Enantioselective Ruthenium-BINAP-Catalyzed Carbonyl Reductive Coupling of Alkoxyallenes: Convergent Construction of syn-sec,tert-Diols via (Z)-σ-Allylmetal Intermediates

Diols via (Z )‑σ -Allylmetal Intermediates

Article

Enantioselective Ruthenium-BINAP-Catalyzed Carbonyl Reductive

Coupling of Alkoxyallenes: Convergent Construction of syn-sec,tert-

‡

Ming Xiang, Dana E. Pfa ﬃ nger, Eliezer Ortiz, Gilmar A. Brito, and Michael J. Krische*

Cite This: J. Am. Chem. Soc. 2021, 143, 8849 −8854

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sı Supporting Information

ABSTRACT: The ﬁrst catalytic enantioselective ruthenium-catalyzed carbonyl

reductive couplings of allene pronucleophiles is described. Using an iodide-modiﬁed

ruthenium-BINAP-catalyst and O-benzhydryl alkoxyallene 1a, carbonyl (α-alkoxy)-

allylation occurs from the alcohol or aldehyde oxidation level to form enantiomerically

enriched syn-sec,tert-diols. Internal chelation directs intervention of (Z)-σ-alkoxyallyl-

ruthenium isomers, which engage in stereospeciﬁc carbonyl addition.

INTRODUCTION

Scheme 1. Potential Multiplicity of Chair-Like Transition

Structures in Ruthenium-Catalyzed Carbonyl (α-

Alkoxy)allylation To Form syn-sec,tert-Diols

■

Convergent construction of enantiomerically enriched acylic

stereodiads bearing fully substituted carbon stereocenters

remains a persistent challenge in chemical synthesis. Among

such motifs, syn -sec,tert -diols appear ubiquitously as substruc-

tures across diverse secondary metabolites, especially type I

polyketides. One approach to their preparation involves

stereospeciﬁc aldehyde addition of geometrically deﬁned γ,γ-

disubstituted chiral allylboron reagents through closed chairlike

transition structures (Figure 1). Corresponding catalytic

enantioselective processes that generate syn-sec,tert-diols from

tractable alkoxyallene pronucleophiles represents an alternate

approach that is hitherto undescribed. In connection with our

studies of carbonyl reductive coupling via hydrogenation,

transfer hydrogenation, and hydrogen autotransfer, which

includes the use of allene pronucleophiles, an iridium-

catalyzed reductive coupling of 1,1-disubstituted allenes with

ﬂuoral to form acyclic stereodiads bearing quaternary carbon

centers was developed.₈We posited that the enhanced

oxaphilicity of ruthenium might enable asymmetric couplings

Received: April 2, 2021

Published: June 1, 2021

Figure 1. Stoichiometric vs catalytic synthesis of enantiomerically

enriched syn-sec,tert-diols, a pervasive substructure among type I

polyketide natural products.

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 8849−8854

849

Journal of the American Chemical Society

Article

Table 1. Selected Optimization Experiments in the

preserve syn-diastereoselectivity, carbonyl addition must be fast

relative to (Z)-to-(E)-isomerization of the ﬂuxional allylruthe-

nium intermediates. Furthermore, as described by Marek,

Enantioselective Ruthenium-Catalyzed C−C Coupling of

Alkoxyallene 1a with Alcohol 2a

for γ,γ-disubstituted allylmetal nucleophiles gauche interactions

associated with the developing C−C bond can reverse the

equatorial vs axial preference of the aldehyde substituent to

erode or invert diastereoselectivity. Despite these challenges, we

herewith report ruthenium-BINAP-catalyzed syn-diastereo- and

enantioselective carbonyl reductive couplings of O-benzhydryl

-alkoxy-1,2-butadiene to form syn-sec,tert-diols from primary

Entry Solvent [M] Additive T (°C) (Yield)

alcohol reactants (via hydrogen autotransfer) or aldehyde

reactants (via 2-propanol-mediated reductive coupling).

CPME [0.4]

THF [0.4]

THF [0.3]

−

18%

50%

76%

80%

56%

65%

73%

75%

78%

72%

4:1

6:1

7:1

8.5:1

6:1

8:1

9.5:1

9:1

73%

59%

79%

86%

58%

87%

89%

90%

88%

13,14

LiCI

LiBr

Lil

−

Lil

These processes represent the first catalytic enantioselective

ruthenium-catalyzed carbonyl reductive couplings of allene

,6,7,15,16

pronucleophiles.

RESULTS AND DISCUSSION

■

Recently, we found that ruthenium catalysts bearing iodide

9:1 (10:1)

counterions display enhanced selectivity and productivity in

7.5:1

anti-diastereo- and enantioselective couplings of primary alcohol

Yields are of material isolated by silica gel chromatography.

proelectrophiles with arylpropynes to form products of aldehyde

Diastereoselectivities were determined by H NMR of crude reaction

mixtures. Enantioselectivities were determined by chiral stationary

(

α-aryl)allylation. This observation suggested the feasibility of

utilizing chiral ruthenium iodide complexes to catalyze alcohol-

mediated carbonyl reductive couplings of O-benzhydryl 3-

alkoxy-1,2-butadiene 1a. Branch-selective couplings of this type

would generate fully substituted carbon stereocenters in the

form of monoprotected syn-sec,tert-diols. With these thoughts in

mind, a series of experiments were conducted to assess the

inﬂuence of counterion in reactions of alkoxy allene 1a with p-

bromo benzyl alcohol 2a using the catalyst assembled from

H Ru(CO)(PPh ) (5 mol %) and (R)-BINAP (5 mol %) in

phase HPLC analysis. Diastereoselectivity was determined after

chromatographic puri ﬁ cation. HClRu(CO)(PPh ) (5 mol %). See

Supporting Information for experimental details.

to unactivated aldehydes. In the case of alkoxyallenes, such

oxaphilicity might also result in internal chelation to form (Z)-σ-

allylmetal nucleophiles (Scheme 1). Hence, to accommodate

aldehyde binding, such chelation must be reversible and, to

,10

3 3

Table 2. Diastereo- and Enantioselective Ruthenium-Catalyzed C−C Coupling of Alkoxyallene 1a with Benzylic Alcohols 2a−2p

and Aryl Aldehydes 3a−3p To Form Mono-protected syn-sec,tert-Diols 4a−4p

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of puri ﬁ ed materials.

Enantioselectivities were determined by chiral stationary phase HPLC. Standard conditions: 0.2 mmol scale. See Supporting Information for

experimental details. 10% catalyst. 48 h.

850

J. Am. Chem. Soc. 2021, 143, 8849−8854

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Table 3. Diastereo- and Enantioselective Ruthenium-Catalyzed Reductive C−C Coupling of Alkoxyallene 1a with Aliphatic

Aldehydes 3q−3jj To Form Mono-protected syn-sec,tert-Diols 4q−4jj Mediated by 2-Propanol

^aYields are of material isolated by silica gel chromatography. Diastereoselectivities were determined by ¹H NMR of puri ﬁ ed materials.

Enantioselectivities were determined by chiral stationary phase HPLC. Standard conditions: 0.2 mmol scale. See Supporting Information for

experimental details. 10% catalyst. 48 h.

Scheme 2. Total Synthesis of (−)-Citreodiol

with the outcome observed using H Ru(CO)(PPh ) and LiCl

2 3 3

(

Table 1, entry 2 vs 5). The stereoselectivities obtained upon

addition of LiI to either H Ru(CO)(PPh ) or HClRu(CO)-

3 3

(

PPh ) are also strikingly similar (Table 1, entry 4 vs 6),

3 3

corroborating eﬃcient formation of the halide-modiﬁed catalyst.

As slightly better performance was observed using H Ru(CO)-

(

PPh ) , subsequent optimization focused on this precatalyst.

3 3

Conducting the reaction in THF (Table 1, entry 7), increasing

temperature (Table 1, entry 8), and slightly decreasing

concentration were all beneﬁcial, enabling formation of 4a in

8% yield with excellent control of syn-diastereo- and

enantioselectivity (Table 1, entry 9). The catalyst derived

from HClRu(CO)(PPh and LiI gave 4a in similar, but slightly

cyclopentyl methyl ether (CPME) solvent at 70 °C. In the

absence of added halide ion, the anticipated product of (α-

alkoxy)crotylation 4a was formed in 18% yield with an

enantiomeric enrichment of 73% (Table 1, entry 1). Notably,

a 4:1 mixture of diastereomers in favor of the syn-isomer was

observed. Under these conditions, the introduction of the halide

additives LiX = Cl, Br, I (10 mol %) led to progressively higher

yields and stereoselectivities (Table 1, entries 2−4), with the

iodide-bound catalyst providing 4a in 80% yield, 8.5:1

diastereomeric ratio, and 86% ee (Table 1, entry 4). The

selectivities obtained using HClRu(CO)(PPh ) as precatalyst

)

3 3

lower, yields and selectivities (Table 1, entry 10).

Optimal conditions identiﬁed for the formation of 4a were

applied to structurally diverse benzylic and heterobenzylic

alcohols 2b−2p (Table 2). As illustrated by the formation of

adducts 4a−4g, diverse substitution patterns of the benzene

ring, including ortho-substituents, are tolerated. Additionally, as

demonstrated by the formation of adduct 4b, the reaction

conditions are suﬃciently mild that pinacol boronates are

tolerated. Adducts 4h−4p derived from heterobenzylic alcohols

incorporating furan, thiophene, benzothiazole, pyrrole, pyrazole,

pyridine, and pyrimidine rings also were formed in an eﬃcient

(

for which chloride is preinstalled) are in excellent alignment

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J. Am. Chem. Soc. 2021, 143, 8849−8854

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Scheme 3. General Catalytic Mechanism As Corroborated by Isotopic Labeling Studies

and selective manner. The conversion of alcohols 2a−2p to

adducts 4a−4p represent redox-neutral hydrogen autotransfer

processes. The corresponding aldehydes 3a−3p also can be

transformed to adducts 4a−4p via 2-propanol-mediated

reductive coupling under otherwise identical reaction con-

ditions. Notably, reactions conducted from the aldehyde

oxidation level generally displayed slightly higher yields and

stereoselectivities, which is attributed to more eﬃcient capture

of the transient allylruthenium nucleophiles.

Aliphatic alcohols did not react eﬃciently under the optimal

conditions for the formation of 4a. To facilitate the carbonyl

addition process, the reaction was conducted from the aldehyde

oxidation level at slightly higher catalyst loadings in a less Lewis

basic solvent, DIPE (diisopropyl ether), to promote association

of the aldehyde with the allylruthenium intermediate (see

Supporting Information for selected optimization experiments).

Under these conditions, aliphatic aldehydes 3q−3ee engage in

eﬃcient 2-propanol-mediated reductive coupling with allene 1a

to furnish adducts 4q−4ee (Table 3). syn-Diastereoselectivities

ranging from 8:1 to 15:1 were accompanied by excellent levels of

enantioselectivity (87−99% ee). Additionally, a series of chiral

β-stereogenic aldehydes 3ﬀ, 3gg, 3hh, 3ii, and 3jj were subjected

to reductive coupling with allene 1a using catalysts modiﬁed by

experiments, deuterium loss is attributed to H/D-exchange

involving adventitious water and, in the former experiment, the

hydroxyl functional group of the primary alcohol reactant. It is

notable that deuterium is incorporated at H but not H in both

experiments, suggesting strong kinetic stereocontrol in the

allene hydroruthenation event, possibly due to coordination of

ruthenium to the ether oxygen.

Based on these data, the indicated reaction mechanism is

proposed (Scheme 3). Hydroruthenation of alkoxyallene 1a

delivers (Z)-σ-allylruthenium species I in which internal

coordination of the benzhydryl ether oxygen to ruthenium

deﬁnes alkene stereochemistry. Aldehyde coordination triggers

carbonyl addition by way of a closed six-centered transition

structure II, resulting in the formation of the homoallylic

ruthenium alkoxide III. Exchange with a primary alcohol

reactant releases product and forms the ruthenium alkoxide

IV, which upon β-hydride elimination generates the aldehyde

and the ruthenium hydride V. That internal chelation deﬁnes

(

Z)-stereochemistry of the transient allylruthenium intermedi-

ate is corroborated by reactions of alkoxyallenes 1a vs 1b (eq 1).

(

R)- and (S)-BINAP. In each case, excellent levels of catalyst-

directed asymmetric induction were observed. The utility of this

method is highlighted by conversion of adduct 4r to

(

−)-citreodiol, a secondary metabolite of the ascomycetous

19,20

fungi Penicillium citreoviride B (Scheme 2).

To corroborate the catalytic mechanism, a series of deuterium

labeling experiments were performed (Scheme 3). Under

Alkoxyallene 1b contains a smaller benzyl ether and, hence, is

anticipated to form a more stable chelate than alkoxyallene 1a,

which incorporates a larger benzhydryl ether. Indeed, the

reaction of the less hindered alkoxyallene 1b proceeds with

higher levels of syn-diastereoselectivity but with signiﬁcantly

lower levels of enantioselectivity. A related bis(1-naphthyl)-

alkoxyallene was prepared, but coupling product was not

observed upon exposure to 3a under standard conditions.

Preparation of tertiary allenic ethers could not be achieved, as

lithiation occurs predominately at the γ-position. Attempted

synthesis of the ethyl-substituted allene via lithiation of the

monosubstituted alkoxyallene followed by reaction with ethyl

iodide resulted in incomplete ethylation, possibly due to

competing elimination.

standard reaction conditions, d -3-furfuryl alcohol deuterio-2h

is converted to deuterio-4h-I which completely retains

deuterium at the carbinol position. Deuterium is transferred to

the internal vinylic position (56% H at H ) and the terminal

vinylic position (13% H at H ). These data suggest

dehydrogenation of the primary alcohol is irreversible due to

rapid allene hydroruthenation at the central allene carbon atom,

and that the secondary alcohol product is resistant to

dehydrogenation due to internal coordination of the alkene. In

a related experiment, 3-furfural 3h is subjected to standard

reductive coupling conditions mediated by d -2-propanol.

Deuterium is transferred to the internal vinylic position (71%

H at H ) and the terminal vinylic position (7% H at H ). The

CONCLUSIONS

absence of deuterium at the carbinol position again suggests the

secondary alcohol product is inert with respect to dehydrogen-

ation and that allylruthenium generation occurs via hydro-

ruthenation at the central allene carbon atom. In both

■

In summary, we report the ﬁrst enantioselective ruthenium-

catalyzed carbonyl reductive couplings of allene pronucleo-

philes. This method employs an inexpensive ruthenium-BINAP-

852

J. Am. Chem. Soc. 2021, 143, 8849−8854

Journal of the American Chemical Society

(a) Marek, I.; Sklute, G. Creation of Quaternary Stereocenters in

Article

catalyst and O-benzhydryl 3-alkoxy-1,2-butadiene 1a, which can

be prepared in 2 steps from benzhydryl alcohol on >15 g scale

ACKNOWLEDGMENTS

■

The Robert A. Welch Foundation (F-0038), the NIH-NIGMS

RO1-GM093905, 1 S10 OD021508-01).

(

see Supporting Information )attributes that make this

(

method a practical protocol for the generation of enantiomeri-

cally enriched syn-sec,tert-diols, which appear ubiquitously

among type I polyketide natural products. Two remarkable

eﬀects were uncovered: (a) the enhanced selectivity and

productivity of ruthenium catalysts bearing iodide counter-

ions, and (b) the oxaphilicity of the ruthenium(II) center is

suﬃcient to direct internal chelation to form (Z)-σ-alkoxyallyl-

ruthenium intermediates. The physical basis of the “iodide

eﬀect” remains unclear; however, due to its size and stronger

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(

ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c03480.

Experimental procedures and spectral data for all new

compounds; X-ray diﬀraction data for compounds 4b, 4j,

and 4hh (PDF)

11 , 7774 −7854. (e) Huo, H.-X.; Duvall, J. R.; Huang, M.-Y.; Hong, R.

Accession Codes

CCDC 2043407 and 2068895−2068896 contain the supple-

mentary 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 Cambridge Crystallographic Data Centre, 12

Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Catalysed, Direct Functionalisation of Allenes via Allyl Copper

Intermediates. Chem. Sci. 2017, 8 , 5240 −5247. (c) Holmes, M.;

Schwartz, L. A.; Krische, M. J. Intermolecular Metal-Catalyzed

Reductive Coupling of Dienes, Allenes and Enynes with Carbonyl

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for the Synthesis of Natural Products. Curr. Org. Chem. 2020 , 23 ,

AUTHOR INFORMATION

■

Corresponding Author

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

976 −3003. (e) Li, G.; Huo, X.; Jiang, X.; Zhang, W. Asymmetric

Synthesis of Allylic Compounds via Hydrofunctionalisation and

Difunctionalisation of Dienes, Allenes, and Alkynes. Chem. Soc. Rev.

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020 , 49 , 2060 −2118. (f) Blieck, R.; Taillefer, M.; Monnier, F. Metal-

Ming Xiang − University of Texas at Austin, Department of

Chemistry, Austin, Texas 78712, United States

Dana E. Pfaﬃnger − University of Texas at Austin, Department

of Chemistry, Austin, Texas 78712, United States;

orcid.org/0000-0003-1668-0939

Eliezer Ortiz − University of Texas at Austin, Department of

Chemistry, Austin, Texas 78712, United States

Gilmar A. Brito − University of Texas at Austin, Department of

Chemistry, Austin, Texas 78712, United States

Catalyzed Intermolecular Hydrofunctionalization of Allenes: Easy

Access to Allylic Structures via the Selective Formation of C-N, C-C

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(

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Meyer, C. C.; Krische, M. J. Feedstock Reagents in Metal-Catalyzed

Carbonyl Reductive Coupling: Minimizing Preactivation for Efficiency

in Target-Oriented Synthesis. Angew. Chem., Int. Ed. 2019, 58, 14055−

Complete contact information is available at:

https://pubs.acs.org/10.1021/jacs.1c03480

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Notes

The authors declare no competing ﬁnancial interest.

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