Enantioselective α-Carbonylative Arylation for Facile Construction of Chiral Spirocyclic β,β′-Diketones

Article abstract of DOI:10.1002/anie.202101668

We herein describe the first enantioselective α-carbonylative arylation, providing a diverse set of chiral spiro β,β′-diketones bearing various ring sizes and functionalities in high yields and good to excellent enantioselectivities. Calculations suggest the transformation proceeds through reductive elimination instead of nucleophilic addition pathway.

Full text of DOI:10.1002/anie.202101668

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 9978–9983
International Edition:
German Edition:
doi.org/10.1002/anie.202101668
doi.org/10.1002/ange.202101668
Asymmetric Carbonylation
Enantioselective a-Carbonylative Arylation for Facile Construction of
Chiral Spirocyclic b,b’-Diketones
Ting Wu, Qinghai Zhou, and Wenjun Tang*
Abstract: We herein describe the first enantioselective a-
carbonylative arylation, providing a diverse set of chiral spiro
b,b’-diketones bearing various ring sizes and functionalities in
high yields and good to excellent enantioselectivities. Calcu-
lations suggest the transformation proceeds through reductive
elimination instead of nucleophilic addition pathway.
selective intramolecular a-carbonylative arylation would
provide an efficient method for constructing chiral spirocyclic
b,b’-diketones bearing a quaternary carbon.[3] Herein we
detail the first enantioselective a-carbonylative arylation to
form a series of chiral spirocyclic b,b’-diketones in excellent
yields and enantioselectivities.
The enantioselective palladium-catalyzed carbonylations
of arenes are among most attractive transformations in
forming chiral carbonyls in organic synthesis.[4] Although no
stereogenic centers are formed between the aryl and carbonyl
connection, employment of desymmetrization strategy[5] or
combination with other enantioselective transformation
through a domino process have become an effective way of
developing novel asymmetric carbonylation reactions
E
nantioselective a-arylation has become one of most
effective transformations for construction of stereogenic
quaternary carbons in organic synthesis (Scheme 1).[1] Con-
sequently, developing variants of enantioselective a-arylation
for construction of valuable chiral building blocks has become
a subject of interest. By incorporating a CO insertion into the
catalytic cycle of a-arylation, the resulting a-carbonylative
arylation has become an effective method in delivering 1,3-
dicarbonyl compounds,[2] however, its enantioselective ver-
sion has not been reported. We envisioned that an enantio-
(Scheme 2).[6] Recent development of C H carbonylative
À
desymmetrization,[7] enantioselective oxy Heck/Heck-car-
bonylation,[8] and enantioselective carbonylative-Heck reac-
tion[8] have led to the synthesis of various chiral cyclic
carbonyls (Scheme 2). Chiral spirocyclic b,b’-diketones are
a class of valuable building blocks in organic synthesis and
such scaffolds have never been prepared via asymmetric
carbonylation to our knowledge.[10] Two main enantioselec-
tive methods included Smithꢀs enantioselective synthesis of
chiral spirobiindanones through counterion-directed intra-
molecular enolate C-acylation with a limited substrate
scope,[11] and Sunꢀs preparation of chiral spirocyclic diketones
through an enantioselective manganese-catalyzed oxidation
with spirocyclic indanones/tetralones as the starting materi-
Scheme 1. Design of enantioselective a-carbonylative arylation.
[*] T. Wu, Prof. Dr. W. Tang
State Key Laboratory of Bio-Organic and Natural Products Chemistry,
Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences
345 Ling Ling Rd, Shanghai 200032 (China)
E-mail: tangwenjun@sioc.ac.cn
Prof. Dr. Q. Zhou
College of Chemistry and Materials Science, Shanghai Normal
University
106 Guilin Road, Shanghai 200233 (China)
Prof. Dr. W. Tang
School of Chemistry and Materials Science, Hangzhou Institute for
Advanced Study, University of Chinese Academy of Sciences
1 Sub-lane Xiangshan, Hangzhou 310024 (China)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101668.
Scheme 2. Asymmetric carbonylation of arenes.
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983
9978
ꢀ 2021 Wiley-VCH GmbH

Angewandte
Communications
Chemie
als.[12] Herein we report the synthesis of such scaffold by
reaction (entries 1–4), chiral bisphosphorus ligands including
enantioselective a-carbonylative arylation.
Duanphos and QuinoxP* proved to be equally inefficient
(entries 5 and 6). Delightedly, when (S)-BINAPINE was
employed as the ligand, the desired cyclization product 2a
was afforded in 10% yield and 66% ee (entry 7). Further
screening showed that Josiphos (L5) and MeO-BIBOP (L6)
were also effective, albeit with poor yields and enantioselec-
tivities (entries 8 and 9). Interestingly, BINAP led to a good
yield (75%), although a poor enantioselective control was
observed (18% ee, entry 10). To our delight, the employment
of (R,R)-Ph-BPE, an ethylene-bridged chiral bisphospholane,
led to the synthesis of 2a in a high yield (92%) and excellent
ee (88%) (entry 11). Next, different bases were employed to
the asymmetric cyclization. It was found that NaHMDS and
KOtBu proved to be equally effective (entries 12 and 13),
affording similarly high yields and enantioselectivities, while
weaker bases such as DBU and K3PO4 resulted in low or no
reactivities. A higher pressure (5 atm) of carbon monoxide
lowered the yield (40% yield), while the enantioselectivity
was maintained (89% ee, entry 14). A significant additive
effect of molecular sieves was observed. In the absence of 4 ꢁ
MS, both the yield (60%) and the enantioselectivity (57%)
dropped sharply, indicating a role of MS as the base and
cation source for the transformation[6b,14] (entry 15). When the
reaction was performed at 808C, no formation of product was
observed (entry 16). A diminished yield (80%) and a slightly
better enantioselectivity (90%) were observed when a lower
reaction temperature (908C) was employed (entry 17). Aro-
matic solvents such as PhCl and anisole provided better
enantioselectivities (94% and 90%), although the yields were
moderate (57% and 30%) (entries 18 and 19). When a mixed
solvent (diglyme/PhCl 1/1) was employed, the desired car-
bonylative product was isolated in 90% yield and 92% ee
(entry 20).
Under the optimized reaction conditions, the scope of the
enantioselective Pd-catalyzed a-carbonylative arylation were
studied. As shown in Table 2, a diverse set of chiral spirocyclic
b,b’-diketones with various sizes of ring systems, substituents,
and functionalities at various positions were synthesized in
excellent yields (67–94%) and enantioselectivities (71–96%
eeꢀs). Tetralone substrates 1b–d with either an electron-
withdrawing or -donating substituent at 6’ or 7’ position were
all applicable. Good yields and high eeꢂs were all achieved on
products 2e–g bearing nitrile, amide and ester moieties. A
quinolinone substrate 1h was also suitable, providing the
spiro[4.5]tetracyclic b,b’-diketone 2h in excellent yield and
decent ee (71%). Various substituents could also be installed
on the bromoaryl ring and the corresponding cyclization
products 2i–k were obtained in moderate to high yields and
good to excellent eeꢀs. Notably, a trifluoromethyl or chloro
substituent was well tolerated and products 2m,n were
obtained in satisfactory yields and excellent eeꢀs (96% vs.
95%). Heterocyclic bromides 1o,p, containing furan or
thiophene rings were also transformed into corresponding
products 2o,p in moderate yields and good eeꢀs. A benzo-
heptanone 1q was also viable, providing a spiro[4,6] tetracy-
clic b,b’-diketone in 86% yield and 80% ee. Encouragingly,
a spiro tricyclic product 2r was formed in 72% yield and 82%
ee, which could not be synthesized by other reported
The enantioselective Pd-catalyzed a-carbonylative aryla-
tion (Table 1) of 2-(2-bromobenzyl)-3,4-dihydronaphthalen-
1(2H)-one (1a) was studied under CO (1.5 atm) at 1058C with
NaOtBu as the base and 4 ꢁ MS as additives in the presence
of Pd2dba3 (2.5 mol%) and a phosphorus ligand (6 mol%). It
turned out that the phosphorus ligand played an essential role
for both reactivity and enantioselectivity of the transforma-
tion (entries 1–8). While monophosphorus ligands such PPh3,
PtBu3, and BI-DIME[13] (L1) did not promote the desired
Table 1: Palladium-catalyzed a-carbonylative arylation of 2-(2-bromo-
benzyl)-3,4-dihydronaphthalen-1(2H)-one (1a): optimization of the
reaction conditions.[a]
Entry
Ligand
CO
Additive
Solvent
Yield
ee
[atm]
[%][b] [%][c]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14
15
16[f]
17[g]
18
19
20
–
PPh3
PtBu3·HBF4
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
5
1.5
1.5
1.5
1.5
1.5
1.5
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
–
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
diglyme
PhCl
–
–
–
–
–
–
–
–
–
–
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
–
–
10
15
35
75
92
93
92
40
60
trace
80
57[h]
30
À66
À21
9
18
88
88
87
89
57
–
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
4 ꢀ MS
90
94
90
92
Anisole
4 ꢀ MS Diglyme:PhCl 90[h]
[a] Unless otherwise specified, all reactions were performed in an
autoclave at 1058C for 12 h in the selected solvent (1 mL) with 1a
(0.05 mmol), Pd2dba3 (2.5 mol%), L (6 mol%), NaOtBu (1.5 equiv) and
additive (80 mg). The absolute configurations of 2a was assigned by
comparing the sign of its optical rotation with reported data. [b] Yields
were determined by 1H NMR. [c] Determined by HPLC on a chiralcel IC
column. [d] NaHMDS as the base. [e] KOtBu as the base. [f] 808C.
[g] 908C. [h] Isolated yield.
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 9979

Angewandte
Communications
Chemie
Table 2: Chiral spirocyclic b,b’-diketones by enantioselective Pd-cata-
lyzed a-carbonylative arylation.[a]
alkene group 1v was also applicable, forming product 2v in
45% yield and 54% ee. Indanone substrates were also
employed. Because of the poor solubility of these substrates
in chlorobenzene, diglyme was used as the sole solvent and
NaOtAm was chosen as the base. A series of C1-symmetric
spirodiindanones 2w–z were formed in satisfactory yields and
enantioselectivities. Furthermore, a series of C2-symmetric
spirodiindanones were synthesized. Product 2aa was formed
in 90% yield and 83% ee, while 2ab with two additional
methyl substituents was obtained in 92% yield and 80% ee.
Spirodiindanones 2ac–e bearing chloro or fluoro substituents
at various positions were also formed in high yields (81%,
88%, 94%) and excellent eeꢀs (90%, 88%, 93%). A
diminished yield (68%) and ee (72%) were obtained on
spirodiindanone 2af bearing two methoxy substituents. When
a spiro[5,5]tetracyclic b,b’-diketone product was targeted,
a competition between a-carbonylative arylation and a-
arylation pathway was observed (See SI).
The chiral spirocyclic b,b’-diketones with various func-
tionalities are versatile intermediates for further transforma-
tions (Figure 1). For example, 2r was prepared from 1r in
80% ee and 62% yield at a gram scale, which was converted
into enone 3 upon IBX oxidation. Wittig olefination of 2r led
to olefin 4 as a single product. A subsequent reaction of 4 with
an in situ generated iodine isocyanate, followed by treatment
with amine, furnished 5 with an aminooxazoline sub-structure
in 48% overall yield,[16] Since aza-spiro ketones exist widely in
the structures of numerous natural products,[3b] we studied the
synthesis of such scaffold from 2n. Condensation of 2r with
hydroxylamine hydrochloride led to an oxime, which under-
went Beckmann rearrangement by treatment with PPA to
form a pair of spiro lactams 6a and 6b at a ratio of 1:4. Spiro
lactones 7a and 7b were also formed at a ratio of 4:1 from 2r
through a Baeyer–Villiger oxidation.
Because spirocyclic b,b’-diketones possess two carbonyl
functionalities in their structures, an interesting idea was
whether both carbonyls could be installed via carbonylation.
We envisioned that the aryl bromide containing the ketone
moiety 1ae could also be prepared through a carbonylation
reaction. Thus, bromo olefin 8ae proceeded smoothly
through a carbonylative Heck reaction with a Pd/tBu3P
catalyst followed by a homogeneous hydrogenation in the
presence of a Wilkinson catalyst, affording 1ae in 70% yield
[a] Unless otherwise specified, all reactions were performed in an
autoclave under CO (1.5 atm) at 1058C for 12 h with aryl bromides 1b–
1af (0.05 mmol), Pd2dba3 (2.5 mol%), L8 (6 mol%), NaOtBu
(1.5 equiv), 4 ꢀ MS (80 mg) in diglyme (0.5 mL) and PhCl (0.5 mL).
Isolated yields after silica gel column chromatography. Ee values were
determined by chiral HPLC. The absolute configurations of 2n and 2ae
were determined by X-ray crystallography.[15] The absolute configurations
of 2b–v were assigned by analogy on the basis of 2n. The absolute
configurations of 2w–z, 2aa–af were assigned by analogy on the basis of
2ae. [b] Pd(TFA)2 was used as palladium source. [c] The reactions were
performed at 0.5 mmol scale. [d] T=1008C, solvent: 1,4-dioxane. [e] ent-
L8 was used as the ligand. [f] NaOtAm as the base and diglyme as the
solvent.
protocols,[10,11] demonstrating the generality of this trans-
formation. Bromide 1s with an electron-withdrawing group
led to the formation of 2s in 60% yield and 86% ee. A
methoxy-substituted product 2t was obtained in 55% yield
and 73% ee. A benzofused spiro[4,4] tricyclic b,b’-diketone
2u was formed in 70% yield and 73% ee. A bromide with an
Figure 1. Synthetic utility of chiral carbonylative product 2r.
9980 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983

Angewandte
Communications
Chemie
Scheme 3. Gram-scale synthesis of 2ae via carbonylative Heck-hydro-
genation and enantioselective a-carbonylative arylation.
(Scheme 3). Enantioselective a-carbonylative arylation of
1ae at a gram scale was performed using Pd-L8 catalyst at
1 mol% palladium loading provided the desired spirocyclic
diketone 2ae in 93% ee and 90% yield. Thus we accom-
plished the synthesis of chiral spirocyclic b,b’-diketones by
double carbonylation at a gram scale, demonstrating the
practicality of this method.
A mechanism of the Pd-catalyzed a-carbonylative aryla-
tion was proposed in Figure 2. Oxidative addition of the Pd0-
L8 species I with 1a leads to the formation of the palladium-
(II) species II. A subsequent CO coordination and insertion
generate an acylpalladium(II) complex III. Ligand exchange
and isomerization under basic conditions forms either the a-
pallado ketone IV or the palladium(II) enolate V. As
proposed by Skrydstrup in their studies,[2e,f] there could be
two possible pathways from IV/V in forming the cyclization
product 2a and regenerating the palladium(0) species I:
reductive elimination of IV (Path A) or intramolecular
nucleophilic addition of V (Path B). To rationalize which
reaction pathway is favored as well as the stereochemical
model of the asymmetric transformation, energetics of
transition states of both pathways were computed at M06/6-
31 + G*/SDD level with the simplified ligand model and at
M06/6-311 + G(d,p) level with the full ligand model.[17] As
shown in Figure 3a, preliminary DFT studies with the
simplified ligand model demonstrated that the cyclization
from intermediate IV (IV-s-TS, 15.3 kcalmolÀ1) are much
lower in corrected Gibbs free energy than that from
intermediate V (V-s-TS, 24.9 kcalmolÀ1), indicating reductive
elimination of IVa viable pathway. With the full ligand model
of L8 (Figure 3b), the Re-face IV-TS-Re is lower in energy by
2.7 kcalmolÀ1 than that the Si-face IV-TS-Si, which was
Figure 3. (a) DFT calculations on cyclization via possible intermediate
IV/V at M06/6-31+G(d)/SDD (solvent=Et2O,SMD)//M06/6-31+G-
(d)/SDD (vacuum) with the simplified ligand model (Ph in L8 replaced
with H). Energy unit: kcalmolÀ1. (b) Key cyclization transition state via
possible intermediate IV at M06/6-311+G(d,p)/SDD (solvent=E-
t2O,SMD)// M06/6-311+G(d,p)/SDD (vacuum) with full ligand model
of L8 (Bond lengths are in angstroms). Energy unit: kcalmolÀ1
.
consistent to the observed enantioselectivities. (ee value of
90% in Entry 17 of Table 1 corresponds to a DDGexp value of
2.1 kcalmolÀ1 at 908C.)
In conclusion, we have developed the first enantioselec-
tive a-carbonylative arylation that have provided access to
a wide range of spirocyclic b,b’-diketones in high yields and
good to excellent enantioselectivities. The reaction has
provided a practical synthetic method for constructing chiral
spirocyclic scaffolds with quaternary carbon centers. Calcu-
lations suggest that the transformation proceeds through
reductive elimination instead of nucleophilic addition path-
way. Further development of enantioselective carbonylative
reactions for the synthesis of valuable chiral synthons are
ongoing in our laboratory.
Acknowledgements
We are grateful to the Strategic Priority Research Program
of the Chinese Academy of Sciences XDB20000000, CAS
(QYZDY-SSW-SLH029), NSFC (21725205, 21432007,
21572246), STCSM-18520712200, and K.C. Wong Education
Foundation.
Conflict of interest
The authors declare no conflict of interest.
Keywords: bisphosphorus ligands ·
carbonylative Heck reaction ·
enantioselective a-carbonylative arylation · palladium ·
spirocyclic b,b’-diketones
Figure 2. A proposed mechanism.
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org
9981

Angewandte
Communications
Chemie
g) G. Cebers, R. C. Alexander, S. B. Haeberlein, D. Han, R.
Goldwater, L. Ereshefsky, T. Olsson, N. Ye, L. Rosen, M.
Russell, J. Maltby, S. Eketjꢃll, A. R. Kugler, J. Alzheimer’s Dis.
2016, 55, 1039 – 1053.
[1] a) M. Palucki, S. L. Buchwald, J. Am. Chem. Soc. 1997, 119,
11108 – 11109; b) B. C. Hamann, J. F. Hartwig, J. Am. Chem. Soc.
1997, 119, 12382 – 12383; c) A. M. Taylor, R. A. Altman, S. L.
Buchwald, J. Am. Chem. Soc. 2009, 131, 9900 – 9901; d) X. Luan,
L. Wu, E. Drinkel, R. Mariz, M. Gatti, R. Dorta, Org. Lett. 2010,
12, 1912; e) S. Ge, J. F. Hartwig, J. Am. Chem. Soc. 2011, 133,
16330 – 16333; f) Z. Huang, Z. Liu, J. S. Zhou, J. Am. Chem. Soc.
2011, 133, 15882 – 15885; g) Z. Huang, Z. Chen, L. H. Lim,
G. C. P. Quang, H. Hirao, J. S. Zhou, Angew. Chem. Int. Ed.
2013, 52, 5807 – 5812; Angew. Chem. 2013, 125, 5919 – 5924; h) J.
Cornella, E. P. Jackson, R. Martin, Angew. Chem. Int. Ed. 2015,
54, 4075 – 4078; Angew. Chem. 2015, 127, 4147 – 4150; i) Z. Jiao,
J. J. Beiger, Y. Jin, S. Ge, J. S. Zhou, J. F. Hartwig, J. Am. Chem.
Soc. 2016, 138, 15980 – 15986; j) C. I. Jette, I. Geibel, S. Bach-
man, M. Hayashi, S. Sakurai, H. Shimizu, J. B. Morgan, B. M.
Stoltz, Angew. Chem. Int. Ed. 2019, 58, 4297 – 4301; Angew.
Chem. 2019, 131, 4341 – 4345; k) R.-R. Liu, B.-L. Li, J. Lu, C.
Shen, J.-R. Gao, Y.-X. Jia, J. Am. Chem. Soc. 2016, 138, 5198 –
5201; l) C. Zhu, W. Wang, Y. Zhao, W.-Y. Sun, Z. Shi, J. Am.
Chem. Soc. 2017, 139, 16486 – 16489; m) M. Wang, J. Chen, Z.
Chen, C. Zhong, P. Lu, Angew. Chem. Int. Ed. 2018, 57, 2707 –
2711; Angew. Chem. 2018, 130, 2737 – 2741; n) X. Huang,
W. R. J. J. Oh, J. S. Zhou, Angew. Chem. Int. Ed. 2018, 57,
7673 – 7677; Angew. Chem. 2018, 130, 7799 – 7803; o) X. Rao, N.
Li, H. Bai, C. Dai, Z. Wang, W. Tang, Angew. Chem. Int. Ed.
2018, 57, 12328 – 12332; Angew. Chem. 2018, 130, 12508 – 12512;
p) T. Wu, X. Kang, H. Bai, W. Xiong, G. Xu, W. Tang, Org. Lett.
2020, 22, 4602 – 4607; q) Q. Wei, J. Cai, X.-D. Hu, J. Zhao, H.
Cong, C. Zheng, W.-B. Liu, ACS Catal. 2020, 10, 216 – 224;
r) C. C. C. Johansson, T. J. Colacot, Angew. Chem. Int. Ed. 2010,
49, 676 – 707; Angew. Chem. 2010, 122, 686 – 718; s) Y.-J. Hao, X.-
S. Hu, Y. Zhou, J. Zhou, J.-S. Yu, ACS Catal. 2020, 10, 955 – 993.
[2] a) T.-A. Kobayashi, M. Tanaka, Tetrahedron Lett. 1986, 27,
4745 – 4748; b) E. Negishi, C. Copret, T. Sugihara, I. Shimoyama,
Y. Zhang, G. Wu, J. M. Tour, Tetrahedron 1994, 50, 425 – 436;
c) E. Negishi, H. Makabe, I. Shimoyama, G. Wu, Y. Zhang,
Tetrahedron 1998, 54, 1095 – 1106; d) Z. Zheng, H. Alper, Org.
Lett. 2009, 11, 3278 – 3281; e) T. M. Gøgsig, R. H. Taaning, A. T.
Lindhardt, T. Skrydstrup, Angew. Chem. Int. Ed. 2012, 51, 798 –
801; Angew. Chem. 2012, 124, 822 – 825; f) D. U. Nielsen, C.
Lescot, T. M. Gogsig, A. T. Lindhardt, T. Skrydstrup, Chem. Eur.
J. 2013, 19, 17926 – 17938; g) J. Schranck, A. Tlili, H. Neumann,
P. G. Alsabeh, M. Stradiotto, M. Beller, Chem. Eur. J. 2012, 18,
15592 – 15597; h) S. Korsager, D. U. Nielsen, R. H. Taaning, T.
Skrydstrup, Angew. Chem. Int. Ed. 2013, 52, 9763 – 9766; Angew.
Chem. 2013, 125, 9945 – 9948; i) S. Korsager, D. U. Nielsen, R. H.
Taaning, A. T. Lindhardt, T. Skrydstrup, Chem. Eur. J. 2013, 19,
17687 – 17691; j) D. U. Nielsen, S. Korsager, A. T. Lindhardt, T.
Skrydstrup, Adv. Synth. Catal. 2014, 356, 3519 – 3524; k) X.
Jusseau, H. Yin, A. T. Lindhardt, T. Skrydstrup, Chem. Eur. J.
2014, 20, 15785 – 15789; l) Z. Lian, S. D. Friis, T. Skrydstrup,
Angew. Chem. Int. Ed. 2014, 53, 9582 – 9586; Angew. Chem.
2014, 126, 9736 – 9740; m) Z. Lian, S. D. Friis, T. Skrydstrup,
Chem. Commun. 2015, 51, 3600 – 3603; n) J. Schranck, M.
Burhardt, C. Bornschein, H. Neumann, T. Skrydstrup, M.
Beller, Chem. Eur. J. 2014, 20, 9534 – 9538.
[4] a) “Carbonylation”: W. Bertleff, M. Roeper, X. Sava, in
Ullmannꢀs Encyclopedia of Industrial Chemistry, Wiley-VCH,
Weinheim, 2007; b) R. Franke, D. Selent, A. Bçrner, Chem. Rev.
2012, 112, 5675 – 5732; c) X.-F. Wu, H. Neumann, M. Beller,
Chem. Rev. 2013, 113, 1 – 35; d) J.-B. Peng, F.-P. Wu, X.-F. Wu,
Chem. Rev. 2019, 119, 2090 – 2127; e) J.-B. Peng, H. Q. Geng, X.-
F. Wu, Chem 2019, 5, 526 – 552; f) S. D. Friis, A. T. Lindhardt, T.
Skrydstrup, Acc. Chem. Res. 2016, 49, 594 – 605; g) D. Tian, R.
Xu, J. Zhu, J. Huang, W. Dong, J. Claverie, W. Tang, Angew.
Chem. Int. Ed. 2021, 60, 6305 – 6309; Angew. Chem. 2021, 133,
6375-6379;h) Y.-H. Yao, H.-Y. Yang, M. Chen, F. Wu, X.-X. Xu,
Z.-H. Guan, J. Am. Chem. Soc. 2021, 143, 85 – 91.
[5] T. Suzuki, Y. Uozumi, M. Shibasaki, J. Chem. Soc. Chem.
Commun. 1991, 1953 – 1955.
[6] a) L.-L. Li, D. Ding, J. Song, Z.-Y. Han, L.-Z. Gong, Angew.
Chem. Int. Ed. 2019, 58, 7647 – 7651; Angew. Chem. 2019, 131,
7729 – 7733; b) B. Yang, Y. Qiu, T. Jiang, W. D. Wulff, X. Yin, C.
Zhu, J. Bꢃckvall, Angew. Chem. Int. Ed. 2017, 56, 4535 – 4539;
Angew. Chem. 2017, 129, 4606 – 4610.
[7] a) H. Han, T. Zhang, S.-D. Yang, Y. Lan, J.-B. Xia, Org. Lett.
2019, 21, 1749 – 1754; b) X.-F. Bai, Q.-C. Mu, Z. Xu, K.-F. Yang,
L. Li, Z.-J. Zheng, C.-G. Xia, L.-W. Xu, ACS Catal. 2019, 9,
1431 – 1436.
[8] a) R. C. Carmona, O. D. Kçster, C. R. D. Correia, Angew. Chem.
Int. Ed. 2018, 57, 12067 – 12070; Angew. Chem. 2018, 130, 12243 –
12246; b) H. Hu, F. Teng, J. Liu, W. Hu, S. Luo, Q. Zhu, Angew.
Chem. Int. Ed. 2019, 58, 9225 – 9229; Angew. Chem. 2019, 131,
9323 – 9327; c) M. Chen, X. Wang, P. Yang, X. Kou, Z.-H. Ren,
Z.-H. Guan, Angew. Chem. Int. Ed. 2020, 59, 12199 – 12205;
Angew. Chem. 2020, 132, 12297 – 12303.
[9] T. Hayashi, J. Tang, K. Kato, Org. Lett. 1999, 1, 1487 – 1489.
[10] By chemical resolution: a) H. Gerlach, Helv. Chim. Acta 1968,
51, 1587; b) H. Gerlach, W. Mꢄller, Helv. Chim. Acta 1972, 55,
2277; c) N. Harada, N. Ochiai, K. Takada, H. Uda, J. Chem. Soc.
Chem. Commun. 1977, 495; d) J. A. Nieman, B. A. Keay,
Tetrahedron: Asymmetry 1993, 4, 1973; e) A. S. C. Chan, C.-C.
Lin, J. Sun, W. Hu, Z. Li, W. Pan, A. Mi, Y. Jiang, T.-M. T.-K.
Yang, J.-H. Chen, Y. Wang, G.-H. Lee, Tetrahedron: Asymmetry
1995, 6, 2953; f) X. M. Feng, D. C. Zeng, Z. Li, Y. Z. Jiang, Chin.
Chem. Lett. 1999, 10, 559; g) J. A. Nieman, B. A. Keay, Synth.
Commun. 1999, 29, 3829; By kinetic resolution: h) Z. Han, Z.
Wang, K. Ding, Adv. Synth. Catal. 2011, 353, 1584; By
asymmetric Nazarov cyclization/semipinacol rearrangement:
i) B.-M. Yang, P.-J. Cai, Y.-Q. Tu, Z.-X. Yu, Z.-M. Chen, S.-H.
Wang, S.-H. Wang, F.-M. Zhang, J. Am. Chem. Soc. 2015, 137,
8344 – 8347.
[11] B. F. Rahemtulla, H. F. Clark, M. D. Smith, Angew. Chem. Int.
Ed. 2016, 55, 13180 – 13183; Angew. Chem. 2016, 128, 13374 –
13377.
[12] B. Qiu, D. Xu, Q. Sun, C. Miao, Y.-M. Lee, X.-X. Li, W. Nam, W.
Sun, ACS Catal. 2018, 8, 2479 – 2487.
[13] a) N. Hu, G. Zhao, Y. Zhang, X. Liu, G. Li, W. Tang, J. Am.
Chem. Soc. 2015, 137, 6746 – 6749; b) G. Xu, W. Fu, G. Liu, C. H.
Senanayake, W. Tang, J. Am. Chem. Soc. 2014, 136, 570 – 573;
c) K. Li, M. Nie, W. Tang, Green Synth. Catal. 2020, 1, 171 – 174;
d) G. Xu, C. H. Senanayake, W. Tang, Acc. Chem. Res. 2019, 52,
1101 – 1112.
[14] a) Y. Koga, M. Sodeoka, M. Shibasaki, Tetrahedron Lett. 1994,
35, 1227 – 1230; b) H. Uraka, N.-X. Hu, H. Maekawa, T.
Fuchikami, Tetrahedron Lett. 1991, 36, 4733 – 4736; c) B. A.
Steinhoff, A. E. King, S. S. Stahl, J. Org. Chem. 2006, 71, 1861 –
1868.
[3] For the importance of spirocyclic scaffolds: a) P.-W. Xu, J. S. Yu,
C. Chen, Z.-Y. Cao, F. Zhou, J. Zhou, ACS Catal. 2019, 9, 1820;
b) Z. Guo, X. Guan, Z. Chen, Tetrahedron: Asymmetry 2006, 17,
468 – 473; c) M. Alimova, I. A. Israilov, Chem. Nat. Compd.
1982, 18, 608 – 609; d) G. Guella, F. Dini, F. Pietra, Angew. Chem.
Int. Ed. 1999, 38, 1134 – 1136; Angew. Chem. 1999, 111, 1217 –
1220; e) G. Guella, E. Callone, G. Di Giuseppe, R. Frassanito,
F. P. Frontini, I. Mancini, F. Dini, Eur. J. Org. Chem. 2007, 5226 –
5234; f) K. C. Nicolaou, H. Zhang, A. Ortiz, Angew. Chem. Int.
Ed. 2009, 48, 5642 – 5647; Angew. Chem. 2009, 121, 5752 – 5757;
9982 www.angewandte.org
ꢀ 2021 Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983

Angewandte
Communications
Chemie
[15] Deposition numbers 2020502 and 2026503 contain the supple-
Davey, K. Kolmodin, J. Holenz, M. E. Duggan, S. B. Haeberlein,
mentary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access
Structures service.
R. W. Bꢄrli, J. Med. Chem. 2018, 61, 3491 – 3502; d) D. King, C.
Iwuagwu, J. Cook, T. M. McDonald, R. Mate, F. C. Zusi, M. D.
Hill, H. Fang, R. Zhao, B. Wang, A. E. Easton, R. Miller, D. Post-
Munson, R. J. Knox, L. Gallagher, R. Westphal, T. Molski, J. Fan,
W. Clarke, Y. Benitex, K. A. Lentz, R. Denton, D. Morgan, R.
Zaczek, N. J. Lodge, L. J. Bristow, J. E. Macor, R. E. Olson, ACS
Med. Chem. Lett. 2017, 8, 366 – 371.
[16] a) H. Huang, D. S. La, A. C. Cheng, D. A. Whittington, V. F.
Patel, K. Chen, T. A. Dineen, O. Epstein, R. Graceffa, D.
Hickman, Y.-H. Kiang, S. Louie, Y. Luo, R. C. Wahl, P. H. Wen,
S. Wood, R. T. Fremeau, Jr., J. Med. Chem. 2012, 55, 9156 – 9169;
b) J. D. Low, M. D. Bartberger, K. Chen, Y. Cheng, M. R.
Fielden, V. Gore, D. Hickman, Q. Liu, E. A. Sickmier, H. M.
Vargas, J. Werner, R. D. White, D. A. Whittington, S. Wood,
A. E. Minatti, MedChemComm 2017, 8, 1196 – 1206; c) P.
Johansson, K. Kaspersson, I. K. Gurrell, E. Bꢃck, S. Eketjꢃll,
C. W. Scott, G. Cebers, P. Thorne, M. J. McKenzie, H. Beaton, P.
[17] See Supporting Information for more computational details.
Manuscript received: February 3, 2021
Accepted manuscript online: February 17, 2021
Version of record online: March 17, 2021
Angew. Chem. Int. Ed. 2021, 60, 9978 –9983
ꢀ 2021 Wiley-VCH GmbH
www.angewandte.org 9983