Stereoselective total synthesis of cis- and trans-3-hydroxypipecolic acid

Article abstract of DOI:10.1021/jo051725u

3-Hydroxypipecolic acid, a nonproteinogenic cyclic α-amino acid, is a common structural moiety found in a large number of natural and synthetic compounds of medicinal significance. Utilizing D-serine as a chiral template, the present research describes ef

Full text of DOI:10.1021/jo051725u

target of several synthetic efforts4 due to the presence of
this structural motif in compounds with diverse biological
activities.5 For example, the antitumor antibiotic tetra-
zomine contains a cis-3-hydroxypipecolic acid component,4f
whereas (-)-swainsonine, a potent inhibitor of R-D-
mannosidase, is derivable from the corresponding trans-
configured 3-hydroxypipecolic acid.6
Stereoselective Total Synthesis of cis- and
trans-3-Hydroxypipecolic Acid
Ningning Liang and Apurba Datta*
Department of Medicinal Chemistry, The University of
Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045
Among the several syntheses of the various stereoiso-
meric 3-hydroxypipecolic acids reported in the literature,4
a majority of the approaches have utilized chiral building
blocks as starting materials for the desired synthesis. In
a very efficient example, Williams and co-workers4g have
developed a short-step sequence to both the enantiomers
of trans-3-hydroxypipecolic acids, employing the enan-
tiomeric, commercially available (albeit relatively expen-
sive: 1 g ) $64.40-$67.40; Aldrich catalog) (2S,3R)- and
(2R,3S)-benzyl-6-oxo-2,3-diphenyl-4-morpholinecarboxy-
lates as chiral starting materials. In another example,
in an L-serine-mediated chiral pool approach, Jourdant
and Zhu developed synthetic routes to both cis- and trans-
3-hydroxypipecolic acids in 15 and 13 linear reaction
steps, respectively.4e In a recent publication, Kumar and
Bodas described asymmetric synthetic routes to both the
enantiomers of trans-3-hydroxypipecolic acids in about
15 reaction steps.4a Except for the above-mentioned
syntheses by Williams and co-workers (five steps, 25-
28% overall yields),4g most of the other reported (stereo-
selective) syntheses of the 3-hydroxypipecolic acids re-
quired 9-15 reaction steps, affording the desired products
in approximately 10-30% overall yields.4
adutta@ku.edu
Received August 14, 2005
3-Hydroxypipecolic acid, a nonproteinogenic cyclic R-amino
acid, is a common structural moiety found in a large number
of natural and synthetic compounds of medicinal signifi-
cance. Utilizing D-serine as a chiral template, the present
research describes efficient and straightforward routes to
cis- and trans-3-hydroxypipecolic acids in enantiopure form.
The key steps in the syntheses involve chelation-controlled
addition of a homoallyl Grignard reagent to a protected
serinal derivative toward stereoselective formation of the
corresponding syn-amino alcohol adduct 3. On the other
hand, zinc borohydride-mediated chelation-controlled reduc-
tion of a serine-derived R-aminoketone precursor leads to
the formation of the corresponding anti-amino alcohol adduct
4 with high stereoselectivity. Following an efficient sequence
of reactions, the above amino alcohol derivatives were
subsequently transformed to the corresponding cis- and
trans- title compounds, respectively.
In continuation of our interest in the amino acid chiral
template-assisted synthesis of natural and nonnatural
bioactive compounds,7 we have developed efficient routes
to both the cis-(2S,3R)- and trans-(2S,3S)-3-hydroxy-
(3) (a) Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R.
H. Org. Lett. 2004, 6, 4941. (b) Brooks, C. A.; Comins, D. L. Tetrahedron
Lett. 2000, 41, 3551. (c) Haddad, M.; Larcheveque, M. Tetrahedron:
Asymmetry 1999, 10, 4231. (d) Gillard, J.; Abraham, A.; Anderson, P.
C.; Beaulieu, P. L.; Bogri, T.; Bousquet, Y.; Grenier, L.; Guse, I.;
Lavalle´e, P. J. Org. Chem. 1996, 61, 2226, and references therein.
(4) For some recent synthetic studies, see: (a) Kumar, P.; Bodas,
M. S. J. Org. Chem. 2005, 70, 360. (b) Bodas, M. S.; Kumar, P.
Tetrahedron Lett. 2004, 45, 8461. (c) Koulocheri, S. D.; Magiatis, P.;
Skaltsounis, A.-L.; Haroutounian, S. A. Tetrahedron 2002, 58, 6665.
(d) Haddad, M.; Larcheveque, M. Tetrahedron Lett. 2001, 42, 5223.
(e) Jourdant, A.; Zhu, J. Tetrahedron Lett. 2000, 41, 7033. (f) Horikawa,
M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40, 3843.
(g) Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998,
39, 3659. (h) Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi,
G.; Fava, G. G.; Ferrari, M. B.; Casiraghi, G. Tetrahedron: Asymmetry
1997, 8, 2975. (i) Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett.
1996, 37, 4001 and references therein.
The hydroxypipecolic acid structural framework is
found in a wide variety of natural and synthetic com-
pounds of biomedical significance.1 In conformational and
ligand binding studies involving bioactive peptides and
peptidomimetics, these chimeric amino acid building
blocks are often utilized as hydroxylated homoproline
analogues or as constrained analogues of serine.2 Con-
sequently, development of methods for the stereoselective
construction of various hydroxypipecolic acids is an active
area of research.3 In particular, 3-hydroxypipecolic acid,
a cyclic â-hydroxy-R-amino acid derivative, has been the
(1) (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. (b) Schneider, M. J. Pyridine and Piperidine
Alkaloids: An Update. In Alkaloids: Chemical and Biological Perspec-
tives; Pelletier, S. W., Ed.; Pergamon: Oxford, 1996; Vol. 10, p 155. (c)
Morton, T. C. Biochem. Syst. Ecol. 1998, 26, 379. (d) Zografou, E. N.;
Tsiropoulos, G. J.; Margaritas, L. H. Entomol. Exp. Appl. 1998, 87,
125.
(2) For some leading references, see: (a) Sugisaki, C. H.; Caroll, P.
J.; Correia, C. R. D. Tetrahedron Lett. 1998, 39, 3413. (b) Copeland, T.
D.; Wondrak, E. M.; Toszer, J.; Roberts, M. M.; Oraszan, S. Biochem.
Biophys. Res. Commun. 1990, 169, 310. (c) Hanesian, S.; McNaughton-
Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetrahedron 1997, 53, 12789.
(d) Mahara, G. M.; Marshall, G. R. Tetrahedron Lett. 1997, 38, 5069.
(5) For representative examples, see: (a) Dragovich, P. S.; Parker,
J. E.; Incacuan, M.; Kalish, V. J.; Kissinger, C. R.; Knighton, D. R.;
Lewis, C. T.; Moomaw, E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins,
T. J.; Showalter, R. E.; Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E.
J. Med. Chem. 1999, 39, 1872. (b) Shilvock, J. P.; Nash, R. J.; Lloyd,
J. D.; Winters, A. L.; Asano, N.; Fleet, J. W. Tetrahedron: Asymmetry
1998, 9, 3505. (c) Ho, B.; Zabriskie, T. M. Bioorg. Med. Chem. Lett.
1998, 8, 739. (d) Ninomiya, I.; Kiguchi, T.; Naito, T. Alkaloids 1998,
50, 317. (e) Lamarre, D.; Croteau, G.; Bourgon, L.; Thibeult, D.;
Wardrop, E.; Clouette, C.; Vaillancourt, M.; Cohen, E.; Pargellis, C.;
Yoakim, C.; Anderson, P. C. Antimicrob. Agents Chemother. 1997, 41,
965. (f) Skiles, J. W.; Giannousis, P. P.; Fales, K. R. Bioorg. Med. Chem.
Lett. 1996, 6, 963 and references therein.
(6) Ferreira, F.; Greck, C.; Genet, J. P. Bull. Soc. Chim. Fr. 1997,
134, 615.
10.1021/jo051725u CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/15/2005
10182
J. Org. Chem. 2005, 70, 10182-10185

SCHEME 1
FIGURE 1. Retrosynthetic strategy and approach.
pipecolic acid (1 and 2; Figure 1) in enantiomerically pure
form. Our synthetic strategy (Figure 1) and the details
of the syntheses are described herein.
Starting from D-serine, a key step in the synthesis of
1 was envisioned to be the initial formation of the syn-
amino alcohol intermediate 3 through a stereocontrolled
addition of homoallylmagnesium bromide to an ap-
propriately protected D-serinal derivative. Subsequent
heterocyclization involving the strategically located amine
functionality and the terminal olefinic moiety is expected
to afford the desired cis-product 1. Similarly, stereose-
lective construction of the trans-amino alcohol derivative
4, utilizing a chelation-controlled reduction of an ap-
propriate ketone intermediate, followed by heterocycliza-
tion would result in the corresponding trans-3-hydroxy-
pipecolic acid (2).
Accordingly, synthesis of the cis-pipecolic acid deriva-
tive 1 was initiated by conversion of readily available
D-serine to the corresponding protected aminodiol 5
(Scheme 1).8 The next critical step in the sequence
required stereoselective construction of the syn-1,2-amino
alcohol functionality as depicted in the desired inter-
mediate 3. In previous research from our group, we
demonstrated that under appropriate reaction conditions,
reaction of in situ generated N-protected chiral R-ami-
noaldehydes with Grignard reagents results in a chela-
tion-controlled addition of the organometallic nucleophile
to the aldehyde carbonyl, leading to the formation of the
corresponding enantiopure 1,2-amino alcohol adduct with
high syn-selectivity.9 Following this protocol, oxidation
of 5 to the corresponding aldehyde and its reaction with
an excess of homoallylmagnesium bromide afforded the
required syn-amino alcohol derivative 3 with good dia-
stereoselection (>9:1). The assigned stereochemistry of
3 was confirmed by its conversion to the corresponding
oxazolidinone 3A and subsequent 1H NMR study, wherein
secondary hydroxy group of 3 afforded the silyl ether
derivative 6 in high yield. As per our synthetic strategy,
the Boc-amino group and the terminal olefinic moiety of
the δ-alkenylcarbamate 6 represent strategic function-
alities to achieve the required six-membered heterocyclic
ring-forming reaction. Accordingly, treatment of 6 with
catalytic osmium tetroxide followed by oxidative cleavage
of the resulting diol with silica gel supported sodium
periodate11 resulted in the direct formation of the cyclic
carbinolamine 7 in good overall yield. Reductive deoxy-
genation12 of 7 was found to form a mixture of two
products containing the expected amine derivative along
with some quantities of the further silyl-deprotected (at
the primary hydroxy site) product 8. To simplify the
purification process, the crude reaction mixture from the
above reaction was therefore directly treated with cam-
phorsulfonic acid13 to cleanly afford the selectively depro-
tected free primary alcohol derivative 8 in good overall
yield.
Subsequent oxidation of the primary hydroxy group
under standard conditions14 provided the corresponding
carboxylic acid 9. Interestingly, the secondary silyl ether
linkage was found to be cleaved during the reaction.15
Considering that, under similar reaction conditions, the
silyl ether group remained unaffected in case of the
corresponding trans-product (vide infra), the newly gen-
erated syn-oriented carboxylic acid moiety of 9 probably
facilitated cleavage of the neighboring silyl ether func-
tionality. Finally, acidic hydrolysis of the carbamate
culminated in an efficient synthesis of the desired
(2S,3R)-cis-3-hydroxypipecolic acid hydrochloride 10.
the coupling constant between the ring protons (J4,5
)
4.53 Hz, after decoupling H-5 from 1′-CH2) was in good
agreement with the reported values.10 Protection of the
(7) For some recent examples, see: (a) Bhaket, P.; Morris, K.;
Stauffer, C. S.; Datta, A. Org. Lett. 2005, 7, 875. (b) Bhaket, P.;
Stauffer, C. S.; Datta, A. J. Org. Chem. 2004, 69, 8594. (c) Khalaf, J.
K.; Datta, A. J. Org. Chem. 2004, 69, 387 and references therein.
(8) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.; Zurbano,
M. M. Synthesis 1997, 1146.
(9) For representative examples, see: (a) Datta, A.; Veeresa, G. J.
Org. Chem. 2000, 65, 7609. (b) Kiran Kumar, K.; Datta, A. Tetrahedron
1999, 55, 13899. (c) Ravi Kumar, J. S.; Datta, A. Tetrahedron Lett.
1999, 40, 1381 and references therein. For a pioneering report, see:
Denis, J.-N.; Correa, A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939.
(10) Datta, A.; Ravi Kumar, J. S.; Roy, S. Tetrahedron 2001, 57,
1169.
(11) Zhong, Y.-L.; Shing, T. K. M. J. Org. Chem. 1997, 62, 2622.
(12) Pedregal, C.; Ezquerra, J.; Escribano, A.; Carreno, M. C.; Ruano,
J. L. G. Tetrahedron Lett. 1994, 35, 2053.
(13) Nelson, T. D.; Crouch, R. D. Synthesis 1996, 1031-1069.
(14) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahe-
dron: Asymmetry 1998, 9, 629.
J. Org. Chem, Vol. 70, No. 24, 2005 10183

SCHEME 2
derivative 8 (Scheme 1), during the present reaction the
secondary silyloxy functionality remained unaffected.
Finally, simultaneous removal of both the protecting
groups under acidic conditions completed the synthesis
of the target (2S,3S)-trans-3-hydroxypipecolic acid hy-
drochloride 18.
In conclusion, starting from readily available D-serine
and following a practical sequence of reactions, efficient
synthetic routes to enantiopure cis- and trans-3-hydroxy-
pipecolic acids have been developed. In terms of brevity
and efficiency (cis-10: 11 steps, 24% overall; trans-18:
12 steps, 20% overall), the described methods compare
well with the literature reported routes4 and are expected
to be attractive alternatives to the existing methods for
the synthesis of the title compounds. Additionally, start-
ing from L-serine, the above method can also be readily
extended to synthesize the corresponding enantiomers
of both the 3-hydroxypipecolic acids described, thereby
providing easy access to all possible stereoisomers of
these novel amino acid derivatives of structural and
biological significance.
Experimental Procedure
(2R,3R)-2-(tert-Butoxycarbonylamino)-1-(tert-butyldim-
ethylsilyloxy)-3-hydroxyhept-6-ene (3). To a stirred solution
of oxalyl chloride (2.43 mL, 27.88 mmol) in anhydrous CH2Cl2
(50 mL) at -78 °C under nitrogen atmosphere was added DMSO
(2.33 mL, 32.8 mmol) dropwise. After being stirred for 30 min,
a solution of the amino alcohol 58 (5 g, 16.4 mmol) in CH2Cl2
(97 mL) was added to the reaction mixture over 30 min. The
mixture was then warmed to -35 °C and stirred for 30 min at
the same temperature, followed by dropwise addition of diiso-
propylethylamine (14.9 mL, 114.8 mmol) over 5 min. The
reaction mixture was then warmed to 0 °C over 15 min and
transferred through a cannula to a room-temperature solution
of homoallymagnesium bromide (prepared from Mg (3.9 g, 164
mmol) and 4-bromo-1-butene (8.26 mL, 82 mmol) in THF (54
mL)). After being stirred for 2 h at room temperature, the
reaction was quenched by addition of saturated aqueous NH4Cl
solution (100 mL). The organic layer was separated, the aqueous
layer was extracted with CHCl3 (3 × 30 mL), and the combined
organic extracts were washed with brine and dried over Na2SO4.
Solvent was removed under vacuum, and the residue was
purified by careful flash column chromatography (EtOAc/hexane
) 15:85) to yield the aminodiol derivative 3 as a light yellow oil
A slightly different strategy was followed to achieve
the formation of the pivotal anti-amino alcohol derivative
13, as needed for the synthesis of the target trans-3-
hydroxypipecolic acid (2). Thus, following a reported
method,16 D-serine was converted to the corresponding
N,O-protected Weinreb amide 11 (Scheme 2). Its conver-
sion to the known ketone 12, via addition of homoallyl-
magnesium bromide, was achieved under standard re-
action conditions.10 Stereoselective formation of the 1,2-
anti-amino alcohol functionality was achieved by reduction
of the ketone 12 with zinc borohydride, affording the
product 13 with high stereocontrol (>93:7).7b,c,10
Selective removal of the acetonide protecting group to
form 4, and subsequent silyl protection of the resulting
primary hydroxyl functionality, afforded the fully pro-
tected aminodiol 14 in high overall yield. Following the
same sequence of reactions as described in Scheme 1,
heterocyclization to form the piperidine framework 15
and its deoxygenation resulted in the mono-O-silyl-
protected piperidine derivative 16. Subsequent conver-
sion of the primary hydroxy group to carboxylic acid
afforded the N,O-diprotected hydroxypipecolic acid 17.
Notably, unlike in the case of the corresponding cis-
(3.8 g, 64%): [R]D25 -23 (c 1.3, CHCl3); IR (neat) 3442, 1693 cm-1
;
1H NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.90 (s, 9H), 1.45 (s,
9H), 1.47-1.63 (m, 2H), 2.14-2.19 (m, 2H), 3.38 (s, 1H), 3.52
(br s, 1H), 3.79-3.97 (m, 3H), 4.95-5.19 (m, 2H), 5.12 (d, J )
8.8 Hz, 1H), 5.78-5.98 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ
-5.2, 18.5, 26.1, 26.2, 28.5, 28.8, 30.2, 33.4, 53.8, 66.9, 73.1, 79.7,
115.3, 138.6, 156.4; HRMS calcd for C18H37NO4SiNa m/z (M +
Na) 382.2390, found 382.2376.
Conversion of 6 to the Piperidinol Derivative 7. Step
1. To a room-temperature solution of 6 (320 mg, 0.68 mmol) and
NMO (228 mg, 1.69 mmol) in acetone/H2O (4 mL/1 mL) was
added OsO4 (5% solution in toluene, 0.173 mL, 0.0195 mmol)
with stirring. The yellow solution slowly turned orange. After
being stirred for 2 h, the reaction mixture was diluted with
EtOAc (10 mL) followed by the addition of 10% aqueous NaHSO3
(1 mL). The resulting mixture was allowed to stir for a few
minutes, the organic layer was separated, and the aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic
layer was dried over Na2SO4 and concentrated under vacuum.
The crude diol thus obtained was carried to the next step without
further purification.
(15) One of the reviewers of the manuscript wondered why the free
secondary hydroxy group (at C-3) of compound 9, generated during
the conversion of 8 f 9, did not undergo further oxidation to the
corresponding ketone derivative. A couple of plausible explanations
could be as follows: (i) the relatively short reaction time employed for
the conversion of 8 f 9 (30 min) could probably be insufficient for
carrying out the two-step process of initial cleavage of the silyl
protecting group to unmask the hydroxy and subsequent oxidation of
this relatively hindered secondary hydroxy to the corresponding ketone.
(ii) A second possibility could be an intramolecular hydrogen bond
interaction between the favorably placed (and newly generated)
carboxylic acid moiety at C-2 and the free hydroxy group at C-3 of
compound 9, resulting in the prevention or rate retardation of the
oxidation of the hydroxy group. However, additional experiments will
have to be carried out to find out the exact reason for the above reaction
stopping at product 9.
Step 2. Silica gel-supported NaIO4 (1.36 g; prepared according
to ref 11) was added to a room-temperature solution of the diol
(∼345 mg, 0.68 mmol; as obtained from the above reaction) in
(16) Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T. M.; Taylor,
R. J. K. J. Org. Chem. 2002, 67, 1802.
10184 J. Org. Chem., Vol. 70, No. 24, 2005

CH2Cl2 (5 mL). After being stirred for 90 min, the reaction
mixture was filtered through a sintered funnel, the residue was
washed thoroughly with CHCl3, and the combined filtrate was
concentrated under vacuum. The residual oil was purified by
flash column chromatography (EtOAc/hexane ) 5:95 to 10:90)
to afford the cyclic carbinolamine 7 as a light yellow oil (269
was cooled to room temperature and extracted once with CH2Cl2
(10 mL) to remove any organic soluble impurities. Concentration
of the aqueous layer under high vacuum followed by overnight
drying under high vacuum afforded the product 10 as a light
yellow solid (57 mg, quantitative): [R]25 -25 (c 1.3, H2O); 1H
D
NMR (400 MHz, D2O) δ 1.53-1.72 (m, 2H), 1.73-1.90 (m, 2H),
2.82-2.94 (m, 1H), 3.24-3.34 (m, 1H), 3.93 (s, 1H), 4.42 (s, 1H);
13C NMR (100.6 MHz, D2O) δ 16.0, 28.5, 43.9, 60.9, 64.0, 170.5;
HRMS calcd for C6H12NO3 m/z (M + H) 146.0817 (free amine +
H), found 146.0814.
1
mg, 83% over two steps): IR (neat) 3400, 1697 cm-1; H NMR
(400 MHz, CDCl3) (mixture of anomers) δ 0.07, 0.10, and 0.12
(3s, 12H), 0.91 and 0.94 (2s, 18H), 1.49 (s, 9H), 1.51-1.70 (m,
2H), 1.84-1.92 (m, 1H), 2.14 (m, 1H), 3.71-3.83 (m, 2H), 4.08-
4.19 (m, 2H), 5.37 (d, J ) 10.5 Hz, 1H), 5.49-5.63 (m, 1H); 13C
NMR (100.6 MHz, CDCl3) (mixture of anomers) δ -4.9, -4.6,
18.5, 18.7, 25.4, 26.2, 26.3, 28.7, 31.6, 55.6, 61.1, 69.8, 73.2, 80.9,
155.4; calcd for C23H50NO5Si2 m/z (M + H) 476.3228, found
476.3242.
Reduction of Ketone 12 to the anti-Amino Alcohol
Derivative 13. To a solution of the homoallyl ketone 12 (540
mg, 1.70 mmol) in MeOH (10 mL) was added CeCl3‚7H2O (190
mg, 0.51 mmol) in one portion, and the resulting solution was
cooled to 0 °C with continuous stirring. An ethereal solution of
zinc borohydride (0.20 M in Et2O, 25.5 mL, 5.10 mmol) was then
added dropwise to the reaction mixture (30 min), and stirring
was continued at the same temperature for another 2 h. The
reaction was quenched by slow addition of saturated aqueous
NH4Cl solution (10 mL), and the resulting solution was allowed
to attain room temperature. The organic layer was separated,
and the aqueous layer was extracted with EtOAc (3 × 50 mL).
The combined organic extract was washed with brine, dried over
anhydrous Na2SO4, and concentrated under vacuum. Purifica-
tion of the crude residue by flash chromatography (EtOAc/
hexane ) 15:85 to 30:70) yielded the pure amino alcohol 13 as
a light yellow oil (488 mg, 90%): [R]25D 27.5 (c 1.13, CHCl3); IR
(neat) 3471, 1681; 1H NMR (400 MHz, CDCl3) (mixture of
rotamers) δ 1.47-1.65 (m, 8H), 2.01-2.30 (m, 2H), 3.58 (br s,
1H), 3.77-4.17 (m, 4H), 4.91-5.23 (m, 4H), 5.65-5.93 (m, 1H),
7.31-7.41 (m, 5H); 13C NMR(100.6 MHz, CDCl3) (mixture of
rotamers) δ 22.9, 24.4, 26.3, 30.2, 32.0, 32.9, 61.2, 62.8, 64.0,
64.7, 67.0, 67.8, 71.4, 72.1, 94.6, 115.0, 128.1, 128.2, 128.3, 128.6,
134.9, 137.1, 137.9, 138.4, 154.2, 155.1; HRMS calcd for
C18H26N1O4 m/z (M + H) 320.1862, found 320.1852.
Reductive Deoxygenation of the Carbinolamine 7 To
Form the Piperidine Diol 8. A solution of 7 (250 mg, 0.53
mmol) and triethylsilane (0.17 mL, 1.06 mmol) in anhydrous
CH2Cl2 (10 mL) was cooled to -78 °C, and borontrifluoride
etherate (0.15 mL, 1.17 mmol) was added to it dropwise under
nitrogen atmosphere. After being stirred for 30 min at the same
temperature, a second lot of triethylsilane (0.17 mL, 1.06 mmol)
and borontrifluoride etherate (0.15 mL, 1.17 mmol) were added
to the reaction mixture. The resulting mixture was stirred for 3
h at -78 °C, followed by quenching the reaction with saturated
aqueous NaHCO3 solution (2 mL). The mixture was diluted with
CH2Cl2 (10 mL), and the organic layer was separated, dried over
Na2SO4, and concentrated. The residue was dissolved in MeOH/
CH2Cl2 (2 mL:2 mL) and cooled to 0 °C followed by addition of
camphorsulfonic acid (4 mg, 0.07 mmol) with stirring. The
reaction mixture was maintained at pH 3 at 0 °C for 2 h and
then brought to neutral pH with the addition of saturated
aqueous NaHCO3 (2 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated. The residue was purified by flash column chromatogra-
phy (EtOAc/hexane ) 2:8 to 4:6) to yield the piperidine 8 as a
colorless oil (132 mg, 72%): [R]25D -16 (c 0.7, CHCl3); IR (neat)
3454, 1693 cm-1; 1H NMR (400 MHz, CDCl3) δ 0.1 and 0.12 (2s,
6H), 0.91 (s, 9H), 1.48 (s, 9H), 1.68-1.76 (m, 4H), 2.45 (s, 1H,
exchangeable with D2O), 2.63-2.78 (m, 1H), 3.63-4.02 (m, 4H),
4.29-4.52 (m, 1H); 13C NMR (100.6 MHz, CDCl3) δ -5.6, -5.5,
18.0, 23.9, 25.8, 28.4, 28.9, 29.2, 38.0, 39.4, 55.7, 56.6, 59.2, 70.0,
70.8, 80.0, 155.2, 156.0; HRMS calcd for C17H35N1O4SiNa m/z
(M + Na) 368.2233, found 368.2214.
Conversion of the Carbinolamine 15 to the Piperidine
Derivative 16. Starting from the carbinolamine derivative 15
(375 mg, 0.74 mmol), we followed the same procedure as that
for compound 8. Column chromatographic purification resulted
in the piperidine 16 (196 mg, 70%) as a colorless oil: [R]25D -11
(c 1, CHCl3); IR (neat) 3439, 1680 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 0.06 (s, 6H), 0.88 (s, 9H), 1.32-1.42 (m, 1H), 1.56-
1.69 (m, 2H), 1.89-2.04 (m, 1H), 2.83-3.01 (m, 1H), 3.70-3.82
(m, 2H), 3.93 (s, 1H), 4.0-4.14 (m, 1H), 4.22-4.34 (m, 1H), 5.15
(dd, J ) 12.5 and 18.1 Hz, 2H), 7.30-7.40 (m, 5H); 13C
NMR(100.6 MHz, CDCl3) δ -4.6, -4.5, 18.4, 19.6, 26.1, 28.5,
40.5, 60.9, 65.5, 67.5, 128.1, 128.3, 128.8, 137.3, 157.3; HRMS
calcd for C20H34NO4Si m/z (M + H) 380.2257, found 380.2254.
(2S,3S)-3-Hydroxypipecolic Acid Hydrochloride (18).
The N,O-protected piperidine carboxylic acid derivative 17 (100
mg, 0.25 mmol) was taken in 6 N HCl (6 mL) and refluxed for
2 h. The reaction mixture was cooled to room temperature and
extracted once with CH2Cl2 (10 mL) to remove any organic
soluble impurities. The aqueous layer was concentrated under
vacuum, and the residue dried under high vaccum overnight to
afford the desired product 18 as a light yellow solid (41 mg,
91%): [R]25D 14.2 (c 0.95, H2O); 1H NMR (400 MHz, D2O) δ 1.50-
1.68 (m, 2H), 1.82-1.94 (m, 2H), 2.90-3.00 (m, 1H), 3.19-3.30
(m, 1H), 3.72 (d, J ) 7.6 Hz, 1H), 3.94-4.03 (m, 1H); 13C NMR
(100.6 MHz, D2O) δ 19.0, 29.2, 42.9, 61.1, 65.9, 170.1; HRMS
calcd for C6H12NO3 m/z (M + H) 146.0817, found 146.0808.
Oxidation of 8 to (2S,3R)-N-tert-Butoxycarbonyl-3-hy-
droxypipecolic Acid (9). To a suspension of NaIO4 (235 mg,
1.1 mmol) in CH3CN/CCl4/H2O (4.8 mL; 1:1:10) was added
RuCl3‚H2O (11.4 mg, 0.055 mmol) in small portions, and the
mixture was stirred at room temperature for 45 min. The
resulting solution was added to the alcohol 8 (191 mg, 0.55 mmol)
dissolved in CH3CN (3 mL), followed by the addition of a second
portion of NaIO4 (118 mg, 0.55 mmol). The resulting mixture
was stirred at room temperature for 30 min and filtered through
Celite, and the Celite layer was washed thoroughly with EtOAc.
The combined filtrate was dried over Na2SO4 and concentrated.
The crude product thus obtained was purified by flash column
chromatography (MeOH/CHCl3 ) 5:95 to 20:80) to yield the pure
acid 9 (97 mg, 72%) as a semisolid: [R]25D -8 (c 0.6, CHCl3); IR
1
(neat) 3365, 1695 cm-1; H NMR (400 MHz, CDCl3-CD3OD) δ
1.47 (s, 9 H), 1.50-1.60 (m, 2H), 1.64-1.78 (m, 1H), 1.83-1.94
(m, 1H), 2.88-3.08 (m, 1H), 3.75 (br s, 1H), 3.87 (d, J ) 7.6 Hz,
1H), 4.71-4.86 (m, 1H); 13C NMR (100.6 MHz, CD3OD) (mixture
of rotamers) δ 22.9, 23.4, 24.8, 29.3, 29.4, 29.8, 39.5, 40.6, 57.4,
58.7, 71.8, 78.0, 79.9, 155.7, 155.8, 174.5, 174.7; HRMS calcd
for C11H19NO5Na m/z (M + Na) 268.1161, found 268.1162.
(2S,3R)-3-Hydroxypipecolic Acid Hydrochloride (10).
The Boc-protected acid 9 (78 mg, 0.32 mmol) was taken in 6 N
HCl (10 mL) and heated at 70 °C for 2 h. The reaction mixture
Supporting Information Available: General experimen-
tal methods, experimental procedures and characterization
1
data for compounds 6, 12, 4, 14, 15, and 17, and copies of H
and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO051725U
J. Org. Chem, Vol. 70, No. 24, 2005 10185