Asymmetric 1,4-reductions of hindered β-substituted cycloalkenones using catalytic SEGPHOS-ligated CuH

Article abstract of DOI:10.1021/ol0400185

The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unpreced

Full text of DOI:10.1021/ol0400185

ORGANIC
LETTERS
2004
Vol. 6, No. 8
1273-1275
Asymmetric 1,4-Reductions of Hindered
â-Substituted Cycloalkenones Using
Catalytic SEGPHOS−Ligated CuH
Bruce H. Lipshutz,* Jeff M. Servesko, Tue B. Petersen, Patrick P. Papa, and
Andrew A. Lover
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
lipshutz@chem.ucsb.edu
Received February 4, 2004
ABSTRACT
The reagent combination of catalytic amounts of copper hydride ligated by a nonracemic SEGPHOS ligand leads in situ to an extremely
reactive species capable of effecting asymmetric hydrosilylations of conjugated cyclic enones in very high ees. An unprecedented substrate-
to-ligand ratio as high as 275 000:1 for this transformation has been documented.
Control of asymmetry â- to the carbonyl group in a cyclic
ketone is usually reserved for one of several powerful
methods relying on conjugate addition from metals such as
Cu1 and Rh2 or via use of nonracemic Lewis acid catalysts.3
An alternative strategy is based on conjugate reduction of a
â-substituted system and offers considerable flexibility in
synthesis.4 Recently, we described the remarkable accelerat-
ing effect imparted by nonracemic biaryl ligands such a
Takasago’s DTBM-SEGPHOS (1)5 and Roche’s xyl-MeO-
BIPHEP (2)6 on CuH toward aryl ketones,7a resulting in a
highly effective Cu(I)-catalyzed method for asymmetric
hydrosilylation. Although such reactions of ketones are likely
to be mechanistically distinct from those of either cyclic or
acyclic7b R,â-unsaturated ketones, the same reagent combina-
tion might offer greater reactivity along with higher levels
of enantioselectivity than currently available.8 Substrate-to-
ligand (S/L) ratios might be greatly increased and ees
enhanced as well. It was also conceivable that far more
hindered educts not amenable to existing procedures would
participate. We now disclose that, indeed, asymmetric
hydrosilylations of cyclic enones take place using SEGPHOS
1-ligated CuH at unprecedented S/L levels with high enan-
tioselectivities even in very sterically demanding cases.
Using preformed (Ph3P)CuH9 or generating CuH in situ
in the usual fashion from 1% CuCl, 1% NaO-t-Bu,10 and
(1) Feringa, B. L.; Naasz, R.; Imbos, R.; Arnold, L. A. In Modern
Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH: Weinheim, 2002;
pp 224-258.
(2) (a) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2003,
68, 1901. (b) Iguchi, Y.; Itooka, R.; Miyaura, N. Synthesis 2003, 1040.
(3) Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. Engl. 1997,
36, 1236.
(4) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(5) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(6) Schmid, R.; Broger, E. A.; Cereghetti, M.; Crameri, Y.; Foricher, J.;
Lalonde, M.; Muller, R. K.; Scalone, M.; Schoettel, G.; Zutter, U. Pure.
Appl. Chem. 1996, 68, 131.
(7) (a) Lipshutz, B. H.; Noson, K.; Chrisman, W. Lower, A. J. Am. Chem.
Soc. 2003, 125, 8779. (b) Lipshutz, B. H.; Servesko, J. M. Angew. Chem.,
Int. Ed. 2003, 41, 4789.
(8) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am.
Chem. Soc. 2000, 122, 6797.
(9) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron 2000, 56, 2153.
10.1021/ol0400185 CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/20/2004

lower temperatures afforded especially selective reductions.13
Comparisons with literature examples (3 and 6-8)8 that do
not include any cases analogous to 5,5-disubstituted cyclo-
hexenones reflect the far greater pace at which DTBM-
SEGPHOS accelerates these asymmetric reductions relative
to other bis-phosphines used previously (p-tol-BINAP,
BIPHEMP).8 Isophorone itself, for example, reacts with
modest selectivity and to a limited extent under the influence
of CuH‚BIPHEMP/PMHS (14% in 10 h at 0 °C; 47% ee).
Moreover, unlike prior art,8 there is no sensitivity to excess
silane and, hence, no over-reduction in the presence of 2
equiv of PMHS.
Solvents other than toluene were also screened, with results
being illustrated in Scheme 1. While the level of induction
stoichiometric polymethylhydrosiloxane (PMHS),11 the pres-
ence of 0.1-0.5 mol % 1 (or S/L ) 200:1 to 1000:1) in
toluene at 0 °C was sufficient to provide a reagent capable
of delivering hydride in a 1,4-sense with excellent levels of
stereoinduction. Table 1 illustrates the cases studied. Note-
worthy is the observation that highly hindered examples such
as isophorone (4) and related substrates (e.g., 5)12 led to good
ees from reactions run at 0 °C, while those carried out at
Scheme 1
Table 1. 1,4-Reductions of Hindered Cyclic Enones
dropped somewhat in CH2Cl2, both THF and especially THF/
dioxane mixtures (2:1) led to appreciably greater ees than
in toluene, notwithstanding higher reaction temperatures.
These data suggest that considerable latitude exists in
choosing a medium and temperature for these reductions.
Although the standard protocol for preparing CuH calls
for the 1:1 ratio of CuCl/NaO-t-Bu so as to initially generate
CuO-t-Bu, we recently found that the trivial base NaOMe
can serve in the same capacity.14 Use of this inexpensive
alternative en route to ligated CuH affords, in the case of a
cyclopentenone, a similar level of selectivity as indicated
by product 9 (eq 1; compare with Table 1, products 7 and
8).
A S/L ratio of 250:1 was routinely used in the examples
above, a ratio chosen solely on the basis of accuracy in
measuring the milligram quantities of phosphine ligand
required per reaction. To test the limits of catalysis, an
(10) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473.
(11) Lawrence, N. J.; Drew, M. D.; Bushell, S. M. J. Chem. Soc., Perkin
Trans. 1 1999, 3381.
(12) Use of ligand 2 required 96 h to obtain an ee of 97%, whereas
ligand 1 led to 5 at -35 °C in 99.5% ee after 16 h.
(13) Using ligand 1, absolute stereochemistry was confirmed by com-
parisons of rotation data with known products. 3 (R): comparison with
commercial material. 4: (R) (Allinger, N. L.; Riew, C. K. J. Org. Chem.
1975, 40, 1316). 6: (R). 7: (S). 8: (S) (cf. ref 8).
a Isolated, chromatographically pure material. b Determined by chiral GC
analyses.
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Org. Lett., Vol. 6, No. 8, 2004

experiment was conducted on 64.76 g of isophorone in the
presence of only 2 mg of DTBM-SEGPHOS (Scheme 2).
Scheme 4
Scheme 2
At this unprecedented S/L ratio of 275,000:1,14 which also
involved only 2 equiv of PMHS, conjugate reduction and
the associated hydrolytic workup proceeded uneventfully to
afford the expected product in 88% (distilled) yield and with
an ee of 98.5%.
Interestingly, the rates of these hydrosilylations could be
dramatically increased when the ratio of base to CuCl was
raised to an optimized 6:1 level.15 As illustrated in Scheme
3, isophorone reacted completely at -35 °C within 1 h while
In summary, an especially effective case of ligand-
accelerated catalysis has been uncovered for carrying out
conjugate reductions of (hindered) â-substituted cyclic
enones based on either an in situ-generated SEGPHOS-
chelated CuH or a SEGPHOS-modified form of Stryker’s
reagent.9 High catalyst turnovers have been realized, very
mild conditions prevail, and both yields and enantioselec-
tivities are the highest reported to date for these substrates.
Acknowledgment. Financial support provided by the
NSF (CHE 0213522) is warmly acknowledged. We are
indebted to Dr. T. Saito and Mr. H. Shimizu (Takasago) and
Drs. R. Schmid and M. Scalone (Roche) for providing the
SEGPHOS and BIPHEP ligands, respectively, used in this
study. T.B.P. thanks the Danish Chemical Society for travel
funds.
Scheme 3
Supporting Information Available: Procedures and
spectral data for all new products. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL0400185
(14) Representative Procedure: Large-Scale Hydrosilylation of Iso-
phorone (275,000:1 S/L). To a 500 mL round-bottomed flask, flame-dried
and purged with argon, were added CuCl (426 mg, 4.30 mmol), NaO-t-Bu
(412 mg, 4.29 mmol), and (R)-DTBM-SEGPHOS (2.0 mg, 0.0017 mmol),
Dry, distilled toluene (215 mL) was added and the solution stirred at rt for
20 min, during which time the mixture changed from clear white to pale
yellow. The mixture was cooled to -35 °C (Cryocool refrigeration), and
isophorone (distilled, neat, 64.76 g, 70.30 mL, 469.27 mmol) was added
dropwise, during which time the mixture turned dark black. PMHS (distilled,
56 mL, 938 mmol) was introduced via cannula. The mixture was stirred at
-35 °C for 5 h and analyzed by GC, which indicated 60% conversion.
The reaction was allowed to continue and was analyzed at various times:
18 h (72% conversion), 30 h (80%), 48 h (87%), 72 h (92%), 80 h (99%),
after which time it was warmed to 0 °C and then quenched by pouring into
cold, saturated bicarbonate and Et2O (without stirring). The mixture slowly
evolved gas over 6 h and was then stirred vigourously for 6 h. The aqueous
layer was extracted three times with Et2O, and the combined organic layers
were washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated by rotary evaporation with caution due to slight volatility. The
residue was purified by fractional distillation to afford 58.14 g (88.5%) of
the title compound. Analysis by chiral GC (Chiraldex B-DM 75) indicated
an ee of 98.5%.
maintaining high S/L levels. At the more typical 1:1 ratio, 8
h were needed for 100% conversion at 0 °C (cf. Table 1).
Likewise, product 10 was obtained in essentially enantio-
merically pure form in good isolated yield in the same time
frame.
Last, we note that the initial outcome to these asymmetric
reductions is a silyl enol ether derivative of PMHS, which
requires subsequent hydrolytic workup to arrive at product
ketones. To obviate this step, we have found that pinocolbo-
rane (in place of PMHS) can function as the stoichiometric
source of hydride without impact on the levels of stereoin-
duction (Scheme 4). The presumed labile boron enolate is
lost upon workup to directly afford the desired ketones.
DTBM-SEGPHOS (1) was found to enhance the rates of
these asymmetric reductions relative to xyl-MeO-BIPHEP
(2) as well in both of the â,â-disubstituted enones examined.
(15) Lipshutz, B. H.; Caires, C. C.; Kuipers, P.; Chrisman, W. Org. Lett.
2003, 5, 3085.
Org. Lett., Vol. 6, No. 8, 2004
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