Diastereo- And enantioselective ruthenium-catalyzed C-C coupling of 1-arylpropynes and alcohols: Alkynes as chiral allylmetal precursors in carbonyl anti-(α-Aryl)allylation

Article abstract of DOI:10.1021/jacs.0c12242

Highly tractable 1-aryl-1-propynes, which are readily accessible via Sonogashira coupling, serve as chiral allylmetal pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereo- and enantioselective aldehyde (α-aryl)allylations with primary aliphatic or benzylic alcohol proelectrophiles. This method enables convergent construction of homoallylic sec-phenethyl alcohols bearing tertiary benzylic stereocenters. Both steric and electronic features of aryl sulfonic acid additives were shown to contribute to the efficiency with which a more selective and productive iodide-bound ruthenium catalyst is formed. As corroborated by isotopic labeling studies, a dual catalytic process is operative in which alkyne-to-allene isomerization is followed by allene-carbonyl reductive coupling via hydrogen auto-transfer. Crossover of ruthenium hydrides emanating from these two discrete catalytic events is observed. The utility of this method is illustrated by conversion of selected reaction products to the corresponding phenethylamines and the first total syntheses of the neolignan natural products (-)-crataegusanoids A-D.

Full text of DOI:10.1021/jacs.0c12242

pubs.acs.org/JACS
Article
Diastereo- and Enantioselective Ruthenium-Catalyzed C‑C Coupling
of 1‑Arylpropynes and Alcohols: Alkynes as Chiral Allylmetal
Precursors in Carbonyl anti-(α-Aryl)allylation
Ming Xiang, Ankan Ghosh, and Michael J. Krische*
Cite This: J. Am. Chem. Soc. 2021, 143, 2838−2845
Read Online
ACCESS
Metrics & More
Article Recommendations
*
sı Supporting Information
ABSTRACT: Highly tractable 1-aryl-1-propynes, which are readily
accessible via Sonogashira coupling, serve as chiral allylmetal
pronucleophiles in ruthenium-JOSIPHOS-catalyzed anti-diastereo-
and enantioselective aldehyde (α-aryl)allylations with primary
aliphatic or benzylic alcohol proelectrophiles. This method enables
convergent construction of homoallylic sec-phenethyl alcohols
bearing tertiary benzylic stereocenters. Both steric and electronic
features of aryl sulfonic acid additives were shown to contribute to
the efficiency with which a more selective and productive iodide-
bound ruthenium catalyst is formed. As corroborated by isotopic
labeling studies, a dual catalytic process is operative in which alkyne-
to-allene isomerization is followed by allene-carbonyl reductive
coupling via hydrogen auto-transfer. Crossover of ruthenium hydrides emanating from these two discrete catalytic events is observed.
The utility of this method is illustrated by conversion of selected reaction products to the corresponding phenethylamines and the
first total syntheses of the neolignan natural products (−)-crataegusanoids A−D.
INTRODUCTION
■
Carbonyl addition is the Proteus of metal-mediated C-C
1
couplings. Recent analysis of >9 million patents from the
pharmaceutical industry shows that carbonyl addition (along-
side the Suzuki coupling) persists as one of the most widely
utilized methods for C−C bond formation in process R&D.
7
2
asymmetric carbonyl allylation, enantioselective carbonyl (α-
aryl)allylations are largely limited to isolated examples that
embody moderate levels of asymmetric induction and deliver
Despite its importance, the majority of methods for carbonyl
addition require preformed carbanions, which can be hazard-
ous and are often generated using multiple sacrificial reagents,
for example, through halogenation-metalation-transmetalation
sequences. Metal-catalyzed carbonyl reductive coupling of
unsaturated pronucleophiles has emerged as an alternative to
stoichiometric carbanions, but many reductants used in such
processes are not ideal for chemical manufacture on scale (e.g.,
simple aryl fragments. These methods fall into two categories:
a) those involving chiral auxiliaries and (b) catalytic
In the former category, one
systematic study involving allylbenzene pronucleophiles was
reported by Gong, but this method is restricted to aryl
aldehydes (Figure 1). In the latter category, systematic studies
are limited to activated aldehydes (glyoxamides, form-
fluoral and difluoroacetaldehyde ) and a
Nozaki−Hiyama−Kishi (α-aryl)allylation to form quaternary
benzylic stereocenters. Catalytic enantioselective carbonyl (α-
aryl)allylations applicable to both aliphatic and aromatic
aldehydes are unknown, and would enable convergent
8
(
9,10
enantioselective protocols.
8g
9e
3,4
Mn, Zn, Et B, Et Zn, SiR ). We have advanced a broad, new
10a
10b
3
2
3
aldehyde,
family of metal-catalyzed carbonyl reductive couplings that
exploit feedstock pronucleophiles in combination with feed-
stock reductants (H , 2-PrOH, HCO H), as well as related
9i
2
2
hydrogen auto-transfer processes wherein alcohols serve dually
4
as reductants and carbonyl proelectrophiles. These efforts
include processes that exploit alkynes as allylmetal pronucleo-
philes.
Given the tractability of 1-aryl-1-propynes and their wide
availability via Sonogashira coupling (eq 1), we sought to
develop catalytic enantioselective carbonyl (α-aryl)allylations
via transfer hydrogenative couplings of 1-aryl-1-propynes with
primary alcohols (Figure 1). Despite decades of work on
5
−7
Received: November 23, 2020
Published: February 8, 2021
©
2021 American Chemical Society
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845
2
838

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 2. Influence of Arylsulfonic Acid in the Reaction of
-(4-CF -phenyl)-1-propyne 1a and Alcohol 2a to Form the
1
3
a
Product of Carbonyl (α-Aryl)allylation 3a
a
Yields of material isolated by silica gel chromatography.
Enantioselectivities were determined by chiral stationary phase
1
HPLC analysis. Diastereoselectivities were determined via H NMR
b
analysis of crude reaction mixtures. Conditions described in Scheme
1
, eq 3, were applied using H Ru(CO)(PPh ) (5 mol %), SL-J009-1
2 3 3
c
Figure 1. Convergent construction of sec-phenethyl alcohols bearing
tertiary benzylic stereocenters via enantioselective carbonyl anti-(α-
aryl)allylation of unactivated aldehydes.
(5 mol %), Bu NI (10 mol %). DIPPF (10 mol %) was used as
4
ligand.
construction of tertiary benzylic stereocenters and stereogenic
C−O bonds, which are ubiquitous among natural products and
FDA approved drugs. Here, using a ruthenium catalyst
modified by the JOSIPHOS ligand SL-J009-1, we report that
diverse 1-aryl-1-propynes engage in C-C coupling with primary
aliphatic or benzylic alcohols to furnish products of (α-
aryl)allylation bearing relatively complex aryl moieties in good
yield with complete anti-diastereoselectivity and high levels of
enantioselectivity.
that exists in equilibrium with a ruthenium(0) complex. This
ruthenium(0) species promotes two discrete catalytic events:
(a) alkyne-to-allene isomerization and (b) transfer hydro-
genative allene-carbonyl reductive coupling by way of a
transient oxaruthenacycle. This process converts alkyl-sub-
stituted alkynes and primary alcohols to linear secondary (Z)-
6c
homoallylic alcohols (Scheme 1, eq 2). Remarkably, in the
presence of iodide and a chelating phosphine ligand, an
alternate dual catalytic process becomes operative in which
alkyne-to-allene isomerization is followed by hydrometalation
of the transient allene to form an allylruthenium(II) species.
This process converts alkyl-substituted alkynes and primary
alcohols to branched secondary homoallylic alcohols with
excellent control of regio-, diastereo-, and enantioselectivity
RESULTS AND DISCUSSION
■
6c
In prior work from our laboratory, it was found that
protonation of H Ru(CO)(PPh ) by the aryl sulfonic acid
2
3 3
i
2
,4,6-( Pr) PhSO H delivers a cationic ruthenium(II) complex
3 3
6e
(
Scheme 1, eq 3). As corroborated by deuterium labeling
studies, both processes involve alkyne-to-allene isomerization.
The fate of the resulting allene largely depends on the
intervention of cationic vs neutral ruthenium complexes, which
partition entry into catalytic cycles involving either allene-
carbonyl oxidative coupling or allene hydrometalation,
Scheme 1. Alkynes as Latent Allenes in Alcohol-Mediated
Hydrohydroxyalkylation to Form Linear or Branched
Homoallylic Alcohols (Ar = 2,4,6-Triisopropylphenyl)
6c,e,11
respectively.
Both catalytic processes are largely restricted to α-branched
alkyl-substituted propynes, such as 4-methyl-2-pentyne. We
speculate that α-branched alkyl groups at the acetylenic
position may facilitate alkyne-to-allene isomerization by
favorably influencing the regioselectivity of alkyne hydro-
metalation. Initial attempts to exploit 1-aryl-1-propynes as
pronucleophiles for asymmetric carbonyl (α-aryl)allylation
were inefficient, and especially low isolated yields were
observed for 1-aryl-1-propynes bearing electron deficient
aromatic rings. To overcome this limitation, efforts to optimize
the carbonyl (α-aryl)allylation of 1-(4-CF -phenyl)-1-propyne
3
1
a and primary aliphatic alcohol 2a were undertaken (Scheme
2
). Under conditions effective for couplings of 4-methyl-2-
pentyne (but without 2-PrOH, which is used to reduce
6d
uncoupled aldehyde so it can reenter the catalytic cycle), the
product of carbonyl (α-aryl)allylation 3a was obtained in 17%
2
839
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Table 1. Ruthenium-Catalyzed Coupling of 1-Aryl-1-propynes 1a−1ff with Primary Alcohols 2a−2ff to Form Enantiomerically
a
Enriched Phenethyl Alcohols 3a−3ff
a
Yields of material isolated by silica gel chromatography. Enantioselectivities were determined by chiral stationary phase HPLC analysis.
1
Diastereoselectivities were determined via H NMR analysis of crude reaction mixtures. For standard conditions, see Scheme 2, entry 7, 0.2 mmol
scale, 48 h. See the Supporting Information for further experimental details. 75 °C. 90 °C. SL-J009-2. 65 °C.
b
c
d
e
yield with only modest levels of enantiomeric enrichment
Scheme 2, entry 1). When the catalyst loading was doubled, a
proportionate increase in the yield of 3a was observed
iodide-bound catalyst is generated through the acid-base
reaction of the ruthenium dihydride with the arylsulfonic
acid, followed by substitution by iodide (eq 4). Notably, the
(
12
i
(
Scheme 2, entry 2). Replacing 2,4,6-( Pr) PhSO H with 4-
3 3
MePhSO H and 4-NO PhSO H led to successive improve-
3
2
3
ments (Scheme 2, entries 3 and 4, respectively). These data are
significant, as they reveal both steric and electronic features of
the catalyst impact efficiency and enantioselectivity. Using
more acidic, less hindered arylsulfonic acid 4-NO PhSO H
2
3
i
2
,4,6-( Pr) PhSO H in DME, slightly higher enantioselectivity
appears to enhance the efficiency of this process, allowing
temperature to be reduced, augmenting enantioselectivity
without diminishing conversion (Scheme 2, entry 7). Under
3
3
was observed (Scheme 2, entries 2 vs 5), but lower
temperatures limited conversion (Scheme 2, entry 6). The
2
840
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Scheme 3. Conversion of Phenethyl Alcohols 3d, 3j, and 3r to Phenethylamines 5d, 5j, and 5r
a
Yields of material isolated by silica gel chromatography. See the Supporting Information for further experimental details.
Scheme 4. Total Syntheses of Neolignan Natural Products
these conditions, moving from THF to DME solvent, 3a could
be obtained in 85% yield with >20:1 anti-diastereoselectivity
and high enantioselectivity (88% ee) (Scheme 2, entry 8).
a
(−)-Crataegusanoids A−D
Omission of Bu NI led to a significant decrease in yield and
4
selectivity that could not be fully restored through use of
Bu NCl or Bu NBr (Scheme 2, entries 9−11). Racemic
4
4
product was obtained using the achiral ligand DIPPF in
combination with (+)-camphor sulfonic acid (Scheme 2, entry
1
2). The collective data suggest both conversion and
enantioselectivity depend on the efficiency with which the
iodide-bound catalyst is formed.
13
Under these conditions, the ruthenium-catalyzed coupling of
diverse 1-aryl-1-propynes 1a−1ff with primary alcohols 2a−2ff
to form enantiomerically enriched phenethyl alcohols 3a−3ff
was explored (Table 1). As illustrated by the formation of
phenethyl alcohols 3c, 3x, and iso-3x, ortho-substituted aryl
propynes are competent partners for C-C coupling. Hetero-
aryl-substituted propynes are converted to adducts 3d−3h, 3p,
and 3s, establishing compatibility with Lewis basic sulfur (3d)
and nitrogen (3e−3h, 3p, 3s) functional groups. Additionally,
as demonstrated by the formation of adducts 3g−3o, primary
alcohols bearing a tethered N-Boc amine (3g) or pyrazole
a
Yields of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details.
Scheme 5. Experiments Corroborating Intervention of
Allenes as Reactive Intermediates
a
(
3h), 2-aminopyridine (3i), oxazole (3j), furan (3k),
thiophene (3l), and indole (3m−3o) moieties are competent
partners for arylpropyne-mediated asymmetric (α-aryl)-
allylation. Notably, adducts 3j and 3n derive from the FDA
approved therapeutic agents oxaprozin and indomethacin,
respectively, highlighting the potential applicability of this
method to drug discovery. Adducts derived from primary
alcohols that incorporate strained saturated ring systems,
including cyclopropanes (3t), difluorocyclobutanes (3u),
azetidines (3r, 3v), and oxetanes (3w), were well tolerated.
Whereas low conversion was associated with the use of acyclic
α-stereogenic primary alcohols, the corresponding β-stereo-
genic primary alcohols were converted to products of (α-
aryl)allylation (3x, iso-3x, 3y, iso-3y) with high levels of
catalyst-directed diastereoselectivity. Finally, primary benzylic
alcohols undergo (α-aryl)allylation as shown by the formation
of adducts 3aa−3ff. Here, compatibility of pinacolboronate
functional groups, as demonstrated by formation of 3bb and
3
ff, is significant. In certain cases, minor decreases or increases
in reaction temperature were made to improve enantioselec-
tivity or increase conversion, respectively. The assignment of
absolute stereochemistry for adducts 3a−3ff is made in analogy
to that determined for compound 3r by single crystal X-ray
diffraction analysis. Attempted coupling of the more highly
substituted aryl alkyne, 1-phenyl-1-butyne, results in internal
redox-isomerization to form the terminal π-allyl, delivering
products of carbonyl anti-(α-benzyl)allylation in low yield.
Phenethylamines represent a broad class of psychoactive
a
Yields of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details.
14
substances. To further illustrate the potential utility of this
2
841
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Scheme 6. Proposed Catalytic Cycle for Ruthenium-Catalyzed C-C Coupling of 1-Arylpropynes with Primary Alcohols to
Form Products of Carbonyl (α-Aryl)allylation
method to discovery efforts in pharmaceutical research,
representative adducts 3d, 3j, and 3r were transformed to
the corresponding N-Boc-protected phenethylamines (Scheme
regioselectivity. In alignment with this interpretation, the
reaction of alkyne 1ee with the deuterated furfuryl alcohol
deuterio-2ee (eq 7) also results in transfer of deuterium to the
2
3
). The phenethyl alcohols 3d, 3j, and 3r were exposed to
internal vinylic position (50% H at H ), and hydrogen-
c
diphenylphosphoryl azide in the presence of diisopropyl
azodicarboxylate and triphenylphosphine to furnish the azides
deuterium exchange occurs at the carbinol position of the
2
2
primary alcohol in both reactions (7% H at H
, eq 6; 90% H
e
18
4d, 4j, and 4r with complete inversion of stereochemistry and
at H , eq 7) likely via reversible alcohol dehydrogenation. In
e
only trace quantities of competing elimination to form the
eq 6, deuterium content is not completely conserved, which
may be due to exchange with adventitious water.
15
16
conjugated dienes. One-pot Staudinger reduction of 4d, 4j,
and 4r, followed by treatment with di-tert-butyl dicarbonate,
provided phenethylamines 5d, 5j, and 5r, respectively, in good
yield.
The collective data are consistent with the indicated catalytic
cycle (Scheme 6). Ruthenium-catalyzed alkyne-to-allene
isomerization is followed by allene hydrometalation to form
17
19
(
−)-Crataegusanoids A−D were recently isolated from the
fluxional σ-allyl- and π-allylruthenium complexes I. Aldehyde
fruit of the Chinese mountain hawthorn tree, Crataegus
pinnatifida, which are used to make “haw flakes,” a traditional
candy from northern China. In an in vitro evaluation against
two human hepatocellular carcinoma cell lines, HepG2 and
Hep3B, (−)-crataegusanoids A and B displayed moderate
cytotoxicity. To further illustrate the utility of the present
method for asymmetric alkyne-mediated carbonyl (α-aryl)-
allylation, total syntheses of neolignan natural products
coordination, followed by stereospecific carbonyl addition by
way of the (E)-σ-allyliridium through the chairlike transition
structure II, delivers a homoallylic ruthenium alkoxide III,
which, upon exchange with the primary alcohol, releases the
product of carbonyl (α-aryl)allylation and forms the ruthenium
alkoxide IV. β-Hydride elimination from ruthenium alkoxide
IV delivers the ruthenium hydride V along with aldehyde to
close the catalytic cycle. The π-bound alkene in III prevents β-
hydride elimination at this stage by occupying the adjacent
coordination site. Notably, two discrete catalytic events are
operative: (a) alkyne-to-allene isomerization and (b) transfer
hydrogenative carbonyl addition. Yet, as demonstrated by
deuterium labeling studies (eqs 5 and 6), crossover of
ruthenium hydrides that arise in these two catalytic processes
is observed.
(
−)-crataegusanoids A−D were undertaken (Scheme 4). To
this end, phenethyl alcohol ent-3aa was subjected to
ozonolysis, followed by treatment with NaBH , to provide a
4
1
,3-diol. Acetal or ketal formation, followed by concomitant
cleavage of the TIPS silyl ether and phenolic tosylate moieties,
delivered (−)-crataegusanoids A−D.
A series of experiments were performed to probe the
reaction mechanism (Scheme 5). Under standard reaction
conditions, allene iso-1r is converted to the product of carbonyl
CONCLUSIONS
■
(
α-aryl)allylation 3r in 45% yield (eq 5). This experiment
demonstrates that allenes are competent partners for carbonyl
α-aryl)allylation, corroborating their role as reactive inter-
In summary, we report that abundant, tractable 1-aryl-1-
propynes serve as chiral allylmetal pronucleophiles in reactions
with primary alcohol proelectrophiles to form products of
carbonyl (α-aryl)allylation. These hydrogen auto-transfer
processes enable access to homoallylic phenethyl alcohols
with excellent control of diastereo- and enantioselectivity. This
method was successfully applied to the synthesis of psycho-
active phenethylamines, as well as the neolignan natural
products (−)-crataegusanoids A−D. Both steric and electronic
features of the aryl sulfonic acid additive were shown to
contribute to the efficiency with which a more productive and
selective iodide-bound ruthenium catalyst is formed. As
established by deuterium labeling studies, the present
processes contribute to a growing class of enantioselective
metal-catalyzed C-C and C-X coupling reactions in which
alkynes serve as reservoirs for less abundant and less stable
(
mediates. Notably, the yield of 3r obtained from allene iso-1r is
significantly lower than the yield of 3r obtained from the
corresponding 1-aryl-1-propyne 1r (eq 5). These data highlight
the value of utilizing tractable 1-aryl-1-propynes as reservoirs
for less stable and less abundant aryl-substituted allenes.
Exposure of deuterio-1ee to furfuryl alcohol 2ee under standard
conditions delivers deuterio-3ee-I (eq 6). Deuterium is
2
transferred to the internal vinylic position (50% H at H )
c
2
and allylic positions (20% H at H ). These data corroborate
d
alkyne isomerization through successive, reversible alkyne
hydrometalation-β-hydride elimination, and that the ruthenium
hydrides initiating hydrometalation and arising via β-hydride
elimination can emanate from either the alkyne or the alcohol.
5
,6
Additionally, a small, but significant, loss of deuterium is
allenes. Future work will focus on the development of related
2
observed at the olefinic terminus (93.5% H at H ), indicating
catalytic C-C couplings of π-unsaturated feedstocks that occur
a,b
4
,20,21
allene hydrometalation occurs reversibly with incomplete
in the absence of stoichiometric organometallic reagents.
2
842
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
tional Analysis of Medicinal Chemists’ Bread and Butter. J. Med.
Chem. 2016, 59, 4385−4402.
ASSOCIATED CONTENT
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c12242.
■
*
(
3) For selected reviews on metal-catalyzed carbonyl reductive
coupling, see: (a) Montgomery, J. Nickel-Catalyzed Reductive
Cyclizations and Couplings. Angew. Chem., Int. Ed. 2004, 43, 3890−
3908. (b) Kimura, M.; Tamaru, Y. Nickel-Catalyzed Reductive
Coupling of Dienes and Carbonyl Compounds. Top. Curr. Chem.
Experimental procedures and spectroscopic data for all
1
13
new compounds ( H NMR, C NMR, IR, HRMS),
including images of NMR spectra and HPLC traces for
racemic and enantiomerically enriched compounds.
Single crystal X-ray diffraction data for compound 3r
2
007, 279, 173−207. (c) Jeganmohan, M.; Cheng, C.-H. Cobalt- and
Nickel-Catalyzed Regio- and Stereoselective Reductive Coupling of
Alkynes, Allenes, and Alkenes with Alkenes. Chem. - Eur. J. 2008, 14,
1
0876−10886. (d) Moragas, T.; Correa, A.; Martin, R. Metal-
(PDF)
Catalyzed Reductive Coupling Reactions of Organic Halides with
Carbonyl-Type Compounds. Chem. - Eur. J. 2014, 20, 8242−8258.
Accession Codes
(e) Nguyen, K. D.; Park, B. Y.; Luong, T.; Sato, H.; Garza, V. J.;
CCDC 2021653 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
Krische, M. J. Metal Catalyzed Reductive Coupling of Olefin-Derived
Nucleophiles: Reinventing Carbonyl Addition. Science 2016, 354,
aah5133. (f) Holmes, M.; Schwartz, L. A.; Krische, M. J.
Intermolecular Metal-Catalyzed Reductive Coupling of Dienes,
Allenes, and Enynes with Carbonyl Compounds and Imines. Chem.
Rev. 2018, 118, 6026−6052.
(4) For a recent review on metal-catalyzed carbonyl reductive
AUTHOR INFORMATION
Corresponding Author
coupling mediated by H , 2-PrOH, or through hydrogen auto-
■
2
transfer, see: Doerksen, R. S.; Meyer, C. C.; Krische, M. J. Feedstock
Reagents in Metal-Catalyzed Carbonyl Reductive Coupling: Minimiz-
ing Preactivation for Efficiency in Target Oriented Synthesis. Angew.
Chem., Int. Ed. 2019, 58, 14055−14064.
Michael J. Krische − University of Texas at Austin,
Department of Chemistry, Austin, Texas 78712, United
States; orcid.org/0000-0001-8418-9709;
Email: mkrische@mail.utexas.edu
(5) For a review on the use of alkynes as π-allyl precursors in
catalysis, see: Haydl, A. M.; Breit, B.; Liang, T.; Krische, M. J. Alkynes
as Electrophilic or Nucleophilic Allylmetal Precursors in Transition
Metal Catalysis. Angew. Chem., Int. Ed. 2017, 56, 11312−11325.
Authors
Ming Xiang − University of Texas at Austin, Department of
Chemistry, Austin, Texas 78712, United States
Ankan Ghosh − University of Texas at Austin, Department of
Chemistry, Austin, Texas 78712, United States
(6) For alkynes as latent nucleophilic allylmetal equivalents in metal-
catalyzed carbonyl reductive coupling and related redox-neutral
processes, see: (a) Obora, Y.; Hatanaka, S.; Ishii, Y. Iridium-Catalyzed
Coupling Reaction of Primary Alcohols with 1-Aryl-1-propynes
Leading to Secondary Homoallylic Alcohols. Org. Lett. 2009, 11,
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c12242
3
510−3513. (b) Obora, Y.; Sawaguchi, T.; Tsubakimoto, K.; Yoshida,
H.; Ogawa, S.; Hatanaka, S. Iridium-Catalyzed Synthesis of ω-
Hydroxy Homoallylic Alcohols. Synthesis 2013, 45, 2115−2119.
Author Contributions
M.X. and A.G. contributed equally to this work.
Notes
(c) Park, B. Y.; Nguyen, K. D.; Chaulagain, M. R.; Komanduri, V.;
Krische, M. J. Alkynes as Allylmetal Equivalents in Redox-Triggered
C-C Couplings to Primary Alcohols: (Z)-Homoallylic Alcohols via
Ruthenium Catalyzed Propargyl C-H Activation. J. Am. Chem. Soc.
The authors declare no competing financial interest.
2
014, 136, 11902−11905. (d) Chen, Q.-A.; Cruz, F. A.; Dong, V. M.
ACKNOWLEDGMENTS
Alkyne Hydroacylation: Switching Regioselectivity by Tandem
■
Ruthenium Catalysis. J. Am. Chem. Soc. 2015, 137, 3157−3160.
The Robert A. Welch Foundation (F-0038) and the NIH-
NIGMS (RO1-GM069445) are acknowledged for partial
support of this research. Mr. Shisuke Goto is acknowledged
for skillful technical assistance.
(
e) Liang, T.; Nguyen, K. D.; Zhang, W.; Krische, M. J.
Enantioselective Ruthenium Catalyzed Carbonyl Allylation via
Alkyne-Alcohol C-C Bond Forming Transfer Hydrogenation: Allene
Hydrometallation vs. Oxidative Coupling. J. Am. Chem. Soc. 2015,
1
37, 3161−3164. (f) Liang, T.; Zhang, W.; Chen, T.-Y.; Nguyen, K.
REFERENCES
D.; Krische, M. J. Ruthenium Catalyzed Diastereo- and Enantiose-
lective Coupling of Propargyl Ethers with Alcohols: Siloxy-Crotylation
via Hydride Shift Enabled Conversion of Alkynes to π-Allyls. J. Am.
Chem. Soc. 2015, 137, 13066−13071. (g) Liang, T.; Zhang, W.;
Krische, M. J. Iridium Catalyzed C-C Coupling of a Simple Propargyl
Ether with Primary Alcohols: Enantioselective Homoaldol Addition
via Redox-Triggered (Z)-Siloxyallylation. J. Am. Chem. Soc. 2015, 137,
16024−16027. (h) Zhang, W.; Chen, W.; Xiao, H.; Krische, M. J.
Carbonyl anti-(α-Amino)allylation via Ruthenium Catalyzed Hydro-
gen Auto-Transfer: Use of an Acetylenic Pyrrole as an Allylmetal
Pronucleophile. Org. Lett. 2017, 19, 4876−4879.
(7) For selected reviews on enantioselective carbonyl allylation, see:
(a) Denmark, S. E.; Fu, J. Catalytic Enantioselective Addition of
Allylic Organometallic Reagents to Aldehydes and Ketones. Chem.
Rev. 2003, 103, 2763−2794. (b) Hall, D. G. Lewis and Brønsted Acid
Catalyzed Allylboration of Carbonyl Compounds: From Discovery to
Mechanism and Applications. Synlett 2007, 2007, 1644−1655.
(c) Hargaden, G. C.; Guiry, P. J. The Development of the
Asymmetric Nozaki−Hiyama−Kishi Reaction. Adv. Synth. Catal.
■
(
1) For selected reviews on carbonyl addition chemistry, see:
a) Noyori, R.; Kitamura, M. Enantioselective Addition of Organo-
metallic Reagents to Carbonyl Compounds: Chirality Transfer,
Multiplication and Amplification. Angew. Chem., Int. Ed. Engl. 1991,
(
3
0, 49−69. (b) Soai, K.; Shibata, T. Alkylation of Carbonyl Groups. In
Comprehensive Asymmetric Catalysis I-III, Vol. 2; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag Berlin Heidelberg:
Germany, 1999; pp 911−922. (c) Pu, L.; Yu, H.-B. Catalytic
Asymmetric Organozinc Additions to Carbonyl Compounds. Chem.
Rev. 2001, 101, 757−824. (d) Denmark, S. E.; Fu, J. Catalytic
Enantioselective Addition of Allylic Organometallic Reagents to
Aldehydes and Ketones. Chem. Rev. 2003, 103, 2763−2793. (e) Trost,
B. M.; Weiss, A. H. The Enantioselective Addition of Alkyne
Nucleophiles to Carbonyl Groups. Adv. Synth. Catal. 2009, 351, 963−
9
83. (f) Comprehensive Organic Synthesis, 2nd ed., Vols. 1 and 2;
Knochel, P., Molander, G. A., Eds.; Elsevier: Oxford, 2014.
2) Schneider, N.; Lowe, D. M.; Sayle, R. A.; Tarselli, M. A.;
Landrum, G. A. Big Data from Pharmaceutical Patents: A Computa-
(
2
843
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
2
007, 349, 2407−2424. (d) Yus, M.; Gonzal
́
ez-Gómez, J. C.; Foubelo,
Discrimination. J. Am. Chem. Soc. 2016, 138, 3655−3658. (b) Cabrera,
J. M.; Tauber, J.; Zhang, W.; Xiang, M.; Krische, M. J. Selection
between Diastereomeric Kinetic vs Thermodynamic Carbonyl
Binding Modes Enables Enantioselective Iridium-Catalyzed anti-(α-
Aryl)allylation of Aqueous Fluoral Hydrate and Difluoroacetaldehyde
Ethyl Hemiacetal. J. Am. Chem. Soc. 2018, 140, 9392−9395.
(11) For an exhaustive summary of ruthenium-catalyzed transfer
hydrogenative carbonyl reductive couplings of allene pronucleophiles,
see ref 3f.
F. Catalytic Enantioselective Allylation of Carbonyl Compounds and
Imines. Chem. Rev. 2011, 111, 7774−7854. (e) Huo, H.-X.; Duvall, J.
R.; Huang, M.-Y.; Hong, R. Catalytic Asymmetric Allylation of
Carbonyl Compounds and Imines with Allylic Boronates. Org. Chem.
Front. 2014, 1, 303−320. (f) Spielmann, K.; Niel, G.; de Figueiredo,
R. M.; Campagne, J.-M. Catalytic Nucleophilic ‘Umpoled’ π-Allyl
Reagents. Chem. Soc. Rev. 2018, 47, 1159−1173.
(
8) (a) Riediker, M.; Duthaler, R. O. Enantioselective Allylation of
Carbonyl Compounds with Titanium-Carbohydrate Complexes.
Angew. Chem., Int. Ed. Engl. 1989, 28, 494−495. (b) Hafner, A.;
Duthaler, R. O.; Marti, R.; Rihs, G.; Rothe-Streit, P.; Schwarzenbach,
F. Enantioselective syntheses with titanium carbohydrate complexes.
Part 7. Enantioselective Allyltitanation of Aldehydes with Cyclo-
pentadienyldialkoxyallyltitanium Complexes. J. Am. Chem. Soc. 1992,
(12) For acid-base reactions of ruthenium dihydrides with Brønsted
acids, see: (a) Dobson, A.; Robinson, S. R.; Uttley, M. F. Complexes
of the Platinum Metals. V. Perfluorocarboxylato Derivatives. J. Chem.
Soc., Dalton Trans. 1975, 370−377. (b) McInturff, E. L.; Yamaguchi,
E.; Krische, M. J. Chiral Anion Dependent Inversion of Diastereo- and
Enantioselectivity in Carbonyl Crotylation via Ruthenium Catalyzed
Butadiene Hydrohydroxyalkylation. J. Am. Chem. Soc. 2012, 134,
20628−20631.
1
14, 2321−2336. (c) Sebelius, S.; Szabó, K. J. Allylation of Aldehyde
and Imine Substrates with In Situ Generated Allylboronates − A
Simple Route to Enatioenriched Homoallyl Alcohols. Eur. J. Org.
Chem. 2005, 2005, 2539−2547. (d) Vogt, M.; Ceylan, S.; Kirschning,
A. Stereocontrolled Palladium-Catalysed Umpolung Allylation of
Aldehydes with Allyl Acetates. Tetrahedron 2010, 66, 6450−6456.
(13) Maitlis, P. M.; Haynes, A.; James, B. R.; Catellani, M.; Chiusoli,
G. P. Iodide Effects in Transition Metal Catalyzed Reactions. Dalton
Trans. 2004, 3409−3419.
(14) For selected reviews on phenethylamines, see: (a) Aghajanian,
G. K.; Marek, G. J. Serotonin and Hallucinogens. Neuropsychophar-
macology 1999, 21 (2s), 16S−23S. (b) Trachsel, D. Fluorine in
Psychedelic Phenethylamines. Drug Test. Anal. 2012, 4, 577−590.
(c) King, L. A. New Phenethylamines in Europe. Drug Test. Anal.
2014, 6, 808−818. (d) Inan, F.; Brunt, T. M.; Contrucci, R. R.;
Hondebrink, L.; Franssen, E. J. F. Novel Phenethylamines and Their
Potential Interactions With Prescription Drugs: A Systematic Critical
Review. Ther. Drug Monit. 2020, 42, 271−281.
(15) Lal, B.; Pramanik, B. N.; Manhas, M. S.; Bose, A. K.
Diphenylphosphoryl Azide: A Novel Reagent for The Stereospecific
Synthesis of Azides from Alcohols. Tetrahedron Lett. 1977, 18, 1977−
1980.
(e) Haddad, T. D.; Hirayama, L. C.; Singaram, B. Indium-Mediated
Asymmetric Barbier-Type Allylations: Additions to Aldehydes and
Ketones and Mechanistic Investigation of the Organoindium
Reagents. J. Org. Chem. 2010, 75, 642−649. (f) De Sio, V.; Massa,
A.; Scettri, A. Chiral Sulfoxides as Activators of Allyl Trichlorosilanes
in the Stereoselective Allylation of Aldehydes. Org. Biomol. Chem.
2
010, 8, 3055−3059. (g) Li, L.-L.; Tao, Z.-L.; Han, Z.-Y.; Gong, L.-Z.
Double Chiral Induction Enables a Stereoselective Carbonyl
Allylation with Simple Alkenes under the Sequential Catalysis of
Palladium Complex and Chiral Phosphoric Acid. Org. Lett. 2017, 19,
1
02−105. (h) Tekle-Smith, M. A.; Williamson, K. S.; Hughes, I. F.;
Leighton, J. L. Direct, Mild, and General n-Bu NBr-Catalyzed
4
Aldehyde Allylsilylation with Allyl Chlorides. Org. Lett. 2017, 19,
(16) For a review on the Staudinger reduction, see: Gololobov, Y.
G.; Zhmurova, I. N.; Kasukhin, L. F. Sixty Years of Staudinger
Reaction. Tetrahedron 1981, 37, 437−472.
6
(
024−6027.
9) With the exception of refs 9e and 9i, only isolated examples of
catalytic enantioselective carbonyl (α-aryl)allylations have been
described: (a) KANAJIMA, M.; SAITO, M.; HASHIMOTO, S.
One-Pot Enantioselective Synthesis of Optically Active Homoallylic
Alcohols from Allyl Halides. Chem. Pharm. Bull. 2000, 48, 306−307.
(17) Guo, R.; Shang, X.-Y.; Lv, T.-M.; Yao, G.-D.; Lin, B.; Wang, X.-
B.; Huang, X. X.; Song, S.-J. Phenylpropanoid Derivatives from The
Fruit of Crataegus pinnatifida Bunge and Their Distinctive Effects on
Human Hepatoma Cells. Phytochemistry 2019, 164, 252−261.
(18) Tse, S. K. S.; Xue, P.; Lin, Z.; Jia, G. Hydrogen/Deuterium
Exchange Reactions of Olefins with Deuterium Oxide Mediated by
the Carbonylchlorohydrido- tris(triphenylphosphine)ruthenium(II)
Complex. Adv. Synth. Catal. 2010, 352, 1512−1522.
(b) Zanoni, G.; Gladiali, S.; Marchetti, A.; Piccinini, P.; Tredici, I.;
Vidari, G. Enantioselective Catalytic Allylation of Carbonyl Groups by
Umpolung of π-Allyl Palladium Complexes. Angew. Chem., Int. Ed.
2
004, 43, 846−849. (c) Zhu, S.-F.; Yang, Y.; Wang, L.-X.; Liu, B.;
Zhou, Q.-L. Synthesis and Application of Chiral Spiro Phospholane
Ligand in Pd-Catalyzed Asymmetric Allylation of Aldehydes with
Allylic Alcohols. Org. Lett. 2005, 7, 2333−2335. (d) Hemelaere, R.;
Carreaux, F.; Carboni, B. Cross-Metathesis/Isomerization/Allylbora-
tion Sequence for a Diastereoselective Synthesis of Anti-Homoallylic
Alcohols from Allylbenzene Derivatives and Aldehydes. Chem. - Eur. J.
(19) For the reaction of HXRu(CO)(PR ) (X = Cl, Br) with allenes
3
3
and dienes to form π-allylruthenium species, see: (a) Hiraki, K.; Ochi,
N.; Sasada, Y.; Hayashida, H.; Fuchita, Y.; Yamanaka, S.
Organoruthenium(II) Complexes Formed by Insertion Reactions of
Some Vinyl Compounds and Conjugated Dienes into a Hydrido−
Ruthenium Bond. J. Chem. Soc., Dalton Trans. 1985, 873−877.
(b) Hill, A. F.; Ho, C. T.; Wilton-Ely, I. D. E. T. The Coupling of
Methylene and Vinyl Ligands at a Ruthenium(II) Centre. Chem.
Commun. 1997, 2207−2208. (c) Xue, P.; Bi, S.; Sung, H. H. Y.;
2
014, 20, 14518−14523. (e) Evans, D. A.; Aye, Y.; Wu, J.
Asymmetric, anti-Selective Scandium-Catalyzed Sakurai Additions to
Glyoxyamide. Applications to The Syntheses of N-Boc d-Alloisoleu-
cine and d-Isoleucine. Org. Lett. 2006, 8, 2071−2073. (f) Bai, B.; Zhu,
H.-J.; Pan, W. Structure Influence of Chiral 1,1′-Biscarboline-N,N′-
dioxide on The Enantioselective Allylation of Aldehydes with
Allyltrichlorosilanes. Tetrahedron 2012, 68, 6829−6836. (g) Miura,
T.; Nishida, Y.; Morimoto, M.; Murakami, M. Enantioselective
Synthesis of Anti Homoallylic Alcohols from Terminal Alkynes and
Aldehydes Based on Concomitant Use of a Cationic Iridium Complex
and a Chiral Phosphoric Acid. J. Am. Chem. Soc. 2013, 135, 11497−
3
Williams, I. D.; Lin, Z.; Jia, G. Isomerism of [Ru(η -allyl)Cl(CO)-
(PPh ) ]. Organometallics 2004, 23, 4735−4743.
3
2
(20) In an exciting advance, unactivated olefins were used as
allylmetal pronucleophiles in branch-selective asymmetric carbonyl
additions. These processes exploit a ternary hybrid catalyst system
comprising a photoredox catalyst, a hydrogen-atom-transfer catalyst,
and a chromium complex. A single example of carbonyl (α-aryl)
allylation was reported (>20:1 dr, 72% ee). For this and related
photoredox-mediated carbonyl allylations, see: Tanabe, S.;
Mitsunuma, H.; Kanai, M. Catalytic Allylation of Aldehydes Using
Unactivated Alkenes. J. Am. Chem. Soc. 2020, 142, 12374−12381 and
references cited therein.
11500. (h) Tan, Z.; Wan, X.; Zang, Z.; Qian, Q.; Deng, W.; Gong, H.
Ni-Catalyzed Asymmetric Reductive Allylation of Aldehydes with
Allylic Carbonates. Chem. Commun. 2014, 50, 3827−3830. (i) Xiong,
Y.; Zhang, G. Enantioselective Synthesis of Quaternary Stereocenters
via Chromium Catalysis. Org. Lett. 2016, 18, 5094−5097.
(21) A referee of the present paper brought to our attention an
“archived preprint” (not yet peer-reviewed) on enantioselective
cobalt-BPE-catalyzed carbonyl (α-aryl)allylation employing allylben-
(10) (a) Garza, V. J.; Krische, M. J. Hydroxymethylation beyond
Carbonylation: Enantioselective Iridium Catalyzed Reductive Cou-
pling of Formaldehyde with Allylic Acetates via Enantiotopic π-Facial
zenes as allylmetal pronucleophiles. Sacrificial AlMe (150 mol%) is
3
2
844
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
required to mediate π-allyl formation. Relatively modest yields and
stereoselectivities are observed (typically 50−60% yield, 90:10 dr,
8
0% ee): Zhang, H.; Huang, J.; Meng, F. Cobalt-Catalyzed Diastereo-
and Enantioselective Allyl Addition to Aldehydes and α-Ketoesters
through Allylic C−H Functionalization. DOI: 10.21203/rs.3.rs-
58188/v1.
2
845
https://dx.doi.org/10.1021/jacs.0c12242
J. Am. Chem. Soc. 2021, 143, 2838−2845