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T1 - Multistep one-pot reactions combining biocatalysts and chemical catalysts for asymmetric synthesis

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methods for synthesis is a rapidly growing area of research.

The applicabilityof the ωTAs was shown in a short chemoenzymaticsynthesis of (S)-rivastigmine, which was preparedwithin a linear sequence of three steps employing either PD-ωTAor VF-ωTA in the asymmetric key step (45 mM substrate concentration;100 mg scale) (Scheme ). The primary (S)-amine was obtained therebywith perfect optical purity (>99% ee) and excellentconversions (up to >99%), which was subsequently dimethylated toatertiary amine by chemical means. (S)-Rivastigmineis used for the symptomatic treatment of mild to moderate Alzheimer’sdisease and dementia due to Parkinson’s disease.

Y. AsanoSyntheses of amino acids by new microbial enzymes (in Japanese), 66, 1117-1118 (1992).

A related ozonolysis approach (in this case cleaving only one double bond) has been followed in the synthesis of the iminocyclitols (+)-kifunensine (100), (+)-mannojirimycin (101), (+)-1-deoxygalactonojirimycin (102), and (–)-1-deoxymanno-jirimycin (103, ), which are glycosidase inhibitors with potential anti-viral properties.

This evolution is impacting synthetic chem.

The first asymmetric synthesis of an alkaloid from an arene cis-dihydrodiol was reported by Hudlicky et al. in 1990: The authors prepared both enantiomers of acetonide-protected trihydroxyheliotridane 98, in nine steps for the (+)-isomer and twelve for its (–)-counterpart, from chlorobenzene 93. Thereby, they made elegant use of ozonolysis and selective redox transformations to obtain either enantiomer of the key intermediate 96 from the same cis-dihydrodiol ().

Arene cis-dihydrodiols are versatile chiral building blocks offering ample possibilities for further functionalisation (). While the asymmetric preparation of these labile compounds represents an enormous challenge for chemical methods, they are formed with excellent selectivity from the corresponding arenes by the action of bacterial dioxygenases. Toluene dioxygenase (TDO) from Pseudomonas putida is the best-known of these enzymes, and the cis-dihydroxylation of various simple arenes by Pseudomonas has been reported by David Gibson and co-workers as early as 1968. It took almost two decades until the preparative value of this biotransformation was recognised, but since the late 1980s, biocatalytically prepared arene cis-dihydrodiols have been used in the asymmetric synthesis of numerous natural products, including many alkaloids. Early studies relied on Pseudomonas putida 39/D, a mutant strain developed by Gibson's group, for fermentative production of the desired metabolites, but later the responsible toluene dioxygenase has been cloned and heterologously expressed in E. coli, which soon became the preferred biocatalyst. Today, several optically pure arene cis-dihydrodiols (obtained by TDO catalysis) are commercially available.

Asymmetric Syntheses Aided by Biocatalysts - …

Over the last 20 years, Hudlicky's research group has made extensive use of arene cis-dihydrodiols as building blocks in natural product synthesis, most notably in the preparation of the cytotoxic Amaryllidaceae alkaloids pancratistatin (104), narciclasine (105), lycoricidine (106), and their analogues (), which exhibit potent in vitro and in vivo anti-cancer activity.,

Hatakeyama and co-workers have devised a synthetic sequence towards the antimalarial Hydrangea alkaloids (+)-febrifugine (86) and (+)-isofebrifugine (87), in which the nitrone 84 is a key intermediate (). Kinetic resolution of alcohol 81 using immobilised Candida antarctica lipase B (CAL-B; Novozym 435) provided the corresponding (S)-acetate 82 in 43% yield and 91% ee (enantioselectivity E = 50). The key step of the synthesis is a cascade nitrone formation–cycloaddition reaction, which joins three molecules and sets up two rings and two chiral centres in one operation, albeit in only moderate diastereoselectivity. The mixture of isomers obtained was transformed into the target alkaloids 86 and 87 in six additional steps. An even more elegant one-pot procedure forms the cornerstone of Kita's asymmetric synthesis of (–)-rosmarinecine (92): the racemic hydroxynitrone 88 was stereoselectively acylated with the maleate ester 89 using immobilised CAL-B (Chirazyme L-2), and the acylation product underwent a spontaneous intramolecular (3 + 2)-cycloaddition to afford compound 91, featuring 4 contiguous stereocentres, as a single diastereomer in 58% yield and 92% ee (). Recrystallisation and minor functional group interconversions completed the synthesis of optically pure 92, which was obtained in 45% overall yield from rac-88. An improved procedure for the preparation of rac-88 published some years later even rendered the use of protective groups unnecessary.

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Biocatalytic Asymmetric Synthesis of Chiral Amines from ..

Optically active nitrones represent chiral building blocks that are particularly interesting for the synthesis of nitrogen heterocycles. The nitrone moiety can react with olefins in inter- or intramolecular (3 + 2)-cycloadditions, which often proceed with excellent regio- and diastereoselectivity, and furthermore this functional group can provide a nitrogen atom present in the target molecule. These features were exploited by Holmes and co-workers, who prepared nitrone 76 from the chiral alcohol (R)-75 (), which was obtained in 47% yield and 92% ee by kinetic resolution of the racemate using lipase PS35 under previously reported conditions. Intramolecular cyclisation of 76 afforded a separable mixture of isomers, of which the major one (77, 32%) was converted into the indolizidine (–)-79, and further into the dendrobate frog alkaloid (+)-allopumiliotoxin 323B′ (80).

biocatalysts in organic syntheses ..

Sardzik, Robert; Sharma, Ritu; Kaloo, Sara; Voglmeir, Josef; Crocker, Paul R.; Flitsch, Sabine L. “Chemoenzymatic synthesis of sialooligosaccharides on arrays for studies of cell surface adhesion” CHEMICAL COMMUNICATIONS. 47(19); 5425 – 5427. – 2011

Principles and Applications of Asymmetric Synthesis

In all these synthetic studies, the biocatalytically prepared cis-diol served as precursor for the C-ring of the target compounds, while different strategies were explored for the construction of ring B: (i) In the case of (+)-lycoricidine (106), the first Amaryllidaceae alkaloid obtained by this chemo-enzymatic approach, the piperonyl unit 108 was attached to the diol building block 107via an acyl-nitroso–diene [4 + 2] cycloaddition (nitroso-Diels–Alder reaction). Subsequent closure of the B-ring by a Heck reaction proved problematic, as desilylation and transacetylation occurred as side reactions, resulting in a yield of only 27% (). (ii) Later studies focused on nucleophilic opening of aziridines derived from the arene cis-diol as a way to connect rings A and C, and this approach was first used in the asymmetric synthesis of (+)-pancratistatin (104): The tosylaziridine 112, obtained in 4 steps from bromobenzene, was coupled with the cyanocuprate 113, whose dimethylamide moiety was meant to serve as direct precursor of the amide functionality in the target compound. However, the intended intramolecular transamidation on intermediate 114 could not be achieved, making various additional functional group interconversions necessary (). (iii) This problem was addressed in the synthesis of 7-deoxypancratistatin (122, ), where the tosylaziridine was replaced by the corresponding carbomethoxy analogue 117, and cyanocuprate 118–lacking the amide moiety of 113–was used as electrophile. Ring-closure was achieved in fair yield (61%) by a Bischler–Napieralski-type cyclisation. (iv) The same method for closing ring B was employed in the synthesis of narciclasine (105, ), while the strategy for coupling the diol and piperonyl units was again changed: The presence of an additional bromine atom in the acetonide 123 made Suzuki coupling possible, avoiding the need for the rather unstable cyanocuprate. For the construction of 123, the authors returned to a nitroso-Diels–Alder approach, providing an elegant means of differentiating between the two vinylic bromide moieties of the TDO-derived cis-diol. (v) In the synthesis of 10b-epi-7-deoxypancratistatin the B ring was constructed via an aza-Payne rearrangement on aziridine 127 and Lewis-acid catalysed intramolecular epoxide ring-opening on the resulting tosylamide 130 ()., Several derivatives of the natural Amaryllidaceae alkaloids have been prepared following variations of these synthetic strategies, including a carboline analogue, derivatives featuring various functional groups at C1, and others.,

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