Ruthenium Catalyzed Diastereo- and Enantioselective Coupling of Propargyl Ethers with Alcohols: Siloxy-Crotylation via Hydride Shift Enabled Conversion of Alkynes to π-Allyls

Article abstract of DOI:10.1021/jacs.5b08019

The first enantioselective carbonyl crotylations through direct use of alkynes as chiral allylmetal equivalents are described. Chiral ruthenium(II) complexes modified by Josiphos (SL-J009-1) catalyze the C-C coupling of TIPS-protected propargyl ether 1a with primary alcohols 2a-2o to form products of carbonyl siloxy-crotylation 3a-3o, which upon silyl deprotection-reduction deliver 1,4-diols 5a-5o with excellent control of regio-, anti-diastereo-, and enantioselectivity. Structurally related propargyl ethers 1b and 1c bearing ethyl- and phenyl-substituents engage in diastereo- and enantioselective coupling, as illustrated in the formation of adducts 5p and 5q, respectively. Selective mono-tosylation of diols 5a, 5c, 5e, 5f, 5k, and 5m is accompanied by spontaneous cyclization to deliver the trans-2,3-disubstituted furans 6a, 6c, 6e, 6f, 6k, and 6m, respectively. Primary alcohols 2a, 2l, and 2p were converted to the siloxy-crotylation products 3a, 3l, and 3p, which upon silyl deprotection-lactol oxidation were transformed to the trans-4,5-disubstituted γ-butyrolactones 7a, 7l, and 7p. The formation of 7p represents a total synthesis of (+)-trans-whisky lactone. Unlike closely related ruthenium catalyzed alkyne-alcohol C-C couplings, deuterium labeling studies provide clear evidence of a novel 1,2-hydride shift mechanism that converts metal-bound alkynes to π-allyls in the absence of intervening allenes.

Full text of DOI:10.1021/jacs.5b08019

Article
pubs.acs.org/JACS
Ruthenium Catalyzed Diastereo- and Enantioselective Coupling
of Propargyl Ethers with Alcohols: Siloxy-Crotylation via Hydride
Shift Enabled Conversion of Alkynes to π‑Allyls
Tao Liang, Wandi Zhang, Te-Yu Chen, Khoa D. Nguyen, and Michael J. Krische*
Department of Chemistry, University of Texas at Austin, 1 University Station, Welch Hall A5300, Austin, Texas 78712, United States
S
* Supporting Information
ABSTRACT: The first enantioselective carbonyl crotylations
through direct use of alkynes as chiral allylmetal equivalents are
described. Chiral ruthenium(II) complexes modified by Josiphos
(SL-J009-1) catalyze the C−C coupling of TIPS-protected propargyl
ether 1a with primary alcohols 2a−2o to form products of carbonyl
siloxy-crotylation 3a−3o, which upon silyl deprotection-reduction
deliver 1,4-diols 5a−5o with excellent control of regio-, anti-
diastereo-, and enantioselectivity. Structurally related propargyl
ethers 1b and 1c bearing ethyl- and phenyl-substituents engage
in diastereo- and enantioselective coupling, as illustrated in the
formation of adducts 5p and 5q, respectively. Selective mono-
tosylation of diols 5a, 5c, 5e, 5f, 5k, and 5m is accompanied by
spontaneous cyclization to deliver the trans-2,3-disubstituted furans 6a, 6c, 6e, 6f, 6k, and 6m, respectively. Primary alcohols
2a, 2l, and 2p were converted to the siloxy-crotylation products 3a, 3l, and 3p, which upon silyl deprotection-lactol oxidation
were transformed to the trans-4,5-disubstituted γ-butyrolactones 7a, 7l, and 7p. The formation of 7p represents a total synthesis of
(+)-trans-whisky lactone. Unlike closely related ruthenium catalyzed alkyne-alcohol C−C couplings, deuterium labeling studies
provide clear evidence of a novel 1,2-hydride shift mechanism that converts metal-bound alkynes to π-allyls in the absence of
intervening allenes.
π-unsaturated reactants as redox pairs for the generation of
carbonyl−organometal pairs en route to products of carbonyl
addition.5k On the basis of this concept of “redox-triggered
carbonyl addition,” reactions of primary alcohols with α-methyl
allyl acetate9a−c or butadiene9d−f to form products of carbonyl
crotylation were developed (Figure 1, eq B). In this account,
we report the first direct alkyne mediated carbonyl crotylations
(Figure 1, eq C).10 These transformations display high levels
of anti-diastereo- and enantioselectivity and operate through
a novel mechanism wherein metal-bound alkynes are converted
to π-allylmetal species in the absence of intervening allenes
(Figure 1, eq D).
In recent work from our laboratory, ruthenium catalysts
were found to promote the redox-triggered coupling of primary
alcohols with allenes to form homoallylic alcohols.11,12 During
these studies, Obora and Ishii described the iridium catalyzed
coupling primary alcohols with aryl propynes to form products
of (α-aryl)allylation.13 This work suggested the feasibility of
a dual ruthenium-based catalytic cycle wherein alkyne-to-allene
isomerization occurs in tandem with redox-triggered carbonyl
addition. Two key modifications to our previously reported
ruthenium(II) based catalyst fulfilled efforts toward this goal
(Scheme 1). First, using the catalyst generated in situ upon acid
INTRODUCTION
■
Polyketides and their semisynthetic congeners are used extensively
in human medicine.1 With one exception,2 all commercial
polyketides derive from soil bacteria, yet less than 5% of soil
bacteria are amenable to culture, with many phyla having eluded
culture entirely.3 As techniques for bacterial culture improve,
the number of medicinally relevant polyketides is anticipated to
expand. Presently, all polyketides used in human medicine, again
with one exception,3 are prepared via fermentation or through
modification of fermentation products.1 Although de novo
chemical synthesis offers a gateway to otherwise inaccessible
structural variants, conceptual advances beyond the first-generation
lexicon of synthetic methods are required for the design of more
efficient, cost-effective routes to these important secondary
metabolites.1d
Among methods for de novo polyketide construction,4
diastereo- and enantioselective carbonyl crotylation has proven
especially effective (Figure 1).5 Beginning with the pioneering
studies of Hoffmann,6 the majority of asymmetric crotylation
protocols employ crotylmetal reagents that incorporate chiral
modifiers (Figure 1, eq A).5 Catalytic enantioselective crotylations,
including umpoled reactions of crotyl halides or carboxylates,7,8
were subsequently developed. These too rely on the use of
stoichiometric metals, specifically, crotylmetal reagents5 or metallic
terminal reductants.7,8 In a significant departure from prior
art, we have introduced the concept of engaging alcohols and
Received: July 30, 2015
© XXXX American Chemical Society
A
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Scheme 1. Dual Ruthenium-Based Catalytic Cycles wherein
Alkyne-to-Allene Isomerization Occurs in Tandem with
a
Redox-Triggered C−C Bond Formation
a
ArSO3H = 2,4,6-(2-Pr)3PhSO3H.
ligand, which suppresses oxidative coupling while maintaining
catalytic alkyne-to-allene isomerization. Allenes generated
under these conditions participate in hydrometallative pathways
en route to branched homoallylic allylic alcohols.14b It should
be emphasized that in both cases isotopic labeling studies and
other experiments corroborate intervention of allenes as discrete
intermediates.14
RESEARCH DESIGN AND METHODS
■
For hydrometallative pathways en route to branched homoallylic
allylic alcohols, the 2-alkyne must be branched at propargylic
position to suppress numerous side-reactions. However, the
TIPS-protected propargyl ether 1a was not subject to this
constraint. Exposure of propargyl ether 1a to p-bromobenzyl
alcohol 2c under conditions used in the asymmetric couplings
of 4-methyl-2-pentyne14b delivered the product of “siloxy-
crotylation” 3c with complete control of regio- and diaster-
eoselectivity as a 3:1 (Z:E) mixture of olefin geometrical isomers
in 70% isolated yield. The (Z)- and (E)-alkenes each displayed
high levels of enantiomeric enrichment: 87% ee and 94% ee,
respectively. This result was surprising given the large number
of regio- and stereoisomers potentially formed in this trans-
formation. Further optimization was undertaken.15 Although
(Z)- and (E)-selectivity was insensitive to variation of the ether
Figure 1. Overview of methods for carbonyl crotylation and the
discovery of alkyne mediated crotylation.
base reaction of H2Ru(CO) (PPh3)3 and 2,4,6-(2-Pr)3PhSO3H,9e
ruthenium(0) species became accessible via H-X (X = ArSO3)
reductive elimination, enabling alkyne-to-allene isomerization
by ruthenium(0) mediated propargyl C−H oxidative addition−
reductive elimination pathways. Allenes generated under these
conditions engage in ruthenium(0) mediated oxidative coupling
with carbonyl partners to form linear (Z)-homoallylic alcohols.14a
A second key modification to the catalyst involves the intro-
duction of iodide and an electron rich chelating phosphine
Scheme 2. Regio-, Diastereo-, and Enantioselectivity in the Redox-Triggered C−C Coupling of Propargyl Ether 1a and
a
p-Bromobenzyl Alcohols 2c
a
ArSO3H = 2,4,6-(2-Pr)3PhSO3H. R = p-BrPh. Yield refers to a mixture (Z)-anti-3c and (E)-anti-3c and their enantiomers isolated by silica gel
chromatography. See Supporting Information for further experimental details.
B
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substituent, reactions conducted at lower temperatures and
slightly higher loadings of 2,4,6-(2-Pr)3PhSO3H delivered
(Z)- and (E)-anti-3c in 80% isolated yield and 90% ee and
96% ee, respectively (Scheme 2). The (Z)- and (E)- selectivity is
inconsequential, as fluoride assisted cleavage of the enol in the
presence of NaBH4 enabled convergence of (Z)- and (E)-anti-3c
to diol 5c in quantitative yield and 92% ee.16 The requirement
of 2-propanol merits discussion. In the absence of 2-propanol,
unreacted aldehyde accumulates due to competing transfer hydro-
genation of propargyl ether 1a. As the allylruthenium-aldehyde
intermediates are generated in a pairwise manner, introduction
of 2-propanol returns the aldehyde to the alcohol oxidation level,
enabling reentry into the catalytic C−C coupling pathway.
Under these optimal conditions, propargyl ether 1a was
exposed to benzylic alcohols 2a−2h, allylic alcohols 2i−2l,
and aliphatic alcohols 2m−2o (Table 1). The respective enol
silanes 3a−3o were converted to diols 5a−5o, which were
formed with complete levels of regio- and anti-diastereose-
lectivity and uniformly high levels of enantioselectivity (87−
96% ee). The stereochemical assignment of diols 5a−5o was
made in analogy to that determined for compound 5c by
single-crystal X-ray diffraction analysis. Both TBS and TBDPS
ethers participate in coupling, but isolated yields were lower by
roughly 20%. Application of these conditions to O-alkyl pro-
pargyl ethers led to complex mixtures. However, as illustrated
in the coupling of ethyl- and phenyl-substituted propargyl
alcohols 1b and 1c, variation of the acetylenic substituent
is tolerated (see equations 1 and 2). Here, use of a BINAP
modified ruthenium catalyst enables formation of adducts 5p
and 5q in highly enantiomerically enriched form.
To illustrate the utility of this methodology, diols 5a, 5c, 5e,
5f, 5k, and 5m were exposed to p-toluenesulfonyl chloride
in pyridine solvent, resulting in highly chemoselective mono-
tosylation of the primary alcohol and spontaneous cyclization to
form the corresponding trans-2,3-disubstituted furans 6a, 6c,
6e, 6f, 6k, and 6m (Table 2). Only in the formation of 6f
was any erosion in enantiomeric purity observed. Notably,
2,3-disubstituted furans that incorporate 3-methyl substituents
Table 1. Regio-, anti-Diastereo- and Enantioselective
Coupling of Alkyne 1a with Alcohols 2a−2o To Form
a
Diols 5a−5o
Table 2. Conversion of Adducts 5a, 5c, 5e, 5f, 5k, and 5m to
a
trans-2,3-Disubstituted Furans 6a, 6c, 6e, 6f, 6k, and 6m
a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further details.
Table 3. Conversion of Alcohols 2a, 2l, and 2p to trans-4,5-
a
Disubstituted γ-Butyrolactones 7a, 7l, and 7p
a
b
Yields are of material isolated by silica gel chromatography. 48 h.
c
See Supporting Information for further details. H2Ru(CO) (PPh3)3
a
(6 mol %), SL-J009−1 (6 mol %), ArSO3H (9 mol %), Bu4NI (12 mol %).
Yields are of material isolated by silica gel chromatography over the
d
2-PrOH was omitted.
two-step sequence. See Supporting Information for further details.
C
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appear frequently as substructures in type I polyketide natural
products.17 Coupling of primary alcohols 2a, 2l, and 2p under
standard conditions followed by exposure to TBAF led to crude
hemiacetals, which upon treatment with pyridinium chlorochromate
(PCC) delivered the trans-4,5-disubstituted γ-butyrolactones
7a, 7l, and 7p (Table 3). The formation of 7p represents a
total synthesis of (+)-trans-whisky lactone.18 Similarly, crude
hemiacetals obtained in the aforesaid manner can be treated
with mesyl chloride in the presence of triethylamine to form
trans-4,5-disubstituted-2,3-dehydrofurans, as illustrated in the
formation of 8a (equation 3). Finally, crude hemiacetal can be
treated with the indicated stabilized Wittig reagent to deliver the
enoate 9a with complete alkene (E)-stereoselectivity (equation 4).
Scheme 3. Deuterium Labelling Studies Exclude Allenes As
Discrete Intermediates and Are Consistent with a Hydride
Shift Mechanism
a
a
Yields are of material isolated by silica gel chromatography. See
Supporting Information for further details.
MECHANISM
■
Unlike the asymmetric couplings of 4-methyl-2-pentyne,14b the
products obtained in reactions of propargyl ether 1a are in-
consistent with the intervention of a terminal allene such as 1d.
Initially, it was assumed that siloxy-crotylation proceeded by way of
the internal 1,3-disubstituted allene 1e or diene 1f. However,
deuterium labeling studies exclude allene 1e or diene 1f as inter-
mediates (Scheme 3).19 If allene 1e or diene 1f were discrete inter-
mediates, the reaction of propargyl ether 1a should result in
deuterium incorporation at Hb or Hd of adduct deuterio-3c, res-
pectively, but it does not. Rather, the reaction of deuterio-1a with
alcohol 2c results in deuterium transfer to Ha and Hb of adduct
deuterio-3c. These data clearly corroborate the indicated 1,2-
hydride shift mechanism.20−22 To our knowledge, direct conversion
of metal-bound alkynes to π-allyls via 1,2-hydride shift is unique.
The question as to whether the 1,2-hydride shift mechanism
is at all operative in related asymmetric alkyne−alcohol C−C
couplings14b merits consideration. Here, it is instructive to
consider the respective patterns of deuterium incorporation
observed upon use of d2-benzylic alcohols. For the related
asymmetric alkyne−alcohol C−C couplings (equation 5),14b
wherein hydrometalation of a discrete allene intermediate is
proposed to generate a nucleophilic allylruthenium species, the
pattern of deuterium closely resembles that observed in the parent
allene-alcohol C−C couplings (equation 6).11b The analogous
isotopic labeling experiment using propargyl ether 1a does not
result in deuterium incorporation at the interior vinylic position.
These data exclude allene hydrometalation in the present cou-
plings of propargyl ether 1a and suggest the 1,2-hydride shift
mechanism is likely inoperative in the previously developed alkyne-
alcohol C−C couplings.23
On the basis of this novel pattern of reactivity, a general
catalytic mechanism for asymmetric ruthenium catalyzed siloxy-
crotylation via redox-triggered carbonyl addition was proposed
(Scheme 4). A ruthenium(II) complex mediates alcohol
dehydrogenation to form aldehyde and LnRu(II)HX. Elimi-
nation of HX delivers a zerovalent ruthenium complex that binds
the π-acidic alkyne. A high degree of π-backbonding between
ruthenium(0) and the bound alkyne promotes metallacyclopro-
pene or carbenoid character which induces 1,2-hydride shift
to form a vinyl carbene. The n → σ* interaction between the
oxygen lone pair and the propargylic C−H bond appears to
be important in terms of promoting 1,2-hydride shift, as in
the absence of the silyl ether alkyne-to-allene isomerization
is observed.14 Protonation of the vinyl carbene delivers a
nucleophilic siloxy-substituted allylruthenium(II) complex.
Aldehyde addition occurs by way of a Zimmerman−Traxler type
transition structure from the σ-bound allylruthenium haptomer
D
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Scheme 4. General Catalytic Mechanism As Corroborated by Deuterium Labeling Experiments
wherein ruthenium resides at the oxygen-bearing carbon atom.
This haptomeric preference is presumably due to the negative
inductive effect of oxygen. Protonolytic cleavage of the result-
ing homoallylic ruthenium(II) alkoxide releases the product and
regenerates the starting ruthenium(II) complex.
REFERENCES
■
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CONCLUSIONS
■
In summary, we report a direct alkyne-mediated carbonyl
(siloxy)crotylation via redox-triggered carbonyl addition that
is enabled through a unique 1,2-hydride-shift mechanism. This
method directly converts primary alcohols to secondary alcohols
bearing a propionate-based monoketide structural motif. Com-
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by uniformly high levels of enantioselectivity using a Josiphos
(SL-J009-1) modified ruthenium(II) catalyst. Deuterium label-
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b08019.
■
S
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AUTHOR INFORMATION
Corresponding Author
*mkrische@mail.utexas.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) and the Center for Green Chemistry
and Catalysis are acknowledged for partial support of this
research.
(9) For catalytic diastereo- and enantioselective redox-triggered
carbonyl crotylation using α-methyl allyl acetate or butadiene
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transfer hydrogenation, see: (a) Skucas, E.; Bower, J. F.; Krische, M. J.
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(15) See Supporting Information for further optimization experi-
ments, including results obtained under standard conditions with
different chiral ligands.
(16) Similar racemic products of hydroxymethyl crotylation are
formed through the nickel catalyzed coupling of dienes and aldehydes
mediated by B2(pin)2: Cho, H. Y.; Morken, J. P. J. Am. Chem. Soc.
2008, 130, 16140.
́
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under standard reaction conditions. Dehydrogenation of alcohol 2c
was observed, but products of C−C coupling were not detected.
(20) A related hydride shift was observed in the ruthenium catalyzed
internal redox isomerization of propargyl alcohols to form conjugated
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11970.
(21) The indicated mechanism involving propargyl C−H oxidative
addition followed by internal hydrometalation from the allenylruthe-
nium haptomer was considered and cannot be excluded on the basis of
the isotopic labelling studies. However, such internal hydrometalations
of allenic species do not appear geometrically feasible.
(22) For rhodium catalyzed isomerization of 1-alkynes to allenes,
which are then converted to electrophilic π-allyls, see: (a) Lumbroso,
A.; Koschker, P.; Vautravers, N. R.; Breit, B. J. Am. Chem. Soc. 2011,
133, 2386. (b) Xu, K.; Khakyzadeh, V.; Bury, T.; Breit, B. J. Am. Chem.
Soc. 2014, 136, 16124. (c) Koschker, P.; Kahny, M.; Breit, B. J. Am.
̈
Chem. Soc. 2015, 137, 3131.
(23) In these isoptopic labelling studies, it should be noted that
protons from the reactant alcohol or adventitious water may
contribute to diminished levels of deuterium incorporation: Tse, S.
K. S.; Xue, P.; Lin, Z.; Jia, G. Adv. Synth. Catal. 2010, 352, 1512.
F
DOI: 10.1021/jacs.5b08019
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX