Diastereospecific nazarov cyclization of fully substituted dienones: Generation of vicinal all-carbon-atom quaternary stereocenters

Article abstract of DOI:10.1002/anie.201305218

No vacancy: Fully substituted dienones that are highly polarized by a vinylogous carbonate group were found to undergo a remarkably rapid and diastereospecific Nazarov cyclization that led to cyclopentenones with vicinal all-carbon-atom quaternary centers (see example; SEM=2-(trimethylsilyl) ethoxymethyl, Tf=trifluoromethanesulfonyl). Copyright

Full text of DOI:10.1002/anie.201305218

Angewandte
Chemie
DOI: 10.1002/anie.201305218
Synthetic Methods
Diastereospecific Nazarov Cyclization of Fully Substituted Dienones:
Generation of Vicinal All-Carbon-Atom Quaternary Stereocenters**
Anais Jolit, Saleta Vazquez-Rodriguez, Glenn P. A. Yap, and Marcus A. Tius*
The joining of two carbon atoms through a s bond so as to
form vicinal all-carbon-atom quaternary centers remains
a difficult challenge in organic synthesis.[1] An effective
strategy to address the problem is to exploit an orbital-
symmetry-controlled process.[2] We describe herein
a diastereospecific Nazarov cyclization[3] that leads to cyclo-
pentenones bearing adjacent all-carbon-atom quaternary
centers.
We are aware of only three examples of Nazarov
cyclizations that lead to two contiguous all-carbon-atom
quaternary stereocenters during the ring-forming step
(Scheme 1). The efforts of Harding and co-workers [Eqs. (1)
and (2), Scheme 1] culminated in the total synthesis of dl-
trichodiene.[4] The reaction conditions in both cases were
harsh, but the yield of cyclic products 2 and 4, which lack
sensitive functionality, was high. In both reactions the
C3a,C3b relative configuration (see compound 2) was deter-
mined by the conrotation that is required by the selection rule
governing the thermal 4p-electron process. The third example
is the oxidative Nazarov cyclization of allenyl ether 5 that was
reported by Frontier and co-workers in 2011 [Eq. (3) in
Scheme 1].[5] The oxyallyl zwitterion that forms spontane-
ously from the allene oxide following the treatment of 5 with
dimethyldioxirane (DMDO) underwent stereospecific cycli-
zation to 6 in moderate yield. The zwitterion intermediate is
strongly polarized, hence the mild reaction conditions.
Frontier and co-workers also described a diastereoselec-
tive tandem Nazarov–Wagner–Meerwein reaction that leads
to cyclopentenones bearing vicinal all-carbon-atom stereo-
centers.[6] Finally, there are two reported examples of the
Nazarov cyclization of 3,5-dibromo-2,6-dimethylhepta-2,5-
dien-4-one; in each case the reaction led to vicinal gem-
dimethyl groups in the cyclic product.[7,8] To the best of our
knowledge, the formation of adjacent quaternary carbon
atoms during the Nazarov cyclization is limited to this very
small number of examples. These cyclizations represent
a special challenge because the two “inside” substituents, R1
and R6 [Eq. (4)], destabilize the U-shaped s-trans/s-trans
conformer of the dienone that is able to form a ring, thereby
displacing the equilibrium to the s-cis conformers, which
cannot cyclize. Herein we will demonstrate how this problem
can be overcome through judicious experimental design.
It has been shown that polarized dienones undergo
accelerated Nazarov cyclizations.[9,10] An especially effective
way to activate the dienone toward cyclization is to incorpo-
rate a “push–pull” vinylogous carbonate.[11] A synthesis of
activated dienones that are ideally suited for the present
application is shown in Scheme 2. Metalation of the 2-
(trimethylsilyl)ethoxymethyl (SEM) enol ether 7 according
to a procedure described by Knochel and Bresser[12] and
Scheme 1. Generation of vicinal all-carbon-atom quaternary stereocen-
ters in the Nazarov cyclization.
[*] A. Jolit, S. Vazquez-Rodriguez, Dr. G. P. A. Yap, Prof. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
E-mail: tius@hawaii.edu
Dr. G. P. A. Yap
Department of Chemistry and Biochemistry, University of Delaware
236 Brown Laboratory, Newark, DE 19716 (USA)
Prof. M. A. Tius
University of Hawaii Cancer Center
701 Ilalo Street, Honolulu, HI 96813 (USA)
[**] We thank the NIH-NIGMS (R01 GM57873) for partial support and
the NSF for CRIF-MRI 1048367.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201305218.
Scheme 2. Preparation of the dienone substrate. TMP=2,2,6,6-tetra-
methylpiperidinyl.
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subsequent exposure to (E)-2-methyl-3-phenylbut-2-enoyl
chloride (8) led to dienone 9 in 88% yield from the carboxylic
acid as a single (E,E) geometrical isomer. The isomeric purity
of 9 is critical because contamination by the geometrical
isomer of either double bond would erode the stereoisomeric
purity of the derived cyclic product. The substituted acryloyl
chlorides used in this study were synthesized according to
reported procedures from the appropriate acetoacetate
esters.[13]
investigations we used the conditions described in entry 6 of
Table 1. The requirement of a high acid concentration is
consistent with the cyclization of a diprotonated intermediate
of the type that West and co-workers postulated for certain
Nazarov cyclizations.[14,15]
The reaction scope is indicated by the examples in
Scheme 3 of compounds obtained under the optimized
reaction conditions (Table 1, entry 6). All compounds were
We optimized the reaction conditions for the Nazarov
cyclization by using dienone 9 (Table 1). No special effort was
made to exclude traces of water from the reaction mixture.
Table 1: Optimization of the reaction conditions.
Entry
Acid (equiv)
T [8C]
t [min][a]
Yield [%][b]
1[c]
2[c]
3[c]
4[c]
5[d]
6[e]
7[f]
TFA (90)
TFA (4)
0
0
0
0
0
1
10
2
2
2
63
–
81
–
–
80
78
Tf2NH (4)
Tf2NH (1)
Tf2NH (0.2)
Tf2NH (0.2)
Tf2NH (0.1)
23
23
60
180
[a] Total reaction time. [b] Yield of isolated 10. [c] The acid was added
neat. [d] Triflimide was added as a 0.27m solution in CH2Cl2. [e] Inverse
addition at 5 mLminꢀ1 of a 1m solution of 9 to a 1m solution of triflimide.
[f] Inverse addition at 1.7 mLminꢀ1 of a 1m solution of 9 to a 1m solution
of triflimide. Tf=trifluoromethanesulfonyl.
The first conditions that were examined, trifluoroacetic acid
(TFA; 90 equiv) in dichloromethane at 08C, were successful
and led to the a-hydroxycyclopentenone 10 as a single
diastereomer in 63% yield after a reaction time of 1 min
(Table 1, entry 1). A reduction in the amount of acid used to
4 equivalents resulted in a slower reaction that led to
a mixture in which 10 was a minor product (Table 1,
entry 2). One of the by-products appeared to be the acyclic
a-diketone resulting from loss of the SEM group. We
reasoned that a Brønsted acid with a less nucleophilic
counterion would suppress this unwanted reaction. Support
for this hypothesis was obtained by the exposure of 9 to
triflimide (4 equiv), which led to the production of 10 in 81%
yield as a single diastereomer (Table 1, entry 3). In an effort to
reduce the amount of acid required, the reaction was
conducted in the presence of 1 and 0.2 equivalents of
triflimide (Table 1, entries 4 and 5), but in each case mixtures
of products were observed. Because the reaction was only
successful when excess acid was used, the mode of addition
was changed. When a solution of 9 was added with a syringe
pump to a concentrated solution of triflimide (0.2 equiv;
Table 1, entry 6), 10 was produced in 80% yield by the time
the transfer was complete. When even less triflimide was used
(0.1 equiv), it was necessary to increase the addition time, and
the yield of 10 was 78% (Table 1, entry 7). For all subsequent
Scheme 3. Products formed with vicinal quaternary carbon atoms in
the Nazarov cyclization.
formed as single diastereomers, and their configuration was
determined by NMR spectroscopy on the basis of NOE data.
The configuration of 10 was confirmed by single-crystal X-ray
crystallographic analysis.[16] The yield of the cyclic products
varied from 53 to 88%. The cyclization is surprisingly tolerant
of sterically demanding substrates. For example, even cyclo-
pentenone 16, which bears isopropyl and 2-naphthyl groups
on adjacent carbon atoms, was formed in 53% yield.
Significantly, there is no requirement for a b aryl group to
activate the dienone, as demonstrated by examples 17–22.
The success of these Nazarov reactions rests in a delicate
balance, as the following examples demonstrate. Exposure of
dienone 23, which differs from 9 only in the presence of an
isopropyl group in place of the phenyl group, to the optimized
cyclization conditions led to an approximately 1.5 :1 mixture
of the anticipated product 24 and its diastereomer 25 in 81%
yield [Eq. (5)]. The appearance of 25 is evidence of the
occurrence of double-bond isomerization in 23 in competition
with cyclization. It is unlikely that isomerization of the enol
ether took place, because this isomerization would then have
2
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been observed for some of the compounds in Scheme 3 under
the identical reaction conditions. Furthermore, double-bond
isomerization was observed during the preparation of (E)-
2,3,4-trimethylpent-2-enoyl chloride in the presence of an
acid.[17] There is a higher barrier to the isomerization of 9
because it requires the disruption of conjugation to the phenyl
group. The formation of 25 is remarkable, because it
demonstrates that cyclization can even take place efficiently
with an “inside” isopropyl group [see Eq. (4)].
The use of lactone 26 as a substrate revealed an
unanticipated process [Eq. (6)]. Cyclization according to the
predicted pathway led to nearly equal amounts of a single
diastereomer of 27 and by-product 28. The ketene acetal 28
may have been formed by means of an intramolecular
Michael addition of the oxygen atom of the lactone carbonyl
group. This process is facile in this example because of the
enforced coplanarity of the lactone carbonyl group with the
dienone. It is also possible that 28 was formed through an
electrocyclization.[18]
On the basis of these results, it appears that the Nazarov
cyclization to produce vicinal all-carbon-atom quaternary
centers is successful and diastereospecific within a carefully
defined range of reaction parameters. The strongly polarized
“push–pull” vinylogous carbonate is required to lower the
barrier to cyclization. The SEM group also plays a critical role
by collapsing rapidly through the loss of ethylene and
formaldehyde to suppress processes that lead to erosion of
the stereochemical integrity of the cyclic product. Inverse
addition of the dienone to the acid leads to a rapid cyclization
that suppresses undesired competing acid-catalyzed process-
es. The examples described in Scheme 3 suggest broad
synthetic utility, and it is also likely that other “push–pull”
alkenes can be used in place of the vinylogous carbonates that
have been described herein. This study greatly expands the
scope of the Nazarov reaction by making highly congested
cyclopentenones readily available. An asymmetric version of
this cyclization is under investigation.[20]
Experimental Section
A reaction vial equipped with a membrane cap was loaded with
Tf2NH (15 mg, 0.054 mmol, 0.2 equiv) in dry CH2Cl2 (0.05 mL, 1m). A
small needle was inserted through the cap to relieve pressure. A
solution of dienone 9 (112 mg, 0.268 mmol, 1 equiv) in dry CH2Cl2
(0.27 mL, 1m) was added dropwise with a syringe pump (5 mLminꢀ1
)
to the solution of Tf2NH at room temperature. The reaction mixture
was placed on a vortex stirrer during the addition. The reaction
mixture was then diluted with CH2Cl2 (2 mL) and quenched with 5%
aqueous NaHCO3. The aqueous layer was extracted twice with
CH2Cl2. The combined layers were washed with water and brine and
then dried over Na2SO4. Evaporation of the solvent and column
chromatography (silica gel, 2% Et2O/CH2Cl2) afforded 10 (61 mg,
80%) as a white solid. M.p.: 141–1458C; 1H NMR (300 MHz, CDCl3):
d = 7.28–7.06 (m, 5H), 5.31 (s, 1H, OH), 3.49–3.39 (m, 1H), 3.32–3.18
(m, 1H), 1.90 (s, 3H), 1.61 (s, 3H), 1.46 (s, 3H), 0.83 ppm (t, J =
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 200.4, 170.8, 148.2,
147.5, 141.5, 128.0 (2C), 127.8 (2C), 127.1, 61.5, 60.8, 52.7, 21.3, 18.4,
Diethylamide 29 failed to undergo cyclization even upon
exposure to triflimide (4 equiv) for 24 h and was recovered
from the reaction mixture [Eq. (7)]. This result demonstrates
the effect of double-bond polarization on the rate of cycliza-
tion. The amide group, which is less electron withdrawing
than the ester, apparently does not enable the cyclization
under the same conditions.
~
13.4, 10.9 ppm; IR (neat): n ¼3366, 2982, 1708, 1661, 1445, 1404, 1363,
1249, 1193, 1083, 777, 733 cmꢀ1; HRMS (ESI+): m/z calcd for
C17H20O4: 311.1260 [M+Na]+; found: 311.1253.
Received: June 18, 2013
Revised: July 23, 2013
In dienone 31, the SEM group has been replaced with a 4-
methoxyphenyl group [Eq. (8)]. Cyclization proceeded in
good yield but led to an approximately 1:3 mixture of
diastereomers 32 and 33. This result underscores the critical
role that the SEM group plays in the successful cyclization.
Favorably polarized 31 is expected to cyclize as fast as 9, but
the hydrolytic loss of the 4-methoxyphenyl group is probably
slower than SEM cleavage, which does not require the
participation of water. A slow termination step leading to
a reversible Nazarov–retro-Nazarov[19] process might provide
an opportunity for enol ether isomerization in 31 to compete
with cyclization.
Published online: && &&, &&&&
Keywords: diastereoselectivity · Nazarov cyclization ·
.
quaternary stereocenters · rearrangement · synthetic methods
[1] A. Peterson, L. E. Overman, Proc. Natl. Acad. Sci. USA 2004,
101, 11943 – 11948.
[2] For an especially elegant example, see: J. R. Fuchs, R. L. Funk, J.
Am. Chem. Soc. 2004, 126, 5068 – 5069.
[3] For reviews of the Nazarov reaction, see: a) W. T. Spencer III, T.
Vaidya, A. J. Frontier, Eur. J. Org. Chem. 2013, 3621 – 3633; b) T.
Vaidya, R. Eisenberg, A. J. Frontier, ChemCatChem 2011, 3,
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.
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1531 – 1548; c) N. Shimada, C. Stewart, M. A. Tius, Tetrahedron
2011, 67, 5851 – 5870; d) W. Nakanishi, F. G. West, Curr. Opin.
Drug Discovery Dev. 2009, 12, 732 – 751; e) T. N. Grant, C. J.
Rieder, F. G. West, Chem. Commun. 2009, 5676 – 5688; f) A. J.
Frontier, C. Collison, Tetrahedron 2005, 61, 7577 – 7606; g) H.
Pellissier, Tetrahedron 2005, 61, 6479 – 6517; h) M. A. Tius, Eur.
J. Org. Chem. 2005, 2193 – 2206; i) M. Harmata, Chemtracts 2004,
17, 416 – 435.
[10] M. A. Tius, C.-K. Kwok, X.-q. Gu, C. Zhao, Synth. Commun.
1994, 24, 871 – 885.
[11] A. K. Basak, N. Shimada, W. F. Bow, D. A. Vicic, M. A. Tius, J.
Am. Chem. Soc. 2010, 132, 8266 – 8267.
[12] P. Knochel, T. Bresser, Angew. Chem. 2011, 123, 1954 – 1958;
Angew. Chem. Int. Ed. 2011, 50, 1914 – 1917.
[13] a) D. Babinski, O. Soltani, D. E. Frantz, Org. Lett. 2008, 10,
2901 – 2904; b) M. Ide, M. Nakata, Synlett 2001, 1511 – 1515.
[14] Y. K. Wu, T. Niu, F. G. West, Chem. Commun. 2012, 48, 9186 –
9188.
[15] R. L. Davis, D. J. Tantillo, Curr. Org. Chem. 2010, 14, 1561 –
1577.
[16] CCDC 949925 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[4] 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.
[5] W. T. Spencer III, M. D. Levin, A. J. Frontier, Org. Lett. 2011, 13,
414 – 417.
[6] a) D. Leboeuf, V. Gandon, J. Ciesielski, A. J. Frontier, J. Am.
Chem. Soc. 2012, 134, 6296 – 6308; b) D. Leboeuf, J. Huang, V.
Gandon, A. J. Frontier, Angew. Chem. 2011, 123, 11173 – 11177;
Angew. Chem. Int. Ed. 2011, 50, 10981 – 10985.
[7] a) C. W. Shoppee, R. E. Lack, J. Chem. Soc. C 1969, 1346 – 1349;
b) M. Pawlowski, J. K. Maurin, A. Leniewski, K. Wojtasiewicz,
Z. Czarnocki, Heterocycles 2005, 65, 9 – 22.
[8] For an example of a Nazarov cyclization that creates vicinal
quaternary carbon atoms bearing a heteroatom, see: W. He, X.
Sun, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 300 – 308.
[9] W. He, I. R. Herrick, T. A. Atesin, P. A. Caruana, C. A.
Kellenberger, A. J. Frontier, J. Am. Chem. Soc. 2008, 130,
1003 – 1011.
[17] To suppress isomerization, the acid chloride in this case was
prepared via the sodium carboxylate.
[18] We thank a referee for pointing out this possibility.
[19] a) M. Harmata, D. R. Lee, C. L. Barnes, Org. Lett. 2005, 7, 1881 –
1883; b) M. Harmata, P. R. Schreiner, D. R. Lee, P. L. Kirch-
hoefer, J. Am. Chem. Soc. 2004, 126, 10954 – 10957; c) M.
Harmata, D. R. Lee, J. Am. Chem. Soc. 2002, 124, 14328 – 14329.
[20] Optically enriched 11 (e.r. 74:26) has been formed with a chiral
Brønsted acid catalyst.
4
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Synthetic Methods
A. Jolit, S. Vazquez-Rodriguez,
G. P. A. Yap, M. A. Tius*
&&&& — &&&&
Diastereospecific Nazarov Cyclization of
Fully Substituted Dienones: Generation
of Vicinal All-Carbon-Atom Quaternary
Stereocenters
No vacancy: Fully substituted dienones
that are highly polarized by a vinylogous
carbonate group were found to undergo
a remarkably rapid and diastereospecific
Nazarov cyclization that led to cyclopen-
tenones with vicinal all-carbon-atom
quaternary centers (see example; SEM=
2-(trimethylsilyl)ethoxymethyl, Tf=tri-
fluoromethanesulfonyl).
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
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