Good Timing in Total Synthesis: The Case of Phoslactomycin A

Abstract

The importance for the right order of functional group introduction and manipulation (good timing) was demonstrated in the course of a total synthesis of phoslactomycin A. The synthetic strategy comprised a Cu(I)-thiophene carboxylate (CuTC, Liebeskind's reagent)-mediated coupling to introduce the Z,Z-diene at the final stage of the synthesis in the presence of a protected phosphate. Key features for the assembly of the C1-C13 fragment were an asymmetric dihydroxylation, an Evans-aldol reaction and an advanced protective group strategy. The C14-C21 fragment was accessible via an asymmetric 1,2-addition to cyclohexenone and a subsequent diastereoselective ketone reduction. One crucial task was the dihydroxylation of the C8-C9 alkene, the introduction of the C6-C7 double bond and the generation of the C25-nitrogen functionality. A second example consisted of the best sequence for the generation of the functional groups in the core part (first phosphorylation, second iodo-olefination, third azide/carbamate conversion). The synthetic solutions from this approach are compared with the already existing contributions in the phoslactomycin area.

Total Synthesis of the Postulated Structure of Fulicineroside

“…18 The regioselective arene borylation reaction has been used as a key step in natural product synthesis 19. One task of interest for the fulicineroside project was the optimal timing20 for the borylation step (Figure 2). Earlier experiments21 had shown that the iridium‐catalyzed borylation of a benzofuran 36 results in an attack at the neighboring position to the dibenzofuran oxygen atom, which is not appropriate to the present strategy.…”

Asymmetric synthesis of 3,3,5,5-tetrasubstituted 1,2-dioxolanes: total synthesis of epiplakinic acid F

“…Reductive work-up with PPh 3 gave the aldehyde, and then the Wittig olefination with excess NaHMDS-ICH 2 PPh 3 I afforded the key central core (+)-19 as a single Z-isomer in 70% yield over two steps. 21 With the central core (+)-19 and side chain (+)-18 in hand, a modified Negishi reaction afforded the desired (+)-17 in 77% yield. Then, desilylation using p-TsOH furnished alcohol (+)-33 in 89% yield.…”

Hypervalent iodine reagents in the total synthesis of natural products

“…D M P , C H 2 Cl 2 , pyr alkenes, 81,84,92,106,[160][161][162][163][164][165] dienes, 92,166 alkynes, 160 tertiary alcohols, 106 ethers, 92,94,161,162,164,166,167 aldehydes, 92 a,b-unsaturated ketones, 92 esters, 98,166 a-hydroxy esters, 168 amides, 166 lactones, 161 a,bunsaturated lactones, 92,165 macrolactones, 114 lactams, 168 carbamates, 98 amines, 168 alkyl halides, 94 phosphates, 165 azides, 165 acetals, 81,88,106,160 sulfides, 81 and epoxides. 84 Scheme 2 77,83,85,[89][90][91][92]…”

“…DMP, CH 2 Cl 2 , pyr ROTMS, 165,167 ROTBS, 84,94,160,166 ROTES, 81,84,160,166 ROTBDPS, 81,84,94,160 ROTIPS, 81,94,165 ROMe, 84,166 ArOMe, 168 ROBn, 106,160 ROPMB, 81,84,165 ROAlloc, 84 ROBec, 84 ROMOM, 106,168 silyl acetal, 167 and R 2 NBoc. 98 Although DMP tolerates several functional groups, Grieco and Piñeiro-Nuñez reported that the oxidation of a hydroxy carboxylate intermediate (formed by ring opening the corresponding lactone) was best performed with the less popular fluorinated iodine(V) compound.…”

“…with 5 equiv of DMP in benzene at 80 C (Scheme 7). 210,211 An important feature of DMP oxidations is the possibility to prepare aldehydes and ketones bearing an a-stereocenter without epimerization or racemization (DMP/ CH 2 Cl 2 , 91,93,97,98,103,114,121,123,132,137,159,174,184,185,188,192,195,198 DMP/ CH 2 Cl 2 /NaHCO 3 , 142,146,147,149,152,159 and DMP/CH 2 Cl 2 /pyridine 88,94,102,161,165,166,212 ). This was exemplified in the oxidation of a diol to the corresponding dicarbonylic derivative in the synthesis of (+)-peloruside A (Scheme 8).…”