Highly enantioselective hydrogenation of 3,5-diketo esters: A formal synthesis of tetrahydrolipstatin

Article abstract of DOI:10.1016/j.tetlet.2004.03.128

Compound 4, obtained via a sequence of two consecutive alkylations of methyl 3,5-dioxohexanoate (5), was transformed into the enantiomerically pure lactone (3S,4S,6R)-2 being the precursor of tetrahydrolipstatin (1). The reaction sequence involves asymmetric catalytic hydrogenation of 4 as a crucial step.

Full text of DOI:10.1016/j.tetlet.2004.03.128

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3873–3875
Highly enantioselective hydrogenation of 3,5-diketo esters:
a formal synthesis of tetrahydrolipstatin
Jolanta Polkowska,a Ewa Łukaszewicz,a Jarosław Kiegiela and Janusz Jurczaka,b,
*
aDepartment of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland
bInstitute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
Received 26 January 2004; revised 18 March 2004; accepted 22 March 2004
Abstract—Compound 4, obtained via a sequence of two consecutive alkylations of methyl 3,5-dioxohexanoate (5), was transformed
into the enantiomerically pure lactone (3S,4S,6R)-2 being the precursor of tetrahydrolipstatin (1). The reaction sequence involves
asymmetric catalytic hydrogenation of 4 as a crucial step.
ꢀ 2004Elsevier Ltd. All rights reserved.
NHCHO
Asymmetric catalytic hydrogenation of keto esters is an
O
OH
ideal method for preparation of the corresponding
synthetically significant alcohols. In the last decade, high
catalytic activity and excellent enantioselectivity have
been obtained by means of chiral phosphine-Ru com-
plexes.1
O
C6H13
O
O
C6H13
O
H23C11
H23C11
1
2
Recently, we have demonstrated that 3-keto esters2 and
4-keto esters3 as well as 3,5-diketo esters4 were efficiently
hydrogenated in the presence of cationic BINAP-Ru(II)
complexes, affording almost enantiomerically pure (95–
99% ee) hydroxy esters, useful intermediates for the
preparation of pheromones.
OH OH
O
O
O
H23C11
O
O
O
H23C11
C6H13
C6H13
3
4
Now we report a new application of this methodology to
the highly stereoselective synthesis of tetrahydrolipstatin
(1),5 a saturated derivative of lipstatin6;7 isolated from
Streptomyces toxytricini, an inhibitor of pancreatic lip-
ases.
O
O
O
O
5
Scheme 1.
Based on the retrosynthetic analysis of tetrahydrolip-
statin (1) as shown in Scheme 1, we concluded that the
hydroxy lactone 2,8;9 readily accessible via asymmetric
hydrogenation of the suitably substituted 3,5-diketo
ester 4,10 would be a suitable intermediate for the target
compound 1.
In the first step of the synthesis, we converted 3,5-di-
oxohexanoic acid methyl ester (5) into its racemic 2,6-
dialkyl derivative 4 (Scheme 2). The reaction of ester 5
with copper(II) diacetate resulted in formation of com-
plex 6, which was then subjected to alkylation with
n-hexyl bromide.11 The racemic compound 7 obtained was
then alkylated with n-decyl bromide, to give the desired
derivative 4 in 40% overall yield. The intermediate 4 can
be prepared in similar yield by changing the reaction
sequence to 5 fi 8 fi 9 fi 4 (Scheme 2).
Keywords: Tetrahydrolipstatin; Asymmetric synthesis; 3,5-Diketo est-
ers; Enantioselective catalysis.
* Corresponding author. Tel./fax: +48-22-8230944; e-mail: jjurczak@
chem.uw.edu.pl
0040-4039/$ - see front matter ꢀ 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.128

3874
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%.

J. Polkowska et al. / Tetrahedron Letters 45 (2004) 3873–3875
3875
6. Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.;
Lengsfeld, H. J. Antibiot. 1987, 40, 1081.
10. Batelaan, J. G. Synth. Commun. 1976, 6, 81.
11. Carvello, J.; Marquet, J.; Moreno-Manas, M. Tetrahedron
1990, 46, 2035.
7. Hochuli, E.; Kupfer, E.; Maurer, R.; Meister, W.; Mer-
cadal, Y.; Schmidt, K. J. Antibiot. 1987, 40, 1086.
8. Barbier, P.; Schneider, F. J. Org. Chem. 1988, 53, 1218.
9. Chadha, N. K.; Batcho, A. D.; Tang, P. C.; Courtney,
L. F.; Cook, C. M.; Wovkulich, P. M.; Uskokovic, M. R.
J. Org. Chem. 1991, 56, 4714.
12. Selected analytical data for (3S,4S,6R)-2: mp 95–96 ꢁC
27
D
1
(from ether/hexane); ½aŠ 43.0 (c 0.32, CHCl3); H NMR
(CDCl3, 200 MHz):
d
4.4–4.3 (dt, 1H, Jaa ¼ 8:5,
Jae ¼ 3:5 Hz), 4.3–4.1 (m, 1H), 2.5–2.1 (m, 2H), 2.0–1.9
(m, 1H), 1.8–1.2 (m, 31H), 0.88 (t, 6H, J ¼ 7 Hz).