Ee

Hyp(t-Bu) Hphe GlnfTrt) d-Thr(t-Bu) Thr(t-Bu) Chg Cha AsnfTrt)

Fig. 33.2. Screening by positional optimization of various peptide Schiff base ligands for enantioselectivity in the addition ofTMSCN to cyclohexane oxide (5).

=

=

=

- 1

s

l

3

=

_

_

_

B

=

ss

3

1

1

s

s

=

=

=

=

=

=

I

CHO CHO

Ct CI

33.2. (continued)

33.3 Peptidic Schiff Bases as Chiral Ligands | 999 Optimized ligands for catalytic enantioselective addition of TMSCN to meso epoxides.

Entry Substrate Product ee (%) Yield (%) Optimized ligand

33.3 Peptidic Schiff Bases as Chiral Ligands | 999 Optimized ligands for catalytic enantioselective addition of TMSCN to meso epoxides.

Entry Substrate Product ee (%) Yield (%) Optimized ligand

Conditions: 20 mol% Ti(OiPr)4, 20 mol% ligand, TMSCN, 4 °C, toluene, 6-20 h.

program that allows a fairly comprehensive assessment of a ligand framework with respect to a specific asymmetric reaction in a finite and predictable period of time.

When we applied the above search strategy to various other meso epoxide substrates, a number of crucial observations were made (see Table 33.1) [10]. One significant trend that emerged from these studies was that, for each epoxide substrate, a similar but unique chiral catalyst was identified. This type of catalyst/substrate selectivity is akin to that observed in Nature where many reactions have their own unique enzymes. The high levels of selectivity observed with enzymatic reactions is often accompanied by the lack of substrate generality. In this instance, however, because ligand modification is relatively straightforward, substrate specificity does not necessarily imply lack of generality. Another noteworthy issue raised by the data in Table 33.1 is that the search for a ''truly general catalyst'' is perhaps unrealistic: catalysts that afford exceptional selectivity do so because they associate with specific structures with great fidelity. To expect high specificity and broad range generality may be somewhat contradictory.

Our studies indicate that the above method of catalyst identification increases the frequency with which unexpected observations are made. For example, as illustrated in Scheme 33.4, a subtle alteration in the structure - and not the stereochemical identity - of the peptide ligand leads to inversion of stereochemistry in the epoxide-opening reaction (compare reaction with ligands 9 and 17). These observations validate our choice of individually synthesizing and testing each catalyst, as mixtures of catalysts can lead to racemic products.

Scheme 33.4. Subtle modifications in the structure of a peptide ligand may unexpectedly lead to significant variations in selectivity.

Ti-Catalyzed Enantioselective Addition of Cyanide to Imines

In the second phase of our program, we applied the above screening technology to identify specific Ti-peptide complexes that catalyze the addition of cyanide to imines [11, 12]. As the representative cases in Scheme 33.5 illustrate, the reactions proceed efficiently and with outstanding enantioselectivity. In addition to arylimines (e.g. formation of 19 and 22 in Scheme 33.5), acyclic a,b-unsaturated imines are effective substrates for these asymmetric C-C bond-forming reactions (cf. formation of 25 and 28 in Scheme 33.5). Initially, our catalyst-screening approach led us to identify catalysts that deliver amino nitriles with 90-97% ee, but in low conversion (< 25% conversion in 18 h) [13]. Based on certain mechanistic considerations, which ironically later proved to be incorrect, we argued that addition of protic additives may lead to an enhancement in reactivity. The latter hypothesis was based on the fact that when reactions are carried out in relatively large scale, where adventitious water is more easily avoided, conversions are lower. Thus, the effect of a variety of alcohols and amines on reaction efficiency and selectivity were systematically screened. These studies led us to establish that the Ti-catalyzed cyanide additions are significantly more efficient if one equivalent of iPrOH is added to the reaction mixture slowly (see below for mechanistic details). Accordingly, reactions of arylimines and unsaturated aliphatic imines were effected with high enantioselectivity and in good yield, as represented by the examples in Scheme 33.5. It is important to note that in the course of these studies we established that an NnBu amide terminus provides the same levels of reactivity and efficiency as when Gly occupies the AA3 site.

Scheme 33.5. Ti-catalyzed enantioselective addition of cyanide to imines promoted by modular peptidic Schiffbase ligands.

The majority of the optically enriched amino nitrile intermediates can be easily recrystallized to enantiopurity. The Ti-catalyzed asymmetric process is of notable utility in organic synthesis, since after a single hydrolysis/deprotection step optically pure amino acids can be obtained; the example shown in Scheme 33.6 is illustrative. It is worth noting that such amino acids cannot be accessed by the celebrated catalytic asymmetric hydrogenation protocols [14].

With effective and highly enantioselective catalytic Strecker reactions in hand, we set out to explore the mechanistic details of these important transformations [15]. It is our conviction that a better mechanistic appreciation, along with the ability to prepare and screen large collections of catalyst candidates, will allow us to extend the scope of this versatile class of chiral ligands to include a number of other critical catalytic enantioselective processes. Thus, kinetic, structural, and ster-

eochemical studies of Ti-catalyzed addition of cyanide to imines in the presence of Schiff base peptides were carried out. Noteworthy among our findings is that it is likely HCN (not TMSCN) which serves as the active nucleophile; the slow addition of iPrOH leads to the formation of the reactive HCN. Moreover, detailed kinetic studies suggest the reaction is first order only in the Ti-ligand complex. These studies also reveal a AS| = —45.6 + 4.1 cal K—1 mol-1, indicating a highly organized transition structure for the turnover-limiting step of the catalytic cycle.

Scheme 33.6. Synthesis of nonproteinogenic a-amino acids by Ti-catalyzed Strecker reaction.

Various structural features of the chiral peptide ligand were systematically altered and the corresponding relative rates and enantioselectivities were measured. These studies, summarized in Scheme 33.7, led to several important findings: (1) not only is the presence of the AA2 moiety critical to reactivity and enantioselectivity (compare reaction of 33 with that of 34), its stereochemical identity is of notable significance as well (compare reaction of 33 with those of 35 and 36); (2) the presence of a more Lewis basic amide carbonyl (vs. a carboxylic ester) has an influence on the rate of asymmetric CN addition, e.g. the initial rate of reaction (90 min) with ligand 7 is 2.3 times faster than that for the derived methyl ester 37.

The importance of AA2 and the influence of local chirality suggest that the peptide segment of the ligand actively participates in the asymmetric C-C bond-forming reaction. That is, the Ti-Schiff base coordinates with the substrate while an amide moiety within the neighboring peptide segment associates and delivers HCN to the activated imine. A mechanistic model consistent with the kinetic and stereochemical data is presented in Fig. 33.3. These findings thus underline the significance of the peptidic moiety of this class of chiral ligands - not as passive providers of a chiral environment, but as active participants in the asymmetric C-C bond formation. These data provide a solid mechanistic basis regarding the importance of available diversity at the two peptidic sites and the practical utility of the non-C2-symmetric structure of these chiral ligands. The above findings are significant, since they demonstrate that, by virtue of their structural and stereo-chemical identity, peptidic Schiff bases may serve as bifunctional catalysts to deliver appreciable reactivity and high enantioselectivity. The above mechanistic par-

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