An interesting approach to transform the B ring of bryostatins to the C ring has been developed. The key tactics of the approach feature an intramolecular Csp3–H bond amination to form spirocyclic hemiaminal, which undergoes ring opening to afford the C ring found in bryostatin 17. The subsequent epoxidation/oxidation sequence results in Z to E isomerization of the exo-cyclic enoate, delivering the common precursor, which could be transformed into the C ring found in bryostatins 1, 2, 4–9, 12, 14, and 15.

Enantioselective synthesis of crotyl geminal bis(silane) 4 has been developed by an asymmetric [1, 5]-hydride shift of allylic hydrazine. SnCl4-promoted Sakurai allylation of (R)-4 with acetals leads to chemoselective desilylation of SiMe3, generating E-syn-(S, R)-5 in good yields with high E/Z-, diastereo- and enantioselectivity.Download high-res image (128KB)Download full-size image

Enantioselective synthesis of SiMe3/SiPh2Me-substituted crotyl geminal bis(silane) has been developed. This compound is a useful reagent for Ph3C+B(C6F5)4−-catalyzed asymmetric Sakurai allylation and one-pot Sakurai allylation/Prins cyclization processes. Chemoselective desilylation of SiPh2Me leads to efficient chirality transfer.

The unique steric effect of geminal bis(silane) [(R3Si)2CH] allows an exo-selective intermolecular Diels–Alder reaction of geminal bis(silyl) dienes with α,β-unsaturated carbonyl compounds. The approach shows good generality to form ortho–trans cyclohexenes in good yields with high exo-selectivity and high enantioselectivity in some asymmetric cases. The excellent exo-stereocontrol aptitude of (R3Si)2CH group is highlighted by comparing with R3SiCH2 and R3Si groups, which leads to endo-selectivity predominantly. The conformational analysis of dienes suggests that (R3Si)2CH group effectively shields both sides of the diene moiety, ensuring the desired exo-selectivity. Moreover, the geminal bis(silane) can be further functionalized to transform the resulting ortho–trans cycloadducts into useful synthons, which makes the approach hold great potential for organic synthesis.

An efficient approach to synthesize benzosiloline has been developed using a visible light-promoted radical cyclization reaction of silicon-tethered alkyl iodide and phenyl alkyne.

Two contrasting pathways in a SnCl4-catalyzed reaction of geminal bis(silyl) enol derivatives with β,γ-unsaturated ketoesters have been achieved by tuning the R group in the enol moiety. While the electron-donating Bn-substituted enol ether undergoes an exo-selective inverse-electron-demand Diels–Alder (IEDDA) reaction to give dihydropyran, the electron-withdrawing Ac-substituted enol ester reacts as an allylsilane to provide a Sakurai-allylated product with predominant syn-selectivity.

•(S)-(−)-Diphenylprolinol is shown as an efficient auxiliary to ensure the high diastereoselectivity of alkylation.•A range of optically pure chiral α-monosilyl amides were obtained in good yields with high diastereoselectivity.•The approach is applicable to synthesize sterically congested chiral α-bis(silyl) amides.Asymmetric alkylation or silylation of (S)-(−)-diphenylprolinol-derived α-silyl amide has been developed to synthesize optically pure α-monosilyl or bis(silyl) amides in good yields with high diastereoselectivity.

A geminal bis(silane)-controlled regio- and stereoselective oxidative Heck reaction of enol ethers with terminal alkenes has been developed. The reaction proceeds with α,β-coupling regioselectivity to give push–pull Z,E-1,3-dienes in good yields. The product showed valuable utility in Sakurai homoallylation with acetals to generate α-substituted-γ-keto esters with good anti-selectivity.

A TMSBr/InBr3-promoted Prins cyclization/homobromination reaction of dienyl alcohol with aldehyde has been developed to construct a unique cis-E THP shown as the A ring in (−)-exiguolide and the B ring in bryostatins.

A concise total synthesis of (−)-exiguolide has been completed in an overall 2.8% yield over 20 steps in the longest linear path. The key strategies involve (1) Prins cyclization/homobromination of dienyl alcohol with the B ring-substituted aldehyde, prepared by Prins cyclization/bromination, to construct the A ring with excellent cis-Z stereochemical control and (2) an unusual side chain installation/macrocyclization strategy featuring Sonogashira cross-coupling followed by a ring-closing metathesis reaction to deliver the target.

An efficient synthesis of functionalized γ-lactones has been developed involving Sakurai exo-cyclization/rearrangement of 3,3-bis(silyl) enol esters with a tethered acetal. While the steric and electronic effects of geminal bis(silane) favor the desired Sakurai pathway, the methoxy species formed in the deprotection step also facilitates both cyclization and rearrangement. The synthetic value of this approach has been demonstrated by efficiently transforming the E-vinylsilane into enyne and the γ-lactone moiety into multisubstituted THF.

A regioselective 1,4-hydroiodination of dienyl alcohols has been developed using trimethylsilyl iodide as Lewis acid and iodide source. A range of homoallylic alcohols containing a multisubstituted Z-alkene was synthesized with good to excellent configurational control. The approach was applied in sequential hydroiodination/Prins cyclization to afford multisubstituted tetrahydropyrans diastereoselectively.

An organosilane-based strategy has been used to accomplish the convergent total synthesis of (−)-exiguolide. The key steps involve: (1) geminal bis(silyl) Prins cyclization to construct the A ring; (2) silicon-protected RCM reaction to construct the 20-membered macrocycle; and (3) Hiyama–Denmark cross-coupling of vinylsilane with vinyliodide to install the triene side chain.

The C–Si bond activation via a direct transition metal insertion has recently gained growing attention in the organic chemical community. The process not only shows a new and unique entry to functionalize the C–Si bond, but also presents a powerful method to synthesize diverse organosilanes via formation of a new C–Si bond. This Digest is intended to highlight some elegant advances, which are categorized into strained silacycles, acyclic C(sp3)–Si, acyclic C(sp2)–Si, and C(sp)–Si bond activation.

An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur compounds.

A [1,5]-anion relay has been achieved in 3,3-bis(silyl) benzyl enol ether. Deprotonation at the sterically more accessible benzyl position triggers an intramolecular proton transfer to generate the thermodynamically more stable 3,3-bis(silyl) allyloxy lithium. This endo-oriented allyl anion is stable at −78 °C and undergoes diastereoselective syn-addition at the γ-position with aldehydes and ketones to give monobenzyl-substituted 1,2-diols.

A regioselective nucleophilic addition to 3-geminal bis(silyl) N-acyl pyridinium has been described. Geminal bis(silane) shows contrasting roles that lead to different regioselectivities for the addition of different nucleophiles: its steric effect dominates to favor 1,6-addition of alkyl, vinyl, and aryl organometallic reagents; its directing effect dominates to favor 1,2-addition of less sterically demanding alkynyl Grignard reagents.

A remarkable α-effect of silicon has been discovered that results in soft nucleophilicity at the Cγ of 3,3-bis(silyl) allyloxy lithium 1. The addition of 1 to α,β-unsaturated carbonyl compounds, including enals, proceeds in a 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium 4 undergoes complete 1,2-addition. The results from DFT calculations of HMPA-complexed 1 and 4 provide the rationale to explain this different regioselectivity.

An unusual [1,5]-Brook rearrangement of the lithium alkoxide of geminal bis(silyl) homoallylic alcohol is described. The unique steric and electronic effects of geminal bis(silane) were found to be crucial for promoting this long-range silyl migration, as well as for facilitating the subsequent γ/Z-selective addition of silyl allyllithium with carbonyl compounds to synthesize diverse configurationally defined Z-vinylsilanes.

Geminal bis(silyl) enal 2a is shown to be a useful scaffold for anion relay chemistry (ARC) aimed at the stereoselective synthesis of C3,O1-disilylated allylic alcohols. The ARC reaction is initiated by the addition of an alkyllithium to the aldehyde and features a CuCN-promoted Csp2-to-O 1,4-silyl migration to generate a vinylcuprate that reacts with activated electrophiles.

Among macrocyclic natural products, bryostatins have excellent bioactivities and unique structures that make them highly attractive to synthetic chemists. Particularly challenging for the total synthesis of bryostatins is the B-ring, which features a cis-tetrahydropyran containing a geometrically defined exocyclic Z-methyl enoate. Synthetic chemists have recently displayed great prowess in their efforts to construct this ring, and here we summarize the progress towards this goal.

The [1,5]-anion relay/[2,3]-Wittig rearrangement of 3,3-bis(silyl) enol allyl ethers has been developed. This reaction provides an efficient method to synthesize versatile vinyl bissilanes, which can be transformed into trisubstituted vinylsilanes through a [1,4]-Brook rearrangement/alkylation protocol using a wide range of electrophiles.

A highly stereoselective approach to novel tetrasubstituted (Z)-β-hydroxy-α-TMS silyl enol ethers is described. The reaction proceeds via a sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of TMS-substituted oxiranyl anions with acylsilanes.

An oxidative rearrangement of cyclic tertiary α-hydroxy allylsilanes has been carried out in refluxing ClCH2CH2Cl with pyridinium chlorochromate (PCC). The reaction provides a convenient method to synthesize cyclic β-silylenones in modest to excellent yields.

A highly stereoselective approach to tetrasubstituted (E)-β-hydroxy silyl enol ethers is described. The reaction proceeds via a sequential addition/[1,2]-Brook rearrangement/epoxide-opening process of aryl-substituted oxiranyl anions with acylsilanes.

A facile and highly stereoselective retro-[1,4] Brook rearrangement of 3-silyl allyloxysilanes has been discovered. While basic hydrolysis of the formed (Z)-3,3-bissilyl lithium enolates provides 3,3-bissilyl carbonyl compounds efficiently, trapping the species with various electrophiles including alkyl halides leads to the exclusive O-substituted (Z)-3,3-bissilyl enol derivatives that can undergo a Sakurai reaction with aldehyde to produce the synthetically useful 1,2-diol diastereoselectively.

A remarkable α-effect of silicon has been discovered that results in soft nucleophilicity at the Cγ of 3,3-bis(silyl) allyloxy lithium 1. The addition of 1 to α,β-unsaturated carbonyl compounds, including enals, proceeds in a 1,4- over 1,2-manner with medium to good regioselectivity, whereas the parent allyloxy lithium 4 undergoes complete 1,2-addition. The results from DFT calculations of HMPA-complexed 1 and 4 provide the rationale to explain this different regioselectivity.

An efficient approach to synthesize benzosiloline has been developed using a visible light-promoted radical cyclization reaction of silicon-tethered alkyl iodide and phenyl alkyne.

Two contrasting pathways in a SnCl4-catalyzed reaction of geminal bis(silyl) enol derivatives with β,γ-unsaturated ketoesters have been achieved by tuning the R group in the enol moiety. While the electron-donating Bn-substituted enol ether undergoes an exo-selective inverse-electron-demand Diels–Alder (IEDDA) reaction to give dihydropyran, the electron-withdrawing Ac-substituted enol ester reacts as an allylsilane to provide a Sakurai-allylated product with predominant syn-selectivity.

An organosilane-based strategy has been used to accomplish the convergent total synthesis of (−)-exiguolide. The key steps involve: (1) geminal bis(silyl) Prins cyclization to construct the A ring; (2) silicon-protected RCM reaction to construct the 20-membered macrocycle; and (3) Hiyama–Denmark cross-coupling of vinylsilane with vinyliodide to install the triene side chain.

An unusual [1,5]-Brook rearrangement of the lithium alkoxide of geminal bis(silyl) homoallylic alcohol is described. The unique steric and electronic effects of geminal bis(silane) were found to be crucial for promoting this long-range silyl migration, as well as for facilitating the subsequent γ/Z-selective addition of silyl allyllithium with carbonyl compounds to synthesize diverse configurationally defined Z-vinylsilanes.

A TMSBr/InBr3-promoted Prins cyclization/homobromination reaction of dienyl alcohol with aldehyde has been developed to construct a unique cis-E THP shown as the A ring in (−)-exiguolide and the B ring in bryostatins.

Among macrocyclic natural products, bryostatins have excellent bioactivities and unique structures that make them highly attractive to synthetic chemists. Particularly challenging for the total synthesis of bryostatins is the B-ring, which features a cis-tetrahydropyran containing a geometrically defined exocyclic Z-methyl enoate. Synthetic chemists have recently displayed great prowess in their efforts to construct this ring, and here we summarize the progress towards this goal.

A geminal bis(silane)-controlled regio- and stereoselective oxidative Heck reaction of enol ethers with terminal alkenes has been developed. The reaction proceeds with α,β-coupling regioselectivity to give push–pull Z,E-1,3-dienes in good yields. The product showed valuable utility in Sakurai homoallylation with acetals to generate α-substituted-γ-keto esters with good anti-selectivity.

Enantioselective synthesis of SiMe3/SiPh2Me-substituted crotyl geminal bis(silane) has been developed. This compound is a useful reagent for Ph3C+B(C6F5)4−-catalyzed asymmetric Sakurai allylation and one-pot Sakurai allylation/Prins cyclization processes. Chemoselective desilylation of SiPh2Me leads to efficient chirality transfer.