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. Author manuscript; available in PMC: 2014 Aug 14.
Published in final edited form as: Chem Commun (Camb). 2012 Apr 30;48(45):5578–5580. doi: 10.1039/c2cc32225k

Chiral Proton Catalysis of Secondary Nitroalkane Additions to Azomethine: Synthesis of a Potent GlyT1 Inhibitor

Tyler A Davis a, Michael W Danneman a, Jeffrey N Johnston a,*
PMCID: PMC4133115  NIHMSID: NIHMS612809  PMID: 22543734

Abstract

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 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 doing 3) assign the absolute configuration of the more potent enantiomer of 1. A motivation to achieve the first of these goals was the opportunity to develop an enantioselective addition of 3-nitro azetidines 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.4,5,6 In the case of BAM catalysis, 2-nitropropane was used to initially evaluate the feasibility of the approach (Scheme 2).7 Catalyzed addition of 2-nitropropane to N-Boc imine 5a at 23 °C delivered the addition product (6a) with 71% ee using PBAM·HOTf (7a·HOTf) (67% yield). The free base form of the catalyst (7a) provided the addition product with lower 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.

Scheme 1.

Scheme 1

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Retrosynthetic analysis of GlyT1 inhibitor 1

Scheme 2.

Scheme 2

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Enantioselective 2-nitropropane additions

Preparation of a protected 3-nitroazetidine was targeted next. 3-Hydroxyazetidine is a relatively inexpensive, commercially available 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

Scheme 3.

Scheme 3

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Synthesis of 3-nitroazetidine from 3-hydroxyazetidine

With the desired nitroalkane in hand, conditions analogous to those in Scheme 2 were applied. Use of PBAM·HOTf at room temperature provided the addition product (12) with good enantioselection (78% ee). The time to completion of this reaction was noted to be very short (70 minutes) relative to the addition of 2-nitropropane to aryl N-Boc imines (reaction times of ~24 hours). 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 °C 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 catalyst7(MeO)PBAM·HOTf (7b·HOTf) led to appreciably higher enantioselection at the 92% ee level with excellent yield.

Scheme 4.

Scheme 4

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Development of highly enantioselective 3-nitroazetidine additions

With enantiomerically enriched aza-Henry product 12 in hand, a stannane-mediated reductive denitration was attempted (Scheme 5).11,12,6b 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 derivatives 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 incidently more potent inhibitor.1

Scheme 5.

Scheme 5

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Completion of the synthesis of GlyT1 inbibitor (−)-1

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.

Supplementary Material

SI 1
SI 2

Acknowledgments

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.

Footnotes

†

Electronic Supplementary Information (ESI) available: full preparative and analytical details for all new compounds. See DOI: 10.1039/b000000x/

Notes and references

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

SI 1
NIHMS612809-supplement-SI_1.pdf (188.5KB, pdf)
SI 2
NIHMS612809-supplement-SI_2.pdf (376.4KB, pdf)

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