The sketches show how he introduced mathematical concepts into architecture and turned the design of buildings from being cla**ed as being simply a part of the building trade to a profession in its own right.
His last known drawing of St Paul's was made in 1690, 20 years before the cathedral's completion.
Dr Anthony Gerbino, an expert on architectural history at Worcester College, Oxford, said this indicated how Wren worked as a designer who delegated much of the work to draughtsmen, pre-empting modern architectural methods.
"Wren's working practice was to give his draughtsmen basic instructions about what he wanted and then to let them come up with their own proposals. These would then be discussed further with a view to refining or adopting them," he said.
"The important point about this is how closely it resembles modern 'office' practice. Architecture in the 17th century was still very much tied to the construction trade."
He added: "The fact that a commission of this magnitude was being directed not by a master mason but by a gentleman amateur is unusual enough.
"The fact that Wren was directing the project from an even further remove – via a team of draughtsmen – is unprecedented."
He suggested the reason lay in necessity: at the time Wren was working simultaneously on various important projects throughout the capital after the Great Fire of 1666.
"Wren had to develop efficient ways of coping with these demands," said Dr Gerbino.
"Delegating the production of working drawings was one of these. From a historical point of view, once this practice took root, in the 18th century and particularly in the 19th century, it would help to define the modern profession of architecture, essentially severing it from the building trades."
Wren's 1690 sketch shows the dome plotted as a parabola on an x-y graph. It is one of the earliest examples of a 'modern' approach to structural engineering, in which mathematical science is used in the design of an actual building, according to Laura Ashby of the Museum of the History of Science in Oxford, which is exhibiting the drawings.
However, Dr Gerbino stressed that the use of mathematical calculations "as a control over the design process" came long after Wren's d**h.
A range of architectural sketches of St Paul's, some never seen in public before, have now gone on display at the Museum of the History of Science. They are part of an exhibition called Compa** and Rule, into the growing influence of mathematics on architecture between 1500 and 1750, which runs until September 6.