Regioselectivity clysen 2011

8/6/2019 Regioselectivity clysen 2011

1/7

DOI: 10.1002/chem.201002757

Regioselectivity of the Claisen Rearrangement in meta-Allyloxy ArylKetones: An Experimental and Computational Study, and Application in the

Synthesis of (R)-()-Pestalotheol D

Catherine L. Lucas, Barry Lygo, Alexander J. Blake, William Lewis, andChristopher J. Moody*[a]

Introduction

In the century since its discovery,[1] the thermal rearrange-

ment of aryl allyl ethers, universally known as the Claisenrearrangement, has been the subject of numerous studiesand has found wide application in organic synthesis.[2] Nev-ertheless there are still some features of this well known re-action that are poorly understood. For example, the alkenegeometry resulting from rearrangement ofa,a-disubstitutedallyl ethers seems difficult to predict or control, whilst theregioselectivity in the rearrangement of meta-substitutedaryl allyl ethers remains unreliably predictable in spite ofexperimental and computational studies.[36]

In connection with a planned synthesis of the furo[2,3-g]chromene pestalotheol D (see below), it was reasoned

that the dihydrofuran ring of the natural product could beaccessed using the Claisen rearrangement methodology pre-

viously used by us in the synthesis of other natural prod-ucts,[715] with the requirement for a regioselective sigma-tropic rearrangement to C7 rather than C5 in the Claisen

precursor 1 (Scheme 1). We had previously observed goodregioselectivity in the related Claisen rearrangement of di-methyl allyl ether 3,[12] and we now describe a detailed ex-perimental and computational study of the Claisen rear-rangement of 3-allyloxy aryl ketones leading to a successful

Abstract: A study of the regioselectivi-ty of the Claisen rearrangement ofmeta-allyloxy aryl ketones showed thatthe electron-withdrawing carbonylgroup has a major influence andstrongly directs rearrangement to themore hindered ortho position. Howev-er, when the ketone is part of a ringstructure, its electronic effect can be

negated by conversion into its triiso-propylsilyl enol ether, which dramati-cally reverses the regiochemistry of theClaisen rearrangement. DFT calcula-

tions suggest that the effect is electron-ic although there is also a steric effectof the bulky silyl group. This strategyfor influencing the regiochemical out-come of the Claisen rearrangementwas then employed in a short synthesisof the furo[2,3-g]chromene, ()-pesta-lotheol D, that confirms the absolutestereochemistry of the natural product.

Keywords: Claisen rearrangement heterocycles natural product total synthesis

[a] C. L. Lucas, Prof. Dr. B. Lygo, Prof. Dr. A. J. Blake, Dr. W. Lewis,Prof. Dr. C. J. MoodySchool of Chemistry, University of NottinghamUniversity Park, Nottingham NG7 2RD (UK)Fax: (+44)114-951-3564E-mail: [email protected]

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201002757: Full experimentaldetails, X-ray crystal structures of ()-32 and (R)-31 (including .ciffiles), HPLC data, coordinates for all transition-state structures re-ported, and copies of 1H and 13C NMR spectra).

Scheme 1. Regioselective Claisen rearrangements: a) required for a syn-thesis of pestalotheol D; b) previously observed regioselectivity in a re-lated rearrangement.

2011 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 197219781972


2/7

synthesis of pestalotheol D, confirming both its structureand absolute stereochemistry.

Results and Discussion

Regioselectivity in the Claisen rearrangement of 3-allyloxyaryl ketones : Starting from the known chromanone 4, a nat-ural product isolated from Calea cuneifolia,[16] and readilyprepared from 2,5-dihydroxyacetophenone using a litera-ture procedure,[17] the dimethylallyl moiety was then incor-porated via a copper-mediated alkylation[18,19] to give the in-termediate alkyne 5, followed by hydrogenation over Lin-dlars catalyst to give the intermediate dimethyl allyl ether 1in 78% over the two steps. Claisen rearrangement of 1under microwave irradiation occurred with complete regio-selectivity, but unfortunately to the undesired 5-positionrather than the 7-position of the chromanone ring, givingcompound 6 in good yield (Scheme 2).

Clearly the rearrangement of the chromanone derivative1 (Scheme 2) is very different to that of chromene 3 previ-ously studied in our laboratory (Scheme 1),[12] and presuma-bly reflects the electronic effect of the chromanone carbonyl

group. Although the regiochemistry of the Claisen rear-rangement ofmeta-substituted phenyl allyl ethers is not easyto predict, there is limited evidence that, generally, electron-withdrawing meta-substituents favored rearrangement to themore hindered ortho-position, with electron-releasing meta-substituents favoring rearrangement to the para-position.[3,4]

In order to negate the apparently detrimental effect of thechromanone carbonyl group, two strategies were considered.The first involved reduction of the ketone in chromanone 1to the corresponding chromanol 7 with sodium borohydride,subsequently protected as its bulky tert-butyldiphenylsilyl(TBDPS) ether 8. The subsequent Claisen rearrangementsof these two substrates, carried out under microwave heat-

ing in DMF, gave a mixture of regioisomeric products 9 and10, easily separable and distinguishable by 1H NMR spec-troscopy, with the 5-prenyl isomer 10 predominating forboth the alcohol and silyl ether substrates (Scheme 3). Al-though this strategy does influence the outcome of theClaisen rearrangement and produce some of the desired re-

gioisomer 9, the selectivity remains poor, and, significantly,it involves an unattractive and avoidable change of oxida-tion state in the substrate.

We therefore adopted an alternative strategy that in-volved temporary masking of the chromanone carbonyl asits triisopropylsilyl (TIPS) enol ether 11, readily preparedfrom chromanone 1 in excellent yield. This silyl enol ether11 was then subjected to microwave irradiation in DMF togive a mixture of 7- and 5-prenyl chromenes 12 and 13 in a1:1 ratio, albeit in poor 26 % yield. Pleasingly, however, boththe yield and selectivity were vastly improved by switchingto toluene as solvent, and this gave an excellent yield (98%)of separable regioisomers in 5.5:1 ratio in favor of the de-sired 7-prenyl isomer 12 (Scheme 4).

Notwithstanding the aforementioned general effect ofmeta electron-withdrawing versus electron-releasing groups,this tactic of temporary removal of the electron-withdrawingproperties of a carbonyl substituent on an aromatic ring inorder to influence the regiochemical outcome of the Claisenrearrangement has apparently not been employed previous-ly, and therefore we briefly explored its generality, both ex-perimentally and by computation. Thus, 7-hydroxy-1-tetra-lone was converted into the propargyl ether 14 and hencethe allyl ether 15. Heating ether 15 in toluene under micro-wave irradiation resulted in a highly regioselective Claisenrearrangement in favor of the 8-prenyl isomer 17 in excel-lent yield (92%; ratio 16/17 1:7.5). On the other hand, the

Scheme 2.

Scheme 3.

Chem. Eur. J. 2011, 17, 1972 1978 2011 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim www.chemeurj.org 1973

FULL PAPER
http://www.chemeurj.org/http://www.chemeurj.org/


3/7

readily prepared TIPS enolether 18 underwent regioselec-tive Claisen rearrangement inthe opposite sense, with the 6-prenyl isomer 19 predominating(100% yield; ratio 19/20 4.6:1)

(Scheme 4). Hence in the relat-ed chromanone and tetraloneseries of compounds, a verysimilar pattern of reactivity isobserved, and on switching thep-acceptor properties of a car-bonyl substituent to the p-do-nating enol ether, the regiose-lectivity of the Claisen rear-rangement is inverted.

Since it was not clear wheth-er the observed change in re-gioselectivity was entirely elec-

tronic (p-acceptor vs p-donor)in nature, or whether steric1 ef-fects are also involved, addi-tional examples were sought.Consequently, the rearrange-ment of the simplest possiblemeta-acyl aryl dimethyl allylether was investigated. 3-Hy-droxyacetophenone was con-verted into the allyl ether 22 byway of the propargyl derivative21. Heating in toluene gave amixture (80%) of Claisen rear-

rangement products 23 and 24with, as expected, the 2-prenylisomer predominating (ratio 23/24 1:2.4). Conversion of ketone22 into the corresponding TIPSenol ether 25 followed by heat-ing in toluene gave a very simi-lar mixture of regioisomericClaisen rearrangement products26 and 27 in the ratio 1:2.2(Scheme 4). Hence in this case,the conversion of the methyl

ketone into its silyl enol etherhas little effect on the regiose-lectivity of the Claisen rearrangement. This suggests thatsteric factors do play a role, since the conformational con-straints provided by the chromanone or tetralone ringsensure that the steric effect of the bulky silyl group in enolethers 11 and 18 is more pronounced than in the enol ether25 where it can rotate out of the way.

Computational Study

In an attempt to distinguish steric and electronic factors forthe observed changes in regioselectivity, we performed aseries of DFT transition-state calculations in which we com-pared the effects of an electron-withdrawing ketone sub-stituent with the corresponding enol and silyl enol ethers(Table 1). This study was performed using B3LYP/6-31G*,as previous studies on the Claisen rearrangement of allylphenyl ethers have indicated that this method gives consis-tent results,[20,21] and because computation using a larger

Scheme 4.

1 Although the difference in regioselectivity in the Claisen rearrange-ments of the alcohol 7 and its TBDPS-ether 8 suggests that steric fac-tors may play a role, the substituents are at an sp3 center and thereforegeometrically distinct from the examples in question (1 vs 11, 15 vs 18)that involve substituents on an sp2 center.

www.chemeurj.org 2011 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 197219781974

C. J. Moody et al.


4/7

basis set (B3LYP/6-311++G**) on selected examples(Table 1, entries 13, 6) gavenear identical results. The pre-dicted relative energies of thechair-transition states for the

two rearrangement pathwaysfor a series of related 3-allyloxyaryl ketones and their enol de-rivatives, including substrates 1,15, 18, 22 and 25 that had beenstudied experimentally as de-scribed above, are shown inTable 1.

The results of these calcula-tions are broadly consistentwith the experimental resultsand clearly support the conclu-sion that both electronic and

steric effects contribute to theoverall regioselectivities. Specif-ically, the calculations suggestthat:

i) The keto group has astrong directing effect fa-voring the ortho-substitutedproduct (entry 1 vs entry 3).

ii) The gem-dimethyl has littleinfluence on the regiochem-istry of the rearrangement(entry 2 vs entry 3, entry 6

vs entry 7, and entry 9 vsentry 10).

iii) Switching from ketone toenol significantly reducesthe preference for theortho-substituted product(entry 2 vs entry 6, entry 3vs entry 7, and entry 4 vsentry 8).

iv) A combination of the elec-tronic effect and the stericbulk of the TIPS-group

would appear to be primar-ily responsible for theswitch in selectivity to the

para-substituted product(entry 7 vs entry 10 vsentry 11).

v) Rotation about the ArCbond allows the acyclicenol ether to minimize thislatter effect (entry 3 vsentry 5 and entry 11 vsentry 12).

Table 1. Relative transition-state energies leading to ortho- and para-Claisen rearrangement products.

Entry Substrate Relative energy [kcal mol1]ortho-TS para-TS

1 0.0 0.8

2 0.0 3.2

3 0.0 3.1

4 0.0 3.9

5 0.0 2.5

6 0.0 0.3

7 0.0 0.4

8 0.0 0.8

9 0.0 0.6

10 0.0 0.4


FULL PAPERClaisen Rearrangement in meta-Allyloxy Aryl Ketones


5/7

Comparison with experimental data suggests that, for themost part, the calculations predict the observed trends.However, it has previously been suggested that B3LYP/6-31G* may overestimate breaking and forming bond-lengths

in the transition state of the aromatic Claisen rearrangementby ca. 0.05 .[21] This may result in an over-estimation of theamount of the ortho-product, as increased steric compres-sion in a tighter transition state structure would be expectedto impact more on the pathway leading to the ortho-prod-ucts.

Synthesis of the furo[2,3-g]chromene natural product pesta-lotheol D : The pestalotheols were isolated in 2008 from Pes-talotiopsis theae fungal spores growing on an unidentifiedtree on a mountain in Hainan Province in China,[22] and as-signed the unusual highly oxygenated structures 2831(Scheme 5), three of which contain the furo[2,3-g]chromenenucleus. The structure of pestalotheol A 28 was confirmedby X-ray crystallographic analysis, and the absolute configu-rations of the secondary alcohols in both pestalotheols Aand C were determined as (R) by the use of the modifiedMosher method, thereby allowing assignment of the stereo-

chemistry of the other chiralcenters in the compounds byNMR spectroscopy. Althoughthe absolute stereochemistry ofpestalotheol D (31) was not re-ported,[22] we assumed that it

would also have the (R)-config-uration at C2, and in continua-tion of our interest in other nat-urally occurring chromenes,[14,23]

we set out to confirm the struc-ture and stereochemistry ofpestalotheol D by synthesisusing the regioselective Claisenrearrangement strategy devel-

oped in the above studies.With the 7-prenylchromene derivative 12 now available,

silyl deprotection using tetra-n-butylammonium fluoride inthe presence of water restored the ketone 2, poised for the

introduction of the dihydrofuran ring (Scheme 6). Initiallythis was carried out to give racemic pestalotheol D by epoxi-dation (64%) using mCPBA, followed by treatment of theepoxide 32 under basic conditions to effect ring closure. Thestructure of ( )-epoxide 32 was confirmed by X-ray crystal-lography (Figure 1). Alternatively, direct treatment of the

crude product from the epoxidation reaction with base obvi-ates the need for isolation of epoxide 32, and gives racemic

pestalotheol D (

)-31 in 88% yield over the two steps(Scheme 6). The compound had identical 1H and 13C NMRspectra to those reported in the literature.[22]

It remained to perform an asymmetric functionalizationof the prenyl double bond, and we elected to use the relia-ble Sharpless asymmetric dihydroxylation methodology.[24]

Initial studies into the dihydroxylation of phenol 2 were un-successful, and we had to resort to its protection as thebenzyl ether 33. Thereafter, dihydroxylation in the presenceof AD-mix-b proceeded smoothly, though owing to the in-solubility of benzyl ether 33, some tert-butyl methyl ether(MTBE) was added as a substitute for some of the tert-buta-nol component of the usual solvent mixture.[25] This deliv-

Table 1. (Continued)

Entry Substrate Relative energy [kcal mol1]ortho-TS para-TS

11 0.5 0.0

12 0.0 2.0

Scheme 5. Structures of pestalotheols AD; although the stereochemistryof pestalotheol D (31) was not reported,[22] we propose it to have the(R)-configuration at C2 as shown.

Figure 1. X-ray crystal structure of ()-7-((3,3-dimethyloxiran-2-yl)-methyl)-6-hydroxy-2,2-dimethylchroman-4-one (32).

www.chemeurj.org 2011 Wiley-VCH Verlag GmbH& Co. KGaA, Weinheim Chem. Eur. J. 2011, 17, 197219781976

C. J. Moody et al.


6/7

ered the (R)-diol 34 in excellent yield and 93% ee (byHPLC comparison with the racemate), the stereochemistrybeing assigned on the ample precedent when using AD-mix-

b, and confirmed by X-ray crystallography of the final prod-uct (Figure 2). With the desired chirality installed, the secon-dary hydroxyl was converted into the corresponding mesy-late (used without purification), and hence the (S)-epoxide35 (Scheme 7). Finally the chiral epoxide 35 was hydrogeno-lyzed under basic conditions to effect the required 5-exo-tet

ring closure of the resulting phenolic epoxide in situ to pro-vide (R)-pestalotheol D in excellent yield. Comparison withthe racemic sample by HPLC on a chiral stationary phasesuggested that the material had an enantiomeric excess of87%, and its optical rotation [a]23D 7.16 (c = 0.2, MeOH)is close to that reported.[22] Although the natural productwas described as a gum, we were able to recrystallize it, andhence confirm the absolute configuration of our syntheticmaterial as (R) by X-ray crystallography (Flack parameter=0.05; Figure 2).

The successful synthesis described herein not only con-firms the absolute stereochemistry of the natural product,but also features a new strategy for influencing the regio-chemical outcome of the Claisen rearrangement of meta-al-lyloxy aryl ketones.

Experimental Section

Full experimental details are given in the Supporting Information.

Acknowledgements

We thank the EPSRC for support of this work via the DTA Scheme.

[1] L. Claisen, Ber. Dtsch. Chem. Ges. 1912, 45, 3157.[2] A. M. Martn Castro, Chem. Rev. 2004, 104, 2939.[3] W. N. White, C. D. Slater, J. Org. Chem. 1961, 26, 3631.[4] J. M. Bruce, Y. Roshan-Ali, J. Chem. Soc. Perkin Trans. 1 1981,

2677.

Scheme 6. Synthesis of racemic pestalotheol D.

Scheme 7. Synthesis of (R)-pestalotheol D.

Figure 2. X-ray crystal structure of (R)-pestalotheol D (31).


FULL PAPERClaisen Rearrangement in meta-Allyloxy Aryl Ketones
http://dx.doi.org/10.1002/cber.19120450348http://dx.doi.org/10.1002/cber.19120450348http://dx.doi.org/10.1002/cber.19120450348http://dx.doi.org/10.1002/cber.19120450348http://dx.doi.org/10.1002/cber.19120450348http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1039/p19810002677http://dx.doi.org/10.1039/p19810002677http://dx.doi.org/10.1039/p19810002677http://dx.doi.org/10.1039/p19810002677http://www.chemeurj.org/http://www.chemeurj.org/http://dx.doi.org/10.1039/p19810002677http://dx.doi.org/10.1039/p19810002677http://dx.doi.org/10.1021/jo01068a004http://dx.doi.org/10.1002/cber.19120450348


7/7

Regioselectivity clysen 2011

Documents

Transcript of Regioselectivity clysen 2011