Palladium-Catalyzed Asymmetric (4 + 2) Annulation of γ-Methylidene-δ-valerolactones with Alkenes: Enantioselective Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles

Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles

Letter

Palladium-Catalyzed Asymmetric (4 + 2) Annulation of

γ‑Methylidene-δ-valerolactones with Alkenes: Enantioselective

Zhi-Long Jia, Xian-Tao An, Yu-Hua Deng, Lin-Han Pang, Chun-Fang Liu, Le-Le Meng, Jia-Kun Xue,

Xian-He Zhao,* and Chun-An Fan*

Cite This: Org. Lett. 2021, 23, 745 −750

Read Online

ACCESS

Metrics & More

Article Recommendations

sı Supporting Information

ABSTRACT: An unprecedented asymmetric catalytic (4 + 2)

annulation reaction of aryl-substituted γ-methylidene-δ-valerolac-

tones (GMDVs) with isatin-derived para-quinone methides (p-

QMs) has been developed under the catalysis of palladium(0) and

(S,S,S)-(−)-Xyl-SKP, oﬀering a new approach for the diastereo-

and enantioselective synthesis of chiral cyclohexadienone-fused

cyclohexyl spirooxindoles. Signiﬁcantly, three highly congested

contiguous tetrasubstituted carbon atoms embedded in bispir-

ocyclic skeleton, of which two are vicinal quaternary stereogenic

centers, are forged in an eﬀective and selective manner (up to 99%

yield, up to 95% ee, >20/1 dr). The current reaction represents the

ﬁrst exploration of enantioselective catalytic (4 + 2) annulation

forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

he asymmetric catalytic (4 + 2) annulation reaction has

been recognized as one of the most prevailing and

isatin-derived p-QMs under the palladium catalysis (Scheme

1b). Noteworthy is that the current methodology also

constitutes the ﬁrst exploration of asymmetric catalytic (4 +

2) annulation forging the six-membered carbocycles in the

chemistry of p-QMs. This reaction could provide an eﬀective,

diastereo- and enantioselective access to densely functionalized

cyclohexyl spirooxindoles bearing three contiguous all-carbon

quaternary centers. Herein, we report our preliminary results

on this subject.

As tabulated in Table 1, we initially investigated the

designed asymmetric (4 + 2) annulation by using phenyl-

substituted GMDV 1a as a four-carbon synthon and isatin-

derived p-QM 2a as a two-carbon synthon in the presence of

powerful tools for the enantioselective synthesis of highly

functionalized chiral six-membered all-carbon rings, and

hence the development of new and eﬀective (4 + 2) annulation

reactions is a topic of interest in organic synthesis. Recently, γ-

methylidene-δ-valerolactones (GMDVs) as C4 synthons,

which were ﬁrst introduced by the group of Shintani and

Hayashi, have become an emerging focus in asymmetric

catalysis. As seen in Scheme 1a, several palladium-catalyzed

asymmetric versions have been elegantly revealed, including (4

2) annulation of GMDVs with aryl isocyanates (route 1) or

ketones (route 2), (4 + 3) annulation of GMDVs with 1,1-

dicyanocyclopropanes and aziridines (route 3) or nitrones

Pd(dba) as a catalyst and toluene as a solvent at ambient

(

route 4), and (4 + 6) annulation of GMDVs with tropones

temperature. Among chiral ligands screened for this model

route 5). Despite such elegant progress, to our knowledge,

reaction, the ﬁrst use of C -like symmetric axially chiral

the catalytic enantioselective (4 + 2) annulation of GMDVs

with alkenes for constructing the functionalized chiral six-

membered carbocycles has not been reported in organic

chemistry.

monophosphoramidite L1 gave the desired annulation product

aa in 95% yield and >20:1 dr, but with 10% ee (entry 1, Table

). When chiral phosphinooxazoline (R)-Ph-PHOX L2 was

employed, no reactivity was observed (entry 2). To improve

Stimulated by the synthetic importance and biological

potential of cyclohexyl chiral spirooxindoles existing in

Received: November 30, 2020

Published: January 21, 2021

many bioactive compounds (e.g., MDM2-p53 interaction

inhibitor, progesterone receptor agonist) and natural products

(

e.g., gelsemine, koumine) (Scheme 1c), together with our

continuing interest in the chemistry of para-quinone methides

1−13

(p-QMs),

we design and explore an unprecedented

asymmetric catalytic (4 + 2) annulation of GMDVs with

2021 American Chemical Society

Org. Lett. 2021, 23, 745−750

Organic Letters

Letter

Scheme 1. Previous Known Asymmetric Catalytic Modes of

GMDVs and Our Design

further surveyed, but unfortunately there was no positive result

observed in these cases. To our delight, while using C -like-

symmetric bidentate spiroketal bisphosphine (S,S,S)-(−)-Xyl-

15,16

SKP L5 (entry 5),

the desired annulation product 3aa was

obtained with high yield (98%) and promising stereoselectivity

>20:1 dr, 70% ee). Additionally, various solvents were also

(

examined (entries 6−12), and most of the solvents, except for

CH CN, are compatible with the current annulation reaction,

wherein EtOAc as the reaction media (entry 7) could lead to

an excellent yield (99%) with increased stereoselectivity

(

>20:1 dr, 85% ee) for 3aa. Signiﬁcantly, further improvement

in reaction enantioselectivity could be achieved by lowering

the reaction temperature, aﬀording an optimal result (99%

yield, >20:1 dr, 95% ee, entry 13) for this model annulation

reaction. Notably, the absolute conﬁguration of the product

aa was assigned by the X-ray crystallographic analysis of de-

Boc intermediate 4 (CCDC 2026616), which was obtained by

acidic removal of the N-Boc group of 3aa.

With the above reaction conditions optimized for asym-

metric catalytic (4 + 2) annulation reaction, as shown in

Scheme 2, the scope of p-QMs 2a−2t was preliminarily

Scheme 2. Scope of para-Quinone Methides (p-QMs)

Table 1. Optimization of Reaction Conditions

entry ligand

solvent

PhCH₃

time

2 h

12 h

yield (%)

ee (%)

>20:1

−

PhCH₃

CH Cl

−

trace

−

10 min

20 h

>20:1

−

EtOAc

THF

5 min

20 h

Et O

1,4-dioxane

CH CN

acetone

EtOAc

20 h

6 h

>20:1

evaluated in the presence of GMDV 1a. In general, the desired

annulation products 3aa−3as could be obtained in good to

high yields (80−98%) with good stereoselectivities (>20:1 dr,

Unless otherwise noted, the reaction was performed with 1a (0.2

mmol), 2a (0.1 mmol), Pd(dba) (0.005 mmol), and ligand (0.005

mmol) under an argon atmosphere in the indicated solvent (1.0 mL)

0−95% ee). For example, compared with p-QM 2a bearing an

electron-deﬁcient N-protecting group (R = Boc), a series of

substituted p-QMs 2b−2e bearing diﬀerent electron-releasing

N-protecting groups (e.g., R = Me, Bn, allyl, and propargyl)

were examined, and N-substituted annulation products 3ab−

at room temperature.^I^s^o^l^a^t^e^d^yⁱ^e^l^d^.e Determined by H NMR.

Determined by chiral HPLC analysis. Performed at −20 °C. NR =

No reaction.

ae have been obtained in 90−98% yields with >20:1 dr and

the enantioselectivity, typical C -symmetric axially bidentate

chiral phosphine (R)-BINAP L3 (entry 3) and centrally

bidentate chiral phosphine (R,R)-DIOP L4 (entry 4) were

83−95% ee.

In addition, p-QMs with electron-withdrawing groups (X =

F, Cl, and Br) and electron-donating groups (X = CH and

Org. Lett. 2021, 23, 745−750

Organic Letters

Letter

OCH ) at the C5, C6, or C7 position of the phenyl ring were

also investigated, and the corresponding bispirocyclic products

Scheme 4. Gram-Scale Synthesis and Its Transformations

af−3as were achieved in 80−99% yields with >20:1 dr and

7−94% ee. Meanwhile, the absolute conﬁguration of 3ar was

clearly conﬁrmed by X-ray crystallographic analysis (CCDC

026617 ). Notably, while using p-QMs 2at with the

substituent (X = Cl) at the C4 position, no reactivity was

observed in this case, mostly due to the unfavorable eﬀect of

steric hindrance.

To expand the reaction scope, as shown in Scheme 3,

various aryl-substituted GMDVs 1b−1i were also probed for

Scheme 3. Scope of Substituted γ-Methylidene-δ-

valerolactones (GMDVs)

ester group in 3ab gave the alcohol 4ab (94% ee, >20:1 dr,

74% yield). Interestingly, its treatment with ICl could deliver

the bridged tetracyclic product 5ab (93% ee, >20:1 dr, 77%

yield).

On the basis of the crystallographically determined absolute

conﬁgurations of products 3ar (Scheme 2), 3fa (Scheme 3),

and 4 (Table 1), a mechanistic model is proposed to explain

the stereochemical outcome exemplifying the formation of 3aa

in this asymmetric catalytic (4 + 2) annulation reaction. As

shown in Scheme 5, 1,4-zwitterionic species A is initially

Scheme 5. Proposed Mechanism

Performed at rt. Performed at 0 °C.

this asymmetric catalytic (4 + 2) annulation. The title reaction

proceeded readily to aﬀord the expected bispirocyclic products

3ba−3ia in good to excellent yields (75−99%) with good to

high stereoselectivities (>20:1 dr, 70−95% ee), in which

somewhat decreased enantioselectivities in products 3ga (75%

ee, >20:1 dr, 90% yield) and 3ha (70% ee, >20:1 dr, 85%

yield) were observed in the examples using the lactone-

containing GMDVs (1g and 1h) with the stronger electron-

rich methoxy group (X = OCH ) at the C4 or C3/C4 position.

Analogously, the absolute conﬁguration of 3fa was determined

by X-ray crystallographic analysis (CCDC 2026618). Mean-

while, heteroaryl-substituted GMDVs 1j (Ar = 3-thienyl) and

k (Ar = N-benzylindol-3-yl) were also examined, smoothly

aﬀording the expected bispirocyclic products 3ja (89% ee,

20:1 dr, 72% yield) and 3ka (91% ee, >20:1 dr, 92% yield).

To explore the practical utility of this protocol, a gram-scale

reaction of 1a with 2a was performed under standard

conditions (Scheme 4a), and the desired (4 + 2) annulation

product 3aa was obtained in high yield (92%) and high

stereoselectivity (>20:1 dr, 95% ee). With 3aa and 3ab in

hand, their further transformations were then pursued

generated in situ through decarboxylative oxidative addition of

palladium(0) to GMDV1a. Due to the C -like symmetric

15a,16b

backbone of (S,S,S)-(−)-Xyl-SKP L5,

as depicted in

transition state TS-1, an enantioselective 1,6-conjugate

addition of the Si face of 1,4-zwitterionic species A to the Si

face of the p-QM 2a moiety occurs favorably. After subsequent

intramolecular dearomative Friedel−Crafts-type cyclization via

reductive elimination in TS-2, the desired cyclohexyl

(

Scheme 4b). The exocyclic double bond in 3aa underwent

a stereoselective epoxidation to deliver the epoxide 5 (93% ee,

:1 dr, 72% yield). Besides, the chemoselective reduction of

Org. Lett. 2021, 23, 745−750

Organic Letters

Complete contact information is available at:

Letter

spirooxindole 3aa is achieved with the release of the

palladium(0) catalyst for the next catalytic cycle.

In conclusion, an asymmetric catalytic (4 + 2) annulation

reaction of substituted γ-methylidene-δ-valerolactones

Le-Le Meng − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

Jia-Kun Xue − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

(

GMDVs) with isatin-derived para-quinone methides (p-

QMs) has been designed and developed for the ﬁrst time,

providing an eﬀective approach for the synthesis of chiral

cyclohexadienone-fused cyclohexyl spirooxindoles in good to

high yields and stereoselectivities (up to 99% yield, >20:1 dr,

up to 95% ee). Signiﬁcantly, three highly congested contiguous

tetrasubstituted carbon atoms, two of which are vicinal all-

carbon quaternary stereocenters, are eﬃciently installed in the

polycyclic spirooxindole skeleton. This reaction forming the

highly functionalized six-membered carbocycles not only

represents the ﬁrst exploration of enantioselective catalytic (4

https://pubs.acs.org/10.1021/acs.orglett.0c03963

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We are grateful for ﬁnancial support from NSFC (21825104,

1801103, 22071091), and PCSIRT (IRT_15R28).

2) annulation of GMDVs with alkenes but also demonstrates

the unprecedented design in asymmetric catalytic (4 + 2)

annulation of p-QMs with four-carbon zwitterionic synthons.

REFERENCES

■

Asymmetric Diels-Alder Reactions. Chem. Rev. 1992 , 92 , 1007 −1019.

1) For selected reviews, see: (a) Kagan, H. B.; Riant, O. Catalytic

(b) Lautens, M.; Klute, W.; Tam, W. Transition Metal-Mediated

ASSOCIATED CONTENT

sı Supporting Information

■

Cycloaddition Reactions. Chem. Rev. 1996 , 96 , 49 −92. (c) Fruhauf,

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03963.

H.-W. Metal-Assisted Cycloaddition Reactions in Organotransition

Metal Chemistry. Chem. Rev. 1997 , 97 , 523 −596. (d) Moyano, A.;

Rios, R. Asymmetric Organocatalytic Cyclization and Cycloaddition

Reactions. Chem. Rev. 2011, 111, 4703−4832.

Experimental procedures and spectral data (PDF)

Accession Codes

(2) For reviews of the chemistry of GMDVs, see: Allen, B. D. W.;

Lakeland, C. P.; Harrity, J. P. A. Utilizing Palladium-Stabilized

Zwitterions for the Construction of N-Heterocycles. Chem. - Eur. J.

017, 23, 13830−13857.

3) For the ﬁrst example of GMDVs in asymmetric catalysis, see:

Shintani, R.; Murakami, M.; Hayashi, T. γ -Methylidene-δ -valerolac-

tones as a Coupling Partner for Cycloaddition: Palladium-Catalyzed

[4 + 3] Cycloaddition with Nitrones. J. Am. Chem. Soc. 2007, 129,

CCDC 2026616 −2026618 contain the supplementary crys-

tallographic 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.

(

2356−12357.

4) (a) Shintani, R.; Park, S.; Shirozu, F.; Murakami, M.; Hayashi, T.

AUTHOR INFORMATION

■

Palladium-Catalyzed Asymmetric Decarboxylative Lactamization of γ -

Methylidene-δ -valerolactones with Isocyanates: Conversion of Race-

mic Lactones to Enantioenriched Lactams. J. Am. Chem. Soc. 2008,

Corresponding Authors

Chun-An Fan − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China; orcid.org/

30, 16174−16175. (b) Shintani, R.; Ito, T.; Nagamoto, M.; Otomo,

H.; Hayashi, T. Palladium-catalyzed asymmetric synthesis of 2-

pyrrolidinones with a quaternary carbon stereocenter. Chem.

Commun. 2012, 48, 9936−9938.

000-0003-4837-3394 ; Email: fanchunan@lzu.edu.cn

Xian-He Zhao − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China;

Email: zhaoxh@lzu.edu.cn

5) Shintani, R.; Hayashi, S.; Murakami, M.; Takeda, M.; Hayashi, T.

Stereoselective Synthesis of Spirooxindoles by Palladium-Catalyzed

Decarboxylative Cyclization of γ -Methylidene-δ -valerolactones with

Isatins. Org. Lett. 2009, 11, 3754−3756.

(

6) For a very recent example on enantioselective catalytic

Authors

construction of chiral spirocyclic functionalized tetrahydropyrans via

Pd-catalyzed (4 + 2) cycloaddition, see: Mao, B.; Liu, H.; Yan, Z.; Xu,

Y.; Xu, J.; Wang, W.; Wu, Y.; Guo, H. Palladium-Catalyzed

Asymmetric [4 + 2] Cycloaddition of 2-Methylidenetrimethylene

Carbonate with Alkenes: Access to Chiral Tetrahydropyran-Fused

Spirocyclic Scaffolds. Angew. Chem., Int. Ed. 2020, 59, 11316−11320.

(7) Shintani, R.; Murakami, M.; Tsuji, T.; Tanno, H.; Hayashi, T.

Palladium-Catalyzed Decarboxylative [4 + 3] Cyclization of γ -

Methylidene-δ -valerolactones with 1,1-Dicyanocyclopropanes. Org.

Lett. 2009, 11, 5642−5645.

Zhi-Long Jia − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

Xian-Tao An − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

Yu-Hua Deng − Key Laboratory of Medicinal Chemistry for

Natural Resource, Ministry of Education, School of Chemical

Science and Technology, Yunnan University, Kunming

(

8) Yang, L.-C.; Wang, Y.-N.; Liu, R.; Luo, Y.; Ng, X.; Yang, B.;

Rong, Z.-Q.; Lan, Y.; Shao, Z.; Zhao, Y. Stereoselective access to

5.5.0] and [4.4.1] bicyclic compounds through Pd-catalysed

divergent higher-order cycloadditions. Nat. Chem. 2020, 12, 860−868.

9) For selected examples on the synthesis of chiral cyclohexyl

50091, China; orcid.org/0000-0002-1983-8490

[

Lin-Han Pang − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

Chun-Fang Liu − State Key Laboratory of Applied Organic

Chemistry, College of Chemistry and Chemical Engineering,

Lanzhou University, Lanzhou 730000, China

(

spirooxindoles under the transition metal catalysis, see: (a) Zheng, J.;

Lin, L.; Fu, K.; Zheng, H.; Liu, X.; Feng, X. Synthesis of Optically

Pure Spiro[cyclohexane-oxindoline] Derivatives via Catalytic Asym-

metric Diels −Alder Reaction of Brassard-Type Diene with Methyl-

Org. Lett. 2021, 23, 745−750

Organic Letters

H.; Wang, S.; Zhou, Y.; Dong, S.; Feng, X. Asymmetric Catalytic

Letter

eneindolines. J. Org. Chem. 2015, 80, 8836−8842. (b) Luo, Y.; Zhang,

Diverse Ring Opening/Cycloadditions of Cyclobutenones with (E )-

Alkenyloxindoles and (E )-Dioxopyrrolidines. Org. Lett. 2020, 22,

G.; McComas, C. C.; Mugford, C. A.; Slayden, O. D.; Yudt, M.;

Zhang, Z.; Zhang, P.; Zhu, Y.; Winneker, R. C.; Wrobel, J. E. Design,

Synthesis, and SAR of New Pyrrole-Oxindole Progesterone Receptor

Modulators Leading to 5-(7-Fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-

1H-indol-5-yl)-1-methyl-1H-pyrrole-2-carbonitrile (WAY-255348). J.

Med. Chem. 2008, 51, 1861−1873. (g) Liu, J.-J.; Zhang, Z.

Spiroindolinone Derivatives (Hoffmann-La Roche AG), PCT Int.

Appl. WO 2008/055812, 2008. (h) Bencivenni, G.; Wu, L.-Y.;

Mazzanti, A.; Giannichi, B.; Pesciaioli, F.; Song, M.-P.; Bartoli, G.;

Melchiorre, P. Targeting Structural and Stereochemical Complexity

by Organocascade Catalysis: Construction of Spirocyclic Oxindoles

Having Multiple Stereocenters. Angew. Chem., Int. Ed. 2009, 48,

7200−7203.

645−2650. For selected examples on the synthesis of chiral

cyclohexyl spirooxindoles under the organocatalysis since 2015, see:

c) Zhou, R.; Wu, Q.; Guo, M.; Huang, W.; He, X.; Yang, L.; Peng,

(

F.; He, G.; Han, B. Organocatalytic cascade reaction for the

asymmetric synthesis of novel chroman-fused spirooxindoles that

potently inhibit cancer cell proliferation. Chem. Commun. 2015, 51,

13113−13116. (d) Sun, Q.-S.; Chen, X.-Y.; Zhu, H.; Lin, H.; Sun, X.-

W.; Lin, G.-Q. Asymmetric synthesis of poly-substituted spirocyclo-

hexane oxindole via a squaramide catalyzed cascade Michael −

Michael −aldol sequence. Org. Chem. Front. 2015, 2, 110−113.

(11) Baeyer, A.; Villiger, V. Dibenzalaceton und Triphenylmethan.

Ber. Dtsch. Chem. Ges. 1903, 36, 2774−2796.

(e) Chintalapudi, V.; Galvin, E. A.; Greenaway, R. L.; Anderson, E. A.

Combining cycloisomerization with trienamine catalysis: a regio-

chemically flexible enantio- and diastereoselective synthesis of

hexahydroindoles. Chem. Commun. 2016, 52, 693−696. (f) Zhang,

L.-L.; Zhang, J.-W.; Xiang, S.-H.; Guo, Z.; Tan, B. Stereoselective

Construction of Complex Spirooxindoles via Bisthiourea Catalyzed

Three-Component Reactions. Chin. J. Chem. 2018, 36, 1182 −1186.

(12) For very recent reviews on the chemistry of p -QMs, see:

(a) Parra, A.; Tortosa, M. para -Quinone Methide: a New Player in

Asymmetric Catalysis. ChemCatChem 2015 , 7 , 1524 −1526. (b) Car-

uana, L.; Fochi, M.; Bernardi, L. The Emergence of Quinone

Methides in Asymmetric Organocatalysis. Molecules 2015 , 20 , 11733 −

11764. (c) Chauhan, P.; Kaya, U.; Enders, D. Advances in

Organocatalytic 1,6-Addition Reactions, Enantioselective Construc-

tion of Remote Stereogenic Centers. Adv. Synth. Catal. 2017, 359,

888−912. (d) Lima, C. G. S.; Pauli, F. P.; Costa, D. C. S.; de Souza, A.

S.; Forezi, L. S. M.; Ferreira, V. F.; de Carvalho da Silva, F. para -

Quinone Methides as Acceptors in 1,6-Nucleophilic Conjugate

Addition Reactions for the Synthesis of Structurally Diverse

Molecules. Eur. J. Org. Chem. 2020, 2020 , 2650 −2692. (e) Wang,

J.-Y.; Hao, W.-J.; Tu, S.-J.; Jiang, B. Recent developments in 1,6-

addition reactions of para -quinone methides (p -QMs). Org. Chem.

Front. 2020, 7, 1743−1778.

(13) For the ﬁrst report on 1,6-conjugate addition of p-QMs in

asymmetric catalysis, see: Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-

H.; Zeng, C.; Du, J.-Y.; Zhang, G.-B.; Wang, F.-X.; Ma, X.-Y.; Fan, C.-

A. Asymmetric Catalytic 1,6-Conjugate Addition/Aromatization of

para -Quinone Methides: Enantioselective Introduction of Function-

alized Diarylmethine Stereogenic Centers. Angew. Chem., Int. Ed.

2013, 52, 9229−9233.

g) Mei, H.; Lin, L.; Shen, B.; Liu, X.; Feng, X. Highly

enantioselective desymmetrization of prochiral cyclic α ,α -dicyanoal-

kenes via the direct vinylogous Michael/cyclization domino reaction.

Org. Chem. Front. 2018, 5, 2505−2509. (h) Yue, J.-F.; Ran, G.-Y.;

Yang, X.-X.; Du, W.; Chen, Y.-C. Asymmetric Diels −Alder cyclo-

additions of benzofulvene-based 2,4-dienals via trienamine activation.

Org. Chem. Front. 2018, 5, 2676−2679. (i) Zhang, L.-L.; Zhang, J.-W.;

Xiang, S.-H.; Guo, Z.; Tan, B. Remote Control of Axial Chirality:

Synthesis of Spirooxindole −Urazoles via Desymmetrization of ATAD.

Org. Lett. 2018, 20, 6022−6026. (j) Zuo, X.; Liu, X.-L.; Wang, J.-X.;

Yao, Y.-M.; Zhou, Y.-Y.; Wei, Q.-D.; Gong, Y.; Zhou, Y. Organo-

catalytic Reaction of Chromone-Oxindole Synthon: Access to

Chromanone-Based Spirocyclohexaneoxindoles with Five Adjacent

Stereocenters. J. Org. Chem. 2019, 84, 6679−6688. (k) Liu, X.-L.;

Zhou, G.; Gong, Y.; Yao, Z.; Zuo, X.; Zhang, W.-H.; Zhou, Y.

Stereocontrolled Synthesis of Bispirooxindole-Based Hexahydroxan-

thones with Five Contiguous Stereocenters. Org. Lett. 2019, 21,

528−2531. (l) Zhou, Z.; He, Q.; Jiang, Y.; Ouyang, Q.; Du, W.;

(14) For nonasymmetric (4 + 2) annulations of p-QMs to construct

the six-membered carbocycles, see: (a) Hatchard, W. R. Syntheses by

Free-radical Reactions. The Reaction of 2,6-Di-t-butyl-4-methylphe-

nol and 2,6-Di-t-butyl-4-isopropylphenol with Chloroprene. J. Am.

Chem. Soc. 1958 , 80 , 3640 −3642. (b) McClure, J. D. Synthesis of

Spiroundecatrienones from 2,6-Di-t-butylquinone Methide and

Butadienes. J. Org. Chem. 1962 , 27 , 2365 −2368. (c) Roper, J. M.;

Everly, C. R. Direct Synthesis of Spiro[5.5]undeca-l,4,7-trienones

from Phenols via a Quinone Methide Intermediate. J. Org. Chem.

1988, 53, 2639 −2642. (d) Baik, W.; Lee, H. J.; Yoo, C. H.; Jung, J.

W.; Kim, B. H. New approach to p -hydroxybenzylation of arenes via a

quinomethane generated in situ from a Mannich base. J. Chem. Soc.,

Perkin Trans. 1 1997 , 587 −589. (e) Baik, W.; Lee, H. J.; Koo, S.; Kim,

Chen, Y.-C. Double Thiol-Chiral Brønsted Base Catalysis: Asym-

metric Cross Rauhut −Currier Reaction and Sequential [4 + 2]

Annulation for Assembly of Different Activated Olefins. Org. Lett.

019, 21, 7184−7188. (m) Liu, X.-L.; Wei, Q.-D.; Zuo, X.; Xu, S.-W.;

Yao, Z.; Wang, J.-X.; Zhou, Y. Organocatalytic Michael/Michael

Cycloaddition Enabled Asymmetric Construction of Hexahydrox-

anthones with Skeletal Diversity. Adv. Synth. Catal. 2019, 361, 2836−

2843. (n) Yang, S.-M.; Karanam, P.; Wang, M.; Jang, Y.-J.; Yeh, Y.-S.;

Tseng, P.-Y.; Ganapuram, M. R.; Liou, Y.-C.; Lin, W. A vinylogous

Michael addition-triggered quadruple cascade reaction for the

enantioselective generation of multiple quaternary stereocenters.

Chem. Commun. 2019, 55, 1398−1401. (o) He, T.; Peng, L.; Li, S.;

Hu, F.; Xie, C.; Huang, S.; Jia, S.; Qin, W.; Yan, H. Chiral Naphthyl-

C2-Indole as Scaffold for Phosphine Organocatalysis: Application in

Asymmetric Formal [4 + 2] Cycloaddition Reactions. Org. Lett. 2020,

B. H. LiAlH Promoted Reductive Deoxygenation of Hydroxybenzyl

Alcohols via Benzoquinone Methide Intermediates. Tetrahedron Lett.

1998, 39, 8125 −8128. (f) Baik, W.; Lee, H. J.; Jang, J. M.; Koo, S.;

Kim, B. H. NBS-Promoted Reactions of Symmetrically Hindered

Methylphenols via p -Benzoquinone Methide. J. Org. Chem. 2000, 65,

108−115. (g) Ghotekar, G. S.; Shirsath, S. R.; Shaikh, A. C.;

Muthukrishnan, M. 1,6-Conjugate addition initiated formal [4 + 2]

annulation of p -quinone methides with sulfonyl allenols: a unique

access to spiro[5.5]undeca-1,4-dien-3-one scaffolds. Chem. Commun.

2020, 56, 5022−5025.

(15) For examples of catalytic asymmetric preparation of SKP, see:

(a) Wang, X.; Han, Z.; Wang, Z.; Ding, K. Catalytic Asymmetric

Synthesis of Aromatic Spiroketals by SpinPhox/Iridium(I)-Catalyzed

Hydrogenation and Spiroketalization of α ,α ′-Bis(2-hydroxyarylidene)

Ketones. Angew. Chem., Int. Ed. 2012 , 51 , 936 −940. (b) Wang, X.;

Guo, P.; Wang, X.; Wang, Z.; Ding, K. Practical Asymmetric Catalytic

Synthesis of Spiroketals and Chiral Diphosphine Ligands. Adv. Synth.

Catal. 2013, 355, 2900−2907. (c) Wang, X.; Ding, K. Making

of the Structure of Gelsemine Hydrohalides. Tetrahedron Lett. 1959 , 1

2, 6966−6971.

10) (a) Lovell, F. M.; Pepinsky, R.; Wilson, A. J. C. X-Ray Analysis

4), 1 −5. (b) Conroy, B.; Chakrabarti, J. K. The Structure and

Biogenesis of the Alkaloid Gelsemine. Tetrahedron Lett. 1959, 1 (4),

−13. (c) Liu, C.-T.; Wang, Q.-W. Structure of Koumine. J. Am.

Winneker, R.; Wrobel, J.; Zhang, P.; Zhang, Z.; Zhu, Y. New

Chem. Soc. 1981, 103, 4634−4635. (d) Fensome, A.; Bender, R.;

Cohen, J.; Collins, M. A.; Mackner, V. A.; Miller, L. L.; Ullrich, J. W.;

Progesterone Receptor Antagonists: 3,3-Disubstituted-5-aryloxin-

doles. Bioorg. Med. Chem. Lett. 2002 , 12 , 3487 −3490. (e) Lin, H.;

Danishefsky, S. J. Gelsemine: A Thought-Provoking Target for Total

Synthesis. Angew. Chem., Int. Ed. 2003, 42, 36−51. (f) Fensome, A.;

Adams, W. R.; Adams, A. L.; Berrodin, T. J.; Cohen, J.; Huselton, C.;

Illenberger, A.; Kern, J. C.; Hudak, V. A.; Marella, M. A.; Melenski, E.

Org. Lett. 2021, 23, 745−750

Organic Letters

Spiroketal-based Diphosphine (SKP) Ligands via a Catalytic

Letter

Asymmetric Approach. Chin. J. Chem. 2018, 36, 899−903.

(

16) For selected examples of SKP in asymmetric catalysis, see:

(

a) Wang, X.; Meng, F.; Wang, Y.; Han, Z.; Chen, Y.-J.; Liu, L.; Wang,

Z.; Ding, K. Aromatic Spiroketal Bisphosphine Ligands: Palladium-

Catalyzed Asymmetric Allylic Amination of Racemic Morita −Baylis −

Hillman Adducts. Angew. Chem., Int. Ed. 2012, 51, 9276−9282.

b) Wang, X.; Guo, P.; Han, Z.; Wang, X.; Wang, Z.; Ding, K.

Spiroketal-Based Diphosphine Ligands in Pd-Catalyzed Asymmetric

Allylic Amination of Morita −Baylis −Hillman Adducts: Exceptionally

High Efficiency and New Mechanism. J. Am. Chem. Soc. 2014 , 136 ,

405 −411. (c) Liu, J.; Han, Z.; Wang, X.; Wang, Z.; Ding, K. Highly

Regio-and Enantioselective Alkoxycarbonylative Amination of Termi-

nal Allenes Catalyzed by a Spiroketal-Based Diphosphine/Pd(II)

Complex. J. Am. Chem. Soc. 2015, 137, 15346−15349. (d) Wang, X.;

Wang, X.; Han, Z.; Wang, Z.; Ding, K. Palladium-Catalyzed

Asymmetric Allylic Allylation of Racemic Morita −Baylis −Hillman

Adducts. Angew. Chem., Int. Ed. 2017, 56, 1116 −1119. (e) Liu, J.;

Han, Z.; Wang, X.; Meng, F.; Wang, Z.; Ding, K. Palladium-Catalyzed

Asymmetric Construction of Vicinal Tertiary and All-Carbon

Quaternary Stereocenters by Allylation of β -Ketocarbonyls with

Morita −Baylis −Hillman Adducts. Angew. Chem., Int. Ed. 2017, 56,

050 −5054. (f) Wang, X.; Wang, X.; Han, Z.; Wang, Z.; Ding, K.

Palladium-catalyzed asymmetric allylic amination: enantioselective

synthesis of chiral α -methylene substituted β -aminophosphonates.

Org. Chem. Front. 2017, 4, 271−276.

(

17) The intensity data were collected on an Agilent SuperNova

(

Dual, Cu at zero, Eos) diﬀractometer using graphite-monochromated

Cu Kα (λ = 1.54184 Å) radiation.