morpholine ring. The synthesis of SSR 241586 was planed from
the nucleophilic substitution of alcohol I with the appropriately
substituted piperidine SSR 241579. Alcohol I would be obtained
by homologation of ester II, and the construction of the morpholine
ring would be achieved from the ꢀ-nitro alcohol III, which would
be the result of an enantioselective Henry reaction applied to R-keto
ester IV (Scheme 1).
Scheme 2. Synthesis of the Optically Active Intermediate (R)-4
Scheme 1. Retrosynthesis of SSR 241586
the corresponding amino alcohol 5. Under hydrogenation condi-
tions, using Raney nickel (H2, Raney Ni/EtOH), a retro-Henry
reaction was observed. On the contrary, when the reduction of the
nitro group was performed using zinc dust in acetic acid, the amino
alcohol 5 was isolated without any racemization. N-Acetylation
of the resulting primary amine (ClCH2COCl, Et3N, CH2Cl2, rt, 4 h)
produced amide 6 (99%) which, after treatment with NaH, afforded
the cyclic amide 7 in 75% yield and with an enantiomeric excess
of 96%. The amide and ester groups were reduced by BH3·THF
(6 equiv, THF, reflux, 3 h) to produce the 2,2-disubstituted
morpholine 8 in 88% yield (Scheme 3).
In order to synthesize SSR 241586, compound 8 has to
be transformed to its homologue 11. Thus, 8 was treated
with di-tert-butyl dicarbonate (Boc2O, Et3N, MeOH, rt, 16 h)
to produce the N-protected morpholine 9 (93% yield). An
oxidation step [Dess-Martin periodinane (DMP), CH2Cl2,
rt, 1 h] followed by a Wittig reaction (KHMDS, BrPPh3CH3,
THF) provided olefin 10 (82% for the two steps), and after
an oxidative hydroboration (BH3·Me2S, then H2O2, NaOH),
alcohol 11 was isolated in 64% yield. In order to introduce
the N-benzoyl group present in the final product, a depro-
tection/protection step was achieved.
The synthesis of SSR 241586 started with the transforma-
tion of commercially available ethyl chlorooxoacetate (1) to
ethyl R-oxo-1H-imidazole-1-acetate (2).8 When 2 was treated
with 3,4-dichlorophenylmagnesium bromide, the desired
R-keto ester 3 was isolated in 74% yield. An organo-
catalyzed Henry reaction was subsequently applied to R-keto
ester 3. Quinine-derived compound A was chosen as the
appropriate catalyst due to its ability to furnish Henry adducts
with high enantiomeric excess on a broad range of sub-
strates.9 Thus, treatment of 3 with nitromethane (10 equiv)
in the presence of catalyst A (5 mol %) in CH2Cl2 at
-20 °C produced ꢀ-nitro alcohol 410 in 76% yield and with
an enantiomeric excess of 96% (Scheme 2).
The synthesis of the morpholine ring was achieved in four steps
from nitro alcohol 4. At first, this latter was selectively reduced to
Thus, N-tert-butyl carbamate 11 was treated with TFA (CH2Cl2,
rt, 1 h), and the resulting morpholine was then transformed into
the N-benzoylmorpholine 13 (PhCOCl, Et3N, CH2Cl2, rt, 1.25 h)
in 45% yield (for the two steps) (Scheme 4).
(3) (a) Emonds-Alt, X.; Proietto, V.; Steinberg, R.; Oury-Donzt, F.; Vige´,
X.; Vilain, P.; Naline, E.; Daoui, S.; Advenier, C.; Le Fur, G.; Maffrand,
J.-P.; Soubrie´, P.; Pascal, M. J. Pharmacol. Exp. Ther. 2002, 303, 1171–
1179. (b) Steinberg, R.; Alonso, R.; Rouquier, L.; Desvignes, C.; Michaud,
J.-C.; Cudennec, A.; Jung, M.; Simiand, J.; Griebel, G.; Emonds-Alt, X.;
Le Fur, G.; Soubrie´, P. J. Pharmacol. Exp. Ther. 2002, 303, 1180–1188.
(4) Takemoto, T.; Iio, Y.; Nishi, T. Tetrahedron Lett. 2002, 41, 1785–
1788, and references cited therein.
We have to point out that the straightforward access to SSR
241586 from 8, by transforming the latter in N-benzoylmor-
pholine, was not possible. Indeed, after transformation of 8 to
N-benzoylmorpholine 9′, this compound was converted to olefin
10′ in two steps (DMP, CH2Cl2; BrPPH3CH3, t-BuOK, THF),
but unfortunately, the oxidative hydroboration of 10′ was not
successful as 13 was not formed (Scheme 5).
The formation of SSR 241586 was completed from 13 in
two steps. After mesylation (MsCl, Et3N, CH2Cl2, rt, 1 h)
and treatment of the resulting mesylate with piperidine SSR
(5) Nishi, T.; Ishibashi, K.; Nakajima, K.; Iio, Y.; Fukazawa, T.
Tetrahedron: Asymmetry 1998, 9, 3251–3262.
(6) Okachi, T.; Murai, N.; Onaka, M. Org. Lett. 2003, 5, 85–87.
(7) Takamura, M.; Yabu, K.; Nishi, T.; Yanagisawa, H.; Kanai, M.;
Shibasaki, M. Synlett 2003, 353–356.
(8) Nimitz, J. S.; Mosher, H. S. J. Org. Chem. 1981, 46, 211–213.
(9) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732–733.
(10) The (R) absolute configuration of the stereogenic center was
determined by comparison of the [R]D to a previously described compound.
See the Supporting Information for details. Nicewicz, D. A.; Yates, C. M.;
Johnson, J. S. J. Org. Chem. 2004, 69, 6548–6555.
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Org. Lett., Vol. 12, No. 16, 2010
Cochi, Anne
