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Published in final edited form as: Tetrahedron Lett. 2001 Feb 28;42(7):1227–1231. doi: 10.1016/S0040-4039(00)02227-9

Ester derived titanium enolate aldol reaction: chelation controlled diastereoselective synthesis of syn-aldols

Arun K Ghosh 1,*, Jae-Hun Kim 1
PMCID: PMC6625521  NIHMSID: NIHMS1024689  PMID: 31303686

Abstract

A chelation controlled and highly diastereoselective synthesis of syn-aldols is described. Aldol reaction of commercially available L-phenylalaninol derived esters with a variety of bidentate oxyaldehydes proceeded with excellent syn-diastereoselectivities and isolated yields.

The asymmetric aldol reaction is one of the most powerful carbon–carbon bond forming reactions in organic synthesis.1 Both syn- and anti-aldols are often inherent to numerous biologically active natural products and a number of stereoselective methodologies have been developed for their effective synthesis.2,3 We recently reported a cis-1-arylsulfonamido-2-indanyl ester derived titanium enolate based novel stereoselective anti-aldol reaction.4a Subsequently, utilizing the same chiral auxiliary, we developed an efficient syn- aldol reaction with bidentate oxyaldehydes.4b Based upon our proposed chelated transition-state assembly, we speculated that the presence of an indane ring or the presence of an α-chiral center may not be critical to high observed syn-diastereoselectivities with the bidentate oxyaldehydes. To further understand the origin of syn-selectivities, we have now investigated aldol reactions of phenylalaninol derived sulfonamido esters with a view to generating syn-aldols diastereoselectively by a chelation through the β-sulfonamide functionality. To extend the utility of these aldol processes, we herein report that the reaction of sulfonamido ester derived titanium enolates with a number of bidentate oxyaldehydes provided syn-aldol products with excellent diastereoselectivities (up to 99% de) and isolated yields. Mild saponification resulted in various optically active syn-α-alkyl-β-hydroxy acids and full recovery of the chiral auxiliary without loss of optical purity. The ready availability of both enantiomers of phenylalaninol, as well as the use of inexpensive titanium tetrachloride reagent make the present syn-aldol process particularly useful.

As depicted in Scheme 1, commercially available and optically active (2S)-phenylalaninol was reacted with p-toluenesulfonylchloride and triethylamine in CH2Cl2 in the presence of a catalytic amount of DMAP to provide optically pure (2S)-sulfonamide 1 in 95% isolated yield ([α]23D=−29.4, c 2.5, CHCl3). Reaction of sulfonamide 1 with propionyl chloride and triethylamine in CH2Cl2 at 0°C for 1 h afforded the propionate ester 2a in 93% yield after silica gel chromatography. Acylation of 1 with hydrocinnamic acid and 4-methylvaleric acid with DCC and DMAP afforded the respective esters 2b and 2c in 86 and 87% yield. The corresponding titanium enolates of these esters were generated by slightly modified conditions. For example, propionyl ester 2a was reacted with 1 M TiCl4 (1.05 equiv.) in CH2Cl2 at 0°C and after 15 min, N,N-diisopropylethylamine (3 equiv.) was added and the resulting mixture was stirred at 0°C for 1 h. Complete enolization under these conditions was established by 1H NMR (500 MHz) studies of the titanium enolate generated in a mixture of CDCl3 and CH2Cl2. We speculated that the enolization proceeds through formation of a N–Ti bond followed by intramolecular Lewis acid activation of the ester carbonyl. The enolate is a seven-membered metallocycle 3, presumably with a Z-enolate geometry.5 The enolate so formed was reacted with various oxyaldehydes precomplexed with TiCl4 (2.1 equiv.) at −78°C for 2 h to provide the respective aldol products in good to excellent isolated yields. As can be seen in Table 1, reaction of propionate ester 2a with bidentate benzyloxyacetaldehyde proceeded with near complete syn-diastereoselectivity (98:2 ratio by HPLC; 400 MHz 1H NMR revealed only one diastereomer, entry 1) with 80% isolated yield after silica gel chromatography.6 Similarly, reaction with benzyloxypropionaldehyde (entry 2) also afforded aldol product with excellent syn-diastereoselectivity and isolated yields. In comparison, reaction with benzyloxybutyraldehyde (entry 3) furnished the syn-aldol product 5c with slightly lower selectivity and yield. The reaction of hydrocinnamate derivative 2b and 4-methylvalerate derivative 2c with benzyloxyacetaldehyde also proceeded with excellent syn-diastereoselectivities (entries 4 and 5).

Scheme 1.

Scheme 1.

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(a) CH3CH2COCl, Et3N, CH2Cl2, 0°C, 1 h for 2a; RCO2H, DCC, DMAP, CH2Cl2, 23°C, 18–24 h for 2b and 2c; (b) TiCl4, iPr2NEt, 0°C, 1 h then R1CHO and TiCl4, CH2Cl2, −78°C, 2 h; (c) LiOH, THF–H2O, 23°C, 2–3 h; (d) LiBH4, THF, 23°C.

Table 1.

Aldol reaction of various esters 2a–c with representative aldehydes

Entry Ester Aldehyde Compda % Yieldb Syn:Anti (5/4)c
1. 2a BnOCH2CHO 5a 80 98: 2
2. 2a BnO(CH2)2CHO 5b 81 97: 3
3. 2a BnO(CH2)3CHO 5c 58 91: 9
4. 2b BnOCH2CHO 5d 63 97; 3
5. 2c BnOCH2CHO 5e 60 96: 4
6. 2a graphic file with name nihms-1024689-t0005.jpg 5f 84 99: 1
7. 2a graphic file with name nihms-1024689-t0006.jpg 4g 59 30: 70d
8. 2a graphic file with name nihms-1024689-t0007.jpg 5h 78 99: 1
9. 2a graphic file with name nihms-1024689-t0001.jpg 5i 81 83: 17d
10. 2a iBuCHO 4j 70 30: 70d
11. 2a Ph-C= C-CHO 4k 60 15: 85d
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a

Major isolated product; 5a (R=Me, R1=CH2OBn); 5b (R=Me, R1=(CH2)2OBn); 5c (R=Me, R1=(CH2)3OBn); 5d (R=Bn, R1=CH2OBn); 5e (R=iBu, R1=CH2OBn); 4j and 5j (R=Me, R1=iBu); 4k and 5k (R=Me, R1= C≡ C-Ph);

b

Isolated yield after chromatography.

c

Ratios determined by 1H-NMR and HPLC analysis before and after chromatography. Reaction time = 1.5–2 h;

d

Ratio after removal of chiral auxiliary.

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 2a (Fig. 1). Aldol reaction of the propionate ester 2a and 2(S)-benzyloxypropionaldehyde (stereochemically matched case) under identical conditions afforded virtually a single (by HPLC and 400 MHz 1H NMR analysis) aldol product 5f (entry 6) in 84% yield after silica gel chromatography. In a mismatched case, the reaction of 2a and 2(R)-benzyloxypropionaldehyde, however, afforded a 30:70 mixture of (syn:anti) isomers in 59% isolated yield (entry 7). Matched stereochemical effects are also evident in the aldol reaction of 2a with 2(R)-methyl benzyloxypropionaldehyde (single diastereomer, entry 8). The corresponding reaction with 2(S)-methylbenzyloxy-propionaldehyde (mismatched pair) also proceeded in good selectivity (83:17 mixture, entry 9).7 In contrast, reaction of 2a with monodentate aldehydes such as isovaleraldehyde and phenylpropargyl aldehyde provided the corresponding anti-isomer as the major product. However, anti-diastereoselectivity is significantly diminished compared to constrained 1-amino-2-indanol derived chiral auxiliary.4a

Figure 1.

Figure 1.

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Saponification of the aldolates with aqueous lithium hydroxide in THF at 23°C for 2–3 h furnished the corresponding β-hydroxyacids (85–92% yield). Various aldolates were also converted to their corresponding alcohols 7 by lithium borohydride reduction in THF at 23°C for 2–4 h. In either case, the chiral auxiliary was fully recovered without loss of optical purity. The relative and absolute stereochemistry of various syn aldolates 5 were assigned by comparison of optical rotation, as well as 1H and 13C NMR spectra of the resulting acids or diols with literature values.8 The transfer of chirality and observed diastereoselectivity can be rationalized by a Zimmerman–Traxler type transition state model A as postulated previously.4,9 As shown in Fig. 2, the metallocycle adopts a chair-like conformation and chirality transfer proceeds through the sulfonamide bearing chiral center through effective metal chelation with the bidentate aldehydes.10 Higher syn-selectivity for benzyloxyacetaldehyde or benzyloxypropionaldehyde as opposed to benzyloxybutyraldehyde is due to rigid five- or six-membered rather than flexible seven-membered metal chelation. Furthermore, the observed diastereoselectivities resulting from the double stereo-differentiating experiments are consistent with this model. As is evident in the model, the lack of syn-selectivity for the 2(S)-benzyloxypropionaldehyde is due to destabilizing non-bonded interaction between the methyl (R1=Me) group and the benzyl side chain of the chiral template in the transition state. The choice of benzyl side chain in the chiral auxiliary is not critical since L-valinol derived propionyl ester enolate also provided comparable syn-diastereoselectivity (syn:anti ratio >99:1; 74% isolated yield) with benyloxyacetaldehyde under similar reaction conditions.

Figure 2.

Figure 2.

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In conclusion, we devised a chelation controlled ester derived Ti-enolate based highly diastereoselective (82–98% de) syn-aldol reaction with bidentate oxyaldehydes. The methodology is convenient since inexpensive reagents and readily available optically active chiral auxiliaries were utilized. The scope of the reaction can also be extended to other bidentate aldehydes. Further studies including synthetic applications are in progress.

Acknowledgements

Financial support for this work was provided by the National Institutes of Health (GM 55600).

References

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  • 6.All new compounds gave satisfactory spectroscopic and analytical results. Preparation of syn-aldol 5a: To a stirred solution of propionate ester 2a (550 mg, 1.52 mmol) in CH2Cl2 (15 ml) at 0°C was added a 1 M solution of TiCl4 (1.6 ml, 1.6 mmol) dropwise under a N2 atmosphere. The resulting solution was stirred for an additional 15 min. To this solution was added N,N-diisopropylethylamine (0.8 ml, 4.6 mmol) in a dropwise manner. The mixture was stirred for 1 h at 0°C and then was warmed to 23°C. In a separate flask, to a stirred solution of benzyloxyacetaldehyde (457 mg, 3.04 mmol) in CH2Cl2 (20 ml) at −78°C under a N2 atmosphere, was added a 1 M solution of TiCl4 (3.2 ml, 3.2 mmol). After stirring for 10 min, the above enolate solution was added to this aldehyde solution dropwise via syringe over 8 min. The mixture was stirred at −78°C for 1.5 h before quenching by aqueous NH4Cl. The resulting mixture was warmed to 23°C and the layers were separated. The aqueous layer was extracted twice with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the aldol products. Silica gel chromatography of the crude product yielded the syn aldol product 5a (620 mg, 80%) as a viscous oil. [α]23D −4.9 c 1.2, CHCl; 1H NMR (500 MHz, CDCl3): δ, 1.19 (d, 3H, J=7.1 Hz), 2.41 (s, 3H), 2.68 (m, 1H), 2.76 (d, 2H, J=7.2 Hz), 3.17 (d, 1H, J=4.0 Hz), 3.53 (d, 2H, J=5.8 Hz), 3.72 (m, 1H), 3.97–4.05 (m, 2H), 4.20 (m, 1H), 4.57 (dd, 2H, J=11.8, 20.5 Hz), 5.58 (d, 1H, J=8.1 Hz), 7.03–7.05 (m, 2H), 7.20–7.25 (m, 5H), 7.31–7.39 (m, 5H), 7.68 (d, 2H, J=8.3); 13C NMR (125 MHz, CDCl3) δ, 11.5, 21.9, 38.9, 42.6, 54.5, 65.4, 71.1, 72.1, 73.8, 127.2, 127.4, 128.3, 128.9, 129.1, 129.7, 130.1, 136.9, 138.0, 138.3, 143.7, 175.1; IR (neat): 3508, 3282, 1731, 1328, 1159 cm−1.
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