Enantioselective Mannich Reaction using Silyl Ketene Acetals

Enantioselective Mannich Reaction Using Silyl Ketene Acetals 

In addition to proline, other types of organocatalyst have been found to catalyze the Mannich-type reaction efficiently. The Jacobsen group developed an elegant and highly enantioselective route to N-Boc-/i-amino acid esters via nucleophilic ad- 

Imines are, preferably, used in the N-Boc-protected form less electrophilic N-allyl and N-benzyl imines gave unsuccessful results [36], The tert-butyldimethyl-silyl ketene acetals are the most suitable silyl ketene acetal substrates. It should be added that a low temperature is required to suppress an undesired uncatalyzed reaction that leads to racemates. 

Another type of organocatalyst, which is suitable for the Mannich reaction with ketene silyl acetals, is a chiral binaphthyl phosphoric acid [38c]. Very recently, it has been reported that high enantioselectivity of up to 96% ee can be obtained with this type of catalyst [38c]. 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

---

Three years after the discovery of the asymmetric BINOL phosphate-catalyzed Mannich reactions of silyl ketene acetals or acetyl acetone, the Gong group extended these transformations to the use of simple ketones as nucleophiles (Scheme 25) [44], Aldehydes 40 reacted with aniline (66) and ketones 67 or 68 in the presence of chiral phosphoric acids (R)-3c, (/ )-14b, or (/ )-14c (0.5-5 mol%, R = Ph, 4-Cl-CgH ) to give P-amino carbonyl compounds 69 or 70 in good yields (42 to >99%), flnfi-diastereoselectivities (3 1-49 1), and enantioselectivities (72-98% ee). 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

It must be noted that chiral thiourea catalysts have been used earlier to catalyze the asymmetric Mannich reaction. Jacobsen and Wenzel reported the enantioselective synthesis of A-Boc-protected p-amino acids from silyl ketene acetals and A-Boc-protected imines using the thiourea catalyst 123 (Scheme 11.24). Here, the chiral thiourea-derived Brpnsted acid catalyst (the application of chiral Brpnsted acids in the... 

The scope of the Brpnsted acid-catalyzed asymmetric Mannich reaction was later extended by Gong and colleagues, which used instead of silyl ketene acetals or acetyl acetone simple ketones as nucleophiles [95]. The combination of various cycloketones, phenylamines, and aldehydes in the presence of the chiral phosphoric acid catalyst 134 or 135, respectively, afforded the corresponding anti-Mamich products in high yields with good enantioselectivities (75-98% ee)... 

The first catalytic enantioselective Mannich reaction was documented by Kobayashi, using the conveniently assembled BINOL-derived Zr catalyst 212 (Scheme 11.32) [150]. This catalyst was highly effective in enantioselective additions of silyl ketene acetals to N-(o-hydroxyphenyl)-aldimines such as 210. In a further expansion of the reaction scope, ( )- and (Z)-substituted a-alkoxy silyl enol ethers were observed to undergo diastereoselective additions to aldimines, giving syn and anti amino alcohols, respectively [151]. These processes were utilized in the rapid assembly of (2R,3S)-3-phenyliso-serine (214), a precursor of the C,3 side chain of paclitaxel, known to be essential for its anticancer activity. 

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

Chiral BBA (30) has been shown to be effective as a Bronsted acid catalyst for Mannich-type reaction of ketene silyl acetals and aldimines and good enantioselectivity was observed (up to 77% ee) using 3.5 or 10mol% of chiral BBA (30) (Scheme 1.35). 

---