A three component, convergent synthesis of the isoquinoline alkaloid morphine was designed which incorporated the ten-membered silicon-containing epoxide [figure 1], the diene diol [figure 2], and the known oxazolone [figure 3].

See: Figures 1, 2, and 3

Diene diol [figure 2] was isolated in the amount of 200 mg/L from the fermentation of (2-bromoethyl)benzene by Pseudomonas putida 39/D (Pp 39/D) and the absolute stereochemistry was proven by conversion to and comparison with a known compound.

See: Figure 4

The silicon-tethered enediyne [figure 4] was prepared as a model for use in the well-known Bergman cyclization reaction as a "latent benzene reagent". Bergman cycloaromatization of similar enediynes has been demonstrated and the cyclization temperatures to form the benzenoid diradicals lies in the region 40-70°C. Cache molecular modeling of [figure 4] did indeed predict a cyclization temperature around 65°C. Enediyne [figure 4] did not undergo Bergman cyclization at such low temperatures and even survived heating for several days in a sealed tube at 150°C.

See: Figure 5 ⟶ Figure 6

This approach was abandoned because it was shown in a related study that the tandem cyclization of [figure 5] to [see figure 6] proceeded without stereocontrol and in poor yield. (Compound [figure 6] resembled the intermediate radical that would have been obtained in the Bergman study). The aforementioned difficulties led to the revision of the approach to morphine to yield the second generation strategy in which the radical cyclization was carried out in separate steps.

See: Figure 2 ⟶ Figure 7⟶ Figure 8 ⟶ Figure 9

For the second generation approach, diene diol [figure 7] was isolated in the yields of 2 mg/L and 440 mg/L from fermentation of o-bromo-(2-bromo)-1-ethylbenzene by Pp 39/D and JM109 respectively. Its absolute stereochemistry was proven by conversion to the benzofuran derivative [figure 7] which was found identical to that obtained from [figure 2].

See: Figure 9 ⟶ Figure 10 ⟶ Figure 11a, 11b

The new diol [figure 9] was transformed to the protected derivative [figure 10]. The radical cyclization of [figure 10] gave the isoquinolines [figure 11a] and [figure 11b] in better yields (60% and 30% respectively) while attempted deprotection of [figure 10] was surprisingly accompanied by an intramolecular cyclization and produced the interesting oxazapine [figure 11]. The absolute stereochemistry of 11b was proven by x-ray. Both isomers are being used through further conversion to both enantiomers of morphine.

See: Figure 9 ⟶ Figure 12 ⟶ Figure 13