Photochemical route to the synthesis of thiolane 1-oxides

Article abstract of DOI:10.1021/ja060962r

The preparation of thiolane 1-oxide 10 by photochemically mediated rearrangement of sulfoxide 9 in high yield is described. The efficient construction of quaternary carbon centers underscores the utility of this methodology in organic synthesis. Further m

Full text of DOI:10.1021/ja060962r

Published on Web 06/21/2006
Photochemical Route to the Synthesis of Thiolane 1-Oxides
Jeffrey D. Winkler* and Esther C. Y. Lee1
Department of Chemistry, UniVersity of PennsylVania, Philadelphia, PennsylVania 19104
Received February 9, 2006; E-mail: winkler@sas.upenn.edu
During the course of our studies on a second-generation synthesis
triplet 6 to the ipso carbon of the aromatic ring leads to the
formation of 7, which can undergo fragmentation with concomitant
rearomatization to generate 8, leading to the observed product 5
upon radical recombination. Both sensitization and quenching
experiments are consistent with the reaction proceeding through a
triplet state. Without acetone, the reaction does not occur, and the
addition of piperylene suppresses it. This mechanistic scheme is
also consistent with the high yield obtained on irradiation of
sulfoxide 4b since the sulfinyl group is known to be an excellent
radical stabilizing group as indicated in 8 (X ) O; Y ) --).7
of ingenol,2,3 we have described the intramolecular photocycload-
dition of dioxenone 1 (R ) i-Bu) to give photoadduct 2 (R ) i-Bu)
in 31% yield.4 We report herein that the outcome of the photocy-
cloaddition of 1 depends critically on the nature of the sulfur R
group. In the case of aromatic sulfides, irradiation of 1 (R )
p-MeOPh) leads not to the formation of the expected [2 + 2]
photocycloaddition products corresponding to 2 (R ) p-MeOPh),
but instead to the formation of highly substituted thiolanes, such
as 3 (R ) p-MeOPh).5 We also present preliminary results on the
manipulation of these thiolane photoproducts.
Scheme 2
Scheme 1
We next extended these studies to the examination of the enone
chromophore, as shown in 98 (Scheme 3). Irradiation of 9 leads to
thiolane 1-oxide 10 (obtained as a ca. 1:1 mixture of epimeric
sulfoxides) in 81% yield, attesting to the scope of this novel
photochemical transformation. We note that the rearrangement also
occurs using substrate 11, which lacks the electron-donating group
on the aromatic ring, to provide 12 in comparable yield (89%).
That the enone photocycloaddition reaction proceeds through the
triplet state is supported by analogous quenching experiments with
piperylene. Sensitization is not required in the enone case, but the
reaction also proceeds in the presence of acetone.
The lack of participation of the 5-hexenyl moiety in the
photocycloaddition of 1 led us to examine the reactivity of the
simplified sulfide 4a,6 which we anticipated would generate
analogous thiolane structures. In the event, irradiation of 4a led to
the formation of thiolane 5a in 53% yield. We next examined the
role of the oxidation state of sulfur on this novel photochemically
induced rearrangement. We were delighted to find that irradiation
of the sulfoxide 4b led to the formation of 5b as a 1.2:1 mixture of
epimeric sulfoxides in 98% yield as confirmed by X-ray crystal-
lographic analysis. The reaction of sulfone 4c proceeded to give
the corresponding sulfone product 5c in lower yield (22%).
Scheme 3
Table 1. Survey of the Sulfur Oxidation State
rxn
4
X
Y
time
5
yield (%)
1
2
3
4a
4b
4c
--
O
O
--
--
O
1 h
15 min
15 min
5a
5b
5c
53
98 (1.2:1 â:R)
22
In an effort to further extend the utility of this process, we have
examined the effect of different heteroatom substitution on the
aromatic ring of 9, as outlined in Scheme 4. Irradiation of 13 leads
to the formation of hemiketal 14 in excellent yield, which undergoes
The formation of 5 is consistent with the mechanistic proposal
shown in Scheme 2. Addition of the â radical of the dioxenone
9
9040
J. AM. CHEM. SOC. 2006, 128, 9040-9041
10.1021/ja060962r CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
a second Pummerer reaction into this sequence. Oxidation of 15
provides the Pummerer substrate 20. Addition of allyltrimethylsilane
to sulfoxide 20 under Pummerer conditions (BF3-Et2O; TFAA)
furnishes the highly functionalized thiolane system 21 (Scheme 5).
Other carbon nucleophiles can also be employed, that is, addition
of the trimethylsilyl enol ether of acetophenone to 20 in the presence
of trimethylsilyl triflate generated 22. The stereoselectivities
observed in the formation of both 21 and 22 are consistent with
addition of both nucleophiles from the convex face of the
thiohydrindane (6/5) ring system.
These studies describe a novel photochemically mediated
transformation that affords a general route for the construction of
thiolane heterocycles. These preliminary results establish the
versatility of this ring system for the generation of diverse structural
types. Further applications of this methodology in synthesis are
currently underway, and our results will be reported in due course.
Pummerer rearrangement to give tetracyclic thiolane 15. Desulfu-
rization of 15 with Raney nickel leads to the efficient formation of
the angularly substituted reduced dibenzofuran 16.
Acknowledgment. We are grateful to the NIH, GlaxoSmith-
Kline, Wyeth-Ayerst, Merck, Amgen, Boehringer Ingelheim, and
Novartis for their generous support of this work.
We have also examined the photochemical rearrangement of the
analogous ortho-amino substrate 17, irradiation of which leads to
the formation of 18 as a mixture of sulfoxide epimers in quantitative
yield. In contrast to the facile Pummerer rearrangement of 14, we
found that 18 did not undergo the analogous rearrangement reaction.
Removal of sulfur without rearrangement was then examined.
Desulfurization of 18 using Raney nickel afforded hemiaminal 19
in 31% yield. The modest yield for the formation of 19 is consistent
with the work of Simpkins9 and prompted us to examine alternative
desulfurization protocols. Exposure of 18 to nickel boride led to
the formation of the desulfurized hemiaminal 19 in 56% yield.
To underscore the versatility of the thiolane products that result
from this photochemical-Pummerer cascade, we have incorporated
Scheme 5
Supporting Information Available: Experimental procedures and
spectral data for 1, 3-5, and 9-22 (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) Recipient of the Novartis Graduate Fellowship in Organic Chemistry,
2004-2005.
(2) For the first synthesis of ingenol, see: Winkler, J. D.; Rouse, M. B.;
Greaney, M. F.; Harrison, S. J.; Jeon, Y. T. J. Am. Chem. Soc. 2002, 124,
9726-9728.
(3) For more recent total syntheses of ingenol, see: (a) Tanino, K.; Onuki,
K.; Miyashita, M.; Nakamura, T.; Takahashi, Y.; Kuwajima, I. J. Am.
Chem. Soc. 2003, 125, 1498-1500. (b) Nickel, A.; Maruyama, T.; Tang,
H.; Murphy, P.; Greene, B.; Yusuff, N.; Wood, J. L. J. Am. Chem. Soc.
2004, 126, 16300-16301.
(4) A preliminary report on our second-generation approach to the synthesis
of ingenol has appeared: Winkler, J. D.; Lee, E. C. Y.; Nevels, L. I. Org.
Lett. 2005, 7, 1489-1491.
(5) For examples of the photochemistry of enone aryl sulfides, see: Dittami,
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57, 1151-1158. Dittami, J. P.; Luo, Y.; Moss, D.; McGimpse, W. G. J.
Org. Chem. 1996, 61, 6256-6260.
(6) Sulfide 4a was prepared by conjugate addition of 4-methoxythiophenol
to 2,2-dimethyl-6-vinyl-[1,3]dioxen-4-one, which is available via diox-
enone formation from 3-oxo-pent-4-enoic acid tert-butyl ester using TFAA,
TFA, Ac2O, and acetone.
(7) Guo, Y.; Jenks, W. S. J. Org. Chem. 1995, 60, 5480-5486. Guo, Y.;
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(8) Sulfoxide 9 was prepared by conjugate addition of 4-methoxythiophenol
to 3-vinylcyclohex-2-enone followed by oxidation of the sulfide with
m-CPBA.
(9) Armer, R.; Begley, M. J.; Cox, P. J.; Persad, A.; Simpkins, N. S. J. Chem.
Soc., Perkin Trans. 1 1993, 3105-3112.
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