Enantioselective synthesis of trans-4-methylpipecolic acid

Article abstract of DOI:10.1021/jo071220z

(Chemical Equation Presented) An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).

Full text of DOI:10.1021/jo071220z

Enantioselective Synthesis of trans-4-Methylpipecolic Acid
Carlos Alegret, Ferran Santacana, and Antoni Riera*
Unitat de Recerca en S´ıntesi Asime`trica (URSA-PCB), Institute for Biomedical Research (IRB) and
Departament de Qu´ımica Orga`nica, UniVersitat de Barcelona, Parc Cient´ıfic de Barcelona c/Josep
Samitier, 1-5, 08028 Barcelona, Spain
ariera@pcb.ub.es
ReceiVed June 13, 2007
An asymmetric synthesis for the preparation of both enantiomers of trans-methylpipecolic acids is
described. It is based on Sharpless epoxidation as a chirality source, regioselective ring opening with
allylamine, and ring-closing metathesis to construct the piperidine ring. The stereogenic center at C-4 is
set by stereoselective hydrogenation that is directed by the alcohol functionality of an intermediate and
proceeds with good diastereomeric control (trans/cis 16/1). Crystallization of the Boc-protected amino
acid afforded the target products with excellent chemical (98% de) and enantiomeric purity (99% ee).
Introduction
structure. The largest subgroup of pipecolic acid derivatives is
the 4-substituted class of compounds. Biologically active
compounds such as Palinavir,6 a potent HIV inhibitor, and some
components of the antibiotic Virginamycin S7 contain 4-hy-
droxypipecolic acids. Although lesser known than 4-hydroxy-
pipecolic acids, trans-4-methylpipecolic acid 1 is a key com-
ponent in the structure of antitumor agents8a as well as of
Cyclic R-amino acids bearing a piperidine ring are present
in many biologically important compounds.1 Pipecolic acids,2
also called homoprolines, are non-proteogenic amino acids found
as metabolites in several biological systems (e.g., plants, fungi,
and human physiological fluids) and often exhibit interesting
pharmacological activities. The immunosuppressors Rapamycin3
and FK506,4 and the antitumor antibiotic Sandramycin,5 are
examples of compounds with a pipecolic acid fragment in their
(4) (a) Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am.
Chem. Soc. 1993, 115, 7906. (b) Ireland, R. E.; Gleason, J. L.; Gegnas, L.
D.; Highsmith, T. K. A. J. Org. Chem. 1996, 61, 6856.
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Winters, A. L.; Asano, N.; Fleet, J. W. Tetrahedron: Asymmetry 1998, 9,
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(c) Ninomiya, I.; Kiguchi, T.; Naito, T. Alkaloids 1998, 50, 317. (d) Lamarre,
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Antimicrob. Agents Chemother. 1997, 41, 965. (e) Dragovich, P. S.; Barker,
J. E.; French, J.; Imbacuan, 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.
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P.; Singh, K.; Ve´niza, C. J. Antibiot. 1983, 36, 351.
(2) For recent reviews about pipecolic acids, see: (a) Kadouri-Puchot,
C.; Comesse, S. Amino Acids 2005, 29, 101-130. (b) Couty, F. Amino
Acids 1999, 16, 297-320 and references cited therein.
(3) (a) Smith, A. B., III; Adams, C. M. Acc. Chem. Res. 2004, 37, 365.
(b) Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L.; Leahy,
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Lamarre, D.; Croteau, G.; Bourgon, L.; Thibeault, D.; Wardrop, E.; Clouette,
C.; Vaillancourt, M.; Cohen. E.; Pargellis, C.; Yoakim, C.; Anderson, P.
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1971, 28, 2687.
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10.1021/jo071220z CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/06/2007
7688
J. Org. Chem. 2007, 72, 7688-7692

EnantioselectiVe Synthesis of trans-4-Methylpipecolic Acid
FIGURE 1. Structures of Argatroban and trans-(2R,4R)-4-methylpipe-
colic acid.
thrombin inhibitors such as (2R,4R)-MQPA and Argatroban
(Figure 1).8b-d Few syntheses of this amino acid have been
described to date,9,10 the majority of which are racemic, since
the optical isomers are normally obtained through chiral
resolution. To the best of our knowledge, only three asymmetric
syntheses have been described to date, all of which have low
stereoselectivity.10 Herein we describe a practical asymmetric
synthesis of both enantiomers of N-Boc-trans-4-methylpipecolic
acid which we developed working on a project devoted to the
synthesis of unnatural amino acids and biologically active amino
alcohols from unsaturated epoxy alcohols.11 The key steps of
our synthesis comprise Sharpless epoxidation,12 ring-closing
metathesis (RCM),13 and diastereoselective hydrogenation.
FIGURE 2. Retrosynthetic analysis of 4-methylpipecolic acids.
SCHEME 1. Synthesis of Epoxy Alcohol 2
Results and Discussion
compound and its enantiomer, (+)-2, were prepared by Sharp-
less asymmetric epoxidation of allyl alcohol 3, which is readily
available from propargyl alcohol and 3-bromo-2-methylpropene
by a sequence of coupling and hydride reduction.14 This reaction
sequence was performed in multigram scale (up to 50 g) in 58%
overall yield (three steps), and the optical purity of the epoxide
was determined to be 93% ee.
We based our approach on the retrosynthetic analysis shown
in Figure 2. We envisaged that the stereogenic center at C-4
could be conveniently set by diastereoselective hydrogenation
of a dehydropipecolic acid derivative directed by the 2-sub-
stituent at the same face, and that the ring could be assembled
by RCM of the diene readily obtained by regio- and stereose-
lective ring opening of epoxy alcohol 2. The chirality of the
stereogenic center at C-2 would be set by Sharpless asymmetric
epoxidation.
Nucleophilic ring opening at C-3 of epoxy alcohol 2 with
allylamine, followed by protection of the secondary amine with
Boc2O to avoid unwanted side reactions during oxidation or
RCM, was next studied. Using standard Crotti conditions15
(LiClO4 in ACN), N-Boc-amine 5 was obtained in 68% yield
with modest regioselectivity (C-3/C-2 6/4), clearly lower than
that obtained for related compounds,11h due to the â-methyl
substitution. Sharpless conditions16 (Ti(OiPr)4 in DCM) provided
slightly higher selectivity but lower yield (C-3/C-2 7/3, 56%
yield). Using LiClO4 without any solvent was the most practical
procedure for large-scale reactions. Since it was not easy to
separate the regioisomers 5a and 5b by column chromatography,
the mixture was used directly in subsequent chemistry, and the
undesired product was eventually eliminated (Scheme 2). As
in the synthesis of other unsaturated amino acids,11h,17 the diol
fragment in 5a was oxidatively cleaved to the corresponding
acid by the standard sequence of NaIO4 treatment, to give
aldehyde 6 in quantitative yield, which was then oxidized with
sodium chlorite.18 At this point, the undesired 2-amino-1,3-diol
The synthesis thus began with the preparation of the enan-
tiomerically enriched epoxy alcohol (-)-2 (Scheme 1). This
(9) (a) Caddy, D. E.; Utley, J. H. P. J. Chem. Soc., Perkin Trans. 2 1973,
1258. (b) Schuman, R. T.; Ornstein, P. L.; Paschal, J. W.; Gesellchen, P.
D. J. Org. Chem. 1990, 55, 738. (c) Nazih, A.; Schneider, M. R.; Mann, A.
Synlett 1998, 1337. (d) Hu, L. Y.; Ryder, T. R.; Nikam, S. S.; Millerman,
E.; Szoke, B. G.; Rafferty, M. F. Bioorg. Med. Chem. Lett 1999, 9, 1121.
(e) Cossy, J.; Belotti, D. Tetrahedron Lett. 2001, 42, 2119. (f) Tamura, K.;
Inoue, K.; Sato, H. Jpn. Kokai Tokkyo Koho JP2003160560, 2003, CAN
138:401611.
(10) (a) Bailey, P. D.; Wilson, R. D.; Brown, G. R. J. Chem. Soc., Perkin
Trans. 1 1991, 1337. (b) Bailey, P. D.; Brown, G. R.; Korber, F.; Reed,
A.; Wilson, R. D. Tetrahedron: Asymmetry 1991, 2, 1263. (c) Agami, C.;
Bisaro, F.; Comesse, S.; Guesne, S.; Kadouri-Puchot, C.; Morgentin, R.
Eur. J. Org. Chem. 2001, 2385.
(11) (a) Alegret, C.; Benet-Buchholz, J.; Riera, T. Org. Lett. 2006, 8,
3069. (b) Alonso, M.; Riera, A. Tetrahedron: Asymmetry 2005, 16, 3908.
(c) Alonso, M.; Santacana, F.; Rafecas, L.; Riera, A. Org. Process Res.
DeV. 2005, 9, 690. (d) Mart´ın, R.; Murruzzu, C.; Perica`s, M. A.; Riera, A.
J. Org. Chem. 2005, 70, 2325. (e) Ginesta, X.; Perica`s, M. A.; Riera, A.
Synth. Commun. 2005, 35, 289. (f) Ginesta, X.; Pasto´, M.; Perica`s, M. A.;
Riera, A. Org. Lett. 2003, 5, 3001. (g) Mart´ın, R.; Alco´n, M.; Perica`s, M.
A.; Riera, A. J. Org. Chem. 2002, 67, 6896. (h) Ginesta, X.; Perica`s, M.
A.; Riera, A. Tetrahedron Lett. 2002, 43, 779.
(14) (a) Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron:
Asymmetry 1999, 10, 4639. (b) Zhang, Y.; Wu, G. Z.; Agnel, G.; Negishi,
E. I. J. Am. Chem. Soc. 1990, 112, 8590. (c) Itoh, Y.; Jang, S.; Ohba, S.;
Mikami, K. Chem. Lett. 2004, 33, 776.
(12) (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765. (b) Katsuki, T.;
Mart´ın, V. S. Org. React. 1996, 48, 1-299.
(13) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (c) Ivin, K. J.
J. Mol. Catal. A: Chem. 1998, 133, 1. (d) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036. (e) Grubbs, R. H.; Miller, S. J.; Fu,
G. C. Acc. Chem. Res. 1995, 28, 446.
(15) (a) Chini, M.; Crotti, P.; Macchia, F. J. Org. Chem. 1991, 56, 5939.
(b) Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.; Macchia,
F.; Pineschi, M. J. J. Org. Chem. 1993, 58, 1221.
(16) (a) Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557-
1560. (b) Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Perica`s, M.
A.; Riera, A. Tetrahedron Lett. 1991, 32, 6931.
(17) Alco´n, M.; Moyano, A.; Perica`s, M. A.; Riera, A. Tetrahedron:
Asymmetry 1999, 10, 4639.
J. Org. Chem, Vol. 72, No. 20, 2007 7689

Alegret et al.
SCHEME 2. Synthesis of Methyl Ester 9 from Epoxy
Alcohol 2
FIGURE 3. Structures of olefin metathesis catalysts.
At this point, we decided to adapt our approach to perform
the hydrogenation with other functionalities. We reasoned that
a hydroxyl group would coordinate to the metal catalyst better
than would the ester, thus providing greater trans selectivity.
Accordingly, compound 5a (with 5b as impurity) was subjected
to RCM to give the unsaturated piperidino diol 10a. In this case,
it was necessary to use the second generation Grubbs catalyst
(Scheme 3) since, when using the conventional catalyst, higher
loadings (20 mol %) and longer reaction times (up to 2 days)
were needed for complete conversion. Ruthenium byproducts
were removed by first treating the reaction mixture with DMSO,
followed by flash chromatography.20 In this case, the regioiso-
mer 5b also reacted to give a seven-membered ring, 10b,21
which could not be separated from the product. The resulting
mixture was hydrogenated with PtO2 in EtOAc to afford 11a
with good selectivity (trans/cis 10/1). This compound was then
oxidatively cleaved with NaIO4/KMnO4 to give the desired
N-Boc-methyl pipecolic acid 12. To facilitate the purification
and determination of the enantiomeric ratio, the acid was
derivatized to methyl ester 9, which was obtained in a
remarkable 42% overall yield from 5a (based on the amount of
5a present in the starting mixture) in four steps (Scheme 3).
SCHEME 3. Synthesis of Methyl Ester 9a from Aminodiol
5a
Although the stereoselectivity of the hydrogenation was quite
satisfactory, the RCM, which required use of the second
generation Grubbs catalyst, remained a drawback of our strategy.
Moreover, although the sequence gave an excellent overall yield,
all intermediates until the Boc-amino acid 12 were contaminated
with the byproducts derived from 5b. We therefore investigated
a third route: we reasoned that the diastereoselectivity could
be maintained or even improved with a smaller group with the
same coordinating properties at the C-2 position of the cyclic
olefin. Accordingly, the mixture of diols 5a and 5b was
oxidatively cleaved with NaIO4, and the intermediate aldehyde
6 was reduced with sodium borohydride to give the alcohol 13
in near quantitative yield. The unwanted regioisomer 5b was
easily separated by column chromatography. This sequence
could be easily scaled up. Starting from 33 g of crude epoxy
alcohol (-)-2 obtained by Sharpless epoxidation, all steps,
except the last one, were performed without chromatographic
purifications yielding a remarkable 46% in four steps (27 g) of
pure (-)-13. Then alcohol (-)-13 was submitted to RCM.
Gratifyingly, on this substrate, the reaction proceeded in
excellent yield using either the first generation Grubbs catalyst
product (5b), which did not react under the oxidative conditions,
was easily removed by simple extraction of the carboxylate salt
into aqueous base solution. After acidification, the acid was
protected with MeI to give methyl ester 7 in excellent yield
and without any loss of enantiomeric purity (monitored by
HPLC, Chiracel-AD).
Compound 7 was subjected to RCM using the first generation
Grubbs catalyst (4 mol %) to give 8 in nearly quantitative yield
(Figure 3).
With this cyclic olefin in hand, we tested several hydrogena-
tion conditions to obtain trans selectivity. Using PtO2 as a
catalyst, compound 9 was obtained in 90% yield but with
disappointingly low selectivity (trans/cis 1.5/1), thus indicating
that chelation of the methoxycarbonyl with the catalyst had not
occurred. Unfortunately, similar reactions employing various
transition metal complexes usually used in directed hydrogena-
tions ([Ph3P]3RhCl, [Rh(NBD)(Diphos-4)]‚BF4, or [Ir(COD)-
(Pyr)]‚PF6 in EtOAc, DCM or MeOH)19 only resulted in poor
yields and selectivities at moderate hydrogen pressures.
(20) Ahn, Y. M.; Yang, K.; Georg, G. I. Org. Lett. 2001, 3, 1411.
(21) Structures of compounds 10b and 11b are:
(18) (a) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron 1981,
37, 2091. (b) Dinh, T. Q.; Du, X.; Smith, C. D.; Armstrong, R. W. J. Org.
Chem. 1997, 62, 6773.
(19) For a review in the use of these catalysts, see: Brown, J. M. Angew.
Chem., Int. Ed. Engl. 1987, 26, 190.
.
7690 J. Org. Chem., Vol. 72, No. 20, 2007

EnantioselectiVe Synthesis of trans-4-Methylpipecolic Acid
TABLE 1. Hydrogenation of 14 to 15
Experimental Section
pressure time conva
(2R,3R)-N-Allyl-N-tert-butoxycarbonyl-3-amino-5-methyl-5-
hexen-1,2-diol (5a). A mixture of allylamine (85.5 mL, 1.28 mol),
epoxy alcohol (-)-2 (33.0 g, 0.257 mol), and LiClO4 (54.8 g, 0.515
mol) was warmed to 40 °C and stirred for 16 h. Water (60 mL)
was then added, and the resulting solution was extracted with DCM
(4 × 100 mL), dried over MgSO4, and concentrated in vacuo to
yield a brown oil. The oil was solvated in MeOH (800 mL), and
NaHCO3 (55.8 g, 0.664 mol) and Boc2O (72.5 g, 0.332 mol) were
added at 60 °C under stirring. After 16 h, the reaction mixture was
filtered through Celite, washed with Et2O, and the solvent was
evaporated, yielding 69 g of an oil containing (2R,3R)-5a, which
was used in the next step without purification. 5a: IR (film) νmax
3416, 2976, 2931, 1692, 1665 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.45 (s, 9H), 1.73 (s, 3H), 2.42 (dd, J ) 11.7, 15.2 Hz, 1H), 2.59
(d, J ) 15.5 Hz, 1H), 3.24 (br s, 2H), 3.56-3.63 (m, 3H), 3.67 (d,
J ) 6.0 Hz, 2H), 4.01 (m, 1H), 4.72 (s, 1H), 4.81 (s, 1H), 5.08 (d,
J ) 10.2 Hz, 1H), 5.12 (d, J ) 17.3 Hz, 1H), 5.73 (tdd, J ) 6.3,
10.2, 16.6 Hz, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 22.3
(CH3), 28.3(CH3), 35.8 (CH2), 47.8 (CH2), 55.9 (CH), 63.1 (CH2),
73.3 (CH), 80.8 (C), 112.3 (CH2), 116.9 (CH2), 135.1 (CH), 142.6
(C), 157.2 (C) ppm; MS (ESI+) m/z 286 [(M + H)+, 33%], 230
[(M - 55)+, 100%]; HRMS (ESI+) calcd for C15H27NO4Na
308.1832, found 308.1832.
entry
catalyst (%)
Pd/C (10)
PtO2 (10)
PtO2 (10)
PtO2 (10)
PtO2 (10)
PtO2 (2)
PtO2 (2)
(bar)
(h)
(%) trans/cisa
1
2
3
4
5
6
7
8
1
1
2
4
40
3
22
1
1
1
1
100
100
100
100
98
4/1
7/1
8/1
9/1
9/1
13/1
16/1
8/1
16
8
100
93
4
Rh(NBD)(Diphos-4)BF4 (7)
40
24
100
a Measured by GC.
(4 mol %, up to 88% yield) or the industrially available Neolyst
M122 catalyst (4 mol %, 74% yield).
Hydrogenation of the cyclic olefin 14 was carefully studied.
Pd/C gave 15 in good yield, but diastereoselectivities were
modest (Table 1, entry 1). PtO2 in EtOAc gave better diaste-
reoselectivities (7/1 trans/cis working at 1 bar of hydrogen
pressure). Monitoring of the reaction by GC allowed us to detect
the formation of one intermediate that was finally converted to
the final product. We thought that this intermediate could be
formed by isomerization of the double bond to the enamine
which was subsequently hydrogenated. Working at 4 bar with
lower catalyst loadings (2 mol %), the stereoselectivity increased
to 16/1 trans/cis. Further increasing the pressure and the use of
a homogeneous catalyst did not improve the results. Wilkinson
catalyst gave no selectivity, whereas Rh(NBD)(Diphos-4)BF4
afforded 15 in a 8/1 diastereomeric ratio.
(2R)-N-Allyl-N-tert-butoxycarbonyl-2-amino-4-methyl-4-penten-
1-ol [(-)-13]. To a solution of a mixture of (2R,3R)-5a/5b (62 g,
as described above) in 1:3 THF/H2O (700 mL) was added under
stirring NaIO4 (70 g, 327 mmol). After 2 h at rt (TLC monitoring),
H2O (200 mL) and EtOAc (80 mL) were added. The aqueous layer
was extracted with EtOAc (3 × 100 mL). The combined organic
layers were dried over MgSO4 and concentrated in vacuo. The crude
product (+)-(2R)-N-allyl-N-tert-butoxycarbonyl-2-amino-4-methyl-
4-pentenaldehyde ((+)-6) was solvated in MeOH (350 mL) at 0
°C, and NaBH4 (8.3 g, 218 mmol) was added. The reaction was
stirred for 30 min (TLC monitoring), and then 1 M aq NaH2PO4
(300 mL) and toluene (60 mL) were added. The aqueous layer was
extracted with toluene (3 × 50 mL), and the combined organic
layers were concentrated in vacuo. The crude product was purified
by flash chromatography to yield the alcohol (-)-13 (27 g, 46% in
four steps from epoxide (-)-2) as a colorless oil: [R]D ) -15.1 (c
1.0, CHCl3); IR (film) νmax 3446, 2976, 2931, 1693, 1670, 1171
Alcohol 15 was then oxidized with NaClO2 and catalytic
amounts of Tempo/NaClO23 to give the protected N-Boc-
pipecolic acid (+)-12, which after crystallization in hexane
showed a 99% enantiomeric purity (HPLC of the methyl ester
derivative 9, Chiracel-AD) and 99/1 trans/cis diastereomeric
ratio. If desired, acid hydrolysis of the carbamate can give trans-
4-methylpipecolic acid 1 in good yield (Scheme 4).
In summary, we have developed a new and practical
asymmetric synthesis for the preparation of both enantiomers
of trans-methylpipecolic acids (available using ethyl D- or
L-tartrate in the Sharpless epoxidation). Our approach is based
on Sharpless epoxidation, regioselective ring opening with
allylamine, and RCM to construct the piperidine ring. The
stereogenic center at C-4 is set by stereoselective hydrogenation
that is directed by the alcohol functionality of an intermediate
and proceeds with excellent diastereomeric control (trans/cis
16/1). Crystallization of the final Boc-protected pipecolic acid
afforded the target products with excellent chemical (98% de)
and enantiomeric purity (99% ee).
1
cm-1; H NMR (CDCl3, 400 MHz) δ 1.46 (s, 9H), 1.76 (s, 3H),
2.12-2.46 (m, 2H), 2.82 (br s, 1H), 3.56-3.81 (m, 4H), 4.00-
4.12 (m, 1H), 4.74 (s, 1H), 4.80 (s, 1H), 5.10-5.24 (m, 2H), 5.76-
6.00 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 22.5 (CH3),
28.6 (CH3), 37.3 (CH2), 48.8 (CH2), 57.2 (CH), 65.2 (CH2), 80.3
(C), 113.3 (CH2), 116.4 (CH2), 135.9 (CH), 142.4 (C), 158.2 (C)
ppm; MS (CI+) m/z 256 [(M + H)+, 72%], 200 [(M - 55)+,
100%]; HRMS (ESI+) calcd for C14H25NO3Na 278.1727, found
278.1729.
N-tert-Butoxycarbonyl-(6R)-1,2,3,6-tetrahydro-4-methylpyri-
din-2-yl)methanol [(-)-14]. To a stirring solution of diene (-)-
13 (7.00 g, 27.4 mmol) in dry DCM (3000 mL) at room temperature
SCHEME 4. Synthesis of trans-4-Methylpipecolic Acid 1
J. Org. Chem, Vol. 72, No. 20, 2007 7691

Alegret et al.
was added a solution of first generation Grubbs catalyst (0.900 g,
4 mol %) in dry DCM (200 mL). After 16 h, DMSO (3.6 mL, 50.5
mmol, 50 catalytic equiv) was added, and the reaction mixture was
stirred for 16 h. The crude product was concentrated in vacuo and
chromatographed to afford (-)-14 (4.9 g, 79%) as a colorless oil:
[R]D ) -6.0 (c 1.4, CHCl3); IR (film) νmax 3440, 2975, 2931, 1697,
mL) was added, and the pH was adjusted to 8.0 with 1 M NaOH.
The reaction was quenched by pouring into cold (0 °C) aq Na2SO3
(7.6 g in 14 mL of H2O) and then stirred for 0.5 h at rt. The mixture
was washed with EtOAc (3 × 50 mL), acidified with 1 M aq HCl
to pH 3 to 4, and extracted with EtOAc (3 × 50 mL). The combined
organic layers were dried over MgSO4 and concentrated in vacuo
to give carboxylic acid (+)-12 (5.3 g, 63%) as a white solid. This
solid can be crystallized from hot hexane, yielding pure (+)-12
(99% ee and 98% dr): [R]D ) +44.0 (c 1.0, CHCl3); mp ) 109.8
1
1160 cm-1; H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 1.71 (s,
3H), 1.85 (d, J ) 17.2 Hz, 1H), 2.35 (dd, J ) 2.3, 17.4 Hz, 1H),
3.48-3.66 (m, 3H), 4.05-4.23 (m, 1H), 4.41-4.54 (m, 1H), 5.30-
5.37 (m, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 23.5 (CH3),
28.7 (CH3), 30.2 (CH2), 40.7 (CH2), 50.2 (CH), 63.2 (CH2), 80.2
(C), 117.2 (CH), 130.3 (C), 156.6 (C) ppm; MS (CI+) m/z 228
[(M + H)+, 42%], [(M - 55)+, 38%], [(M - 99)+, 18%]; HRMS
(CI+) calcd for C12H22NO3 228.1600, found 228.1598.
°C; IR (film) νmax 3197, 2956, 2928, 2872, 1746, 1700, 1161 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 0.94 (d, J ) 6.3 Hz, 3H), 1.01-
1.16 (m, 1H), 1.25-1.42 (m, 2H), 1.44 (s, 9H), 1.47* (s, 9H), 1.55-
1.70 (m, 1H), 2.19 (t, J ) 14.9 Hz, 1H), 2.87-3.06 (m, 1H), 3.94
(d, J ) 12.6 Hz, 1H), 4.04* (d, J ) 12.6 Hz, 1H), 4.79 (d, J ) 5.0
Hz, 1H), 4.96* (d, J ) 4.9 Hz, 1H) ppm; 13C NMR (CDCl3, 100
MHz) δ 22.0 (CH3), 27.5 (CH), 28.5 (CH3), 28.6* (CH3), 33.3
(CH2), 33.5* (CH2), 34.8 (CH2), 35.0* (CH2), 41.3 (CH2), 42.2*
(CH2), 54.0 (CH), 55.0* (CH), 80.6 (C), 155.7 (C), 156.3* (C),
177.8 (C), 178.0* (C) ppm; MS (ESI+) m/z 244 [(M + H)+, 16%],
188 [(M - 55)+, 40%], 144 [(M - 99)+, 100%]; HRMS (ESI+)
calcd for C12H21NO4Na 266.1363, found 266.1358. Anal. Calcd
for C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C, 59.11; H,
8.63; N, 5.66.
(2R,4R)-4-Methylpipecolic acid [(-)-1]. Acid (+)-12 (0.040 g,
0.164 mmol) was treated with a solution of 1 M HCl in MeOH
(3.5 mL) and stirred for 2 h at rt. The crude product was
concentrated in vacuo and then purified on a Dowex 50WX8 ion-
exchange resin (strong acid resin; elution with 1-3% aq ammonia)
to afford methylpipecolic acid (-)-1 (0.017 g, 74%) as a white
solid: [R]D ) -20.0 (c 0.5, 2 N HCl) {lit.10c [R]D ) -20.0 (c 0.3,
2 N HCl)}; mp ) 262.4 °C; 1H NMR (D2O, 400 MHz) δ 1.02 (d,
J ) 6.5 Hz, 3H), 1.43 (dt, J ) 7.6, 14.0 Hz, 1H), 1.63-1.73 (m,
1H), 1.86-1.93 (m, 2H), 2.08-2.18 (m, 1H), 3.23-3.30 (m, 2H),
3.93 (t, J ) 5.37 Hz, 1H) ppm; 13C NMR (D2O, 100 MHz) δ 20.2
(CH3), 26.5 (CH), 30.2 (CH2), 33.8 (CH2), 42.0 (CH2), 56.7 (CH),
175.4 (C) ppm; MS (ESI+) m/z 144 [(M + H)+, 100%]; HRMS
(ESI+) calcd for C7H14NO2 144.1019, found 144.1016.
N-tert-Butoxycarbonyl-(2R,4R)-4-methylpiperidin-2-yl)metha-
nol [(+)-15]. A mixture of (-)-14 (5.20 g, 22.89 mmol) and PtO2‚
H2O (0.104 g, 2% weight) in EtOAc (200 mL) was stirred under
1
the desired pressure of H2 (3 bar). After 16 h (GC or NMR H
control), the mixture was filtered through Celite and concentrated
in vacuo. The crude product was purified by flash chromatography
to afford (+)-15 (4.63 g, 88%, trans/cis 13/1) as a colorless oil:
[R]D ) +35.2 (c 1.2, CHCl3); IR (film) νmax 3442, 2951, 2926,
2871, 1691, 1669 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.90 (d, J
) 6.15 Hz, 1H), 1.06 (dddd, J ) 4.6, 13.3, 13.5, 13.5 Hz, 1H),
1.18-1.33 (m, 1H), 1.46 (s, 1H), 1.54-1.73 (m, 1H), 2.84 (t, J )
13.2 Hz, 1H), 3.59 (dd, J ) 5.7, 10.9 Hz, 1H), 3.81 (dd, J ) 9.5,
10.9 Hz, 1H), 4.02 (d, J ) 11.79 Hz, 1H), 4.34-4.45 (m, 1H)
ppm; 13C NMR (CDCl3, 100 MHz) δ 22.5 (CH3), 26.1 (CH), 28.6
(CH3), 34.0 (CH2), 34.1 (CH2), 39.3 (CH2), 40.2* (CH2), 52.3
(CH), 53.1* (CH), 61.8 (CH2), 62.5* (CH2) 80.0 (C), 157.1 (C)
ppm; MS (CI+) m/z 230 [(M + H)+, 100%], 174 [(M - 55)+,
86%]; HRMS (ESI+) calcd for C12H23NO3Na 252.1570, found
252.1577.
(2R,4R)-N-tert-Butoxycarbonyl-4-methylpipecolic acid [(+)-
12]. A solution of alcohol (+)-15 (7.9 g, 34.4 mmol), TEMPO
(0.538 g, 3.44 mmol, 10 mol %) and sodium phosphate buffer (125
mL, 0.67 M, pH ) 6.7) in ACN (160 mL) was heated to 35 °C.
Sodium chlorite (7.78 g, 80%, 68.8 mmol) in H2O (35 mL) and
dilute bleach (18 mL, 0.048 M, 2 mol %) were then added
simultaneously over 45 min (Caution! Do not mix bleach and
NaClO2 before addition of each to the reaction mixture). The
mixture was stirred at 35 °C for 18 h, then cooled to rt; H2O (100
Acknowledgment. We thank MEC (CTQ2005-000623) and
Enantia S.L. for financial support. C.A. thanks DURSI (Gen-
eralitat de Catalunya) for a fellowship.
Supporting Information Available: Experimental procedures
and characterization of compounds 2-9. 1H and 13C NMR spectra
of compounds 1-4, 6-9, and 12-15. This material is available
free of charge via the Internet http://pubs.acs.org.
(22) (a) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (b) Fu¨rstner,
A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.; Gabor, B.; Mynott, R.
Chem.sEur. J. 2001, 7, 4811.
(23) Zhao, M.; Li, J.; Mano, E.; Song, Z.; Tschaen, D. M.; Grabowski,
E. J. J.; Reidor, P. J. J. Org. Chem. 1999, 64, 2564.
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