An enantioseletive, biomimetic synthesis of (-)-longithorone A has been achieved using an intermolecular/transannular Diels-Alder sequence which provides some support for the proposed biosynthesis. The cycloaddition precursors were two [12]-paracyclophanes that were constructed with atropisomer control during ene-yne metathesis macrocyclizations.

We present a full report of our enantioselective synthesis of (؊)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared atropselectively, providing examples of ene-yne metathesis macrocyclization. The 1,3-disubstituted dienes produced from the macrocyclizations represent a previously unreported substitution pattern for intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were used as removable atropisomer control elements and were installed by using a highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and 27.A n intriguing question in natural product biosynthesis is whether nature uses Diels-Alder reactions. The answer to this question appears to be yes, because there are many examples of spontaneous Diels-Alder reactions in biosyntheses (1) as well as recently documented examples (2-4) of enzymatically influenced Diels-Alder reactions. Longithorone A (1) is a marine natural product that attracted our attention because of its unusual structure, but even more so because of the biosynthetic proposal of Schmitz and co-workers (5, 6) that invoked two Diels-Alder reactions. Schmitz has proposed that 1 arises from the combination of [12]-paracyclophane quinones 2 and 3 by an intermolecular Diels-Alder reaction, affording ring E, and a transannular (7) Diels-Alder reaction, generating rings A, C, and D (Fig. 1).We viewed this interesting proposal as an opportunity to use organic synthesis to make protected versions of 2 and 3 and test, in the laboratory, the feasibility of the proposed Diels-Alder reactions (8). In particular, we were hopeful that our experiments might suggest whether the intermolecular Diels-Alder reaction occurs preferentially between compound 4, which has already undergone a transannular Diels-Alder, and paracyclophane 2 to generate 1 or between paracyclophanes 3 and 2 to generate 5, followed by a transannular Diels-Alder to afford 1.The isolation (5) of longithorones B (9) and C, [12]-paracyclophane quinones that closely resemble the structures of 2 and 3, provided some support for the proposed biosynthesis of longithorone A (Fig. 2).We found it intriguing that longithorones B and C exhibit atropisomerism (10-12) and are single enantiomers. From these observations, we recognized that 2 and 3 must be constructed atropselectively to test whether the absolute and relative stereochemistry of 1 is derived solely from the planar chirality of 2 and 3. Finally, the isolation of longithorone I suggested that the biosynthesis of 1 may first involve an intermolecular Diels-Alder reaction between 2 and 3 followed by a...

The single-crystal X-ray structures of 6-(4-(dimethylamino)phenyl)-6-methylfulvene (2) and of two polymorphs of 6-(4-(dimethylamino)phenyl)-6-phenylfulvene (3(P21/c) and 3(Pca21)) have been determined and the structures of a series of 6-arylfulvenes (1−8) have been optimized at the HF/6-31G level. Analysis of these structures reveals how resonance and crystal lattice effects influence the degree of coplanarity between the aryl and fulvene rings. The torsional angles at the aryl−fulvene bonds are significantly larger in the optimized structures than in the X-ray structures. Natural bond orbital π charges and dipole moments calculated for the X-ray and optimized structures show that the crystalline environment enhances molecular polarization. Qualitative responses for second harmonic generation in powder samples have been observed in 2, 3(Pca21), and 5. Compounds 2 and 3(Pca21) have similar packing motifs despite packing in different space groups.