Synthesis of C4C5 Cycloalkyl‐Fused and C6‐Modified Chromans via ortho‐Quinone Methides

Abstract

Starting from 3,5-dimethoxybenzaldehyde, some functionalized 2,3,4-trisubstituted tricyclic 4,5-cycloalkyl-fused and 6-modified chromans could be prepared via ortho-quinone methides (o-QMs)/hetero-Diels-Alder (HDA) reactions of the appropriate precursors. The bromide at C6 served as a handle for introducing other substituents through palladium-catalyzed cross-coupling reactions and other functional-group transformations. Moderate to high yields (up to 80%) and diastereoselectivities (up to >99:1) could be obtained under [PtCl4 ] catalysis. The preferred endo transition state during the cycloaddition reaction played an important role in governing the stereochemical outcomes at C2 - C3 - C4. The configurationally fixed E geometry of the bicyclic o-QMs influenced the cycloaddition reactions to favor the C2 - C4 cis relationship.

Divergent Strategy for the Diastereoselective Synthesis of the Tricyclic 6,7-Diaryltetrahydro-6H-benzo[c]chromene Core via Pt(IV)-Catalyzed Cycloaddition of o-Quinone Methides and Olefin Ring-Closing Metathesis

“…Mp (EtOAc/hexanes): 74.5−76.6 °C. 1 H NMR (300 MHz, CDCl 3 ): δ −0.06 (s, 9H, major), 0.11 (s, 9H, minor), 3.768 (s, 3H, major), 3.774 (s, 3H, major), 3.81 (s, 3H, major), 3.83 (s, 3H, minor), 3.84 (s, 3H, major), 3.856 (s, 3H, minor), 3.862 (s, 3H, minor), 4.14 (dd, J = 11.0, 10.0 Hz, 1H, major), 4.39 (dd, J = 11.0, 1.0, 1H, major), 5.11 (d, J = 10.0, 1H, major), 5.55 (d, J = 9.2 Hz, 1H, minor), 6.51, (s, 1H, major), 6.52 (s, 1H, minor), 6.70 (d, J = 8.2 Hz, 1H, major), 6.79 (d, J = 8.9 Hz, 2H, major), 6.84 (d, J = 1.9 Hz, 1H, major), 6.89 (dd, J = 8.2, 1.9 Hz, 1H, major), 6.98 (d, J = 2.0 Hz, 1H, minor), 7.04 (dd, J = 8.3, 2.0 Hz, 1H, minor), 7.41 (s, 1H, minor), 7.49 (d,J = 8.3 Hz,1H,minor), 7.70 (d, J = 1.0 Hz, 1H, major), 7.75 (d, J = 8.9 Hz, 2H, major), 7.84 (d, J = 8.9 Hz, 2H, minor). 13 C NMR (75 MHz, CDCl 3 ): δ −0.4 (major), −0.2 (minor), 31.8 (minor), 33.9 (major), 48.1 (minor), 50.6 (major), 55.4 (major), 55.5 (minor), 55.…”

“…Following the general procedure for the PtCl 4catalyzed o-QM/[4 + 2] cycloaddition reaction using chalcone 23g, benzyl acetate 15 (0.021 g, 0.050 mmol) furnished chroman 24g as a 8:1 (2,4-cis:2,4-trans) inseparable mixture of diastereomers as a yellow sticky gum (0.030 g, 0.049 mmol, 98%). 1 H NMR (300 MHz, CDCl 3 ): δ −0.07 (s, 9H, major), 0.12 (s, 9H, minor), 3.70 (s, 3H, major), 3.78 (s, 3H, minor), 3.83 (s, 3H, minor), 3.84 (s, 3H, major), 3.85 (s, 3H, major), 3.87 (s, 3H, major), 3.90 (s, 3H, major), 3.93 (s, 3H, minor), 4.11 (dd, J = 11.0, 10.0 Hz, 1H, major), 4.21 (dd, J = 9.0, 5.3 Hz, 1H, minor), 4.39 (dd, J = 11.0, 1.0 Hz, 1H, major), 5.14 (d, J = 10.0 Hz, 1H, major), 5.56 (d, J = 9.0 Hz, 1H, minor), 6.50 (s, 1H, major), 6.51 (s, 1H, minor), 6.70−6.79 (m, 3H, major), 6.86 (d, J = 8.4 Hz, 1H, major), 6.87 (d,J = 8.7 Hz,2H,minor),3H,major),7.40 (dd,J = 8.4,1.8 Hz,1H,major), 7.48 (dd, J = 8.4, 2.0 Hz, 1H, minor), 7.70 (d, J = 1.0 Hz, 1H, major). 13 C NMR (75 MHz, CDCl 3 ): δ −0.4 (major), −0.2 (minor), 32.0 (minor), 34.0 (minor), 48.1 (minor).…”

“…Following the general procedure for the PtCl 4 -catalyzed o-QM/[4 + 2] cycloaddition reaction using chalcone 23l, benzyl acetate 15 (0.021 g, 0.050 mmol) furnished chroman 24l as a 5:1 (2,4-cis:2,4-trans) inseparable mixture of diastereomers as a yellow sticky gum (0.015 g, 0.021 mmol, 41%). 1 H NMR (300 MHz, CDCl 3 ): δ −0.44 (s, 9H, major), 0.13 (s, 9H, minor), 3.72 (s, 3H, major), 3.75 (s, 6H, major), 3.82 (s, 6H, major), 3.85 (s, 6H, minor), 3.856 (s, 3H, major), 3.861 (s, 3H, major), 3.88 (s, 6H, minor), 3.92 (s, 3H, minor), 4.08 (dd, J = 11.0, 10.0 Hz, 1H, major), 4.43 (dd, J = 11.0, 1.0 Hz, 1H, major), 5.08 (d, J = 10.0 Hz, 1H, major), 5.51 (d,J = 8.6 Hz,1H,minor),6.54 (s,1H,major),6.56 (s,2H,major),6.69 (s,2H,minor),6.94 (s,2H,major),7.10 (s,2H,minor),7.44 (s,1H,minor),7.71 (d,J = 1.0 Hz,1H,major). 13 C NMR (75 MHz, CDCl 3 ): δ −0.4 (major), −0.2 (minor), 31.7 (minor), 33.7 (major), 48.2 (minor), 51.4 (major), 56.1 (major), 56.2 (major), 56.29 (minor), 56.34 (major), 56.4 (minor), 60.7 (major), 60.85 (major), 60.92 (minor), 80.4 (major), 89.2 (major), 100.7 (major), 100.9 (minor), 103.2 (major), 103.8 (major), 104.4 (major), 104.9 (minor), 105.7 (minor), 105.9 (major), 113.9 (minor), 114.…”

“…Following the general procedure for the desilylation using Cs 2 CO 3 , ketone chroman TMS acetylide 24e (0.188 g, 0.309 mmol) was converted to the corresponding ketone chroman alkyne 35a, which was obtained as a yellow sticky gum (0.143 g, 0.266 mmol, 86%). 1 H NMR (300 MHz, CDCl 3 ): δ 2.16 (d, J = 2.4 Hz, 1H), 3.75 (s, 6H), 3.76 (s, 3H), 3.84 (s, 3H), 4.17 (dd, J = 10.6, 9.9 Hz, 1H), 4.47 (ddd, J = 10.6, 2.4, 0.7 Hz, 1H), 5.02 (d, J = 9.9 Hz, 1H), 6.52 (s, 1H), 6.68 (d, J = 8.2 Hz, 1H), 6.81 (d, J = 1.8 Hz, 1H), 6.86 (dd, J = 8.2, 1.8 Hz, 1H), 6.99 (dd, J = 8.2, 1.8 Hz, 1H), 7.17 (d,J = 1.8 Hz,1H),7.20 (dd,J = 8.2,7.8 Hz,1H),7.29 (br d,J = 7.8 Hz,1H),7.73 (d,J = 0.7 Hz,1H). 13 C NMR (75 MHz, CDCl 3 ): δ 32.4, 51.4, 55.3, 55.79, 55.81, 56.3, 72.2, 80.4, 82.1, 100.8, 103.2, 110.0, 110.9, 112.4, 113.8, 119.7, 120.2, 120.9, 129.2, 129.4, 132.5, 139.1, 148.9, 149.3, 153.7, 155.9, 159.4, 200.3.…”

Total Synthesis of Palodesangren B Trimethyl Ether and D Dimethyl Ether via a Late-Stage Formation of 2H-Pyran-2-one of the Tetrahydrobenzo[c]pyranochromenone Core

“…Our research group has been involved in the synthesis of 2-arylchromans and their derivatives via the intermediacy of ortho -quinone methides by PTS-Si-mediated or PtCl 4 -catalyzed intermolecular/intramolecular formal [4 + 2]-cycloaddition reactions with some appropriately activated olefins . In addition, such methodology has been extended to the preparation of the structurally relevant tricyclic cores of palodesangren with 9-H ( 8 ) or 9-Me ( 9 ) groups (Scheme , I ) .…”