Stereoselective synthesis of L-733,060

Article abstract of DOI:10.1016/S0040-4039(02)02772-7

Enantioselective synthesis of non-peptidic neurokinin NK1 receptor antagonist L-733,060 is described using ring-closing metathesis as a key step, starting from L-phenylglycine.

Full text of DOI:10.1016/S0040-4039(02)02772-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 915–917
Stereoselective synthesis of L-733,060ꢀ
G. Bhaskar and B. Venkateswara Rao*
Organic Division III, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 9 September 2002; revised 25 November 2002; accepted 6 December 2002
Abstract—Enantioselective synthesis of non-peptidic neurokinin NK1 receptor antagonist L-733,060 is described using ring-clos-
ing metathesis as a key step, starting from -phenylglycine. © 2003 Elsevier Science Ltd. All rights reserved.
L
The non-peptidic neurokinin NK1 receptor antagonists
1 and 2 are known for having a variety of biological
activities including neurogenic inflammation,1 pain
transmission and regulation of the immune response.2
They have been implicated in a variety of disorders
including migraine,3 rheumatoid arthritis4 and pain.5
The commercially available L-phenylglycine 4 was con-
verted to N-Boc methyl ester 5 in the presence of acetyl
chloride, methanol and (Boc)2O, then the ester 5 was
reduced to alcohol 6 using LiBH4. Swern oxidation of 6
followed by in situ reaction of the resulting aldehyde with
vinylmagnesium bromide yielded the corresponding
allylic alcohol 7 with good diastereoselection (9:1
diastereomers from NMR, separated by column chro-
matography) in favour of the syn isomer, which is in
accordance with an earlier reported observation.8 The
spectral data of 7 was in agreement with reported values.9
The hydroxy group of 7 was protected with TBDMS-Cl
in the presence of imidazole giving 8, which was treated
with allyl bromide in the presence of NaH to give
N-allylic compound 9. Desilylation of 9 gave 10. Ring-
closing metathesis10,11 of 10 yielded 11, then hydrogena-
tion of the alkene produced intermediate N-Boc
(2S,3S)-3-hydroxy-2-phenylpiperidine 3. Protection of
hydroxy group with 3,5-bis(trifluoromethyl)benzyl bro-
mide in the presence of DMF and NaH yielded 12.
Finally, deprotection of the Boc group under standard
conditions culminated in an efficient synthesis of the
The cis-relationship between the two substituents on the
piperidine ring is essential for high-affinity binding to the
human NK1 (hNK1) receptor. Due to its potent biolog-
ical activity, compound 1 is a good synthetic target. Only
two total syntheses of 1 have been reported. The first
synthesis6a by Harrison et al., describes a preparation of
1 in which the crucial chiral hydroxy piperidine interme-
diate was obtained by resolution, whereas the second
synthesis6b by Tomooka et al., describes the preparation
of 1 in racemic form. A few more formal syntheses of 1
have been reported where the intermediate (2S,3S)-3-
hydroxy-2-phenylpiperidine and its Boc derivative 37
were prepared. Herein we report a stereoselective synthe-
sis of L-733,060 using vinyl Grignard reagent and ring-
closing metathesis as key steps, from
This is the first synthesis of 1 using metathesis and
-phenylglycine as a starting material.
L-phenylglycine.
1
L
target L-733,060 1 (Scheme 1), whose H, 13C NMR
ꢀ IICT Communication Number 020907.
* Corresponding author. Fax: +91-40-27160512; e-mail: venky@iict.ap.nic.in
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02772-7

916
G. Bhaskar, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 915–917
Scheme 1. Reagents and conditions: (a) AcCl, MeOH then (Boc)2O, Et3N, THF, 0°C–rt, 8 h, 97%; (b) LiCl, NaBH4, EtOH, THF,
0°C–rt, 12 h, 87%; (c) DMSO, (COCl)2, DCM, i-Pr2NEt then CH2ꢀCHMgBr, THF, 2 h, rt, 61%; (d) TBDMS–Cl, imidazole,
DCM, 0°C–rt, 24 h, 90%; (e) CH2ꢀCHCH2Br, NaH, DMF, 0°C–rt, 24 h, 90%; (f) TBAF–AcOH, THF, 0°C–rt, 24 h, 85%; (g)
Grubbs’ catalyst, DCM, rt, 6 h, 82%; (h) Pd/C, H2, EtOH, 4 h, rt, 65%; (i) 3,5-bis(trifluoromethyl)benzyl bromide, NaH, DMF,
80°C, 13 h, 80%; (j) trifluoroacetic acid, rt, 1 h, 79%.
spectral data were in agreement with the reported
values.12,13
Harrison, T.; Swain, C.; William, B. J. EP Appl. 1993 EP
528,495A1.
8. Denis, J. N.; Correa, A.; Greene, A. E. J. Org. Chem.
1991, 56, 6939–6942.
In summary, we have accomplished the synthesis of
L-733,060 1 using ring-closing metathesis starting from
9. Mp 56–58°C (lit.8 Mp 56–57°C); [h]2D5 +0.31 (c 1.5,
CHCl3) (lit.8 [h]D25 +0.3 (c 1.6, CHCl3)).
L
-phenylglycine. This strategy may also be helpful for
the synthesis of analogues.
10. For recent reviews on metathesis, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413–4450; (b) Arm-
strong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371–
388; (c) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39,
3012–3043.
Acknowledgements
G. Bhaskar thanks the CSIR, New Delhi, for a research
fellowship (S.R.F.). We also thank Dr. J. S. Yadav and
Dr. G. V. M. Sharma for their support and
encouragement.
11. For syntheses of piperidine moieties using ring-closing
metathesis, see: (a) Pernerstorfer, J.; Schuster, M.;
Blechert, S. Synthesis 1999, 138–144; (b) Zumpe, F. L.;
Kazmaier, U. Synthesis 1999, 1785–1791; (c) Felpin, F.;
Girard, S.; Vo-Thanh, G.; Robins, R. J.; Villieras, J.;
Lebreton, J. J. Org. Chem. 2001, 66, 6305–6312; (d)
Banba, Y.; Abe, C.; Nemoto, H.; Kato, A.; Adachi, I.;
Takahata, H. Tetrahedron: Asymmetry 2001, 12, 817–819;
(e) Cossy, J.; Willis, C.; Bellosta, V.; BouzBouz, S. J.
Org. Chem. 2002, 67, 1982–1992; (f) Ginesta, X.; Pericas,
M. A.; Riera, A. Tetrahedron Lett. 2002, 43, 779–782; (g)
Davies, S. G.; Iwamoto, K.; Smethurst, C. A. P.; Smith,
A. D.; Rodriguez-Solla, H. Synlett 2002, 1146–1148.
12. Tomooka, K.; Nakazaki, A.; Nakai, T. J. Am. Chem.
Soc. 2000, 122, 408–409, see supporting information.
13. Spectral data for some key compounds:
References
1. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1988,
241, 1218–1221.
2. Perianan, A.; Snyderman, R.; Malfroy, B. Biochem. Bio-
phys. Res. Commun. 1989, 161, 520–524.
3. Moskowitz, M. A. Trends Pharmacol. Sci. 1992, 13,
307–311.
4. Lotz, M.; Vaughan, J. H.; Carson, D. A. Science 1987,
235, 893–895.
5. Otsuka, M.; Yanagisawa, M. J. Physiol. (London) 1988,
395, 255–270.
6. (a) Harrison, T.; Williams, B. J.; Swain, C. J.; Ball, R. G.
Bioorg. Med. Chem. Lett. 1994, 4, 2545–2550; (b)
Tomooka, K.; Nakazaki, A.; Nakai, T. J. Am. Chem.
Soc. 2000, 122, 408–409.
7. (a) Calvez, O.; Langlois, N. Tetrahedron Lett. 1999, 40,
7099–7100; (b) Stadler, H.; Bos, M. Heterocycles 1999,
51, 1067–1071; (c) Lee, J.; Hoang, T.; Lewis, S.; Weiss-
man, S. A.; Askin, D.; Volante, R. P.; Reider, P. J.
Tetrahedron Lett. 2001, 42, 6223–6225; (d) Baker, R.;
Compound 10: [h]2D5=+11.31 (c 1.1, CHCl3); IR (neat,
cm−1): 3400, 2970, 1670, 1445, 1400, 1350, 1245, 1160,
915, 680; 1H NMR (200 MHz, CDCl3): l 1.44 (s, 9H),
3.52–3.86 (m, 3H), 4.72 (br s, 2H), 4.96–5.19 (m, 3H),
5.36 (d, 1H, J=17.7 Hz), 5.52–5.96 (m, 2H), 7.20–7.42
(m, 5H); FAB-MS m/z: 304 (M+1), 246, 230, 204, 190.
Compound 11: [h]2D5=+64.10 (c 1.05, CHCl3); IR (neat,
1
cm−1): 3415, 2984, 1676, 1400, 1350, 1150; H NMR (200
MHz, CDCl3): l 1.44 (s, 9 H), 3.54 (ddd, 1H, J=1.4, 3.9,
19.0 Hz), 4.16 (ddd, 1H, J=3.2, 5.6, 19.0 Hz), 4.66 (br s,

G. Bhaskar, B. Venkateswara Rao / Tetrahedron Letters 44 (2003) 915–917
917
1H), 5.53 (d, 1H, J=6.7 Hz), 5.70–5.98 (m, 2H), 7.14–
7.48 (m, 5H).
Hz), 4.75 (d, 1H, J=12.6 Hz), 5.67 (d, 1H, J=4.8 Hz),
7.18–7.38 (m, 3H), 7.44–7.58 (m, 2H), 7.69 (s, 2H), 7.76
(s, 1H); FAB-MS m/z: 504 (M+1), 448, 402, 387.
Compound 1: [h]2D5=+34.29 (c 1.32, CHCl3); IR (neat,
cm−1): 2950, 1370, 1277, 1170, 1123, 877, 660; 1H
NMR (200 MHz, CDCl3): l 1.44–2.04 (m, 3H), 2.22
(br d, 1H, J=13.4 Hz), 2.62 (br s, 1H), 2.83 (dt, 1H,
J=3.0,11.9,11.9 Hz), 3.22–3.38 (m, 1H), 3.66 (br s,
1H), 3.84 (br s, 1H), 4.12 (d, 1H, J=12.6 Hz), 4.52 (d,
1H, J=12.6 Hz), 7.18–7.48 (m, 7H), 7.69 (s, 1H); 13C
NMR (75 MHz, CDCl3): l 20.25, 28.27, 46.86, 64.06,
69.96, 77.40, 121.12 (m), 123.22 (q, J=272.6 Hz),
126.72, 127.16, 127.37, 128.11, 131.26 (q, J=33.3),
141.11, 141.41; FAB-MS m/z: 404 (M+1), 227, 176,
160.
Compound 3: [h]2D5=+38.30 (c 1.92, CHCl3); IR (neat,
cm−1): 3430, 2910, 1692, 1400, 1350,1230, 1160; 1H
NMR (200 MHz, CDCl3): l 1.37 (s, 9H), 1.58–1.88 (m,
5H), 3.01 (ddd, J=4.5,11.5,13.5 Hz, 1H), 3.88–4.16 (m,
2H), 5.27 (d, J=5.6 Hz, 1H), 7.18–7.48 (m, 5H); 13C
NMR (75 MHz, CDCl3): l 23.12, 27.65, 28.29, 39.43,
59.17, 70.05, 79.87, 127.09, 128.29, 128.37, 138.45,
155.39; FAB-MS m/z: 278 (M+1), 222, 204, 176. Com-
pound 12: [h]2D5=+30.38 (c 1.55, CHCl3); IR (neat,
cm−1): 2920, 1677, 1384, 1350, 1250, 1170, 1125, 875,
1
665; H NMR (200 MHz, CDCl3): l 1.42 (s, 9H), 1.44–
1.78 (m, 2H), 1.88–2.08 (m, 2H), 2.74 (ddd, 1H, J=4.3,
12.0, 13.4 Hz), 3.80–3.98 (m, 2H), 4.68 (d, 1H, J=12.6