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A concise synthesis of (-)-methylenolactocin and (-)-phaseolinic acid, the common members of the paraconic acids, is described. The synthesis is based on regioselective asymmetric dihydroxylation and the orthoester Johnson-Claisen rearrangement of allyl alcohol with a vicinal diol functionality as the key steps. The synthesis was completed in 10 steps with overall yields of 4.1% for (-)-methylenolactocin and 4.3% for (-)-phaseolinic acid. (C) 2011 Elsevier Ltd. All rights reserved.

Herein, we report efficient acyclic stereocontrol in tandem 1,4-addition-aldol reactions triggered by catalytic asymmetric organometallic addition. Grignard reagents add to alpha,beta-unsaturated thioesters in a 1,4-fashion and the resulting magnesium enolatesare trapped with aromatic or aliphatic aldehydes. The process provides a range of tandem products bearing three contiguous stereocenters with excellent control of relative and absolute stereochemistry. The various diastereomeric products have been fully characterized using single-crystal X-ray analysis and the origins of stereocontrol in this tandem protocol are discussed. The versatility and efficiency of this methodology are demonstrated in the first catalytic asymmetric synthesis of (-)-phaseolinic acid with 54% overall yield via a short and concise route.

A concise approach to (-)-phaseolinic acid starting from commercially available (S)-oct-1-yn-3-ol is disclosed. The key steps are a ring-closing metathesis reaction to prepare a C(2)-symmetrical allylic diol and its desymmetrization to a gamma-butyrolactone by using an Ireland-Claisen rearrangement. The 2S,3S,4S configuration of the levogyre natural product has been confirmed.

The vicinal dianion 2 derived from triethyl ethanetricarboxylate reacted regioselectively with aldehydes and ketones at C(β) to provide paraconic acid derivatives 5a–f in moderate to high yields as mixtures of diastereoisomers. The paraconic acid derivatives 5e and 5f were utilized as the starting materials for the syntheses of (±)-lichesterinic acid (12), (±)-phaseolinic acid (13), (±)-nephromopsinic acid (14), (±)-rocellaric acid (15), and (±)-dihydroprotolichesterinic acid (16).

(±)-Methylenolactocin was prepared in five steps involving an indium-mediated allylation reaction as the key step.

(+)- and (−)-Phaseolinic acid ( 1 ) have been prepared in an enantioselective fashion from acetylenic acid 26 (or ent- 26 ) by a three step sequence involving lactonization, epimerization at C 3 , and oxidative cleavage. 26 was obtained as a single enantiomer using a Nicholas-Schreiber reaction.

Enantiopure phaseolinic acid was synthesized from ( R )-4′-chloro-1′- n -pentyl-2′-butenyl 3-trimethylsilyl-2-propynoate by palladium (II) catalyzed cyclization reaction as the key step.

As N. Selvakumar of Dr. Reddy’s Laboratories, Ltd., Hyderabad approached (Tetrahedron Lett. 2007, 48, 2021) the synthesis of phaseolinic acid 6, there was some concern about the projected cyclization of 2 to 3, as this would involve the coupling of two electron-deficient alkenes. In fact, the Ru-mediated ring-closing metathesis proceeded efficiently. The product unsaturated lactone 3 could be reduced selectively to either the trans product 4 or the cis product 5. There has been relatively little work on the synthesis of the higher branched sugars, such as the octalose 13, a component of several natural products. The synthesis of 13 (Organic Lett. 2007, 9, 4777) by Ulrich Koert of the Philipps-University Marburg also began with a Baylis-Hillman product, the easily-resolved secondary alcohol 8. As had been observed in other contexts, cyclization of the protected allylic alcohol 9a failed, but cyclization of the free alcohol 9b proceeded smoothly. V-directed epoxidation then set the relative configuration of the stereogenic centers on the ring. Ring-closing metathesis to construct tetrasubstituted alkenes has been a challenge, and specially-designed Ru complexes have been put forward specifically for this transformation. Oliver Reiser of the Universität Regensburg was pleased to observe (Angew. Chem. Int. Ed. 2007, 46, 6361) that the second-generation Grubbs catalyst itself worked well for the cyclization of 17 to 18. Again in this synthesis, catalytic V was used to direct the relative configuration of the epoxide. Intramolecular alkyne metathesis is now well-established as a robust and useful method for organic synthesis. It was also known that Ru-mediated metathesis of an alkyne with ethylene could lead to the diene. The question facing (Angew. Chem. Int. Ed . 2007, 46, 5545) Alois Fürstner of the Max-Planck-Institut, Mülheim was whether these transformations could be carried out on the very delicate epoxy alkene 21. In fact, the transformations of 21 to 22 and of 22 to 23 proceeded well, setting the stage for the total synthesis of Amphidinolide V 25.

(+)- and (−)-Phaseolinic acid ( 1 ) have been prepared in an enantioselective fashion from acetylenic acid 26 (or ent- 26 ) by a three step sequence involving lactonization, epimerization at C 3 , and oxidative cleavage. 26 was obtained as a single enantiomer using a Nicholas-Schreiber reaction.

(±)-Methylenolactocin was prepared in five steps involving an indium-mediated allylation reaction as the key step.

(-)-Phaseolinic acid is a metabolite of a fungus, Macrophomina phaseolina, and (-)-methylenolactocin is an antitumoral antibiotic from Penicillum sp. In the course of our studies aimed at the synthesis of enantiomerically pure g-butyrolactones4 we focused our attention on the synthesis of both enantiomers of phaseolinic acid and on the determination of their absolute configuration by means of chemical and spectroscopic correlations. The strategy was to correlate (-)-phaseolinic acid with (-)-methylenolactocin