Highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton and ring-opening of the bridged ring via C–O bond cleavage

We report herein a highly efficient strategy for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton through [3 + 2] IMCC (intramolecular [3 + 2] cross-cycloaddition), and the substituents and/or stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the rhamnofolane, tigliane and daphnane diterpenoids. Furthermore, ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage was also successfully achieved.

Rhamnofolane, tigliane, and daphnane are three families of diterpenoids displaying a broad range of biological activities such as antiviral, anticancer, anti-HIV, immunomodulatory and neurotrophic activities. 1 Three representative members are neoglabrescin A 2 and curcusones I/J. 3 The unique structural features of these three compounds include a 5-7-6 tricyclic carbon skeleton with a trans-fused 5-7 bicyclic skeleton, a 4,7bridged oxa-[3.2.1]octane skeleton and a methylene (methyl) group at C-6 ( Fig. 1). Some other related natural products include crotophorbolone, 4 phorbol, 5 prostratin, 6 resiniferatoxin 7 and curcusone A. 8 Due to their remarkable biological activities and unique and complex structures, these types of diterpenoids have drawn considerable attention from organic chemists, and many creative strategies have been developed for construction of the 5-7-6 tricycles with desirable substituents and stereochemistries on C-4, C-6, C-7 and C-10. 9   We have previously reported a highly efficient construction of 5-7-6 tricyclic carbon skeleton with an intramolecular [4 + 3] IMPC (intramolecular [4 + 3] parallel-cycloaddition) of cyclopropane with dendralene/Diels-Alder [4 + 2] cycloaddition strategy. 17 With this strategy, the fused 5-7 bicycle was efficiently constructed which matched the trans-stereochemisty, however a C-4 oxygen atom was not be direct. Following our previously developed [3 + 2] IMCC strategy, 18a-h we have recently reported a novel and efficient construction of a bridged aza-[3.2.1]octane-embedded 5-7-6 tricyclic carbon skeleton with desirable substituents and stereochemistries toward total syntheses of calyciphylline D-type Daphniphyllum alkaloids (Scheme 3). 18i Herein, we report the application of the [3 + 2] IMCC strategy for efficient construction of the bridged oxa-[3.2.1]octane-embedded 5-7-6 tricycle with stereochemistries on C-4, C-7 and C-10, as well as a methylene (methyl) group at C-6 matching those in neoglabrescin A, curcusones I/J and related rhamnofolane/tigliane/daphnane diterpenes.
We started the research from benzyl bromide 2 which was prepared from a known compound 1 according to our recently reported method (Scheme 4). 18i Compound 2 was then oxidized with NMO to afford aldehyde 3 which was used directly in the next step without further purication. Under catalysis of Sc(OTf) 3 (0.2 equiv.), the [3 + 2] IMCC of aldehyde 3 was successfully carried out to afford compound 4 in 82% yield over two steps. The structure of 4 was conrmed by X-ray crystal structure analysis. 19 Hereto, the bridged oxa-[3.2.1] octane-embedded 5-7-6 tricycle have been successfully constructed, the substituents and stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the corresponding natural products.
aldehyde 6 in 85% yield. To our delight, the oxa-bridge was opened under catalysis of TMSOTf 20 at À5 C and a dehydration product 7 was obtained in 16% yield (brsm 53%) ( Table 1, entry  1). Unfortunately, we failed to obtain compound 9 in several attempts either under acidic or basic 21 conditions (Table 1, entries 2-8).
We have also explored the ring-opening of compound 5 under several conditions ( Table 2). Both basic condition and single electron transfer reduction 22 could not give 10a ( Table 2, entries 1-3). Fortunately, we found that treatment of 5 with acetic toluene-p-sulfonic anhydride 23 afforded compound 8 in 98% yield, as a mixture of two diastereoisomers ( Table 2, entry 4). The ratio of the trans-/cis-isomers was 3 : 2 which could be conrmed with 1 H NMR and density functional theory (DFT) calculations (see ESI ‡). During the synthesis of viridin, 24 Akai et al. found that the ring-opening product of a similar oxabridged compound was unstable. Methylation of the resultant oxyanion in situ with MeOTf gave a more stable product. However, we failed to get 10b by using this method ( Table 2, entries 5 and 6).
In conclusion, we have developed a highly efficient strategy for construction of the bridged oxa-[3.2.1]octane-embedded 5-7-6 tricyclic carbon skeleton through the [3 + 2] IMCC, the substituents and stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the corresponding natural products. Furthermore, the ring-opening of the bridged oxa-[3.2.1]octane via C-O bond cleavage was also successfully achieved. We strongly believe that this study will provide a novel and efficient strategy toward the total syntheses of related rhamnofolane, tigliane and daphnane diterpenoids.

Conflicts of interest
There are no conicts to declare. a Ethylenediamine. b Acetic toluene-p-sulfonic anhydride, prepared by acetyl chloride and PTSA. 25