Intramolecular cycloadditions of azides with 1,3-dienes: A novel method for the synthesis of alkaloids.

A general synthesis of the pyrrolizidine and indolizidine substructures of certain alkaloids using an intramolecular (4+1) approach has been developed. The key transformation involves a 1,3-dipolar cycloaddition of an azide onto the proximal double bond of a tethered 1,3-butadiene. The resultant triazoline may rearrange, giving 1-azabicyclo(3.3.0) oct-3-enes and 1-azabicyclo(4.3.0) non-3-enes in one operation. A heteroatom substituted at the 2-position of the 1,3-butadiene is crucial for the outcome of the cyclization. The electronic effect and stereochemistry of oxygen substituted dienes in the cyclization were examined and compared with those of sulfur substituted dienes. The findings were: (1) Z-7-azido-3-(1-ethoxy)ethoxy-1,3-heptadienes gave tetrahydro-7-(1-ethoxy)ethoxy-1H-pyrrolizines along with E-5-(1-(1-ethoxy)ethoxy-1-propenyl) -1-pyrrolines. E-7-Azido-3-(1-ethoxy)ethoxy-1,3-heptadienes gave 6-(1-ethoxy)ethoxy-1,9,10-triazabicyclo(5.3.0) deca-5,9-diene; (2) Z-7-Azido-3-phenyloxy-1,3-heptadiene gave more tetrahydro-7-phenyloxy-1H-pyrrolizine than the corresponding sulfur substituted dienes. Z-7-Azido-3-(p-methoxyphenyl)oxy-1,3-heptadiene gave exclusively tetrahydro-7-(p-methoxyphenyl)oxy-1H-pyrrolizines; (3) The higher temperature requirement and geometry dependence in the oxygen series diminished the effectiveness in the cyclization. Attempts to construct indolizidine rings were not successful; (4) The diastereoselectivity of cyclizations of dienes with substituent were studied. Thermolysis of $(1E,3Z)$-7-azido-1-phenyl-3-(phenyloxy)-1,3-heptadiene gave selectively (5R*,7aR*)-5-phenyl-2,3,5,7a-tetrahydro-7-phenyloxy-1H-pyrrolizine. The application of this method for the synthesis of complex molecules has been demonstrated in a model study directed towards the total synthesis of gephyrotoxin. Extremely high diastereoselectivity was realized in the construction of this tricyclic fused ring skeleton by proper manipulation of the precursor molecule. Heating (E)-6-((1$\sp\prime$S*,2$\sp\prime$R*)-2$\sp\prime$-azido-6$\sp\prime$ -spiro-2$\sp{\prime\prime}$-(5$\sp{\prime\prime}$,5$\sp {\prime\prime}$-dimethyl-1$\sp{\prime\prime}$,3$\sp {\prime\prime}$-dioxane)-1$\sp\prime$-cyclohexyl) -3-(phenylthio)-1,3-hexadiene gave a single isomer of (1,3aS*,4,5,5aR*,7,8,9,9aR*) nonahydro-3-(phenylthio)-6-spiro-2$\sp\prime$-(5$\sp\prime$,5$\sp\prime $-dimethyl-1$\sp\prime$,3$\sp\prime$-dioxane)pyrrolo(1,2-a) quinoline, which incorporates the basic features of gephyrotoxin. A stereoselective synthesis of 1-alkyl-2-(phenylthio)-1,3-butadienes has been developed. The allylborane, derived from a reaction of 1-(phenylthio)-1-(trimethylsilyl)-1,2-propadiene with 9-borabicyclo(3.3.1) nonane (9BBN) was allowed to condense with a variety of aldehydes. The presumed intermediate $\beta$-boronoxysilane was treated with acid to produce Z-dienes whereas base workup gave the E-dienes in high yields and excellent selectivities.PhDChemistryUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/105264/1/9116274.pdfDescription of 9116274.pdf : Restricted to UM users only