

L

yield. However, these oxidative processes are limited to

the availability of starting materials (chiral pool). Alter-

natively, it is possible to construct the pyrrolidine ring

in a stereoselective way. We¹¹and others¹²have been

exploring the utility of nitrones as starting materials for

the preparation of 5-substituted-3-hydroxy-2-pyrrolidi-

nones according to the general route depicted in

Scheme 1.

These compounds, in addition to their potential as

synthetic intermediates, constitute an entry to g-substi-

tuted glutamic acid analogues. Thus, g-hydroxyglu-

tamic acids (the open-chain form of 1) have been

reported to be amenable to conventional resolution

using alkaloids⁵and the (4S)-isomer has been prepared

using chiral auxiliary methodology.⁶There is only one

reported synthesis of racemic 4-hydroxypyroglutamic

acids⁷and three reports on their preparation in

* Corresponding authors. Tel.: +34 976 762 075; fax: +34 976 762

075; e-mail: pmerino@posta.unizar.es

PII: S0957-4166(02)00088-5

174

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

idene- -glyceraldehyde nitrone 2a and methyl acrylate

D

3a was reported by White et al. in 1986,¹⁵the stereo-

chemistry of the adducts not being assigned unequivo-

cally. Subsequent studies by the same authors¹⁶clariﬁed

the absolute conﬁguration of the major adduct. How-

ever, only two products were reported to be obtained

from the reaction.

A detailed inspection of the crude mixture of the reac-

tion revealed to us the formation of at least four

isomers consisting of one major product (ca. 63% of the

total isomeric amount) besides the other minor prod-

ucts (Table 1, entry 1). HPLC allowed high accuracy in

measuring isomeric ratios. Moreover, when the reaction

was carried out on a multigram scale (ca. 10 g) traces of

a minor 3,4-regioisomer could be detected. All isomers

were separated and fully characterized (see Section 4).

Scheme 1.

In this vein, we have reported the ﬁrst enantioselective

synthesis of the cis-isomer ent-1b formally derived from

The relative cis/trans conﬁguration of the isoxazolidine

ring substituents has been assigned on the basis of NOE

experiments (Fig. 1). Thus, for trans compounds 4a and

4d, irradiation of H-3 produced a strong enhancement

of only H-4a (15–17%) and irradiation of H-5 produced

enhancement of only H-4b (11–13%). In addition, irra-

diation of H-4a and H-4b in the same experiment

produced enhancements of H-3 (9–11%) and H-5 (8–

12%). For compound 4e, irradiation of H-4 produced

an enhancement of only H-5a and no NOE was

observed between H-3 and H-4 upon irradiation of

H-3. For cis compounds 4b and 4c, irradiation of H-4a

produced strong enhancements of both H-3 (14–16%)

and H-5 (9–12%). Irradiation of H-5 produced

enhancement of H-4a (14–17%) and a much smaller

enhancement of H-4b (2–3%, not indicated in Fig. 1).

Irradiation of H-3 only produced enhancement of H-4a

(12–14%).

D

-pyroglutamic acid, by using Oppolzer’s sultam as a

chiral auxiliary and the furan ring as an effective car-

boxyl group equivalent.¹³Herein, we report the synthe-

sis of enantiomerically pure protected derivatives of 1b

by using a diastereoselective version of the approach

illustrated in Scheme 1. We use as starting materials

D

-glyceraldehyde derived nitrones 2 and acrylates 3.

The choice of the starting materials was made upon

three criteria: (i) the oxygen atom of the nitrone should

allow the installation of the hydroxyl group at the

3-position of the pyrrolidine ring; (ii) the nitrogen atom

of the cycloadduct should carry an easily removable

substituent to facilitate the construction of unprotected

derivatives and (iii) the 1,3-dioxolane moiety should be

used as both a chiral inductor and as a surrogate of the

carboxyl group.¹⁴The methodology is amenable to

large scale synthesis. The preparation of other 4-

hydroxy pyroglutamates 1 is described and a DFT

study of the key reaction, i.e. the 1,3-dipolar cycloaddi-

tion between 2 and 3 is also presented.

The relative conﬁguration between isoxazolidine and

1,3-dioxolane rings could not be determined by spectro-

scopic means but the major isomer crystallized and was

shown by X-ray crystallography¹⁷to be the (3S,5S,1%S)

isomer 4a (Fig. 2).¹⁸This assignment also served to

conﬁrm the absolute conﬁguration of the other trans-

isomer 4d. The absolute conﬁguration of cis adducts 4b

2. Results and discussion

2.1. 1,3-Dipolar cycloadditions

The 1,3-dipolar cycloaddition between 2,3-O-isopropyl-

Table 1. 1,3-Dipolar cycloaddition of nitrones 2 with dipolarophiles 3^a

Entry

Nitrone

Acrylate^b

a:b:c:d^c,d

Adduct

Yield (%)^e

1

2

3

4

5

6

7

2a

2b

2c

2d

2a

2e

3a

3b

3a

3c

3a

63:23:11:3

53:20:16:11

35:25:20:20

75:15:8:2

25:25.25:25

60:20:20:0

52:18:15:15

4

5

6

7

8

95

66

88

94

93

94

93

9

10

^aAll reactions were carried out neat except for entry 6 which was carried out in toluene as a solvent.

^b20 equiv. of dipolarophile were used except for 3c (10 equiv.).

^ca:b:c:d ratio corresponds to anti–trans/anti–cis/syn–cis/syn–trans.

^dRatios of products were determined by HPLC chromatography.

^eAll yields are based on mixtures of adducts isolated by radial chromatography.

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

175

A survey of reported stereoselective nitrone cycloaddi-

tion reactions with a-alkoxy nitrones indicates that

substituents at both the nitrone nitrogen and the dipo-

larophile inﬂuence the steric course of the reaction.¹⁹

Armed with this observation we studied differentially

substituted nitrones and acrylates (Scheme 2). The

results are collected in Table 1.

When tert-butyl acrylate was employed as dipolar-

ophile (entry 2), the reaction showed similar

diastereoselectivity as was observed with 3a. In addi-

tion, lower chemical yields were obtained for this reac-

tion due to considerable thermally induced

polymerization of the dipolarophile.²⁰Increasing the

bulk of the nitrogen substituent of the nitrone led to a

considerable lack of selectivity (entry 3). No substantial

changes were observed with nitrone 2e (entry 7). Dou-

ble chiral induction experiments were also carried out

(entries 4–6) and in the case of cycloaddition between

nitrone 2c and methyl acrylate 3a, an increasing

amount of the major adduct 8a was obtained (entry 4),

the reaction showing good diastereofacial selectivity

(anti/syn, 90:10). No selectivity was observed with

nitrone 2d (entry 5). With nitrone 2a, a better diastereo-

facial selectivity was obtained by using the chiral acryl-

ate 3c (entry 6).

Figure 1. Selected NOE observed for 4 (h_obsgiven as percent

of h_max).

Not all the isomeric cycloadducts corresponding to

entries 2–7 in Table 1 could be separated, and the yields

reported in Table 1 refer to the yield of the mixture of

isomers after puriﬁcation of the crude product by

column chromatography. The isomeric ratio was mea-

sured by NMR spectroscopy or HPLC, when possible.

Compounds 5a, 5d, 6a, 7a–d, 8a–c, 9a and 10a–d were

separated and fully characterized (see Section 4).

and 4c was determined by chemical correlation as dis-

cussed below. For the 3,4-regioisomer 4e, although the

cis/trans stereochemistry has been conﬁrmed by NOE

experiments, the assignment of the absolute conﬁgura-

tion is only tentative.

Figure 2. Perspective view (ORTEP) of 4a. Non-hydrogen atoms are drawn as 50% thermal ellipsoids while hydrogens are drawn

at an arbitrary size. Only the atoms reﬁned with anisotropic thermal parameters are drawn with the principal axes indicated; the

isotropic atoms are represented as simple circles.

176

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

Scheme 2.

sistent with the relative cis/trans assignments made for

C(3) and C(5) substituents of the pyrrolidinone ring.

The stereochemical assignments of compounds 5–9

were made by their further conversion into the corre-

sponding 3-hydroxy-2-pyrrolidinones 11, which can

also be obtained in pure form from compounds 4a–d

(Scheme 3). Both isolated compounds and mixtures of

adducts were cyclized into 11. In all instances the

observed ratio of isomers determined by HPLC was

maintained after the cyclization process. In the case of

cyclization of mixtures of isomers, compounds 11 were

more easily separated by chromatographic methods

than the precursor isoxazolidines. In the case of com-

pounds 10a–d, the conﬁgurational assignment was

made by transformation of pure compounds into the

corresponding isopropylidene derivatives 4a–d (Scheme

4).

2.2. Synthesis of 4-hydroxy pyroglutamic acid

derivatives

Our initial target was the isoxazolidine 16, from which

pyroglutamic acid 1b can be obtained by

hydrogenolytic NꢀO bond cleavage and subsequent

cyclization.²¹In a ﬁrst attempt, the conversion of the

major adduct of the cycloaddition 4a to 14 was accom-

plished in two steps by using catalytic p-toluenesulfonic

The absolute conﬁguration of the cis-isomers 11a and

11d was known since the isoxazolidine precursors (4a

and 4d, respectively) had been unequivocally identiﬁed

by NMR spectroscopy and X-ray analysis, as indicated

above. The stereoconﬁguration of trans-isomers 11b

and 11c was determined by transformation of 11b into

the corresponding p-nitrobenzoyl derivative 12 (Scheme

5). This compound proved to be identical to that

obtained from 11a by Mitsunobu reaction with p-

nitrobenzoic acid.

Since the absolute conﬁguration of 11a was known, the

reactions shown in Scheme 5 demonstrated the anti

relative conﬁguration between the dioxolane ring and

the isoxazolidine ring in 11b. Thus, the absolute

conﬁgurations of 11b and, by extension, that of 11c

were also conﬁrmed. Complementary NOE experiments

performed on compounds 11a–d and 12 are fully con-

Scheme 3. (i) H₂/Pd(OH)₂–C/MeOH/150 bar/24 h.

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

177

carbonyl derivative 20.²²The failure of 11a to undergo

N-protection can be rationalized by the presence of an

intramolecular hydrogen bond interaction which com-

promises the lone pair of the lactam nitrogen.

Scheme 4. (i) (1) HCl/MeOH; (2) acetone/p-TosOH/MgSO₄.

Scheme 6. (i) MeOH, p-TosOH; (ii) NaIO₄; (iii) NaBH₄.

Exposure of 18a to the acidic conditions needed for the

transformation of the dioxolane ring into the carboxyl

group (the ﬁrst step should be deacetalyzation) led to

loss of the TBS group. On the other hand, release of the

carboxylic function could be made by treatment of 18b

with periodic acid and subsequent in situ oxidation of

the resulting aldehyde with sodium chlorite, according

to a protocol previously described by us.^14bAfter ester-

iﬁcation with diazomethane the protected (2S,4S)-4-

hydroxy pyroglutamic acid 19 was obtained.

Scheme 5. (i) 4-Nitrobenzoyl chloride/Py/CH₂Cl₂; (ii) 4-

nitrobenzoic acid/DIAD. Ar: p-nitrobenzoyl.

acid in MeOH and subsequent treatment of the result-

ing 1,2-diol 13 with NaIO₄(Scheme 6).

Unfortunately, attempted oxidation of formyl isoxazo-

lidine 14 with KMnO₄, NaClO₂or TEMPO/BAIB led

to extensive decomposition. Alternatively, we explored

the oxidation of the completely reduced diol 15,

obtained by reduction of 14 with sodium borohydride.

Also in this case, all the oxidation conditions examined

failed. These unsuccessful results are probably due to

the presence of a basic nitrogen, which may suffer

collateral oxidations. Therefore, we decided to change

the strategy and to form the pyrrolidine ring before

oxidizing the dioxolane moiety.

The pyrrolidinone derivative 11a was protected with

both tert-butyldimethylsilyl and benzoyl groups to give

compounds 17a and 17b, respectively. These products

were treated with di-tert-butyldicarbonate to afford the

completely protected pyrrolidinones 18a and 18b

(Scheme 7).

Scheme 7. (i) TBSCl, DMF; (ii) PhCOCl, CH₂Cl₂; (iii)

Boc₂O, DMAP; (iv) H₅IO₆, then NaClO₂, NaH₂PO₄, then

CH₂N₂.

Attempts to introduce the Boc group at the nitrogen

atom prior to O-protection only led to O-tert-butoxy-

178

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

Nevertheless, the protecting groups present in 19 can-

not be considered to be orthogonal, since two ester

functionalities are present in the molecule. As a conse-

quence, competitive reactions might be found in further

synthetic transformations. In order to avoid these trou-

bles a different protecting group system was studied.

protocol was repeated for all adducts obtained from the

cycloaddition reaction (Scheme 8). Also, for the reduc-

tion of adducts 4b and 4c minor amounts of deaceta-

lyzed isoxazolidines 22b and 22c were obtained,

respectively. Only reduction of 4d afforded pure pyrro-

lidinone 21d. In all cases, the products were isolated

and fully characterized as the corresponding acetylated

derivatives 23b–d.

As an alternative, it is also possible to reduce the NꢀO

bond in adducts 4 without debenzylating the nitrogen

atom. Thus, treatment of the major adduct 4a with zinc

in acidic media provided a mixture of pyrrolidinone 21a

and deprotected isoxazolidine 13 (Scheme 8). Because

of the nature of this reduction reaction, we were unable

to ﬁnd conditions that avoided concomitant deprotec-

tion of the acetonide moiety, although in any case the

yield of 13 was higher than 10%, the total chemical

yield of the reaction being 86%.

Finally, all of the possible isomers of 4-hydroxy pyro-

glutamic acid were prepared by unmasking the carboxyl

group. Conversion of the dioxolane moiety into the

carboxylic functionality was achieved by treatment of

compounds 23a–d with periodic acid and sodium chlor-

ite, as described above for compound 18b. Both 25a

and 25b, and their antipodes were prepared. Com-

pounds 25b and ent-25a had been prepared previously

in our laboratories.¹³Thus, this also served to conﬁrm

previous conﬁgurational assignments. The orthogonal

protection of compounds 25 should allow their further

use as building blocks in organic synthesis.

Due to difﬁcult chromatographic separation, puriﬁca-

tion of compounds 21a and 13 was made as the corre-

sponding acetylated derivatives 23a and 24a. This

Scheme 8. (i) Zn, AcOH; (ii) Ac₂O, Py; (iii) H₅IO₆, then NaClO₂, NaH₂PO₄, then CH₂N₂.

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

179

2.3. Theoretical study

ring has been chosen. We considered two reaction

channels, ortho and meta, corresponding to the forma-

tion of 3,5- and 3,4-disubstituted isoxazolidines, respec-

tively. Endo and exo approaches by Re and Si faces

completed the study. The nomenclature used for deﬁn-

ing stationary points is given in Scheme 9. Starting

from TS1–TS8, the minima associated with the ﬁnal

cycloadducts, P1–P8 have also been located. The opti-

mized geometries of transition states TS1–TS4, leading

to the formation of the 3,5-cycloadducts, are

displayed³¹in Fig. 3 (the geometries of TS5–TS8, P1–

P8 and the reagents are available from the authors

upon request). The values of total and relative energies

for the different stationery points as well as selected

geometrical parameters are given in Table 2. In all cases

the cycloaddition reactions are exothermic in the range

of −17 to −20 kcal/mol, the most stable product being

the (3R,5S)-isomer. Slightly higher energy differences

are observed for 3,5-cycloadducts (ortho channel) with

respect to the reagents, than for 3,4-cycloadducts (meta

channel). Clearly, the most favoured reaction channel

corresponds to the ortho one, through an endo

approach by the Si face of the nitrone. The energy

activation value for the corresponding transition state

TS1 is 11.7 kcal/mol. From the analysis of the other

activation energies, in several cases not different

enough for the calculation errors, a mixture of products

can be expected. Thus, although TS6 and TS8 can be

discarded, very close energy barriers are observed for

TS2, TS3, TS4, TS5 and TS7 (0.4 kcal/mol maximum

difference).

In order to rationalize the above 1,3-dipolar cycloaddi-

tions we have also performed a computational study of

the reaction between 2a and 3a using transition state

(TS) modelling. Several studies concerning 1,3-dipolar

cycloadditions of nitrones with electron-rich²³and elec-

tron-poor²⁴dipolarophiles have recently been carried

out.²⁵From these and other^26–28related work, we found

B3LYP/6-31G(d) level of theory to be quite promising

in this respect. Therefore, stationery points (reactants,

transition structures and products) were fully

characterized²⁹as minima or ﬁrst-order saddle points

by diagonalizing the Hessian matrices of the optimized

structures at that level.³⁰All transition structures were

found to have only one negative eigenvalue with the

corresponding eigenvector involving the formation of

the newly created CꢀC and CꢀO bonds. Vibrational

frequencies were calculated (1 atm, 298.15 K) for all

B3LYP/6-31G(d) optimized structures and used,

unscaled, to compute both ZPVE and activation ener-

gies. The only simpliﬁcation of the calculations con-

sisted of replacement of the benzyl group by a methyl

group.

We studied all types of selectivity, i.e. regio- and

diastereoselectivity, the latter including both endo/exo

and p-facial selectivity. Consequently, a total of eight

transition states leading to the eight corresponding

cycloadducts, have been located. For each transition

state the most stable conformation of the dioxolane

Scheme 9.

180

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

,

Figure 3. Optimized (B3LYP/6-31G(d) transition structures (bond lengths in A) for cycloaddition of nitrone 2a and methyl

acrylate 3a. Only transition structures, TS1, TS2, TS3 and TS4, leading to 3,5-regiosiomers are shown.

Table 2. Total energies (au), relative energies (kcal/mol) and selected geometrical parameters for the reactants, transition

structures and products of the cycloaddition between NI and MA

Total energy

Relative energy^a

O1–N2

N2–C3

C4–C5

O1–C5

O1–C4

C3–C4

C3–C5

w imag

NI

−554.696533

−306.365295

−861.043148

−861.041232

−861.040746

−861.040979

−861.041129

−861.038162

−861.041445

−861.034063

−861.091394

−861.088992

−861.091521

−861.093299

−861.090914

−861.090124

−861.090188

−861.087840

1.280

–

1.306

–

MA

TS1

TS2

TS3

TS4

TS5

TS6

TS7

TS8

P1

P2

P3

P4

P5

P6

P7

P8

1.335

1.390

1.389

1.390

1.389

1.400

1.404

1.406

1.535

1.530

1.538

1.544

1.546

1.544

1.536

1.556

11.7

12.9

13.2

13.1

13.0

14.9

12.8

17.4

−18.6

−17.0

−18.6

−19.7

−18.3

−17.8

−16.3

1.285

1.288

1.281

1.282

1.311

1.315

1.313

1.479

1.476

1.485

1.470

1.440

1.438

1.464

1.352

1.350

1.352

1.353

1.337

1.335

1.332

1.333

1.476

1.492

1.473

1.480

1.476

1.467

1.485

1.478

2.337

2.320

2.291

2.295

–

1.414

1.416

1.411

1.413

–

2.053

2.081

2.086

2.102

–

1.533

1.549

1.533

1.549

–

−395.1

−397.0

−378.8

−378.7

−418.5

−416.6

−388.7

−378.7

–

1.961

1.948

1.883

1.882

–

1.435

1.445

1.418

1.414

2.288

2.340

2.369

2.404

–

1.566

1.569

1.545

1.569

^aRelative to NI+MA.

31G(d) calculations. Nevertheless, DFT calculations are

the only ones that correctly predicted the preferential

formation of P1. Hartree–Fock calculations or DFT

single point calculations using the same basis set (6-

31G(d)) suggest the formation of other cycloadducts

(data corresponding to lower level calculations are

available from the authors upon request). This strong

These results are in agreement with the experimental

observations, since the energy of TS1 is only 1.2 kcal/

mol higher than that of TS2, thus justifying the prefer-

ential, but not only, formation of P1. However, the

proximity of energy values mentioned above means that

the experimentally observed 3,5-regioselectivity cannot

be said to be completely predictable by B3LYP/6-

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

181

dependence on the method for predicting regioselectiv-

ity in 1,3-dipolar cycloadditions of nitrones has previ-

ously been described and discussed by Marco and

Domingo,²⁵and Cossio.²⁸

(10–15 microns) as stationary phase, and the eluting

solvents were delivered by the pump at a ﬂow rate of

16–20 mL min⁻¹. Preparative centrifugally accelerated

radial thin-layer chromatography (PCAR-TLC) was

performed with a Chromatotron^®Model 7924 T (Har-

rison Research, Palo Alto, CA, USA); the rotors (1 or

2 mm layer thickness) were coated with silica gel Merck

grade type 7749, TLC grade, with binder and ﬂuores-

cence indicator (Aldrich 34,644-6) and the eluting sol-

vents were delivered by the pump at a ﬂow rate of

0.5–1.5 mL min⁻¹. All solvents used for preparative

chromatography were distilled prior to use. HPLC

analyses were carried out using a Waters 2695 Alliance

System, peaks being detected with a 2996 photodiode

The geometry of the transition structures is consistent

with a rather asynchronous process. For TS1–TS4

(ortho channel), the CꢀO forming bond is longer than

the CꢀC forming bond. On the other hand, for TS5–

TS8 (meta channel), the CꢀC bond is longer than the

CꢀO bond. Although differences of values of forming

bonds are not comparable for measuring asynchronicity

since CꢀO bonds are shorter than CꢀC bonds, what is

clear is that the cycloaddition reaction has a high

character of Michael addition of the nitrone to the

dipolarophile.³²In all cases the shorter forming bond

corresponds to that in which C(3) of methyl acrylate is

involved. Marco and Domingo²⁵have described this

observation previously for other electron-poor

dipolarophiles.

1

array detector. Melting points are uncorrected. H and

¹³C NMR spectra were recorded on a Varian Unity or

on a Bruker 300 instrument in CDCl₃at 55°C. Chemi-

cal shifts are reported in ppm (l) relative to CHCl₃

(l=7.26) in CDCl₃. Optical rotations were obtained at

25°C on a Perkin–Elmer 241 polarimeter. Elemental

analyses were performed on a Perkin Elmer 240B

microanalyzer.

The imaginary frequencies for the transition states are

in the range of −378.7 to −418.5, indicating that the

processes are associated with displacement of heavy

atoms. Those values corresponding to the ortho channel

(−378.7 to −397.0) are slightly lower than those corre-

sponding to the meta channel (−388.7 to −418.45).

4.1. 1,3-Dipolar cycloaddition of nitrones 2 with acryl-

ates 3. General procedure

The corresponding nitrone (20 mmol) was dissolved in

acrylate (20 equiv.) and the resulting solution was

stirred under reﬂux until no more nitrone was observed

(TLC). (In the case of cycloaddition with acrylamide

3c, the reaction was conducted in toluene (600 mL) at

reﬂux.) The reaction mixture was evaporated to dryness

and the residue puriﬁed by MPLC to give the adducts

(eluent is given in brackets). In the case of nitrone 2a

the reaction was repeated with 10.6 g (45 mmol) of

starting material and the same results were obtained.

3. Conclusions

We have studied in detail the stereoselective 1,3-dipolar

cycloadditions of

D-glyceraldehyde-derived nitrones

with methyl acrylate and other dipolarophiles. This

study has allowed us to assign unequivocally the abso-

lute conﬁguration of the obtained adducts. The

observed regio- and stereochemical results can be

explained by means of computational methods using

density functional theory. In addition, the present

method offers a facile route for the stereoselective

preparation of protected (2S,4S)-4-hydroxy pyroglu-

tamic acids. Since the (2R,4R)- and (2S,4R)-isomers

can be readily prepared as described before by us¹³and

others,¹⁰respectively, the present strategy provides a

complementary method for constructing advanced syn-

thetic intermediates such as polyfunctionalized

pyrrolidines.

4.1.1. (3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester

4a. (hexane/EtOAc, 90:10); 3.856 g (60%); mp 72–74°C;

1

[h]²_D⁵+20 (c 0.17, CHCl₃); H NMR (CDCl₃) l 1.31 (s,

3H), 1.37 (s, 3H), 2.62 (ddd, 1H, J=2.2, 7.7, 15.5 Hz),

2.75 (ddd, 1H, J=7.3, 8.4, 15.5 Hz), 3.23 (ddd, 1H,

J=2.2, 7.3, 8.6 Hz), 3.50 (dd, 1H, J=5.1, 8.3 Hz), 3.74

(s, 3H), 3.76 (d, 1H, J=12.9 Hz), 3.91 (ddd, 1H,

J=5.1, 6.2, 8.6 Hz), 4.00 (dd, 1H, J=6.2, 8.3 Hz), 4.21

(d, 1H, J=12.9 Hz), 4.58 (dd, 1H, J=7.7, 8.4 Hz),

7.30–7.50 (m, 5H). ¹³C NMR (CDCl₃) l 25.2, 26.9,

34.2, 52.6, 62.7, 67.4, 68.2, 75.5, 77.3, 109.6, 127.8,

128.6, 129.4, 137.0, 173.2. Anal. calcd for C₁₇H₂₃NO₅:

C, 63.54; H, 7.21; N, 4.36. Found: C, 63.48; H, 7.11; N,

4.49%.

4. Experimental

The reaction ﬂasks and other glass equipment were

heated in an oven at 130°C overnight and assembled in

a stream of Ar. All reactions were monitored by TLC

on silica gel 60 F254; the position of the spots was

detected with 254 nm UV light or by spraying with one

of the following staining systems: 50% methanolic sul-

furic acid, 5% ethanolic phosphomolybdic acid and

iodine. Preparative ﬂash column chromatography was

performed on silica gel (40–60 microns) columns.

Preparative medium pressure liquid chromatography

(MPLC) was performed on a Buchi B-680 chromatog-

raphy system using dry-ﬁlled columns with silica gel

4.1.2. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester

4b. (hexane/EtOAc, 90:10); 1.414 g (22%); oil; [h]²_D⁵−12

1

(c 0.18, CHCl₃); H NMR (CDCl₃) l 1.32 (s, 3H), 1.38

(s, 3H), 2.56 (ddd, 1H, J=2.7, 5.6, 13.3 Hz), 2.79 (ddd,

1H, J=8.0, 9.9, 13.3 Hz), 3.16 (ddd, 1H, J=2.7, 8.0,

8.3 Hz), 3.51 (dd, 1H, J=5.3, 8.2 Hz), 3.77 (s, 3H), 3.82

(d, 1H, J=12.9 Hz), 4.00 (dd, 1H, J=5.3, 8.2 Hz), 4.04

(d, 1H, J=12.9 Hz), 4.05 (ddd, 1H, J=5.3, 6.2, 8.3

Hz), 4.79 (dd, 1H, J=5.6, 9.9 Hz), 7.30–7.50 (m, 5H).

182

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

¹³C NMR (CDCl₃) l 25.2, 26.8, 34.7, 52.4, 61.3, 66.4,

67.9, 75.5, 76.3, 109.2, 127.8, 128.5, 129.1, 136.2, 171.5.

Anal. calcd for C₁₇H₂₃NO₅: C, 63.54; H, 7.21; N, 4.36.

Found: C, 63.46; H, 7.38; N, 4.25%.

137.1, 171.8. Anal. calcd for C₂₀H₂₉NO₅: C, 66.09; H,

8.04; N, 3.85. Found: C, 65.96; H, 8.11; N, 3.69%.

4.1.7. (3S,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl

ester 5b and (3R,5S)-2-benzyl-3-[(4S)-2,2-dimethyl-1,3-

dioxolan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl

ester 5c. (hexane/EtOAc, 85:15); 1.743 g (24%) of a

mixture of 5b and 5c was obtained: 5b (selected signals):

¹H NMR (CDCl₃) l 1.28 (s, 3H), 1.39 (s, 3H), 1.48 (s,

9H), 2.26 (ddd, 1H, J=4.8, 7.2, 12.7 Hz); 2.74 (ddd,

1H, J=8.0, 9.5, 12.7 Hz), 3.16 (q, 1H, J=7.6 Hz), 3.50

(dd, 1H, J=5.1, 8.1 Hz), 3.95 (d, 1H, J=13.8 Hz),

4.10–4.28 (m, 2H), 4.29 (d, 1H, J=13.8 Hz), 4.49 (dd,

1H, J=4.2, 8.1 Hz), 7.20–7.50 (m, 5H).

4.1.3. (3R,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester

4c. (hexane/EtOAc, 90:10); 0.643 g (10%); mp 40–42°C;

1

[h]²_D⁵+61 (c 0.10, CHCl₃); H NMR (CDCl₃) l 1.31 (s,

3H), 1.38 (s, 3H), 2.25 (ddd, 1H, J=5.5, 6.5, 13.2 Hz),

2.58 (ddd, 1H, J=8.5, 9.1, 13.2 Hz), 3.08 (dd, 1H,

J=6.5, 8.5 Hz), 3.71 (dd, 1H, J=6.8, 8.0 Hz), 3.75 (s,

3H), 4.00 (d, 1H, J=14.5 Hz), 4.00 (dd, 1H, J=6.4, 8.0

Hz), 4.10 (ddd, 1H, J=6.4, 6.8, 8.0 Hz), 4.36 (d, 1H,

J=14.5 Hz), 4.57 (dd, 1H, J=5.5, 9.1 Hz), 7.19–7.44

(m, 5H). ¹³C NMR (CDCl₃) l 25.1, 26.6, 34.8, 52.1,

60.8, 66.6, 66.9, 74.2, 76.8, 109.8, 127.1, 128.1, 129.3,

136.9, 172.2. Anal. calcd for C₁₇H₂₃NO₅: C, 63.54; H,

7.21; N, 4.36. Found: C, 63.65; H, 7.44; N, 4.28%.

1

5c (selected signals): H NMR (CDCl₃) l 1.32 (s, 6H),

1.47 (s, 9H), 2.49–2.61 (m, 2H), 3.19 (dt, 1H, J=2.4,

7.2 Hz), 3.74 (dd, 1H, J=6.4, 8.3 Hz), 3.84 (d, 1H,

J=13.3 Hz), 4.10–4.30 (m, 2H), 4.32 (d, 1H, J=13.3

Hz), 4.64 (dd, 1H, J=4.8, 9.5 Hz), 7.20–7.50 (m, 5H).

4.1.4. (3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidine-5-carboxylic acid methyl ester

4d. (hexane/EtOAc, 90:10); 0.193 g (3%); oil; [h]²_D⁵+57

4.1.8. (3R,5R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl

ester 5d. (hexane/EtOAc, 85:15); 0.508 g (7%); oil; [h]_D²⁵

1

(c 0.18, CHCl₃); H NMR (CDCl₃) l 1.33 (s, 3H), 1.39

(s, 3H), 2.35 (ddd, 1H, J=7.0, 9.1, 15.9 Hz), 2.50 (ddd,

1H, J=5.5, 7.6, 15.9 Hz), 3.25 (q, 1H, J=7.3 Hz), 3.73

(dd, 1H, J=6.5, 8.3 Hz), 3.76 (s, 3H), 3.98 (dd, 1H,

J=6.5, 8.3 Hz), 4.08 (q, 1H, J=6.8 Hz), 4.14 (d, 1H,

J=13.6 Hz), 4.20 (d, 1H, J=13.6 Hz), 4.51 (dd, 1H,

J=5.5, 9.1 Hz), 7.29–7.39 (m, 5H). ¹³C NMR (CDCl₃)

l 25.2, 26.8, 33.9, 53.0, 62.4, 66.5, 67.8, 75.4, 75.9,

109.9, 127.4, 128.3, 129.2, 137.1, 172.0. Anal. calcd for

C₁₇H₂₃NO₅: C, 63.54; H, 7.21; N, 4.36. Found: C,

63.32; H, 7.32; N, 4.50%.

1

+44 (c 0.28, CHCl₃); H NMR (CDCl₃) l 1.33 (s, 3H),

1.39 (s, 3H), 1.49 (s, 9H), 2.36 (ddd, 1H, J=7.1, 8.8,

12.7 Hz); 2.45 (ddd, 1H, J=5.6, 7.6, 12.7 Hz), 3.24 (q,

1H, J=7.4 Hz), 3.71 (dd, 1H, J=6.9, 8.0 Hz), 4.00 (t,

1H, J=8.1 Hz), 4.18 (q, 1H, J=6.6 Hz), 4.20 (s, 2H),

4.42 (dd, 1H, J=5.6, 8.8 Hz), 7.29–7.40 (m, 5H). ¹³C

NMR (CDCl₃) l 25.3, 26.5, 28.0, 35.2, 62.7, 66.3, 66.6,

76.5, 76.8, 81.9, 109.7, 127.3, 128.3, 129.2, 137.6, 171.2.

Anal. calcd for C₂₀H₂₉NO₅: C, 66.09; H, 8.04; N, 3.85.

Found: C, 66.13; H, 8.25; N, 3.96%.

4.1.5. (3S,4R)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidine-4-carboxylic acid methyl ester

4e. (hexane/EtOAc, 90:10); traces (when the reaction

was conducted with 10 g of 2a, ca. 80 mg (about 0.6%)

of 4e could be isolated); white foam; [h]_D+18 (c 0.15,

4.1.9. (3S,5S)-2-[Bis-(4-methoxyphenyl)-methyl]-3-(2,2-

dimethyl-[1,3]dioxolan-4-yl)-isoxazolidine-5-carboxylic

acid methyl ester 6a. (hexane/EtOAc, 80:20); 2.834 g

1

(31%); oil; [h]²_D⁵+28 (c 0.56, CHCl₃); H NMR (CDCl₃)

1

CHCl₃); H NMR (CDCl₃) l 1.28 (s, 3H), 1.35 (s, 3H),

l 1.24 (s, 3H), 1.30 (s, 3H), 2.70–2.80 (m, 2H), 3.35

(ddd, 1H, J=2.9, 4.8, 8.6 Hz), 3.51 (dd, 1H, J=5.7, 8.1

Hz), 3.62 (s, 3H), 3.74 (s, 6H), 3.99 (dt, 1H, J=6.2, 8.6

Hz), 4.10 (dd, 1H, J=6.4, 8.1 Hz), 4.54 (t, 1H, J=8.1

Hz), 4.94 (s, 1H), 6.76–6.84 (m, 4H), 7.22–7.26 (m, 2H),

7.38–7.42 (m, 2H). ¹³C NMR (CDCl₃) l 25.4, 26.7,

33.3, 52.4, 55.2 (2C), 65.7, 68.5, 72.7, 75.7, 77.8, 109.4,

113.7, 114.3, 128.2, 129.0, 133.9, 135.1, 158.3, 159.2,

173.2. Anal. calcd for C₂₅H₃₁NO₇: C, 65.63; H, 6.83; N,

3.06. Found: C, 63.70; H, 7.00; N, 3.29%.

3.24 (ddd, 1H, J=4.8, 6.0, 8.8 Hz), 3.56 (dd, 1H,

J=4.8, 6.2 Hz), 3.74 (s, 3H), 3.80 (dd, 1H, J=6.0, 8.8

Hz), 3.99 (dd, 1H, J=6.0, 8.8 Hz), 4.10 (q, 1H, J=6.0

Hz), 4.12 (d, 2H, J=14.8 Hz), 4.13 (t, 1H, J=8.8 Hz),

4.25 (dd, 1H, J=7.0, 8.8 Hz), 7.24–7.39 (m, 5H). ¹³C

NMR (CDCl₃) l 24.6, 26.2, 49.9, 52.4, 53.7, 60.7, 65.9,

68.9, 69.6, 109.5, 127.5, 128.3, 129.3, 136.7, 173.2. Anal.

calcd for C₁₇H₂₃NO₅: C, 63.54; H, 7.21; N, 4.36.

Found: C, 63.39; H, 7.41; N, 4.58%.

4.1.6.

(3S,5S)-2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

4.1.10.

(3S,5S)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2-

olan-4-yl)]-isoxazolidine-5-carboxylic acid tert-butyl

ester 5a. (hexane/EtOAc, 85:15); 2.542 g (35%); oil;

[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic

acid

methyl ester 7a. (hexane/EtOAc, 90:10); 4.763 g (71%);

1

[h]²_D⁵+33 (c 0.56, CHCl₃); H NMR (CDCl₃) l 1.29 (s,

oil; [h]²_D⁵+79 (c 0.28, CHCl₃); H NMR (CDCl₃) l 1.17

3H), 1.32 (s, 3H), 1.49 (s, 9H), 2.62 (dt, 1H, J=7.6,

12.9, 12.7 Hz); 2.73 (ddd, 1H, J=2.0, 8.5, 12.9 Hz),

3.22 (dt, 1H, J=2.0, 7.4 Hz), 3.50 (dd, 1H, J=5.2, 8.3

Hz), 3.79 (d, 1H, J=13.3 Hz), 3.93 (ddd, 1H, J=5.2,

6.1, 7.4 Hz), 4.01 (dd, 1H, J=6.1, 8.3 Hz), 4.26 (d, 1H,

J=13.3 Hz), 4.50 (t, 1H, J=7.3 Hz), 7.26–7.40 (m,

5H). ¹³C NMR (CDCl₃) l 25.2, 26.8, 28.0, 34.1, 62.7,

67.2, 68.1, 75.4, 78.0, 81.9, 109.4, 127.6, 128.4, 129.3,

(s, 3H), 1.24 (s, 3H), 1.51 (d, 3H, J=6.3 Hz), 2.55 (ddd,

1H, J=7.5, 8.8, 12.9 Hz), 2.70 (ddd, 1H, J=0.8, 9.6,

12.9 Hz), 3.14 (td, 1H, J=0.8, 8.5 Hz), 3.26 (dd, 1H,

J=5.8, 8.5 Hz), 3.79 (s, 3H), 3.83 (ddd, 1H, J=5.8, 6.3,

8.3 Hz), 3.85 (q, 1H, J=6.3 Hz), 3.95 (dd, 1H, J=6.3,

8.5 Hz), 4.60 (dd, 1H, J=7.5, 8.5 Hz), 7.20–7.40 (m,

5H). ¹³C NMR (CDCl₃) l 21.3, 25.2, 26.5, 33.3, 52.1,

65.6, 66.2, 68.2, 75.6, 76.5, 109.1, 127.7, 127.8, 128.6,

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

183

142.9, 173.1. Anal. calcd for C₁₈H₂₅NO₅: C, 64.46; H,

7.51; N, 4.18. Found: C, 64.38; H, 7.49; N, 4.02%.

NMR (CDCl₃) l 19.1, 19.9, 25.3, 26.3, 26.5, 26.7, 26.9,

36.5, 44.6, 47.8, 48.9, 53.0, 53.8, 61.4, 62.9, 66.5, 68.8,

75.4, 109.4, 127.5, 128.9, 129.3, 136.8, 171.0. Anal.

calcd for C₂₆H₃₆N₂SO₆: C, 61.88; H, 7.19; N, 5.55.

Found: C, 61.74; H, 7.32; N, 5.40%.

4.1.11.

(3S,5R)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2-

[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic

acid

methyl ester 7b. (hexane/EtOAc, 90:10); 0.939 g (14%);

1

oil; [h]²_D⁵+36 (c 0.21, CHCl₃); H NMR (CDCl₃) l 1.15

4.1.15. (3S,5S)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-yl)-

isoxazolidine-5-carboxylic acid methyl ester 10a. (hex-

ane/EtOAc, 85:15); 3.470 g (48%); oil; [h]²_D⁵−1 (c 0.22,

(s, 3H), 1.22 (s, 3H), 1.45 (d, 3H, J=6.3 Hz), 2.53 (ddd,

1H, J=1.8, 5.5, 13.2 Hz), 2.66 (ddd, 1H, J=7.7, 9.9,

13.2 Hz), 3.06 (ddd, 1H, J=1.8, 7.7, 8.8 Hz), 3.23 (dd,

1H, J=5.8, 9.1 Hz), 3.73 (q, 1H, J=6.3 Hz), 3.76 (s,

3H), 3.95 (dd, 1H, J=6.3, 9.1 Hz), 3.99 (ddd, 1H,

J=5.8, 6.3, 8.8 Hz), 4.60 (dd, 1H, J=5.5, 9.9 Hz),

7.24–7.39 (m, 5H). ¹³C NMR (CDCl₃) l 21.1, 25.4,

26.8, 34.5, 52.3, 64.2, 65.6, 68.4, 75.7, 76.6, 109.0, 127.9,

128.2, 128.8, 142.4, 171.3. Anal. calcd for C₁₈H₂₅NO₅:

C, 64.46; H, 7.51; N, 4.18. Found: C, 64.48; H, 7.77; N,

4.26%.

1

CHCl₃); H NMR (CDCl₃) l 1.28–1.63 (m, 10H), 2.68

(dt, 1H, J=7.8, 12.7 Hz), 2.76 (ddd, 1H, J=2.0, 8.3,

12.7 Hz), 3.25 (dt, 1H, J=2.0, 7.8 Hz), 3.50 (dd, 1H,

J=5.4, 8.3 Hz), 3.76 (s, 3H), 3.78 (d, 1H, J=13.2 Hz),

3.92 (ddd, 1H, J=5.4, 6.3, 7.8 Hz), 4.00 (dd, 1H,

J=6.3, 8.3 Hz), 4.22 (d, 1H, J=13.2 Hz), 4.58 (t, 1H,

J=8.1), 7.23–7.36 (m, 5H). ¹³C NMR (CDCl₃) l 23.7,

23.9, 25.1, 34.3, 34.8, 36.6, 52.1, 53.8, 62.7, 67.6, 67.7,

75.2, 110.0, 127.5, 128.3, 129.2, 137.1, 172.9. Anal.

calcd for C₂₀H₂₇NO₅: C, 66.46; H, 7.53; N, 3.88.

Found: C, 66.39; H, 7.50; N, 3.71%.

4.1.12.

(3R,5S)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2-

acid

[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic

methyl ester 7c. (hexane/EtOAc, 90:10); 0.537 g (8%);

oil. This compound was impuriﬁed with 10% of 7d

4.1.16.

(3S,5R)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-

yl)-isoxazolidine-5-carboxylic acid methyl ester 10b.

1

which could not be separated. H NMR (CDCl₃) l 1.36

(hexane/EtOAc, 85:15); 1.229 g (17%); oil; [h]²_D⁵+16 (c

0.35, CHCl₃); H NMR (CDCl₃) l 1.10–1.61 (m, 10H),

1

(s, 3H), 1.43 (s, 3H), 1.57 (d, 3H, J=6.8 Hz), 2.29 (ddd,

1H, J=5.5, 8.8, 12.9 Hz), 2.44 (ddd, 1H, J=6.3, 8.1,

12.9 Hz), 3.40 (dt, 1H, J=5.9, 8.5 Hz), 3.59 (dd, 1H,

J=7.0, 8.4 Hz), 3.71 (q, 1H, J=6.8 Hz), 3.74 (s, 3H),

3.99 (dd, 1H, J=6.5, 8.4 Hz), 4.11 (q, 1H, J=6.6 Hz),

4.40 (dd, 1H, J=6.3, 8.4 Hz), 7.23–7.40 (m, 5H). ¹³C

NMR (CDCl₃) l 21.6, 25.4, 26.5, 34.5, 52.0, 62.9, 64.2,

66.5, 74.3, 75.6, 109.7, 127.1, 127.9, 128.6, 142.1, 171.7.

2.58 (ddd, 1H, J=2.9, 5.5, 13.2 Hz), 2.78 (ddd, 1H,

J=8.3, 9.8, 13.2 Hz), 3.17 (dt, 1H, J=2.9, 8.1 Hz), 3.50

(dd, 1H, J=4.9, 8.1 Hz), 3.74 (s, 3H), 3.82 (d, 1H,

J=13.2 Hz), 3.98 (d, 1H, J=13.2 Hz), 4.02 (dd, 1H,

J=5.1, 8.1 Hz), 4.10 (dt, 1H, J=5.0, 8.1 Hz), 4.74 (dd,

1H, J=5.5, 9.8 Hz), 7.19–7.37 (m, 5H). ¹³C NMR

(CDCl₃) l 23.7, 24.0, 25.1, 34.6, 34.8, 36.6, 52.4, 61.4,

66.6, 67.6, 75.4, 75.9, 109.8, 127.7, 128.5, 129.1, 136.3,

171.5. Anal. calcd for C₂₀H₂₇NO₅: C, 66.46; H, 7.53; N,

3.88. Found: C, 66.32; H, 7.68; N, 3.75%.

4.1.13.

(3R,5R)-3-(2,2-Dimethyl-[1,3]dioxolan-4-yl)-2-

[(1R)-1-phenylethyl]-isoxazolidine-5-carboxylic

acid

methyl ester 7d. (hexane/EtOAc, 90:10); 0.134 g (2%);

1

oil; [h]²_D⁵+46 (c 0.14, CHCl₃); H NMR (CDCl₃) l 1.35

4.1.17.

(3R,5S)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-

(s, 3H), 1.42 (s, 3H), 1.56 (d, 3H, J=6.4 Hz), 2.15 (dt,

1H, J=6.6, 12.8 Hz), 2.31 (dt, 1H, J=8.1, 12.8 Hz),

3.18 (dt, 1H, J=6.8, 7.8 Hz), 3.63 (dd, 1H, J=6.6, 8.5

Hz), 3.70 (q, 1H, J=6.4 Hz), 3.75 (s, 3H), 3.98 (dd, 1H,

J=6.6, 8.5 Hz), 4.15 (q, 1H, J=6.8 Hz), 4.33 (dd, 1H,

J=6.6, 8.5 Hz), 7.26–7.41 (m, 5H). ¹³C NMR (CDCl₃)

l 20.8, 25.3, 26.7, 35.1, 52.2, 63.5, 63.6, 66.7, 74.3, 75.4,

109.8, 127.4, 128.0, 129.2, 140.7, 171.8. Anal. calcd for

C₁₈H₂₅NO₅: C, 64.46; H, 7.51; N, 4.18. Found: C,

64.42; H, 7.41; N, 4.29%.

yl)-isoxazolidine-5-carboxylic acid methyl ester 10c.

(hexane/EtOAc, 85:15); 1.012 g (14%); oil; [h]²_D⁵+2 (c

0.31, CHCl₃); H NMR (CDCl₃) l 1.15–1.63 (m, 10H),

1

2.25 (ddd, 1H, J=5.4, 7.3, 12.7 Hz), 2.56 (dt, 1H,

J=8.8, 12.7 Hz), 3.06 (q, 1H, J=7.3 Hz), 3.68 (dd, 1H,

J=6.8, 8.3 Hz), 3.73 (s, 3H), 4.00 (dd, 1H, J=6.8, 8.3

Hz), 4.01 (d, 1H, J=14.3 Hz), 4.11 (q, 1H, J=6.8 Hz),

4.38 (d, 1H, J=14.3 Hz), 4.54 (dd, 1H, J=5.4, 8.8 Hz),

7.22–7.45 (m, 5H). ¹³C NMR (CDCl₃) l 23.7, 24.0,

25.1, 34.8, 34.9, 36.4, 52.0, 60.9 (2C), 66.4, 66.9, 74.3,

109.9, 127.3, 128.3, 129.1, 137.3, 173.6. Anal. calcd for

C₂₀H₂₇NO₅: C, 66.46; H, 7.53; N, 3.88. Found: C,

66.56; H, 7.59; N, 3.93%.

4.1.14. (3S,5S)-{2-Benzyl-3-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-isoxazolidin-5-yl}-(10,10-dimethyl-3,3-dioxo-

3l⁶-thia-4-azatricyclo[5.2.1.0^1,5]dec-4-yl)-methanone 9a.

(hexane/EtOAc, 80:20); 5.652 g (56%); oil; [h]²_D⁵−8 (c

4.1.18.

(3R,5R)-2-Benzyl-3-(1,4-dioxa-spiro[4.5]dec-2-

1

0.33, CHCl₃); H NMR (CDCl₃) l 0.93 (s, 3h), 1.10 (s,

yl)-isoxazolidine-5-carboxylic acid methyl ester 10d.

3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.50–1.60 (m, 2H),

1.80–1.90 (m, 2H), 2.03 (dd, 1H, J=8.0, 13.6 Hz),

2.08–2.12 (m, 1H), 2.38 (ddd, 1H, J=6.3, 8.5, 12.9 Hz),

2.70 (ddd, 1H, J=5.5, 7.7, 12.9 Hz), 3.32 (t, 1H, J=7.0

Hz), 3.35 (d, 1H, J=13.6 Hz), 3.46 (d, 1H, J=13.6 Hz),

3.68 (dd, 1H, J=7.0, 8.2 Hz), 3.85 (dd, 1H, J=5.2, 7.7

Hz), 4.00 (dd, 1H, J=6.6, 8.2 Hz), 4.10 (q, 1H, J=7.0

Hz), 4.17 (d, 1H, J=14.3 Hz), 4.23 (d, 1H, J=14.3 Hz),

4.97 (dd, 1H, J=5.2, 8.5 Hz), 7.20–7.38 (m, 5H). ¹³C

(hexane/EtOAc, 85:15); 1.012 g (14%); oil; [h]²_D⁵−5 (c

0.11, CHCl₃); H NMR (CDCl₃) l 1.29–1.60 (m, 10H),

1

2.48 (ddd, 1H, J=4.4, 7.8, 12.7 Hz), 2.54 (ddd, 1H,

J=8.3, 9.2, 12.7 Hz), 3.35 (q, 1H, J=7.8 Hz), 3.65 (dd,

1H, J=6.4, 8.3 Hz), 3.79 (s, 3H), 4.04 (dd, 1H, J=6.3,

8.3 Hz), 4.29 (d, 1H, J=14.1 Hz), 4.50 (d, 1H, J=14.1

Hz), 4.71 (dd, 1H, J=4.4, 8.3), 7.25–7.40 (m, 5H). ¹³C

NMR (CDCl₃) l 23.5, 24.1, 24.8, 33.8, 34.5, 37.2, 52.9,

55.1, 64.6, 67.5, 69.3, 74.9, 110.1, 127.2, 128.1, 129.3,

184

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

137.0, 173.1. Anal. calcd for C₂₀H₂₇NO₅: C, 66.46; H,

7.53; N, 3.88. Found: C, 66.68; H, 7.43; N, 3.80%.

J=7.7, 12.9 Hz), 2.38 (ddd, 1H, J=1.5, 8.1, 12.9 Hz),

3.53 (m, 1H), 3.74 (dd, 1H, J=5.3, 8.2 Hz), 4.00, 4.11

(m, 2H), 4.40 (t, 1H, J=8.0 Hz), 6.20 (bs, 1H), 7.02 (bs,

1H). ¹³C NMR (CDCl₃) l 25.0, 26.5, 32.4, 53.6, 65.7,

68.6, 78.9, 109.8, 177.9. Anal. calcd for C₉H₁₅NO₄: C,

53.72; H, 7.51; N, 6.96. Found: C, 53.76; H, 7.42; N,

7.25%.

4.2. Synthesis of pyrrolidin-2-ones

4.2.1. (3S,5S)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-

hydroxy-pyrrolidin-2-one 11a. A solution of 4a (1.0 g,

3.11 mmol) in methanol (50 mL) was treated with

Pearlman’s catalyst, Pd(OH)₂–C (120 mg), and stirred

under hydrogen at room temperature and 2000 psi.

After 24 h the reaction mixture was ﬁltered through a

pad of Celite, which was washed with methanol. The

ﬁltrate was evaporated and the residue was puriﬁed by

ﬂash chromatography on silica gel (EtOAc/MeOH, 5:1)

to afford pure 11a (0.576 g, 92%) as a white solid; mp

The same procedure was applied to 7c (0.5 g, 1.49

mmol) and pure 11c (0.276 g, 92%) was obtained, the

physical and spectroscopic properties being identical to

those obtained for the compound prepared from 4c.

4.2.4. (3R,5R)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-

3-hydroxypyrrolidin-2-one 11d. The same procedure

described above for the conversion of 4a to 11a was

applied to 4d (0.150 g, 0.47 mmol). After ﬂash chro-

matography (EtOAc/MeOH, 5:1) of the crude product,

pure 11d (87 mg, 92%) was obtained as a white solid;

mp 133–135°C; [h]²_D⁵−19 (c 0.99, CHCl₃); ¹H NMR

(CDCl₃) l 1.32 (s, 3H), 1.40 (s, 3H), 1.64 (dt, 1H,

J=8.0, 15.8 Hz), 2.46 (ddd, 1H, J=6.7, 8.3, 15.8 Hz),

3.52 (m, 1H), 3.70 (dd, 1H, J=4.9, 8.3 Hz), 3.97 (q, 1H,

J=6.7 Hz), 4.05 (dd, 1H, J=6.4, 8.3 Hz), 4.31 (t, 1H,

J=8.3 Hz), 4.40 (bs, 1H, ex. D₂O), 6.70 (bs, 1H). ¹³C

NMR (CDCl₃) l 25.1, 26.7, 32.3, 53.8, 65.9, 69.0, 79.1,

110.1, 177.4. Anal. calcd for C₉H₁₅NO₄: C, 53.72; H,

7.51; N, 6.96. Found: C, 53.91; H, 7.46; N, 6.84%.

1

148–149°C; [h]_D−5 (c 0.92, CHCl₃); H NMR (CDCl₃)

l 1.33 (s, 3H), 1.43 (s, 3H), 1.68 (dt, 1H, J=8.0, 16.0

Hz), 2.56 (ddd, 1H, J=6.8, 8.3, 16.0 Hz), 3.10 (bs, 1H,

ex. D₂O), 3.74 (dddd, 1H, J=1.8, 4.4, 6.8, 8.0 Hz), 3.79

(dd, 1H, J=6.3, 8.5 Hz), 4.02 (dd, 1H, J=6.5, 8.5 Hz),

4.14 (dt, 1H, J=4.4, 6.4 Hz), 4.32 (t, 1H, J=8.2 Hz),

6.69 (bs, 1H). ¹³C NMR (CDCl₃) l 24.7, 26.3, 32.3,

52.1, 64.9, 69.1, 77.3, 109.7, 177.8. Anal. calcd for

C₉H₁₅NO₄: C, 53.72; H, 7.51; N, 6.96. Found: C, 53.60;

H, 7.58; N, 7.13%.

The same procedure was applied to 5a (1.0 g, 2.75

mmol), 6a (1.0 g, 2.19 mmol), 7a (1.0 g, 2.98 mmol) and

9a (1.0 g, 1.98 mmol), and pure 11a (0.498 g, 90%;

0.405 g, 92%; 0.540 g, 90% and 0.351 g, 88%, respec-

tively) was obtained in all cases, the physical and

spectroscopic properties being identical to those

obtained for the compound prepared from 4a.

The same procedure was applied to 7d (0.12 g, 0.36

mmol) and pure 11d (62 mg, 86%) was obtained, the

physical and spectroscopic properties being identical to

those obtained for the compound prepared from 4d.

4.2.2. (3S,5R)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-

3-hydroxy-pyrrolidin-2-one 11b. The same procedure

described above for the conversion of 4a to 11a was

applied to 4b (1.0 g, 3.11 mmol). After ﬂash chromatog-

raphy (EtOAc/MeOH, 5:1) of the crude product, pure

11b (0.563, 90%) was obtained as a white solid; mp

118–120°C; [h]²_D⁵−30 (c 0.43, CHCl₃); ¹H NMR

(CDCl₃) l 1.31 (s, 3H), 1.40 (s, 3H), 2.12 (ddd, 1H,

J=7.6, 8.6, 16.3 Hz), 2.42 (ddd, 1H, J=2.6, 8.4, 16.3

Hz), 3..80 (bs, 1H, ex. D₂O), 3.63 (m, 1H), 3.75 (m,

1H), 4.03 (m, 2H), 4.36 (t, 1H, J=8.2 Hz), 7.07 (bs,

1H). ¹³C NMR (CDCl₃) l 24.9, 26.4, 31.4, 53.3, 65.9,

68.3, 77.4, 109.9, 178.7. Anal. calcd for C₉H₁₅NO₄: C,

53.72; H, 7.51; N, 6.96. Found: C, 53.81; H, 7.60; N,

7.08%.

4.3. Transketalization of isoxazolidines 10a–d

A solution of the corresponding isoxazolidine 10 (0.5 g,

1.38 mmol) in dry acetone (50 mL) was treated with

p-toluensulfonic acid (30 mg, 0.174 mmol) and the

resulting solution was stirred at ambient temperature

for 8 h, at which time saturated aqueous sodium bicar-

bonate (10 mL) was added. The reaction mixture was

evaporated under reduced pressure and the residue was

partitioned between EtOAc (100 mL) and brine (100

mL). The organic layer was separated, dried over mag-

nesium sulphate and evaporated. The crude product

was puriﬁed by ﬂash chromatography (hexane/EtOAc,

4:1) to give the corresponding isoxazolidines 4. Starting

from 10a, 10b, 10c and 10d, compounds 4a (0.390 g,

88%), 4b (0.381 g, 86%), 4c (0.392 g, 88%) and 4d (0.373

g, 84%) were obtained, respectively. In all cases, the

physical and spectroscopic properties of these com-

pounds were identical to those obtained for the corre-

sponding compounds prepared from nitrone 2a.

The same procedure was applied to 7b (0.9 g, 2.68

mmol) and pure 11b (0.491 g, 91%) was obtained, the

physical and spectroscopic properties being identical to

those obtained for the compound prepared from 4b.

4.2.3. (3R,5S)-5-((4S)-2,2-Dimethyl-1,3-dioxolan-4-yl)-

3-hydroxy-pyrrolidin-2-one 11c. The same procedure

described above for the conversion of 4a to 11a was

applied to 4c (0.5 g, 1.56 mmol). After ﬂash chromatog-

raphy (EtOAc/MeOH, 5:1) of the crude product, pure

11c (0.292 g, 93%) was obtained as a white solid; mp

112–114°C; [h]²_D⁵−22 (c 0.21, CHCl₃); ¹H NMR

(CDCl₃) l 1.40 (s, 3H), 1.31 (s, 3H), 1.62 (dt, 1H,

4.4. 4-Nitrobenzoic acid (3R,5S)-5-[(4R)-2,2-dimethyl-

1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 12

From 11a: To a stirred solution of 11a (0.2 g, 1 mmol),

triphenylphosphine (1.28 g, 4.92 mmol) and p-nitroben-

zoic acid (0.730 g, 4.38 mmol) in dry toluene (30 mL) at

ambient temperature was added slowly diisopropyl-

azodicarboxylate (1.30 g, 6.4 mmol). After 6 h, the

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

185

reaction mixture was evaporated to dryness and the

residue was puriﬁed by ﬂash chromatography (hexane/

EtOAc, 2:3) to give pure 12 (0.235 g, 67%) as a white

by column chromatography on silica gel to give pure 15

as a light yellow oil (188 mg, 80%). [h]²_D⁵+8 (c 0.78,

CHCl₃); ¹H NMR (CDCl₃+D₂O) l 2.22 (ddd, 1H,

J=1.8, 7.3, 13.2 Hz), 2.36 (ddd, 1H, J=3.4, 8.8, 13.2

Hz), 3.22 (m, 1H), 3.56 (dd, 1H, J=6.4, 14.8), 3.59 (dd,

1H, J=6.2, 14.8), 3.62 (dd, 1H, J=6.8, 14.8 Hz), 3.81

(dd, 1H, J=6.5, 14.8), 4.03 (d, 1H, J=14.4), 4.12 (d,

1H, J=14.4 Hz), 4.21 (m, 1H), 7.15–7.32 (m, 5H). ¹³C

NMR (CDCl₃) l 30.0, 32.7, 62.7, 64.1, 66.6, 79.0, 127.8,

128.7, 129.3, 137.8. Anal. calcd for C₁₂H₁₇NO₃: C,

64.55; H, 7.67; N, 6.27. Found: C, 64.70; H, 7.80; N,

6.10%.

1

foam; [h]²_D⁵−19 (c 0.40, CHCl₃); H NMR (CDCl₃) l

1.35 (s, 3H), 1.50 (s, 3H), 2.26 (dt, 1H, J=8.8, 13.9 Hz),

2.65 (ddd, 1H, J=1.8, 8.5, 13.9 Hz), 3.67 (dd, 1H,

J=5.9, 8.5 Hz), 3.84 (ddd, 1H, J=1.8, 3.7, 8.8 Hz), 4.10

(dd, 1H, J=7.0, 8.5 Hz), 4.19 (ddd, 1H, J=3.7, 5.9, 7.0

Hz), 5.62 (t, 1H, J=8.6 Hz), 6.28 (s, 1H), 7.40–7.51 (m,

2H), 8.00–8.13 (m, 2H). ¹³C NMR (CDCl₃) l 24.7, 26.4,

30.2, 38.6, 53.0, 67.1, 69.5, 109.9, 125.6, 131.4, 138.3,

151.6, 165.7, 172.1. Anal. calcd for C₁₆H₁₈N₂O₇: C,

54.86; H, 5.18; N, 8.00. Found: C, 54.92; H, 5.33; N,

8.42%.

4.7. (3S,5S)-5-((4R)-2,2-Dimethyl-1,3-dioxolan-4-yl)-3-

(tert-butyldimethylsiloxy)-pyrrolidin-2-one 17a

From 11b: A solution of 11b (0.2 g, 1 mmol) in dry

dichloromethane (20 mL) was treated with 4-nitroben-

zoyl chloride (0.223 g, 1.2 mmol) and pyridine (0.158 g,

2 mmol), and the resulting solution was stirred at

ambient temperature for 12 h. The reaction mixture was

washed sequentially with 2N HCl and saturated

aqueous sodium bicarbonate. The organic layer was

separated, dried over magnesium sulphate and concen-

trated to dryness. The residue was puriﬁed by radial

chromatography (hexane/EtOAc, 2:3) to give pure 12

(0.287 g, 82%). The physical and spectroscopic proper-

ties of this compound were identical to those obtained

for the compound prepared from 11a.

A solution of 11a (0.402 g, 2 mmol) in DMF (15 mL)

was treated with imidazole (0.756 g) and tert-

butyldimethylsilyl chloride (0.452 g, 3 mmol). The

resulting solution was stirred at 70°C until no more

starting material was observed by TLC (ca. 4 h).

Methanol (5 mL) and water (50 mL) were added and the

resulting mixture was extracted with EtOAc (3×40 mL).

The organic layers were combined, dried over magne-

sium sulfate and evaporated under reduced pressure to

give crude 17a, which was puriﬁed by ﬂash chromatog-

raphy (hexane/EtOAc, 2:3) to afford pure 17a (0.467 g,

74%) as an oil; [h]²_D⁵+9 (c 0.28, CHCl₃); ¹H NMR

(CDCl₃) l 0.12 (s, 3H), 0.14 (s, 3H), 0.89 (s, 9H), 1.33

(s, 3H), 1.42 (s, 3H), 1.66 (dt, 1H, J=7.4, 13.1 Hz), 2.50

(ddd, 1H, J=7.1, 8.1, 13.1 Hz), 3.68 (dt, 1H, J=4.5, 7.3

Hz), 3.83 (dd, 1H, J=6.0, 8.2 Hz), 4.03 (dd, 1H, J=6.2,

8.2 Hz), 4.07 (q, 1H, J=6.1 Hz), 4.27 (t, 1H, J=7.8 Hz),

6.8 (bs, 1H). ¹³C NMR (CDCl₃) l −5.2, −4.6, 18.2, 24.9,

25.7, 26.5, 34.1, 51.8, 65.2, 70.1, 77.9, 109.4, 176.5. Anal.

calcd for C₁₅H₂₉NO₄Si: C, 57.11; H, 9.27; N, 4.44.

Found: C, 57.03; H, 9.42; N, 4.37%.

4.5. (3S,5S)-2-Benzyl-3-formyl-isoxazolidine-5-carboxy-

lic acid methyl ester 14

To a solution of 4a (0.32 g, 1 mmol) in MeOH (60 mL)

was added p-TsOH (43 mg, 0.25 mmol) and the result-

ing solution was heated under reﬂux for 4 h. The

reaction mixture was cooled at room temperature and

neutralized with Amberlite IRA-400. The mixture was

ﬁltered and the ﬁltrate was evaporated under reduced

pressure. The crude diol 13 (¹H NMR (CDCl₃+D₂O) l

2.58 (dt, 1H, J=7.3, 13.2 Hz), 2.81 (ddd, 1H, J=3.4,

8.8, 13.2 Hz), 3.29 (m, 1H), 3.51 (m, 2H), 3.74 (s, 3H),

3.85 (d, 1H, J=12.7 Hz), 4.16 (m, 1H), 4.23 (d, 1H,

J=12.7 Hz), 4.58 (dd, 1H, J=7.3, 8.8 Hz), 7.15–7.32

(m, 5H) was taken up into a 1:1 mixture of MeOH:H₂O

(30 mL), cooled at 0°C and treated with NaIO₄(0.214

g, 1 mmol). The resulting suspension was stirred at 0°C

for 1 h, ﬁltered and rotatory evaporated to give 14 as a

4.8. Benzoic acid (3S,5S)-5-[(4R)-2,2-dimethyl-1,3-diox-

olan-4-yl]-2-oxo-pyrrolidin-3-yl ester 17b

The same procedure described above for the conversion

of 11b to 12 was applied to 11a (0.402 g, 2 mmol). After

ﬂash chromatography (hexane/EtOAc, 2:3) of the crude

product, pure 17b (0.519 g, 85%) was obtained as a

white foam; [h]²_D⁵+17 (c 0.20, CHCl₃); ¹H NMR

(CDCl₃) l 1.34 (s, 3H), 1.43 (s, 3H), 1.90 (dt, 1H,

J=7.8, 13.7 Hz), 2.86 (ddd, 1H, J=6.8, 8.8, 13.7 Hz),

3.84 (dt, 1H, J=6.7, 8.0 Hz), 3.88 (dd, 1H, J=6.4, 8.3

Hz), 4.05 (dd, 1H, J=6.4, 8.3 Hz), 4.18 (q, 1H, J=6.4

Hz), 5.54 (t, 1H, J=8.3 Hz), 7.40 (bs, 1H), 7.48–7.52

(m, 3H), 7.59–7.63 (m, 2H). ¹³C NMR (CDCl₃) l 24.8,

26.4, 30.5, 38.1, 52.2, 65.0, 70.6, 109.8, 128.4, 129.2,

129.9, 1233.4, 165.8, 173.2. Anal. calcd for C₁₆H₁₉NO₅:

C, 62.94; H, 6.27; N, 4.59. Found: C, 63.10; H, 6.11; N,

4.70%.

1

yellow oil (0.19 mg; 78%). H NMR (CDCl₃) l 2.40

(ddd, 1H, J=2.2, 4.4, 13.2 Hz), 2.60 ( ddd, 1H, J=6.4,

8.8, 13.2), 3.54 (m, 1H), 3.74 (s, 3H), 3.78 (d, 1H,

J=12.4 Hz), 3.82 (d, 1H, J=12.4), 4.42 (dd, 1H, J=4.4,

8.8 Hz), 7.15–7.45 (m, 5H), 9.42 (bs, 1H). The aldehyde

was immediately used in the next step without further

puriﬁcation.

4.6. (3S,5S)-2-Benzyl-3,5-bis(hydroxymethyl-isoxazol-

idine 15

4.9. (3S,5S)-1-(tert-Butoxycarbonyl)-5-((4R)-2,2-

dimethyl-1,3-dioxolan-4-yl)-3-(tert-butyldimethylsiloxy)-

pyrrolidin-2-one 18a

A solution of 14 (0.19 g, 0.76 mmol) in aqueous

methanol (10 mL) was cooled to 0°C and treated with

NaBH₄(0.117 g, 3 mmol). After stirring at the same

temperature for 2 h, the reaction mixture was concen-

trated under reduced pressure. The residue was puriﬁed

A solution of 17a (0.4 g, 1.27 mmol) in CH₂Cl₂(20 mL)

was treated with Boc₂O (0.44 g, 2 mmol), Et₃N (0.30

mL, 2 mmol) and DMAP (0.244 g, 2 mmol). The

186

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

reaction mixture was stirred at ambient temperature for

12 h, at which time 1N KHSO₄(20 mL) was added.

The organic layer was separated, washed with water

(1×15 mL) and brine (1×15 mL), dried over magnesium

sulfate and evaporated to give crude 8, which was

puriﬁed by ﬂash chromatography (hexane/EtOAc, 4:1)

to afford pure 18a (0.464 g, 88%) as a solid which

solidiﬁed upon standing; mp 69–71°C; [h]²_D⁵−44 (c 0.48,

residue which was taken up in diethyl ether (20 mL)

and treated with a freshly distilled ethereal solution of

diazomethane at 0°C for 5 min. The solvent was

removed under reduced pressure and the residue was

subjected to puriﬁcation by radial chromatography

(hexane/EtOAc, 9:1) to give the pure 19 (0.218 g, 60%)

1

as a colorless oil; [h]²_D⁵−10 (c 0.19, CHCl₃); H NMR

(CDCl₃) l 1.49 (s, 9H), 2.40 (dt, 1H, J=6.8, 13.7 Hz),

2.85 (dt, 1H, J=8.3, 13.7 Hz), 3.75 (s, 3H), 4.59 (dd,

1H, J=6.8, 7.8 Hz), 5.57 (dd, 1H, J=7.3, 8.3), 7.38–

7.41 (m, 3H), 7.97–8.04 (m, 2H). ¹³C NMR (CDCl₃) l

27.8, 27.9, 52.7, 55.8, 70.1, 84.5, 128.5, 130.0, 133.7,

149.0, 165.3, 168.1 (2C), 170.8. Anal. calcd for

C₁₈H₂₁NO₇: C, 59.50; H, 5.83; N, 3.85. Found: C,

59.37; H, 5.72; N, 4.75%.

1

CHCl₃); H NMR (CDCl₃) l 0.12 (s, 3H), 0.14 (s, 3H),

0.89 (s, 9H), 1.31 (s, 3H), 1.40 (s, 3H), 1.52 (s, 9H), 2.11

(dt, 1H, J=4.9, 13.6 Hz), 2.24 (dt, 1H, J=7.9, 13.6

Hz), 3.75 (dd, 1H, J=7.2, 8.6 Hz), 4.01 (dd, 1H,

J=6.2, 8.6 Hz), 4.05 (ddd, 1H, J=4.6, 6.2, 7.8 Hz),

4.23 (dd, 1H, J=5.1, 8.0 Hz), 4.40 (dt, 1H, J=6.2, 7.2

Hz). ¹³C NMR (CDCl₃) l −5.2, −4.5, 18.2, 25.5, 25.8,

26.4, 28.1, 29.4, 56.8, 67.7, 71.1, 79.4, 83.7, 109.1, 150.7,

172.5. Anal. calcd for C₂₀H₃₇NO₆Si: C, 57.80; H, 8.97;

N, 3.37. Found: C, 57.96; H, 9.12; N, 3.12%.

4.12. Carbonic acid tert-butyl ester (3S,5S)-5-[(4S)-2,2-

dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester

20

4.10. (3S,5S)-5-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-3-

(benzoyloxy)-2-oxo-pyrrolidine-1-carboxylic acid tert-

butyl ester 18b

The same procedure described above for the conversion

of 17a to 18a was applied to 11a (0.2 g, 1 mmol). After

radial chromatography (hexane/EtOAc, 1:1) of the

crude product, pure 20 (0.223 g, 74%) was obtained as

The same procedure described above for the conversion

of 17a to 18a was applied to 17b (0.410 g, 1.17 mmol).

After ﬂash chromatography (hexane/EtOAc, 4:1) of the

crude product, pure 18b (0.403 g, 85%) was obtained as

1

an oil; [h]²_D⁵−4 (c 0.14, CHCl₃); H NMR (CDCl₃) l

1.28 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1.67 (dt, 1H,

J=8.4, 16.7 Hz), 2.57 (ddd, 1H, J=6.7, 8.6, 16.7 Hz),

3.53 (ddd, 1H, J=6.7, 7.4, 8.4 Hz), 3.66 (dd, 1H,

J=4.6, 8.3 Hz), 3.93 (ddd, 1H, J=4.6, 6.4, 7.4 Hz),

4.00 (dd, 1H, J=6.4, 8.3 Hz), 5.11 (t, 1H, J=8.7 Hz),

6.70 (bs, 1H). ¹³C NMR (CDCl₃) l 25.1, 26.7, 27.7,

30.0, 53.4, 65.7, 72.1, 78.8, 83.2, 110.2, 152.7, 171.9.

Anal. calcd for C₁₄H₂₃NO₆: C, 55.80; H, 7.69; N, 4.65.

Found: C, 55.62; H, 7.48; N, 4.45%.

1

an oil; [h]²_D⁵−49 (c 0.57, CHCl₃); H NMR (CDCl₃) l

1.29 (s, 3H), 1.34 (s, 3H), 1.57 (s, 9H), 2.24 (dt, 1H,

J=4.9, 5.9, 14.2 Hz), 2.63 (ddd, 1H, J=8.3, 9.3, 14.2

Hz), 3.70 (dd, 1H, J=6.8, 8.8 Hz), 4.10 (dd, 1H,

J=6.8, 8.8 Hz), 4.24 (ddd, 1H, J=3.9, 4.9, 8.3 Hz),

4.60 (dt, 1H, J=3.9, 6.8 Hz), 5.55 (dd, 1H, J=5.9, 9.3

Hz), 7.44–7.55 (m, 3H), 7.60–7.63 (m, 2H). ¹³C NMR

(CDCl₃) l 24.7, 26.0, 27.9, 36.6, 38.1, 56.5, 66.8, 70.6,

84.2, 109.6, 128.4, 129.9 (2C), 133.4, 150.1, 165.6, 169.1.

Anal. calcd for C₂₁H₂₇NO₇: C, 62.21; H, 6.71; N, 3.45.

Found: C, 62.42; H, 6.61; N, 3.55%.

4.13. Reduction of isoxazolidines 4

4.11. (2S,4S)-4-(Benzoyloxy)-5-oxo-pyrrolidine-1,2-

dicarboxylic acid 1-tert-butyl ester 2-methyl ester 19

4.13.1. (3S,5S)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21a and (3S,5S)-2-

benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb-

oxylic acid methyl ester 13. A solution of 4a (0.82 g,

2.55 mmol) in THF (25 mL) was treated with glacial

acetic acid (40 mL) and Zn dust (0.196 g, 3 mmol); the

resulting solution was heated at 60°C for 1 h. After

cooling at ambient temperature, the reaction mixture

was treated with a saturated aqueous solution of

sodium carbonate and the resulting mixture was

extracted with EtOAc (3×50 mL). The combined

organic layers were washed with brine, dried over mag-

nesium sulfate and evaporated to yield a residue which

after a short ﬂash chromatography (hexane/EtOAc, 1:4)

afforded a 90:10 mixture of compounds 21a and 13,

which were used in the next acetylation step without

further puriﬁcation.

To a well-stirred suspension of periodic acid (0.536 g,

2.35 mmol) in dry diethyl ether (50 mL), compound 18b

(0.450 g, 1 mmol) was added at ambient temperature

under an argon atmosphere in one portion. Stirring was

maintained for additional 4 h at which time the reac-

tion mixture was ﬁltered. The ﬁltrate was evaporated

under reduced pressure and the residue was dissolved in

CH₃CN (5 mL). To the resulting mixture, a solution of

NaClO₂(0.133 g, 1.53 mmol) in water (5 mL) was

added dropwise. The resulting mixture was then treated

with a solution of NaH₂PO₄(29 mg, 0.25 mmol) in

H₂O (2 mL) and 35% H₂O₂(82 mL, 0.88 mmol) keeping

the temperature of the mixture below 10°C. After stir-

ring for 1 h, Na₂SO₃(9 mg, 0.17 mmol) was added and

the resulting mixture was acidiﬁed (pH 2–3) with 10%

aqueous HCl. The resulting mixture was partitioned

between brine (30 mL) and EtOAc (30 mL), the layers

were separated and the aqueous layer was extracted

with EtOAc (3×25 mL). The combined organic extracts

were washed with brine, dried over magnesium sulfate

and concentrated under reduced pressure to give a

1

21a: H NMR (CDCl₃+D₂O) l (selected signals) 1.30

(s, 3H), 1.46 (s, 3H), 1.88 (td, 1H, J=6.3, 12.7 Hz), 2.35

(td, 1H, J=7.8, 12.7 Hz), 3.50 (m, 1H), 3.98 (dd,

1H, J=6.5, 8.9 Hz), 4.14 (d, 1H, J=15.1 Hz), 4.30–

4.40 (m, 3H), 5.05 (d, 1H, J=15.1 Hz), 7.15–7.32 (m,

5H).

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

187

1

13: The H NMR spectra of this compound was identi-

13.7 Hz), 3.43 (q, 1H, J=7.3 Hz), 3.57 (1H, J=7.8 Hz),

3.91 (dd, 1H, J=6.8, 8.1 Hz), 4.12 (q, 1H, J=6.8 Hz),

4.38 (t, 1H, J=7.8 Hz), 4.47 (d, 1H, J=14.6 Hz), 4.91

(d, 1H, J=14.6 Hz), 7.33–7.41 (m, 5H).

cal to that observed for the same product obtained

from 4a as described above.

4.13.2. (3R,5S)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21b and (3S,5R)-2-

benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb-

oxylic acid methyl ester 22b. The same procedure

described above for the conversion of 4a to 21a and 13

was applied to 4b (0.68 g, 2.12 mmol). After a short

ﬂash chromatography (hexane/EtOAc, 1:4) of the crude

product, a 93:7 mixture of 21b and 22b was obtained

and used in the next acetylation step without further

puriﬁcation.

4.14. Acetylation of pyrrolidin-2-ones 21 and diols 22

4.14.1. Acetic acid (3S,5S)-1-benzyl-5-[(4S)-2,2-dime-

thyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 23a

and (3S,5S)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]-isoxa-

zolidine-5-carboxylic acid methyl ester. The above

described mixture of compounds 21a and 13 was dis-

solved in dry dichloromethane (30 mL) and treated

with acetic anhydride (2.44 g, 24 mmol) and pyridine

(3.20 g, 40 mmol), and the resulting solution was stirred

at ambient temperature for 12 h. The reaction mixture

was washed sequentially with 2N HCl and saturated

aqueous sodium bicarbonate. The organic layer was

separated, dried over magnesium sulfate and concen-

trated to dryness. The residue was puriﬁed by MPLC

(hexane/EtOAc, 3:2) to give pure 23a and 24a.

1

21b: H NMR (CDCl₃+D₂O) l (selected signals) 1.29

(s, 3H), 1.42 (s, 3H), 1.87 (dt, 1H, J=8.8, 13.2 Hz), 2.40

(ddd, 1H, J=1.9, 8.2, 13.2 Hz), 3.45 (dt, 1H, J=2.3,

8.6 Hz), 3.54 (dd, 1H, J=6.3, 8.5 Hz), 3.93 (dd, 1H,

J=7.3, 8.5 Hz), 4.09 (d, 1H, J=15.1 Hz), 4.27 (dt, 1H,

J=2.2, 7.0 Hz), 4.59 (t, 1H, J=8.5 Hz), 5.0 (sd, 1H,

J=15.1 Hz), 7.32–7.45 (m, 5H).

1

23a: 0.621 g (73%); oil; [h]²_D⁵−45 (c 0.26, CHCl₃); H

1

NMR (CDCl₃) l 1.25 (s, 3H), 1.47 (s, 3H), 1.85 (td,

1H, J=7.4, 13.2 Hz), 2.12 (s, 3H), 2.50 (ddd, 1H,

J=7.3, 8.8, 13.2 Hz), 3.50 (dt, 1H, J=2.9, 7.0 Hz), 3.54

(dd, 1H, J=6.6, 8.5 Hz), 3.96 (dd, 1H, J=7.0, 8.5 Hz),

4.10 (d, 1H, J=15.4 Hz), 4.30 (dt, 1H, J=2.9, 6.6 Hz),

5.12 (d, 1H, J=15.4 Hz), 5.32 (dd, 1H, J=7.4, 8.8 Hz),

7.30–7.40 (m, 5H). ¹³C NMR (CDCl₃) l 20.9, 24.6,

26.0, 26.5, 44.9, 54.9, 65.4, 70.1, 73.4, 109.8, 127.8,

127.9, 128.8, 135.6, 170.4, 170.8. Anal. calcd for

C₁₈H₂₃NO₅: C, 64.85; H, 6.95; N, 4.20. Found: C,

64.69; H, 6.80; N, 4.38%.

22b: H NMR (CDCl₃+D₂O) l (selected signals) 2.25–

2.65 (m, 2H), 3.19 (dt, 1H, J=5.1, 8.5 Hz), 3.56–3.63

(m, 2H), 3.75 (s, 3H), 3.91 (d, 1H, J=12.8 Hz), 3.98 (m,

1H), 4.05 (d, 1H, J=12.8 Hz), 4.72 (dd, 1H, J=5.5, 8.8

Hz), 7.31–7.42 (m, 5H).

4.13.3. (3S,5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21c and (3R,5S)-2-

benzyl-3-[(1S)-1,2-dihydroxy-ethyl]-isoxazolidine-5-carb-

oxylic acid methyl ester 22c. The same procedure

described above for the conversion of 4a to 21a and 13

was applied to 4c (0.44 g, 1.36 mmol). After a short

ﬂash chromatography (hexane/EtOAc, 1:4) of the crude

product, a 90:10 mixture of 21c and 22c was obtained

and used in the next acetylation step without further

puriﬁcation.

24a: 65 mg (7%); oil; [h]²_D⁵−56 (c 0.51, CHCl₃); ¹H

NMR (CDCl₃) l 1.82 (s, 3H), 2.03 (s, 3H), 2.50 (ddd,

1H, J=2.6, 8.8, 13.2 Hz), 2.66 (td, 1H, J=7.4, 13.2

Hz), 3.49 (dt, 1H, J=2.2, 7.7 Hz), 3.77 (s, 3H), 3.80 (d,

1H, J=12.9 Hz), 4.12 (dd, 1H, J=4.8, 12.1 Hz), 4.21

(d, 1H, J=12.9 Hz), 4.26 (dd, 1H, J=2.6, 12.1 Hz),

4.58 (t, 1H, J=8.5 Hz), 4.94 (ddd, 1H, J=2.9, 4.8, 7.9

Hz), 7.31–7.46 (m, 5H). ¹³C NMR (CDCl₃) l 20.6, 20.9,

33.3, 52.5, 62.3, 62.8, 63.3, 70.4, 76.9, 127.7, 128.5,

129.4, 136.5, 170.3, 170.5, 172.7. Anal. calcd for

C₁₈H₂₃NO₇: C, 59.17; H, 6.34; N, 3.83. Found: C,

59.28; H, 6.26; N, 3.91%.

21c: ¹H NMR (CDCl₃+D₂O) l (selected signals) 1.31 (s,

3H), 1.37 (s, 3H), 1.85–2.10 (m, 2H), 3.30 (m, 1H), 3.56

(dd, 1H, J=6.3, 8.6 Hz), 4.11 (dd, 1H, J=4.8, 8.6 Hz),

4.30 (d, 1H, J=14.7 Hz), 4.31 (m, 1H), 4.50 (t, 1H,

J=8.5 Hz), 5.13 (d, 1H, J=14.7 Hz), 7.28–7.39 (m,

5H).

1

22c: H NMR (CDCl₃+D₂O) l (selected signals) 2.34

4.14.2. Acetic acid (3R,5S)-1-benzyl-5-[(4S)-2,2-dime-

thyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl ester 23b

and (3S,5R)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]-isoxa-

zolidine-5-carboxylic acid methyl ester 24b. The same

procedure described above for the conversion of the

mixture of 21a and 13 to 23a and 24a was applied to

the mixture of 21b and 22b. After MPLC (hexane/

EtOAc, 3:2) pure 24b and 24b were obtained.

(ddd, 1H, J=2.2, 5.5 12.9 Hz), 2.76 (1H, J=8.1, 9.6,

12.9 Hz), 3.43, 3.60 (m, 3H), 3.78 (s, 3H), 3.84 (d, 1H,

J=13.0 Hz), 4.08 (d, 1H, J=13.0 Hz), 4.11 (m, 1H),

4.78 (dd, 1H, J=5.5, 9.6 Hz), 7.30–7.40 (m, 5H).

4.13.4. (3R,5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-diox-

olan-4-yl]-3-hydroxy-pyrrolidin-2-one 21d. The same

procedure described above for the conversion of 4a to

21a and 13 was applied to 4d (0.3 g, 0.94 mmol). After

a short ﬂash chromatography (hexane/EtOAc, 1:4) of

the crude product, only 21d was obtained and used in

the next acetylation step without further puriﬁcation.

¹H NMR (CDCl₃+D₂O) l 1.30 (s, 3H), 1.34 (s, 3H),

1.58 (dt, 1H, J=7.3, 13.7 Hz), 2.36 (dt, 1H, J=7.8,

1

23b: 0.516 g (73%); oil; [h]²_D⁵+18 (c 0.41, CHCl₃); H

NMR (CDCl₃) l 1.26 (s, 3H), 1.48 (s, 3H), 1.83 (dt,

1H, J=8.8, 12.9 Hz), 2.13 (s, 3H), 2.58 (dd, 1H, J=8.5,

12.9 Hz), 3.43 (dt, 1H, J=1.8, 9.2 Hz), 3.51 (dd, 1H,

J=5.9, 8.5 Hz), 3.96 (dd, 1H, J=78.4, 8.5 Hz), 4.08 (d,

1H, J=15.1 Hz), 4.30 (ddd, 1H, J=2.2, 5.9, 7.7 Hz),

188

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

5.08 (d, 1H, J=15.1 Hz), 5.47 (dd, 1H, J=8.5, 9.2 Hz),

7.32–7.40 (m, 5H). ¹³C NMR (CDCl₃) l 20.9, 24.3,

25.9, 27.5, 44.7, 56.1, 65.7, 70.8, 72.9, 110.2, 127.8,

127.9, 128.8, 135.5, 170.3, 170.9. Anal. calcd for

C₁₈H₂₃NO₅: C, 64.85; H, 6.95; N, 4.20. Found: C,

64.69; H, 6.80; N, 4.38%.

(s, 3H), 2.50 (ddd, 1H, J=7.3, 8.8, 13.7 Hz), 3.50 (q,

1H, J=7.3 Hz), 3.52 (dd, 1H, J=6.8, 8.3 Hz), 3.86 (dd,

1H, J=6.8, 8.3 Hz), 4.10 (q, 1H, J=6.8 Hz), 4.46 (d,

1H, J=14.6 Hz), 4.90 (d, 1H, J=14.6 Hz), 5.25 (dd,

1H, J=7.0, 8.8 Hz), 7.32–7.41 (m, 5H). ¹³C NMR

(CDCl₃) l 20.9, 25.2, 26.3, 28.1, 45.8, 56.9, 65.8, 70.2,

78.8, 110.5, 127.6, 128.5, 128.7, 136.6, 170.3, 170.6.

Anal. calcd for C₁₈H₂₃NO₅: C, 64.85; H, 6.95; N, 4.20.

Found: C, 64.96; H, 6.88; N, 4.16%.

24b: 46 mg (6%); oil; [h]²_D⁵+3 (c 0.33, CHCl₃); ¹H NMR

(CDCl₃) l 1.82 (s, 3H), 1.99 (s, 3H), 2.43 (ddd, 1H,

J=3.3, 4.7, 13.6 Hz), 2.73 (ddd, 1H, J=8.1, 9.9, 13.6

Hz), 3.38 (dt, 1H, J=2.9, 7.7 Hz), 3.75 (s, 3H), 3.85 (d,

1H, J=12.9 Hz), 4.12 (d, 1H, J=12.9 Hz), 4.15 (dd

1H, J=4.8, 12.1 Hz), 4.32 (dd, 1H, J=2.9, 12.1 Hz),

4.75 (dd, 1H, J=4.7, 9.9 Hz), 4.99 (ddd, 1H, J=2.9,

4.8, 7.7 Hz), 7.33–7.42 (m, 5H). ¹³C NMR (CDCl₃) l

20.8, 21.2, 36.1, 51.4, 63.0, 63.5(2C), 69.7, 73.1, 127.6,

128.4, 129.5, 136.0, 170.1, 170.6, 173.0. Anal. calcd for

C₁₈H₂₃NO₇: C, 59.17; H, 6.34; N, 3.83. Found: C,

59.08; H, 6.43; N, 3.69%.

4.15. Synthesis of N-benzyl pyroglutamates 25

4.15.1. (2S,4S)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-

carboxylic acid methyl ester 25a. The same procedure

described above for the conversion of 18b to 19 was

applied to 23a (0.2 g, 0.6 mmol). After radial chro-

matography (hexane/EtOAc, 4:1) pure 25a (0.115 g,

66%) was obtained as an oil; [h]²_D⁵+17 (c 0.46, CHCl₃);

¹H NMR (CDCl₃) l 2.00 (dt, 1H, J=6.4, 13.9 Hz), 2.07

(s, 3H), 2.77 (dt, 1H, J=8.5, 13.9 Hz), 3.65 (s, 3H), 3.92

(dd, 1H, J=6.4, 8.5 Hz), 4.13 and 5.13 (2d, 2H, J=14.9

Hz), 5.29 (dd, 1H, J=6.4, 8.5), 7.10–7.30 (m, 5H); ¹³C

NMR (CDCl₃) l 20.6, 29.9, 45.8, 52.5, 55.4, 69.5,

128.0, 128.4, 128.7, 134.8, 170.0, 170.1, 170.8. Anal.

calcd for C₁₅H₁₇NO₅: C, 61.85; H, 5.88; N, 4.81.

Found: C, 61.62; H, 5.99; N, 4.67%.

4.14.3. Acetic acid (3S,5R)-1-benzyl-5-[(4S)-2,2-

dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl

ester

21c and (3R,5S)-2-benzyl-3-[(1S)-1,2-diacetoxy-ethyl]-

isoxazolidine-5-carboxylic acid methyl ester 22c. The

same procedure described above for the conversion of

the mixture of 21a and 13 to 23a and 24a was applied

to the mixture of 21c and 22c. After MPLC (hexane/

EtOAc, 3:2) pure 23c and 24c were obtained.

4.15.2. (2S,4R)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-

carboxylic acid methyl ester 25b. The same procedure

described above for the conversion of 18b to 19 was

applied to 23b (0.15 g, 0.45 mmol). After radial chro-

matography (hexane/EtOAc, 4:1) pure 25b (90 mg,

69%) was obtained as an oil; [h]²_D⁵−7 (c 0.50, CHCl₃);

¹H NMR (CDCl₃) l 2.15 (dt, 1H, J=8.9, 13.4 Hz), 2.15

(s, 3H), 2.64 (ddd, 1H, J=1.5, 8.9, 13.4 Hz), 3.67 (s,

3H), 4.00 (dd, 1H, J=1.5, 8.9 Hz), 4.06 and 4.98 (2d,

2H, J=14.8 Hz), 5.46 (t, 1H, J=8.9), 7.20–7.40 (m,

5H); ¹³C NMR (CDCl₃) l 20.8, 30.6, 46.2, 52.7, 55.9,

69.7, 128.1, 128.7, 128.8, 134.7, 170.2, 170.5, 171.3.

Anal. calcd for C₁₅H₁₇NO₅: C, 61.85; H, 5.88; N, 4.81.

Found: C, 61.95; H, 6.02; N, 4.74%.

1

23c: 0.304 g (67%); oil; [h]²_D⁵−49 (c 0.38, CHCl₃); H

NMR (CDCl₃) l 1.32 (s, 3H), 1.38 (s, 3H), 1.95 (dt,

1H, J=8.8, 13.7 Hz), 2.13 (s, 3H), 2.18 (ddd, 1H,

J=2.4, 9.3, 13.7 Hz), 3.46 (ddd, 1H, J=2.4, 7.3, 8.8

Hz), 3.55 (dd, 1H, J=5.6, 8.3 Hz), 4.00 (dd, 1H,

J=6.8, 8.3 Hz), 4.09 (q, 1H, J=6.4 Hz), 4.29 (d, 1H,

J=15.1 Hz), 5.12 (d, 1H, J=15.1 Hz), 5.40 (t, 1H,

J=8.3 Hz), 7.29–7.41 (m, 5H). ¹³C NMR (CDCl₃) l

20.8, 25.0, 26.4, 29.7, 45.9, 56.4, 66.6, 70.2, 79.0, 110.58,

127.7, 128.4, 128.7, 136.1, 170.4, 170.6. Anal. calcd for

C₁₈H₂₃NO₅: C, 64.85; H, 6.95; N, 4.20. Found: C,

64.73; H, 6.86; N, 4.15%.

24c: 35 mg (7%); oil; [h]²_D⁵+27 (c 0.27, CHCl₃); ¹H

NMR (CDCl₃) l 1.92 (s, 3H), 2.02 (s, 3H), 2.41 (ddd,

1H, J=5.9, 10.3, 13.2 Hz), 2.73 (dt, 1H, J=9.2, 13.2

Hz), 3.39 (ddd, 1H, J=5.5, 9.2, 10.3 Hz), 3.8 (s, 3H),

3.91 (d, 1H, J=13.2 Hz), 4.05 (d, 1H, J=13.2 Hz), 4.08

(dd, 1H, J=5.1, 12.1 Hz), 4.18 (dd, 1H, J=4.0, 12.1

Hz), 4.70 (dd, 1H, J=5.9, 9.2 Hz), 5.04 (dt, 1H, J=4.0,

5.3 Hz), 7.30–7.40 (m, 5H). ¹³C NMR (CDCl₃) l 20.6,

20.9, 34.1, 52.5, 61.5, 63.1, 63.2, 72.0, 75.3, 127.7, 128.5,

129.1, 136.2, 170.3, 170.4, 171.0. Anal. calcd for

C₁₈H₂₃NO₇: C, 59.17; H, 6.34; N, 3.83. Found: C,

59.04; H, 6.31; N, 3.95%.

4.15.3. (2R,4S)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-

carboxylic acid methyl ester ent-25b. The same proce-

dure described above for the conversion of 18b to 19

was applied to 23c (0.12 g, 0.36 mmol). After radial

chromatography (hexane/EtOAc, 4:1) pure ent-25b (70

mg, 67%) was obtained. The physical and spectroscopic

properties of this compound were identical to those of

23b except for the sign of the optical rotation: [h]²_D⁵+7

(c 0.22, CHCl₃). Anal. calcd for C₁₅H₁₇NO₅: C, 61.85;

H, 5.88; N, 4.81. Found: C, 61.79; H, 6.00; N, 4.89%.

4.15.4. (2R,4R)-4-Acetoxy-1-benzyl-5-oxo-pyrrolidine-2-

carboxylic acid methyl ester ent-25a. The same proce-

dure described above for the conversion of 18b to 19

was applied to 23d (0.14 g, 0.42 mmol). After radial

chromatography (hexane/EtOAc, 4:1) pure ent-25a (86

mg, 70%) was obtained. The physical and spectroscopic

properties of this compound were identical to those of

23a except for the sign of the optical rotation: [h]²_D⁵−16

(c 0.40, CHCl₃). Anal. calcd for C₁₅H₁₇NO₅: C, 61.85;

H, 5.88; N, 4.81. Found: C, 61.83; H, 5.81; N, 4.90%.

4.14.4. Acetic acid (3R,5R)-1-benzyl-5-[(4S)-2,2-

dimethyl-1,3-dioxolan-4-yl]-2-oxo-pyrrolidin-3-yl

ester

23d. The same procedure described above for the con-

version of the mixture of 21 and 13 to 23a and 24a was

applied to 21d. After ﬂash chromatography (hexane/

EtOAc, 3:2) pure 23d (0.235 g, 75%) was obtained as an

1

oil; [h]²_D⁵−27 (c 0.32, CHCl₃); H NMR (CDCl₃) l 1.29

(s, 3H), 1.33 (s, 3H), 1.46 (dt, 1H, J=7.0, 13.7 Hz), 2.14

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

189

Acknowledgements

10. Zhang, X.; Schmitt, C.; Jiang, W. Tetrahedron Lett. 2001,

42, 5335–5338.

11. (a) Merino, P.; Anoro, S.; Merchan, F.; Tejero, T. Hete-

rocycles 2000, 53, 861–875; (b) Tejero, T.; Dondoni, A.;

Rojo, I.; Merchan, F. L.; Merino, P. Tetrahedron 1997,

53, 3301–3318; (c) Casuscelli, F.; Di Bella, M. R.;

Romeo, G.; Chiacchio, U.; Resciﬁna, A. Gazz. Chim.

Ital. 1977, 127, 367–371.

The authors gratefully acknowledge the ﬁnancial sup-

port by the DGI (Project CASANDRA, MCYT,

Madrid), DGA (Project P116-2001, Zaragoza),

MURST (Roma) and Italian CNR (Roma).

References

12. (a) Shimazaki, M.; Okazaki, F.; Nakasima, F.; Ishikawa,

T.; Ohta, A. Heterocycles 1993, 36, 1823–1836; (b) White,

J. D.; Badger, R. A.; Kezar, H. J., III; Pallenberg, A. J.;

Schieser, G. A. Tetrahedron 1989, 45, 6631–6644; (c)

Burdisso, M.; Gamba, A.; Gandolﬁ, R.; Oberti, R. Tetra-

hedron 1988, 44, 3735–3748; (d) Herczegh, P.; Kovacs, I.;

Szilagyi, L.; Varga, T.; Dinya, Z.; Sztaricskai, F. Tetra-

hedron Lett. 1993, 34, 1211–1214; (e) Coutouli-Argyro-

poulou, E.; Malamidou-Xenikaki, E.; Stampelos, X. N.;

Alexopoulou, I. N. Tetrahedron 1997, 53, 707–718.

13. Merino, P.; Anoro, S.; Franco, S.; Merchan, F. L.;

Tejero, T.; Tunon, V. J. Org. Chem. 2000, 65, 1590–1596.

14. For recent examples of a similar use of the 1,3-dioxolane

moiety, see inter alia: (a) Merino, P.; Castillo, E.; Franco,

S.; Merchan, F. L.; Tejero, T. Tetrahedron 1998, 54,

12301–12322; (b) Merino, P.; Castillo, E.; Franco, S.;

Merchan, F. L.; Tejero, T. J. Org. Chem. 1998, 63,

2371–2374.

15. Schiehser, G. A.; White, J. D.; Matsumoto, G.; Pezzanite,

J. O.; Clardy, J. Tetrahedron Lett. 1986, 27, 5587–5590.

16. White, J. D.; Badger, R. A.; Kezar, H. S., III; Pallenberg,

A.; Schieser, G. A. Tetrahedron 1989, 45, 6631–6644.

17. The authors have deposited the atomic coordinates for

this structure with the Cambridge Crystallographic Data

Centre, CCDC 179303. The coordinates can be obtained

on request from the Director, Cambridge Crystallo-

graphic Data Centre, 12 Union Road, Cambridge CB2

1EZ, UK.

1. (a) Soloshonok, V. A.; Cai, C.; Hruby, V. J. Angew.

Chem., Int. Ed. Engl. 2000, 39, 2172–2175; (b) Cai, C.;

Soloshonok, V. A.; Hruby, V. J. J. Org. Chem. 2001, 66,

1339–1350.

2. For some recent examples: (a) Jacobi, P. A.; Lee, K. J.

Am. Chem. Soc. 2000, 122, 4295–4303; (b) Honda, T.;

Kimura, M. Org. Lett. 2000, 2, 3925–3927. For an excel-

lent review, see: Najera, C.; Yus, M. Tetrahedron: Asym-

metry 1999, 10, 2245–2303.

3. (a) Ali, A.; Ahmad, V. U.; Ziemer, B.; Liebscher, J.

Tetrahedron: Asymmetry 2000, 11, 4365–4375; (b) Dyer,

J.; Keeling, S.; Moloney, M. G. Chem. Commun. 1998,

461–462; (c) Bailey, J. H.; Cherry, D. T.; Dyer, J.;

Moloney, M. G.; Bamford, M. J.; Keeling, S.; Lamont,

R. B. J. Chem. Soc., Perkin Trans. 1 2000, 2783–2792; (d)

Dyer, J.; King, A.; Keeling, S.; Moloney, M. G. J. Chem.

Soc., Perkin Trans. 1 2000, 2793–2804; (e) Goswami, R.;

Moloney, M. G. Chem. Commun. 1999, 2333–2334.

4. (a) Snider, B. B.; Gu, Y. Org. Lett. 2001, 3, 1761–1763;

(b) Soloshonok, V. A.; Cai, C.; Hruby, V. J.; Meervelt, L.

V.; Yamazaki, T. J. Org. Chem. 2000, 65, 6688–6696; (c)

Fujita, M.; Kitagawa, O.; Yamada, Y.; Izawa, H.;

Hasegawa, H.; Taguchi, T. J. Org. Chem. 2000, 65,

1108–1114; (d) Kim, Y. J.; Takatsuki, A.; Kogoshi, N.;

Kitahara, T. Tetrahedron 1999, 55, 8353–8364; (e) Dudot,

B.; Chiaroni, A.; Royer, J. Tetrahedron Lett. 2000, 41,

6355–6359; (f) Ostendorf, M.; Dijkink, J.; Rutjes, F. P. J.

T.; Hiemstra, H. Eur. J. Chem. 2000, 115–124; (g) Lan-

glois, N.; Moro, A. Eur. J. Chem. 1999, 3483–3488; (h)

Chan, P. W. H.; Cottrell, I. F.; Moloney, M. G. Tetra-

hedron: Asymmetry 1999, 10, 3887–3891; (i) Bryans, J. S.;

Large, J. M.; Parsons, A. F. J. Chem. Soc., Perkin Trans.

1 1999, 2905–2910.

18. The graphic view showed in Fig. 2 was made with

ORTEP3 software. Copyright by Farrugia, L. J. Univer-

sity of Glasgow, 1997–2000.

19. For representative 1,3-dipolar cycloadditions of a-alkoxy

nitrones, see inter alia: (a) Kuban, J.; Blanarikova, I.;

Fisera, L.; Jaroskova, L.; Fengler-Veith, M.; Jager, V.;

Kosizek, J.; Humpa, O.; Pronayova, N.; Langer, V.

Tetrahedron 1999, 55, 9501–9514; (b) Bruche, L.; Arnone,

A.; Bravo, P.; Panzeri, W.; Presenti, C.; Viani, F. Eur. J.

Chem. 1999, 1665–1670; (c) Borrachero, P.; Cabrera, F.,

Dianez, M. J.; Estrada, M. D.; Gomez-Guillen, M.;

Lopez-Castro, A.; Moreno, J. M.; de Paz, J. L.; Perez-

Garrido, S. Tetrahedron: Asymmetry 1999, 10, 77–98; (d)

Torrente, S.; Noya, B.; Paredes, M. D.; Alonso, R. J.

Org. Chem. 1997, 62, 6710–6711; (e) Xu, Z.; Johannes, C.

W.; La, D. S.; Hoﬁlena, G. E.; Hoveyda, A. H. Tetra-

hedron 1997, 53, 16377–16390; (f) Saito, S.; Ishikawa, T.;

Kishimoto, N.; Kohara, T.; Moriwake, T. Synlett 1994,

282–283; (g) Goti, A.; Cicchi, S.; Brandi, A.;

Pietrusiewicz, K. M. Tetrahedron: Asymmetry 1991, 2,

1371–1378; (h) DeShong, P.; Li, W.; Kennington, J. W.,

Jr.; Ammon, H. L.; Leginus, J. M. J. Org. Chem. 1991,

56, 1364–1373; (i) Fray, M. J.; Jones, R. H.; Thomas, E.

J. J. Chem. Soc., Perkin Trans. 1 1985, 2753–2761; (j)

DeShong, P.; Dicken, C. M.; Leginus, J. M.; Whittle, R.

R. J. Am. Chem. Soc. 1984, 106, 5598–5602; (h) Chiac-

chio, U.; Corsaro, A.; Gumina, G.; Resciﬁna, A.; Ian-

5. Lee, Y. K.; Kaneko, T. Bull. Chem. Soc. Jpn. 1973, 46,

3494–3498.

6. Gefﬂaut, T.; Bauer, U.; Ariola, K.; Koskinen, A. M. P.

Tetrahedron: Asymmetry 1996, 7, 3099–3102.

7. Heinz, L. J.; Lunn, W. H.; Murff, R. E.; Paschal, J. W.;

Spangle, L. A. J. Org. Chem. 1996, 61, 4838–4841.

8. Ohta, T.; Hosoi, A.; Nozoe, S. Tetrahedron Lett. 1988,

29, 329–332.

9. Avent, A. G.; Bowler, A. N.; Doyle, P. M.; Marchand, C.

M.; Young, D. W. Tetrahedron Lett. 1992, 33, 1509–

1512. We have also conﬁrmed in our laboratories low

chemical yields for this reaction in agreement with Young

et al. See: Merino, P.; Franco, S.; Merchan, F. L.;

Revuelta, J.; Tejero, T. Proceedings of ECSOC-5, The

Fifth International Electronic Conference on Synthetic

Organic Chemistry, http://www.mdpi.org/ecsoc-5.htm,

September 1–30, 2001. Kappe, O.; Merino, P., Marzinzik,

A.; Wennemers, H.; Wirth, T.; Vanden Eynde, J.-J.; Lin,

S.-K., Eds.; CD-ROM, ISBN 3-906980-06-5. Paper

A0010.

190

P. Merino et al. / Tetrahedron: Asymmetry 13 (2002) 173–190

nazzo, D.; Piperno, A.; Romeo, G.; Romeo, R. J. Org.

Chem. 1999, 64, 9321–0327

20. Even in the presence of an inhibitor such as 2,6-di-tert-

butyl-4-methylphenol, polymerization was observed to a

great extent.

21. Conversion of 16 into 1b only should require catalytic

hydrogenation, since the formation of the lactam ring is

preferred to the formation of the lactone ring (see Ref.

11c).

22. For a complete study on the reaction of di-tert-butyldi-

carbonate with amines and alcohols in the presence of

DMAP, see: Basel, Y.; Hassner, A. J. Org. Chem. 2000,

65, 6368–6380.

23. Domingo, L. R. Eur. J. Org. Chem. 2000, 2265–2272.

24. (a) Kanemasa, S.; Ueno, N.; Shirahase, M. Tetrahedron

Lett. 2002, 43, 657–660; (b) Tanaka, J.; Kanemasa, S.

Tetrahedron 2001, 57, 899–905.

25. For a recent report with references to previous related

articles, see: Carda, M.; Portoles, M.; Murga, J.; Uriel,

S.; Marco, J. A.; Domingo, L. R.; Zaragoza, R. J.;

Roper, H. J. Org. Chem. 2000, 65, 7000–7009.

26. Rastelli, A.; Gandolﬁ, R.; Sarzi-Amade, M.; Carboni, B.

J. Org. Chem. 2001, 66, 2449–2458.

Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J.

A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.;

Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M.

C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.;

Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clif-

ford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.;

Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.;

Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,

J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;

Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.;

Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,

A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;

Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.;

Gonzalez, C.; Head-Gordon, M.; Replogle, E. S.; Pople,

J. A. Gaussian, Inc., Pittsburgh PA, 1999.

30. Structures were optimized through step by step calcula-

tions starting with the semi-empirical calculations (PM3),

then moving to the ab initio calculation with a low level

of basis set using Hartree Fock methods (HF/3-21G) and

ﬁnally the calculation was completed at a higher level of

theory using density functional methods (B3LYP/6-

31G(d)). For the purpose of comparison single points

calculations were also carried out at HF/6-31G(d)//3-21G

and B3LYP/6-31G(d)//HF/3-21G levels.

27. Di Valentin, C.; Freccero, M.; Gandolﬁ, R.; Rastelli, A.

31. The graphic views showed in Fig. 3 were made with

2000.

J. Org. Chem. 2000, 65, 6112–6120.

28. Cossio, F.; Morao, I.; Jiao, H. J. Am. Chem. Soc. 1999,

121, 6737–6746.

32. A nitrone is isoelectronic with an allylic anion; so it can

be considered as a nucleophile when it is made to react

with electron-poor dipolarophiles.

29. All calculations were performed using the Gaussian 98

Revision A.9 suite of programs. Frisch, J.; Trucks, G.

W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;

Article Doi

Experimental and theoretical study of the 1,3-dipolar cycloaddition between D-glyceraldehyde nitrones and acrylates. Diastereoselective approach to 4-hydroxy pyroglutamic acid derivatives

DOI: 10.1016/S0957-4166(02)00088-5

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0957-4166(02)00088-5

Full text of DOI:10.1016/S0957-4166(02)00088-5

Products guided by the article

R&D Labs maybe for 455942-10-6

Relevant to this article

Hot Product