Asymmetric synthesis of (+)-L-733, 060 and (+)-CP-99, 994 based on a new chiral 3-piperidinol synthon.

Article abstract of DOI:10.1021/ol034505g

[reaction: see text] Selective and potent neurokinin substance P receptor antagonists (+)-L-733, 060 (1) and (+)-CP-99, 994 (2) have been synthesized starting from a new (3S)-piperidinol synthon derived from l-glutamic acid. The methods featured a C-2 reg

Full text of DOI:10.1021/ol034505g

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1927-1929
Asymmetric Synthesis of (+)-L-733, 060
and (+)-CP-99, 994 Based on a New
Chiral 3-Piperidinol Synthon†
Pei-Qiang Huang,* Liang-Xian Liu, Bang-Guo Wei, and Yuan-Ping Ruan
Department of Chemistry, Xiamen UniVersity, Xiamen, Fujian 361005, P. R. China
pqhuang@xmu.edu.cn
Received March 23, 2003
ABSTRACT
Selective and potent neurokinin substance P receptor antagonists (+)-L-733, 060 (1) and (+)-CP-99, 994 (2) have been synthesized starting
from a new (3S)-piperidinol synthon derived from L-glutamic acid. The methods featured a C-2 regioselective reduction of glutarimide (9),
Lewis acid-promoted Si to C-2 phenyl group migration of 10, and stereoselective reduction of acetylated oxime 19 as the key steps.
2-Alkyl-3-hydroxyl piperidines and 2-alkyl-3-aminopip-
eridines are structural units found in numerous bioactive
natural products, drugs, and drug candidates. For example,
(+)-L-733, 060 (1)1 and (+)-CP-99, 994 (2)2 are selective
and potent neurokinin substance P receptor antagonists,
which have been shown to possess potent antiemetic activity;
febrifugine (3) and isofebrifugine (4) are well-known can-
didates of an antimalarial agent isolated from Chinese
medicinal plants Dichroa febrifuga. The important bio-
activities1-3 associated both (+)-L-733, 060 (1) and (+)-
CP-99, 994 (2) have stimulated the development of synthetic
approaches.1,2,4,5 However, only two racemic total synthesis1,4c
The success in the development of protected (S)-malimide-
of (()-L-733, 060 and one asymmetric total synthesis of (+)-
based synthetic methodology from these laboratories6 led us
L-733, 060 have been reported very recently.4e
to consider the protected 3-hydroxyglutarimide 9 as a suitable
† Dedicated to Professor Wei-Shan Zhou on the occasion of his 80th
birthday.
(1) (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C. J.;
Williams, B. J. EP 0 528, 495A1, 1993. (b) Harrison, T.; Williams, B. J.;
Swain, C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4, 2545.
(2) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K. P.; Snider,
R. M. J. Med. Chem. 1992, 35, 4911.
(3) (a) Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988, 241, 1218.
(b) Perianan, A.; Snyderman, R.; Malfroy, B. Biochem. Biophys. Res.
Commun. 1989, 161, 520. (c) Moskowitz, M. A. Trends Pharmacol. Sci.
1992, 13, 307. (d) Zaman, S.; Woods, A. J.; Watson, J. W.; Reynolds, D.
J. M.; Andrews, P. L. R. Neuropharmacology 2000, 39, 316.
(4) (a) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40, 7099. (b)
Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067. (c) Tomooka, K.;
Nakazaki, A.; Nakai, T. J. Am. Chem. Soc. 2000, 122, 408. (d) Lee, J.;
Hoang, T.; Lewis, S.; Weissman, S. A.; Askin, D.; Volante, R. P.; Reider,
P. J. Tetrahedron Lett. 2001, 42, 6223. (e) Bhaskar, G.; Rao, B. V.
Tetrahedron Lett. 2003, 44, 915.
(5) (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett. 1999, 40,
5071. (b) Tsuritani, N.; Yamada, K.; Yoshikawa, N.; Shibasaki, M. Chem.
Lett. 2002, 276. (c) Yamazaki, N.; Atobe, M.; Kibayashi, C. Tetrahedron
Lett. 2002, 43, 7979. For the synthesis of racemic CP-99, 994, see: (d)
Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L. Tetrahedron Lett. 1993, 34,
5831.
10.1021/ol034505g CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/07/2003

multifunctional 3-hydroxypiperidine synthon. We now report
the asymmetric synthesis of (+)-L-733, 060 and (+)-CP-
99, 994 based on this new chiral nonracemic 3-piperidinol
synthon.
In the malimide-based methodology, (S)-malic acid6 has
been conveniently used as the chiral pool. For the synthesis
of (S)-3-hydroxyglutarimide (8), although the requisite higher
homologue of malic acid is not a naturally occurring
compound, it occurred to us that this compound could be
derived from inexpensive and easily available (S)-glutamic
acid via the well-established diazodation method.7 Thus, (S)-
glutamic acid was selected as the chiral pool for our
synthesis.
enantiomeric excess of (S)-8 was at least 98%, as determined
by chiral HPLC analysis [Chirex (S)-leu and (S)-NEA] by
comparing with a partially racemized sample of (S)-8. The
hydroxyl group in 8 was protected with tert-butyldiphenyl
silyl chloride under standard conditions (TBDPSCl, imid-
azole, CH2Cl2), which afforded glutarimide (S)-9 in 94%
yield.
Protected glutarimide 9 was reduced with sodium boro-
hydride at low temperatures (between -20 and -10 °C, 50
min), which afforded predominantly the desired regioisomer
10 in 10:1 regioselectivity (Scheme 2). The regioisomer 10
Scheme 2
Scheme 1
consisted of two separable diastereomers in 82:18 ratio. The
stereochemistry of the major diastereomer was tentatively
assigned as cis on the basis of the smaller coupling constants
(J5, 6 ) 2.2 Hz) of major diastereomer (J5, 6 ) 3.1 Hz for
minor diastereomer). Both diastereomers of 10 could be
purified by recrystallization {major diastereomer, mp 165-
166 °C, [R]20 -54.8° (c 1.3, CHCl3); minor diastereomer,
D
mp 174.5-175.5 °C, [R]20 +31.7° (c 0.9, CHCl3)}. The
D
deoxygenative phenylation of 10 was first attempted using
Tomooka’s conditions.4c Since the reaction was presumed
to proceed via an N-acyliminium,4c,8 which could be derived
from both diastereomers of 10, the diastereomeric mixture
of 10 could be used as it was. Thus, in the presence of
montmorillonite clay (K10) and 4 Å molecular sieves, the
diastereomeric mixture of 10 was treated with benzyl alcohol.
However, the desired phenyl migration product was not
observed, we obtained instead aza-acetal 11 as a diastereo-
meric mixture. Since the reaction depended, on one hand,
on the formation of the N-acyliminium and, on the other
hand, the attack of a nucleophile (e.g., benzyl alcohol) at
silicon atom (which enhances the migration of the phenyl
group), to facilitate the nucleophilic attack at hindered silicon
atom, water was selected as a smaller nucleophile. However,
when stirring a suspension of 10, water, and K10, we
observed only the epimerization of cis-10 to thermodynami-
cally more stable trans-10. Although the reaction did not
lead to the desired phenyl migration product, the observed
epimerization allowed to confirm the cis stereochemistry
assigned previously for the major diastereomer of 10.
At this stage, the use of Lewis acid as a promoter was
considered. Gratefully, when 10 was stirred with BF3‚OEt2
at room temperature for 3 days, the phenyl migration
proceeded smoothly, and 13 was isolated in 80% yield
(>95% cis) after workup (Scheme 3). Reduction of 13 with
The synthesis started with (S)-glutamic acid (Scheme 1).
Thus, (S)-glutamic acid (5) was converted to (S)-6 by
the well-established diazodation procedure.7 Treatment of
γ-lactone-carboxylic acid (S)-6 with thionyl chloride at 60
°C provided the corresponding acid chloride, which without
further purification, was treated with p-methoxybenzylamine
to give lactone-amide (S)-7 {mp 92-93 °C, [R]20 -4.9°
D
(c 0.9, CHCl3)}. The overall yield from (S)-6 to (S)-7 was
70%. The ring expansion for the conversion of lactone-amide
(S)-7 to glutarimide (S)-8 was achieved via the treatment of
(S)-7 with LDA at -78 °C. In this way, the yield of (S)-8
was about 50%. Better results could be obtained by using
0.2-0.5 molar equiv of potassium tert-butoxide at low
temperature (-78 °C). In this manner, the desired glutarimide
(S)-8 could be obtained in excellent yield {90%, colorless
crystalline, mp 98-99 °C, [R]20D -70° (c 1.0, CHCl3)}. The
(6) (a) Huang, P.-Q.; Wang, S. L.; Zheng, H.; Fei, X. S. Tetrahedron
Lett. 1997, 38, 271. (b) Huang, P.-Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.;
Huang, Y. Q.; Zheng, H.; Gao, J. X. Tetrahedron 1998, 54, 12547. (c)
Huang, P.-Q.; Wang, S. L.; Ruan, Y. P.; Gao, J. X. Nat. Prod. Lett. 1998,
11, 101. (d) Huang, P.-Q.; Ye, J. L.; Chen, Z.; Ruan, Y. P.; Gao, J. X.
Synth. Commun. 1998, 28, 417. (e) Huang, P. -Q.; Chen, Q. F.; Chen, C.-
L.; Zhang, H.-K. Tetrahedron: Asymmetry 1999, 10, 3827. (f) Huang, P.-
Q.; Zheng, X.; Wang, S. L.; Ye, J. L.; Jin, L. R.; Chen, Z. Tetrahedron:
Asymmetry 1999, 10, 3309. (g) Zheng, X.; Huang, P.-Q.; Ruan, Y. P.; Lee,
A. W. M.; Chan, W. H. Heterocycles 2001, 55, 1505. (h) Zheng, X.; Huang,
P.-Q.; Ruan, Y. P.; Lee, A. W. M.; Chan, W. H. Nat. Prod. Lett. 2002, 16,
53. (i) Huang, P.-Q.; Zheng, X. ArkiVoc 2003, Part ii, 7 (http://www.arkat-
usa.org).
(7) Gringore, O. H.; Rouessac, F. P. In Organic Synthesis; Freeman, J.
P. Ed.; John Wiley & Sons: New York, 1990; Coll. Vol. VII, p 99.
(8) For a recent review, see: Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817.
1928
Org. Lett., Vol. 5, No. 11, 2003

Scheme 3
Scheme 5
(2S,3S)-3-Aminopiperidine derivative 20 was then sub-
jected to reductive alkylation conditions (o-CH3OC6H4CHO,
THF; NaBH4, MeOH, rt), which afforded, surprisingly, an
adduct of the desired 22 with o-methoxybenzyl alcohol in
lithium aluminum hydride at room temperature then provided
piperidine (2S,3S)-14 in 81% yield.
When 14 was subjected to hydrogenolysis conditions [H2,
l atm, 20% Pd(OH)2, MeOH] in the presence of (Boc)2O,
one-pot selective N-debenzylation-butoxycarbonylation oc-
curred. In this way, (2S,3S)-15 {mp 71-72 °C, [R]D +53.8°
(c 1.0, CHCl3); lit.4e [R]D +38.3° (c 1.92, CHCl3)} was
obtained in a yield of 88% (Scheme 4).
80% yield {colorless oil, [R]28 +25.7° (c 0.9, CHCl3)}
D
(Scheme 6). Finally, treatment of the 22-o-methoxybenzyl
Scheme 6
Scheme 4
alcohol adduct with a methanolic solution of hydrochloric
acid at room temperature gave the desired (+)-(2S,3S)-CP-
99, 994 (2) in 96% yield, which was characterized as its
The following step involved the etherification. This was
achieved by sodium hydride deprotonation of 15 followed
by reaction with 3,5-bis(trifluoromethyl)benzyl bromide,
which gave 16 in 75% yield {[R]28D +36.9° (c 1.0, CHCl3);
lit.4e [R]D +30.38° (c 1.55, CHCl3)}. Finally, N-Boc depro-
tection of 16 using TFA afforded the desired (2S, 3S)-L-
733, 060 (1), which was characterized as its hydrochloride
dihydrochloride {mp 253-254 °C; [R]28 +75.1° (c 0.6,
D
MeOH); lit.2 mp 255 °C; [R]23 +77° (c 1.0, MeOH); lit.5c
D
mp 254.5 °C; [R]23 +75.5° (c 1.1, MeOH)}.
D
In conclusion, (+)-L-733, 060 and (+)-CP-99, 994 were
synthesized from easily available chiral building block (S)-
8. Work is in progress for further application of this new
chiral 3-piperidinol synthon in the asymmetric synthesis of
other 3-piperidinol-related natural products.
{mp 213-215 °C; lit.1a 215-216 °C; [R]28 +84.5° (c 0.8,
D
MeOH); lit.1a [R]23 +87.3° (c 1.0, MeOH)}.
D
The synthesis of (+)-CP-99, 994 began with the key
intermediate (2S,3S)-15 (Scheme 5). (2S,3S)-3-Piperidinol
15 was converted to oxime (S)-18 by Swern oxidation
[DMSO, (COCl)2, i-Pr2NEt, CH2Cl2, -78 °C], followed by
reaction with hydroxylamine hydrochloride (HONH2‚HCl,
K2CO3, MeCN). Oxime 18 was then acetylated to afford 19.
The key reduction step was achieved using borane dimethyl
sulfite complex5c (H3B‚SMe2, 65%), which established the
2,3-cis-stereochemistry of 20.
Acknowledgment. The authors are grateful to the Na-
tional Science Fund for Distinguished Young Investigators,
the NNSF of China, and the Fund for doctoral sites of the
Ministry of Education for financial support.
9
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(9) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651.
Org. Lett., Vol. 5, No. 11, 2003
OL034505G
1929