Unnatural natural products from the transannular cyclization of lathyrane diterpenes

The potential of macrocyclic diterpenoids to afford natural product-like polycyclic compounds was demonstrated by the conversion of two lathyrane Euphorbia factors into a series of densely functionalized diterpenoids of unnatural skeletal type. Apparently, Nature is far from having fully exploited the built-in reactivity of these compounds to generate chemical diversity.     

Synthesis and transannular diels-alder reaction of a cis-trans-trans 13-membered macrocyclic trienone

Upon heating at 300°C, CTT macrocyclic trienone 17 underwent 1,5-H shift and/or transannular Diels-Alder yielding three tricyclic isomers 18, 19, and 20.     

Synthesis and transannular diels-alder reaction of a trans-cis-cis 13-membered macrocyclic trienono

Upon heating at 300°C, TCC trienone 14 gave tricyclic ketone 15.     

Synthesis of the core structure of apicularen a by transannular cyclization

[reaction: see text] An approach to the macrocyclic core of apicularen A is described. Thus, cross-coupling of the aryl triflate 7 with the vinylstannane 19 provided the styrene 20. Deprotection led to the dihydroxy acid 22. Through a size-selective macrolactonization, the 12-membered macrolactone 23 was obtained. Treatment of 24 with N-phenyl selenophthalimide gave the desired trans-pyran 24. This approach might parallel the biosynthetic pathway.     

Isolation and structure of koshikalide,a 14-membered macrolide from the marine cyanobacterium Lyngbya sp.

A 14-membered macrolide, koshikalide (1), was isolated from the marine cyanobacterium Lyngbya sp., and its planar structure was elucidated by spectroscopic analysis. The relative stereochemistry of C-11 and C-13 was elucidated by NOESY experiments and by an analysis of ¹H–¹H coupling constants. Koshikalide (1) exhibited weak cytotoxicity against HeLa S₃ cells.     

Synthesis of an austrodorane sesquiterpenoid core via a transannular Prins cyclization

The bicyclo[4.3.0]nonane core of the austrodorane family of sesquiterpenoids has been synthesized via a novel transannular Prins cyclization. This strategy formed the fused 5,6-ring system and installed the required quaternary stereocentre at the ring fusion in a single step.     

Oxiranylcarbinyl rearrangement: the effect of precursor stereochemistry

Rigid, bisected oxiranylcarbinyl mesylates solvolyzed $\text{via}$ an apparent oxiranylcarbinyl cation which rearranged to a 2-oxahomoallyl cation, while the perpendicular isomers gave displacement with inversion.     

Synthesis of the core of actinophyllic acid using a transannular acyl radical cyclization

A synthetic study of actinophyllic acid based on an original strategy has been described. A transannular acyl radical cyclization allowed us to obtain a key bicyclo[3.3.2] framework, and construction of a core of the target alkaloid has been accomplished by subsequent introduction of a C2 unit.     

Construction of bicyclic ring systems via a transannular SmI2-mediated ketone-olefin cyclization strategy

The development of novel methods and strategies for the formation of polycyclic ring structures is of utmost importance in organic synthesis. The present study describes the investigation of a transannular cyclization strategy for constructing bicyclic ring systems. To test the viability of the approach, the SmI2-mediated ketone-olefin coupling reaction, a method previously developed in this laboratory, was examined. Investigation of the transannular cyclization of cyclooctene, cyclodecene, and cycloundecene derivatives revealed that the process proceeds with high yield and diastereoselectivity, and in the case of larger ring-sized compounds, with excellent regioselectivity. The regioselectivity of the annulation process could be rationalized based on examining the low energy conformations of the keto alkene starting materials. These results demonstrate the efficiency and the potential of the transannular cyclization tactic for the creation of bicyclic ring systems.     

Synthesis and transannular diels-alder reaction of a 13-membered macrocyclic triene having a tetrasubstituted enol ether as a dienophile

Cyclization of TTC allylic chloride 22 gave TTC macrocycle 24 which was directly converted into a mixture of tricycles TST 25 and CSC 26.     

Iriomoteolide-3a, a cytotoxic 15-membered macrolide from a marine dinoflagellate amphidinium species

A 15-membered macrolide, iriomoteolide-3a (1), with an allyl epoxide has been isolated from a marine benthic dinoflagellate Amphidinium sp. (strain HYA024), and the structure was assigned by detailed analyses of 2D NMR data. Relative and absolute configurations were elucidated on the basis of conformational studies of 1 and its acetonide (2) and modified Mosher's method of 1, respectively. Iriomoteolide-3a (1) and the acetonide (2) exhibited potently cytotoxic activity against antitumor cells.     

Syntheses of second generation, 14-membered ring beta-turn mimics

Efficient solid phase syntheses of the constrained beta-turn peptidomimetics 1-3 were devised, and the conformational properties of three representative compounds in DMSO were determined.     

Synthesis and stereochemical elucidation of a 14-membered ring phosphonate

[structure: see text]. We report the synthesis and stereochemical elucidation of a 14-membered ring phosphonate. The key step in the synthesis of the macrolide phosphonate was the cyclization of the acyclic precursor using the Mitsunobu reaction, a mild reaction for the preparation of mixed phosphonates.     

A strategy towards the synthesis of plumarellide based on biosynthesis speculation,featuring a transannular 4+2 type cyclisation from a cembranoid furanoxonium ion intermediate

In studies towards a biomimetic synthesis of plumarellide 1, acid-catalysed rearrangement of the furanobutenolide-based acetonide 10b led to the ring system 15b in plumarellide together with the cycloheptene-based ring system 11 found in rameswaralide 4, in a combined yield of 60%. RCM of the ω-dienes 30a and 30b led to the macrocycles 38a and 38b, respectively with the Z-configuration. Treatment of the vinyl bromide/vinyl stannanes 32a and 47 under Stille conditions failed to give the macrocycles 31a and 48, respectively. Reactions of the macrocycles 38a and 38b with TFA containing water produced the 5,6,7-tricyclic compounds 56a and 56b, respectively in >90% yield, instead of the plumarellide-based ring system 52. A summary and perspective on possible pathways from the C-13 acetoxy furanocembranoid 66 and from the C13–C14 unsaturated enol ether/cyclic hemiketal 9/59 to plumarellide 1 in vivo is given.     

The stereochemistry of the methylenecyclopropane rearrangement: evidence against the orthogonal-allylic intermediate

The rearrangements of two optically pure derivatives of Feist's acid were studied: that of dimethyl trans-methylenecyclopropane-2,3-dicarboxylate (TRANS-diester) and trans-2,3-dicyano-methylenecyclopropane (TRANS-dinitrile). The optical purity and configuration of the products, methyl (Z)- and (E)2-carbomethoxyclopropylideneacetate (SYN- and ANTI-diesters) and (Z)- and (E)-2-cyanocyclopropylideneacetonitrile (SYN- and ANTI-dinitriles), establish that the rearrangements occur with predominant, but not exclusive, inversion of configuration at the migrating center. Investigation of the interconversions of (SYN)- and ANTI-diesters and dinitriles reveal that racemic product is not obtained, as would be expected from an orthogonal-allylic diradical intermediate, but that the enantiomer corresponding to antarafacial migration is slightly favored. All of the stereochemical results are explicable by application of the Doering-Sachdev diradical transition state hypothesis     

Synthesis of a novel 14-membered highly constrained cyclic peptidic scaffold

The synthesis and NMR analysis of a novel highly constrained scaffold is described. The 14-membered macrocyclic ring structure was inspired by many medicinally relevant natural products that also contain the bi-aryl ether moiety. The synthesis required only commercially available starting materials and involved a base mediated S_NAr cyclization. A conformational search was performed, which indicated a strong preference for a single conformation, which was consistent with observed ROE signals by NMR.     

Synthesis, reactivity and stereochemistry of new phosphorus heterocycles with 5- or 6-membered rings

Syntheses of novel phosphorus heterocycles containing α-amino or α-hydroxyphosphonic or phosphinic acids motifs are developed. 2,3-dihydro-1,3-oxaphospholes (1) and 1,4,2-oxazaphosphinanes (2) exhibit a reactive part, respectively the enolether moiety and the P-H bond, which allows various structural modifications: (i) for 1a, by introduction of amino substituents, (ii) for 2a, by hydroxy- or aminoalkylation, by Michael addition or by P-arylation. These reactions present generally a good or even an excellent kinetic diastereoselectivity which can often be predicted by molecular models of the transition states.