Scalable synthesis of (-)-trans-3-hydroxypipecolic acid via a useful chiral building block

Article abstract of DOI:10.1016/j.tet.2014.02.020

A scalable synthesis of (-)-trans-2-(hydroxymethyl)-1,2,3,6- tetrahydropyridin-3-ol, a versatile chiral building block is described along with its transformation to (-)-trans-3-hydroxypipecolic acid.

Full text of DOI:10.1016/j.tet.2014.02.020

Tetrahedron 70 (2014) 2444e2448
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Scalable synthesis of (ꢀ)-trans-3-hydroxypipecolic acid via a useful
chiral building block
*
Oskari K. Karjalainen, Ari M.P. Koskinen
Aalto University School of Chemical Technology, Kemistintie 1, 02150 Espoo, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
A scalable synthesis of (ꢀ)-trans-2-(hydroxymethyl)-1,2,3,6-tetrahydropyridin-3-ol, a versatile chiral
building block is described along with its transformation to (ꢀ)-trans-3-hydroxypipecolic acid.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 November 2013
Received in revised form 27 January 2014
Accepted 10 February 2014
Available online 18 February 2014
Keywords:
Amino alcohol
Diastereoselective synthesis
Hydroxypipecolic acid
1. Introduction
streamlined version of the synthesis we used to synthesize
deoxyaltronojirimycin.4
Tetrahydropyridinol 1, or its variously protected forms, is
a common key building block or intermediate in numerous papers
targeting the synthesis of nojirimycin analogs 2 and other imino-
sugars including sialic acid analogs 3 (Fig. 1).1,2
2. Results and discussion
The synthesis is outlined in Scheme 1 and begins with Garner’s
aldehyde 4.5 Garner’s aldehyde, while expensive to purchase, is
readily prepared at moderate scale.6 The largest batches prepared
were in excess of 130 mmol with >98% ee through DIBAL-H re-
duction of the corresponding methyl ester. Lithium acetylide
(1.3 equiv) generated from silyl protected propargyl alcohol was
reacted with 4 to give the propargylic alcohol as a mixture of di-
astereomers (ca. 15:1 anti:syn by 1H NMR spectroscopy) in high
yield (typically >95%). This reaction was originally described by
Jurczak7 and we found that improved anti selectivity is obtained by
using THF as the solvent and slowly adding the aldehyde as a pre-
cooled solution. The crude product was treated with NaH in the
presence of BnBr/NaI in a DMF/THF mixture to introduce the benzyl
protection. After work up, the reaction mass was filtered through
a pad of silica gel to remove any polar impurities/color that might
have formed during the previous step. The greasy nature of the
compound is highly advantageous as it permits extraction of the
product from aqueous DMF mixtures with hydrocarbon solvents,
such as hexane and facilitates the silica gel filtration. The silyl
protecting group was removed by treatment with ammonium
bifluoride in methanol. Ammonium bifluoride is inexpensive and
does not generate bothersome tetrabutylammonium impurities
associated with TBAF. The crude mass was then loaded on a pad of
silica gel and washed with hexane to remove non-polar impurities
Fig. 1. Uses for the chiral building block 1.
We required an economical, scalable access to 8 in enantio- and
diastereopure form as part of one of our projects. The project was
discontinued sometime after successful delivery of over 10 g of the
target compound (8) in one batch. Due to the continued interest of
the synthetic community in derivatives of 1,3 we wish to convey the
full details for the preparation of 8. The synthesis is a modified and
* Corresponding author. E-mail address: ari.koskinen@aalto.fi (A.M.P. Koskinen).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.020

O.K. Karjalainen, A.M.P. Koskinen / Tetrahedron 70 (2014) 2444e2448
2445
(e.g., excess BnBr) to give 5 in high purity and yield (91% crude yield
from 4) avoiding fractionation by column chromatography.
The protecting groups were most efficiently removed using
methanolic HCl generated from acetyl chloride. Other acids tested
(TFA, TsOH) complicated the product isolation after cyclization,
which was accomplished by treating a methanolic solution of the
crude acid with basic ion exchange resin at elevated temperature.
i
This enabled the cyclization and after crystallization from PrOH/
EtOH the product was obtained as a stable, non-hygroscopic hy-
drochloride salt in 69% isolated yield. The use of ion exchange resin
was highly beneficial as traditional bases (TEA, DIPEA) caused the
hydrochloride salt to be contaminated with the salt of the base,
requiring multiple crystallizations to upgrade the purity. Use of
inorganic bases (K2CO3, NaHCO3) avoided that problem, but con-
taminated the crystalline material with inorganics. Otherwise the
crystallization is robust, efficiently removing impurities from the
upstream chemistry (e.g., the isomeric impurity from the hydro-
genation) even at elevated levels.
The utility of 8 was demonstrated by transforming it into trans-
3-hydroxypipecolic acid 10 (Scheme 3).9 We initially attempted to
oxidize 8 directly to 9 under various conditions with little success.
Either the reactions did not proceed or more often were messy with
plenty of over oxidized compounds detected. On the other hand,
the high solubility of 9 into aqueous phases limited our choice of
oxidants to organic ones. Therefore, compound 8 was Boc protected
and then subjected to TEMPO catalyzed oxidation with bis(acetoxy)
iodobenzene (BAIB) as the terminal oxidant to relatively cleanly
give the carboxylic acid.10 We found it useful to perform the re-
action under biphasic conditions in the presence of sodium bi-
carbonate. This way the workup was facilitated and the product
was partly protected from over oxidation as the sodium carboxylate
had very limited solubility in the reaction mixture. After extractive
workup the transient Boc-group was cleaved by exposure to HCl in
acetonitrile. The crude 9 was efficiently purified by slurrying it in
iPrOHeheptane mixture to give pure 9 as a white powder in 63%
yield over three steps. Final hydrogenation delivered 10 as a color-
less crystalline solid entirely without chromatography.
Scheme 1. Reagents and conditions: a) HC^CCH2OTBS, n-BuLi, THF, ꢀ78 ꢁC, then 4; b)
NaH, BnBr, NaI, DMF/THF, 0 ꢁC; c) NH4$HF2, MeOH, rt, then silica gel, 91% over 3 steps;
d) Lindlar’s catalyst, quinoline, H2, benzene, rt, 98%; e) POCl3, DMF, rt 81%. f) AcCl,
MeOH; rt. g) Basic ion exchange resin, MeOH, then cryst from iPrOH/EtOH, 69% over
two steps.
Lindlar reduction was used to introduce the Z-double bond into
the molecule.8 Typically 5% of the E-double bond was formed as
evidenced by 1H NMR spectroscopy, but this is of no consequence
as this impurity is completely removed during the final crystalli-
zation. High purity 6 was obtained in 98% crude yield after filtering
off the catalyst and acidic washings, thus obviating any need for
purification.
A leaving group had to be introduced to the allylic position.
We first considered preparing sulfonate esters (mesylate, tosy-
late) of the primary alcohol. They both worked admirably in the
pivotal cyclization, but both gave the same impurity during their
formation. The impurity was readily identified as the allyl
chloride 7. The chloride possessed improved stability and cleaner
reaction profile during the cyclization over the sulfonate esters
and was targeted for the synthesis. Initial experiments for the
chlorination were conducted with PCl5 and showed promising
results on small scale (>90% isolated yield). However, on scale-
up, the yields unexplainably dropped to about 50%. Most likely
the traces of chlorine in the reagent were the culprit. Fortu-
nately, POCl3 in DMF proved to be an excellent replacement,
providing the allyl chloride in high yield. Interestingly, no re-
action took place with 1 equiv of POCl3. With 2 equiv fast for-
mation of an intermediate product was first seen with slower
conversion to the chloride. The intermediate was isolated and
identified as the formate ester 60. Thus, the alcohol is initially
formylated with the Vilsmeier reagent produced from POCl3 and
DMF (Scheme 2). The formate is then displaced by chloride to
give the product and formic acid. We encountered a slight
problem during the workup on scale; too rapid addition of NaOH
caused partial hydrolysis of the product back to the allyl alcohol
or a related compound. Fortunately, the impurity could be re-
moved during product isolation. The allyl chloride 7 was ob-
tained in 81% crude yield.
Scheme 3. Reagents and conditions: a) Boc2O, NEt3, CH2Cl2, rt; b) cat. TEMPO, BAIB,
NaHCO3, CH2Cl2/H2O, 0 ꢁC to rt; c) HCl, MeCN, rt to 50 ꢁC, 63% over three steps; d) Pd/C,
H2, EtOH, rt, 97%.
3. Conclusion
In conclusion, we have developed a scalable route to tetrahy-
dropyridinol 8 in seven steps from Garner’s aldehyde and in 50%
overall yield. The absence of chromatography enables rapid pro-
cessing (<1.5 weeks by a single person) and the robust crystalli-
zation ensures high product quality. These factors, coupled with
low-cost reagents, make this route highly desirable for lab-scale
synthesis of this intermediate. Furthermore, the intermediate 8
was quickly transformed into trans-3-hydroxypipecolic acid in 60%
yield also entirely without chromatography.
4. Experimental section
4.1. General
Dry dichloromethane and tetrahydrofuran were obtained from
a solvent drier (MB SPS-800, neutral alumina). Dimethyl formamide
was froma freshlyopened bottle. Other solvents used in reactionsand
in chromatography were of p.a. quality. Reagents were obtained from
Scheme 2. Chlorination of 6 via a formate ester.

2446
O.K. Karjalainen, A.M.P. Koskinen / Tetrahedron 70 (2014) 2444e2448
SigmaeAldrich or from Acros Organics and used as such, unless
otherwise stated. TLC monitoring was performed on Merck silica gel
4.09e4.15 (m, 0.5H rotamers), 4.01 (app t, J¼8.2 Hz, 1H), 3.95e3.99
(m, 0.5H, rotamers), 1.66e1.28 (m, 15H), 0.91 (app d, J¼4.8 Hz, 9H),
60 F254 (230e400 mesh, aluminum) plates. UV-light (l¼254 nm), and
0.13 (app d, J¼5.5 Hz); 13C NMR (100 MHz, CDCl3):
d 152.7, 152.0, 138.3,
permanganate (3 g KMnO4, 20 g K2CO3, 5 mL 1 M NaOH, diluted to
300 mL with water) or vanillin (3 g vanillin, 2.5 mL concd H2SO4,
1.5 mL acetic acid, 125 mL EtOH) stains were used to visualize the
plates. Flash chromatography was performed on Merck Silica Gel 60
silica. The Celite used in filtrations was either Fluka Celite 501 or
SigmaeAldrich Celite 535 Coarse. NMR spectra were recorded on
Bruker Avance 400 spectrometer. The spectra were calibrated either
137.9, 128.9, 128.7, 128.5, 128.3, 128.0, 95.4, 94.8, 81.8, 80.7, 80.3, 71.4,
71.2, 68.3, 67.7, 65.1, 64.7, 61.1, 60.8, 52.2, 28.8, 26.6, 26.3, 26.2, 26.0,
25.6, 24.1, 18.7, ꢀ4.6 (ca. 2:1 mixture of rotamers); 13C NMR
(Cl2DCCDCl2, 90 ꢁC):
d 137.9, 128.2, 128.1, 127.7, 127.4, 94.5, 86.2, 81.5,
79.8, 71.0, 64.2, 60.6, 53.3, 51.5, 28.3, 25.9, 25.7, 25.5, 18.0, ꢀ5.2 (the
carbonyl group resonance islostatthistemperature); HRMS: calcd for
C
27H43NO5SiþNa 512.2832, found 512.282.
to TMS (1H:
13C: 77.0 ppm), Cl2CDCDCl2 (1H:
(1H: 2.09 ppm,13 : 20.4) or to D2O (1H:
d
0.00 ppm), MeOD (1H: TMS, 13
6.00 ppm, 13
4.70 ppm,13C:
d
C
d
: 49.86 ppm), CDCl3
: 73.8), toluene-d8
49.5 ppm,
The product from the previous reaction (52.8 g, assumed circa
(
d
d
C
d
98 mmol,100 mol %) was dissolved in MeOH (80 mL) under ambient
conditions. NH4$HF2 (11.5 g, 200 mmol, 200 mol %) was added and
the resulting mixture was stirred for 18 h. To quench the reaction,
30 g of silica gel was added to the reaction mixture. After 30 min of
stirring, the solution was diluted with 350 mL of CH2Cl2, passed
through a pad of silica (washed with 10% MeOH/CH2Cl2) and con-
centrated. The crude product was dissolved in 20% EtOAc/hexanes
and loaded onto a pad of silica gel, which was washed with hexanes
followed by EtOAc. After concentration a yellow oil was obtained
(34.0 g, 91% over three steps). An analytical sample was prepared by
flash chromatography (25% EtOAc/hexanes) to afford a colorless oil.
d
C
d
d
MeOH as internal standard) depending on the used solvent. Spectra
were recorded at 25 ꢁC, unless otherwise stated. Heating of the NMR-
samples was performed using a probe heater. IR spectra were recor-
ded on PerkineElmer Spectrum One FTIR machine. Optical rotations
were measured with PerkineElmer 343 polarimeter using sodium
lamp and a 10 cm quartz cuvette. Melting points were measured with
Stuart SMP30 melting point apparatus. HRMS spectra were recorded
on Waters Micromass LCT Premier (ESI/TOF) mass spectrometer.
4.2. (S)-tert-Butyl 4-((R)-1-(benzyloxy)-4-hydroxybut-2-yn-1-
yl)-2,2-dimethyloxazolidine-3-carboxylate (5)
Rf 0.47 (1:1 EtoAc/Hex); ½a D20
ꢃ
ꢀ54.9 (c 1.0, CH2Cl2); IR (film): 3436,
2978, 1683, 1392, 1366 cmꢀ1 1H NMR (400 MHz, CDCl3, 50 ꢁC):
;
d
7.21e7.40 (m, 5H), 4.80 (d, J¼12.1 Hz 1H), 4.52 (d, J¼12.1 Hz, 1H),
4.12e4.36 (m, 4H), 3.93e4.06 (m, 1H), 1.27e1.70 (m, 15H); 13C NMR
(100 MHz, CDCl3): 152.5, 151.5, 137.6, 137.3, 128.3, 128.2, 128.0,
127.8, 127.7, 127.6, 94.9, 94.2, 85.7, 85.4, 82.5, 80.4, 79.9, 70.9, 67.9,
97.8, 64.6, 64.4, 60.4, 60.1, 50.7, 28.3, 26.5, 25.5, 24.8, 23.5 (rotamers);
HRMS: calcd for C21H29NO5þNa 398.1943, found 398.1953.
A flame-dried flask under argon was charged with O-TBS
propargyl alcohol (23.7 g, 138 mmol, 130 mol-%) and 275 mL of dry
THF. The solution was cooled to ꢀ78 ꢁC and n-BuLi (57.5 mL,
135 mmol, 125 mol %, 2.35 M in hexanes) was added over 10 min.
The resulting mixture was stirred for an hour. Then 4 (22.7 g,
98.8 mmol, 100 mol %) was added as a THF solution (115 mLþ20 mL
for washing, precooled to ꢀ78 ꢁC) via cannula over 1 h. The
resulting solution was stirred for 1 h and then quenched by adding
100 mL of satd NH4Cl. The cooling bath was removed and replaced
with a warm water bath. After reaching room temperature, the
aqueous layer was extracted with EtOAc (2ꢂ50 mL). The combined
organic phases were dried over Na2SO4 and concentrated to yield
42.3 g of crude product as slightly yellow oil. An analytical sample
was prepared by flash chromatography (10% EtOAc/hexanes) to
d
4.3. (S)-tert-Butyl 4-((R,Z)-1-(benzyloxy)-4-hydroxybut-2-en-
1-yl)-2,2-dimethyloxazolidine-3-carboxylate (6)
A 500 mL flask was charged with benzene (50 mL), Pd/CaCO3/Pb
(2.54 g, 1.2 mmol, 1.5 mol %, 5% in Pd) and quinoline (3.3 mL,
27.8 mmol, 35 mol %). The mixture was degassed three times and left
to stir under argon for 30 min. Then 5 (29.8 g, 79.5 mmol,100 mol %)
was added in a benzene solution (200 mL) and H2 atmosphere was
introduced. The mixture was stirred vigorously for 2.75 h (rxn
complete by NMR), filtered through a pad of Celite and concentrated.
The residue was dissolved in EtOAc (150 mL) and washed with 1 M
HCl (100 mL) to remove quinoline. The organic layer was dried over
Na2SO4 and concentrated to give the crude product (29.4 g, 98%) as
a slightly yellow oil. An analytical sample was prepared by flash
chromatography (20% EtOAc/hexanes) to afford a colorless oil. Rf 0.43
afford a colorless oil. Rf 0.56 (2:1 Hex/EtOAc); ½a D20
ꢀ39.6 (c 2.50,
ꢃ
1
CH2Cl2) lit.7 ꢀ40.7 (c 1.1 CDCl3); H NMR (400 MHz, C6D6, 60 ꢁC):
d
4.64 (br s,1H), 4.21 (d, J¼2.0, 2H), 4.00 (m, 2H), 3.72 (dd, J¼8.5, 7.2,
1H), 1.69 (s, 3H), 1.46 (s, 3H), 1.39 (s, 9H), 0.94 (s, 9H), 0.09 (s, 6H);
13C NMR (100 MHz, CDCl3, 25 ꢁC):
d
154.1, 94.9, 84.5, 52.5, 81.3, 65.0,
64.1, 62.5, 51.6, 28.3, 25.7, 25.8 (rotamers), 25.2, 18.2, ꢀ5.2; HRMS:
calcd for C20H37NO5SiþNa 422.2339, found 422.2337.
A flask under argon was charged with the crude product from the
previous reaction (42.3 g, assumed circa 98.0 mmol, 100 mol %), and
dry DMF (100 mL). The solution was cooled to 0 ꢁC and benzyl bro-
mide (15.4 mL, 130 mmol, 130 mol %) was added together with KI
(830 mg, 5 mmol, 5 mol %). Finally sodium hydride (4.8 g, 120 mmol,
120 mol %, 60% dispersion in mineral oil) was added in a single por-
tion. After gas evolution had stopped the slurry was diluted with
100 mL of dry THF. After 1 h of stirring, the reaction was quenched by
adding 60 mL of satd NaHCO3 (dropwise at first, until gas no longer
forms) and then diluted with 150 mL of water. The mixture was
extracted with EtOAc (3ꢂ100 mL). The combined organic phases were
washed with water (200 mL) and brine, dried over Na2SO4 and con-
centrated. The residue was filtered through a pad of silica gel (eluted
with 5% EtOAc/Hexanes) to yield 52.4 g of light yellow oil. An ana-
lytical sample was prepared by flash chromatography (5% EtOAc/
(80% Et2O/Hex); ½a D20
ꢃ
ꢀ65.0 (c 1.00, Et2O); IR: 3436, 1698, 1391,
1366 cmꢀ1; 1H NMR (400 MHz, CDCl3, rt):
d
7.30e7.12 (m, 5H), 5.79
(dddd, J¼0.9, 6.1, 7.3, 11.3 Hz, 1H), 5.43 (t, J¼9.2 Hz, 1H), 4.52 (d,
J¼11.7 Hz,1H), 4.43 (br s, 0.5H), 4.27 (d, J¼11.7 Hz,1H), 4.21e3.96 (m,
4H), 3.91e3.72 (m, 2H), 2.82 (br s, 0.5H),1.57e1.23 (m,15H); 1H NMR
(400 MHz, Cl2CDCDCl2, 80 ꢁC):
d
7.40e7.28 (m, 5H), 5.89 (dddd, J¼1.1,
6.2, 7.0, 11.3 Hz, 1H), 5.56 (tdd, J¼1.3, 9.5, 11.0 Hz, 1H), 4.63 (d,
J¼12.1 Hz, 1H), 4.52 (br s, 1H), 4.45 (d, J¼11.7 Hz, 1H), 4.28e4.12 (m,
3H), 4.01e3.91 (m, 2H),1.60 (s, 3H),1.53 (s, 3H),1.50 (s, 9H); 13C NMR
(100 MHz, Cl2CDCDCl2, 80 ꢁC):
d
152.3,138.3,133.2,130.6,128.1,127.6,
127.4, 94.1, 80.0, 74.1, 70.8, 64.2, 60.5, 58.5, 28.3, 26.6; HRMS: calcd for
21H31NO5þNa 400.2100, found 400.2115.
C
4.4. (S)-tert-Butyl 4-((R,Z)-1-(benzyloxy)-4-chlorobut-2-en-1-
yl)-2,2-dimethyloxazolidine-3-carboxylate (7)
hexanes) to afford a colorless oil. Rf 0.66 (30% EtOAc/Hex); ½a D20
ꢃ
ꢀ76.5
(c 2.0, CH2Cl2); IR (film): 1705, 1390, 1366, 1089 cmꢀ1
;
1H NMR
To an ice cooled, stirred solution of 6 (29.4 g, 77 mmol,
100 mol %) in DMF (210 mL) was added POCl3 (15.6 mL, 170 mmol,
220 mol %) under argon. The cooling bath was removed and the
solution was stirred overnight. The bright orange reaction was
(400 MHz, CDCl3):
4.69e4.74 (m, 0.5H, rotamers), 4.51 (dd, J¼12.1, 7.2 Hz, 1H), 4.45e4.48
(m, 0.5H, rotamers), 4.37 (d, J¼13.4 Hz, 2H), 4.23e4.29 (m, 1H),
d
7.21e7.39 (m, 5H), 4.83 (app. t, J¼11.3 Hz, 1H),

O.K. Karjalainen, A.M.P. Koskinen / Tetrahedron 70 (2014) 2444e2448
2447
quenched by cooling to 0 ꢁC and slowly adding 2 M NaOH (ca.
250 mL) to a pH of >7. The mixture was extracted with EtOAc
(3ꢂ180 mL). The combined organic phases were dried over Na2SO4
and concentrated. During the neutralization another product had
formed, with Rf value similar to the starting material. Filtration
through a pad silica (eluted with 15% EtOAc/hexanes) yielded the
product (24.7 g, 81%) as a colorless oil. No trace of the byproduct
could be found. An analytical sample was prepared by flash chro-
matography (20% EtOAc/hexanes) to afford a colorless oil. Rf 0.59
followed by Boc2O (2.42 g, 11.1 mmol, 125 mol %). The mixture was
stirred for 2 h and then poured into 1 N HCl (20 mL). The organic
phase was washed with 1 N HCl (20 mL) and the combined aqueous
phases were back extracted with CH2Cl2 (1ꢂ20 mL). The combined
organic phases were dried over Na2SO4 and concentrated to give
3.42 g of crude as a light yellow oil.
The crude (assumed 8.85 mmol, 100 mol %) was dissolved in
CH2Cl2 (30 mL). NaHCO3 (1.50 g, 17.7 mmol, 200 mol %) was added
as a solution in water (30 mL). The resulting vigorously stirred bi-
phasic mixture was cooled to 0 ꢁC and TEMPO (275 mg, 1.77 mmol,
20 mol %) was added followed by BAIB (6.27 g, 19.5 mmol,
220 mol %). After circa 20 min of reaction a thick slurry had formed,
which is most likely the sodium salt of the product. The mixture
was stirred for 16 h and then quenched with 10% aqueous Na2S2O3
(8 mL). 2 N KOH (20 mL) was added and the phases were separated.
The organic phase was diluted with MTBE (30 mL) and extracted
with 2 N KOH (1ꢂ20 mL). The combined aqueous phases were
washed with MTBE (1ꢂ30 mL) and carefully acidified with 3 N HCl
at 0 ꢁC. The turbid mixture was extracted with MTBE (3ꢂ35 mL)
and the combined organic phases were dried over Na2SO4 and
concentrated to give 2.17 g of the crude acid as slightly yellow oil.
The crude product (2.17 g, assumed 6.5 mmol, 100 mol %) was
dissolved in MeCN (15 mL) and then HCl (2.3 mL, 22.8 mmol, 32%
aq) was added at 0 ꢁC. The solution was allowed to warm to rt and
then gently heated to 50 ꢁC for 2 h to finish the deprotection. The
mixture was concentrated to a cream colored solid. The solid was
slurried in a mixture of i-PrOH and heptane (1:2, 10 mL) at 50 ꢁC for
2 h, then cooled to rt and placed in an ice bath to finalize the
precipitation. The product was isolated by filtration and the filter
cake was washed with 50% EtOAc/heptane to give 9 (1.52 g, 63%
over three steps) as a white powder. Mp 187e189 ꢁC (decomp.);
(60% Et2O/Hex); ½a D20
ꢃ
ꢀ61.5 (c 1.00, CH2Cl2); IR (film) 1699, 1384,
1365 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d 7.31e7.16 (m, 5H),
5.88e5.73 (m, 1H), 5.54 (q, J¼11.2 Hz, 1H), 4.54 (dd, J¼8.1, 11.7 Hz,
1H), 4.40e4.32 (m, 0.5H), 4.29 (d, J¼11.7 Hz, 1H), 4.26e4.19 (m,
0.5H), 4.13e3.73 (m, 5H), 1.57e1.28 (m, 16H); 13C NMR (100 MHz,
CDCl3):
d 152.6, 151.9, 137.9, 137.6, 132.5, 130.2, 129.8, 128.5, 128.3,
128.0, 127.9, 127.6, 94.5, 93.8, 80.1, 73.3, 70.8, 64.8, 64.2, 60.4, 59.8,
39.9, 38.9, 28.4, 28.3, 27.1, 26.6, 24.6, 23.0 (rotamers); 1H NMR
(400 MHz, Cl2CDCDCl2, 90 ꢁC):
d 7.41e7.29 (m, 5H), 5.94e5.86 (m,
1H), 5.65 (dd, J¼9.5, 10.6 Hz, 1H), 4.65 (d, J¼11.7 Hz, 1H), 4.54e4.48
(m, 1H), 4.45 (d, J¼12.1 Hz, 1H), 4.21 (dd, J¼8.4, 11.3 Hz, 1H), 4.16 (d,
J¼6.6 Hz, 1H), 4.11 (dd, J¼7.3, 12.1 Hz, 1H), 3.96 (td, J¼6.2, 6.3 Hz,
1H), 4.01e3.93 (m, 1H), 1.61 (s, 3H), 1.55 (s, 3H), 1.51 (s, 9H); 13C
NMR (100 MHz, Cl2CDCDCl2, 90 ꢁC):
d 138.1, 132.5, 129.6, 128.2,
127.7, 127.5, 94.1, 79.9, 73.9, 71.0, 64.3, 60.3, 39.2, 28.3, 26.7; HRMS
calcd for C21H30NO4ClþNa 418.1761, found 418.1736.
4.5. ((2S,3R)-3-(Benzyloxy)-1,2,3,6-tetrahydropyridin-2-yl)
methanol hydrochloride (8)
Acetyl chloride (30 mL, 420 mmol) was added to ice cooled
methanol (90 mL) under argon over 10 min. The solution was
stirred for 30 min and then poured over neat 7 (24.7 g, 62.0 mmol,
100 mol-%). After 30 min of stirring at room temperature, the
starting material was completely consumed according to TLC. The
solvent was evaporated in vacuo to yield 18.9 g of crude product as
a blood red/brown glassy substance.
½
a 2D0
1420, 1211 cmꢀ1; 1H NMR (400 MHz, D2O):
ꢃ
ꢀ105.8 (c 1.00, MeOH); IR (KBr disc) 2965, 1743, 1567, 1440,
d
7.51e7.40 (m, 5H), 6.11
(ddt, J¼10.5, 4.5, 2.2 Hz, 1H), 6.01 (dt, J¼10.6, 2.9 Hz, 1H), 4.77 (d,
J¼11.3 Hz, 1H), 4.73 (d, J¼11.3 Hz, 1H), 4.58 (t, J¼4.0 Hz, 1H), 4.40 (d,
J¼4.0 Hz, 1H), 3.97 (ddd, J¼17.7, 4.3, 2.1 Hz, 1H), 3.81e3.72 (m, 1H);
The crude product was dissolved in methanol. Then ion exchange
resin (Merck ionenaustauscher II; weakly basic tertiary amine resin,
20 g, 5 meq/g, moist, ca. 200 mol %) was added and the mixture was
vigorously stirred until the solution became neutral. Then the mix-
ture was filtered through a sintered glass funnel and concentrated.
The residue was dissolved in 15 mL i-PrOH and 15 mL EtOH and
stirred for 16 h at 75 ꢁC. Upon cooling 3.4 g of fine microcrystalline
powder was obtained. The mother liquor was concentrated and
dissolved in methanol. Another 20 g batch of the resin was added to
neutralize the pH. The mixture was heated to reflux and after 2 h
filtered through a sintered glass funnel and concentrated. The now
solid crude was crystallized from i-PrOH/EtOH to yield 6.7 g of me-
dium sized needles. A second cropyielded 840 mg of the said needles
for a total of 10.94 g (69%, 50% over seven steps). Rf 0.66 (10% MeOH/
1H NMR (400 MHz, CD3OD):
d
7.45e7.28 (m, 5H), 6.11 (ddt, J¼10.6,
4.6, 2.3 Hz, 1H), 5.99 (dt, J¼10.6, 3.1 Hz, 1H), 4.74 (d, J¼11.7 Hz, 1H),
4.69 (d, J¼11.7 Hz, 1H), 4.55 (d, J¼3.5 Hz, 1H), 4.46 (t, J¼4.1 Hz, 1H),
3.96 (ddd, J¼17.7, 4.0, 2.4 Hz, 1H), 3.72 (dddd, J¼17.7, 3.3, 2.4, 1.1,
1H); 13C NMR (100 MHz, CD3OD):
d 168.5, 138.8, 129.5, 129.3, 129.1,
125.5, 125.3, 72.5, 69.4, 57.3, 41.2; HRMS calcd for C13H15NO3þH
234.1330, found 234.1131.
4.7. (2R,3R)-3-Hydroxypiperidine-2-carboxylic acid (10)
To a solution of 9 (1.0 g, 3.7 mmol, 100 mol %) in MeOH (15 mL)
was added Pd/C (200 mg, 0.19 mmol, 5 mol %, 10 w % Pd) after
which the solution was vacuum degassed followed by introduction
of H2 atmosphere. The mixture was stirred under H2 for 16 h and
then filtered through a pad of Celite and concentrated to give
652 mg (97%) of yellowish partly crystalline solid. The purity was
upgraded by suspending the solids in EtOH/CHCl3 (1:3, 5 mL) at
75 ꢁC for 1 h. Then the mixture was cooled to room temperature
and filtered. The filter cake was washed with cold EtOH/CHCl3 (1:3)
and dried to give 10 (635 mg, 95%) as a white microcrystalline
CH2Cl2þ1% 25% aqueous ammonia); mp: 196 ꢁC; ½a D20
ꢀ109.1 (c 1.00,
ꢃ
MeOH); IR (KBr disc) 3320, 1585, 1087 cmꢀ1 1H NMR (400 MHz,
;
CD3OD):
d
7.40e7.26 (m, 5H), 6.14 (dddd, J¼1.1, 7.4, 8.7, 11.0 Hz, 1H),
5.96e5.89 (m, 1H), 4.71 (d, J¼11.5 Hz, 1H), 4.63 (d, J¼11.5 Hz, 1H),
4.24e4.18 (m, 1H), 3.87 (dd, J¼11.9, 3.8 Hz, 1H), 3.79e3.70 (m, 2H),
4.23 (ddt, J¼17.4, 3.5,1.8 Hz,1H), 3.42 (dt, J¼6.7, 3.8 Hz,1H); 13C NMR
(100 MHz, CD3OD):
d
139.9,130.3,130.0,129.9,128.4,124.5, 73.3, 70.4,
powder with a hint of rosy color. Mp: 178e181 ꢁC (decomp.); ½a D20
ꢃ
59.4, 59.3, 42.8; HRMS: calcd for C13H17NO2þH 220.1338, found
220.1340; Anal. Calcd for C13H18ClNO2: C, 61.05; H, 7.09; N, 5.48;
found: C, 61.22; H, 6.84; N, 5.46.
ꢀ14.6 (c 1.10, H2O), lit. for the enantiomer: þ14.2 (c 0.95, H2O),9f
þ14.5 (c 0.4, H2O);9e IR (KBr disc) 3173, 2981, 1744, 1404, 1280,
1081 cmꢀ1
;
1H NMR (400 MHz, CD3OD):
d
4.17 (ddd, J¼6.4, 6.4,
3.1 Hz, 1H), 3.91 (d, J¼6.4 Hz, 1H), 3.37e3.32 (m, 1H), 3.16e3.06 (m,
4.6. (2R,3R)-3-(Benzyloxy)-1,2,3,6-tetrahydropyridine-2-
carboxylic acid hydrochloride (9)
1H), 3.15e3.06 (m, 1H), 2.15e2.03 (m, 1H), 1.92e1.81 (m, 1H),
1.80e1.65 (m, 2H); 13C NMR (100 MHz, CD3OD):
d
67.0, 62.9, 44.2,
30.4, 20.1; (The carbonyl carbon was not visible when run in
MeOD); 1H NMR (400 MHz, D2O):
4.07 (dt, J¼8.1, 2.9 Hz, 1H), 3.75
(d, J¼7.9 Hz, 1H), 3.31 (ddd, J¼12.8, 6.6, 3.8 Hz, 1H), 4.40 (ddd,
To a stirred mixture of 8 (2.00 g, 8.85 mmol,100 mol %) in CH2Cl2
(20 mL) was added triethylamine (2.78 mL, 19.9 mmol, 225 mol %)
d

2448
O.K. Karjalainen, A.M.P. Koskinen / Tetrahedron 70 (2014) 2444e2448
J¼12.7, 9.2, 3.1 Hz, 1H), 2.01e1.90 (m, 2H), 1.74e1.56 (m, 2H); 13C
Guaragna, A.; D’Alonzo, D.; Paolella, C.; Palumbo, G. Tetrahedron Lett. 2009, 50,
2045e2047; (j) Ferreira, F.; Botuha, C.; Chemla, F.; Perez-Luna, A. J. Org. Chem.
ꢀ
NMR (100 MHz, D2O):
d 170.5, 66.0, 61.4, 43.0, 29.2, 19.1; HRMS
2009, 74, 2238e2241; (k) Rengasamy, R.; Curtis-Long, M. J.; Pyu, H. W.; Oh, K.
Y.; Park, K. H. Bull. Korean Chem. Soc. 2009, 30, 1351e1354; (l) Singh, A.; Kim, B.;
Lee, W. K.; Ha, H.-J. Org. Biomol. Chem. 2011, 9, 1372e1380; (m) van den Berg, R.
J. B. H. N.; Wennekes, T.; Ghisaidoobe, A.; Donker-Koopman, W. E.; Strijland, A.;
Boot, R. G.; van der Marel, G. A.; Aerts, J. M. F. G.; Overkleeft, H. S. ACS Med.
Chem. Lett. 2011, 2, 519e522; (n) Chattopadhyay, S. K.; Roy, S. P.; Saha, T. Syn-
thesis 2011, 2664e2670; (o) Jarvis, S. B. D.; Charette, A. B. Org. Lett. 2011, 13,
3830e3833; (p) Kalamkar, N. B.; Dhavale, D. D. Tetrahedron Lett. 2011, 52,
6363e6365; (q) Ramalingam, S.; Bhise, A. D.; Show, K.; Kumar, P. ARKIVOC 2013,
calcd for C6H12NO3þH 146.0817, found 146.0815.
Acknowledgements
Funding from the National Graduate School of Organic Chem-
istry and Chemical Biology (to O.K.K.) is gratefully acknowledged.
ꢀ
ii, 220e227; (r) de la Fuente, A.; Martin, R.; Mena-Barragan, T.; Verdaguer, X.;
ꢀ
Supplementary data
Garcia Fernandez, J. M.; Ortiz Mellet, C.; Riera, A. Org. Lett. 2013, 15, 3638e3641.
4. Karjalainen, O. K.; Koskinen, A. M. P. Org. Biomol. Chem. 2011, 9, 1231e1236.
5. (a) Liang, X.; Andersch, J.; Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136e2157;
(b) Reginato, G.; Meffre, P.; Gaggini, F. Amino Acids 2005, 29, 81e87; (c) Passi-
niemi, M.; Koskinen, A. M. P. Beilstein J. Org. Chem. 2013, 9, 2641e2659.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.02.020.
€
6. For reductive approach see: Koskinen, A. M. P.; Hassila, H.; Myllymaki, V. T.;
Rissanen, K. Tetrahedron Lett. 1995, 36, 5619e5622 For oxidative approach see:
Dondoni, A.; Perrone, D. Org. Synth. 2000, 77, 64e73; Org. Synth. 2004; Collect.
Vol. 10, 320e326.
7. Gruza, H.; Kiciak, K.; Krasinski, A.; Jurczak, J. Tetrahedron: Asymmetry 1997, 8,
2627e2631.
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