Gold-catalyzed deoxygenative Nazarov cyclization of 2,4-dien-1-als for stereoselective synthesis of highly substituted cyclopentenes

Article abstract of DOI:10.1021/ja806415t

Treatment of 2,4-dien-1-als with allylsilanes and PPh₃AuSbF ₆ (3 mol %) led to formation of 1,4-bis(allyl)cyclopentenyl products; this gold catalyst is superior to commonly used Lewis acids according to catalyst screening. Such gold-catalyzed deoxygenative cyclizations are compatible with various oxygen-, amine-, sulfur-, hydrogen-, and carbon-based nucleophiles. The value of this new catalysis is demonstrated by the diverse annulations of 2,4-dien-1-als with electron-rich alkenes and arenes, providing an easy access to complicated cyclopentenyl frameworks. Structural analysis of annulation products reveals evidence for the participation of Nazarov cyclization. This deoxygenative cyclization is extensible to a tandem intramolecular cyclization/nucleophilic addition cascade, giving polycyclic carbo- or oxacyclic compounds with controlled stereochemistry. This new gold catalysis is applied to a short synthesis of natural compounds of the brazilane family, including brazilane, O-trimethyl-, and O-tetramethyl brazilane.

Full text of DOI:10.1021/ja806415t

Published on Web 11/11/2008
Gold-Catalyzed Deoxygenative Nazarov Cyclization of
2,4-Dien-1-als for Stereoselective Synthesis of Highly
Substituted Cyclopentenes
Chung-Chang Lin,† Tse-Min Teng,† Chung-Chih Tsai,† Hsin-Yi Liao,‡ and
Rai-Shung Liu*,†
Department of Chemistry, National Tsing-Hua UniVersity, Hsinchu, Taiwan, ROC and Department of
Science Education, National Taipei UniVersity of Education, Taipei, Taiwan, ROC
Received August 13, 2008; E-mail: rsliu@mx.nthu.edu.tw
Abstract: Treatment of 2,4-dien-1-als with allylsilanes and PPh3AuSbF6 (3 mol %) led to formation of 1,4-
bis(allyl)cyclopentenyl products; this gold catalyst is superior to commonly used Lewis acids according to
catalyst screening. Such gold-catalyzed deoxygenative cyclizations are compatible with various oxygen-,
amine-, sulfur-, hydrogen-, and carbon-based nucleophiles. The value of this new catalysis is demonstrated
by the diverse annulations of 2,4-dien-1-als with electron-rich alkenes and arenes, providing an easy access
to complicated cyclopentenyl frameworks. Structural analysis of annulation products reveals evidence for
the participation of Nazarov cyclization. This deoxygenative cyclization is extensible to a tandem
intramolecular cyclization/nucleophilic addition cascade, giving polycyclic carbo- or oxacyclic compounds
with controlled stereochemistry. This new gold catalysis is applied to a short synthesis of natural compounds
of the brazilane family, including brazilane, O-trimethyl-, and O-tetramethyl brazilane.
Introduction
molecules possess doubly nucleophilic character; reported
examples are scarce.8,9
Metal-catalyzed cyclization with a nucleophile is commonly
used to construct new carbo- or heterocyclic ring with additional
functionality.1,2 Such reactions are typically implemented with
electrophilic metals to facilitate the addition of a CdX (X )
C, O, NR) or Ct C bond to π-alkynes and π-alkenes to generate
a carbocation that traps a nucleophile.3-5,6,7 Catalytic cyclization
with a sequential generation of two carbocations enables
formation of a bicyclic ring because many electron-rich
Lewis acid-catalyzed Nazarov cyclization of 1,4-dien-3-ones
provides cyclopentenones stereoselectively;10,11 its use is dem-
onstrated by application to the synthesis of several natural
(5) Addition of a CdO bond to π-alkynes: (a) Asao, N.; Aikawa, H.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458. (b) Kusama, H.;
Funami, H.; Shido, M.; Hara, Y.; Takaya, J.; Iwasawa, N. J. Am. Chem.
Soc. 2005, 127, 2709. (c) Asao, N.; Sato, K. Org. Lett. 2006, 8, 5361.
(d) Hildebrandt, D.; Hu¨ggenberg, W.; Kanthak, M.; Plo¨ger, T.; Mu¨ller,
I. M.; Dyker, G. Chem. Commun. 2006, 2260. (e) Asao, N.; Sato, K.;
Menggenbateer; Yamamoto, Y. J. Org. Chem. 2005, 70, 3682. (f) Sato,
K.; Asao, N.; Yamamoto, Y. J. Org. Chem. 2005, 70, 8977.
(6) For addition of a CdN bond to π-alkynes, see selected examples: (a)
Asao, N.; Yudha S, S.; Nogami, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 5526. (b) Kamijo, S.; Sasaki, Y.; Yamamoto, Y.
Tetrahedron Lett. 2004, 45, 35. (c) Kusama, H.; Miyashita, Y.; Takaya,
J.; Iwasawa, N. Org. Lett. 2006, 8, 289. (d) Ding, Q.; Wu, J. Org.
Lett. 2007, 9, 4959.
† National Tsing-Hua University, Hsinchu, Taiwan, ROC.
‡ National Taipei University of Education, Taipei, Taiwan, ROC.
(1) For carbocyclic frameworks, see reviews: (a) Jime´nez-Nu´n˜ez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333. (b) Hashmi, A. S. K.
Chem. ReV. 2007, 107, 3180. (c) Zhang, L.; Sun, J.; Kozmin, S. A.
AdV. Synth. Catal. 2006, 348, 2271. (d) Fu¨rstner, A.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410.
(2) For heterocyclic frameworks, see reviews: (a) Nakamura, I.; Yama-
moto, Y. Chem. ReV 2004, 104, 2127. (b) Patil, N. T.; Yamamoto, Y.
Chem. ReV. 2008, 108, 3395. (c) Gorin, D. J.; Toste, F. D. Nature
2007, 446, 395.
(7) For addition of a CdX (X ) C, O, N) bond to π-alkenes, see
examples: (a) Luzung, M. R.; Mauleo´n, P.; Toste, F. D. J. Am. Chem.
Soc. 2007, 129, 12402. (b) Piera, J.; Persson, A.; Caldentey, X.;
Ba¨ckvall, J. E. J. Am. Chem. Soc. 2007, 129, 14120. (c) Lin, G.-Y.;
Yang, C.-Y.; Liu, R.-S. J. Org. Chem. 2007, 72, 6753. (d) Zhu, J.;
Germain, A. R.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2004, 43,
1239.
(3) For addition of a Ct C bond to π-alkynes, see selected examples: (a)
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2003, 125, 11516. (b)
Trost, B. M.; Rudd, M. T. J. Am. Chem. Soc. 2005, 127, 4763. (d)
Odedra, A.; Wu, C.-J.; Pratap, T. B.; Huang, C.-W.; Ran, Y.-F.; Liu,
R.-S. J. Am. Chem. Soc. 2005, 127, 3406. (e) Chang, H.-K.; Liao,
Y.-C.; Liu, R.-S. J. Org. Chem. 2007, 72, 8139. (f) Chang, H.-K.;
Datta, S.; Das, A.; Odedra, A.; Liu, R.-S. Angew. Chem., Int. Ed. 2007,
46, 4744.
(8) Double nucleophilic additions to 1,3-dienes or 1,4-diacetyl-2-alkenes
were reported for Pd(II), Pd(0) or Ga(III) catalysts, but these examples
did not involve a cyclization of starting substrates. See: (a) Jonasson,
C.; Roon, M.; Backvall, J.-E. J. Org. Chem. 2000, 65, 2122. (b)
Verboom, R. C.; Persson, B. A.; Backvall, J.-E. J. Org. Chem. 2004,
69, 3102. (c) Nguyen, R.-V.; Li, C.-J. J. Am. Chem. Soc. 2005, 127,
17184. (d) Beniazza, R.; Dunet, J.; Robert, F.; Schenk, K.; Landais,
Y. Org. Lett. 2007, 9, 3913.
(4) For addition of a CdC bond to π-alkynes, see examples: (a) Trost,
B. M.; Brown, R. E.; Toste, F. D. J. Am. Chem. Soc. 2000, 122, 5877.
(b) Toullec, P. Y.; Genin, E.; Leseurre, L.; Geneˆt, J.-P.; Michelet, V.
Angew. Chem., Int. Ed. 2006, 45, 7427. (c) Horino, Y.; Luzung, M. R.;
Toste, F. D. J. Am. Chem. Soc. 2006, 128, 11364. (d) Amijs, C. H. M.;
Ferrer, C.; Echavarren, A. M. Chem. Commun. 2007, 698. (e) Buzas,
A. K.; Istrate, F. M.; Gagosz, F. Angew. Chem., Int. Ed. 2007, 46,
1141.
(9) For metal-catalyzed carbocyclizations with two nucleophilic additions,
see: (a) Bhunia, S.; Wang, K.-C.; Liu, R.-S. Angew. Chem., Int. Ed.
2008, 47, 5063. (b) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2007, 129, 1413. (c) Hsu, Y.-C.; Datta,
S.; Ting, C.-M.; Liu, R.-S. Org. Lett. 2008, 10, 512.
9
10.1021/ja806415t CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 16417–16423 16417

A R T I C L E S
Lin et al.
Scheme 1
Scheme 2
Scheme 3
products.12 In the course of this cyclization, the resulting
oxyallyl cation (II) can be trapped by one nucleophile to produce
a functionalized cyclopentenone, named as an interrupted
Nazarov cyclization.13,14 Nazarov cyclization of 2,4-dien-1-als
or their ketone analogues, unlike 1,4-dien-3-ones, remains
unclear.15,16 We report here an unprecedented gold-catalyzed
deoxygenative carbocyclization of 2,4-dien-1-als, which gener-
ates two allylic cations sequentially to facilitate double nucleo-
philic additions, as depicted in Schemes 1 and 2. In this process,
a loss of oxo (O2-) from 2,4-dien-1-als is accompanied by
formation of water or (R3Si)2O. Accordingly, starting 2,4-dien-
1-als are equivalent to cyclopentyl dications, which enables one-
pot synthesis of bicyclic cyclopentenyl derivatives though
versatile [3 + 2], [4 + 2], and [4 + 3]-annulations with suitable
alkenes and arenes. In this full account,17 we report the scope
of such annulations in both inter- and intramolecular systems,
Scheme 4
which clearly involve a Nazarov pathway. This new method is
applicable to one-pot synthesis of natural compounds of
brazilane family.18
(10) Reviews for Nazarov cyclization: (a) Habermas, K. L.; Denmark, S. E.;
Jones, T. K. Org. React. 1994, 45, 1. (b) Frontier, A. J.; Collison, C.
Tetrahedron 2005, 61, 7577. (c) Tius, M. A. Eur. J. Org. Chem. 2005,
2193.
Results and Discussions
(I) Carbocyclization with Addition of Two Nucleophiles.
Scheme 3 shows the substrates used in this study, including
2,4-dien-1-als (1a-1e) and electron-rich benzenes (1f-1h). For
catalyst screening, aldehyde 1d was selected in the allylation
test because its dimethyl groups impede nucleophilic addition
on an initially generated allylic cation; this steric effect allows
an easy discrimination of the catalyst activity. We screened
Lewis acids commonly used in Nazarov cyclizations.11,12 In the
presence of allylsilanes (3 equiv),19 PPh3AuCl/AgSbF6 ef-
ficiently produced the desired 1,4-diallylation product 2a in 78%
(11) (a) Occhiato, E. G.; Prandi, C.; Ferrali, A.; Guarna, A.; Venturello, P.
J. Org. Chem. 2003, 68, 9728. (b) Liang, G. X.; Gradl, S. N.; Trauner,
D. Org. Lett. 2003, 5, 4931. (c) Prandi, C.; Ferrali, A.; Guarna, A.;
Venturello, P.; Occhiato, E. G. J. Org. Chem. 2004, 69, 7705. (d)
Bee, C.; Leclerc, E.; Tius, M. Org. Lett. 2003, 5, 4927. (e) Kim, S. H.;
Cha, J. K. Synthesis 2000, 2113.
(12) (a) Harding, K. E.; Clement, K. S.; Tseng, C. Y. J. Org. Chem. 1990,
55, 4403. (b) Harrington, P. E.; Tius, M. A. J. Am. Chem. Soc. 2001,
123, 8509. (c) Brady, S. F.; Singh, M. P.; Janso, J. E.; Clardy, J. J. Am.
Chem. Soc. 2000, 122, 2116. (d) Srikrishna, A.; Dethe, D. H. Org.
Lett. 2003, 5, 2295. (e) He, W.; Sun, X. F.; Frontier, A. J. J. Am.
Chem. Soc. 2008, 130, 1814. (f) Tius, M. A.; Drake, D. J. Tetrahedron
1996, 52, 14651. (g) Nakazaki, A.; Sharma, U.; Tius, M. A. Org. Lett.
2002, 4, 3363. (h) Crisp, G. T.; Scott, W. J.; Stille, J. K. J. Am. Chem.
Soc. 1984, 106, 7500.
·
yield in CH2Cl2 (23 °C Scheme 4). AgSbF6, AuCl3, BF3 Et2O
and other catalysts including AuCl, HOTf, Me3SiOTf, PtCl2,
and PdCl2(CH3CN)2 were ineffective because of either competi-
tive cycloisomerization products c1-c3, or unreacted 1d (see
Table S1, Supporting Information). Attempts to alter the
chemoselectivty of HOTf and Me3SiOTf in cold CH2Cl2 (-20
°C, 24 h) were unsuccessful. Polar DMSO and DMF solvents
completely inhibited the nucleophilic cyclization or cycloi-
somerization for both PPh3AuCl/AgSbF6 and BF3 ·Et2O.20
The dicationic character of 2,4-dien-1-al 1b is reflected by
its compatibility with oxygen, sulfur-, and amine-based nucleo-
(13) Intermolecular interrupted Nazarov reactions: (a) Giese, S.; Kastrup,
L.; Stiens, D.; West, F. G. Angew. Chem., Int. Ed. 2000, 39, 1970.
(b) Song, D.; Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129,
12019. (c) Rieder, C. J.; Fradette, R. J.; West, F. G. Chem. Commun.
2008, 1572.
(14) Intramolecular interrupted Nazarov reactions: (a) Bender, J. A.; Arif,
A. M.; West, F. G. J. Am. Chem. Soc. 1999, 121, 7443. (b) Browder,
C. C.; Marmsa¨ter, F. P.; West, F. G. Org. Lett. 2001, 3, 3033. (c)
Bender, J. A.; Bliz, A. E.; Browder, C. C.; Giese, S.; West, F. G. J.
Org. Chem. 1998, 63, 2430. (d) Nair, V.; Bindu, S.; Sreekumar, V.;
Chiaroni, A. Org. Lett. 2002, 4, 2821.
(15) Cycloisomerization of cis-2,4-dien-1-als with hard Lewis acids gave
2-cyclopentenone products exclusively,16a which could not verify
Nazarov pathway. Although we obtained 3-cyclopentenone efficiently
using PtCl2, structural analysis of products excluded the participation
of Nazarov cyclization.16b In this study, we obtain evidence for
Nazarov cyclization for one class of annulation using cationic gold
catalyst (Table 2 and Scheme 10). Since the other cyclizations share
the same initial step, Nazarov cyclization is likely involved therein.
(16) (a) Miller, A. K.; Banghart, M. R.; Beaudry, C. M.; Suh, J. M.; Trauner,
D. Tetrahedron 2003, 59, 8919. (b) Lo, C.-Y.; Lin, C.-C.; Cheng,
H.-M.; Liu, R.-S. Org. Lett. 2006, 8, 3153.
(18) (a) Huang, Y.; Zhang, J.; Pettus, T. R. R. Org. Lett. 2005, 7, 5841.
(b) Chatterjea, J. N.; Robinson, R.; Tomlinson, M. L. Tetrahedron
1974, 30, 507. (c) Xu, J.; Yadan, J. C. Tetrahedron Lett. 1996, 37,
2421.
(19) Treatment of allylSiMe3 and PPh3AuSbF6 did not generate
PPh3Au(allyl) species through an allyl exchange; see ref 9c.
(20) We also screened catalyst activities for the cyclization of 2,4-dien-1-
al 1d with methanol; only PPh3AuCl/AgSbF6 (3 mol %) gave 1,4-
dimethoxycyclopentyl product in satisfactory yield (88%) among these
acidic catalysts. For detailed information, see Table S2 in Supporting
Information.
(17) Preliminary communication of this work: Lin, C.-C.; Teng, T.-M.;
Odedra, A.; Liu, R.-S. J. Am. Chem. Soc. 2007, 129, 3798.
9
16418 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Gold-Catalyzed Deoxygenative Nazarov Cyclization
A R T I C L E S
Scheme 5
Scheme 7
Table 1. Gold-Catalyzed [4 + 3]-Annulation of cis-2,4-Diene-1-als
with 2-Substituted Allylsilanes
Scheme 6
philes using PPh3AuCl/AgSbF6 (3 mol %) in CH2Cl2 (25 °C,
20-30 min), giving 1,4-difunctionalized cyclopentyl products
2b-2d in 76-86% yields (Scheme 5). This carbocyclization
is also applicable to Et3SiH and allylSiMe3, generating two C-H
and C-C bonds regioselectively in the newly cyclized cyclo-
pentyl products 2e and 2f (>67% yields). Satisfactory diaster-
eomeric ratios (dr >6.3) were obtained for its methoxy and
tosylamide adducts 2b and 2c through thermodynamic control.
We envisage that the C-O and C-N bonds of products 2b
and 2c are reversibly cleaved and formed in the presence of
PPh3AuSbF6. Benzaldehyde 1g likewise undergoes gold-
catalyzed carbocyclization with the same nucleophiles, giving
difunctionalized indanyl derivatives 3a-3d with yields exceed-
ing 65% except bisallyl Indane 3e (52%). Additional examples
for nucleophilic carbocyclizations of 2,4-dien-1-als 1a-1e and
benzaldehydes 1f and 1h are provided in Supporting Information
(Table S3).
a [Substrate] ) 0.01 M in CH2Cl2, silane (1.1 equiv), AuClPPh3/
AgSbF6 (4 mol %), 25 °C, 1 h. b Products are reported after separation
on a silica column. c Silane (2.5 equiv) was used.
Scheme 6 shows an asymmetric double allylation of 2,4-dien-
1-al 1d with allylsilane (3 equiv) catalyzed by (R-binap)Au2Cl2/
AgSbF6 (5/10 mol %) in CH2Cl2 at 28 °C; desired product 2a
was obtained in 82% yield with 73% ee. A lower temperature
(15 °C) increased the ee up to 99%. On the basis of this
observation, we propose a mechanism involving a transfer of
the chirality from initial species A to the remaining intermediates
B-E, as depicted in Scheme 7. The chiral gold catalyst likely
catalyzes an enantioselective cyclization to give allylic cation
A bearing a chiral CH(OAuL) substituent. An addition of
allylsilane to species A proceeds from the less hindered face to
form intermediate B with the trans-configuration. We envisage
that the olefin-coordinated Me3Si+ undergoes metal exchange
with OAuL to give species C bearing a siloxy group. The
released AuL+ catalyzes ionization of species C to regenerate
allylic cation D bearing a chiral allyl, which ultimately gives
species E and final product 2a after a second allylation.
(II) [4 + 3], [3 + 2], and [4 + 2]-Annulations with
Electron-Rich Alkenes and Arenes. This use of this new gold
catalysis is widespread because of the diversity of annulations
of these aldehydes with suitable alkenes and arenes, forming
complicated polycyclic frameworks. Table 1 summarizes the
results for gold-catalyzed annulations of aldehydes 1a-1d and
1f-1g with 2-substituted allylsilanes (1.0 equiv); the concentra-
tion was maintained at 1.0 × 10-2 M to minimize undesired
double allylation products. NMR spectra indicated the resulting
products 4a-4d and 5a-5f to bear [4 + 3] annulated
frameworks. The structures of annulated products 4c and 5f were
determined by H NOE spectra. Aldehydes 5e appears to be
more stable than the other diastereomer as it remains as the
dominant species upon heating with Et3N (10 mol%) in THF.
Notably, treatment of 2,4-dien-1-al (1b) with 2-siloxymethyla-
llylsilane and this gold catalyst gave oxacyclic compound 4e
in 61% yield, resulting from a [4 + 2]-annulation.
Scheme 8 rationalizes the stereochemistry of annulated
products 4c and 4d, which arise from the addition of allylsilane
to the first allylic cation A′ from the less hindered face, giving
intermediate C′. After gold-catalyzed ionization, the second
allylic cation D′ undergoes a facile intramolecular cyclization
to give tertiary carbocation F, ultimately delivering observed
products 4c and 4d. To rationalize the stereochemistry of
aldehydes 5e and 5f, we propose that stereocontrol of this
21
1
1
(21) The structures of key products were determined by H NOE spectra,
which are provided in Supporting Information.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16419

A R T I C L E S
Lin et al.
Scheme 8
Table 2. Gold-Catalyzed [3 + 2]-Annulation of 2,4-Diene-1-als with
Alkenes
pinacol-type rearrangement22 stems from a 1,2-hydride shift
along the axial position to give oxonium cation G bearing an
equatorial aldehyde.23
Under the same conditions, gold-catalyzed annulations of
aldehydes 1a and 1b with electron-rich alkenes formed reor-
ganized tricyclic tetrahydrofurans 6a-6f; their [3 + 2]-annulated
frameworks were confirmed by their NMR and high-resolution
mass spectra. We isolated [4 + 3]-annulated compounds 4b,
4c, 4f, and 4g in minor proportions.24 As shown in Table 2,
these annulations work for various 2-arylpropene (Ar ) Ph,
4-MeOC6H4, 3-thienyl), giving annulated products 6a-6e in
56-81% yields. We obtained satisfactory dr values (dr ) 7
and 20) for 2-thienylfuran 6e and 6f respectively; the stereo-
a [Substrate] ) 0.03 M in DCM, Nu-E (1.1 equiv), 4 mol %
AuClPPh3/AgSbF6, 20 °C, 1 h. b Products are reported after separation
on a silica column. c This structure represents the major diastereomer,
and the minor isomer arises from the different stereochemistry at the C*
carbon.
Scheme 9
(22) (a) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003, 68, 7143.
(b) Kirsch, S. F.; Binder, J. T.; Crone, B.; Duschek, A.; Haug, T. T.;
Lie´bert, C.; Menz, H. Angew. Chem., Int. Ed. 2007, 46, 2310. (c)
Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398. (d) Nicolaou,
K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006,
45, 7134.
(23) Formation of the [4 + 2]-annulated product 4e from cis-dienal is
proposed to follow the mechanism below. The key step involves an
metal exchange between allylic cation and 2-siloxymethylallylsilane
to give cation A′′ and Au(I)-alkoxy species. This Au(I)-alkoxy
species is highly nucleophilic to undergo nucleophilic addition to form
species C′′, and ultimately forms observed cycloadduct 4e.
21
1
chemistry of 6f was elucidated by H NOE spectra. Gold-
catalyzed annulation of 2,4-dien-1-al (1b) with 2,3-dimethylb-
utadiene similarly gave highly substituted tetrahydrofuran
compound 6f as a single isomer (37% yield).
To elucidate the formation mechanism of tricyclic tetrahe-
drofuran 6b, we prepared 18O-labeled 2,4-dien-1-al (1b) (66%
18O content, Scheme 9). In the presence of water (1 equiv), the
resulting 6b has the furan oxygen containg a ca. 50% 18O content
according to its mass spectra,25 which indicates that the aldehyde
of starting 1b serves as the primary source of oxygen. Accord-
ingly, we propose a mechanism in Scheme 10, involving an
initial Nazarov cyclization of gold-coordinated aldehyde H,
which undergoes a conrotatory cyclization to give allylic cation
I bearing an OAuL substituent trans to its butyl group. Addition
of olefin to cation I from the less hindered face generates
trisubstituted cyclopentenyl species J, with its tertiary cation
subject to an attack of the tethered O-AuL terminus to furnish
oxacyclic intermediate K. A subsequent gold-catalyzed 1,3-
oxygen shift of species K gives desired products 6b and 6d-f
via formation of intermediate L. Control of the diastereoselec-
tivity of this reaction stems from the less hindered orientation
of PhMeC+ of species J relative to its OAuL fragment that is
favored on the same side as the CH(nBu) group. The lack of
diastereoselectivity of compounds 6b and 6d (Ar ) Ph,
(24) The annulated compounds 4b, 4c, 4f, and 4g were obtained as minor
products according to the mechanism below.
(25) The complete mass spectra of 18O-enriched 1b and 6b are provided
in Supporting Information.
9
16420 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Gold-Catalyzed Deoxygenative Nazarov Cyclization
A R T I C L E S
Table 4. [4 + 2]-Annulation with 3-Hydromethyl Heteroarenes
Scheme 10
Table 3. [3 + 2]-Annulation of 2,4-Diene-1-als with Phenols,
Substituted Allylic Alcohols, and Propargyl Alcohols
a [Substrate] ) 0.03 M in CH2Cl2, arenes (1.1 equiv), 4 mol %
AuClPPh3/AgSbF6, 20 °C, 1 h. b Products are reported after separation
on a silica column.
allylic alcohols, as depicted in entries 7-12, the regiochemistry
in such annulations is distinct from those of phenol and
1-naphthol.
We obtained good yields (65-83%) of oxacyclic products
8a-8f, of which the CH and quaternary carbons of the
cyclopentenyl ring, respectively, are liked to the oxygen and
carbon atoms of allylic alcohols. 3-Phenylprop-2-yn-1-ol (2
equiv) requires two molecules to give desired products 8g and
8h in 68 and 52% yields respectively; the C- and O-linkage
modes resembles those adducts derived from allylic alcohols.
The new [4 + 2] annulations, presented in Table 4, show the
versatility of this gold catalysis. There are two distinct annu-
lations for 2,4-dien-1-als 1a and 1b with 3-hydromethyl
heteroarenes, which provide tricyclic pyran products 9a-9f and
10a-10c with satisfactory yields in most cases. For furan,
thiophene, and benzofuran bearing a 3-hydroxymethyl substitu-
ent, the resulting [4 + 2] annulated products 9a-9f are similar
to allylic alcohol products 8a-8h in the O- and C-linkage modes
whereas products 10a-10c generated from benzothiophene and
indole resemble phenol adducts 7a and 7f in the linkage mode.
We prepared 2,4-dien-1-al 1b bearing a 10% 13C content at
its aldehyde; the resulting product 7b contained equal 13C-
content (ca. 5%) at its CHC6H4 and dCH carbons. As depicted
in Scheme 11, treatment of 1,4-diphenoxycyclopentyl compound
2m with PPh3AuCl/AgSbF6 (5 mol %) delivered desired [3 +
2]-annulated product 7a. This 13C-labeling result indicates that
the phenol annulation involves an initial formation of a 1,4-
addition product 2m, which subsequently forms [4 + 3]-annu-
lated intermediate O, followed by a 1,3-oxygen migration,
ultimately giving observed product 7a.
a [Substrate] ) 0.01 M in DCM, alcohols (1.1 equiv), 4 mol %
AuClPPh3/AgSbF6, 20 °C, 1 h. b Products are reported after separation
on a silica column. c This structure represents the major diastereomer,
and the minor isomer arises from the different stereochemistry at the C*
carbon.
4-MeOC6H4) resulted from the facile formation of cation M to
induce epimerization. Structural analysis of these tricyclic
tetrahydrofuran products provides evidence for the participation
of Nazarov cyclization.
The value of this new gold catalysis is also manifested by
the regio- and stereocontrolled [3 + 2]-annulation of 2,4-dien-
1-als 1a-1c with phenols, substituted allylic alcohols and
2-alkyn-1-ol catalyzed by PPh3AuCl/AgSbF6 (4 mol %) in
CH2Cl2 (25 °C, 1 h). In Table 3 (entries 1-6), 13C NMR analysis
of oxacyclic products 7a-7f indicates that phenol and 1-naph-
thol are annulated with substrates through the oxygen and carbon
atoms, respectively, linked to the quaternary carbons and CH
of the cyclopentenyl ring. Although we observed equally
efficiently stereocontrolled annulations with 2- and 3-substituted
Table 5 shows the feasibility of dialkoxylated carbocyclization
of 2,4-dien-1-als 1a-1b with diol-based nucleophiles. In the
case of phenylboric acid and trichloroacetaldehyde hydrate, we
obtained their annulated products 11a-11d in good yields. We
were unable to determine the stereochemistry of the major
1
isomers of species 11c and 11d with H NOE spectra because
of severe overlap of key proton signals. With this gold catalysis,
we also obtained annulated compounds 11e-11f from ethandiol
in 83-86% yields.
9
J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16421

A R T I C L E S
Lin et al.
Scheme 11
Table 6. Gold-Catalyzed Intramolecular Carbocycliztion of
2,4-Diene-1-als with One External Nucleophile
Table 5. Annulation of cis-2,4-Dien-1-als with Diol Derivatives
a [Substrate] ) 0.03 M in DCM, Nu-E (1.1 equiv), 4 mol %
AuClPPh3/AgSbF6, 25 °C, 1 h. b Products are reported after separation
on a silica column.
Table 7. Intramolecular Heterocyclization of cis-2,3-Diene-1-als
with External Nucleophiles
a [Substrate] ) 0.05 M in CH2Cl2, Nu-E (1.1 equiv), 4 mol %
AuClPPh3/AgSbF6, 25 °C, 1 h. b Products are reported after separation
on a silica column.
Scheme 12
a [Substrate] ) 0.03 M in CH2Cl2, Nu-H (1.5 equiv), 4 mol %
AuClPPh3/AgSbF6, 25 °C, 1 h. b Products are reported after separation
on a silica column.
favoring an anti-configuration (anti/syn > 4). The structure of
21
1
compound 13c was confirmed with H NOE NMR spectra.
Stimulated by this stereocontrolled intramolecular carbocy-
clization, we prepared aldehyde substrates 12b-12d tethered
with a furan, thiophene or pyrrole. Deoxygenative carbocy-
clizations of these aldehydes with suitable nucleophiles generate
products in yields >65%. Gratifyingly, we obtained only anti-
isomeric products 13d-13k bearing three stereocenters, but the
use of allylSiMe3 gave no clean reaction (Table 6). This gold-
catalyzed carbocyclization is applicable to benzaldehyde sub-
strate 12e, which underwent cyclization with HSiEt3, allylSiMe3,
and MeOH to afford corresponding products 13l-13n in
78-82% yields (anti/syn dr ) 3-20).
(III) Intramolecular Cyclization with an External Nucleo-
phile. Additional new polycyclic frameworks are available from
intramolecular cyclizations of 2,4-dien-1-al 12a, followed by
single nucleophilic additions; representative examples appear
in Scheme 12. The cyclization chemoselectivity is controlled
by a prior attack of tethered phenoxy on the first allylic cation
Q, followed by external nucleophilic addition of allylSiMe3,
H-SiEt3 and MeOH on the second allylic cation S. The resulting
carbocyclic compounds 13a-13c are stereochemically defined,
9
16422 J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008

Gold-Catalyzed Deoxygenative Nazarov Cyclization
A R T I C L E S
Scheme 13
Table 7 shows one-pot construction of complex oxacyclic
frameworks based on intramolecular carbocyclizations. For 2,4-
dien-1-als 14a and 14b comprising a tethered alcohol, MeOH
and tosylamine are superior to other nucleophiles in the
cyclization efficiency and chemoselectivity; resulting products
15a-15d were obtained only as trans-isomers in 78-84%
yields. Benzaldehyde substrates 14c-14d maintained the same
cyclization efficiencies with MeOH and tosylamine, giving
desired oxacyclic products 15e-15h in 67-82% yields, in favor
of anti-isomer (dr ) 2-20).
(IV) Synthesis of Brazilanes. With these complicated frame-
works in hand, we accentuate their synthetic worth with a short
synthesis of natural compounds of the brazilane family,18
including brazilane, O-trimethyl- and O-tetramethyl brazilane,
as depicted in Scheme 13. The tethered 3,4-dimethoxybenzene
of starting aldehydes 16a-16c did not diminish the Lewis
acidity herein; we obtained desired compound 17a, and O-
trimethyl- and O-tetramethyl brazilanes 18b and 18c in 57-63%
yields. Conversion of 17a to brazilane 18a was achieved in 84%
yield with BBr3 (3.5 equiv) in CH2Cl2 (25 °C).
philic addition. We reported here the deoxygenative Nazarov
cyclization of 2,4-dien-1-als, to accommodate double additions
with oxygen-, amine-, sulfur-, hydrogen-, and carbon-based
nucleophiles. The important development of this catalysis is the
versatility of annulation modes with arene- and alkene-based
nucleophiles, which provide one-pot construction of complicated
cyclopentenyl frameworks with stereochemical control. The
structural analysis of some annulated products provides evidence
for the participation of Nazarov cyclization. This new gold
catalysis is applicable to a tandem intramolecular cyclization/
nucleophilic addition cascade, giving polycyclic carbo- and
oxacyclic compounds with controlled stereochemistry. We
applied this method to a short synthesis of natural compounds
of the brazilane family.
Acknowledgment. We thank the National Science Council,
Taiwan for support of this work.
Supporting Information Available: Tables S1-S3, experi-
mental procedures for synthesis of cis-2,4-dien-1-al substrates
and catalytic operations, NMR spectra, and spectral data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Conclusions
Before this work, metal-catalyzed interrupted Nazarov cy-
clization of 1,4-dien-3-ones was limited strictly to one nucleo-
JA806415T
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J. AM. CHEM. SOC. VOL. 130, NO. 48, 2008 16423