Organocopper-Triggered Cyclisation of Conjugated Diene-ynes: Diastereo- and Enantioselective Synthesis of Indenes

Article abstract of DOI:10.1002/adsc.201500556

Organocopper reagents react with readily available chiral conjugated diene-ynes to give indene derivatives bearing two stereogenic centres. The investigation of this original reaction in optically pure series demonstrates that a double transfer of chirality is operating. A stereocontrolled cascade involving S_N2′ followed by carbocupration and conjugate addition reactions accounts for the total recovery of the initial chirality. The scope and limitations of the reaction were investigated. The high diastereofacial discrimination in the cyclisation step allowed the construction of the quaternary stereocentre with excellent dr and ee, with the opposite configuration depending on the E- or Z-configuration of the alkene in the starting material. Post-functionalisation of indenes allowed the synthesis of indanyl derivatives containing four contiguous stereocentres.

Full text of DOI:10.1002/adsc.201500556

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DOI: 10.1002/adsc.201500556
Organocopper-Triggered Cyclisation of Conjugated Diene-ynes:
Diastereo- and Enantioselective Synthesis of Indenes
Tanzeel Arif,a Cyril Borie,a Aura Tintaru,a Jean-Val›re Naubron,b
Nicolas Vanthuyne,c Mich›le P. Bertrand,a,* and Malek Nechaba,*
a
Aix-Marseille UniversitØ, CNRS, Institut de Chimie Radicalaire, UMR 7273, 13390 Marseille cedex 20, France
Fax: (+33)-4-9128-8309; e-mail: michele.bertrand@univ-amu.fr or malek.nechab@univ-amu.fr
FØdØration de Chimie Marseille; 13390 Marseille cedex 20, France
Aix-Marseille UniversitØ, CNRS, Institut des Sciences MolØculaires de Marseille, UMR 7313, 13390 Marseille, France
b
c
Received: June 8, 2015; Published online: October 20, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500556.
Abstract: Organocopper reagents react with readily discrimination in the cyclisation step allowed the
available chiral conjugated diene-ynes to give indene construction of the quaternary stereocentre with ex-
derivatives bearing two stereogenic centres. The in- cellent dr and ee, with the opposite configuration de-
vestigation of this original reaction in optically pure pending on the E- or Z-configuration of the alkene
series demonstrates that a double transfer of chirality in the starting material. Post-functionalisation of in-
is operating. A stereocontrolled cascade involving denes allowed the synthesis of indanyl derivatives
SN2’ followed by carbocupration and conjugate addi- containing four contiguous stereocentres.
tion reactions accounts for the total recovery of the
initial chirality. The scope and limitations of the re- Keywords: carbocycles; chirality; cuprates; cycliza-
action were investigated. The high diastereofacial tion; enynes
Introduction
cursors of cyclopentadienyl ligands for transition
metal catalysts.[11] Egi and co-workers have very re-
Chirality transfer in the construction of carbocyclic cently reported a two-step synthesis of chiral indenes
and heterocyclic frameworks is still a challenge for bearing a quaternary stereocentre.[12] However, the
synthetic chemists.[1] Allene chemistry, due to the enantioselective synthesis of this class of compounds
unique electronic and chiroptical properties of the cu- is far from being widespread.[13]
mulated diene motif, finds its rightful place in the de-
velopment of asymmetric synthesis.[2,3] An increasing
number of enantioselective cyclisations based on Results and Discussion
chiral allenes has been reported over the last
decade.[1,4,5]
The presence of a Michael acceptor is the key struc-
Our interest in enantioselective cascade rearrange- tural feature to build the indenyl framework. It is
ments of conjugated enediynes based on the memory worth noting that 1,4-conjugate additions of organo-
of chirality phenomenon,[6] has recently led us to in- cuprate reagents to enoates are very popular reactions
vestigate whether the axial chirality of a transient and their mechanism has been widely studied.[14] Syn-
allene could be transferred to the central chirality of theses in which their intramolecular counterpart is in-
the cyclic products in these reactions. This study re- corporated in
a
tandem process are not so
sulted in the discovery of an original dialkyl cuprate- common,[15] and those occurring with transfer of chir-
promoted bis-alkylating route to chiral benzofulvene ality are even scarcer.[16]
derivatives.[7]
The stereocontrolled SN2’ displacement of an enan-
We report in this article an approach to the synthe- tiopure propargylic carbonate by an alkylcopper re-
sis of chiral indenes based this time on the organocop- agent was used to generate in situ a transient chiral
per-promoted cyclisation of conjugated diene-ynes.[8] allenic moiety from the diene-yne starting material
Indene scaffolds are present in natural products[9] and 1 (Table 1).
in bioactive compounds.[10] They are also used as pre-
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Tanzeel Arif et al.
Table 1. Reaction scope.[a]
enantiomeric excess of the starting material was
almost entirely recovered in both the major and the
minor diastereomers 2a (79 and 80% ee, respectively)
(Table 1, entry 1). The scope of the reaction is illus-
trated in Table 1. Whenever it was possible to mea-
sure the ee of each diastereomer, the same range of
chirality transfer was observed from substrates 1a–c.
Racemic 1b was used as starting material to high-
light the possible impact of the electronic effect of the
substituent in the para position on the aryl group on
the diastereoselectivity. No effect was noted since the
1
same dr was observed from H NMR analysis of the
crude reaction mixture (Table 1, entry 6).
Entry[a]
1
R3
dr[b] 2 [ee][c]
Yield [%]
The introduction of chemical diversity by varying
the nature of the organocopper reagent was then ex-
plored. Two methyl groups were successfully intro-
duced according to a procedure involving a dialkylcup-
rate (procedure A) instead of MeCu·Et3B.[17] The ad-
dition of Et3B resulted in a complex mixture. Un-
fortunately, the ee of the product could not be mea-
sured by chiral HPLC (entry 2). The product bearing
two isobutyl groups was synthesized in 68% yield
(entry 3) and the two diastereomers were enantioen-
riched (81% and 80% ees, respectively).
Remarkably, despite the bulkiness of tert-butyl
groups, the product resulting from the reaction of 1a
with t-BuCu·BEt3 was isolated in 65% yield and the
dr was 80:20 (entry 4). In this process, a nearly total
chirality transfer was also registered (79% ee from
82% ee). It is important to recall that the reaction of
enediyne analogues with the tert-butylcopper reagent
stopped at the allene formation stage and thus, no
benzofulvene was obtained.[7a]
The TMS-functionalized copper reagent was also
successfully employed (entry 5). It afforded the high-
est diastereoselectivity in the series (90:10). The level
of chirality transfer could not be determined because
of the lack of polarity that renders the HPLC separa-
tion of enantiomers difficult. However, the reaction
of substrate 1c and TMSCH2Cu·Et3B afforded a high
chirality transfer (entry 9), so we can reasonably
assume a similar behaviour with 1a.
1
2
3
4
5
6
7
8
9
10
1a
1a
1a
1a
1a
n-Bu
Me[e]
i-Bu
t-Bu
73:27 2aa(79/80)
76:24 2ab
76:24 2ac (81/80)
65[d]
47
68
80:20 2ad (79/nd) 65
CH2TMS 90:10 2ae (nd)
63
(Æ)-1b n-Bu[e]
70:30 2ba
70:30 2ca (81/81)
65:35 2cc (78/82)
43
1c
1c
1c
n-Bu
i-Bu
67[f]
67[f]
CH2TMS 75:25 2ce (77.5/79) 61[f]
(Æ)-1d i-Bu
84:16 2dc
55
[a]
Conditions: a THF solution of diene-yne 1 was added
dropwise to a solution of R3CuLi·Et3B in THF at À788C,
then the reaction mixture was allowed to warm to room
temperature for 1 h and the reaction was quenched with
NH4OH/NH4Cl (1/10).
Diastereomeric ratio measured by H NMR analysis on
the crude reaction mixture.
Enantiomeric excess (of each diastereomer) measured by
chiral HPLC; nd=not determined.
The two diastereomers were separated by preparative
HPLC.
A THF solution of Me2CuLi·LiI in THF was added drop-
wise to a solution of diene-yne 1 at 08C then the reaction
mixture was allowed to warm to room temperature for
1 h and the reaction was quenched with NH4OH/NH4Cl
(1/10).
[b]
[c]
[d]
[e]
1
[f]
The two diastereomers were separated by preparative
TLC.
Initially, carbonate 1a was selected to test various
The use of chalcone derived substrate 1c led to the
experimental conditions and optimise the reaction. desired products in 61 to 67% yields with a dr ranging
The most significant results are detailed in the Sup- from 65:35 to 75:25. Again, a high level of chirality
porting Information.[17] The best yields were obtained transfer was reached with all the organocopper re-
by adding Et3B (i.e., n-BuCu·Et3B, 2.6 equiv. instead agents (entries 7–9).
of organocuprate reagent).
The nature of the substituent at the stereogenic
As selectivity is a continual challenge, it is impor- centre in the starting material also influences the dia-
tant to highlight that this reaction is completely regio- stereoselectivity of the cyclisation. Regarding the ad-
and chemoselective. The SN2’ displacement of the car- dition of i-BuCu·Et3B, the replacement of the phenyl
bonate is favoured over direct 1,4-addition of the or- group (substrate 1a) by a methyl group (substrate 1d)
ganocopper and this avoids the formation of unde- resulted in an increase of the dr from 76:24 to 84:16
sired by-products.
(Table 1, entries 3 and 10).
The formation of the enantio-enriched indene 2a
The scope of the reaction was further expanded to
was envisaged from the enantio-enriched cinnamate the trisubstituted diene-yne 1e with the aim to con-
1a [82% enantiomeric excess (ee)]. Interestingly, the struct challenging targets bearing a quaternary stereo-
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Organocopper-Triggered Cyclisation of Conjugated Diene-ynes
E-1e the diastereoselectity was nearly total (>5:95)
but with a reversal as regard to the preferred
isomer.[18] The product 2ea was isolated in 65% yield,
and most importantly, a high level of chirality transfer
(92%) was observed from the enantiopure starting
material. Thus the reaction also enables the control of
the quaternary indenyl stereocentre. Similarly, a total-
ly diastereoselective bis-alkylating cyclisation of
(S,E)-1e
was
achieved
by
reaction
with
TMSCH2Cu·Et3B. It is interesting to highlight that the
natural product dichroanal B bears an indenyl core
with all-carbon quaternary stereocentre like in 2ea.
To further explore the methodology limitations,
substrate 3 was exposed to the optimised experimen-
tal conditions (Scheme 2). In this case, the chemose-
lectivity of the organocopper nucleophilic attack
changes and the 1,4-addition leading to enolate 4 be-
comes faster than the SN2’ displacement of the prop-
argyl carbonate. Intramolecular SN2’ substitution of
the carbonate only occurs in the second elementary
step to promote the formation of the allene 5 in 82%
yield as a 56:44 mixture of two diastereomers.[19]
Scheme 1. Synthesis of an indene bearing an all-carbon qua-
ternary stereocentre.
centre. The results are given in Scheme 1. Interesting-
We propose the stepwise mechanism shown in
ly, when Z-1e was reacted with the n-butylcopper re- Scheme 3 for the synthesis of 2aa. Although two reac-
agent, the indene 2ea was isolated in 54% yield as tions can formally compete (1,4-addition and SN2 re-
a mixture of two diastereomers in 62:38 ratio. With action), it is the chemoselective SN2’ displacement of
Scheme 2. 1,4-Addition-triggered allenylindene synthesis.
Scheme 3. Mechanism proposed for the formation of indene 2aa.
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Tanzeel Arif et al.
the carbonate that occurs first and allows the forma- E-1e and Z-1e and the result discussed above allowed
tion of a transient allene 6a with a central-to-axial us to confirm this assumption.
chirality transfer (Scheme 3).[20] The regio-, chemo-
Finally, post-functionalisation of racemic indene
and stereoselective carbocupration of the allene 2ae was achieved (Scheme 4). The indanyl skeleton is
moiety leads to 7a as single enantiomer through known to exhibit interesting biological activities.[24]
a second chirality transfer (axial-to-central).[21] The in- Indeed, hydrogenation of the double bond afforded
tramolecular 1,4-addition leads to the lithium enolate the expected indane with a high diastereoselective
8a. The presence of this enolate in the crude reaction control and a good yield (86%).[25] An nOe analysis
mixture was confirmed by ESI-HR-MS.[17]
allowed the syn-syn relative stereochemistry of the
The coordination of copper to the conjugated C=C indane in 9 to be established. Furthermore, the
bond, should play a crucial role in the determination double bond could be epoxidised to give 10, which
of the stereochemical outcome of the cyclisation step. bears 4 stereocentres with a good diastereocontrol.
The formation of the p-complex has been proposed
and demonstrated by Krause for intermolecular 1,4-
addition to acyclic a,b-unsaturated systems.[22]
Conclusions
The determination of absolute configurations (AC)
was mandatory to propose a mechanism. Different In conclusion, we have devised a new method for the
techniques enable AC determination; we have been synthesis of chiral indenes bearing two stereogenic
interested by ECD and VCD.[23]
centres from readily available conjugated diene-ynes.
On the basis of previous work,[7a] we could guess This bis-alkylating cycloisomerisation, triggered by al-
that the R-absolute configuration of the exocyclic ste- kylcopper reagents, involves the cascade combination
reogenic centre (bearing the n-Bu group) in 2 resulted of SN2’ displacement of an enantiopure propargylic
from the R-starting material (anti SN2’ followed by carbonate/carbocupration of the resulting allene/con-
syn-carbocupration). The absolute configurations of jugate addition to the activated double bond. It
2aa diastereomers were assigned by ECD analyses allows the isolation of enantio-enriched indenes
and confirmed by VCD.[17] We were thus able to as- through a double transfer of chirality followed by
certain that the configuration of the stereocentre C- a diastereoselective cyclisation. The substrate present-
1 is S in the major diastereomer and R in the minor ing an E-trisubstituted double bond afforded the ex-
diastereomer resulting from R-1a. As expected, the pected target bearing a quaternary stereocentre with
configuration of the exocyclic stereogenic centre is R a high level of chirality transfer.
in both diastereomers. Accordingly, we assume that
the stereochemical outcome is controlled by the
allene axis. The 1,3-allylic strain should control the
conformation around the C C pivot bearing the ste-
reogenic centre in the vinyl copper intermediate 7
(Scheme 3). The spatial orientation of the phenyl and
Experimental Section
À
Synthesis of Indenes 2aa–2ee
butyl groups would explain the facial selectivity in the Procedure A: In a dried flask, carbonate 1a (1 equiv.) was
dissolved in freshly distilled THF (15 mLmmolÀ1). The solu-
conjugate addition.
tion was cooled to 08C. In another dried Schlenk flask, dis-
The diastereofacial discrimination in the cyclisation
tilled THF (15 mLmmolÀ1) was added to CuBr·Me2S
step should also depend on the Z or E-stereochemis-
(1.3 equiv.). To this stirred solution, cooled to À208C, MeLi
(2.6 equiv., 1.6M in ether) was added. The solution was
stirred for 5 min. The solution of Me2CuLi·LiBr was quickly
added via syringe to the solution of carbonate 1a. The re-
sulting mixture was stirred for 5 min at 08C and then the re-
action was allowed to warm to room temperature for 1 h.
The reaction was quenched with a 10:1 solution of NH4Cl/
NH4OH, and stirred for 30 min. After extraction with Et2O,
the organic layer was dried over MgSO4, filtered, and the
solvent was evaporated under reduced pressure and the
crude product was purified by chromatography.
try of the Michael acceptor.[18] The availability of both
Procedure B: An oven-dried Schlenk tube was charged
with CuBr·Me2S (2.6 equiv.), evacuated and refilled with
argon three times followed by addition of freshly distilled
THF (15 mLmmolÀ1). The resulting homogeneous solution
was cooled to –408C and RLi (2.6 equiv.) was added drop-
wise. The solution was stirred for 5 min at À408C and then
cooled to À788C. Et3B (2.6 equiv., 1M in hexanes) was
added drop-wise. After 5 min at À788C, a precooled solu-
Scheme 4. Post-functionalisation of indene 2.
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Organocopper-Triggered Cyclisation of Conjugated Diene-ynes
tion (À788C) of carbonate 1a in THF (15 mLmmolÀ1) was
quickly added via syringe to RCu·BEt3, stirred for 5 min,
then the cooling bath was removed and the reaction mixture
was allowed to warm to room temperature over 15 min.
After 1 h at room temperature, the reaction mixture was
quenched with saturated aqueous NH4Cl/NH4OH (10:1) and
further stirred for 30 min. The aqueous layer was extracted
with Et2O, dried (MgSO4), filtered, evaporated under re-
duced pressure and the crude product was purified by chro-
matography.
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Acknowledgements
We thank Aix-Marseille UniversitØ, CNRS, and ANR (JCJC
MOCER2) for support of our research programme. T.A.
gratefully acknowledges RØgion Paca for financial support.
We also thank M. Jean for HPLC analysis as well as C.
Chendo and V. Monnier for HR-MS.
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SN2’ see ref.[15b]
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Y. Okuda, Y. Morizawa, K. Oshima, H. Nozaki, Tetra-
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[17] For details: see the Supporting Information.
[18] For the influence of double bond configuration on the
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