Versatile methodology to synthesize oxygen-bridged nine- and ten-membered cycloalkanes by the hypoiodite reaction

FULL PAPER

DOI: 10.1002/ejoc.200700172

Versatile Methodology to Synthesize Oxygen-Bridged Nine- and Ten-

Membered Cycloalkanes by the Hypoiodite Reaction

[a]

[b]

[c]

Ángel M. Montaña,* Stefano Ponzano, Gabriele Kociok-Köhn, Mercè Font-Bardia,

and Xavier Solans^[

c]

Keywords: β-Fragmentation / Hypoiodite reaction / Ring contraction / Cycloaddition / 1,7-Epoxycyclononane / 1,8-Epoxy-

cyclodecane

C-3 derivatives of 6-hydroxy-2,7-dimethyl-11-oxatricy-

clo[6.2.1.0²]undecan-4-one reacted with lead tetraacetate

arrangement, affording 1,8-epoxycyclodecanes. The trans-

formation of the carbonyl group on C-4 to acetate avoided

radical additions and rearrangements affording, in high

,6

(LTA) and iodine to afford, in good yield, 1,7-epoxycy-

clononanes, which are the result of a β-fragmentation of the yield, the corresponding cyclodecanes. By this methodology,

C2–C6 bond adjacent to the tertiary hydroxy group on C-6.

This β-fragmentation is followed by a ring contraction from

a ten- to a nine-membered ring system, by a free-radical ad-

dition to the carbonyl group on C-4. The reaction of precur-

sors (not functionalized on C-3) with LTA and iodine pro-

duced a β-fragmentation without any further structural re-

either 1,7-epoxycyclononane or 1,8-epoxycyclodecane could

be synthesized, in good yield, by choosing the appropriate

substitution pattern on C-3 in the substrate.

Germany, 2007)

[

5]

Introduction

cyclic framework appear in the literature. Worth noting

[

6]

are the physalins (Figure 2), a large family of natural seco-

steroids with a wide range of biological activities. Physalins

are natural products isolated from different species of Phys-

The 1,8-epoxycyclodecane systems are structural units

which are present in a wide range of terpenoids. Most of

these natural products present interesting pharmacological

activities like the well-known eleutherobin^[(Figure 1),

which possesses antitumor properties closely related to

those of paclitaxel. Other examples of bioactive natural

products having this oxabicyclic framework worth noting

are goiazensolides, which are secondary metabolites of

plants, and sclerophytins^[and other antineoplasic diterpe-

nic cembranoids of marine origin, found in soft corals (Fig-

ure 1). Bioactive products containing the 1,8-epoxycyclo-

decane framework have a growing interest among synthetic

chemists and several total syntheses of this type of mole-

cules have been described.^[

[7]

alis solanaceae, abundant on the American continent.

1]

These compounds have an important cytotoxic activity

which has generated a special interest among the scientific

community.

In this context, several methodologies have appeared in

the literature to synthesize the oxabicyclic frameworks of

[2]

3]

1

,8-epoxycyclodecane and 1,7-epoxycyclononane (i.e. 11-

oxabicyclo[6.2.1]undecane and 10-oxabicyclo[5.2.1]decane).

Many of these methodologies only can be used for a certain

type of substrate or they are not compatible with some

functional groups. For these reasons it is necessary to con-

sider all possible synthetic solutions to face the synthetic

and structural challenges represented by the aforemen-

tioned target molecules. Among these synthetic methodolo-

gies are worth noting the following: (a) 1,4-elimination reac-

tions mediated by a base in the presence of a good leaving

4]

On the other hand, the 1,7-epoxycyclononane framework

is considerably less widespread than its 1,8-epoxycyclodec-

ane homologue among natural products; however, a few ex-

amples of interesting compounds containing this oxabi-

[

8]

[9]

group (this is a kind of Grob fragmentation that affords

[

a] Unidad de Química Orgánica Industrial y Aplicada, De- good results if the disposition of the hydrogen atom to be

partamento de Química Orgánica, Universidad de Barcelona,

Martí i Franquès 1–11, 08028 Barcelona, Spain

Fax: +34-93-3397878

abstracted and the leaving group are adequate), (b) retro-

[

10]

aldol reactions,

cycloreversion reaction, (d) transannular ring expansion

(c) cyclobutane thermolysis by a [2+2]

[

11]

[12]

E-mail: angel.montana@ub.edu

[

b] Department of Chemistry, University of Bath,

Bath, BA2 7AY, UK

induced by electrophiles,

(e) transannular cyclization in

[

13]

c] Departamento de Cristalografía, Mineralogía y Depósitos Min- acidic media,

(f) ring expansion mediated by hydrogen

erales, Universidad de Barcelona,

[14]

peroxide, (g) intramolecular reductive coupling mediated

Martí i Franquès s/n, 08028 Barcelona, Spain

Supporting information for this article is available on the

WWW under http://www.eurjoc.org or from the author.

[

15]

[16]

^b^y^S^m^I2^,

(h) anionic oxy-Cope rearrangement (this re-

action is less reversible than the conventional Cope re-

Eur. J. Org. Chem. 2007, 4383–4401

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Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

Figure 1. Examples of 1,8-epoxycyclodecanes with antitumour activity.

lecular free-radical addition to a carbonyl group. Moreover,

it is reported how the modification of the substrate by a

carbonyl group transformation into a protected alcohol (in

order to avoid free radical additions and rearrangements)

afforded, in high yield, the corresponding 1,8-epoxycyclo-

decanes. Thus, by this methodology, either 1,7-epoxycy-

clononane or 1,8-epoxycyclodecane could be synthesized in

good yield from a versatile precursor.

The main objective of the present work was to develop a

synthetic methodology in order to prepare a selected library

of potential antitumor compounds, analogues of the afore-

mentioned bioactive natural products, containing the 1,7-

Figure 2. Examples of physalins with cytotoxic activity.

arrangement because the initially formed enol tautomerises epoxyxyclononane and 1,8-epoxycyclodecane frameworks,

to afford the corresponding ketone), and (i) the hypoiodite with the purpose of carrying out structure-activity relation-

[

17]

reaction.

ship studies. To reach this objective, compound I was con-

In the present work, a new methodology to synthesize sidered a key versatile precursor, from the retrosynthetic

1,7-epoxycyclononane and 1,8-epoxycyclodecane systems is point of view, to the target molecules II and III (Scheme 1).

reported. Also, interesting structural and mechanistic as- In a first approach, these oxatricyclic starting materials I

pects are included, which involve the contraction of a ten- could be transformed into the desired 1,7-epoxycy-

membered ring into a nine-membered ring, by an intramo- clononanes, precursors of physalins, and 1,8-epoxycyclo-

Scheme 1. Key oxatricyclic precursor I to generate 1,7-epoxycyclononanes (II) and 1,8-epoxycyclodecanes (III) by β-fragmentation reactions.

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Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

decanes, precursors of eleutherobin, goiazensólides and

The major diastereomer 4a has both methyl groups in a

sclerophytins by a β-fragmentation of the C2–C6 bond diequatorial disposition for a boat-like conformation of the

(

Scheme 1).

1-oxan-4-one ring, and it is easily separable from 4b by col-

umn chromatography. Halo ketone 2 was obtained in 80%

yield by bromination of cheap and commercially available

Results and Discussion

[20]

3-pentanone (1) under acid catalysis. Catalytic hydrogen-

ation of the C6–C7 double bond afforded in quantitative

yield the cycloheptanone 5.

Synthesis of Key Precursors 16–18

We have developed a synthetic methodology to construct

The oxabicycle 5 was efficiently converted into the silyl

1-oxatricyclo[6.2.1.0 ]decane skeletons (I), conveniently enol ether 6, in 98% yield, by its treatment at –78 °C with

2

,6

1

functionalized. We report here the application of this syn- LDA followed by the quenching of the formed enolate with

thetic strategy to the preparation of oxamacrobicycles trimethylsilyl chloride (Ͼ99% pure), under extremely anhy-

which are the framework of the aforementioned large fam- drous conditions. This methodology can be applied in an

[

22]

ily of natural products with important biological activities. enantioselective manner by using a chiral base,

instead

It is a methodology based on two key reactions: (1) a [4+3] of LDA, which allows the desymmetrisation of the meso-

[

18]

cycloaddition [to generate the seven-membered ring (see oxabicycle 5 in an early stage of the synthetic pathway.

[

19]

Scheme 2)] and (2) the Nicholas reaction, to electrophil-

The three-carbon subunit, necessary to assemble the five-

ically insert the propargyl entity which will, in turn, facili- membered ring of the 11-oxabicyclo[6.2.1.0²]decane sys-

,6

tate the construction of the five-membered ring by an intra- tem, was introduced by an electrophilic attack of the pro-

molecular cyclization (Scheme 2).

pargyl cations (stabilized as hexacarbonyldicobalt com-

Moreover, it is a versatile synthetic strategy, because by plexes) on silyl enol ether 6 (Nicholas reaction).^[¹⁹^]These

choosing an adequate substitution pattern in the propargyl, propargyl cations were generated in situ from cobalt com-

[

23]

furan and dihalo ketone (for preparation of the 2-oxyallyl plexes 12, 13 and 15 by reaction with BF ·OEt . Cobalt

3

2

cation) precursors it is possible to prepare a wide range of complexes 12 and 13 were prepared, in quantitative yield,

related structures. An active effort in this research field has from the precursory acetylenic acetals 10 and 11, respec-

[

20,24]

been carried out in our laboratory.

tively, which were readily obtained from acrolein

(see

The cycloheptane moiety of our bicyclic system was pre- Scheme 3). The preparation of cobalt complex 15 was

pared by a [4C(4π)+3C(2π)] cycloaddition reaction between straightforward, starting from propargyl alcohol (14, see

furan (3) and 1,3-dimethyl-2-oxyallyl cation (Scheme 2), Scheme 3). The Nicholas propargylation of 6 produced in

generated in situ by the reduction of 2,4-dibromo-3-penta- high yield a 1:1 diastereomeric mixture of 16a/16b and 17a/

none (2) with Cu/NaI at 55 °C.^[This reaction afforded a 17b, which are pairs of epimers at C-1Ј, starting from cobalt

20]

mixture of diastereomers 4a/4b (cis-diequatorial/cis-diaxial) complexes 12 and 13, respectively. Also, propargylation

in an 80:20 ratio and in 95% yield (Scheme 3).^[

21]

product 18 was obtained from the reaction of cobalt com-

Scheme 2. Retrosynthesis of the five- and seven-membered rings of the bicyclo[5.3.0]decane framework.

Eur. J. Org. Chem. 2007, 4383–4401

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4385

Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

Scheme 3. Synthetic methodology to prepare substrates 25, 26 and 27. (a) Br

chromatographic separation; (c) H , Pd/C (10%), EtOH, room temp.; (d) LDA, –78 °C, THF, then TMSCl; (e) Br

MeOH or HC(OEt) in EtOH, 0–5 °C; (f) NaOH, Bu NHSO , H O/Et O, room temp.; (g) Co (CO) , pentane, room temp.; (h) BF

CH Cl , 0 °C; (i) CAN, Et N, acetone, 0 °C; (j) Hg p-toluenesulfamidate, EtOH/H O (85:15), reflux; (k) anh. KOH, abs. EtOH, room

temp. For yields of steps h–k see Table 1.

2

(2 equiv.), PBr

3

(cat.), 0 °C; (b) furan, NaI, Cu, 55 °C,

, then HC(OMe) in

·OEt

2

3

4

II

4

2

8

3

2

,

2

3

2

plex 15 (see Scheme 4 and Table 1). The epimeric ratio (a/ purposes as explained below. In this reaction two stereo-

b) may vary with reaction conditions (temperature and re- centres were generated, thus, four diastereomers could be

action time) but both of them are useful for our synthetic theoretically possible as products. However, due to the

Scheme 4. Preferential attack of the hexacarbonyldicobalt(propargylium) cation by the exo face of the π-system of silyl enol ether 6.

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Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

Table 1. Reaction outcome and yields of the Nicholas reaction, demetallation of cobalt complexes, hydration of acetylenes and aldol

cyclization of methyl ketones in the synthesis of substrates 25, 26 and 27.

R

Substrate

Products and yields [%]^[^a^]

Step h: Nicholas reaction^[^b^]Step i: demetallation^[^c^]

Step j: triple bond hydration

Step k: aldol cyclization^[^d^]

OEt

OMe

H

12

13

15

16a/16b

17a/17b

18

75–79

70–98

95–98

19a/19b

20a/20b

21

80–84

71–94

90–95

22a/22b

23a/23b

24

80–85

70–86

25

26

27

80–95

78–80

75–78

[

a] The range of yields was obtained from five different trials for each substrate. [b] The yield in this step depends on both the reaction

time and the work scale. [c] In this step the variation of yields depends on the type of workup. [d] The yield depends on the reaction

time. Conversion was not complete in most cases.

bulkiness of the organocobalt cluster, the attack of the pro- the hydration of the triple bond was performed under neu-

[

26]

II

chiral propargylium cation is only possible by the exo face tral conditions

of silyl enol ether 6, forming only two diastereomers (see afford diketones 22a/22b (1:1), 23a/23b (1:1) and 24 in good

Scheme 4). yield (see Table 1). Under these conditions, the epimeric

by using Hg p-toluenesulfonamidate to

Compounds 16a and 16b or 17a and 17b were separated pairs of methyl ketones were configurationally stable and

by column chromatography for their physical and spectro- no modification of stereocentres at C-4 and C-1Ј was ob-

scopic characterization, but for synthetic purposes both of served. This behaviour was confirmed by performing the

them were allowed to react as a mixture. In Table 1 the hydration reaction on separated acetylenes 20a and 20b and

yields are quoted for the different trials of this reaction. We obtaining in each case only one product 23a and 23b,

have observed that, for the same molar ratio among rea- respectively.

gents, when increasing the reaction time beyond 2 h the

yield decreases. On the other hand, when increasing the and 24 by using anhydrous KOH in absolute ethanol

scale of work the yield also increased. formed oxatricyclic compounds 25, 26 and 27, respectively,

The aldol cyclization of methyl ketones 22a/22b, 23a/23b

The cobalt complexes 16a/16b, 17a/17b and 18 were de- in high yield (see Table 1), as a unique product. It is worth

metallated with cerium(IV) ammonium nitrate (CAN) and noting that this aldol reaction is stereo-convergent and both

NEt in acetone affording acetylenes 19a/19b, 21b/20b and epimers gave the same final products: 22a and 22b afforded

3

21 in good yield (see Table 1). Under these conditions both 25, 23a and 23b formed 26, and 24 generated 27. This phe-

pairs of epimers were configurationally stable and the ratio nomenon could probably take place through a keto-enol

among acetylenes was identical to that of the complexes. In equilibrium involving precursor methyl ketone 23b, which

the next step, the pairs of epimers 19a/19b and/or 21b/20b could epimerize to 23a and/or at the level of the aldol inter-

were allowed to react as mixtures, but for their characteriza- mediate, to evolve to a more stable Me–C-2 vs. RЈO–C-3

tion the individual compounds were also separated and trans relationship. To evaluate both possibilities we carried

purified by column chromatography. If Nicholas coupling out the aldol reaction on both epimers 23a and 23b sepa-

and demetallation reactions were carried out in one pot the rately, stopping the reaction at 50% conversion of substrate,

[

23]

overall yield of both steps could be improved by 10%. It in order to detect possible intermediates. In the case of the

is worth noting that the type of workup in the demetallation reaction of 23a we exclusively observed unchanged 23a and

process may influence the yield of the resulting acetylene. aldol 26. On the other hand, in the reaction mixture coming

The typical workup that involves the addition of water to from 23b we observed unreacted 23b (8%), its epimer 23a

the reaction mixture and extraction with diethyl ether is the (42%) and product 26 (50%). According to these findings

one that affords the worst results due to the formation of both keto-enol equilibria are responsible for this interesting

thick emulsions, induced by cobalt or cerium salts. Centri- thermodynamically driven stereo-convergence. According

fugation of these emulsions improves the results of the iso- to these studies we can conclude that long reaction times

lation of the products. We have found a much better alter- are necessary (24 h) to reach a complete conversion and a

native in the direct filtration of the crude reaction mixture high degree of isomerization, by enolisation, in order to

®

through a three-layer short pad of Celite , alumina, and convert all possible aldols into the thermodynamically most

silica gel, in this order and eluting with acetone. All the stable stereoisomer. If shorter reaction times are used a cer-

cobalt salts and most of the cerium salts are retained in this tain percentage of other isomers, epimers at C-3 or C-7,

way. The yield of demetallated product after this workup were observed.

protocol was improved by 50% relative to those of the pre-

vious procedure.

Hydration of a triple bond is usually carried out by using

II

[25]

H SO /H O/AcOH systems in the presence of Hg salts.

β-Fragmentation Reactions

2

4

2

These reaction conditions afforded in our case a low yield

of products and propitiated polymerization of acetylenes

The desired C2–C6 fragmentation in the substrates 25,

and epimerization of stereocentres, by the enolization of 26 and 27 could be accomplished by using several oxidizing

[

27–32]

ketones, among other side processes. To avoid this problem, agents

such as CAN, lead tetraacetate (LTA) or by the

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Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

use of the hypoiodite reaction conditions^[¹⁷^,³³^]in the pres- mers of each other, and the non-iodinated products 29a and

ence of the tandem reagents HgO/I and/or LTA/I among 29b, which are also epimers of each other at the asymmetric

2

[

33a,33c]

others.

All the aforementioned reagents were evalu- acetal carbon atom. In a similar way, from substrate 26 four

ated under several reaction conditions and the system LTA/ compounds were isolated: the iodinated epimers 30a and

I₂showed to be the most efficient one for our substrates, 30b and the non-halogenated epimers 31a and 31b (see

resulting in shorter reaction times and higher yields than Table 2).

with the other alternatives. Thus, substrates 25 and 26 were

The reaction of substrate 25 with LTA/I under milder

2

dissolved in anhydrous benzene and treated with LTA and conditions (using a 1:1:1 molar ratio of substrate/LTA/I₂)

iodine in a 3:1 molar ratio, submitting the mixture to irradi- at room temperature (without 100 W lamp irradiation) for

ation with two 100 W lamps. After workup, the crude mix- 2 h, afforded the non-iodinated aldehyde 32 as the major

ture was fractionated by column chromatography on silica product in a 50% yield (see Table 2). Compound 32 was

gel and four compounds were separated, which were physi- characterized and its structure confirmed by X-ray diffrac-

1

13

cally and spectroscopically characterized ( H NMR,

NMR, DEPT, COSY, HETCOR, IR, MS and EA). From

C

tion analysis (Figure 4).

Different parameters and reaction conditions were modi-

substrate 25 two pairs of reaction products were isolated fied in order to understand and to optimize the β-fragmen-

and identified: the iodinated compounds 28a and 28b, epi- tation reaction. Thus, the reactivity of 27 was studied by

Table 2. Products resulting from the β-fragmentation of substrates 25 and 26.

2

Table 3. Results from the reaction of 27 with LTA/I .

Trial

Molar ratio

Substrate/LTA/I

Scale

[mg]

hν^[^a^]

T

[°C]

t

[h]

Yield

[%]

Conversion

[%]

Product ratio

I/acetate derivatives

3a,b/34a,b

2

33a/33b

3

1

2

3

4

5

6

1:3:1

1:1:1

100

200

yes

no

45

20

1

0.5

1

41

50

67

76

68

60

100

84

82

83

87

43:57

100:0

1:1

7:3

45:55

1:1

2

[a] Irradiation with two 100 W lamps.

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Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

performing different trials in which the following experi- Assignment of the Relative Stereochemistry in the β-

mental conditions were modified: reaction temperature and Fragmentation Products

time, use or not of two 100 W lamps (to induce radical for-

mation) and the number of equiv. of LTA and iodine. The

The skeleton and functionality of 33a and 33b were es-

first three trials were performed using small amounts of 27 tablished by a careful comparative study of the spectro-

1

13

(

100 mg); however, trials 4 and 5 were run on a larger scale scopic data ( H NMR, C NMR, IR and MS). The relative

200 mg) in order to know the influence of the scale-up on stereochemistry in both compounds was determined by a

1

13

the outcome and yield of the reaction. The results and con- careful correlation of H and C NMR spectroscopic data

ditions of these reactions are quoted in Table 3.

according to the following protocol:

The first important observation from Table 3 was that in (a) Unequivocal assignment of the H and ¹³C NMR sig-

all products 33a,b and 34a,b a 1,8-epoxycyclodecane skel- nals by 2D experiments (g-COSY, HETCOR, HMBC,

eton was present. The use of high molar ratios of LTA/ HMQC and NOESY).

1

substrate gave low yields of the desired products. Moreover, (b) Conformational analysis by MM2, MOPAC, and

in order to obtain good selectivity it was preferable to work GAUSSIAN computational methods in order to know the

under milder conditions, even though the conversion was minimum energy conformers for 33a and/or 33b that have

not complete, because the starting material could be reco- the highest weighed contribution to observed δ (ppm) and

vered (trials 3–5 in Table 3). Increasing the scale of work J (Hz) values in solution.

slightly increased the yield, and shorter reaction times pro- (c) Comparative study of the NMR spectroscopic data from

pitiated the formation of a higher proportion of epimer 33a all diastereomers. Analysis of significant differences and

vs. 33b (see trials 3 and 4 vs. 1, 2 and 5 in Table 3). Only in correlation studies. Δδ (δ₃₃_a– δ₃₃_b) was calculated (see

trial 1, performed at a high molar ratio of oxidizing agent, Table 4) to know what structural changes would induce the

with heating and simultaneous irradiation with two 100 W main differences in chemical shifts between epimers at C-

lamps, was it possible to observe the formation of a pair of 7. Thus, it was possible to understand how changes in the

epimeric acetoxy derivatives 34a,b together with the analo- configuration at the C-7 stereocenter or how modifications

gous iodinated cyclodecane products 33a,b. When increas- in the conformation of the larger ring of the bicyclic system

1

13

ing the reaction time, maintaining constant the other reac- should determine the Δδ values observed for H and

C

tion parameters (see Table 3, trials 4, 5 and 6), a higher NMR spectroscopic data.

conversion was observed but the reaction yield was not im- (d) Study of the configuration-dependent stereoelectronic

proved. effects responsible for the significant and diagnostic ΔJ

Table 4. H NMR and ¹³C NMR correlation studies for 33a and 33b; δ values in ppm.

1

Proton

δ

33a

δ

33b

Δδ (δ33a – δ33b

)

Carbon

δ

33a

δ

33b

Δδ (δ33a – δ33b)

1

2

4.30

3.48

3.40

3.84

2.55

2.76

4.48

1.45

1.78

2.30

2.00

0.97

1.99

4.37

3.35

3.42

3.59

2.72

3.59

4.23

2.25

1.82

2.25

1.97

0.96

2.35

–0.07

0.13

–0.02

0.25

–0.17

–0.83

0.25

–0.80

–0.04

0.05

1

2

3

4

5

6

7

8

9

10

12

13

–

82.82

47.99

209.70

67.20

197.65

48.66

44.23

91.59

25.99

25.68

12.58

35.04

–

88.74

47.89

209.46

66.98

197.93

50.38

46.79

85.70

32.03

25.04

12.89

35.50

–

–5.92

0.10

0.24

0.22

–0.28

–1.72

–2.56

5.89

–6.04

0.64

–0.31

–0.46

–

4

6

α

β

α

β

8

9

α

β

1

0α

0β

0.03

0.01

–0.6

1

2

13

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Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

(

Hz) and Δδ (ppm) variations among diastereomers in their (f) Confirmation of the validity of the previous stereochem-

minimum-energy conformations. ical assignments by X-ray diffraction analysis on single

e) Assignment of the relative stereochemistry that should crystals of certain key products.

(

be consistent with all data and observations from the pre-

vious studies.

The main differences were observed in the chemical shifts

of 4β-H (Δδ = 0.25 ppm), 6β-H (Δδ = –0.83 ppm), 8-H (Δδ

Figure 3. Physical interactions that explain the H and ¹³C NMR chemical shift differences between 33a and 33b.

1

Figure 4. X-ray ORTEP figures with IUPAC numbering of compounds 25, 28a, 32 and 37.

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Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

=

0.25 ppm), 9α-H (Δδ = –0.80 ppm) and 13-H (Δδ = stereomers and the assignment of stereochemistry has been

–

0.36 ppm). On the other hand, the largest differences in confirmed by X-ray diffraction analysis in the case of 25,

C chemical shifts were observed for C-1, C-7, C-8 and 28a, 32 and 37 (see Figure 4 and Table 6. See also Tables

1

3

C-9, with Δδ values of –5.92, –2.56, 5.89 and –6.04 ppm,

respectively. All these chemical shift differences were pro-

S1 and S2 of the Supporting Information).

duced by the following main physical phenomena^[

34,35]

(see

Mechanistic Studies

Figure 3): (a) The concomitant δ-gauche shielding ef-

[

35a,36]

fect

between Me–C-7 and 9-H and the deshielding ef-

The before-mentioned results could be interpreted on the

fect exerted by iodine on 8-H in 33a by steric compres- basis of the following proposed mechanism. In this mecha-

[

35a,35c,36]

[35a,36a,36c]

[17]

sion

and electric-field

interaction and (b) nism, the hypoiodite reaction

is a key step in which the

the deshielding effect produced in 33b by the bridging oxy- free tertiary alcohol of 27 reacts with an iodonium cation,

gen atom on 13-H by a linear electric-field effect and the generated in situ from LTA and iodine, and forms the corre-

3

deshielding effect exerted by the iodine atom on 9-H by sponding hypoiodite A (see Scheme 5). Subsequently, with

both a steric compression (responsible for the pull-push the help of light and/or heating, the molecule undergoes a

electron-density shift) and an electric-field interaction.

homolytic breakdown of the O–I bond, forming an alkoxy

The protocol described above has been successfully ap- radical and releasing an iodine radical. This alkoxy radical

[

29]

plied to the 28a,b, 29a,b, 30a,b and 31a,b series of dia- undergoes a β-fragmentation

by a homolytic scission of

Scheme 5. Proposal of a formation mechanism of 1,7-epoxycyclononanes and 1,8-epoxycyclodecanes from substrates 25, 26 and 27.

4391

Eur. J. Org. Chem. 2007, 4383–4401

www.eurjoc.org

Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

the C2–C6 bond and a new carbon radical on position C-7 an intramolecular free-radical addition to that position.

of intermediate C is formed. This last secondary radical re- The ketone group in 25 was reduced by NaBH in high

4

acts, by a radical termination reaction, with the previously yield and in a diastereospecific manner (Scheme 6) and the

released iodine radical to generate the neutral epimeric resulting alcohol 35 was quantitatively acetylated to obtain

compounds 33a and 33b (path b, Scheme 5), in a stereo- compound 36. The obtained acetylated product was treated

selective manner, depending on the reaction time (see with LTA/I (molar ratio of 1:1:1 at room temperature for

2

Table 3). In a similar way (path b), the acetoxy derivatives 3 h) to obtain cyclodecane 37 in 75% yield and complete

34a and 34b could be formed (see trial 1 in Table 3).

stereoselectivity regarding the insertion of an iodine atom

It is worth noting the difference in reactivity between into the newly formed stereocenter at C-7 (no other stereo-

substrates 25, 26 and 27. The only structural difference be- isomers of 37 were detected). The stereoselectivity in the

tween these compounds is the absence of the alkoxy substit- formation of 37 could be explained by the high steric de-

uent in compound 27. According to the obtained results, mand of the iodine atom, which in the epimer of 37 would

when precursors 25 and 26 reacted with LTA and I in a strongly interact with both the hydrogen atoms on C-9 and

2

3:1 ratio or in a 1:1 ratio, they underwent a β-fragmentation C-10 and the ethoxy group on C-6. The stereochemistry of

with a structural rearrangement to a nine-membered ring 37 has been confirmed by X-ray diffraction analysis.

system. On the other hand, when compound 27 was treated

with LTA and I in a 1:1 or 3:1 molar ratio, the expected

2

ten-membered ring was generated in good yield. To explain

the ring contraction undergone by the substrates 25 and 26,

it seems reasonable to suggest that the formation of the free

radical C on C-7 should be followed by its attack and ad-

dition to the ketone carbonyl group at C-5 (path a,

[

37]

Scheme 5). The intermediate cyclopropyloxy free radical

D then undergoes a β-scission to afford the cyclononane

ring. The new secondary radical E (Scheme 5) could sub-

sequently react with an acetoxy free radical, generated from

the photodecomposition of LTA, following path (c) to give

the non-iodinated diketone (29a, 29b, 31a, or 31b). The

iodo derivatives (28a, 28b, 30a, 30b) probably form by a

keto-enol tautomerisation and subsequent attack of an

iodine molecule on the double bond of the corresponding

enol G. This unusual kind of structural rearrangement in-

volving the contraction from a ten- to a nine-membered

[

38]

ring has been only reported in two previous examples.

In the aforementioned reaction pathway, the alkoxy

Scheme 6. Reduction, acetylation and β-fragmentation of 25 to

group could play several roles.^[³⁷^,³⁸^c^]It may facilitate the generate 37.

radical addition to the ketone on C-5, by activating the car-

bonyl group, and it can assist in the ring opening of the

It is also important to remark that when working under

intermediate cyclopropyloxy free radical by stabilizing the mild reaction conditions (room temp. and no irradiation

resulting free radical in E (Scheme 5). Apart from the pos- with artificial light), the formation of iodinated products

[

39]

sible electronic effects, some kind of Thorpe–Ingold

ef- was preferred to the formation of the acetoxylated ones ir-

fect could be responsible for the “facilitation” of the cycli- respective of the molar ratio of substrate/LTA/I (1:1:1 or

2

zation process to afford the cyclopropyloxy radical. Accord- 1:3:1). Thus, when substrates 25 and 26 were allowed to

ing to studies by Beckwith and Hay,^[

38d]

the cycloaddition react under these mild conditions aldehyde 32 was isolated

of free radicals to a carbonyl group are much slower than as the major product due to the reaction mechanism ac-

the ring openings of the resultant cyclic alkoxy radicals. cording to the proposed path (d) instead of path (c) (see

Thus, the driving force to facilitate the approach of the car- Scheme 5). The aldehyde formation could be understood by

bonyl carbon atom and the carbon atom bearing the free considering the formation of an unstable iodinated interme-

radical could be the presence of sterically demanding sub- diate F (instead of the stable acetals 29a,b or 31a,b) which

[

40]

[41]

stituents α to the carbonyl group. A captodative effect,

could be easily hydrolyzed, during workup, to afford the

could ex- formylated compound.

plain the different behaviour of substrate 27 and 25 or 27 The possible reason for the preference of path (d) over

involving steric and electronic contributions,^[

39,40]

and 26 upon exposure to LTA/I . These aspects are being the path (c) could be the fact that the low concentration of

2

studied now in our laboratory, by introducing bulkier sub- acetoxy free radicals present in the reaction medium due to

·

stituents different from OEt or OMe α to the ketone in Pb(OAc) does not decompose into Pb(OAc) and AcO un-

4

2

precursors 25 or 26.

der mild reaction conditions. For this same reason, when

To confirm some aspects of the proposed mechanism, 27 was treated with LTA/I₂under mild conditions (see

the ketone group at C-4 in 25 was reduced in order to avoid Table 3), only the iodinated products 33a,b were isolated.

4392

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Eur. J. Org. Chem. 2007, 4383–4401

Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

Moreover, when compound 36 was submitted to the afore- decreasing within the series R = OEt Ͻ R = OMe Ͻ R =

mentioned reaction conditions, the iodinated product 37 H (see Entries 10–12, Table 5). However, in the last case (R

was formed as a unique product and no diacetoxy deriva- = H) the formation of intermediate D is more unfavourable

tives were detected in the crude reaction mixture. Com- than in the other two cases. This could be one of the

pound 37 was physically and spectroscopically charac- reasons that justifies in some way the preference of path (a)

terized and its structure was confirmed by X-ray diffraction for substrates with R = OEt, OMe.

analysis on single crystals (Figure 4).

(3) The transformation A Ǟ B is thermodynamically fav-

In order to evaluate a possible thermodynamic driving oured in all cases but without differences in ΔH among

r

force for the different mechanism paths to take place, calcu- substrates (see Entries 4–6, Table 5). However, the transfor-

lations were performed to estimate the inner energy and mation B Ǟ C requires the absorption of energy to generate

formation enthalpy of key intermediates.^[³⁸^d^,⁴²^]The inner the tertiary free radical C and the process takes place with-

energy was calculated by using an MM2 program (the mo- out appreciable differences amid the three types of sub-

lecular mechanics algorithm was modified by the inclusion strates due to the fact that the C-8 position in C is not

of adequate parameters for carbon-centred free radicals) involved in the β-scission reaction.

and the formation enthalpy by the semi-empirical quantum (4) In the transformation D Ǟ E (second β-scission), the

chemistry package MOPAC, using an AM1 algorithm and variation of enthalpy (ΔH ) is more favourable in the case

r

UHF functions for the intermediate free radicals. The ob- of R = OEt or R = OMe than it is for R = H. This could

tained data are expressed in kcal/mol and quoted in Table 5. be due to the virtual formation of a highly unstable primary

These data, with the limitations established by the accuracy free radical E in the case of R = H. This may be the other

of the calculation methods, support the proposed mecha- reason to justify the preference of substrate 27 (R = H) for

nism in the following aspects:

the reaction path (b) (Scheme 5).

(1) According to the calculated formation enthalpy data, (5) The preference of path (c) over path (d) is consistent

the stability of intermediates A–F increases within the series with the higher formation enthalpy of products 29a,b/31a,b

R = H Ͻ R = OMe Ͻ R = OEt. So, the size and type compared with that of F or 32. Moreover, there is a great

of substituent R certainly influences the stability of these difference between the reaction enthalpies (ΔH ) of trans-

r

intermediates.

formations E Ǟ F (Entries 16–18, Table 5) vs. the enthalpy

(2) The inner energy of cyclopropyloxy radical D, as ex- of process E Ǟ 29 or E Ǟ 31 (Entries 19–22, Table 5). The

pected, is much higher than that of the other intermediates difference in stability between F and 29a,b or 31a,b is cor-

due to the annular strain of the cyclopropane subunit (see roborated also by the experimental or empirical observa-

Entries 7–9 in Table 5). On the other hand, the transforma- tion. Thus, F could be detected but could not be isolated

tion C Ǟ D affords a positive reaction enthalpy (ΔH_r), because it was readily transformed into 32 under the reac-

Table 5. Inner energy and formation enthalpies calculated for the intermediates of the proposed reaction mechanism.

2

1

Entry

Intermediate

Inner energy Formation enthalpy

Reaction enthalpies ΔH

Transformations

A Ǟ B B Ǟ C C Ǟ D D Ǟ E E Ǟ F F Ǟ 32 E Ǟ 29 E Ǟ 31 C Ǟ 33 C Ǟ 34

r f f

= ΔH – ΔH [kcal/mol]

{MOPAC (AM1)}^[

a]

(MM2)

[kcal/mol]

1

2

3

4

5

6

7

8

9

A (R = OEt)

A (R = OMe)

A (R = H)

B (R = OEt)

B (R = OMe)

B (R = H)

C (R = OEt)

C (R = OMe)

C (R = H)

D (R = OEt)

D (R = OMe)

D (R = H)

E (R = OEt)

E (R = OMe)

E (R = H)

F (R = OEt)

F (R = OMe)

F (R = H)

52.53

52.03

44.16

46.31

45.81

38.01

33.13

32.65

28.16

178.42

177.98

174.04

43.88

44.65

31.94

53.25

47.69

35.64

68.61

70.33

68.31

69.57

43.75

31.44

36.47

31.40

35.54

–131.56

–126.15

–91.05

–

0.77

–

–179.60

–174.02

–138.76

–148.93

–143.36

–108.29

–132.50

–126.84

–89.96

–48.04

–47.87

–47.71

–

30.67

30.66

30.47

–

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

16.43

16.52

18.33

–144.81

–138.68

–95.41

–

–12.31

–11.84

–5.45

–144.04

–134.96

–112.46

–230.53

–230.26

–224.74

–224.69

–150.25

–112.19

–211.57

–107.63

–210.23

–

3.72

–17.05

–

(1ЈR)-29a (R = OEt)

(1ЈS)-29b (R = OEt)

(1ЈR)-31a (R = OMe)

(1ЈS)-31b (R = OMe)

32

(7S)-33a (R = H)

(7S)-34a (R = H)

(7R)-33b (R = H)

(7R)-34b (R = H)

–

–85.72

–85.45

–

–86.06

–86.01

–

–6.21

–

–3.90

–

0.66

–

–103.28

–

–101.94

[a] In the case of free radicals a UHF function was used.

Eur. J. Org. Chem. 2007, 4383–4401

www.eurjoc.org

4393

Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

tion conditions, meanwhile 29 and 31 were quite stable squares method using the SHELXS-97 computer program,^[⁴³^]on

the basis of the non-equivalent reflections by symmetry (very nega-

compounds, which could be isolated, purified and charac-

tive intensities were not assumed). The function minimized was:

terized without any decomposition problems.

2

2 2

2

–1

Σw[(F

P = [(F

o

) – (F

c

) ] , where w = [σ (I) + (0.0745P) + 0.4463P) , and

2

o

) + 2(F

c

) ]/3; f, fЈ and fЈЈ were taken from the International

[44]

Tables of X-ray Crystallography. All the H atom positions were

computed and refined, using a riding model, with isotropic tem-

perature factor equal to 1.2 times the equivalent temperature factor

of the atoms to which they are linked. The final R (on F) factors

and goodness of fit are shown in Table 5. The number of refined

parameters was 127; max. shift/esd = 0.00; mean shift/esd = 0.00.

Conclusions

A versatile methodology based on the hypoiodite reac-

tion has been developed to synthesize either 1,7-epoxycy-

clononanes or 1,8-epoxycyclodecanes with a high level of

functionalisation, starting from the same tricyclic precursor,

2

The refinement of F was performed against all reflections. The

2

which is available, in good yield and in enantiomerically weighted R factor, wR, and goodness of fit, S, are based on F ;

pure form, by a procedure also developed by the authors conventional R factors R are based on F, with F set to zero for

2

negative F . The threshold expression of F Ͼ 2σ(F ) is used only

for calculating R factors for observed reflections and is not relevant

to the choice of reflections for refinement. R factors based on F

are statistically about twice as large as those based on F, and R

factors based on all data are even larger. All esds (except the esd

in the dihedral angle between two least-squares planes) are esti-

mated using the full covariance matrix. The cell esds are taken into

account individually in the estimation of esds in distances, angles

and torsion angles; correlations between esds in cell parameters are

based on three key steps: a [4+3] cycloaddition followed by

a Nicholas reaction and a stereoconvergent aldol cycliza-

tion. A systematic study of the reaction conditions has been

performed and the main factors controlling the reaction

outcomes have been unveiled. Also, a possible mechanism

to explain the ring contraction has been proposed and cor-

roborated by the implication of a free-radical addition to

the ketone on C-5 of intermediate C, by reducing the corre-

2

sponding carbonyl group in the substrate 25 and protecting only used when they are defined by crystal symmetry. An approxi-

the resultant alcohol. Thus, no rearrangements and ring mate (isotropic) treatment of cell esds is used for estimating esds

involving least-squares planes. The main X-ray data are quoted in

contractions were observed for substrate 36, but only the β-

Table 6. Selected bond lengths and bond angles for compounds 25,

fragmentation product 37 was obtained in 75% yield.

28a, 32 and 37 are quoted in Tables S1 and S2, respectively, in the

Supporting Information (the numbering is in agreement with the

IUPAC nomenclature). CCDC-622959, -622960, -622961 and

Experimental Section

-

622962 for compounds 25, 28a, 32 and 37, respectively, contain

the supplementary crystallographic data for this paper. These data

can be obtained free of charge from The Cambridge Crystallo-

graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

General Experimental Procedures: Unless otherwise noted, all reac-

tions were conducted under dry nitrogen or argon in oven-dried

glassware. All solvents were purified using standard techniques be-

fore use; diethyl ether, tetrahydrofuran, hexane and pentane were

distilled under nitrogen from sodium/benzophenone. Acetonitrile

Synthetic Methodology to Prepare the Oxatricyclic Compounds: The

methodology to synthesize compounds 25, 26 and 27 is exemplified

for the preparation of 27. The intermediates and final products

described herein are all new compounds, characterized by the first

time. The understanding of proton and carbon assignments in the

NMR spectra can be facilitated by looking at the numbering of

atoms in Figure 4, Table 4 and Scheme 4.

was distilled under nitrogen from CaH

corded with an FT-IR Nicolet 510 spectrophotometer as thin films

between NaCl plates. NMR spectra were recorded in CDCl with

2

. Infrared spectra were re-

3

Varian spectrometers at 200 MHz (Gemini-200), 400 MHz (Mer-

1

cury-400) or 500 MHz (Uunity-500) for H NMR, and at 50 MHz

or 100 MHz for ¹³C NMR spectroscopy. For H NMR tetramethyl-

1

4

Synthesis

of Hexacarbonyl{μ-[η -(1-hydroxyprop-3-yne)]}dico-

13

silane was used as an internal standard. C NMR spectra were

referenced to the δ = 77.0 ppm resonance of chloroform. Mass

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

trometer using chemical ionization. GC analyses were performed

with an HP-8790 gas chromatograph equipped with a Hewlett–

Packard crosslinked 5% MePhe-Silicone capillary column (L =

balt(Co–Co) (15): In a 100 mL round-bottomed flask, fitted with

magnetic stirring bar, nitrogen inlet and equalizing-pressure

addition funnel, hexacarbonyldicobalt (0.73 g, 2.142 mmol) was

dissolved in anhydrous hexane (15 mL). Propargyl alcohol (14,

0.1 g, 1.725 mmol), dissolved in anhydrous hexane (5 mL), was

then added dropwise. The reaction mixture was stirred at room

temperature for 3 h (monitored by TLC). Afterwards, the reaction

mixture was percolated through a short pad of activated neutral

alumina and eluted with anhydrous diethyl ether, in order to re-

move the possible excess of hexacarbonyldicobalt. The organic

solutions were combined and concentrated to dryness in a rotary

evaporator (without heating!). Thus, a dark red oil of product 15

was obtained (630 mg, conversion 100%, yield 100%). IR (film): ν˜

25 m, D = 0.2 mm, thickness = 2.5 μm) using helium as a carrier

gas and an FID detector (T = 250 °C, P_H₂= 4.2 psi, Pair = 2.1 psi).

Elemental analyses were obtained with a Fisons elemental analyzer,

model Na-1500. The samples were previously pyrolised at 1000 °C

under oxygen, and the content of carbon and hydrogen was deter-

mined by the evaluation of the combustion gases by gas chromatog-

raphy using an FID detector.

3

X-ray Diffraction Analysis: Suitable crystals (0.1ϫ0.1ϫ0.2 mm)

from compounds 25, 28a, 32 and 37 were selected and mounted

on a MAR345 apparatus with an image plate detector. Unit-cell

parameters were determined from automatic centring of reflections

and refined by the least-squares method. Intensities were collected

= 3395 (O–H, st), 2909, 2855 (Csp –H, st), 2099, 2016 (CϵC, st),

–

1 1

1341, 1034 (C–O, st) cm . H NMR (200 MHz, CDCl

= 4.81 (dd, J = 0.6, J = 6.2 Hz, 2 H, 1-H), 6.07 (s, 1 H, 3-H)

ppm. C NMR (50 MHz, CDCl , 25 °C): δ = 63.2 (C-1), 71.3 (C-

3), 199.4, 201.5 (C-2) ppm. MS (DIP-CI-NH , 70 eV, 150 °C): m/z

(%) = 314 (1) [M – CO], 230 (13) [M – 4 CO]. TLC (SiO

diethyl ether, 3:7; developed with anisaldehyde): R

Co

3

, 25 °C): δ

1

2

1

3

with graphite-monochromatised Mo-K

α

radiation. Lorentz-polar-

2

; hexane/

f

= 0.48.

ization and absorption corrections were made. The structures were

solved by direct methods and refined by the full-matrix least-

C

9

H

4

2 7

O (341.99): calcd. C 31.6, H 1.18; found C 31.58, H 1.21.

4394

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Eur. J. Org. Chem. 2007, 4383–4401

Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

Table 6. Crystal data refinement for 25, 28a, 32 and 37.

25

28a

32

37

Temperature

Wavelength

Crystal system

Space group

150(2) K

0.71073 Å

orthorhombic

150(2) K

0.71073 Å

orthorhombic

150(2) K

0.71073 Å

triclinic

293(2) K

0.71073 Å

orthorhombic

¯

P2 2 2

1 1 1

P2 2 2

1 1 1

P1

1 1 1

P2 2 2

Unit cell dimensions

a = 6.30400(10) Å, α = 90°

b = 13.5660(2) Å, β = 90°

c = 15.8370(3) Å, γ = 90°

1354.38(4) Å³

a = 11.9860(2) Å, α = 90°

b = 12.3380(2) Å, β = 90°

c = 12.3940(2) Å, γ = 90°

a = 6.47900(10) Å, α = 13.3290(10)° a = 9.070(4) Å, α = 90°

b = 9.0520(2) Å, β = 104.4530(10)°

c = 10.4950(2) Å, γ = 91.3010(10)°

b = 15.521(6) Å, β = 90°

c = 26.457(6) Å, γ = 90°

3

Volume

1832.87(5) Å

542.165(18) Å

3724(2) Å

Z

4

2

8

1.247 Mg/m³

1.588 Mg/m

1.773 mm

880

3

1.374 Mg/m

0.103 mm

240

3

1.513 Mg/m

1.738 mm

1712

3

Calculated density

Absorption coefficient

F(000)

0.090 mm^–¹

552

–1

Crystal size

θ range for data collection

Limiting indices

0.30ϫ0.15ϫ0.10 mm

3.48–27.49°

–8 Յ h Յ 8

0.25ϫ0.15ϫ0.10 mm

3.78–30.99°

–16 Յ h Յ 17

–17 Յ k Յ 17

–17 Յ l Յ 17

19536

5759 [R (int) = 0.0444]

30.99° (99.3%)

0.8426/0.6656

0.50ϫ0.25ϫ0.10 mm

5.56–29.17°

–8 Յ h Յ 8

–12 Յ k Յ 12

–14 Յ l Յ 14

15755

2882 [R (int) = 0.0319]

29.17° (98.6%)

0.9898/0.9505

0.2ϫ0.1ϫ0.1 mm

2.71 to 30.00°

0 Յ h Յ 11

0 Յ k Յ 20

0 Յ l Յ 36

27047

27047 [R (int) = 0.0584]

30.00° (82.7%)

–

17 Յ k Յ 17

20 Յ l Յ 20

Reflections collected

Independent reflections

Completeness to θ

Max./min. transmission

Refinement method

22345

3094 [R (int) = 0.0808]

27.49° (99.7%)

0.9911/0.9735

full-matrix least squares on F²full-matrix least squares on F

2

full-matrix least squares on F

2

full-matrix least squares on F

2

Data/restraints/parameters

Goodness-of-fit on F

3094/0/167

1.061

5759/0/208

1.025

2882/0/147

1.051

4491/0/208

1.066

2

Final R indices [IϾ2σ(I)]

R indices (all data)

Absolute structure parameter –0.4(12)

R

1

= 0.0497, wR

= 0.0634, wR

2

= 0.1125

= 0.1175

R

1

= 0.0296, wR

2

= 0.0608

= 0.0626

R

–

1

= 0.0357, wR

= 0.0404, wR

2

= 0.0940

= 0.0975

R

–

1

= 0.0632, wR = 0.1774

2

= 0.0780, wR = 0.1898

2

1

2

1

= 0.0338, wR

2

1

2

1

–0.009(14)

0.570/–1.026 eÅ

0.545/–0.535 eÅ^–³

–3

0.0305/–0.174 eÅ

–3

0.618/–0.691 eÅ

–3

Largest diff. peak/hole

4

Synthesis of Hexacarbonyl(μ-{η -[2,4-dimethyl-2-(prop-2-yn-1-yl)-8-

oxabicyclo[3.2.1]octan-3-one]})dicobalt(Co–Co) (18): In a 50 mL

flask fitted with magnetic stirring bar, argon inlet and septum,

compound 15 (150 mg, 0.440 mmol) was dissolved in anhydrous

dichloromethane (2 mL). Then, 2,4-dimethyl-3-[(trimethylsilyl)-

oxy]-8-oxabicyclo[3.2.1]oct-2-ene (6, 90 mg, 0.4 mmol), dissolved in

anhydrous dichloromethane (2 mL), was added by cannula. The

(monitored by TLC) was observed by a change of colour from a

dark red oil to an orange one. The reaction mixture was percolated

through a three-layer short pad of Celite , alumina and silica gel

®

in this order, eluting with acetone. The solvent was evaporated in

vacuo. The residue was dissolved in water/diethyl ether, decanted,

and the aqueous solution was extracted with diethyl ether

(4ϫ20 mL). The organic phases were combined, dried with anhy-

drous sodium sulfate, filtered and concentrated to dryness to obtain

21 (57 mg, conversion 100%, yield 95%). IR (film): ν˜ = 3287, 2979,

mixture was cooled to 0 °C, and BF

added all at once. The reaction mixture was maintained at 0 °C for

min and then allowed to warm to room temperature. After 2 h

monitored by TLC), the reaction mixture was quenched at 0 °C

3 2

·OEt (300 μL, 2.0 mmol) was

3

5

(

2938 (Csp –H, st), 2118 (CϵC st), 1713 (C=O, st), 1472 (C–C,

–

1 1

deform.), 1026, 1045, 931, 901 (C–O, st) cm . H NMR (200 MHz,

by the addition of triethylamine (400 μL, 2.5 mmol) and washed

CDCl , 25 °C): δ = 0.94 (d, J = 6.8 Hz, 3 H, 10-H), 1.08 (s, 3 H,

3

with iced water. The organic solution was dried with anhydrous

MgSO , filtered and then percolated through a short pad of acti-

4

9-H), 1.30–1.80 (m, 6-H and 7-H, 4-H), 2.03 (d, J = 2.8 Hz, 1 H,

3Ј-H), 2.69 (dd, J = 14, J = 2.8 Hz, 1 H, 1Ј-H), 2.94 (dq, 1 H, 4-

H), 3.02 (dd, J = 14, J = 2.8 Hz, 1 H, 1Ј-H), 4.27 (d, J = 6.6 Hz,

vated neutral alumina, eluting with dichloromethane. The organic

solution was concentrated to dryness in a rotary evaporator (with-

out heating!), giving 18 as a dark red oil (190 mg, conversion 100%,

1

3

1 H, 1-H), 4.46 (dd, 1 H, 5-H) ppm. C NMR (50 MHz, CDCl

25 °C): δ = 9.9 (C-10), 16.7 (C-9), 24.3 (C Ј), 25.0 (C-7), 27.6 (C-

6), 47.9 (C-4), 71.4 (C-3Ј), 81.0 (C-5), 82.4 (C-1) ppm. MS (DIP-

CI-NH , 70 eV, 150 °C): m/z (%) = 190 (2) [M], 207 (22) [M +

NH ], 258 (100) [M + N 12]. GC (T = 50 °C, t = 1 min, rate =

0-H), 1.09 (s, 3 H, 9-H), 1.30–1.80 (m, 4 H, 6-H and 7-H), 2.93 5 °C/min, T = 290 °C, t = 10 min): t = 15.35 min. TLC (SiO

= 0.46.

(192.25): calcd. C 74.97, H 8.39; found C 75.01,

3

,

1

3

yield 98%). IR (film): ν˜ = 2983 (Csp –H, st), 2093, 2053, 2024

–

1

(

CϵC st),1711 (C=O, st), 1381, 1157, 1028, 1047 (C–O, st) cm .

3

1

H NMR (200 MHz, CDCl

3

, 25 °C): δ = 0.94 (d, J = 7 Hz, 3 H,

3

4

H

i

1

(

1

(

f

R

2

;

m, 1 H, 4-H), 3.33 (d, J = 14 Hz, 1 H, 1Ј-H), 4.00 (d, J = 14 Hz, hexane/diethyl ether, 8:2; developed with anisaldehyde): R

H, 1Ј-H), 4.25 (d, J = 7 Hz, 1 H, 1-H), 4.55 (dd, 1 H, 5-H), 5.59

s, 1 H, 3Ј-H) ppm. TLC (SiO ; hexane/diethyl ether, 8:2; developed

= 0.44. C18 (478.95): calcd. C

f

12 16 2

C H O

2

H 8.35.

Synthesis of 2,4-Dimethyl-2-(2-oxopropyl)-8-oxabicyclo[3.2.1]octan-

-one (24): In a 100 mL three-necked round-bottomed flask, fitted

with anisaldehyde): R

f

2 8

H16Co O

45.21, H 3.37; found C 45.25, H 3.41.

3

Preparation of 2,4-Dimethyl-2-(prop-2-yn-1-yl)-8-oxabicyclo[3.2.1]-

octan-3-one (21): In a 25 mL round-bottomed flask, fitted with

magnetic stirring bar, nitrogen inlet and septum, compound

with magnetic stirring bar and Dimroth condenser, compound 21

(250 mg, 1.30 mmol) was dissolved in ethanol/water (85:15, 30 mL).

II

To this solution, Hg

bis(p-toluenesulfonamidate) (0.914 g,

1

8 (100 mg, 0.21 mmol) was dissolved in anhydrous acetone

1.7 mmol) was added all at once, and the mixture was maintained

at reflux for 24 h. Afterwards, the reaction mixture was cooled to

(5 mL). The solution was cooled to 0 °C, and triethylamine (55 μL,

0.42 mmol) was added all at once. At this temperature, CAN room temperature, and ammonium sulfide (1.5 mL, 2.1 mmol) was

(

575 mg, 1.05 mmol) was added (portionwise!) under vigorous stir-

added, and the precipitation of a black solid of mercury(II) sulfide

was observed. The reaction mixture was percolated through a

three-layer short pad of Celite /alumina/silica gel (1:1:1), and the

ring. The addition lasted 2 h, and the reaction mixture was main-

tained at 0 °C for an additional 1 h until complete demetallation

®

Eur. J. Org. Chem. 2007, 4383–4401

www.eurjoc.org

4395

Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

resultant clear solution was concentrated to dryness. The residue

was dissolved in diethyl ether and washed with aqueous NaOH

with anisaldehyde): R

H 8.63; found C 68.49, H 8.67.

f 18 3

= 0.24. C12H O (210.27): calcd. C 68.54,

(

2 m, 2ϫ25 mL). The alkaline aqueous phase was extracted with

diethyl ether (2ϫ10 mL), and all organic phases were combined,

dried with anhydrous MgSO , filtered and concentrated to dryness.

General Procedure for the Synthesis of 28a, 28b, 29a and 29b by β-

Fragmentation Reactions: Into a 100 mL flask, previously heated

under vacuum and purged with argon, compound 25 (159 mg,

4

The resultant crude oil was purified by flash column chromatog-

raphy on silica gel, eluting with mixtures of hexane and diethyl

ether of increasing polarity, to isolate product 24 (244 mg, conver-

sion 100%, yield 86%). IR (film): ν˜ = 2975 (Csp –H, st) 1711

(

J = 6.6 Hz, 3 H, 10-H), 1.02 (s, 3 H, 9-H), 1.60–1.85 (m, 4 H, 6-H

and 7-H), 2.13 (s, 1 H, 3Ј-H), 2.87 (d, J = 16.4 Hz, 2 H, 1Ј-H), 3.0

(

0.62 mmol) was added. Subsequently, LTA (824 mg, 1.86 mmol)

and I (157 mg, 0.62 mmol) were added all at once under an argon

2

flow. The resulting solid mixture was dissolved in anhydrous ben-

zene (2 mL) and irradiated with two 100 W lamps for 2 h. The reac-

tion temperature was stabilized at 45–50 °C, and the reaction was

monitored by TLC. When the reaction was complete (100% con-

version of 1), the mixture was allowed to cool to room temperature,

and then the reaction mixture was percolated through a short col-

3

C=O, st), 1472 (C–C, deform.), 1360, 1374, 1315, 1180, 1034, 1045

–1 1

3

C–O, st) cm . H NMR (200 MHz, CDCl , 25 °C): δ = 0.94 (d,

dq, 1 H, 4-H), 3.23 (d, J = 16.4 Hz, 1 H, 1Ј-H), 4.32 (d, J = 6 Hz,

®

umn of Celite , eluting with diethyl ether. The organic solution

13

1

3

H, 1-H), 4.46 (dd, 1 H, 5-H) ppm. C NMR (50 MHz, CDCl ):

was then concentrated in a rotary evaporator to a volume of 20 mL

δ = 9.7 (C-10), 16.8 (C-9), 24.4 (C-6Ј), 24.5 (C-7), 31.5 (C-3Ј), 47.0

C-1Ј), 50.4 (C-4), 50.3 (C-2), 81.7 (C-5), 83.0 (C-1), 210.5 (C-2Ј)

and subsequently extracted with aq. NaHCO

aq. Na (5% w/w, 4ϫ25 mL) and finally with distilled water

25 mL). The organic phase was dried with anhydrous MgSO , fil-

tered and concentrated to dryness to afford 245 mg of product. The

product was submitted to flash column chromatography (SiO ),

3

(1.2 m, 3ϫ20 mL),

(

2 2 3

S O

+

ppm. MS (DIP-EI, 70 eV, 150 °C): m/z (%) = 210 (11) [M] , 195

5) [M – CH ], 180 (6) [M – 2 CH ], 154 (14) [M – CH COCH ],

24 (2) [M – C 10O], 107 (100) [M – C ]. GC (T = 100 °C,

= 1 min, rate = 10 °C/min, T = 250 °C, t = 10 min): t

2.77 min. TLC (SiO ; hexane/diethyl ether, 8:2; developed with an-

isaldehyde): R = 0.57. C12 (210.27): calcd. C 68.54, H 8.63;

found C 68.60, H 8.61.

(

4

(

1

3

2

3

5

H

5

H

11

O

2

i

2

t

i

f

R

=

eluting with mixtures of hexane (H) and diethyl ether (E) of in-

creasing polarity to isolate 114 mg of 28a (with H/E, 60:40), 43 mg

of 28b (with H/E 30: 70), 53.6 mg of 29a (with H/E, 50:50) and

1

2

f

18 3

H O

25.8 mg of 29b (with H/E, 20:80).

Synthesis of 2,7-Dimethyl-6-hydroxy-11-oxatricyclo[6.2.1.0²^,⁶]unde- (R)-(Ethoxy){(1R,2S,4R,6R,7S)-4-iodo-2,6-dimethyl-3,5-dioxo-10-

can-4-one (27). (a) Preparation of Anhydrous KOH: In a 100 mL

flask, commercial KOH (3 g), in lentils, was dissolved in absolute

ethanol (10 mL). Afterwards, benzene (15 mL) was added, and the

flask was connected to a Dean–Stark system. The azeotropic distil-

lation was maintained in such a way that first the azeotrope ben-

zene/ethanol/water (74.1:18.5:7.4) with a b.p. of 64.6 °C distilled

and then the benzene/ethanol azeotrope (67.6:32.4) with a b.p. of

oxabicyclo[5.2.1]dec-2-yl}methyl Acetate (28a): IR (film): ν˜ = 3459

3

(O–H, st), 2981, 2938 (Csp –H, st), 1733 (C=O, st), 1701 (C=O),

–

1 1

1231 (C–O, st), 1105, 1061, 1028 (C–O, st) cm

. H NMR

(400 MHz, CDCl , 25 °C): δ = 1.01 (d, J = 6.6 Hz, 3 H, 11ЈЈ-H),

3

1.08 (s, 3 H, 12ЈЈ-H), 1.26 (t, J = 7.2 Hz, 3 H, 2ЈЈЈ-H), 1.75–2.14

(m, 4 H, 8ЈЈ-H and 9ЈЈ-H), 2.11 (s, 3 H, 2-H), 3.34 (dq, J = 6.6, J

= 6.5 Hz, 1 H, 6ЈЈ-H), 3.84 (dq, J = 10.25, J = 7 Hz, 1 H, 1ЈЈЈ-H),

3.89 (dq, J = 9.8, J = 7 Hz, 1 H, 1ЈЈЈ-H), 4.31 (dd, J = 8, J =

7.6 Hz, 1 H, 1ЈЈ-H), 4.45–4.54 (m, 1 H, 7ЈЈ-H), 5.69 (s, 1 H, 1Ј-H),

68.3 °C distilled. Finally, the solution was concentrated to dryness,

and the resulting white solid was dried in vacuo for 6 h, ground

and readily used. (b) Aldol Cyclization: In a 25 mL round-bottomed

flask, fitted with magnetic stirring bar, argon inlet and septum, 24

1

3

6.73 (s, 1 H, 4ЈЈ-H) ppm. C NMR (100 MHz, CDCl , 25 °C): δ

3

= 11.9 (C-12ЈЈ), 12.1 (C-11ЈЈ), 15.09 (C-2ЈЈЈ), 21.7 (C-2), 25.6 and

(

175 mg, 0.82 mmol) was placed. Freshly prepared anhydrous KOH

642 mg, 11.48 mmol), dissolved in absolute ethanol (10 mL), was

26.6 (C-8ЈЈ and C-9ЈЈ), 33.7 (C-1Ј), 53.3 (C-6ЈЈ), 66.9 (C-1ЈЈЈ), 82.3

and 83.6 (C-1ЈЈ and C-7ЈЈ), 96.1 (C-4ЈЈ), 171.0 (C-1), 197.0 (C-3ЈЈ),

then added all at once by cannula. The reaction mixture was main-

tained at room temperature for 18 h (monitored by TLC). The sol-

vent was removed in a rotary evaporator, and the residue was dis-

solved in water. The aqueous solution was neutralized with 2 m

HCl. The organic solution was extracted with diethyl ether

201.4 (C-5ЈЈ) ppm. MS (DIP-CI-NH , 70 eV, 150 °C): m/z (%) =

3

+

456 (10) [M + NH ] , 438 (1) [M], 379 (22) [M – C O H ], 311 (9)

4

2

3

[M – I], 207 (100) [M – I – C O H – C H ]. C H IO (438.25):

2

3

2

5

16 23

6

calcd. C 43.85, H, 5.29; found 43.91, H 5.32.

S)-(Ethoxy){(1R,2S,4R,6R,7S)-4-iodo-2,6-dimethyl-3,5-dioxo-10-

oxabicyclo[5.2.1]dec-2-yl}methyl Acetate (28b): IR (film): ν˜ = 2981,

(

(5ϫ20 mL), the organic phases were combined, dried with anhy-

drous MgSO , filtered and concentrated to dryness to obtain a

4

3

2

1

2

1

2

935 (Csp –H, st), 1733 (C=O, st), 1701 (C=O), 1234 (C–O, st),

white solid, which was purified by flash column chromatography

on silica gel, eluting with mixtures of hexane and diethyl ether of

increasing polarity. Pure product 27 was isolated (134 mg, conver-

–

1 1

3

106, 1062, 1009 (C–O, st) cm . H NMR (400 MHz, CDCl ,

5 °C): δ = 1.01 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H), 1.08 (s, 3 H, 12ЈЈ-H),

.23 (t, J = 7.0 Hz, 3 H, 2ЈЈЈ-H), 1.8–2 (m, 4 H, 8ЈЈ-H and 9ЈЈ-H),

.18 (s, 3 H, 2-H), 3.35 (dq, J = 6.2, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.63

3

sion 95%, yield 78%). IR (film): ν˜ = 3442 (O–H, st), 2952 (Csp –

–

1 1

H, st) 1742 (C=O, st) 1256, 1167, 1107, 1045 (C–O, st) cm . H

NMR (200 MHz, CDCl , 25 °C): δ = 0.92 (d, J = 6.8 Hz, 3 H, 13-

H), 1.01 (s, 3 H, 12-H), 1.60–2.00 (m, 4 H, 9-H and 10-H), 1.90

dq, J = 4 Hz, 1 H, 7-H), 2.02 (d, J = 19 Hz, 1 H, 5-H), 2.30 (d, J

(

dq, J = 9.4, J = 7 Hz, 1 H, 1ЈЈЈ-H), 3.7 (dq, J = 9.2, J = 7.0 Hz,

3

1

H, 1ЈЈЈ-H), 4.03 (dd, J = 8.0, J = 8.0 Hz, 1 H, 1ЈЈ-H), 4.4–4.5 (m,

1

3

H, 7ЈЈ-H), 5.79 (s, 1 H, 1Ј-H), 6.76 (s, 1 H, 4ЈЈ-H) ppm. C NMR

, 25 °C): δ = 12.0 (C-12ЈЈ), 12.4 (C-11ЈЈ), 15.1 (C-

ЈЈЈ), 21.3 (C-2), 25.8 and 26.8 (C-8ЈЈ and C-9ЈЈ), 32.6 (C-1ЈЈ), 53.2

(

(100 MHz, CDCl

3

=

17.8 Hz, 1 H, 3-H), 2.37 (dd, J = 17.8 Hz, 1 H, 3-H), 3.13 (d, J

19 Hz, 1 H, 5-H), 3.93 (d, J = 6 Hz, 1 H, 1-H), 4.13 (dd, J = 3,

2

(

9

C-6ЈЈ), 63.8 (C-2ЈЈ), 66.2 (C-1ЈЈЈ), 82.1 and 83.9 (C-1ЈЈ and C-7ЈЈ),

6.1 (C-4ЈЈ), 170.9 (C-1), 196.7 (C-3ЈЈ), 201.8 (C-5ЈЈ) ppm. MS

13

J = 6.8 Hz, 1 H, 8-H) ppm. C NMR (50 MHz, CDCl

9.9 (C-13), 18.9 (C-12), 23.8 (C-10), 24.6 (C-9), 39.8 (C-2), 45.8

C-7), 50.4 (C-3), 51.4 (C-5), 76.3 (C-8), 79.0 (C-1) 209.0 (C-4)

3

, 25 °C): δ

=

(

+

(

C

DIP-CI-NH

1) [M], 379 (22) [M – C

– C ]. C16

found C 43.95, H, 5.40.

3

, 70 eV, 150 °C): m/z (%) = 456 (10) [M + NH

4

] , 438

], 311 (9) [M – I], 207 (100) [M – I –

(438.25): calcd. C 43.85, H, 5.29;

2

O

2

H

3

+

ppm. MS (DIP-EI, 70 eV, 150 °C): m/z (%) = 210 (16) [M] , 155

12) [M – CH COCH ], 139 (26) [M – C ], 124 (37) [M –

], 109 (75) [M – C ], 93 (100) [M – C ]. GC

= 100 °C, t = 1 min, rate = 10 °C/min, T = 250 °C, t

= 19.49 min. TLC (SiO

2

O

2

H

3

2

H

5

H

23IO

6

(

C

2

3

3 5 2

H O

4

H

8

O

2

5

H

11

O

2

6 14 2

H O

(T

i

f

= 10 min): (R)-{(1R,2S,6R,7S)-2,6-Dimethyl-3,5-dioxo-10-oxabicyclo[5.2.1]-

2

; hexane/diethyl ether, 7:3; developed dec-2-yl}(ethoxy)methyl Acetate (29a): IR (film): ν˜ = 3449 (O–H,

t

R

4396

www.eurjoc.org

Eur. J. Org. Chem. 2007, 4383–4401

Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

, 25 °C): δ = 12.1 (C-12ЈЈ), 12.3 (C-11ЈЈ), 21.8 (C-

3

st), 2978, 2936 (Csp –H, st), 1725 (C=O, st), 1695 (C=O), 1233 (C–

(100 MHz, CDCl

3

O, st), 1107, 1062, 1010 (C–O, st) cm^–¹. H NMR (400 MHz,

1

2), 25.8 and 26.8 (C-8ЈЈ and C-9ЈЈ), 33.9 (C-1Ј), 53.4 (C-6ЈЈ), 58.9

CDCl

3

, 25 °C): δ = 0.94 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H), 1.02 (s, 3 H, (C-1ЈЈЈ), 63.9 (C-2ЈЈ), 82.6 and 83.9 (C-1ЈЈ and C-7ЈЈ), 97.7 (C-4ЈЈ),

1

2ЈЈ-H), 1.27 (t, J = 7.2 Hz, 3 H, 2ЈЈЈ-H), 1.75–2.0 (m, 4 H, 8ЈЈ-H 171.3 (C-1), 197.2 (C-3ЈЈ), 201.7 (C-5ЈЈ) ppm. MS (DIP-CI-NH ,

3

+

and 9ЈЈ-H), 2.01 (s, 3 H, 2-H), 2.98 (d, J = 8.4 Hz, 1 H, 4ЈЈ-H),

70 eV, 150 °C): m/z (%) = 442 (100) [M + NH

AcO], 297 (8) [M – I]. C15 (424.23): calcd. C 42.47, H 4.99;

Hz, 1 H, 1ЈЈЈ-H), 3.87 (dq, J = 9.4, J = 7.0 Hz, 1 H, 1ЈЈЈ-H), 4.29 found C 42.55, H 5.07.

4

] , 365 (72.5) [M –

3.30 (dq, J = 6.4, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.79 (dq, J = 9.6, J =

H21IO

6

7

(

2

(

9

7

C

dd, J = 8.0, J = 8.0 Hz, 1 H, 1ЈЈ-H), 4.4–4.5 (m, 1 H, 7ЈЈ-H), 4.57

(

S)-{(1R,2S,4R,6R,7S)-4-Iodo-2,6-dimethyl-3,5-dioxo-10-oxabi-

d, J = 8.4 Hz, 1 H, 4ЈЈ-H) 6.75 (s, 1 H, 1Ј-H) ppm. ¹C NMR

3

cyclo[5.2.1]dec-2-yl}(methoxy)methyl Acetate (30b): IR (film): ν˜ =

3

1

100 MHz, CDCl

ЈЈЈ), 21.2 (C-2), 25.9 and 26.9 (C-8ЈЈ and C-9ЈЈ), 54.2 (C-6ЈЈ), 57.9

C-4ЈЈ), 63.1 (C-2ЈЈ), 66.9 (C-1ЈЈЈ), 82.9 and 84.1 (C-1ЈЈ and C-7ЈЈ),

3

, 25 °C): δ = 11.6 (C-12ЈЈ), 11.6 (C-11ЈЈ), 15.3 (C-

3

419 (O–H, st), 2939 (Csp –H, st), 1731 (C=O, st), 1699 (C=O),

–

1 1

236 (C–O, st), 1107, 1061, 1007 (C–O, st) cm

. H NMR

(400 MHz, CDCl

3

, 25 °C): δ = 0.97 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H),

3

7.6 (C-1Ј), 199.8 (C-3ЈЈ), 203.0 (C-5ЈЈ) ppm. MS (DIP-CI-NH ,

1

2

.06 (s, 3 H, 12ЈЈ-H), 1.8–2 (m, 4 H, 8ЈЈ-H and 9ЈЈ-H), 2.2 (s, 3 H,

-H), 3.35 (dq, J = 6.4, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.44 (s, 3 H, 1ЈЈЈ-

+

0 eV, 150 °C): m/z (%) = 330 (11) [M + NH

4

] , 270 (47) [M –

], 222 (30) [M – C – C ].

24 6

O (312.36): calcd. C 61.52, H 7.74; found C 61.35, H 7.85.

2

H

2

O], 253 (100) [M – C

2

O

2

H

3

2

O

2

H

3

2 5

H

H), 4.04 (dd, J = 8.0, J = 8.0 Hz, 1 H, 1ЈЈ-H), 4.40–4.60 (m, 1 H,

16

H

1

3

7

(

2

ЈЈ-H), 5.79 (s, 1 H, 1Ј-H), 6.65 (s, 1 H, 4ЈЈ-H) ppm. C NMR

100 MHz, CDCl , 25 °C): δ = 12.0 (C-12ЈЈ), 12.4 (C-11ЈЈ), 21.2 (C-

), 25.9 and 26.8 (C-8ЈЈ and C-9ЈЈ), 32.2 (C-1Ј), 53.2 (C-6ЈЈ), 57.9

(S)-{(1R,2S,6R,7S)-2,6-Dimethyl-3,5-dioxo-10-oxabicyclo[5.2.1]dec-

3

2

-yl}(ethoxy)methyl Acetate (29b): IR (film): ν˜ = 3391 (O–H, st),

3

(C-1ЈЈЈ), 63.6 (C-2ЈЈ), 82.1 and 83.1 (C-1ЈЈ and C-7ЈЈ), 97.2 (C-4ЈЈ),

171.01 (C-1), 197.0 (C-3ЈЈ), 201.4 (C-5ЈЈ) ppm. MS (DIP-CI-NH ,

7

AcO], 297 (26) [M – I]. C15

found C 42.58, H 4.87.

979, 2937 (Csp –H, st), 1748, 1725 (C=O, st), 1694 (C=O), 1239

–1

1

(

C–O, st), 1106, 1062, 1001 (C–O, st) cm . H NMR (400 MHz,

CDCl , 25 °C): δ = 0.93 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H), 1.03 (s, 3 H,

2ЈЈ-H), 1.12 (t, J = 7.0 Hz, 3 H, 2ЈЈЈ-H), 1.5–2.0 (m, 4 H, 8ЈЈ-H

and 9ЈЈ-H), 2.18 (s, 3 H, 2-H), 3.18 (d, J = 8.0 Hz, 1 H, 4ЈЈ-H),

3

+

0 eV, 150 °C): m/z (%) = 442 (100) [M + NH

4

], 365 (80) [M –

3

1

6

H21IO (424.23): calcd. C 42.47, H 4.99;

3

7

.33 (dq, J = 6.4, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.56 (dq, J = 9.6, J =

Hz, 1 H, 1ЈЈЈ-H), 3.72 (dq, J = 9.6, J = 7.0 Hz, 1 H, 1ЈЈЈ-H), 3.99

(

R)-{(1R,2S,6R,7S)-2,6-Dimethyl-3,5-dioxo-10-oxabicyclo[5.2.1]-

dec-2-yl}(methoxy)methyl Acetate (31a): IR (film): ν˜ = 3359 (O–H,

st), 2940 (Csp –H, st), 1725 (C=O, st), 1696 (C=O), 1233 (C–O,

st), 1109, 1060, 1011 (C–O, st) cm . H NMR (400 MHz, CDCl ,

3

2

1

=

3

4

(

4

(

2

dd, J = 6.8, J = 6.8 Hz, 1 H, 1ЈЈ-H), 4.34–4.42 (m, 1 H, 7ЈЈ-H),

3

.54 (d, J = 8.0 Hz, 1 H, 4ЈЈ-H) 6.83 (s, 1 H, 1Ј-H) ppm. ¹C NMR

100 MHz, CDCl , 25 °C): δ = 11.4 (C-12ЈЈ), 11.5 (C-11ЈЈ), 14.9 (C-

ЈЈЈ), 21.2 (C-2), 25.8 and 26.6 (C-8ЈЈ and C-9ЈЈ), 53.9 (C-6ЈЈ), 57.4

3

–1 1

3

5 °C): δ = 0.94 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H), 1.00 (s, 3 H, 12ЈЈ-H),

.2–1.9 (m, 4 H, 8ЈЈ-H and 9ЈЈ-H), 2.00 (s, 3 H, 2-H), 3.31 (dq, J

6.2, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.00 (d, J = 8.0 Hz, 1 H, 4ЈЈ-H)

(

C-4ЈЈ), 65.8 (C-1ЈЈЈ), 82.4 and 83.7 (C-1ЈЈ and C-7ЈЈ), 96.3 (C-1Ј)

ppm. MS (DIP-CI-NH , 70 eV, 150 °C): m/z (%) = 330 (12) [M +

NH O], 253 (100) [M –

]⁺, 313 (3) [M + 1], 270 (40) [M – C

]. C16 (312.36): calcd. C 61.52, H 7.74; found C

1.64, H 7.69.

3

.59 (s, 3 H, 1ЈЈЈ-H), 4.29 (dd, J = 7.6, J = 7.6 Hz, 1 H, 1ЈЈ-H),

4

2 2

H

.40–4.48 (m, 1 H, 7ЈЈ-H), 4.57 (d, J = 8.8 Hz, 4ЈЈ-H, H), 6.6 (s, 1

C

6

2

O

2

H

3

H

24

O

6

13

3

H, 1Ј-H) ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 11.6 (C-

1

5

2ЈЈ), 11.6 (C-11ЈЈ), 21.1 (C-2), 25.9 and 26.9 (C-8ЈЈ and C-9ЈЈ),

4.2 (C-6ЈЈ), 57.9 (C-4ЈЈ), 58.6 (C-1ЈЈЈ), 63.1 (C-2ЈЈ), 82.8 and 84.0

Synthesis of β-Fragmentation Products 30a, 30b, 31a and 31b: Into

a 100 mL flask, previously heated under vacuum and purged with

argon, compound 26 (141 mg, 0.59 mmol) was placed. Sub-

sequently, LTA (781 mg, 1.76 mmol) and I (149 mg, 0.59 mmol)

2

were added all at once under argon. The resulting solid mixture

was dissolved in anhydrous benzene (2 mL) and irradiated with two

(

5

C-1ЈЈ and C-7ЈЈ), 98.9 (C-1Ј), 171.1 (C-1), 199.6 (C-3ЈЈ), 203.0 (C-

ЈЈ) ppm. MS (DIP-CI-NH , 70 eV, 150 °C): m/z (%) = 327 (3) [M

3

+

(

C

2

H

5

] , 339 (1) [M + C

2 7 22 6

H ] , 239 (100) [M – AcO]. C15H O

298.33): calcd. C 60.39, H 7.43; found C 60.25, H 7.57.

(

S)-{(1R,2S,6R,7S)-2,6-Dimethyl-3,5-dioxo-10-oxabicyclo[5.2.1]dec-

1

5

00 W lamps for 2 h. The reaction temperature was kept at 45–

0 °C, and the reaction was monitored by TLC. Once the reaction

2

1

=

(

-yl}(methoxy)methyl Acetate (31b): IR (film): ν˜ = 3360 (O–H, st),

3

945 (Csp –H, st), 1724 (C=O, st), 1700 (C=O), 1250 (C–O, st),

was complete, the mixture was allowed to cool to room tempera-

ture, and then it was percolated through a short pad of Celite ,

–1 1

105, 1070 (C–O, st) cm . H NMR (400 MHz, CDCl

0.95 (d, J = 7.2 Hz, 3 H, 11ЈЈ-H), 1.01 (s, 3 H, 12ЈЈ-H), 1.2–2.0

m, 4 H, 8ЈЈ-H and 9ЈЈ-H), 2.19 (s, 3 H, 2-H), 3.26–3.34 (m, 1 H,

ЈЈ-H), 3.28 (d, J = 8.8 Hz, 1 H, 4ЈЈ-H) 3.39 (s, 3 H, 1ЈЈЈ-H), 3.99

dd, J = 7.6, J = 7.6 Hz, 1 H, 1ЈЈ-H), 4.40–4.50 (m, 1 H, 7ЈЈ-H),

3

, 25 °C): δ

®

eluting with diethyl ether. The organic solution was then concen-

trated to a volume of 20 mL and subsequently washed with aq.

NaHCO

and distilled water (25 mL). The organic fraction was dried with

MgSO , filtered and concentrated to dryness to afford 227 mg of

an oily product. The product was submitted to flash column

chromatography on silica gel to obtain 82.5 mg of 30a (with H/E,

5

6

(

3 2 2 3

(1.2 m, 3ϫ20 mL), aq. Na S O (5 % w/w, 4 ϫ25 mL)

13

4

(

2

8

1

.53 (d, J = 8.8 Hz, 1 H, 4ЈЈ-H), 6.74 (s, 1 H, 1Ј-H) ppm. C NMR

100 MHz, CDCl , 25 °C): δ = 11.5 (C-12ЈЈ), 11.4 (C-11ЈЈ), 21.1 (C-

), 54.01 (C-6ЈЈ), 57.5 (C-4ЈЈ), 57.6 (C-1ЈЈЈ), 63.1 (C-2ЈЈ), 82.4 and

3.7 (C-1ЈЈ and C-7ЈЈ), 97.6 (C-1Ј) ppm. MS (DIP-CI-NH , 70 eV,

4

3

0:50), 57.5 mg of 30b (with H/E, 30:70), 40.4 mg of 31a (with H/

+

50 °C): m/z (%) = 327 (8) [M + C

2 5 2 7

H ], 339 (5) [M + C H ], 239

E, 40:60) and 36.9 mg of 31b (with H/E, 20:80).

(

100) [M – AcO]. C15

H

22

O

6

(298.33): calcd. C 60.39, H 7.43; found

C 60.25, H 7.57.

(

R)-{(1R,2S,4R,6R,7S)-4-Iodo-2,6-dimethyl-3,5-dioxo-10-oxabi-

cyclo[5.2.1]dec-2-yl}(methoxy)methyl Acetate (30a): IR (film): ν˜ =

Synthesis of (1R,2S,6R,7S)-2,6-Dimethyl-3,5-dioxo-10-oxabicyclo-

[5.2.1]decane-2-carbaldehyde (32): Into a 100 mL flask, previously

3

399 (O–H, st), 2978, 2942 (Csp –H, st), 1741 (C=O, st), 1703

–1 1

(

C=O), 1233 (C–O, st), 1109, 1060, 1019 (C–O, st) cm . H NMR heated under vacuum and purged with argon, compound 25

400 MHz, CDCl , 25 °C): δ = 1.00 (d, J = 6.8 Hz, 3 H, 11ЈЈ-H), (100 mg, 0.39 mmol) was placed. Subsequently, LTA (174 mg,

.06 (s, 3 H, 12ЈЈ-H), 1.7–2 (m, 4 H, 8ЈЈ-H and 9ЈЈ-H), 2.12 (s, 3 0.39 mmol) and I (99.06 mg, 0.39 mmol) were added all at once

H, 2-H), 3.33 (dq, J = 6.2, J = 6.4 Hz, 1 H, 6ЈЈ-H), 3.59 (s, 3 H, under argon. The resulting solid mixture was dissolved in anhy-

ЈЈЈ-H), 4.30 (dd, J = 8, J = 8 Hz, 1 H, 1ЈЈ-H), 4.46–4.52 (m, 1 H, drous benzene (2 mL) and stirred at room temperature for 3.5 h.

(

3

1

2

1

7

ЈЈ-H), 5.69 (s, 1 H, 1Ј-H), 6.64 (s, 1 H, 4ЈЈ-H) ppm. ¹C NMR Once the reaction was complete, the reaction mixture was perco-

3

Eur. J. Org. Chem. 2007, 4383–4401

www.eurjoc.org

4397

Á. M. Montaña, S. Ponzano, G. Kociok-Köhn, M. Font-Bardia, X. Solans

FULL PAPER

®

lated through a short column of Celite , eluting with diethyl ether.

The organic solution was then concentrated to a volume of 20 mL

(d, J = 14.0 Hz, 1 H, 4α-H), 3.59 (d, J = 12.0 Hz, 1 H, 4β-H), 3.59

(d, J = 12.0 Hz, 1 H, 6β-H), 3.35 (dq, J = 6.5, J = 5.0 Hz, 1 H, 2-

H), 4.23 (dd, J = 11.0, J = 5.6 Hz, 1 H, 8-H), 4.34–4.40 (m, 1 H,

and subsequently washed with aq. NaHCO

Na (5% w/w, 4ϫ25 mL) and distilled water (25 mL). The

organic fraction was dried with MgSO , filtered and concentrated

3

(1.2 m, 3ϫ20 mL), aq.

1

3

2

S

2

O

3

1-H) ppm. C NMR (100 MHz, CDCl , 25 °C): δ = 12.9 (C-12),

4

25.0 (C-10), 32.0 (C-9), 35.5 (C-13), 46.8 (C-7), 47.9 (C-2), 50.4 (C-

to dryness resulting in 130 mg of the crude product. This product

was purified by flash column chromatography on silica gel, eluting

with mixtures of hexane and diethyl ether of increasing polarity

6), 67.01 (C-4), 85.7 (C-8), 88.7 (C-1), 197.9 (C-5), 209.5 (C-3) ppm.

+

MS (DIP-CI-NH

3

, 70 eV, 150 °C): m/z (%) = 354 (100) [M + NH

4

] ,

337 (27) [M + 1], 209 (13) [M – I]. C12

42.87, H 5.10; found C 42.91, H 5.24.

3

H17IO (336.16): calcd. C

(

with H/E, 70:30) to obtain 32 (19.2 mg, 49% yield for a 100%

3

conversion of 25). IR (film): ν˜ = 3421, 2978 (Csp –H, st), 1718,

Reduction of the C-4 Ketone Group in 25. Synthesis of

–

1 1

1

695 (C=O), 1266 (C–O, st), 1133, 1060, 1006 (C–O, st) cm . H

NMR (400 MHz, CDCl , 25 °C): δ = 0.95 (d, J = 6.8 Hz, 3 H, 12Ј-

H), 1.10 (s, 3 H, 11Ј-H), 1.3 (m, 1 H, 9Ј-H), 1.8 (m, 1 H, 8Ј-H), 1.9

m, 1 H, 8Ј-H), 2.0 (m, 1 H, 9Ј-H), 3.29 (d, J = 8.8 Hz, 1 H, 4Ј-

(

[

1R,2S,3S,4R,6R,7R,8S)-3-Ethoxy-2,7-dimethyl-11-oxatricyclo-

3

2,6

6.2.1.0 ]undecane-4,6-diol (35): In a 25 mL flask, NaBH

4

(

107.9 mg, 2.86 mmol) was dissolved in anhydrous methanol

1 mL). The system was purged with nitrogen and cooled to 0 °C.

(

H), 4.54 (d, J = 8.8 Hz, 1 H, 4Ј-H), 3.27 (m, 1 H, 6Ј-H), 4.65 (dd,

J = 7.8, J = 7.8 Hz, 1 H, 1Ј-H), 4.4–4.5 (m, 1 H, 7Ј-H), 9.78 (s, 1

Subsequently, compound 25 (120.6 mg) was added by cannula, dis-

solved in MeOH (1.5 mL). The reaction was monitored by TLC

and when complete, 3–4 drops of water were added to quench the

excess of NaBH . After 15 min, the solution was concentrated to

4

dryness by rotary evaporation. The resulting solid was lixiviated

H, 1-H) ppm. ¹³C NMR (100 MHz, CDCl

1

(

, 25 °C): δ = 11.5 (C-

2Ј), 14.1 (C-11Ј), 25.7 and 26.6 (C-8Ј and C-9Ј), 54.0 (C-6Ј), 48.7

C-1), 60.0 (C-4Ј), 82.2 and 84.7 (C-1Ј and C-7Ј) ppm. MS (DIP-

CI-NH , 70 eV, 150 °C): m/z (%) = 225 (100) [M + 1], 253 (15) [M

3

with ethyl acetate (8ϫ10 mL). The organic extract was dried with

anhydrous MgSO , filtered and concentrated to dryness to obtain

4

+

C

2

H

5

] , 265 (7) [M + C

3 5 16 4

H ] , 195 (23) [M – CHO]. C12H O

(224.25): calcd. C 64.27, H 7.19; found C 64.15, H 7.03.

product 35 (116.9 mg, 96% yield, 100% conversion of starting ma-

terial). IR (film): ν˜ = 3421 (OH, st), 2936, 2888 (C-H, st), 1102,

Synthesis of 1,8-Epoxycyclodecanes 33a and 33b: In a 100 mL

round-bottomed flask, previously heated under vacuum and

purged with argon, compound 27 (134 mg, 0.64 mmol) was placed.

–

1 1

1

=

3

075, 1041 (C–O, st) cm . H NMR (400 MHz, CDCl

3

, 25 °C): δ

0.86 (d, J = 7.2 Hz, 3 H, 13-H), 0.97 (s, 3 H), 1.25 (t, J = 7.0 Hz,

H, 2Ј-H), 1.55 (dd, J = 14.4, J = 3.6 Hz, 1 H, 5-H), 1.60–1.85

2

Afterwards, LTA (284 mg, 0.64 mmol) and I (162 mg, 0.64 mmol)

(

m, 9-H and 10-H), 2.00–2.10 (m, 9-H and 10-H), 1.70 (m, 1 H, 7-

H), 2.40 (dd, J = 14.2, J = 7.8 Hz, 1 H, 5-H), 3.66 (dq, J = 7.0, J

6.9 Hz, 1 H, 1Ј-H), 3.68 (dq, J = 7.0, J = 6.9 Hz, 1 H, 1Ј-H),

3.95 (d, J = 7.6 Hz, 1 H, 1-H), 4.00–4.04 (m, 1 H, 8-H), 4.06–4.12

were added under argon. The solid mixture was dissolved in anhy-

drous benzene (2 mL) and stirred at room temperature for 30 min.

Once the reaction was complete, the reaction mixture was filtered

=

®

through Celite , eluting with diethyl ether. The organic solution

1

3

(

2

(

m, 1 H, 4-H), 4.30 (d, J = 6.8 Hz, 1 H, 4-H) ppm. C NMR

100 MHz, CDCl , 25 °C): δ = 10.2 (C-13), 12.5 (C-12), 15.9 (C-

Ј), 24.1 (C-10), 24.6 (C-9), 41.5 (C-7), 47.6 (C-5), 49.2 (C-2), 66.3

C-4), 67.2 (C-1Ј), 78.1 (C-1), 79.7 (C-8), 80.5 (C-3) ppm. MS (DIP-

was concentrated to a volume of 20 mL and successively washed

with aq. NaHCO

3

(1.2 m, 3 ϫ 20 mL), aq. Na

2 2 3

S O (5 % w/w,

3

4

ϫ25 mL) and distilled water (25 mL). The organic phase was

4

dried with MgSO , filtered and concentrated to dryness to afford

+

CI-NH

3

, 70 eV, 150 °C): m/z (%) = 274 (100) [M + NH

4

] , 257 (69)

260 mg of an oily crude product. The product was purified by flash

[

M + 1], 239 (60) [M – OH]. C14 (256.34): calcd. C 65.60, H

24 4

H O

column chromatography on silica gel, eluting with hexane/diethyl

ether mixtures of increasing polarity to obtain 94 mg of 33a (with

H/E, 40:60) and 40 mg of 33b (with H/E, 65:35) in a 76% overall

yield for both isomers. Also, 24 mg of starting material 27 was reco-

vered (82% conversion).

9.44; found C 65.72, H 9.55.

Synthesis of (1R,2S,3S,4R,6R,7R,8S)-3-Ethoxy-6-hydroxy-2,7-di-

2,6

methyl-11-oxatricyclo[6.2.1.0 ]undec-4-yl Acetate (36): In a 50 mL

flask, compound 35 (20 mg), pyridine (63 μL), acetic anhydride

(

73 μL) and a catalytic amount of DMAP were placed and dis-

(

3

1S,2R,7S,8R)-7-Iodo-2,7-dimethyl-11-oxabicyclo[6.2.1]undecane-

,5-dione (33a): IR (film): ν˜ = 3379 (O–H, st), 2978, 2919 (Csp –

3

solved in anhydrous dichloromethane (0.5 mL). The reaction mix-

ture was stirred under nitrogen at room temperature for 72 h (mon-

itored by TLC until complete conversion). The reaction mixture

was cooled to 0 °C and aq. HCl (1 m, 0.5 mL) was added. The

solution was stirred for 5 min and then extracted with ethyl acetate

H, st), 1691 (C=O), 1233 (C–O, st), 1109, 1060, 1019 (C–O, st)

cm . H NMR (400 MHz, CDCl

–1 1

3

, 25 °C): δ = 0.97 (d, J = 7.2 Hz,

3

9

1

5

8

H, 12-H), 1.99 (s, 3 H, 13-H), 1.45 (m, 1 H, 9α-H), 1.78 (m, 1 H,

β-H), 2.00 (m, 1 H, 10β-H), 2.30 (m, 1 H, 10α-H), 2.55 (d, J =

4 Hz, 1 H, 6α-H), 2.76 (d, J = 14 Hz, 1 H, 6β-H), 3.40 (d, J =

2 Hz, 1 H, 4α-H), 3.84 (d, J = 12 Hz, 1 H, 4β-H), 3.48 (dq, J =

.2, J = 6.9 Hz, 1 H, 2-H), 4.30 (dd, J = 11 Hz, J = 5.8 Hz, 1 H,

(

5ϫ3 mL). The organic extracts were combined, dried with anhy-

drous MgSO , filtered and concentrated to dryness to obtain prod-

uct 36 (27.2 mg, quantitative yield, 100% conversion of 35). IR

(film): ν˜ = 3453 (OH, st), 2936 (C–H, st), 1740 (C=O, st), 1244,

1

=

4

1

3

-H), 4.30 (ddd, J = 2, J = 5.2, J = 9.2 Hz, 1 H, 1-H) ppm.

, 25 °C): δ = 12.6 (C-13), 25.7 and 26.01

C-9 and C-10), 35.0 (C-12), 44.2 (C-7), 48.01 (C-2), 48.7 (C-6),

C

–

1 1

105, 1043 (C–O, st) cm . H NMR (400 MHz, CDCl

3

, 25 °C): δ

0.87 (d, J = 7.2 Hz, 3 H, 13Ј-H), 0.99 (s, 3 H, 12Ј-H), 1.13 (t, J

7.0 Hz, 3 H, 2ЈЈ-H), 1.55 (dd, J = 14.6, J = 3.8 Hz, 1 H, 5Ј-H),

NMR (100 MHz, CDCl

(

3

6

7.2 (C-4), 82.8 (C-1), 91.6 (C-8), 197.6 (C-5), 209.7 (C-3) ppm.

+

1.66–1.74 (m, 9Ј-H), 1.70 (m, 1 H, 7Ј-H), 2.02–2.16 (m, 9Ј-H and

0Ј-H), 2.07 (s, 3 H, 2-H), 2.45 (dd, J = 14.8, J = 8.4 Hz, 1 H, 5Ј-

H), 3.49 (dq, J = 9.6, J = 6.9 Hz, 1 H, 1ЈЈ-H), 3.58 (dq, J = 9.2, J

7.1 Hz, 1 H, 1ЈЈ-H), 3.95 (d, J = 7.6 Hz, 1 H, 1Ј-H), 4.04 (dd, J

= 7.6 Hz, 1 H, 8Ј-H), 4.27 (d, J = 7.2 Hz, 1 H, 3Ј-H), 5.18–5.25

MS (DIP-CI-NH

3

4

3

, 70 eV, 150 °C): m/z (%) = 365 (1) [M + C

37 (27) [M + 1], 209 (100) [M – I]. C12 (336.16): calcd. C

2.87, H 5.10; found C 42.95, H 4.97.

2 5

H ] ,

1

H17IO

3

=

(

3

1S,2R,7R,8R)-7-Iodo-2,7-dimethyl-11-oxabicyclo[6.2.1]undecane-

3

13

,5-dione (33b): IR (film): ν˜ = 3396 (O–H, st), 2977, 2929 (Csp –

(m, 1 H, 4Ј-H) ppm. C NMR (100 MHz, CDCl

H, st), 1692 (C=O), 1142, 1045, 1021 (C–O, st) cm . H NMR (C-13Ј), 12.01 (C-12Ј), 15.7 (C-2ЈЈ), 21.3 (C-2), 24.1 (C-9Ј), 24.6 (C-

400 MHz, CDCl , 25 °C): δ = 0.96 (d, J = 7.2 Hz, 3 H, 12-H), 10Ј), 41.4 (C-7Ј), 45.1 (C-5Ј), 49.3 (C-2Ј), 67.2 (C-1ЈЈ), 69.4 (C-4Ј),

.35 (s, 3 H, 13-H), 1.82 (m, 1 H, 9β-H), 2.25 (m, 2 H, 9α-H, H- 77.7 (C-1Ј), 79.5 (C-8Ј), 79.8 (C-3Ј), 170.7 (C-1) ppm. MS (DIP-

3

, 25 °C): δ = 10.1

–1 1

(

2

1

3

+

0α), 1.97 (m, 1 H, 10β-H), 2.72 (d, J = 14.0 Hz, 1 H, 6α-H), 3.42

3 4

CI-NH , 70 eV, 150 °C): m/z (%) = 316 (9) [M + NH ] , 299 (100)

4398

www.eurjoc.org

Eur. J. Org. Chem. 2007, 4383–4401

Oxygen-Bridged Nine- and Ten-Membered Cycloalkanes

FULL PAPER

[

M + 1], 239 (62) [M – OAc]. C16

H

26

O

5

(298.37): calcd. C 64.41,

L. E. Overman, L. D. Pennington, J. Am. Chem. Soc. 2001,

123, 9033–9044; c) F. Gallow, D. W. C. Macmillan, L. E. Over-

H 8.78; found C 64.54, H 8.91.

man, L. A. Paquette, L. D. Pennington, J. Yang, Org. Lett.

001, 3, 135–137; d) D. Friedich, R. W. Doskotch, L. A. Pa-

Synthesis of (1R,2R,3R,4R,7R,8S)-3-Ethoxy-2-iodo-2,7-dimethyl-6-

oxo-11-oxabicyclo[6.2.1]undec-4-yl Acetate (37): In a 100 mL

round-bottomed flask, previously heated under vacuum and

purged with argon, compound 36 (25.5 mg, 0.86 mmol), LTA

2

quette, Org. Lett. 2000, 2, 1879–1882; e) L. E. Overman, L. D.

Pennington, Org. Lett. 2000, 2, 22683–22686; f) J. S. Clark,

Y. S. Wong, Chem. Commun. 2000, 1079–1080.

(

37.9 mg, 0.86 mmol) and I

2

(21.7 mg, 0.86 mmol) were placed. The

[4] a) X. T. Chen, S. K. Bhattacharya, B. Zhou, C. E. Gutteridge,

T. R. R. Pettus, S. J. Danishefsky, J. Am. Chem. Soc. 1999, 121,

solid mixture was dissolved in anhydrous benzene (1 mL), and the

resulting solution was stirred at room temperature for 3 h. Once

the reaction was complete (monitored by TLC), the reaction mix-

ture was filtered through a short pad of Celite^®in a column, eluting

with diethyl ether. The volume of the ethereal solution was reduced

6

563–6579; b) S. K. Bhattacharya, X. T. Chen, C. E. Gut-

teridge, S. J. Danishefsky, Tetrahedron Lett. 1999, 40, 3313–

316; c) K. C. Nicolaou, T. Ohshima, S. Hosokawa, F. L.

3

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to 20 mL and successively washed with aq. NaHCO

ϫ20 mL), aq. Na (5% w/w, 4ϫ25 mL) and distilled water

25 mL). The organic phase was dried with anhydrous MgSO , fil-

3

(1.2 m,

3

(

2 2 3

S O

4

tered and concentrated to dryness to afford 119.4 mg of crude

product. The product was purified by flash column chromatog-

raphy on silica gel, eluting with mixtures of hexane and diethyl

ether of increasing polarity (with H/E, 60:40) to obtain 27.1 mg of

3

2

O, st) cm . H NMR (400 MHz, CDCl

7

1

7 (75% yield for a 100% conversion of 36). IR (film): ν˜ = 2975,

930 (C–H, st), 1740, 1703 (C=O, st), 1238, 1074, 1047, 1020 (C–

–1 1

3

, 25 °C): δ = 0.94 (d, J =

.2 Hz, 3 H, 13Ј-H), 1.24 (t, J = 7 Hz, 3 H, 2ЈЈ-H), 1.66–1.75 (m,

H, 10Ј-H), 1.84–2.07 (m, 2 H, 9Ј-H and 10Ј-H), 2.09 (s, 3 H, 12Ј-

H), 2.09 (s, 3 H, 2-H), 2.21 (dd, J = 11.8, J = 7.0 Hz, 1 H, 9Ј-H),

4521.

2

9

1

(

2

5

(

.66–2.78 (m, 1 H, 5Ј-H), 3.45–3.54 (m, 1 H, 7Ј-H), 3.56 (dq, J =

.2, J = 7.0 Hz, 2 H, 1ЈЈ-H), 3.72 (dq, J = 9.2, J = 7.1 Hz, 1 H,

ЈЈ-H), 4.02 (br. s, 1 H, 3Ј-H), 4.13–4-17 (m, 1 H, 8Ј-H), 4.24–4.29

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(

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50 °C): m/z (%) = 442 (96) [M + NH

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H25IO

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5.29, H 5.94; found C 45.41, H 5.86.

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Versatile methodology to synthesize oxygen-bridged nine- and ten-membered cycloalkanes by the hypoiodite reaction

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