Synthesis of a bicyclic oxo-γ-lactam from a simple caprolactam derivative

Article abstract of DOI:10.1039/c7nj02348k

The synthesis of the 6-azabicyclo[3.2.1]octane ring system, via Dieckmann cyclization, is described. Ring closure involves reaction of a caprolactam enolate with a C-6 ester, the reactive axial conformation of which is promoted by the presence of an N-tert-butyloxycarbonyl group on the lactam nitrogen. The results will enable the synthesis of new bridged caprolactams for testing as antibacterials and nucleophilic enzyme inhibitors.

Full text of DOI:10.1039/c7nj02348k

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“
Synthesis of a bicyclic oxo-γ-lactam from a simple caprolactam derivative”
a,b
a
c
d
Christian Weck, Franziska Obst, Elisa Nauha, Christopher J. Schofield, and Tobias
a,b*
Gruber,
a
Institute of Organic Chemistry, Technische Universität Bergakademie Freiberg, Leipziger
Straβe 29, Freiberg/Sachsen, Germany
b
School of Pharmacy, University of Lincoln, Joseph Banks Laboratories, Green Lane,
Lincoln LN6 7DL, United Kingdom.
c
School of Chemistry, University of Lincoln, Joseph Banks Laboratories, Green Lane,
Lincoln LN6 7DL, United Kingdom.
d
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12
Mansfield Road, Oxford OX1 3TA, United Kingdom.
*Correspondence: tgruber@lincoln.ac.uk (TG)
Electronic Supplementary Information (ESI) available: CCDC 1528320 and 1522636. For
synthetic procedures, crystallographic and spectroscopic data see DOI: 10.1039/x0xx00000x
Abstract
The synthesis of the 6ꢀazabicyclo[3.2.1]octane ring system, via Dieckmann cyclization, is
described. Ring closure involves reaction of a caprolactam enolate with a Cꢀ6 ester, the
reactive axial conformation of which is promoted by the presence of an Nꢀtertꢀ
butyloxycarbonyl group on the lactam nitrogen. The results will enable the synthesis of new
bridged caprolactams for testing as antibacterials and nucleophilic enzyme inhibitors.
1

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Introduction
The βꢀlactams remain the most important antibacterials; they work by reaction with a
nucleophile serine residue in penicillin binding proteins (PBPs), which catalyse essential
transpeptidase reactions during bacterial cellꢀwall peptidoglycan biosynthesis. A common
mechanism of resistance to the βꢀlactam antibacterials, involves βꢀlactamases, which catalyse
βꢀlactam hydrolysis. All clinically used PBP inhibitors are βꢀlactams and until recently this
1
has been the case for βꢀlactamase inhibitors. Following on from synthetic γꢀlactam analogues
of the βꢀlactams and the discovery of the natural product lactivicin, the cyclic urea avibactam
2
has recently been introduced as a broad spectrum serine βꢀlactamase inhibitor. However,
while the βꢀlactam based inhibitors react irreversibly with the nucleophile serine of the PBPs
3
and βꢀlactamases, avibactam reacts reversibly with its target serine βꢀlactamases. The
discovery of avibactam has stimulated interest in non βꢀlactam inhibitors of the serine βꢀ
lactamases and PBPs. We have been interested in bridged lactams as inhibitors of
nucleophilic serine / threonine / cysteine enzymes; however, for ring sizes > 6 there are only
limited reports on their synthesis. Here we describe the synthesis of the 6ꢀ
azabicyclo[3.2.1]octane bridged ring system, starting from a readily available caprolactam
precursor (Fig. 1).
Fig. 1 Examples of βꢀlactam antibacterials, βꢀlactam
inhibitors and nonꢀβꢀlactam analogues: a) penicillins, b)
carbapenems, c) an inactive γꢀlactam analogue, d) an active
γꢀlactam analogue, e) avibactam and f) the target of the
current work (1) which has a 6ꢀazabicyclo[3.2.1]octane core
ring system.
The 6ꢀazabicyclo[3.2.1]octane ring system is present in a wide range of biologically active
compounds and is isomeric with the tropane nucleus present in alkaloids, including cocaine
4
and atropine. Preparation of respective 6ꢀazabicyclo[3.2.1]octane derivatives and related
5
compounds is restricted to the intramolecular ring closure of γꢀlactam derivatives, amide
2

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6
formation in substituted cyclohexanes , and DielsꢀAlder reaction of appropriately unsaturated
7
γꢀlactams with acrylic acid. There is only one reported route to a 7,8ꢀdioxoꢀ6ꢀ
azabicyclo[3.2.1]octane derivative of (1), which employs semipinacol rearrangement of a βꢀ
8
lactam precursor. We envisaged bicycle 1 could be succinctly prepared from of a simple
caprolactam via Dieckmann cyclization. We anticipated that then Dieckmann cyclization may
only proceed efficiently, when the ester group adopts an axial position (Fig. 2a/b/c).
a)
b)
polymorph I
polymorph II
c)
d)
Fig. 2 Proposed Dieckmann cyclisation to give the 6ꢀazabicyclo[3.2.1]octane ring system. a) The two
energetically favoured ‘pseudo chair’ conformations of an Nꢀsubstituted caprolactam methylester. b) Synthesis
of 1 via Dieckmann cyclization. c) Only the axially positioned ester group can react via the desired Dieckmann
cyclization. d) View from a crystal structure of 3 showing that the –COOMe group adopts an axial conformation,
as observed for both polymorphs. In solution an equilibrium between the ‘axial’ and ‘equatorial’ conformers (70
1
2
%
: 30 %) is observed.
3

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Results and Discussion
Caprolactams can adopt (pseudo) chair, boat or transition (twist boat) forms. In the ‘chair‘
9
1,N
4
4
form, two energetically favoured conformations are manifested ( C and C1,N) assuming an
1
0
planar amide. Similar to cyclohexane chair conformations, caprolactams feature axial and
equatorial positions of ring hydrogens and respective substituents. The axial substituents are
1
1
higher in energy than equatorial ones as shown for Cꢀ2/Cꢀ6 monosubstituted caprolactams.
1
2
In a previous study, we investigated the influence of a second substituent on the
conformation of the Cꢀ6 caprolactam methylester ( ) (Fig. 3). Especially promising for our
purposes proved to be the introduction of a tertꢀbutyloxycarbonyl (Boc) group which delivers
. After substitution of the amide proton with the bulky Boc, the ꢀCOOMe and
the ꢀCOOC(CH ) on the nitrogen atom are in the trans position to each other. This can be
2
3
3
3
explained by the steric demand of both groups, with the Boc carbonyl being coplanar to the
amide segment forcing the former equatorial ester pendant of into the normally energetically
disfavoured axial position. Note the short distance of 2.53 Å (polymorph I) and 2.66 Å
polymorph II, Tabs. S1 and S2, Scheme S1, ESI), respectively, between the Cꢀ6 ester
carbonyl and the axial Cꢀ2 hydrogen as observed by Xꢀray crystallography (Fig. 2d), which
seems to be necessary for a transannular reaction. Indeed, treatment of with LiHDMS
lithium bis(trimethylsilyl)amide) produced the desired bicyclic lactam in its protected form
1a) in low (8 %) yield (Fig. 3). In order to optimise the reaction, several attempts to improve
2
1
2
(
3
(
(
the yield of the cyclization by the use of different solvents (increase to 11 % yield for toluene)
and the variation of temperature (higher temperatures prevent the cyclization). Furthermore,
we varied the amount of base (increase to 12 % yield for 2.1 equivalents) (Table 1).
O
O
O
O
O
O
O
NH
O
Boc O, DMAP, toluene,
N
O
LiHDMS,
THF, -78 °C
N
2
Hunig's base,
,
86 %
8 %
OMe
OMe
O
2
3
1a
a)
b)
Fig. 3 a) Synthetic pathway to bicycle 1a. b) Alternative substrates subjected to the here described
cyclization conditions.
It had been shown that the introduction of a Boc group at the lactam nitrogen activates the Cꢀ2
1
3
position for an electrophilic attack. However, other studies have proven that the lithium ion
of LiHDMS can prevent related reactions by forming a complex with the amide carbonyl and
1
4
the Boc group of the substrate. To test this theory for our system we used the related bases
NaHDMS and KHDMS featuring larger cations than LiHDMS. The yield of 1a did only
4

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increase slightly when higher amounts of base were used as observed above, ruling out that
complexformation with the respective alkali ion is the reason for the low yield.
Furthermore, we suspected, the formation of the smallest possible ketone, i.e. the five
membered ring could compete with the formation of the dimer, i.e. the 10ꢀmembered ring, as
1
5
well as oligomers. Inspired by high dilution conditons know from macroketone syntheses,
we varied the concentration of the educt with the outcome being displayed in Tab. S3 (ESI).
Interestingly, the concentration did not seem to influence the yield significantly.
Table 1 Conditions for the optimization of the here presented Dieckmann cyclization
Cyclization conditions
Expt.
No.
Isolated yields of
bicycle (%)
substrate
protecting
group
equivalents temperature
base
solvent
of base (eq)
(°C)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
3
3
7
7
7
8
9
10
LiHDMS
LiHDMS
LiHDMS
LiHDMS
LiHDMS
LiHDMS
LiHDMS
LiHMDS
KHMDS
KHMDS
NaHDMS
NaHDMS
LiHDMS
KHMDS
KHMDS
LiHDMS
LiHDMS
LiHDMS
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Bn
THF
nꢀhexane
toluene
THF
1.1
1.3
1.3
1.1
1.1
1.3
1.3
2.1
1.3
2.1
1.3
2.1
1.3
1.3
2.1
1.3
1.1
1.1
ꢀ78
ꢀ85
ꢀ85
rt
8
8
11
0
THF
0
0
THF
ꢀ85
ꢀ100
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
ꢀ85
8
THF
7
THF
12
8
THF
10
11
12
13
14
15
16
17
18
THF
13
7
THF
THF
11
0
THF
Bn
THF
0
Bn
THF
0
Boc
Boc
Boc
THF
0
THF
0
THF
15
In order to study the influence of the amide protecting group, the ring size and the flexibility
of the caprolactam rings on the here described Dieckmann cyclization, we prepared the
related lactams
this substrates, no cyclization was observed. This leads to the interesting observation, that the
benzyl group on seems to prevent an electrophilic attack in Cꢀ2 position as already shown
7ꢀ9 (Fig. 3b). Although, when applying the standard cyclization conditions on
7
13
for the respective butyrolactam. Moreover, smaller rings and less flexible caprolactams do
not undergo the Dieckmann cyclization when applying above reaction conditons.
Caprolactam
3 features two CꢀH acidic position (Cꢀ2 and Cꢀ6) and a competing deprotonation
may be another reason for the low yield of the bicyclic lactam 1a in the cyclisation step. To
investigate the proposal of competing Cꢀ6 deprotonation, Bocꢀprotected ethylester 10 (Fig. 3)
was prepared. Thus, caprolactam methylester
2 was saponified to yield the free acid, which
was esterified with EtOH and, subsequently, treated with Boc anhydride. When 10 was
5

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subjected the Dieckmann cyclization, a higher yield of 1a (15 %) was achieved, likely due to
reduced Cꢀ6 deprotonation relative to due to the higher steric demand of the ethyl ester.
3
1
13
H and C NMR (Fig. S1, ESI) as well as COSY analyses (Fig. S2, ESI) support the assigned
1
structure of 1a. Of note, the H spectrum exhibits a ‘doublet of doublets of doublets‘ (ddd)
coupling for H2 and H6. The third coupling likely results from J
coupling
couple with J values of 4.89 and J=4.88 Hz respectively; the analogous value for
cyclobutanone is 4.8 Hz. By contrast the Jꢀcouplings are rather low, both for the coupling
of H2 with H3/H3’ ( J=2.50/1.95 Hz) and of H2 with H6 ( J=1.88/1.33 Hz) (Fig. 4; Fig. S3,
4
longꢀrange ‘W’
H,H
1
6,17
of H2 with H6 over the keto bridge. For the bicyclic lactam 1a, H2 and H6
4
4
1
8
3
3
3
ESI).
1
Fig. 4 Close up view from the H NMR (125
MHz) spectrum of 1a; the H2 signal with the
respective ddd coupling pattern and the
3
4
respective JH,H and JH,H values is shown.
Bicycle 1a crystallized from ethyl acetate and cyclohexane as its corresponding hydrate 1b
4
(
Fig. 5a), a phenomenon which was already observed with a related compound. The plate
like twinned crystals are in space group Pꢀ1 with molecules featuring (R,R) and (S,S)
stereochemistry. As expected, the fiveꢀmembered ring of 1b adopts an envelope
conformation, while the caprolactam adopts the rarer boat conformation (Fig. 5b). A
comprehensive comparison of bond lengths and angles with related compounds can be found
in the Supplementary Material (Tab. S4, ESI). The molecules of 1b arrange in hydrogen
bonded ribbons running in the direction of the crystallographic a axis. In the ribbons two diols
2
face each other making an R ꢀ8ꢁ motif and these dimers then bond into C6 chains via the ring
2
carbonyl groups (Fig. 5c; Tab. S5, ESI). The ribbons stack up on each other with only weak
CꢀHꢁꢁꢁO(ꢀH) hydrogen bonds in the direction of the crystallographic b axis. The tertꢀbutyl
groups point outward from the sheet assembled via these interactions and stacking errors of
these sheets cause the crystals to be twinned.
6

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a)
b)
c)
Fig. 5 a) Molecular formula of the hydrate of 1a, i.e. 1b.
b) Ortep plot at 50 % probability of crystal structure of 1b.
c) Hydrogen bonded ribbons of 1b running along the
crystallographic a axis.
Conclusions
Overall, we have described the concise synthesis of a bridged caprolactam ring system, via
Dieckmann cyclization. This route builds upon work that has defined the transformations of
readily accessible caprolactam derivatives. Closure to give the 6ꢀazabicyclo[3.2.1]octane ring
system involves the reaction of a caprolactam enolate with an Cꢀ6 ester in an axial
conformation. The presence of the reactive axial conformation is promoted by an Nꢀ
butyloxycarbonyl group on the caprolactam nitrogen. The yield is increased slightly by the
use of nonꢀpolar solvents, higher amounts of base and an ethyl, rather than a methyl, ester,
likely due to diminished Cꢀ6 deprotonation with the ethyl ester. Future work will focus on a
deeper understanding of the mechanism and minimising side reactions. The results will enable
the synthesis of 6ꢀazabicyclo[3.2.1]octane ring derivatives for testing as antibacterials and
nucleophilic enzyme inhibitors.
7

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Experimental
Here we present the cyclization procedure for the optimization experiment delivering the
highest yield.
tert-Butyl 7,8-dioxo-6-azabicyclo[3.2.1]octane-6-carboxylate (1a). To a stirred solution
of the appropriate Bocꢀprotected lactam ethylester 10 (172 mg, 0.60 mmol) in dry THF (30
ml) at ꢀ78 °C was added a 1
ethylbenzene/THF (660 µl, 0.66 mmol, 1.1 eq.). The reaction mixture was then stirred at ꢀ78
C for 3 h. Subsequently, the reaction was quenched with sat. aqueous ammonium chloride
M solution of lithium hexamethyldisilazide (LiHDMS) in
°
solution (30 ml) at ꢀ78 °C and extracted with ethyl acetate (3x30 ml). The combined organic
phases were dried (Na SO ), then filtered. Evaporation of the solvent yielded a dark, oily
2
4
residue which was separated by flash column chromatography (SiO
2
; nꢀhexane/ethyl acetate =
1
0
1
3
1
1
2
1
:1
ꢀ
ethyl acetate) to yield 15 % (22 mg, 0.092 mmol) of a white solid. Mp. 93ꢀ94 °C. R
f
=
13
.30 (SiO ; nꢀhexane/ethyl acetate = 1:1). C NMR (125 MHz, CDCl3):
68.9 (CONCOO Bu), 148.4 (NCOO Bu), 84.1 (CH ) , 64.9 (COCHCO), 55.0 (NCHCO),
3.2 (CH
H, NHCH), 2.99 (m, 1H, COCHCO), 2.44ꢀ2.31 (m, 2H, CH
.88 (m, 1H, CH ), 1.84ꢀ1.75 (m, 2H, CH ), 1.54 (s, 9H, C(CH ) ). IR: 3391, 2992, 2932,
δ
= 207.3 (CO),
2
t
t
3
3
1
2
), 32.7 (CH
2
), 28.0 (CH
3
)
3
, 17.1 (CH
2
). H NMR (500 MHz, CDCl
3
):
δ
= 4.39 (m,
2
), 2.05ꢀ1.96 (m, 1H, CH
2
), 1.95ꢀ
2
2
3 3
874, 1769, 1752, 1713, 1448, 1393, 1365, 1326, 1305, 1249, 1220, 1154, 1089, 1068, 1052,
014, 993, 975, 953, 888, 865, 712. m/z = 238.11 [MꢀH ], calc. 238.12.
+
X-ray crystallography
Bicycle 1a was crystallized from ethyl acetate and cyclohexane using the vapor diffusion
approach resulting in hydrate 1b. Crystals suitable for single crystal Xꢀray diffraction studies
of polymorph II of compound
3 were obtained by crystallization from ethyl acetate/nꢀhexane
(
1:2) and have a melting point of 69ꢀ71 °C; this is about 20 K higher than observed for
1
2
polymorph I (CSD refcode: BOLHOB).
Single crystal Xꢀray diffraction was performed at 173K with a Bruker D8 Venture
1
9
diffractometer using a CuꢀK
α
source. Structure solution was carried out with shelxt and
2
0
21
structure refinement with shelxl was finished using ShelXle software. The twin matrix for
1b was acquired from twinrotmat in Platon. For crystal data and refinement parameters see
2
2
ESI. CCDC numbers 1528320 (1b) and 1522636 (3).
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
FO thanks the ‘Verein der Freunde und Förderer der TU Bergakademie Freiberg’ for a travel
scholarship. CW and TG gratefully acknowledge financial support from the Institute of
Organic Chemistry, University of Freiberg and the School of Pharmacy, University of
Lincoln. Furthermore, the authors are indebted to Dr Erica Brendler, Institute of Analytical
Chemistry, University of Freiberg, for recording the 2D NMR spectra and for her helpful
advice. CJS thanks the Medical research Council for support.
8

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Reaction of caprolactams with an axial ester
substituent with base gives the 6-azabicyclo-
3.2.1]octane ring system via Dieckmann cyclization.
[