Gold(I)-catalysed cycloisomerisation of 1,6-cyclopropene-enes

Article abstract of DOI:10.1002/chem.201200566

The gold(I)-catalysed cycloisomerisation of appropriately substituted 1,6-cyclopropene-enes proceeds through regioselective electrophilic ring opening of the three-membered ring to generate an alkenyl gold carbenoid that achieves the intramolecular cyclopropanation of the remote olefin. This strategy allows straightforward, highly efficient and diastereoselective access to a variety of substituted 3-oxaand 3-azabicycloachtungtrenung[4.1.0]heptanes, as well as to bicycloachtungtrenung[4.1.0]heptan-3-ol derivatives. Since the isopropylidene group in the resulting cycloisomerisation products can be subjected to ozonolysis, 3,3-dimethylcyclopropenes behave as interesting surrogates for a-diazoketones.

Full text of DOI:10.1002/chem.201200566

DOI: 10.1002/chem.201200566
Gold(I)-Catalysed Cycloisomerisation of 1,6-Cyclopropene-enes
Frꢀdꢀric Miege, Christophe Meyer,* and Janine Cossy*[a]
Abstract: The gold(I)-catalysed cyclo-
isomerisation of appropriately substi-
tuted 1,6-cyclopropene-enes proceeds
through regioselective electrophilic
ring opening of the three-membered
ring to generate an alkenyl gold carbe-
noid that achieves the intramolecular
cyclopropanation of the remote olefin.
This strategy allows straightforward,
highly efficient and diastereoselective
access to a variety of substituted 3-oxa-
and 3-azabicyclo
ACHTUNGERTN[NUNG 4.1.0]heptanes, as well
as to bicyclo[4.1.0]heptan-3-ol deriva-
AHCTUNGTRENNUNG
tives. Since the isopropylidene group in
the resulting cycloisomerisation prod-
ucts can be subjected to ozonolysis,
3,3-dimethylcyclopropenes behave as
interesting surrogates for a-diazo-
ketones.
Keywords: carbenoids · cyclopropa-
nation · cyclopropenes · gold cataly-
sis · strained molecules
Introduction
This strategy, which is useful for the preparation of
bicyclo[n.1.0]alkanones C also provides unique access to
AHCTUNGTRENNUNG
The development of efficient synthetic routes toward struc-
turally diverse compounds containing a bicycloACHTNUTRGNE[NUG n.1.0]alkane
moiety has elicited considerable interest due to their occur-
rence in many natural products and/or bioactive substances,
as well as their use as key building blocks in organic synthe-
sis.[1–4] Catalytic processes that involve stereoselective access
cyclopropyllactones or cyclopropyllactams (Y=O or
N-EWG, EWG=electron-withdrawing group).[4] By compar-
ison, the reactivity of diazoketones bearing a heteroatom at
the a-position of the carbonyl group (Z=O or N-EWG) has
been much less well investigated.[6]
Due to the potential hazards associated with the handling
of diazo compounds, or some of the reagents involved in
their preparation, alternative processes have been devel-
to substituted bicyclo
precursors are particularly attractive and in this context,
transition-metal-catalysed reactions play prominent
ACHTUNGTRENN[UNG n.1.0]alkanes from readily available
a
oped. Formation of compounds possessing a bicyclo-
role.[3–5] The intramolecular cyclopropanation of an olefin by
an a-oxo carbene B, generated by decomposition of an
a-diazo carbonyl compound A in the presence of a transi-
tion-metal catalyst, is arguably the most commonly em-
ployed method (Scheme 1).[4]
ACHTUNGTREN[NUNG n.1.0]alkane moiety has often been observed in transition-
metal-catalysed reactions involving enynes as substrates.[7,8]
In recent years, we have witnessed increased interest in plat-
inum and gold complexes as catalysts for such reactions that
proceed through cyclopropyl metal carbenoid intermediates.
The bicycloACTHNUGRTNEUNG[n.1.0]alkane core of these intermediates can be
retained in the final products upon oxidation with diphenyl
sulfoxide,[9] trapping with an alkene by inter- or intramolecu-
lar cyclopropanation[10] or when evolution by a C H inser-
À
tion[11] or 1,2-hydride shift[12] reaction can occur. However,
only propargylic carboxylates D behave as real surrogates
for a-diazoketones since for these substrates, whether the
1,2-acyloxy shift follows[13] or precedes enyne cyclisation,[14]
the final products E invariably possess an enol carboxylate
Scheme 1. Formation of bicycloACTHNURTGNEU[GN n.1.0]alkanes from a-diazocarbonyl
compounds A.
moiety, which is
a precursor of a carbonyl group
(Scheme 2). It is worth pointing out that since an acyloxy
[a] Dr. F. Miege, Dr. C. Meyer, Prof. Dr. J. Cossy
Laboratoire de Chimie Organique
ESPCI ParisTech, CNRS (UMR 7084)
10 rue Vauquelin 75231 Paris Cedex 05 (France)
Fax: (+33)140794660
E-mail: christophe.meyer@espci.fr
janine.cossy@espci.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201200566. It contains the full
experimental details, compound characterisation and copies of the
NMR spectra of all new compounds.
Scheme 2. Cycloisomerisation of enynes
carboxylate.
D possessing a propargylic
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FULL PAPER
group is required at the propargylic position in substrates D,
the opportunities to incorporate a heteroatom within the
enyne tether, which would potentially allow access to het-
erocycles, are restricted.
with carbenoids generated from 3,3-disubstituted cyclopro-
penes have also been reported by using a copper(I) cata-
lyst[23] and, more recently, in the presence of gold(I) com-
plexes.[24,25] In 1981, Padwa et al. disclosed an intramolecular
version in which 1,2-diphenylcyclopropenes J bearing an
allylic chain at C3 were converted into 1,2-diphenylbicyclo-
In the presence of an electrophilic gold(I) catalyst and an
appropriate oxidising agent, such as 8-methylquinoline
N-oxide, alkynes generate a-oxo gold carbenoids[15] that can
achieve intramolecular olefin cyclopropanations. This pro-
cess was first reported for enynes F, connected through an
aromatic ring or a Z alkene[16] and, more recently, in the
case of alkynyl ketones or amides H, for which formation of
a gold carbenoid substituted by two electron-withdrawing
groups has been observed (Scheme 3).[17] It is worth men-
tioning that an alternative synthesis of the resulting com-
AHCTUNGTRE[GNNUN 3.1.0]hex-2-enes K upon treatment with AgClO4 as a result
of stereospecific intramolecular cyclopropanation of the
alkene by an intermediate silver carbenoid (Scheme 5).[26]
pounds I has also been disclosed that uses a palladium
ACHTUNGTNER(NUNG II/
IV)-catalysed cyclisation of enynes H (Scheme 3).[18]
Scheme 5. Intramolecular cyclopropanation of an olefin with a silver car-
benoid generated by ring opening of a cyclopropene.
However, the scope of the intramolecular cyclopropana-
tion of an olefin with a metal carbenoid generated by ring
opening of an appropriately substituted cyclopropene has
remained relatively unexplored despite its high synthetic
potential to access various heterocycles and carbocycles
possessing a bicycloACTHNUTRGNE[NUG n.1.0]alkane core. With the aim of de-
vising cyclopropenes that would behave as a-diazoketone
surrogates, we became interested in investigating the cyclo-
isomerisation of 3,3-dimethylcyclopropene-enes L (X=O or
N-EWG; Scheme 6). For such substrates possessing a mono-
substituted endocyclic alkene, we reasoned that the electro-
philic ring opening of the cyclopropene should occur in a re-
gioselective manner to provide alkenyl carbenes M in which
the metal is linked to the less-substituted terminus. Addi-
tionally, gem-dimethyl substitution at C3 was selected in
order to handle stable substrates and avoid the formation of
geometric isomers of the newly generated tetrasubstituted
alkene. The intramolecular cyclopropanation of the remote
Scheme 3. Intramolecular cyclopropanation of olefins by a-oxo gold car-
benoids.
With the goal of developing other transition-metal-cata-
lysed reactions leading to bicycloACTHNUGTRNEUNG[n.1.0]alkanes that involve
the intramolecular cyclopropanation of an olefin but do not
rely on the use of diazo compounds,[19] cyclopropenes
appear to be an interesting class of substrate. Indeed, it is
known that in the presence of electrophilic transition-metal
complexes, cyclopropenes undergo ring-opening reactions to
provide metal carbenoids that can be viewed as resonance
hybrids between metal-stabilised allylic carbocations and al-
kenyl metal carbenes (Scheme 4).[20,21]
olefin should provide bicycloACTHNUTRGNEUGN[4.1.0]heptanes N and subse-
Scheme 4. Generation of alkenyl metal carbenoids by ring opening of
cyclopropenes.
In 1974, Binger and McMeeking disclosed the first exam-
ples of intermolecular cyclopropanation of electron-deficient
olefins with carbenoids generated by ring opening of 3,3-di-
methylcyclopropene by using a nickel(0) catalyst.[22] Addi-
tional examples of intermolecular olefin cyclopropanation
Scheme 6. Cyclopropenes as a-diazoketone surrogates in intramolecular
olefin cyclopropanation (EWG= electron-withdrawing group).
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J. Cossy, C. Meyer and F. Miege
quent oxidative cleavage of the isopropylidene group would
then deliver the corresponding bicyclo[4.1.0]heptanones O
(Scheme 6). Interestingly, this approach would be comple-
mentary to the scarcely studied transition-metal-catalysed
intramolecular cyclopropanation of diazoketones P. For sub-
cient
1,6-cyclopropene-ene 4a into the desired 3-oxabicyclo-
ACHTUNGTREN[NUGN 4.1.0]heptane 5a (79–93%) but the best results were ob-
tained with simple gold salts, such as AuCl, AuCl3 or
AuBr3.[27] The reaction was then complete in less than
15 min in CH2Cl2 at 08C and compound 5a was isolated in
almost quantitative yield (97–99%; Scheme 8). Although
catalysts
for
the
cycloisomerisation
of
AHCTUNGTRENNUNG
À
strates P, 1,5-insertion of the carbenoid into an allylic C H
bond leading to heterocycles Q occurs predominantly when
rhodium(II) complexes are used as catalysts[6b,c] but
Pd(OAc)2 or [CuACHTUNGTRENNUNG(acac)2] (acac=acetylacetonate) favour in-
tramolecular cyclopropanation of the olefin (Scheme 6).[6a]
Herein, we report a full account of our studies on the de-
velopment of highly diastereoselective gold-catalysed cyclo-
isomerisation of 1,6-cyclopropene-enes, as an efficient route
towards either 3-hetero-substituted bicyclo
ACHTUNGTREN[NUGN 4.1.0]heptanes or
bicyclo[4.1.0]heptan-3-ol derivatives, in which the 3,3-dime-
ACHTUNGTRENNUNG
thylcyclopropenyl group behaves as a synthetically useful
surrogate of an a-diazoketone.[27]
Results and Discussion
Synthesis and gold-catalysed cycloisomerisation of allyl
cyclopropenylcarbinyl ethers: Our investigations began by
studying the behaviour of allylic ethers of type L (X=O),
derived from 3,3-dimethylcyclopropenylcarbinols. A model
substrate was prepared in three steps from commercially
available 1-bromo-2-methylpropene (1), which underwent
dibromocyclopropanation under phase-transfer catalysis
(HCBr3, 50% aqueous NaOH, cetrimide, CH2Cl2, RT) to
provide tribromocyclopropane 2 in 67% yield (Scheme 7).
Treatment of 2 with nBuLi (1.9 equiv) in Et2O (À788C to
À108C) generated 3,3-dimethylcyclopropenyllithium in situ
and after addition of benzyloxyacetaldehyde (À508C to
Scheme 8. Gold-catalysed cycloisomerisation of cyclopropene-ene 4a,
determination of the relative configuration of 5a and ozonolysis of the
isopropylidene group (PNB=para-nitrobenzoyl, DMPU=N,N’-dimethyl-
propyleneurea, DCC=N,N’-dicyclohexylcarbodiimide, DMAP=4-di-
methylaminopyridine).
RT), cyclopropenylcarbinol
3
was obtained (75%;
Scheme 7).[28] Subsequent alkylation with allyl bromide
(tBuOK, THF, 08C to RT)[29] provided the corresponding
allyl cyclopropenylcarbinyl ether 4a in 89% yield
(Scheme 7).
AuCl does not lead to a well-defined gold species in
CH2Cl2,[30] it was selected as the catalyst in our subsequent
studies because it is considerably less hygroscopic than
AuCl3 and hence is easier to handle and to accurately weigh
on small scale.[31] Remarkably, the 3-oxabicyclo-
AHCTUNGTREG[NNNU 4.1.0]heptane 5a was formed as a single detectable diaste-
reomer (diastereomeric ratio (d.r.)>95:5), in which the rela-
tive orientation of the cyclopropane and the benzyloxy-
methyl substituent was anti.[32] The relative configuration of
5a, which could not be determined by NMR spectroscopy
due to the absence of an observable nuclear Overhauser
effect (nOe), was unambiguously established by X-ray
diffraction analysis of the crystalline para-nitrobenzoate 7,
synthesised by debenzylation of 5a under Birch conditions,
followed by esterification of the primary alcohol 6 with
para-nitrobenzoic acid (Scheme 8).
To demonstrate that the 3,3-dimethylcyclopropenyl
moiety could indeed behave as an a-diazoketone surrogate,
the oxidative cleavage of the isopropylidene group in com-
pound 5a was achieved by ozonolysis (O3/O2, CH2Cl2,
À788C), followed by reduction of the resulting ozonide with
PPh3 (À788C to RT; Scheme 8). Under these conditions,
ketone 8 was isolated in 86% yield (d.r.>95:5) and its rela-
Scheme 7. Synthesis of model allyl cyclopropenylcarbinyl ether 4a (Bn=
benzyl).
In previous studies, gold(I) complexes, such as
[(Ph3P)AuOTf] (Tf=trifluoromethanesulfonyl), [(Ph3P)Au-
ACHTUNGTRENNUNG(SbF6)] and [(Ph3P)AuNTf2], were identified as highly effi-
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Cycloisomerisation of 1,6-Cyclopropene-enes
FULL PAPER
tive configuration, which could be determined by NMR
(nOe) spectroscopy, confirmed that no epimerisation oc-
curred. Cyclopropyl ketones constitute an interesting class
of compounds that can undergo ring opening of the three-
membered ring, as illustrated by the reaction of compound 8
with SmI2 (THF/DMPU, RT),[33] which led to the formation
of trans-2,5-disubstituted tetrahydropyran-3-one 9 in 42%
yield (unoptimised; Scheme 8).
sessing a,a-disubstituted (4b), a,b-disubstituted (4c, 4d) or
a,b,b-trisubstituted (4e, 4 f, 4g) allylic ethers, generally in
good yields (65–92%), except for compound 4c (26%) for
which incomplete conversion was observed but the reaction
was not optimised (Table 1).
Table 1. Synthesis of substituted allylic ethers 4b–g from cyclopropenyl-
carbinol 3.
The formation of 3-oxabicycloACTHNUGRTNEUNG[4.1.0]heptane 5a can be ex-
plained by an initial regioselective electrophilic ring opening
of the cyclopropene 4a upon coordination of the gold cata-
lyst, leading to the gold carbenoid intermediate 10
(Scheme 9).[25] Subsequent intramolecular cyclopropanation
R1
R2
R3
Cyclopropene-enes
AHCTUNGTRENNG(UN Yield [%])
H
Ph
H
H
H
Me
Me
Me
H
H
H
H
4b (92)
4c (86)
4d (26)
4e (89)
4 f (74)
4g (65)
CH2OTBDPS[a]
Me
N
N
H
Other secondary cyclopropenylcarbinols were also syn-
thesised by addition of in situ generated 3,3-dimethylcyclo-
propenyllithium (from tribromocyclopropane 2 and nBuLi)
to various aldehydes. Cyclopropenylcarbinol 12, bearing
a benzyl ether at a remote position, was easily synthesised
from 4-benzyloxybutanal (11,[35] 42%; Scheme 10). When
aldehyde 13, derived from the (S)-Roche ester, was used as
Scheme 9. Rationalisation of the stereochemical outcome.
of the terminal olefin should then proceed through a six-
membered cyclic transition state. A chair-like transition
state TS’1 was initially considered but this model predicts
the formation of the epimeric cycloisomerisation product
5’a, which is not observed. In fact, transition state TS’1 may
be disfavoured due to a 1,3-diaxial interaction between the
CH2OBn group and the gold centre, which are both forced
to occupy pseudo-axial positions to minimise A1,3 strain with
the methyl groups of the isopropylidene substituent.[34] In
contrast, a twist-boat-like transition-state model TS1 would
avoid this unfavourable interaction and effectively explain
the stereoselective formation of 3-oxabicycloACTHNURTGNEU[GN 4.1.0]heptane
5a (Scheme 9). Although conformations in the solid state
and in solution may be different, it is worth noting that the
5-isopropylidene-3-oxabicycloACTHNUTRGNEUGN[4.1.0]heptane 7 crystallises in
a twist-boat conformation similar to that drawn for the tran-
sition-state model TS1. Thus, it appears that gem-dimethyl
substitution at C3 in the 1,6-cyclopropenene-enes of type L
may act as a key element in the control of the diastereo-
selectivity.
In our subsequent studies, the scope of the gold-catalysed
cycloisomerisation of the 3,3-dimethylcyclopropene-enes
was evaluated for substrates possessing substituents on the
allylic ether moiety and derived from various secondary
Scheme 10. Synthesis of the secondary cyclopropenylcarbinols 12, 14 and
15 and configurational assignment of 14 and 15 (TBHP=tert-butylhydro-
peroxide, (+)-DET=diethyl l-tartrate, DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone, MS=molecular sieves, PMB=para-methoxybenzyl,
PMP=para-methoxyphenyl).
cyclopropropenylcarbinols. Cyclopropenylcarbinol
3 was
alkylated with commercially available or readily prepared
allylic bromides in the presence of tBuOK (THF, 08C to
RT) to afford the corresponding 1,6-cyclopropene-enes pos-
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J. Cossy, C. Meyer and F. Miege
the electrophile,[36] a mixture of epimeric cyclopropenylcar-
binols 14 and 15 was obtained in a 30:70 ratio (83% overall
yield; Scheme 10), which were separated by MPLC
(MPLC=medium pressure liquid chromatography). To
assign their relative configuration, an equimolar mixture of
epimeric alcohols 14 and 15 was subjected to Sharpless ki-
netic resolution in the presence of (+)-DET, which showed
that the major epimer 15 was selectively oxidised to enal 16
under those conditions (Scheme 10).[37] This result indicated
an S configuration for the hydroxyl-substituted stereocentre
in alcohol 15. Additionally, hydroalumination of the minor
cyclopropenylcarbinol 14[38] and subsequent treatment of the
resulting compound 17 with DDQ (anhydrous conditions)
provided para-methoxybenzylidene acetal 18 (52%, 83:17
epimeric mixture at the acetal stereocentre), the relative
oxymethyl substituent in previous substrates 4b–4g synthe-
sised from 3.
The effect of substitution on the olefin of the allylic ether
was first examined. The gold-catalysed cycloisomerisation of
methallyl ether 4b provided a mixture of the corresponding
diastereomeric oxabicyclic compounds 5b and 5’b in an
87:13 ratio, from which the major diastereomer 5b was iso-
lated in 72% yield (Scheme 11). The moderate diastereose-
1
configuration of which was confirmed by H NMR spectros-
copy (Scheme 10).
Application of the Felkin–Anh model[39] would have pre-
dicted cyclopropenylcarbinol 14 to be the major diastereo-
mer, which is not experimentally observed. Due to the pres-
ence of the para-methoxybenzyloxy ether at the b position
of the carbonyl group, a Cram-chelate model could explain
the modest diastereoselectivity in favour of cyclopropenyl-
carbinol 15.[39,40]
Scheme 11. Cycloisomerisation of methallyl cyclopropenylcarbinyl ether
4b.
The secondary cyclopropenylcarbinols 12, 14 and 15 were
then alkylated with various allylic bromides to provide
a new series of allyl cyclopropenylcarbinyl ethers 19–26 (70–
93%; Table 2), bearing alternative side chains to the benzyl-
lectivity for the intramolecular cyclopropanation of an a,a-
disubstituted alkene may be due to a steric interaction be-
tween the benzyloxymethyl side chain and the methyl sub-
stituent of the methallyl ether in the twist-boat-like transi-
tion state TS2. Thus, cyclopropanation may competitively
proceed through the chair-like transition state TS’2 in which
the methyl group occupies an axial position. The latter is
not too disfavoured since the presence of the oxygen atom
and the isopropylidene group avoids 1,3-diaxial interactions
with the methyl group (Scheme 11).
Table 2. Synthesis of substituted allyl cyclopropenylcarbinyl ethers 19–
26.
Under similar conditions, the gold-catalysed cycloisomeri-
sation of all other allyl cyclopropenylcarbinyl ethers 4c–4g,
proceeding with intramolecular cyclopropanation of a,b-di-
substituted or a,b,b-trisubstituted olefins, delivered the cor-
Cyclopropenylcarbinols R1
R2
Cyclopropene-enes
AHCTUNGTRENNG(UN Yield [%])
responding 3-oxabicycloACTHUNRGTNE[NUG 4.1.0]heptanes 5c–5g in excellent
yields (93–99%) and with high diastereoselectivities (d.r.>
95:5; Table 3). The trans relative orientation of the hydrogen
atoms at C1 and C7 in the oxabicyclic compounds 5c and
5d, arising from the gold-catalysed cycloisomerisation of the
(E)-allylic ethers 4c and 4d, indicates that the intramolecu-
lar cyclopropanation proceeds with retention of the olefin
geometry (Table 3, entries 1 and 2). The stereospecificity of
the intramolecular cyclopropanation process was demon-
strated in the case of the geranyl ether 4 f and the neryl
ether 4g, which eventually provided the 3-oxabicyclo-
12
H
H
19 (93)
14
14
H
Me
H
Me
20 (87)
21 (87)
AHCTUNGTRENNUNG
15
15
15
15
15
H
Ph
Me
H
H
Me
22 (84)
23 (70)
24 (74)
25 (72)
26 (79)
enes 19–26, derived from various secondary cyclopropenyl-
carbinols, also delivered the corresponding 3-oxabicyclo-
AHCTUNGTRENNUNG
AHCTUNGTREN(GUNN CH2)2CH= Me
CMe2
Me
ACHTUNGTRENNUNG
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Cycloisomerisation of 1,6-Cyclopropene-enes
FULL PAPER
Table 3. Gold-catalysed cycloisomerisation of cyclopropene-enes 4c–4g.
Table 4. Gold-catalysed cycloisomerisation of cyclopropene-enes 19-26.
Cyclopropene-enes
Products
Yield
[%]
Cyclopropene-enes
Reaction Products
time
Yield
[%]
93
87
92
93
84
90
1
2
3
15 min
15 min
15 min
93
97
98
4
5
15 min
90 min
97
99
nature of the substituent (linear or branched) at the a posi-
tion relative to the oxygen atom, as well as the nature and
location of the benzylic ether (OBn or OPMB) on the chain
(Table 4).
Thus, the scope of the gold-catalysed cycloisomerisation
of the allylic ethers derived from secondary 3,3-dimethyl-
cyclopropenylcarbinols appears rather broad and the reac-
tion provides a remarkably efficient route to substituted
98
97
3-oxabicycloACHTUNGTRENNUNG[4.1.0]heptanes. To determine the limits of the
method, the behaviour of three other 1,6-cyclopropene-enes
bearing a different substitution pattern was examined.
Upon treatment with AuCl (5 mol%; CH2Cl2, 08C), allyl
cyclopropenylcarbinyl ether 35,[29] lacking gem-dimethyl sub-
stitution at C3 and possessing instead a disubstituted endo-
cyclic olefin, was found to provide a complex mixture of
products (inseparable) in which the presence of a 75:25 dia-
a-methyl-substituted gold carbenoid formed at C2 could not
achieve the intramolecular cyclopropanation of the remote
alkene and presumably evolved by competing pathways. Ex-
posure of the tetrasubstituted cyclopropene 37 to AuCl de-
livered a very complex mixture of unidentified products that
do not contain any cyclopropane rings (Scheme 12). Thus, in
the presence of gem-dimethyl substitution at C3, a disubsti-
tuted gold carbenoid generated either at C1 or C2 cannot be
involved in an intramolecular cyclopropanation of the
remote alkene, presumably due to conformational restric-
tions (Scheme 12).
stereomeric mixture of the 3-oxabicycloACTHNUTRGNEUNG[3.1.0]hexanes 36/36’
was detected (Scheme 12). These compounds (accounting
for ca. 50% of the mixture) arise from intramolecular cyclo-
propanation of the remote olefin by a gold carbenoid
formed at C1. However, since several other signals corre-
sponding to vinylic protons (including those of the unaffect-
1
ed allylic ether moiety) were visible in the H NMR spec-
The reactivity of the allylic ether 39, derived from the
tertiary cyclopropenylcarbinol 38, easily prepared by addi-
tion of 3,3-dimethylcyclopropenyllithium to benzyloxyace-
trum of the crude product, the ring opening of cyclopropene
35 was probably not regioselective but the regioisomeric
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J. Cossy, C. Meyer and F. Miege
Table 5. Synthesis of N-allyl-N-tosyl-cyclopropenylcarbinylamines 45–50.
Sulfonamide
R1
R2
R3
Products
AHCTUNGTRENNG(UN Yield [%])
43
44
43
44
44
44
H
H
H
H
H
H
H
H
H
H
Me
Me
H
45 (99)
46 (91)
47 (99)
48 (95)
49 (96)
50 (99)
Scheme 12. Behaviour of allyl cyclopropenylcarbinyl ethers 35 and 37 in
the presence of a gold catalyst.
CH2OTBDPS
H
H
CH2OTBDPS
H
tone, was also investigated (Scheme 13). As anticipated, the
gold-catalysed cycloisomerisation of 39 proceeded with low
diastereoselectivity and provided the corresponding 3-oxa-
81% and 71% yield, respectively (Table 5). Alkylation of
the nitrogen atom with various allylic bromides was subse-
quently achieved under mild conditions in the presence of
K2CO3 (DMF, RT) to afford the corresponding substituted
N-allylsulfonamides 45–50 in excellent yields (91–99%;
Table 5).
As the tosyl group may be difficult to cleave in the final
cycloisomerisation products,[43] the preparation of an N-allyl-
cyclopropenylcarbinylamine in which the nitrogen atom is
protected as a tert-butyl carbamate was carried out. Treat-
ment of benzyloxyacetaldehyde with tert-butyl carbamate
and sodium para-toluenesulfinate in the presence of formic
acid (MeOH/H2O (1:2), RT) afforded the unstable adduct
51 (61%, Scheme 14).[44] Thus, this compound was directly
treated with an excess of 3,3-dimethylcyclopropenyllithium
(4 equiv), which generated the unstable N-Boc-imine 52 in
situ. Subsequent addition of the organolithium to 52 took
place to afford carbamate 53 in 71% yield. Not surprisingly,
allylation of the nitrogen atom of the carbamate required
the use of a stronger base (KHMDS, DMF, 08C to RT) than
the sulfonamides and the desired N-Boc-N-allylcycloprope-
nylcarbinylamine 54 was isolated in 99% yield (Scheme 14).
Having secured an efficient route to nitrogen-tethered
1,6-cyclopropene-enes, their gold-catalysed cycloisomerisa-
tion was achieved by treatment with a catalytic amount of
Scheme 13. Cycloisomerisation of the tertiary allyl cyclopropenylcarbinyl
ether 39.
bicyloACHTUNGTRENNUNG[4.1.0]heptanes 40a and 40’a in good yield (77%) as
a 60:40 mixture of diastereomers. This ratio presumably re-
flects the difference in A1,3 strain energies between the
vinylic methyl group of the isopropylidene substituent and
either the methyl or the benzyloxymethyl group at the
allylic position, in the possible twist-boat transition states
TS3 and TS’3, respectively (Scheme 13).
With the goal of further extending the scope of the gold-
catalysed cycloisomerisation of 1,6-cyclopropene-enes, the
possibility to access 3-azabicycloACTHNUTRGNEUNG[4.1.0]heptanes from
N-allyl-substituted cyclopropenylcarbinylamine derivatives
was explored.
Synthesis and gold-catalysed cycloisomerisation of N-allyl-
cyclopropenylcarbinylamine derivatives: A straightforward
route toward this class of substrates relies on the nucleo-
philic addition of in situ generated 3,3-dimethylcycloprope-
nyllithium to activated imines (bearing an electron-with-
drawing group on the nitrogen atom). Thus, starting from
N-tosylimines 41[41] and 42,[42] derived from benzaldehyde
and benzyloxyacetaldehyde, the corresponding N-tosyl-
cyclopropenylcarbinylamines 43 and 44 were obtained in
Scheme 14. Preparation of the N-Boc-N-allyl-cyclopropenylcarbinylamine
54 (KHMDS=potassium hexamethyldisilazide, Boc=tert-butoxycarbonyl,
Ts=tosyl).
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Cycloisomerisation of 1,6-Cyclopropene-enes
FULL PAPER
AuCl (5 mol%) under the previously used conditions
(CH2Cl2, 08C, 15 min). Regardless of the nature of the sub-
stituent at the a position of the nitrogen atom (Ph or
CH2OBn), the substituted N-allylsulfonamides 45 and 46
diastereoselectivity of the cycloisomerisation was not as
high as previously observed for oxygen-tethered 1,6-cyclo-
propene-enes, although the diastereomeric ratio (d.r.=
90:10) remains acceptable. In contrast, the isomer 50 of Z
configuration delivered the corresponding 3-azabicyclo-
gave rise to the corresponding 3-azabicycloACTHNUGRTENUNG[4.1.0]heptanes
55 and 56 as single diastereomers (d.r.>95:5), which were
isolated in high yields (99 and 93%, respectively; Table 6,
entries 1 and 2). As anticipated, a slight loss of diastereose-
lectivity was observed in the cycloisomerisation of the
N-methallyl-substituted sulfonamides 47 and 48, which de-
livered the corresponding azabicyclic compounds as a mix-
ture of diastereomers 57/57’ (92:8 ratio, 99%) and 58/58’
(95:5 ratio, 89%), respectively (Table 6, entries 3 and 4).
However, the levels of diastereoselectivity were much better
than the cycloisomerisation of methallyl cyclopropenylcar-
binyl ether 4b (Scheme 11). Cyclopropene 49, possessing
a remote a,b-disubstituted alkene of E configuration, was
converted into a 90:10 mixture of diastereomers 59 and 59’,
which were separated and isolated in 83 and 8% yield, re-
spectively (Table 6, entry 5). For this class of substrates, the
ACHTUNGTREN[NUGN 4.1.0]heptane 60 (97%), an epimer of 59 at C7, as a single
detectable diastereomer (d.r.>95:5; Table 6, entry 6).
To illustrate again that 3,3-dimethylcyclopropenes can
behave as useful a-diazoketone surrogates in intramolecular
olefin cyclopropanation, the ozonolysis of the isopropyl-
idene group in compound 55 was carried out to afford the
corresponding 3-azabicyclo
ACHTUNGTRNE[NUNG 4.1.0]heptan-5-one 61 in almost
quantitative yield (Scheme 15).
Scheme 15. Synthesis of 3-azabicycloACTHNUTRGNEUNG[4.1.0]heptan-5-one 61.
Attempts to achieve the clean reductive cleavage of the
tosyl group in compound 55 to access the corresponding
free secondary cyclic amine were unsuccessful.[43a,b] Fortu-
nately, the gold-catalysed cycloisomerisation of carbamate
54 was found to proceed smoothly, albeit at a slower rate
(CH2Cl2, 08C, 2 h; Scheme 16) than that observed for the
Table 6. Gold-catalysed cycloisomerisation of cyclopropene-enes 45–50.
Cyclopropene-enes Products
(Yield [%])
d.r.
AHCTUNGTRENNUNG
1
2
>95:5
Scheme 16. Gold-catalysed cycloisomerisation of cyclopropene-ene 54.
>95:5
structurally related sulfonamide substrate 45 (08C, 15 min;
Table 6, entry 1). Subsequent cleavage of the Boc group
could be achieved in a one-pot manner by treatment with
trifluoroacetic acid to deliver the corresponding 3-aza-
bicycloACHTNUTRGNE[UNG 4.1.0]heptane 62 as a single diastereomer (d.r.>
95:5), isolated in 83% overall yield (two steps from 54;
Scheme 16).
We have demonstrated that the gold-catalysed cycloiso-
merisation of appropriately substituted 1,6-cyclopropenes
affords a straightforward and remarkably efficient route to
3
4
92:8
95:5
3-hetero-substituted bicycloACTHNUTRGNEUGN[4.1.0]heptanes in excellent
5
6
90:10
yields and with high diastereoselectivities. It is noteworthy
that the unsaturated olefinic side chain present in the requi-
site substrates is easily introduced by a simple alkylation of
the heteroatom in the readily available cyclopropenylcarbi-
nols and cyclopropenylcarbinylamine derivatives by using an
allylic bromide.
>95:5
Gold-catalysed cycloisomerisation of 1,6-cyclopropene-enes
[a] Isolated yield of combined diastereomers.
leading to substituted bicycloACTHNGUTRENNU[G 4.1.0]heptan-3-ols: To further
Chem. Eur. J. 2012, 18, 7810 – 7822
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7817

J. Cossy, C. Meyer and F. Miege
extend the scope of the gold-catalysed cycloisomerisation of
1,6-cyclopropene-enes, the synthesis of bicyclo-
[4.1.0]heptanes devoid of a heteroatom within the bicyclic
ring system was examined. In particular, bicyclo-
ACHTUNGTRENNUNG[4.1.0]heptan-3-ols R were selected as targets because they
On the other hand, the allylic glycolate 70[48] was engaged
in an Ireland–Claisen rearrangement (KHMDS, TMSCl,
THF, À788C to RT)[49] to afford, after work up and treat-
ment with trimethylsilyl diazomethane,[50] the g,d-unsatu-
rated methyl ester 71 (98%; Scheme 20). After reduction
ACHTUNGTRENNUNG
could potentially arise from the gold-catalysed cycloisomeri-
sation of cyclopropenylcarbinol derivatives S, which in turn
would be prepared by nucleophilic addition of 3,3-dimethyl-
cyclopropenyllithium to g,d-unsaturated aldehydes
T
(Scheme 17).
Scheme 17. Synthesis of bicycloACTHUNRTGNEUNG[4.1.0]heptan-3-ols R from 1,6-cyclopro-
pene-enes S.
Scheme 20. Preparation of cyclopropenylcarbinols 74 and 75 (TMS=tri-
methylsilyl).
Preparation of the simplest substrate of type S was ach-
ieved by addition of in situ generated 3,3-dimethylcyclopro-
penyllithium (from tribromocyclopropane 2 and nBuLi) to
4-pentenal (63), which afforded cyclopropenylcarbinol 64
(57%; Scheme 18). Other g,d-unsaturated aldehydes T can
with excess DIBAL-H, the resulting primary alcohol 72
(71%) was oxidised with Dess–Martin periodinane (DMP)
to provide the desired g,d-unsaturated aldehyde 73 (85%).
The nucleophilic addition of 3,3-dimethylcyclopropenyllithi-
um to aldehyde 73 proceeded with moderate Felkin–Anh
control and provided a 65:35 mixture of the epimeric secon-
dary alcohols 74 and 75, which could be isolated in 47 and
29% yield, respectively, after separation by flash column
chromatography (Scheme 20). To confirm the stereochemi-
cal assignment made for these two alcohols, 3,3-dimethyl-
cyclopropenyllithium was transmetalated with an excess of
MgBr2·OEt2 and addition of the corresponding Grignard to
aldehyde 73 effectively reverted the stereochemical outcome
(74/75=10:90). The major diastereomer 75 was isolated in
65% yield and its preferential formation under the latter
conditions can be reasonably attributed to Cram-chelate
control (Scheme 20).[39,40]
Scheme 18. Preparation of cyclopropenylcarbinol 64.
also be conveniently prepared by a Claisen rearrange-
ment.[45] Thus, the Johnson–Claisen rearrangement of the
ketene acetal generated from allylic alcohol 65[46] and tri-
ethyl orthoacetate afforded the (E)-g,d-unsaturated ester 66
(79%; Scheme 19). After formation of the Weinreb amide[47]
The behaviour of the 1,6-cyclopropene-ene 64 was exam-
ined in the presence of AuCl (5 mol%). Cycloisomerisation
efficiently took place under the usual conditions (CH2Cl2,
08C) and analysis of the crude reaction mixture, after partial
evaporation of the solvent, indicated the formation of an
87:13 mixture of the diastereomeric bicycloACTHNUGRTENUNG[4.1.0]heptan-3-
ols 76 and 76’ (Scheme 21). However, these compounds
were volatile and therefore acetylation of the hydroxy group
and ozonolysis of the isopropylidene moiety were subse-
quently carried out in the same pot to provide a-acetoxy-
Scheme 19. Preparation of cyclopropenylcarbinol 69.
67 (92%) and subsequent reduction with DIBAL-H, the re-
sulting aldehyde 68 was directly condensed with 3,3-di-
methylcyclopropenyllithium to furnish the corresponding
1,6-cyclopropene-ene 69 in 46% yield (two steps from
amide 67; Scheme 19).
Scheme 21. Gold-catalysed cycloisomerisation of cyclopropenylcarbinol
64.
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Cycloisomerisation of 1,6-Cyclopropene-enes
FULL PAPER
ketone 77 in 66% overall yield (three steps from 64) as
a single diastereomer. The putative minor epimer arising
from 76’ could not be isolated (Scheme 21). The relative
configuration of 77 was unambiguously ascertained by com-
1
parison of its H and 13C NMR data with those previously
reported in the literature for both diastereomers.[51]
Although the reactivity of cyclopropenylcarbinol 64 indi-
cated that a free hydroxyl group was compatible with the
gold-catalysed cycloisomerisation of 1,6-cyclopropene-enes,
cyclopropenylcarbinol 69, possessing a remote a,b-disubsti-
tuted alkene, was completely unreactive in the presence of
AuCl. When a more reactive cationic gold catalyst, generat-
ed from [(Ph3P)AuCl] (5 mol%) and AgSbF6 (5 mol%), was
Scheme 23. Gold-catalysed cycloisomerisation of 1,6-cyclopropene-enes
82 and 83.
used, the bicycloACHTUNGTRENNUNG[4.1.0]hept-2-ene 79 was isolated in 68%
yield (Scheme 22). This product presumably results from an
These results demonstrate that the scope of the gold-cata-
lysed cycloisomerisation of 1,6-cyclopropene-enes can be ex-
tended to the preparation of bicycloACTHUNTGRNEUNG[4.1.0]heptan-3-ol deriv-
atives. However, protection of the free hydroxyl group in
the cyclopropenylcarbinols S is usually required and a silyl
(TBS) ether can effectively serve this purpose. Although
synthetically useful (d.r.=85:15–91:9), the levels of diaste-
reoselectivity observed are not as high as when a carbon
chain was present at the allylic position, presumably because
the magnitude of the A1,3 strain interaction between the
methyl group of the isopropylidene residue and a hydroxy
or a silyloxy group, instead of an alkyl substituent, is lower
(Scheme 24).
Scheme 22. Gold-catalysed cycloisomerisation of 1,6-cyclopropene-enes
69 and 80 (TBS=tert-butyldimethylsilyl).
isomerisation of the initially generated bicycloACHTUNTRGNEU[GN 4.1.0]heptan-
3-ol 78, although this was not further investigated. Protec-
tion of the secondary alcohol as a tert-butyldimethylsilyl
ether prevented this isomerisation and AuCl could again be
used as the catalyst to achieve the gold-catalysed cycloiso-
merisation of 80, which led to an 85:15 mixture of diastereo-
mers 81 and 81’ in 93% yield (Scheme 22). Their relative
configuration was assigned on the basis of previous results
with cyclopropenylcarbinol 64.
Scheme 24. Stereochemical outcome of the gold-catalysed cycloisomerisa-
tion of 1,6-cyclopropene-enes derived from cyclopropenylcarbinols S.
The epimeric cyclopropenylcarbinols 74 and 75 were also
found to be inert upon treatment with catalytic amounts of
AuCl. Therefore, these two alcohols were first silylated
(TBSOTf, 2,6-lutidine, CH2Cl2, 08C) to afford the tert-butyl-
dimethylsilyl ethers 82 (73%) and 83 (61%). The gold-cata-
lysed cycloisomerisation of these two substrates then pro-
ceeded smoothly in the presence of AuCl (5 mol%) under
the usual conditions (CH2Cl2, 08C, 0.5–1 h; Scheme 23).
Compound 82 delivered a mixture of the selectively protect-
Since silyl ethers derived from cyclopropenylcarbinols
were compatible with the reaction, we reasoned that gold-
catalysed cycloisomerisation of cyclopropene-enes by using
unsaturated silyl ethers derived from secondary cycloprope-
nylcarbinols as substrates would be worth investigating.[52]
ed diastereomeric bicyclo
G
Gold-catalysed cycloisomerisation of unsaturated silyl ethers
in a 90:10 ratio (82%; Scheme 23). The relative configura-
tion of the two stereocenters in 82 and 83 had almost no in-
fluence on the reactivity since the epimeric 1,6-cyclopro-
pene-ene substrate 83 produced a mixture of the protected
bicycloACHTUNGTRENNUNG[4.1.0]heptane-3,4-diols 85 and 85’ in a 91:9 ratio
(75%; Scheme 23).
derived from cyclopropenylcarbinols: Condensation of
cyclopropenylcarbinol
3
with chlorodimethylvinylsilane
(Et3N, catalytic DMAP, CH2Cl2) provided vinyldimethylsilyl
ether 86 (Scheme 25). This compound underwent a smooth
cycloisomerisation reaction (CH2Cl2, 08C, 15 min) catalysed
by AuCl (5 mol%), leading to the 3-oxa-2-silabicyclo-
AHCTUNGTERG[NNUN 4.1.0]heptane 87 as a single detectable diastereomer
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7819

J. Cossy, C. Meyer and F. Miege
produced the 1,5-diol 93 (82%). Upon treatment with MsCl
(1.1 equiv) in the presence of an excess of Et3N (2.2 equiv)
(CH2Cl2, 08C to RT), compound 93 was converted into the
previously synthesised 3-oxabicycloACTHNUTRGNEUNG[4.1.0]heptane 5a (78%)
due to a remarkably smooth intramolecular nucleophilic dis-
placement of the initially formed mesylate by the secondary
alcohol (Scheme 26). This result indicated that the gold-cat-
alysed cycloisomerisation of the 1,7-cyclopropene-ene 90 led
to the 3-sila-4-oxabicycloACTHNURTGNEU[GN 5.1.0]octane 91 in which the cyclo-
propane and the benzyloxymethyl substituent are anti
(Scheme 26), as previously observed in all cycloisomerisa-
tions involving 1,6-cyclopropene-enes as substrates.
Scheme 25. Gold-catalysed cycloisomerisation of dimethylvinylsilyl ether
86.
Conclusion
The gold-catalysed cycloisomerisation of a variety of substi-
tuted 1,6-cyclopropene-enes has been explored. The sub-
strates are readily prepared by addition of in situ generated
3,3-dimethylcyclopropenyllithium to aldehydes or activated
imines, followed by alkylation of the heteroatom with an
allylic bromide, or by addition to g,d-unsaturated aldehydes.
The cycloisomerisation proceeds with regioselective ring
opening of the cyclopropene and intramolecular cyclopropa-
nation of the remote olefin by the generated vinyl gold
carbenoid. The reaction allows remarkably efficient access
(d.r.>95:5), which was isolated in 88% yield (Scheme 25).
The relative configuration of this compound was reasonably
assigned by analogy with the results disclosed previously for
allyl cyclopropenylcarbinyl ethers. Ring opening of the
cyclic siloxane 87 was readily achieved with MeLi or PhLi
(THF, 08C) to provide the corresponding cis-1,2-disubstitut-
ed cyclopropylsilanes 88 (96%) and 89 (87%), respectively
(Scheme 25). Therefore, the presence of the silicon atom
had no adverse effects on the efficiency and the diastereose-
lectivity of the cycloisomerisation reaction.
Condensation of cyclopropenylcarbinol 3 was also ach-
ieved with allylchlorodimethylsilane to provide allydimeth-
ylsilyl ether 90 (94%; Scheme 26), which gave us the oppor-
tunity to explore the gold-catalysed cycloisomerisation of
a 1,7-cyclopropene-ene for the first time. We were pleased
to find that treatment of compound 90 with AuCl (5 mol%)
under our standard conditions led to a 90:10 diastereomeric
to 3-oxa- or 3-azabicyclo
and usually with high levels of diastereoselectivity, as well as
to substituted bicyclo[4.1.0]heptan-3-ol derivatives. Since the
ACHTUNGTRENN[UNG 4.1.0]heptanes in excellent yields
AHCTUNGTRENNUNG
isopropylidene substituent, which is invariably present in the
cycloisomerisation products, can be readily converted into
a carbonyl group by ozonolysis, the 3,3-dimethylcyclopro-
penyl moiety can be considered to be an interesting and syn-
thetically useful a-diazoketone surrogate.
mixture of the corresponding 3-sila-4-oxabicycloACTHNUGRTNEUNG[5.1.0]-
octanes, from which the major component 91 was isolated in
66% yield (Scheme 26). Ring opening of 91 by treatment
with MeLi (THF, 08C) afforded cyclopropylmethylsilane 92
in 81% yield. To assign the relative configuration of 91,
a chemical correlation was carried out and this compound
was first engaged in a Tamao–Fleming oxidation,[53] which
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Cycloisomerisation of 1,6-Cyclopropene-enes
FULL PAPER
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Received: February 20, 2012
Published online: May 15, 2012
7822
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