Asymmetric synthesis of the dihydroisocoumarin moiety of AI-77-B via copper-mediated gross-coupling and sharpless asymmetric dihydroxylation

Full text of DOI:10.1021/jo951999p

J . Org. Chem. 1996, 61, 3183-3186
3183
Notes
Asym m etr ic Syn th esis of th e
Dih yd r oisocou m a r in Moiety of AI-77-B via
Cop p er -Med ia ted Cr oss-Cou p lin g a n d
Sh a r p less Asym m etr ic Dih yd r oxyla tion
Stefano Superchi,†,§ Filippo Minutolo,†,‡ Dario Pini,† and
Piero Salvadori†,*
F igu r e 1.
C.N.R. Centro Studi Macromolecole Stereordinate ed
Otticamente Attive, Dipartimento di Chimica e Chimica
Industriale, Universita` di Pisa, via Risorgimento 35,
I-56126 Pisa, Italy and Scuola Normale Superiore, piazza
dei Cavalieri 7, I-56127 Pisa, Italy
respectively, a triflate5a and an epoxy alcohol,5b and the
regioselective carboxylation of the aromatic ring.
In the course of studies on the synthesis and biological
activity of dihydroisocoumarins,7 we planned an alterna-
tive asymmetric route to 2, based on the regioselective
anionic allylation of N,N′-diethylbenzamides for the
formation of the carbon skeleton,8 and on Sharpless
asymmetric dihydroxylation of the resulting olefin for the
introduction of the chiral centers9 (Scheme 1).
Received November 10, 1995
AI-77s are a small family of antibiotics isolated from
Bacillus pumilus which present as a common structural
feature a dihydroisocoumarin moiety linked to acyl
hydroxy amino acid chains which are different for the
various members of the family.1 The major compound
of this group, named AI-77-B (1), has shown potent
antiulcerogenic action against stress ulcer in rats without
any anticholinergic, antihistaminergic or central sup-
pressive effects.2 Nowadays this compound presents a
renewed interest in light of recent studies on antibiotic
treatment for ulcer diseases.3
A number of total syntheses of 1 have been reported,4
as well as some alternative procedures for the prepara-
tion of both the dihydroisocoumarin moiety 25 and the
hydroxy amino acidic portion.6 Most of the approaches
reported for the preparation of 2 involve as a key step
the addition of o-toluic anions of esters or oxazolines to
N-protected leucinal.4 Nevertheless this approach pre-
sents some disadvantages, such as low yields, configu-
rational lability of the required leucinal, and a low degree
of diastereoselectivity in the toluate anion attack on the
amino aldehyde, which usually gives a mixture of the two
epimers at C-3. Recently two similar approaches to the
synthesis of the dihydroisocoumarin 2 have been re-
ported,5 which present as key steps the reaction of
3-alkoxyphenyl Grignard reagents with chiral substrates,
Resu lts a n d Discu ssion
The regioselective ortho-alkylation of N,N′-diethyl-2-
methoxybenzamide (3) was performed via a sequence of
ortho-lithiation and copper-transmetalation of the amide.
As a matter of fact, the widely used ortho-lithiated
benzamides10 cannot be used in cross-coupling reactions
with aliphatic halides, whereas we showed that this
reaction proceeds smoothly with the corresponding aryl
cyanocuprate derivatives.8 Amide 3 was lithiated by
treatment with s-BuLi-TMEDA 1:111 and was then
treated with a THF solution of CuCN‚LiCl 1:1 complex.
(E)-1-Bromo-5-methyl-2-hexene was added to the copper
intermediate affording, in a one-pot sequence, the o-
allylbenzamide 4 with a high yield. The stereoselective
dihydroxylation of olefin 4, performed in accordance with
the Sharpless procedure,12 produced simultaneously the
two stereogenic centers present in the target molecule,
with a very high degree of enantioselectivity. In detail,
the allylbenzamide 4 was catalytically dihydroxylated in
t-BuOH/H2O solution, using K2OsO2(OH)4 and 9-O-(9′-
phenanthryl)-10,11-dihydroquinine (DHQ-PHN) as chiral
ligand in the presence of K3Fe(CN)6 and K2CO3. The
reaction afforded the amido-diol 5 of the desired (S,S)
configuration, as confirmed by chemical correlation with
the target compound 2 (vide infra), whose stereochem-
istry had already been assigned by X-ray analysis.1
Besides, this stereochemical outcome was in agreement
with the empirical rule reported by Sharpless.12 It was
not possible to determine the enantiomeric excess of 5
directly, because the hindered rotation of the benzamido
* To whom correspondence should be addressed.
† C.N.R.-C.S.M.S.O.A., Universita` di Pisa.
‡ Scuola Normale Superiore.
§ Present address: Dipartimento di Chimica, Universita` della
Basilicata, via Nazario Sauro, 85, I-85100 Potenza, Italy.
(1) (a) Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M.; Iitaka,
Y. Tetrahedron Lett. 1982, 23, 5435. (b) Shimojima, Y.; Hayashi, H.;
Ooka, T.; Shibukawa, M. Agric. Biol. Chem. 1982, 46, 1823. (c)
Shimojima, Y.; Hayashi, H.; Ooka, T.; Shibukawa, M. Tetrahedron
1984, 40, 2519.
(2) (a) Shimojima, Y.; Hayashi, H. J . Med. Chem. 1983, 26, 1370.
(b) Shimojima, Y.; Shirai, T.; Baba, T.; Hayashi, H. J . Med. Chem. 1985,
28, 3.
(3) Talley, N. J . Chem. Ind. 1994, 259 and references therein.
(4) (a) Ward, R. A.; Procter, G. Tetrahedron Lett. 1992, 33, 3359.
(b) Ward, R. A.; Procter, G. Tetrahedron 1995, 51, 12301. (c) Broady,
S. D.; Rexhausen, J . E.; Thomas, E. J . J . Chem. Soc., Chem. Commun.
1991, 708. (d) Hamada, Y.; Hara, O.; Kawai, A.; Kohno, Y.; Shioiri, T.
Tetrahedron 1991, 47, 8635.
(5) (a) Kotsuki, H.; Miyazaki, A.; Ochi, M. Chem. Lett. 1992, 7, 1255.
(b) Bertelli, L.; Fiaschi, R.; Napolitano, E. Gazz. Chim. Ital. 1993, 123,
669.
(7) Superchi, S.; Pini, D.; Salvadori, P.; Marinelli, F.; Rainaldi, G.;
Zanelli, U.; Nuti-Ronchi, V. Chem. Res. Toxicol. 1993, 6, 46.
(8) Pini, D.; Superchi, S.; Salvadori, P. J . Organomet. Chem. 1993,
452, C4.
(9) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
1994, 94, 2483 and references therein.
(10) Snieckus, V. Chem. Rev. 1990, 90, 879.
(6) (a) Gesson, J . P.; J acquesy, J . C.; Mondon, M. Tetrahedron Lett.
1989, 30, 6503. (b) Kawai, A.; Hara, O.; Hamada, Y.; Shioiri, T.
Tetrahedron Lett. 1988, 29, 6331. (c) Hamada, Y.; Kawai, A.; Matsui,
T.; Hara, O.; Shioiri, T. Tetrahedron 1990, 46, 4823.
(11) Beak, P.; Brown, R. D. J . Org. Chem. 1986, 51, 3566.
(12) Sharpless, K. B.; Amberg, W.; Beller, M.; Chen, H.; Hartung,
J .; Kawanami, Y.; Lu¨bben, D.; Manoury, E.; Ogino, Y.; Shibata, T.;
Ukita, T. J . Org. Chem. 1991, 56, 4585.
S0022-3263(95)01999-2 CCC: $12.00 © 1996 American Chemical Society

3184 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
Sch em e 1a
Sch em e 2a
a
Key: (a) s-BuLi/TMEDA, THF, -78 °C, 30 min; (b) CuCN‚LiCl,
-78 °C, 45 min; (c) (Z)-1-bromo-5-methyl-2-hexene, -78 °C f rt,
4 h; (d) DHQ-PHN, K2OsO2(OH)4, t-BuOH/H2O (1:1), K3Fe(CN)6,
K2CO3, 0 °C, overnight; (e) 50% NaOHaq/EtOH (1:1), reflux, 36
h.
in only 40% ee.17 The azido-derivative 9 was obtained
in one step from 8 by a further Mitsunobu reaction with
hydrazoic acid16b and the amine intermediate 10 by the
catalytic hydrogenation of 9. A sequence of demethyla-
tion with BBr3 of the methyl aryl ether 10 and treatment
with a methanolic solution of 10% HCl finally gave the
target compound 2 as a hydrochloride, which showed an
optical purity of 93%.
According to this synthetic procedure, a double inver-
sion of configuration at C-1′ is required in order to obtain
the right stereoisomer of 2. This double step could have
been skipped by starting the synthesis from the cis olefin
11, as shown in Scheme 2.
a
Key: (a) s-BuLi/TMEDA, THF, -78 °C, 30 min; (b) CuCN‚LiCl,
-78 °C, 45 min; (c) (E)-1-bromo-5-methyl-2-hexene, -78 °C f rt,
4 h; (d) DHQ-PHN, K2OsO2(OH)4, t-BuOH/H2O (1:1), K3Fe(CN)6,
K2CO3, 0 °C, overnight; (e) 50% NaOHaq/EtOH (1:1), reflux, 36
h; (f) p-nitrobenzoic acid, PPh3, DEAD, toluene, rt, 2 h; (g) MeONa/
MeOH, rt, 30 min; (h) Amberlite IR-120-H+; (i) HN3, PPh3, DEAD,
toluene, 0 °C f rt, overnight; (j) H2, 5% Pd/C, MeOH, rt, 3 h; (k)
BBr3, CH2Cl2, -78 °C, 15 min; (l) 10% HCl in MeOH.
We actually tried this path, which appeared to be more
direct to the final product. The (Z) olefin 11, prepared
with a good yield from 3 and (Z)-1-bromo-5-methyl-2-
hexene by the same procedure described for its (E) isomer
4, was asymmetrically dihydroxylated as above. The diol
12 with the (3S,1′R) configuration was obtained with a
good chemical yield, but with modest enantiomeric
purity, as verified in the next cyclized product 8 (38%
ee). This result is in agreement with the findings
reported by other authors, in which cis-olefins, and
especially the acyclic aliphatic ones, always give a low
degree of enantioselectivity in the dihydroxylation reac-
tion.9 For this reason it was necessary to follow the
longer, but more enantiospecific, approach reported in
Scheme 1.
group13 in this molecule generates an additional atropo-
isomeric chiral center, complicating both the HPLC and
the NMR analysis. The diol 5 was cyclized in basic
conditions14 (EtOH/50% NaOH aq 1:1) to the dihydroiso-
coumarin 6, which, after a single crystallization, showed
an ee > 99% by HPLC analysis. The configuration of
the chiral center bearing the OH-group had to be
inverted, in order to obtain the target molecule 2. The
inversion was achieved by a Mitsunobu15 esterification
of the alcoholic functionality, using p-nitrobenzoic acid
as the nucleophile,16 to obtain the ester 7, which was
subsequently saponified with a diluted methanolic solu-
tion of sodium methoxide, to give the 1′-hydroxydihy-
droisocoumarin 8, in 91% ee. It is worth nothing that
hydrolysis of ester 7 in these conditions caused a minimal
racemization of the substrate, whereas, carrying out the
same reaction with sodium ethoxide in ethanol, we got 8
The procedure described in this paper for the synthesis
of the dihydroisocoumarin portion common to AI-77
antibiotics appears to be very efficient and stereoselec-
tive. This approach is also potentially versatile for the
preparation of different regio- and stereoisomers of 2. As
a matter of fact the regioselectivity of benzamide alky-
lation is independent from the position of the methoxy
group on the ring, allowing the synthesis of different
regioisomers of 2, while the choice of the appropriate
dihydroxylation catalyst combined with selective epimer-
ization of the chiral centers can lead to four possible
stereoisomers of the molecule. This potential of the
approach reported can be very interesting in order to
(13) Oki, M. Application of Dynamic NMR Spectroscopy to Organic
Chemistry; VCH Publishers: Weinheim, Germany, 1985; pp 178-182
and references therein.
(14) Watanabe, M.; Sahara, M.; Kubo, M.; Furukawa, S.; Billedeau,
R. J .; Snieckus, V. J . Org. Chem. 1984, 41, 742.
(15) Mitsunobu, O. Synthesis 1981, 1.
(16) (a) Martin, S. F.; Dodge, J . A. Tetrahedron Lett. 1991, 32, 3017.
(b) Bessodes, M.; Sa¨ıah, M.; Antonakis, K. J . Org. Chem. 1992, 57,
4441.
(17) As a referee pointed out, racemization of 8 probably proceeds
via an elimination-addition process, initiated by deprotonation. As
EtO- is a stronger base than MeO-, it can more effectively promote
racemization.

Notes
J . Org. Chem., Vol. 61, No. 9, 1996 3185
(3S)-3-[(1′S)-1′-Hyd r oxy-3′-m eth ylbu tyl]-8-m eth oxy-3,4-
d ih yd r oisocou m a r in (6). Diol 5 (2.0 g, 5.9 mmol) was treated
with a mixture of 50% aqueous NaOH (60 mL) and EtOH (60
mL) and the mixture heated under reflux for 36 h. Then EtOH
was distilled off and the residue neutralized with concd HCl at
0 °C. The aqueous phase was extracted three times with EtOAc,
and the collected organic solutions were washed with saturated
aqueous NaHCO3 and brine and dried over Na2SO4. After
evaporation of solvent, the solid residue was purified by flash-
chromatography (petroleum ether/EtOAc 1:2) yielding 1.25 g
(80% yield) of the dihydroisocoumarin 6. Upon recrystallization
from Et2O was collected 968 mg of 6 as colorless needles, which
conduct systematic studies on the structure-activity
relationship of AI-77s and related compounds.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points are uncorrected. 1H
NMR (200 MHz) and 13C NMR (50 MHz) spectra were recorded
in CDCl3 unless otherwise stated. Analytical TLC was per-
formed on 0.2 mm silica gel plate Merck 60 F-254 and flash
chromatography18 was carried out with silica gel Merck 60 (230-
400 mesh). Enantiomeric purity of products was determined by
HPLC using chiral column Daicel Chiralpak (+) AD. Metala-
tions were performed using syringe-septum cap techniques
under argon atmosphere. sec-Butyllithium (Aldrich) was a 1.3
M solution in cyclohexane-heptane, whose exact titer was
determined by titration using 2,5-dimethoxybenzyl alcohol.19
TMEDA (Aldrich) was distilled from CaH2 and stored over 4 Å
molecular sieves. THF and toluene were distilled over sodium
immediately before use, and CH2Cl2 was distilled and stored over
CaCl2. The solution of anhydrous HN3 in benzene was prepared
according to a literature procedure.20 (E)- and (Z)-1-bromo-5-
methyl-2-hexene were prepared, respectively, from (E)-21 and (Z)-
5-methyl-2-hexen-1-ol,22 and N,N′-diethyl-2-methoxybenzamide
(3) from o-anisic acid.
showed ee > 99%: mp 98-99 °C; [R]25 ) -145.7° (c 0.18, CH3-
D
OH); UV (CH3OH, 0.45 mg mL-1) λmax (nm) (ꢀmax, M-1 cm-1) 208
(23000), 245 (8000), 309 (4000); CD (CH3OH, 0.45 mg mL-1) λmax
(nm) (∆ꢀmax, M-1 cm-1): 200 (-8.0), 226 (0), 237 (+1.6), 245 (0),
257 (-3.6), 284 (-1.1), 304 (-1.6), 331 (0); 1H NMR δ 0.95 (d, J
) 6.5 Hz, 3H), 0.97 (d, J ) 6.6 Hz, 3H), 1.2-1.4 (m, 2H), 1.8-
2.0 (m, 1H), 2.23 (d, J ) 7.0 Hz, 1H), 2.78 (dd, J ) 16.0, 2.6 Hz,
1H), 3.18 (dd, J ) 16.0, 12.4 Hz, 1H), 3.7-3.9 (m, 1H), 3.96 (s,
3H), 4.26 (ddd, J ) 12.4, 4.5, 2.6 Hz, 1H), 6.84 (d, J ) 8.0 Hz,
1H), 6.93 (d, J ) 8.0 Hz, 1H), 7.48 (t, J ) 8.0 Hz, 1H); 13C NMR
δ 21.69, 23.49, 24.24, 31.02, 41.61, 56.15, 70.76, 80.79, 110.84,
113.50, 119.40, 134.66, 141.86, 161.16; MS (EI) m/ z 264 (M+,-
10), 177 (100), 149 (81), 91 (16). Anal. Calcd for C15H20O4: C,
68.16; H, 7.63. Found: C, 68.10; H, 7.57.
(E )-2-(5′-Me t h yl-2′-h e xe n yl)-6-m e t h oxy-N ,N ′-d ie t h yl-
ben za m id e (4). To a solution of s-BuLi (1.3 M, 10 mL, 13 mmol)
and TMEDA (1.96 mL, 13 mmol) in dry THF (50 mL) was slowly
added, at -78 °C, a solution of N,N′-diethyl-2-methoxybenz-
amide (3) (2.45 g, 11.8 mmol) in THF (15 mL), and the mixture
was stirred for 30 min. Then was added a solution of CuCN
(1.164 g, 13 mmol) and LiCl (551 mg, 13 mmol) in THF (20 mL).
After 45 min of stirring was added a solution of (E)-1-bromo-5-
methyl-2-hexene (2.30 g, 13 mmol) in THF (25 mL). The mixture
was then slowly warmed to room temperature while stirring and
after 4 h quenched with water and diluted with Et2O. The
organic layer was repeatedly treated with saturated aqueous
NH4Cl and brine and dried over Na2SO4. Evaporation of solvent
afforded an oily residue which, after flash-chromatography
(petroleum ether/EtOAc 2:1), yielded 2.89 g of olefin 4 (81% yield)
as a viscous oil: 1H NMR δ 0.87 (d, J ) 6.6 Hz, 6H), 1.02 (t, J
) 7.1 Hz, 3H), 1.25 (t, J ) 7.1 Hz, 3H), 1.5-1.7 (m, 1H), 1.8-
1.9 (m, 2H), 3.0-3.5 (m, 5H), 3.7-3.8 (m, 1H), 3.79 (s, 3H), 5.4-
5.5 (m, 2H), 6.73 (d, J ) 8.1 Hz, 1H), 6.85 (d, J ) 7.9 Hz, 1H),
7.23 (t, J ) 8.0 Hz, 1H); 13C NMR δ 12.72, 13.64, 22.23, 28.34,
35.70, 38.34, 41.84, 42.57, 55.38, 108.21, 121.47, 128.81, 129.05,
129.14, 131.11, 138.81, 155.25, 168.03; MS (EI) m/ z 303 (M+,
(3S)-3-[(1′R)-1′-p-Nitr oben zoyl-3′-m eth ylbu tyl]-8-m eth oxy-
3,4-d ih yd r oisocou m a r in (7). To a solution of dihydroisocou-
marin 6 (450 mg, 1.70 mmol) in dry toluene (20 mL) were added
PPh3 (1.077 g, 4.08 mmol) and p-nitrobenzoic acid (611 mg, 3.65
mmol). To the resulting heterogeneous mixture was dropwise
added DEAD (0.65 mL, 4.1 mmol), and the yellow solution was
stirred for 2 h at room temperature. The solvent was evapo-
rated, and the recovered residue was purified by flash-chroma-
tography (petroleum ether/EtOAc 1:1) yielding 577 mg (82%
yield) of the dihydroisocoumarin 7 as a slightly yellow solid: mp
) 103-104 °C; [R]25 ) -87.6° (c 0.26, CH3OH); UV (CH3OH,
D
0.47 mg mL-1) λmax (nm) (ꢀmax, M-1 cm-1) 205 (34000), 247
(16000), 279 (7800), 297 (5800); CD (CH3OH, 0.47 mg mL-1) λmax
(nm) (∆ꢀmax, M-1 cm-1) 200 (-9.7), 222 (0), 235 (+0.82), 241 (0),
255 (-2.7), 275 (-1.0), 303 (-3.1), 338 (0); 1H NMR δ 0.98 (d, J
) 6.2 Hz, 3H), 0.99 (d, J ) 6.3 Hz, 3H), 1.6-1.8 (m, 2H), 1.9-
2.1 (m, 2H), 2.90 (dd, J ) 16.0, 2.8 Hz, 1H), 3.14 (dd, J ) 16.0,
11.9 Hz, 1H), 3.94 (s, 3H), 4.58 (ddd, J ) 11.9, 4.2, 2.8 Hz, 1H),
5.4-5.6 (m, 1H), 6.83 (d, J ) 7.6 Hz, 1H), 6.93 (d, J ) 8.5 Hz,
1H), 7.47 (dd, J ) 8.5, 7.6 Hz, 1H), 8.2-8.3 (m, 4H); 13C NMR δ
21.93, 23.33, 24.59, 30.42, 38.56, 56.20, 73.92, 78.09, 111.17,
113.52, 119.92, 123.60, 130.90, 134.76, 135.21, 140.96, 150.73,
161.33, 164.11; MS (EI) m/ z 413 (M+, 21), 246 (7), 203 (20), 177
(100), 149 (97), 91 (56). Anal. Calcd for C22H23NO7: C, 63.92;
H, 5.61; N, 3.39. Found: C, 63.88; H, 5.60; N 3.35.
78), 260 (90), 231 (33), 174 (100), 91 (26). Anal. Calcd for C19H29
-
NO2: C, 76.74; H, 7.80; N, 4.71. Found: C, 76.73; H, 7.82; N,
4.69.
2-[(2′S,3′S)-2′,3′-Dih yd r oxy-5′-m et h ylh exyl]-6-m et h oxy-
N,N′-d ieth ylben za m id e (5). A mixture of olefin 4 (2.43 g, 8
mmol), DHQ-PHN23 (330 mg, 0.66 mmol), K2OsO2(OH)4 (22 mg,
0.06 mmol), K3Fe(CN)6 (7.90 g, 24 mmol), and K2CO3 (3.32 g,
24 mmol) in H2O/t-BuOH 1:1 (100 mL) was stirred overnight at
0 °C and then warmed at room temperature, and NaHSO3 (11.4
g) was added. The mixture was stirred 45 min at room
temperature and then diluted with EtOAc and water. The
aqueous phase was extracted with EtOAc, and the organic
phases were washed with 1 M H2SO4, 10% aqueous NaHCO3,
and brine and dried over Na2SO4. The residue was collected
after evaporation of solvent and was purified by flash-chroma-
tography (petroleum ether/EtOAc 1:1), affording 2.34 g (87%
yield) of diol 5: MS (EI) m/ z: 337 (M+, 26), 305 (39), 262 (43),
175 (100), 149 (66). Anal. Calcd for C19H31NO4: C, 67.63; H,
9.26; N, 4.15. Found: C, 67.51; H, 9.34; N, 4.06.
(3S)-3-[(1′R)-1′-Hyd r oxy-3′-m eth ylbu tyl]-8-m eth oxy-3,4-
d ih yd r oisocou m a r in (8). The nitrobenzoyl ester 7 (530 mg,
1.28 mmol) was dissolved in dry methanol (35 mL) and treated
with
a solution of sodium methoxide (8.35 mL, 1.3 M in
methanol, 11 mmol). The mixture was stirred 30 min at room
temperature and then neutralized with Amberlite IR-120-H+ and
filtered, the solvent evaporated. The collected residue was
purified by flash-chromatography (petroleum ether/EtOAc 1:1)
yielding 250 mg (74% yield) of the dihydroisocoumarin 8 as
colorless solid, which showed 91% ee: mp 99-101 °C; [R]25
)
D
-148.8° (c 0.13, CH3OH) {lit.5a [R]21D ) -155.6° (c 0.64, CHCl3)};
UV (CH3OH, 0.46 mg mL-1) λmax (nm) (ꢀmax, M-1 cm-1) 208
(23000), 243 (8000), 311 (4000); CD (CH3OH, 0.46 mg mL-1) λmax
(nm) (∆ꢀmax, M-1 cm-1) 200 (-6.2), 227 (0), 239 (+1.7), 247 (0),
1
259 (-3.2), 283 (-0.86), 304 (-1.5), 332 (0); H NMR δ 0.94 (d,
J ) 6.7 Hz, 3H), 0.98 (d, J ) 6.9 Hz, 3H), 1.2-1.3 (m, 1H), 1.4-
1.6 (m, 1H), 1.8-1.9 (m, 1H), 2.35 (d, J ) 3.7 Hz, 1H), 2.78 (dd,
J ) 16.4, 2.6 Hz, 1H), 3.20 (dd, J ) 16.4, 12.6 Hz, 1H), 3.95 (s,
3H), 4.0-4.1 (m, 1H), 4.31 (ddd, J ) 12.6, 3.3, 2.4 Hz, 1H), 6.85
(d, J ) 7.6 Hz, 1H), 6.92 (d, J ) 8.5 Hz, 1H), 7.47 (dd, J ) 8.5,
7.6 Hz, 1H); 13C NMR δ 21.63, 23.49, 24.24, 31.02, 41.61, 56.15,
70.76, 80.79, 110.84, 113.50, 119.40, 134.66, 141.86, 161.16; MS
(EI) m/ z 264 (M+, 11), 177 (100), 149 (81). Anal. Calcd for
(18) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(19) Winkle, M. R., Lansinger, J . M., Ronald, J . M. J . Chem. Soc.,
Chem. Commun. 1980, 87.
(20) Wollf, H. Org. React. 1947, 3, 327.
(21) Halling, K.; Torssell, K. B. G.; Hazell, R. G. Acta Chem. Scand.
1991, 45, 736. For a recent synthesis of related trans allylic alcohols,
see: Chini, M.; Crotti, P.; Flippin, L. A.; Gardelli, C.; Giovani, E.;
Macchia, F.; Pineschi, M. J . Org. Chem. 1993, 58, 1221.
(22) Malanga, C.; Menicagli, R.; Lardicci, L. Gazz. Chim. Ital. 1992,
122, 45.
C
15H20O4: C, 68.16; H, 7.63. Found: C, 68.08; H, 7.72.
(3S)-3-[(1′S)-1′-Azid o-3′-m et h ylb u t yl]-8-m et h oxy-3,4-d i-
h yd r oisocou m a r in (9). To a mixture of 8 (230 mg, 0.87 mmol)
and PPh3 (457 mg, 1.74 mmol) in dry toluene (20 mL) was
(23) The use of (DHQ)2-PHAL, a more recent chiral ligand in the
AD reaction, did not improve the enantioselectivity.

3186 J . Org. Chem., Vol. 61, No. 9, 1996
Notes
dropwise added DEAD (0.27 mL, 1.7 mmol) at 0 °C, followed by
a solution of HN3 (1.32 mL, 1.13 M in benzene, 1.5 mmol). The
mixture was stirred overnight at room temperature and then
diluted with n-hexane. The formed precipitate was filtered off
and the solvent evaporated. The residue was purified by flash-
chromatography (petroleum ether/EtOAc 1:1) yielding 205 mg
ion-spray MS/MS: m/z 250 (M - Cl-, 84), 232 (33), 176 (97),
162 (100), 133 (87). Anal. Calcd for C14H20NO3Cl: C, 58.84; H,
7.05; N, 4.90; Cl, 12.41. Found: C, 59.03; H, 7.12; N, 4.98; Cl,
12.07.
(Z)-2-(5′-Me t h yl-2′-h e xe n yl)-6-m e t h oxy-N ,N ′-d ie t h yl-
ben za m id e (11). To a solution of s-BuLi (1.3 M, 8.2 mL, 11
mmol) and TMEDA (1.6 mL, 11 mmol) in dry THF (60mL) was
slowly added at -78 °C a solution of N,N′-diethyl-2-methoxy-
benzamide (3) (2.0 g, 9.6 mmol) in THF (20 mL). The resulting
mixture was stirred for 30 min and then was added a solution
of CuCN (0.96 g, 11 mmol) and LiCl (454 mg, 11 mmol) in THF
(20 mL). After 45 min of stirring, a solution of (Z)-1-bromo-5-
methyl-2-hexene (1.9 g, 11 mmol) in THF (15 mL) was added.
The mixture was then slowly warmed to rt while stirring and,
after 4 h, was quenched with water and diluted with Et2O. The
organic layer was repeatedly washed with saturated aqueous
NH4Cl solution and brine and dried over anhyd Na2SO4.
Evaporation of solvent afforded an oily residue which, after flash
chromatography (n-hexane/EtOAc 1:1), yielded 2.43 g of olefin
11 (82% yield) as a colorless oil: 1H NMR δ 0.89 (d, J ) 6.6 Hz,
6H), 1.02 (t, J ) 7.2 Hz, 3H), 1.24 (t, J ) 7.2 Hz, 3H), 1.5-1.7
(m, 2H), 1.9-2.0 (m, 1H), 3.0-3.2 (m, 2H), 3.2-3.5 (m, 3H), 3.7-
3.8 (m, 1H), 3.77 (s, 3H), 5.5-5.6 (m, 2H), 6.72 (d, J ) 8.2 Hz,
1H), 6.83 (d, J ) 7.9 Hz, 1H), 7.21 (t, J ) 8.1 Hz, 1H); 13C-NMR
δ 12.71, 13.63, 22.32, 28.56, 30.18, 36.28, 38.39, 42.53, 55.39,
108.26, 121.19, 127.70, 129.12, 130.03, 138.85, 155.22, 168.02;
MS (EI) m/ z 303 (M+, 58), 260 (64), 232 (100), 175 (76), 161
(79). Anal. Calcd for C19H29NO2: C, 76.74; H, 7.80; N, 4.71.
Found C, 76.65; H, 7.92; N, 4.66.
2-[(2′S,3′R)-2′,3′-Dih yd r oxy-5′-m eth ylh exyl]-6-m eth oxy-
N,N′-d ieth ylben za m id e (12). A mixture of olefin 11 (1.00 g,
3.30 mmol), DHQ-PHN (138 mg, 0.275 mmol), K2OsO2(OH)4 (9.1
mg, 0.025 mmol), K3Fe(CN)6 (3.26 g, 9.90 mmol), and K2CO3
(1.37 g, 9.90 mmol) in t-BuOH/H2O 1:1 (50 mL) was stirred
overnight at 0 °C, and then NaHSO3 (5.5 g) was added. The
mixture was warmed at rt and stirred for 1 h and then diluted
with EtOAc and water. The aqueous phase was repeatedly
extracted with EtOAc. The organic phases were washed with 1
M H2SO4, 10% aqueous NaHCO3, and brine and dried over Na2-
SO4. The solid residue, collected after evaporation of solvent,
was purified by flash-chromatography (petroleum ether/EtOAc
1:1) affording 0.93 g (84% yield) of diol 12. MS (EI) m/ z 337
(M+, 19), 250 (41), 221 (35), 206 (56), 175 (100), 149 (66). Anal.
Calcd for C19H31NO4: C, 67.63; H, 9.26; N, 4.15. Found: C,
67.47; H, 9.33; N, 4.08.
(81% yield) of the azide 9 as colorless glass: [R]25 ) -202° (c
D
0.11, CH3OH) {lit.5a [R]22D ) -169.6° (c 1.12, CHCl3)}; UV (CH3-
OH, 0.51 mg mL-1) λmax (nm) (ꢀmax, M-1 cm-1) 205 (23000), 244
(9600), 298 (3700); CD (CH3OH, 0.51 mg mL-1) λmax (nm) (∆ꢀmax
,
M-1 cm-1) 200 (-14.6), 226 (0), 237 (+1.5), 243 (0), 256 (-5.0),
1
284 (-1.6), 302 (-2.5), 333 (0); H NMR δ 0.95 (d, J ) 6.4 Hz,
3H), 0.97 (d, J ) 6.5 Hz, 3H), 1.2-1.3 (m, 1H), 1.5-1.6 (m, 1H),
1.8-2.0 (m, 1H), 2.76 (dd, J ) 16.0, 2.6 Hz, 1H), 3.17 (dd, J )
16.0, 12.4 Hz, 1H), 3.4-3.5 (m, 1H), 3.92 (s, 3H), 4.39 (ddd, J )
12.4, 4.1, 2.6 Hz, 1H), 6.81 (d, J ) 7.5 Hz, 1H), 6.91 (d, J ) 8.6
Hz, 1H), 7.45 (dd, J ) 8.6, 7.5 Hz, 1H); 13C NMR δ 21.56, 23.07,
24.79, 31.15, 38.21, 56.12, 61.33, 78.84, 110.95, 113.34, 119.25,
134.66, 141.27, 161.16; MS (EI) m/ z 289 (M+, 35), 261 (70), 177
(100), 149 (99), 91 (81). Anal. Calcd for C15H19N3O3: C, 62.27;
H, 6.62; N, 14.52. Found: C, 62.22; H, 6.65; N, 14.63.
(3S)-3-[(1′S)-1′-Am in o-3′-m eth ylbu tyl]-8-m eth oxy-3,4-d i-
h yd r oisocou m a r in (10). A mixture of 9 (130 mg, 0.45 mmol)
and 5% Pd/C (63 mg, 0.03 mmol) in methanol was stirred 3 h in
a hydrogen atmosphere. The mixture was then filtered over
Celite, the residue washed with methanol, and the filtrate
evaporated, yielding 112 mg of 10 (94% yield) as a viscous oil,
which was used without further purification: [R]25 ) -50° (c
D
0.17, CH3OH); UV (CH3OH, 0.43 mg mL-1) λmax (nm) (ꢀmax, M-1
cm-1) 201 (23000), 240 (11000), 295 (3600); CD (CH3OH, 0.43
mg mL-1) λmax (nm) (∆ꢀmax, M-1 cm-1) 200 (+1.2), 204 (0), 211
(-2.1), 220 (0), 226 (+0.44), 233 (+0.13), 242 (+0.76), 251 (0),
1
274 (-1.9), 279 (-0.91), 290 (-1.2), 325 (0); H NMR δ 0.80 (d,
J ) 6.5 Hz, 3H), 0.86 (d, J ) 6.5 Hz, 3H), 1.2-1.8 (m, 3H), 2.71
(dd, J ) 13.3, 9.6 Hz, 1H), 3.07 (dd, J ) 13.2, 6.9 Hz, 1H), 3.1-
3.2 (m, 1H), 3.87 (s, 3H), 3.9-4.0 (m, 1H), 6.76 (d, J ) 7.5 Hz,
1H), 6.89 (d, J ) 7.9 Hz, 1H), 7.29 (t, J ) 7.8 Hz, 1H); 13C NMR
δ 22.24, 22.92, 24.57, 38.32, 40.87, 53.31, 56.09, 75.29, 110.93,
121.00, 123.21, 131.37, 136.80, 157.97, 169.32; MS (EI) m/ z 263
(M+, 58), 220 (100), 177 (68), 149 (46). Anal. Calcd for C15H21
-
NO3: C, 68.42; H, 8.04; N, 5.32. Found: C, 68.28; H, 8.20; N,
5.41.
(3S)-3-[(1′S)-1′-Am in o-3′-m eth ylbu tyl]-8-h yd r oxy-3,4-d i-
h yd r oisocou m a r in Hyd r och lor id e (2‚HCl). The dihydroiso-
coumarin 10 (95 mg, 0.36 mmol) was dissolved in dry CH2Cl2
(35 mL), and a solution of BBr3 (0.14 mL, 1.5 mmol) in CH2Cl2
(5 mL) was dropwise added at -78 °C. The mixture was stirred
at that temperature for 15 min and then quenched with H2O (5
mL), diluted with CH2Cl2, and washed with saturated aqueous
NaHCO3. The aqueous phase was extracted with CH2Cl2, and
the combined organic phases were washed with brine and dried
over Na2SO4. After evaporation of solvent, the recovered residue
was dissolved again in CH2Cl2 and treated with 10% methanolic
HCl. The mixture was then concentrated recovering 101 mg of
2‚HCl (97% yield) as a slightly brown solid, whose spectroscopic
and analytical data were in agreement with those reported:4c,5b
mp ) 204-205 °C; [R]25 ) -44.1° (c 0.13, MeOH) {lit.4c: [R]22
Ack n ow led gm en t. The authors would like to thank
Dr. S. Pucci and Dr. A. Raffaelli for mass spectrometry
and M. F. Zini for experimental help in the synthesis
of some intermediates. F.M. gratefully acknowledges
E.N.I.-Rome for a fellowship. This work was supported
in part by the Ministero della Ricerca Scientifica e
Tecnologica (MURST), Rome, and by Consiglio Nazio-
nale delle Ricerche, Progetto Strategico “Tecnologie
Chimiche Innovative”.
D
D
) -47.42° (c 0.11, MeOH)}; ion-spray MS m/z 250 (M - Cl-);
J O951999P