Michael T. Crimmins

Asymmetric Aldol−Ring-Closing Metathesis Strategy for the Enantioselective Construction of Six- to Nine-Membered Oxygen Heterocycles

The ring closing metathesis reaction has rapidly become an important transformation in organic synthesis.1 Examples of many ring sizes with a variety of functional appendages2 have been constructed by this powerful method, largely because of the advent of the functionally tolerant ruthenium3 and molybdenum4 carbene complexes. Even kinetically and thermodynamically disfavored eight-membered rings have been prepared by ringclosing metathesis. However, virtually all5 successful eight-membered ring closures have required the incorporation of cyclic conformational constraints6 or rigid acyclic conformational control elements to avoid formation of dimers or oligomers.7 It is noteworthy that cyclic constrained dienes underwent more efficient ringclosing metathesis to form eight-membered rings when the two olefinic chains were positioned trans on the cyclic constraint than when they were cis.7 Grubbs6a has attributed this effect to a greater difference in energy between the diene and the cyclic olefin in the cissubstituted substrate. We reasoned that dienes with an appropriate acyclic conformational bias might allow eight (or nine)-membered ring formation and avoid the additional strain imposed by a fused ring attached to the newly formed cyclic olefin. We recently reported an asymmetric aldol-ring-closing metathesis strategy for the enantioselective synthesis of the carbocyclic fragment of the nucleoside analogue 1592U89.8 In view of the importance of enantioselective approaches to cyclic ethers of all sizes, particularly eightand nine-membered ring metabolites that are abundant in marine algae,9 an extension of the aldol-metathesis strategy to oxygen heterocycles seemed in order. We report here an efficient, general strategy for the asymmetric synthesis of sixto nine-membered cyclic ethers.10

Ring closing metathesis for the formation of medium ring ethers: The total synthesis of (-)-isolaurallene

Abstract The total synthesis of the marine metabolite (−)-isolaurallene is described. Two approaches to the core nine-membered ether are presented both of which are based on a ring closing metathesis to close the cyclic ether.

Total synthesis of brevetoxin A.

A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an expeditious selective oxidative process followed by methylenation.

Asymmetric total synthesis of pyranicin.

The asymmetric total synthesis of pyranicin (1) is reported. The butenolide ring was constructed via an asymmetric alkylation/ring-closing metathesis strategy. The three stereocenters in the left-hand tetrahydropyran ring were installed by sequential chiral auxiliary-mediated aldol reactions. Closure of the tetrahydropyran and fusion of the alkyl backbone were affected via a sequential ring-closing metathesis-cross-metathesis strategy.

Synthesis of the AB Spiroketal Subunit of Spongistatin 1 (Altohyrtin A): The Pyrone Approach

Abstract The synthesis of the AB spiroketal fragment of spongistatin 1 (altohyrtin A) has been accomplished utilizing the addition of a metalated pyrone to an aldehyde followed by acid catalyzed spirocyclization. A stereoselective copper ( I ) promoted conjugate addition of vinylmagnesium bromide was used to establish the C11 stereogenic center.

Strategies for the total synthesis of C2-C11 cyclized cembranoids.

The C2-C11 cyclized cembranoids, which include the eunicellins (also known as the cladiellins), briarellins, asbestinins, and sarcodictyins, are secondary metabolites isolated from gorgonian octocorals and soft corals. An unusual oxatricyclic ring system containing a hydroisobenzofuran and an oxonene unit with stereogenic centers residing at C1-3, 9, 10, and 14 is common to the eunicellins, briarellins, and asbestinins. However, the location of the cyclohexyl methyl groups (C11 versus C12) and the oxidation level of the sixand nine-membered rings differ among the three classes. Faulkner has proposed that the cyclization of the cembranoid diterpene skeleton initiates a biosynthetic pathway that leads to all four subclasses of these unusual molecules (Figure 1). Beginning with the cembrane skeleton, C2-C11 cyclization provides the cladiellin framework. An intramolecular etherification of the cladiellin tricycle affords the tetracyclic framework of the briarellin subclass, and a subsequent 1,2-suprafacial methyl shift of the briarellin structure is postulated to deliver the asbestinins as the class that is furthest evolved from the cembrane skeleton. The presence of multiple structural types in a common organism provides circumstantial evidence for Faulkner’s proposed biosynthetic pathway. The isolation of a cembrane metabolite with cladiellin metabolites in Alcyonium molle and with asbestinin metabolites in Briareum steckii are specific examples. The sarcodictyins are also proposed to arise from a C2-C11 cyclization of the cembrane skeleton; however, in these systems, the cyclization results in a fused cyclohexane and oxonane in place of the hydroisobenzofuran of the cladiellins, briarellins, and asbestinins. As a result of this significant structural variation of the sarcodictyins, the synthetic approaches to these molecules are quite different than those for the other three related subclasses. This review will cover efforts toward the eunicellins, briarellins, and asbestinins but will not cover efforts toward the total synthesis of the sarcodictyins. Eunicellin was the first reported member of the C2-C11 cyclized cembranoid natural products, isolated in 1968 by Djerassi and co-workers from the soft coral Eunicella stricta found off the coast of Banyuls-sur-Mer in France. Since this discovery, over 100 unique secondary metabolites of gorgonian octocorals have been characterized, including the first asbestinin in 1980 and the first briarellin in 1995. A wide range of structural diversity is displayed by this group of marine natural products. The natural role of these cembranoids is proposed, based upon mollusk and fish lethality assays, to involve predation deterrence. Upon further investigation, several of the members of these subclasses have demonstrated significant pharmacological potential. Particularly, these diterpenes have been shown to exhibit in vitro cytotoxicity against various cancer cell lines, anti-inflammatory properties, antimicrobial activities, and histamine and acetylcholine antagonism. The fascinating molecular architecture of these cembranoids, as well as their potential as therapeutic agents, has sparked much interest in the synthetic community over the past decade. A variety of approaches toward these challenging structural motifs have been investigated and several total syntheses have been accomplished. Efforts toward the total synthesis of the cladiellins, briarellins, and asbestinins are the subject of this review.

Total Synthesis of Irciniastatin A (Psymberin)

The total synthesis of (+)-iriciniastatin A (psymberin) is reported in 19 steps and 6% overall yield. Key reactions include a highly convergent enolsilane-oxocarbenium ion union to generate the C8-C25 fragment and a late-stage coupling of a hemiaminal and acid chloride to complete the synthesis.

Enantioselective Total Synthesis of Brevetoxin A: Unified Strategy for the B, E, G, and J Subunits

Brevetoxin A is a decacyclic ladder toxin that possesses 5-, 6-, 7-, 8-, and 9-membered oxacycles, as well as 22 tetrahedral stereocenters. Herein, we describe a unified approach to the B, E, G, and J rings based upon a ring-closing metathesis strategy from the corresponding dienes. The enolate technologies developed in our laboratory allowed access to the precursor acyclic dienes for the B, E, and G medium-ring ethers. The strategies developed for the syntheses of these four monocycles ultimately provided multigram quantities of each of the rings, supporting our efforts toward the completion of a convergent synthesis of brevetoxin A.

An Improved Synthetic Preparation of 3-Butenal

Abstract A convenient synthesis of 3-butenal from aqueous glyoxal and allyl bromide is described. The preparation readily provides multigram quantities of 3-butenal.

A convenient synthesis of unsymmetrical, substituted γ-pyrones from Meldrum's acid

Abstract A unique approach to the synthesis of mono and disubstituted γ-pyrones from acylated Meldrums acid and vinyl ethers has been developed. The convenient one pot synthesis of these versatile polyketide equivalents is accomplished without strong base or low temperatures.