A short enantioselective synthesis of (+)-L-733,060 via Shi epoxidation of a homoallylic carboxylate

Article abstract of DOI:10.1016/j.tetlet.2008.07.086

A short and efficient enantioselective synthesis of (+)-L-733,060 in 92% ee via Shi epoxidation of a homoallylic carboxylate is described. Johnson-Claisen rearrangement was employed to obtain the required carbon backbone, whilst intramolecular reductive O-to-N-ring expansion of a δ-azidolactone was used in the construction of the piperidine moiety.

Full text of DOI:10.1016/j.tetlet.2008.07.086

Tetrahedron Letters 49 (2008) 5736–5738
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A short enantioselective synthesis of (+)-L-733,060 via Shi
epoxidation of a homoallylic carboxylate
*
Lourdusamy Emmanuvel, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, 411 008 Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short and efficient enantioselective synthesis of (+)-L-733,060 in 92% ee via Shi epoxidation of a homo-
allylic carboxylate is described. Johnson–Claisen rearrangement was employed to obtain the required
carbon backbone, whilst intramolecular reductive O-to-N-ring expansion of a d-azidolactone was used
in the construction of the piperidine moiety.
Received 2 June 2008
Revised 11 July 2008
Accepted 16 July 2008
Available online 19 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
1,2-Aminoalcohols
Asymmetric epoxidation
3,3-Sigmatropic rearrangement
Lactone
The neurokinin substance P, an 11 amino acid peptide, has been
associated with a variety of biological effects including smooth
muscle contraction, neurogenic inflammation and pain transmis-
sion. Recently, (+)-L-733,060 (1)1 and (+)-CP-99,994 (2)2 possess-
ing 2-alkyl-3-hydroxypiperidine and 2-alkyl-3-aminopiperidine
structural units, respectively, have proven to be selective and
potent non-peptide neurokinin substance P receptor antagonists.
Also, they have been implicated in a variety of disorders including
migraine, rheumatoid arthritis and pain.3 Recent studies4 have
shown that (+)-L-733,060 (1) can act both as an antitumour agent
and as a promising new target for the treatment of retinoblastoma.
In view of these potential pharmacological applications, several
reports on the synthesis of 1 and 2, both in racemic and in optically
active forms, have been published.5 However, most of the reports
deal with chiral pool strategies, classical resolution of racemates,
use of expensive transition-metal complexes often involving
lengthy steps. Herein, we report a practical, enantioselective
synthesis of (+)-L-733,060 (1) via Shi epoxidation of homoallylic
carboxylate 6 using ketone 12, derived from
D-fructose, as the
chiral catalyst.
The retrosynthetic analysis of 1 reveals syn aminoalcohol 3 as a
key intermediate (Scheme 1). We thus planned to employ intramo-
lecular reductive cyclization of azidolactone 4 under Staudinger
reduction conditions for the construction of the 6-membered het-
erocyclic ring in 3. The azidolactone 4 can be readily made from the
corresponding hydroxy lactone 5 by SN2 displacement. We envis-
aged introduction of the chirality in 5 with trans stereochemistry
via Shi epoxidation of potassium 5-phenylpent-4-enoate (6).
Our synthesis of L-733,060 (1) commenced with allylic alcohol
7, which was subjected to Johnson–Claisen [3,3]-sigmatropic rear-
rangement6 (trimethyl orthoacetate, catalytic amount of CH3CH2-
CO2H, 135 °C) to give exclusively E-homoallylic ester 5 in 82% yield
(Scheme 2). Alkaline hydrolysis of ester 8 using aq KOH furnished
potassium alkenoate 6, which was subjected to Shi epoxidation7
using
D-fructose-derived ketone 12 as the chiral catalyst
(30 mol %) and Oxone as the stoichiometric oxidant to afford
hydroxylactone 5 in 62% yield and 92% ee [%ee was determined
HN
HN
CF3
from the 1H NMR of the corresponding Mosher’s ester and ½a 2D5
ꢀ
ꢁ53.3 (c 0.22, CHCl3)].8 Mesylation (MsCl, Et3N) of alcohol 5 gave
the mesylate 9, which was subjected to SN2 displacement with
HN
O
NaN3 (DMF, 60 °C) to afford azidolactone 4 {½a D25
ꢀ
+163.49 (c 0.7,
CF3
CHCl3)} with inversion of configuration. Reduction of azide 4 under
either Staudinger conditions (PPh3, THF, 25 °C, then H2O, reflux) or
catalytic hydrogenation [H2 (1 atm.), 10% Pd/C] at ambient condi-
tions produced lactam 10 in 91% yield, presumably via intramo-
lecular O-to-N-ring expansion9 of the amine generated in situ.
OMe
2
1
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.086

L. Emmanuvel, A. Sudalai / Tetrahedron Letters 49 (2008) 5736–5738
5737
N3
HN
CF3
BocN
Reductive
cyclization
O
O
OH
CF3
O
4
3
1
OH
OH
O
Shi' epoxidation
O-K+
O
O
7
6
5
Scheme 1. Retrosynthesis of (+)-L-733,060 (1).
OR
OH
O
e
c
a
OR
O
O
8 R = Me
5 R = H
9 R = Ms
7
d
b
6 R = K
O
N3
BocN
h
HN
f
g
O
OH
O
OH
4
3
10
O
RN
CF3
O
O
O
O
O
CF3
O
11 R = Boc
R = H
12
i
1
Scheme 2. Reagents and conditions: (a) CH3C(OMe)3, propanoic acid, 135 °C, 6 h, 82%; (b) aq KOH, reflux; (c) pH 10–11, Oxone, 12, KOH, CH3CN, ꢁ5 °C, 1 h, then 15 °C, 5 h,
62%; (d) MsCl, Et3N, CH2Cl2, 0 °C, 2 h, 96%; (e) NaN3, DMF, 60 °C, 12 h, 94%; (f) PPh3, THF, 25 °C , 2 h, then H2O reflux 3 h, 91%; (g) (i) Me2SꢂBH3, THF, reflux, 6 h; (ii) (Boc)2O,
Et3N, cat. DMAP, CH2Cl2, 0–25 °C, 73% over two steps; (h) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, DMF/THF (3:1), 0 °C, 6 h; (i) TFA, CH2Cl2, 18 h, 81% over two steps.
Reduction of lactam 10 with BH3ꢂSMe2 in THF followed by the
Acknowledgements
protection of the secondary amine with (Boc)2O gave the syn
aminoalcohol 3 in 73% yield over two steps.
L. Emmanuvel thanks CSIR, New Delhi, for the award of research
fellowship (S.R.F.). The authors also thank Dr. B. D. Kulkarni, Head,
Chemical Engineering and Process Development, for his constant
support and encouragement.
Having constructed the piperidine ring with the desired syn
stereochemistry, O-alkylation of 3 with 3,5-bis(trifluoromethyl)-
benzyl bromide in the presence of NaH was performed to yield
11 {½a 2D5
ꢀ
+27.9 (c 0.8, CHCl3); lit.5h
Finally, deprotection of the Boc group under acidic conditions
½
a 2D5
+30.38 (c 1.55, CHCl3)}.
ꢀ
References and notes
afforded L-733,060 (1) in 81% yield {½a D25
ꢀ
+31.7 (c 0.5, CHCl3); lit.5h
a 2D5 +34.29 (c 1.32, CHCl3)}. 1H, 13C NMR and other spectral data
ꢀ
1. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C. J.; Williams, B. J. EP 528
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½
were in complete agreement with the reported values.
In conclusion, the enantioselective synthesis of (+)-L-733,060
(1) has been achieved using Shi epoxidation of homoallylic carbox-
ylate 6 as the chiral inducing step. Intramolecular reductive cycli-
zation of azidolactone 9 was used to construct the piperidine ring,
whilst a Johnson–Claisen rearrangement was employed to gener-
ate the required carbon backbone. The synthetic strategy described
herein has significant potential for further extension to piperidine-
based bioactive molecules as well as other NK1 receptor
antagonists.

5738
L. Emmanuvel, A. Sudalai / Tetrahedron Letters 49 (2008) 5736–5738
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a 2D5
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