Further observations on the rhodium (I)-catalysed tandem hydrosilylation-intramolecular aldol reaction

Tetrahedron 60 (2004) 2673–2692

Further observations on the rhodium (I)-catalysed tandem

hydrosilylation-intramolecular aldol reaction

a

Marta Freirıa, Andrew J. Whitehead, Derek A. Tocher and William B. Motherwell

b

a

,

*

´

^aDepartment of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK

^bChemical Development Division, GlaxoSmithKline Research and Development, Gunnels Wood Road, Stevenage,

Hertfordshire SG1 2NY, UK

Received 3 October 2003; revised 3 December 2003; accepted 18 December 2003

Abstract—The rhodium (I) catalysed tandem hydrosilylation-intramolecular aldol reaction provides a simple strategy for construction of a

range of usefully functionalised ﬁve-membered rings from readily prepared 6-oxo-2-hexenoates in good yield and with good to excellent

stereoselectivity. A series of silanes and rhodium catalysts have been investigated. Stereoselectivity proved to be highly dependant on the

catalyst as well as on the substitution pattern of the parent substrate. The extension of this methodology for the synthesis of larger ring sizes

has also been evaluated.

1. Introduction

well as in attempted cyclisations to give larger rings.

Furthermore, competitive decarbonylation of the rhodium

acyl complex generated after initial oxidative addition to the

aldehyde can lead to undesired side reactions, and since the

catalyst is then rendered inactive, relatively large amounts

(20–50 mol%) have often been required for many

examples.

Highly stereoselective cyclisation methods provide a

powerful tool for the construction of the carbocyclic

skeletons found in both natural and non-natural molecules

of biological importance. Moreover, the dictates of modern

day organic synthesis also require that the overall process

should be highly efﬁcient in terms of atom economy. Within

this context, the rhodium catalysed intramolecular hydro-

acylation reaction of 4-alkenals, ﬁrst introduced by Sakai,¹

(Scheme 1, R¼R⁰¼alkyl, Z¼H) provides a very good

example of an extremely powerful method for the

preparation of functionalised cyclopentanone deriva-

tives,^2–9especially in view of the cis stereoselectivities

observed and the elegant studies by Bosnich¹⁰and Sakai¹¹

on the development of chiral catalysts for the asymmetric

variant.

In light of the above constraints, we therefore, sought to

develop an alternative general methodology through the

incorporation of ester functionality at the alkene terminus of

the 4-pentenal unit (Scheme 1, Z¼ester). The selection of a

6-oxo-2-hexenoate unit such as 1 then provides the

opportunity for a tandem sequence involving transition

metal mediated hydrosilylation followed by intramolecular

aldol reaction as a route to substituted cycloalkanols

(Scheme 2). Such an approach does of course ﬁnd

intermolecular precedent in terms of the sequential

reductive aldol reaction which has witnessed spectacular

development in recent years.¹²From the outset of our own

study, even although it is often falsely assumed that an

intramolecular variant of any given reaction will

automatically follow on from its intermolecular congener,

we were aware that chemoselectivity issues such as

competing reduction of the aldehydic carbonyl group

remained to be assessed, especially given that stepwise

Scheme 1. General representation of the rhodium (I)-catalysed intramo-

lecular hydroacylation of 4-alkenals.

On closer inspection, however, this protocol does suffer

from some limitations, which include poorer yields for

substrates either with heteroatom substituents or with

additional groups located at the alkene terminus (Z), as

Keywords: Tandem hydrosilylation; Aldol; Rhodium; intramolecular;

catalytic.

*

Corresponding author. Tel.: þ44-207-6797533; fax: þ44-207-6797524;

Scheme 2. General representation of the rhodium (I)-catalysed tandem

hydrosilylation-intramolecular aldol reaction of 6-oxo-2-hexenoates.

e-mail address: w.b.motherwell@ucl.ac.uk

doi:10.1016/j.tet.2003.12.057

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2674

introduction of substrates is not possible in the intra-

molecular mode.

addition-aldol processes and similar variants.^16,20They are

traditionally prepared either by Wittig oleﬁnation²¹or by

relatively long multistep sequences.²²For our present study,

we elected to develop the simple atom efﬁcient route²³

shown in Scheme 3 which requires acid catalysed

condensation of a 2-hydroxy-3-butenoate ester with an

aldehyde followed by in situ Claisen rearrangement of the

allyl alkenyl ether intermediate (Scheme 3).

Within the large manifold of cascade reactions,¹³stereo-

selective tandem conjugate addition–cyclisation reactions

have been extensively studied.¹⁴In particular, Michael

addition followed by intramolecular aldolisation has proven

to be a very useful strategy. Such ring closing reactions are

believed to proceed via 1,4-addition of the organometallic

or heteronucleophilic reagent to the enoate, with subsequent

addition of the resultant enolate to the aldehyde.¹⁵Murphy¹⁶

has recently reported a tandem Michael-intramolecular

aldol mediated by secondary amines, thiols and phosphines.

Lithium thiolates¹⁴ⁿand TiCl₄–R₄NX combinations¹⁷have

also been used to initiate such cyclisations; however, these

heteronucleophiles remain covalently attached in the

cyclisations products. There are also several examples in

the literature of non-catalysed tandem Michael-intra-

molecular aldol reactions using stoichiometric amounts of

organometallic hydrides such as Stryker’s reagent [(Ph₃-

Scheme 3. General synthesis of substituted 6-oxo-2-hexenoates.

The required 2-hydroxy-3-butenoates 2a–b were easily

accessed from commercially available 2-acetoxy-3-butene-

nitrile using a literature method²⁴involving dissolution in a

saturated hydrochloric acid solution of the appropriate

alcohol. A mixture of 2 with slightly more than one molar

equivalent of the carbonyl compound was then reﬂuxed in

toluene for 48 h in the presence of a catalytic amount of

p-toluenesulfonic acid and using a Dean and Stark trap for

azeotropic removal of water. The corresponding 6-oxo-2-

hexenoate products, produced as a mixture of geometric

isomers, were then isolated by ﬂash chromatography. Thus,

as indicated in Table 1, aliphatic and aromatic 5,5-

disubstituted 6-oxo-2-hexenoates 4, 5a, 5b and 6 were

obtained from the corresponding aldehydes in 49–64%

yield in a 2:1 ratio (entries 1, 2 and 3). Synthesis of the

parent unsubstituted derivative 7 was ﬁrst attempted using

acetaldehyde. However, this attempt was unsuccessful

presumably due to the high volatility of acetaldehyde.

However, when acetaldehyde was replaced by its less

P)CuH]₆and di-n-butyliodotin hydride (n-Bu₂SnIH).¹⁹

18

We now report, in full detail¹⁵the results of our own study

in which inexpensive and more environmentally benign

organosilanes were selected for the initial conjugate

addition step. An essentially contemporaneous parallel

investigation by an American group²⁰has also adopted a

similar tandem-hydrosilylation intramolecular aldol

sequence but chosen to investigate oxo-enone substrates

and to use cobalt catalysts.

2. Results and discussion

2.1. Preparation of cyclisation substrates

Substituted 6-oxo-2-hexenoate units such as 3 are proving to

be especially valuable for a variety of tandem Michael

Table 1. Substituted 6-oxo-hexenoate derivatives produced via Scheme 3

Entry

Electrophile

Product

Yield (%)^a

Ratio E/Z

1

4

53

2:1

2

3

4

5a (5b)

49 (61)^b

1.5:1

2:1

64

6

46^c

2.2:1

Only E

7

8

5

58

a

Isolated yields.

Yield of the correspondent isopropyl ester derivative starting from butenoate 2b.

˚

The reaction was carried out using a Soxhlet extractor in the presence of 4 A MS for the removal of ethanol.

b

c

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2675

volatile diethyl acetal congener, reaction proceeds to give 7

in 46% yield in a 2.2:1 ratio (entry 4). 6-Oxo-2,7-

octadienoate 8 was also synthesised in 58% yield from

benzylideneacetone as a single E diastereomer (entry 5).

Additional examples and further preparative and stereo-

chemical aspects on this [3,3] sigmatropic route have been

discussed in our preliminary study.²³

from allyl alcohol and isobutyraldehyde via Claisen

rearrangement of the allyl alkenyl ether intermediate.³¹

Subsequent Horner–Wadsworth–Emmons oleﬁnation of

the aldehyde with trimethylphosphonoacetate in the

presence of sodium hydride afforded 17 in 88% yield as a

single E diastereoisomer. Selective ozonolysis of the

terminal alkene in 17 afforded compound 15 in 48% yield

(Scheme 6). This method offers the advantage of permitting

substituent variation at C-4 of the resulting 6-oxo-2-

hexenoates of type 15 by a simple choice of the appropriate

starting aldehyde.

Substitution at C-3 was also sought and two different

cyclisation substrates 9 and 10 were accordingly selected.

Thus, 4-bromo-2(5H)-furanone 11 was prepared from

tetronic acid following the procedure of Jas using oxalyl

bromide and a catalylic amount of dimethylformamide in

dichloromethane (Scheme 4).²⁵Subsequent palladium-

catalysed substitution reaction of 11 with a homoallylzinc

reagent afforded 12 as described by Negishi.²⁶Finally, 3-(5-

oxo-2,5-dihydrofuran-3-yl)-propionaldehyde

9

was

obtained in 49% yield by selective ozonolysis of the

terminal double bond of alkene 12 in the presence of one

volume percent of pyridine.²⁷Methyl 3-methyl-6-oxo-2-

hexenoate 10 was prepared from commercially available

5-hexen-2-one. We note parenthetically that the Horner–

Wadsworth–Emmons oleﬁnation using trimethyl-

phosphonoacetate and sodium hydride proceeded much

more efﬁciently (87% vs. 43%) when the reaction was

conducted in reﬂuxing tetrahydrofuran rather than in 1,2-

dimethoxyethane as previously reported for the correspond-

ing ethyl ester.²⁸Intermediate 13 was obtained as a 2:1

mixture of E and Z isomers, which were separated by

chromatography (Scheme 5). Selective ozonolysis of 13

followed by reductive work up afforded 10 in 41% yield.

Scheme 6. Synthesis of methyl (E)-4,4-dimethyl-6-oxo-2-hexenoate.

Substrates 18 and 19 were also prepared from aldehyde 15

by Corey sulfur ylide epoxidation³²and Horner–

Wadsworth–Emmons oleﬁnation, respectively, (Scheme 7).

Scheme 4. Synthesis of 3-(5-oxo-2,5-dihydrofuran-3-yl)propionaldehyde.

Scheme 7. Syntheses of methyl (E)-4,4-dimethyl- 5-oxiranyl-2-pentenoate

and methyl (E)-4,4-dimethyl-8-oxo-2,6-nonadienoate.

In order to assess the feasibility of generating even more

strained bicyclic systems in the tandem cyclisation

sequence, substrate 20 was synthesised from commercially

available cis-cyclohexane-1,2-dioic acid anhydride

(Scheme 8). Lactone 21 was obtained in 70% yield by

reduction of the corresponding anhydride with sodium

borohydride, using the general procedure of Bailey and

Scheme 5. Syntheses of methyl (E)-3-methyl-6-oxo-2-hexenoate and

methyl (E)-6-oxo-2-heptenoate from 5-hexen-2-one.

Methyl (E)-6-oxo-2-heptenoate 14 was also prepared from

5-hexen-2-one following a literature procedure.²⁹

The synthesis of methyl 4,4-dimethyl-6-oxo-2-hexenoate 15

has already been reported by a multistep process which

includes several protection and deprotection steps.³⁰We

have prepared it by an alternative procedure in three steps

starting from isobutyraldehyde and allyl alcohol. Thus, 2,2-

dimethyl-4-pentanal 16, which is also commercially avail-

able, was synthesised by the method reported by Brannock

Scheme 8. Synthesis of methyl (E)-3-(2-formyl-cyclohexyl)-acrylate.

´

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2676

Johnson.³³Treatment of lactone 21 with DIBAL in ether at

220 8C resulted in rapid and quantitative reduction to the

lactol, which was subsequently reacted with methyl(tri-

phenylphosphoranylidene)acetate in acetonitrile to afford

alcohol 22 in an overall 68% yield as the single E isomer.

Oxidation of alcohol 22 with pyridinium chlorochromate

(PCC) gave the desired aldehyde 20 in 76% yield with some

epimerization at the a centre of the newly formed aldehyde

(cis/trans, 6:1). The viability of using a completely

conjugated system in our cyclisation reaction was tested

by selection of substrate 23 which was envisaged via a Heck

strategy. In the ﬁrst instance, 1-cyclohexene-1-carboxalde-

hyde and ethyl (Z)-3-iodo-propenoate, both commercially

available, were stirred in acetonitrile at room temperature in

the presence of 0.05 equiv. of palladium acetate and

1.5 equiv. of silver carbonate (Scheme 9). Coupling failed

to occur and only starting material was recovered after 3

days. The yields and rates of reaction in Heck couplings are

known to decrease with increasing size and number of

substituents around the double bond in the oleﬁn.³⁴

Coupling was, therefore, attempted between 2-bromo-1-

cyclohexenecarboxaldehyde 24 and a monosubstituted

oleﬁn, methyl acrylate, in the presence of triethylamine

and a catalytic amount of Pd[(PPh₃)₃]₂(OAc)₂at reﬂux. In

this way, the desired substrate 23b was obtained in 55%

yield as a single E diastereoisomer. The required aldehyde

24 was available from cyclohexanone by the bromo

analogue of the Vilsmeier reaction according to the

procedure of Arnold and Holy.³⁵

pentenal 27 was accessible from ^D-ribose by a literature

procedure (Scheme 11).³⁷Substrate 28 was prepared from

commercially available racemic a-hydroxy-g-butyro-

lactone, which was ﬁrstly protected using benzyl bromide

in the presence of a catalytic quantity of tetrabutyl-

ammonium iodide. The resulting a-benzyloxy-g-butyro-

lactone 29 was then reduced to the corresponding lactol 30

with DIBAL, which gave a mixture of cis and trans

diastereoisomers in a 2:1 ratio. The observed cis selectivity

presumably arises via subsequent equilibration which

favours the cis lactol. Wittig oleﬁnation of lactol 30 with

carbomethoxymethyltriphenylphosphonium bromide and

potassium tert-butoxide gave 31 in 78% yield as a mixture

of diastereoisomers. Subsequent oxidation of 31 with PCC

afforded substrate 28 in 67% yield as two separable

diastereoisomers.

Scheme 11. Methyl (4S, 5S)-6-oxo-4,5-isopropylidenedioxy-2-hexenoate

and methyl 4-benzyloxy-6-oxo-2-hexenoate.

Finally, methyl 7-oxo-2-heptenoate 32 and its higher

homologue 33 were prepared in order to explore the

feasibility of constructing larger ring sizes. Thus, substrate

32 was prepared by a general route from 1-hydroxypyran

34,³⁸which was obtained by acid hydrolysis of commer-

cially available 3,4-dihydropyran (Scheme 12).³⁹

Ruthenium trichloride catalysed oxidative cleavage of

cyclohexene⁴⁰followed by subsequent Horner–

Wadsworth–Emmons oleﬁnation of resultant adipaldehyde,

provided (E)-methyl 8-oxo-2-octenoate 33 in one step in

55% yield, accompanied by the doubly substituted diester

(ca. 20%), which was easily separated by chromatography

on silica gel.

Scheme 9. Synthesis of methyl (E)-3-(2-formyl-cyclohex-1-enyl)-acrylate

Benzoannulated substrate 25 was then prepared from

o-bromobenzaldehyde in order to investigate the compati-

bility of a 4,5-fused aromatic ring in the cyclisation reaction.

Although Rodrigo³⁶has observed that formation of the

doubly substituted product 26 is favoured over the

conventional Heck product 25 when the reaction is run in

a concentrated solution in the presence of excess methyl

acrylate (Scheme 10), the use of moderate amounts of

methyl acrylate and more dilute solutions led to the

optimum yield of our desired Heck product 25 which was

obtained in 69% yield in pure form after chromatography.

Scheme 10. Synthesis of methyl (E)-3-(2⁰-formylphenyl)-propenoate

Isopropylidene and benzyl ether functionalities were chosen

to investigate whether tandem hydrosilylation cyclisation

was compatible with heteroatomic substituents. Homochiral

Scheme 12. Methyl 7-oxo-2-heptenoate and methyl (E)-8-oxo-2-octenoate.

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2677

2.2. Cyclisation studies

the catalyst (entry 11). Although the observed preference in

our preliminary study^15awas relatively modest (cis/trans,

1:2) further work using carefully prepared rhodium catalyst

now reproducibly favours the trans product in high yield

and with excellent selectivity (cis/trans, 1.0:11.0).

In our preliminary study of the rhodium (I)-catalysed

tandem hydrosilylation intramolecular aldol reaction, opti-

mal conditions for the reaction of the model substrate

methyl (E)-6-oxo-2-hexenoate (E)-7 with Wilkinson’s

catalyst using triethylsilane as the hydride donor were ﬁrst

developed and these are summarized in Scheme 13 and

Table 2 (entry 1). The signiﬁcant observation was also made

that the stereochemical outcome of the reaction was not

altered when the (Z) geometrical isomer of 7 was employed

as substrate in an otherwise identical reaction, thereby

indicating that the initial alkene geometry does not play a

crucial role in inﬂuencing the possible transition states

adopted for the subsequent intramolecular aldol reaction.

Since E/Z mixtures of a,b-unsaturated esters can, therefore,

be used, this aspect is also clearly of preparative value.

We then elected to examine the synthetic utility of the

reaction using both Wilkinson’s catalyst⁴¹and hydrido-

tetrakis(triphenylphosphine) rhodium (I).⁴²The variety of

variously functionalised substituted 6-oxo-2-hexenoate

derivatives previously described were accordingly sub-

mitted to our optimised cyclisation conditions (2.1 M equiv.

of triethylsilane and 1 mol% of rhodium catalyst in toluene

at 50 8C) in order to probe such issues as chemoselectivity

and the inﬂuence of the substitution pattern on the tandem

sequence. The results are shown in Table 3.

Thus, comparison of entries 2–5 reveals that whilst geminal

substitution at C-5 (entries 2–4) leads to a reduction in yield

relative to the unsubstituted parent (entry 1) this is not

necessarily the case for the C-4 gem dimethyl group (entry

5). Although all four cases might be anticipated to beneﬁt

from the Thorpe–Ingold effect,⁴³it would, therefore, appear

that the intramolecular aldol step is more sensitive to the

presence of a neighbouring quaternary carbon atom than is

the initial hydrosilylation step. Entry 3 also demonstrates

that no signiﬁcant difference in yield was observed when the

methyl ester 5a was replaced by its iso-propyl analogue in

5b. Contrastingly, our examination of substrates possessing

a trisubstituted a,b-unsaturated lactone or ester (entries 6

and 7) reveals that the incorporation of additional alkyl

substitution at this site completely blocks the conjugate

addition step and simple hydrosilylation of aldehydic

functionality then becomes the dominant process. Compari-

son of entries 8, 9 and 10 reveals that the success of the

intramolecular aldol addition step can be subject to very

subtle conformational and stereoelectronic restrictions.

Thus, whilst entries 8 and 10 provide a very encouraging

basis for construction of the linearly fused bicyclo [4,3,0]

system in both the hydrindane 42 (entry 8) and indane

skeletons 44 (entry 10), the isolation of the hexahydro-

benzo[c]oxepin 43 from the fully conjugated precursor 23b

was unexpected. In this latter instance, cyclisation of the

ester enolate via oxygen to give the seven membered ring is

clearly favoured, and formation of the silyl ether function-

ality in the product must be fast and hence preclude the

reverse reaction. Finally, in view of the ever increasing

importance of constructing carbocycles from the chiral pool

of carbohydrates,^44–48it was also of interest to examine

substrates containing ancillary isopropylidene (entry 11)

and benzyl ether (entry 12) functionality. The functional

group tolerance exhibited in these latter two cyclisations

provides an indication that this approach may be of promise

for cyclopentanoid construction from carbohydrates. In

terms of stereoselectivity, comparison of the two catalysts A

and B reinforces the observation made in the parent system

(entry 1) that the outcome can be signiﬁcantly inﬂuenced by

this choice. Thus, whilst Wilkinson’s catalyst consistently

exhibits a modest cis preference for formation of the

b-triethylsiloxy ester unit, selection of hydrido-

tetrakis(triphenylphosphine) rhodium (I) generally favours

the trans congener. However, the diastereoisomeric ratios

with the latter catalyst are evidently much more strongly

Scheme 13. Rhodium (I)-catalysed tandem hydrosilylation-intramolecular

aldol reaction of methyl (E)-6-oxo-2-hexenoate.

Table 2. Silane and catalyst screen

Entry

Silane^a

Catalyst^b

Ligand^cYield^d(%) c-35/t-35

1

2

3

4

5

6

7

8

Et₃SiH

Me₂PhSiH RhCl(PPh₃)₃

MePh₂SiH RhCl(PPh₃)₃

RhCl(PPh₃)₃

—

81

62

49

42

79

78

27

53

61

51

81

2.0:1.0

2.4:1.0

2.8:1.0

1.5:1.0

2.5:1.0

3.3:1.0

1.0:2.0

2.0:1.0

1.0:1.6

2.0:1.0

1.0:11.0

Ph₃SiH

Et₃SiH

RhCl(PPh₃)₃

e

[RhCl(C₈H₁₄)₂]₂PCy₃

e

[RhCl(C₈H₁₄)₂]₂DIPHOS^f

e

[RhCl(C₈H₁₄)₂]₂pTol₃P

e

[RhCl(C₈H₁₄)₂]₂pTol₃P

e

9

10

11

[RhCl(C₈H₁₄)₂]₂pAn₃P^g

e

[RhCl(C₈H₁₄)₂]₂pAn₃P^g

h

RhH(PPh₃)₄

—

a

2.1 equiv. of silane used.

b

c

d

e

f

1 mol% catalyst unless otherwise stated.

4 equiv. ligand w.r.t. catalyst unless otherwise stated.

Yield of isolated products.

2.5 mol% catalyst.

2 equiv. ligand w.r.t. catalyst, DIPHOS (1,2-bis(diphenylphos-

phino)ethane).

An, anisole.

Reaction complete after 6 h.

g

h

At this stage, examination of the results from a catalyst and

silane screen (Table 2) revealed some useful trends. Thus, in

reactions employing Wilkinson’s catalyst, the use of silanes

of increasing steric bulk (entries 1–4) led to reduced yields

of the cyclopentanol 35, even although the cis selectivity

was maintained. Variation of the ancillary phosphine was

also studied using triethylsilane and chlorobis(cyclooctene)

rhodium (I) dimer (entries 5–10), and found to play a

signiﬁcant role, with the best combination of yield and cis

stereoselectivity achieved through selection of the bidentate

DIPHOS ligand (entry 6). The most intriguing observation

of all, however, was that a complete reversal of stereo-

selectivity in favour of trans-35 was noted when hydrido-

tetrakis(triphenylphosphine) rhodium (I) was employed as

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2678

Table 3. Rhodium (I)-catalysed tandem cyclisation of substituted 6-oxo-2-hexenoate derivatives

Entry

1

Substrate

Product

Catalyst^a

A

Yield (%)^b

81

cis/trans^c

3.0:1.0

7

4

35

36

B

81

1.0:11.0

A

B

56

62

1.0:1.0

6.4:1.0

2

5a

5b

37a

37b

A

B

54

59

2.0:1.0

1.0:2.0

3

4

5

6

38

39

B

68

1.0:2.5

A

B

93

61

2.2:1.0

15

1.0:11.0

6

7

9

40

41

A

43

—

A

B

35

39

—

10

8

9

20

42

43

B

81^d

88

—

23b

A

B

61^e

69^e

1.5:1.0

10

11

25

44

1.0:20.0

A

B

65

81

2.0:5.4:2.0:1.0^f

5.4:4.0:2.0:1.0^f

27

28

45

46

A

B

81

72

1.7:1.5:1.0:1.0^g

1.2:1.0:1.2:1.7^g

12

a

A, RhCl(PPh₃)₃; B, RhH(PPh₃)₄.

b

c

d

e

f

Isolated yields after chromatography on silica gel.

Diastereomeric ratio in the crude material determined by ¹H NMR.

Isolated as a complex mixture of diastereoisomers.

Using 3 mol% of catalyst.

See Figure 2 for assignment of the structures, a/b/c/d.

Relative stereochemistry: OBn/OSiEt₃–OSiEt₃/CO₂Me; trans–trans/cis–cis/cis–trans; trans–cis.

g

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2679

inﬂuenced by the exact nature of the substrate substitution

pattern and can, at times, be excellent (entries 1, 5 and 10).

In all cases, the structure of the major diastereoisomer was

assigned on the basis of the values of coupling constants

measured in ¹H NMR. In general, coupling constant J(H¹–

H²)¼3.5–6.5 Hz indicates cis relative stereochemistry,

whereas J(H¹–H²)¼5.5–9.5 Hz accounts for the trans

isomer. This assignment could be conﬁrmed by X-ray

crystallographic analysis of compound 38, since the minor

cis diastereoisomer crystallised out of the mixture of

isomers giving suitable crystals (Fig. 1).

Figure 3. NOE mesurements of 45.

The structure of isomer 45c was unequivocally assigned on

the basis of a typical coupling constant J(H₁–H₂)¼12.4 Hz

for diaxial conﬁguration. The minor isomer 45d was

not isolated but its structure was tentatively deduced as

the all-cis isomer.

At this stage, in order to extend the scope of the reaction,

cyclisation was also carried out on several substrates where

the aldehyde functionality was replaced by alternative

electrophilic acceptor groups. The construction of six- and

seven-membered rings was also attempted. The results are

shown in Table 4.

In the event, aldehyde functionality proved to be crucial in

order to achieve cyclisation. Thus, as shown in entries 1 and

2, replacement of the aldehyde either by a methyl ketone or

by an epoxide did not lead to the formation of cyclic

products, even although the reduction of the acrylate unit by

the silane in both cases implies formation of a hydro-

metallated ester enolate intermediate. In the case of the

methyl ketone 14 (entry 1), the regiospeciﬁc and highly

stereoselective formation of the silyl enol ether product was

not anticipated but certainly of interest, especially since the

control of regioselectivity in the case of unsymmetrical

ketones⁴⁹is always useful in organic synthesis. In order to

understand this transformation commercially available

5-hexen-2-one was also subjected to the standard

cyclisation conditions in the presence of Wilkinson’s

catalyst. As shown in Scheme 14, regiospeciﬁc silyl enol

ether formation with concomitant double bond reduction

occurred once again in excellent yield and with moderate

stereoselectivity, thereby establishing that the ester group is

not essential for this reaction to occur. A speculative

intermediate is shown in Figure 4 and implies that substrate

coordination around a silyl hydridorhodium intermediate

may well direct the regiospeciﬁcity of the sequence and also

produce molecular hydrogen for subsequent reduction of the

double bond. At this stage, however, the reasons for the

totally divergent behaviour of the aldehydic substrate 7 and

its ketonic congener 14 still require further investigation.

Figure 1. Crystal structure of compound 38.

When more than two stereogenic centres are present, proton

assignment and subsequent determination of all possible

diastereoisomers by experimental means was extremely

difﬁcult. To our delight, however, careful column chroma-

tography allowed the separation of three of the four possible

isomers of substrate 45 and their structure and relative

1

predominance (Table 3, entry 11) was determined by H

NMR (Fig. 2).

The two enone substrates 8 and 19 shown in entries 3 and 4

were initially selected with the intention of probing a (non-

rhodium catalysed) tandem hydrometallation–Michael

addition sequence in which, as demonstrated by Evans^12a

for hydroboration, the a,b-unsaturated ketone unit should

be the ﬁrst point of attack. In the event, however, only

acyclic products derived from 1,4-addition of the organo-

silane to the enones were isolated in the rhodium catalysed

reactions and no evidence for a subsequent tandem Michael

reaction was adduced. Interestingly, the use of Wilkinson’s

catalyst (entry 3) led to reduction of both the enone and the

enoate whereas in the presence of hydridotetrakis(tri-

phenylphosphine) rhodium (I) (entry 4) reduction occurred

Figure 2. Structure of the four diastereoisomers of 45.

A coupling constant J(H₂–H₃)¼0.0–0.7 Hz was observed

for both isomers 45a and 45b, indicating a dihedral angle

close to 90 8C, which implies the equatorial conﬁguration of

H₂. The conﬁguration of H₁was assigned on the basis of

NOE experiments (Fig. 3). A strong NOE effect between H₁

and H_5eqin 45a indicates that H₁occupies an axial position,

whereas in 45b the NOE effect was observed between

H₁and H_5ax, indicating that, in this case, it occupies an

equatorial position.

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2680

Table 4. Rhodium (I)-catalysed tandem cyclisation of alternative acceptors and construction of larger ring sizes

Entry

1

Substrate

Product

Catalyst^a

Yield (%)^b

cis/trans^c

A

B

83

61

5.0:1.0^d

14

18

8

47

48

49

50

A

B

68

60

—

2

3

4

A

B

74

91

—

19

51

A

66

1.0:4.6

5

32

33

52

53

B

65

68

1.0:3.0

2.5:1.0

6

a

A, RhCl(PPh₃)₃; B, RhH(PPh₃)₄.

b

c

d

Isolated yields after chromatography on silica gel.

Diastereomeric ratio in the crude material determined by ¹H NMR.

Z/E ratio.

65% with trans selectivity. In similar fashion, octenoate 33

furnished the seven-membered ring analogue 53 in

comparable yield (68%) but with a reversal in terms of

stereoselectivity relative to the six-membered ring congener

(entry 6). Signiﬁcantly, and in contrast to the hydroacylation

protocol, the applicability of this approach for the

preparation of substituted ﬁve-, six- and seven-membered

rings is, therefore, possible.

Scheme 14. Formation of silyl enol ether 54 from 5-hexen-2-one.

2.3. Mechanistic considerations and stereochemistry

From a mechanistic standpoint, it was of interest to

determine whether the transformation described was indeed

a consequence of intermolecular hydrosilylation followed

by an intramolecular aldol reaction, and not in fact

intramolecular hydroacylation followed by hydrosilylation.

To this end, reduction of the ester, methyl-2-oxocyclo-

pentane carboxylate, was attempted using an excess of

triethylsilane in the presence of 1 mol% of Wilkinson’s

catalyst. Under identical conditions to those that yielded

81% of the products c-35 and t-35 from methyl (E)-6-oxo-2-

hexenoate 7, only traces of the b-triethylsiloxy ester were

formed. We have also demonstrated that the cis-substituted

cyclopentanol c-35 was not interconverted to the trans-

isomer t-35 when resubmitted to the reaction conditions,

neither in the presence of Wilkinson’s catalyst nor in the

presence of RhH(PPh₃)₄.

Figure 4. Speculative intermediate for the formation of 54 from 5-hexen-2-

one.

exclusively at the enone moiety. The contrasting behaviour

of the two rhodium catalysts and the necessity for rigorous

puriﬁcation prior to their use was further highlighted in the

case of 7-oxo-2-heptenoate 32 (entry 5). In our preliminary

study,^15aonly a low yield of cyclised product was described

using Wilkinson’s catalyst. The results obtained under more

stringent conditions reveal that, as in entry 1, the major

product using Wilkinson’s catalyst is the analogous reduced

silyl enol ether 51. To our delight, however, selection of

hydridotetrakis-(triphenylphosphine) rhodium (I) affords

the desired 2-carbomethoxycyclohexanol derivative 52 in

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2681

As in the intermolecular variant of this reaction using

enones and aldehydes,⁵⁰the intermediacy of an oxygen

bound rhodium ester enolate of the type suggested by

Heathcock⁵¹seems most likely. The inﬂuence of the

ancillary phosphine ligands, and the replacement of the

chlorine atom by a hydride ligand on the stereochemical

outcome of our reactions both provide strong support for

this possibility. A possible pathway for the catalytic aldol

cycloreduction is depicted in Scheme 15. Thus, oxidative

addition of the silane to the rhodium (I) catalyst provides the

hydridosilyl rhodium (III) intermediate Ia. 1,4 hydride

transfer of the hydridosilyl rhodium (III) species to the a,b-

unsaturated ester then generates a rhodium ester enolate IIa.

Intramolecular aldol reaction followed by reductive

elimination liberates the carbocyclic silyl ether product

with concomitant regeneration of the active catalyst. It is

interesting that the rhodium complex may catalyse both, the

1,4-addition and the aldol reaction, in one catalytic cycle.

The chemoselectivity for both steps is very high, the

intermediates Ia and IIa reacting with the a,b-unsaturated

ester and the aldehyde, respectively, with perfect selectivity.

Although in the ﬁrst instance it could be argued that the two

rhodium complexes used in this study might well have

converged to a common catalytic intermediate through

oxidative addition of the silane to Wilkinson’s catalyst and

subsequent reductive elimination of chlorotriethylsilane, the

experimental observations clearly do not substantiate this

hypothesis. Consequently, the presence or absence of the

rhodium chlorine bond will clearly inﬂuence the outcome of

the reaction both in terms of the polarity of the rhodium

hydride bond and the stereochemical outcome in the initial

hydrometallation step as well as altering the Lewis acidic

nature of the chelated rhodium intermediate postulated for

the intramolecular aldol step.

3. Conclusion

In summary, we have developed a highly stereoselective

cyclisation sequence via a rhodium (I)-catalysed tandem

hydrosilylation-intramolecular aldol reaction that can be

used to prepare a range of usefully functionalised ﬁve-, six-

and seven-membered rings in good yields under very mild

conditions. Moreover, in many instances the required

precursors can be easily prepared in a highly atom efﬁcient

way using the [3,3] sigmatropic rearrangement sequence.

The scope and limitations of this novel reaction have been

established. A range of substituents in the substrates is

tolerated, however, aldehyde functionality proved to be

crucial. The stereochemical outcome is highly dependant on

the catalyst precursor, RhH(PPh₃)₄is an efﬁcient precatalyst

for tandem hydrosilylation-aldol reaction and gave the best

results in terms of selectivity. Further studies into the

mechanism and stereochemistry of the tandem cyclisation

and its applications in synthesis are ongoing.

The stereochemical outcome of this reaction can be

formally rationalised in terms of the preferential formation

of one stereoisomer of the rhodium ester enolate 55

(Scheme 16). Thus, (Z)-enolate 56 undergoes the intra-

molecular aldol reaction via a chelated transition state and

provides the cis-carbocyclic product 58a in which one of the

substituents occupies an axial position. On the other hand,

(E)-enolate 57 cyclises with an all-equatorial orientation

leading to the trans-substituted product 58b.

4. Experimental

4.1. General

All cyclisations and air and/or moisture sensitive reactions

were carried out in oven-dried glassware under a nitrogen

atmosphere using standard Schlenk techniques. Unless

otherwise noted, chemicals were commercially available

and used without further puriﬁcation. Solvents were

distilled before use and degassed immediately prior to use.

Toluene was distilled from sodium. Tetrahydrofuran and

diethyl ether were distilled from sodium-benzophenone

ketyl, methylene chloride and acetonitrile from calcium

hydride and ethanol and methanol were used as supplied

from Aldrich. RhCl(PPh₃)₃was prepared according to

Scheme 15. Mechanism of rhodium (I)-catalysed tandem hydrosilylation-

intramolecular aldol reaction.

Scheme 16. Stereochemistry of rhodium (I)-catalysed tandem hydrosilylation-intramolecular aldol reaction.

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2682

Wilkinson’s procedure⁴¹and RhH(PPh₃)₄to Levison’s

procedure.⁴²

(300 MHz, CDCl₃) d 1.05 (s, 6H, C(CH₃)₂), 2.83 (dd,

J¼7.8, 1.6 Hz, 2H, CH₂), 3.65 (s, 3H, OCH₃), 5.84 (dt,

J¼11.6, 1.6 Hz, 1H, vCHCO₂CH₃), 6.11 (dt, J¼11.6,

7.8 Hz, 1H, CHvCHCO₂CH₃), 9.50 (s, 1H, CHO); ¹³C

NMR (75.5 MHz, CDCl₃) d 21.7 (C(CH₃)₂), 35.9 (CH₂),

46.6 (C(CH₃)₂), 51.5 (OCH₃), 122.2 (vCHCO₂CH₃), 145.0

(CHvCHCO₂CH₃), 166.9 (CO₂CH₃), 205.5 (CHO); FTIR

(ﬁlm) n 1797, 1724, 1656 cm²¹; LRMS (EI^þ) m/z 170 (M,

8), 141 (58), 109 (87), 81 (70), 41 (100); HRMS (EI^þ) calcd

for C₉H₁₄O₃(M^þ) 170.09429, found 170.09417.

Nuclear magnetic resonance spectra were recorded using a

Bruker AMX-300 or a Bruker AMX-400 or a Bruker

Avance 500. Chemical shifts (d) are quoted in parts per

1

million (ppm) relative to tetramethylsilane. The H NMR

spectra are reported relative to residual chloroform at

7.26 ppm. Coupling constants are reported in Hertz. ¹³C

NMR spectra were fully decoupled and are referenced to the

middle peak of chloroform at 77.0 ppm. Splitting patterns

are designated as s, singlet; d, doublet; t, triplet; q, quartet;

m, multiplet; and a combination of these. Melting points

were determined using a Reichert hot stage or Electro-

thermal 9100 apparatus and are uncorrected. Optical

rotations were recorded on a Perkin–Elmer 241 polarimeter

(using the sodium D line; 589 nm) and [a]^T_Dare given in

units of 10²¹deg dm²g²¹. IR spectra were recorded on a

Perkin–Elmer 1605 FT-IR spectrometer as thin ﬁlms on

NaCl or as KBr discs and are reported in cm²¹. Mass spectra

were recorded on a Micromass 70-SE spectrometer using a

cesium ion gun for FAB. X-ray crystallography was

performed using a Bruker Smart Apex, CDD diffractometer.

Elemental analyses and accurate mass measurements were

performed at Christopher Ingold Laboratories, University

College London.

4.2.3. Methyl (E)-4-(1-formyl-cyclohexyl)-2-butenoate

((E)-5a). According to the general procedure A, reaction

of methyl 2-hydroxy-3-butenoate 2a (3.0 g, 25.8 mmol) and

cyclohexanecarboxaldehyde (2.90 g, 25.8 mmol) gave, after

puriﬁcation by column chromatography eluting with P.E.

30–40 8C/EtOAc (80:20), the aldehyde 5a (2.66 g, 49%) as

two single diastereomers in a E/Z 1.5:1 ratio as a colorless

oil. R_f0.28 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

(300 MHz, CDCl₃) d 1.24–1.50 (m, 4H, CH₂), 1.62–1.70

(m, 4H, CH₂), 1.96–2.00 (m, 2H, CH₂), 2.44 (dd, J¼8.0,

1.3 Hz, 2H, CH₂CHv), 3.84 (s, 3H, OCH₃), 5.96 (dt,

J¼15.6, 1.3 Hz, 1H, vCHCO₂CH₃), 6.93 (dt, J¼15.6,

8.0 Hz, 1H, CHvCHCO₂CH₃), 9.66 (s, 1H, CHO); ¹³C

NMR (75.5 MHz, CDCl₃) d 22.6 (CH₂), 25.8 (CH₂), 31.4

(CH₂), 38.8 (CH₂), 50.1 (CCy), 51.9 (OCH₃), 124.6

(vCHCO₂CH₃), 143.7

(CHvCHCO₂CH₃), 166.7

Column chromatography was performed using BDH silica

gel (40–60 mm). Analytical thin layer chromatography was

performed on pre-coated aluminium-backed plates (Merck

Keisekgel 60 F₂₅₄) and visualised by 254 nm UV or by

staining with basic potassium permanganate solution

followed by heat.

(CO₂CH₃), 206.1 (CHO); FTIR (ﬁlm) n 1799, 1732,

1656 cm²¹; LRMS (APCI^þ) m/z 211 (M^þþH, 44), 179

(100), 149 (39); HRMS (CI^þ) calcd for C₁₂H₁₉O₃(M^þþH)

211.13341, found 211.13323.

4.2.4. i-Propyl (E)-4-(1-formyl-cyclohexyl)-2-butenoate

((E)-5b). As for general procedure A. Reaction of i-propyl

2-hydroxy-3-butenoate 2b (3.0 g, 20.8 mmol) and cyclo-

hexanecarboxaldehyde (2.33 g, 20.8 mmol) gave, after

puriﬁcation by column chromatography eluting with P.E.

30–40 8C/EtOAc (80:20), the aldehyde 5b (3.02 g, 61%) as

two single diastereomers in a E/Z 1.5:1 ratio as a colorless

oil. R_f0.58 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

4.2. General procedure A for the synthesis of cyclisation

substrates via Claisen rearrangement

A mixture of methyl 2-hydroxy-3-butenoate 2a (2.0 g,

17.2 mmol), isobutyraldehyde (1.86 g, 25.8 mmol) and a

small amount of p-toluenesulfonic acid (10 mg) in 10 mL of

toluene, was heated under reﬂux for 48 h with provision of a

Dean and Stark apparatus for the removal of water. After

evaporation of the solvent under reduced pressure, the crude

oil was puriﬁed by ﬂash column chromatography employing

P.E. 30–40 8C/EtOAc (80:20) as eluant to afford the desired

product 4 (1.54 g, 53%) as two single diastereomers in a E/Z

2:1 ratio as a colorless oil.

(300 MHz, CDCl₃)

d

1.18 (d, J¼6.3 Hz, 6H,

OCH(CH₃)₂), 1.19–1.32 (m, 4H, CH₂), 1.39–1.57 (m,

4H, CH₂), 1.78–1.90 (m, 2H, CH₂), 2.24 (dd, J¼7.8,

1.2 Hz, 2H, CH₂), 4.97 (m, 1H, OCH(CH₃)₂); 5.73 (dt,

J¼15.5, 1.2 Hz, 1H, vCHCO₂iPr), 6.70 (dt, J¼15.5,

7.8 Hz, 1H, CHvCHCO₂iPr), 9.41 (s, 1H, CHO); ¹³C

NMR (75.5 MHz, CDCl₃) d 22.2 (OCH(CH₃)₂), 22.6 (CH₂),

25.8 (CH₂), 31.2 (CH₂), 38.9 (CH₂CHv), 50.1 (CCy), 68.1

(OCH(CH₃)₂), 125.6 (vCHCO₂iPr), 143.0 (CHvCHCO₂-

iPr), 165.8 (CO₂iPr), 206.2 (CHO); FTIR (ﬁlm) n 2934,

2856, 1798, 1719, 1655, 1452, 1273, 1200 cm²¹; LRMS

(CI^þ) m/z 239 (M^þþH, 58), 209 (83), 167 (100); HRMS

(CI^þ) calcd for C₁₄H₂₃O₃(M^þþH) 239.16471, found

239.16435.

4.2.1. Methyl (E)-5,5-dimethyl-6-oxo-2-hexenoate ((E)-4).

R_f0.20 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR (300 MHz,

CDCl₃) d 1.14 (s, 6H, C(CH₃)₂), 2.41 (dd, J¼7.8, 1.4 Hz, 2H,

CH₂), 3.79 (s, 3H, OCH₃), 5.93 (dt, J¼15.6, 1.4 Hz, 1H,

vCHCO₂CH₃), 6.93 (dt, J¼15.6, 7.8 Hz, 1H, CHvCHCO_2-

CH₃),9.60(s, 1H, CHO);¹³CNMR(75.5 MHz, CDCl₃)d21.8

(C(CH₃)₂), 39.7 (CH₂), 46.2 (C(CH₃)₂), 51.9 (OCH₃),

124.6 (vCHCO₂CH₃), 144.2 (CHvCHCO₂CH₃), 166.8

(CO₂CH₃), 205.0 (CHO); FTIR (ﬁlm) n 1803, 1730,

1645 cm²¹; LRMS (EI^þ) m/z 171 (M^þþ1, 50), 139 (100),

109 (79), 81 (73), 41 (33); HRMS (EI^þ) calcd for C₉H₁₄O₃

(M^þ) 170.09429, found 170.09400.

4.2.5. i-Propyl (E)-5,5-diphenyl-6-oxo-2-hexenoate ((E)-

6). According to the general procedure A, reaction of

i-propyl 2-hydroxy-3-butenoate 2b (1.5 g, 10.4 mmol) and

2,2-diphenylacetaldehyde (2.04 g, 10.4 mmol) gave, after

puriﬁcation by column chromatography eluting with P.E.

30–40 8C/EtOAc (90:10), aldehyde 6 (2.15 g, 64%) as two

isomers in a E/Z 2:1 ratio as a yellow oil. R_f0.53 (P.E.

4.2.2. Methyl (Z)-5,5-dimethyl-6-oxo-2-hexenoate ((Z)-

4). R_f0.25 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

1

30–40 8C/EtOAc, 90:10); H NMR (300 MHz, CDCl₃) d

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2683

1.11 (d, J¼6.3 Hz, 6H, CH(CH₃)₂), 3.11 (dd, J¼7.4, 1.1 Hz,

2H, CH₂), 4.88 (m, 1H, CH(CH₃)₂), 5.62 (dt, J¼15.6,

1.1 Hz, 1H, vCHCO₂iPr), 6.62 (dt, J¼15.6, 7.4 Hz, 1H,

CHvCHCO₂iPr), 7.08–7.33 (m, 10H, Ph), 9.74 (s, 1H,

CHO); ¹³C NMR (75.5 MHz, CDCl₃) d 22.2 (CH(CH₃)₂),

37.4 (CH₂), 63.9 (CPh₂), 67.8 (CH(CH₃)₂), 125.4

(vCHCO₂iPr), 128.1 (Ph), 129.3 (Ph), 139.3 (Ph), 144.1

(CHvCHCO₂iPr), 165.9 (CO₂iPr), 197.9 (CHO); FTIR

(ﬁlm) n 2982, 2936, 1796, 1720, 1656, 1277, 908,

735 cm²¹; LRMS (FAB^þ) m/z 323 (M^þþH, 23), 307

(12), 263 (16), 245 (5), 167 (17), 154 (100); HRMS (FAB^þ)

calcd for C₂₁H₂₃O₃(M^þþH) 323.16471, found 323.16428.

mixture becomes viscous near the end of the addition, but

redissolved on continued stirring. After the addition was

ﬁnished, the reaction mixture was stirred for further 1 h at

0 8C. Then, a solution of 5-hexen-2-one (10.0 g,

101.9 mmol) in 150 mL of dry tetrahydrofuran was added

dropwise. The cold mixture was stirred for further 15 min

after the addition. Then, it was slowly brought to reﬂux and

stirred overnight. The clear ether layer was decanted from

the oil. The remaining oil was dissolved in warm water and

the upper organic layer was separated. The aqueous layer

was extracted with ether. The combined organic layers

were washed with saturated NaHCO₃, dried over Na₂SO₄,

ﬁltered and the solvents were removed in vacuo. Puri-

ﬁcation by ﬂash column chromatography employing P.E.

30–40 8C/EtOAc (80:20) as eluant afforded the enoate 13

(13.67 g, 87%) as two single diastereomers in a E/Z 2:1 ratio

as a colorless oil.

4.2.6. Methyl (E)-6-oxo-2-hexenoate ((E)-7). According to

the general procedure A, methyl 2-hydroxy-3-butenoate 2a

(2.0 g, 17.2 mmol) and acetaldehyde diethyl acetal (3.05 g,

25.8 mmol) were heated under reﬂux using a Soxhlet

˚

extractor containing freshly conditioned 4 A molecular

sieves for 4 days. The sieves were replaced ﬁve times with a

freshly conditioned batch. Puriﬁcation by column chroma-

tography eluting with P.E. 30–40 8C/EtOAc (60:40) gave

the aldehyde 7⁵²(1.13 g, 46%) as two single diastereomers

in a E/Z 2.2:1 ratio as a colorless oil. R_f0.50 (P.E.

4.3.1. Methyl (E)-3-methyl-2,6-heptadienoate ((E)-13).

R_f0.73 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR (500 MHz,

CDCl₃) d 2.09 (d, J¼1.3 Hz, 3H, CH₃), 2.16–2.18 (m, 4H,

CH₂), 3.61 (s, 3H, OCH₃), 4.89 (dq, J¼10.1, 1.8 Hz, 1H,

CHvCH_cisH), 4.96 (dq, J¼17.1, 1.8 Hz, 1H,

CHvCHH_trans), 5.60 (m, 1H, vCHCO₂CH₃), 5.66–5.78

(m, 1H, CHvCH₂); ¹³C NMR (125 MHz, CDCl₃) d 18.7

(CH₃), 31.4 (CH₂), 40.1 (CH₂), 50.7 (OCH₃), 115.3

(vCH₂), 115.4 (vCHCO₂CH₃), 137.2 (CHvCH₂), 159.4

(CvCHCO₂CH₃), 167.1 (CO₂CH₃); FTIR (ﬁlm) n 3078,

2926, 2853, 1720, 1651, 1435, 1225, 1151 cm²¹; LRMS

(DCI^þ) m/z 155 (M^þþH, 100), 139 (8), 123 (26), 95 (63);

HRMS (DCI^þ) calcd for C₉H₁₅O₂(M^þþH) 155.10719,

found 155.10696.

1

30–40 8C/EtOAc, 60:40); H NMR (300 MHz, CDCl₃) d

2.73–2.78 (m, 2H, CH₂CHv), 2.85 (t, J¼7.3 Hz, 2H,

CH₂CHO), 3.94 (s, 3H, OCH₃), 6.08 (dt, J¼15.7, 1.5 Hz,

1H, vCHCO₂CH₃), 7.16 (dt, J¼15.7, 6.7 Hz, 1H,

CHvCHCO₂CH₃), 9.97 (s, 1H, CHO); ¹³C NMR

(75.5 MHz, CDCl₃) d 24.8 (CH₂CHv), 42.2 (CH₂CHO),

51.9 (OCH₃), 122.4 (vCHCO₂CH₃), 147.0 (CHvCHCO₂-

CH₃), 167.0 (CO₂CH₃), 200.5 (CHO); FTIR (ﬁlm) n 2953,

2849, 2731, 1724, 1659, 1437, 1165 cm²¹

.

4.2.7. Methyl (2E,7E)-6-oxo-8-phenyl-2,7-octadienoate

(8). According to the general procedure A, reaction of

methyl 2-hydroxy-3-butenoate 2a (2.0 g, 17.2 mmol) and

benzylideneacetone (2.48 g, 17.2 mmol) gave, after puri-

ﬁcation by column chromatography eluting with P.E.

30–40 8C/EtOAc (80:20), the ketone 8 (2.44 g, 58%) as a

single E-diastereomer as a yellow oil. R_f0.37 (P.E.

4.3.2. Methyl (E)-4,4-dimethyl-2,6-heptadienoate (17).

According to the general procedure B, reaction of 4,4-

dimethyl pentenal 16 (23.0 g, 205.0 mmol) with a mixture

of 80% sodium hydride dispersion in oil (6.77 g,

225.6 mmol) and trimethylphosphonoacetate (41.0 g,

225.6 mmol) gave, after puriﬁcation by column chromato-

graphy eluting with P.E. 30–40 8C/EtOAc (80:20), the

enoate 17 (30.3 g, 88%) as a single E-isomer as a colorless

oil. R_f0.67 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

(300 MHz, CDCl₃) d 0.98 (s, 6H, C(CH₃)₂), 2.04 (d,

J¼7.4 Hz, 2H, CH₂CHv), 3.66 (s, 3H, OCH₃), 4.92–5.02

(m, 2H, CHvCH₂), 5.56–5.72 (m, 1H, CHvCH₂), 5.66 (d,

J¼15.7 Hz, 1H, vCHCO₂CH₃), 6.88 (d, J¼15.7 Hz, 1H,

CHvCHCO₂CH₃); ¹³C NMR (75.5 MHz, CDCl₃) d 26.4

(C(CH₃)₂), 37.1 (C(CH₃)₂), 46.8 (CH₂), 51.8 (OCH₃), 117.9

(vCHCO₂CH₃), 118.2 (vCH₂), 134.6 (CHvCH₂), 158.3

(CHvCHCO₂CH₃), 167.9 (CO₂CH₃); FTIR (ﬁlm) n 2964,

2872, 1719, 1653, 1265 cm²¹; LRMS (APCI^þ) m/z 169

(M^þþH, 10), 137 (10), 127 (63), 109 (100); HRMS (ES^þ)

calcd for C₁₀H₁₇O₂(M^þþH) 169.1239, found 169.1232.

1

30–40 8C/EtOAc, 80:20); H NMR (300 MHz, CDCl₃) d

2.56 (qd, J¼6.9, 1.4 Hz, 2H, CH₂CHv), 2.82 (t, J¼6.9 Hz,

2H, CH₂CO), 3.70 (s, 3H, OCH₃), 5.86 (dt, J¼15.6, 1.4 Hz,

1H, vCHCO₂CH₃), 6.72 (d, J¼16.2 Hz, 1H, CHvCHPh),

6.99 (dt, J¼15.6, 6.9 Hz, 1H, CHvCHCO₂CH₃), 7.37–

7.54 (m, 5H, Ph), 7.60 (d, J¼16.2 Hz, 1H, CHvCHPh); ¹³C

NMR (75.5 MHz, CDCl₃) d 26.7 (CH₂CHv), 39.1

(CH₂CHO), 51.8 (OCH₃), 122.1 (vCHCO₂CH₃), 126.2

(CHvCHPh), 128.7 (Ph), 129.3 (Ph), 131.0 (Ph), 134.8

(Ph), 143.3 (CHvCHPh), 148.0 (CHvCHCO₂CH₃), 167.2

(CO₂CH₃), 198.4 (CO); FTIR (ﬁlm) n 3055, 1719, 1659,

1612, 1578, 1265, 739, 704 cm²¹; LRMS (FAB^þ) m/z 245

(M^þþH, 100), 213 (78), 167 (39); HRMS (FAB^þ) calcd for

C₁₅H₁₇O₃(M^þþH) 245.11776, found 245.11782.

4.4. General ozonolysis procedure C for the synthesis of

cyclisation substrates

4.3. General oleﬁnation procedure B for the synthesis of

cyclisation substrates

A solution of 4-but-3-enyl-5H-furan-2-one 12 (0.6 g,

4.3 mmol) and pyridine (0.2 mL, 1% vol) in anhydrous

dichloromethane (20 mL) was cooled to 278 8C. A stream

of ozone was bubbled through the solution, and the reaction

was carefully monitored by TLC. After consumption of the

starting material the ﬂask was ﬂushed with nitrogen.

A suspension of 80% sodium hydride dispersion in mineral

oil (3.64 g, 121.2 mmol) in 100 mL of dry tetrahydrofuran

under a positive nitrogen pressure was stirred in an ice bath

while trimethylphosphonoacetate (22.07 g, 121.2 mmol) in

100 mL of dry tetrahydrofuran was added dropwise. The

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2684

Dimethylsulﬁde was added (0.27 g, 43.4 mmol) and the

mixture was allowed to warm to room temperature

overnight. The solution was then extracted with dichloro-

methane. The combined organic layers were dried over

Na₂SO₄, ﬁltered and the ﬁltrate concentrated under reduced

pressure. The resulting crude oil was puriﬁed by ﬂash

column chromatography eluting with EtOAc to afford the

aldehyde 9 (0.33 g, 49%) as a yellow oil.

freezing and then cooled in an ice–salt bath. A solution of

trimethyl sulfonium iodide (0.66 g, 3.2 mmol) in 3 mL of

dry dimethylsulfoxide was added and the mixture stirred for

5 min. The aldehyde 15 was then added (0.5 g, 2.9 mmol)

and stirring was continued at salt–ice temperature for

further 15 min, then for 1 h at room temperature. The

mixture was diluted with 3 volumes of water and extracted

with ether. The combined organic layers were dried over

Na₂SO₄, ﬁltered and the ﬁltrate concentrated under reduced

pressure. The resulting crude oil was puriﬁed by ﬂash

column chromatography eluting with P.E. 30–40 8C/EtOAc

(90:10) to afford the epoxide 18 (0.18 g, 33%) as a colorless

oil. R_f0.28 (P.E. 30–40 8C/EtOAc, 90:10); ¹H NMR

(300 MHz, CDCl₃) d 1.11 (s, 3H, CH₃), 1.20 (s, 3H,

CH₃), 1.47–1.54 (m, 2H, CH₂), 2.34 (dd, J¼5.0, 2.7 Hz,

1H, CH_aHO), 2.66 (dd, J¼5.0, 4.1 Hz, 1H, CHH_bO), 2.80–

2.82 (m, 1H, CHO), 3.67 (s, 3H, OCH₃), 5.67 (d,

J¼16.0 Hz, 1H, vCHCO₂CH₃), 6.93 (d, J¼16.0 Hz, 1H,

CHvCHCO₂CH₃); ¹³C NMR (75.5 MHz, CDCl₃) d 26.7

(CH₃), 27.3 (CH₃), 37.0 (C(CH₃)₂), 45.2 (CH₂), 47.0

(CH₂O), 49.4 (CHO), 51.9 (OCH₃), 118.3 (vCHCO₂CH₃),

157.6 (CHvCHCO₂CH₃), 167.7 (CO₂CH₃); FTIR (ﬁlm) n

4.4.1. 3-(5-Oxo-2,5-dihydrofuran-3-yl)propionaldehyde

(9). R_f0.35 (EtOAc); ¹H NMR (300 MHz, CDCl₃) d

2.50–2.57 (m, 2H, CH₂CH₂CHO), 2.70 (t, J¼7.4 Hz, 2H,

CH₂CHO), 4.93 (d, J¼1.5 Hz, 2H, OCH₂), 6.04–6.06 (m,

1H, vCHCO₂R), 9.79 (s, 1H, CHO); ¹³C NMR (75.5 MHz,

CDCl₃) d 21.1 (CH₂CH₂CHO), 41.4 (CH₂CHO), 73.4

(OCH₂), 116.4 (vCHCO₂R), 168.7 (CvCHCO₂R), 173.8

(CO₂R), 199.4 (CHO); FTIR (ﬁlm) n 2853, 1744, 1636,

1391, 1182 cm²¹; HRMS (FAB^þ) calcd for C₇H₉O₃

(M^þþH) 141.05516, found 141.05505.

4.4.2. Methyl (E)-3-methyl 6-oxo-2-hexenoate (10).

According to the general procedure C, ozonolysis of methyl

(E)-3-methyl-2,6-heptadienoate 13 (15.0 g, 97.3 mmol)

gave, after puriﬁcation by column chromatography

eluting with P.E. 30–40 8C/EtOAc (90:10), the

aldehyde 10⁵³(6.23 g, 41%) as a colorless oil. R_f0.37

(P.E. 30–40 8C/EtOAc, 90:10); ¹H NMR (500 MHz,

CDCl₃) d 2.15 (d, J¼1.3 Hz, 3H, CH₃), 2.45 (td, J¼7.6,

1.1 Hz, 2H, CH₂CHO), 2.61 (td, J¼7.6, 1.3 Hz, 2H,

CH₂CH₂CHO), 3.65 (s, 3H, OCH₃), 5.61 (m, 1H,

vCHCO₂CH₃), 9.77 (t, J¼1.1 Hz, 1H, CHO); ¹³C NMR

(125 MHz, CDCl₃) d 19.1 (CH₃), 33.0 (CH₂), 41.8 (CH₂),

51.3 (OCH₃), 116.4 (vCHCO₂CH₃), 157.7 (CvCHCO₂-

CH₃), 167.2 (CO₂CH₃), 200.8 (CHO); FTIR (ﬁlm) n 2951,

3054, 2969, 2931, 2874, 1717, 1652, 1436, 1265 cm²¹

;

LRMS (FAB^þ) m/z 185 (M^þþH, 66), 169 (8), 154 (100);

HRMS (FAB^þ) calcd for C₁₀H₁₇O₃(M^þþH) 185.11775,

found 185.11746.

4.5.2. Methyl (E)-4,4-dimethyl-8-oxo-2,6-nonadienoate

(19). According to the general procedure B, reaction of

methyl (E)-4,4-dimethyl-6-oxo-2-hexenoate 15 (1.5 g,

8.9 mmol) with a mixture of 80% sodium hydride dispersion

in oil (0.26 g, 9.7 mmol) and dimethyl-(2-oxopropyl)-

phosphonate (1.6 g, 9.7 mmol) gave, after puriﬁcation by

column chromatography eluting with P.E. 30–40 8C/EtOAc

(90:10), the enoate 19⁵⁵(1.7 g, 92%) as a colorless oil. R_f

2845, 2729, 1719, 1649, 1437, 1362, 1229, 1153 cm²¹

.

1

0.66 (P.E. 30–40 8C/EtOAc, 90:10); H NMR (300 MHz,

4.4.3. Methyl (E)-4,4-dimethyl-6-oxo-2-hexenoate (15).

According to the general procedure C, ozonolysis of methyl

(E)-4,4-dimethyl-2,6-heptadienoate 17 (30.0 g, 178.3

mmol) gave, after puriﬁcation by column chromatography

eluting with P.E. 30–40 8C/EtOAc (90:10), the aldehyde

15⁵⁴(14.57 g, 48%) as a colorless oil. R_f0.28 (P.E.

CDCl₃) d 1.10 (s, 6H, C(CH₃)₂), 2.22 (s, 3H, CH₃CO), 2.28

(dd, J¼7.6, 1.2 Hz, 2H, CH₂CHv), 3.74 (s, 3H, OCH₃),

5.76 (d, J¼16.0 Hz, 1H, vCHCO₂CH₃), 6.07 (dt, J¼15.8,

1.2 Hz, 1H, vCHCOCH₃), 6.65 (dt, J¼15.8, 7.6 Hz, 1H,

CHvCHCOCH₃), 6.93 (d, J¼16.0 Hz, 1H, CHvCHCO₂-

CH₃); ¹³C NMR (75.5 MHz, CDCl₃) d 26.8 (C(CH₃)₂), 27.5

(COCH₃), 37.5 (C(CH₃)₂), 45.2 (CH₂), 51.9 (OCH₃), 118.7

1

30–40 8C/EtOAc, 90:10); H NMR (300 MHz, CDCl₃) d

1.30 (s, 6H, C(CH₃)₂), 2.52 (d, J¼2.7 Hz, 2H, CH₂CHO),

3.83 (s, 3H, OCH₃), 5.89 (d, J¼16.0 Hz, 1H, vCHCO₂-

CH₃), 7.13 (d, J¼16.0 Hz, 1H, CHvCHCO₂CH₃), 9.84 (t,

J¼2.7 Hz, 1H, CHO); ¹³C NMR (125 MHz, CDCl₃) d 27.2

(C(CH₃)₂), 36.2 (C(CH₃)₂), 52.0 (OCH₃), 54.6 (CH₂), 118.9

(vCHCO₂CH₃), 155.9 (CHvCHCO₂CH₃), 167.3

(CO₂CH₃), 201.6 (CHO); FTIR (ﬁlm) n 2930, 2853, 2729,

1730, 1654, 1462 cm²¹; LRMS (APCI^þ) m/z 171 (M^þþH,

8), 155 (46), 139 (100); HRMS (ES^þ) calcd for C₉H₁₅O₃

(M^þþH) 171.1007, found 171.1011.

(vCHCO₂CH₃),

134.3

(vCHCOCH₃),

143.6

(CHvCHCOCH₃), 156.9 (CHvCHCO₂CH₃), 167.5

(CO₂CH₃), 198.4 (COCH₃); FTIR (ﬁlm) n 2964, 2845,

1724, 1655, 1628, 1437, 1367, 1256, 1171 cm²¹; LRMS

(ES^þ) m/z: 233 (M^þþNa, 96), 211 (M^þþH, 65), 179 (100);

HRMS (ES^þ) m/z: requires 211.1335 for C₁₂H₁₉O₃

(M^þþH), found 211.1334.

4.5.3. Methyl (E)-cis-3-(2-hydroxymethyl-cyclohexyl)-

acrylate (22). To a stirred solution of hexahydro-isobenzo-

furan-1-one (5.5 g, 38.7 mmol) in 100 mL of anhydrous

ether at 220 8C under positive nitrogen pressure, DIBAL

(1.22 M solution in toluene) (33.3 mL, 40.6 mmol) was

added dropwise over 1 h. The resulting solution was stirred

at 220 8C for an additional 0.5 h, and was then quenched by

the addition of methanol (30 mL). The solution was allowed

to warm to room temperature and stirred overnight. The

resulting suspension was diluted with 50 mL of 30%

aqueous solution of Rochelle’s salt and was stirred for

30 min. The organic layer was separated and washed with

4.5. Synthesis of other cyclisation substrates

4.5.1. Methyl (E)-4,4-dimethyl-5-oxiranyl-2-pentenoate

(18). A mixture of 60% sodium hydride dispersion in

mineral oil (0.13 g, 3.2 mmol) and excess anhydrous

dimethylsulfoxide (5 mL) was stirred under nitrogen at

75 8C until the evolution of hydrogen ceases (1 h). The

solution was then cooled down to room temperature, diluted

with an equal volume of dry tetrahydrofuran to avoid

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2685

30% aqueous solution of Rochelle’s salt. The combined

aqueous layers were extracted with ether. The organic layers

were dried over Na₂SO₄, ﬁltered and the ﬁltrate concen-

trated under reduced pressure to afford the crude lactol

that was added to a stirred solution of methyl(triphenyl-

phosphoranylidene)acetate (18.55 g, 55 mmol) in 150 mL

of dry acetonitrile and heated at reﬂux under a nitrogen

atmosphere for 2 days. The heat was removed and most of

the solvent was evaporated in vacuo. Ether (25 mL) was

added and the mixture was stirred for an additional 2 h. The

resulting mixture was ﬁltered and the ﬁltrate washed with

15 mL of ether. The solvent was removed in vacuo and

20 mL of 70% ether in pentane was added. After stirring for

further 30 min, the suspension was ﬁltered again and the

ﬁltrate concentrated under reduced pressure. The resulting

crude oil was puriﬁed by ﬂash column chromatography

eluting with P.E. 30–40 8C/EtOAc (80:20) to afford the

alcohol 22 (5.22 g, 68%) as a single E diastereoisomer as a

122.0 (vCHCO₂CH₃, cis), 149.7 (CHvCHCO₂CH₃, cis),

151.0 (CHvCHCO₂CH₃, trans), 167.1 (CO₂CH₃, cisþ

trans), 203.6 (CHO, trans), 204.1 (CHO, cis); FTIR (ﬁlm) n

2937, 2858, 1719, 1655, 1437, 1277, 1175 cm²¹; LRMS

(FAB^þ) m/z 197 (M^þþH, 15), 181 (24), 165 (30); HRMS

(FAB^þ) calcd for C₁₁H₁₇O₃(M^þþH) 197.11776, found

197.11916.

4.5.5. Methyl (E)-3-(2-formyl-cyclohex-1-enyl)-acrylate

(23b). A mixture of 2-bromo-cyclohexene-1-carboxalde-

hyde 24 (1.5 g, 7.9 mmol), methyl acrylate (0.81 g,

9.5 mmol), triethylamine (0.96 g, 9.5 mmol), palladium

acetate (18 mg, 0.079 mmol) and triphenylphosphine

(42 mg, 0.158 mmol), was heated at reﬂux under a positive

pressure of nitrogen for 3 days. The heat was removed and

the reaction mixture was diluted with ether and ﬁltered. The

solids were washed several times with small portions of

ether, and the ﬁltrate was concentrated under reduced

pressure. The resulting crude oil was puriﬁed by ﬂash

column chromatography eluting with P.E. 30–40 8C/EtOAc

(90:10) to afford the aldehyde 23b (0.85 g, 55%) as a

1

colorless oil. R_f0.33 (P.E. 30–40 8C/EtOAc, 80:20); H

NMR (300 MHz, CDCl₃) d 1.30–1.74 (m, 8H, CH₂), 1.86–

1.97 (m, 1H, CHCH₂OH), 2.72–2.78 (m, 1H, CHCHv),

3.52 (d, J¼7.2 Hz, 2H, CH₂OH), 3.80 (s, 3H, OCH₃), 5.95

(dd, J¼15.6, 0.8 Hz, 1H, vCHCO₂CH₃), 7.23 (dd, J¼15.6,

9.0 Hz, 1H, CHvCHCO₂CH₃); ¹³C NMR (75.5 MHz,

CDCl₃) d 22.7 (CH₂), 25.1 (CH₂), 25.5 (CH₂), 30.7 (CH₂),

29.7 (CHCH₂OH), 43.0 (CHCHv), 51.8 (OCH₃), 65.3

(CH₂OH), 121.9 (vCHCO₂CH₃), 150.4 (CHvCHCO₂-

CH₃), 167.4 (CO₂CH₃); FTIR (ﬁlm) n 3423, 2928, 2858,

1707, 1649, 1437, 1375, 1271, 1238, 1172 cm²¹; LRMS

(EI^þ) m/z 198 (M^þ, 3), 167 (53), 81 (95), 67 (100); HRMS

(EI^þ) calcd for C₁₁H₁₈O₃(M^þ) 198.12558, found

198.12538.

1

colorless oil. R_f0.39 (P.E. 30–40 8C/EtOAc, 90:10); H

NMR (300 MHz, CDCl₃) d 1.54–1.67 (m, 4H, CH₂), 2.29–

2.36 (m, 4H, CH₂), 3.73 (s, 3H, OCH₃), 6.07 (d, J¼15.6 Hz,

1H, vCHCO₂CH₃), 8.22 (d, J¼15.6 Hz, 1H, CHvCHCO_2-

CH₃), 10.35 (s, 1H, CHO); ¹³C NMR (75.5 MHz, CDCl₃) d

21.5 (CH₂), 22.0 (CH₂), 23.8 (CH₂), 27.3 (CH₂), 52.3

(OCH₃), 122.2 (vCHCO₂CH₃), 138.9 (CHvCHCO₂CH₃),

141.0 (vCCHO), 148.2 (CvCCHO), 167.2 (CO₂CH₃),

190.3 (CHO); FTIR (ﬁlm) n 2937, 2864, 1720, 1668, 1622,

1587, 1435, 1375, 1300, 1277, 1175 cm²¹; LRMS (EI^þ) m/z

195 (M^þþH, 8), 165 (38), 135 (100); HRMS (EI^þ) calcd for

C₁₁H₁₅O₃(M^þþH) 195.10210, found 195.10196.

4.5.4. Methyl (E)-3-(2-formyl-cyclohexyl)-acrylate (20).

To a stirred suspension of pyridinium chlorochromate

(1.95 g, 9.1 mmol) and celite (2.1 g) in 15 mL of anhydrous

dichloromethane, was added at room temperature and under

a positive pressure of nitrogen, a solution of methyl (E)-cis-

4.5.6. Methyl (E)-3-(2⁰-formylphenyl)-propenoate (25).

Tetrabutylammonium bromide (0.56 g, 1.7 mmol),

potassium carbonate (0.80 g, 5.8 mmol), palladium acetate

(156 mg, 0.69 mmol) and methyl acrylate (2.97 g,

34.8 mmol) were stirred for 5 min under nitrogen, forming

a dark orange solution. A solution of o-bromobenzaldehyde

(1.28 g, 6.9 mmol) in 4 mL of degassed dimethylformamide

was then added and the reaction was stirred at 70 8C for

16 h. The resulting mixture was diluted with ethyl acetate

and ﬁltered through a short pad of celite. The ﬁltrate was

diluted with water and extracted with ethyl acetate. The

combined organic extracts were dried over MgSO₄, ﬁltered

and the ﬁltrate concentrated under reduced pressure.

Puriﬁcation by ﬂash column chromatography eluting with

P.E. 30–40 8C/EtOAc (90:10) enabled o-bromobenzalde-

hyde to be removed from the crude mixture, with the desired

aldehyde being isolated in 69% yield (when adjusted for

recovered starting material). All spectroscopic and analyti-

cal data were in agreement with the literature values.³⁶R_f

3-(2-hydroxymethyl-cyclohexyl)-acrylate

22

(1.2 g,

6.1 mmol) in 3 mL of dichloromethane. The reaction

mixture was stirred for 2 h at room temperature and was

then diluted with 50 mL of ether. The resulting suspension

was ﬁltered through a short pad of Florisil^w, rinsed with

several portions of ether and the solvent concentrated

under reduced pressure. The resulting crude oil was

puriﬁed by ﬂash column chromatography eluting with P.E.

30–40 8C/EtOAc (80:20) to afford the aldehyde 20 (0.90 g,

76%) as a colorless oil. R_f0.67 (P.E. 30–40 8C/EtOAc,

1

80:20); H NMR (300 MHz, CDCl₃) d 1.52–1.98 (m, 8H,

CH₂, cisþtrans), 2.28–2.37 (m, 1H, CHCHO, trans), 2.49–

2.61 (m, 1H, CHCHv, trans), 2.64–2.67 (m, 1H, CHCHO,

cis), 2.86–2.89 (m, 1H, CHCHv, cis), 3.79 (s, 3H, OCH₃,

trans), 3.80 (s, 3H, OCH₃, cis), 5.91 (dd, J¼15.8, 1.2 Hz,

1H, vCHCO₂CH₃, trans), 5.94 (dd, J¼15.8, 1.3 Hz, 1H,

vCHCO₂CH₃, cis), 6.94 (dd, J¼15.8, 8.0 Hz, 1H,

CHvCHCO₂CH₃, trans), 7.20 (dd, J¼15.8, 7.3 Hz, 1H,

CHvCHCO₂CH₃, cis), 9.64 (d, J¼2.3 Hz, 1H, CHO,

trans), 9.73 (s, 1H, CHO, cis); ¹³C NMR (75.5 MHz,

CDCl₃) d 23.7 (CH₂, cis), 23.9 (CH₂, cis), 24.3 (CH₂, cis),

24.9 (CH₂, trans), 25.1 (CH₂, trans), 25.9 (CH₂, trans), 29.6

(CH₂, cis), 31.3 (CH₂, trans), 39.5 (CHCHO, cis), 40.5

(CHCHO, trans), 51.9 (OCH₃, cisþtrans), 52.2 (CHCHv,

cis), 54.2 (CHCHv, trans), 121.5 (vCHCO₂CH₃, trans),

1

0.32 (P.E. 30–40 8C/EtOAc, 90:10); H NMR (300 MHz,

CDCl₃) d 3.85 (s, 3H, OCH₃), 6.40 (d, J¼15.9 Hz, 1H,

vCHCO₂CH₃), 7.56–7.91 (m, 4H, Ph), 8.55 (d,

J¼15.9 Hz, 1H, CHvCHCO₂CH₃), 10.31 (s, 1H, CHO);

FTIR (ﬁlm) n 1728, 1699, 1621 cm²¹

.

4.5.7. a-Benzyloxy-g-butyrolactone (29). A suspension of

60% sodium hydride dispersion in mineral oil (2.15 g,

54 mmol) and a-hydroxy-g-butyrolactone (5.0 g, 49 mmol)

in dry tetrahydrofuran (50 mL) was stirred at 0–5 8C for

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M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2686

0.5 h. Benzyl bromide (7.3 mL, 61.3 mmol) and tetrabutyl-

ammonium iodide (1.18 g, 4.9 mmol) were then added. The

resulting suspension was stirred at ambient temperature for

3 h, and then a saturated NaHCO₃solution (50 mL) was

cautiously added. The aqueous layer was extracted with

dichloromethane and the combined organic extracts were

dried over MgSO₄, ﬁltered and the ﬁltrate concentrated

under reduced pressure. The resulting brown oil was

puriﬁed by ﬂash column chromatography eluting with P.E.

30–40 8C/EtOAc (60:40) to afford the product 29 (5.70 g,

61%) as a colorless oil. R_f0.34 (P.E. 30–40 8C/EtOAc,

with dichloromethane. The combined organic extracts were

dried over MgSO₄, ﬁltered and the ﬁltrate concentrated

under reduced pressure. Puriﬁcation of the pale green oil by

ﬂash column chromatography eluting with P.E. 30–

40 8C/EtOAc (60:40) afforded the title compound as a

mixture of Z and E isomers in a 1:4.3 ratio (1.89 g, 78%). R_f

1

0.29 (P.E. 30–40 8C/EtOAc, 60:40); H NMR (400 MHz,

CDCl₃) d 1.82–1.88 (m, 2H, CH₂CH₂OH), 3.73–3.79 (m,

5H, CH₂OH and OCH₃), 4.23 (q, J¼7.0 Hz, 1H, BnOCH,

E), 4.41–4.57 (dd, J¼11.0, 6.0 Hz, 2H, PhCH₂O, Z), 4.31–

4.65 (dd, J¼11.0, 6.0 Hz, 2H, PhCH₂O, E), 5.19–5.25 (q,

J¼7.0 Hz, 1H, BnOCH, Z); 5.95 (d, J¼12.0 Hz, 1H,

vCHCO₂CH₃, Z), 6.05–6.10 (d, J¼17.0 Hz, 1H,

vCHCO₂CH₃, E), 6.25 (dd, J¼12.0, 6.0 Hz, 1H,

CHvCHCO₂CH₃, Z), 6.90 (dd, J¼17.0, 6.0 Hz, 1H,

CHvCHCO₂CH₃, E), 7.28–7.38 (m, 5H, Ph); ¹³C NMR

(100 MHz, CDCl₃) d 37.2 (CH₂CH₂OH, E), 37.3 (CH₂-

CH₂OH, Z), 51.7 (OCH₃, Z), 51.8 (OCH₃, E), 59.8 (CH₂OH,

E), 60.0 (CH₂OH, Z), 71.4 (CHOBn, E), 71.7 (CHOBn, Z),

74.5 (PhCH₂O, Z), 76.7 (PhCH₂O, E), 121.3 (vCHCO₂-

CH₃, Z), 122.0 (vCHCO₂CH₃, E), 127.9 (Ph, E), 128.0 (Ph,

Z), 128.5 (Ph, Z), 128.6 (Ph, E), 137.6 (Ph, E), 137.7 (Ph, Z),

147.7 (CHvCHCO₂CH₃, E), 150.9 (CHvCHCO₂CH₃, Z),

166.5 (CO₂CH₃, E), 166.6 (CO₂CH₃, Z); FTIR (ﬁlm) n

3431, 1730, 738, 699 cm²¹; LRMS (ES^þ) m/z 268

(M^þþNH₄, 38), 251 (M^þþH, 100), 233 (17), 210 (13);

HRMS (ES^þ) calcd for C₁₄H₂₂NO₄(M^þþNH₄) 268.1549,

found 268.1549.

1

60:40); H NMR (400 MHz, CDCl₃) d 2.24–2.56 (m, 2H,

CH₂CH₂O), 4.15–4.26 (m, 2H, OCH₂CH₂), 4.43 (t,

J¼8.0 Hz, 1H, OCHCH₂), 4.74 (d, J¼12.0 Hz, 1H, PhCH_a-

H_bO), 4.95 (d, J¼12.0 Hz, 1H, PhCH_aH_bO), 7.30–7.42 (m,

5H, Ph); ¹³C NMR (100 MHz, CDCl₃) d 29.9 (CH₂), 65.5

(CH₂OCO), 72.2 (OCH₂Ph), 72.5 (OCH), 128.1 (Ph), 128.2

(Ph), 128.6 (Ph), 137.0 (Ph), 175.0 (CO₂R); FTIR (ﬁlm) n

1781, 1175, 1142, 699 cm²¹; LRMS (ES^þ) m/z 210

(M^þþNH₄, 100), 193 (M^þþH, 31), HRMS (ES^þ) calcd

for C₁₁H₁₃O₃(M^þþH) 193.0852, found 193.0860.

4.5.8. a-Benzyloxy-g-butyrolactol (30). DIBAL (1.22 M

solution in toluene) (13.9 mL, 21 mmol) was added

dropwise to a stirred solution of a-benzyloxy-g-butyrol-

actone 29 (3.66 g, 19 mmol) in toluene (55 mL) at 275 8C

under positive nitrogen pressure. The resulting solution was

stirred at 270 8C for 3 h, and was then quenched by the

addition of methanol (1.5 mL). The mixture was allowed to

warm 210 to 0 8C, treated with 20% (w/v) aqueous solution

of Rochelle’s salt (50 mL) and the resulting mixture stirred

at ambient temperature for 30 min. The biphasic mixture

was separated, the aqueous layer extracted with toluene and

the combined organic layers washed with water. The

combined water washes were back extracted with toluene

and the combined organics dried over Na₂SO₄, ﬁltered and

the ﬁltrate concentrated under reduced pressure to afford a

pale green oil of sufﬁcient purity for further use (3.19 g,

4.5.10. Methyl 6-oxo-4-benzyloxy-2-hexenoate (28). To a

stirred suspension of pyridinium chlorochromate (2.1 g,

9.6 mmol) in 10 mL of anhydrous dichloromethane, was

added at room temperature and under a positive pressure of

nitrogen, a solution of methyl 6-hydroxy-4-benzyloxy-2-

hexenoate 31 (1.6 g, 6.4 mmol) in 10 mL of dichloro-

methane. The reaction mixture was stirred for 12 h at room

temperature and the solvent removed under reduced

pressure. The resulting crude oil was puriﬁed by ﬂash

column chromatography eluting with P.E. 30–40 8C/EtOAc

(80:20) which allowed separation of Z and E isomers as

clear oils (1.08 g, 67%).

1

87%). R_f0.27 (P.E. 30–40 8C/EtOAc, 60:40); H NMR

(400 MHz, CDCl₃) d 1.96–2.28 (m, 2H, CH₂CH₂O), 2.49

(d, J¼2.5 Hz, 1H, OH), 3.80–3.86 (m, 1H, BnOCHCH₂,

trans), 4.00–4.12 (m, 3H, BnOCHCH₂, cis and CH₂O), 4.57

(s, 2H, PhCH₂O, cis), 4.63 (d, J¼6.0 Hz, 2H, PhCH₂O,

trans), 5.35 (dd, J¼17.0, 6.0 Hz, 1H, CHOH, trans), 5.45 (d,

J¼2.5 Hz, 1H, CHOH, cis), 7.25–7.40 (m, 5H, Ph); ¹³C

NMR (100 MHz, CDCl₃) d 29.9 (CH₂, cisþtrans), 64.8

(CH₂O, trans), 67.0 (CH₂O, cis), 71.4 (OCH₂Ph, cis), 72.5

(OCH₂Ph, trans), 78.1 (OCH, trans), 83.4 (OCH, cis), 96.3

(HOCH, trans), 100.7 (HOCH, cis), 127.9 (Ph, cis), 128.1

(Ph, trans), 128.2 (Ph, cisþtrans), 128.5 (Ph, cis), 128.6 (Ph,

trans), 137.2 (Ph, trans), 137.9 (Ph, cis); FTIR (ﬁlm) n

3397, 1071, 739, 699 cm²¹; LRMS (ES^þ) m/z 218

(M^þþNH₄), 195 (M^þþH), 177 (M^þ2H₂O).

Z isomer. R_f0.48 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

(400 MHz, CDCl₃) d 2.60–2.84 (m, 2H, CH₂CHO), 3.75 (s,

3H, OCH₃), 4.45–4.63 (dd, J¼12.0, 6.0 Hz, 2H, PhCH₂O),

5.50–5.63 (m, 1H, BnOCHCH₂); 6.00 (d, J¼12.0 Hz, 1H,

vCHCO₂CH₃), 6.80–6.95 (m, 1H, CHvCHCO₂CH₃),

7.25–7.38 (m, 5H, Ph), 9.75 (s, 1H, CHO); ¹³C NMR

(100 MHz, CDCl₃) d 48.4 (CH₂CHO), 51.6 (OCH₃), 71.0

(CHOBn), 71.7 (PhCH₂O), 121.5 (vCHCO₂CH₃), 127.9

(Ph), 128.4 (Ph), 137.7 (Ph), 149.7 (CHvCHCO₂CH₃),

166.1 (CO₂CH₃), 200.8 (CHO); FTIR (ﬁlm) n 2952, 1725,

698 cm²¹; LRMS (ES^þ) m/z 514 (2M^þþNH₄, 43), 266

(M^þþNH₄, 100), 249 (M^þþH, 27), 210 (14); HRMS (ES^þ)

calcd for C₁₄H₁₇O₄(M^þþH) 249.1116, found 249.1127.

4.5.9. Methyl 6-hydroxy-4-benzyloxy-2-hexenoate (31).

A

solution of a-benzyloxy-g-butyrolactol 30 (1.8 g,

9.3 mmol) in toluene (10 mL) was added to a stirred

suspension of carbomethoxymethyl triphenylphosphonium

bromide (4.25 g, 10 mmol) and potassium t-butoxide

(1.12 g, 10 mmol) in dry tetrahydrofuran (40 mL) which

were premixed at 0 8C for 30 min. The resulting suspension

was heated at 80 8C for 3 h, then cooled to ambient

temperature, diluted with water (30 mL), and extracted

E isomer. R_f0.45 (P.E. 30–40 8C/EtOAc, 80:20); ¹H NMR

(400 MHz, CDCl₃) d 2.68–2.90 (m, 2H, CH₂CHO), 3.77

(s, 3H, OCH₃), 4.42–4.65 (dd, J¼12.0, 6.0 Hz, 2H,

PhCH₂O), 5.50–5.63 (m, 1H, BnOCHCH₂); 6.15 (d,

J¼17.0 Hz, 1H, vCHCO₂CH₃), 6.85–6.98 (m, 1H,

CHvCHCO₂CH₃), 7.21–7.45 (m, 5H, Ph), 9.78 (s, 1H,

CHO); ¹³C NMR (100 MHz, CDCl₃) d 48.4 (CH₂CHO),

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2687

51.8 (OCH₃), 71.5 (CHOBn), 73.0 (PhCH₂O), 122.7

(vCHCO₂CH₃), 127.9 (Ph), 128.5 (Ph), 137.3 (Ph), 146.2

(CHvCHCO₂CH₃), 166.3 (CO₂CH₃), 199.0 (CHO);

HRMS (ES^þ) calcd for C₁₄H₁₇O₄(M^þþH) 249.1116,

found 249.1125.

2 M aqueous sodium hydroxide (10 mL) and extracted with

dichloromethane (60 mL). The combined organic extracts

were dried over MgSO₄, ﬁltered and the ﬁltrate concentrated

under reduced pressure. The resulting crude oil was puriﬁed

by ﬂash column chromatography eluting with P.E. 30–

40 8C/EtOAc (90:10) to afford the product 32 (0.73 g, 81%)

as a 3:1 mixture of cis and trans diastereomers as a colorless

oil. An identical procedure was followed when using

hydridotetrakis(triphenylphosphine) rhodium (I).

4.5.11. Methyl (E)-8-oxo-2-octenoate (33). To a stirred

mixture of cyclohexene (2.5 g, 30.4 mmol) and aqueous

ruthenium trichloride stock solution (130 mg, 0.627 mmol,

0.035 M) in 1,2-dichloroethane (120 mL) and distilled

water (90 mL), was added, in portions, sodium periodate

(9.75 g, 45.7 mmol) over a period of 5 min at room

temperature. The colour turned from black to yellow

immediately. The reaction was monitored by TLC. After

completion in 3 h, the reaction was quenched with a

saturated aqueous solution of Na₂S₂O₃and the two layers

were separated. The aqueous layer was extracted with 1,2-

dichloroethane (3£30 mL). The organic layers were dried

over anhydrous Na₂SO₄, ﬁltered and the ﬁltrate containing

the crude adipaldehyde was directly used without further

puriﬁcation. A suspension of 60% sodium hydride dis-

persion in mineral oil (0.49 g, 12.2 mmol) in 25 mL of dry

1,2-dichloroethane under a positive nitrogen pressure, was

stirred in an ice bath while trimethylphosphonoacetate

(2.22 g, 12.2 mmol) in 25 mL of dry 1,2-dichloroethane was

added dropwise. After the addition was ﬁnished, the

reaction mixture was stirred for further 1 h at 0 8C. Then,

the solution of crude adipaldehyde in 1,2-dichloroethane

was added dropwise. The cold mixture was stirred for

further 15 min after the addition. Then, it was slowly

brought to reﬂux and stirred overnight. The clear organic

layer was decanted from the oil. The remaining oil was

dissolved in warm water and the upper organic layer was

separated. The aqueous layer was extracted with dichloro-

methane. The combined organic layers were washed with

saturated NaHCO₃, dried over anhydrous Na₂SO₄, ﬁltered

and the solvents were removed in vacuo. The resulting crude

oil was puriﬁed by ﬂash column chromatography eluting

with P.E. 30–40 8C/EtOAc (80:20) to afford the aldehyde

33⁵⁴(2.85 g, 55%) as a colorless oil. R_f0.66 (P.E. 30–

40 8C/EtOAc, 80:20); ¹H NMR (300 MHz, CDCl₃) d

1.38–1.46 (m, 2H, CH₂CH₂CHv), 1.55–1.62 (m, 2H,

CH₂CH₂CHO), 2.17 (qd, J¼7.1, 1.4 Hz, 2H, CH₂CHv),

2.39 (td, J¼7.3, 1.5 Hz, 2H, CH₂CHO), 3.66 (s, 3H, OCH₃),

5.76 (dt, J¼15.7, 1.4 Hz, 1H, vCHCO₂CH₃), 6.87 (dt,

J¼15.7, 7.1 Hz, 1H, CHvCHCO₂CH₃), 9.69 (t, J¼1.5 Hz,

1H, CHO); ¹³C NMR (75.5 MHz, CDCl₃) d 21.9 (CH₂),

27.8 (CH₂), 32.2 (CH₂), 43.9 (CH₂), 51.8 (OCH₃), 121.8

4.6.1. 2-Triethylsilyloxy-cyclopentane carboxylic acid

methyl ester (35). R_f0.69 (P.E. 30–40 8C/EtOAc, 90:10);

¹H NMR (400 MHz, CDCl₃) d 0.48–0.72 (q, J¼6.0 Hz, 6H,

OSiCH₂CH₃, cisþtrans), 0.98–1.02 (t, J¼6.0 Hz, 9H,

OSiCH₂CH₃, cisþtrans), 1.49–2.05 (m, 6H, CH₂, cisþ

trans), 2.70–2.81 (m, 1H, CHCO₂CH₃, cisþtrans), 3.67 (s,

3H, OCH₃, cis), 3.68 (s, 3H, OCH₃, trans), 4.40 (q,

J¼6.0 Hz, 1H, CHOSi, trans), 4.50 (q, J¼4.0 Hz, 1H,

CHOSi, cis); ¹³C NMR (100 MHz, CDCl₃) d 3.6 (OSiCH₂-

CH₃, trans), 3.8 (OSiCH₂CH₃, cis), 5.6 (OSiCH₂CH₃,

trans), 5.7 (OSiCH₂CH₃, cis), 21.7 (CH₂CH₂CH₂, cis),

22.7 (CH₂CH₂CH₂, trans), 23.4 (CH₂CH₂CH, cis), 28.1

(CH₂CH₂CH, trans), 34.5 (OCHCH₂, cis), 35.5 (OCHCH₂,

trans), 50.5 (CHCO₂CH₃, cis), 50.6 (OCH₃, cis), 51.1

(OCH₃, trans), 53.1 (CHCO₂CH₃, trans), 74.3 (CHOSi, cis),

78.3 (CHOSi, trans), 172.3 (CO₂CH₃, cis), 174.6 (CO₂CH₃,

trans); FTIR (ﬁlm) n 2955, 2878, 1738, 1200, 1007 cm²¹

;

LRMS (FAB^þ) m/z 259 (M^þþH, 5), 229 (10), 115 (40), 87

(100); HRMS (FAB^þ) calcd for C₁₃H₂₇O₃Si (M^þþH)

259.1729, found 259.1710.

4.6.2. 3,3-Dimethyl-2-triethylsilyloxy-cyclopentane car-

boxylic acid methyl ester (36). R_f0.63 (P.E. 30–40 8C/

1

EtOAc, 90:10); H NMR (500 MHz, CDCl₃) d 0.55 (q,

J¼7.9 Hz, 6H, OSiCH₂CH₃, cis), 0.56 (q, J¼7.9 Hz, 6H,

OSiCH₂CH₃, trans), 0.87 (s, 3H, CH₃, cis), 0.92 (s, 3H,

CH₃, trans), 0.93 (t, J¼7.9 Hz, 9H, OSiCH₂CH₃, cis), 0.94

(t, J¼7.9 Hz, 9H, OSiCH₂CH₃, trans), 0.97 (s, 3H, CH₃,

trans), 0.98 (s, 3H, CH₃, cis), 1.50 (dd, J¼7.4, 8.4 Hz, 2H,

CH₂CH₂CH, cisþtrans), 1.67–1.71 (dq, J¼13.6, 7.4 Hz,

1H, CH_eqH_axCHCO₂CH₃, cis), 1.69–1.72 (m, 1H, CH_eq-

H_axCHCO₂CH₃, trans), 1.97 (ddt, J¼13.6, 10.8, 8.4 Hz,

1H, CH_eqH_axCHCO₂CH₃, cis), 2.12–2.21 (m, 1H, CH_eq-

H_axCHCO₂CH₃, trans), 2.73 (dt, J¼10.8, 7.4 Hz, 1H,

CHCO₂CH₃, cis), 2.96 (td, J¼10.4, 7.0 Hz, 1H, CHCO₂-

CH₃, trans), 3.66 (s, 3H, OCH₃, cis), 3.67 (s, 3H, OCH₃,

trans), 3.94 (d, J¼10.4 Hz, 1H, CHOSi, trans), 3.94 (d,

J¼7.4 Hz, 1H, CHOSi, cis); ¹³C NMR (125 MHz, CDCl₃) d

4.9 (OSiCH₂CH₃, cis), 5.0 (OSiCH₂CH₃, trans), 6.8

(OSiCH₂CH₃, cis), 6.9 (OSiCH₂CH₃, trans), 19.7

(CH₂CH, trans), 21.1 (CH₃, cis), 22.9 (CH₃, trans), 24.7

(CH₂CH, cis), 26.7 (CH₃, cis), 27.7 (CH₃, trans), 36.9

(CH₂CH₂CH, cis), 37.0 (CH₂CH₂CH, trans), 42.3

(C(CH₃)₂, cis), 43.7 (C(CH₃)₂, trans), 49.8 (CHCO₂CH₃,

trans), 50.8 (CHCO₂CH₃, cis), 51.4 (OCH₃, trans), 51.5

(OCH₃, cis), 83.1 (CHOSi, trans), 83.5 (CHOSi, cis), 174.3

(CO₂CH₃, trans), 176.9 (CO₂CH₃, cis); FTIR (ﬁlm) n

1738 cm²¹; LRMS (FAB^þ) m/z 287 (M^þþH, 3), 257 (10),

255 (5), 155 (18), 125 (60), 95 (100); HRMS (CI^þ) calcd for

C₁₅H₃₁O₃Si (M^þþH) 287.20423, found 287.20397.

(vCHCO₂CH₃), 149.0

(CHvCHCO₂CH₃), 167.4

(CO₂CH₃), 202.5 (CHO); FTIR (ﬁlm) n 2949, 2862, 2725,

1724, 1655, 1437, 1275 cm²¹; LRMS (ES^þ) m/z 188

(M^þþNH₄, 38), 171 (M^þþH, 100), 139 (19).

4.6. Typical procedure for the rhodium catalysed

tandem hydrosilylation-aldol reaction

Triethylsilane (0.86 g, 7.4 mmol, 2.1 equiv.) was added

slowly to a stirred solution of methyl (E)-6-oxo-hexenoate

(E)-7 and tris(triphenylphosphine) rhodium (I) chloride

(48 mg, 0.05 mmol, 1 mol%) in anhydrous, degassed

toluene (20 mL) at ambient temperature. The resulting

solution was heated for 16 h at 50 8C and then cooled to

room temperature. The reaction mixture was diluted with

4.6.3. 2-Triethylsilyloxyspiro[4.5]decane carboxylic acid

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2688

methyl ester (37a). R_f0.60 (P.E. 30–40 8C/EtOAc, 90:10);

¹H NMR (500 MHz, CDCl₃) d 0.55–0.60 (q, J¼7.8 Hz, 6H,

OSiCH₂CH₃, cisþtrans), 0.94 (t, J¼7.8 Hz, 9H, OSiCH₂-

CH₃, trans), 0.95 (t, J¼7.8 Hz, 9H, OSiCH₂CH₃, cis), 1.23–

1.31 (m, 6H, CH₂, cisþtrans), 1.44–1.49 (m, 1H, CH_eq-

H_axCH₂CH, cisþtrans), 1.53–1.58 (m, 4H, CH₂, cisþ

trans), 1.62–1.65 (m, 1H, CH_eqH_axCH₂CH, cisþtrans),

1.69–1.74 (m, 1H, CH_eqH_axCHCO₂CH₃, cis), 1.75–1.81

(m, 1H, CH_eqH_axCHCO₂CH₃, trans), 1.89–1.97 (m, 1H,

CH_eqH_axCHCO₂CH₃, trans), 2.12–2.20 (m, 1H, CH_eq-

H_axCHCO₂CH₃, cis), 2.74 (td, J¼10.4, 7.9 Hz, 1H, CHCO₂-

CH₃, trans), 2.99 (td, J¼9.0, 5.3 Hz, 1H, CHCO₂CH₃, cis),

3.64 (s, 3H, OCH₃, cis), 3.65 (s, 3H, OCH₃, trans), 3.90 (d,

J¼7.9 Hz, 1H, CHOSi, trans), 3.98 (d, J¼5.3 Hz, 1H,

CHOSi, cis); ¹³C NMR (125 MHz, CDCl₃) d 5.4 (OSiCH₂-

CH₃, trans), 5.5 (OSiCH₂CH₃, cis), 7.0 (OSiCH₂CH₃,

trans), 7.1 (OSiCH₂CH₃, cis), 22.8 (CH₂, Cy, trans), 23.3

(CH₂, Cy, cis), 23.7 (CH₂, Cy, cis), 23.9 (CH₂CH, cis), 24.2

(CH₂, Cy, trans), 25.0 (CH₂CH, trans), 26.8 (CH₂, Cy, cis),

26.9 (CH₂, Cy, trans), 30.0 (CH₂, Cy, trans), 31.9 (CH₂-

CH₂CH, trans), 32.2 (CH₂CH₂CH, cis), 32.3 (CH₂, Cy, cis),

36.4 (CH₂, Cy, cis), 36.6 (CH₂, Cy, trans), 46.2 (CCy,

trans), 47.9 (CCy, cis), 49.7 (CHCO₂CH₃, cis), 50.7

(CHCO₂CH₃, trans), 51.4 (OCH₃, cis), 51.7 (OCH₃,

trans), 83.9 (CHOSi, cis), 84.4 (CHOSi, trans), 175.7

(CO₂CH₃, cis), 178.8 (CO₂CH₃, trans); FTIR (ﬁlm) n

1738 cm²¹; LRMS (CI^þ) m/z 326 (M^þ, 10), 298 (100), 195

(49), 135 (54); HRMS (CI^þ) calcd for C₁₈H₃₄O₃Si (M^þ)

326.22771, found 326.22536.

boxylic acid i-propyl ester (38). R_f0.73 (P.E. 30–40 8C/

EtOAc, 95:5); ¹H NMR (500 MHz, CDCl₃) d 0.09–0.26 (q,

J¼7.8 Hz, 6H, OSiCH₂CH₃, cisþtrans), 0.56 (t, J¼7.8 Hz,

9H, OSiCH₂CH₃, cis), 0.59 (t, J¼7.8 Hz, 9H, OSiCH₂CH₃,

trans), 1.02 (d, J¼6.3 Hz, 3H, CH₃, trans), 1.03 (d,

J¼6.3 Hz, 3H, CH₃, cis), 1.05 (d, J¼6.3 Hz, 3H, CH₃,

trans), 1.06 (d, J¼6.3 Hz, 3H, CH₃, cis), 1.42–1.48 (m, 1H,

CH_eqH_axCHCO₂iPr, cis), 1.49–1.54 (m, 1H, CH_eqH_ax-

CHCO₂iPr, trans), 1.79–1.86 (m, 1H, CH_eqH_axCHCO₂iPr,

trans), 2.11–2.16 (m, 1H, CH_eqH_axCHCO₂iPr, cis), 2.17

(dt, J¼12.9, 7.7 Hz, 1H, CH_eqH_axCH₂CH, trans), 2.27 (ddd,

J¼12.9, 7.7, 5.9 Hz, 1H, CH_eqH_axCH₂CH, trans), 2.29–

2.32 (m, 1H, CH_eqH_axCH₂CH, cis), 2.68 (ddd, J¼12.0, 11.0,

9.2 Hz, 1H, CH_eqH_axCH₂CH, cis), 2.70 (dt, J¼11.0, 6.3 Hz,

1H, CHCO₂iPr, trans), 2.89 (ddd, J¼11.0, 7.4, 3.7 Hz, 1H,

CHCO₂iPr, cis), 4.74–4.82 (m, 1H, OCH(CH₃)₂, cisþ

trans), 4.85 (d, J¼6.3 Hz, 1H, CHOSi, trans), 5.13 (d,

J¼3.7 Hz, 1H, CHOSi, cis), 6.93–7.19 (m, 10H, Ph,

cisþtrans); ¹³C NMR (125 MHz, CDCl₃) d 5.2 (OSiCH₂-

CH₃, trans), 5.4 (OSiCH₂CH₃, cis), 7.2 (OSiCH₂CH₃,

trans), 7.4 (OSiCH₂CH₃, cis), 22.2 (CH₃, trans), 22.3

(CH₃, cis), 22.5 (CH₂CH₂CH, cis), 25.7 (CH₂CH₂CH,

trans), 32.8 (CH₂CHCO₂iPr, cis), 35.5 (CH₂CHCO₂iPr,

trans), 50.2 (CHCO₂iPr, cis), 51.7 (CHCO₂iPr, trans), 59.5

(CPh₂, trans), 61.7 (CPh₂, cis), 68.2 (OCH(CH₃)₂, cis), 68.3

(OCH(CH₃)₂, trans), 81.2 (CHOSi, cis), 82.1 (CHOSi,

trans), 126.1 (Ph, cisþtrans), 126.4 (Ph, cisþtrans), 126.9

(Ph, cis), 127.8 (Ph, trans), 127.9 (Ph, trans), 128.0 (Ph,

trans), 128.4 (Ph, cis), 128.6 (Ph, cis), 128.9 (Ph, cis), 129.8

(Ph, trans), 145.1 (Ph, trans), 145.8 (Ph, cis), 146.6 (Ph,

cis), 146.8 (Ph, trans), 172.6 (CO₂iPr, cis), 175.2 (CO₂iPr,

trans); FTIR (ﬁlm) n 3059, 3028, 2955, 2912, 2876, 1728,

4.6.4. 2-Triethylsilyloxyspiro[4.5]decane carboxylic acid

i-propyl ester (37b). R_f0.75 (P.E. 30–40 8C/EtOAc,

90:10); ¹H NMR (500 MHz, CDCl₃) d 0.50–0.54 (q,

J¼7.8 Hz, 6H, OSiCH₂CH₃, cisþtrans), 0.86–0.90 (t,

J¼7.8 Hz, 9H, OSiCH₂CH₃, trans), 0.95 (t, J¼7.8 Hz, 9H,

OSiCH₂CH₃, cis), 1.15–1.21 (m, 12H, CH₂, (CH₃)₂,

cisþtrans), 1.24–1.41 (m, 1H, CH_eqCH_axCH₂CH, cisþ

trans), 1.42–1.56 (m, 4H, CH₂, cisþtrans), 1.57–1.61 (m,

1H, CH_eqCH_axCH₂CH, cisþtrans), 1.64–1.71 (m, 1H,

CH_eqH_axCHCO₂iPr, cisþtrans), 1.85–1.93 (m, 1H, CH_eq-

H_axCHCO₂iPr, trans), 2.07–2.12 (m, 1H, CH_eqH_axCHCO₂-

iPr, cis), 2.60 (dt, J¼10.4, 7.3 Hz, 1H, CHCO₂iPr, trans),

2.84 (td, J¼9.2, 5.2 Hz, 1H, CHCO₂iPr, cis), 3.88 (d,

J¼7.3 Hz, 1H, CHOSi, trans), 3.89 (d, J¼5.2 Hz, 1H,

CHOSi, cis), 4.89 (m, 1H, OCH(CH₃)₂, cis), 4.91 (m, 1H,

OCH(CH₃)₂, trans); ¹³C NMR (125 MHz, CDCl₃) d 4.1

(OSiCH₂CH₃, trans), 4.2 (OSiCH₂CH₃, cis), 5.9 (OSiCH₂-

CH₃, trans), 6.0 (OSiCH₂CH₃, cis), 20.0 (CH₃, trans), 20.8

(CH₃, cis), 21.6 (CH₂, Cy, trans), 22.0 (CH₂, Cy, cis), 22.3

(CH₂, Cy, cis), 22.6 (CH₂CH, cis), 22.7 (CH₂, Cy, trans),

24.1 (CH₂CH, trans), 25.3 (CH₂, Cy, cis), 25.5 (CH₂, Cy,

trans), 27.9 (CH₂, Cy, trans), 30.9 (CH₂CH₂CH, trans),

31.1 (CH₂CH₂CH, cis), 33.1 (CH₂, Cy, cis), 34.8 (CH₂, Cy,

trans), 35.4 (CH₂, Cy, cis), 45.0 (CCy, trans), 46.2 (CCy,

cis), 48.9 (CHCO₂iPr, cis), 50.0 (CHCO₂iPr, trans), 66.4

(OCH(CH₃)₂, cis), 66.5 (OCH(CH₃)₂, trans), 82.3 (CHOSi,

trans), 82.4 (CHOSi, cis), 171.8 (CO₂iPr, cis), 174.7

(CO₂iPr, trans); FTIR (ﬁlm) n 2934, 2858, 1717, 1452,

1375, 1107, 908 cm²¹; LRMS (CI^þ) m/z 355 (M^þþH, 80),

313 (18), 283 (39), 223 (100); HRMS (CI^þ) calcd for

C₂₀H₃₉O₃Si (M^þþH) 355.26683, found 355.26676.

1661, 1651, 1599, 1495, 1447, 1373, 1265, 1109 cm²¹

;

LRMS (FAB^þ) m/z 439 (M^þþH, 33), 409 (42), 367 (25),

349 (38), 219 (77); HRMS (FAB^þ) calcd for C₂₇H₃₉O₃Si

(M^þþH) 439.26680, found 439.26640; Crystal data for

C₂₇H₃₈O₃Si,⁵⁶M¼438.66, triclinic, a¼8.6086(11) A,

˚

3

˚

b¼8.9819(12) A,

c¼17.411(2) A,

U¼1285.6(3) A ,

T¼293 K, space group P 1, Z¼2, m(Mo Ka) 0.115 mm²¹

,

11181 reﬂections measured, 5848 unique F ²values used in

reﬁnement (R_int¼0.0210), R₁[4707 with F ².2s]¼0.0543,

wR₂(all data)¼0.1570.

4.6.6. 4,4-Dimethyl-2-triethylsilyloxy-cyclopentane

carboxylic acid methyl ester (39). R_f0.59 (P.E.

1

30–40 8C/EtOAc, 90:10); H NMR (500 MHz, CDCl₃) d

0.50–0.56 (q, J¼7.9 Hz, 6H, OSiCH₂CH₃, cisþtrans),

0.88–0.93 (t, J¼7.9 Hz, 9H, OSiCH₂CH₃, cisþtrans),

0.95 (s, 3H, CH₃, cis), 1.05 (s, 3H, CH₃, trans), 1.06 (s,

3H, CH₃, trans), 1.13 (s, 3H, CH₃, cis), 1.45 (dd, J¼12.9,

7.2 Hz, 1H, CH_eqH_axCHOSi, trans), 1.54 (dd, J¼12.9,

7.7 Hz, 1H, CH_eqH_axCHCO₂CH₃, cis), 1.56 (dd, J¼13.3,

3.7 Hz, 1H, CH_eqH_axCHOSi, cis), 1.58 (dd, J¼12.9,

10.0 Hz, 1H, CH_eqH_axCHCO₂CH₃, trans), 1.71 (dd,

J¼13.3, 5.7 Hz, 1H, CH_eqH_axCHOSi, cis), 1.77 (dd,

J¼12.9, 7.2 Hz, 1H, CH_eqH_axCHOSi, trans), 1.79 (dd,

J¼12.9, 8.9 Hz, 1H, CH_eqH_axCHCO₂CH₃, trans), 2.09 (dd,

J¼12.9, 11.0 Hz, 1H, CH_eqH_axCHCO₂CH₃, cis), 2.83 (ddd,

J¼10.0, 8.9, 7.2 Hz, 1H, CHCO₂CH₃, trans), 2.93 (ddd,

J¼11.0, 7.7, 5.7 Hz, 1H, CHCO₂CH₃, cis), 3.63 (s, 3H,

OCH₃, cis), 3.65 (s, 3H, OCH₃, trans), 4.45 (q, J¼7.2 Hz,

1H, CHOSi, trans), 4.53 (td, J¼5.7, 3.7 Hz, 1H, CHOSi,

cis); ¹³C NMR (125 MHz, CDCl₃) d 4.4 (OSiCH₂CH₃, cis),

4.6.5. 3,3-Diphenyl-2-triethylsilyloxy-cyclopentane car-

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2689

4.6 (OSiCH₂CH₃, trans), 6.4 (OSiCH₂CH₃, cis), 6.7

(OSiCH₂CH₃, trans), 27.3 (CH₃, cis), 30.3 (CH₃, trans),

36.6 (C(CH₃)₂, cis), 37.2 (C(CH₃)₂, trans), 40.6 (CH₂, cis),

43.0 (CH₂, trans), 50.1 (CH₂, trans), 50.5 (CH₂, cis), 50.8

(CHCO₂CH₃, cis), 51.2 (OCH₃, cis), 51.5 (CHCO₂CH₃,

trans), 53.2 (OCH₃, trans), 75.4 (CHOSi, cis), 76.5 (CHOSi,

trans), 173.1 (CO₂CH₃, cis), 175.9 (CO₂CH₃, trans); FTIR

(ﬁlm) n 2955, 2876, 1740, 1460, 1435, 1171 cm²¹; LRMS

(FAB^þ) m/z 287 (M^þþH, 3), 257 (10), 255 (5), 155 (18),

125 (60), 95 (100); HRMS (CI^þ) calcd for C₁₅H₃₁O₃Si

(M^þþH) 287.20423, found 287.20397.

(q, J¼7.9 Hz, 6H, OSiCH₂CH₃), 0.88 (t, J¼7.9 Hz, 9H,

OSiCH₂CH₃), 1.51–1.54 (m, 4H, CH₂CH₂CH₂CH₂), 1.90–

1.94 (m, 2H, CH₂CH₂Cv), 2.08–2.11 (m, 2H, CH₂CH₂-

Cv), 2.95 (d, J¼6.6 Hz, 2H, vCCH₂CHv), 3.59 (s, 3H,

OCH₃), 5.35 (t, J¼6.6 Hz, 1H, CH₂CHv), 6.02 (s, 1H,

OCHOSi); ¹³C NMR (75.5 MHz, CDCl₃) d 4.8 (OSiCH₂-

CH₃), 6.8 (OSiCH₂CH₃), 28.5 (CH₂), 28.8 (CH₂), 31.9

(CH₂), 35.3 (CH₂), 37.3 (vCCH₂CHv), 51.8 (OCH₃),

116.2 (CHvC(O)OCH₃), 119.4 (CH₂CvCCH₂), 132.4

(OCHOSi), 138.4 (CH₂CvCCH₂), 174.1 (vC(O)OCH₃);

FTIR (ﬁlm) n 2934, 2878, 1736, 1439, 1265, 1173 cm²¹

;

LRMS (ES^þ) m/z 328 (M^þþNH₄, 18), 311 (M^þþH, 100),

246 (11); HRMS (ES^þ) calcd for C₁₇H₃₁O₃Si (M^þþH)

311.2042, found 311.2439.

4.6.7. 4-(3-Triethylsilanyloxy-propyl)-5H-furan-2-one

(40). R_f0.62 (EtOAc); ¹H NMR (300 MHz, CD₂Cl₂) d

0.49 (q, J¼7.8 Hz, 6H, OSiCH₂CH₃), 0.88 (t, J¼7.8 Hz, 9H,

OSiCH₂CH₃), 1.70–1.75 (m, 2H, CH₂CH₂OSi), 2.42 (td,

J¼7.9, 1.8 Hz, 2H, CH₂CH₂Cv), 3.58 (t, J¼7.8 Hz, 2H,

CH₂OSi), 4.67 (d, J¼1.8 Hz, 2H, vCCH₂O), 5.71–5.76

(m, 1H, vCHCO₂R); ¹³C NMR (75.5 MHz, CD₂Cl₂) d 3.2

(OSiCH₂CH₃), 5.7 (OSiCH₂CH₃), 24.4 (CH₂CH₂OSi), 29.6

(CH₂CH₂Cv), 60.8 (CH₂OSi), 72.4 (OCH₂Cv), 114.3

(vCHCO₂R), 170.0 (CvCHCO₂R), 173.1 (CO₂R); FTIR

(ﬁlm) n 2957, 2876, 1747, 1655, 1456, 1414, 1379, 1238,

1074 cm²¹; LRMS (DCI^þ) m/z 257 (M^þþH, 81), 227 (47),

197 (12), 115 (15); HRMS (DCI^þ) calcd for C₁₃H₂₅O₃Si

(M^þþH) 257.15728, found 257.15669.

4.6.11. 2-Triethylsilyloxy-3,4-phenyl-cyclopentane

carboxylic acid methyl ester (44). R_f0.79 (P.E. 30–

40 8C/EtOAc, 90:10); ¹H NMR (500 MHz, CDCl₃) d 0.62 (q,

J¼7.9 Hz, 6H, OSiCH₂CH₃, cisþtrans), 0.91 (t, J¼7.9 Hz,

9H, OSiCH₂CH₃, cisþtrans), 2.88 (dd, J¼11.2, 7.8 Hz, 1H,

CH_eqH_axCHCO₂CH₃, cis), 2.98 (dd, J¼15.0, 8.5 Hz, 1H,

CH_eqH_axCHCO₂CH₃, trans), 3.11 (dt, J¼8.5, 6.7 Hz,

1H, CH₂CHCO₂CH₃, trans), 3.19 (dd, J¼15.0, 8.5 Hz, 1H,

CH_eqH_axCHCO₂CH₃, trans), 3.28 (dt, J¼7.8, 6.2 Hz, 1H,

CH₂CHCO₂CH₃, cis), 3.47 (dd, J¼11.2, 7.8 Hz, 1H, CH_eq-

H_axCHCO₂CH₃, cis), 3.68 (s, 3H, OCH₃, trans), 3.73 (s, 3H,

OCH₃, cis), 5.34 (d, J¼6.2 Hz, 1H, CHOSiEt₃, cis), 5.51 (d,

J¼6.7 Hz, 1H, CHOSiEt₃, trans), 7.13–7.64 (m, 4H, Ph,

cisþtrans); ¹³C NMR (125 MHz, CDCl₃) d 4.0 (OSiCH₂CH₃,

trans), 5.7 (OSiCH₂CH₃, trans), 33.2 (CH₂, trans), 50.6

(OCH₃, trans), 53.6 (CHCO₂CH₃, trans), 78.2 (CHOSiEt₃,

trans), 123.0 (Ph, trans), 123.4 (Ph, trans), 126.1 (Ph,

trans), 127.5 (Ph, trans), 138.6 (Ph, trans), 142.9 (Ph,

trans), 174.0 (CO₂CH₃); FTIR (ﬁlm) n 2955, 2877,

1731, 1637, 1437, 1351, 909 cm²¹; LRMS (ES^þ) m/z

324 (M^þþNH₄, 100), 307 (M^þþH, 44), 246 (61), 175

(93); HRMS (ES^þ) calcd for C₁₇H₂₇O₃Si (M^þþH)

307.1729, found 307.1735.

4.6.8. Methyl (E)-3-methyl-6-triethylsilanyloxy-hex-2-

enoate (41). R_f0.70 (P.E. 30–40 8C/EtOAc, 95:5); ¹H

NMR (300 MHz, CDCl₃) d 0.52 (q, J¼7.8 Hz, 6H,

OSiCH₂CH₃), 0.89 (t, J¼7.8 Hz, 9H, OSiCH₂CH₃), 1.60–

1.65 (m, 2H, CH₂CH₂OSi), 2.09 (d, J¼1.2 Hz, 3H, CH₃),

2.14 (td, J¼7.8, 1.1 Hz, 2H, CH₂CH₂Cv), 3.52 (t,

J¼6.5 Hz, 2H, CH₂OSi), 3.61 (s, 3H, OCH₃), 5.61–5.64

(m, 1H, vCHCO₂CH₃); ¹³C NMR (75.5 MHz, CDCl₃) d

3.5 (OSiCH₂CH₃), 5.7 (OSiCH₂CH₃), 17.8 (CH₃), 29.7

(CH₂CH₂OSi), 36.3 (CH₂CH₂Cv), 49.7 (OCH₃), 61.1

(CH₂OSi), 114.2 (vCHCO₂CH₃), 159.0 (CvCHCO₂CH₃),

166.2 (CO₂CH₃); FTIR (ﬁlm) n 2876, 1728, 1651, 1435,

1360, 1101 cm²¹; LRMS (DCI^þ) m/z 273 (M^þþH, 100),

258 (5), 243 (34), 132 (28); HRMS (DCI^þ) calcd for

C₁₄H₂₉O₃Si (M^þþH) 273.18858, found 273.18821.

4.6.12. Methyl (1S,2S,3S,4S)-2-triethylsilyloxy-3,4-iso-

propylidene-dioxy-cyclopentane carboxylate (45a). R_f

1

0.53 (P.E. 30–40 8C/EtOAc, 95:5); H NMR (500 MHz,

CDCl₃) d 0.51 (q, J¼7.7 Hz, 6H, OSiCH₂CH₃), 0.86 (t,

J¼7.7 Hz, 9H, OSiCH₂CH₃), 1.21 (s, 3H, CH₃), 1.35 (s, 3H,

CH₃), 1.89 (dd, J¼13.8, 6.3 Hz, 1H, CH_eqH_axCHCO₂CH₃),

2.24 (ddd, J¼13.8, 10.7, 5.4 Hz, 1H, CH_eqH_axCHCO₂CH₃),

3.02 (ddd, J¼10.7, 6.3, 4.0 Hz, 1H, CHCO₂CH₃), 3.60 (s,

3H, OCH₃), 4.20 (d, J¼5.4 Hz, 1H, CHCHOSiEt₃), 4.28 (d,

J¼4.0 Hz, 1H, CHOSiEt₃), 4.67 (t, J¼5.4 Hz, 1H,

CH₂CHO); ¹³C NMR (125 MHz, CDCl₃) d 3.7 (OSiCH₂-

CH₃), 5.7 (OSiCH₂CH₃), 22.8 (CH₃), 25.1 (CH₃), 30.8

(CH₂), 46.2 (CHCO₂CH₃), 50.4 (OCH₃), 76.8 (CHOSiEt₃),

78.2 (CH₂CHO), 84.9 (OCHCHOSiEt₃), 108.9 (OC(CH₃)₂),

171.1 (CO₂CH₃); FTIR (ﬁlm) n 2936, 2878, 1733, 1439,

1376, 1262, 902 cm²¹; LRMS (FAB^þ) m/z 331 (M^þþH,

20), 301 (100), 241 (15), 211 (10), 187 (10); HRMS (FAB^þ)

calcd for C₁₆H₃₁O₅Si (M^þþH) 331.19406, found

331.19408; [a]²_D⁰: 220.7 (c¼0.50, CHCl₃/MeOH 9:1).

4.6.9. Methyl 1-triethylsilanyloxy-octahydro-indene-2-

carboxylate (42). R_f0.80 (P.E. 30–40 8C/EtOAc, 90:10);

¹H NMR (500 MHz, CDCl₃) d 0.55–0.58 (q, J¼7.8 Hz, 6H,

OSiCH₂CH₃), 0.90–0.97 (t, J¼7.8 Hz, 9H, OSiCH₂CH₃),

1.05–2.34 (m, 12H, CH₂and CH), 2.58–3.10 (m, 1H,

CHCO₂CH₃), 3.64–3.68 (s, 3H, OCH₃), 3.73–4.39 (m, 1H,

CHOSi); ¹³C NMR (125 MHz, CDCl₃) d 3.4–3.9 (OSiCH₂-

CH₃), 5.7–5.8 (OSiCH₂CH₃), 19.9–33.5 (CH₂), 33.9–52.3

(CH, OCH₃), 75.6 (CHOSi), 77.7 (CHOSi), 78.2 (CHOSi),

78.3 (CHOSi), 78.5 (CHOSi), 80.2 (CHOSi), 172.9

(CO₂CH₃), 173.2 (CO₂CH₃), 173.6 (CO₂CH₃), 175.7

(CO₂CH₃), 176.2 (CO₂CH₃), 176.4 (CO₂CH₃); FTIR

(ﬁlm) n 3053, 2930, 2878, 2855, 1732, 1435, 1265 cm²¹

;

LRMS (FAB^þ) m/z 313 (M^þþH, 8), 283 (100), 267 (5), 251

(31), 221 (34), 207 (25); HRMS (FAB^þ) calcd for

C₁₇H₃₃O₃Si (M^þþH) 313.21988, found 313.21948.

4.6.13. 2-Triethylsilanyloxy-4-benzyloxy-cyclopentane

carboxylic acid methyl ester (46a). R_f0.68 (P.E. 30–

4.6.10. Triethyl-(3-methoxy-1,5,6,7,8,9-hexahydro-

benzo[c]oxepin-1-yloxy)-silane (43). R_f0.57 (P.E. 30–

1

40 8C/EtOAc, 90:10); H NMR (500 MHz, CDCl₃) d 0.54

(q, J¼7.7 Hz, 6H, OSiCH₂CH₃), 0.90 (t, J¼7.7 Hz, 9H,

1

40 8C/EtOAc, 90:10); H NMR (300 MHz, CDCl₃) d 0.56

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2690

OSiCH₂CH₃), 1.71 (ddd, J¼13.6, 7.0, 6.6 Hz, 1H, CH_eq-

H_axCHOSiEt₃), 1.93 (ddd, J¼13.3, 9.9, 6.5 Hz, 1H, CH_eq-

H_axCO₂CH₃), 2.09 (ddd, J¼13.3, 8.1, 3.6 Hz, 1H,

CH_eqH_axCO₂CH₃); 2.31 (ddd, J¼13.6, 7.2, 6.7 Hz, 1H,

CH_eqH_axCHOSiEt₃), 2.92 (ddd, J¼9.9, 8.1, 7.8 Hz, 1H,

CHCO₂CH₃), 3.64 (s, 3H, OCH₃), 3.95 (m, 1H, CHOBn),

4.29 (ddd, J¼7.8, 7.2, 7.0 Hz, 1H, CHOSiEt₃), 4.42 (s, 2H,

ArCH₂O); 7.29–7.42 (m, 5H, Ph); ¹³C NMR (100 MHz,

CDCl₃) d 4.6 (OSiCH₂CH₃), 6.7 (OSiCH₂CH₃), 34.6 (CH₂),

42.0 (CH₂), 51.1 (OCH₃), 51.7 (CHCO₂CH₃), 70.7

(OCH₂Ph), 74.5 (CHOBn), 76.9 (CHOSiEt₃), 127.5 (Ph),

127.6 (Ph), 128.4 (Ph), 138.5 (Ph), 175.6 (CO₂CH₃); FTIR

(ﬁlm) n 2953, 2912, 2876, 1739, 1496, 1455, 1436, 1354,

1116, 1058, 736, 697 cm²¹; LRMS (ES^þ) m/z 382

(M^þþNH₄, 72), 365 (M^þþH, 100), 251 (10); HRMS

(ES^þ) calcd for C₂₀H₃₆NO₄Si (M^þþNH₄) 382.2414, found

382.2404.

OSiCH₂CH₃), 0.90 (t, J¼7.8 Hz, 9H, OSiCH₂CH₃), 1.40–

1.62 (m, 4H, CH₂CH₂CH₂CH₂), 1.96–2.02 (m, 2H, CH₂-

C(OSiEt₃)v), 2.24 (t, J¼7.2 Hz, 2H, CH₂CO₂CH₃), 3.31

(d, J¼7.1 Hz, 1H, vCHCH₂Ph), 3.59 (s, 3H, OCH₃), 4.55

(t, J¼7.1 Hz, 1H, vCHCH₂Ph), 7.09–7.28 (m, 5H, Ph); ¹³

C

NMR (75.5 MHz, CDCl₃) d 5.7 (OSiCH₂CH₃), 7.2

(OSiCH₂CH₃), 27.0 (CH₂), 31.9 (CH₂), 34.6 (CH₂), 36.7

(CH₂), 51.9 (OCH₃), 54.8 (CH₂Ph), 107.0 (vCHCH₂Ph),

128.6 (Ph), 128.7 (Ph), 129.0 (Ph), 132.6 (Ph), 151.1

(C(OSiEt₃)vCH), 167.1 (CO₂CH₃); FTIR (ﬁlm) n 3051,

2930, 2876, 1736, 1435, 1264, 1016 cm²¹; LRMS (CI^þ)

m/z 363 (M^þþH, 30), 348 (28), 332 (19), 232 (14); HRMS

(CI^þ) calcd for C₂₁H₃₅O₃Si (M^þþH) 363.23553, found

363.23519.

4.6.17. (2E)-4,4-Dimethyl-triethylsilanyloxy-nona-2,7-

dienoic acid methyl ester (50). R_f0.79 (P.E. 30–40 8C/

1

EtOAc, 90:10); H NMR (300 MHz, CDCl₃) d 0.56 (q,

4.6.14. 6-Triethylsilanyloxy-5-heptenoate (47). R_f0.69

(P.E. 30–40 8C/EtOAc, 90:10); ¹H NMR (500 MHz,

CDCl₃) d 0.62–0.66 (q, J¼8.0 Hz, 6H, OSiCH₂CH₃,

cisþtrans), 0.94–0.99 (t, J¼8.0 Hz, 9H, OSiCH₂CH₃,

cisþtrans), 1.62–1.65 (m, 2H, CH₂CH₂CH₂, cisþtrans),

1.71 (d, J¼1.0 Hz, 3H, CH₃, trans), 1.77 (d, J¼1.1 Hz, 3H,

CH₃, cis), 1.95 (q, J¼7.5 Hz, 2H, CH₂CH₂CHv, trans),

2.02 (q, J¼7.2 Hz, 2H, CH₂CH₂CHv, cis), 2.29 (t,

J¼7.5 Hz, 2H, CH₂CO₂CH₃, cisþtrans), 3.65 (s, 3H,

OCH₃, cis), 3.66 (s, 3H, OCH₃, trans), 4.33 (tq, J¼7.2,

1.1 Hz, 1H, CHvC(OSi)CH₃, cis), 4.60 (tq, J¼7.5, 1.0 Hz,

1H, CHvC(OSi)CH₃, trans); ¹³C NMR (125 MHz, CDCl₃)

d 4.9 (OSiCH₂CH₃, cis), 5.0 (OSiCH₂CH₃, trans), 6.4

(OSiCH₂CH₃, cis), 6.5 (OSiCH₂CH₃, trans), 17.6 (CH₃,

trans), 22.6 (CH₃, cis), 24.6 (CH₂CH₂Cv, cis), 25.6

(CH₂CH₂CH₂, cisþtrans), 26.5 (CH₂CH₂Cv, trans), 33.3

(CH₂CO₂CH₃, trans), 33.7 (CH₂CO₂CH₃, cis), 51.3 (OCH₃,

cis), 51.4 (OCH₃, trans), 106.4 (CHvC(OSi)CH₃, trans),

107.0 (CHvC(OSi)CH₃, cis), 147.5 (CHvC(OSi)CH₃,

cis), 148.7 (CHvC(OSi)CH₃, trans), 174.2 (CO₂CH₃,

trans), 174.3 (CO₂CH₃, cis); FTIR (ﬁlm) n 3053, 2955,

2914, 2878, 1732, 1670, 1437, 1362, 1265 cm²¹; LRMS

(CI^þ) m/z 273 (M^þþH, 51), 243 (24), 103 (100); HRMS

(CI^þ) calcd for C₁₄H₂₉O₃Si (M^þþH) 273.18858, found

273.18830.

J¼7.9 Hz, 6H, OSiCH₂CH₃), 0.89 (t, J¼7.9 Hz, 9H,

OSiCH₂CH₃), 0.99 (s, 6H, C(CH₃)₂), 1.25–1.32 (m, 2H,

CH₂CH₂CHv), 1.70 (s, 3H, CH₃C(OSiEt₃)vCH), 1.79–

1.80 (m, 2H, CH₂CHv), 3.68 (s, 3H, OCH₃), 4.24 (t,

J¼6.6 Hz, 1H, CH₂CHv), 6.65 (d, J¼15.8 Hz, 1H,

vCHCO₂CH₃), 6.84 (d, J¼15.8 Hz, 1H, CHvCHCO₂-

CH₃); ¹³C NMR (75.5 MHz, CDCl₃) d 6.0 (OSiCH₂CH₃),

7.1

(OSiCH₂CH₃),

21.0

(CH₂CH₂CHv),

23.1

(CHvCCH₃), 26.6 (C(CH₃)₂), 37.2 (C(CH₃)₂), 42.6

(CH₂CHv), 51.8 (OCH₃), 108.5 (vCHCH₂), 117.7

(vCHCO₂CH₃), 147.2

(CHvC(CH₃)OSiEt₃), 167.5 (CO₂CH₃); FTIR (ﬁlm) n

2959, 2914, 2877, 1717, 1651, 1465, 1437, 1380, 902 cm²¹

(CHvCHCO₂CH₃), 159.0

;

LRMS (FAB^þ) m/z 327 (M^þþH, 100), 297 (60), 253 (34),

225 (21), 185 (79); HRMS (CI^þ) calcd for C₁₈H₃₅O₃Si

(M^þþH) 327.23553, found 327.23496.

4.6.18. Methyl 7-triethylsilanyloxy-6-heptenoate (51). R_f

1

0.70 (P.E. 30–40 8C/EtOAc, 90:10); H NMR (500 MHz,

CDCl₃) d 0.53–0.67 (q, J¼7.9 Hz, 6H, OSiCH₂CH₃,

cisþtrans), 0.88–0.98 (t, J¼7.9 Hz, 9H, OSiCH₂CH₃,

cisþtrans), 1.27–1.40 (m, 2H, CH₂CH₂CHv, cisþtrans),

1.56–1.68 (m, 2H, CH₂CH₂CO₂CH₃, cisþtrans), 1.83–

1.92 (qd, J¼7.4, 1.0 Hz, 2H, CH₂CHv, trans), 2.05–2.11

(qd, J¼7.2, 1.3 Hz, 2H, CH₂CHv, cis), 2.25–2.35 (m, 2H,

CH₂CO₂CH₃, cisþtrans), 3.65 (s, 3H, OCH₃, cisþtrans),

4.41 (q, J¼7.2 Hz, 1H, vCHCH₂, cis), 4.96 (dt, J¼12.0,

7.4 Hz, 1H, vCHCH₂, trans), 6.21 (d, J¼7.2 Hz, 1H,

vCHOSi, cis), 6.24 (d, J¼12.0 Hz, 1H, vCHOSi, trans);

¹³C NMR (75.5 MHz, CDCl₃) d 4.4 (OSiCH₂CH₃, cis), 5.4

(OSiCH₂CH₃, trans), 6.9 (OSiCH₂CH₃, cis), 7.1 (OSiCH₂-

CH₃, trans), 23.5 (CH₂), 24.7 (CH₂), 24.9 (CH₂), 27.3

(CH₂), 29.5 (CH₂), 30.3 (CH₂), 34.3 (CH₂), 34.4 (CH₂), 51.7

(OCH₃, cisþtrans), 110.4 (vCHCH₂, cis), 111.3

(vCHCH₂, trans), 139.0 (vCHOSi, cis), 140.6 (vCHOSi,

trans), 174.3 (CO₂CH₃, cis), 174.6 (CO₂CH₃, trans); FTIR

(ﬁlm) n 2937, 2877, 1732, 1652, 1436, 907 cm²¹; LRMS

(CI^þ) m/z 273 (M^þþH, 25), 243 (19), 211 (12); 175 (60);

HRMS (CI^þ) calcd for C₁₄H₂₉O₃Si (M^þþH) 273.18858,

found 273.18832.

4.6.15. Methyl 4,4-dimethyl-5-oxiranyl-pentanoate (48).

R_f0.28 (P.E. 30–40 8C/EtOAc, 90:10); ¹H NMR (500 MHz,

CDCl₃) d 0.91 (s, 3H, CH₃), 0.93 (s, 3H, CH₃), 1.34–1.36

(m, 2H, CH₂CHOCH₂), 1.56–1.66 (m, 2H, CH₂CH₂CO₂-

CH₃); 2.20–2.27 (m, 2H, CH₂CH₂CO₂CH₃); 2.35 (dd,

J¼5.0, 2.7 Hz, 1H, CH_aHO), 2.69 (dd, J¼5.0, 4.1 Hz, 1H,

CHH_bO), 2.89–2.90 (m, 1H, CHO), 3.59 (s, 3H, OCH₃);

¹³C NMR (125 MHz, CDCl₃) d 26.8 (CH₃), 26.9 (CH₃),

29.3 (CH₂CH₂CO₂CH₃); 32.8 (CH₂CO₂CH₃); 36.6

(C(CH₃)₂), 44.4 (CH₂), 46.7 (CH₂O), 49.2 (CHO),

51.6 (OCH₃), 174.5 (CO₂CH₃); FTIR (ﬁlm) n 2958,

2924, 2850, 1730, 1463, 1436, 1264, 1172 cm²¹; LRMS

(ES^þ) m/z 187 (M^þþH, 100), 204 (M^þþNH₄, 25);

HRMS (ES^þ) calcd for C₁₀H₁₉O₃(M^þþH) 187.1320,

found 187.1328.

4.6.19. Methyl 2-triethylsilyloxycyclohexanecarboxylate

(52). R_f0.55 (P.E. 30–40 8C/EtOAc, 90:10); ¹H NMR

(500 MHz, CDCl₃) d 0.50–0.57 (q, J¼7.9 Hz, 6H, OSiCH₂-

CH₃, cisþtrans), 0.89–0.92 (t, J¼7.9 Hz, 9H, OSiCH₂CH₃,

4.6.16. 7-Phenyl-6-triethylsilanyloxy-6-heptenoic acid

methyl ester (49). R_f0.76 (P.E. 30–40 8C/EtOAc, 90:10);

¹H NMR (300 MHz, CDCl₃) d 0.60 (q, J¼7.8 Hz, 6H,

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2691

cisþtrans), 1.15–1.90 (m, 8H, CH₂, cisþtrans), 2.27–2.30

Acknowledgements

(m, 1H, CHCO₂CH₃, cis), 2.30–2.34 (ddd, J¼9.7, 9.2,

3.5 Hz, 1H, CHCO₂CH₃, trans), 3.63 (s, 3H, OCH₃, cis),

3.64 (s, 3H, OCH₃, trans), 3.77 (dt, J¼9.7, 4.3 Hz, 1H,

CHOSi, trans), 3.96–4.00 (m, 1H, CHOSi, cis); ¹³C NMR

(125 MHz, CDCl₃) d 4.4 (OSiCH₂CH₃, cis), 4.9 (OSiCH₂-

CH₃, trans), 6.5 (OSiCH₂CH₃, cis), 6.8 (OSiCH₂CH₃,

trans), 19.7 (CH₂, cis), 22.0 (CH₂, cis), 24.3 (CH₂, trans),

24.4 (CH₂, trans), 24.5 (CH₂, cis), 28.6 (CH₂, trans), 33.6

(CH₂, cis), 35.2 (CH₂, trans), 48.4 (CHCO₂CH₃, cis), 51.2

(OCH₃, cis), 51.3 (OCH₃, trans), 52.5 (CHCO₂CH₃, trans),

68.2 (CHOSi, cis), 72.2 (CHOSi, trans), 174.3 (CO₂CH₃,

cis), 175.6 (CO₂CH₃, trans); FTIR (ﬁlm) n 2937, 2876,

1740, 1435, 1173 cm²¹; LRMS (CI^þ) m/z 272 (M^þ, 14),

243 (35), 175 (10), 57 (100); HRMS (CI^þ) calcd for

C₁₄H₂₈O₃Si (M^þ) 272.18076, found 272.17809.

We wish to thank GlaxoSmithKline for the provision of a

studentship to M. F.

References and notes

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4.6.20. 2-Triethylsilyloxy-cycloheptane carboxylic acid

methyl ester (53). R_f0.70 (P.E. 30–40 8C/EtOAc, 90:10);

¹H NMR (500 MHz, CDCl₃) d 0.54 (q, J¼7.9 Hz, 6H,

OSiCH₂CH₃, cisþtrans), 0.92 (t, J¼7.9 Hz, 9H, OSiCH₂-

CH₃, trans), 0.93 (t, J¼7.9 Hz, 9H, OSiCH₂CH₃, cis), 1.34–

1.88 (m, 10H, CH₂, cisþtrans), 2.50–2.55 (m, 1H,

CHCO₂CH₃, cisþtrans), 3.65 (s, 3H, OCH₃, cis), 3.66 (s,

3H, OCH₃, trans), 4.00 (dt, J¼8.3, 3.6 Hz, 1H, CHOSi,

trans), 4.00 (dt, J¼6.8, 3.4 Hz, 1H, CHOSi, cis); ¹³C NMR

(125 MHz, CDCl₃) d 3.9 (OSiCH₂CH₃, cis), 4.0 (OSiCH₂-

CH₃, trans), 5.7 (OSiCH₂CH₃, trans), 5.8 (OSiCH₂CH₃,

cis), 21.0 (CH₂, trans), 21.3 (CH₂, cis), 22.3 (CH₂, cis), 25.1

(CH₂, trans), 25.6 (CH₂, cis), 26.3 (CH₂, trans), 26.8

(CH₂, trans), 27.4 (CH₂, cis), 35.1 (CH₂, cis), 35.6

(CH₂, trans), 50.3 (OCH₃, cis), 50.8 (OCH₃, trans), 50.9

(CHCO₂CH₃, cis), 53.6 (CHCO₂CH₃, trans), 70.7

(CHOSi, cis), 73.7 (CHOSi, trans), 174.1 (CO₂CH₃,

cis), 175.4 (CO₂CH₃, trans); FTIR (ﬁlm) n 2937, 2878,

1734, 1458, 1437, 1007, 908 cm²¹; LRMS (FAB^þ) m/z

287 (M^þþH, 18), 257 (100), 115 (45), 87 (69); HRMS

(FAB^þ) calcd for C₁₅H₃₁O₃Si (M^þþH) 287.20420,

found 287.20413.

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4.6.21. Triethyl-(1-methyl-pent-1-enyloxy)-silane (54). R_f

1

0.86 (P.E. 30–40 8C/EtOAc, 90:10); H NMR (500 MHz,

CDCl₃) d 0.61–0.68 (q, J¼8.1 Hz, 6H, OSiCH₂CH₃,

cisþtrans), 0.86 (t, J¼7.4 Hz, 3H, CH₂CH₃, trans), 0.87

(t, J¼7.4 Hz, 3H, CH₂CH₃, cis), 0.93–0.97 (t, J¼8.1 Hz,

9H, OSiCH₂CH₃, cisþtrans), 1.27–1.34 (m, 2H, CH₂CH₂-

CH₃, cisþtrans), 1.71 (d, J¼0.7 Hz, 3H, CH₃, trans), 1.77

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cis), 4.63 (tq, J¼7.2, 0.7 Hz, 1H, CHvC(OSi)CH₃, trans);

¹³C NMR (125 MHz, CDCl₃) d 4.9 (OSiCH₂CH₃, cis), 5.0

(OSiCH₂CH₃, trans), 6.4 (OSiCH₂CH₃, cis), 6.6 (OSiCH₂-

CH₃, trans), 13.6 (CH₃, trans), 13.9 (CH₃, cis), 17.6

(CH₃Cv, trans), 22.7 (CH₃Cv, cis), 23.0 (CH₂CH₂CH₂,

cis), 23.6 (CH₂CH₂CH₂, trans), 27.4 (CH₂CH₂Cv, cis),

29.3 (CH₂CH₂Cv, trans), 107.7 (CHvC(OSi)CH₃, trans),

108.4 (CHvC(OSi)CH₃, cis), 146.6 (CHvC(OSi)CH₃,

cis), 147.8 (CHvC(OSi)CH₃, trans); FTIR (ﬁlm) n 2957,

2878, 1670, 1460, 1240 cm²¹

;

LRMS (CI^þ) m/z

215 (M^þþH, 21), 185 (41), 157 (14), 115 (68); HRMS

(CI^þ) calcd for C₁₂H₂₇OSi (M^þþH) 215.18310, found

215.18272.

´

M. Freirıa et al. / Tetrahedron 60 (2004) 2673–2692

2692

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Article Doi

Further observations on the rhodium (I)-catalysed tandem hydrosilylation-intramolecular aldol reaction

DOI: 10.1016/j.tet.2003.12.057

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