Asymmetric Aza-MBH Reactions

Very few efficient catalytic enantioselective versions of MBH reaction were known up to 1999 despite a considerable amount of efforts devoted to the field. A breakthrough came in 1999 when Hatakeyama and coworkers discovered that p isocupreidine (P ICD) is an efficient catalyst for the MBH reaction [11]. Meanwhile, the use of small organic molecules as catalysts to perform asymmetric transformations has received increasing attention over the past decade. Therefore, chiral multifunctional orga nocatalysts have also been developed rapidly to promote successful enantioselective MBH/aza MBH processes. This chapter mainly summarizes recent advances in the design and synthesis of small organic molecules for the enantioselective aza MBH reactions from 2000. On the basis of these enantioselective aza MBH reactions, a variety of chiral amines can be easily prepared under mild conditions. 

---

M. Shi and Y.-L. Shi reported the synthesis and application of new bifunctional axially chiral (thio) urea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman (MBH) reaction [176, 177] of N-sulfonated imines with methyl vinyl ketone (MVK), phenyl vinyl ketone (PVK), ethyl vinyl ketone (EVK) or acrolein [316]. The design of the catalyst structure is based on axially chiral BINOL-derived phosphines [317, 318] that have already been successfully utilized as bifunctional catalysts in asymmetric aza-MBH reactions. The formal replacement of the hydrogen-bonding phenol group with a (thio)urea functionality led to catalysts 166-168 (Figure 6.51). 

Scheme 6.159 Representative products obtained from the 166-catalyzed asymmetric aza-MBH reaction between N-sulfonated imines a,(i-unsaturated ketones and acrolein.

The Hatakeyama group later reported the use of catalyst 103 for the asymmetric aza-MBH reactions of HFIPA with activated aromatic imines [96]. The aza-MBH reactions of four different diphenylphosphinoyl aryl imines (109) with HFIPA were promoted using 10 mol% 103 and afforded the corresponding a-methylene-/ -amino acid derivatives (110) in reasonable yields (42-97%) and moderate -values (54-73% Scheme 6.13). Aliphatic imines were not suitable substrates for the reaction due to imine lability. (For experimental details see Chapter 14.10.3). 

General Procedure for the / -ICD-Mediated Asymmetric Aza-MBH Reaction ofTosyl Aryl Aldimines and Methyl Acrylate [44] (pp. 177 and 233)... 

Tablel3.1 The scope of asymmetric aza MBH reaction of N sulfonated imine with MVK catalyzed by [3 ICD.

Sasai and coworkers reported that a chiral BINOL derived amine 16a catalyzed asymmetric aza MBH reaction of N tosyl imines with acrolein and alkyl vinyl ketones [22]. The corresponding aza MBH adducts were obtained in good to excellent yields with high enantiomeric excesses (Table 13.4). Replacing the tPr group with other substituents in amine 16a provided less effective catalysts regarding yield or enantioselectivity [23]. 

Table 13.8 Asymmetric aza MBH reaction of N sulfonated imines with MVK, phenyl vinyl ketone,...

Scheme 13.22 Asymmetric aza MBH reaction catalyzed by other chiral multifunctional phosphine catalysts.

Catalytic asymmetric aza MBH reactions and related reactions provide a direct and efficient synthetic approach to a variety of functionalized nonamino acid derived chiral amines under mild conditions. These novel chiral amines can be directly used to prepare many other useful chiral building blocks in organic synthesis. A variety of transformations of the chiral aza MBH adducts were recently demonstrated by Raheem and Jacobsen (Scheme 13.30) [9]. 

Due to the low activity of (3 substituted a,(3 unsaturated ketone or ester, the asymmetric aza MBH reaction using (3 substituted a,(3 unsaturated ketone or ester is still a challenge [47]. 

This field is developing at a rapid pace and further progress will surely be forthcoming. It can be envisioned that the catalytic asymmetric aza MBH reaction will be used more often in the near future. 

Explain why bifunctional activation using a basic and a protic center is a viable strategy for catalyst design in the asymmetric aza MBH reaction. 

Contrary to the view that applying chiral solvents in synthesis cannot result in appreciable enantioselectivities, Leitner et al. have reported the first example of an asymmetric reaction in which a chiral reaction medium induces a high level of enantioselectivity. Using a specifically designed ionic liquid (312) with a chiral anion as the only source of chirality, up to 84% ee was obtained in the aza-MBH reaction of N-Ts arylaldimines with MVK (Scheme 1.124), which is comparable with values obtained with the best catalysts for the asymmetric aza-MBH reaction in conventional solvents (94% ee, 83% ee ). Possible bifunctional interaction of the zwitterionic intermediate of the aza-MBH reaction with the chiral anion of a CIL-312 containing a hydrogen-bond donor was proposed (Figure 1.6). 

In 2003, we first demonstrated that l,l -bi-2,2 -naphthol (BINOL)-derived chiral LBBA (Lewis base and Bronsted add) bifunctional phosphine CP17 (LB = PPhs, BA = Ph-OH) could be used as an effective catalyst in asymmetric aza-MBH reaction of A-tosylimines with MVK and phenyl acrylate, affording the corresponding adducts in good yields with high ees (Scheme 2.119). The addition of molecular sieves increased chemical yields because they removed the ambient moisture that caused the decomposition of A-sulfonated imines. The asymmetric induction of this catalyst is comparable to that of the quinidine... 

On the basis of the same working hypothesis, Sasai et al. have functionalized the 3-position of BINOL with a series of aryl phosphines. Catalyst CP42 was found to catalyze effectively the asymmetric aza-MBH reaction of A-tosyl-imines with vinyl ketones (Scheme 2.132). ... 

In screening thiourea catalysts for the asymmetric aza-MBH reaction, Jacobsen et have developed a highly enantioselective catalytic aza-MBH reaction of various A-nosyl imines with methyl acrylate. High enantioselectivities... 

A phosphine sulfonamide derived from L-threonine promotes aza-Morita-Baylis-Hillman (aza-MBH) reactions of sulfinylimines in up to 96% yield and 97% ee. A review describes the synthesis of chiral amines under mild conditions via catalytic asymmetric aza-MBH reactions. Proline/DABCO (l,4-diazabicyclo[2.2.2]octane) co-catalysis of enantioselective aza-MBH reactions gives good to high yields and up to 99%... 

An asymmetric aza-MBH reaction of isatin-derived A-Boc ketimines with methyl vinyl ketone has been developed, giving 3-amino-2-oxindoles bearing quaternary stere-ogenic centres (22), using chiral amine or phosphine catalysts. (S)... 

Shi and coworkers almost simultaneously demonstrated the similar asymmetric aza-MBH reaction of N-protected imines 78 or N-protected a-amidoalkyl phenyl sulfones 80 with MVK catalyzed by 3-ICD or catalyst 81, affording highly enanti-oselective aza-MB H products in good yields with high enantioselectivities (Scheme 31,25) [34], Besides mild reaction conditions and operational simplicity since it avoided the handing of unstable preformed imines, the reaction was found to be general with respect to various N-protected imines. Subsequently, Shi s group reported a [3-ICD-catalyzed asymmetric MBH reaction of isatin derivatives 83 with... 

---