Amino-sugar modular ligands - Useful cores for the formation of asymmetric copper 1,4-addition catalysts

Article abstract of DOI:10.1039/b813137f

Modular phosphine ligands, synthesised rapidly from commercial N-acetylglucosamine, are very effective in copper(I)-catalysed 1,4-additions of ZnR₂ to linear aliphatic enones (87-95% ee). The Royal Society of Chemistry.

Full text of DOI:10.1039/b813137f

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Amino-sugar modular ligands—useful cores for the formation of
asymmetric copper 1,4-addition catalystsw
Antonella De Roma,a Francesco Ruffoa and Simon Woodward*b
Received (in Cambridge, UK) 30th July 2008, Accepted 22nd August 2008
First published as an Advance Article on the web 17th September 2008
DOI: 10.1039/b813137f
Modular phosphine ligands, synthesised rapidly from commercial
N-acetylglucosamine, are very effective in copper(I)-catalysed
1,4-additions of ZnR2 to linear aliphatic enones (87–95% ee).
The amino-sugar family LA–C,F,G was compared against the
amino-sugar precursors LD–E and the nearest commercial analo-
gues of such architectures, the ‘Trost ligands’ LH–I (Scheme 2).
Despite the success of systems 1–3 (which provide ee values of
80–98% for a range of enones7) there is still a need to identify
easily obtained variable architectures: firstly, to circumvent the
limitations of single enantiomeric series ligand sets (e.g. 1–3); and
secondly, to attain catalysts of increased activity through greater
One key requirement in the efficient design of new catalytic
asymmetric processes is ready access to a library of chiral
ligands showing enough molecular diversity to allow the
attainment of synthetically useful stereoselectivities (490%
ee) in initial screening. In the past 10 years significant attention
has been turned towards the use of chiral ligands based on
natural carbohydrates.1 Large numbers of ‘sugar-cores’ have
been developed (e.g. 430 types leading to ca. 200 ligands in
ref. 1) that deliver diverse coordination architectures. Highly
successful asymmetric hydrogenations (96–499% ee),2 allyla-
tions (up to 99% ee),3 aldehyde methylations (up to 94% ee),4
Heck reactions (up to 99% ee)5 and other processes have
resulted from the use of these ligands.1 However, recent
attempts to apply such ligands to asymmetric conjugate addi-
tion (ACA) reactions were not as successful.6 As a number of
the most successful ligands in highly enantioselective ACA
reactions include potential nitrogen-based donor sets (1–3,7
Scheme 1) we sought to explore the unprecedented use of
amino-sugar8 based ligands in such ACA transformations.9
Scheme 1
a
`
Dipartimento di Chimica ‘‘Paolo Corradini’’, Universita di Napoli
‘‘Federico II’’, Complesso Universitario di Monte S. Angelo, via
Cintia, 80126 Napoli, Italy. E-mail: ruffo@unina.it;
Fax: +39-081674090
b School of Chemistry, The University of Nottingham, Nottingham,
UK NG7 2RD. E-mail: simon.woodward@nottingham.ac.uk;
Fax: +44-(0)115-9513564; Tel: +44-(0)115-9513541
w Electronic supplementary information (ESI) available: Full experi-
mental, spectroscopic and chiral GC data for all compounds pre-
sented. See DOI: 10.1039/b813137f
Scheme 2
ꢀc
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Table 2 Representative additions of methyl nucleophiles to enonesa
Run
Ligand
R1
R2
R3
Yield (%)
Ee (%)b
1
2
3
4
5
6
7
8
LA
LG
LA
LG
LA
LG
LA
LG
LA
LG
LA
LG
LG
C5H11
C5H11
C5H11
C5H11
C6H13
C6H13
C6H13
C6H13
iPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Et
70
75
80
80
57
52
95
99
47
33
79
66
78
95 (R)
92 (R)
91 (R)
87 (R)
91 (R)
90 (R)
93 (R)
90 (R)
89 (R)
94 (R)
93 (R)
88 (R)
91 (S)
Et
Me
Me
Et
Scheme 3
Et
9
Me
Me
Et
Et
Et
ligand acceleration effects. The amino-sugar ligands of Scheme 2
are highly attractive as they are readily available in only a few
simple, high yielding steps from very low cost N-acetyl-D-glucos-
amine (B0.5 Euro gꢁ1) (Scheme 3 and ESIw).z
10
11
12
13
a
iPr
iPr
iPr
Me
ZnMe2 (0.24 mmol, 2.0 equiv.), enone (0.12 mmol), ligand (7.5 mmol,
5 mol%) and Cu(OTf)2 (3.0 mmol, 5 mol%) in toluene (2 mL). Yields
by GC against calibrated internal standard (undecane). All conver-
The library of Scheme 2 was screened in demanding addi-
tions of methyl nucleophiles to (E)-nonen-2-one (Table 1).y
No activity was found for 1,4-additions of AlMe3; the
behaviour of LA and LG is representative of all the ligands
tried. The situation with ZnMe2 was radically different. In
toluene and the presence of the air-stable, non-hygroscopic
CuI precursor Cu(OTf)2, the amino-sugar library conformed
as expected delivering 424 : 1 stereoselectivities with ligands LA
and LG. The attainment of such selectivities in all alkyl sub-
strates is rare.7 The presence of the phosphorus donor (LA,G vs.
LD–E) was vital as was the inclusion of an O,N-linker set as
opposed to N,N versions (LA vs. the ‘Trost’ ligands LH–I).
Previously, we have proposed that the presence of appropriately
placed free hydroxide functions in bimetallic cuprate complexes
can be beneficial.11 Removal of the diphenylphosphinobenzoic
ester fragment led to a highly significant reversal in the stereo-
b
sions 499% except for runs 6 (84%) and 10 (82%). Stereochemical
correlation by direct comparison with authentic samples of (R)-
product (see ESI).
selectivity: +95 to ꢁ61% ee (LA vs. LF). However, removal of
the 4,6-acetal unit led to a loss in selectivity (LA vs. LC).
The generality of the best ligand architectures was further
tested against a range of demanding substrates (Table 2).
It was noted that the most successful ligands LA and LG
were effective for the addition of both ZnMe2 and ZnEt2 to a
class of enones possessing only aliphatic substituents with
minimal steric profiles and that the reactions were technically
very simple to carry out—only air stable Cu(OTf)2 is required.
In general, for all substrates ligand LA gave better yields (up to
95%, run 7) and enantioselectivities (up to 95%, run 1). An
exception was LG which gave a superior result in ZnMe2
i
addition to the branched enone R1 = Pr (run 10). The
Table 1 Representative additions of methyl nucleophiles to (E)-
nonen-2-onea
selectivity was also affected by the presence of a bigger
substituent R2. In fact when both R2 and R3 have increased
steric profile only ligand LG gives good results (run 13; with LA
we obtained only 67% ee).
An attempt was made to further simplify the ligand struc-
ture to LJ which can be easily prepared in only two steps from
the commercial source methyl-a-D-glucoside (B0.2 Euro gꢁ1).12
High enantioselectivity (up to 94% ee) was attained but in the
present protocol the yields were unsatisfactory (B30%). At
present the ligands LA,G are optimal but further studies with
LJ will be targeted in the future due to its low cost and ready
availability.
Ligand
Me source Conditions
Yield (%) Ee (%)b
LA
LG
LA
LB
LC
LD
LE
LF
LG
LH
LI
AlMe3
AlMe3
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
THF, 22 1C, 12 h
THF, 22 1C, 12 h
o5
o5
70
10
25
o5
o5
78
75
o5
—
—
95 (R)
17 (S)
53 (S)
—
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
Toluene, 22 1C, 12 h
—
61 (S)
92 (R)
—
o5
—
a
ZnMe2 (0.24 mmol, 2.0 equiv.), (E)-nonen-2-one (0.12 mmol), ligand
(7.5 mmol, 5 mol%) and Cu(OTf)2 (3.0 mmol, 5 mol%) in toluene
(2 mL). Yields by GC against calibrated internal standard (undecane).
b
All conversions 499%. Stereochemical correlation by direct com-
parison with an authentic sample of (R)-product (ref. 10).
ꢀc
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In conclusion, we have described for the first time use of
amino-sugar phosphine ligands in asymmetric 1,4-additions of
diorganozinc species to acyclic enones. Excellent enantioselec-
tivities (up to 95% ee) and yields were obtained with ligands
LA and LG for these demanding substrates.
6 (a) Y. Meta, M. Die
´
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¨
M. Die
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T. den Hartog, K. Geurts, A. J. Minnaard and B. L. Feringa,
Chem. Rev., 2008, 108, 2824. Specific cases: (c) H. Mizutani, S. J.
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SW thanks the EPSRC for support through grant EP/
F033478/1. ADeR and FR thank MIUR for financial support
(Prin 2007). SW acknowledges valuable input from the COST
D40 Innovative Catalysis Programme.
8 For an excellent introduction to amino-sugar chemistry see: Com-
prehensive Glycoscience, ed. J. P. Kamerling, G. J. Boons, Y. C.
Lee, A. Suzuki, N. Taniguchi and A. G. J. Voragen, Elsevier,
Amsterdam, 2006, vol. 1, ch. 1.01, pp. 1–37, ch. 1.13, pp. 490–540.
9 Use of amino-sugar ligands in other areas has been reported. (a)
Allylic substitution: K. Glegola, E. Framery, C. Goux-Henry, K.
M. Pietrusiewicz and D. Sinou, Tetrahedron, 2007, 63, 7133; (b)
S. A. Johannesen, K. Glegola, D. Sinou, E. Framery and T.
Skrydstrup, Tetrahedron Lett., 2007, 48, 3569, and references
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E. Framery, C. Goux-Henry, A. Iourtchenko and D. Sinou,
J. Organomet. Chem., 2003, 687, 384; (d) hydrovinylation reaction:
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Chem. Synth. 2002–2007, 2007, 5, 293, and references therein; (f)
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F. Ruffo, ChemSusChem, 2008, 1, 425.
Notes and references
z For details of ligand synthesis and spectroscopic data see the ESI.w
y General procedure for asymmetric conjugate additions (ACA) to
enones:
a solution of the copper-catalyst precursor Cu(OTf)2
(1 mol%, 0.003 mmol) and the corresponding ligand (2.5 equiv.,
0.0075 mmol) in 2 mL of dry toluene was stirred for 30 min at room
temperature. The alkylating organometallic reagent ZnR2 (2 equiv.
2 M toluene or 1 M hexane solutions, 0.24 mmol) was added dropwise
and then the substrate (0.12 mmol). After 12 h the reaction was
quenched with 2 M HCl (2 mL). Undecane or dodecane (10 mL) was
then added as an internal standard and the organic layer filtered twice
through a plug of silica. Yields and enantiomeric excesses were
measured by GC using an octakis(6-O-methyl-2,3-di-O-pentyl)-g-CD
column (method of ref. 10c).
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Soc., 2002, 124, 779; (b) S. M. W. Bennett, S. M. Brown, A.
Cunningham, M. R. Dennis, J. P. Muxworthy, M. A. Oakley and
S. Woodward, Tetrahedron, 2000, 56, 2847; (c) P. K. Fraser and S.
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ꢀc
This journal is The Royal Society of Chemistry 2008
5386 | Chem. Commun., 2008, 5384–5386