Construction of 1-Tetralols Bearing Two Contiguous Quaternary Chiral Centers through a Rhodium-Catalyzed Enantioselective Desymmetrization Cascade Reaction

Letter

Construction of 1‑Tetralols Bearing Two Contiguous Quaternary

Chiral Centers through a Rhodium-Catalyzed Enantioselective

Desymmetrization Cascade Reaction

Aymane Selmani and Sylvain Darses*

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00638

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sı Supporting Information

ABSTRACT: A novel and eﬃcient access to polyfunctionnalized

chiral 1-tetralols, bearing two contiguous quaternary carbon

stereocenters, has been developed from various and easily accessible

alkynyl-1,3-diketones, through a cascade process including a

regioselective alkyne insertion, a 1,4-Rh shift, and a nucleophilic

addition step via the desymmetrization of the 1,3-diketone moiety

thanks to an appropriate rhodium−chiral diene complex in the

presence of arylboronic acids.

wing to their remarkable presence in many complex

Scheme 1. Proposed Approach to Chiral 1-Tetralols via

Arylative Desymmetrization

natural products, molecules containing contiguous

quaternary stereogenic centers arouse great interest from a

synthetic approach. As this speciﬁc motif is essential for the

expression of their biological activities, the catalytic and

asymmetric construction of such scaﬀolds has to be modular

and diversiﬁable, as this would oﬀer many opportunities in the

elaboration of these complex structures.

However, simple and reliable methods for the selective

assembly of these motifs are scarce because of the diﬃcult

formation of these crowded C−C bonds. Hence, only a few

methods have proven to be eﬀective for the catalytically and

asymmetrically access to contiguous quaternary stereogenic

centers, such as alkylation or cycloaddition reactions. Indeed,

the development of reliable methodologies for the stereo-

selective construction of such patterns still represents an

important challenge.

an easy, rapid, and straightforward strategy to access highly

In our continuous interest in rhodium-catalyzed arylative

complex chiral molecules, but catalytic approaches involving

cascade cyclization, we wondered if contiguous quaternary

desymmetrization have been scarcely explored. Here, we

chiral centers would be accessible via a cascade reaction

involving regioselective alkyne insertion, rhodium 1,4-

report the diastereo- and enantioselective cascade reaction of

alkynyl substituted 1,3-diketones with arylboronic acids,

promoted by a chiral diene−rhodium complex through the

desymmetrization of cyclic and acyclic 1,3-diketones.

c,d,f,5

shift

to generate an arylrhodium intermediate, and

desymmetrization of alkynyl-substituted diketones (Scheme 1).

Such a strategy has been attempted by Lam et al. in a

In order to access such 1-tetralols via the previously

proposed approach (Scheme 1), the regioselectivity of alkyne

racemic variant, but led to moderate yields using a

rhodium(I) catalyst, because of the formation of signiﬁcant

amounts of side products. Even if the iridium(I) catalysis

allowed an increase of the yields, the development of an

asymmetric version, using chiral biphosphine ligands, was not

conclusive as only moderate catalytic activities were observed

despite high enantioselectivities, and only cyclic diketones were

tolerated.

insertion has to be totally controlled. It has been shown that

Received: February 18, 2020

Rhodium-catalyzed arylative cascade cyclizations of bifunc-

tionalized substrates, initiated by arylboronic acids, represent

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

the regioselectivity could be modulated by tuning the steric

and electronic properties of the R substituent. For example, we

have previously shown that, in the arylative cyclization of N-

and O- tethered yne-enoate derivatives, the presence of a 2-

methylphenyl substituent allowed a reverse alkyne insertion,

Table 1. Chiral Dienes in the Desymmetrization of Alkynyl-

1,3-diketones

4c,f

leading to other cyclization products.

However, for the

cyclization of alkynylmalonates, where the alkyne substituent

was a 2-methylphenyl, the formation of a mixture of the two

possible regioisomers was observed. We showed that the

presence of a triﬂuoromethyl group in ortho-position was

essential to reach a total regioselectivity in favor of the desired

tetralones.

Based on our previous results, we ﬁrst evaluated 2-

triﬂuoromethylphenyl as an alkyne substituent in the arylative

cascade reaction of alkynyl-1,3-diketone 1a with phenylboronic

entry

L_nor Ar-MSBod (Ar = )

yield (%)

ee (%)

acid in the presence of the [Rh(OH)(cod)] complex in

^L1

− 51

MeOH at 60 °C (Scheme 2).

L₂

²^-^M^e^C^H4

Scheme 2. Evaluation of 2-Triﬂuoromethylphenyl as Alkyne

Substituent

²^-ⁱ^P^r^O^C^H4

2,3-(Me) C H

2,6-(MeO) C H

2-Me-4-MeOC H₃

3,5-(tBu) C H

3,5-(CF ) C H

4-CF C H

4-NO C H

The reaction was conducted with 1a (0.15 mmol) and phenyl-

boronic acid (0.3 mmol), in the presence of in situ generated chiral

L*-rhodium complex (3 mol % Rh) in degassed methanol at 60 °C.

Gratifyingly, the expected 1-tetralol has been isolated in 92%

yield with total regioselective control. No trace of other

regioisomers or side products issued from the insertion/

protonation process were detected. Moreover, the reaction

appeared to be diastereoselective, as only one diastereoisomer

Isolated yields. Ee values were determined by SFC analysis using a

chiral stationary phase (see Supporting Information).

Scheme 3. Evaluation of Alkylnyl-1,3-diketones with

Phenylboronic Acid

(and its enantiomer) was observed, corresponding to the 1-

tetralol where the two junctions of the cyclopentanone moiety

are syn.

Encouraged by these results, we envisioned the development

of an asymmetric version to access enantioenriched 1-tetralols

(

Table 1).

As the reaction was sluggish in the presence of chiral

phosphine ligands, we envisaged the use of chiral dienes which

have been really useful in such rhodium-catalyzed cascade

reactions. (S,S)-Phbod* or another disubstituted chiral diene

L₂, developed by Hayashi, gave encouraging results, as the

expected 1-tetratol 2a was obtained with 72% and 51% ee,

respectively (entries 1 and 2). The use of the C -symmetric

chiral Ar-MSBod dienes allowed us to reach higher

enantioselectivities, especially the ones bearing an ortho-

substituted aromatic (entries 3−7). We were pleased to ﬁnd

that the ligand 2-Me-4-MeOC H -MSBod aﬀorded the

expected compound 2a with an excellent yield and 84%

enantiomeric excess in the rhodium-catalyzed enantioselective

desymmetrization of alkynyl-1,3-diketone 1a (entry 7).

With these reaction conditions in hand, the enantioselective

desymmetrization cascade reaction proceeded in a selective

manner for a variety of alkynyl substituted 1,3-diketones and

arylboronic acids (Scheme 3). Substrates, containing a

cycloalkyl-1,3-dione moiety (5- or 6-membered rings), reacted

smoothly with phenylboronic acid to provide the desired chiral

The reactions were conducted with 1,3-diketone (0.15 mmol) and

arylboronic acid (0.3 mmol), in the presence of in situ generated

chiral L*-rhodium complex (3 mol % Rh) in degassed methanol at 60

°C. Isolated yields indicated and ee were determined by SFC analysis

using a chiral stationary phase (see Supporting Information).

-tetralols with high yields and enantioselectivities. Diversity

can be introduced through the modulation of the substituent in

the 2 position. It seems that a benzyl substituent allows slightly

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

higher enantiomeric excesses compared to the corresponding

methyl-substituted substrate. Moreover, less reactive acyclic

alkynyl-1,3-diketones can also participate in the reaction,

oﬀering desired polycyclic compounds with high stereo-

selectivity.

expected chiral heterocyclic tetrahydroisoquinolin-1-ol

(

Scheme 5).

Scheme 5. Access to Chiral Tetrahydroisoquinolin-1-ol

The scope of the arylative cascade reaction was then

explored with respect to the arylboronic acid (Scheme 4).

Scheme 4. Chiral 1-Tetralols from Rh/Chiral Diene-

Catalyzed Arylative Desymmetrization of 1

The structure of 1-tetralol 2k was conﬁrmed unambiguously

by single-crystal X-ray analysis (Figure 1). The absolute

conﬁguration of the stereogenic center of 2k was determined

to be (R,R) when 2-Me-4-MeOC H -MSBod was used as the

ligand.

Figure 1. X-ray crystal structure of (R,R)-2k.

To demonstrate the synthetic utility of 1-tetralols, we

evaluated further transformations of these molecules (Scheme

). In addition to the easily convertible ketone functionality,

Scheme 6. Further Transformations of 1-Tetralols

The reactions were conducted with 1,3-diketone (0.15 mmol) and

arylboronic acid (0.3 mmol), in the presence of in situ generated

chiral L*-rhodium complex (3 mol % Rh) in degassed methanol at 60

C. Isolated yields indicated and ee were determined by SFC analysis

using a chiral stationary phase (see Supporting Information).

Diversely 4-substituted arylboronic acids are tolerated with no

inﬂuence on the reaction eﬃciency, as these conditions are

compatible with electron-withdrawing or -donating groups and

halides. These carbon−halogen bonds constitute powerful

synthetic entry for further functionalization via cross-coupling

reactions. The process is not limited to 4-substituted

arylboronic acids, as various 3-substituted and disubstituted

boron reagents have been successfully evaluated and led to the

corresponding 6-substituted 1-tetralols in high yields and

enantioselectivities (2h−j, 2n−p, and 2v−x). In such case, it

should be noted that the 1,4-rhodium migration occurred at

the least hindered site in a total regioselective manner.

Noteworthy, even the more challenging and sterically

demanding ortho-substituted 2-ﬂuorophenylboronic acid

proved to be robust and allowed the formation of the 1-

tetralol 2y in 83% yield and 80% ee. Heteroarylboronic acids

can be successfully employed in this arylative cascade reaction.

As an illustration, the indolyl derivative 2q has been

synthesized with good yield and enantioselectivity from the

corresponding alkynyl-1,3-diketone and 5-indolylboronic acid.

Interestingly, the rhodium-catalyzed asymmetric cascade

reaction of phthalimide derivative 1e, less reactive than the

the reactivity of the exocyclic double bond has been examined:

the ruthenium-catalyzed oxidative cleavage of 1-tetralol 2n

aﬀorded the corresponding chiral 4-hydroxy-3,4-dihydronaph-

thalen-1(2H)-one moiety 4n, with no erosion of the

enantioselectivity. A nucleophilic ﬂuorination of the tertiary

alcohol of 1-tetralol 2e has also been achieved, using DAST

(diethylaminosulfur triﬂuoride), and provided the corre-

sponding chiral ﬂuorinated 1-tetralol 5e in 58% yield and an

unchanged enantiomeric excess. In this process, a quaternary

stereogenic carbon center with a carbon−ﬂuoride bond was

formed, and its conﬁguration has been conﬁrmed by NOESY

experiments and X-ray analysis.

,3-diketones, has been successfully achieved aﬀording the

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

Even if the reaction mechanism was not studied, we can

envision formation of the active catalytic species

ASSOCIATED CONTENT

sı Supporting Information

■

hydroxorhodium(I) by ligand exchanges of [RhCl(C H₄)₂]₂

https://pubs.acs.org/doi/10.1021/acs.orglett.0c00638.

with the chiral diene and KOH (Scheme 7). Following a

Experimental procedures, description of the compounds

and X-ray diﬀraction of 2k (PDF)

Scheme 7. Proposed Catalytic Cycle for the Formation of

Chiral 1-Tetralols

Accession Codes

CCDC 1939901 and 1987761 contain 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

Cambridge Crystallographic Data Centre, 12 Union Road,

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

AUTHOR INFORMATION

Corresponding Author

■

Sylvain Darses − PSL Universite

5005 Paris, France; orcid.org/0000-0003-3350-1736;

Email: sylvain.darses@chimie-paristech.fr

Paris, Chimie ParisTech

Author

Aymane Selmani − PSL Universite

5005 Paris, France

Paris, Chimie ParisTech

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c00638

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

A.S. thanks CNRS (Centre National de la Recherche

■

Scientiﬁque) MENESR (Minister

e de l’Education Nationale

ieur et de la Recherche) for a grant.

We gratefully acknowledge Jeremy Forte and Lise-Marie

Chamoreau for the X-ray analyses (Sorbonne Universite,

Paris).

et de l’Enseignement Super

transmetalation step with arylboronic acid, the regioselective

insertion into the carbon−rhodium bond of the arylrhodium

intermediate occurs, leading to the formation of a vinyl-

rhodium species. Then, the 1,4-shift key step generates a new

arylrhodium species which is trapped by a ketone, through an

intramolecular 1,2-addition. The resulting alkoxorhodium

intermediate is protonated to aﬀord the expected 1-tetralol

along with the regeneration of an active alkoxorhodium(I)

complex.

In summary, we have reported a novel and facile access to

densely functionalized 1-tetralols with high levels of enantio-

and diastereoselectivities, from various and easily accessible

cyclic and acyclic alkynyl-1,3-diketones, through a rhodium(I)-

catalyzed regioselective arylative cyclization with arylboronic

acids. This enantioselective desymmetrization reaction leads to

the creation of two contiguous quaternary carbon stereo-

centers, which are controlled thanks to an appropriate

rhodium−chiral diene complex. The synthesized 1-tetralols

are versatile, as the tertiary alcohol has been successfully

converted to more interesting ﬂuorine without any erosion of

the enantioselectivity. Moreover, the oxidative cleavage of the

exocyclic oleﬁn has been achieved to provide an enantioen-

riched 4-hydroxy-3,4-dihydronaphthalen-1(2H)-one scaﬀold.

REFERENCES

■

1) Reviews: (a) Peterson, E. A.; Overman, L. E. Contiguous

stereogenic quaternary carbons: A daunting challenge in natural

products synthesis. Proc. Natl. Acad. Sci. U. S. A. 2004 , 101 , 11943 −

11948. (b) Long, R.; Huang, J.; Gong, J.; Yang, Z. Direct construction

of vicinal all-carbon quaternary stereocenters in natural product

synthesis. Nat. Prod. Rep. 2015, 32, 1584−1601. (c) Buschleb, M.;

Dorich, S.; Hanessian, S.; Tao, D.; Schenthal, K. B.; Overman, L. E.

Synthetic Strategies toward Natural Products Containing Contiguous

Stereogenic Quaternary Carbon Atoms. Angew. Chem., Int. Ed. 2016,

55, 4156−4186.

(

2) For methodologies for the construction of quaternary stereo-

centers, see: (a) Trost, B. M.; Jiang, C. Catalytic Enantioselective

Construction of All-Carbon Quaternary Stereocenters. Synthesis 2006,

369−396. (b) Marek, I.; Minko, Y.; Pasco, M.; Mejuch, T.; Gilboa,

N.; Chechik, H.; Das, J. P. All-Carbon Quaternary Stereogenic

Centers in Acyclic Systems through the Creation of Several C −C

Bonds per Chemical Step. J. Am. Chem. Soc. 2014 , 136 , 2682 −2694.

c) Quasdorf, K. W.; Overman, L. E. Catalytic enantioselective

synthesis of quaternary carbon stereocentres. Nature 2014, 516 , 181 −

91. (d) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M. Catalytic

Enantioselective Construction of Quaternary Stereocenters: Assembly

of Key Building Blocks for the Synthesis of Biologically Active

Molecules. Acc. Chem. Res. 2015, 48, 740−751. (e) Vetica, F.; de

Figueiredo, R.; Orsini, M.; Tofani, D.; Gasperi, T. Recent Advances in

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Organocatalytic Cascade Reactions toward the Formation of

Letter

Quaternary Stereocenters. Synthesis 2015 , 47 , 2139 −2184. (f) Ling,

T.; Rivas, F. All-carbon quaternary centers in natural products and

medicinal chemistry: recent advances. Tetrahedron 2016 , 72 , 6729 −

(5) For some examples of reactions involving a 1,4-shift, see:

(a) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. Rhodium-

catalyzed hydroarylation of alkynes with arylboronic acids: 1,4-shift of

rhodium from 2-aryl-1-alkenylrhodium to 2-alkenylarylrhodium

intermediate. J. Am. Chem. Soc. 2001 , 123 , 9918 −9. (b) Shintani,

R.; Okamoto, K.; Hayashi, T. Rhodium-catalyzed isomerization of

alpha-arylpropargyl alcohols to indanones: involvement of an

unexpected reaction cascade. J. Am. Chem. Soc. 2005 , 127 , 2872 −3.

3,4-dihydrocoumarins by rhodium-catalyzed reaction of 3-(2-

hydroxyphenyl)cyclobutanones. J. Am. Chem. Soc. 2007 , 129 ,

12086 −7. (d) Panteleev, J.; Menard, F.; Lautens, M. Ligand Control

in Enantioselective Desymmetrization of Bicyclic Hydrazines:

Rhodium(I)-Catalyzed Ring-OpeningversusHydroarylation. Adv.

Synth. Catal. 2008, 350, 2893−2902. (e) Sasaki, K.; Nishimura, T.;

Shintani, R.; Kantchev, E. A. B.; Hayashi, T. Rhodium/diene-

catalyzed tandem 1,4-shift/1,4-addition of (E)-1,2-diphenylethenyl-

boronic acid to enones: density functional theory modeling and

asymmetric catalysis. Chem. Sci. 2012 , 3 , 1278 −1283. (f) Miwa, T.;

Shintani, R. Rhodium-Catalyzed Synthesis of Silicon-Bridged 1,2-

Dialkenylbenzenes via 1,4-Rhodium Migration. Org. Lett. 2019, 21,

1627−1631. (g) Zhang, S. S.; Hu, T. J.; Li, M. Y.; Song, Y. K.; Yang,

X. D.; Feng, C. G.; Lin, G. Q. Asymmetric Alkenylation of Enones and

Imines Enabled by A Highly Efficient Aryl to Vinyl 1,4-Rhodium

Migration. Angew. Chem., Int. Ed. 2019, 58, 3387−3391.

6777. (g) Pierrot, D.; Marek, I. Synthesis of Enantioenriched Vicinal

Tertiary and Quaternary Carbon Stereogenic Centers within an

Acyclic Chain. Angew. Chem., Int. Ed. 2020, 59, 36−49.

(3) For some selected examples, see: (a) Trost, B. M.; Osipov, M.

Palladium-Catalyzed Asymmetric Construction of Vicinal All-Carbon

Quaternary Stereocenters and its Application to the Synthesis of

Cyclotryptamine Alkaloids. Angew. Chem., Int. Ed. 2013 , 52 , 9176 −

9181. (b) Ohmatsu, K.; Imagawa, N.; Ooi, T. Ligand-enabled

multiple absolute stereocontrol in metal-catalysed cycloaddition for

construction of contiguous all-carbon quaternary stereocentres. Nat.

Chem. 2014, 6 , 47 −51. (c) Jolit, A.; Walleser, P. M.; Yap, G. P. A.;

Tius, M. A. Catalytic Enantioselective Nazarov Cyclization:

Construction of Vicinal All-Carbon-Atom Quaternary Stereocenters.

Angew. Chem., Int. Ed. 2014, 53, 6180 −6183. (d) Khan, A.; Yang, L.;

Xu, J.; Jin, L. Y.; Zhang, Y. J. Palladium-Catalyzed Asymmetric

Decarboxylative Cycloaddition of Vinylethylene Carbonates with

Michael Acceptors: Construction of Vicinal Quaternary Stereocenters.

Angew. Chem., Int. Ed. 2014, 53, 11257−11260. (e) Zhao, J.; Fang, B.;

Luo, W.; Hao, X.; Liu, X.; Lin, L.; Feng, X. Enantioselective

Construction of Vicinal Tetrasubstituted Stereocenters by the

Mannich Reaction of Silyl Ketene Imines with Isatin-Derived

Ketimines. Angew. Chem., Int. Ed. 2015, 54, 241−244. (f) Zheng, J.;

Lin, L.; Dai, L.; Tang, Q.; Liu, X.; Feng, X. Nickel-Catalyzed

Conjugate Addition of Silyl Ketene Imines to In Situ Generated

Indol-2-ones: Highly Enantioselective Construction of Vicinal All-

Carbon Quaternary Stereocenters. Angew. Chem., Int. Ed. 2017, 56,

(6) (a) Partridge, B. M.; Solana Gonzalez, J.; Lam, H. W. Iridium-

catalyzed arylative cyclization of alkynones by 1,4-iridium migration.

Angew. Chem., Int. Ed. 2014, 53, 6523−7. As we were about to submit

our article a similar work has been published: (b) Groves, A.; Sun, J.;

Parke, H. R. I.; Callingham, M.; Argent, S.; Taylor, L.; Lam, H. W.

Chem. Sci. 2020, DOI: 10.1039/C9SC06309A .

13107−13111. (g) Ye, L.; Gu, Q.-S.; Tian, Y.; Meng, X.; Chen, G.-C.;

Liu, X.-Y. Radical asymmetric intramolecular α -cyclopropanation of

aldehydes towards bicyclo[3.1.0]hexanes containing vicinal all-carbon

quaternary stereocenters. Nat. Commun. 2018, 9, 227−250. (h) Chen,

S.-K.; Ma, W.-Q.; Yan, Z.-B.; Zhang, F.-M.; Wang, S. H.; Tu, Y.-Q.;

Zhang, X.-M.; Tian, J.-M. Organo-Cation Catalyzed Asymmetric

Homo/Heterodialkylation of Bisoxindoles: Construction of Vicinal

All-Carbon Quaternary Stereocenters and Total Synthesis of

(7) For some examples, see: (a) Cauble, D. F.; Gipson, J. D.;

Krische, M. J. Diastereo- and enantioselective catalytic carbometalla-

tive aldol cycloreduction: tandem conjugate addition-aldol cyclization.

J. Am. Chem. Soc. 2003, 125, 1110−1. (b) Shintani, R.; Okamoto, K.;

Otomaru, Y.; Ueyama, K.; Hayashi, T. Catalytic asymmetric arylative

cyclization of alkynals: phosphine-free rhodium/diene complexes as

efficient catalysts. J. Am. Chem. Soc. 2005 , 127 , 54 −5. (c) Miura, T.;

Shimada, M.; Murakami, M. Acyl 1,3-Migration in Rhodium-

Catalyzed Reactions of Acetylenic β -Ketoesters with Aryl Boronic

Acids: Application to Two-Carbon-Atom Ring Expansions. Angew.

Chem., Int. Ed. 2005, 44, 7598 −7600. (d) Shintani, R.; Tsurusaki, A.;

Okamoto, K.; Hayashi, T. Highly chemo- and enantioselective

arylative cyclization of alkyne-tethered electron-deficient olefins

catalyzed by rhodium complexes with chiral dienes. Angew. Chem.,

Int. Ed. 2005 , 44 , 3909 −12. (e) Miura, T.; Shimada, M.; Murakami,

M. Rhodium-catalyzed arylative cyclization of alkynones induced by

addition of arylboronic acids. Tetrahedron 2007, 63, 6131−6140.

(f) He, Z. T.; Tian, B.; Fukui, Y.; Tong, X.; Tian, P.; Lin, G. Q.

Rhodium-catalyzed asymmetric arylative cyclization of meso-1,6-

dienynes leading to enantioenriched cis-hydrobenzofurans. Angew.

Chem., Int. Ed. 2013 , 52 , 5314 −8. (g) Johnson, T.; Choo, K. L.;

Lautens, M. Rhodium-catalyzed arylative cyclization for the

enantioselective synthesis of (trifluoromethyl)cyclobutanols. Chem. -

Eur. J. 2014 , 20 , 14194 −7. (h) Li, Y.; Xu, M. H. Rhodium-catalyzed

asymmetric tandem cyclization for efficient and rapid access to

underexplored heterocyclic tertiary allylic alcohols containing a

tetrasubstituted olefin. Org. Lett. 2014, 16, 2712−5. (i) Jadhav, S.

B.; Thopate, S. B.; Nanubolu, J. B.; Chegondi, R. Rh-Catalyzed

diastereoselective desymmetrization of enone tethered-cyclohexadie-

nones via tandem arylative cyclization. Org. Biomol. Chem. 2019, 17,

1937−1946.

i) Panda, S.; Ready, J. M. Tandem Allylation/1,2-Boronate

−)-Chimonanthidine. J. Am. Chem. Soc. 2018 , 140 , 10099 −10103.

Rearrangement for the Asymmetric Synthesis of Indolines with

Adjacent Quaternary Stereocenters. J. Am. Chem. Soc. 2018, 140,

3242−13252. (j) Chan, W. L.; Tang, X.; Zhang, F.; Quek, G.; Mei,

G. J.; Lu, Y. Phosphine-Catalyzed (3 + 2) Annulation of Isoindigos

with Allenes: Enantioselective Formation of Two Vicinal Quaternary

Stereogenic Centers. Angew. Chem., Int. Ed. 2019 , 58 , 6260 −6264.

(k) Zehra, S. T.; Zhang, G.; Yang, S.; Fang, X. Kinetic resolution of β -

ketoesters with quaternary stereocenters viaa carbene-catalyzed

benzoin reaction. Org. Biomol. Chem. 2019, 17, 2169−2173.

(4) (a) Serpier, F.; Brayer, J. L.; Folleas, B.; Darses, S. Access to

Polyfunctionalized Chiral Piperidines through Enantioselective

Addition-Carbocyclization Cascade Reaction Catalyzed by a

Rhodium(I)-Diene Complex. Org. Lett. 2015, 17, 5496 −9. (b) Serpier,

F.; Flamme, B.; Brayer, J. L.; Folleas, B.; Darses, S. Chiral pyrrolidines

and piperidines from enantioselective rhodium-catalyzed cascade

arylative cyclization. Org. Lett. 2015 , 17 , 1720 −3. (c) Claraz, A.;

Serpier, F.; Darses, S. Organoboron Initiated Rh-Catalyzed Asym-

metric Cascade Reactions: A Subtle Switch in Regioselectivity

Leading to Chiral 3-Benzazepine Derivatives. ACS Catal. 2017 , 7 ,

410 −3413. (d) Selmani, A.; Darses, S. Enantioenriched 1-Tetralones

via Rhodium-Catalyzed Arylative Cascade Desymmetrization/Acyla-

tion of Alkynylmalonates. Org. Lett. 2019 , 21 , 8122 −8126.

(e) Selmani, A.; Darses, S. Access to chiral cyano-containing five-

(8) (a) Bocknack, B. M.; Wang, L. C.; Krische, M. J.

Desymmetrization of enone-diones via rhodium-catalyzed diastereo-

and enantioselective tandem conjugate addition-aldol cyclization.

Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 5421−4. (b) He, Z. T.; Tian,

B.; Fukui, Y.; Tong, X.; Tian, P.; Lin, G. Q. Rhodium-catalyzed

asymmetric arylative cyclization of meso-1,6-dienynes leading to

enantioenriched cis-hydrobenzofurans. Angew. Chem., Int. Ed. 2013,

membered rings through enantioconvergent rhodium-catalyzed

cascade cyclization of a diastereoisomeric E/Z mixture of 1,6-enynes.

Org. Chem. Front. 2019 , 6 , 3978 −3982. (f) Selmani, A.; Serpier, F.;

Darses, S. From Tetrahydrofurans to Tetrahydrobenzo[ d]oxepines

via a Regioselective Control of Alkyne Insertion in Rhodium-

Catalyzed Arylative Cyclization. J. Org. Chem. 2019, 84, 4566−4574.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

2 , 5314 −8. (c) Keilitz, J.; Newman, S. G.; Lautens, M.

Letter

(14) (a) Shreeve, J. n. M.; Singh, R. P. Recent Advances in

Nucleophilic Fluorination Reactions of Organic Compounds- Using

Deoxofluor and DAST. Synthesis 2002 , 2561 −2578. (b) Liang, T.;

Neumann, C. N.; Ritter, T. Introduction of fluorine and fluorine-

containing functional groups. Angew. Chem., Int. Ed. 2013, 52, 8214−

64.

Enantioselective Rh-catalyzed domino transformations of alkynylcy-

clohexadienones with organoboron reagents. Org. Lett. 2013, 15,

Enantioselective Nickel-Catalyzed anti-Carbometallative Cyclizations

of Alkynyl Electrophiles Enabled by Reversible Alkenylnickel E/Z

Isomerization. J. Am. Chem. Soc. 2016, 138, 8068−71. (e) Karad, S.

N.; Panchal, H.; Clarke, C.; Lewis, W.; Lam, H. W. Enantioselective

Synthesis of Chiral Cyclopent-2-enones by Nickel-Catalyzed

Desymmetrization of Malonate Esters. Angew. Chem., Int. Ed. 2018,

148 −51. (d) Clarke, C.; Incerti-Pradillos, C. A.; Lam, H. W.

7 , 9122 −9125. (f) O ’Brien, L.; Karad, S. N.; Lewis, W.; Lam, H. W.

Rhodium-catalyzed arylative cyclization of alkynyl malonates by 1,4-

rhodium(i) migration. Chem. Commun. 2019, 55, 11366−11369.

(9) For the regioselective insertion of aryl-substituted alkynes, see:

(a) Hayashi, T.; Inoue, K.; Taniguchi, N.; Ogasawara, M. Rhodium-

catalyzed hydroarylation of alkynes with arylboronic acids: 1,4-shift of

rhodium from 2-aryl-1-alkenylrhodium to 2-alkenylarylrhodium

intermediate. J. Am. Chem. Soc. 2001 , 123 , 9918 −9. (b) Lautens,

M.; Yoshida, M. Regioselective rhodium-catalyzed addition of

arylboronic acids to alkynes with a pyridine-substituted water-soluble

ligand. Org. Lett. 2002 , 4 , 123 −5. (c) Lautens, M.; Yoshida, M.

Rhodium-catalyzed addition of arylboronic acids to alkynyl aza-

heteroaromatic compounds in water. J. Org. Chem. 2003 , 68 , 762 −9.

d) Genin, E.; Michelet, V.; Genet, J.-P. Efficient synthesis of

trisubstituted alkenes in an aqueous −organic system using a versatile

and recyclable Rh/ m -TPPTC catalyst. Tetrahedron Lett. 2004, 45,

157−4161. (e) Arcadi, A.; Aschi, M.; Chiarini, M.; Ferrara, G.;

Marinelli, F. Rhodium- and Palladium-Catalyzed Hydroarylation of

Propargylic Amines with Arylboronic Acids. Adv. Synth. Catal. 2010 ,

52 , 493 −498. (f) Panteleev, J.; Zhang, L.; Lautens, M. Domino

rhodium-catalyzed alkyne arylation/palladium-catalyzed N arylation: a

mechanistic investigation. Angew. Chem., Int. Ed. 2011, 50, 9089−92.

(10) (a) Tokunaga, N.; Otomaru, Y.; Okamoto, K.; Ueyama, K.;

Shintani, R.; Hayashi, T. C2-symmetric bicyclo[2.2.2]octadienes as

chiral ligands: their high performance in rhodium-catalyzed

asymmetric arylation of N-tosylarylimines. J. Am. Chem. Soc. 2004 ,

26 , 13584 −5. (b) Okamoto, K.; Hayashi, T.; Rawal, V. H. Simple

chiral diene ligands provide high enantioselectivities in transition-

metal-catalyzed conjugate addition reactions. Org. Lett. 2008 , 10 ,

4387 −9. (c) Okamoto, K.; Hayashi, T.; Rawal, V. H. Electronic and

steric tuning of chiral diene ligands for rhodium-catalyzed asymmetric

arylation of imines. Chem. Commun. 2009, 4815−7. (d) Roy, I. D.;

Burns, A. R.; Pattison, G.; Michel, B.; Parker, A. J.; Lam, H. W. A

second-generation ligand for the enantioselective rhodium-catalyzed

addition of arylboronic acids to alkenylazaarenes. Chem. Commun.

11) (a) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. Readily

014, 50, 2865−8.

available [2.2.2]-bicyclooctadienes as new chiral ligands for Ir(I):

catalytic, kinetic resolution of allyl carbonates. J. Am. Chem. Soc. 2004,

126, 1628−9. (b) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.

P.; Darses, S. C1-symmetric monosubstituted chiral diene ligands in

asymmetric rhodium-catalyzed 1,4-addition reactions. Angew. Chem.,

Int. Ed. 2008 , 47 , 7669 −72. (c) Selmani, A.; Serpier, F.; Darses, S.

Chiral Bicyclo[2.2.2]octa-2,5-dienyltrifluoroborate Derivative as a

Useful and Stable Precursor of C1-Symmetric Chiral Dienes. Org. Lett.

(

019, 21, 4378−4382.

12) For recent examples, see: (a) Kalvet, I.; Magnin, G.;

Schoenebeck, F. Rapid Room-Temperature, Chemoselective Csp2

Csp2 Coupling of Poly(pseudo)halogenated Arenes Enabled by

Palladium(I) Catalysis in Air. Angew. Chem., Int. Ed. 2017, 56 , 1581 −

585. (b) Keaveney, S. T.; Kundu, G.; Schoenebeck, F. Modular

Functionalization of Arenes in a Triply Selective Sequence: Rapid

C(sp(2)) and C(sp(3)) Coupling of C-Br, C-OTf, and C-Cl Bonds

Enabled by a Single Palladium(I) Dimer. Angew. Chem., Int. Ed. 2018,

7, 12573−12577. (c) Diehl, C. J.; Scattolin, T.; Englert, U.;

Schoenebeck, F. C-I-Selective Cross-Coupling Enabled by a Cationic

Palladium Trimer. Angew. Chem., Int. Ed. 2019 , 58 , 211 −215.

(13) Yang, D.; Zhang, C. Ruthenium-catalyzed oxidative cleavage of

olefins to aldehydes. J. Org. Chem. 2001, 66, 4814−8.