Regioselectivity in the Syntheses of Enantiopure 2-Benzopyrans through Intramolecular Cyclization of Tethered Lactaldehydes. Conformations of the Products

Abstract

Using titanium tetraisopropoxide, the enantiopure tethered lactaldehyde (α′ S,2S)-2-(3′-hydroxy-α′-methyl-benzyloxy)propanal (6) is cyclized with complete regio- and diastereoselectivity ortho to the phenolic hydroxyl group to give (1S,3S,4R)-3,4-dihydro-1,3-dimethyl-2-benzopyran-4,5-diol (7). Similar cyclization of the epimeric (α′ R,2S)-lactaldehyde (25) yields solely the corresponding (1R,3S,4R)-4,5-diol (34). The 4,5-diacetate (26), but not (35), undergoes conformational inversion of the heterocyclic ring through significant 4,5-peri interactions between the adjacent acetoxy substituents. Spontaneous cyclizations of the corresponding phenoxide ions of the lactalde-hydes (6) and (25), generated by fluoride from their silyl ethers, led to the related 4,7-diols with high regioselectivity through ring-closure para to the aromatic oxygen.

Scalable Total Synthesis of (−)-Triptonide: Serendipitous Discovery of a Visible-Light-Promoted Olefin Coupling Initiated by Metal-Catalyzed Hydrogen Atom Transfer (MHAT)

“…The established protocol for synthesizing 1 from alcohol 3 via (−)-triptonide ( 2 ), a congener recently showing promise as a reversible nonhormonal male contraceptive agent, inspired us to conceive a novel approach toward 3 or alike structures (Figure b). − To this end, an aldol-like cyclization of aldehyde 4 was devised to forge the C7 stereogenic center . We envisaged that the C5–C10 bond in 4 could be constructed through a metal-catalyzed hydrogen atom transfer (MHAT)-initiated reductive cyclization process, − whereas C3–C4 olefin was strategically saturated to secure the correct stereogenic centers of C5 and C10, tracing back to aldehyde 5 as a key precursor.…”

“…Even though 14 could be converted to 4 to finish the synthesis (Scheme S1), we decided to introduce the C3–C4 olefin at a later stage of synthesis by considering the step- and redox-economy . Consequently, deprotection of the phenol silyl ether in 14 by NEt 3 ·3HF followed by the treatment with Ti­(OiPr) 4 successfully materialized the aldol-type cyclization, and subsequent addition of aqueous solution of NaIO 4 into the same flask direct afforded 16 as the final isolable product in 55% yield as a single diastereomer. , Epoxidation of C9–C11 olefin afforded 17 , the crude product of which was further oxidized to introduce the C12–C13 epoxide in a diastereoselective manner . The epimerization of the C3 stereogenic center by DBU before the treatment of H 2 O 2 /K 2 CO 3 was essential to prevent the hydrolysis of lactone during the scale-up, providing 18 in 53% yield over two steps.…”

“…8−10 To this end, an aldol-like cyclization of aldehyde 4 was devised to forge the C7 stereogenic center. 12 We envisaged that the C5−C10 bond in 4 could be constructed through a metal-catalyzed hydrogen atom transfer (MHAT)-initiated reductive cyclization process, 13−15 whereas C3−C4 olefin was strategically saturated to secure the correct stereogenic centers of C5 and C10, tracing back to aldehyde 5 as a key precursor. The intermediate 5 could in turn be prepared via the alkylation reaction of lactone 7 and allyl bromide 6 followed by deprotection.…”

Syntheses in enantiopure form of four diastereoisomeric naphthopyranquinones derived from aphid insect pigments

“…In a recent study 24, 25 we showed that the phenolic lactaldehyde 49 unsubstituted para to the phenolic hydroxyl group cyclised with complete diastereoselectivity to give the cis-1,3dimethylbenzopyran-4,5-diol 42 in good yield, none of the epimeric C-4 diol 47 being formed, whereas an earlier study 9 showed that the corresponding methoxy lactaldehyde 50 cyclised with lower diastereoselectivity to afford the pair of C-4 epimeric cis-1,3-dimethylbenzopyran-4,5-diols 43 and 48 in a ratio of 75 : 25, with the pseudoequatorial alcohol still predominating. In the present study the diastereoselectivity is even less, with cyclisation of the corresponding brominated benzyloxy derivative yielding the two C-4 epimeric cis-1,3-dimethylbenzopyrans 39 and 44 in a ratio of 62 : 38.…”