The photo-nazarov reaction: Scope and application

Article abstract of DOI:10.1002/chem.201402993

The reaction conditions and scope of the photo-Nazarov reaction of aryl vinyl ketones were investigated. In contrast to the conventional acid-catalyzed methods, this photolytic electrocyclization proceeds in the neutral or basic conditions. Irradiating substrates bearing various aromatic rings, acid-sensitive groups, cyclohexenyl, cycloheptenyl, and unsaturated pyran with UV-light (254 nm) smoothly yielded hexahydrofluorenones and related structures. This photo-Nazarov reaction could also be applicable to the substrates carrying β-alkyl groups on the enone, which gave corresponding polycyclic rings containing quaternary centers. These photo-electrocyclized products may prove useful for synthesizing a variety of natural products and their derivatives. Further application of this mild photo-Nazarov reaction in the synthesis of taiwaniaquinol B was achieved.

Full text of DOI:10.1002/chem.201402993

DOI: 10.1002/chem.201402993
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&
Photochemistry
The Photo-Nazarov Reaction: Scope and Application
Shujun Cai,[a] Zheming Xiao,[a] Yingbo Shi,[a] and Shuanhu Gao*[a, b]
Abstract: The reaction conditions and scope of the photo-
Nazarov reaction of aryl vinyl ketones were investigated. In
contrast to the conventional acid-catalyzed methods, this
photolytic electrocyclization proceeds in the neutral or basic
conditions. Irradiating substrates bearing various aromatic
rings, acid-sensitive groups, cyclohexenyl, cycloheptenyl, and
unsaturated pyran with UV-light (254 nm) smoothly yielded
hexahydrofluorenones and related structures. This photo-
Nazarov reaction could also be applicable to the substrates
carrying b-alkyl groups on the enone, which gave corre-
sponding polycyclic rings containing quaternary centers.
These photo-electrocyclized products may prove useful for
synthesizing a variety of natural products and their deriva-
tives. Further application of this mild photo-Nazarov reaction
in the synthesis of taiwaniaquinol B was achieved.
Introduction
The Nazarov reaction is one of the most effective methods for
constructing the cyclopentenone group,[1] a common structural
subunit of small molecules. Typically in this method, divinyl
ketone 1 is treated with Lewis or Brønsted acids to give a pen-
tadienyl cation 2, which undergoes 4-p-electron cyclization fol-
lowed by protonation to yield the cylopentenone 3 or 4
([Eq. (1)], Scheme 1).[2] This reaction has been extensively stud-
ied[3] and applied to natural product synthesis[4] over the years.
The electrocyclization of aromatic vinyl ketones proceeds
through a different process than the classical Nazarov reaction.
In 1997, Ohwada and co-workers reported the superacid-medi-
ated cyclization of 1-phenyl-2-propen-1-ones (5) to indanones
(7) ([Eq. (2)], Scheme 1).[5] They demonstrated that this electro-
cyclization involves an oxonium–carbenium dication species 6,
consistent with ab initio calculations. This mechanistic work ex-
plained why the Nazarov cyclization of aromatic vinyl ketones
always requires the use of strong acids and high temperature.
Therefore, it is particularly challenging to use the Nazarov cycli-
zation to construct indanones, hexahydrofluorenones, polycyc-
lic heteroaromatic structures, and related skeletons.
Scheme 1. Nazarov reactions.
Nazarov reaction of aryl vinyl ketones ([Eq. (3)], Scheme 1).[6]
Mechanistic studies by the group of Leitich and Schaffner re-
vealed that selective photolytic activation of the enone group
leads to formation of the highly active isomerized intermediate
9, which induces the electrocyclization to hexahydrofluorenone
10.[7] According to these mechanistic studies, we considered
that the cycloalkene ring is required and crucial to this photo-
lysis, which generates the unusual trans-olefin in a cyclohexene
ring and facilitates the electrocyclization due to a more favora-
ble orbital overlap. For the substrates bearing the acyclic al-
kenes, this photolytic activation will just lead the isomerization
of Z/E configuration. In contrast to the conventional acid-cata-
lyzed methods, this photolytic electrocyclization proceeds
under neutral or basic conditions, and has been successfully
used in the substrates with acid-sensitive groups during our
syntheses of Nakiterpiosion (11) and Nakiterpiosinone (12)
(Figure 1).[8]
An important step towards the synthesis of such skeletons
came in 1973, when Smith and Agosta reported the photo-
[a] S. Cai, Z. Xiao, Y. Shi, Prof. Dr. S. Gao
Shanghai Key Laboratory of Green Chemistry and Chemical Processes
Department of Chemistry, East China Normal University
3663N Zhongshan Road, Shanghai 200062 (P.R. China)
Fax: (+86)21-62604784
E-mail: shgao@chem.ecnu.edu.cn
[b] Prof. Dr. S. Gao
State Key Laboratory of Bioorganic and Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
345 Lingling Road, Shanghai 200032 (P.R. China)
Furthermore, the hydrofluorenone motif frequently exists in
bioactive-containing natural products, including abeo-abietane
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402993.
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Table 1. Optimization of the reaction conditions for the photo-Nazarov
reaction of aryl vinyl ketone 19.
Entry
l
Solvent[a]
Base
c
t
Conv.[b] Yield
[%]
[nm]
[mgmLÀ1
]
[%][b]
1
2
3
4
5
6
7
8
254 CH3CN
254 CH3OH
254 CH3COCH3
254 Et2O
254 CH2Cl2
254 CH2Cl2
254 ClCH2CH2Cl
254 ClCH2CH2Cl iPr2NH
254 ClCH2CH2Cl Et3N
254 ClCH2CH2Cl DBU
254 ClCH2CH2Cl TMEDA
300 ClCH2CH2Cl
366 ClCH2CH2Cl
254 ClCH2CH2Cl
254 ClCH2CH2Cl
254 ClCH2CH2Cl
–
–
–
–
–
–
–
2
2
2
2
2
2
2
2
2
2
2
2
2
2
8
16
3 h
1.5 h
1 h
100
–
97
23
0
24
0
1 h
89
30 min
15 min
20 min
1 h 40 min 100
1 h 40 min 100
1 h 40 min 91
1 h 40 min 100
40 min
3 h
20 min
1 h
100
100
93
68
59
74
37
69
60
44
65
65
87
92
88
9
10
11
12
13
14
15
16
Figure 1. Hydrofluorenone-containing natural products.
–
–
–
–
–
100
100
100
100
100
diterpenoids (taiwaniaquinoid B (13)),[9] Asterogynin A (14),[10]
B
(15),[10] and exiguaquinol (16).[11] Structurally related alkaloids,
kanamycin A (17)[12] and gracilamine (18),[13] could also be
easily derived from corresponding hydrofluorenone cores.
We believe that the photo-Nazarov reaction is a beneficial
supplement of the conventional Nazarov reaction. We system-
atically investigated the reaction conditions and scope of the
photo-Nazarov reaction of aryl vinyl ketones, and show here
that the photo-Nazarov cyclization reaction is generally appli-
cable to the synthesis of hydrofluorenones and polycyclic het-
eroaromatic structures that are not easily accessible by the tra-
ditional methods. We further demonstrate its utility and syn-
thetic potential with the synthesis of taiwaniaquinol B (13).[4a,9]
1.5 h
[a] All the photo reactions were run under degassed solvent. [b] Conver-
sion and yields were determined by 1H NMR spectroscopic crude analysis
using CH2Br2 as an internal standard, unless noted.
16 mgmLÀ1 gave a reasonable yield (entry 16) and allowed the
solvent to be recovered without any contamination.
As a comparison, the Nazarov cyclization of 19 under various
Lewis or Brønsted acid-promoted conditions was also explored
(see details in the Supporting Information). Unsurprisingly, we
found that the reaction requires a large excess of strong acid
(e.g., 20 equiv concentrated H2SO4 or tert-butyldimethylsilyl tri-
fluoromethanesulfonate (TBSOTf)) at high temperature (>
1008C) and that even under these conditions, the process
gives 20 in low yields (up to 48%). Such harsh conditions are
incompatible in preparation of hexahydrofluorenones, especial-
ly those with acid-sensitive groups. The photo-Nazarov reac-
tion provides effective solutions under milder conditions at
neutral or basic pH.
Results and Discussion
We began our studies by evaluating the photo-Nazarov reac-
tion of 1-cyclohexenyl p-trifluoromethylphenyl ketone (19) and
found that solvent and light source strongly affected the effi-
ciency of photo-electrocyclization (Table 1). Irradiating a solu-
tion of 19 (2.0 mgmLÀ1) in degassed acetonitrile with UV-light
at 254 nm for 3 h gave 20 in 23% yield as a single diastereo-
mer (Table 1, entry 1). This photo-Nazarov reaction occurred in
neutral solution, albeit in low yield. Although we observed no
improvement with using methanol, acetone, or ether as the
solvent (Table 1, entries 2–4), performing this reaction in di-
chloromethane, chloroform, or 1,2-dichloroethane (entries 5–7)
dramatically improved the yield of 20 with a shortened reac-
tion time. Encouraged by this result, we explored photolysis
under basic conditions by adding stoichiometric amount of
We then investigated the scope of the photo-Nazarov reac-
tion with respect to: 1) functional-group tolerance, 2) aromatic
ring compatibility, 3) cycloalkene ring size, and 4) b-substituted
groups on the enone. Under the optimized photolytic condi-
tions, we found that the photolysis tolerated substrates with
hydroxyl- (21, Table 2) and ketone (24) functional groups and
acid-sensitive protecting groups such as ketal (25), tert-butyldi-
methylsilyl ether (OTBS) (23), and even the highly acid-sensi-
tive tert- trimethylsilyl ether (OTMS) groups (22), producing
the corresponding hexahydrofluorenones in good yields. These
results provide further evidence that the photo-Nazarov reac-
tion allows effective electrocyclization of substrates containing
acid-sensitive groups. With respect to the electron density of
aromatic rings, we observed that both electron-withdrawing
(CF3À, FÀ, ClÀ) and -donating (ÀOMe) substituents on the
phenyl rings (26–34) did not affect the reaction. The desired
electrocyclized products were obtained in acceptable yield.
iPr2NH,
Et3N,
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),
N,N,N’,N’-tetramethylethylenediamine (TMEDA) to the system
(Table 1, entries 8–11). Yields were similar to those obtained
under neutral conditions. The reaction can also be done by ir-
radiating with longer wavelength (300 or 366 nm) UV-light
(Table 1, entries 12 and 13) at the expense of reaction time.
The reaction yield was improved slightly by using anhydrous
solvent (Table 1, entry 15); increasing the concentration to
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Table 2. Photo-Nazarov reaction of substrates with various of functional
Table 3. Photo-Nazarov reaction of substrates with various heteroaromat-
groups and aromatic rings.
ic and cycloalkene rings.
dent on the electron density of the aromatic rings. Aromatic
rings with electron-donating groups like ÀOMe (46 and 47),
naphthyl (49 and 50), and electron-rich heteroaromatic rings
(48, 51, and 52) facilitated electrocyclization and gave the de-
sired cyclized products in good yields. Conversely, no reaction
occurred in the presence of an electron-withdrawing group,
for example, trifluoromethyl. The major diastereomer of the
photolysis has a cis configuration, which was confirmed by the
corresponding X-ray structure of 47 (Figure 2).
Naphthyl vinyl ketones also reacted smoothly to give the de-
sired products in excellent yield (35 and 36).
To further explore the scope of the reaction, various hetero-
aromatic vinyl ketones were tested (Table 3). We were pleased
to find that substrates containing pyridine (37), quinoline (38
and 39), thiophene (40), benzothiophene (41), and indole (42)
reacted efficiently in the photolysis, yielding the corresponding
fused heteroaromatic cycles in good yields as single regioisom-
ers. Based on the obtained products, we concluded that the
regioselectivity of this photolytic electrocyclization always
occurs on the electron-rich carbons of the aromatic rings.
Changing the cyclohexenyl ring to the corresponding unsatu-
rated pyran was also applicable, and the related polycyclic
rings (43–45) were obtained in acceptable yields. The relative
stereochemistries of the hexahydrofluorenones obtained were
determined unambiguously by using X-ray crystallographic
analysis of 33, 34, and 44 (Figure 2).
Next we investigated the potential influence of different ring
size by using cyclopentenyl, cycloheptenyl, and cyclooctenyl
phenyl ketones. We found that irradiating cyclopentenyl and
cyclooctenyl phenyl ketones under the optimized photolytic
conditions failed to give the electrocyclization products under
either neutral or basic conditions. We speculate that photolytic
isomerization of the enone in the cyclopentenyl ring may be
forbidden due to ring strain, and that a medium-sized cyclooc-
tenyl ring may allow a rapid photo-isomerization equilibrium
but low reactivity. Interestingly, we found that photolysis of cy-
cloheptenyl phenyl ketones gave the desired products in a mix-
ture of two diastereomers, and the reaction was highly depen-
We next examined this photo-Nazarov reaction using vinyl
ketones, which carry a b-substituted group on the enone. After
a systematic study of properties of the substituted groups and
electronic effect of the aromatic rings (Table 4), we conclude
that irradiation of substrates with b-alkyl groups on the enone,
such as methyl group, led to their corresponding products in
good to excellent yields, whereas substrates with alkenyl or
phenyl groups showed no reactivity. We also found that the
stereo-effect of substituted groups was related to the yield of
the electrocyclization. When a b-methyl group on the enone
(54) was replaced with isopropyl (55) or cyclohexyl (56), the
yields of the photo-Nazarov decreased from 70 to 30%. Sub-
strates with a b-tert-butyl group showed no reactivity. Sub-
strates with electron-rich aromatic rings of cyclohexenyl, unsa-
turated pyran, and cycloheptenyl ketones facilitated the pho-
tolysis, whereas strong electron-withdrawing groups like tri-
fluoromethyl were inert. As a result, photolysis proceeded
much faster for substrates with electron-rich aromatic rings (À
OCH2OÀ, 53, t=0.5 h; ÀOMe, 54, t=1.5 h) than for those with
electron-deficient aromatic rings (59, t=5 h) under identical
conditions. Photolysis of naphthyl vinyl ketones yielded tetra-
cyclic rings (57, 58, 65, 66, and 68). These photolytic products
containing quaternary centers were obtained as single diaste-
reomers, in which the relative stereochemistry of 64 was con-
firmed by using X-ray crystallographic analysis (Figure 2). Nota-
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products may prove useful for synthesizing a variety
of natural products and their derivatives.
To demonstrate the practicability and reliability of
this photo-Nazarov reaction, we irradiated 19 on the
gram scale (1.5 g, 5.9 mmol) under the optimized
condition and a comparable yield (1.3 g, isolated in
88% yield) of 20 was obtained. Compound 63 could
also be prepared on a large scale (0.9 g, 0.4 mmol)
with an acceptable yield (75%) under the standard
photolytic conditions. Notably, irradiation of sub-
strates on a large scale always requires a longer reac-
tion time in a concentrated solution (see details in
the Supporting Information).
We further demonstrated the synthetic utility of
this photo-Nazarov reaction with the formal synthesis
of taiwaniaquinoids. In 2006, the group of Liang and
Trauner reported that treating 69 with a Lewis acid
(TMSOTf) at 1058C followed by desilylation gave 70
in 70% yield.[4a] We found that irradiating 69 with
light at 254 nm under neutral condition gave 70 di-
rectly in 79% yield. The NMR spectrum of 70 was
fully consistent with reported data, and it was con-
firmed by using X-ray crystallography. The formal syn-
thesis of taiwaniaquinol B (13) was completed follow-
ing the procedures reported by the group of Liang
and Trauner (Scheme 2).[4a]
Figure 2. X-ray structures of 33, 34, 44, 47, 64, and 70.
Conclusion
The photo-Nazarov cyclization of vinyl aryl ketones
proceeds under neutral or basic conditions. In con-
trast, the traditional Brønsted- or Lewis acid-promot-
ed Nazarov cyclization reactions require much harsh-
er conditions. Irradiating substrates bearing various
aromatic rings, acid-sensitive groups, cyclohexenyl,
unsaturated pyran, and cycloheptenyl with UV-light
(254 nm) smoothly yielded hexahydrofluorenones
and related structures. This photo-Nazarov reaction
could also be applicable to the substrates carrying b-
alkyl groups on the enone, which gave correspond-
ing polycyclic rings containing quaternary centers.
The photo-Nazarov reaction is particularly useful for
preparing hexahydrofluorenones and related struc-
tures. We are currently studying the asymmetric
photo-Nazarov reaction and further applications in
the related natural products synthesis.
Table 4. Photo-Nazarov reaction of b-alkyl-substituted vinyl substrates.
Acknowledgements
Financial support was provided by the NSFC
(21272076, 21102045), the Qi Ming Xing Foundation
of Shanghai Ministry of Science and Technology
bly, the structural features of these photo products are identi-
cal to the basic skeleton of taiwaniaquinols, asterogynins, and
C-nor-D-homo-steroids. Thus, these photo-electrocyclized
(14A1401400), the Program for professor of special appoint-
ment (Eastern Scholar) at Shanghai institutions of higher learn-
ing, Program for Changjiang Scholars and Innovative Research
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[7] a) J. Leitich, I. Heise, S. Werner, C. Krꢂger, K. Schaffner, J. Photochem.
Photobiol. A 1991, 57, 127–151; b) J. Leitich, I. Heise, J. Rust, K. Schaff-
ner, Eur. J. Org. Chem. 2001, 2719–2726.
[8] a) S. Gao, Q. Wang, L. Lum, C. Chen, J. Am. Chem. Soc. 2010, 132, 371–
383; b) S. Gao, Q. Wang, C. Chen, J. Am. Chem. Soc. 2009, 131, 1410–
1412; c) S. Gao, Q. Wang, G. Wang, B. Lomenick, J. Liu, C. Fan, L. Deng,
J. Huang, L. Lum, C. Chen, Synlett 2012, 23, 2298–2310; For another ex-
ample of application; see d) F. Churruca, M. Fousteris, Y. Ishikawa, M.
von Wantoch Rekowski, C. Hounsou, T. Surrey, A. Giannis, Org. Lett.
2010, 12, 2096–2099.
[9] For the synthesis of taiwaniaquinols, see: a) M. Banerjee, R. Mukhopad-
hyay, B. Achari, A. K. Banerjee, Org. Lett. 2003, 5, 3931–3933; b) E. Fil-
lion, D. Fishlock, J. Am. Chem. Soc. 2005, 127, 13144–13145; c) M. Bane-
rjee, R. Mukhopadhyay, B. Achari, A. K. Banerjee, J. Org. Chem. 2006, 71,
2787–2796; d) L. Planas, M. Mogi, H. Takita, T. Kajimoto, M. Node, J. Org.
Chem. 2006, 71, 2896–2898; e) R. M. McFadden, B. M. Stoltz, J. Am.
Chem. Soc. 2006, 128, 7738–7739; f) S. L. Li, P. Chiu, Tetrahedron Lett.
2008, 49, 1741–1744; g) S. Tang, Y. Xu, J. He, Y. He, J. Zheng, X. Pan, X.
She, Org. Lett. 2008, 10, 1855–1858; h) G. Majetich, J. M. Shimkus, Tetra-
hedron Lett. 2009, 50, 3311–3313; i) E. Alvarez-Manzaneda, R. Chah-
boun, E. Cabrera, E. Alvarez, R. Alvarez-Manzaneda, R. Meneses, H. Es-
Samti, A. Fernandez, J. Org. Chem. 2009, 74, 3384–3388; j) E. Alvarez-
Manzaneda, R. Chahboun, E. Cabrera, E. Alvarez, A. Haidour, J. M.
Ramos, R. Alvarez-Manzaneda, Y. Charrah, H. Es-Samti, Org. Biomol.
Chem. 2009, 7, 5146–5155; k) M. Node, M. Ozeki, L. Planas, M. Nakano,
H. Takita, D. Mori, S. Tamatani, T. Kajimoto, J. Org. Chem. 2010, 75, 190–
196; l) C. K. Jana, R. Scopelliti, K. Gademann, Synthesis 2010, 2223–
2232; m) C. K. Jana, R. Scopelliti, K. Gademann, Chem. Eur. J. 2010, 16,
7692–7695; n) X. Liao, L. M. Stanley, J. F. Hartwig, J. Am. Chem. Soc.
2011, 133, 2088–2091; o) E. Alvarez-Manzaneda, R. Chahboun, E. Cab-
rera, E. Alvarez, A. Haidour, J. M. Ramos, R. Alvarez-Manzaneda, M. Hma-
mouchi, H. Es-Samti, Chem. Commun. 2009, 592–594; p) E. Alvarez-
Manzaneda, R. Chahboun, E. Alvarez, R. Tapia, R. Alvarez-Manzaneda,
Chem. Commun. 2010, 46, 9244–9246; q) R. Tapia, J. J. Guardia, E. Alvar-
ez, A. Haidour, J. M. Ramos, R. Alvarez-Manzaneda, R. Chahboun, E. Al-
varez-Manzaneda, J. Org. Chem. 2012, 77, 573–584; r) J. Deng, R. Li, Y.
Luo, J. Li, S. Zhou, Y. Li, J. Hu, A. Li, Org. Lett. 2013, 15, 2022–2025.
[10] S. Cao, L. Ross, G. Tamayo, J. Clardy, Org. Lett. 2010, 12, 4661–4663.
[11] For the isolation of exiguaquinol, see: a) P. de Almeida Leone, A. R. Car-
roll, L. Towerzey, G. King, B. M. McArdle, G. Kern, S. Fisher, N. A. Hooper,
R. J. Quinn, Org. Lett. 2008, 10, 2585–2588; For the synthetic study of
exiguaquinol, see: b) G. M. Schwarzwalder, S. E. Steinhardt, H. V. Pham,
K. N. Houk, C. D. Vanderwal, Org. Lett. 2013, 15, 6014–6017.
Scheme 2. Synthesis of taiwaniaquinol B using the photo-Nazarov reaction.
Team in University (PCSIRT), and the Program for New Century
Excellent Talents in University (NCET-13-0199).
Keywords: cyclization · electrocyclic reactions · ketones ·
natural products · photochemistry · synthetic methods
[1] I. N. Nazarov, I. I. Zaretskaya, Izv. Akad. Nauk. SSSR Ser. Khim. 1941, 211–
224.
[2] For reviews of Nazarov reaction, see: a) K. L. Habermas, S. E. Denmark,
T. K. Jones, Org. React. 1994, 45, 1–158; b) C. Santelli-Rouvier, M. Santel-
li, Synthesis 1983, 429–442; c) Comprehensive Organic Synthesis, Vol. 5,
(Eds.: S. E. Denmark, B. M. Trost, I. Fleming), Pergamon, Oxford, 1991,
pp. 751; d) A. J. Frontier, C. Christina, Tetrahedron 2005, 61, 7577–7606;
e) H. Pellissier, Tetrahedron 2005, 61, 6479–6517; f) M. A. Tius, Eur. J.
Org. Chem. 2005, 2193–2206; g) N. Nakanishi, F. G. West, Curr. Opin.
Drug Discovery Dev. 2009, 12, 732; h) N. Shimada, C. Stewart, M. A. Tius,
Tetrahedron 2011, 67, 5851–5870; i) T. Vaidya, R. Eisenberg, A. J. Frontier,
ChemCatChem 2011, 3, 1531–1548.
[3] For the chemoselectivity of Nazarov reactions, see: a) T. K. Jones, S. E.
Denmark, Helv. Chim. Acta 1983, 66, 2377–2396; b) S. E. Denmark, R. C.
Klix, Tetrahedron 1988, 44, 4043–4060; c) S. E. Denmark, M. A. Wallace,
C. B. Walker, J. Org. Chem. 1990, 55, 5543–5545; d) 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; For the enantioselectivity of Nazarov reac-
tions, see: e) S. E. Denmark, M. A. Wallace, C. B. Walker, J. Org. Chem.
1990, 55, 5543–5545; f) H. Hu, D. Smith, R. E. Cramer, M. A. Tius, J. Am.
Chem. Soc. 1999, 121, 9895–9896; g) P. E. Harrington, M. A. Tius, Org.
Lett. 2000, 2, 2447–2450; h) P. E. Harrington, M. A. Tius, J. Am. Chem.
Soc. 2001, 123, 8509–8514; i) P. E. Harrington, T. Murai, C. Chu, M. A.
Tius, J. Am. Chem. Soc. 2002, 124, 10091–10100; j) V. K. Aggarwal, A. J.
Belfield, Org. Lett. 2003, 5, 5075–5078; k) G. Liang, D. Trauner, J. Am.
Chem. Soc. 2004, 126, 9544–9545; For selective examples of Lewis acid-
promoted Nazarov reactions, see: l) G. Liang, S. N. Gradl, D. Trauner,
Org. Lett. 2003, 5, 4931–4934; m) W. He, X. Sun, A. J. Frontier, J. Am.
Chem. Soc. 2003, 125, 14278–14279; n) M. Janka, W. He, A. J. Frontier,
R. Eisenberg, J. Am. Chem. Soc. 2004, 126, 6864–6865.
[4] For recent examples using Nazarov cyclization in natural products syn-
theses, see: a) G. Liang, Y. Xu, I. B. Seiple, D. Trauner, J. Am. Chem. Soc.
2006, 128, 11022–11023; b) W. He, J. Huang, X. Sun, A. J. Frontier, J.
Am. Chem. Soc. 2007, 129, 498–499; c) J. A. Malona, K. Cariou, A. J.
Frontier, J. Am. Chem. Soc. 2009, 131, 7560–7561; d) W. He, J. Huang, X.
Sun, A. J. Frontier, J. Am. Chem. Soc. 2008, 130, 300–308; e) A. P.
Marcus, A. S. Lee, R. L. Davis, D. J. Tantillo, R. Sarpong, Angew. Chem.
2008, 120, 6479–6483; Angew. Chem. Int. Ed. 2008, 47, 6379–6383;
f) W.-D. Z. Li, W.-G. Duo, C.-H. Zhuang, Org. Lett. 2011, 13, 3538–3541;
for a review of natural product synthesis using photochemical reactions
as key steps, see: g) T. Bach, J. P. Hehn, Angew. Chem. 2011, 123, 1032–
1077; Angew. Chem. Int. Ed. 2011, 50, 1000–1045.
[5] T. Suzuki, T. Ohwada, K. Shudo, J. Am. Chem. Soc. 1997, 119, 6774–6780.
[6] a) A. B. Smith III, W. C. Agosta, J. Am. Chem. Soc. 1973, 95, 1961–1968;
For related photo-Nazarov cyclization reactions, see: b) J. K. Crandall,
R. P. Haseltine, J. Am. Chem. Soc. 1968, 90, 6251–6253; c) R. Noyori, M.
Katꢁ, Tetrahedron Lett. 1968, 9, 5075–5077.
¯
[12] For the isolation of kinamycins, see: a) S. Ito¯, T. Matsuya, S. Omura, M.
¯
Otani, A. Nakagawa, J. Antibiot. 1970, 23, 315–317; b) T. Hata, S. Omura,
Y. Iwai, A. Nakagawa, M. Otani, S. Ito¯, T. Matsuya, J. Antibiot. 1971, 24,
¯
353–359; c) S. Omura, A. Nakagawa, H. Yamada, T. Hata, A. Furusake,
Chem. Pharm. Bull. 1973, 21, 931–940; d) A. Furusaki, M. Marsui, T. Wa-
¯
tanabe, S. Omura, A. Nakagawa, T. Hata, Isr. J. Chem. 1972, 10, 173–187;
e) S. J. Gould, N. Tamayo, C. R. Melville, M. C. Cone, J. Am. Chem. Soc.
1994, 116, 2207–2208; f) S. Mithani, G. Weeratunga, N. J. Taylor, G. I.
Dmitrienko, J. Am. Chem. Soc. 1994, 116, 2209–2210; For the synthetic
studies, see: g) X. Lei, J. A. Porco, J. Am. Chem. Soc. 2006, 128, 14790–
14791; h) T. Kumamoto, Y. Kitani, H. Tsuchiya, K. Yamaguchi, H. Seki, T.
Ishikawa, Tetrahedron 2007, 63, 5189–5199; i) K. C. Nicolaou, H. Li, A. L.
Nold, D. Pappo, A. Lenzen, J. Am. Chem. Soc. 2007, 129, 10356–10357;
j) C. M. Woo, L. Lu, S. L. Gholap, D. R. Smith, S. B. Herzon, J. Am. Chem.
Soc. 2010, 132, 2540–2541; k) S. S. Scully, J. A. Porco, Angew. Chem.
2011, 123, 9896–9900; Angew. Chem. Int. Ed. 2011, 50, 9722–9726; l) N.
Chen, M. B. Carriere, R. S. Laufer, N. J. Taylor, G. I. Dmitrienko, Org. Lett.
2008, 10, 381–384; m) S. S. Scully, J. A. Porco, Org. Lett. 2012, 14, 2646–
2649; n) C. M. Woo, S. L. Gholap, L. Lu, M. Kaneko, Z. Li, P. C. Ravikumar,
S. B. Herzon, J. Am. Chem. Soc. 2012, 134, 17262–17273.
˙
[13] For the isolation of gracilamine, see: a) N. ꢃnver, G. I. Kaya, Turk. J.
Chem. 2005, 29, 547–553; For the total synthesis of gracilamine, see:
b) S. Tian, W. Zi, D. Ma, Angew. Chem. 2012, 124, 10288–10291; Angew.
Chem. Int. Ed. 2012, 51, 10141–10144.
Received: February 8, 2014
Published online on June 12, 2014
Chem. Eur. J. 2014, 20, 8677 – 8681
www.chemeurj.org
8681
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