Toshiharu Yoshino

Synthetic studies of huperzine A and its fluorinated analogues. 1. Novel asymmetric syntheses of an enantiomeric pair of huperzine A

Abstract Syntheses of an enantiomeric pair of huperzine A were accomplished by employing two types of methods which feature the tandem Cinchona alkaloids-promoted asymmetric Michael addition / aldol reaction of the β-keto ester 3 with methacrolein (4) (max. 64% ee, 3+4→5 , Scheme 2) and the asymmetric bicycloannulation of 3 with 2-methylene-1,3-propanediol diacetate (7) catalyzed by palladium catalysts carrying chiral ferrocenylphosphine ligands (max. 64% ee, 3+7→8 , Scheme 3) as the key steps. Recrystallization of the partially optically active tricycles (+)- and (−)-6 derived from the products of the asymmetric reactions, readily provided the corresponding optically pure samples (both >99% ee). According to the reported method, the total synthesis of an enantiomeric pair of 1 [(−)- and (+)-1] was completed starting with optically pure (+)- and (−)-6 (Scheme 4).

Total synthesis of natural (+)-FR900482. 2. Efficient syntheses of the aromatic and the optically active aliphatic fragments

Abstract The synthesis of the aromatic fragment 4 was achieved starting from commercially available 5-hydroxy-isophthalic acid (6) by utilizing Claisen rearrangement of 9, bromolactonization of 12, and modified Curtius rearrangement of 16 as key steps. Furthermore, the optically active aliphatic fragment 5 was synthesized in an optically pure form starting with l -diethyl tartrate (7) by featuring epoxide formation of 26, nucleophilic epoxide opening of 27 with an azide anion, reduction of the azide function in 33 to an amine, and formation of the N-protected 1,3-oxazolidine 35.

A novel enantioselective synthesis of the key intermediate of (−)-huperzine a employing asymmetric palladium-catalyzed bicycloannulation

Abstract The key intermediate (+)- 5 of (−)-huperzine A 1 was prepared in an enantiomerically pure form via the asymmetric palladium-catalyzed bicycloannulation of the β-keto ester 2 with 2-methylene-1,3-propanediol diacetate 3 . The chiral ferrocenyl-phosphine ligand 7d gave the highest enatioselectivity of 64% ee in the asymmetric bicycloannulation.

A novel biogenetic type synthesis of (+)-hydantocidin

Abstract The title synthesis was accomplished by featuring the proposed biosynthetic pathway. The synthesis commenced with the D-psicose derivative readily obtainable from D-fructose and employed intramolecular N, O-spiroketal formation of the open-chain N-acylurea derivative as a key step.

Total synthesis of an enantiomeric pair of FR900482. 1. Synthetic and end-game strategies☆

Abstract A synthetic strategy for an enantiomeric pair of FR900482 (1) was developed, which features a convergent and enantioselective sequence starting from 5-hydroxyisophthalic acid (16) and each enantiomer of diethyl tartrate (17 and ent-17). The proposed key intermediate 10 was synthesized from FK973 (3), the triacetyl derivative of 1, and successful reconversion of 10 into 1 was also achieved. These preliminary studies definitely demonstrated that 10 is suitable as a potential advanced key intermediate for 1 and that the crucial final sequence of reactions ( 10→1 ) involving delicate deprotection and oxidation steps can be realized.

Total synthesis of an enantiomeric pair of FR900482. 2. Syntheses of the aromatic and the optically active aliphatic segments

Abstract The synthesis of the aromatic segment 4 was achieved starting from commercially available 5-hydroxyisophthalic acid (6) by utilizing Claisen rearrangement of 9, bromolactonization of 12, and modified Curtius rearrangement of 16 as the key steps. Furthermore, the optically active aliphatic segments 5 and ent-5 were synthesized in enantiomerically pure forms starting with natural (2R,3R)- and unnatural (2S,3S)-diethyl tartrate (7 and ent-7), respectively: The synthetic scheme features epoxide formation of 26, nucleophilic epoxide opening of 27 with an azide anion, reduction of the azide function in 33 to an amine, and formation of the N-protected 1,3-oxazolidine 35.

TOTAL SYNTHESIS OF NATURAL (+)-FR900482. 1. SYNTHETIC AND END-GAME STRATEGIES

Abstract A synthetic strategy for natural (+)-FR900482 ( 1 ) was developed by featuring a convergent and enantioselective sequence which commences with 5-hydroxyisophthalic acid and L-diethyl tartrate. The proposed key intermediate 4 was synthesized starting from FK973, the triacetyl derivative of 1 , and successful reconversion of 4 into 1 was also achieved. These preliminary studies definitely demonstrated that 4 is suitable as a potential relay compound toward 1 and that the crucial final sequence of reactions ( 4→1 ) involving delicate deprotection and oxidation steps can be realized.

A highly practical synthesis of natural PGE1, Δ2-trans-PGE1 and 2,2,3,3-tetradehydro-PGE1 via two-component coupling process using zinc-copper reagents

Abstract A highly practical synthesis of natural PGE 1 , Δ 2 -trans-PGE 1 and 2,2,3,3-tetradehydro-PGE 1 has been achieved in which the 1,4-addition reaction of the corresponding functionalized zinc-copper reagents to the enones 2 and/or 4 plays a key role.

Total synthesis of natural (+)-FR900482. 3. Completion of the synthesis

Abstract The title synthesis was accomplished by featuring (i) coupling of the aromatic fragment 2 with the optically active aliphatic fragment 3 to install the requisite carbon unit ( 2+3→4 ); (ii) intramolecular aldol reaction of the highly functionalized dialdehyde 10 to produce the desired eight-membered ring system 11 (10→11); (iii) epimerization of the C-7 position of hydroxy ketone 14 to obtain the correct stereochemistry (14→15); (iv) internal hemiacetal formation of hydroxylamino ketone 23 in situ generated from ketone 22 to construct the requisite tetracyclic ring system 24 (23→24) as key steps.

Total synthesis of an enantiomeric pair of FR900482. 3. Completion of the synthesis by assembling the two segments

Abstract The title synthesis was accomplished by a method which features (i) coupling of the aromatic segment 2 with the enantiomerically pure aliphatic segment 3 to install the requisite carbon unit ( 2+3→4 ); (ii) intramolecular aldol reaction of the highly functionalized dialdehyde 10 to elaborate the desired eight-membered ring system 12 ( 10→12 ); (iii) epimerization at the C-8 position of the hydroxy ketone 15 to obtain the correct stereochemistry ( 15→16 ); (iv) internal hemiacetal formation of the N-hydroxylamino ketone 25 in situ generated from the ketone 24 to construct the requisite tetracyclic ring system 26 ( 24→25→26 ) as the key steps. The in vitro cytotoxicity assay of the synthesized compounds (1, ent-1, 31, ent-31, 32, and ent-32) against P388 murine leukemia cells disclosed that FR900482 (1) and its congeners 31, 32 bearing natural absolute configuration are 100 times more cytotoxic than the corresponding unnatural enantiomers (ent-1, ent-31, ent-32).