The Art of Problem Solving in Organic Chemistry, 2nd Ed. Supplementary Material for Problem Miguel E. Alonso Amelot PROBLEM 21

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1 PROBLEM 21 [SUPPL Problem 21 # 1] In Perspective Compounds 2 and 3 are C 20 terpenoids, that is diterpenes, isolated from a tropical marine organism Pseudopterogorgia elisabethae [1]. This species was captured near the Caribbean island of San Andrés. Perhaps because this is part of Colombia s insular territory compound 2 was appropriately baptized as colombiasin A. Several other metabolites with rearranged molecular skeletons are also produced by this animal. More interesting than this compound s name is its potent activity against fearsome Mycobacterium tuberculosis strains resistant to antibiotics, a serious threat to society at this point. The complex structure of these terpenoids possessing 6 and 7 chiral carbons has attracted much attention from the synthetic community. Professor David Harrowven s group at the University of Southampton, UK, managed to obtain these two compounds in optically pure form from (-)-dihydrocarvone, taking advantage of the two asymmetric centers of this compound and building the stereo-complexity from such a humble start. The reaction of Scheme 21.1 collects the most remarkable step of the total synthesis of (-)-colombiasin A and its mate, (-)-elisapterosin B (3) after very few manipulations on carefully built cyclobutenone 1 without resorting to sophisticated reagents. Intuitively, compounds 2 and 3 seem structurally related in some way, an idea compounded by their common origin. Both compounds comprise four rings. Clockwise, 2 has a 6,6,6,5-membered structure whereas 3 possesses 5,6,6,5-membered carbocycles.

2 In both, clear traits of a p-quinone, four methyls and, most importantly, similar oxidation level as shown by functionality numbers [FN t (2) = FN t (3) = 9] are discernible. This perception strongly suggests common mechanistic features leading to either compound, so solving 1 2 should pave the way to 1 3. Synthesis of 1. The synthesis of this squarate derivative is of additional interest to this problem. A first retrosynthetic sketch (Scheme SP21.1.1) shows the composing pieces of this particular design [2]. A series of more or less classical steps from the obvious precursor: (-)- dihydrocarvone (VI) give rise to dienyl ketone II (see Scheme SP21.1.2). The chirality of this compound, carried over from VI must exert stereochemical control of reactions performed on I. SCHEME SP However, this idea includes the coupling of two LEDZ carbons at the II + III level. Often we have encountered such a combination with a variety of ideas to come round. Here is an additional method to achieve this addition reaction, which turns the

3 C=O in II into a potent nucleophile: the Shapiro reaction. In this particular instance, however, it failed to yield a decent yield of adduct I so it had to be modified by employing trimethylsilylhydrazine instead of Shapiro s tosylhydrazine to succeed. The n-buli treatment was effected at -20 ºC. Can you work out the mechanism of this particular reaction (IX I)? The answer is shown in Scheme SP21.1.3, on next page. SCHEME SP21.1.2

4 SCHEME SP First, pay attention to excess nbuli employed (4 eq.) which supports the dianion proposal. Secondly, in a non symmetrical substrate like IX, two anions in the cyclohexyl scaffold are possible, defining diverging routes A and B. This touches upon the old question of thermodynamic vs. kinetic anions in unsymmetrical ketones and their homologs like hydrazone IX. At -20 ºC kinetic control should supersede thermodynamic governance favoring route B, in accordance with experimental evidence [2].

5 REFERENCES [1] Rodríguez AD, Ramírez C, Rodríguez II, Barnes CL. J. Org. Chem. 2000;65: [2] Harrowven DC, Pascoe DD, Denurtas D, Bourne HO. Angew. Chem. Int. Ed. 2005;44: