Double transfer of chirality in organocopper-mediated bis(alkylating) cycloisomerization of enediynes

Article abstract of DOI:10.1002/anie.201310530

An original synthesis of chiral benzofulvenes triggered by organocopper reagents is reported. These enantiopure products are available through a highly chemo-, regio-, diastereo-, and enantioselective bis(alkylating) cycloisomerization process. A double chirality transfer (central-to-axial-to- central) is observed. Double duty: An original synthesis of chiral benzofulvenes was developed through the highly chemo-, regio-, diastereo-, and enantioselective double transfer of alkyl groups to electrophilic enediynes. This organocopper-triggered cycloisomerization proceeds with double transfer of chirality (central-to-axial-to-central).

Full text of DOI:10.1002/anie.201310530

Angewandte
Chemie
DOI: 10.1002/anie.201310530
Synthetic Methods
Hot Paper
Double Transfer of Chirality in Organocopper-Mediated
bis(Alkylating) Cycloisomerization of Enediynes**
Damien Campolo, Tanzeel Arif, Cyril Borie, Dominique Mouysset, Nicolas Vanthuyne,
Jean-Valꢀre Naubron, Michꢀle P. Bertrand,* and Malek Nechab*
Dedicated to Prof. Max Malacria on the occasion of his 65th birthday
Abstract: An original synthesis of chiral benzofulvenes
triggered by organocopper reagents is reported. These enan-
tiopure products are available through a highly chemo-, regio-,
diastereo-, and enantioselective bis(alkylating) cycloisomeri-
zation process. A double chirality transfer (central-to-axial-to-
central) is observed.
We have recently investigated memory of chirality in
cascade rearrangements of chiral enediynes.[6] These reactions
proceed with central-to-central chirality transfer. They are
based on the multistep combination of in situ allene moiety
formation, Saito–Myers cyclization, 1,5-hydrogen atom trans-
fer, and radical recombination, which leads to polycyclic
derivatives bearing one or two contiguous stereogenic
centers. During the course of these rearrangements, the initial
stereogenic center is trigonalized, but the key radical
intermediate is generated in a transiently chiral conformation
and is long-lived to ensure the memory of chirality during the
transformation. The continuation of this work was to extend
the process to axially chiral enyne-allenes (generated in situ
from suitable enediynes) with the prospect of promoting
axial-to-central chirality transfer in this polar/radical cross-
over cascade.
T
he ever-growing interest in atom-economical reactions
explains the popularity of cycloisomerization reactions. This
generic term embraces a large variety of rearrangements of
polyunsaturated substrates leading to cyclic or polycyclic
frameworks.[1] The literature bears witness to the tremendous
advances made in this field. More and more complex building
blocks are now available from such processes. These reactions
can be promoted by electrophilic activation by a wide range of
p-philic transition-metal complexes which can be used either
as catalytic or as stoichiometric reagents. Despite the prolific
literature dedicated to this topic, there are very few reports
where an organocopper reagent was used as reagent to trigger
a cycloisomerization process.[2,3] Moreover, no example
involving chirality transfer in copper-triggered cycloisomeri-
zations has ever been reported so far.
Among the methodologies available to prepare enan-
tioenriched allenes, the standard laboratory methodology
developed by Crabbꢀ 45 years ago has seen a rapid expan-
sion.[7] The SN2’ displacement of enantiopure propargyl
carbonate (of type 1; for structure see Scheme 1) by organo-
An organocopper-mediated bis(alkylating) cycloisomeri-
zation of chiral enediynes, which proceeds with double
chirality transfer from central-to-axial-to-central, is disclosed
herein. Chirality transfer from one site to another refers to
a process in which a new chiral element is created while the
original chiral element is destroyed.[4,5]
[*] Dr. D. Campolo, Dr. T. Arif, C. Borie, Dr. D. Mouysset,
Prof. M. P. Bertrand, Dr. M. Nechab
Aix-Marseille Universitꢀ, CNRS, Institut de Chimie Radicalaire
UMR7273, 13390 Marseille (France)
E-mail: michele.bertrand@univ-amu.fr
malek.nechab@univ-amu.fr
Scheme 1. Cycloisomerization of (R,R)-1a.
Dr. N. Vanthuyne
Aix-Marseille Universitꢀ, CNRS, Institut des Sciences Molꢀculaires
de Marseille UMR 7313, 13390 Marseille (France)
copper reagents offers numerous advantages such as high
yields, efficient central-to-axial chirality transfer, and use of
inexpensive and easily accessible starting materials.[8] The
envisaged substrates were thus synthesized in three to four
steps using Sonogashira coupling reactions from commer-
cially available compounds.
When the enediyne (R,R)-1a was reacted with lithium
dimethylcuprate,[9] the enyne-allene 2aa was not isolated
(Scheme 1). In the preliminary experiments, we were sur-
Dr. J.-V. Naubron
Spectropole
Fꢀdꢀration de Chimie Marseille (France)
[**] We thank Aix-Marseille Universitꢀ, CNRS, and ANR (JCJC MOCER2)
for financial support. T.A. gratefully acknowledges Rꢀgion Paca for
a grant. We also thank M. Jean, C. M. Giorgi, C. Chendo, and V.
Monnier for HPLC, X-Ray analyses, and HRMS.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310530.
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Table 1: Transfer of chirality in the cycloisomerization of the enediynes
1a–d.[a]
prised to not detect any of the products which would have
resulted from 2aa undergoing Saito–Myers or Schmittel
cyclization.[10] Instead, the benzofulvene (R,R)-3aa, where
two methyl groups were incorporated, was isolated together
with trace amounts of 3’aa. Much to our delight, (R,R)-3aa
was formed as a single diastereomer, thus showing that
a highly regio- and stereoselective bis(alkylating) cycloiso-
merization had been achieved. The R,R absolute configura-
tion of 3aa was demonstrated by VCD and ECD spectros-
copies combined with DFT calculations (see the Supporting
Information). The 98% ee of the product gave evidence that
the tandem process occurred with a highly efficient trans-
mission of the initial chiral information.[11] It is to be noted
that, under optimized experimental conditions, (S,S)-3aa was
isolated with 97% ee in 55% yield when starting from the
enantiomeric S,S substrate. During the optimization studies it
was observed that performing the reaction at room temper-
ature in ether (or THF) gave the optimal yield. The screening
of different experimental conditions is detailed in the
Supporting Information.
Product (R,R)-3aa belongs to the class of fulvene
derivatives, which constitute an important family of cross-
conjugated olefins. The latter are attractive because their
properties have found applications in important fields.[12–14]
The availability of chiral fulvenes will open new prospects.
The most common method used to access these frameworks is
the condensation of cyclopentadienes onto carbonyl
groups.[15] Other strategies, based on the above-cited Schmit-
tel cyclization of hindered enediynes[16,17] or more recent
metal-catalyzed procedures, have been developed.[18] No
example of chiral fulvene formation through a cycloisomeri-
zation reaction has been reported to date.
Entry R1
R2
1
3[b]
Yield
[%]
(S,S)-1a
(d.r.>95:5)
(R,S)-1a
(d.r.>95:5)
(R,S)-1a
(S,S)-3ab
(d.r.>95:5)
(R,S)-3ac
(d.r.>95:5)
(R,S)-3ad
(d.r.>95:5)
(R,S)-3ae
1
2
nBu
iBu
51
48
3
4
nHex
57
55
(d.r.>95:5)
(R,S)-1a
CH2TMS
(d.r.>95:5) (d.r.=85:15)
(R)-1b
(98 %ee)
(R)-1b
(98 %ee)
(R)-1b
(98 %ee)
(R)-1b
(98 %ee)
(rac)-1b
(R)-3bb
(96 %ee)
(R)-3bc
(95 %ee)
(R)-3bd
(90 %ee)
(R)-3be
(93 %ee)
2bf[d]
5
6
nBu
iBu
42[c]
51
7
8
9
nHex
48
43
45
CH2TMS
tBu
(R)-1c
(90 %ee)
(R)-3cb
(86 %ee)
10
11
nBu
nBu
62
48
(S,S)-1d
(d.r.>95:5)
(S,S)-3 db
(d.r.>95:5)
[a] Reaction conditions: a solution of R2 CuLi·LiI in THF was added
2
We then considered the incorporation of other alkyl
groups as a variable in this cyclization. Dibutyl-, diisobutyl-,
and dihexylcuprates were found to be efficient in triggering
the cycloizomerization. The benzofulvenes 3ab, 3ac, and 3ad
were isolated in 51, 48, and 57% yield, respectively (entries 1-
3, Table 1). A high level of diastereoselectivity (> 95:5) was
observed for each case. The applied bis(alkylating) cyclo-
isomerization also proceeded with the organocuprate pre-
pared from TMSCH2Li. The diastereomeric ratio of the
product was only 85:15 in this case (entry 4).
dropwise to a solution of the enediyne 1 in THF at 08C. The reaction
mixture was warmed to RT for 1 h and quenched with NH4OH/NH4Cl
(10:1). Complete conversion was observed in all experiments. [b] The
configurations were assumed by analogy with the structures of 3aa and
3bb established by VCD and ECD, and XRD, respectively (see the
Supporting Information). [c] The allene 4bb (4%) was also isolated (see
Ref. [19]). [d] The allene 2bf was the only product. THF=tetrahydro-
furan, TMS=trimethylsilyl, Ts=4-toluenesulfonyl.
Because of its remoteness, the chiral auxiliary was
unlikely to participate in the control of the chirality transfer.
To confirm this assumption, we investigated the reactivity of
the Gilmanꢁs reagent prepared from n-butyl lithium with
respect to the carbonate 1b, bearing only one stereocenter in
the propargylic position, so that the formation of a transient
chiral allene could be controlled by chirality transfer without
any suspicion of a possible diastereoselective process.
The cycloisomerization of 1b (entry 5, Table 1) led to 3bb
with both efficient chirality transfer and Z/E control. The
level of chirality transfer (product ee divided by substrate ee)
was close to 98% since 3bb was isolated with 96% ee when
starting from 1b (98% ee). This indicated that a double
transfer of chirality was operative: the first transfer occurring
from the stereogenic center to the axis of chirality of the
transient allene, and the second one from this axis to the new
stereogenic center. It can be noted that the allene 4bb was
also isolated. It is likely to result from the elimination of
a [Cu]N(Ts)Me species from a vinyl copper intermediate.[19]
This side-product was less abundant in THF (this explains
why THF was selected as solvent rather than Et2O). Again,
isobutyl and n-hexyl groups were efficiently transferred (97%
and 91% level of chirality transfer, respectively; entries 6 and
7). The reaction of (TMSCH2)2CuLi·LiI with 1b afforded the
desired product in moderate yield and 93% ee (entry 8).
Interestingly, when di-tert-butylcuprate was used, the
allene 2bf (Figure 1) was the only product (45% yield) and
no further cyclization was observed (entry 9, Table 1). In all
likelihood, the subsequent alkylating cyclization suffers from
steric impediment in this case. This assertion is consistent with
the proposed mechanism (see below). The conversion of 2bf
into benzofulvene by addition of nBu2CuLi·LiI or MeCuI was
not successful, and the starting material was recovered
unreacted.
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precursor of (R,R)-1a in the presence of an excess of
dimethylcuprate. Carbocupration of the triple bond bearing
the oxazolidinone ring leading to (R,R)-5aa was observed in
79% yield [this experiment was performed on (R,R)-1a;
Figure 1]. This result supports the hypothesis that the
cyclization only proceeds after the SN2’ displacement of the
propargylic carbonate has occurred.
Figure 1. Structures of 2b, 3cg, and 5aa.
A tentative mechanism is proposed in Scheme 3 to
rationalize the experimental data. According to the well-
The scope of the transformation was further illustrated by
varying the nature of the R1 group. Extension to the propargyl
succinimide 1c led to the highest yield of isolated product.
The product 3cb was isolated in 62% yield with overall 95%
of chirality transfer (entry 10, Table 1). The incorporation of
two phenyl groups from two equivalents of lithium diphenyl-
cuprate afforded the achiral fulvene 3cg (Figure 1) in accept-
able yield (52%). The enantiopure amide 1d, derived from
alanine methyl ester, was also efficiently converted into 3 db
(entry 11). It is interesting to mention that no competitive
conjugate addition of the organocuprate to the conjugated
triple bond was observed. The SN2’ substitution of the
propargylic carbonate proceeded much faster. The product
was isolated as a single Z diastereomer in 48% yield
(diastereomeric ratio superior to 95:5).
Scheme 3. Mechanistic rationale.
To exclude the assistance of any chelating atom in this
process, we investigated the cyclization of the enediynes 1e
and 1 f (R2 = H and nBu, respectively; Scheme 2). These
documented anti SN2’ displacement of propargylic carbonates,
the reaction should proceed with central-to-axial chirality
transfer via the CuIII-allenic intermediate 6, which should
evolve through reductive elimination to afford the transient
allene 7.[7,21] In the SN2’ process, the Gilmanꢀs reagent
(R2 CuLi·LiI) releases the monoorganocopper species,
2
R2Cu, which is reported to be much less reactive than its
precursor.[22] This issue was initially considered as the main
drawback to the use of organocuprate in nucleophilic
substitutions. Remarkably, the two alkyl groups were trans-
ferred in the process leading to the product 3 and thereby the
initial limitation was overcome.
Scheme 2. Cycloisomerization of (S)-1e, (R)-1 f, and (S)-1g.
In the present study, the reactivity of the released MeCuI
species might be enhanced through the template effect of the
enyne-allene moiety by the formation of 7. The stereoselec-
tive carbocupration of methoxyallene in Et2O, reported by
Normant and Alexakis, was shown to be controlled by the
coordination of the methoxy group with copper.[23] Similarly,
the coordination of the metal to the triple bond would govern
the stereochemical outcome of the cycloizomerization. Sub-
sequent cis carbocupration of the terminal allene p bond
would lead to the vinyl organocopper 8.[24] A second intra-
molecular cis carbocupration of the triple bond, proceeding
according to the 5-exo-mode, would produce the vinyl copper
9 as a precursor of 3 (path a, Scheme 3).[25] The Z stereo-
chemistry of the exocyclic double bond was unambiguously
assigned from NOESY 2D NMR spectroscopy and is in good
agreement with the proposed sequence.
enediynes cyclized with moderate yields (43 and 44%).[20] The
ee values of the products 3eb and 3 fb could not be
determined because of their low polarity, however, their
[a]D25 values [À75 (0.1, CDCl3) and + 14 (0.9, CDCl3)] are
indicative of chirality transfer.
To further evaluate the versatility of the reaction, we
explored the reactivity of the substrate (S)-1g where a methyl
substituent replaced the phenyl group at the propargylic
carbon atom. Under similar experimental conditions, the
fulvene (R)-3gb was isolated in 51% yield (Scheme 2). The
R absolute configuration was assumed by analogy with the
mechanism evidenced for 1b. NOESY 2D NMR spectroscopy
confirmed the stereochemistry of the alkene moiety. The
presence of the phenyl group is not compulsory for the
alkylating cycloisomerization to proceed.
Masked zwitterions can be involved in transition-metal-
promoted rearrangement of enediynes and enyne-
allenes.[26,27] The metal coordination would facilitate zwitter-
ionic pathways. Gold-catalyzed Schmittel cyclization pro-
Conversely, the presence of the leaving group is crucial for
the cyclization to proceed. A completely different outcome
was observed when the reaction was performed on the alcohol
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ceeds at low temperature.[27b] Thus, alternatively, the con-
certed cyclization of 7 might be viewed as the equivalent to
a zwitterionic Schmittel rearrangement leading directly to 9
through the transition state 10 (path b, Scheme 3). It is
difficult to choose between the stepwise and concerted metal-
promoted pathways, which are both consistent with the
observed axial-to-central chirality transfer. The development
of a positive charge on the carbon atom, in a zwitterionic-like
cyclization, might explain why the second methyl group could
be so easily transferred from the R2CuI species released in the
SN2’ step.
When deuteriolysis of the vinyl copper 9cb was achieved
during work-up, the product [D]-3cb was completely and
stereoselectively labeled at the exocyclic double bond.
Similarly, the iodination of 9aa leading to 11aa confirmed
the mechanistic hypothesis according to which a stoichiomet-
ric amount of copper reagent is needed. It is worth mention-
ing that the iodide 11aa offers opportunity for further
transformations through cross-coupling or radical reactions.
It must be emphasized that in all cases a total conversion
was observed, thus demonstrating that the two alkyl groups of
the organocuprate reagent are actually transferred. Compet-
itive side-polymerization of the product could explain why the
overall reaction yield did not exceed 62%.[20]
process is likely to involve SN2’ displacement, two stepwise
intramolecular carbocupration steps, and electrophilic trap-
ping of the resulting fulvenyl copper species, and proceeds
with high diastereo- and enantioselectivity. As expected from
the well-documented anti-SN2’ and cis carbocupration, the
stereochemical outcome of the reaction is controlled by
a double transfer of chirality from central-to-axial-to-central.
A concerted metal-promoted zwitterionic-like Schmittel
cyclization might be proposed as an alternative pathway. It
is worth mentioning that in this process the two alkyl groups
of the dialkylcuprate reagent were transferred, a process
which has never been observed before in the presence of only
1.2 equivalents of reagent. Theoretical calculations are under-
way, and they will probably help to determine the lowest
energy pathway involved.
Received: December 4, 2013
Revised: January 21, 2014
Published online: February 19, 2014
Keywords: alkynes · carbocycles · chirality · copper ·
.
cycloisomerization
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the absolute configurations (AC) assigned by VCD and ECD
spectroscopies for (R,R)-3aa and by the X-ray data for (R)-
3bb (Figure 2).[28] This data supports the regio- and stereo-
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Angew. Chem. Int. Ed. 2014, 53, 3227 –3231
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