Asymmetric synthesis of (+)-deoxoprosopinine

Full text of DOI:10.1021/jo015834u

J . Org. Chem. 2001, 66, 6829-6832
6829
Sch em e 1a
Asym m etr ic Syn th esis of
(+)-Deoxop r osop in in e
Daniel L. Comins,* Matthew J . Sandelier, and
Teresa Abad Grillo
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
daniel_comins@ncsu.edu
Received J une 13, 2001
Several 2,6-disubstituted piperidin-3-ol alkaloids have
been isolated from Prosopis africana,1 whose leaves have
been used in Africa to treat toothaches.2 Among these
various naturally occurring compounds are (+)-prosopi-
nine (1) and (()-prosophylline (2). These alkaloids pos-
sess antibiotic and anesthetic properties and have at-
tracted considerable interest as synthetic targets.3
A
reduction analogue of prosopinine, (+)-deoxoprosopinine
(3), also exhibits similar biological properties, and a
number of syntheses of this derivative have been re-
ported.4
a
Reagents and conditions: (a) 5 (2-Th ) 2-thienyl), THF, -78
°C; 10% HCl (70%). (b) NaOMe, MeOH, reflux; HCl, i-PrOH
(100%). (c) n-BuLi, PhOCOCl, THF, -78 °C (94%). (d) Pb(OAc)4,
toluene, reflux (57%). (e) HCO2H, reflux, 3.5 h; then NH3, MeOH,
0 °C (73%). (f) (-)-TCC ) (1R,2S)-2-(1-methyl-1-phenylethyl)cy-
clohexanol.
4-pyridones has been well-established in the past through
the asymmetric syntheses of various indolizidine,5 quino-
lizidine,6 and piperidine7 alkaloids. This study further
demonstrates that utility through the asymmetric syn-
thesis of 3 via the key intermediate dihydropyridone 9.
The 1-acylpyridinium salt 48 was treated with higher
order cyanocuprate 59 to afford dihydropyridone 6 in 70%
yield (Scheme 1). Reaction with sodium methoxide fol-
lowed by aqueous acid provided dihydropyridone 7 in
quantitative yield. N-Acylation of 7 with n-BuLi and
phenyl chloroformate gave a 94% yield of enantiopure
carbamate 8.
We describe here a short and efficient total synthesis
of enantiopure 3, which bears a 2,3-trans-3,6-cis config-
uration. The synthetic utility of chiral N-acyl-2,3-dihydro-
(1) Khuong-Huu, Q.; Ratle, G.; Monseur, X.; Goutarel, R. Bull. Soc.
Chim. Belg. 1972, 81, 425.
(2) Ayer, W. A.; Habgood, T. E. In The Alkaloids; Manske, R. H.,
Ed.; Academic Press: London, 1968; Vol. 11, p 492.
Treatment of 8 with Pb(OAc)410 afforded 9 in 57% yield
(>98% de; J H2-3 ) 1.5 Hz). Acetoxylation was carried out
(3) Previous synthesis of 1: (a) Cook, J . R.; Beholz, L. G.; Stille, J .
R. Tetrahedron Lett. 1994, 35, 1669 and references cited therein. (b)
Hirai, Y.; Watanabe, J .; Nozaki, T.; Yokoyama, H.; Yamaguchi, S. J .
Org. Chem. 1997, 62, 776. (c) Ojima, I.; Vidal, E. S. J . Org. Chem.
1998, 63, 7999. Previous synthesis of 2: (a) Natsume, M.; Ogawa, M.
Heterocycles 1981, 16, 973. (b) Yang, C.; Liao, L.; Xu, Y.; Zhang, H.;
Xia, P.; Zhou, W. Tetrahedron: Asymmetry 1999, 10, 2311.
(4) Previous synthesis of 3: (a) Saitoh, Y.; Moriyama, Y.; Takahashi,
T. Tetrahedron Lett. 1980, 21, 75. (b) Saitoh, Y.; Moriyama, Y.;
Takahashi, T.; Khuong-Huu, Q. Bull. Chem. Soc. J pn. 1981, 54, 488.
(c) Holmes, A. B.; Thompson, J .; Baxter, A. J . G.; Dixon, J . J . Chem.
Soc., Chem. Commun. 1985, 1, 37. (d) Ciufolini, M. A.; Hermann, C.
W.; Whitmire, K. H.; Byrne, N. E. J . Am. Chem. Soc. 1989, 111, 3473.
(e) Tadano, K.; Takao, K.; Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda,
K.; Ogawa, S. Synlett 1993, 565. (f) Tadano, K.; Takao, K.; Nigawara,
Y.; Nishino, E.; Takagi, I.; Maeda, K.; Ogawa, S. Tetrahedron 1994,
50, 5681. (g) Terakado, M.; Murai, K.; Miyazawa, M.; Yamamoto, K.
Tetrahedron 1994, 50, 5705. (h) Yuasa, Y.; Ando, J .; Shibuya, S.
Tetrahedron: Asymmetry 1995, 6, 1525. (i) Yuasa, Y.; Ando, J .;
Shibuya, S. J . Chem. Soc., Perkin Trans. 1 1996, 793. (j) Kadota, I.;
Kawada, M.; Muramatsu, Y.; Yamamoto, Y. Tetrahedron Lett. 1997,
38, 7469. (k) Kadota, K.; Kawada, M.; Muramatsu, Y.; Yamamoto, Y.
Tetrahedron: Asymmetry 1997, 8, 3887. (l) Agami, C.; Couty, F.;
Mathieu, H. Tetrahedron Lett. 1998, 39, 3505. (m) For an asymmetric
synthesis of (+)-2-epi-deoxoprosopinine, see: Enders, D.; Kirchhoff, J .
H. Synthesis 2000, 2099.
(5) (a) Comins, D. L.; Chen, X.; Morgan, L. A. J . Org. Chem. 1997,
62, 7435. (b) Comins, D. L.; Zhang, Y. J . Am. Chem. Soc. 1996, 118,
12248. (c) Comins, D. L.; Hong, H. J . Am. Chem. Soc. 1991, 113, 6672.
(d) Comins, D. L.; LaMunyon, D. H.; Chen, X. J . Org. Chem. 1997, 62,
8182. (e) Comins, D. L.; Fulp, A. B. Presented at the 217th National
Meeting of the American Chemical Society, Anaheim, CA, March 21-
25, 1999; ORGN 505.
(6) (a) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.; Goehring, R. R.
Org. Lett. 1999, 1, 229. (b) Comins, D. L.; Libby, A. H.; Al-awar, R. S.;
Foti, C. J . J . Org. Chem. 1999, 64, 2184. (c) Comins, D. L.; Dehghani,
A. J . Chem. Soc., Chem. Commun. 1993, 1838. (d) Comins, D. L.;
LaMunyon, D. H. J . Org. Chem. 1992, 57, 5807.
(7) (a) Comins, D. L.; Green, G. M. Tetrahedron Lett. 1998, 40, 217.
(b) Comins, D. L.; Zhang, Y.; Zheng, X. J . Chem. Soc., Chem. Commun.
1998, 2509. (c) Comins, D. L.; Hong, H. J . Org. Chem. 1993, 58, 5035.
(d) Al-awar, R. S.; J oseph, S. P.; Comins, D. L. Tetrahedron Lett. 1992,
33, 7635. (e) Comins, D. L.; Radi Benjelloun, N. Tetrahedron Lett. 1994,
35, 829.
(8) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc.
1994, 116, 4719.
(9) Compound 5 was prepared from benzyl chloromethyl ether by
Kaufman’s procedure (Kaufman, T. S. Synlett 1997, 1377), followed
by transmetalation to the organolithium and then to 5. All attempts
at forming the corresponding R-hetero-Grignard reagent were unsuc-
cessful.
10.1021/jo015834u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/06/2001

6830 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
Sch em e 2a
pands the considerable scope of N-acyl-2,3-dihydro-4-
pyridones as chiral building blocks for the enantioselec-
tive preparation of alkaloid natural products.
Exp er im en ta l Section
All reactions described in this section were performed using
oven-dried glassware under an argon or dry nitrogen atmo-
sphere. THF, toluene, and diethyl ether were dried by distillation
from sodium/benzophenone. Other reagents and solvents were
stored over molecular sieves under argon and used directly.
Radial PLC was done using a model 7924T Chromatotron
(Harrison Research, Palo Alto, CA) using thin layers of silica
gel-gypsum. Elemental analyses were performed by Atlantic
Microlabs, Norcross, GA.
(2S-1-[(1R,2S)-tr a n s-2-(r-Cu m yl)cycloh exyloxycar bon yl]-
2-(ben zyloxym eth yl)-5-(tr iisop r op ylsilyl)-2,3-d ih yd r o-4-p y-
r id on e (6). To a stirred solution of benzyloxymethyltributyl-
stannane (308 mg, 0.75 mmol) in THF cooled to -78 °C was
added 0.375 mL of n-butyllithium (2.0 M solution in hexanes).
After 30 min of stirring at -78 °C, 3.0 mL of lithium 2-thienyl-
cyanocuprate (0.25 M solution in diethyl ether) was added
dropwise. The mixture was allowed to stir for an additional 30
a
Reagents and conditions: (a) (1) NaBH4, CeCl3‚7H2O, MeOH,
-40 °C; (2) Ac2O, Et3N, DMAP, CH2Cl2 (98%, two steps). (b) (1)
BF3‚OEt2, CH2Cl2, -78 °C, 13; (2) H2, Pt/C, EtOH (71%, two steps).
(c) KOH, EtOH, 140 °C (85%).
prior to cyclization of the carbamate ring in order to
achieve the required stereochemistry at C-3. The stereo-
selectivity results because the C-2 substituent of 8 is in
an axial position as a result of A(1,3) strain.10 Cyclization
of 9 was effected by a one-pot procedure involving
cleavage of the benzyl ether and formation of a formate
ester via refluxing formic acid and subsequent treatment
with ammonia in MeOH at 0 °C to afford 10 in 73% yield.
The oxazolidinone ring in bicyclic compound 10 is critical
in controlling the introduction of the final stereocenter
at C-6.
min at -78 °C. In
a separate flask, a stirred solution of
4-methoxy-3-(triisopropylsilyl)pyridine (132.8 mg, 0.50 mmol) in
toluene was cooled to -30 °C, and 0.52 mL of (-)-TCC chloro-
formate8 (1.0 M solution in toluene) was added dropwise. This
solution was allowed to stir at -30 °C for 1 h, and then it was
cooled to -78 °C. Through a double-tipped stainless steel needle,
surrounded by a layer of dry ice, the cuprate solution was slowly
transferred to the pyridinium salt solution. The resulting
mixture was stirred for 1 h, at which point TLC showed complete
disappearance of starting material. The reaction was quenched
with 10% aqueous hydrochloric acid, and the mixture was stirred
for 1 h. The solution was diluted with EtOAc and then washed
with water and brine. The combined aqueous layers were
extracted twice with EtOAc, and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. Purification
by radial PLC (2-10% EtOAc/hexanes) yielded a colorless oil
that solidified upon standing. Recrystallization from methanol
afforded 215 mg (70%) of 6 as a white solid, mp 84-85 °C. A
small amount (16 mg, 5%) of the minor diastereomer was also
isolated. HPLC analysis of the crude reaction mixture showed
a de of 82%. [R]2D3 -30.9 (c 0.12, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.73 (s, 1H), 7.10-7.31 (m, 10H), 4.79 (m, 1H), 4.32 (s,
2H), 2.97-3.10 (m, 3H), 2.40 (m, 1H), 2.18 (m, 2H), 2.00 (m, 1H),
The allylic acetate 11 was generated in 98% yield by
selective 1,2-reduction11 of enone 10 and subsequent
acylation (Scheme 2). The bicyclic system in 11 forces the
2-substituent into a pseudoequatorial orientation, and
thus the subsequent C-6 addition occurs via a stereo-
electronically controlled axial attack12 to produce the
desired trans-2,6-product. Lewis acid promoted addition
of allylsilane 1313 to the N-acyliminium ion14 generated
in situ from 11 and BF3‚OEt2 afforded 14 in 71% yield
after catalytic hydrogenation of the diene intermediate.
The addition is completely stereoselective as none of the
corresponding cis diastereomer was observed.15 Finally,
saponification in aqueous NaOH of both the acetate ester
and the oxazolidinone ring afforded 3 in 85% yield. The
1.61-1.74 (m, 4H), 1.17-1.35 (m, 9H), 0.99-1.04 (m, 22H); 13
C
NMR (75 MHz, CDCl3) δ 196.2, 152.5, 147.7, 137.7, 128.4, 128.0,
127.9, 127.7, 125.2, 110.1, 77.8, 73.0, 58.4, 51.0, 50.9, 39.4, 38.1,
33.1, 30.8, 26.7, 25.8, 24.6, 21.5, 18.9, 11.2; IR (thin film, NaCl)
2942, 2863, 1716, 1659 cm-1. Anal. Calcd for C38H55:NO4Si: C,
73.86; H, 8.97; N, 2.27. Found: C, 73.92; H, 9.17; N, 2.34. HRMS
calcd for C38H55NO4Si 618.3979 (M + H)+, found 618.3986.
(2S)-2-(Ben zyloxym eth yl)-2,3-d ih yd r o-4-p yr id on e (7). To
a stirred solution of 6 (370 mg, 0.6 mmol) in MeOH (15 mL)
was added 1.37 mL of sodium methoxide (4.36 M solution in
MeOH). The solution was heated to reflux, and the reaction was
stirred for 18 h. The reation mixture was cooled to room
temperature, and 6 N HCl in 2-propanol was added dropwise
until the solution reached a pH of 1. This solution was allowed
to stir at room temperature for 1.25 h, after which the pH was
returned to 7 by the slow addition of solid Na2CO3. The solution
was concentrated in vacuo, and the resulting residue was
dissolved in EtOAc and filtered through Celite. Concentration
in vacuo and purification by radial PLC (50-100% EtOAc/
hexanes) gave 134 mg (100%) of 7 as a white solid, mp 107.8-
108.3 °C. [R]2D3 +285.3 (c 0.38, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.30-7.40 (m, 5H), 7.16 (d, 1H, J ) 7.0 Hz), 5.34 (br s,
1H), 5.02 (d, 1H, J ) 7.5 Hz), 4.56 (s, 1H), 3.92 (m, 1H), 3.56
(m, 2H), 2.34 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 191.7, 150.8,
137.4, 128.6, 128.1, 127.9, 99.5, 73.5, 71.6, 52.8, 38.4; IR (thin
mp, [R]D, and H and 13C NMR spectra of our synthetic 3
1
were in agreement with the literature data.4b,k
A highly stereocontrolled asymmetric synthesis of (+)-
deoxoprosopinine (3) has been carried out in 10 steps
from readily available starting materials. The synthetic
strategy should be amenable to the preparation of other
Prosopis africana alkaloids. This synthesis further ex-
(10) Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle, C. L.
Tetrahedron Lett. 1998, 39, 5693.
(11) (a) Luche, J .-L.; Gemal, A. L. J . Am. Chem. Soc. 1979, 101, 5848.
(b) Comins, D. L.; Hong, H.; Salvador, J . M. J . Org. Chem. 1991, 56,
7197.
(12) (a) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983; Chapter 6. (b) Kuethe, J . T.;
Comins, D. L. Org. Lett. 1999, 1, 1031.
(13) (a) Colvin, E. W. Silicon Reagents in Organic Synthesis;
Academic Press: San Diego, 1988; Chapter 5. (b) Smith, J . G.; Drozda,
S. E.; Petraglia, S. P.; Quinn, N. R.; Rice, E. M.; Taylor, B. S.;
Viswanathan, M. J . Org. Chem. 1984, 49, 4112.
(14) Comins, D. L.; Chung, G.; Foley, M. A. Heterocycles 1994, 37,
1121.
film, NaCl) 3255, 3036, 2858, 1619 cm-1. Anal. Calcd for C13H15
-
NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.58; H, 6.92; N,
6.37.
(2S)-2-(Ben zyloxym et h yl)-1-(p h en oxyca r b on yl)-2,3-d i-
h yd r o-4-p yr id on e (8). To a solution of 7 (16 mg, 0.0736 mmol)
(15) The C2, C6 trans stereochemistry in 14 was confirmed by the
observation of an NOE interaction between the C6 side chain protons
and the C2 proton.

Notes
J . Org. Chem., Vol. 66, No. 20, 2001 6831
in 1.0 mL of THF, cooled to -78 °C, was added 0.03 mL of
n-butyllithium (2.5 M solution in hexanes), and the mixture was
stirred for 20 min. Phenyl chloroformate (0.010 mL, 0.078 mmol)
was added, and the solution was stirred for 30 min. The reaction
was quenched with saturated NaHCO3 and then warmed to
room temperature. The solution was extracted with EtOAc,
washed with water (3×), dried over MgSO4, and concentrated
in vacuo. Purification by radial PLC (10-20% EtOAc/hexanes)
gave 23.2 mg (94%) of 8 as colorless oil. [R]2D3 -44.4 (c 2.17,
(CDCl3, 300 MHz) δ 6.73 (dd, J ) 2.1, 8.1 Hz, 1H), 5.65 (d, J )
2.4 Hz, 1H), 5.47 (d, J ) 2.4 Hz, 1H), 4.87 (d, J ) 8.8 Hz, 1H),
4.49 (t, J ) 8.1 Hz, 1H), 4.43 (m, 1H), 4.05 (t, J ) 8.1 Hz, 1H),
2.16 (s, 3H), 2.05 (s, 3H). EIMS (m/z) 256 (M)+ (100); HRMS
calcd for C11H23NO3 256.0821, found 256.0812.
Acetic Acid (2R,5R,8S)-5-Dod ecyl-3-oxo-h exa h yd r o-ox-
a zolo[3,4-a ]p yr id in -8-yl Ester (14). A solution of 13 (282.5 mg,
1.17 mmol) in CH2Cl2 (4 mL) was added via cannula to a
precooled (-78 °C) solution of 11 in CH2Cl2 (2.35 mL) under Ar,
followed by dropwise addition of BF3‚OEt2 (0.10 mL, 0.7 mmol).
After 1 h at -78 °C, the reaction was gradually warmed to -10
°C over a period of 3 h. The solution was cooled again to -30 °C
and then quenched with an aqueous saturated solution of
ammonium chloride. The reaction mixture was warmed to room
temperature and extracted with CH2Cl2 (3 × 5 mL). The
combined extracts were washed with brine and dried (Na2SO4).
The solvent was removed under vacuo to give the crude product,
which was unstable on silica gel (1H NMR (CDCl3, 500 MHz) δ
5.87 (dd, J ) 2.5, 9.2 Hz, 1H), 5.70 (d, J ) 10.2 Hz, 1H), 5.17
(dd, J ) 1.8, 7.6 Hz, 1H), 4.44 (t, J ) 8.9 Hz, 1H), 4.30 (dd, J )
4.8, 9.4 Hz, 1H), 4.22 (m, 1H), 3.70 (m, 1H), 2.35 (t, J ) 6.7 Hz,
2H), 2.12 (s, 3H), 1.98 (q, J ) 7.1 Hz, 2H), 1.32 (br s, 14H), 0.85
(t, J ) 6.6 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 170.6, 156.9,
135.4, 130.7, 125.5, 124.4, 69.4, 67.6, 52.7, 50.7, 36.9, 32.8, 32.1,
29.9, 29.8, 29.7, 29.6, 22.9, 21.2, 14.3). A solution of the crude
product in EtOH (4 mL) was added to a mixture of 5% Pt on
carbon (4.6 mg, 0.02 mmol of Pt) in ethanol (7 mL). The mixture
was stirred under H2 (1 atm) for 5 h and then filtered through
a Celite pad. The solvent was removed, and the residue was
purified by chromatography (silica gel, 20% EtOAc/hexanes) to
give 14 as a white solid (61 mg, 71%, 2 steps), mp 77.5-78.5 °C.
[R]2D3 +20.4 (c 0.225, CHCl3); 1H NMR (300 MHz, CDCl3) δ 4.48
(m, 1H), 4.35 (m, 1H), 4.11 (m, 1H), 3.91 (m, 1H), 3.68 (m, 1H),
2.06 (s, 3H), 1.58-1.81 (m, 5H), 1.45 (m, 1H), 1.25 (br s, 20H),
0.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 170.3, 157.0, 72.7,
66.4, 53.9, 49.1, 32.1, 30.0, 29.9, 29.8, 29.7, 29.6, 26.5, 24.9, 22.9,
21.2, 14.3; IR (thin film, NaCl) 2922, 2850, 1738 cm-1; HRMS
calcd for C22H38NO4 368.2801 (M + H)+, found 368.2799.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.88 (d, J ) 8.0 Hz, 1H),
7.21-7.38 (m, 8H), 7.05 (m, 2H), 5.39 (d, J ) 8.2 Hz, 1H), 4.95
(m, 1H), 4.51 (q, J ) 11.9 Hz, 2H), 3.72 (m, 1H), 3.60 (m, 1H),
2.92 (dd, J ) 6.9, 16.6 Hz, 1H), 2.62 (d, J ) 16.8 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 192.4, 151.5, 150.6, 141.7, 137.6, 129.6,
128.6, 127.9, 126.4, 121.4, 108.0, 73.5, 68.5, 52.9, 37.5; IR (thin
film, NaCl) 3064, 2864, 1738, 1674, 1608 cm-1. Anal. Calcd for
C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C, 71.19; H, 5.67;
N, 4.08.
(2R,3R)-3-Acetoxy-2-(ben zyloxym eth yl)-1-(p h en oxyca r -
bon yl)-2,3-d ih yd r o-4-p yr id on e (9). To a flask containing 8 (27
mg, 0.080 mmol) under a dry nitrogen atmosphere was added
Pb(OAc)4 (92 mg, 0.21 mmol, freshly recrystallized from glacial
acetic acid and dried in vacuo). Toluene (15 mL) was added, and
the mixture was heated at reflux for 18 h. By TLC, the reaction
was not complete, and no active Pb(OAc)4 appeared to be present.
Additional Pb(OAc)4 (35 mg, 0.080 mmol) was added, and
refluxing was resumed for another 6 h. After cooling to room
temperature, the solution was filtered through silica gel with
EtOAc and concentrated in vacuo. Purification by radial PLC
(20% EtOAc/hexanes) gave 18 mg (57%) of 9 as a colorless oil.
[R]2D3 +88.5 (c 2.055, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.03
(d, 1H, J ) 8.4 Hz), 7.25-7.42 (m, 10H), 7.07 (m, 2H), 5.50 (d,
1H, J ) 8.6 Hz), 5.29 (s, 1H), 4.91 (br s, 1H), 4.53 (s, 2H), 3.77
(m, 2H), 2.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 186.6, 169.6,
150.5, 142.7, 137.3, 129.8, 128.7, 128.1, 127.9, 126.7, 121.4, 106.5,
73.7, 70.1, 67.5, 58.1, 21.2; IR (thin film, NaCl) 3076, 2920, 2858,
1745, 1677 cm-1. Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35;
N, 3.54. Found: C, 66.77; H, 5.34; N, 3.49.
(2R,3S,6R)-6-Dod ecyl-2-h yd r oxym eth yl-p yp er id in -3-ol,
(+)-Deoxop r osop in in e (3). A solution of 14 (27.5 mg, 0.075
mmol) in a mixture of EtOH (2.7 mL) and 8 M aqueous KOH
(2.7 mL) was heated at 140 °C in a sealed tube for 12 h. After
cooling to room temperature, the solution was diluted with H2O
(60 mL) and extracted with CH2Cl2 (3 × 30 mL). The combined
extracts were dried and concentrated in vacuo. The residue was
purified by chromatography (silica gel, CH2Cl2/MeOH/NH4OH
) 9:1:1) to give 3 (19.3 mg, 86%) as colorless crystals, mp 88.5
(8R,9R)-8-Acet oxy-8,8a -d ih yd r o-1H -oxa zolo[3,4-r]p yr i-
d in e-3,7-d ion e (10). A solution of 9 (342 mg, 0.865 mmol) in
formic acid (9 mL) was refluxed for 3.5 h. The solution was
concentrated in vacuo. The residue was dissolved in MeOH and
cooled to 0 °C. To this solution was added 0.432 mL of ammonia
(2.0 M solution in methanol), and the mixture was stirred for
30 min. The ammonia was then quenched with a few drops of
glacial acetic acid, and the solution was concentrated in vacuo.
Purification by radial PLC and recrystallization from EtOAc
afforded 134 mg (73%) of 10 as a white solid, mp 180.8-182.0
°C. [R]2D3 +374.5 (c 0.235, MeOH); 1H NMR (300 MHz, CDCl3) δ
7.64 (d, 1H, J ) 7.8 Hz), 5.56 (d, 1H, J ) 7.7 Hz), 5.42 (d, 1H,
J ) 13.0 Hz), 4.69 (t, 1H, J ) 13.0 Hz), 4.69 (t, 1H, J ) 8.0 Hz),
4.48 (m, 1H), 4.34 (t, 1H, J ) 9.2 Hz), 2.23 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 187.4, 169.7, 151.9, 139.2, 107.4, 72.7, 67.9, 55.1,
°C. [R]2D3 +12.2 (c 0.015, CHCl3); H NMR (500 MHz, CDCl3) δ
1
3.60-3.67 (m, 2H), 3.54 (m, 1H), 2.87 (br q, J ) 6.0 Hz, 1H),
2.76 (br q, J ) 5.0 Hz, 1H), 2.00 (br s, 3H), 1.47-1.77 (m, 4H),
1.26 (br s, 22H), 0.88 (t, J ) 6.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 68.3, 62.5, 58.3, 50.0, 34.2, 32.2, 29.8, 29.6, 28.8, 27.6,
26.6, 22.9, 14.3; EIMS (m/z) 300.0 (M)+ (100); HRMS calcd for
C18H37NO2 300.2903, found 300.2916.
20.7; IR (thin film, NaCl) 2915, 2849, 1777, 1752, 1677 cm-1
.
Anal. Calcd for C9H9NO5: C, 51.19; H, 4.30; N, 6.63. Found: C,
51.27; H, 4.50; N, 6.35.
1-Ch lor o-d od ec-2-en e (12).13 To a solution of trans-2-dode-
cen-1-ol (184.3 mg, 1 mmol) in CH2Cl2 (10 mL) at room
temperature was added CCl4 (0.3 mL, 3 mmol) followed by Ph3P
(393.4 mg, 1.5 mmol). After 16 h of stirring, the solvent was
removed under reduced pressure, and the residue was purified
by chromatography (silica gel, 10% EtOAc/hexanes) to give 12
Acetic Acid (2R,8R)7-Acetoxy-3-oxo-1,7,8,8a -tetr a h yd r o-
oxa zolo[3,4-a ]p yr id in -8-yl Ester (11). Solid CeCl3‚7H2O (353
mg, 0.94 mmol) was added to a solution of 10 (100 mg, 0.47
mmol) in anhydrous MeOH (29 mL). Once homogeneous, NaBH4
(53.8 mg, 1.42 mmol) was added to the resulting solution at -40
°C. After 30 min of stirring at -40 °C, the reaction was quenched
by addition of acetone (1 mL) and allowed to warm to room
temperature. The mixture was concentrated ,and dry CH2Cl2 (5
mL) was added under Ar. Triethylamine (0.19 mL, 1.41 mmol)
was added followed by Ac2O (0.13 mL, 1.41 mmol) and DMAP
(catalytic amount) at room temperature. After 12 h the mixture
was concentrated, and the residue was purified by chromatog-
raphy (silica gel, 15% EtOAc/hexanes) to give 11 as a diaster-
eomeric mixture of acetate esters (118 mg, 98%). Major diaste-
reomer: 1H NMR (CDCl3, 300 MHz) δ 6.69 (dd, J ) 2.0, 7.8 Hz,
1H), 5.64 (d, J ) 7.8 Hz, 1H), 5.18 (dd, J ) 8.1, 10.2 Hz, 1H),
4.95 (dd, J ) 2.1, 8.1 Hz, 1H), 4.51 (t, J ) 9.0 Hz, 1H), 4.27 (t,
J ) 9.0 Hz, 1H), 4.13 (m, 1H), 2.10 (s, 3H), 2.07 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ 170.8, 170.3, 153.2, 123.6, 105.95, 71.2,
70.25, 67.15, 54.1, 21.1, 20.8. Minor diastereomer: 1H NMR
1
(183.0 mg, 90%) as a colorless oil. H NMR (CDCl3, 300 MHz) δ
5.76 (m, 1H), 5.60 (m, 2H), 4.03 (d, J ) 7.2 Hz, 2H), 2.05 (dd, J
) 6.2, 13.6 Hz, 2H), 1.26 (br s, 14H), 0.88 (t, J ) 6.6 Hz, 3H);
13C NMR (CDCl3, 75 MHz) δ 136.4, 126.0, 45.6, 32.2, 32.1, 29.7,
29.6, 29.5, 29.3, 29.0, 22.8, 14.2.
Tr im eth yl-(1-n on yl-a llyl)-sila n e (13).13 To a stirred solu-
tion of hexamethyldisilane (0.46 mL, 2.25 mmol) in HMPA (2.8
mL) at 0 °C was added methyllithium (1.5 mL, 2.25 mmol, 1.5
M MeLi‚LiBr complex in ether) dropwise. After 3 min, the red
solution was treated with CuBr‚Me2S (462.0 mg, 2.25 mmol) in
Me2S (1 mL), and the resulting black reaction mixture was
stirred for 3 min. Ether (5.6 mL) was added, and the reaction
mixture was cooled to -60 °C and stirred for 5 min. A solution
of 12 (183.0 mg, 0.90 mmol) in ether (0.9 mL) was added
dropwise, and the mixture was stirred for 1 h at -60 to -40 °C.
The cold solution was poured into a mixture of hexanes (50 mL)

6832 J . Org. Chem., Vol. 66, No. 20, 2001
Notes
and saturated ammonium chloride solution (50 mL, buffered to
pH 8 by the addition of ammonium hydroxide), and the mixture
was stirred vigorously for 1 h. The aqueous phase was extracted
with hexanes, and the combined organic extracts were dried
(Na2SO4) and concentrated. Purification by chromatography
(silica gel, hexanes) gave 13 (129.7 mg, 54%) as a colorless oil.
1H NMR (CDCl3, 300 MHz) δ 5.60 (m, 1H), 4.84 (m, 2H), 1.32
(m, 2H), 1.26 (br s, 15H), 0.88 (t, J ) 6.6 Hz, 3H), -0.03 (s, 9H);
13C NMR (CDCl3, 75 MHz) δ 140.8, 111.8, 35.4, 32.4, 30.2, 29.9,
29.8, 29.5, 22.8, 14.3, -2.2.
Islands Government (Consejer´ıa de Educacio´n, Cultura
y Deportes) for fellowship support to T.A.G. NMR and
mass spectra were obtained at NCSU instrumentation
laboratories, which were established by grants from the
North Carolina Biotechnology Center and the National
Science Foundation (grants CHE-9121380 and CHE-
9509532).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for 3, 11, and 14. This material is available free
of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. We express appreciation to the
National Institutes of Health (grant GM 34442) for
financial support of this research. We thank the Canary
J O015834U