Asymmetric synthesis of 4- and 5-substituted pipecolic esters by ring-closing metathesis and palladium-catalyzed formate reduction

Article abstract of DOI:10.1021/jo8008885

(Chemical Equation Presented) Asymmetric synthesis of 4- and 5-substituted pipecolic esters was achieved by the sequence of allylation, ring-closing metathesis, and palladium-catalyzed formate reduction.

Full text of DOI:10.1021/jo8008885

Asymmetric Synthesis of 4- and 5-Substituted
Pipecolic Esters by Ring-Closing Metathesis and
Palladium-Catalyzed Formate Reduction
Chong-Si Sun, Yu-Shiang Lin, and Duen-Ren Hou*
Department of Chemistry, National Central UniVersity,
300 Jhong-Da Rd. Jhong-Li, Taoyuan, Taiwan
drhou@ncu.edu.tw
ReceiVed April 28, 2008
FIGURE 1. Compounds containing 4- and 5-substituted pipecolic acids.
the 4-methylenelactone 1 serves as the key synthetic intermedi-
ate.5 Recently, we reported the sequence of ring-closing
metathesis (RCM) and the following regioselective palladium-
catalyzed formate reduction to form N-heterocycles bearing an
exo-olefin.6 Therefore, the problem of regioselectivity in
modifying the cycloalkenes formed by RCM is circumvented.
We report herein our progress in applying this methodology to
prepare the lactone 1 and the corresponding 5-methylenepipe-
colic acid derivative 2.
Asymmetric synthesis of 4- and 5-substituted pipecolic esters
was achieved by the sequence of allylation, ring-closing
metathesis, and palladium-catalyzed formate reduction.
Synthesis of 4- and 5-substituted pipecolic acids has received
attention because these compounds are components of some
biologically very potent molecules.1 For example, the FDA-
approved thrombin inhibitor Argatroban contains 4-methylpipe-
colic acid, and human immunodeficiency virus (HIV) protease
inhibitor Palinavir incorporates 4-hydroxypipecolic acid.2,3
5-Hydroxypipecolamide was found in TNF-R, an effective tumor
necrosis-converting enzyme inhibitor (Figure 1).4 Kadouri-
Puchot’s group developed a clever method to synthesize
4-methyl- and 4-hydroxypipecolic acids asymmetrically, where
The chiral glycine enolate synthon, 5-phenylmorpholin-2-one
(3),7 was alkylated with 2-(iodomethyl)allyl benzoate (4)8 to
give diastereomerically pure 5 (Scheme 1). The Boc protecting
group was removed with trifluoroacetic acid, and diene 6 for
RCM was generated after N-allylation. Several common prac-
tices for the allylation on the secondary amine were tested (Table
1). We found that the typical reaction conditions for N-alkylation
provided a low yield and product accompanied by the hydro-
lyzed lactone.9 Instead, using the sterically hindered diisopro-
pylethylamine and anhydrous acetonitrile as the reaction solvent
provided the desired product cleanly. Later, we found that
microwave irradiation at 150 °C improved the yield to 70%.10
Ring-closing metathesis under acidic conditions gave the oxazin-
(1) Review: Kadouri-Puchot, C.; Comesse, S. Amino Acids 2005, 29, 101,
and references cited thereinRecent progress: (a) Occhiato, E. G.; Scarpi, D.;
Guarna, A. Eur. J. Org. Chem. 2008, 524. (b) Alegret, C.; Santacana, F.; Riera,
A. J. Org. Chem. 2007, 72, 7688. (c) Jung, J.-C.; Avery, M. A. Tetrahedron:
Asymmetry 2006, 17, 2479.
(2) (a) Okamoto, S.; Hijikata, A.; Kikumoto, R.; Tonomura, S.; Hara, H.;
Ninomiya, K.; Maruyama, A.; Sugano, M.; Tamao, Y. Biochem. Biophys. Res.
Commun. 1981, 101, 440. (b) Kikumoto, R.; Tamao, Y.; Tezuka, T.; Tonomura,
S.; Hara, H.; Ninomiya, K.; Hijikata, A.; Okamoto, S. Biochemistry 1984, 23,
85. (c) Hilpert, K.; Ackermann, J.; Banner, D. W.; Gast, A.; Gubernator, K.;
Hadvary, P.; Labler, L.; Mu¨ller, K.; Schmid, G.; Tschopp, T. B.; van de
Waterbeemd, H. J. Med. Chem. 1994, 37, 3889. (d) Di Nisio, M.; Middeldorp,
S.; Bueller, H. R. N. Engl. J. Med. 2005, 353, 1082.
(3) (a) 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.
(b) Beaulieu, P. L.; Lavalle´e, P.; Abraham, A.; Anderson, P. C.; Boucher, C.;
Bousquet, Y.; Duceppe, J.-S.; Gillard, J.; Gorys, V.; Grand-Maitre, C.; Grenier,
L.; Guindon, Y.; Guse, I.; Plamondon, L.; Soucy, F.; Valois, S.; Wernic, D.;
Yoakim, C. J. Org. Chem. 1997, 62, 3440.
(4) Letavic, M. A.; Axt, M. Z.; Barberia, J. T.; Carty, T. J.; Danley, D. E.;
Geoghegan, K. F.; Halim, N. S.; Hoth, L. R.; Kamath, A. V.; Laird, E. R.;
Lopresti-Morrow, L. L.; McClure, K. F.; Mitchell, P. G.; Natarajan, V.; Noe,
M. C.; Pandit, J.; Reeves, L.; Schulte, G. K.; Snow, S. L.; Sweeney, F. J.; Tan,
D. H.; Yu, C. H. Bioorg. Med. Chem. Lett. 2002, 12, 1387.
1
1-one 7. The stereochemistry of 7 was confirmed by H-1H
COSY and NOE experiment. The key intermediate, exo-olefin
1, was produced after the palladium-catalyzed formate reduction.
Use of 2-di-tert-butylphosphino-2′-methylbiphenyl (8) as a
(6) Cheng, H.-Y.; Sun, C.-S.; Hou, D.-R. J. Org. Chem. 2007, 72, 2674.
(7) Dellaria, J. F.; Santarsiero, B. D. J. Org. Chem. 1989, 54, 3916.
(8) (a) Sun, C.-S.; Cheng, H.-Y.; Lin, Y.-S.; Hou, D.-R. J. Chin. Chem. Soc.
2008, 55, 435. (b) Singh, R.; Whitesides, G. M. J. Am. Chem. Soc. 1990, 112,
1190.
(9) (a) Faul, M. M.; Kobierski, M. E.; Kopach, M. E. J. Org. Chem. 2003,
68, 5739. (b) Nilsson, J. W.; Kvarnstro¨m, I.; Musil, D.; Nilsson, I.; Samulesson,
B. J. Med. Chem. 2003, 46, 3985.
(5) (a) Agami, C.; Bisaro, F.; Comesse, S.; Guesne´, S.; Kadouri-Puchot, C.;
Morgentin, R. Eur. J. Org. Chem. 2001, 2385. (b) Agami, C.; Bihan, D.;
Morgentin, R.; Kadouri-Puchot, C. Synlett 1997, 799. (c) Partogyan-Halim, P.;
Besson, L.; Aitken, D. J.; Husson, P. Eur. J. Org. Chem. 2003, 268.
(10) Recent examples for microwave assisted amine alkylation: Cardullo,
F.; Donati, D.; Fusillo, V.; Merlo, G.; Paio, A.; Salaris, M.; Solinas, A.; Taddei,
M. J. Comb. Chem. 2006, 8, 834.
10.1021/jo8008885 CCC: $40.75
Published on Web 07/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6877–6880 6877

SCHEME 1. Asymmetric Synthesis of 1
SCHEME 3. Asymmetric Synthesis of 2
TABLE 1. Reaction Conditions for N-Allylation To Prepare 6
entry
base
solvent temp (°C) time (h) yield (%)
1
2
3
4
5
Na2CO3, Bu4NBr CH3CN
75
60
14
14
14
0.8
0.6
13a
Ag2O, CaSO4
(i-Pr)2NEt
(i-Pr)2NEt
(i-Pr)2NEt
C6H6
0b
CH3CN
CH3CN
CH3CN
75
14
25
70
a primary amine that smoothly underwent N-allylation with 14
to afford diene 15. Subsequent protection followed by RCM
gave the unsaturated pipecolic ester 16 in good yield.13
Palladium-catalyzed, regioselective formate reduction then
yielded 5-methylenepipecolic ester 2,14 which could be oxidized
to the ketone 17.15 This could be selectively reduced in turn to
the cis-5-hydroxypipecolic ester 18.16
120c
150c
a Accompanied with hydrolyzed lactone (41%). b Starting material
recovered. c Microwave irradiation (150 W, sealed tube).
SCHEME 2. Epimerization of 7
In conclusion, both 4- and 5-substituted pipecolic acids can
be prepared by the sequence of asymmetric allylation, ring-
closing metathesis and palladium-catalyzed, regioselective for-
mate reduction. The ability to form both isomeric methylene-
pipecolic acids by this methodology demonstrates the generality
of the reaction. The introduction of the functionalized allyl
halides 4 or 148 makes conversion of the endo olefin to the exo
position practical and clearly increases the synthetic application
of metathesis.
Experimental Section
complexing agent gave 1 as the only product. Its oxidation was
achieved with osmium tetroxide and sodium periodate to provide
ketone 9,5a the precursor to (2R,4S)-4-hydroxypipecolic acids.
To form the other enantiomeric pipecolic acids, the 9a stereo-
center of 7 was inverted by a deprotonation/protonation protocol
to give diastereomer 10,11 which was then converted to the exo-
olefin 11 (Scheme 2).
Alternating the sequence of the two allylations also allows
the preparation of 5-substituted pipecolic acids (Scheme 3).
Thus, allylation of 3 with allyl bromide proceeded readily to
give 12.11 However, N-allylation of the deprotected 12 with 4
was difficult. To facilitate the second allylation, the chiral
auxiliary was removed to generate the methyl allylglycinate 13,12
(3R,5R)-tert-Butyl 3-(2-Benzoyloxymethylallyl)-2-oxo-5-phenyl-
morpholine-4-carboxylate (5). To a solution of 3 (390 mg, 1.4
mmol), allyl iodide 4 (510 mg, 1.7 mmol), and hexamethylphos-
phoramide (HMPA, 367 µL, 2.1 mmol) in THF (5 mL) was added
sodium bis(trimethylsilyl)amide (NaHMDS, 2 M in THF, 1.05 mL,
2.1 mmol) at -78 °C. The reaction mixture was stirred for another
2 h at -78 °C, quenched with sat. NH4Cl(aq) (5 mL), warmed to rt,
diluted with water (5 mL), and extracted with diethyl ether (3 ×
(12) (a) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995,
51, 9179. (b) Ma, D.; Tian, H.; Zou, G. J. Org. Chem. 1999, 64, 120.
(13) The alternative sequence: RCM of the protonated 15 then Boc-protection,
gave 40% yield.
(14) The previously reported ligand, 2-di-tert-butylphosphinobiphenyl (ref
6), provided a lower exo:endo ratio (80:20) for this substrate.
(15) Nunˇez, M. T.; Martn˜, V. S. J. Org. Chem. 1990, 55, 1928.
(16) Corre, L. L.; Dhimane, H. Tetrahedron Lett. 2005, 46, 7495.
(11) Hou, D. R.; Hung, S.-Y.; Hu, C.-C. Tetrahedron: Asymmetry 2005, 16,
3858.
6878 J. Org. Chem. Vol. 73, No. 17, 2008

10 mL). The combined organic layer was washed with sat. NaCl(aq)
(10 mL), dried (Na2SO4), filtered, and concentrated. The crude
product was purified by column chromatography (SiO2, EtOAc/
hexanes, 1:3; Rf 0.27) to give 5 (292 mg, 0.65 mmol, 46%) as a
colorless solid. Mp 117.0-120.0 °C; [R]20D -130.0 (c 2.51, CHCl3);
1H NMR (500 MHz, CDCl3) δ 8.01 (d, J ) 7.5 Hz, 2H), 7.55 (t,
J ) 7.4 Hz, 1H), 7.43 (t, J ) 7.7 Hz, 2H), 7.33-7.24 (m, 3H),
7.07 (d, J ) 7.4 Hz, 2H), 5.32 (s, 1H), 5.18 (s, 1H), 5.17-5.04
(m, 2H), 4.94-4.88 (m, 2H), 4.83 (d, J ) 11.8 Hz, 1H), 4.38 (d,
J ) 8.2 Hz, 1H), 2.91 (d, J ) 10.4 Hz, 1H), 2.77 (s, 1H), 1.24-1.11
(m, 9H); 13C NMR (125 MHz, CDCl3) δ 168.4, 166.1, 153.5, 139.9,
138.9, 133.0, 129.9, 129.7, 128.8, 128.3, 127.7, 125.3, 117.2, 81.3,
69.7, 66.4, 55.9, 54.7, 37.7, 27.8; HRMS-FAB (m/z) [M + H]+
calcd for C26H30O6N 452.2073, found 452.2082; IR (neat) 3031,
µL, 0.99 mmol), and 7 (60 mg, 0.17 mmol) in DMF (1.1 mL) were
added in that order. After being stirred at 10 °C for 6 h and rt for
16 h under nitrogen, the reaction mixture was concentrated and
purified by column chromatography (SiO2, EtOAc/hexanes, 1:3;
Rf 0.47) to give 1 (20.2 mg, 0.083 mmol, 51%). [R]20D -38 (c 0.9,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.38-7.29 (m, 5H), 4.75
(s, 1H), 4.69 (s, 1H), 4.64 (dd, J ) 11.0, 4.4 Hz, 1H), 4.47 (dd, J
) 11.0, 5.5 Hz, 1H), 4.10 (t, J ) 4.9 Hz, 1H), 3.34 (dd, J ) 10.9,
3.8 Hz, 1H), 2.91 (d, J ) 11.6 Hz, 1H), 2.67 (dd, J ) 13.5, 3.5
Hz, 1H), 2.52-2.48 (m, 1H), 2.29 (td, J ) 11.5, 3 Hz, 1H),
2.24-2.18 (m, 1H), 2.04 (d, J ) 16.5 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 169.8, 143.4, 135.0, 128.8, 128.5, 109.8, 72.8, 59.2,
58.5, 51.5, 35.1, 32.1; HRMS-FAB (m/z) [M + H]+ calcd for
C15H18NO2 244.1338, found 244.1342; IR (neat) 3030, 2947, 2908,
2976, 2930, 1757, 1716, 1698, 1270, 1119 cm-1
.
1742, 1653, 1494, 1455, 1224 cm-1
.
(3R,5R)-2-(4-Allyl-2-oxo-5-phenylmorpholin-3-ylmethyl)allyl Ben-
zoate (6). A solution of 5 (447.3 mg, 0.93 mmol) and trifluoroacetic
acid (2 mL) in dichloromethane (2 mL) was stirred at rt for 1 h.
The solvent and TFA were removed under vacuum. The solution
of deprotected 5, allyl bromide (560 mg, 4.6 mmol), diisopropyl-
ethyl amine (360 mg, 2.78 mmol), and acetonitrile (3.5 mL) was
placed in a pressure tube that was heated to 150 °C (150 W,
monitored by IR temperature sensor) over 10 min, then this
temperature was maintained for another 40 min. After cooling to
rt, the reaction mixture was concentrated and purified by column
chromatography (SiO2, EtOAc/hexanes, 1:3; Rf 0.45) to give 6
(254.5 mg, 0.65 mmol, 70%) as a colorless oil. [R]20D -8.4 (c 1.9,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.05 (dd, J ) 8.3, 1.2 Hz,
2H), 7.55 (t, J ) 7.5 Hz, 1H), 7.44-7.41 (m, 2H), 7.34-7.27 (m,
5H), 5.70-5.62 (m, 1H), 5.32 (d, J ) 0.9 Hz, 1H), 5.23 (d, J )
0.65 Hz, 1H), 5.14-5.08 (m, 2H), 4.90 (q, J ) 10.9 Hz, 2H), 4.66
(dd, J ) 11.5, 5.1 Hz, 1H), 4.45-4.41 (m, 1H), 4.28-4.25 (m,
1H), 3.99 (t, J ) 6.9 Hz, 1H), 3.21 (dd, J ) 14.0, 6.0 Hz, 1H),
3.09 (dd, J ) 14, 6.5 Hz, 1H), 2.77 (d, J ) 6.9 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 171.1, 166.1, 140.0, 137.7, 134.3, 133.1,
130.0, 129.6, 128.8, 128.4, 128.0, 127.3, 118.8, 116.3, 70.2, 67.1,
58.3, 56.8, 52.4, 32.6; HRMS-FAB (m/z) [M + H]+ calcd for
C24H26NO4 392.1862, found 392.1852; IR (neat) 3064, 3030, 2952,
(4R,9aR)-4-Phenylhexahydropyrido[2,1-c][1,4]oxazine-1,8-di-
one (9). To a solution of 1 (28 mg, 0.115 mmol) in THF (0.7 mL)
and water (0.7 mL) were added osmium tetroxide (OsO4 2.5 wt %
in t-BuOH, 59 µL, 5.7 × 10-3 mmol) and sodium periodate (NaIO4,
123.2 mg, 0.58 mmol). The reaction mixture was stirred at rt for
1.5 h, quenched with sat. Na2S2O3 (3 mL), and extracted with ether
(3 × 5 mL). The combined organic layer was dried (Na2SO4),
filtered, and concentrated. The crude product was purified by
column chromatography (SiO2, EtOAc/hexanes, 1:1; Rf 0.47) to
give 9 (21 mg, 0.086 mmol, 74%) as a colorless oil. [R]20 -2.0
D
1
(c 0.53, CHCl3); H NMR (500 MHz, CDCl3) δ 7.40-7.34 (m,
5H), 4.61 (dd, J ) 11.3, 4.3 Hz, 1H), 4.48 (dd, J ) 11.3, 7.1 Hz,
1H), 4.16 (dd, J ) 7.1, 4.3 Hz, 1H), 3.84 (dd, J ) 8.5, 6.9 Hz,
1H), 3.15 (dd, J ) 7.7, 5.0 Hz, 1H), 2.81 (d, J ) 8.5 Hz, 2H),
2.69-2.64 (m, 1H), 2.49-2.43 (m, 1H), 2.32-2.24 (m, 1H); 13C
NMR (125 MHz, CDCl3) δ 205.3, 168.8, 134.8, 129.7, 129.1, 128.1,
72.5, 58.9, 57.5, 48. 9, 41.0, 39.5; HRMS-FAB (m/z) [M + Na]+
calcd for C14H15NO3Na 268.0950, found 268.0949; IR (neat) 2960,
2922, 1746, 1723, 1577, 1455, 1227 cm-1
.
(4R,9aS)-8-Benzoyloxymethyl-4-phenyl-3,4,9,9a-tetrahydro-6H-
pyrido[2,1-c][1,4]oxazin-1-one (10). Potassium bis(trimethylsilyl)a-
mide (KHMDS, 0.5 M in toluene, 368 µL, 0.18 mmol) was added
to a solution of 7 (33.4 mg, 0.092 mmol) in THF (2 mL) at -78
°C, and this solution was stirred for 0.5 h. Hexamethylphosphora-
mide (HMPA, 33 µL, 0.18 mmol) and acetic acid (80%, 35 µL,
0.46 mmol) were added to the solution at -78 °C. After the
addition, the mixture was stirred for 15 min, quenched with sat.
NH4Cl(aq) (3 mL), and warmed to rt. The reaction mixture was
diluted with water (5 mL) and extracted with ether (3 × 5 mL).
The combined organic layer was washed with water (10 mL) and
sat. NaCl(aq) (10 mL), dried (Na2SO4), filtered, and concentrated.
The crude product was purified by column chromatography (SiO2,
EtOAc/hexanes, 1:3; Rf 0.41) to give 10 (10 mg, 0.028 mmol, 30%)
as a colorless oil. [R]20D -118.2 (c 1, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 8.05-8.02 (m, 2H), 7.57-7.52 (m, 1H), 7.45-7.35 (m,
7H), 5.66 (dd, J ) 3.2, 1.1 Hz, 1H), 4.75 (s, 2H), 4.36 (t, J ) 11.2
Hz, 1H), 4.24 (dd, J ) 11.2, 3.7 Hz, 1H), 3.63 (dd, J ) 10.8, 3.7
Hz, 1H), 3.37-3.32 (m, 1H), 3.19-3.12 (m, 1H), 2.86-2.80 (m,
1H), 2.63-2.54 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 169.1,
166.2, 135. 5, 133.1, 131.3, 129.9, 129.7, 129.0, 128.9, 128.4, 128.4,
122.4, 72.7, 67.2, 64.1, 60.3, 51.6, 30.1; HRMS-FAB (m/z) [M +
Na]+ calcd for C22H21NO4Na 386.1368, found 386.1372; IR (neat)
1749, 1720, 1653, 1601, 1451, 1270, 1111 cm-1
.
(4R,9aR)-8-Benzoyloxymethyl-4-phenyl-3,4,9,9a-tetrahydro-6H-
pyrido[2,1-c][1,4]oxazin-1-one (7). Five drops of 1 N hydrochloric
acid was added to a solution of 6 (90 mg, 0.23 mmol) in CH2Cl2
(2 mL), and the solvent and excess HCl were then removed under
vacuum to give the protonated 6. Another 4 mL of CH2Cl2 and
Grubbs catalyst17 (9.5 mg, 0.115 mmol) were added to the flask,
and the resulting solution was refluxed for 3 h. After being cooled
to rt, the reaction mixture was diluted with CH2Cl2 (10 mL), washed
with sat. NaHCO3(aq) (5 mL), dried (Na2SO4), filtered, and
concentrated. The crude product was purified by column chroma-
tography (SiO2, EtOAc/hexanes, 1:3; Rf 0.22) to give 7 (80 mg,
0.22 mmol, 96%) as a colorless solid. Mp 147.0-148.0 °C(dec;
[R]20 +42.5 (c 2, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
8.03-8.01 (m, 2H), 7.54 (t, J ) 7.4 Hz, 1H), 7.41 (t, J ) 7.7 Hz,
2H), 7.37-7.29 (m, 5H), 5.71 (s, 1H), 4.72 (s, 2H), 4.65 (dd, J )
11.1, 4.5 Hz, 1H), 4.59 (dd, J ) 11.1, 6.2 Hz, 1H), 4.05-4.03 (m,
1H), 3.75 (t, J ) 7.5 Hz, 1H), 3.18 (s, 2H), 2.59 (d, J ) 6.3 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 170.0, 166.2, 135.2, 133.1,
130.2, 129.9, 129.6, 128.9, 128.6, 128.5, 128.4, 122.8, 72.8, 67.4,
58.0, 55.1, 48.3, 26.9; HRMS-FAB (m/z) [M + Na]+ calcd for
C22H21NO4Na 386.1368, found 386.1374; IR (neat): 3061, 3030,
3030, 2932, 2852, 1742, 1717, 1652, 1456, 1269, 1100 cm-1
.
(4R,9aS)-8-Methylene-4-phenylhexahydropyrido[2,1-c][1,4]oxazin-
1-one (11). The procedure used to prepare 1 was followed. Starting
with 10 (10 mg, 0.028 mmol), the exo-olefin 11 (4.0 mg, 0.016
mmol, 60%) was produced after column chromatography (SiO2,
2953, 2925, 2801, 1743, 1718, 1600, 1452, 1270, 1110 cm-1
.
4R,9aR)-8-Methylene-4-phenylhexahydropyrido[2,1-c][1,4]oxazin-
1-one (1) .5a Allyl palladium chloride dimer (6.05 mg, 0.017 mmol)
and 2-di-tert-butylphosphino-2′-methylbiphenyl (20.6 mg, 0.066
mmol) were dissolved in DMF (0.5 mL) and the mixtue was stirred
for 5 min. Formic acid (37.4 µL, 0.99 mmol), triethylamine (139
EtOAc/hexanes, 1:3; Rf 0.78) as a light yellow oil. [R]20 -126.3
D
1
(c 0.25, CHCl3); H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m,
5H), 4.80 (d, J ) 1.5 Hz, 1H), 4.72 (d, J ) 1.8 Hz, 1H), 4.35-4.18
(m, 2H), 3.57 (dd, J ) 10.5, 3.9 Hz, 1H), 2.99-2.90 (m, 2H),
2.85-2.79 (m, 1H), 2.44-2.35 (m, 1H), 2.20-2.08 (m, 2H), 1.71
(td, J ) 11.4, 3.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.9,
143.9, 136.3, 129.0, 128.7, 128.3, 109.9, 72.9, 64.7, 64.3, 53.0,
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
J. Org. Chem. Vol. 73, No. 17, 2008 6879

36.6, 33.6; HRMS-FAB (m/z) [M + H]+ calcd for C15H18NO2
trated. The crude product was purified by column chromatography
(SiO2, EtOAc/hexanes, 1:5; Rf 0.23) to give 17 (10.7 mg, 0.042
mmol, 53%) as a colorless oil. [R]20D +2.4 (c 0.5, CHCl3); 1H NMR
(500 MHz, CDCl3) δ (rotamer) 4.80-4.75 (m, 0.5H), 4.58-4.55
(m, 0.5H), 4.38 (d, J ) 18.9 Hz, 0.5H), 4.27 (d, J ) 18.9 Hz,
0.5H), 3.88 (dd, J ) 25.3 Hz, 19 Hz, 1H), 3.75 (s, 3H), 2.45-2.37
(m, 2H), 2.37-2.31 (m, 1H), 2.17-2.07 (m, 0.5H), 2.07-2.02 (m,
0.5H), 1.43-1.37 (m, 9H); 13C NMR (125 MHz, CDCl3) δ
(rotamer) 205.5, 172.5, 172.2, 162.7, 154.8, 154.3, 81.4, 54.5, 53.0,
52.4, 52.3, 50.9, 35.9, 35.7, 28.2, 23.8, 23.6; IR (neat) 2956, 2922,
244.1338, found 244.1335; IR (neat) 3069, 2945, 1746, 1455, 1179
cm-1
.
(R)-Methyl N-(tert-Butyloxycarbonyl)-4-methylenepiperidine-
2-carboxylate (2). Allyl palladium chloride dimer (4.3 mg, 0.012
mmol) and 2-di-tert-butylphosphino-2′-methylbiphenyl (14.6 mg,
0.047 mmol) were dissolved in DMF (0.4 mL) and the mixture
was stirred for 5 min. Formic acid (26.6 µL, 0.7 mmol), triethy-
lamine (98.1 µL, 0.70 mmol), and 16 (44 mg, 0.12 mmol) in DMF
(770 µL) were added in that order. After being stirred at 10 °C for
6 h and rt for 16 h under nitrogen, the reaction mixture was
concentrated and purified by column chromatography (SiO2, EtOAc/
2851, 1742, 1713, 1152 cm-1
.
hexanes, 1:9; Rf 0.31) to give 2 (17.2 mg, 0.068 mmol, 58%) as a
Acknowledgment. This research was supported by the
National Science Council (NSC 95-2113-M-008-007), Taiwan.
The authors thank Prof. John C. Gilbert, Santa Clara University,
for helpful comments. We are grateful to Ms. Ping-Yu Lin at
the Institute of Chemistry, Academia Sinica, and Valuable
Instrument Center in National Central University for obtaining
mass analysis. Thanks are also due to the National Center for
High-performance Computing for computer time and facilities.
1
light yellow oil. [R]20 +61.8 (c 1, CHCl3); H NMR (500 MHz,
D
CDCl3) δ 4.89 (s, 0.5H), 4.84 (d, J ) 14.7 Hz, 1H), 4.75 (s, 1H),
4.68 (s, 0.5H), 4.37 (d, J ) 13 Hz, 0.5H), 4.25 (d, J ) 15.1 Hz,
0.5H), 3.72 (s, 3H), 3.69-3.57 (m, 1H), 2.26-2.23 (m, 2H),
2.08-2.02 (m, 1H), 1.76 (s, 1H), 1.45-1.41 (m, 9H); 13C NMR
(125 MHz, CDCl3) δ (rotamer) 172.4, 155.5, 141.6, 110.2, 110.0,
80.3, 54.8, 53.6, 52.1, 48.2, 46.9, 29.7, 28.3, 27.3; HRMS-FAB
(m/z) [M + H]+ calcd for C13H22O4N 256.1549, found 256.1551;
IR (neat) 3075, 2973, 2929,, 1745, 1702, 1659, 1172 cm-1
.
Supporting Information Available: Experimental procedure
for preparing compounds 13, 15, and 16, and characterizing data
(R)-Methyl N-(tert-Butyloxycarbonyl)-4-oxopiperidine-2-car-
boxylate (17).16 To a solution of 2 (20 mg, 0.08 mmol) in CCl4
(100 µL), acetonitrile (100 µL), and water (0.7 mL) were added
ruthenium(III) chloride (0.8 mg, 3.9 × 10-3 mmol) and periodic
acid (53.6 mg, 0.24 mmol). The reaction mixture was stirred at rt
for 2.5 h, diluted with CH2Cl2 (5 mL) and washed with water (3
mL). The organic layer was dried (Na2SO4), filtered, and concen-
including 1H-1H COSY and NOE spectra of 7 and 1H and 13
C
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO8008885
6880 J. Org. Chem. Vol. 73, No. 17, 2008