Asymmetric synthesis of the four stereoisomers of 4-hydroxypipecolic acid

Article abstract of DOI:10.1055/s-2000-8710

The asymmetric synthesis of all four stereoisomers of 4-hydroxypipecolic acid (1) from the polyfunctionalized chiral building blocks δ-amino β-keto esters (S(S),R)-(+)-5 or (R(S),S)-(-)-5 is described. Key steps in the synthesis are the stereoselective reductions of b-phenylpiperidine-2,4-dione (6) and N-sulfinyl δ-amino β-keto esters 5 to cis 4-hydroxy 2-piperidinone 7 and syn-δ-amino β-hydroxy ester 9, respectively. The only protecting/deprotecting group chemistry required is related to the oxidation step.

Full text of DOI:10.1055/s-2000-8710

2106
SPECIAL TOPIC
Asymmetric Synthesis of the Four Stereoisomers of 4-Hydroxypipecolic Acid
Franklin A. Davis,* Tianan Fang, Bin Chao, David M. Burns
Department of Chemistry, Temple University, Philadelphia, PA 19122, USA
Fax +1(215)2041532; E-mail: fdavis@astro.ocis.temple.edu
Received 11 August 2000
Only a few syntheses of enantiomerically enriched 4-hy-
Abstract: The asymmetric synthesis of all four stereoisomers of 4-
droxypipecolic acids (1) have been described.8 These in-
hydroxypipecolic acid (1) from the polyfunctionalized chiral build-
ing blocks d-amino b-keto esters (SS,R)-(+)-5 or (RS,S)-(-)-5 is de-
scribed. Key steps in the synthesis are the stereoselective reductions
clude the transformation of 4-oxopipecolic acid (2),9 a
constituent of the virginiamycins family of cyclopep-
of b-phenylpiperidine-2,4-dione (6) and N-sulfinyl d-amino b-keto tides,10 cyclization of chiral N-acyliminium ions11 and
esters 5 to cis 4-hydroxy 2-piperidinone 7 and syn-d-amino b-hy-
droxy ester 9, respectively. The only protecting/deprotecting group
chemistry required is related to the oxidation step.
other procedures which start from D-glucoheptono-1,4-
lactone,12 glycidol,13 or a chiral 1-acylpyridinium salt.14
Unfortunately many of these methods suffer from limita-
tions which include classical resolutions,15 inefficient sep-
aration of diastereoisomers, expensive reagents and/or
lengthy synthetic procedures. Furthermore, none of these
syntheses provide easy access to all four stereoisomers of
1.
Key words: stereoselective reductions, hydrides, cyclization,
asymmetric synthesis, piperidines
Interest in the synthesis of cyclic a-amino acids stems
from the effects these acids have on biological activity
once incorporated into peptides.1 The 4-hydroxypipecolic
acids 1 are of particular relevance because naturally oc-
curring cis-(2S,4R)-(-)-1 is found in cyclodepsipeptide
antibiotics such as virginiamycin S2,2 which is used in the
synthesis of N-methyl-D-aspartic acid (NMDA) receptor
antagonists3a and in the synthesis of the palinavir, a new
class of HIV protease inhibitor.4 Its enantiomer (2R,4S)-
(+)-1 is an intermediate in the synthesis of 4-(phospho-
nonoalkyl)-2-piperidinecarboxylic acids which are potent
NMDA receptor antagonists of interest for the treatment
of CNS disorders.3a trans-(2S,4S)-4-Hydroxypipecolic
acid (1) was isolated from leaves of the Acacia species,5
and its 4-sulfate is also a selective NMDA receptor ago-
nist.6 In addition, these cyclic amino acids are of impor-
tance as building blocks for the synthesis of piperidine
alkaloids.7
As part of a program to design and synthesize polyfunc-
tionalized chiral building blocks, we recently introduced
N-sulfinyl d-amino b-keto esters for alkaloid synthe-
sis.16,17 These building blocks are prepared from sulfin-
imines (N-sulfinyl imines)18 and are used in the highly
efficient asymmetric synthesis of (R)-(+)-2-phenylpiperi-
dine, (-)-SS20846A,16 and the quinolizidine alkaloid
(-)-lasubine II.17 In particular (SS,R)-(+)-methyl 3-oxo-5-
phenyl-5-(p-toluenesulfinylamino)pentanoate (5) was
prepared in one-pot by treatment of sulfinimine (S)-(+)-3
with an excess of the sodium enolate of methyl acetate in
THF/Et2O (Scheme 1).16 Alternatively, 5 can be prepared
from the b-amino acid (SS,R)-(+)-4. Treatment of (+)-5
with trifluoroacetic acid (TFA)/MeOH, passing the solu-
tion through a short plug of silica gel to remove the sulfi-
nate byproduct, and addition of aqueous saturated
NaHCO3 solution in THF afforded (R)-(+)-6-phenylpipe-
ridine-2,4-dione (6) in 90% yield for the two steps. Our
plan then consisted of stereoselectively reducing the
4-oxo group in 6 to the cis or trans hydroxy derivatives 7
and using the phenyl group as a carboxylic acid equiva-
lent.19 Herein we describe the asymmetric synthesis of all
four stereoisomers of 4-hydroxypipecolic acid 1 from
(SS,R)-(+)-5 and its enantiomer (RS,S)-(-)-5.
R1 R2
R1 R2
HO2C
N
H
HO2C
N
H
(2S,4R)-(-)-1: R1 = H, R2 = OH
(2S,4S)-(-)-1: R1 = OH, R2 = H
(2R,4S)-(+)-1: R1 = OH, R2 = H
(2R,4R)-(+)-1: R1 = H, R2 = O H
It appears that there have been no reports on the stereose-
lective reduction of piperidine-2,4-diones such as 6. In
contrast, several studies on the reduction of 2-substituted
and 2,6-disubstituted 4-oxo piperidines have appeared. In
one study a 2-substituted NH 4-oxo piperidine with L-Se-
lectride gave the cis-product (cis/trans = 90:10), while an
N-protected derivative afforded the trans-isomer (cis/
trans = 5:95).20 In another study a 2-substituted N-PMP-
4-oxopiperidine gave a 89:11 cis/trans ratio of products
with L-Selectride, and with NaBH4/CeCl3 the ratio was re-
versed (cis/trans = 30:70).21 On the other hand 2,6-disub-
stituted 4-oxo piperidines give the cis- and trans-products
O
N
H
CO2H
2
Figure 1 Structures of 4-Hydroxypipecolic acids 1 and 4-oxopipe-
colic acid (2)
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Synthesis of the Four Stereoisomers of 4-Hydroxypipecolic Acid
2107
with NaBH4 and L-Selectride, respectively.22 Despite
these encouraging results all attempts to produce the
trans-isomer (4S,6R)-7 as the major product were unsuc-
cessful (Table). Indeed all reducing reagents tested afford-
ed a predominance of the cis-isomer (4R,6R)-7 with
maximum selectivity (97:3) being observed with NaBH4
and Zn(BH4)2 (Entries 1, 4 and 5). It proved impossible to
remove the minor isomer by chromatography, and crystal-
lization from i-PrOH/pentane gave (4R,6R)-7 in only 50%
yield. For this reason it was found more efficient to move
on to the next step with crude material, where the minor
isomer was eliminated (see below). The maximum
amount of the trans-(4S,6R)-7 was observed with L-Selec-
tride, but the 1:1 cis/trans ratio was synthetically unac-
ceptable (Entry 8). We believe that axial attack is
particularly favorable in 8, not only because torsional
strain is relieved, but a bulky reducing reagent encounters
a single 5-axial hydrogen on approach. Flattening of the
piperidine ring, as a consequence of enolate-elongation
due to the acidity of the 3 protons, may also enhance axial
attack.
O
S
O
S
H
p-Tolyl
NH
CH3CO2Me
CO2Me
p-Tolyl
N
Ph
Ph
NaHMDS
-78 °C, Et2O
(84%, >97% de)
(S)-(+)-3
(SS,R)-(+)-4
4 equiv.
CH3CO2Me
4 equiv NaHMDS
(93%, >97% de)
O
S
5 equiv CH3CO2Me
6 equiv NaHMDS
p-Tolyl
NH
O
O
Ph
OMe
(89%, >97% de)
(SS,R)-(+)-5
R2
R1
O
1) TFA/MeOH
2 )NaHCO3
[H]
Ph
N
H
(90%)
O
Ph
N
H
O
cis-(4R,6R)-(+)-7: R1 = OH, R2 = H
trans-(4S,6R)-(+)-7: R1 = H, R2 = OH
(R)-(+)-6
While a nitrogen substituent may alter the conformation
of the piperidine-2,4-dione ring to minimize A1,3 strain,
and favor equatorial (trans) attack, this would require ad-
ditional steps.23 For this reason we explored the syn and
Scheme 1
Table Reduction of (R)-(+)-6 and (SS,R)-(+)-5
Entry
Reducing Agents/Conditions
From (R)-(+)-6
From (SS,R) (+)-5
cis/trans 7a (% yield)
syn/anti 9a (% yield)
1
2
NaBH4/THF, -78°C, 2 h (42 h)b
NaBH4/AcOH, -78°C, 2 h
97:3 (92) [51]c
85:15 (92)
95:5 (82)
66:34 (90)
3
NaBH4/CeCl3/MeOH, -78 to 0°C, 10 min (1.5 h)
Zn(BH4)2, THF, -78°C, 1 h (5 h )
Zn(BH4)2/CH2Cl2, -78°C, 1 h (4 h)
L-Selectride (5 equiv)/THF, -78°C, 6 h (6 h)
L-Selectride (5 equiv)/CH2Cl2, -78°C, 6 h
L-Selectride (5 equiv)/THF, r.t., 6 h
DIBAL-H/THF, -78°C, 6 h (6 h)
DIBAL-H/ZnCl2/THF, -78°C, 6 h
Ph2MeSiH/THF/TFA, r.t., 12 h
67:33 (15)
4
97:3 (90)
77:23 (90) [69]c
88:12 (90)
5
97:3 (90)
6
no reaction
70:30 (98)
1:1 (70)
no reaction
7
8
9
no reaction
89:11 (20)
10
11
12
12
14
15
16
complex mixture
70:30 (30)
Me4NBH4/THF, -78°C, 2 h
45:55 (85)
33:67 (50)
9:91 (46)
LiEt3BH/THF, -78°C, 5 h
LiEt3BH/Et2O, -78°C, 8 h
LiEt3BH/t-BuOH/THF, -78°C, 6 h
NaEt3BH/THF, -78°C, 6 h
no reaction
55:43 (42)
a Determined from the NMR of the crude mixtures.
b Time for reduction of (+)-5.
c Isolated yield of the major diastereoisomer.
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

2108
F. A. Davis et al.
SPECIAL TOPIC
ratio of 9:91 (Entry 14). However, it was difficult to ob-
tain reproducible results, particularly in larger scale reac-
tions, because the sulfinyl and/or methoxycarbonyl
groups were being reduced.
axial (cis)
H-
H
Ph
MeO2C
O
O
O
M
HN
Ph
N
S(O)-p-Tolyl
equatorial
Reduction of cis- and trans-7 with LiAlH4 for 36 hours
gave diastereomerically pure cis- and trans- 11 in 62 and
64% yields, respectively (Scheme 3). Differential protec-
tion of the amino and hydroxy groups was accomplished
by sequential treatment of 11 with trifluoroacetic anhy-
dride (TFAA) and acetic anhydride to give 12.13,26 Oxida-
tion of the phenyl groups in 12 was accomplished using
NaIO4/RuCl3, followed by deprotection of the hydroxyl
and amino groups with K2CO3/MeOH.13 4-Hydroxypipe-
colic acids cis-(2R,4S)-(+)-1 and trans- (2R,4R)-(+)-1
were isolated by ion exchange (Dowex 50W X8 resin) in
61% and 79% yields, respectively. Their properties were
in agreement with literature values.
(trans)
8
10
Figure 2 Proposed structure 8 for the preferential formation of
trans-(4S,6R)-7 in the reduction with L-Selectride and the structure of
the six-membered chelate 10
anti reduction of d-amino b-keto ester 5 to d-amino b-hy-
droxy ester 9 (Scheme 2). Although there are many stud-
ies on the reduction of acyclic b-hydroxy ketones21 there
are no reports on the reduction of d-amino b-keto esters
and only a few studies on the reduction of acyclic b-amino
ketones.24,25 For the reduction of acyclic b-hydroxy ke-
tones, high syn selectivity was observed with reagents that
deliver an external hydride ion [NaBH4, Zn(BH4)2], and
anti selectivity was observed when hydride was delivered
intramolecularly (LiAlH4).21 In our case, we needed syn-9
because on cyclization it gives the desired trans isomer
(4S,6R)-(+)-7. The choice of reducing reagent was limited
to those that were unlikely to cleave the sulfinyl group
and/or reduce the ester functionality. These results are
summarized in the Table.
OH
OH
b
a
cis (+)-7
or
trans (+)-7
Ph
N
H
Ph
N
H
(2R,4S)-(+)-11
(2R,4R)-(+)-11
OAc
OAc
(2R,4S)-(+)-1
or
c
or
Ph
N
Ph
N
(SS,R)-(+)-5
COCF3
COCF3
(2R,4R)-(+)-1
[H]
(2R,4S)-(+)-12
(2R,4R)-(+)-12
O
S
O
S
Reagents and conditions: (a) LiAlH4, 36 h, (cis or trans: 62 or 64%);
(b) i) TFAA/Et3N, ii) K2CO3/THF, iii) Ac2O/Et3N/DMAP (83% or
80%); (c) i) NaIO4/RuCl3/CCl4/MeCN/H2O, ii) K2CO3, iii) Dowex 50
X8 resin (79% or 61% yield)
p-Tolyl
NH OH O
p-Tolyl
NH OH O
+
Ph
OMe
Ph
OMe
syn-(SS,3S,5R)-(+)-9
anti-(SS,3R,5R)-(+)-9
Scheme 3
1) TFA/MeOH
2) NaHCO3
(92%)
The advantage of using d-amino b-keto esters as chiral
building blocks for alkaloid synthesis is that both enanti-
omers are easily available. Thus, beginning with d-amino
b-keto ester (RS,S)-(-)-5, 4-hydroxypipecolic acids
cis-(2S,4R)-(-)-1 and trans-(-)-(2S,4S)-(-)-1 were pre-
pared in a similar manner in 61% and 68% yields, respec-
tively (Scheme 4).
H
OH
Ph
N
H
O
In summary, the asymmetric synthesis of all four stereoi-
somers of 4-hydroxypipecolic acid 1 has been achieved
from the polyfunctionalized chiral building blocks d-ami-
no b-keto esters (SS,R)-(+)-5 or (RS,S)-(-)-5. It is note-
worthy that the only protection/deprotection group
chemistry necessary is related to the oxidation step, serv-
ing to illustrate the utility of these building blocks for the
efficient asymmetric synthesis of alkaloids.
trans- (4S,6R)-(+)-7
Scheme 2
Good syn selectivity was observed only for Zn(BH4)2
(77:23) (Entries 1 and 4), which afforded, after flash chro-
matography, (SS,3S,5R)-(+)-9 in 69% yield (entries 4).
This result is consistent with formation of a six-membered
chelate 10 and external delivery of hydride. Treatment of
syn-(+)-9 with TFA/MeOH followed by NaHCO3 gave
(4S,6R)-(+)-7 in 97% yield. The best anti selectivity was
observed for lithium triethylborohydride to give a syn/anti
Column chromatography was performed on silica gel, Merck grade
60(230-400 mesh). Analytical and preparative TLC were per-
formed on precoated silica gel plates (250 and 400 mm) purchased
from Analtech Inc. TLC plates were visualized by quenching of UV
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Synthesis of the Four Stereoisomers of 4-Hydroxypipecolic Acid
2109
was added slowly via syringe and stirred vigorously for 40 min.
Et2O (5.4 mL) was added followed by addition of (S)-(+)-N-(ben-
zylidene)-p-toluenesulfinamide28 (0.59 g, 2.42 mmol) in THF
(5 mL) via cannula. The reaction mixture was stirred at -78 °C for
3 h and monitored by TLC. If the starting material was absent, but
(+)-4 was present, the reaction temperature was raised to -42 °C for
an additional 3 h and quenched with aq sat NH4Cl solution (5 mL).
H2O (5 mL) was added and the aq. phase was washed with EtOAc
(2 î 10 mL). The combined organic phases were washed with brine
(10 mL), dried (Na2SO4), concentrated, and the residue was purified
by flash chromatography (30% EtOAc/hexane) to give 0.74 g
O
S
O
S
a
p-Tolyl
NH
O
O
p-Tolyl
NH OH O
Ph
OMe
Ph
OMe
(RS,S)-(-)-5
(RS,3R,5S)-(-)-9
b
O
OH
OH
c
20
(85%) of an oil in >98% de; Rf 0.12 (40% EtOAc/hexanes); [a]D
77.0 (c = 1.6, CHCl3); [Lit.16 [a]D20 +73.6 (c = 1.63, CHCl3)].
N
H
O
N
O
N
O
Ph
Ph
Ph
H
H
Methyl (RS,S)-(-)-3-Oxo-5-(p-toluenesulfinylamino)-5-phenyl-
(S)-(-)-6
(4S,6S)-(-)-7
(4R,6S)-(-)-7
pentanoate (5)
20
Yield: 81%; oil; >98% de; Rf 0.12 (40% EtOAc/Hexanes); [a]D
-79.6 (c = 1.5, CHCl3). Spectral properties were identical to (+)-5.
d
d
(R)-(+)-6-Phenylpiperidine-2,4-dione (6)
(2S,4R)-(-)-11
(2S,4S)-(-)-11
In a 50 mL one-necked round-bottomed flask equipped with a mag-
netic stir bar was placed (SS,R)-(+)-5 (1.14 g, 3.16 mmol) in MeOH
(20 mL). The mixture was cooled to 0 °C and TFA (1.22 mL,
15.8 mmol) was added. After stirring at r.t. for 1 h, the mixture was
concentrated and residue was loaded onto a short pad of silica gel
that was then washed with 30% EtOAc/hexane (40-50 mL) until
the TLC indicated the absence of the methyl p-toluenesulfinate
byproduct. Elution with MeOH (50 mL) and concentration gave a
residue that was then dissolved in THF (20 mL) and treated with aq
sat NaHCO3 solution (5 mL). After stirring for 1 h, the solution was
diluted with EtOAc (50 mL) and the aqueous layer was acidified
with concd HCl to pH ~3. The mixture was washed with EtOAc (2
î 20 mL), and the combined organic phases were washed with brine
(10 mL), dried (Na2SO4) and concentrated to give 0.54 g (90%) of
a white solid; mp 166-168 °C; Rf 0.17 (40% EtOAc/CH2Cl2);
e
e
(2S,4R)-(-)-12
(2S,4S)-(-)-12
f
f
(2S,4S)-(-)-1
(2S,4R)-(-)-1
Reagents: (a) Zn(BH4)2 (72%); (b) i) TFA, ii) NaHCO3 (91 and 96%);
(c) NaBH4 (96%); (d) LAH (64 and 59%); (e) i) TFAA/Et3N,
ii) K2CO3, iii) Ac2O/Et3N, (78 and 84%); (f) i) NaIO4/RuCl3/CCl4/
MeCN/H2O, ii) K2CO3, iii) Dowex 50 X8 resin, (61 and 68% yield).
Scheme 4
20
20
[a]D +123.4 (c = 0.35, CHCl3); [Lit.16 mp 167-169 °C; [a]D
+124.3 (c = 0.37, CHCl3)].
(S)-(-)-6-Phenylpiperidine-2,4-dione (6)
fluorescence (lmax 254 nm), staining with I2 or with 0.5% ninhydin
20
Yield: 91%; Rf 0.17 (40% EtOAc/CH2Cl2); mp 166-168 °C; [a]D
in EtOH. IR spectra were obtained using NaCl plates or KBr discs
1
and recorded on a Mattson 4020 FTIR spectrometer. H and 13C
-122.7 (c = 1.0, CHCl3). Spectral properties were identical to (+)-6.
NMR were recorded on a General Electric Omega 500, operating at
500 MHz and 125 MHz, respectively. The spectra were referenced
to solvent residues as internal standards. HRMS analyses were per-
formed in the Department of Chemistry, Drexel University, Phila-
delphia, PA using a Fissions ZAB HF double focusing mass
spectrometer. Melting points were recorded on a MEL-TEMP appa-
ratus and are uncorrected. Optical rotations were measured on a Per-
kin-Elmer 341 polarimeter and elemental analyses were performed
in the Department of Chemistry, University of Pennsylvania, Phila-
delphia, PA.
(4R,6R)-(+)-4-Hydroxy-6-phenylpiperidin-2-one (cis-7)
In a 50 mL one-necked round-bottomed flask equipped with a mag-
netic stir bar, rubber septum, and an argon balloon was placed
(R)-(+)-6 (0.32 g, 1.69 mmol) in THF (15 mL). The solution was
cooled to -78 °C and NaBH4 (0.70 g, 18.5 mmol) was added. After
stirring at this temperature for 5 h, aq sat NH4Cl solution (5 mL),
and H2O (5 mL) were added, and the phases were separated. The
aqueous phase was extracted with EtOAc (2 î 20 mL), and the com-
bined organic phases were washed with brine (10 mL), dried
(Na2SO4) and concentrated. The residue was crystallized from i-
PrOH/hexanes to give 0.165 g (51%) of a solid in >98% de; mp
THF and Et2O were freshly distilled under an inert atmosphere from
a purple solution of sodium/benzophenone ketyl. Anhyd CH2Cl2
was obtained by refluxing over CaH2 followed by distillation under
an inert atmosphere. Zn(BH4)2 was prepared according to a litera-
ture procedure.27 All other reagents were obtained from commercial
sources and used without further purification. Reactions were per-
formed under an inert atmosphere of argon unless otherwise stated
and all glassware was vacuum or oven dried prior to use.
20
213 °C [Lit.29 mp 212-214 °C for ( )-7]; [a]D +52.3 (c = 0.88,
MeOH).
1H NMR (CD3OD): d = 1.60 (ddd, J = 11.7, 11.7, 11.4 Hz, 1 H),
2.23-2.31 (m, 2 H), 2.66-2.71 (ddd, J = 16.9, 5.5, 2.2 Hz, 1 H),
4.06-4.12 (m, 1 H), 4.48 (dd, J = 11.7, 4.4 Hz, 1 H), 7.23-7.38 (m,
5 H).
13C NMR (CD3OD): d = 41.4, 42.6, 56.2, 65.5, 127.4, 129, 129.9,
Methyl (SS,R)-(+)-3-Oxo-5-phenyl-5-(p-toluenesulfinylamino)-
pentanoate (5)
143.5, 173.4.
This procedure is a modification of an earlier procedure.16 In a
100 mL one-necked round-bottomed flask equipped with a magnet-
ic stirring bar, rubber septum, and argon inlet was placed a 1 M so-
lution of NaHMDS in THF (12.1 mL, 12.1 mmol) in THF (10 mL)
and cooled to -78 °C. Anhyd methyl acetate (0.96 mL, 12.1 mmol)
(4S,6S)-(-)-4-Hydroxy-6-phenylpiperidin-2-one (cis-7)
20
Yield: 96%; mp 211-213 [Lit.29 mp 212-214 °C for ( )-7]; [a]D
-51.9 (c = 0.56, MeOH). Spectral properties were identical to cis-
(+)-7.
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

2110
F. A. Davis et al.
SPECIAL TOPIC
Methyl (SS,3S,5R)-(+)-3-Hydroxy-5-phenyl-5-(p-toluenesulfin-
ylamino)pentanoate (syn-9)
EtOAc/hexane (40-50 mL) until the TLC indicated the absence of
methyl p-toluenesulfinate. Elution with MeOH (50 mL) and con-
centration gave a residue which was dissolved in THF (30 mL) and
treated with aq sat NaHCO3 solution (7.5 mL). The mixture was
stirred at r.t. for 2 h, diluted with EtOAc (100 mL), washed with
brine (20 mL), dried (Na2SO4) and concentrated to give 0.256 g
(97%) of a white solid; mp 195-198 °C; [a]D20 +29.9 (c = 0.67,
MeOH).
IR (KBr): n = 3238, 1621, 1470, 1327, 1158, 1055 cm-1.
1H NMR (CD3OD): d = 1.84 (m, 1 H), 2.10 (m, 1 H), 2.38 (m, 1 H),
2.66 (dd, J = 18.0, 4.4 Hz, 1 H), 4.21 (m, 1 H), 4.78 (dd, J = 9.9, 4.8
Hz, 1 H), 7.38-7.26 (m, 5 H).
In a 250 mL one-necked round-bottomed flask was placed
(SS,R)-(+)-5 (1.04 g, 2.89 mmol) in Et2O (30 mL) and THF (50 mL).
The solution was cooled to -78 °C and Zn(BH4)227 (0.14 M in Et2O,
41 mL, 5.74 mmol) was added dropwise. The reaction mixture was
stirred at -78 °C for 5 h, quenched by addition of aq sat NH4Cl so-
lution (20 mL), H2O (20 mL) and extracted with EtOAc (2 î 50
mL). The combined organic phases were washed with brine
(20 mL), dried (Na2SO4) and concentrated to give 9 as a 77:23 mix-
ture of diastereomers. Purification by flash chromatography (20-
40% EtOAc/CH2Cl2) afforded 0.725 g (69%) of syn-(+)-9 as a col-
20
orless oil; Rf 0.18 (40% EtOAc/CH2Cl2); [a]D +63.6 (c = 01.1,
13C NMR (CD3OD): d = 39.4, 40.0, 54.2, 63.8, 127.4, 128.8, 129.9,
143.9, 174.1.
CHCl3).
IR (neat): n = 3249, 3021, 2362, 1733, 1439, 1216, 1054, 760 cm-1.
1H NMR (CDCl3): d = 1.80 (ddd, J = 14.3, 4.8, 1.8 Hz, 1 H), 1.98
(ddd, J = 14.3, 10.3, 8.8 Hz, 1 H), 2.30-2.46 (m, 5 H), 3.66 (s, 3 H),
3.90 (br s, 1 H), 4.17 (m, 1 H), 4.78 (m, 1 H), 5.42 (d, J = 2.6 Hz, 1
H), 7.15 (d, J = 8.4 Hz, 2 H), 7.23-7.57 (m, 7 H).
13C NMR (CDCl3): d = 22.03, 42.51, 45.18, 52.43, 58.30, 68.09,
126.12, 128.32, 129.40, 129.91, 130.81, 141.90, 142.79, 143.16,
173.17.
HRMS: m/z calcd for C11H13NO2 (M + Na) 214.0844, found
214.0843.
(4R,6S)-(-)-4-Hydroxy-6-phenylpiperidine-2-one (trans-7)
Yield: 98%; mp 196-198 °C; [a]D20 -30.4 (c = 1.2, MeOH). Spec-
tral properties were identical to (+)-7.
(2R,4S)-(+)-2-Phenylpiperidine-4-ol (cis-11)
In a 25 mL single neck round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum and argon-filled balloon was
placed cis-(+)-7 (0.433 g, 2.26 mmol) in THF (4 mL). The solution
was cooled to -78 °C, and a 1 M solution of LiAlH4 in THF
(11.3 mL, 11.3 mmol) was added slowly via syringe, and the mix-
ture was stirred at r.t. for 36 h. At this time the solution was cooled
to 0 °C, quenched with aq sat Na2SO4 solution (2 mL), stirred for
0.5 h and filtered through Celite. The filtrate was washed with
EtOAc (50 mL), and the organic phase was washed with 2 N NaOH
(10 mL), brine (10 mL), dried (Na2SO4) and concentrated. The res-
idue was purified by flash chromatography (90:10:2, CH2Cl2/
MeOH/28% NH4OH) to afford 0.25 g (62%) of a white solid; mp
101-102 °C (Lit.13 mp 101-102 °C for the enantiomer of cis-11);
[a]D20 20.2 (c = 0.56, MeOH) [Lit.13 [a]D20 -10.9 (c = 0.53, MeOH)
for its enantiomer (2S,4R)-11]. Physical and spectral properties
were in agreement with literature values.13
HRMS: m/z calcd for C19H23NO4S (M + H): 362.1426; found
362.1417.
Methyl (SS,3R,5R)-(+)-3-Hydroxy-5-phenyl-5-(p-toluenesulfin-
ylamino)pentanoate (anti-9)
Yield: 0.221 g (21%); colorless oil; Rf 0.28 (40% EtOAc/CH2Cl2);
[a]D20 +95.5 (c = 0.56, CHCl3).
IR (neat): n = 3265, 3029, 2952, 1733, 1439, 1057 cm-1.
1H NMR (CDCl3): d = 1.80 (br s, 1 H), 1.89 (ddd, J = 14.7, 9.2, 3.3
Hz, 1 H), 2.01 (ddd, J = 14.7, 9.5, 4.0 Hz, 1 H), 2.40-2.45 (m, 4 H),
2.58 (dd, J = 16.5, 8.8 Hz, 1 H), 3.67 (s, 3 H), 4.15-4.20 (m, 1 H),
4.83 (m, 1 H), 4.98 (d, J = 6.6, 1 H), 7.26-7.40 (m, 7 H), 7.61(d,
J = 8.4, 2 H).
13C NMR (CDCl3): d = 22.0, 41.7, 44.9, 52.6, 56.6, 65.4, 126.2,
127.6, 128.1, 129.3, 130.4, 142.1, 142.9, 143.4, 173.4.
(2R,4R)-(+)-2-Phenylpiperidine-4-ol (trans-11)
Methyl (RS,3R,5S)-(-)-3-Hydroxy-5-phenyl-5-(p-toluenesulfin-
ylamino)pentanoate (syn-9)
Following the same procedure described for the preparation of cis-
(+)-11, trans-(+)-7 gave 0.23 g (64%) of a white solid; mp 107-
108 °C; [a]D20 +65.6 (c = 0.5, CHCl3).
IR (KBr): n = 3427, 3170, 1455, 1316, 1115 cm-1.
20
Yield: 72%; Rf 0.18 (40% EtOAc/CH2Cl2); [a]D -62.8 (c = 1.1,
CHCl3). Spectral properties were identical to syn-(+)-9.
1H NMR (CDCl3): d = 1.65 (br s, 1 H), 1.74-1.93 (m, 4 H), 3.01
(ddd, J = 2.6, 4.8, 11.7 Hz, 1 H), 3.26 (dt, J = 2.9, 12.3 Hz, 1 H),
3.52 (s, 1 H), 4.11 (dd, J = 2.9, 11.4 Hz, 1 H), 4.30 (m, 1 H), 7.27-
7.43 (m, 5 H).
13C NMR (CDCl3): d = 145.6, 129.1, 127.8, 127.4, 66.1, 56.2, 42.3,
42.1, 33.5.
Methyl (RS,3S,5S)-(-)-3-Hydroxy-5-phenyl-5-(p-toluenesulfin-
ylamino)pentanoate (anti-9)
In a 10 mL one-necked round-bottomed flask equipped with a mag-
netic stirring bar, rubber septum, and argon inlet was placed
(RS,S)-(-)-5 (0.027 g, 0.075 mmol) in Et2O (1.5 mL) and cooled to
-78 °C. LiEt3BH (Super-Hydride) (190 mL, 0.19 mmol), was added
dropwise and the reaction mixture was stirred for 5 h. At this time
the solution was quenched by addition of a few drops of MeOH fol-
lowed by H2O (5 mL), and the mixture was extracted with EtOAc
(3 î 5 mL). The combined organic phases were washed with brine
(10 mL), dried (Na2SO4) and concentrated to give a 91:9 mixture of
diastereomers that were separated by flash chromatography (20-
40% EtOAc/CH2Cl2) affording 0.012 g (44%) of anti-9 as a color-
HRMS: m/z calcd for C11H15NO (M+H) 178.1232, found 178.1235.
(2S,4R)-(-)-2-Phenylpiperidine-4-ol (cis-11)
Yield: 64%; mp 101-102 °C; [a]D20 -19.5 (c = 0.70, MeOH). Phys-
ical and spectral properties were in agreement with literature val-
ues.13
(2S,4S)-(-)-2-Phenylpiperidine-4-ol (trans-11)
20
less oil; Rf 0.28 (40% EtOAc/CH2Cl2); [a]D -96.1 (c = 1.2,
Yield:59%; mp 107-108 °C; [a]D20 -64.8 (c = 0.81, CHCl3). Spec-
tral properties were identical to (2R,4R)-(+)-11.
CHCl3). Spectral properties were identical to anti-(+)-9.
(4S,6R)-(+)-4-Hydroxy-6-phenylpiperidine-2-one (trans-7)
In a 100 mL one-necked round-bottomed flask was placed
syn-(+)-9 (0.5 g, 1.38 mmol) in MeOH (30 mL). The mixture was
cooled to 0 °C and TFA (0.53 mL, 6.86 mmol) was added. After
stirring at r.t. for 1 h, the mixture was concentrated and residue was
loaded onto a short pad of silica gel which was washed with 30%
(2R,4S)-(+)-4-Acetoxy-2-phenyl-1-trifluoroacetylpiperidine
(cis-12)
This procedure is a modification of an earlier procedure.13 To an ice
cold solution of cis-(+)-11 (0.104 g, 0.59 mmol, 1.0 equiv) in
CH2Cl2 (10 mL) containing Et3N (0.49 mL, 3.52 mmol, 6 equiv)
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

SPECIAL TOPIC
Asymmetric Synthesis of the Four Stereoisomers of 4-Hydroxypipecolic Acid
2111
and 4-dimethylaminopyridine (3 mg) was added trifluoroacetic an-
hydride (0. 33 mL, 2.34 mmol, 4.0 equiv) via a syringe. After stir-
ring at r.t. for 12 h, H2O (1 mL) was added and the solution was
washed with brine (5 mL), dried (Na2SO4) and concentrated. The
residue was dissolved in THF (10 mL), K2CO3 (0.162 g (1.17 mmol,
2.0 equiv) and H2O (0.8 mL) were added, and the mixture was
stirred for 5 h. At this time H2O (2 mL) was added, the solution was
washed with CH2Cl2 (2 î 5 mL), and dried (Na2SO4). After filter-
ing into a one-neck 25 mL round bottomed flask, Et3N (0.33 mL,
2.37 mmol, 4.0 equiv) and dimethylaminopyridine (3mg) were add-
ed. The mixture was cooled to 0 °C, Ac2O (0.11 mL, 1.17 mmol,
2.0 equiv) was added and the solution was stirred at r.t. for 12 h. At
this time H2O (1 mL) was added, the solution was washed with
brine (5 mL). The organic phases were dried (Na2SO4), filtered and
concentrated to give an oil that was purified by preparative TLC
(EtOAc/pentane, 30:70) to give 0.154 g (83%) of cis-(+)-12 as a
colorless oil; [a]D20 49.3 (c = 1.1, CH2Cl2); [Lit.13 [a]D20 -45.5 (c =
1.05, CH2Cl2) for the enantiomer].
1H NMR (CDCl3) (it existed as rotamers): d = 1.44 (s, 0.9 H), 1.51
(s, 2.1 H), 1.72-1.96 (m, 2 H), 2.11-2.16 (m, 1 H), 2.87-2.99 (m,
1 H), 3.33 (m, 0.3 H), 3.68 (q, J = 12.8 Hz, 0.7 H), 3.92 (d, J = 13.6
Hz, 0.7 H), 4.54 (d, J = 11.7 Hz, 0.3 H), 5.07 (s, 1 H), 5.34 (br s, 0.3
H), 5.85 (d, J = 5.1 Hz, 0.7 H), 7.12-7.36 (m, 5 H).
13C NMR (CDCl3): d = 171.0, 157.5 (m), 139.3, 138.8, 129.4, 127.5,
125.7, 117.3 (q, J = 288 Hz), 66.9, 54.5, 51.8, 38.5, 35.7, 32.6, 31.7,
30.8, 29.9, 21.2.
solved in methanol (5 mL), 0.368 g (2.66 mmol) of K2CO3 was add-
ed, and the mixture was stirred at r.t. for 12 h. The solution was
concentrated, acidified with 1 N HCl, purified using a Dowex 50W-
X8 resin (50-100 mesh) and eluted with 5% NH4OH (150 mL). The
ninhydrin positive fractions were combined and evaporated in vac-
uo to give a solid which was washed with activated carbon (1.0 g)
in hot H2O (20 mL). Concentration and drying under vacuum gave
20
0.039 g (61%) of (2R,4S)-(+)-1 as a white gum; [a]D +19.3 (c =
0.7, H2O) [Lit.13 [a]D22 -17.2 (c = 1.05, H2O) for the enantiomer].
(2S,4R)-(-)-4-Hydroxypipecolic Acid (cis-1)
Yield: 61%; white gum; [a]D -18.9 (c = 0.7, H2O) [Lit.13 [a]D
20
20
-17.2 (c = 1.05, H2O)].
(2R,4R)-(+)-4-Hydroxypipecolic Acid (trans-1)
Yield: 79%; white gum; [a]D20 +12.6 (c = 0.8, H2O) [Lit.5 [a]D
20
-13 0.4 (1% in H2O) for the enantiomer]. Spectral properties were
in agreement with literature values.30
(2S,4S)-(-)-4-Hydroxypipecolic Acid (trans-1)
Yield: 68%; white gum; [a]D -12.6 (c = 0.8, H2O) [Lit.5 [a]D
20
20
-13 0.4 (1% in H2O) for the enantiomer]. Spectral properties were
in agreement with literature values.30
Acknowledgement
We thank Professor R. O. Hutchins, Drexel University, for helpful
discussions. This work was supported by the National Institutes of
Health (GM 51982).
(2S,4R)-(-)-4-Acetoxy-2-phenyl-1-trifluoroacetylpiperidine
(cis-12)
20
Yield: 78%; colorless oil; [a]D -47.9 (c = 1.1, CH2Cl2). Physical
References
and spectral properties were identical to (2R,4S)-(+)-12.
(1) For a review, see: Hanessian, S.; McNaughton-Smith, G.;
Lombart, H-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(2) Vanderhaeghe, H.; Janssen, G.; Compernolle, F. Tetrahedron
Lett. 1971, 28, 2687.
(3) (a) Hays, S. J. Malone, T. C.; Johnson, G. J. Org. Chem. 1991,
56, 4084.
(2R,4R)-(+)-4-Acetoxy-2-phenyl-1-trifluoroacetylpiperidine
(trans-12)
Yield: 80%; colorless oil; [a]D20 +80.7 (c = 1.95, CH2Cl2).
IR (neat): n = 1736, 1690, 1455, 1243, 1204, 1142, 1046 cm-1.
1H NMR (CDCl3) (it existed as rotamers): d = 1.63-1.71 (m, 1 H),
1.86-2.14 (m, 4 H), 2.75-3.12 (m, 2 H), 3.90 (br d, J = 14.7 Hz, 0.7
H), 4.51 (br d, J = 13.9 Hz, 0.3 H), 4.96-5.08 (m, 1 H), 5.43 (br s,
0.3 H), 6.04 (br s, 0.7 H), 7.26-7.42 (m, 5 H).
13C NMR (CDCl3): d = 171.1, 157.1 (q, J = 34.6 Hz), 137.0, 136.8,
131.0, 129.9, 128.5, 128.4, 127.0, 126.7, 117.3 (q, J = 288.9 Hz),
67.7, 56.2, 53.4, 40.8, 38.7, 34.0, 32.6, 32.3, 31.6, 21.7.
(b) Ornstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Leander,
J. D.; Lodge, D.; Paschal, J. W.; Elzey, T. J. Med. Chem. 1991,
34, 90.
(4) Beaulieu, P. L.; Lavallee, P.; Abraham, A.; Anderson, P. C.;
Boucher, C.; Bousquet, Y.; Duceppe, J.-S.; Gillard, J.; Gorys,
V.;Grand-Matre, C.; Grenier, L.; Guindon, Y.; Guse, I.;
Palmondom, L.; Soucy, F.; Valois, S.; Wernic, D.; Yoakim, C.
J. Org. Chem. 1997, 62, 3440.
(5) Clark-Lewis, J. W.; Mortimer, P. I. J. Chem. Soc. 1961, 189.
(6) Pellicciri, R.; Natalini, B.; Constantino, G.; Garzon, A.;
Uinela, R.; Mahmoud, M. R.; Marinozzi, M.; Roberti, M.;
Rosato, G. C.; Shiba, S. A. FARMACO 1993, 48, 151.
(7) (a) Baruenga, J.; Aznar, F.; Valdes, C.; Ribas, C. J. Org.
Chem. 1998, 63, 3918.
Anal. calcd for C15H16F3NO3: C 57.14; H, 5.12; N, 4.44. Found: C,
57.04; H, 5.36; N, 4.46.
2S,4S)-(-)-4-Acetoxy-2-phenyl-1-trifluoroacetylpiperidine
(trans-12)
Yield: 84%; colorless oil; [a]D20 -81.2 (c = 1.1, CH2Cl2).
IR (neat): n = 1736, 1690, 1455, 1243, 1204, 1142, 1046 cm-1.
1H NMR (CDCl3) (it existed as rotamers): d = 1.63-1.71 (m, 1 H),
1.86-2.14 (m, 4 H),2.75-3.12 (m, 2 H), 3.90 (br d, J = 14.7 Hz, 0.7
H), 4.51 (br d, J = 13.9 Hz, 0.3 H), 4.96-5.08 (m, 1 H), 5.43 (br s,
0.3 H), 6.04 (br s, 0.7 H), 7.26-7.42 (m, 5 H);
13C NMR (CDCl3): d = 171.1, 157.1 (q, J = 34.6 Hz), 137.0, 136.8,
131.0, 129.9, 128.5, 128.4, 127.0, 126.7, 117.3 (q, J = 288.9 Hz),
67.7, 56.2, 53.4, 40.8, 38.7, 34.0, 32.6, 32.3, 31.6, 21.7.
(b) Angle, S. R.; Henry, R. M. J. Org. Chem. 1997, 62, 8549.
(c) Holmes, A. B.; Swithenbank, C.; Williams, S. F. J. Chem.
Soc. Chem. Commun. 1986, 265.
(d) Herdeis, C.; Nagel, U. Heterocycles 1983, 20, 2163.
(8) For a review on the asymmetric synthesis of pipecolic acid and
derivatives, see: Couty, F.; Amino Acids 1999, 16, 297.
(9) (a) Bousquet, Y.; Anderson, P. C.; Bogri, T.; Duceppe, J-S.;
Grenier, L.; Guse, I. Tetrahedron 1997, 46, 15671.
(b) Golubev, A. S.; Sewald, N.; Burger, K. Tetrahedron 1996,
52, 14757.
(2R,4S)-(+)-4-Hydroxypipecolic Acid (cis-1)
In a 25 mL one-necked round bottom flask equipped with a magnet-
ic stir bar was placed cis-(+)-12 (0.14 g, 0.44 mmol), CCl4 (2 mL),
MeCN (2 mL), and H2O (3 mL). NaIO4 (1.42 g, 6.64 mmol) and
RuCl2·H2O (0.0046 g, 0.022 mmol), were added and the solution
was stirred vigorously for 8 h. The solution was filtered through a
Celite, and rinsed with CH2Cl2 (20 mL). The combined organic
phases were dried (MgSO4) and concentrated. The residue was dis-
(c) Machetti, F.; Cordero, F. M.; DeSarlo, F.; Guarna, A.;
Brandi, G. Tetrahedron Lett. 1996 37, 4205.
(d) Golubev, A; Sewald, N.; Burger, K, Tetrahedron Lett.
1995, 36, 2037.
(10) Reed, J. W.; Purvis, M. B.; Kingston, D. G. I.; Biot, A.;
Gossele, F. J. Org. Chem. 1989, 54, 116.
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York

2112
F. A. Davis et al.
SPECIAL TOPIC
(11) Rutjes, F. P. J. T.; Veerman, J. J. N.; Meester, W. J. N.;
Hiemstra, H.; Schoemaker, H. E. Eur. J. Org. Chem. 1999,
1127.
(12) Di Nardo, C.; Varela, O. J. Org. Chem. 1999, 64, 6119.
(13) Haddad, M.; Larcheveque, M. Tetrahedron: Asymmetry 1999,
10, 4231.
(14) Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41,
3551.
(15) Gillard, J.; Abraham, A.; Anderson, P. C.; Beaulieu, P. L.;
Bogri, T.; Bousquet, Y.; Grenier, L. Guse, I.; Lavallee, P. J.
Org. Chem. 1996, 61, 2226.
(16) Davis, F. A.; Chao, B.; Fang, T.; Szewczyk, J. M. Org. Lett.
2000, 2, 1041.
(17) Davis, F. A.; Chao, B. Org. Lett. 2000, 2, 2623.
(18) For reviews on the chemistry of sulfinimines, see:
(a) Zhou, P.; Chen, B.-C; Davis, F. A. Adv.Sulfur Chem. 2000,
2, 249.
(a) Ciblat, S.; Besse, P.; Canet, J-L.; Torin, Y.; Veschambre,
H.; Gelas, J. Tetrahedron: Asymmetry 1999, 10, 2225.
(b) Tawara, J. N.; Lorenz, P.; Stermitz, F. R. J. Nat. Prod.
1999, 62, 321.
(23) Greeves, N. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 8,
pp 1-24.
(24) For a review see Tramontini, M. Synthesis 1982, 605.
(25) Barluenga, J.; Aguilar, E.; Fustero, S.; Olano, B.; Viado, A. L.
J. Org. Chem. 1992, 57, 1219.
(26) Attempt to oxidize the trifluoroacetate-N-trifluoroamide
resulted in decomposition.
(27) Gensler, W. J.; Johnson, F. A.; Sloan, A. D. B. J. Am. Chem.
Soc. 1960, 82, 6074.
(28) (a) Davis, F. A.; Zhang, Y.; Andemichael, Y.; Fang, T.;
Faneli, D. L.; Zhang, H. J. Org. Chem. 1999, 64, 1403.
(b) Fanelli, D. L.; Szewczyk, J. M.; Zhang, Y.; Reddy, G. V.;
Burns, D. M. Davis, F. A. Org. Synth.1999, 77, 50.
(29) Ashton, M. J.; Hills, S. J.; Newton, C. G.; Taloy, J. B.; Tondu,
S. C. D. Heterocycles 1989, 28, 1015.
(b) Hua, D. H.; Chen, Y.; Millward, G. S. Sulfur Reports 1999,
21, 211.
(c) Davis, F. A.; Zhou, P.; Chen, B-C. Chem. Soc. Rev. 1998,
27, 13.
(30) Esch, P. M.; Boska, I. M.; Hiemstra, H.; De Boer, R. F.;
Speckamp, W. N. Tetrahedron 1991, 47, 4039.
(19) (a) Nunez, M. T.; Martin, V. S. J. Org. Chem. 1990, 55, 1928.
(b) Chakraborti, A. K. Ghatak, U. R. Synthesis 1983, 746.
(20) Ripoche, I.; Ganet, J-L.; Aboab, B.; Gelas, J.; Troin, Y. J.
Chem. Soc. Perkin Trans. 1 1998, 3485.
Article Identifier:
(21) Takemoto, Y.; Ueda, S.; Takeuchi, J.; Yasutaka, B.; Iwata, C.
Chem. Pharm. Bull. 1997, 45, 1906.
1437-210X,E;2000,0,14,2106,2112,ftx,en;C03000SS.pdf
Synthesis 2000, No. 14, 2106–2112 ISSN 0039-7881 © Thieme Stuttgart · New York