Diastereoselective synthesis of 2-alkylated 4-silyloxyproline esters

Article abstract of DOI:10.1039/b105238c

Treatment of the 4-silyloxy-N-Boc-L-proline methyl ester 1 with allyl bromide in the presence of LDA in THF at -78°C gives a mixture of the (2S,4R)- and (2R,4R)-2-(prop-2-enyl)-4-silyloxy-N-Boc-L-proline esters 2a and 2b in 75% combined yield in the ratio 53:47. In contrast, similar treatment of the (-)- and (+)-menthyl esters 5 and 6 gives a mixture of allylated products 7a,b and 8a,b in the ratio 75:25 and 89:11, respectively. Reaction of 6 with methyl iodide and propyl iodide also give the corresponding 2-alkylated esters 16a and 16b in a highly diastereoselective manner (94:6 and 93:7, respectively).

Full text of DOI:10.1039/b105238c

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Diastereoselective synthesis of 2-alkylated 4-silyloxyproline esters
Tatsunori Sato,*a Satomi Kawasaki,a Nobuo Oda,a Shôko Yagi,a Serry A. A. El Bialy,b
Jun’ichi Uenishi,a Masashige Yamauchic and Masazumi Ikeda*a
1
a Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8414, Japan
b Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt
c Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295, Japan
Received (in Cambridge, UK) 14th June 2001, Accepted 15th August 2001
First published as an Advance Article on the web 4th October 2001
Treatment of the 4-silyloxy-N-Boc--proline methyl ester 1 with allyl bromide in the presence of LDA in THF at
Ϫ78 ЊC gives a mixture of the (2S,4R)- and (2R,4R)-2-(prop-2-enyl)-4-silyloxy-N-Boc--proline esters 2a and 2b
in 75% combined yield in the ratio 53 : 47. In contrast, similar treatment of the (Ϫ)- and (ϩ)-menthyl esters 5 and
6 gives a mixture of allylated products 7a,b and 8a,b in the ratio 75 : 25 and 89 : 11, respectively. Reaction of 6
with methyl iodide and propyl iodide also give the corresponding 2-alkylated esters 16a and 16b in a highly
diastereoselective manner (94 : 6 and 93 : 7, respectively).
Introduction
Optically active 2-alkylprolines and related compounds are
important intermediates in the syntheses of alkaloids1 as well
as of conformationally restricted peptides2 which have been of
great interest in the field of medicinal chemistry in recent years.
Although several methods for the synthesis of such compounds
have been developed,3 there had been only a few general
methods reported for the synthesis of 2-alkylated 4-hydroxy-
prolines which involve either alkylation of O-protected N-Boc-
4-hydroxyproline methyl esters4 or benzylation of O-silylated
N-benzoyl-4-hydroxyproline methyl esters.5 The former method
proceeds with low diastereomeric excess during alkylation
(de < 20%). Although the latter proceeds in a highly diastereo-
selective manner (de ≈ 90%) affording N-benzoyl-2-benzyl-4-
hydroxyproline esters, harsh conditions might be required for a
cleavage of the N-protecting group (a tertiary amide) to liberate
the free amino acids from the alkylation products. For practical
purposes the 4-hydroxyproline derivatives carrying the carb-
amate protecting group such as a Boc instead of a benzoyl group
on the nitrogen atom would be desirable. In connection with
our studies on the total synthesis of alkaloids,6 optically active
2-(prop-2-enyl)-4-silyloxyproline esters were required. There-
Scheme 1 Reagents and conditions: i, LDA, THF; ii, allyl bromide; iii,
TMSI, MeCN; iv, ArCOCl, Et3N, benzene.
fore, we have examined the diastereoselectivity in alkylation of
trans-4-silyloxy-N-Boc--proline esters.
4-silyloxyproline esters 7a and 7b in 93% combined yield
(Scheme 2). The diastereomeric ratio was determined to be
75 : 25 by HPLC analysis after reduction of the mixture with
LiAlH4 to the corresponding alcohols 9a,b, whose stereo-
chemistries were separately confirmed by a direct comparison
with authentic samples prepared by LiAlH4 reduction of 2a,b.
The major isomer was the (2S)-isomer 7a; that is, the allylation
took place preferentially from the same side as the 4-silyloxy
group.
On the other hand, similar treatment of 6 with allyl bromide
gave a mixture of the proline esters 8a and 8b in 98% combined
yield, and the diastereomeric ratio increased to 89 : 11. The
major product was again assigned to be the (2S)-isomer 8a.
For comparison, we then examined the diastereoselectivity of
N-Boc--proline (ϩ)-menthyl ester 10. Treatment of 10, which
was prepared by condensation of N-Boc--proline with (ϩ)-
menthol by use of DCC, with allyl bromide in the presence
of LDA in THF at Ϫ78 ЊC gave an inseparable mixture of
Results and discussion
We initiated our investigation by examining allylation of
the methyl ester 1. Treatment of 14 with allyl bromide in the
presence of LDA in THF at Ϫ78 ЊC gave two diastereomeric
2-(prop-2-enyl)proline methyl esters 2a and 2b in 75% yield
in the ratio 53 : 47, which could be separated by column
chromatography. The stereochemistry of 2a,b was determined by
conversion of each ester into the known N-(o-bromobenzoyl)-
prolines 3a,b7 (Scheme 1).
To improve the diastereoselectivity of this reaction, we next
examined the allylation of 4-silyloxy-N-Boc-proline (Ϫ)- and
(ϩ)-menthyl esters 5 and 6, which were prepared by hydrolysis
of 1 with lithium hydroxide in aq. methanol followed by re-
esterification of the acid 4 with (Ϫ)- and (ϩ)-menthol in the
presence of DCC and DMAP in methylene dichloride.
Treatment of 5 with allyl bromide in the presence of LDA in
THF at Ϫ78 ЊC gave an inseparable mixture of 2-(prop-2-enyl)-
DOI: 10.1039/b105238c
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631
This journal is © The Royal Society of Chemistry 2001
2623

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12a,b {[α]2D6 ϩ16.4 (c 1.29, CHCl3)} with that of an authentic
sample of 12b {[α]2D0 Ϫ31.8 (c 2.00, CHCl3)} prepared from
-proline using Seebach’s procedure.3b Thus, the allylation
took place again on the α-face of the enolate derived from 10
to afford preferentially 11a. These results indicate that the 4-
silyloxy group enhances the diastereoselectivity in the allylation
of 5 and 6 to some extent.
Interestingly, in all cases the electrophile attacks the inter-
mediate enolate from the same direction to afford allylated
products bearing the same stereochemistry (S configuration
for 7a and 8a, R configuration for 11a) at the C-2 position,
suggesting that the steric bulkiness of the ester group rather
than the absolute configuration of the chiral auxiliary might
play a crucial role in enhancing the selectivity, and that there
might be a so-called ‘matching’ character for the (ϩ)-menthyl
group with the 4-silyloxy group and a ‘mismatching’ one for
the (Ϫ)-menthyl group in directing the electrophile to attack,
although the exact reason for this interaction is obscure at the
moment.
In order to evaluate the steric factor of the menthyl group of
the ester 6 in amplifying the diastereoselectivity in the alkyl-
ation, we then examined the allylation of compound 13 bearing
a sterically demanding adamantyl group in place of the menthyl
group. When the ester 13, which was prepared from 4 and
1-adamantyl bromide in the presence of silver() oxide, was
subjected to the allylation under similar conditions to those
described above, a diastereomeric mixture of 14 and 15 was
obtained in 78% yield, together with 14% recovery of 13
(Scheme 4). The diastereomeric ratio of the mixture was deter-
Scheme 2 Reagents and conditions; i, LiOH, aq. MeOH; ii, (Ϫ)- or
(ϩ)-menthol, DCC, DMAP, CH2Cl2; iii, LDA, THF, Ϫ78 ЊC; iv, allyl
bromide; v, LiAlH4, Et2O, 0 ЊC.
2-(prop-2-enyl)proline (ϩ)-menthyl esters 11a and 11b in 93%
combined yield (Scheme 3). The diastereomeric ratio of the
Scheme 4 Reagents and conditions: i, 1-adamantyl bromide, Ag2O,
Et2O; ii, LDA, THF; iii, allyl bromide; iv, LiAlH4, Et2O, 0 ЊC.
mined as the corresponding alcohols 9a and 9b after LiAlH4
reduction and shown to be 64 : 36. To our surprise the diastereo-
selectivity in the allylation of 13 is extremely low, contrary to
our expectation, and this result led us to assume that the steric
requirement of the ester group might not be the only critical
factor in controlling the diastereoselectivity in the alkylation.
This selectivity in the allylation of the (ϩ)-menthyl ester
6 has been further investigated by molecular modelling. The
conformation of the intermediate enolate was optimised using
semi-empirical PM3 calculations,8,9 in which the carbamate
nitrogen atom has a slightly pyramidal structure, and is shown
in Fig. 1. The optimal conformer with the N-Boc group trans to
the silyloxy group (A) is the lowest in energy. It appears from
the conformer A that the steric and/or electronic factor of the
N-Boc group would be more crucial rather than that of
the silyloxy or ester moieties in the attack on the electrophilic
Scheme 3 Reagents and conditions: i, (ϩ)-menthol, DCC, DMAP,
CH2Cl2; ii, LDA, THF, Ϫ78 ЊC; iii, allyl bromide; iv, LiAlH4, Et2O,
0 ЊC.
mixture and the stereochemistry of each isomer were deter-
mined as follows. LiAlH4 reduction of the mixture gave a
mixture of the alcohols 12a and 12b, whose enantiomeric
ratio was shown to be 66 : 34 by HPLC analysis on a chiral
column (CHIRALPAK AD-RH, DAICEL). The absolute
configuration of the major isomer of 12a,b was deduced from
a comparison of the specific optical rotation of the mixture of
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J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631

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Table 1 Reaction of 6 with various electrophiles
Entry
R-X
Products
Yield (%)
Ratioa
1
2
3
4
5
CH2᎐᎐CHCH2Br
MeI
PrI
BnBr
EtOCOCH2Br
8a and 8b
98
96
94
93
96
89 : 11b
94 : 6
16a and 17a
16b and 17b
16c and 17c
16d and 17d
93 : 7b
53 : 47c
69 : 31b
a Determined as the corresponding alcohols 18a–d and 19a–d after
LiAlH4 reduction. b The absolute stereochemistry at the 2-position was
unambiguously determined by comparison with authentic samples.
c The stereochemistry was not determined.
Scheme 5 Reagents and conditions: i, LDA, THF, Ϫ78 ЊC; ii, RX; iii,
LiAlH4, Et2O, 0 ЊC.
Boc-proline esters to the synthesis of optically active alkaloids
is now in progress.
Fig. 1 The optimised structure (A) of the enolate with 1,4-trans
configuration. Grey circles, carbon; black circles, nitrogen; white circles,
oxygen. Only silicon is labelled by a symbol.
Experimental
Mps are uncorrected. IR spectra were recorded on a JASCO-
IR-A-100 or a JASCO FT/IR-410 spectrophotometer. 1H
NMR (60, 300 and 400 MHz) and 13C NMR (75.4 and 100.5
MHz) spectra were measured on a JEOL JNM-PMX 60, a
Varian XL-300, or a Varian UNITY INOVA 400NB spec-
trometer for solutions in CDCl3. δ-Values quoted are relative
carbon centre. The preferential formation of 8a might be thus
due to a shielding of the syn-face (si face) of the enolate by the
N-Boc group.
Finally, we investigated the reaction of the 4-silyloxyproline
(ϩ)-menthyl ester 6 with other electrophiles under the same
conditions as described above. The results are summarised in
Table 1 in which the diastereomeric ratios were again deter-
mined as the corresponding alcohols 18 and 19, after LiAlH4
reduction of the mixture of esters 16 and 17, by either HPLC
analysis or chromatographic separation (Scheme 5). For entries
3 and 5, the structures of 16b,d and 17b,d were unambiguously
confirmed by comparison with authentic samples synthesised
separately from 2a and 2b (see Experimental section). Reaction
of 6 with methyl iodide gave a mixture of the (2S,4R)- and
(2R,4R)-2-methyl-4-silyloxy-N-Boc-proline esters 16a and 17a
in 96% combined yield in the ratio 94 : 6 (entry 2). Similar
treatment with propyl iodide gave a mixture of 16b and 17b also
in a highly diastereoselective manner (93 : 7) (entry 3). On the
other hand, alkylation with ethyl bromoacetate and with benzyl
bromide showed lower or no diastereoselectivity (entries 4 and
5).10 In other words, the reaction with electrophiles bearing no
π-electron system proceeds with high diastereoselectivity
(entries 2 and 3), whereas with electrophiles containing a π-
electron system the diastereoselectivity in alkylation decreased
either to some extent or significantly (entries 1, 4 and 5), sug-
gesting that there might be an n–π or π–π repulsive interaction
between the lone pair of the nitrogen or carbamate π-electron
system and that of the electrophile.
to tetramethylsilane (δ 0) and CDCl3 (δC 77.02) for 1H and 13
C
NMR, respectively, and J-values are given in Hz. Column
chromatography was performed on Silica gel 60 PF254 (Nacalai
Tesque) under pressure. Optical rotations were measured on
a JASCO DIP-360 polarimeter; [α]D-values are given in units
of 10Ϫ1 deg cm2 gϪ1. Exact mass determinations (FAB mass
spectra) were obtained on a JEOL-SX 102A instrument using
3-NOBA as matrix.
Methyl (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldimethyl-
silyloxy)pyrrolidine-2-carboxylate [trans-4-(tert-butyldimethyl-
silyloxy)-N-Boc-L-proline methyl ester] 1
To a suspension of trans-4-hydroxy--proline methyl ester hydro-
chloride (10.6 g, 458.1 mmol) in methylene dichloride (50 cm3)
was added triethylamine (8.82 g, 87.2 mmol) at room tem-
perature and then the mixture was stirred for 10 min. DMAP
(709 mg, 5.8 mmol) and a solution of di-tert-butyl dicarbonate
(13.95 g, 63.9 mmol) in methylene dichloride (15 cm3) were then
added at 0 ЊC to this mixture which was allowed to warm
to room temperature and stirred overnight. After filtration to
remove the precipitate the filtrate was evaporated to give a
residue, which was dissolved in ethyl acetate (50 cm3) and
washed successively with 3% aq. HCl, saturated aq. NaHCO3,
and brine and dried (MgSO4). Concentration of the mixture
gave the N-protected ester (11.3 g, 79%) which was used for the
next step without further purification, δH(60 MHz) 1.44 (9 H, s,
OBut), 1.9–2.4 (2 H, m, 3-H2), 3.4–3.8 (2 H, m, 5-H2), 3.75 (3 H,
s, OMe) and 4.2–4.6 (2 H, m, 2- and 4-H).
In summary, we have shown that the 4-silyloxy-N-Boc--
proline (ϩ)-menthyl ester 6, on treatment with LDA in THF
and then with simple electrophiles such as allyl bromide, methyl
iodide, and propyl iodide, gave (2S,4R)-2-alkyl-4-silyloxy-N-
Boc-proline esters in a highly diastereoselective manner almost
quantitatively. Application of (2S,4R)-2-alkyl-4-silyloxy-N-
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631
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The Boc-protected ester (11.3 g, 46.1 mmol) thus obtained
was dissolved in DMF (50 cm3) and to this solution were added
imidazole (6.27 g, 92.2 mmol) and tert-butyldimethylsilyl
chloride (7.47 g, 50.8 mmol) at room temperature. The mixture
was stirred overnight, then diluted with AcOEt (50 cm3),
washed successively with water and saturated aq. NH4Cl, dried
(MgSO4), and concentrated. The crude material was chromato-
graphed on silica gel to give 14 (16.6 g, quant.) as a colourless
oil, δH(60 MHz) 0.07 (6 H, s, SiMe2), 0.88 and 0.91 (total
9 H, both s, SiBut), 1.44 (9 H, s, OBut), 1.9–2.3 (2 H, m, 3-H2),
3.3–3.8 (2 H, m, 5-H2), 3.73 (3 H, s, OMe) and 4.2–4.6 (2 H, m,
2- and 4-H).
extract was dried (MgSO4) and concentrated in vacuo to give
the amine, which was dissolved in benzene (4 cm3). This
solution was treated with triethylamine (32 mg, 0.31 mmol),
DMAP (1.5 mg, 0.01 mmol) and a solution of o-bromobenzoyl
chloride (30 mg, 0.14 mmol) in benzene (4 cm3) at 0 ЊC, and the
whole was stirred at room temperature overnight. The mixture
was then diluted with diethyl ether (10 cm3) and the organic
layer was washed successively with 5% aq. HCl, saturated
aq. NaHCO3 and brine, dried (MgSO4) and concentrated. The
residue was chromatographed on silica gel [hexane–AcOEt
(10 : 1)] to give 3a7 (9 mg, 18%).
Methyl (2R,4R)-1-(o-bromobenzoyl)-4-(tert-butyldimethyl-
silyloxy)-2-(prop-2-enyl)pyrrolidine-2-carboxylate 3b
Allylation of 1
Following the same procedure described above for the prepar-
ation of 3a, 2b (50 mg, 0.12 mmol) was treated with trimethyl-
silyl iodide (31 mg, 0.03 mmol) and the resulting crude amine
was acylated with o-bromobenzoyl chloride (30 mg, 0.14 mmol)
in the presence of triethylamine (32 mg, 0.31 mmol) and
DMAP (1.5 mg, 0.01 mmol) to give 3b7 (18 mg, 30%).
General procedure. To a stirred solution of LDA [3.34 mmol,
prepared from diisopropylamine (338 mg, 3.34 mmol) and a
1.6 mol dmϪ3 solution of n-butyllithium in hexane (2.09 cm3,
3.34 mmol) at 0 ЊC] in THF (5 cm3) at Ϫ78 ЊC was added
a solution of 1 (500 mg, 1.39 mmol) in THF (5 cm3) and the
whole was stirred at Ϫ20 to Ϫ30 ЊC for 1 h. After cooling of the
mixture again to Ϫ78 ЊC, allyl bromide (337 mg, 2.78 mmol)
was added dropwise to the solution, and the mixture was stirred
for 2 h during which time the bath was allowed to warm to
room temperature. After dilution with diethyl ether, the reac-
tion mixture was quenched with 5% aq. HCl, then the organic
phase was separated and washed successively with saturated aq.
NaHCO3 and brine, dried (MgSO4), and concentrated in vacuo.
The residue was chromatographed on silica gel [hexane–AcOEt
(7 : 1)]. The first eluate gave methyl (2R,4R)-1-(tert-butoxy-
carbonyl )-4-(tert-butyldimethylsilyloxy)-2-(prop-2-enyl )pyrrol-
idine-2-carboxylate 2b (196 mg, 35%) as a colourless oil [Found:
(M ϩ H)ϩ, 400.2510. C20H38NO5Si requires MHϩ, 400.2519];
[α]2D4 Ϫ15.8 (c 3.0, CHCl3); νmax(CCl4)/cmϪ1 1745 and 1700;
δH(300 MHz; CDCl3, a mixture of two rotamers in the ratio
60 : 40) 0.01 (6 H × 6/10, s, SiMe2), 0.02 (6 H × 4/10, s, SiMe2),
0.84 (9 H × 6/10, s, SiBut), 0.85 (9 H × 4/10, s, SiBut), 1.40 (9 H ×
6/10, s, OBut), 1.44 (9 H × 4/10, s, OBut), 2.04 (0.4 H, dd, J 12.9
and 6.1, one of 3-H2), 2.11 (0.6 H, dd, J 12.9 and 6.1, one of
3-H2), 2.17 (0.6 H, dd, J 12.9 and 6.1, one of 3-H2), 2.22 (0.4 H,
dd, J 12.9 and 6.1, one of 3-H2), 2.52 (1 H, dd, J 14.0 and 8.8),
2.89 (0.6 H, br dd, J 14.1 and 6.0), 3.09 (0.4 H, br dd, J 14.1 and
6.0), 3.27 (0.4 H, dd, J 10.5 and 6.2, one of 5-H2), 3.36 (0.6 H,
dd, J 10.9 and 5.8, one of 5-H2), 3.58 (0.4 H, dd, J 10.5 and 6.2,
one of 5-H2), 3.64 (0.6 H, dd, J 10.9 and 6.2, one of 5-H2), 3.69
(3 H × 4/10, s, OMe), 3.70 (3 H × 6/10, s, OMe), 4.29 (1 H,
(2S,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
pyrrolidine-2-carboxylic acid 4
To a solution of 1 (5.879 g, 16.35 mmol) in MeOH (30 cm3) was
added a solution of LiOHؒH2O (1.029 g, 24.53 mmol) in water
(10 cm3) and the solution was heated at 45 ЊC for 1 h. After
cooling of the mixture to 0 ЊC and acidification with 5% aq.
HCl the precipitate was extracted with diethyl ether. The extract
was dried (MgSO4) and concentrated to give (2S,4R)-1-(tert-
butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)pyrrolidine-2-
carboxylic acid 4 (5.411 g, 96%), which was used for the next
step without further purification.
(؊)-Menthyl (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyl-
dimethylsilyloxy)pyrrolidine-2-carboxylate 5
To a solution of the carboxylic acid 4 (1.03 g, 3.00 mmol)
in methylene dichloride (10 cm3) were added sequentially (Ϫ)-
menthol (469 mg, 3.00 mmol) and DMAP (367 mg, 3.00 mmol)
at room temperature, then a solution of DCC (681 mg, 3.30
mmol) in methylene dichloride (5 cm3) at 0 ЊC, and the whole
was stirred at room temperature overnight. The precipitate was
filtered off and the filtrate was concentrated in vacuo. The resi-
due was redissolved in ethyl acetate, washed successively with
5% aq. HCl and saturated aq. NaHCO3, and dried (MgSO4).
After evaporation of the mixture the crude material was chrom-
atographed on silica gel [hexane–AcOEt (12 : 1)] to give 5
(1.13 g, 78%) as a colourless oil [Found: (M ϩ H)ϩ, 484.3449.
C26H50NO5Si requires MHϩ, 484.3458]; [α]2D3 Ϫ62.3 (c 1.77,
CHCl3); νmax(CCl4)/cmϪ1 1750 and 1705; δH(300 MHz; CDCl3,
a mixture of two rotamers in the ratio 69 : 31) 0.05 (6 H, s,
SiMe2), 0.74–1.14 (2 H, m), 0.76 (3 H, d, J 7.0, CMe), 0.87 (9 H,
s, SiBut), 0.88 (6 H × 31/100, d, J 7.0), 0.90 (6 H × 69/100, d,
J 7.0), 1.32–1.57 (2 H, m), 1.43 (9 H × 69/100, s), 1.46 (9 H ×
31/100, s), 1.63–2.30 (7 H, m), 3.26 (0.31 H, dd, J 10.5 and 4.1),
3.39 (0.69 H, dd, J 10.8 and 4.0), 3.59 (0.31 H, dd, J 10.5 and
5.8), 3.62 (0.69 H, dd, J 10.8 and 5.5), 4.31–4.45 (2 H, m, 2- and
4-H) and 4.64–4.77 (1 H, m, 1Ј-H).
quintet, J 6.1, 4-H), 5.08–5.16 (2 H, m, CH᎐CH ) and 5.61–5.72
᎐
2
(1 H, m, CH᎐CH ). The second eluate gave methyl (2S,4R)-1-
᎐
2
(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-2-(prop-2-
enyl )pyrrolidine-2-carboxylate 2a (222 mg, 40%) as a colourless
oil [Found: (M ϩ H)ϩ, 400.2513]; [α]D23 ϩ37.2 (c 2.65, CHCl3);
νmax(CCl4)/cmϪ1 1745 and 1700; δH(300 MHz; CDCl3, a mixture
of two rotamers in the ratio 70 : 30) 0.050 (6 H × 7/10, s, SiMe2),
0.055 (6 H × 3/10, s, SiMe2), 0.87 (9 H × 7/10, s, SiBut), 0.88
(9 H × 3/10, s, SiBut), 1.41 (9 H × 7/10, s, OBut), 1.44 (9 H ×
3/10, s, OBut), 2.01–2.21 (2 H, m, 3-H2), 2.69 (1 H, br dd, J 14.3
and 7.5), 2.86 (0.7 H, dd, J 14.3 and 7.3), 3.03 (0.3 H, dd, J 14.3
and 6.9), 3.10 (1 H, dd, J 10.8 and 6.6), 3.71 (3 H, s, OMe), 3.78
(0.3 H, dd, J 10.8 and 6.9), 3.90 (0.7 H, dd, J 10.8 and 6.6), 4.40
(0.3 H, quintet, J 7.0, 4-H), 4.41 (0.7 H, quintet, J 7.0, 4-H),
5.09–5.18 (2 H, m, CH᎐CH ) and 5.76–5.94 (1 H, m, CH᎐CH ).
᎐
᎐
2
2
(؉)-Menthyl (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldi-
methylsilyloxy)pyrrolidine-2-carboxylate 6
Methyl (2S,4R)-1-(o-bromobenzoyl)-4-(tert-butyldimethyl-
Following the procedure described for the preparation of 5, 6
(6.82 g, 86%) was obtained from the carboxylic acid 4 (5.65 g,
16.4 mmol), (ϩ)-menthol (2.56 g, 16.4 mmol), DCC (3.71 g,
18.0 mmol) and DMAP (2.00 g, 16.4 mmol) as a colourless oil
[Found: (M ϩ H)ϩ, 484.3453]; [α]D23 Ϫ1.7 (c 1.55, CHCl3);
νmax(CCl4)/cmϪ1 1740 and 1700; δH(300 MHz; CDCl3, a mixture
of two rotamers in the ratio 62 : 38) 0.06 (6 H, s, SiMe2), 0.74
silyloxy)-2-(prop-2-enyl)pyrrolidine-2-carboxylate 3a
To a solution of 2a (50 mg, 0.12 mmol) in acetonitrile (3 cm3)
was added trimethylsilyl iodide (31 mg, 0.15 mmol) at 0 ЊC
and, after the mixture had been stirred for 15 min, methanol
(0.3 cm3) and saturated aq. NaHCO3 (6 cm3) were added; the
mixture was then extracted with methylene dichloride. The
2626
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631

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(3 H × 38/100, d, J 6.8), 0.75 (3 H × 62/100, d, J 6.8), 0.82–1.14
(2 H, m), 0.87 (9 H, s, SiBut), 0.90 (6 H × 62/100, d, J 6.8), 0.91
(6 H × 38/100, d, J 6.8), 1.32–1.57 (3 H, m), 1.42 (9 H × 62/100,
s), 1.46 (9 H × 38/100, s), 1.62–1.74 (2 H, m), 1.86 (1 H, d of
septet, J 7.0 and 2.8), 1.93–2.07 (2 H, m), 2.11–2.25 (1 H, m),
3.28 (0.38 H, br dd, J 10.9 and 4.0), 3.40 (0.62 H, br dd, J 10.9
and 4.0), 3.58 (0.38 H, dd, J 10.9 and 5.1), 3.61 (0.62 H, dd,
J 10.9 and 5.1), 4.28–4.44 (2 H, m, 2- and 4-H) and 4.65–4.78
(1 H, m, 1Ј-H).
4.2, one of 5-H2), 3.45 (1 H, dd, J 11.7 and 5.5, one of 5-H2),
3.63 (0.33 H, br d, J 12.0, one of CH2O), 3.70 (0.67 H, dd,
J 11.5 and 9.7, one of CH2O), 3.83 (0.67 H, d, J 11.5, one of
CH2O), 3.98 (0.33 H, dd, J 10.0 and 8.5, one of CH2O), 4.22–
4.28 (1 H, m, 4-H), 5.08–5.15 (2 H, m, CH᎐CH ) and 5.59–5.77
᎐
2
(1 H, m, CH᎐CH ).
᎐
2
Reduction of a mixture of 7a and 7b
Following the procedure described for the preparation of 9a,
a mixture of 7a and 7b (109 mg, 0.21 mmol) was treated with
LiAlH4 (32 mg, 0.83 mmol) in diethyl ether (4 cm3) to afford a
crude product (116 mg, quant.) containing 9a, 9b, and (Ϫ)-
menthol, which was subjected to HPLC analysis carried out on
an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC) using an
acetonitrile–water (80 : 20) system as eluent. The diastereo-
meric ratio of 9a : 9b was shown to be 75 : 25.
Allylation of 5
Following the general procedure, 5 (300 mg, 0.62 mmol) was
treated with LDA [1.49 mmol, prepared from diisopropylamine
(151 mg, 1.49 mmol) and a 1.59 mol dmϪ3 solution of n-butyl-
lithium in hexane (0.94 cm3, 1.49 mmol) at 0 ЊC] and then allyl
bromide (135 mg, 1.12 mmol). The crude product was purified
by column chromatography on silica gel [hexane–AcOEt
(10 : 1)] to give an inseparable mixture of (Ϫ)-menthyl (2S,4R)-
and (2R,4R)-1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyl-
oxy)-2-(prop-2-enyl )pyrrolidine-2-carboxylate 7a and 7b (301
mg, 93%) as a colourless oil [Found: (M ϩ H)ϩ, 524.3779.
C29H54NO5Si requires MHϩ, 524.3771]; νmax(film)/cmϪ1 1738
and 1703. The presence of at least two rotamers for each
diastereomer makes the 1H NMR spectrum highly complex
and the mixtute was directly reduced with LiAlH4 to the corre-
sponding alcohols 9a and 9b to determine the diastereomeric
ratio in the allylation.
Allylation of 6
Following the general procedure, 6 (332 mg, 0.69 mmol) was
treated with LDA [1.66 mmol, prepared from diisopropylamine
(168 mg, 1.66 mmol) and a 1.59 mol dmϪ3 solution of n-butyl-
lithium in hexane (1.04 cm3, 1.49 mmol) at 0 ЊC] and then allyl
bromide (149 mg, 1.24 mmol). The crude product was purified
by column chromatography on silica gel [hexane–AcOEt
(10 : 1)] to give an inseparable mixture of (ϩ)-menthyl (2S,4R)-
and (2R,4R)-1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyl-
oxy)-2-(prop-2-enyl )pyrrolidine-2-carboxylate 8a and 8b (353
mg, 98%) as a colourless oil [Found: (M ϩ H)ϩ, 524.3765.
C29H54NO5Si requires MHϩ, 524.3771]; νmax(film)/cmϪ1 1738
and 1703. The presence of at least two rotamers for each
diastereomer makes the 1H NMR spectrum highly complex and
the diastereomeric ratio of 8a and 8b was determined as for a
mixture of 7a and 7b.
(2S,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-(prop-2-enyl)pyrrolidine-2-methanol 9a
To a suspension of LiAlH4 (19 mg, 0.50 mmol) in diethyl
ether (2 cm3) was added dropwise a solution of 2a (50 mg,
0.13 mmol) in diethyl ether (4 cm3) at 0 ЊC and the mixture was
stirred at the same temperature for 20 min. Water was carefully
added to decompose excess of reagent. The inorganic material
was filtered off and washed with diethyl ether. The filtrate was
dried (MgSO4) and concentrated. The residue was chromato-
graphed on silica gel [hexane–AcOEt (7 : 1)] to give 9a (38 mg,
80%) as a colourless oil [Found: (M ϩ H)ϩ, 372.2574.
C19H38NO4Si requires MHϩ, 372.2570]; [α]2D6 ϩ9.8 (c 1.7,
CHCl3); νmax(film)/cmϪ1 3404, 1695 and 1672; δH(400 MHz;
CDCl3) 0.068 (3 H, s, one of SiMe2), 0.070 (3 H, s, one of
SiMe2), 0.90 (9 H, s, SiBut), 1.46 (9 H, s, OBut), 1.59 (1 H, dd,
J 13.4 and 5.9, one of 3-H2), 2.00 (1 H, ddd, J 13.4, 4.0 and 1.1,
one of 3-H2), 2.71 (1 H, dd, J 13.1 and 8.6), 2.90 (1 H, dd, J 13.1
and 6.4), 3.28 (1 H, ddd, J 11.7, 3.7 and 1.1, one of 5-H2), 3.56
(1 H, dd, J 11.7 and 5.5, one of 5-H2), 3.57 and 3.62 (1 H each,
ABq, J 11.7, CH2O), 4.23–4.28 (1 H, m, 4-H), 5.11 (1 H, dd,
Reduction of a mixture of 8a and 8b
Following the procedure described for the preparation of 9a,
a mixture of 8a and 8b (95 mg, 0.18 mmol) was treated with
LiAlH4 (28 mg, 0.73 mmol) in diethyl ether (4 cm3) to afford
a crude product (100 mg, quant.) containing 9a, 9b, and (ϩ)-
menthol, which was subjected to HPLC analysis carried out on
an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC) using
an acetonitrile–water (80 : 20) system as eluent. The diastereo-
meric ratio of 9a : 9b was determined to be 89 : 11. Further-
more, the crude mixture was chromatographed on silica gel
[hexane–AcOEt (15 : 1)]. The first fraction gave a mixture of 9b
and (ϩ)-menthol (35 mg). The second fraction gave 9a (57 mg,
85%).
J 10.1 and 2.2, one of CH᎐CH ), 5.16 (1 H, br d, J 17.2, one of
᎐
2
(؉)-Menthyl (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-
carboxylate 10
CH᎐CH ) and 5.84 (1 H, dddd, J 17.2, 10.1, 8.6 and 6.4, CH᎐
᎐
᎐
2
CH2).
To a solution of N-Boc--proline (2.00 g, 9.29 mmol) and (ϩ)-
menthol (1.45 g, 9.29 mmol) in methylene dichloride (30 cm3)
were added DMAP (1.14 g, 9.29 mmol) and a solution of DCC
(2.11 g, 10.22 mmol) in methylene dichloride (10 cm3) at 0 ЊC
and the whole was stirred at room temperature for 16 h. The
precipitate was filtered off and the filtrate was concentrated
in vacuo. The residue was redissolved in ethyl acetate, washed
successively with 5% aq. HCl and saturated aq. NaHCO3, and
dried (MgSO4). After evaporation of the mixture the crude
material was chromatographed on silica gel [hexane–AcOEt
(15 : 1)] to give 10 (1.60 g, 49%) as a white solid, mp 66.5–
67.2 ЊC [from light petroleum (30–70 ЊC)] (Found: C, 67.87;
H, 10.01; N, 4.26. C20H35NO4 requires C, 67.95; H, 9.98; N,
3.96%); [α]D24 Ϫ6.6 (c 0.68, CHCl3); νmax(film)/cmϪ1 1743 and
1703; δH(400 MHz; CDCl3, a mixture of two rotamers in the
ratio 69 : 31) 0.74 (3 H × 31/100, d, J 6.8, CMe), 0.76 (3 H ×
69/100, d, J 6.8, CMe), 0.87, 0.89 and 0.91 (total 6 H, all d,
J 7.0, 2 × CMe), 0.85–1.11 (2 H, m), 1.33–1.58 (3 H, m), 1.43
(2R,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-(prop-2-enyl)pyrrolidine-2-methanol 9b
Following the procedure described for the preparation of 9a,
9b (46 mg, 77%) was obtained from 2b (65 mg, 0.16 mmol)
and LiAlH4 (24 mg, 0.66 mmol) as a colourless oil [Found:
(M ϩ H)ϩ, 372.2567]; [α]D25 Ϫ35.7 (c 1.3, CHCl3); νmax(film)/cmϪ1
3406, 1695 and 1670; δH(400 MHz; CDCl3, a mixture of
two rotamers in the ratio 67 : 33) 0.07 (6 H × 67/100, s, SiMe2),
0.11 (6 H × 33/100, s, SiMe2), 0.89 (9 H × 67/100, s, SiBut),
0.90 (9 H × 33/100, s, SiBut), 1.46 (9 H × 67/100, s, OBut), 1.50
(9 H × 33/100, s, OBut), 1.60 (0.67 H, ddd, J 13.6, 4.4 and 1.5,
one of 3-H2), 1.91 (0.33 H, br d, J 13.6, one of 3-H2), 2.16 (1 H,
dd J 13.6 and 5.7, one of 3-H2), 2.33 (0.33 H, dd, J 14.1 and
5.1), 2.44 (0.67 H, dd, J 13.6 and 7.5), 2.68 (0.33 H, br dd, J 13.6
and 5.9), 2.76 (0.67 H, dd, J 13.6 and 7.3), 3.32 (0.67 H, ddd,
J 11.7, 3.7 and 1.5, one of 5-H2), 3.42 (0.33 H, dd, J 11.7 and
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631
2627

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(9 H × 69/100, s, OBut), 1.46 (9 H × 31/100, s, OBut), 1.63–1.73
(2 H, m), 1.81–2.05 (5 H, m), 2.13–2.28 (1 H, m), 3.34–3.58
(2 H, m, 5-H2), 4.22 (0.69 H, dd, J 8.9 and 3.2), 4.30 (0.31 H,
J 8.9 and 3.2) and 4.66–4.74 (1 H, m, 1Ј-H).
(M ϩ H)ϩ, 520.3463. C29H50NO5Si requires MHϩ, 520.3458];
νmax(film)/cmϪ1 1736 and 1703. The presence of at least two
rotamers for each diastereomer makes the H NMR spectrum
1
highly complex and the diastereomeric ratio of 14 and 15 was
determined as for a mixture of 7a and 7b.
Allylation of 10
Reduction of a mixture of 14 and 15
Following the general procedure, 10 (100 mg, 0.28 mmol) was
treated with LDA [0.68 mmol, prepared from diisopropylamine
(69 mg, 0.68 mmol) and a 1.6 mol dmϪ3 solution of n-butyl-
lithium in hexane (0.43 cm3, 0.68 mmol) at 0 ЊC] and then allyl
bromide (62 mg, 0.51 mmol). The crude product was purified by
column chromatography on silica gel [hexane–AcOEt (10 : 1)]
to give an inseparable mixture of (ϩ)-menthyl (R)- and (S)-1-
(tert-butoxycarbonyl )-2-(prop-2-enyl )pyrrolidine-2-carboxylate
11a and 11b (103 mg, 93%) as a colourless oil [Found: (M ϩ
H)ϩ, 394.2948. C23H40NO4 requires MHϩ, 394.2957]; νmax(film)/
cmϪ1 1734 and 1699. The presence of at least two rotamers
for each diastereomer makes the 1H NMR spectrum highly
complex and the diastereomeric ratio of 11a and 11b was
determined as for a mixture of 7a and 7b.
Following the procedure described for the preparation of 9a,
a mixture of 14 and 15 (115 mg, 0.22 mmol) was treated with
LiAlH4 (34 mg, 0.88 mmol) in diethyl ether (4 cm3) to afford
a crude product (120 mg, quant.) containing 9a, 9b and
adamantan-1-ol, which was subjected to HPLC analysis carried
out on an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC)
using an acetonitrile–water (80 : 20) system as eluent. The
diastereomeric ratio of 9a : 9b proved to be 64 : 36. In addition,
the mixture was further chromatographed on silica gel [hexane–
AcOEt (15 : 1)]. The first fraction gave 9b (23 mg, 28%).
The second fraction gave an inseparable mixture of 9a and
adamantan-1-ol (74 mg).
Alkylation of 6
Reduction of a mixture of 11a and 11b
With methyl iodide. Following the general procedure, 6
(400 mg, 0.83 mmol) was treated with LDA [1.66 mmol, pre-
pared from diisopropylamine (200 mg, 1.98 mmol) and a
1.60 mol dmϪ3 solution of n-butyllithium in hexane (1.24 cm3,
1.98 mmol) at 0 ЊC] and then methyl iodide (940 mg, 6.62
mmol). The crude product was purified by column chrom-
atography on silica gel [hexane–AcOEt (12 : 1)] to give an
inseparable mixture of (ϩ)-menthyl (2S,4R)- and (2R,4R)-1-
(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-2-methyl-
pyrrolidine-2-carboxylate 16a and 17a (396 mg, 96%) as a
colourless oil [Found: (M ϩ H)ϩ, 498.3608. C27H52NO5Si
requires MHϩ, 498.3615]; νmax(film)/cmϪ1 1738 and 1703; δH for
16a (300 MHz; CDCl3, a mixture of two rotamers in the ratio
60 : 40) 0.058 (6 H × 3/5, s, SiMe2), 0.064 (6 H × 2/5, s, SiMe2),
0.74 (3 H × 2/5, d, J 7.1, CMe), 0.77 (3 H × 3/5, d, J 7.1, CMe),
0.80–1.55 (11 H, m), 0.88 (9 H × 3/5, s, SiBut), 0.89 (9 H × 2/5,
s, SiBut), 1.43 (9 H × 3/5, s, OBut), 1.44 (9 H × 2/5, s, OBut),
1.60–1.74 (2 H, m), 1.64 (3 H × 3/5, s, 2-Me), 1.67 (3 H × 2/5, s,
2-Me), 1.84–2.16 (3 H, m), 2.25 (1 H, ddd, J 13.2, 8.0 and 5.9),
3.31 (0.4 H, ddd, J 11.0, 4.2 and 0.8, one of 5-H2), 3.39 (0.6 H,
ddd, J 11.0, 4.7 and 0.8, one of 5-H2), 3.68 (0.4 H, dd, J 11.0
and 5.9, one of 5-H2), 3.77 (0.6 H, dd, J 11.0 and 5.9, one of
5-H2), 4.32–4.42 (1 H, m, 4-H) and 4.60–4.74 (1 H, m, 1Ј-H).
Following the procedure described for the preparation of 9a, a
mixture of 11a and 11b (50 mg, 0.13 mmol) was treated with
LiAlH4 (20 mg, 0.53 mmol) in diethyl ether (4 cm3) to afford
a crude product (49 mg), which was chromatographed on silica
gel [hexane–AcOEt (7 : 1)] to give 1-tert-butyl 2-hydroxymethyl-
2-(prop-2-enyl )pyrrolidine-1-carboxylate 12a,b1e (23 mg, 74%)
as a colourless oil, [α]2D6 ϩ16.4 (c 1.29, CHCl3). HPLC analysis
performed on a CHIRALPAK AD-RH (4.6 × 150 mm,
DAICEL) using an acetonitrile–water (80 : 20) system as eluent
showed that the enantiomeric ratio of 12a and 12b was 66 : 34.
1-Adamantyl (2S,4R)-1-(tert-butoxycarbonyl)-4-(tert-butyldi-
methylsilyloxy)pyrrolidine-2-carboxylate 13
To a solution of 4 (962 mg, 2.78 mmol) and 1-adamantyl
bromide (897 mg, 4.17 mmol) in diethyl ether (10 cm3) was
added portionwise silver() oxide (774 mg, 3.34 mmol) at 0 ЊC
and the whole was stirred at room temperature for 30 h. The
insoluble materials were filtered off and the filtrate was concen-
trated in vacuo. The residue was chromatographed on silica gel
[hexane–AcOEt (10 : 1)] to give ester 13 (1.42 g, quant.) as
a colourless oil (Found: C, 64.10; H, 9.42; N, 3.18. C26H45-
NO5Siؒ1/2 H2O requires C, 63.90; H, 9.49; N, 2.87%) [Found:
(M ϩ H)ϩ, 480.3141. C26H46NO5Si requires MHϩ, 480.3145];
[α]D24 Ϫ31.8 (c 0.83, CHCl3); νmax(film)/cmϪ1 1739 and 1705;
δH(400 MHz; CDCl3, a mixture of two rotamers in the ratio
67 : 33) 0.056 and 0.060 (total 6 H, both s, SiMe2), 0.87 (9 H, s,
SiBut), 1.44 (9 H × 67/100, s, OBut), 1.46 (9 H × 33/100,
s, OBut), 1.63–1.68 (6 H, unresolved m), 1.96–2.04 (1 H, m),
2.08–2.21 (10 H, unresolved m), 3.26 (0.33 H, br dd, J 11.0 and
3.8, one of 5-H2), 3.35 (0.67 H, ddd, J 11.0, 3.8 and 0.9, one
of 5-H2), 3.56 (0.33 H, dd, J 11.0 and 5.3, one of 5-H2), 3.60
(0.67 H, dd, J 11.0 and 5.3, one of 5-H2), 4.19 (0.67 H, dd,
J 8.1 and 6.1, 2-H), 4.27 (0.33 H, dd, J 8.1 and 5.6, 2-H) and
4.40 (1 H, dtd, J 5.8, 5.3 and 3.8, 4-H).
With propyl iodide. Following the general procedure, 6
(500 mg, 1.03 mmol) was treated with LDA [2.48 mmol, pre-
pared from diisopropylamine (251 mg, 2.48 mmol) and a
1.60 mol dmϪ3 solution of n-butyllithium in hexane (1.60 cm3,
2.48 mmol) at 0 ЊC] and then propyl iodide (1.41 g, 8.27 mmol).
The crude product was purified by column chromatography on
silica gel [hexane–AcOEt (15 : 1)] to give an inseparable mixture
of (ϩ)-menthyl (2S,4R)- and (2R,4R)-1-(tert-butoxycarbonyl )-
4-(tert-butyldimethylsilyloxy)-2-propylpyrrolidine-2-carboxylate
16b and 17b (504 mg, 94%) as a colourless oil [Found:
(M ϩ H)ϩ, 526.3931. C29H56NO5Si requires MHϩ, 526.3928];
νmax(film)/cmϪ1 1736 and 1703; δH for 16b (400 MHz; CDCl3, a
mixture of two rotamers in the ratio 60 : 40) 0.04 (6 H × 3/5, s,
SiMe2), 0.06 (6 H × 2/5, s, SiMe2), 0.74 (3 H × 3/5, d, J 7.0,
CMe), 0.77 (3 H × 2/5, d, J 7.0, CMe), 0.82–1.60 (13 H, m), 0.87
(9 H × 3/5, s, SiBut), 0.89 (9 H × 2/5, s, SiBut), 1.41 (9 H × 3/5,
s, OBut), 1.44 (9 H × 2/5, s, OBut), 1.62–2.33 (11 H, m), 3.07
(0.4 H, dd, J 10.4 and 7.5, one of 5-H2), 3.09 (0.6 H, dd, J 10.4
and 7.7, one of 5-H2), 3.78 (0.4 H, br dd, J 10.4 and 7.1, one of
5-H2), 3.91 (0.6 H, br dd, J 10.4 and 7.1, one of 5-H2), 4.26–4.45
(1 H, m, 4-H) and 4.59–4.74 (1 H, m, 1Ј-H).
Allylation of 13
Following the general procedure, 13 (100 mg, 0.20 mmol) was
treated with LDA [0.50 mmol, prepared from diisopropylamine
(51 mg, 0.50 mmol) and a 1.6 mol dmϪ3 solution of n-
butyllithium in hexane (0.31 cm3, 0.50 mmol) at 0 ЊC] and then
allyl bromide (46 mg, 0.38 mmol). The crude product was puri-
fied by column chromatography on silica gel [hexane–AcOEt
(15 : 1)]. The first fraction gave an inseparable mixture of
1-adamantyl (2S,4R)- and (2R,4R)-1-(tert-butoxycarbonyl )-4-
(tert-butyldimethylsilyloxy)-2-(prop-2-enyl )pyrrolidine-2-carb-
oxylate 14 and 15 (84 mg, 78%) as a colourless oil [Found:
With benzyl bromide. Following the general procedure, 6
(522 mg, 1.14 mmol) was treated with LDA [2.74 mmol,
2628
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631

View Article Online
prepared from diisopropylamine (277 mg, 2.74 mmol) and a
1.60 mol dmϪ3 solution of n-butyllithium in hexane (1.71 cm3,
2.74 mmol) at 0 ЊC] and then benzyl bromide (390 mg, 2.28
mmol). The crude product was purified by column chrom-
atography on silica gel [hexane–AcOEt (50 : 1)] to give an
inseparable mixture of (ϩ)-menthyl (2S,4R)- and (2R,4R)-
2-benzyl-1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-
pyrrolidine-2-carboxylate 16c and 17c (610 mg, 93%) as a
colourless oil [Found: (M ϩ H)ϩ, 574.3937. C33H56NO5Si
requires MHϩ, 574.3928]; νmax(film)/cmϪ1 1737 and 1700. The
presence of at least two rotamers for each diastereomer makes
(M ϩ H)ϩ, 374.2722. C19H40NO4Si requires MHϩ, 374.2727];
[α]D22 Ϫ2.2 (c 1.15, CHCl3); νmax(film)/cmϪ1 3404, 1695 and 1670;
δH(400 MHz; CDCl3) 0.06 (6 H, s, SiMe2), 0.89 (9 H, s, SiBut),
0.94 (3 H, t, J 7.3, CMe), 1.12–1.30 (2 H, m), 1.46 (9 H, s,
OBut), 1.62 (1 H, dd, J 13.4 and 5.8, one of 3-H2), 1.88 (1 H, td,
J 12.7 and 4.4), 1.92 (1 H, ddd, J 13.4, 4.3 and 0.7, one of 3-H2),
2.07 (1 H, td, J 12.7 and 4.5), 3.25 (1 H, ddd, J 11.7, 3.8 and
0.7, one of 5-H2), 3.54 (1 H, br d, J 11.5, one of CH2O), 3.57
(1 H, dd, J 11.7 and 5.8, one of 5-H2), 3.64 (1 H, dd, J 11.5 and
9.5, one of CH2O), 4.25 (1 H, tt, J 5.8 and 4.0, 4-H) and 5.15
(1 H, br d, J 9.5, OH).
1
the H NMR spectrum highly complex and the diastereomeric
ratio of 16c and 17c was determined after the reduction to 18c
and 19c as for a mixture of 7a and 7b.
(2R,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-propylpyrrolidine-2-methanol 19b
Following the procedure described for the synthesis of 18b, 2b
(64 mg, 0.16 mmol) was hydrogenated and then treated with
LiAlH4 (13 mg, 0.34 mmol). The crude product was purified by
column chromatography on silica gel [hexane–AcOEt (5 : 1)] to
give alcohol 19b (59 mg, 95%) as a colourless oil [Found: (M ϩ
H)ϩ, 374.2719]; [α]2D5 Ϫ3.3 (c 2.0, CHCl3); νmax(film)/cmϪ1 3394,
1691 and 1672; δH(400 MHz; CDCl3, a mixture of mainly two
rotamers in the ratio ≈73 : 27) 0.07 (6 H × 73/100, s, SiMe2),
0.11 (6 H × 27/100, s, SiMe2), 0.89 (9 H × 73/100, s, SiBut), 0.90
(9 H × 27/100, s, SiBut), 0.94 (3 H, t, J 6.9, CMe), 1.06–1.51
(2 H, m), 1.45 (9 H × 73/100, s, OBut), 1.49 (9 H × 27/100, s,
OBut), 1.63 (0.73 H, ddd, J 13.6, 4.2 and 1.3, one of 3-H2),
1.70–1.90 (2 H, m), 1.95 (0.27 H, br d, J 14.0, one of 3-H2), 2.10
(0.73 H, dd, J 13.6 and 5.5, one of 3-H2), 2.27 (0.27 H, dd,
J 14.0 and 5.3, one of 3-H2), 3.34 (0.73 H, ddd, J 11.7, 3.4 and
1.5, one of 5-H2), 3.43–3.51 (0.27 H, m, one of 5-H2), 3.47 (1 H,
dd, J 11.7 and 5.0, one of 5-H2), 3.63 (0.27 H, br d, J 11.5,
CH2O), 3.69 (0.73 H, dd, J 11.5 and 9.9, CH2O), 3.82 (0.73 H,
d, J 11.5, CH2O), 3.94 (0.27 H, dd, J 10.2 and 8.2), 4.21–4.28
(1 H, m, 4-H) and 5.18 (1 H, br d, J 10.2, OH).
With ethyl bromoacetate. Following the general procedure, 6
(500 mg, 1.03 mmol) was treated with LDA [2.48 mmol,
prepared from diisopropylamine (251 mg, 2.48 mmol) and a
1.60 mol dmϪ3 solution of n-butyllithium in hexane (1.60 cm3,
2.48 mmol) at 0 ЊC] and then ethyl bromoacetate (311 mg,
1.86 mmol). The crude product was purified by column
chromatography on silica gel [hexane–AcOEt (50 : 1)] to give an
inseparable mixture of ethyl (2S,4R)- and (2R,4R)-1-(tert-
butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-2-((ϩ)-menthyl-
oxycarbonyl )pyrrolidine-2-acetate 16d and 17d (570 mg, 96%)
as a colourless oil [Found: (M ϩ H)ϩ, 570.3831. C30H56NO7Si
requires MHϩ, 570.3826]; νmax(film)/cmϪ1 1737 and 1703. The
presence of at least two rotamers for each diastereomer makes
1
the H NMR spectrum highly complex and the diastereomeric
ratio of 16d and 17d was determined after the reduction to 18d
and 19d as for a mixture of 7a and 7b.
Determination of the diastereomeric ratios of 16a–d and 17a–d
Reduction of a mixture of 16a and 17a. Following the pro-
cedure described for the preparation of 9a, a mixture of 16a
and 17a (120 mg, 0.24 mmol) was treated with LiAlH4 (37 mg,
0.96 mmol) in diethyl ether (4 cm3) to afford a crude product
(121 mg, quant.) containing 18a, 19a and (ϩ)-menthol, which
was subjected to HPLC analysis carried out on an ODS-AM-
302 column (5 µm; 4.6 × 150 mm, YMC) using an acetonitrile–
water (80 : 20) system as eluent. The diastereomeric ratio
of 18a : 19a proved to be 94 : 6. Furthermore, the mixture
was chromatographed on silica gel [hexane–AcOEt (15 : 1)].
The first fraction gave an inseparable mixture of 19a and
(ϩ)-menthol (39 mg). The second fraction gave (2S,4R)-
1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-2-methyl-
pyrrolidine-2-methanol 18a (69 mg, 83%) as a colourless oil
[Found: (M ϩ H)ϩ, 346.2405. C17H36NO4Si requires MHϩ,
346.2413]; [α]D24 Ϫ15.3 (c 2.7, CHCl3); νmax(film)/cmϪ1 3419, 1695
and 1671; δH(400 MHz; CDCl3) 0.07 (6 H, s, SiMe2), 0.90 (9 H,
s, SiBut), 1.46 (9 H, s, OBut), 1.48 and 1.54 (total 3H, both s,
2-Me), 1.74 (1 H, ddd, J 13.2, 2.8 and 1.7, one of 3-H2), 1.83
(1 H, dd, J 13.2 and 5.1, one of 3-H2), 3.40 (1 H, br d, J 11.9,
one of 5-H2), 3.52 (1 H, dd, J 11.9 and 5.0, one of 5-H2), 3.58
(2 H, s) and 4.23–4.33 (1 H, br, 4-H); δC(100 MHz; CDCl3)
Ϫ4.92, Ϫ4.81, 17.9, 20.8, 25.7 (3 × Me), 28.6 (3 × Me), 46.1,
57.4, 64.8, 69.1, 70.6, 80.1 and 155.8.
Reduction of a mixture of 16b and 17b
Following the procedure described for the preparation of 9a, a
mixture of 16b and 17b (100 mg, 0.19 mmol) was treated with
LiAlH4 (29 mg, 0.76 mmol) in diethyl ether (4 cm3) to afford
the crude product (104 mg, quant.) containing 18b, 19b, and
(ϩ)-menthol, which was subjected to HPLC analysis carried
out on an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC)
using an acetonitrile–water (80 : 20) system as eluent. The
diastereomeric ratio of 18b : 19b proved to be 93 : 7. Further-
more, the mixture was chromatographed on silica gel [hexane–
AcOEt (15 : 1)]. The first fraction gave an inseparable mixture
of 19b and (ϩ)-menthol (34 mg). The second fraction gave 18b
(55 mg, 77%).
(2S,4R)-2-Benzyl-1-(tert-butoxycarbonyl)-4-(tert-butyldimethyl-
silyloxy)pyrrolidine-2-methanol 18c
Following the general procedure, 1 (500 mg, 1.39 mmol) was
treated with LDA [3.34 mmol, prepared from diisopropylamine
(338 mg, 3.34 mmol) and a 1.60 mol dmϪ3 solution of n-butyl-
lithium in hexane (2.09 cm3, 3.34 mmol) at 0 ЊC] and then benzyl
bromide (476 mg, 2.78 mmol). The crude product was purified
by column chromatography on silica gel [hexane–AcOEt
(10 : 1)] to give an inseparable mixture of methyl (2S,4R)- and
(2R,4R)-2-benzyl-1-(tert-butoxycarbonyl )-4-(tert-butyldimethyl-
silyloxy)pyrrolidine-2-carboxylate (554 mg, 80%) as a colourless
oil. A portion of the diastereomeric mixture was further puri-
fied by column chromatography on silica gel (chloroform) to
afford the single diastereomer (polar one) methyl (2S,4R)-
2-benzyl-1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)-
pyrrolidine-2-carboxylate (50 mg) [Found: (M ϩ H)ϩ, 450.2684.
C24H40NO5Si requires MHϩ, 450.2676]; [α]2D5 Ϫ57.0 (c 2.05,
CHCl3); νmax(film)/cmϪ1 1745 and 1701; δH(400 MHz; CDCl3,
a mixture of two rotamers in the ratio 63 : 37) Ϫ0.23 (3 H ×
(2S,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-propylpyrrolidine-2-methanol 18b
A solution of 2a (53 mg, 0.13 mmol) in ethyl acetate (5 cm3)
was hydrogenated in the presence of 10% Pd–C (50 mg) under
pressure (4.8 kg cmϪ2) for 2 h. After the catalyst had been
removed by filtration, the filtrate was concentrated to afford the
crude product (44 mg), which was directly reduced with LiAlH4
(10 mg, 0.26 mmol) according to the same procedure as that
for the preparation of 9a. The crude product was purified by
column chromatography on silica gel [hexane–AcOEt (5 : 1)]
to give alcohol 18b (37 mg, 75%) as a colourless oil [Found:
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631
2629

View Article Online
63/100, s, one of SiMe2), Ϫ0.21 (3 H × 63/100, s, one of SiMe2),
Ϫ0.20 (3 H × 37/100, s, one of SiMe2), Ϫ0.18 (3 H × 37/100, s,
one of SiMe2), 0.71 (9 H × 63/100, s, SiBut), 0.74 (9 H × 37/100,
s, SiBut), 1.49 (9 H × 63/100, s, OBut), 1.51 (9 H × 37/100, s,
OBut), 1.98 (0.37 H, dd, J 12.2 and 8.6, one of 3-H2), 2.05 (0.63
H, ddd, J 12.7, 9.0 and 0.7, one of 3-H2), 2.14–2.20 (0.37 H, m,
one of 3-H2), 2.18 (0.63 H, dd, J 12.7 and 6.5, one of 3-H2),
2.87–3.01 (1 H, m, 4-H), 3.01 (0.37 H, d, J 13.7, one of CH2Ph),
3.02 (0.67 H, d, J 13.9, one of CH2Ph), 3.04 (0.37 H, dd, J 9.7
and 7.9, one of 5-H2), 3.09 (0.67 H, dd, J 10.1 and 8.1, one of
5-H2), 3.23 (0.37 H, ddd, J 9.7, 6.7 and 1.1, one of 5-H2), 3.36
(0.63 H, ddd, J 10.1, 7.1 and 0.7, one of 5-H2), 3.51 (0.63 H, d,
J 13.9, one of CH2Ph), 3.69 (0.37 H, d, J 13.7, one of CH2Ph),
3.75 (3 H × 37/100, s, OMe), 3.76 (3 H × 67/100, s, OMe), 7.10–
7.14 (2 H, m, ArH) and 7.23–7.33 (3 H, m, ArH).
This ester (38 mg, 0.08 mmol) was treated with LiAlH4
(13 mg, 0.34 mmol) in diethyl ether (5 cm3) following the pro-
cedure described for the preparation of 9a and the resulting
crude product was purified by column chromatography on
silica gel [hexane–AcOEt (7 : 1)] to give (2S,4R)-2-benzyl-1-
(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)pyrrolidine-
2-methanol 18c (37 mg, quant.) as a colourless oil [Found:
(M ϩ H)ϩ, 422.2733. C23H40NO4Si requires MHϩ, 422.2726];
[α]D25 Ϫ93.0 (c 1.4, CHCl3); νmax(film)/cmϪ1 3394, 1693 and 1670;
δH(400 MHz; CDCl3, a mixture of two rotamers in the ratio 79 :
21) Ϫ0.09 (3 H × 79/100, s, one of SiMe2), Ϫ0.08 (3 H × 79/100,
s, one of SiMe2), Ϫ0.01 (6 H × 21/100, br s, SiMe2), 0.80 (9 H ×
79/100, s, SiBut), 0.84 (9 H × 21/100, SiBut), 1.52 (9 H × 79/100,
s, OBut), 1.55 (0.79 H, dd, J 13.4 and 6.4, one of 3-H2), 1.59
(9 H × 21/100, s, OBut), 1.86 (0.21 H, br d, J 14.0, one of 3-H2),
2.11 (0.79 H, dd, J 13.4 and 6.1, one of 3-H2), 2.21 (0.21 H, dd,
J 13.7 and 5.4, one of 3-H2), 2.50 (0.21 H, d, J 13.6), 2.69 (0.79
H, d, J 13.6), 3.08 and 3.09 (1 H each, both s), 3.38 (0.21 H, d,
J 13.6), 3.44 (0.79 H, quintet, J 6.0, 4-H), 3.55 (0.79 H, d,
J 13.6), 3.56 (0.21 H, d, J 10.8), 3.70–3.75 (0.21 H, m, 4-H), 3.77
and 3.87 (0.79 H each, ABq, J 11.5), 4.08 (0.21 H, d, J 10.8),
7.10–7.13 (2 H × 21/100, m, ArH), 7.14–7.18 (2 H × 79/100, m,
ArH) and 7.21–7.31 (3 H, m, ArH); δC(100 MHz; CDCl3, for a
major rotamer) Ϫ5.1, Ϫ5.0, 17.9 (quaternary), 25.7 (3 × Me),
28.5 (3 × Me), 38.2, 43.2, 56.4, 67.4, 68.4, 70.4, 80.3, 126.5,
128.3, 130.4, 138.0 and 155.9.
was washed with saturated aq. NaHCO3, dried (MgSO4) and
concentrated. The residue was chromatographed on silica gel
[hexane–AcOEt (5 : 1)] to give methyl (2R,4R)-2-formylmethyl-
1-(tert-butoxycarbonyl )-4-(tert-butyldimethylsilyloxy)pyrrol-
idine-2-carboxylate (45 mg, 90%) as a colourless oil.
This aldehyde (45 mg, 0.11 mmol) was then reduced with
LiAlH4 (13 mg, 0.34 mmol) following the procedure described
for the preparation of 9a. The crude product was chromato-
graphed on silica gel [hexane–AcOEt (3 : 2)] to afford diol 18d
(37 mg, 75% from 2a) as a colourless oil [Found: (M ϩ H)ϩ,
376.2513. C18H38NO5Si requires MHϩ, 376.2519]; [α]D22 Ϫ3.7
(c 2.0, CHCl3); νmax(film)/cmϪ1 3408 and 1668; δH(400 MHz;
CDCl3) 0.07 (6 H, s, SiMe2), 0.88 (9 H, s, SiBut), 1.46 (9 H, s,
OBut), 1.69 (1 H, dd, J 13.2 and 5.2, one of 3-H2), 1.80 (1 H,
ddd, J 14.6, 5.1 and 4.7), 2.16 (1 H, dd, J 13.2 and 5.6, one of
3-H2), 2.45 (1 H, ddd, J 14.6, 7.7 and 5.1), 3.31 (1 H, dd, J 11.5
and 4.0, one of 5-H2), 3.52 (1 H, dd, J 11.5 and 5.3, one of
5-H2), 3.64–3.75 (3 H, m), 3.90 (1 H, d, J 12.0) and 4.24–4.30
(1 H, m, 4-H).
(2R,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-(hydroxymethyl)pyrrolidine-2-ethanol 19d
Following the procedure described for the preparation of 18d,
2b (50 mg, 0.12 mmol) was subjected to ozonolysis followed by
treatment with LiAlH4 (28 mg, 0.73 mmol). The crude product
was purified by column chromatography on silica gel [hexane–
AcOEt (3 : 2)] to afford diol 19d (26 mg, 58% ) as a colourless
oil [Found: (M ϩ H)ϩ, 376.2526]; [α]D23 Ϫ14.3 (c 2.2, CHCl3);
νmax(film)/cmϪ1 3398 and 1668; δH(400 MHz; CDCl3) 0.066
(3 H, s, one of SiMe2), 0.070 (3 H, s, one of SiMe2), 0.88 (9 H, s,
SiBut), 1.46 (9 H, s, OBut), 1.70 (1 H, dd, J 13.7 and 5.4, one
of 3-H2), 2.03 (1 H, br d, J 13.7, one of 3-H2), 2.27 (1 H, ddd,
J 14.6, 5.4 and 3.4), 2.51 (1 H, ddd, J 14.6, 8.5 and 4.2), 3.38
(1 H, br d, J 12.2, one of 5-H2), 3.57 (1 H, dd, J 12.2 and 5.1,
one of 5-H2), 3.63 and 3.69 (1 H each, ABq, J 12.3), 3.66–3.77
(2 H, m) and 4.25–4.30 (1 H, m, 4-H).
Reduction of a mixture of 16d and 17d
Following the procedure described for the preparation of 9a, a
mixture of 16d and 17d (100 mg, 0.17 mmol) was treated with
LiAlH4 (20 mg, 0.53 mmol) in diethyl ether (5 cm3) to afford a
crude product (105 mg, quant.) containing 18d, 19d, and (ϩ)-
menthol, which was subjected to HPLC analysis carried out on
an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC) using
an acetonitrile–water (80 : 20) system as eluent. The diastereo-
meric ratio of 18d : 19d proved to be 69 : 31.
Reduction of a mixture of 16c and 17c
Following the procedure described for the preparation of 9a, a
mixture of 16c and 17c (200 mg, 0.34 mmol) was treated with
LiAlH4 (27 mg, 0.70 mmol) in diethyl ether (5 cm3) to afford
a crude product (210 mg, quant.) containing 18c, 19c and (ϩ)-
menthol, which was subjected to HPLC analysis carried out
on an ODS-AM-302 column (5 µm; 4.6 × 150 mm, YMC) using
an acetonitrile–water (80 : 20) system as eluent. The diastereo-
meric ratio of 18c : 19c proved to be 53 : 47. Furthermore, the
mixture was chromatographed on silica gel [hexane–AcOEt
(20 : 1)]. The first fraction gave (ϩ)-menthol (55 mg, 100%
recovery). The second fraction gave a mixture of (2S,4R)-
and (2R,4R)-2-benzyl-1-(tert-butoxycarbonyl )-4-(tert-butyldi-
methylsilyloxy)pyrrolidine-2-methanol 18c and 19c (125 mg,
87%).
Notes and references
1 (a) G. M. Coppola and H. F. Schuster, Asymmetric Synthesis,
Wiley, New York, 1987; (b) P. N. Confalone, E. M. Huie, S. S. Ko
and G. M. Cole, J. Org. Chem., 1988, 53, 482; (c) M. Ikeda,
K. Matsubayashi, T. Imoto, K. Kitao, H. Ishibashi and T. Sato,
Heterocycles, 1994, 38, 1237; (d ) N. Isono and M. Mori, J. Org.
Chem., 1995, 60, 115; (e) M. Ikeda, S. A. A. El Bialy, K. Hirose,
M. Kotake, T. Sato, S. M. M. Bayomi, I. A. Shehata, A. M. Abdelal,
L. M. Gad and T. Yakura, Chem. Pharm. Bull., 1999, 47, 983.
2 (a) S. Thairivongs, D. T. Pals, J. A. Lawson, S. R. Turner and
D. W. Harris, J. Med. Chem., 1987, 30, 536; (b) P. Ward, G. B. Ewan,
C. C. Jordan, S. J. Ireland, R. M. Hagan and J. R. Brown, J. Med.
Chem., 1990, 33, 1848; (c) M. G. Hinds, J. H. Welsh, D. M.
Brennand, J. Fisher, M. J. Glennie, N. G. J. Richards, D. L. Turner
and J. A. Robinson, J. Med. Chem., 1991, 34, 1777; (d ) M. J. Genin
and R. L. Johnson, J. Am. Chem. Soc., 1992, 114, 8778;
(e) D. Gramberg, C. Weber, R. Beeli, J. Inglis, C. Bruns and J. A.
Robinson, Helv. Chim. Acta, 1995, 78, 1588; ( f ) L. D. Rutledge,
J. H. Perlman, M. C. Gershenorn, G. R. Marshall and K. D.
Moeller, J. Med. Chem., 1996, 39, 1571; (g) F. Emery, C. Bisang,
M. Favre, L. Jiang and J. A. Robinson, Chem. Commun., 1996,
2155; (h) E. M. Khalil, W. H. Ojala, A. Pradhan, V. D. Nair,
W. B. Gleason, R. K. Mishra and R. L. Johnson, J. Med. Chem.,
1999, 42, 628.
(2S,4R)-1-(tert-Butoxycarbonyl)-4-(tert-butyldimethylsilyloxy)-
2-(hydroxymethyl)pyrrolidine-2-ethanol 18d
A stream of ozone-enriched oxygen was passed through a solu-
tion of 2a (50 mg, 0.12 mmol) in methanol (5 cm3) at Ϫ78 ЊC for
10 min. After purging of unchanged excess ozone by nitrogen
flow, sodium iodide (38 mg, 0.25 mmol) and acetic acid
(0.1 cm3) were added simultaneously to the reaction mixture.
The whole was allowed to warm to room temperature after
which 10% aq. Na2S2O3 was added until the colour of the
liberated iodine disappeared. Methanol was evaporated off and
the resulting solution was extracted with AcOEt. The extract
2630
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3 (a) D. Seebach and R. Naef, Helv. Chim. Acta, 1981, 64, 2704;
(b) D. Seebach, M. Boes, R. Naef and W. B. Schweitzer, J. Am.
Chem. Soc., 1983, 105, 5390; (c) T. Weber and D. Seebach,
Helv. Chim. Acta, 1985, 68, 155; (d ) J. Bajgrowicz, A. El Achquar,
M. L. Roumestant, C. Pigiere and P. Viallefont, Heterocycles,
1986, 24, 2165; (e) U. Schellkopf, R. Hinrichs and R. Lonsky,
Angew. Chem., Int. Ed. Engl., 1987, 26, 143; ( f ) S. Shatzmiller,
B.-Z. Dolithsky and E. Bahar, Liebigs Ann. Chem., 1991, 375;
(g) K. D. Moeller and L. D. Rutledge, J. Org. Chem., 1992, 57, 6360;
(h) M. J. Genin, P. W. Baures and R. L. Johnson, Tetrahedron Lett.,
1994, 35, 4967; (i) V. Ferey, P. Vedrenne, L. Toupet, T. Le Gall and
C. Mioskowski, J. Org. Chem., 1996, 61, 7244; (j) Y. Matsumura,
T. Kinoshita, Y. Yanagihara, N. Kanemoto and M. Watanabe,
Tetrahedron Lett., 1996, 37, 8395; (k) H. Wang and J. P. Germanas,
Synlett, 1999, 33.
methyl ester appeared, see S. Nagumo, M. Mizukami, N. Akutsu,
A. Nishida and N. Kawahara, Tetrahedron Lett., 1999, 40, 3209.
6 M. Ikeda, Y. Kugo, Y. Kondo, T. Yamazaki and T. Sato, J. Chem.
Soc., Perkin Trans. 1, 1997, 3339. See also ref. 1e.
7 T. Sato, Y. Kugo, E. Nakaumi, H. Ishibashi and M. Ikeda, J. Chem.
Soc., Perkin Trans. 1, 1995, 1801.
8 Implemented in the MOPAC 97.00 computer package.
9 Using this method we also carried out the calculation for the
transition-state structure for alkylation of 6, but no significant
difference in energy could be observed.
10 Quite recently, Ishibashi has reported that the benzylation of
the enolate derived from (2S,4R)-4-(tert-butyldimethylsilyloxy)-
N-(benzyloxycarbonyl)proline methyl ester with o-bromobenzyl
bromide proceeded stereoselectively to afford the (2R,4R)-2-(o-
bromobenzyl)-4-(silyloxy)proline ester in 96% yield, carrying the
o-bromobenzyl group at the 2 position trans to the 4-silyloxy group.
This selectivity might be attributed to the π–π stacking interaction
between the Cbz group and o-bromobenzyl bromide (H. Ishibashi,
personal communication).
4 C. R. Noe, M. Knollmuller, H. Vollenkle, N. Noe-Letschnig,
A. Weigand and J. Muhl, Pharmazie, 1996, 51, 800.
5 During the course of our investigation, a preliminary report on
the diastereoselective alkylation of a 4-silyloxy-N-Boc--proline
J. Chem. Soc., Perkin Trans. 1, 2001, 2623–2631
2631