Background and Originality Content
Pharmaceutical ingredients and natural products embodying a wealth of angularly fused tricyclic subunits have been disclosed in the literature, demonstrating potent biological activities. Examples include (+)-waihoensene (1 ),1 madreporanone (2 ), 2 penarine A (3 )3 and lycojaponicumin C (4 )4 (Scheme 1). These natural products feature 5-7/5/5 tricyclic scaffolds with both cis -ring AB and cis -ring BC system. Preparation of these fused tricyclic scaffold is challenging due to their continuous 3-4 stereo-centers, two of which are quaternary centers. Although several elegant tandem strategies have been established to construct these tricyclic skeletons,5-10 a photo-induced cascade cyclization has less been explored. In 2021, Lou and Cheng reported a photoredox-catalyzed cascade reaction involving aryl radical to install 6/6/5/6 ring system which resulted in total syntheses of (±)-norascyronone A and (±)-eudesmol. 10 However, the reactivity was sensitive to the substrate structure.
Photo-induced electron transfer (PET) of silyl enol ethers provided a mild and green protocol to construct C-C bond. 11Although this synthetic strategy has also been applied to accomplish several fused ring systems, it has limited synthetic value due to its narrow substrate scope,11c, 11d low product yields,11c, 11f unsatisfactory stereo- and regio- selectivity.11g, 11h For example, the Mattay’s group found silyl enolates, such as compounds 5 and 6 when excited with light at 450 nm in a mixed solvent of CH3CN/iPrOH (17:3), went through an intramolecular 5-exo -trig cyclization to yield cyclized products in low yields (20% and 29%, respectively) (Scheme 2A).11f They noted that the addition of alcoholic additive favored 5-exo -trig cyclization over 6-endo -trig one due to kinetically favored factor. Given that the rate constant of the radical cyclization step is 1000 times faster than the saturation step (kcyc. = 2×109 s-1 vs ksat. = 1.5×10 6 s-1),11jwe conceive that the introduction of extra propargyl group as a side chain on proper position of the silyl enol ether might quickly capture the carbon radical that in situ generated from first cyclization, leading to angular fused tricyclic compound. Our designed protocol is shown in scheme 2B. A PET-triggered SET (single electron transfer) process of 9 followed by alcohol-mediated removal of TMS would give α-carbonyl radical INT-1 .11g This intermediate underwent 5-exo-trig cyclization to produce INT2 . The carbon radical in INT-2 attacks alkyne moiety via 5-exo -dig cyclization to arrive at INT-3 which is finally reduced by PS (photo-sensitizer) anion radical followed by protonation to give rise to target tricyclic compound 10 . Herein, we present a PET-triggered radical cascade cyclization of enol silyl ether to achieve syntheses of angularly fused tricyclic skeletons. To the best of our knowledge, a cascade reaction to construct angularly fused tricyclic compounds with both alkene and ketone moiety at the described position in scheme 1 has not been disclosed. These tricyclic skeletons with preinstalled functional groups have the
Scheme 1 Natural Products with 5-7/5/5 Tricyclic System.
Scheme 2 Mattay’s discovery of 5-exo -trig cyclization through PET-triggered α-carbonyl radical intermediate from enol silyl ether and our synthetic design
Table 1 . PET-triggered cascade cyclization to synthesize angularly fused tricyclic compound. a
a The reaction was performed on a 0.03 mmol scale. b Determined by 1 H NMR integration against an internal standard (3,4-dimethoxy-acetophenone). c Isolated yield. Phen. = Phenanthrene, Anth. = Anthracene, Naph. = Naphthalene
Scheme 3 Reaction Scope for the Formation of Angularly Fused Tricyclic Scaffold 10 .a
a The reaction is performed on 0.036 mmol scale. b Two-step overall yield from enone precursor (see supporting information for details).c 10k is not stable in column chromatography. So, the yield is determined via NMR.
edge on preparing structurally-related complex molecules with minimum functional group manipulations.
Based on our design, we began our investigation using compound9a as the model substrate (Table 1). Initially, we evaluated different solvents with DCA (I ) 11f as photosensitizer in a wave-length of 430 nm (entry 1-7). We found the use of CH3CN as solvent could give rise to target product in moderate yield (42%), albeit with a 1:2 ratio of E/Z mixture (The complete optimization data see Supporting Information). The E/Z ratio for this reaction is inconsequential since the TMS group could be feasibly removed via treatment with aq. HF. Given that the co-sensitizer was reported to promote the charge separation, leading to an improved efficiency in some C-C bond transformations, 11a we then examined the reactivity of various co-sensitizers. Pleasingly, we identified phenanthrene could greatly improve the efficiency, promoting the product yield from 42% to 81% (entry 8). However, further investigation of other co-sensitizers, such as anthracene and naphthalene, resulted in inferior yields (entry 9-10). By probing different photo-sensitizers, we found DCA (I ) outperformed DCB (II ), DCN (III ), IV and V (entries 11-14). Mattay et al noted that the alcoholic additive favored 5-exo -trig cyclization. 11e Accordingly, the mixed solvent systems were examined (entries 15 – 18) where identified MeCN/MeOH was optimized one, generating the target product with pleasing 90% yield (NMR) albeit with 80% isolated yield. A lowered reaction concentration afforded target compound with a parallel yield (entry 19) while increasing the reaction concentration slightly diminished the reaction efficiency (entry 20), but still generated a synthetically useful yield (85%, NMR). Finally, we selected entry 15 as optimized condition.
The substrate scope of this radical cascade was evaluated. Besides10a , the methyl substituent at R2 also smoothly delivered the corresponding tricyclic compound 10b . Pleasingly, we found terminal alkyne also tolerated in this reaction. The substrates 9c and 9d without terminal TMS moiety also provided the corresponding 10c and 10d in 72% and 61%, respectively. Evaluation of the substitutions R2-R5 on the six-membered ring was found compatible to afford tricyclic product 10e -10g . Alteration of the terminal alkene to internal di- and tri- substituted alkene 9i-9l did not show disadvantageous effect on the cascade reaction, delivering 10h-10l in moderate to good yields (47%-91%). The relative configuration of 10l was unambiguously determined by single- crystal X-ray diffraction analysis. Moreover, this catalytic system was compatible with enol silyl ether bearing a seven-membered ring to generate the desired product10m . Notably, 10m could be prepared on gram scale with 81% yield. Pleasingly, the method was adapted to a non-cyclized precursor 9n , where the desired cyclized product 10nwas obtained in 61% yield with a moderate dr value (2:1). To determine the relative configuration of 10k , we condensed 10kwith hydrazine hydrate 12 to produce a dimer10k’ whose structure was unambiguously determined by single- crystal X-ray diffraction analysis (Scheme 4).
Scheme 4 Determination of the Relative Stereochemistry of the Product10k .
To further demonstrate the synthetic utility of this protocol, we treated ketone 11 with TMSOTf/Et3N in situ to form enol silyl ether 12 , which was then heated with enophile 13 at 130 ℃ to
Scheme 5 Construction of Fused Tetracyclic Compounds.
Figure 1. Energy Diagram of kJ/mol in Gibbs Energies and Optimized Structures in Cyclization Steps
Scheme 6. The Stereochemical Analysis of Product
induce a Diels-Alder reaction, thus providing cis -6/6 ring system14 (scheme 5). Since chromatographic purification of enol silyl ether 14 on SiO2 proved challenging where partial 14 would decompose, we directly subjected 14to the following PET- triggered radical cyclization. To our delight, the tetracyclic compound 15 and its stereoisomer 15’ were obtained with the yield of 35% and 18%, respectively in an overall four-step conversion from 11 . The relative configuration of15 was unambiguously determined by single- crystal X-ray diffraction analysis.
To gain a deeper insight into excellent regio-selectivity of this reaction, the DFT calculation is performed at the UB3LY- D3(PCM)/6-31G (d, p) level 13 while utilized Int-I as model intermediate. 14 The energy diagram and the optimized structures in cyclization steps are shown in Fig. 1. The reaction starts with a radical regio-selective cyclization. In path A (blue curve), the radical 5-exo-trig -cyclization via A-TS1 generatesA-IM1 with a ΔG of 40.0 KJ/mol. Then the carbon-centered radical attacks alkyne moiety in A-IM1 , thus providing a tricyclic radical A-IM2 with a ΔG of 26.0 KJ/mol viaA-TS2 . Finally, A-IM2 is reduced by PS (DCA) anion radical to afford 5-exo-pro . In path B (green curve), the 6-endo-trig -cyclization via B-TS1 gives rise toB-IM1 with a ΔG of 48.5 KJ/mol. Similar to path A, a 5-exo -dig cyclization of B-IM1 via B-TS2leads to B-IM2 with a ΔG of 54.6 KJ/mol. The6-endo-pro is produced from B-IM2 via a reduction with PS (DCA) anion radical. The calculation suggests that 5-exo-trig - cyclization is favored than 6-endo-trig - cyclization. In addition, A-IM1 overcomes lower relative energies thanB-IM1 to achieve 5-exo-dig -cyclization. Collectively,6-endo-pro is thermo- dynamically favored while5-exo-pro is kinetically favored. The reaction favors5-exo-pro product in the mild condition which is in line with our findings.
We took 9c as an example to elucidate the stereochemistry of the product (scheme 6). A PET- triggered SET process of 9caffords a radical cation i , 11f which is then de-protected by MeOH to produce α-carbonyl radical ii . The following radical 5-exo- trig -cyclization of ii viaiii or iv zips up the ring B, thus affording the cyclized radical species v and vi . For v , the carbon radical is in a cis -conjunction with propargyl moiety while a tran s- conjunction one in vi . So, v is kinetically favored and proceeds the following 5-exo -digcyclization to furnish 10c as desired compound. The analysis of the relative stereochemistry of 10c is consistent with its characteristic data, where both ring AB and ring BC are in acis -conjunction.
Conclusions
We have devised a radical cascade cyclization to expeditiously synthesize angularly fused tricyclic compounds on the basis of Mattay’s preliminary discovery of PET-triggered 5-exo -trigcyclization of silyl enolate. The reaction demonstrated good substrate scope and stereoselectivity. The excellent regio-/stereo- selectivity is rationalized via DFT calculation and conformational analysis. The work provides a versatile synthetic tool for accessing a broad range of pharmaceutical derivatives with related polycyclic structures.
Experimental
(Main Text Paragraphs) Please include all the experimental details here excluding those in Supporting Information.
Supporting Information
The supporting information for this article is available on the WWW under https://doi.org/10.1002/cjoc.2023xxxxx.
Acknowledgement
This work was supported by NSFC (21925106, U19A2014), Sichuan University (2020SCUNL204) and Department of Science and Technology of Sichuan Province (2023NSFSC0105).
References
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  13. See supporting information for detailed calculation.
  14. Int-I is derived from 9c via PET-induced SET desilylation.