Diastereo- and enantioselective anti-alkoxyallylation employing allylic gem-dicarboxylates as allyl donors via iridium-catalyzed transfer hydrogenation

Article abstract of DOI:10.1021/ja9097675

(Chemical Equation Presented) Enantioselective transfer hydrogenation of gem-dibenzoate 1e in the presence of aromatic, α,β-unsaturated, or aliphatic aldehydes 2a-i mediated by isopropyl alcohol and employing a cyclometalated iridium C,O-benzoate derived from allyl acetate, 4-cyano-3-nitrobenzoic acid, and (R)-SEGPHOS delivers products of alkoxyallylation 3a-i, 4a, 4e, 4f, and 4i in good isolated yields (62-82%) with good to excellent diastereoselectivities (7:1 to 18:1 dr) and exceptional enantioselectivities (90-99% ee). This protocol provides an alternative to the use of premetalated nucleophiles in carbonyl alkoxyallylation. Copyright

Full text of DOI:10.1021/ja9097675

Published on Web 01/25/2010
Diastereo- and Enantioselective anti-Alkoxyallylation Employing Allylic
gem-Dicarboxylates as Allyl Donors via Iridium-Catalyzed Transfer
Hydrogenation
Soo Bong Han, Hoon Han, and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received November 17, 2009; E-mail: mkrische@mail.utexas.edu
Table 1. Optimizing Anti Diastereoselectivity in the Alkoxyallylation
Enantioselective carbonyl allylation represents an important class
of C-C bond-forming reactions that have found broad use in organic
synthesis.1 Among allylation protocols, enantioselective aldehyde
R-alkoxyallylation provides an efficient means of generating allylic
vicinal diol substructures. To date, asymmetric syn-additions of this
type have employed chirally modified alkoxy-substituted allylmetal
reagents based on boron,2 aluminum,3 titanium,4 indium,5 or tin.6
Indirect enantioselective aldehyde R-alkoxyallylation can be achieved
using chirally modified reagents that promote aldehyde R-silylallylation
or R-borylallylation followed by oxidation of the C-Si or C-B bond,
respectively.7-9 For direct methods, stereocontrolled access to anti-
alkoxyallylation products is problematic because of difficulties en-
countered in the synthesis of the requisite E-configured allylmetal
reagents.10 This fact has motivated alternate approaches to the anti-
1-ene-2,3-diol functional group array. For example, enantioselective
catalytic dihydroxylation of conjugated dienes was attempted,11 but
syn-1-ene-2,3-diols were formed. To our knowledge, only Duthaler’s
chiral allyltitanium reagent4 has been employed in direct enantiose-
lective anti-alkoxyallylation; however, only a single highly stereose-
lective example was reported, and use of this allylmetal reagent is
attended by considerable “preactivation”.12 To date, catalytic enanti-
oselective methods for aldehyde syn- or anti-R-alkoxyallylation remain
elusive.13
of Aldehydes Employing gem-Dicarboxylates Derived from
Acroleina
entry
gem-dicarboxylate
yield of 3c (a-e)
dr (anti/syn)
1
2
3
4
5
1a, R ) COMe
1b, R ) COEt
1c, R ) COiPr
1d, R ) COtBu
1e, R ) COPh
74%
65%
32%
15%
82%
4:1
5:1
8:1
10:1
11:1
a Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further details.
the reaction conditions, exhaustive acetylation was performed in
situ upon complete consumption of 2c, and the product was isolated
as the vicinal diacetate. In an effort to enhance the diastereoselec-
tivity, a series of acrolein gem-dicarboxylates were assayed under
identical conditions. It was hoped that a sufficiently large carboxy
group would direct the partitioning of (E)- and (Z)-σ-allyl iridium
intermediates to favor the (E)-σ-allyl isomer, which upon addition
to the aldehyde through a Zimmerman-Traxler-type transition
structure17 would deliver the anti-diastereomer. Indeed, gem-
dicarboxylates 1a-d, which incorporate acetyl, propionyl, isobu-
tyryl, and pivaloyl moieties, respectively, delivered products of
alkoxyallylation with increasing levels of anti-diastereoselectivity.
However, decreasing conversion in response to the increased steric
demand of the carboxy moiety was observed. As earlier studies
suggest that carbonyl addition is turnover-limiting,15b,c it is likely
that increased steric demand of the carboxy group impedes carbonyl
addition. The best level of anti-diastereoselectivity and conversion
was observed using gem-dibenzoate 1e (11:1 dr), perhaps because
it is large enough to direct formation of the (E)-σ-allyl isomer yet
does not impede approach of the aldehyde due to the flat topography
of aromatic ring (Table 1).
After identification of acrolein gem-dibenzoate 1e as an effective
reagent for anti-diastereoselective alkoxyallylation, enantioselective
variants of this process were explored. Accordingly, representative C2-
symmetric phosphine ligands were used to prepare a small set of chiral
iridium C,O-benzoate complexes that were assayed for their ability to
promote efficient anti-diastereo- and enantioselective alkoxyallylation.
The complex (R)-SEGPHOS-I proved superior to all others assayed
and was used to establish the reaction scope. It was found that aromatic,
heteroaromatic, R,ꢀ-unsaturated, and aliphatic aldehydes 2a-i were
converted to the corresponding alkoxyallylation products 3a-i in good
isolated yields (63-82%) with good to excellent diastereoselectivities
In connection with ongoing efforts to develop C-C bond-forming
hydrogenations beyond hydroformylation,14 we recently disclosed
enantioselective protocols for carbonyl allylation,15a,b,e-h crotyl-
ation,15c,f and tert-prenylation15d,f under transfer hydrogenation
conditions employing an ortho-cyclometalated iridium C,O-ben-
zoate catalyst. Here, using the ortho-cyclometalated iridium catalyst
generated from [Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid, allyl
acetate, and the chiral phosphine ligand (R)-SEGPHOS,16 we report
that allylic gem-dibenzoate 1e engages in reductive coupling to
diverse aldehydes to furnish products of anti-alkoxyallylation with
good levels of diastereocontrol and exceptional levels of enan-
tioenrichment.
In an initial experiment, acrolein gem-diacetate 1a was subjected
to isopropyl alcohol-mediated transfer hydrogenation in the presence
of aldehyde 2c employing the ortho-cyclometalated iridium C,O-
benzoate derived from [Ir(cod)Cl]2, 4-cyano-3-nitrobenzoic acid,
allyl acetate, and 2,2′-bis(diphenylphosphino)biphenyl (BIPHEP).
To our delight, the product of reductive coupling (3c(a), R ) Ac)
was obtained in 74% yield with complete branched regioselectivity
as a 4:1 mixture of diastereomers favoring the anti-stereoisomer.
Because partial migration of the acetyl moiety was observed under
9
1760 J. AM. CHEM. SOC. 2010, 132, 1760–1761
10.1021/ja9097675  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. anti-Diastereo- and Enantioselective Alkoxyallylation of
Aldehydes Employing gem-Dibenzoate 1e Derived from Acroleina
Acknowledgment is made to the Robert A. Welch Foundation
and the NIH-NIGMS (RO1-GM069445). Takasago is thanked for
the generous donation of (R)-SEGPHOS.
Supporting Information Available: Experimental procedures,
HPLC data, and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Yields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by chiral stationary phase HPLC
analysis. See the Supporting Information for further details. b Reaction
time 72 h.
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Table 3. anti-Diastereo- and Enantioselective Alkoxyallylation of
Aldehydes To Furnish Diol Products 4a, 4e, 4f, and 4ia
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between a reagent or reactant and the parent feedstock(s).
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a Yields are of material isolated by silica gel chromatography.
Enantiomeric excess was determined by chiral stationary phase GC
analysis. See the Supporting Information for further details.
(10:1 to 18:1 dr) and exceptional enantioselectivities (90-99% ee)
(Table 2). Generation of the cyclometalated catalyst in situ, as
previously reported,15a-c led to poor isolated yields of product. In the
absence of isopropyl alcohol, primary alcohols were not suitable
substrates due to benzoyl transfer.
To access the diol products directly, an alternate protocol involving
saponification in situ was explored. Here, aldehydes 2a, 2e, 2f, and 2i
were exposed to the standard reaction conditions employing gem-
dibenzoate 1e as the allyl donor. Upon complete consumption of the
aldehyde, methanol and potassium carbonate were added to the reaction
mixture. The diol-containing products 4a, 4e, 4f, and 4i were obtained
in good isolated yields and with anti-diastereo- and enantioselectivities
roughly equivalent with those observed for the corresponding diben-
zoates 3a, 3e, 3f, and 3i (Table 3).
In summary, under the conditions of iridium-catalyzed transfer
hydrogenation employing isopropyl alcohol as the terminal reductant,
gem-dibenzoate 1e reductively couples to aldehydes 2a-i to furnish
products of anti-alkoxyallylation with excellent relative and absolute
stereocontrol. This protocol provides an alternative to the use of
premetalated nucleophiles and chiral auxiliaries in asymmetric carbonyl
alkoxyallylation, providing direct stereocontrolled access to the anti-
1-ene-2,3-diol functional group array under catalytic conditions.
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