Aplyviolene (1) and macfarlandin E (2, Figure 1A) are representative of the more complex members of the rearranged spongian diterpene class of natural products.[1,2] These diterpenes are structurally defined by attached cis-perhydroazulene and 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one fragments. The substantial challenge in assembling these structures centers on the construction of the sensitive bicyclic lactone subunit and the formation of the C8–C14 σ-bond joining the two ring systems, a challenge augmented by the quaternary nature of C8.[3] We previously reported preparation of the lactone subunits of 1 and 2 by the synthesis of truncated congeners 3 and 4 (Figure 1A),[4] as well as the first total synthesis of aplyviolene (outlined in Figure 1B).[5] In this latter effort, the key C8–C14 σ-bond was formed by Michael addition of tertiary enolate 5 to enone 6.[6] Subsequent elaboration of product 7 provided intermediate 8, which was converted to (−)-aplyviolene along the lines of our earlier synthesis of 3. Undesirable aspects of this first-generation synthesis are the lengthy preparation of the cis-perhydroazulene unit and the need to remove the extraneous ketone carbonyl group from the product of the fragment-coupling step.

/pdf/a-concise-synthesis-of-aplyviolene-facilitated-by-a-2zczjk5jif.pdf

A concise synthesis of (-)-aplyviolene facilitated by a strategic tertiary radical conjugate addition.

b. Ring Closures of the Two-Carbon Bridge 42 c. Ring Closures of the One-Carbon Bridge 44 9. Free Radical-based Methods 44 a. Reductive Methods 44 b. Oxidative Methods 47 10. Organometallic-Based Methods 48 a. Iron Carbonyl Chemistry 48 b. Palladium Chemistry 49 11. Miscellaneous Methods 50 a. Wittig Olefination 50 b. Photochemical Rearrangements 51 c. Prins Reaction 51 IV. Cycloadditions and Other Electrocyclizations 51 1. [4+2] Cycloadditions 51 2. [5+2] Cycloadditions 52 3. [4+3] Cycloadditions 53 4. [3+2] Cycloadditions 54 5. [2+2+2] Cycloadditions 54 6. Ene-Type Cyclizations 54 7. Sigmatropic Rearrangements 55 V. Ring Expansion of Bicyclo[2.2.1]heptanes 55 VI. Rearrangement of Polycyclic Intermediates 58 1. Isomerization of Bicyclo[2.2.2]octanes 58 2. From Cyclopropane-Containing Intermediates 60 3. From Cyclobutane-Containing Intermediates 61 4. From Bridged Bicyclononane Precursors 62 VII. Reactivity 63 1. Fragmentations Leading to Nonbridged Carbocycles 63

Synthesis of Functionalized Bicyclo[3.2.1]octanes and Their Multiple Uses in Organic Chemistry.

Asymmetric catalysis provides outstanding tools to introduce chiral information to a substrate by using only catalytic amounts of a chiral transition-metal complex. The success of these efficient asymmetric processes relies on the development of chiral ligands that form a complex with the metal; until very recently phosphorus-, nitrogen-, and oxygen-containing chiral ligands were the only ones available. Recently, the groups of Hayashi and Carreira independently reported the use of chiral dienes in asymmetric catalysis: high levels of enantioselectivity were achieved in both the iridiumcatalyzed kinetic resolution of allyl carbonates and the rhodium-catalyzed 1,4-additions of organoboron reagents to Michael acceptors. Major efforts in the development of these chiral diene ligands have been focused on the latter reaction and on the related rhodium-catalyzed addition of organoboron reagents to imines. In comparison to the use of phosphorus ligands, diene ligands allowed reactions to be conducted at room temperature with low catalytic amounts of the rhodium catalyst. In the rhodium-catalyzed asymmetric 1,4-additions, only C2-symmetric (or C2-like) disubstituted dienes allowed high levels of enantioselectivity. Although such dienes are easily accessed, their syntheses are generally low yielding, requires either chiral chromatographic separation, asymmetric catalysis, or the introduction of the first substituent early in the synthesis, therefore preventing straightforward access to diene libraries. Moreover, it appeared that ligands derived from a bicyclo[2.2.1]heptadiene core showed moderate stability, and that the bicyclo[2.2.2]octadiene framework was the most suitable for the rhodium-catalyzed addition of organometallic reagents to Michael acceptors in terms of the enantioselectivity. 8] The space around the rhodium center coordinated to C2-symmetric chiral dienes is quite similar to that of the rhodium coordinated to a conventional C2-symmetric chiral phosphorous ligands such as 2,2’-bis(diphenylphosphanyl)1,1’-binaphthyl (binap). In the bis(phosphanyl), chirality is frequently controlled by the face/edge orientation of the aryl substituents at the phosphorus atom; whereas for dienes, the chirality is controlled by the substituents attached to the double bonds. 8] Because of their straightforward preparation, we wondered if C1-type diene ligands, bearing only one substituent could be employed in rhodium-catalyzed 1,4-addition reactions with comparable efficiency. Actually, such C1-type diene ligands proved useful only in the iridiumcatalyzed kinetic resolution of allyl carbonates. In our continuing work on rhodium-catalyzed reactions involving organoboron reagents, we report herein that the C2-symmetry of a chiral diene ligand is not necessary to achieve high enantioselectivities in rhodium-catalyzed 1,4-additions, and that easily accessible (only four steps) monosubstituted dienes withC1-symmetry compare favorably to these disubstituted dienes. The synthesis of chiral monosubstituted diene ligands was inspired by the work of Carreira and co-workers. Enantiopure ketoneA (Scheme 1) was prepared in two steps on large

C1‐Symmetric Monosubstituted Chiral Diene Ligands in Asymmetric Rhodium‐Catalyzed 1,4‐Addition Reactions

In modern drug discovery, antibodies or libraries of simple synthetic organic compounds, mostly of heterocyclic origin, are favored. Natural products play an increasingly inferior role as they are considered structurally too complex, limited in quantity, and difficult to synthesize, manipulate, and derivatize. Thus it was a sensation when a Merck research group reported that classical screening of metabolites from Streptomyces platensis has unearthed a low-molecular-weight organic compound with remarkable antibiotic properties.

Synthesis of Platensimycin

Intramolecular free radical conjugate additions

Radical cyclization of the bromo enones 2a-e, obtained by regiospecific bromoetherification reaction on theelectron-rich double bond of (S)-carvone (l), furnished regio- and stereospecifically bicyclo[3.2.1]octan-3-ones 3a-e and 4a-e. Analogously, radical cyclizations of the alcohols 6 and 7 gave bicyclo[3.2.1]octan-3-ols 8 and 9,and the bromo enones lla,b gave the bridgehead-substituted bicyclo[3.2.l]octan-3-ones 12a,b and 13a,b.

Chiral synthons from carvone. Part 4. Radical cyclization strategies to bridged systems. Synthesis of bicyclo[3.2.1]octan-3-ones from (S)-carvone

Intramolecular alkylation reaction of the bromoenone 12, obtained from S-carvone in three steps furnished the bicycle[222] octenone 13 Contrary to the anticipated radical annulation reaction, the bicyclic bromides 14 and 15, obtained from the enone 13, generated exclusively the cyclopropane product 18 via a 3-exo trig radical cyclization on reaction with nBu3SnH and AIBN, even in the presence of a large excess of a radicophile On the other hand, bromoenone 24, synthesized from R-carvone via S-naphthylcarvone 21, underwent radical annulation reaction in the presence of radicophiles to furnish the isotwistanes 25-28 in a regio- and stereospecific manner Hydrogenation of the olefin 34, obtained from the diketone 27 via a regiospecific Wittig reaction, furnished the naphthyl-5-epipupukean-9-one 33, whereas stereoselective hydrogenation of the enone 36, prepared from the keto ester 25 via a Grignard reaction and dehydration sequence, generated the naphthylpupukeanone 32

Chiral synthons from carvone. 9. Radical annulation strategy to chiral pupukeanones: total synthesis of (+)-10-exo-(1-naphthyl)pupukean-9-one and (+)-10-exo-(1-naphthyl)-5-epipupukean-9-ones

Generation of the thermodynamic dienolate of 9-bromocarvone derivatives 5,7 and 11 furnished the chiral bicyclo[2.2.2]octenones 6, 8 and 9 and 12 and 13 containing a bridgehead methyl group via an intramolecular alkylation reaction. In an analogous manner intramolecular alkylation reaction of the bromo enones 15a–e, obtained from carvone 2 by 1,3-alkylative enone transposition (→14) followed by a regiospecific bromoetherification reaction, furnished the bicyclo[2.2.2]oct-5-en-2-ones 16a–e and 17a–e.

Synthesis of chiral bicyclo[2.2.2]oct-5-en-2-ones via an intramolecular alkylation reaction

A regiospecific radical annulation strategy to functionalised chiral bicyclo[3.3.l]nonanes

A regio and stereospecific radical annulation route to chiral tricyclo[4.3.1.o3,7]decane (isotwistane) system1 synthesis of (+)-10-α-Naphthyl-5-epi-Pupukean-9-one

P. Hemamalini

Papers

Chiral synthons from carvone. Part 4. Radical cyclization strategies to bridged systems. Synthesis of bicyclo[3.2.1]octan-3-ones from (S)-carvone

Chiral synthons from carvone. 9. Radical annulation strategy to chiral pupukeanones: total synthesis of (+)-10-exo-(1-naphthyl)pupukean-9-one and (+)-10-exo-(1-naphthyl)-5-epipupukean-9-ones

Synthesis of chiral bicyclo[2.2.2]oct-5-en-2-ones via an intramolecular alkylation reaction

A regiospecific radical annulation strategy to functionalised chiral bicyclo[3.3.l]nonanes

A regio and stereospecific radical annulation route to chiral tricyclo[4.3.1.o3,7]decane (isotwistane) system1 synthesis of (+)-10-α-Naphthyl-5-epi-Pupukean-9-one