Synthesis of (-)-epibatidine and its derivatives from chiral allene-1,3-dicarboxylate esters

Article abstract of DOI:10.1248/cpb.54.399

(-)-Epibatidine, an excellent candidate of non-opioidal anesthesia, was formally synthesized in short steps from di-(l)-menthyl (R)-allene-1,3- dicarboxylate that was facilely prepared as a single isomer by means of crystallization-induced asymmetric tran

Full text of DOI:10.1248/cpb.54.399

March 2006
Notes
Chem. Pharm. Bull. 54(3) 399—402 (2006)
399
Synthesis of (ꢀ)-Epibatidine and Its Derivatives from Chiral Allene-1,3-
dicarboxylate Esters
Hiroyuki KIMURA, Toshio FUJIWARA, Takahiro KATOH, Kiyoharu NISHIDE, Tetsuya KAJIMOTO, and
Manabu NODE*
Department of Pharmaceutical Manufacturing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University;
1 Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607–8412, Japan.
Received October 18, 2005; accepted December 6, 2005
(ꢀ)-Epibatidine, an excellent candidate of non-opioidal anesthesia, was formally synthesized in short steps
from di-(l)-menthyl (R)-allene-1,3-dicarboxylate that was facilely prepared as a single isomer by means of crys-
tallization-induced asymmetric transformation from a diastereomer mixture of (R)- and (S)-allene-1,3-dicar-
boxylates. Taking advantage of the chiral synthesis, derivatives of (ꢀ)-epibatidine were also prepared for target-
ing diagnostic agents that could bind nicotinic acetylcholine receptors (nAChRs) in the mammalian central nerve
system.
Key words (ꢀ)-epibatidine; non-opioidal anesthesia; chiral allene-1,3-dicarboxylate; crystallization induced asymmetric trans-
formation
(ꢀ)-Epibatidine (1) is an alkaloid isolated from the am- the (l)-menthyl group in the dienophile 2.26) After hydrogena-
phibian skin of the Equadorian poison frog, Epipedobates tion of the isolated double bond of the endo adduct (ꢀ)-4,
tricolor,1) of which collection is forbidden by the interna- the obtained diester 5 was ozonolyzed to b-ketoester 6,
tional treaty for the protection of endangered species since it which was derived to a known synthetic intermediate 7 of
was enacted in 1984. Combined with the restrictions under (ꢀ)-epibatidine by dealkoxycarbonylation and successive re-
the treaty, the scarce availability in nature and the exciting bi- protection of the secondary amino group with the Boc2O. All
ological properties including anesthetic activity2—4) required of the physical and spectral data of 7 were in complete agree-
facile synthetic routes to 1 and its derivatives for further bio- ment with those in the literature.7) In order to avoid the gen-
logical and pharmaceutical investigation. Although much eration of presumed by-products caused by excessive ozonol-
progress has been attained in the last decade providing prac- ysis of the enol form derived from b-ketoester 6, the syn-
tical synthetic methods,5—24) optically pure (ꢀ)-1 still re- thetic route was revised to circumvent keto-enol tautomeriza-
mains as an attractive synthetic target because it is focused tion of the product in the ozonolysis. Namely, 5 was first re-
on as an excellent candidate of non-opioidic analgesic agent duced with lithium aluminum hydride to afford diol 8, of
for clinical use in accordance with the development of bio- which the double bond of the allylic alcohol moiety was next
logical studies.
ozonolyzed to give b-keto alcohol 9. Thus, it was oxidized
In the present paper, we would like to report the asymmet- by Jones oxidation and successively decarboxylated by heat-
ric synthesis of (ꢀ)-1 and its derivatives by means of the ing in toluene to yield (ꢀ)-7. Although the overall yield from
crystallization-induced asymmetric transformation of allene- 5 to 7 was not substantially improved, the synthetic route af-
1,3-dicarboxylates, of which a practical method was estab- forded high reproducibility reflecting the fact that the tedious
lished by our group.25)
A mixture of (S)- and (R)-isomers of di-(l)-menthyl allene- (Chart 1).
procedure of isolation in each step could be dispensed with
1,3-dicarboxylate (diastereo ratioꢁ5 : 4) prepared from di-
Meanwhile, the structure of (ꢀ)-epibatidine [(ꢀ)-1] and
(l)-menthyl 1,3-acetonedicarboxylate by reaction with 2- its analogues, such as 3-(2(S)-azetidinylmethoxy)pyridine
chloro-1,3-dimethylimidazolinium chloride (DMC) and tri- (10) (Fig. 1.),27,28) must be labeled with radio isotopes, e.g.,
ethylamine was crystallized in the presence of triethylamine 123I, to develop further studies on binding to nicotinic acetyl-
(0.01 eq) at low temperature to afford di-(l)-menthyl (R)-al- choline receptors (nAChRs) in the mammalian central nerve
lene-1,3-dicarboxylate (2) as a single crystal. Repeating the system by using single photon emission computed tomogra-
same procedure three times gave 2 in total 90% yield. En- phy (SPECT), the most useful bioimaging method in vivo.
couraged by the results, we adopted the chiral allene-1,3-di- Thus, (ꢀ)-epibatidine derivative 11 was designed as a novel
carboxylates 2 as a dienophile of Diels–Alder reaction with diagnostic agent for pharmaceutical studies of (ꢀ)-1, and
N-Boc-pyrrole 3. Fortunately, the Diels–Alder reaction con- preparation from (ꢀ)-7 using 126I instead of 123I as a model
ducted in the presence of AlCl3 at ꢀ78 °C in CH2Cl2 af- synthesis of radioactive 11 was attempted. Namely, (ꢀ)-7
forded endo-adduct 4 as the sole product in good yield while was treated with 2-bromo-5-iodopyridine29,30) in the presence
the same reaction of methyl allene-1,3-dicarboxylate and 3 of n-butyl lithium to give tert-alcohol 12,7) of which the
gave an inseparable mixture of almost the same amounts of bromine group on the pyridine ring was replaced with iodine
the endo and exo adducts both at low temperature (ꢀ78 °C) by the reaction with sodium iodide and hydrochloric acid in
with the assistance of AlCl3 in CH2Cl2 and at high tempera- refluxed acetonitrile to afford 11.32) Having the secondary
ture (90 °C) in the absence of the Lewis acid in toluene. The amino group, it was protected again with a tert-butyloxycar-
significant difference in endo/exo selectivity could be attrib- bonyl group to afford 13 for facile isolation (Chart 2).
uted to the steric repulsion between the Boc group of 3 and
∗ To whom correspondence should be addressed. e-mail: node@mb.kyoto-phu.ac.jp
© 2006 Pharmaceutical Society of Japan

400
Vol. 54, No. 3
Chart 1
Chart 2
silica gel column chromatography (hexane : ethyl acetateꢁ10 : 1) to afford
(ꢀ)-4 (5.6 g, 88%) as colorless crystals.
mp 143—144 °C (methanol); 1H-NMR (300 MHz, CDCl3) d: 0.70 (3H, d,
Jꢁ6.6 Hz), 0.75 (3H, d, Jꢁ6.6 Hz), 0.86 (6H, d, Jꢁ6.6 Hz), 0.91 (6H, d,
Jꢁ6.9 Hz), 0.85—1.09 (6H, m), 1.31—1.44 (3H, m), 1.41 (9H, s), 1.55 (1H,
s), 1.64 (2H, s), 1.68 (2H, s), 1.84—2.04 (4H, m), 4.06 (1H, s), 4.55 (1H, dt,
Fig. 1
Experimental
General Infrared (IR) spectra were recorded on a Shimadzu FTIR-8300 Jꢁ10.8, 4.3 Hz), 4.63 (1H, dt, Jꢁ11.0, 4.5 Hz), 4.90 (1H, s), 5.0 (1H, s),
diffraction grating infrared spectrophotometer and 1H-NMR spectra were 6.04 (1H, d, Jꢁ1.7 Hz), 6.30 (1H, dd, Jꢁ2.0, 5.7 Hz), 6.40 (1H, d,
Jꢁ3.5 Hz). 13C-NMR (75 MHz, CDCl3) d: 16.1, 16.4, 20.6, 20.8, 21.92,
21.95, 23.1, 23.5, 25.6, 26.1, 28.1 (3), 31.3, 31.4, 34.19, 34.22, 40.5, 40.8,
obtained on a JEOL JNM-AL300, a Varian XL-300, or a JEOL JNM-LA
500 spectrometer with tetramethylsilane as an internal standard. 13C-NMR
spectra were obtained on a JEOL JNM-AL300 spectrometer with CDCl3 as
an internal standard. Mass spectra (MS) were determined on a JEOL JMS-
SX 102A QQ or a JEOL JMS-GC-mate mass spectrometer. Specific rota-
46.8, 46.9, 49.8, 62.5, 67.1, 74.1, 74.8, 81.0, 115.6, 133.2, 135.2, 151.3,
154.1, 165.4, 168.3. IR (CHCl3) cmꢀ1: 2958, 2930, 1705, 1369, 1175. FAB-
MS m/z: 572.3955 (Calcd for C34H54NO6: 572.3951). MS (FAB) m/z: 572
tions were recorded on a Horiba SEPA-200 automatic digital polarimeter. (MꢂꢂH, 9). [a]1D7 ꢀ3.2° (cꢁ0.68, CHCl3). Anal. Calcd for C34H53NO6: C,
Wakogel C-200 (silica gel) (100—200 mesh, Wako) was used for open col- 71.42; H, 9.34; N, 2.45; O, 16.79. Found: C, 71.60; H, 9.17; N, 2.38; O,
umn chromatography. Flash column chromatography was performed by 16.64.
using Silica Gel 60N (Kanto Chemical Co., Inc.) as a solid support of immo-
(1S,2R,3E,4R)-(ꢀ)-(l)-Menthyl 7-tert-Butoxycarbonyl-3-[2ꢁ-(l)-men-
bile phase. Kieselgel 60 F-254 plates (Merck) were used for thin-layer chro- thyloxy-2ꢁ-oxyethylidene]-7-azabicyclo[2.2.1]heptan-2-carboxylate [(ꢀ)-
matography (TLC). Preparative TLC (PTLC) was conducted with Kieselgel 5] A catalytic amount of 10% Pd–C was added to a solution of (ꢀ)-4
60 F-254 plate (0.25 mm, Merck) or Silica gel 60 F-254 plate (0.5 mm,
(1.00 g, 1.75 mmol) in ethyl acetate (24.0 ml), and the mixture was stirred
Merck). Unless purification with silica gel gave a compound of sufficiently under hydrogen atmosphere. After 1 h, the mixture was filtered to remove
purity, the compounds were further treated with a recycle HPLC (JAI LC- the catalyst and condensed in vacuo. The residue was purified with silica gel
908) on GPC column (JAIGEL 1H and 2H). In the case it is possible, di-
column chromatography (hexane : ethyl acetateꢁ10 : 1) to afford (ꢀ)-5
astereomeric mixtures were also separated by a recycle HPLC (JAI LC-908) (1.00 g, 99%) as colorless crystals.
on silica gel column (Kusano Si-10) after the purification mentioned above.
(1S,2R,3E,4R)-(ꢀ)-(l)-Menthyl 7-tert-Butoxycarbonyl-3-[2ꢁ-(l)-men- Jꢁ6.9 Hz), 0.77 (3H, d, Jꢁ6.9 Hz), 0.87—1.41 (18H, m), 1.43 (9H, s),
thyloxy-2ꢁ-oxoethylidene]-7-azabicyclo[2.2.1]hept-5-ene-2-carboxylate 1.49—2.15 (16H, m), 4.00 (1H, s), 4.50—4.54 (2H, m), 4.63 (2H, tt,
mp 152—153 °C (methanol); 1H-NMR (500 MHz, CDCl3) d: 0.72 (3H, d,
[(ꢀ)-4] Aluminum chloride (1.78 g, 13.4 mmol) was added to a solution of
(R)-(ꢀ)-bis-(l)-menthyl 2,3-pentadiendioate [(ꢀ)-2] (4.5 g, 11.1 mmol) in
dichloromethane (50 ml) at ꢀ78 °C, and the mixture was stirred for 30 min.
Jꢁ10.6, 4.2 Hz), 5.88 (1H, d, Jꢁ2.6 Hz). 13C-NMR (75 MHz, CDCl3) d:
16.0, 16.4, 20.6, 20.9, 21.95, 21.98, 23.0, 23.5, 25.0, 25.6, 26.1, 27.4, 28.2
(3), 31.3, 31.4, 34.2, 34.2, 40.7, 40.9, 46.8, 46.9, 53.1, 58.9, 63.6, 73.8, 74.8,
1-tert-Butoxycarbonylpyrrole (18.6 g, 111.2 mmol) was added slowly, and 80.6, 112.6, 154.9, 157.0, 165.5, 168.6. IR (CHCl3) cmꢀ1: 2959, 2872, 1701,
the reaction mixture was stirred at ꢀ78 °C. The mixture was poured into ice- 1369, 1161. FAB-MS m/z: 574.4113 (Calcd for C34H56NO6: 574.4113). MS
water after 2 d and extracted with chloroform. The organic layer was dried (FAB) m/z: 574 (MꢂꢂH, 10). [a]1D7 ꢀ75.1° (cꢁ1.2, CHCl3). Anal. Calcd for
over sodium sulfate and condensed in vacuo. The residue was purified with C34H55NO6: C, 71.17; H, 9.66; N, 2.44; O, 16.73. Found: C, 71.12; H, 9.50;

March 2006
401
N, 2.40; O, 16.45.
and the residue was purified by silica gel column chromatography (chloro-
(1S,4R)-(l)-Menthyl 7-tert-Butoxycarbonyl-3-oxo-7-azabicyclo[2.2.1]- form : methanolꢁ15 : 1) to afford (ꢀ)-7 (156 mg, 54%).
heptan-2-carboxylate (6) Ozone gas was passed through a solution of
(ꢀ)-5 (100 mg, 0.17 mmol) in dichloromethane (20 ml) at ꢀ78 °C until the
(1R,2S,4S)-(ꢂ)-2-(2
bicyclo[2.2.1]heptan-2-ol [(ꢂ)-12] n-Buthyl lithium (1.6 M solution in
ꢁ-Bromopyridin-5ꢁ-yl)-7-tert-butoxycarbonyl-7-aza-
blue color remained in the solution, and then nitrogen gas was bubbled. Di- hexane, 1.48 ml, 2.37 mmol) was added to a solution of 2-bromo-5-iodopyri-
methyl sulfide (54 mg, 0.87 mmol) was added, and the mixture was stirred at dine (673 mg, 2.37 mmol) in diethyl ether (5.0 ml) and tetrahydrofuran
room temperature for 1 d. The organic solvent was evaporated off, and the (5.0 ml) at ꢀ78 °C, and the mixture was stirred for 20 min. A solution of
residue was purified with silica gel column chromatography (hexane : ethyl (ꢀ)-7 (250 mg, 1.18 mmol) in tetrahydrofuran (2.0 ml) was added to the so-
acetateꢁ7 : 1) to afford 6 (23 mg, 52%) as colorless oil, and the spectral data
showed it to be a mixture of exo- and endo-isomers (1 : 1).
lution, and the mixture was stirred at ꢀ50 °C for 30 min. After the reaction,
the reaction mixture was poured into saturated aqueous solution of ammo-
1H-NMR (300 MHz, CDCl3) d: 0.75 (3H, d, Jꢁ6.8 Hz), 0.88—1.26 (7H, nium chloride and extracted with chloroform. The organic layer was dried
m), 1.46 (9H, s), 1.43—1.52 (1.5H, m), 1.63—1.73 (5H, m), 1.88—2.05 over sodium sulfatesodium sulfate and condensed in vacuo. The residue was
(6H, m), 2.97 (0.5H, s), 3.43 (0.5H, d, Jꢁ5.2 Hz), 4.31 (0.5H, d, Jꢁ5.6 Hz),
purified by silica gel column chromatography (chloroform : methanolꢁ
15 : 1) to afford (ꢂ)-12 (423 mg, 97%) as colorless crystals.
4.37 (0.5H, m), 4.68—4.77 (2ꢃ0.5H, m), 4.84 (0.5H, m). IR (CHCl3) cmꢀ1
:
2959, 1778, 1717, 1701, 1369, 1221, 1161. FAB-MS m/z: 394.2607 (Calcd
mp 152—153 °C (methanol); 1H-NMR (500 MHz, CDCl3) d: 1.39 (9H,
s), 1.65—1.67 (3H, m), 1.82 (1H, br s), 2.27—2.30 (1H, m), 2.39—2.43
(1H, m), 3.62 (1H, br s), 4.18 (1H, s), 4.27 (1H, s), 7.40 (1H, d, Jꢁ8.4 Hz),
7.74 (1H, dd, Jꢁ8.4, 1.7 Hz), 8.47 (1H, s). 13C-NMR (75 MHz, CDCl3) d:
for C22H36O5N: 394.2594). MS (FAB) m/z: 394 (MꢂꢂH, 7).
(1R,4S)-(ꢀ)-7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]heptan-2-one
[(ꢀ)-7] 10% Hydrochloric acid (1.5 ml) was added to
6 (59 mg,
0.15 mmol) and the mixture was refluxed. Ethanol was added to the mixture 22.6, 28.2 (3), 28.8, 48.0, 57.2, 65.6, 78.0, 80.3, 127.4, 136.2, 140.3, 143.2,
after 12 h, and the solvent was evaporated off. The residue was dried and 147.7, 154.9. IR (CHCl3) cmꢀ1: 2985, 2930, 1705, 1369, 1175. FAB-MS
dissolved in dichloromethane (4.0 ml), to which triethylamine (46 mg, m/z: 369.0817 (Calcd for C16H22N2O3Br: 369.0814). MS (FAB) m/z:
0.45 mmol) and di-tert-butyl dicarbonate (65 mg, 0.30 mmol) were added.
After stirring the mixture for 1 d at room temperature, the reaction mixture
was poured into saturated aqueous solution of sodium chloride and extracted
with chloroform. The organic layer was dried over sodium sulfate and con-
369 (MꢂꢂH, 100). [a]2D2 ꢂ17.6° (cꢁ1.0, CHCl3). Anal. Calcd for
C16H21N2O3Br: C, 52.04; H, 5.73; N, 7.59; O, 13.00; Br, 21.64. Found: C,
51.74; H, 5.66; N, 7.37; O, 13.27; Br, 21.52.
(1R,2S,4S)-(ꢂ)-2-(2ꢁ-Iodopyridin-5ꢁ-yl)-7-tert-butoxycarbonyl-7-aza-
densed in vacuo. The residue was purified with silica gel column chromatog- bicyclo[2.2.1]heptan-2-ol [(ꢂ)-13] Sodium iodide (2.436 g, 16.2 mmol)
raphy (hexane : ethyl acetateꢁ7 : 1) to afford (ꢀ)-7 (23 mg, 72%) as color- and 35% hydrochloric acid (2 portion) were added to a solution of (ꢀ)-12
less oil.7)
(600 mg, 1.62 mmol) in acetonitrile (20 ml), and the mixture was refluxed for
1H-NMR (500 MHz, CDCl3) d: 1.45 (9H, s), 1.57—1.67 (2H, m), 1.94— 1 d. After the reaction, the reaction mixture was poured into saturated aque-
2.06 (3H, m), 2.47 (1H, dd, Jꢁ17.4, 5.2 Hz), 4.24 (1H, d, Jꢁ4.9 Hz), 4.55
ous solution of sodium bicarbonate and extracted with chloroform. The or-
(1H, t, Jꢁ4.5 Hz). 13C-NMR (75 MHz, CDCl3) d: 24.3, 27.4, 28.0 (3), 45.0, ganic layer was washed with saturated aqueous solution of sodium thiosul-
55.9, 63.8, 80.6, 154.9, 209.3. IR (CHCl3) cmꢀ1: 1760, 1690. FAB-MS m/z: fate, dried over sodium sulfatesodium sulfate, and condensed in vacuo to
212.1297 (Calcd for C11H18NO3: 212.1287). MS (FAB) m/z: 212 (MꢂꢂH, give a crude of (1R,2S,4S)-2-(2ꢄ-iodopyridin-5ꢄ-yl)-7-azabicyclo[2.2.1]hep-
25). [a]1D7 ꢀ74.5° (cꢁ1.0, CHCl3). Anal. Calcd for C11H17NO3: C, 62.54; H, tan-2-ol (11). To a solution of this crude product in dichloromethane (14 ml)
8.11; N, 6.63; O, 22.72. Found: C, 62.47; H, 7.92; N, 6.61; O, 22.45.
(1R,3S,4S)-(ꢂ)-7-tert-Butoxycarbonyl-2-(2ꢁ-hydroxyethylidene)-3-hy- (530 mg, 2.43 mmol), and the mixture was stirred at room temperature. After
droxymethyl-7-azabicyclo[2.2.1]heptane [(ꢂ)-8] To suspension of 10 h, the reaction mixture was poured into saturated aqueous solution of
were added triethylamine (246 mg, 2.43 mmol) and di-tert-butyl dicarbonate
a
lithium aluminum hydride (595 mg, 15.7 mmol) in tetrahydrofuran (10 ml), a sodium chloride and extracted with chloroform. The organic layer was dried
solution of (ꢀ)-5 (4.50 g, 7.84 mmol) in tetrahydrofuran (5 ml) was added over sodium sulfate, and condensed in vacuo. The residue was purified by
dropwise, and the mixture was stirred at room temperature. After 24 h, satu-
rated aqueous solution of sodium sulfate was added to the reaction mixture
which was dried over sodium sulfate, filtrated, and evaporated. The residue
was purified by silica gel column chromatography (chloroform :
methanolꢁ20 : 1) to afford (ꢂ)-8 (2.11 g, 90%) as colorless oil.
silica gel column chromatography (chloroform : methanolꢁ20 : 1) to afford
(ꢂ)-13 (492 mg, 73%) as colorless crystals.
mp 194 °C (methanol); 1H-NMR (500 MHz, CDCl3) d: 1.41 (9H, s),
1.61—1.69 (4H, m), 2.20 (1H, s), 2.36—2.41 (2H, m), 4.22 (1H, s), 4.32
(1H, s), 7.54 (1H, dd, Jꢁ8.2, 2.4 Hz), 7.66 (1H, d, Jꢁ8.2 Hz), 8.56 (1H, d,
1H-NMR (300 MHz, CDCl3) d: 1.44 (9H, s), 1.45—2.05 (6H, m), 2.97— Jꢁ2.4 Hz). 13C-NMR (75 MHz, CDCl3) d: 22.7, 28.2 (3), 28.8, 48.1, 57.3,
3.02 (1H, m), 3.68—3.79 (2H, m), 4.02—4.13 (2H, m), 4.29—4.41 (2H, m), 65.4, 78.2, 80.3, 116.2, 134.2, 135.3, 143.4, 148.6, 154.9. IR (CHCl3) cmꢀ1
:
5.96 (1H, dt, Jꢁ4.7, 2.8 Hz). 13C-NMR (75 MHz, CDCl3) d: 23.5, 28.2 (3), 3584, 3391, 2982, 1693, 1450, 1369, 1161, 1080, 760. FAB-MS m/z:
28.7, 46.7, 58.7, 59.7, 61.6, 64.2, 80.1, 118.8, 145.4, 155.5. IR (CHCl3) 417.0681 (Calcd for C16H22N2O3I: 417.0675). MS (FAB) m/z: 417 (MꢂꢂH,
cmꢀ1: 3030, 3012, 2885, 1683, 1367, 1165. FAB-MS m/z: 270.1713 (Calcd
for C14H24NO4: 270.1705). MS (FAB) m/z: 270 (MꢂꢂH, 20). [a]D25 ꢂ47.1°
(cꢁ1.0, CHCl3).
100). [a]2D2 ꢂ11.7° (cꢁ1.1, CHCl3).
Acknowledgements This research was financially supported in part by
(1R,3S,4S)-(ꢀ)-7-tert-Butoxycarbonyl-3-hydroxymethyl-7-azabicy- Frontier Research Program and the 21st Century Center of Excellence Pro-
clo[2.2.1]heptan-2-one [(ꢀ)-9] Ozone gas was passed through a solution gram “Development of Drug Discovery Frontier Integrated from Tradition
of 8 (760 mg, 2.82 mmol) in dichloromethane (30 ml) at ꢀ78°C until the
to Proteome” of the Ministry of Education, Culture, Sports and Technology,
blue color was remained in the solution, and then nitrogen gas was bubbled. Japan.
Dimethyl sulfide (876 mg, 14.1 mmol) was added, and the mixture was
stirred at room temperature for 1 d. The organic solvent was evaporated off, References and Notes
and the residue was purified with silica gel column chromatography (chloro-
form : methanolꢁ15 : 1) to afford (ꢀ)-9 (630 mg, 93%) as colorless oil.
1H-NMR (300 MHz, CDCl3) d: 1.46 (9 H, s), 1.53—1.59 (1H, m), 1.79—
1.94 (2H, m), 2.01—2.13 (1H, m), 2.77—2.83 (1H, m), 2.94 (1H, br s), 3.64
(1H, dd, Jꢁ8.4, 11.4 Hz), 3.87 (1H, dd, Jꢁ5.3, 11.4 Hz), 4.27 (1H, d,
Jꢁ5.7 Hz), 4.60 (1H, s). 13C-NMR (75 MHz, CDCl3) d: 22.6, 25.4, 28.0 (3),
56.1, 58.4, 59.1, 64.6, 80.9, 154.8, 210.7. IR (CHCl3) cmꢀ1: 3032, 2984,
2361, 1751, 1699, 1369, 1209. FAB-MS m/z: 242.1399 (Calcd for
C12H20NO4: 242.1393). MS (FAB) m/z: 242 (MꢂꢂH, 22). [a]2D5 ꢀ70.8°
(cꢁ1.5, CHCl3). Anal. Calcd for C12H19NO4: C, 59.73; H, 7.94; N, 5.81; O,
26.52. Found: C, 59.73; H, 7.87; N, 5.70; O, 26.67.
Chemical Conversion from (ꢀ)-9 to (ꢀ)-7 Jones reagent (5 ml) was
added to a solution of (ꢀ)-9 (332 mg, 1.38 mmol) in acetone (30 ml) at 0 °C
and the mixture was stirred for 1.5 h at room temperature. After the reaction,
2-propanol (0.2 ml) was added to the reaction mixture, which was dried over
sodium sulfate and evaporated. The residue was dissolved in toluene (30 ml)
and the solution was refluxed for 24 h. The organic solvent was evaporated
1) Spande T. F., Garraffo H. M., Edwards M. W., Yeh H. J. C., Pannel L.,
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S. A., Daley D. C., Sarshar S., J. Org. Chem. Soc., 58, 5600—5603
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