Retention of configuration in photolytic decarboxylation of peresters to form chiral acetals and ethers

Article abstract of DOI:10.1021/ol802745n

(Chemical Equation Presented) Peresters generate ethers in good yields when photolyzed in the absence of solvent using short wavelength UV light. At -78 °C or below, the process proceeds predominantly with retention of configuration at the site adjacent to the carbonyl where the decarboxylation occurs, but increase in temperature results in loss of stereochemical control. Chiral acyclic acetals can be prepared using precursors derived from tartaric or malic acids.

Full text of DOI:10.1021/ol802745n

ORGANIC
LETTERS
2009
Vol. 11, No. 3
645-648
Retention of Configuration in Photolytic
Decarboxylation of Peresters to Form
Chiral Acetals and Ethers
M. Daniel Spantulescu, Marc A. Boudreau, and John C. Vederas*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
john.Vederas@ualberta.ca
Received November 27, 2008
ABSTRACT
Peresters generate ethers in good yields when photolyzed in the absence of solvent using short wavelength UV light. At -78 °C or below,
the process proceeds predominantly with retention of configuration at the site adjacent to the carbonyl where the decarboxylation occurs, but
increase in temperature results in loss of stereochemical control. Chiral acyclic acetals can be prepared using precursors derived from
tartaric or malic acids.
Photolysis of diacyl peroxides derived from glutamic and/
or aspartic acids provides a convenient method for generation
of unusual chiral R-amino acids (Scheme 1).1,2 Interestingly,
an aspartic peracid derivative used as a precursor in the
synthesis of such diacyl peroxides is also useful for chiral
epoxidations.3 During our studies, we observed that pho-
tolysis of analogous peresters results in homolytic cleavage
of the peroxide bond followed by decarboxylation and radical
coupling to give ether derivatives of serine or homoserine.1a
As coupling of the radicals derived from the diacyl perox-
ides1,2 proceeds with excellent retention of configuration at
low temperature in the absence of solvent, it seemed that
the corresponding reaction of peresters having a stereogenic
center adjacent to the carbonyl could allow generation of
chiral ethers. In the present study, we investigate the scope
of this reaction with derivatives of glutamic acid, malic acid
and tartaric acid for preparation of ethers, chiral acyclic
acetals and deoxy sugar derivatives. Although excellent
stereochemical control of formation of cyclic acetals (e.g.,
sugars) is often readily achieved with the assistance of
stereoelectronic effects, this is more difficult with acyclic
systems. Previous syntheses of chiral acyclic acetals have
been realized via the Baeyer-Villiger oxidation of optically
active R-alkoxy ketones,4 the enantioselective reduction and
acetylation of esters,5 or the methoxyselenenylation of alkyl
vinyl ethers.6 These methodologies are useful, but employ
different starting materials. In addition, they can sometimes
necessitate either lengthy syntheses to access the required
(1) (a) Spantulescu, M. D.; Jain, R. P.; Derksen, D. J.; Vederas, J. C.
Org. Lett. 2003, 5, 2963–2965. (b) Jain, R. P.; Vederas, J. C. Org. Lett.
2003, 5, 4669–4672. (c) Stymiest, J. L.; Mitchell, B. F.; Wong, S.; Vederas,
J. C. J. Org. Chem. 2005, 70, 7799–7809. (d) Martin, N. I.; Woodward,
J. J.; Winter, M. B.; Beeson, W. T.; Marletta, M. A. J. Am. Chem. Soc.
2007, 129, 12563–12570
.
(2) For related studies on other peroxides see: (a) Feldhues, M.; Scha¨fer,
H. J. Tetrahedron 1985, 41, 4213–4235. (b) Feldhues, M.; Scha¨fer, H. J.
Tetrahedron 1986, 42, 1285–1290. (c) Lomo¨lder, R.; Scha¨fer, H. J. Angew.
(4) Matsutani, H.; Ichikawa, S.; Yaruva, J.; Kusumoto, T.; Hiyama, T.
Chem., Int. Ed. Engl. 1987, 26, 1253–1254
.
J. Am. Chem. Soc. 1997, 119, 4541–454.
(3) (a) Peris, G.; Jakobsche, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007,
129, 8710–8711. (b) Jakobsche, C. E.; Peris, G.; Miller, S. J. Angew. Chem.,
Int. Ed. 2008, 47, 6707–6711. (c) Berkessel, A. Angew. Chem., Int. Ed.
2008, 47, 3677–3679.
(5) Rychnovsky, S. D.; Bax, B. M. Tetrahedron Lett. 2000, 41, 3593–
3596.
(6) Uchiyama, M.; Satoh, S.; Ohta, A. Tetrahedron Lett. 2001, 42, 1559–
1562.
10.1021/ol802745n CCC: $40.75
Published on Web 12/29/2008
2009 American Chemical Society

Scheme 1
.
Preparation and Low Temperature (-78 to -196 °C)
Scheme 3. Proposed Mechanisms of Decomposition of
Photolysis of Diacyl Peroxides in the Absence of Solvent and
Corresponding Formation and Photolysis of Peresters
R-Alkoxy (R3 ) Alkyl), R-Hydroxy (R3 ) H) and Mono
R-N-Acylamino (R4 ) Acyl) Perestersa
a Peresters such a 6 bearing two acyl substituents on nitrogen are much
more stable.
substrates or can suffer from limited scope and modest
stereoselectivity.
oxygen (e.g., hydroxy or alkoxy) is present at the R-carbon
of the acid, attempted perester formation leads to heterolytic
decomposition to an N-acyl iminium ion or oxonium ion,
respectively (Scheme 3).8 These then swiftly react with a
nucleophile. Substitution of the nitrogen with an additional
acyl group (e.g., phthalimido or succinimido)8a does stabilize
these systems such that peracids or peresters can be isolated.
Hence it is possible to prepare the t-butyl perester of a bis-
Boc protected R-amino acid such as 6 after a tedious series
of protection and deprotection steps. Fortunately, peresters
having an acylated oxygen R to the carbonyl are considerably
more stable and easier to prepare. Syntheses of such peresters
proceeds reasonably from the corresponding acids and
hydroperoxides under standard conditions.
Scheme 2
.
Examples of Synthesis of Peresters from Protected
Glutamates
We previously reported preparation of t-butyl ethers of
protected serine and homoserine (e.g., 7) by photolysis of
the corresponding t-butyl peresters of protected aspartate and
glutamate (e.g., 2) (Scheme 4).1a To further examine the
scope of this reaction, 4 and 5 were photolyzed in the absence
of solvent at -196 °C to afford the corresponding ho-
moserine ethers 8 and 9. The yields are lower upon going
from a tertiary to a primary or secondary hydroperoxide. This
may be a result of a higher propensity for side reactions to
occur with these less-substituted radical intermediates. The
results demonstrate that a large variety of chiral R-amino
acids with an ether oxygen in the side chain are readily
accessible by this method.
To examine the stereochemical outcome of photolyses of
O-acylated R-hydroxy peresters, commercially available
tartaric and malic acid derivatives were converted to corre-
sponding protected t-butyl peresters (Scheme 5). Typically,
the R,R-tartaric acid (10), its benzoylated derivative 11, or
alternatively, meso-tartaric acid (21) can be cyclized with
Syntheses of functionalized peresters that do not have an
oxygen or nitrogen substituent on the R-carbon adjacent to
a perester carbonyl usually proceed uneventfully from the
corresponding acid and hydroperoxide using a standard ester
formation method, such as dicyclohexylcarbodiimide (DCC)
and N,N-dimethylaminopyridine (DMAP) (Scheme 2).7
Primary and tertiary hydroperoxides typically give better
yields of perester (95-99%) than secondary hydroperoxides
(50%). In contrast, if a monoacylated nitrogen or nonacylated
(8) (a) Ru¨chardt, C.; Hamprecht, G. Chem. Ber. 1968, 101, 3957–3962.
(b) Formaggio, F.; Crisma, M.; Scipionato, L.; Antonello, S.; Maran, F.;
Toniolo, C. Org. Lett. 2004, 6, 2753–2756.
(7) Greene, F. D.; Kazan, J. J. Org. Chem. 1963, 28, 2168–2171.
646
Org. Lett., Vol. 11, No. 3, 2009

Scheme 4
.
Synthesis of Homoserine Derivatives via Photolysis
of Glutamate-Derived Peresters
Scheme 5
.
Syntheses of t-Butyl Peresters Derived from Tartaric
and Malic Acids
acetic anhydride or pivaloyl chloride to produce the tartaric
anhydrides 12-14 or 22 and 23, respectively. Opening of
the ring with methanol affords the corresponding acylated
monoesters with one free carboxylic acid group 15-17 or
24-rac and 25-rac. Compounds 15-17 are optically pure,
but 24 and 25 are produced as racemates because nucleo-
philic attack proceeds equally well at either the carbonyl
adjacent to the R center or to the S center. Standard
esterification with t-butyl hydroperoxide and DCC gives
reasonable yields of the corresponding peresters 18-20 or
26-rac and 27-rac. Esterification of benzyl S-(O-acetyl)
malate (28) with methanol and DCC to generate diester 29
followed by hydrogenolysis affords 30, which can be
similarly converted to the perester 31.
Photolysis in the absence of solvent of the peresters
(usually not crystalline) at -196 °C, efficiently gives the
product acetals in good to excellent yields with nearly full
retention of stereochemistry at the R-center (Table 1). Such
reaction of diacetoxy tartaric perester 18 gives acetals 32
and 33 in a diastereomeric ratio (d.r.) of 19:1 (Entry 1), as
determined from the integration ratio of nonoverlapping
1
signals in the H NMR spectrum. Photolysis of its diaste-
reomer 26-rac gives the expected opposite stereochemistry
(Entry 4). As observed with diacyl peroxides,1 retention of
stereochemistry presumably arises from homolytic cleavage
of the peroxide bond followed by decarboxylation and cage
recombination of the radicals. Hence, increasing the size of
the protecting groups would be expected to further restrict
movement in the viscous solid state, leading to an increase
in diastereoselectivity. However, this is not the case, as
dibenzoyl tartaric ester 19 gives the corresponding acetals
34 and 35 with the same d.r. as for 18 upon photolysis (Entry
2), and dipivaloyl tartaric peresters 20 and 27-rac result in
only a slight increase in the d.r. (Entries 3 and 5, respec-
tively). Apparently, the restriction of movement of the
interemediate radicals is not significantly different. However,
a major erosion of diastereoselectivity is observed upon
increasing the temperature, with a d.r. of approximately 2:1
at room temperature (results not shown). Photolysis of
R-acetoxy malic perester 31 gives acetals 42 and 43 with an
enantiomeric ratio (e.r.) of 9:1, as determined using a chiral
NMR shift reagent. The lower stereoselectivity compared
to the tartaric peresters appears to arise because of the
absence of the extra substituent ꢀ to the perester. Presumably
the more compact structure has fewer intermolecular interac-
tions that would further restrict bond rotation and consequent
inversion of the intermediate radical.
In summary, this methodology is readily accessible and
requires no specialized equipment. As described in Support-
ing Information, the neat perester precursor can usually be
placed in a small polyethylene bag, covered with liquid
nitrogen in a dewar and photolyzed with common com-
mercial UV lamps. The approach offers a convenient route
to functionalized ethers, for example, R-amino acids bearing
an alkoxy group in the side chain. Significantly, it also affords
Org. Lett., Vol. 11, No. 3, 2009
647

ethers, used as mixtures of stereoisomers, are useful inter-
mediates for formation of oxycarbenium ions that can be
trapped with a large variety of nucleophiles or utilized in
Prins cyclizations.9 They also offer intriguing potential as
enzyme inhibitors or pharmaceutical agents, as some corre-
sponding chiral O,S-acetals are drug candidates or precur-
sors.10
Table 1. Photolysis of Tartaric and Malic Perestersa
Acknowledgment. Financial support was provided by the
Natural Sciences and Engineering Research Council of
Canada (NSERC), the Alberta Heritage Foundation for
Medical Research (AHFMR), and the Canada Research Chair
in Bioorganic and Medicinal Chemistry.
Supporting Information Available: Experimental details
and spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL802745N
(9) (a) Kopecky, D. J.; Rychnovsky, S. D. Org. Syn. 2003, 80, 177–
183. (b) Jasti, R.; Anderson, C. D.; Rychnovsky, S. D. J. Am. Chem. Soc.
2005, 127, 9939–9945.
a Conditions: neat, -196 °C, 16-24 h
(10) (a) Brand, S.; Jones, M. F.; Rayner, C. M. Tetrahedron Lett. 1997,
38, 3595–3598. (b) Larsen, R. D.; Corley, E. G.; King, A. O.; Carroll, J. D.;
Davis, P.; Verhoeven, T. R.; Reider, P. J.; Labelle, M.; Gauthier, J. Y.;
Xiang, Y. B.; Zamboni, R. J. J. Org. Chem. 1996, 61, 3398–3405. (c)
Gauthier, J. Y.; Jones, T.; Champion, E.; Charette, L.; Dehaven, R.; Ford-
Hutchinson, A. W.; Hoogsteen, K; Lord, A.; Masson, P.; Piechuta, H.; Pong,
S. S.; Springer, J. P.; Thbrien, M.; Zamboni, R.; Young, R. N. J. Med.
Chem. 1990, 33, 2841–2845. (d) Gauthier, J. Y.; Martins, E. O.; Young,
R. N.; Zamboni, R. J. SynLett 2002, 984–986.
a facile approach to synthesis of chiral acyclic acetals with
high optical purity. Such compounds, having a stereogenic
center at the noncyclic acetal carbon, are often difficult to
obtain with high enantiomeric excess.4-6 Acyclic R-acyloxy
648
Org. Lett., Vol. 11, No. 3, 2009