Baldwin's Rules - Department of Medicinal Chemistry

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Table 22. Literature Examples of 5-exo/6-endo-dig Anionic
Closure with Respect to the Environment of the Anionic Center a
a x marks denote gaps in the literature. Motif structures are given in
Scheme 1, and D E do not apply to anionic closures.
Figure 20. Electronegativity effects on the M05 2X/6-31+G** potential
energy surfaces for the 5-exo-/6-endo-dig anionic cyclizations of
C- (black solid, bold), N- (blue dashed, italics), and O- (red dashed,
underlined) centered anions with terminal alkynes.
According to DFT calculations, carbanionic 5-exo-dig closure
is barrierless in the case of the Ph-substituted alkyne but not
Table 23. Activation, Reaction, and Intrinsic Energies (kcal/
mol) for the Parent 5-exo- and 6-endo-dig Radical Digonal
Cyclizations at the B3LYP/6-31+G(d,p) and M05-2X/6-31
+G(d,p) Levels of Theory a
a
The M05-2X data are given in parentheses and the ring-closing bond is
shown in red.
so for the analogous H, Me, and TMS-substituted alkynes. The
most important effect of the anion-stabilizing terminal phenyl
group is that its presence renders this 5-exo-dig closure >12 kcal/mol
more exothermic than the other 5-exo-dig closures in (Table 23,
Table 24). Marcus theory readily demonstrates that the effect of
this additional product stabilization should be sufficient to make
the reaction barrier disappear. Indeed, once the reaction energy
and the intrinsic barrier 169 for this reaction are substituted to the
Marcus eq 1, the reaction barrier vanishes. 24
The cyclizations of alkyl lithium reagents, generated from
alkyl iodides 170 and connected to an alkyne via a fully saturated
linker, proceeds exclusively via the 5-exo-dig pathway (motif
A). Bailey and co-workers have analyzed this anionic competition
comprehensively and found no evidence for the formation
of 6-endo-dig products. For alkyl substituted alkynes, the
cyclization is relatively sluggish at the room temperature, in a
full agreement with the measured activation parameters (a halflife
of ∼7minat∼29 °C, ΔH q =23( 0.9 kcal/mol, ΔS q =+4(
3.3 eu). The relatively high activation barriers are likely to
reflect the effects of aggregation, solvation as well as nature of
the counterions. The phenyl-substituted analogue cyclizes
much faster (a half-life ∼6 minat 51 °C, suggesting ∼10 6
times acceleration at the low temperatures). 171 TMS-substituted
alkyne also shows complete 5-exo regioselectivity and
∼95% yield (Scheme 46). 96,172 Stereoselective syn-addition is
observed, suggesting that the Li atom is transferred intramolecularly
to the developing carbanionic center. Physical basis for
these results has been suggested to lie in the stereochemical
requirements of the ring closure transition state. This intramolecular
coordination could not occur in the 6-endo-dig transition
state and may be one of the factors that aid in the complete
regioselectivity observed. 24 With a bulky group at the propargylic
carbon, the well-defined TS allows for stereoselective
synthesis of chiral cyclopentanoid building blocks in 70 99%
yields (Scheme 46). 173
AB dx.doi.org/10.1021/cr200164y |Chem. Rev. XXXX, XXX, 000–000