Highly chemoselective copper-catalyzed conjugate reduction of stereochemically labile α,β-unsaturated amino ketones

Article abstract of DOI:10.1021/jo9017588

(Chemical Equation Presented) Highly chemoselective conjugate reduction of chiral α,β-unsaturated amino ketones has been developed by using triisopropyl phosphite ligated copper hydride complex. The highlights of the method are wide substrate compatibilit

Full text of DOI:10.1021/jo9017588

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and catalytic [CuH(PPh3)]6 in the presence of hydrogen
Highly Chemoselective Copper-Catalyzed Conjugate
Reduction of Stereochemically Labile
r,β-Unsaturated Amino Ketones
gas10 or silanes11 can also be used for 1,4-reduction. None
of the known methods exhibited the necessary selectivity and
mildness in the context of our recent total synthesis of
amaminol A,12 where problems were encountered with se-
lective reduction of an enone containing epimerizable stereo-
centers and other double bonds (Scheme 1). Among the
many different methods tested, copper hydride based reduc-
tions turned out to be the most promising. As a result we used
the modified conditions from Lee and Jun for preparing
Stryker’s reagent in situ using copper(II) acetate monohy-
drate, triphenylphosphine, and diethoxymethylsilane as the
hydride source.13 We decided to further investigate this new
modified protocol for a wider range of substrates, containing
additional electron-rich as well as electron-poor C-C double
bonds. As a result we describe a highly chemoselective and
mild nonepimerizing method for conjugate reduction of
stereochemically labile R,β-unsaturated amino ketones using
unprecedented (previously unused) phosphite ligated copper
hydride, which turned out to be the key for high chemos-
electivity.
ꢀ
Andrejs Pelss, Esa T. T. Kumpulainen, and
Ari M. P. Koskinen*
Department of Chemistry, Helsinki University of Technology,
P.O. Box 6100, FIN-02015 HUT, Espoo, Finland
ari.koskinen@tkk.fi
Received August 14, 2009
Highly chemoselective conjugate reduction of chiral R,β-
unsaturated amino ketones has been developed by using
triisopropyl phosphite ligated copper hydride complex.
The highlights of the method are wide substrate compat-
ibility and exceptional chemoselectivity.
SCHEME 1. Original Conditions As Used in Total Synthesis
Chemoselective reduction of variously conjugated and
isolated C-C double bonds presents a significant challenge
in organic chemistry even with the plethora of available
methods since the report by Adkins on the use of nickel
catalysts for reduction of mesityl oxide to methyl isobutyl
ketone, among other substrates.1 Several reagents are
known for achiral conjugate reduction of unsaturated car-
bonyl compounds such as triethylsilane, using catalytic
(Ph3P)3RhCl,2 K-selectride,3 hydrogen gas,4 and trialkylam-
monium formates5 in the presence of Pd/C, sodium dithio-
nite,6 Raney nickel,7 and various silanes in the presence of
catalytic amounts of rhodium(bisoxazolinylphenyl) com-
plexes.8 Stoichiometric [CuH(PPh3)]6 (Stryker’s reagent)9
We initially decided to investigate the effects of the
phosphine and phosphite ligands on the reactivity and
selectivity of the catalyst using the cyclohexanal derived
aminoketone 4 as the model substrate. The ligand screening
reactions were monitored with a gas chromatograph. The
ratios of silylated intermediates 5, 6, and 7 corresponding to
1,4-reduction, 1,2-reduction, and fully reduced products
were measured (Table 1). Isolated yields of hydrolyzed
products were also measured.
Ligands with different numbers of coordination sites were
tested. Monodentate ligands Ph3P L1, P(Oi-Pr)3 L4, and
P(OEt)3 L5 showed comparable reaction times and high
selectivity (Table 1). Triethyl phosphite L5 showed some
side reactions which lowered the yield. A reaction with DPPE
monoxide L2 was slower retaining high selectivity, whereas
DPPP monoxide L3 gave faster reaction but was slightly less
selective toward 1,4-reduction. Bidentate ligands DPPE L7,
DPPB L8, and the o-BDPPB ligand L9 recently reported by
(1) Covert, L. W.; Connor, R.; Adkins, H. J. Am. Chem. Soc. 1932, 54,
1651–1663.
(2) Ojima, I.; Kogure, T.; Nagai, Y. Tetrahedron Lett. 1972, 13, 5035–
5038.
(3) Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41, 2194–2200.
(4) See e.g.: (a) Marker, R. E.; Rohrmann, E. J. Am. Chem. Soc. 1940, 62,
518–520. (b) Marker, R. E.; Tsukamoto, T.; Turner, D. L. J. Am. Chem. Soc.
1940, 62, 2525–2532.
(5) Cortese, N. A.; Heck, R. F. J. Org. Chem. 1978, 43, 3985–3987.
(6) Camps, F.; Coll, J.; Guitart, J. Tetrahedron 1986, 16, 4603–4609.
(7) Barrero, A. F.; Alvarez-Manzaneda, E. J.; Chanboun, R.; Meneses,
R. Synlett 1999, 10, 1663–1666.
(8) Kanazawa, Y.; Nishiyama, H. Synlett 2006, 19, 3343–3345.
(9) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291–293. (b) Njardarson, J. T.; Gaul, C.; Shan, D.; Huang,
X.-Y.; Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 1038–1040. (c) Kraft,
P.; Eichenberger, W. Eur. J. Org. Chem. 2004, 354–365.
(10) (a) Mahoney, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111,
8818–8823. (b) Chen, J.-X.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M.
Tetrahedron 2000, 56, 2153–2166.
(11) For recent reviews on CuH-catalyzed reactions see: (a) Deutsch, C.;
Krause, N.; Lipshutz, B. H. Chem. Rev. 2008, 108, 2916–2927. (b) Lipshutz,
B. H. Synlett 2009, 509–524. For other leading references, see: (c) Lipshutz,
B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett. 1998, 39, 4627–4630.
(d) Lipshutz, B. H.; Crisman, W.; Noson, K.; Papa, P.; Sclafani, J. A.; Vivian,
R. W.; Keith, J. M. Tetrahedron 2000, 56, 2779–2788. (e) Mori, A.; Fujita, A.;
Kajiro, H.; Nishihara, Y.; Hiyama, T. Tetrahedron 1999, 55, 4573–4582. (f)
Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755–1757.
(12) Kumpulainen, E. T. T.; Koskinen, A. M. P.; Rissanen, K. Org. Lett.
2007, 9, 5043–5045.
(13) Lee, D.-W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037–2039.
7598 J. Org. Chem. 2009, 74, 7598–7601
Published on Web 09/09/2009
DOI: 10.1021/jo9017588
r
2009 American Chemical Society

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Pelss et al.
JOCNote
TABLE 1. Ligand Screening
SCHEME 2. Comparison Experiment with Stryker’s Reagent
were easily converted to ketones with good isolated yields. A
similar enone 15 containing a benzyloxy group at the γ-position
required longer reaction time (10 h) possibly due to nonbene-
ficial coordination to the catalyst. Sterically congested enones
(subtrates 17 and 19) derived from L-serine were also easily
reduced to the corresponding ketones. An R,γ-diunsaturated
ketone with an endocyclic and an exocyclic double bond
produced only 1,4-reduction product 22. Simple fully conju-
gated aromatic enone 23 gave rapid 1,4-reduction to ketone 24
(76%) with also some 19% of 1,2-reduction product 33. For
comparison, we executed reduction of 23 using in situ generated
Stryker’s reagent (Scheme 2). In this reaction we observed
slightly poorer selectivity toward 1,4-reduction and only 61%
of ketone 24 was recovered. Heteroaromatic compounds 25,
27, and 29 were found to be much more challenging substrates.
These reactions required higher Me(EtO)2SiH (3 equiv)
amounts and elevated temperatures.
The new conditions were tested also on complex advanced
intermediates 1 and 31. On nearly a gram scale 1 was
smoothly reduced to the corresponding ketone in 86% yield.
No epimerization of labile C-2 and C-6 stereocenters were
observed. Finally as the ultimate test a substrate 31 contain-
ing both an enone and an R,β-unsaturated ester was selec-
tively reduced to the monoreduced product 32 in 81% yield.
This is a rare example of a catalytic system able to distinguish
between two electronically similar double bonds and selec-
tively reduce only one of them when careful control of
hydride equivalents was used.18 There is also a possibility
of reductive Michael cyclization,19 which we did not observe
in this case.
In summary, we have developed a highly chemoselective
nonracemizing conjugate reduction of easily epimerizable un-
saturated R-aminoketones using triisopropyl phosphite ligated
copper hydride as the catalyst. The method shows very good
substrate compatibility: substrates containing free N-H groups
(acyclic and heterocyclic) as well as basic pyridine groups can be
reduced. Furthermore, we have shown that the method is
selective enough to reduce only an enone in the presence of
multiple less and more electron-rich olefins and even an enoate.
Therefore our method complements the recent Lipshutz meth-
od, which can be used when high efficiency and low catalyst
loading is required, whereas our method may find use in cases
where high chemoselectivity and mildness is required in redu-
cing complex and sensitive substrates.
Y (%)b
Entry Ligand Premix timea Time Ratio of 5:6:7 keto:alcohol
1
2
3
4
5
6
7
8
9
10
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
1 h
1.5 h
4 h
50 min
55 min
2 h
94:6:0
96:4:0
91:8:1
96:4:0
96:4:0
92:6:2
48:50:2
54:46:0
49:49:2
10:81:9
79:8
65:5
83:7
95:3
77:4
82:9
43:49
43:36
42:43
9:71
1.5 h
2 h
4 h
4 h
1.5 h
1 h
2 h
1 h
1 h
9 h
15 min
3.5 h
35 min
18 h
aTime needed for catalytically active species to be formed (copper salt
fully dissolved and occurrence of color change). bIsolated yields after 1.5
equiv of TBAF/5 equiv of AcOH quench and silica gel chromatography
for ketone 8 (from 5) and diastereomeric alcohols (from 6 and 7).
the Lipshutz group14 showed unselective reactions giving
roughly equal amounts of 1,2- and 1,4-reduction products.
These results show that ligands with two carbons between
phosphorus atoms provide the fastest reaction times (in
accord with literature) but surprisingly lack any selectivity
(entries 7 and 9). As an exception for bidentate ligands, the
DPPM L6 mediated reaction proceeded slowly, but with
much higher selectivity. Interestingly a tridentate tripho-
sphine ligand L10 gave a reaction that was mainly selective
toward 1,2-reduction. From these ligands P(Oi-Pr)3 L4
turned out to be the most selective giving also the highest
isolated yields. Although inexpensive and industrially avail-
able P(Oi-Pr)3 L4 is known to produce stable copper hydride
species,15 it has not been used as a copper catalyst ligand in
conjugate reductions to the best of our knowledge. It is also
of importance to note that epimerization16 of the potentially
vulnerable stereogenic center at C2 was not observed during
the conjugate reduction reaction.17
With the optimized conditions in hand we set out to
determine the substrate scope for this reaction (Table 2).
Since the use of 1.5 equiv of Me(EtO)2SiH provided the same
results and was more economical, with few exceptions we
used this amount of hydride donor in further experiments.
Both sterically demanding (substrates 4 and 13) and non-
demanding (substrates 9 and 11) enones derived from L-alanine
Experimental Section
Typical Conditions for Conjugate Reduction Reaction. A flame-
dried round-bottomed flask was charged with Cu(OAc)2 H2O
3
(14) Baker, A. B.; Boskovic, Z. V.; Lipshutz, B. H. Org. Lett. 2008, 10,
289–292.
(15) It is known that (i-PrO)3P forms crystalline complexes with copper
hydride of type (i-PrO)3PCuH, [(i-PrO)3P]2CuH, and [(i-PrO)3P]2(CuH)3.
(a) Malykhina, I. G.; Kazankova, M. A.; Lutsenko, I. F. Zh. Obshch. Khim.
1971, 41, 2103–2104. (b) Lutsenko, I. F.; Kazankova, M. A.; Malykhina, I.
G. Zh. Obshch. Khim. 1967, 37, 2364–2365.
(16) Epimerization of an R-stereocenter of a ketone has been observed
during copper hydride catalysis due to strongly basic copper alkoxides. See
ref 10b for details.
(18) (a) Eiter, K. Liebigs Ann. Chem. 1962, 658, 91–99. (b) Lee, H.-Y.; An,
M. Tetrahedron Lett. 2003, 44, 2775–2778. (c) Yang, J. W.; Hechavarria, F.;
List, B. J. Am. Chem. Soc. 2005, 127, 15036–15037.
(19) (a) Baik, T.-G.; Luis, A. L.; Wang, L.-C.; Krische, M. J. J. Am.
Chem. Soc. 2001, 123, 5112–5113. (b) Wang, L.-C.; Jang, H.-Y.; Roh, Y.;
Lynch, V.; Schultz, A. J.; Wang, X.; Krische, M. J. J. Am. Chem. Soc. 2002,
124, 9448–9453. (c) Miura, K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett
2004, 1985–1989. (d) Lee, H.; Jang, M.-S.; Hong, J.-T.; Jang, H.-Y. Tetra-
hedron Lett. 2008, 49, 5785–5788.
(17) See the Support Information for details.
J. Org. Chem. Vol. 74, No. 19, 2009 7599

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Pelss et al.
JOCNote
TABLE 2. Reduction of Different R-Chiral Enonesa
aTypical conditions: 1 mol % of Cu(OAc)2 H2O, 2 mol % of P(Oi-Pr)3, 1,5 equiv of Me(EtO)2SiH, toluene, rt. bIsolated yields after 1.5 equiv of
3
TBAF/5 equiv of AcOH quench and silica gel chromatography. cHF/pyridine was used for workup. d3 equiv of Me(EtO)2SiH was used. e3 equiv of
Me(EtO)2SiH was used at 40 °C. f3 equiv of Me(EtO)2SiH was used at 70 °C. g0.83 g (2.2 mmol) of 1 was used. h1.25 equiv of Me(EtO)2SiH was used.
(1.4 mg, 7.1 μmol) and evacuated under vacuum and refilled
with argon. Then 2 mL of dry toluene was added followed
by triisopropyl phosphite (3.3 μL, 14.2 μmol) and Me(EtO)2-
SiH (0.17 mL, 1.07 mmol). The mixture was stirred at room
temperature under positive pressure of argon for 3-4 h until
the color changed from blue through light green to light brown.
Then 0.20 g (0.71 mmol) of substrate 3 was cannulated into the
reaction mixture as a solution in toluene (2 mL). After 1 h of
reaction time acetic acid (0.20 mL, 3.55 mmol) was added. After
5 min 1 M TBAF (1.09 mL, 1.09 mmol) in THF was added to
quench the reaction. The mixture was stirred for 15 min and
evaporated to dryness. The residue was purified by silica gel
chromatography (10% EtOAc/hexanes) furnishing 0.18
(90%) of reduction product 8. Rf 0.62 (33% EtOAc/hexanes);
g
IR (thin film, cm-1) 3354, 2978, 2925, 2852, 1710, 1508,
1
1498, 1450, 1367, 1248, 1171; H NMR (400 MHz, CDCl3) δ
5.34 (d, J = 6.4 Hz, 1H), 4.20 (dq, J = 6.9, 6.7 Hz, 1H), 2.32-
2.47 (m, 2H), 1.48-1.58 (m, 5H), 1.34-1.40 (m, 2H), 1.32
(s, 9H), 1.20 (d, J = 7.2 Hz, 3H), 1.00-1.16 (m, 4H), 0.73-
0.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 209.8, 155.0,
7600 J. Org. Chem. Vol. 74, No. 19, 2009

ꢀ
Pelss et al.
JOCNote
Chemical Biology, Orion Farmos Research Foundation, and
79.3, 54.8, 37.1, 36.5, 32.9, 32.9, 30.7, 28.2, 26.3, 26.0, 17.7;
HRMS (ESI) calcd for [M þ Na] C16H29NO3Na 306.2045, found
306.2040.
€ €€ €
Tekniikan Edistamissaatio (TES).
Supporting Information Available: Experimental details
and characterization data for new compounds. This mate-
rial is available free of charge via the Internet at http://pubs.
acs.org.
Acknowledgment. This work was supported by the Acad-
emy of Finland (Grants 111198 and 123485). E.T.T.K. is a
recipient of The Graduate School of Organic Chemistry and
J. Org. Chem. Vol. 74, No. 19, 2009 7601