Asymmetric Mn(III)-based radical synthesis of functionalized 2,3-dihydrofurans

Article abstract of DOI:10.1016/S0040-4039(00)01729-9

The oxidative radical addition of alkyl acetoacetates to p-methoxycinnamoyl oxazolidinones promoted by Mn(III) has been studied. It only gives trans-disubstituted 2,3-dihydrofurans, with d.r. ranging from 2:1 to 9:1, depending on the substituent of the chiral auxiliary. After chromatographic separation of the two diastereomers, the oxazolidinone can be removed to afford enantiopure dihydrofuranyl esters in good overall yield. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01729-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9803–9807
Asymmetric Mn(III)-based radical synthesis of
functionalized 2,3-dihydrofurans
Fre´de´ric Garzino, Alain Me´ou and Pierre Brun*
Laboratoire de Synthe`se Organique Se´lective, GCOMM, UMR-CNRS 6114, Faculte´ des Sciences de Luminy,
163 Avenue de Luminy, F-13288 Marseille Cedex 9, France
Received 28 July 2000; accepted 28 September 2000
Abstract
The oxidative radical addition of alkyl acetoacetates to p-methoxycinnamoyl oxazolidinones promoted
by Mn(III) has been studied. It only gives trans-disubstituted 2,3-dihydrofurans, with d.r. ranging from
2:1 to 9:1, depending on the substituent of the chiral auxiliary. After chromatographic separation of the
two diastereomers, the oxazolidinone can be removed to afford enantiopure dihydrofuranyl esters in good
overall yield. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: optically active trans-2,3-disubstituted dihydrofurans; radical asymmetric synthesis; oxidative cyclization;
manganese(III) acetate.
The tetrahydrofuran ring is a ubiquitous motif which can be found in numerous natural
products (e.g. polyether antibiotics, nucleosides, lignans).1 Clearly, general methods to prepare
non-racemic substituted THF are needed in order to address the extraordinary diverse pattern
of stereochemistry and substitutions existing in these THF-containing natural products. One
such approach could consist of the initial synthesis of functionalized chiral 2,3-dihydrofuran
precursors whose functionalities and remaining double bond could be subsequently
manipulated.
The Mn(OAc)3-mediated oxidative free radical addition of acetoacetic esters to alkenes
represents one such useful synthetic reaction as it cleanly furnishes, in one step, 2,3-dihydro-
furans as the sole products (provided that the reaction is performed in the absence of oxygen,
in order to prevent the formation of unwanted cyclic peroxides).2 Furthermore, when using
methyl cinnamates as substrates, it has been shown to be totally regio- and diastereoselective,
giving a single diastereomer (possessing two esters of markedly different chemical reactivity and
two vicinal stereocenters in a trans relative relationship) in fair to good yield depending
essentially on the nature of Ar (Scheme 1).3
* Corresponding author. Fax: (33)491829415; e-mail: brun@chimlum.univ-mrs.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01729-9

9804
Scheme 1.
Surprisingly, no results could be found in the literature concerning the control of the absolute
configuration of these stereocenters in the case of intermolecular additions and very little work
has been published on intramolecular versions of this reaction.4
We thus endeavoured to study this control by using chiral auxiliaries linked to the cinnamoyl
moiety (a selectivity)5 choosing, in this communication, to evaluate the capability of oxazolidi-
nones as these chiral controllers (despite the fact that, in the only previous case when they were
tried in an intramolecular Mn(III)ꢀCu(II) oxidative cyclization, the substrate failed to react).4a–c
Indeed, oxazolidinones constitute excellent chiral auxiliaries due to the diversity and ready
availability of precursor amino acids (natural and unnatural), their ease of grafting onto the
substrate and cleavage from the intermediate product. Moreover, their robustness could enable
them to survive the acidic conditions, the elevated temperature and the duration necessary to
carry out this reaction. Their usefulness for acyclic diastereoselection in other radical addition
reactions is well documented5 but, in order to obtain significant diastereoselectivities, it is quite
often necessary to use them in conjunction with an added Lewis acid to chelate the two
carbonyls of the N-acyloxazolidinone thereby restricting the number of possible rotamers.6
Nonetheless, we hoped that Mn salts might somehow exhibit a chelating role thus obviating the
need for an extra Lewis acid.
In order to determine which factors control the diastereoselectivity, we decided to react alkyl
acetoacetates7 with p-methoxycinnamoyl oxazolidinones,8 varying the nature of the R1 sub-
stituent on the oxazolidinone and of the R2 substituent on the ester. Our results are summarized
in Scheme 2 and Table 1.9
Scheme 2.

9805
Table 1
Addition of acetoacetic esters 2 on cinnamoyloxazolidinones 1. Relative ratio of diastereomers 3:4
Entry
1 (R1)
2 (R2)
3:4a
Yield (%)
Unreacted 1 (%)
1
2
3
4
5
6
7
8
9
PhCH2
PhCH2
PrI
Me
Pri
2:1
80b
72c
75b
69c
80b
74c
65c
80c
75c
8
9
5
2:1
2.7:1
2.7:1
5.3:1
5.3:1
5.3:1
9:1
Me
PrI
Pri
15
10
10
10
Traces
5
But
Me
Pri
But
But
Add
Me
Pri
Ph2CH
Ph2CH
9:1
1
a Determined on the crude product by H and 13C NMR (250 MHz) and GC on an SE30 capillary column.
b Purified mixture of non separable 3+4.
c Pure isolated 3 and 4.
d Ad=1-adamantyl.
As can be seen, the regio- and trans diastereoselectivities as well as the overall yield of isolated
dihydrofurans are retained on going from an achiral p-methoxycinnamate (Scheme 1) to a chiral
one. In each case, 3 and 4 are the only products formed in a relative ratio depending exclusively
on the R1 substituent of the oxazolidinone: the d.r. increases (from 2:1 to 9:1) with the bulkiness
of R1 while the R2 group on the radical precursor plays no part in the discriminative step
(compare entries 1/2, 3/4, 5/6/7, 8/9). This is in good accord with a proposed model accounting
for the sense of diastereoselection in radical additions using N-enoyloxazolidinones and a
chelating agent,6 positioning R1 in such a way as it will preferentially shield one of the
diastereotopic faces of the enoyl moiety.10
In all instances where R2=Pri, the two diastereomers 3 and 4 could be readily separated by
chromatography and the oxazolidinone removed by methanolysis to give enantiopure 5 and
ent. 5, respectively (Scheme 3).11
Scheme 3.
Determination of the absolute configuration
As in any of the cases already tested, neither 3 nor 4 could be induced to crystallize, we
prepared enantiomerically pure crystalline 7 (75% overall yield) by selective monosaponification

9806
of enantiopure 5 into the monoacid 6, formation of its acid chloride and in situ reaction with
the sodium salt of (−)-10,2-camphorsultam12 (Scheme 4).
Scheme 4.
An X-ray structure determination of 7 allowed to unambiguously establish the absolute
configuration of the stereocenters on the dihydrofuran moiety as being 2R and 3R. It follows
that 5 is (2R,3R) and ent. 5 (2S,3S) as depicted in Scheme 3.
We have shown for the first time that the intermolecular Mn(III)-mediated oxidative addition
of acetoacetic esters to alkenes can afford a high level of stereocontrol like its intramolecular
counterpart. The reaction gives rise to enantiopure 2,3-dihydrofuranyl diesters in good overall
yield. In order to extend its synthetic scope, the study of other chiral auxiliaries is underway.
References
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1999, 16, 75–96. (d) Elliott, M. C. J. Chem. Soc., Perkin Trans. 1 2000, 1291–1318.
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7. Except for commercially available methyl acetoacetate, alkyl acetoacetates 2 were prepared from 2,2,6-trimethyl–
4H-1,3-dioxin-4-one and the appropriate alcohol in refluxing xylene.

9807
8. Cinnamoyloxazolidinones 1 were obtained by reaction of p-methoxycinnamoyl chloride and the lithium salt of
oxazolidinones derived from (S)-phenylalaninol (R1=PhCH2), (S)-valinol (R1=Pri), (S)-tert-leucinol (R1=But)
and (R)-serine methyl ester (R1=Ph2CH) in THF.
9. General procedure: N-cinnamoyloxazolidinone 1 (1 mmol), alkyl acetoacetate 2 (1 mmol) and Mn(OAc)3·2H2O
(590 mg, 2.2 mmol) in acetic acid (10 mL) were heated at 70°C under nitrogen for 3 h. After cooling, water was
added and the mixture extracted with diethyl ether. The organic extracts were washed with aqueous NaHCO3 and
dried over MgSO4. Evaporation of the solvent afforded the crude product which was purified by flash
chromatography (hexane/ether: from 16:1 to 1:1) giving first unreacted 1 then 3 and 4. All new compounds
exhibited spectral (IR, NMR) and analytical characteristics consistent with their structure.
10. It was shown that the reaction of N-acetoacetyloxazolidinones with methyl p-methoxycinnamate gives two
diastereomeric dihydrofurans in lower combined yield (40–45%) and with a poor d.r. (1.5:1), independently of R1
(PhCH2, Pri, But). This result demonstrates that the diastereoselectivity is essentially substrate-controlled.
11. Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 2093–2125.
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