Chiral 3-hydroxypyrrolidin-2-ones from a Baylis-Hillman adduct: Convergent, stereoselective synthesis of a glycosidase inhibitor

Article abstract of DOI:10.1016/j.tetasy.2004.08.016

The O-silyl derivative 4b, prepared starting from the Baylis-Hillman adduct 4a, underwent cyclization on treatment with (S)-phenylethylamine, to give to an equimolar mixture of the 4,5-cis-disubstituted pyrrolidin-2-ones 9 and 10, exclusively, which after

Full text of DOI:10.1016/j.tetasy.2004.08.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3249–3256
Chiral 3-hydroxypyrrolidin-2-ones from a Baylis–Hillman
adduct: convergent, stereoselective synthesis of a glycosidase
inhibitor
Roberta Galeazzi, Gianluca Martelli, Giovanna Mobbili,
Mario Orena* and Samuele Rinaldi
`
Dipartimento di Scienze dei Materiali e della Terra, Universita Politecnica delle Marche, Via Brecce Bianche, I-60131 Ancona, Italy
Received 16 July 2004; accepted 2 August 2004
Available online 1 October 2004
Abstract—The O-silyl derivative 4b, prepared starting from the Baylis–Hillman adduct 4a, underwent cyclization on treatment with
(S)-phenylethylamine, to give to an equimolar mixture of the 4,5-cis-disubstituted pyrrolidin-2-ones 9 and 10, exclusively, which
after separation by silica gel chromatography were both converted into the 3-hydroxy-4-hydroxymethylpyrrolidine 1 a glycosidase
inhibitor.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
HO
OH
In recent years, new approaches to 3-hydroxy-4-
hydroxymethyl pyrrolidin-2-ones have been reported,
since these products are useful intermediates to bioactive
compounds with interesting pharmacological proper-
ties.1 Moreover polyhydroxy pyrrolidin-2-ones can be
precursors to polyhydroxy pyrrolidines, that are iso-
steres of pentoses, the removal of the carbonyl group
being a well-established pathway.2 These latter com-
pounds are inhibitors of glycosidases, enzymes that are
present in almost all organisms and are essential in
processing oligo- and polysaccharides, glycolipids and
glycoproteins,3 whereas their inhibition allows obesity,
diabetes and other metabolic disorders to be controlled.4
In addition, infection and inflammation can be pre-
vented, since these products block the biogenesis of
membrane glycoproteins in fungi, bacteria and viruses.5
Within this class, compound 1 has been prepared in
enantiomerically pure form and displays activity as an
inhibitor of glycosidases and could be employed as an
antiviral drug (Fig. 1).6,7
N
H
1
Figure 1.
2. Results and discussion
Recently, 3,4-disubstituted pyrrolidin-2-ones have at-
tracted an increased attention in our group in connec-
tion with the design of conformationally restricted
analogs of bioactive amino acids.8 Moreover, 4-
hydroxymethyl pyrrolidin-2-ones were employed as
intermediates in the synthesis of bioactive nonproteino-
genic amino acids.9 In this context, and as a part of a re-
search program aimed at the synthesis of new
peptidonucleic acids, we first devised that the reaction
of the anion of the chiral pyrrolidin-2-one 29 with oxaz-
iridine10,11 or MoOPD12 could afford the compound 3
suitable to be converted into 1. However, this product
was invariably obtained in very low yield as an erratic
diastereomeric mixture whose chromatographic separa-
tion was very difficult (Scheme 1).
Thus, we envisaged that compound 1 could be obtained
in enantiomerically pure form starting from the Baylis–
Hillman adduct 4.13–15 However, when 4a was treated
with (S)-phenylethylamine,16 an equimolar mixture of
*
Corresponding author. Tel.: +39 071 2204720; fax: +39 071
2204714; e-mail: m.orena@univpm.it
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.016

3250
R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
by the conformational search performed either in polar
HO
OBn
OBn
and apolar medium for the analogous compound where
OMe was changed for OTBDMS.20 In fact in all the
most stable conformers an intramolecular H-bond takes
place leading to a chair-like six-membered ring (interme-
diate A), whose protonation gives the more stable
di-equatorial substitution pattern (Scheme 3).
i
O
N
O
N
3
2
Ph
Ph
Scheme 1. Reagents and conditions: (i) LiHDMS, THF, ꢀ78ꢁC, then
phenyloxaziridine or MoOPD, 10–15% yield as inseparable diastereo-
meric mixture.
O
MeO
COOEt
4b
+
pyrrolidin-2-ones 5–8 was obtained and only compound
8 could be separated by silica gel chromatography, the
rest being an inseparable mixture of 5–7.17 Thus, in
order to improve the stereoselection of the cyclization,
the derivative 4b, easily prepared starting from 4a,
underwent cyclization with (S)-phenylethylamine lead-
ing to an equimolar mixture of cis-3,4-disubstituted dia-
stereomeric pyrrolidin-2-ones, 9 and 10 (Scheme 2).
H
OTBDMS
N
H
(S)-phenylethylamine
A
Ph
COOEt
OTBDMS
MeOOC
H
N
Ph
COOMe
COOMe
HO
O
HO
O
9
OTBDMS
COOMe
+
+
N
N
N
N
6
5
EtOOC
Ph
Ph
Ph
Ph
HN
COOMe
HO
COOMe
HO
O
Ph
O
Scheme 3.
7
8
On the contrary, the conformational search carried out
on the adduct 4a in both polar and apolar medium, evi-
denced that within 25kJ/mol stable conformations hav-
ing an intramolecular H-bond between the hydroxy and
the methoxycarbonyl groups are not present. Thus, a
six-membered ring cannot arise, probably due to the
constrictions of the conjugate planar moiety. Moreover,
the most stable conformers of the Baylis–Hillman ad-
duct 4a21 in both polar and apolar medium showed an
intramolecular H-bond, involving both the hydroxy
and the ethoxycarbonyl groups, leading a very stable
five-membered ring. This result is in agreement with
the absorptions observed in the FT-IR spectra
(1732cmꢀ1 for 4a vs 1740cmꢀ1 for 4b), that remain un-
changed when methanol is changed for chloroform.
After conjugate addition, both diastereotopic faces of
the enolate anion B are similarly hindered as evidenced
by three very similar conformers observed within
0.64kcal/mol.22,23 Therefore protonation of the enolate
anion can occur from both sides, leading to both iso-
mers 5 and 6 (or to 7 and 8, depending on the configu-
ration at C-2), via the products C and D, respectively,
that were not isolated. This latter process is much faster
than formation of hydrogen bond between alcoholic
oxygen and ammonium ion, which would constrain
the intermediate to a six-membered ring (Scheme 4).
i
OR
COOMe
EtOOC
4 a, R = H
b, R = TBDMS
ii
RO
RO
O
COOMe
COOMe
+
O
10
N
N
9
Ph
Ph
Scheme 2. Reagents and conditions: (i) R = H (S)-phenylethylamine,
MeOH, rt, 20h, 8 (21% by silica gel chromatography, the rest being an
inseparable mixture of compound 5, 6 and 7). (ii) R = TBDMS. (a) (S)-
Phenylethylamine, MeOH, rt, 24h; (b) refluxing toluene, 4h, 9 (40%),
10 (38%).
After separation by silica gel chromatography, the con-
figurational assignment of products 9 and 10 was made
on the basis of 1H NMR spectral data and supported by
NOE experiments.18 The stereoselective formation of
cis-isomers 9 and 10 can be explained by inspection of
the reaction intermediates, supported by molecular
mechanics calculations.19 In fact, the conjugate addition
of (S)-phenylethylamine to 4b seems to be directed by a
hydrogen bond involving both the amino group and
the oxygen of the silyl ether, leading to a six-membered
enolate intermediate. This hypothesis was confirmed
Thus, having both 9 and 10 in hand, a stereoconvergent
route was carried out in order to obtain product 1. In
fact, when pyrrolidin-2-one 9 was treated with an equi-
molar amount of NaBH4 in dry ethanol, the corre-
sponding trans-3,4-disubstituted derivative 11 was

R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
HO COOCH3
3251
HO
COOCH3
OEt
O
iii
iv
H
O
O
N
N
H
H
OH
MeOOC
12
13
N
Ph
Ph
v
Ph
MeOOC
H
O
+
4a
H
9
COOEt
RO
RO
(S)-phenylethylamine
OH
OR
vi
i
ii
O
O
N
N
OH
OH
11
R = TBDMS
14
COOMe
COOMe
Ph
Ph
EtOOC
EtOOC
HN
+
AcO
HN
OAc
vii
C
D
1
HCl
Ph
Ph
N
15
Ph
5
6
Scheme 5. Reagents and conditions: (i) NaBH4, dry ethanol, 0ꢁC, 12h,
81%. (ii) TBDMSCl, imidazole, DCM, rt, 5h, 93%. (iii) 6M HCl,
MeOH, rt, 12h, 88%. (iv) DBU, toluene, 70ꢁC, 12h, 80%. (v) (a)
LiAlH4, THF, 0ꢁC, 2h; (b) TBDMSCl, imidazole, DCM, rt, 5h, 78%.
(vi) (a) LiAlH4, refluxing THF; (b) AcCl, Et3N, DMAP, DCM, 0ꢁC,
2h, 65%. (vii) (a) Chloroethylchlorocarbonate, DCM, 0ꢁC, 30min; (b)
refluxing methanol, 40min; (c) 12M HCl, MeOH, rt, 1h, 68%.
Scheme 4.
obtained in high yield,24 and the epimerization at C-4,
which precedes the reduction step, was ascribed to a
small amount of sodium alkoxide in the reaction mix-
ture. The configurational assignment of 11 was per-
formed by means of NOE effects and eventually
confirmed by the known specific rotatory power of 1.
In fact, desilylation of the ester 9, performed with 6M
HCl in methanol, afforded the corresponding cis-hydr-
oxy ester 12, which by treatment with DBU in toluene
at 70ꢁC was quantitatively isomerized to the corre-
sponding trans-derivative 13. Subsequent treatment with
LiAlH4 followed by silylation of the raw reaction prod-
uct gave 14, which was identical with the compound
obtained by silylation of 11. Deoxygenation and cleav-
age of the silyl protecting groups, performed with
LiAlH4 in refluxing THF,25 afforded the aminodiol,
which was isolated as the corresponding diacetyl deriva-
tive 15.
TBDMSO
OR
iii
i
ii
10
O
N
16, R = H
17, R = Bn
Ph
HO
HO
OBn
iv
OBn
v
HCl
1
O
N
N
18
19
Ph
Ph
Scheme 6. Reagents and conditions: (i) LiAlH4, THF, 0ꢁC, 80%. (ii) n-
BuLi, THF, 0ꢁC, 5min, then BnBr, refluxing THF, 80%. (iii) KOH,
refluxing MeOH–H2O, 30h, 58%. (iv) LiAlH4, refluxing THF. (v) (a)
Pd(OH)2, 20% on C, H2; (b) 3M HCl, 94%.
Removal of the phenylethyl group was performed by
reaction with chloroethyl chloroformate26 and eventual
treatment of the raw reaction product with 12M HCl
gave 1 as hydrochloride, whose physical and spectral
data were identical with those reported in the literature
(Scheme 5).
separation of 8 from the reaction mixture, followed by
silylation leading to 10, the products 5–7 were silylated
and the mixture, containing 9, 20 and 21, was treated
with LiAlH4 at 0ꢁC. Under these conditions, both
trans-derivatives 20 and 21 were converted into the
hydroxymethyl derivatives 11 and 22, respectively,
whereas the ester 9 remained unchanged, and all com-
pounds could be separated by silica gel chromatography
(Scheme 7).27 Therefore, since compounds 9, 10 and 11
were converted into 1 as described above, the cyclization
carried out starting from the adduct 4a could also be
effective for the preparation of 1, but the sole product
22 proved useless to this goal.
With product 1 in hand, we focused our attention on the
synthesis of 1 starting from the pyrrolidin-2-one 10. A t
first, compound 10 was converted into the hydroxy-
methyl derivative 16, which, after benzylation, gave
the benzyloxymethyl derivative 17. Epimerization at C-
3, performed with methanolic KOH, afforded the
trans-isomer 18 since complete removal of the protecting
group TBDMS occurred under reaction conditions.
Eventual reduction of the lactam to pyrrolidine, fol-
lowed by removal of the protecting groups, led to 1 in
good yield as the corresponding hydrochloride (Scheme
6).
3. Conclusions
Next, we explored a simple conversion of compounds 5–
8, arising from the cyclization of 4a, into 1. Thus, after
An efficient, stereoselective strategy exploiting the Bay-
lis–Hillman adducts 4a and 4b allowed chiral 3,4-disub-

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R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
4.3. 1-Ethyl-4-methyl-2-tert-butyldimethylsilyloxy-3-
methylenebutanedioate 4b
5 + 6 + 7
i
To a solution containing the ester 4a (2.5g; 37mmol)
and imidazole (2.5g; 37mmol) in DCM (35mL) at rt,
tert-butyldimethylchlorosilane (5.6g; 37mmol) was
added, and the mixture was stirred for 4h. After re-
moval of the solvent under reduced pressure, the residue
was dissolved in ethyl acetate (50mL), brine (50mL) was
added and the mixture was extracted with ethyl acetate
(2 · 100mL). After drying (Na2SO4), the solvent was re-
moved in vacuo and the residue was purified by silica gel
chromatography (cyclohexane:ethyl acetate 90:10), to
give the compound 4b (8.6g; 95% yield) as a colorless
COOMe RO
COOMe
RO
ii
+
O
N
9
O
N
+
21
20
Ph
Ph
R = TBDMS
RO
RO
OH
OH
+
O
N
O
N
+
9
11
22
Ph
Ph
1
oil. IR (neat): 1740, 1639cmꢀ1. H NMR: 0.06 (s, 3H),
Scheme 7. Reagents and conditions: (i) TBDMSCl, imidazole, DCM,
rt, 91%. (ii) LiAlH4, THF, 0ꢁC, 40min, 9 (18%), 11 (23%), 22 (21%).
0.10 (s, 3H), 0.87 (s, 9H), 1.21 (t, 3H, J = 7.1), 3.72 (s,
3H), 4.13 (q, 2H, J = 7.1), 5.03 (s, 1H), 6.0 (s, 1H),
6.31 (s, 1H); 13C NMR: ꢀ5.4, ꢀ5.2, 13.9, 25.5, 51.8,
61.1, 70.1, 125.9, 138.9, 165.8, 170.5. EIMS: m/z 288
(2, MH+ꢀ15), 246 (39), 189 (34), 174 (43), 157 (57), 74
(100). Anal. Calcd for C14H26O5Si: C, 55.60; H, 8.66.
Found: C, 55.56; H, 8.61.
stituted c-lactams and pyrrolidines, which converged to
the glycosidase inhibitor 1, to be prepared. The applica-
tion of this method to the preparation of new peptido-
nucleic acids and peptidomimetics is currently
underway and results will be reported in due course.
4.4. (3S,4S,10S)-3-Hydroxy-4-methoxycarbonyl-1-(10-
phenylethyl)pyrrolidin-2-one 8
4. Experimental
4.1. General
To a solution containing the ester 4a (3.76g; 20mmol) in
dry MeOH (20mL), (S)-phenylethylamine (2.4g;
20mmol) was added at rt and the mixture was stirred
for 20h. After removal of the solvent under reduced
pressure, the residue was dissolved in ethyl acetate
(50mL) that was washed with 3M HCl. The solvent
was dried (Na2SO4) and evaporated in vacuo and the
residue was purified by silica gel chromatography (cyclo-
hexane:ethyl acetate 60:40) to give pure pyrrolidin-2-one
8 (1.1g; 21% yield) as a crystalline solid (mp 73–75ꢁC),
the rest being an inseparable mixture of compounds 5, 6
and 7. 1H NMR: 1.54 (d, 3H, J = 7.1), 3.19–3.43 (m, 4H,
3H + OH), 3.59 (s, 3H), 4.58 (d, 1H, J = 7.9), 5.49 (q,
1H, J = 7.1), 7.20–7.37 (m, 5 ArH); 13C NMR: 16.0,
41.6, 42.9, 49.4, 51.8, 70.8, 127.1, 127.5, 128.3, 138.7,
170.5, 172.3; [a]D = ꢀ187.9 (c 1.1, CHCl3); EIMS: m/z
263 (3, M+), 246 (4), 221 (8), 187 (21), 134 (16), 121
(19), 106 (70), 70 (100). Anal. Calcd for C14H17NO4:
C, 63.87; H, 6.51; N, 5.32. Found: C, 63.83; H, 6.46;
N, 5.26.
Melting points were measured on an Electrothermal IA
9000 apparatus and are uncorrected. IR spectra were re-
corded in CHCl3 on a Nicolet Fourier Transform Infra-
red 20-SX spectrophotometer. Unless otherwise noted,
1
NMR spectra (200MHz for H, 50MHz for 13C, chem-
ical shifts as ppm in the d scale, coupling constants J in
Hz) were recorded at 25ꢁC in CDCl3 solutions on a
Varian Gemini 200 spectrometer. Diastereomeric purity
was determined by GLC analysis by using a Chrompack
9001 gas-chromatograph equipped with a capillary col-
umn Chrompack 7720 (50m · 0.25mm i.d.; stationary
phase CP-Sil-5 CB). Optical rotations were measured
on a Perkin–Elmer 241 polarimeter. EIMS analyses were
carried out on a Hewlett–Packard spectrometer model
5890, series II. Column chromatography was performed
using Kieselgel 60 Merck (230–400 mesh ASTM).
4.2. 1-Ethyl-4-methyl-2-hydroxy-3-methylenebutanedio-
ate 4a
4.5. (3R,4R,10S)-3-tert-Butyldimethylsilyloxy-4-meth-
oxycarbonyl-1-(10-phenylethyl)pyrrolidin-2-one 9 and its
(3S,4S,10S)-isomer 10
In a one-necked flask (100mL) ethyl glyoxylate (50%
solution in toluene, 20.4g; 100mmol), methyl acrylate
(8.6g; 100mmol) and DABCO (1.0g; 10mmol) were
added and the mixture was allowed to react for 12h.
The oil was then purified by silica gel chromatography
(cyclohexane:ethyl acetate 80:20) to give 4a (11.8g;
63% yield) as a colorless oil. IR (neat): 3490, 1732,
To a solution containing the silyl derivative 4b (6.0g;
20mmol) in methanol (50mL), (S)-phenylethylamine
(2.4g; 20mmol) was added and the mixture was stirred
for 24h at rt. After removal of the solvent, the residue
was dissolved in toluene (50mL) and the solution was
refluxed for 4h. The solvent was then evaporated under
reduced pressure, and the residue was dissolved in ethyl
acetate (50mL) that was washed with 3M HCl. The sol-
vent was dried (Na2SO4) and evaporated in vacuo and
the residue was purified by silica gel chromatography
(cyclohexane:ethyl acetate 90:10), to give compound 9
(2.1g; 40% yield) as a yellow oil. Further elution gave
1636cmꢀ1 1H NMR: 1.24 (t, 3H, J = 7.2), 3.51 (d,
.
1H, OH, J = 6.2), 3.76 (s, 3H), 4.22 (q, 2H, J = 7.2),
4.83 (d, 1H, J = 6.2), 5.92 (s, 1H), 6.34 (s, 1H); 13C
NMR: 14.0, 52.0, 62.2, 71.2, 128.8, 138.1, 165.6,172.2;
EIMS: m/z 188 (2, M+), 143 (22), 116 (40), 84 (100).
Anal. Calcd for C8H12O5: C, 51.06; H, 6.43. Found:
C, 51.01; H, 6.39.

R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
3253
compound 10 (2.0g; 38% yield) as a yellow oil. EIMS:
m/z 378 (1, MH+), 363 (2), 321 (40), 218 (16), 217 (100),
160 (15), 106 (88). Anal. Calcd for C20H31NO4Si: C,
63.63; H, 8.28; N, 3.71. Found: C, 63.57; H, 8.32; N,
3.66. Compound 9: 1H NMR: 0.14 (s, 3H), 0.18 (s, 3H),
0.88 (s, 9H), 1.56 (d, 3H, J = 7.2), 2.99 (dd, 1H, J = 7.3.
J = 9.4), 3.04–3.16 (m, 1H), 3.87 (s, 3H), 3.69 (dd, 1H,
J = 7.6, J = 9.4), 4.45 (d, 1H, J = 6.7), 5.44 (q, 1H,
J=7.2), 7.23–7.36 (m, 5 ArH); 13C NMR: ꢀ5.6, ꢀ4.7,
15.5, 25.5, 41.2, 44.1, 49,3, 51.6, 72.1, 127.0, 127.5,
128.5, 139.5, 169.7, 170.3; [a]D = ꢀ33.1 (c 8.1, CHCl3).
M+), 246 (4), 221 (8), 187 (21), 134 (16), 121 (19), 106
(70), 70 (100). Anal. Calcd for C14H17NO4: C, 63.87;
H, 6.51; N, 5.32. Found: C, 63.81; H, 6.47; N, 5.28.
4.8. (3R,4S,10S)-3-Hydroxy-4-methoxycarbonyl-1-(10-
phenylethyl)pyrrolidin-2-one 13
To a solution containing the ester 12 (1.3g, 5.0mmol) in
toluene (50mL), DBU (0.75g, 5.0mmol) was added and
the mixture was stirred at 70ꢁC for 12h. Then ethyl ace-
tate (50mL) was added and the organic layer was
washed with 3M HCl (15mL). After drying (Na2SO4)
and removal of the solvents, the residue was purified
by silica gel chromatography (cyclohexane:ethyl acetate
50:50), to give 13 (1.05g; 80%) yield as a colorless oil. 1H
NMR: 1.56 (d, 3H, J = 7.1), 2.12 (br s, 1H, OH), 2.95–
3.10 (m, 1H), 3.19 (dd, 1H, J = 8.5, J = 8.5), 3.54 (dd,
1H, J = 8.5, J = 8.5), 3.71 (s, 3H), 4.61 (d, 1H,
J = 8.5), 5.47 (q, 1H, J = 7.1), 7.20–7.38 (m, 5 ArH);
13C NMR: 15.8, 41.2, 45.9, 50.0, 52.4, 72.5, 127.0,
127.8, 128.5, 128.6, 128.7, 138.8, 171.7, 172.5;
[a]D = ꢀ27.8 (c 1.0, CHCl3); EIMS: m/z 263 (3, M+),
246 (4), 221 (8), 187 (21), 134 (16), 121 (19), 106 (70),
70 (100). Anal. Calcd for C14H17NO4: C, 63.87; H,
6.51; N, 5.32. Found: C, 63.83; H, 6.47; N, 5.28.
1
Compound 10: H NMR: 0.13 (s, 3H), 0.17 (s, 3H),
0.84 (s, 9H), 1.53 (d, 3H, J = 7.1), 3.14–3.26 (m, 1H),
3.30 (dd, 1H, J = 9.5, J = 9.6), 3.39 (dd, 1H, J = 6.8,
J = 9.6), 3.63 (s, 3H), 4.47 (d, 1H, J = 6.4), 5.45 (q, 1H,
J = 7.1), 7.25–7.35 (m, 5 ArH); 13C NMR: ꢀ5.6, ꢀ4.7,
16.2, 25.4, 41.2, 44.3, 48.9, 51.6, 72.1, 126.9, 127.0,
127.4, 128.3, 139.2, 169.6, 170.6; [a]D = ꢀ148.8 (c 3.0,
CHCl3).
4.6. (3R,4R,10S)-3-tert-Butyldimethylsilyloxy-4-hydroxy-
methyl-1-(10-phenylethyl)pyrrolidin-2-one 11
To a solution containing compound 9 (1.13g; 3mmol) in
dry ethanol (10mL) NaBH4 (0.48g; 12mmol) was added
at rt. After 6h, the reaction mixture was poured in water
(30mL) and extracted with ethyl acetate (3 · 25mL).
After drying (Na2SO4), the solvent was removed under
reduced pressure and the residue was purified by silica
gel chromatography (cyclohexane:ethyl acetate 80:20),
to give pure 11 (0.85g; 81% yield) as a white solid. Mp
4.9. (3R,4R,10S)-3-tert-Butyldimethylsilyloxy-4-tert-but-
yldimethylsilyloxymethyl-1-(10-phenylethyl)pyrrolidin-2-
one 14 from 11
To
3.0mmol) in DCM (20mL) imidazole (0.2g; 3.0mmol)
and subsequently tert-butyldimethylchlorosilane
a solution containing compound 11 (1.05g;
1
84–86ꢁC. H NMR: 0.20 (s, 3H), 0.26 (s, 3H), 0.98 (s,
9H), 1.57 (d, 3H, J = 7.2), 2.21 (br s, 1H, OH), 2.31–
2.49 (m, 1H), 2.73 (dd, 1H, J = 8.5, J = 9.8), 3.42 (dd,
1H, J = 8.1, J = 9.8), 3.63 (dd, 1H, J = 6.8, J = 10.5),
3.81 (dd, 1H, J = 4.5, J = 10.5), 4.18 (d, 1H, J = 8.3),
5.49 (q, 1H, J = 7.2), 7.28–7.43 (m, 5 ArH); 13C NMR:
ꢀ5.2, ꢀ4.1, 16.0, 25.8, 41.4, 44.6, 49.4, 61.9, 73.1,
127.1, 127.5, 128.5, 139.8, 172.5; [a]D = ꢀ68.7 (c 1.0,
CHCl3); EIMS: m/z 335 (2, MH+ꢀ15), 293 (81), 150
(16), 122 (13), 106 (100), 70 (74). Anal. Calcd for
C19H31NO3Si: C, 65.29; H, 8.94; N, 4.01. Found: C,
65.25; H, 8.88; N, 4.08.
(0.44g; 3.0mmol) were added at rt. After 5h the mixture
was poured in ice water and extracted with ethyl acetate
(3 · 30mL). The solvent was dried (Na2SO4) and after
evaporation under reduced pressure the residue was
purified by silica gel chromatography (cyclohexane:ethyl
acetate 70:30), to give the compound 14 (1.3g; 93%
yield) as a colorless oil. 1H NMR: ꢀ0.07 (s, 3H),
ꢀ0.03 (s, 3H), 0.15 (s, 3H), 0.22 (s, 3H), 0.78 (s, 9H),
0.92 (s, 9H), 1.53 (d, 3H, J = 7.1), 2.18–2.37 (m, 1H),
2.72 (dd, 1H, J = 8.2, J = 9.5), 3.24 (dd, 1H, J = 8.6,
J = 9.5), 3.61 (d, 2H, J = 4.3), 4.24 (d, 1H, J = 8.1),
5.47 (q, 1H, J = 7.1), 7.18–7.42 (m, 5 ArH); 13C NMR:
ꢀ5.7, ꢀ5.6, ꢀ5.2, ꢀ4.1, 15.9, 25.7, 25.8, 40.8, 44.3,
49.2, 60.7, 72.1, 127.0, 127.4, 128.5, 140.0, 172.7;
[a]D = ꢀ28.7 (c 1.0, CHCl3); EIMS: m/z 464 (1, MH+),
348 (6), 219 (32), 187 (23), 121 (16), 106 (100). Anal.
Calcd for C25H45NO3Si2: C, 64.74; H, 9.78; N, 3.02.
Found: C, 64.69; H, 9.73; N, 3.06.
4.7. (3R,4R,10S)-3-Hydroxy-4-methoxycarbonyl-1-(10-
phenylethyl)pyrrolidin-2-one 12
To a solution containing compound 9 (2.26g; 6.0mmol)
in MeOH (15mL), 6M HCl (10mL) was added and the
mixture was stirred for 12h at rt. Then MeOH was par-
tially removed under reduced pressure and the mixture
was extracted with ethyl acetate (2 · 50mL). After dry-
ing (Na2SO4), the solvent was removed under reduced
pressure and the residue was purified by silica gel chro-
matography (cyclohexane:ethyl acetate 50:50), to give
the compound 12 (1.39g; 88% yield) as a colorless oil.
1H NMR: 1.60 (d, 3H, J = 7.3), 3.04 (dd, 1H, J = 7.1,
J = 10.1), 3.30 (ddd, 1H, J = 4.1, J = 7.1, J = 7.8), 3.53
(br s, 1H, OH), 3.64 (dd, 1H, J = 4.1, J = 10.1), 3.74
(s, 3H), 4.56 (d, 1H, J = 7.8), 5.47 (q, 1H, J = 7.3),
7.22–7.42 (m, 5 ArH); 13C NMR: 15.5, 41.8, 42.9,
49.7, 52.0, 70.8, 127.0, 127.7, 128.6, 139.1, 170.5,
171.9; [a]D = ꢀ72.6 (c 1.1, CHCl3); EIMS: m/z 263 (3,
4.10. (3R,4R,10S)-3-tert-Butyldimethylsilyloxy-4-tert-
butyldimethylsilyloxymethyl-1-(10-phenylethyl)pyrrolidin-
2-one 14 from 13
To
a solution containing compound 13 (1.18g;
4.5mmol) in dry THF (10mL), LiAlH4 (0.19g;
4.5mmol) was added under stirring at 0ꢁC and then
temperature raised to rt. After 1h, methanol (1mL)
was added, followed by 3M HCl (20mL). The mixture
was then extracted with ethyl acetate (3 · 50mL), the
solvent was dried (Na2SO4) and removed under

3254
R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
reduced pressure. The residue was dissolved in DCM
(20mL) containing imidazole (0.61g; 9.0mmol) and
subsequently tert-butyldimethylchlorosilane (1.36g;
9.0mmol) was added at rt. After 6h the mixture was
poured in ice water and extracted with ethyl acetate
(3 · 50mL). The solvent was dried (Na2SO4) and after
evaporation under reduced pressure the residue was
purified by silica gel chromatography (cyclohexane:ethyl
acetate 70:30), to give the compound 14 (1.37g; 78%
yield) as a colorless oil. EIMS: m/z 464 (1, MH+), 348
(6), 219 (32), 187 (23), 121 (16), 106 (100). Anal. Calcd
for C25H45NO3Si2: C, 64.74; H, 9.78; N, 3.02. Found:
C, 64.70; H, 9.83; N, 2.98.
4.43 (m, 1H); 13C NMR (D2O, DSS): 46.5, 47.8, 52.0,
60.8, 71.8; [a]D = +18.3 (c 0.7, CH3OH) [lit.6b +19.0 (c
1.0, CH3OH)]; EIMS (CI): m/z 118 (MH+), 100, 82.
4.13. (3S,4R,10S)-3-tert-Butyldimethylsilyloxy-4-
hydroxymethyl-1-(10-phenylethyl)pyrrolidin-2-one 16
To a solution containing compound 10 (1.5g; 4.0mmol)
in dry THF (15mL), LiAlH4 (0.17g; 4.0mmol) was
added at 0ꢁC. After 3h methanol (1mL) was added fol-
lowed by a saturated solution of Seignette salt (20mL).
The mixture was then extracted with ethyl acetate
(3 · 50mL), the organic layer dried (Na2SO4) and even-
tually removed under reduced pressure. The residue was
purified by silica gel chromatography (cyclohexane:ethyl
acetate 70:30), to give the product 16 (1.12g; 80% yield)
4.11. (3R,4R,10S)-3-Acetoxy-4-acetoxymethyl-1-(10-phen-
ylethyl)pyrrolidine 15
1
as a colorless oil. H NMR: 0.19 (s, 3H), 0.22 (s, 3H),
To
a
solution containing compound 14 (1.37g;
0.91 (s, 9H), 1.48 (d, 3H, J = 7.1), 2.41–2.54 (m, 1H),
2.60 (br s, 1H, OH), 2.82 (dd, 1H, J = 3.7, J = 10.1),
3.25 (dd, 1H, J = 7.1, J = 10.1), 3.50 (dd, 1H, J = 5.5,
J = 11.3), 3.65 (dd, 1H, J = 6.5, J = 11.3), 4.48 (d, 1H,
J = 7.4), 5.42 (q, 1H, J = 7.1), 7.23–7.34 (m, 5 ArH);
13C NMR: ꢀ5.5, ꢀ4.5, 16.0, 25.7, 38.7, 41.8, 49.0,
61.4, 73.5, 126.9, 127.4, 128.4, 139.4, 171.7;
[a]D = ꢀ170.2 (c 1.9, CHCl3); EIMS: m/z 335 (2,
M+ꢀ15), 293 (54), 189 (82), 150 (11), 106 (100), 82
(67). Anal. Calcd for C19H31NO3Si: C, 65.29; H, 8.94;
N, 4.01. Found: C, 65.24; H, 8.92; N, 4.06.
3.0mmol) in dry THF (15mL), LiAlH4 (0.15g;
3.5mmol) was added and the mixture was refluxed for
6h. Then methanol (1mL) was added, followed by a sat-
urated solution of Seignette salt (20mL), and the mix-
ture was eventually extracted with ethyl acetate
(3 · 50mL). After drying (Na2SO4) and removal of the
solvent under reduced pressure, the residue was dis-
solved in DCM (10mL) containing Et3N (1.78g;
17mmol) and DMAP (0.24g; 2mmol) and acetyl chlo-
ride (1.17g; 13.5mmol) was added at rt. After 2h the
mixture was poured in ice water and extracted with ethyl
acetate (3 · 50mL). The organic layer was separated and
dried (Na2SO4) and solvents were eventually removed
under reduced pressure. The residue was purified by sil-
ica gel chromatography (cyclohexane:ethyl acetate
50:50), to give 15 (0.54g; 65% yield) as a colorless oil.
1H NMR: 1.35 (d, 3H, J = 6.5), 2.02 (s, 3H), 2.05 (s,
3H), 2.12–2.53 (m, 3H), 2.62–2.84 (m, 2H), 3.21 (q,
1H, J = 6.5), 4.04 (dd, 1H, J = 7.0, J = 11.0), 4.16 (dd,
1H, J = 6.3, J = 11.0), 4.93 (m, 1H), 7.18–7.34 (m, 5
ArH); 13C NMR: 20.8, 21.9, 22.7, 44.1, 54.5, 58.4,
64.5, 65.0, 75.7, 101.4, 127.0, 127.1, 128.3, 144.6,
170.7, 170.8; [a]D = ꢀ7.4 (c 1.0, CHCl3); EIMS: m/z
305 (3, MH+), 290 (5), 246 (13), 231 (14), 154 (62), 121
(32), 106 (100). Anal. Calcd for C17H23NO4: C, 66.86;
H, 7.59; N, 4.59. Found: C, 66.80; H, 7.56; N, 4.55.
4.14. (3S,4R,10S)-4-Benzyloxymethyl-3-tert-butyldimeth-
ylsilyloxy-1-(10-phenylethyl)pyrrolidin-2-one 17
To
a solution containing compound 16 (1.12g;
3.2mmol), HMPA(2mL) and triphenylmethane
(100mg) in dry THF (10mL), n-BuLi (1.6M in hexanes;
2.4mL) was added at 0ꢁC. After 10min benzyl bromide
(0.66g; 3.84mmol) was added and then the mixture was
refluxed for 1h. The reaction mixture was poured in
H2O (20mL) and extracted with ethyl acetate
(3 · 40mL). After drying (Na2SO4), the solvent was re-
moved under reduced pressure and the residue was puri-
fied by silica gel chromatography (cyclohexane:ethyl
acetate 70:30) to give compound 17 (1.12g; 80% yield)
1
as a colorless oil. H NMR: ꢀ0.14 (s, 3H), ꢀ0.07 (s,
3H), 0.80 (s, 9H), 1.53 (d, 3H, J = 7.2), 2.46–2.64 (m,
1H), 2.98 (dd, 1H, J = 3.9, J = 9.9), 3.21 (dd, 1H,
J = 6.5, J = 9.9), 3.33 (dd, 1H, J = 9.9, J = 10.2), 3.77
(dd, 1H, J = 5.5, J = 10.2), 4.17 (d, 1H, J = 7.0), 4.89
(ABq, 2H, J = 12.0), 5.51 (q, 1H, J = 7.2), 7.22–7.43
(m, 10 ArH); 13C NMR: ꢀ5.7, ꢀ5.6, 16.1, 25.8, 39.5,
41.9, 48.9, 60.0, 76.8, 127.0, 127.4, 127.5, 127.6, 127.8,
128.3, 128.5, 138.0, 139.7, 171.7; [a]D = ꢀ56.0 (c 1.0,
CHCl3); EIMS: m/z 383 (19, MH+ꢀC4H9), 303 (9),
279 (12), 150 (12), 106 (73), 92 (82), 85 (74), 70 (100).
Anal. Calcd for C26H37NO3Si: C, 71.03; H, 8.48; N,
3.19. Found: C, 71.07; H, 8.42; N, 3.16.
4.12. (3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidine
hydrochloride 1
To a solution of 15 (0.54g; 1.75mmol) in dry DCM
(10mL) chloroethyl chlorocarbonate (0.5g; 3.5mmol)
was added at 0ꢁC and after 30min the solvent was re-
moved under reduced pressure. The residue was dis-
solved in methanol (5mL), the solution was refluxed
for 40min and eventually 12M HCl (1mL) was added.
After 1h at rt, solvents were evaporated under reduced
pressure, the residue was dissolved in H2O (5mL) and
the aqueous solution was extracted with ethyl acetate
(2 · 10mL). The organic layers were discarded and
water was removed under reduced pressure, to give com-
4.15. (3R,4R,10S)-4-Benzyloxymethyl-3-hydroxy-1-phen-
ylethylpyrrolidin-2-one 18
1
pound 1 (0.18g; 68% yield) as a low-melting solid. H
NMR (D2O, DSS): 2.43–2.55 (m, 1H), 3.16 (dd, 1H,
J = 5.8, J = 12.2), 3.26 (dd, 1H, J = 2.7, J = 12.6), 3.43
(dd, 1H, J = 5.1, J = 12.6), 3.55–3.66 (m, 3H), 4.38–
To a solution of methanol (18mL) and water (2mL)
containing KOH (1.4g; 25mmol), compound 17
(1.12g; 2.56mmol) was added, dissolved in methanol

R. Galeazzi et al. / Tetrahedron: Asymmetry 15 (2004) 3249–3256
3255
(2mL). The mixture was refluxed for 30h and after cool-
ing methanol was partially removed under reduced pres-
sure. After extraction with ethyl acetate (3 · 30mL), the
organic layer was dried (Na2SO4) and evaporation car-
ried out under reduced pressure gave a residue, which
was purified by silica gel chromatography (cyclohex-
ane:ethyl acetate 70:30), to give compound 18 (0.48g;
the silyl derivative 10 (1.4g; 94% yield) was obtained
as a yellow oil. [a]D = ꢀ148.6 (c 3.0, CHCl3).
4.19. (3R,4R,10S)-3-tert-Butyldimethylsilyloxy-4-
hydroxymethyl-1-(10-phenylethyl)pyrrolidin-2-one 11 and
its (3S,4S,10S)-isomer 21
1
58% yield) as a colorless oil. H NMR: 1.54 (d, 3H,
To a solution containing the diastereomeric compounds
5, 6 and 7 (2.37g; 9.0mmol overall) in DCM (20mL),
imidazole (0.82g; 12mmol) and tert-butyldimethylchlo-
rosilane (1.8g; 12mmol) were added, and the mixture
was stirred for 4h at rt. Then water (20mL) was added
and the mixture was extracted with ethyl acetate
(3 · 30mL). After drying (Na2SO4) and removal of the
solvent under reduced pressure, the residue was dis-
solved in dry THF (30mL) and LiAlH4 (0.38g;
9.0mmol) was slowly added at 0ꢁC. After 40min MeOH
(1mL) was added and subsequently a saturated solution
of the Seignette salt (20mL). The mixture was extracted
with ethyl acetate (3 · 30mL), the solvent dried
(Na2SO4) and eventually removed under reduced pres-
sure. The residue was purified by silica gel chromatogra-
phy (cyclohexane:ethyl acetate 80:20) to give first
unchanged 9 (0.56g; 18% yield) followed by 11 (0.6g;
23% yield) and 22 (0.66g; 21% yield). Compound 11:
EIMS: m/z 335 (2, MH+ꢀ15), 293 (81), 150 (16), 122
(13), 106 (100), 70 (74). Anal. Calcd for C19H31NO3Si:
C, 65.29; H, 8.94; N, 4.01. Found: C, 65.24; H, 8.89;
J = 7.2), 2.05 (br s, 1H, OH), 2.34–2.53 (m, 1H), 2.67
(dd, 1H, J = 7.4, J = 9.8), 3.39 (dd, 1H, J = 8.2,
J = 9.8), 3.50 (dd, 1H, J = 6.4, J = 10.8), 3.62 (dd, 1H,
J = 5.4, J = 10.8), 3.96 (d, 1H, J = 7.6), 4.96 (ABq, 2H,
J = 11.7), 5.48 (q, 1H, J = 7.2), 7.22–7.44 (m, 10 ArH);
13C NMR: 16.0, 41.7, 41.9, 49.3, 62.1, 72.5, 77.6,
127.1, 127.6, 127.8, 128.2, 128.4, 128.5, 128.6, 138.0,
139.7, 172.1; [a]D = ꢀ35.0 (c 0.5, CHCl3); EIMS: m/z
326 (4, MH+), 311 (3), 235 (7), 150 (12), 106 (62), 70
(100). Anal. Calcd for C20H23NO3: C, 73.82; H, 7.12;
N, 4.30. Found: C, 73.77; H, 7.08; N, 4.33.
4.16. (3R,4R,10S)-4-Benzyloxymethyl-3-hydroxy-1-phen-
ylethylpyrrolidine 19
To
a solution containing compound 18 (0.48g,
1.48mmol) in dry THF (7mL), LiAlH4 (60mg,
1.5mmol) was added and the mixture was refluxed for
6h. Then methanol (1mL) was added, followed by a sat-
urated solution of Seignette salt (20mL), and the mix-
ture was eventually extracted with ethyl acetate
(3 · 30mL). After drying (Na2SO4) and removal of the
solvent under reduced pressure, the residue was purified
by silica gel chromatography (cyclohexane:ethyl acetate
1
N, 3.96. Compound 22: white solid. Mp 96–98ꢁC. H
NMR: 0.20 (s, 3H), 0.25 (s, 3H), 0.96 (s, 3H), 1.51 (d,
3H, J = 7.1), 2.18–2.36 (m, 1H), 2.89 (br s, 1H, OH),
2.99–3.16 (m, 2H), 3.69 (dd, 1H, J = 6.5, J = 10.6),
3.82 (dd, 1H, J = 4.1, J = 10.6), 4.27 (d, 1H, J = 8.7),
5.44 (q, 1H, J = 7.1), 7.27–7.43 (m, 5 ArH); 13C NMR:
ꢀ5.1, ꢀ4.1, 16.1, 25.8, 41.0, 44.4, 49.2, 61.2, 72.8,
127.0, 127.5, 128.5, 139.6, 172.8; [a]D = ꢀ180.3 (c 1.1,
CHCl3); EIMS: m/z 335 (2, M+ꢀ15), 293 (74), 150
(11), 106 (100), 70 (67). Anal. Calcd for C19H31NO3Si:
C, 65.29; H, 8.94; N, 4.01. Found: C, 65.26; H, 8.98;
N, 4.05.
1
50:50), to give 19 (0.33g, 71%) as a colorless oil. H
NMR: 1.39 (d, 3H, J = 6.6), 2.29–2.37 (m, 2H), 2.73
(dd, 1H, J = 6.9, J = 8.9), 2.73–3.02 (m, 2H), 3.20 (br
s, 1H, OH), 3.27 (q, 1H, J = 6.6), 3.66 (dd, 1H,
J = 4.3, J = 10.3), 3.79 (dd, 1H, J = 4.1, J = 10.3), 4.00
(ddd, 1H, J = 2.0, J = 4.6, J = 6.6), 4.44 (s, 2H), 7.18–
7.43 (m, 10 ArH); 13C NMR: 22.6, 46.1, 54.8, 59.7,
65.2, 66.1, 71.2, 81.0, 126.9, 127.1, 127.6, 128.3, 128.4,
138.1, 144.3; [a]D = ꢀ108.0 (c 0.3, CHCl3); EIMS: m/z
311 (19, M+), 249 (4), 173 (5), 123 (64), 106 (100), 78
(71). Anal. Calcd for C20H25NO2: C, 77.14; H, 8.09;
N, 4.50. Found: C, 77.08; H, 8.03; N, 4.46.
Acknowledgements
This work was supported by M.I.U.R. (Italy) within the
framework COFIN 2002. The authors are indebted to
Prof. Giorgio Tosi for FT-IR spectra of compounds
4a and b.
4.17. (3R,4R)-3-Hydroxy-4-hydroxymethylpyrrolidine
hydrochloride 1
To
a solution containing compound 19 (0.31g;
1.0mmol) in CH3OH (10mL), Pd(OH)2 (20% on char-
coal, 50mg) was added and the reaction was stirred
under H2 for 4d. The catalyst was removed by filtration
and washed with 3M HCl (3mL). The filtrates were
combined and evaporated under reduced pressure to
give compound 1 (1.44g; 94%) yield as a low-melting so-
lid. [a]D = +18.2 (c 0.7, CH3OH) [lit.7 +19.0 (c 1.0,
CH3OH)]; EIMS (CI): m/z 118 (MH+), 100, 82.
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20. This change was required owing to the lack of parameters
for the Si atom.
21. Selected dihedral angles values for the most stable
conformer of adduct 4a: in H2O: (C-1)–(C-2)–(C-3)–(C-
4) = 18.1ꢁ; (O-2)–(C-2)–(C-3)–(C-4) = ꢀ104.8ꢁ; (O-2)–(C-
2)–(C-3)–(@CH2) = 74.8ꢁ; (H-2)–(C-2)–(C-3)–(@CH2) =
ꢀ43.4ꢁ. In CHCl3: (C-1)–(C-2)–(C-3)–(C-4) = 9.4ꢁ; (O-
2)–(C-2)–(C-3)–(C-4) = ꢀ112.2ꢁ;
(O-2)–(C-2)–(C-3)–
(@CH2) = 87.4ꢁ; (H-2)–(C-2)–(C-3)–(@CH2) = ꢀ50.7ꢁ.
22. AM1 within Hyperchem 5.0-Chemplus 5.2 releases,
Hypercube, Gainesville, FL, USA.
8. (a) Cardillo, B.; Galeazzi, R.; Mobbili, G.; Orena, M.
Synlett 1995, 1159–1160; (b) Galeazzi, R.; Mobbili, G.;
Orena, M. Tetrahedron 1996, 52, 1069–1084; (c) Galeazzi,
R.; Geremia, S.; Mobbili, G.; Orena, M. Tetrahedron:
Asymmetry 1996, 7, 79–88; (d) Galeazzi, R.; Geremia, S.;
Mobbili, G.; Orena, M. Tetrahedron: Asymmetry 1996, 7,
3573–3584; (e) Galeazzi, R.; Mobbili, G.; Orena, M.
Tetrahedron: Asymmetry 1997, 8, 133–137; (f) Galeazzi,
R.; Mobbili, G.; Orena, M. Tetrahedron 1999, 55, 261–
270; (g) Galeazzi, R.; Mobbili, G.; Orena, M. Tetrahedron
1999, 55, 4029–4042; (h) Fava, C.; Galeazzi, R.; Mobbili,
G.; Orena, M. Tetrahedron: Asymmetry 2003, 14, 3697–
3703.
9. (a) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.;
Rinaldi, S. Tetrahedron: Asymmetry 2003, 14, 3353–3358;
(b) Galeazzi, R.; Martelli, G.; Mobbili, G.; Orena, M.;
Panagiotaki, M. Heterocycles 2003, 60, 2485–2498.
10. (a) Davis, F. A.; Lamendola, J., Jr.; Nadir, U.; Kluger, E.
W.; Sedergran, T. C.; Panunto, T. W.; Billmeres, R.;
Jenkins, R., Jr.; Turchi, I. J.; Watson, W. H.; Chen, J. S.;
Kimura, M. J. Am. Chem. Soc. 1980, 102, 2000–2005; (b)
Evans, D. A.; Morrissey, M. M.; Dorow, R. L. J. Am.
Chem. Soc. 1985, 107, 4346–4348.
23. Selected dihedral angles values for the lowest energy
conformer of the anion B: (En = 0.0kcal/mol), (C-1)–(C-
2)–(C-3)–(CH2N) = 54.1ꢁ; (O-2)–(C-2)–(C-3)–(CH2N) =
ꢀ63.0ꢁ; (O-2)–(C-2)–(C-3)–(C-4) = 118.5ꢁ; (H-2)–(C-2)–
(C-3)–(C-4) = ꢀ3.8ꢁ. Another two similar conformers
were also observed: B-1 (En = 0.35kcal/mol): (C-1)–(C-
2)–(C-3)–(CH2N) = 49.2ꢁ; (O-2)–(C-2)–(C-3)–(CH2N) =
ꢀ67.9ꢁ; (O-2)–(C-2)–(C-3)–(C-4) =112.2ꢁ; (H-2)–(C-2)–
(C-3)–(C-4) = ꢀ9.9ꢁ; B-2 (En = 0.67kcal/mol): (C-1)–(C-
2)–(C-3)–(CH2N) = 59.8ꢁ; (O-2)–(C-2)–(C-3)–(CH2N) =
ꢀ57.9ꢁ; (O-2)–(C-2)–(C-3)–(C-4) = 121.6ꢁ; (H-2)–(C-2)–
(C-3)–(C-4) = ꢀ1.0. The corresponding HOMO frontier
electron density at C-2 are, respectively, for B: F rHOMO
¼
0:717; eHOMO = ꢀ8.13317eV; F Hr OMO ¼ 8:70 ꢁ 10ꢀ2; for
B-1: F Hr OMO ¼ ꢀ0:722; eHOMO = ꢀ8.23054eV; F rHOMO
¼
8:77 ꢁ 10ꢀ2
;
for B-2: F Hr OMO ¼ 0:716; eHOMO
=
ꢀ8.09239eV; F Hr OMO ¼ 8:85 ꢁ 10ꢀ2
.
24. (a) For reductions of a-hydroxy esters with NaBH4, see:
Mandal, S. B.; Achari, B.; Chattopadhyay, S. Tetrahedron
Lett. 1992, 33, 1647–1650; (b) Tsuboi, S.; Furutani, H.;
Ansari, M. H.; Sakai, T.; Utaka, M.; Takeda, A. J. Org.
Chem. 1993, 58, 486–492; (c) Bonini, B. F.; Carboni, P.;
Gottarelli, G.; Masiero, S.; Spada, G. P. J. Org. Chem.
1994, 59, 5930–5936; (d) Boger, D. L.; Honda, T.;
Menezes, R. F.; Colletti, S. L.; Dang, Q.; Yang, W. J.
Am. Chem. Soc. 1994, 116, 82–92.
11. (a) Davis, F. A.; Sheppard, A. C.; Chen, B. C.; Haque, M.
S. J. Am. Chem. Soc. 1990, 112, 6679–6690; (b) Davis, F.
A.; Chen, B. C. Chem. Rev. 1992, 92, 919–934.
12. Hara, O.; Takizawa, J.; Yamatake, T.; Makino, K.;
Hamada, Y. Tetrahedron Lett. 1999, 40, 7787–7790.
13. Perlmutter, P.; Tabone, M. Tetrahedron Lett. 1988, 29,
949–952.
25. (a) Laib, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63,
`
1709–1713; (b) Andres, G. M.; Pedrosa, R. Tetrahedron
1998, 54, 5607–5616; (c) Andres, G. M.; Pedrosa, R.
`
14. Jungheim, L. N. Tetrahedron Lett. 1989, 30, 1889–1892.
15. (a) Amri, H.; El Gaied, M. M.; Ben Ayed, T.; Villieras, J.
Tetrahedron: Asymmetry 1998, 9, 2493–2498.
26. Jang, B. V.; OÕRourke, D.; Li, J. Synlett 1993, 195–
196.
´
Tetrahedron Lett. 1992, 33, 7345–7346; (b) Beji, F.;
Lebreton, J.; Villieras, J.; Amri, H. Tetrahedron 2001,
´
57, 9959–9962.
16. Nielsen, L.; Brehm, L.; Krogsgaard-Larsen, P. J. Med.
Chem. 1990, 33, 71–77.
27. It is worth mentioning however that by raising the
temperature or with longer reaction times the selection is
lost and also the lactam 9 undergoes reduction.