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Tetrahedron: Asymmetry 11 (2000) 2409±2420

Synthesis of various 2H-benzopyran compounds and their

kinetic resolution by asymmetric hydrolysis of their racemic

acetates mediated by lipases

J. Y. Goujon, F. Zammattio* and B. Kirschleger

Laboratoire de SyntheÁse Organique, CNRS UMR 6513, FaculteÂ des Sciences et des Techniques, 2 rue de la HoussinieÁre,

44072 Nantes Cedex 03, France

Received 21 April 2000; accepted 5 May 2000

Abstract

The preparation of 2H-benzopyrans from bromophenols and tertiary allylic alcohols is described. The

reaction is characterised by its mildness, good yields and ease of work-up. Kinetic resolution of the latter

up to 95% ee was obtained by using enzyme-catalysed enantioselective hydrolysis. # 2000 Elsevier Science

1. Introduction

The central role of heterocycles in life sciences and natural product chemistry provides a

constant drive for the development of even more ecient methods for their preparation. Among

them, benzopyran and 3,4-dihydrobenzopyran nuclei are present in many biologically active com-

pounds, such as a -tocopherol or vitamin E, 1 levcromakalim, 2 cannabichromene 3 and ubichromenol

or cordiachromene 1e. 4 This latter compound was ®rst isolated from Cordia alliodora, which is a

tropical American tree whose wood is known for its durability in marine use. Moreover, cordia-

chromene exhibits high anti-in¯ammatory activity, 5 which seems to be due to a selective inhibition

of cyclooxygenase. 5

In the course of our interest concerning the development of new methods for the construction

of benzopyran nuclei, we became interested in the preparation of substituted-3,4-dihydro-

benzopyrans of type 1, 2 and 3 with various R substituents. In addition, we also wanted to study

the in¯uence of relative and absolute stereochemistry of the stereogenic centre on the inhibition of

cyclooxygenase.

* Corresponding author. Fax: 02 51 12 54 12; e-mail: fancoise.zammattio@chimie.univ-nantes.fr

PII: S0957-4166(00)00176-2

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The most used strategies for the synthesis of 3,4-dihydrobenzopyran nuclei involve a Claisen

rearrangement of propargyl ethers 6 or a cyclisation of substituted quinones in re¯uxing pyridine. 7

To try to introduce aryl diversity using readily available phenols, we envisaged a particularly

attractive approach, similar to the one reported by SaaÁ , 8 based on a palladium-catalysed reaction

of a tertiary allylic alcohol with an ortho-bromophenol. This strategy has been used in order to

circumvent the lack of availability of 2-iodophenols, which are the starting materials in the SaaÁ 8

route. Moreover, to explore the scope and limitations of this process as well as its ability to

facilitate the synthesis of various 3,4-dihydrobenzopyran, we systematically investigated the

reaction of various tertiary allylic alcohols with diverse ortho-bromophenols using palladium

acetate as the precatalyst.

In this paper, we are reporting our results concerning syntheses of compounds 1, 2 and 3 and

enzymatic kinetic resolution of 1e and 2b as an alternative for their stereocontrolled construction.

2. Results and discussion

2.1. Synthesis of 2H-1-benzopyran derivatives 1 to 3

Chiral racemic allylic alcohols 9, 10 and 11 were prepared as shown in Scheme 1. The treatment

of 4 with bromine 9 in methylene chloride provided the desired 2-bromophenols 5 in high yields.

Heck reaction of 5 with 2 mol equiv. linalool 6 in CH 3 CN in the presence of CsCO 3 (0.5 equiv.)

Scheme 1. Synthesis of compounds 1, 2 and 3

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420

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and 5 mol% of Pd(OAc) 2 at 100 C for 3 h gave the corresponding allylic alcohols 9 in satisfactory

yields (Table 1: entries 1±4). These results show that the Heck coupling reaction works well with

2-bromophenols bearing electron withdrawing or donating groups. On the other hand, it is

noteworthy that the same conditions could be applied to the preparation of analogues 10 and 11

(Table 1: entries 5 and 6) from the nerolidol 7 or the geranyl linalool 8, respectively.

Table 1

Heck reaction of bromophenols 5 with allylic alcohols 6, 7 and 8

Finally, conversion of 9, 10 and 11 to the corresponding 2H-1-benzopyrans 1, 2 and 3 was

simply achieved in quantitative yields by heating pure 9, 10 or 11 at 120 C, under vacuum for 30

min.

2.2. Kinetic resolution of 1e and 2b

With the desired 1a and 2a in hand, we turned our attention to their kinetic resolution as an

alternative to their asymmetric synthesis. With this aim, removal of the benzyl-protecting group

was ®rst undertaken. The Lewis acid deprotection 10 of 1a and 2a aorded compounds 1e and 2b

(Table 2) which served as key starting materials for our enzymatic resolution. Then, three lipases

were tested for the enantioselective hydrolysis of racemic acetate ( þ )-12 generated from 1e (Table 2).

As shown by the results listed in Table 2, the lipase from Candida cylindracea (CCL) was found to

be the most eective one, even if ( + )-12 and ( ^ )-12 were not resolved with the same eciency,

leaving the enantiopure acetate ( ^ )-12 in satisfactory chemical yield and enantiomeric excess

(Table 2: entry 2). Acetate ( ^ )-12 gave 2H-1-benzopyran ( ^ )-1e in quantitative yield on K 2 CO 3

mediated methanolysis. With the success of this kinetic resolution, we applied this methodology to

the trans racemic acetate ( þ )-13 generated from the trans ( þ )-2b (Table 2). Subsequently, enzymatic

hydrolysis and methanolysis of the pure trans enantiomer ( ^ )-13 aorded the corresponding trans

2H-1-benzopyran ( ^ )-2b (>98% ee) in 20% yield (Table 2: entry 4). The hydrolysis of substrates

was followed by HPLC analysis. As an example, the HPLC analysis of a sample of acetate 12 is

reported in Figs. 1 and 2.

2.3. Absolute con®guration of 1e and 2b

Since optically active 2H-1-benzopyrans 1e, 2b, 12 and 13 have never been described, we could

not, at this stage of our study, assign the absolute con®guration of the stereogenic centre (C2).

Nevertheless, the (S) preference observed with lipase AY in the case of enantioselective hydrolysis

of (RS)-tocol acetate, 11 which is very similar to substrates (RS)-12 and (RS)-13, supports the

hypothesis that these latter substrates could be hydrolysed with the same enantioselectivity. To

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J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420

Table 2

Lipase-catalysed kinetic resolution of 2H-1-benzopyran acetates ( þ )-12 and 13

Figure 1. HPLC analysis of racemic acetate 12

J. Y. Goujon et al. / Tetrahedron: Asymmetry 11 (2000) 2409±2420

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Figure 2. HPLC analysis of hydrolysis reaction mixture containing ( ^ )-12 and ( þ )-1e (Chiralcel OD-H, hexane:propan-

2-ol, 95:5, ¯ow 0.5 ml/min, l 254 nm)

con®rm the enantiopreference of lipases AY and CCL, kinetic resolution of racemic acetate 15,of

which both the relative and absolute con®guration of each enantiomer were known, 12b was carried

out. Racemic acetate 15 was prepared as reported 12a and submitted to lipase hydrolysis. From the

reaction mixture, recovered ( + )-15 could be isolated in 15% yield and 70% ee (Scheme 2). The

con®guration of the pure enantiomer ( + )-15 was unequivocally established as (R) by comparison

of its speci®c rotation with that of an authentic sample of (R)-( + )-15. 12b This result con®rmed the

(S) enantiopreference of the enzyme and allows us to assign the (R) con®guration at C2 for ( ^ )-12

and ( ^ )-13 as well as for ( ^ )-1e and ( ^ )-2b.

Scheme 2. Lipase-catalysed kinetic resolution of (RS)-15. (a) Ac 2 O, DMAP, Et 3 N, CH 2 Cl 2 ,25 C; (b) lipase CCL, IPE/

H 2 O

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