A novel class of azatricyclononanes: pentasubstituted cyclopropanes from an uncatalysed reaction

Article abstract of DOI:10.1016/j.tetasy.2009.02.037

The direct and versatile stereoselective synthesis of a novel class of cyclopropyl derivatives of pyroglutamic acid is reported, using substituted diaryldiazo compounds. The course of the reaction has been investigated, and yields of substituted fluorenyl

Full text of DOI:10.1016/j.tetasy.2009.02.037

Tetrahedron: Asymmetry 20 (2009) 726–729
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A novel class of azatricyclononanes: pentasubstituted cyclopropanes
from an uncatalysed reaction
*
Lawrence Harris, Martin Gilpin, Amber L. Thompson, Andrew R. Cowley, Mark G. Moloney
The Department of Chemistry, Chemistry Research Laboratory, The University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The direct and versatile stereoselective synthesis of a novel class of cyclopropyl derivatives of pyroglu-
tamic acid is reported, using substituted diaryldiazo compounds. The course of the reaction has been
investigated, and yields of substituted fluorenylcyclopropanes are greater than those of diphenylmethyl-
cyclopropane analogues.
Received 2 February 2009
Accepted 19 February 2009
Available online 1 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor George
Fleet, on the occasion of his 65th birthday
1. Introduction
quired diaryl diazomethanes 2a–d and 9-diazo-9H-fluorenes 3a–f
(Scheme 2) were easily generated by conversion of the correspond-
We have shown that pyroglutamic acid derivatives provide use-
ful templates for the effective preparation of compound libraries
with diverse functionality and controlled stereochemistry by alkyl-
ing ketone either to the hydrazone followed by yellow mercuric
oxide oxidation, or to the tosylhydrazone followed by basic elimi-
nation. Upon reaction of enone 1a with diphenyldiazomethane 2c
in acetone solvent at reflux, we found that cyclopropane product 4
was obtained in 23% yield, along with the olefin product 6, in 26%
yield.23 Also isolated was pyrazoline 5 in 26% yield, which is indef-
initely stable at room temperature; however heating at reflux in
toluene quantitatively yielded cyclopropane 4; the alternative pyr-
azoline was not isolated. Similar reaction of diazofluorene 3 gave
cyclopropyl adduct 7 in good yield (66%).
A range of substituted diazo compounds were reacted with acti-
vated enone 1b (Scheme 2);23 it should be noted that 1b is very
much prone to dimerisation (with 10 obtained as a single diaste-
reomer), and needs to be used immediately after preparation. With
both the diphenylmethyl-2a–d and fluorenyl-series 3a–f of diazo
compounds, the reactions were found to be significantly faster
than for lactam 1a, and no pyrazoline adducts analogous to 5 were
isolated. An increase in the electron density in the diazo series 2
(2a?2d) gives significantly increased yields of cyclopropyl 8 rela-
tive to enone 9, so that for example, diazo 2d gave cyclopropane 8d
in 64% yield, along with only 16% of 9d (Table 1). Olefin substitu-
tion products 9c,d were obtained with diazo compounds 2c and
2d in 46% and 16% yields, respectively. Notably, only dimerised
starting material 10 was isolated on reaction with diazo 8a, indi-
cating that this cycloaddition process is not without synthetic lim-
itation. It should be noted that the reaction of enone 1b with a
range of substituted diazofluorenes yielded the cyclopropane prod-
ucts exclusively (Table 2), in yields ranging from 41% for 3f (unop-
timised) to 97% (optimised) for 3e, and this was a significantly
superior outcome to the diphenylmethyl series.
ation reactions at the a
-position1–5 and conjugate additions of car-
bon, oxygen and nitrogen nucleophiles at the b-position6–10 of the
lactam carbonyl; these substrates may also undergo fully stereose-
lective cycloaddition reactions.4 We have demonstrated that this
approach provides access to novel kainoid and amino acid ana-
logues1,3,11,12 and conformationally well-defined amino acid ana-
logues,10 and of interest to us was the possibility that this
approach might be extendable to even more conformationally re-
stricted systems. The cyclopropyl unit is an important means for
the introduction of rigidity, and conformationally well-defined
amino acids13 and peptides14,15 and analogues of cytosine16 have
been identified. Recently, cyclopropyl annulated prolines have
been shown to possess antibacterial activity,17 and of interest to
us was the development of methodology for the rapid access to
cyclopropyl derivatives of pyroglutamate and proline. Literature
precedent clearly indicated that these compounds might be of
interest, which have been accessed by Madalengoitia using sulfur
ylid additions.18–22 Herein we report that azabicyclo[3.1.0]hexanes
may be formed by the direct cyclopropanation of pyroglutamate
derivatives using substituted diaryldiazo compounds and without
metal catalysis; this process is highly stereoselective.
2. Results and discussion
Our approach commences from the unsaturated lactams 1a,b
(Schemes 1 and 2), prepared as previously reported.4,3 The re-
The best yields were obtained using the more electron-rich dia-
zofluorene systems 3a,b, in reactions which were also notable for
* Corresponding author. Tel.: +44 1865 275656.
E-mail address: mark.moloney@chem.ox.ac.uk (M.G. Moloney).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.037

L. Harris et al. / Tetrahedron: Asymmetry 20 (2009) 726–729
727
Ph
Ph
N
N
Ph
Ph
N
Ph
Ph
O
Acetone , N2, Reflux
N2
O
O
+
+
N
N
O
O
O
Ph
5 (26%)
Ph
Ph
6 (26%)
4 (23% (49%))
2
Toluene, Reflux (100%)
O
N
O
N2
Ph
Ph
1a
N
N
N
Ph
3
O
O
N
Acetone, N2, Reflux
O
O
Ph
Ph
Not isolated
7 (66%)
Scheme 1.
Y
Y
Y
Y
Y
EtO2C
EtO2C
Y
N2
+
EtO2C
O
O
O
2a Y = NO
2b Y = I
2
N
N
Ph
9a-d
O
O
2c
2d
Y = H
Y = OMe
N
Ph
O
8a-d
Ph
1b
N2
C
B
D
A
Product
11
A
B
CH
C
D
D
H
CH
H
A
Ph
N
B
C
12a
12b
13a
13b
14
15a
15b
16
H
C(CH OH) CH
H
2
H
CH
C(CH OH) H
CH
CH
O
EtO2C
2
O
A
H
H
B
CH
C
D
H
H
Br CH
H
Br
Br
H
H
H
EtO2C
O
3a
3b
3c
CH
H
CH
O
N
C(CH OH) CH
Br CH
CH
CH
N
2
CO2Et
Br CH
CH
CH
CH
N
H
H
N
CH
N
O
3d Br CH
Br
H
H
H
H
N
Ph
11-16
3e
3f
H
H
N
N
N
O
10
Ph
Scheme 2.
Table 1
Reactions of lactam 1b with diazo compounds 2a–d
Table 2
Reactions of lactam 1b with diazo compounds 3a–f
Diazo
Y
Yield product (%)
Yield product (%)
Dimer isolated
Diazo
Product
Yield of diastereomer (%)
2a
2b
2c
2d
NO2
I
H
8a (0)
8b (19)
8c (29)
8d (64)
—
—
Yes
Yes
—
3a
3b
11
95
36a
36a
45
24
64
58
39
41
12a
12b
13a
13b
14
15a
15b
16
9c (46)
9d (16)
OMe
—
3c
3d
3e
the absence of products of type 9. We also noted the higher stabil-
ity of diazofluorenones over diphenyldiazomethanes under these
reaction conditions (unreacted diazofluorenone was frequently ob-
tained at the end of the reaction) and the former are therefore
3f
a
Low overall yield due to the need for extensive chromatography to separate
diastereomers.

728
L. Harris et al. / Tetrahedron: Asymmetry 20 (2009) 726–729
OH
H
H
H
OH
OH
H
O
H
O
H
N
H
H
O
O
H
H
H
EtO2C
O
EtO2C
O
H
O
O
H
H
N
N
N
O
O
N
Ph
O
Ph
O
Ph
Ph
15b
12a
Figure 1.
N2
N2
N
N
CO2Et
EtO2C
O
HN
MeO2C
CO2Me
CO2Et
18
EtO2C
19
No reaction
O
N
O
O
Ph
Ph
17
1b
Scheme 3.
more likely to be longer lived under the reaction conditions, giving
rise to higher overall yield.
pounds decompose at >120 °C, and some are stable even to
>165 °C). In favourable cases (e.g., 3b,c,e), unreacted diazoalkane
may even be isolated inpure form fromthe reaction mixture. Further-
more, the rate of reaction of enone 1b is greater than 1a, consistent
with a concerted pathway, in which formation of one regioisomer
of the pyrazoline product as a result of steric and/or electronic factors
is preferred, and that this immediately collapses leading to the forma-
tion of the observed products 8 and 9. In the case of 1a, both pyrazo-
lines are formed, one of which immediately collapses to the products
4 and 6, and the other 5 (which can easily be isolated) only does so at
elevated temperature. The collapse of pyrazolines to cyclopropanes
has been investigated in detail.26 The formation of both pyrazoline
and cyclopropyl products has been observed in the reactions of diazo
compounds with unsaturated maleimide systems.27
The exo-stereochemistry of the cyclopropane products was con-
firmed by single crystal X-ray analysis for 4, 7, 8b–d, 11, 14 and
15b,24 which is consistent with a sterically preferred outcome). It
should be noted that in the 1H NMR spectrum, the signal at ca. d
3.5, diagnostic of H-6, always occurred as a singlet, as a result of
its orthogonal relationship to H-5; a similar structural feature
has been previously reported.14 With unsymmetrical diazo com-
pounds 3b,c,e, two diastereomeric exo-cyclopropanes were ob-
tained (Table 2). Although the determination of the
stereochemistry of 15b was readily possible by NOE irradiation
of the H-6 proton, giving an enhancement to a single identifiable
aromatic proton, and this stereochemical outcome confirmed by
X-ray analysis, the two non-crystalline diastereomers 12a,b were
separable and distinguishable by 1H NMR spectroscopy only with
difficulty. The assignment of stereochemistry in this case required
a series of NOE and TOCSY experiments (Fig. 1), utilising firstly, the
existence of the key NOE enhancement observed via irradiation of
the d 3.5 singlet for H-6 to identify the proximal aromatic hydro-
gen, secondly NOE from the aromatic CH2OH to flanking hydro-
gens, and a TOCSY to identify which of the three possible
aromatic rings on which these hydrogens were located (Fig. 1).
In contrast to the reactivities of diaryldiazomethanes and flu-
orenyldiazomethanes towards 1b, ethyl diazoacetate 18 furnished
2-pyrazoline 17, which is presumably the most stable tautomer,
and whose regiochemistry was established on the basis of careful
analysis of 13C shift data (Scheme 3). This is a similar outcome to
the cycloaddition reaction with 4-naphthoxybutenolide.25 How-
ever, dimethyl diazomalonate 19 gave no such reaction, even when
used as the solvent, and only 10 was formed.
3. Conclusion
We have demonstrated that direct cyclopropanation of elec-
tronrically activated unsaturated pyrrolidinones using diaryl diazo
compounds allows stereoselective access to conformationally well-
defined structures. These compounds are likely to find application
in diverse areas. This work complements work recently reported
by Fleet et al., who demonstrated novel methodology for the pro-
tection of carbohydrates using diaryldiazomethanes, highlighting
the importance of these under-utilised reagents.30
Acknowledgements
L.H. gratefully acknowledges CASE studentship support from
the EPSRC and GSK (Harlow).
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