Sequential Norrish type II photoelimination and intramolecular aldol cyclization of 1,2-diketones in carbohydrate systems: Stereoselective synthesis of cyclopentitols

Article abstract of DOI:10.1002/anie.200803696

(Chemical Equation Presented) Opened and closed: Visible-light photo-stimulation of 2,3-diuloses I triggers an unprecedented sequential rearrangement: A Norrish type II photoelimination to give an isolable acyclic photoenol intermediate II is followed by an intramolecular enolexo aldolization. The contraction of the pyranose ring in this process leads to a new type of cyclopentitol derivative III. R = acyl, alkyl, silyl group.

Full text of DOI:10.1002/anie.200803696

Angewandte
Chemie
DOI: 10.1002/anie.200803696
Carbohydrates
Sequential Norrish Type II Photoelimination and Intramolecular Aldol
Cyclization of 1,2-Diketones in Carbohydrate Systems: Stereoselective
Synthesis of Cyclopentitols**
Dimitri lvarez-Dorta, Elisa I. León,* Alan R. Kennedy, Concepción Riesco-Fagundo, and
Ernesto Suµrez*
The photochemical behavior of 1,2-diketones differs consid-
erably from that of monoketones and has received a great
deal of attention from a theoretical viewpoint over the
years.[1] Suitably substituted aliphatic 1,2-diketones exhibit
remarkable regioselectivity of intramolecular 1,5-hydrogen-
atom transfer, and the 1,4-biradical intermediate yields
almost exclusively 2-hydroxycyclobutanones (Norrish–Yang
photocyclization).[2] Another important difference between
1,2-diketones and monoketones is that the former compounds
do not undergo Norrish type II photoelimination to a large
extent.[3] In our opinion, two principal drawbacks have
hampered the development of synthetic applications of this
1,5-hydrogen-atom transfer:[4] First, rate constants for the
hydrogen abstraction are only about 1% as large as for
monoketones.[5] Second, some aliphatic 1,2-diketones are not
Scheme 1. Photochemistry of the nono-2,3-diulose 1.
very stable and are difficult to prepare by standard methods,
especially from sensitive substrates.
Within this context, and in connection with our ongoing
research programs on the reactivity of 1,2-diketones[6] and
hydrogen-atom transfer (HAT) promoted by alkoxyl radicals
in carbohydrate chemistry,[7] the aim of the present study has
been to explore the photochemical reactivity of nono-2,3-
diuloses (e.g. 1, Scheme 1).[8] It is generally accepted that
hydrogen-atom abstraction by an excited carbonyl group
closely resembles HAT by alkoxyl radicals.[1a] Therefore, in a
1,2-diketone, such as 1, inasmuch as the hydrogen atom at C5
is blocked stereochemically, one would expect the hydrogen
atom at C8 to be abstracted by the external carbonyl group
via a seven-membered transition state (TS). Hydrogen-atom
abstraction by the internal carbonyl group via a six-mem-
bered TS, which should lead to acyl cyclobutanones, has never
been observed.
In contrast, earlier research by our group showed that
both processes are possible with alkoxyl radicals. C-Glyco-
sides that contained hydroxymethyl[9] and 1-hydroxyethyl[10]
tethers cyclized to give 6,8-dioxabicyclo[3.2.1]octane and 2,9-
dioxabicyclo[3.3.1]nonane derivatives, respectively.
Photochemical experiments were carried out with a
variety of 4,8-anhydronono-2,3-diuloses (Table 1). 1,2-Dike-
tones 1–6 were prepared from the corresponding non-2-
ynitols by oxidation of the triple bond with ozone[11] or
[12]
[*] D. lvarez-Dorta, Dr. E. I. León, Dr. C. Riesco-Fagundo,
Prof. Dr. E. Suµrez
RuO2·H2O/NaIO4
(see the Supporting Information).
1,2-Diketones 2–4 with benzyl ether protecting groups were
better prepared by oxidation of the triple bond with
RuO2·H2O/NaIO4 than by oxidation with ozone. The
1,2-diketones were obtained as yellow oils and are stable for
at least several months when stored at À258C under nitrogen
in the dark. They can be purified by rapid silica-gel column
chromatography, although a significant loss of material was
observed. In all the 1,2-diketones, the conformation of the
pyranose ring was determined to be 4C1 by careful analysis of
coupling constants; thus, the hydrogen atom H-C8 and the
diketone tether are in a 1,3-diaxial relationship.
In a preliminary experiment, the 1,2-diketone 1 was
irradiated with a daylight lamp[13] at 308C until the yellow
color faded. The bicyclic compound 7 was formed as a single
diastereoisomer, and no other isomers were detected by
1H NMR spectroscopy of the crude reaction mixture
Instituto de Productos Naturales y Agrobiología del CSIC
Carretera de La Esperanza 3, 38206 La Laguna, Tenerife (Spain)
Fax: (+34)922-260-135
E-mail: eila@ipna.csic.es
esuarez@ipna.csic.es
Dr. A. R. Kennedy
WestCHEM, Department of Pure and Applied Chemistry
University of Strathclyde
295 Cathedral Street, Glasgow G1 1XL, Scotland (UK)
[**] This research was supported by the Investigation Program (nos.
CTQ2004-06381/BQU, CTQ2004-02367/BQU, and CTQ2007-
67492/BQU) of the Ministerio de Educación y Ciencia, Spain and
cofinanced by the Fondo Europeo de Desarrollo Regional (FEDER).
D.A.-D. and C.R.-F. thank the Ministerio de Ciencia e Innovación,
Spain and the I3P-CSIC Program, respectively, for fellowships.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803696.
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Table 1: Sequential Norrish type II photoelimination and intramolecular
warming of the reaction mixture to room temperature, these
signals disappeared rapidly and completely. The cyclized
product 7 was the only observable product after a few
minutes.
aldol cyclization.[a]
Entry Diketone
t [h] Product
Yield [%]
The reaction does not seem to be influenced greatly by the
steric demand of the substituents, at least in this stereochem-
ical environment (Table 1, entries 1–4). Although the reaction
yield increased slightly when the 6-deoxy derivative 5 was
used as the substrate, it decreased with the apparently less-
hindered 6,7-dideoxy derivative 6 (Table 1, entries 5 and 6).
The polarity of the substituent at C9 was also found to have
relatively little effect on the yield of the reaction (Table 1,
entries 3 and 4).
1
2
3
4
1 R=R1 =Me
3
2
3
1
7 R=R1 =Me
8 R=R1 =Bn
52
58
2 R=R1 =Bn
3 R=Bn, R1 =TBDPS
4 R=Bn, R1 =Ac
9 R=Bn, R1 =TBDPS 65[b]
10 R=Bn, R1 =Ac
67[c]
The most unexpected results were observed for the deoxy
compounds 5 and 6, which were transformed into photoenols
13 and 14 upon irradiation at between 15 and 308C
(Scheme 2).[19] Compounds 13 and 14, which are surprisingly
5
6
5 R2 =TBDPSO
6 R2 =H
4.5 11 R2 =TBDPSO
12 R2 =H
75
61
5
[a] A solution of the 1,2-diketone in C6D6 or CDCl3 in a NMR tube was
irradiated with a daylight lamp (Philips master PL electronic, 23W/865)
placed at 2 cm. [b] Compound 9 was obtained as a 5:1 mixture of
isomers at C2. [c] Compound 10 was obtained as a 1:1 mixture of
isomers at C2. Bn=benzyl.
(Scheme 1). The photoreaction was completely inhibited by
pyrene as triplet quencher: No reaction was observed upon
irradiation at 308C for 12 h. Compound 7 is a crystalline solid
whose structure and stereostructure were elucidated by
extensive NMR spectroscopic studies and confirmed unam-
biguously by X-ray crystallographic analysis.[14] The config-
uration at the quaternary carbon atom of the hemiacetal is
stabilized by an intramolecular hydrogen bond between the
hydroxy group of the hemiacetal and the oxygen atom at C9,
as indicated by the X-ray crystal structure. We propose a
sequential mechanism for this transformation: A Norrish
type II photoelimination of the biradical intermediate I leads
to the photoenol II, which undergoes an intramolecular
enolexo aldol reaction (Scheme 1).[15] Finally, but probably
very importantly for the overall yield of the reaction, the
acetalization of the regenerated diketone moiety avoids the
possible absorption of visible light by the product.[16] The
hydrogen atom at C8 in 1 may be extracted by the external
carbonyl group to produce a 1,5-biradical, which rearranges
to the 1,4-biradical I by a well-known reaction of a-hydroxy
radicals,[17] or may be extracted directly by the internal
carbonyl group. The Norrish type II photoelimination of
1,2-diketones is an extremely rare reaction. We found a single
example in the literature in which the hydrogen atom appears
to be abstracted by the internal carbonyl group.[3b] Curiously,
the stereocenters at C4 and C8 destroyed in the photoreaction
are regenerated diastereoselectively with inversion of config-
uration in the aldol-cyclization step.
Scheme 2. Synthesis of photoenols 13 and 14. TBDPS=tert-butyldi-
phenylsilyl.
stable at room temperature for prolonged periods, could be
isolated without significant contamination by either the
starting material or the respective cyclized product. The oily
crude residues did not withstand chromatographic purifica-
tion, but were pure enough to enable complete analytical and
spectroscopic characterization (see the Supporting Informa-
tion). An NOE interaction between the methyl ketone and
the vinyl hydrogen atom is indicative of a Z configuration of
the double bond (Scheme 2). Both photoenols cyclized upon
heating in benzene with protection from light: 13 at 408C and
14, which is considerably more stable, at 608C. The aldol
reaction proceeded with a high degree of diastereoselectivity
to give the syn aldols 11 and 12 as single diastereoisomers, as
expected from Z-configured enolates.[20]
Oxidative degradation of the masked 1,2-diketone can be
realized with H5IO6 in MeOH. The oxidation of compounds 7
and 11 under these conditions and subsequent treatment with
diazomethane afforded 15 and 16, which represent a new type
of cyclopentitol (Scheme 3).[21] In the case of compound 11,
better results were obtained by b fragmentation induced by
the alkoxyl radical formed at the hydroxy group of the
hemiacetal in the presence of the reagent system PhI(OAc)2/
I2.[22]
We believe that the examples shown in Table 1 demon-
strate the general efficiency and usefulness of this method-
ology for the diastereoselective synthesis of densely function-
alized cyclopentitols of this new type from the pyranose series
of carbohydrates. The irradiation of nono-2,3-diuloses with
visible light results in a sequential rearrangement involving
unprecedented processes: a very unusual Norrish type II
We monitored the reaction by 1H NMR spectroscopy but
were unable to detect any of the photoenol II under these
reaction conditions (308C). Nevertheless, at 08C we observed
two signals assignable to the transient photoenol: a doublet at
d = 5.56 ppm (J = 9 Hz) and a broad singlet at d = 6.73 ppm
due to a hydrogen atom exchangeable with D2O.[18] Upon
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Received: July 29, 2008
Published online: October 9, 2008
Keywords: 1,2-diketones · aldol reaction · carbohydrates ·
.
photochemistry · radicals
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