Enantiodivergent Synthesis of Either Enantiomer of ABCDE-Ring Analogue of Antitumor Antibiotic Fredericamycin A via Intramolecular [4 + 2] Cycloaddition Approach

Abstract

[reaction: see text] An intramolecular enantiodivergent synthesis of both enantiomers of the ABCDE-ring analogue 22 of fredericamycin A is reported. Key steps involve an intramolecular [4 + 2] cycloaddition of 17 and an aromatic Pummerer-type reaction of 19. A lipase-catalyzed enantioselective desymmetrization of prochiral diol 2 using 1-ethoxyvinyl 2-furoate 3 led to the pivotal intermediate (R)-4.

Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

“…[10] It is worth noting that among the large number of synthetic studies towards the asymmetric total synthesis of natural 1 as well as its analogues, [9] successful examples have been limited to only our two routes (Scheme 1). During this and our previous studies, [13,29] we have disclosed the latent risk of racemization of the stereogenic quaternary carbon center of the compounds, such as 39, bearing an a,a-disubstituted b-hydroxycarbonyl moiety. The racemization took place under basic conditions by the retro-aldolaldol process; however, these issues were solved by the choice of the proper reaction conditions.…”

“…[13] With these promising results in hand, we intended to apply this desymmetrization protocol to the prochiral 1,3-diol 9 a, [25] followed by the conversion of the product to the pivotal dione intermediate (S)-8. However, the reaction conducted under similar conditions (iPr 2 O at 408C) was very sluggish due to the very poor solubility of 9 a, and provided the product with unsatisfactory enantioselectivity Scheme 2.…”

“…[13] Thus, the treatment of (R)-25 (96 % ee) with lithium phenylthioacetylide at À78 8C, followed by the warming of the resulting reaction mixture to room temperature, produced the adduct 39 b (28 % yield) as the only identifiable product (Scheme 8). In this case, the optical purity of 39 b could be determined by HPLC analysis by using a chiral column.…”

“…This follows our previous report on the enantiodivergent synthesis of both enantiomers of the ABCDE-ring analogue by a similar intramolecular cycloaddition pathway. [13] This protocol features the following advantages: 1) the enantiodivergent preparation of either enantiomer can be achieved with perfect retention configuration and 2) this methodology is applicable to various analogues by changing the A-ring moiety [12a,e] or the DE(F)-ring diols, and provides an effective alternative to our intermolecular cycloaddition pathway. [10] It is worth noting that among the large number of synthetic studies towards the asymmetric total synthesis of natural 1 as well as its analogues, [9] successful examples have been limited to only our two routes (Scheme 1).…”

“…The majority of these total syntheses, and the related model studies, involved the construction of the spiro C-or D-ring during the final stage of the synthesis; however, the lack of sufficient methods that can distinguish between the enantiotopic faces of the highly symmetrical ABC-plane has been the most probable obstacle in the application of these methods to asymmetric synthesis. To date, no group besides our own (vide infra), [10][11][12][13] has succeeded in the asymmetric construction of the optically active spiro system of 1, and even the methods that could be potentially applicable to the asymmetric synthesis of 1 are few. [9h, 14] Boger and his colleagues reported that the L1210 cytotoxic activities of 1 and its enantiomer were similar, and that a racemic ABCDE-ring analogue was less potent.…”