The domino chemistry approach to molecular complexity: high-yielding bis-hetero intramolecular Diels–Alder reactions with ketone components

The bis-keto-hetero-IMDA option, with two ketone components (both the heterodiene and heterodienophile moieties) has been examined in several representative domino templates with the aim of ultimately developing efficient methods for the synthesis of structurally complex natural products. The domino sequence could also be activated efficiently by utilizing the less toxic iodobenzene diacetate as the oxidative cleavage/[4+2] promoter while it is unbiased to the nature of substitution around the bicyclic framework.

The bis-ketone option of a domino generated intramolecular bis-hetero Diels–Alder reaction, allowing for a stereodefined construction of oxygen heterocycles is described.Figure optionsDownload as PowerPoint slide

8a′-Methyl-6′-vinyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC15H22O4Ee = 71%[α]D20=-22 (c 0.56, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6S,7R,8aS)

8a′-Methyl-6′-vinyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC15H22O4Ee = 71%[α]D20=+108 (c 1.0, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6R,7R,8aS)

8a′-Methyl-6′-vinyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC15H22O4Ee = 71%[α]D20=-68 (c 1.1, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6S,7R,8aS)

6′-Hydroxy-6′-((methoxymethoxy)methyl)-8a′-methyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-one3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC16H24O6Ee = 71%[α]D20=-37 (c 1.37, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6R,8aS)

6′-Hydroxy-8a′-methyl-6′-vinyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC15H20O4Ee = 71%[α]D20=-164 (c 1.07, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6S,8aS)

6′-Hydroxy-8a′-methyl-6′-vinyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC15H20O4Ee = 71%[α]D20=+167 (c 0.92, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6R,10S)

6′-Hydroxy-6′,8a′-dimethyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC14H20O4Ee = 71%[α]D20=-11 (c 0.74, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6R,8aS)

6′-Hydroxy-8a′-methyl-6′-(prop-1-en-2-yl)-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC16H22O4Ee = 71%[α]D20=+265 (c 0.93, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-8a′-methyl-6′-vinyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC21H35O5SiEe = 71%[α]D20=-124 (c 1.42, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-8a′-methyl-6′-(prop-1-ynyl)-3′,4′,8′,8a′-tetrahydro-2′H- spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC22H34O5SiEe = 71%[α]D20=-114 (c 1.19, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6R,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-8a′-methyl-6′-(prop-1-ynyl)-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC22H34O5SiEe = 71%[α]D20=+129 (c 1.11, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-((methoxymethoxy)methyl)-8a′-methyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC22H40O7SiEe = 71%[α]D20=-10 (c 1.59, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (2R,6S,7R,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-6′-((methoxymethoxy)methyl)-8a′-methyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC22H38O7SiEe = 71%[α]D20=-31 (c 0.65, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-8a′-methyl-6′-(prop-1-en-2-yl)-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC22H36O5SiEe = 71%[α]D20=-131 (c 1.05, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-8a′-methyl-6′-(prop-1-en-2-yl)-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC22H36O5SiEe = 71%[α]D20=-117 (c 0.67, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6R,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′,8a′-dimethyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC20H36O5SiEe = 71%[α]D20=-34 (c 1.05, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (2R,6R,7S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′,8a′-dimethyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC20H36O5SiEe = 71%[α]D20=-5 (c 1.02, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (2R,6S,7R,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′,8a′-dimethyl-3′,4′,6′,7′,8′,8a′-hexahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-6′,7′-diolC20H36O5SiEe = 71%[α]D20=-38 (c 1.05, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (2R,6S,7S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-6′,8a′-dimethyl-3′,4′,8′,8a′- tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC20H34O5SiEe = 71%[α]D20=+43 (c 1.03, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6R,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-6′,8a′-dimethyl-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC20H34O5SiEe = 71%[α]D20=-14 (c 1.16, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aS)

4′-(tert-Butyldimethylsilyloxy)-6′-hydroxy-6′,8a′-dimethyl-8′-methylene-3′,4′,8′,8a′-tetrahydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalen]-7′(6′H)-oneC21H34O5SiEe = 71%[α]D20=-80 (c 1.02, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (4R,6S,8aR)

6-Methyl-10-vinyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC15H20O4Ee = 71%[α]D20=-15 (c 1.01, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8R)

6-Methyl-10-prop-1-ynyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC16H20O4Ee = 71%[α]D20=-44 (c 0.94, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8R)

10-Isopropenyl-6-methyl-9,12-dioxa- tricyclo[6.3.1.00,0]dodec-10-en-5-oneC16H22O4Ee = 71%[α]D20=-16 (c 0.50, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8R)

10-Butyl-6-methyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC17H26O4Ee = 71%[α]D20=-29 (c 1.20, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8R)

10-Allyl-6-methyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC16H22O4Ee = 71%[α]D20=+37 (c 0.20, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8R)

10-Methoxymethoxymethyl-6,8-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC17H26O6Ee = 71%[α]D20=-20 (c 0.45, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8S)

10-Methoxymethoxymethyl-6,8-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC15H22O5Ee = 71%[α]D20=-7 (c 0.35, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,6S,8S)

6,8-Dimethyl-10-vinyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC16H22O4Ee = 71%[α]D20=+2 (c 0.54, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8R)

8-Methoxymethoxymethyl-6-methyl-10-vinyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC18H26O6Ee = 71%[α]D20=-10 (c 1.24, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8S)

8-Methoxymethoxymethyl-6,10-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC17H26O6Ee = 71%[α]D20=-24 (c 0.45, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8S)

8-Allyl-6,10-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC17H24O4Ee = 71%[α]D20=+56 (c 0.40, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8R)

8-Butyl-6,10-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC18H28O4Ee = 71%[α]D20=-7 (c 0.51, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8R)

8-Allyl-10-isopropenyl-6-methyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC19H26O4Ee = 71%[α]D20=+1 (c 0.44, CHCl3)Source of chirality:(S)-(−)-prolineAbsolute configuration:(1R,6S,8R)

2-(tert-Butyl-dimethyl- silanyloxy)-6-methyl-10-prop-1-ynyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC22H34O5SiEe = 71%[α]D20=-38 (c 1.23, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

2-(tert-Butyl-dimethyl-silanyloxy)-10-methoxymethoxymethyl-6-methyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC20H34O6SiEe = 71%[α]D20=-39 (c 1.50, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

8-Allyl-2-(tert-butyl-dimethyl-silanyloxy)-6-methyl-10-vinyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC24H38O5SiEe = 71%[α]D20=-4 (c 1.23, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

8-Allyl-2-(tert-butyl-dimethyl-silanyloxy)-6-methyl-10-prop-1-ynyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC25H38O5SiEe = 71%[α]D20=-17 (c 1.29, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

2-(tert-Butyl-dimethyl-silanyloxy)-10-methoxymethoxymethyl-6,8-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC23H40O7SiEe = 71%[α]D20=-10 (c 0.36, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

2-(tert-Butyl-dimethyl-silanyloxy)-10-methoxymethoxymethyl-6,8-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5- oneC21H36O6SiEe = 71%[α]D20=-12 (c 1.55, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

8-Allyl-2-(tert-butyl-dimethyl-silanyloxy)-10-isopropenyl-6-methyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC25H40O5SiEe = 71%[α]D20=-6 (c 1.59, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

2-(tert-Butyl-dimethyl-silanyloxy)-8-methoxymethoxymethyl-6,10-dimethyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC23H40O7SiEe = 71%[α]D20=-3 (c 0.73, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8S)

2-(tert-Butyl-dimethyl-silanyloxy)-6,10-dimethyl-7-methylene-9,12-dioxa-tricyclo-[6.3.1.00,0]dodec-10-en-5-oneC21H34O5SiEe = 71%[α]D20=-40 (c 1.08, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

2-(tert-Butyl-dimethyl-silanyloxy)-6,10-dimethyl-8-isopropenyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC23H38O5SiEe = 71%[α]D20=+1 (c 0.98, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8S)

2-(tert-Butyl-dimethyl-silanyloxy)-6,10-dimethyl-8-propyl-9,12-dioxa-tricyclo[6. 3.1.00,0]dodec-10-en-5-oneC23H38O5SiEe = 71%[α]D20=-6 (c 0.80, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

But-2-enedioic acid 8-allyl-6-methyl-5-oxo-10-vinyl-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC24H30O8Ee = 71%[α]D20=-5 (c 1.24 CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

But-2-enedioic acid 8-allyl-10-isopropenyl-6-methyl-5-oxo-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-5-oneC25H32O8Ee = 71%[α]D20=-33 (c 1.17, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6S,8R)

C27H44O3Si[α]D20=+30 (c 1.37, CHCl3)mp = 91–93 °CSource of chirality: chiral poolAbsolute configuration: (2R,5R,8S,9S,10R)

C30H48O3Si[α]D20=+32 (c 1.70, CHCl3)Source of chirality: chiral poolAbsolute configuration: (2R,5R,8S,9S,10R)

C28H46O3Si[α]D20=+40 (c 1.73 CHCl3)Source of chirality: chiral poolAbsolute configuration: (2R,5R,8S,9S,10R)

tert-Butyl-(10-methoxymethoxymethyl-6,8-dimethyl-5-methylene-9,12-dioxa-tricyclo[6.3.1.00,0]dodec-10-en-2-yloxy)-dimethyl-silaneC22H38O5SiEe = 71%[α]D20=-33 (c 0.55, CHCl3)Source of chirality: (S)-(−)-prolineAbsolute configuration: (1R,2R,6R,8R)