Highly Stereoselective and Efficient Addition of Organocerium Reagents to syn-β-Alkyl-β-hydroxy-α-methyl Ketones by Way of Their Titanium Alkoxides − Synthesis of Complex 1,3-Diol Units with Three Stereodefined Centres

Abstract

A highly efficient and stereoselective technique for additions to syn‐β‐alkyl‐β‐hydroxy‐α‐methyl ketones is now available. The methodology is based on the conversion of the starting material into a trichlorotitanium alkoxide derivative, which is able to assume a stable cyclic arrangement exhibiting high stereofacial discrimination towards nucleophilic alkyl transfer by an appropriate organometallic species. The use of Grignard reagents has serious limitations; in fact, highly hindered and basic reagents do not work well with enolizable substrates. Organocerium compounds can obviate these drawbacks, since side processes such as enolization or interaction with titanium(IV) are almost completely suppressed. The method permits the introduction of a large variety of carbon systems, including primary, secondary and tertiary alkyl chains, as well as aromatic, alkynyl and benzylic moieties, in high yields and with good stereoselectivities.

Short, Enantioselective Total Synthesis of (+)-Ineleganolide

“…Further comprehensive investigation into the effects of additives, temperature, concentration, and solvents led to no appreciable improvement. In contrast, a markedly enhanced diastereoselectivity ratio (dr, 9:1) with higher combined yield (92%) for undesired stereoisomer 13′ was observed when TiCl 4 was used as the chelating metal source (see Scheme insert). Preferential formation of 13 was ultimately achieved by in situ generation of a TBS silyl ether prior to lithiate addition, producing enynes 13 and 13′ in 66% and 22% yield, respectively.…”

Short, Enantioselective Total Synthesis of (+)-Ineleganolide

“…Further comprehensive investigation into the effects of additives, temperature, concentration, and solvents led to no appreciable improvement. In contrast, a markedly enhanced diastereoselectivity ratio (dr, 9:1) with higher combined yield (92%) for undesired stereoisomer 13′ was observed when TiCl 4 was used as the chelating metal source (see Scheme insert). Preferential formation of 13 was ultimately achieved by in situ generation of a TBS silyl ether prior to lithiate addition, producing enynes 13 and 13′ in 66% and 22% yield, respectively.…”

Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

“…Tertiary alcohol 28 was then prepared under Bartoli's conditions in a 70% yield with 3:1 diastereoselectivity on 14 g scale by pseudo-axial addition of a methyl nucleophile to the 6-membered titanium chelate (TS-II). 32 In preparation for the ensuing biaryl bond formation, we installed a cyclic borinic ester to tether the C9-alcohol over a two-step sequence, and then selectively deprotected the phenol to direct halogenation at C16. 33 The ensuing intramolecular Suzuki coupling was then catalyzed by Buchwald's SPhos Pd G2 pre-catalyst 34 in conjunction with additional ligand and potassium phosphate (K 3 PO 4 ) to afford 30 in 87% yield on 6 g scale.…”

Applications of CeCl3as an Environmental Friendly Promoter in Organic Chemistry

“…103 Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn-β-alkyl-β-hydroxy-R-methyl ketones. 104 The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in R-positions, using RLi or RMgX, has been studied by Guanti and co-workers. 105 The authors found that the reaction proceeds with high selectivity, but often in very low yields due to the extensive occurrence of an enolization process, especially when a saturated alkyl chain is bound to the prochiral carbonyl group.…”

“…Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn -β-alkyl-β-hydroxy-α-methyl ketones . The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in α-positions, using RLi or RMgX, has been studied by Guanti and co-workers .…”

Short, Enantioselective Total Synthesis of (+)-Ineleganolide

“…Further comprehensive investigation into the effects of additives, temperature, concentration, and solvents led to no appreciable improvement. In contrast, a markedly enhanced diastereoselectivity ratio (dr, 9:1) with higher combined yield (92%) for undesired stereoisomer 13′ was observed when TiCl 4 was used as the chelating metal source (see Scheme insert). Preferential formation of 13 was ultimately achieved by in situ generation of a TBS silyl ether prior to lithiate addition, producing enynes 13 and 13′ in 66% and 22% yield, respectively.…”

Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

“…Tertiary alcohol 28 was then prepared under Bartoli's conditions in a 70% yield with 3:1 diastereoselectivity on 14 g scale by pseudo-axial addition of a methyl nucleophile to the 6-membered titanium chelate (TS-II). 32 In preparation for the ensuing biaryl bond formation, we installed a cyclic borinic ester to tether the C9-alcohol over a two-step sequence, and then selectively deprotected the phenol to direct halogenation at C16. 33 The ensuing intramolecular Suzuki coupling was then catalyzed by Buchwald's SPhos Pd G2 pre-catalyst 34 in conjunction with additional ligand and potassium phosphate (K 3 PO 4 ) to afford 30 in 87% yield on 6 g scale.…”

Applications of CeCl3as an Environmental Friendly Promoter in Organic Chemistry

“…103 Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn-β-alkyl-β-hydroxy-R-methyl ketones. 104 The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in R-positions, using RLi or RMgX, has been studied by Guanti and co-workers. 105 The authors found that the reaction proceeds with high selectivity, but often in very low yields due to the extensive occurrence of an enolization process, especially when a saturated alkyl chain is bound to the prochiral carbonyl group.…”

“…Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn -β-alkyl-β-hydroxy-α-methyl ketones . The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in α-positions, using RLi or RMgX, has been studied by Guanti and co-workers .…”

Short, Enantioselective Total Synthesis of (+)-Ineleganolide

“…Further comprehensive investigation into the effects of additives, temperature, concentration, and solvents led to no appreciable improvement. In contrast, a markedly enhanced diastereoselectivity ratio (dr, 9:1) with higher combined yield (92%) for undesired stereoisomer 13′ was observed when TiCl 4 was used as the chelating metal source (see Scheme insert). Preferential formation of 13 was ultimately achieved by in situ generation of a TBS silyl ether prior to lithiate addition, producing enynes 13 and 13′ in 66% and 22% yield, respectively.…”

Mimicking Noncanonical Oxidations with Redox-Neutral Photocatalysis

“…Tertiary alcohol 28 was then prepared under Bartoli's conditions in a 70% yield with 3:1 diastereoselectivity on 14 g scale by pseudo-axial addition of a methyl nucleophile to the 6-membered titanium chelate (TS-II). 32 In preparation for the ensuing biaryl bond formation, we installed a cyclic borinic ester to tether the C9-alcohol over a two-step sequence, and then selectively deprotected the phenol to direct halogenation at C16. 33 The ensuing intramolecular Suzuki coupling was then catalyzed by Buchwald's SPhos Pd G2 pre-catalyst 34 in conjunction with additional ligand and potassium phosphate (K 3 PO 4 ) to afford 30 in 87% yield on 6 g scale.…”

Applications of CeCl3as an Environmental Friendly Promoter in Organic Chemistry

“…103 Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn-β-alkyl-β-hydroxy-R-methyl ketones. 104 The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in R-positions, using RLi or RMgX, has been studied by Guanti and co-workers. 105 The authors found that the reaction proceeds with high selectivity, but often in very low yields due to the extensive occurrence of an enolization process, especially when a saturated alkyl chain is bound to the prochiral carbonyl group.…”

“…Because of the outstanding diastereoselectivities often reached with organocerium compounds in addition reactions to carbonyl compounds, we investigated the suitability of these organometallics for a highly efficient and stereoselective addition to syn -β-alkyl-β-hydroxy-α-methyl ketones . The introduction of an alkyl group into O-protected β-hydroxy ketone systems with stereocenters in α-positions, using RLi or RMgX, has been studied by Guanti and co-workers .…”