Contiguous Quaternary Centers from a AuI-Catalyzed Nazarov Cyclization

Article abstract of DOI:10.1002/ejoc.201800604

The cationic Au^I-catalyzed cyclization of highly substituted enynes has been shown to provide cyclopentenones with up to two contiguous, all-carbon atom quaternary centers in a diastereospecific process. In the more challenging examples in whic

Full text of DOI:10.1002/ejoc.201800604

A Journal of
Accepted Article
Title: Contiguous Quaternary Centers from a Au(I)-Catalyzed Nazarov
Cyclization
Authors: Marcus Antonius Tius and Jonathan Congmon
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10.1002/ejoc.201800604
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COMMUNICATION
Contiguous Quaternary Centers from a Au(I)-Catalyzed Nazarov
Cyclization
Jonathan Congmon, and Marcus A. Tius*[a]
Abstract: The cationic Au(I)-catalyzed cyclization of highly
substituted enynes has been shown to provide cyclopentenones with
up to two contiguous, all-carbon atom quaternary centers in a
diastereospecific process. In the more challenging examples in
which two contiguous quaternary centers are formed during
cyclization, the essential role of a carboethoxy group to control the
reaction outcome has been demonstrated. The less challenging
examples that lead to a single quaternary center in the ring require
no activation by aryl or by electron withdrawing groups.
We questioned whether enynyl acetates such as 3 and 5[11]
would be capable of undergoing Au(I)-catalyzed cyclization, or
whether other rearrangements might compete. In Zhang’s
reaction [1,2]-hydride migration takes place immediately
following cyclization. An analogous [1,2]-alkyl or aryl migration
that might have taken place during the rearrangement of 3 or 5
could have led to complex product mixtures.[12] Even if five-
membered ring formation represented the dominant reaction
pathway for enynes 3 and 5, it seemed likely that the reaction of
5 would lead to mixtures of diastereomers. Very surprisingly, the
cyclization of 5 and of all related enynes that we examined led to
single diastereomers of the cyclopentenone product.
The Nazarov cyclization continues to provide efficient access to
cyclopentenones more than 70 years after its discovery.[1] In
some cases the relative and the absolute stereochemistry of the
product can be controlled,[2] rendering the method especially
valuable in total synthesis.[3] Nazarov cyclizations leading to
cyclopentenones bearing one or more all-carbon atom
quaternary centers represent the most difficult case. We have
recently developed asymmetric Pd(0)- and chiral Bronsted acid
(CBA)-catalyzed diastereo- and enantioselective Nazarov
cyclizations. The CBA-catalyzed cyclization leads to products
with adjacent all-carbon atom quaternary centers.[4] Predictably,
the reaction is slower for highly congested systems, enabling
competing processes to take place. Our preliminary results
indicated that a heavy catalyst load is required in the Pd(0)-
catalyzed reaction in order to prepare cyclopentenones bearing
adjacent all-carbon atom quaternary centers, suggesting the
need for more reactive catalysts.
Our search for a more effective way to assemble adjacent
all-carbon atom quaternary centers led us to the 2006 report by
Zhang and Wang describing the cationic Au(I)-catalyzed
cyclization of enynyl acetate 1 to cyclopentenone 2 (Scheme
1).[5] Since 2006 a number of related Au(I)- and Au(III)-catalyzed
Nazarov reactions have been described,[6] including one that
demonstrates good levels of asymmetry transfer.[6c] Asymmetry
transfer has also been demonstrated for the related Au(I)-
catalyzed Rautenstrauch rearrangement.[7,8] In the majority of
cases cyclization is initiated either by [1,3]- or by [1,2]-oxa
migration, typically of acetate, that is triggered through alkyne
activation by the catalyst. There appears to be a delicate
balance between the factors that favor [1,3]- over [1,2]-oxa
migration.[9,10]
Scheme 1. Cationic Au(I)-Catalyzed Nazarov Cyclizations.
The conditions for the cyclization were optimized using
enyne 3 (Table 1). The cationic Au(I) catalyst in each case was
prepared in situ from equimolar quantities of the appropriate
ligated AuCl and silver(I) triflimide that were delivered as
standard solutions in dichloromethane.[13] A significantly faster
reaction was observed in the case of the triphenylphosphino
complex (entry 1), but under identical conditions the yield of 4
was better with the aryl phosphite ligand (entry 3), so it was
chosen.[14] Since there was no significant difference between
1,2-dichloroethane and dichloromethane (entries 3, 4)
dichloromethane was selected.[15] The Au(I) catalyst was in all
cases highly reactive and as little as 0.5 mol% led to acceptable
results (entry 7).[16] Entries 8–10 refer to control experiments that
showed that both Au(I) and Ag(I) were necessary in order for
reaction to take place. Since AgNTf2 might have been the source
of a small amount of the strong Bronsted acid Tf2NH, the control
experiment of entry 10 was carried out. Within 10 min of
exposure to 1 equivalent of Tf2NH all of 3 had been consumed,
[a]
Mr. J. Congmon, Prof. Dr. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
E-mail: tius@hawaii.edu
Prof. Dr. M. A. Tius
University of Hawaii Cancer Center
701 Ilalo Street, Honolulu, HI 96813 (USA)
Supporting information for this article is given via a link at the end
of the document.
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10.1002/ejoc.201800604
European Journal of Organic Chemistry
COMMUNICATION
and no 4 was detected by TLC in the complex reaction mixture,
making it unlikely that 4 is formed through Bronsted acid
catalysis. The reaction conditions of entries 4 and 6 were used
for slow- and fast-reacting enynes, respectively.
participation of the acetoxy group. Rearrangement to
pentadienyl cation 25[22] is followed by cyclization to 26. Proton
loss from the exocyclic carbon atom results in protiodeauration
of 27 with formation of dienol acetate 28 and regeneration of the
catalyst. Whereas enol acetate cleavage was required as a
separate step in the case of 6 and 18–23, in all other cases
hydrolytic cleavage of the acetate through adventitious water
took place during the reaction, and the odor of acetic acid was
detected during workup. Adding 0.5 g/mmol of powdered 4Å
molecular sieves to the reaction mixture made it possible to
isolate the enol acetate in all cases. If a significant amount of
water is present during the reaction, cyclization is not observed,
presumably because protiodeauration takes place prematurely.
For example, in wet dichloromethane dienone 29 was formed as
the sole product in 70% yield as a single geometrical isomer
from the corresponding enyne. The Z stereochemistry was
assigned on the basis of the positive nOe between the C2-H and
C3-Me.[23]
Table 1. Optimization of the Reaction Conditions.
Entry
LAuCl (mol %)[a]
Solvent
Time
Yield
(%)
1
2
3
4
5
6
7
8
9
10
Ph3PAuCl (5)
DCE
DCE
DCE
DCM
DCM
DCM
DCM
DCE
DCE
DCE
30 min
1 h
70
IPrAuCl (5)
71
Table 2. Examples of the Cyclization.
(ArO)3PAuCl (5)
1 h
76
(ArO)3PAuCl (5)
1 h
81[b]
68
(ArO)3PAuCl (2.5)
(ArO)3PAuCl (1)
4 h
16 h
3 d
67
(ArO)3PAuCl (0.5)
no AgNTf2; (ArO)3PAuCl (5)
no Au(I); AgNTf2 (5)
no Au(I), Ag(I); Tf2NH (100)
65[c]
no rxn
no rxn
[d]
3 h
3 h
3 h
[a] Equimolar amounts of Au(I) and Ag(I) were used unless stated
otherwise. All reactions with 5 mol% catalyst were performed on a 0.2
mmol scale. Reactions with 2.5, 1 and 0.5 mol% catalyst were performed
on a 1 mmol scale. [b] Performed on a 0.3 mmol scale. [c] 5 mol% of Ag(I)
was used. [d] No 3 or 4 was detected by TLC after 10 min. The same
decomposition products were detected when 5 mol% Tf2NH was used.
DCE, 1,2-dichloroethane; DCM, dichloromethane; IPr, 1,3-Bis(2,6-
diisopropylphenyl)imidazol-2-ylidene; Ar, 2-tert-butylphenyl.
Table 2 summarizes our findings. The carboethoxy group
was not required and a moderately activated substrate led to 7,
albeit in a slower reaction and in slightly lower yield. Compounds
bearing n  vinyl bromine atom (9–11) were formed readily.[17]
The activating aryl group was not required, and the all-aliphatic
cases (11–13, 18 and 20–23) all proceed in good yield.
Cyclization to -trifluoromethyl cyclopentenones 14-16 took
place in good yield.[18,19] Cyclopentenones 6 and 18–23 deserve
special mention. Because the loss of a proton from one of the
carbon atoms in the ring is not possible, in these examples the
reaction is terminated through proton loss from an exocyclic
carbon atom. Significantly, all compounds in this series were
isolated as single diastereomers of adjacent, all-carbon atom
quaternary centers.[20] The stereochemical assignment in 6, 18,
19 and 28 (Scheme 2) was made on the basis of the positive
nOe between the two cis methyl groups. This has implications
for the mechanism, which we postulate to follow the pathway
outlined in Scheme 2.[21] Complexation of the cationic Au(I)
catalyst to the alkyne function of 5 leads to 24 through
(a) (ArO)3PAuCl/AgNTf2 (1 mol%), DCM, 12 h. (b) (ArO)3PAuCl/AgNTf2 (5
mol%), DCM, 1 h. (c) 1. (ArO)3PAuCl/AgNTf2 (1 mol%) 2. K2CO3, EtOH, rt, 3 h,
yield over
2 steps. Ar, 2-tert-butylphenyl; DCM, dichloromethane; TIPS,
triisopropylsilyl.
Enynes 30–32 represent examples that failed to undergo
cyclization and that were recovered intact from the reaction
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10.1002/ejoc.201800604
European Journal of Organic Chemistry
COMMUNICATION
mixture in each case. In the case of 30 the two trifluoromethyl
groups presumably inhibit the formation of the cation and no
reaction was observed after 2 d under the optimized reaction
conditions. The nucleophilic carbonyl oxygen atom of the
morpholino amide in 31 probably intercepts the alkyne-gold
complex more effectively than the acetate, thus inhibiting the
[1,3]-oxa migration. No reaction was observed after 1 d.
Aromatic  bonds also appear to be unreactive as evidenced by
the inertness of 32 that was recovered unchanged after 2 d.
gives tertiary, benzylic, bis-allylic acetate 37 that loses acetic
acid to form 34. A comparison of the reactions of 33 and of 5
highlights the essential role of the carboethoxy group that
accelerates the desired cyclization to cyclopentenone 6.
Scheme 3. Anomalous cyclization of 33.
Conclusions. Of the compounds shown in Table 2, only
cyclopentenone 7 represents a known structure.[24] The novelty
of this cyclization is showcased by
cyclopentenones substituted by a trifluoromethyl group or that
incorporate
a -bromovinyl. Significantly, the method also
provides access to compounds bearing contiguous, all-carbon
atom quaternary centers as single diastereomers. The high
diastereoselectivity of the process is the result of rapid
isomerization, relative to cyclization, of the intermediate
pentadienyl carbocation that is bonded to the gold atom, e.g. 25.
This is likely due to the same effect that we had observed during
our study of a Pd(0)-catalyzed Nazarov-type cyclization in which
electron pair-electron pair repulsions between ester carbonyl
and hydroxyl oxygen atoms strongly favor a single geometrical
isomer of an alkene.[25,26] In Scheme 2 the repulsive interaction
between the covalently bonded Au atom and the carboethoxy
group results in the formation of a single geometrical isomer of
25, ultimately leading to a single diasteroisomer of 28. The
Scheme 2. Postulated Mechanism.
The rearrangement that leads to the examples of Table 2 is
a delicately balanced process, as indicated by the results that
are summarized in Scheme 3. Although the preparation of 7
(Table 2) shows that the presence of an electron withdrawing
preparation of 29 as
a single C2-C3 geometrical isomer
suggests that this effect may be exploited for the synthesis of
trisubstituted alkenes.[27] The stereochemical outcome in 6 and
in 18–23 provides experimental evidence that this family of
Au(I)-catalyzed cyclizations are conrotatory processes. Control
of the stereochemistry of adjacent, all-carbon atom quaternary
centers is still a very challenging problem for which this work
provides an efficient solution. The ability to prepare the enyne
starting materials easily and in good yield through several
different routes, as well as the indication that it will be possible to
develop an effective catalytic asymmetric version of the reaction
suggest that it will be valuable in synthesis.[28]
group is not a strict requirement for the success of the
cyclization to cyclopentenones bearing a single quaternary
center, we wished to determine whether a carboethoxy group
was required for the preparation of the far more challenging
products that incorporate adjacent quaternary carbon atoms.
Accordingly, enyne 33 was exposed to the optimized reaction
conditions. No cyclopentenone was produced but instead
hydrocarbon 34 was formed in 73% yield as a ca. 2:1 mixture of
geometrical isomers. We assume that pentadienyl cation 35 was
formed as an intermediate according to the postulated
mechanism, and differing from 25 only in having an isobutyl
group in place of carboethoxy. In the absence of the favorable
polarization by an electron withdrawing carboethoxy group,
cation 35 undergoes a competitive aromatic Nazarov cyclization
through conformer 36. Proton loss followed by protiodeauration
Experimental Section
Experimental Details. Alkyne 5 (94 mg, 0.30 mmol, 1 equiv.) was
dissolved in CH2Cl2 (2 mL) and 1 mL of the standard solution of the
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10.1002/ejoc.201800604
European Journal of Organic Chemistry
COMMUNICATION
active gold catalyst was added. The reaction mixture was allowed to stir
at room temperature overnight. The volatiles were removed in vacuo and
the product was purified by silica gel column chromatography (3%
EtOAc/hexanes to 5% EtOAc/hexanes) to provide cyclopentene 28 (74
mg, 78%) as a pale yellow oil. To enol acetate 28 (60 mg, 0.19 mmol, 1
equiv.) in EtOH was added K2CO3 (40 mg, 0.29 mmol, 1.5 equiv.) in one
portion at room temperature. After stirring for 3 h at room temperature,
the reaction mixture was washed with water and extracted with EtOAc
(x3). The combined organic extracts were washed with water, brine, dried
over Na2SO4, and concenrated in vacuo. The product was purified by
silica gel column chromatography (10% EtOAc/hexanes) to provide
cyclopentenone 6 (50 mg, 96%; 75% overall) as a pale yellow oil. 1H
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[5]
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NMR (300 MHz, CDCl3)
0.99 (t, J = 7.2 Hz, 3H), 1.35 (s, 3H), 1.74 (s,
3H), 2.27 (d, J = 18.1 Hz, 1H), 3.07 (d, J = 18.1 Hz, 1H), 3.78 (dq, J = 7.2,
0.8 Hz, 2H), 5.35 (s, 1H), 6.39 (s, 1H), 7.12 – 7.36 (m, 5H); 13C NMR (75
MHz, CDCl3)
13.6, 20.3, 23.3, 46.8, 52.5, 53.5, 60.8, 119.9, 127.0,
127.2, 128.0, 143.6, 152.7, 174.2, 204.1; IR (neat, cm–1) 3025, 2979,
1723, 1641, 1450, 1387, 1289, 1213, 1028; HRMS (ESI+) m/z calculated
for C17H21O3 [M+H]+: 273.1491; found: 273.1619.
[7]
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Acknowledgements
We thank the National Science Foundation for their support of
the chemistry department’s NMR facility (NSF-MRI 1532310).
What distinguishes the Rautenstrauch rearrangement from the Au-
catalyzed Nazarov cyclization is the formation during the former of an
intermediate in which the gold atom is bonded to one of the two carbon
atoms that close the ring. a) V. Rautenstrauch, J. Org. Chem. 1984, 49,
950 – 952; b) C. Bürki, A. Whyte, S. Arndt, A. S. K. Hashmi, M. Lautens,
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Keywords: Nazarov • cationic Au(I) • quaternary carbon •
cyclization • diastereoselectivity
[1]
I. N. Nazarov, I. I. Zaretskaya, Izv. Akad. Nauk SSSR, Ser. Khim. 1941,
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W. Boyle, P. W. H. Chan, Chem. Eur. J. 2016, 22, 6532 – 6536.
Gary
A
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Chem. 2013, 3621 – 3633; e) N. Shimada, C. Stewart, M. A. Tius,
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[10] There are
Nazarov cyclizations as well. a) B. Jacques, D. Hueber, S. Hameury, P.
Braunstein, P. Pale, A. Blanc, P. de Fremont, Organometallics 2014, 33,
a few reports of Au(III)-catalyzed Rautenstrauch and
[2]
For examples of catalytic asymmetric Nazarov cyclizations, see: a) T.
Takeda, S. Harada, A. Nishida, Org. Lett.ˆ∫2015, 17, 5184 – 5187; b) A.
Jolit, P. M. Walleser, G. P. A. Yap, M. A. Tius, Angew. Chem. Int. Ed.
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Kawatsura, K. Kajita, S. Hayase, T. Itoh, Synlett 2010, 1243 – 1246.
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[11] The synthesis of the enyne starting materials is described in the S.I.
[12] D. Leboeuf, C. M. Wright, A. J. Frontier, Chemistry – Eur. J. 2013, 19,
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[13] P. Mauleón, R. M. Zeldin, A. Z. González, F. D. Toste, J. Am. Chem.
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[3]
[14] We performed a limited screen of counterions and found that the
catalysts that had been generated from AgNTf2 and AgSbF6 led to
equivalent results, whereas catalysts generated from AgBF4 and AgOTf
led to slower reactions and to a minor byproduct. See: Z. Lu, J. Han, O.
E. Okoromoba, N. Shimizu, H. Amii, C. F. Tormena, G. B. Hammond, B.
Xu, Org. Lett. 2017, 19, 5848 – 5851.
[15] We screened several solvents with the following results: in PhMe or
Et2O the reaction was slow with a trace of product formed after 24 h;
there was no reaction in EtOAc; a slow reaction took place in MeNO2
leading to ca. 20% conversion to product after 24 h; MeCN led to a
complex reaction mixture containing none of the desired product after
24 h; in DMF or THF after 24 h little reaction took place, but there was
no desired product formed.
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10.1002/ejoc.201800604
European Journal of Organic Chemistry
COMMUNICATION
[16] Enyne 5 did not react after 24 h at room temperature in the presence of
[24] J. Matsuo, M. Kawano, R. Okuno, H. Ishibashi, Org. Lett. 2010, 12,
3960 – 3962.
5
mol% of the catalyst derived from an equimolar mixture of
IPrAu(III)(biphenyl)Cl and AgNTf2. See: C-Y. Wu, T. Horibe, C. B.
Jacobsen, F. D. Toste, Nature, 2015, 517, 449 – 454.
[25] The difference in A values between methyl and carboethoxy groups is
0.5 – 0.6 kcal/mol. “Stereochemistry of Organic Compounds”, E. L. Eliel
and S. H. Wilen, John Wiley & Sons, Inc., New York, 1994; pp. 695 –
697.
[17] D. J. Schatz, Y. Kwon, T. W. Scully, F. G. West, J. Org. Chem. 2016,
81, 12494 – 12498. See also: G. Alachouzos, A. J. Frontier, Angew.
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[26] For
a related example of electron pair-electron pair repulsions
[18] Examples of Nazarov cyclizations leading to trifluoromethyl
cyclopentenones: (a) J. Ichikawa, M. Fujiwara, T. Okauchi, T. Minami,
Synlett 1998, 927 – 929; (b) M. A. Tius, H. Hu, J. K. Kawakami, J.
Busch-Petersen, J. Org. Chem. 1998, 63, 5971 – 5976.
controlling the geometry of a tetrasubstituted alkene see: a) A. K.
Basak, N. Shimada, W. F. Bow, D. A. Vicic, M. A. Tius, J. Am. Chem.
Soc. 2010, 132, 8266 – 8267; b) A.H. Asari, Y. Lam, M. A. Tius, K. N.
Houk, J. Am. Chem. Soc. 2015, 137, 13191 – 13199.
[19] Occhiato and coworkers have prepared a compound related to indole
17 through a Au(I)-catalyzed cyclization. See reference 6a.
[20] a) M. Bueschleb, S. Dorich, S. Hanessian, D. Tao, K. B. Schenthal, L. E.
Overman, Angew. Chem. Int. Ed. 2016, 55, 4156 – 4186; b) K. W.
Quasdorf, L. E. Overman, Nature 2014, 516, 181 – 191.
[27] Compare with the results of Malacria, Fensterbank and coworkers in
which isomerization of an allyl group Z to the gold precedes cyclization.
See Scheme 10 in reference 7c.
[28] A limited screen of chiral, non-racemic ligands for Au(I) was performed.
In the presence of 5 mol% each of the 2 to 1 complex of AuCl with (R)-
(+)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl and AgNTf2 in
dichloromethane cyclopentenone 9 was formed in 67/33 e.r. See the S.I.
and M. J. Johansson, D. J. Gorin, S. T. Staben, F. D. Toste, J. Am.
Chem. Soc. 2005, 127, 18002 – 18003.
[21] A significant difference between the mechanism of Scheme 2 the
following in that no [1,2]-hydride migration step takes place: F-Q. Shi, X.
Li, Y. Xia, L. Zhang, Z-X. Yu, J. Am. Chem. Soc. 2007, 129, 15503 –
15512.
[22] Loss of cationic Au(I) from 24 in a reversible process may lead to an
allene which reacts with the catalyst to give 25.
[23] See the S.I.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800604
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
The cationic Au(I) catalyzed
cyclization of substituted enynes
leads to cyclopentenones through a
cascade of reactions. The highly
diastereoselective synthesis of
cyclopentenones bearing adjacent,
all-carbon atom quaternary centers is
reported.
Jonathan Congmon, Marcus A. Tius*
Page No. – Page No.
Contiguous Quaternary Centers from
a Au(I)-Catalyzed Nazarov
Cyclization
This article is protected by copyright. All rights reserved.