Synthesis of methyl N-Boc-(2 S,4 R)-4-methylpipecolate

Article abstract of DOI:10.1021/jo102038q

An efficient stereoselective synthesis of fully protected (2S,4R)-4-methylpipecolic acid has been developed. The synthesis was achieved by initial asymmetric α-alkylation of glycine with a chiral iodide, affording the linear precursor as a single stereoisomer. Subsequent aldehyde formation using OsO₄/NaIO₄ followed by immediate intramolecular cyclization afforded an enamine that was then subjected to hydrogenation to give the final compound in 23% yield over 10 steps.

Full text of DOI:10.1021/jo102038q

pubs.acs.org/joc
5
sandramycin, and the anti-HIV cyclodepsipeptide homo-
Synthesis of Methyl N-Boc-(2S,4R)-4-methylpipecolate
6
phymia A. Pipecolic acid, 1, is also a synthetic precursor
to compounds including the amyloglucosidase inhibitor
Kuo-yuan Hung, Paul W. R. Harris, and
Margaret A. Brimble*
7
lentiginosine, and the anticonvulsant pipradol. Among the
8
9
vast variety of pipecolic acid derivatives described to date,
Department of Chemistry, The University of Auckland,
2
4-substituted pipecolic acids are currently the most prevalent
subgroup. Good examples are 4-hydroxy and 4-oxopipecolic
acid derivatives 2 and 3 that are present in the highly potent
3 Symonds Street, Auckland, New Zealand
1
0
m.brimble@auckland.ac.nz
Received October 17, 2010
HIV inhibitor palinavir, and the cyclic antibiotic virgini-
1
1
amycin S, respectively. While numerous syntheses of both
-hydroxy and 4-oxopipecolic acid have been reported, little
attention has focused on the formation of the less known
4
4-methylpipecolic acid, 4, the key component of the potent
and selective thrombin inhibitor argatroban, 5.
12
An efficient stereoselective synthesis of fully protected
2S,4R)-4-methylpipecolic acid has been developed. The
(
Despite several racemic syntheses of 4-methylpipecolic
1
synthesis was achieved by initial asymmetric R-alkylation
of glycine with a chiral iodide, affording the linear pre-
cursor as a single stereoisomer. Subsequent aldehyde
formation using OsO /NaIO followed by immediate intra-
3
acid, only a limited number of asymmetric syntheses have
been described. Asymmetric synthesis of 4-methylpipecolic
14
acid has been accomplished by aza-Diels-Alder reaction,
intramolecular ene-iminium cyclization, and Sharpless
4
4
15
molecular cyclization afforded an enamine that was then
subjected to hydrogenation to give the final compound in
16
epoxidation followed by ring-closing metathesis. Dis-
appointingly, most of these methods proceed with low overall
stereoselectivity. Given that the chirality at both the 2- and
23% yield over 10 steps.
(7) Pastuszak, I.; Molyneux, R. J.; James, L. F.; Elbein, A. D. Biochemistry
1
990, 29, 1886–1891.
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1
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(
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(
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7
8
728 J. Org. Chem. 2010, 75, 8728–8731
Published on Web 11/23/2010
DOI: 10.1021/jo102038q
r 2010 American Chemical Society

Hung et al.
JOCNote
SCHEME 1. Formation of (2S)-Pipecolic Acid, 6, upon Hydro-
genation of Aldehyde Precursor 7
SCHEME 3. Synthesis of Iodide 14 from (1S,2S)-Pseudoephedrine
1
9
SCHEME 2. Retrosynthetic analysis of (2S,4R)-4-methylpipe-
colic acid
with propionic anhydride to afford amide 15 in 97% yield.
Subsequent asymmetric alkylation of 15 using commercially
19
available allyl iodide afforded olefin 16 in 88% yield. Finally,
reduction of 16 by the borane-ammonia complex gave alco-
hol 17 which was converted to the desired iodide 14 without
further purification in 57% yield over two steps.
Several methods have been developed for the asymmetric
1
9,20
2
1
R-alkylation of glycine. Among those reported, use of the
Ni(II) complex 18 as a template was deemed a suitable
2
2
method for the present investigation. It was reported that
the Ni(II) complex 18 effects the R-alkylation of glycine with
excellent diastereomeric excess. Furthermore, the alkylation
reaction can be carried out using inexpensive reagents under
mild conditions with simple flash column chromatography
employed for the desired product isolation. Also importantly,
4-position of 4-methylpipecolic acid has a significant effect on
the biological activity,
stereoselective synthesis of 4-methylpipecolic acid.
(
19) Myers, A. G.; Yang, B. H.; Chen, Y. H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496–6511.
20) Smith, A. B., III; Adams, C. M.; Kozmin, S. A.; Paone, D. V. J. Am.
Chem. Soc. 2001, 123, 5925–5937.
21) (a) Sutherland, A.; Willis, C. L. Nat. Prod. Rep. 2000, 17, 621–631.
(b) Beller, M.; Eckert, M. Angew. Chem., Int. Ed. 2000, 39, 1010–1027.
12a,b
our aim was to establish an efficient
(
Recently, Sutherland reported that protected (2S)-pipecolic
acid, 6, could be formed in moderate yield upon hydrogenation
of its aldehyde precursor 7 in the synthesis of (S)-gizzerosine
(
(
(
c) Kawabata, T.; Fuji, K. Synth. Org. Chem. Jpn. 2000, 58, 1095–1099.
d) Kazmaier, U.; Maier, S.; Zumpe, F. L. Synlett 2000, 1523–1535. (e) Yao,
1
7
(Scheme 1). The analogues of aldehyde intermediate 8 were
shown to be unstable and underwent intramolecular cyclization
S. L.; Saaby, S.; Hazell, R. G.; Jorgensen, K. A. Chem.;Eur. J. 2000, 6,
2435–2448. (f ) Abellan, T.; Chinchilla, R.; Galindo, N.; Guillena, G.; Najera,
C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2689–2697. (g) Rutjes, F. P. J. T.;
Wolf, L. B.; Schoemaker, H. E. J. Chem. Soc., Perkin Trans. 1 2000, 4197–
4212. (h) Shioiri, T.; Hamada, Y. Synlett 2001, 184–201. (i) Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH: New York,
1
8
to give derivatives of the enamine product 9.
With this idea in mind, a new asymmetric synthesis of
-methylpipecolic acid based on late-stage cyclization of an
4
2
000. ( j)Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
aldehyde was proposed. As depicted in scheme 2, the target
compound 10 can be obtained from hydrogenation of
enamine 11 generated in situ from cyclization of the aldehyde
intermediate 12. Aldehyde 12 in turn is derived from olefin 13
which can then be assembled from asymmetric R-alkylation of
glycine by iodide 14. This retrosynthetic strategy was envisaged
to provide the desired stereoisomer with excellent stereo-
selectivity as both the asymmetric synthesis of iodide 14 and
asymmetric R-alkylation of glycine are well documented.
Herein we report the synthesis of fully protected (2S,4R)-
Yamamoto, H., Eds.; Springer: Berlin/Heidelberg, 1999. (k) O’Donnell,
M. J. Aldrichimica Acta 2001, 34, 3–15. (l) Hruby, V. J., Soloshonok,
V. A., Guest Eds. Asymmetric Synthesis of Novel Sterically Constrained
Amino Acids. Tetrahedron Symposia-in-Print; #88; Tetrahedron 2001, 57
(30). (m) O’Donnell, M. J.; Drew, M. D.; Cooper, J. T.; Delgado, F.; Zhou,
C. J. Am. Chem. Soc. 2002, 124, 9348–9349. (n) Bull, S. D.; Davies, S. G.;
Garner, C. A.; O’Shea, M. D.; Savory, E. D.; Snow, E. J. J. Chem. Soc.,
Perkin Trans. 1 2002, 2442–2448. (o) O’Donnell, M. J.; Cooper, J. T.; Mader,
M. M. J. Am. Chem. Soc. 2003, 125, 2370–2371.
(22) (a) Belokon’, Y. N.; Zeltzer, I. E.; Bakhmutov, V. I.; Saporovskaya,
M. B.; Ryzhov, M. G.; Yanovsky, A. I.; Struchkov, Y. T.; Belikov, V. M.
J. Am. Chem. Soc. 1983, 105, 2010–2017. (b) Belokon’, Y. N.; Bulychev,
A. G.; Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.; Timofeeva, T. V.;
Tsyryapkin, V. A.; Ryzhov, M. G.; Lysova, L. A.; Bakhmutov, V. I.; Belikov,
V. M. J. Am. Chem. Soc. 1985, 107, 4252–4259. (i) Belokon’, Y. N.;
Bakhmutov, V. I.; Chernoglazova, N. I.; Kochetkov, K. A.; Vitt, S. V.;
Garbalinskaya, N. S.; Belikov, V. M. J. Chem. Soc.. Perkin Trans. I 1988,
4-methylpipecolic acid from the readily available and in-
expensive starting materials (1S,2S)-pseudoephedrine and
L-proline. As shown in scheme 3, the synthesis of chiral iodide
14 began with simple acylation of (1S,2S)-pseudoephedrine
3
05–312. (c) Belokon’, Y. N. Janssen Chim. Acta 1992, 10, 4. (d) Bolokon’,
Yu. N. Pure Appl. Chem. 1992, 64, 1917. (e) Collet, S.; Bauchar, P.;
Danion-Bougot, R.; Danion, D. Tetrahedron: Asymmetry 1998, 9, 2121–
2131. (f ) Belokon’, Y. N.; Tararov, V. I.; Maleev, V. I.; Savel’eva, T. F.;
Ryzhov, M. G. Tetrahedron: Asymmetry 1998, 9, 4249–4252. (g) Ueki, H.;
Ellis, T. K.; Martin, C. H.; Boettiger, T. U.; Bolene, S. B.; Soloshonok, V. A.
J. Org. Chem. 2003, 68, 7104–7107. (h) Qin, W.; Cao, F.; Li, Z.; Zhou, H.;
Wan, H.; Wei, P.; Shi, Y.; Ouyang, P. J. Chem. Crystal. 2006, 36, 61–65.
(
17) Fanning, K. N.; Sutherland, A. Tetrahedron Lett. 2007, 48, 8479–
481.
18) (a) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5043–5048.
b) Mori, K.; Sugai, T.; Maeda, Y.; Okazaki, T.; Noguchi, T.; Naito, H.
Tetrahedron 1985, 41, 5307–5311.
8
(
(
J. Org. Chem. Vol. 75, No. 24, 2010 8729

Hung et al.
JOCNote
SCHEME 4. Synthesis of Linear Backbone of (2S,4R)-4-Methyl-
pipecolic Acid 21 from Commercially Available L-Proline
SCHEME 5. Synthesis of N-Boc (2S,4R)-4-Methylpipecolic
Methyl Ester 10
aldehyde intermediate 12 and hydrogenation of the enamine
11 proceeded smoothly, affording the target compound 10 in
the chiral auxiliary 19 can be recycled following the release of
the R-substituted chiral glycine.
Thus, the Ni(II) complex 18 was synthesized in 69% over-
10 steps in 23% overall yield. The synthesis employed allows
for versatile access to a range of analogues, by varying the
20,27
nature of the alkyl iodide
complex.
and the chirality of the Ni(II)
22e-g
22b
all yield over three steps starting from L-proline (Scheme 4).
The key asymmetric alkylation was carried out using sodium
hydroxide in acetonitrile, affording olefin 20 as a single diaster-
eomer in 91% yield. Subsequent acid hydrolysis of 20 using 2 M
HCl solution afforded olefin 21 in 83% yield and recovered the
chiral auxiliary 19 quantitatively.
Experimental section
2
R)-1-Iodo-2-methylpent-4-en 14. . To a solution of alcohol
0
(
1
7 (1.89 g, 18.88 mmol) in dry dichloromethane (35 mL) at 0 °C
under nitrogen was added triphenylphosphine (5.47 g, 20.86 mmol),
imidazole (1.43 g, 20.98 mmol), and iodine in three portions
Prior to aldehyde formation and further cyclization of the
key acyclic precursor 21, the amine and acid functionality
were both protected as a Boc group (Boc O in MeCN) and
(
5.35 g, 21.07 mmol). The resulting suspension was warmed to
2
room temperature and stirred for 4 h. The reaction mixture was
passed through a sintered funnel packed with silica gel using a
mixture of pentane/diethyl ether (5:1). After removal of the
solvent under reduced pressure (750 mmHg, 40 °C), bulb-to-bulb
distillation (20 mmHg, 50-80 °C) afforded compound 14 (2.26 g,
57% from amide 16) as a colorless liquid; TLC (hexane/ethyl
methyl ester (SOCl in MeOH), respectively, affording pro-
2
2
3
tected olefin 13 in 82% yield over two steps (Scheme 5).
Initial attempts to synthesize aldehyde 12 followed by intra-
2
molecular cyclization from olefin 13 using ozonolysis or
4
2
5
OsO , 2,6-lutidine/NaIO
were unsuccessful. Pleasingly,
formation of diol 22 from olefin 13 using OsO and NMO
4
4
20
D
28
acetate 3:1) R
f
= 0.9; [R]
-6.7 (c 1.40, CHCl
3
); νmax (neat)/
4
-1
cm 2960, 1640, 1437, 1194, 993, 914, 721, 694; δ (300 MHz;
2
6
H
followed by treatment with NaIO4 afforded enamine 11 via
aldehyde intermediate 12 in almost quantitative yield. En-
amine 11 was subjected to hydrogenation to give the target
compound 10 in 85% yield over two steps without further
CDCl
CHCH
ICH CH), 5.03-5.13 (2H, m, CH
3
) 1.00 (3H, d, J = 6.6 Hz, CHCH
), 1.98-2.19 (2H, m, CHCH CHdCH
CHdCH ), 5.66-5.80 (1H, m,
3
), 1.51-1.66 (1H, m,
), 3.13-3.26 (2H, m,
3
2
2
2
2
2
CH CHdCH ); δ (75 MHz; CDCl ) 16.7 (CH , ICH CH), 20.3
2
2
C
3
2
2
1
7
purification.
(CH , CHCH ), 34.6 (CH, CHCH
3 3
3
), 40.6 (CH , CHCH
2
2
CHd
In summary, an efficient stereoselective synthesis of
Boc protected methyl (2S,4R)-4-methylpipecolate has been
developed via asymmetric R-alkylation of glycine with a chiral
unsaturated iodide followed by intramolecular cyclization of
the derived aldehyde. The key asymmetric R-alkylation of
glycine afforded the linear backbone 21 of (2S,4R)-4-methyl-
pipecolic acid in 91% yield as a single stereoisomer. Following
oxidative cleavage of diol 22, intramolecular cyclization of the
CH
(
2
), 116.9 (CH , CH
2
S)-Glycine-nickel-(S)-2-[N-(N -benzylpropyl)amino]benzo-
2
CHdCH ), 135.8 (CH, CH
2
2
CHdCH ).
2
0
22g
phenone-(R)-2-methyl-pent-4-en complex 20. . To a suspension
of compound 18 (3.52 g, 7.08 mmol) and powdered sodium
hydroxide (0.71 g, 17.69 mmol) in acetonitrile (60 mL) was added
iodide 14 (2.23 g, 10.61 mmol) under nitrogen. After stirring
at room temperature for 2 h, 0.1 M aqueous hydrochloric acid
(55 mL) was added, and the solution mixture was stirred for 30 min.
Following extraction with dichloromethane (3 ꢀ 100 mL), the
combined organic extracts were dried over anhydrous Na SO ,
2
4
(
23) Kokotos, G.; Padr oꢀ on, J. M.; Martı
V. S. J. Org. Chem. 1998, 63, 3741–3744.
24) Xu, L. F.; Huang, W. F.; Wei, B. G.; Lin, G. Q. Synlett 2009, 8, 1307–
310.
´
n, T.; Gibbons, W. A.; Martı
´
n,
filtered, and concentrated under reduced pressure. Purified by
(
1
(27) (a) Fettes, A.; Carreira, E. M. J. Org. Chem. 2003, 68, 9274–9283.
(b) Smith, A. B., III; Kozmin, S. A.; Adams, C. M.; Paone, D. V. J. Am.
Chem. Soc. 2000, 122, 4984–4985.
(25) Yu, W.; Mei, Y.; Kang, Y.; Hua, Z.; Jin, Z. Org. Lett. 2004, 6, 3217–
219.
3
(26) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski, J. A.;
Scheidt, K. A. J. Org. Chem. 2002, 67, 4275–4283.
(28) The optical rotation for (S)-1-iodo-2-methylpent-4-en was found to
2
0
be þ6.3 (c 1.4, CHCl
3
).
8
730 J. Org. Chem. Vol. 75, No. 24, 2010

Hung et al.
JOCNote
andethyl acetate (10mL). The organiclayerwasseparatedandthe
silicagelcolumnchromatographyusingdichloromethane/acetone
(
4:1) as eluent afforded compound 20 (3.74 g, 91%) as a blood-red
amorphous solid; TLC (dichloromethane/acetone 4:1) R = 0.38;
þ2266.4 (c 0.12, MeOH); mp 89.4-93.7 °C; vmax (neat)/
aqueous layer was extracted with ethyl acetate (2 ꢀ 10 mL). The
f
2 4
combined organic extracts were dried over anhydrous Na SO ,
2
0
[
R]
D
filtered and concentrated under reduced pressure to afford an oily
residue. To this residue dissolved in ethanol (20 mL) under
hydrogen was added 10% Pd/C (33.9 mg, 0.03 mmol) and the
mixture was stirred for 16 h. The reaction mixture was passed
through a thin layer of Celite and washed with ethanol. The
solvent was removed under reduced pressure and the residue was
purified by silica gel column chromatography using hexane/ethyl
acetate (9:1) as eluent to afford compound 10 (32.2 mg, 85%) as a
-
1
cm 2957, 1671, 1637, 1589, 1439, 1330, 1256, 1165, 1063, 913,
7
1
52, 702; δ (300MHz; CDCl ) 0.84 (3H, d, J=6.7 Hz, CHCH ),
H 3 3
.36-1.45 (1H, m, CH
2
CHCH
), 1.85-1.95 (2H, m, CHCH
3
), 1.64-1.74 (2H, m, CHCH
2
-
CHCH
3
2
CHdCH ), 2.01-2.21 (2H,
2
m, Proδ-H, Proγ-H), 2.34-2.43 (1H, m, Proβ-H), 2.46-2.61
1H, m, Proβ-H), 2.71-2.81 (1H, m, Proγ-H), 3.43-3.72 (4H,
m, Proδ-H, NCH Ph, GlyR-H), 3.92-3.96 (1H, dd, J = 9.8,
.7 Hz, ProR-H), 4.43 (1H, d, J = 12.6 Hz, NCH Ph), 4.71-4.86
2H, m, CH CHdCH ), 5.34-5.48 (1H, m, CH CHdCH ),
(
2
2
0
4
(
6
2
yellow oil; TLC (hexane/ethyl acetate 9:1) R
(c 0.66, CHCl
3
f
= 0.34; [R]
); νmax (neat)/cm 2954, 2929, 1745, 1695, 1393,
1366, 1155, 1130.20, 1070, 865, 777; δ (300 MHz; CDCl ) 0.91
(3H, d, J = 6.6 Hz, CHCH ), 1.23-1.34 (1H, m, CH
C], 1.66-1.84 (3H, m, CHCH
, CH CH CHCH
), 3.32-3.41 (1H, m, CH
N), 3.70 (3H, s, OCH ), 4.31 (1H, t, J = 6.3 Hz,
(75 MHz; CDCl ) 18.9 (CH , CHCH ), 26.0 (CH,
CH ), 28.2 [CH , (CH C], 30.8 (CH , CH CH
), 33.2 (CH , CHCH CHCH ), 38.9 (CH , CH CH N),
51.9 (CH , OCH ), 54.2 (CH, NCHCO), 80.1 [C, (CH C], 155.8
(C, CON), 173.4 (C, CO
D
-23.6
-
1
2
2
2
2
.58-6.68 (2H, m, Ph), 6.92 (1H, d, J = 5.3 Hz, Ph), 7.09-7.15
H
3
(
(
2H, m, Ph), 7.17-7.20 (1H, d, J = 7.5 Hz, Ph), 7.26-7.36
4H, m, Ph), 7.42-7.54 (4H, m, Ph), 8.06 (3H, d, J = 7.4 Hz, Ph);
3
2
CH
2
-
-
CHCH
3
), 1.42 [9H, s, (CH
, CH CHCH CH
CHCH
(1H, m, CH CH
NCHCO); δ
CH CHCH
CHCH
3 3
)
2
δ (75 MHz; CDCl ) 20.5 (CH , CHCH ), 23.9 (CH , Proγ-C),
CHCH
3
2
3
2
2
2
3
), 1.91-1.97 (1H,
CH N), 3.52-3.58
C
3
3
3
2
2
CHCH
Proδ-C), 62.9 (CH
8.9 (CH, CH
2
CHCH
3
), 30.7 (CH
2
, Proβ-C), 39.5 (CH
CHdCH ), 57.1 (CH
Ph), 69.0 (CH, ProR-C), 70.3 (CH,
2
,
m, CHCH
2
3
2
2
2
CHCH
3
), 43.9 (CH
, NCH
2
, CHCH
2
2
2
,
2
2
3
2
2
C
3
3
3
GlyR-C), 116.1 (CH , CH CHdCH ), 120.7 (CH, Ph), 123.7
2
3
2
3
3
)
3
2
2
2
-
2
2
2
(
(
(
(
CH, Ph), 126.6 (C, Ph), 127.6 (CH, Ph), 127.9 (CH, Ph), 128.8
CH, Ph), 128.9 (CH, Ph), 128.9 (CH, Ph), 129.0 (CH, Ph), 129.7
CH, Ph), 131.5 (CH, Ph), 131.9 (CH, Ph), 133.1 (CH, Ph), 133.2
C, Ph), 133.5 (C, Ph), 136.2 (CH, CH CHdCH ), 142.1 (C, Ph),
3
2
2
3
2
2
2
)
3 3
3
3
þ
2
Me); m/z (EI) 280 (100%, M þ Na),
258 (3), 224 (19), 180 (20), 158 (64), 128 (4) and 98 (9); HRMS (EI,
M þ Na) found 280.1523, calcd for C13H23NNaO 280.1519’.
2
2
þ
1
6
69.6 (C, Ph CN), 179.1 (C, CO), 180.2 (C, Pro-CON); m/z (EI)
2
4
þ
02 (10%, M þ Na), 584 (10), 583 (16), 582 (45), 581 (38), 580
þ
(
for C H N NaNiO 602.1924.
100) and 366 (6); HRMS (EI, M þ Na) found 602.1906, calcd
Acknowledgment. Financial support from a University
of Auckland Doctoral Scholarship (KYH) is gratefully
acknowledged.
33
35
3
3
(
,2-dicarboxylate 10. . Sodium (meta)periodate (0.13 g, 0.59 mmol)
2S,4R)-1-tert-Butyl-2-(carbonylmethyl)-4-methylpiperid ine-
17
1
was added to a solution of compound 22 (45.2 mg, 0.15 mmol) in a
mixture of THF/pH 7 buffer solution (5:1, v/v, 6 mL). After
stirring vigorously at room temperature for 10 min, the solvent
was removed and the solid residue was dissolved in water (10 mL)
Supporting Information Available: General experimental
1
13
procedures, and H and C spectra for individual compounds
can be obtained in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 24, 2010 8731