Stereocontrolled synthesis of trisubstituted cyclopropanes: Expedient, atom-economical, asymmetric syntheses of (+)-bicifadine and DOV21947

Article abstract of DOI:10.1021/ol061650w

An expedient, atom-economical, asymmetric synthesis of 1-aryl-3- azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.

Full text of DOI:10.1021/ol061650w

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3885-3888
Stereocontrolled Synthesis of
Trisubstituted Cyclopropanes:
Expedient, Atom-Economical,
Asymmetric Syntheses of (
and DOV21947
+)-Bicifadine
Feng Xu,* Jerry A. Murry, Bryon Simmons, Edward Corley, Kenneth Fitch,
Sandor Karady, and David Tschaen
Department of Process Research, Merck Research Laboratories,
Rahway, New Jersey 07065
feng_xu@merck.com
Received July 5, 2006
ABSTRACT
An expedient, atom-economical, asymmetric synthesis of 1-aryl-3-azabicyclo[3.1.0]hexanes, including (+)-Bicifadine and DOV21947, in a single-
stage through process without isolation of any intermediates has been developed. The key of this synthesis is the in-depth mechanistic
understanding of the complicated epoxy nitrile coupling at each reaction stage. Therefore, the desired trisubstituted cyclopropane can be
prepared in high ee and yield by controlling the reaction pathway through manipulating the nitrile anion aggregation state.
Bicifadine (1a) is a potent inhibitor of both the serotonin
and norepinephrine reuptake transporters and an N-methyl-
D-aspartate (NMDA) antagonist with a nonnarcotic profile.1
DOV21947 (1b) is a potent triple reuptake inhibitor, blocking
the serotonin, norepinephrine, and dopamine reuptake trans-
porters.2 Bicifadine and DOV21947 are currently undergoing
clinical evaluation1a,2 for the treatment of pain and other
diseases related to these neurotransporters, respectively.
The reported syntheses of Bicifadine and DOV21947 are
racemic and inefficient.1 Asymmetric preparation of these
functionalized cyclopropanes remains a challenging topic,
although several methods have been reported.3 We envi-
sioned that compound 1 could arise from cyclodehydration
of the corresponding cyclopropylamino alcohol 2 which in
turn could come from reduction of the hydroxyl nitrile 3.
This hydroxyl nitrile could potentially be derived from
coupling an appropriately substituted arylacetonitrile with a
chiral halohydrin (Scheme 1).
Similar transformations have been reported,4 although the
protocols are not scalable and attempts to optimize the
conditions have resulted in a poor yield and/or ee.4a As a
(3) For a superb review, see: Lebel, H.; Marcoux, J. F.; Molinaro, C.;
Charette, A. B. Chem. ReV. 2003, 103, 977. For recent examples, see: (a)
Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 3240. (b)
Zheng, J.; Liao, W.; Tang, Y.; Sun, X.; Dai, L. J. Am. Chem. Soc. 2005,
127, 12222. (c) Kim, H. Y.; Lurain, A. E.; Garcia-Garcla, P.; Carroll, P. J.;
Walsh, P. J. J. Am. Chem. Soc. 2005, 127, 13138.
(4) (a) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada, H.;
Yamsihita, K.; Matsuda, A. J. Org. Chem. 1996, 61, 915. (b) For a leading
reference of racemic synthesis, see: Langer, P.; Freifeld, I. Org. Lett. 2001,
3, 3903 and references therein.
(1) (a) Sorbera, L. A.; Castaner, J.; Leeson, P. A. Drugs Future 2005,
30, 7. (b) Epstein, J. W.; Brabander, H. J.; Fanshawe, W. J.; Hofmann, C.
M.; McKenzie, T. C.; Safir, S. R.; Osterberg, A. C.; Cosulich, D. B.; Lovell,
F. M. J. Med. Chem. 1981, 24, 481.
(2) Skolnick, P.; Popik, P.; Janowsk, A.; Beer, B.; Lippa, A. Eur. J.
Pharmacol. 2003, 461, 99; Life Sci. 2003, 73, 3175.
10.1021/ol061650w CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/25/2006

Scheme 1. Retrosynthetic Analysis
Table 1. Counter Metal Ion Effects on Epoxy Nitrile Coupling
metal ion
Na+, K+
bases (2 equiv)
productsa
NaNH2, NaHMDS, NaOtBu,
NaH, KHMDS, KOtBu
n-BuLi, LiHMDS, LDA
3b/7b only
Li+
Major: 5b/8b;
Minor: 3b/7b
8b only
Mg2+
i-PrMgCl, NaHMDS/MgBr2
a All reactions were carried out at -15 °C to room temperature in the
presence of 2 equiv of bases in THF. Isolation of 5b depends on the aging
period. For further discussion on lithium’s aggregates, see more in the text.
of the lithium alkoxide was slow and provided a mixture of
3b, 7b, and 8b;6 (3) the use of sodium or potassium bases
gave solely cyclopropanes in 96% ee, which indicated that
reaction was occurring via attack at C3 of epichlorohydrin
because reaction at C1 would generate the opposite enanti-
omer via ent-6b.
result, we decided to carry out a systematic investigation on
this transformation to gain mechanistic insight and ultimately
to arrive at an optimized, scaleable protocol. Scheme 2
Scheme 2. Pathways to (+)- or (-)-cis/trans-Cyclopropanes
and (()-Cyclobutanes
Further studies revealed that the mode of addition played
a pivotal role to achieve a clean cyclopropanation: the best
conditions involved addition of 1.3 equiv of NaHMDS to a
solution of 4b and (+)-epichlorohydrin at -20 to -15 °C
which afforded 3b/7b (cis/trans ) 85:15) in 95% assay yield
(96% ee).7 Surprisingly, utilizing similar conditions for 4a
(Ar ) p-MePh) proVided the product 3a in only 75% ee.
This striking result encouraged us to further explore the
relationship between the nucleophilicity of arylacetonitrile
anions and the regioselectivity (C1 vs C3 attack on epichlo-
rohydrin) which is reflected in the er of 3 (Figure 1).
Focusing first on the effect of nucleophilicity on enanti-
oselectivity, analysis of Figure 1 provides clear insight that
the more basic carbanion reacts with epichlorohydrin less
selectively7b (C1 vs C3 attack). This trend could reflect subtle
electronic effects on hard/soft selectivity, ion-pairing effects,
and/or changes in solvation of the carbanion with the shifting
of electron density from the nitrile to the aromatic ring with
more electron-withdrawing groups present. As further out-
lined below, this effect is a combination of a solvation/ion-
pairing phenomenon and an electronic effect.
With lithium bases, chlorohydrin 5 is a discrete intermedi-
ate and conversion to epoxide 6 is slow (Table 1). In fact,
the Li-O bond in the aggregates8 is sufficiently strong9 that
lithium alkoxide 5 is unreactiVe at -25 °C.7 Charging an
additional equivalent of NaHMDS to the above reaction
mixture led to cyclobutanes 8/9 (major) at <-15 °C, due to
depicts the challenges for this transformation: (1) to suppress
the competitive C1 attack pathway to form the enantiomer
of 6 (ent-6) and therefore to afford 3 in high ee; (2) to block
formation of cyclobutane 8 via SNi ring closure of 5; (3) to
gain the cis/trans control (3 vs 7) of the SNi epoxide opening
of 6. Herein, we report our understanding of the epoxy nitrile
coupling at each stage, which results in an expedient, atom-
economical, asymmetric synthesis of 1-aryl-3-azabicyclo-
[3.1.0]hexanes.
In an attempt to decouple these factors, the metal coun-
terion effects were first probed utilizing substrate 4b (Ar )
3,4-Cl2Ph) and epichlorohydrin as summarized in Table 1.
Surprisingly, the reaction pathway can be dramatically altered
by the choice of counter metal ion: (1) Mg2+ counterions
provided the achiral, cis/trans-cyclobutanes 8 presumably
through the intermediacy of 5b;5 (2) lithium bases provided
the chlorohydrin 5b at -15 °C; however, subsequent reaction
(5) For an example of magnesium halides as Lewis acids to open epoxide,
see: Corbel, B.; Durst, T. J. Org. Chem. 1976, 41, 3648.
(6) For other examples of using lithium bases, also see: (a) Jeffery, J.
E.; Kerrigan, F.; Miller, T. K.; Smith, G. J.; Tometzki, G. B. J. Chem.
Soc., Perkin Trans. 1 1996, 2583. (b) Kusumoto, T.; Nakayama, A.; Sato,
K.; Hiyama, T.; Takehara, S.; Osawa, M.; Nakamura, K. Chem. Lett. 1992,
2047.
(7) (a) (+)-Epichlorohydrin was 98% ee. (b) See Supporting Information.
(8) For a recent review, see: Fleming, F. F.; Shook, B. C. Tetrahedron
2002, 58, 1. For leading references, see: (a) Reich, H. J.; Biddle, M. M.;
Edmonston, R. J. J. Org. Chem. 2005, 70, 3375. (b) Carlier, P. R.; Lo, C.
W. J. Am. Chem. Soc. 2000, 122, 12819 and references therein.
(9) If the reaction mixture was quenched in aqueous MeCN, 5 was
converted to 6 as promoted by OH- generated from water quenching.
3886
Org. Lett., Vol. 8, No. 17, 2006

Figure 2. Ortho substituent’s effects on cyclopropanation.7 Re-
agents and conditions: 4 f 3/7, NaHMDS, THF, -15 °C.
selectivity, as evidenced by 4k,l vs 4f,h (Figure 1).7,8
However, for substrates 4m vs 4c, the unaffected cis/trans
selectivity is believed to be due to the chelation between
o-OMe and the metal ion.
In an attempt to isolate these parameters and further
understand the selectivity of the intramolecular cyclopropa-
nation, we next studied the isolated epoxide diastereomers
6b and the tosylate 9 which bears a more bulky CH2OTBS
group. Subjecting 6b and 9 to various bases and solvents,7b
we found a turnover in selectivity depending on the solvent
employed in the reaction (Table 2). The more significant
Figure 1. Substituent’s effects on cyclopropanation.7 y-axis )
log[er % or cis %]. Reagents and conditions: (a/b) 4 f 3,
NaHMDS, THF, -15 °C. (c) 4 f 5 f 3 (vide infra), LiHMDS,
t-BuOMe, -25 °C; NaHMDS, THF, -15 °C.
the M-O aggregation change. Alternatively, after removal
of Li+ through aqueous workup, the crude 5a was exposed
to NaHMDS/(MeOCH2)2/THF at -15 °C and afforded the
desired 3a with >97% ee (cis/trans ) 85:15). This strategy
was successfully applied to other substrates such as 4e-g
to obviate the substituent effects on the ee, generating the
cyclopropanes 3e-g in >97% ee (Figure 1, line c).7
Therefore, by changing the counterion, the erosion in ee is
eliminated, indicating that the original trend on nucleophi-
licity (Figure 1, line a), contributed from electronic effects,
could be overridden by ion-pairing/solvation factors.
Line b in Figure 1 depicts the effect of carbanion
nucleophilicity on the cis/trans ratio. A larger amount of the
cis isomer is produced as the substituents become more
electron-withdrawing. The cis/trans ratio is set in the SNi
epoxide-opening step (6b to 3b/7b) and is therefore de-
coupled from the factors which control the enantioselectivity.
As outlined below, the cis/trans ratio is also affected by
sterics, solvation, and ion pairing.
Table 2. Selected Data of Cyclopropanation of 6b or 97b
entry
Ar
base
solvent
PhMe
cis/trans
1
2
3
4
5
6
7
8
6b 3,4-Cl2Ph KHMDS
6b 3,4-Cl2Ph t-BuOK
9a 3,4-Cl2Ph KHMDS
2.2:1
4.3:1
1:4.9
1.4:1
1.6:1
7.3:1
1:5.7
9:1
THF/DMPU
PhMe
9a 3,4-Cl2Ph NaHMDS THF
9a 3,4-Cl2Ph LiHMDS
9a 3,4-Cl2Ph t-BuOK
THF
THF/DMPU
PhMe
9b Ph
9b Ph
KHMDS
t-BuOK
THF/DMPU
Ortho-substituted substrates were studied to probe the role
of steric factors in controlling the cis/trans ratio. As shown
in Figure 2, ortho substituents have a dramatic influence on
the cis/trans selectivity as a result of steric hindrance as
shown in the eclipsed conformations A and B. The solvated
metal ion M occupies the position opposite to the ortho
substituent Y to minimize steric interactions, which creates
subsequent repulsion with the methylene in A and therefore
reduces the energy difference with B to give lower cis/trans
effect on the selectivity on 9a,b vs epoxide 6b is consistent
with the stereochemical analysis (Figure 2), as the aggregates
are drastically affected by solvent polarity.8
We next returned our attention to the application of this
methodology toward the synthesis of 1 (Scheme 3). Direct
treatment of the crude cyclopropanation products with BH3‚
Me2S afforded a mixture of 2/11 in one pot. Efficient
chlorination7b was achieved in almost quantitative yield by
controlling the concentration of amino alcohol 2/11 free base
Org. Lett., Vol. 8, No. 17, 2006
3887

was immediately cyclized to 1 upon adjusting the pH to
>8.5. Thus, (+)-Bicifadine and DOV21947 HCl salt (>99%
purity) were directly isolated in 65% and 57% overall
yield, respectively, whereas 12 was rejected through
crystallization.7b
Scheme 3. Single-Stage Through Process
In summary, we have developed an expedient, atom-
economical, asymmetric synthesis of 1-aryl-3-azabicyclo-
[3.1.0]hexanes in a single-stage through process without
isolation of any intermediates. The counter metal ion, solvent,
and substituents’ effects on the epoxy nitrile coupling were
further investigated, and cyclopropanes 3 were thus prepared
in high ee and yield by controlling the reaction pathway
through manipulating the nitrile anion aggregation state.
Further mechanistic studies toward further understanding the
aggregation effects on enantio- and diastereoselectivity are
ongoing.
Acknowledgment. We gratefully acknowledge Drs. D.
Hughes and K. Hansen (Merck & Co., Inc.) for helpful
discussions.
Supporting Information Available: Experimental pro-
cedures/discussions including an alternative synthesis of
DOV21947, characterization data, and methods. This material
is available free of charge via the Internet at http://pubs.acs.org.
through slow subsurface addition to a solution of SOCl2
in i-PrOAc at ambient temperature. The cis-chloride 13
OL061650W
3888
Org. Lett., Vol. 8, No. 17, 2006