“…We began our synthesis ( Scheme 3 ) by treating 5 with MOMCl in the presence of DIPEA/TBAI [ 28 ] to afford MOM-protected lactone 9a , followed by reduction with i Bu 2 AlH [ 20 ] to produce the corresponding hemiacetal 11 in 95% yield in two steps on 2 g scale as an inconsequential mix of diastereoisomers (2:1). Despite the screening of different catalytic acidic conditions previously used in dehydrations of hemiacetals [ 29 ], 12 could not be obtained cleanly without removing the MOM-protecting group. Fortunately, the activation of the hemiacetal using MsCl and subsequent elimination with an excess of Et 3 N at high temperatures [ 30 ] afforded the desired enol ether 12 in a modest 65% yield on a 2 g scale after passage through a short silica pad.…”
Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki–Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.
“…We began our synthesis ( Scheme 3 ) by treating 5 with MOMCl in the presence of DIPEA/TBAI [ 28 ] to afford MOM-protected lactone 9a , followed by reduction with i Bu 2 AlH [ 20 ] to produce the corresponding hemiacetal 11 in 95% yield in two steps on 2 g scale as an inconsequential mix of diastereoisomers (2:1). Despite the screening of different catalytic acidic conditions previously used in dehydrations of hemiacetals [ 29 ], 12 could not be obtained cleanly without removing the MOM-protecting group. Fortunately, the activation of the hemiacetal using MsCl and subsequent elimination with an excess of Et 3 N at high temperatures [ 30 ] afforded the desired enol ether 12 in a modest 65% yield on a 2 g scale after passage through a short silica pad.…”
Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki–Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.
“…However, only a few short studies about the synthesis of cyclic enol ethers with different substitution patterns have been reported . First we chose two synthetic routes developed by Wenkert et al and Zenk and Wiley for the formation of an ethyl-substituted pyran and furan ring system (Scheme 1) to compare them in the cyclopropanation with diazo esters. …”
A set of cyclic enol ethers derived from 2,3-dihydrofuran 35 and 3,4-dihydropyran 8 with a varying substitution pattern at the olefinic system were synthesized. Evans's ligand 5 with Cu(I)OTf was found to be an effective catalyst in the cyclopropanation reaction between cyclic enol ethers 14, 19, 28-31, and 33 and ethyl diazoacetate 6 to give diastereoselectivities up to exo/endo = 95:5 and enantioselectivities higher than 95% in nearly all cases. Because of the selective building of a quarternary carbon center and good yields in the formation of bicyclic structures 34c-h, the reaction was used as a key step in the asymmetric synthesis of (+)-quebrachamine 7, an indole alkaloid of the Aspidosperma family. After acid-induced ring opening of bicyclic compound 34f to lactone 40 followed by LiAlH(4) reduction to the masked aldehyde 41, a reaction with tryptamine gave intermediate 42. This alcohol was efficiently converted into the indole alkaloid (+)-quebrachamine 7 in an overall yield of 37% starting from the chiral synthon 34f. Moreover it revealed the absolute configuration of the quarternary center of the cyclopropanation product 34f to be S.
“…Tris(dibenzylideneacetone)dipalladium (0) (Pd 2 (dba) 3 ), palladium (II) acetate (Pd(OAc) 2 ), tetrakis(acetonitrile)palladium(II) tetrafluoroborate ((MeCN) 4 Pd(BF 4 ) 2 ), 9,9-dimethyl-4,5-bis (diphenylphosphino)xanthene (XANTPhos), alpha, alpha'-bis(di-tert-butylphosphino)-ortho-xylene (97+%) (DtBPX), tricyclohexylphosphine (97+%) (PCy 3 ), and 1,4-bis(diphenylphosphino)butane (dppb) were purchased from Strem and used as received. 2-Methylvalerolactone [53][54][55] and 2-ethylbutyrolactone [56] were synthesized according to literature procedures.…”
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