Cu-catalyzed asymmetric addition of sp2-hybridized zirconium nucleophiles to racemic allyl bromides

Article abstract of DOI:10.1039/c5cc00421g

Alkenylzirconium nucleophiles made in situ by the hydrozirconation of terminal alkynes undergo dynamic kinetic asymmetric allylic alkenylation with racemic allyl bromides to give enantioenriched products.

Full text of DOI:10.1039/c5cc00421g

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Cu-catalyzed asymmetric addition of
sp2-hybridized zirconium nucleophiles
Cite this:DOI: 10.1039/c5cc00421g
to racemic allyl bromides†
Received 15th January 2015,
Accepted 13th February 2015
Mireia Sidera and Stephen P. Fletcher*
DOI: 10.1039/c5cc00421g
www.rsc.org/chemcomm
Alkenylzirconium nucleophiles made in situ by the hydrozircona- much less developed – very few examples of relevant AAAs can
tion of terminal alkynes undergo dynamic kinetic asymmetric allylic be found in the literature.5 Our group has developed highly
alkenylation with racemic allyl bromides to give enantioenriched enantioselective conjugate addition reactions using alkyl-
products.
zirconium reagents,6 and recently reported Cu-catalyzed AAA
of these nucleophiles to racemic cyclic allyl chlorides to give
Transition metal catalyzed asymmetric allylic alkylation (AAA) enantioenriched products (Fig. 1b).7
reactions have proven to be useful and versatile methods for
To the best of our knowledge no AAAs have ever been
C–C bond formation.1 In particular, Pd-catalyzed AAAs in which reported using sp2-hybridized nucleophiles in combination with
enantiopure products are obtained from racemic mixtures chiral racemic starting materials, although Rh-catalyzed conju-
of starting materials are exceptionally powerful and have been gate additions of boron-species are well-developed8 and Cu-9 and
extensively developed.2 The use of stabilized nucleophiles Ir-catalyzed10 AAAs of vinyl-nucleophiles to prochiral substrates
(pKa o 25) in these processes is well-established (Fig. 1a).1b,3 are known. Given our recent DYKATs with alkylzirconocene
These dynamic kinetic asymmetric transformations (DYKATs) nucleophiles we speculated that this method may be extended
convert both enantiomers of a starting material into one enantiomer to alkenylzirconocene reagents (Fig. 1c) and here we report the
of a new product without producing resolved starting material.3,4 exploration and optimization of this system.
The use of non-stabilized nucleophiles in these procedures is
We began our studies using 5-phenyl-1-pentyne and 3-chloro-
cyclohex-1-ene. We first examined conditions previously optimised
for AAAs using alkyl nucleophiles where a combination of CuI
(10 mol%) and (R,R,R)-L1 (10 mol%) were used in chloroform
(Table 1, entry 1).7 Under these conditions the starting material
was nearly consumed, but no AAA product 1 was detected. Instead
significant amounts of 2 (15%), arising from the dimerization of
the alkenyl zirconocene, and 3 (6%), presumably from isomeriza-
tion of 1, were observed. We reasoned that other copper salts could
favour the formation of 1 but found that CuNTf2, CuOTf, CuBF4,
CuSbF6 also mainly gave 2 as well as 4, the homocoupled product
of the starting allyl chloride (Table 1, entries 2–5). CuTC was found
to give slightly lower conversion and the vinyl-dimer 2 as the major
product in 20% yield (entry 6).
It appeared that dimerisation was significantly faster than AAA
and we hypothesised that more reactive leaving groups could
provide better results. Several cyclic allyl compounds bearing
different leaving groups (Br, OAc, O(CO)CF3, OP(O)(OEt)2, OBoc)
were examined using 10 mol% L1 and CuI in chloroform and
only the allyl bromide was found to give the desired product 1
in appreciable amounts.
Fig. 1 Dynamic kinetic asymmetric allylic alkylations.
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
12 Mansfield Road, Oxford OX1 3TA, UK. E-mail: stephen.fletcher@chem.ox.ac.uk;
Tel: +44 (0)18652 75642
When using cyclohexenyl bromide and our standard conditions
very low enantioselectivity (54 : 46 er, Table 2, entry 1) was obtained
† Electronic supplementary information (ESI) available: Materials and methods,
procedures, characterization data and spectra. See DOI: 10.1039/c5cc00421g
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Table 1 Selected screening reactionsa
Table 2 Optimisation of the reaction conditionsa
Entry CuI
Conversionb (%) 1 (%) 2 (%) 3 (%) 4 (%)
1
2
3
4
5
6
CuI
84
—
—
—
—
—
—
15
43
36
24
23
20
6
8.4
0
8.3
8.4
3.7
—
14
24
17
20
0
CuCl/AgNTf2 100
CuCl/AgOTf
CuCl/AgBF4
CuCl/AgSbF6
CuTC
94
86
92
81
Entry M
Ligand Solvent
Conversion (%) er (%)
1
2
CuI
CuCl
L1
L1
L1
CHCl3
92b
81b
74b
100b
93c
83c
79c
89c
90c
88c
94c
92c
87c
87c
33c
25c
30c
35c
8c
54 : 46
55 : 45
50 : 50
57 : 43
55 : 45
60 : 40
63 : 37
65 : 35
74 : 26
61 : 39
72 : 28
76 : 24
55 : 45
56 : 44
36 : 64
66 : 34
61 : 39
61 : 39
67 : 33
21 : 79d
19 : 81d
a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Et2O
Reaction conditions: 5-phenylpent-1-yne (2.5 eq.), Cp2ZrHCl (2.0 eq.),
b
3
4
5
6
CuCl2
CuI (10 mol%), (R,R,R)-L1 (10 mol%) in chloroform. Determined by
proton NMR spectroscopy.
CuCl + AgNTf2 L1
CuCl + AgBF4 L1
CuCl + AgOMs L1
7
8
9
CuTC
CuCl + AgOTs L1
CuTC L2
CuCl + AgOTs L2
CuTC L3
CuCl + AgOTs L3
CuTC
CuTC
CuCl + AgOTs L6
CuTC L7
CuCl + AgOTs L3
CuCl + AgOTs L3
CuCl + AgOTs L3
CuCl + AgOTs L3
CuCl + AgOTs L3
L1
however only traces of diene 2 were observed. Several copper
salts were employed using L1 in CH2Cl2. Other copper halides
did not improve the results (entries 2 and 3). The use of more
reactive copper sources also provided very low enantiomeric
ratios (entries 4–6). The role of the silver salt in these reactions
is to exchange the counterion with CuCl. The use of CuTC and
CuOTs (obtained premixing CuCl and AgOTs) gave slightly
better er (entries 8 and 9). Using these copper sources several
ligands were tested. L2 gave an er of 74 : 26 with CuTC (entry 9)
but with CuOTs the er was slightly lower (entry 10, 61 : 39) while
L3 gave better er both with CuTC and CuOTs (entries 11 and
12). L4 and L56b gave a lower er (entries 13 and 14) and other
phosphoramidite ligands also did not give better results than
L3 (not shown). We also explored diphosphine ligands such as
(R)-SegPhos (L6) and p-tol-BINAP L7. In these cases the yield
10
11
12
13
14
15
16
17
18
19
20
21
L4
L5
2-MeTHF
Toluene
CH2Cl2, 0 1C
90c
CH2Cl2, À40 1C 90c
a
Reaction conditions: 5-phenylpent-1-yne (2.5 eq.), Cp2ZrHCl (2.0 eq.),
b
M (10 mol%), ligand (10 mol%) in chloroform. Determined by proton
NMR spectroscopy. Determined by HPLC. Using (R,R,R)-L3.
c
d
dropped significantly although similar enantioselectivities Several simple linear alkynes were tested but it was difficult to
were observed (entries 15 and 16). Using L3 and CuOTs and find suitable analytical HPLC or GC methods for the products.
changing the solvent did not improve enantioselectivities over In our previously reported AAAs (ref. 7) we often measured the
those previously observed (entries 17–19). However, significant enantiomeric ratios of the cyclic products by epoxidation of the
improvement was achieved by lowering the temperature to 0 1C double bond. Epoxidation produced a diastereomeric mixture
(entry 20), and the best selectivity (81 : 19) was obtained at À40 1C (a total of 4 isomers) but was found to make measurement of
(entry 21). Under these ‘‘optimized’’ conditions, 1 was obtained in the isomer ratios much easier. In this case however, since the
78% isolated yield. At lower temperatures, the er was comparable product contains two double bonds, epoxidation would give eight
but the conversion dropped considerably.
total stereoisomers complicating the analysis. An alternative way
When we attempted to explore the scope and limitations of to establish the enantioselectivity (and overcome these analytical
this procedure it quickly became apparent that the use of alkenyl difficulties) would be to use an enantiomerically pure chiral
nucleophiles in these hydrometallation AAA procedures was alkyne, which would produce a diastereoisomeric mixture of
more challenging than initially expected. The AAA products products (Fig. 2), and measure the resulting diastereomeric ratio
are very non-polar making separation of the enantiomers by (dr) by NMR spectroscopy to obtain the ‘enantioselectivity’.
HPLC on a chiral non-racemic stationary phase complicated. We first prepared enantiomerically pure alkyne (S)-5, which
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Fig. 2 dr determination by 13C NMR spectroscopy.
undergoes non-selective allylic alkylation in the presence of
stoichiometric CuBrÁMe2S to afford 6. Unfortunately, all 13C
NMR (126 MHz) signals of diastereomers 6 almost completely
overlap preventing meaningful dr determination. It was envisaged
that use of a shorter chiral alkyne such as (S)-711 might overcome
this problem. As shown in Fig. 2 it is possible to clearly differentiate
the diastereomers of 8 by 13C NMR spectroscopy.
We prepared both enantiomers of alkyne 7 in enantiomerically
pure form (499 : 1 er) and subjected each of these to optimised
AAA conditions using both enantiomers of L3. This gave all four
possible stereoisomers as shown in Scheme 1. The configuration
of the protected alcohol on the alkyne has no effect on the
stereochemistry of the new C–C bonds so that stereoselectivity
is entirely determined by the catalyst used. Here the yields
are uniformly high and selectivity (usually 88 : 12 er) is higher
than with the 5-phenyl-1-pentyne, which was used to optimize
the system.
Scheme 1 Use of enantiopure chiral alkynes in dynamic kinetic asym-
metric allylic alkenylation. Conditions: AAA of 3-bromo-1-cyclohexene
(1.0 eq.) using 2.5 eq. of alkyne 7, Cp2ZrHCl (2.0 eq.), CuCl (0.1 eq.), AgOTs
(0.11 eq.) and L3 (0.1 eq.) in CH2Cl2 at À40 1C for 18 h.
A 7-membered ring product 9 was prepared using this procedure
with a similar level of stereoselectivity (Scheme 2). We were
unable to isolate 3-bromocyclopent-1-ene in high enough purity
to test the reaction conditions on a five-membered ring.
In our previously reported AAAs (Fig. 1b),7 the mechanism of
CuI-mediated DYKAT appears to involve racemization of the
starting material (via a rapidly interconverting allyl iodide
intermediate) and CuL* mediated selection of one of the two
enantiomers for AAA. In the reaction described here, a related
scenario where racemization occurs through an allyl tosylate
intermediates seems unlikely as ÀOTs is not generally considered
to be nucleophilic, and enantioselectivity increases as the reaction
is cooled from room temperature to À40 1C (Table 2, entries 12, 20
and 21), which would presumably inhibit racemization. It therefor
seems more likely that this DYKAT occurs through formation of
interconverting allyl-copper intermediates3a,c,5a or through enantio-
convergent transformations,5c,f or a combination of mechanisms.
Further studies are required to gain insight.
Scheme 2 7-Membered ring example.
We have applied alkenylzirconocene nucleophiles in asymmetric
allylic alkylation reactions with racemic starting materials to give
enantioenriched products. The method is not generally applicable
but it does demonstrate that sp2-hybridized nucleophiles may
be used in dynamic kinetic asymmetric transformations. Further
experiments are under way.
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Chem. Commun.
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