LETTER
Asymmetric Synthesis of Prelactone B and V
2183
In conclusion, we succeeded in developing a flexible
and highly selective synthesis of triketide d-lactones like
prelactone B and V. In six steps we achieved highly func-
tionalized building blocks based on the SAMP/RAMP-
hydrazone methodology.
H3CO
H3CO
N
O
N
O
N
N
R
O
Ot-Bu
a,b
O
O
Acknowledgment
H3C CH3
H3C CH3
2
3a,b
We thank the Deutsche Forschungsgemeinschaft (SFB 380) and the
Fonds der Chemischen Industrie for financial support and the com-
panies Degussa AG, BASF AG and Bayer AG for the donation of
chemicals. We thank Dr. J. Runsink for the NOE measurements.
78%; 4a
80%; 4b
over 3 steps
c
References
O
CH2
R
Ot-Bu
(1) Bindseil, K. U.; Zeeck, A. Helv Chim. Acta 1993, 76, 150.
(2) (a) Hanefeld, U.; Hooper, A. M.; Staunton, J. Synthesis
1999, 401. (b) Chakraborty, T. K.; Tapadar, S. Tetrahedron
Lett. 2003, 44, 2541. (c) Fournier, L.; Gaudel-Siri, A.;
Kocienski, P. J.; Pons, J.-M. Synlett 2003, 107.
R
Ot-Bu
d
72%; 5a
81%; 5b
O
O
O
O
O
O
H3C CH3
H3C CH3
5a,b
4a,b
(d) Fournier, L.; Gaudel-Siri, A.; Kocienski, P. J.; Pons, J.-
M. Synlett 2003, 584.
78%; 6a
75%; 6b
(3) (a) Enders, D.; Bockstiegel, B.; Gatzweiler, W.; Jegelka, U.;
Dücker, B.; Wortmann, L. Chim. Oggi/Chem. Today 1997,
15, 20. (b) Enders, D.; Bockstiegel, B. Synthesis 1989, 493.
(c) Enders, D.; Hundertmark, T.; Lampe, C.; Jegelka, U.;
Scharfbillig, I. Eur. J. Org. Chem. 1998, 2839. (d) Enders,
D.; Hundertmark, T.; Lazny, R. Synlett 1998, 721.
(e) Enders, D.; Gatzweiler, W.; Jegelka, U. Synthesis 1991,
1137.
(4) Job, A.; Janeck, C. F.; Bettray, W.; Peters, R.; Enders, D.
Tetrahedron 2002, 58, 2253.
(5) Enders, D.; Voith, M. Synlett 2002, 29.
(6) (a) Urabe, H.; Matsuka, T.; Sato, F. Tetrahedron Lett. 1992,
33, 4183. (b) Karanewsky, D. S. Tetrahedron Lett. 1991, 32,
3911.
e
O
O
O
O
f
67%; 1a
79%; 1b
HO
R
HO
R
CH3
CH2
6a,b
1a, de > 93%(> 98%)a; ee > 98%
1b, de, ee > 98%
a: R = i-Pr
b: R = Me
a
after recrystallization
Scheme 1 Reagents and conditions: a) t-BuLi, THF, –78 °C, 2 h;
RI, –100 °C to r.t. over 15 h. b) t-BuLi, THF, –78 °C, 2 h;
BrCH2CO2t-Bu, –100 °C to r.t. over 15 h. c) (CO2H)2 (aq), Et2O, r.t.
d) Ph3P=CH2, THF, –78 °C to r.t. over 15 h. e) TFA, CH2Cl2–H2O, r.t.
f) H2, Crabtree’s-cat., CH2Cl2, r.t.
(7) Haas, M. Diploma Thesis; RWTH-Aachen: Germany, 2001.
(8) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51, 2655.
(9) General Procedure for 4,6-Disubstituted 2,2-Dimethyl-
1,3-dioxan-5-ones: t-BuLi (5 mmol, 15% in pentane) was
added dropwise to a solution of RAMP-hydrazone (5 mmol)
in anhyd THF (25 mL) at –78 °C. After stirring for 2 h the
mixture was cooled to –100 °C and the electrophile (6 mmol)
was added slowly. The mixture was allowed to warm up to
r.t. over 15 h. The reaction mixture was quenched with a
buffer solution (pH = 7, 5 mL) and diluted with Et2O (30
mL). The aq layer was extracted with Et2O. The combined
organic layers were washed with brine, dried over MgSO4
and concentrated in vacuo. For alkylation at a¢-position the
procedure was repeated. The product hydrazone was
dissolved in Et2O (50 mL) and a sat. aq solution of oxalic
acid was added at r.t. The bi-phase system was stirred
vigorously at r.t. until the reaction was completed (TLC
control). The layers were separated and the aq phase was
extracted with Et2O. The combined organic layers were
washed with brine and dried over MgSO4. The solvent was
removed under reduced pressure. Purification was carried
out by flash chromatography (SiO2; pentane–Et2O, 2:1).
(10) Prelactone B (1a): Mp 90 °C; [a]D25 +37.8 (c 1.10, MeOH).
IR: 3473, 2970, 2929, 2882, 1717, 1468, 1383, 1310, 1273,
1230, 1192,3, 1103, 1064, 1004, 847, 819, 705, 620, 579
cm–1. 1H NMR (400 MHz, CDCl3): d = 0.93 (d, J = 6.9 Hz,
3 H, 6-CH3), 1.07 (d, 3 H, J = 6.6 Hz, 4-CH3), 1.10 (d, 3 H,
J = 7.1 Hz, 6-CH3), 1.75 (ddq, J = 10.2 Hz, 8.2, 6.6, 1 H, H-
4), 1.99 (dsept, J = 2.2 Hz, 7.0, 1 H, H-5), 2.49 (dd, J = 7.9
Hz, 17.3, 1 H, H-2a), 2.93 (dd, J = 6.0 Hz, 17.3, 1 H, H-2b),
stereoisomer 1a was obtained (de, ee > 98%). The ee val-
ue was determined by gas chromatography on chiral sta-
tionary phase (Lipodex E; 0.25 mm × 25 m).
The relative configuration was confirmed by a NOE-ex-
periment on prelactone V (Figure 2). All substituents of
the d-lactone are equatorial.
1.3%
H
1.6%
HO
O
H
H
6.0%
H3C
H
O
CH3
3.2%
H
2.0%
Figure 2 Selected NOE-enhancements of prelactone V
Synlett 2003, No. 14, 2182–2184 © Thieme Stuttgart · New York