NMR spectroscopic investigations of mixed aggregates underlying highly enantioselective 1,2-additions of lithium cyclopropylacetylide to quinazolinones.
The solution structures of mixed aggregates derived from lithium alkoxides and lithium acetylides were investigated as part of a program to develop practical syntheses of quinazolinone-based nonnucleoside reverse transcriptase inhibitors. Low-temperature (6)Li, (13)C, and (15)N NMR spectroscopies reveal that mixtures of lithium cyclopropylacetylide (RCCLi), a (+)-carene-derived amino alkoxide (ROLi), and lithium hexamethyldisilazide (LiHMDS) in THF/pentane afford a (RCCLi)(3)(ROLi) mixed tetramer, a C(2)-symmetric and asymmetric (RCCLi)(2)(ROLi)(2) mixed tetramer, and a C(3)-symmetric (RCCLi)(ROLi)(3) mixed tetramer. Analogous mixtures of RCCLi/ROLi in Et(2)O and Me(2)NEt also provide 3:1, 2:2, and 1:3 mixed tetramers. The stereochemistry of aggregation is highly sensitive to the medium. The C(2)-symmetric (RCCLi)(2)(ROLi)(2) mixed tetramer is formed in Et(2)O, whereas the asymmetric isomer is formed in Me(2)NEt. LiHMDS in THF is shown to be an efficient proton scavenger without forming LiHMDS-RCCLi or LiHMDS-ROLi mixed aggregates. LiHMDS-RCCLi mixtures form mixed aggregates in Me(2)NEt.
Parsons
R L
RL
DuPont Pharmaceuticals, Chemical Process Research and Development, Chambersworks, PRF-112, Deepwater, New Jersey 08023, USA.
Fortunak
J M
JM
Dorow
R L
RL
Harris
G D
GD
Kauffman
G S
GS
Nugent
W A
WA
Winemiller
M D
MD
Briggs
T F
TF
Xiang
B
B
Collum
D B
DB
D005663:Furans; D008094:Lithium / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
D005663:Furans; D011799:Quinazolines; D018894:Reverse Transcriptase Inhibitors; C018674:tetrahydrofuran; D008094:Lithium