A short enantioselective synthesis of N-boc-(2R,3R)-3-methyl-3- hydroxypipecolic acid from geraniol

Article abstract of DOI:10.1021/jo800080t

(Chemical Equation Presented) The asymmetric synthesis of (2R,3R)-3-methyl-3-hydroxypipecolic acid, a key intermediate in the synthesis of dual MMP-13/aggrecanase inhibitors, is described. The title compound is prepared in seven steps with an overall yield of 41% starting from geraniol. Key steps in the synthesis include Sharpless asymmetric epoxidation, which establishes the chiral centers, and a one-pot oxidative olefin cleavage/reductive amination sequence that closes the piperidine ring.

Full text of DOI:10.1021/jo800080t

available chiral piperidines with appropriate substitution for
simple functional group manipulation to give rise to 1 forced
us to consider methods for stereoselective construction of the
piperidine ring. Of the several methods considered, (1) cycliza-
tion to form bond a through an aldol-type process, (2) ring
closure via metathesis and reduction to establish bond b, or (3)
reductive amination to form bond c, the latter was found to be
most amenable for development of a short enantioselective
synthesis.
A Short Enantioselective Synthesis of
N-Boc-(2R,3R)-3-Methyl-3-Hydroxypipecolic Acid
from Geraniol
Mark C. Noe,* Joel M. Hawkins, Sheri L. Snow, and
Lilli Wolf-Gouveia
Pfizer Global Research and DeVelopment, Eastern Point Road,
Groton, Connecticut 06340
mark.c.noe@pfizer.com
ReceiVed January 15, 2008
The asymmetric synthesis of (2R,3R)-3-methyl-3-hydroxyp-
ipecolic acid, a key intermediate in the synthesis of dual
MMP-13/aggrecanase inhibitors, is described. The title
compound is prepared in seven steps with an overall yield
of 41% starting from geraniol. Key steps in the synthesis
include Sharpless asymmetric epoxidation, which establishes
the chiral centers, and a one-pot oxidative olefin cleavage/
reductive amination sequence that closes the piperidine ring.
Pipecolic acid derivatives are present in a variety of biologi-
cally active compounds, such as the immunosuppresant FK-
5061 and the antitumor antibiotic WF-3161,2 and methods for
their enantioselective synthesis are of considerable interest to
the pharmaceutical industry.3 Functionalized cyclic amino acids
have also been used for the construction of conformationally
constrained peptides and for further elaboration into stere-
ochemically complex natural products, such as (-)-swainso-
nine.4 During the course of our studies on matrix metallopro-
teinase (MMP) inhibitors as therapeutic agents for the treatment
of osteoarthritis and cancer, we desired a short enantioselective
synthesis of N-Boc-(2R,3R)-3-methyl-3-hydroxypipecolic acid
(1). This protected amino acid forms the nucleus for 2, which
was found to be a potent inhibitor of MMP-13, a key mediator
of cartilage-collagen breakdown in osteoarthritis.5 Although
several methods have been reported for the enantioselective
preparation of 3-hydroxypipecolic acid derivatives, asymmetric
methods to prepare simple 3-alkyl-3-hydroxypipecolic acids
have not been reported in the literature.6-10 The lack of readily
The synthesis of 1 began with the known Sharpless asym-
metric epoxidation of geraniol to form the epoxy alcohol 3 in
99% yield and 91% ee (Scheme 1).11 The crude epoxide was
directly converted to its carbamate derivative 4 using benzyl
isocyanate and triethylamine in methylene chloride solution. The
presence of the phenyl chromophore allowed convenient as-
sessment of the enantiomeric purity of the chiral epoxide by
chiral HPLC with UV detection. Base-catalyzed cyclization of
4 to establish one of the C-N bonds of the piperidine ring was
initially attempted using sodium hydride as base in tetrahydro-
furan.12 We found that large-scale reactions (>10 g) required
(8) Knight, D. W.; Lewis, N.; Share, A. C.; Haigh, D. Tetrahedron:
Asymmetry 1993, 4, 625-628.
(9) Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi, G.; Gasparri,
Fava, G.; Belichi Ferrari, M.; Casiraghi, G. Tetrahedron: Asymmetry 1997,
8, 2975-2987.
(10) For other methods of producing 3- and 4-hydroxypipecolic acid,
see: (a) Brooks, C. A.; Comins, D. L. Tetrahedron Lett. 2000, 41, 3551-
3553. (b) Battistini, L.; Zanardi, F.; Rassu, G.; Spanu, P.; Pelosi, G.; Gasparri
Fava, G.; Belicchi Ferrari, M.; Casiraghi, G. Tetrahedron: Asymmetry 1997,
8, 2975-2987. (c) Kumar, P.; Bodas, M. J. Org. Chem. 2005, 70, 360-
363. (d) Liang, N.; Datta, A. J. Org. Chem. 2005, 70, 10182-10185. (e)
Agami, C.; Couty, F.; Mathieu, H. Tetrahedron Lett. 1996, 37, 4001-4002.
(f) Haddad, M.; Larcheveque, M. Tetrahedron Lett. 2001, 42, 5223-5225.
(g) Bodas, M. S.; Kumar, P. Tetrahedron Lett. 2004, 45, 8461-8463. (h)
Horikawa, M.; Busch-Petersen, J.; Corey, E. J. Tetrahedron Lett. 1999, 40,
3843-3846. (i) Kadouri-Puchot, C.; Cornesse, S. Amino Acids 2005, 29,
101-130 and references cited therein.
(1) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto,
T.; Hashimoto, M.; Taga, T. J. Am. Chem. Soc. 1987, 109, 5031-5033.
(2) Kawai, M.; Pottorf, R. S.; Rich, D. H. J. Med. Chem. 1986, 29, 2409-
2411.
(3) Hanessian, S.; M-Smith, G.; Lombart, H.-G.; Lubell, W. D. Tetra-
hedron 1997, 53, 12789.
(4) Ferreira, F.; Greck, C.; Genet, J. P. Bull. Soc. Chim. Fr. 1997, 134,
615-621.
(5) Noe, M. C.; Letavic, M. A.; Hawkins, J. M. Eur. Pat. Appl. EP
1081137 A1, 2001.
(6) Greck, C.; Ferreira, F.; Genet, J. P. Tetrahedron Lett. 1996, 37, 2031-
2034.
(11) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922-
1925.
(7) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1989, 54, 1866-1875.
(12) Roush, W. R.; Adam, M. A. J. Org. Chem. 1985, 50, 3752-3757.
10.1021/jo800080t CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/14/2008
J. Org. Chem. 2008, 73, 3295-3298
3295

SCHEME 1. Synthesis of N-Boc-(2R,3R)-3-Methyl-3-Hydroxypipecolic Acid from Geraniol
SCHEME 2. Intermediates in the Hydrolysis and
Ozonolysis Steps
mediate quench with dimethyl sulfide and subsequent workup,
afforded the bicyclic aminal 7 in good yield. Prolonged stirring
of 7 after the dimethyl sulfide quench resulted in its conversion
to the methoxyaminal 9. The methoxyaminal 9 was found to
be very difficult to reduce using borohydride reagents, and
catalytic hydrogenation using 10% Pd/C under either neutral
or acidic conditions resulted in debenzylation without reduction
of the aminal. Fortunately, the reduction of 7 to piperidine 8
was readily accomplished using sodium triacetoxyborohydride
in methylene chloride at room temperature and could be
performed with concomitant debenzylation using hydrogen and
10% Pd/C. It was subsequently found that oxidative cleavage
of the double bond and reduction of the hemiaminal intermediate
could be performed in high yield in one pot by quenching the
ozonolysis at -78 °C with a solution of sodium borohydride
and sodium acetate in water, thereby obviating the concern of
formation of 9 during the dimethylsulfide quench. Attempts to
effect the transformation of 6 to 7 using OsO4 and sodium
periodate resulted in much lower yields.
an induction period of 1-3 h, during which time very little of
5 is formed and after which cyclization proceeds rapidly. The
induction period observed in this reaction is likely due to the
fact that the reaction mixture is heterogeneous, and the depro-
tonation of the carbamate nitrogen atom of 4 by sodium hydride
is slow. The addition of small amounts of isopropanol to
generate sodium isopropoxide resulted in only a modest
improvement. Concerned about the adverse safety implications
of large-scale exothermic reactions having inductions, we turned
to homogeneous reaction conditions to optimize this step. Thus,
using sodium methoxide as the base in refluxing methanol
resulted in smooth conversion of 4 to 5 and also allowed the
subsequent carbamate hydrolysis to be conducted in situ by the
addition of water and potassium hydroxide without isolation
of 5.
The oxidative cleavage of double bonds in the presence of
unprotected secondary amines is not well precedented due to
the propensity of the amine nitrogen to undergo oxidation itself.
We reasoned that protonation of the amine nitrogen of 6 via
salt formation would protect it from oxidation and facilitate
formation of a bicyclic aminal intermediate (Scheme 2). Ganem
reported a similar ozonolysis-reductive amination sequence for
the synthesis of a chiral piperidine-based hexosaminidase
inhibitor.13 In the event, ozonolysis of 6-HCl at -78 °C in
methanol-methylene chloride solution, followed by an im-
The protection of the piperidine nitrogen as its N-Boc
derivative proceeded uneventfully using di-tert-butyldicarbonate
and DMAP in acetonitrile. Oxidation of the hydroxymethyl
group to the carboxylic acid using sodium chlorite under
catalysis by TEMPO and bleach afforded 1 in good yield.14
In conclusion, we have developed a short enantioselective
synthesis of 1 from geraniol in seven steps with an overall yield
of 41%. This synthesis highlights catalytic asymmetric epoxi-
dation, regioselective delivery of nitrogen to the epoxide, and
a one-pot oxidative alkene cleavage-intramolecular reductive
amination as key steps.
Experimental Section
(2R,3R)-Epoxygeraniol N-Benzylcarbamate (4). A mixture of
21.2 g of crushed 4 Å molecular sieves and 588 mL of methylene
chloride at -10 °C was treated with (-)-diethyl tartrate (4.9 mL,
5.9 g, 29 mmol), titanium isopropoxide (5.6 mL, 5.4 g, 19 mmol),
and tert-butylhydroperoxide (74 mL, 5.5 M in nonane, 0.41 mol).
After stirring for 30 min, the mixture was cooled to -30 °C, and
a solution of geraniol (50 g, 0.32 mol) in 50 mL of methylene
chloride was added dropwise. The mixture was slowly warmed to
-10 °C over 1 h. The mixture was diluted with 240 mL of water,
warmed to 23 °C, and was treated with 30 mL of 30% aqueous
NaOH. After stirring for 1 h, the mixture was filtered through a
(14) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D.; Grabowski, E.
J. J.; Reider, P. J. J. Org. Chem. 1999, 64, 2564-2566.
(13) Bernotas, R.; Ganem, B. J. Org. Chem. 1987, 52, 312-316.
3296 J. Org. Chem., Vol. 73, No. 8, 2008

pad of Celite, and the filtrate was transferred to a separatory
funnel. The organic phase was separated, and the aqueous phase
was extracted twice with methylene chloride. The combined
organic phases were dried over MgSO4, filtered, and concentrated
in vacuo. The crude (2R,3R)-epoxygeraniol thus obtained was
dissolved in 1 L of methylene chloride and was treated with
triethylamine (90 mL, 66 g, 0.65 mol), benzyl isocyanate
(42 mL, 46 g, 0.34 mol), and a few crystals of N,N-dimethylami-
nopyridine (DMAP). After stirring for 24 h at room temperature,
an additional 5 mL of benzyl isocyanate was added, and the mixture
was stirred for an additional 24 h. The mixture was washed
with saturated aqueous NH4Cl and 1 M HCl, and the aqueous phase
was extracted twice with methylene chloride. The combined
organic phases were dried over Na2SO4, filtered, and concentrated
in vacuo. The residue was taken up in 750 mL of hot hexanes, and
the supernatant was decanted and diluted with an additional 400
mL of hexanes. The mixture was cooled to 4 °C, allowed to
crystallize, and was stored at - 20 °C for 3 h. Filtration of the
solids afforded 88 g (94%) of (2R,3R)-epoxygeraniol N-benzyl-
carbamate (4) as a light yellow solid with 91% ee as determined
by chiral HPLC analysis (Chiralcel OJ column, 5 cm, 10% i-PrOH/
times with methylene chloride. The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentrated
in vacuo, affording 75 g (100%) of N-benzyl-(2S,3R)-3-methyl-3-
hydroxypiperidine-2-methanol (8) as a light yellow solid. An
analytically pure sample was obtained by recrystallization from
hot isopropyl ether: RD23 +14° [c ) 0.60, MeOH]; mp 88-91 °C;
1
IR (thin film) 3388, 2928, 1451, 1370, 1025, 752, 700 cm-1; H
NMR (500 MHz, CDCl3) δ 7.34-7.29 (m, 4H), 7.27 (m, 1H), 3.91
(m, 3H), 3.69 (dd, 1H, J ) 5.0, 11 Hz), 3.2 (br s, 2H), 2.73 (app
t, 1H, J ) 6.0 Hz), 3.56-2.50 (m, 2H), 1.89 (m, 1H), 1.59-1.52
(m, 2H), 1.43 (m, 1H), 1.22 (s, 3H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 139.7, 129.0, 128.7, 127.4, 70.3, 69.9,
59.9, 58.1, 45.2, 34.6, 26.2, 20.0 ppm; HRMS calcd for [C14H21-
NO2 + H]+ 236.1650, observed 236.1664. Anal. Calcd for C14H21-
NO2: C, 71.46; H, 8.99; N, 5.95. Observed: C, 71.07; H, 9.26; N,
5.93.
(2S,3R)-3-Methyl-3-hydroxypiperidine-2-methanol (10). A
solution of N-benzyl-(2S,3R)-3-methyl-3-hydroxypiperidine-2-
methanol (8) (50 g, 0.20 mol) in 630 mL of methanol was char-
ged with a mixture of 10% palladium on carbon (5 g) and ethanol
(20 mL) and was shaken under 50 psi of hydrogen for 16 h. The
mixture was filtered and concentrated in vacuo to an oil. Residual
solvent was removed azeotropically with toluene, and the residue
was dried in vacuo, affording 31 g (100%) of (2S,3R)-3-methyl-
3-hydroxypiperidine-2-methanol (10) as a colorless oil that subse-
hexanes, λ ) 214 nM, 3.45 min (major), 4.37 min (minor)); RD
23
+15° [c ) 0.61, MeOH]; mp 49.4-49.6 °C; IR (thin film) 3331,
2967, 2913, 2855, 1685, 1542, 1450, 1254, 1145, 1043, 695 cm-1
;
1H NMR (500 MHz, CDCl3) δ 7.37-7.28 (m, 5H), 5.09 (br t, 1H,
J ) 7.5 Hz), 4.40 (m, 3H), 4.05 (dd, 1H, J ) 7.0, 12 Hz), 3.02
(dd, 1H, J ) 4.5, 7.0 Hz), 2.09 (m, 2H), 1.70 (s, 3H), 1.68 (m,
1H), 1.62 (s, 3H), 1.50 (m, 1H), 1.33 (s, 3H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 156.5, 138.6, 132.4, 128.9, 127.8 (2C), 123.5,
64.2, 60.8, 60.3, 45.4, 38.6, 25.9, 23.9, 17.9, 17.1 ppm; HRMS
calcd for C18H25NO3 303.1834, observed 303.1827. Anal. Calcd
for C18H25NO3: C, 71.26; H, 8.31; N, 4.62. Observed: C, 71.23;
H, 8.60; N, 4.62.
quently crystallized on standing: RD -43° [c ) 0.44, MeOH];
23
IR (thin film) 3300, 2933, 2857, 1440, 1370, 1322, 1192, 1121,
1
1067, 1026, 1004, 989, 927, 898, 829, 753, 586, 532 cm-1; H
NMR (500 MHz, CD3OD) δ 4.89 (dd, 1H, J ) 4.2, 10.8 Hz), 3.43
(dd, 1H, J ) 8.7, 10.4 Hz), 3.0 (d, 1H, J ) 12 Hz), 2.59-2.54 (m,
2H), 1.73-1.71 (m, 1H), 1.65-1.62 (m, 1H), 1.57-1.49 (m, 2H),
1.16 (s, 3H) ppm; 13C NMR (CD3OD, 125 MHz) δ 69.6, 66.6,
61.2, 45.7, 40.5, 23.9, 19.7 ppm; Anal. Calcd for C7H15NO2 +
1/2H2O: C, 54.52; H, 10.46; N, 9.08. Observed: C, 55.21; H, 10.94;
N, 9.00.
(2S,3R)-2-Benzylamino-3,7-dimethyl-oct-6-ene-1,3-diol hy-
drochloride (6). A mixture of (2R,3R)-epoxygeraniol N-benzyl-
carbamate (4) (100 g, 0.33 mol) and sodium methoxide (90 g, 1.7
mol) in 1.65 L of methanol was refluxed for 1.5 h. After cooling
to 23 °C, a solution of potassium hydroxide (320 g, 5.7 mol) in
850 mL of water was added, and the resulting mixture was stirred
at reflux for 2 days. The mixture was cooled to 23 °C, concentrated
in vacuo, and the aqueous residue was extracted three times
with 500 mL of ether. The combined organic layers were dried
over magnesium sulfate, filtered, and cooled to 0 °C. The solution
was treated with HCl gas, at which point a crystalline solid
precipitated, affording 78.5 g (76% yield) of (2S,3R)-2-benzy-
N-Boc-(2S,3R)-3-Methyl-3-hydroxypiperidine-2-methanol (11).
To a solution of (2S,3R)-3-methyl-3-hydroxypiperidine-2-methanol
(10) (1 g, 6.9 mmol) in 34 mL of acetonitrile at room temperature
was added di-tert-butyldicarbonate (1.6 g, 7.5 mmol) in one portion.
The mixture was stirred for 24 h, diluted with water, and the mixture
was extracted with three portions of ethyl acetate. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
in vacuo, affording 1.1 g (68%) of N-Boc-(2S,3R)-3-methyl-3-
hydroxypiperidine-2-methanol (11) as a colorless oil that crystallized
on standing: RD +30° [c ) 0.57, MeOH]; mp 108 °C; FTIR
23
lamino-3,7-dimethyl-oct-6-ene-1,3-diol hydrochloride (6): RD
3409, 2973, 2931, 1663, 1425, 1366, 1151 cm-1; H NMR (500
1
23
-1.2° [c ) 0.55, MeOH]; mp 142 °C; IR (thin film) 3315, 2970,
2928, 1578, 1454, 1384, 1122, 1044, 751, 700, 536 cm-1; 1H NMR
(500 MHz, CD3OD) δ 7.58-7.56 (m, 2H), 7.50-7.46 (m, 3H),
5.14-5.10 (m, 1H), 4.49 (d, 1H, J ) 13 Hz), 4.38 (d, 1H, J ) 13
Hz), 3.93-3.83 (m, 2H), 3.06-3.04 (m, 1H), 2.16-2.09 (m, 1H),
2.06-2.0 (m, 1H), 1.68 (s, 3H), 1.63 (s, 3H), 1.58-1.39 (m, 2H),
1.23 (s, 3H) ppm; 13C NMR (CD3OD, 125 MHz) δ 131.6, 131.1,
130.4, 129.5, 129.0, 123.9, 70.9, 67.3, 57.8, 51.2, 36.4, 24.7, 23.5,
21.6, 16.5 ppm. Anal. Calcd for C17H28ClNO2: C, 65.05; H, 8.99;
N, 4.46; Cl, 11.30. Observed: C, 64.65; H, 9.02; N, 4.60%; Cl,
11.24.
N-Benzyl-(2S,3R)-3-Methyl-3-hydroxypiperidine-2-metha-
nol (8). A solution of (2S,3R)-2-benzylamino-3,7-dimethyl-oct-6-
ene-1,3-diol hydrochloride (6) (100 g, 319 mmol) in 800 mL of
methanol was diluted with 800 mL of methylene chloride and
cooled to -78 °C. Ozone was added through a sparge tube until a
light blue color persisted. After stirring for 5 min, the mixture
was purged with nitrogen until colorless, and a solution of sodium
borohydride (60 g, 1.57 mol) and sodium acetate (52.3 g, 650 mmol)
in 1.1 L of water was added over 5 min. The mixture was warmed
to room temperature and was stirred for 12 h. The mixture
was treated with 10 g of solid sodium hydroxide, extracted three
MHz, CDCl3) δ 4.2 (br s, 1H), 4.0 (br s, 1H), 3.75-3.70 (m, 2H),
3.9-3.8 (m, 1H), 2.1-2.2 (m, 1H), 1.9-1.8 (m, 1H), 1.54-1.53
(m, 2H), 1.49 (s, 9H), 1.21 (s, 3H) ppm; 13C NMR (CDCl3, 125
MHz) δ 158, 80.5, 69.1, 63, 59.6, 39, 33.2, 28.6, 27.3, 20.8 ppm;
Anal. Calcd for C12H23NO4: C, 58.75; H, 9.45; N, 5.71. Ob-
served: C, 59.09; H, 9.91; N, 5.72.
N-Boc-(2R,3R)-3-Methyl-3-hydroxypiperidine-2-carboxylic acid
(1). To a mixture of N-Boc-(2S,3R)-3-methyl-3-hydroxypipe-
ridine-2-methanol (11) (1.1 g, 4.4 mmol), acetonitrile (22 mL), and
pH 7 phosphate buffer (0.5 M, 16.9 mL) were added NaClO2 (795
mg, 8.8 mmol) and 2,2,6,6-tetramethylpiperidinyloxy free radical
(TEMPO) (47 mg, 0.3 mmol). An aqueous solution of NaOCl (4%,
3 mL) was added dropwise, and the mixture was heated to
40 °C for 6 h. After cooling to 23 °C, the mixture was treated with
1 N NaOH and ca. 1 g of Na2SO3. The aqueous mixture was poured
into ether and was extracted once with 1 M NaOH. The aqueous
layer was carefully acidified with 6 M HCl and was extracted
three times with ethyl acetate. The combined organic layers were
dried with Na2SO4, filtered, and concentrated in vacuo, affording
955 mg (84%) of N-Boc-(2R,3R)-3-methyl-3-hydroxypiperidine-
2-carboxylic acid (1) as a colorless oil that crystallized on
standing: RD +20° [c ) 0.35, MeOH]; mp 143 °C; FTIR
23
J. Org. Chem, Vol. 73, No. 8, 2008 3297

3425 (br s), 2977, 2935, 1716, 1670, 1394, 1368, 1282, 1169,
1145,969 cm-1; 1H NMR (500 MHz, DMSO) δ 4.7-4.5 (m, 2H),
3.97 (m, 1H), 3.12 (m, 1H), 1.8-1.59 (m, 3H), 1.47 (s, 9H), 1.42
(s, 3H) ppm; 1H NMR at 60 °C (500 MHz, DMSO) δ 4.52 (s, 1H),
4.43 (br s, 1H), 3.81 (d, 1H, J ) 8.8 Hz), 3.16 (m, 1H), 1.87-1.78
(m, 1H), 1.58-1.47 (m, 2H), 1.39 (s, 9H), 1.21 (s, 3H) ppm; 13C
NMR (DMSO, 125 MHz) δ 173.3, 156.0, 155.7, 79.5, 67.3, 65.3,
64.0, 40.9, 33.4, 29.0, 28.9, 28.7, 20.0, 19.7 ppm. Anal. Calcd for
C12H21NO5: C, 55.58; H, 8.l6; N, 5.40. Observed: C, 55.72; H,
8.39; N, 5.44.
Supporting Information Available: Proton and carbon NMR
spectra of reported compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800080T
3298 J. Org. Chem., Vol. 73, No. 8, 2008