Catalytic Enantioselective Nazarov Cyclization

Article abstract of DOI:10.1002/ejoc.201701117

A detailed account of an asymmetric Nazarov cyclization that leads to α-hydroxycyclopentenones bearing either vicinal, all-carbon quaternary centers, or vicinal quaternary and tertiary centers is given. The all-aliphatic examples represent the greatest challenge, as the dienone starting materials are not activated toward cyclization by an aryl group. The rational design and optimization of the substrates in parallel with optimization of the chiral Br?nsted acid catalyst is also described, as well as a series of diastereoselective transformations of a fully substituted cyclopentenone product.

Full text of DOI:10.1002/ejoc.201701117

A Journal of
Accepted Article
Title: Catalytic Enantioselective Nazarov Cyclization
Authors: Anais Jolit, Cody F. Dickinson, Kei Kitamura, Patrick M.
Walleser, Glenn P.A. Yap, and Marcus Antonius Tius
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701117
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
Catalytic Enantioselective Nazarov Cyclization
Anais Jolit,[a] Cody F. Dickinson,[a] Kei Kitamura,[a] Patrick M. Walleser,[a] Glenn P. A. Yap,[b] and Marcus
A. Tius*[a, c]
Abstract: The detailed account of an asymmetric Nazarov
cyclization that leads to -hydroxycyclopentenones bearing either
vicinal, all-carbon atom quaternary centers, or vicinal quaternary and
tertiary centers is described. The all-aliphatic examples represent
the greatest challenge as the dienone starting materials are not
activated toward cyclization by an aryl group. The rational design
and optimization of the substrates in parallel with the optimization of
the chiral Brønsted acid catalyst is also described as well as a series
and on the effectiveness of transmission of stereochemical
information from the catalyst to the product. It is essential that
the dienone starting materials (cf. 1, Scheme 1) be single
geometric isomers. Since the cyclization takes place by means
of a conrotation, the presence of an isomer at only one of the
double bonds will lead to the formation of a diastereomeric
product, whereas the presence of geometric isomers at both
double bonds will lead to enantiomers. Competition between
double bond isomerization and cyclization will result in a non-
stereoselective reaction. It was therefore important that
cyclization takes place exclusively within the sterically restrictive
active site of the catalyst within which double bond isomerization
is suppressed. In all Nazarov cyclizations the fate of the
intermediate cyclic cation must be controlled. If the cation is
long-lived, Wagner-Meerwein rearrangements may take place.[6]
Our design of the dienones addresses this issue very effectively.
In the case of 1, loss of the benzhydryl cation terminates the
reaction rapidly. Also, the enol ether function in 1 polarizes the
dienone thereby activating it toward cyclization.[7]
of diastereoselective transformations of
cyclopentenone product.
a
fully substituted
Introduction
In a preliminary communication in 2014 we reported the
first catalytic enantioselective Nazarov cyclization leading to
cyclopentenones bearing vicinal all-carbon atom quaternary
stereocenters.[1-3] A typical reaction is summarized in Scheme 1,
in which dienone 1 was exposed to catalyst (R)-3a at room
temperature for 24 h. Nazarov cyclization to 2 was accompanied
by loss of the diphenylmethyl group as a stable benzhydryl
cation that was scavenged by 2-(tert-butyl)phenol. The product
was formed in 80% yield as a single diastereomer and in 98:2 er.
In what follows we will present a more detailed account of the
work. In addition, we will describe the synthesis of
cyclopentenones bearing vicinal all-aliphatic all-carbon atom
quaternary stereocenters.[4] These represent the most
challenging examples, because aromatic substituents activate
the substrates toward cyclization. We will also describe the
preparation of cyclopentenones bearing adjacent quaternary and
tertiary all-carbon atom stereocenters. We will present some
regio- and stereospecific manipulations of one of the
cyclopentenone products to demonstrate the value of this class
of multifunctional, highly substituted compounds in total
synthesis.[5]
Scheme 1. Enantio- and diastereoselective Nazarov cyclization catalysed by
Brønsted acid (R)-3a.
We hypothesized that through systematic changes of the three
variable elements of our system, the aryl group on the catalyst,
the enol ether and the ester, we would be able to define
conditions for an effective catalytic asymmetric Nazarov
cyclization. Our assumption that the changes in each of these
three areas would lead to a cumulative effect was borne out.
At the inception of our work we were inspired by Rueping’s
report of an enantioselective Nazarov cyclization catalyzed by a
BINOL-derived N-triflyl phosphoramide.[8] Several features of this
catalyst motif were attractive: the low cost of its optically active
precursor, the ease of access to modified substituents at the C3
and C3’ positions, and the bidentate H-bonding with the
dienone.[9] The strong acidity of the N-triflyl phosphoramide
function[10] recommended its use because we had determined
that the more weakly acidic BINOL-derived phosphoric acids did
not catalyze the cyclization. Our preliminary screen of enol
ethers was performed with N-triflyl phosphoramide 3b (R = 9-
phenanthryl; Table 1).
Results and Discussion
Development and Optimization of a Catalyst. There are
several considerations that bear on the efficiency of the reaction
[a]
C. F. Dickinson, Dr. K. Kitamura, Dr. A. Jolit, Dr. P. M. Walleser,
Prof. Dr. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
Dr. G. P. A. Yap
Department of Chemistry and Biochemistry, University of Delaware
236 Brown Laboratory, Newark, DE 19716 (USA)
Prof. Dr. M. A. Tius
[b]
[c]
Exposure of SEM ether 4[11] (entry 1, R2 = Et) to 20 mol% of
(R)-3b in dichloromethane at room temperature led to the
racemate of 5. It is likely that the trimethylsilyl cation that is
generated during cleavage of the SEM group from the cyclic
cationic intermediate acted as a Lewis acid to induce cyclization
of the dienone and competed with the asymmetric Nazarov
cyclization. Exposure of the PMP ether to the same conditions
University of Hawaii Cancer Center
701 Ilalo Street, Honolulu, HI 96813 (USA)
E-mail: tius@hawaii.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
led to a 1:3 mixture of cis-5 and trans-6 diastereoisomers (entry
2). The electron donating effect of the PMP group apparently led
however, a comparison between ethyl and phenyl esters 4A and
4G indicated a substantial benefit for the latter, especially with
to isomerization of the enol ether double bond prior to cyclization. catalyst 3f. Of the five fast reactions that led to products in
Because cleavage of the PMP group from the cyclic
intermediate is slow and requires water, the formation of
diastereomers in this case may be an indication of a reversible
cyclization, which could lead to the loss of stereochemical
integrity of the starting material. An encouraging result was
obtained when the PMB ether was treated with (R)-3b (entry 3),
leading to cyclopentenone 5 as the single cis diastereoisomer in
66:34 er. Following this we concentrated our efforts on benzyl
ethers.
enantiomeric ratios of 80:20 or better and that have been
highlighted in Table 2, three were observed with catalyst 3f. The
9-anthrylmethyl, PMB and diphenylmethyl ethers performed
approximately the same with 3f. Although increasing the size of
the substituents on the aryl ring of the catalyst from isopropyl
(3d) to cyclopentyl (3e) led to a slight improvement for the
cyclization of 4B, the synthesis of such catalysts was
We planned to vary the ether group first, and then make
changes to the ester, hoping to identify trend(s) in
enantioselectivity and reactivity. We quickly determined that the
N-triflyl phosphoramides derived from unsubstituted BINOL or
from 3,3’-bis-(triphenylsilyl) BINOL led to racemic or nearly
racemic product, so we screened aryl substituted catalysts 3b-f
against the seven dienones 4 shown in Table 2. The reactions
that have been summarized in Table 2 were allowed to proceed
in dichloromethane (0.2 M) for 24 h in the presence of 10 mol%
catalyst and were not worked up. Reactions that were complete
after 24 h, as judged by thin layer chromatography (TLC), have
been identified in Table 2 as fast (F) whereas reactions that
were incomplete after a day have been identified as slow (S).
Several trends became evident. Dienones incorporating 1- or
2-naphthylmethyl ether groups (4C and 4D) were slow to react
with all catalysts, and were not given further consideration. In
contrast, the 9-anthrylmethyl ether 4B was fast reacting and led
to promising enantiomeric ratios in the case of catalysts 3d, 3e
and 3f. Note that catalysts 3d and 3e, both of which incorporate
a 2,4,6-trisubstituted aryl group and were derived from (R)-
BINOL like all others led to inverted ratios of enantiomers. This
is an indication of mechanistic complexity that we did not delve
into. The isopropyl ester of 4F did not offer an advantage,
Table 2. Screen of dienones 4 against catalysts 3b–f.
3b[a]
3c
3d
3e
3f
4A 34:66, F 56:44, F
4B 53:47, F 58:42, F
25:75, F
20:80, F
19:81, S
18:82, S
24:76, F
25:75, F
27:73, F
24:76, F
12:88, F
20:80, S
22:78, S
24:76, F
--[c]
65:35, F
80:20, F
61:39, S
57:43, S
80:20, F
66:34, S
82:18, F
4C
4D
4E
4F
--[b], S
--[b], S
49:51, S
47:53, S
67:33, F 59:41, F
34:66, F 55:45, F
4G 45:55, F 59:41, F
23:77, F
[a] er = enantiomeric ratio, F/S = fast or slow reaction; [b] complex reaction
mixture; [c] this reaction was not performed
challenging. It was not clear that a substantial increase in the
steric bulk of the catalyst could be made beyond 3e, should it
have been desirable to do so. The large number of byproducts
observed during the cyclization of the 9-anthrylmethyl ether
dienone was also concerning. Consequently we narrowed our
focus to catalyst 3f and proceeded to determine the influence of
the ester group on the enantioselectivity. We hypothesized that
combining the phenyl ester with the bulky diphenylmethyl ether
in dienone 1 (see Scheme 1) would lead to some improvement
and indeed with catalyst 3f the er improved to 90:10. Catalyst 3f
was subsequently optimized for the cyclization of dienone 1 by
varying the para substituent on the C3 and C3’ aryl groups as
we have described.[1] A substantial improvement in er to 96:4
was observed with catalyst (R)-3a (Ar = 4-tert-butylphenyl) which
was chosen for all subsequent work.
A solvent screen revealed that the optical purity of products
was higher in solvents of low dielectric constant that promote
stronger ion pairing, thereby leading to more efficient chirality
transfer. Although the best er (99:1) was observed in carbon
tetrachloride, toluene was almost as good (er 98:2) and was
used instead. On small scale (<20 mg) the diphenylmethyl cation,
loss of which terminates the reaction, was probably scavenged
Table 1. Preliminary screen of ether groups.
Entry
R1
R2
Et
Products
only 5
er of 5[a]
1
2
3
SEM
PMP
PMB
50:50
[c]
Me
Et
5:6 = 1:3[b]
only 5
–
66:34
[a] enantiomeric ratios (er) were determined by chiral HPLC; [b] dr determined
by 1H NMR integration of methyl ester singlets; [c] mixture of 4 isomers not
separable by chiral HPLC.
SEM = 2-(trimethylsilyl)ethoxymethyl, PMP = para-methoxyphenyl, PMB =
para-methoxybenzyl
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10.1002/ejoc.201701117
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by water that was present in the reaction medium. Upon scaling
up the reaction to 100 mg of dienone the product appeared to be
contaminated by impurities derived from the diphenylmethyl
fragment, making it necessary to add 2-tert-butylphenol to
scavenge the cation.[11]
C2 is required for good enantioselectivity. The capacity of the
catalyst active site starts to be exceeded in the case of 11 and
16. Most cyclopentenones were formed in less than 24 h at
room temperature with 10 mol% catalyst. Cyclopentenones 12 –
16 that are substituted at C1 by an n-butyl group were slow to
undergo cyclization (48 – 120 h at room temperature) and the
optical purity of the products was attenuated. The reaction
mixtures leading to 13 – 15 also contained a number of
byproducts.[14] Cyclopentenones 17 and 18 demonstrate that a
phenyl substituent at C2 restores good optical activity even in
the case of the large isobutyl group in 18. Moderate
enantioselectivity was observed in the case of bicyclic
We screened the cyclization of 1 under the influence of (R)-
3a at varying temperatures, hoping to see an improvement in the
optical activity of the product at lower temperatures. The
cyclization at 0 °C in the presence of 10 mol% catalyst was not
complete after 48 h, and led to product 2 of identical optical
purity as the room temperature reaction (er 98:2). We also
screened the reaction at higher temperatures and noted that the
time to completion diminished with increasing temperature,
whereas the optical purity of the product remained constant.[11]
This was somewhat surprising, and indicates that the difference
H‡ in the enthalpies of activation for the transition states
leading to each of the enantiomers of 2 is very small, therefore
the enantioselectivity of this cyclization is due to the difference in
the entropies of activation of the transition states leading to the
two enantiomers.[12]
cyclopentenone 19. Finally,
a C1 cyclohexyl substituent
apparently excludes the dienone from the catalyst active site; we
were unable to prepare 20 even after heating the reaction
mixture to 100 °C.
The results of Table 3 are consistent with the recently
published computational model of the transition state for the
enantioselective cyclization of 1 to 2.[15] Krenske and coworkers
located the transition state that correctly predicts the formation
of the observed enantiomer of 2. In the preferred transition state
the methyl groups at C1 and C2 are directed towards one of the
tert-butyl groups of (R)-3a whereas the C2 phenyl and phenyl
ester groups are largely excluded from the catalyst pocket. The
most important non-covalent interaction in the transition state
that determines the absolute stereochemistry of the product is
between the C2 methyl and one of the homotopic tert-butyl
groups of the catalyst. When the two groups at C2 are of similar
size as they are in 7 and 8, diastereomeric transition states of
similar energy can form, leading to enantiomeric mixtures.[16]
Synthesis of C1,C5-Trisubstituted Cyclopentenones. The
cyclopentenones in Table 4 were prepared in order to determine
whether (R)-3a would be useful for the synthesis of less highly
substituted dienones. The cyclization to 21 was used to optimize
the reaction conditions. We attributed the inconsistent reaction
times and er’s that we observed in our first experiments to the
presence of variable amounts of water in the reaction medium.
Accordingly, the inclusion of protic additives (i.e., MeOH, H2O,
AcOH) led to a sharp decrease in the optical purity of the
product, whereas sodium sulfate had the opposite effect. We
traced some irreproducible early results to the quality of the
catalyst. We found that samples of (R)-3a that had been stored
at room temperature in air for 6 months or longer had undergone
some decomposition leading to a catalyst with diminished
activity that provided products that were either racemic or were
of very low optical purity. We were able to identify the
phosphoric acid in samples of old catalyst, so we assume that
hydrolysis of the N-triflyl phosphoramide by adventitious water
had taken place. Catalyst that was stored under argon was
stable indefinitely.[17] The optimized conditions that were used to
prepare all examples in Table 4 were essentially the same as for
Table 3. The reaction could also be carried out using 3 mol% of
(R)-3a without any erosion of the er.[11]
Table 3. C1,C2-Tetrasubstituted Cyclopentenones.[a]
[a]The reactions were performed at room temperature in toluene at 0.1 M
concentration of dienone in the presence of 10 – 30 mol% (R)-3a, 1.2
equivalents of 2-tert-butylphenol and 0.5 g/mmol of crushed 5Å molecular
]
sieves (vide infra).[13
Synthesis of C1,C2-Tetrasubstituted Cyclopentenones. The
examples shown in Table 3 were prepared to determine the
effectiveness of the catalyst for the all-aliphatic case. All
compounds were formed as single diastereomers. Comparing
the results for 7 and 8 with those for 9 and 10 suggests that a
substantial difference in size between the two substituents on
All the cyclopentenones of Table 4 were formed as single
diastereomers. Both 23 and 30 were formed in low yield and in
both cases a substantial amount of diketoester, the product of
enol ether hydrolysis, was present in the reaction mixture. It
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
appears that the branched isobutyl group at C1 in both cases
suppresses cyclization, allowing competing processes to
consume the starting material. Cyclopentenones 22 and 32 that
incorporate a C1 n-butyl group were also formed in slow
reactions. In light of these results it is surprising that C1,C2-
tetrasubstituted cyclopentenone 18 that also is substituted by an
isobutyl group is formed in 60% yield and in good optical purity
(Table 3). With the exception of the products referred to above
and of 29, all other cyclopentenones substituted by an aryl group
at C5 are formed in good to moderate yields and er’s. The all-
alkyl cyclopentenones 33 – 37 were formed in good or excellent
(99:1) er’s, however, yields were low. The absolute
stereochemistry of 25 was determined by X-ray crystallography
(CCDC 1561850).[11] The absolute stereochemistry of all other
compounds in Table 4 has been assigned by analogy to 25.
Table 4. C1,C5-Trisubstituted Cyclopentenones.[a]
opportunities for further elaboration, and 38 could lead to
cyclopentanes with three contiguous quaternary stereogenic
carbon atoms. The major anticipated difficulty was related to the
steric compression that results from the enforced proximity of
fully substituted carbon atoms within a rigid ring. The presence
of ketone and ester groups in 38 presented a smaller challenge
of performing chemoselective reactions on the ketone.
The enolic -diketone in 38 suggests that C3 should be
nucleophilic, however, the derived lithium or potassium enolates
proved to be very stable and were unreactive to iodomethane or
ethyl cyanoformate. Chlorine gas reacted with 38 nearly
instantaneously at 23 °C leading to chlorodiketone 39 as a
single diastereomer in 90% yield.[19] The reason for the
stereospecificity of the chlorination remains unclear. To probe
whether 39 might have been formed in a kinetically controlled
process, a sample in toluene-d8 was heated in an NMR tube at
80 °C for 1 h, then at 105 °C overnight, but no change was
detected.
The enol function of 38 reacted with distilled DMDO [20] and
after 12 h -diketone 40 was isolated in 94% yield as a single
diastereomer. The oxidation was complete within 30 min or less
and led initially to a 1:1 mixture of C3 diastereomeric tertiary
alcohols. Over time the reaction mixture became enriched in 40
and after 12 h this was the only detected product.[21]
Exposure of 38 to trimethylsilyldiazomethane led to methyl
ether 41 in 83% yield. Subsequent treatment with methyllithium
at −78 °C led to tertiary alcohol 43 as a single isomer in 92%
yield. Products 39, 40 and 43 have three contiguous quaternary
carbon atoms.
[a]The reactions were performed at room temperature in toluene at 0.1 M
concentration of dienone in the presence of 10 mol% (R)-3a, 1.2 equivalents
of 2-tert-butylphenol and 0.5 g/mmol of crushed 5Å molecular sieves.
Selective Modifications of a Cyclopentenone. Although we
have demonstrated the utility of the hydroxyenone products that
are formed in the acid- and palladium-catalyzed Nazarov
cyclizations by using the reaction as the key step in a number of
natural product syntheses,[18] to date we have not disclosed a
systematic study of their stereo- and regioselective modifications.
Scheme 2. Functionalization of cyclopentenone 38. (a) Cl2 gas, CH2Cl2; 90%
of 39; (b) DMDO, CH2Cl2; 94% of 40; (c) TMSCHN2, MeOH, PhH; 83%; (d)
KHMDS, 18-crown-6, THF, −78 °C; MeI; 92%; (e) MeLi, THF, −78 °C; 92%; (f)
MOM-Cl, Et3N, cat DMAP, CH2Cl2; 96%; (g) NaBH4, MeOH, 40 °C; 85%; (h)
We
chose
to
explore
the
reactivity
of
the
hydroxycyclopentenones using racemic 38 as an example
(Scheme 2). The -hydroxyenone functionality offers many
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
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Tf2O, i-Pr2NEt, CH2Cl2; 94%; (i) PhB(OH)2, cat Pd(OAc)2, cat PCy3, KF, THF;
55%; (j) n-C5H11OZnBr, n-C5H11ZnBr, THF; 67%. DMDO = dimethyl dioxirane;
and led to the discovery that inclusion of 5Å molecular sieves
had a beneficial effect on the enantioselectivity. The asymmetric
KHMDS
=
potassium
hexamethyldisilylamide;
DMAP
=
4-
synthesis
of
single
diastereomers
of
all-aliphatic
dimethylaminopyridine.
cyclopentenones 7 – 16 and 19 that lack an activating C2 aryl
group is noteworthy. These compounds define new solutions to
an enduring challenge in organic synthesis, the enantio- and
diastereoselective synthesis of adjacent, all-carbon atom
quaternary centers.
Finally, the transformations that have been summarized in
Scheme 2 can be applied to the other cyclopentenone products
of this Nazarov cyclization. We have shown that up to three
adjacent quaternary carbon atoms can be incorporated into the
five-membered ring, two of which are all-carbon atom. Being
able to control the reactivity of the vinylic C3 methyl group in 38
so that it can function either as a nucleophile (see 42) or as an
electrophile (see 48) offers exceptional flexibility. All the
compounds shown in Tables 2 and 3 and in Scheme 2 represent
new structures. The predictable nature of these efficient,
diastereospecific reactions suggests broad utility of this method
in synthesis.
Whereas 41 was reactive, the methoxymethyl ether 44 that
was prepared in 96% yield from 38 reacted only sluggishly with
methylmagnesium bromide. No detectable reaction took place at
−78 °C or even at 0 °C. Tertiary alcohol was only observed when
the reaction mixture was allowed to warm to 23 °C and was
formed as a ca. 1:1 mixture of diastereomers in 60% yield.
Reduction of 44 by treatment with 20 equivalents of sodium
borohydride at 40 °C in methanol led to secondary alcohol 45 as
a single diastereomer in 85% yield.[22] The marked difference in
reactivity towards nucleophiles between 41 and 44 must be a
consequence of the chelating methoxymethyl group in 44.
Enol ether 38 was converted to triflate 46 to explore the
feasibility of performing cross-coupling reactions. These were
unexpectedly challenging. All attempts to perform Stille coupling
with tri-(n-butyl)stannylbenzene failed. Bases,[23] catalysts,[24]
solvents[25] and temperature regimes were explored for the
Suzuki coupling of 46 with phenylboronic acid, all without
success.[26] In most cases positive control reactions were
performed that were always successful, suggesting that the
oxidative addition to 46 had failed to take place. When the
Suzuki coupling was performed using Fu’s improved
conditions[27] with electron-rich PCy3 that accelerates the
oxidative addition, -phenyl enone 47 was formed in 55% yield.
One unsuccessful attempt was made to perform the Negishi
coupling of n-pentylzinc bromide with triflate 46 in the presence
of Pd(PPh3)4. None of the desired product was obtained and
ether 53 was isolated instead. When palladium was omitted from
the reaction mixture and 46 was exposed to the reagent for 30
min at 23 °C, ether 48 was isolated in 67% yield. The n-
pentylzinc bromide came from an old sample that had been
exposed to air and was contaminated with the alkoxide. The
residual n-pentylzinc bromide or the alkoxide derived from it,
acting as a base, presumably led to the extended enolate of 46.
Subsequent elimination of trifluoromethanesulfinate led to a
highly reactive Michael acceptor that was attacked by the zinc
alkoxide, now acting as a nucleophile. Products 42 and 48
showcase the reversal of polarity of the C3 methyl group.[28]
Experimental Section
General Methods: All moisture sensitive reactions were performed
under an argon atmosphere in oven-dried or flame-dried glassware.
Tetrahydrofuran (THF), dichloromethane (DCM), diethyl ether (Et2O),
n-hexane, toluene, and dimethylformamide (DMF) were dried using a
Glass Contour solvent purification system. 1H NMR and 13C NMR spectra
were measured on a Varian Mecury-300
(300 MHz/75 MHz) or Varian
INOVA-500 (500 MHz/125 MHz) spectrometers at ambient temperature.
Chemical shifts are reported in parts per million (ppm) and are
referenced to the solvent (e.g., 7.26 for CHCl3; 77.0 for CDCl3). 31P NMR
were measured on a Varian Mercury-300 (121 MHz) or Varian INOVA-
500 (202 MHz) spectrometer and are reported in ppm relative to 85%
H3PO4 (0.0 ppm). 19F NMR were measured on a Varian Mercury-300
(282 MHz) and reported in ppm relative to TFA (−76.5 ppm). Multiplicities
are indicated as follows: br (broadened), s (singlet), d (doublet), t (triplet),
q (quartet), sept (septet), or m (multiplet). Coupling constants (J) are
reported in Hertz (Hz). Infrared (IR) spectra were recorded on a Perkin
Elmer 1600 FT-IR spectrophotometer. Optical rotations ([α]D) were
measured on
a JASCO-DIP-370 polarimeter. High-resolution mass
spectra (HRMS) were obtained with an Agilent 1100 quaternary LC
system. Melting points (mp) were recorded on a DigiMelt MPA160
instruments. High performance liquid chromatography (HPLC) analyses
were performed using a Thermo-Fisher UltiMate 3000 instrument using
Chiralpak AD-H, OD-H, or OJ-H columns (4.6 mm x 250 mm, UV
detection at 261 nm) and i-PrOH and hexane as eluents. Thin layer
chromatography (TLC) was performed on glass plates, 250 μm, particle
size 5-17 μm, pore size 60 Å. Flash column chromatography was
Conclusions
In this full account of an enantioselective, Brønsted acid-
catalyzed Nazarov cyclization we have described the rational
development and optimization of our catalyst and the expansion
of the scope of the reaction. Optically enriched all-aliphatic
performed on silica gel, 200-400 mesh or premium silica gel, 60 Å, 40-75
1
μm. Purity and homogeneity of all materials was determined from TLC,
H NMR, and 13C NMR.
-
C1,C2-tetrasubstituted
and
C1,C5-trisubstituted
cyclopentenones can be prepared. C1 substituents other than
methyl often led to attenuated product yield and/or optical purity.
This is not surprising since the catalyst was optimized using 1, a
C1 methyl compound. Even so, good or excellent asymmetric
induction was achieved in some cases (e.g. 16 – 18). The
unexpected finding that C1,C5-trisubstituted were more sensitive
to the quality of the catalyst than the C1,C2-tetrasubstituted
cyclopentenones prompted us to explore the role of additives
Representative Procedure for the Enantioselective Brønsted Acid
Catalyzed Nazarov Cyclization:
(1S,5S)-Phenyl 3-hydroxy-1,4-dimethyl-2-oxo-5-phenylcyclopent-3-
enecarboxylate (21): To a vigorously stirred solution of dienone (244 mg,
0.50 mmol, 1.0 eq) and 2-(t-butyl)phenol (113 mg, 0.75 mmol, 1.5 eq) in
toluene (5.0 mL) were added activated molecular sieves 5Å (250 mg, 0.5
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
g/mmol dienone). The mixture was stirred for five minutes at room
temperature before (R)-3a (37 mg, 0.5 mmol, 10 mol%) was added all at
once. The reaction mixture was kept stirring at room temperature until
completion as determined by TLC analysis. The reaction mixture was
directly purified using flash column chromatography (silica gel, 10-20%
ethyl acetate in hexanes) to provide cyclopentenone 21 (124 mg, 77%, er
96:4) as a white solid. The enantiomeric ratio was determined by HPLC
analysis on a chiral stationary phase (Chiralpak AD-H® column, 4.6 × 250
mm, UV detection at 261 nm, eluent: hexane/i-PrOH (90:10), flow:: 1
mLmin−1, tR1 (major) = 9.7 min, tR2 (minor) = 17.9 min). [α]D20 = +21.8 (c =
1.0, CHCl3, er 96:4); m.p. 148 – 149 ºC (hexane/Et2O); 1H NMR (300
MHz, CDCl3): δ = 7.32 – 7.37 (m, 3H), 7.21 – 7.27 (m, 2H), 7.04 – 7.17
(m, 3H), 6.22 – 6.27 (m, 2H), 6.20 (brs, 1H), 3.86 (s, 1H), 1.97 (d, J = 1.2
Hz, 3H), 1.72 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 199.8, 168.5,
149.8, 148.8, 143.0, 136.6, 129.6, 128.9, 128.7, 127.9, 125.7, 121.1,
58.7, 58.3, 22.2, 13.0 ppm; IR (neat) ṽ = 3326, 1755, 1707, 1658, 1493,
1454, 1405, 1361, 1300, 1191, 1164, 1072, 993, 833, 746, 702 cm–1;
HRMS (ESI+) m/z calcd for C20H19O4 ([M+H]+): 323.1278; found:
323.1294.
3H), 1.41 – 1.64 (m, 3H), 1.42 (s, 3H), 1.64 – 1.80 (m, 2H), 1.70 (s, 3H),
6.48 (brs, 1H), 6.86 (t, J = 7.3 Hz, 1H), 7.02 (t, J = 7.5 Hz, 2H), 7.14 ppm
(d, J = 8.0 Hz, 2H); 13C NMR (75 MHz, C6D6) δ = 11.8, 17.3, 22.3, 26.2,
27.0, 27.5, 29.5, 30.0, 46.3, 52.0, 60.4, 121.4, 125.6, 129.2, 145.6, 147.5,
150.9, 169.8, 198.9ppm; IR (neat) ṽ = 3338, 2928, 2852, 1762, 1700,
1654, 1651, 1593, 1495, 1446, 1205, 1362, 1261, 1240, 1190, 1161,
1081, 1059, 1023 cm–1; HRMS (ESI+) m/z calcd for C21H26NaO4 [M+Na]+:
365.1729; found: 365.1721; HPLC (Chiralpak OD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR2 = 5.7 min
(major), tR1 = 5.2 min (minor).
(1S,2S)-Phenyl
2-(tert-butyl)-4-hydroxy-1,2,3-trimethyl-5-
oxocyclopent-3-ene-1-carboxylate (11): Colorless oil (61% yield; 29
mg); er 88:12; 1H NMR (500 MHz, C6D6) δ = 0.73 (brs, 9H), 1.18 (s, 3H),
1.79 (s, 3H), 1.81 (s, 3H), 6.60 (brs, 1H), 6.81 – 6.86 (m, 1H), 6.90 – 6.96
ppm (m, 4H); 13C NMR (125 MHz, C6D6) δ = 13.6, 16.7, 18.3, 26.2 (brs),
28.6, 40.4, 55.1, 65.4, 121.6, 125.9, 129.5, 145.9, 151.1, 170.8, 199.5
ppm; IR (neat) ṽ = 3342, 2990, 2964, 2925, 1749, 1696, 1652, 1592,
1493, 1457, 1404, 1232, 1188, 1164, 1116, 1066, 1024, 1005 cm–1
;
HRMS (ESI+) m/z calcd for C19H24NaO4 [M+Na]+: 339.1572; found:
339.1563; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 7.3 min (major), tR2 = 9.8
min (minor).
(1S,2R)-Phenyl 2-ethyl-4-hydroxy-1,2,3-trimethyl-5-oxocyclopent-3-
ene-1-carboxylate (7): White foam (55% yield; 27 mg); er 75:25; 1H
NMR (300 MHz, C6D6) δ = 0.55 (t, J = 7.4 Hz, 3H), 1.07 (s, 3H), 1.10 –
1.30 (m, 2H), 1.49 (s, 3H), 1.62 (s, 3H), 6.48 (brs, 1H), 6.79 – 6.87 (m,
1H), 6.92 – 6.98 ppm (m, 4H); 13C NMR (75 MHz, C6D6) δ = 9.6, 9.9,
16.4, 21.1, 29.1, 47.7, 59.9, 121.4, 125.6, 129.1, 147.5, 148.0, 150.7,
170.4, 199.6 ppm; IR (neat) ṽ = 3387, 3066, 2983, 2946, 2887, 1825,
1778, 1751, 1704, 1653, 1593, 1493, 1457, 1393, 1265, 1190, 1162,
1148, 1071, 1059 cm–1; HRMS (ESI+) m/z calcd for C17H20NaO4 [M+Na]+:
311.1259; found 311.1253; HPLC (Chiralpak OD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (98:2), flow: 1 mLmin−1), tR1 = 14.7 min
(minor), tR2 = 15.9 min (major).
(1S,2S)-Phenyl 1,2-dibutyl-4-hydroxy-2,3-dimethyl-5-oxocyclopent-3-
ene-1-carboxylate (12): Colorless oil (76% yield; 36 mg); er 72:28; 1H
NMR (500 MHz, C6D6) δ = 0.72 (t, J = 7.3 Hz, 3H), 0.84 (t, J = 7.3 Hz,
3H), 1.02 (s, 3H), 1.06 – 1.27 (m, 6H), 1.34 – 1.43 (m, 1H), 1.47 – 1.57
(m, 2H), 1.62 (s, 3H), 1.73 (ddd, J = 16.5, 12.5, 4.3 Hz, 1H), 1.88 – 1.98
(m, 1H), 2.30 (dt, J = 12.5, 4.1 Hz, 1H), 5.56 (brs, 1H), 6.84 – 6.90 (m,
1H), 7.03 (t, J = 7.5 Hz, 2H), 7.13 – 7.14 ppm (m, 2H); 13C NMR (125
MHz, C6D6) δ = 9.8, 14.0, 14.1, 20.0, 23.5, 23.6, 27.3, 27.5, 36.5, 40.1,
48.8, 62.5, 121.8, 125.9, 129.6, 143.2, 147.1, 151.1, 168.9, 197.3 ppm;
IR (neat) ṽ = 3362, 2960, 2932, 2872, 1768, 1740, 1702, 1661, 1593,
1493, 1457, 1404, 1360, 1190, 1162, 1090, 1025 cm–1; HRMS (ESI+) m/z
calcd for C22H30NaO4 [M+Na]+: 381.2042 ; found: 381.2032; HPLC
(Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (98:2),
flow: 1 mLmin−1), tR2 = 49.2 min (major), tR1 = 42.5 min (minor).
(1S,2S)-Phenyl 2-ethyl-4-hydroxy-1,2,3-trimethyl-5-oxocyclopent-3-
ene-1-carboxylate (8): White foam (64% yield; 53 mg); er 77:23; 1H
NMR (300 MHz, C6D6) δ = 0.74 (s, 3H), 0.76 (t, J = 7.5 Hz, 3H), 1.42 (s,
3H), 1.44 – 1.55 (m, 1H), 1.57 – 1.72 (m, 1H), 1.64 (s, 3H), 6.81 – 7.03
ppm (m, 6H); 13C NMR (75 MHz, C6D6) δ = 9.1, 9.6, 18.9, 20.6, 29.2,
48.2, 59.3, 121.4, 125.6, 129.2, 147.3, 149.6, 150.8, 170.0, 199.7 ppm;
IR (neat) ṽ = 3348, 3064, 2973, 2925, 2885, 2854, 1754, 1700, 1654,
(1S,2S)-Phenyl
1-butyl-4-hydroxy-2-isopropyl-2,3-dimethyl-5-
1592, 1494, 1406, 1361, 1229, 1191, 1162, 1147, 1080, 1072 cm–1
;
oxocyclopent-3-ene-1-carboxylate (13): Colorless oil (37% yield; 37
mg); er 77:23; 1H NMR (300 MHz, C6D6) δ = 0.76 – 0.82 (m, 9H), 1.07 (s,
3H), 1.11 – 1.55 (m, 5H), 1.67 (s, 3H), 2.08 (sept, J = 6.7 Hz, 1H), 2.37
(dt, J = 12.1, 3.5 Hz, 1H), 6.87 (t, J = 7.3 Hz, 1H), 7.01 (t, J = 7.4 Hz, 2H),
7.12 ppm (d, J = 8.9 Hz, 2H); 13C NMR (75 MHz, C6D6) δ = 11.6, 13.7,
16.3, 19.3, 19.5, 23.1, 27.0, 37.0, 37.5, 52.6, 63.6, 121.4, 125.5, 129.2,
142.8, 147.9, 150.8, 168.8, 197.8 ppm; IR (neat) ṽ = 3353, 2962, 2932,
2874, 1767, 1740, 1699, 1659, 1593, 1493, 1460, 1457, 1403, 1360,
1269, 1232, 1189, 1163, 1101, 1087, 1030, 1005 cm–1; HRMS (ESI+) m/z
calcd for C21H28NaO4 [M+Na]+: 367.1885; found: 367.1896; HPLC
(Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10),
flow: 1 mLmin−1), tR2 = 10.0 min (major), tR1 = 6.8 min (minor). Note: The
exchangeable proton of the hydroxyl group was not observed in the 1H
NMR.
HRMS (ESI+) m/z calcd for C17H20NaO4 [M+Na]+: 311.1259; found
311.1252; HPLC (Chiralpak OD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (95:5), flow: 1 mLmin−1), tR1 = 9.2 min (minor), tR2 = 10.2
min (major).
(1S,2S)-Phenyl 4-hydroxy-2-isobutyl-1,2,3-trimethyl-5-oxocyclopent-
3-ene-1-carboxylate (9): Colorless oil (41% yield; 64 mg); er 93:7; 1H
NMR (500 MHz, C6D6) δ = 0.70 (d, J = 6.4 Hz, 3H), 0.76 (d, J = 6.4 Hz,
3H), 0.86 (s, 3H), 1.44 (s, 3H), 1.47 – 1.64 (m, 3H), 1.67 (s, 3H), 6.84 (t,
J = 7.3 Hz, 1H), 6.98 (t, J = 7.5 Hz, 2H), 7.07 ppm (d, J = 8.7 Hz, 2H);
13C NMR (125 MHz, C6D6) δ = 10.4, 20.6, 21.8, 24.8, 24.9, 25.4, 46.3,
49.2, 59.9, 121.7, 125.9, 129.5, 147.3, 148.8, 151.1, 169.8, 199.6 ppm;
IR (neat) ṽ = 3356, 2958, 2917, 2870, 2849, 1757, 1700, 1653, 1498,
1404, 1358, 1306, 1226, 1191, 1161, 1119, 1080, 1068, 1048 cm–1
;
HRMS (ESI+) m/z calcd for C19H24NaO4 [M+Na]+: 339.1572; found:
339.1565; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 7.3 min (minor), tR2 = 7.7
min (major). Note: The exchangeable proton of the hydroxyl group was
not observed in the 1H NMR.
(1S,2S)-Phenyl
1-butyl-4-hydroxy-2-isobutyl-2,3-dimethyl-5-
oxocyclopent-3-ene-1-carboxylate (14): Colorless oil (34% yield; 32
mg); er 86:14; 1H NMR (500 MHz, C6D6) δ = 0.61 (d, J = 6.3 Hz, 3H),
0.71 (d, J = 6.7 Hz, 3H), 0.81 (t, J = 7.3 Hz, 3H), 1.03 (s, 3H), 1.13 – 1.20
(m, 2H), 1.28 (dd, J = 14.8, 8.5 Hz, 1H), 1.36 (dt, J = 12.8, 4.2 Hz, 1H),
1.45 – 1.57 (m, 2H), 1.67 (s, 3H), 1.80 (dd, J = 14.8, 1.7 Hz, 1H), 1.82 –
1.94 (m, 1H), 2.32 (dt, J = 12.6, 4.0 Hz, 1H), 6.89 (t, J = 7.4 Hz, 1H), 7.04
– 7.06 (m, 3H), 7.16 ppm (d, J = 7.7 Hz, 2H); 13C NMR (125 MHz, C6D6)
δ = 10.6, 14.0, 20.5, 23.3, 23.7, 24.6, 25.4, 27.3, 37.4, 49.2, 49.5, 62.7,
(1S,2S)-Phenyl
2-cyclohexyl-4-hydroxy-1,2,3-trimethyl-5-
oxocyclopent-3-ene-1-carboxylate (10): Colorless oil (60% yield; 105
mg); er 92:8; 1H NMR (300 MHz, C6D6) δ = 0.71 – 1.16 (m, 6H), 0.92 (s,
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10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
121.8, 125.9, 129.5, 144.2, 147.4, 151.1, 168.3, 198.0 ppm; IR (neat) ṽ =
3359, 2960, 2930, 2870, 1769, 1739, 1700, 1659, 1593, 1493, 1457,
1404, 1358, 1189, 1162, 1090, 1029 cm–1; HRMS (ESI+) m/z calcd for
C22H30NaO4 [M+Na]+: 381.2042; found: 381.2035; HPLC (Chiralpak AD-
H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10), flow: 1
mLmin−1), tR1 = 7.1 min (major), tR2 = 7.6 min (minor).
OD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10), flow: 1
mLmin−1), tR2 = 5.5 min (major), tR1 = 4.6 min (minor).
(1S,7aS)-Phenyl 3-hydroxy-1,7a-dimethyl-2-oxo-2,4,5,7a-tetrahydro-
1H-indene-1-carboxylate (19): White foam (59% yield; 54 mg); er 88:12;
1H NMR (300 MHz, C6D6) δ = 0.83 (s, 3H), 1.48 (s, 3H), 1.66 – 2.05 (m,
4H), 2.89 (dd, J = 12.8, 4.9 Hz, 1H), 5.35 (ddd, J = 10.0, 5.0, 2.0 Hz, 1H),
5.55 (dd, J = 10.0, 1.9 Hz, 1H), 6.80 – 6.99 ppm (m, 6H); 13C NMR (75
MHz, C6D6) δ = 14.5, 19.8, 25.4, 26.3, 45.8, 59.8, 121.5, 125.5, 127.3,
129.0, 130.0, 146.0, 150.1, 150.9, 169.7, 199.3 ppm; IR (neat) ṽ = 3356,
2970, 1753, 1710, 1661, 1592, 1493, 1449, 1398, 1339, 1237, 1192,
1160, 1129, 1107, 1067, 1035, 1001 cm–1; HRMS (ESI+) m/z calcd for
C18H19O4 [M+H]+: 299.1278; found: 299.1271; HPLC (Chiralpak AD-H®,
4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (98:2), flow: 1 mLmin−1),
tR1 = 32.5 min (major), tR2 = 39.4 min (minor).
(1S,2S)-Phenyl
1-butyl-2-cyclohexyl-4-hydroxy-2,3-dimethyl-5-
oxocyclopent-3-ene-1-carboxylate (15): Colorless oil (34% yield; 35
mg); er 80:20; 1H NMR (500 MHz, C6D6) δ = 0.59 – 0.72 (m, 1H), 0.83 (t,
J = 7.4 Hz, 3H), 0.87 – 1.08 (m, 4H), 1.11 (s, 3H), 1.14 – 1.26 (m, 2H),
1.36 (dt, J = 12.7, 4.f4 Hz, 1H), 1.42 – 1.51 (m, 3H), 1.56 – 1.64 (m, 1H),
1.72 (s, 3H), 1.74 – 1.89 (m, 4H), 2.38 (dt, J = 12.7, 4.0 Hz, 1H), 6.64
(brs, 1H), 6.89 (t, J = 7.5 Hz, 1H), 7.05 (t, J = 7.5 Hz, 2H), 7.20 ppm (d, J
= 7.5 Hz, 2H); 13C NMR (125 MHz, C6D6) δ = 12.1, 14.1, 16.1, 23.4, 26.5,
27.2, 27.3, 28.1, 29.8, 31.0, 37.8, 47.7, 52.8, 64.2, 121.8, 125.9, 129.6,
142.7, 148.0, 151.1, 169.0, 197.7ppm; IR (neat) ṽ = 3365, 2956, 2931,
2856, 1767, 1707, 1653, 1593, 1493, 1452, 1401, 1325, 1305, 1188,
1162 cm–1; HRMS (ESI+) m/z calcd for C24H32NaO4 [M+Na]+: 407.2198;
found: 407.2189; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR2 = 9.9 min (major), tR1 = 7.6
min (minor).
(1S,5S)-Phenyl
1-butyl-3-hydroxy-4-methyl-2-oxo-5-
phenylcyclopent-3-ene-1-carboxylate (22): White solid (48% yield; 132
mg); er 86:14; 1H NMR (300 MHz, C6D6) δ = 0.84 (t, J = 7.2 Hz, 3H), 1.19
– 1.65 (m, 4H), 1.70 (s, 3H), 2.01 (td, J = 12.5, 4.1 Hz, 1H), 2.45 (td, J =
12.5, 4.4 Hz, 1H), 3.63 (s, 1H), 6.36 – 6.42 (m, 2H), 6.73 – 6.80 (m, 1H),
6.85 – 6. 93 (m, 2H), 6.97 – 7.09 (m, 5H), 7.24 ppm (brs, 1H); 13C NMR
(75 MHz, C6D6) δ = 13.1, 14.4, 23.8, 26.6, 36.7, 57.0, 62.9, 122.2, 126.1,
128.2, 129.1, 129.5, 130.5, 137.9, 143.7, 151.1, 168.8, 200.5 ppm; IR
(neat) ṽ = 3326, 3062, 3030, 2958, 2931, 2872, 2862, 1754, 1706, 1659,
(1S,2S)-Phenyl
2-(tert-butyl)-1-butyl-4-hydroxy-2,3-dimethyl-5-
oxocyclopent-3-ene-1-carboxylate (16): Colorless oil (72% yield; 126
mg); er 85:15; 1H NMR (300 MHz, C6D6) δ = 0.86 (brs, 9H), 0.90 (t,
J = 7.2 Hz, 3H), 1.20 (s, 3H), 1.26 – 1.41 (m, 2H), 1.54 – 1.67 (m, 1H),
1.82 (s, 3H), 2.09 (dt, J = 10.7, 2.8 Hz, 1H), 2.35 – 2.56 (m, 2H), 6.82 –
6.90 (m, 1H), 6.95 – 7.01 ppm (m, 4H); 13C NMR (75 MHz, C6D6) δ =
13.3, 13.8, 18.3, 24.0, 26.3 (brs), 28.0, 33.3, 40.4, 55.7, 68.8, 121.4,
125.6, 129.2, 143.4, 150.6, 150.8, 169.6, 200.0 ppm; IR (neat) ṽ = 3357,
3064, 2960, 2932, 2874, 1750, 1699, 1659, 1592, 1493, 1457, 1404,
1360, 1229, 1186, 1163, 1118, 1099, 1094, 1065 cm–1; HRMS (ESI−) m/z
calcd for C22H29O4 [M−H]−: 357.2066; found: 357.2070; HPLC (Chiralpak
OD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (95:5), flow: 1
mLmin−1), tR2 = 6.0 min (major), tR1 = 5.6 min (minor).
1592, 1493, 1456, 1405, 1362, 1210, 1188, 1162, 1096, 1025 cm–1
;
HRMS (ESI+) m/z calcd for C23H24NaO4 [M+Na]+ : 387.1572; found:
387.1571; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 8.2 min (major), tR2 = 11.1
min (minor).
(1S,5S)-Phenyl
3-hydroxy-1-isobutyl-4-methyl-2-oxo-5-
phenylcyclopent-3-ene-1-carboxylate (23): White solid (31% yield; 67
mg); er 81:19; 1H NMR (500 MHz, C6D6) δ = 0.92 (d, J = 6.6 Hz, 3H),
1.08 (d, J = 6.7 Hz, 3H), 1.60 – 1.64 (m, 3H), 1.84 – 1.90 (m, 1H), 1.94 –
2.04 (m, 1H), 2.46 (dd, J = 14.1, 8.4 Hz, 1H), 3.59 (s, 1H), 6.40 (d, J =
7.6 Hz, 2H), 6.76 (t, J = 7.4 Hz, 1H), 6.89 (t, J = 7.6 Hz, 2H), 6.99 – 7.06
ppm (m, 5H); 13C NMR (125 MHz, C6D6) δ = 13.0, 23.8, 25.5, 46.3, 58.2,
62.6, 122.1, 126.1, 127.9, 128.9, 129.1, 129.5, 130.5, 137.9, 141.3,
150.2, 151.2, 168.9, 199.1 ppm; IR (neat) ṽ = 3351, 3071, 3032, 2956,
2870, 1748, 1706, 1654, 1493, 1406, 1355, 1315, 1223, 1208, 1187,
1102, 1026 cm–1; HRMS (ESI+) m/z calcd for C23H24NaO4 [M+Na]+:
387.1572; found: 387.1566; HPLC (Chiralpak OD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 5.7 min
(minor), tR2 = 6.5 min (major). Note: The exchangeable proton of the
hydroxyl group was not observed in the 1H NMR.
(1S,2S)-Phenyl
1-butyl-4-hydroxy-2,3-dimethyl-5-oxo-2-
phenylcyclopent-3-enecarboxylate (17): Colorless oil (56% yield; 42
mg); er 94:6; 1H NMR (300 MHz, CDCl3) δ = 0.93 (t, J = 7.5 Hz, 3H), 1.27
– 1.42 (m, 4H), 1.59 – 1.73 (m, 1H), 1.76 (s, 3H), 1.82 (s, 3H), 2.32 –
2.43 (m, 1H), 6.02 (brs, 1H), 6.18 – 6.23 (m, 2H), 7.03 – 7.18 (m, 3H),
7.27 – 7.33 ppm (m, 5H); 13C NMR (75 MHz, CDCl3) δ = 10.4, 13.9, 19.5,
23.2, 26.9, 35.0, 52.9, 64.5, 121.1, 125.6, 127.3, 127.9, 128.3, 128.9,
142.2, 145.3, 147.7, 149.7, 168.2, 198.5 ppm; IR (neat) ṽ = 3352, 2960,
1747, 1705, 1662, 1593, 1493, 1404, 1361, 1269, 1187, 1103, 1071,
1030, 948, 752, 700 cm–1; HRMS (ESI+) m/z calcd for C24H27O4 [M+H]+:
379.1904; found: 379.1904; HPLC (Chiralpak OD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR2 = 5.6 min
(major), tR1 = 4.7 min (minor).
(1S,2S)-Phenyl
2-(4-fluorophenyl)-4-hydroxy-1,3-dimethyl-5-
oxocyclopent-3-ene-1-carboxylate (24): White solid (67% yield; 64
mg); er 93:7; 1H NMR (500 MHz, C6D6) δ = 1.52 (s, 3H), 1.58 – 1.60 (m,
3H),
3.24 – 3.28 (m, 1H), 6.36 – 6.43 (m, 2H), 6.65 – 6.73 (m, 5H),
(1S,2S)-Phenyl
4-hydroxy-1-isobutyl-2,3-dimethyl-5-oxo-2-
6.79 – 6.86 (m, 2H), 6.98 ppm (brs, 1H); 13C NMR (125 MHz, C6D6) δ =
12.6, 22.0, 57.7, 58.5, 115.5 (d, JCF = 21.4 Hz), 121.5, 125.9, 129.2,
131.6 (d, JCF = 7.9 Hz), 132.7 (d, JCF = 2.9 Hz), 142.5, 149.7, 150.5,
162.7 ppm (d, JCF = 246 Hz), 168.5, 200.1; 19F NMR (470 MHz, C6D6) δ =
−115.2 ppm; IR (neat) ṽ = 3332, 3070, 3042, 2981, 2934, 2873, 1752,
1707, 1655, 1599, 1508, 1493, 1457, 1405, 1362, 1297, 1268, 1235,
1192, 1164, 1074 cm–1; HRMS (ESI+) m/z calcd for C20H17FNaO4
[M+Na]+: 363.1009; found: 363.1004; HPLC (Chiralpak AD-H®, 4.6
phenylcyclopent-3-ene-1-carboxylate (18): Colorless oil (60% yield; 54
mg); er 93.5:6.5; H NMR (300 MHz, C6D6) δ = 0.93 (d, J = 6.5 Hz, 3H),
1
1.16 (d, J = 6.5 Hz, 3H), 1.37 (s, 3H), 1.54 (s, 3H), 1.51 – 1.60 (m, 1H),
2.15 – 2.30 (m, 1H), 2.36 (dd, J = 13.2, 8.2 Hz, 1H), 6.40 (d, J = 7.9 Hz,
2H), 6.77 (t, J = 7.3 Hz, 1H), 6.90 (t, J = 7.6 Hz, 2H), 6.95 – 7.10 (m, 4H),
7.17 – 7.27 ppm (m, 2H); 13C NMR (75 MHz, C6D6) δ = 10.0, 19.0, 22.9,
24.8, 25.3, 44.0, 53.5, 64.2, 121.3, 125.3, 127.0, 128.1, 128.3, 128.7,
142.6, 144.4, 148.8, 150.4, 168.4, 198.6 ppm; IR (neat) ṽ = 3348, 3059,
2958, 2927, 2870, 1748, 1705, 1662, 1592, 1493, 1404, 1361, 1303,
1223, 1189, 1165, 1111, 1103, 1072, 1031 cm–1; HRMS (ESI+) m/z calcd
for C24H26NaO4 [M+Na]+: 401.1729; found: 401.1722; HPLC (Chiralpak
mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1
9.7 min (major), tR2 = 17.4 min (minor).
=
(1S,2S)-Phenyl
2-(4-bromophenyl)-4-hydroxy-1,3-dimethyl-5-
oxocyclopent-3-enecarboxylate (25): Colorless plate, (41% yield; 33
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
mg); er 89:11; mp 146 – 147 ºC (hexane/CH2Cl2); [α]D20 = +43.3 (c 1.07,
CHCl3); 1H NMR (300 MHz, CDCl3) δ = 1.71 (s, 3H), 1.95 (s, 3H), 3.82 (s,
1H), 6.20 (brs, 1H), 6.26 – 6.31 (m, 2H), 7.08 – 7.27 (m, 5H), 7.46 – 7.51
ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 12.9, 22.1, 58.0, 58.2, 120.9,
122.1, 125.9, 129.1, 131.2, 131.8, 135.6, 142.0, 148.9, 149.7, 168.4,
199.3 ppm; IR (neat) ṽ = 3340, 1755, 1710, 1661, 1488, 1407, 1362,
1292, 1191, 1163, 1072, 1012, 911, 844, 735 cm–1; HRMS (ESI+) m/z
calcd for C20H17BrNaO4 [M+Na]+: 423.0202; found: 423.0194; HPLC
(Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10),
flow: 1 mLmin−1), tR1 = 8.9 min (major), tR2 = 15.7 min (minor).
HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH
(90:10), flow: 1 mLmin−1), tR1 = 11.2 min (major), tR2 = 23.6 min (minor).
(1S,2S)-Phenyl 2-(4-chlorophenyl)-4-hydroxy-1-isobutyl-3-methyl-5-
oxocyclopent-3-ene-1-carboxylate (30): White solid (26% yield; 77
mg); er 94:6; 1H NMR (300 MHz, C6D6) δ = 0.89 (d, J = 6.7 Hz, 3H), 1.05
(d, J = 6.5 Hz, 3H), 1.54 (s, 3H), 1.78 (dd, J = 14.1, 4.1 Hz, 1H), 1.85 –
2.02 (m, 1H), 2.38 (dd, J = 14.1, 8.5 Hz, 1H), 3.42 (s, 1H), 6.26 (brs, 1H),
6.40 (d, J = 7.8 Hz, 2H), 6.69 – 6.76 (m, 3H), 6.88 (t, J = 7.7 Hz, 2H),
6.89 ppm (d, J = 8.4 Hz, 2H); 13C NMR (75 MHz, C6D6) δ = 13.2, 24.0,
25.6, 25.6, 46.3, 57.5, 62.7, 122.0, 126.5, 129.5, 129.8, 132.1, 134.5,
136.4, 142.7, 151.0, 151.1, 168.9, 200.2 ppm; IR (neat) ṽ = 3359, 3066,
2959, 2872, 1754, 1710, 1663, 1592, 1492, 1405, 1365, 1306, 1265,
1190, 1162, 1092, 1025 cm–1; HRMS (ESI)− m/z calcd C23H22ClO4
[M−H]−: 397.1207; found: 397.1208; HPLC (Chiralpak OJ-H®, 4.6
(1S,5S)-Phenyl
3-hydroxy-1,4-dimethyl-5-(4-nitrophenyl)-2-
oxocyclopent-3-ene-1-carboxylate (26): Pale yellow solid (45% yield;
1
10 mg); er 96:4; H NMR (500 MHz, C6D6) δ = 1.47 (s, 3H), 1.48 – 1.50
(m, 3H), 3.17 (s, 1H), 6.26 (d, J = 7.5 Hz, 2H), 6.42 (brs, 1H), 6.62 (d, J =
8.6 Hz, 2H), 6.66 (t, J = 7.4 Hz, 1H), 6.74 (t, J = 7.4 Hz, 2H), 7.72 ppm (d,
J = 8.8 Hz, 2H); 13C NMR (125 MHz, C6D6) δ = 12.5, 21.9, 57.7, 58.3,
121.0, 123.6, 126.2, 129.3, 130.5, 140.6, 143.8, 147.8, 149.8, 150.2,
168.0, 199.1 ppm; IR (neat) ṽ = 3357, 3107, 3076, 2977, 2932, 2855,
1756, 1717, 1663, 1598, 1521, 1493, 1405, 1348, 1190, 1163, 1072 cm–
1; HRMS (ESI+) m/z calcd for C20H17NNaO6 [M+Na]+: 390.0954; found:
390.0949; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (60:40), flow: 1 mLmin−1), tR1 = 5.6 min (major), tR2 = 7.7
min (minor).
mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1
6.5 min (major), tR2 = 8.6 min (minor).
=
(1S,5S)-Phenyl
3-hydroxy-1,4-dimethyl-5-(naphthalen-2-yl)-2-
oxocyclopent-3-enecarboxylate (31): Colorless oil (66% yield; 30 mg);
20
er 93:7; [α]D = +59.4 (c 0.97, CHCl3); 1H NMR (300 MHz, CDCl3) δ =
1.78 (s, 3H), 2.00 (d, J = 1.5 Hz, 3H), 4.03 (q, J = 1.5 Hz, 1H), 6.00 –
6.05 (m, 2H), 6.29 (brs, 1H), 6.91 – 6.96 (m, 3H), 7.33 (dd, J = 8.4, 1.8
Hz, 1H), 7.46 – 7.53 (m, 2H), 7.72 (s, 1H), 7.76 – 7.87 ppm (m, 3H); 13
C
NMR (75 MHz, CDCl3) δ = 13.1, 22.2, 58.4, 58.8, 120.9, 125.6, 126.3,
126.4, 127.1, 127.6, 127.8, 128.3, 128.7, 128.8, 132.9, 133.2, 133.9,
142.9, 148.9, 149.7, 168.6, 199.7 ppm; IR (neat) ṽ = 3345, 1755, 1706,
1659, 1592, 1493, 1456, 1404, 1362, 1296, 1233, 1191, 1163, 1074, 991,
911, 860, 826, 732, 689 cm–1; HRMS (ESI+) m/z calcd for; C24H21O4
[M+H]+: 373.1434; found: 373.1448; HPLC (Chiralpak AD-H®, 4.6
(1S,5S)-Phenyl 3-hydroxy-1,4-dimethyl-2-oxo-5-(o-tolyl)cyclopent-3-
ene-1-carboxylate (27): Colorless oil (65% yield; 45 mg); er 93:7; [α]D
20
= –17.2 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) δ = 1.78 (s, 3H), 1.94
(s, 3H), 2.49 (s, 3H), 4.13 (s, 1H), 6.17 – 6.20 (m, 2H), 7.00 – 7.15 (m,
5H), 7.21 – 7.27 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 13.3, 20.4,
23.3, 54.2, 58.2, 121.1, 125.7, 126.1, 127.6, 128.8, 128.9, 130.8, 135.3,
138.2, 144.3, 148.7, 149.8, 168.9, 200.5 ppm; IR (neat) ṽ = 3347, 1755,
1706, 1660, 1592, 1493, 1457, 1405, 1362, 1265, 1191, 1164, 1075, 993,
912, 818, 747, 689 cm–1; HRMS (ESI+) m/z calcd for C21H21O4 [M+H]+:
337.1434; found: 337.1446; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 7.4 min
(major), tR2 = 10.5 min (minor). Note: The exchangeable proton of the
hydroxyl group was not observed in the 1H NMR.
mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1
11.2 min (major), tR2 = 26.1 min (minor).
=
(1S,5S)-Phenyl
1-butyl-3-hydroxy-4-methyl-5-(naphthalen-2-yl)-2-
oxocyclopent-3-ene-1-carboxylate (32): Colorless oil (50% yield; 144
mg); er 85:15; 1H NMR (300 MHz, C6D6) δ = 0.86 (t, J = 7.3 Hz, 3H), 1.29
(sext, J = 7.3 Hz, 2H), 1.39 – 1.52 (m, 1H), 1.56 – 1.69 (m, 1H), 1.76 (s,
3H), 2.07 (dt, J = 13.2, 4.1 Hz, 1H), 2.50 (dt, J = 13.2, 4.4 Hz, 1H), 3.82
(s, 1H), 6.14 – 6.20 (m, 2H), 6.55 – 6.66 (m, 3H), 7.18 – 7.27 (m, 2H),
7.45 – 7.60 ppm (m, 5H); 13C NMR (75 MHz, C6D6) δ = 12.5, 13.7, 23.2,
26.0, 36.0, 56.4, 62.3, 121.2, 125.3, 126.1, 126.2, 127.5, 127.5, 127.9,
128.2, 128.6, 128.9, 133.0, 133.4, 134.6, 143.3, 150.2, 150.5, 168.2,
200.0 ppm; IR (neat) ṽ = 3337, 3059, 3026, 2958, 2931, 2873, 2862,
1757, 1707, 1660, 1593, 1493, 1362, 1266, 1213, 1189, 1162, 1095,
1025 cm–1; HRMS (ESI+) m/z calcd for C27H26NaO4 [M+Na]+: 437.1729;
found: 437.1723; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 9.6 min (major), tR2 = 17.9
min (minor). Note: The exchangeable proton of the hydroxyl group was
not observed in the 1H NMR.
(1S,5S)-Phenyl 3-hydroxy-1,4-dimethyl-2-oxo-5-(m-tolyl)cyclopent-3-
20
enecarboxylate (28): Colorless oil (84% yield; 57 mg); er 92:8; [α]D
=
+22.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ = 1.71 (s, 3H), 1.97 (s,
3H), 2.29 (s, 3H), 3.82 (s, 1H), 6.25 – 6.30 (m, 2H), 6.46 (brs, 1H), 7.01 –
7.10 (m, 3H), 7.12 – 7.18 (m, 3H), 7.21 – 7.27 ppm (m, 1H); 13C NMR (75
MHz, CDCl3) δ = 13.0, 21.3, 22.2, 58.3, 58.6, 121.0, 125.6, 126.7, 128.5,
128.6, 128.9, 130.2, 136.4, 138.3, 143.4, 148.7, 149.9, 168.5, 200.0
ppm; IR (neat) ṽ = 3346, 1757, 1706, 1659, 1592, 1493, 1457, 1405,
1362, 1296, 1192, 1164, 1078, 993, 912, 815, 748, 689 cm–1; HRMS
(ESI+) m/z calcd for C21H21O4 [M+H]+: 337.1434; found: 337.1427; HPLC
(Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (90:10),
flow: 1 mLmin−1), tR1 = 7.7 min (major), tR2 = 14.2 min (minor).
(1S,5S)-Phenyl
3-hydroxy-1,4,5-trimethyl-2-oxocyclopent-3-
20
enecarboxylate (33): Colorless oil (49% yield; 14 mg); er 86:14; [α]D
=
(1S,2S)-Phenyl
2-([1,1'-biphenyl]-4-yl)-4-hydroxy-1,3-dimethyl-5-
+27.3 (c 0.71, CHCl3); 1H NMR (500 MHz, CDCl3) δ = 1.35 (d, J = 7.5 Hz,
3H), 1.52 (s, 3H), 2.03 (d, J = 1.5 Hz, 3H), 2.66 (dq, J = 7.5, 1.5 Hz, 1H),
5.81 (brs, 1H), 7.02 – 7.06 (m, 2H), 7.19 – 7.24 (m, 1H), 7.31 – 7.37 ppm
(m, 2H); 13C NMR (125 MHz, CDCl3) δ = 12.0, 13.9, 20.6, 46.3, 56.2,
121.3, 126.1, 129.4, 145.8, 147.0, 150.2, 169.8, 199.6 ppm; IR (neat) ṽ =
3363, 2977, 1756, 1700, 1653, 1494, 1457, 1405, 1361, 1309, 1235,
1191, 1164, 1108, 1073, 986, 816, 744, 689 cm–1; HRMS (ESI+) m/z
calcd for C15H16NaO4 [M+Na]+: 283.0941; found: 283.0932; HPLC
(Chiralpak OJ-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (80:20),
flow: 1 mLmin−1), tR2 = 25.2 min (major), tR1 = 12.7 min (minor).
oxocyclopent-3-enecarboxylate (29): Colorless oil (74% yield; 53 mg);
20
er 77:23; [α]D = +40.6 (c 1.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ =
1.75 (s, 3H), 2.02 (d, J = 1.5 Hz, 3H), 3.92 (q, J = 1.5 Hz, 1H), 6.22 –
6.25 (m, 2H), 6.28 (brs, 1H), 7.02 – 7.12 (m, 3H), 7.31 (d, J = 8.5 Hz, 2H),
7.36 – 7.40 (m, 1H), 7.45 – 7.49 (m, 2H), 7.55 – 7.59 ppm (m, 4H); 13C
NMR (125 MHz, CDCl3) δ = 13.1, 22.2, 58.3, 58.4, 121.0, 125.7, 127.0,
127.4, 127.5, 128.8, 128.9, 130.0, 135.5, 140.6, 141.1, 142.9, 148.8,
149.8, 168.6, 199.7 ppm; IR (neat) ṽ = 3382, 1755, 1700, 1658, 1486,
1408, 1362, 1298, 1191, 1164, 1073, 1009, 910, 852, 734, 689 cm–1;
HRMS (ESI+) m/z calcd for C26H23O4 [M+H]+: 399.1591; found: 399.1586;
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701117
European Journal of Organic Chemistry
FULL PAPER
(1S,2S)-Phenyl
2-ethyl-4-hydroxy-1,3-dimethyl-5-oxocyclopent-3-
Acknowledgements
20
enecarboxylate (34): Colorless oil (63% yield; 20 mg); er 94:6; [α]D
1
+7.7 (c 0.96, CHCl3); H NMR (300 MHz, CDCl3) δ = 1.12 (t, J = 7.5 Hz,
3H), 1.54 (s, 3H), 1.73 (ddq, J = 14.5, 10.0, 7.5 Hz, 1H), 1.95 (ddq, J =
14.5, 4.5, 7.5 Hz, 1H), 2.05 (d, J = 1.5 Hz, 3H), 2.51 (ddq, J = 10.0, 4.5,
1.5 Hz, 1H), 5.97 (brs, 1H), 7.00 – 7.04 (m, 2H), 7.19 – 7.24 (m, 1H),
7.32 – 7.36 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 12.7, 13.0, 21.4,
22.1, 53.9, 55.9, 121.3, 126.0, 129.4, 146.2, 147.2, 150.3, 169.8, 199.7
ppm; IR (neat) ṽ = 3354, 2975, 1757, 1701, 1653, 1494, 1457, 1406,
1362, 1265, 1192, 1164, 1116, 1081, 990, 816, 738, 689 cm–1; HRMS
(ESI+) m/z calcd for; C16H19O4 [M+H]+: 275.1278; found: 275.1277; HPLC
(Chiralpak OJ-H®, 4.6 mm×250 mm, UV 261 nm, hexane/i-PrOH (80:20),
flow: 1 mLmin−1), tR2 = 12.2 min (major), tR1 = 8.0 min (minor).
K.K. thanks the Yamada Science Foundation for a fellowship.
Jonathan Congmon and Yonghai Hui are acknowledged for
experimental assistance. We thank Christine Brotherton-Pleiss
for assistance with HRMS.
Keywords: asymmetric catalysis • chiral Brønsted acid •
Nazarov cyclization • quaternary stereocenters
[1]
[2]
A. Jolit, P. M. Walleser, G. P. A. Yap, M. A. Tius, Angew. Chem. Int. Ed.
2014, 53, 6180 – 6183.
Reviews of the Nazarov reaction: a) D. R. Wenz, J. Read de Alaniz, Eur.
J. Org. Chem. 2015, 23 – 37; b) F. G. West, O. Scadeng, Y.-K. Wu, R.
J. Fradette, S. Joy, in Comprehensive Organic Synthesis, 2nd Edition
(Eds: P. Knochel, G. A. Molander) Elsevier, 2014, 5, pp. 827 – 866; c)
M. A. Tius, Chem. Soc. Rev. 2014, 43, 2979 – 3002; d) W. T. Spencer
III, T. Vaidya, A. J. Frontier, Eur. J. Org. Chem. 2013, 3621 – 3633; e)
N. Shimada, C. Stewart, M. A. Tius, Tetrahedron 2011, 67, 5851 –
5870.
(1S,5S)-Phenyl 3-hydroxy-5-isobutyl-1,4-dimethyl-2-oxocyclopent-3-
ene-1-carboxylate (35): Colorless oil (42% yield; 63 mg); er 96:4; 1H
NMR (500 MHz, C6D6) δ = 0.75 (d, J = 6.4 Hz, 3H), 0.79 (d, J = 6.5 Hz,
3H), 1.31 (ddd, J = 14.2, 9.8, 4.3 Hz, 1H), 1.48 (s, 3H), 1.65 (ddd,
J = 14.2, 10.4, 4.2 Hz, 1H), 1.70 (d, J = 1.5 Hz, 3H), 1.70 – 1.77 (m, 1H),
2.30 – 2.37 (m, 1H), 6.79 – 6.85 (m, 1H), 6.92 – 6.97 (m, 2H), 7.01 –
7.04 ppm (m, 2H); 13C NMR (125 MHz, C6D6) δ = 12.4, 21.2, 21.6, 23.8,
26.2, 38.6, 49.4, 56.6, 121.7, 126.0, 129.5, 147.2, 148.3, 151.0, 170.0,
200.6 ppm; IR (neat) ṽ = 3353, 2958, 2933, 2869, 1757, 1700, 1652,
[3]
We are aware of only three prior examples of Nazarov reactions that
result in the diastereoselective formation of all-carbon atom quaternary
centers. (a) K. E. Harding, K. S. Clement, C. Y. Tseng, J. Org. Chem.
1990, 55, 4403 – 4410; b) K. E. Harding, K. S. Clement, J. Org. Chem.
1984, 49, 3870 – 3871; c) W. T. Spencer, III, M. D. Levin, A. J. Frontier,
Org. Lett. 2011, 13, 414 – 417.
1592, 1493, 1457, 1408, 1356, 1192, 1163, 1119, 1086, 1070 cm–1
;
HRMS (ESI+) m/z calcd for C18H22NaO4 [M+Na]+: 325.1416; found:
325.1411; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm, UV 261 nm,
hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR2 = 5.7 min (major), tR1 = 4.1
min (minor). Note: The exchangeable proton of the hydroxyl group was
not observed in the 1H NMR.
[4]
[5]
E. A. Peterson, L. E. Overman, Proc. Natl. Acad. Sci. 2004, 101, 11943
– 11948.
Some examples of the use of the Nazarov cyclization in total synthesis
during the past 10 years: a) M-L. Tang, P. Peng, Z-Y. Liu, J. Zhang, J-
M. Yu, X. Sun, Chem. Eur. J. 2016, 22, 14535 – 14539; b) A.
Shvartsbart, A. B. Smith, III, J. Am. Chem. Soc. 2015, 137, 3510 –
3519; c) B. N. Kakde, P. Kumari, A. Bisai, J. Org. Chem. 2015, 80,
9889 – 9899; d) Y. Shi, B. Yang, S. Cai, S. Gao, Angew. Chem. Int. Ed.
2014, 53, 9539 – 9543; e) B. J. Moritz, D. J. Mack, L. Tong, R. J.
Thomson, Angew. Chem. Int. Ed. 2014, 53, 2988 – 2991; f) J. A.
Malona, K. Cariou, W. T. Spencer, III, A. J. Frontier, J. Org. Chem.
2012, 77, 1891 – 1908; g) W-D. Z. Li, W-G. Duo, C-H. Zhuang, Org.
Lett. 2011, 13, 3538 – 3541; h) H. M. Cheng, W. Tian, P. A. Peixoto, B.
Dhudshia, D. Y-K. Chen, Angew. Chem. Int. Ed. 2011, 50, 4165 –
4168; i) K. Yaji, M. Shindo, Tetrahedron 2010, 66, 9808 – 9813; j) W.
He, J. Huang, X. Sun, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 300
– 308; k) D. R. Williams, L. A. Robinson, C. R. Nevill, J. P. Reddy,
Angew. Chem. Int. Ed. 2007, 46, 915 – 918.
(1S,2S)-Phenyl
2-cyclohexyl-4-hydroxy-1,3-dimethyl-5-
oxocyclopent-3-ene-1-carboxylate (36): Colorless oil (32% yield; 46
mg); er 98:2; 1H NMR (300 MHz, C6D6) δ = 0.76 – 1.20 (m, 6H), 1.47 (s,
3H), 1.49 – 1.58 (m, 3H), 1.71 – 1.89 (m, 2H), 1.77 (s, 3H), 2.16 (s, 1H),
6.31 (brs, 1H), 6.83 (t, J = 7.2 Hz, 1H), 6.98 (t, J = 7.6 Hz, 2H), 7.11 ppm
(d, J = 7.9 Hz, 2H); 13C NMR (75 MHz, C6D6) δ = 14.7, 23.8, 26.1, 26.5,
27.2, 29.5, 33.7, 39.6, 56.7, 58.3, 121.4, 125.7, 129.2, 143.1, 148.4,
150.8, 170.0, 199.3 ppm; IR (neat) ṽ = 3343, 2975, 2931, 2854, 1752,
1696, 1648, 1591, 1493, 1452, 1400, 1362, 1296, 1238, 1189, 1161,
1080, 1069 cm–1; HRMS (ESI+) m/z calcd for C20H24NaO4 [M+Na]+:
351.1572; found: 351.1574; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 7.4 min
(major), tR2 = 8.1 min (minor).
(1S,7aS)-Phenyl 3-hydroxy-1-methyl-2-oxo-2,4,5,6,7,7a-hexahydro-
1H-indene-1-carboxylate (37): White foam (30% yield; 30 mg); er 99:1;
1H NMR (300 MHz, CDCl3) δ = 1.25 – 1.52 (m, 3H), 1.55 (s, 3H), 1.95 –
2.29 (m, 4H), 2.48 (dd, J = 12.1, 3.7 Hz, 1H), 3.03 – 3.14 (m, 1H), 6.24
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a) D. Leboeuf, C. M. Wright, A. J. Frontier, Chem. Eur. J. 2013, 19,
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(brs, 1H),
7.03 – 7.14 (m, 2H), 7.23 (t, J = 7.4 Hz, 1H), 7.32 –
7.42 ppm (m, 2H); 13C NMR (75 MHz, CDCl3) δ = 20.9, 25.3, 25.4, 25.7,
29.3, 49.3, 55.3, 121.4, 126.1, 129.4, 144.6, 148.7, 150.3, 169.6, 200.5
ppm; IR (neat) ṽ = 3346, 3062, 2936, 2861, 1755, 1706, 1653, 1592,
1493, 1456, 1397, 1350, 1306, 1256, 1234, 1191, 1164, 1124, 1100,
1071, 1030 cm–1; HRMS (ESI+) m/z calcd for C17H18NaO4 [M+Na]+:
309.1103; found: 309.1107; HPLC (Chiralpak AD-H®, 4.6 mm×250 mm,
UV 261 nm, hexane/i-PrOH (90:10), flow: 1 mLmin−1), tR1 = 11.8 min
(major), tR2 = 13.3 min (minor).
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CCDC 1561850 (for 25) contains the supplementary crystallographic
data for this paper.
[8]
See the Supporting Information for additional experimental details.
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10.1002/ejoc.201701117
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M. Rueping, W. Ieawsuwan, A. P. Antonchick, B. J. Nachtsheim,
J. Am. Chem. Soc. 2001, 123, 8509 – 8514. Madindolines: d) L. Wan,
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[21] The postulated mechanism of isomerization is shown in the Supporting
Information.
[11] See Supporting Information.
[12] This can be expressed by the following equation in which kR and kS are
the rates of formation of (R) and (S) enantiomers, respectively:
[22] The stereochemistry of all products for which this is an issue was
determined by nOe.
≠
≠
(−∆∆퐻
∆∆푆
) ∗ 푒(
Wolf, C. Dynamic Stereochemistry of
[푅]
[푆]
푘푅
푘푆
[23] Bases: t-BuOK, K3PO4, Et3N.
)
푅푇
푅
.
=
= 푒
[24] Catalysts: Pd2(dba)3, Pd2(dba)3 + PPh3, Pd(PPh3)4, Pd(OAc)2 + PPh3,
PEPPSITM-IPr, PdCl2dppf. dba = dibenzalacetone ; PEPPSI = Pyridine-
Enhanced Precatalyst Preparation Stabilization and Initiation; dppf =
Chiral Compounds: Principles and Applications; The Royal Society of
Chemistry, Cambridge, UK, 2008; pp. 183 – 186.
1,1'-Bis(diphenylphosphino)ferrocene;
diisopropylphenylimidazolium.
IPr
=
2,6-
[13] The role of molecular sieves in modulating the outcome of catalytic
enantioselective reactions has been noted by others: a) J. Itoh, K.
Fuchibe, T. Akiyama, Angew. Chem. Int. Ed. 2008, 47, 4016 – 4018; b)
K. V. Gothelf, R. G. Hazell, K. A. Jørgensen, J. Org. Chem. 1998, 63,
5483 – 5488.
[25] Solvents: THF, THF/CH2Cl2, dioxane, dioxane/H2O, iPrOH, MeOH,
DMF; 23 °C to reflux.
[26] A successful palladium-catalyzed carbonylation in a related system has
been described. See reference 5g.
[14] Cyclopentenones 17
– 22 underwent some decomposition during
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4028.
storage at room temperature.
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Edstrom, T. Yu, J. Org. Chem. 1995, 60, 5382 – 5383; and for
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9970.
[16] Krenske and coworkers’ data also suggests the presence of an offset 
stacking interaction between the C2 phenyl and phenyl ester groups
which would explain the beneficial effect on product optical purity that is
conferred by the latter.
[17] The cyclization leading to C1,C2-tetrasubstituted cyclopentenones was
much less sensitive to the quality of the catalyst.
[18] Rocaglamide: a) Z. Zhou, M. A. Tius, Angew. Chem. Int. Ed. 2015, 54,
6037-6040; b) Z. Zhou, D. D. Dixon, A. Jolit, M. A. Tius, Chem. Eur. J.
2016, 22, 15929 – 15936. Roseophilin: c) P. E. Harrington, M. A. Tius,
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Asymmetric Nazarov
Anais Jolit, Cody F. Dickinson, Kei
Kitamura, Patrick M. Walleser, Glenn P.
A. Yap, Marcus A. Tius*
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The asymmetric Nazarov cyclization that is catalyzed by a BINOL-derived N-triflyl
phosphoramide leads to cyclopentenones with all-aliphatic all-carbon atom vicinal
stereocenters in up to 99:1 enantiomeric ratios. The cyclic products can be modified
through a number of highly specific reactions to form sterically congested
cyclopentenones incorporating up to three contiguous quaternary centers.
Catalytic Enantioselective Nazarov
Cyclization
*one or two words that highlight the emphasis of the paper or the field of the study Contiguous Quaternary Stereocenters
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