A-Aminoaldehydes

The principal difficulty associated with this type of synthesis is in the availability of a-aminoacyl compounds, e.g. a-aminoaldehydes, a-aminoketones, etc., and most type B syntheses rely on the generation of these compounds in situ, where the self-condensation occurs spontaneously. A large number of research groups have addressed themselves to this problem and a variety of routes are now available. 

Scheme 25 Anti-Felkin-Anh selectivity in the reductive aldol reaction of a-alkoxy and a-aminoaldehydes...

Schme 9.2. Passerini condensation involving protected a-aminoaldehydes. 

In contrast to lithiated allenes, the corresponding titanium species and carbonyl compounds furnished the regioisomeric y-addition products [68,69]. Thus, reaction of a-aminoaldehydes 63 with the titanated intermediate 75 gave methoxyalkynes 76, which smoothly cydized in the presence of acid and provided lactones 77, again with high anti selectivity (Scheme 8.21) [69]. The regioselectivity depends on the aldehyde used. 

SCHEME 21. Synthesis of N-protected a-amino acids and aldehydes by stereoselective addition of bromohthioalkene 5 -41 to sulfonyhmines. Mukaiyama aldol reaction of a-aminoaldehydes... 

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)"" . 

SCHEME 25. Addition of Uthiated methoxyaUene 183 to A-protected a-aminoaldehydes 188. R = Me, PhCH2, Me2CHCH2... 

Figure 4.13 Amine 245 was obtained by reaction of a trimethoxy-indole functionalized amino-acid with an a-aminoaldehyde.

At low temperatures, the Zn enolate derived from dimethyl 3-methylpent-2-endioate 39 reacts with aldehydes in a one-pot aldolisation and cyclisation to yield the syn-dihydropyran-2-one 40. At the higher temperatures necessary to achieve reaction with a-aminoaldehydes, the anri-products predominate indicating thermodynamic control (Scheme 22) <99T7847>. An aldol condensation features in the asymmetric synthesis of phomalactone. The key step is the reaction of the enolate of the vinylogous urethane 41 with crotonaldehyde which occurs with 99% syn-diastereoselectivity and in 99% ee (Scheme 23) <99TL1257>. 

Dess-Martin periodinane has a very low tendency to induce ot-epimer-ization of sensitive carbonyl compounds, being particularly useful in the obtention of epimerization-sensitive aldehydes and ketones without erosion of the enantiomeric or diastereomeric excess.71 Thus, in a detailed study aimed at finding the ideal oxidant for the obtention of racemization-prone TV-protected a-aminoaldehydes with a maximum of enantiomeric excess, Dess-Martin periodinane in wet CH2CI2 at room temperature was found to be the oxidant of choice. 

S)-Prolinc-dcrivcd phosphoramides catalyse enantioselective allylation of aromatic aldehydes with allylic trichlorosilanes.90 Chiral a-aminoaldehydes have been allylated diastereoselectively with various reagents.91... 

Protected a-aminoaldehydes follow the same trend, although a notable exception is represented by the reaction of compound 43 with a bulky isonitrile, affording 44 in a 3 1 ratio (the relative configuration of the major product was not determined)... 

The Hulme group reported an efficient three-step, one-pot solution-phase synthesis of 2-imidazolines employing the UDC strategy [62], The reaction between N-Boc-protected a-aminoaldehydes, amines, acids, and isocyanides afforded the N-Boc-protected a-acylamino amides 94 which, upon heating in addic medium, underwent N-deprotection and cyclization to 2-imidazolines 95 (Scheme 2.34). This procedure was adapted to combinatorial synthesis in a rack of 96 reaction vials. 

In this three-step procedure the key feature is the use of N-Boc-protected a-aminoaldehydes as the carbonyl input in an Ugi-4CR (Scheme 2.53). 

S)-Proline-catalyzed cross-aldol reaction of aldehydes followed by Mukaiyama aldol reaction sequence was used for the synthesis of prelactone B [27]. The products of the aldol reactions of O-protected a-oxyaldehydes are protected carbohydrates, and were also transformed to highly enantiomerically enriched hexose derivatives, again through a second Mukaiyama aldol reaction (Scheme 2.5) [28]. The products of the aldol reactions of N-protected a-aminoaldehyde donor were easily converted to the corresponding highly enantiomerically enriched /Miydroxy-a-amino acids and their derivatives (Scheme 2.6) [24]. (For experimental details see Chapter 14.1.1). 

The discovery route20 21,29 to aliskiren targeted three key intermediates, a-aminoaldehyde 11, the isopropyl-substituted propane unit 12, and the P-aminopropan amide 13. The union of 11 and the Grignard reagent derived from 12 establishes the full contiguous carbon backbone of aliskiren and the C4 stereocenter. Following oxidation-state manipulation, P-aminopropanamide 13 is introduced by a peptide coupling. 

Treatment of the a-aminoaldehyde (125) with potassium thiocyanate gave 3//-imidazoIe-2-thione (126) (Marckwald synthesis), which produced the 5-acetyl derivative of (127) hydrolysis gave (127) itself (54JCS3283). 

The BF3-catalyzed reaction of a-aminoaldehydes with 10 is valuable for highly stereoselective synthesis of 2,3,5-trisubstituted pyrrolidines with all -cis configurations (Equation (50)).197 The stereochemical outcome like chelation-controlled stereochemistry might result from the inherent conformational arrangement of the aldehyde-BF3 complex. />-Quinoneimines, o-quinones, and a-alkoxyhydroperoxides undergo similar types of [3 + 2]-cycloadditions with allylsilanes to afford dihydro indoles, dihydrobenzofurans, and 1,2-dioxolanes, respectively.164,175,198... 

Chiral aldehydes such as N-protected a-aminoaldehydes and a-alkoxyalde-hydes as well as chiral butadienes derived from sugars by a Wittig reaction have also been used in the hetero Diels-Alder reactions successfully with the inducing stereogenic centers remaining in the obtained cycloadducts. 

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