Asymmetric synthesis of both the enantiomers of trans-3-hydroxypipecolic acid

Article abstract of DOI:10.1021/jo0485381

(Chemical Equation Presented). Both the enantiomers of trans-3- hydroxypipecolic acid have been synthesized employing the Sharpless asymmetric dihydroxylation and epoxidation as the key steps starting from a commercially available starting material 1,4-bu

Full text of DOI:10.1021/jo0485381

droxypipecolic acid is found in a number of biologically
important products. For example, the cis-isomer 2 forms
a part of the structure of tetrazomine 3, an antitumor
antibiotic,5 while the trans isomer 1 is a precursor of (-)-
swainsonine 4, which has shown potent and specific R-D-
mannosidase inhibitory activity,6 and it is also found in
the structure of febrifugine 5, a potent antimalarial
agent7 (Figure 1).
Asymmetric Synthesis of Both the
Enantiomers of trans-3-Hydroxypipecolic
Acid†
Pradeep Kumar* and Mandar S. Bodas
Division of Organic Chemistry: Technology, National
Chemical Laboratory, Pune 411 008, India
As a consequence, a practical route providing an easy
access to the title compounds should be highly desirable,
also considering that these compounds might be precious
scaffolds to be incorporated into conformationally re-
stricted peptidomimetics of biological relevance.
tripathi@dalton.ncl.res.in
Received August 20, 2004
From a synthetic point of view, only a few enantiose-
lective synthesis of 1 or its isomers have been reported.
While the majority of their earlier syntheses utilize either
chiral pool as starting material5-8 or the enzymatic
resolution,9 reports in which all the stereogenic centers
are constructed by asymmetric synthesis are rather
scarce.10 Despite recent improvements in the synthetic
methodology for the control of the two stereocenters in
the target molecule 1, most of them suffer either from
poor diastereoselectivity, low overall yields, and/or a large
number of steps involved. As a part of our research
program aimed at developing enantioselective syntheses
of naturally occurring amino alcohols,11 we became
interested in developing a simple and feasible route to
trans-3-hydroxypipecolic acid. Herein we wish to report
a new and highly enantioselective synthesis of 1 employ-
ing the Sharpless asymmetric dihydroxylation and ep-
oxidation as the source of chirality.
Both the enantiomers of trans-3-hydroxypipecolic acid have
been synthesized employing the Sharpless asymmetric di-
hydroxylation and epoxidation as the key steps starting from
a commercially available starting material 1,4-butanediol.
Functionalized piperidines are among the most ubiq-
uitous heterocyclic building blocks in natural products
and synthetic compounds with important activities.
Therefore, a huge amount of synthetic effort has been
put on the preparation of these systems.1 Hydroxylated
piperidine alkaloids are frequently found in living sys-
tems and display a wide range of biological activities due
to their ability to mimic carbohydrate substrates in a
variety of enzymatic processes.2 Selective inhibition of a
number of enzymes involved in the binding and process-
ing of glycoproteins has rendered piperidine alkaloids
important tools in the study of biochemical pathways.3
3-Hydroxypipecolic acids 1 and 2, six-membered cyclic
R-amino-â-hydroxy acids, constitute non-natural variants
of a structural motif often encountered in a variety of
functional molecules and may be regarded as expanded
hydroxylated proline or a conformationally restricted
serine derivative and may affect the physiological and
pathological processes.4 The piperidine unit of 3-hy-
The synthesis of the target compound 1 commenced
from the allylic alcohol 9 which in turn could be easily
derived from a commercially available starting material
1,4-butanediol. Thus, as illustrated in Scheme 1, 1,4-
butanediol 6 was treated with p-methoxybenzyl bromide
(4) (a) Sugisaki, C. H.; Caroll, P. J.; Correia, C. R. D. Tetrahedron
Lett. 1998, 39, 3413. (b) Hanessian, S.; McNaughton-Smith, G.;
Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(5) Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998,
39, 3659.
(6) Ferreira, F.; Greck, C.; Genet, J. P. Bull. Soc. Chim. Fr. 1997,
134, 615.
(7) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033 and
references therein.
(8) (a) Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi, G.;
Fava, G. G.; Ferrari, M. B.; Casiraghi, G. Tetrahedron: Asymmetry
1997, 8, 2975. (b) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1989,
54, 1866. (c) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996,
37, 4001. (d) Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahe-
dron Lett. 1999, 40, 3843. (e) Haddad, M.; Larcheveque, M. Tetrahedron
Lett. 2001, 42, 5223.
(9) (a) Knight, D. W.; Lewis, N.; ShareDavidHaigh, A. C. Tetrahe-
dron: Asymmetry 1993, 4, 625. (b) Scott, J. D.; Williams, R. M.
Tetrahedron Lett. 2000, 41, 8413.
(10) Greck, C.; Ferreira, F.; Genet, J. P. Tetrahedron Lett. 1996, 37,
2031.
(11) (a) Fernandes, R. A.; Kumar, P. Tetrahedron: Asymmetry 1999,
10, 4797. (b) Fernandes, R. A.; Kumar, P. Eur. J. Org. Chem. 2000,
3447. (c) Fernandes, R. A.; Kumar, P. Tetrahedron Lett. 2000, 41,
10309. (d) Pandey, R. K.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2002, 43, 4425. (e) Naidu, S. V.; Kumar, P. Tetrahedron Lett. 2003,
44, 1035. (f) Kandula, S. V.; Kumar, P. Tetrahedron Lett. 2003, 44,
1957. (g) Pandey, R. K. Upadhyay, P. K.; Kumar, P. Tetrahedron Lett.
2003, 44, 6245. (h) Gupta, P.; Fernandes, R. A.; Kumar, P. Tetrahedron
Lett. 2003, 44, 4231. (i) Bodas, M. S.; Upadhyay, P. K.; Kumar, P.
Tetrahedron Lett. 2004, 45, 987. (j) Pandey, S. K.; Kandula, S. V.;
Kumar, P. Tetrahedon Lett. 2004, 45, 5877.
* Corresponding author: Tel: +91-20-25893300 ext 2050. Fax: +91-
20-25893614.
† Dedicated to Professor Hiriyakkanavar Ila on the occasion of her
60th birthday.
(1) (a) Pinder, A. R. Nat. Prod. Rep. 1989, 6, 67. (b) Pinder, A. R.
Nat. Prod. Rep. 1992, 9, 17. (c) Pinder, A. R. Nat. Prod. Rep. 1992, 9,
491. (d) Nadin, A. Contemp. Org. Synth. 1997, 4, 387. (e) Bailey, P.
D.; Millwood, P. A.; Smith, P. D. J. Chem. Soc., Chem. Commun. 1998,
633. (f) Bols, M. Acc. Chem. Res. 1998, 31, 1. (g) Mitchinson, A.; Nadin,
A. J. Chem. Soc., Perkin Trans. 1 1999, 2553.
(2) (a) Fodor, G. B.; Colasanti, B. The Pyridine and Piperidine
Alkaloids: Chemistry and Pharmacology. In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley-Interscience: New
York, 1985; Vol. 3, pp 1-90. (b) Schneider, M. J. Pyridine and
Piperidine Alkaloids: An Update. In Alkaloids: Chemical and Biologi-
cal Perspectives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol.
10, pp 155-299.
(3) (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J.
Tetrahedron: Asymmetry 2000, 11, 1645. (b) El Ashry, E. S. H.; Rashed,
N.; Shobier, A. H. S. Pharmazie 2000, 55, 331.
10.1021/jo0485381 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/26/2004
360
J. Org. Chem. 2005, 70, 360-363

SCHEME 3a
FIGURE 1. Structures of trans- and cis-3-hydroxypipecolic
acid, 1 and 2, tetrazomine 3, (-)-swainsonine 4, and febrifug-
ine 5.
a Reagents and conditions: (a) Ti(i-OPr)4, (-)-DIPT, TBHP,
CH2Cl2, -20 °C, 20 h, 67%; (b) (i) TBDMSCl, Et3N, DMAP, CH2Cl2,
10 h, rt, (ii) DDQ, CH2Cl2, H2O, 3 h, rt, 90%, two steps; (c) (i) MsCl,
Et3N, CH2Cl2, rt, (ii) NaN3, DMF, 70 °C, 82%, two steps; (d) Ph3P,
THF/H2O (1:1), rt, 48 h; then Boc2O, NaOH; TBAF, THF, rt, 1 h,
48%; (e) ref 7.
SCHEME 1a
the transformation of a hydroxy group into an azido one,
with concomitant reversal of stereochemistry at the
2-position. To this end, protection of 10 as a benzylidene
derivative was effected using benzaldehyde dimethyl
acetal in the presence of a catalytic amount of p-TSA to
afford a mixture of 1,3- and 1,2-benzylidene compound
in 9:1 ratio. The desired major 1,3-benzylidene compound
11 was separated by silica gel column chromatography.
Compound 11 was then converted into O-mesylate de-
rivative which on reaction with sodium azide in DMF
afforded compound 12 with the desired stereochemistry
at the 5-position. The p-methoxybenzyl protecting group
was cleaved by treating 12 with DDQ. The free hydroxyl
group thus obtained was mesylated and subjected to the
reductive ring closure, cleavage of benzylidene group and
in situ Boc protection of the free amine to afford 4-deoxy-
fagomine 13 in overall 59% yield. Transformation of
compound 13 into the target molecule 1 was readily
accomplished by the Boc deprotection and subsequent
oxidation of primary alcohol into the acid using the
literature method.7
a Reagents and conditions: (a) DMF, NaH, p-OMeC6H4CH2Br,
80%; (b) (i) PCC, NaOAc, Celite, CH2Cl2, 6 h, rt, (ii) Ph3Pd
CHCO2Et, benzene, reflux 4 h, 80%; (c) DIBAL-H, CH2Cl2, rt, 1
h, 80%.
SCHEME 2a
In an alternative strategy to the synthesis of the target
molecule 1, the Sharpless asymmetric epoxidation of 9
was employed as the key step (Scheme 3). Thus, the
allylic alcohol 9 was treated with titanium tetraisopro-
poxide and tert-butyl hydroperoxide in the presence of
(-)-DIPT under the Sharpless asymmetric epoxidation
reaction conditions14 to give the enantiomerically en-
riched epoxide 1415 in 67% yield.
The subsequent tert-butyldimethylsilyl protection of
the hydroxyl group followed by deprotection of the
p-methoxybenzyl group with DDQ gave the desired
compound 15 in 90% yield. The free hydroxyl group of
15 was then mesylated and subjected to nucleophilic
a Reagents and conditions: (a) K2CO3, K3FeCN6, CH3SO2NH2,
(DHQ)2PHAL (1 mol %), 0.1 M OsO4 (0.4 mol %), t-BuOH/H2O
(1:1), 0 °C, 18 h, 71%; (b) C6H5CH(OMe)2, CH2Cl2, TsOH, rt, 85%;
(c) (i) MsCl, Et3N, DMAP, CH2Cl2, rt, (ii) NaN3, DMF, 80 °C, 24
h, 80%; (d) (i) DDQ, CH2Cl2, H2O, 3 h, rt, (ii) MsCl, Et3N, DMAP,
CH2Cl2, rt, (iii) H2/10% Pd-C, MeOH, 30 h, then Boc2O, 59%, three
steps; (e) ref 7.
in the presence of NaH to give 7 in 80% yield. The alcohol
7 was subjected to PCC oxidation followed by two carbon
homologation using Wittig reaction to afford the R,â-
unsaturated ester 8 in excellent yield. The ester 8 was
reduced with DIBAL-H to furnish the corresponding
allylic alcohol 9 in 80% yield.
Scheme 2 summarizes the synthesis of target com-
pound 1 from the allylic alcohol 9. Thus, the dihydroxy-
lation of olefin 9 with osmium tetraoxide and potassium
ferricyanide as co-oxidant in the presence of 1,4-bis-
(dihydroquinin-9-O-yl)phthalazine [(DHQ)2PHAL] ligand
under the Sharpless asymmetric dihydroxylation reaction
conditions12 gave the (2S,3S)-triol 10 in 71% yield and
92% ee.13
(12) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483. (b) Torii, S.; Liu, P.; Bhuvaneswari, N.; Amatore,
C.; Jutand, A. J. Org. Chem. 1996, 61, 3055.
(13) The enantiomeric excess was determined by converting the free
secondary hydroxyl group of compound 11 into its Mosher’s derivative
and analyzing the 19F NMR spectrum. The ee was found to be 92%.
(14) (a) Katsuki, T.; Sharplesss, K. B. J. Am. Chem. Soc. 1980, 102,
5974. (b) Pfenninger, A. Synthesis 1986, 89. (c) Baker, S. R.; Boot, J.
R.; Morgan, S. E.; Osborne, D. T.; Ross, W. J.; Shrubsall, P. R.
Tetrahedron Lett. 1983, 24, 4469.
(15) The Sharpless asymmetric epoxidation of the allylic alcohol 9
is reported to give the corresponding epoxide 14 in 92% ee; see:
Lindsay, K. B.; Pyne, S. G. J. Org. Chem. 2002, 67, 7774.
Furthermore in order to achieve the synthesis of
3-hydroxypipecolic acid 1 from the triol 10, we required
J. Org. Chem, Vol. 70, No. 1, 2005 361

2H), 3.84-3.88 (m, 1H), 4.04-4.26 (m, 1H), 4.46 (s, 2H), 5.56
(s, 1H), 6.89 (d, 2H, J ) 9 Hz), 7.28 (d, 2H, J ) 9 Hz), 7.39 (t,
3H, J ) 8 Hz), 7.51 (d, 2H, J ) 9 Hz). 13C NMR (125 MHz,
CDCl3): δ 25.0, 27.7, 54.9, 65.0, 69.6, 72.3, 79.5, 100.9, 113.6,
125.8, 127.9, 128.5, 129.0, 130.1, 159.0. MS (ESI): 376 (M +
NH4+), 316, 279, 237, 183. Anal. Calcd for C21H2605: C, 70.37;
H, 7.31. Found: C, 70.31; H, 7.35.
(2R,3S)-5-Azido-4-[3-(4-methoxybenzyloxy)propyl]-2-
phenyl-1,3-dioxane (12). To a solution of 1,3-protected alcohol
11 (1.0 g, 2.79 mmol) in dry CH2Cl2 (30 mL) at 0 °C were added
methanesulfonyl chloride (0.48 g, 4.2 mmol), Et3N (0.57 g, 5.63
mmol), and DMAP (cat.). The reaction mixture was stirred at
room temperature overnight and then poured into an Et2O‚H2O
mixture. The organic phase was separated and the aqueous
phase extracted with Et2O (3 × 30 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated to a yellow syrupy liquid, which was used as such in the
next step.
azide displacement to furnish the azido compound 16 in
82% yield. The azide 16 was treated with triphenylphos-
phine in the presence of water, resulting in its reduction
to amine followed by subsequent epoxide ring opening
by amine and in situ cyclization and Boc protection to
afford deoxyfagomine ent-13 in 48% yield. As expected,
only the product derived from a 6-endo-tet cyclization was
detected, and this observation was found to be in accord
with those reported.16 The subsequent conversion to the
target compound ent-1 is already reported in the litera-
ture.7 Thus, the merits of this synthesis are ready access
to the required stereogenic centers, high enantioselec-
tivity and various possibilities available for structural
modification. A short reaction sequence and high overall
yield of the target compound render our strategy a good
alternative to the known methods.
To the solution of above mesylate in dry DMF (30 mL) was
added sodium azide (1.36 g, 20.95 mmol), and the reaction
mixture was stirred at 80 °C for 24 h. It was then cooled, poured
into water, and extracted with Et2O (3 × 50 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (8:2) as eluent furnished
the azide 12 (0.86 g, 80%) as pale yellow oil. [R]20D: -6.3 (c 1.32,
CHCl3). IR. (CHCl3, cm-1): νmax 2100, 2882, 2940, 3338. 1H NMR
(500 MHz, CDCl3): 1.72-1.89 (m, 4H), 3.42-3.56 (m, 4H), 3.73
(s, 3H), 3.75-3.98 (m, 1H), 4.18-4.24 (m, 1H), 4.46 (s, 2H), 5.57
(s, 1H), 6.89 (d, 2H, J ) 9 Hz), 7.26-7.28 (m, 2H), 7.40 (t, 3H,
J ) 9 Hz), 7.50 (d, 2H, J ) 9 Hz). 13C NMR (125 MHz, CDCl3):
δ 26.2, 27.6, 29.3, 51.6, 55.0, 63.4, 66.8, 69.0, 72.4, 78.0, 103.9,
113.7, 126.3, 128.2, 129.1, 129.3, 130.4. MS (ESI): 383 (M+), 370,
356, 279, 234, 204, 161, 149. Anal. Calcd for C21H25N304: C,
65.78; H, 6.57; N, 10.96. Found: C, 65.84; H, 6.55; N, 11.02.
(2R,3S)-3-Hydroxy-2-hydroxymethylpiperidine-1-car-
boxylic Acid tert-Butyl Ester (13). To a solution of azide 12
(1.0 g, 2.61 mmol) in CH2Cl2 (30 mL) and H2O (1.2 mL) at 0 °C
was added DDQ (0.652 g, 2.87 mmol) in portions. The resultant
mixture was stirred at room temperature for 3 h, and then satd
aq NaHCO3 (10 mL) was added. The phases were separated,
and the aqueous phase was extracted with CH2Cl2 (3 × 50 mL).
The combined organic extracts were washed with brine, dried
(Na2SO4), and concentrated. Silica gel column chromatography
of the crude product using petroleum ether/EtOAc (6:4) as eluent
afforded the azido alcohol (0.62 g, 90%) as a pale yellow oil.
To a solution of azido alcohol (0.5 g, 1.90 mmol) in dry CH2-
Cl2 (20 mL) at 0 °C were added methanesulfonyl chloride (0.33
g, 2.89 mmol), Et3N (0.385 g, 3.8 mmol), and DMAP (cat.). The
reaction mixture was stirred at room temperature overnight and
then poured into the Et2O‚H2O mixture. The organic phase was
separated and the aqueous phase extracted with Et2O (3 × 20
mL). The combined organic phases were washed with brine,
dried (Na2SO4), and concentrated to a syrupy liquid, which was
used as such in the next step.
In summary, a practical and enantioselective synthesis
of (2S,3S)- and (2R,3R)-3-hydroxypipecolic acid has been
achieved using Sharpless asymmetric dihydroxylation
and epoxidation. To the best of our knowledge, this is
the first asymmetric synthesis of 3-hydroxypipecolic acid
using Sharpless asymmetric dihydroxylation and epoxi-
dation as the source of chirality. The synthetic strategy
described has significant potential for further extension
to other isomers and related analogues. Currently studies
are in progress in this direction.
Experimental Section
(2S,3S)-6-(4-Methoxybenzyloxy)hexane-1,2,3-triol (10).
To a mixture of K3Fe(CN)6 (8.37 g, 25.44 mmol), K2CO3 (3.51 g,
25.44 mmol), and (DHQ)2PHAL (66 mg, 1 mol %, 0.085 mmol)
in tert-butyl alcohol/H2O (1:1, 100 mmol) at 0 °C was added OsO4
(0.1 M solution in toluene, 0.64 mL, 0.4 mol %), followed by
methanesulfonamide (0.805 g, 8.47 mmol). After being stirred
for 2 min at 0 °C, the allylic alcohol 9 (2.0 g, 8.47 mmol) was
added in one portion. The reaction mixture was stirred at 0 °C
for 18 h and then quenched with sodium sulfite (4 g). The stirring
was continued for an additional 30 min, and then the solution
was extracted with EtOAc (3 × 75 mL). The combined organic
extracts were washed with 10% KOH and brine, dried (Na2SO4),
and concentrated. Silica gel column chromatography of the crude
product using petroleum ether/EtOAc (3:7) as eluent gave the
triol 10 (1.6 g, 71%) as thick liquid. [R]20D: -5.3 (c 0.84, CHCl3).
IR (CHCl3, cm-1): νmax 3018, 3389. 1H NMR (300 MHz, CDCl3):
1.62-1.78 (m, 4H), 3.07 (brs, 3H), 3.48-3.54 (m, 2H), 3.67-3.71
(m, 4H), 4.46 (s, 2H), 6.88 (d, 2H, J ) 9 Hz), 7.26 (d, 2H, J ) 9
Hz). 13C NMR (125 MHz, CDCl3): δ 25.8, 30.0, 55.0 63.9, 69.9,
71.4, 72.2, 74.1, 113.5, 129.2, 129.0, 158.9. MS (ESI): 270(M+),
234, 142, 91. Anal. Calcd for C14H2205: C, 62.20; H, 8.20.
Found: C, 62.28; H, 8.45.
To the solution of above mesylate in methanol was added 10%
Pd/C (10 w/w, 80 mg). The reaction mixture was stirred for 30
h under H2 (1 atm.), tert-butyl dicarbonate (0.54 g, 2.47 mmol)
was added to the resultant mixture, and stirring was continued
for an additional 12 h. The reaction mixture was filtered through
a Celite pad and the filtrate concentrated. Silica gel column
chromatography of the residue using CHCl3/MeOH (19:1) as
eluent furnished deoxyfagomine 13 (0.255 g, 59%) as thick
syrupy liquid. [R]25D: +5.2 (c 0.25, MeOH). IR (CHCl3, cm-1):
νmax 1675, 2854, 2987, 3359, 3478. 1H NMR (500 MHz, CDCl3 +
DMSOD6): δ 1.46 (s, 9H), 1.73-1.81 (m, 4H), 2.98-3.01 (m, 1H),
3.32-3.38 (m, 1H), 3.45-3.53 (m, 1H), 3.67-3.71 (m, 2H), 3.91-
3.95 (m, 1H). 13C NMR (125 MHz, CDCl3 + DMSOD6): δ 20.1,
28.6, 29.2, 32.6, 42.1, 62.3, 64.0, 80.8, 156.5. Anal. Calcd for
C11H21NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 57.23; H, 9.18;
N, 6.27.
(2S,3S)-4-[3-(4-Methoxybenzyloxy)propyl]2-phenyl-1,3-
dioxan-5-ol (11). To a solution of triol 10 (1.5 g, 5.56 mmol) in
dry CH2Cl2 (80 mL) were added p-TsOH (150 mg) and benzal-
dehyde dimethyl acetal (1.02 g, 6.7 mmol). The reaction mixture
was stirred at room temperature overnight. Subsequently, it was
neutralized with satd aq NaHCO3 (20 mL). The organic phase
was separated and the aqueous phase extracted with CH2Cl2 (2
× 50 mL). The combined organic extracts were washed with aq
NaHCO3 and brine, dried (Na2SO4), and concentrated. Silica gel
column chromatography of the crude product using petroleum
ether/EtOAc (7:3) as eluent afforded 1,3-protected alcohol 11,
the major product (1.55 g, 85%) as pale yellow thick liquid.
[R]20D:-7.4 (c 0. 4, CHCl3). IR (CHCl3, cm-1): νmax 1247, 1512,
1612, 1713, 2857, 2933, 3452. 1H NMR (500 MHz, CDCl3): δ
1.75-1.89 (m, 4H), 3.49-3.54 (m, 3H), 3.82 (s, 3H), 3.83 (m,
(2R,3R)-{3-[3-(4-Methoxybenzyloxy)propyl]oxiranyl}-
methanol (14). To a solution of Ti(Oi-Pr)4 (4.33 g, 5.25 mmol)
in CH2Cl2 (40 mL) at -20 °C was added (-)-DIPT (4.47 g, 19.08
(16) Somfai, P.; Marchand, P.; Torsell, S.; Lindstro¨m, U. M. Tetra-
hedron 2003, 59, 1293.
362 J. Org. Chem., Vol. 70, No. 1, 2005

mmol). After the mixture was stirred for 10 min, allylic alcohol
9 (3.0 g, 12.71 mmol) was added. After the mixture was stirred
for 20 min at -20 °C, t-BuOOH (5.0 M in decane, 5.1 mL, 2.292
g, 25.43 mmol) was added and the reaction mixture was stirred
for 20 h at -20 °C. The resultant mixture was then quenched
by addition of satd aq NaHCO3 (40 mL) and Et2O (80 mL). The
resultant mixture was stirred for 1 h at room temperature after
which it was filtered through a pad of Celite. The filtrate was
diluted with Et2O (80 mL) and stirred for 20 min with 1 M NaOH
(50 mL). The phases were separated, and the aqueous phase
was extracted twice with Et2O. The combined organic extracts
were washed with brine, dried (Na2SO4), and concentrated. Silica
gel column chromatography using petroleum ether/EtOAc (1:1)
as eluent afforded the epoxide 14 (2.1 g, 67%) as a colorless oil.
[R]20D: +21.5 (c 1, CHCl3) [lit.15 [R]29D: +21 (c 2.2, CHCl3)]. IR
(CHCl3, cm-1): νmax 1578, 1684, 2856, 2924, 3458. 1H NMR (500
MHz, CDCl3): δ 1.76-2.05 (m, 4H), 3.47 (q, 2H, J ) 5 Hz), 3.68-
3.78 (m, 2H), 3.81 (s, 3H), 3.86 (q, 1H, J ) 10 Hz), 3.95 (q, 1H,
J ) 5 Hz), 4.60 (s, 2H), 6.89 (d, 2H, J ) 10 Hz), 7.28 (d, 2H, J
) 10 Hz). 13C NMR (125 MHz, CDCl3): δ 25.5, 27.5, 54.8, 62.0,
67.9, 72.0, 80.4, 113.7, 129.2, 130.4, 131.7, 158.9. MS (ESI): 252
(M+), 230, 200, 121. Anal. Calcd for C14H2004: C, 66.65; H, 7.99.
Found: C, 66.60; H, 8.00.
(2R,3R)-3-[3-(tert-Butyldimethylsilanyloxymethyl)-
oxiranyl]propan-1-ol (15). To an ice-cold solution of Et3N (1.45
g, 14.33 mmol) in CH2Cl2 (40 mL) were added DMAP (cat.) and
TBDMSCl (1.8 g, 11.94 mmol). After 5 min, the epoxide 14 (2.0
g, 7.94 mmol) in CH2Cl2 (10 mL) was added. The resultant
mixture was stirred at room temperature for 10 h and then
poured into satd aq NaHCO3, and the phases were separated.
The aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The
combined organic phases were washed with brine, dried (Na2-
SO4), and concentrated. Silica gel column chromatography using
petroleum ether/EtOAc (9:1) furnished the TBS-protected ep-
oxide (2.61 g, 90%) as a colorless oil.
to room temperature and then poured into Et2O‚H2O (50 mL
1:1). The phases were separated, and the aqueous phase was
extracted with Et2O (3 × 30 mL). The combined organic extracts
were washed with H2O and brine, dried (Na2SO4), and concen-
trated. Silica gel column chromatography of the residue using
petroleum ether/EtOAc (7:3) afforded the azido epoxide 16 (0.9
g, 82%) as a pale yellow oil. [R]20D: +11.2 (c 0.4, CHCl3). IR
(CHCl3, cm-1): νmax 1225, 1347, 2100, 2836, 2953. 1H NMR (500
MHz, CDCl3): δ 0.08 (s, 6H), 0.90 (s, 9H), 1.72-2.07 (m, 4H),
3.48-3.49 (m, 2H) 3.79 (m, 4H). 13C NMR (125 MHz, CDCl3): δ
-5.7, 18.0, 25.5, 26.2, 28.9, 52.4, 64.5, 68.8, 79.1.
(2S,3R)-3-Hydroxy-2-hydroxymethylpiperidine-1-car-
boxylic Acid tert-Butyl Ester (ent-13). To a solution of azido
epoxide 16 (0.500 g, 1.84 mmol) in THF (9 mL) and H2O (1 mL)
was added triphenylphosphine (0.73 g, 2.78 mmol). The reaction
mixture was stirred at room temperature for 48 h after which
tert-butyl dicarbonate (0.48 g, 2.21 mmol) and sodium hydroxide
(0.09 g, 2.25 mmol) were added and the stirring was continued
for additional 12 h. The reaction mixture was neutralized by
addition of 10% solution of KHSO4 and diluted with CH2Cl2. The
organic phase was separated and the aqueous phase extracted
with CH2Cl2 (3 × 30 mL). The combined organic extracts were
washed with brine, dried (Na2SO4), and concentrated. To this
crude product in THF (10 mL) was added TBAF (0.8 mL, 1.0 M
in THF) and the reaction mixture stirred for 1 h at room
temperature. TLC analysis at this point indicated the deprotec-
tion of the TBDMS group. The reaction was quenched with aq
satd NH4Cl (5 mL), and the phases were separated. The aqueous
phase was extracted with EtOAc (4 × 15 mL). The combined
organic extracts were washed with brine, dried (Na2SO4), and
concentrated. Silica gel column chromatography of the residue
using CHCl3/MeOH (19:1) as eluent afforded the cyclized product
ent-13 (0.2 g, 48%) as thick syrupy liquid. [R]20D: -5.2 (c 0.25,
MeOH). Spectroscopic data obtained is same as that of compound
13.
To a solution of TBS-protected epoxide (2.0 g, 5.46 mmol) in
CH2Cl2 (40 mL) and H2O (2.0 mL) at 0 °C was added DDQ (1.364
g, 60.08 mmol) in portions. The resultant mixture was stirred
at room temperature for 3 h, and then satd aq NaHCO3 (10 mL)
was added. The phases were separated, and the aqueous phase
was extracted with CH2Cl2 (3 × 60 mL). The combined organic
extracts were dried (Na2SO4) and concentrated. Silica gel column
chromatography of the residue using petroleum ether/EtOAc (3:
1) as eluent furnished the alcohol 15 (1.21 g, 90%) as a pale
yellow oil. [R]20D: + 13.9 (c 0.46, CHCl3). IR (CHCl3, cm-1): νmax
1604, 1686, 2874, 2932, 3412. 1H NMR (500 MHz, CDCl3): δ
0.08 (s, 6 H), 0.90 (s, 9 H), 1.89-1.97 (m, 4H), 3.21 (brs, 1H),
3.60-3.85 (m, 6H). 13C NMR (125 MHz, CDCl3): δ -5.7, 18.0,
25.5, 25.6, 26.8, 64.5, 68.0, 73.0, 78.9. MS (ESI): 264 (M + NH4+),
254, 230, 200, 121. Anal. Calcd for C12H2603Si: C, 58.49; H, 10.63;
Si, 11.40. Found: C, 58.52; H, 10.59; Si, 11.30.
(2R,3R)-[3-(3-Azidopropyl)oxiranyl]methanol (16). To a
solution of epoxide 15 (0.750 g, 3.05 mmol) in CH2Cl2 (30 mL)
at 0 °C were added Et3N (0.617 g, 6.09 mmol) and methane-
sulfonyl chloride (0.524 g, 4.574 mmol). The resultant mixture
was stirred overnight at room temperature and the aqueous
phase extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were washed with brine, dried (Na2SO4), and concen-
trated to a yellow oil that was used as such for the next step.
To the solution of the above mesylate in dry DMF (20 mL)
was added sodium azide (1.0 g, 15.4 mmol), and the reaction
mixture was stirred at 70 °C overnight. The solution was cooled
(2S,3S)-3-Hydroxypipecolic Acid (1). Mp: 232-236 °C
(lit.8a mp 230-238 °C). [R]20D: +13.5 (c 0.2, 10% aq HCl) [lit.8a
[R]20D +12.9 (c 0.23, 10% aq HCl)]. IR (CHCl3, cm-1): 2500, 2846,
2983, 3364. 1H NMR (200 MHz, D2O): δ 1.62-1.66 (m, 2H),
1.89-1.93(m. 2H), 2.84-2.99 (m, 1H), 3.82-3.83 (m, 1H), 4.10-
4.15 (m, 1H), 4.32(brs, 1H). 13C NMR (50 MHz, D2O): δ 20.1,
29.9, 46.4, 62.0, 66.4, 176.4.
(2R,3R)-3-Hydroxypipecolic Acid (ent-1). Mp: 235-239
°C [lit.8a mp 234-239 °C]. [R]20D: -13.5 (c 0.2, 10% aq HCl) [lit.8a
[R]20 -13.0 (c 0.2, 10% aq HCl)].
D
Acknowledgment. M.S.B. thanks CSIR, New Delhi,
for the award of Senior Research Fellowship. P.K. is
thankful to Department of Science and Technology, New
Delhi, for generous funding of the project (Grant No.
SR/S1/OC-52/2003). We are grateful to Dr. M. K. Gurjar
for his support and encouragement. This is NCL com-
munication no. 6672.
Supporting Information Available: Spectroscopic data
and full experimental procedure for compounds 7-9. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO0485381
J. Org. Chem, Vol. 70, No. 1, 2005 363