TY - JOUR
T1 - An intramolecular coupling approach to alkyl bioisosteres for the synthesis of multisubstituted bicycloalkyl boronates
AU - Yang, Yangyang
AU - Tsien, Jet
AU - Hughes, Jonathan M.E.
AU - Peters, Byron K.
AU - Merchant, Rohan R.
AU - Qin, Tian
N1 - Funding Information:
Financial support for this work was provided by the Welch Foundation (I-2010-20190330), the National Institutes of Health (R01GM141088) and UT Southwestern Eugene McDermott Endowed Scholarship. We thank F. Lin (UTSW) for assistance with NMR spectroscopy, H. Baniasadi (UTSW) for HRMS and V. Lynch (UT-Austin) for X-ray crystallographic analysis. We thank the Chen, Tambar, Ready, De Brabander, Smith and Falck groups (UTSW) for generous access to equipment, and helpful discussions. We are grateful to K. Campos, L.-C. Campeau, P. Fier, C. Zarate Saez and K. McClymont (Merck & Co., Inc., Kenilworth, NJ, USA) for feedback on this manuscript.
Publisher Copyright:
© 2021, Merck Sharp & Dohme corp. under exclusive licence to Springer Nature Limited.
PY - 2021/10
Y1 - 2021/10
N2 - Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons. [Figure not available: see fulltext.].
AB - Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons. [Figure not available: see fulltext.].
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U2 - 10.1038/s41557-021-00786-z
DO - 10.1038/s41557-021-00786-z
M3 - Article
C2 - 34584254
AN - SCOPUS:85115860894
SN - 1755-4330
VL - 13
SP - 950
EP - 955
JO - Nature Chemistry
JF - Nature Chemistry
IS - 10
ER -