Enantioselective total synthesis of (-)-tetrahydrolipstatin using Oppolzer's sultam directed aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2007.11.051

A highly practical and concise stereoselective total synthesis of (-)-tetrahydrolipstatin is achieved using Oppolzer's sultam directed aldol reaction as the key step.

Full text of DOI:10.1016/j.tetlet.2007.11.051

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 327–330
Enantioselective total synthesis of (ꢀ)-tetrahydrolipstatin
using Oppolzer’s sultam directed aldol reaction
G. Kumaraswamy* and B. Markondaiah
Organic Division III, Fine Chemicals Laboratory, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 3 October 2007; revised 30 October 2007; accepted 7 November 2007
Available online 13 November 2007
Abstract—A highly practical and concise stereoselective total synthesis of (ꢀ)-tetrahydrolipstatin is achieved using Oppolzer’s
sultam directed aldol reaction as the key step.
Ó 2007 Elsevier Ltd. All rights reserved.
Natural products such as lipstatin 1a, valilactone 1c,
esterastin 1d and the lipstatin derivative, tetrahydrolipst-
atin 1b, possessing a trans-b-lactone moiety, inhibit gas-
tric and pancreatic lipases by blocking the hydrolysis of
anticancer activity.2 The postulated mechanism for this
potent inhibitory activity is due to irreversible covalent
binding to an active site serine of pancreatic lipase.
Owing to the significant activity of these molecules, a
number of approaches have been reported for their
synthesis.3
triglycerides. Among these, tetrahydrolipstatin,
a
reduced form of lipstatin is identified as an antiobesity
agent, being the first over-the-counter weight-loss medi-
cation and approved by the FDA under the trade name
Xenical (Fig. 1).1
Chiral auxiliary mediated asymmetric C–C bond forma-
tion as the key step has been used extensively for the
synthesis of various biologically active compounds.4
Recently, we developed an efficient method for the syn-
thesis of belactosin C and its congeners possessing the
trans-b-lactone moiety using D-(2R)-sultam as a chiral
auxiliary for generating anti and syn diastereomers. This
Of late, these trans-b-lactones have generated renewed
interest among synthetic chemists due to the recent find-
ings that they are specific inhibitors of fatty acid syn-
thase (FAS-TE), an approved drug target for
NHCHO
NHCHO
O
O
O
O
O
O
O
O
R
1c
H2N
= R, 1a
= R, 1b
NHAc
O
O
O
O
O
R
= R, 1d
Figure 1.
Keywords: trans-b-Lactone; Tetrahydrolipstatin; D-(2R)-Sultam; Antiobesity agent; Pancreatic lipases; Anticancer activity.
*
Corresponding author. Tel.: +91 40 27193154; fax: + 91 40 27193275; e-mail: gkswamy_iict@yahoo.co.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.051

328
G. Kumaraswamy, B. Markondaiah / Tetrahedron Letters 49 (2008) 327–330
NHCHO
OBn OH
O
O
O
OH
O
O
11
1b
O
OH
O
N
N
OBn
OHC
+
S
OBn
S
O
O
O
O
2
5
3
Scheme 1.
TiCl4 (3 equiv)
Pr2NEt (2.2 equiv)
O
O
OH
i
O
OH
N
N
+
OBn
N
S
OBn
S
OHC
(3 equiv)
CH2Cl2 , -78 oC
S
2
OBn
O
O
O
O
O
O
3
4
5
de: <7 : >93
Scheme 2.
process is significant in that the Lewis acid employed
leads to different enantiomers depending on the stoichio-
metry.5 This prompted us to consider the same metho-
dology for the synthesis of (ꢀ)-tetrahydrolipstatin 1b
and our retrosynthetic approach is shown in Scheme 1.
Table 1. Study of varying the amounts of TiCl4 and iPr2NEt and the
effect on the syn:anti ratio in the reaction of acylsultam 3 and
benzyloxypropanal 2 (3 equiv)
Entry
TiCl4
iPr2NEt
Ratio 4:5a de
Yieldb,c
(%)
(equiv)
(equiv)
1
2
3
1
2
3
1.2
1.2
2.2
95:5
10:90
<7:>93
75
40
58
We began our study following the previously developed
protocol5 (Scheme 2). Acylsultam 3 was treated with
1 equiv of TiCl4 and 1.2 equiv of diisopropylethylamine
at ꢀ78 °C and the resulting mixture was stirred for 1.5 h
followed by the addition of 3 equiv of benzyloxyprop-
anal 2. As expected, after work-up, the syn-aldol 4 was
isolated as the major product in 75% yield.
a The de was determined from the 1H NMR spectrum of the crude
residue. The stereochemical assignment of the major diastereomer
was made by analogy with our previous work.5
b Yields refer to the major isomer after column chromatography.
c All reactions were carried out at ꢀ78 °C.
In another reaction, the Ti-enolate was generated at
ꢀ78 °C using 1 equiv of acylsultam 3, 2 equiv of TiCl4
and 1.2 equiv of diisopropylethylamine and the
sultam-enolate was quenched with 3 equiv of benzyloxy-
propanal 2. The expected anti-aldol was isolated in 40%
yield. However, reaction with 3 equiv of TiCl4 and
2.2 equiv of diisopropylethylamine under otherwise
identical conditions, not only showed improved de
(4:5, <7:>93) but also increased the yield in favour of
the anti-aldol 5 (Table 1).
M
O
R
H
OBn
M = Ti,
H
N
= Xc
S
Xc OM
O
O
A#
=
R
Figure 2.
The formation of anti-aldol 5 can be rationalized on the
basis of open transition state A# as proposed by Oppol-
zer and Lienard (Fig. 2).4a
DMSO to give the aldehyde 7. The Grignard reagent
generated using undecyl bromide and Mg in THF at
0 °C, was added to aldehyde 7 to furnish the corre-
sponding alcohol as a diastereomeric mixture. This
was subjected to oxidation with IBX in DMSO to give
the corresponding ketone7 8 in 90% yield. A highly syn
stereoselective 1,3-asymmetric reduction was carried
out using LiI–LAH in ether at ꢀ100 °C to provide the
desired 1,3-syn product 9 in 80% yield (syn:anti
Reductive cleavage of anti-aldol adduct 5 with LAH
gave the 1,3-diol6 in 75% yield. This was protected with
2,2-DMP/CSA in CH2Cl2 to afford 6 in 90% yield. Deb-
enzylation of 6 in Li/Liq NH3 gave the corresponding
alcohol in 82% yield, which was oxidized with IBX in

G. Kumaraswamy, B. Markondaiah / Tetrahedron Letters 49 (2008) 327–330
329
i, ii
O
O
O
iii, iv
OBn O
O
v, vi
5
H
7
6
OH
O
O
O
O
O
viii, ix
vii
9
8
OBn OH
O
OBn OH OH
x
xi
OH
11
10
O
OBn O
xii, xiii
1b
12
Scheme 3. Reagents and conditions (i) LAH/ether, 0 °C to rt, 3 h, 75%; (ii) CSA, 2,2-DMP, CH2Cl2, 0 °C, 6 h, 90%; (iii) Li, NH3, THF, 1 h, 82%; (iv)
IBX, DMSO, CH2Cl2, rt, 4 h, 90%; (v) Mg, undecyl bromide, THF, 0 °C to rt, 12 h, 70%; (vi) IBX, DMSO, CH2Cl2, rt, 4 h, 90%; (vii) LiI, LAH,
ether, ꢀ100 °C, 30 min, 80%; (viii) BnBr, NaH, THF, 0 °C to reflux, 6 h, 80%; (ix) 1 N HCl/THF (1:1) 0–60 °C, 3 h, 88%; (x) TEMPO, BAIB,
CH2Cl2, rt, 2 h; then NaClO2, 20%NaH2PO4Æ2H2O, t-BuOH, 0 °C to rt, 4 h, 90%; (xi) BOPCl, Et3N, CH2Cl2, 23 °C, 1 h, 75%; (xii) Pd(OH)2/C, H2,
EtOAc/EtOH (9:1), 12 h, 92%; (xiii) DCC, DMAP, (S)-N-formyl leucine, CH2Cl2, rt, 24 h, 80%.
85:158). The hydroxy group was protected as its benzyl
ether using NaH/BnBr and a catalytic amount of TBAI,
and the acetonide cleaved with 1 N HCl/THF (1:1) at
0–60 °C to give the corresponding diol9 10 in 88% yield.
Chemoselective oxidation of 10 with TEMPO and
bis(acetoxy)iodobenzene (BAIB) in CH2Cl2 followed
by further oxidation of the resulting aldehyde with
perchlorite/dihydrogen orthophosphate furnished the
b-hydroxy acid10 11 in 90% yield (Scheme 3).
T. K. Chakraborty for his support. B.M. is thankful to
UGC (New Delhi) for awarding the fellowship.
Supplementary data
Experimental procedures and spectral data of 3, 4, 5, 6,
7, 8, 9, 10, 11, 12 and 1b and copies of the spectra of 4, 5,
9, 12 and 1b. Supplementary data associated with this
article can be found, in the online version, at doi:
10.1016/j.tetlet.2007.11.051.
The b-hydroxy acid 11 was lactonized with bis(2-oxo-3-
oxazolidinyl)phosphinic chloride (BOPCl) to furnish the
known b-lactone 12 in 75% yield. Debenzylation of this
b-lactone with Pd(OH)2/C, H2 in EtOAc/EtOH (9:1)
gave the corresponding alcohol in 92% yield. Finally,
the free alcohol of b-lactone 12 was coupled with (S)-
N-formylleucine using DCC/ DMAP11 in CH2Cl2 to
give (ꢀ)-tetrahydrolipstatin 1b in 80% yield.12 The ana-
lytical data of 1b was in full agreement with the reported
data for the natural product.3a
References and notes
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In conclusion, we have developed a concise stereo-
selective total synthesis of (ꢀ)-tetrahydrolipstatin using
Oppolzer’s sultam directed aldol reaction as the key
step. Application of this methodology to synthesize
various cis and trans-substituted b-lactones to study
their activity profiles is under progress.
Acknowledgements
We are grateful to Dr. J. S. Yadav, Director, IICT, for
his constant encouragement. Thanks are also due to Dr.

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25
20
12. Spectral data of 1b: ½aꢁD ꢀ31.3 (c 0.001, CHCl3) (lit.3a ½aꢁD
ꢀ33 (c 0.65, CHCl3)). 1H NMR (200 MHz, CDCl3): d 8.22
(1H, s), 6.02 (1H, d, J = 8.5 Hz), 5.02 (1H, m), 4.68 (1H,
m), 4.28 (1H, m), 3.22 (1H, dt, J = 7.6, 3.7 Hz), 2.25–2.11
(1H, m), 2.02 (1H, m), 1.80–1.15 (33H, m), 0.95 (6H, d,
J = 5.2 Hz), 0.87 (6H, distorted t); 13C NMR (75 MHz,
CDCl3): d 171.9, 170.8, 160.7, 74.8, 72.6, 56.9, 49.7, 41.4,
38.7, 34.0, 31.8, 31.2, 29.6, 29.5, 29.4, 29.3, 29.2, 28.8, 27.7,
26.8, 25.2, 24.9, 22.8, 22.7, 22.5, 21.7, 14.1,14.0; IR (KBr):
3447, 2925, 2855, 1822, 1670, 1461, 1213, 1122, 759 cmꢀ1
;
ESIMS: m/z 518 (M+Na+); HRMS (M+Na+) calcd for
C29H53NO5Na 518.3821, found 518.3827.