Enantioselective C-H crotylation of primary alcohols via hydrohydroxyalkylation of butadiene

Article abstract of DOI:10.1126/science.1219274

The direct, by-product-free conversion of basic feedstocks to products of medicinal and agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum cracking and is produced on an enormous scale (about 12 × 10⁶ metric tons annually). Here, with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of carbonyl crotylation with high levels of anti- diastereoselectivity and enantioselectivity in the absence of stoichiometric by-products.

Full text of DOI:10.1126/science.1219274

Enantioselective C-H Crotylation of Primary Alcohols via
Hydrohydroxyalkylation of Butadiene
Jason R. Zbieg et al.
Science 336, 324 (2012);
DOI: 10.1126/science.1219274
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REPORTS
(5, 6). Accordingly, systematic efforts toward the
discovery and development of carbon-carbon
bond–forming hydrogenations were initiated in
our laboratory (7, 8). We have found that di-
verse p-unsaturated reactants reductively cou-
ple to carbonyl compounds and imines under
hydrogenation conditions or transfer hydrogen-
ation conditions employing a sacrificial reductant
(such as isopropanol), offering an alternative to
the use of stoichiometric organometallic reagents.
Most significantly, under transfer hydrogenation
conditions, primary alcohols serve dually as hy-
drogen donors and aldehyde precursors, enabling
carbonyl addition directly from the alcohol ox-
idation level in the absence of stoichiometric
by-products.
Enantioselective C-H Crotylation
of Primary Alcohols via
Hydrohydroxyalkylation of Butadiene
Jason R. Zbieg, Eiji Yamaguchi, Emma L. McInturff, Michael J. Krische*
The direct, by-product–free conversion of basic feedstocks to products of medicinal and
agricultural relevance is a broad goal of chemical research. Butadiene is a product of petroleum
cracking and is produced on an enormous scale (about 12 × 106 metric tons annually). Here,
with the use of a ruthenium catalyst modified by a chiral phosphate counterion, we report
the direct redox-triggered carbon-carbon coupling of alcohols and butadiene to form products of
carbonyl crotylation with high levels of anti-diastereoselectivity and enantioselectivity in the
absence of stoichiometric by-products.
In the course of advancing hydrogenative
methods for polyketide construction, anti-
diastereoselective and enantioselective carbonyl
lthough many important methods for cat- relevance; in particular, the ability to transform crotylations from the alcohol or aldehyde oxida-
alytic asymmetric carbon-carbon bond for- abundant, ideally renewable, feedstocks to value- tion level were developed, using a-methyl allyl
mation exist, much of this technology is added products in the absence of stoichiometric
A
not well suited for implementation on a large by-products (1–4). This quality is embodied by
scale. Consequently, there is a need to discover alkene hydroformylation, the prototypical carbon-
and develop carbon-carbon–forming reactions that carbon bond–forming hydrogenation and largest-
Department of Chemistry and Biochemistry, University of Texas
at Austin, Austin, TX 78712, USA.
*To whom correspondence should be addressed. E-mail:
embody the principal characteristics of process volume application of homogenous catalysis mkrische@mail.utexas.edu
Fig. 1. Direct and indirect carbonyl crotylation. IPC,
(-)-isopinocampheyl; DBU, 1,8 diazabicyclo[5.4.0]undec-
7-ene; dppf, 1,1,-bis(diphenylphosphino)ferrocene,
TBAF, tetrabutylammonium fluoride; MW, molecular
weight; dr, diastereomeric ratio.
324
20 APRIL 2012 VOL 336 SCIENCE www.sciencemag.org

REPORTS
acetate as the crotyl donor (9–11). Butadiene-
alcohol carbon-carbon coupling potentially enables
by-product–free access to identical crotylation
products. However, although catalytic systems dis-
playing the essential reactivity were defined
(12–14), stereocontrolled hydrohydroxyalkyla-
tion of butadiene has proven elusive when both
iridium (12) and ruthenium (13, 14) catalysts
were used. Here we report that ruthenium cat-
alysts bearing C1-symmetric 1,1'-bi-2-naphthol
(BINOL)–derived phosphate counterions (15–22)
promote anti-diastereoselective and enantioselec-
tive carbonyl crotylations from the alcohol or al-
dehyde oxidation level. This protocol bypasses
the use of premetallated reagents for carbonyl
crotylation, which are prepared from 2-butene or
butadiene itself (23–28) (Fig. 1).
Eq. 1.
In ruthenium-catalyzed carbonyl syn-crotylation
from the alcohol or aldehyde oxidation level (14),
2-silyl-butadienes were required to enforce the
intervention of a single geometrical isomer at
the stage of the transient s-crotylruthenium spe-
cies, which appears to engage in stereospecific
carbonyl addition through a closed transition struc-
ture. Although the (E)- and (Z)-s-crotylruthenium
intermediates obtained upon butadiene hydro-
metallation are considerably closer in energy and
thus harder to discriminate, increasing steric con-
gestion at the ruthenium center should bias for-
mation of the thermodynamically more stable
(E)-isomer. Based on this reasoning, we further pos-
tulated that ruthenium complexes bearing coun-
terions of variable size could be prepared in situ
through the acid-base reaction of H2Ru(CO)(PPh3)3
and HX (Eq. 1) (29, 30), enabling a systematic
evaluation of diastereoselectivity in response to the
steric demand of the counterion. As revealed in the
hydrohydroxyalkylation of butadiene employing
ruthenium catalysts modified by benzenesulfonate,
mesitylsulfonate (mesityl = 2,4,6-trimethylphenyl),
and trisylsulfonate (trisyl = triisopropylphenyl)
counterions, diastereoselectivity increases with the
increasing size of the counterion. In the case of the
trisylsulfonate, concentration-dependent diastereo-
selectivity is attributed to a steric inhibition of the
acid-base reaction (Fig. 2).
Fig. 2. Enhanced anti-diastereoselectivity in response to increasing steric demand of the ruthenium
counterion in the hydrohydroxyalkylation of benzylic alcohol 1b. Yields are of material isolated by silica
gel chromatography. Diastereomeric ratios were determined by 1H NMR analysis of crude reaction mix-
tures. See the supplementary materials for further details.
Table 1. Optimization of anti-diastereoselectivity and enantioselectivity in the hydrohydroxyalkylation of
benzylic alcohol 1b using BINOL-derived phosphate counterions. Yields are of material isolated by silica
gel chromatography. Diastereomeric ratios were determined by 1H NMR analysis of crude reaction mix-
tures. ERs (er) were determined by chiral stationary-phase high-performance liquid chromatography
analysis. These data represent only a small sampling of conditions and phosphoric acids that were screened.
For additional details, see supplementary materials text.
These data suggested the feasibility of direct-
ing both relative and absolute stereochemistry,
using BINOL-derived phosphate counterions.
Whereas the parent (R)-BINOL phosphoric acid
A1 conferred poor stereoselectivity, the corre-
sponding 3,3′-diphenyl derivative A2 promoted
promising levels of diastereoselectivity and a 57:43
enantiomeric ratio (ER) (Table 1, entries 1 and 2).
The related C1-symmetric phosphoric acid, which
incorporates only a single phenyl moiety at the
3-position A3, displayed higher enantioselectivity
than A1 or A2 (Table 1, entries 1 to 3). Based on
this observation, the 3-mesityl phosphoric acid
A4 was prepared and assayed, revealing an ER of
87:13 (Table 1, entry 4). The loading of butadiene
can be decreased to 100 mol % with little impact
on yield and stereoselectivity, although 400 mol %
loadings provided optimal results and facilitated
transfer of the volatile reagent on a small scale
www.sciencemag.org SCIENCE VOL 336 20 APRIL 2012
325

REPORTS
(Table 1, entries 4 to 7). At higher loadings of
Table 2. Direct anti-diastereoselective and enantioselective carbonyl crotylation via hydrohydroxyalkyl-
ation of butadiene and related aldehyde-reductive couplings using the BINOL-derived phosphate coun-
terion A9. Characterization methods were as described in Table 1.
butadiene (800 mol %), catalytic efficiency is de-
creased, presumably due to nonproductive co-
ordination of butadiene to coordination sites on
the catalyst required for binding of the transient
aldehyde. Increasing the size of the 3-aryl substit-
uent did not improve stereoselectivity (see the
supplementary materials for additional experi-
ments); however, enhanced diastereoselectivity
was observed in connection with the 3-mesityl-
3′-methyl phosphoric acid A5 and 3-mesityl-3′-
ethyl phosphoric acid A6 (Table 1, entries 8 and
9). Further, we found that the 3-mesityl-H8-BINOL
A7 promoted higher enantioselectivity (89:11 ER)
than the corresponding H4-derivative A4 (87:13
ER) (Table 1, entry 10). An improvement in di-
astereoselectivity was observed in connection
with the 3′-methyl and 3′-ethyl H8-derivatives A8
and A9, yet a slight decrease in enantioselec-
tivity was observed (Table 1, entries 11 and 12).
Attributing decreased enantioselectivity to an
incomplete acid-base reaction for such sterically
demanding acids, we explored higher loadings
of acid (10 mol %), using the H4-derivative A6
and the H8-derivatives A7 and A9 (Table 1, en-
tries 13 to 15), which ultimately led to identifi-
cation of A9 as the chiral acid of choice (Table 1,
entry 16).
Using the chiral acid A9, benzylic alcohols 1a
to 1f were assayed in the hydrohydroxyalkylation
of butadiene to form the products of carbonyl
crotylation 3a to 3f. The purity of alcohols 1a
to 1f proved to be important, because trace
quantities of carboxylic acid contribute to a
racemic background reaction. Also, 31P nuclear
magnetic resonance (NMR) analysis was essential
in terms of evaluating the purity of the chiral acid
A9, because 1H NMR was ineffective in this re-
gard. With attention to these precautions, crotylation
proceeds in good yield with anti-diastereoselectivities
ranging from 5:1 to 9:1 and ERs ranging from
93:7 to 96:4 (Table 2). An identical set of adducts
3a to 3f are accessible from aromatic aldehydes
2a to 2f upon the use of 1,4-butanediol (31)
(200 mol %) as the terminal reductant under
otherwise identical conditions. Comparable anti-
diastereoselectivities (4:1 to 8:1) and ERs (94:6
to 93:7) are observed (Table 2).
A plausible catalytic mechanism is depicted in
Fig. 3. Hydrometallation of butadiene, as observed
in stoichiometric reactions of RuHCl(CO)(PPh3)3
with 1,2- and 1,3-dienes (32, 33), delivers the
p-allylruthenium complex. Counterion-dependent
partitioning of the (E)- and (Z)-s-crotylruthenium
isomers precedes stereospecific carbonyl addi-
tion by way of the s-crotylruthenium haptomer
through a closed transition structure. The result-
ing homoallylic ruthenium alkoxide, which re- the ruthenium hydride to close the catalytic cycle crotylation, alcohol-butadiene hydrohydroxy-
sists dehydrogenation because all coordination (Fig. 3).
alkylations enhance synthetic efficiency by remov-
sites at the metal center are occupied, partici- Because organic molecules are compounds ing the degrees of separation between reagent and
pates in alkoxide exchange with a reactant alcohol composed of carbon and hydrogen, the formation feedstock, while bypassing discrete alcohol oxi-
to release the product of crotylation and provide of carbon-carbon bonds under hydrogenation and dation and the generation of stoichiometric by-
a pentacoordinate ruthenium alkoxide. The va- transfer hydrogenation conditions is a natural end products. These initial findings set the stage for
cant coordination site at this stage enables de- point in the evolution of strategies for organic the development of catalysts that exhibit en-
hydrogenation to form an aldehyde and regenerate synthesis. As illustrated here in the case of carbonyl hanced stereoselectivities and substrate scope.
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REPORTS
Fig. 3. Proposed mechanism for
ruthenium-catalyzed hydrohydroxy-
alkylation of butadiene, illustrating
the counterion-dependent partition-
ing of (E)- and (Z)-s-crotylruthenium
isomers.
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Acknowledgments: The Robert A. Welch Foundation
(grant F-0038) and the NIH’s National Institute of General
Medical Sciences (grant RO1-GM069445) are acknowledged
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