In the early 1960s, Woodward began work on what was the most complex natural product synthesized to date—vitamin B. In a remarkable collaboration with his colleague Albert Eschenmoser in Zurich, a team of almost one hundred students and postdoctoral workers worked for many years on the synthesis of this molecule. The work was finally published in 1973, and it marked a landmark in the history of organic chemistry. The synthesis included almost a hundred steps, and involved the characteristic rigorous planning and analyses that had always characterised Woodwards work. This work, more than any other, convinced organic chemists that the synthesis of any complex substance was possible, given enough time and planning (see also palytoxin, synthesized by the research group of Yoshito Kishi, one of Woodwards postdoctoral students).  As of 2019, no other total synthesis of Vitamin B has been published.
That same year, based on observations that Woodward had made during the B synthesis, he and Roald Hoffmann devised rules (now called the Woodward–Hoffmann rules) for elucidating the stereochemistry of the products of organic reactions. Woodward formulated his ideas (which were based on the symmetry properties of molecular orbitals) based on his experiences as a synthetic organic chemist; he asked Hoffman to perform theoretical calculations to verify these ideas, which were done using Hoffmann's Extended Hückel method. The predictions of these rules, called the "Woodward–Hoffmann rules" were verified by many experiments. Hoffmann shared the 1981 Nobel Prize for this work along with Kenichi Fukui, a Japanese chemist who had done similar work using a different approach; Woodward had died in 1979 and Nobel Prizes are not awarded posthumously.