Enantioselective Alkoxycyclization of 1,6-Enynes with Gold(I)-Cavitands: Total Synthesis of Mafaicheenamine C

Article abstract of DOI:10.1002/anie.202017035

Chiral gold(I)-cavitand complexes have been developed for the enantioselective alkoxycyclization of 1,6-enynes. This enantioselective cyclization has been applied for the first total synthesis of carbazole alkaloid (+)-mafaicheenamine C and its enantiomer, establishing its configuration as R. The cavity effect was also evaluated in the cycloisomerization of dienynes. A combination of experiments and theoretical studies demonstrates that the cavity of the gold(I) complexes forces the enynes to adopt constrained conformations, which results in the high observed regio- and stereoselectivities.

Full text of DOI:10.1002/anie.202017035

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 9339–9344
International Edition: doi.org/10.1002/anie.202017035
German Edition: doi.org/10.1002/ange.202017035
Asymmetric Synthesis
Enantioselective Alkoxycyclization of 1,6-Enynes with Gold(I)-
Cavitands: Total Synthesis of Mafaicheenamine C
Inmaculada Martꢀn-Torres, Gala Ogalla, Jin-Ming Yang, Antonia Rinaldi, and
Antonio M. Echavarren*
[
14]
[15]
Abstract: Chiral gold(I)-cavitand complexes have been devel-
oped for the enantioselective alkoxycyclization of 1,6-enynes.
This enantioselective cyclization has been applied for the first
total synthesis of carbazole alkaloid (+)-mafaicheenamine C
and its enantiomer, establishing its configuration as R. The
cavity effect was also evaluated in the cycloisomerization of
dienynes. A combination of experiments and theoretical studies
demonstrates that the cavity of the gold(I) complexes forces the
enynes to adopt constrained conformations, which results in the
high observed regio- and stereoselectivities.
NHC-gold(I) complexes, chiral counteranions, and chiral
rotaxanes.
[
16]
From the outset, achieving satisfactory levels in the
enantioselective gold(I)-catalyzed alkoxycyclization of 1,6-
enynes proved to be difficult. Thus, using [Tol-BINAP-
(AuCl) ] as precatalyst we only achived good results with
2
[
17]
one substrate with a phenyl-substituted alkyne. Since then,
other groups achieved moderate enantioselectivities with
[
18,19]
chiral gold(I) catalysts,
the exception being the recent
elegant work of Sollogoub, Fensterbank, and Mouriꢀs-
Mansuy using NHC-capped b-cyclodextrin gold(I) catalysts,
which led to up to 94–98% ee in the hydroxy- and meth-
T
he design of supramolecular entities that mimic the activity
[
14d,e]
of enzymes is an attractive approach for enhancing the
oxycyclization of 1,6-enynes.
However, being based on
[1]
selectivity of metal catalysts. In this regard, gold(I) cav-
cyclodextrins, these catalysts only provide one of the two
possible enantiomeric forms of the final cyclized products.
We explored the prospect of achieving enantioselectivity
in gold(I) catalysis by employing gold(I) complexes with
chiral resorcin[4]arene phosphoramidite as ligands
(Scheme 1). Specifically, our aim was to enantioselectively
activate 1,6-enynes with terminal alkynes in reactions with
alcohols (alkoxycyclization) to form 1-methylene-2,3-dihy-
dro-1H-indenes, whose oxidative cleavage would furnish
synthetically useful chiral indanones. Herein, we report an
enantioselective alkoxycyclization of 1,6-enynes by using
itands based on resorcin[4]arene skeletons have been applied
[
2]
[3]
for cross-dimerization and hydration of alkynes, cycliza-
[4]
tion of alkynyl carboxylic acids, and intramolecular arene–
alkyne reactions. However, gold(I) cavitands have not yet
been applied in the context of more challenging asymmetric
transformations.
Our group reported the use of non-C -symmetrical chiral
digold(I) and pyrrolidinyl–biphenyl phosphine gold(I) com-
plexes in enantioselective [2+2] and [4+2] cycloadditions
and cycloisomerization reactions. Other approaches in asym-
metric gold(I) catalysis are based on the use of monodentate
chiral phosphoramidites, chiral cationic phosphonites,
axially chiral monodentate phosphine ligands with a remote
[
5]
[
6]
2
[7]
[
8]
[9]
[10]
[
11]
cooperative functionality,
mides, helically chiral phosphine ligands, cyclodextrin-
catalysts with chiral sulfina-
[
12]
[13]
[*] I. Martꢀn-Torres, G. Ogalla, Dr. J.-M. Yang, A. Rinaldi,
Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ)
Barcelona Institute of Science and Technology
Av. Paꢁsos Catalans 16, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
I. Martꢀn-Torres, G. Ogalla
Departament de Quꢀmica Analꢀtica i Quꢀmica Orgꢂnica
Universitat Rovira i Virgili
C/ Marcel·lꢀ Domingo s/n, 43007 Tarragona (Spain)
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.202017035.
ꢃ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution Non-Commercial
NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-
commercial and no modifications or adaptations are made.
Scheme 1. Gold(I)-cavitand catalysts for the enantioselective alkoxycyc-
lization of 1,6-enynes and application to the total synthesis of (+)- and
(À)-mafaicheenamine C.
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Figure 1. Structures of gold(I) complexes and selected X-ray diffraction structures of complexes T, N, and U.
chiral mono-cationic gold(I) resorcin[4]arene phosphorami-
dite complexes as catalysts. To demonstrate their potential,
we have completed the first total synthesis of (+)-mafaichee-
namine C as well as its non-natural enantiomer, establishing
the absolute configuration of the natural product. (+)-Mafai-
cheenamine C belongs to a family of bioactive carbazole
metal inside the cavity, and I with the metal outside. In the
case of dinuclear gold(I) complexes, we also synthesized in–in
J–M and in–out complexes N–Q. To determine the effect of
the cavity, we prepared achiral R and chiral S complexes with
electronically similar active sites (Figure 1C). Cationic gold-
(I) cavitands T and U were obtained by treatment of the
[20]
alkaloids isolated from the plant Clausena lansium, which
neutral digold complexes with AgSbF in acetonitrile. Dicat-
6
also produces compounds such as mafaicheenamine A and
claulansines B and D.
ionic gold(I) complex V with a bridged phthalonitrile ligand
(Figure 1D) and the enantiomers of J, N, and U were also
synthesized. The structure of A, D, E, F, H, I, J, N, O, R, S, T,
[
21,22]
Mono- and dinuclear achiral complexes A–F (Figure 1A)
and chiral gold(I)-cavitand complexes G–Q (Figure 1B) were
prepared by the methods developed by the group of
[24]
and U was confirmed by X-ray diffraction.
We first tested the activity of the gold(I) cavitands in the
cyclization of (Z)-1,6-dienyne 1a (Table 1). Reaction of 1a
with [Au(PPh )Cl], [Au(P(OMe) )Cl], or R and AgSbF
[23]
Iwasawa. In addition to those with quinoxaline walls, we
also prepared gold(I)-cavitand complexes with naphthoqui-
none walls B, F, G, J, L, M, N, P, and Q. Chirality in G–Q was
introduced via the phosphoramidites derived from either R,R-
or S,S-bis(1-arylethyl)amines. For the chiral mononuclear
gold(I) complexes, we prepared complexes G and H, with the
3
3
6
selectively gave 2a as the product of exocyclic single-cleavage
[
25]
skeletal rearrangement
(Table 1, entries 1–3). However,
gold(I) cavitand A led to the preferred formation of
endocyclic single-cleavage skeletal rearrangement product
9
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Table 1: Exo/endo Selectivity in the cyclization of (Z)-1,6-dienyne 1a.
complexes (S,S)-G and (S,S)-H with AuCl inside the cavity
gave 4a in good yield but with low enantioselectivity (Table 2,
entries 1 and 2). With complex (S,S)-I, in which gold is outside
the cavity, low yield and enantioselectivity were obtained
(36%, 45:55 er) (Table 2, entry 3). The best results were
achieved with dinuclear complexes with both AuCl located
inside the cavity. Precatalyst (S,S,S,S)-J afforded 4a with
[
a]
Entry
[Au]
2 mol%)
AgSbF6
[mol%]
Yield [%]
(2a/2b)
(
8
9:11 er in 90% yield (Table 2, entry 4). The effect of the
1
2
3
4
5
6
7
8
9
[Au(PPh )Cl]
2
2
2
2
2
2
2
4
4
–
65 (11:1)
56 (>20:1)
77 (>20:1)
95 (1:5)
3
cavitand walls was studied by replacing the naphthoquinone
units for quinoxalines (complex (S,S,S,S)-K), obtaining 4a
with 86:14 er in 80% yield (Table 2, entry 5). Replacing the
phenyl groups for naphthyl groups in (S,S,S,S)-L and M
afforded 4a in 74:26 er and 88:12 er, respectively (Table 2,
entries 6 and 7). Dinuclear cavitands with one AuCl moiety
inside the pocket and the other one outside led to lower
enantioselectivities (Table 2, entries 8–11). Simple chiral
complex (S,S)-S with an electronically similar active site led
to 4a with very low enantioselectivity (48%, 57:43 er; Table 2,
entry 12), confirming the cavity effect in these reactions.
[
b]
[Au(P(OMe) )Cl]
3
R
A
B
C
D
E
F
89 (8:1)
79 (1:2)
83 (1:1)
92 (1:1)
87 (3:1)
[
c]
1
0
T
97 (1:5)
1
[
a] Yields determined by H NMR with Ph CH as internal standard.
2
2
[b] 67% conversion. [c] Isolated yield.
Using lower amounts of AgSbF led to very similar results
6
[
26]
2
b
(Table 1, entry 4). Significant ammounts of 2a were also
(Table 2, entry 13). Cationic gold(I) cavitand (S,S,S,S)-U
showed the same activity as the one formed in situ from
(S,S,S,S)-J. However, with dicationic gold(I) complex
(S,S,S,S)-V both yield and enantioselectivity slightly
decreased (74%, 81:19 er; Table 2, entry 15). Lowering the
temperature to À508C with complex (S,S,S,S)-U further
improved the enantioselectivity, leading to 4a in 90% yield
and 96:4 er (Table 2, entry 16).
The reaction of different enynes and nucleophiles was
performed using (S,S,S,S)-U (Scheme 2). We observed a slight
decrease in enantioselectivity using nucleophiles less bulky
than ethanol. Thus, reaction a (E)-1,6-dienyne 3a with
obtained with mono- or dinuclear complexes B–F (Table 1,
entries 5–9). The fact that complex R, with an electronically
very similar ligand to those of gold(I)-cavitand complexes,
gives 2a exclusively (Table 1, entry 3) shows that the cavity of
the cavitands plays a major role in the change of the exo- to
endo-selectivity. As expected, complex T (the cationic
derivative of A) showed the same selectivity as cavitand A,
leading to 2a/2b in excellent yield (Table 1, entry 10).
Chiral gold(I)-cavitand complexes were investigated in
the enantioselective alkoxycyclization of 1,6-enyne 3a using
ethanol as nucleophile (Table 2).
[
24]
Mononuclear cavitand
Table 2: Enantioselective alkoxycyclization of E-1,6-dienyne 3a.
[
b]
Entry
[Au]
3 mol%)
AgSbF6
[mol%]
T
[8C]
t
[h]
Yield
[%]
er
[
a]
(
1
2
3
4
5
6
7
8
9
(S,S)-G
(S,S)-H
(S,S)-I
3
3
3
6
6
6
6
6
6
6
6
3
3
–
–
–
23
23
23
23
23
23
23
23
23
23
23
23
23
23
23
À50
1
1
1
1
1
1
1
1
1
1
1
1
1
1
3
18
83
74
36
90
80
84
83
86
69
67
91
48
88
89
74
51:49
59:41
45:55
89:11
86:14
74:26
88:12
55:45
57:43
68:32
53:47
57:43
89:11
89:11
81:19
96:4
(S,S,S,S)-J
(S,S,S,S)-K
(S,S,S,S)-L
(S,S,S,S)-M
(S,S,S,S)-N
(S,S,S,S)-O
(S,S,S,S)-P
(S,S,S,S)-Q
(S,S)-S
(S,S,S,S)-J
(S,S,S,S)-U
(S,S,S,S)-V
(S,S,S,S)-U
10
11
12
13
14
15
16
[
c]
90
1
[
[
a] Yields determined by H NMR using Ph CH as internal standard.
2 2
b] Enantiomeric ratios determined by HPLC. [c] 3a (0.4 mmol scale),
Scheme 2. Reaction scope of the enantioselective alkoxycyclization.
isolated yield.
[a] Solvent/nucleophile: acetone/H O 1:1 at À208C.
2
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methanol or water led to 4b and 4e in 91:9 er, whereas
reaction with 2-propanol and allyl alcohol gave 4c,d with
essentially the same er to that of 4a. We also tested dienyne
3
4
b, the Z diastereomer of 3a, which led stereospecifically to
f in 97:3 er. Similar results were observed in the formation of
compounds 4g–p, with the exception of products of methoxy-
4h) and hydroxycyclization (4k), which were obtained with
lower enantioselectivities. Enynes 1b,c led to 5a,b in 85:15 to
9:11 er.
The products of alkoxycyclization were converted into
(
8
a variety of enantioenriched structures (Scheme 3). Thus,
ozonolysis of 4g cleanly afforded indanone 6, whereas
[27]
cyclopropanation of 4g via retro-Buchner reaction
pro-
vided 7 with excellent diastereoselectivity (> 20:1). Tetrahy-
dro-1H-fluorene 8 was obtained by ring closing metathesis of
nd
4
a using 2 generation Grubbs catalyst. On the other hand,
hydroboration-oxidation of 4o led diastereoselectively to
alcohol 9, whose crystalline p-bromobenzoate 10 allowed
assigning its absolute configuration by X-ray diffraction.
To demonstrate the application of this enantioselective
alkoxycyclization, we completed the first total synthesis of
Scheme 4. Total synthesis of (+)-mafaicheenamine C. DMBA=dime-
thylbarbituric acid.
(
(
1
+)-mafaicheenamine C (15) in an enantioselective manner
Scheme 4). We started from known carbazole aldehyde
[
22c]
1.
Reaction of 11 with the Bestmann–Ohira reagent
Finally, we studied the origin of enantioselectivity by DFT
calculations at the B3LYP/6-31G(d,p) (C, H, P, O, Cl, N),
SDD (Au) (SMD = ethanol) level of theory using enyne 3c
and simplified gold(I) cavitand (S,S,S,S)-U without aliphatic
provided 12 (77% yield), whose reaction with allyl alcohol in
the presence of (R,R,R,R)-U at À508C led to ether 13 in 84%
yield and 95:5 er. Pd-catalyzed deallylation led to alcohol 14.
Final oxidative cleavage of the exocyclic alkene gave
[24]
chains. The enantiodetermining step of the process is the
initial cyclization leading to carbocationic gold(I) intermedi-
(
+)-mafaicheenamine C (15), whose absolute configuration
[
20]
[28]
was assigned as R by X-ray diffraction. We also obtained
the non-natural antipode (À)-mafaicheenamine C in 96:4 er
using chiral gold(I) catalyst (S,S,S,S)-U in the alkoxycycliza-
ates II or IV from the two most favorable orientations of
the coordinated enyne, with the aryl ring outside the cavity.
À1
TSI–II was found to be 2.1 kcalmol lower in energy than
[
24]
tion reaction.
TSIII–IV, which is consistent with the selective formation of the
enantiomer observed experimentally (Scheme 5). NCI plot
Scheme 3. Transformation of products 4a,g,o into 6–9 and assignment
of the absolute configuration by X-ray diffraction via ester 10.
TMCHT=1,3,5-trimethylcyclohepta-1,3,5-triene, DCE=1,2-dichloro-
ethane, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
DMPA=4-dimethylaminopyridine.
I
Scheme 5. Free-energy profile for the Au -catalyzed alkoxycyclization
À1
reaction of 3c (kcalmol at 258C). Transition state representations by
CYLview.
9
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studies of the two possible transition states show attractive
interactions between the cavitand and the aromatic ring of the
enyne and non-covalent interactions within the complex itself
[9] a) I. Alonso, B. Trillo, F. Lꢁpez, S. Montserrat, G. Ujaque, L.
Castedo, A. Lledꢁs, J. L. MascareÇas, J. Am. Chem. Soc. 2009,
31, 13020 – 13030; b) A. Z. Gonzꢄlez, F. D. Toste, Org. Lett.
1
[
29]
2010, 12, 200 – 203; c) A. Z. Gonzꢄlez, D. Benitez, E. Tkatchouk,
W. A. Goddard, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 5500 –
in TSI–II, which are weaker in TSIII–IV
.
To sum up, we have designed a new family of achiral and
chiral gold(I)-cavitand complexes, easily synthesized in either
enantiomeric form in a modular manner from resorcin-
5507.
[
10] a) L. D. M. Nicholls, M. Marx, T. Hartung, E. Gonzꢄlez-Fernꢄn-
dez, C. Golz, M. Alcarazo, ACS Catal. 2018, 8, 6079 – 6085; b) T.
Hartung, R. Machleid, M. Simon, C. Golz, M. Alcarazo, Angew.
Chem. Int. Ed. 2020, 59, 5660 – 5664; Angew. Chem. 2020, 132,
5709 – 5713; c) J. Zhang, M. Simon, C. Golz, M. Alcarazo,
Angew. Chem. Int. Ed. 2020, 59, 5647 – 5650; Angew. Chem.
[
4]arenes and commercially available chiral secondary
amines. While new selectivity was uncovered in the cycliza-
tion of dienynes with achiral gold(I)-cavitand complexes, the
chiral catalysts allowed to develop an enantioselective
alkoxycyclization of 1,6-enynes, which has been applied for
the first total synthesis of (+)- and (À)-mafaicheenamine C,
assigning the absolute configuration of the natural compound.
The stereochemical outcome of the transformation is sup-
ported by a theoretical model which suggests that the high
enantioselectivity results from stabilizing non-covalent inter-
actions.
2020, 132, 5696 – 5699.
[
11] a) Z. Wang, C. Nicolini, C. Hervieu, Y.-F. Wong, G. Zanoni, L.
Zhang, J. Am. Chem. Soc. 2017, 139, 16064 – 16067; b) X. Cheng,
Z. Wang, C. D. Quintanilla, L. Zhang, J. Am. Chem. Soc. 2019,
141, 3787 – 3791.
[12] a) Y. Wang, P. Zhang, X. Di, Q. Dai, Z.-M. Zhang, J. Zhang,
Angew. Chem. Int. Ed. 2017, 56, 15905 – 15909; Angew. Chem.
2017, 129, 16121 – 16125; b) Y. Wang, Z.-M. Zhang, F. Liu, Y. He,
J. Zhang, Org. Lett. 2018, 20, 6403 – 6406; c) P.-C. Zhang, Y.
Wang, Z.-M. Zhang, J. Zhang, Org. Lett. 2018, 20, 7049 – 7052.
[
13] a) K. Yavari, P. Aillard, Y. Zhang, F. Nuter, P. Retailleau, A.
Voituriez, Angew. Chem. Int. Ed. 2014, 53, 861 – 865; Angew.
Chem. 2014, 126, 880 – 884; b) P. Aillard, D. Dova, V. Magnꢃ, P.
Retailleau, S. Cauteruccio, E. Licandro, A. Voituriez, A.
Marinetti, Chem. Commun. 2016, 52, 10984 – 10987.
Acknowledgements
We thank the Ministerio de Ciencia e Innovaciꢁn (PID2019-
1
04815GB-I00) and FPI fellowship to I.M.-T., Severo Ochoa
Excellence Accreditation (CEX2019-000925-S), H2020-
Marie Sklodowska-Curie contract to J.-M. Y. (Grant
[14] a) M. Guitet, P. Zhang, F. Marcelo, C. Tugny, J. Jimꢃnez-
Barbero, O. Buriez, C. Amatore, V. Mouriꢀs-Mansuy, J.-P.
Goddard, L. Fensterbank, Y. Zhang, S. Roland, M. Mꢃnand,
M. Sollogoub, Angew. Chem. Int. Ed. 2013, 52, 7213 – 7218;
Angew. Chem. 2013, 125, 7354 – 7359; b) P. Zhang, C. Tugny, J.
Meijide Suꢄrez, M. Guitet, E. Derat, N. Vanthuyne, Y. Zhang, O.
Bistri, V. Mouriꢀs-Mansuy, M. Mꢃnand, S. Roland, L. Fenster-
bank, M. Sollogoub, Chem 2017, 3, 174 – 191; c) Z. Kaya, L.
Andna, D. Matt, E. Bentouhami, J. Djukic, D. Armspach, Chem.
Eur. J. 2018, 24, 17921 – 17926; Z. Kaya, L. Andna, D. Matt, E.
Bentouhami, J. Djukic, D. Armspach, Eur. J. Org. Chem. 2019,
7
02524), the European Research Council (Advanced Grant
No. 835080), the AGAUR (2017 SGR 1257), and CERCA
Program/Generalitat de Catalunya for financial support. We
thank Dr. Cristina Garcꢂa-Morales and Dr. Imma Escofet for
assistance with DFT calculations and useful discussions. We
also thank the ICIQ X-ray diffraction unit.
4
528 – 4537; d) C. Tugny, N. del Rio, M. Koohgard, N. Van-
Conflict of interest
thuyne, D. Lesage, K. Bijouard, P. Zhang, J. Meijide Suꢄrez, S.
Roland, E. Derat, O. Bistri-Aslanoff, M. Sollogoub, L. Fenster-
bank, V. Mouriꢀs-Mansuy, ACS Catal. 2020, 10, 5964 – 5972;
e) X. Zhu, G. Xu, L. Chamoreau, Y. Zhang, V. Mouriꢀs-Mansuy,
L. Fensterbank, O. Bistri-Aslanoff, S. Roland, M. Sollogoub,
Chem. Eur. J. 2020, 26, 15901 – 15909.
The authors declare no conflict of interest.
Keywords: alkoxycyclization · asymmetric synthesis ·
gold(I) cavitands · natural product synthesis
[
15] a) G. L. Hamilton, E. J. Kang, M. Mba, F. D. Toste, Science 2007,
3
17, 496 – 499; b) K. Aikawa, M. Kojima, K. Mikami, Angew.
[
1] a) N. Natarajan, E. Brenner, D. Sꢃmeril, D. Matt, J. Harrowfield,
Eur. J. Org. Chem. 2017, 6100 – 6113; b) T. Iwasawa, Tetrahedron
Lett. 2017, 58, 4217 – 4226; c) A. C. H. Jans, X. Caumes, J. N. H.
Reek, ChemCatChem 2019, 11, 287 – 297.
2] a) M. P. Schramm, M. Kanaura, K. Ito, M. Ide, T. Iwasawa, Eur.
J. Org. Chem. 2016, 813 – 820; b) N. Endo, M. Kanaura, M. P.
Schramm, T. Iwasawa, Eur. J. Org. Chem. 2016, 2514 – 2521.
3] N. Endo, M. Inoue, T. Iwasawa, Eur. J. Org. Chem. 2018, 1136 –
Chem. Int. Ed. 2009, 48, 6073 – 6077; Angew. Chem. 2009, 121,
6
5
Zhang, V. Smal, P. Retailleau, A. Voituriez, G. Frison, A.
Marinetti, X. Guinchard, J. Am. Chem. Soc. 2020, 142, 3797 –
189 – 6193; c) X.-F. Tu, L.-Z. Gong, Angew. Chem. Int. Ed. 2012,
1, 11346 – 11349; Angew. Chem. 2012, 124, 11508 – 11511; d) Z.
[
3
805.
16] a) M. Galli, J. E. M. Lewis, S. M. Goldup, Angew. Chem. Int. Ed.
015, 54, 13545 – 13549; Angew. Chem. 2015, 127, 13749 – 13753;
[
[
2
1140.
b) A. W. Heard, S. M. Goldup, Chem 2020, 6, 994 – 1006.
17] M. P. MuÇoz, J. Adrio, J. C. Carretero, A. M. Echavarren,
Organometallics 2005, 24, 1293 – 1300.
[
[
[
4] T. D. Ho, M. P. Schramm, Eur. J. Org. Chem. 2019, 5678 – 5684.
5] L. E. Rusali, M. P. Schramm, Tetrahedron Lett. 2020, 61, 152333.
6] a) W. Zi, F. D. Toste, Chem. Soc. Rev. 2016, 45, 4567 – 4589; b) Y.-
M. Wang, A. D. Lackner, F. D. Toste, Acc. Chem. Res. 2014, 47,
[
[
18] a) Y. Matsumoto, K. B. Selim, H. Nakanishi, K. Yamada, Y.
Yamamoto, K. Tomioka, Tetrahedron Lett. 2010, 51, 404 – 406;
b) K.-I. Yamada, Y. Matsumoto, K. B. Selim, Y. Yamamoto, K.
Tomioka, Tetrahedron 2012, 68, 4159 – 4165; c) B. W. Gung,
M. R. Holmes, C. A. Jones, R. Ma, C. L. Barnes, Tetrahedron
Lett. 2016, 57, 3912 – 3915; d) M. Nakada, N. Okitsu, T. Yoshida,
K. Usui, Heterocycles 2016, 92, 720; e) J.-Q. Zhang, Y. Liu, X.-W.
Wang, L. Zhang, Organometallics 2019, 38, 3931 – 3938.
889 – 901.
[
7] C. Garcꢂa-Morales, B. Ranieri, I. Escofet, L. Lꢁpez-Suarez, C.
Obradors, A. I. Konovalov, A. M. Echavarren, J. Am. Chem.
Soc. 2017, 139, 13628 – 13631.
8] G. Zuccarello, J. G. Mayans, I. Escofet, D. Scharnagel, M. S.
Kirillova, A. H. Pꢃrez-Jimeno, P. Calleja, J. R. Boothe, A. M.
Echavarren, J. Am. Chem. Soc. 2019, 141, 11858 – 11863.
[
Angew. Chem. Int. Ed. 2021, 60, 9339 –9344
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Angewandte
Communications
Chemie
II
[
19] Pioneering work on the asymmetric Pt -catalyzed hydroxy- and
[25] C. Nieto-Oberhuber, M. P. MuÇoz, S. Lꢁpez, E. Jimꢃnez-NfflÇez,
C. Nevado, E. Herrero-Gꢁmez, M. Raducan, A. M. Echavarren,
Chem. Eur. J. 2006, 12, 1677 – 1693.
[26] N. Cabello, E. Jimꢃnez-NfflÇez, E. BuÇuel, D. J. Cꢄrdenas, A. M.
Echavarren, Eur. J. Org. Chem. 2007, 4217 – 4223.
[27] M. Mato, A. M. Echavarren, Angew. Chem. Int. Ed. 2019, 58,
2088 – 2092; Angew. Chem. 2019, 131, 2110 – 2114.
[28] For a recent discussion of the nature of the intermediates in
cyclizations of 1,6-enynes, see: I. Escofet, H. Armengol-Relats,
H. Bruss, M. Besora, A. M. Echavarren, Chem. Eur. J. 2020, 26,
15738 – 15745.
[29] NCI plots of the transition states showed stabilization by non-
covalent interactions between the cavity and the substrate. A
similar effect was found in a Cu-cyclodextrin system: G. Xu, S.
Leloux, P. Zhang, J. M. Suꢄrez, Y. Zhang, E. Derat, M. Mꢃnand,
O. Bistri-Aslanoff, S. Roland, T. Leyssens, O. Riant, M.
Sollogoub, Angew. Chem. Int. Ed. 2020, 59, 7591 – 7597;
Angew. Chem. 2020, 132, 7661 – 7667.
methoxycyclization of 1,6-enynes: L. Charruault, V. Michelet, R.
Taras, S. Gladiali, J.-P. GenÞt, Chem. Commun. 2004, 850 – 851.
20] S. Laphookhieo, W. Maneerat, Heterocycles 2010, 81, 1261 –
[
[
1269.
21] a) H. Liu, C.-J. Li, J.-Z. Yang, N. Ning, Y.-K. Si, L. Li, N.-H.
Chen, Q. Zhao, D.-M. Zhang, J. Nat. Prod. 2012, 75, 677 – 682;
b) D.-Y. Shen, Y.-Y. Chan, T.-L. Hwang, S.-H. Juang, S.-C.
Huang, P.-C. Kuo, T.-D. Thang, E.-J. Lee, A.-G. Damu, T.-S. Wu,
J. Nat. Prod. 2014, 77, 1215 – 1223.
22] For synthetic work in this area, see: a) D. Mal, J. Roy, Org.
Biomol. Chem. 2015, 13, 6344 – 6352; b) Y. Abbas, N. Mansha, N.
Ullah, RSC Adv. 2016, 6, 26104 – 26110; c) Y. Liu, Y. Guo, F. Ji,
D. Gao, C. Song, J. Chang, J. Org. Chem. 2016, 81, 4310 – 4315;
d) S. B. Markad, N. P. Argade, J. Org. Chem. 2018, 83, 382 – 387.
23] M. P. Schramm, M. Kanaura, K. Ito, M. Ide, T. Iwasawa, Eur. J.
Org. Chem. 2016, 813 – 820.
24] See Supporting Information for additional details and deposition
numbers. The deposition Numbers contain the supplementary
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 www.ccdc.cam.ac.uk/structures.
[
[
[
Manuscript received: December 23, 2020
Accepted manuscript online: February 12, 2021
Version of record online: March 11, 2021
9
344 www.angewandte.org ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH
Angew. Chem. Int. Ed. 2021, 60, 9339 –9344