Chiral proton catalysis of secondary nitroalkane additions to azomethine: Synthesis of a potent GlyT1 inhibitor

Article abstract of DOI:10.1039/c2cc32225k

The first enantioselective synthesis of a potent GlyT1 inhibitor is described. A 3-nitroazetidine donor is used in an enantioselective aza-Henry reaction catalyzed by a bis(amidine)-triflic acid salt organocatalyst, delivering the key intermediate with 92% ee. This adduct is reductively denitrated and converted to the target through a short sequence, thereby allowing assignment of the absolute configuration of the more potent enantiomer.

Full text of DOI:10.1039/c2cc32225k

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COMMUNICATION
Chiral proton catalysis of secondary nitroalkane additions to azomethine:
synthesis of a potent GlyT1 inhibitorwz
Tyler A. Davis, Michael W. Danneman and Jeffrey N. Johnston*
Received 27th March 2012, Accepted 5th April 2012
DOI: 10.1039/c2cc32225k
The first enantioselective synthesis of a potent GlyT1 inhibitor is
described. A 3-nitroazetidine donor is used in an enantioselective
aza-Henry reaction catalyzed by a bis(amidine)-triflic acid salt
organocatalyst, delivering the key intermediate with 92% ee.
This adduct is reductively denitrated and converted to the target
through a short sequence, thereby allowing assignment of the
absolute configuration of the more potent enantiomer.
Azetidine 1 is a potent GlyT1 inhibitor first prepared by
Lindsley1 as part of a program aimed at the discovery of
novel, potent GlyT1 inhibitors. Inhibition of GlyT1 can
increase glycine levels and NMDA signaling, thereby providing
a promising therapeutic target for the treatment of schizophrenia.2
The racemate was prepared by a short synthetic sequence, and
chromatographic separation of enantiomers using a chiral
stationary phase led to the determination that one enantiomer
is not only a potent inhibitor (IC50 = 29 pM), but also inhibits
glycine reuptake 104 times better than its antipode.1 We established
Scheme 1 Retrosynthetic analysis of GlyT1 inhibitor 1.
initially evaluate the feasibility of the approach (Scheme 2).7
three goals: (1) develop an enantioselective preparation of
the substituted aminomethyl azetidine core, (2) synthetically
convert this core to the potent GlyT1 inhibitor 1, and in so
Catalyzed addition of 2-nitropropane to N-Boc imine 5a at
23 1C delivered the addition product (6a) with 71% ee using
doing (3) assign the absolute configuration of the more potent
enantiomer of 1. A motivation to achieve the first of these
PBAMꢀHOTf (7aꢀHOTf) (67% yield). The free base form of
the catalyst (7a) provided the addition product with lower
goals was the opportunity to develop an enantioselective
addition of 3-nitroazetidines to imines using Bis(AMidine)
[BAM] based chiral proton catalysis.
Our broader interest in the application of Brønsted acid
catalysis to the development of therapeutics3 motivated an
approach to this molecule using an asymmetric aza-Henry reaction
between an imine (3) and nitroazetidine (4) (Scheme 1). Subsequent
denitration of the resulting tertiary nitroalkane 2 might then give
the underlying structural foundation of target 1. The catalyzed,
enantioselective addition of secondary nitroalkanes is rare and
remains limited to 2-nitropropane additions to N-Boc imines.4–6
In the case of BAM catalysis, 2-nitropropane was used to
Department of Chemistry & Vanderbilt Institute of Chemical Biology
Vanderbilt University, Nashville, TN 37235-1822, USA.
E-mail: jeffrey.n.johnston@vanderbilt.edu;
Web: http://www.johnstonchemistry.org; Fax: (+1) 615 343 6361
w Electronic supplementary information (ESI) available: full prepara-
tive and analytical details for all new compounds. See DOI: 10.1039/
c2cc32225k
z This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Scheme 2 Enantioselective 2-nitropropane additions.
c
5578 Chem. Commun., 2012, 48, 5578–5580
This journal is The Royal Society of Chemistry 2012

With the desired nitroalkane in hand, conditions analogous
to those in Scheme 2 were applied. Use of PBAMꢀHOTf at
23 1C provided the addition product (12) with good enantio-
selection (78% ee). The time to completion of this reaction was
noted to be very short (70 min) relative to the addition
of 2-nitropropane to aryl N-Boc imines (reaction times of
B24 h). The improved reactivity provided the opportunity to
lower the reaction temperature as a means to increase the
observed enantioselection. In the event, the addition product could
be acquired with 86% ee at ꢁ20 1C and a one day reaction time.
An additional BAM catalyst was evaluated in this context to
further improve enantioselection (Scheme 4). The 7-methoxy
quinoline-derived PBAM catalyst 7(MeO)PBAMꢀHOTf (7bꢀHOTf)
led to appreciably higher enantioselection at the 92% ee level
with excellent yield.
Scheme 3 Synthesis of 3-nitroazetidine from 3-hydroxyazetidine.
With enantiomerically enriched aza-Henry product 12 in
hand, a stannane-mediated reductive denitration was attempted
(Scheme 5).6b,11,12 This reaction proceeded smoothly to furnish
denitrated product 13 in 69% yield. The preparation of 13
provides the key scalemic substituted aminomethyl azetidine
scaffold common to target 1 as well as any number of deriva-
tives through subsequent derivatization.13 To establish the
validity of the former, the Cbz group of 13 was removed by
hydrogenolysis before acylation with sulfonyl chloride 15 to
provide 16 (56% yield over two steps). Acid-promoted Boc
deprotection and subsequent acylation with 18 provided the
GlyT1 inhibitor (–)-1 in 27% yield over two steps (unoptimized).
Material prepared in this way, using (R,R)-catalyst 7b, delivers
the levorotatory enantiomer. Using HPLC retention times for
comparison, this material corresponds to the faster eluting, and
incidentally more potent inhibitor.1
Scheme 4 Development of highly enantioselective 3-nitroazetidine
additions.
enantioselection (52% ee, 63% yield).8 A more direct application
of this synthetic approach to 1 would involve an appropriate
N-acyl imine, and the feasibility of this was investigated using
N-benzoyl imine 5b. Unfortunately, this electrophile resulted
in an addition product (6b) with low enantioselection, regardless of
the protonation state of the electron rich BAM ligand (11% ee and
ꢁ15% ee, Scheme 2). Our approach therefore relied on the use of
an N-Boc imine electrophile which would offer the advantage of
providing the fundamental aminomethyl azetidine backbone
should alternative derivatives be desired for further medicinal
chemistry studies.
Preparation of a protected 3-nitroazetidine was targeted next.
3-Hydroxyazetidine is a relatively inexpensive, commercially avail-
able substance as its hydrochloride salt (8),9 and it was converted
to 9 in 95% yield using Cbz-Cl under basic conditions. For
reasons not clear, conversion of N-Cbz derivative 9 to the
corresponding bromide or iodide using triphenyl phosphine and
carbon tetrabromide or iodine, respectively, failed. And while the
mesylate was readily prepared, it was not a competent precursor to
the iodide or nitroazetidine through substitution. Nitroazetidine
11 was ultimately prepared by triflation of the alcohol (87% yield),
conversion of the triflate to iodide 10 (89% yield), and substitution
using the Kornblum protocol (40% yield, Scheme 3).10
In summary, the more potent enantiomer of 1 was prepared
using an aza-Henry addition for strategic convergency. This
step proceeded with good enantioselection (92% ee) in a
rare example of a secondary nitroalkane addition to an imine.
This key intermediate, following reductive denitration, was
converted to the desired small molecule inhibitor in four steps
and used to assign the absolute configuration of (–)-1 as
depicted. Differentially protected, constrained 1,3-diamine 13
may also find broader use as a chiral nonracemic small
molecule now readily accessible.
Scheme 5 Completion of the synthesis of GlyT1 inbibitor (–)-1.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5578–5580 5579

We are grateful for the generous financial support provided
by the NIH (GM 084333). This work is dedicated to our
colleague Craig Lindsley with respect and admiration.
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5580 Chem. Commun., 2012, 48, 5578–5580
This journal is The Royal Society of Chemistry 2012