Controlling regiochemistry in the gold-catalyzed synthesis of unsaturated spiroketals

Article abstract of DOI:10.1021/ol5024954

A novel gold-catalyzed synthesis of unsaturated spiroketals that addresses regioselectivity issues commonly reported in metal-catalyzed spiroketalization of alkynes is reported. The reaction sequence is regulated by an acetonide protecting group which und

Full text of DOI:10.1021/ol5024954

Letter
pubs.acs.org/OrgLett
Controlling Regiochemistry in the Gold-Catalyzed Synthesis of
Unsaturated Spiroketals
Paulo H. S. Paioti, John M. Ketcham, and Aaron Aponick*
Department of Chemistry, Center for Heterocyclic Compounds, University of Florida, Gainesville, Florida 32611, United States
S
* Supporting Information
ABSTRACT: A novel gold-catalyzed synthesis of unsaturated
spiroketals that addresses regioselectivity issues commonly reported
in metal-catalyzed spiroketalization of alkynes is reported. The
reaction sequence is regulated by an acetonide protecting group
which undergoes extrusion of acetone to deliver the desired
spiroketals in good yields and diastereoselectivities. The reaction,
which is carried out under very mild conditions employing AuCl as
the catalyst, should be widely applicable in the synthesis of a broad
range of spiroketals.
piroketals are an important class of compounds that appear
in myriad biologically relevant molecules, most notably
Scheme 1. Metal-Catalyzed Synthesis of Spiroketals
S
natural products and their analogues.1 Within this class of
compounds, monounsaturated spiroketals represent a structural
motif with increasing significance and can be found in natural
products such as okadaic acid,2 salinomycin,3 spirastrellolides,4
phorbaketals,5 alotaketals,6 and others.7 In addition to this
natural occurrence, the presence of a double-bond moiety is
synthetically useful, enabling complexity-building functionaliza-
tion or simple reduction to generate saturated derivatives.8
Despite this importance, methods for synthesizing both
saturated and unsaturated spiroketals rely mostly on the
Brønsted-acid catalyzed dehydration of ketodiols, which has
been demonstrated to be a reliable strategy for the synthesis of
natural products.1 While dehydration is effective, transition
metal-catalyzed reactions have been developed to allow the use
of triple bonds as carbonyl surrogates, and this strategy
provides a popular alternative.9 Utimoto’s seminal report in this
area demonstrated the spiroketalization of alkynediols 1
(Scheme 1A),10 in a process now catalyzed by a wide range
of metal complexes based on palladium,11 gold,12 mercury,13
rhodium,14 and iridium.14 Although these reactions are
generally functional group tolerant and high yielding, complex
mixtures of spiroketals are often observed due to regioselec-
tivity issues associated with hydroalkoxylation of internal
alkynes.15 The problem arises from the fact that regioselectivity
is dictated by relative rates of cyclization when forming different
ring sizes.9−14 To address this problem, a platinum-catalyzed
cyclization of monoprotected alkynediols was later reported.16
However, controlling the separate cyclization and in situ
deprotection events can be quite challenging.
first observed by our group (Scheme 1B)18 and later by the
groups of Trost21 and Forsyth22 during total syntheses.
Although spiroketal syntheses from alkynediols and triols are
well known, a general solution to the regioselectivity problem is
lacking. To overcome these issues, we postulated that
competing reactions could be precluded by a method where
the rates of cyclization no longer dictate the product
distribution. To this end, we decided to explore the feasibility
of a gold-catalyzed reaction of acetonides 8 for the selective
formation of [6,6]-monounsaturated spiroketals (Scheme 2).
We reasoned that the acetonide moiety could mask the
competing nucleophile and allow a stepwise spiroketalization
that proceeds in a predictable manner. More specifically, with
As part of our program focused on dehydrative reactions,17
we developed a highly regioselective cyclization of monop-
ropargylic triols 4 to form monounsaturated spiroketals.18
19
Reports using Hg(OTf)2 and Au complexes in the presence
of a surfactant in water20 have since appeared. While most
substrates generally work quite well, low regioselectivity was
Received: August 23, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
yield with 5 mol % loading (entry 5). Increasing the catalyst
loading to 10 mol % AuCl (entries 5−7) improved the yield to
67%, and these conditions were deemed optimal. This substrate
appears to be fairly challenging, as it was later observed that 5
mol % loadings were often satisfactory (vide infra), but the
improvement here over the triol is striking.
Scheme 2. Spiroketalization of Propargyl Acetonides
Having established the optimal conditions, the scope of the
reaction was studied. For reference, it was important to
compare results from the acetonides with the corresponding
triols. The triols 12a and 12b were prepared and, based on
previous examples, predicted to behave differently under these
conditions.18 As anticipated, a 95% yield of the desired
spiroketal 14a was isolated from the anti diol substrate 12a
and 30% yield from syn diol 12b, and the remainder of the
material was converted to undesired saturated spiroketals
(Table 2, entries 1,2). Under the optimal conditions with 5 mol
substrates such as 8, we hypothesized that the free alcohol
would cyclize prior to the extrusion of acetone, which would
then reveal the second nucleophile, thus controlling any
competition between the two hydroalkoxylation events. Herein
we report our efforts in this area that reveal a straightforward
approach to controlling the regiochemistry in the Au-catalyzed
synthesis of monounsaturated spiroketals.
At the outset, a suitable substrate was required for initial
studies. The triol 923 was prepared, and it was found that under
our previously reported conditions18 the desired spiroketal 10
is formed in only 20−25% yield (Scheme 3). Although the
a
Table 2. Reaction Scope
Scheme 3. Spiroketalization of Triol 9
yields for these reactions were very low, triol 9 was completely
consumed in both cases, resulting in the formation of a complex
mixture of saturated spiroketals, likely due to competing initial
5-exo and 6-endo-dig cyclization reactions.
With this result as a point of comparison, compound 9 was
easily transformed into the acetonide 11 to probe our
hypothesis.23 Several gold(I) complexes, including phosphine,
phosphite, NHC-carbene, and sulfide as ligands, were screened
(Table 1, entries 1−4); however, employing AuCl as a catalyst
gave the best yield and furnished the desired product in 48%
Table 1. Optimization Studies
a
See Supporting Information for determination of stereochemistry.
b
c
d
e
MS 4 Å used as an additive. Isolated yield. 5 mol % AuCl. Et2O
f
used as solvent. 1:1 mixture of diastereomers 12/13e used as
substrate. Spiroketal 14e detected as the exclusive product with
g
reduced yield due to volatility.
a
entry
catalyst
additive
loading (mol %)
yield (%)
% AuCl, both the 1,3-trans acetonide 13a (entry 1) and the 1,3-
cis acetonide 13b (entry 2) provided the product 14a as a single
diastereomer in 72% and 74% yield, respectively, with no trace
of saturated spiroketal byproducts. These results demonstrate
that the relative stereochemistry of the triol is important. A
rationale for this dependence was provided by Forsyth, which
suggests that 5-exoalkoxyauration is disfavored in the successful
diastereomer, thereby avoiding saturated spiroketal byprod-
ucts.22 In contrast, with the acetonide, substrate stereo-
chemistry appears to be inconsequential and a mixture of the
1
2
3
4
5
6
7
I
AgOTf
AgBF4
AgOTf
5
5
35
25
25
41
48
52
67
II
III
5
DMS·AuCl
AuCl
10
5
AuCl
7
AuCl
10
a
Isolated yield.
B
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Letter
diastereomeric acetonides 13a and 13b could be successfully
utilized. By removing the requirement for a specific
diastereomer, a significant advantage is achieved, allowing
substrate preparation by very basic methods.24
present in 16 will exclusively act as the nucleophile because the
competing nucleophile is masked in the form of an acetonide.
The vinyl gold intermediate 17 then likely undergoes
elimination of gold and extrusion of acetone to form the
allenyl ether 18, concomitantly revealing the second hydroxyl
group. π-Complex 18 may then isomerize to the vinylgold
oxocarbenium ion 19 and cyclize to form 20 or undergo
addition to form 20 directly. Protodeauration then turns over
the catalyst to yield spiroketal 21. Alternatively, the free allene
analogous to 18 may undergo Brønsted acid catalyzed
cyclization to furnish the spiroketal 21.26
To provide insight into the mechanism, we evaluated the
likelihood of forming the allenyl ether intermediate 18. It is
probable that 18 undergoes rapid cyclization, so an alternative
substrate was envisioned to preclude this possibility. To this
end, 22 was prepared and a silyl ether was incorporated as a
leaving group to reduce the chance of gold-catalyzed Meyer−
Schuster rearrangement with a propargyl alcohol,27 and also to
reduce the ability of the group eliminated to act as a
nucleophile in Au-catalyzed hydroalkoxylation28 or hydration
reactions.25b,29 When compound 22 was submitted to Au
catalysis conditions,30 the formation of a new compound was
observed in 20 min (Scheme 5). While the reaction product
As substrate stereochemistry can affect the spiroketalization,
additional substitution patterns were explored. Triols 12c and
12d, as well as the corresponding acetonides 13c and 13d, were
prepared and exposed to the reaction conditions. With these
substrates, the difference between the triols and the acetonides
was even more pronounced. The cyclization of the triols 12c
and 12d furnished the desired spiroketal 14b in only 15% yield,
whereas the cyclization of the 1,2-cis acetonide 13c and the 1,2-
trans acetonide 13d gave the desired unsaturated spiroketal 14b
in 77% and 67% yields, respectively (entries 3−4). Substrates
12/13e, containing the stereochemistry found in the
spirastrellolides,4 were also tested (entry 5). Cyclization of
the triol 12e proved to be difficult, and the spiroketal 14c could
be isolated in only 10% yield, in clear contrast to the cyclization
of the acetonide 13e, which delivered 14c in 52% yield. Both
reactions resulted in a 16:1 dr, suggesting that the reaction is
under thermodynamic control.
One additional set of experiments was conducted to
determine if the acetonide adversely affected substrates that
work reasonably well as the triols (entries 6,7). When exposed
to the reaction conditions, substrates 12/13f both delivered
spiroketal 14d in satisfactory yields and 12/13g also both
similarly provided 14e. These reactions proceeded smoothly,
and no alternate, saturated spiroketals were observed. In these
examples, the geminal diphenyl- and dimethyl-groups likely
accelerate the rate of cyclization of the distal alcohol to the
point where controlling the order of cyclization events by
employing the acetonide is unnecessary.
Scheme 5. Mechanistic Studies
Mechanistically, it is postulated that the gold catalyst
activates the triple bond in 15 for nucleophilic attack of the
pendant hydroxyl25 to generate the vinyl gold intermediate 17
via a 6-exo-dig cyclization (Scheme 4). The free hydroxyl
Scheme 4. Proposed Catalytic Cycle
was not the allene but instead 23, the result was intriguing as 23
was likely formed from a gold-catalyzed formal [2 + 2]-
cycloaddition of two molecules of the allenyl ether 24.31 Shi
and co-workers recently reported a similar [2 + 2] process that
generates allenes by rearrangement of propargyl acetates,32 but
this type of reactivity is unknown for propargyl alcohols and
ethers.
In summary, the chemistry outlined here demonstrates that it
is possible to overcome the problematic regiochemical issues in
the metal-catalyzed spiroketalization of alkynes. The method
utilizes an acetonide to function as a regioselectivity regulator in
the production of monounsaturated spiroketals. It is fortuitous
that this common protecting group serves this purpose and that
either saturated or functionalized spiroketals can easily be
prepared from these compounds. For these reasons, we believe
that this method will have broad applicability for the
preparation of a wide range of spiroketals. Application of this
method in the synthesis of natural products is ongoing in our
laboratories and will be reported in due course.
C
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Organic Letters
Letter
6849. (e) Aponick, A.; Biannic, B. Org. Lett. 2011, 13, 1330.
(f) Biannic, B.; Ghebreghiorgis, T.; Aponick, A. Beilstein J. Org. Chem.
2011, 7, 802. (g) Ghebreghiorgis, T.; Biannic, B.; Kirk, B. H.; Ess, D.
H.; Aponick, A. J. Am. Chem. Soc. 2012, 134, 16307. (h) Ketcham, J.
M.; Biannic, B.; Aponick, A. Chem. Commun. 2013, 49, 4157.
(i) Ketcham, J. M.; Cardoso, F. S. P.; Biannic, B.; Piras, H.; Aponick,
A. Isr. J. Chem. 2013, 53, 923.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(18) Aponick, A.; Li, C.-Y.; Palmes, J. A. Org. Lett. 2009, 11, 121.
(19) Ravindar, K.; Reddy, M. S.; Deslongchamps, P. Org. Lett. 2011,
13, 3178.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aponick@chem.ufl.edu.
(20) Minkler, S. R. K.; Isley, N. A.; Lippincott, D. J.; Krause, N.;
Lipshutz, B. H. Org. Lett. 2014, 16, 724.
(21) Trost, B. M.; O’Boyle, B. M.; Hund, D. J. Am. Chem. Soc. 2009,
131, 15061.
Notes
The authors declare no competing financial interest.
(22) Fang, C.; Pang, Y.; Forsyth, C. J. Org. Lett. 2010, 12, 4528.
(23) See Supporting Information for the synthesis of substrates and
for the determination of the stereochemistry of substrates and
products.
(24) Guillarme, S.; Ple, K.; Banchet, A.; Liard, A.; Haudrechy, A.
Chem. Rev. 2006, 106, 2355.
ACKNOWLEDGMENTS
■
We thank the Herman Frasch Foundation (647-HF07) and the
James and Ester King Biomedical Research Program (09KN-
01) for their generous support of our programs.
(25) (a) Furstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46,
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