Chiron approach to the synthesis of (2S,3R)-3-hydroxypipecolic acid and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine from D-glucose

Article abstract of DOI:10.1021/jo702749r

(Chemical Equation Presented) The first chiron approach from D-glucose for the total synthesis of (2S,3R)-3-hydroxypipecolic acid (-)-1a and (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine (-)-2a is reported. The synthetic pathway involves conversion of D-glucose into 3-azidopentodialdose (5) followed by the Wittig olefination and reduction to give the piperidine ring skeleton (8) with a sugar appendage that on cleavage of an anomeric carbon followed by oxidation gives (-)-1a which on reduction affords (-)-2a.

Full text of DOI:10.1021/jo702749r

Chiron Approach to the Synthesis of
(2S,3R)-3-Hydroxypipecolic Acid and
(2R,3R)-3-Hydroxy-2-hydroxymethylpiperidine
from D-Glucose
Navnath B. Kalamkar, Vijay M. Kasture, and Dilip
D. Dhavale*
Department of Chemistry, Garware Research Centre,
UniVersity of Pune, Pune - 411 007, India
FIGURE 1. 3-Hydroxypipecolic acid analogues.
ddd@chem.unipune.ernet.in
are promising glycosyltransferases and glycosidase inhibitors.6
The (2R,3R)-3-hydroxy-2-hydroxymethylpiperidine 2a is also
found in the structure of the antimalarial isofebri-
fugine 4.7
ReceiVed December 26, 2007
A number of asymmetric as well as chiron approaches for
the synthesis of both 1 and 2 and their stereoisomers are known
in the literature. In general, the asymmetric methodologies for
trans-configured 1 and 2 are prevalent probably due to the easy
outcome of the relative trans stereochemistry, on the adjacent
carbon atoms, in the asymmetric pathways8 that involve either
dihydroxylation or epoxidation followed by attack of the
nitrogen nucleophile. As an alternative, chiron approaches3,5,9
(4) For some leading references, see: (a) McNaughton-Smith, G; Hanessian,
S.; Lombart, H. G.; Lubell, W. D. Tetrahedron 1997, 53, 12789. (b) Copeland,
T. D.; Wondrak, E. M.; Toszer, J.; Roberts, M. M.; Oraszan, S. Biochem. Biophys.
Res. Commun. 1990, 169, 310. (c) Quibell, M.; Benn, A.; Flinn, N.; Monk, T.;
Ramjee, M.; Wang, Y.; Watts, J. Bio-org. Med. Chem. 2004, 12, 5689.
(5) For 2a and 2b, see: (a) Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.;
Adachib, I.; Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817. (b) Takahata,
H.; Banba, Y.; Ouchi, H.; Nemoto, H. Org. Lett. 2003, 5, 2527. (c) Takahata,
H.; Banba, Y.; Ouchi, H.; Nemoto, H.; Adachib, A. J. Org. Chem. 2003, 68,
3603. (d) Takahata, H.; Banba, Y.; Sasatani, M.; Nemoto, H.; Katoc, A.; Adachic,
I. Tetrahedron 2004, 60, 8199.
The first chiron approach from D-glucose for the total
synthesis of (2S,3R)-3-hydroxypipecolic acid (-)-1a and
(2R,3R)-3-hydroxy-2-hydroxymethylpiperidine (-)-2a is re-
ported. The synthetic pathway involves conversion of D-
glucose into 3-azidopentodialdose (5) followed by the Wittig
olefination and reduction to give the piperidine ring skeleton
(8) with a sugar appendage that on cleavage of an anomeric
carbon followed by oxidation gives (-)-1a which on
reduction affords (-)-2a.
(6) (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Chem. ReV. 2000, 100, 4683.
(b) Naoki-Asano, R. J.; Nash, R. J.; Molyneux, G.; Fleet, W. J. Tetrahedron:
Asymmetry 2000, 11, 1645.
(7) (a) Kuehl, F. A., Jr.; Spencer, C. F.; Folkers, K. J. Am. Chem. Soc. 1948,
70, 2091. (b) Kobayashi, Sh.; Ueno, M.; Suzuki, R. Tetrahedron Lett. 1999, 40,
2175.
The six membered cyclic R-amino-ꢀ-hydroxy acids, namely
3-hydroxypipecolic acids 1a and 1b (Figure 1), and their
stereoisomers are attractive chiral building blocks for the
synthesis of various biologically active natural products.1 For
example, cis isomer 1a is an important constituent of a naturally
occurring antitumor antibiotic tetrazomine 3,2 while the trans-
configured acid 1b is a precursor for potent R-D-mannosidase
inhibitor (-)-swainsonine.3 In an addition, R-amino-ꢀ-hydroxy
acid unit embedded in 1 considered as a ring-expanded
homologue of hydroxyproline or constrained analogue of serine
and permits their use in conformational and ligand-binding
studies involving bioactive peptides and peptidomimetics.4 The
carboxyl group reduced analogues of 1, namely 3-hydroxy-2-
hydroxymethylpiperidine 2, are known as fagomine congeners5a
due to their resemblance to the piperidine iminosugars which
(8) For trans isomer 1b and its enantiomer, see: (a) Horikawa, M.; Busch-
Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843. (b) Kumar, P.; Bodas,
M. S. J. Org. Chem. 2005, 70, 360. (c) Bodas, M. S.; Kumar, P. Tetrahedron
Lett. 2004, 45, 8461. (d) Koulocheri, S. D.; Magiatis, P.; Skaltsounis, A L.;
Haroutounian, S. A. Tetrahedron 2002, 58, 6665. (e) Haddad, M.; Larcheveque,
M. Tetrahedron Lett. 2001, 42, 5223. (f) Battistini, L.; Zanardi, F.; Rassu, G.;
Spanu, P.; Pelosi, G.; Fava, G. G.; Ferrari, M. B.; Casiraghi, G. Tetrahedron:
Asymmetry 1997, 8, 2975. (g) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron
Lett. 1996, 37, 4001. (h) Sugisaki, C. H.; Caroll, P. J.; Correia, C. R. Tetrahedron
Lett. 1998, 39, 3413. (i) Kim, I. S.; Ji, Y. J.; Jung, Y. H. Tetrahedron Lett.
2006, 47, 7289. (j) Kim, I. S.; Oh, J. S.; Zee, O. P.; Jung, Y. H. Tetrahedron
2007, 63, 2622. (k) Drummond, J.; Johnson, G.; Nickell, D. G.; Ortwine, D. F.;
Bruns, R. F.; Welbaum, B. J. Med Chem. 1989, 32, 2116. (l) Makara, G. M.;
Marshall, G. R. Tetrahedron Lett. 1997, 38, 5069. (m) Scott, J. D.; Williams,
R. M. Tetrahedron Lett. 2000, 41, 8413. (n) Asano, G. K.; Ogawa, H.; Takalmshi,
A.; Nozoe, S.; Yokoyama, K. Chem. Pharm. Bull. 1987, 35, 3482.
(9) For 1a and 1b, see: (a) Liang, N.; Datta, A. J. Org. Chem. 2005, 70,
10182. (b) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033. For the
enantiomer of 1a, see: (c) Knight, D. W.; Lewis, N.; Share, A. C.; Haigh, D.
Tetrahedron: Asymmetry 1993, 4, 625. This paper does not describe the synthesis
of the free amino acid but the protected version: N-t-BOC (2R,3S)-3-hydroxym-
ethylpipecolate: (d) Roemmele, R. C.; Rapoport, H. J. J. Org. Chem. 1989, 54,
1866. For the enantiomer of 2b, see: (e) Mocerino, M.; Stick, R. V. Aust. J. Chem.
1990, 43, 1183. For the enantiomer of 2a, see: (f) Enders, D.; Jegelka, U. Synlett
1992, 999. (g) Knight, D. W.; Lewis, N.; Share, A. C.; Haigh, D. J. Chem. Soc.,
Perkin Trans. 1 1998, 3673. This paper does not describe the synthesis of the
free amino piperidine diol but the protected version: N-t-BOC (2S,3S)-3-hydroxy-
2-hydroxymethylpiperidine. Also see ref 8j.
(1) (a) Schneider, M. J. Pyridine and Piperidine Alkaloids: An Update. In
Alkaloids: Chemical and Biological PerspectiVes; Pelletier, S. W., Ed.; Pergamon:
Oxford, 1996; Vol. 10, p 155. (b) Zografou, E. N.; Tsiropoulos, G. J.; Margaritas,
L. H. Entomol. Exp. Appl. 1998, 87, 125. and references therein.
(2) Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998, 39,
3659.
(3) Ferreira, F.; Greck, C.; Genet, J. P. Bull. Soc. Chim. Fr. 1997, 134, 615.
10.1021/jo702749r CCC: $40.75
Published on Web 03/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3619–3622 3619

SCHEME 1. Retrosynthetic Analysis
aldehyde C, an immediate precursor with required functionalities
and chirality, that on oxidation will afford (-)-1a, while
reduction will give (-)-2b. Our synthetic efforts in this direction
are described herein.
The required 3-azido-3-deoxy-1,2-O-isopropylidene-R-D-xylo-
pentodialdo-1,4-furanose 5 was prepared from D-glucose as
reported earlier.12 The Wittig olefination of 5 using (carbe-
thoxymethylene)triphenylphosphorane afforded R,ꢀ-unsaturated
ester 6 as a diastereomeric mixture13 of E and Z isomer in a
ratio 6:4 as an evident from 1H NMR of crude product (Scheme
2). Hydrogenation of R,ꢀ-unsaturated ester 6 using 10% Pd/C
in methanol at 80 psi afforded a tricyclic δ-lactam 7 as a white
solid.14 This one-pot three-step process involves reduction of
the double bond, conversion of an azide to amine functionality,
and concomitant lactamization to give 7 in high yield. The
relative cis sterochemistry at the 6/5-ring junction in 7 is
established by a NOESY 1D experiment wherein irradiation of
H-3 at δ 3.85 showed 2.9% NOE with H-4 at δ 4.57. In the
next step, reduction of the δ-lactam functionality in 7 with LAH
in THF afforded piperidine ring skeleton 8 which on reaction
with benzyl chloroformate and sodium bicarbonate in ethanol–
water gave N-Cbz-protected amine 9.
make use of amino acids, in particular D- or L-serine, in
enantioselective synthesis of 1 and 2. We were particularly
interested in the synthesis of cis-configured (-)-1a and (-)-2a
because of the fact that (i) the literature scrutiny indicates only
a few methods for cis isomers 1a/2a and (ii) no chiron approach
starting from the carbohydrate precursor, to the best of our
knowledge, is reported for the synthesis of either 1 or 2. The
first enantioselective synthesis of (-)-1a, accomplished by
Corey et al., involves an aldol condensation of silyl ketene acetal
of tert-butylglycinate with different achiral aldehydes using
cinchonidine alkaloid derived catalyst as a key step to get good
stereoselectivity.8a Drummond et al.8k as well as Marshall and
Makara8l reported the synthesis of racemic (()-1a from 3-hy-
droxypicolinic acid that was later enzymatically resolved by
Williams and co-workers using lipase PS.8m Recently, Liang
and Datta used D-serine as a chiral template, wherein addition
of the homoallyl Grignard reagent to D-serinal afforded high
diastereoselectivity in favor of syn-amino alcohol that was
elaborated to (-)-1a.9a In the case of 2a, Takahata and
co-workers have reported different approaches for 2a and its
stereoisomers starting from Garner aldehyde and by exploiting
the ring-closing metathesis approach.5 In another synthesis,
O’Doherty and co-workers10 utilized the Sharpless asymmetric
aminohydroxylation strategy with 2-vinylfurans to give ꢀ-hy-
droxyfurfurylamine in high enantioexcess in the synthesis of
tosyl salt of 2a.
As a part of our continuous interest in the synthesis of
iminosugars by using carbohydrate as precursors,11 we have
devised an altogether different strategy for the synthesis of 1a
and 2a using D-glucose as a chiral template. We envisioned that
the D-glucose type of symmetry is hidden in the target molecules
wherein the required relative cis stereochemistry at C2 and C3
of the vicinal amino acid/alcohol functionalities in 1a and 2a
is found to be embedded at C3 and C4, respectively, of 3-azido-
3-deoxy-1,2-O-isopropylidene-R-D-xylo-pentodialdo-1,4-fura-
nose A, easily prepared from D-glucose (Scheme 1). Thus, as
shown in the retrosynthetic analysis, the two-carbon Wittig
homologation of A with Ph3PCHCOOEt followed by hydro-
genation will give access to sugar-substituted δ-lactam B.
Reduction of the lactam functionality, removal of 1,2-acetonide
protection, and cleavage of an anomeric carbon atom by
oxidative cleavage will provide N-protected R-amino-ꢀ-hydroxy
Treatment of 9 with TFA-water (3:2) at room temperature
afforded an anomeric mixture of hemiacetals (as an evident from
1
the H NMR of crude product) that was directly subjected to
oxidative cleavage using sodium metaperiodate in acetone–water
(to cleave the anomeric carbon) to give R-aminal 10 as a thick
oil. The N-Cbz-protected R-aminal 10 was found to be relatively
unstable and therefore was immediately reacted with sodium
chlorite and 30% H2O2 using sodium dihydrogen phosphate as
a buffer in acetonitrile-water to afford N-Cbz-protected (2S,3R)-
3-hydroxypipecolic acid derivative 11 as a sticky gum. In the
final step, hydrogenolysis of 11 using 10% Pd/C in methanol
at 80 psi afforded (-)-1a as a solid in high yield. The spectral
and analytical data for (-)-1a was found to be in consonance
with that reported: [R]25D -73.8 (c 0.10, 1 M HC1) [lit.2 [R]20
D
-72.3 (c 0.10, 1 M HCl)], [R]25 -54.1 (c 0.6, H2O) [lit.8a
D
[R]D -52.8 (c 0.6, H2O)].
While targeting to the synthesis of (-)-2a, the N-Cbz-
protected R-aminal 10 was treated with sodium borohydride in
methanol–water that afforded N-Cbz-protected piperidine diol
12 as a white solid. Finally, hydrogenolysis of 12 using 10%
Pd/C in methanol gave (2R,3R)-3-hydroxy-2-hydroxymethylpi-
peridine (-)-2a. The spectral and analytical data of (-)-2a was
found to be in good agreement with that reported: [R]25D -13.2
(c 2.51, H2O) [lit.10 [R]21 -12.4 (c 2.51, H2O)].
D
In conclusion, we have demonstrated the first chiron approach
from D-glucose for the total synthesis of (-)-1a and (-)-2a in
15 linear steps with 27% and 25% overall yield, respectively.
The sequence involves simple reagents and minimum column
purification, high yielding steps that can be elaborated for large
scale preparation. The methodology could be readily extended
(12) Tronchet, J. M. J.; Gentile, B.; Ojha-Poncet, J.; Moret, G.; Schwarza-
nbach, D.; Barblat-Ray, F. Carbohydr. Res. 1977, 59, 87.
(13) Our attempts to separate the diastereomeric mixture of 6 by flash
chromatography were unsuccessful due to the close Rf values; however, we have
isolated the E-isomer in a small quantity, and its data are given in the
Experimental Section. Compound 6 (E-isomer) is known; however, no data are
reported to be the same. See: Chanderasekhar, S.; Samala, J. P.; Chennamaneni,
L. R. J. Org. Chem. 2006, 71, 2196.
(10) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3, 401.
(11) For our recent reports, see: (a) Dhavale, D. D.; Markad, S. D.; Karanjule,
N. S.; PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760. (b) Karanjule, N. S.;
Markad, S. D.; Dhavale, D. D. J. Org. Chem. 2006, 71, 6273. (c) Karanjule,
N. S.; Markad, S. D.; Shinde, V. S.; Dhavale, D. D. J. Org. Chem. 2006, 71,
4667. (d) Dhavale, D. D.; Ajish Kumar, K. S.; Chaudhari, V. D.; Sharma, T.;
Sabharwal, S. G.; PrakashaReddy., J. Org. Biomol. Chem. 2005, 3, 3720. (e)
Ajish Kumar, K. S.; Chaudhari, V. D.; Puranik, V. G.; Dhavale, D. D. Eur. J.
Org. Chem. 2007, 29, 4895. and references cited therein.
(14) Compound 7 is prepared by a different method in which the nature of
the compound and specific rotation is not given; see ref 13. We have isolated
compound 7 as a white solid and characterized it independently. The data are
given in the Experimental Section.
3620 J. Org. Chem. Vol. 73, No. 9, 2008

SCHEME 2. Synthesis of (-)-1a and (-)-2a
0 °C, allowed to attain at room temperature (25 °C), and then
refluxed at 80 °C. After 7 h, reaction mixture was cooled to 25 °C
and quenched by slow addition of ethyl acetate (50 mL) followed
by saturated solution of aq ammonium chloride (15 mL) and stirred
for 2 h. The solution was filtered through Celite, the residue was
washed with ethyl acetate, and the filtrate was evaporated under
vacuum with column chromatography purification using n-hexane/
ethyl acetate ) 3/7 to give amine 8 (3.32 g, 89%) as a pale yellow
oil: Rf 0.3 (CHCl3/MeOH ) 8/2); [R]D + 1.5 (c 1.25, CH2Cl2); IR
(neat) 3439, 1087 and 1020 cm-1; 1H NMR (300 MHz, CDCl3) δ
1.25 (s, 3H), 1.45 (s, 3H), 1.53–1.80 (m, 2H), 1.82–2.10 (m, 1H),
2.25 (bd, J ) 14.3 Hz, 1H), 2.70 (bt, J ) 12.3 Hz, 1H), 3.30 (bd,
J ) 12.3 Hz, 1H), 3.40 (d, J ) 1.5 Hz, 1H), 4.30 (d, J ) 1.5 Hz,
1H), 4.7 (d, J ) 3.6 Hz, 1H), 6.15 (d, J ) 3.6 Hz, 1H), 6.75 (bs,
1H); 13C NMR (75 MHz, CDCl3) δ 17.3, 23.7, 26.1, 26.3, 43.2,
59.3, 71.2, 82.5, 104.6, 111.8. Anal. Calcd for C10H17NO3: C, 60.28;
H, 8.60. Found: C, 60.09; H, 8.55.
for the synthesis of naturally occurring (2S,3R)-ꢀ-hydroxylysine
and cis-3-hydroxyproline, and work in this direction is in
progress.
Experimental Section
(E:Z)-Ethyl-1,2-O-isopropylidene-3-azido-3,5,6-trideoxy-r-D-
xylo-hept-5-enofuranuronate-pentodialdo-1,4-furanose (6). To
a stirred solution of 3-azido-3-deoxy-1,2-O-isopropylidene-R-D-
xylo-pentodialdo-1,4-furanose 5 (5 g, 23.47 mmol) in dry dichlo-
romethane (80 mL) was added (carbethoxymethylene)triphe-
nylphosphorane (11.55 g, 35.21 mmol). The reaction mixture was
refluxed for 30 min and cooled to 26 °C. Solvent was evaporated
under reduced pressure, and the residue on flash column chroma-
tography (n-hexane/ethyl acetate ) 97/3) afforded the E-isomer
(0.2 g, 03%) and a diastereomeric mixture of E:Z, R,ꢀ unsaturated
ester 6 as an oil (5.9 g, 89%). Data for E-isomer: Rf 0.6 (n-hexane/
ethyl acetate ) 9/1); [R]D -1.09 (c 0.95, CHCl3); IR (neat) 2108,
2,2-Dimethylperhydro[1,3]dioxolo-N-benzyloxycarbonyl[4′,5′:
4,5]furo[3,2-b]pyridine (9). To an ice-cooled solution of 8 (3.2 g,
16.08 mmol) and sodium bicarbonate (5.4 g, 64.32 mmol) in
ethanol–water (3:1, 40 mL) was added benzyloxycarbonyl chloride
(4.1 g, 24.12 mmol) in ethanol (10 mL). After 3 h, ethanol was
removed on a rotary evaporator, and the residue was extracted with
dichloromethane (3 × 20 mL). Usual workup and purification by
column chromatography (n-hexane/ethyl acetate ) 97/3) gave 9
(5.2 g, 98%) as a colorless thick liquid: Rf 0.5 (n-hexane/ethyl
acetate ) 8/2); [R]D -54.8 (c 0.75, CH2Cl2); IR (neat) 1705, 1419,
1
1717, 1635 cm-1; H NMR (300 MHz, CDCl3) δ 1.29 (t, J ) 7.2
Hz, 3H), 1.34 (s, 3H), 1.51 (s, 3H), 3.95 (d, J ) 3.3 Hz, 1H), 4.2
(q, J ) 7.2 Hz, 2H), 4.70 (d, J ) 3.6 Hz, 1H), 4.84–4.92 (m, 1H),
5.96 (d, J ) 3.6 Hz, 1H), 6.22 (dd, J ) 15.6, 4.5 Hz, 1H), 6.91
(dd, J ) 15.6, 4.7 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.2,
26.6, 26.5, 60.6, 67.2, 78.5, 83.4, 104.4, 112.2, 124.1, 139.6, 165.4.
Anal. Calcd for C12H17N3O5: C, 50.88; H, 6.05. Found: C, 50.96;
H, 6.28.
2,2-Dimethylperhydro[1,3]dioxolo[4′,5′:4,5]furo[3,2-b]pyridin-
7-one (7). The azido ester 6 (5.8 g, 20.49 mmol) and 10% Pd/C
(0.1 g) in methanol (25 mL) was subjected to hydrogenation at
room temperature (25 °C) at 80 psi. After 12 h, the solution was
filtered through Celite and the residue washed with methanol.
Evaporation of solvent on a rotary evaporator and crystallization
with n-hexane/ethyl acetate ) 3/7 gave tricyclic sugar appended
δ-lactam 7 (4.18 g, 96%) as a white solid: mp 185–187 °C; Rf 0.3
(ethyl acetate); [R]D -92.85 (c 0.75, CH2Cl2); IR (KBr) 1668, 1411,
1
1269, 1078 cm-1; H NMR (300 MHz, CDCl3) δ 1.30 (s, 3H),
1.50 (s, 3H), 1.54–1.86 (m, 3H), 2.0–2.12 (m, 1H), 3.20–3.35 (m,
1H), 3.50–3.64 (m, 1H), 4.08 (d, J ) 4.9 Hz, 1H), 4.48–4.58 (m,
1H), 4.67 (bd, J ) 3.0 Hz, 1H), 5.16 (AB quartet, J ) 12.4 Hz,
2H), 5.81 (d, J ) 3.8 Hz, 1H), 7.25–7.40 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 17.8, 21.9, 26.3, 26.8, 40.1, 60.7, 67.2, 73.4, 86.2,
104.3, 111.1, 127.8, 127.93, 128.4, 136.4, 156.3. Anal. Calcd for
C18H23NO5: C, 64.85; H, 6.95. Found: C, 65.03; H, 7.16.
1
cm-1; H NMR (300 MHz, CDCl3) δ 1.30 (s, 3H), 1.49 (s, 3H),
(2S,3R)-N-Benzyloxycarbonyl-3-hydroxypiperidine-2-carbox-
ylic Acid (11). An ice-cold solution of 9 (4.9 g, 14.71 mmol) in
TFA-H2O (40 mL, 3:2) was stirred for 15 min and at 25 °C for
7 h. Trifluoroacetic acid was coevaporated with toluene at rotary
evaporator using high vacuum to furnish hemiacetal as a thick liquid
(crude wt ) 3.6 g). To an ice-cooled solution of hemiacetal (2 g,
6.8 mmol) in acetone/water (10 mL, 5:1) was added sodium
metaperiodate (2.19 g, 10.23 mmol), and the solution was stirred
for 30 min at 25 °C. Ethylene glycol (0.2 mL) was added, solvent
was evaporated on rotary evaporator, and the residue was extracted
with chloroform (3 × 15 mL). Usual workup afforded R-aminal
10 as a thick liquid (1.5 g). To a stirred solution of 10 (0.46 g,
1.83–1.98 (m, 1H), 2.20–2.32 (m, 2H), 2.52 (ddd, J ) 17.6, 12.9,
6.3 Hz, 1H), 3.81 (d, J ) 3.7 Hz, 1H), 4.48 (d, J ) 3.7 Hz, 1H),
4.58 (bs, 1H), 5.87 (d, J ) 3.7 Hz, 1H), 6.88 (bs, 1H); 13C NMR
(75 MHz, CDCl3) δ 22.4, 25.6, 26.3, 26.8, 60.4, 71.8, 85.3, 104.8,
112.0, 172.0. Anal. Calcd for C10H15NO4: C, 56.33; H, 7.09. Found:
C, 56.62; H, 7.29.
2,2-Dimethylperhydro[1,3]dioxolo[4′,5′:4,5]furo[3,2-b]pyri-
dine (8). To a stirred, ice-cold suspension of lithium aluminum
hydride (2.14 g, 56.33 mmol) in dry THF (20 mL) was added
δ-lactam 7 (4 g, 18.77 mmol) in dry THF (25 mL) over a period
of 10 min. The reaction mixture was then stirred for 15 min at
J. Org. Chem. Vol. 73, No. 9, 2008 3621

1.74 mmol) in acetonitrile (10 mL) was added the solution of
sodium dihydrogen phosphate (0.05 g, 0.31 mmol) in water (3 mL)
and 30% H2O2 (0.15 mL, 1.92 mmol). The mixture was stirred
and cooled at -10 °C, NaClO2 (0.25 g, 2.72 mmol) in water (3.5
mL) was added dropwise over 30 min, the reaction mixture was
then stirred at 15 °C, and the reaction was monitored by the
evolution of oxygen with a bubbler connected to the apparatus.
After 10 h, the reaction was decomposed by addition of a small
amount of Na2SO3 (0.1 g) and acidified with 10% aq HC1 (5 mL).
The organic layer was separated, aqueous layer was extracted
with ethyl acetate (4 × 5 mL), the combined organic layer was
evaporated, and the residue was dissolved in 10% NaHCO3 solution
(25 mL). The bicarbonate layer was washed with ethyl acetate (15
mL) and then made acidic to pH 2 and extracted with ethyl acetate
(3 × 15 mL). Usual workup gave 11 (0.46 g, 95%) as a sticky
gum: Rf 0.5 (CHCl3/MeOH ) 8/2); [R]D -13.9 (c 0.42, CH2Cl2);
IR (KBr) 3600–2870 (br), 1708, 1676, cm-1; 1H NMR (300 MHz,
CDClδ 1.40–1.60 (m, 2H), 1.62–1.80 (m, 1H), 1.92– 2.12 (m, 1H),
2.75–3.05 (m, 1H), 3.80–4.10 (m, 2H), 4.95–5.20 (m, 3H),
6.80–8.20 (br, 2H, exchangeable with D2O), 7.30 (s, 5H); 13C NMR
(75 MHz, CDCl3) δ 23.4, 29.6, 40.9, 57.6, 68.1, 68.5, 127.6, 127.9,
methanol/water (5 mL, 3:1), maintained at -10 °C, was added
sodium borohydride (0.1 g, 2.85 mmol) in portions during 20 min.
The resulting solution was stirred for 30 min and allowed to attain
room temperature (25 °C). Solvent was evaporated, and the residue
was extracted with chloroform (3 × 5 mL). Evaporation of solvent
and column purification using n-hexane/ethyl acetate ) 6.5/3.5 gave
12 (0.47 g, 94%) as a white solid: mp 105–107 °C; Rf 0.5 (n-hexane/
ethyl acetate ) 2/8); [R]D +6.24 (c 0.25, CH2Cl2); IR (KBr) 3429,
1
1670, 1435, 1251, cm-1; H NMR (300 MHz, CDCl3 + drop of
D2O), δ 1.35–1.90 (m, 4H), 2.9 (bs, 1H), 3.75 (dd, J ) 11.2, 6.6
Hz, 1H), 3.80–3.98 (m, 2H), 4.10 (dd, J ) 11.2, 6.1 Hz, 1H), 4.
38– 4.52 (bm, 1H), 5.12 (s, 2H), 7.30 (s, 5H); 13C NMR (75 MHz,
CDCl3) δ 23.7, 28.3, 40.0, 56.6, 59.1, 67.5, 69.1, 127.7, 128.0,
128.4, 136.3, 156.0. Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22.
Found: C, 63.68; H, 7.33.
(2R,3R)-2-(Hydroxymethyl)piperidin-3-ol (-)-2a. A solution
of 12 (0.3 g, 1.13 mmol) and 10% Pd/C (0.03 g) in methanol (7
mL) was hydrogenolized as described for (-)-1a. Column chro-
matography purification using CHCl3/MeOH ) 7/3 afforded (-)-
2a (0.14 g, 98%) as a thick liquid: Rf 0.25 (CHCl3/MeOH/30%
NH4OH ) 3/4/3); [R]25D -13.2 (c 2.51, H2O); [lit.10 [R]21D -12.4
(c 2.51, H2O)].
1
128.4, 135.7, 156.5, 172.1. The H NMR showed broadening of
the signals and 13C NMR showed doubling of signals. This could
be attributed to the presence of N-Cbz functionality resulting into
the rotamers. Anal. Calcd for C14H17NO5: C, 60.21; H, 6.14. Found:
C, 60.50; H, 6.38.
Acknowledgment. We are grateful to Prof. M. S. Wadia for
helpful discussions. We are thankful to DST (GOI-A-492), New
Delhi, for financial support. N.B.K. and V.M.K. are thankful
to CSIR, New Delhi, for Junior Research Fellowships.
(2S,3R)-3-hydroxypiperidine-2-carboxylic Acid (-)-1a. A
solution of 11 (0.19 g, 0.68 mmol) and 10% Pd/C (0.025 g) in
methanol (5 mL) was hydrogenolized at 80 psi for 12 h at 25 °C.
The catalyst was filtered through Celite. Evaporation of solvent
afforded (-)-1a (96 mg, 98%) as a solid: Rf 0.21 (CHCl3/MeOH/
Supporting Information Available: General experimental
methods and the copies of 1H and 13C NMR spectra of
compounds 6-11, (-)-1a, 12, and (-)-2a. This material is
available free of charge via the Internet at http://pubs.acs.org.
30% NH4OH ) 3/5/2); [R]25D -73.8 (c 0.10, 1 M HC1) [lit.2 [R]20
D
-72.3 (c 0.10, 1 M HCl)], [R]25 -54.1 (c 0.6, H2O) [lit.8a [R]D
D
-52.8 (c 0.6, H2O)].
(2R,3R)-N-Benzyloxycarbonyl-3-hydroxy-2-hydroxymethylpi-
peridine (12). To a stirred solution of 10 (0.5 g, 1.9 mmol) in
JO702749R
3622 J. Org. Chem. Vol. 73, No. 9, 2008