Synthesis of enantiomerically pure β-lactones by the tandem aldol- lactonization. A highly efficient access to (3S,4S)-3-hexyl-4[(2S)-2- hydroxytridecyl]oxetan-2-one, the key intermediate for the enzyme inhibitors tetrahydrolipstatin and tetrahydroesterastin

Full text of DOI:10.1021/jo980292a

J . Org. Chem. 1999, 64, 5301-5303
5301
Syn th esis of En a n tiom er ica lly P u r e
Ch a r t 1
â-La cton es by th e Ta n d em
Ald ol-La cton iza tion . A High ly Efficien t
Access to (3S,4S)-3-Hexyl-4-
[
(2S)-2-h yd r oxytr id ecyl]oxeta n -2-on e, th e
Key In ter m ed ia te for th e En zym e
In h ibitor s Tetr a h yd r olip sta tin a n d
Tetr a h yd r oester a stin †
,1
‡
Christine Wedler, Burckhard Costisella, and
Hans Schick*
WITEGA Angewandte Werkstoff-Forschung g. GmbH,
Rudower Chaussee 5, D-12484 Berlin, Germany
Received February 18, 1998
During the last 20 years it has become evident that
(3S,4S)-3-alkyl-4-[(2S)-2-hydroxyalkyl]oxetan-2-ones es-
terified in the side chain with various N-formylated or
N-acetylated R-amino acids form a steadily growing
family of structurally closely related esterase and lipase
inhibitors of microbial origin. Whereas the 4-alkyl side
2
3,4
chains of esterastin (1) and lipstatin (2) are unsatur-
5
ated, the 4-alkyl side chains of valilactone (5) and of the
recently detected panclicins (6, panclicin D) are fully
6
saturated. The saturated derivatives of 1 and 2, tetrahy-
droesterastin (3)2 and tetrahydrolipstatin (4),
,7
3,7-10
ex-
hibit comparable pharmacological properties, but are
more stable than the parent compounds. Especially
tetrahydrolipstatin (4) is now approved as an antiobesity
agent.11 Due to its promising pharmacological properties,
this lipase inhibitor has served during the past decade
as a target for the demonstration of the usefulness and
7
,12-19
versatility of new â-lactone syntheses.
*
Corresponding Author. Tel: 00 49/30/63 92 41 30. Fax: 00 49/30/
6
3 92 41 03. E-mail: schick@aca.fta-berlin.de.
A common feature of these syntheses is the construc-
tion of a (3S,4S)-oxetan-2-one with trans-orientated alkyl
groups and an (S)- or (R)-configured hydroxy group in
the 2-position of the 4-alkyl chain. The configuration of
the hydroxy group determines whether the final esteri-
fication with an R-amino acid derivative requires inver-
sion or retention of the configuration of this stereogenic
center.
†
This paper is dedicated to Professor Sigfrid Schwarz, J enapharm,
on the occasion of his 65th birthday.
Present address: Universit a¨ t Dortmund, Fachbereich Chemie,
D-44221 Dortmund, Germany.
‡
(1) Synthesis of â-Lactones. 9. For part 8, see Wedler, C.; Ludwig,
R.; Schick, H. Pure Appl. Chem. 1997, 69, 605-608. For part 7, see
Wedler, C.; Kleiner, K.; Gr u¨ ndemann, E.; Schick, H. J . Chem. Soc.,
Perkins Trans 1 1997, 1963-1967.
(2) Kondo, S.; Uotani, K.; Miyamoto, M.; Hazato, T.; Naganawa, H.;
Aoyagi, T.; Umezawa, H. J . Antibiot. 1978, 31, 797-800.
3) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.; Lengsfeld,
H. J . Antibiot. 1987, 40, 1081-1085.
4) Hochuli, E.; Kupfer, E.; Maurer, R.; Meister, W.; Mercadal, Y.;
Schmidt, K. J . Antibiot. 1987, 40, 1086-1091.
5) (a) Kitahara, M.; Asano, M.; Naganawa, H.; Maeda, K.; Hamada,
M.; Aoyagi, T.; Umezawa, H.; Iitaka, Y.; Nakamura, H. J . Antibiot.
987, 40, 1647-1650. (b) Bates, R. W.; Fern a´ ndes-Moro, R.; Ley, S. V.
Tetrahedron Lett. 1991, 32, 2651-2654.
6) (a) Mutoh, M.; Nakada, N.; Matsukuma, S.; Oshima, S.; Yosa-
hinari, K.; Watanabe, J .; Arizawa, M. J . Antibiot. 1994, 47, 1369-
375. (b) Yoshinari, K.; Aoki, M.; Ohtsuka, T.; Nakayama, N.; Itezono,
Y.; Mutoh, M.; Watanabe, J .; Yokose, K. J . Antibiot. 1994, 47, 1376-
(
On the basis of the one-step tandem aldol-lactoniza-
tion of lithium enolates of activated carboxylic acid
(
derivatives with aldehydes, developed in this laboratory
(
1,20
during the last five years,
we now are able to present
1
(13) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim. Acta 1987,
70, 1412-1418.
(
(14) Fleming, I.; Lawrence, N. J . Tetrahedron Lett. 1990, 31, 3645-
1
3648.
(15) Case-Green, S. C.; Davies, S. G.; Hedgecock, C. J . R. Synlett
1991, 781-782.
1
384. (c) Yang, H. W.; Romo, D. J . Org. Chem. 1997, 62, 4-5.
(
7) Barbier, P.; Schneider, F. J . Org. Chem. 1988, 53, 1218-1221.
(16) 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,
4714-4718.
(8) Hadvary, P.; Sidler, W.; Meister, W.; Vetter, W.; Wolfer, H. J .
Biol. Chem. 1991, 266, 2021-2027.
9) L u¨ thi-Peng, Q.; M a¨ rki, H. P.; Hadv a´ ry, P. FEBS Lett. 1992, 299,
(
(17) Hanessian, S.; Tehim, A.; Chen, P. J . Org. Chem. 1993, 58,
7768-7781.
1
11-115.
(
10) L u¨ thi-Peng, Q.; Winkler, F. K. Eur. J . Biochem. 1992, 205, 383-
(18) Pommier, A.; Pons, J .-M.; Kocienski, P.; Wong, L. Synthesis
1994, 1294-1300.
3
90.
(11) (a) Zhi, J .; Melia, A. T.; Guerciolini, R.; Chung, J .; Kinberg, J .;
(19) Landi, J . J .; Garofalo, L. M.; Ramig, K. Tetrahedron Lett. 1993,
34, 277-280.
Hauptman, J . B.; Patel, I. H. Clin. Pharm. Ther. 1994, 56, 82-85. (b)
Budzinski, A. Eur. Chem. 1997, 13, 12.
(20) Wedler, C.; Kleiner, K.; Kunath, A.; Schick, H. Liebigs Ann.
1996, 881-885 and references therein.
(12) Barbier, P.; Schneider, F. Helv. Chim. Acta 1987, 70, 196-202.
1
0.1021/jo980292a CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/24/1999

5
302 J . Org. Chem., Vol. 64, No. 14, 1999
Notes
Sch em e 1
Sch em e 2
a very efficient three-step procedure for the synthesis of
3S,4S)-3-hexyl-4-[(2S)-2-hydroxytridecyl]oxetan-2-one (11),
the common intermediate for the enzyme inhibitors 3 and
(
4
, starting from methyl (S)-3-hydroxytetradecanoate (7).
According to the protocol of the tandem aldol-lacton-
for the spontaneous intramolecular cyclization. Inexpen-
sive chiral leaving groups of this type could not be found
so far. The synthesis of lactones such as 11 or 12
according to this protocol can therefore not be based on
double diastereoselection. It is restricted to simple dia-
stereoselection based only on the directing influence of
the stereogenic center of the O-protected 3-hydroxy
aldehyde. Nevertheless, the overall economy of the
process seems to be much better than that of processes
2
1
ization, methyl (S)-3-hydroxytetradecanoate (7) was
treated with an excess of 2-methoxypropene22 in the
presence of a catalytic amount of pyridinium p-toluene-
sulfonate and converted into the O-protected ester 8. This
was reduced with diisobutylaluminum hydride to the
aldehyde 9 and then reacted with the amide enolate
generated from 1-octanoylbenzotriazole 10 and lithium
hexamethyldisilazide. During the acidic workup, the very
labile O-protecting group was spontaneously split off, and
a 4:1 mixture of the diastereomeric oxetan-2-ones 11 and
2
0
1
3,15
requiring chiral auxiliaries for double stereoselection,
R-silyl ketenes for the construction of the hexyl side
chain,18 or sophisticated organometallic reagents.
The preferential formation of the desired oxetan-2-one
11 from the O-protected aldehyde 7 may be explained
14,15
1
2 was obtained. Separation by flash chromatography
and recrystallization from pentane/hexane afforded both
oxetan-2-ones in diastereomerically pure form. The struc-
ture of these two diastereoisomers with anti-arrangement
of the side chains could be unambiguously assigned on
2
5
on the basis of the Zimmerman-Traxler model. It
seems to be reasonable that the Re-face of the aldehyde
is attacked by the Re-face of the R-methine group of the
(E)-enolate 13 as depicted in Scheme 2. Only this
approach gives rise to the chairlike transition state 14
with the two alkyl side chains in equatorial position and
allows by elimination of lithium benzotriazolide the
subsequent formation of the oxetan-2-one 11 with the
side chains in anti-position. It seems to be possible that
the lithiation of the benzotriazolide 10 forms the required
(E)-enolate 13 with high selectivity. It was already
observed in an earlier investigation that the application
of benzotriazolides in the tandem aldol-lactonization
exhibits a higher anti-selectivity than the application of
the corresponding phenyl esters.20
1
the basis of their H NMR spectra and comparison with
published data.1 The isolated yield of 11 amounted to
8
3
3
5%, the yield of 12 to about 5% (related to methyl (S)-
-hydroxytetradecanoate).
In comparison to the known syntheses for the oxetan-
-ones 11 and 12 the synthesis outlined here is extremely
2
short. It requires only three steps from methyl 3-hydroxy-
tetradecanoate, a starting material used also in several
earlier multistep reactions.1
3,15,18,19
The number of steps
could be reduced by application of the tandem aldol-
lactonization and the use of the very labile 2-methoxy-
prop-2-oxy protecting group, which does not require an
additional deprotection step.
The protocol of the tandem aldol-lactonization re-
quires an activated carboxylic acid derivative such as an
A consideration of the Zimmerman-Traxler model
allows understanding of the preferred formation of the
(3S,4S)-oxetan-2-one starting from the (S)-configured
aldehyde 9. The 2-methoxyprop-2-oxy group protects the
Si-face of the aldehyde against an attack by the amide
enolate 13, thus disfavoring the formation of the unde-
sired anti-oxetan-2-one 12.
S-phenyl ester,23 a phenyl ester, or a benzotriazolide
24
20
(
21) Tai, A.; Nakahata, M.; Harada, T.; Izumi, Y. Chem. Lett. 1980,
125-1126.
22) Dujardin, G.; Rossignol, S.; Brown, E. Tetrahedron Lett. 1995,
6, 1653-1656.
23) (a) Danheiser, R. L.; Nowick, J . S. J . Org. Chem. 1991, 56,
176-1185. (b) Danheiser, R. L.; Nowick, J . S.; Lee, J . H.; Miller, R.
1
3
1
(
(
As a consequence of the preferred formation of the
(3S,4S)-configured oxetan-2-one starting from methyl
F.; Huboux, A. H.; Mathre, D. J .; Shinkai, I. Org. Synth. 1995, 73,
6
7
1-72.
(
24) Wedler, C.; Kunath, A.; Schick, H. J . Org. Chem. 1995, 60, 758-
(25) Zimmermann, H. E.; Traxler, M. D. J . Am. Chem. Soc. 1957,
79, 1920.
60.

Notes
J . Org. Chem., Vol. 64, No. 14, 1999 5303
(
1
3S)-hydroxytetradecanoate (7), the final conversion of
1 into tetrahydrolipstatin (4) by esterification of the
hydroxy group can be performed with formyl leucin
phase was separated and extracted with ethyl acetate (3 × 20
mL). The combined organic phases were washed with water (10
2 4
mL), dried (Na SO ), and concentrated under reduced pressure.
The residual colorless oil (13.7 g, containing still traces of
toluene) was used in the next step without further purification.
without prior conversion of the configuration.1
garding the molecular economy, this is a further advan-
tage of the outlined procedure.
4-16
Re-
25
1
[
R]
J ) 7 Hz, 3H), 1.24-1.69 (m, 26H), 3.08 (s, 3H), 4.17-4.21 (m,
1H), 9.67 (t, J ) 2 Hz, 1H). The signal of the 2-CH -group is
hidden by the signals of DMSO; 13C NMR (DMSO-d
) δ 13.9,
2.1, 24.5, 24.9, 25.0, 28.7, 28.9, 28.97, 29.00, 29.04, 31.3, 35.6,
8.5, 48.9, 66.3, 100.5, 202.8. Anal. Calcd for C18 : C, 71.95;
D
+4.89 (c ) 0.5 in hexane); H NMR (DMSO-d
6
) δ 0.86 (t,
With the synthesis of a 4:1 mixture of the (3S,4S)- and
2
(
3R,4R)-oxetan-2-ones 11 and 12 from (S)-3-(2-methoxy-
prop-2-oxy)tetradecanal 9 and the lithium enolate of
-octanoylbenzotriazole 10, we were able to demonstrate
6
2
4
36 4
H O
1
H, 12.08. Found: C, 72.05; H, 12.28.
that the tandem aldol-lactonization affords enantiomeri-
cally pure â-lactones with an acceptable diastereoselec-
tivity. From the four possible diastereoisomers only the
two anti-compounds were formed with a distinct prefer-
ence of the diastereoisomer 11, useful as common inter-
mediate for the synthesis of the enzyme inhibitors
tetrahydroesterastin (3) and tetrahydrolipstatin (4). Us-
ing 2-methoxypropene for the protection of the hydroxy
group, methyl (S)-3-hydroxytetradecanoate could be con-
verted in three steps into the intermediate 11 with an
isolated yield of 35%.
(
3S ,4S )-3-H e xyl-4-[(2S )-2-h yd r oxyt r id e cyl]oxe t a n -2-
on e (11) a n d (3R,4R)-3-Hexyl-4-[(2S)-2-h yd r oxytr id ecyl]-
oxeta n -2-on e (12). The crude aldehyde 9 (13.7 g, prepared from
0 mmol of 7) was dissolved in dry THF (10 mL) and cooled to
50 °C. The solution was then added within 1 h to a solution of
4
-
2
0
the lithium enolate of the benzotriazolide 10, maintaining the
temperature of the reaction mixture by cooling with a slurry of
ethanol in liquid nitrogen at -95 to -100 °C. After complete
addition, the mixture was kept at this temperature for 30 min
and allowed to warm to room-temperature overnight. Aqueous
HCl (2 N) (50 mL) was added under cooling with ice water, and
the mixture was stirred for 20 min. Diethyl ether (20 mL) was
added. The aqueous phase was separated and extracted with
diethyl ether (3 × 25 mL). The organic phase and the extracts
Exp er im en ta l Section
were combined, washed with brine (2 × 20 mL), dried (Na
2 4
SO ),
and concentrated under reduced pressure. Flash chromatogra-
phy of the residue on silica gel (350 g) with hexane/ethyl acetate
Gen er a l. H and 13C NMR spectra were recorded at 500 or
1
1
25 MHz, respectively, with HMDS as internal standard in
(
3 L, 4:1) as eluent afforded the more polar oxetan-2-one 11 and
CDCl , if not stated otherwise. Flash chromatography was
3
the less polar oxetan-2-one 12 (overall yield of 11 and 12: 7.66
g, 54%), which were finally purified by recrystallization from
pentane/hexane (1:1).
performed on silica gel 60 (0.04-0.063 mm, E. Merck). The
reactions with diisobutylaluminum hydride and butyllithium
were carried out in an atmosphere of dry argon. Methyl (S)- and
1
4-16
1
1:
yield 4.93 g, 35% (related to methyl ester 7), colorless
(R)-3-hydroxytetradecanoate were supplied by Hoffmann-La
2
2
1
crystals, mp 63-64 °C; [R]
D
3
-14.66 (c 0.4 in CHCl ); H NMR
Roche, Basel. All other chemicals were purchased from Fluka
or Aldrich.
(
(
1
300 MHz) δ 0.84-0.90 (m, 6H), 1.26-2.07 (m, 33H), 3.28-3.35
m, 1H), 3.76-3.80 (m, 1H), 4.44-4.50 (m, 1H); 13C NMR δ 14.1,
Meth yl (S)-3-(2-Meth oxyp r op -2-oxy)tetr a d eca n oa te (8).
Pyridinium p-toluenesulfonate (200 mg) was added to an ice cold
solution of the methyl ester 7 (10.32 g, 40 mmol) in 2-methoxy-
propene (40 mL). After being stirred for 5-10 min, the reaction
mixture was extracted first with a saturated aqueous solution
of sodium hydrogen carbonate (2 mL) and then with water (2 ×
4.2, 22.6, 22.7, 25.5, 26.9, 27.9, 29.0, 29.4, 29.59, 29.63 (2
signals), 29.69, 29.71, 31.6, 32.0, 37.7, 41.2, 56.9, 69.4, 76.4,
71.7. Anal. Calcd for C22
4.68; H, 11.94.
1
7
42 3
H O : C, 74.52; H, 11.94. Found: C,
7
,13,18
1
2:
crystals, mp 57-59 °C; [R]
300 MHz, CDCl ) δ 0.86-0.90 (m, 6H), 1.26-1.97 (m, 33H),
.23-3.29 (m, 1H), 3.74-3.85 (m, 1H), 4.47-4.53 (m, 1H);
NMR δ 14.1, 14.2, 22.6, 22.7, 25.5, 26.8, 27.8, 29.0, 29.4, 29.55,
9.62 (two signals), 29.68, 29.70, 31.6, 32.0, 38.2, 41.9, 56.7, 68.6,
yield 0.65 g, 5% (related to methyl ester 7), colorless
2
2
1
D
3
+40.74 (c 0.4 in CHCl ); H NMR
2
2 4
mL). The combined organic phases were dried (Na SO ) and
(
3
3
concentrated under reduced pressure. The residual colorless oil
1
3
C
(
12.96 g, 98%) was used in the next step without further
2
5
1
purification. [R]
d
2
D
+10.01 (c ) 0.5 in hexane); H NMR (DMSO-
2
6
, 75 MHz) δ 0.86 (t, J ) 7 Hz, 3H), 1.24-1.46 (m, 26H), 2.42-
.47 (m, 2H), 3.09 (s, 3H), 3.58 (s, 3H), 4.03-4.05 (m, 1H); 13
75.7, 172.0. Anal. Calcd for C22
Found: C, 74.66; H, 11.94.
42 3
H O : C, 74.52; H, 11.94.
C
6
NMR (DMSO-d ) δ 13.9, 22.0, 22.1, 24.3, 24.9, 28.7, 28.9, 28.97,
2
8.98, 29.0, 30.9, 31.3, 35.1, 40.2, 48.5, 51.2, 67.7, 100.4, 171.6.
Anal. Calcd for C19
H, 11.63.
H
38
O
4
: C, 69.05; H, 11.59. Found: C, 69.00;
Ack n ow led gm en t. This work was supported by the
Federal Ministry of Education, Science, Research, and
Technology of the Federal Republic of Germany and the
Berlin Senate Department for Science, Research, and
Culture (Project No 03C3005). Financial support by the
Fonds der Chemischen Industrie as well as assistance
of Mrs. Adelheid Rheden and Mrs. Katharina Kleiner
are also gratefully acknowledged. The authors are
grateful to Dr. P. Barbier (F. Hoffmann-La Roche, Basel,
Switzerland) for a generous gift of methyl (S)-3-hy-
droxytetradecanoate.
(
S)-3-(2-Meth oxyp r op -2-oxy)tetr a d eca n a l (9). Diisobutyl-
aluminum hydride (10.7 mL, 60 mmol) dissolved in toluene (30
mL) was precooled to -70 °C and added during 1 h at a
temperature of -70 °C to a solution of the crude ester 8 (12.96
g, 40 mmol) in toluene (100 mL), obtained according to the
foregoing described procedure. After complete addition the
mixture was stirred for an additional 30 min, diluted with
methanol (15 mL), and allowed to warm to room temperature.
A saturated aqueous solution of sodium chloride (40 mL) was
added and the precipitate removed by filtration over a pad of
fine sand. The filter cake was washed with ethyl acetate (5 ×
1
5 mL). Filtrate and washings were combined. The aqueous
J O980292A