C O M M U N I C A T I O N S
Table 2. Oppenauer Oxidation/Brook Rearrangement/Aldolization
simple crossover experiment shown in eq 4. Exposing the magne-
sium alkoxide of n-hexanol to 1 and isobutyraldehyde resulted in
an approximately equimolar mixture of aldols 3a and 3b, revealing
that dissociation of the aldehyde from the magnesium center is faster
than Brook rearrangement and aldolization (eq 4).18
Reactionsa
In summary, a new direct aldol reaction has been accomplished
between the enolate obtained from an Oppenauer/MPV-induced
[1,2]-Brook rearrangement of a silylglyoxylate and the carbonyl
product of that redox reaction. The concept of symbiotic reagent
activation may be applicable to other reaction classes. This
possibility is the topic of ongoing investigations.
Acknowledgment. Funding for this work was provided by the
National Institutes of Health (National Institute of General Medical
Sciences, GM068443). Research support from Eli Lilly, Amgen,
and GSK is gratefully acknowledged. J.S.J. is an Alfred P. Sloan
Fellow and a Camille Dreyfus Teacher-Scholar.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
a Alcohol (1.5 equiv), EtMgBr (2.0 equiv), 0 °C f rt; then 1 (1.0 equiv).
b Isolated yield. c Determined by 1H NMR spectroscopy; the major isomer
is shown. d Reaction solvent: 2:1 THF/CH2Cl2.
References
Table 3. Reaction Initiation via Aldehyde Alkylation
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(3) For a recent example, see: Kagawa, N.; Ihara, M.; Toyota, M. Org. Lett.
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(5) Nicewicz, D. A.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 6170-
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a Isolated yields. b Determined by 1H NMR spectroscopy; the major
isomer is shown.
(6) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J. Synthesis
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(7) Adkins, H.; Franklin, R. C. J. Am. Chem. Soc. 1941, 63, 2381-2383.
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(10) Brook, A. G. Acc. Chem. Res. 1974, 7, 77-84.
alkoxide was formed via Grignard addition to aldehydes (Table
3).17 This simple one-step protocol facilitated access to more
complex ketone aldol adducts with no reduction in reaction
efficiency. In the case where significant steric differentiation exists
between R′ and R′′, promising levels of diastereocontrol may be
achieved (entry 3).
Epoxides may also serve as the alkoxide progenitor in conjunc-
tion with a Cu(I)-catalyzed alkylation (eq 3). On the basis of the
similar yield for 12a beginning from either an epoxide (eq 3) or an
aldehyde (Table 3, entry 1), it appears that CuI does not interfere
with the subsequent steps.
(11) Ooi, T.; Otsuka, H.; Miura, T.; Ichikawa, H.; Maruoka, K. Org. Lett. 2002,
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(12) Oppenauer, R. U.S. Patent 2,384,335, 1945.
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4) contrast a recent example where Mg f Zn transmetalation was required
to initiate silyl migration: Unger, R.; Cohen, T.; Marek, I. Org. Lett. 2005,
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(14) For a complete survey of conditions, see the Supporting Information.
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(17) Byrne, B.; Karras, M. Tetrahedron Lett. 1987, 28, 769-772.
(18) A separate control experiment between nhexOMgBr and iPrCHO yielded
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Preliminary conclusions regarding the relative rates of the
individual steps of the reaction sequence may be drawn from a
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