monoisopropylidene compound 18,14 prepared using the same
procedure as for the equivalent xylose derivative.7
CO2But
+
NH2
Cl–
NHR
iv
N
i
When 20 was treated with cyclohexa-1,3-diene in the
presence of water, the cycloadduct (+)-4 was isolated in 76%
yield, together with ketone 19 (86%). The ee of (+)-4 was
estimated as !97% by derivatization with (+)-camphor-
10-sulfonyl chloride.4a It thus appears that the two ketones 1
and 19 can be used to gain ready access to the two enantiomeric
series through cycloadditions of the pseudoenantiomeric chlor-
onitroso compounds 2 and 20.
We thank the EPRSC for a studentship (A. H.) and for access
to the National Mass Spectrometry Service Centre, Organon
Laboratories Ltd for additional financial support, and Dr
Georgina Rosair for X-ray crystallography.
Me
ii
(–)-7
HO
HO
HO
11
8
9 R = CO2Bn
iii
v
10 R = Me
CO2But
COPh
NMe
N
N
Me
Me
vi
vii
OH
O
O
(–)-14
(–)-13
12
Scheme 3 Reagents and conditions: i, H2, Pd(OH)2/C, MeOH; ii, ClCO2Bn,
Na2CO3, acetone; iii, LiAlH4, THF, reflux; iv, (ButOCO)2O, EtNPri2,
CH2Cl2; v, PCC, CH2Cl2; vi, TFA, then Na2CO3 aq; vii, BzCl, pyridine,
CH2Cl2
Notes and References
† E-mail: cherhw@bonaly.hw.ac.uk
‡
The analogous chloronitroso compound derived from di-
O-isopropylidene- -glucose behaved very similarly to 2 in the reactions of
both Schemes 1 and 2.
D
tion of 10 with Jones’ reagent10 gave (2)-13, but the isolation
of the product in good yield was troublesome and the sequence
shown in Scheme 3, involving protection of the basic nitrogen,
gave (2)-13 {[a]D 250.0 (c 0.46, CH2Cl2)}§ in higher overall
yield. Benzoylation of (2)-13 gave the crystalline N-benzoyl
derivative (2)-14, [a]D 279.4 (c 0.97, CH2Cl2) {lit. for the
enantiomer, [a]D +78.0 (c 0.44, CHCl3),11 [a]D +95.6 (c 1.3,
CHCl3)9c}.
§ The specific rotation of physoperuvine does not seem to have been
previously reported. Small negative values have been reported for the
hydrochloride of both natural {[a]D 20.8 (c 1.0, MeOH)} [ref. 9(b)] and
synthetic {[a]D 20.98 (c 1.28, MeOH)} (ref. 11) S-physoperuvine,
although a small positive value has also been quoted in a different solvent
{[a]D +1.2 (c 1.3, H2O)} [ref. 9(a)]. Our results imply that natural
(S)-physoperuvine, as the free base, is significantly dextrorotatory.
The potent non-opioid analgesic activity shown by (2)-epi-
batidine [(2)-17], isolated from the poison frog Epipedobates
tricolor, has led to many syntheses,12 including some enantiose-
lective approaches.13 The availability of essentially enantiomer-
ically pure cycloadduct (2)-4 permitted a formal synthesis of
(+)-epibatidine [(+)-17] (Scheme 4). Reductive cleavage of the
N–O bond, and reaction with di-tert-butyl dicarbonate gave 15
(67%), and benzoylation of this gave (2)-16, mp 78–79 °C,
[a]D 287.6 (c 0.89, CH2Cl2), enantiomeric with an inter-
mediate {mp 78–79 °C, [a]D +86.6 (c 1.26, CH2Cl2)} used, via
ent-15, in Trost and Cook’s synthesis of (2)-epibatidine.13b
1 D. L. Boger and S. M. Weinreb, Hetero-Diels–Alder Methodology in
Organic Synthesis, Academic Press, San Diego, 1987; H. Waldman,
Synthesis, 1994, 535; J. Streith and A. Defoin, Synthesis, 1994, 1107.
2 e.g. J. Li, F. Lang and B. Ganem, J. Org. Chem., 1998, 63, 3403 and
references cited therein; A. Ghosh and M. J. Miller, Tetrahedron Lett.,
1995, 36, 6399 and references cited therein; S. F. Martin, M. Hartmann
and J. A. Josey, Tetrahedron Lett., 1992, 33, 3583 and references cited
therein; V. Gouverneur, G. Dive and L. Ghosez, Tetrahedron:
Asymmetry, 1991, 2, 1173; A. Defoin, A. Brouillard-Poichet and J.
Streith, Helv. Chim. Acta, 1991, 74, 103; V. Gouverneur and L. Ghosez,
Tetrahedron: Asymmetry, 1990, 1, 363; A. Miller and G. Procter,
Tetrahedron Lett., 1990, 31, 1043.
3 M. Sabuni, G. Kresze and H. Braun, Tetrahedron Lett., 1984, 25,
5377.
4 (a) H. Braun, H. Felber, G. Kresze, F. P. Schmidtchen, R. Prewo and A.
Vasella, Liebigs Ann. Chem., 1993, 261; (b) A. Defoin, T. Sifferlen and
J. Streith, Synlett, 1997, 1294.
NHCO2But
NHCO2But
NH
Cl
ref. 13(b)
i, ii
iii
(–)-4
N
5 For amendment of an initially erroneous assignment of absolute
configuration to the bicyclic adduct 4 see H. Braun, R. Charles, G.
Kresze, M. Sabuni and J. Winkler, Liebigs Ann. Chem., 1987, 1129.
6 For a review on the use of sugar-based auxiliaries, see: P. G. Hultin,
M. A. Earle and M. Sudharshan, Tetrahedron, 1997, 53, 14823.
7 J. Moravková, J. Capková and J. Stanek, Carbohydr. Res., 1994, 263,
61.
8 A. Gieren and H.-J. Siebels, Angew. Chem., Int. Ed. Engl. 1976, 15,
760.
9 (a) M. Sahai and A. B. Ray, J. Org. Chem., 1980, 45, 3265; (b) A. B.
Ray, Y. Oshima, H. Hikino and C. Kabuto, Heterocycles, 1982, 19,
1233; (c) A. T. McPhail and A. R. Pinder, Tetrahedron, 1984, 40,
1661.
10 D. E. Justice and J. R. Malpass, J. Chem. Soc., Perkin Trans. 1, 1994,
2559, and references cited therein.
11 K. Hiroya and K. Ogasawara, J. Chem. Soc., Chem. Commun., 1995,
2205.
12 N. S. Sirisoma and C. R. Johnson, Tetrahedron Lett., 1998, 39, 2059 and
references cited therein; G. M. P. Giblin, C. D. Jones and N. S.
Simpkins, Synlett, 1997, 589.
13 (a) C. Szántay, Z. Kardos-Balogh, I. Moldvai, C. Szántay, Jr., E.
Temesvári-Major and G. Blaskó, Tetrahedron, 1996, 52, 11053; (b)
B. M. Trost and G. R. Cook, Tetrahedron Lett., 1996, 37, 7485; (c) H.
Kosugi, M. Abe, R. Hatsuda, H. Uda and M. Kato, Chem. Commun.,
1997, 1857; (d) S. Aoyagi, R. Tanaka, M. Naruse and C. Kibayashi,
Tetrahedron Lett., 1998, 39, 4513.
(–)-16
OBz
(+)-17
15
OH
Scheme 4 Reagents and conditions: i, Zn, AcOH; ii, (ButOCO)2O, Na2CO3,
acetone–MeOH; iii, BzCl, DMAP, pyridine, CH2Cl2
Although the use of a chiral auxiliary derived from
leads in both the above syntheses to the enantiomers of the
natural products, the commercial availability of -xylose makes
it possible to employ identical chemistry in either enantiomeric
series. However, -xylose is relatively expensive, and so we
have prepared (Scheme 5) a chloronitroso compound 20
D
-xylose
L
L
pseudoenantiomeric with 2 from the cheap
L
-sorbose, via the
Me
Me
+
O
Cl–
O
NH2
O
Me
O
Me
O
O
O
i,ii
v
X
Y
TBDMSOH2C
HOH2C
CH2OTBDMS
CH2OH
(+)-4
OH
+
19
19 X, Y = O
18
iii,iv
20 X = NO, Y = Cl
Scheme 5 Reagents and conditions: i, TBDMSCl, Et3N, DMF; ii, PCC,
mol. sieves, CH2Cl2; iii, NH2OH·HCl, NaHCO3, EtOH–H2O; iv, ButOCl,
CH2Cl2, 0 °C; v, cyclohexa-1,3-diene, CHCl3–PriOH–H2O (100:100:1),
0°C
14 T. Reichstein and A. Grüssner, Helv. Chim. Acta, 1934, 17, 311.
Received in Liverpool, UK, 7th August 1998; 8/06326E
2252
Chem. Commun., 1998