J. E. Jackson, B. Borhan et al.
tives, solvent, and temperature. Eyring plot analyses suggest
that enthalpy–entropy tradeoffs play a central role in the
striking solvent-dependent stereodiscrimination seen in
these reactions. Overall, increasing temperature favors for-
mation of the R product in both media. The stereoselectivi-
ties of the S-selective cyclization in alcoholic solvents are
dominated by variations in the enthalpies of activation
(DDHRꢀS), whereas DDSRꢀS governs the stereodiscrimination
for the R-selective reaction in chloroform/hexanes. Further
work to probe the mechanism of this rare enantioswitching
process is underway and will be reported in due course.
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¼
¼
Experimental Section
General procedure for the catalytic asymmetric chlorocyclization of car-
bamates in nPrOH: A screw-capped vial equipped with a stirring bar was
charged with
a
stock solution of (DHQD)2PHAL (1.3 mL of
0.21 mgmLꢀ1
)
in nPrOH [0.30 mg (DHQD)2PHAL, 1 mol%]. After
cooling to ꢀ308C in an immersion cooler, DCDMH (9.5 mg, 0.041 mmol,
1.3 equiv) and benzoic acid (2.3 mg, 0.019 mmol, 0.5 equiv) were added
sequentially. After stirring vigorously for 10 min, the substrate
(0.037 mmol, 1.0 equiv) in nPrOH (0.2 mL, pre-cooled to the reaction
temperature) was added in a single portion. The vial was capped and the
stirring was continued at ꢀ308C until the reaction was complete, as
judged by TLC (increasing the amount of DCDMH to 2.0 equivalents
shortens the reaction time from 25 to 8 min (substrate 1a) without affect-
ing % ee). The reaction was quenched by the addition of aqueous NaOH
(2%, 3 mL) and diluted with CH2Cl2 (3 mL). The organic compounds
were separated and the aqueous layer was extracted with CH2Cl2 (3ꢂ
3 mL). The combined organic compounds were dried over anhydrous
Na2SO4 and concentrated in the presence of a small quantity of silica gel.
Pure products were isolated by column chromatography on a short silica
gel column by using EtOAc/hexanes (1:4 to 1:1 gradient) as the eluent.
Note: For reactions in 1:1 CHCl3/hexanes, the catalyst loading was in-
creased to 20 mol% to outcompete the background reaction at 08C. Fur-
thermore, the acid additive was not included, however, the rest of the
procedure was identical to those reported in the Supporting Information
for CHCl3/hexanes-mediated reactions.
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[8] These results match those reported by Sharpless and co-workers in
the asymmetric dihydroxylation reaction: H. C. Kolb, P. G. Ander-
[9] CCDC-890236 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
data_request/cif.
[10] Based on control experiments without the catalyst, at most a 2%
yield could arise from the uncatalyzed background reaction by the
time the catalyzed reaction is complete.
Acknowledgements
The authors would like to thank Dr. R. J. Staples for the X-ray structure
analysis, Mr. Jacob Matsil for assistance in the synthesis of some of the
substrates, and the MSU Mass Spectrometry facility for HR-MS analysis.
Generous support was provided by the NSF (CHE-0957462).
[11] Importantly, errors associated with individual data points (all triply
replicated) were small relative to the large displacements among
these segments.
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[12] a) A minimal scenario that has the mathematical flexibility to show
such behavior is one in which each path (pro-R and pro-S) consists
of two sequential reactions, as discussed by Ridd et al (see below,
refs. [12b,c]). Over the temperature range studied, these processes
would trade roles as the rate-determining steps (RDS). This switch
in RDS represents a change in the (kinetic) mechanism (although
the sequence of events may be the same), and if the pro-R and pro-
S switchover occurs at different temperatures, it allows for three re-
gimes (i.e., slope segments) as seen in the Eyring plots in Figure 2.
We cannot assign specific mechanistic events to its kinetic steps, nor
rule out alternative multistep schemes. In future efforts to map out
not only enantioselectivities, but also molecularity and absolute
rates as a function of solvent, temperature, chlorinating agent, and
substrate structures, we hope to develop a step-by-step mechanistic
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9020
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 9015 – 9021