Asymmetric synthesis of (+)-CP-99,994 and (+)-L-733,060 from enantiomerically pure (3S,4S)-4-(tert-butylcarbamoyl)-4-phenyl-1-buten-3-ol

Article abstract of DOI:10.1055/s-2006-956453

Asymmetric syntheses of neurokinin substance P receptor antagonists (+)-CP-99,994 and (+)-L-733,060 have been accomplished starting from enantiomerically pure (3S,4S)-4-(tert-butylcarbamoyl)-4-phenyl-1-buten-3-ol. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-956453

LETTER
3395
Asymmetric Synthesis of (+)-CP-99,994 and (+)-L-733,060 from Enantio-
merically Pure (3S,4S)-4-(tert-Butylcarbamoyl)-4-phenyl-1-buten-3-ol
A
symmetric Sy
e
nthesis of
(
t
+
)-CP-
s
99, 994
a
n
u
d (+)-L-733,0
t
60 a Oshitari, Tadakatsu Mandai*
Department of Life Science, Kurashiki University of Science & the Arts, 2640 Nishinoura, Tsurajima, Kurashiki 712-8505, Japan
Fax +81(86)4401062; E-mail: ted@chem.kusa.ac.jp
Received 19 September 2006
ture–activity relationship (SAR) study. Thirdly, the
efficient processes associated with mild reaction condi-
tions are highly desirable that lead to environmentally
benign processes.
Abstract: Asymmetric syntheses of neurokinin substance P recep-
tor antagonists (+)-CP-99,994 and (+)-L-733,060 have been accom-
plished starting from enantiomerically pure (3S,4S)-4-(tert-
butylcarbamoyl)-4-phenyl-1-buten-3-ol.
Key words: 1,2-amino alcohols, 1,2-diamines, hydroformylations, We have recently established a practical access to 4-(tert-
neurokinin-1 antagonists, piperidines
butylcarbamoyl)-1-alken-3-ols with exceedingly high
enantiomeric purity by virtue of the lipase-catalyzed ki-
netic resolution.5 This protocol has paved a way for man-
made chirons having three consecutive functionalities
(i.e. amino, hydroxy and vinyl groups) of high synthetic
value, otherwise difficult to obtain from natural amino ac-
ids. Thus, we envisaged to synthesize 1 and 2 by taking
advantage of (3S,4S)-4-(tert-butylcarbamoyl)-4-phenyl-
1-buten-3-ol (5)5 (>99% ee) as a common starting materi-
al.
2,3-Disubstituted piperidines, structural units found in
several drug candidates and natural products, have attract-
ed considerable attention as synthetic targets because of
their unique biological activities. For example, (+)-CP-
99,994 (1)1 and (+)-L-733,060 (2)1g,2 are potent neuroki-
nin substance P receptor antagonists.3 Febrifugine (3)4
and isofebrifugine (4)4 are well-known antimalarial
agents (Figure 1).
The success in the synthesis of 1 seemed to depend strong-
ly upon the regio- and stereoselective introduction of a ni-
trogen functionality in the C-3 position of 5, for which we
planned to utilize palladium-catalyzed C–O to C–N bond
transformation developed by us.6–8 Thus, syn 3-benzoyl-
oxy-4-phenyl-4-(3-tosylureido)-1-buten (7) was derived
from 5 through a sequence of reactions involving benzoyl-
ation, deprotection of the Boc group followed by the
amino group protection with p-tosyl isocyanate. The
palladium-catalyzed intramolecular attack of the nitrogen
anion on a p-allylpalladium intermediate took place very
smoothly to afford a mixture of trans imidazolidin-2-one
8a (89%) and cis isomer 8b (7%) as shown in Scheme 1.
CF3
H
N
O
CF3
OCH3
N
H
Ph
N
H
Ph
(+)-CP-99,994 (1)
(+)-L-733,060 (2)
OH
O
N
O
OH
N
O
N
N
N
H
N
H
O
febrifugine (3)
isofebrifugine (4)
NHBoc
NHBoc
b, c
a
Figure 1 Biologically active 2,3-disubstituted piperidines
Ph
Ph
97%
97%
OBz
OH
Although all these compounds belong to a class of small
molecules with simple structural units, efficient synthetic
methods for their preparation have not yet been estab-
lished. In designing the syntheses of such compounds,
several points should be taken into consideration. Firstly,
it would be absolutely important to synthesize them in
enantiomerically pure forms, neither in racemic nor in
non-racemic forms, from a biological standpoint. Second-
ly, the synthetic processes should be flexible and scalable
5
6
O
O
O
HN
HN
HN
NHTs
d
NTs
NTs
+
Ph
Ph
Ph
OBz
7
8a
89%
8b
7%
for the syntheses of relevant compounds such as diaste- Scheme 1 Palladium-catalyzed C–O to C–N bond transformation.
Reagents and conditions: (a) BzCl, pyridine, r.t., 10 h; (b) TFA,
CH2Cl2, r.t., 1 h; (c) p-TsNCO, THF, r.t., 2.5 h; (d) Pd2(dba)3 (2.5
reomers, enantiomers and analogues requisite for struc-
mol%), dppp (10 mol%), DBU, DMSO, 50 °C, 4 h.
SYNLETT 2006, No. 20, pp 3395–3398
1
8
.1
2
.2
0
0
6
Advanced online publication: 08.12.2006
DOI: 10.1055/s-2006-956453; Art ID: U10806ST
© Georg Thieme Verlag Stuttgart · New York

3396
T. Oshitari, T. Mandai
LETTER
Optimum conditions with regard to the solvent and the the reductive cleavage of N-tosyl group with sodium
base were examined, in which a combination of dimethyl naphthalenide. This attempt, however, was unsuccessful
sulfoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a complex mixture was obtained. Thus, the tosyl-
proved to give the satisfactory yield with high diastereo- amino group was further protected with (Boc)2O–4-(N,N-
selectivity.9 It is worth noting that the forerunning fraction dimethylamino)pyridine (DMAP) to give 11a, whose
8b could be easily removed by medium-pressure column p-tosyl group was smoothly removed by treatment with
chromatography.
sodium naphthalenide in tetrahydrofuran at –78 °C.
Carbamate 11b thus obtained was deprotonated with
sodium hydride in tetrahydrofuran–N,N-dimethylform-
amide (1:3) at room temperature and carefully treated
with 2-methoxybenzyl chloride in the presence of tetra-
butylammonium iodide (TBAI) at 0 °C for 18 hours to
produce 12 (87%).17,18 Finally, treatment of 12 with tri-
fluoroacetic acid at room temperature for two hours
provided 119 (Scheme 2) in 95% yield {mp (dihydro-
chloride): 253–254.5 °C; [a]D24 +77.5 (dihydrochloride,
c = 1.05, MeOH)} {Lit.1a mp (dihydrochloride): 255 °C,
OH
NHBoc
BocN
Ph
a, b
c
8a
Ph
93%
NHTs
NHTs
9
BocN
d
BocN
Ph
h
e, f
84%
Ph
87%
95%
25
[a]D +77 (dihydrochloride, c = 1.0, MeOH); Lit.1e mp
NHTs
NRBoc
23
(dihydrochloride): 254.5 °C, [a]D +75.5 (dihydro-
g
96%
10
11a: R = Ts
11b: R = H
16
chloride, c = 1.1, MeOH); Lit.1g [a]D +75.1 (dihydro-
chloride, c = 0.6, MeOH); Lit.1j mp: 236 °C, [a]D20 –73.0
(hydrochloride of ent-1, c = 1.0, MeOH)}.
Boc
N
i
On the other hand, the synthesis of 2 was successfully
achieved as shown in Scheme 3, in which the piperidine
framework was also constructed through the aforemen-
tioned hydroformylation. The hydroformylation of ben-
zoate 620 under the same conditions as that of 9 proceeded
smoothly to provide enamide 1321,22 (95%). In this case,
13 was obtained in a straightforward manner without the
treatment with CSA. Hydrogenation of 13 followed by al-
kaline hydrolysis gave piperidine 14.23 Finally, 3,5-bistri-
fluoromethylbenzylation provided 15,24 whose Boc group
was removed to give 225 {yield: 85% for two steps; mp
1
95%
OMe
N
Ph
Boc
12
Scheme 2 Synthesis of (+)-CP-99,994. Reagents and conditions:
(a) Ethylenediamine (50 mol equiv), 160 °C (autoclave), 6 h; (b)
Boc2O, CH2Cl2, r.t., 12 h; (c) Rh(acac)(CO)2 (3 mol%), biphephos (6
mol%), THF, CO–H2 (5 atm), 65 °C, 8 h; (d) cat. CSA, THF, r.t., 9 h;
(e) H2 (1 atm), 10% Pd–C, EtOH, r.t., 12 h; (f) Boc2O, cat. DMAP,
THF, r.t., 6 h; (g) Na, naphthalene, THF, –78 °C, 1 h; (h) 2-methoxy-
benzyl chloride, NaH, TBAI, THF–DMF (1:3), 0 °C, 18 h; (i) TFA,
r.t., 2 h; NaHCO3, 95%.
23
(hydrochloride): 215–217 °C, [a]D +87.1 (hydrochlo-
24
ride, c = 1.0, MeOH), [a]D +73.7 (free base, c = 1.3,
CHCl3)}{Lit.1g mp 213–215 °C, [a]D28 +84.5 (hydrochlo-
With enantiomerically pure 8a in hand, we then tried to
cleave the imidazolidinone ring. The attempted known
procedures such as acid10a or base-mediated10b,c hydroly-
sis, however, had no effect on 8a. Eventually, the success-
ful ring cleavage of 8a was accomplished with a large
excess of ethylenediamine in an autoclave at 160 °C,11
giving a mono-N-Ts-protected 1,2-diamine.12 To the best
of our knowledge, the ring-cleavage reaction of imidazo-
lidinones through amine-exchange protocol has never
been reported, but would be of high synthetic value. The
free amine thus obtained was protected by a Boc group to
afford 9.
23
ride, c = 0.8, MeOH); Lit.2a 215–216 °C, [a]D +87.3
25
(hydrochloride, c = 1, MeOH); Lit.2d [a]D +34.29 (free
base, c = 1.32, CHCl3); Lit.2e [a]D25 +32.65 (free base, c =
20
1.0, CHCl3); Lit.1i mp 200–202 °C, [a]D –83.9 (hydro-
BocN
Ph
BocN
Ph
b, 90%
c, 92%
a
6
95%
OBz
13
OH
14
CF3
Next we stepped into the piperidine ring formation, for
which we selected a Rh-catalyzed hydroformylation.13
Compound 9 underwent smooth hydroformylation with a
catalytic system of Rh(acac)(CO)2 (3 mol%) and biphe-
phos (6 mol%)14 under five atmospheres of CO–H2 (1:1),
giving a mixture of the N-Boc-protected aminal and en-
amide 10 as major products.15 The crude reaction mixture
was submitted to 10-camphorsulfonic acid (CSA)-cata-
lyzed dehydration to afford 1016 in 84% yield. Enamide 10
was hydrogenated in quantitative yield to provide a
saturated 3-tosylaminopiperidine, which was subjected to
O
d
e
CF3
2
91%
93%
N
Ph
Boc
15
Scheme 3 Synthesis of (+)-L-733,060. Reagents and conditions: (a)
Rh(acac)(CO)2 (3 mol%), biphephos (6 mol%), CO–H2 (5 atm), THF,
65 °C, 5 h; (b) 10% Pd–C, H2(1 atm), EtOH, r.t., 20 h; (c) 1 M NaOH–
MeOH–1,4-dioxane, (2:3:6), r.t., 1 h; (d) 3,5-(CF3)2C6H3CH2Br,
NaH, THF–DMF (1:3), 0 °C, 6 h; (e) TFA, r.t., 1.5 h, NaHCO3.
Synlett 2006, No. 20, 3395–3398 © Thieme Stuttgart · New York

LETTER
Asymmetric Synthesis of (+)-CP-99,994 and (+)-L-733,060
3397
chloride of ent-2, c = 0.99, MeOH); Lit.1j mp 210 °C,
[a]D20 –86.0 (hydrochloride of ent-2, c = 1.0, MeOH)}.
Urushibara, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2001, 3, 953. (k) Sugiura, M.; Kobayashi, S. Org.
Lett. 2001, 3, 477. (l) Okitsu, O.; Suzuki, R.; Kobayashi, S.
J. Org. Chem. 2001, 66, 809. (m) Sugiura, M.; Hagio, H.;
Hirabayashi, R.; Kobayashi, S. J. Am. Chem. Soc. 2001, 123,
12510. (n) Huang, P.-Q.; Wei, B.-G.; Ruan, Y.-P. Synlett
2003, 1663. (o) Katoh, M.; Matsune, R.; Nagase, H.; Honda,
T. Tetrahedron Lett. 2004, 45, 6221. (p) Ashoorzadeh, A.;
Caprio, V. Synlett 2005, 346. (q) Takeuchi, Y.; Oshige, M.;
Azuma, K.; Abe, H.; Harayama, T. Chem. Pharm. Bull.
2005, 53, 868.
In conclusion, we have successfully established an effi-
cient synthetic method for (+)-CP-99,994 and (+)-L-
733,060 from enantiomerically pure (3S,4S)-4-(tert-bu-
tylcarbamoyl)-4-phenyl-1-buten-3-ol as a common start-
ing material without loss of optical purity.
Acknowledgment
(5) (a) Oshitari, T.; Mandai, T. Synlett 2003, 2374. (b) The
enantiomeric purity of 5 was determined to be >99% ee by
HPLC [CHIRALCEL OD-H; hexane–i-PrOH = 9:1; l = 220
nm; flow rate: 0.8 mL/min; tR(5) = 6.36 min; tR(ent-5) = 8.71
min]. (c) Compound 5 was also prepared from (S)-(+)-
phenylglycine. See: Denis J.-N., Correa A., Greene A. E.; J.
Org. Chem.; 1991, 56: 6939; Greene and co-workers
reported therein that 5 was obtained in moderate yield with
complete retention of enantiomeric purity by the addition of
the crude Swern-oxidation product of N-Boc phenylglycinol
to a large excess of vinylmagnesium bromide. Bhaskar et al.
adopted this method for the preparation of compound 5 in
their synthesis of 2,2d whose enantiomeric purity can be
estimated below 50% ee in comparison with our own data.
Ham and co-workers also synthesized 2 via an oxazoline
derivative starting from N-benzoyl phenylglycinol.2e The
optical rotation of 2 was in agreement with that reported in
ref. 2d. These observations clearly imply that special care is
required for employing easily racemizable phenylglycinal
derivatives as a source of chiron approach.
(6) Oshitari, T.; Akagi, R.; Mandai, T. Synthesis 2004, 1325.
(7) For preparation of 1,2-amino alcohol arrays from vinyl
epoxides or 1,3-amino alcohol arrays from 4-pentene-1,3-
diol carbonates via the intramolecular reaction of a nitrogen-
containing nucleophile with a p-allylpalladium complex,
see: (a) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc.
1987, 109, 3792. (b) Trost, B. M.; Sudhakar, A. R. J. Am.
Chem. Soc. 1988, 110, 7933. (c) Bando, T.; Harayama, H.;
Fukazawa, Y.; Shiro, M.; Fugami, K.; Tanaka, S.; Tamaru,
Y. J. Org. Chem. 1994, 59, 1465.
This work was financially assisted in part by a grant from Institute
of Nippon Chemiphar Co., Ltd.
References and Notes
(1) (a) Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo, K.
P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911. (b) Rosen,
T.; Seeger, T. F.; McLean, S.; Desai, M. C.; Guarino, K. J.;
Bryce, D.; Pratt, K.; Heym, J.; Chalabi, P. M.; Windels, J.
H.; Roth, R. W. J. Med. Chem. 1993, 36, 3197. For
synthesis of racemic 1, see: (c) Desai, M. C.; Thadeio, P.
F.; Lefkowitz, S. L. Tetrahedron Lett. 1993, 34, 5831.
(d) Chandrasekhar, S.; Mohanty, P. K. Tetrahedron Lett.
1999, 40, 5071. (e) Yamazaki, N.; Atobe, M.; Kibayashi, C.
Tetrahedron Lett. 2002, 43, 7979. (f) Tsuritani, N.;
Yamada, K.-I.; Yoshikawa, N.; Shibasaki, M. Chem. Lett.
2002, 276. (g) Huang, P.-Q.; Liu, L.-X.; Wei, B.-G.; Ruan,
Y.-P. Org. Lett. 2003, 5, 1927. (h) Atobe, M.; Yamazaki,
N.; Kibayashi, C. J. Org. Chem. 2004, 69, 5595. For
syntheses of ent-1 and ent-2, see: (i) Lemire, A.; Grenon,
M.; Pourashraf, M.; Charette, A. B. Org. Lett. 2004, 6,
3517. (j) Takahashi, K.; Nakano, H.; Fujita, R. Tetrahedron
Lett. 2005, 46, 8927.
(2) (a) Baker, R.; Harrison, T.; Swain, C. J.; Williams, B. J. Eur.
Patent, 0528495A1, 1993. (b) Harrison, T.; Williams, B. J.;
Swain, C. J.; Ball, R. G. Bioorg. Med. Chem. Lett. 1994, 4,
2545. (c) Tomooka, K.; Nakazaki, A.; Nakai, T. J. Am.
Chem. Soc. 2000, 122, 408. For the synthesis of racemic 2,
see: (d) Bhaskar, G.; Rao, B. V. Tetrahedron Lett. 2003, 44,
915. (e) Yoon, Y.-J.; Joo, J.-E.; Lee, K.-Y.; Kim, Y.-H.; Oh,
C.-Y.; Ham, W.-H. Tetrahedron Lett. 2005, 46, 739. (f) For
the synthesis of 14, see: Stadler, H.; Bös, M. Heterocycles
1999, 51, 1067. For the synthesis of deprotected 14, see:
(g) Lee, J.; Hoang, T.; Lewis, S.; Weissman, S. A.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 2001, 42,
6223. (h) Tsai, M.-R.; Chen, B.-F.; Cheng, C.-C.; Chang,
N.-C. J. Org. Chem. 2005, 70, 1780.
(8) For preparation of 1,2-diamine arrays from 5-vinyloxazol-
idinones via intermolecular reaction of a nitrogen-containing
nucleophile with a p-allylpalladium complex, see:
(a) Cook, G. R.; Shanker, P. S.; Pararajasingham, K. Angew.
Chem. Int. Ed. 1999, 38, 110. (b) Cook, G. R.;
Sankaranarayanan, S. Org. Lett. 2001, 3, 3531. (c)Cook, G.
R.; Yu, H.; Sankaranarayanan, S.; Shanker, P. S. J. Am.
Chem. Soc. 2003, 125, 5115.
(9) In our preliminary investigation, DMSO was proven to be
more effective solvent than toluene, THF and DMF. In
addition, we found that DBU, soluble in above solvents, was
much superior to other bases such as NaH, t-BuOK and
Cs2CO3.
(10) (a) Dunn, P. J.; Häner, R.; Rapoport, H. J. Org. Chem. 1990,
55, 5017. (b) Seo, R.; Ishizuka, T.; Abdel-Aziz, A. A.-M.;
Kunieda, T. Tetrahedron Lett. 2001, 42, 6353. (c) Katahira,
T.; Ishizuka, T.; Matsunaga, H.; Kunieda, T. Tetrahedron
Lett. 2001, 42, 6319.
(11) The reaction under heating at refluxing temperature in a
flask overnight provided 4-phenyl-4-(3-aminopropion-
amido)-3-tosylamino-1-butene as the sole product.
(12) After removal of ethylenediamine in vacuo, a mixture of the
mono-N-Ts-protected 1,2-diamine and 2-imidazolidone was
afforded, which was subjected to the next step without
further purification.
(3) For a review, see: Datar, P.; Srivastava, S.; Coutinho, E.;
Govil, G. Curr. Top. Med. Chem. 2004, 4, 75.
(4) (a) For a review, see: Takeuchi, Y.; Harayama, T. J. Synth.
Org. Chem., Jpn. 2001, 59, 569. For recent syntheses of 3
and/or 4, see: (b) Kobayashi, S.; Ueno, M.; Suzuki, R.;
Ishitani, H. Tetrahedron Lett. 1999, 40, 2175.
(c) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.; Kim,
H.-S.; Wataya, Y. J. Org. Chem. 1999, 64, 6833.
(d) Takeuchi, Y.; Abe, H.; Harayama, T. Chem. Pharm. Bull.
1999, 47, 905. (e) Takeuchi, Y.; Hattori, M.; Abe, H.;
Harayama, T. Synthesis 1999, 1814. (f) Takeuchi, Y.;
Azuma, K.; Takakura, K.; Abe, H.; Harayama, T. Chem.
Commun. 2000, 1643. (g) Okitsu, O.; Suzuki, R.;
Kobayashi, S. Synlett 2000, 989. (h) Taniguchi, T.;
Ogasawara, K. Org. Lett. 2000, 2, 3193. (i) Takeuchi, Y.;
Azuma, K.; Takakura, K.; Abe, H.; Kim, H.-S.; Wataya, Y.;
Harayama, T. Tetrahedron 2001, 57, 1213. (j) Ooi, H.;
Synlett 2006, No. 20, 3395–3398 © Thieme Stuttgart · New York

3398
T. Oshitari, T. Mandai
LETTER
(13) For recent reviews, see: (a) Breit, B.; Seiche, W. Synthesis
2001, 1. (b) Breit, B. Acc. Chem. Res. 2003, 36, 264. For
syntheses of piperidines through Rh-catalyzed
7.3 Hz, 1 H), 7.15 (dt, J = 1.5, 8.2 Hz, 1 H), 7.20–7.31 (m,
5 H). 13C NMR (free base, CDCl3): d = 20.4, 28.2, 46.7, 47.8,
54.7, 54.8, 64.0, 109.8, 120.0, 126.3, 126.5, 127.8, 128.2,
129.6, 142.4, 157.6.
hydroformylation, see: (c) Ojima, I.; Tzamarioudaki, M.;
Eguchi, M. J. Org. Chem. 1995, 60, 7078. (d) Ojima, I.;
Iula, D. M.; Tzamarioudaki, M. Tetrahedron Lett. 1998, 39,
4599. (e) Ojima, I.; Vidal, E. S. J. Org. Chem. 1998, 63,
7999.
(20) Protection of C3-hydroxyl group as a benzoate was of choice
for the subsequent hydroformylation.
(21) Compound 13: colorless viscous oil; [a]D24 –152.3 (c = 1.02,
CHCl3). 1H NMR (CDCl3): d = 1.25 (br s, 6 H), 1.40–1.55
(br m, 3 H), 2.05–2.25 (m, 1 H), 2.40 (m, 1 H), 4.83 (br m,
0.33 H), 4.93 (br m, 0.67 H), 5.40 (br m, 0.33 H), 5.46–5.63
(m, 1.67 H), 7.00–7.35 (m, 6 H), 7.40 (m, 2 H), 7.55 (m, 1
H), 7.90 (m, 2 H). 13C NMR (CDCl3): d = 23.7, 24.0, 27.9,
28.2, 56.0, 57.3, 69.2, 81.3, 100.4, 126.1, 126.4, 127.5,
127.6, 128.0, 128.35, 128.38, 129.69, 129.71, 129.8, 133.1,
138.6, 152.3, 165.6. Anal. Calcd for C23H25NO4: C, 72.80;
H, 6.64; N, 3.69. Found: C, 72.76; H, 6.84; N, 3.66.
(22) Five-membered aminals (4%) were also isolated.
(23) Compound 14: colorless viscous oil; [a]D22 +56.7 (c = 1.3,
(14) {[3,3¢-di-tert-Butyl-2¢-(diphenoxymethoxy)-5,5¢-
dimethoxybiphenyl-2-yl]oxy}dibenzo[d,f][1,3]dioxepine.
(a) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. U. S. Patent,
4668651, 1987. (b) Billig, E.; Abatjoglou, A. G.; Bryant, D.
R. U. S. Patent, 4769498, 1988. (c) Cuny, G. D.; Buchwald,
S. L. J. Am. Chem. Soc. 1993, 115, 2066.
(15) Five-membered N-Boc-enamide (2%) and five-membered
N-Boc-aminals (5%) were also isolated after the treatment
with CSA. N-Ts-enamide and N-Ts-aminals were not
obtained at all.
(16) Compound 10: colorless foam; [a]D22 –206.0 (c = 1.00,
CHCl3). 1H NMR (CDCl3): d = 1.21 (br s, 6.3 H), 1.41 (br s,
2.7 H), 1.77–1.85 (m, 1 H), 1.89–2.10 (br m, 1 H), 2.45 (s, 3
H), 3.87 (m, 1 H), 3.97 (d, J = 10.1 Hz, 1 H), 4.71 (br, 0.3
H), 4.78 (br, 0.7 H), 4.98 (br, 0.7 H), 5.15 (br, 0.3 H), 6.89–
7.22 (m, 2 H), 7.28–7.38 (m, 5 H), 7.78 (m, 2 H). 13C NMR
(CDCl3): d = 21.6, 25.5, 26.1, 27.9, 28.2, 49.8, 57.5, 58.9,
77.2, 81.3, 81.5, 101.0, 126.2, 126.6, 127.0, 128.0, 128.5,
129.9, 137.3, 137.7, 138.1, 143.7, 152.1. Anal. Calcd for
C23H28N2O4S: C, 64.46; H, 6.59; N, 6.54. Found: C, 64.37;
H, 6.71; N, 6.54.
(17) In the absence of TBAI, the N-alkylation was very slow at
0 °C. Compound 12, however, was afforded in 81% yield at
r.t. in 5 h with the significant loss of enantiomeric purity
(77% ee), which was probably caused by the elimination–
addition sequence of the N-2-methoxybenzyl-tert-butyl
carbamoyl group.
CHCl3) {Lit.1g [a]D15 +53.77 (c = 1.0, CHCl3); Lit.2d [a]D
25
+38.30 (c = 1.92, CHCl3)}. 1H NMR (CDCl3): d = 1.37 (s, 9
H), 1.54–1.62 (m, 1 H), 1.69 (m, 1 H), 1.76–1.87 (m, 3 H),
3.04 (m, 1 H), 4.01 (dd, J = 5.8, 12.8 Hz, 1 H), 4.09 (m, 1 H),
5.32 (d, J = 5.8 Hz, 1 H), 7.27 (m, 1 H), 7.37–7.32 (m, 2 H),
7.45 (m, 2 H). 13C NMR (CDCl3): d = 23.1, 27.7, 28.3, 39.5,
59.3, 70.1, 79.9, 127.2, 128.4, 138.5, 155.4. Anal. Calcd for
C16H23NO3: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.21; H,
8.59; N, 4.77. The enantiomeric purity of 14 was determined
to be >99% ee by HPLC [CHIRALCEL OJ-H; hexane–i-
PrOH = 9:1; l = 220 nm; flow rate: 1.0 mL/min; tR(14) =
4.80 min; tR(ent-14) = 5.75 min].
(24) Compound 15: colorless oil; [a]D23 +43.3 (c = 1.60, CHCl3)
{Lit.1g [a]D28 +36.90 (c = 1.0, CHCl3)}. 1H NMR (CDCl3):
d = 1.46 (s, 9 H), 1.58–1.76 (m, 2 H), 1.94–2.05 (m, 2 H),
2.77 (ddd, J = 3.3, 13.4, 13.4 Hz, 1 H), 3.88 (m, 1 H), 3.95
(dd, J = 3.3, 13.4 Hz, 1 H), 4.71 (d, J = 12.5 Hz, 1 H), 4.75
(d, J = 12.5 Hz, 1 H), 5.70 (br s, 1 H), 7.25–7.36 (m, 3 H),
7.54 (br s, 1 H), 7.56 (br s, 1 H), 7.71 (br s, 2 H), 7.78 (br s,
1 H). 13C NMR (CDCl3): d = 24.2, 25.8, 28.4, 39.2, 55.4,
69.1, 78.7, 80.1, 121.4 (m), 123.3 (q, J = 272 Hz), 127.0,
127.2, 128.28, 128.32, 131.6 (q, J = 32.9 Hz), 138.0, 141.0,
155.3. The enantiomeric purity of 15 was determined to be
>99% ee by HPLC [CHIRALPAK IA; hexane–i-PrOH =
30:1; l = 220 nm; flow rate: 0.3 mL/min; tR(15)= 14.1 min;
tR(ent-15) = 16.6 min)].
(18) Compound 12: colorless foam; [a]D21 –105.2 (c = 1.32,
CHCl3). 1H NMR (CDCl3): d = 1.19–1.70 (m, 21 H), 1.85 (br
m, 1 H), 3.14 (br m, 1 H), 3.33 (br m, 1 H), 3.65 (s, 3 H), 3.75
(br m, 0.45 H), 3.99–4.10 (m, 1.65 H), 4.25 (br m, 0.45 H),
4.50 (br m, 0.45 H), 5.45 (br s, 0.9 H), 5.64 (br s, 0.1 H), 6.71
(m, 1 H), 6.86 (m, 1 H), 7.03 (m, 1 H), 7.12 (m, 1 H), 7.37–
7.25 (m, 5 H). 13C NMR (CDCl3): d = 22.4, 24.6, 28.2, 41.0,
41.6, 42.1, 55.1, 56.2, 57.0, 57.5, 77.2, 79.6, 109.8, 120.2,
126.4, 127.0, 128.0, 128.4, 140.2, 141.2, 155.9. Anal. Calcd
for C29H40N2O5: C, 70.13; H, 8.12; N, 5.64. Found: C, 69.90;
H, 8.28; N, 5.54. The enantiomeric purity of 12 was
determined to be >99% ee by HPLC [CHIRALCEL OD;
hexane–i-PrOH = 30:1; l = 220 nm; flow rate: 1.0 mL/min;
tR(12) = 6.8 min; tR(ent-12) = 11.0 min].
(25) L-733,060 (2): 1H NMR (free base, CDCl3): d = 1.53 (m, 1
H), 1.66–1.75 (m, 1 H), 1.88 (m, 1 H), 2.22 (br d, J = 14.0
Hz, 1 H), 2.85 (ddd, J = 3.1, 12.5, 12.5 Hz, 1 H), 3.29 (m, 1
H), 3.68 (br m, 1 H), 3.85 (d, J = 1.2 Hz, 1 H), 4.13 (d, J =
12.5 Hz, 1 H), 4.52 (d, J = 12.5 Hz, 1 H), 7.25–7.29 (m, 1 H),
7.30–7.35 (m, 2 H), 7.35–7.39 (m, 2 H), 7.44 (br s, 2 H), 7.69
(br s, 1 H). 13C NMR (free base, CDCl3): d = 20.5, 28.4, 47.1,
64.2, 70.0, 77.3, 121.1 (hept, J = 4.1 Hz), 123.2 (q, J = 271
Hz), 126.7, 127.0, 127.4 (m), 128.1, 131.2 (q, J = 32.9 Hz),
141.2, 141.9.
(19) (+)-CP-99,994 (1): 1H NMR (free base, CDCl3): d = 1.40 (br
d, J = 13.2 Hz, 1 H), 1.60 (m, 1 H), 1.76 (br s, 2 H), 1.93 (m,
1 H), 2.14 (br d, J = 13.1 Hz, 1 H), 2.76–2.83 (m, 2 H), 3.27
(m, 1 H), 3.41 (d, J = 13.8 Hz, 1 H), 3.44 (s, 3 H), 3.67 (d,
J = 13.8 Hz, 1 H), 3.88 (d, J = 2.1 Hz, 1 H), 6.68 (br d, J =
8.2 Hz, 1 H), 6.80 (br t, J = 7.3 Hz, 1 H), 6.97 (dd, J = 1.5,
Synlett 2006, No. 20, 3395–3398 © Thieme Stuttgart · New York