Enantioselective synthesis temperature

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

To explore the validity of the ring formation strategy, we drew up plans and carried out an enantioselective synthesis of diene 77 (Scheme 19). Initially, based on previous studies on similar medium- and large-ring syntheses, we surmised that elevated temperatures would be necessary for effective macrocycliza-... 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

The stereospecific desulfinylation of sulfinyloxiranes has been widely reported and used in stereo- and enantioselective synthesis . When the reaction is performed at low temperature with an excess of f-BuLi, the resulting lithiooxirane can be trapped by various electrophiles including carbonyl compounds, chloroformates and chlorocarbamates as well as TMSCl (Scheme 56). Here again, retention of configuration was observed at -100°C. 

Special cases arc the enantioselective synthesis of chiral aldehydes using 1-phenyl-l-ethanamine under optimized conditions (see Table 5), and the remarkable asymmetric induction observed in the alkylation of polymer-bound imines at room temperature (see Table 2). 

As is often found in asymmetric synthesis, temperature is an experimental parameter that can increase enantioselectivity. Here, however, a decrease in the reaction temperature does not always increase the enantioselectivity. An optimum temperature was found to be -20°C to -25°C for the oxidation of methyl p-tolyl sulfide [17], and this temperature range was retained for the standard oxidations. In the case of the monooxidation of dithianes, the maximum enantioselectivity was obtained at ca. —40°C [29] (Scheme 6C.1). 

Contrary to most allocolchicinoids which lack a C-ll substituent, compounds 78 and 80 show stable axial chirality. The above study constitutes the first example in the allocolchicinoid series where both configurations at the biaryl axis can be obtained from a given stereochemistry at C-7. In the natural alio series, free rotation around the biaryl axis is often possible at room temperature, and the configuration of the biaryl axis is controlled by the stereochemistry at C-7 due to conformational constraints in the C-ring [14]. While several total enantioselective syntheses of colchicine address the control of the stereochemistry at C-7 [106], no direct enantioselective synthesis of natural allocolchicines has been reported to date. ... 

As early as 1984 the porcine pancreas lipase-catalysed enantioselective synthesis of (R)-glycidol was described. At pH 7.8 and ambient temperatures the reaction was allowed to proceed to 60% conversion (Scheme 6.9). This means that the enzyme was not extremely enantioselective, otherwise it would have stopped at 50% conversion. Nonetheless, after workup the (R)-glycidol was obtained in a yield of 45% with an ee of 92% [42]. This was a remarkable achievement and the process was developed into an industrial multi-ton synthesis by Andeno-DSM [34, 43]. While on the one hand a success story, it also demonstrated the shortcomings of a kinetic resolution. Most enzymes are not enantiospecific but enantioselective and thus conversions do not always stop at 50%, reactions need to be fine-tuned to get optimal ees for the desired product [28]. As mentioned above kinetic resolutions only yield 50% of the product, the other enantiomer needs to be recycled. As a result of all these considerations this reaction is a big step forward but many steps remain to be done. 

The same CALB preparation was appUed in many dynamic kinetic resolutions combining two types of catalysts with each other. In the presence of homogeneous transition metal catalysts that catalyze the racemization and heterogeneous acids or bases or immobilized transition metals Novozym 435 was not deactivated [1, 26-28]. This is all the more remarkable since the reactions catalyzed by these catalysts include redox reactions at elevated temperatures (>60°C). When Novozym 435 was applied for the enantioselective synthesis of cyanohydrin acetates (10) from aliphatic aldehydes (7), good results were achieved (Scheme 2.2) for this dynamic kinetic resolution (DKR) [29]. Here NaCN is used as the base for the dynamic racemic formation and degradation of the cyanohydrins (6 and 8). 

Synthesis of Substituted Pyrrolidines. A cycloaddition/red-uction sequence between nitroalkenes and vinyl ethers derived from DCP, i.e., 2 can effect the enantioselective synthesis of substituted pyrrolidines. 2-Substituted 1-nitroalkenes undergo highly efficient and diastereoselective Lewis-acid-promoted [4 + 2] cycloaddition with DCP-derived vinyl ethers to afford cyclic ni-tronates 5 in high yields. Subsequent reduction with Pt02 (7.5 mol%), under 160 psi of H2 at room temperature for 24 h, affords the optically active 3-substituted pyrrolidines (6) (71-97%, both as the free base and V-protected derivatives), and the chiral auxiliary 1 (eq 3). 

Overman s group has reported a highly enantioselective synthesis of iV-tosyl-substituted 2-oxazolidinones from linear precursors. The reaction is catalyzed by a structurally unique Pd(ll) catalyst COP-OAc 302. At room temperature and with 5 mol% of the catalyst, iV-tosylcarbamate 301 cyclized to give 2-oxazolidinone 303 with high yield and ee (Equation 23) <2005]OC2859>. 

The high activity of some of the nickel catalysts, which allows the reactions to he carried out at low temperature, will presumably preclude their use on a technical scale and these systems will have to be modified to give acceptable results at higher temperatures. In this respect, it should be noted that the cationic systems [ArNi(PR3)2(MeCN)]" [28] and [( -allyl)Pd(PR3)2] [19] give satisfactory results at ambient temperatures, whereby only the latter has as yet been modified for enantioselective synthesis. 

The BF3-promoted reaction of aldehydes or acetals, methyl carbamate, and homochiral crotylsilanes is valuable for highly diastereo- and enantioselective synthesis of homoallylamines (Scheme 10.147) [419]. Interestingly, reaction using aromatic aldehydes or their acetals at low temperature forms stereo-controlled functionahzed pyrrolidines predominantly by a formal [3-1-2] cycloaddition (Section 10.3.3.1). 

Our first attempt was an enantioselective synthesis of (k)-(+)-carnegine [7,8]. Michael addition of 2-(3,4-dimethoxyphenyl)ethylamine (7) to (R)-(+)-l took place readily at room temperature in chloroform (Scheme 5). Without isolation of any intermediate, the reaction mixture was treated with excess trifluoroacetic acid to effect the cyclization. Depending on the reaction conditions and the aryl substituent of the chiral sulfoxide, different levels of diastereoselectivity were observed. The results are summarized in Table 1. Under proper conditions (TFA, 0°C, 4h), 10b could be obtained in 65% yield as the only isolated product (Scheme 5) (Table 1). 

Using tryptamine as the nucleophile, the Michael addition-cyclization strategy was extended to the enantioselective synthesis of the /J-carboline alkaloid system. Michael addition of tryptamine to the chiral acetylenic sulfoxides took place smoothly at room temperature. Either trifluoroacetic acid or p-toluene-sulfonic acid was effective as a catalyst for the cyclization step (Scheme 7). The results of the Michael addition-cyclization reaction sequence are summarized in Table 3. In general, we found that the indole moiety is more reactive than the dimethoxyaryl ring used in the tetrahydroisoquinoline synthesis. Therefore, the cyclization step could take place at a temperature as low as -60 °C. Also, p-tolu-enesulfonic acid resulted in a better diastereoselectivity. However, the diastereo-selectivity of the system is much less sensitive to the aryl substituents of the acetylenic sulfoxides compared to that of the tetrahydroisoquinoline system. Also, to our surprise, the steric factor on the chiral acetylenic sulfoxide has little effect on the diastereoselectivity. Even with the bulky 2-methoxy-naphthyl acetylenic sulfoxide lc [11], the diastereoselectivity still remained roughly the same as for 1 a and 1 b (Scheme 7) (Table 3). 

Arguably one of the most valuable exploitations of an amination reaction is in the formation of amino acids. Wu and Zhang have employed chiral reverse micelles as asymmetric microenvironments for enantioselective synthesis of 2-phthalimides-esters 72.33 Hydrazinolysis and hydrolysis of the esters then lead to a-amino acids. It was found that asymmetric induction varied according to the reaction temperature, the alkyl chain of the surfactants, and the structure of the surfactants. 

An enantioselective synthesis of chiral QUINAP 234 was reported by Knochel et al. (07SL2655). The organolithium species obtained from l-(2-bromo-l-naphthyl)isoquinoline by treatment with f-BuLi reacted with (—)-menthyl (S)-p-toluene-sulfinate at-78 °C. The resulting diastereomers were separated via column chromatography. One pot sulfoxide lithium exchange at low temperature, Ph2PCl reaction, sulfur protection with Ss and a Raney-Ni desulfurization step afforded optically pure QUINAP (99% ee) in 60% yield. The s)mthetic route avoided the use of Pd complexes for the resolution. The ees were determined after resulfurization on Chiralcel OD-H. 

It catalyses the aminolysis of epoxides in an extraordinarily efficient manner in aprotic solvents (e.g. toluene, CH2CI2) with complete trans stereoselectivity and high regioselectivity [Chini et al. Tetrahedron Lett 35 433 1994], It also catalyses the trans addition of indole (at position 3) to epoxides (e.g. to phenoxymetltyloxirane) in >50% yields at 60° (42 hours) under pressure (10 Kbar) and was successfully applied for an enantioselective synthesis of (+)-diolmycin A2 [Kotsuki Tetrahedron Lett 37 3727 799(5]. Of the ten lanthanide triflates, Yb(OTf)3 gave the highest yields (> 90%, see above) of condensation products by catalytically activating formaldehyde, and a variety of aldehydes, in hydroformylations and aldol reactions, respectively, with trimethylsilyl enol-ethers in THF at room temperature. All the lanthanide triflates can be recovered from these reactions for re-use. [Kobayashi Hachiya J Org Chem 59 3590 1994.]... 

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