An asymmetric synthesis of the novel H3 agonist (+)-(3R,4R)-3-(4-imidazolyl)-4-methylpyrrolidine dihydrochloride (Sch 50971)

Article abstract of DOI:10.1016/S0957-4166(00)00380-3

A short, high yielding, enantioselective synthesis of the novel H₃ agonist Sch 50971 1 is described. The key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin. Copyright (C) 2000 Elsevier Scie

Full text of DOI:10.1016/S0957-4166(00)00380-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3867–3871
An asymmetric synthesis of the novel H3 agonist
(+)-(3R,4R)-3-(4-imidazolyl)-4-methylpyrrolidine
dihydrochloride (Sch 50971)
Robert Aslanian,a,* Gary Lee,b,* Radha V. Iyer,b Neng-Yang Shih,a John J. Piwinski,a
Richard W. Draperb and Andrew T. McPhailc
aDepartment of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth,
NJ 07033, USA
bDepartment of Chemical Process Development, Schering-Plough Research Institute, 2015 Galloping Hill Road,
Kenilworth, NJ 07033, USA
cDepartment of Chemistry, P. M. Gross Chemical Laboratory, Duke University, Durham, NC 27708, USA
Received 30 August 2000; accepted 1 September 2000
Abstract
A short, high yielding, enantioselective synthesis of the novel H3 agonist Sch 50971 1 is described. The
key enantiodifferentiating step is the 1,4-addition of a chiral N-propionyloxazolidinone to a nitroolefin.
© 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The histamine H3 receptor is a presynaptic autoreceptor that controls the release of histamine
as well as other neurotransmitters such as serotonin, noradrenaline and acetylcholine.1 Although
the therapeutic applications of agonists and antagonists of the H3 receptor have yet to be fully
elucidated, potential areas of interest include obesity, Alzheimer’s disease, attention deficit/
hyperactivity disorder, sleep related disorders, and migraine.2,3 We recently described a new
class of H3 agonists exemplified by the chiral pyrrolidine (+)-(3R,4R)-3-(4-imidazolyl)-4-
methylpyrrolidine, dihydrochloride (Sch 50971, 1).4 Compound 1 is a potent ligand in vitro (Ki
(H3)=2.3 nM, pD2=7.5) and in vivo (ED50=0.3 mg/kg) and is selective for the H3 receptor over
the H1 and H2 receptors (Ki (H1)>10 000 nM, pD2<4.0, ED50>100 mg/kg; pD2 (H2)<3).4,5
Furthermore, 1 is effective at potentiating pentobarbital-induced sleep in the guinea pig
(ED40=7 mg/kg orally), a measure of the sedation profile of a compound.6 Although the
synthesis of 1 was previously reported,4 we required a more practical route to 1 that would
* Corresponding authors. Fax: (908) 740-7152; e-mail: robert.aslanian@spcorp.com
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00380-3

3868
R. Aslanian et al. / Tetrahedron: Asymmetry 11 (2000) 3867–3871
provide sufficient quantities of material to further define its biological and pharmacokinetic
parameters. This paper describes an approach to the synthesis of 1 which utilizes the asymmetric
Michael addition of a chiral acylated oxazolidinone to a substituted nitroolefin to set the
required absolute stereochemistry at the adjacent chiral centers in 1.
2. Chemistry
Compound 1 was initially obtained by resolution of its racemic di-t-Boc derivative using a
Chiralcel OD column followed by removal of the Boc groups. Single-crystal X-ray analysis of
this material demonstrated that 1 possesses the (3R,4R) configuration. Using this approach, we
were able to obtain sufficient amounts of 1 for our preliminary biological investigations.
However, chromatographic resolution was far from ideal for the synthesis of larger amounts of
1 since 50% of the material was lost in the resolution step. Therefore, we set out to develop a
more efficient enantioselective approach to 1. Chiral pyrrolidines are a common structural motif
and, consequently, there are a number of approaches reported for their synthesis.7 One method
in particular seemed amenable to the problem at hand. Mulzer and co-workers found that
addition of the sodium enolate of the chiral oxazolidinone 2 to a b-substituted nitroolefin
proceeded with good diastereoselectivity (94:6) at the b-center to give the adduct 3 in 65% yield
(Scheme 1).8 This intermediate was further transformed into the chiral pyrrolidinone Rolipram.
Scheme 1.
The application of a similar strategy to our synthesis of 1 would involve the use of the chiral
propionate oxazolidinone 4 thus requiring complete stereocontrol of both the a and the b
stereogenic centers. In fact, Evans has shown excellent stereocontrol of the a center in chiral
propionate additions to several Michael acceptors using TiCl3(Oi-Pr).9 However, he reports this
methodology did not show any control over the b stereogenic center in the addition to prochiral
a,b-unsaturated ketones. Regardless, given the precedent for excellent control of the b center
with nitroolefins with the Rolipram synthesis, we sought to investigate the feasibility of the
Evans chiral propionate in the Michael addition to nitroolefins toward the preparation of 1.

R. Aslanian et al. / Tetrahedron: Asymmetry 11 (2000) 3867–3871
3869
Our initial attempt at effecting the Michael reaction of oxazolidinone 4 with nitroolefin 5
utilized the conditions originally outlined by Evans and co-workers for the Michael addition of
an oxazolidinone to an a,b-unsaturated ester, nitrile or ketone [Eq. (1), TiCl3(Oi-Pr), diiso-
propylethylamine (DIPEA), CH2Cl2].9 Utilizing two equivalents of the enolate led to a reason-
able chemical yield of the desired product 6 and moderate diastereoselectivity (entry 1, Table 1).
A study was then undertaken in which the transition metal, ligand stoichiometry, temperature,
and solvent conditions were varied to improve the diastereoselectivity of the reaction. Use of
DMF as co-solvent ensured homogeneity of the reaction, but led to no addition product (entry
2). Use of other solvents and bases had a deleterious effect on the product yields (entries 3–6),
while reversing the order of addition of TiCl4, Ti(Oi-Pr)4, and oxazolidinone resulted in a less
stereoselective reaction (entry 7). We next investigated the effect that the metal and ligand ratio
had on the selectivity of the reaction. The boron enolate gave high diastereoselectivity with
rather modest yields (entry 8). Varying the chloride:isopropoxide ratio on titanium from 4:0 to
3:1 to 1:1 suggested a trend toward greater diastereoselectivity with increasing number of
isopropoxide ligands (entries 10, 1, 11). The maximum selectivity was obtained utilizing
TiCl2(Oi-Pr)2, which provided a 12:1 diastereomer ratio (entry 11). The optimum conditions
determined by this study were the use of TiCl2(Oi-Pr)2 at 4°C in CH2C12, with DIPEA as base
to give 6 and 7 in a 16:1 ratio and 77% yield (entry 13).10 Purification of the crude material by
crystallization from isopropanol/hexane raised the ratio of 6:7 to 22:1.
(1)
Table 1
Entry
Solvent
TiCl4/Ti(Oi-Pr)4
Temp.
R3Na
% Yield
6:7b
1
2
3
4
5
6
7
8
9
10
11
12
13
CH2Cl2
CH2Cl2/DMF
DME
C6H5Cl
CHCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3:1
3:1
3:1
3:1
3:1
3:1
0°C“rt
0°C“rt
0°C“rt
0°C“rt
0°C“rt
0°C“rt
0°C“rt
0°C“rt
0“15°C
0°C“rt
0°C“rt
0°C“rt
0“4°C
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
TEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
77
0
0
5
0
49
50
33
75
80
76
10
77
6:1
–
–
6:1
–
5:1
3:2
10:1
9:1
3:2
12:1
–
3:1c
BBu2Tf
3:1
4:0
1:1
1:3
1:1
16:1
a DIPEA=diisopropylethylamine, TEA=triethylamine.
b Product ratios were determined by HPLC and NMR.
c Inverse addition.

3870
R. Aslanian et al. / Tetrahedron: Asymmetry 11 (2000) 3867–3871
The completion of the asymmetric synthesis of 1 is given in Scheme 2. The Michael product
6 was reductively cyclized with no change in the diastereomer ratio to give compound 8 in 72%
yield. Although reduction of the lactam could be accomplished by a number of different
reagents such as LAH, RedAl, borane–methyl sulfide, or borane–methyl sulfide/BF3·Et2O, LAH
was the most effective giving 9 in 88% yield. Deprotection of 9 gave 1 as a hygroscopic white
powder in 69% yield after crystallization from isopropanol/hexane.11
Scheme 2. (a) Ra-Ni, H2, EtOH, 72%; (b) LAH, THF, 88%; (c) 4N HCl, 69%
3. Conclusion
In conclusion, we have found that Evans’ chiral propionate derivatives give excellent
enantioselective and diastereoselective control in the addition to nitroolefins. The application of
this methodology toward preparing the novel H3 agonist 1 resulted in the development of a
practical, high yielding synthesis which has allowed for the production of over 0.6 kg of 1 to
support preclinical and toxicological studies.
References
1. For reviews of the H3 receptor see, for example: (a) Hill, S. J.; Ganellin, C. R.; Timmerman, H.; Schwartz, J. C.;
Shankley, N. P.; Young, J. M.; Schunack, W.; Levi, R.; Haas, H. L. Pharmacol. Rev. 1997, 49, 253; (b) Leurs,
R.; Vollinga, R. C.; Timmerman, H. In Progress in Drug Research; Jucker, J., Ed.; Birkhauser: Basel, 1995; Vol.
45, pp. 107–165. (c) Leurs, R.; Smit, M. J.; Timmerman, H. Pharmacol. Ther. 1995, 66, 413.
2. Leurs, R.; Blandina, P.; Tedford, C.; Timmerman, H. TiPS 1998, 19, 177.
3. Matsubara, T.; Moskowitz, M. A.; Herang, Z. Eur. J. Pharmacol. 1992, 224, 145.
4. Shih, N.-Y.; Aslanian, R.; Lupo, A. T.; Orlando, S.; Piwinski, J. J.; Green, M. J.; Ganguly, A. K.; West, R.;
Tozzi, S.; Kreutner, W.; Hey, J. A. Bioorg. Med. Chem. Lett. 1998, 8, 243.
5. Hey, J. A.; Aslanian, R.; Bolser, D. C.; Chapman, R. W.; Egan, R. W.; Rizzo, C. A.; Shih, N.-Y.; Fernandez,
X.; McLeod, R. L.; West, R.; Kreutner, W. Arzneim.-Forsch/Drug Res. 1998, 48, 881.
6. McLeod, R. L.; Aslanian, R.; Del Prado, M.; Duffy, R.; Egan, R. W.; Kreutner, W.; McQuade, R.; Hey, J. A.
J. Pharmacol. Exp. Ther. 1998, 287, 43.
7. See, for example: (a) Meyers, A. I.; Fray, A. H. Bull. Soc. Chim. Fr. 1997, 134, 283–298; (b) Denmark, S. E.;
Marcin, L. R. J. Org. Chem. 1995, 60, 3221–3225; (c) Chastanet, J.; Fathallah, H.; Negron, G.; Roussi, G.
Heterocycles 1992, 34, 1565–1572; (d) Hirai, Y.; Terada, T.; Yamazaki, T.; Momose, T. J. Chem. Soc., Perkin
Trans. 1 1992, 509–516; (e) Calderari, G.; Seebach, D. Helv. Chim. Acta 1985, 68, 1592–1604.
8. Mulzer, J.; Zuhse, R.; Schmiechen, R. Angew. Chem., Int. Ed. Engl. 1992, 31, 870–872.
9. Evans, D. A.; Bilodeau, M. T.; Somers, T. C.; Clardy, J.; Cherry, D.; Kato, Y. J. Org. Chem. 1991, 56,
5750–5752.
10. A typical procedure is as follows: TiCl4 (1.3 mol, 143 mL) was added dropwise to an ice-cold solution of
Ti(Oi-Pr)4 (1.3 mol, 387 mL) in methylene chloride (4 L). After stirring for 1 hour at this temperature, there was
sequentially added diisopropylamine (2.6 mol, 453 mL), a solution of 4 (2.6 mol, 606 g) in methylene chloride (1.4

R. Aslanian et al. / Tetrahedron: Asymmetry 11 (2000) 3867–3871
3871
L), and a solution of 5 (1.3 mol, 497 g) in methylene chloride (7 L). After stirring overnight at 0–7°C, the reaction
was quenched by the addition of glacial acetic acid (890 mL) and warmed to room temperature over 3 hours.
Water (14 L) was added and the organic layer was separated. The aqueous layer was extracted a further two
times with methylene chloride (500 mL each). The combined organic layers were washed sequentially with water
(10 L), saturated aqueous sodium bicarbonate (5 L), and brine (5 L). The organic layer was dried (MgSO4),
filtered, and concentrated to give an oil which was crystallized from 1:1 hexane:ethyl acetate to give compound
6 (488 g) as a white solid. The mother liquor from the crystallization was passed through a silica plug (load, 2:1;
10“50% EtOAc/hexane) and crystallized as above to give additional 6 (113 g, total yield 601 g, 75%). M.p.
82–92°C; IR (film) 1735, 1700, 1550, 1390, 1245 cm−1 1H NMR (400 MHz, DMSO) l 7.47–7.26 (15H, m),
;
7.10–7.07 (6H, m), 6.86 (1H, d, J=1.3 Hz), 4.95 (1H, dd, J=10.2, 12.4 Hz), 4.84 (1H, dd, J=4.5, 12.5 Hz),
4.71–4.67 (1H, m), 4.35 (1H, t, J=8.4 Hz), 4.20 (1H, dd, J=3.1, 8.8 Hz), 4.08 (1H, p, J=7.0 Hz), 3.90–3.86 (1H,
m), 3.09 (1H, dd, J=3.3, 10.1 Hz), 2.81 (1H, dd, J=8.8, 13.8 Hz), 2.57 (1H, p, J=1.8 Hz), 1.06 (3H, d, J=7.0
Hz); 13C NMR (75 MHz, CD3OD) l 174.971, 152.880, 142.204, 139.033, 136.874, 135.349, 129.673, 129.362,
128.933, 128.061, 128.049, 127.310, 120.238, 77.489, 75.293, 66.165, 55.463, 40.211, 39.540, 38.015, 15.563;
HRMS [FAB] calcd for C37H35O5N4 [M+H]+=615.2607; found 615.2626; [h]2D5 =−46.7 (c=0.5, MeOH).
1
11. Analytical data for compound 1: H NMR (300 MHz, CD3OD) l 8.96 (s, 1H), 7.66 (s, 1H), 4.9 (br s, 4 H), 3.84
(dd, J1=11 Hz, J2=7.2 Hz, 1H), 3.70 (dd, J1=11 Hz, J2=7.8 Hz, 1H), 3.4 (m, 2H), 3.1 (t, J=11 Hz, 1H), 2.6
(m, 1H), 1.2 (d, J=6.6 Hz, 3H); 13C NMR (75 MHz, CD3OD) l 135.732, 131.988, 117.840, 52.320, 50.362,
42.205, 40.081, 14.889. LRMS [electrospray] m/z=152 [M+H]+; anal. calcd for C8H15Cl2N3·0.6H2O: C, 40.90; H,
6.95; N, 17.89; found: C, 40.93; H, 6.90; N, 17.62; [h]2D5=+ 43.5 (c=0.34, MeOH).
.
.