Scheme 2. Michael Additions of R-Heterosubstituted Imines
Scheme 3. Condensation of Imine 13 with Methyl Acrylate
and Methyl Vinyl Ketonea
We began our work with the preparation of chiral imine
1
3, starting from commercially available 2-methyltetra-
hydrothiophen-3-one 12 and enantiopure (R)-1-phenylethyl-
amine 2 (cyclohexane, 100 h at 20 °C, in the presence of a
a
Reagents and conditions: (a) 2, catalyst, 20 °C. (b) H
Me, 45 °C, then 20% AcOH (63% for two steps). (c)
MeONH Cl, AcONa (90%). (d) NCS, CCl (83%). (e) MVK, 20
C, then 20% AcOH (25%). (f) 3% KOH, MeOH, 60 °C. (g) (i) aq
NaOH; (ii) 2 N HCl (quantitative). (h) Ac O, AcONa (70%). (i) 2
equiv of LiCH PO(OMe) , THF, -78 °C (57%).
2
Cd-
1
q
mixture of 5 Å molecular sieves, basic Al
Addition of crude imine 13 to methyl acrylate (neat, 70 h at
5 °C) furnished, after hydrolytic workup (20% aqueous
2 3 2
O , and SiO ).
CHCO
2
3
4
°
4
2
AcOH, 20 °C), adduct (S)-14 in 63% overall yield. The ee
1
2
2
in 14 (g95%) was determined by H NMR spectroscopy,
3
with addition of Eu(hfc) as a shift reagent, at the level of
the O-methyloxime derivative 15 (prepared as a single (E)-
isomer by condensing 14 with MeONH Cl in the presence
3
of AcONa). The configuration of 14 was founded on the
heuristic stereochemical rule we have proposed in this series.1
Conversion of 14 into enone (S)-16, a potential intermediate
in the synthesis of thiotetronic acids was achieved smoothly
(
1) Reviews: (a) d’Angelo, J.; Desma e¨ le, D.; Dumas, F., Guingant, A.
+
-
Tetrahedron: Asymmetry 1992, 3, 459-505. (b) d’Angelo, J.; Cav e´ , C.;
Desma e¨ le, D.; Dumas, F. In Trends in Organic Synthesis; Pandalai, S. G.,
Ed.; Trivandrum: India, 1993; Vol 4, pp 555-615. For recent developments,
see: (c) Desma e¨ le, D.; Cav e´ , C.; d’Angelo, J.; Dumas, F. Enantiomer 2001,
6
, 289-298. (d) Keller, L.; Camara, C.; Pinheiro, A.; Dumas, F.; d’Angelo,
J. Tetrahedron Lett. 2001, 42, 381-383. (e) Tori, M.; Makino, G.; Hisazuni,
K.; Sono, M.; Nakashima, K. Tetrahedron: Asymmetry 2001, 12, 301-
by subjecting 14 to N-chlorosuccinimide (CCl
4
, 15 min at
3
07. (f) Schenato, R. A.; dos Santos, E. M.; Tenius, B. S. M.; Costa, P. R.
2
0 °C, 83% yield). Condensation of 13 with methyl vinyl
R.; Caracelli, I.; Zukerman-Schpector, J. Tetrahedron: Asymmetry 2001,
2, 579-584. (g) Nour, M.; Tan, K.; Jankowski, R.; Cav e´ , C. Tetra-
hedron: Asymmetry 2001, 12, 765-769. (h) Christoffers, J.; Mann, A.;
Chem. Eur. J. 2001, 7, 1014-1027. (i) Keller, L.; Dumas, F.; d’Angelo, J.
Tetrahedron Lett. 2001, 42, 1911-1913. (j) R e´ vial, G.; Jabin, I.; Redolfi,
M.; Pfau, M.; Tetrahedron: Asymmetry 2001, 12, 1683-1688. (k) Ishizaki,
M.; Iwahara, K.; Niimi, Y.; Satoh, H.; Hoshino, O. Tetrahedron 2001, 57,
1
2
ketone (Et O, 24 h at 20 °C, then 20% aqueous AcOH) led
to adduct (S)-17 in 25% yield, along with a substantial
amount of side products. This disappointing result can be
interpreted by invoking a competitive retro-Michael process
that possibly affects the regio- and stereochemical features
2
729-2738. (l) Tan, K.; Alvarez R.; Nour, M.; Cav e´ , C.; Chiaroni, A.;
Riche, C.; d’Angelo, J. Tetrahedron Lett. 2001, 42, 5021-5023. (m) Jabin,
1l
of the reaction, an assumption reinforced by the fact that
I.; R e´ vial, G.; Pfau, M.; Netchita ¨ı lo, P. Tetrahedron: Asymmetry 2002, 13,
the condensation of imine 6, the oxygen counterpart of 13,
with methyl vinyl ketone led to a three-component mixture
consisting of regioisomeric “monoalkylated” and “di-
5
63-567. (n) Camara, C.; Joseph, D.; Dumas, F.; d’Angelo, J.; Chiaroni,
A. Tetrahedron Lett. 2002, 43, 1445-1448. (o) Thominiaux, C.; Chiaroni,
A.;. Desma e¨ le, D. Tetrahedron Lett. 2002, 43, 4107-4110. (p) Christoffers,
J.; Scharl, H. Eur. J. Org. Chem. 2002, 1505-1508 (q) Keller, L.; Dumas,
F.; d’Angelo, J. Eur. J. Org. Chem 2003, 2488-2497. (r) Camara, C.; Keller,
L.; Dumas, F. Tetrahedron: Asymmetry 2003, 14, 3263-3266. (s) Danet,
M.; Normand-Bayle, M.; Mahuteau, J.; d’Angelo, J.; Morgant. G.; Desma e¨ le,
D. Eur. J. Org. Chem. 2004, 1911-1922. (t) Hendra, F.; Nour, M.; Baglin,
I.; Morgant, G.; Cav e´ , C. Tetrahedron: Asymmetry 2004, 15, 1027-1032.
2
alkylated” adducts. Cyclization of 17 (3% KOH in MeOH,
2
h, 60 °C) next furnished bicyclic enone (S)-18, though
contaminated by minor impurities. In view of the cumber-
some separation of 17 from byproducts, an alternative
synthetic route to 18, a potential CD synthon for the
construction of 17-thiasteroids, was developed, starting from
keto ester (S)-14. Saponification of latter compound (NaOH,
MeOH then 2 N HCl) gave the corresponding keto acid,
(2) Desma e¨ le, D.; d’Angelo, J.; Bois, C. Tetrahedron: Asymmetry 1990,
1
, 759-762.
(
3) Desma e¨ le, D.; d’Angelo, J. Tetrahedron Lett. 1989, 30, 345-348.
(4) Nour, M.; Tan, K.; Cav e´ , C.; Villeneuve, D.; Desma e¨ le, D.; d’Angelo,
J.; Riche, C. Tetrahedron: Asymmetry 2000, 11, 2015-2021.
(
5) Jogdeo, P. S.; Bhide, G. V. Steroids 1980, 35, 133-138. See also:
Cachoux, F.; Ibrahim-Ouali, M.; Santelli, M. Synlett 2000, 418-420.
which was then converted into enol lactone (S)-19 (Ac
2
O,
(
6) Paquette, L. A. Austr. J. Chem. 2004, 57, 7-17.
AcONa, 2 h at 120 °C). Treatment of 19 with 2 equiv of
(7) Jones, S. M.; Urch, J. E.; Brun, R.; Harwood, J. L.; Berry, C.; Gilbert,
I. H. Bioorg. Med. Chem. 2004, 12, 683-692.
LiCH
2
PO(OMe)
2
(1 h, -78 °C, followed by 1 h at -20 °C,
2422
Org. Lett., Vol. 6, No. 14, 2004