A Mild, Diastereoselective Construction of Cyclic and Spirocyclic Ketals Employing a Tandem Photoisomerization/Cyclization Tactic

Article abstract of DOI:10.1021/ol503116q

The cyclization of trans-δ-hydroxy enones to cyclic mixed ketals routinely requires superstoichiometric strong acid. By operating under a photoisomerization regime, the cyclization of trans-δ-hydroxy enones proceeds under catalytic Bronsted acid to provid

Full text of DOI:10.1021/ol503116q

Letter
pubs.acs.org/OrgLett
A Mild, Diastereoselective Construction of Cyclic and Spirocyclic
Ketals Employing a Tandem Photoisomerization/Cyclization Tactic
Bo Li,† Brett D. Williams,† and Amos B. Smith, III*
Department of Chemistry, Laboratory for Research on the Structure of Matter and Monell Chemical Senses Center, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: The cyclization of trans-δ-hydroxy enones to
cyclic mixed ketals routinely requires superstoichiometric
strong acid. By operating under a photoisomerization regime,
the cyclization of trans-δ-hydroxy enones proceeds under
catalytic Brønsted acid to provide cyclic ketals or unsaturated
spiroketals in a highly diastereoselective fashion. A one-pot, two-step protocol was thus developed to provide cyclic methoxy
ketals with a free β-hydroxy group for future functionalization.
groups.4c,d However, broad utilization of trans-δ-hydroxy enones
yclic and spirocyclic ketals comprise ubiquitous structural
1
Cmotifs in polyketide natural products (Figure 1). Often as cyclic ketal precursors in natural product synthesis has been
limited due to the harsh conditions required to achieve
cyclization. We became interested in developing a mild protocol
for the cyclization of trans-δ-hydroxy enones during our total
synthesis of (+)-18-epi-latrunculol A.4c,d The strategy level
cyclization in the synthesis was highly diastereoselective yet
moderate in yield due to competitive decomposition pathways
under the strongly acidic conditions.
decorated with substituents and a rich array of stereochemistry,
the synthesis of such ketals within a natural product framework
demands high functional group tolerance and diastereoselectiv-
ity.
To develop mild cyclization conditions, we first examined the
accepted reaction mechanism.7 Importantly, the cyclization of
trans-δ-hydroxy enones to cyclic ketals initiates through
protonation of the enone carbonyl, which enables the subsequent
Scheme 1. Synthesis of Cyclic Ketals
Figure 1. Natural products containing a cyclic hemiacetal and
unsaturated spiroketal.
Dihydroxy ketones are commonly employed as precursors to
cyclic ketals (Scheme 1a).2 Such aldol products typically undergo
cyclization upon exposure to catalytic acid in alcoholic or
aqueous solvents. Synthesis of the requisite dihydroxy ketones
necessitates tedious protecting group manipulations and the
handling of sensitive intermediates. Moreover, the stereogenicity
of the requisite δ-hydroxy-α-unsubstituted ketones often arises
from an acetate aldol reaction.2b,c While major advances have
been achieved,3 in many cases the acetate aldol reaction remains
modestly diastereoselective. Alternatively, δ-hydroxy enones
have also been recognized as viable precursors to cyclic ketals
(Scheme 1b).4 These enones are of interest as they can be readily
constructed through olefination5 or vinylogous aldol reactions,6
which effectively telescope the synthesis of cyclic ketals. Notably,
the cross-metathesis reaction has also been employed to prepare
trans-δ-hydroxy enones without the requirement for protecting
Received: October 24, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
intermolecular addition of water. The overall requirement for
strong acidic conditions is presumably due both to the low
basicity of the carbonyl oxygen and to the poor nucleophilicy of
water. To circumvent this constraint, we envisioned that the
photoisomerization of trans-δ-hydroxy enones in acidic media8
held promise for the formation of a dynamic equilibrium, in
which the cis-enone would cyclize and hydrate under milder
conditions (Scheme 1c). We were encouraged by early reports
from Snider et al. on their elegant synthesis of peroxy ketals.9
Moreover, during the development of our work, Rueping10 and
Rovis11 reported cyclization reactions utilizing tandem photo-
isomerization/cyclization strategies. Herein, we report a mild,
acid-catalyzed photoisomerization/cyclization sequence that
permits the cyclization of trans-δ-hydroxy enones to cyclic ketals
or unsaturated spiroketals.
plored. The subsequent investigation revealed that the bis-
benzyloxy ketal (2; R = OBn) could be converted in situ to a
methoxy ketal containing a free secondary alcohol after a solvent
swap for a methanol/THF mixture and hydrogenation employ-
ing catalytic palladium on carbon (Table 1, entry 7).
The scope of the devised photoisomerization/cyclization to
provide bis-methoxy ketals, as well as the two-step, one-pot
reaction, was next evaluated with several trans-δ-hydroxy enones
(Scheme 2). Enones containing various functional groups were
subjected to the cyclization protocol to provide methyl ketals
with a β-methoxy group in high yields. The two-step, one-pot
protocol also provided several ketals with a free β-hydroxyl group
as a functional group handle in high yields. Excellent
diastereoselectivies were obtained for all reactions (>20:1 dr,
1
via H NMR). Additionally, the optimized reaction conditions
The development of the envisioned photoisomerization/
cyclization protocol began with racemic trans-enone 1 as a
substrate (Table 1). As expected, no cyclization occurred when 1
was exposed to catalytic toluene sulfonic acid monohydrate (p-
TsOH·H2O) in methanol. Irradiation of 1 at 355 nm for 30 min
(without acid) quickly demonstrated the proposed effective
isomerization of the enone geometry. Indeed, irradiation of 1 in
methanol with 10 mol % of p-TsOH·H2O provided quantitative
conversion, as measured by 1H NMR, to bis-methoxy ketal 2 as a
single observable diastereomer.
can tolerate sterically encumbering groups adjacent to the
secondary alcohol (Scheme 2, 4 and 8), although diminished
yields were obtained. Interestingly, while steric bulk next to the
carbonyl is tolerated in the cyclization, the ensuing hydro-
genation is significantly slower.
Scheme 2. Scope of Photoisomerization/Cyclization
Table 1. Evaluation of a Photoisomerization-Assisted
Cyclization
entry
1
conditions
yield (%)
NR
MeOH, p-TsOH·H2O (10 mol %), rt,
overnight
2
3
4
MeOH, hν (355 nm), rt, 4 h
4:1 E/Z
a
MeOH, p-TsOH·H2O (10 mol %), hν, rt, 4 h
THF/H2O, p-TsOH·H2O (10 mol %), hν,
rt, 4 h
100; R1, R2 = Me
b
−
b
5
6
7
allyl alcohol, p-TsOH·H2O (10 mol %), hν,
rt, 4 h
−
a
BnOH (25 equiv), THF p-TsOH·H2O
(10 mol %), hν, rt, 4 h
94, 5:1 dr R1, R2 = Bn
(i) BnOH (25 equiv), THF, p-TsOH·H2O
(10 mol %), hν, rt, 4 h
83%, ≥20:1 dr R1 = H,
R2 = Me
(ii) Pd/C, H2 (600 psi), MeOH, rt, 1.5 h
a
Determined by 1H NMR analysis using hexamethyldisilane as an
b
internal standard. A complex mixture was obtained.
While chiral methyl ethers are indeed prevalent in nature,1a we
were cognizant that obtaining a free secondary hydroxyl from this
cyclization would enable greater diversification of the cyclized
products. Toward this end, 1 was irradiated in the presence of
aqueous acid; unfortunately, a complex mixture of products was
obtained. We turned to alcohol solvent with potentially
removable alkyl groups, such as allyl alcohol and benzyl alcohol.
Allyl alcohol provided substantial decomposition upon irradi-
ation; alternatively, employing a mixture of benzyl alcohol and
THF delivered bis-benzylated ketal 2 (R1 and R2 = Bn) in a 94%
yield (5:1 dr). To obtain a ketal with a free secondary hydroxyl
(2; R1 = H) from the reaction, the development of a two-step,
one-pot cyclization/hydrogenation procedure was then ex-
Having developed an approach to cyclic ketals with varying
functionality, we turned to the possibility of utilizing enones with
two free hydroxyl groups, in what appears to be an
unprecedented method to construct unsaturated spiroketals.
Moreover, given our interest in the total synthesis of
spirastrellolide (Figure 1),12 we were familiar with the require-
ment for mild conditions to perform such spirocyclizations.
Toward this end, subjecting diol 11a (Scheme 3) to catalytic p-
TsOH·H2O in THF under irradiation (355 nm) resulted in the
smooth formation of the unsaturated spiroketal 12 in 75% yield
as a single diastereomer. Exploration of the scope of this
transformation yielded 6,5- and 6,6-unsaturated spiroketals (12−
B
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Organic Letters
Letter
15) in good yields with varying steric constraints next to the
secondary alcohol. The reaction also tolerated the use of an
additional unprotected hydroxyl group to provide spiroketal
(−)-15.
ASSOCIATED CONTENT
* Supporting Information
Experimental details and spectroscopic and analytical data for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
Scheme 3. Photoisomerization/Spirocyclization Sequence
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: smithab@sas.upenn.edu.
Author Contributions
†B.L. and B.D.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the Institutes of General
Medical Sciences through grant GM-029028. We also thank Drs.
George Furst and Rakesh Kohli at the University of
Pennsylvannia for help obtaining the high-resolution NMR and
mass spectral data, respectively and the China Scholarship
Council for a scholarship to Bo Li (CSC No. 2012-06200031).
Finally, to explore the mechanism of this protocol (vide
supra), trans-enone 1 (Scheme 4a) was irradiated (355 nm) to
give the expected mixture of olefin isomers (Scheme 4b). This
mixture was then treated with 10 mol % of p-TsOH·H2O and
stirred in the dark. In accordance with our proposal, the cis-
isomer preferentially underwent cyclization, thus enriching the
remaining enone mixture with the trans-isomer.
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In summary, we have developed a mild photochemical
protocol for the cyclization of δ-hydroxy enones to cyclic ketals
or unsaturated spiroketals. The reaction proceeds with high
functional group tolerance, requires only catalytic acid, and
provides cyclic products in moderate to high yields with high
diastereoselectivities. Efforts directed at the expansion of this
work, employing alternative nucleophiles, is currently underway.
C
dx.doi.org/10.1021/ol503116q | Org. Lett. XXXX, XXX, XXX−XXX