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. 2022 Mar 25;12(16):9519–9523. doi: 10.1039/d2ra01315k

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†,‡

Yi Cui 1, Jiayuan Lv 1, Tianhang Song 1, Jun Ren 1, Zhongwen Wang 1,✉
PMCID: PMC8985103  PMID: 35424922

Abstract

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.

We reported a highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with a full match of the substituents and stereochemistries on C-4/-6/-7/-10 with those in the rhamnofolane/tigliane/daphnane diterpenoids.graphic file with name d2ra01315k-ga.jpg

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 A2 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 4,7-bridged 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 resiniferatoxin7 and curcusone A.8

Fig. 1. Representative rhamnofolane/tigliane/daphnane diterpenes with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton (corresponding structures with a ring-opening of the oxa-[3.2.1]octane via C–O cleavage) and a methylene (methyl) group at C-6.

Fig. 1

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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 Dai et al. reported the total syntheses of curcusones I and J by using an intramolecular Au-catalysed [4 + 3] cycloaddition for construction of the oxa-[3.2.1]octane-embedded 5–7-fused carbon skeleton and Diels–Alder [4 + 2] cycloaddition for construction of the additional 6-membered carbocycle (Scheme 1).10a Some other natural products have been reported by the groups of Wender (phorbol, resiniferatoxin and prostratin),11 Cha (phorbol),12 Baran (phorbol),13 Xu/Li (prostratin),14 Liu (crotophorbolone),15 Inoue (crotophorbolone, resiniferatoxin, prostratin and related molecules)16 and Dai/Adibekian (curcusones A–D).10b The groups of West9c and Maimone9h have reported attempts toward the total syntheses of related molecules through construction of a 4,7-bridged oxa-[3.2.1]octane skeleton respectively (Scheme 2).

Scheme 1. Representative total syntheses of rhamnofolane/tigliane/daphnane diterpenes containing a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton and a 4,7-bridged oxa-[3.2.1]octane skeleton.

Scheme 1

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Scheme 2. Representative synthetic strategies for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries.

Scheme 2

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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.

Scheme 3. Proposed [3 + 2] IMCC strategy for construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with suitable substituents and stereochemistries on C-4, C-6, C-7 and C-10.

Scheme 3

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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 purification. 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 confirmed 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.

Scheme 4. Construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle.

Scheme 4

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With compound 4 in hand, we started to investigate the ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage (Scheme 5). Krapcho decarboxylation of 4 afforded monoester 5 in 88% yield as a mixture of two diastereoisomers in a ratio of nearly 1 : 1. Reduction of 5 with DIBAL-H at −78 °C afforded aldehyde 6 in 85% yield. To our delight, the oxa-bridge was opened under catalysis of TMSOTf20 at −5 °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 basic21 conditions (Table 1, entries 2–8).

Scheme 5. Ring-opening of the oxa-[3.2.1]octane via C–O bond cleavage.

Scheme 5

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Ring-opening of the compound 6.

graphic file with name d2ra01315k-u1.jpg
Entry Solvent Temperature Reagents Yield
1 DCM −5 °C TMSOTf 7, 16%
2 DCM r.t. TMSOTf, Et3N n.r.
3 DCM −78 °C to −10 °C TMSOTf Complex
4 MeOH r.t. ∼ reflux NaOMe n.r.
5 THF −78 °C LDA n.r.
6 THF 0 °C LDA Complex
7 THF 0 °C DIBAL-H Decom.
8 DCM 0 °C TIPSOTf n.r.
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We have also explored the ring-opening of compound 5 under several conditions (Table 2). Both basic condition and single electron transfer reduction22 could not give 10a (Table 2, entries 1–3). Fortunately, we found that treatment of 5 with acetic toluene-p-sulfonic anhydride23 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 confirmed with 1H 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 oxa-bridged 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).

Ring-opening of the compound 5.

graphic file with name d2ra01315k-u2.jpg
Entry Solvent Temperature Reagents Yield
1 THF 0 °C LDA Decom.
2 DME r.t. Li, EDAa Decom.
3 DME 0 °C Li, EDA Decom.
4 CH3CN r.t. Anhydrideb 8, 98% (trans : cis = 3 : 2)
5 THF −78 °C to 0 °C LHMDS, MeOTf Decom.
6 THF −78 °C to 0 °C LDA, MeOTf Decom.
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a

Ethylenediamine.

b

Acetic toluene-p-sulfonic anhydride, prepared by acetyl chloride and PTSA.25

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 conflicts to declare.

Supplementary Material

RA-012-D2RA01315K-s001
RA-012-D2RA01315K-s002

Acknowledgments

The authors gratefully acknowledge the financial support from the National Key Research and Development Program of China (No. 2021YFD1700103) and National Natural Science Foundation of China (No. 21572103).

†

Dedicated to the 60th Anniversary of Institute of Elemento-Organic Chemistry of Nankai University.

‡

Electronic supplementary information (ESI) available: Experimental details, DFT calculations, NMR spectra and X-ray crystal structure and data. CCDC 2110705. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d2ra01315k

Notes and references

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

RA-012-D2RA01315K-s001
RA-012-D2RA01315K-s001.pdf (2.3MB, pdf)
RA-012-D2RA01315K-s002
RA-012-D2RA01315K-s002.cif (28.8KB, cif)

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