The Art of Problem Solving in Organic Chemistry, 2nd Ed. Supplementary Material for Problem Miguel E. Alonso Amelot PROBLEM 56

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1 PROBLEM 56 [SUPPL Problem 56 # 1] In Perspective The central issue here is the construction of five membered carbocycles, something of an obsession among several synthetic chemists. Why is this? Very many natural products contain this structural motif, and plant and marine organism secondary metabolites have always been and continue to be luminous beacons to guide organic chemistry from its early beginnings once chemists got tired of extracting coal tar compounds in the XIX th century (fossil natural products anyway...). A few examples are depicted in Figure SP56.1.1, remarkable as they are because of potent biological activities or owing to their structural complexity, an enticing challenge for many. These compounds are found in small amounts in nature and their study demand newer, selective and higher yielding methods for a battery of tests. Arabic compound numbers in TAPSOC, Roman numerals in Supplementary material FIGURE SP A few relevant cyclopentanoid secondary metabolites

2 Numerous fragrances and pharmaceuticals are synthesized from substituted cyclopentanes and cyclopentanones. A few recently published syntheses of cyclopentenones with good control over the substituents are depicted in Scheme SP Some of them share in common the intramolecular condensation of HEDZ and LEDZ at five carbons distance, while others take more ingenious and rearrangement pathways. The first example (VI VII) is a classical transannular condensation of adipic acid followed by decarboxylation [1]. The conceptual basis was established by Charles Friedel in 1862, the mechanism. If this is an elementary old reaction the mechanism is still a subject of debate. Besides, it provides a useful profit for an accumulative and cheap feedstock obtained from industrial oxidations of cyclohexene. The chiral carbon maintains its integrity all along. In cases where only catalytic amounts of a given compound, Na 2 CO 3 in this case, following the fate of he catalytic species is essential to clarify the mechanism as shown in Scheme SP SCHEME SP A conceptually more interesting synthesis is the radical-mediated cyclization of aldehydes on alkenes with a sensitive group an alkene- at appropriate distance to

3 prompt the ring closing. Five and six membered ketones are generated in fair to good yield. The mechanism is interesting in that the process goes through a radical relay mechanism starting with AIBN (see below), then on to an aliphatic thiol which finally reaches the aldehyde substrate (Scheme SP56.1.2) [2]. Interaction between this carbonyl radical and the neighboring alkene finish the process. A variety of five and six-membered rings are accessible by this procedure. Upon heating one mole of AIBN provides two moles of 2-cyanopropane radicals which can be used more safely than benzoyl peroxide, and a good substitute of tributyltin hydride (TBTH), NBS and others. Radicals from AIBN can be used in combination with TBTH in a variety of radical reactions including anti-markovnikov additions to alkenes (during halogenations, for instance). Having n-bush in the reaction of Scheme SP56.1.2, the radical transfer down to C=O in the organic substrate needs to be accounted for (part I of this scheme). This takes place via two step propagation. Overall the thiol is recovered for another catalytic cycle. The rest of the sequence is rather trivial. Please pay attention to the regioselectivity difference between the anionic and radical reactions on the same substrate (XVII). Transannulation to cyclopentanones worked well with aryl or EWG near the alkene, but if the distance between C=O and C=C was such that chanced the six vs seven-membered ring dilemma (as in XXII XXIII/XXIV), cyclohexanones were the main product.

4 SCHEME SP Reactions for cyclopentane synthesis in the natural products field have come a long way to include the construction of three fused cyclopentanoid scaffolds in one single step as Scheme SP portrays [3].

5 SCHEME SP Having solved so many problems in this workbook by now the mechanics of this reaction should be quite easy for you. Anyhow, a cursory explanation is pictured on next page after the references. Please pay attention to stereochemistry. REFERENCES [1] Renz M, Corma A. Eur. J. Org. Chem. 2004; [2] Yoshikai K, Hayama T, Nishimura K, Yamada K, Tomioka K. J. Org. Chem. 2005;70: [3] This reaction is part of an extended study of professor R. Little and his collaborators in the 80 s on the synthesis of twisted polycyclic natural products chiefly by radical intermediates. For this particular reaction see: Van Hijfte, L, Little RD. J. Org. Chem. 1985;50: ; Van Hijfte, L, Little RD, Petersen JL, Moeller KD. J. Org. Chem. 1987;52:

6 SCHEME SP56.1.4