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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9719–9723
Asymmetric Synthesis
Hot Paper
Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion:
A Concise Route to Chiral g-Lactams
Jan Sietmann+, Mike Ong+, Christian Mück-Lichtenfeld, Constantin G. Daniliuc, and
Abstract: Asymmetric access to g-lactams is achieved via
a
cyclobutanone ring expansion using widely available
(1S,2R)-1-amino-2-indanol for chiral induction. Mechanistic
analysis of the key N,O-ketal rearrangement reveals a Curtin–
Hammett scenario, which enables a downstream stereoinduc-
tion (up to 88:12 dr) and is corroborated by spectroscopic,
crystallographic, and computational studies. In combination
with an easy deprotection protocol, this operationally simple
sequence allows the synthesis of a range of optically pure g-
lactams, including those bearing all-carbon quaternary stereo-
centers. In addition, the formal synthesis of drug molecules
baclofen, brivaracetam, and pregabalin further demonstrates
the synthetic utility and highlights the general applicability of
the presented method.
Introduction
In light of the importance of cyclic networks in nature,
ring expansions rank among the most attractive transforma-
tions in chemistry. In many cases, these ring expansions
represent the preferred route to medium rings that are
kinetically difficult to access by ring closure.[1] Additionally,
five- to seven-membered rings can be synthesized from
smaller rings harnessing the inherent ring strain as a driving
force for reaction progress. As such, rearrangements of
prochiral cyclobutanones are particularly intriguing, as they
allow for distal stereoinduction through a desymmetrization
strategy.[2] An archetypal example is the Baeyer–Villiger
oxidation, which has found numerous applications for the
synthesis of chiral g-lactones under remarkably mild condi-
Scheme 1. Access to chiral g-lactams via nitrogen-based ring expansion
of cyclobutanones.
tions (Scheme 1a, top).[3,4] The related asymmetric nitrogen-
based ring expansion, which leads to chiral g-lactams,
represents an underexplored obstacle, despite the significance
of this motif in drug discovery.[5,6] To date, many approved and
investigational drugs such as brivaracetam,[7] rolipram,[8] or
carmegliptin[9] contain b-substituted g-lactams providing
further incentive for the development of such ring-expansions
(Scheme 1a, bottom). The lack of general methods in this
area plausibly arises from the highly acidic reaction media
required for Beckmann and Schmidt rearrangements, which
poses a considerable challenge when performing these
reactions asymmetrically.[10]
[*] M. Sc. J. Sietmann,[+] M. Sc. M. Ong,[+] Dr. C. Mück-Lichtenfeld,
Dr. C. G. Daniliuc, Prof. Dr. J. M. Wiest
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Corrensstrasse 36, 48149 Münster (Germany)
Prof. Dr. J. M. Wiest
Department Chemie, Johannes Gutenberg-Universität
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: wiest@uni-mainz.de
To address this problem, we envisaged a synthetic strategy
based on a bi-functionalized amine bearing a suitable leaving
group and a chiral auxiliary Xc (Scheme 1b).[11] In contrast to
the classical Beckmann reaction, we hypothesized that due to
the inherent ring strain, rearrangement can occur from
a hemiaminal intermediate (and prior to oxime formation)
when using an adequately potent leaving group.[12] Migration
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
À
of one of the two prochiral C C bonds can then be directed by
the chiral auxiliary enabling, after separation of the diaste-
reomers and deprotection, a concise route to enantiopure
lactams.[13,14] In this Research Article, our results on identify-
Angew. Chem. Int. Ed. 2021, 60, 9719 –9723
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
9719