A practical stereocontrolled synthesis of (+)-discodermolide (1) has been completed in 10.3% overall yield (23 steps longest linear sequence). The absolute stereochemistry of the C(1)-C(6) (7), C(9)-C(16) (8), and C(17)-C(24) (9) subunits was established via substrate-controlled, boron-mediated, aldol reactions of the chiral ethyl ketones 10, 11, and 12. Key fragment coupling reactions were a lithium-mediated, anti-selective, aldol reaction of aryl ester 8 (under Felkin-Anh induction from the aldehyde component 9), followed by in situ reduction to produce the 1,3-diol 40, and a (+)-diisopinocampheylboron chloride-mediated aldol reaction of methyl ketone 7 (overturning the inherent substrate induction from the aldehyde component 52) to give the (7S)-adduct 58. The flexibility of our overall strategy is illustrated by the synthesis of a number of diastereomers and structural analogues of discodermolide, which should serve as valuable probes for structure-activity studies.

A practical synthesis of (+)-discodermolide and analogues: fragment union by complex aldol reactions.

A novel total synthesis of the complex polyketide (+)-discodermolide, a promising anticancer agent of sponge origin, has been completed in 7.8% overall yield over 24 linear steps, with 35 steps altogether. This second-generation approach was designed to rely solely on substrate control for introduction of the required stereochemistry, eliminating the use of all chiral reagents or auxiliaries. The common 1,2-anti-2,3-syn stereotriad found in each of three subunits, aldehyde 9 (C1−C5), ester 40 (C9−C16), and aldehyde 13 (C17−C24), was established via a boron-mediated aldol reaction of ethyl ketone 15 and formaldehyde, followed by hydroxyl-directed reduction to give 1,3-diol 14. Alternatively, a surrogate aldehyde 22 was employed for formaldehyde in this aldol reaction, leading to the β-hydroxy aldehyde 20 as a common building block, corresponding to the discodermolide stereotriad. Key fragment unions were achieved by a lithium-mediated anti aldol reaction of ester 40 and aldehyde 13 under Felkin−Anh control...

A Second-Generation Total Synthesis of (+)-Discodermolide: The Development of a Practical Route Using Solely Substrate-Based Stereocontrol

A stereoselective synthesis of (+)-norrisolide is presented. This natural product belongs to a family of marine spongiane diterpenes the structure of which is characterized by a fused gamma-lactone-gamma-lactol ring system attached to a bicyclic hydrophobic core. Our studies led to the development of a expedient synthesis of such gamma-lactone-gamma-lactol motifs based on ring expansion of a fused cyclopropyl ester. Highlights of the synthetic strategy toward norrisolide include the coupling of the two bicyclic systems by constructing a sterically demanding C9-C10 bond and the installation of the C19 oxygen at the last step of the synthesis via a Baeyer-Villiger oxidation.

Norrisolide: total synthesis and related studies.

Synthetic Reactions of Aldonolactones

Stereochemically defined γ-butyrolactones have served as key building blocks in the syntheses of many types of natural products, including alkaloids, macrocyclic antibiotics, lignan lactones, pheromones, anti-leukemics, and flavor components. Accordingly, there are a large number of methods for the enantioselective preparation of substituted γ-butyrolactones: from simple natural products such as amino acids, tartaric acid, ascorbic acids, carbohydrates, or ribonolactones; from chiral sulfoxides, epoxides, or substituted acetylenic acids; and by various enzymatic or synthetic reductions, oxidations, and hydrolyses. This review will summarize these enantioselective methods of lactone synthesis and for each briefly show how the resultant lactone fits into the synthetic scheme for a particular natural product synthesis.

Enantiomerically pure γ-butyrolactones in natural products synthesis

The preparation of the chiral butenolide (4b) is described, together with its use in annulation reactions yielding stereochemically defined bicyclo[4.3.0], [3.3.0], and [3.1.0] ring systems; the synthetic utility of these species is indicated.

Chiral bicycles from ribonolactone

A novel approach to cis-chrysanthemic acids

We describe the synthesis of (–)-5-O-diphenyl-t-butylsiloxymethyl-5H-furan-2-one (4) from D-ribonolactone; conversion of this chiral butenolide into (+)-(IR,6S,7S)-7-diphenyl-t-butylsiloxymethyl-8-oxabicyclo[4.3.0]non-3-en-9-one (10)(by means of a Diels-Alder reaction with butadiene); and thence via an efficient six-step sequence into (+)-(IR,2S,5S)-2-diphenyl-t-butylsiloxymethyl-3-oxabicyclo[3.3.0]octan-7-one (15). A structure proof for this final product was provided by X-ray structural analysis. The crystals are triclinic, space group P1 with Z= 2, a= 8.351(9), b= 17.400(8), c= 8.591 (8)A; α= 77.8(1), β= 71.1(1), γ= 93.8(1)° 3423 Independent reflections were measured on a diffractometer and the structure has been refined to R 0.069. In the two independent molecules, the 3-oxabicyclo[3.3.0]octan-7-one fragments have strikingly different conformations.

Chiral oxabicyclic systems from ribonolactone

(1R,2S,5S)-2-Diphenyl-t-butylsiloxymethyl-3-oxabicyclo[3.3.0]octan-7-one (3), prepared from D-ribonolactone, has been converted in six steps into the biologically active prostacyclin analogue (15RS)-11-deoxy-11-oxacarbacyclin methyl ester (2; X = O).

Alison Thomas

Papers

Chiral bicycles from ribonolactone

A novel approach to cis-chrysanthemic acids

Chiral oxabicyclic systems from ribonolactone

Synthesis of (15RS)-11-deoxy-11-oxacarbacyclin methyl ester

Chiral Oxabicyclic Systems from Ribonolactone.