Diastereo- and enantioselective hydrogenative aldol coupling of vinyl ketones: Design of effective monodentate TADDOL-like phosphonite ligands

Article abstract of DOI:10.1021/ja710862u

We report the first enantioselective reductive aldol couplings of vinyl ketones, which were achieved through the design of a novel monodentate TADDOL-like phosphonite ligand. Specifically, hydrogenation of commercially available methyl vinyl ketone (MVK) or ethyl vinyl ketone (EVK) in the presence of aldehydes 1a-7a using cationic rhodium catalysts modified by chiral TADDOL-like phosphonite ligands AP-I and AP-IV produces aldol adducts 1b-7b and 1c-7c with excellent control of relative and absolute stereochemistry. The absolute stereochemical assignments of the aldol adducts are made in analogy to that determined for the 5-bromophthalimido derivative of aldol adduct 1b and the 2-bromo-5-nitrobenzoate of 3b, which were established by single-crystal X-ray diffraction analysis using the anomalous dispersion method. Copyright

Full text of DOI:10.1021/ja710862u

Published on Web 02/12/2008
Diastereo- and Enantioselective Hydrogenative Aldol Coupling of Vinyl
Ketones: Design of Effective Monodentate TADDOL-Like Phosphonite
Ligands
Cisco Bee, Soo Bong Han, Abbas Hassan, Hiroki Iida, and Michael J. Krische*
UniVersity of Texas at Austin, Department of Chemistry and Biochemistry, Austin, Texas 78712
Received December 5, 2007; E-mail: mkrische@mail.utexas.edu
Table 1. Key Results in the Optimization of Ligand Substructures
The reductive coupling of R,â-unsaturated carbonyl compounds
in an Enantioselective Aldol Coupling of MVK to Aldehyde 1aa
to aldehydes and ketones, termed the “reductive aldol reaction”,
has become the topic of intensive investigation.1 Following seminal
studies by Revis (1987),2a catalysts for reductive aldol coupling
based on rhodium,2,3 cobalt,4a-e iridium,4f ruthenium,4g palladium,4h
copper,4i-p nickel,4q and indium4r,s have been developed. Enanti-
oselective variants of the reductive aldol coupling only have
been achieved in connection with the use of R,â-unsaturated
esters.2d,h,j-m,4f,j,l,m-o Enantioselective reductive aldol couplings of
vinyl ketones, such as methyl vinyl ketone (MVK), would enable
access to branched aldol adducts, providing a regiochemical
complement to direct organocatalytic and metal catalyzed aldol
couplings of nonsymmetric ketones, such as 2-butanone, which
furnish linear aldol adducts.5 HoweVer, to date, enantioselectiVe
reductiVe aldol couplings of Vinyl ketones haVe not been deVised.
a Cited yields are of isolated material. Enantioselectivities were deter-
mined by chiral stationary phase HPLC analyses made in comparison to
racemic diastereomeric mixtures, and g30:1 syn-diastereoselectivity was
observed in each case. See Supporting Information for detailed experimental
b
procedures. Reaction was conducted at 0 °C.
In 2002, we reported that catalytic hydrogenation of vinyl ketones
in the presence of aldehydes results in reductive aldol coupling to
furnish branched aldol adducts as diastereomeric mixtures.3a Later
(2006), it was found that high levels of syn-diastereoselectivity in
hydrogen-mediated reductive aldol couplings of vinyl ketones are
obtained through the use of tri-2-furylphosphine (Fur3P) ligated
rhodium catalysts.3e-g,6 Efforts toward enantioselective variants of
such hydrogenative aldol couplings were especially challenging due
to the fact that (a) only trace quantities of product are obtained
using chelating phosphine ligands, (b) π-acidic ligands such as
Fur3P are required to enforce high levels of diastereoselection,6 yet
(c) commercially available π-acidic chiral monodentate ligands, for
example, BINOL-derived phosphites and phosphoramidites, are
presumably too π-acidic and provide only trace quantities of
product. Hence, the design, preparation and assay of novel chiral
monodentate P-based ligands was undertaken.
Over a period of years numerous ligands were assayed, yet those
displaying promising levels of asymmetric induction were not
amenable to facile and systematic structural variation. Hence, a
versatile template enabling well-defined structure-selectivity trends
was sought. TADDOL-like phosphonites7 present three structural
elements that may be independently optimized: (a) the P-aryl
moiety, (b) the ketal substructure, and (c) the groups appended to
the tertiary carbinol center. In terms of enantioselectivity, the
2-benzothienyl moiety was best. The role of the ketal moiety was
examined next. Here, improved selectivity is observed using the
diethyl ketal. Finally, for substituents at the carbinol center, groups
larger than the dimethyl carbinol moiety confer a substantial
decrease in reactivity. Gratifyingly, using ligand AP-I (“AbbasPhos-
I”), which combines the optimal 2- benzothienyl, diethyl ketal, and
dimethyl carbinol substructures, aldehyde 1a is transformed to the
syn-aldol 1b with exceptional levels of relative and absolute
stereocontrol (Table 1).
The scope of ligand AP-I was examined in reductive aldol
couplings of MVK and EVK to diverse aldehydes.8 Optimal
efficiencies and selectivities were observed using the preformed
complex [Rh(cod)(AP-I)2]OTf as a precatalyst. Beyond aldehydes
1a and 2a, â-heteroatom substituted aldehydes 3a, 4a and R-(het-
ero)aryl aldehydes 5a, 6a, and 7a were found to engage in highly
diastereo- and enantioselective hydrogenative aldol additions (Table
2).9 Interestingly, using the first generation ligand AP-I, only
moderate enantioselectivities were observed for aldehyde 4a. Single-
crystal X-ray diffraction analysis of [Rh(cod)(L)2]OTf (L ) the
acetonide of AP-I) reveals a C2-symmetric arrangement (Figure
1). Based upon the hypothesis that a similar metal-ligand arrange-
ment is evident in the stereo-determining event, ligands AP-II and
AP-IV were designed. For ligands AP-II and AP-IV the (benzo)-
thiophene moiety is substituted such that the purported chiral pocket
is deepened, potentially conferring heightened levels of enantiose-
lection. The veracity of this analysis is supported by the fact that
AP-II and AP-IV are both found to induce higher levels of optical
enrichment, whereas AP-III, which projects the methyl residue into
9
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J. AM. CHEM. SOC. 2008, 130, 2746-2747
10.1021/ja710862u CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Diastereo- and Enantioselective Aldol Coupling of MVK
and EVK to Aldehydes 1a-7aa
(RO1-GM069445), and the Higher Education Commission, Pakistan
for partial support of this research. Quan Truong is acknowledged
for skillful technical assistance.
Supporting Information Available: Experimental procedures,
spectral and HPLC data for new compounds, X-ray diffraction data
for 5-bromophthalimido 1b, the 2-bromo-5-nitrobenzoate of 3b, and
[Rh(cod)(L)2]OTf. This material is available free of charge via the
Internet at http://pubs.acs.org.
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performed at 0 °C using the preformed complex [Rh(cod)(Ligand)2]OTf
and were reproduced a minimum of two times. See Supporting Information
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Figure 1. Structure of [Rh(cod)(L)2]OTf (L ) the acetonide of AP-I)
determined by X-ray diffraction reveals C2-symmetric arrangement. The
figure graphics are depictions of crystallographic data imported into
ChemDraw Ultra 9.0. For clarity, the following substructures were omitted.
Top: The methyl groups and triflate ion. Front: The methyl groups, triflate
ion, and COD. Side: The methyl groups, triflate ion, dioxolane rings, and
phosphonite oxygen atoms.
Table 3. Effect of Ligands AP-I, AP-II, AP-III, and AP-IV in the
Enantioselective Aldol Coupling of MVK to Aldehyde 4aa
(5) (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M.
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a As described in Table 2 footnotes.
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(8) Aromatic aldehydes display good reactivity and diastereoselectivity, but
poor enantioselectivities are observed. Additionally, unactivated aliphatic
aldehydes exhibit poor reactivity, providing diminished yields of product.
Studies aimed at addressing these deficiencies are in progress.
(9) The absolute stereochemical assignments of the aldol adducts are made
in analogy to that determined for the 5-bromophthalimido derivative of
aldol adduct 1b and the 2-bromo-5-nitrobenzoate of 3b, which were
established by single crystal X-ray diffraction analysis using the anomalous
dispersion method.
an inactive volume of space, displays selectivities comparable to
those of AP-I (Table 3).
In summary, we report the first enantioselective reductive aldol
coupling of vinyl ketones, which were achieved through the design
of an effective new class of TADDOL-like phosphonite ligands.
This study further demonstrates that organometallics arising
transiently in the course of catalytic hydrogenation offer a byprod-
uct-free alternative to preformed organometallic reagents, for
example enol(ate) derivatives, employed routinely in classical
CdX (X ) O, NR) addition processes.
Acknowledgment. Acknowledgment is made to the Robert A.
Welch Foundation, Johnson & Johnson, Merck, the NIH-NIGMS
JA710862U
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