Asymmetric Total Syntheses of Two 3-Acyl-5,6- dihydro-2H-pyrones: (R)-Podoblastin-S and (R)- Lachnelluloic Acid with Verification of the Absolute Configuration of (−)-Lachnelluloic Acid

Abstract

Expedient asymmetric total syntheses of both (R)-podoblastin-S and (R)-lachnelluloic acid, representative of natural 3-acyl-5,6-dihydro-2H-pyran-2-ones, were performed. Compared with the reported total synthesis of (R)-podoblastin-S (14 steps, overall 5% yield), the present study was achieved in only five steps in an overall 40% yield and with 98% ee (HPLC analysis). In a similar strategy, the first asymmetric total synthesis of the relevant (R)-lachnelluloic acid was achieved in an overall 40% yield with 98% ee (HPLC analysis). The crucial step utilized readily accessible and reliable Soriente and Scettri’s Ti(OiPr)4/(S)-BINOL‒catalyzed asymmetric Mukaiyama aldol addition of 1,3-bis(trimethylsiloxy)diene, derived from ethyl acetoacetate with n-butanal for (R)-podoblastin-S and n-pentanal for (R)-lachnelluloic acid. With the comparison of the specific rotation values between the natural product and the synthetic specimen, the hitherto unknown absolute configuration at the C(6) position of (−)-lachnelluloic acid was unambiguously elucidated as 6R.

Divergent Asymmetric Total Synthesis of All Four Pestalotin Diastereomers from (R)-Glycidol

“…On the other hand, there are three natural 3-acyl-4-hydroxy-5,6-dihydroxy-pyran-2-one products relevant to 4-methoxy-5,6-dihydroxy-pyran-2-ones: (R)-podoblastins [19], (R)-lachnelluloic acid [20], and alternaric acid [21] (Figure 2). We previously reported asymmetric total syntheses of all these natural products utilizing a catalytic asymmetric Mukaiyama aldol reaction and an asymmetric Ti-Claisen condensation as the crucial steps [22,23]. Consistent with our expeditious total syntheses of all these compounds, we envisaged a divergent synthetic access to all four chiral pestalotin diastereomers starting from a common and readily-available chiral building block, i.e., (R)-glycidol.…”

“…With (S)-aldehyde 1 in hand, we next investigated a catalytic asymmetric Mukaiyama aldol reaction using readily-available Chan's diene 2 [13] with 1 (Scheme 3). For this purpose, we employed the procedure applied for the asymmetric syntheses of (R)-podoblastin-S and (R)-lachnelluloic acid [22], as well as that described in Organic Syntheses, recently [26]. The reaction by using catalysis of Ti(iOPr) 4 (2 mol%)/(S)-BINOL (2 mol%)/LiCl (4 mol%) and subsequent treatment with PPTS/MeOH afforded the desired aldol adduct syn-3 in 31% yield with high diastereoselectivity and enantioselectivity [syn/anti = 93:7, 85% ee (C-5 position) by HPLC analysis].…”

“…On the other hand, there are three natural 3-acyl-4-hydroxy-5,6-dihydroxy-pyran-2-one products relevant to 4-methoxy-5,6-dihydroxy-pyran-2-ones: (R)-podoblastins [19], (R)-lachnelluloic acid [20], and alternaric acid [21] (Figure 2). We previously reported asymmetric total syntheses of all these natural products utilizing a catalytic asymmetric Mukaiyama aldol reaction and an asymmetric Ti-Claisen condensation as the crucial steps [22,23].…”

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

“…Later, a formal synthesis of 3 was reported [ 14 ]. Recently, the chiral total syntheses of ( R )-podoblastin S ( 2d ) and ( R )-lachnelluloic acid were performed utilizing catalytic asymmetric Mukaiyama aldol reactions [ 15 ].…”

Special Issue: Asymmetric Synthesis 2017

“…The process is based on the asymmetric addition of terminal alkynes to aldehydes catalyzed by chiral zinc complexes, achieving excellent enantioselectivities [ 4 ]. Fujiwara et al have developed an expedient and efficient asymmetric total synthesis of both natural antifungal ( R )-podoblastin-S and ( R )-lachnelluloic acid, the crucial step of the methodology being an enantioselective Mukaiyama aldol reaction catalyzed by a chiral titanium-based complex [ 5 ]. Kraft et al show in their research article the preparation of two novel carbohydrate-derived oxazolines and their application as chiral ligands in a highly enantioselective palladium-catalyzed Tsuji-Trost allylic alkylation reaction [ 6 ].…”