Stereoselective syntheses of (-)-tetrahydrolipstatin via Prins cyclisations

Article abstract of DOI:10.1016/j.tetlet.2006.05.116

Stereoselective syntheses of (-)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cyclisations as the key steps. PCC mediated oxidative cleavage, Frater alkylation, Keck allylation, Sharpless asymmetric epoxidation and allylic cleavage were the other key steps employed.

Full text of DOI:10.1016/j.tetlet.2006.05.116

Tetrahedron Letters 47 (2006) 4995–4998
Stereoselective syntheses of (ꢀ)-tetrahydrolipstatin
via Prins cyclisations
J. S. Yadav,* M. Sridhar Reddy and A. R. Prasad
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 14 April 2006; revised 10 May 2006; accepted 18 May 2006
Abstract—Stereoselective syntheses of (ꢀ)-tetrahydrolipstatin have been achieved via two divergent approaches through Prins cycli-
sations as the key steps. PCC mediated oxidative cleavage, Frater alkylation, Keck allylation, Sharpless asymmetric epoxidation and
allylic cleavage were the other key steps employed.
Ó 2006 Elsevier Ltd. All rights reserved.
(ꢀ)-Tetrahydrolipstatin (THL), a potent and irreversible
lipase inhibitor, is the saturated analogue of lipstatin
isolated from Streptomyces toxytricini in 1987.1 Re-
cently, THL has been marketed in several countries as
an anti-obesity agent under the name Xenical. Due to
its biological activity, THL has been the target of several
synthetic chemists.2 In our ongoing program on the util-
isation of the highly stereoselective Prins cyclisation
reaction, a well established method for constructing
multi-substituted tetrahydropyrans,3 for the synthesis
of polyketide motifs,4 we have undertaken the total syn-
thesis of (ꢀ)-THL.
Our first approach is outlined in Scheme 2. Cu mediated
regioselective opening5 of (R)-benzyl glycidyl ether 116
with vinyl magnesium bromide resulted in HAA 6. Prins
cyclisation of HAA 6 with dodecanal in the presence of
TFA followed by hydrolysis of the resulting trifluoro-
acetate gave trisubstituted pyran 12.3a,4a Protection of the
secondary alcohol as the TBS ether 13 using TBSCl,
imidazole and catalytic DMAP followed by cleavage
of the primary benzyl ether using Na in ammonia pro-
duced pyranyl methanol 14. PCC mediated oxidative
cleavage4a,7 of 14 in refluxing benzene provided triketide
d-lactone 5. Methanol addition to the lactone was car-
ried out in the presence of TEA and resulted in the cor-
responding d-hydroxy ester which without work-up but
after removal of MeOH under reduced pressure, was
protected as its MOM ether 15 in the presence of DI-
PEA and MOMCl in DCM. Attempts to isolate the
intermediate MeOH addition product were unsuccessful
as it cyclised back to lactone 5. Cleavage of the silyl
ether in 15 using TBAF in THF yielded b-hydroxy ester
4. The dianion of 4, formed on treatment with LDA in
THF, was alkylated with hexyl iodide to give 16 as the
predominant diastereomer in 75% yield after a flash col-
umn chromatography.8 The crude reaction product
revealed ꢁ2% of the other diastereomer.
The retrosynthetic analysis is outlined in Scheme 1. Not
surprisingly, our first disconnection involved cleavage of
the (S)-N-formyl amino acid portion to reveal the key
triketide fragment 2 and acid 3. It was envisioned that
2 could be obtained in two different ways. First, we spec-
ulated that the alkyl stereocentre could be created by
controlled alkylation on 4 which could be easily ob-
tained from lactone 5 which in turn is available through
Prins cyclisation from simple homoallylic alcohol 6 and
dodecanal. We also envisioned that the triketide 2 could
be obtained, via allylic cleavage, from tetrasubstituted
pyran 7 which in turn could be accessed from homoally-
lic alcohol (HAA) 8 and trans-2-hexenal. Homoallylic
alcohol 8 would be easily obtained from chiral allylated
9 or from Sharpless asymmetric epoxidation product 10.
Hydroxy ester 16 was transformed into b-lactone 18 by
hydrolysis of the ester group using LiOH followed by
treatment of acid 17 with PhSO2Cl in the presence of
pyridine in THF. b-Lactone 18 on cleavage of the
MOM ether with BF3ÆOEt2 and ethane dithiol9 in
DCM produced alcohol 2 which on esterification with
(S)-N-formyl leucine 3 under Mitsunobu conditions10
Keywords: Anti-obesity; Homoallylic alcohol; Prins cyclisation and
allylic cleavage.
*
Corresponding author. Tel.: +91 40 27193030; fax: +91 40
27160512; e-mail: yadavpub@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.116

4996
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4995–4998
NHCHO
O
O
NHCHO
O
OH
O
O
O
O
+
n-C11H23
n-C6H13
HO
3
n-C11H23
2
n-C6H13
(-)-tetrahydrolipstatin 1
OMOM
MOMO
n-C11H23
OH
OMOM
n-C3H7
COOMe
4
O
n-C11H23
7
OTBS
OH
+
trans-2-hexenal
8
n-C11H23
OH
O
O
n-C11H23
5
n-C11H23
n-C11H23
OH
dodecanal
+
BnO
O
6
10
OH
9
OH
Scheme 1.
OH
dodecanal
MgBr
TFA, DCM then
K2CO3, MeOH
CuCN, THF
BnO
BnO
BnO
O
OH
6
rt, 2 h, 64%
-78 oC-rt, 4 h, 84%
O
n-C11H23
11
12
OTBS
OTBS
TEA, MeOH
rt, 12 h then
TBSCl, imidazole
DMAP, DCM
PCC, benzene
reflux, 6 h, 65%
RO
0 oC-rt, 6 h, 96%
DIPEA, MOMCl
DMAP, DCM,
O
O
O
5
n-C11H23
n-C11H23
R=Bn
R=H
0 oC-rt, 2 h, 90%
13
14
Na, NH3, THF
-33 oC, 5 min, 92%
OH
MOMO
n-C11H23
MOMO
n-C11H23
OR
LDA, n-C6H13I
COOR
PhSO2Cl, Py, THF
0 oC, 12 h, 76%
COOMe
THF, -78 to-20 oC
3 h, 75%
n-C6H13
R=Me
R=H
16
17
LiOH, THF, H2O,
rt, 12 h, 88%
R=TBS
TBAF, THF
0 oC-rt, 6 h, 98%
15
4
R=H
O
O
(S)-N-formyl leucine 3
O
OH
.
O
MOMO
n-C11H23
BF3 OEt2, (CH2SH)2
1
DIAD, TPP, THF
n-C11H23
0 oC-rt, 1 h, 88%
n-C6H13
n-C6H13
0 oC-rt, 3 h, 90%
2
18
Scheme 2.
furnished (ꢀ)-THL 1. The spectral and physical data of
1 were in good agreement with those reported.11
ester 19. An alternative method was also successful for
the conjugated ester 19. Two-carbon homologation of
dodecanal using ethoxycarbonylmethylenetriphenyl-
phosphorane in benzene gave a conjugated ester which
on reduction with DIBAL-H yielded allyl alcohol 20.
Sharpless asymmetric epoxidation14 of 20 with D-(ꢀ)-
DET produced epoxy alcohol 10. Regioselective reduc-
tion of the epoxide using Red-Al yielded 1,3-diol 21 which
on one-pot chemoselective oxidation of the primary hy-
droxy group using TEMPO and bis(acetoxy)iodobenzene
(BAIB) in DCM and two-carbon Wittig homologation
An alternative strategy, devised for the synthesis of (ꢀ)-
THL 1, is delineated in Schemes 3 and 4. The strategy
again utilised the Prins cyclisation installing the key alkyl
centre and a hydroxy group in a highly stereocontrolled
manner. Thus, Keck allylation12 of dodecanal gave
HAA 9 which on subjection to one-pot ozonolysis–Wittig
olefination13 with the stable ylide, ethoxycarbonylmethyl-
enetriphenylphosphorane furnished the a,b-unsaturated

J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4995–4998
4997
O3, TPP, DCM, -78 oC
Ti(OiPr)4, (S)-BINOL
CO2Et
OH
n-C10H21
n-C10H21
dodecanal
dodecanal
allyltributyltin
-20 oC, 78%
OH
OH
19
then Ph3PCHCOOEt,
rt, 78%
9
D-(-)-DET, Ti(OPri)4,
TBHP, DCM
Ph3PCHCO2Et, benzene
0 oC-rt, 6 h, 84%
OH
n-C10H21
n-C10H21
O
-20 oC, 4 h, 88%
DIBAL-H, DCM,
0 oC-rt, 1 h, 90%
20
10
TEMPO, BAIB, DCM
rt, 2 h then added
Red-Al, THF, 0 oC-rt
2 h, 92%
OH
n-C10H21
19
Ph3PCHCO2Et
0 oC-rt, 6 h, 58%
OH
21
Scheme 3.
OR
O
trans-2-hexenal
OH
OR
DIBAL-H, DCM
TFA, DCM then
19
0 oC-rt, 1 h, 84%
OH
n-C11H23
8
K2CO3, MeOH
rt, 58%
n-C3H7
n-C11H23
DIPEA, MOMCl,
DMAP, DCM
0 oC-rt, 98%
R=H
22
7
R=MOM
OMOM
OR OMOM
PtO2, H2, EtOAc
rt, 1 h, 95%
Na, NH3, THF
45 min, 90%
OMOM
n-C11H23
OMOM
n-C6H13
OH
n-C11H23
R=H
24
23
NaH, BnBr, TBAI
THF, 0 oC-rt, 94%
n-C4H9
R=Bn
25
OBn OH
OBn OH
O
TEMPO, BAIB
BF3.OEt2, (CH2SH)2
0 oC-rt, 1 h, 92%
DCM, rt then
NaClO2, NaH2PO4
58%
n-C11H23
OH
n-C6H13
n-C11H23
OH
27
26
n-C6H13
O
OR
O
PhSO2Cl, Py
0 oC, 12 h, 78%
(S)-N-formyl leucine 3
DIAD, TPP, THF
n-C11H23
1
n-C6H13
R=Bn
R=H
0 oC-rt, 3 h, 90%
28
2
Pd(OH)2, H2,
EtOAc, 12 h, 91%
Scheme 4.
on addition of the stable ylide, ethoxycarbonylmethylene-
using NaH, BnBr and catalytic TBAI followed by
deprotection of the MOM ether linkages with BF3ÆOEt2
and ethane dithiol in DCM produced diol 26.9 Chemo-
selective oxidation of the primary alcohol with TEMPO
and BAIB in DCM followed by further oxidation of the
resulting crude aldehyde with NaH2PO4 and NaClO2
furnished hydroxy acid 27.15 Treatment of 27 with
PhSO2Cl in pyridine yielded beta-lactone 28 which on
benzyl ether cleavage with Pd(OH)2 in EtOAc followed
by esterification with (S)-N-formyl leucine 3 under Mits-
unobu conditions completed the total synthesis of (ꢀ)-
THL 1, whose spectral and physical data were again in
good agreement with those reported.11
triphenylphosphorane resulted in hydroxy ester 19.15
DIBAL-H mediated reduction of conjugated ester 19 led
to the allylic alcohol 8. Prins cyclisation of 8 with trans-
2-hexenal using TFA in DCM followed by hydrolysis of
the crude trifluoroacetate with K2CO3 in MeOH
resulted in tetrasubstituted pyran 22. Pyran 22 was
converted in to its di-MOM ether 7 in the presence of
DIPEA, MOMCl and catalytic DMAP in DCM which
on subjection to Na in ammonia, underwent allylic
cleavage to yield acyclic alcohol 23 as a 1:1 mixture of
diastereomers with respect to the migrated double
bond.4b However, reduction of the double bond with
PtO2 in EtOAc yielded a single diastereomer of 24. Pro-
tection of the free hydroxy group as its benzyl ether 25
Thus, we have achieved the total synthesis of (ꢀ)-THL 1
via Prins cyclisation using two divergent routes from

4998
J. S. Yadav et al. / Tetrahedron Letters 47 (2006) 4995–4998
F.; Neugnot, B.; Solladie, G. Org. Lett. 2003, 5, 629–633;
(h) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 501–504; (i)
Rychnovsky, S. D. Chem. Rev. 1995, 95, 2021–2040; (j)
Yet, L. Chem. Rev. 2003, 103, 4283–4306; (k) Dias, L. C.;
de Oliveira, L. G.; Vilcachagua, J. D.; Nigsch, F. J. Org.
Synth. 2005, 70, 2225–2234; (l) Keck, G. E.; Truong, A. P.
Org. Lett. 2005, 7, 2153–2156, and references cited therein.
4. (a) Yadav, J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron
Lett. 2005, 46, 2133–2136; (b) Yadav, J. S.; Reddy, M. S.;
Prasad, A. R. Tetrahedron Lett., in press; (c) Yadav, J. S.;
Reddy, M. S.; Rao, P. P. Prasad, A. R. Tetrahedron Lett.,
in press.
completely different starting materials showing the con-
venience of the strategy. The total syntheses of similar
polyketide molecules using this strategy are currently
being pursued.
Acknowledgements
M.S.R. thanks CSIR, New Delhi, for the award of
fellowship.
5. Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullex, M.;
Colobert, F.; Solladie, G. Tetrahedron Lett. 2003, 44,
2695–2697.
References and notes
6. Furrow, M. E.; Schaus, S. E.; Jacobsen, E. N. J. Org.
Chem. 1998, 68, 6776–6777.
1. (a) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.;
Lengsfeld, H. J. Antibiot. 1987, 40, 1081–1085; (b)
Hochuli, E.; Kupfer, E.; Maurer, R.; Meister, W.; Mer-
cadal, Y.; Schmidt, K. J. Antibiot. 1987, 40, 1086–1091.
2. (a) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim.
Acta 1987, 70, 1412–1418; (b) Barbier, P.; Schneider, F.;
Widmer, U. Helv. Chim. Acta 1987, 70, 196–202; (c)
Barbier, P.; Schneider, F. J. Org. Chem. 1988, 53, 1218–
1221; (d) Dirat, O.; Kouklovsky, C.; Langlois, Y. Org.
Lett. 1999, 1, 753–755; (e) Ghosh, A. K.; Liu, C. Chem.
Commun. 1999, 1743–1744; (f) Paterson, I.; Doughty, V.
A. Tetrahedron Lett. 1999, 40, 393–394; (g) Wedler, C.;
Costisella, B.; Schick, H. J. Org. Chem. 1999, 64, 5301–
5303; (h) Parsons, P. J.; Cowell, J. K. Synlett 2000, 107–
109; (i) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2, 2405–
2407; (j) Bodkin, J. A.; Humphries, E. J.; McLeod, M. D.
Aust. J. Chem. 2003, 56, 795–803; (k) Bodkin, J. A.;
Humphries, E. J.; McLeod, M. D. Tetrahedron Lett. 2003,
44, 2869–2872; (l) Thadani, A. N.; Batey, R. A. Tetra-
hedron Lett. 2003, 44, 8051–8055; (m) Polkowska, J.;
Lukaszewicz, E.; Kiegiel, J.; Jurczak, J. Tetrahedron Lett.
2004, 45, 3873–3875, and references cited therein.
3. (a) Barry, C. St. J.; Crosby, S. R.; Harding, J. R.; Hughes,
R. A.; King, C. D.; Parker, G. D.; Willis, C. L. Org. Lett.
2003, 5, 2429–2432; (b) Yang, X.-F.; Mague, J. T.; Li,
C.-J. J. Org. Chem. 2001, 66, 739–747; (c) Yadav, J. S.;
Reddy, B. V. S.; Sekhar, K. C.; Gunasekar, D. Synthesis
2001, 6, 885–888; (d) Yadav, J. S.; Reddy, B. V. S.; Reddy,
M. S.; Niranjan, N. J. Mol. Catal. A: Chem. 2004, 210, 99–
103; (e) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.;
Niranjan, N.; Prasad, A. R. Eur. J. Org. Chem. 2003,
1779–1783; (f) Rychnovsky, S. D.; Powell, N. A. J. Org.
Chem. 1997, 62, 6460–6461; (g) Obringer, M.; Colobert,
7. (a) Baskaran, S.; Chandrasekaran, S. Tetrahedron Lett.
1990, 31, 2775–2778; (b) Ali, S. M.; Ramesh, K.; Bor-
chardt, R. T. Tetrahedron Lett. 1990, 31, 1509–1512.
8. (a) Frater, G. Helv. Chim. Acta 1979, 62, 2825–2828; (b)
Frater, G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40,
1269–1277.
9. (a) Naito, H.; Kawahara, E.; Maruta, K.; Maeda, M.;
Sasaki, S. J. Org. Chem. 1995, 60, 4419–4427; (b) Fuji, K.;
Kawabata, T.; Fujita, E. Chem. Pharm. Bull. 1980, 28,
3662–3664.
10. Mitsunobu, O. Synthesis 1981, 1–28.
11. Selected data for compound 1: White solid, Rf 0.14
(20% ethyl acetate/hexane); mp 39–41 °C (lit.2a,b mp 40–
20
20
42 °C); ½aꢂD ꢀ32.0 (c 0.96, CHCl3) (lit.2a,b ½aꢂD ꢀ33
(c 0.65, CHCl3)). 1H NMR (200 MHz, CDCl3): d 8.22
(s, 1H), 6.02 (d, 1H, J = 8.5 Hz, NH), 5.02 (m, 1H), 4.68
(m, 1H), 4.28 (m, 1H), 3.22 (dt, 1H, J = 7.6, 3.9 Hz), 2.25–
2.11 (m, 1H), 2.02 (m, 1H), 1.80–1.15 (m, 33H), 0.95 (d, 6H,
J = 5.2 Hz), 0.87 (distorted t, 6H). 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, 31.9, 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. ESIMS:
m/z 496 [M+H]. IR (KBr): 1832, 1740, 1691 cmꢀ1
.
12. Keck, G. E.; Tarbet, K. H.; Geraci, L. S. J. Am. Chem.
Soc. 1993, 115, 8467–8468.
13. Hon, Y. S.; Lu, L.; Li, S. Y. J. Chem. Soc., Chem.
Commun. 1990, 1627–1628.
14. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765–5780.
15. Vatele, J.-M. Tetrahedron Lett. 2006, 47, 715–718.