DYKAT reactions

Later, they also successfully employed aliphatic alcohols 166 as competent nucleophiles in the Pd-catalyzed DYKAT reaction, the utility of which was demonstrated by a concise total synthesis of the gastrulation inhibitor ( + )-hippospongic acid A (Scheme 5.31). Key intermediate 165 was prepared in good yield from aldehyde 164 via a MBH analogous reaction in the presence of HMPA and DIBAL-H. 

By analogy to the DYKAT reactions with vinyl epoxides, Trost et al. have developed the Pd-eatalysed asymmetric dynamic kinetic allylic amination and acyl migration of vinyl aziridines with benzoyl imido carboxylates. As shown in Scheme 2.51, the process afforded the corresponding protected vicinal diamines in high yields and enantioselectivities of up to 93% ee. This methodology was demonstrated to be a platform for the formal synthesis of (-I- )-balanol and analogues. 

In addition, the palladium-catalysed DYKAT reaction between phthalimide and a divinyl carbonate yielded the corresponding amino alcohol as a single diastereomer (Scheme 2.52), which was a key intermediate in a total synthesis of a potent antitumor agent, 1-epi ( + )-FR900482. ... 

Just like palladium, the molybdenum-catalyzed reaction has been extended to an asymmetric variant. Following development of the reaction by Trost and co-workers,they reported a concise and efficient synthesis of the HIV therapeutic tipranavir (119). While the key tetrasubstituted centre in compound 115 was constructed by a palladium-boron co-catalyzed DYKAT reaction, the stereogenic centre in nitroaromatic 117 was installed in a molybdenum-catalyzed DYKAT reaction. Both compounds were subsequently elaborated to tipranavir (119). While it has been determined that the molybdenum-catalyzed reaction proceeds with overall retention, the stereochemistry of each step has not been extensively studied. Recent studies have suggested a retention-retention pathway may be in operation. ... 

Trost, B.M., Machacek, M.R., and Tsui, H.C. (2005) Development of aliphatic alcohols as nucleophiles for palladium-catalyzed DYKAT reactions Total synthesis of (-l-)-hippospongic add A. J. Am. Chem. Soc., 127, 7014-7024. 

Ins(l,4,5)P3. A number of phosphates, e.g. (37), which act as inositol monophosphatase inhibitors have been synthesised from the l,6-epoxy-4-benzyloxycyc-lohexan-2-ol (36)7" Conduritol derivatives (39) are useful synthetic building blocks. However, the enantioselective palladium-catalysed allyl alkylation and similar reactions of (38) are complex due to C2 symmetry. It has now been reported that dynamic kinetic asymmetric transformation (DYKAT) of racemic... 

One good example of the application of this technology is in the AAA reaction of a racemic vinyl epoxide. The epoxide undergoes a dynamic kinetic asymmetric transformation (DYKAT) by reaction with p-methoxybenzyl alcohol, the standard ligand, and a palladium source. The product is obtained in 69% yield and 98% e.e. After further manipulations a key building block for the nonpeptidic protease inhibitor tipranavir was produced. Coupling of this intermediate with a synthon obtained using a molybdenum-catalyzed DYKAT process led to an advanced intermediate in a total synthesis of tipranavir (Scheme 20.14). ... 

The naphthyl ligand provided more challenges in developing a scalable process, but this was achieved.This hgand is superior for the amination of racemic epoxybutene, by a DYKAT process. We have developed this reaction to work on a kilogram scale at an acceptable S/C ratio of 1000 1. The product from this reaction, phthalimidovinylglycinol... 

Scheme 5.48 Rh-catalyzed DYKAT of racemic allene/C—H activation/diastereose-lective imine addition reaction reported by Cramer.

Aryl alcohols are competent nucleophiles in the palladium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic MBH derivatives. As an extension of this strategy, the palladium-catalyzed intramolecular DYKAT of MBH adducts was further explored. As shown in Scheme 4.96, reactions were carried out in dioxane at 25 °C with chiral ligand affording 300 in up to 45% yields and 98% ee via a highly selective kinetic resolution interestingly, when reactions were performed at 80 °C, up to 94% yield with 91% ee of 300 was obtained by the DYKAT process. 

With their efficient procedure for deracemization of MBH adducts, Trost and coworkers have applied dynamic asymmetric kinetic transformation (DYKAT) to the total synthesis of furaquinodn E. As shown in Scheme 5.28, the asymmetric palladium-catalyzed alkylation of phenols combined with a reductive Heck reaction delivered an effident approach to the synthesis of the key synthon, which is the core structure of the furaquinocins. A general synthetic route to furaquinocin E was established in 14 steps from MBH adduct 159. Their work highlighted the ability to use racemic MBH adducts for asymmetric synthesis. They further extended the scope of their strategy by developing the synthesis of three more analogs of... 

The same group has successfully applied similar conditions to the Pd-cata-lysed asymmetric synthesis of allylic alcohols from unsymmetrical and symmetrical allylic carbonates and acetates, as shown in Scheme 2.57. Moreover, Trost et al. have demonstrated that the DYKAT palladium-catalysed reactions of conduritol B tetracarboxylates provided ready access to a variety of enan-tiomerically pure conduritol B derivatives. ... 

In 2003, Trost and Frandrick developed a novel type of DYKAT based on the asymmetric palladium-catalysed cycloaddition between isocyanates and vinylaziridines. Performed in the presence of a chiral diphosphine as the ligand, the reaction allowed the access to a broad array of imidazolidin-2-ones with high yields and enantioselectivities of up to 95% ee, as shown in Scheme 2.58. In 2005, the same authors applied this methodology to the total synthesis of (-I- )-pseudodistomin D. ... 

Another highly efficient DYKAT was reported in 2009 by Shibasaki s group based on a barium-catalysed aldol/retro-aldol reaction.Thus, a-alkylidene-j9-hydroxy esters were obtained by reaction of aryl, heteroaryl, alkenyl and alkyl aldehydes with )S,y-unsaturated esters in both excellent enantio- and... 

Finally, Griengl s group has developed the synthesis of aromatic 1,2-amino alcohols on the basis of a bienzymatic DYKAT process. The reaction occurred between a benzaldehyde derivative and glycine in the presence of L-threonine aldolase from Pseudomonas putida and L-tyrosine decarboxylase from either Enterococcus faecalis or two genes from Enterococcus faecium. The best results were obtained for the production of (5)-octopamine (99%, ee = 81%), and (5)-noradrenaline (76%, ee = 79%), as shown in Scheme 3.64. 

Among asymmetric version of barium-catalyzed aldol reactions, the direct aldol reaction of y3,y-unsaturated esters with aldehydes is promising due to the DYKAT (dynamic kinetic asymmetric transformation). Shibasaki and coworkers (147) established an optimized catalyst system for the DYKAT involving aldol/retro-aldol reaction, that a Ba(0-iPr)2/BIN0L mixture gave excellent enan-tioinduction and conversion (Scheme 32). a-Alkylidene-y3-hydroxy esters were obtained under proton-transfer conditions via DYKAT in 87-99% ee. 

Perhaps the most important mechanistic implication of all is the very fact that the allylpalladium complexes can interconvert via n-G-n equilibration. This enables chiral racemic material to be transformed into products of enantiopurity through a dynamic kinetic asymmetric transformation (DYKAT). This powerful strategy has facilitated the construction of numerous complex, asymmetric molecules from simple racemic starting materials. Dynamic kinetic asymmetric transformations are extremely rare in other asymmetric reactions, highlighting the importance of the AAA reaction. 

Carboxylates have also proven to be suitable nucleophiles in the AAA reaction, especially with cyclic electrophiles.For example, DYKAT of conduritol B tetracarboxylate facilitated a synthesis of O-znyo-inositol 1,4,5-triphosphate (66). Racemic substrate 64 was transformed to the enantiopure disubstituted product 65 in 80% yield. This was a key intermediate in the preparation of ZJ-wyo-inositol 1,4,5-triphosphate (66), a key component of intracellular signalling. 

The Shvo catalyst 1 was successfully used in the transfer hydrogenation of 1,3-diones to the corresponding 1,3-diols with isopropanol as the hydrogen donor (2) [36, 37], This reaction is synthetically useful for the reduction of cyclic diones since reduction of these diketones by LiAlIli preferentially gives the aUyUc alcohol [36]. Also piperidine-3,5-diones were efficiently reduced to the corresptMiding diols by isopropanol using 1 as catalyst [37], and these diols were subsequently used in dynamic kinetic asymmetric transformatimis (DYKATs) to provide stereodefined 3,5-disubstituted piperidines [36, 37],... 

Recently, Lin et al. demonstrated that the propargyl alcohol could participate in such a transformation for the synthesis of chiral dihydrofurans [53]. The reaction began with a challenging oxa-Michael addition to cinnamaldehyde derivatives, which was followed by a secondary amine/Pd complex-catalyzed nucleophilic addition/ isomerization of the alkyne moiety in excellent yields and enantioseleclivities (Scheme 9.58). Since the oxa-Michael addition of propargyl alcohol to 0[,P-unsaturated aldehydes was a slow process, this cascade reaction proceeded through a dynamic kinetic asymmetric transformation (DYKAT) process, whereby it made the overall reaction proceed efficiently and with high stereocontrol using the second reaction with precise stereocontrol to shift the first reversible oxa-Michael addition selectively. 

Very recently, Sun et al. developed a cascade reaction with a binary catalytic system combining a secondary amine and a palladium catalyst for the synthesis of dihydropyrrole enantioselectively [54]. The reaction began with a Jprgensen-Hayashi catalyst promoted N-Ts propargyl amine-involved aza-Michael addition to cinnamaldehydes and ended with subsequent PdCl and Jprgensen-Hayashi catalyst co-promoted car-bocyclization (Scheme 9.59). The chemistry presented here also involved a DYKAT process and provided an alternative to chiral dihyropyrrole synthesis. 

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