Stereospecific, flexible and redox-economic asymmetric synthesis of cis- And trans-3-hydroxypipecolic acids and analogs

Article abstract of DOI:10.1002/ejoc.200900231

Both cis- and trans-3-hydroxy-L-pipecolic acids are synthesized from, a common chiral intermediate 7 by a short: and flexible route. The stereospecific inversion of C-3 was achieved by the formation of an oxazoline followed by acidic ring cleavage. The ov

Full text of DOI:10.1002/ejoc.200900231

FULL PAPER
DOI: 10.1002/ejoc.200900231
Stereospecific, Flexible and Redox-Economic Asymmetric Synthesis of cis- and
trans-3-Hydroxypipecolic Acids and Analogs
Bing Wang*[a] and Run-Hua Liu[a]
Keywords: Asymmetric synthesis / Amino acids / Amino alcohols / Total synthesis
Both cis- and trans-3-hydroxy-
L
-pipecolic acids are synthe-
ing blocks are also accessible by this diastereodivergent syn-
thesis. Unlike the chiral pool approach, our synthetic strategy
is not limited by the availability of starting materials.
sized from a common chiral intermediate 7 by a short and
flexible route. The stereospecific inversion of C-3 was
achieved by the formation of an oxazoline followed by acidic
ring cleavage. The overall yields are 27% and 30%, respec-
tively, in 12 and 10 linear steps. Several versatile chiral build-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
which was inevitably limited by the availability of the start-
ing material, while asymmetric synthesis was rather rare.[7]
More importantly, flexible synthetic strategies that are ap-
plicable to both 1 and 2 are in demand.[6b,6d,6f,7b,7f] As a
part of our ongoing projects on the synthesis of polyhy-
droxylated alkaloids,[9] herein we report the stereodivergent
synthesis of both cis- and trans-3-hydroxy--pipecolic acids
as well as their reduced analogues such as 3 and 4.
We have recently developed an efficient method for the
construction of syn-vicinal amino alcohols in enantiopure
form, which culminated in a facile synthesis of -(+)-
733,060, a 2-phenyl-3-hydroxypiperidine derivative.[9a] Nat-
urally, we envisioned that by replacing the phenyl ring with
a carboxylic acid group, this strategy would constitute an
efficient synthesis of 3-hydroxypipecolic acids (Scheme 1).
Introduction
Multisubstituted chiral piperidines are of pivotal impor-
tance to medicinal chemistry and organic synthesis.[1] Hy-
droxypipecolic acids are an important family of nonpro-
teinogenic cyclic α-amino acids with a chiral substituted
piperidine skeleton.[2] Within the 3-hydroxy--series, both
cis (1) and trans (2) isomers are structural units found in
diverse natural products and biologically significant mole-
cules such as tetrazomine[3] and febrifugine[4] (Figure 1). In
addition, they are also conformationally constrained amino
acids relevant to the study of peptide structure and drug
design.[5]
Figure 1. 3-Hydroxypipecolic acids and related structures.
In view of their significance, numerous efforts have been
devoted to the synthesis of these chiral scaffolds.[6–8] Most
of the reported routes utilized the chiral pool approach,[6]
Scheme 1. Retrosynthetic analysis for 1–4.
Although Huang[6a] and Jung[7b] have employed furanyl
and p-methoxyphenyl, respectively, as masked carboxylic
groups, we prefer using a properly protected hydroxymethyl
as a latent carboxyl function because it could also provide
simple access to 2-hydroxymethylpiperidines 3 and 4
without involving unnecessary adjustment of the oxi-
[a] Department of Chemistry, Fudan University,
220 Handane Road, Shanghai 200433, P. R. China
Fax: +86-21-54237570
E-mail: wangbing@fudan.edu.cn
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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B. Wang, R.-H. Liu
FULL PAPER
dation state. On the other hand, the C-3 configuration was ther recrystallization to remove inseparable diastereomers
also fully controllable by this route. The absolute stereo- (in fact, compound 7 was an oil). This beneficial effect of
chemistry of anti-1,2-amino alcohol A mapped onto the α-alkoxy substitution might be ascribed to its chelating role
trans-isomer 2, whereas the cis-isomer 1 required B by for the SmIII species, and might work for other analogous
unambiguous inversion of the C-3 hydroxy in A at an sulfinimine substrates.
early stage obviating a late-stage oxidation–reduction se-
The removal of the sulfinyl auxiliary followed by the se-
quence,[6f] which was less efficient. Thus, A served as the lective N-protection with Boc2O afforded 8 in high yield
common starting point in our stereospecific, flexible and (88%). We then blocked the secondary hydroxy by TBS and
redox-economic[10] synthesis. In addition, as both enantio- removed the Piv protection of the terminal primary alcohol
mers of tert-butanesulfinamide are commercial reagents at by K2CO3 in refluxing MeOH.[13] Without further purifica-
affordable prices, switching the chiral auxiliary would easily tion, we mesylated and subjected the crude product to ring
provide the antipodes of 1–4. Therefore, this strategy repre- closure using tBuOK.[7a] Thus, we obtained 10, a 2,3-disub-
sents a comprehensive and unified solution to this class of stituted piperidine, in a satisfactory yield of 79% over 3
2,3-disubstituted piperidines.
steps. Using NaH as the base required a longer reaction
time (48 h); apparently, the potassium derivative was more
dissociated than its sodium counterpart. For the ring clo-
sure, we also tested the Mitsunobu reaction (Ph3P, DIAD
and THF). However, it was less effective, probably due to
high steric hindrance around the amino group. Notably, the
primary and secondary hydroxyls in 10 were orthogonally
protected, which rendered this trifunctional compound a
versatile building block. Routine debenzylation afforded 2-
(hydroxymethyl)piperidine 11 in near quantitative yield.
RuVIII-catalyzed oxidation[14] to the carboxylic acid fol-
lowed by global deprotection completed the total synthesis
of 2 in 10 linear steps with an overall yield of 30%.
The synthesis of cis-1 is shown in Scheme 3. The depro-
tection of 7 and subsequent N-selective benzoylation pro-
duced benzamide 12 (83% over 2 steps). Chiral HPLC
analysis of the latter established the ee of 7 to be Ͼ98%.
Considering the difficulty encountered in the removal of N-
PMB from a 2-substituted piperidine,[9a] this time we em-
ployed the simpler benzoyl group instead of the PMB
group, and the subsequent transformations of the oxazoline
were also totally different from our previous work. Instead
of undergoing reductive ring opening to form benzylamine,
we hydrolyzed the 2-phenyloxazoline 13 under acidic condi-
tions to give a benzoate,[15] liberating the primary amino
group, which we in turn protected with Boc2O to afford 14.
At this stage, the required stereogenic centers of the target
molecule had already been set up unambiguously. We car-
ried out the selective deprotection of the O-benzoyl group
under mild basic conditions (K2CO3/MeOH/r.t.) without
affecting the primary pivalate, and the resulting secondary
alcohol underwent TBS protection to afford 15, which was
actually the C-3 epimer of 9. In the same vein, we smoothly
converted 15 to 16 by a 3-step sequence in a satisfactory
yield of 73%. Hydrogenolysis removed the Bn protection
for the primary alcohol without incident. After Ru-cata-
lyzed oxidation and global deprotection, we obtained cis-3-
hydroxy--pipecolic acid 1 in 12 linear steps with an overall
yield of 27% from the common key intermediate 7.
Results and Discussion
We commenced the synthesis of trans-2 from the asym-
metric pinacol-type reductive coupling[11] of aldehyde 5 and
α-benzyloxy tert-butylsulfinyl imine 6 (Scheme 2). We in-
tended to use benzyl (Bn) and pivaloyl (Piv) groups for the
protection of C-1 and C-6 primary alcohols in the coupling
product, respectively, for easy and orthogonal removal. As
expected, we obtained anti-vicinal amino alcohol 7, pos-
sessing two correct stereogenic centers, in good yield (65%)
and excellent optical purity (Ͼ98% ee) as determined by
chiral HPLC of the corresponding N-benzoyl derivative (see
below and the Supporting Information).
Scheme 2. Asymmetric synthesis of 2.
The syntheses of the reduced analogs of our title com-
We note that the diastereoselectivity[12] for the coupling pounds were straightforward (Scheme 4). Global deprotec-
using substrate 6, which has a benzyloxy substitution adja- tion (2  HCl/MeOH) of intermediates 17[6d] and 11[7a] fur-
cent to the sulfinyl imine, was higher than that of tert-butyl- nished 3[16] and 4,[17] respectively, in excellent yields
sulfinyl benzaldimine reported earlier.[9a] Therefore, there (Ͼ95%). The spectroscopic data of these compounds were
was no need to refine the chromatographed product by fur- also consistent with those reported previously.
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Eur. J. Org. Chem. 2009, 2845–2851

Asymmetric Synthesis of cis- and trans-3-Hydroxypipecolic Acids
Conclusions
In summary, we have accomplished a diastereodivergent
asymmetric synthesis of cis- and trans-3-hydroxy--pipec-
olic acids and their reduced analogs from a common chiral
intermediate 7. The overall yields are 27% and 30% in 12
and 10 linear steps, respectively. Our route featured a
stereospecific inversion of a secondary hydroxy group for
the construction of cis-2,3-disubstituted piperidines. As
both enantiomers of tert-butanesulfinamide are commer-
cially available at affordable prices, by simple switching the
chirality of the sulfinyl auxiliary, enantiomers of all the tar-
get molecules are easily accessible. The orthogonally pro-
tected compounds 10, 11 and 16–19 can also serve as versa-
tile building blocks for the asymmetric synthesis of related
alkaloids.
Experimental Section
General Information: All reactions were performed in oven-dried
glassware under an atmosphere of argon. All 1H NMR and 13C
NMR spectra were recorded at ambient temperature in CDCl3 un-
less noted otherwise. Chemical shifts are reported in parts per mil-
lion (ppm) as follows: chemical shift, multiplicity (s singlet, d doub-
let, t triplet, q quartet, m multiplet, br. broad), coupling constant,
and integration. Optical rotations were measured at ambient tem-
perature, and concentrations are reported in g per 100 mL. Melting
points are uncorrected. THF was distilled from sodium benzo-
phenone ketyl, CH2Cl2 and DMF were distilled from CaH2, all
other solvents and chemical reagents were used as received. Com-
pound 5[20] and 6[21] were prepared according to the literature pro-
cedures.
Scheme 3. Asymmetric synthesis of 1.
(4S,5R)-6-(Benzyloxy)-4-hydroxy-5-[(S)-2-methylpropan-2-ylsulfin-
amido]hexyl Pivalate (7): To a cooled (–78 °C) solution of SmI2
(30 mmol) in THF (50 mL) under Ar was added dropwise a solu-
tion of 5 (3.87 g, 22.5 mmol), 6 (3.795 g, 15 mmol) and tBuOH
(1.9 mL) in THF (50 mL). The mixture was stirred for 6 h at
–78 °C, quenched by saturated aq. Na2S2O3, extracted with EtOAc
(3ϫ50 mL), and the combined organic phases were washed with
brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (EtOAc/hexanes = 1:2 to 1:1) to yield 7 (4.173 g,
Scheme 4. Syntheses of 3 and 4.
Finally, as depicted in Scheme 5, we smoothly converted
intermediates 10 and 16 into useful chiral building blocks
18 and 19, respectively, upon treatment with inexpensive
NH4F[18] in methanol to selectively remove the TBS protec-
tion of the C-3 hydroxy group. Only one synthesis of the
cis-isomer 19 has been documented before, which used
phenylglycinol as the chiral auxiliary.[19]
1
65%) as a pale-yellow liquid. [α]2D3 = +29.7 (c = 1.30, CHCl3). H
NMR (300 MHz, CDCl3): δ = 7.38–7.28 (m, 5 H), 4.61–4.42 (AB,
JAB = 11.7 Hz, 2 H), 4.09–3.99 (m, 2 H), 3.96 (d, J = 8.4 Hz, 1 H),
3.90 (dd, J = 9.6, 3.6 Hz, 1 H), 3.79–3.65 (m, 2 H), 3.30 (m, 1 H),
1.91–1.33 (m, 4 H), 1.22 (s, 9 H), 1.16 (s, 9 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 178.5, 137.4, 128.5, 127.9, 127.8, 73.5, 72.7,
70.2, 64.2, 59.4, 56.0, 38.7, 30.3, 27.1, 25.1, 22.6 ppm. HR-ESI-MS:
calcd. for C22H37NNaO5S [M + Na]+ 450.2290; found 450.2283.
(4S,5R)-6-(Benzyloxy)-5-(tert-butoxycarbonyl)-4-hydroxyhexyl Piv-
alate (8): To a solution of 7 (1.498 g, 3.5 mmol) in MeOH (5 mL)
was added a methanolic solution of HCl (2 , 7 mL) at room tem-
perature, stirring was continued for 4 h, and the solution was con-
centrated under reduced pressure. The residue was dissolved in
CH2Cl2 (10 mL). To this was added NaHCO3 (588 mg, 7.0 mmol)
and Boc2O (1.11 g, 5.3 mmol) at room temperature, and the mix-
ture was stirred overnight, filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (EtOAc/hexanes = 1:3) to afford 8 (1.303 g, 88%)
1
Scheme 5. Syntheses of 18 and 19.
as a pale-yellow liquid. [α]2D3 = –13.5 (c = 1.36, CHCl3). H NMR
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(300 MHz, CDCl3): δ = 7.38–7.24 (m, 5 H), 5.31 (br. d, J = 6.9 Hz, (EtOAc/hexanes = 1:4) to afford 11 (292 mg, 98%) as a colorless
1 H), 4.49 (AB, JAB = 11.7 Hz, 2 H), 4.12–3.98 (m, 2 H), 3.78 (br. liquid. [α]2D3 = –16.0 (c = 0.74, CHCl3); NMR peaks were broad-
d, J = 7.5 Hz, 1 H), 3.72–3.56 (m, 3 H), 2.94 (br. d, J = 7.5 Hz, 1
ened due to the presence of rotamers. 1H NMR (300 MHz, CDCl3):
δ = 4.18 (m, 1 H), 4.00 (m, 1 H), 3.88 (d, J = 2.7 Hz, 1 H), 3.76–
H), 1.95–1.43 (m, 4 H), 1.43 (s, 9 H), 1.17 (s, 9 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 178.5, 155.8, 137.3, 136.3, 128.5, 128.0, 3.57 (m, 2 H), 2.83 (t-like, 1 H), 2.40 (br. s, 1 H), 2.00–1.82 (m, 1
127.7, 79.6, 73.7, 73.3, 70.2, 64.1, 53.5, 38.7, 30.8, 28.3, 27.2, 25.3
ppm. HR-ESI-MS: calcd.for C23H37NNaO6 [M + Na]+ 446.2519;
found 446.2518.
H), 1.68–1.55 (m, 2 H), 1.45 (s, 9 H), 1.40–1.29 (m, 1 H), 0.88 (s,
9 H), 0.08 (s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 156.2, 79.6, 65.2, 60.7, 60.0, 39.6, 28.4, 28.2, 25.7,
19.2, 18.0, –4.9, –5.0 ppm. HR-ESI-MS: calcd.for C17H35NNaO4Si
[M + Na]+ 368.2233; found 368.2230.
(4S,5R)-6-(Benzyloxy)-5-(tert-butoxycarbonyl)-4-(tert-butyldimeth-
ylsilyloxy)hexyl Pivalate (9): To a solution of 8 (1.00 g, 2.36 mmol)
and imidazole (327 mg, 4.73 mmol) in DMF (8 mL), was added
TBSCl (534 mg, 3.55 mmol) in one portion, and the solution was
stirred overnight, quenched by H2O, extracted with diethyl ether
(2ϫ30 mL), and the combined organic phases were washed with
brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (EtOAc/hexanes = 1:20) to afford 9 (1.181 g, 93%)
as a colorless liquid. [α]2D3 = –7.5 (c = 0.74, CHCl3); NMR peaks
were broadened due to the presence of rotamers. 1H NMR
(300 MHz, CDCl3): δ = 7.39–7.24 (m, 5 H), 4.80 (br. d, J = 7.5 Hz,
1 H), 4.50 (AB, JAB = 12.0 Hz, 2 H), 4.03 (t, J = 6.0 Hz, 2 H), 3.90
(m, 1 H), 3.78 (m, 1 H), 3.66 (dd, J = 9.6, 5.1 Hz, 1 H), 3.53 (dd,
J = 9.6, 3.9 Hz, 1 H), 1.86–1.45 (m, 4 H), 1.44 (s, 9 H), 1.19 (s, 9
H), 0.88 (s, 9 H), 0.06 (s, 6 H) ppm. 13C NMR (CDCl3, 125 MHz):
δ = 178.5, 155.5, 138.1, 128.3, 127.6, 79.2, 73.0, 71.4, 68.5, 64.6,
53.1, 38.7, 30.2, 28.4, 27.2, 25.8, 23.8, 18.0, –4.4, –4.8 ppm. HR-
ESI-MS: calcd.for C29H51NNaO6Si [M + Na]+ 560.3383; found
560.3370.
(2S,3S)-3-Hydroxypiperidine-2-carboxylic Acid Hydrochloride (2):
To a well-stirred suspension of 11 (85 mg, 0.25 mmol) and NaIO4
(216 mg, 1.0 mmol) in CCl4 (0.6 mL), MeCN (0.6 mL) and H2O
(0.9 mL) was added RuCl3·3H2O (2 mg) in one portion, and the
mixture was stirred for 1 h at room temperature, diluted with di-
ethyl ether (30 mL), filtered through celite and concentrated under
reduced pressure. The residue was refluxed with aq. HCl (6 ,
5.0 mL) for 2 h, cooled and washed with CH2Cl2 (10 mL). The
aqueous phase was concentrated under reduced pressure to afford
2 as a white solid; m.p. 232–234 °C. [α]2D3 = +14.5 (c = 0.40, H2O),
ref.[6d] [α]2D3 = +14.2 (c = 0.95, H2O). H NMR (300 MHz, D2O):
1
δ = 4.15–4.02 (m, 1 H), 3.82 (d, J = 7.8 Hz, 1 H), 3.40–3.27 (m, 1
H), 3.10–2.95 (m, 1 H), 2.05–1.85 (m, 2 H), 1.80–1.55 (m, 2 H)
ppm. 13C NMR (D2O, 125 MHz): δ = 171.1, 67.0, 62.2, 44.1, 30.4,
20.1 ppm. HR-ESI-MS: calcd.for C6H12NO3 [M + H]+ 146.0817;
found 146.0813.
(2R,3S)-2-(Hydroxymethyl)piperidin-3-ol (4): To a solution of 11
(74 mg, 0.21 mmol) in MeOH (2 mL), was added a methanolic
solution of HCl (2 , 0.5 mL) at room temperature, stirring was
continued for 6 h, and the solution was concentrated under reduced
pressure and basified with 2 drops of aq. NaOH (30%). The residue
was purified by silica gel flash column chromatography (MeOH/
CH2Cl2 = 1:2) to afford 4 (27 mg, 96%) as a white solid; m.p. 153–
154 °C. [α]2D3 = +57.0 (c = 0.56, MeOH), ref.[16a] [α]2D3 = +58.3 (c =
(2R,3S)-tert-Butyl 2-(benzyloxymethyl)-3-(tert-butyldimethylsilyl-
oxy) Piperidine-1-carboxylate (10): A mixture of 9 (707 mg,
1.32 mmol) and K2CO3 (35 mg, 0.25 mmol) in MeOH (14 mL) was
refluxed for 10 h and filtered through a short pad of silica gel,
which was subsequently rinsed with CH2Cl2. The combined filtrate
was concentrated, redissolved in CH2Cl2 (40 mL), cooled in an ice
bath, and Et3N (0.36 mL, 2.6 mmol) was added followed by MsCl
(0.14 mL, 1.8 mmol). After 1 h at 0 °C, the reaction was quenched
by H2O, diluted with CH2Cl2 (40 mL), washed with brine, dried
(Na2SO4), filtered and concentrated under reduced pressure. To a
cooled (0 °C) solution of the crude mesylate in THF (25 mL) was
added tBuOK (295 mg, 2.63 mmol), and the whole was warmed to
room temperature over 1 h and stirred at this temperature for an-
other 3 h. The reaction was quenched with sat. aq. NH4Cl, ex-
tracted with CH2Cl2 (2ϫ25 mL), and the combined organic phases
were washed with brine, dried (Na2SO4), filtered and concentrated
under reduced pressure. The residue was purified by silica gel flash
column chromatography (EtOAc/hexanes = 1:20) to afford 10
(452 mg, 79%) as a colorless liquid. [α]2D3 = –14.0 (c = 0.90, CHCl3);
1
1.06, MeOH). H NMR (300 MHz, CDCl3): δ = 3.86 (AB-d, JAB
= 10.8, J = 3.9 Hz, 1 H), 3.54 (AB-d, JAB = 10.8, J = 6.9 Hz, 1
H), 3.35–3.23 (m, 2 H), 3.00–2.92 (m, 1 H), 2.50 (td, J = 12.0,
2.7 Hz, 1 H), 2.38 (ddd, J = 9.6, 7.2, 3.3 Hz, 1 H), 2.06–1.96 (m, 1
H), 1.75–1.65 (m, 1 H), 1.58–1.42 (m, 1 H), 1.40–1.27 (m, 1 H)
ppm. 13C NMR (CD3OD, 125 MHz): δ = 69.7, 65.0, 63.8, 46.4,
34.9, 26.2 ppm. HR-ESI-MS: calcd.for C6H14NO2 [M + H]+
132.1025; found 132.1019.
(2R,3S)-tert-Butyl 2-(Benzyloxymethyl)-3-hydroxypiperidine-1-car-
boxylate (18): A solution of 10 (34 mg, 0.08 mmol) and NH4F
(38 mg, 1.0 mmol) in MeOH/H2O (10:1, 2 mL) was heated at 60 °C
for 48 h, cooled, diluted with diethyl ether, washed successively with
H2O and brine, dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was purified by silica gel flash col-
umn chromatography (EtOAc/hexanes = 1:2) to afford 18 (20 mg,
80%) as a colorless liquid. [α]2D3 = –33.8 (c = 0.40, CHCl3); NMR
1
NMR peaks were broadened due to the presence of rotamers. H
NMR (300 MHz, CDCl3): δ = 7.39–7.25 (m, 5 H), 4.53 (AB, JAB
= 13.8 Hz, 2 H), 4.33 (br. s, 1 H), 4.13–3.94 (m, 2 H), 3.59–3.44
(m, 2 H), 2.70 (t-like, J = 12.6 Hz, 1 H), 2.00–1.80 (m, 1 H), 1.63–
1.52 (m, 2 H), 1.44 (s, 9 H), 1.34–1.23 (m, 1 H), 0.89 (s, 9 H), 0.08
(s, 3 H), 0.05 (s, 3 H) ppm. 13C NMR (CDCl3, 125 MHz): δ =
155.5, 138.3, 128.3, 127.5, 127.4, 79.1, 72.8, 68.0, 65.2, 56.7 (br),
39.3 (br), 28.4, 27.5, 25.8, 18.9, 18.0, –4.9, –5.0 ppm. HR-ESI-MS:
calcd.for C24H41KNO4Si [M + K]+ 474.2442; found 474.2434.
1
peaks were broadened due to the presence of rotamers. H NMR
(500 MHz, CDCl3): δ = 7.39–7.25 (m, 5 H), 4.53 (s, 2 H), 4.40 (br.
m, 1 H), 4.03 (br. m, 1 H), 3.98 (br. d, J = 12.7 Hz, 1 H), 3.55 (AB,
JAB = 10.7 Hz, 2 H), 2.77 (td, J = 13.1, 2.5 Hz, 1 H), 1.96 (br. s, 1
H), 1.90–1.60 (m, 4 H), 1.45 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 156.0, 138.0, 128.4, 127.6, 127.5, 79.8, 73.0, 67.9,
65.3, 56.8, 39.6, 28.4, 26.5, 18.8 ppm. HR-ESI-MS: calcd.for
C18H28NO4 [M + H]+ 322.2018; found 322.2012.
(2R,3S)-tert-Butyl 3-(tert-Butyldimethylsilyloxy)-2-(hydroxymeth-
yl)piperidine-1-carboxylate (11): A suspension of 10 (376 mg,
0.86 mmol) and 10% Pd/C (40 mg) in MeOH (10 mL) was stirred
under a H2 atmosphere at room temperature for 5 h, filtered
through celite and concentrated under reduced pressure. The resi-
due was purified by silica gel flash column chromatography
(4S,5R)-5-Benzamido-6-(benzyloxy)-4-hydroxyhexyl Pivalate (12):
To a solution of 7 (1.662 g, 3.89 mmol) in MeOH (5 mL) was added
a methanolic solution of HCl (2 , 10 mL) at room temperature,
stirring was continued for 4 h, and the solution was concentrated
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Asymmetric Synthesis of cis- and trans-3-Hydroxypipecolic Acids
under reduced pressure. The residue was dissolved in CH2Cl2
(15 mL), and to this solution was added successively Et3N
1.65 mmol) in MeOH (50 mL) was treated with K2CO3 (1.14 g,
8.3 mmol) at room temperature for 3 h. The mixture was quenched
(2.33 mL), DMAP (10 mg) and Bz2O (877 mg, 3.88 mmol) at 0 °C. by sat. aq. NH4Cl, extracted with CH2Cl2 (3ϫ30 mL), and the
The solution was warmed to room temperature over 1 h, stirred
overnight, diluted with CH2Cl2 (50 mL), washed successively with
sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered and concen-
trated under reduced pressure. The residue was purified by silica
gel flash column chromatography (EtOAc/hexanes = 1:2) to afford
12 (1.371 g, 83%) as a pale-yellow liquid. [α]2D3 = –16.3 (c = 1.44,
CHCl3); HPLC: Chiralpak OD-H column; detected at 214 nm; elu-
ent: n-hexane/2-propanol = 80:20 (v/v), flow rate: 0.7 mL/ min, t1
= 7.9 min (major), t2 = 10.6 min (minor). 1H NMR (300 MHz,
combined organic layers were washed with brine, dried (Na2SO4),
filtered and concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (EtOAc/hexanes
= 1:4) to afford the debenzoylated intermediate (601 mg, 86%) as
a colorless liquid. To a solution of the above alcohol (531 mg,
1.26 mmol) and imidazole (174 mg, 2.52 mmol) in DMF (4 mL)
was added TBSCl (283 mg, 1.88 mmol) in one portion, and the
solution was stirred overnight, quenched by H2O, extracted with
diethyl ether (2ϫ30 mL), and the combined organic phases were
CDCl3): δ = 7.77 (d, J = 6.6 Hz, 2 H), 7.55–7.25 (m, 7 H), 7.01 (d, washed with brine, dried (Na2SO4), filtered and concentrated under
J = 8.1 Hz, 1 H), 4.52 (AB, JAB = 11.7 Hz, 2 H), 4.20 (m, 1 H), reduced pressure. The residue was purified by silica gel flash col-
4.14–4.02 (m, 2 H), 3.92 (dd, J = 9.9, 3.3 Hz, 1 H), 3.83–3.70 (m,
2 H), 3.20 (d, J = 8.7 Hz, 1 H), 1.99–1.49 (m, 4 H), 1.17 (s, 9 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 178.5, 167.2, 137.1, 131.6,
128.6, 128.5, 127.8, 127.0, 73.8, 73.3, 69.8, 64.0, 52.8, 38.7, 30.9,
27.1, 25.3 ppm. HR-ESI-MS: calcd.for C25H34NO5 [M + H]+
428.2437; found 428.2437.
umn chromatography (EtOAc/hexanes = 1:20) to afford 15
(617 mg, 91%) as a colorless liquid. [α]2D3 = –2.9 (c = 0.90, CHCl3);
1
NMR peaks were broadened due to the presence of rotamers. H
NMR (300 MHz, CDCl3): δ = 7.40–7.23 (m, 5 H), 4.78 (d, J =
9.3 Hz, 1 H), 4.51 (AB, JAB = 12.0 Hz, 2 H), 4.09–3.81 (m, 4 H),
3.52–3.38 (m, 2 H), 1.72–1.50 (m, 4 H), 1.46 (s, 9 H), 1.20 (s, 9 H),
0.89 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 178.4, 155.7, 138.1, 128.3, 127.6, 127.5, 79.2, 73.0,
70.0, 69.3, 64.2, 51.9, 38.7, 30.7, 28.4, 27.2, 25.8, 24.7, 18.0, –4.3,
–4.8 ppm. HR-ESI-MS: calcd.for C29H51NNaO6Si [M + Na]+
560.3383; found 560.3376.
3-[(4R,5R)-4-(Benzyloxymethyl)-2-phenyl-4,5-dihydrooxazol-5-yl]-
propyl Pivalate (13): To a cooled (0 °C) solution of 12 (1.271 g,
2.98 mmol) and Et3N (2.4 mL, 16 mmol) in CH2Cl2 (30 mL) was
added dropwise MsCl (0.32 mL, 4.6 mmol), and the mixture was
stirred at room temperature overnight, quenched with saturated aq.
NaHCO3, and the aq. phase was extracted with CH2Cl2
(2ϫ15 mL). The combined organic phases were washed with H2O
and brine, dried (Na2SO4), filtered and concentrated under reduced
pressure. The residue was purified by silica gel flash column
chromatography (EtOAc/hexanes = 1:4) to afford 13 (1.051 g, 87%)
(2R,3R)-tert-Butyl 2-(Benzyloxymethyl)-3-(tert-butyldimethylsilyl-
oxy)piperidine-1-carboxylate (16): Starting from 15 (568 mg,
1.06 mmol), following the same procedure as for compound 10, the
crude product was purified by silica gel flash column chromatog-
raphy (EtOAc/hexanes = 1:20) to afford 16 (336 mg, 73%) as a
colorless liquid. [α]2D3 = +5.3 (c = 0.66, CHCl3); NMR peaks were
1
as a colorless liquid. [α]2D3 = = +46.7 (c = 0.78, CHCl3). H NMR
1
broadened due to the presence of rotamers. H NMR (300 MHz,
(300 MHz, CDCl3): δ = 7.94 (d, J = 6.9 Hz, 2 H), 7.51–7.35 (m, 3
H), 7.35–7.25 (m, 5 H), 4.61–4.52 (m, 3 H), 4.17–4.02 (m, 3 H),
3.76 (dd, J = 9.3, 4.5 Hz, 1 H), 3.47 (dd, J = 9.3, 7.8 Hz, 1 H), 1.92–
1.71 (m, 4 H), 1.18 (s, 9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ
= 178.4, 164.0, 138.0, 131.3, 128.4, 128.3, 128.2, 127.8, 127.6 (2 C),
82.9, 73.4, 72.1, 71.6, 63.8, 38.7, 31.8, 27.1, 24.5 ppm. HR-ESI-
MS: calcd.for C25H32NO4 [M + H]+ 410.2331; found 410.2329.
CDCl3): δ = 7.37–7.21 (m, 5 H), 4.72–4.37 (m, 3 H), 4.06–3.62 (m,
4 H), 2.76 (m, 1 H), 1.76–1.56 (m, 2 H), 1.55–1.40 (m, 2 H), 1.46
(s, 9 H), 0.87 (s, 9 H), 0.07 (s, 3 H), 0.06 (s, 3 H) ppm. 13C NMR
(CDCl3, 125 MHz): δ = 155.3, 138.7, 128.2, 127.3 (2 C), 79.3, 72.6,
69.4, 64.5, 56.1, 37.4, 29.6, 28.4, 25.7, 24.0, 18.0, –4.9 ppm. HR-
ESI-MS: calcd.for C24H41KNO4Si [M + K]+ 474.2442; found
474.2438.
(2R,3R)-1-(Benzyloxy)-2-(tert-butoxycarbonyl)-6-(pivaloyloxy)-
hexan-3-yl Benzoate (14): A stirred solution of 13 (950 mg,
2.3 mmol) in THF (15 mL) was treated with aq. HCl (2 , 8 mL)
at room temperature for 16 h. The mixture was cooled to 0 °C,
basified by the slow addition of NaHCO3 (12.0 g), and diluted with
H2O (40 mL). To this mixture was added a solution of Boc2O
(1.01 g, 4.6 mmol) in THF (9 mL) at room temperature, the mix-
ture was stirred for 2 h, extracted with CH2Cl2 (50 mL), and the
organic phase was washed with brine, dried (Na2SO4), filtered and
concentrated under reduced pressure. The residue was purified by
silica gel flash column chromatography (EtOAc/hexanes = 1:4) to
afford 14 (1.151 g, 94%) as a colorless liquid. [α]2D3 = –9.4 (c = 1.40,
(2R,3R)-tert-Butyl 3-(tert-Butyldimethylsilyloxy)-2-(hydroxymeth-
yl)piperidine-1-carboxylate (17): A suspension of 16 (240 mg,
0.55 mmol) and 10% Pd/C (30 mg) in MeOH (8 mL) was stirred
under a H2 atmosphere at room temperature for 5 h, filtered
through celite and concentrated under reduced pressure. The resi-
due was purified by silica gel flash column chromatography
(EtOAc/hexanes = 1:4) to afford 17 (187 mg, 98%) as a colorless
liquid. [α]2D3 = –15.9 (c = 1.20, CHCl3), ref.[6d] [α]2D5 = –16.0 (c =
0.70, CHCl3); NMR peaks were broadened due to the presence of
rotamers. 1H NMR (300 MHz, CDCl3): δ = 4.55–4.30 (m, 1 H),
4.14–3.78 (m, 3 H), 3.71 (m, 1 H), 2.85–2.43 (m, 2 H), 1.83–1.54
(m, 4 H), 1.47 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 3 H), 0.10 (s, 3 H)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 156.0, 80.0, 70.8, 59.3,
56.6, 38.0, 28.9, 28.4, 25.7, 23.9, 18.0, –4.8, –5.1 ppm. HR-ESI-MS:
calcd.for C17H35NNaO4Si [M + Na]+ 368.2233; found 368.2228.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 8.02 (d, J = 7.5 Hz, 2
H), 7.56 (t, J = 7.8 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 2 H), 7.30–7.20
(m, 5 H), 5.45 (m, 1 H), 4.94 (d, J = 9.6 Hz, 1 H), 4.46 (AB, JAB
= 12.3 Hz, 2 H), 4.14–4.00 (m, 3 H), 3.57 (AB-d, JAB = 9.3, J =
3.9 Hz, 1 H), 3.48 (AB-d, JAB = 9.3, J = 5.4 Hz, 1 H), 1.83–1.63
(m, 4 H), 1.35 (s, 9 H), 1.17 (s, 9 H) ppm. 13C NMR (CDCl3,
125 MHz): δ = 178.4, 166.1, 155.6, 137.6, 133.0, 130.0, 129.7, 128.3
(2 C), 127.7 (2 C), 79.6, 73.4, 73.3, 69.7, 63.8, 52.5, 38.7, 28.2, 28.0,
27.2, 24.6 ppm. HR-ESI-MS: calcd.for C30H41NNaO7 [M + Na]+
550.2781; found 550.2765.
(2S,3R)-3-Hydroxypiperidine-2-carboxylic Acid Hydrochloride (1):
Starting from 17 (98 mg, 0.28 mmol), following the same procedure
as for compound 2, virtually pure product 1 (30 mg, 72%) was
obtained as a white solid. [α]2D3 = –24.5 (c = 0.60, H2O), ref.[6d]
[α]2D3 = –25 (c = 1.3, H2O); H NMR (300 MHz, D2O): δ = 4.42 (s,
1
1 H), 3.93 (s, 1 H), 3.29 (m, 1 H), 2.88 (m, 1 H), 1.93–1.73 (m, 2
H), 1.73–1.50 (m, 2 H) ppm. 13C NMR (D2O, 125 MHz): δ = 171.6,
(4R,5R)-6-(Benzyloxy)-5-(tert-butoxycarbonyl)-4-(tert-butyldimeth- 65.1, 62.0, 45.0, 29.7, 17.1 ppm. HR-ESI-MS: calcd.for C6H12NO3
ylsilyloxy)hexyl Pivalate (15): A stirred solution of 14 (870 mg,
[M + H]+ 146.0817; found 146.0810.
Eur. J. Org. Chem. 2009, 2845–2851
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2849

B. Wang, R.-H. Liu
FULL PAPER
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(2R,3R)-2-(Hydroxymethyl)piperidin-3-ol (3): Starting from 17
(82 mg, 0.24 mmol), following the same procedure as for com-
pound 4, the crude product was purified by silica gel flash column
chromatography (MeOH/CH2Cl2 = 1:2) to afford 3 (30 mg, 95%)
as a colorless liquid. [α]2D3 = –12.2 (c = 0.30, H2O), ref.[16a] [α]2D1
=
–12.4 (c = 2.51, H2O); 1H NMR (500 MHz, D2O): δ = 4.61 (s, 1
H), 4.37–4.26 (m, 2 H), 3.68 (d, J = 13.0 Hz, 1 H), 3.47 (m, 1 H),
3.30 (m, 1 H), 2.55–2.47 (m, 1 H), 2.45–2.30 (m, 2 H), 2.18–2.12
(m, 1 H) ppm. 13C NMR (D2O, 125 MHz): δ = 67.4, 64.3, 61.7,
46.6, 32.3, 21.8 ppm. HR-ESI-MS: calcd.for C6H14NO2 [M + H]+
132.1025; found 132.1017.
[5]
[6]
(2R,3R)-tert-Butyl
2-(Benzyloxymethyl)-3-hydroxypiperidine-1-
carboxylate (19): A solution of 16 (47 mg, 0.11 mmol) and NH4F
(52 mg, 1.4 mmol) in MeOH/H2O (10:1, 2 mL) was heated at 60 °C
for 36 h, cooled, diluted with diethyl ether, washed successively with
H2O and brine, dried (Na2SO4), filtered and concentrated under
reduced pressure. The residue was purified by silica gel flash col-
umn chromatography (EtOAc/hexanes = 1:2) to afford 19 (31 mg,
91%) as a colorless liquid. [α]2D3 = –38.9 (c = 0.76, CHCl3). 1H
NMR (500 MHz, CDCl3): δ = 7.39–7.25 (m, 5 H), 4.62 (br. m, 1
H), 4.54 (AB, JAB = 12.0 Hz, 2 H), 3.90 (m, 1 H), 3.89 (dd, J =
9.8, 7.4 Hz, 1 H), 3.82 (dt, J = 11.5, 5.0 Hz, 1 H), 3.67 (dd, J =
9.7, 6.1 Hz, 1 H), 3.07 (br. s, 1 H), 2.66 (t-like, J = 12.8 Hz, 1 H),
1.88 (m, 1 H), 1.66 (m, 1 H), 1.57 (m, 1 H), 1.47 (m, 1 H), 1.44 (s,
9 H) ppm. 13C NMR (CDCl3, 125 MHz): δ = 154.9, 137.7, 128.4,
127.7, 127.6, 79.8, 73.2, 69.5, 66.6, 53.2, 39.0, 28.8, 28.4, 23.9 ppm.
HR-ESI-MS: calcd.for C18H28NO4 [M + H]+ 322.2018; found
322.2016.
[7]
Supporting Information (see also the footnote on the first page of
1
this article): H and 13C NMR spectra for the new compounds 7–
10, 12–16, and 18.
[8]
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Acknowledgments
Funding from the National Natural Science Foundation of China
(20602008, 20832005) and Fudan University (EYH1615003) are
gratefully acknowledged.
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2850
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2845–2851

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Received: March 4, 2009
Published Online: April 21, 2009
Eur. J. Org. Chem. 2009, 2845–2851
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2851