Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion: A Concise Route to Chiral γ-Lactams

Article abstract of DOI:10.1002/anie.202100642

Asymmetric access to γ-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 stereoinduction (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 γ-lactams, including those bearing all-carbon quaternary stereocenters. 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.

Full text of DOI:10.1002/anie.202100642

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 9719–9723
International Edition: doi.org/10.1002/anie.202100642
German Edition: doi.org/10.1002/ange.202100642
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
Johannes M. Wiest*
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:
https://doi.org/10.1002/anie.202100642.
ꢀ 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-
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ing a suitable amine motif are presented, along with detailed
mechanistic analysis, deprotection protocols, and synthetic
applications.
halogen source was studied indicating a less fruitful outcome
for reactions with brominating agents such as N-bromosuccin-
imide (NBS; Table 1, entry 8). On the other hand, N-
chlorosuccinimide (NCS) and TCICA performed equally
well (Table 1, entry 9). However, TCICA is considerably
cheaper and bears three active chlorine atoms, which were all
transferred during the reaction making it an atom efficient
oxidizing agent and thus our preferred choice.[17]
Results and Discussion
We commenced our study by exploring different leaving
groups at the nitrogen atom to better understand their ability
to trigger the postulated rearrangement (cf. Scheme 1b).
Hydroxylamine derivatives bearing an acetate or benzoate
group were generally not potent enough and no rearrange-
ment was observed (see SI for further information). Based on
Fujiokaꢀs studies concerning halonium-initiated rearrange-
ments of cyclobutanone aminals and ketals,[15] we started
exploring chiral aminoalcohols that can be activated in situ by
an appropriate halogen source. Thus, we identified amino-
indanol 2 and trichloroisocyanuric acid (TCICA) as a formi-
dable combination to convert prochiral 3-phenylcyclobuta-
none 1a to the corresponding g-lactam 3a (Table 1).[16]
To better understand the reaction outcome, we continued
elucidating the details of the stereochemical induction
process by spectroscopic and computational means. Pre-
mixing of cyclobutanone 1a and indanol 2 was essential and
lower yields for premature addition of TCICA were observed
indicating a condensation prior to rearrangement. Indeed,
a mixture of N,O-ketals 4a and epi-4a was formed in an
approximately 75:25 dr when equimolar amounts of the
respective starting materials were gently heated (Scheme 2).
Assignment of the relative configuration of the major
diastereomer 4a was possible by NOE correlations revealing
an anti-relationship between the NH and phenyl groups.
Further structural information was collected by X-ray dif-
fraction, which indicated a puckered cyclobutane placing the
phenyl group in a pseudo equatorial position (see SI for
further information). In our initial mechanistic hypothesis, we
expected a stereospecific reaction sequence commencing with
the chlorination of ketal 4a from its sterically accessible side
to furnish chloroamine 5a. Due to stereoelectronic consid-
Table 1: Reaction optimization using (1S,2R)-1-amino-2-indanol for
asymmetric induction.
erations (sCÀC!s* Cl), the subsequent rearrangement was
À
N
À
believed to occur via migration of the anti C C bond to
provide oxocarbenium 6a as indicated by the gray arrows.
Based on a previous study on hydrolysis of related cations,[18]
we concluded that lactam 3a must thus be formed as the
major diastereomer, which was unambiguously confirmed by
X-ray analysis.
Entry Change from
standard conditions[a]
Yield [%][b]
3a+epi-3a
dr[b]
Yield [%][b,c]
of major 3a
1
2
3
4
5
6
7
8
9
–
96
n.d.
24
80:20 77 (69)
80:20 (68)
85:15 20
87:13 59
77:23 39
87:13 42
81:19 62
78:22 43
80:20 78
9.0 mmol scale
THF instead of MeOH
CH2Cl2 instead of MeOH 68
DMF instead of MeOH
À308C instead of rt
No water added
NBS instead of TCICA
NCS instead of TCICA
50
48
77
55
98
[a] Reactions were run on a 1.0 mmol scale in 5.0 mL of solvent (0.2 m).
[b] Determined by 1H NMR using mesitylene as an internal standard.
[c] Yield of isolated major isomer 3a in parentheses. THF=tetrahydro-
furan, DMF=dimethylformamide, n.d.=not determined.
Under the optimized conditions (see SI for further
information), high yield was achieved on small as well as
gram-scale (Table 1, entries 1 and 2). Considering the dis-
tance of the stereocenters, the diastereomeric ratio (dr) of
80:20 was quite pleasing, especially since both isomers were
easily separable by column chromatography. Changing the
solvent as well as decreasing the temperature led to incom-
plete conversions and/or the formation of side-products
(Table 1, entries 3–6). While some solvents (e.g. dichloro-
methane, THF) outperformed methanol in terms of selectiv-
ity, the overall yield of the major isomer was considerably
lower, which was also observed when no water was added
along with TCICA (Table 1, entry 7). Finally, the effect of the
Scheme 2. Initial hypothesis via a stereospecific reaction trajectory.
ds=diastereomer. CCDC 2051973 (mixture of 4a/epi-4a, only structure
4a shown), 2051970 (3a), and 2051971 (epi-3a).
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Interestingly, we were able to monitor the formation of
intermediates 5a/epi-5a and 6a/epi-6a by NMR spectroscopy
in d4-methanol. Assignment of the corresponding carbenium
ions is based on similarities to literature precedent[19] as well
as computed 13C NMR shifts (see SI for further information),
which correlate well with our spectroscopic data. In contrast
to the proposed reaction sequence in Scheme 2, the spectro-
scopically observed selectivity was different for every pair of
intermediates indicating a more complex mechanism. An
induction of selectivity from 49:51 dr for chloroamines 5a/epi-
5a to 80:20 dr for oxocarbenium 6a/epi-6a was particularly
intriguing (Scheme 3). This enhancement can be rationalized
Scheme 4. Nitrogen-based ring expansion of cyclobutanones to access
chiral g-lactams. Yield of the isolated major diastereomer. Combined
yield and diastereoselectivity (in parentheses) was established by NMR
analysis of the crude reaction mixture using mesitylene as an internal
standard. [a] 708C instead of rt. [b] CCDC 2051972 (3o). [c] Diastereo-
mers were not separable. BOM=benzyloxymethyl.
Scheme 3. Explanation for a downstream induction based on the
Curtin–Hammett principle with calculated relative energies in brackets
(DG298(THF) in kcalmolÀ1). Energies were obtained by using the
following method: PW6B95-D3//TPSS-D3/def2-TZVP+COSMO-RS.
[a] Epimer (epi-7a) is not shown for clarity.
for the parent compound, the diastereomers were all separa-
ble and diasteromerically pure g-lactams 3b, 3c, and 3d were
accessible. Next, we examined halogens that are interesting as
bioisosteres (fluorine) and as a handle for cross-coupling
reactions (chlorine and bromine). Although for the para-
chloro and para-bromo cyclobutanone higher temperature
was required to ensure full conversion, we were pleased to
isolate lactams 3e, 3 f, and 3g in good yields. Besides aryl,
alkyl substitution was well tolerated revealing a bump in
selectivity (up to 87:13 dr) when going from primary (3h and
3i) to secondary (3j) and tertiary scaffolds (3k). In addition,
functional groups such as ether (3l and 3m) and ester (3n)
were compatible with the oxidative reaction medium, albeit
with lower selectivity. Finally, lactams 3o, 3p, and spirolactam
3q containing quaternary all-carbon stereocenters were
constructed. Substrate 3o further underlines the downstream
stereoinduction as its N,O-ketal was formed in 59:41 dr
improving to 84:16 dr for the g-lactam (absolute configura-
tion was established through X-ray analysis, see SI for further
information). The good compatibility with fully substituted
stereocenters not only highlights the complementary nature
of the presented approach (previous procedures are focused
under the premise of the Curtin–Hammett principle,[20] which
was evaluated by calculating the transition state energies
using the def2-TZVP basis set. While inversion at the
nitrogen stereocenter prior to rearrangement led to energeti-
cally less favorable trajectories (not shown, see SI for further
information), it was found that interconversion of chloro-
amines 5a and epi-5a can occur via an iminium species such as
7a. This process depends on protonation of the oxygen atom
prior to ring opening and is presumably initiated by HCl that
is formed over the course of the reaction. The 49:51 dr
between chloroamines 5a and epi-5a can thus be explained by
their relative stabilities, which differ by only 0.2 kcalmolÀ1.
Furthermore, the calculated energetic difference between the
stereodetermining transition states TS1 and TS2 was found to
be 0.9 kcalmolÀ1, which translates well to the downstream
selectivity of 80:20 dr for the oxocarbenium and lactam
species.
Based on the aforementioned downstream stereoinduc-
tion, we became interested in exploring the scope of the
reaction (Scheme 4). First, we evaluated the steric influence
of ortho, meta, and para-methyl groups at the phenyl ring. As
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even though it is known that the two isomers have different
activity.[27a] In analogy, brivaracetam (11, Briviactꢁ),[7] which
was released in 2016 to treat partial-onset seizures, was
formally accessed from key intermediate 8h.
Conclusion
Overall, this study enables the asymmetric nitrogen-based
ring expansions of prochiral cyclobutanones to a variety of g-
lactams. While the cyclobutanoneꢀs strain energy was crucial
for this unusual rearrangement to occur, the key for
selectivity was found in the widely available 2-amino-1-
indanol. An induction downstream the reaction trajectory
was identified, which led to good selectivity even when
quaternary all-carbon stereocenters were forged. Moreover,
this method does not require potentially toxic transition
metals making it ideally suited for the synthesis of drug
molecules. Along this line, baclofen, brivaracetam, and
pregabalin were formally synthesized to highlight the ex-
pected impact on future applications in g-lactam syntheses.
Acknowledgements
Generous financial support from the Westfälische Wilhelms-
Universität Münster, the Johannes Gutenberg-Universität
Mainz, and the Fonds der Chemischen Industrie (Liebig
fellowship to J.M.W.) is acknowledged. Open access funding
enabled and organized by Projekt DEAL.
Scheme 5. Deprotection protocols and application of the method.
on the synthesis of b-monosubstituted g-lactams)[21] but also
elegantly tackles this challenge in asymmetric synthesis.[22]
To ensure a synthetically useful reaction, establishing
a practical protocol for the removal of the indanyl unit was
inevitable (Scheme 5, top). Although it is known that benzyl-
protected lactams can be liberated under Birch conditions, we
evaluated more practical possibilities first.[23] While hydro-
genolysis, even under harsh conditions, was not successful, we
were surprised to find cerium ammonium nitrate (CAN) as
a viable mediator to provide 8a in 60% yield and > 99%
enantiomeric excess (see SI for further information). Inter-
estingly, the methylated counterpart 9a did not undergo
deprotection (< 10% yield) emphasizing the crucial role of
the hydroxy group for successful cleavage. Similarly, lactams
8 f and 8h, key intermediates for the synthesis of drug
molecules (see below), were obtained in 70% and 55% yield,
respectively. A complementary deprotection was also found
in a sequence of reduction and protecting-group swap
yielding chiral pyrrolidine 10a in 67% yield over the two
steps.[24]
Conflict of interest
The authors declare no conflict of interest.
Keywords: asymmetric synthesis ·cyclobutanone ·
desymmetrization · g-lactams
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Manuscript received: January 14, 2021
Accepted manuscript online: February 4, 2021
Version of record online: March 10, 2021
Angew. Chem. Int. Ed. 2021, 60, 9719 –9723
ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org
9723