Quick access to optically pure 2-(1-hydroxybenzyl)piperidine and pyrrolidine

Article abstract of DOI:10.1055/s-2006-926306

Optically pure 2-(1-hydroxybenzyl)piperidine and pyrrolidine were prepared by reaction of oxygenated 2-(p-tolylsulfinyl)benzyl carbanions with the appropriate chlorinated N-sulfinylimines followed by subsequent elimination of the sulfinyl groups. The main reaction is a tandem process involving nucleophilic addition of the sulfinylbenzyl carbanion to the C=N bond followed by intramolecular elimination of the chlorine by the resulting amide. The matched pair of the reagents (exhibiting the same configuration at their respective sulfinyl moieties) evolves with a complete control of the stereoselectivity at the two newly created chiral carbons. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926306

PAPER
687
Quick Access to Optically Pure 2-(1-Hydroxybenzyl)piperidine and
Pyrrolidine
Q
uick Acc
o
ess to Optica
s
lly Pure
2
é
-(1-Hydroxybenz
L
yl)piperidine
a
n
u
d Pyrrolidin
i
e
s García Ruano,* José Alemán, M. Belén Cid
Departamento de Química Orgánica, Universidad Autónoma de Madrid, Cantoblanco, 28049-Madrid, Spain
Fax +34(914)973966; E-mail: joseluis.garcia.ruano@uam.es
Received 28 July 2005; revised 1 September 2005
aldehyde, but this reaction was only applied to the racemic
series.9 Ookawa described the synthesis of 1 from proline
according to a sequence involving five steps, with good de
(94%) for the key asymmetric step (addition of the
Abstract: Optically pure 2-(1-hydroxybenzyl)piperidine and pyr-
rolidine were prepared by reaction of oxygenated 2-(p-tolylsulfi-
nyl)benzyl carbanions with the appropriate chlorinated N-
sulfinylimines followed by subsequent elimination of the sulfinyl
groups. The main reaction is a tandem process involving nucleo- Grignard compound) but only moderate overall yield.10
philic addition of the sulfinylbenzyl carbanion to the C=N bond fol-
lowed by intramolecular elimination of the chlorine by the resulting
Maybe the best method so far reported is that of Lee et al.
who prepared 1 in a four-step synthesis starting from
amide. The matched pair of the reagents (exhibiting the same con-
alkynes in 63% overall yield and a good enantioselectivity
figuration at their respective sulfinyl moieties) evolves with a com-
for the Jacobsen’s epoxidation (94% ee), which is the key
plete control of the stereoselectivity at the two newly created chiral
carbons.
asymmetric step involving the simultaneous formation of
the two chiral centers.11 Finally, Chemla et al. described
their synthesis from proline in five steps with good overall
yields.12
Key words: piperidines, pyrrolidines, benzyl carbanion, N-sulfi-
nylimines, tandem AN/SNi reaction
Some methods, inducing low de, have been reported for
the synthesis of racemic 2-(1-hydroxybenzyl)piperidine
2,8,13 but only two reports concern the synthesis of the op-
tically pure 2. The first synthesis6 described refers to a
method based on the addition of PhMgBr to 2-carboxypy-
ridines, followed by hydrogenation of the pyridine ring
(de range from 60% to 80%) and resolution of each dias-
tereoisomer by chiral HPLC. A similarly low diastereose-
lectivity was reported by Delgado et al.14 starting from
piperidinecarbonitrile derivatives and using a rather long
synthetic sequence. Therefore, there seems to be an obvi-
ous interest in the search of new and efficient methods to
prepare 1 and 2 in enantiomerically pure form.
Enantiomerically pure pyrrolidines1 and piperidines2 rep-
resent a widespread structural motif in alkaloid chemistry.
Specially remarkable are 2-(1-hydroxybenzyl)pyrro-
lidines and piperidines because they are interesting sub-
units contained in many biologically active alkaloids and
azasugar analogues.3 Thus the pyrrolidine 1 and piperi-
dine 2 (Figure 1) exhibit interesting biological activities4,5
and are efficient as chiral ligands for asymmetric process-
es.6,7 Additionally, 2-(1-hydroxybenzyl)pyrrolidines have
been used as precursors of interesting 1,2-disubstituted pi-
peridines.8
H
H
We have recently reported that ortho-sulfinylbenzyl carb-
anions are highly efficient in transferring chiral benzyl
groups to different electrophiles.15,16 In their reactions
with the N-sulfinylimines, these carbanions solve the
problem of the stereoselective benzylation of C=N bond
as well as the synthesis of propylamines and anti-1,2-ami-
no alcohols containing two chiral centers with a complete
control of the stereoselectivity.16 As compounds 1 and 2
have a structure of anti-1,2-amino alcohols, we reasoned
that they could be prepared making use of the same short
synthetic sequence, starting from the O-silylated benzyl-
sulfinyl carbanion and the appropriated imines. The re-
sults we have obtained in this study are reported in this
paper.
N
N
Ph
Ph
OH
OH
1
2
Figure 1 2-(1-Hydroxybenzyl)pyrrolidine 1 and piperidine 2
Despite their importance, only a few methods for synthe-
sizing these compounds in an enantiomerically pure form
have been reported. Several syntheses have been reported
for preparing pyrrolidine 1. (S)-Methyl pyroglutamate
was used as starting material in a three-step sequence
which created the chiral center (reduction of the 2-keto-
pyrrolidine into the corresponding amino alcohol) with a
good overall yield (70%) but moderate stereoselectivity
(de = 68–76%).7a Sanner et al. reported a higher de (90%)
for the reaction of a-lithiopyrrolidine amidines with benz-
As the nucleophile we have used the 2-(p-tolylsulfi-
nyl)benzyl carbanion derived from (R)-3 (Scheme 1).
This compound can be easily prepared in a multigram
scale (2 mmol) in its two possible configurations follow-
ing a short synthetic sequence, from commercially avail-
able starting materials and in 61% overall yield according
to the procedure we had previously reported.15a Its reac-
SYNTHESIS 2006, No. 4, pp 0687–0691
Advanced online publication: 19.01.2006
DOI: 10.1055/s-2006-926306; Art ID: P10705SS
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x
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x
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© Georg Thieme Verlag Stuttgart · New York

688
J. L. García Ruano et al.
PAPER
tion with 1-azacyclohexene did not take place. Thus, we
decided to explore the creation of the C–C bond by reac-
tion with the acyclic N-sulfinylimines 4 and 5 and further
ring closure.
LDA, –78 °C
OTIPS
OTIPS
S
SOTol
O
Tol
(S)-3
O
S
Tol
Cl
N
H
(S)-4
TolOS
TolOS
Figure 2 Ortep diagram for compound 7. Hydrogen atoms, except
H-1 and H-2, are omitted for clarity.
N
NaH, 18-crown-6
0 °C to r.t.
NH
Cl
OTIPS
TolOS
OTIPS
TolOS
8. This result suggested the possibility to perform the two
steps of Scheme 3 in one pot without using the basic cat-
alyst. After a detailed study of conditions, we found that
piperidines 7 and 9 could be directly obtained from 3
when the reactions were initiated at –78 °C and then left
overnight allowing to reach the room temperature. Com-
pounds 7 and 9 were isolated in 66 and 71% yields, re-
spectively (Scheme 3).
7 (78%)
6 (77%)
Scheme 1
The synthesis of (S)-4 and (S)-5 was easily performed ac-
cording to the sequence depicted in Scheme 2. Commer-
cially available 4-chlorobutanol and 5-chloropentanol
were oxidized into their corresponding unstable alde-
hydes.17 They were immediately condensed with com-
mercial (S)-N-p-tolylsulfinylamide (also available in its R
configuration) by using a slight modification18 of the
Davis methodology.19
TolOS
( )n
a) LDA, –78 °C
SOTol
N
OTIPS
b)
N
( )
n H
Cl
SOTol
OTIPS
SOTol
(S)-4 (n = 1)
(S)-5 (n = 0)
SOTol
N
7 (n = 1) 66%
9 (n = 0) 71%
(S)-3
a) PCC, CH2Cl2
b) NH2SOTol
Cl
OH
( )n
( )n
–78 °C to r.t.
overnight
Cl
H
(S)-4 (n = 1) 51% yield
(R)-5 (n = 0) 59% yield
Scheme 3
Scheme 2
The sulfinyl groups present in compounds 7 and 9 can be
removed in good yields by using Ra-Ni, under smooth
conditions (THF, r.t., 2 h, Scheme 4). The optical purity of
the resulting compounds 10 and 11 was established as
higher than 98% from the 1H NMR study of their Mosher
amides 12a/b and 13a/b. It allowed us to conclude that
desulfinylation had been preceded without epimerization
at their chiral carbons.22
We first studied the reaction of compound 4. Sulfoxide
(S)-3 was treated with LDA in THF at –78 °C (the forma-
tion of a purple solution of the carbanion was immediately
observed) followed by the addition of N-sulfinylimine
(S)-4.20 After 5 minutes, the reaction was treated with sat-
urated NH4Cl at –78 °C. Compound anti-6 was isolated in
77% yield as a single diastereoisomer (determined by 1H
NMR spectroscopy). The N-sulfinylamide anti-6 was then
reacted with sodium hydride in the presence of 18-crown-
6, which resulted in the formation of the substituted pipe-
ridine 7 (78%) without significant racemization at any of
their chiral centers (Scheme 1). The anti absolute config-
uration was confirmed for compound 7 by X-ray analysis
(Figure 2).21
Finally we performed the deprotection of the hydroxy
group with TBAF/CH2Cl2 or CsF/THF, obtaining the de-
sired pyrrolidine 1 and piperidine 2 in good yields
(Scheme 4). Their spectroscopic data and optical rotations
are identical to those reported in the literature.23
In conclusion, we have reported a new and very short
method (3 steps, 50% overall yield) to prepare optically
pure 2-(1-hydroxybenzyl)piperidine 1 and pyrrolidine 2
from the sulfoxide (R)-3 and the N-p-tolylsulfinyl imines
4 and 5. The key step is a tandem reaction AN/SNi which
evolves with a complete control of the stereoselectivity at
the two simultaneously formed chiral centers. The starting
Surprisingly, when the N-sulfinylimine (S)-5 was used as
electrophile under identical conditions, a mixture of two
inseparables products 8 and 9 was formed. Compound 8 is
the expected anti amino alcohol derivative, whereas com-
pound 9 is the pyrrolidine resulting in the cyclization from
Synthesis 2006, No. 4, 687–691 © Thieme Stuttgart · New York

PAPER
Quick Access to Optically Pure 2-(1-Hydroxybenzyl)piperidine and Pyrrolidine
689
H
for 20 min, the mixture was cooled to –78 °C and then a solution of
H
( )n
TolOS
( )n
( )n
NBu4F
CH2Cl2
N
N
sulfoxide 3 (200 mg, 0.50 mmol) in THF (2 mL) was added. After
stirring for 1 h, the electrophile [N-sulfinylimine 4, 135 mg, 0.52
mmol] dissolved in THF (4 mL) was added at –78 °C. When the re-
action was complete, the mixture was hydrolyzed with H2O (2 mL),
and extracted with Et2O (3 × 10 mL). The combined organic ex-
tracts were washed with brine (2 × 10 mL), dried (MgSO4) and the
solvent evaporated. The residue was purified by flash column chro-
matography (n-hexane–EtOAc, 5:2); yield: 233 mg (77%); yellow
oil; [a]D20 +39.6 (c = 0.2, CHCl3).
N
Ra-Ni
THF Ph
Ph
OH
OTIPS
OTIPS
TolOS
7 (n = 1)
9 (n = 0)
10 (n = 1), 77% (>98% de)
11 (n = 0), 79% (>98% de)
1 (n = 1), 95%
2 (n = 0), 91%
O
MeO
F3C
Ph
IR (film): 3442 (br s), 1642, 1492, 1461 cm–1.
(Ph)
(CF3)
( )n
N
1H NMR: d = 8.00 (m, 1 H), 7.70 (m, 1 H), 7.59 (m, 3 H), 7.26 (d,
J = 8.3 Hz, 2 H), 7.08 (d, J = 8.3 Hz, 2 H), 6.90 (d, J = 8.1 Hz, 2 H),
6.78 (d, J = 8.1 Hz, 2 H), 5.24 (d, J = 6.5 Hz, 1 H), 3.46 (m, 2 H),
3.20 (m, 2 H), 2.36 (s, 3 H), 2.25 (s, 3 H), 1.90–1.60 (m, 4 H), 1.30
(m, 2 H), 1.10–0.60 (m, 21 H).
Ph
OTIPS
12a/b (n = 1) ee>98%
13a/b (n = 0) ee>98%
13C NMR: d = 142.3 (2 C), 142.1, 141.8, 141.0, 140.7, 131.4, 129.9,
129.1, 128.7, 128.6, 126.3, 125.3, 125.1, 72.6, 63.3, 44.7, 32.3,
31.8, 22.8, 21.4, 18.0, 17.7, 12.3.
Scheme 4
compounds are easily available from commercial prod- MS (FAB): m/z (%) = 660 (M + 1, 49), 616 (16), 508 (30), 385
(100), 211 (40), 139 (25).
HRMS-FAB: m/z calcd for C35H50NO3S2Si [M + H]+: 660.2690;
found: 660.2779.
ucts in both configurations; the enantiomers of 1 and 2
could also be prepared by this procedure.
Melting points are uncorrected. H and 13C NMR spectra were re-
1
One-Pot Preparation of 7 and 9; General Procedure
corded at 300 MHz and 75 MHz, respectively. Chemical shifts (d)
are reported in ppm relative to CDCl3 (7.26 and 77.0 ppm). Mass
spectra were determined at an ionizing voltage of 70 eV. All reac-
tions were carried out in anhyd solvents and under argon. THF and
Et2O were distilled from sodium-benzophenone under argon.
CH2Cl2 was distilled from P2O5. Flash column chromatography was
performed using silica gel Mecrk-60 (230–400 mesh) and Varian
SCX column. n-BuLi (2.5 M solution in hexanes) was purchased
from Aldrich.
A solution of n-BuLi (260 mL, 0.60 mmol, 2.3 M in hexane) was
added to a solution of i-Pr2NH (129 mL, 0.89 mmol) in THF (3 mL)
at 0 °C. After stirring for 30 min, the mixture was cooled to –78 °C.
A solution of the sulfoxide 3 (200 mg, 0.50 mmol) in THF (2 mL)
was then added. After stirring for 1 h, the electrophile [N-sulfi-
nylimine (4 or 5), 0.52 mmol] dissolved in THF (4 mL) was added
at –78 °C. Then the mixture was warmed to r.t. during 24 h. The
mixture was then hydrolyzed with H2O (2 mL), and extracted with
Et2O (3 × 10 mL). The combined Et2O extracts were washed with
brine (2 × 10 mL), dried (MgSO4) and the solvent was evaporated.
The residue was purified by flash column chromatography (n-hex-
ane–EtOAc, 3:1).
(S)-(+)-N-(4-Chlorobutylidene)-p-toluenesulfinamide (5)
In an oven-dried 100 mL round-bottom flask, equipped with a mag-
netic stirring bar, was placed 4-chlorobutanol (300 mg, 2.5 mmol)
in CH2Cl2 (15 mL). PCC (687 mg, 130 mol%) and Celite (700 mg)
previously mixed, were slowly added at 0 °C. The mixture was al-
lowed to come to r.t. and when the reaction was complete, it was fil-
tered over Celite. The dark oil was dissolved in CH2Cl2 (15 mL) in
an oven-dried 100 mL round-bottom flask, equipped with a magnet-
ic stirring bar, a rubber septum, and argon balloon. Then, (S)-p-tol-
uenesulfinamide (390 mg, 100 mol%) and Ti(OEt)4 (2.6 g, 300
mol%) were added. The reaction progress was monitored by TLC
and when the reaction was complete, MeOH (5 mL) and some drops
of sat. aq NaHCO3 were added and filtered through a pad of anhyd
Na2SO4. The crude mixture was chromatographed (n-hexane–
EtOAc, 4:1), to give the N-sulfinylimine 5; yield: 384 mg (59%);
yellow oil; [a]D20 +36.7 (c = 0.3, MeOH).
(2R,1¢S)-N-[(S)-p-Tolylsulfinyl]-2-[(2-p-tolylsulfinylphenyl)tri-
isopropylsilyloxymethyl]piperidine (7)
Purified by column chromatography (n-hexane–EtOAc, 3:1); yield:
71%; yellow oil; [a]D20 +125.0 (c = 0.2, CHCl3).
1H NMR: d = 7.80 (d, J = 7.7 Hz, 1 H), 7.63 (t, J = 8.2 Hz, 1 H), 7.42
(m, 2 H), 7.01 (d, J = 8.2 Hz, 2 H), 6.92 (m, 4 H), 6.47 (d, J = 8.2
Hz, 2 H), 6.02 (d, J = 9.1 Hz, 1 H), 4.09 (m, 1H), 2.90 (d, J = 13.5
Hz, 1 H), 2.47 (d, J = 13.5 Hz, 1 H), 2.33 (s, 3 H), 2.32 (m, 1 H),
2.31 (s, 3 H), 1.98 (m, 1 H), 1.70 (m, 3 H), 1.42 (m, 1 H), 1.10–0.80
(m, 21 H).
13C NMR: d = 145.1, 144.4, 141.2, 140.9, 140.5, 139.9, 132.5,
129.6, 129.3, 129.2, 128.2, 127.7, 125.9, 125.7, 67.6, 66.2, 41.5,
26.7, 25.6, 21.2, 19.6, 18.1, 17.7, 12.5.
IR (film): 3158, 2958, 1622, 1595, 1492 cm–1.
1H NMR: d = 8.19 (t, J = 4.1 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 2 H),
7.23 (d, J = 8.3 Hz, 2 H), 3.48 (td, J = 6.6, 1.6 Hz, 2 H), 2.59 (m, 2
H), 2.32 (s, 3 H), 2.03 (q, J = 6.7 Hz, 2 H).
MS (FAB): m/z = 624 (M + 1, 17), 484 (100), 401 (98), 222 (37),
139 (37), 84 (45).
HRMS-FAB: m/z calcd for C35H49NO3S2Si [M + H]+: 624.2923;
13C NMR: d = 165.2, 141.4, 129.5, 124.2, 43.7, 32.7, 27.6, 21.1.
found: 624.3018.
Anal. Calcd for C11H14ClNOS: C, 54.20; H, 5.79; N, 5.75; S, 13.16.
Found: C, 54.25; H, 5.74; N, 5.80; S, 13.35.
(2R,1¢S)-N-[(S)-p-Tolylsulfinyl]-2-[(2-p-tolylsulfinylphenyl)tri-
isopropylsilyloxymethyl]pyrrolidine (9)
Yield: 71%; colorless oil; [a]D20 +85.6 (c = 0.9, CHCl3).
[1R,2S,(S)S)]-N-{1-(4-Chlorobutyl)-2-[(S)-2-(p-toluenesulfi-
nyl)phenyl]-2-triisopropylsilyloxyethyl}-p-toluenesulfinamide
(6)
A solution of n-BuLi (260 mL, 0.60 mmol, 2.5 M in hexane) was
added to i-Pr2NH (0.89 mmol) in THF (3 mL) at 0 °C. After stirring
IR (film): 3300, 2944, 1597, 1462 cm–1.
1H NMR: d = 7.80 (m, 2 H), 7.52 (m, 2 H), 7.36 (d, J = 8.2 Hz, 2 H),
7.07 (d, J = 7.9 Hz, 2 H), 7.01 (d, J = 7.9 Hz, 2 H), 6.91 (d, J = 8.2
Hz, 2 H), 5.53 (d, J = 6.5 Hz, 1 H), 4.10 (dt, J = 6.6, 2.9 Hz, 1 H),
Synthesis 2006, No. 4, 687–691 © Thieme Stuttgart · New York

690
J. L. García Ruano et al.
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3.30 (m, 1 H), 2.35 (s, 3 H), 2.28 (s, 3 H), 2.12 (m, 1 H), 1.99 (m, 1
H), 1.89 (m, 1 H), 1.75 (m, 1 H), 1.64 (m, 1 H), 1.10–0.80 (m, 23 H).
(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)piperidine-N-
(R)-MTPA Amide (12b)
Prepared from 10; yield: 76%; yellow oil.
13C NMR: d = 143.2, 142.4, 141.4, 140.9, 140.7 (2 C), 131.2, 129.9,
129.2, 129.1, 128.9, 125.8, 125.7, 125.1, 71.4, 69.2, 41.3, 28.7,
25.1, 21.2, 18.0, 17.8, 12.5.
1H NMR: d = 7.52–7.35 (m, 5 H), 7.20 (tt, J = 7.7, 1.0 Hz, 1 H), 7.04
(t, J = 8.31 Hz, 2 H), 6.46 (d, J = 7.7 Hz, 2 H), 5.15 (m, 1 H), 4.95
(d, J = 9.5 Hz, 1 H), 3.68 (s, 3 H), 3.41 (m, 2 H), 2.30 (m, 2 H),
1.75–1.40 (m 4 H), 1.1–0.8 (m, 21 H).
MS (FAB): m/z (%) = 610 (M + 1, 12), 470 (100), 385 (42), 334
(70), 211 (30), 160 (74).
HRMS-FAB: m/z calcd for C34H47NO3S2Si [M + H]+: 610.2767;
found: 610.2855.
(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)pyrrolidine-
N-(S)-MTPA Amide (13a)
Prepared from 11; yield: 55%; yellow oil.
Double Desulfinylation; General Procedure
1H NMR: d = 7.52–7.35 (m, 10 H), 5.65 (d, J = 1.9 Hz, 1 H), 4.22
(td, J = 7.5, 1.9 Hz, 1 H), 3.70 (s, 3 H), 3.53 (m, 1 H), 3.22 (m, 2 H),
2.28 (m, 1 H), 1.69 (m, 1 H), 1.47 (m, 1 H), 1.10–0.80 (m, 21 H).
To a stirred solution of 7 or 9 (0.2 mmol) in THF (2 mL) was added
a suspension of activated Raney-nickel (1.2 g). The reaction was
stirred 2 h, and then the crude product was purified by SCX column
to afford the amine.
(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)pyrrolidine-
N-(R)-MTPA Amide (13b)
Prepared from 11; yield: 55%; yellow oil.
1H NMR: d = 7.60–7.21 (m, 10 H), 5.44 (d, J = 2.2 Hz, 1 H), 4.22
(td, J = 6.2, 2.2 Hz, 1 H), 3.60 (m, 2 H), 3.54 (s, 3 H), 3.41 (m, 1 H),
2.54 (m, 1 H), 2.15 (m, 1 H), 1.80–1.70 (m, 1 H), 1.20–0.80 (m, 21
H).
(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)piperidine
(10)
Yield: 77%; colorless oil; [a]D20 +22.9 (c = 0.4, CHCl3).
IR (film): 3583, 3416, 2942, 1601, 1462, 1198 cm–1.
1H NMR: d = 7.45–7.20 (m, 5 H), 4.72 (d, J = 6.5 Hz, 1 H), 3.58 (br
s, 1 H), 3.13 (m, 1 H), 2.74 (m, 1 H), 2.55 (td, J = 8.9, 2.4 Hz, 1 H),
1.99 (m, 1 H), 1.85 (m, 1 H), 1.60–1.30 (m, 4 H), 1.10–0.90 (m, 21
H).
13C NMR: d = 141.8, 128.2, 127.9, 127.4, 78.1, 63.5, 46.8, 27.7,
25.3, 24.1, 18.0, 17.9, 12.4.
(1R,2S¢)-a-(Pyrrolidin-2-yl)benzyl Alcohol (1)23
A solution of compound 11 (31 mg, 0.1 mmol) in CH2Cl2 (2 mL)
was treated with a 1 M solution of NBu4F (100 mL, 1.2 mmol). After
stirring the mixture for 3 h at r.t., the solvent was evaporated. The
residue was extracted with CH2Cl2 (4 mL), and washed with H2O
(2 × 10 mL). The aqueous phase was treated with NaOH (5 mL)
and extracted with EtOAc (3 × 5 mL). The solvent was dried and
removed under reduced pressure, affording the corresponding
alcohol; yield: 16 mg (91%); [a]D20 +55.0 (c = 0.90, MeOH)
{enantiomer of 1; Lit.23 [a]D20 +56.9 (c = 0.98, MeOH)}.
MS (FAB): m/z (%) = 348 (M + 1, 100) 174 (94), 84 (42).
HRMS-FAB: m/z calcd for C21H38NOSi [M + H]+: 348.2722;
found: 348.2738.
(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)pyrrolidine
(11)
Yield: 79%; colorless oil; [a]D20 +30.2 (c = 0.3, MeOH).
(1R,2S¢)-a-(Piperidin-2-yl)benzyl Alcohol (2)23
A solution of compound 10 (33 mg, 0.1 mmol) in CH2Cl2 (2 mL)
was treated with a 1 M solution of NBu4F (100 mL, 1.2 mmol). After
stirring the mixture for 3 h at r.t., the solvent was evaporated. The
residue was extracted with CH2Cl2 (4 mL), and washed with H2O
(2 × 10 mL). The aqueous phase was treated with NaOH (5 mL)
and extracted with EtOAc (3 × 5 mL). The solvent was dried and
removed under reduced pressure, affording the corresponding
alcohol; yield: 18 mg (95%); [a]D20 +20.0 (c = 1.00, H2O)
{enantiomer of 1; Lit.23 [a]D20 –22.0 (c = 1.30, H2O)}.
IR (film): 3420, 2944, 1456 cm–1.
1H NMR: d = 7.48 (d, J = 8.2 Hz, 2 H), 7.33 (m, 3 H), 5.05 (d,
J = 6.1 Hz, 1 H), 3.69 (m, 1 H), 3.07 (m, 1 H), 2.30–1.80 (m, 5 H),
1.20–0.90 (m, 21 H).
13C NMR: d = 140.3, 128.6, 128.3, 127.3, 74.8, 65.6, 46.0, 27.2,
23.7, 18.0, 12.4.
Anal. Calcd for C20H35NOSi: C, 72.01; H, 10.58; N, 4.20. Found: C,
72.20; H, 10.48; N, 4.40.
MTPA Amides of 10 and 11; General Procedure
Acknowledgment
A solution of compound 10 or 11 (0.01 mmol) in CH2Cl2 (1 mL)
was added to Et3N (5 mL, 0.02 mmol) and (S)-MTPA-Cl or (R)-
MTPA-Cl under argon (6 mL, 0.02 mmol). When the reaction was
complete, the mixture was hydrolyzed with 5% HCl (1 mL), and ex-
tracted with CH2Cl2 (3 × 1 mL). The combined organic extracts
were washed with sat. aq NaHCO3 (2 × 2 mL), dried (Na2SO4) and
the solvent evaporated. The residue was purified by flash column
chromatography (EtOAc–hexane, 1:15).
We thank the Spanish Government for financial support (Grant
BQU2003-4012). J.A. and M.B.C. thank the Ministerio de Ciencia
y Tecnología for a predoctoral fellowship and Ramón y Cajal con-
tract, respectively.
References
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(2R,1¢S)-(1¢-Phenyl-1¢-triisopropylsilyloxymethyl)piperidine-N-
(S)-MTPA Amide (12a)
Prepared from 10; yield: 66%; yellow oil.
1H NMR: d = 7.52–7.20 (m, 10 H), 5.16 (m, 1 H), 4.98 (d, J = 9.6
Hz, 1 H), 3.68 (m, 1 H), 3.42 (m, 1 H), 2.66 (td, J = 13.3, 2.8 Hz, 1
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drops of NaHCO3 until precipitation of the titanium salts.
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solvent evaporated and the residue purify by flash
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(20) Compounds with these configurations had been shown to be
the consonant pair in other previously studied reactions (see
reference 16).
(21) The authors have deposited atomic coordinates for 7 at the
Cambridge Crystallographic Data Centre (deposition
number CCDC 277170). The coordinates can be obtained on
request from the Director Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
(22) Epimerization at chiral centers in the hydrogenolysis of the
C–S bonds with Ra-Ni has been observed in some cases, see:
García Ruano, J. L.; Paredes, C. G.; Hamdouchi, C.
Tetrahedron: Asymmetry 1999, 10, 2935; and references
cited therein.
(23) For piperidine 2, see: (a) Bojadziev, S. E.; Tsankov, T. D.;
Ivanov, P. M.; Berova, N. D. Bull. Chem. Soc. Jpn. 1987, 60,
2651. (b) See also reference 14a. (c) For pyrrodiline 1, see:
reference 10.
Synthesis 2006, No. 4, 687–691 © Thieme Stuttgart · New York