Stereoinversion of tertiary alcohols to tertiary

1
Stereoinversion of tertiary alcohols to tertiary
alkyl isonitriles and amines
Sergey V. Pronin, Christopher A. Reiher, Ryan A.
Shenvi
The Scripps Research Institute, La Jolla,
California.
Nature 501, 2013, 195199.
2
Ryan A. Shenvi
B.S in chemistry at Penn State with Prof. Raymond
L. Funk Ph.D. from The Scripps research
Institute with Prof. Phil S. Baran Postdoctoral
fellowship in Harvard University with Prof. Elias
J. Corey Assistant Professor (2010 -
), Department of Chemistry, The Scripps Research
Institute. Research Interests Total synthesis
of terpenes, Alkaloids and natural products
targeting neglected tropical diseases
3
Isonitrile containing secondary terpenoid
metabolites
4
Common methods to access isonitriles
5
tert-Isonitrile synthesis in Natural products
6
A direct conversion of alcohols to isonitriles
Kitano, Y. Kazuhiro, C. Tada, M. Tet. Lett.
1997 39, 1911-1912
7
Lewis acid modification
8
Lewis acid screening
9
Lewis acid modification
10
Substrate Scope
11
Substrate Scope
12
Transformations of formed isonitriles
13
Limitations
14
Mechanistic rationale
15

• Increase in fluorination of the substrate ester
  has an effect on the selectivity
• towards inversion
• Use of TMSOTf instead of Sc(OTf)3 did promote
  any reaction.
• Addition of 2-6-di-t-butyl pyridine (31 with
  catalyst) did not inhibit product formation,
• which excludes Bronsted acid catalysis.
• Addition of stoichiometic TMSOTf did not affect
  the reaction
• Reaction seems to be unique to TMSCN as
  nucleophile/solvent No reaction when MeCN
• is used as nucleophile, TMSN3 and TMSSCN gave
  complex mixtures

16
Conclusions

• The methodology can be used for
• Stereoslective conversion of 3 o alcohols to
  isonitriles and amines
• Is chemoselective to 3 o alcohols in the
  presence of 1 o and 2 o alcohols
• Works best with minmally branched acylic
  alcohols and conformationally
• inflexible alicyclic alcohols

17
Other examples from literature for SN2 at
tert-center
18
(No Transcript)