CuH-catalyzed enantioselective intramolecular reductive aldol reactions generating three new contiguous asymmetric stereocenters

Article abstract of DOI:10.1021/ja8045475

Treatment of β,β-disubstituted-α,β-unsaturated ketones bearing a ketone residue with in situ generated, catalytic CuH ligated by a nonracemic ligand leads to three newly created adjacent chiral centers. Excellent des and ees are obtained for several examples studied. Copyright

Full text of DOI:10.1021/ja8045475

Published on Web 10/11/2008
CuH-Catalyzed Enantioselective Intramolecular Reductive Aldol Reactions
Generating Three New Contiguous Asymmetric Stereocenters
Bruce H. Lipshutz,* Benjamin Amorelli, and John B. Unger
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received June 24, 2008; E-mail: lipshutz@chem.ucsb.edu
Asymmetric reductive aldol reactions provide powerful inroads
to stereocontrolled centers of considerable value in synthesis.1
Invariably, the ꢀ-site in an R,ꢀ-unsaturated carbonyl derivative
either is unsubstituted or at most contains a single E- or Z-
substituent. Hence, initial conjugate reduction, regardless of hydride
source (e.g., pinacolborane),1h is of no stereochemical consequence.
Rather, the in situ formed nonracemic enolate is the species that
controls the subsequent aldol event, thereby giving rise to the
anticipated two new centers of central chirality. We now describe
the first hydrometallative intramolecular cycloreduction leading to
three new contiguous stereocenters in a one-pot process, based on
a nonracemically ligated (L*) catalytic source of CuH (eq 1).
Figure 1. Josiphos ligands: I ) (S,R)-PPF-P(t-Bu)2; II ) (R,S)-(4-
CF3Ph)2PF-P(t-Bu)2.
Table 1. Optimization: Enantioselective Reductive Aldol
Cyclizationsa
temp
(°C)
time
(h)
yield
(%)b
ee
(%)c
entry
1 (%)
silane
solvent
1d
2
1
1
0.5
1
1
DEMS
DEMS
DEMS
PhSiH3
DEMS
DEMSf
toluene
toluene
toluene
toluene
THF
0
0
6
6
12
6
12
8
81
91
87
65
35
85
93
93
96
97
96
96
Our approach derives from known conjugate reductions of ꢀ,ꢀ-
disubstituted, R,ꢀ-unsaturated ketones2 and related prochiral educts,3
catalyzed by ligand-stabilized copper hydride. Facial discrimination
in the initial 1,4-hydride addition generates an intermediate chiral
(presumably copper) enolate that subsequently participates in an
intramolecular aldol addition to ketones.4a Transmetalation of the
resulting copper alkoxide with a particular stoichiometric silane as
reductant regenerates ligated CuH.4b
Reactions of (E)-ꢀ,ꢀ-disubstituted enone 1 with CuH ligated by
the Solvias5 bis-phosphine (S,R)-PPF-P(t-Bu)2 (I; Figure 1) in the
presence of diethoxymethylsilane (DEMS)6 gave a single dia-
stereomer in high ee’s (Table 1). Yields of the newly formed six-
membered ring cycloadduct 2 were somewhat depressed when
reactions were conducted at concentrations above 0.25 M, presum-
ably due to competition between silyl enol ether formation (i.e.,
transmetalation from the copper enolate)7 and aldol cyclization
(Table 1, entry 1). However, a good yield was obtained (91%)
without loss of ee employing DEMS (1.5 equiv) with 0.5 mol %
catalyst I in toluene (0.25 M) at 0 °C (entry 2). Further cooling to
-10 °C raised the ee to 96% (entry 3). Reaction in the presence of
phenylsilane (PhSiH3) in toluene also gave a high ee, although the
efficiency suffered (entry 4). Excess silane and ligand were required
upon changing solvent from toluene to THF (entries 5, 6). Thus,
further studies were conducted in toluene at -10 °C with DEMS
as the source of mild hydride.
3
-10
4e
5
0
-10
-10
6
2
THF
a All reactions were quenched with NH4F-MeOH. b Isolated yields.
c Determined by chiral HPLC analysis (see Supporting Information).
d 0.5 M in toluene. e 1.0 M in toluene. f 5 equiv.
demanding groups located at both the ꢀ-position and adjacent to
the enone carbonyl were tolerated (entry 5). Aryl enones (entries
6, 7) gave modest ee’s that were difficult to improve regardless of
bis-phosphine ligand. On the other hand, the reaction involving the
E-n-butyl enone (entry 9) that also initially afforded a lower ee
with ligand I (64% ee) could be significantly improved by switching
to Josiphos analogue II8 (97% ee). The inverted sense of chirality
(entry 9) follows from use of the (R,S)-enantiomer of this ligand.
The five-membered ring precursor 3 gave rise to two isolable
diastereomers, the ee for each was >90% (entry 10).
Scheme 1. Heterogeneous and Aqueous Asymmetric Reductive
Aldol Reactions
Representative reductive cyclizations of various ꢀ,ꢀ-disubstituted
enones using 1 mol % catalyst are illustrated in Table 2. Both E-
and Z-methyl enone pairs (entries 1 and 2; entries 3 and 4) gave
enantiomeric products in good yields and ee’s. The sense of
stereoinduction was similar to that predicted based on previous
studies with the related substrate/ligand combination,2 despite any
influence of the pendant carbonyl residue. X-ray data confirmed
this trend (see Supporting Information, SI). Sterically more
9
14378 J. AM. CHEM. SOC. 2008, 130, 14378–14379
10.1021/ja8045475 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Cycloreductions Using Catalytic CuHaa
In summary, we have described the first asymmetric conjugate
reduction/intramolecular aldol reactions of acyclic ꢀ,ꢀ-disubstituted
keto enones, catalyzed by nonracemic bis-phosphine-ligated copper
hydride. Yields, de’s, and ee’s for six-membered rings containing
three newly fashioned contiguous asymmetric centers, in particular,
are uniformly high. This sequence can also be carried out both
heterogeneously with Cu/C and in pure water as solvent in the
presence of the commercially available amphiphile PTS.11
Acknowledgment. Financial support provided by the NSF (CHE
05-50232) and Zymes, LLC is warmly acknowledged. We also
sincerely thank Solvias for a generous supply of the ligands used
in this study.
Supporting Information Available: Experimental details, spectro-
scopic data for all products, and X-ray data (Table 2, entries 1 and 4).
This material is available free of charge via the Internet at http://
pubs.acs.org.
References
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a Conditions: 3-5% Cu(OAc)2 ·H2O, 1% (S,R)-PPF-P(t-Bu)2 (I), 1.5
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ca. 4 equiv of DEMS in toluene to afford 2 (84% yield, 98% ee).
Raising the temperature to ambient, surprisingly, did not signifi-
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asymmetric reductive aldol could also be run entirely in water
notwithstanding the water-insoluble nature of educt Z-1. Thus, in
the presence of nanomicelle-forming PTS10 (a nonionic, vitamin
E based surfactant; 2% by weight), 1,4-reduction/cyclization in the
presence of excess PhSiH3 at 5 °C led to adduct ent-2 in comparable
yield and ee (cf. Table 2, entry 2, using toluene at -10 °C).
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(8) For a listing of the ligands examined, see the SI.
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(11) Sigma-Aldrich catalog no. 698717.
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