Application of Heterocyclic derived ROPHy/SOPHy Oxime Ethers in the Asymmetric Addition of Diethylzinc to Benzaldehyde

James C. A. Hunt and Christopher J. Moody

Department of Chemistry, University of Exeter, Exeter, Devon. EX4 4QD.

Abstract

Our investigations into additions to ROPHy/SOPHy oxime ethers have shown that high diastereoselectivity can be achieved (de's up to >96%).¹ This ability has been utilised in the asymmetric synthesis of a-amino acids,² b-amino acids³ and the piperidine alkaloids (-)-coniine and (+)-pseudoconhydrine.⁴

We now report a new ability of ROPHy/SOPHy oxime ethers, to act as ligands in asymmetric synthesis. A standard reaction of the addition of diethylzinc to benzaldehyde with a chiral oxime ether catalyst to give chiral alcohols (Scheme 1). Preliminary results show moderate ee's using O-(1-phenylbutyl)-2-pyridylcarboxaldoxime ether (Figure 1). Further ligands are discussed.

**Scheme 1**
Et₂Zn, Chiral Catalyst, Toluene

**Figure 1**

Contents

Abstract

Introduction

Results and Discussion

Summary

References

Introduction

In recent years the asymmetric addition of diorganozinc reagents to aldehydes using chiral ligands to produce enantiopure secondary alcohols has seen much activity.^5,6 A wide variety of ligands have been employed with a range of enantioselectivities. b-Amino alcohols have been popular due to their accessibility and the ability to routinely produce ee's of 99% with near quantitative yields.⁷ Chiral ferrocene amino alcohols, piperazines, quaternary ammonium salts, 1,2-diols, oxazaborolidines and transition metal complexes have all been employed giving a range of stereoselectivity.⁶ With the rise in popularity of solid phase synthesis, polymer supported catalysts have seen application with good results.

Heterocyclces have seen much use in ligands in asymmetric catalysis, specifically bipyridines and oxazolidines. We wanted to examine whether novel ligands derived from oxime ethers and heterocycles could exhibit stereoselectivity in organic reactions.

In this poster we aim to exhibit preliminary results from our work on the asymmetric addition of diethylzinc to benzaldehyde using oxime ethers as chiral catalysts.

Results and Discussion

Preparation of Oxime Ethers
: Oxime ethers 1-4, 7, 8, 10 (Figure 2)were prepared by our standard method as described in the literature.¹ Treatment of ROPHy/SOPHy with the corresponding aldehydes gave oxime ethers in moderate to excellent yields. Oxime ethers 5, 6 and 9 were prepared by condensation with a new hydroxylamine SOPHEA, (S)-O-(2-Hydroxy-1-PHenylEthyl)hydroxylAmine 11, which was prepared from (R)-phenylethan-1,2-diol as described by Scheme 2.; Each ligand was subjected to examination in a standard reaction. The addition of diethylzinc to benzaldehyde provided a simple tool to examine the catalytic stereoselectivity of each. Initially ligands were used in small quantity, 5mol%, but yields were poor and the amount of ligand was raised to 20 mol% when yields became more acceptable (Table 1, entries 1 and 2). As a consequence the stereoselectivity also increased.

**Figure 2**
1	2
3	4
5	6
7	8
9	10

**Table 1**⁸
Entry	Catalyst	Amount/mol%	T/°C	Yield/%^a	ee/%^a,b
1	(R)-1	5	0-rt	50	2
2	(R)-1	20	0-rt	98	12
3	(R)-1	20	-78-rt	23	9
4	(S)-2	20	0-rt	7	1
5	(S)-3	20	0-rt	75	3
6	*(R,R)-4*	20	0-rt	31	9
7	*(S,S)-5*	20	0-rt	25	<1
8	*(S,S)-6*	20	0-rt	51	17
9	(R)-7	5	0-rt	15	21
10	(R)-7	20	0-rt	100	30
11	(R)-7	20	-78-rt	26	31
12	(R)-8	20	0-rt	60	0
13	(R)-9	5	0-rt	4	17
12	*(R,R)-10*	20	0-rt	11	2

Use of the 2-pyridyl oxime ether 1 at room temperature exhibited good catalytic properties giving a high yield (98%) and some enantioselectivity (ee 12%). Unexpectedly, reaction at low temperature (Table 1, entry 3) failed to enhance the selectivity.

Ligands chelating through sulfur have seen good selectivity in diethylzinc additions⁹and we explored the activity through a 2-thienyl oxime ether 2. However yield and stereoselectivity were poor (Table 1, entry 4) which is probably explained due to the lack of availability of the sulfur lone pair to chelate. The thiazole ring in oxime ether 3 alleviates this problem, the sulphur lone pair is tied up in the ring system whilst the nitrogen lone pair is available for chelation. Compared to the thiophene derived oxime ether 2, the thiazole oxime ether 3 had greater catalytic activity increasing the yield to 75% but the enantioselectivity was unchanged.

C₂ symmetric ligands have seen much application in this type of reactions.¹⁰ We thought that preparation and use of similar ligands based on our oxime ether template would be of use in our standard reaction. We prepared three ligands one derived from ROPHy 4 and the others from O-protected SOPHEA, 6 and the free alcohol, 5. Reaction with 4 some enantioselectivity and a poor yield. This was disappointing as we had expected the ee to have been enhanced. Reaction with 6 however was more encouraging. An increase in both yield and ee was observed. The increase stereoselectivity may have been due to the two large silyl groups present in the ligand causing reaction to occur more favourably on one face of benzaldehyde. The deprotected version 5 surprisingly gave virtually no stereoselectivity.

Oxime ethers 7, 8, 9 and 10 were also prepared and were included in the study for completeness. The C₂ symmetric ligand 10 gave unexpectedly poor results a low ee and a poor yield. The SOPHEA derived oxime ether 9 gave good enantioselectivity but gave a poor yield. The salicaldehyde derived ROPHy oxime ether 7 gave encouraging results at 5mol% (Table 1, entry 13). Increasing the amount of catalyst used gave a quantitative yield and an ee of 30%. Unexpectedly repetition of the experiment at low temperature failed to give a higher ee and also reduced the yield. The importance of an ortho chelating group was examined with the o-anisyl oxime ether 8, it was thouhgt that the O-methyl group would prevent chelation to the zinc. As expected the yield was decreased and there was a complete failure to induce stereoselectivity.

Summary

We have demonstrated that our ROPHy and SOPHEA oxime ethers have the potential to be good ligands in the asymmetric addition of diethylzinc to benzaldehyde. The most promising ligands are 6 and 7 both gave indication that catalytic asymmetric induction can be observed with these compounds. Further studies into catalytic asymmetric induction involving chiral oxime ethers are underway.

References

1. Gallagher, P. T.; Hunt, J. C. A.; Lightfoot, A. P.; Moody, C. J., J. Chem. Soc., Perkin Trans. 1, 1997, 2633-2637.

2. Gallagher, P. T.; Lightfoot, A. P.; Moody, C. J., Synlett, 1997, 659-660.

3. Hunt, J. C. A.; Moody, C. J., in press.

4. Gallagher, P. T.; Lightfoot, A. P.; Moody, C. J., J. Org. Chem., 1997, 62, 746-748.

5. Anderson, J. C; Harding, M., J. Chem. Soc., Chem. Commun., 1998, 393 and references cited therein.

6. Soai, K.; Newa, S., Chem. Rev., 1992, 92, 833-856.

7. Wilken, J., Kossenjans, M., Groger, H.; Martens, J., Tetrahedron: Asymmetry, 1997, 8, 2007-2015 and references cited therein.

8. a) After column chromatography, b) ee's obtained from HPLC results of purified alcohol.

9. Anderson, J. C.; Harding, M., J. Chem. Soc., Chem. Comm., 1998, 393.

10. Noyori, R.; Kitamura, M., Angew. Chem. Int. Ed. Engl., 1991, 30, 49-69.