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COMMUNICATION
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catalyst L2. A screening of Lewis acid showed a remarkable
influence on the reaction outcome (entries 7-14). In particular,
catalytic amounts of Er(OTf)3 afforded compound 8b with a
good yield and a high regio- and stereoselectivity (entry 13).
Racemic threo-methylphenidate hydrochloride (Ritalin) is a mild
nervous system stimulant and the eutomer (2R, 2’R) is known
to be 5 to 38 times more active than its enantiomer.
Notwithstanding its clinical significance, to our knowledge, only
one catalytic asymmetric synthesis has been so far described.14
The optimized reaction conditions developed by us for an
effective generation of 5,6-dihydropyridinium ion starting from
pro-electrophile 7 afforded 1,2,5,6-tetrahydropyridine 8b-Ac
with an excellent regioselectivity and a high stereoselectivity.
After chromatographic purification, single diastereoisomer 8b-
Ac-syn (93 % ee) was easily converted into threo (2R, 2’R)-N-
Boc-ritalinol 10,15 which is a known precursor to threo-(2R, 2’R)
methylphenidate hydrochloride 11 (Scheme 1).15,16
DOI: 10.1039/C5CC04416B
Meng, C. Li, H. Lou, and L. Liu, Angew. Chem. Int. Ed., 2015, 54,
6012.
(a) E. Ichikawa, M. Suzuki, K. Yabu, M. Albert, M. Kanai, and M.
Shibasaki, J. Am. Chem. Soc., 2004, 126, 11808; (b) E. L. Myers, J.
G. de Vries, and V. K. Aggarwal, Angew. Chem. Int. Ed., 2007, 46,
1893; (c) Z. Sun, S. Yu, Z. Ding, and M. Da, J. Am. Chem. Soc.,
2007, 129, 9300; (d) D. A. Black, R. E. Beveridge, and B. A.
Arndtsen, J. Org. Chem., 2008, 73, 1906; (e) M. A. Fernández-
Ibáñez, B. Maciá, M. G. Pizzuti, A. J. Minnard, and B. L: Feringa,
Angew. Chem. Int. Ed., 2009, 48, 9339; (f) C. Nadeau, S. Aly, and
K. Belyk, J. Am. Chem. Soc., 2011, 133, 2878; (g) S. T Chau, J. P.
Lutz, K. Wu, and A. G. Doyle, Angew. Chem. Int. Ed., 2013, 52,
9153; (h) S.-L Shi, X.F. Wei, Y. Shimizu, and M. Kanai, J. Am.
Chem. Soc., 2012, 134, 17019; (i) M. Hussain, T. S.-L. Banchelin,
H. Andersson, R. Olsson, and F. Almqvist, Org. Lett., 2013, 15,
54.
M. R. Monaco, P. Renzi, D. M. Scarpino Schietroma, and M.
Bella, Org. Lett., 2011, 13, 4546.
Reviews: (a) A. E. Allen, and D. W. MacMillan, Chem. Sci., 2012,
3, 633; (b) Z. Du, and Z. Shao, Chem. Soc. Rev., 2013, 42, 1337;
(c) A. Gualandi, L. Mengozzi, C. M. Wilson, and P. G. Cozzi,
Chem. Asian. J., 2014, 9, 984.
6
7
1)Er(OTf)3(20 mol%)
α/γ = 98/2
syn/anti 90/10
OH
L2 (20 mol%), PhCH2CHO
toluene, 0 °C, 1h
2) NaBH4, MeOH, 0°C, 40 min
3) Ac2O, Py
8
9
S. Crotti, F. Berti, and M. Pineschi, Org. Lett., 2011, 13, 5152.
In accordance with the literature, the TMS cleavage of the
diarylprolinol silyl ether was not observed in these reaction
conditions. See: M. H. Haindl, M. B. Schmid, K. Zeitler, and R. M.
Gschwind, RSC Adv., 2012, 2, 5941.
N
OAc
N
Cbz Ph
Cbz
8b-Ac, 78%, 93% ee
7
1)
H2/Pd(C)
MeOH rt, 8 h
O
10 The relative configuration of 1,2 adducts 3aa-syn (major
product) and 3aa-anti (minor product) was initially assigned by
1H and 13C NMR after oxidation (NaClO2/H2O2) to similar known
carboxylic acid derivatives: A. Schmidt, D. Michalik, S. Rotzoll, E.
Ullah, C. Fischer, H. Reinke, H. Görls, and P. Langer, Org. Biomol.
Chem., 2008, 6, 2804 (see ESI for details).
ref. 16
8b-Ac-syn
2) Boc2O, THF, NEt3
3) NaOH, MeOH
N
OH
N
H
O
HCl
Boc Ph
Ph
11
(2R, 2'R)-Ritalin
10
(50% overall from 7)
11 CCDC 1057075. An X-ray diffraction study on a single crystal of
5dc led to the molecular structure shown in Figure 1. In the
measurement, performed at room temperature, a certain
degree of conformational disorder was present in the ethoxyl
group. The conformation of the rest of the molecule is affected
by the hydrogen interaction between O(3) and O(1), the
O(3)···O(1) distance being 2.911(4) Å. The absolute
configuration R,R of the chiral centers C(5) and C(13) was
established on the basis of the Flack’s parameter (0.017(11)).
12 For NMR study of the formation of prolinol ether enamine with
propanal, see: M. B. Schmid, K. Zeitler, and R. M. Gschwind, J.
Am. Chem. Soc., 2011, 133, 7065.
Scheme 1. Short asymmetric formal synthesis of threo-
methylphenidate.
To sum up, we have successfully developed mild, fast and
highly enantioselective organocatalyzed α-alkylations of
aldehydes with quinolinium and dihydropyridinium ions. The
methodology uses easily available pro-electrophiles activated in
situ with Lewis or Brønsted acids and allows the unprecedented
syntheses
of
carbamoyl
dihydroquinoline
and
tetrahydropyridine derivatives with introduction of chirality at
the attacking carbon framework.
13 See ESI for details and expanded Table.
14 H. M. L. Davies, T. Hansen, D. W. Hopper, and S. A. Panaro, J.
Am. Chem. Soc., 1999, 121, 6509.
15 The optical rotatory power for this compound was [α]D20= +11.2
(c= 1.5, CH2Cl2) with respect to [α]D20= +12.4 (c= 2.20, CH2Cl2)
reported in: D. L. Thai, M. T. Sapko, C. T. Reiter, D. E. Bierer, and
J. M. Perel, J. Med. Chem., 1998, 41, 591.
We acknowledge the financial support from the University of
Pisa.
16 M. Prashad, H.-Y., Kim, Y. Lu, Y. Liu, D. Har, O. Repic, T. J.
Blacklock, and P. Giannousis, J. Org. Chem., 1999, 64, 1750.
Notes and references
1
Review: Y. S. Lee, M. M. Alam, and R. S. Keri, Chem. Asian J.,
2013, 8, 2906.
2
(a) J. Zhang, B. Tiwari, C. Xing, X. Chen, and Y. R. Chi, Angew.
Chem. Int. Ed., 2012, 51, 3649; (b) L. Mengozzi, A. Gualandi, and
P. G. Cozzi, Chem. Sci., 2014, 5, 3915; (c) A. Gualandi, L.
Mengozzi, E. Manoni, and P. G. Cozzi, Catal. Lett., 2015, 145,
398.
3
For example see: I. Kumar, P. Ramaraju, N. A. Mir, D. Singh, V. K.
Gupta, and Rajnikant, Chem. Commun., 2013, 49, 5645 and
references cited therein.
4 | J. Name., 2012, 00, 1-3
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