A concise stereospecific synthesis of repinotan (BAYx3702)

Article abstract of DOI:10.1016/j.tetlet.2003.09.130

A concise synthesis of the 2-[aminomethyl]chroman derivative BAYx3702 (3), a potent 5-hydroxytryptamine (5-HT_1A) antagonist is described. Utilization of a Mitsunobu reaction of phenol (11) with the non-racemic allylic alcohol (12) and consequen

Full text of DOI:10.1016/j.tetlet.2003.09.130

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8563–8565
A concise stereospecific synthesis of repinotan (BAY×3702)ꢀ
Jonathan L. Gross*
Chemical and Screening Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA
Received 27 August 2003; accepted 16 September 2003
Abstract—A concise synthesis of the 2-[aminomethyl]chroman derivative BAY×3702 (3), a potent 5-hydroxytryptamine (5-HT1A
)
antagonist is described. Utilization of a Mitsunobu reaction of phenol (11) with the non-racemic allylic alcohol (12) and
consequent ring-closing metathesis furnishes the chroman-2-yl framework of 3 in optically active form.
© 2003 Published by Elsevier Ltd.
2-(Aminomethyl)-1,4-benzodioxans (e.g. 1 and 2, Fig.
1) have long been recognized as important pharmaco-
logic tools with significant utility possessing the ability
to modulate receptor activity at adrenergic, serotoner-
gic, and dopaminergic receptors.1 The ability of this
moiety to function as a stereogenic bioisosteric replace-
ments for another important neuropharmacologic
agent, the arylpiperazine, has been documented.2 Con-
sequently, there exist numerous methods for the
efficient, asymmetric synthesis of these compounds.3
More recently, the closely related structural analogs,
2-(aminomethyl)chromans (e.g. 3 and 4, Fig. 1) have
emerged as relevant biological agents and has generated
increased pharmacological interest.4 The lack of an
efficient preparation for these molecules, coupled with
their neuropharmacologic relevance and stereoselectiv-
ity of the target receptor families, has actuated syn-
thetic effort toward their asymmetric synthesis.5
The 2-(aminomethyl)chroman derivative, BAY×3702
(repinotan, 3), a high affinity 5-HT1A receptor agonist,6
currently in phase III clinical trials, is being developed
by Bayer as a potential treatment for ischemic stroke
and traumatic brain injury.7 The development of
repinotan as the (−)-enantiomer illustrates the potential
biodiscrimination that exists for this class of molecules,
and further emphasizes the importance of an asymmet-
ric synthesis.
The previously reported synthesis of repinotan (3) out-
lined in Scheme 1 involves the formation of acid chlo-
ride (6) from chroman-2-carboxylic acid (5) via
treatment with thionyl chloride.8 Reaction of 6 with
(S)-phenethylamine affords
a
1:1 mixture of
diastereomers. Separation (fractional crystallization) of
the mixture provides the desired epimer in high optical
purity. Subsequent reduction of the amide with dibo-
rane provides benzyl amine (7) followed by hydrogenoly-
sis of 7 to afford (R)-2-(aminomethyl)chroman (8).
Alkylation of 8 with N-(4-bromobutyl)saccharin pro-
vides repinotan (3), isolated as the hydrochloride salt.
Figure 1. Selected 2-(aminomethyl)chromans/-1,4-benzodi-
oxans.
Although interest in enantiomerically pure 2-
(aminomethyl)chromans as pharmacologic agents has
increased, their preparation generally relies upon opti-
cal resolution of a suitably functionalized 2-chromanyl
ꢀ Supplementary data associated with this article can be found at
doi:10.1016/j.tetlet.2003.09.130
* Tel.: 732-274-4331; fax: 732-274-4505; e-mail: grossj@wyeth.com
0040-4039/$ - see front matter © 2003 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2003.09.130

8564
J. L. Gross / Tetrahedron Letters 44 (2003) 8563–8565
Interest in utilization of the extant methodology indi-
cated that 2-‘styrene-like’ phenols (i.e. 12, Scheme 3)
would also serve as exemplary substrates for elabora-
tion into 2-(aminomethyl)chromans such as 3. Rear-
rangement of the double bond present in 11 is
accomplished
by
treatment
with
bis(acetoni-
trile)dichloropalladium(II) in refluxing dichloromethane
to afford styrene (12).11 Mitsunobu reaction of 12 with
the commercially available (S)-2-hydroxy-3-buten-1-yl
p-tosylate (13) provided the requisite diene (14) for the
envisioned RCM.12 Cyclization of 14 was effected using
0.2 equiv. of Grubb’s catalyst to afford the metathesis
adduct 2-(hydroxymethyl)chromene (15) as the p-tolu-
enesulfonyl ester.13 Azide displacement of the tosylate
in 15 followed by subsequent reduction of the azido
group with concomitant reduction of the chromene
provided 2-(aminomethyl)chroman (8). Alkylation of 8
with N-[4-bromobutyl]saccharin and conversion to the
hydrochloride salt provides repinotan (3) as a single
enantiomer.
Scheme 1. Bayer synthesis of BAY×3702. Reagents and condi-
tions: (a) SOCl2. (b) (S)-Phenethylamine. (c) BH3/THF. (d)
H2, Pd–C. (e) N-(4-bromobutyl)saccharin, Et3N. (f) HCl.
derivative, as demonstrated for repinotan.9 Although
resolution ultimately provides the desired enantiomer,
the remaining material is inevitably discarded. It is
noted for repinotan that ‘epimerization of the undesired
diastereomer is feasible’. However, the axiomatic impli-
cation of this iterative cycle demonstrates an inherent
shortcoming of resolution.
The unmediated preparation of styrenes such as 12
from their corresponding phenols via allylation, Claisen
rearrangement, and olefin rearrangement significantly
expands the pool of available phenols. This observa-
tion, coupled with the ability of these compounds to
serve as reacting partners in the RCM further amplifies
the number of targets accessible utilizing this process.
Finally, the utility of the chiral, non-racemic allylic
alcohol (13) serves as the cornerstone for this synthesis
of repinotan, affording the opportunity for extraneous
installation of the stereogenic center present in 3. The
allylic alcohol present in 13 undergoes stereospecific
inversion of configuration to provide a single enan-
tiomer. Additionally, the functional differentiation of
the diol permits facile preparation of diene 14 and,
following metathesis cyclization, straightforward con-
version to amine 8.
Of the many reports of chromene synthesis, Grubb’s
and co-workers have demonstrated a non-stereospecific,
facile and practical methodology via ring-closing olefin
metathesis (RCM) of a series of 2-styrenyl allyl ethers
(9, Scheme 2) to afford chromene derivatives (10).10
In summary, this paper describes a stereospecific syn-
thesis of repinotan (3), a 2-(aminomethyl)chroman
reported to be in development for stroke. The synthesis
of 3 is achieved in 25% overall yield in six steps,
beginning with 2-allyl phenol (11). This approach pro-
vides a succinct route to a single stereoisomer, demon-
strating an effective method for the preparation of a
diverse array of derivatives in this class of molecules.
Scheme 2. Grubb’s synthesis of chromenes.
1. Supplementary material
Experimental procedures and characterization data for
compounds 3, 8, 14, and 15.
Acknowledgements
Scheme 3. Asymmetric synthesis of BAY×3702. Reagents and
conditions: (a) PdCl2(MeCN)2, CH2Cl2. (b) (S)-2-Hydroxy-3-
buten-1-yl p-tosylate (13), PPh3, DEAD, PhMe (64%). (c)
Cl2(PCy3)2RuꢀCHPh, CH2Cl2 (78%). (d) NaN3, DMSO. (e)
H2, Pd–C, MeOH (83%, two steps). (f) N-[4-Bro-
mobutyl]saccharin, DMSO then HCl/Et2O (62%).
Sincere thanks to Wyeth Research, Dr. Gary Stack for
helpful discussion, and gratitude to Dr. Al Bach, James
Mattes, Teresa Kleintop, Melanie Bissette, Donald
Herold, and Diane Andraka for analytical support.

J. L. Gross / Tetrahedron Letters 44 (2003) 8563–8565
8565
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