Stereodivergent Synthesis of Tertiary Fluoride-Tethered Allenes via Copper and Palladium Dual Catalysis

Copper and Palladium Dual Catalysis

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Stereodivergent Synthesis of Tertiary Fluoride-Tethered Allenes via

†

Shao-Qian Yang, Yi-Fan Wang, Wei-Cheng Zhao, Guo-Qiang Lin,* and Zhi-Tao He*

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sı Supporting Information

ABSTRACT: Herein we describe a protocol for the unprecedented stereodivergent synthesis of tertiary ﬂuoride-tethered allenes

bearing a stereogenic center and stereogenic axis via Cu/Pd synergistic catalysis. A broad scope of conjugated enynes are coupled

with various α-ﬂuoroesters in high yields with high diastereoselectivities and generally >99% ee. In addition, the four stereoisomers

of the allene products ensure precise access to the corresponding four stereoisomers of the ﬂuorinated hydrofurans via a novel

stereodivergent axial-to-central chirality transfer process.

tereogenic centers exist ubiquitously in natural products,

synthetic intermediates, biologically active molecules, and

Scheme 1. Stereodivergent Synthesis via Dual Catalysis

agrochemicals. Precise stereocontrol over one or multiple

chiral centers in a molecule has been a long-standing research

theme in organic synthesis because diﬀerent stereoisomers of a

candidate compound might exhibit totally diﬀerent pharmaco-

logical eﬀects in medicinal chemistry. Among the diverse

methods developed to access all stereoisomers of a target

molecule, a highly eﬃcient proof-of-concept strategy, i.e.,

stereodivergent synthesis via dual catalysis, was demonstrated

by the Carreira group in 2013. This synergistic concept

allowed all four stereoisomers of aldehydes bearing α,β-vicinal

stereogenic centers to be obtained from the same starting

materials via simple and independent permutations of the

enantiomers of the two chiral catalysts. Soon after, the

Carreira, Zhang, Hartwig, Dong, Wang, and other groups

reported using a combination of a transition metal catalyst and

organocatalyst or two metal catalysts in a series of elegant

−7

works.

Recently, the Zi group described the eﬃcient

stereodivergent coupling of 1,3-dienes or allenes with aldimine

4o,u

esters via dual-metal catalysts.

Lee et al. further extended

stereodivergent C−C bond formation via dual organo-

catalysts. However, all of the reported studies focused on

the stereodivergent synthesis of motifs bearing two stereogenic

centers (Scheme 1a). The potential of stereodivergent

synthesis to generate motifs with two diﬀerent types of

stereochemistry, i.e., a combination of a stereogenic center and

a stereogenic axis, remains unknown.

Because ﬂuorine-containing stereocenters exist widely in

biologically active molecules but are diﬃcult to construct, we

envisioned that hydrocarbonation of a conjugated enyne with a

ﬂuorine-containing enolate as a nucleophile over copper and

palladium dual catalysts might stereodivergently provide chiral

In addition, chiral allenes are valuable skeletons because of

their abundance in natural molecules, functional materials, and

versatile precursors of various structures. Although Pd-

catalyzed hydrofunctionalization of conjugated enynes was

discovered as an eﬃcient route for the preparation of allenes by

Yamamoto et al. decades ago, the corresponding enantiose-

lective processes were recently realized by the Malcolmson and

Received: March 25, 2021

Published: May 10, 2021

−11

Tsukamoto groups independently.

In contrast, a more

complex diastereoselective process using a prochiral nucleo-

phile to tether chiral allenes to another stereogenic center has

not yet been explored.

2021 American Chemical Society

J. Am. Chem. Soc. 2021, 143, 7285−7291

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Journal of the American Chemical Society

Communication

allenes bearing an additional fully substituted F-containing

stereogenic center (Scheme 1b). The enyne would ﬁrst insert

into the palladium hydride generated in situ regioselectively to

give an allylpalladium species. Meanwhile, the Cu-coordinated

ﬂuorinated enolate would serve as an outer-sphere nucleophile.

Both transition metal catalysts should independently exert

precise stereocontrol over the conﬁgurations of the related

electrophiles and nucleophiles and thus enable access to all

four possible stereoisomers. Herein, we report our studies on

this unexplored stereodivergent synthesis of motifs containing

a stereogenic center and axis via synergistic Cu/Pd-catalyzed

diastereoselective hydrofunctionalization of conjugated enynes.

We initiated this reaction with ﬂuorinated ester 1a and

and >99% ee, although the yield was only 47% (entry 6). Next,

a series of solvents, including dichloromethane (DCM),

toluene, 2-methyltetrahydrofuran (2-MeTHF), and cyclo-

pentyl methyl ether (CPME), were investigated (entries 7−

10). Using CPME as the solvent further improved the yield to

62% with excellent selectivities (entry 10). Surprisingly,

extending the reaction time from 12 to 20 h led to a higher

yield of 3a (82%), but the diastereoselectivity was slightly

reduced to 16:1 (entry 11). This fact suggested that the

palladium catalyst might slowly epimerize the formed stereo-

genic axis when the reaction time is elongated. Therefore,

time control should be important for balancing the yield and

diastereoselectivity. Finally, a catalytic amount of DBU was

crucial to this coupling reaction. The conversion of 1a was low

without DBU, and no reaction occurred when 1 equiv of DBU

was used (entries 12 and 13). Although it was assumed that a

strong base like DBU was unfavorable for the generation of

conjugated enyne 2a as substrates, Et N and 1,8-

diazabicyclo[5.4.0]undec-7-ene (DBU) as bases, and copper

and palladium catalysts (Table 1). A set of chiral bisphosphine

ligands were ﬁrst evaluated (entries 1−6), and the bulky

electron-rich ligand L6 was found to provide 3a with >20:1 dr

PdH species, a catalytic amount of DBU was necessarily used

as an eﬃcient base to facilitate the deprotonation of ﬂuorinated

ester 1a. Meanwhile, the excess weaker base Et N might help

Table 1. Evaluation of the Reaction Conditions for the

transfer protons and promote the generation of the PdH

catalyst. Thus, to obtain the highest yield and selectivity for 3a,

Hydrocarbonation of Enynes

the reaction should be conducted with ﬂuorinated ester 1a (1.0

equiv), conjugated enyne 2a (2.0 equiv), [Pd]/L6/NaBAr (5

mol %), [Cu]/BPE (5 mol %), Et N (2.0 equiv), and DBU (5

mol %) in CPME at room temperature for a suitable reaction

time.

Conjugated enynes containing a broad range of aryl

substituents underwent smooth hydrofunctionalization with

ﬂuorinated nucleophile 1a, and the results are summarized in

Table 2. A series of electron-donating and electron-with-

drawing groups at varying positions on the aryl units were well-

tolerated, providing the allene products (3a−p, 3x) in 62−99%

yield with 10:1 to >20:1 dr and exclusively >99% ee. For the

electrophiles, functional groups such as CF , halide, OTBS,

alkoxycarbonyl, acetal and NHBoc, among others, were highly

compatible with this hydrocarbonation process, aﬀording the

chiral allenes in good yields with good diastereoselectivities

and excellent enantioselectivities (3d−i, 3k, 3x). In particular,

enyne 2i with a bromoaryl unit was smoothly coupled with 1a

without producing a detectable byproduct from the oxidative

addition of the aryl bromide to palladium; hence, the reaction

gave 3i in 99% yield with >20:1 dr and >99% ee. Heteroaryl

enyne 2q was also suitable for this transformation. Similarly,

alkyl-substituted enynes 2r−t showed high coupling reactivity,

and the corresponding allenes 3r−t were prepared in 77−89%

yield with 9:1 to 11:1 dr and 92−96% ee.

Enynes derived from diverse biologically active molecules

were evaluated via this stereodivergent synthetic method. For

example, when enynes tethered to commercial drugs such as

isoxepac, febuxostat, ibuprofen, naproxen, ketoprofen, and

oxaprozin were employed in the coupling, the allene products

entry

solvent

THF

DCM

Toluene

2-MeTHF

CPME

yield (%)

1:1

ee (%)

1.1:1

16:1

>20:1

7:1

>20:1

7:1

>20:1

16:1

>20:1

>99

(

3v, 3w, 3y, 3z, 3aa, 3bb) were synthesized in good yields with

14−17

excellent diastereo- and enantioselectivities.

Moreover,

electrophiles bearing a Mosher ester, camphanic acid, D-

galactopyranose, and estrone reacted to give the corresponding

products (3u, 3cc−ee) in 58−90% yield with 10:1 to >20:1 dr.

Next, the scope of α-ﬂuoroesters was evaluated for the

construction of tertiary ﬂuoride-tethered allenes. A set of α-

ﬂuoro nucleophiles bearing pyridinyl, pyrazinyl, quinolinyl,

pyrimidinyl, and benzothiazolyl groups underwent hydro-

carbonation in up to 98% yield with >20:1 dr and exclusively

>99% ee (4b−e, 4i−k). High reaction yields and relative and

The reactions were performed with 1a (0.1 mmol), 2a (0.2 mmol),

Cu(MeCN) PF (5 mol %), (S,S)-BPE (5 mol %), [Pd(allyl)Cl] (2.5

mol %), L (5 mol %), NaBAr (Ar = 3,5-(CF ) Ph, 5 mol %), Et N

0.2 mmol), and DBU (5 mol %) in the solvent (0.5 mL) at RT for 20

h. The yields were determined by H NMR analysis of the crude

reaction mixtures. The dr values were determined by H NMR or

NMR analysis, and the ee values were determined by chiral HPLC.

(

12 h. Isolated yield. Without DBU. With 1 equiv of DBU.

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Table 2. Scope of the Substrates that Undergo Stereoselective Coupling

Isolated yields are shown. The dr values were determined by H NMR or ¹⁹F NMR analysis, and ee values were determined by chiral HPLC. See

the Supporting Information for details.

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J. Am. Chem. Soc. 2021, 143, 7285−7291

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Communication

absolute stereoselectivities were obtained from all of the

ﬂuorinated nucleophiles with diverse substituents on the

pyridinyl group (4f−h). When the nucleophile with a methyl

group or a halogen atom like Cl was used instead of the F atom

in ﬂuoroester 1a, the hydrofunctionalization processes still

occurred in moderate to good yields with high stereo-

selectivities (4l, 4m).

Scheme 2. Kinetic Studies of the Hydrofunctionalization

Reaction

The stereodivergent control of products with a tertiary

ﬂuoride stereogenic center and a chiral allene unit was

demonstrated by the coupling of two diﬀerent enynes (2d

and 2i) with α-ﬂuoroester 1a (Table 3). By permutating the

Table 3. Stereodivergent Synthesis

corresponding de value decreased slowly from 94% at 3 h to

only 72% at 83 h. Because the fully substituted F-containing

stereogenic center was unable to undergo epimerization, the

reduced de should be caused by the epimerization of the

stereogenic axis. We proposed that the Pd−H complex formed

in situ might epimerize the allene and thus reduce the de value

via PdH hydrometalation of the allene and β-hydride

elimination, which was similarly observed in the racemization

processes of allenes catalyzed by palladium and other transition

metals. The unchanging >99% ee of 3g observed during the

whole reaction process conﬁrmed that the tertiary ﬂuoride

stereocenter remained unchanged under the standard reaction

conditions.

Fluorinated hydrofurans are key skeletons in many bio-

logically active molecules such as the anti-HCV drug

sofosbuvir. To highlight the synthetic utility of this reaction,

allene product 3d was eﬃciently transformed into enantiopure

ﬂuorinated hydrofuran 9 via axial-to-central chirality transfer in

18,19

two steps (Scheme 3).

In particular, the power of this

methodology was further showcased by a second intriguing

stereodivergent synthesis of ﬂuorinated hydrofurans from the

four corresponding stereoisomers of the allene products. All

four stereoisomers of the ﬂuorinated hydrofurans were

produced with >20:1 dr and >99% ee.

See the Supporting Information for details.

In summary, we established a feasible protocol for the

previously unreported stereodivergent synthesis of motifs

bearing both a stereogenic center and a stereogenic axis via

the Cu/Pd-cocatalyzed diastereoselective hydrofunctionaliza-

tion of conjugated enynes. The coupling of α-ﬂuoroesters with

conjugated enynes aﬀorded tertiary ﬂuoride-tethered allenes in

high yields with high diastereoselectivities and generally >99%

ee. The scope is broad, and a variety of natural and biologically

active molecules were well-tolerated. Preliminary kinetic

studies uncovered the time dependences of the reaction yield

and diastereoselectivity due to the slow epimerization of the

allene product on the Pd−H catalyst. In addition, a novel

stereodivergent axial-to-central chirality transfer route enabled

the precise construction of all four stereoisomers of valuable

ﬂuorinated hydrofurans from the corresponding chiral allene

products. We believe that this work will stimulate extensive

absolute conﬁguration of the ligand of each transition metal

catalyst, all four stereoisomers were precisely obtained in high

yields with high diastereoselectivities and enantioselectivities.

Although a good 8:1 dr was obtained for both 5d and 5i using

the standard combination of chiral ligands, excellent

diastereoselectivities were observed for these two compounds

(

18:1 dr for 5d and 20:1 dr for 5i) when (S)-L5 was used

instead of the original (S)-L6.

As discovered in the reaction development, the diaster-

eoselectivity of the allene product slowly eroded over time. To

elucidate this phenomenon, a kinetic study of the reaction

yield, diastereoselectivity, and enantioselectivity of 3g over

time was conducted, as shown in Scheme 2. It is obvious that

the yield of 3g increased over time, reaching a maximum of

5% at 27 h, and then remained stable. In contrast, the

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J. Am. Chem. Soc. 2021, 143, 7285−7291

Journal of the American Chemical Society

https://pubs.acs.org/10.1021/jacs.1c03157

Communication

Scheme 3. Stereodivergent Axial-to-Central Chirality

Transfer

China; orcid.org/0000-0003-2375-9557; Email: hezt@

sioc.ac.cn

Authors

Shao-Qian Yang − CAS Key Laboratory of Synthetic

Chemistry of Natural Substances, Center for Excellence in

Molecular Synthesis, Shanghai Institute of Organic

Chemistry, University of Chinese Academy of Sciences,

Shanghai 200032, China

Yi-Fan Wang − CAS Key Laboratory of Synthetic Chemistry of

Natural Substances, Center for Excellence in Molecular

Synthesis, Shanghai Institute of Organic Chemistry,

University of Chinese Academy of Sciences, Shanghai 200032,

China

Wei-Cheng Zhao − CAS Key Laboratory of Synthetic

Chemistry of Natural Substances, Center for Excellence in

Molecular Synthesis, Shanghai Institute of Organic

Chemistry, University of Chinese Academy of Sciences,

Shanghai 200032, China

Complete contact information is available at:

Author Contributions

†

S.-Q.Y. and Y.-F.W. contributed equally.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We acknowledge the National “Young Thousand Talents

Plan”, the Shanghai Rising-Star Program (20QA1411300), the

National Natural Science Foundation of China (22071262,

1871284, and 91956113), the Science and Technology

studies exploring the potential of combining other types of

stereochemistry in the future and thus break through the

limitations of stereodivergent synthesis.

Commission of Shanghai Municipality (18401933502), the

Strategic Priority Research Program of the Chinese Academy

of Sciences (XDB 20020100), CAS Key Laboratory of

Synthetic Chemistry of Natural Substances, and Shanghai

Institute of Organic Chemistry for ﬁnancial support. We thank

Ye-Wei Chen for reproducing the syntheses of products 3j and

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/jacs.1c03157.

■

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