Ready access to enantiopure 5-substituted-3-pyrrolin-2-ones from N- benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN)

Article abstract of DOI:10.1016/S0957-4166(98)00150-5

The reaction of the lithiated salt of methyl propiolate with N-benzyl- 2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN) afforded the corresponding propargyl hydroxylamines in a stereocontrolled way depending on the nature of the Lewis acid used as an additive. Subsequent reduction of the obtained hydroxylamines provided chiral 5-substituted-3-pyrrolin-2-ones, in high overall yields.

Full text of DOI:10.1016/S0957-4166(98)00150-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 1759–1769
Ready access to enantiopure 5-substituted-3-pyrrolin-2-ones from
N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde nitrone
(BIGN)
Pedro Merino,∗ Elena Castillo, Santiago Franco, Francisco L. Merchan and Tomas Tejero
Departamento de Química Orgánica, ICMA, Facultad de Ciencias, Universidad de Zaragoza, E-50009 Aragon, Spain
Received 25 March 1998; accepted 17 April 1998
Abstract
The reaction of the lithiated salt of methyl propiolate with N-benzyl-2,3-O-isopropylidene-D-glyceraldehyde
nitrone (BIGN) afforded the corresponding propargyl hydroxylamines in a stereocontrolled way depending on the
nature of the Lewis acid used as an additive. Subsequent reduction of the obtained hydroxylamines provided chiral
5-substituted-3-pyrrolin-2-ones, in high overall yields. © 1998 Elsevier Science Ltd. All rights reserved.
1. Introduction
Optically active 3-pyrrolin-2-ones are ubiquitous structural subunits found in a wide range of nat-
ural products including alkaloids, nucleosides, antineoplastic agents or immunosupresants.1 The α,β-
unsaturated-γ-butyrolactam moiety exists as a substructural unit in several biologically active natural
products, e.g. biliverdin,2 leuconolactam,3 showdomycin,4 dysidin,5 pandamarine,6 dolastatin 15,7 or
microcolins.8
Moreover, chiral 5-substituted-3-pyrrolin-2-ones are ideally suited as building blocks, as the com-
bination of the chirality and inherent topology of a cyclic system provides a high degree of regio-
and stereocontrol for the systematic functionalization of predetermined sites in the molecule. The α,β-
unsaturated lactam moiety can be utilized as a Michael acceptor of a variety of nucleophiles including
stabilized carbanions,9 nitrogen nucleophiles10–13 or several types of organocuprates.14–17 Additionally,
the double bond of the heterocycle is susceptible to both epoxidation18,19 and hydroxylation20–24 thus
leading to polyhydroxylated compounds. More elaborated products are also accessible by using 3-
pyrrolin-2-ones as substrates in cycloaddition reactions.25–27
∗
Corresponding author. Fax: +34 976 761194; e-mail: pmerino@posta.unizar.es
0957-4166/98/$19.00 © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00150-5

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Therefore, the synthesis of such optically active building blocks are currently receiving considerable
attention.28–30 Thus, the preparation of several differentially protected 5-substituted-3-pyrrolin-2-ones
1 and 2 has been described using pyroglutamic acid as the starting material.16,29,31,32 Derivative 3 has
been prepared both starting from (S)-malic acid27 and by enzymatic resolutions of racemic lactams.30
Casiraghi and co-workers prepared compounds 4, bearing a polyhydroxylated side chain at C-5, by
condensing a pyrrole derivative, designed as a four-carbon synthon, with α-alkoxy aldehydes33 and α-
amino aldehydes.34
In connection with our efforts on the syntheses of biologically active nitrogenated compounds, starting
from nitrones, we have developed new synthetic routes for diamines,35 (hydroxyamino) nitriles,36
complex nucleosides,37 diamino acids,38 and analogues of nucleosides.39 All these strategies were based
on nucleophilic addition reactions to chiral nitrones. In this context, we have recently reported, in a
preliminary form, a new approach to 3-pyrrolin-2-ones.40 Our strategy was based on the nucleophilic
addition of a methyl propiolate acetylide to the N-benzyl nitrone derived from 2,3-O-isopropylidene-
D-glyceraldehyde; during the course of our investigations quite similar chemistry was independently
adopted by Vallee and co-workers in a study designed to provide a general means to prepare γ-amino-
α,β-ethylenic acid derivatives.41
Herein we report in full the stereocontrolled addition of organometallic derivatives of methyl propiolate
to N-benzyl 2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN) 5, which makes it possible to fur-
nish propargyl hydroxylamines in excellent diastereomeric excess. We also explored the transformations
of the products obtained towards 3-pyrrolin-2-ones bearing a polyhydroxylated chain at C-5; the utility
of such compounds has been well-demonstrated by Casiraghi and co-workers in recent years.23,24,34,42
2. Results and discussion
Lithiated methyl propiolate 6a was generated by treatment of methyl propiolate with n-butyllithium
in THF at −80°C. Nitrone 5 was added to the mixture at −80°C, and aqueous work-up after 15 min
provided syn-hydroxylamine 7a in quantitative yield (Scheme 1).
Scheme 1.
The absolute configuration of 7a was established by comparison of the physical and spectroscopic
properties of a further derivative with a known compound (vide infra). The diastereoselectivity was

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 1759–1769
1761
Table 1
Stereoselective addition of metallated methyl propiolates to BIGN 5
sufficiently high so that the minor diastereomer was not observed. In such instances the minimal
diastereomeric ratio is given as >20:1, the limit of detectability by 13C NMR spectroscopy.†
Lithiated derivative 6a also added smoothly to BIGN 5 when the latter was precomplexed with Lewis
acids (Table 1). According to our previous results43 on the addition of organometallic compounds to
5, prior treatment of the nitrone with ZnBr2 also led to the syn-adduct (Table 1, entry 2). Guided by our
previous experiments44 and in order to reverse the diastereoselectivity of the addition, we used Et2AlCl as
a precomplexing agent of the nitrone (Table 1, entries 3 and 4). The syn:anti ratio of 30:70, when diethyl
ether was used as a solvent, demonstrates that Et2AlCl displays reasonable diastereofacial selectivity,
comparable to that of other addition reactions to 5 in the presence of such an additive.43,44 The Grignard
derivative 6b was also examined both in the presence and in the absence of Et2AlCl (Table 1, entries 5
and 6). Slight reductions in both the diastereoselectivities and chemical yields were observed. All these
behaviours are fully consistent with those of the previously reported nucleophilic additions to BIGN
5.38,43–45 In consequence, the results can be rationalized by applying models previously proposed by
us.43
One possible method to convert propargyl hydroxylamines 7 into preparatively useful 3-pyrrolin-2-
ones is the reduction with a considerable excess (20 equiv.) of Zn in the presence of a protic and acidic
solvent system (e.g. AcOH–MeOH, AcOH–H2O or HCO2H–H2O). This strategy has been successfully
applied to propargyl hydroxylamines derived from α-amino nitrones.41
However, when we evaluated this procedure for concomitant reduction and cyclization of 7a, mod-
erately useful results were obtained by using a 1:9 AcOH–MeOH mixture as a solvent, compound 8
being isolated in only 40% chemical yield (Scheme 2). Moreover, the three by-products 9–11 could be
identified from the reaction mixture. Compound 9 was obtained as a consequence of the partial E/Z
selectivity of the reaction. A deacetonization with elimination to the allyl alcohol derivative 10 was also
observed.‡ Likewise, the considerable excess of reducing agent presumably induces partial elimination
of the hydroxyamino moiety, thus leading to 11 which was identified as an E–Z mixture of compounds.
Subjection of hydroxylamine 7b to a range of similar conditions (Table 2), including those using the
Zn–Cu(II) couple (Table 2, entry 4),46 led only to increasing amounts of undesired side products.
In order to circumvent these troubles we turned our attention to the two-step procedure previously
devised in our laboratory.40 The strategy that exclusively provides the cyclized product 8, is outlined in
Scheme 3. Optimum conditions for the reduction of the triple bond involved catalytic hydrogenation at
†
This is the signal-to-noise limit of detection. For previous use of 13C NMR in the determination of diastereomeric ratios see:
Hiemstra, H.; Wynberg, H. Tetrahedron Lett. 1977, 18, 2183–2186.
‡
The E-stereochemistry of the exocyclic double bond in 10 was confirmed by NOE experiments.

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Scheme 2.
Table 2
Reduction of hydroxylamine 7aa
atmospheric pressure using Lindlar’s catalyst for 45 min.¶ This led to intermediate 12 in quantitative
yield, no purification being needed for its further use. Finally, reduction of the hydroxyamino moiety in
12 by using a 20% aqueous solution of TiCl3, as described,47 provided the targeted 3-pyrrolin-2-one 8 in
91% isolated yield after column chromatography. Thus compound 8 has been synthesized in three steps
from BIGN 5 in an overall yield of 91% and with total diastereoselectivity.
Scheme 3.
The unsaturated lactam 8 has proven to be a useful intermediate in organic synthesis (Scheme 3).
Saturated pyrrolidin-2-one 13 was obtained from 8 after catalytic hydrogenation (H2, Pd–C) of the
double bond; subsequent debenzylation by using Li in liquid ammonia furnished deprotected lactam
14. The physical and spectroscopic properties of 14 were identical to those reported in the literature48
¶
It should be noted that this reaction was quite sensitive to reaction time. Hydrogenation for less than 45 min resulted in
recovery of starting material. Above the indicated time an over-reduced product appeared: the longer the reaction time, the
higher the amount of saturated derivative.

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 1759–1769
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for the same compound (see Experimental), thus confirming the syn arrangement of the heteroatoms
at the stereogenic centres. This result also establishes that the previously assigned stereochemistry for
hydroxylamines 7 was correct. Compound 14 was also characterized as the corresponding N-(tert-
butoxycarbonyl) derivative 15. Hydroxylation of 8 was carried out with KMnO4 following Casiraghi’s
conditions.34 A 70:30 mixture of diastereomeric diols 16 was obtained, the stereochemistry of the adducts
being assumed on the basisꢀof§the absolute configuration of the side chain at C-5 and conformational
analysis of 8 using Chem3D™.
In order to illustrate the convenience of the two-step reduction sequence of propargyl hydroxylamines
we also prepared the anti-diastereomer 18 from 7b as indicated in Scheme 4. Hydrogenation of 7b in the
presence of Lindlar’s catalyst was accomplished in 40 min and compound 17 was obtained in quantitative
yield. Treatment of 17 with aqueous TiCl3 afforded anti-18 in 91% isolated yield. The overall yield for
the synthesis of 18 from BIGN 5 was 58.6% (three steps).
Scheme 4.
3. Conclusions
In conclusion, we have developed a short and efficient synthesis (three steps) of epimeric 5-substituted-
3-pyrrolin-2-ones 8 (91% overall yield) and 18 (58.6% overall yield) from the N-benzyl nitrone derived
from 2,3-O-isopropylidene-D-glyceraldehyde. We expect 3-pyrroline-2-ones 8 and 18 to find utility for
the synthesis of highly functionalized pyrrolidines. The efficiency and convenience of this chemistry
recommends this approach for the synthesis of these and related systems.
4. Experimental
4.1. General methods
All moisture-sensitive reactions were performed under an argon atmosphere using oven-dried glass-
ware. Solvents were dried over standard drying agents49 and freshly distilled prior to use. Melting points
are uncorrected. 1H and 13C NMR spectra were recorded on a 300 Varian Unity spectrometer in CDCl3,
at room temperature, unless otherwise specified. Chemical shifts are given in parts per million downfield
from tetramethylsilane. Optical rotations were measured using a Perkin–Elmer 214 polarimeter with a
thermally jacketed 10 cm cell at 25°C (concentration c given as g/100 mL). Elemental analyses were
performed on a 1106 Microanalyzer Carlo Erba. All reactions were monitored by TLC on silica gel
plates (Merck kiesel gel 60 F254) and visualized with iodine or by spraying with 1 M aqueous KMnO4
and heating. Flash column chromatography was performed on silica gel 60 F254.50 N-Benzyl 2,3-O-
isopropylidene-D-glyceraldehyde nitrone 5 was prepared as described.44
§
ꢀ
We use semiempirical methods (MOPAC 97™ꢀ, PM3 and AM1) in Chem3D Pro™ v. 4.0.

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4.2. Methyl (4R,5S)-N-benzyl-5,6-dihydroxy-4-(hydroxyamino)-5,6-O-isopropylidene-2-hexynoate 7a
To a solution of methyl propiolate (0.716 g, 8.52 mmol) in THF (25 mL) at −80°C was added n-
butyllithium (5.4 mL, 1.6 M in hexanes, 8.64 mmol), the resulting solution being stirred for 15 min. A
cold (−80°C) solution of nitrone 5 (1.0 g, 4.26 mmol) in THF (40 mL) was then quickly added with
a cannula over a period of 15 min. The solution turned yellow and orange as the addition progressed.
Stirring at −80°C was continued for an additional 15 min until all the nitrone was consumed (TLC). The
reaction mixture was quenched with saturated NH4Cl (5 mL) and allowed to warm to room temperature.
The reaction mixture was partitioned between Et2O (25 mL) and saturated aqueous NH4Cl (50 mL) and
then shaken vigorously. The layers were separated and the aqueous layer was further extracted with Et2O
(3×25 mL). The organic extracts were combined, washed with brine, dried (MgSO4) and filtered. The
solvent was removed under reduced pressure to give a slightly yellow oil (ds ≥20:1 by NMR). The crude
product was chromatographed on silica gel (hexane:ethyl acetate=85:15) to give the hydroxylamine 7a
1
as a clear oil (1.36 g, 100%): [α]D −49.1 (c 0.36, CHCl3); H NMR (CDCl3) δ 1.27 (s, 3H), 1.31 (s,
3H), 3.69 (d, 1H, J=7.4 Hz), 3.79 (s, 3H), 3.91 (d, 1H, J=12.4 Hz), 3.96 (dd, 1H, J=5.3, 9.0 Hz), 4.08 (dd,
1H, J=6.2, 9.0 Hz), 4.15 (d, 1H, J=12.4 Hz), 4.40 (ddd, 1H, J=5.3, 6.4, 7.4 Hz), 6.20 (bs, 1H, ex. D2O),
7.28–7.35 (m, 5H); 13C NMR (CDCl3) δ 25.5, 26.6, 52.8, 60.5, 62.5, 67.1, 75.1, 79.4, 81.6, 109.9, 127.9,
128.5, 129.6, 135.6, 153.4. Anal. calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found: C, 64.10; H,
6.55; N, 4.61.
4.3. Methyl (4S,5S)-N-benzyl-5,6-dihydroxy-4-(hydroxyamino)-5,6-O-isopropylidene-2-hexynoate 7b
To a well-stirred solution of nitrone 5 (1.0 g, 4.26 mmol) in diethyl ether (80 mL), Et2AlCl (4.3 mmol,
4.3 mL of a 1.0 M solution in hexanes) was added in one portion at room temperature and the resulting
mixture was stirred for 5 min. The mixture was cooled to −80°C and a solution of lithiated methyl
propiolate [prepared as described above from methyl propiolate (0.716 g, 8.52 mmol) and n-butyllithium
(5.4 mL, 1.6 M in hexanes, 8.64 mmol)], was then quickly added with a cannula over a period of 15
min. The mixture was stirred for 1 h at −80°C and then treated with 1 N aqueous NaOH (25 mL). After
additional stirring for 15 min at ambient temperature the mixture was extracted with diethyl ether (3×30
mL). The combined organic extracts were washed with brine, dried (MgSO4) and the solvent evaporated
in vacuo to give the crude product. The diastereoselectivity (ds=70%) was established by NMR analysis.
Purification by column chromatography on silica gel (hexane:diethyl ether=70:30) gave pure 7b (0.88 g,
1
65%) as a white solid: mp 116–118°C; [α]D +6.9 (c 0.35, CHCl3); H NMR (CDCl3) δ 1.35 (s, 3H),
1.45 (s, 3H), 3.64 (dd, 1H, J=7.2 Hz), 3.81 (s, 3H), 3.87 (d, 1H, J=12.9 Hz), 4.01 (dd, 1H, J=4.9, 8.9 Hz),
4.07 (dd, 1H, J=6.1, 8.9 Hz), 4.15 (d, 1H, J=12.9 Hz), 4.41 (ddd, 1H, J=4.9, 6.1, 7.2 Hz), 4.85 (bs, 1H,
ex. D2O), 7.22–7.39 (m, 5H); 13C NMR (CDCl3) δ 25.3, 26.7, 52.8, 61.4, 62.5, 67.2, 75.9, 78.9, 82.3,
110.4, 127.9, 128.6, 129.4, 136.2, 153.6. Anal. calcd for C17H21NO5: C, 63.94; H, 6.63; N, 4.39. Found:
C, 63.79; H, 6.59; N, 4.54.
4.4. Methyl (4R,5S)-(Z)-N-benzyl-5,6-dihydroxy-4-(hydroxyamino)-5,6-O-isopropylidene-2-hexenoate
12
A mixture of the hydroxylamine 7a (0.80 g, 2.50 mmol) and 5% palladium on calcium carbonate,
poisoned with lead (Lindlar’s catalyst) (80 mg) in ethyl acetate (50 mL) was degassed under vacuum
and saturated with hydrogen three times. The resulting suspension was stirred in a Parr hydrogenation
apparatus at ambient temperature for 45 min at atmospheric pressure, then filtered through a plug of

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 1759–1769
1765
Celite, and concentrated to give the crude product, which was purified by column chromatography on
silica gel (hexane:diethyl ether=70:30) to afford 0.804 g (100%) of pure 12 as a colourless oil: [α]D
+69.3 (c 0.22, CHCl3); 1H NMR (CDCl3) δ 11.34 (s, 3H), 1.38 (s, 3H), 3.63 (s, 3H), 3.76 (d, 1H, J=12.2
Hz), 3.82 (dd, 1H, J=6.8, 8.6 Hz), 3.86 (d, 1H, J=12.2 Hz), 3.87 (dd, 1H, J=6.6, 8.6 Hz), 4.37 (ddd, 1H,
J=6.6, 6.8, 7.1 Hz), 4.63 (dd, 1H, J=7.1, 10.1 Hz), 6.11 (d, 1H, J=11.9 Hz), 6.21 (bs, 1H, ex. D2O), 6.53
(dd, 1H, J=10.1, 11.9 Hz), 7.20–7.40 (m, 5H); 13C NMR (CDCl3) δ 25.7, 26.5, 51.2, 62.2, 64.1, 66.4,
76.4, 109.4, 124.2, 127.2, 128.2, 129.4, 137.6, 142.1, 166.2. Anal. calcd for C17H23NO5: C, 63.54; H,
7.21; N, 4.36. Found: C, 63.48; H, 7.00; N, 4.29.
4.5. (5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-pyrrolin-2-one 8
Method A (from 7a). To a solution of the hydroxylamine 7a (1.0 g, 3.14 mmol) in an AcOH:MeOH
(1:9) mixture (10 mL), Zn dust (4.1 g, 62.8 mmol) was added and the mixture was stirred for 60 min at
60°C. After cooling to 0°C the solution was made alkaline (pH=9) by the addition of 1 M NaOH. The
resulting solution was extracted with ethyl acetate (3×20 mL); the combined extracts were washed with
saturated aqueous EDTA (3×25 mL) and with brine (25 mL). The organic layer was dried (MgSO4) and
the solvent evaporated under reduced pressure to give the crude product which was purified by column
chromatography on silica gel (hexane:ethyl acetate=50:50).
Eluted first (Rf=0.75, hexane:ethyl acetate=50:50) was 11 (60:40 mixture of E:Z isomers): 32 mg
(5%). E-Isomer: 1H NMR (CDCl3), selected signals δ 1.37 (s, 3H), 1.41 (s, 3H), 3.10 (m, 2H), 3.61 (m,
1H), 3.67 (s, 3H), 4.04 (m, 1H), 4.50 (m, 1H), 5.60 (m, 1H), 5.90 (dt, 1H, J=7.1, 15.4 Hz). Z-Isomer: 1H
NMR (CDCl3), selected signals δ 1.38 (s, 3H), 1.41 (s, 3H), 3.20 (m, 2H), 3.63 (m, 1H), 3.68 (s, 3H),
4.02 (m, 1H), 4.53 (m, 1H), 5.53 (ddd, 1H, J=7.3, 9.6, 11.0 Hz), 5.80 (dt, 1H, J=7.6, 11.0 Hz).
Eluted second (Rf=0.40, hexane:ethyl acetate=50:50) was 9: 96 mg (10%); oil; [α]D −49.0 (c 0.44,
1
CHCl3); H NMR (CDCl3) δ 1.30 (s, 3H), 1.33 (s, 3H), 2.16 (bs, 1H, ex. D2O), 3.22 (ddd, 1H, J=0.8,
7.0, 8.3 Hz), 3.57 (d, 1H, J=13.4 Hz), 3.74 (s, 3H), 3.75 (dd, 1H, J=5.6, 8.3 Hz), 3.84 (d, 1H, J=13.4 Hz),
3.92 (dd, 1H, J=6.4, 8.3 Hz), 4.04 (ddd, 1H, J=5.6, 6.4, 7.0 Hz), 6.02 (dd, 1H, J=0.8, 15.8 Hz), 6.72 (dd,
1H, J=8.3, 15.8 Hz), 7.22–7.38 (m, 5H); 13C NMR (CDCl3) δ 25.3, 26.7, 51.1, 51.7, 61.6, 66.4, 76.8,
109.7, 124.2, 127.1, 128.1, 128.4, 139.7, 146.5, 166.3. Anal. calcd for C17H23NO4: C, 66.86; H, 7.59; N,
4.59. Found: C, 66.75; H, 7.42; N, 4.71.
Eluted third (Rf=0.25, hexane:ethyl acetate=50:50) was 8: 342 mg (40%); oil; [α]D +32.1 (c 0.75,
1
CHCl3); H NMR (CDCl3) δ 1.29 (s, 3H), 1.40 (s, 3H), 3.48 (dd, 1H, J=5.1, 8.5 Hz), 3.76 (dd, 1H,
J=6.1, 8.5 Hz), 4.06–4.20 (m, 2H), 4.44 (d, 1H, J=15.0 Hz), 4.97 (d, 1H, J=15.0 Hz), 6.30 (dd, 1H, J=1.5,
6.1 Hz), 6.90 (dd, 1H, J=1.5, 6.1), 7.19–7.35 (m, 5H); 13C NMR (CDCl3) δ 24.7, 26.2, 44.9, 64.3, 64.9,
75.5, 110.2, 127.6, 128.0, 128.7, 129.5, 137.6, 143.7, 171.6. Anal. calcd for C16H19NO3: C, 70.31; H,
7.01; N, 5.12. Found: C, 70.46; H, 6.88; N, 5.27.
1
Eluted fourth (Rf=0.12, hexane:ethyl acetate=50:50) was 10: 34 mg (5%); oil; H NMR (CDCl3) δ
2.58 (bs, 1H, ex. D2O), 4.36 (d, 2H, J=7.5 Hz), 4.83 (s, 2H), 5.49 (dt, 1H, J=1.5, 7.5 Hz), 6.31 (dd, 1H,
J=1.5, 5.9 Hz), 7.11–7.29 (m, 5H), 7.32 (d, 1H, J=5.9 Hz); 13C NMR (CDCl3) δ 42.7, 58.1, 113.1, 124.5,
126.8, 127.4, 128.7, 133.1, 136.9, 140.8, 170.3. Anal. calcd for C13H13NO2: C, 72.54; H, 6.09; N, 6.51.
Found: C, 72.65; H, 5.89; N, 6.63.
Method B (from 12). To a solution of 12 (0.8 g, 2.48 mmol) in methanol (10 mL), water (9 mL)
and sodium acetate (2.48 g, 30 mmol) were added and the resulting mixture was vigorously stirred at
ambient temperature while 3.8 mL of a 20% TiCl3 solution in water was added dropwise. After 1 h,
the suspension was poured into 35 mL of water and then extracted with ethyl acetate (3×30 mL). The
combined organic extracts were washed with saturated aqueous sodium bicarbonate (25 mL) and brine

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(25 mL), dried (MgSO4) and evaporated under reduced pressure. Purification of the crude material by
column chromatography (hexane:ethyl acetate=50:50) afforded pure 8 (0.612 g, 91%) as an oil. The
physical and spectroscopic properties of the obtained compound were identical to those of the same
compound obtained from 12 as described above.
4.6. (5R)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-pyrrolidinone 13
A mixture of compound 8 (0.60 g, 2.20 mmol) and 20% palladium on charcoal (50 mg) in methanol
(30 mL) was degassed under vacuum and saturated with hydrogen three times. The resulting suspension
was stirred in a Parr hydrogenation apparatus at ambient temperature for 24 h at atmospheric pressure,
then filtered through a plug of Celite, and concentrated to give the crude product, which was purified
by column chromatography on silica gel (hexane:ethyl acetate=60:40) to afford compound 13 (0.606 g,
1
100%) as an oil: [α]D −134.9 (c 1.17, CHCl3); H NMR (CDCl3) δ 1.30 (s, 3H), 1.35 (s, 3H), 1.55
(dddd, 1H, J=4.9, 6.0, 9.8, 13.3 Hz), 2.00 (dddd, 1H, J=7.3, 8.4, 9.9, 13.3 Hz), 2.36 (ddd, 1H, J=6.0, 9.9,
17.1 Hz), 2.50 (ddd, 1H, J=7.3, 9.8, 17.1 Hz), 3.45 (ddd, 1H, J=4.9, 8.4, 7.5 Hz), 3.53 (dd, 1H, J=6.9, 8.4
Hz), 3.93 (dd, 1H, J=6.6, 8.4 Hz), 4.11 (ddd, 1H, J=6.6, 6.9, 7.5 Hz), 4.34 (d, 1H, J=14.7 Hz), 4.98 (d,
1H, J=14.7 Hz), 7.20–7.31 (m, 5H); 13C NMR (CDCl3) δ 20.6, 25.2, 26.4, 29.9, 45.4, 59.5, 66.3, 79.0,
110.2, 127.3, 128.4, 128.5, 137.3, 175.1. Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09. Found:
C, 69.57; H, 7.52; N, 5.19.
4.7. (5R)-5-[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]-2-pyrrolidinone 14
A solution of pyrrolidinone 13 (0.606 g, 2.20 mmol) in THF (15 mL) was added dropwise to liquid
ammonia (75 mL), cooled to −35°C. Then lithium in small portions was added slowly until a blue colour
persisted for 15 min. At this time absolute ethanol (5 mL) was added and the solution became colourless.
The solvent was evaporated and the residue partitioned between brine (25 mL) and ethyl acetate (25
mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×25 mL). The
combined organic extracts were dried (MgSO4) and concentrated in vacuo. Purification of the residue by
column chromatography (hexane:ethyl acetate=20:80) afforded the saturated lactam 14 (0.354 g, 87%) as
an oil which solidified upon standing: mp 103–105°C; [α]D −52.1 (c 0.67, CHCl3) [lit.48 mp 102–104°C;
[α]D −54 (c 0.10, CHCl3)]; 1H NMR (CDCl3) δ 1.33 (s, 3H), 1.42 (s, 3H), 1.65–1.74 (m, 1H), 2.05–2.15
(m, 1H), 2.20–2.34 (m, 2H), 3.59 (dd, 1H, J=6.2, 8.1 Hz), 3.63 (dd, 1H, J=5.1, 8.1 Hz), 3.92 (pseudo q,
1H, J=6.5 Hz), 4.11 (pseudo q, 1H, J=6.6 Hz), 6.44 (bs, 1H); 13C NMR (CDCl3) δ 20.9, 24.8, 26.6, 28.7,
47.1, 59.4, 79.4, 110.2, 174.8. Anal. calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56. Found: C, 58.19;
H, 7.83; N, 7.74.
4.8. (5R)-1-(tert-Butoxycarbonyl)-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-pyrrolidinone 15
To a solution of 14 (0.354 g, 1.91 mmol) in dichloromethane (30 mL) were added triethylamine (0.27
mL, 1.91 mmol), di-tert-butyldicarbonate (0.83 g, 15.8 mmol), and 4-(dimethylamino)pyridine (0.23 g,
1.91 mmol). The solution was stirred for 7 h at 25°C under an argon atmosphere at which time the
reaction mixture was treated with 1 M aqueous solution of KHSO4 (25 mL). The organic layer was
separated and washed with brine (25 mL), dried (MgSO4) and evaporated under reduced pressure. The
residue was purified by column chromatography (hexane:ethyl acetate=60:40) to give 15 (0.512 g, 94%)
1
as an oil: [α]D +47.9 (c 1.17, CHCl3); H NMR (CDCl3, 55°C) δ 1.26 (s, 3H), 1.31 (s, 3H), 1.47 (s,
9H), 1.90–2.14 (m, 3H), 2.64 (ddd, 1H, J=9.6, 10.6, 17.6 Hz), 3.75 (dd, 1H, J=6.6, 8.8 Hz), 3.90 (dd,

P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 1759–1769
1767
1H, J=6.4, 8.8 Hz), 4.23 (pseudo dt, 1H, J=3.3, 6.5 Hz), 4.31 (ddd, 1H, J=1.7, 3.4, 8.9 Hz); 13C NMR
(CDCl3, 55°C) δ 21.7, 25.3, 25.9, 28.0, 32.2, 57.5, 65.9, 78.4, 82.9, 109.4, 150.6, 174.2. Anal. calcd for
C14H23NO5: C, 58.93; H, 8.12; N, 4.91. Found: C, 59.05; H, 8.26; N, 4.76.
4.9. (3R,4R,5S)-1-Benzyl-3,4-dihydroxy-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-pyrrolidinone 16a
and (3S,4S,5S)-1-benzyl-3,4-dihydroxy-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-pyrrolidinone 16b
To a solution of 8 (0.60 g, 2.20 mmol) in anhydrous dichloromethane (20 mL) were added cis-
dicyclohexano-18-crown-6 ether (0.16 g, 0.44 mmol) and powdered potassium permanganate (0.21 g,
1.31 mmol) under an argon atmosphere at −12°C. After stirring at this temperature for 12 h, a saturated
aqueous Na2SO3 solution and a 5% citric acid solution were added to the reaction mixture. The resulting
mixture was extracted with dichloromethane (3×30 mL) and the combined organic extracts were washed
with brine (30 mL), dried (MgSO4) and evaporated in vacuo. The diastereoselectivity (ds=70%) was
established by NMR analysis. The crude product was chromatographed on silica gel (hexane:ethyl
acetate=40:60) to afford pure diols 16.
Eluted first (Rf=0.32, hexane:ethyl acetate=50:50) was 16a (0.332 g, 49%) as a sticky foam; [α]D
−62.5 (c 0.98, CHCl3); 1H NMR (CDCl3) δ 1.31 (s, 3H), 1.36 (s, 3H), 3.20 (bs, 2H, ex. D2O), 3.40 (d,
1H, J=6.1 Hz), 3.76 (dd, 1H, J=5.0, 8.1 Hz), 4.01–4.10 (m, 3H), 4.21 (d, 1H, J=15.4 Hz), 4.51–4.55 (m,
1H), 5.19 (d, 1H, J=15.4 Hz), 7.20–7.36 (m, 5H); 13C NMR (CDCl3) δ 25.0, 26.3, 45.9, 64.8, 66.8, 69.8,
70.2, 75.0, 110.5, 127.6, 128.1, 128.7, 135.1, 174.3. Anal. calcd for C16H21NO5: C, 62.53; H, 6.89; N,
4.56. Found: C, 62.47; H, 7.09; N, 4.61.
Eluted second (Rf=0.26, hexane:ethyl acetate=50:50) was 16b (0.142 g, 21%) as a sticky oil; [α]D
−31.5 (c 0.65, CHCl3); 1H NMR (CDCl3) δ 1.29 (s, 3H), 1.34 (s, 3H), 2.80 (bs, 2H, ex. D2O), 3.49 (dd,
1H, J=3.8, 8.1 Hz), 3.71 (d, 1H, J=3.8 Hz), 4.03–4.12 (m, 2H), 4.24 (d, 1H, J=14.7 Hz), 4.24–4.31 (m,
2H), 4.90 (d, 1H, J=14.7 Hz), 7.20–7.36 (m, 5H); 13C NMR (CDCl3) δ 25.3, 26.5, 45.2, 62.7, 66.6, 67.3,
70.6, 75.9, 109.7, 127.4, 128.3, 128.4, 136.9, 174.0. Anal. calcd for C16H21NO5: C, 62.53; H, 6.89; N,
4.56. Found: C, 62.67; H, 7.14; N, 4.39.
4.10. Methyl (4S,5S)-(Z)-N-benzyl-5,6-dihydroxy-4-(hydroxyamino)-5,6-O-isopropylidene-2-hexenoate
17
The hydroxylamine 7b (0.8 g, 2.50 mmol) was treated as described above for the preparation of 12.
Column chromatography on silica gel (hexane:diethyl ether=70:30) of the crude product gave 0.803 g
1
(100%) of 16 as a white solid: mp 83°C; [α]D −80.5 (c 0.41, CHCl3); H NMR (CDCl3) δ 1.31 (s,
3H), 1.34 (s, 3H), 3.66 (s, 3H), 3.82 (s, 2H), 3.95 (dd, 1H, J=5.8, 8.6 Hz), 4.07 (dd, 1H, J=6.2, 8.6 Hz),
4.41 (ddd, 1H, J=5.8, 6.2, 6.6 Hz), 4.69 (ddd, 1H, J=0.8, 6.6, 10.0 Hz), 4.98 (bs, 1H, ex. D2O), 6.10
(dd, 1H, J=0.8, 11.8 Hz), 6.59 (dd, 1H, J=10.0, 11.8 Hz), 7.22–7.29 (m, 5H); 13C NMR (CDCl3) δ 25.4,
26.3, 51.3, 62.0, 65.6, 67.6, 76.6, 109.5, 124.4, 127.3, 128.3, 129.4, 137.7, 143.1, 166.4. Anal. calcd for
C17H23NO5: C, 63.54; H, 7.21; N, 4.36. Found: C, 63.62; H, 7.43; N, 4.49.
4.11. (5S)-1-Benzyl-5-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-pyrrolin-2-one 18
The hydroxylamine 17 (0.8 g, 2.48 mmol) was treated as described above for the preparation of 8.
Column chromatography on silica gel (hexane:ethyl acetate=50:50) of the crude product gave 0.62 g
(91%) of 18 as an oil; [α]D −20.3 (c 1.05, CHCl3); 1H NMR (CDCl3) δ 1.30 (s, 3H), 1.41 (s, 3H), 3.64
(dd, 1H, J=6.0, 8.5 Hz), 3.92 (dd, 1H, J=6.6, 8.5 Hz), 4.12 (dd, 1H, J=1.8, 6.0 Hz), 4.25 (d, 1H, J=15.1

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P. Merino et al. / Tetrahedron: Asymmetry 9 (1998) 1759–1769
Hz), 4.26 (ddd, 1H, J=1.8, 6.0, 6.6 Hz), 5.20 (d, 1H, J=15.1 Hz), 6.26 (dd, 1H, J=1.7, 6.0 Hz), 6.99 (dd,
1H, J=1.7, 6.0 Hz), 7.20–7.37 (m, 5H); 13C NMR (CDCl3) δ 24.6, 26.0, 44.7, 63.1, 65.3, 74.8, 109.7,
127.5, 128.0, 128.5, 128.7, 137.3, 144.7, 172.1. Anal. calcd for C16H19NO3: C, 70.31; H, 7.01; N, 5.12.
Found: C, 70.57; H, 7.21; N, 4.98.
Acknowledgements
Financial support from DGICYT (MEC, Madrid, Spain) is gratefully acknowledged. One of us (S.F.)
also acknowledges the Ministerio de Educacion y Cultura (Madrid, Spain) for a contract.
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