Pergamon T~~FIu&~: Asymmeby Vol. 5. No. IO, pp. 18751876, 1994

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New Chiral Ligand For Optically Active &Hydroxy Esters

Synthesis By Enantioselective Reformatsky Reactions

Abatra& The cheap coumm&& available (1S,2S)-l-phenyl-2-aminctl,~plopanediol2 appears to be a

convenient pmursor for the synthesis of chiral auxihsries for the pteparation of optically active phydmxy

esters by asymmelric Refomatsky reactions. The N,N-dimethyl derivative of TBDMS-2 gave pmducts with

enantiomeric excesses up to 65 % .

Enantioselective Reformat&y reactions may be one of the most in-g and tmfui proceduns for

converting aldehydes and ketones to apticaUy active &hydroxy ested, but, to the best of our knowledge only

in two cases have satisfactory mmlts been obtaiuedm. We nport hen an enantioselective RefomatsQ m&n

using as new chiral &and, the edgy pure (lS~S~l-p~yl-2-N,N~~y~~

~u~~~y~y~xy-l,3-~~01(4) easily pxepaml from (1S2S)-1-~ny1-2-~1~~012

in two steps (scheme ). Indeed the chiral auxillauy 2 has been showa to be a very good chiral precursor for

several ssymmetric processes’ and we undertook to study the possible applications of 4 as a suitable chiral

auxiliary far the Reformat&y mction.

When bemaldehyde was treated with 3 mol equivtdent of Reformat&y reagent in the preseme of 1 mol

equivalent of homchiral aminoalcohol 4 in THF at VC, (S)-(-)-‘butyl3-hydroxy-3-phenylprqanoate with 65%

e.e. was obtained in 100% yield, (table. Entry 1). A further lowering of the temperatm fi7mloT to -3YC

abates the conversion (70%) without improvement of the he. of the product 1. In the presence of different

mm& aldehydcs such ss 2-n~h~~, l-~~~~, ~~-~~~h~ ~-p~nyl~h~

and cinnamaldehyde, e.e.s ranging from 2140 per cent wem obtai& (table. Entries 2.3,4,5 and 8). It is

worthy of note that in the case of cinnmaldehyde complete l&additkm +oselectivity of the reaction was

1875

1876

observed. If an equimolar ratio

the reaction was completely

D. PINI et al.

aldehyde/Reformatsky reagent/chiral ligand 4 was employed,

inhibited. As shown in entries 6 and 7, the presence of

electrondonor groups drastically reduces the conversion (7-lo%), whereas the e.e. is not affected (32% and

35 % respectively). Also a catalytic run in the presence of 0.1 mol equivalent of 4 was carried out: (S)-1 (AI

= Ph) in quantitative yield and 15% e.e. was obtained. A typical experimental procedure is as follows:

‘butoxycarbonylmethylzinc bromide has been prepared by adding a THF solution (21 ml) of ‘butyl

bromoacetate (5.67 ml, 0.042 mol) to commercial Zn dust activated by washing it rapidly with aqueous HCl.

The pure cristalline organometallic reagent can be isplated by filtration under nitrogen atmosphere and stored

at -20°C. A THF solution (10 ml) of above Reformatsky reagent (1,47 mmol) was added to a THF mixture

(10 ml) of aldehyde (0,49 mmol) and ligand 4 (0,49 mmol), stirring it for 15-20 h at 0°C. The reaction was

quenched with 10 % HCl (10 ml), and the mixture was extracted with ethylacetate. The organic layer was

washed until neutral with NaHC4 (10 96) and H,O, dried (Na$O,) and evaporated under reduced pressure.

By purification of the crude product on Silica gel LC using dichloromethane as eluent, the pure fi-hydroxy

ester 1 was obtained and the chiral ligand 4 recovered.

Table. Enantioselective Reformat&y reaction in presence of chiral aminoalcohol 4

A b) I$O+ 1

entry’ Ar yield %b e.e. %’ entry Ar yield% e.e. 96

1 Ph 100 65 (S)J 5 pPh-C,H, 100 29

2 2 Naph 100 40 6 pMeO-CSH, 7 32

3 1 Naph 60 33 7 oMeO-C& 10 35

4 pCF,C& 90 31 8 C,&-CH=CH- 100 21

’ Molar ratio. Ald.: A : 4 = 1: 3 : 1. b Determind by capillary GC analysis on erode product.’ D&mined by ‘H NMR analysis using quinine anhydrous as chital solvating agent. ’ Determined by the sign of optical rotation of the isolated product.

In conclusion, this preliminary study has shown the ready accesibiiity of the new and cheap chiral ligand 4

which is able to promote the enantioselective addition of Reformatsky reagent to a large number of aromatic

aldehydes with different characteristics, providing asymmetric 8-hydroxy esters in very good chemical yield

and with e.e.s ranging from 21 to 65 per cent.

References 1. Review. Hczthcock, C.H. in “Asymmetric Synthesis”, Ed. by J.D. Morrison, Vol. 3,Academic

Press, Orlando, 1984, p.144

2. Guette., M.; Capillon, J.; Guetk, J.P. Tetrahedron 1973, 29, 3659

3. Soai, K.; Kawase, Y.; Tetrahedron: Asymmetry 1991, 2, 781

4. Meyers, A.I.; “Asymmetric Carbon Carbon Forming Reactions via Chiral Oxaz.ohes” in Aqmmetric Reactions and Processes in Chemistry (E.L. Eliel, S. Otsuka, eds.), J. Am. them. l&x.,

Washington, 1982

(Received in UK 11 July 1994)