Use of the p-Tolylsulfinyl group as a chiral inductor in stereoselective [4+3] cycloaddition reactions: Preparation of enantiopure polysubstituted 8-oxabicyclo[3.2.1]oct-6-en-3-one systems having up to five stereocenters

FULL PAPER

DOI: 10.1002/ejoc.201301814

Use of the p-Tolylsulfinyl Group as a Chiral Inductor in Stereoselective [4+3]

Cycloaddition Reactions: Preparation of Enantiopure Polysubstituted

8-Oxabicyclo[3.2.1]oct-6-en-3-one Systems Having up to Five Stereocenters

Ángel M. Montaña,*^[a]Pedro M. Grima,^[b]Consuelo Batalla,^[a]Francisca Sanz,^[c]and

Gabriele Kociok-Köhn^[d]

Keywords: Cycloaddition / Chirality / Oxygen heterocycles / Sulfoxides

The use of the p-tolylsulfinyl group as a chiral inductor in

stereoselective [4+3] cycloaddition reactions has made pos-

sible the preparation of enantiopure polysubstituted 8-oxa-

bicyclo[3.2.1]oct-6-en-3-one systems having up to five

stereocenters. The presence in the furan diene of a susbtitu-

ent at the 3-position bearing an atom with lone-pair electrons

propitiates the coordination of a metallic atom by the sulfox-

ide and the R³“ligand” group. This chelation effect, together

with the stereoelectronic demand of the R³and sulfoxide

groups, considerably decreases the degree of conformational

freedom of the diene moiety in the cyclic transition state

leading to the observed stereoselectivity. By choosing appro-

priate substituents in the furan ring, it is possible to obtain

100:0 cis-trans and 100:0 endo-exo diastereoselectivities. Up

to 100% π-facial diastereoselectivity (enantioselectivity after

removal of the sulfoxide group) could be reached. Yields lie

within the range of 50–80%, depending on the furan sub-

strate. However, if the furan diene is fitted with deactivating

electron-withdrawing substituents, low conversions were ob-

served under certain reaction conditions, but always with ex-

cellent-to-complete chemo- and stereoselectivities. The con-

version and yield increase on introduction of an electron-do-

nating substituent at the C-3 of the furan ring.

attached to C-3 of 2-(p-tolylsulfinyl)furan on the stereo-

chemical outcome of the [4+3] cycloaddition reactions of

these dienes with an oxyallyl cation as dienophile. Using the

results of this work, we plan in the future to modulate the

reactivity and stereoselectivity of conveniently function-

alized 2- and/or 3-substituted furans in this type of reac-

tion.

The idea of using disubstituted furans was based on the

observation that groups attached to the 2-position of the

furan ring show large conformational freedom. This fact

meant that stereodifferentiation of the ring faces was very

difficult. Therefore we designed furan dienes doubly func-

tionalized: at C-2 by a chiral group (inductor) and at C-3

by groups (chiral or not) that, through steric hindrance or

interaction with the sulfinyl group at C-2, should reduce its

conformational freedom.

Introduction

A new contribution to the induction of asymmetry in the

[4+3] cycloaddition reaction is presented herein. Extending

our previous studies on the use of a furan diene with a

chiral auxiliary attached to C-2,^[1]we have chosen the asym-

metric sulfoxide group (in particular the p-tolylsulfinyl

group) as a chiral inductor due to its great potential and

wide applications.^[2]Since the resolution of (–)-menthyl

(S_S)-p-tolylsulfinate and its enantiomer in 1925, these two

compounds have been the most common source of a chiral

sulfoxide group in organic synthesis.^[3,4]

In this paper we present the results of our study on the

influence of the coordinating nature of the functional group

The (S)-p-tolylsulfinyl group was used as a chiral induc-

tor for several reasons. In the first place, it is the inductor

that showed the higher degree of π-facial diastereoselectiv-

ity in our previous studies with chiral C-2 monosubstituted

furans.^[1]In the second place, the very different nature of

substituents at the asymmetric sulfur atom (phenyl group,

oxygen, and electron lone-pair) allows possible intense ef-

fects of asymmetric induction to be foreseen (due to both

steric and electronic effects). A strong interaction with the

substituent at C-3 could be envisioned and, therefore, an

effective reduction of the conformational freedom of the

diene system may be expected. The commercial availability

[a] Unidad de Química Orgánica Industrial y Aplicada,

Departamento de Química Orgánica, Facultad de Química,

Universidad de Barcelona,

c/Martí i Franquès 1–11, 08028 Barcelona, Spain

E-mail: angel.montana@ub.edu

http://ww w .qo.ub.es/personals/amontana.htm

[b] Medicinal Chemistry Department, Laboratorios Ferrer

Internacional,

c/Juan de Sada 28–32, 08028 Barcelona, Spain

[c] Servicio de Difracción de Rayos X, Facultad de Ciencias

Químicas, Universidad de Salamanca,

Plaza de la Merced s/n, 37008 Salamanca, Spain

[d] Department of Chemistry, University of Bath,

Bath, BA2 7AY, UK

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201301814.

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Stereoselective [4+3] Cycloaddition Reactions

Scheme 1. Derivatization and interconversion of enantiomerically pure chiral [4+3] cycloadducts.

of both enantiomeric forms of menthyl p-toluenesulfinate tential to create cyclic systems in one step (by a concerted

makes possible the obtention of both enantiomers of 2-(p- or stepwise process) and in high yield. When five-membered

toluenesulfinyl)furan.^[4]Finally, the direct binding of the cyclic dienes are used as starting materials, it is possible

furan ring to a heteroatom (sulfur in the present model) to further functionalize the cycloadducts in a regio- and

favors the synthetic strategy designed by our research group stereoselective manner due to the lack of conformational

for the opening of the generated oxabicyclic cycloadduct freedom in the resultant bicyclic system because of the pres-

(see Scheme 1).^[5,6]

ence of a bridge (carbo- or heterocyclic).

The use of the configurationally stable p-tolylsulfinyl

In the past we evaluated the [4+3] cycloaddition of fur-

group as a chiral inductor in stereoselective [4+3] cycload- ans functionalized at C-2 in order to prepare cycloadducts

dition reactions allowed us to obtain enantiomerically pure having an oxabicyclic structure with an acetalic bridge

polyfunctionalized oxabicyclic systems strategically func- head, which is prone to transformation into a variety of

tionalized at C-1 in order to allow the opening of the oxy- valuable molecules^[8]in a diastereo- and/or enantioselective

gen bridge and also further derivatization and/or function- manner. In those studies we were able to draw conclusions

alization (Scheme 1). These compounds were prepared in a on the influence of the stereoelectronic nature of the C-2

stereoselective manner starting from C-2, C-3, and/or C-5 substituents on the yield and stereoselectivity of the re-

functionalized furans as dienes and 2,4-dihalo-3-pent- sulting [4+3] cycloadducts. Thus we studied the π-facial dia-

anones as precursors of oxyallyl cations.^[7]

stereoselectivity of the [4+3] cycloaddition reactions of 13

The use of cycloheptane synthons as precursors of natu- different chiral 2-substituted furans with oxyallyl cations

ral and unnatural products with biological activity has been under sonochemical and/or thermal conditions. Almost all

an objective of many chemists for a long time, and we have the studied furans showed a cis diastereospecificity and a

also made contributions to this field in recent years.^[8]

high endo diastereoselectivity. Decreasing the distance be-

Several approaches have been developed for the prepara- tween the stereocenter closest to the chiral auxiliary and the

tion of cycloheptane synthons; among these approaches the reactive C-2 atom of the furan ring led to an increase in

[4+3] cycloaddition methodology is worth noting.^[9]This the π-facial diastereoselectivity, especially when using chiral

synthetic method has, as an important advantage, the po- furyl sulfoxides.^[1]

Figure 1. Derivatives of (S)-2-(p-tolylsulfinyl)furan substituted at C-3 or C-5, used as diene substrates in [4+3] cycloaddition reactions.

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Our main goal in this work was to evaluate the inductive process initiated by an electrophilic attack of the oxyallyl

effects of p-tolylsulfinyl attached at C-2 of furan as well as cation on the furan diene followed by ring-closure. Before

the coordination effect of both the sulfinyl group itself and closure, the conformation of the side-chain of the interme-

the functional group attached at C-3, which have been diate may be modified, the methyl groups of the oxyallyl

shown to be important to the stereochemical outcome of moiety being re-orientated to decrease the steric interac-

this reaction.^[10]This coordination effect is supposed to act tions to afford the two possible trans isomers (see Fig-

on the metallic counter ion of the oxyallyl cation. For this ure 3).^[9]

purpose, 11 chiral, enantiomerically pure, sulfinylfurans

(Figure 1) were prepared and evaluated under the [4+3] cy-

cloaddition reaction conditions.

The endo/exo ratio is conditioned by the ease of diene–

dienophile π-stacking and the minimization of the steric in-

teractions in the approach of the diene and dienophile.^[12]

The formation of trans cycloadducts is conditioned by the

facilitation of the stepwise mechanism by a modification of

the electron density of the diene and the electrophilic nature

of the oxyallyl cation (electron-rich dienes and highly elec-

trophilic cations facilitate stepwise processes).^[12]The induc-

tive and mesomeric effects, if they are activating (+I, +M)

or deactivating (–I, –M), will favor preferential attack at C-

2 or C-5 of the furan diene (in the electrophilic addition

through the stepwise process) and the intermediates A or B

(Figure 3) will be stabilized or destabilized, respectively. On

the other hand, apart from these orientating effects, the

presence of +I groups will favor the stepwise mechanism

and –I groups will act in the opposite direction due to the

modification of the electron density of the furan ring.^[12,13]

Moreover, not only are steric interactions and inductive ef-

fects important to determine the ratio of endo/exo isomers,

but also the chelation or coordination phenomena that

could take place between the substituents at C-2 and/or C-

3 and the counter ion of the oxyallyl cation (dienophile).^[10]

On the other hand, the stereochemical outcome of the

[4+3] cycloaddition reaction (diastereoisomeric pro-

portions) could be influenced by several factors: 1) The na-

ture of the reducing metal (and thus the electrophilic nature

of the oxyallyl cation, changing the nature of the metallic

counter ion), 2) the type of solvent and its solvating proper-

ties, and 3) the presence of weak Lewis acids.

Results and Discussion

Stereochemical Outcome of the [4+3] Cycloaddition of the

3-Substituted (S)-2-(p-tolylsulfinyl)furans

The [4+3] cycloaddition reactions of 3-substituted (S)-

2-(p-tolylsufinyl)furans and a symmetric α,αЈ-disubstituted

oxyallyl cation, generated in situ from the corresponding

α,αЈ-dihalo ketone by a reducing metal, would afford eight

types of possible diastereoisomers (see Figure 2). In this

work we used the symmetric 1,3-dimethyl-2-oxyallyl cation

to simplify the reaction outcome and to obviate the regio-

chemical diversity, otherwise up to 16 diastereoisomeric cy-

cloadducts would be possible.

The cis stereoselectivity is conditioned and determined

by the predominance of the W configuration adopted by

the oxyallyl cation in its coupling with the furan diene by a

concerted process. The Z,Z or W configuration of the oxy-

allyl cation is preferred because it is the configuration of

lowest energy, the methyl groups being far apart from each

other. It has been estimated that 98% of the dienophile

molecules have this Z,Z configuration in equilibrium.^[11]

The cis-diequatorial (endo) isomer is formed by a con-

certed [4C(4π)+ 3C(2π)] cycloaddition via a compact late

transition state that affords a cycloadduct with both Me

groups in an equatorial disposition and the 4-pyranone ring

We observed complete cis/trans and endo/exo diastereo-

in a chair-like conformation. The cis-diaxial (exo) stereoiso- selectivity in all the [4+3] cycloaddition reactions carried

mer is formed from an extended transition state (TS) that out with the enantiomerically pure 3-substituted (S)-2-(p-

affords a cycloadduct with the 4-pyranone ring in a boat- tolylsufinyl)furans, which can be explained on the basis of

like conformation. The trans isomers arise from a stepwise the phenomena previously discussed. Below we will de-

Figure 2. Possible stereoisomers resulting from the [4+3] cycloaddition of 3-substituted (S)-2-(p-tolylsufinyl)furans and the 1,3-dimethyl-

2-oxyallyl cation.

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Stereoselective [4+3] Cycloaddition Reactions

Figure 3. Mechanisms for the formation of the cis and trans diastereoisomeric cycloadducts.

scribe the π-facial selectivity observed in this work as a re-

sult of the preferential attack of the oxyallyl cation by one

of the faces of furan ring (Figure 4).

Substituted 2-(p-Tolylsulfinyl)furans as Diene Substrates

Nine enantiopure furan derivatives were used as sub-

strates, all of them functionalized at the 2-position by the

configurationally stable (S)-p-tolylsulfinyl group (see Fig-

ure 1) and substituted at C-3 by a chelating function. For

comparison, two additional furans, 1 and 2, unsubstituted

at C-3, were synthesized. Thus, their π-facial stereodifferen-

tiation would correspond to a system with “conformational

freedom”. The brominated derivative 3 was prepared to an-

alyze the effect of steric hindrance on the conformational

freedom and also the influence of its inductive effect. The

other dienes, all of them substituted at the 3-position by

groups containing chelating heteroatoms, were designed to

analyze whether there were effects arising from bidentate

coordination to Zn²⁺ions present in the cycloaddition reac-

tion medium (in the case of using Zn or the ZnCu couple

Figure 4. Diastereoisomers I and V result from the attack by the

oxyallyl cation on 3-substituted (S)-2-(p-tolylsufinyl)furans on the

C2(Re) and C2(Si) face, respectively. The π-facial selectivity is de-

termined by the preferential attack by one of the two faces due to

stereoelectronic effects. The same model could be drawn for the

formation of diastereoisomeric pairs II and VI, III and VII, and

IV and VIII.

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Á. M. Montaña, P. M. Grima, C. Batalla, F. Sanz, G. Kociok-Köhn

FULL PAPER

as a reducing agent) or hydrogen-bonding effects (as in the ence of sodium iodide (Hoffmann’s method^[9a]), and 3) the

case of sulfinylfuran 4). use of copper in the presence of a weak Lewis acid like

The (S)-p-tolylsulfinyl chiral auxiliary was introduced at trimethylsilyl chloride (see entries 1–3 in Table 1).

C-2 of the furan ring by a highly stereoselective S_N2 reac-

tion with commercially available (–)-menthyl (S_S)-p-tolyl-

sulfinate.^[14]An additional functional group at C-3 was in-

troduced starting from different furans like 3-(hy-

droxymethyl)furan or 3-furoic acid, among other furan sub-

strates.^[15]

The strong reaction conditions used, due to the high re-

ducing potential and the long reaction time, led to the for-

mation of the expected cycloaddition products, but also to

reduced p-tolylsulfenyl byproducts, as shown in Schemes 2–

4.

Based on the results obtained under the conditions de-

scribed by Hoffmann (using copper and sodium iodide as

the reducing system at 60 °C in acetonitrile as solvent), it

was possible to infer that the reaction evolved through an

initial cycloaddition, followed by a partial reduction of the

initially formed cycloadducts. Thus, the reaction crude con-

tained both the p-tolylsulfinyl- and p-tolylsulfenyloxab-

icyclic compounds. Meanwhile, only the presence of (S)-2-

(p-tolylsulfinyl)furan was detected and not 2-(p-tolylsulf-

enyl)furan, which means that reduction of the cycloadduct

occurred and not of the starting furan (Scheme 2). This was

confirmed by the nonracemic nature of the reduction prod-

ucts. If the reaction had evolved through the reduction of

the furan diene with subsequent cycloaddition of 2-(p-tolyl-

sulfenyl)furan, the obtained crude product would be a cis-

endo racemic mixture (because the diene precursor would

be an achiral species). However, experimentally the p-tolyl-

sulfenyloxabicyclic compounds 13a and 13b (Scheme 2)

showed optical activity, which is consistent with a late re-

duction, as commented before.

Optimization of the Reaction Conditions for the [4+3]

Cycloaddition of (S)-2-(p-Tolylsulfinyl)furans

The [4+3] cycloaddition reactions of (S)-2-(p-tolylsulf-

inyl)furans as dienes were conducted under different condi-

tions with the 1,3-dimethyl-2-oxyallyl cation, generated in

situ from 2,4-dibromo- or 2,4-diiodo-3-pentanone, to study,

on the one hand, the stability of the tolylsulfinyl group un-

der the reducing reaction conditions and, on the other

hand, the reactivity, performance, and outcome of this sys-

tem (conversion, yield, chemo- and diastereoselectivity).

[4+3] Cycloaddition Reaction under Strong Reducing

Conditions

Owing to the electron-withdrawing character of the tolyl-

sulfinyl group, the diene used is disadvantaged for the [4+3]

cycloaddition; thus, strong reducing reaction conditions

were initially studied for this reaction, for example: 1) the

The selective reduction of the cycloadducts over the

use of [Fe₂(CO)₉] as reducing agent (method described by starting furan diene can be interpreted in terms of the

Noyori and Hayakawa^[9b]), 2) the use of copper in the pres- greater stability of the latter, the sulfoxide group being dou-

Table 1. Variation of the experimental conditions in the cycloaddition reaction of (S)-2-(p-tolylsulfinyl)furan (1) to afford cycloadduct

12.

[a] Heating and stirring. [b] Ultrasound sonication. [c] Conversion with respect to the furan diene. The dihalo ketone underwent 100%

conversion in all cases and the excess reacted to give oligomeric and/or decomposition products. [d] Chemoselectivity: Yield of cycload-

ducts with respect to converted diene. The nonconverted furan substrate was recovered by CC and reused. [e] Diastereoselectivity was

determined by GC and/or ¹H NMR spectroscopy. [f] π-Facial [endo(5R)/endo(5S)] de. [g] Reduction product (sulfenyl cycloadduct). [h]

The furan diene was used as the limiting reagent because it was the substance of highest added value. All molar ratios refer to 1 equiv.

of furan diene. [i] In all studied cases (entries 1–12), a complete 100:0 cis/trans diastereoselectivity was observed.

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Stereoselective [4+3] Cycloaddition Reactions

Scheme 2. Results of the [4+3] cycloaddition of (S)-2-(p-tolylsulfinyl)furan under the conditions described by Hoffmann.

bly stabilized electronically by two aromatic rings. In this

case, the observed cis/trans and endo/exo diastereoselectivi-

ties are complete (100%) because only (reduced and nonre-

duced) cycloadducts with a cis-endo stereochemistry were

detected. The π-facial diastereoselectivity observed in the

process was 73:27 [de = 46% for the endo(5R) cycloadduct].

The same reasoning applied to the results obtained under

the reaction conditions described by Noyori and Hayakawa

(using diiron nonacarbonyl as the reducing agent at 80 °C

in benzene as solvent)^[16]confirms that, in this case, re-

duction of the (S)-2-(p-tolylsulfinyl)furan occurs, which is

reduced to 2-(p-tolylsulfenyl)furan (1Ј). The obtention of

two monothioacetalic oxabicycle diastereoisomers, as race-

mic mixtures (Ϯ)-13a,b (cis-endo) and (Ϯ)-13c,d (cis-exo),

confirmed that these cycloadducts were not produced by

the reduction of the cycloadduct derived from the (S)-2-(p-

tolylsulfinyl)furan but by the cycloaddition of 2-(p-tolyl-

sulfenyl)furan (Scheme 3). This is rationalized by taking

into account the fact that by using a powerful reducing

agent, the reduction of (S)-2-(p-tolylsulfinyl)furan is much

faster than its cycloaddition.

Scheme 4. Results of the [4+3] cycloaddition of (S)-2-(p-tolylsulf-

inyl)furan using the Zn/Cu couple as reducing agent in the presence

of trimethylsilyl chloride.

Scheme 3. Results of the [4+3] cycloaddition of (S)-2-(p-tolylsulfinyl)furan under the conditions described by Noyori and Hayakawa.

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FULL PAPER

Scheme 5. Independent experiments to confirm the stereochemical outcome observed in the cycloaddition reactions performed under

strong reducing conditions.

When using the more strongly reducing Hoffmann’s both the reaction temperature and the reducing capacity of

modified conditions (zinc/copper couple as a reducing the metals used, as summarized in Table 1, in order to im-

agent in the presence of trimethylsilyl chloride at 0 °C in prove the results and to avoid the formation of reduced cy-

acetonitrile as solvent), the formation of the reduced cis- cloadducts.

Thus, a series of experiments were carried out to evaluate

the influence of the reaction conditions on the reaction out-

come (conversion, yield, chemo- and stereoselectivity): Mo-

lar ratio of reagents, nature of solvent, concentration, tem-

perature, and reaction time.

In addition to the three above-mentioned reactions (en-

tries 1–3, Table 1), a number of reactions were tested in

which several of the reaction parameters were changed: The

reducing agent (Cu or Zn/Cu couple), the use of TMSCl as

an activator, the molar ratios of the dihalo ketone (DHK),

furan diene, and reducing agent, or the concentration (0.1,

0.2, 0.4, and 2 molL^–1) and reaction temperature (–40, 0,

20 °C and reflux of solvent).

Comparing entries 6 and 7 (Table 1) and working with a

molar ratio DHK/furan diene of 4:1 at 0 °C, it was possible

to observe how the conversion of the furan substrate in-

creased from 18 to 31% when the concentration rose from

0.2 to 0.4 molL^–1. The same observation was made by using

a different DHK and reducing metal, for which changing

the concentration from 0.4 to 2.0 molL^–1led to an increase

in the conversion of the furan diene from 17 to 30% (en-

tries 8 and 9). Thus, by increasing the concentration by a

factor of Ն2, the conversion almost doubled. However, the

π-facial selectivity did not change from 75:25, even though,

in all the cases compared, complete cis/trans and endo/exo

diastereoselectivities were observed. On the other hand, by

endo cycloadduct was again observed as a racemic mixture

(Scheme 4). In this case, note that the reaction occurs with

complete cis/trans and endo/exo diastereoselectivity, and

with a much better performance than in the previous case,

affording higher conversions and yields of racemic sulfenyl

cycloadducts, possibly due to the lower temperature em-

ployed, which largely prevents the decomposition of prod-

ucts.

The cis/endo and π-facial stereochemistries of previously

obtained cycloadducts were confirmed by independent ex-

periments in which separated samples of the two diastereo-

isomers 12a,b were reduced in the presence of the zinc/cop-

per couple and trimethylsilyl chloride (see Scheme 5) to the

corresponding enantiomeric reduction products 13a and

13b, which have physical and spectroscopic properties iden-

tical to those of the products previously obtained (see

Schemes 2–4). On the other hand, substrate 1 was reduced

to 1Ј with Zn/Cu and TMSCl (in ACN at 20 °C) or by using

nickel boride, generated in situ from NiCl₂and NaBH₄(in

THF at 0 °C).^[17]The resulting sulfenylfuran 1Ј was submit-

ted to a [4+3] cycloaddition reaction with the 1,3-dimethyl-

2-oxyallyl cation in the presence of the zinc/copper couple

and trimethylsilyl chloride to afford cycloadduct 13 as a

racemic mixture (Scheme 5).

Cycloaddition Under Mild Reaction Conditions

The results obtained previously (entries 1–3, Table 1) al- comparing entries 4 and 5, it was possible to conclude that

lowed us to design milder reaction conditions, modifying by maintaining the concentration of furan substrate but

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Stereoselective [4+3] Cycloaddition Reactions

doubling the molar ratio of DHK/furan from 4:1 to 8:1, the ity. This is important because unreacted furan substrate is

conversion increased from 47 to 51% for the same reaction completely recovered by column chromatography and re-

time (4 h) and temperature (20 °C).

used.

No relationship was found between the magnitude of the

If entries 4 and 6 are compared, it is possible to reach

the conclusion that temperature has an important influence diastereoselectivity and the electrophilic character of the

on the π-facial selectivity; thus, by lowering the reaction oxyallyl cation, the nature of the dihalo ketone precursor,

temperature from 20 to 0 °C, the π-facial selectivity in- or the type of reducing metal. The sense of π-facial dia-

creases from 75:25 to 88:22. Similar behavior is observed stereoselectivity observed, assuming the assignment of ab-

when comparing entries 10 and 11. However, if the tem- solute stereochemistry of the proposed diastereoisomers,

perature is increased gradually from 0 to 20 °C (entry 12), shows that the C2(Re) face is the most favored in the ap-

the π-facial selectivity does not change (in comparison with proach to the furan diene. This result can be explained by

entry 10; cf. also entries 10–12). With the aim of achieving the oxyallyl cation approaching the diene in the conforma-

even better π-facial diastereoselectivity, a couple of reac- tion in which the aromatic group linked to the sulfoxide is

tions were performed at lower temperature (–40 °C), but at oriented towards the C2(Si) face (conformation II in Fig-

this temperature the reaction did not take place (entries 13 ure 5), leading to the major cycloadduct 12a. A careful con-

and 14), even when using a very strong source of energy formational analysis (see below and also in Exp. Sect.) led

(entry 13) such as high power ultrasound sonication in an us to conclude that the oxygen atom of the sulfoxide is ori-

ultrasound reaction horn.

ented in an s-cis manner with respect to the oxygen atom

After analyzing all these data it is possible to conclude of furan. Also, the chelation of metal ions (Zn), present in

that to improve the conversion of furan diene into cycload- the reaction medium, to both oxygen atoms of 2-(p-tolyl-

ducts it is necessary to increase the molar ratio of DHK/ sulfinyl)furan in the s-cis conformation could contribute to

furan or to increase the concentration, however, these modi- the driving force for the observed π-facial selectivity (see

fications of the reaction conditions do not affect the stereo- Figure 5). The formation of the minor cycloadduct 12b

chemical outcome. In addition, by lowering the reaction could be envisioned as arising from the conformation V

temperature it is possible to increase the π-facial diastereo- (Figure 5) in which the p-tolyl group is oriented towards the

selectivity, but only up to a certain extent, because if we C2(Re) face of the furan ring.

decrease the temperature too much, the reaction does not

take place. Another drawback is that a decrease in tempera-

ture also leads to a lower conversion. This influence of tem-

perature on the π-facial selectivity could be related to the

conformational equilibrium of 2-(p-tolylsulfinyl)furan at

the C2–S bond, as will be explained below.

Versatile Transformation of 2-(p-Tolylsulfinyl)furan into a

Large Chemical Library of Diastereoisomeric Oxabicyclic

Cycloadducts

The furan diene system is poorly activated for cycload-

As mentioned before, depending on the conditions of the

dition reactions and, as a consequence, the conversion with cycloaddition reaction, cycloadducts are formed in which

respect to the furan diene is generally low, although conver- the tolylsulfinyl group has been reduced to tolylsulfenyl. To

sion of the oxyallyl cation precursor is complete in all cases. extend this study and to appreciate the versatility of the

This fact can be explained by taking into account the fact sulfinyl and sulfenyl cycloadducts formed, reduction reac-

that due to the low reactivity of the furan diene, the oxyallyl tions were also conducted by using metal couples and also

cation may react with itself to form oligomers and poly- commercial hydrides (Scheme 6).

mers. These side-reactions are of importance as the more

To confirm this strategy for synthetic diversification, dia-

reactive is the precursor of the oxyallyl cation, the greater stereoisomeric 12a and 12b were separated by column

is the proportion of these byproducts, and therefore less fa- chromatography and 12a was transformed into 13a or enan-

vored is the formation of cycloadducts under the tested re- tiomerically pure diastereoisomers 14a/14b. By using lith-

action conditions. The design of new electron-richer furan ium aluminium hydride to reduce 12a, the sulfoxide group

dienes by substitution with electron-donating groups at C- was transformed into the corresponding sulfenyl group and

3 and/or C-5 of the furan ring in order to increase the con- simultaneously the ketone at C-3 was reduced to an alcohol

version, yield, and diastereoselectivity of the [4+3] cycload- to give diastereoisomers 15a and 15b. This reduction took

dition reactions will be discussed below.

place with low stereoselectivity (3S/3R = 58:42). As can be

Higher yields of nonreduced cycloadducts were obtained observed, there is a small preference for attack on the exo

under the milder reaction conditions of entries 4–12 in face of the carbonyl group. However, when using sodium

Table 1 compared with entries 1–3. This fact is attributed to borohydride, only the carbonyl group was reduced, in a

the higher stability of the tolylsulfinyl group under these stereoselective manner, to yield almost exclusively the

new modified reaction conditions, with no reduction of the alcohol resulting from the attack of the hydride on the exo

sulfinyl group to thioether being observed. Note that in en- face of the oxabicyclic system.^[18]Further reduction of the

tries 4–11, the chemoselectivity S, that is, the yield of cy- separated (major and minor) diastereoisomers of this sulf-

cloadducts with respect to the converted furan, is 100%. In inyl alcohol with lithium aluminium hydride afforded the

other words, all converted furan substrate was transformed corresponding sulfenyl alcohols as single products with

into the desired cycloadduct with complete chemoselectiv- well-defined stereochemistry. Note that all the diastereoiso-

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FULL PAPER

Scheme 6. Chemical library of distereoisomeric oxabicyclic cycloadducts and their reduction products.

mers were separable by column chromatography. Isomer the furan diene, which would improve conversion and also

14a was obtained as the major product by using NaBH₄as afford higher π-facial selectivity, propitiated by chelation,

reducing agent (MeOH, room temp., 95% yield, ds = 98:2), hydrogen bonds, and/or steric conformational restriction ef-

but when DIBAL-H/ZnCl₂(3:0.5 equiv., THF, –78 °C) was fects exerted by substituents at C-3. (S)-5-Methyl-2-(p-tolyl-

used, 14b was generated as the major reduction product sulfinyl)furan was used with the aim of increasing the con-

(90% yield, ds = 30:70).^[19]

version of the process by using a more active diene 2, given

This same sequence of reactions could be applied to 12b its higher electron density (due to the inductive effect of the

to generate a series of derivatives analogous to those de- methyl group as an electron donor). However, as shown in

scribed before for 12a (but having the opposite configura- Table 2, the cycloaddition reaction of this substrate did not

tion at C-1, C-2, C-4, and C-5). Thus, as illustrated in take place under the reaction conditions used for the non-

Scheme 6, starting from the cycloaddition products of (S)- substituted sulfinylfuran 1 (see Table 1). This has been at-

2-(p-tolylsulfinyl)furan, it is possible to obtain, in an enan- tributed to the additional steric hindrance exerted by the

tiomerically pure form, several derivatives that may be used methyl group at the 5-position with respect to that already

in the synthesis of natural or non-natural molecules with exerted by sulfinyl group. The combined steric hindrance at

very diverse stereochemistry, high degree of functionaliza- C-2 and C-5 (reaction centers) inhibits the approach of the

tion, and high added value. In addition, if (R)-2-(p-tolylsulf- oxyallyl cation to the diene system. Thus, this steric effect

inyl)furan is prepared from the commercially available (+)- has a greater effect than the electron-donating effect of the

(1S,2R,5S)-menthyl (R)-p-toluenesulfinate, the enantiomers methyl group.

of the sulfinyl cycloadducts 12a,b and 14a,b could also be

obtained. This synthetic strategy is currently being investi-

gated in our laboratory, as well as a search for bioactive

molecules from these enantiopure cycloheptane synthons.

On the other hand, when a substituent is introduced at

the 3-position, the reaction center C-5 exerts no steric hin-

drance and, moreover, the C-3 group would allow, a priori,

conformational constraint of the sulfoxide at C-2. Thus,

only a few conformations would be preferred because of

steric constraints. In addition, the C-3 groups were designed

to contain heteroatoms with lone-pair electrons able to co-

ordinate to the Zn ion that acts as a counter ion of the

oxyallyl cation. This would determine the approach

of the oxyallyl species within a compact transition state

(Figure 3), affording the cycloadduct with an endo configu-

ration.

[4+3] Cycloaddition of 3- and/or 5-Substituted (S)-2-(p-

Tolylsulfinyl)furan

Once the results of the [4+3] cycloaddition experiments

with (S)-2-(p-tolylsulfinyl)furan had been analyzed and

correlated, it was concluded that by modifying the reaction

conditions it was possible to achieve a moderate conversion

(51%; entry 5, Table 1) and a π-facial diastereoselectivity of

Thus, several 3-substituted (S)-2-(p-tolylsulfinylfuran)

88:22 and de = 66 (entries 6 and 7, Table 1). Thus, several derivatives were synthesized and their [4+3] cycloaddition

3-substituted (S)-2-(p-tolylsulfinyl)furan derivatives were reactions with the 1,3-dimethyloxyallyl cation evaluated un-

designed and synthesized to modify the electron density of der different reaction conditions. All the reactions per-

2734

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Eur. J. Org. Chem. 2014, 2726–2746

Stereoselective [4+3] Cycloaddition Reactions

Table 2. Reaction conditions and outcome of the [4+3] cycloaddition reactions of 5- and/or 3-substituted (S)-2-(p-tolylsulfinyl)furans.

Entry^[a]Furan DHK

DHK

Metal

Conc.

[mol/L]

T

[°C]

t [h]

Cycload-

duct

C^[c]

[%]

Y [%]

S^[d]

[%]

de [%]

[equiv.]^[b]

(π-facial)^[e]

1

2

diiodo

4

12

0.2

0

4

16

0

–

3

diiodo

4

12

0.2

0

4

17

0

–

4

5

6

4

diiodo

dibromo

4

8

12

25

0.4

20

4

18

60

70

80

60

70

74

100

92

100

7

8

9

10

11

5

diiodo

dibromo

4

12

25

0.4

0

20

4

6

10

4

19

0

–

4^[f]

4

8

4

12

13

14

15

7

diiodo

dibromo

4

8

12

25

0.2

0.8

0

4

20

10

15

20

35

10

15

20

35

100

20

16

10

dibromo

8

25

0.4

20

4

21

0

–

17

18

9

dibromo

4

8

12

25

0.2

0.4

0

20

4

22

5

21

5

21

100

19

11

dibromo

8

25

0.4

20

4

23

65

50

77

100

[a] In all entries, the Zn/Cu couple was used as reducing agent. [b] Molar ratios of DHK and the Zn/Cu metallic couple are with respect

to 1 equiv. of furan diene. [c] Conversion with respect to the furan diene. The conversion of the dihalo ketone precursor of the oxyallyl

cation was complete in all cases and the excess reacted to generate oligomers and decomposition products. [d] Chemical selectivity S,

that is, yield with respect to the converted furan. The unconverted furan was completely recovered by column chromatography and

reused.^[20][e] de cis/trans and endo/exo 100% in all cases. [f] Experiment carried out in the presence of 0.25 equiv. of triethylamine.

formed showed complete cis/trans and endo/exo diastereo- was increased by using, as precursor of the oxyallyl cation,

selectivities, and, which is worth noting, also complete π- 2,4-dibromo-3-pentanone instead of 2,4-diiodo-3-pentan-

facial diastereoselectivity, irrespective of the degree of con- one. However, in the case of amine 5, cycloaddition was

version of the starting material (see Table 2).

not observed under a variety of conditions. This different

The brominated sulfinylfuran 3 did not undergo cycload- behavior of 4 and 5 may be explained by the high steric

dition under conditions that afforded moderate conversion hindrance of the diethyl groups, together with the possible

of (S)-2-(p-tolylsulfinyl)furan. This could be due to the in- protonation of the amine to generate the corresponding am-

ductive deactivation of the furan ring exerted by the brom- monium salt (a product that was isolated in the reaction

ine atom.

crude), which electronically deactivates the furan diene. In

Furans 4 and 5, with activating hydroxymethyl and dieth- one experiment (entry 9), triethylamine was added to

ylaminomethyl groups, respectively, despite their electronic quench traces of halo acid generated in the reaction me-

similarity, gave different results. Thus, in the case of alcohol dium, however, the conversion was not improved.

4, cycloaddition reactions took place in a stereoselective

Total diastereoselectivity was again observed in the cy-

manner, with good yields (60–74%) and moderate-to-good cloaddition of carboxylic acid derivatives 7, 9, 10, and 11.

conversions (60–80%; entries 4–6, Table 2). The conversion In the cases of substrates 7 and 10, both esters, only the

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FULL PAPER

methyl ester gave cycloaddition products due to its smaller S for the 2-(p-tolylsulfinyl)furan. Having established the

steric hindrance, and with good chemoselectivity S, but low configuration at the sulfur atom, it is important to explain

conversion (10–35%), which could be rationalized in terms why the attack of the oxyallyl cation takes place exclusively

of a double electron deactivation of the furan ring (due to by the C2(Re) face of the sulfinylfuran diene. For this pur-

the presence of two electron-withdrawing groups). In the pose it was necessary to carry out a conformational analysis

case of amides 9 and 11, cycloaddition took place on both of the furan precursor, especially of the C2–S bond (see

substrates, with higher conversions than with the esters (un- Figure 5).

der the same conditions), possibly due to reduced deactiva-

tion of the furan ring. In addition, monosubstituted amide

11 underwent [4+3] cycloaddition with a higher conversion

and yield than 9 due to less steric hindrance.

In the case of 2-(p-tolylsulfinyl)furan (1) as substrate, the

π-facial diastereoselectivity [cis-endo(5R)/cis-endo(5S)] ob-

tained was between 73:27 and 88:22. When the furan deriv-

ative used was 4, bearing a hydroxymethyl group at C-3, the

π-facial selectivity was total. This could be explained by

taking into account the fact that the presence of a 3-substit-

uent decreases the conformational freedom of the sulfinyl

group. However, the question of why the C2(Si) face of the

furan diene is blocked to attack of the oxyallyl cation still

remains.

Proposed Mechanism for the Observed Complete π-Facial

Stereoselectivity in 3-Substituted 2-Sulfinylfurans

As will be described later, the absolute configuration at

the sulfur center of the chiral sulfoxide was established by

An intensive conformational analysis and a wide-ranging

anomalous X-ray diffraction analysis and was found to be bibliographic search helped us to conclude that the oxygen

Figure 5. Origin of the π-facial selectivity based on the decrease in the conformational freedom of the sulfinyl group by introduction of

the C-3 substituent. The preferred conformations of (S)-3-hydroxymethyl-2-(p-tolylsulfinyl)furan, conditioning the approach of the oxy-

allyl cation to both faces of the furan ring.

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Stereoselective [4+3] Cycloaddition Reactions

Figure 6. Preferred conformation of (S)-3-hydroxymethyl-2-(p-tolylsulfinyl)furan (4). Possible chelation effects in the TS for the compact

approach of the oxyallyl cation to the C2(Re) face of the furan diene during the formation of cycloadduct 18.

atom of the sulfoxide is oriented in an s-cis manner with (1S,2R,5S)-menthyl (R_S)-p-toluenesulfinate, the enantio-

respect to the oxygen atom of furan, but twisted by 29.2° mers of the sulfinylfurans described herein could also be

in the most populated conformation. This O,O-cis confor- available by applying the same chemistry developed in this

mation is the major one in solution, in which solvation (in work.

polar solvents) completely compensates the dipolar destabi-

lization. However, in the gas phase or in nonpolar solvents,

the population of the O,O-trans conformation could be sig-

nificant.^[21]It is the adoption of the O,O-cis (s-cis) confor-

mation that determines that the tolyl group should be per-

pendicular to the furan ring, blocking the C2(Si) face and

hindering the attack of the electrophile. At the same time,

the hydroxy group may be orientated opposite to the phenyl

group and in a position that could facilitate its coordination

to the Zn ion, which acts as a counter ion of the oxyallyl

cation, determining the approach of the oxyallyl species in

a compact mode and affording the cycloadduct the endo

configuration (see Figure 3 and Figure 5). In addition, a

possible chelation of the aforementioned O,O-cis system by

Zn ions, present in the reaction medium, may be envisioned,

which would help by decreasing the conformational free-

dom of sulfinylfuran, thereby facilitating the formation of

the single stereoisomer 18 (Figure 6).^[22]

The cis/trans and endo/exo relative stereochemistries were

1

unequivocally assigned by H and ¹³C NMR correlation^[24]

in the cycloadducts, however, the absolute configuration

was confirmed by anomalous X-ray diffraction analysis^[25]

of single crystals of enantiopure cycloadduct 18. The abso-

lute configurations of all the other cycloadducts were estab-

lished by correlation to this model. Based on a favorable

Flack parameter^[26](very close to 0, see Table 3), obtained

by high-resolution low-temperature acquisitions, it was pos-

sible to establish the absolute configuration S for the chiral

sulfur atom of sulfinylfurans and the cycloadducts.

A view of the crystal structure of compound 18 is shown

in Figure 7; all the bond lengths and angles are within the

normal ranges. In the crystal packing, the molecules are

arranged parallel to each other along the c axis and are

related by a binary axis along the direction [001], as shown

in Figure 8. Also, a hydrogen bond between the hydroxy

group on C-10 and the sulfoxide oxygen can also be ob-

served in the crystal cell (see Figure 9). The crystal data and

structure refinement for enantiopure cycloadduct 18 are

presented in Table 3. The molecular illustrations (Fig-

ures 7–9) were prepared by using the MERCURY soft-

Establishment of the Absolute Configuration at the Chiral

Sulfur Atom of the Sulfoxide Group

As mentioned in the Introduction, the commercially ware.^[27]Note in the crystal lattice that molecules of cy-

available (–)-(1R,2S,5R)-menthyl (S_S)-p-toluenesulfinate cloadduct 18 adopt an O,O-cis disposition between the sulf-

precursor was used to prepare enantiomerically pure sulfin- oxide oxygen and the oxygen atom of the bridge, similar to

ylfurans with an S_Sconfiguration, by an S_N2 reaction, with that of conformation III proposed in solution for the block-

complete inversion of configuration.^[23]Owing to the avail- age of the C2(Si) face of sulfinylfuran, based on calcula-

ability of the other enantiomer of the precursor, that is, (+)- tions (compare Figure 6 and Figures 7 or 9).

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Á. M. Montaña, P. M. Grima, C. Batalla, F. Sanz, G. Kociok-Köhn

FULL PAPER

Figure 7. a) X-ray structure of 18. b) Ellipsoid diagram drawn at the 50% probability level for 18, showing the atom-labeling scheme; the

numbering assigned by the data processing software is not IUPAC numbering.

Figure 9. Hydrogen bond between the hydroxy group on C-10 and

the sulfoxide oxygen of a neighboring molecule in the crystal cell

of 18.

Conclusions

The use of the p-tolylsulfinyl group as a chiral inductor

in [4+3] cycloaddition reactions has allowed us to obtain

enantiomerically pure oxabicyclic cycloadducts, which are

the precursors of a large chemical library of polyfunction-

alized cycloheptane synthons with up to five stereocenters.

These systems were synthesized by diastereoselective reac-

Figure 8. Crystal packing of 18 along the [100] direction.

2738

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Stereoselective [4+3] Cycloaddition Reactions

Table 3. Crystal data and structure refinement for 18.

enantiopure bioactive molecules, are under way in our labo-

ratory.

Chemical formula

C₁₇H₂₀O₄S

Formula mass

Crystal system, Space group

a [Å]

b [Å]

c [Å]

320.39

monoclinic, C2

14.7011(7)

6.8414(3)

16.3801(8)

90

Experimental Section

General Methods: Unless otherwise noted, all reactions were con-

ducted under dry nitrogen or argon in oven-dried glassware. Raw

materials were obtained from commercial suppliers and used as

received. All solvents were purified by using standard techniques

before use: diethyl ether, tetrahydrofuran, hexane, and pentane were

distilled under nitrogen from sodium/benzophenone. Acetonitrile

was distilled under nitrogen from CaH₂. IR spectra were recorded

with an FT-IR NICOLET 510 spectrophotometer as thin films on

NaCl plates. NMR spectra were recorded in CDCl₃with Varian

spectrometers at 200 MHz (GEMINI 200), 300 MHz (INOVA-

300), and/or 400 MHz (MERCURY-400) for ¹H NMR and at 50

and/or 100 MHz for ¹³C NMR spectroscopy. For ¹H NMR, tet-

ramethylsilane was used as internal standard. ¹³C NMR spectra

were referenced to the 77.0 ppm resonance of chloroform. When

necessary, assignments were established by DEPT, ¹H–¹H COSY,

and HMBC or gHMQC ¹³C–¹H correlation experiments. Mass

spectra were recorded with a Hewlett–Packard 5890 mass spec-

trometer using the chemical ionization technique and ammonia as

ionizing gas. GC analyses were performed with an HP-8790 gas

chromatograph equipped with a Hewlett-Packard cross-linked Me-

α [°]

β [°]

γ [°]

91.646(3)

90

1646.77(13)

150(2)

Unit cell volume [Å³]

Temperature [K]

Number of formula units per unit cell, Z

Density (calcd.) [gcm^–3]

Radiation type

4

1.292

Mo-K_α

0.211

15505

2965

0.0777

0.0385

0.0884

0.0478

0.0942

1.080

Absorption coefficient, μ [mm^–1]

N umber of reflections measured

Number of independent reflections

R_int

Final R₁values [IϾ2σ(I)]

Final wR(F²) values [IϾ2σ(I)]

Final R₁values (all data)

Final wR(F²) values (all data)

Goodness of fit on F²

Flack parameter

–0.03(6)

Phe-silicone capillary column (L = 25 m, Φ_ID= 0.2 mm, δ_film

=

2.5 μm) using helium as gas carrier and an FID detector (T =

250 °C, P_H2= 4.2 psi, P_air= 2.1 psi). The chiral GC analyses of

the furan derivatives and cycloadducts were carried by using an

positions as a single stereoisomer (with complete cis/trans,

endo/exo, and π-facial diastereoselectivities) in which the

conformational freedom of the inductor was restricted. In

addition, the reactions of 2-monosubstituted sulfinylfuran

generated the two possible cis-endo diastereoisomers, re-

sulting from π-facial stereoselectivity, in a ratio from 73:27

to 88:22, which could be easily separated by conventional

chromatographic techniques. A possible explanation for this

π-facial stereoselectivity, resulting from preferential attack

by the C2(Re) face, could be the O,O-cis disposition of the

oxygen atom of the furan ring and the sulfoxide oxygen. In

addition, the potential chelation of both oxygen atoms by

Zn metal could be postulated.

The results of the reaction performed under different re-

action conditions confirmed the low activation of the furan

diene in the cycloaddition process. Thus, although the con-

version of the dihalo ketone, precursor of the oxyallyl cat-

ion, was total in all cases, the conversion with respect to the

diene was low. With regard the performance of the reaction,

except when using strong reducing conditions (under which

the reduction of sulfoxide to the thioether group takes

place), very high chemical selectivities were observed in al-

most all cases, even if the overall yield was moderate or low.

In the case of furan substrates such as 4 in which the ring

is slightly more activated by induction, the conversion,

yield, and stereoselectivity were high with excess of both

dihalo ketone and the Zn/Cu pair, at high concentration,

and at room temperature. When the temperature was low-

ered to 0 °C, the chemical selectivity and diastereoselectivity

improved, but the conversion decreased considerably.

Further efforts to activate the furan ring towards [4+3]

cycloaddition and to optimize the reaction conditions, as

ALLTECH Chirasil-Val^®capillary column (L = 25 m, Φ_ID

=

0.25 mm , δ_film= 0.16 μm) in the range of 40 to 220 °C. The work-

ing conditions are specified for each compound. The elemental

analyses were carried out with a Fisons elemental analyzer, Model

Na-1500. The samples were previously pyrolized at 1000 °C under

oxygen and the contents of carbon, hydrogen, sulfur, and nitrogen

were determined by evaluation of the combustion gases by gas

chromatography using an FID detector. Melting points were deter-

mined with a GALLENKAMP apparatus, Model 5A 6797.

X-ray Crystal Structure Analysis of 18: Enantiomerically pure cy-

cloadduct 18 was dissolved in a minimum amount of ethyl acetate

at room temperature. A few drops of hexane were added and the

saturated solution kept in a refrigerator at 4 °C. Suitable crystals

for X-ray diffraction studies grew over a period of 1 week.

Intensity data were collected at 150 K with a Nonius–Kappa CCD

diffractometer equipped with an Oxford Cryosystem using graph-

ite-monochromated Mo-K_αradiation (λ = 0.71073 Å). The data

were processed by using the Nonius software.^[28]A symmetry-re-

lated (multiscan) absorption correction was applied. The structures

were solved by direct methods (SIR-97)^[29]and refined by full-ma-

trix least-squares techniques against F²(SHELXL-2013)^[30]using

the program platform SHELXle.^[31]Non-hydrogen atoms were an-

isotropically refined. Heteroatom and hydrogen atoms were located

in the difference Fourier map and were isotropically refined all

others were placed onto calculated positions. The crystal data and

a summary of the intensity data collection for 18 are summarized

in Table 3. Data for crystal and structure refinements, atomic coor-

dinates, bond lengths, bond angles, anisotropic displacement pa-

rameters, and hydrogen coordinates are included in the Supporting

Information.

CCDC-959636 (for 18) contains the supplementary crystallo-

well as to apply these synthons to the preparation of graphic data for this paper. These data can be obtained free of

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2739

Á. M. Montaña, P. M. Grima, C. Batalla, F. Sanz, G. Kociok-Köhn

FULL PAPER

charge from The Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

nitrile (11 mL). The mixture was cooled to 0 °C and the furan de-

rivative (1 mmol) added at once. Then 2,4-dibromo-3-pentanone

(258 mg, 1.06 mmol) was added dropwise. The reaction mixture

was homogenized by stirring and maintained at the working tem-

perature by using a heating/cooling bath with a temperature ered

finished after observing a constant conversion in successive analy-

ses.

Activation of Reducing Metals and Preparation of Metallic Couples

Activation of Copper:^[32]Copper powder from Sigma–Aldrich (10 g,

0.152 mol) was treated with a solution of iodine (2 g, 7.8 mmol) in

acetone (100 mL). The suspension was stirred for 15 min and fil-

tered through a Büchner funnel. The violaceous solid obtained was

washed with a 1:1 mixture of conc. HCl (37%) and cold acetone

(50 mL), and then with acetone (100 mL) and diethyl ether

(100 mL). The resulting solid was dried under high vacuum and

kept away from light under argon. The activated copper has a met-

allic luster and was used immediately.

In experiments in which the reducing agent is copper, the products

were isolated in the following way. The mixture was cooled to 0 °C

and dichloromethane was added under constant stirring. The mix-

ture was added over a 1:1 mixture of water/ice (30 mL approx.) and

filtered through a porous sintered plate (filtering plate number 4)

under vacuum to remove excess copper powder. The phases were

decanted and the aqueous phase was extracted with dichlorometh-

ane until discoloration of the organic phase (4ϫ 30 mL) was ob-

served. The organic phases were combined and washed successively

with a 3% aqueous solution of NH₃(3ϫ 20 mL) until no blue

color [due to tetraammincopper(II) complex] was observed in the

aqueous washing extracts, followed by ice–water (2ϫ 20 mL). Fi-

nally, the organic phase was dried with anhydrous MgSO₄, filtered,

and concentrated to dryness to give a single product or a mixture

of diastereoisomers, depending on the furan substrate. The oil ob-

tained was submitted to flash column chromatography on silica gel

using mixtures of hexane and ethyl acetate of increasing polarity,

eluting with hexane/ethyl acetate (95:5) and (90:10) the endo, trans,

and exo stereoisomers (generally in this order).

Activation of Zinc:^[33]Zinc powder (10 g, 0.152 mol) was suspended

in diluted aqueous HCl (50 mL, 3% w/v) and vigorously stirred for

1 min; the release of hydrogen was observed. The process was re-

peated two more times and finally the solid was filtered through a

Büchner funnel and washed with distilled water (100 mL), absolute

ethanol (100 mL), and diethyl ether (100 mL). The solid was then

dried under vacuum in the dark for 3 h to give a fine grey solid

that was used immediately. Occasionally it was stored in a desicca-

tor under argon but it is preferable to activate it prior to use.

Preparation of the Zinc/Copper Couple:^[34–36]Zinc (10 g, 0.152 mol),

activated as described above, was suspended in an aqueous solution

of copper(II) sulfate (100 mL, 4% w/v) and vigorously stirred for

15 min. The zinc powder rapidly darkened, turning from light grey

to black, and the blue copper solution completely discolored. The

solid was filtered through a Büchner funnel and successively

washed with distilled water (2ϫ 50 mL), acetone (4ϫ 50 mL), ab-

solute ethanol (4ϫ 50 mL), and diethyl ether (4ϫ 50 mL). Finally,

the solid was dried under vacuum and in the dark for 3 h to give

a fine black powder that was used immediately. Occasionally it was

stored in a desiccator under argon and in the dark for a short

period of time. Analysis of this solid by atomic absorption spec-

troscopy showed the following composition: Zn = 72%, Cu = 28%.

Experimental Procedure 2-Cu: Cycloaddition by Reduction of 2,4-

Diiodo-3-pentanone with Copper Powder: The melting point of 2,4-

diiodo-3-pentanone is close to 0 °C, and in many cases the addition

of this reagent is not possible at the reaction temperature in the

liquid state. Therefore, the addition procedure was modified in the

following way. In a two-necked flask fitted with a magnetic stirrer

and under nitrogen, freshly activated copper (210 mg, 3.32 mmol)

was placed and suspended in acetonitrile (5 mL). The suspension

was cooled to 0 °C and the furan derivative (1 mmol) added at

once. Then 2,4-diiodo-3-pentanone (360 mg, 1.06 mmol) dissolved

in acetonitrile (6 mL) was added dropwise. The total volume of the

solvent used was the same as in the previous procedure (1-Cu) so

that the total dilution of the system remained the same. The work-

up and purification procedure of the products were identical to

those described for procedure 1-Cu.

Methodologies Used for the [4+3] Cycloaddition Reactions: 2,4-Di-

bromo- and 2,4-diiodo-3-pentanone, used as precursors of the oxy-

allyl cation, were prepared according to literature procedures.^[11,12]

For the optimization of the [4+3] cycloaddition, several reaction

conditions were used and are summarized in Table 4.

Experimental Procedures Using Copper as a Reducing Agent

Experimental Procedure 1-Cu: Cycloaddition by Reduction of 3,4-

Dibromo-3-pentanone with Copper Powder: In a two-necked flask

fitted with a magnetic stirrer and under nitrogen, freshly activated

copper (210 mg, 3.32 mmol) was added and suspended in aceto-

Experimental Procedure 3-Cu: Cycloaddition by Reduction of 2,4-

Dibromo-3-pentanone with Copper Powder in the Presence of So-

dium Iodide: This procedure is analogous to the one described for

1-Cu, however, note the presence of insoluble salts in the medium,

Table 4. Reaction conditions used for the cycloaddition reaction.

Reaction procedure

Reducing metal

Dihalo ketone

Solvent

Other reagents

1-Cu

2-Cu

3-Cu

4-Cu

Cu (powder, bronze or submicron)

dibromo ketone

diiodo ketone

dibromo ketone

diiodo ketone

ACN

–

NaI

1-Zn

2-Zn

3-Zn

4-Zn

5-Zn

6-Zn

Zn or metallic couples Zn/Cu

dibromo ketone

diiodo ketone

dibromo ketone

diiodo ketone

dibromo ketone

diiodo ketone

ACN

–

NaI

TMSCl

1-Fe

Fe₂(CO)₉

dibromo ketone

benzene

2740

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Eur. J. Org. Chem. 2014, 2726–2746

Stereoselective [4+3] Cycloaddition Reactions

which provoke changes in the rheology and color of the reaction

crude. In a two-necked flask fitted with a magnetic stirrer and un-

der nitrogen, freshly activated copper (210 mg, 3.32 mmol) and so-

dium iodide (957 mg, 6.36 mmol) were added and suspended in

acetonitrile (11 mL). The mixture was cooled to 0 °C and the furan

derivative (1 mmol) added at once. Then 2,4-dibromo-3-pentanone

(258 mg, 1.06 mmol) was added dropwise. A yellowish solid was

formed immediately and the reaction mixture became turbid. The

mixture became opaque and turned brown. The reaction mixture

was homogenized by stirring and maintained at the working tem-

perature by using a heating/cooling bath with a temperature stabi-

lizing system. The reaction was monitored by both TLC and GC.

The reaction was considered finished after observing a constant

conversion in successive analyses. The products were isolated as

described in previous procedures.

perature (i.e., 0 °C), the furan substrate (1 mmol), trimethylsilyl

chloride (135 μL, 1.06 mmol), and 2,4-dibromo-3-pentanone

(258 mg, 1.06 mmol) were sequentially added through a microsy-

ringe. The reaction mixture was kept in a bath stabilized at the

working temperature and the course of the reaction was periodi-

cally monitored by gas chromatography. The reaction was consid-

ered finished after observing a constant conversion in several suc-

cessive analyses. The work-up and product isolation were carried

out by CC as described in the previous section.

Experimental Procedure 6-Zn: Cycloaddition by Reduction of 2,4-

Diiodo-3-pentanone with Zn in the Presence of Trimethylsilyl Chlor-

ide: The procedure is similar to 5-Zn, but with the modification

described in procedure 2-Cu.^[9e,9f,37]

Experimental Procedure 1-Fe: Cycloaddition by Using 2,4-Dibromo-

3-pentanone and [Fe₂(CO)₉] as Reducing Agent:^[22]The furan sub-

strate (1.06 mmol) in benzene (10 mL/mmol of diene) was added to

a two-necked round-bottomed flask fitted with a magnetic stirrer, a

Dimroth condenser, and under argon. Then [Fe₂(CO)₉] (1.75 mmol/

mmol of diene) was added at room temperature. This addition had

to be conducted inside an Atmosbag® because the diiron nona-

carbonyl is highly pyrophoric. Finally, neat 2,4-dibromo-3-pent-

anone was added dropwise at room temperature in a stoichiometric

quantity with respect to the furan derivative. The reaction mixture

was then heated at reflux and periodically monitored by gas

chromatography. The reaction was considered terminated after ob-

serving constant conversion in various successive analyses. The re-

action mixture was then percolated through a short pad of neutral

alumina, eluting with ethyl acetate (100 mL) and methanol

(50 mL). The organic phases were combined and concentrated to

dryness. The fractions containing the reaction products were

treated with ammonium cerium nitrate and triethylamine in acet-

one for 1 h to destroy traces of the diiron nonacarbonyl complex.

The mixture was concentrated to dryness, dissolved in ethyl acetate,

and washed with water. The organic phases were combined, dried

with anh. MgSO₄, filtered, and concentrated under vacuum. The

oil obtained was submitted to column chromatography (using silica

gel and eluting with mixtures of hexane and ethyl of increasing

polarity) to efficiently separate the diastereoisomeric cycloadducts.

Experimental Procedure 4-Cu: Cycloaddition by Reduction of 2,4-

Diiodo-3-pentanone with Copper Powder in the Presence of Sodium

Iodide: The procedure is similar to 3-Cu, but with the modification

of the addition as described in method 2-Cu.

Experimental Procedures Using Zinc or Metallic Couples of Zinc as

Reducing Agents

Experimental Procedures 1-Zn to 4-Zn: In the same way as de-

scribed for the procedures using copper as a reducing agent (pro-

cedures 1-Cu to 4-Cu), four different procedures were used for the

cycloaddition reactions performed in the presence of zinc powder

(procedures 1-Zn to 4-Zn). The only difference between these four

procedures is the method used for the isolation of products from

the reaction crude. Thus, because copper salts have not been gener-

ated (not even when the reducing agent is a zinc/copper couple),

the washing process with an aqueous solution of ammonia was

not necessary. Next, two work-up procedures were used for these

experiments. The first was used in those cases in which the final

product is labile and could be altered during aqueous treatment

(during work-up), whereas the second method was chosen in those

cases in which the zinc byproducts were formed by fine particles

that they pass through percolation columns.

Purification Method 1: Once the reaction was complete, as observed

by GC, ethyl acetate (100 mL) was added to stop the reaction and

the mixture submitted to percolation across a column packed with

a small amount of silica and alumina. Mixtures of ethyl acetate/

dichloromethane were used as eluents. Then the organic phase was

concentrated to dryness and the oil obtained was submitted to flash

column chromatography on silica gel, eluting with mixtures of hex-

ane and ethyl acetate of increasing polarity.

(S_s)-2,4-Dimethyl-1-(p-tolylsulfinyl)-8-oxabicyclo[3.2.1]oct-6-en-3-

one (12a and 12b): Cycloadducts 12a,b were synthesized by using

the modified Hoffmann’s cycloaddition method (method 1-Zn,

whilst stirring at 20 °C). The cycloadducts were separated by col-

umn chromatography on silica gel. The minor diastereoisomer 12b

was eluted with hexane/ethyl acetate (50:50) and the major dia-

stereoisomer 12a was eluted with hexane/ethyl acetate (60:40). The

reaction conditions and outcome are presented in Table 1. See also

the description of general methods of [4+3] cycloaddition in the

previous sections.

Purification Method 2: Once the substrate had been converted,

water was added (5 mL) to quench the reaction and the solid was

filtered through a porous plate (filter plate number 4). Then the

liquid phase was extracted with dichloromethane (5ϫ 15 mL). The

organic phases were combined and washed with brine (2ϫ 25 mL),

dried with anhydrous MgSO₄, and concentrated to dryness. The oil

obtained was submitted to flash column chromatography on SiO₂,

eluting with mixtures of hexane and ethyl acetate of increasing po-

larity.

12a: [α]²_D¹= +211.0 (c = 0.9, CHCl₃). GC (100 °C, 1 min, 10 °C/

min, 290 °C, 15 min): t_R= 18.52 min. TLC (SiO₂, hexane/ethyl

acetate, 80:20): R_f= 0.11 (developed as a blue spot with anisal-

dehyde/sulfuric acid). IR (film): ν = 3100, 2975, 2936, 1713 (C=O,

˜

st), 1653, 1597, 1559, 1495, 1456, 1379, 1157, 1086, 1057, 1040,

1016, 985 cm^–1. ¹H NMR (200 MHz, CDCl₃): δ = 0.93 (d, J =

Experimental Procedure 5-Zn: Cycloaddition by Reduction of 2,4- 7 Hz, 3 H, 10-H), 1.30 (d, J = 7 Hz, 3 H, 9-H), 2.41 (s, 3 H, 7Ј-H),

Dibromo-3-pentanone with Zn and the Zn/Cu Couple in the Presence

of Trimethylsilyl Chloride: Trimethylsilyl chloride was added to a

few experiments in which zinc (or the zinc/copper couple) was used

as reducing agent to accelerate the reaction.^[10]In a two-necked

flask fitted with a magnetic stirrer and under nitrogen, a freshly

prepared zinc/copper couple (217 mg, 3.32 mmol) was suspended

in the solvent used (i.e., acetonitrile, 11 mL). At the reaction tem-

2.81 (dq, J₁= 4.8, J₂= 7.0 Hz, 1 H, 4-H), 3.21 (q, J = 7.0 Hz, 1

H, 2-H), 4.85 (dd, J₁= 4.8, J₂= 1.4 Hz, 1 H, 5-H), 6.25 (d, J =

6.0 Hz, 1 H, 7-H), 6.30 (dd, J₁= 6.0, J₂= 1.4 Hz, 1 H, 6-H), 7.30

(d, J = 8.2 Hz, 2 H, 2Ј-H and 6Ј-H), 7.53 (d, J = 8.2 Hz, 2 H, 3Ј-

H and 5Ј-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 10.3 (C-9),

11.0 (C-10), 21.2 (C-7Ј), 49.3 (C-4), 54.8 (C-2), 83.6 (C-5), 99.6 (C-

1), 126.3 (C-2Ј and C-6Ј), 129.5 (C-3Ј and C-5Ј), 129.8 (C-6), 134.1

Eur. J. Org. Chem. 2014, 2726–2746

www.eurjoc.org

2741

Á. M. Montaña, P. M. Grima, C. Batalla, F. Sanz, G. Kociok-Köhn

FULL PAPER

(C-4Ј), 135.1 (C-7), 142.0 (C1Ј), 208.1 (C-3) ppm. MS [GC– R_f= 0.63 (developed as a blue spot with anisaldehyde/sulfuric

MS(CI), CH₄, 70 eV, 150 °C]: m/z (%) = 291 (100) [M + 1]⁺, 207

(5) [M – 85]⁺, 151 (29) [M – C₇H₇OS]⁺. C₁₆H₁₈O₃S (290.38): calcd.

C 66.18, H 6.25; found C 66.00, H 6.19.

acid). IR (film): ν = 2975 (C_sp3–H, st), 1715 (C=O), 1493, 1457 (C–

˜

C deform.), 1376 (C–H deform.), 1154, 1032 (C–O, st), 810,

1

741 cm^–1. H NMR (200 MHz, CDCl₃): δ = 1.14 (d, J = 7.4 Hz, 3

H, 9-H), 1.33 (d, J = 7.4 Hz, 3 H, 10-H), 2.35 (s, 3 H, 7Ј-H), 2.75

(q, J = 7.4 Hz, 1 H, 2-H), 2.77 (q, J = 7.4 Hz, 1 H, 4-H), 4.76 (d,

J = 1.8 Hz, 1 H, 5-H), 6.07 (d, J = 5.6 Hz, 1 H, 7-H), 6.25 (dd, J₁

= 5.6, J₂= 1.8 Hz, 1 H, 6-H), 7.14 (d, J = 8.5 Hz, 2 H, 2Ј-H and

6Ј-H), 7.51 (d, J = 8.5 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 10.3 (C-9), 10.8 (C-10), 21.2 (C-7Ј), 48.8 (C-

4), 53.3 (C-2), 83.3 (C-5), 98.6 (C-1), 129.2 (C-7), 129.4 (C-6), 129.7

(C-2Ј and C-6Ј), 135.1 (C-3Ј and C-5Ј), 138.7 (C-4Ј), 139.1 (C-1Ј),

207.1 (C-3) ppm. MS [GC–MS(CI), NH₃, 70 eV, 150 °C]: m/z (%)

= 292 (20) [M + NH₄]⁺, 275 (100) [M + H]⁺. C₁₆H₁₈O₃S (290.38):

calcd. C 66.18, H 6.25; found C 66.23, H 6.21.

12b: [α]²_D⁵= +5.52 (c = 1.04, CHCl₃). GC (100 °C, 1 min, 10 °C/

min, 290 °C, 15 min): t_R= 18.57 min. TLC (SiO₂, hexane/ethyl

acetate, 80:20): R_f= 0.09 (developed as a blue spot with anisal-

dehyde/sulfuric acid). IR (film): ν = 3100, 2977, 2936, 1715 (C=O,

˜

st), 1597, 1493, 1456, 1379, 1456, 1086, 1043, 969, 812 cm^–1. ¹H

NMR (200 MHz, CDCl₃): δ = 0.93 (d, J = 7 Hz, 3 H, 9-H), 1.22

(d, J = 7.2 Hz, 3 H, 10-H), 2.43 (s, 3 H, 7Ј-H), 2.56 (q, J = 7.0 Hz,

1 H, 2-H), 2.70 (dq, J₁= 4.8, J₂= 7.2 Hz, 1 H, 4-H), 4.98 (br. d,

J = 4.8 Hz, 1 H, 5-H), 6.47 (br. d, J = 6.2 Hz, 1 H, 6-H), 6.50 (br.

d, J = 6.2 Hz, 1 H, 7-H), 7.32 (d, J = 8.0 Hz, 2 H, 2Ј-H and 6Ј-H),

7.59 (d, J = 8.0 Hz, 2 H, 3Ј-H and 5Ј-H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 9.8 (C-9), 10.3 (C-10), 21.5 (C-7Ј), 49.5 (C-4), 52.3 (C-

2), 83.8 (C-5), 103.2 (C-1), 126.5 (C-2Ј and C-6Ј), 129.5 (C-3Ј and

C-5Ј), 130.4 (C-6), 134.9 (C-4Ј), 136.7 (C-7), 142.5 (C-1Ј), 206.4 (C-

3) ppm. MS [GC–MS(CI), CH₄, 70 eV, 150 °C]: m/z (%) = 291

(100) [M + 1]⁺, 167 (7), 152 (3) [M – C₇H₇OS + H]⁺, 151 (23) [M –

C₇H₇OS]⁺. C₁₆H₁₈O₃S (290.38): calcd. C 66.18, H 6.25; found C

66.05, H 6.12.

(S_S)-2,4-Dimethyl-1-(p-tolylsulfinyl)-8-oxabicyclo[3.2.1]oct-6-en-3-

ol (14): NaBH₄(31 mg, 0.82 mmol) suspended in dry MeOH

(1 mL) was added to a 10 mL oven-dried round-bottomed flask

fitted with a magnetic stirrer and under nitrogen,. Then enantio-

merically pure cis-endo-(5R,S_S)-2,4-dimethyl-1-(p-tolylsulfinyl)-8-

oxabicyclo[3.2.1]oct-6-en-3-one (12a; 30 mg, 0.10 mmol) in dry

methanol (2 mL) was added through a cannula at room tempera-

ture and the reaction mixture was stirred for 1.5 h (control by TLC

and IR). The solvent was eliminated under vacuum and the re-

sulting solid was suspended in ethyl acetate (10 mL). The solid was

filtered through a cannula and the mother liquor percolated

through a short column of silica gel, washing with ethyl acetate.

The organic solution was concentrated to dryness to give the re-

duction product as a white solid (30 mg, yield = 95%). The crude

product was then submitted to column chromatography on silica

gel, eluting with mixtures of hexane and ethyl acetate, isolating

as a pure product the major diastereoisomeric alcohol cis-endo-

(3S,5R,S_S)-14a (29.2 mg, isolated yield = 95 %, conversion =

100%). Diastereoselectivity: (3S)/(3R) = 98:2. GC (100 °C, 1 min,

2,4-Dimethyl-1-(p-tolylsulfenyl)-8-oxabicyclo[3.2.1]oct-6-en-3-one

(13): Racemic cis-endo-13a,b and cis-exo-13c,d cycloadducts were

synthesized by using Hoffmann’s cycloaddition method (method

1-Cu; see Table 4). Under these reaction conditions, the sulfoxide

function of the enantiomerically pure furan substrate [(S)-2-(p-tol-

ylsulfinyl)furan] was reduced prior to cycloaddition, destroying the

sulfur asymmetric center, because diastereomeric cycloadducts were

isolated as optically inactive compounds. The endo-exo isomers

were separated by column chromatography on silica gel by elution

with hexane/ethyl acetate (90:10). The reaction conditions and out-

come are presented in Table 1. See also the description of general

methods of [4+3] cycloaddition in the previous sections.

10 °C/min, 250 °C, 15 min): t_R= 20.30 min (major isomer), t_R

=

13a,b (cis-endo isomers): GC (100 °C, 1 min, 10 °C/min, 290 °C,

15 min): t_R= 18.70 min. TLC (SiO₂, hexane/ethyl acetate, 80:20):

R_f= 0.51 (developed as a blue spot with anisaldehyde/sulfuric

19.82 min (minor isomer). It was not possible to isolate a pure sam-

ple of the minor alcohol 14b for characterization due to the small-

scale nature of the work.

acid). IR (film): ν = 3102, 2977, 2938, 2876, 1713 (C=O, st), 1653,

˜

1593, 1506, 1493, 1456, 1377, 1339, 1292, 1153, 1032, 989, 962, 943,

14a: [α]²_D⁵= +166.35 (c = 0.1, CHCl₃). GC (100 °C, 1 min, 10 °C/

min, 250 °C, 15 min): t_R= 20.30 min. TLC (SiO₂, hexane/ethyl

acetate, 50:50): R_f= 0.04 (developed as a purple spot with anisal-

1

885 cm^–1. H NMR (300 MHz, CDCl₃): δ = 0.93 (d, J = 7.2 Hz, 3

H, 10-H), 1.14 (d, J = 6.9 Hz, 3 H, 9-H), 2.33 (s, 3 H, 7Ј-H), 2.73

(q, J = 7.2 Hz, 1 H, 4-H), 2.76 (dq, J₁= 4.8, J₂= 6.9 Hz, 1 H, 2-

H), 4.91 (dd, J₁= 4.8, J₂= 1.8 Hz, 1 H, 5-H), 6.10 (d, J = 6.0 Hz,

1 H, 7-H), 6.23 (dd, J₁= 6.0, J₂= 1.8 Hz, 1 H, 6-H), 7.12 (d, J =

8.1 Hz, 2 H, 2Ј-H and 6Ј-H), 7.49 (d, J = 8.2 Hz, 2 H, 3Ј-H and

5Ј-H) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 10.3 (C-9), 11.0 (C-

10), 21.2 (C-7Ј), 49.5 (C-4), 54.8 (C-2), 82.8 (C-5), 98.6 (C-1), 129.5

(C-2Ј and C-6Ј), 134.1 (C-7), 135.0 (C-6), 135.4 (C-3Ј and C-5Ј),

138.5 (C-4Ј), 138.9 (C-1Ј), 208.1 (C-3) ppm. MS [GC–MS(CI),

NH₃, 70 eV, 150 °C]: m/z (%) = 292 (17) [M + NH₄]⁺, 275 (100) [M +

H]⁺, 202 (12) [M – 72]⁺. C₁₆H₁₈O₃S (290.38): calcd. C 66.18, H

6.25; found C 66.09, H 6.18.

dehyde/sulfuric acid). IR (film): ν = 3421 (O–H, st), 2932, 2880,

˜

1653, 1597, 1559, 1495, 1456, 1086, 1036, 1014, 978, 808, 731 cm^–1.

¹H NMR (200 MHz, CDCl₃): δ = 0.92 (d, J = 7.4 Hz, 3 H, 10-H),

1.30 (d, J = 7.2 Hz, 3 H, 9-H), 2.28–2.32 (m, 1 H, 2-H), 2.37 (s, 3

H, 7Ј-H), 2.68 (dq, J₁= 5.2, J₂= 7.4 Hz, 1 H, 4-H), 3.82 (dt, J₁=

4.4, J₂= 5.2 Hz, 1 H, 3-H), 4.48 (t, J = 1.8 Hz, 1 H, 5-H), 6.27 (d,

J = 6.2 Hz, 1 H, 7-H), 6.38 (dd, J₁= 6.2, J₂= 1.8 Hz, 1 H, 6-H),

7.25 (d, J = 8.0 Hz, 2 H, 2Ј-H and 6Ј-H), 7.47 (d, J = 8.0 Hz, 2 H,

3Ј-H and 5Ј-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 12.2 (C-9),

12.4 (C-10), 21.4 (C-7Ј), 38.3 (C-2 and C-4), 73.1 (C-3), 84.7 (C-5),

102.9 (C-1), 126.4 (C-2Ј and C-6Ј), 129.1 (C-3Ј and C-5Ј), 131.5 (C-

6), 134.7 (C-4Ј), 137.6 (C-7), 141.6 (C-1Ј) ppm. MS [GC–MS(CI),

CH₄, 70 eV, 150 °C]: m/z (%) = 293 (74) [M + 1]⁺, 275 (7)

13c,d (cis-exo isomers): GC (100 °C, 1 min, 10 °C/min, 290 °C,

15 min): t_R= 18.32 min. TLC (SiO₂, hexane/ethyl acetate, 80:20):

2742

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Eur. J. Org. Chem. 2014, 2726–2746

Stereoselective [4+3] Cycloaddition Reactions

[M – 17]⁺, 153 (13) [M – C₇H₇OS]⁺, 139 (3) [M – 153]⁺. C₁₆H₂₀O₃S 137.3 (C-7), 138.4 (C-4Ј) ppm. MS [GC–MS(CI), CH₄, 70 eV,

(292.39): calcd. C 65.72, H 6.89; found C 65.78, H 6.80.

150 °C]: m/z (%) = 277 (2) [M + 1]⁺, 276 (9) [M]⁺, 153 (7) [M –

C₇H₇OS]⁺. C₁₆H₂₀O₂S (276.39): calcd. C 69.53, H 7.29; found C

69.41, H 7.18.

2,4-Dimethyl-1-(p-tolylsulfenyl)-8-oxabicyclo[3.2.1]oct-6-en-3-ol

(15): LiAlH₄(8.3 mg, 0.20 mmol) suspended in dry diethyl ether

(1 mL) was added to a 10 mL oven-dried round-bottomed flask

fitted with a magnetic stirrer and under nitrogen. Then cis-endo-

(5R,S_S)-2,4-dimethyl-1-(p-tolylsulfinyl)-8-oxabicyclo[3.2.1]oct-6-

en-3-one (12a; 30 mg, 0.10 mmol) in dry diethyl ether (4 mL) was

added through a cannula at room temperature. The reaction mix-

ture was stirred at room temperature for 1 h and for an additional

1 h at reflux (control by TLC). Excess LiAlH₄was quenched by

the addition of ethyl acetate (25 mL) followed by the addition of

water (10 mL) to protonate the alkoxides. The resulting suspension

was filtered through a cannula and the solid washed with diethyl

ether (2ϫ 10 mL). The organic phases were combined, dried with

anh. MgSO₄, filtered, and concentrated to dryness under vacuum

to afford a thick oil formed by a diastereoisomeric mixture of the

alcohols [26 mg, yield 95%, conversion = 100%, diastereoselectiv-

ity (3S)/(3R) = 58:42 by GC]. These diastereoisomers were sepa-

rated by flash column chromatography on silica gel, eluting with

mixtures of hexane and ethyl acetate of increasing polarity. The 3R

diastereoisomer was eluted with 80:20 hexane/ethyl acetate and the

3S diastereoisomer with 50:50 hexane/ethyl acetate.

(S_S)-2,4-Dimethyl-7-hydroxymethyl-1-(p-tolylsulfinyl)-8-oxabicy-

clo[3.2.1]oct-6-en-3-one (18): Compound 18 was prepared from

furan 4 by the modified Hoffmann’s method (method 2-Zn, whilst

stirring at 20 °C; see Table 4). The reaction conditions and outcome

are presented in Table 2. See also the description of general meth-

ods of [4+3] cycloaddition in the previous sections. The product

was isolated by column chromatography on silica gel, eluting with

a mixture of hexane and ethyl acetate of increasing polarity. The

product was isolated as a white solid as a single stereoisomer, m.p.

160–161 °C (ethyl acetate/hexane). [α]²_D¹= +76.0 (c = 0.4, CHCl₃).

TLC (SiO₂, hexane/ethyl acetate, 50:50, two elutions): R_f= 0.46

(developed as a blue spot with anisaldehyde/sulfuric acid). IR

(film): ν = 3400 (O–H, st), 2980, 2920, 2860, 1725 (C=O, st), 1580,

˜

1450, 1380, 1330, 1160, 1080, 1000, 940, 800 cm^–1

(200 MHz, CDCl₃): δ = 0.92 (d, J = 7 Hz, 3 H, 10-H), 1.30 (d, J

= 7 Hz, 3 H, 9-H), 2.44 (s, 3 H, 7Ј-H), 2.68 (dq, J₁= 5.0, J₂

.

¹H NMR

=

7.0 Hz, 1 H, 4-H), 2.78 (q, J = 7.0 Hz, 1 H, 2-H), 4.48 (br. s, 2 H,

11-H), 4.93 (dd, J₁= 5.0, J₂= 1.8 Hz, 1 H, 5-H), 6.36 (br. s, 1 H,

6-H), 7.36 (d, J = 8.0 Hz, 2 H, 2Ј-H and 6Ј-H), 7.68 (d, J = 8.0 Hz,

2 H, 3Ј-H and 5Ј-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 8.7

(C-9), 10.1 (C-10), 21.5 (C-7Ј), 49.0 (C-4), 52.1 (C-2), 59.2 (C-11),

83.1 (C-5), 100.8 (C-1), 126.8 (C-2Ј and C-6Ј), 129.8 (C-3Ј and C-

5Ј), 132.0 (C-4Ј), 132.5 (C-6), 143.1 (C-1Ј), 145.9 (C-7), 206.8 (C-

3) ppm. MS [GC–MS(CI), NH₃, 70 eV, 150 °C]: m/z (%) = 338 (15)

[M + NH₄]⁺, 322 (19) [M + 2]⁺, 321 (100) [M + 1]⁺. C₁₇H₂₀O₄S

(320.40): calcd. C 63.73, H 6.29; found C 63.60, H 6.51.

15a: GC (100 °C, 1 min, 10 °C/min, 290 °C, 15 min): t_R

=

19.10 min. TLC (SiO₂, hexane/ethyl acetate, 50:50): R_f= 0.52 (de-

veloped as a brown spot with anisaldehyde/sulfuric acid). IR (film):

ν = 3492 (O–H, st), 2942, 1493, 1452, 1402, 1103, 1076, 1028, 976,

˜

1

808 cm^–1. H NMR (200 MHz, CDCl₃): δ = 0.94 (d, J = 7.4 Hz, 3

H, 10-H), 1.14 (d, J = 7.2 Hz, 3 H, 9-H), 2.26–2.30 (m, 2 H, 2-H

and 4-H), 2.32 (s, 3 H, 7Ј-H), 3.73 (dt, J₁= 4.9, J₂= 4.9 Hz, 1 H,

3ЈH), 4.58 (t, J = 1.8 Hz, 1 H, 5-H), 6.23 (d, J = 6.0 Hz, 1 H, 7-

H), 6.39 (dd, J₁= 6.0, J₂= 1.8 Hz, 1 H, 6-H), 7.09 (d, J = 8.0 Hz,

2 H, 2Ј-H and 6Ј-H), 7.46 (d, J = 8.0 Hz, 2 H, 3Ј-H and 5Ј-H) ppm.

¹³C NMR (50 MHz, CDCl₃): δ = 12.6 (C-9), 13.9 (C-10), 21.2 (C-

7Ј), 38.8 (C-4), 42.5 (C-2), 73.4 (C-3), 84.1 (C-5), 98.2 (C-1), 129.3

(C-2Ј and C-6Ј), 131.7 (C-1Ј), 135.4 (C-3Ј and C-5Ј), 136.4 (C-6),

137.3 (C-7), 138.4 (C-4Ј) ppm. MS [GC–MS(CI), CH₄, 70 eV,

150 °C]: m/z (%) = 277 (2) [M + 1]⁺, 276 (9) [M]⁺, 153 (7) [M –

C₇H₇OS]⁺. C₁₆H₂₀O₂S (276.39): calcd. C 69.53, H 7.29; found C

69.50, H 7.20.

Methyl (S_S)-2,4-Dimethyl-3-oxo-1-(p-tolylsulfinyl)-8-oxabicy-

clo[3.2.1]oct-6-ene-7-carboxylate (20): Compound 20 was prepared

from furan 7 by the modified Hoffmann’s method (method 2-Zn,

whilst stirring at 20 °C, see Table 4). The reaction conditions and

outcome are presented in Table 2. See also the description of gene-

15b: GC (100 °C, 1 min, 10 °C/min, 290 °C, 15 min): t_R

=

18.95 min. TLC (SiO₂, hexane/ethyl acetate, 50:50): R_f= 0.61 (de-

veloped as a brown spot with anisaldehyde/sulfuric acid). IR (film):

ν = 3492 (O–H, st), 2942, 1493, 1452, 1402, 1103, 1076, 1028, 976, ral methods of [4+3] cycloaddition in the previous sections. The

˜

1

808 cm^–1. H NMR (200 MHz, CDCl₃): δ = 0.91 (d, J = 7.0 Hz, 3 product was isolated by column chromatography on silica gel, elut-

H, 10-H), 1.10 (d, J = 7.0 Hz, 3 H, 9-H), 2.27–2.31 (m, 2 H, 2-H

and 4-H), 2.32 (s, 3 H, 7Ј-H), 3.70–3.76 (m, 1 H, 3-H), 4.64 (dd,

J₁= 4.0, J₂= 1.8 Hz, 1 H, 5-H), 5.98 (d, J = 6.0 Hz, 1 H, 7-H),

6.15 (dd, J₁= 6.0, J₂= 1.8 Hz, 1 H, 6-H), 7.09 (d, J = 8.0 Hz, 2

H, 2Ј-H and 6Ј-H), 7.46 (d, J = 8.0 Hz, 2 H, 3Ј-H and 5Ј-H) ppm.

ing with a mixture of hexane and ethyl acetate of increasing po-

larity. The product was isolated as a thick oil and as a single stereo-

isomer. [α]²_D¹= +6.1 (c = 0.08, CHCl₃). TLC (SiO₂, hexane/ethyl

acetate, 50:50): R_f= 0.38 (developed as blue spot with anisal-

dehyde/sulfuric acid). IR (film): ν = 2981, 1719 (C=O, st), 1653

˜

1

¹³C NMR (50 MHz, CDCl₃): δ = 14.0 (C-9), 14.8 (C-10), 21.6 (C- (COO), 1559, 1456, 1437, 1277, 1254, 1099, 1084 cm^–1. H NMR

7Ј), 40.9 (C-4), 44.6 (C-2), 78.8 (C-3), 83.7 (C-5), 98.6 (C-1), 129.3 (300 MHz, CDCl₃): δ = 0.97 (d, J = 7.0 Hz, 3 H, 10-H), 1.36 (d, J

(C-2Ј and C-6Ј), 132.7 (C-1Ј), 135.4 (C-3Ј and C-5Ј), 136.4 (C-6), = 7.2 Hz, 3 H, 9-H), 2.38 (s, 3 H, 7Ј-H), 2.98 (dq, J₁= 5.4, J₂=

Eur. J. Org. Chem. 2014, 2726–2746

www.eurjoc.org

2743

Á. M. Montaña, P. M. Grima, C. Batalla, F. Sanz, G. Kociok-Köhn

conditions and outcome are presented in Table 2. See also the de-

FULL PAPER

7.0 Hz, 1 H, 4-H), 3.59 (q, J = 7.2 Hz, 1 H, 2-H), 3.78 (s, 3 H,

OCH₃), 4.92 (dq, J₁= 5.0, J₂= 2.1 Hz, 1 H, 5-H), 6.99 (d, J = scription of general methods of [4+3] cycloaddition in the previous

2.1 Hz, 1 H, 6-H), 7.24 (d, J = 9.0 Hz, 2 H, 3Ј-H and 5Ј-H), 7.53 sections. The product was isolated by column chromatography on

(d, J = 9.0 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. ¹³C NMR (50 MHz, silica gel, eluting with a mixture of hexane and ethyl acetate of

CDCl₃): δ = 9.5 (C-9), 10.1 (C-10), 21.5 (C-7Ј), 49.2 (C-4), 51.7 (C-

increasing polarity. The product of interest was obtained from the

2), 52.4 (OCH₃), 82.5 (C-5), 102.9 (C-1), 127.2 (C-2Ј and C-6Ј), column in the polar fractions eluted with hexane/ethyl acetate

129.2 (C-3Ј and C-5Ј), 135.0 (C-4Ј), 137.3 (C-7), 142.3 (C-1Ј), 146.2

(30:70) and pure ethyl acetate. The product was isolated as a thick

oil and as a single stereoisomer. TLC (SiO₂, hexane/ethyl acetate,

(C-6), 161.9 (C-11), 206.8 (C-3) ppm. MS [GC–MS(CI), NH₃,

70 eV, 150 °C]: m/z (%) = 366 (4) [M + NH₄]⁺, 365 (17) [M + 50:50): R_f= 0.12 (developed with anisaldehyde/sulfuric acid as a

NH₃]⁺, 349 (24) [M + 1]⁺, 348 (100) [M]⁺. C₁₈H₂₀O₅S (348.41): white spot on a pink background). IR (film): ν = 3307 (N–H, st),

˜

calcd. C 62.05, H 5.79; found C 62.25, H 5.66.

3062, 2979, 2936, 1717 (C=O, st), 1653 (N–C=O), 1609 (C=C),

1

1533, 1495, 1452, 1381, 1157, 1086, 1038, 997, 812 cm^–1. H NMR

(300 MHz, CDCl₃): δ = 0.94 (d, J = 7.2 Hz, 3 H, 10-H), 1.27 (d, J

= 7.2 Hz, 3 H, 9-H), 1.62 (d, J = 7.2 Hz, 3 H, 2ЈЈ-H), 2.41 (s, 3 H,

7Ј-H), 2.80 (dq, J₁= 7.0, J₂= 5.4 Hz, 1 H, 4-H), 3.11 (q, J =

7.0 Hz, 1 H, 2-H), 4.89 (dd, J₁= 5.4, J₂= 2.0 Hz, 1 H, 5-H), 5.14

(q, J = 7.2 Hz, 1 H, 1ЈЈ-H), 7.07 (d, J = 1.8 Hz, 1 H, 6-H), 7.31–

7.42 (m, 7 H, 3Ј-H, 5Ј-H, 4ЈЈ-H, 5ЈЈ-H, 6ЈЈ-H, 7ЈЈ-H, 8ЈЈ-H), 7.61

(d, J = 8.0 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. ¹³C NMR (50 MHz,

CDCl₃): δ = 9.7 (C-9), 10.1 (C-10), 21.5 (C-7Ј), 21.9 (C-2ЈЈ), 49.2

(C-4), 49.8 (C-2), 55.1 (C-1ЈЈ), 81.8 (C-5), 101.0 (C-1), 126.3 (C-

6ЈЈ), 126.7 (C-4ЈЈ and C-8ЈЈ), 127.3 (C-2Ј and C-6Ј), 128.6 (C-5ЈЈ

and C-8ЈЈ), 129.4 (C-3Ј and C-5Ј), 133.9 (C-4Ј), 141.1 (C-7), 142.6

(C-1Ј), 142.7 (C-3ЈЈ), 143.2 (C-6), 159.2 (C-11), 205.0 (C-3) ppm.

MS [GC–MS(CI), NH₃, 70 eV, 150 °C]: m/z (%) = 455 (6) [M +

NH₃]⁺, 438 (100) [M]⁺. C₂₅H₂₇NO₄S (437.55): calcd. C 68.63, H

6.22, S 7.33, N 3.20; found C 68.71, H 6.18, S 7.38, N 3.17.

(S_S)-N,N-diethyl-2,4-dimethyl-3-oxo-1-(p-tolylsulfinyl)-8-oxabi-

cyclo[3.2.1]oct-6-ene-7-carboxamide (21): Compound 21 was pre-

pared from furan 9 by the modified Hoffmann’s method (method

2-Zn, whilst stirring at 20 °C, see Table 4). The reaction conditions

and outcome are presented in Table 2. See also the description of

general methods of [4+3] cycloaddition in the previous sections.

The product was isolated by column chromatography on silica gel,

eluting with mixture of hexane and ethyl acetate of increasing po-

larity. The product of interest was obtained from the column in the

polar fractions eluted with ethyl acetate. The product was isolated

as a thick oil and as a single stereoisomer. TLC (SiO₂, hexane/ethyl

acetate, 50:50): R_f= 0.22 (developed with anisaldehyde/sulfuric acid

as a white spot on a pink background). IR (film): ν = 2975, 2936,

˜

1717 (C=O, st), 1701 (N–C=O), 1653, 1636, 1559, 1506, 1489, 1456,

1

1381, 1084, 1049 cm^–1. H NMR (200 MHz, CDCl₃): δ = 1.01 (d,

J = 7 Hz, 3 H, 10-H), 1.13–1.27 (m, 9 H, 9-H, NCH₂CH₃), 2.39 (s,

3 H, 7Ј-H), 2.92 (dq, J₁= 5.0, J₂= 7.0 Hz, 1 H, 4-H), 3.40–3.60

(m, 5 H, 2-H, NCH₂CH₃), 4.90 (dq, J₁= 5.0, J₂= 1.8 Hz, 1 H, 5-

H), 6.30 (d, J = 1.8 Hz, 1 H, 6-H), 7.36 (d, J = 8.0 Hz, 2 H, 3Ј-H

and 5Ј-H), 7.82 (d, J = 8.0 Hz, 2 H, 2Ј-H and 6Ј-H) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 8.7 (C-9), 10.5 (C-10), 12.9 (N- NCH₂CH₃),

21.4 (C-7Ј), 43.5 (NCH₂CH₃), 49.8 (C-2), 50.8 (C-4), 83.1 (C-5),

115.9 (C-1), 126.1 (C-2Ј and C-6Ј), 128.3 (C-3Ј and C-5Ј), 136.1 (C-

4Ј), 137.0 (C-7), 142.5 (C-1Ј), 149.3 (C-6), 165.8 (C-11), 209.8 (C-

3) ppm. MS [GC–MS(CI), NH₃, 70 eV, 150 °C]: m/z (%) = 390 (4)

[M + 1]⁺, 389 (2) [M]⁺. C₂₁H₂₇NO₄S (389.51): calcd. C 64.76, H

6.99, S 8.23, N 3.60; found C 64.81, H 7.01, S 7.92, N 3.58.

Computational Calculations: The conformational optimizations and

calculations reported herein were performed by using the

Gaussian 03W Revision E.01 (version 6.1) software.^[38]All molecu-

lar ground-state and transition-state structures were energy preop-

timized by using molecular mechanics MM2 followed by the semi-

empirical quantum mechanical PM6 algorithm^[39]implemented in

the MOPAC software, and optimizing to the TS. DFT-based meth-

ods at the B3LYP/6-311⁺⁺G(d) level of theory^[40]were used for sub-

sequent full refinements. Analysis of all data and plotting of the

molecular structures were performed by using the Gaussian View

4.1 program.

Supporting Information (see footnote on the first page of this arti-

1

cle): IR, H and ¹³C NMR, DEPT and MS spectra of the cycload-

ducts and derivatives.

Acknowledgments

The authors thank the University of Barcelona for financial sup-

port (grant number UB-VRR-2012/AR000126).

(S_S,1ЈЈS)-N-(1-Phenylethyl)-2,4-dimethyl-3-oxo-1-(p-tolylsulfinyl)-

8-oxabicyclo[3.2.1]oct-6-ene-7-carboxamide (23): Compound 23 was

prepared from furan 11 by the modified Hoffmann’s method

(method 2-Zn, whilst stirring at 20 °C, see Table 4). The reaction

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2744

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Received: December 5, 2013

Published Online: February 25, 2014

Minor changes have been made in Figure 1 after publication in

Early View.

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Article Doi

Use of the p-Tolylsulfinyl group as a chiral inductor in stereoselective [4+3] cycloaddition reactions: Preparation of enantiopure polysubstituted 8-oxabicyclo[3.2.1]oct-6-en-3-one systems having up to five stereocenters

DOI: 10.1002/ejoc.201301814

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