Reactions of hexadehydro-Diels-Alder benzynes with structurally complex multifunctional natural products

Abstract

An important question in organic chemistry concerns the extent to which benzynes-one of the classical reactive intermediates in organic chemistry-can react in discriminating fashion with trapping reagents. In particular, whether these species can react selectively with substrates containing multiple functional groups and possible sites of reactivity has remained unanswered. Natural products comprise a palette of multifunctional compounds with which to address this question. Here, we show that benzynes produced by the hexadehydro-Diels-Alder (HDDA) reaction react with many secondary metabolites with a preference for one among several pathways. Examples demonstrating such selectivity include reactions with: phenolics, through dearomatizing ortho-substitution; alkaloids, through Hofmann-type elimination; tropolone and furan, through cycloaddition; and alkaloids, through three-component fragmentation-coupling reactions. We also demonstrate that the cinchona alkaloids quinidine and quinine give rise to products (some in as few as three steps) that enable subsequent and rapid access to structurally diverse polyheterocyclic compounds. The results show that benzynes are quite discriminating in their reactivity-a trait perhaps not broadly enough appreciated.

Figure 1. The two-stage hexadehydro-Diels-Alder (HDDA) cascade

Thermal activation of appropriate triyne substrates leads, through initial (and rate limiting) cycloisomerization, to highly reactive benzyne intermediates (stage I) that efficiently engage trapping agents (stage II) by reaction with a variety of common functional groups. a, This work: the benzyne trapping agents comprise various, multifunctional natural products that present multiple potential sites for reaction. b, Representative, known examples of trapping reactions of HDDA-benzynes with common functional groups.

Figure 2. Different modes of reaction between a benzyne (2 or 8) and various phenolics

Phenols react with HDDA benzynes by either a phenol-ene type of process or, in the presence of a tertiary amine that outcompetes this ene reaction, by providing a proton that then leads to a three-component reaction. a, Phenol (3a) or 2,4,6-trimethylphenol (3b) is trapped by benzyne 2 through a phenol-ene-like reaction. b, Vitamin E (7) is engaged by both benzynes 8 and 2 in the same manner; the internal bond angles x and y at the sp-hybridized carbon atoms in benzyne 8 were computed by density functional theory (DFT, M06-2X/6-31+G**). c, Estradiol derivatives 11a and 11b are trapped by 2 and 8, respectively, to produce phenolic ene adducts 12 and 13. d, In a three-component process initiated by attack of 1,4-diazabicyclo[2.2.2]octane (DABCO, 14), zwitterion 16 is protonated by, in this case, benzotriazole (15); ring-opening within the ion pair 17 gives 18. e, In the presence of DABCO, vitamin E (7) [or estradiol (11c)] plays a new role, that of proton-donor and nucleophile to capture the more rapidly formed zwitterion 16; ring-cleavage of the quaternary ammonium ion (cf. 17) by the phenoxide counterion then gives 19 (or 20).

Figure 3. Reactions with tertiary amines

Alkaloids with tertiary amines are fragmented via Hofmann-type elimination reactions. a, b, c, Tropinone (21) reacts with 6 (via 8), o-benzyne, or 25 (via 26) to give adduct 23, 24, or 27a–b; each of these products contains a substituted cycloheptenone, a relatively rare substructural moiety, that is functionalized in a manner that allows for subsequent chemical modification. d, Scopolamine (28) and 8 give diastereomeric adducts 30a and 30b (ca. 1:1) via zwitterion 29; this shows the compatibility of alcohols as well as vinylic epoxides in the reaction medium. e, Sinomenine (31) and 8 give the isomeric dienone adducts 33a and 33b via the diastereomeric 1,3-zwitterions 32a and 32b, respectively.

Figure 4. Three-component reactions involving complex alkaloids

Three component reactions similar to those described above for DABCO (Fig. 2d and 2e) can be extended to structurally complex tertiary amine nitrogen centers such as those present in brucine (34) and reserpine (39). a, Brucine (34) and one of various phenols give adducts 37-Δ²⁰ and/or 37-Δ²¹ (and 38) via 35 and the allylic aza-ylide 36. b, The HDDA-benzyne activates the CD-fusion bond in reserpine (39) toward cleavage; the iminium ion 40 is then trapped by the in situ-generated Nuc⁻ counterion from a phenol or benzotriazole to produce the azecane derivative 41.

Figure 5. Net cycloaddition reactions between benzynes and conjugated π-systems

The cycloheptatrienone in colchicine (42) reacts in an unexpected fashion with a HDDA benzyne, whereas the furan in limonin (48) behaves in a well-precedented mode. a, Tropolone-containing colchicine (42) and the HDDA-benzyne 8 gives the all-fused hexacycle 45. b, Colchicine and o-benzyne [via Kobayashi generation] leads, instead, to a product, 46, having a bridged motif. c, Colchicine and triyne 25 gives the benzofuran 47 (via benzyne 26). d, The furan in limonin (48) is efficiently trapped by the benzyne 8 to give the DA cycloadducts 49.

Figure 6. Quinidine (50) and quinine (54) derivatizations via benzynes 8 and 56

Cinchona alkaloids present at least six different sites for reaction with an HDDA benzyne, so it is remarkable that they react largely through a single mode. a, Quinidine (50) is trapped by the distorted benzyne 8 to give the epoxide 52 as the predominant product, presumably through the intermediate 51; similarly quinine (54) leads to the bis-epimeric epoxide 53 (not explicitly shown, see SI). b, Quinine traps the less distorted benzyne 56 competitively at both benzyne carbon atoms to give the (easily separable) constitutional isomers 57a and 57b. c, Examples of products having diverse substructural units that arise from straightforward modification of 57b (58 and 60), 53 (59), or 57a (61 and 62).