Amino esters from aldehydes

A large-scale, robust enantioselective synthesis of /i-subs(.Hu(.cd-/i-amino esters from aldehydes via imine formation with a chiral amme has been reported.21... 

While the Lewis acid-catalyzed reactions of imines with silyl enolates are one of the most efficient methods for the preparation of b-amino esters, many imines are hygroscopic, unstable at high temperatures, and difficult to purify by distillation or column chromatography. It is desirable from a synthetic point of view that imines, generated in situ from aldehydes and amines, immediately react with silyl enolates and provide b-amino esters in a one-pot reaction. However, most Lewis acids cannot be used in this reaction because they decompose or deactivate in the presence of the amines and water that exist during imine formation. Due to the unique properties of Ln(OTf)3, their use as catalysts for the above one-pot preparation of b-amino esters from aldehydes was planned. 

A general scheme of the one-pot synthesis of b-amino esters from aldehydes is shown in Scheme 4 [42]. In the presence of a catalytic amount of Yb(OTf)3 and an additive (a dehydrating reagent such as MS 4 A or MgS04), an aldehyde was treated with an amine and then with a silyl enolate in the same vessel. Several examples are shown in Tables 13 and 14, and the following characteristic features of this reaction are noted. 

Table 13. One-pot synthesis of b-amino esters from aldehydes ...

Thus, the one-pot synthesis of b-amino esters from aldehydes has been achieved by using lanthanide triflate catalysis. The high efficiency using simple starting materials and a catalytic amount of a reusable catalyst is especially noteworthy. 

Zhang and co-workers [186] reported a microwave-assisted one-pot, three-component [3-f2] cycloaddition reaction of a fluorous amino ester, an aldehyde and a maleimide to afford bicyclic prolines 135 in yields up to 94%. Fluorous solid phase extraction (F-SPE) has been used effectively to separate the product from the reaction mixture (Scheme 105). 

It is interesting to compare the endo selectivities of two closely related types of dipoles. The ylides 47, derived by an imine-azomethine ylide tautomerism of the imines of a-amino esters (Section II,C), are typical dipoles that exhibit high endo selectivity in cycloadditions to cyclic olefins. On the other hand, N-substituted derivatives 79, derived by the deprotonation route (Section II,D) from N-substituted a-amino esters and aldehydes, are very poor in endo selectivity. The N-unsubstituted dipoles 47 are involved in the cycloadditions as ( , )-ylides (or syn-ylides), while the N-substituted dipoles 79 as ( ,Z)-ylidic forms (or anti -ylides). However, the difference in ylide geometry is not the only reason for the lowered endo selectivity of 79, since the anti forms of heteroaromatic N-ylides undergo exclusive endo-selective cycloadditions with cyclic cis-olefins (83H1907 84CL465 85BCJ3137). 

The Mannich and related reactions provide one of the most fundamental and useful methods for the synthesis of y -amino ketones and esters [46]. Although the classical protocols include some severe side reactions, new modifications using preformed iminium salts and imines have improved the process. Some of these materials are, however, unstable and difficult to isolate, and deaminations of the products that occur under the reaction conditions still remain as problems. The direct synthesis of /5-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view [47, 48]. Our working hypothesis is that aldehydes could react with amines in the hydrophobic micellar system in the presence of a catalytic amount of lanthanide triflate and a surfactant to produce imines, which could react with hydrophobic silyl enolates [49]. 

Potassium tert-biitoxide a-Aminocarboxylic acid esters from aldehydes and isocyanoacetic acid esters via c(-amino-a, -ethylenecarboxylic acid esters... 

Gong et al. have confirmed that oxygen-linked bisphosphoric acid (274) provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of a-amino esters (275), aldehydes (276), and various electron deficient dipolarophiles (277). This reaction actually represents one of the most enantioselective catalytic... 

A very elegant approach has been developed by Kanerva et al. DKR of N-hetrocyclic a-amino esters is achieved using CAL-A [54]. Racemization occurs when acetaldehyde is released in situ from the acyl donor. In this case aldehyde-catalyzed racemization of the product cannot occur (Figure 4.28). This is one of the few examples reported for DKR of secondary amines (For a recent example see the above text and Ref. [38]). 

A stereochemical behavior similar to that of the 1-bromo-l-lithio aUcene 164 with regard to chiral aldehydes is shown by the hthiated methoxyallene 183. When added to iV,iV-dibenzylated a-aminoaldehydes 188, it reacts with non-chelate control so that awh -carbinols 189 are obtained predominantly. Diastereomeric ratios of 189 190 range from 80 20 to 95 5. As outlined above, the hydroxyalkylated allenes 189/190 can be converted into furanones 191/192 upon treatment with potassium f-butoxide and subsequent acid hydrolysis" . When, on the other hand, the adducts of 183 to the aldehydes 193 are submitted to an ozonolysis, A-protected a-hydroxy-/3-amino esters 194/195 result (Scheme 25)"" . 

Further investigation with various silyl ketene acetals is summarized in Table 6. Silyl ketene acetals derived from various esters were reacted with /V-benzyloxy-carbonylamino sulfones 1 in the presence of 0.5-1 mol% Bi(0Tf)3-4H20. The corresponding (3-amino esters 24 were obtained in moderate to good yields (Table 6). Silyl enolates derived from esters as well as thioesters reacted smoothly to give the adducts. The /V - be n z v I o x v c ar bo n v I a m i n o sulfone derived from n-butvraldehyde lp led to moderate yields of (3-amino esters when reacted with (thio)acetate-derived silyl ketene acetals (Table 6, entries 1 and 2). A very good yield was obtained when the same sulfone was subjected to a tetrasubstituted silyl ketene acetal (Table 6, entry 3). The latter afforded moderate to good yields of (3-amino esters 24 with phenylacetaldehyde, / -tolu aldehyde, and o-tolualdehyde-derived sulfones (Table 6, entries 4-6). 

Examples of the Bronsted-acid catalysts and hydrogen-bond catalysts are shown in Figure 2.1. We have recently reported the Mannich-type reaction of ketene silyl acetals with aldimines derived from aromatic aldehyde catalyzed by chiral phosphoric acid 7 (Figure 2.2, Scheme 2.6) [12]. The corresponding [5-amino esters were obtained with high syn-diastereoselectivities and excellent enantioselectivities. 

Similar products could be generated via azomethine yhdes derived by a formal 1,2-H shift from the precusor imine, rather than by the decarboxylative approach outlined above (82,83). For example (83), condensation of aldehyde 272 with the requisite amino ester 273 led to the intermediate ylide, which dehvered adducts 274 and 275 in a 1.2 1 ratio in 75% yield. Grigg has once again applied this protocol to the synthesis of a wide range of complex molecular frameworks (276... 

The carbonyl ylide generated from metal carbene can also add to C=0 or C=N bonds. The [2 + 3]-cycloaddition of carbonyl ylide with G=0 bond has been used by Hodgson and co-workers in their study toward the synthesis of zaragozic acid as shown in Scheme n 27a,27d Recently, a three-component reaction approach to syn-a-hydroxy-f3-amino ester based on the trapping of the carbonyl ylide by imine has been reported.The reaction of carbonyl ylide with aldehyde or ketone generally gives l,3-dioxolanes. Hu and co-workers have reported a remarkable chemoselective Rh2(OAc)4-catalyzed reaction of phenyl diazoacetate with a mixture of electron-rich and electron-deficient aryl aldehydes. The Rh(ii) carbene intermediate reacts selectively with electron-rich aldehyde 95 to give a carbonyl ylide, which was chemospecifically trapped by the electron-deficient aldehyde 96 to afford 1,3-dioxolane in a one-pot reaction (Equation (12)). 

The enantioselective synthesis of a somewhat more complex renin inhibitor starts with the reduction of the ester group in the chiral amino-ester (19-1) by means of diisobutyl aluminum hydride in the cold. The aldehyde product (19-2) is then reacted with prior isolation with the ylide from phosphonium salt (19-3) and a strong base... 

Aldol products do not have to come from an aldol condensation. In another example of catalysis by a small organic molecule, Jeffrey Bode of UC Santa Barbara reports (J- Am. Chem. Soc. 2004,126, 8126) that the thioazolium salt 7 effects the rearrangement of an epoxy aldehyde such as 6 to the aldol product 8. This is a net oxidation of the aldehyde, and reduction of the epoxide. As epoxy aldehydes such as 6 are readily available by Sharpless asymmetric epoxidation, this should be a general route to enantiomerically-aldol products. The rearrangement also works with an aziridine aldehyde such as 9, to give the ff-amino ester 10. 

From haloaziridine, homologation 160 Opening 92,193 Synthesis, enantioselective 92 Aziridine aldehyde to amino ester 115... 

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