Cu(I)-catalyzed reductive aldol cyclizations: Diastereo- and enantioselective synthesis of β-hydroxylactones

Article abstract of DOI:10.1021/ol051649h

(Chemical Equation Presented) Copper bisphosphine complexes catalyze the intramolecular reductive aldol reaction of α,β-unsaturated esters with ketones, affording five-and six-membered β-hydroxylactones in high stereoselectivities. Utilization of chiral nonracemic bisphosphines render the cyclizations enantioselective.

Full text of DOI:10.1021/ol051649h

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4225-4228
Cu(I)-Catalyzed Reductive Aldol
Cyclizations: Diastereo- and
Enantioselective Synthesis of
â
-Hydroxylactones†
Hon Wai Lam* and Pekka M. Joensuu
School of Chemistry, UniVersity of Edinburgh, The King’s Buildings,
West Mains Road, Edinburgh EH9 3JJ, United Kingdom
h.lam@ed.ac.uk
Received July 13, 2005
ABSTRACT
Copper bisphosphine complexes catalyze the intramolecular reductive aldol reaction of
r
,
â
-unsaturated esters with ketones, affording five-
and six-membered
enantioselective.
â-hydroxylactones in high stereoselectivities. Utilization of chiral nonracemic bisphosphines render the cyclizations
The hydrometalation of R,â-unsaturated carbonyl compounds
has proven to be a mild and versatile method of enolate
generation, one that is amenable to catalysis and that may
be applied to a range of reductive carbon-carbon bond
constructions.1-3 Since the seminal report of the rhodium-
catalyzed intermolecular reductive aldol reaction by Revis
and Hilty,1a a number of related processes have been
described,1b-h including enantioselective variants.2 Intramo-
lecular versions of these processes have also been utilized
by a number of groups to prepare a range of carbocyclic
products, often in high diastereomeric purities.1f,h,3 During
the course of a natural product synthesis program, we became
interested in the possibility of applying reductive aldol
cyclizations to the preparation of heterocyclic products.4
Herein we wish to report a highly diastereoselective synthesis
of â-hydroxylactones and our preliminary attempts at render-
ing the cyclizations enantioselective.
Our initial studies focused upon the cyclization of substrate
1, containing an R,â-unsaturated carbonyl moiety tethered
to a ketone through an ester linkage (eq 1). Reductive aldol
† Dedicated to Prof. Gerald Pattenden on the occasion of his 65th
birthday.
(1) For reports of catalytic intermolecular reductive aldol reactions, see:
(a) Revis, A.; Hilty, T. K. Tetrahedron Lett. 1987, 28, 4809-4812. (b)
Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 2005-2008. (c) Matsuda,
I.; Takahashi, K.; Sato, S. Tetrahedron Lett. 1990, 37, 5331-5334. (d)
Kiyooka, S.; Shimizu, A.; Torii, S. Tetrahedron Lett. 1998, 39, 5237-
5238. (e) Ooi, T.; Doda, K.; Sakai, D.; Maruoka, K. Tetrahedron Lett. 1999,
40, 2133-2136. (f) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am.
Chem. Soc. 2002, 124, 15156-15157. (g) Shibata, I.; Kato, H.; Ishida, T.;
Yasuda, M.; Baba, A. Angew. Chem., Int. Ed. 2004, 43, 711-714. (h) Miura,
K.; Yamada, Y.; Tomita, M.; Hosomi, A. Synlett 2004, 1985-1989.
(2) (a) Nishiyama, H.; Shiomi, T.; Tsuchiya, Y.; Matsuda, I. J. Am. Chem.
Soc. 2005, 127, 6972-6973. (b) Russell, A. E.; Fuller, N. O.; Taylor, S. J.;
Aurriset, S.; Morken, J. P. Org. Lett. 2004, 6, 2309-2312. (c) Zhao, C.-
X.; Duffey, M. O.; Taylor, S. O.; Morken, J. P. Org. Lett. 2001, 3, 1829-
1831. (d) Taylor, S. J.; Duffey, M. O.; Morken, J. P. J. Am. Chem. Soc.
2000, 122, 4528-4529.
cyclizations of this type would allow the stereoselective
synthesis of tertiary-alcohol-containing lactones, which could
serve as potentially versatile chemical building blocks.
Although reductive aldol reactions have been mediated by a
variety of metal catalysts,1-3 phosphine-stabilized copper
hydride complexes appeared to be a good choice for
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evaluation in the present reaction for a number of reasons.
First, Chiu and co-workers have demonstrated the ability of
[(Ph3P)CuH]6 (commonly known as Stryker’s reagent5), used
either in stoichiometric fashion or catalytically in the presence
of stoichiometric siloxane, to promote reductive aldol cyl-
izations in carbocycle synthesis.3d,f Second, recent develop-
ments in asymmetric reduction reactions catalyzed by chiral
copper(I)-bisphosphine complexes6 suggested that in prin-
ciple a highly enantioselective process might also be realized
in the present case through identification of an appropriate
ligand.
Table 1. Catalytic Reductive Aldol Cyclizations To Form
â-Hydroxylactonesa
We began our investigation by surveying a number of
copper salts,7 siloxanes,8 and bisphosphine ligands9 in order
to identify a suitable catalyst system. From these studies,
Cu(OAc)2‚H2O,10 1,1,3,3-tetramethylhydrosiloxane (TMDS),
and either 1,1′-bis(diphenylphosphino)ferrocene (DPPF) or
racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (rac-
BINAP) in THF emerged as suitable reagent combinations
to promote the desired cyclization, giving lactone 2 in good
yields (eq 1).11 DPPF was arbitrarily chosen for subsequent
experiments.
Under these conditions, a range of substrates underwent
cyclization to give â-hydroxy-δ-valerolactone products (Table
(3) (a) Koech, P. K.; Krische, M. J. Org. Lett. 2004, 6, 691-694. (b)
Huddleston, R. R.; Krische, M. J. Org. Lett. 2003, 5, 1143-1146. (c) 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. (d) Chiu, P.; Leung, S. K.
Chem. Commun. 2004, 2308-2309. (e) Freir´ıa, M.; Whitehead, A. J.;
Tocher, D. A.; Motherwell, W. B. Tetrahedron 2004, 60, 2673-2692. For
an example of a stoichiometric reductive aldol reaction, see: (f) Chiu, P.;
Szeto, C.-P.; Geng, Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901-1903. For
an example of a stoichiometric reductive Michael reaction, see: (g)
Kamenecka, T. M.; Overman, L. E.; Ly Sykata, S. K. Org. Lett. 2002, 4,
79-82.
a Reactions were conducted using 1.0 mmol of substrate, 5 mol % Cu,
5 mol % ligand, and 1.0 mmol TMDS in 5 mL THF for 13-30 h. b Unless
otherwise stated, only one diastereoisomer of product was observed by 1H
NMR spectroscopy. c Isolated yield of diastereomerically pure material.
d Product formed as an 8:1 mixture of diastereoisomers. e Product isolated
as an inseparable 10:1 mixture of diastereoisomers. PMP ) p-methoxyphe-
nyl.
(4) For the formation of a tetrahydropyran from a reductive aldol
cyclization, see ref 3b.
(5) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291-295.
(6) For examples of enantioselective conjugate reductions, see: (a)
Lipshutz, B. H.; Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126,
8352-8353. (b) Rainka, M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 5821-5823. (c) Czekelius, C.; Carreira, E. M. Org.
Lett. 2004, 6, 4575-4577. For examples of enantioselective ketone
reductions, see: (d) Wu, J.; Ji, J.-X.; Chan, A. S. C. Proc. Natl. Acad. Sci.
U.S.A. 2005, 102, 3570-3575. (e) Lee, D.-w.; Yun, J. Tetrahedron Lett.
2004, 45, 5415-5417. (f) Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower,
A. J. Am. Chem. Soc. 2003, 125, 8779-8789. (g) Sirol, S.; Courmarcel, J.;
Mostefai, N.; Riant, O. Org. Lett. 2001, 3, 4111-4113. For an example of
enantioselective imine reduction, see: (h) Lipshutz, B. H.; Shimizu, H.
Angew. Chem., Int. Ed. 2004, 43, 2228-2230.
1, entries 1-9). R,â-Unsaturated ester components containing
aromatic (entries 1 and 2), heteroaromatic (entry 3), and alkyl
(entries 4 and 5) substituents were tolerated in the reaction,
as was the trisubstituted enoate 3f (entry 6). Replacement
of the methyl ketone with a phenyl ketone also permitted
cyclization to take place (entries 7-9), though in the case
of substrates 3h and 3i the reactions did not proceed to
completion (entries 8 and 9). Surprisingly, the process could
also be applied to the formation of five-membered lactones
(entries 10-13), despite these cyclizations formally being
disfavored 5-(enolendo)-exo-trig ring closures according to
Baldwin’s rules.12
(7) Copper salts examined included CuCl2‚2H2O, CuF2, Cu(OAc)2‚H2O,
Cu(2-ethylhexanoate)2, Cu(OBz)2, and Cu(acac)2.
(8) The inexpensive siloxanes polymethylhydrosiloxane (PMHS) and
1,1,3,3-tetramethylhydrosiloxane (TMDS) were evaluated.
(9) The following bisphosphine ligands were studied: 1,2-bis(diphen-
ylphosphino)ethane (DPPE), 1,2-bis(diphenyl-phosphino)butane (DPPB),
1,1′-bis(diphenylphosphino)ferrocene (DPPF), racemic 2,2′-bis(diphen-
ylphosphino)-1,1′-binaphthyl (rac-BINAP), and (+)-1,2-bis((2S,5S)-2,5-
diethylphospholano)benzene ((S,S)-Et-DuPhos).
The reactions proceeded at room temperature and except
in the cases of substrates 3h and 3i were highly diastereo-
1
selective (>95:5 by H NMR analysis of the unpurified
(10) Cu(OAc)2‚H2O has shown to be a particularly convenient copper
source for copper hydride generation. See refs 6b and 6e.
reaction mixtures).13 However, the desired â-hydroxylactones
were often accompanied by small quantities of uncyclized
side products that had undergone reduction at the enoate and
(11) Preliminary experiments were conducted in THF using PMHS as
the siloxane. Of the copper salts examined, only Cu(OAc)2‚H2O and Cu-
(2-ethylhexanoate)2 resulted in high conversions, with Cu(OAc)2‚H2O being
preferred for economic considerations. rac-BINAP and DPPF performed
with similar efficacy, with very low conversions being observed with DPPE,
DPPB, and (S,S)-Et-DuPhos. For substrate 1, PMHS and TMDS were found
to be equally effective. However, subsequent studies showed TMDS to give
slightly cleaner reactions for a wider range of substrates. Toluene, CH2Cl2,
and MeCN proved to be inferior solvents, although DME was similar to
THF.
(12) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38, 2939-2947. A
possible explanation for the ready cyclization of substrates 3j-m is that
the copper enolate intermediate (depicted as an oxa-π-allylcopper species
in Scheme 1) has significant C-bound character, which reduces its planarity
and better enables ring closure.
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Org. Lett., Vol. 7, No. 19, 2005

in some cases at the ketone, resulting in moderate yields.
This observation indicates that the rate of σ-bond metathesis14
of the intermediate copper enolate with the siloxane is
competitive with the rate of aldol cyclization (see Scheme
1, vide infra).
Table 2. Catalytic Asymmetric Reductive Aldol Cyclizationsa
entry
substrate
ligand
yield (%)
ee (%)
1
2
1
5
6
7
8
9
5
6
7
9
5
6
7
9
7
72
73
69
64
62
79
71
71
73
60
60
61
68
51
62
1
73
3
1
70b
77b
74
4
1
5
1
6
3b
3b
3b
3b
3e
3e
3e
3e
3m
73
7
76
8
83b
82
9
10
11
12
13
14
72
73
80b
80
49b
a Reactions were conducted using 0.2 mmol of substrate, 5 mol % Cu,
5 mol % ligand, and 0.2 mmol TMDS in 2 mL THF for 24 h. b The
enantiomer opposite to that depicted was obtained.
Figure 1. Bisphosphine ligands evaluated in asymmetric cycliza-
tions.
asymmetric induction in these reactions was determined by
Having established the viability of the basic process, we
next turned our attention to the use of nonracemic chiral
bisphosphine ligands to generate enantiomerically enriched
products. A selection of bisphosphines 5-9 incorporating a
biaryl backbone15 (Figure 1) were evaluated in the asym-
metric cyclizations of substrates 1, 3b, 3e, and 3m, and the
results are presented in Table 2.
X-ray crystallography of the chlorine-containing lactone 4b.18
Scheme 1. Proposed Catalytic Cycle
In general, the chiral ligands performed with efficiency
comparable to that of the achiral ligand DPPF, affording the
products in similar yields. However, at our current level of
optimization, the enantioselectivies obtained remain modest.
While (S)-BINAP (5) gave the lactone 2 in 62% ee (entry
1), the Roche MeO-BIPHEP ligands 6-816 and Takasago’s
SEGPHOS ligand 917 led to slight improvements in enantio-
selectivity (entries 2-5). Similar patterns were observed for
two other substrates (entries 6-13), with the best result of
83% ee being obtained using ligand 7 in the cyclization of
3b (entry 8). In the case of the formation of the five-
membered lactone 4m using ligand 7, the enantiomeric
excess was only 49% (entry 14). The absolute sense of
(13) The relative configurations of lactones 4b, 4e, and 4f were confirmed
by X-ray crystallography, and the relative configurations of 2, 4j and 4l
were confirmed by NOESY experiments. The stereochemistries of the
remaining products were assigned by analogy. See Supporting Information
for details.
(14) Lipshutz, B. H.; Chrisman, W.; Noson, K. J. Organomet. Chem.
2001, 624, 367-371.
A plausible catalytic cycle for the process is presented in
Scheme 1. Presumably, in the presence of bisphosphine and
TMDS, reduction of copper(II) occurs19 to generate a copper-
(I)-bisphosphine hydride complex 10, which then engages
(15) For a recent review of biaryl-type bisphosphine ligands, see:
Shimizu, H.; Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405-5432.
(16) 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, 131-138.
(17) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264-267.
(18) See Supporting Information for details.
Org. Lett., Vol. 7, No. 19, 2005
4227

in hydrometalation with the substrate 11 to generate the
copper enolate 12. Carbonyl addition results in the copper
aldolate 13, which then undergoes σ-bond metathesis14 with
the siloxane to liberate the silylated product 14 (which is
deprotected upon workup), regenerating the copper(I) com-
plex 10. However, we do not rule out alternative mechanisms
that invoke the participation of copper species such as silyl
hydrido cuprates 15.6f Furthermore, the role played by the
acetate counterions is unclear. The observed stereochemistry
of the products13 presumably arises from preferential forma-
tion of the Z-copper enolate, coupled with chelation in the
carbonyl addition step (as in 12).
tions of the general process and to identify other catalyst
systems that deliver improved activities, higher yields, and
higher levels of enantioselection.
Acknowledgment. This work was supported by the
University of Edinburgh, the Nuffield Foundation (NAL/
00827/G), and the Royal Society (2004/R1). AstraZeneca
and Merck Sharp & Dohme are gratefully acknowledged for
generous research funding. We thank Dr. Rudolf Schmid
(Hoffmann-La Roche) and Dr. Hideo Shimizu (Takasago)
for supplying the MeO-BIPHEP and SEGPHOS ligands,
respectively, used in this study. The EPSRC National Mass
Spectrometry Service Centre at the University of Wales,
Swansea is thanked for their assistance.
In summary, we have developed diastereo- and enantio-
selective copper-catalyzed reductive aldol cyclizations that
afford five- and six-membered â-hydroxylactones. Efforts
are underway in our laboratory to discover further applica-
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds, and
crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) Consistent with this hypothesis is the observation of the characteristic
emerald green color of a solution of Cu(OAc)2‚H2O (blue) and DPPF
(yellow) in THF being quickly converted into a yellow solution upon
addition of TMDS, which is indicative of the reduction of copper(II) and
the disappearance of the associated blue color.
OL051649H
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Org. Lett., Vol. 7, No. 19, 2005