Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols via asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/S0957-4166(01)00367-6

Asymmetric 1,3-dipolar cycloadditions of chiral azomethine ylides to 3-benzyloxy-substituted alkenoylcamphorsultams are described. trans-3,4-Disubstituted pyrrolidines containing a protected hydroxyl group at C(4) of the pyrrolidine ring are obtained in high diastereomeric ratios. Such compounds can serve as chiral building blocks for the syntheses of enantiopure bioactive pyrrolidines. This is exemplified by a short synthetic route to a known glycosidase inhibitor, (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol and its enantiomer.

Full text of DOI:10.1016/S0957-4166(01)00367-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1977–1982
Synthesis of enantiomerically pure 4-substituted pyrrolidin-3-ols
via asymmetric 1,3-dipolar cycloaddition
Staffan Karlsson* and Hans-Erik Ho¨gberg*
Chemistry, Department of Natural and Environmental Sciences, Mid Sweden University, SE-851 70 Sundsvall, Sweden
Received 14 August 2001; accepted 20 August 2001
Abstract—Asymmetric 1,3-dipolar cycloadditions of chiral azomethine ylides to 3-benzyloxy-substituted alkenoylcamphorsultams
are described. trans-3,4-Disubstituted pyrrolidines containing a protected hydroxyl group at C(4) of the pyrrolidine ring are
obtained in high diastereomeric ratios. Such compounds can serve as chiral building blocks for the syntheses of enantiopure
bioactive pyrrolidines. This is exemplified by a short synthetic route to a known glycosidase inhibitor, (3R,4R)-4-(hydroxy-
methyl)pyrrolidin-3-ol and its enantiomer. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
(e.g. compounds 3 or 4, Scheme 1) has a higher LUMO
energy than the analogous cinnamoyl derivative,
because of the electron donating nature of the ether
oxygen. Thus, when the reaction is controlled by inter-
actions between HOMO (azomethine ylide) and LUMO
(dipolarophile), and when a dipolarophile containing
an electron-rich vinyl ether is used, lower reactivity
should result. We have recently shown that compound
3 can serve as a dipolarophile in a reaction with a
sulphur-containing 1,3-dipolar compound,3d and that
the resulting cycloadduct can serve as the starting mate-
rial in the synthesis of a pheromone of the pine sawfly.8
Asymmetric 1,3-dipolar cycloadditions are among the
most efficient reactions for the construction of enan-
tiopure five-membered ring heterocycles.1–3 The chiral-
ity of the products of these reactions can be introduced
through enantioselective catalysis, e.g. by the use of
either chiral Lewis acids4 or enantiopure organic cata-
lysts.5 Alternatively, chiral auxiliaries can be used.1,2
Using the latter approach, we have recently studied the
reactions of chiral ylides with chiral dipolarophiles in
an attempt to improve the diastereoselectivity in reac-
tions of azomethine ylides with dipolarophiles, which
are attached to chiral auxiliaries.3b,3c Chiral non-
racemic azomethine ylides show significantly higher
diastereoselectivity than achiral ones when reacting
with some a,b-unsaturated cycloalkenoic derivatives
attached to chiral auxiliaries.3c,6 In reactions with
acyclic alkenoic substrates, however, the effect of using
non-racemic ylides is small.3b The enantiomers of 1-
phenylethylamine, which are comparatively inexpensive
starting materials for the preparation of the ylide pre-
cursors, can, however, be used with some advantage in
place of achiral benzylamine.
A 1,3-dipolar cycloaddition reaction of a 3-benzyl-
oxypropenoyl derivative, e.g. 3 or 4, with an azome-
thine ylide (derived from either of the precursors 1 or 2)
would result in a pyrrolidine cycloadduct containing an
ether group at the 4-position of the heterocyclic ring
formed. Substituted pyrrolidines of this type should be
useful intermediates for further manipulation into enan-
tiopure alkaloids and bioactive substances. For exam-
ple, racemic and non-racemic derivatives of such
pyrrolidines have been prepared and found to have an
inhibitory effect on certain enzymes9–11 as well as on the
glial GABA uptake systems.12 These pyrrolidines have
also been used as building blocks for further syntheses
of compounds with antibacterial activity.13,14
The reaction of an unstabilised azomethine ylide with a
dipolarophile, such as an a,b-unsaturated acyl com-
pound, is controlled by interaction of the HOMO of
the azomethine ylide with the LUMO of the dipolar-
ophile.7 A dipolarophile containing a vinyl ether group
We now present some doubly diastereoselective 1,3-
dipolar cycloadditions of the chiral azomethine ylide
precursor 1 and its enantiomer 2 to the b-benzyloxy-
substituted a,b-unsaturated compound 3 and its enan-
tiomer 4. The diastereoselectivity of these reactions as a
function of the solvent polarity is also discussed.
* Corresponding authors. Tel.: +46(60)148704; fax: +46(60)148802;
e-mail: staffan.karlsson@mh.se; hans-erik.hogberg@mh.se
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00367-6

1978
S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 12 (2001) 1977–1982
Me3Si
N
R1
OMe
CF3COOH
cat
1 R1 = (R)-1-phenylethyl
2 R1 = (S)-1-phenylethyl
O
O
BnO
BnO
Xc
Xc
O
N
R1
+
+
BnO
Xc
3 Xc = A
N
R1
N
R1
Chiral
ylide
4 Xc = B
5
8
9
R1 = (R)-1-phenylethyl, Xc = A
R1 = (S)-1-phenylethyl, Xc = B
R1 = (S)-1-phenylethyl, Xc = A 10
6
7
N H H N
S
O O
A-H
S
O O
B-H
Scheme 1.
Finally, a short synthesis of a known glycosidase
inhibitor, (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol15
15, and its enantiomer 14 is provided.
either of the ylide precursors 1 or 2 are presented in
Table 1.
A linear relationship was approached (Fig. 1), when the
logarithm of the diastereomeric ratio (log d.r.) was
plotted as a function of the empirical solvent polarity
parameter, ET(30),18 of the solvent used.
2. Results and discussion
2.1. Diastereoselectivity and solvent effects
Table 1. Diastereomeric ratio (d.r.) as a function of the
ET(30) value of the solvent in the 1,3-dipolar cycloaddi-
tion reaction of the dipolarophile 3 with either of the
ylide precursors 1 and 2
The two enantiomers 3 and 4 (Scheme 1) of the dipolaro-
phile were prepared from 3-benzyloxypropenoyl chlo-
ride and the appropriate enantiomer of camphorsultam
(A-H and B-H) as described.3d,8 When the ylide precur-
sor 1 (or 2) was treated with a catalytic amount of
trifluoroacetic acid (TFA) in the presence of the dipo-
larophile 3 (or 4) in CH2Cl2, the major cycloadduct 5
(or 7) was formed along with the minor diastereomer 6
(or 8) in an 83:17 diastereomeric ratio and a 94%
combined isolated yield (Scheme 1).† The two products
were separated by column chromatography to give the
pure individual diastereoisomers each having d.r. of
>200:1.
Entrya,b Solvent
ET(30) [kcal
mol−1 c
D.r.d 5:6 (9:10)
]
1
2
3
4
5
6
7
8
Heptanee
31.1
30.9
32.4
36.0
33.9
34.5
39.1
38.1
37.4
40.7
42.2
45.6
43.2
45.1
63:37 (65:35)
64:36 (62:38)
61:39 (50:50)
79:21 (61:39)
70:30 (52:48)
70:30 (54:46)
74:26 (69:31)
78:22 (58:42)
75:25 (58:42)
83:17 (71:29)
85:15 (73:27)
88:12 (75:25)
87:13 (71:29)
86:14 (76:24)
Cyclohexanee
e
CCl4
1,4-Dioxane
Toluene
Diethyl ethere
CHCl3
EtOAc
THF
CH2Cl2
Acetone
CH3CN
DMF
9
When the 1,3-dipolar cycloaddition reactions were per-
formed in non-polar solvents such as CCl4 and heptane,
considerably lower diastereoselectivity (d.r. of 61:39
and 63:37, respectively) was observed. However, when
more polar solvents were used, (e.g. CH3CN or DMF),
higher diastereoselectivity (d.r. of up to 88:12) was
obtained. The same relationship has been observed in
Diels–Alder reactions with another camphorsultam
derived dienophile.16 However, a reverse solvent effect
was observed in a similar 1,3-dipolar cycloaddition of a
nitrile oxide to a camphorsultam derived acrylate.17 The
results of the reactions of the dipolarophile 3 with
10
11
12
13
14
DMSO
a Compounds 1 or 2 (50–75 mmol) was added to a solution of 3 (25
mmol) in the solvent specified (0.5 mL). Trifluoroacetic acid (TFA,
2 mL) was then added at ambient temperature. After stirring for 1 h
the reaction was quenched by the addition of Na2CO3 (aq. satd 3
mL) and the mixture was diluted with EtOAc (5 mL).
Diastereomeric ratios were measured on the crude products.
b The reactions were performed on a small scale and, therefore, not
completed by means of conversion. Approximately 10–50% conver-
sion was achieved in all cases. However, complete conversions and
more efficient reactions could be achieved, if the reactions were
performed on a large scale, following the details in Section 4.
c Ref. 18.
† As expected, we observed a lower reactivity with the 3-benzyl-
oxypropenoyl compound 3 (or 4) than with the corresponding
cinnamoyl compound. In order to obtain a reasonable yield of the
minor diastereomer 6 (or 8) for further manipulation, we performed
the reaction on
a large scale in CH2Cl2 even though better
d Determined by GC analyses.
diastereoselectivity could be obtained in more polar solvents, as will
be presented below.
e Low solubility of 3.

S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 12 (2001) 1977–1982
1979
15 was verified by comparing the [h]D value of its
hydrochloride with that of an authentic sample.15,‡
2.3. Cycloaddition reaction pathway
When not chelated or complexed with Lewis acids,
N-enoyl sultams are proposed to react with dipolar
compounds in a conformation where the carbonyl oxy-
gen and the sulfone moiety are trans-located in relation
to the CꢀN amide bond (Fig. 2).19,20 Reagents such as
nitrile oxides then attack the re–re face, probably due
to unfavourable interactions between the incoming
dipole and the axially oriented Oa sulfone oxygen (see
Fig. 2).21 Thus, in our experiments and in the major
pathway, the azomethine ylide probably reacts on the
re–re face of compound 3 in the conformation shown in
Fig. 2. The location of the partially charged sultam
oxygens (Oa and Ob) in relation to the p-bond has been
proposed to account for the facial selectivity in cam-
phorsultam-derived acrylates.17,20 Dipole–dipole inter-
Figure 1. Log (d.r.) as a function of the ET(30) value of the
solvent in the reaction of 1 with 3.
Thus, solvents with great structural differences but with
roughly the same polarity gave nearly the same
diastereoselectivity (e.g. cyclohexane versus heptane). In
a series of structurally similar solvents, the diastereose-
lectivity increased with the polarity of the solvent (e.g.
entries 3, 7 and 10, Table 1).
actions caused by
a more polar solvent might,
therefore, have a great impact on the stabilisation of
the transition state.
2.2. Preparation of an enantiomerically pure glycosi-
dase inhibitor
The chiral sultam auxiliaries Xc, constituting parts of
the cycloadducts 5, 6 and 7, were removed reductively
on reaction with LiAlH4, leaving the individual enan-
tiomers 11 and 13 and the diastereomer 12, respectively,
in approximately 90% yield along with a near quantita-
tive recovery of the camphorsultam (Scheme 2).
Figure 2.
Reductive cleavage of the benzyl and the 1-phenylethyl
groups of 11–13 using 10% Pd/C under an atmosphere
of hydrogen furnished the pyrrolidinediol 14 and its
enantiomer 15 (Scheme 2). The latter is a known15
inhibitor of glycosidase. The absolute configuration of
3. Conclusion
In summary, the electron-rich dipolarophiles 3 or 4
containing a vinyl ether group were accepted as reac-
Scheme 2.
‡ An independently prepared sample of the N-Fmoc-4-trityloxymethyl derivative of (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol 15 (supplied by Dr
Y. Ishikawa) was deprotected through treatment with 20% Et3N/MeOH, followed by treatment with 1 M HCl/MeOH. This furnished 15·HCl.15

1980
S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 12 (2001) 1977–1982
tion partners in the 1,3-dipolar cycloaddition with the
chiral azomethine ylide derived from the precursor 1 or
2, respectively. Provided that the appropriate solvent
was used, the major diastereomeric cycloadducts 5 or 7,
respectively, were obtained in high diastereoselectivity
along with the minor diastereomers 6 or 8, respectively.
When highly polar solvents, such as DMF, DMSO and
CH3CN, were used, the cycloadducts were obtained
with a diastereoselectivity of up to 88:12 d.r. Using
these adducts as starting materials, we prepared an
enantiomerically pure glycosidase inhibitor, (3R,4R)-4-
(hydroxymethyl)pyrrolidin-3-ol 15, as well as its enan-
tiomer 14, in a two-step synthetic sequence in 87%
overall yield.
crude reaction mixture indicated a diastereomeric ratio
of 83:17 of the two diastereomers 7 and 8. The residue
was purified by column chromatography (silica gel,
EtOAc/cyclohexane 5“80% as eluent) to give the indi-
vidual pure diastereomers 7 (3.05 g, 5.8 mmol, 75%)
and 8 (0.71 g, 1.4 mmol, 18%; see below), each
diastereomer in >99% d.e. (GC), as semi-crystalline
compounds. Major isomer 7: [h]2D5 +62.7 (c 0.56,
1
CHCl3); H NMR (CDCl3): l 0.92 (s, 3H), 1.05 (s, 3H),
1.31 (d, 3H, J=6.5 Hz), 1.31–1.42 (m, 2H), 1.79–1.91
(m, 3H), 2.02–2.07 (m, 2H), 2.60–2.74 (m, 2H), 2.80–
2.87 (m, 1H), 3.09 (t, 1H, J=9.1 Hz), 3.28 (q, 1H,
J=6.5 Hz), 3.41 (d, 1H, J=14.0 Hz), 3.47 (d, 1H,
J=14.0 Hz), 3.62–3.71 (m, 1H), 3.88 (t, 1H, J=6.2
Hz), 4.36 (d, 1H, J=11.5 Hz), 4.53 (d, 1H, J=11.5 Hz),
4.57–4.62 (m, 1H), 7.16–7.31 (m, 10H); 13C NMR
(CDCl3): l 19.7, 20.5, 22.4, 26.3, 32.5, 38.2, 44.3, 47.6,
48.3, 50.8, 52.8, 56.2, 58.5, 64.3, 64.9, 71.2, 78.9, 126.8,
127.0, 127.4, 127.8, 128.2, 138.0, 144.6, 172.2; MS (EI):
m/z (%) 523 (27) [M++H], 507 (25), 416 (14), 202 (8),
174 (100), 105 (87), 91 (70). Anal. calcd for
C30H38N2O4S: C, 68.9; H, 7.3; N, 5.4. Found: C, 68.9;
H, 7.4; N, 5.3%.
4. Experimental
4.1. General
All chemicals and solvents were used as received unless
otherwise stated. THF (K, benzophenone), toluene
(CaH2), CH2Cl2 (CaH2), acetone (CaH2) and diethyl
ether (LiAlH4) were distilled under argon from the
1
drying agents indicated. H and 13C NMR spectra were
4.2.2.
N-[[(3R,4S)-4-Benzyloxy-1-(1(S)-phenylethyl)-
1
recorded with a Bruker DMX 250 (250 MHz H and
pyrrolidin-3-yl]carbonyl]-(2%S)-bornane-10,2-sultam
8.
62.9 MHz 13C) instrument. Preparative liquid chro-
matography was performed on straight phase silica gel
(Merck 60, 230–400 mesh, 0.040–0.063 mm) using an
increasing concentration of distilled ethyl acetate in
distilled cyclohexane as eluent. GC analyses were car-
ried out using a capillary column EC-5, 30 m, 0.32 mm
i.d., df=0.25 mm, carrier gas N2. The elemental analyses
(C, H and N) were performed by Mikro Kemi AB,
SE-752 28 Uppsala, Sweden. Boiling points were uncor-
rected and were given as air bath temperatures (bath
temp./mbar) in a bulb to bulb (Bu¨chi GKR-51) appara-
tus. Optical rotations were measured with a Perkin–
Elmer 241 MC polarimeter in a 10 cm cell. Mass
spectra were recorded on a Saturn 2000 instrument,
operating in the EI or CI (acetonitrile as chemical
ionisation gas) mode, coupled to a Varian 3800 GC
instrument. Compounds 1 and 2 were prepared using
the procedure reported by Hosomi and Sakurai et al.22
The work up was completed following an alternative
method.23 Compound 3 and its enantiomer 4 were
obtained as previously described.3d
Minor diastereomer from sultam 4 and ylide precursor
1
2: [h]2D5 +14.7 (c 1.04, CHCl3); H NMR (CDCl3): l
0.98 (s, 3H), 1.19 (s, 3H), 1.29–1.44 (m, 2H), 1.37 (d,
3H, J=6.5 Hz), 1.81–2.09 (m, 5H), 2.51 (t, 1H, J=8.3
Hz), 2.68–2.75 (m, 2H), 3.22–3.43 (m, 2H), 3.44 (d, 1H,
J=13.8 Hz), 3.55 (d, 1H, J=13.8 Hz), 3.77–3.93 (m,
2H), 4.26–4.32 (m, 1H), 4.34 (d, 1H, J=11.7 Hz), 4.55
(d, 1H, J=11.7 Hz), 7.18–7.36 (m, 10H); 13C NMR
(CDCl3): l 19.8, 21.0, 23.0, 26.4, 32.9, 38.6, 44.7, 47.7,
48.3, 51.1, 53.2, 56.3, 58.9, 65.1, 65.3, 71.0, 82.5, 126.9,
127.1, 127.5, 127.7, 128.3 (2C), 137.8, 144.8, 173.5; MS
(EI): m/z (%) 523 (2) [M++H], 507 (22), 416 (8), 202
(10), 174 (100), 105 (73), 91 (72). Anal. calcd for
C30H38N2O4S: C, 68.9; H, 7.3; N, 5.4. Found: C, 68.7;
H, 7.4; N, 5.3%.
4.2.3.
N-[[(3R,4S)-4-Benzyloxy-1-(1(R)-phenylethyl)-
5.
pyrrolidin-3-yl]carbonyl]-(2%R)-bornane-10,2-sultam
Major diastereomer from sultam 3 and ylide precursor
1: [h]2D5 −61.0 (c 0.37, CHCl3). All other data for 5 were
identical to those of the enantiomer described under
Section 4.2.1.
4.2. 1,3-Dipolar cycloadditions
4.2.4.
N-[[(3S,4R)-4-Benzyloxy-1-(1(R)-phenylethyl)-
6.
4.2.1.
N-[[(3S,4R)-4-Benzyloxy-1-(1(S)-phenylethyl)-
7.
pyrrolidin-3-yl]carbonyl]-(2%R)-bornane-10,2-sultam
pyrrolidin-3-yl]carbonyl]-(2%S)-bornane-10,2-sultam
Minor diastereomer from sultam 3 and ylide precursor
1. [h]2D5 −13.0 (c 0.45, CHCl3). All other data for 6 were
identical to those of the enantiomer described in Sec-
tion 4.2.2.
Over a period of 0.5 h, (S)-N-(1-phenylethyl)-N-
(methoxymethyl)-N-(trimethylsilyl)methylamine 2 (2.6
g, 10.3 mmol) was added under argon to a stirred
solution of (E)-3-benzyloxypropenoyl-(2%S)-bornane-
10,2-sultam3d 4 (2.9 g, 7.7 mmol) in a 5 mM TFA/
CH2Cl2 solution (40 mL) at rt. After stirring the
mixture for an additional 0.5 h, the reaction was
quenched by addition of Na2CO3 (200 mL aq. satd),
followed by extraction with EtOAc (200+100 mL). The
combined organic phase was dried over MgSO4, filtered
and concentrated at 150°C/1 mbar. GC analysis of the
4.3. Reductive cleavage of the enoyl camphorsultams
4.3.1.
(3R,4R)-[4-(Benzyloxy)-1-[(S)-1-phenylethyl]-
pyrrolidin-3-yl]methanol 13. Compound 7 (2.93 g, 5.6
mmol), dissolved in dry THF (40 mL), was added
under argon to a stirred solution of LiAlH4 (0.64 g,
16.9 mmol) in THF (25 mL) at 0°C. After 0.5 h at rt,

S. Karlsson, H.-E. Ho¨gberg / Tetrahedron: Asymmetry 12 (2001) 1977–1982
1981
the reaction was quenched by the addition of H2O (5
mL). The mixture was diluted with EtOAc (150 mL)
and extracted with 1 M HCl solution (7×40 mL). The
organic phase was dried over MgSO4 and concentrated
to give recovered (+)-camphorsultam (1.09 g, 5.06
mmol, 90%) in >99% purity as judged by GC analysis.
The aqueous phases were combined, basified with
NaOH (6 M) and extracted with EtOAc (3×80 mL).
The organic phase was dried (MgSO4) and concen-
trated. The residue was purified by column chromatog-
raphy (silica gel, EtOAc/cyclohexane 10–100% as
eluent) to give 1.52 g (4.9 mmol, 88%) of 13 as a
colourless oil in purity >99% (GC); bp 215°C/0.8 mbar;
hydrochloric acid (aq.); [h]2D5 +19.0 (c 1.0, MeOH,
hydrochloride); 1H NMR (hydrochloride, D2O): l
2.44–2.53 (m, 1H), 3.17 (dd, 1H, J=5.8, 12.3 Hz), 3.27
(dd, 1H, J=2.7, 12.7 Hz), 3.44 (dd, 1H, J=5.0, 12.7
Hz), 3.55–3.67 (m, 3H), 4.39–4.44 (m, 1H); 13C NMR
(hydrochloride, D2O): l 46.5, 47.8, 52.0, 60.8, 71.8.
This compound was in all respects identical to an
authentic sample of 15·HCl prepared from an indepen-
dently prepared sample of N-FMOC protected
(3R,4R)-4-(trityloxymethyl)pyrrolidin-3-ol15 by treat-
ment with Et3N/MeOH, followed by acid treatment (1
M HCl/MeOH).
1
[h]2D5+6.2 (c 0.70, MeOH); H NMR (CDCl3): l 1.39 (d,
4.4.2. (3S,4S)-4-(Hydroxymethyl)pyrrolidin-3-ol 14.
Using a procedure analogous to that described in Sec-
tion 4.4.1, Compound 11 gave the title compound. [h]D25
−49.0 (c 0.48, MeOH, free base). [h]2D5 −18.7 (c 1.2,
MeOH, hydrochloride). All other data for 14 were
identical to those of the enantiomer described in Sec-
tion 4.4.1.
3H, J=6.6 Hz), 2.28–2.36 (m, 2H), 2.72 (dd, 1H,
J=6.8, 9.0 Hz), 2.90 (dd, 1H, J=2.6, 9.1 Hz), 2.97 (dd,
1H, J=6.7, 10.2 Hz), 3.26 (q, 1H, J=6.6 Hz), 3.65 (dd,
1H, J=4.1, 10.2 Hz), 3.70 (s, 1H, br), 3.78 (dd, 1H,
J=4.2, 10.2 Hz), 3.95–4.03 (m, 1H), 4.43 (s, 2H),
7.20–7.35 (m, 10H); 13C NMR (CDCl3): l 22.7, 46.0,
54.9, 59.8, 65.2, 66.1, 71.2, 81.0, 127.0, 127.1, 127.6
(2C), 128.4 (2C), 138.1, 144.3; MS (EI): m/z (%) 312 (5)
[M++H], 296 (80), 205 (20), 134 (100), 105 (92), 91 (85).
Anal. calcd for C20H25NO2: C, 77.1; H, 8.1; N, 4.5.
Found: C, 76.9; H, 8.4; N, 4.6%.
Acknowledgements
4.3.2.
(3R,4R)-[4-(Benzyloxy)-1-[(R)-1-phenylethyl]-
procedure
We are grateful to Dr. Yoshitaka Ichikawa for a gift of
a sample of the N-FMOC protected (3R,4R)-4-(trityl-
oxymethyl)pyrrolidin-3-ol. This work was supported
by the Swedish Natural Science Research Council
(NFR) and the Mid Sweden University.
pyrrolidin-3-yl]methanol 12. Using
a
analogous to that described in Section 4.3.1, compound
6 (4.2.4) gave the title compound as a colourless oil of
>99% purity (GC); bp 210°C/0.8 mbar; [h]2D5 +53.0 (c
1
0.44, MeOH); H NMR (CDCl3): l 1.38 (d, 3H, J=6.6
Hz), 2.20–2.29 (m, 1H), 2.37–2.49 (m, 2H), 2.66 (dd,
1H, J=6.8, 9.3 Hz), 3.25 (q, 1H, J=6.6 Hz), 3.36 (dd,
1H, J=6.6, 9.9 Hz), 3.58–3.70 (m, 2H), 3.60 (s, br, 1H),
References
4.07–4.13 (m, 1H), 4.49 (s, 2H), 7.21–7.38 (m, 10H); 13
C
NMR (CDCl3): l 22.6, 45.7, 55.5, 59.1, 65.4, 66.2, 71.3,
81.2, 126.9, 127.2, 127.7 (2C), 128.4, 128.5, 138.1, 144.5;
MS (EI): m/z (%) 312 (4) [M++H], 296 (62), 205 (25),
134 (100), 105 (87), 91 (75). Anal. calcd for C20H25NO2:
C, 77.1; H, 8.1; N, 4.5. Found: C, 76.7; H, 8.3; N, 4.6%.
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procedure
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a
analogous to that described in Section 4.3.1, compound
5 (4.2.3) gave the title compound as a colourless oil of
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