The field of total synthesis has a rich history and a vibrant future. Landmark advances and revolutionary strides in the logic of synthesis have put the practicing chemist in the enviable position of being able to create nearly any molecule with enough time and effort. The stage is now set for organic chemists to aim for "ideality" in the way molecules are synthesized. This perspective presents a simple and informative definition of "ideality" and demonstrates its use during the self-evaluation of several syntheses from our laboratory.

Aiming for the Ideal Synthesis

The longstanding challenge posed by the complex diterpene vinigrol has been answered for the first time. The notorious difficulty in synthesizing vinigrol stems from its unprecedented decahydro-1,5-butanonaphthalene ring system, eight contiguous stereocenters, and highly congested functionality. This Communication delineates a stereocontrolled 23-step route to vinigrol that is scalable (>5 g prepared of a late-stage intermediate), minimally reliant on protecting group chemistry, and facilitated by a number of unique and chemoselective transformations.

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Total Synthesis of Vinigrol

2.2.2. Hetero [4 + 2] Cycloadditions 1711 2.2.3. Other [4 + 2] Cycloaddition Reactions 1712 3. [n + m] Cycloaddition Reactions 1713 3.1. [3 + 2] Dipolar Cycloadditions 1713 3.1.1. 1,3-Dipolar Cycloaddition of Nitrones 1713 3.1.2. Metal-Catalyzed [3 + 2] Cycloadditions 1714 3.2. [5 + 2] Cycloadditions 1714 3.3. [8 + 2] Cycloadditions 1715 3.4. [4 + 3] Cycloadditions 1716 3.5. [6 + 3] Cycloadditions 1717 3.6. [6 + 4] Cycloadditions 1717 4. Molecular Rearrangements 1717 4.1. Ring Rearrangements 1717 4.2. Schmidt Reactions 1719 4.3. Pinacol Rearrangements 1720 4.4. Claisen/Diels-Alder Cascade Process 1720 4.5. Polonovski Rearrangements 1720 4.6. Prins-Type Reactions 1720 5. Free-Radical Reactions 1722 5.1. Intramolecular Radical Cycloadditions 1722 5.2. Other Radical Reactions 1723 6. Transition-Metal-Catalyzed Cyclization Reactions 1724 6.1. Gold-Catalyzed Reactions 1724 6.2. Cu(II)-Catalyzed Cyclizations 1724 6.3. Rhodium-Catalyzed Reactions 1724 6.3.1. Rh(II)-Catalyzed Reactions 1724 6.3.2. Rh(I)-Catalyzed Reactions 1725 6.4. Palladium-Catalyzed Reactions 1725 7. Other Reactions 1726 7.1. Iodine-Promoted Cyclizations 1726 7.2. Pictet-Spengler Cyclizations 1727 7.3. Nucleophilic Substitutions 1727 7.4. Nucleophilic Additions 1729 7.5. Aldol-Type Condensation Reactions 1730 7.6. Friedel-Crafts Cyclizations 1731 7.7. Ring-Closing Metathesis 1731 8. Important Classes of Compounds 1732 8.1. Reactions in Synthesis of FR66979 and FR900482 1732

Novel syntheses of bridge-containing organic compounds.

The coupling of building blocks 15 and 36e in the presence of MgBr2·OEt2 at 0 °C proceeds with an exo stereoselectivity (3.2:1) considerably more advantageous for the acquisition of carbinol 37e than in the absence of the additive (exo/endo = 1:5.7). The pivotal transformation that sets all of the relevant stereocenters of the cis-octalin 55 is the oxyanionic-accelerated [3,3]-sigmatropic rearrangement of 37e. A salient feature is the structurally enforced adoption of a boatlike transition state that serves to properly set four vicinal methine hydrogens in an all-cis arrangement. The ensuing conversion of 55 into iodo sulfone 62 has permitted X-ray crystallographic confirmation of all absolute stereochemical assignments since the isopropyl substituent was initially installed enantioselectively via the Evans oxazolidinone protocol. No intramolecular anionic cyclization of 62 to generate the tricyclic framework was seen. This absence of reactivity is attributed to conformational factors that inhibit attainm...

Convergent enantioselective synthesis of vinigrol, an architecturally novel diterpenoid with potent platelet aggregation inhibitory and antihypertensive properties. 1. Application of anionic sigmatropy to construction of the octalin substructure.

In 1987 Hashimoto and co-workers isolated the unusual diterpene vinigrol (1) from the fungal strain Virgaria nigra F5408. The promising biological properties of 1 combined with its unique terpene framework has attracted significant attention from the synthetic community (17 publications and 4 dissertations on studies towards 1, no total synthesis reported). From a chemical standpoint, vinigrol provides a particularly difficult challenge, as it is the only natural product to contain the decahydro-1,5-butanonaphthalene carbon skeleton. As such, it holds a special place alongside other historically challenging diterpene systems such as the ingenanes, taxanes, and phomactins (see Figure 1). Although 1 is

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A Concise Approach to Vinigrol

The first synthesis of a functionalized tricyclic skeleton of vinigrol is described. The key step involved an anionic oxy-Cope rearrangement of bicyclic allylic alcohol 18, readily prepared by highly stereoselective addition of vinyl magnesium chloride to the hydroxy enone 15b. Introduction of the tertiary hydroxy group at carbon 8a was achieved by an unexpected hydration of 30 with aqueous trifluoroacetic acid.

Studies toward the Synthesis of Vinigrol. First Construction of the Tricyclic Ring System

Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

An unexpected acid-catalysed rearrangement of the tricyclic system of vinigrol to the fusoxysporone skeleton

Studies Toward the Synthesis of Vinigrol. First Construction of the Tricyclic Ring System.

An unprecedented remote effect of the hydroxyl group on π-facial selectivity was observed in the addition of Grignard reagents to bicyclo[2.2.2]octan-2-ones, where nucleophilic attack occured from the slerically more hindered face.

J.‐F. Devaux

Papers

Studies toward the Synthesis of Vinigrol. First Construction of the Tricyclic Ring System

Unexpected effect of an hydroxyl group on π-facial selectivity in the nucleophilic addition to bicyclo[2.2.2]octan-2-ones

An unexpected acid-catalysed rearrangement of the tricyclic system of vinigrol to the fusoxysporone skeleton

Studies Toward the Synthesis of Vinigrol. First Construction of the Tricyclic Ring System.

Unexpected Effect of an Hydroxyl Group on π-Facial Selectivity in the Nucleophilic Addition to Bicyclo(2.2.2)octan-2-ones.