Chelation-controlled ester-derived titanium enolate aldol reaction: diastereoselective syn-aldols with mono- and bidentate aldehydes

Abstract

A chelation-controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of (S)-valinol-derived ester with a variety of aldehydes proceeded with high syn-diastereoselectivities (up to 99:1) and isolated yields (94%).

Optically active syn- and anti-2-alkyl-3-hydroxycarbonyl units are inherent to numerous biologically active natural products.¹ As a consequence, a number of stereoselective methodologies have been developed for their syntheses.^2,3 In our recent work on ester-derived titanium enolate aldol reactions⁴ we have demonstrated that the aldol reactions of phenylalaninol-derived sulfonamido esters with a number of bidentate oxyaldehydes provided syn-aldols diastereoselectively. The corresponding reactions with monodentate aldehydes, however, have shown little syn-selectivities. The chirality transfer presumably proceeds through chelation by the β-sulfonamide functionality. In our continuing effort to further develop these ester-derived titanium enolate aldol reactions, we have subsequently investigated the effect of a β-chiral substituent on aldol stereochemistry by replacing the phenylmethyl substituent of phenylalaninol with other alkyl groups. Herein, we report that the aldol reaction of an (S)-valinol-derived sulfonamido ester with a variety of mono- and bidentate aldehydes proceeded with good to excellent syn-diastereoselectivities and isolated yields. Removal of the chiral auxiliary by mild saponification provided optically active syn-α-alkyl-β-hydroxy acids and full recovery of the chiral auxiliary. The ready availability of valinol and use of inexpensive TiCl₄ make this methodology practical and provide rapid access to syn-aldols in optically active form.

Optically active N-p-tosyl-(2S)-valinol 1 was prepared in multigram quantities by reduction of l-valine with LiAlH₄ and followed by sulfonylation of the amine functionality with p-toluenesulfonyl chloride and tri ethylamine in the presence of DMAP at 0°C for 2 h (89% yield). As shown in Scheme 1, reaction of sulfonamide 1 with propionylchloride and triethylamine afforded propionyl ester 2 in 85% yield after silica gel chromatography (mp 78°C, ${\left[\alpha \right]}_{\text{D}}^{23}=-19.1$ (c 0.92, CHCl₃)). The corresponding titanium enolate of 2 was prepared by treatment with TiCl₄ (1.1 equiv., 1 M solution in CH₂Cl₂) in CH₂Cl₂ at 0°C followed by addition of N,N’-diisopropylethylamine (3 equiv.) after 10 min and stirring of the resulting mixture at 0°C for 1 h. The enolate so formed was reacted with a variety of aldehydes precomplexed with TiCl₄ (3 equiv.) at −78°C for 1.5–2 h. Interestingly, aldol reaction of 2 with various aldehydes proceeded with excellent diastereoselectivity and isolated yields; the results are summarized in Table 1. Out of four possible diastereomers, formation of syn-diastereomer 3 (major) and anti-diastereomer 4 were observed by ¹H and ¹³C NMR as well as HPLC analysis before and after chromatography. Reaction of 2 with monodentate aldehydes exhibited high syn-diastereoselectivity (entries 1–5)⁸ except with phenylpropargyl aldehyde which afforded the anti-isomer as the major product (entry 6). Furthermore, reaction with bidentate aldehydes such as benzyloxyacetaldehyde and benzyloxypropionaldehyde provided a single syn-aldolate in high yield (entries 7 and 8). We have also carried out double stereodifferentiating experiments in which an oxyaldehyde bearing an α-chiral center was reacted with the chiral enolate derived from propionate ester 2. Aldol reaction of 2 and 2(S)-benzyloxypropionaldehyde (stereochemically matched case) under identical conditions afforded virtually a single (by HPLC and 400 MHz ¹H NMR analysis) aldol product 3h (entry 9) in 77% yield after silica gel chromatography. However, the reaction of 2 and 2(R)-benzyloxypropionaldehyde, a mismatched case, afforded a 34:64 mixture of syn and anti isomers in 82% isolated yield (entry 10). Because of the marked stereo-chemical preference (matched isomer), we then attempted reaction of 2 (1 equiv.) with racemic benzyloxypropionaldehyde (2 equiv.) at −78°C for 0.5 h (Scheme 2).

Scheme 1.

Reagents and conditions: (a) CH₃CH₂COCl, Et₃N, CH₂Cl₂, 0°C, 2 h; (b) TiCl₄, iPr₂NEt, 0°C, 1 h, then RCHO and TiCl₄, CH₂Cl₂, −78°C, 2 h; (c) LiOH, THF–H₂O, 23°C, 2–3 h; (d) CH₂N₂, Et₂O, 23°C, 30 min; (e) LiBH₄, THF–MeOH, 23°C, 2 h.

Table 1.

Aldol reaction of ester 2 with representative aldehydes

Entry	Aldehyde	Compda	Yield (%)b	syn:anti (3/4)c
1	Me2CHCHO	3a	89	90:10
2	Me2CHCH2CHO	3b	93	95:5
3	trans-PhCH=CHCHO	3c	89	96:4
4	PhCHO	3d	94	88:12
5	Me(CH2)6CHO	3e	96	82:18
6	Ph-C≡C-CHO	3f	86	36:64d
7	BnOCH2CHO	3g	74	99:1
8	BnOCH2CH2CHO	3h	81	99:1
9		3i	77	99:1
10		3j	82	34:66d

^aMajor isolated product.

^bIsolated yield after chromatography.

^cRatios determined by ¹H MR and HPLC analysis before and after chromatography. Reaction time=1.5–2 h.

^dRatio after removal of chiral auxiliary.

Scheme 2.

Interestingly, 2-derived Ti-enolate reacted exclusively with the 2(S)-benzyloxypropionaldehyde (1 equiv.) under these reaction conditions providing only diastereomer 3i (matched case) in 82% isolated yield after silica gel chromatography. Separation and purification of the corresponding unreacted enantioenriched 2(R)-benzyloxypropionaldehyde was difficult due to overlapping by-product. Subsequently, the crude aldehyde was reduced with NaBH₄ in ethanol at 23°C to afford 2(R)-(benzyloxy)propanol with an enantiomeric excess of 81% ee (41% recovered, ${\left[\alpha \right]}_{\text{D}}^{23}=-36.2$ (c 1.9, CHCl₃); lit.:⁹ ${\left[\alpha \right]}_{\text{D}}^{20}=-45$ (c 1.0, CHCl₃).

The relative and absolute stereochemistry of various syn-aldolates (3) were established based upon comparison of optical rotation as well as ¹H and ¹³C NMR spectra of the resulting acids, esters or diols with literature values.⁵ Thus, saponification of the above aldolates with aqueous lithium hydroxide in THF at 23°C for 2 h furnished the corresponding β-hydroxy acids (5). Treatment of these acids with CH₂N₂ afforded the corresponding methyl esters (6). Various aldolates were converted to diols 7 by treatment with LiBH₄ at 23°C for 2–4 h. In either case, the chiral auxiliary was fully recovered without loss of optical activity.

We subsequently investigated substituent effects on the chiral auxiliary as well as the influence of various achiral and chiral bases on diastereoselectivity. As shown in Scheme 3, we have examined ester enolate aldol reactions of N-p-tosyl-(S)-tert-leucinol and N-p tosyl-(S)-leucinol-derived esters and a number of aldehydes. The results of these various aldol reactions are illustrated in Table 2. As can be seen, the sterically demanding tert-leucinol-derived chiral auxiliary exhibited lower yield over leucinol-derived auxiliary; however, stereoselectivities were comparable (entries 1 and 2). The phenylalaninol-derived chiral auxiliary has also shown comparable syn-diastereoselectivity under the reaction conditions described above (entry 3). Interestingly however, the same aldol reaction with fewer equivalents of TiCl₄ precomplexed to isovaleraldehyde displayed anti-diastereoselectivity.¹⁰ Such reversal in diastereoselectivity is not totally unexpected as the Lewis acid to aldehyde ratio is known to effect aldol stereoselectivity.¹¹ The choice of base is quite important for reaction yield but does not seem to effect observed stereoselectivity (entries 3–5). The chirality on the base has little influence on diastereoselectivities. Bidentate oxyaldehydes are in general very good substrates for ester enolate aldol reactions, providing syn-aldolates in excellent yields and diastereoselectivities (entry 8). The valinol-derived chiral auxiliary has also shown very good syn-diastereoselectivity and reaction yield with isocaproate ester (entry 9).

Scheme 3.

Table 2.

Aldol reaction of various esters with representative aldehydes

Entry	Ester	Aldehyde	Base (equiv.)	Yield (%)a	syn:anti (9/10)b
1	R1=tBu, R2=Me	Me2CHCHO	DIPEA (3)	35	90:10
2	R1=iBu, R2=Me	Me2CHCHO	DIPEA (2.5)	73	85:15
3	R1=Bn, R2=Me	Me2CHCHO	DIPEA (2.5)	86	86:14
4	R1=iBu, R2=Me	Me2CHCHO	(−)-Spartein (2.2)	63	88:12
5	R1=iBu, R2=Me	Me2CHCHO	Et3N (2.5)	83	88:12
6	R1=iBu, R2=Me	PhCHO	Et3N (2.5)	77	85:15
7	R1=iBu, R2=Me	Ph-C≡C-CHO	Et3N (2.5)	83	14:86
8	R1=iBu, R2=Me	BnOCH2CHO	DIPEA (3)	80	99:1
9	R1=iPr, R2=iBu	Me2(CH2)2CHO	DIPEA (3)	97	87:13

^aIsolated yield after chromatography.

^bRatios determined by ¹H NMR before and after chromatography.

In summary, we devised a chelation-controlled ester-derived titanium enolate-based highly diastereoselective syn-aldol reaction with various aldehydes. The current methodology is quite practical due to the ready availability of optically pure chiral auxiliary and use of inexpensive TiCl₄ as the key reagent. Further mechanistic investigations, effects of various sulfonamido functionalities and synthetic applications are underway in our laboratories.