Importance of the timing of bond breaking and bond making in acetal templates. Enantiodivergent synthesis of steroidal side chains

The First In(OTf)3-Catalyzed Conversion of Kinetically Formed Homoallylic Alcohols into the Thermodynamically Preferred Regioisomers: Application to the Synthesis of 22α-Sterols

“…Interestingly, the stereochemistry at C-22 (3) was assigned as 22a. In other words, the allyl fragment attaches to the steroid in an anti-Cram manner, [9] which excludes the possibility of re-addition of the allyl anion to the aldehyde. Therefore, a pericyclic pathway was invoked to account for this stereochemical outcome, for which the 2-oxonia [3,3]-sigmatropic rearrangement proposed by Nokami et al [10] was adopted.…”

“…This method can be utilized for the construction of steroidal side chains with anti-Cram stereoselectivity. Hence, efficient access to 22a-oxygenated steroidal side chains, such as those in ecdysone derivatives, [9] is facilitated. As opposed to the previously proposed mechanisms involving transfer of allyl anions or concerted rearrangement for the equilibration of branched and linear homoallylic alcohols, our study of this thermodynamic conversion suggests that both retro-cleavage to generate the parent aldehyde in situ and a concerted rearrangement are involved, plausibly a retro-ene reaction followed by a 2-oxonia [3,3]-sigmatropic rearrangement in this case.…”

B-Allyl-9-borabicyclo[3.3.1]nonane

“…Treatment of the chiral steroidal acetal (S,R,R) isomer, prepared from the steroidal aldehyde and (2R,4R)-(−)-pentanediol, with allyl-9-BBN in the presence of Titanium(IV) Chloride followed by the usual workup gave the (S,S) isomer exclusively (eq 5). 9 On the other hand, the reaction of the (S,S,S) acetal isomer, prepared from the steroid aldehyde and (2S,4S)-(+)-pentanediol, with allyl-9-BBN produced an 88:12 mixture of the (S,S) and (S,R) isomers, suggesting that the 1,2asymmetric induction is primarily controlled by the Cram rule rather than the chiral acetal template. The TiCl 4 -mediated reaction of the chiral acetal (S,R,R) isomer, prepared from (3S)-3-t-butyldimethylsiloxybutanol and (2R,4R)-(−)-pentanediol, with allyl-9-BBN gave the corresponding homoallyl alcohol in 90% yield with predominant formation (90:10) of the chelation product, 10 indicating that the 1,3asymmetric induction is dictated by chelation rather than the acetal template.…”

The First In(OTf)3-Catalyzed Conversion of Kinetically Formed Homoallylic Alcohols into the Thermodynamically Preferred Regioisomers: Application to the Synthesis of 22α-Sterols

“…Interestingly, the stereochemistry at C‐22 was assigned as 22 α . In other words, the allyl fragment attaches to the steroid in an anti‐Cram manner,9 which excludes the possibility of re‐addition of the allyl anion to the aldehyde. Therefore, a pericyclic pathway was invoked to account for this stereochemical outcome, for which the 2‐oxonia [3,3]‐sigmatropic rearrangement proposed by Nokami et al10 was adopted.…”

“…This method can be utilized for the construction of steroidal side chains with anti‐Cram stereoselectivity. Hence, efficient access to 22 α ‐oxygenated steroidal side chains, such as those in ecdysone derivatives,9 is facilitated. As opposed to the previously proposed mechanisms involving transfer of allyl anions or concerted rearrangement for the equilibration of branched and linear homoallylic alcohols, our study of this thermodynamic conversion suggests that both retro‐cleavage to generate the parent aldehyde in situ and a concerted rearrangement are involved, plausibly a retro‐ene reaction followed by a 2‐oxonia [3,3]‐sigmatropic rearrangement in this case.…”