Asymmetric synthesis of (-)-tetrahydrolipstatin from a β-hydroxy- δ-oxo sulfoxide

Article abstract of DOI:10.1055/s-0029-1216722

An asymmetric synthesis of (-)-tetrahydrolipstatin is described. A palladium-catalyzed regioselective oxidation of an alkene to a ketone, highly diastereoselective reduction of a β-hydroxy ketone, selective oxidation of a diol, and modular synthesis are the key features of the synthesis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216722

LETTER
1285
Asymmetric Synthesis of (–)-Tetrahydrolipstatin from a b-Hydroxy-d-oxo
Sulfoxide
Synthesis of (–
a
)-Tetrahyd
d
rolipstatin agopan Raghavan,* Kailash Rathore
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: sraghavan@iict.res.in
Received 13 November 2008
tone ring late in the synthesis. The key intermediate 2 can
be prepared by Frater–Seebach alkylation from a triol de-
rivative 3 which can be obtained from allyl alcohol 4.
Abstract: An asymmetric synthesis of (–)-tetrahydrolipstatin is
described. A palladium-catalyzed regioselective oxidation of an
alkene to a ketone, highly diastereoselective reduction of a b-
hydroxy ketone, selective oxidation of a diol, and modular synthesis
are the key features of the synthesis.
The synthesis commenced by condensing the lithium an-
ion of (R)-methyl phenyl sulfoxide5 5 with the unsaturated
ester6 6 following Solladie’s protocol7 to furnish b-keto
Key words: asymmetric synthesis, sulfoxide, palladium, tetra-
hydrolipstatin, Frater–Seebach alkylation
25
sulfoxide 7 {[a]D +51 (c 0.7, CHCl3)}. Diastereoselec-
tive reduction of 7 using DIBAL-H in the presence of an-
8
hydrous ZnCl2 yielded allyl alcohol
4
{P = 4-
25
Tetrahydrolipstatin (THL, 1), the stable saturated deriva-
tive of lipstatin that was isolated from Streptomyces toxy-
tricini,1 is a potent irreversible inhibitor of pancreatic
lipase.2 The b-lactone moiety of THL reacts with the
serine hydroxyl group present in the active site of lipases
forming an ester bond, thereby slowing the hydrolysis of
triglycerides and thus blocks the absorption of dietary fat.
It is currently marketed as an anti-obesity drug under the
name of Xenical®. The important biological properties
and its unique structural features have led to total synthe-
ses by a number of groups adopting varied strategies.3
MeOC6H4CH2 (PMB), >95% de, [a]D +62.6 (c 2.3,
CHCl3)}. The Wacker-type oxidation of 4 proceeded
cleanly under the standard conditions9 developed by us to
25
afford b-hydroxy ketone 8 {[a]D +84.9 (c 0.35,
CHCl3)}.10 Diastereoselective syn reduction of 8 using
NaBH4 in the presence of Et2BOMe11 furnished diol 9
{[a]D25 +56 (c 2.25, CHCl3)}.10 Acetylation of 9 furnished
the diacetate 10. Attempted introduction of the decyl
chain exploiting the ene reaction12 on the intermediate re-
sulting from a Pummerer reaction on diacetate 10 met
with failure probably due to competing activation of the
PMB group by SnCl4 resulting in its deprotection and oth-
er side reactions (Scheme 2).
As part of our continuing interest in exploring sulfoxide
chemistry,4 we report herein a diastereoselective and nov-
el synthesis of (–)-tetrahydrolipstatin. The salient features
of the reported synthesis are (a) the use of (R)-methyl phe-
nyl sulfoxide as the only original source of chirality, (b) a
regioselective Wacker-type oxidation of an unsaturated
sulfoxide using a Pd catalyst, (c) a diastereoselective re-
duction of a b-hydroxy ketone, and (d) its modularity. As
depicted in Scheme 1, we envisioned closing the b-lac-
Exploring an alternative route, the diol 9 was protected as
the acetal 3 {P1, P2 = 4-MeOC6H4CH, [a]D25 +34.4 (c 1.4,
CHCl3)} by DDQ oxidation of the PMB group under an-
hydrous conditions.13 Compound 3 on Pummerer reaction
followed by a one-pot hydrolysis, and reduction of the re-
sulting intermediate afforded the diol 11 {[a]D25 –21.8 (c
1.3, CHCl3)}. Selective tosylation of the primary hydroxy
H
OP1 OH
O
N
Me
O
OHC
Me
Me
O
Me
O
10
O
O
Me
Me
Me
4
10
5
1
2
OH OH OP2
S
O
S
OH
Ph
OP3
Ph
OP4
3
4
P = protecting groups
Scheme 1
SYNLETT 2009, No. 8, pp 1285–1288
x
x.
x
x.
2
0
0
9
Advanced online publication: 17.04.2009
DOI: 10.1055/s-0029-1216722; Art ID: S11708ST
© Georg Thieme Verlag Stuttgart · New York

1286
S. Raghavan, K. Rathore
LETTER
O
O
S
O
O
O
S
OH
LDA, THF, 0 °C
60%
DIBAL-H, ZnCl2
+
S
Ph
Me
Ph
OPMB
EtO
OPMB
OH
OPMB
Ph
–78 °C, THF, 75%
5
7
6
4
O
S
OH OH
O
S
O
PdCl2, CuCl
O2, aq. DMF, 50 °C
Ac2O, Et3N
cat. DMAP
NaBH4, Et2BOMe
THF, MeOH, –78 °C, 80%
Ph
OPMB
Ph
OPMB
CH2Cl2
r.t., 90%
70%
8
9
O
S
OAc OAc
TFAA, CH2Cl2, 0 °C
complex mixture
of products
Ph
OPMB
Me
then
7
10
and SnCl4
Scheme 2
group using N-Ts imidazole followed by treatment of the acid 18 {[a]D25 +14 (c 0.53, CHCl3)}, b-lactone formation
tosylate with decylmagnesium bromide in the presence of using BOPCl18 proceeded cleanly to yield compound 19
25
CuCN in an one-pot operation14 furnished the triol deriv- {[a]D –4 (c 0.97, CHCl3)} identical to the product re-
25
ative 12 {[a]D –14.9 (c 1.1, CHCl3)}.10 The secondary ported by Kumaraswamy and co-workers.3r Debenzyl-
hydroxy group in 12 was protected as its benzyl ether 13 ation and esterification19 using N-formyl leucine
25
{[a]D25 –14 (c 0.3, CHCl3)} and the acetal hydrolyzed un- furnished (–)-THL {[a]D25 –31 (c 0.1, CHCl3; lit.3d [a]D
der mild acidic conditions to yield diol 14 {[a]D25 +25.3 (c –33.04 (c 0.79, CHCl3)} with physical characteristic in
2.65, CHCl3)}. Selective oxidation of the primary in the complete agreement to those reported in the literature3d
presence of the secondary hydroxy group was effected us- (Scheme 4).
ing PhI(OAc)2/Tempo15 to furnish the corresponding al-
In summary, we have described a diastereoselective route
25
dehyde 15 {[a]D +2.6 (c 1.05, CHCl3)}. Subsequent
to THL. The key steps include the Wacker-type oxidation
oxidation to the acid 16 using Pinnick protocol16 and es-
of an alkene to a ketone regioselectively, stereoselective
syn reduction of b-hydroxy ketone, and diastereoselective
Frater–Seebach alkylation. The synthesis is flexible and
terification with ethereal diazomethane yielded ester 17
{[a]D25 +27.5 (c 1, CHCl3), Scheme 3}.
The synthesis of THL was completed employing a alkyl chains of variable lengths can be introduced at two
straightforward sequence of known reactions. Diastereo- positions using an advanced intermediate to access ana-
selective alkylation of 17 employing Frater–Seebach logues of THL.
25
protocol17 afforded the hexyl derivative 2 {P = Bn, [a]D
+19.2 (c 1.25, CHCl3)} in good yield (dr >90:10). Hydro-
lysis of the ester using aq 1 N LiOH afforded the hydroxy
PMP
O
H
O
PMP
O
H
O
TFAA, Et3N, 0 °C
O
S
OH OH
DDQ, CH2Cl2, r.t.
61%
OH
O
S
OH
HO
then aq. NaHCO3, NaBH4
50%
Ph
OPMB
Ph
11
9
3
Ts
N
PMP
H
O
PhI(OAc)2, cat. TEMPO
CH2Cl2, 0 °C to r.t.
cat. PPTS
aq MeOH, 70 °C
CH2Cl2
OBn OH OH
N
OP
O
Me
Me
65%
60%
then Me (CH2)9MgBr
cat. CuCN, THF
–10 to 0 °C, 70%
10
10
14
12, P = H
13, P = Bn
NaH, BnBr
THF, 0 °C to r.t.
72%
OBn OH
O
OBn OH
O
NaClO2, cyclohexene
t-BuOH, H2O, 0 °C to r.t.
Me
Me
OR
10
10
75%
15
16, R = H
CH2N2, Et2O
90%
17, R = Me
Scheme 3
Synlett 2009, No. 8, 1285–1288 © Thieme Stuttgart · New York

LETTER
Synthesis of (–)-Tetrahydrolipstatin
1287
O
OP
OH
O
OP
O
OBn OH
O
BOPCl, Et3N, CH2Cl2, r.t.
65%
LiHMDS, THF, –55 to –15 °C
then C6H13I, HMPA,
Me
R
Me
Me
Me
5
O
OMe
10
10
10
–55 to 0 °C, 70%
Me
17
4
19, P = Bn
20, P = H
H2, Pd(OH)2/C
EtOAc, EtOH
r.t., 80%
aq LiOH (1 N)
THF, 65 °C
70%
2, R = Me
18, R = H
H
H
N
N
Me
O
Me
OHC
OHC
Me
O
HO2C
Me
O
O
DCC, cat. DMAP
CH2Cl2, r.t., 72%
Me
Me
5
10
1
Scheme 4
(6) The unsaturated ester 6 was prepared by a three-step
Supporting Information for this article is available online at
sequence. Selective protection of 1,3-propane diol as its
p-methoxybenzyl ether followed by Swern oxidation and
Wittig olefination afforded 6 in 40% overall yield.
(7) Solladie, G.; Frechou, C.; Hutt, J.; Demailly, G. Bull. Soc.
Chim. Fr. 1987, 827.
(8) (a) Solladie, G.; Demailly, G.; Greck, C. Tetrahedron Lett.
1985, 26, 435. (b) Solladie, G.; Frechou, C.; Demailly, G.;
Greck, C. J. Org. Chem. 1986, 51, 1912. (c) Carreno,
M. C.; Garcia Ruano, J. L.; Martin, A. M.; Pedregal, C.;
Rodriguez, J. H.; Rubio, A.; Sanchez, J.; Solladie, G. J. Org.
Chem. 1990, 55, 2120.
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
S.R. is thankful to Dr. J. M. Rao, Head Org. Div. I and Dr. J. S.
Yadav, Director, IICT for constant support and encouragement.
K.R. is thankful to the CSIR, New Delhi for fellowships. Financial
assistance from DST (New Delhi) is gratefully acknowledged. We
thank Dr. A. C. Kunwar for the NMR spectra.
(9) Raghavan, S.; Krishnaiah, V.; Rathore, K. Tetrahedron Lett.
2008, 49, 4999.
References and Notes
(10) Synthesis of Compound 8
(1) (a) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.;
Lengsfeld, H. J. Antibiot. 1987, 40, 1081. (b) Hochuli, E.;
Kupfer, E.; Maurer, R.; Meister, W.; Mercadal, Y.; Schmidt,
K. J. Antibiot. 1987, 40, 1086.
A suspension of PdCl2 (352 mg, 1.98 mmol) and CuCl (1.96
g, 19.8 mmol) in a mixture of DMF and H2O (1:1, 20 mL)
was stirred under an O2 atmosphere for 1 h. A solution of
allyl alcohol 4 (7.13 g, 19.8 mmol) in DMF and H2O (1:1, 10
mL) was added to the above, and the reaction mixture was
stirred at 50 °C for 4 h. The reaction mixture was extracted
with Et2O (3 × 75 mL), washed successively with H2O
(2 × 20 mL), brine (20 mL), and dried over anhyd Na2SO4.
Evaporation of the solvent in vacuo afforded the crude
product which was purified by column chromatography
using 60% EtOAc–hexane as the eluent to furnish b-hydroxy
ketone 8 (5.21 g, 13.9 mmol) in 70% yield as a viscous oil.
TLC: Rf = 0.15 (70% EtOAc–hexane); [a]D +84.9 (c 0.35,
CHCl3). IR (neat): 3138, 2925, 2657, 1630, 1384, 1245,
1088, 1029, 754 cm–1. 1H NMR (200 MHz, CDCl3): d =
7.67–7.59 (m, 2 H), 7.56–7.48 (m, 3 H), 7.16 (d, J = 8.8 Hz,
2 H), 6.80 (d, J = 8.8 Hz, 2 H), 4.52 (quin, J = 5.9 Hz, 1 H),
4.39 (s, 2 H), 3.78 (s, 3 H), 3.66 (t, J = 5.9 Hz, 2 H), 2.98–
2.73 (m, 4 H), 2.66 (t, J = 5.9 Hz, 2 H). 13C NMR (50 MHz,
CDCl3): d = 208.62, 159.34, 143.63, 131.33, 129.93, 129.43,
129.35, 123.99, 113.87, 72.91, 64.73, 61.99, 55.28, 49.02,
43.67. ESI–MS: 399 [M + Na]+. ESI–HRMS: m/z [M + Na]+
calcd for C20H24O5NaS: 399.1242; found: 399.1240.
Synthesis of Compound 9
To a solution of b-hydroxy ketone 8 (5.21 g, 13.9 mmol) in
THF (110 mL) cooled at –78 °C was added diethylmethoxy-
borane (1 M in THF, 15.4 mL, 15.4 mmol) followed by
MeOH (28 mL), and stirred for 30 min. Then solid NaBH4
(577 mg, 15.3 mmol) was added in three portions and the
mixture stirred for 2 h at the same temperature. The reaction
was quenched using a mixture of pH 7 phosphate buffer (20
mL), MeOH (30 mL), and 30% (w/v) H2O2 soln (10 mL).
This mixture was allowed to warm to r.t. and stirred at r.t. for
further 18 h. The organic solvent was evaporated in vacuo,
(2) (a) Hadvary, P.; Sidler, W.; Meister, W.; Vetter, W.; Wolfer,
H. J. Biol. Chem. 1991, 266, 2021. (b) Hadvary, P.;
Lengsfeld, H.; Wolfer, H. Biochem. J. 1988, 256, 357.
(c) Borgstrom, B. Biochim. Biophys. Acta 1988, 96, 308.
(3) (a) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim. Acta
1987, 70, 1412. (b) Barbier, P.; Schneider, F.; Widmer, U.
Helv. Chim. Acta 1987, 70, 196. (c) Barbier, P.; Schneider,
F. J. Org. Chem. 1988, 53, 1218. (d) Hanessian, S.; Tehim,
A.; Chen, P. J. Org. Chem. 1993, 58, 7768. (e) Dirat, O.;
Kouklovsky, C.; Langlois, Y. Org. Lett. 1999, 1, 753.
(f) Ghosh, A. K.; Liu, C. Chem. Commun. 1999, 1743.
(g) Paterson, I.; Doughty, V. A. Tetrahedron Lett. 1999, 40,
393. (h) Wedler, C.; Costisella, B.; Schick, H. J. Org. Chem.
1999, 64, 5301. (i) Parsons, P. J.; Cowell, J. K. Synlett 2000,
107. (j) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2, 2405.
(k) Bodkin, J. A.; Humphries, E. J.; McLeod, M. D. Aust. J.
Chem. 2003, 56, 795. (l) Bodkin, J. A.; Humphries, E. J.;
McLeod, M. D. Tetrahedron Lett. 2003, 44, 2869.
(m) Thadani, A. N.; Batey, R. A. Tetrahedron Lett. 2003, 44,
8051. (n) Polkowska, J.; Lukaszewicz, E.; Kiegiel, J.;
Jurczak, J. Tetrahedron Lett. 2004, 45, 3873. (o) Yadav,
J. S.; Vishweshwar Rao, K.; Sridhar Reddy, M.; Prasad,
A. R. Tetrahedron Lett. 2006, 47, 4393. (p) Yadav, J. S.;
Vishweshwar Rao, K.; Prasad, A. R. Synthesis 2006, 3888.
(q) Yadav, J. S.; Sridhar Reddy, M.; Prasad, A. R.
Tetrahedron Lett. 2006, 47, 4995. (r) Kumaraswamy, G.;
Markondaiah, B. Tetrahedron Lett. 2008, 49, 327.
(4) Raghavan, S.; Sreekanth, T. Tetrahedron Lett. 2008, 49,
1169.
(5) Drago, C.; Caggiano, L.; Jackson, R. F. W. Angew. Chem.
Int. Ed. 2005, 44, 7221.
Synlett 2009, No. 8, 1285–1288 © Thieme Stuttgart · New York

1288
S. Raghavan, K. Rathore
LETTER
and brine (25 mL). The aqueous layers were re-extracted
and the aqueous layer was extracted with Et2O (3 × 75 mL).
The combined organic layers were washed with brine (20
mL) and dried over anhyd Na2SO4. Evaporation of the
solvent in vacuo yielded the crude product, which was
purified by column chromatography using 65% EtOAc–
hexane as the eluent to afford the syn 1,3-diol 9 (3.82 g, 10.1
mmol) in 73% yield as a viscous oil. TLC: Rf = 0.2 (70%
EtOAc–hexane); [a]D +56 (c 2.25, CHCl3). IR (neat): 3386,
2923, 2856, 2362, 1611, 1512, 1441, 1303, 1246, 1175,
1088, 1030, 820, 753, 691, 503 cm–1. 1H NMR (300 MHz,
CDCl3): d = 7.67–7.62 (m, 2 H), 7.55–7.46 (m, 3 H), 7.18 (d,
J = 8.3 Hz, 2 H), 6.82 (d, J = 8.3 Hz, 2 H), 4.41 (s, 2 H),
4.36–4.24 (m, 1 H), 3.78 (s, 3 H), 3.69–3.53 (m, 3 H), 3.03
(dd, J = 7.6, 12.8 Hz, 1 H), 2.80 (dd, J = 4.5, 12.8 Hz, 1 H),
1.86–1.62 (m, 4 H). 13C NMR (75 MHz, CDCl3): d = 159.37,
143.86, 131.21, 129.84, 129.36, 124.08, 113.93, 77.01,
73.05, 71.54, 68.43, 63.42, 55.28, 42.71, 29.68. ESI–MS:
401 [M + Na]+. ESI–HRMS: m/z [M + Na]+ calcd for
C20H26O5NaS: 401.1398; found: 401.1405.
with Et2O (2 × 25 mL), and the combined organic layers
were dried over anhyd Na2SO4. Evaporation of the solvent in
vacuo furnished the crude residue which was purified by
column chromatography using 10% EtOAc–hexane as the
eluent to afford triol 12 (846 mg, 2.1 mmol) in 70% yield as
a viscous oil. TLC: Rf = 0.5 (20% EtOAc–hexane); [a]D
–14.9 (c 1.1, CHCl3). IR (neat): 3447, 2922, 2853, 1634,
1459, 558 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.31 (d,
J = 9.1 Hz, 2 H), 6.82 (d, J = 9.1 Hz, 2 H), 5.45 (s, 1 H), 4.22
(dd, J = 4.5, 12.1 Hz, 1 H), 4.13–4.02 (m, 1 H), 3.92 (dt,
J = 2.3, 12.1 Hz, 1 H), 3.86–3.80 (m, 1 H), 3.78 (s, 3 H),
1.92–1.23 (m, 24 H), 0.88 (distorted t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.83, 130.67, 127.15,
113.57, 101.07, 78.10, 71.36, 66.98, 55.32, 42.77, 37.66,
31.56, 29.72, 29.69, 29.42, 25.51, 22.76, 14.22. ESI–MS:
393 [M + H]+. ESI-HRMS: m/z [M + Na]+ calcd for
C24H40O4Na: 415.2824; found: 415.2804.
(11) Chen, K.; Harttmann, G.; Prasad, K.; Repic, O.; Shapiro,
Synthesis of Compound 12
H. J. Tetrahedron Lett. 1987, 28, 155.
To a suspension of NaH (60% in Nujol, 310 mg, 7.7 mmol)
in anhyd THF (10 mL), cooled at 0 °C, was added a solution
of diol 11 (810 mg, 3.1 mmol) in THF (20 mL) dropwise.
The mixture was gradually allowed to warm to r.t. and
further stirred for 1 h at the same temperature. It was then
recooled at 0 °C and N-Ts-Imd (686 mg, 3.1 mmol) was
added in three equal potions over a period of 20 min. The
mixture was warmed to r.t. and stirred for 40 min, then
CuCN (55 mg, 0.61 mmol) was added. After stirring for an
additional 5 min, the mixture was cooled at –10 °C, and a
freshly prepared solution of decylmagnesium bromide (0.7
M in Et2O, 13.3 mL, 9.31 mmol) was added via syringe. The
reaction mixture was kept at the same temperature for 2 h
and then allowed to warm to 0 °C gradually over a period of
1 h. The reaction was quenched by the addition of aq sat.
NH4Cl solution (10 mL) and diluted with Et2O (65 mL). The
separated organic phase was washed with H2O (2 × 25 mL)
(12) (a) Raghavan, S.; Mustafa, S. Tetrahedron 2008, 64, 10055.
(b) Ishibashi, H.; Komatsu, H.; Ikeda, M. J. Chem. Res.,
Synop. 1987, 296.
(13) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 889.
(14) Cink, R. D.; Forsyth, C. J. J. Org. Chem. 1995, 60, 8122.
(15) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.;
Piancatelli, G. J. Org. Chem. 1997, 62, 6974.
(16) Bal, B. S.; Childers, W. E.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
(17) (a) Frater, G. Helv. Chim. Acta 1979, 62, 2828.
(b) Seebach, D.; Wasmuth, D. Helv. Chim. Acta 1980, 63,
197.
(18) (a) Colucci, W. J.; Tung, R. D.; Petri, J. A.; Rich, D. H.
J. Org. Chem. 1990, 55, 2895. (b) Tung, R. D.; Rich, D. H.
J. Am. Chem. Soc. 1985, 107, 4342.
(19) Wu, Y.; Sun, Y.-P. J. Org. Chem. 2006, 71, 5748.
Synlett 2009, No. 8, 1285–1288 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.