transformation meeting these specifications.6,7 The locus of
the double bonds in the dienol reactants determines their
position in the product, and the particular transition state
during the [3,3] sigmatropic shift is stereochemically relevant.
The controlling features to be described here were
uncovered in the course of a projected total synthesis of the
limonoid diterpene known as dumsin.8 According to the
plan, one of the focal points involved 1,2-addition of the
vinyllithium reagent 2 to norbornenone 1 (Scheme 1). At
Table 1. Prototypical Deprotonation Studies Involving 4 as the
Reactant
amount of ratio yield,
run quantity of 4
base
base
6/9
%
A. Direct Quencha
tert-BuLib
1
2
3
4
5
6
96 mg
(0.17 mmol)
95 mg
0.19 mmol 5:1
(1.1 equiv)
60
69
58
60
49
44
(1 M in pentane)
tert-BuLib
0.18 mmol 5:1
(0.17 mmol)
50 mg
(1 M in pentane)
LiHMDSc
(1.05 equiv)
0.10 mmol 8:1
(1.1 equiv)
0.32 mmol 8:1
(2.1 equiv)
0.23 mmol 1:99
(0.09 mmol)
85 mg
(0.15 mmol)
116 mg
(1 M in THF)
NaHMDSc
(1 M in THF)
KHMDSc
Scheme 1. Formation and Stereoselective Protonation of
Lithium Enolate 5
(0.21 mmol) (0.66 M in toluene) (1.1 equiv)
100 mg
KHMDSc
0.16 mmol 1:99
(0.18 mmol) (0.66 M in toluene) (0.9 equiv)
B. Inverse Quenchd
7
8
30 mg
tert-BuLib
0.08 mmol 5:1
66
40
(0.05 mmol) (1.7 M in pentane) (1.5 equiv)
310 mg
(0.56 mmol)
KHMDSc
0.72 mmol 1:99
(0.5 M in toluene)
(1.3 equiv)
C. Homogeneous Quenche
9
30 mg
(0.05 mmol)
KHMDSc
0.06 mmol 1:99
44
(0.5 M in toluene)
(1.2 equiv)
a The enolate solution is cooled to -78 °C at which point aqueous NH4Cl
solution is introduced. b Reaction conducted in THF at -78 °C to room
temperature. c Reaction conducted in THF at 0 °C to room temperature.
d The cold (-78 °C) enolate anion solution is transferred to the solution of
NH4Cl via cannula. e The enolate anion solution was cooled to -78 °C,
and a solution of acetic acid in THF was introduced. The mixture was
allowed to warm to room temperature, diluted with ether, and washed
successively with NaHCO3 and NaCl solutions.
The noteworthy level of stereocontrol found to be operative
during the protonation of Li+5- and Na+5- (run 4) prompted
comparable scrutiny of the response of the related potassium
enolate 8. This species was generated by proton abstraction
from 4 with approximately a molar equivalent of potassium
hexamethyldisilazide in THF at a temperature (0 °C) suf-
ficiently elevated to promote rapid and irreversible oxy-
anionic Cope rearrangement (Scheme 2, runs 5 and 6).
-78 °C in ether, nucleophilic capture proceeds from the less
sterically congested endo surface to generate lithium alkoxide
3. Although carbinol 4 produced in this way can be
conveniently isolated after quenching at low temperature and
deprotonated on its own (as 4 to 3), we soon recognized
that the substantial strain in 3 is adequate to allow direct
conversion to 5 to materialize simply upon warming to room
temperature.
Scheme 2. Generation and Protonation Stereoselectivity
Realized with Potassium Enolate 8
Following the rapid introduction of saturated NH4Cl
solution, 6 was isolated as the major rearrangement product
in 78% yield. In a follow-up experiment, the norbornenol 4
dissolved in anhydrous THF was treated with an equivalent
of tert-butyllithium in pentane at -78 °C. The processing
of this reaction mixture in a parallel manner furnished a two-
component mixture of ketones dominated by the â-isomer
(6/9 ) 5:1, Table 1, runs 1 and 2).9 Continued dominance
of the product ratio by 6 was seen when recourse was made
to approximately equimolar levels of lithium hexamethyld-
isilazide in THF (run 3).
Of direct concern was the proper assessment of the change
in reactivity brought on by this seemingly modest structural
modification. In fact, the protonolysis of 8 with aqueous NH4-
Cl solution gave the R-methyl ketone uniquely without any
indication of the coproduction of epimer 6. This striking
demarcation in the partitioning involving 6 and 9 proved to
be scale dependent when potassium ions were involved. As
long as the quantity of 4 was kept low (100-300 mg), the
unidirectional conversion to 9 could be cleanly and repeatedly
(6) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette, L. A.
Angew. Chem., Int. Ed. Engl. 1990, 29, 609. (c) Paquette, L. A. Synlett
1990, 67. (d) Paquette, L. A. Chem Soc. ReV. 1995, 9.
(7) (a) Wilson, S. R. Org. React. 1993, 43, 93. (b) Hill, R. K. In
CompressiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 5, Chapter 7.1.
(8) Paquette, L. A.; Hong, F.-T. J. Org Chem. 2003, 68, 6905.
(9) The R/â nomenclature is adapted from the field of steroid chemistry.
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Org. Lett., Vol. 8, No. 13, 2006