Synthesis of Functionalized Alkylidenecyclopropanes by Ireland-Claisen Rearrangement of Cyclopropenylcarbinyl Esters

Article abstract of DOI:10.1021/acs.orglett.5b01759

Glycolates or glycinates derived from diversely substituted secondary cyclopropenylcarbinols have been involved for the first time in an Ireland-Claisen rearrangement. This reaction allows an efficient and stereoselective access to highly functionalized a

Full text of DOI:10.1021/acs.orglett.5b01759

Letter
pubs.acs.org/OrgLett
Synthesis of Functionalized Alkylidenecyclopropanes by Ireland−
Claisen Rearrangement of Cyclopropenylcarbinyl Esters
Guillaume Ernouf,† Jean-Louis Brayer,‡ Benoît Folleas,‡ Jean-Pierre Demoute,‡ Christophe Meyer,*,†
́
and Janine Cossy*,†
†Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI), ESPCI ParisTech, CNRS (UMR8231),
PSL Research University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
‡Diverchim, 6 rue du Noyer, ZAC du Moulin, 95700 Roissy-en-France, France
S
* Supporting Information
ABSTRACT: Glycolates or glycinates derived from diversely sub-
stituted secondary cyclopropenylcarbinols have been involved for the
first time in an Ireland−Claisen rearrangement. This reaction allows an
efficient and stereoselective access to highly functionalized alkylidene-
cyclopropanes possessing an α-hydroxy or α-amino acid subunit, which
in turn are valuable precursors of substituted cyclopropanes by
diastereoselective hydrogenation of the exocyclic alkene.
Scheme 1. [3,3]-Sigmatropic Rearrangements of Cyclo-
propenylcarbinol Derivatives
he fascinating reactivity of alkylidenecyclopropanes con-
1
Ttinues to elicit considerable interest in organic synthesis,
notably in transition-metal-catalyzed processes allowing either
the construction of complex molecular architectures by cyclo-
additions2 or efficient challenging acyclic stereocontrol.3 By
additions across the CC bond, alkylidenecyclopropanes can
serve as useful precursors of substituted cyclopropanes,4 which
are widely encountered in natural and/or bioactive compounds.5
Among the different synthetic routes toward alkylidenecyclo-
propanes, transformations relying on cyclopropenes as pre-
cursors are thermodynamically favored owing to the relief of ring
strain occurring upon migration of the double bond to the
exocyclic position.1,6 Nucleophilic displacements of
cyclopropenylcarbinol derivatives proceeding with allylic shift
(SN2′ or addition−elimination mechanisms) are undoubtedly
the most documented transformations.7 Surprisingly, by analogy
with allylic alcohols, examples of [3,3]-sigmatropic rearrange-
ments involving cyclopropenylcarbinol derivatives are scarce and
restricted to the synthesis of heterosubstituted alkylidene-
cyclopropanes.8,9 Marek et al. reported the [3,3]-sigmatropic
transposition of cyclopropenylcarbinyl acetates (or a benzoate)
which occurs with complete chirality transfer in the case of
enantioenriched substrates (Scheme 1, eq 1).8 Recently, Hyland
et al. disclosed the rearrangement of trichloroacetimidates
derived from cyclopropenylcarbinols bearing an electron-rich
or -neutral aromatic substituent (Scheme 1, eq 2).9 The
substrates involved in these rearrangements were derivatives of
cyclopropenylcarbinols lacking substituents at C3, the presence
of which may have a dramatic influence on the reactivity by either
raising the activation barrier10 or inducing competitive rearrange-
ment pathways.9
substituted alkylidenecyclopropanes B, incorporating an α‑hy-
droxy or α-amino acid subunit (Scheme 1, eq 3).
The Ireland−Claisen rearrangement of glycolate 3a, arising
from the coupling of cyclopropenylcarbinol 1a with the glycolic
acid derivative 2 (94%), was investigated first. The silyl ketene
acetal 4a was generated by addition of an excess of KHMDS (4
equiv) to a solution of glycolate 3a and TMSCl (4 equiv) (THF,
−78 °C).12 Upon warming to rt, 4a underwent a [3,3]-
sigmatropic rearrangement leading to the trimethylsilyl ester
5a (86%). After an acidic aqueous workup, the resulting crude
carboxylic acid was treated with trimethylsilyldiazomethane to
afford methyl ester 6a.13 Analysis of the 1H NMR spectrum of the
Herein, we report our investigations on the reactivity of
glycolates or glycinates A, derived from secondary cyclo-
propenylcarbinols, in the Ireland−Claisen rearrangement11
with the goal of synthesizing highly functionalized and diversely
Received: June 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01759
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Organic Letters
Letter
crude reaction product indicated the formation of 6a as a single
detectable diastereomer (dr >96:4). The Z configuration of the
exocyclic alkene in 6a was established by NMR (NOESY),
whereas the relative configuration of the two newly formed
stereocenters was assigned by a chemical correlation. Cleavage of
the PMB ether in 6a and subsequent iodoetherification afforded
the oxabicyclic compound 7,14 whose relative configuration was
readily established by NMR (NOESY). The stereochemical
outcome was in agreement with a [3,3]-sigmatropic rearrange-
ment of the Z silyl ketene acetal 4a proceeding through a
chairlike transition state T1 in which the substituent at the α
position of the cyclopropene preferentially occupies a pseudo-
equatorial orientation.11,12 We checked that the rearrangement
of glycolate (R)-3a, derived from cyclopropenylcarbinol (R)-1a
(ee = 88%), proceeded with chirality transfer and afforded the
enantioenriched glycolate 6a (ee = 87%) (Scheme 2).
Scheme 3. Competition between an Alkene and a
Cyclopropene in the Ireland−Claisen Rearrangement of 3b
without erosion of the optical purity (ee = 97%). The
alkylidenecyclopropane 6d arising from the Ireland−Claisen
rearrangement of the sterically hindered 2,3,3-trimethylcyclo-
propenycarbinyl glycolate was also obtained in excellent yield
(91%). The Ireland−Claisen rearrangement accommodates a
variety of substituents at the α position of the oxygen atom, as
illustrated with the formation of 6e (84%) and 6f (60%) with
alkyl chains containing a protected alcohol, of the benzylidene-
cyclopropanes 6g (93%) and 6h (90%), as well as of compounds
6i (67%), 6j (72%), and 6k (60%) incorporating heteroaryl
groups.18 The gem-dimethyl substitution could be varied, in
particular by embedding the C3 atom into a nitrogen
heterocycle,19 as illustrated with the formation of the
alkylidene-azaspirocycles 6l (88%) and 6m (77%) (Scheme 4).
Scheme 2. Ireland−Claisen Rearrangement of Cyclo-
propenylcarbinyl Glycolate 3a
Scheme 4. Ireland−Claisen Rearrangement of Substituted
Cyclopropenylcarbinyl Glycolates 3c−l
It is worth noting that an excess of base could be used with no
adverse effect despite the substantial acidity of the vinylic C−H
bond in cyclopropenes.15 Moreover, disubstitution at C3, which
hampered the thermal [2,3]-sigmatropic shift of cyclopropenyl-
carbinyl phosphonites,10 is well accommodated by the Ireland−
Claisen rearrangement. It was observed that the rearrangement
of 3a, although favored by the relief of ring strain, did not
experience significant rate acceleration compared to regular
allylic glycolates.12,16 For a more meaningful comparison, the
Ireland−Claisen rearrangement of glycolate 3b substituted by a
styryl group was studied. After hydrolysis and esterification,
analysis of the crude product by 1H NMR spectroscopy indicated
the exclusive formation of vinylcyclopropene 8, which was
isolated in 60% yield. This competition experiment indicates the
higher reactivity of an α,β-disubstituted alkene, compared to the
more sterically hindered 3,3-dimethylcyclopropene, in the
Ireland−Claisen rearrangement (Scheme 3).17
The Ireland−Claisen rearrangement of diversely substituted
glycolates 3c−3l was then investigated to address the scope of
this transformation. Not surprisingly, the rearrangement occurs
in the absence of gem-dimethyl substitution at C3 though the
presence of a substituent at C2, such as a methyl group in 3c, is
required to ensure substrate stability. We checked that the
rearrangement of the enantioenriched glycolate (R)-3c (ee =
97%)7d afforded the optically active alkylidenecyclopropane 6c
a
b
Obtained from (R)-3c (ee = 97%). Overall isolated yield from the
corresponding cyclopropenylcarbinol (three steps, glycolate precursor
c
not purified). KHMDS (2 equiv) and TMSCl (2 equiv) were used.
d
Workup with H2O.
The reactivity of glycolate 12 substituted by two methyl esters
at C3 deserves particular comments. The requisite cyclo-
propenylcarbinol precursor 11 was obtained by a sila−Morita−
Baylis−Hillman reaction between silylcyclopropene 9 and
hydrocinnamaldehyde, catalyzed by tris(2,4,6-trimethyl-phenyl)-
phosphine (TTMPP),20 followed by desilylation (46%). Under
the previous conditions, a sigmatropic rearrangement effectively
took place and delivered, after workup and esterification,
alkylidenecyclopropane 15 (56%) incorporating a TMS group
B
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Letter
on the three-membered ring. The formation of 15 can be
explained by the initial deprotonation of the cyclopropene 12
with KHMDS (4 equiv), due to the increase of acidity provided
by the negative inductive effect of the carbomethoxy groups at
C3. Related metalated cyclopropenes are known to undergo
rapid ring cleavage to the corresponding metalated alkynyl
malonates but can be trapped in situ with reactive electrophiles
such as TMSCl.21 Thus, the resulting silylcyclopropene 13 would
undergo Ireland−Claisen rearrangement, through the silyl
ketene acetal intermediate 14, to provide alkylidene-
(silylcyclopropane) 15. Lowering the quantity of KHMDS (2
equiv) induced quantitative silylation of cyclopropene 12 but
resulted in an incomplete Ireland−Claisen rearrangement of 13,
thereby confirming that silylation of 12 precedes the [3,3]-
sigmatropic rearrangement. Desilylation of 15 could be
accomplished using n-Bu4NF buffered with AcOH to afford
alkylidenecyclopropane 16 (92%) (Scheme 5).
azabicyclic compound 24 (65%).25 The relative configuration of
24, which was assigned by NMR spectroscopy (NOESY),
confirmed that the stereochemical outcome of the Ireland−
Claisen rearrangement of cyclopropenylcarbinyl glycolates and
glycinates is similar (Scheme 6).12,23
Scheme 6. Ireland−Claisen Rearrangement of N,N-diBoc-
Glycinates 17 and 18
Scheme 5. Ireland−Claisen Rearrangement of Glycolate 11
Possessing gem-Diester Substitution at C3
To demonstrate the synthetic utility of the functionalized
alkylidenecyclopropanes arising from the Ireland−Claisen
rearrangement of cyclopropenylcarbinyl esters, the hydro-
genation of the exocyclic alkene was investigated to access
substituted cyclopropanes. In the presence of Pd/C, hydro-
genation of alkylidenecyclopropane 19 proceeded uneventfully
and stereoselectively afforded the cis-cyclopropane 25 (99%), as
a result of hydrogen addition on the less-hindered face of the
trisubstituted alkene. By contrast, hydrogenation of alkylidene-
cyclopropane 6a led to a 90:10 mixture of cis- and trans-
cyclopropanes 26 and 26′ (99%) and occurred with concomitant
cleavage of the PMB group. In this latter case, we reasoned that
the diastereoselectivity could be improved if the PMB ether was
not cleaved during the reaction. Indeed, by switching to Rh/C as
the catalyst, hydrogenolysis of the PMB ether was suppressed
and the hydrogenation of 6a could be achieved with high
diastereoselectivity to provide the cis-cyclopropane 27 (95%).
Conversely, deprotection of the alcohol in 6a with DDQ enabled
a hydroxyl-directed hydrogenation in the presence of Crabtree’s
catalyst [Ir]-I26 which secured a highly diastereoselective access
to the trans-cyclopropane 26′ (26′/26 = 97:3) (72%, two steps
from 6a) (Scheme 7).
In summary, we have reported the first examples of Ireland−
Claisen rearrangement of esters derived from secondary
cyclopropenylcarbinols which complement the repertoire of
sigmatropic rearrangements in which these latter substrates have
been involved so far. The [3,3]-sigmatropic rearrangement of the
silyl ketene acetals generated from cyclopropenylcarbinyl
glycolates and N,N-diBoc glycinates provides a straightforward
and diastereoselective access to a wide variety of highly
functionalized alkylidenecyclopropanes which are valuable
precursors of substituted cyclopropanes. Other functionaliza-
tions of the alkylidenecyclopropanes arising from these
sigmatropic rearrangements are currently investigated.
Replacement of the glycolate by a glycinate derivative was also
briefly examined to further highlight the interest of the [3,3]-
Ireland−Claisen rearrangement of cyclopropenylcarbinol de-
rivatives. The N,N-diBoc glycinates 17 and 18 were selected as
substrates for this study.22,23 The Ireland−Claisen rearrange-
ment was triggered by formation of the corresponding silyl
ketene acetals using LiHMDS in the presence of TMSCl (THF,
−78 °C to rt).23 After a mild acidic aqueous workup and
esterification (TMSCHN2), alkylidenecyclopropane 19 (78%)
and benzylidenecyclopropane 20 (91%) were obtained with high
diastereoselectivity (dr >96:4). To elucidate the stereochemical
outcome, transformation of compound 20 into a cyclic derivative
was considered, which entailed cleavage of the Boc protecting
groups. This operation was accomplished in a stepwise manner
by treatment with TFA under mild conditions, to avoid
jeopardizing the acid-sensitive benzylidene moiety, and sub-
sequent reaction of the N-Boc derivative 21 (97%) with
TMSOTf in the presence of 2,6-lutidine.24 The resulting ester
22 (99%) possessing a free amino group underwent reductive
amination with benzaldehyde, and the N-benzyl amine 23 (69%)
was engaged in a stereoselective iodocyclization leading to the
C
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and spectral data for all new
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01759.
■
S
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: christophe.meyer@espci.fr.
*E-mail: janine.cossy@espci.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
G.E. thanks Diverchim for a CIFRE grant.
■
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DOI: 10.1021/acs.orglett.5b01759
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