Mild protocols for generating molecular complexity: A comparative study of hetero-domino reactions based on the oxidant and the substitution pattern

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Mild Protocols for Generating Molecular Complexity: A Comparative Study of

Hetero-Domino Reactions Based on the Oxidant and the Substitution Pattern

José I. Candela Lena,^[a]Elena M. Sánchez Fernández,^[a]Alwar Ramani,^[a]

Nicolas Birlirakis,^[a]Alejandro F. Barrero,^[b]and Siméon Arseniyadis*^[a]

Keywords: Domino reactions / Glycol fission reagents / Ring expansion / Synthetic methods

A bicyclic unsaturated 1,2-diol framework was found to un-

dergo an interesting set of domino reactions on treatment

with oxidants. One-pot syntheses of seven-membered-ring-

containing frameworks were achieved by a Pb(OAc)₄-medi-

ated domino process, while with other oxidants investigated,

such as Mn(OAc)₃, Dess–Martin periodinane, PhI(OAc)₂,

Ph₃Bi(CO)₃, NaIO₄, and NaBiO₃, the domino process was in-

terrupted halfway through. Finally, tetrapropylammonium

perruthenate (TPAP-NMO), Pd(OAc)₂, pyridinium dichro-

mate (PDC), and pyridinium chlorochromate (PCC) gave only

allylic oxidation and further diketone formation without any

of the bond cleavage that is necessary to initiate the domino

process. The substrates were chosen to test the limits of reac-

tivity of various unsaturated 1,2-diol derivatives and to pro-

vide guidelines for their use in constructing complex syn-

thetic targets. In this article we provide details of the reaction

conditions, preparation of the starting materials and charac-

terization of the products, along with new, unpublished re-

sults. Information is assembled to facilitate comparison be-

tween the various oxidants, solvents and substitution pat-

terns.

Germany, 2005)

?with a series of ene-diols can lead to a cascade of reactions

that provides an entry into a variety of molecular architec-

tures. The direct fragmentation of octaline diols provides

access to a range of functionalized cycloheptanes,^[6]as well

as bicyclo[3.2.2]nonanes. The domino sequence can be con-

trolled by changing the stoichiometry: using only one equiv-

alent of the reagent generates the isolable, and stable, cyclic

ene-acetal III, the so-called “half-cascade” intermediate,

while two equivalents lead to the ring-expanded product II

(Scheme 1). These rearrangements are of interest in view of

the synthesis of a number of bis-angularly substituted bicy-

clic lactones V, as well as heavily substituted bridged and

fused seven-membered-ring-containing systems such as IV

and VI. Tricyclic lactones of type VII are the only bypro-

ducts obtained so far. The octalone-derived unsaturated

diol system I was chosen to initiate this study because it

presents optimum opportunities to examine the processes

as the “half-cascade” intermediate III is isolable and stable

in this series.

The mechanistic pathways involved in both the oxidative-

cleavage-induced domino transformations and in the base-

induced ring-system interchange reactions have been dis-

cussed in previous papers.^[7]An overview of the mechanism

deduced from earlier studies is portrayed in Scheme 1 to

assist the reader’s understanding. The domino process is

shown to proceed by a cleavage/[4+2] cycloaddition/oxy-

plumbation/deplumbation/ring-expansion sequence, all the

steps of which are initiated by a multi-task reagent: lead

tetraacetate.

Introduction

Domino reactions continue to be a topic of substantial

interest and intensive exploration.^[1]Their usefulness in syn-

thesis stems from their ability to maximize molecular com-

plexity while minimizing waste. This has significantly

broadened their applicability for multi-step syntheses of

natural compounds. The reaction of lead tetraacetate with

olefins, as well as the glycol fission reaction, were originally

investigated by Criegee^[2]and subsequently studied by sev-

eral other chemists. There is considerable precedent in the

literature for cleaving glycols, such as the Malaprade reac-

tion (periodic acid cleavage) or the Rigby oxidation (glycol

fission with sodium bismuthate), and others.^[3]The presence

of an adjacent olefin considerably increases the range of

products accessible.^[4]Unsaturated 1,2-diols undergo glycol

fission upon treatment with Pb(OAc)₄, which initiates a

domino process under very mild conditions. In our efforts

to generate high molecular complexity in a one-pot reaction

we examined the unsaturated bicyclic diol system I

(Scheme 1), which is a versatile template for the domino

transformations during lead tetraacetate mediated oxidative

cleavage in the synthesis of highly elaborated cyclic systems

containing six- or seven-membered rings.^[5]We have already

?shown in several publications that the reaction of Pb(OAc)₄

[a]

Institut de Chimie des Substances Naturelles, CNRS,

91198 Gif-sur-Yvette, France

E-mail: simeon.arseniyadis@icsn.cnrs-gif.fr

[b]

Universidad de Granada,

Avda. Fuentenuevas/n, 18071 Granada, Spain

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DOI: 10.1002/ejoc.200400549

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Scheme 1. Reagents and conditions: (a) 2.4 equiv. Pb(OAc)₄, MeCN, 0 °C to room temp.; (b) 1.2 equiv. Pb(OAc)₄, MeCN, 0 °C to room

temp.; (c) K₂CO₃/MeOH/H₂O, room temp.; (d) O₃, CH₂Cl₂at –78 °C, then K₂CO₃/MeOH/H₂O, room temp.; (e) LiAlH₄, THF, reflux

then H⁺-acetone room temp.

To extend the scope of the process, it was essential to acetoxy-enone 1 was converted into the unsaturated diol 2

this study that some other oxidants, less toxic than lead by a simple low temperature treatment with methyllithium

tetraacetate, were studied in various solvents. To this aim, (THF, –78 °C); similarly, 4 gave the unsaturated diol 5. The

the effect of the oxidant was examined using a number of next target, the unsaturated bicyclic diol 7, was synthesized

known reagents employed in glycol cleavage. This paper de- in a three-step sequence from 6, which, in turn, was pre-

scribes the synthesis of several variously substituted 2,3-di- pared from commercially available dimedone on a large

hydroxy-4-ene bicyclic frameworks, and the rearrangements scale using the Heathcock procedure.^[10]

that these systems undergo when treated with an oxidant.

Previously described methods were used to prepare oc-

taline-diol 3, its free-ketone counterpart 8 and hence the

exo-methylene derivative 9 from the well known Wieland–

Miescher ketone.^[11]The four-step process from 3 was ef-

fected in 78% overall yield (Scheme 2). The allylically sub-

stituted substrates 11, 12, and 26 (Table 1) were generated

from the corresponding acetoxy-enones by way of the inter-

mediate dienol acetate species, using known procedures.^[12]

The dienol acetates, obtained by heating of the acetoxy-

enones in pyridine in the presence of acetic anhydride and

4-(dimethylamino)pyridine (DMAP), were then epoxidized

with methyltrioxorhenium (MTO) as catalyst and aqueous

hydrogen peroxide as terminal oxidant.^[13]

As the effectiveness of the process could be further im-

proved if the resulting complex heterocycle is poised to un-

dergo spirocyclization, we came to favor octaline-diol 18,

obtained by an asymmetric Robinson annulation,^[14]as a

subgoal of the synthesis of spirocycles. This intermediate

would provide a platform structure for evaluating possibil-

ities for the construction of the spirocyclic frameworks

found in many natural products. The elaboration of the tar-

get octaline diol 18 began with the known bicyclic enone

alcohol 13a,^[15]which was converted into the bis-OTBS pro-

tected acetoxy-enone 17 in four steps by the sequence

shown in Scheme 3. TBS protection of the secondary hy-

droxyl group (TBSCl, DMF/imidazole, 0 °C, 24 h) followed

by hydroboration (BH₃·Me₂S, H₂O₂/NaOH, EtOH, 8 h),

Preparation of Substrates

We thus embarked on the synthesis of a set of substrates

for investigating the effect of stoichiometry, oxidant, substi-

tution pattern, solvent, temperature, and reaction time. Di-

ols of type 2, 3, 5, 7, 8, 9, 11, 12 (Scheme 2), and 18

(Scheme 3) were studied in order to optimize the condi-

tions. On the whole, for the preparation of the bicyclic un-

saturated 1,2-diols − the required domino substrates − the

well-known Robinson annulation procedure was used,^[8]

starting from the appropriate cyclic ketone and methyl vinyl

ketone. The required diols were prepared, in a straightfor-

ward manner, from the bicyclic enones thus obtained fol-

lowing our previously published procedure.^[9]To prepare

acetoxy-enones (such as 1 Scheme 2), Pb(OAc)₄and the

corresponding enones were heated in benzene at reflux, un-

der Dean–Stark conditions for water removal. Acetoxylated

compounds were isolated in good yields (70–90% yield)

along with unreacted starting material. The diols were then

obtained by reduction with lithium aluminum hydride in

diethyl ether at 0 °C. Exploratory studies focused on the

synthesis of diols 2, 3, 5, 7, 8, 9, 11, and 12. The unsaturated

diols 2 and 5, which possess a tertiary-secondary diol sys-

tem, were obtained from the acetoxy-enone 1 and acyloin

4, respectively (intermediates in our earlier studies).^[9]Thus,

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Scheme 2. Reagents and conditions: (a) MeLi, THF, –78 °C (86–90%); (b) LiAlH₄/Et₂O, 0 °C (99%); (c) 10% HCl/THF, 1:1, 4 °C, 12 h

(99%); (d) TBSCl, DMF/imidazole, 0 °C, 2 h (87%); (e) PPh₃MeBr, tBuOK, PhMe, room temp., 4 h (94%); (f) TBAF/THF, 60 °C, 4 h

(96%); (g) ethylene glycol, p-TosH, room temp. (95%); (h) 4 equiv. Pb(OAc)₄, benzene, 90 °C, 4 d (85%); (i) Ac₂O, Py, 4-DMAP, 80–

100 °C (90%). (j) MTO, 30% H₂O₂, Py, CH₂Cl₂, room temp.(70%); (k) TMSOTf, collidine, PhMe, –40 °C (95%)

Scheme 3. Reagents and conditions: (a) TBSCl, DMF/imidazole, 0 °C, 24 h (89%). (b) BH₃·Me₂S, H₂O₂/NaOH, EtOH, 8 h (78%). (c) i.

PCC, 3,5-DMP, 0 °C (62%), ii. TBSCl, DMF/imidazole, 0 °C, 1.5 h (91%); (d) Pb(OAc)₄, PhH, reflux, 4 d (90%); (e) LiAlH₄/Et₂O, 0 °C,

30 min (99%); (f) (S)-2-acetoxypropionyl chloride, DMAP, CH₂Cl₂, 0 °C, 30 min.

selective allylic oxidation (3,5-DMP, PCC, 0 °C), and TBS The Oxidant

protection of the primary hydroxyl group as above. Conver-

sion to the requisite diol was then accomplished by re-

duction with LiAlH₄.

It is clear that the Pb(OAc)₄-induced domino reaction is

an effective one, but the use of two equivalents of Pb(OAc)₄

For the synthesis of the (R)-(–)-carvone derived unsatu- is a potentially hazardous process due to the toxicity of

rated bicyclic diols 19 and 20 (Table 1) a slightly modified this oxidant. To satisfy Tietze’s requirements,^[17]various ox-

de Groot procedure was employed.^[16]Unsaturated diols idants known to be efficient glycol fission reagents^[18]were

21–26 (Table 1) and their Pb(OAc)₄-mediated domino pro- screened and compared for these domino reactions.^[19]Ac-

ducts, described in our previous work, were also examined cordingly, we undertook a systematic study with four oxi-

in order to more fully document the functional-group com- dants (Table 1); studies with triphenylbismuth carbonate,

patibility of this domino process.

which produces triphenylbismuth as a byproduct that is

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Table 1. Reagents and conditions: 1) 1.2 equiv. of PhI(OAc)₂, in sometimes difficult to remove chromatographically, and so-

acetonitrile, 15–24 h at room temp.; 2) 4 equiv. of Mn(OAc)₃in

dium bismuthate, which is much less efficient, are not in-

refluxing PhH; 3) 2 equiv. of Dess–Martin periodinane in dry

cluded in the table. A series of experiments were addressed

PhMe, room temp. to 72 °C; 4) 1.5 equiv. of Pb(OAc)₄in dry PhMe

to assess the factors involved in these domino transform-

at room temp.

ations. The variables examined include: a) treatment of each

one of the four possible diastereomers (two with a cis- and

two with a trans-1,2-diol relationship) with the oxidant

separately and as a diastereomeric mixture, b) a tempera-

ture range from room temperature to 85 °C, c) various sol-

vents (MeCN, CH₂Cl₂, AcOH, CHCl₃, C₆H₆, toluene, tri-

fluorotoluene, DMSO/toluene), and d) tuning of the stoi-

chiometry.

Table 1 illustrates a wide range of substrates that undergo

an efficient glycol fission/intramolecular bis-hetero Diels–

Alder process when treated with iodobenzene diacetate

(IBD), manganese(iii) acetate, Dess–Martin periodinane

(DMP), or lead tetraacetate (LTA); they all give good to

excellent yields.

The product distribution for the oxidation of vicinal un-

saturated diols with DMP as oxidant under various condi-

tions was examined first.^[20]Glycol cleavage using Dess–

Martin periodinane was reported several years ago by

Grieco et al.^[21]Recently, Frigerio and Santagostino have

reported that o-iodoxybenzoic acid (IBX) in DMSO is cap-

able of oxidizing primary and secondary alcohols to alde-

hydes and ketones, and also 1,2-diols to either 1,2-dicar-

bonyl compounds or acyloins, without any oxidative cleav-

age of the glycol bond.^[22]Recent work from Nicolaou et

al. has shown that IBX is effective in converting saturated

alcohols to α,β-unsaturated carbonyl systems^[23]and in me-

diating processes for amino sugar construction,^[24]and that

IBX and DMP promote molecular diversity when treated

with anilides and related compounds.^[25]

Starting from a diastereomeric mixture of steroidal un-

saturated 1,2-diol 25 in acetonitrile, the reaction with three

equivalents of DMP was sluggish and only 15% of the cor-

responding cyclic ene-acetal 45 was obtained after stirring

at ambient temperature for 20 h. The byproduct in this re-

action was acyloin 50, which arises as a consequence of

allylic oxidation and which is further transformed to the

ene-dione exclusively in its keto-enol form 51 (Scheme 4).

with CH₂Cl₂as solvent, in the presence of pyridine and a

threefold excess of DMP, the half-cascade intermediate 45

was obtained in 40% isolated yield after stirring at room

temperature for four hours. Better yields and faster rates

were obtained in benzene or toluene (20 mL mmol^–1). In

the optimized conditions, the experiments undertaken with

two equivalents of DMP, in dry toluene (20 mL mmol^–1)

from room temperature to 72 °C in about one hour uni-

formly gave rise to the type-45 “half-cascade” intermedi-

ates, type-50 acyloins, and type-51 cross-conjugated

hydroxydienones as the only detectable products

(Scheme 4). The glycol fission is stereochemistry dependent;

nevertheless, it constitutes a useful method for glycol fission

and offers molecular complexity.

Running the reaction with only one equivalent of DMP

repeatedly afforded a greater than 50% yield of tricyclic

enol ether 45 along with the corresponding acyloin and the

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Scheme 4. Reagents and conditions: (a) 2 equiv. Dess–Martin periodinane in dry PhMe, room temp. to 72 °C

resulting cross-conjugated 2-hydroxydienone 51 (approx. and PhI(OAc)₂give glycol fission regardless of the stereo-

20% combined yield), thus corroborating a cyclic complex chemistry of the starting diols. Unsaturated diols 19, with

formation, such as 54 (Scheme 4), similar to the periodic a cis-1,2-OH relationship, afforded 41 (72%) cleanly, while

acid mechanism proposed by Buist and Bunton.^[26]Analo- the trans 1,2-diol 19β-trans gave only allylic oxidation,

gous results were obtained starting from the diastereomeric which further evolved towards the hydroxydienone 53 (the

mixture 19, the byproduct being the keto-enol form (53) of keto-enol form of the corresponding diketone 52), with no

the diketone 52, along with a small amount (Ͻ5%) of the glycol fission (Scheme 6). The DMP oxidation of diastereo-

allylic oxidation product as above.

The domino transformations carried out on diastereo- tical course as for the carvone derived analogs.

meric mixtures (all isomers present in various ratios, not To obtain stable derivatives in the keto-enol form, the 2-

merically pure diols 5β-trans and 5β-cis followed an iden-

always determined) proceeded in 42–76% isolated yields. To acetoxy cross-conjugated dienone 55 was prepared from the

explore the influence of the 1,2-diol stereochemistry on pro- steroidal diol 25α-trans. This could be achieved either step-

duct distribution and reaction rate, (R)-(–)-carvone derived wise or in one pot by adding Ac₂O/pyridine to the reaction

diastereomerically pure diols 19, as well as diols 5 and 23 mixture once formation of the enedione 52 was complete

derived from the Wieland–Miescher ketone and testoster- (TLC monitoring). Yields of enol-acetates generated by

one (25), were prepared and subjected separately to the either the direct or two-step approach are comparable.

Dess–Martin periodinane mediated oxidative cleavage. When used as a diastereomeric mixture, 25 gave 72% of 45

Some of the diastereomerically pure unsaturated 1,2-diols along with 15% of the 2-hydroxy cross-conjugated dienone

examined are portrayed in Scheme 5.

51. The 2-acetoxy cross-conjugated dienone 48 was also

The reactivity pattern of four vicinal 1,2-diols 19 (19β- prepared straightforwardly, by a route similar to that em-

trans, 19α-trans, 19β-cis, and 19α-cis), as well as 5, 23, ployed for the synthesis of 55, from the corresponding diol

and 25 was examined. The trans isomers 23α-trans and 25α- 19β-trans. This method is valid for all the unsaturated

trans are completely resistant to both the glycol splitting diols investigated in this study. The process tolerates a vari-

reagents DMP and Ph₃Bi(CO)₃, while Pb(OAc)₄, Mn(OAc)₃, ety of substitution patterns and protecting groups (entries

Scheme 5. Some of the diastereomerically pure unsaturated 1,2-diols examined

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Scheme 6. Reagents and conditions: (a) Dess–Martin periodinane (2 equiv.), dry PhMe, room temp. to 72 °C, ca. 1 h, then cool to 0 °C,

Ac₂O/py, DMAP

1–16, Table 1). More interestingly, the oxidative-pericyclic despite a clean TLC) observed with manganese(iii) acetate

hetero-domino reaction was successfully employed for the mediated tandem transformations can be attributed to the

conversion of the tertiary-secondary unsaturated diols 2 use of an excess of reagent and its purity.^[30]

and 5 to 32 and 34 in 67% and 76% yield, respectively, that

The process tolerates a variety of substitution patterns

is, the bis-hetero-intramolecular-Diels–Alder stage of the and protecting groups. The tertiary-secondary unsaturated

domino reaction, with a ketone component, carried out on diols 2, 5, as well as the ketal-protected 7 and the bis-TBS-

a diastereomeric mixtures of the starting diols, works in protected 18 furnished 32, 34, 35, and 40, respectively,

high yields and offers stereo-cleaning and room for further cleanly. Starting from steroidal unsaturated diol 25, the

selective transformations of the highly functionalized, rigid other products formed alongside 45 were assigned as the

tricyclic framework. Even though such hetero-Diels–Alder allylic oxidation product 50 and the corresponding ene-di-

cycloadditions are rare due to steric and electronic one, sometimes exclusively in its keto-enol form 51. In all

reasons,^[27]intramolecular versions form part of an elegant cases investigated the Mn(OAc)₃-mediated reaction fur-

multicomponent domino sequence developed by Tietze et nished the cyclic ene-acetals (half-cascade intermediates)

al.^[28]The process accommodates free carbonyl 8, ketal pro- together with the allylic oxidation product and the keto-

tective groups (2, 3, and 7), a cyano group (19), an ester enol form of the corresponding diketone in variable yields

group (22), and an exocyclic double bond (9, 20, Table 1). (ca. 15%) that were not dependent upon the composition

The mechanism of cleavage by DMP is consistent with a of the starting diastereomeric mixture.

cyclic five-membered ring intermediate such as 54

The next oxidant studied was iodobenzene diacetate.

(Scheme 4). Support for this proposal comes from the fact Even though we did not find precedent for manganese(iii)

that the cis isomers of the bicyclic unsaturated diols are acetate mediated glycol cleavage in the literature, the

more reactive than the trans isomers: 19α-cis and 19β-cis PhI(OAc)₂-mediated oxidation of 1,2-diols has been known

undergo oxidative cleavage, while their 25α-trans and 19β- for a long time as a clean method for the cleavage of gly-

trans counterparts, which cannot form a cyclic intermediate, cols.^[31]Treatment of a series of unsaturated diols with iodo-

are inert towards cleavage (Scheme 6).

benzene diacetate (PhI[OAc]₂), in dichloromethane, aceto-

The Mn(OAc)₃-mediated^[29]oxidative cleavage of unsatu- nitrile, benzene, or toluene, at room temperature, gave cyclic

rated diols (Table 1) again generated molecular diversity ene-acetals by a sequential oxidative cleavage-intramolecu-

along with the α-dicarbonyl derivatives and the correspond- lar [4+2] cycloaddition.^[32]Starting from carvone-derived

ing cross-conjugated hydroxydienones as byproducts, in diols 19 (entry 10), variation of the solvents gave the follow-

about 10–15% yield. Studies conducted on a series of dia- ing results: in MeCN an 86% yield of 41 was obtained after

stereomerically pure diols showed that the yields and ratios chromatography, while yields were lower in toluene (75%),

are similar to those obtained starting from a diastereomeric benzene (69%), trifluorotoluene (65%), dichloromethane

mixture of diols. This clearly shows that the cleavage pro- (57%), and AcOH (53%). As a consequence of the above

cess is not dependent on the diol stereochemistry. The results, the optimized procedure involves use of dry acetoni-

choice of solvent was found to be important in these trans- trile and stirring, under an inert atmosphere, at room tem-

formations: replacing acetonitrile with benzene led to a de- perature for about 24 h. As with the two previous oxidants

crease of the amount of side products and improved yields. [DMP and Mn(OAc)₃], the process tolerates a variety of

When unsaturated diols were treated with four equivalents substitution patterns and protecting groups. The reaction is

of Mn(OAc)₃in dry and degassed benzene at reflux under easy to perform, can be scaled up safely, and occurs ef-

argon, the reactions were generally complete within less ficiently irrespective of the diol stereochemistry. Domino

than four hours. The rather low isolated yields (ca. 60%, transformations carried out on diastereomeric mixtures of

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all the unsaturated 1,2-diols investigated (entries 1–16), uni-

Oxidation of diol 23 with NaIO₄leads to the dialdehyde

formly gave rise to the “half-cascade” intermediates 32–46, 57, along with about 20–30% of tricyclic enol ether 45. Al-

as the only detectable products in 60–89% yields (Table 1). lowing this reaction mixture to stand gave no more 45, even

Taking into account the level of molecular complexity at- after addition of further oxidant. Instead, a geometrical

tained in a one-pot transformation, the yields are quite isomerization of the initially formed dialdehyde was ob-

high.

served. This result probably indicates that, in the lead tetra-

Finally, in the closing stage of this comparative study, acetate mediated domino transformations, a catalytic action

the oxidative cleavage of unsaturated diols 23 with bismuth exists in the cyclization process, with the Pb⁴⁺playing the

reagents was also evaluated in the hope of finding mechan- role of a Lewis acid to catalyze the intramolecular bis-het-

istic similarities between Pb⁴⁺and Bi⁵⁺, two 5d¹⁰oxidants. ero [4+2] cycloaddition after previously acting as an oxid-

Watt et al. have investigated cleavage of unsaturated α-ke- izer.

tols using sodium periodate, sodium bismuthate, manganese

dioxide, and lead tetraacetate, and found sodium periodate

to be the best reagent.^[33]Considerably lower yields of type-

45 “half-cascades” were obtained in the reaction of diol

23α, derived from the Wieland–Miescher ketone, (and vari-

ous diols from Table 1) and Ph₃BiCO₃, while a new com-

pound was also obtained when sodium bismuthate was used

as the oxidant.

Thus, using the procedure of Watt, 23α was treated with

NaBiO₃in 50% aqueous AcOH at room temperature for

19 h (Scheme 7) to afford 15% of the half-cascade 45, 5%

of dialdehyde 57, 28% of starting material 23, and 44% of

58 (anomeric mixture). The latter was acetylated to the cor-

responding acetate 59 nearly quantitatively for characteriza-

tion (pyridine, Ac₂O and a catalytic amount of DMAP,

room temperature stirring while TLC monitoring; the ste-

reochemistry of the major acetate is as depicted).

The last three oxidants we tried were PDC, PCC, and a

mixture of tetra-N-propylammonium perruthenate and N-

methylmorpholine N-oxide (TPAP-NMO). It is known that

chromium-based reagents lead to a cleavage of vicinal di-

ols,^[34]but in our hands PDC or PCC failed to produce any

glycol fission, as did a mixture of tetra-N-propylammonium

perruthenate (TPAP) and N-methylmorpholine N-oxide

(NMO), which has been used by Wiberg et al. for glycol

fission in their studies on bridged spiropentanes.^[35]

Thus, after a detailed examination of various oxidants

and substrates, Pb(OAc)₄was found to be the only oxidant

capable of completing the present domino reaction to give

the ring-expanded products of type II; the others stopped

at the halfway domino system, the cyclic ene-acetals of type

III (Scheme 1). From a synthetic point of view it would, of

course, be more environmentally friendly to be able to at

least effect a consecutive domino transformation using two

oxidants of different toxicity. We therefore examined the

combined use of other oxidants and discovered that a com-

bination of manganese(iii) acetate and Pb(OAc)₄or iodo-

benzene diacetate and Pb(OAc)₄proved to be as effective as

Pb(OAc)₄alone. Scheme 8, which illustrates the notion of

incorporating a (supposedly) less-toxic oxidant, such as

Mn(OAc)₃or PhI(OAc)₂, that is capable of carrying out the

first two hetero-domino transformations, details our first

attempts at reducing this concept to practice.

The reaction was carried out in a single reaction vessel

and the best yields were obtained using acetonitrile as sol-

vent for the octaline-diol series, while toluene was equally

efficient for the hydrindene-diol series. The equilibrium

mixture of 29b and 30, obtained from diols 24 upon treat-

ment with either Mn(OAc)₃or PhI(OAc)₂, readily under-

Scheme 7. Reagents and conditions: a) NaBiO₃, AcOH(H₂O, room

temp., 19 h; b) Ac₂O, Py, DMAP, room temp., 3 h; c) 50 °C, 2 Torr,

5 h.

Scheme 8. Reagents and conditions: (a) 2.4 equiv. of Pb(OAc)₄in dry MeCN, –20 °C to room temp.; (b) 1.2 equiv. of PhI(OAc)₂in

acetonitrile, 15–24 h at room temp.; (c) 4 equiv. of Mn(OAc)₃in refluxing MeCN; (d) 1.2 equiv. of Pb(OAc)₄in dry MeCN at room temp.

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went oxyplumbation-ring expansion upon addition of one vent, although the required reaction time for the domino

equivalent of Pb(OAc)₄to the reaction vessel to give the process to complete was much higher (15 h versus 48 h

full-cascade product 31 in remarkably high yield (ca. 82%). respectively). Toluene, benzene, and trifluorotoluene gave

The cyclic ene-acetal 30 in the hydrindene-diol series could mainly half-cascade products, even after prolonged treat-

only be characterized as an equilibrium mixture with its ment. The dramatic reduction in reaction time when using

dialdehyde counterpart 29b by NMR techniques, although carboxylic acids as solvent is noteworthy. The observed sol-

a few exceptions exist (entry 13, Table 1). In the higher vent effect on the rate of cascade transformations can be

homologue, octaline-diol series, all the half-cascade pro- rationalized by examining the proposed mechanism of this

ducts are isolable and stable, and some interesting chemistry reaction sequence.^[7]

can be done to give access to bicyclic or steroidal lac-

The question of whether a change in substitution pattern

tones.^[36]Thus, treatment of octaline-diols 23 with either can alter the reaction course of the domino transformation

manganese(iii) acetate or iodobenzene diacetate yielded the has already been the concern of our preliminary communi-

half-cascade intermediates 27 cleanly (54 and 89% yield, cations. As we reported, the pathway of such Pb(OAc)₄-

respectively, compared to a 95% yield obtained with lead mediated domino reactions depends crucially on the sub-

tetraacetate), which was converted into the ring-expanded strate’s substitution pattern^[37]and the solvent.^[38]An inter-

intermediate 28 upon subsequent addition (one pot) of esting feature of the domino reaction is that it can be ef-

Pb(OAc)₄. Based on the above results, a hetero-domino re- fected on angularly alkoxy-substituted unsaturated diol sys-

action initiated by iodobenzene diacetate, Dess–Martin tems such as 18. Thus, we chose to examine an allyl group

periodinane, or Mn(OAc)₃(oxidative/pericyclic), and an- in the angular position, since this group might be trans-

other one upon addition of lead tetraacetate (oxidative/cat- formed later into a variety of functional groups via 65,

ionic), can be performed sequentially to afford high mole- which is obtainable by a reductive treatment followed by a

cular complexity after a ring expansion. According to Tiet- selective acetonide formation according to our published

ze’s classification, the process is a consecutive hetero-domino procedures. This intermediate would provide a platform

reaction where the olefin is the sine qua non for the genera- structure for evaluating possibilities for stereocontrolled

tion of diversity, while Pb(OAc)₄remains the reagent that spirocycle construction. The angularly functionalized al-

affords the highest degree of diversity. In the absence of the koxy octaline-diol 18 underwent clean hetero-domino trans-

latter the process is interrupted halfway through and the formations, modulable by stoichiometry, to afford either cy-

resulting products of type 27 or 30 are called “half-cascade” clic ene-acetal 40 or the spirocyclic precursor 60 in good

products in our earlier publications. Prolonged stirring at yields upon treatment with 1.2 or 2.4 equiv. of lead tetraac-

room temperature in the presence of a threefold excess of etate, respectively (Scheme 9). The half-cascade intermediate

iodobenzene diacetate did not produce any traces of the 40 can be recycled, as pre-formation of 40 under the

type-28 or -31 ring-expanded products, even after refluxing 1.2 equiv. conditions and further treatment with lead tetra-

for three days in acetonitrile, benzene, or toluene. However, acetate led to an efficient domino transformation to deliver

heating at reflux in acetic acid gave ring-expanded products 60. In the case of diols 9, the alternative rearrangement

in the hydrindene-diol series, albeit in very low yields (ca. pathway^{[ 36 ]}leading to 61 (52%) competes to a minor, al-

20%). The one-pot preparation of the ring-expanded mole- though significant, extent with the normal mode of re-

cule 31 was accomplished on a large scale (10–20 g) by a arrangement involving ring expansion, to produce the re-

controlled iodobenzene diacetate oxidative cleavage of the arranged species 62 (6%). This was the first case of a dom-

unsaturated diols 24 and subsequent lead tetraacetate medi- ino reaction with a β-face attack of the metal and was a

ated ring enlargement.

worrisome outcome until we realized that is almost surely

due to the absence of the OtBu substituent which pushes

the angular methyl group closer to the olefin (competing

C5–C10 and 1,2-oxygen migrations). Pre-formation of half-

cascade 37 (80% yield) upon treatment with one equivalent

of Pb(OAc)₄also led to an efficient domino transformation

The Substitution Pattern

Pb(OAc)₄-mediated cleavage in acetic acid, followed by (oxidative/cationic) to deliver 61 in 55% yield. In both cases,

hydrolytic treatment, was successfully used in our previous the ring-enlarged compound 61 was produced as the major

studies to form seven-membered-ring carbocycles.^[5]The component of a chromatographically separable mixture of

process generally afforded three compounds, among which two rearrangement products. Taking into account the level

the ring-expanded type-II (Scheme 1) derivatives were the of molecular complexity attained in an one-pot transform-

major products of the reaction. Minor products were iden- ation, the yields are quite good to high.

tified as the type-VII lactone and the type-III half-cascade

Treatment of diols 7 with lead tetraacetate in acetic acid,

derivatives, which could be re-subjected to the domino con- at room temperature, cleanly afforded the corresponding

ditions to afford more type-II products. The choice of sol- ring-expanded intermediate 64 in 50% isolated yield along

vent was found to be crucial in these transformations: with the cyclic ene-acetal 35 (6%), which could be resub-

Pb(OAc)₄gave the ring-expanded derivatives in yields of jected to the domino conditions to give more of the ring-

45–82% from the diols if acetic acid was used as solvent, expanded product. The other product formed alongside 35

and a similar yield was obtained with acetonitrile as sol- and 64 was assigned as the lactone 63 (20%).

690

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Scheme 9. Reagents and conditions: (a) 2.4 equiv. Pb(OAc)₄, AcOH, room temp., 17 h; (b) 1.2 equiv. Pb(OAc)₄, AcOH, room temp., 17 h

The presence of allylic or vinylic substituents (entries 1, the half-cascade intermediates could be recovered from the

3, 7, 8, 12, 13, and 16) is a chief factor controlling the com- reaction mixture even after prolonged reaction time (up to

petition between “half” and “full cascade”, while the distri- three days) and heating. From these results, it is highly

bution is not altered by the presence of either an electron- likely that completion of the domino process (oxyplumb-

donating or -withdrawing group (entries 12 and 13). Thus, ation-ring expansion) is affected by the steric accessibility

substitution at the allylic position and at the olefin resulted of the electron-rich olefin resulting from the [4+2] cycload-

in the interruption of the domino process at the half-cas- dition. Since both donors or acceptors lead to the same

cade levels (32, 34, 38, 39, 43, 44, and 46 in Table 1) even reaction outcome, electronic factors can be ruled out.

after addition of excess lead tetraacetate and prolonged stir- Formation of 60, 61, and 64 shows that the process accom-

ring or heating. In all these cases, upon addition of extra modates primary-secondary TBS protective groups, an

oxidant [up to three more equivalents of Pb(OAc)₄] the sec- olefin, and

a

ketal-protective group, respectively

ond half of the domino process was sluggish and mainly (Scheme 10).^[39]

Scheme 10. Reagents and conditions: 2.4 equiv. Pb(OAc)₄in AcOH at room temp.

Eur. J. Org. Chem. 2005, 683–700

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691

S. Arseniyadis et al.

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gon. Experiments that required an inert atmosphere were carried

out under dry argon in a flame-dried glass system. Flash chroma-

tography was run on silica gel (Merck 60, 230–400 mesh) with the

solvent mixture indicated. Thin layer chromatography was per-

formed on commercial silica gel plates that were developed by im-

mersion in 5% phosphomolybdic acid in 95% ethanol. “Usual

workup” means washing of the organic layer with brine, drying

with anhydrous MgSO₄, and evaporating in vacuo with a rotary

evaporator at aspirator pressure. NMR spectra were run in CDCl₃

and specific rotations were measured in chloroform at 20 °C, unless

otherwise noted. Experimental evidence favoring the structures in-

As shown in Scheme 10, oxidative cleavage furnished

good yields of ring-expanded “full-cascade” intermediates

in cases where R²= R³= H, R₁϶ H, and R, R⁴= a

plethora of functional or protecting groups (60, 61, 64, 65,

66, 68, and 69), while the process was completely interrup-

ted at the half-cascade stage in the presence of allylic or

vinylic substituents (e.g. 34, 38, 43, and 46). The main re-

sults of this and previous work, assembled in Scheme 10,

demonstrate a marked substituent effect.

1

vestigated came from a comprehensive range of H and ¹³C NMR

Conclusions

spectroscopic data (400, 300, 250 and 100, 75, 69.5 MHz respec-

tively, 1D and 2D experiments) and corroborated by spatial prox-

imity (n.O.e) studies using mainly the 1D NOEDIFF technique.^[41]

¹H (800 MHz) and ¹³C NMR (200 MHz) experiments were carried

out on a Bruker Avance DRX-800 spectrometer, equipped with tri-

ple resonance H/C/N probeheads and a three-axis pulsed field gra-

dient modules. Gradients were used for the coherence transfer path-

way selection in HMBC and HMQC experiments. In the latter,

broadband decoupling was performed by using adiabatic WURST-

40 pulses. For all compounds investigated, multiplicities of ¹³C res-

onances were assigned by the SEFT technique.^[42]Electron spray

mass spectra were obtained in instances where electron impact and

chemical ionization failed to produce molecular ions. Mass spectra

acquired in the positive-ion mode under electron spray ionization

(ES⁺) using a mobile phase of methanol, are abbreviated as ESIMS

(MeOH). HR is added for the high-resolution mass measurements

(HRESIMS).

We have investigated the feasibility of our domino pro-

cess with a number of other oxidants, the majority of which

are known to promote glycol fission. The key observations

are simply summarized as follows: among the oxidants scre-

ened, Dess–Martin periodinane, Mn(OAc)₃, PhI(OAc)₂,

NaIO₄, NaBiO₃, and Ph₃BiCO₃cause cleavage of vicinal

diols, while TPAP-NMO, PDC, PCC, or Pd(OAc)₂give al-

lylic oxidation essentially quantitatively and no cleavage is

detected. The Mn(OAc)₃-, DMP-, and PhI(OAc)₂-mediated

transformations differ from those mediated by Pb(OAc)₄in

several fundamental respects, such as the degree of molecu-

lar diversity generated, the reaction rate, the temperature,

the yields, and finally the side products. While no side-pro-

duct formation was observed with lead tetraacetate and

iodobenzene diacetate, manganese(iii) acetate (irrespective

of the diol stereochemistry) and Dess–Martin periodinane

(depending on the stereochemistry of starting diols) gave

rise to allylic oxidation and subsequent re-oxidation toward

the corresponding diketone, and hence to the cross-conju-

gated analog, albeit in low yields. The most noteworthy dif-

ference between the oxidants used in this investigation is

the fact that Mn(OAc)₃, Dess–Martin’s periodinane,

PhI(OAc)₂, Ph₃Bi(CO)₃, NaIO₄, and NaBiO₃failed to ef-

fect the “full cascade” leading to the ring-expanded pro-

ducts normally obtained from Pb(OAc)₄-mediated domino

transformations. Attempts to replace Pb(OAc)₄entirely

with other, less-toxic oxidants, especially PhI(OAc)₂, failed

under the same mild conditions. On the other hand,

Pb(OAc)₄and PhI(OAc)₂both effect the cleavage in a vari-

ety of solvents at room temperature irrespective of the ste-

reochemistry of the hydroxyl groups.

The required unsaturated diols were prepared straightforwardly, in

their optically pure form, following published procedures.^[23]Com-

mercial Mn(OAc)₃, PhI(OAc)₂, and Pb(OAc)₄were used without

purification. The acetic acid content of the latter (introduced in

excess of 0.2 equiv.) was mostly removed under vacuum in the reac-

tion vessel. The assignment of the stereochemistry of the ring sys-

tem was made on the basis of diagnostic NOEs of the various struc-

tural isomers. The relative stereochemistry was deduced from the

magnitudes of vicinal coupling constants and corroborated by 1D

difference NOE experiments.

General Procedure for the Acetoxylation with LTA to Form Acetoxy

Octalones: A dry three-necked flask, equipped with a Dean–Stark

apparatus, was charged with the octalone (12.0 mmol) and

Pb(OAc)₄(48.0 mmol, 4.0 equiv.). It was then evacuated and

flushed with argon before dry benzene (80 mL) was added and the

reaction mixture was heated at 90 °C (oil bath temperature should

not exceed 100 °C) for three days. After cooling, a large volume of

diethyl ether was added and the reaction mixture stirred for an

additional hour, filtered, and the filtrate washed with brine and

water, dried with MgSO₄, concentrated, and purified by chroma-

tography on silica with heptane/EtOAc (5:1) as eluent to afford 70–

90% of a nearly 1:1 mixture of the desired acetoxy enones.

None of the alternative conditions proved superior to

Pb(OAc)₄, which ensures the mildest conditions, the highest

yields, and the highest molecular diversity due to its ability

to perform different tasks − it acts as an oxidizing agent

and as a Lewis acid − during the same reaction. Of the

other oxidants investigated, those based on hypervalent iod-

ine proved the most satisfactory.^[40]The domino reaction

is very sensitive to the substitution pattern of the byciclic

framework; we have demonstrated that allylic and vinylic

substitution interrupts the process at the half-cascade level.

General Procedure for the Reduction of Acetoxy Enones: A solution

of the acetoxy enone (4.0 mmol, 1.0 equiv.) in anhydrous diethyl

ether (50 mL) was added dropwise to a magnetically stirred suspen-

sion of LiAlH₄(8.0 mmol, 2.0 equiv.) in 50 mL of anhydrous Et₂O,

cooled to nearly 0 °C. After stirring at this temperature for 30–

40 min (TLC monitoring) the mixture was diluted with wet Et₂O

and treated with a small amount of 6 n NaOH solution (for each

gram of LiAlH₄1 mL of water, 1 mL of 6 n NaOH, and 3 mL

more of water were added). The organic layer was worked up as

usual to give, after silica gel chromatography (eluent: heptane/

EtOAc), yields of more than 95% of the desired diols.

Experimental Section

General: All solvents and reagents used in this work were purified

according to standard literature techniques and stored under ar-

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Domino Transformations: The yields given in Table 1 refer to spec- cooled to 0 °C. Acetic acid (5 mL) was added, the cooling bath

FULL PAPER

troscopically and chromatographically (silica gel) homogeneous

materials.

removed soon after, and the reaction mixture stirred for 17 h at

room temperature. The mixture was diluted with EtOAc and

washed carefully with sat. NaHCO₃solution to neutral pH, and

then washed again with brine. The organic layer was concentrated

under reduced pressure, dried with MgSO₄, and purified by flash

chromatography using heptane/EtOAc as eluent to afford the ring-

expanded intermediate as the major component of a mixture of

three compounds, which also contains the half-cascade product,

which can be recycled, and a lactone derivative.

General Experimental Procedure for the Lead Tetraacetate Medi-

ated Oxidative Cleavage. Modulation by Stoichiometry: The solid

unsaturated diol (1.0 mmol) and Pb(OAc)₄(1.2 mmol) were placed

in a flame-dried flask, which was evacuated and then flushed with

argon. The flask was then cooled to –20 °C and 5 mL of acetoni-

trile was added. The ice bath was removed soon afterwards and the

mixture was stirred at room temperature whilst monitoring by

TLC. After TLC analysis indicated consumption of the starting

diol and conversion of the intermediate dialdehyde into the cyclic

ene-acetal (ca. 12 h), the reaction mixture was diluted with acetoni-

trile, filtered through Celite, and the filtrate concentrated and puri-

fied by silica gel chromatography using heptane/EtOAc as eluent to

afford the desired half-cascade intermediate in high yields. Similar

results were obtained running the domino reaction in toluene, tri-

fluorotoluene, benzene, dichloromethane, or acetic acid. No side

products were produced.

Preparation of Acetoxy Enones 1: The acetoxylation was performed

according to the general procedure for the acetoxylation of oc-

talones on a 12 mmol (26.64 g) scale to afford the α- and β-acetates

(30.24 g, 90%) in a nearly 1:1 ratio. An analytical sample was puri-

fied on SiO₂by flash chromatography (eluent: EtOAc/heptane, 1:1).

1α-OAc: IR (film): ν = 2951, 2878, 1751, 1695, 1669, 1620, 1446,

˜

1376, 1334, 1223, 1158, 1116, 1073, 1052, 1020, 949, 916, 874 cm^–1.

¹H NMR (300 MHz): δ = 1.47 (s, 3 H), 1.53–1.94 (m, 4 H), 1.88

(dd, J = 5.6, 12.4 Hz, 1 H), 2.15 (s, 3 H), 2.21–2.46 (m, 2 H), 2.37

(t, J = 13.3 Hz, 1 H), 3.80–4.09 (m, 4 H), 5.42 (dd, J = 5.6, 14.3 Hz,

1 H), 5.79 (d, J = 1.8 Hz, 1 H) ppm. Diagnostic NOEs: {Me-10}:

H-2, H-1β eq.; {H-2}: Me-10. ¹³C NMR (75 MHz): δ = 20.5, 20.6,

21.1, 28.9, 30.7, 32.2, 46.6, 64.6, 65.1, 71.1, 111.3, 123.2, 167.2,

169.7, 192.8 ppm. ESIMS (MeOH): m/z (%) = 319 (25) [MK]⁺, 303

(100) [MNa]⁺, 281 (6) [MH]⁺. C₁₅H₂₀O₅(280.13): calcd. C 64.27,

H 7.19; found C 64.16, H 7.22.

General Experimental Procedure for Oxidation with Mn(OAc)₃: A

dry flask was charged with 1.0 mmol of diol and 4.0 mmol of

Mn(OAc)₃, then evacuated and flushed with argon several times.

Sodium-dried, degassed benzene (20 mL) was then added and the

resulting mixture was stirred at reflux, whilst removing water with

a Dean–Stark trap, until TLC monitoring showed no remaining

starting material (ca. 4 h). The cooled mixture was diluted with

EtOAc, filtered through Celite, and washed with 1 n HCl, saturated

aq. NaHCO₃, and brine. The organic layers were dried (MgSO₄),

filtered, concentrated in vacuo, and purified by silica gel flash col-

umn chromatography (eluent: heptane/EtOAc). Regardless of the

diol stereochemistry, 2-hydroxy cross-conjugated dienones were ob-

served as side products.

1β-OAc: IR (film): ν = 2953, 2876, 1750, 1695, 1669, 1620, 1334,

˜

1225, 1154, 1118, 1075, 1052, 1020, 916, 871 cm^–1. ¹H NMR

(300 MHz): δ = 1.32 (s, 3 H), 1.50–1.74 (m, 1 H), 1.62 (t, J =

13.5 Hz, 1 H), 1.79–1.92 (m, 3 H), 2.15 (s, 3 H), 2.22 (m, 1 H), 2.47

(dd, J = 2.5, 12.3 Hz, 1 H), 2.55 (dd, J = 6.6, 13.8 Hz, 1 H), 3.90–

4.20 (m, 4 H), 5.78 (dd, J = 6.6, 12.9 Hz, 1 H), 5.85 (d, J = 1.6 Hz,

1 H) ppm. Diagnostic NOEs: {Me-10}: H-1β axial (inverted half-

chair) ppm. ¹³C NMR (75 MHz): δ = 20.6, 23.3, 26.0, 30.1, 31.2,

34.3, 46.6, 64.5, 65.3, 71.6, 113.5, 122.5, 166.5, 169.7, 193.8 ppm.

ESIMS (MeOH): m/z (%) = 319 (33) [MK]⁺, 303 (100) [MNa]⁺,

281 (4) [MH]⁺. C₁₅H₂₀O₅(280.13): calcd. C 64.27, H 7.19; found

C 64.02, H 7.30.

General Experimental Procedure for Oxidation with DMP: A dry

flask was charged with the starting diol (1.0 mmol) and DMP

(2.0 mmol, 2.0 equiv.), then evacuated and flushed with argon sev-

eral times. Sodium-dried toluene (20 mL) was then added and the

reaction mixture was gently heated to 72 °C (oil bath temperature)

in about 20 min, and stirred at this temperature for 30–60 min, at

which point TLC indicated complete consumption of the starting

diol. After cooling, dilution with EtOAc, washing with a saturated

aqueous solution of sodium hydrogen carbonate and brine, drying

over MgSO₄, and concentration under reduced pressure gave crude

product which was purified on silica gel by flash column chroma-

tography (eluent: heptane/EtOAc). Depending on the diol stereo-

chemistry, 2-hydroxy cross-conjugated dienones were observed as

side products.

Preparation of Tertiary-Secondary Alcohols 2 and 5 and Their Oxi-

dative Cleavage: The tertiary-secondary alcohol 2b- cis was pre-

pared straightforwardly. THF (10 mL) and MeLi (1.5 m, 37 mL,

55.7 mmol, 12 equiv.) were added dropwise to a stirred solution of

the acetoxy enone 1β-OAc (1.30 g, 4.64 mmol) cooled to –78 °C

under argon. The reaction mixture was stirred at –78 °C for 30

minutes, quenched with sat. NH₄Cl solution, diluted with EtOAc,

and worked up as usual. Silica gel flash column chromatography

with heptane/EtOAc (3:1) as eluent afforded 1.06 g (90%) of the

desired diol.

General Experimental Procedure for Oxidation with PhI(OAc)₂: A

dry flask was charged with 1.0 mmol of unsaturated diol and

1.2 mmol of PhI(OAc)₂, then evacuated, flushed with argon several

times, and cooled to 0 °C. Acetonitrile (10 mL) was then added and

the cooling bath removed soon after. It should be pointed out that

when the reactions were run without special precautions, such as

solvent degassing, drying of the reagent, and vacuum-flushing cy-

cles, the yields were comparable. The mixture was stirred at room

temperature for 24 h (TLC monitoring), then diluted with dichloro-

methane, washed with a saturated aqueous solution of NaHCO₃,

water, and brine, and then dried and concentrated. The residue was

chromatographed on silica gel using heptane/EtOAc as eluent. No

side products were produced.

2b-cis: M.p. 144–145 °C (hexane/EtOAc). IR (film): ν = 3401, 2937,

˜

2885, 1664, 1461, 1440, 1370, 1342, 1181, 1117, 1093, 1077, 1062,

938, 872, 859 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 1.20 (s, 6 H),

1.19 (dd, J = 10.4, 14.3 Hz, 1 H), 1.41 (m, 1 H), 1.55–1.80 (m, 3

H), 1.97 (m, 1 H), 2.16 (dd, J = 4.6, 14.2 Hz, 1 H), 2.26 (m, 1 H),

2.35 (br. s, 2 H), 3.86–4.04 (m, 4 H), 3.95 (dd, J = 4.6, 10.5 Hz, 1

H), 5.37 (d, J = 1.5 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 21.6,

23.5, 25.8, 30.0, 30.2, 35.4, 45.0, 64.5, 65.0, 72.5, 73.6, 113.3, 128.5,

141.5 ppm. ESIMS (MeOH): m/z (%) = 277 (100) [MNa]⁺.

C₁₄H₂₂O₄(254.15): calcd. C 66.12, H 8.72; found C 66.31, H 8.87.

1

General Experimental Procedure for the Full-Cascade: A dry flask

was charged with unsaturated diol (1.0 mmol) and Pb(OAc)₄

(2.4 mmol), then evacuated, flushed with argon several times, and

While the initial H and ¹³C NMR characterization of 2b-cis was

done with CDCl₃as solvent, the assignment of the stereostructure

for 2b-cis was made in C₆D₆as tentative assignment of the C2/C3-

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693

S. Arseniyadis et al.

FULL PAPER

diol stereochemistry by analogy to the OtBu counterpart 5 did not-

34: [α]²_D⁰= –7 (c = 2.24, CHCl ). IR (film): ν = 2972, 2940, 2870,

˜

3

allow an unambiguous assignment for the configurations at C-2 1671, 1464, 1448, 1383, 1365, 1296, 1253, 1193, 1141, 1066, 1016,

and C-3 to be made. In both solvents the ring protons resonate 943, 875, 788 cm^–1. ¹H NMR (300 MHz): δ = 1.04 (s, 3 H), 1.18 (s,

as distinct multiplets, whereas the two methyl groups resonate as 9 H), 1.25–1.80 (m, 7 H), 1.71 (s, 3 H), 2.40 (dd, J = 5.9, 14.2 Hz,

overlapping singlets at δ = 1.20 ppm in CDCl₃and undergo a 1 H), 3.37 (dd, J = 3.5, 11.5 Hz, 1 H), 4.51 (s, 1 H), 5.61 (d, J =

solvent shift in C₆D₆such that they appear as singlets at δ = 1.31 5.8 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 12.7, 18.9, 19.8, 29.0,

and 1.40 ppm, which can be assigned to the C-10 and C-3 methyl 29.2 (3C), 29.7, 46.6, 55.2, 72.8, 73.5, 84.3, 99.0, 104.5, 146.6 ppm.

groups, respectively.

ESIMS (MeOH): m/z (%) = 305 (35) [MK]⁺, , 289 (55) [MNa]⁺,

267 (28) [MH]⁺. HRESIMS calcd. for C₁₆H₂₆NaO₃: m/z =

289.1779; found 289.1772.

¹H NMR (300 MHz, C₆D₆): δ = 1.31 (s, 3 H), 1.40 (s, 3 H), 1.46

(dd, J = 10.4, 14.3 Hz, 1 H), 1.92 (m, 1 H), 1.50–1.76 (m, 4 H),

2.06–2.2 (m, 4 H), 2.47 (dd, J = 4.6, 14.3 Hz, 1 H), 3.44–3.67

(m, 4 H), 5.53 (d, J = 1.4 Hz, 1 H) ppm. Diagnostic NOEs: {Me-

3}: H-4; {Me-10}: H-1β; {H-2}: H-1β; {H-1β}: H1; {H-4}: Me-

3, H-6 eq. ¹³C NMR (75 MHz, C₆D₆): δ = 22.5, 24.0, 25.9, 30.4,

30.9, 35.7, 45.2, 64.7, 65.0, 72.2, 74.2, 114.0, 129.0, 142.0 ppm.

Preparation and Oxidative Cleavage of 7: The gem-dimethyl sub-

strate 7 prepared using the Heathcock procedure was acetoxylated

and then reduced to the diol following the general procedures

above. Oxidative cleavage of 7 was achieved using the general pro-

cedures (see Table 1 for yields) to afford 35 [silica gel flash column

chromatography with heptane/EtOAc (8:1) as eluent].

Oxidative cleavage of 2 was achieved following the general pro-

cedures (see Table 1 for yields) to afford 32 [silica gel flash col-

umn chromatography with heptane/EtOAc (7:1) as eluent].

35: IR (film): ν = 2951, 2897, 1628, 1459, 1437, 1387, 1279, 1212,

˜

1200, 1131, 1081, 1054, 1034, 949, 915, 860, 824, 725 cm^–1. ¹H

NMR (300 MHz): δ = 0.95 (s, 3 H), 1.20 (s, 3 H), 1.25 (d, J =

1.8 Hz, 3 H), 1.30 (d, J = 15.3 Hz, 1 H), 1.39 (d, J = 14.0 Hz, 1

H), 1.52 (d, J = 14.0 Hz, 1 H), 1.79 (d, J = 13.8 Hz, 1 H), 1.86 (d,

J = 15.3 Hz, 1 H), 2.52 (ddd, J = 1.6, 5.8, 13.8 Hz, 1 H), 3.76–3.90

(m, 2 H), 3.93–4.07 (m, 2 H), 4.75 (dd, J = 1.8, 6.1 Hz, 1 H), 5.57

(d, J = 5.8 Hz, 1 H), 6.18 (dd, J = 1.6, 6.1 Hz, 1 H) ppm. ¹³C

NMR (75 MHz): δ = 17.4, 27.5, 31.1, 34.6, 40.2, 40.9, 43.2, 56.5,

62.8, 65.0, 85.0, 99.6, 110.8, 111.5, 139.7 ppm. ESIMS: m/z (%) =

266 (0.04) [M]⁺, 237 (0.03), 223 (0.20), 127 (22), 56 (30), 55 (36),

53 (26), 45 (34), 43 (54), 41 (100). ESIMS (MeOH): m/z (%) = 289

(100) [MNa]⁺. HRESIMS calcd. for C₁₅H₂₂NaO₄: m/z = 289.1416;

found 289.1410.

32: M.p. 114–115 °C (heptane/diethyl ether). IR (film): ν = 2951,

˜

1667, 1438, 1381, 1258, 1170, 1141, 1110, 1068, 1050, 1032, 996,

953, 936, 918, 892 cm^–1. H NMR (300 MHz): δ = 1.26 (s, 3 H),

1

1.28–2.03 (m, 7 H), 1.72 (s, 3 H), 2.48 (dd, J = 5.8, 13.7 Hz, 1 H),

3.84–3.91 (m, 2 H), 3.96–4.05 (m, 2 H), 4.57 (s, 1 H), 5.60 (d, J =

5.8 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 17.3, 18.4, 19.0, 28.7

(2C), 43.4, 57.2, 63.1, 65.3, 83.8, 99.6, 105.0, 111.2, 147.0 ppm.

ESIMS: m/z (%) = 252 (0.5) [M]⁺, 99 (50), 55 (30), 43 (100).

C₁₄H₂₀O₄(252.13): calcd. C 66.65, H 7.99; found C 66.95, H 8.18.

A dry flask was charged with hydroxy enone 1β-OH (400 mg,

1.6 mmol), evacuated, flushed with argon, and then cooled to

–78 °C. THF (10 mL) was added and the reaction mixture was

stirred at this temperature for 5 min, after which time a 1.5 m solu-

tion of MeLi (4.5 mL, 6.8 mmol, 4.3 equiv.) was added dropwise.

The resulting mixture was stirred at –78 °C for 30 min, then

quenched with a saturated solution of NH₄Cl, diluted with EtOAc,

and worked up as usual. Flash chromatography (eluent: heptane/

EtOAc, 3:1) afforded 365 mg (86%) of a mixture of 5-cis and 5-

trans in a nearly 1:1 ratio.

Oxidative cleavage of 7 (268 mg, 1.0 mmol) with 2.4 equiv. of lead

tetraacetate in acetic acid at room temperature for 22 h gave, after

silica gel flash column chromatography with heptane/EtOAc (4:1)

as eluent, 35 (15.6 mg, 6%) along with lactone 63 (56.4 mg, 20%)

and the ring-expanded full-cascade intermediate 64 (192.0 mg,

50%).

63: IR (film): ν = 2951, 1751, 1375, 1333, 1287, 1256, 1221, 1207,

˜

1

1129, 1073, 1044, 1000, 957 cm^–1. H NMR (300 MHz): δ = 1.04

5β-cis: M.p. 100–102 °C (heptane/EtOAc). [α]²_D⁰= –21 (c = 2.25,

(s, 3 H), 1.13 (s, 3 H), 1.14 (s, 3 H), 1.43 (d, J = 13.9 Hz, 1 H),

1.57–1.67 (m, 3 H), 2.02 (d, J = 14.6 Hz, 1 H), 2.53 (d, J = 18.0 Hz,

1 H), 2.64 (dd, J = 4.6, 14.6 Hz, 1 H), 2.72 (d, J = 18.0 Hz, 1 H),

3.80–4.10 (m, 4 H), 5.82 (d, J = 4.6 Hz, 1 H) ppm. ¹³C NMR

(75 MHz): δ = 19.0 (2C), 29.9, 32.9, 38.9, 41.8, 42.3, 45.8, 48.2,

64.1, 64.9, 87.3, 102.1, 112.2, 167.8 ppm. ESIMS: m/z (%) = 282

(0.5) [M]⁺, 127 (46), 86 (10), 69 (12), 55 (33), 43 (100). ESIMS

(MeOH): m/z (%) = 305 (100) [MNa]⁺. HRESIMS calcd. for

C₁₅H₂₂NaO₅: m/z 305.1365; found 305.1362.

CHCl ). IR (film): ν = 3401, 2973, 1659, 1469, 1362, 1231, 1190,

˜

3

1070, 1050, 1018, 967, 894, 858 cm^–1. ¹H NMR (300 MHz): δ =

1.10 (s, 3 H), 1.21 (s, 9 H), 1.31 (s, 3 H), 1.42 (dd, J = 11.6, 13.8 Hz,

1 H), 1.45–1.95 (m, 7 H), 2.12 (dd, J = 3.6, 13.8 Hz, 1 H), 2.21

(dd, J = 4.6, 13.8 Hz, 1 H), 3.20 (dd, J = 4.6, 10.9 Hz, 1 H), 3.52

(dd, J = 3.6, 11.6 Hz, 1 H), 5.31 (s, 1 H) ppm. Diagnostic NOEs:

{Me-3}: H-2, H-4; {H-2}: H-9; {H-9}: H-2. ¹³C NMR (75 MHz):

δ = 20.8, 25.6, 26.6, 29.0 (3C), 30.6, 31.1, 36.9, 42.7, 69.4, 71.0,

73.3, 74.1, 125.1, 147.9 ppm. ESIMS: m/z (%) = 268 (0.1) [M]⁺,

194 (40), 161 (24), 57 (100). C₁₆H₂₈O₃(268.20): calcd. C 71.60, H

10.52; found C 71.89, H 10.53.

64: IR (film): ν = 2956, 2894, 1755, 1704, 1673, 1583, 1369, 1211,

˜

1159, 1139, 1069, 988 cm^–1. ¹H NMR (300 MHz): δ = 1.06 (s, 3

H), 1.07 (s, 3 H), 1.40 (s, 3 H), 1.69 (d, J = 15.5 Hz, 2 H), 1.89 (d,

J = 15.5 Hz, 1 H), 2.06 (s, 3 H), 2.12 (s, 3 H), 2.43 (d, J = 11.1 Hz,

1 H), 2.46 (dd, J = 4.6, 15.5 Hz, 1 H), 2.62 (d, J = 11.1 Hz, 1 H),

2.81 (d, J = 3.9 Hz, 1 H), 3.78–4.16 (m, 4 H), 6.38 (d, J = 3.9 Hz,

1 H), 6.44 (d, J = 4.6 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ =

20.9, 21.1, 23.6, 31.6, 31.7, 32.2, 41.5, 43.9, 54.8, 56.3, 64.9, 65.1,

88.2, 92.0, 113.4, 168.9, 169.1, 205.7 ppm. ESIMS: m/z (%) = 384

(0.1) [M]⁺, 324 (0.10), 127 (55), 86 (50), 55 (45), 43 (100). ESIMS

(MeOH): m/z (%) = 407 (100) [MNa]⁺. HRESIMS calcd. for

C₁₉H₂₈NaO₈: m/z = 407.1682; found 407.1697.

5β-trans: [α]²_D⁰= –12 (c = 2.05, CHCl ). IR (film): ν = 3401, 2974,

˜

3

2935, 1651, 1469, 1388, 1363, 1246, 1188, 1068, 1017, 937, 894,

845 cm^–1. ¹H NMR (300 MHz): δ = 1.00 (s, 3 H), 1.21 (s, 9 H),

1.24 (s, 3 H), 1.50–2.00 (m, 6 H), 2.15 (bdt, J = 4.1, 12.9 Hz, 1 H),

2.27 (dd, J = 4.1, 13.9 Hz, 1 H), 2.75–3.00 (m, 2 H), 3.23 (dd, J =

4.6, 10.7 Hz, 1 H), 3.78 (dd, J = 4.1, 12.9 Hz, 1 H), 5.25 (s, 1 H)

ppm. Diagnostic NOEs: {Me-3}: H-1β, H-4; {H-2}: H-9; {H-9}:

H-2. ¹³C NMR (75 MHz): δ = 21.1, 22.0, 25.6, 29.0 (3C), 30.7,

30.8, 37.2, 43.0, 72.7, 73.3, 73.7, 73.9, 126.9, 144.0 ppm. HRESIMS

calcd. for C₁₆H₂₈NaO₃: m/z = 291.1936; found 291.1941.

Oxidative cleavage of 5 was achieved following the general pro-

cedures (see Table 1 for yields) to afford 34 [silica gel flash column

chromatography with heptane/EtOAc (8:1) as eluent].

Preparation of Unsaturated Diols 3, 8, and 9 and Their Oxidative

Cleavage: Diol 3 was obtained by reduction of acetoxy enone 1

using the general procedure for the reduction of acetoxy enones.

694

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Eur. J. Org. Chem. 2005, 683–700

Mild Protocols for Generating Molecular Complexity

FULL PAPER

Oxidative cleavage of 3 was achieved following the general pro-

cedures (see Table 1 for yields) to afford 33 [silica gel flash column

chromatography with heptane/EtOAc (4:1) as eluent].

28.4, 29.7, 31.9, 32.7, 42.9, 72.3, 75.1, 106.1, 123.5, 143.8, 156.2

ppm. ESIMS (MeOH): m/z (%) = 461 (17) [MK]⁺, 445 (100)

[MNa]⁺. HRESIMS calcd. for C₂₄H₄₆O₂NaSi₂: m/z = 445.29339;

found 445.29342.

33: M.p. 60–62 °C (heptane/diethyl ether/EtOAc). IR (film): ν =

˜

3066, 2952, 2882, 1627, 1460, 1440, 1375, 1286, 1212, 1127, 1071,

1

1047, 946, 818, 727 cm^–1. H NMR (500 MHz): δ = 1.28 (s, 3 H),

TBS Deprotection: Tetrabutylammonium fluoride (1 m in THF;

1.9 mL, 1.9 mmol) was added to the bis-TBS protected alcohol

(200 mg, 0.47 mmol) under argon, and the reaction mixture imme-

diately heated to 60 °C (oil bath) for 4 h. After cooling to room

temperature, the reaction mixture was diluted with EtOAc, and

washed with brine till neutral. Usual work up and SiO₂flash chro-

matography (heptane/EtOAc, 1:2) of the residue gave 9 (87.6 mg,

96% yield). A major component of a diastereomeric mixture (rela-

tive stereochemistry of hydroxyl group bearing carbons unassigned)

1.30–1.72 (m, 5 H), 1.80 (d, J = 13.7 Hz, 1 H), 2.00 (br. d, J =

16.0 Hz, 1 H), 2.51 (dd, J = 5.8, 13.7 Hz, 1 H), 3.88 (t, J = 6.4 Hz,

2 H), 4.00 (t, J = 6.4 Hz, 2 H), 4.81 (d, J = 6.0 Hz, 1 H), 5.59 (d,

J = 5.8 Hz, 1 H), 6.19 (d, J = 6.0 Hz, 1 H) ppm. ¹³C NMR

(125 MHz): δ = 16.9, 18.2, 28.4, 28.6, 43.3, 57.2, 63.0, 65.2, 83.8,

99.8, 110.3, 111.0, 139.6 ppm. ESIMS: m/z (%) = 238 (7) [M]⁺, 237

(9), 149 (40), 137 (51), 122 (53), 121 (87), 119 (92), 109 (100), 107

(96), 106 (70), 91 (73). C₁₃H₁₈O₄(238.12): calcd. C 65.53, H 7.61;

found C 65.54, H 7.67.

after chromatography is described.

1

9: IR (film): ν = 3352, 2925, 1636, 1461, 1376, 1056, 893 cm^–1. H

˜

Ketal deprotection of 3 (1.20 g, 5.0 mmol) in 20 mL of 10% HCl/

THF (1:1) at 0 °C for 12 h afforded, after stirring at room tempera-

ture overnight, the free keto octaline diol 8 (970.2 mg, 99%), which

was subjected to oxidative cleavage following the general pro-

cedures (see Table 1 for yields) to afford 36 [silica gel flash column

chromatography with heptane/EtOAc (4:1) as eluent].

NMR (300 MHz): δ = 1.31 (s, 3 H), 1.33–2.56 (m, 10 H), 3.84 (m,

1 H), 4.01 (dd, J = 2.0, 7.9 Hz, 1 H), 4.68 (br. s, 1 H), 4.71 (br. s,

1 H), 5.18 (d, J = 1.6 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ =

28.4, 29.7, 31.8, 32.7, 39.4, 41.2, 71.7, 74.4, 106.5, 121.2, 145.5,

153.1 ppm. ESIMS: m/z (%) = 233 (8) [MK]⁺, 217 (100) [MNa]⁺.

HRESIMS calcd. for C₁₂H₁₈NaO₂: m/z

= 217.1204; found

36: IR (film): ν = 2957, 2877, 1710, 1632, 1458, 1442, 1393, 1363,

˜

217.1203.

1312, 1279, 1260, 1214, 1135, 1101, 1061, 1002, 965, 913, 833,

771 cm^–1. H NMR (300 MHz): δ = 1.31 (s, 3 H), 1.76–2.40 (m, 4

1

Oxidative cleavage of 9 was achieved following the general pro-

cedures (see Table 1 for yields) to afford 37 [Silica gel flash column

chromatography with heptane/EtOAc (1:1) as eluent].

H), 1.86 (d, J = 14.1 Hz, 1 H), 2.01 (td, J = 1.2, 13.2 Hz, 1 H),

2.49 (dt, J = 6.2, 13.2 Hz, 1 H), 3.32 (ddd, J = 0.7, 5.9, 14.1 Hz, 1

H), 4.91 (dd, J = 0.7, 6.1 Hz, 1 H), 5.56 (d, J = 5.9 Hz, 1 H), 6.25

(dd, J = 0.9, 6.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 18.0,

20.2, 28.5, 37.1, 43.0, 64.1, 84.8, 98.7, 107.6, 140.3, 212.9 ppm.

CIMS: m/z (%) = 195 (52) [M + H]⁺, 149 (80), 137 (100), 95 (32).

HRCIMS calcd. for C₁₁H₁₅O₃: m/z = 195.1021; found 195.1023.

37: IR (film): ν = 2936, 2868, 1630, 1452, 1391, 1370, 1214, 1135

˜

1104, 1068, 1043, 1007, 993, 924, 876, 830, 724 cm^–1. ¹H NMR

(300 MHz): δ = 1.20 (s, 3 H), 1.37–1.72 (m, 3 H), 1.98 (d, J =

13.7 Hz, 1 H), 2.01–2.30 (m, 3 H), 2.82 (dd, J = 5.3, 13.7 Hz, 1 H),

4.70 (br. s, 1 H), 4.76 (d, J = 5.3 Hz, 1 H), 4.79 (br. s, 1 H), 5.51

(d, J = 5.3 Hz, 1 H), 6.15 (d, J = 5.4 Hz, 1 H) ppm. ¹³C NMR

(75 MHz): δ = 20.9, 21.3, 29.7, 32.1, 45.7, 55.9, 82.7, 98.6, 108.3,

109.4, 139.4, 152.5 ppm. ESIMS: m/z (%) = 231(5) [MK]⁺, 215

(100) [MNa]⁺. HRESIMS calcd. for C₁₂H₁₆NaO₂: m/z = 215.1048;

found 215.1043.

Functional-Group Interconversion

Preparation of the Octaline Diol 9. TBS-Protection: tert-Butyldime-

thylsilyl chloride (10.34 g, 68.6 mmol) was added to a solution of

imidazole (9.35 g, 137.3 mmol) and the alcohol (4.49 g, 22.9 mmol)

in DMF (73 mL) at room temperature (TLC monitoring). The re-

action mixture was stirred for 36 h then diluted with hexane,

washed with brine, and dried with MgSO₄. Concentration under

reduced pressure and flash chromatography (heptane/EtOAc, 9:1)

of the residue gave the title compound (8.41 g, 87% yield) as a white

solid.

Oxidative cleavage of 9 (194 mg, 1 mmol) using 2.4 equiv. of lead

tetraacetate in 5 mL of acetic acid at room temperature for 21 h

gave 61 (161.2 mg, 52%), along with the alternative full-cascade

intermediate 62 (18.6 mg, 6%), after silica gel flash column chroma-

tography with heptane/EtOAc (2:1) as eluent.

Wittig Methylenation and Desilylation: A dry flask was charged

with methyltriphenylphosphonium bromide (2.81 g, 7.9 mmol),

tBuOK (2.79 g, 23.6 mmol), and a stir bar under argon. Dry PhMe

(56 mL) was added from a syringe, and the suspension was stirred

for 1 h at room temperature. The reaction mixture was cooled to

0 °C, and a solution of the ketone (2.20 g, 5.2 mmol) in PhMe

(56 mL) was added over a few seconds. The ice bath was removed

and the reaction mixture was stirred at room temperature under

argon (TLC monitoring). After dilution with EtOAc, water

(56 mL) was added slowly, and the product was extracted with

EtOAc, the organic phase was worked up as usual. Chromatogra-

phy on silica gel eluting with heptane/EtOAc (10:1) gave 9-bis-

(OTBS) (2.06 g, 94%) along with unreacted starting material. An

analytical sample was characterized.

61: IR (film): ν = 2938, 2864, 1753, 1717, 1451, 1438, 1371, 1346,

˜

1229, 1173, 1114, 1064, 990, 944, 917, 731 cm^–1. ¹H NMR

(300 MHz): δ = 1.09–1.54 (m, 2 H), 1.37 (s, 3 H), 1.81 (d, J =

14.5 Hz, 1 H), 2.01 (s, 3 H), 2.04 (s, 3 H), 2.23–2.53 (m, 5 H), 3.16

(d, J = 3.0 Hz, 1 H), 4.72 (br. s, 1 H), 4.82 (br. s, 1 H), 6.26 (d, J

= 3.0 Hz, 1 H), 6.38 (br. d, J = 3.6 Hz, 1 H) ppm. ¹³C NMR

(75 MHz): δ = 20.9, 21.2, 28.1 (2C), 31.0, 32.9, 37.4, 45.5, 53.1,

88.1, 92.8, 111.8, 155.9, 168.9, 169.0, 207.8 ppm. ESIMS (MeOH):

m/z (%) = 349 (40) [MK]⁺, 333 (100) [MNa]⁺. HRESIMS calcd.

for C₁₆H₂₂NaO₆: m/z = 333.1314; found 333.1314.

62: IR (film): ν = 3054, 2928, 2856, 1742, 1461, 1372, 1265, 1155,

˜

1004, 938, 896, 738, 705 cm^–1. ¹H NMR (500 MHz): δ = 1.34–1.47

(m, 1 H), 1.48 (s, 3 H), 1.51–1.71 (m, 2 H), 2.13 (s, 3 H), 2.17 (s, 3

H), 2.19 (m, 1 H), 2.26 (m, 1 H), 2.32 (m, 1 H), 2.47 (d, J = 14.4 Hz,

1 H), 2.95 (dd, J = 6.4, 14.4 Hz, 1 H), 4.84 (s, 1 H), 4.89 (s, 1 H),

4.99 (s, 1 H), 5.44 (d, J = 6.2 Hz, 1 H), 5.85 (s, 1 H) ppm. ¹³C

NMR (75 MHz): δ = 20.9 (2C), 21.2, 23.5, 27.5, 32.9, 43.2, 47.4,

69.9, 85.2, 92.3, 98.3, 109.5, 154.5, 168.7, 170.0 ppm. ESIMS

(MeOH): m/z (%) = 349 (40) [MK]⁺, 333 (100) [MNa]⁺. HRESIMS

calcd. for C₁₆H₂₂O₆Na: m/z = 333.1314; found 333.1312.

9-Bis(OTBS): IR (film): ν = 3086, 2931, 2857, 1636, 1462, 1388,

˜

1361, 1253, 1211, 1093, 1062, 1006, 938, 883, 836, 775, 742,

671 cm^–1. ¹H NMR (300 MHz): δ = 0.11 (s, 6 H), 0.12 (s, 6 H),

0.93 (s, 9 H), 0.94 (s, 9 H), 1.30 (s, 3 H), 1.71–2.52 (m, 8 H), 3.84

(ddd, J = 3.2, 7.3, 11.1 Hz, 1 H), 4.05 (d, J = 7.3 Hz, 1 H), 4.64

(br. s, 1 H), 4.68 (br. s, 1 H), 5.07 (br. s, 1 H) ppm. ¹³C NMR

(75 MHz): δ = –4.7, –4.6, –3.9, –3.7, 18.1, 18.4, 26.2 (6 C), 26.8,

Eur. J. Org. Chem. 2005, 683–700

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695

S. Arseniyadis et al.

FULL PAPER

Angularly Functionalized Substrates

15β-OH: [α]²_D⁰= +46 (c = 1.3, CHCl ). IR (film): ν = 3338, 2935,

˜

3

2858, 2709, 2240, 1660, 1471, 1462, 1449, 1407, 1388, 1361, 1251,

1197, 1087, 1006, 976, 914, 836, 773, 734, 668, 644 cm^–1. ¹H NMR

(300 MHz): δ = 0.01 (s, 6 H), 0.85 (s, 9 H) 1.12–2.46 (m, 15 H),

3.49–3.61 (m, 4 H), 4.09 (m, 1 H), 5.48 (s, 1 H) ppm. ¹³C NMR

(75 MHz): δ = –5.02, –4.07, 25.4, 25.8 (3C), 26.2, 26.7, 27.2, 28.9,

30.7, 31.6, 44.1, 53.4, 63.6, 66.9, 75.8, 127.5, 143.6 ppm. ESIMS:

m/z (%) = 379 (5) [MK]⁺, 363 (100) [MNa]⁺. HRESIMS calcd. for

C₁₉H₃₆NaO₃Si: m/z = 363.2331; found 363.2339.

Preparation of the Octaline Diol 18. Determination of the Optical

Purity of 13a: Prepared according to Hanselmann and Benn,^[14]

scalemic (first obtained in ca. 80% ee) 13a (199 mg, 0.96 mmol) was

dissolved in dry CH₂Cl₂(20 mL) at 0 °C. NEt₃(976 mg, 9.6 mmol),

DMAP (236 mg, 1.9 mmol), and, 10 min later, (S)-2-acetoxypro-

pionyl chloride, (725 mg, 4.8 mmol) were then added at 0 °C. After

25 min at this temperature (TLC monitoring) the reaction mixture

was quenched with a saturated solution of aqueous NaHCO₃. Ex-

traction with CH₂Cl₂, washing with 1 n aq. HCl, NaHCO₃, water,

and brine, and finally drying with MgSO₄afforded a crude residue

which was purified on silica gel (heptane/EtOAc, 3:1) to yield a

15α-OH: [α]²_D⁰= +6 (c = 1.3, CHCl ). IR (film): ν = 3338, 2935,

˜

3

2857, 1659, 1471, 1462, 1388, 1361, 1254, 1194, 1094, 1070, 1005,

957, 931, 914, 889, 866, 834, 814, 773, 734, 666, 645 cm^–1. ¹H NMR

(300 MHz): δ = 0.00 (s, 6 H), 0.86 (s, 9 H), 1.09–2.15 (m, 14 H),

2.96 (br. s, 2 H), 3.34 (dd, J = 5.4, 9.8 Hz, 1 H), 3.44–3.65 (m, 2 H),

4.05(m, 1 H), 5.55 (d, J = 3.5 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ

= –4.9, –4.1, 18.0, 25.2, 25.8 (3 C), 26.8, 27.4, 28.0, 28.5, 31.0, 31.6,

44.0, 63.6, 65.5, 77.5, 125.8, 145.1 ppm. ESIMS: m/z (%) = 379 (12)

[MK]⁺, 363 (100) [MNa]⁺. HRESIMS calcd. for C₁₉H₃₆NaO₃Si:

m/z = 363.2331; found 363.2330.

1

mixture of lactates 14 (285 mg, 93%). Integration of the H NMR

spectrum at 800 MHz gives an acceptable optical purity (90% ee).

¹H NMR (800 MHz): δ = 1.50 (m, 1 H), 1.527 (d, J = 7.1 Hz, 3

H), 1.786 (ddd, J = 5.4, 11.3, 14.1 Hz, 1 H), 1.865 (m, 1 H), 1.940–

2.050 (m, 2 H), 2.102 (dt, J = 6.0, 14.2 Hz, 1 H), 2.15 (s, 3 H),

2.257 (m, 1 H), 2.359 (m, 1 H), 2.403 (dd, J = 8.1, 14.5 Hz, 1 H),

2.460 (dd, J = 5.5, 11.3 Hz, 1 H), 2.477 (dd, J = 5.5, 11.3 Hz, 1

H), 2.677 (dd, J = 6.7, 14.5 Hz, 1 H), 4.842 (dd, J = 4.7, 11.8 Hz,

1 H), 5.066 (q, J = 7.1 Hz, 1 H), 5.084 (d, J = 10.0 Hz, 1 H), 5.143

(d, J = 16.9 Hz, 1 H), 5.776 (dddd, J = 6.7, 8.1, 10.0, 16.9 Hz, 1

H), 5.925 (d, J = 1.6 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 16.8,

20.4, 23.4, 26.4, 30.1, 31.8, 33.7, 36.6, 43.5, 68.5, 79.4, 118.1, 127.1,

133.6, 163.8, 169.9, 170.1, 198.5 ppm. TOFESIMS: m/z (%) = 663

(18) [2MNa]⁺, 343 (100) [MNa]⁺. HRESIMS calcd. for

C₁₈H₂₄NaO₅: m/z = 343.1521; found 343.1531.

Selective allylic oxidation was achieved by adding 3,5-DMP

(631 mg, 6.6 mmol) and PCC (1.28 g, 6.0 mmol) to a stirred a solu-

tion of 15α,β (1.02 g, 3.0 mmol) in CH₂Cl₂at 0 °C. The reaction

mixture was stirred at 0 °C for 40 min, then diluted with CH₂Cl₂

and worked up as usual. Silica gel flash column chromatography

with heptane/EtOAc (1:4) as eluent afforded the desired enone 16a

(0.63 g, 62%), along with some enone aldehyde, which could be

easily recycled.

16a: [α]²_D⁰= +52 (c = 1.14, CHCl ). IR (film): ν = 3420, 2937, 2859,

TBS Protection: tert-Butyldimethylsilyl chloride (4.834 g,

˜

3

1660, 1558, 1495, 1457, 1255, 1099, 832, 774 cm^–1. ¹H NMR

(300 MHz): δ = 0.01 (s, 6 H), 0.85 (s, 9 H), 1.04–2.29 (m, 12 H),

2.10–2.43 (m, 3 H), 3.46–3.65 (m, 3 H), 5.81 (s, 1 H) ppm. ¹³C

NMR (75 MHz): δ = –5.0 (2 C), 17.9, 24.0, 25.7 (3 C), 27.7, 27.9,

30.4 (2 C), 32.4, 34.2, 45.2, 63.1, 78.1, 126.1, 168.1, 199.7 ppm.

ESIMS: m/z (%) = 377 (17) [MK]⁺, 361 (100) [MNa]⁺, 339 (98)

[MH]⁺. HRESIMS calcd. for C₁₉H₃₄NaO₃Si: m/z = 361.2174;

found 361.2179.

32.0 mmol) was added to

a solution of imidazole (4.36 g,

64.1 mmol) and the alcohol (3.30 g, 16.0 mmol) in DMF (25 mL)

at 0 °C (TLC monitoring). After 6 h, one more equivalent of tert-

butyldimethylsilyl chloride (2.42 g) was added. The reaction mix-

ture was stirred for 36 h then diluted with CH₂Cl₂, washed with

1 n HCl, sat. NaHCO₃, and brine, and dried with MgSO₄. Concen-

tration under reduced pressure and flash chromatography (heptane/

AcOEt, 9:1) of the residue gave 4.30 g (84%) of 13b. [α]²_D⁰= +77 (c

= 1.19, CHCl ). IR (film): ν = 3412, 3076, 2953, 2856, 2357, 1686,

˜

3

TBS Protection: Proceeding as above, tert-butyldimethylsilyl chlo-

ride (1.03 g, 6.8 mmol) was added to a solution of imidazole

(931 mg, 13.7 mmol) and the alcohol (1.16 g, 3.4 mmol) in DMF

(25 mL) at 0 °C (TLC monitoring). The reaction mixture was

stirred at 0 °C for 1 h 35 min then diluted with CH₂Cl₂, washed

with 1 n HCl, sat NaHCO₃, and worked up as usual. SiO₂flash

chromatography (heptane/AcOEt, 5:1) of the residue gave 1.41 g

1683, 1674, 1661, 1651, 1634, 1622, 1615, 1471, 1463, 1455, 1435,

1389, 1360, 1330, 1252, 1221, 1193, 1098, 1005, 911, 867, 835, 814,

773, 667 cm^–1. ¹H NMR (300 MHz): δ = 0.06 (s, 6 H), 0.91 (s, 9

H), 1.24–1.47 (m, 2 H), 1.73–1.96 (m, 4 H), 2.12–2.59 (m, 6 H),

3.53 (t, J = 7.6 Hz, 1 H), 5.02 (t, J = 10.0 Hz, 1 H), 5.09 (d, J =

16.9 Hz, 1 H), 5.82 (m, 1 H), 5.86 (s, 1 H) ppm. ¹³C NMR

(75 MHz): δ = –5.1, –4.1, 17.9, 23.7, 25.7 (3C), 30.6, 31.6, 32.3,

34.3, 36.3, 45.4, 78.5, 117.2, 126.5, 135.1, 166.4, 199.5 ppm. ES-

IMS: m/z (%) = 320 (0.5) [M]⁺, 222 (76), 221 (46), 171 (22), 143

(13), 129 (21), 115 (13), 91 (20), 75 (99), 73 (100), 59 (21), 45 (13),

41 (33). HRESIMS calcd. for C₁₉H₃₂NaO₂Si: m/z = 343.2069;

found 343.2075.

(91%) of 16b. [α]²_D⁰= +43 (c = 1.66 CHCl ). IR (film): ν = 2929,

˜

3

1684, 1653, 1472, 1361, 1256, 1191, 1102, 1003, 940, 831, 774,

668 cm^–1. ¹H NMR (300 MHz): δ = 0.03 (s, 6 H), 0.04 (s, 6 H),

0.88 (s, 9 H), 0.89 (s, 9 H), 1.16–2.40 (m, 14 H), 3.50–3.64 (m, 3

H), 5.85 (s, 1 H) ppm. ¹³C NMR (75 MHz): δ = –5.0 (2C), –4.0

(2C), 17.2 (2C), 24.1, 25.1 (6C), 27.9 (2C), 30.5, 32.4, 34.4, 45.3,

63.4, 68.4, 78.1, 126.3, 167.8, 199.6 ppm. ESIMS: m/z (%) = 491

(8) [MK]⁺, 475 (24) [MNa]⁺, 453 (100) [MH]⁺. HRESIMS calcd.

for C₂₅H₄₈NaO₃Si₂: m/z = 475.3039; found 475.3032.

Hydroboration-oxidation was carried out using standard literature

techniques. Hydroboration was achieved by dropwise addition of

BH₃·Me₂S (7.3 mL, 14.7 mmol) to 13b (3.14 g, 9.8 mmol) in hep-

tane (48 mL) under argon at 0 °C. Following the addition of the

hydride the cooling bath was removed and the solution stirred for

2.5 h. EtOH (48 mL) was then added followed by careful addition

of 3 n NaOH (5 L, 14.7 mmol). After cooling to 0 °C in an ice-

water bath, hydrogen peroxide (30% aqueous solution; 5 mL,

1.50 g, 44 mmol) was added at such a rate that the reaction mixture

warmed to 25–35 °C. Immediately afterwards the cooling bath was

removed and the mixture heated at reflux for 1.5 h. Extraction with

EtOAc and usual work up followed by silica gel flash column chro-

matography with heptane/EtOAc (1:1) as eluent afforded 2.59 g

(78%) of 15α-OH and 15β-OH.

Acetoxylation, performed on a 12 mmol (5.42 g) scale according to

the general procedure, afforded the α- and β-acetates 17 {4.41 g,

72%; IR (film): ν = 2932, 2858, 1750, 1698, 1623, 1470, 1369, 1254,

˜

1191, 1108, 1006, 940, 836 cm^–1. ESIMS: m/z (%) = 549 (22) [MK]⁺,

533 (100) [MNa]⁺} which were used as such in the subsequent re-

duction to the diol 18 (4.06 g, 99%), using the general procedure

for acetoxy enone reduction.

18: IR (film): ν = 3390, 2926, 2856, 1738, 1469, 1362, 1254, 1093,

˜

1

957, 912, 872, 836 cm^–1. H NMR (300 MHz): δ = 0.05 (s, 12 H),

0.90 (s, 18 H), 1.30–2.18 (m, 13 H), 3.47 (dd, J = 5.6, 9.9 Hz, 1 H),

696

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Mild Protocols for Generating Molecular Complexity

FULL PAPER

3.57 (m, 3 H), 3.94 (m, 1 H), 4.08 (m, 1 H), 5.58 (d, J = 3.8 Hz, 1

H) ppm. ¹³C NMR (300 MHz): δ = –5.3 (2 C), –4.8, –4.0, 18.3 (2

C), 24.3, 25.9 (6 C), 27.9, 28.3, 30.8, 31.2, 37.0, 45.8, 63.8, 66.5,

68.0, 80.7, 122.1, 147.0 ppm. ESIMS (MeOH): m/z (%) = 509 (5)

[MK]⁺, 493 (27) [MNa]⁺. HRESIMS calcd. for C₂₅H₅₀NaO₄Si₂:

m/z = 493.3145; found 493.3149.

(250 MHz): δ = 1.04 (s, 3 H), 1.15 (s, 9 H), 1.60–1.90 (m, 2 H),

1.90 (d, J = 14.3 Hz, 1 H), 2.00–2.20 (m, 1 H), 2.37 (dd, J = 5.0,

14.3 Hz, 1 H), 2.85–3.05 (m, 1 H), 3.68 (s, 3 H), 3.85 (t, J = 8.0 Hz,

1 H), 5.72 (d, J = 5.0 Hz, 1 H), 7.44 (s, 1 H) ppm. ¹³C NMR

(62.5 MHz): δ = 13.9, 25.2, 28.8 (3C), 33.0, 48.2, 50.9, 62.9, 72.5,

78.7, 93.7, 102.2, 110.0, 153.2, 165.5 ppm. ESIMS: m/z (%) = 296

(14) [M⁺], 196 (77), 154 (99), 57 (100). HREIMS calcd. for

C₁₆H₂₄O₅: m/z = 296.1624; found 296.1629.

Oxidative cleavage of 18 was achieved using the general procedures

(see Table 1 for yields) to afford 40 [silica gel flash column chroma-

tography with heptane/diethyl ether (1:1) as eluent]. [α]²_D⁰= +9 (c

Preparation and Domino Reactions of the Allyl-Substituted Sub-

strates 11 and 12: The procedures used for the synthesis of 26^[13e]

was repeated and allyl-functionalized bicyclic unsaturated diols 11

and 12 were synthesized from 10 by way of the intermediate dienol

acetate species. Installation of the allylic hydroxy group was then

carried out by treatment with methyltrioxorhenium and its protec-

tion was performed without separation of the major and minor

isomers with TMSOTf (trimethylsilyl trifluoromethanesulfonate) in

the presence of collidine. The required unsaturated diols 11 and 12

were then prepared using the general procedure for reduction of

acetoxy enones. Silica gel flash column chromatography with hep-

tane/EtOAc (1:1) as eluent afforded pure 11 (slower eluting) and

12 (faster eluting).

= 2.0, CHCl ). IR (film): ν = 2929, 2856, 1630, 1471, 1388, 1256,

˜

3

1095, 934, 835 cm^–1. ¹H NMR (300 MHz): δ = 0.05 (s, 12 H), 0.88

(s, 9 H), 0.90 (s, 9 H), 1.13–1.96 (m, 10 H), 2.08 (d, J = 14.2 Hz, 1

H), 2.30 (dd, J = 5.7, 14.2 Hz, 1 H), 3.49–3.59 (m, 2 H), 3.64 (dd,

J = 4.0, 11.4 Hz, 1 H), 4.78 (d, J = 6.1 Hz, 1 H), 5.64 (d, J =

5.5 Hz, 1 H), 6.17 (d, J = 6.1 Hz, 1 H) ppm. ¹³C NMR (75 MHz):

δ = –5.2 (2 C), –4.8, –4.0, 18.0, 18.3, 19.8, 24.1, 26.0 (6 C), 29.3,

30.6, 31.6, 44.7, 58.4, 64.22, 76.6, 84.8, 99.5, 109.9, 139.4 ppm.

ESIMS: m/z (%) = 507 (18) [M + K]⁺, 491 (100) [M + Na]⁺. HRES-

IMS calcd. for C₂₅H₄₈NaO₄Si₂: m/z = 491.2989; found 491.2991.

Oxidative cleavage of 18 (0.94 g, 2 mmol) with 2.4 equiv. of lead

tetraacetate in acetic acid (10 mL) at room temperature for 19 h

gave 60 (609 mg, 52%), along with the half-cascade intermediate 40

(205 mg, 22%), after silica gel flash column chromatography with

heptane/EtOAc (5:1) as eluent.

11: M.p. 179–181 °C (heptane/diethyl ether). IR (film): ν = 3371,

˜

2975, 1454, 1389, 1365, 1254, 1190, 1076, 1045, 998, 921, 890,

841 cm^–1. ¹H NMR (300 MHz): δ = 0.13 (s, 9 H), 1.12 (s, 3 H),

1.17 (s, 9 H), 1.20–1.34 (m, 3 H), 1.42 (t, J = 12.7 Hz, 1 H), 1.55–

1.92 (m, 3 H), 1.99 (dd, J = 3.4, 12.7 Hz, 1 H), 3.10 (dd, J = 4.3,

11.2 Hz, 1 H), 3.62–3.72 (m, 1 H), 4.04–4.15 (m, 2 H), 5.58 (s, 1

H) ppm. Diagnostic NOEs: {Me-10}: H-2, H-6, H-1eq; {H-2}: H-

1 eq., Me-10; {H-6 + H-3}: Me-10. ¹³C NMR (75 MHz): δ = –0.02

(3 C), 19.4, 28.6, 29.2 (3 C), 33.8, 43.2, 43.9, 68.7, 71.6, 73.2, 74.8,

78.0, 120.0, 146.3 ppm. TOFESIMS: m/z (%) = 365 (100) [MNa]⁺.

HRESIMS calcd. for C₁₈H₃₄O₄Si: m/z = 365.2124; found 365.2124.

C₁₈H₃₄O₄Si (342.22): calcd. C 63.11, H 10.00; found C 63.10, H

10.19.

60: [α]²_D⁰= –4 (c = 1.59, CHCl ). IR (film): ν = 2930, 2858, 1765,

˜

3

1692, 1472, 1368, 1257, 1074, 949, 835, 774 cm^–1. ¹H NMR

(300 MHz): δ = 0.05 (s, 12 H), 0.88 (s, 9 H), 0.89 (s, 9 H), 1.22–

2.02 (m, 7 H), 2.07 (s, 3 H), 2.08 (s, 3 H), 2.30 (dd, J = 2.6, 13.9 Hz,

1 H), 2.49–2.59 (m, 2 H), 2.81 (d, J = 3.8 Hz, 1 H), 3.50–3.70 (m,

3 H), 3.91 (s, 1 H), 4.26 (dd, J = 4.5, 8.8 Hz, 1 H), 6.27 (dd, J = 2.6,

7.2 Hz, 1 H), 6.43 (d, J = 3.8 Hz, 1 H) ppm. ¹³C NMR: (75 MHz): δ

= –5.3, –5.2 (2 C), –4.0, 18.1, 18.2, 20.3, 20.9 (2 C), 25.9 (6 C),

27.3, 31.9, 33.6, 33.8, 40.8, 44.5, 56.3, 63.4, 75.3, 88.8, 91.7, 168.3,

168.9, 208.6 ppm. ESIMS: m/z (%) = 625 (32) [MK]⁺, 609 (100)

[MNa]⁺. HRESIMS calcd. for C₂₉H₅₄NaO₈Si₂: m/z = 609.32548;

found 609.32541.

12: M.p. 131–133 °C (heptane/diethyl ether). IR (film): ν = 3369,

˜

2973, 1458, 1387, 1362, 1250, 1191, 1074, 1041, 999, 966, 923, 891,

840 cm^–1. ¹H NMR (300 MHz): δ = 0.06 (s, 9 H), 1.17 (s, 9 H),

1.26 (s, 3 H), 1.35 (t, J = 12.9 Hz, 1 H), 1.43 (m, 1 H), 1.53 (br.

dd, J = 3.2, 13.1 Hz, 1 H), 1.72 (br. dd, J = 2.8, 13.6 Hz, 1 H),

1.93 (dd, J = 3.2, 12.6 Hz, 1 H), 1.97 (m, 1 H), 2.80 (br. s, 2 H),

3.05 (dd, J = 3.8, 11.4 Hz, 1 H), 3.74 (ddd, J = 3.5, 8.1, 11.6 Hz,

1 H), 3.99 (d, J = 7.8 Hz, 1 H), 4.08 (t, J = 3.3 Hz, 1 H), 5.33 (s,

1 H) ppm. Diagnostic NOEs: {Me-10}: H-2, H-1 eq.; {H-2}: Me-

10. ¹³C NMR (75 MHz): δ = 0.3 (3 C), 20.6, 24.9, 29.2 (3 C), 32.7,

42.7, 44.6, 71.4, 72.3, 73.0, 74.5, 78.8, 126.2, 145.8 ppm. ESIMS:

m/z (%) = 342 (0.6) [M]⁺, 268 (12), 230 (10), 229 (45), 228 (25), 211

(66), 210 (30), 193 (25), 75 (20), 73 (24), 57 (100), 41 (42).

C₁₈H₃₄O₄Si (342.22): calcd. C 63.11, H 10.00; found C 63.03, H

10.21.

Oxidative Cleavage of 21: Obtained as a diastereomeric mixture

from an intermediate used in our previous work, unsaturated diol

21 was subjected to oxidative cleavage, using the general procedures

(see Table 1 for yields), without prior diastereomeric separation.

Silica gel flash column chromatography with heptane/EtOAc (4:1)

as eluent afforded 43. IR (film): ν = 3024, 2971, 2944, 2864, 1656,

˜

1457, 1450, 1390, 1364, 1224, 1145, 1111, 1085, 1025, 1005, 972,

965, 925, 753 cm^–1. ¹H NMR (300 MHz): δ = 1.05 (s, 3 H), 1.19 (s,

9 H), 1.20–1.40 (m, 2 H), 1.54 (d, J = 1.5 Hz, 3 H), 1.55–1.80 (m,

4 H), 1.82 (d, J = 14.2 Hz, 1 H), 2.43 (dd, J = 5.7, 14.2 Hz, 1 H),

3.35 (dd, J = 3.6, 11.6 Hz, 1 H), 5.61 (d, J = 5.7 Hz, 1 H), 6.01 (d,

J = 1.5 Hz, 1 H) ppm. ¹³C NMR (75 MHz): δ = 12.8, 15.4, 19.6,

26.5, 29.3 (3C), 30.0, 46.7, 55.9, 72.8, 73.7, 86.1, 98.8, 115.1, 134.8

ppm. ESIMS: m/z (%) = 266 (100) [M]⁺, 211 (6), 210 (30), 209 (19),

166 (95), 57 (98). HREIMS calcd. for C₁₆H₂₆O₃: m/z = 266.18818;

found 266.1882.

Oxidative cleavage of 11 was achieved using the general procedures

(see Table 1 for yields) to afford 38 [silica gel flash column chroma-

tography with heptane/diethyl ether (8:1) as eluent]. IR (film): ν =

˜

2967, 2872, 1639, 1463, 1389, 1377, 1363, 1250, 1212, 1197, 1144,

1126, 1090, 1070, 1049, 1033, 994, 967, 933, 919, 869, 840 cm^–1. ¹H

NMR (300 MHz): δ = 0.14 (s, 9 H), 1.09 (s, 3 H), 1.17 (s, 9 H),

1.34–1.51 (m, 1 H), 1.60–1.92 (m, 3 H), 1.86 (dd, J = 1.0, 14.2 Hz,

1 H), 2.40 (dd, J = 5.9, 14.2 Hz, 1 H), 3.39 (dd, J = 3.8, 11.6 Hz,

1 H), 3.59 (dd, J = 5.1, 11.6 Hz, 1 H), 4.77 (d, J = 6.4 Hz, 1 H),

5.65 (d, J = 5.6 Hz, 1 H), 6.24 (d, J = 6.4 Hz, 1 H) ppm. ¹³C NMR

(75 MHz): δ = 0.5 (3 C), 12.6, 28.8, 28.9, 29.2 (3 C), 46.8, 57.7,

71.3, 72.8, 73.1, 86.0, 99.4, 108.4, 140.3 ppm. ESIMS: m/z (%) =

340 (0.3) [M]⁺, 238 (15), 194 (19), 175 (19), 151 (21), 150 (45), 137

(25), 95 (46), 73 (68), 57 (100), 41 (47). TOFESIMS: m/z (%) = 363

Diol 22 was obtained in 69% yield from its corresponding acetoxy

enone^[9]by a Luche reduction (NaBH₄/CeCl₃, 0 °C, 30 min) and

used as a crude diastereomeric mixture for the next operation. This

unsaturated diol, belonging to the hydrindene diol series, was incor-

porated into this study because the tricyclic enol ether intermediate

is stable and easily isolable.

Oxidative Cleavage of 22: Oxidative cleavage using the general pro-

cedures (see Table 1 for yields) afforded 44. [α]²_D⁰= –75 (c = 1.01,

CHCl ). IR (film): ν = 3021, 2976, 2953, 2360, 1701, 1604,

˜

3

1438, 1216, 1186, 1146, 1103, 1071, 1026 cm^–1. ¹H NMR

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S. Arseniyadis et al.

FULL PAPER

(100) [MNa]⁺; 703 (96) [2M + Na]⁺. HRESIMS (MeOH) calcd.

1

1675, 1653, 1458, 1362, 1205, 1153, 1074, 871, 755 cm^–1. H NMR

for C₁₈H₃₂NaO₄Si: m/z = 363.1967; found 363.1968.

(300 MHz): δ = 0.78 (s, 3 H), 1.12 (s, 9 H), 1.30 (s, 3 H), 0.79–2.57

(m, 15 H), 2.26 (s, 3 H), 3.35 (t, J = 7.8 Hz, 1 H), 6.11 (s, 1 H),

6.73 (s, 1 H) ppm. ¹³C NMR (75 MHz): δ = 11.5, 19.0, 20.4, 22.5,

23.8, 28.5 (3C), 30.9, 32.2, 33.0, 35.1, 36.6, 42.5, 44.6, 49.8, 52.7,

72.1, 80.3, 123.2, 141.3, 144.2, 168.4, 169.2, 179.0 ppm. ESIMS:

m/z (%) = 400 (1) [M]⁺, 137 (25), 57 (100). C₂₅H₃₆O₄(400.26):

calcd. C 74.96, H 9.06; found C 74.89, H 9.14.

Oxidative cleavage of 12 was achieved using the general procedures

(see Table 1 for yields) to afford 39 [silica gel flash column chroma-

tography with heptane/diethyl ether (8:1) as eluent]. IR (film): ν =

˜

2972, 2923, 1631, 1461, 1387, 1378, 1362, 1251, 1197, 1135, 1111,

1081, 1067, 1040, 947, 843 cm^–1. ¹H NMR (400 MHz): δ = 0.09 (s,

9 H), 1.17 (s, 3 H), 1.20 (s, 9 H), 1.47 (m, 1 H), 1.58 (m, 1 H), 1.80

(d, J = 14.2 Hz, 1 H), 1.75–1.83 (m, 2 H), 2.43 (dd, J = 14.2,

5.8 Hz, 1 H), 3.34 (dd, J = 11.0, 3.7 Hz, 1 H), 3.90 (t, J = 2.4 Hz,

1 H), 5.22 (d, J = 6.2 Hz, 1 H), 5.58 (d, J = 5.7 Hz, 1 H), 6.22 (d,

J = 6.2 Hz, 1 H) ppm. Diagnostic NOEs: {Me-10}: H-1β; {H-1α}:

H-1β, H-9; {H-9}: H-1α, H-7α; {H-6}: H-4, H-7α, H-7β. ¹³C NMR

(75 MHz): δ = 0.3 (3 C), 13.1, 24.2, 28.6, 29.3 (3 C), 29.8, 47.3,

68.7, 73.0, 73.7, 84.7, 99.6, 108.0, 139.6. TOFESIMS: m/z (%) =

363 (100) [MNa]⁺; 703 (88) [2M + Na]⁺. HRESIMS (MeOH)

calcd. for C₁₈H₃₂NaO₄Si: m/z = 363.1967; found 363.1966.

The above procedure was repeated with 19β-trans (249 mg,

1.0 mmol) to give 48 (241 mg, 84%) after silica gel flash column

chromatography with heptane/EtOAc (6:1) as eluent. M.p. 155–

157 °C (heptane/diethyl ether). [α]²_D⁰= –78 (c = 1.01, CHCl₃). IR

(film): ν = 2964, 2894, 2235, 1767, 1678, 1659, 1617, 1462, 1440,

˜

1

1371, 1206, 1148, 896 cm^–1. H NMR (300 MHz): δ = 0.83 (d, J =

6.6 Hz, 3 H), 0.87 (d, J = 6.4 Hz, 3 H), 1.22–1.39 (m, 1 H), 1.47

(3 , 3 H), 1.57–1.68 (m, 1 H), 2.02 (dt, J = 4.4, 13.3 Hz, 1 H), 2.11–

2.21 (m, 1 H), 2.23 (s, 3 H), 2.53 (d, J = 3.8 Hz, 2 H), 2.64 (dd, J

= 4.0, 13.1 Hz, 1 H), 6.13 (s, 1 H), 6.36 (s, 1 H) ppm. ¹³C NMR

(75 MHz): δ = 20.3 (2C), 20.5, 20.7, 25.5, 27.1, 33.6, 34.5, 41.0,

41.8, 118.9, 126.8, 138.1, 145.1, 160.5, 168.1, 178.1 ppm. ESIMS

(MeOH): m/z (%) = 326 (72) [MK]⁺, 310 (83) [MNa]⁺, 288 (100)

[MH]⁺. C₁₇H₂₁NO₃(287.15): calcd. C 71.06, H 7.37; found C

70.99, H 7.51.

Identification of the Side Products Obtained by Mn(OAc)₃- and

Dess–Martin Periodinane-Mediated Oxidative Cleavage: The for-

mer oxidant produced side products regardless of the substrate’s

stereochemistry, while the latter produced them as the only new

products starting from the trans diols, although not at all starting

from cis-diols. We will first describe the stepwise preparation of 2-

hydroxy cross-conjugated dienone 51, which exists exclusively in its

keto-enol form, and its subsequent acetylation into 55, and then

the one-pot procedure leading directly to the 2-acetoxy cross-conju-

gated derivatives.

Oxidative Cleavage of 23a with Sodium Bismuthate: Using the pro-

cedure of Watt,^[33]NaBiO₃(1.231 g, 4.39 mmol) was added to 23-

α (535 mg, 2.1 mmol) in 21 mL of 50% aqueous AcOH. The mix-

ture was stirred at room temperature for 19 h, diluted with EtOAc,

and worked up as usual. The product was chromatographed on

silica gel with heptane/EtOAc (1:1) as eluent to afford half-cascade

45 (79.4 mg, 15%), dialdehyde 57 (26.5 mg, 5%), starting material

23-α (149.8 mg, 28%), and 58 (249 mg, 44%; anomeric mixture).

The latter was acetylated for characterization. A mixture contain-

ing 58 (210 mg, 0.78 mmol), 2.5 mL of pyridine, 2.5 mL of Ac₂O,

and a catalytic amount of DMAP was stirred at room temperature

whilst monitoring by TLC. The corresponding acetate 59 (241 mg)

was obtained in nearly quantitative yield after silica gel flash chro-

matography (eluent: heptane/EtOAc, 4:1). The stereochemistry of

Using the general procedure for the Dess–Martin periodinane-me-

diated oxidative cleavage, 25α-trans (664 mg, 2 mmol) afforded 51

(465 mg, 71%) and the allylic oxidation product, the acyloin 50

(99 mg, 15%), after silica gel flash column chromatography on sil-

ica gel with heptane/EtOAc (7:1) as eluent.^[13e,19]

51: M.p. 146–147 °C (hexane/diethyl ether). [α]²_D⁰= +3 (c = 0.98,

CHCl ). IR (film): ν = 3379, 2972, 2937, 2851, 1644, 1428, 1360,

˜

3

1304, 1251, 1227, 1194, 1074, 884 cm^–1. H NMR (300 MHz): δ =

1

0.78 (s, 3 H), 1.12 (s, 9 H), 1.24 (s, 3 H), 0.81–2.02 (m, 13 H), 2.35–

2.53 (m, 2 H), 3.35 (t, J = 7.8 Hz, 1 H), 6.17 (s, 1 H), 6.33 (s, 2 H)

ppm. ¹³C NMR (75 MHz): δ = 11.5, 19.6, 22.8, 23.8, 28.6 (3C),

31.0, 32.7, 33.4, 35.2, 36.7, 42.6, 44.0, 49.9, 53.8, 72.1, 80.3, 120.9,

124.5, 146.0, 173.0, 181.4 ppm. ESIMS: m/z (%) = 358 (6) [M]⁺,

302 (8), 147 (20), 137 (60), 57 (100). C₂₃H₃₄O₃(358.25): calcd. C

77.05, H 9.56; found C 76.61, H 9.61.

the major acetate is as depicted in Scheme 7). IR (film): ν = 2969,

˜

2931, 2864, 1752, 1365, 1246, 1232, 1164, 1150, 1052, 1036, 941,

875 cm^–1. ¹H NMR (600 MHz): δ = 1.10 (s, 3 H), 1.18 (s, 9 H),

1.29 (m, 1 H), 1.36 (dd, J = 5.5, 14.3 Hz, 1 H), 1.51 (m, 1 H), 1.56

(dt, J = 3.6, 13.4 Hz, 1 H), 1.66 (dd, J = 9.4, 13.6 Hz, 1 H), 1.72

(m, 1 H), 1.84 (m, 1 H), 1.87 (d, J = 15.0 Hz, 1 H), 1.91 (dd, J =

4.3, 13.6 Hz, 1 H), 2.09 (s, 3 H), 2.38 (dd, J = 6.3, 15.0 Hz, 1 H),

3.25 (dd, J = 3.5, 11.6 Hz, 1 H), 5.47 (d, J = 6.3 Hz, 1 H), 6.16

(dd, J = 4.3, 9.3 Hz, 1 H) ppm. ¹³C NMR (150 MHz): δ = 12.7,

19.6, 21.1, 29.4 (3C), 29.6, 32.0, 39.1, 43.8, 46.7, 73.1, 75.9, 85.2,

88.2, 98.7, 169.5 ppm. ESIMS: m/z (%) = 312 (16) [M]⁺, 253 (8),

252 (10), 197 (16), 196 (54), 195 (18), 179 (26), 178 (52), 150 (100),

59 (46). HREIMS calcd. for C₁₇H₂₈O₅: m/z = 312.1937; found

312.1941.

The 2-hydroxy cross-conjugated dienone 51 (143 mg, 0.6 mmol,

1 equiv.) was further acetylated with Ac₂O (2.70 g, 26.5 mmol,

2.5 mL) in the presence of DMAP (143 mg, 1.12 mmol, 2 equiv.),

in pyridine (2.93 g, 37.1 mmol, 3.0 mL) under argon at 0°C. Fol-

lowing stirring for 55 min, dilution with EtOAc and usual work up

furnished 55 (201.6 mg, 84%) after silica gel flash column chroma-

tography with heptane/EtOAc (6:1) as eluent,.

Experimental Procedure for the “One-Pot” Formation of 2-Acetoxy-

1,4-dien-3-one: Proceeding as above, 25α-trans (362 mg, 1.0 mmol)

and DMP (852 mg, 2.0 mmol) in sodium-dried toluene (20 mL)

were gently heated to 72 °C over 20 min and then stirred at this

temperature for 30 min (TLC monitoring). After cooling the yellow

suspension to 0 °C DMAP (242 mg, 1.6 mmol), pyridine (6 mL),

and Ac₂O (4 mL) were added and the reaction mixture was stirred

at 0 °C for 2 h. Dilution with diethyl ether, washing with 1 n HCl

and saturated aq. NaHCO₃solution, and usual work up gave 55

(344 mg, 86%) after silica gel flash column chromatography (eluent:

heptane/EtOAc, 4:1). M.p. 177–178 °C (heptane/diethyl ether).

Acknowledgments

Dr. J. I. Martin Hernando, Dr. M. Rico Ferreira, and Mr. E. Alti-

nel are gratefully acknowledged for their participation in the initial

steps of this study. The authors thank the European Commission

for a Research Training Grant to J. I. Candela Lena and Professor

Jean-Yves Lallemand for his kind interest and constant encourage-

ment.

[α]_D²⁰= +22 (c = 1.1, CHCl ). IR (film): ν = 2971, 2936, 2851, 1769,

˜

3

698

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Eur. J. Org. Chem. 2005, 683–700

Mild Protocols for Generating Molecular Complexity

FULL PAPER

[17]

[18]

“the first stereogenic center must be introduced catalytically,

[1]

Tietze proposed the following definition: “a domino reaction is

a process involving two or more bond-forming transformations

(usually C–C bonds) which take place under the same reaction

conditions without adding additional reagents and catalysts,

and in which the subsequent reactions result as a consequence

of the functionality formed in the previous step.” a) L. F.

Tietze, U. Beifuss, Angew. Chem. Int. Ed. Engl. 1993, 32, 131–

163; b) L. F. Tietze, Chem. Rev. 1996, 96, 115–136; c) L. F.

Tietze, A. Modi, Med. Res. Rev. 2000, 20, 304–322; d) L. F.

Tietze, F. Haunert, in Stimulating Concepts in Chemistry (Eds.:

M. Shibasaki, J. F. Stoddart, F. Vögtle), Wiley-VCH,

Weinheim, 2000, p. 39–64.

a) R. Criegee, Chem. Ber. 1931, 64, 260–266; b) R. Criegee,

Angew. Chem. 1958, 70, 173; c) R. Criegee, in Oxidation in

Organic Chemistry (Ed.: K. B. Wiberg), Part A, Academic

Press, New York, 1965, p. 277.

For cleavage of 1,2-glycols, see: a) M. L. Malaprade, Bull. Soc.

Chim. Fr. 1928, 43, 683–696; b) W. Rigby, J. Chem. Soc. 1950,

1907–1913.

and the process must be elegant, efficient, and non-polluting”.^[1]

W. Rigby, J. Chem. Soc. 1950, 1907; Rigby has defined the

efficiency of such reagents as oxidants “which concern elements

which (a) can reasonably be envisaged as capable of forming a

preliminary cyclic compound with the glycol, and (b) exist in

two stable oxidation states which are two valency units apart,

the lower representing a substance which is not an oxidizing

agent under ordinary conditions (Pb^II, Bi^III) or which no

–

longer fulfils condition (a) (the IO₃ion)”.

[19]

[20]

Preliminary notes a) J. I. Candela Lena, M. Rico Ferreira, J. I.

Martín Hernando, E. Altınel, S. Arseniyadis, Tetrahedron Lett.

2001, 42, 3179–3182; b) J. I. Candela Lena, J. I. Martín Her-

nando, M. Rico Ferreira, E. Altınel, S. Arseniyadis, Synlett

2001, 597–600; c) J. I. Candela Lena, E. Altınel, N. Birlirakis,

S. Arseniyadis, Tetrahedron Lett. 2002, 43, 1409–1412.

J. I. Candela Lena, J. I. Martín Hernando, M. Rico Ferreira, E.

Altınel, S. Arseniyadis, Synlett 2001, 597–600. We opted to use

DMP rather than IBX as oxidant due to the much better solu-

bility of the former and the ease of its preparation.

[2]

[3]

[4]

[5]

S. Arseniyadis, D. V. Yashunsky, L. Toupet, Q. Wang, P. Potier,

Tetrahedron Lett. 1995, 36, 8783–8786.

[21]

[22]

P. A. Grieco, J. L. Collins, D. E. Moher, T. J. Fleck, R. S. Gross,

J. Am. Chem. Soc. 1993, 115, 6078.

a) S. Arseniyadis, D. V. Yashunsky, R. Pereira de Freitas, M.

Muñoz-Dorado, P. Potier, L. Toupet, Tetrahedron 1996, 52,

12443–12458; b) S. Arseniyadis, R. Brondi Alves, R. Per-

eira de Freitas, M. Muñoz-Dorado, D. V. Yashunsky, P. Potier,

L. Toupet, Heterocycles 1997, 46, 727–764; c) J. I. Cand-

ela Lena, M. Rico Ferreira, J. I. Martín Hernando, S. Arseni-

yadis, Tetrahedron: Asymmetry 2001, 12, 3281–3291.

For routes to gain synthetic entry to systems containing seven-

membered ring, see: P. A. Wender, A. J. Dyckman, C. O. Hus-

feld, M. J. C. Scanio, Org. Lett. 2000, 2, 1609–1611; P. A.

Wender, A. J. Dyckman, C. O. Husfeld, M. J. C. Scanio, Org.

Lett. 2001, 3, 2105–2108 and references cited therein.

a) L. Finet, J. I. Candela, T. Kaoudi, N. Birlirakis, S. Arseni-

yadis, Chem. Eur. J. 2003, 9, 3813–3820; b) C. Unaleroglu, V.

Aviyente, S. Arseniyadis, J. Org. Chem. 2002 67, 2447–2452.

a) W. S. Rapson, R. Robinson, J. Chem. Soc. 1935, 1285; b)

Z. G. Hajos, D. R. Parrish, J. Org. Chem. 1973, 38, 3239–3243;

c) U. Eder, G. Sauer, R. Wiechert, Angew. Chem. Int. Ed. Engl.

1971, 10, 496–497; d) J. Gutzwiller, P. Buchschacher, A. Fürst,

Synthesis 1977, 167.

a) S. Arseniyadis, R. Rodriguez, M. Muñoz Dorado, R.

Brondi Alves, J. Ouazzani, G. Ourisson, Tetrahedron 1994, 50,

8399–8426; b) S. Arseniyadis, R. Rodriguez, R. Brondi Alves,

R. Spanevello, J. Ouazzani, G. Ourisson, Microbial Reagents in

Organic Synthesis (Ed.: S. Servi), NATO ASI Series C, vol. 381,

Kluwer Academic Publishers, Dordrecht, 1992, pp. 313–321.

a) T. G. Halsall, D. B. Thomas, J. Chem. Soc. 1956, 2431; b)

C. H. Heathcock, D. Gray, Tetrahedron 1971, 27, 1239; c) J. E.

Ellis, J. S. Dutcher, C. H. Heathcock, J. Org. Chem. 1976, 41,

2670–2676.

a) M. Frigerio, M. Santagostino, Tetrahedron Lett. 1994, 35,

8019. DMP is best prepared using the Santagostino procedure

(OXONE^®oxidation) for the first step, the IBX formation, and

the Ireland protocol for the second, instead of using the origi-

nal Dess–Martin procedure. b) M. Frigerio, M. Santagostino,

S. Sputore, J. Org. Chem. 1999, 64, 4537; c) R. E. Ireland, L.

Longbin, J. Org. Chem. 1993, 58, 2899.

K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, J. Am. Chem. Soc.

2000, 122, 7596.

K. C. Nicolaou, P. S. Baran, P. S. Baran, Y.-L. Zhong, J. A.

[6]

[23]

[24]

[25]

Vega, Angew. Chem. Int. Ed. 2000, 39, 2525.

[7]

[8]

K. C. Nicolaou, Y.-L. Zhong, P. S. Baran, Angew. Chem. Int.

Ed. 2000, 39, 622Ͻ/jnl; K. C. Nicolaou, Y.-L. Zhong, P. S. Ba-

ran, Angew. Chem. Int. Ed. 2000, 39, 625.

a) G. J. Buist, C. A. Bunton, J. H. Miles, J. Chem. Soc. 1959,

743; b) G. J. Buist, C. A. Bunton, W. C. P. Hipperson, J. Chem.

Soc. B 1971, 2117; G. J. Buist, C. A. Bunton, W. C. P. Hipper-

son, J. Chem. Soc. B 1971, 2128.

For a recent review see: K. A. Jorgensen, Eur. J. Org. Chem.

2004, 2093–2102.

L. F. Tietze, H. Evers, E. Topken, Angew. Chem. Int. Ed. 2001,

40, 903–905.

J. I. Candela Lena, M. Rico Ferreira, M. Martín Hernando, E.

Altınel, S. Arseniyadis, Tetrahedron Lett. 2001, 42, 3179–3182.

For a review see: G. G. Melikyan, Aldrichimica Acta 1998, 31,

50–64.

R. Criegee, H. Beucker, Liebigs Ann. Chem. 1939, 541, 218.

J. I. Candela Lena, E. Altinel, N. Birlirakis, S. Arseniyadis, Tet-

rahedron Lett. 2002, 43, 1409–1412.

R. Floresca, M. Kurihara, D. S. Watt, A. S Demir, J. Org.

Chem. 1993, 58, 2196–2200.

K. B. Wiberg, in Oxidation in Organic Chemistry (Ed.: K. B.

Wiberg); Academic Press, New York, 1965, Part A, pp. 170–

172.

[26]

[27]

[28]

[29]

[30]

[9]

[10]

[31]

[32]

[11]

[12]

P. Wieland, K. Miescher, Helv. Chim. Acta 1950, 33, 2215.

J. B. P. A. Wijnberg, A. de Groot, J. Org. Chem. 1983, 48,

4380–4387 and references cited therein.

[33]

[34]

[13]

a) W. A. Herrmann, R. W. Fischer, D. W. Marz, Angew. Chem.

Int. Ed. Engl. 1991, 30, 1638–1641; b) W. A. Herrmann, J. Or-

ganomet. Chem. 1995, 500, 149; c) W. A. Herrmann, R. W. Fi-

scher, M. U. Rauch, W. Scherer, J. Mol. Catal. 1994, 86, 243;

d) W. A. Herrmann, F. E. Kuhn, Acc. Chem. Res. 1997, 30,

169–180; e) J. I. Martín Hernando, M. Rico Ferreira, J. I. Can-

dela Lena, L. Toupet, N. Birlirakis, S. Arseniyadis, Tetrahe-

dron: Asymmetry 1999, 10, 3977–3989.

For the precursor of 13a, the corresponding angularly func-

tionalized octaline dione, the method of Benn and Hanselmann

(l-proline, DMSO, room temp.) was used, R. Hanselmann, M.

Benn, Synth. Commun. 1996, 26, 945–961.

[35]

[36]

K. B. Wiberg, J. R. Snoonian, J. Org. Chem. 1998, 63, 1402–

1407.

a) S. Arseniyadis, J. Quilez del Moral, R. Brondi Alves, P. Pot-

ier, L. Toupet, Tetrahedron: Asymmetry 1998, 9, 2871–2878; b)

M. Rico Ferreira, J. I. Martín Hernando, J. I. Candela Lena, J.

Quílez del Moral, S. Arseniyadis, Tetrahedron: Asymmetry

1999, 10, 1527–1537.

a) J. I. Martín Hernando, M. Rico Ferreira, J. I. Candela Lena,

L. Toupet, N. Birlirakis, S. Arseniyadis, Tetrahedron: Asym-

metry 1999, 10, 3977–3989; b) M. Rico Ferreira, J. I.

Martín Hernando, J. I. Candela Lena, L. Toupet, N. Birlirakis,

S. Arseniyadis, Tetrahedron Lett. 1999, 40, 7679–7682.

[14]

[37]

[15]

[16]

F. E. Ziegler, O. B. Wallace, J. Org. Chem. 1995, 60, 3626–3636.

H. J. Swarts, A. A. Verstegen-Haaksma, B. J. M. Jansen, A.

de Groot, Tetrahedron 1994, 50, 10083–10094.

Eur. J. Org. Chem. 2005, 683–700

www.eurjoc.org

699

S. Arseniyadis et al.

FULL PAPER

[38] J. I. Candela Lena, Ö. Sesenoglu, N. Birlirakis, S. Arseniyadis,

Tetrahedron Lett. 2001, 42, 21–24.

[39] Oxidation of alkenes by lead tetraacetate on heating is well

known; the olefin remains unaltered at room temperature.

[40] In no case was the ring-expanded product detected in the reac-

tion mixtures employing oxidants known to promote glycol fis-

sion, including iodobenzene diacetate, though we cannot rule

out their production in very minor amounts upon prolonged

heating at reflux with the latter oxidant.

[41] L. D. Hall, J. K. M. Sanders, J. Am. Chem. Soc. 1980, 102,

5703–5711.

[42] C. LeCocq, J.-Y. Lallemand, J. Chem. Soc. Chem. Commun.

1981, 150–152.

Received August 2, 2004

700

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Article Doi

Mild protocols for generating molecular complexity: A comparative study of hetero-domino reactions based on the oxidant and the substitution pattern

DOI: 10.1002/ejoc.200400549

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