Asymmetric total synthesis of ent-Tetrahydrolipstatin from an epoxy alkenol

Article abstract of DOI:10.1055/s-0031-1290407

A highly efficient asymmetric total synthesis of ent-tetrahydrolipstatin (THL) was accomplished from the known epoxy alkenol. The β-lactone portion of THL was synthesized by the epoxide opening with cyanide and stereoselective enolate alkylation method. The side chain was introduced by cross metathesis of the alkene part with 1-decene. Coupling with a protected leucine completed the synthesis of ent-tetrahydrolipstatin.

Full text of DOI:10.1055/s-0031-1290407

1832▌
LETTER
lAettserymmetric Total Synthesis of ent-Tetrahydrolipstatin from an Epoxy
Alkenol
Total Synthesis of ent-Tetrahydrolipstatin
Hyemi Kim, Kyeonghwan Choi, Jinsung Tae*
Department of Chemistry, Yonsei University, Seoul 120-749, Korea
Fax +82(2)3647050; E-mail: jstae@yonsei.ac.kr
Received: 12.04.2012; Accepted after revision: 07.05.2012
chain elongation by cross metathesis, and final coupling
with a protected leucine would furnish ent-THL (1). In
this strategy, the lipophilic side chain is introduced by
cross metathesis at the final stage, which could allow us
Abstract: A highly efficient asymmetric total synthesis of ent-
tetrahydrolipstatin (THL) was accomplished from the known epoxy
alkenol. The β-lactone portion of THL was synthesized by the ep-
oxide opening with cyanide and stereoselective enolate alkylation
method. The side chain was introduced by cross metathesis of the easy access to the different lipophilic groups in the syn-
alkene part with 1-decene. Coupling with a protected leucine com-
pleted the synthesis of ent-tetrahydrolipstatin.
thesis of THL derivatives.
Key words: enolate alkylation, epoxides, metathesis, ent-tetrahy-
NHCHO
drolipstatin, total synthesis
O
O
O
O
O
O
OP
C-M
C6H13
Tetrahydrolipstatin (THL), the first FDA-approved anti-
obesity drug (Orlistat®),3 is a hydrogenated form of the
naturally occurring lipstatin which was isolated from
Streptomyces toxytricini.1 Both THL and lipstatin are
known as potent inhibitors of pancreatic lipases.2 The β-
lactone moiety of THL reacts with the serine hydroxyl
group in the active site of pancreatic lipase, thus the ab-
sorption of dietary fat is blocked. Recent studies show that
THL also has antitumor activity acting as a novel inhibitor
of the thioesterase domain of fatty acid synthase (FAS),
which is strongly linked to tumor progression in cancer
cells.4 Due to these important biological properties and its
unique structural features, several synthetic efforts have
been devoted for the synthesis of THL.5,6
C6H13
2
enolate
alkylation
ent-tetrahydrolipstatin (1)
OP
O
OP
O
CO2R
I
CN
4
3
C6H13
Scheme 1 Retrosynthesis analysis of ent-THL (1)
Firstly, the known epoxy alkenol 57 was protected with a
benzyl group and then reacted with KCN (2 equiv) in a
DMF–H2O (3:1) solution under refluxing conditions8 to
synthesize the β-hydroxy nitrile 6. Subsequent hydrolysis
of nitrile to the corresponding carboxylic acid found to be
difficult. Typical acidic and basic conditions for the hy-
drolysis of the nitrile failed to yield the desired acid. Ei-
ther formation of the corresponding amide under mild
conditions or decomposition under strong conditions was
observed. Fortunately, the hydrolysis reaction of 6 turned
out to be efficient when sodium peroxide (NaOONa) is
used in H2O under mild conditions.9 Thus we obtained the
β-hydroxy carboxylic acid 7 in 93% yield. Following pro-
tection of 7 with AcCl in MeOH provided the β-hydroxy
ester 8 (Scheme 2).
Synthetic approaches for THL are essentially focused on
the stereoselective constructions of the trans-β-lactone
ring system possessing two stereogenic centers and the
stereocenter at the δ-position. Herein, we report a concise
asymmetric total synthesis of THL based on the epoxide-
opening–enolate alkylation–cross-metathesis strategy.
Over the past few years, we have developed efficient
asymmetric routes7 for the synthesis of natural products
possessing 1,3-diol moieties starting from the optically
pure epoxide 4 which is readily prepared by Jacobsen’s
hydrolysis kinetic resolution (HKR) method.
Asymmetric total synthesis of ent-THL could be readily
accessed by the epoxide opening–enolate alkylation–
cross-metathesis strategy starting from the epoxide 4
(Scheme 1). Introduction of the cyano group by epoxide
opening followed by stereoselective alkylation of the di-
anionic enolate could efficiently set up the three stereo-
genic centers of THL. Subsequent β-lactone formation,
With the β-hydroxy ester in hand, we then attempted dian-
ionic alkylation reaction to introduce the C(2) n-hexyl
side chain. Literature procedures for the diastereoselec-
tive dianionic alkylation of β-hydroxy ester10 were
screened. Thus, the β-hydroxy methyl ester 8 was treated
with 2.5 equivalents of base (LiHMDS or LDA) at low
temperature, then n-hexyl iodide in HMPA was added. In
general, the alkylation reactions using LiHMDS gave low
yields of the desired product. Alkylation reactions with
the dianion generated by LDA gave better yields. Optimal
SYNLETT 2012, 23, 1832–1834
Advanced online publication: 04.07.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290407; Art ID: ST-2012-U0319-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Total Synthesis of ent-Tetrahydrolipstatin
1833
Cbz group by catalytic hydrogenation followed by for-
mylation with formic acetic anhydride completed the total
synthesis of ent-THL (1).14 The spectral data of 1 are iden-
tical to those reported for the natural product with the op-
1. BnBr, NaH
THF (93%)
OH
OBn OH
O
CN
2. KCN
DMF–H2O (3:1)
reflux, 2 h (95%)
6
5
(ref. 7)
20
posite optical rotation value {[α]D +30.66 (c 0.36,
NaOONa
H2O, 50 °C
93%
CHCl3); lit.5a [α]D20 –33 (c 0.36, CHCl3)}.
OBn OH
OBn OH
AcCl, MeOH
r.t. (88%)
1. 12 (10 mol%)
1-decene (5 equiv)
CH2Cl2 (0.17 M)
reflux (81%)
O
CO2Me
CO2H
OH
O
8
7
11
C11H23
C6H13
2. H2 (1 atm), Pd/C
THF (85%)
13
Scheme 2 Synthesis of the β-hydroxy ester 8
N
N
NHCbz
Mes
Mes
DCC, DMAP
DMF, r.t.
(82%)
Cl
yield for the alkylation was achieved when the dianion
was generated with 2.5 equivalents of LDA in THF at –40
°C for one hour as shown in Scheme 3. The desired alkyl-
ated product 9 was obtained in 72% yield based on the re-
covered starting material (53% of isolated yield) with
excellent diastereoselectivity.11 Saponification of ester 9
with aqueous KOH, followed by treatment with BOPCl,12
gave the β-lactone 11 in 72% (Scheme 3).
Ru
Cl
Ph
O
14
OH
PCy3
12
NHCbz
1. H2 (1 atm)
Pd/C, THF
O
ent-THL (1)
O
O
O
2. AcOCHO
CH2Cl2
C11H23
C6H13
(77%)
15
OBn OH
Scheme 4 Completion of total synthesis of ent-THL (1)
LDA (2.5 equiv), THF
CO2Me
C6H13
–40 °C, 1 h
8
n-C6H13I (1.5 equiv), HMPA
In summary, we have completed a concise asymmetric to-
tal synthesis of ent-tetrahydrolipstatin starting from the
known epoxy alkenol 5 in 12 steps. Epoxide opening with
cyanide, diastereoselective dianionic alkylation, and
cross-metathesis reactions were employed in the key
steps. In this synthesis, the lipophilic side chain (C11H23)
was introduced at a relatively late stage utilizing cross-
metathesis reaction after rapid construction of three ste-
reogenic centers.
9
0 °C, 12 h (72%)
1 M KOH, EtOH
50 °C
(99%)
O
BOPCl, Et3N
OBn OH
OBn
O
CO2H
C6H13
CH2Cl2, r.t.
(72%)
C6H13
11
10
Scheme 3 Synthesis of the β-lactone 11
Acknowledgment
In the known literature synthesis of THL utilizing the di-
anion alkylation strategy,6 the n-hexyl chain is introduced
after the incorporation of the long lipophilic chain. How-
ever, in this synthesis, we first set up all three stereogenic
centers before the chain elongation. For the introduction
of the lipophilic part, the cross metathesis–hydrogenation
sequence was employed. Reaction of 11 with five equiva-
This work was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (No.2011-
0007015).
Supporting Information for this article is available online at
lents of 1-decene in the presence of second-generation http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoprimntgirSatnoIuipfog
r
t
iornat
Grubbs catalyst 12 (10 mol%) under refluxing dichloro-
methane and subsequent hydrogenation of the isomeric al-
kenes with H2–Pd/C produced the extended alkyl chain.
Under the reaction conditions, the benzyl protecting group
at the δ-hydroxy group was also removed to yield the
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1832–1834

1834
H. Kim et al.
LETTER
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Rf = 0.32 (silica gel, hexane–EtOAc = 7:3); [α]D20 +30.66
(c 0.36, CHCl3); mp 41–42 °C. 1H NMR (400 MHz, CDCl3):
δ = 8.22 (s, 1 H), 5.93 (d, J = 8.0 Hz, 1 H), 5.04–5.02 (m, 1
H), 4.71–4.67 (m, 1 H), 4.31–4.27 (m, 1 H), 3.23–3.21 (m, 1
H), 2.19–2.15 (m, 1 H), 2.03–1.98 (m, 1 H), 1.87–1.54 (m, 7
H), 1.29–1.25 (m, 26 H), 0.98–0.94 (m. 6 H), 0.90–0.86 (m,
6 H). 13C NMR (100.6 MHz, CDCl3): δ = 172.1, 170.9,
160.8, 74.9, 72.9, 57.2, 49.8, 41.7, 38.9, 34.2, 32.1, 31.6,
29.8, 29.7, 29.6, 29.5, 29.1, 27.8, 26.9, 25.2, 25.1, 23.0, 22.8,
22.7, 21.9, 14.3, 14.2. IR (film): 3353, 3025, 2954, 2924,
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1250, 1195, 1126, 877, 815, 761 cm–1. HRMS: m/z calcd for
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Synlett 2012, 23, 1832–1834
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