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J. Polkowska et al. / Tetrahedron Letters 45 (2004) 3873–3875
O
cis,cis-2 and trans,cis-2 diastereoisomers. Chromato-
graphical separation allowed us to obtain analytical
samples of both pure diastereoisomers, however, it was
preparatively ineffective. Therefore, we decided to sub-
ject the resulting mixture of hydroxy lactones 2 to oxi-
dation with Jones reagent, expecting equilibration of the
product 10 to the more thermodynamically stable dia-
stereoisomer. The latter, hydrogenated again in the
presence of Adam’s catalyst, should afford the stereo-
chemically pure product. Indeed, this transformation
gave the required product (3S,4S,6R)-2 in greater than
98% ee. Its analytical data12 were in agreement with the
literature values.8
O
O
O
O
O
O
O
O
O
(a)
Cu
O
O
5
6
(c)
O
(b)
O
O
O
O
O
O
O
H23C11
C6H13
8
7
The sequence of consecutive oxidations and reductions
presented herein allowed us to use both diastereoisomers
of the hydroxy lactone 2 for the synthesis of tetrahydro-
lipstatin (1). The formal synthesis of tetrahydrolipstatin
has been achieved in this manner, since the intermediate
(3S,4S,6R)-2 has been successfully used by Barbier and
Schneider8 in their highly stereoselective synthesis of 1
published earlier.
(a)
(c)
H23C11
O
O
H23C11
O
O
O
O
O
O
(b)
O
Cu
C6H13
O
O
O
H23C11
9
4
Scheme 2. (a) Cu(OAc)2, MeOH/H2O; (b) NaH, C6H13Br, KI,
Bu4NBr, THF, reflux; (c) (i) NaH, BuLi, THF, 0 ꢁC; (ii) C10H21Br,
reflux.
References and notes
1. Ohkuma, T.; Noyori, R. In Comprehensive Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamomoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 1, pp 199–246.
2. Juszkiewicz, G.; Asztemborska, M.; Jurczak, J. Synth.
Commun. 2002, 32, 2605.
3. Juszkiewicz, G.; Asztemborska, M.; Jurczak, J. Polish
J. Chem. 2002, 76, 1707.
4. Juszkiewicz, G.; Jurczak, J. Org. Prep. Proced. Int. 2002,
34, 187.
The key step of the synthesis was the asymmetric
hydrogenation of ester 4 in the presence of (R)-11 as
catalyst1 in methanolic solution at 60 ꢁC under a
hydrogen pressure of 100 atm for 18 h. This resulted in a
mixture of the ester 3 and the hydroxy lactone 2 in a 3:1
ratio in 80% overall yield (Scheme 3). The product
mixture containing the compounds 2 and 3 was in turn
treated with PPTS in toluene to afford a 3:1 mixture of
5. Hogan, S.; Fleury, A.; Hadvary, P.; Lengsfeld, H.; Meier,
M. K.; Triscari, J.; Sullivan, A. C. Int. J. Obes. 1987,
11(Suppl. 3), 35.
O
O
O
OH OH
O
(a)
C11H23
O
C6H13
O
C6H13
H23C11
4
3
+
OH
O
OH
O
OH
(b)
C6H13
C6H13
(c)
C6H13
+
O
O
O
O
H23C11
H23C11
H23C11
(3R,4S,6R)-2
(3S,4S,6R)-2
2
(d)
Ph2
P
P
Ph2
(e)
Cl
Ru
Cl
O
C6H13
O
O
H23C11
(R)-11
10
Scheme 3. (a) H2, (R)-11 (cat), MeOH, 100 atm, 60 ꢁC, 18 h, 80%; (b) PPTS, toluene, 50 ꢁC, 2 h, 92%; (c) chromatographic separation; (d) CrO3,
H2SO4, acetone, 0 ꢁC, 1 h, 0%; (e) H2, Pt (cat), EtOAc, 45 atm, 20 ꢁC, 48 h, 85%.