Full text of DOI:10.1016/S0040-4039(00)01715-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9351–9354
Planar chiral mimetics. A new approach to ligand design for
asymmetric catalysis
Geraint Jones, David C. D. Butler and Christopher J. Richards*
Department of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 31 August 2000; accepted 3 October 2000
Abstract
(S)-Serine methyl ester is readily transformed into 4-(hydroxymethyl)oxazoline ligands containing either
a 2-(h5-cyclopentadienyl)(h4-tetraphenylcyclobutadiene)cobalt or a 2-(1,2,3,4,5-pentaphenyl)-ferrocene
substituent. The influence of the bulky metallocenes result in these ligands mimicking planar chirality, as
demonstrated by their catalysis of the addition of diethylzinc to benzaldehyde resulting in (R)-1-phenyl-
propanol (75% e.e.). © 2000 Published by Elsevier Science Ltd.
Keywords: asymmetry; catalysts; metallocenes; oxazolines.
Planar chiral organometallics, and especially metallocenes such as ferrocene, have been
extensively utilised as the basis of a wide variety of chiral ligands for application in asymmetric
synthesis.1 As part of a programme investigating the synthesis of new planar chiral complexes,
we recently reported that the metallocene appended oxazoline 1 undergoes highly diastereoselec-
tive metallation when heated with palladium acetate to give exclusively palladacycle 2 (Scheme
1).2 The outcome of this reaction was rationalised by the destabilisation of conjugated rotamer
1% over the alternative 1¦ due to an unfavourable interaction in the former between the oxazoline
isopropyl substituent and the tetraphenyl floor of the metallocene.
O
O
2
Pd
N
O
N
N
O
Pd(OAc)2
O
Co
Co
Co
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
AcOH,
95 oC
1'
1''
2
Scheme 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01715-9

9352
As a consequence of this bulky moiety, the oxazoline group of 1 may be regarded as being in
an environment of virtual planar chirality, i.e. as if the heterocycle were covalently bound to a
second position of the cyclopentadienyl ring, as is actually the case in complex 2. This example
of a chiral relay offers the potential to synthesise simple alternatives to planar chiral ligands that
require only a single element of central chirality. In this Letter we report on our initial efforts
towards this goal with the generation of functionalised oxazolines that act as catalysts for the
addition of diethylzinc to benzaldehyde.
Starting from the readily available carboxylic acid 3,2 amide 4 was readily obtained via reaction
of the intermediate acid chloride with (S)-serine methyl ester hydrochloride in the presence of
triethylamine. Dehydrative ring-closure was achieved with DAST3 to give oxazoline 5 in 93%
overall yield (Scheme 2). From this three new ligands 6–8 were readily generated with each
containing a b-hydroxyl group relative to the oxazoline nitrogen,4 an arrangement essentially
identical to the b-hydroxy amines that have been extensively used in conjunction with dialkylzinc
reagents.5
O
CO2Me
OH
DAST
CO2H
N
H
i) (COCl)2, CH2Cl2
Co
Co
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CH2Cl2
99%
ii)
(S)-serine methyl
ester. HCl, NEt3,
CH2Cl2 94%
Ph
3
4
PhMgBr
O
O
6 R = Ph 99%
7 R = Me 94%
R
Et2O, THF
R
N
N
CO2Me
MeMgI
Co
Co
OH
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et2O, THF
LiAlH4
Et2O
8 R = H 96%
5
Scheme 2.
Addition of 1.5 equivalents of diethylzinc to benzaldehyde 9 in the presence of 5 mol% of these
ligands resulted in the clean formation of 10, the highest selectivity of (R) to (S) enantiomers being
obtained with the parent hydroxymethylene complex 8 (Table 1, entry 3). In contrast, phenyl and
methyl substituents adjacent to the hydroxyl group in 6 and 7 result in an erosion of selectivity
correlated to the size of these alternatives to hydrogen (entries 1 and 2)6 (Scheme 3).
Table 1
Addition of diethylzinc to benzaldehydea
Entry
Catalystb
e.e. of 10c (config.)d
1
2
3
4
6
7
8
8 (R)
54 (R)
68 (R)
75 (R)
14
a 9 (1.0 mmol), toluene (5 ml), Et2Zn (1 M in hexanes, 1.5 ml), all reactions gave \90% conversion after 24 h.
b 5 mol%.
c Determined by GC.
d Determined by GC comparison to commercial (R)-1-phenylpropanol.

9353
OH
CHO
Et2Zn
PhMe, RT
9
10
Scheme 3.
Thus we reasoned that an increase in selectivity might alternatively relate to the size of the
floor as defined by the metallocene phenyl substituents. To increase the number of these from
four to five required a switch to the chemistry of pentaphenylferrocene 11. Although first
reported in 1965 by Pauson7 we were surprisingly unable to find any reports on the direct
functionalisation of this complex.8 This however proved to be straight forward as reaction with
2-chlorobenzoyl chloride and aluminium chloride, as previously described for ferrocene itself,9
cleanly gave aryl ketone 12 (Scheme 4). This in turn was hydrolysed to give pentaphenyl-
ferrocene carboxylic acid 13 in 85% overall yield. Use of this as a starting material for the same
chemistry as described above cleanly gave the novel oxazoline complex 14 in excellent yield.
O
Cl
CO2H
Ph
i) tBuOK, DME,
H2O
i) 2-ClC6H4COCl
Fe
Ph
Fe
Fe
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
AlCl3, CH2Cl2
ii) H2O
ii) H3O+
Ph
Ph
Ph
O
11
12
13
85% from 11
O
CO2Me
OH
N
H
N
i) DAST 96%
ii) LiAlH4 95%
i) (COCl)2, CH2Cl2
OH
Fe
Ph
Fe
Ph
Ph
Ph
Ph
Ph
Ph
Ph
ii)
(S)-serine methyl
ester. HCl, NEt3,
CH2Cl2 98%
Ph
14
Ph
Scheme 4.
Application of 14 to the diethylzinc/benzaldehyde reaction as before led to an increase in
selectivity for the (R)-enantiomer (Table 1, entry 4). Increasing the hexane component of the
solvent mixture to 50% and decreasing the reaction temperature to 0°C made no appreciable
difference to the enantioselectivity.
The absolute configuration of the 1-phenylpropanol resulting from these reactions may be
rationalised by considering the two alternative reaction pathways A and B. Orientation of the
oxazoline 4-substituent away from the floor defined by the phenyl groups results in a preference
for the oxazoline–metallocene rotamer drawn in both A and B. Following coordination to zinc,
the ethyl group to be transferred may be aligned either away (A) or towards (B) the
alkoxymethylene arm of the oxazoline. In the former, coordination of benzaldehyde from the
side opposite to the floor results in ethyl transfer to the Re face and formation of the major
R-enantiomer. In the alternative B the coordinated benzaldehyde is in close proximity to the
bulky floor unless the oxazoline rotates into an alternative conformation. This may occur to a
greater extent when methyl and phenyl groups are adjacent to the zinc coordinated alkoxide,

9354
with these substituents favouring alignment of the transferable ethyl group towards the
alkoxymethylene arm. Clearly too much bulk is detrimental to selectivity with this system.
However, for complexes 8 and 14, the ability of the phenyl floor to cover one face of the
heterocycle enables the comparison with planar chirality to be made. This arrangement is
equivalent to the oxazoline itself being p-bonded to a metal/ligand fragment.10
O
O
O
H
H
N
N
OH
OH
O
O
O
Zn
Zn
M
Ph
M
Et
H
ZnEt2
ZnEt2
Ph
Ph
Et
Et
H
Et
Ph
R
S
A
B
In conclusion, we have demonstrated that functionalised oxazoline ligands attached to either
a tetraphenyl/cobalt or a pentaphenyl/iron derived metallocene are readily synthesised in
excellent yield. The presence of the multiple phenyl groups results in a ligand/metal environment
equivalent to that displayed by planar chiral organometallics. The use of related mimetics in
reactions of wider applicability is currently under investigation.
Acknowledgements
We wish to thank the EPSRC for financial support (GR/M55893) and also Rob Jenkins for
his assistance with this work.
References
1. For recent reviews, see: (a) Richards, C. J.; Locke, A. J. Tetrahedron: Asymmetry 1998, 9, 2377. (b) Kagan, H.
B.; Riant, O. Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI Press: Greenwich, CT, 1997; Vol. 2, pp.
189–235.
2. Stevens, A. M.; Richards, C. J. Organometallics 1999, 18, 1346.
3. Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D. R. Org. Lett. 2000, 2, 1165.
4. The use of related 2-alkyl and 2-aryl oxazolines as ligands for the addition of diethylzinc to aldehydes was
recently reported: Imai, Y.; Matsuo, S.; Zhang, W.; Nakatsuji, Y.; Ikeda, I. Synlett 2000, 239.
5. Review: (a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833. See also: (b) Kitamura, M.; Okada, S.; Suga, S.; Noyori,
R. J. Am. Chem. Soc. 1989, 111, 4028.
6. For comparison, (S)-2-methyl-4-(2-(2-hydroxy)propyl)oxazoline led to the formation of (S)-10 in 7% e.e., see
reference 4.
7. McVey, S.; Pauson, P. L. J. Chem. Soc. 1965, 4312.
8. Functionalised heteroleptic pentaphenylferrocene derivatives have been directly synthesised from cyclopentadiene
precursors: Hodous, B. L.; Ruble, J. C.; Fu, G. C. J. Am. Chem Soc. 1999, 121, 2637.
9. Reeves, P. C. Org. Synth. 1977, 56, 28.
10. Planar chiral ligands have been extensively applied to the reaction between dialkylzinc reagents and aldehydes,
see reference 1a. However, the only direct comparison possible, with respect to environment and chelate size, is
with (−)-2-(hydroxymethyl)azaferrocene (absolute configuration unknown). This led to the formation of (S)-10 in
58% e.e.: Dosa, P. I.; Ruble, J. C.; Fu, G. C. J. Org. Chem. 1997, 62, 444.
.