Au-catalyzed cyclization of monoallylic diols

Article abstract of DOI:10.1021/ol703002p

The Ph₃PAuCl/AgOTf-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is reported. The reactions proceed rapidly at temperatures as low as -78° C with catalyst loadings as low as 0.1 mol % to provide the products in 79-99% yield. A broad range of structurally diverse substrates perform well in the reaction. When 2,6-disubstituted tetrahydropyrans are produced, the reaction is highly diastereoselective for the 2,6-cis product.

Full text of DOI:10.1021/ol703002p

ORGANIC
LETTERS
2008
Vol. 10, No. 4
669-671
Au-Catalyzed Cyclization of Monoallylic
Diols
Aaron Aponick,* Chuan-Ying Li, and Berenger Biannic
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
aponick@chem.ufl.edu
Received December 13, 2007
ABSTRACT
The Ph3PAuCl/AgOTf-catalyzed cyclization of monoallylic diols to form tetrahydropyrans is reported. The reactions proceed rapidly at temperatures
as low as 78 C with catalyst loadings as low as 0.1 mol % to provide the products in 79 99% yield. A broad range of structurally diverse
−
°
−
substrates perform well in the reaction. When 2,6-disubstituted tetrahydropyrans are produced, the reaction is highly diastereoselective for
the 2,6-cis product.
The use of gold complexes as catalysts has emerged as a
powerful synthetic method for the formation of C-C and
C-X bonds, characterized by high turnover numbers and
turnover frequencies under mild conditions.1 The reactions
are typically based on the activation of π-bonds, and as such,
a majority of reports involve the use of alkynes or allenes1
and to a lesser extent isolated olefins, although these reactions
usually require higher temperatures and longer reaction
times.2 The utility of this method could be greatly expanded
if new reactions could be developed that employ functional
groups not traditionally used. As part of a program aimed at
expanding the scope of functional groups used in Au-
catalyzed reactions, we began to explore the formation of
tetrahydropyrans.
Saturated oxygen heterocycles are a common structural
feature found in a broad array of natural products and have
therefore been the subject of intense study.3 Tetrahydropy-
rans, in particular, are frequently observed in synthetic targets
that attract significant attention due to their promising
biological activities. Selected examples include spiras-
trellolide A,4a SCH 351448,4b psymberin,4c,d sorangicin A,4e
the bryostatins,4f and the brevetoxins.4g,h Among the strategies
developed for preparing tetrahydropyrans,5 the Au-catalyzed
hydroalkoxylation of allenes (1 f 2, Scheme 1) has recently
been reported as a mild, efficient, and atom-economic
approach.6,7 We envisioned a different strategy that also relies
(3) For reviews on the synthesis of marine natural products, see: (a)
Morris, J. C.; Nicholas, G. M.; Phillips, A. J. Nat. Prod. Rep. 2007, 24, 87.
(b) Yeung, K.-S.; Paterson, I. Chem. ReV. 2005, 105, 4237 and references
cites therein.
(1) For recent reviews on homogeneous Au-catalyzed reactions, see: (a)
Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (b) Gorin, D. J.; Toste, F.
D. Nature 2007, 446, 395. (c) Hashmi, A. S. K. Catal. Today 2007, 122
(3-4), 211. (d) Jimenez-Nunez, E.; Echavarren, A. M. Chem. Commun.
2007, 333. (e) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed.
2006, 45, 7896. (f) Hoffman-Roder, A.; Krause, N. Org. Biomol. Chem.
2005, 3, 387.
(2) For leading references on Au-catalyzed reactions of isolated alkenes,
see: (a) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128, 1798.
(b) Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747.
(c) Bender, C. F.; Widenhoefer, R. A. Chem. Commun. 2006, 4143. (d)
Liu, X.-Y.; Li, C.-H.; Che, C.-M. Org. Lett. 2006, 8, 2707. (e) Bender, C.
F.; Widenhoefer, R. A. Org. Lett. 2006, 8, 5303. (f) Zhang, X.; Corma, A.
Chem. Commun. 2007, 3080. (g) Yang, C.-G.; He, C. J. Am. Chem. Soc.
2005, 127, 6966 and references cited therein.
(4) (a) Williams, D. D.; Roberge, M.; Van Soest, R.; Anderson, R. J. J.
Am. Chem. Soc. 2003, 125, 5296. (b) Hegde, V. R.; Puar, M. S.; Dai, P.;
Patel, M.; Gullo, V. P.; Das, P. R.; Bond, R. W.; McPhail, A. T. Tetrahedron
Lett. 2000, 41, 1351. (c) Cichewicz, R. H.; Valeriote, F. A.; Crews, P. Org.
Lett. 2004, 6, 1951. (d) Pettit, G. R.; Xu, J. P.; Chapuis, J. C.; Pettit, R. K.;
Tackett, L. P.; Doubek, D. L.; Hooper, J. N. A.; Schmidt, J. M. J. Med.
Chem. 2004, 47, 1149. (e) Jansen, R.; Wray, V.; Irschik, H.; Reichenbach,
H.; Hofle, G. Tetrahedron Lett. 1985, 26, 6031. (f) For a recent review,
see: Hale, K. J.; Hummersone, M. G.; Manaviazar, S.; Frigerio, M. Nat.
Prod. Rep. 2002, 19, 413. (g) For recent reviews, see: Nakata, T. Chem.
ReV. 2005, 105, 4314. (h) Inoue, M. Chem. ReV. 2005, 105, 4379.
(5) For leading references, see: (a) Clarke, P. A.; Santos, S. Eur. J. Org.
Chem. 2006, 2045. (b) Boivin, T. L. B. Tetrahedron 1987, 43, 3309 and
referenced cited therein.
10.1021/ol703002p CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/25/2008

41% yield, there was no conversion employing Ph3PAuCl
without AgOTf. Additional control experiments (entries 7-9)
provide evidence that in the presence of silver salts or
potentially TfOH,1c,10 the cationic gold(I) complex is the
catalytically active species.
Scheme 1. Allylic Alcohols in Au-Catalyzed Cyclizations
Using the conditions from entry 4 of Table 1, the reaction
of substituted diols was investigated to determine substrate
scope (Table 2). In general, the reactions are rapid and high
yielding at room temperature. Substituting C-7 (entry 2) gives
rise to the 2,6-disubstituted product 9 which was obtained
in 95% yield and 11:1 dr, favoring the cis diastereomer.
The ratio could be improved to >25:1 by reducing the
temperature to -50 °C (entry 3). Additional experiments
focused on obtaining potentially useful synthons (entries
6-13). When the aldol adduct 12 was subjected to the
standard conditions, 13 was obtained in high yield with-
out any elimination product. Surprisingly, this substrate
failed to react at -50 °C, but a 12:1 dr was obtained at
-10 °C (entry 7). The reaction was also attempted with
AuCl3 but was found to require extremely long reaction times
(entry 8), making Ph3PAuCl/AgOTf the preferred catalyst
system.
Further studies were designed to test the effects of
substitution on the allylic alcohol moiety. Interestingly, when
cis-olefin 18 was subjected to the standard conditions, the
trans product 5 was isolated (entry 14) with similar yield
and reaction time to 4. Tertiary allylic alcohols also
performed quite well, providing the trisubstituted olefin 20
in 91% yield (entry 15). This substrate was then used to test
the lower limit of the catalyst loading. We were pleased to
on Au catalysis but instead involves the cyclization of allylic
diols (3 f2, Scheme 1). Both Bronsted and Lewis acid
catalyzed nucleophilic substitution of allylic alcohols have
previously been reported.8 The reactions usually require
strongly acidic conditions8a-c or, in the case of late transition
metal catalysts, high temperatures or further addition of
promoters.8m Intramolecular Pd-catalyzed cyclizations are
known, but limited examples demonstrating substrate scope
and relatively high catalyst loadings are reported.8i-l
The development of a catalytic system with the beneficial
aspects of homogeneous gold catalysis is highly desirable.
Additionally, the potential advantages of using an allylic
alcohol in place of an allene include ease of preparation,
elimination of the possible endo cyclization pathway, and
the potential to form a quaternary carbon by addition to a
tri- or tetrasubstituted olefin. Herein, we report that monoal-
lylic diols are highly reactive substrates, forming tetrahy-
dropyrans in high yield with high diastereoselectivity by the
action of cationic gold(I) complexes.
The desired cyclization was envisioned to proceed by an
SN2′ or cationic mechanism and initial experiments employed
AuCl3 since gold(III) salts are known to be somewhat more
oxophilic than gold(I).9 Gratifyingly, treatment of diol 4 with
as low as 1 mol % AuCl3 cleanly provided the cyclized
product 5 in excellent yield (Table 1, entries 1 and 2). Using
(6) (a) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Qian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066. (b) Zhang, Z.; Widenhoefer, R.
A. Angew. Chem., Int. Ed. 2007, 46, 283. (c) Hamilton, G. L.; Kang, E. J.;
Mba, M.; Toste, F. D. Science 2007, 317, 496. (d) Zhang, Z.; Bender, C.
F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2007, 129, 14148.
(7) Au-catalyzed heterocycle formation by hydration of homopropargylic
ethers with subsequent elimination and Michael addition to the resultant
R,â-unsaturated ketone has also been reported: (a) Jung, H. H.; Floreancig,
P. E. Org. Lett. 2006, 8, 1949. (b) Jung, H. H.; Floreancig, P. E. J. Org.
Chem. 2007, 72, 7359.
Table 1. Optimization and Control Experiments
(8) For leading references involving Brønsted acids, see: (a) Bras, J.
L.; Muzart, J. Tetrahedron 2007, 63, 7942. (b) Sanz, R.; Mart´ınez, A.;
Miguel, D.; AÄ lvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. AdV. Synth. Catal. 2006,
348, 1841. (c) Young, J.-J.; Jung, L.-J.; Cheng, K.-M. Tetrahedron Lett.
2000, 41, 3415. Pd-intermolecular: (d) Muzart, J. Eur. J. Org. Chem. 2007,
3077. (e) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
(f) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 4592. (g) Kayaki, Y.; Koda, T.; Ikariya, T. J. Org. Chem. 2004,
69, 2595. (h) Ozawa, F.; Okamoto, H.; Kawagishi, S.; Yamamoto, S.;
Minami, T.; Yoshifuji, M. J. Am. Chem. Soc. 2002, 124, 10968. Pd-
intramolecular: (i) Kawai, N.; Lagrange, J.-M.; Ohmi, M.; Uenishi, J. J.
Org. Chem. 2006, 71, 4530. (j) Uenishi, J.; Ohmi, M.; Ueda, A.
Tetrahedron: Asymmetry 2005, 16, 1299. (k) Miyazawa, M.; Hirose, Y.;
Narantsetseg, M.; Yokoyama, H.; Yamaguchi, S.; Hirai, Y. Tetrahedron
Lett. 2004, 45, 2883. (l) Yokoyama, H.; Otaya, K.; Kobayashi, H.;
Miyazawa, M.; Yamaguchi, S.; Hirai Y. Org. Lett. 2000, 2, 2427. Other
metals: (m) Qin, H.; Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2007, 46, 409. (n) Guo, S.; Song, F.; Liu, Y. Synlett 2007,
964. (o) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed. 2006,
45, 793. (p) Nay, B.; Collet, M.; Lebon, M.; Cheze, C.; Vercauteren, J.
Tetrahedron Lett. 2002, 43, 2675.
entry
catalyst
AuCl3
loading (mol %)
time
yield (%)
1
2
3
4
5a
6
7
2
1
5
1
1
5
5
5
1
30 min
100 min
20 min
40 min
16 h
16 h
16 h
48 h
40 min
96
87
91
96
41
0
0
0
9
AuCl3
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
AuCl
Ph3PAuCl
AgOTf
8
9b
AgCl
TfOH
a 49% diol 4 recovered. b 46% diol 4 recovered.
(9) (a) Reich, N. W.; Yang, C.-G.; Shi, Z.; He, C. Synlett 2006, 1278.
(b) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005,
127, 10500.
(10) For reports on reactions employing TfOH in comparison to metal
triflates, see: (a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N.
W.; He, C. Org. Lett. 2006, 8, 4175. (b) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett. 2006, 8, 4179
and references cited therein.
Ph3PAuCl/AgOTf (entries 3 and 4), tetrahydropyran 5 was
isolated in greater than 90% yield, and this catalyst system
was deemed optimal vide infra. While AuCl provided 5 in
670
Org. Lett., Vol. 10, No. 4, 2008

highly substituted olefins are also tolerated. Reaction of 21
cleanly provided 22, demonstrating that sterically demanding
2,2,6,6-tetrasubstituted tetrahydropyrans can efficiently be
formed (entry 17). To the best of our knowledge, no
examples of Au-catalyzed exo-hydroalkoxylations of 3,3-
disubstituted allenes to yield quaternary centers have been
reported to date.
Table 2. Reaction Scope
Several mechanistic scenarios are possible. Considering
the fact that the trans-olefin 5 was obtained from the cis-
allylic alcohol 18, the possibility of forming an allyl cation
followed by cyclization of the pendent hydroxyl group
seemed likely. To test this hypothesis, compounds 23 and
24 were prepared, both of which would be predicted to yield
the same cationic intermediate and product. When 23 was
treated under the standard conditions, complete conversion
to 2-vinyltetrahydropyran was effected in 20 min.11 Diol 24
failed to react under both standard conditions or more forcing
conditions with up to 5 mol % Ph3PAuCl/AgOTf, temper-
atures up to 83 °C (DCE), or with AuCl3. This disparity
seems to rule out a cationic mechanism.
These data are consistent, however, with a mechanism that
proceeds by an SN2′ pathway with gold(I) activating the
allylic alcohol by coordination to the oxygen. What remains
unclear is if the metal instead coordinates the olefin, which
then undergoes hydroxyauration followed by elimination of
Ph3PAuOH to provide the product.
In summary, a highly efficient Au-catalyzed cyclization
of monoallylic diols has been reported. The reaction tolerates
a structurally diverse set of substrates and generates 2-vi-
nyltetrahydropyrans in high yield with high diastereoselec-
tivity. The reactions proceed at low temperatures with catalyst
loadings as low as 0.1 mol %. Further investigation of the
mechanism and application of the method to natural product
synthesis is ongoing and will be reported in due course.
Acknowledgment. We gratefully acknowledge the Uni-
versity of Florida for startup funds and the Herman Frasch
Foundation (647-HF07) and the donors of the Petroleum
Research Fund (47539-G1) for their generous support of our
programs.
a Diastereomeric ratios were determined by 1H NMR of the crude reaction
mixtures and by isolated yields when separable. b A trace amount of the
cis olefin was observed with 7. c 1 mol % AuCl3 used as catalyst. d 10%
unreacted diol 12 recovered. e 5 mol % Ph3PAuCl/AgOTf. f 0.1 mol %
Ph3PAuCl/AgOTf.
Supporting Information Available: Experimental pro-
cedures and data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL703002P
find complete consumption of 19 in 48 h using 0.1 mol %
Ph3PAuCl/AgOTf to give 20 in 82% yield (entry 16). More
(11) Cyclization of 23 smoothly provides 2-vinyltetrahydropyran, but
the yield is not reported due to its volatility.
Org. Lett., Vol. 10, No. 4, 2008
671