Info

75% ee, 45% conv Scheme 33.7. Effect of the AA2 moiety on reactivity and enantioselectivity in the Ti-catalyzed addition of cyanide to adigm thus suggests that, in addition to HCN, other reagents such as various alkyl metals may be delivered effectively and enantioselectively to the bound imine substrate. Such a hypothesis led us to the following aspects of our program.

Fig. 33.3. Delivery of HCN by the AA2 moiety of the peptide ligand.

1004 | 33 Diversity-Based Identification of Efficient Homochiral Organometallic Catalysts 33.3.3

Zr-Catalyzed Enantioselective Addition of Dialkyl Zincs to Imines

To determine whether the above mechanistic paradigms can be employed to deliver alkyl metals to imines in an enantioselective fashion, we set out to examine the possibility of developing a catalytic asymmetric alkylation of imines. Such a process would deliver optically enriched or pure amines, a class of compounds that is of great significance to medicine and biology. Screening of parallel libraries was used to establish conditions for an effective set of protocols, including the optimal metal center, solvent, reaction temperature, and amine protecting group [16, 17]. Interestingly, as the representative examples in Scheme 33.8 illustrate, these screening studies indicated that Zr(OiPr)4 is the most appropriate metal center with dipeptide Schiff base 41 serving as the chiral ligand that delivers excellent reactivity and enantioselectivity; the previously employed Ti salt leads to significantly less reactive and enantioselective reactions. An efficient Zr-catalyzed alkylation of arylimines in the presence of 0.1-10 mol% chiral peptidic ligands and Et2Zn was thus established (see 38 ! 39 in Scheme 33.8). These transformations afford the derived amines in >90% ee and >66% isolated yield. As illustrated in Scheme 33.8, oxidative removal of the o-anisyl protecting group delivers the derived optically enriched arylamines (e.g. 40).

Scheme 33.8. Parallel screening points to Zr as the optimal transition metal for enantioselective addition of Et2Zn to imines.

With aryl imines that contain electron-withdrawing or electron-releasing sub-stituents, the Schiff base dipeptides such as 41 are ineffective (amine formation with electron-withdrawing groups and <10% conversion with electron-rich units). When Et2Zn is used in such cases, the imine substrate is simply reduced to afford the achiral amine product; when other dialkyl zinc reagents are employed (e.g. Me2Zn), <2% conversion is detected. The facile reduction of substrates with Et2Zn may be due to b-H elimination of the metal-Et complexes that generate active metal hydrides that in turn promote amine reduction. The observed inefficiency of alkyl zinc reagents that do not bear a b-H (Me2Zn) or carry one that is less active (n-alkyl2Zn) support this hypothesis. Therefore, we speculated that the corresponding amine-based peptide ligand (e.g. 44) may be the active catalyst. Thus, only in cases where it can be efficiently generated (i.e. in the presence of Et2Zn) does the asymmetric alkylation proceed smoothly. Once again, based on a mechanistic hypothesis and because of the modularity of the chiral Schiff base peptide structure, a variety of ligand candidates were screened. As the data in Scheme 33.9 illustrate, we established that the amine-based chiral ligands provide appreciable efficiency as well as enantioselectivity in the presence of all dialkyl zincs, regardless of whether they bear an active b-H or not. It must also be noted that, as was found with the Ti-catalyzed addition of cyanide to imines (Scheme 33.7), initial studies indicate that the AA2 moiety is crucial for achievement of both high reactivity and enantio-selectivity.

Scheme 33.9. With the peptide-based amine ligand a variety of alkyl zincs can be added to imines in an enantioselective and catalytic manner.

The Zr-catalyzed asymmetric alkylation shown in Eq. 1 (48 + 49 ! 50) illustrates two important principles [18]: (1) the catalytic asymmetric protocol can be readily applied to the synthesis of nonaryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols; (2) the catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This possibility, also readily applied to the preparation of arylamines, not only provides an effective solution to the problems associated with the instability of aliphatic imines, but also suggests that such a procedure may be used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion.

Cu-Catalyzed Enantioselective Addition of Dialkyl Zincs to Allylic Phosphates: Pyridyl Dipeptides as Chiral Ligands

Catalytic enantioselective addition of alkyl metals to olefins has been one of the key problems that our research group had been interested in for the past 10 years [19]. With the success of the peptide-based ligands in promoting the addition of alkyl zinc reagents to imines, we set out to examine whether a similar process may be effected with olefinic starting materials. One class of principal interest is the allylic substitution reactions. Within this context, largely due to the scarcity of related protocols, we are particularly interested in transformations that utilize the less explored ''hard'' alkylating agents which can enantioselectively deliver the problematic quaternary carbon centers [20]. Recently, we have identified a new class of Schiff base peptides that accomplishes part of the above objective [21].

We initiated our search for the optimal conditions by using the more reactive and readily accessible disubstituted olefins (vs. trisubstituted alkenes described below). Since CuCN has been demonstrated to exhibit a preference for SN2' mode of addition in related processes with Grignard reagents, it was selected for the preliminary optimization studies [22]. Examination of potential substrates indicated that allylic phosphates are the most suitable starting materials (see 51 ! 52 in Scheme 33.10) [23, 24]. The corresponding chlorides react smoothly with Et2Zn in CH2Cl2, toluene, or Et2O (—30 °C, 18 h, without ligand and Cu salt) and the derived acetates, phenyl ethers, and phenyl carbamates afford < 10% conversion. Since the previously mentioned mechanistic work suggested that the Schiff base portion of the peptidic ligands is likely a metal-ligation site that is critical to reactivity and selectivity, we decided to perform catalyst optimization in the following systematic

OPO(OEt)2 10 mol% Cu 3311

33.3 Peptidic Schiff Bases as Chiral Ligands | 1007 chiral ligand: Me Me o \

Ph ligation site ligation site

^NHBu

FirstPhase Screening (CuCN):

X)H 53 10% ee, 30:1 Sn2':Sn2 Second Phase Screening: 55 as ligand

56 as ligand

X)H 53 10% ee, 30:1 Sn2':Sn2 Second Phase Screening: 55 as ligand

56 as ligand

CuO

17% ee, >99:1 Sn2:Sn2; 30% conv

CuCI

24%

ee, 1

2 Sn2:Sn2; >98% conv

CuBr-Me2S

21 % ee, >99:1 SN2':SN2; 20% conv

CuBr-Me2S

37%

ee, 1

4 Sn2':Sn2; >98% conv

Cul

<5% conv

Cul

38%

ee, 1

3 Sn2:Sn2; >98% conv

CuOAc

<5% conv

CuOAc

27%

ee, 1

5 Sn2':Sn2; >98% conv

(CuOTffe-CeHe

42% ee, >99:1 Sn2:Sn2, 50% conv

(CuOTffe-CeHs

<5%

ee, 1

2 Sn2':Sn2, 14%conv

Third Phase Screening (CuCN):

NHBu

Fourth Phase Screening (CuCN):

O/Pr

NHBu

NHBu

Was this article helpful?

0 0

Post a comment