Au-catalyzed cyclization of monopropargylic triols: An expedient synthesis of monounsaturated spiroketals

Article abstract of DOI:10.1021/ol802491m

The gold-catalyzed cyclization of monopropargylic triols to form olefin-containing spiroketals is reported. The reactions are rapid and high yielding when 2 mol % of the catalyst generated in situ from Au[P(t-Bu) ₂(o-biphenyl)]CI and AgOTf is e

Full text of DOI:10.1021/ol802491m

ORGANIC
LETTERS
2009
Vol. 11, No. 1
121-124
Au-Catalyzed Cyclization of
Monopropargylic Triols: An Expedient
Synthesis of Monounsaturated
Spiroketals
Aaron Aponick,* Chuan-Ying Li, and Jean A. Palmes
Department of Chemistry, UniVersity of Florida, GainesVille, Florida 32611
aponick@chem.ufl.edu
Received October 28, 2008
ABSTRACT
The gold-catalyzed cyclization of monopropargylic triols to form olefin-containing spiroketals is reported. The reactions are rapid and high
yielding when 2 mol % of the catalyst generated in situ from Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf is employed in THF at 0 °C. A range of
differentially substituted triols leading to substituted 5- and 6-membered ring spiroketals were prepared and function well in the reaction.
Spiroketals are a common motif found in many structurally
interesting and biologically significant natural products.1
In addition to the fully saturated analogues, a number of
families of natural products with olefin-containing spiroket-
als have been reported. Select examples include okadaic
acid,2 avermectin,3 aigialospirol,4 and the spirastrel-
lolides.5 These monounsaturated spiroketals with the
general structure 3 have classically been prepared by the
dehydration of R,ꢀ-unsaturated keto diols or cis-olefin-
containing hemiacetals with a pendant-free alcohol.1,6 As
part of our program aimed at devising new gold-catalyzed
dehydrative transformations of unsaturated alcohols, we
began to explore the formation of monounsaturated spiroket-
als 3 from monopropargylic triols 1.
Homogeneous catalysis using gold salts has emerged as a
powerful new area in organic synthesis, with many interesting
and useful new transformations appearing at an extremely
rapid pace.7 Based on our recent work involving the
dehydrative cyclization of allylic diols,8 we hypothesized that
cyclic alkoxyallenes such as 29 could be formed from 1 and,
by the action of the same gold catalyst, cyclize to form the
desired monounsaturated spiroketals 3.
(1) For reviews on spiroketals, see: (a) Kluge, A. F. Heterocycles 1986,
24, 1699. (b) Boivin, T. L. B. Tetrahedron 1987, 43, 3309. (c) Perron, F.;
Albizati, K. F. Chem. ReV. 1989, 89, 1617. (d) Jacobs, M. F.; Kitching,
W. B. Curr. Org. Chem. 1998, 2, 395. (e) Mead, K. T.; Brewer, B. N.
Curr. Org. Chem. 2003, 7, 227. (f) Aho, J. E.; Pihko, P. M.; Rissa, T. K.
Chem. ReV. 2005, 105, 4406.
(2) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikuchi, H.; Van Engen,
D.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981, 103,
2469.
(6) For leading references on additional methods, see: (a) Danishefsky,
S. J.; Pearson, W. H. J. Org. Chem. 1983, 48, 3865. (b) Wincott, F. E.;
Danishefsky, S. J.; Schulte, G. Tetrahedron Lett. 1987, 28, 4951. (c) Whitby,
R.; Kocienski, P. Tetrahedron Lett. 1987, 28, 3619. (d) Whitby, R.;
Kocienski, P. J. Chem. Soc., Chem. Commun. 1987, 906. (e) Baker, R.;
Brimble, M. A. J. Chem. Soc., Perkin Trans. 1 1988, 125. (f) Tu, Y.-Q.;
Bryiel, K. A.; Kennard, C. H. L.; Kitching, W. A. J. Chem. Soc., Perkin
Trans. 1 1995, 1309. (g) Figueroa, R.; Hsung, R. P.; Guevarra, C. G. Org.
Lett. 2007, 9, 4857.
(3) Miller, T. W.; Chaiet, L.; Cole, D. J.; Cole, L. J.; Flor, J. E.;
Goegelman, R. T.; Gullo, V. P.; Joshua, H.; Kempf, A. J.; Krellwitz, R. L.;
Monaghan, R. L.; Ormond, R. E.; Wilson, K. E.; Albers-Schonberg, n/a.;
Putter, I. Antimicrob. Agents Chemother. 1979, 15, 368.
(4) Vongvilai, P.; Isaka, M.; Kittakoop, P.; Srikitikulchai, P.; Kongsaeree,
P.; Thebtaranonth, Y. J. Nat. Prod. 2004, 67, 457.
(5) Warabi, K.; Williams, D. E.; Patrick, B. O.; Roberge, M.; Andersen,
R. J. J. Am. Chem. Soc. 2007, 129, 508.
10.1021/ol802491m CCC: $40.75
Published on Web 12/02/2008
2009 American Chemical Society

Previous reports of transition-metal-catalyzed spiroketal-
ization of alkynyl diols to form saturated spiroketals indicate
that ring size preference can be a challenging issue, forming
mixtures of 5 and 6 from 4.10 Our route was particularly
attractive because the olefin would be precisely placed
according to the general scheme, leaving no ambiguity in
the sizes of the rings formed, and the substrates would be
easily prepared using numerous approaches. If successful,
this method would provide rapid access to the desired
compounds and open a new Au-catalyzed reaction pathway
of propargyl alcohols.
to 1.5 h (entry 2), but the catalyst loading could not be
reduced (entry 3). Although gold salts 9-13 all catalyzed
the reaction, from the results it was clear that 13 was superior
giving the highest yield in the shortest time. Additionally,
the loading could be lowered to 2 mol % with minimal effect
on the yield (entry 8). Control experiments demonstrated that
molecular sieves and AgOTf were necessary (entries 9 and
10) and provided evidence that the cationic gold(I) complex,
not AgOTf or TfOH alone, was the catalytically active
species (entries 11 and 12).
With the optimal conditions established, the substrate
scope was then examined (Table 2). The 1,7-dioxaspiro[5.5]-
Table 2. Reaction Scope
To explore the feasibility of this idea, the triol 7 was
prepared and treated with the cationic gold(I) catalyst system
generated from 5 mol % of Ph3PAuCl/AgOTf in CH2Cl2 at
0 °C (Table 1, entry 1). Gratifyingly, the desired spiroketal
Table 1. Optimization Studies
loadinga
entry catalyst additive (mol %) solvent time (h) yield (%)
1
9
9
9
10
11
12
13
13
13
13
AgOTf
AgOTf
AgOTf
5
5
1
2
2
2
5
2
2
2
2
2
CH2Cl2
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
6
1.5
24
0.5
0.5
24
1.75
1.75
30
59
85
60
51
77
26
91
88
81
0
2
3b
4
5
6
7
8
AgOTf
AgOTf
AgOTf
9c
10
11
12d
a All triols were used in racemic form. b Reaction temperature ) 23
°C. c 5 mol % of catalyst. d Reaction temperature ) 45 °C.
48
48
48
AgOTf
TfOH
0
0
a Loading of both catalyst and additive (1:1). b 29% of triol 7 was
undec-4-ene ring system is likely the most important olefin-
containing spiroketal for natural product synthesis. Using
these conditions, 3 and substituted derivatives 15 and 17
were smoothly formed in greater than 80% yield (Table
2, entries 1-3). As would be needed for okadaic acid, a
trisubstituted alkene was easily prepared (entry 4), and
the other combinations of 5- and 6-membered ring
spiroketals 21 and 23 also proved to be readily available
(entries 5 and 6).
recovered. c Molecular sieves omitted. d 70% of triol 7 was recovered.
8 was obtained in 59% yield after 6 h. Using THF as solvent,
the yield increased to 85% and the reaction time decreased
(7) For recent reviews, see: (a) Muzart, J. Tetrahedron 2008, 64, 5815.
(b) Shen, H. C. Tetrahedron 2008, 64, 3885. (c) Li, Z.; Brouwer, C.; He,
C. Chem. ReV. 2008, 108, 3239. (d) Arcadi, A. Chem. ReV. 2008, 108,
3366. (e) Jimenez-Nunez, E.; Echavarren, A. M. Chem. ReV. 2008, 108,
3326. (f) Gorin, D. J.; Sherry, B. D.; Toste, F. D. Chem. ReV. 2008,
108, 3351.
Since more highly substituted substrates would likely react
at different rates, it was important to further explore the
sterics in more demanding substrates. The cyclization of two
(8) (a) Aponick, A.; Li, C.-Y.; Biannic, B. Org. Lett. 2008, 10, 669. (b)
Aponick, A.; Biannic, B. Synthesis 2008, 20, 3356.
122
Org. Lett., Vol. 11, No. 1, 2009

tertiary alcohols may be predicted to be difficult based on
the proximity of steric bulk to the nucleophilic oxygens. To
test this substitution pattern and demonstrate the utility of
the method we sought to prepare the natural hop oil extract
27 (Scheme 1).11
as determined by HPLC (Scheme 2).14 When this mixture
was exposed to the standard reaction conditions, 29 was
Scheme 2. Chirality in the Au-Catalyzed Spiroketalizations
Scheme 1. Synthesis of the Natural Hop Extract 27
A family of naturally occurring 1,6-dioxaspiro[4.4]-
nonanes, non-3-enes (such as 27), and nona-3,8-dienes
have been reported.6f Spiroketal 27 was originally identi-
fied after extraction from a Japanese hop oil in 196711a
and later from pilsner beer.11b Our synthesis begins from
24 (Scheme 1), prepared by reaction of excess methyl-
magnesium bromide with the corresponding ethyl ester.12
Protection of the tertiary alcohol as its silyl ether followed
by deprotonation of the alkyne and addition to the
aldehyde 2513 then provided the cyclization precursor 26
after deprotection. As was anticipated, the Au-catalyzed
spiroketalization of 26 was more difficult than less
sterically hindered substrates. Using the standard condi-
tions, the reaction took 23 h and afforded 27 in 58% yield.
Fortunately, the rate and yield were improved by using
5% catalyst loading at 45 °C to give the simple natural
product in 74% yield demonstrating that highly substituted
spiroketals are readily prepared by this method.
formed in 83% yield. The relative configuration of the
spiroketal was determined by hydrogenation of the double
bond and comparison to the previously reported data for 30.15
Since both diastereomers 28a/b give the same product, with
this substrate the relative configuration of the propargyl
alcohol apparently has no influence on the course of the
reaction.16
Additionally, the triols 31 and 33 were prepared from
malic acid17 and tested in the reaction (Scheme 2). Exposure
of 31 to the standard conditions smoothly provided the
expected product 32 in 94% yield. The syn-diastereomer 33
showed similar reactivity but unexpectedly gave 34 and 35
in addition to the desired spiroketal 32. Although it was
unclear why the selectivity was affected by this change in
substitution, we hypothesized that the order of the cyclization
events may have significant influence on the outcome of the
reaction.
It was also of interest to determine to what extent the
propargylic alcohol stereochemistry might influence the
reaction of substrates bearing an additional stereogenic center.
To this end, 28 was prepared from TBDPS-protected (S)-
glycidol as an approximately 1:1 mixture of diastereomers
Based on our previous work,8 we initially envisioned that
this transformation would involve an allene intermediate
(9) In a series of seminal reports, Kociensky has previously reported
the preparation, isolation, and cyclization of allenol ethers, which are
described as labile compounds. For leading references, see refs 6c and
6d.
(10) For leading references on transition-metal-catalyzed spiroketaliza-
tion, see: (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (b) Liu, B.;
De Brabander, J. K. Org. Lett. 2006, 8, 4907. (c) Li, Y.; Zhou, F.; Forsyth,
C. J. Angew. Chem., Int. Ed. 2007, 46, 279. (d) Dieguez-Vazquez, A.;
Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew. Chem., Int. Ed. 2008,
47, 209.
(14) Diastereomers 28a/b are indistinguishable by both 1H and 13C NMR.
Proof of this was obtained by Mitsunobu reaction and deprotection. A
mixture of the starting material and product were indistinguishable. HPLC
analysis, while not completely resolved, showed two peaks in ∼1:1 ratio.
See the Supporting Information for full details.
(15) Conway, J. C.; Quayle, P.; Regan, A. C.; Urch, C. J. Tetrahedron
2005, 61, 11910.
(11) (a) Naya, Y.; Kotake, M. Tetrahedron Lett. 1967, 8, 1715. (b) Tressl,
R.; Friese, L.; Fendesack, F.; Koppler, H. J. Agric. Food Chem. 1978, 26,
1422.
(16) To rule out any discrepancies in the event that the material was
not an exact 1:1 mixture, the reaction was performed on substrate obtained
after Mitsunobu inversion of the propargylic alcohol and identical results
were obtained.
(12) Amos, R. A.; Katzenellenbogen, J. A. J. Org. Chem. 1978, 33,
555.
(13) Denmark, S. E.; Stavenger, R. A. J. Am. Chem. Soc. 2000, 122,
8837.
(17) Patron, A. P.; Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.;
Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994, 1147.
Org. Lett., Vol. 11, No. 1, 2009
123

Scheme 3. Catalytic Cycle
(e.g., 2), but cyclization of either of the terminal alcohols
may be possible. A probable catalytic cycle is illustrated in
Scheme 3. For the reaction to proceed through an allene
intermediate, 36 is formed by complexation with the cationic
gold complex generated from 13 and AgOTf. Nucleophilic
addition of the pendent C9 hydroxyl group and loss of water
then gives 39 after electrophilic addition of the catalyst via
the Au-complexed allenol 38.18 The free C1 hydroxyl group
subsequently adds to the oxocarbenium to provide 40 and
the product 3 after protiodeauration. If the C1 alcohol
preferentially cyclizes, intermediate 41 would be produced.
Proton transfer would then give ꢀ-hydroxy Au complex 42
which may first eliminate to form 43 and cyclize to 44 or
alternatively first cyclize then eliminate, also forming 44 and
3 after deprotonation.
Cyclization of 45 provided 46 and the Meyer Schuster rear-
rangement18 product 47 in a combined 91% yield. These
products likely arise by further reaction of an intermediate such
as 38 when the C1 alcohol is not available. Additionally,
treatment of 48 under the reaction conditions yielded 49,19 albeit
in 21% yield. Deprotection and re-exposure of the product to
the reaction conditions gave the expected spiroketal 3. These
data suggest that it is possible for both pathways to be operative
in the reaction. Spiroketals 34 and 35 may be the result of a
competive 5-exo cyclization when the C1 alcohol cyclizes first,
although this can be completely supressed by using the anti-
diol 31 to obtain the same product.
In conclusion, a new mode of reactivity of propargyl
alcohols has been reported that enables a facile preparation
of highly useful monounsaturated spiroketals from propar-
gylic triols by action of the cationic gold(I) complex
generated from Au[P(t-Bu)2(o-biphenyl)]Cl and AgOTf. The
reactions are rapid and generally high yielding, providing a
concise synthesis of useful building blocks in short order.
Further studies on the reaction mechanism and use of the
method in natural product synthesis are underway and will
be reported in due course.
To gain insight on the feasibility of cyclizing the terminal
alcohols, the C1 and C9 monoprotected diols 45 and 48 were
prepared and exposed to the reaction conditions (Scheme 4).
Scheme 4. Control Experiments
Acknowledgment. We gratefully acknowledge the Uni-
versity of Florida, the Herman Frasch Foundation (647-
HF07), and the donors of the Petroleum Research Fund
(47539-G1) for their generous support of our programs.
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.
OL802491M
(18) A gold-complexed ketene acetal was recently proposed as an
intermediate in the Au-catalyzed Meyer Schuster rearrangement. See: (a)
Lopez, S. S.; Engel, D. A.; Dudley, G. B. Synlett 2007, 949. (b) Engel,
D. A.; Dudley, G. B. Org. Lett. 2006, 8, 4027.
(19) The enol ether olefin geometry is assumed based on the trans
hydroalkoxylation mechanism typically presented for Au-catalyzed reactions.
A single olefin isomer was obtained.
124
Org. Lett., Vol. 11, No. 1, 2009