Facile syntheses of enantiopure 3-hydroxypiperidine derivatives and 3-hydroxypipecolic acids

Article abstract of DOI:10.1021/jo902324h

(Chemical Equation Presentation) Facile syntheses of enantiopure trans- and cis-3-hydroxypiperidine derivatives and 3-hydroxypipecolic acids are reported, featuring Rh-catalyzed cyclohydrocarbonylation through common intermediates. A diaxial conformation in a 2,3-disubstituted N-Boc-piperidinyl structure is revealed by an X-ray crystallographic analysis.

Full text of DOI:10.1021/jo902324h

pubs.acs.org/joc
through common intermediates via Rh-catalyzed cyclohy-
drocarbonylation.
Facile Syntheses of Enantiopure 3-Hydroxypiperidine
Derivatives and 3-Hydroxypipecolic Acids
Our syntheses commenced with vinyl addition on serine-
derived Garner’s aldehyde (1),6 readily available in the (S)-
as well as the (R)-form, served as a synthetically useful chiral
precursor for the construction of optically active molecules.
Addition of commercially available vinylmagnesium bro-
mide at -40 °C led to a mixture of two diastereomeric
products 2 in 87% combined yield. Although separation of
two isomers was possible, the separation cost prompted us to
find a better solution. Thus, protection of the resulting
hydroxyl group was carried out by treatment with benzyl
bromide in the presence of 18-crown-6 ether to give benzyl
ether 3 in 88% yield. Addition of the crown ether improved
the yield and reduced the reaction time. Removal of the
acetonide group proceeded smoothly in an acidic condition,
affording separable olefins 4 in 90% combined yield. An
HPLC method has been developed to determine the diaster-
eomeric ratio as 4.0:1 (see the Supporting Information). Both
diastereomers can be easily obtained by column chromatog-
raphy to give the less polar diastereomer as the major
product 4a in 67% isolated yield and the more polar product
as the minor product 4b in 15% isolated yield (Scheme 1).
Wen-Hua Chiou,* Gau-Hong Lin, and Chih-Wei Liang
Department of Chemistry, National Chung Hsing University,
Taichung, Taiwan, R.O.C.
wchiou@dragon.nchu.edu.tw
Received November 4, 2009
Facile syntheses of enantiopure trans- and cis-3-hydro-
xypiperidine derivatives and 3-hydroxypipecolic acids are
reported, featuring Rh-catalyzed cyclohydrocarbonyla-
tion through common intermediates. A diaxial confor-
mation in a 2,3-disubstituted N-Boc-piperidinyl structure
is revealed by an X-ray crystallographic analysis.
SCHEME 1a
Azasugars are carbohydrate analogues in which a nitrogen
atom substitutes for the oxygen atom in the ring, and they
have been found in a number of plants and microorganisms.1,2
Since the first discovery of nojirimycin in 1966,2 azasugars
have received a great deal of attention due to their significant
bioactivity. Their physiological effects result from the simi-
larity with transition-state analogues in many carbohydrate-
processing enzymes such as glycosidases and glycosyltrans-
ferases.3,4 Since azasugars are viewed as possible therapeutic
agents to treat a number of diseases such as diabetes, viral
infections, and tumor metastasis, they have attracted syn-
thetic chemists’ interests to develop various approaches. As a
part of the project devoted to asymmetric syntheses5 of
different azasugars and derivatives for pharmaceutical pur-
poses, here we report the syntheses of enantiopure 3-hydro-
xypiperidine derivatives and 3-hydroxypipecolic acids
aReagents and conditions: (a) CH2dCHMgBr (2.0 equiv), THF,
-40 °C; (b) BnBr (1.5 equiv), NaH (1.8 equiv), 18-crown-6 ether (0.5 equiv),
THF, 0 °C to rt; (c) PTSA (13 mol %), MeOH, rt.
Rh-catalyzed cyclohydrocarbonylation provides a power-
ful tool for preparation of piperidine derivatives.7,8 It can be
viewed as a domino-type reaction, consisting of three con-
secutive reactions (Scheme 2). It starts with linear-selective
hydroformylation of monosubstituted alkene (I) to linear
aldehyde (II), followed by intramolecular addition of a
carbamate to give hemiamidal (III). Hemiamidal (III) may
undergo either solvent substitution to amidal (V, in a protic
solvent), or dehydration to encarbamate (VI, in an aprotic
solvent) via a common iminium intermediate (IV).
(1) For some leading references, see: (a) St€utz, A. E. Iminosugars as
Glycosydase Inhibitors: Nojirimycin and Beyond; Wiley-VCH: Weinheim,
1999. (b) Compain, P.; Martin, O. R. Iminosugars, 1st ed.; John Wiley & Sons
Ltd.: Chichester, 2007 and references cited therein.
(2) Inouye, S.; Tsuruoka, T.; Niida, T. J. Antibiot. 1966, 19, 288–292.
(3) For recent study of azasugar inhibition, see: (a) Heightman, T. D.;
Vasella, A. T. Angew. Chem., Int. Ed. 1999, 38, 750–770. (b) Zechel, D. L.;
Boraston, A. B.; Gloster, T.; Boraston, C. M.; Macdonald, J. M.; Tilbrook,
D. M. G.; Stick, R. V.; Davies, G. J. J. Am. Chem. Soc. 2003, 47, 14313–
14323.
(4) For recent reviews, see: (a) Butters, T. D.; Dwek, R. A.; Platt, F. M.
Chem. Rev. 2000, 12, 4683–4696. (b) Sinnott, M. L. Chem. Rev. 1990, 90,
1171–1202.
(6) (a) Garner, P.; Park, J.-M. J. Org. Chem. 1987, 52, 2361–2364.
(b) Garner, P.; Park, J.-M. In Organic Syntheses; Wiley: New York, 1998;
Collect. Vol. IX, p 300.
(7) (a) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem. 1995, 60,
7078–7079. (b) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63, 7999–8003.
(c) Chiou, W.-H.; Schoenfelder, A.; Sun, L.; Mann, A.; Ojima, I. J. Org.
Chem. 2007, 72, 9418–9425.
(5) For recent reviews of syntheses of piperidine azasugars, see: (a) Pearson,
ꢀ
M. S. M.; Mathe-Allainmat, M.; Fargeas, V.; Lebreton, J. Eur. J. Org.
Chem. 2005, 2005, 2159–2191. (b) Laschat, S.; Dickner, T. Synthesis 2000,
(8) For recent reviews of cyclohydrocarbonylation, see: (a) Ojima, I.;
Commandeur, C.; Chiou, W.-H. In Comprehensive Organometallic Chemistry-III;
Hiyama, T., Ojima, I., Eds.; Elsevier: Oxford, 2006; Chapter 11.15, ;pp 511-556. (b)
Chiou, W.-H.; Lee, S.-Y.; Ojima, I. Can. J. Chem. 2005, 83, 681–692.
1781–1816.
1748 J. Org. Chem. 2010, 75, 1748–1751
Published on Web 02/08/2010
DOI: 10.1021/jo902324h
r
2010 American Chemical Society

Chiou et al.
JOCNote
SCHEME 2. Rh-Catalyzed Cyclohydrocarbonylation
FIGURE 1. ORTEP drawing of diol 8a showing 50% probability.
SCHEME 3a
FIGURE 2. Swainsonine and tetrazomine.
78% yield (Scheme 3). We tried to assign the absolute
structure of 7a by thorough NMR analyses. The ROESY
pointed out clearly a strong signal between H-2 and H-3. It
implied that the relative configuration of 7a was either a cis
arrangement or a trans arrangement in which both of two
substituents were located at pseudodiaxial orientations.
The structure of 7a was determined by the X-ray crystal-
lography of benzyl-free derivative 8a, synthesized by cataly-
tic hydrogenolysis of 7a with palladium on carbon, affording
diol 8a in 90% yield. Solid product 8a was recrystallized from
chloroform-heptane to give a crystal suitable for the X-ray
analysis (Figure 1).
aReagents and conditions: (a) Rh(acac)(CO)2 (0.5 mol %), BIPHE-
PHOS (1.0 mol %), CO (2 atm), H2 (2 atm), toluene, 60 °C, overnight
(∼16 h); (b) Et3SiH (3.0 equiv), BF3 OEt2 (3.0 equiv), CH2Cl2, -78 °C,
3
16 h; (c) (a) in MeOH; (d) Pd/C (5 mol %), H2 (2 atm), MeOH, rt, 6 h.
It clearly revealed that the hydoxymethyl group at C-2 and
the hydroxyl group at C-3 were located at the pseudoaxial
positions of the piperidine, indicating both of H-2 and H-3
adopted pseudodiequatorial orientations. Such a preference
for the diaxial conformation was attributed to a strong A1,3
strain exerted by the C-N bond,11,12 possessing partial
double bond characters in the carbamate group. Since the
absolute configuration of diol 8a had been determined,
parent olefin 4a was unambiguously assigned as an
anti-(2S,3R) configuration.
Piperidine 7a was a versatile building block for syntheses
of indolizidines or piperidines. For example, after removal of
the Boc protecting group, diol 8a could be converted to the
enantiomer of 4-deoxyfagomine, an analogues of fagomine
found as a potent antihyperglycemic compound.13 Swainso-
nine, an inhibitor for mannosidase II, was synthesized from
7a in five additional steps.14 In addition, found in part of a
variety of bioactive compounds, 3-hydroxypipecolate deri-
vatives were valuable intermediates to synthesize antitumor
antibiotics, such as tetrazomine (Figure 2). We described the
With olefin 4a in hand, cyclohydrocarbonylation was
carried out with low loading of Rh-BIPHEPHOS (0.5 mol
%) at 60 °C under 4 atm of CO and H2 (1:1) in toluene to give
a crude product. A 1H NMR analysis9 showed amidal 5a was
the major product, accompanied by a small amount of
enecarbamate 6a (5a/6a = 2.5:1). However, after flash
chromatography on silica gel, encarbamate 6a was obtained
in 76% isolated yield, while bicycloamidal 5a in 18% yield. It
was obvious that isomerization proceeded between 5a and 6a
during purification.10 Subsequent reduction of bicycloami-
dal 5a with triethylsilane-boron trifluoride etherate at
-78 °C afforded functionalized piperidine derivative 7a in
94% yield. To surmount the low yield problem, methanol
was used as the solvent because it would not form 6a. Thus,
switch of toluene to methanol in the cyclohydrocarbonyla-
tion reaction, followed by direct treatment of the crude
product with reducing agents, afforded piperidine 7a in
91% yield over two steps. The identical two-step reaction
sequence was applied to convert olefin 4b to piperidine 7b in
(9) A DFT-B3LYP/6-31G* calculation by Spartan 08 indicated 5a is
more stable than 6a by 8.9 kcal/mol in vacuo and by 8.2 kcal/mol in toluene
using the SM8 model.
(11) Johnson, F. Chem. Rev. 1968, 68, 375–413.
(12) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841–1860.
(10) We did an experiment to confirm the isomerization: treatment of
pure amidal 5 in the mixture solution of ethyl acetate and chloroform (v/v =
1:1) containing silica gel resulted in the formation of encarbamate 6a (5a/6a
∼ 1:1) by 1H NMR analysis.
(13) Asano, N.; Kato, A.; Miyauchi, M.; Kizu, H.; Tomimori, T.; Matsui,
K.; Nash, R. J.; Molyneux, R. J. Eur. J. Biochem. 1997, 248, 296–303.
ꢁ
(14) Martın, R.; Murruzzu, C.; Pericas, M. A.; Riera, A. J. Org. Chem.
´
2005, 70, 2325–2328.
J. Org. Chem. Vol. 75, No. 5, 2010 1749

Chiou et al.
JOCNote
SCHEME 4a
Experimental Section
2-tert-Butyloxycarbonylamino-3-benzyloxypent-4-en-1-ol (4).
To a THF solution (40 mL) of Garner’s aldehyde 1 (1.053 g,
4.59 mmol, 1.00 equiv) under nitrogen at -30 °C was added
dropwise a vinyl magnesium bromide THF solution (0.7 M,
13.1 mL, 9.17 mmol, 2.0 equiv) via a syringe over 30 min. The
reaction mixture was allowed to warm to 0 °C and then stirred in
an ice bath overnight (∼17 h). The reaction was monitored by
TLC analysis. Upon completion of the reaction, the reaction
mixture was poured into a chilled aqueous NH4Cl solution
(20 mL). After separation of the organic layer, the aqueous
layer was extracted with ethyl acetate (50 mL ꢀ 4). The
combined organic layers were washed with brine (50 mL), dried
over Na2SO4, and then concentrated under reduced pressure to
give a crude product. The crude product was purified by flash
chromatography on silica gel using ethyl acetate/n-hexane (Rf =
0.37, ethyl acetate/n-hexane = 1/3) as the eluant to give product
2 as a colorless oil (1.026 g, 87%): GC-MS condition: Set the
initial temperature 50 °C and heating rate as 25 °C per minute to
200 °C and then changed the rate to 10 °C per minute until the
temperature was up to 280 °C and kept the temperature at
280 °C for 2 min, tR: 8.82 min GC-MS m/z (relative intensity,
ion): 242 (<1, Mþ - Me), 200 (30, oxazolidinyl), 57 (100, t-Bu).
To a THF solution (60 mL) of alcohol 2 (2.753 g, 10.7 mmol,
1.00 equiv) in an ice bath under nitrogen was added dropwise
sodium hydride (60%, 769 mg, 19.2 mmol, 1.8 equiv). After the
solution was stirred in an ice bath for 30 min, benzyl bromide
(1.9 mL, 15.9 mmol, 1.5 equiv) was added by a syringe, followed
by addition of 18-crown-6 ether (1.410 g, 5.3 mmol, 0.5 equiv).
The reaction mixture was allowed to warm to room temperature
and then stirred for 5 h. The reaction was monitored by TLC
analysis. Upon completion of the reaction, the reaction mixture
was poured into a chilled aqueous NH4Cl solution (100 mL).
After separation of the organic layer, the aqueous layer was
extracted with ethyl acetate (100 mLꢀ 4). The combined organic
layers were washed with brine (100 mL), dried over Na2SO4, and
then concentrated under reduced pressure to give a crude
residue. The crude product was purified by flash chromatogra-
phy on silica gel using ethyl acetate/n-hexane (Rf = 0.71, ethyl
acetate/n-hexane = 1/3) as the eluant to give product 3 as a
colorless oil (3.271 g, 88%).
aReagents and conditions: (a) TEMPO (20 mol %), KBr (0.5 equiv),
NaOCl (6.0 equiv), NaHCO3, acetone, 4 °C, 3 h; (b) CH2N2; (c) Pd/C
(5 mol %), H2 (2 atm), MeOH, rt, 4 h; (d) (i) 6 N HCl, reflux, (ii) prop-
ylene epoxide, EtOH, reflux.
syntheses of 3-hydroxypipecolate derivatives from piperi-
dines 7 as follows.15
TEMPO-catalyzed bleach reaction16 provided a facile way
to oxidize the hydroxymethyl group to corresponding car-
boxylic acid 9a. We attempted catalytic hydrogenation to
remove the benzyl group of 9a, but the reaction proceeded
too slow to give the desired product. Thus, the synthesis was
modified by treatment of resulting crude carboxylic acid 9a
with diazomethane, affording methyl ester 10a in 90% yield
over two steps. Subsequent debenzylation with hydrogen in
the presence of palladium on carbon gave free alcohol 11a in
86% yield. Global removal of the methyl ester and the BOC
protecting group in an acidic condition, followed by treat-
ment with propylene oxide to neutralize excess hydrogen
chloride gave trans-(2R,3R)-3-hydroxypipecolic acid (12a) in
95% yield, whose structure was unambiguously elucidated
by NMR analyses. This protocol has proven to be applicable
in the synthesis of the other diastereomer. Therefore, the
synthesis of cis-(2R,3S)-3-hydroxypipecolic acid (12b) was
readily achieved using the same procedure (Scheme 4).
In conclusion, we have developed an effective methodo-
logy for the synthesis of enantiopure 3-hydroxypipecolic acid
(12a and 12b) via a useful building block 7, which is also a
precursor to synthesize swainsonine. Either 7a or 7b is easily
synthesized from Garner’s aldehyde in an enantiopure form
through cyclohydrocarbonylation. We are currently apply-
ing this methodology toward other azasugars.
To a MeOH solution (15 mL) of oxazolidine 3 (400 mg,
1.15 mmol, 1.00 equiv) in an ice bath under nitrogen was added
PTSA (27 mg, 0.14 mmol, 13 mol %). The reaction mixture was
stirred at room temperature for 8 h and monitored by TLC
analysis. Upon completion of the reaction, the reaction mixture
was concentrated under reduced pressure to give a crude syrup.
The crude product was purified by flash chromatography on
silica gel using ethyl acetate/n-hexane (1/12) as the eluant to give
major product 4a (238 mg, 67%, Rf = 0.48, ethyl acetate/n-
hexane = 1/3 ꢀ 3) and minor product 4b (54 mg, 15%, Rf =
0.41, ethyl acetate/n-hexane = 1/3 ꢀ 3). HPLC condition:
Supelcosil LC-SI, 250 mm ꢀ 4.6 mm, 5 μm; 1 vol % IPA in
hexane/hexane = 1/1; flow rate 1.5 mL per min; detection UV
210 nm; tR: 41 min for 4a; tR: 54 min for 4b (4a:4b = 4.0:1).
(15) For recent syntheses of 3-hydroxypipecolic acids, see: (a) Greck, C.;
^
Ferreira, F.; Genet, J. P. Tetrahedron Lett. 1996, 37, 2031–2034. (b) Agami,
C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996, 37, 4001–4002.
(c) Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi, G.; Fava, G. G.;
Ferrari, M. B.; Casiraghi, G. Tetrahedron: Asymmetry 1997, 8, 2975–2987.
(d) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033–7036. (e) Bodas,
M. S.; Kumar, P. Tetrahedron Lett. 2004, 45, 8461–8463. (f) Kumar, P.;
Bodas, M. S. J. Org. Chem. 2005, 70, 360–363. (g) Liang, N.; Datta, A. J. Org.
Chem. 2005, 70, 10182–10185. (h) Kim, I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H.
Tetrahedron 2007, 63, 2622–2633. (i) Liu, L.-X.; Peng, Q.-L.; Huang, P.-Q.
Tetrahedron: Asymmetry 2008, 19, 1200–1203. (j) Ohara, C.; Takahashi, R.;
Miyagawa, T.; Yoshimura, Y.; Kato, A.; Adachi, I.; Takahata, H. Bioorg.
Med. Chem. Lett. 2008, 18, 1810–1813. (k) Yoshimura, Y.; Ohara, C.;
Imahori, T.; Saito, Y.; Kato, A.; Miyauchi, S.; Adachi, I.; Takahata, H.
Bioorg. Med. Chem. 2008, 16, 8273–8286.
(2S,3R)-4 (4a): white solid; mp 58-59 °C; [R]23 -66.6 (c
D
1
2.06, CHCl3) [lit.17 [R]25 -51.8 (c 0.953, CHCl3)]; H NMR
D
(600 MHz, 25 °C, CDCl3, δ) 1.40 (s, 9H, -C(CH3)3), 2.62 (brs,
-OH), 3.58-3.66 (m, 2H, H-1 and H-2), 3.90-3.93 (m, 1H, H-
1), 4.03-4.08 (m, 1H, H-3); 4.30 (d, J = 12.0 Hz, 1H,
-OCH2Ph), 4.61 (d, J = 12.0 Hz, 1H, -OCH2Ph), 5.27 (d,
J = 7.2 Hz, 1H, -NHBoc), 5.33-5.38 (m, 2H, H-5), 5.65 (ddd,
J = 7.8, 10.8, 18.0 Hz, 1H, H-4), 7.25-7.33 (m, 5H, -Ph); 13
C
NMR (100 MHz, 25 °C, CDCl3, δ) 28.3 (q, -C(CH3)3), 54.4 (d,
C-2), 61.9 (t, C-1), 71.0 (t, -OCH2Ph), 79.4 (s, -OC(CH3)3),
(16) (a) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559–2562. (b) Sheldon, R. A.; Arends, I. W. C. E.; Brink, G.-J. t.;
Dijksman, A. Acc. Chem. Res. 2002, 35, 774–781. (c) Chiou, W.-H.;
Schoenfelder, A.; Sun, L.; Mann, A.; Ojima, I. J. Org. Chem. 2007, 72,
9418–9425.
(17) Srivastava, A. K.; Panda, G. Chem.;Eur. J. 2008, 14, 4675–4688.
1750 J. Org. Chem. Vol. 75, No. 5, 2010

Chiou et al.
JOCNote
81.9 (d, C-3), 119.2 (t, C-5), 127.7 (d, o-Ph), 127.8 (d, p-Ph),
128.4 (d, m-Ph), 135.0 (d, C-4), 137.6 (s, ipso-Ph), 155.9 (s, O-
and additional bleach (4.5 mL, 1.0 M, 4.5 mmol, 3.2 equiv) were
added. The reaction mixture was stirred in an ice bath for
another 1 h. Concentration of the reaction mixture under
reduced pressure to remove volatile substances gave a clean
aqueous solution. The aqueous solution was washed with ether
(10 mL) and covered with ethyl acetate (20 mL). The solution
with two phases was acidified with an aqueous KHSO4 solution
(2 M) in an ice bath until pH became 2-3. A white precipitate
was observed during acidification. After separation of the
organic layer, the resulting aqueous layer was extracted with
ethyl acetate (30 mL ꢀ 4). The combined organic layers were
washed with brine (10 mL), dried over Na2SO4, and then
concentrated to give crude acid 9a. To the solution of crude
acid 9a in MeOH (∼0.1 M) was added an ether solution of
diazomethane slowly until a yellow color persisted. Concentra-
tion under reduced pressure gave a yellow crude syrup. The
crude product was purified by flash chromatography on silica
gel using ethyl acetate/n-hexane (Rf = 0.38, ethyl acetate/n-
hexane = 1/3) as the eluant to give product 10a as a colorless oil
(330 mg, 90% yield over two steps): [R]25D þ2.1 (c 0.92, CHCl3);
1H NMR (600 MHz, 50 °C, CDCl3, δ) 1.34-1.52 (m, 2H, H-4
and H-5), 1.45 (s, 9H, -C(CH3)3), 1.87-1.96 (m, 2H, H-4 and
H-5), 3.00 (brs, 1H, H-6), 3.73 (s, 3H, -CO2CH3), 4.02 (brs, 1H,
H-6), 4.05 (brs, 1H, H-3), 4.51 (d, J = 12.0 Hz, 1H, -OCH2Ph),
4.64 (d, J = 12.0 Hz, 1H, -OCH2Ph), 5.15 (brs, 1H, H-2),
7.24-7.36 (m, 5H, -Ph); 13C NMR (150 MHz, 50 °C, CDCl3, δ)
18.7 (t, C-5), 26.1 (t, C-4), 28.3 (q, -C(CH3)3), 41.5 (t, C-6), 52.0
(q, -CO2CH3), 57.0 (d, C-2), 70.6 (t, -OCH2Ph), 72.4 (d, C-3),
80.1 (s, -OC(CH3)3), 127.4 (d, o-Ph and p-Ph), 128.3 (d, m-Ph),
138.3 (s, ipso-Ph), 155.9 (s, O-CO-N), 170.8 (s, C-7); EI-HRMS
CO-N); HRMS-FAB (m/z) [M þ H]þ calcd for C17H25NO4 Hþ
3
308.1862, found 308.1852 (Δ = 3.3 ppm).
(2S,3R)-1-tert-Butyloxycarbonyl-2-hydroxymethyl-3-benzylo-
xypiperidine (7a). Rh(acac)(CO)2 (1.1 mg, 4.2 μmol, 0.5 mol %)
and BIPHEPHOS (6.4 mg, 8.1 μmol, 1.0 mol %) were dissolved
in MeOH (2 mL) under nitrogen. The resulting catalyst solution
was degassed by a freeze-thaw procedure at least three times.
Olefin 4a (250 mg, 0.813 mmol, 1.00 equiv) was placed in a
50 mL flask. The catalyst solution was transferred to the
reaction flask containing the substrate by a pipet, and then the
total volume was adjusted to 16 mL with MeOH. The reaction
flask was placed in a 300 mL stainless steel autoclave and then
was pressurized with CO (2 atm) followed by H2 (2 atm). The
reaction mixture was stirred at 60 °C for 16-20 h. Upon
completion of the reaction, the gas was carefully released in a
good ventilated hood. The reaction mixture was concentrated
under reduced pressure to give a crude product, and then diluted
with CH2Cl2 (15 mL). To the CH2Cl2 solution was added
dropwise triethylsilane (Et3SiH, 390 μL, 2.44 mmol, 3.0 equiv)
followed by boron trifluoride etherate (BF3 OEt2, 309 μL,
3
2.44 mmol, 3.0 equiv). The reaction mixture was allowed to be
stirred at -78 °C overnight (∼16 h). The reaction was monitored
by TLC analysis. Upon completion of the reaction, a saturated
NaHCO3 solution (5 mL) was slowly added into the reaction
mixture so that the temperature was kept below -60 °C and
then warmed to room temperature. After separation of the
organic layer, the aqueous layer was extracted with ethyl acetate
(10 mL ꢀ 4). The combined organic layers were washed with
brine (10 mL), dried over Na2SO4, and then concentrated under
reduced pressure to give a crude residue. The crude product was
purified by flash chromatography on silica gel using ethyl
acetate/n-hexane (Rf = 0.49, ethyl acetate/n-hexane = 1/3 ꢀ
3) as the eluant to give product 7a as a colorless oil (239 mg,
91%): [R]23 þ39.5 (c: 1.73, CHCl3) [lit.12 [R]20 -40.1 (c 0.9,
(m/z) [M]þ calcd for C19H27NO5 349.1889, found 349.1892
þ
(Δ = 0.9 ppm).
(2R,3R)-3-Hydroxypipecolinic acid (12a). A solution of meth-
yl ester 11a (48 mg, 0.19 mmol, 1.00 equiv) in a hydrochloric acid
solution (6 N, 4 mL) was stirred under reflux for 1 h and then
concentrated under reduced pressure to give a residue. Reflux
of the crude product in EtOH (3 mL) and propylene oxide
(0.35 mL) gave a brown precipitate. Filtration followed by
washing with cold ether afforded the titled product as a light
brown solid (27 mg, 0.18 mmol, 95%): mp 241 °C dec [lit.15c mp
234-239 °C dec; [R]25D -15.9 (c 2.70, H2O); lit.15k [R]28D -12.9
(c 1.0, H2O)]; 1H NMR (600 MHz, 25 °C, D2O, δ) 1.64-1.76 (m,
2H, H-4 and H-5), 1.90-1.96 (m, 1H, H-4), 1.97-2.04 (m, 1H,
H-5), 3.09 (ddd, J = 3.6, 8.4, 12.0 Hz, 1H, H-6), 3.35 (ddd, J =
4.2, 7.2, 12.0 Hz, 1H, H-6), 3.61 (d, J = 7.2 Hz, 1H, H-2), 4.14
(ddd, J = 3.0, 7.2, 7.2 Hz, 1H, H-3); 13C NMR (150 MHz, 25 °C,
D2O, δ) 18.4 (t, C-5), 28.3 (t, C-4), 42.5 (t, C-6), 62.0 (d, C-2),
66.0 (d, C-3), 172.1 (s, C-7). HRMS-FAB (m/z) [M þ H]þ calcd
D
D
CHCl3)]; 1H NMR (600 MHz, 25 °C, CDCl3, δ) 1.36-1.40 (m,
1H, H-5R), 1.44 (s, 9H, -C(CH3)3), 1.54-1.60 (m, 1H, H-4R),
1.83-1.93 (m, 2H, H-4β and H-5β), 2.33 (brs, 1H, -OH), 2.86
(t, J = 12.6 Hz, 1H, H-6R), 3.56 (d, J = 2.4 Hz, 1H, H-3), 3.61
(dd, J = 6.0, 10.8 Hz, 1H, H-7), 3.74 (dd, J = 8.4, 10.8 Hz, 1H,
H-7), 3.96 (brs, 1H, H-6β), 4.48 (d, J = 12.0 Hz, 1H, -OCH2-
Ph), 4.50 (t, J = 6.0 Hz, 1H, H-2), 4.61 (d, J = 11.4 Hz, 1H,
-OCH2Ph), 7.23-7.33 (m, 5H, -Ph); 13C NMR (100 MHz,
25 °C, CDCl3, δ) 19.5 (t, C-5), 25.1 (t, C-4), 28.3 (q, -C(CH3)3),
39.6 (t, C-6), 55.5 (d, C-2), 60.5 (t, C-7), 70.0 (t, -OCH2Ph), 71.5
(d, C-3), 79.8 (s, -OC(CH3)3), 127.3 (d, p-Ph), 127.4 (d, o-Ph),
128.2 (d, m-Ph), 138.6 (s, ipso-Ph), 156.3 (s, O-CO-N); HRMS-
FAB (m/z) [M þ H]þ calcd for C18H27NO4 Hþ 322.2018, found
for C6H11NO3 H
þ 146.0817, found 146.0810 (Δ: 4.8 ppm).
3
3
322.2007 (Δ = 3.4 ppm).
Acknowledgment. We thank the National Science Coun-
cil, Taiwan (NSC96-2113-M-005-003-MY2 and NSC97-
2113-M-005-004), and the Instrument Center of National
Chung Hsing University for support of this research.
(2R,3R)-1-tert-Butyloxycarbonyl-2-methoxycarbonyl-3-benz-
yloxypiperidine (10a). To a solution of alcohol 7a (337 mg,
1.05 mmol, 1.00 equiv) in acetone (8 mL) in an ice bathwere
added an aqueous NaHCO3 solution (5%, 8 mL), KBr (60 mg,
0.5 mmol, 0.5 equiv), and tetramethylpiperidine nitroxyl free
radical (TEMPO, 30 mg, 0.20 mmol, 0.20 equiv). Then, a
commercial bleach solution (4.5 mL, 1.0 M by titration,
4.5 mmol, 3.2 equiv) was added dropwise via a syringe over
5 min. The solution became white cloudy. After the solution was
stirred for 1 h in an ice bath, additional NaHCO3 (5%, 8 mL)
Supporting Information Available: Experimental proce-
dure, characterization data, as well as 1H and 13C NMR spectra
for all compounds and the crystallographic data of 8a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 75, No. 5, 2010 1751