Asymmetric synthesis of (+)-L-733,060

Article abstract of DOI:10.1016/j.tetlet.2004.12.025

A concise, stereocontrolled synthesis of (+)-L-733,060 was achieved. Key features involve diastereoselective oxazoline formation catalyzed by palladium(0) and intramolecular cyclization by catalytic hydrogenation of an oxazoline.

Full text of DOI:10.1016/j.tetlet.2004.12.025

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 739–741
Asymmetric synthesis of (+)-L-733,060
Youn-Jung Yoon, Jae-Eun Joo, Kee-Young Lee, Yong-Hyun Kim,
Chang-Young Oh and Won-Hun Ham*
College of Pharmacy, SungKyunKwan University, Suwon 440-746, Republic of Korea
Received 28 October 2004; revised 4 December 2004; accepted 8 December 2004
Abstract—A concise, stereocontrolled synthesis of (+)-L-733,060 was achieved. Key features involve diastereoselective oxazoline
formation catalyzed by palladium(0) and intramolecular cyclization by catalytic hydrogenation of an oxazoline.
Ó 2004 Elsevier Ltd. All rights reserved.
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 transmission. Recently, the
development of nonpeptide neurokinin NK-1 receptor
antagonists led to discovery of (+)-L-733,060 (1)1 and
(+)-CP-99,994 (2),2 which have been shown to possess
potent antiemetic activity (Fig. 1). Due to their impor-
tant potential pharmacological applications,1–3 there
have been several reports on the total synthesis of (+)-
L-733,060 (1)4 and (+)-CP-99,994 (2)5 in both racemic
and optically active forms.
CF3
H
N
O
CF3
OCH3
N
H
Ph
N
H
Ph
(+)-L-733,060 (1)
(+)-CP-99,994 (2)
Figure 1.
ylphenylglycinol by employing the palladium(0)-cata-
lyzed intramolecular cyclization reaction.6
Our retrosynthetic analysis of (+)-L-733,060 (1) was in-
spired by our longstanding interest in applying enantio-
pure oxazolines as chiral building blocks to the
stereocontrolled synthesis of natural products (Scheme
1). We focused our initial efforts upon the enantioselec-
tive synthesis of hydroxyphenyl piperidinone 6, envi-
The synthesis of 1 began with ozonolysis of 3 to give the
corresponding aldehyde, which was reacted with trimeth-
ylphosphonoacetate to yield the a,b-unsaturated methyl
ester in 87% yield. 1,4-Reduction7 of 4 with copper bro-
mide, Red-Al and 2-butanol gave the saturated methyl
ester 5 in 83% yield (Scheme 2).8 Hydrogenolysis of 5
with 20% Pd(OH)2 in 1:10AcOH/MeOH was performed
under 70psi of H 2 at ambient temperature. Under these
conditions, we achieved not only hydrogenolysis of
oxazoline moiety but also cyclization of the intermediate
amino ester to piperidin-2-one.9
sioning that it would be accessible via
a
hydrogenolysis of the oxazoline compound 5. It was also
anticipated that the pendant vinyl group of oxazoline 3
could be easily converted to ester 5 in three steps. This
study further demonstrates that utility through the
asymmetric synthesis of 1 via the key intermediate 6.
We have recently developed an efficient preparation of
trans-oxazoline 3 in enantiopure form from L-N-benzo-
Reduction of 6 using borane–methyl sulfide complex
and protection with (Boc)2O led to 710 in 62% yield.
Etherification of hydroxy group with 3,5-bis(trifluoro-
methyl)benzyl bromide in the presence of NaH yielded
8. Finally, N-Boc deprotection of 8 using TFA afforded
(2S,3S)-L-733,060 (1). The spectroscopic (1H and 13C
NMR) data for synthetic 1 were fully identical with
those of synthetic one,4e and the properties of 1 showed
Keywords: Natural product; L-733,060; Asymmetric synthesis; Chiral
oxazoline; Intramolecular cyclization.
*
Corresponding author. Tel.: +82 312907706; fax: +82 312928800;
e-mail: whham@skku.edu
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.025

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Y.-J. Yoon et al. / Tetrahedron Letters 46 (2005) 739–741
CF3
Ph
OH
O
N
O
OH
NHBz
CF3
O
N
H
Ph
Ph
N
H
Ph
1
6
3
Scheme 1. Retrosynthesis of (+)-L-733,060.
O
O
Ph
OMe
OMe
Ph
Ph
d
a, b
c
N
O
N
O
N
O
Ph
Ph
Ph
3
4
5
CF3
CF3
OH
Ph
OH
Ph
O
g
e, f
O
h
CF3
CF3
O
N
H
N
N
Ph
N
H
Ph
Boc
Boc
7
6
8
1
Scheme 2. Reagents and conditions: (a) O3, MeOH, ꢀ78°C then DMS; (b) (MeO)2POCH2CO2Me, LiCl, i-Pr2NEt, CH3CN, 87% for two steps; (c)
CuBr, Red-Al, 2-butanol, THF, 83%; (d) 20% Pd(OH)2/C, 70psi H 2, MeOH/AcOH (10:1), 76%; (e) BH3SMe2, MeOH, THF; (f) (Boc)2O, CH2C12,
62% for two steps; (g) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, DMF, 76%; (h) trifluoroacetic acid, 93%.
25
L. X.; Wei, B. G.; Ruan, Y. P. Org. Lett. 2003, 5, 1927; (g)
good agreements with those reported. (½aŠ þ 32:65
Org. Lett. 2004, 6, 3517.
D
25
D
(c 1.0, CHCl3) [lit.4e ½aŠ þ 34:29 (c 1.32, CHCl3)]).
Lemire, A.; Grenon, M.; Pourashraf, M.; Charette, A. B.
5. (a) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett.
1999, 40, 5071; (b) Tsuritani, N.; Yamada, K.; Yoshikawa,
Acknowledgements
N.; Shibasaki, M. Chem. Lett. 2002, 276; (c) Yamazaki,
N.; Atobe, M.; Kibayashi, C. Tetrahedron Lett. 2002, 43,
7979; (d) Desai, M. C.; Thadeio, P. F.; Lefkowitz, S. L.
Tetrahedron Lett. 1993, 34, 5831.
This work was supported by grant No. R01-2001-000-
00214-0 from Korea Science & Engineering Foundation.
6. (a) Lee, K. Y.; Kim, Y. H.; Park, M. S.; Ham, W. H.
Tetrahedron Lett. 1998, 39, 8129; (b) Lee, K. Y.; Kim, Y.
H.; Park, M. S.; Oh, C. Y.; Ham, W. H. J. Org. Chem.
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References and notes
7. (a) Suh, Y. G.; Jung, J. K.; Kim, S. A.; Shin, D. Y.; Min,
D. H. Tetrahedron Lett. 1997, 38, 3911; (b) Takao, K.;
Nigawara, Y.; Nishino, E.; Takagi, I.; Maeda, K.;
Tadano, K.; Ogawa, S. Tetrahedron 1994, 50, 5681.
1. (a) Baker, R.; Harrison, T.; Hollingworth, G. J.; Swain, C.
J.; Williams, B. J. EP 0528, 495A1, 1993; (b) Harrison, T.;
Williams, B. J.; Swain, C. J.; Ball, R. G. Bioorg. Med.
Chem. Lett. 1994, 4, 2545.
8. Spectral data for some key compounds: compound 4:
2. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.
P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
25
D
½aŠ þ 28:64 (c 1.0, CH2Cl2); IR (neat) mmax: 3030, 2949,
2360, 1725, 1650, 1319, 1273, 1171, 1062, 760, 696 cmꢀ1
;
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.
1H NMR (300 MHz, CDCl3) d: 8.09–7.28 (m, 10H), 7.11
(dd, J = 5.4 Hz, 15.6 Hz, 1H), 6.12 (dd, J = 1.5 Hz,
15.6 Hz, 1H), 5.11 (d, J = 7.8 Hz, 1H), 3.76 (s, 3H); 13C
NMR (75 MHz, CDCl3) d: 166.47, 164.09, 144.52, 141.25,
132.20, 129.26, 128.85, 128.80, 128.36, 127.30, 126.92,
121.94, 86.07, 76.35, 52.17; HRMS m/e calcd for
C19H17NO3: 308.1287; found: 308.1301. Compound
4. (a) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40,
7099; (b) Stadler, H.; Bos, M. Heterocycles 1999, 51, 1067;
(c) Tomooka, K.; Nakaszaki, 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; (f) Huang, P. Q.; Liu,
25
D
5: ½aŠ ꢀ 34:66 (c 1.0, CH2Cl2); IR (neat) mmax
:
3061, 3029, 2949, 1737, 1646, 1494, 1448, 1168, 1063,
1024, 758, 696 cmꢀ1; 1H NMR (300 MHz, CDCl3) d: 8.05–
7.26 (m, 10H), 4.92 (d, J = 6.9 Hz, 1H), 4.53 (m, 1H), 3.66
(s, 3H), 2.62–2.53 (m, 2H), 2.22–2.11 (m, 2H); 13C NMR
(75 MHz, CDCl3) d: 172.46, 164.12, 142.19, 131.89,

Y.-J. Yoon et al. / Tetrahedron Letters 46 (2005) 739–741
741
129.10, 128.74, 128.67, 128.04, 127.86, 126.94, 86.91,
75.86, 52.04, 30.77, 30.37; HRMS m/e calcd for C19H19-
NO3: 310.1443; found: 310.1440.
(ethyl acetate) gave 6 (459 mg, 76%); yellowish solid;
25
D
mp: 87–88 °C; ½aŠ þ 32:48 (c 1.0, CH2Cl2); IR (neat)
m
max: 3282, 2933, 1648, 1455, 1403, 1352, 1321, 1196, 748,
1
9. For the experimental details of piperidin-2-one 6: a solution
of 5 (983 mg, 3.18 mmol) in AcOH/MeOH (1:9, 40mL), to
which was added of 20% Pd(OH)2, was vigorously shaken
under 70psi H 2 for three days at ambient temperature.
The reaction mixture was then filtered through a pad of
silica and concentrated in vacuo. The resulting slurry was
diluted with EtOAc and washed with saturated aqueous
NaHCO3 solution, brine, dried with MgSO4 and evapo-
rated in vacuo. Purification by silica gel chromatography
700 cmꢀ1; H NMR (300 MHz, CDCl3) d: 7.44–7.30(m,
5H), 6.17 (s, 1H), 4.65 (d, J = 3 Hz, 1H), 4.066 (m, 1H),
2.75–2.63 (m, 1H), 2.40–2.31 (m, 1H), 2.17–2.07 (m, 1H),
2.04–1.93 (m, 1H); 13C NMR (75 MHz, CDCl3) d: 172.95,
138.13, 129.33, 128.86, 127.37, 66.42, 62.03, 26.87, 26.32;
HRMS m/e calcd for C11H13NO2: 192.1025; found:
192.1023.
10. The conversion of 7 to 2 has been earlier reported by
Kibayashi and Huang group.4f,5c