Synthesis of a C-9 to C-18 Building Block of the Phenalamides

Abstract

In the context of a synthesis of phenalamide A2, the C-9 to C-18 building block 6 was synthesized. The stereogenic centers were generated by alkylation of an Evans oxazolidinone 12 and by a crotylboration reaction using the enantiomerically pure (E)-achlorocrotylboronate (4).

Highly (E)-Selective BF3·Et2O-Promoted Allylboration of Chiral Nonracemic α-Substituted Allylboronates and Analysis of the Origin of Stereocontrol

“…Similarly, crotylboration with 13b gave alcohol 15b in 70% yield . In both cases, high ( Z )-selectivity (≥10:1) was observed, consistent with Hoffmann’s report . However, when these reactions were performed in the presence of 10% BF 3 ·Et 2 O, reagent 13a provided a 6:1 mixture of δ - chloro-homoallylic alcohols 14a and 15a , and reagent 13b provided a 3:1 mixture of alcohols 14b and 15b …”

“…The asymmetric carbonyl allylboration reaction is a valuable method for C−C bond formation. In the vast majority of cases that have been described, the asymmetric induction derives from the use of chiral auxiliaries attached to boron. , Although not as widely adopted in the literature, the addition of enantioenriched α-substituted allylboronates to carbonyl compounds is a useful alternative. − Pioneered by Hoffmann et al, carbonyl addition reactions of enantioenriched α-substituted allylboronates 3 proceed with near perfect chirality transfer. , A mixture of ( Z )- and ( E )-homoallylic alcohols 4 and 5 can be generated from two competing transition states TS-3 and TS-4 (Figure ). The ratio of the two homoallylic alcohols depends in part on the electronic property of the group at the α-position.…”

“…The ratio of the two homoallylic alcohols depends in part on the electronic property of the group at the α-position. When the α-substituent is a polar group, such as an alkoxy group or halogen atom, allylboration proceeds predominately via TS-3 to give ( Z )-homoallylic alcohol 4 . Although the exact origin of the high ( Z )-selectivity remains unclear, several factors, including steric effects, dipolar effects, and stereoelectronic minimization of π−σ* delocalization in the transition states, have been proposed and supported by computational studies .…”

“…We were intrigued by the possibility that BF 3 ·Et 2 O-promoted aldehyde allylboration could be used to induce ( E )-selectivity with reagents that have much higher intrinsic preference for positioning of the α-substituent in a pseudoaxial position in the allylboration transition state. α-Chloro-substituted allylboronates, such as 13 , are known to give ( Z )-δ - chloro-substituted homoallylic alcohols, e.g., 15 , with high ( Z )-selectivity in allylboration reactions …”

Carbolithiation of Styrenes with N-tert-butyl aldimines

“…Oxalic acid (ca 5-8 g) was added portionwise until the aqueous phase had reached pH 3-4. The resulting mixture was stirred at RT for 3 h. Work-up as described above and further purification by column chromatography afforded 4, [29][30][31][32] 2-Phenethylcyclohexanone (14): 34 Oil, IR (film, ν, cm −1 ) 1721 (C=O). 1 H NMR (CDCl 3 , 300 MHz): δ 7.18-7.32 (m, 5H, Ph), 2.62 (t, J = 7.8 Hz, 2H, CH 2 ), 1.95-2.45 (m, 6H, 3 × CH 2 ), 1.31-1.90 (m, 5H, CH and 2 × CH 2 ); 13…”