Enantioselective preparation

Another example of reagent-induced asymmetric synthesis is the enantioselective preparation of phosphoramides 6 by addition of dialkylzine reagents to A-diphenylphosphinoylimincs 4 in the presence of the enantiomerically pure 1,2-amino alcohols 5a or 5 b (diethylzinc does not add to A-silyl- or A-phenylimines)12. Phosphoramides 6 (crystalline solids) are obtained in moderate to good yield and good enantioselectivity. The latter can be enhanced by recrystallization. Acidic hydrolysis with dilute 3 M hydrochloric acid/tetrahydrofuran provides the corresponding amines 7 without any racemization. 

In order to prove the utility of this method and to ascertain the absolute configuration of the products, (S)-alanine has been enantioselectively prepared. The key step is the addition of methyllithium to the AjA -dimethyl hydrazone acetal 4c, derived from diol 3c. In accordance with 13C-NMR investigations it can therefore be assumed that all major diastereomers resulting from the addition of organolithium reagents to hydrazone acetals 4a-c derived from diols 3a, 3b or 3c (Table 3, entries 1 -6) have an S configuration at the newly formed stereogenic center. 

Imidazole and its derivatives continued to play an important role in asymmetric processes. Optically active pyrroloimidazoles 26 were prepared by the cycloaddition of homochiral imidazolium ylides with activated alkenes <96TL1707>. This reaction was used in the enantioselective preparation of pyrrolidines <96TL1711>. A review of the use of chiral imidazolidines in asymmetric synthesis was published <96PAC531> and the preparation and use of a new camphor-derived imidazolidinone-type auxiliary 27 was reported < 6TL4565> <96TL6931>. 

Until 1987, the (R)-PaHNL from almonds was the only HNL used as catalyst in the enantioselective preparation of cyanohydrins. Therefore, it was of great interest to get access to HNLs which catalyze the formation of (5 )-cyanohydrins. (5 )-SbHNL [EC 4.1.2.11], isolated from Sorghum bicolor, was the first HNL used for the preparation of (5 )-cyanohydrins. Since the substrate range of SbHNL is limited to aromatic and heteroaromatic aldehydes as substrates, other enzymes with (5 )-cyanoglycosides have been investigated as catalysts for the synthesis of (5 )-cyanohydrins. The (5 )-HNLs from cassava (Manihot esculenta, MeHNL) and from Hevea brasiliensis (HbHNL) proved to be highly promising candidates for the preparation of (5 )-cyanohydrins. Both MeHNL and HbHNL have been overexpressed successfully in Escherichia coli, Saccharomyces cerevisiae and Pichia pastoris. 

HNLs currently applied 1 as catalysts in the enantioselective preparation of chiral ... 

Procedures for enantioselective preparation of a-bromo acids based on reaction of NBS with enol derivatives 16A and 16B have been developed. Predict the absolute configuration of the halogenated compounds produced from both 16A and 16B. Explain the basis of your prediction. 

With consideration of the shortcomings and advantages of the Medicinal Chemistry route discussed above, a retrosynthesis of 1 was designed to incorporate the convergent coupling of hydroxypyridine 9 and fluoroarene 11 as the key step (Scheme 8.2). Enantioselective preparation of the a-arylpyrrolidine 12 was identified as the key challenge. 

With the synthesis of the hydroxypyridine 9 progressing in parallel, most of the effort was focused on the investigation of the far more challenging preparation of the chiral oc-arylpyrrolidine 12. At the outset of our studies, very few practical methods for enantioselective preparation of a-arylpyrrolidines were known [5], The four most attractive approaches are summarized in Scheme 8.4. 

Schubert, T., Hummel, W. and Muller, M. (2002) Highly enantioselective preparation of multifunctionalized propargylic building blocks. Angewandte Chemie-International Edition, 41 (4), 634—637. 

The enantioselective preparation of trans-2,4-disubstituted azetidines 4 by treatment of 3 with methanesulfonyl chloride and triethylamine followed by benzylamine at 45 °C has been reported. A-Arylation of the debenzylated 4 has given 5 in yields of 32-96% by use of rac-Binap and moderate reaction temperatures to suppress racemization of the amines . Azetidines can also be formed from certain oxetanes (see 4.2.3) and from P-Iactams (see 4.3 and 4.6) <99JOC9596>. 

The literature presents a large number of examples concerning the use of known oxazolidinones as chiral auxiliaries in many kinds of reactions. Rare is the use of A-amino derivatives of oxazolidinones, which were used to synthesise new A-acylhydrazones 207. Radical addition reactions occurred with high diastereoselectivity <00JA8329>. The use of glycolate oxazolidinones 210 proved to be efficient for the enantioselective preparation of a-alkoxy carboxylic acid derivatives . Photochemical reaction of vinyl... 

The synthetic versatility and significance of the Zr-catalyzed kinetic resolution of exocyc-lic allylic ethers is demonstrated by the example provided in Scheme 6.9. The optically pure starting allylic ether, obtained by the aforementioned catalytic kinetic resolution, undergoes a facile Ru-catalyzed rearrangement to afford the desired chromene in >99% ee [20], Unlike the unsaturated pyrans discussed above, chiral 2-substituted chromenes are not readily resolved by the Zr-catalyzed protocol. Optically pure styrenyl ethers, such as that shown in Scheme 6.9, are obtained by means of the Zr-catalyzed kinetic resolution, allowing for the efficient and enantioselective preparation of these important chromene heterocycles by a sequential catalytic protocol. 

Two formal syntheses of (-)- [80] and (+)-kumausallene [81] followed this route and relied on the enantioselective preparation of the 2,6-dioxabicyclo[3.3.0]octane core 69 starting from diethyl tartrate or an appropriate chiral sulfoxide. In contrast, Evans et al. [82] used a distinct biomimetic approach in their enantioselective synthesis of the natural product (-)-62 (Scheme 18.23). 

Schmid, A., Hofstetter, K., Feiten, H.J., Hollmann, F., and Witholt, B., Integrated hiocatalytic synthesis on gram scale the highly enantioselective preparation of chiral oxiranes with styrene monooxygenase. Adv. Synth. Catal., 2001, 343, 732-737. 

Both, a-hydroxylated lignans of the dibenzyllactone-type and of the biarylcyclooctane-type have been enantioselectively prepared from the corresponding / -benzyl-y-butyrolactones via a-alkylation followed by a-oxy-genation (Scheme 5). The hydroxy group was introduced in two different... 

Two classes of a-hydroxylated lignans have been enantioselectively prepared a) wikstromol (3) [10, 38] and related natural products [39] and b) gomisin A (1) and congeners [40, 41]. In both cases, chiral, non-racemic ita-conic acid derivatives have been synthesized as key compounds for the preparation of -benzyl-y-butyrolactones (either by resolution (g [32]) or by asymmetric hydrogenation (h [25])). 

Last year, a short enantioselective total synthesis of herbarumin III (42) in 11% overall yield was published the approach applied uses Keck s asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a RCM was used to yield 42. Finally, another asymmetric synthesis of herbarumin III (42) was carried out using (R)-cyclohexylidene glyceraldehyde as the chiral template. The key steps of the synthesis were the enantioselective preparation of the... 

Interestingly, while the chiral Rh2(4S-MACIM)4 catalyst gave the desired isomer from the C-H insertion reaction, the achiral Rh2(OAc)4 catalyst afforded the opposite diastereoisomer in low yield. The enantioselective preparation of / -lactams by C-H insertion has also been examined, and some like 34 and 35 are formed with high enan-tiocontrol [68], but the generality of this process has not yet been established. 

Recently, the first examples of catalytic enantioselective preparations of chiral a-substituted allylic boronates have appeared. Cyclic dihydropyranylboronate 76 (Fig. 6) is prepared in very high enantiomeric purity by an inverse electron-demand hetero-Diels-Alder reaction between 3-boronoacrolein pinacolate (87) and ethyl vinyl ether catalyzed by chiral Cr(lll) complex 88 (Eq. 64). The resulting boronate 76 adds stereoselectively to aldehydes to give 2-hydroxyalkyl dihydropyran products 90 in a one-pot process.The diastereoselectiv-ity of the addition is explained by invoking transition structure 89. Key to this process is the fact that the possible self-allylboration between 76 and 87 does not take place at room temperature. Several applications of this three-component reaction to the synthesis of complex natural products have been described (see section on Applications to the Synthesis of Natural Products ). 

Alkylation of the enolates of the amides derived from these chiral auxiliaries is a very useful method for the enantioselective preparation of chiral 2-alkylalkanoic acid derivatives. 

Roszkowski et have described a method for the enantioselective preparation of Praziquantel (PZQ) a pharmaceutical for the treatment of schistosomiasis and soil-transmitted helminthiasis. Starting with the imine (P) (readily available from phenylethyl amine, phthalyl anhydride and glycine) an asymmetric transfer hydrogenation yielded the chiral intermediate in 62 % ee, and the crude product was easily crystallized to the required high ee and converted into the Praziquantel as shown in Figure 1.34. 

Schwink, L. and Knochel, P. Enantioselective Preparation of C2-Symmetrical Ferrocenyl Ligands for Asymmetric Catalysis. Chem. Eur. J. 1998, 4, 950-968. 

This enantioselective preparation of allylic alcohols has been applied to the synthesis of the side chain of prostaglandins . The addition to functionalized aldehydes, such as 483, allows the synthesis of C2-symmetrical 1,4-diols, such as 484, with excellent diastereoselectivity and enantioselectivity . An extension of this method allows the synthesis of C3-symmetrical dioF . Aldol-type products result from the catalytic enantioselective addition of functionalized dialkylzincs to 3-TIPSO-substituted aldehydes, such as 485, followed by a protection-deprotection and oxidation sequence affording 486 in 70% yield and 91% ee (Scheme 118) . The addition to a-alkoxyaldehydes provides a... 

In the last decades, cyanohydrins have become versatile chiral building blocks, not only for laboratory synthesis, but also for a range of pharmaceuticals and agrochemicals. Several methods for the enantioselective preparation of these compounds have been published [1, 2]. The most important synthetic approaches are catalysis by oxynitrilases, also termed hydroxynitrile lyases (HNLs), wording used in this chapter, [3] and by transition metal complexes [4], whereas the relevance of cyclic dipeptides as catalysts is decreasing [2]. 

J. D. Elliott, V. M. F. Choi, and W. S. Johnson, Asymmetric synthesis via acetal templates. 5. Reactions with cyanotrimethylsilane. Enantioselective preparation of cyanohydrins and derivatives, J. Org. Chem. 78 2294 (1983). 

It is noteworthy that stereochemical control of the two new stereogenic centers at C4a and Cl2b ultimately stems from the stereochemistry at Cl through the intramolecular Diels-Alder reaction. Hence, an optically pure 46 should lead to an enantioselective preparation of a-epoxy lactone 48, thereby ultimately leading to an enantioselective synthesis of arisugacin A [1], LAH reduction of ( )-a-epoxy lactone 48 led to epoxy diol 49 in 78%... 

Banwell MG, Edwards AJ, Harfoot GJ, Jolliffe KA, McLeod MD, McRae KJ, Stewart SG, Vogtle M (2003) Chemoenzymatic Methods for the Enantioselective Preparation of Sesquiterpenoid Natural Products from Aromatic Precursors. Pure Appl Chem 75 223... 

Gagnon R, Grogan G et al (1995) Enzymatic Baeyer-Villiger oxidations of some bicyclo [2.2.1]heptan-2-ones using monooxygenases from Pseudomonas putida NCIMB 10007 enantioselective preparation of a precursor of azadirachtin. J Chem Soc Perkin Trans 1 1505-1511... 

The traditional synthesis of cyclic sulfimidates from /3-aminoalcohols and SOCl2 in the presence of amine as a base has been developed further to the preparation of the enantiopure monocyclic as well fused sulfimidates (Schemes 26 and 27). 1,2,3-Oxathiazolidine mono-.Y-oxides are readily oxidized to corresponding sulfamidates by RuCR and NalCb, and the synthesis of sulfamidates can be performed in a one-pot procedure from -aminoalcohols without isolation of intermediate sulfimidates (Equation 37). The reaction of sulfamate esters 145 with PhI(OAc)2 and various catalysts proved to be a reliable method for the enantioselective preparation of cyclic sulfamidates 146 (Equation 35). 

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