Enantioselective syntheses of (-)- and (+)-monomorine I

Article abstract of DOI:10.1021/jo800593n

(Chemical Equation Presented) A concise enantioselective total synthesis of unnatural (-)-monomorine I has been achieved starting from lactam 2 in 54% overall yield. Natural (+)-monomorine I was also synthesized.

Full text of DOI:10.1021/jo800593n

Enantioselective Syntheses of (-)- and (+)-Monomorine I†
Naoki Toyooka,* Dejun Zhou, and Hideo Nemoto
Graduate School of Medicine and Pharmaceutical Sciences, UniVersity of Toyama,
Sugitani 2630, Toyama 930-0194, Japan
toyooka@pha.u-toyama.ac.jp
ReceiVed March 17, 2008
A concise enantioselective total synthesis of unnatural (-)-monomorine I has been achieved starting
from lactam 2 in 54% overall yield. Natural (+)-monomorine I was also synthesized.
Introduction
a 5:1 ratio. Here we disclose a shorter (five-step) synthesis of (-)-1
starting from commercially available lactam 2.6
(+)-Monomorine I (1), a trail pheromone of the widespread
pharaoh’s ant Monomorium pharaonis L.,1 possessing a 3,5-
disubstituted indolizidine skeleton, was detected in 1993, together
with three other diastereomers, in amphibian skin extracts of
Melanophryniscus stelzneri, and all are named as diastereomeric
195B.2 The absolute configurations of the frog 195Bs are unknown.
The absolute stereochemistry of this interesting natural product was
determined by the Husson’s first asymmetric synthesis4d and was
recognized as a target suitable for testing the applicability of the
synthetic concept of Scheme 1.
Results and Discussion
Lactam 2 was converted to the corresponding Cbz-imide 3,
which was transformed into the acyclic ketone 4 using Martin’s
procedure.7 Formation of the 2,5-cis-disubstituted pyrrolidine
5 was accomplished by the stereoselective reduction from less
hindered ꢀ-face of the iminium salt, derived from 4, with
triphenylsilane.7 Cross-metathesis reaction of 5 with methyl
vinyl ketone in the presence of the Grubbs’ second generation
catalyst8 afforded the unsaturated ketone 6, which underwent a
final indolizidine ring closure under catalytic hydrogenation
conditions to afford (-)-monomorine I [(-)-1]. The spectral
data (1H and 13C NMR) of our synthetic (-)-1 showed no
presence of the diastereomer on the 5-position and were identical
with those reported.3,4 (SCHEME 1)
To date several enantioselective syntheses of both natural (+)-3
and unnatural (-)-enantiomers4 of 1 have been reported. Among
them, Blechert5 reported the most effective seven-step enantiose-
lective synthesis of (+)-1 in 35% overall yield; however, the final
and key step in this synthesis provided (+)-1 and its 3-epimer in
† This paper is dedicated to the memory of Dr. John W. Daly, whose many
contributions to the field of poison-frog alkaloids led directly to significant
advances in synthetic organic chemistry and pharmacology.
This methodology can be applied to an enantiodivergent
process as shown in Scheme 2. Thus, the known lactam 79 was
converted to ketone 9 via Cbz-imide 8. Cyclization via an
iminium ion intermediate provided the pyrrolidine 10, which
after Wacker oxidation afforded the methyl ketone 11. By the
same reaction conditions used for the synthesis of (-)-1 from
6 described in Scheme 1, 11 was converted to (+)-1. The
synthetic (+)-1 is identical to (-)-1 in all aspects except the
sign of optical rotation.
(1) Ritter, F. J.; Rotgans, I. E. M.; Tulman, E.; Verwiel, P. E.; Stein, F.
Experientia 1973, 29, 530.
(2) Garraffo, H. M.; Spande, T. F.; Daly, J. W.; Baldessari, A.; Gros, E. G.
J. Nat. Prod. 1993, 56, 357.
(3) (a) Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. Beilstein J.
Org. Chem. 2007, 3, 39. (b) Gourlay, B. S.; Little, I.; Ryan, J. H.; Smith, J. A.
Nat. Prod. Commun. 2006, 1, 831. (c) Conchon, E.; Gelas-Mialhe, Y.; Remuson,
R. Tetrahedron: Asymmetry 2006, 17, 1253. (d) Mori, M.; Akashi, M.; Hori,
M.; Hori, K.; Nishida, M.; Sato, Y. Bull. Chem. Soc. Jpn. 2004, 77, 1655. (e)
Kim, G.; Jung, S.; Lee, E.; Kim, N. J. Org. Chem. 2003, 68, 5395. (f) Amat,
M.; Llor, N. H.; Jose, E., C.; Bosch, J. J. Org. Chem. 2003, 68, 1919. (g)
Riesinger, S. W.; Lofstedt, J.; Pettersson-Fasth, H.; Backvall, J.-E. Eur. J. Org.
Chem. 1999, 3277, and references therein.
(6) This lactam is commercially available and also can be prepared by cross-
coupling reaction of (5S)-(+)-5-iodomethylpyrrolidin-2-one with vinylmagnesium
bromide; see:Kamimura, A.; Nagata, Y.; Kadowaki, A.; Uchida, K.; Uno, H.
Tetrahedron 2007, 63, 11856.
(4) (a) Pattenden, L. S.; Adams, H.; Smith, S. A.; Harrity, J. P. A. Tetrahedron
2008, 64, 2951. (b) Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org.
Chem. 2007, 72, 3133. (c) Jefford, C. W.; Sienkiewicz, K.; Thornton, S. R.
Tetrahedron Lett. 1994, 35, 4759. (d) Royer, J.; Husson, H. P. J. Org. Chem.
1985, 50, 670.
(7) Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60,
7301.
(8) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(9) Hjelmgaard, T.; Søtofte, I.; Tanner, D. J. Org. Chem. 2005, 70, 5688.
(5) Randl, S.; Blechert, S. J. Org. Chem. 2003, 68, 8879.
10.1021/jo800593n CCC: $40.75
Published on Web 05/29/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4575–4577 4575

Toyooka et al.
SCHEME 1. Synthesis of (-)-Monomorine I [(-)-1]a
a Reagents and conditions: (a) LiHMDS, CbzCl, THF, -78 to 0 °C (93%); (b) n-BuMgBr, TMEDA, THF, -78 °C (73%); (c) Ph3SiH, BF3 ·Et2O CH2Cl2,
-78 to rt (96%); (d) methyl vinyl ketone, Grubbs’ second catalyst (10 mol %), CH2Cl2, reflux (95%); (e) 20% Pd(OH)2, H2, 1 atm, EtOH (88%).
SCHEME 2. Synthesis of (+)-1a
a Reagents and conditions: (a) 10% Pd/C, H2, EtOAc, 1 atm; (b) LiHMDS, CbzCl, THF, -78 to 0 °C (96% in two steps); (c) 5-pentenylMgBr, TMEDA, THF,
-78 °C (57%); (d) Ph3SiH, BF3 ·Et2O CH2Cl2, -78 °C to rt (90%); (e) PdCl2, CuCl, O2, H2O-DMF, rt (86%); (f) 20% Pd(OH)2, H2, 1 atm, EtOH (84%).
10% HCl aqueous solution, dried over MgSO4, filtered, and
evaporated to give a residue, which was chromatographed on silica
gel (20 g, hexane/acetone 20:1-10:1) to give 4 (231 mg, 73%) as
a colorless solid (mp 90-92 °C): IR (KBr) 3306, 1704, 1686, 1546,
Conclusion
A concise, five-step enantioselective total synthesis of (-)-
monomorine I (1) in 54% overall yield was achieved starting from
the commercially available lactam 2. An enantiodivergent process
is also reported for the synthesis of (+)-monomorine I [(+)-1].
1
1262 cm-1; H NMR (500 MHz, CDCl3) δ 0.89 (3H, t, J ) 7.2
Hz), 1.28 (2H, sext, J ) 7.2 Hz), 1.52 (2H, quint, J ) 7.2 Hz),
1.63 (1H, m), 1.81 (1H, m), 2.22 (2H, m), 2.36 (2H, t-like, J ) 6.4
Hz), 2.47 (2H, m), 3.68 (1H, br m), 4.60 (1H, br d, J ) 8.5 Hz),
5.08 (4H, m), 5.75 (1H, m), 7.30-7.37 (5H, m); 13C NMR (75
MHz, CDCl3) δ 13.8 (q), 22.2 (t), 25.8 (t), 28.2 (t), 39.2 (t), 39.9
(t), 42.5 (t), 50.5 (d), 66.3 (t), 117.7 (t), 127.7 (d), 127.7 (d), 128.2
(d), 133.7 (d), 136.3 (s), 155.8 (s), 210.5 (s); MS 317 (M+), 276
(100); HRMS calcd for C19H27O3N 317.1989, found 317.1982;
Experimental Section
(2S)-(-)-2-Allyl-5-oxopyrrolidine-1-carboxylic Acid Benzyl
Ester (3). To a stirring solution of 2 (322 mg, 2.58 mmol) in THF
(10 mL) was added a solution of LiHMDS, prepared from HMDS
(0.59 mL, 2.83 mmol) and n-BuLi (1.6 M in hexane, 1.77 mL, 2.83
mmol) in THF (10 mL) at 0 °C for 30 min, at -78 °C, and then the
resulting mixture was stirred at the same temperature for 30 min. To
the reaction mixture was added CbzCl (0.44 mL, 3.10 mmol) at -78
°C, and the reaction mixture was stirred at -78 °C for 0.5 h and
allowed to warm to 0 °C over 1 h. The reaction was quenched with
saturated NaHCO3, and the aqueous mixture was extracted with CH2Cl2
(20 mL × 4). The organic extracts were combined, dried over MgSO4,
filtered, and evaporated to give a residue, which was chromatographed
on silica gel (25 g, hexane/acetone 25:1-10:1) to give 3 (621 mg,
[R]26 -16.86 (c 0.57, CHCl3).
D
(2S,5S)-(-)-2-Allyl-5-n-butylpyrrolidine-1-carboxylic Acid Ben-
zyl Ester (5). To a stirring solution of 4 (171 mg, 0.54 mmol) in
CH2Cl2 (5 mL) was added a solution of BF3 ·Et2O (0.27 mL, 2.16
mmol) and Ph3SiH (280 mg, 1.08 mmol) in CH2Cl2 (5 mL) at -78
°C, and the resulting mixture was stirred at the same temperature
for 0.5 h, and then at room temperature for 2 h. The reaction was
quenched with saturated NaHCO3 aqueous solution at 0 °C, and
the mixture was diluted with Et2O. The organic layer was separated,
and the aqueous layer was extracted with Et2O (10 mL × 3). The
organic extracts were combined, dried over MgSO4, filtered, and
evaporated to give a residue, which was chromatographed on silica
gel (20 g, hexane/acetone 100:1-60:1) to give 5 (156 mg, 96%)
as a colorless oil: IR (neat) 3079, 3029, 1698, 1405 cm-1; 1H NMR
(300 MHz, CDCl3) δ 0.88 (3H, br), 1.27 (5H, br), 1.38-1.80 (3H,
m), 1.81-1.99 (2H, m), 2.16 (1H, m), 2.59 (1H, br), 3.87 (2H, br),
4.99-5.09 (4H, m), 5.74 (1H, br), 7.24-7.40 (5H, m); 13C NMR
(75 MHz, CDCl3) δ 14.1 (q), 22.6 (t), 28.5 (t), 29.2 (t), 35.1 (t),
39.4 (t), 40.0 (t), 57.7 and 58.1 (each d), 59.0 (d), 66.4 (t), 116.8
(t), 127.5 (d), 127.5 (d), 128.1 (d), 134.8 (d), 136.8 (s), 155.0 (s);
MS 301 (M+), 216 (100); HRMS calcd for C19H27O2N 301.2040,
93%) as a colorless oil: IR (neat) 3060, 1791, 1749, 1716, 1293 cm-1
;
1H NMR (500 MHz, CDCl3) δ 1.86 (1H, m), 2.10 (1H, m), 2.34 (1H,
m), 2.47 (1H, m), 2.50 (1H, m), 2.60 (1H, m), 4.27 (1H, m), 5.10
(2H, m), 5.28 (2H, ABq, J ) 12.4 Hz), 5.73 (1H, m), 7.32-7.38 (3H,
m), 7.40-7.44 (2H, m); 13C NMR (75 MHz, CDCl3) δ 21.5 (t), 30.8
(t), 37.4 (t), 56.7 (d), 67.3 (t), 118.3 (t), 127.4 (d), 127.7 (d), 127.9
(d), 132.2 (d), 134.7 (s), 150.6 (s), 173.3 (s); MS 259 (M+), 91 (100);
HRMS calcd for C15H17O3N 259.1207, found 259.1234; [R]26D -76.15
(c 1.00, CHCl3).
(1S)-(-)-[1-(3-Oxo-n-heptyl)but-3-enyl]carbamic Acid Ben-
zyl Ester (4). To a stirring solution of 3 (259 mg, 1.00 mmol) in
THF (5 mL) was added a solution of n-BuMgBr, prepared from
n-BuBr (0.32 mL, 3.00 mmol) and Mg (72 mg, 3.00 mmol) in THF
(10 mL) at reflux, and TMEDA (0.48 mL, 3.00 mmol) in THF at
-78 °C, and the reaction mixture was stirred at the same
temperature for 1.5 h. The reaction was quenched with i-PrOH (1
mL), and diluted with Et2O. The ethereal layer was washed with
found 301.2027; [R]26 -7.83 (c 0.64, CHCl3).
D
(2S,5S)-(-)-2-n-Butyl-5-(4-oxopent-2E-enyl)pyrrolidine-1-car-
boxylic Acid Benzyl Ester (6). To a stirring solution of 5 (47 mg,
0.16 mmol) in CH2Cl2 (5 mL) were added methyl vinyl ketone (0.07
mL, 0.78 mmol) and Grubbs’ second catalyst (14 mg, 0.016 mmol),
4576 J. Org. Chem. Vol. 73, No. 12, 2008

EnantioselectiVe Syntheses of (-)-and (+)-Monomorine I
and the resulting mixture was refluxed for 6 h. After cooling, the
solvent was evaporated, and the residue was chromatographed on silica
gel (20 g, hexane/acetone 80:1-15:1) to give 6 (51 mg, 95%) as a
colorless oil: IR (neat) 3048, 1697, 1405 cm-1; 1H NMR (500 MHz,
CDCl3) δ 0.86 (3H, br), 1.26 (5H, br), 1.66 (3H, br), 1.95 (2H, br),
2.16 and 2.21 (3H, br), 2.40 (1H, br), 2.59 and 2.72 (1H, br), 3.85
(1H, br), 4.02 (1H, br), 5.12 (2H, ABq, J ) 11.5 Hz), 6.05 (1H, br),
6.75 (1H, br), 7.29-7.37 (5H, m); 13C NMR (75 MHz, CDCl3) δ 14.1
(q), 22.6 (t), 26.7 (q), 28.5 (t), 29.3 (t), 29.5 (t), 35.5 (t), 38.2 (t), 57.6
(d), 58.6 and 59.2 (each d), 66.7 (t), 127.6 and 127.8 (each d), 128.3
(d), 133.0 (d), 136.6 (s), 144.2 (d), 144.4 (d), 155.1 (s), 198.1 (s); MS
343 (M+), 216 (100); HRMS calcd for C21H29O3N 343.2148, found
(6H, br m), 1.54-1.71 (3H, m), 1.80 (1H, m), 2.03 (2H, q-like, J )
8.0 Hz), 2.37 (2H, t-like, J ) 6.9 Hz), 2.46 (2H, t-like, J ) 6.9 Hz),
3.58 (1H, br), 4.48 (1H, br d, J ) 10.5 Hz), 4.94-5.08 (4H, m), 5.75
(1H, m), 7.30-7.37 (5H, m); 13C NMR (75 MHz, CDCl3) δ 14.1 (q),
22.6 (t), 22.8 (t), 28.0 (t), 29.1 (t), 33.1 (t), 35.7 (t), 39.5 (t), 42.1 (t),
51.2 (d), 66.5 (t), 115.1 (t), 127.7 (d), 127.9 (d), 128.4 (d), 136.5 (s),
137.8 (d), 156.1 (s), 210.4 (s); MS 345 (M+), 244 (100); HRMS calcd
for C21H31O3N 345.2302, found 345.2315; [R]26 -2.32 (c 0.60,
D
CHCl3).
(2R,5S)-(+)-2-n-Butyl-5-(4-pentenyl)pyrrolidine-1-carboxyl-
ic Acid Benzyl Ester (10). To a stirring solution of 9 (440 mg, 1.27
mmol) in CH2Cl2 (10 mL) was added a solution of BF3 ·Et2O (0.65
mL, 5.10 mmol) and Ph3SiH (664 mg, 2.55 mmol) in CH2Cl2 (20
mL) at -78 °C, and the resulting mixture was stirred at the same
temperature for 0.5 h and then at room temperature for 2 h. The reaction
was quenched with saturated NaHCO3 at 0 °C, and the mixture was
diluted with Et2O. The organic layer was separated, and the aqueous
layer was extracted with Et2O (15 mL × 3). The organic extracts were
combined, dried over MgSO4, filtered, and evaporated to give a residue,
which was chromatographed on silica gel (40 g, hexane/acetone
100:1) to give 10 (376 mg, 90%) as a colorless oil: IR (neat) 3036,
343.2113; [R]26 -34.99 (c 0.90, CHCl3).
D
(3S,5R,9R)-(-)-3-n-Butyl-5-methyloctahydroindolizine ((-)-
Monomorine I, 1). To a stirring solution of 6 (125 mg, 0.36 mmol)
in EtOH (10 mL) was added 20% Pd(OH)2 (50 mg), and the
resulting suspension was hydrogenated at 1 atm for 48 h. The
catalyst was removed by filtration, and the filtrate was evaporated
to give (-)-1 (62.2 mg, 88%) as a pale pinkish oil: IR (neat) 2956,
1
2929, 2859, 1456, 1378, 1319, 1206, 1130 cm-1; H NMR (300
MHz, CDCl3) δ 0.86 (3H, t, J ) 7.1 Hz), 1.12 (3H, d, J ) 6.3
Hz), 1.18-1.38 (6H, m), 1.40-1.85 (6H, br m), 2.07 (1H, br), 2.22
(1H, m), 2.47 (1H, br t-like, J ) 9.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 14.2 (q), 22.7 (q), 22.9 (t), 24.9 (t), 29.5 (t), 29.7 (t),
30.2 (t), 30.7 (t), 35.6 (t), 39.4 (t), 60.4 (d), 63.1 (d), 67.3 (d); MS
1
1698, 1405, 1100 cm-1; H NMR (300 MHz, CDCl3) δ 0.88 (3H,
br), 1.20-1.42 (8H, br m), 1.54-2.14 (8H, br m), 3.83 (2H, br),
4.92-5.12 (4H, m), 5.77 (1H, br), 7.24-7.40 (5H, m); 13C NMR (75
MHz, CDCl3) δ 14.1 (q), 22.6 (t), 25.6 (t), 28.5 (t), 29.4 (t), 29.6 (t),
33.6 (t), 35.3 (t), 58.3 (d), 58.8 (d), 66.3 (t), 114.3 (t), 127.5 (d), 128.1
(d), 136.9 (s), 138.4 (d), 155.1 (s); MS 329 (M+), 228 (100); HRMS
calcd for C21H31O2N 329.2353, found 329.2371; [R]26D +3.53 (c 1.69,
CHCl3).
195 (M+), 138 (100); [R]26D -33.14 (c 0.87, n-hexane), lit.4b [R]26
-35.6 (c 0.5, n-hexane).
D
(2R)-(-)-2-n-Butyl-5-oxopyrrolidine-1-carboxylic Acid Ben-
zyl Ester (8). To a stirring solution of 7 (264 mg, 1.90 mmol) in
EtOAc (15 mL) was added 10% Pd/C (50 mg), and the resulting
suspension was hydrogenated under a hydrogen atmosphere at 1
atm for 45 h. The catalyst was removed by filtration, and the fitrate
was evaporated to give a colorless oil, which was used directly in
the next step. To a stirring solution of this oil in THF (5 mL) was
added a solution of LiHMDS, prepared from HMDS (0.44 mL,
2.10 mmol) and n-BuLi (1.6 M in hexane, 1.31 mL, 2.10 mmol) in
THF (10 mL) at 0 °C for 30 min, at -78 °C, and then the resulting
mixture was stirred at the same temperature for 30 min. To the
reaction mixture was added CbzCl (0.33 mL, 2.28 mmol) at -78
°C, and the reaction mixture was stirred at -78 °C for 0.5 h and
allowed to warm to 0 °C over 1 h. The reaction was quenched
with saturated NaHCO3, and the aqueous mixture was extracted
with CH2Cl2 (15 mL × 4). The organic extracts were combined,
dried over MgSO4, filtered, and evaporated to give a residue, which
was chromatographed on silica gel (25 g, hexane/acetone 25:1-10:
1) to give 8 (500 mg, 96%) as a colorless oil: IR (neat) 3058, 1790,
1749, 1715, 1292 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.87 (3H,
t, J ) 6.9 Hz), 1.19-1.37 (4H, m), 1.42-1.56 (1H, m), 1.71-1.83
(2H, m), 2.10 (1H, quint-like, J ) 8.5 Hz), 2.42 (1H, ddd, J )
17.9, 9.4, 2.8 Hz), 2.60 (1H, ddd, J ) 17.9, 11.2, 9.3 Hz), 4.15-4.21
(1H, m), 5.28 (2H, ABq, J ) 12.4 Hz), 7.29-7.43 (5H, m); 13C
NMR (75 MHz, CDCl3) δ 13.5 (q), 21.9 (t), 22.0 (t), 27.0 (t), 30.7
(t), 32.6 (t), 57.5 (d), 67.1 (t), 126.0 (d), 127.4 and 127.6 (each d),
127.8 (d), 134.7 (s), 150.6 (s), 173.2 (s); MS 275 (M+), 91 (100);
(2R,5S)-(+)-2-n-Butyl-5-(4-oxopentyl)pyrrolidine-1-carboxy-
lic Acid Benzyl Ester (11). To a stirring solution of 10 (98 mg,
0.30 mmol) in DMF (4.5 mL) and H2O (1.5 mL) were added CuCl
(31 mg, 0.30 mmol) and PdCl2 (16 mg, 0.09 mmol), and the
resulting suspension was stirred under oxygen atmosphere at 1 atm
at room temperature for 18 h. The insoluble materials were removed
by filtration, and washed with CH2Cl2. The filtrate was dried over
MgSO4, filtered and evaporated to give a residue, which was
chromatographed on silica gel (20 g, hexane/acetone 30:1-15:1)
to give 11 (88 mg, 86%) as a colorless oil: IR (neat) 1720, 1698,
1
1406, 1096 cm-1; H NMR (300 MHz, CDCl3) δ 0.87 (3H, br),
1.19-1.39 (6H, br m), 1.43-1.69 (5H, br m), 1.93 (3H, br), 2.07
(3H, br), 2.32-2.53 (2H, br), 3.82 (2H, br), 5.11 (2H, s), 7.24-7.39
(5H, m); 13C NMR (75 MHz, CDCl3) δ 14.1 (q), 20.4 (t), 22.6 (t),
28.5 (t), 29.2 (t), 29.8 (q), 35.4 (t), 43.4 (t), 58.4 (d), 66.4 (t), 127.6
(d), 128.2 (d), 136.8 (s), 155.1 (s); MS 345 (M+), 244 (100); HRMS
calcd for C21H31O3N 345.2302, found 345.2298; [R]26 +2.35 (c
D
0.45, CHCl3).
(3R,5S,9S)-(+)-3-n-Butyl-5-methyloctahydroindolizine ((+)-
Monomorine I, 1). To a stirring solution of 11 (88 mg, 0.26 mmol)
in EtOH (10 mL) was added 20% Pd(OH)2 (30 mg), and the
resulting suspension was hydrogenated at 1 atm for 48 h. The
catalyst was removed by filtration, and the filtrate was evaporated
to give (+)-1 (42 mg, 84%) as a pale pinkish oil. The spectral data
for synthetic (+)-1 were identical with those reported. [R]26D +33.32
HRMS calcd for C16H21O3N 275.1520, found 275.1549; [R]26
-67.43 (c 0.60, CHCl3).
D
(c 1.40, n-hexane), lit.5 [R]26 +34.0 (c 1.09, n-hexane).
D
(1R)-(-)-(1-n-Butyl-4-oxonon-8-enyl)carbamic Acid Benzyl
Ester (9). To a stirring solution of 8 (350 mg, 1.27 mmol) in THF
(10 mL) was added a solution of 5-pentenyl-MgBr, prepared from
5-bromo-1-pentene (0.45 mL, 3.81 mmol) and Mg (92 mg, 3.81 mmol)
in THF (20 mL) at reflux, and TMEDA (0.61 mL, 3.81 mmol) in
THF at -78 °C, and the reaction mixture was stirred at the same
temperature for 1.5 h. The reaction was quenched with i-PrOH (3 mL)
and diluted with Et2O. The ethereal layer was washed with 10% HCl
aqueous solution, dried over MgSO4, filtered, and evaporated to give
a residue, which was chromatographed on silica gel (20 g, hexane/
acetone 50:1-30:1) to give 9 (250 mg, 57%) as a colorless solid (mp
75-76 °C): IR (KBr) 3316, 3038, 1707, 1687, 1540, 1253 cm-1; 1H
NMR (500 MHz, CDCl3) δ 0.88 (3H, br t-like, J ) 7.2 Hz), 1.22-1.53
Acknowledgment. We would like to thank Drs. Thomas F.
Spande and H. Martin Garraffo, NIH, for very valuable suggestions
and discussions about this paper. This work was supported in part
by a grant-in-aid for Scientific Research (C, No. 17590004) by
the Japan Society for the Promotion of Science (JSPS).
Supporting Information Available: General experimental
procedures and 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800593N
J. Org. Chem. Vol. 73, No. 12, 2008 4577