Manson's shock departure is a blow to Southwark, as it leaves a vacuum in the management of a £2bn regeneration portfolio.
A spokesperson for Southwark council said: "Fred has been in a very demanding job for the past six years and has expressed the view that he would wish to consider alternative career options.
"Fred is recognised inside and outside the council as an exceptionally talented and creative officer who has given enormous benefit to Southwark."
The spokesperson added that Manson's departure "will be a matter of regret and loss for the council".
Manson's support for private-led regeneration, including housing stock transfers from local authorities to housing associations, is understood to have been at odds with the views of Southwark's director of housing Michael Irvine.
However it is not known if these tensions contributed to Manson's departure.
Manson is rumoured to have been offered a post at the Greater London Authority, although he refused to confirm this.
Projects in development at Southwark are the £1.5bn redevelopment of the Elephant & Castle, the £1bn, 186,000 m2 More London project, which includes the GLA headquarters on the South Bank, the £400m redevelopment of the Aylesbury estate and the £400m mixed-use redevelopment of London Bridge station.
Smaller projects at Peckham Wharf, Bermondsey Spa and Bermondsey Square are in the pipeline.
It is understood that Lambeth council's Hayes was invited to reapply for his job, retitled "director of community renewal", last month but was unsuccessful.
Hayes' post has not been filled and Lambeth council declined to comment on his departure. Hayes' vision of the area around Waterloo Station as a Hong Kong-style office hub is understood to have been opposed by community planners and Waterloo Development Group, a local business and residents body. He is understood to have taken up a private sector consultancy role.
Hayes leaves behind a regeneration portfolio that includes the £200m phased redevelopment of the South Bank Centre, 371,600 m2 of offices planned around Waterloo Station, the Clapham Park Estate redevelopment, a £100m conversion of the Shell headquarters into a leisure and entertainment complex, and a £15m transport interchange at Vauxhall Cross.