A diene-transmissive approach to the quassinoid skeleton

81

A diene-transmissive approach to the quassinoid

skeleton

Claude Spino, Bryan Hill, Pascal Dubé, and Stéphane Gingras

Abstract: Several tetracyclic molecules were prepared by diene-transmissive Diels–Alder cycloadditions. Control over

the stereochemical outcome of the cycloaddition was achieved and the structural features of the precursors affecting the

stereochemistry is discussed. Useful information was gathered concerning the factors governing this stereocontrol,

which will be indispensable for the future of this strategy.

Key words: quassinoid, anticancer agent, diene-transmissive Diels–Alder cycloaddition, oxadiene, hetero Diels–Alder.

Résumé : On a préparé plusieurs molécules tétracycliques en faisant appel à des réactions de cycloaddition de Diels–

Alder à dienes-transmissibles. On a pu contrôler le résultat stéréochimique des cycloadditions et on discute des caracté-

ristiques des structures des précurseurs qui affectent la stéréochimie. Des informations utiles ont été accumulées

concernant les facteurs qui gouvernent ce contrôle stéréochimique et celles-ci seront indispensables pour le futur de

cette stratégie.

Mots clés : quassinoïde, agent antinéoplasique, cycloaddition de Diels–Alder à dienes-transmissibles, oxadiène,

hétéro-Diels–Alder.

[Traduit par la Rédaction] Spino et al. 108

Introduction

[2]

Blomquist and Bailey and co-workers (1) reported the first

diene-transmissive Diels–Alder cycloaddition in 1955. They

coupled the unstable cross-conjugated triene 3-methylene-

1,4-pentadiene 1 with excess maleic anhydride and obtained

tetracyclic adduct 3 in moderate yield (eq. [1]) (1). Later,

Tsuge and co-workers and others (2–4) investigated a series

of intermolecular diene-transmissive [4 + 2]-cycloadditions

on simple substituted cross-conjugated trienes. For several

reasons that are explained in previous publications, this

strategy stayed without a useful application until our report

of a diene-transmissive Diels–Alder approach to the synthe-

sis of anticancer quassinoids (eq. [2]) (5). In this synthetic

route to quassinoids, a cross-conjugated oxadiene 4 was

transformed into tetracycle 6 via an intermolecular hetero

Diels–Alder reaction followed by an intramolecular normal

[4 + 2]-cycloaddition. In 1999, Fallis and co-workers (6) re-

ported the use of diene-transmissive Diels–Alder reactions

for the construction of advanced intermediates toward the

synthesis of other terpenoids.

Quassinoids are formidable synthetic targets. The extent

of the oxygenation of their carbon skeleton contributes to the

synthetic difficulties (7). Subtropical shrubs of the plant

family Simaroubaceae constitute the most common source

for these degraded triterpenoid natural products (8). They

possess a large spectrum of biological activities, including

antiviral, antimalarial, antineoplastic, and insect antifeedant

properties (8). Recently reported biological activities have

increased the interest in the synthesis of this family of tri-

terpenes (9). The vast majority of quassinoids possess a C-

20 picrasane skeleton, of which quassin 7, glaucarubolone 8,

and bruceantin 9 are typical examples (Fig. 1) (8). We report

herein

a

comprehensive investigation of the diene-

[1]

transmissive double Diels–Alder approach to quassinoids.

The quassinoid numbering and lettering shown in Fig. 1,

will be used throughout this manuscript on all structures for

ease of reference to the potential target molecules.

Several stereochemical issues arise from the key cyclo-

addition reactions. The substituents on the cyclohexene ring

in 4 direct the incoming ethylvinyl ether to the α face of the

diene but they may also affect the stereochemical outcome

of the intramolecular Diels–Alder reaction (eq. [2]) (10).

The appendages on the exocyclic chain serve to differentiate

the energies of the two endo transition states (TS) accessible

to the intermediate 5 (Fig. 2). They must be brought in with

Received 13 July 2002. Published on the NRC Research

Press Web site at http://canjchem.nrc.ca on 29 January 2003.

C. Spino,¹B. Hill, P. Dubé, and S. Gingras. Université de

Sherbrooke, Département de Chimie, 2500, boulevard

Université, Sherbrooke, QC J1K 2R1, Canada.

¹Corresponding author (e-mail: claude.spino@USherbrooke.ca).

Can. J. Chem. 81: 81–108 (2003)

doi: 10.1139/V02-196

82

Can. J. Chem. Vol. 81, 2003

Scheme 1.

Fig. 1. Three examples of quassinoids.

Fig. 2. The four chair-like transition states of 5.

the exact stereochemistry shown for all-equatorial α-endo

TS that will lead to the tetracyclic nucleus 6 having the cor-

rect stereochemistry for quassinoids.

part of the Diels–Alder strategy. Several ways to construct

the exocyclic double bonds were envisioned. It was initially

thought that starting with an appropriately substituted cyclo-

hexenone would be most expeditious. In that respect, the

known compound 13 (12), derived from (–)-quinic acid, pre-

sented itself as an attractive starting material (Scheme 1).

Protection of the C-13 alcohol as a TBDPS ether was

achieved, and reduction of the lactone in 14 followed by in

situ oxidative cleavage of the resulting diol afforded a β-

hydroxycyclohexanone, which was dehydrated to the desired

substituted cyclohexenone 15d. For simpler model com-

pounds, 1,4-cyclohexadione monoketal 10 was an adequate

starting material. It was reduced with NaBH₄and then pro-

tected as its silyl ether 11a (TBDPSCl, imid., DMF, quant.),

Synthesis of the precursor oxadienes

Besides the introduction of the ring and chain substituents

in 4 with the correct stereochemistry, the formation of the

exocyclic double bond with the correct geometry represents

a fierce challenge (eq. [2]) (11). Compounding the problem

is the fact that the exocyclic double bond in 4 and 5 should

preferably be a tetra-substituted double bond (R³= Me), oth-

erwise the C-10 methyl group (cf. Fig. 1) would have to be

introduced at a later stage of the synthesis, a more difficult

(though possible) task than introducing the methyl group as

Spino et al.

83

Scheme 2.

benzyl ether 11b (KH, BnBr, THF, 83%), or PMB ether 11c

(KH, PMBCl, THF, 96%). Conversion of 11a–c to 15a–c,

respectively, was straightforward as shown in Scheme 1.

Scheme 3.

Bromination and dehydrobromination of each cyclohex-

enone 15 gave the corresponding vinylbromide 16 in 80–

94% yield (Scheme 2). Subsequent addition of vinyllithium

to 16a–d in the presence of anhydrous CeCl₃afforded 17a–

d, which were converted to the corresponding acetates 18a–

d under standard conditions. Compounds 19a–g, possessing

a tri-substituted exocyclic double bond of E configuration,

were prepared in one of three ways. Cuprate displacements

of allylic acetates 18a–d with alkylcyanocuprates gave the

corresponding products 19a–d in 89–96% yield

(Scheme 2).²Alternatively, the palladium-catalyzed substitu-

tion of 18a with malonate furnished 19e in 81% yield as a

single stereoisomer (Scheme 3). Aldehyde 19f or ester 19g

could be accessed directly from a Claisen rearrangement of

17a.

with DMF to give 20a–d (Scheme 4). The syntheses of 20e

and 20f were reported elsewhere (5a). Compounds 20c and

20d were further transformed in four steps to 24a and 24b,

Vinyl bromides 19a–d were separately treated with n-

BuLi and the resulting vinyllithium intermediates trapped

²Compound 19c was prepared using a racemic cuprate reagent and was isolated as an inseparable mixture of stereoisomers (for clarity, only

the diastereomer of interest is shown in Scheme 2). All isomers of 19c were separated at a later stage (vide infra). Compound 19d was pre-

pared with the enantiomerically pure cuprate reagent and was isolated diastereo- and enantiomerically pure.

84

Can. J. Chem. Vol. 81, 2003

Scheme 4.

Scheme 5.

respectively, and 24a was deprotected under oxidizing con-

ditions to give 25 (Scheme 5).

tions placed the Z-isomer B 5.1 kcal mol^–1above the E-

isomer A for R = Me.

All synthesized alkenes 19a–g had exclusively the E-ge-

ometry. This selectivity is attributable to the flatness of the

structural system 19 that brings the vinylic hydrogen and the

bromine atom in a rigid syn-pentane-like relationship

(Fig. 3). Any group larger than hydrogen is likely to raise

the energy of the system considerably. Basic MM2 calcula-

This finding was corroborated by the fact that not a trace

of product 27 was formed starting from compound 26a or

26b using any of the reactions described in Schemes 2 and 3

under many different reaction conditions (Scheme 6). Most

reactions with 26a and 26b gave the starting material back

or decomposition products under forcing conditions.

Spino et al.

85

Fig. 3. Relative energies of the E and Z geometries in a struc-

tural system like 19.

Scheme 6.

Scheme 7.

McMurry coupling between 16 and 2-butanone also failed to

give any usable yields of an exocyclic alkene (13). The pros-

pect of achieving the stereocontrolled synthesis of this tetra-

substituted double bond appeared bleak. A reaction was

needed that would simultaneously generate the required cyc-

lohexene and the tetra-substituted, exocyclic double bond.

A solution to the problem of the exocyclic, tetra-sub-

stituted double bond was found in the [4 + 2]-cycloaddition

of vinylallene 30 and 32a and 32b. The syntheses of 30 and

32a and 32b starting from α,β-unsaturated ketone 28 are

shown in Scheme 7. The addition of methylcuprate to ace-

tate 29a yielded 30 accompanied with 27% of a product re-

sulting from the addition on the alkene. This side product

was difficult to separate at this stage, but it was innocuous

because it is an enyne incapable of undergoing a Diels–Al-

der reaction. Compounds 29b and 29c were first treated with

fluoride and the resulting alcohols underwent methylcuprate

addition to give high yields of vinylallene 31a and 31b, re-

spectively, as 1:1 mixtures of two diastereomers. This time,

less than 10% of alkene-addition products were formed in

each case.

41 (vide infra). The temperature at which this Diels–Alder

reaction occurs is remarkable considering the steric interac-

tions in the final product. In fact, we have reported the syn-

thesis of a series of cycloadducts like 33, with much larger

substituents around the exocyclic double bond and in some

cycloadducts, the exocyclic double bond was twisted by

more than 20° (14). It can be argued that the Diels–Alder re-

action has an early transition state, the structure of which re-

sembles the starting vinylallene where the severe steric

interactions of the cycloadduct 33 are not present.

The dienophile always comes from the least-hindered face

of the vinylallene in an intermolecular Diels–Alder cyclo-

addition (12, 15). This would give a cycloadduct with the

wrong geometry of the double bond for quassinoid synthesis

(as if R were larger than Me in 33). It was necessary to at-

tach the dienophile to the tether to accomplish the desired

synthesis as shown by the conversion of 32a and 32b to 35a

and 35b, respectively. The yields of cycloadducts 35a and

35b were good to excellent and the stereochemistry was

completely controlled. The stereochemistry of 35a was de-

duced by 2D-NOESY spectroscopy and by analogy with the

NMR spectra with that of 33. Note that the enyne side prod-

uct formed along with 30 and 31a and 31b (cf. Scheme 7)

are easily removed at this stage. Deprotection of the trityl

group in 33 and 35a and oxidation of the resulting alcohols

Vinylallene 30 reacted with methyl fumarate at the

refluxing temperature of benzene to give a single cyclo-

adduct 33 (Scheme 8). The structure of 33 was secured by a

single crystal X-ray diffraction analysis of a later derivative

86

Can. J. Chem. Vol. 81, 2003

Scheme 8.

afforded the required aldehydes 34 and 36 respectively

(Scheme 8). The tether in cycloadduct 35b, was elaborated

to enoate-aldehyde 38, in preparation for the intramolecular

Diels–Alder reaction. The deprotection of 35a and 37

yielded separable diastereomeric alcohols. The subsequent

reactions were performed on each isomer separately.

(except for 13β,14β-40c) and their stereochemistry were

therefore deduced from the stereochemistry of the corre-

sponding final tetracycle adducts 48–52 (vide infra). The

tether in racemic oxadienes 24a and 25 contains a chiral

center that creates up to four possible diastereomers for each

of 40a and 40c, respectively. Oxadiene 24b is homochiral,

however, and there are only two possible diastereomers for

40b (Scheme 9). Table 1 displays the results of the inter-

molecular hetero Diels–Alder cycloadditions of ethylvinyl

ether with 20a, 20b, 20e, 20f, and 24a and 24b, and 25 cata-

lyzed by Yb(FOD)₃. Only the ratios of 14β- to 14α-diastere-

omers are important to the discussion at this stage.

From earlier studies, we knew that a single carbon

substituent R¹was enough to differentiate between the two

faces of the oxadiene (Table 1, entry 3) (5a). However, an al-

cohol or a protected hydroxyl offers little bias for the incom-

ing dienophile, giving nearly equal mixtures of 14β and 14α

adducts (entries 2, 5–7). A bulky protecting group is β-face

selective (entry 1), presumably because of a preferred con-

formation 20-A where the protecting group is eclipsed with

the carbinol hydrogen at C-13, placing the bulky phenyl

rings underneath the oxadiene as drawn in Fig. 4. It seems

Hetero Diels–Alder cycloaddition

With the problem of the exocyclic double bond solved, ef-

forts were directed at the investigation of the hetero Diels–

Alder reaction for the construction of bicyclic adducts. A se-

ries of cycloadditions was performed on model compounds

20 and 24, bearing oxygen or carbon substituents at C-12

and (or) C-13 (Scheme 9). Most quassinoids possess a car-

bon at C-13 (either methyl or carboxy ester) and an oxygen

atom at C-12. The C-13 position is also often linked to an

oxygen atom (cf. Fig. 1). Contrary to oxadienes 20a–f,

oxadienes 24a and 24b and 25 (cf. Scheme 4) bear a teth-

ered dienophile capable of undergoing an intramolecular

Diels–Alder immediately after the hetero Diels–Alder. In

these cases, the intermediates 40a–c are in fact not isolated

Spino et al.

87

Scheme 9.

Table 1. 14α/14β-Ratio of adducts 39a–d and 40a–c from the

hinder sufficiently the β-face of the oxadiene (entry 4) (5a).

In contrast, protected diol 24b gave a 3:1 ratio favoring the

undesired 13β,14α-40b diastereomer (entry 6). Again, the

tert-butyldiphenylsilyl group is likely responsible for this re-

sult, shielding the α-face through a preferred conformation

20-A (R²= OBn, Fig. 4).

In contrast to the results obtained in the hetero Diels–Al-

der cycloadditions of oxadienes 20a, 20b, 20e, 20f, 24a and

24b, and 25, results obtained with compounds 34, 36a and

36b, and 38a and 38b are particularly helpful (Scheme 10).

The cycloadditions of 34, 36a, 36b, 38a, and 38b gave only

one detectable isomer 41, 42a, 42b, 43a, and 43b, respec-

tively. The stereochemistry of 41 was secured from a single

crystal X-ray diffraction analysis. Compounds 42a and 42b

and 43a and 43b were characterized by 2D-NMR experi-

ments and their NMR spectra compared well with that of 41.

Most likely, the oxadienes take on conformations 34-B or

36-B, forcing the methyl group into a pseudo-axial orienta-

tion (Fig. 4).

hetero Diels–Alder reaction (cf. Scheme 9).

Entry

Enal

Product

14β:14α^a

Yield (%)

1:4

1:1.6

4:1

11:1

1:1

1

2

3

4

5

6

7

20a

20b

20e

20f

24a

24b

25

39a

39b

39c

39d

40a

40b

40c

96

82

96

95

92

82

83

1:3

1:1

1

^aDetermined by H NMR.

obvious that if conformation 20-B were preferred, it would

effectively shield the β-face of the oxadiene. To obtain better

results, the oxadiene must be induced to adopt the conforma-

tion 20-B or force the C-13 substituent to orient its atoms

away from the α-face. The latter case is exemplified by the

isopropylidene-protected C-12/C-13 diol 20f that was able to

88

Can. J. Chem. Vol. 81, 2003

Fig. 4. Possible transition states for the intermolecular hetero Diels–Alder reaction of 20a, 34, 36, and 38.

Scheme 10.

the desired α-endo TS (47a, Scheme 11). However, it was

also evident that an α-C-3 substituent (the α-oxygen of the

dioxolane in 47a) should be avoided as it increases the en-

ergy of both α- and β-endo TS to the advantage of the α-exo

TS leading to the formation of 47b.

Intramolecular Diels–Alder cycloaddition

The substituents on ring C and D and the substituents on

the tether are able to affect the stereochemical outcome of

the intramolecular Diels–Alder cycloaddition. This concern

had to be addressed first and two things were known from

earlier studies (5a): (a) in absence of substituent on the

tether and on the ring (44), the β-endo TS (cf. Fig. 1) is fa-

vored by a factor of six leading to the formation of 45b as

the major product (Scheme 11); (b) two tether substituents in

46 are able to completely reverse this selectivity in favor of

Intramolecular Diels–Alder cycloaddition:

Results

Since intermediates 13β,14β–40a, 40b, 40c and 13α,14β–

40a, 40c were not isolated, their structures were deduced

Spino et al.

89

Scheme 11.

Scheme 12.

Scheme 13.

from those of the corresponding tetracycles 48–52 (Schemes

12 and 13). Note that intermediates 13β,14α–40a, 40b, 40c

and 13α,14α–40a, 40c (cf. Scheme 9) are of no interest for

quassinoids because they possess the wrong 14-α stereo-

chemistry. Although their corresponding tetracycles were

isolated and fully characterized, they will not be discussed

further.

Aldehyde 24a (racemic mixture of diastereomers) gave a

mixture of cycloadducts, of which 48a, 48b, and 50b could

be obtained partially pure (Scheme 12). Each cycloadduct

was treated with LiAlH₄and separation of the resulting alco-

hols yielded pure 53a, 53b, and 55a, respectively,

(Scheme 14). The structure of 53a was deduced from a sin-

gle crystal X-ray diffraction analysis, which secured the

structure of 48a. The structure of 48b was correlated with

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Can. J. Chem. Vol. 81, 2003

Scheme 14.

that of 49b (vide infra) because the structure of 53b could

not be determined unambiguously. The primary alcohol in

compound 55a was silylated under standard conditions to

give 55b, for which an X-ray analysis was obtained, con-

firming the structure for 50b. With the structures secured,

we were able to determined the ratios of tetracycles in the

crude mixture of 48 and 50. Tetracycles 48a and 48b were

found in a 1:1 ratio while compound 50b was the sole

tetracycle to emanate from intermediate 13α,14β-40a. All of

48a, 48b, and 50b possess the desired 14β-stereochemistry.

However, 48b and 50b have the wrong configuration at C-5,

C-7, and C-10. As explained later, the OPMB group is re-

sponsible for the formation of these two diastereomers.

Aldehyde 24b (diastereo- and enantiomerically pure) gave

two tetracycles that were desilylated to separate them more

easily. Compound 52a was the sole product having the 14β-

stereochemistry and thus to arise from intermediate 13β,14β–

40b (Scheme 13). The other tetracycle had the 14-α stereo-

chemistry and must have come from intermediate 13β,14α–

40b. The stereochemistry of 52b was determined from care-

ful NMR and 2D-NMR analysis of both tetracycles.

Lastly, aldehyde 25 led to a mixture of cycloadducts, of

which 49a, 49b, and 51a were separated and isolated in a

pure state (Scheme 12). The stereochemistry of 51a was de-

duced from a single crystal X-ray diffraction analysis.

Cycloadduct 49b was silylated to afford 54 that was crystal-

line and amenable to X-ray diffraction analysis (Scheme 14).

Conversion of 49b to 48b confirmed the structure of the lat-

ter. The now known product 48a was converted to 49a using

DDQ, which proved the structure of 49a. With the structure

of each cycloadduct secured, it was established that 49a and

49b were formed in a 2:1 ratio and arose from the

intramolecular Diel–Alder reaction of intermediate 13β,14β-

40c (Scheme 12). Cycloadduct 51a was the sole tetracycle to

emanate from intermediate 13α,14β-40c. All three

diastereomers 49a, 49b, and 51a have the desired 14β-

stereochemistry and only 49b, the minor isomer from 13β,14

β-40c, has the wrong stereochemistry at C-5, C-7, and C-10.

Therefore, removing the PMB group on the C-13 alcohol

proved beneficial.

Intramolecular Diels–Alder cycloaddition:

Analysis

It was clear, from the cycloaddition of 44, that a 14β-

stereochemistry favors a β-face attack of the dienophile (5a).

Fortunately, this trend was partly overcome by the presence

of a single methyl group on the tether at C-4 as shown in the

conversion of 13β,14β-40c into a 2:1 mixture of 49a and 49b

(Scheme 12). With a protected alcohol (13β,14β-40a) the ra-

tio 48a:48b was 1:1. It was particularly informative to ob-

serve the cycloaddition results with alcohol 13α,14β-40c and

PMB-protected alcohol 13α,14β-40a. The free alcohol

13α,14β-40c gave a single isomer 51a arising from an α-

endo transition state (Scheme 12). By contrast, the protected

alcohol 13α,14β-40a underwent the IMDAC to give a single

adduct 50b that emerged from a preferred β-endo transition

state having the methyl axial.

These results are explained as follows (Fig. 5): two α-

endo TS can be considered, namely α-endo TS-I and α-endo

Spino et al.

91

Fig. 5. Possible transition states for the intramolecular DAC of 40a–c.

TS-II. All α-endo TS-Is have the ethoxy group and the

dienophile in close proximity resulting in a steric interac-

tion. It is doubtful that any α-attack would take place via α-

endo TS-I. This is corroborated by MM2 calculations.

Therefore, only the α-endo TS-IIs will be considered in our

analysis and their energies will be compared with that of the

β-endo TSs.

2 kcal mol^–1(cf. 44 → 45b, Scheme 11). An α-C-4 methyl

group will be axial on a β-endo TS and should destabilize it

by roughly 2 kcal mol^–1, approximately counterbalancing the

advantage β-endo TS enjoys when there are no substituents.

This is what was observed, 13β,14β-40a and 13β,14β-40c

giving nearly equal mixtures of adducts regardless of the C-

13 β-substituent. The slight difference between the ratios of

13β,14β-40a and 13β,14β-40c may be attributable to small

conformational perturbations. However, an α-protected

In the absence of substituents on the ring or on the chain,

β-endo TS is favored over α-endo TS-II by approximately

92

Can. J. Chem. Vol. 81, 2003

Scheme 15.

alcohol at C-13 (13α,14β-40a) dramatically raises the energy

of the corresponding α-endo TS-II (or alternatively, it could

force a high-energy conformation like α-endo TS-I). This

explains why compound 13α,14β-40a gave a single tetra-

cycle 50b via a β-endo TS. The fact that 13α,14β-40c gave

only 51a can only be explained by a hydrogen bond in α-

endo TS-II. As a matter of fact, the cycloaddition of alcohol

13β,14β-40c was slower than that of alcohol 13α,14β-40c,

the former requiring benzene at reflux to go to completion

while the latter occurs rapidly at room temperature. This is

consistent with a hydrogen bond activating the ester in β-

endo TS for 13α,14β-40c.

If our analysis is correct, two β-substituents at C-12 and

C-13 (as in 13β,14β-40b) should come together to lead to a

single tetracycle resulting from α-endo TS-II. Indeed, re-

gardless of the conformation of the C-ring, one of the sub-

stituents at C-12 or C-13 has to be pseudoaxial, thereby

significantly raising the energy of the β-endo TS due to

steric interaction with the incoming dienophile (Fig. 5,

right). Comparatively, the energy of the α-endo TS-II should

not be raised as much. We were pleased to find that diene 13

β,14β-40b gave a single tetracycle 52a, thereby confirming

our hypothesis (Scheme 13).

There is now a good indication that a single stereo-

defined substituent on the tether and two β-substituents at C-

12 and C-13 will force the intramolecular Diels–Alder to

take place through an α-endo TS. Adding a methyl group on

the exocyclic double bond should not change anything.

However, it became clear in preliminary studies that such a

methyl substituent considerably slows down the rate of

cycloaddition. For example, compound 41 underwent a clean

Diels–Alder cycloaddition reaction at the refluxing tempera-

ture of xylenes for 5 days to give 56 as a mixture of two

stereoisomers (Scheme 15, ratios and stereochemistry of 56

not determined). While this result indicated that the Diels–

Alder is definitely possible, trials with 43a or 43b always

gave decomposition products because it could not withstand

such harsh conditions. The use of Lewis acids also led to de-

composition products only. We have established that the

main reason for the decomposition of 43a and 43b is the

lability of the C-1 oxygen functionality as shown in

Scheme 15. We are working to build different models in the

hopes of overcoming this obstacle. Those results will be re-

ported in due course.

Experimental section

All reactions were carried out under an argon atmosphere.

Ethyl ether, toluene, and benzene were dried over metallic

sodium using benzophenone as an indicator, while

tetrahydrofuran was dried over both sodium and potassium

using the same indicator. Dichloromethane, dimethyl

formamide, carbon tetrachloride, 1,2-dichloroethane,

triethylamine, pyridine, acetonitrile, and diisopropylamine

were distilled over calcium hydride. Hexanes were pur-

chased in anhydrous form from Aldrich. Ethyl vinyl ether

was distilled prior to use. Cerium trichloride was purchased

in hydrated form and dried at 200°C under high vacuum

overnight. Thin layer chromatography was performed using

0.25 mm Silica Gel 60 F254 (EM Science-Merck) and flash

chromatography using silica gel Kieselgel 60 (230–400

mesh ASTM).

All NMR spectra were taken in deuterated chloroform on

a Brüker AC-300 (¹H (300 MHz), ¹³C (75 MHz)). Chemical

shifts are reported in ppm (δ) downfield from tetra-

methylsilane. The splitting patterns are designated as singlet

(s), doublet (d), triplet (t), quartet (q), multiplet (m), and AB

quartet (ABq). The IR spectra were determined on a Perkin-

Elmer 1600 FT spectrometer. The IR spectra were deter-

mined neat, unless otherwise stated. The melting points were

performed on a Mettler Toledo model 62. High- and low-

resolution mass spectra (HR-MS and LR-MS) were obtained

with a micromass spectrometer ZAB-1F model VG.

Spino et al.

93

248.1408. Anal. calcd. for C₁₅H₂₀O₃: C 72.55, H 8.12, O

19.33; found: C 72.51, H 8.23.

tert-Butyldiphenylsilyl ether 11a

To a cooled 0°C solution of cyclohexanedione, mono-

ethylene ketal (22.1 g, 141 mmol) and methanol was added,

in portions, sodium borohydride (5.35 g, 141 mmol). The re-

action was stirred for 3 h before being brought to pH 7 by

the addition of 1 N HCl. The mixture was partitioned be-

tween dichloromethane and brine, and the aqueous phase ex-

tracted with CH₂Cl₂. The aqueous layer was concentrated

until a precipitate began to form and this layer was extracted

again with CH₂Cl₂. The combined organic layers were dried

over MgSO₄, filtered, and concentrated. The crude alcohol

(22.69 g, 100%) was coevaporated with benzene and used

PMB ether 11c

To an oil-free suspension of KH (3.04 g, 75.8 mmol) in

THF (200 mL) was added a solution of the same alcohol

used to make 11a (10.0 g, 63.2 mmol) in THF (70 mL) via

cannula at 0°C. After hydrogen evolution had ceased (1 h), a

solution of PMBCl (10.4 g, 66.4 mmol) and THF (30 mL)

was added via cannula. The ice bath was removed and the

reaction stirred overnight. The reaction was quenched with

satd. aq NH₄Cl, and the product extracted with ether (3 ×

80 mL). The combined organic layers were washed with

brine, dried over MgSO₄, filtered, and concentrated. Purifi-

cation by flash chromatography (hexanes:EtOAc (3:1 to

1:1)) yielded 16.9 g (96%) of ketal 11c as a clear oil. IR

1

without further purification. H NMR (CDCl₃) δ: 3.85 (s,

4H), 3.67–3.66 (m, 1H), 2.67 (bs, 1H), 1.80–1.68 (m, 4H),

1.61–1.43 (m, 4H). ¹³C NMR (CDCl₃) δ: 108.2 (s), 67.7 (d),

64.0 (t), 31.7 (t), 31.4 (t). LR-MS (m/z (relative intensity)):

158 ([M]⁺, 10), 99 (100). HR-MS calcd. for C₈H₁₄O₃:

158.0943; found: 158.0937. To a solution of this alcohol

(5.00 g, 31.6 mmol), imidazole (5.38 g, 79.0 mmol) in DMF

(20 mL) was added TBDPSCl (9.86 mL, 37.9 mmol) at

room temperature. The mixture was stirred at room tempera-

ture for 4 h before being poured into hexane (30 mL). The

layers were separated and the DMF layer washed with hex-

anes (2 × 30 mL) and ethyl ether (30 mL). The combined

hexanes – ethyl ether layer was washed with brine, dried

over MgSO₄, filtered, and concentrated. The crude residue

was purified by flash chromatography eluted with hex-

anes:EtOAc (9:1) to give 12.5 g (100%) of ketal 11a as a

1

(cm^–1): 2943, 1611, 1513. H NMR (CDCl₃) δ: 7.26 (d, 2H,

J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 4.45 (s, 2H), 3.92 (s,

4H), 3.78 (s, 3H), 3.52–3.47 (m, 1H), 1.86–1.75 (m, 6H),

1.56–1.53 (m, 2H). ¹³C NMR (CDCl₃): δ: 158.9 (s), 131.0

(s), 128.8 (d), 113.6 (d), 108.4 (s), 73.7 (d), 69.4 (t), 64.2 (t),

55.1 (q), 31.2 (t), 28.5 (t). LR-MS (m/z (relative intensity)):

278 ([M]⁺, 10), 86 (100), 121 (90), 99 (90), 142 (65). HR-MS

calcd. for C₁₆H₂₂O₄: 278.1518; found: 278.1515. Anal.

calcd. for C₁₆H₂₂O₄: C 69.04, H 7.97, O 22.99; found: C

69.05, H 7.95.

colourless oil. IR (cm^–1): 3446, 3070, 1589, 1472, 1427. H

1

Ketone 12a

NMR (CDCl₃) δ: 7.73–7.65 (m, 4H), 7.45–7.34 (m, 6H),

3.98–3.85 (m, 5H), 1.97–1.88 (m, 2H), 1.71–1.63 (m, 4H),

1.51–1.43 (m, 2H), 1.06 (s, 9H). ¹³C NMR (CDCl₃) δ: 135.7

(d), 134.8 (d), 134.5 (s), 129.5 (d), 127.6 (d), 127.4 (d),

108.6 (s), 68.4 (d), 64.1 (t), 31.7 (t), 30.8 (t), 26.9 (q), 19.2

(s). LR-MS (m/z (relative intensity)): 339 ([M⁺– C₄H₉], 10),

199 (100), 200 (25). HR-MS calcd. for C₂₀H₂₃O₃Si:

339.1416; found: 339.1412. Anal. calcd. for C₂₄H₃₂O₃Si: C

72.68, H 8.13, O 12.10, Si 7.08; found: C 72.53, H 8.18, O

11.98.

A mixture of ketal 11a (12.5 g, 31.6 mmol), THF

(226 mL), and 1 N HCl (75 mL) was heated to reflux for

3 h. The mixture was cooled, neutralized by the addition of

satd. aq NaHCO₃and extracted with CH₂Cl₂. The combined

organic layers were washed with brine, dried over MgSO₄,

filtered, and concentrated. The product was crystallized by

the addition of petroleum ether. Three crystallizations

yielded 10.8 g (97%) of ketone 12a as a white solid; mp:

1

106.0°C. IR (cm^–1): 3069, 1716, 1427. H NMR (CDCl₃) δ:

7.69–7.67 (m, 4H), 7.45–7.36 (m, 6H), 4.16–4.13 (m, 1H,

J = 2.6 Hz), 2.79–2.69 (m, 2H), 2.25–2.17 (dt, 2H, J = 14.4,

5.3 Hz), 1.99–1.93 (m, 2H), 1.83–1.78 (m, 2H), 1.09 (s, 9H).

¹³C NMR (CDCl₃) δ: 211.5 (s), 135.6 (d), 133.8 (s), 129.7

(d), 127.6 (d), 66.9 (d), 36.9 (t), 33.7 (t), 26.9 (q), 19.2 (s).

LR-MS (m/z (relative intensity)): 295 ([M⁺– C₄H₉], 92),

199 (100). HR-MS calcd. for C₁₈H₁₉O₂Si: 295.1154; found:

295.1151. Anal. calcd. for C₂₂H₂₈O₂Si: C 74.95, H 8.01, O

9.08, Si 7.97; found: C 74.86, H 8.02, O 8.99.

Benzyl ether 11b

To an oil-free suspension of KH (10.19 g, 254 mmol) in

THF (400 mL) was added a solution of the same alcohol

used to make 11a (16.4 g, 102 mmol) in THF (50 mL) via

cannula at 0°C. After hydrogen evolution had ceased, the

mixture was warmed to room temperature and the reaction

stirred for 3 h. Benzyl bromide (18.1 mL, 152 mmol) was

added neat and the reaction stirred overnight. The reaction

was quenched with satd. aq NH₄Cl, and the product ex-

tracted with CH₂Cl₂. The combined organic layers were

washed with brine, dried over MgSO₄, filtered, and concen-

trated. Purification by flash chromatography (hex-

anes:EtOAc (9:1 to 3:1)) yielded 20.8 g (83%) of ketal 11b

Ketone 12b

Followed the same procedure as per 12a, starting with

ketal 11b yielding 7.70 g (94%) of ketone 12b as a colour-

less oil. IR (cm^–1): 3031, 2941, 1716, 1103. ¹H NMR

(CDCl₃) δ: 7.37–7.28 (m, 5H), 4.59 (s, 2H), 3.83–3.79 (m,

1H), 2.67–2.56 (m, 2H), 2.30–2.22 (m, 2H), 2.19–2.09 (m,

2H), 2.00–1.89 (m, 2H). ¹³C NMR (CDCl₃) δ: 211.0 (s),

138.4 (s), 128.3 (d), 127.4 (d), 127.3 (d), 72.1 (d), 70.1 (t),

37.1 (t), 30.3 (t). LR-MS (m/z (relative intensity)): 204 ([M]⁺,

7), 91 (100). HR-MS calcd. for C₁₃H₁₆O₂: 204.1150; found:

204.1152. Anal. calcd. for C₁₃H₁₆O₂: C 76.44, H 7.90, O

15.67; found: C 76.44, H 7.95.

1

as a colourless oil. IR (cm^–1): 3030, 2949, 1370. H NMR

(CDCl₃) δ: 7.34–7.26 (m, 5H), 4.53 (s, 2H), 3.94–3.92 (m,

4H), 3.56–3.50 (m, 1H), 1.89–1.79 (m, 6H), 1.58–1.53 (m,

2H). ¹³C NMR (CDCl₃) δ: 139.0 (s), 128.2 (d), 127.3 (d),

108.4 (s), 74.0 (d), 69.8 (t), 64.2 (t), 31.2 (t), 28.5 (t). LR-

MS (m/z (relative intensity)): 248 ([M]⁺, 5), 99 (100), 86

(98). HR-MS calcd. for C₁₅H₂₀O₃: 248.1412; found:

94

Can. J. Chem. Vol. 81, 2003

hexanes:EtOAc (20:1 to 9:1) gave 9.80 g (93%) of enone

Ketone 12c

1

15a as a clear liquid. IR (cm^–1): 3056, 1824, 1684, 1472. H

A solution of ketal 11c (15.28 g, 54.9 mmol) and PPTS

(4.1 g, 16.5 mmol) in wet acetone (550 mL) was heated to

reflux for 5.5 h. The mixture was cooled and the solvent re-

moved in vacuo. The residue was taken up in ethyl ether and

washed with satd. aq NaHCO₃, and brine, dried over

MgSO₄. Flash chromatography using a mixture of hex-

anes:EtOAc (3:1 to 1:1) procured 11.89 g (92%) of ketone

12c as a white solid; mp: 34.9°C. IR (CHCl₃, cm^–1): 3011,

NMR (CDCl₃) δ: 7.72–7.67 (m, 4H), 7.48–7.38 (m, 6H),

6.78 (dd, 1H, J = 10.2, 2.5 Hz), 5.86 (d, 1H, J = 10.2 Hz),

4.52–4.47 (m, 1H), 2.52 (dt, 1H, J = 16.4, 4.5 Hz), 2.25–

2.17 (m, 1H), 2.15–2.03 (m, 2H), 1.08 (s, 9H). ¹³C NMR

(CDCl₃) δ: 198.8 (s), 153.1 (d), 135.7 (d), 133.3 (s), 129.9

(d), 129.5 (d), 128.7 (d), 127.7 (d), 67.5 (d), 35.2 (t), 32.5

(t), 26.8 (q), 19.0 (s). LR-MS (m/z (relative intensity)): 293

([M⁺– C₄H₉], 65), 199 (100). HR-MS calcd. for C₁₈H₁₇O₂Si:

293.0998; found: 293.0996. Anal. calcd. for C₂₂H₂₆O₂Si: C

75.38, H 7.48, O 9.13, Si 8.01; found: C 75.44, H 7.40, O

9.11.

1

1708, 1612, 1513. H NMR (CDCl₃) δ: 7.29 (d, 2H, J =

8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz), 4.53 (s, 2H), 3.81 (s, 3H),

3.82–3.78 (m, 1H), 2.67–2.56 (m, 2H), 2.31–2.22 (m, 2H),

2.17–2.10 (m, 2H), 2.00–1.91 (m, 2H). ¹³C NMR (CDCl₃) δ:

211.2 (s), 159.0 (s), 130.4 (s), 128.9 (d), 113.7 (d), 71.8 (d),

69.8 (t), 55.1 (q), 37.1 (t), 30.4 (t). LR-MS (m/z (relative in-

tensity)): 234 ([M]⁺, 35), 121 (100). HR-MS calcd. for

C₁₄H₁₈O₃: 234.1256; found: 234.1259. Anal. calcd. for

C₁₄H₁₈O₃: C 71.77, H 7.74, O 20.49; found: C 71.82, H

7.88.

Enone 15b

Following the procedure outlined for enone 15a, enone

15b was prepared starting from ketone 12b. The yield of

enone 15b was 3.18 g (70%) isolated as a colourless oil. IR

1

(cm^–1): 3031, 2954, 2870, 1693, 1454, 1201, 1093. H NMR

(CDCl₃) δ: 7.38 (m, 5H), 7.00–6.96 (m, 1H, J = 10.4 Hz),

5.99 (dt, 1H, J = 10.6, 1.2 Hz), 4.29–4.23 (m, 1H), 2.65–

2.56 (m, 1H), 2.39–2.27 (m, 2H), 2.11–1.98 (m, 1H). ¹³C

NMR (CDCl₃) δ: 198.6 (s), 150.4 (d), 137.7 (s), 129.6 (d),

128.4 (d), 127.8 (d), 127.6 (d), 127.3 (d), 72.4 (d), 70.9 (t),

35.2 (t), 29.1 (t). LR-MS (m/z (relative intensity)): 203

([M + 1], 48), 220 ([M + NH₄], 38), 91 (100). HR-MS calcd.

for C₁₃H₁₅O₂: 203.1072; found: 203.1077. Anal. calcd. for

C₁₃H₁₄O₂: C 77.20, H 6.98, O 15.82; found: C 77.12, H

7.05.

Lactone 14

To a stirred solution of known diol 13 (8.05 g,

30.4 mmol), imidazole (10.3 g, 152.0 mmol), DMAP

(750 mg, 6.08 mmol), and dichloromethane (300 mL) was

added TBDPSCl (7.9 mL, 30.4 mmol) at room temperature.

The reaction was stirred for 7 days before being partitioned

between water and dichloromethane. The aqueous layer was

extracted with dichloromethane, washed with brine, dried

over MgSO₄, filtered, and concentrated. Purification by flash

chromatography eluted with hexanes:EtOAc (9:1 to 6:1 to

1:1) yielded 12.0 g (78%) of silyl ether 14 and 1.82 g (22%)

of starting diol 13, resulting in a corrected overall yield of

100%. [α]_D: –48.4° (c 1.59, CHCl₃). IR (cm^–1): 3439, 3069,

Enone 15c

Followed the same procedure as per 15a yielding 7.80 g

(82%) of enone 15c as a colourless oil. IR (cm^–1): 2999,

2955, 2836, 1681, 1613, 1514, 1249, 1087. ¹H NMR

(CDCl₃) δ: 7.29 (d, 2H, J = 8.6 Hz), 6.96 (d, 1H, J =

10.3 Hz), 6.90 (d, 2H, J = 8.6 Hz), 5.98 (d, 1H, J =

10.3 Hz), 4.58 (AB quartet, 2H, J = 11.4, 5.9 Hz), 4.27–4.21

(m, 1H), 3.81 (s, 3H), 2.64–2.56 (m, 1H), 2.39–2.29 (m,

2H), 2.09–1.98 (m, 1H). ¹³C NMR (CDCl₃) δ: 198.5 (s),

159.2 (s), 150.6 (d), 129.5 (s), 129.3 (d), 129.2 (d), 113.8

(d), 71.9 (d), 70.4 (t), 55.1 (q), 35.1 (t), 28.9 (t). LR-MS

(m/z (relative intensity)): 232 ([M]⁺, 40), 122 (60), 121 (100).

HR-MS calcd. for C₁₄H₁₆O₃: 232.1099; found: 232.1094.

Anal. calcd. for C₁₄H₁₆O₃: C 72.39, H 6.94, O 20.66; found:

C 72.40, H 6.90.

1

1794, 1427. H NMR (CDCl₃) δ: 7.73–7.59 (m, 4H), 7.44–

7.23 (m, 9H), 7.07–7.04 (m, 2H), 4.40 (t, 1H, J = 5.4 Hz),

4.27–4.21 (m, 3H), 3.48–3.41 (m, 1H), 2.84 (d, 1H, J =

11.3 Hz), 2.66 (s, 1H), 2.31–2.13 (m, 3H), 1.08 (s, 9H). ¹³C

NMR (CDCl₃) δ: 177.8 (s), 137.5 (s), 136.0 (d), 135.6 (d),

133.2 (s), 132.4 (s), 129.9 (d), 129.6 (d), 128.0 (d), 127.6

(d), 127.3 (d), 76.1 (d), 73.3 (d), 72.3 (s), 70.7 (t), 65.8 (d),

36.8 (t), 36.5 (t), 26.8 (q), 19.2 (s). LR-MS (m/z (relative in-

tensity)): 445 ([M⁺– C₄H₉], 20), 353 (65), 91 (90), 277

(100). HR-MS calcd. for C₂₆H₂₅O₅Si: 445.1471; found:

445.1465. Anal. calcd. for C₃₀H₃₄O₅Si: C 71.68, H 6.82, O

15.91, Si 5.59; found: C 71.64, H 6.84, O 16.01.

Enone 15a

Enone 15d

To a solution of ketone 12a (10.59 g, 30.0 mmol) and

PhSO₂Me (4.70 g, 30.0 mmol) in THF (70 mL) was added

an oil-free suspension of KH (3.01 g, 75.2 mmol) in THF

(60 mL) via cannula at room temperature. The mixture was

stirred at room temperature for 30 min before being concen-

trated to dryness. The residue was partitioned between di-

chloromethane (100 mL) and 0.5 M aq H₃PO₄(50 mL). The

layers were separated and the aqueous layer extracted with

dichloromethane (2 × 70 mL). The combined organic layers

were dried over MgSO₄, filtered, and concentrated. The

crude residue was taken up in toluene (300 mL) and Na₂CO₃

(15.9 g, 150 mmol) was added. The suspension was heated

to reflux for 30 min, cooled, filtered through Celite, and

concentrated. Purification by flash chromatography using

NaBH₄(499 mg, 13.2 mmol) was added to a 0°C solution

of lactone 14b (6.66 g, 13.2 mmol) and ethyl alcohol

(45 mL). The reaction mixture was stirred at 0°C for a total

of 2 h before being quenched by the slow addition of aq

NH₄Cl. The ice bath was removed and phosphate buffer and

water were added, followed by sodium periodate (3.67 g,

17.1 mmol). The reaction mixture was stirred overnight and

the resulting suspension filtered through Celite. The alcohol

was extracted with dichloromethane, washed with brine,

dried over MgSO₄, filtered, and concentrated. Purification by

flash chromatography (hexanes:EtOAc, 3:1) yielded 4.67 g

(75%) of a keto alcohol as a colourless oil. [α]_D: –22.6° (c

3.16, CHCl₃). IR (cm^–1): 3433, 3061, 2930, 2854, 1714,

1

1471, 1427, 1136, 1112. H NMR (CDCl₃) δ: 7.76–7.67 (m,

Spino et al.

95

4H), 7.45–7.18 (m, 11H), 4.42 (d, 1H, J = 11.7 Hz), 4.32 (d,

1H, J = 11.7 Hz), 4.17–4.15 (m, 1H), 4.08 (dd, 1H, J = 6.4,

2.3 Hz), 3.84–3.79 (m, 1H), 2.91–2.81 (m, 2H), 2.48 (dd,

1H, J = 14.2, 3.9 Hz), 2.31–2.24 (m, 1H), 1.77 (d, 1H, J =

3.1 Hz), 1.10 (s, 9H). ¹³C NMR (CDCl₃) δ: 207.5 (s), 138.0

(s), 136.1 (d), 135.8 (d), 133.6 (s), 132.9 (s), 130.0 (d),

129.8 (d), 128.2 (d), 127.8 (d), 127.5 (d), 127.3 (d), 75.5 (d),

73.5 (d), 70.9 (t), 69.5 (d), 44.8 (t), 43.4 (t), 27.0 (q), 19.3

(s). LR-MS (m/z (relative intensity)): 417 ([M⁺– C₄H₉], 8),

249 (95), 91 (100). HR-MS calcd. for C₂₅H₂₅O₄Si:

417.1522; found: 417.1533. Anal. calcd. for C₂₉H₃₄O₄Si: C

73.38, H 7.22, O 13.48, Si 5.92; found: C 73.41, H 7.35, O

13.32.

Bromoenone 16b

Followed the same procedure as per 16a. Purification by

flash chromatography using a mixture of hexanes:EtOAc

(6:1) gave 7.23 g (78%) of bromoketone 16b as a thick oil.

IR (cm^–1): 3066, 2959, 2871, 1703, 1454, 1317, 1096. H

1

NMR (CDCl₃) δ: 7.45 (dd, 1H, J = 13.0, 1.2 Hz), 7.39–7.32

(m, 5H), 4.64 (s, 2H), 4.29–4.24 (m, 1H), 2.84 (ddd, 1H, J =

16.8, 5.6, 4.5 Hz), 2.53–2.32 (m, 2H), 2.18–2.08 (m, 1H).

¹³C NMR (CDCl₃) δ: 190.4 (s), 150.5 (d), 137.2 (s), 128.5

(d), 128.0 (d), 127.7 (d), 125.0 (s), 73.6 (d), 71.1 (t), 34.7

(t), 29.0 (t). LR-MS (m/z (relative intensity)): 280 ([M]⁺, 5),

282 ([M]⁺, 5), 201 ([M⁺– Br], 40), 175 (100). HR-MS

calcd. for C₁₃H₁₃BrO₂: 280.0099; found: 280.0107.

To a cooled 0°C solution of the keto alcohol (4.51 g,

9.49 mmol), methanesulfonyl chloride (880 µL, 11.4 mmol),

and dichloromethane (32 mL) was added triethylamine

(4 mL, 28.5 mmol). After 15 min at 0°C, the reaction was

quenched with water. After extraction with dichloromethane,

the organic layers were washed with satd. aq NaHCO3, and

brine, dried over MgSO4. Filtration, concentration, and puri-

fication by flash chromatography (hexanes:ethyl acetate,

3:1) yielded 4.03 g (93%) of enone 15d as an oil. [α]_D:

Bromoenone 16c

Same procedure as per 16a. Purification by flash chroma-

tography eluting with a mixture of hexanes:EtOAc (3:1 to

1:1) gave 9.58 g (92%) of 16c as a white solid; mp: 62.7°C.

IR (cm^–1): 2955, 1697, 1611, 1513, 1463, 1318, 1249, 1174,

1032, 1000, 817. ¹H NMR (CDCl₃) δ: 7.42 (d, 1H, J =

3.5 Hz), 7.28 (d, 2H, J = 8.6 Hz), 6.90 (d, 2H, J = 8.6 Hz),

4.57 (s, 2H), 4.27–4.22 (m, 1H), 3.81 (s, 3H), 2.83 (dm, 1H,

J = 16.8, 10.7 Hz), 2.47 (m, 1H, J = 16.8, 11.7 Hz), 2.37–

2.28 (m, 1H), 2.16–2.04 (m, 1H). ¹³C NMR (CDCl₃) δ:

190.4 (s), 159.3 (s), 150.7 (d), 132.0 (s), 129.3 (d), 124.8 (s),

113.9 (d), 73.2 (d), 70.7 (t), 55.2 (q), 34.6 (t), 29.0 (t). LR-

MS (m/z (relative intensity)): 310 ([M]⁺, 8), 136 (27), 121

(100). HR-MS calcd. for C₁₄H₁₅O₃Br: 310.0204; found:

310.0195.

1

+78.1° (c 3.61, CHCl₃). IR (cm^–1): 3069, 1682, 1427. H

NMR (CDCl₃) δ: 7.73–7.65 (m, 4H), 7.47–7.24 (m, 11H),

6.60 (dd, 1H, J = 10.3, 3.2 Hz), 5.93 (d, 1H, J = 10.5 Hz),

4.62 (d, 1H, J = 12.2 Hz), 4.60–4.57 (m, 1H), 4.54 (d, 1H,

J = 12.2 Hz), 3.84–3.80 (m, 1H), 2.89 (dd, 1H, J = 16.5,

7.1 Hz), 2.43 (dd, 1H, J = 16.5, 3.2 Hz), 1.10 (s, 9H). ¹³C

NMR (CDCl₃) δ: 197.1 (s), 148.5 (d), 138.0 (s), 135.8 (d),

133.3 (s), 132.9 (s), 129.9 (d), 129.6 (d), 128.2 (d), 127.7

(d), 127.4 (d), 76.6 (d), 71.3 (t), 68.4 (d), 40.9 (t), 26.8 (q),

19.2 (s). LR-MS (m/z (relative intensity)): 399 ([M⁺– C₄H₉],

8), 231 (38), 91 (100). HR-MS calcd. for C₂₅H₂₃O₃Si:

399.1416; found: 399.1422. Anal. calcd. for C₂₉H₃₂O₃Si: C

76.28, H 7.06, O 10.51, Si 6.15; found: C 76.29, H 7.09, O

10.54.

Bromoenone 16d

Followed the same procedure as per 16a. Flash chroma-

tography eluting with a mixture of hexanes:EtOAc (6:1)

gave 9.27 g (94%) of 16d as a thick oil. [α]_D: +81.9° (c 1.81,

CHCl₃). IR (cm^–1): 3069, 2957, 1700, 1427, 1113, 1066,

741, 702. ¹H NMR (CDCl₃) δ: 7.73–7.63 (m, 4H), 7.48–7.22

(m, 11H), 6.99 (d, 1H, J = 4.2 Hz), 4.58 (d, 1H, J =

12.3 Hz), 4.56–4.52 (m, 1H), 4.50 (d, 1H, J = 12.2 Hz), 3.80

(dt, 1H, J = 7.1, 3.2 Hz), 3.10 (dd, 1H, J = 16.4, 7.7 Hz),

2.60 (dd, 1H, J = 16.4, 3.2 Hz), 1.10 (s, 9H). ¹³C NMR

(CDCl₃) δ: 189.1 (s), 148.7 (d), 137.6 (s), 135.8 (d), 132.9

(s), 132.6 (s), 130.1 (d), 128.3 (d), 127.9 (d), 127.5 (d),

125.1 (s), 75.9 (d), 71.3 (t), 69.7 (d), 40.3 (t), 26.8 (q), 19.3

(s). LR-MS (m/z (relative intensity)): 477 ([M⁺– C₄H₉], 5),

479 ([M⁺– C₄H₉], 5), 311 (30), 309 (30), 91 (100). HR-MS

calcd. for C₂₅H₂₂O₃SiBr: 477.0521; found: 477.0511.

Bromoenone 16a

To a solution of enone 15a (19.0 g, 54.3 mmol) in CCl₄

(500 mL) was added over 1 h a solution of bromine (8.25 g,

51.6 mmol) in CCl₄(100 mL) at 0°C. Once complete the

mixture was stirred for 45 min at 0°C before a solution of

triethylamine (9.89 g, 97.8 mmol) in carbon tetrachloride

(100 mL) was added over a 20 min period. The reaction

mixture was stirred for 20 min and filtered. The filtrate was

washed with 1 N HCl and satd. aq NaHCO₃. The aqueous

layers were extracted with ether and combined organic lay-

ers dried over MgSO₄, filtered, and concentrated. Purifica-

Alcohol 17a

tion by flash chromatography using

a

mixture of

To a 0°C solution of tetravinyl tin (320 mg, 1.41 mmol) in

THF (20 mL) was added 1.08 M n-butyl lithium (4.73 mL,

5.11 mmol). After 30 min at 0°C the ice bath was removed

and the mixture stirred for 1 h. This solution was added via

cannula to a cooled –78°C suspension of CeCl₃(2.86 g,

7.67 mmol) and ketone 16a (1.10 g, 2.55 mmol) in THF

(40 mL). The reaction mixture was stirred for 4 h at –78°C

before being quenched with satd. aq NH₄Cl. The layers were

separated (a portion of 1 N HCl was added for clarification)

and the aqueous layer extracted with ethyl ether. The organic

layers were washed (brine), dried over MgSO₄, filtered, and

concentrated. Flash chromatography eluting with a mixture

of hexanes:EtOAc (9:1) gave 447 mg and 646 mg of two

hexanes:EtOAc (20:1 to 8:1) gave 21.0 g (90%) of bromo-

enone 16a as a white solid and trace amounts of a dibromo-

1

ketone; mp: 78.2°C. IR (cm^–1): 3060, 2955, 1699. H NMR

(CDCl₃) δ: 7.68–7.65 (m, 4H), 7.48–7.38 (m, 6H), 7.20 (d,

1H, J = 3.1 Hz), 4.48 (dt, 1H, J = 6.4, 3.1 Hz), 2.76 (dt, 1H,

J = 16.7, 5.0 Hz), 2.33 (dt, 1H, J = 16.4, 8.2 Hz), 2.13–2.06

(m, 2H), 1.08 (s, 9H). ¹³C NMR (CDCl₃) δ: 190.6 (s), 153.1

(d), 135.7 (d), 132.9 (s), 130.2 (d), 127.9 (d), 124.1 (s), 68.8

(d), 34.7 (t), 32.4 (t), 26.8 (q), 19.1 (s). LR-MS (m/z (rela-

tive intensity)): 373 ([M⁺– C₄H₉], 50), 371 ([M⁺– C₄H₉],

48), 199 (100). HR-MS calcd. for C₁₈H₁₆BrO₂Si: 371.0103;

found: 371.0098.

96

Can. J. Chem. Vol. 81, 2003

diastereomeric alcohols (93%) as thick oils. Less polar iso-

mer: H NMR (CDCl₃) δ: 7.73–7.65 (m, 4H), 7.46–7.35 (m,

Acetate 18b

1

Followed the same procedure as per 18a, starting from

17b. Flash chromatography using a hexanes:EtOAc (8:1 to

4:1) mixture yielded 2.29 g (83%) of a mixture of acetates

18b as a colourless oil. Less polar isomer: ¹H NMR (CDCl₃)

δ: 7.36–7.28 (m, 5H), 6.45 (d, 1H, J = 4.5 Hz), 5.95 (dd, 1H,

J = 10.8, 17.3 Hz), 5.30 (d, 1H, J = 10.8 Hz), 5.28 (d, 1H,

J = 17.5 Hz), 4.59 (s, 2H), 3.88 (q, 1H, J = 4.3 Hz), 2.93–

2.83 (m, 1H), 2.09 (s, 3H), 2.07–1.81 (m, 3H). ¹³C NMR

(CDCl₃) δ: 169.1 (s), 138.3 (s), 136.3 (d), 132.9 (d), 128.4

(d), 127.7 (d), 116.4 (t), 82.4 (s), 71.4 (d), 70.4 (t), 28.5 (t),

24.9 (t), 22.0 (q). More polar isomer: IR (cm^–1): 3030, 1745.

¹H NMR (CDCl₃) δ: 7.36–7.30 (m, 5H), 6.45 (dd, 1H, J =

3.5, 2.3 Hz), 5.90 (dd, 1H, J = 17.3, 10.7 Hz), 5.38 (d, 1H,

J = 17.2 Hz), 5.33 (d, 1H, J = 10.7 Hz), 4.58 (ABq, 2H, J =

22.1 Hz), 4.17 (ddd, 1H, J = 2.3, 5.4, 9.8 Hz), 2.63 (m, 1H,

J = 3.2, 12.9 Hz), 2.14–2.03 (m, 2H), 2.09 (s, 3H), 1.80–

1.68 (m, 1H). ¹³C NMR (CDCl₃) δ: 168.9 (s), 137.8 (s),

136.6 (d), 135.0 (d), 128.3 (d), 127.5 (d), 116.7 (t), 82.2 (s),

74.5 (d), 70.3 (t), 30.5 (t), 26.5 (t), 21.9 (q). LR-MS (m/z

(relative intensity)): 368 ([M + NH₄], 25), 308 ([M + NH₄–

AcOH], 25), 291 ([M⁺– AcOH], 25), 211 (100). HR-MS

calcd. for C₁₇H₂₃NO₃Br: 368.0861; found: 368.0857. Anal.

calcd. for C₁₇H₁₉BrO₃: C 58.13, H 5.45, Br 22.75, O 13.67;

found: C 58.22, H 5.35, O 13.74.

6H), 6.12 (d, 1H, J = 3.6 Hz), 5.72 (dd, 1H, J = 17.1,

10.6 Hz), 5.26 (d, 1H, J = 17.1 Hz), 5.17 (d, 1H, J =

10.6 Hz), 4.15 (q, 1H), 2.18–2.10 (m, 1H), 1.83–1.67 (m,

2H), 1.06 (s, 9H). ¹³C NMR (CDCl₃) δ: 141.2 (d), 135.7 (d),

135.4 (d), 133.7 (s), 131.1 (s), 129.7 (d), 127.6 (d), 114.9 (t),

74.1 (s), 68.3 (d), 33.0 (t), 28.2 (t), 26.9 (q), 19.1 (s). More

polar isomer: IR (cm^–1): 3548, 3435, 3066, 2953, 2861,

1630, 1589, 1471, 1425, 1364, 1323, 1076. ¹H NMR

(CDCl₃) δ: 7.72–7.64 (m, 4H), 7.47–7.35 (m, 6H), 6.10 (d,

1H, J = 3.1 Hz), 5.88 (dd, 1H, J = 17.3, 10.6 Hz), 5.35 (d,

1H, J = 17.2 Hz), 5.27 (d, 1H, J = 10.6 Hz), 4.29–4.23 (m,

1H), 2.07–2.01 (m, 1H), 1.87–1.80 (m, 1H), 1.77–1.70 (m,

2H), 1.06 (s, 9H). ¹³C NMR (CDCl₃) δ: 141.0 (d), 135.9

(d), 135.7 (d), 133.7 (s), 129.8 (d), 127.6 (d), 115.3 (t),

74.4 (s), 69.1 (d), 34.1 (t), 29.0 (t), 26.8 (q), 19.1 (s). LR-

MS (m/z (relative intensity)): 399 ([M⁺– C₄H₉], 5), 199

(100), 200 (41). HR-MS calcd. for C₂₀H₂₀BrO₂Si:

399.0416; found: 399.0424. Anal. calcd. for C₂₄H₂₉BrO₂Si:

C 63.01, H 6.39, Br 17.47, O 6.99, Si 6.14; found: C 62.97,

H 6.40, O 6.95.

Acetate 18a

To a 0°C solution of tetravinyl tin (464 µL, 2.55 mmol) in

THF (30 mL) was added 1.0 M n-butyl lithium (9.30 mL,

9.30 mmol). After 2.5 h at 0°C this solution was added via

cannula to a cooled –78°C suspension of CeCl₃(5.19 g,

13.9 mmol) and ketone 16a (1.99 g, 4.64 mmol) in THF

(70 mL). The reaction mixture was stirred for 5 h at –78°C

before being quenched with acetic anhydride (10 mL) and

warmed to room temperature. After 30 min, satd. aq NH₄Cl

was added and the layers were separated. The aqueous layer

extracted with ethyl ether, and the organic layers washed

with brine, dried over MgSO₄, filtered, and concentrated.

Flash chromatography eluting with a mixture of hex-

anes:EtOAc (15:1) gave 786 mg and 1.05 g (79%) of acetate

Acetate 18c

Followed the same procedure as per acetate 18a, starting

from 17c. Purification by flash chromatography eluting with

hexanes:EtOAc (6:1) yielded 10.01 g (82%) of 20d as a

mixture of two diastereomers. First isomer: ¹H NMR

(CDCl₃) δ: 7.25 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J =

8.6 Hz), 6.42 (d, 1H, J = 1.1 Hz), 5.89 (dd, 1H, J = 17.3,

10.7), 5.37 (d, 1H, J = 18.8 Hz), 5.32 (d, 1H, J = 10.9 Hz),

4.50 (ABq, 2H, J = 13.5 Hz), 4.17–4.10 (m, 1H), 3.80 (s,

3H), 2.68–2.58 (m, 1H), 2.22–2.20 (m, 2H), 2.08 (s, 3H),

1.77–1.65 (m, 1H). ¹³C NMR (CDCl₃) δ: 169.1 (s), 159.1

(s), 136.5 (d), 135.1 (d), 129.8 (s), 129.2 (d), 125.2 (s),

116.7 (t), 113.7 (d), 82.5 (s), 74.2 (d), 70.1 (t), 55.1 (q), 30.4

(t), 26.5 (t), 21.8 (q). Second isomer: IR (cm^–1): 3035, 1744,

1

18a. Less polar acetate: H NMR (CDCl₃) δ: 7.72–7.65 (m,

4H), 7.46–7.35 (m, 6H), 6.10 (d, 1H, J = 4.5 Hz), 5.87 (dd,

1H, J = 10.8, 17.4 Hz), 5.23 (d, 1H, J = 10.8 Hz), 5.17 (d,

1H, J = 17.4 Hz), 4.10 (q, 1H, J = 4.3 Hz), 3.00 (dt, 1H, J =

11.7, 3.2 Hz), 2.12 (s, 3H), 1.97–1.89 (m, 1H), 1.82–1.62

(m, 2H), 1.07 (s, 9H). ¹³C NMR (CDCl₃) δ: 168.9 (s), 136.4

(d), 135.8 (d), 135.7 (d), 135.2 (d), 133.7 (s), 129.7 (d),

127.6 (d), 116.3 (t), 82.3 (s), 66.7 (d), 28.2 (t), 28.0 (t), 26.8

(q), 22.0 (q), 19.1 (s). More polar acetate: IR (cm^–1): 3056,

1

1612, 1513. H NMR (CDCl₃) δ: 7.28 (d, 2H, J = 8.6 Hz),

6.88 (d, 2H, J = 8.6 Hz), 6.43 (d, 1H, J = 4.5 Hz), 5.94 (dd,

1H, J = 17.3, 10.9 Hz), 5.29 (d, 1H, J = 10.3 Hz), 5.25 (d,

1H, J = 17.0 Hz), 4.51 (s, 2H), 3.86 (q, 1H, J = 4.4 Hz),

3.80 (s, 3H), 2.86 (dt, 1H, J = 11.8, 3.4), 2.09 (s, 3H), 2.06–

1.99 (m, 1H), 1.92–1.89 (m, 1H), 1.85–1.79 (m, 1H). ¹³C

NMR (CDCl₃) δ: 168.9 (s), 159.0 (s), 136.2 (d), 132.9 (d),

130.2 (s), 129.1 (d), 128.9 (s), 116.2 (t), 113.6 (d), 82.2 (s),

70.9 (d), 69.9 (t), 55.1 (q), 28.3 (t), 24.7 (t), 21.8 (q). LR-

MS (m/z (relative intensity)): 323 ([M⁺– OAc], 10), 321

([M⁺– OAc], 10), 184 (40), 121 (100). HR-MS calcd. for

C₁₆H₁₈BrO₂: 321.0490; found: 321.0485. Anal. calcd. for

C₁₈H₂₁BrO₄: C 56.70, H 5.55, Br 20.96, O 16.79; found: C

56.85, H 5.71, O 16.90.

1

1743, 1635, 1471. H NMR (CDCl₃) δ: 7.69–7.63 (m, 4H),

7.45–7.34 (m, 6H), 6.25 (d, 1H, J = 2.5 Hz), 5.88 (dd, 1H,

J = 17.3, 10.7 Hz), 5.37 (d, 1H, J = 16.8 Hz), 5.33 (d, 1H,

J = 10.4 Hz), 4.42–4.38 (m, 1H), 2.43 (dt, 1H, J = 13.2,

3.8 Hz), 2.03 (s, 3H), 2.00–1.92 (m, 1H), 1.81–1.69 (m 2H),

1.05 (s, 9H). ¹³C NMR (CDCl₃) δ: 169.1 (s), 137.9 (d),

136.7 (d), 135.7 (d), 133.4 (s), 129.8 (d), 127.7 (d), 127.6

(d), 124.4 (s), 116.6 (t), 82.4 (s), 69.5 (d), 30.6 (t), 29.8 (t),

26.8 (q), 21.9 (q), 19.1 (s). LR-MS (m/z (relative intensity)):

441 ([M⁺– C₄H₉], 18), 443 ([M⁺– C₄H₉], 16), 241 (100),

199 (70). HR-MS calcd. for C₂₂H₂₂O₃BrSi: 441.0521;

found: 441.0529. Anal. calcd. for C₂₆H₃₁BrO₃Si: C 62.52, H

6.26, Br 16.00, O 9.61, Si 5.62; found: C 62.66, H 6.19, O

9.44.

Acetate 18d

Followed the same procedure as per 18a, starting from

17d. Flash chromatography using hexanes:EtOAc (9:1) as

the eluent gave 8.77 g (83%) of a single acetate 18d as a

clear oil. [α]_D: +126.5° (c 4.443, CHCl₃). IR (cm^–1): 3068,

Spino et al.

97

1

1749, 1472. H NMR (CDCl₃) δ: 7.78–7.74 (m, 4H), 7.44–

7.28 (m, 9H), 7.18–7.15 (m, 2H), 5.98 (d, 1H, J = 6.0 Hz),

5.84 (dd, 1H, J = 17.3, 10.7 Hz), 5.20 (d, 1H, J = 10.7 Hz),

5.16 (d, 1H, J = 17.3 Hz), 4.39 (d, 1H, J = 12.0 Hz), 4.30 (d,

1H, J = 12.0 Hz), 4.14–4.12 (m, 1H), 3.38 (dt, 1H, J = 12.2,

3.0 Hz), 3.24 (dd, 1H, J = 12.0, 11.7 Hz), 2.33–2.29 (m,

1H), 2.12 (s, 3H), 1.09 (s, 9H). ¹³C NMR (CDCl₃) δ: 168.4

(s), 138.0 (s), 136.1 (d), 134.1 (s), 133.3 (s), 132.5 (d), 129.6

(d), 129.0 (s), 128.1 (d), 127.4 (d), 116.6 (t), 82.4 (s), 73.1

(d), 69.8 (t), 66.2 (d), 32.7 (t), 26.7 (q), 21.8 (q), 19.3 (s).

LR-MS (m/z (relative intensity)): 547 ([M⁺– C₄H₉], 1), 399

(100). HR-MS calcd. for C₂₉H₂₈BrO₄Si: 547.0940; found:

547.0947. Anal. calcd. for C₃₃H₃₇BrO₄Si: C 65.44, H 6.16,

Br 13.19, O 10.57, Si 4.64; found: C 65.41, H 6.22, O 10.50.

(126 mL) was added a 1.31 M solution of tert-butyl lithium

(20.9 mL, 27.4 mmol). After 5 min this solution was

warmed to 0°C and stirred for 30 min before being cooled to

–78°C. This cooled solution was added via cannula to a

stirred suspension of CuCN (1.22 g, 13.7 mmol) in THF

(103 mL) at –68°C. This suspension was stirred for 1 h fur-

ther before a solution of acetate 18c (3.48 g, 9.13 mmol) in

THF (70 mL) was added via cannula at –50°C. The reaction

mixture was gradually warmed to 0°C over 1 h, and stirred

2 h at 0°C before being quenched with a solution of satd. aq

NH₄Cl:conc. NH₄OH (9:1). The mixture was extracted with

ethyl ether, washed with brine, dried over MgSO₄, filtered,

and concentrated. The crude product was purified by flash

chromatography using hexanes:EtOAc (15:1) to give 4.43 g

(92%) of 19c as a colourless oil. IR (cm^–1): 2952, 2855,

1

1612, 1513, 1462, 1248, 1089, 1038, 835. H NMR (CDCl₃)

Diene 19a

δ: 7.27 (d, 2H, J = 8.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 6.31 (d,

1H, J = 3.7 Hz), 5.97 (t, 1H, J = 7.4 Hz), 4.51 (s, 2H), 4.08–

4.03 (m, 1H), 3.80 (s, 3H), 3.39 (ddd, 2H, J = 9.8, 6.5,

6.0 Hz), 2.66–2.59 (m, 1H), 2.36–2.31 (m, 1H), 2.16–2.09

(m, 2H), 1.98–1.89 (m, 1H), 1.84–1.77 (m, 1H), 1.61–1.52

(m, 1H), 1.46–1.37 (m, 3H), 1.09–1.02 (m, 1H), 0.89 (s,

9H), 0.86 (d, 3H, J = 6.7 Hz), 0.03 (s, 6H). ¹³C NMR

(CDCl₃) δ: 159.1 (s), 133.2 (d), 131.4 (s), 130.7 (d), 130.3

(s), 129.2 (d), 127.3 (s), 113.7 (d), 73.6 (d), 69.9 (t), 68.2 (t),

51.2 (q), 35.6 (d), 32.8 (t), 28.3 (t), 28.0 (t), 26.6 (t), 25.8

(q), 23.0 (t), 18.2 (s), 16.6 (q), –5.4 (q). LR-MS (m/z (rela-

tive intensity)): 465 ([M – C₄H₉], 5), 467 ([M⁺– C₄H₉], 5),

122 (50), 74 (50), 121 (100). HR-MS calcd. for C₂₃H₃₄BrO₃Si:

465.1460; found: 465.1470. Anal. calcd. for C₂₇H₄₃BrO₃Si:

C 61.93, H 8.28, Br 15.26, O 9.17, Si 5.36; found: C 61.99,

H 8.35, O 9.34.

To a suspension of Mg turnings (336 mg, 13.8 mmol) in

ethyl ether (28 mL) was added 1-bromo-5-propene (2.07 g,

13.9 mmol) drop wise, resulting in a refluxing mixture. The

reaction was kept at reflux for 3 h, until all the magnesium

was consumed. The Grignard was cooled and added via can-

nula to a suspension of copper(I) iodide (968 mg, 5.08 mmol)

in ethyl ether (24 mL) at 0°C. After 25 min at 0°C a solution

of acetate 18a (1.269 g, 2.54 mmol) in Et₂O (8 mL) was

added via cannula. The resulting mixture was stirred for 1 h

at 0°C then quenched by the addition of satd. aq NH₄Cl. The

product was extracted with Et₂O, dried over MgSO₄, filtered,

and concentrated. The crude residue was purified by flash

chromatography (100% hexanes to 25:1 hexanes: EtOAc) to

provide 1.24 g (96%) of 19a as a slightly yellow-coloured

1

liquid. IR (cm^–1): 3070, 2930, 2856, 1427, 1105. H NMR

(CDCl₃) δ: 7.69–7.65 (m, 4H), 7.46–7.35 (m, 6H), 6.09 (d,

1H, J = 3.7 Hz), 5.92 (t, 1H, J = 7.4 Hz), 5.79 (ddt, 1H, J =

17.0, 10.2, 6.7 Hz), 5.03–4.92 (m, 2H), 4.33–4.28 (m, 1H),

2.61 (dt, 1H, J = 14.9, 5.9 Hz), 2.23–2.01 (m, 4H), 1.76–

1.69 (m, 2H), 1.45–1.37 (m, 4H), 1.06 (s, 9H). ¹³C NMR

(CDCl₃) δ: 138.8 (d), 135.8 (d), 134.0 (s), 133.9 (s), 133.7

(d), 132.6 (d), 131.7 (s), 129.7 (d), 127.7 (d), 126.1 (s),

114.4 (t), 69.0 (d), 33.6 (t), 31.5 (t), 28.7 (t), 28.6 (t), 27.9

(t), 26.9 (q), 23.0 (t), 19.2 (s). LR-MS (m/z (relative inten-

sity)): 453 ([M⁺– C₄H₉], 6), 451 ([M⁺– C₄H₉], 6), 199

(100), 200 (23). HR-MS calcd. for C₂₉H₃₇OBrSi: 508.1797;

found: 508.1793

Diene 19d

Followed the same procedure as per 19c, starting from

18d. Purified by flash chromatography using hexanes:EtOAc

(25:1) to give 3.79 g (96%) of 19d as a colourless oil. [α]_D:

+94.6 (c 1.80, CHCl₃). IR (cm^–1): 2929, 2856, 1471, 1427,

1

1361, 1250, 1111, 836, 700. H NMR (CDCl₃) δ: 7.76–7.64

(m, 5H), 7.44–7.22 (m, 10H), 6.02 (t, 1H, J = 7.3 Hz), 5.90

(d, 1H, J = 5.5 Hz), 4.51 (d, 1H, J = 12.1 Hz), 4.37 (d, 1H,

J = 12.1 Hz), 4.33–4.30 (m, 1H), 3.49–3.34 (m, 3H), 2.84–

2.81 (m, 1H), 2.62–2.56 (m, 1H), 2.18–2.11 (m, 2H), 1.60–

1.37 (m, 5H), 1.08 (s, 9H), 0.89 (s, 9H), 0.87 (d, 3H, J =

6.6 Hz), 0.03 (s, 6H). ¹³C NMR (CDCl₃) δ: 138.4 (s), 136.0

(d), 134.9 (d), 134.1 (s), 133.6 (s), 130.5 (s), 130.1 (d),

129.7 (d), 128.2 (d), 127.8 (s), 127.6 (d), 75.4 (d), 70.4 (t),

68.2 (t), 67.8 (d), 35.7 (d), 33.0 (t), 28.5 (t), 27.9 (t), 26.9

(q), 26.6 (t), 25.9 (q), 19.4 (s), 18.3 (s), 16.7 (q), –5.3 (q).

LR-MS (m/z (relative intensity)): 691 ([M⁺– C₄H₉], 18),

689 ([M⁺– C₄H₉], 16), 91 (100), 74 (65), 199 (58), 135 (52).

HR-MS calcd. for C₃₈H₅₀BrO₃Si₂: 689.2482; found:

689.2489. Anal. calcd. for C₄₂H₅₉BrO₃Si: C 67.44, H 7.95,

Br 10.68, O 6.42, Si 7.51; found: C 67.65, H 7.90, O 6.38.

Diene 19b

Followed the same procedure as per 19a, starting from

18b. The crude residue was purified by flash chromatogra-

phy (hexanes:EtOAc, 9:1) to provide 737 mg (89%) of 19b

1

as a colourless liquid. H NMR (CDCl₃) δ: 7.36–7.27 (m,

5H), 6.32 (d, 1H, J = 3.8 Hz), 5.98 (t, 1H, J = 7.5 Hz), 5.80

(ddt, 1H, J = 17.0, 10.2, 6.7 Hz), 5.04–4.92 (m, 2H), 4.59 (s,

2H), 4.10–4.06 (m, 1H), 2.65–2.60 (m, 1H), 2.37–2.28 (m,

1H), 2.19–1.91 (m, 5H), 1.87–1.77 (m, 1H), 1.47–1.38 (m,

4H). ¹³C NMR (CDCl₃) δ: 138.7 (d), 138.3 (s), 133.2 (d),

131.5 (s), 130.6 (d), 128.3 (d), 127.6 (d), 114.4 (t), 73.9 (d),

70.2 (t), 33.5 (t), 28.6 (t), 28.0 (t), 27.8 (t), 23.0 (t).

Diene 19e

Oil-free NaH (45 mg, 1.129 mmol) was suspended in

THF (8 mL) and dimethyl malonate (117 µL, 1.03 mmol)

was slowly added at 25°C. The reaction was stirred until gas

evolution ceased. Then, this solution was transfered via can-

Diene 19c

To a cooled –78°C solution of 4-(tert-butyldimethylsilyl-

oxy)-3-methylbutyl iodide (4.51 g, 13.7 mmol) in Et₂O

98

Can. J. Chem. Vol. 81, 2003

nula to a solution of acetate 18a (256 mg, 0.513 mmol) and

Pd(PPh)₄(29 mg, 0.026 mmol). The reaction was stirred at

room temperature for 1 h before the THF was evaporated.

The residue taken up in Et₂O and the organic phase washed

with brine, dried over MgSO₄, filtered, and concentrated un-

der reduced pressure. The crude product was purified by

flash chromatography using hexanes:EtOAc (15:1) to give

faintly yellow-coloured oil. IR (cm^–1): 3069, 2932, 2857,

1696, 1427, 1107. H NMR (CDCl₃) δ: 9.42 (s, 1H), 7.71–

1

7.67 (m, 4H), 7.47–7.37 (m, 6H), 6.64 (t, 1H, J = 7.3 Hz),

6.32 (d, 1H, J = 2.9 Hz), 5.78 (ddt, 1H, J = 16.9, 10.2,

6.7 Hz), 5.01–4.91 (m, 2H), 4.54–4.48 (m, 1H), 2.55 (dt,

1H, J = 15.5, 4.9 Hz), 2.13–1.99 (m, 4H), 1.85–1.77 (m,

1H), 1.73–1.61 (m, 1H), 1.43–1.36 (m, 4H), 1.08 (s, 9H).

¹³C NMR (CDCl₃) δ: 193.9 (d), 151.8 (d), 138.8 (d), 137.1

(s), 135.7 (d), 133.7 (s), 131.3 (d), 129.9 (d), 127.7 (d),

114.3 (t), 68.4 (d), 33.6 (t), 31.2 (t), 28.6 (t), 27.9 (t), 26.8

(q), 22.9 (t), 19.1 (s). LR-MS (m/z (relative intensity)): 458

([M]⁺, 8), 401 ([M⁺– C₄H₉], 25), 199 (100), 241 (95), 86

(49). HR-MS calcd. for C₃₀H₃₈O₂Si: 458.2641; found:

458.2650

1

217 mg (74%) of diester 19e as a colourless oil. H NMR

(CDCl₃) δ: 7.68–7.63 (m, 4H), 7.46–7.33 (m, 6H), 6.13 (d,

1H, J = 3.5 Hz), 5.83 (t, 1H, J = 7.2 Hz), 4.28 (m, 1H), 3.74

(s, 3H), 3.72 (s, 3H), 3.45 (t, 1H, J = 7.6 Hz), 2.73 (t, 2H,

J = 7.6 Hz), 2.7–2.6 (m, 1H), 2.25–2.17 (m, 1H), 1.8–1.65

(m, 2H), 1.06 (s, 9H).

Diene 19f

Aldehyde 20b

To a stirred solution of alcohol 17a (1.74 g, 3.80 mmol),

ethylvinyl ether (50 mL), and triethylamine (1 mL) was

added mercury(II) trifluoroacetate (1.62 g, 3.80 mmol) at

room temperature. The mixture was stirred a total of 3 days

before the solvent was removed in vacuo. The residue was

taken up in ethyl ether, washed with 10% aq KOH and satd.

aq NaHCO₃, dried over MgSO₄, filtered, and concentrated.

Purification by flash chromatography using a mixture of

hexanes:EtOAc (15:1 to 9:1) yielded 1.61 g (88%) of alde-

Followed the same procedure as per aldehyde 20a, start-

ing with 19b. The crude aldehyde was purified by flash

chromatography (hexanes:EtOAc, 15:1) to provide 320 mg

of aldehyde 20b (74%) as a colourless oil. ¹H NMR (CDCl₃)

δ: 9.56 (s, 1H), 7.38–7.30 (m, 5H), 6.69 (t, 1H, J = 7.5 Hz),

6.55 (d, 1H, J = 2.9 Hz), 5.80 (ddt, 1H, J = 17.0, 10.2,

6.7 Hz), 5.02–4.92 (m, 2H), 4.67 (ABq, 2H, J = 18.4 Hz),

4.28–4.26 (m, 1H), 2.62 (m, 1H), 2.19–2.04 (m, 6H), 1.75–

1.68 (m, 1H), 1.45–1.39 (m, 4H). ¹³C NMR (CDCl₃) δ:

193.7 (d), 148.6 (d), 138.7 (d), 137.9 (s), 131.7 (d), 128.4

(d), 127.7 (s), 127.6 (d), 114.2 (t), 73.3 (d), 70.6 (t), 33.5 (t),

28.5 (t), 27.9 (t), 27.7 (t), 22.8 (t).

1

hyde 19f. H NMR (CDCl₃) δ: 9.79 (s, 1H), 7.72–7.68 (m,

4H), 7.48–7.38 (m, 6H), 6.16 (d, 1H, J = 3.7 Hz), 5.87 (t,

1H, J = 7.2 Hz), 4.37–4.31 (m, 1H), 2.70–2.63 (m, 1H),

2.60–2.56 (m, 2H), 2.49–2.42 (m, 2H), 2.26–2.21 (m, 1H),

1.80–1.74 (m, 2H), 1.09 (s, 9H). ¹³C NMR (CDCl₃) δ: 201.2

(d), 135.7 (d), 134.6 (d), 133.8 (s), 132.9 (s), 129.7 (d),

129.6 (d), 127.6 (d), 125.4 (s), 68.8 (d), 43.2 (t), 31.5 (t),

26.8 (q), 22.9 (t), 20.6 (t), 19.1 (s). LR-MS (m/z (relative in-

tensity)): 425 ([M⁺– C₄H₉], 25), 199 (100). HR-MS calcd.

for C₂₂H₂₂O₂BrSi: 425.0572; found: 425.0575.

Aldehyde 20c

Followed the same procedure as per aldehyde 20a, start-

ing with 19c. The residue was purified by flash chromatog-

raphy using hexane:EtOAc (9:1) as the eluent, providing

2.73 g (90%) of aldehyde 20c as a clear colourless oil. IR

(cm^–1): 2953, 2855, 1698, 1612, 1513, 1248, 1090, 836. H

1

Diene 19g

NMR (CDCl₃) δ: 9.55 (s, 1H), 7.29 (d, 2H, J = 8.6 Hz), 6.89

(d, 2H, J = 8.6 Hz), 6.68 (t, 1H, J = 7.4 Hz), 6.52 (d, 1H, J =

2.8 Hz), 4.60 (ABq, 2H, J = 18.2 Hz), 4.28–4.23 (m, 1H),

3.80 (s, 3H), 3.43 (dd, 1H, J = 9.8, 5.9 Hz), 3.35 (dd, 1H,

J = 9.8, 6.5 Hz), 2.63 (dt, 1H, J = 15.3, 4.8 Hz), 2.22–2.05

(m, 4H), 1.73–1.54 (m, 2H), 1.48–1.34 (m, 3H), 1.12–1.02

(m, 1H), 0.89 (s, 9H), 0.86 (d, 3H, J = 6.7 Hz), 0.03 (s, 6H).

¹³C NMR (CDCl₃) δ: 193.8 (d), 159.3 (s), 148.8 (d), 138.0

(s), 131.8 (d), 130.1 (s), 129.3 (d), 127.8 (s), 113.8 (d), 73.0

(d), 70.4 (t), 68.2 (t), 55.2 (q), 35.6 (d), 32.9 (t), 28.5 (t),

27.8 (t), 26.6 (t), 25.9 (q), 22.9 (t), 18.3 (s), 16.6 (q), –5.3

(q). LR-MS (m/z (relative intensity)): 415 ([M⁺– C₄H₉], 3),

122 (50), 74 (54), 121 (100). HR-MS calcd. for C₂₄H₃₅O₄Si:

415.2304; found: 415.2313.

Alcohol 17a was dissolved in toluene (2 mL) along with

propionic acid (2 drops) and ethyl orthoacetate (575 µL,

3.14 mmol). The mixture was refluxed overnight and the sol-

vent was removed in vacuo. Purification by flash chromatog-

raphy using a mixture of hexanes:EtOAc (25:1 to 9:1)

yielded 38.9 mg (21%) of ester 19g and 113 mg of starting

1

alcohol (92% corrected yield). H NMR (CDCl₃) δ: 7.70–

7.65 (m, 4H), 7.46–7.36 (m, 6H), 6.12 (d, 1H, J = 3.7 Hz),

5.88 (t, 1H, J = 7.2 Hz), 4.31 (m, 1H), 4.13 (q, 2H, J =

6.9 Hz), 2.70–2.63 (m, 1H), 2.48–2.38 (m, 4H), 2.29–2.15

(m, 1H), 1.80–1.70 (m, 2H), 1.25 (t, 3H, J = 6.9 Hz), 1.06

(s, 9H).

Aldehyde 20a

Aldehyde 20d

To a cooled –78°C solution of vinyl bromide 19a (1.10 g,

2.17 mmol) in THF (28 mL) was added 2.0 M n-butyl lith-

ium (2.17 mL, 4.34 mmol). After 20 min DMF (1.26 mL,

16.3 mmol) was added at –78°C and the reaction stirred for

1 h further before being quenched with satd. aq NH₄Cl. The

layers were separated and the product extracted with ethyl

ether. The combined organic layers were dried over MgSO₄,

filtered, and concentrated. The crude aldehyde was purified

by flash chromatography (100% hexanes to hexanes:EtOAc

(15:1)) to provide 977 mg (98%) of aldehyde 20a as a

Followed the same procedure as per 20c, starting with

19d. Purification by flash chromatography using hex-

ane:EtOAc (25:1) as the eluent, provided 2.81 g (80%) of al-

dehyde 20d as a clear colourless oil. [α]_D: +47.3° (c 1.10,

CHCl₃). IR (cm^–1): 3070, 2954, 2856, 1700, 1471, 1427,

1

1255, 1112, 836, 702. H NMR (CDCl₃) δ: 9.38 (s, 1H),

7.74–7.65 (m, 4H), 7.46–7.28 (m, 11H), 6.78 (t, 1H, J =

7.4 Hz), 6.15 (d, 1H, J = 3.5 Hz), 4.61–4.58 (m, 1H), 4.56

(ABq, 2H, J = 19.4 Hz), 3.59–3.54 (m, 1H), 3.42 (dd, 1H,

Spino et al.

99

J = 9.7, 5.8 Hz), 3.32 (dd, 1H, J = 9.7, 5.8 Hz), 2.79 (dd,

1H, J = 15.6, 7.2 Hz), 2.24–2.19 (m, 1H), 2.07 (q, 2H, J =

7.2 Hz), 1.57–1.26 (m, 5H), 1.11 (s, 9H), 0.87 (s, 9H), 0.85

(d, 3H, J = 6.6 Hz), 0.02 (s, 6H). ¹³C NMR (CDCl₃) δ:

193.4 (d), 148.6 (d), 138.5 (s), 137.5 (s), 135.9 (d), 133.7

(d), 133.3 (s), 129.9 (d), 128.2 (d), 127.7 (d), 127.4 (d),

125.8 (s), 75.2 (d), 71.1 (t), 69.3 (d), 68.2 (t), 35.6 (d), 33.0

(t), 28.6 (t), 28.1 (t), 26.9 (q), 26.6 (t), 25.9 (q), 19.3 (s),

18.3 (s), 16.6 (q), –5.4 (q). LR-MS (m/z (relative intensity)):

696 ([M]⁺, 20), 639 ([M⁺– C₄H₉], 68), 91 (100), 74 (99),

199 (99), 135 (88), 531 (70), 197 (68). HR-MS calcd. for

C₄₃H₆₀O₄Si₂: 696.4030; found: 696.4037.

([M⁺– C₄H₉], 30), 91 (100). HR-MS calcd. for C₄₁H₅₅O₅Si₂:

683.3588; found: 683.3593.

Alcohol 22a

TBAF (12.6 mL, 12.6 mmol) was added to a solution of

acetal 21a (5.45 g, 10.5 mmol) in THF (105 mL) at room

temperature. After 6 h, a solution of EtOAc:ethyl ether (1:1)

was added to the mixture. The resulting mixture was washed

with satd. aq NH₄Cl, and the aqueous layer extracted once

with EtOAc:ethyl ether (1:1). The combined organic layers

were dried over MgSO₄, filtered, and concentrated. The

crude residue was purified by flash chromatography using a

mixture of hexanes:EtOAc (3:1 to 1:1) as the eluent to give

3.66 g (87% for two steps) of alcohol 22a as a colourless oil.

IR (cm^–1): 3441, 2931, 1613, 1513, 1463, 1247, 1172, 1048,

Acetal 21a

A solution of aldehyde 20c (5.15 g, 10.9 mmol), PPTS

(547 mg, 2.18 mmol), and ethylene glycol (6.07 mL,

109 mmol) in benzene (140 mL) was heated to reflux for

6 h. The solvent was removed in vacuo and the residue taken

up in Et₂O. The ether layer was washed with satd. aq

NaHCO₃, and brine. The combined aqueous layers were ex-

tracted once with ethyl ether. The organic layers were dried

over MgSO₄, filtered, and concentrated to give 5.71 g

(100%) of acetal 21a as an oil. The crude acetal was used in

the next step without further purification. IR (cm^–1): 3030,

1612. ¹H NMR (CDCl₃) δ: 7.28 (d, 2H, J = 8.6 Hz), 6.86 (d,

2H, J = 8.6 Hz), 6.21 (d, 1H, J = 2.9 Hz), 5.69 (t, 1H, J =

7.2 Hz), 5.55 (s, 1H), 4.54 (s, 2H), 4.12–4.07 (m, 1H), 4.04–

3.99 (m, 2H), 3.97–3.92 (m, 2H), 3.80 (s, 3H), 3.43 (dd, 1H,

J = 9.7, 5.8 Hz), 3.33 (dd, 1H, J = 9.7, 6.6 Hz), 2.56 (dt, 1H,

J = 15.4, 5.5 Hz), 2.22–2.07 (m, 3H), 2.04–1.94 (m, 1H),

1.74–1.66 (m, 1H), 1.62–1.54 (m, 1H), 1.46–1.32 (m, 3H),

1.08–1.02 (m, 1H), 0.88 (s, 9H), 0.86 (d, 3H, J = 6.7 Hz),

0.03 (s, 6H). ¹³C NMR (CDCl₃) δ: 158.9 (s), 135.2 (s),

131.4 (s), 130.7 (s), 129.0 (d), 126.9 (d), 126.4 (d), 113.6

(d), 101.2 (d), 72.5 (d), 69.6 (t), 68.1 (t), 64.7 (t), 55.0 (q),

35.5 (d), 32.8 (t), 28.2 (t), 26.8 (t), 25.8 (t and q), 22.8 (t),

18.2 (s), 16.6 (q), –5.4 (q). LR-MS (m/z (relative intensity)):

516 ([M]⁺, 2), 459 ([M – C₄H₉], 8), 186 (70), 74 (75), 121

(100). HR-MS calcd. for C₂₆H₃₉O₅Si: 459.2567; found:

459.2574.

1

821. H NMR (CDCl₃) δ: 7.28 (d, 2H, J = 8.6 Hz), 6.86 (d,

2H, J = 8.6 Hz), 6.21 (d, 1H, J = 2.9 Hz), 5.68 (t, 1H, J =

7.2 Hz), 5.55 (s, 1H), 4.54 (s, 2H), 4.12–4.07 (m, 1H), 4.04–

3.99 (m, 2H), 3.97 (m, 2H), 3.80 (s, 3H), 3.49 (dd, 1H, J =

9.5, 5.8 Hz), 3.41 (dd, 1H, J = 9.5, 6.4 Hz), 2.58 (dt, 1H, J =

15.3, 5.3 Hz), 2.23–2.09 (m, 3H), 2.01–1.94 (m, 1H), 1.74–

1.59 (m, 2H), 1.49–1.35 (m, 3H), 1.17–1.08 (m, 1H), 0.91

(d, 3H, J = 6.7 Hz). ¹³C NMR (CDCl₃) δ: 158.9 (s), 135.2

(s), 131.4 (s), 130.6 (s), 129.1 (d), 126.7 (d), 126.5 (d),

113.6 (d), 101.2 (d), 72.4 (d), 69.6 (t), 67.9 (t), 64.7 (t), 55.1

(q), 35.5 (d), 32.7 (t), 28.1 (t), 26.7 (t), 22.8 (t), 16.4 (q).

LR-MS (m/z (relative intensity)): 402 ([M]⁺, 1), 264 (45),

136 (50), 91 (55), 131 (60), 77 (60), 122 (90), 121 (100).

HR-MS calcd. for C₂₄H₃₄O₅: 402.2406; found: 402.2397.

Anal. calcd. for C₂₄H₂₄O₅: C 71.61, H 8.51, O 19.87; found:

C 71.61, H 8.60.

Alcohol 22b

Followed the same procedure as per 22a, starting with

21b. Flash chromatography (6:1 to 3:1 to 1:1 hexanes:ethyl

acetate, followed by 100% EtOAc) gave 2.10 g (58%) of al-

cohol 22b as a clear colourless oil and 908 mg of diol as a

by-product. [α]_D: +70.6° (c 1.33, CHCl₃). IR (cm^–1): 3439,

1

3069, 1471. H NMR (CDCl₃) δ: 7.81–7.70 (m, 4H), 7.46–

7.27 (m, 11H), 5.88 (d, 1H, J = 6.0 Hz), 5.80 (t, 1H, J =

7.2 Hz), 5.59 (s, 1H), 4.57 (d, 1H, J = 12.3 Hz), 4.44 (d, 1H,

J = 12.3 Hz), 4.46–4.42 (m, 1H), 3.93–3.83 (m, 4H), 3.52–

3.47 (m, 2H), 3.41 (dd, 1H, J = 10.5, 6.4 Hz), 2.86–2.78 (m,

1H), 2.58–2.52 (m, 1H), 2.22–2.15 (m, 2H), 1.73 (s, 1H),

1.65–1.61 (m, 1H), 1.56–1.40 (m, 3H), 1.22–1.15 (m, 1H),

1.12 (s, 9H), 0.94 (d, 3H, J = 6.7 Hz). ¹³C NMR (CDCl₃) δ:

138.7 (s), 136.0 (d), 135.6 (s), 134.4 (s), 133.9 (s), 130.6 (s),

129.4 (d), 128.4 (d), 128.0 (d), 127.4 (d), 127.1 (d), 125.4

(d), 101.1 (d), 75.9 (d), 70.2 (t), 68.0 (t), 66.2 (d), 64.7 (t),

35.5 (d), 32.8 (t), 28.2 (t), 27.3 (t), 26.9 (q), 26.7 (d), 19.3

(s), 16.5 (q). LR-MS (m/z (relative intensity)): 626 ([M]⁺, 1),

569 ([M⁺– C₄H₉], 20), 91 (100), 83 (80), 199 (65). HR-MS

calcd. for C₃₉H₅₀O₅Si: 626.3427; found: 626.3417. Anal.

calcd. for C₃₉H₅₀O₅Si: C 74.72, H 8.04, O 12.76, Si 4.48;

found: C 74.61, H 8.01, O 12.79.

Acetal 21b

Followed the same procedure as per 21a, starting with

20d. Purification by flash chromatography eluting with a

hexanes:EtOAc (15:1 to 6:1) mixture provided 2.46 g (95%)

of acetal 21b as a colourless oil. [α]_D: +105.3° (c 0.74,

1

CHCl₃). IR (cm^–1): 3070, 2954, 1471. H NMR (CDCl₃) δ:

7.77–7.66 (m, 4H), 7.43–7.22 (m, 11H), 5.82 (d, 1H, J =

5.1 Hz), 5.75 (t, 1H, J = 7.1 Hz), 5.54 (s, 1H), 4.52 (d, 1H,

J = 12.2 Hz), 4.41–4.37 (m, 2H), 3.91–3.81 (m, 4H), 3.47–

3.41 (m, 2H), 3.34 (dd, 1H, J = 9.7, 6.6 Hz), 2.80–2.72 (m,

1H), 2.54–2.47 (m, 1H), 2.17–2.12 (m, 2H), 1.59–1.33 (m,

5H), 1.07 (s, 9H), 0.89 (s, 9H), 0.86 (d, 3H, J = 6.7 Hz),

0.03 (s, 6H). ¹³C NMR (CDCl₃) δ: 138.8 (s), 136.1 (d),

135.7 (s), 134.5 (s), 134.0 (s), 130.7 (s), 129.5 (d), 128.6 (d),

128.1 (d), 127.4 (d), 127.2 (d), 125.3 (d), 101.2 (d), 76.0 (d),

70.2 (t), 68.3 (t), 66.2 (d), 64.7 (t), 35.7 (d), 33.0 (t), 28.5

(t), 27.2 (t), 27.0 (q), 26.9 (q), 25.9 (d), 19.3 (s), 18.3 (s),

16.7 (q), –5.3 (q). LR-MS (m/z (relative intensity)): 683

Enoate 23a

To a stirred solution of alcohol 22a (3.02 g, 7.49 mmol) in

dichloromethane (61 mL) at room temperature was added

Dess–Martin periodinane (4.76 g, 11.2 mmol). After 1.5 h,

100

Can. J. Chem. Vol. 81, 2003

ethyl ether (100 mL) was added to the reaction mixture, fol-

lowed by a solution (100 mL) of Na₂S₂O₃(25 g) in satd. aq

NaHCO₃. The mixture was stirred for 5 min until all the sol-

ids had entered solution. The layers were separated and the

aqueous extracted with ethyl ether. The etheric layer was

washed with sad. aq NaHCO₃, water, dried over MgSO₄, fil-

tered, and concentrated, yielding 2.98 g (99%) of an alde-

hyde as a clear colourless oil that was used in the next step

without further purification. IR (cm^–1): 2934, 2861, 1722,

1H), 2.20–2.10 (m, 2H), 1.74–1.69 (m, 1H), 1.51–1.37 (m,

3H), 1.23–1.18 (m, 1H), 1.08 (d, 3H, J = 6.9 Hz), 1.06 (s,

9H). LR-MS (m/z (relative intensity)): 624 ([M]⁺, 1), 567

([M⁺– C₄H₉], 25), 199 (100), 91 (92), 135 (60). HR-MS

calcd. for C₃₉H₄₈O₅Si: 624.3271; found: 624.3261.

The crude enoate from the following step was purified by

flash chromatography eluting with a mixture of hex-

anes:EtOAc (6:1) yielding 1.34 g (66% for two steps) of 23b

as clear colourless oil. [α]_D: +19.5° (c 1.32, CHCl₃). IR (cm^–1):

1

1613, 1513, 1462, 1247, 1058, 945, 821. H NMR (CDCl₃)

3046, 2929, 2856, 1722, 1427, 1272, 1111, 983. H NMR

δ: 9.61 (d, 1H, J = 1.9 Hz), 7.28 (d, 2H, J = 8.6 Hz), 6.87 (d,

2H, J = 8.6 Hz), 6.23 (d, 1H, J = 3.0 Hz), 5.66 (t, 1H, J =

7.2 Hz), 5.53 (s, 1H), 4.54 (s, 2H), 4.13–4.07 (m, 1H), 4.04–

3.99 (m, 2H), 3.97–3.92 (m, 2H), 3.80 (s, 3H), 2.62–2.53

(m, 1H), 2.37–2.31 (m, 1H), 2.22–2.12 (m, 3H), 2.01–1.93

(m, 1H), 1.76–1.62 (m, 2H), 1.50–1.34 (m, 3H), 1.09 (d, 3H,

J = 7.0 Hz). ¹³C NMR (CDCl₃) δ: 205.0 (d), 158.9 (s), 135.0

(s), 131.9 (s), 130.6 (s), 129.0 (d), 126.8 (d), 126.0 (d),

113.6 (d), 101.2 (d), 72.4 (d), 69.7 (t), 64.7 (t), 55.1 (q), 46.0

(d), 30.0 (t), 28.1 (t), 27.8 (t), 26.6 (t), 22.8 (t), 13.1 (q). LR-

MS (m/z (relative intensity)): 400 ([M]⁺, 1), 264 (35), 77

(58), 91 (61), 122 (63), 132 (70), 121 (100). HR-MS calcd.

for C₂₄H₃₂O₅: 400.2250; found: 400.2253.

(CDCl₃) δ: 7.78–7.67 (m, 4H), 7.44–7.23 (m, 11H), 6.87

(dd, 1H, J = 15.7, 8.0 Hz), 5.85 (d, 1H, J = 5.1 Hz), 5.79 (d,

1H, J = 15.9 Hz), 5.74 (t, 1H, J = 7.1 Hz), 5.54 (s, 1H), 4.53

(d, 1H, J = 12.3 Hz), 4.42–4.40 (m, 1H), 4.40 (d, 1H, J =

12.3 Hz), 3.92–3.82 (m, 4H), 3.72 (s, 3H), 3.45 (dt, 1H, J =

10.0, 3.5 Hz), 2.81–2.73 (m, 1H), 2.53–2.47 (m, 1H), 2.34–

2.29 (m, 1H), 2.15–2.13 (m, 2H), 1.42–1.39 (m, 4H), 1.08

(s, 9H), 1.05 (d, 3H, J = 6.7 Hz). ¹³C NMR (CDCl₃) δ:

167.2 (s), 154.7 (d), 138.8 (s), 136.1 (d), 135.7 (s), 134.5 (s),

134.0 (s), 131.0 (s), 129.5 (d), 128.1 (d), 127.4 (d), 127.3

(d), 125.6 (d), 119.3 (d), 101.2 (d), 76.0 (d), 70.3 (t), 66.2

(d), 64.8 (t), 51.4 (q), 36.5 (d), 35.8 (t), 28.1 (t), 27.3 (t),

27.0 (q), 19.4 (q). LR-MS (m/z (relative intensity)): 680

([M]⁺, 2), 623 ([M⁺– C₄H₉], 35), 91 (100). HR-MS calcd.

for C₄₂H₅₂O₆Si: 680.3533; found: 680.3526. Anal. calcd. for

C₄₂H₅₂O₆Si: C 74.08, H 7.70, O 14.10, Si 4.12; found: C

73.97, H 7.77, O 14.12.

To a 0°C suspension of NaH (389 mg, 9.74 mmol) in THF

(40.5 mL) was added MDEPA (1.78 mL, 9.74 mmol). After

1.25 h at 0°C this clear colourless solution was added via

cannula to a solution of the crude aldehyde (2.98 g,

7.49 mmol) in THF (37.5 mL) at 0°C. After 30 min at 0°C

the reaction was quenched with satd. aq NH₄Cl and the lay-

ers separated. The mixture was extracted with ethyl ether

and the combined organic layers dried over MgSO₄, filtered,

and concentrated. The crude residue was purified by flash

chromatography eluting with a mixture of hexanes:EtOAc

(3:1) yielding 2.72 g (80% for two steps) of 23a as a single

Aldehyde 24a

A solution of enoate 23a (2.67 g, 5.84 mmol), PPTS

(440 mg, 1.75 mmol), and wet acetone (117 mL) was heated

to reflux for 3 h. The solvent was removed in vacuo and the

residue taken up in ethyl ether (200 mL) and washed with

saturated aq NaHCO₃(60 mL) and brine (60 mL). The com-

bined aqueous layers were back-extracted once with ether.

The combined organic layers were dried over MgSO₄, fil-

tered, and concentrated. Purification by flash chromatogra-

phy (hexanes:EtOAc, 3:1) yielded 2.23 g (92%) of aldehyde

24a as a colourless oil. IR (cm^–1): 2932, 2857, 1722, 1694,

1

isomer. IR (cm^–1): 3035, 1712, 1655, 1612, 1513. H NMR

(CDCl₃) δ: 7.27 (d, 2H, J = 8.6 Hz), 6.89–6.81 (m, 3H), 6.21

(d, 1H, J = 3.0 Hz), 5.77 (d, 1H, J = 15.7 Hz), 5.65 (t, 1H,

J = 7.1 Hz), 5.53 (s, 1H), 4.54 (s, 2H), 4.12–4.06 (m, 1H),

4.04–3.99 (m, 2H), 3.97–3.92 (m, 2H), 3.80 (s, 3H), 3.72 (s,

3H), 2.59–2.52 (m, 1H), 2.32–2.27 (m, 1H), 2.22–2.10 (m,

3H), 2.00–1.94 (m, 1H), 1.74–1.66 (m, 1H), 1.39–1.36 (m,

4H), 1.03 (d, 3H, J = 6.7 Hz). ¹³C NMR (CDCl₃) δ: 167.1

(s), 158.9 (s), 154.5 (d), 135.1 (s), 131.6 (s), 130.6 (s), 129.0

(d), 126.6 (d), 126.3 (d), 119.2 (d), 113.6 (d), 101.2 (d), 72.4

(d), 69.6 (t), 64.7 (t), 55.0 (q), 51.2 (q), 36.3 (d), 35.6 (t),

28.1 (t), 27.8 (t), 26.9 (t), 22.8 (t), 19.2 (q). LR-MS (m/z

(relative intensity)): 456 ([M]⁺, 15), 320 (30), 77 (55), 91

(60), 122 (80), 121 (100). HR-MS calcd. for C₂₇H₃₆O₆:

456.2512; found: 456.2509. Anal. calcd. for C₂₇H₃₆O₆: C

71.03, H 7.95, O 21.03; found: C 71.00, H 7.92.

1

1656, 1612, 1513, 1435, 1248, 1072, 822. H NMR (CDCl₃)

δ: 9.53 (s, 1H), 7.29 (d, 2H, J = 8.6 Hz), 6.89 (d, 2H, J =

8.6 Hz), 6.84 (dd, 1H, J = 15.7, 8.0 Hz), 6.66 (t, 1H, J =

7.3 Hz), 6.53 (d, 1H, J = 2.8 Hz), 5.77 (d, 1H, J = 15.6 Hz),

4.59 (ABq, 2H, J = 18.4 Hz), 4.28–4.22 (m, 1H), 3.80 (s,

3H), 3.71 (s, 3H), 2.65–2.57 (m, 1H), 2.31–2.26 (m, 1H),

2.20–2.02 (m, 4H), 1.72–1.60 (m, 1H), 1.44–1.37 (m, 4H),

1.03 (d, 3H, J = 6.7 Hz). ¹³C NMR (CDCl₃) δ: 193.7 (d),

167.1 (s), 159.2 (s), 154.5 (d), 149.2 (d), 137.7 (s), 131.1

(d), 129.9 (s), 129.2 (d), 127.9 (s), 119.2 (d), 113.7 (d), 72.8

(d), 70.3 (t), 55.1 (q), 51.2 (q), 36.3 (d), 35.5 (t), 28.0 (t),

27.7 (t), 26.7 (t), 22.8 (t), 19.2 (q). LR-MS (m/z (relative in-

tensity)): 412 ([M]⁺, 3), 122 (100), 121 (75). HR-MS calcd.

for C₂₅H₃₂O₅: 412.2250; found: 412.2247.

Enoate 23b

Followed the same procedure as per 23a, starting with

22b. The aldehyde (clear colourless oil) was used in the next

step without further purification. IR (cm^–1): 3069, 2930,

Aldehyde 24b

1

2856, 1724, 1427, 1116. H NMR (CDCl₃) δ: 9.60 (d, 1H,

Followed the same procedure 24a, starting from 23b. Af-

ter purification by flash chromatography (hexanes:ethyl ace-

tate, 6:1) 467 mg (92%) of aldehyde 24b were collected as a

clear colourless oil. [α]_D: +16.4 (c 0.63, CHCl₃). IR (cm^–1):

J = 1.9 Hz), 7.76–7.65 (m, 4H), 7.44–7.22 (m, 11H), 5.84

(d, 1H, J = 5.1 Hz), 5.73 (t, 1H, J = 7.2 Hz), 5.52 (s, 1H),

4.52 (d, 1H, J = 12.3 Hz), 4.41–4.37 (m, 2H), 3.91–3.81 (m,

4H), 3.49–3.42 (m, 1H), 2.80–2.72 (m, 1H), 2.51–2.45 (m,

1

3069, 2930, 2857, 1722, 1698, 1428, 1272, 1112. H NMR

Spino et al.

101

(CDCl₃) δ: 9.39 (s, 1H), 7.76–7.68 (m, 4H), 7.48–7.24 (m,

11H), 6.86 (dd, 1H, J = 15.7, 8.0 Hz), 6.80 (t, 1H, J =

7.4 Hz), 6.20 (d, 1H, J = 3.5 Hz), 5.78 (d, 1H, J = 15.6 Hz),

4.64–4.62 (m, 1H), 4.59 (ABq, 2H, J = 21.0 Hz), 3.71 (s,

3H), 3.62–3.58 (m, 1H), 2.81 (dd, 1H, J = 15.6, 7.0 Hz),

2.32–2.20 (m, 2H), 2.14–2.05 (m, 2H), 1.46–1.34 (m, 4H),

1.13 (s, 9H), 1.04 (d, 3H, J = 6.8 Hz). ¹³C NMR (CDCl₃) δ:

193.3 (d), 167.1 (s), 154.5 (d), 149.0 (d), 138.4 (s), 137.3

(s), 135.8 (d), 133.5 (s), 133.2 (s), 133.0 (d), 129.8 (d),

127.6 (d), 127.4 (d), 127.3 (d), 125.9 (s), 119.2 (d), 75.1 (d),

71.1 (t), 69.2 (d), 51.2 (q), 36.4 (d), 35.6 (t), 28.1 (t), 26.8

(q), 19.3 (q). LR-MS (m/z (relative intensity)): 636 ([M]⁺,

10), 579 ([M⁺– C₄H₉], 25), 471 (100), 91 (48). HR-MS

calcd. for C₄₀H₄₈O₅Si: 636.3271; found: 636.3277.

chromatography on silica gel eluting with EtOAc and hex-

anes (20:80) yielded a white solid (2.04 g, 84%). IR

1

(neat, cm^–1): 3058, 1747. H NMR (C₆D₆) δ: 7.67–7.62 (m,

6H), 7.15–6.99 (m, 9H), 6.27 (dq, 1H, J = 15.3, 6.6 Hz),

5.92 (dd, 1H, J = 15.3, 1.6 Hz), 3.88 (d, 1H, J = 9.0 Hz),

3.66 (d, 1H, J = 9.0 Hz), 1.71 (s, 3H), 1.54 (dd, 3H, J = 6.6,

1.6 Hz), 1.47 (s, 3H). LR-MS (m/z (relative intensity)): 424

([M]⁺, 2), 243 (100), 165 (55). HR-MS calcd. for C₂₉H₂₈O₃:

424.2038; found: 424.2047.

Acetate 29b

Followed the same procedure as per acetate 29a. Flash

chromatography on silica gel eluting with EtOAc and hex-

anes (10:90) gave 29b as a colourless oil (4.63 g, 90%). IR

1

(neat, cm^–1): 3060, 2930, 1749, 1229, 1100, 837, 704. H

NMR (C₆D₆) δ: 7.49–7.45 (m, 6H), 7.36–7.14 (m, 9H),

6.10–5.97 (m, 1H), 5.63 (dm, 1H, J = 15.4 Hz), 4.59 (qd,

1H, J = 6.5, 2.2 Hz), 3.41–3.28 (m, 2H), 2.02 (s, 3H), 1.72

(dd, 3H, J = 6.6, 1.0 Hz), 1.41 (dd, 3H, J = 6.5, 1.8 Hz),

0.86 (s, 9H), 0.07–0.05 (m, 6H). LR-MS (m/z (relative inten-

sity)): 568 ([M]⁺, 1), 243 (100), 165 (50). HR-MS calcd. for

C₃₆H₄₄O₄Si: 568.3009; found: 568.3000.

Alcohol 25

To a cooled 0°C biphasic mixture of aldehyde 24a

(744 mg, 1.80 mmol), dichloromethane (15 mL), and water

(830 µL) was added DDQ (532 mg, 2.34 mmol) resulting in

a deep green coloured mixture. The mixture was stirred for

2.5 h at which time the colour had become orange and TLC

indicated reaction completion. The mixture was poured into

a separatory funnel containing dichloromethane and satd aq

NaHCO₃. The mixture was vigorously shaken and the layers

separated. After extraction with dichloromethane, a brine

wash, drying over MgSO₄, filtration, and concentration in

vacuo, the crude product was purified by flash chromatogra-

phy (hexanes:EtOAc, 3:1 to 1:1) yielded 367 mg (70%) of

aldehyde 25 as a colourless oil. IR (cm^–1): 3426, 2930, 2858,

Acetate 29c

Followed the same procedure as per acetate 29a. Flash

chromatography on silica gel eluting with EtOAc and hex-

anes (5:95) gave a colourless oil (5.36 g, 85%). IR

1

(neat, cm^–1): 3059, 2928, 1748. H NMR (CDCl₃) δ: 7.48–

7.44 (m, 6H), 7.33–7.21 (m, 9H), 6.10–5.96 (m, 1H), 5.63

(dm, 1H, J = 14.7 Hz), 4.42–4.36 (m, 2H), 3.39 (d, 1H, J =

9.0 Hz), 3.29 (d, 1H, J = 9.0 Hz), 3.23- 3.11 (m, 4H), 2.03

(s, 3H), 1.85–1.49 (m, 6H), 1.72 (d, 3H, J = 6.5 Hz), 0.86 (s,

9H), 0.06–0.04 (m, 6H). LR-MS (m/z (relative intensity)):

700 ([M]⁺, 5), 640 ([M⁺– AcOH], 20), 243 (100), 165

(100). HR-MS calcd. for C₄₁H₅₂O₄S₂Si: 700.3076; found:

700.3085.

1

1719, 1694, 1436, 1274, 1199, 1035, 870. H NMR (CDCl₃)

δ: 9.53 (s, 1H), 6.83 (dd, 1H, J = 15.7, 8.0 Hz), 6.65 (t, 1H,

J = 7.3 Hz), 6.48 (d, 1H, J = 2.9 Hz), 5.75 (d, 1H, J =

15.7 Hz), 4.57–4.51 (m, 1H), 3.70 (s, 3H), 2.56 (dt, 1H, J =

15.4, 4.9 Hz), 2.32–2.02 (m, 6H), 1.58 (dt, 1H, J = 12.3,

4.4 Hz), 1.43–1.33 (m, 4H), 1.02 (d, 3H, J = 6.7 Hz). ¹³C

NMR (CDCl₃) δ: 193.9 (d), 167.3 (s), 154.7 (d), 150.8 (d),

137.5 (s), 131.4 (d), 127.7 (s), 119.2 (d), 66.9 (d), 51.4 (q),

36.5 (d), 35.6 (t), 31.2 (t), 28.1 (t), 26.7 (t), 22.9 (t), 19.3

(q). LR-MS (m/z (relative intensity)): 292 ([M]⁺, 1), 261

([M⁺– MeO], 10), 133 (100), 77 (60), 95 (60). HR-MS

calcd. for C₁₇H₂₄O₄: 292.1674; found: 292.1664. Anal. calcd.

for C₂₇H₃₆O₆: C 71.03, H 7.95, O 21.03; found: C 71.00, H

7.92.

Allene 30

Copper iodide (2.70 g, 14.2 mmol) and lithium bromide

(1.23 g, 14.2 mmol) were suspended in THF (30 mL) and

the suspension was cooled to 0° C. A suspension of magne-

sium bromide (4.73 mL, 3.0 M in Et₂O, 14.2 mmol) was

added and the resulting yellow suspension was stirred for

0.5 h. Acetate 29a (1.00 g, 2.36 mmol) in THF (10 mL) was

added drop wise and the reaction mixture was stirred for an

additional 0.5 h at 0° C. Then, Et₂O was added (40 mL) and

the mixture was poured into a saturated aqueous NH₄Cl–

NH₄OH (9:1) solution and vigourously stirred in an atmo-

sphere of air for 1 h. The phases were separated, the aqueous

phase was extracted with Et₂O, the combined organic frac-

tions were washed with water and brine, dried over MgSO₄,

filtered, and evaporated under reduced pressure to give 1.1 g

of a yellow oil. Flash chromatography on silica gel eluting

with EtOAc and hexanes (5:95) yielded a colourless oil

Acetate 29a

Propyne (1.65 mL, 29.3 mmol) was condensed at –78° C

in a 100 mL round-bottomed flask. THF (15 mL) was added

followed by a solution of n-BuLi (4.66 mL, 1.88 M in

pentane, 8.76 mmol). The resulting white suspension was

stirred for 1 h at –78° C. Then, (E)-1-triphenylmethoxy-3-

penten-2-one 28 (1.96 g, 5.72 mmol) in THF (7 mL) was

added to the white suspension. The reaction mixture was

warmed to –20° C and stirred for 2 h. Acetic anhydride

(1.42 mL, 15.0 mmol) was added and the reaction mixture

warmed to 0°C. The reaction was quenched with saturated

ammonium chloride and the two phases were separated. The

aqueous phase was extracted with Et₂O, the combined or-

ganic fractions were washed with satd. aq NaHCO₃, water

and brine, dried over MgSO₄, filtered, and evaporated under

reduced pressure to give 2.64 g of 29a as a yellow oil. Flash

1

(837 mg, 93%). IR (neat, cm^–1): 3058, 1955, 1491. H NMR

(C₆D₆) δ: 7.66–7.61 (m, 6H), 7.15–6.99 (m, 9H), 6.08 (dd,

1H, J = 15.8, 1.6 Hz), 5.54 (dq, 1H, J = 15.8, 6.6 Hz), 3.96

(s, 2H), 1.74 (s, 6H), 1.54 (dd, 3H, J = 6.6, 1.6 Hz). LR-MS

(m/z (relative intensity)): 380 ([M]⁺, 1), 243 (100). HR-MS

calcd. for C₂₈H₂₈O: 380.2140; found: 380.2147.

102

Can. J. Chem. Vol. 81, 2003

was cooled to 0°C and stirred for 0.5 h. DCC (1.11 g,

5.38 mmol) was added in small portions and the reaction

mixture stirred for 2.5 h during which time a white precipi-

tate formed. The solvent was evaporated and the product pu-

rified by flash chromatography on silica gel eluting with

EtOAc and hexanes (15:85) giving 32a as a colourless oil

(2.24 g, 93%) containing a 1:1 mixture of inseparable

Allene 31a

Acetate 29b (4.60 g, 8.09 mmol) was dissolved in THF

(20 mL). Tetrabutylammonium fluoride (16.17 mL, 1.0 M in

THF, 16.17 mmol) was added and the orange solution was

stirred for 12 h. Then, the mixture was poured into sat.

NH₄Cl, the phases were separated, and the aqueous phase

was extracted with Et₂O. The combined organic fractions

were washed with water and brine, dried over MgSO₄, fil-

tered, and evaporated under reduced pressure to give 3.70 g

of an orange oil. Flash chromatography on silica gel eluting

with EtOAc and hexanes (20:80) gave a fluffy white powder

1

diastereomers. IR (neat, cm^–1): 3039, 1957, 1722, 1449. H

NMR (C₆D₆) δ: 7.64–7.57 (m, 6H), 7.16–7.09 (m, 9H),

7.06–7.00 (m, 2H), 5.93 (dm, 1H, J = 15.8 Hz), 5.74–5.59

(m, 1H), 5.51–5.39 (m, 1H), 3.94–3.92 (m, 2H), 3.90–3.78

(m, 2H), 1.77 (d, 3H, J = 7.8 Hz), 1.45 (dd, 3H, J = 6.6,

1.6 Hz), 1.36 (t, 3H, J = 6.1 Hz), 0.84–0.80 (m, 3H). LR-MS

(m/z (relative intensity)): 537 ([M + 1], 2), 243 (95), 167

(90), 105 (100). HR-MS calcd. for C₃₅H₃₇O₅: 537.2641;

found: 537.2622.

(2.80 g, 76%). IR (neat, cm^–1): 3467, 3023, 1738, 1449. H

1

NMR (C₆D₆) δ: 7.49–7.44 (m, 6H), 7.33–7.22 (m, 9H),

6.10–5.96 (m, 1H), 5.61 (dd, 1H, J = 15.4, 1.6 Hz), 4.63–

4.56 (m, 1H), 3.39–3.30 (m, 2H), 2.04 (s, 3H), 1.73 (dd, 3H,

J = 6.6, 1.6 Hz), 1.46 (d, 3H, J = 6.6 Hz). LR-MS (m/z (rela-

tive intensity)): 454 ([M]⁺, 1), 243 (100), 165 (75). HR-MS

calcd. for C₃₀H₃₀O₄: 454.2144; found: 454.2151.

Diester 32b

The cuprate addition on this compound was performed as

per allene 30. Flash chromatography on silica gel eluting

with EtOAc and hexanes (20:80) gave 31a as a white pow-

der (2.54 g, 100%) as a mixture of two inseparable isomers.

Followed the same procedure as per diester 32a, starting

from 31b. Flash chromatography on silica gel eluting with

EtOAc and hexanes (15:85) gave a colourless oil (1.83 g,

88%) containing a mixture of two isomers. IR (neat, cm^–1):

1

IR (neat, cm^–1): 3588–3146, 3058, 1950, 1448. H NMR

1

3026, 1958, 1723, 1646. H NMR (CDCl₃, integrated for

(C₆D₆) δ: 7.50–7.42 (m, 6H), 7.32–7.21 (m, 9H), 5.85 (dm,

1H, J = 15.7 Hz), 5.49–5.36 (m, 1H), 4.34–4.25 (m, 1H),

3.75–3.65 (m, 2H), 1.86 (d, 3H, J = 1.8 Hz), 1.69 (dd, 3H,

J = 6.6, 1.6 Hz), 1.36 (dd, 3H, J = 6.4, 1.8 Hz). LR-MS (m/z

(relative intensity)): 409 ([M – 1], 10), 259 (50), 243 (100).

HR-MS calcd. for C₂₉H₂₉O₂: 409.2167; found: 409.2149.

two isomers) δ: 7.48–7.42 (m, 12H), 7.32–7.20 (m, 18H),

6.85–6.80 (m, 4H), 5.88–5.73 (m, 2H), 5.47–5.37 (m, 4H),

4.42–4.19 (m, 6H), 3.67 (s, 4H), 3.27–3.10 (m, 8H), 1.95–

1.74 (m, 14H), 1.71–1.64 (m, 6H), 1.55–1.41 (m, 4H), 1.30

(t, 3H, J = 7.1 Hz), 1.29 (t, 3H, J = 7.1 Hz). LR-MS (m/z

(relative intensity)): 623 ([M⁺– OEt], 5), 381 (20), 243

(100). HR-MS calcd. for C₃₈H₃₉O₄S₂: 623.2290; found:

623.2303.

Allene 31b

Followed the same procedure as per allene 31a, starting

from 29c. Flash chromatography of the intermediate alcohol

on silica gel eluting with EtOAc and hexanes (30:70) gave a

white powder (5.09 g, 89%). IR (neat, cm^–1): 3407, 3022,

Cycloadduct 33

Allene 30 (837 mg, 2.2 mmol) and methyl fumarate

(634 mg, 4.4 mmol) were dissolved in benzene (10 mL) and

refluxed for 12 h. Benzene was evaporated to yield 1.6 g of

a yellow oil. Flash chromatography on silica gel eluting with

EtOAc and hexanes (5:95) afforded 1.04 g of a colourless oil

1

1738. H NMR (CDCl₃) δ: 7.48–7.44 (m, 6H), 7.34–7.22

(m, 9H), 6.03 (dq, 1H, J = 15.4, 6.6 Hz), 5.62 (dd, 1H, J =

15.4, 1.7 Hz), 4.44 (q, 1H, J = 5.7 Hz), 4.38 (td, 1H, J = 7.0,

1.8 Hz), 3.39–3.30 (m, 2H), 3.26–3.12 (m, 4H), 2.05 (s, 3H),

1.85–1.70 (m, 4H), 1.74 (dd, 3H, J = 6.6, 1.7 Hz), 1.64–1.52

(m, 2H), 1.56 (s, 1H). LR-MS (m/z (relative intensity)): 568

([M⁺– H₂O]), 3), 508 (5), 243 (100), 105 (100). HR-MS

calcd. for C₃₅H₃₆O₃S₂: 568.2106; found: 568.2114.

(90%). IR (neat, cm^–1): 3059, 1732, 1448. H NMR (CHCl₃)

1

δ: 7.46–7.42 (m, 6H), 7.32–7.19 (m, 9H), 5.92 (d, 1H, J =

2.7 Hz), 4.04 (d, 1H, J = 5.1 Hz), 3.75–3.62 (m, 2H), 3.71

(s, 3H), 3.51 (s, 3H), 2.89 (dd, 1H, J = 7.9, 5.1 Hz), 2.43–

2.33 (m, 1H), 1.76 (s, 3H), 1.43 (s, 3H), 1.20 (d, 3H, J =

7.2 Hz). LR-MS (m/z (relative intensity)): 524 ([M]⁺, 0.5),

443 (1), 243 (100), 165 (5). HR-MS calcd. for C₃₄H₃₆O₅:

524.2563; found: 524.2569.

The alcohol was submitted to the cuprate reaction as per

the alcohol precursor of 31a. Flash chromatography on silica

gel eluting with EtOAc and hexanes (20:80) gave 31b as a

white powder (4.31 g, 93%) containing an inseparable mix-

ture of two isomers. IR (cm^–1): 3559, 3431, 3021, 1952,

Aldehyde 34

1

1597. H NMR (CDCl₃) δ: 7.49–7.42 (m, 12H), 7.32–7.21

Cycloadduct 33 (369 mg, 0.75 mmol) was dissolved in

Et₂O (2 mL). An 88% aqueous solution of formic acid

(23 mL) in Et₂O (17 mL) was added and the mixture was

stirred for 20 min. It was poured into EtOAc (100 mL). The

phases were separated, the organic phase was washed with

water, satd. NaHCO₃and brine, dried over MgSO₄, filtered,

and evaporated under reduced pressure to give 215 mg of a

yellow oil. Flash chromatography on silica gel eluting with

EtOAc and hexanes (30:70) yielded a colourless oil

(m, 18H), 5.86 (dd, 2H, J = 16.0, 1.6 Hz), 5.44 (dm, 2H, J =

16.0 Hz), 4.41 (q, 2H, J = 7.1 Hz), 4.16–4.06 (m, 2H), 3.75–

3.65 (m, 4H), 3.27–3.13 (m, 8H), 1.89–1.72 (m, 4H), 1.83

(s, 6H), 1.71–1.48 (m, 8H), 1.70 (dd, 6H, J = 6.6, 1.6 Hz),

1.55 (s, 2H). LR-MS (m/z (relative intensity)): 542 ([M]⁺, 1),

513 ([M⁺– C₂H₅], 3), 299 (10), 243 (100). HR-MS calcd.

for C₃₄H₃₈O₂S₂: 542.2313; found: 542.2309.

1

Diester 32a

(156 mg, 73%). IR (neat, cm^–1): 3454, 1732, 1435. H NMR

Allene 31a (1.84 g, 4.49 mmol), fumaric acid, monoethyl

ester (775 mg, 5.38 mmol), and DMAP (110 mg,

0.90 mmol) were dissolved in CH₂Cl₂(40 mL). The solution

(CHCl₃) δ: 5.69 (d, 1H, J = 3.1 Hz), 4.48 (dd, 1H, J = 12.3,

5.5 Hz), 4.13 (dd, 1H, J = 12.3, 5.5 Hz), 4.08 (d, 1H, J =

4.9 Hz), 3.72 (s, 3H), 3.67 (s, 3H), 2.73 (dd, 1H, J = 7.0,

Spino et al.

103

4.9 Hz), 2.51–2.39 (m, 1H), 2.28 (t, 1H, J = 5.5 Hz), 1.82 (s,

3H), 1.79 (s, 3H), 1.10 (d, 3H, J = 7.3 Hz). LR-MS (m/z

(relative intensity)): 282 ([M]⁺, 1), 264 ([M⁺– H₂O], 5), 232

(20), 204 (100), 173 (85), 145 (60), 91 (30). HR-MS calcd.

for C₁₅H₂₂O₅: 282.1467; found: 282.1471.

Aldehydes 36a and 36b

Followed the same procedure as for the deprotection of 33

and the Dess–Martin oxidation to 34. Flash chromatography

on silica gel eluting with EtOAc and hexanes (40:60) gave

two diastereomeric alcohols as a colourless oils (each

1

256 mg for a total of 512 mg, 82%). Less polar isomer: H

This alcohol (146 mg, 0.52 mmol) was dissolved in

CH₂Cl₂(5 mL). Dess–Martin periodinane (288 mg,

0.68 mmol) was added and the mixture was stirred for 0.5 h.

Et₂O (10 mL) was added provoking the formation of a white

precipitate. The suspension was neutralized with satd.

NaHCO₃(20 mL) containing 5 g of sodium thiosulfate. The

resulting bilayered mixture was vigorously stirred for 0.5 h.

The phases were separated, the aqueous phase was extracted

with Et₂O, the combined organic fractions were washed with

water and brine, dried over MgSO₄, filtered, and evaporated

under reduced pressure to give 146 mg of 34 as a colourless

oil (146 mg, 100%). IR (neat, cm^–1): 2954, 2713, 1732,

NMR (CDCl₃) δ: 6.27 (d, 1H, J = 7.0 Hz), 5.08 (q, 1H,

6.8 Hz), 4.42–4.31 (m, 2H), 4.21 (q, 1H, J = 7.2 Hz), 4.21

(q, 1H, J = 7.2 Hz), 3.63 (dt, 1H, J = 10.9, 2.5 Hz), 3.04 (dd,

1H, J = 10.9, 4.8 Hz), 2.86–2.74 (m, 1H), 2.03–2.00 (m,

3H), 1.57 (d, 3H, J = 6.8 Hz), 1.48–1.42 (m, 1H), 1.29 (t,

3H, J = 7.2 Hz), 0.94 (d, 3H, J = 7.1 Hz). More polar iso-

mer: IR (neat, cm^–1): 3453, 1732, 1454. ¹H NMR (CDCl₃) δ:

6.20 (d, 1H, J = 6.9 Hz), 4.74 (q, 1H, J = 6.9 Hz), 4.41 (dd,

1H, J = 12.6, 5.2 Hz), 4.32 (dd, 1H, J = 12.6, 6.2 Hz), 4.23

(q, 2H, J = 7.1 Hz), 3.71 (dt, 1H, J = 11.6, 1.8 Hz), 2.94 (dd,

1H, J = 11.6, 5.1 Hz), 2.80–2.69 (m, 1H), 2.04 (d, 3H, J =

2.4 Hz), 1.56 (d, 3H, J = 6.9 Hz), 1.41 (t, 1H, J = 5.8 Hz),

1.30 (t, 3H, J = 7.1 Hz), 0.95 (d, 3H, J = 7.1 Hz). LR-MS

(m/z (relative intensity)): 294 ([M]⁺, 45), 203 (75), 175 (55),

159 (100). HR-MS calcd. for C₁₆H₂₂O₅: 294.1467; found:

294.1473.

1

1694. H NMR (C₆D₆) δ: 9.30 (s, 1H), 6.10 (d, 1H, J =

3.0 Hz), 4.24 (d, 1H, J = 4.2 Hz), 3.26 (s, 3H), 3.20 (s, 3H),

3.05 (dd, 1H, J = 6.3, 4.2 Hz), 2.69 (quint, 1H, J = 7.1,

3.0 Hz), 1.71 (s, 3H), 1.61 (s, 3H), 1.02 (d, 3H, J = 7.3 Hz).

LR-MS (m/z (relative intensity)): 280 ([M]⁺, 50), 221 (65),

161 (100). HR-MS calcd. for C₁₅H₂₀O₅: 280.1311; found:

280.1306.

Each of the isomeric alcohols were oxidized separately

and each crude product obtained was purified by flash chro-

matography on silica gel eluting with EtOAc and hexanes

(30:70) to give a colourless oil. Aldehyde 36a having the α-

methyl group (44 mg, 76%). IR (neat, cm^–1): 2981, 2730,

1732, 1699. ¹H NMR (CDCl₃) δ: 9.55 (s, 1H), 7.04 (d, 1H, J

= 6.3 Hz), 5.11 (q, 1H, J = 6.7 Hz), 4.18 (q, 2H, J = 7.1 Hz),

3.62 (dt, 1H, J = 8.5, 2.6 Hz), 3.16 (dd, 1H, J = 8.5, 4.5 Hz),

2.98–2.86 (m, 1H), 1.81 (s, 3H), 1.59 (d, 3H, J = 6.7 Hz),

1.27 (t, 3H, J = 7.1 Hz), 1.17 (d, 3H, J = 7.2 Hz). LR-MS

(m/z (relative intensity)): 292 ([M]⁺, 20), 247 (25), 86 (90),

78 (100). HR-MS calcd. for C₁₆H₂₀O₅: 292.1311; found:

292.1315. Aldehyde 36b having the β-methyl group (42 mg,

Cycloadducts 35a

Allene 32a (2.32 g, 4.32 mmol) was dissolved in benzene

(100 mL). The solution was refluxed for 15 h. The solvent

was evaporated and the crude product (2.75 g) was purified

by flash chromatography on silica gel eluting with EtOAc

and hexanes (30:70) giving a white powder (1.59 g, 69%)

containing an inseparable mixture of two diastereomers. IR

1

(neat, cm^–1): 3022, 2978, 1732, 1449. H NMR (C₆D₆, inte-

grated for two isomers) δ: 7.57–7.52 (m, 12H), 7.15–7.01

(m, 18H), 6.38 (d, 1H, J = 7.5 Hz), 6.36 (d, 1H, J = 7.5 Hz),

4.17–4.00 (m, 6H), 3.96–3.70 (m, 6H), 3.32 (dd, 1H, J =

11.2, 4.8 Hz), 3.23 (dd, 1H, J = 11.7, 5.0 Hz), 2.77–2.61 (m,

2H), 1.25–1.02 (m, 12H), 0.99 (d, 6H, J = 7.0 Hz), 0.93 (d,

6H, J = 7.0 Hz). LR-MS (m/z (relative intensity)): 536

([M]⁺, 1), 491 ([M⁺– C₂H₅O], 5), 243 (100). HR-MS calcd.

for C₃₃H₃₁O₄: 491.2222; found: 491.2230.

1

70% yield): H NMR (CDCl₃) δ: 9.57 (s, 1H), 6.97 (d, 1H,

J = 6.1 Hz), 4.84 (qd, 1H, J = 7.1, 0.9 Hz), 4.19 (q, 2H, J =

7.1 Hz), 3.69 (dt, 1H, J = 8.4, 2.1 Hz), 3.19 (dd, 1H, J = 8.4,

4.6 Hz), 2.88–2.77 (m, 1H), 1.80 (d, 3H, J = 2.5 Hz), 1.59

(d, 3H, J = 7.1 Hz), 1.28 (t, 3H, J = 7.1 Hz), 1.19 (d, 3H, J =

7.2 Hz).

Enoates 37

Cycloadducts 35b

Mercuric oxide red (520 mg, 2.4 mmol) was dissolved in

THF:water (85:15) (8.2 mL) and BF₃·OEt₂(0.30 mL,

2.4 mmol) was added drop wise. Cycloadduct 35b (800 mg,

1.2 mmol) in THF (2 mL) was slowly added to the orange

mixture, which was stirred for 0.5 h. Et₂O (30 mL) was

added and the resulting precipitate was filtered through a

cintered glass. The organic phase was washed with satd.

NaHCO₃and brine, dried over MgSO₄, filtered, and evapo-

rated under reduced pressure to give a white powder

(711 mg, 100%) containing an inseparable mixture of two

diastereomers. IR (neat, cm^–1): 3060, 2724, 1730, 1709,

1598. ¹H NMR (CDCl₃) δ: 9.77 (s, 2H), 7.48–7.39 (m, 12H),

7.33–7.20 (m, 18H), 6.42 (d, 1H, J = 7.3 Hz), 6.38 (d, 1H,

J = 7.0 Hz), 4.84 (dm, 1H, J = 7.4 Hz), 4.43 (dm, 1H, J =

10.1 Hz), 4.24 (q, 2H, J = 7.1 Hz), 4.23 (q, 2H, J = 7.1 Hz),

3.86–3.73 (m, 4H), 3.65 (dm, 1H, J = 11.7 Hz), 3.60 (dt, 1H,

J = 11.5, 2.4 Hz), 3.03 (dd, 1H, J = 11.5, 4.8 Hz), 2.97 (dd,

1H, J = 11.7, 5.0 Hz), 2.90–2.75 (m, 2H), 2.52 (t, 4H, J =

Followed the same procedure as per 35a, starting from

32b. Flash chromatography on silica gel eluting with EtOAc

and hexanes (20:80) gave a colourless oil (1.41 g, 69%) con-

taining an inseparable mixture of two isomers. IR (neat, cm^–1):

1

3023, 1732, 1597. H NMR (CDCl₃, integrated for two iso-

mers) δ: 7.48–7.38 (m, 12H), 7.33–7.22 (m, 18H), 6.43 (d,

1H, J = 7.3 Hz), 6.38 (d, 1H, J = 7.0 Hz), 4.82 (dm, 1H, J =

8.4 Hz), 4.49–4.40 (m, 3H), 4.24 (q, 2H, J = 7.1 Hz), 4.23

(q, 2H, J = 7.1 Hz), 3.87–3.73 (m, 4H), 3.68 (dm, 1H, J =

11.6 Hz), 3.59 (dt, 1H, J = 11.3, 2.4 Hz), 3.26–3.12 (m, 8H),

3.04 (dd, 1H, J = 11.3, 4.8 Hz), 2.97 (dd, 1H, J = 11.6,

5.0 Hz), 2.89–2.74 (m, 2H), 1.97–1.52 (m, 12 H), 1.60 (s,

3H), 1.57 (s, 3H), 1.32 (t, 3H, J = 7.1 Hz), 1.31 (t, 3H, J =

7.1 Hz), 0.95 (d, 3H, J = 7.0 Hz), 0.93 (d, 3H, J = 7.0 Hz).

LR-MS (m/z (relative intensity)): 668 ([M]⁺, 3), 381 (20),

243 (100). HR-MS calcd. for C₄₀H₄₄O₅S₂: 668.2630; found:

668.2643.

104

Can. J. Chem. Vol. 81, 2003

1

5.9 Hz), 2.00–1.65 (m, 8 H), 1.60 (s, 3H), 1.57 (s, 3H), 1.32

(t, 3H, J = 7.1 Hz), 1.31 (t, 3H, J = 7.1 Hz), 0.95 (d, 3H, J =

6.6 Hz), 0.92 (d, 3H, J = 6.6 Hz). LR-MS (m/z (relative in-

tensity)): 610 ([M + NH₄], 5), 566 (5), 243 (100). HR-MS

calcd. for C₃₈H₄₄NO₆: 610.3168; found: 610.3154.

(180 mg, 87%): IR (neat, cm^–1): 2728, 1738, 1714, 1694. H

NMR (CDCl₃) δ: 9.53 (s, 1H), 7.04 (d, 1H, J = 6.3 Hz), 6.97

(dt, 1H, J = 15.7, 7.0 Hz), 5.87 (d, 1H, J = 15.7 Hz), 4.94

(dm, 1H, J = 8.7 Hz), 4.19 (q, 2H, J = 7.1 Hz), 3.74 (s, 3H),

3.61 (dt, 1H, J = 8.5, 2.6 Hz), 3.15 (dd, 1H, J = 8.5, 4.5 Hz),

2.97–2.86 (m, 1H), 2.31 (q, 2H, J = 7.0 Hz), 2.00–1.82 (m,

3H), 1.79 (s, 3H), 1.78–1.60 (m, 1H), 1.27 (t, 3H, J =

7.1 Hz), 1.16 (d, 3H, J = 7.2 Hz). LR-MS (m/z (relative in-

tensity)): 422 ([M + NH₄], 15), 405 ([M + H⁺], 100). HR-

MS calcd. for C₂₂H₂₉O₇: 405.1913; found: 405.1911. Alde-

hyde 38b with the β-chain (52 mg, 100%): ¹H NMR

(CDCl₃) δ: 9.55 (s, 1H), 6.96 (d, 1H, J = 5.6 Hz), 6.95 (dt,

1H, J = 15.6, 7.0 Hz), 5.86 (d, 1H, J = 15.6 Hz), 4.66 (dm,

1H, J = 9.7 Hz), 4.18 (q, 2H, J = 7.1 Hz), 3.73 (s, 3H), 3.63

(dt, 1H, J = 7.4, 2.2 Hz), 3.27 (dd, 1H, J = 7.4, 4.8 Hz),

2.82–2.72 (m, 1H), 2.34–2.25 (m, 2H), 1.96–1.75 (m, 3H),

1.79 (d, 3H, J = 2.2), 1.72–1.60 (m, 1H), 1.27 (t, 3H, J =

7.1 Hz), 1.22 (d, 3H, J = 7.2 Hz).

Sodium hydride (58 mg, 60% in oil, 1.44 mmol) was sus-

pended in THF (7 mL) at 0°C. Methyl diethoxyphosphono-

acetate (0.27 mL, 1.44 mmol) was added slowly and the

mixture was stirred for 0.5 h. The anion was added via can-

nula to a solution of the above aldehyde (711 mg, 1.2 mmol)

in THF (7 mL) at 0°C. After 1 h, the reaction was poured

into a saturated solution of NH₄Cl, the phases were sepa-

rated and the aqueous phase was extracted with EtOAc. The

combined organic fractions were washed with water and

brine, dried over MgSO₄, filtered, and evaporated under re-

duced pressure to give 800 mg of a yellow powder. Flash

chromatography on silica gel eluting with EtOAc and hex-

anes (20:80) gave 37 as a white powder (544 mg, 70%) con-

taining an inseparable mixture of two isomers. IR (neat, cm^–1):

1

3058, 1729, 1657. H NMR (C₆D₆, integrated for two iso-

Cycloadducts 14β-39a and 14α-39a

mers) δ: 7.45–7.40 (m, 12H), 7.33–7.22 (m, 18H), 6.95 (dt,

1H, J = 15.7, 6.7 Hz), 6.93 (dt, 1H, J = 15.7, 6.8 Hz), 6.42

(d, 1H, J = 7.3 Hz), 6.38 (d, 1H, J = 7.0 Hz), 5.84 (dd, 2H,

J = 15.7, 2.1 Hz), 4.82 (dm, 1H, J = 8.3 Hz), 4.42 (dm, 1H,

J = 10.6 Hz), 4.24 (q, 2H, J = 7.1 Hz), 4.23 (q, 2H, J =

7.1 Hz), 3.86–3.72 (m, 4H), 3.74 (s, 3H), 3.73 (s, 3H), 3.66

(dm, 1H, J = 11.7 Hz), 3.59 (dt, 1H, J = 11.3, 2.4 Hz), 3.04

(dd, 1H, J = 11.3, 4.8 Hz), 2.97 (dd, 1H, J = 11.7, 5.0 Hz),

2.88–2.73 (m, 2H), 2.31–2.19 (m, 4H), 1.93–1.50 (m, 14 H),

1.31 (t, 3H, J = 7.1 Hz), 1.30 (t, 3H, J = 7.1 Hz), 0.95 (d,

3H, J = 7.3 Hz), 0.93 (d, 3H, J = 7.3 Hz). LR-MS (m/z (rela-

tive intensity)): 666 ([M + NH₄], 2), 407 (15), 243 (100),

165 (20). HR-MS calcd. for C₄₁H₄₈NO₇: 666.3431; found:

666.3420.

Followed the same procedure as per the preparation of

cycloadduct 39b. The crude mixture was purified by flash

chromatography (mixture of hexanes:EtOAc, 15:1) to pro-

vide 145 mg (84%) of cycloadducts as an approximate 4:1

1

mixture of two separable diastereomers. 14α-39a: H NMR

(CDCl₃) δ: 7.7–7.3 (m, 10H), 6.51 (d, 1H, J = 0.5 Hz), 5.80

(ddt, 1H, J = 17.0, 10.3, 6.6 Hz), 5.28 (t, 1H, J = 6.8 Hz),

4.97 (dt, 1H, J = 17.0, 1.0 Hz), 4.90 (dt, 1H, J = 10.3,

1.0 Hz), 4.78 (dd, 1H, J = 7.8, 0.5 Hz), 4.09 (m, 1H), 3.88

(dq, 1H, J = 9.5, 7.0 Hz), 3.55 (dq, 1H, J = 9.5, 7.0 Hz),

2.40–2.33 (m, 1H), 2.21–2.17 (m, 3H), 2.06–1.87 (m, 3H),

1.85–1.77 (m, 2H), 1.48–1.37 (m, 1H), 1.36–1.28 (m, 3H),

1.23–1.07 (m, 2H), 1.21 (t, 3H, J = 7.0 Hz), 1.09 (s, 9H). 14

1

β-39a: H NMR (CDCl₃) δ: 7.7–7.3 (m, 10H), 6.60 (d, 1H,

J = 0.5 Hz), 5.81 (ddt, 1H, J = 17.0, 10.3, 6.6 Hz), 5.08–

4.90 (m, 3H), 4.94 (dd, 1H, J = 7.8, 0.5 Hz), 4.03 (m, 1H),

3.96 (dq, 1H, J = 9.5, 7.0 Hz), 3.11 (dq, 1H, J = 9.5,

7.0 Hz), 2.55–2.41 (m, 1H), 2.25–2.00 (m, 4H), 1.85–1.79

(m, 1H), 1.77–1.20 (m, 9H), 1.27 (t, 3H, J = 7.0 Hz), 1.05

(s, 9H).

Aldehydes 38a and 38b

Followed the same procedure as per the deprotection of

33 and oxidation to give 34. Flash chromatography on silica

gel eluting with EtOAc and hexanes (30:70) gave two sepa-

rable alcohols as colourless oils (153 mg, 46% and 153 mg,

1

46%). Less polar isomer: H NMR (CDCl₃) δ: 6.97 (dt, 1H,

J = 15.7, 6.9 Hz), 6.28 (d, 1H, J = 7.0 Hz), 5.86 (d, 1H, J =

15.7 Hz), 4.89 (dm, 1H, J = 8.9 Hz), 4.40–4.30 (m, 2H),

4.21 (q, 2H, J = 7.1 Hz), 3.73 (s, 3H), 3.61 (dt, 1H, J = 10.8,

2.5 Hz), 3.03 (dd, 1H, J = 10.8, 4.8 Hz), 2.84–2.74 (m, 1H),

2.30 (q, 2H, J = 6.9 Hz), 2.00 (s, 3H), 1.99–1.78 (m, 3H),

1.72–1.60 (m, 1H), 1.57 (s, 1H), 1.29 (t, 3H, J = 7.1 Hz),

0.93 (d, 3H, J = 7.1 Hz). More polar isomer: IR (neat, cm^–1):

Cycloadducts 14β-39b and 14α-39b

To

a stirred solution of aldehyde 20b (307 mg,

0.990 mmol) and ethyl vinyl ether (4.6 mL) was added

Yb(FOD)₃(127 mg, 0.120 mmol) at room temperature. The

reaction mixture was stirred for 1 day before a solution of

brine was added. This mixture was stirred for about 1 h then

separated and the product extracted with ethyl ether, dried

over MgSO₄, filtered, and concentrated. The crude mixture

was purified by flash chromatography (mixture of hexanes:

EtOAc, 15:1) to provide 308 mg (81%) of cycloadducts as

an approximate 1:1 mixture of inseparable diastereomers. IR

(neat, cm^–1): 3076, 1640. ¹H NMR (CDCl₃) δ: 7.35–7.24 (m,

5H), 1 isomer 6.44 (d, 1H, J = 2.1 Hz), one isomer 6.39 (d,

1H, J = 1.9 Hz), 5.80 (ddt, 1H, J = 17.0, 10.3, 6.6 Hz),

5.34–5.26 (m, 1H), 5.03–4.91 (m, 2H), 4.85–4.81 (m, 1H),

one isomer 4.67 (d, 1H, J = 11.4 Hz), one isomer 4.64 (d,

1H, J = 12.1 Hz), one isomer 4.47 (d, 1H, J = 11.4 Hz), one

isomer 4.42 (d, 1H, J = 12.2 Hz), 4.01–3.91 (m, 1H), one

isomer 3.64–3.61 (m, 1H), 3.61–3.53 (m, 1H), one isomer

3.20–3.12 (m, 1H), one isomer 2.64 (dt, 1H, J = 14.3,

1

3480, 1732, 1658. H NMR (CDCl₃) δ: 6.95 (dt, 1H, J =

15.7, 7.0 Hz), 6.19 (d, 1H, J = 6.8 Hz), 5.86 (d, 1H, J =

15.7 Hz), 4.54 (dm, 1H, J = 10.2 Hz), 4.42–4.29 (m, 2H),

4.22 (q, 2H, J = 7.1 Hz), 3.73 (s, 3H), 3.67 (dm, 1H, J =

11.4 Hz), 2.95 (dd, 1H, J = 11.4, 5.1 Hz), 2.79–2.69 (m,

1H), 2.34–2.23 (m, 2H), 2.04 (d, 3H, J = 2.5 Hz), 2.00–1.55

(m, 4H), 1.30 (t, 3H, J = 7.1 Hz), 0.94 (d, 3H, J = 7.1 Hz).

LR-MS (m/z (relative intensity)): 406 ([M]⁺, 15), 297 (50),

175 (100). HR-MS calcd. for C₂₂H₃₀O₇: 406.1991; found:

406.1999.

Each alcohol was then oxidized separately. Flash chroma-

tography on silica gel eluting with EtOAc and hexanes

(30:70) gave a colourless oil. Aldehyde 38a with the α-chain

Spino et al.

105

3.5 Hz), 2.54–1.94 (m, 7H), 1.83–1.74 (m, 1H), 1.63–1.52

(m, 1H), 1.44–1.29 (m, 5H), 1.26 (t, 3H, J = 7.1 Hz). ¹³C

NMR (CDCl₃) δ: 138.9 (d), 138.6 (s), 136.7 (d), 136.4 (d),

134.3 (s), 133.9 (s), 128.4 (d), 128.2 (d), 127.8 (d), 127.6

(d), 127.3 (d), 122.3 (d), 121.5 (d), 116.8 (s), 116.2 (s),

114.2 (t), 100.1 (d), 99.9 (d), 82.5 (d), 74.1 (d), 73.7 (d),

71.0 (t), 70.5 (t), 64.5 (t), 64.4 (t), 39.9 (d), 38.8 (d), 33.7

(t), 33.5 (t), 30.9 (t), 30.1 (t), 29.4 (t), 28.5 (t), 27.7 (t), 27.6

(t), 27.4 (t), 25.4 (t), 21.3 (t), 15.2 (q). LR-MS (m/z (relative

intensity)): 382 ([M]⁺, 40), 91 (100). HR-MS calcd. for

C₂₅H₃₄O₃: 382.2520; found: 382.2553.

(t, 3H, J = 7.0 Hz), 1.06 (t, 3H, J = 7.1 Hz), 1.01 (d, 3H, J =

6.8 Hz), 0.89 (d, 3H, J = 7.1 Hz).

Cycloadducts 43a and 43b

Followed the same procedure as per 42a and 42b. Isomers

38a and 38b were reacted separately. Flash chromatography

on silica gel eluting with EtOAc and hexanes (30:70) gave a

white powder. Cycloadduct 43a having the α-chain (41 mg,

1

72%): H NMR (C₆D₆) δ: 6.89 (dt, 1H, J = 15.7, 6.9 Hz),

6.18 (d, 1H, J = 1.6 Hz), 5.80 (d, 1H, J = 15.7 Hz), 4.74 (dd,

1H, J = 7.4, 2.6 Hz), 4.19 (dm, 1H, J = 10.8 Hz), 4.16 (q,

1H, J = 7.1 Hz), 4.07 (q, 1H, J = 7.1 Hz), 3.81 (dq, 1H, J =

9.4, 7.1 Hz), 3.74 (dt, 1H, J = 11.3, 2.3 Hz), 3.45 (s, 3H),

3.32 (dq, 1H, J = 9.4, 7.0 Hz), 3.05 (dd, 1H, J = 11.3,

5.7 Hz), 2.07–1.94 (m, 2H), 1.79–1.71 (m, 1H), 1.70–1.52

(m, 3H), 1.48–1.20 (m, 4H), 1.36 (d, 3H, J = 2.3 Hz), 1.11

(t, 3H, J = 7.0 Hz), 1.06 (t, 3H, J = 7.1 Hz), 0.89 (d, 3H, J =

6.7 Hz). ¹³C NMR (C₆D₆) δ: 173.4 (s), 171.1 (s), 166.6 (s),

148.6 (d), 142.1 (d), 128.8 (s), 126.0 (s), 125.1 (s), 121.8

(d), 99.0 (d), 82.9 (d), 64.2 (t), 60.7 (t), 51.0 (q), 45.0 (d),

39.5 (d), 35.6 (d), 34.5 (d), 33.6 (t), 31.5 (t), 30.9 (t), 24.3

(t), 17.0 (q), 16.6 (q), 15.3 (q), 14.3 (q). Cycloadduct 43b

having the β-chain (40 mg, 71%): IR (neat, cm^–1): 2955,

1729, 1630. ¹H NMR (C₆D₆) δ: 6.97 (dt, 1H, J = 15.7,

6.9 Hz), 6.09 (d, 1H, J = 2.2 Hz), 5.85 (d, 1H, J = 15.7 Hz),

4.76 (dd, 1H, J = 7.8, 2.7 Hz), 4.21 (dm, 1H, J = 7.2 Hz),

4.15 (q, 1H, J = 7.1 Hz), 4.08 (q, 1H, J = 7.1 Hz), 3.82 (dq,

1H, J = 9.4, 7.1 Hz), 3.60 (dt, 1H, J = 11.7, 2.2 Hz), 3.45 (s,

3H), 3.33 (dq, 1H, J = 9.4, 7.1 Hz), 3.11 (dd, 1H, J = 11.7,

5.0 Hz), 2.17–2.07 (m, 1H), 1.98–1.90 (m, 1H), 1.77–1.59

(m, 4H), 1.54–1.40 (m, 1H), 1.42 (d, 3H, J = 2.2 Hz), 1.39–

1.15 (m, 3H), 1.12 (t, 3H, J = 7.1 Hz), 1.05 (t, 3H, J =

7.1 Hz), 0.93 (d, 3H, J = 7.2 Hz). ¹³C NMR (C₆D₆) δ: 173.4

(s), 171.9 (s), 166.7 (s), 148.9 (d), 142.5 (d), 129.2 (s), 129.2

(s), 127.8 (s), 121.7 (d), 99.3 (d), 79.3 (d), 64.1 (t), 60.7 (t),

51.0 (q), 43.2 (d), 41.6 (d), 36.6 (d), 34.7 (d), 34.1 (t), 31.8

(t), 31.1 (t), 24.1 (t), 17.0 (q), 15.3 (q), 14.7 (q), 14.2 (q).

LR-MS (m/z (relative intensity)): 476 ([M]⁺, 1), 432 (65),

305 (100). HR-MS calcd. for C₂₆H₃₇O₈: 477.2488; found:

477.2477.

Cycloadducts 40a–c

These cycloadducts were not isolated because they spon-

taneously underwent the subsequent intramolecular cyclo-

addition. Their stereochemistries were therefore deduced

from the isolation of tetracycles 48–51.

Cycloadduct 41

Aldehyde 34 (140 mg, 0.50 mmol) was dissolved in ethyl

vinyl ether (5 mL) and Yb(FOD)₃(79 mg, 0.075 mmol) was

added. After 12 h, the solvant was evaporated and a colour-

less oil was obtained (260 mg). Flash chromatography on

silica gel eluting with EtOAc and hexanes (10:90) yielded

41 as a white crystalline compound (167 mg, 95%). IR

(neat, cm^–1): 2975, 1733, 1640, 1164, 1132. ¹H NMR (C₆D₆)

δ: 6.47 (d, 1H, J = 2.3 Hz), 4.83 (dd, 1H, J = 9.3, 2.9 Hz),

4.21 (d, 1H, J = 3.1 Hz), 3.90 (dq, 1H, J = 9.5, 7.1 Hz),

3.38–3.27 (m, 2H), 3.32 (s, 3H), 3.32 (s, 3H), 2.36–2.24 (tm,

1H, J = 11.6 Hz), 1.97 (ddd, 1H, J = 12.7, 4.5, 3.1 Hz), 1.80

(s, 3H), 1.76 (s, 3H), 1.75–1.65 (m, 1H), 1.57–1.46 (m, 1H),

1.10 (t, 3H, J = 7.1 Hz), 0.91 (d, 3H, J = 6.5 Hz). ¹³C NMR

(C₆D₆) δ: 175.2 (s), 174.8 (s), 141.6 (d), 129.1 (s), 124.6 (s),

114.2 (s), 100.6 (d), 64.5 (t), 52.1 (q), 51.5 (q), 51.1 (d),

47.1 (d), 36.6 (d), 35.5 (d), 33.4 (t), 23.8 (q), 21.7 (q), 17.7

(q), 15.7 (q). LR-MS (m/z (relative intensity)): 352 ([M]⁺,

60), 221 (80), 189 (50), 161 (100), 129 (40), 91 (40). HR-

MS calcd. for C₂₈H₂₈O: 352.1886; found: 352.1875.

Cycloadducts 42a and 42b

Each aldehyde 36a and 36b were separately submitted to

the same protocol as per cycloadduct 41. Each crude product

was purified by flash chromatography on silica gel eluting

with EtOAc and hexanes (30:70) to give a white powder.

Cycloadduct 42a: IR (neat, cm^–1): 2977, 1735, 1626. ¹H

NMR (C₆D₆) δ: 6.02 (d, 1H, J = 2.3 Hz), 4.74 (dd, 1H, J =

7.5, 3.0 Hz), 4.24 (qd, 1H, J = 7.7, 1.9 Hz), 4.20–4.01 (m,

2H), 3.80 (qd, 1H, J = 9.4, 7.1 Hz), 3.52 (dt, 1H, J = 11.9,

2.5 Hz), 3.31 (qd, 1H, J = 9.4, 7.1 Hz), 3.09 (dd, 1H, J =

11.9, 4.8 Hz), 2.16–2.07 (m, 1H), 1.90–1.82 (m, 1H), 1.74–

1.58 (m, 2H), 1.41 (d, 3H, J = 1.9 Hz), 1.11 (t, 3H, J =

7.1 Hz), 1.07–1.02 (m, 6H), 0.90 (d, 3H, J = 7.2 Hz). LR-

MS (m/z (relative intensity)): 364 ([M]⁺, 10), 318 (90), 78

(100). HR-MS calcd. for C₂₀H₂₈O₆: 364.1886; found:

Tetracycles 53a and 53b

Aldehyde 24a underwent the same procedure as per the

formation of cycloadduct 41. The crude tetracycles 48

(186 mg, 0.384 mmol) were isolated in 92% combined yield

but only two could be obtained pure and characterized.

Therefore, the crude mixture was mixed with LiAlH₄

(32 mg, 0.844 mmol) in THF (4 mL). The yield of the com-

bined reduced tetracycles was 80% and the yield of pure

tetracycle 53 was 45 mg (21% for two steps) and the yield of

53b was 30 mg (14% for two steps). Tetracycle 53a: mp

131.4°C. IR (CHCl₃, cm^–1): 3506, 3008, 2927, 2857, 1612,

1

1513, 1380, 1249, 1066, 1035. H NMR (C₆D₆) δ: 7.24 (d,

2H, J = 8.6 Hz), 6.78 (d, 2H, J = 8.6 Hz), 4.52 (d, 1H, J =

11.4 Hz), 4.44 (dd, 1H, J = 9.6, 2.1 Hz), 4.23 (d, 1H, J =

11.4 Hz), 4.07–4.02 (m, 1H), 3.90 (dd, 1H, J = 9.4, 3.0 Hz),

3.87 (dq, 1H, J = 9.3, 7.0 Hz), 3.67–3.66 (m, 1H), 3.32 (dq,

1H, J = 9.3, 7.0 Hz), 3.28 (s, 3H), 3.01 (ddd, 1H, J = 11.5,

8.3, 3.2 Hz), 2.95 (bs, 1H), 2.63 (ddd, 1H, J = 12.6, 4.8,

2.1 Hz), 2.36 (m, 1H), 2.00–1.93 (m, 1H), 1.83–1.78 (m,

3H), 1.66–1.61 (m, 2H), 1.59–1.26 (m, 5H), 1.25 (s, 3H),

1

364.1888. Cycloadduct 42b: H NMR (C₆D₆) δ: 6.12 (d, 1H,

J = 2.2 Hz), 4.73 (dd, 1H, J = 7.4, 2.6 Hz), 4.28 (qd, 1H, J =

6.8, 1.2 Hz), 4.25–4.02 (m, 2H), 3.79 (qd, 1H, J = 9.4,

7.1 Hz), 3.72 (dt, 1H, J = 11.6, 1.9 Hz), 3.31 (qd, 1H, J =

9.4, 7.1 Hz), 3.07 (dd, 1H, J = 11.6, 6.0 Hz), 2.12–2.01 (m,

1H), 1.93–1.85 (m, 1H), 1.73 (ddd, 1H, J = 13.1, 5.9,

2.6 Hz), 1.62–1.52 (m, 1H), 1.30 (d, 3H, J = 2.4 Hz), 1.10

106

Can. J. Chem. Vol. 81, 2003

1.24–1.00 (m, 3H), 1.06 (t, 3H, J = 7.0 Hz), 0.79–0.70 (m,

1H). ¹³C NMR (acetone d-6) δ: 160.6 (s), 135.2 (s), 132.8

(s), 130.6 (d), 129.2 (s), 114.9 (d), 103.1 (d), 82.0 (d), 74.1

(d), 71.4 (t), 64.9 (t), 63.6 (t), 56.0 (q), 49.7 (d), 47.9 (d),

45.8 (d), 43.1 (d), 40.4 (t), 38.5 (t), 35.2 (d), 30.1 (t), 28.3

(t), 27.9 (t), 27.0 (t), 24.4 (q), 16.2 (q). LR-MS (m/z (relative

intensity)): 456 ([M]⁺, 5), 121 (100), 122 (89). HR-MS

calcd. for C₂₈H₄₀O₅: 456.2876; found: 456.2868. X-ray data

can be found in the supplementary material.³Tetracycle

(CDCl₃) δ: 4.61 (dd, 1H, J = 8.2, 2.3 Hz), 4.03–4.01 (m,

1H), 3.88–3.86 (m, 1H), 3.84 (dq, 1H, J = 9.5, 7.1 Hz), 3.66

(s, 3H), 3.44 (dq, 1H, J = 9.5, 7.0 Hz), 2.73 (dd, 1H, J =

11.5, 7.1 Hz), 2.50–2.47 (m, 1H), 2.28–2.20 (m, 2H), 2.15–

2.07 (m, 1H), 1.99–1.69 (m, 5H), 1.65–1.44 (m, 4H), 1.38–

1.20 (m, 2H), 1.17 (t, 3H, J = 7.1 Hz), 1.12–1.02 (m, 1H),

0.85 (d, 3H, J = 6.5 Hz). ¹³C NMR (CDCl₃) δ: 174.3 (s),

133.0 (s), 123.3 (s), 100.2 (d), 69.8 (d), 66.6 (d), 63.1 (t),

51.1 (q), 49.6 (d), 43.5 (d), 39.6 (d), 38.8 (d), 36.3 (t), 32.3

(t), 29.0 (t), 26.4 (t), 21.5 (t), 20.6 (q), 15.0 (q). LR-MS (m/z

(relative intensity)): 363 ([M⁺– H], 5), 318 (70), 301 (100).

HR-MS calcd. for C₂₁H₃₁O₅: 363.2171; found: 363.2180.

Anal. calcd. for C₂₁H₃₂O₅: C 69.20, H 8.85, O 21.95; found:

C 69.16, H 8.81. X-ray data can be found in the supplemen-

tary material.³

1

53b: H NMR (C₆D₆) δ: 7.25 (d, 2H, J = 8.6 Hz), 6.86 (d,

2H, J = 8.6 Hz), 5.00 (t, 1H, J = 7.3 Hz), 4.60 (d, 1H, J =

11.2 Hz), 4.37–4.33 (m, 2H), 3.84–3.74 (m, 1H), 3.79 (s,

3H), 3.68–3.61 (m, 1H), 3.49 (dq, 1H, J = 9.8, 7.0 Hz), 3.24

(dd, 1H, J = 11.2, 2.6 Hz), 3.08 (ddd, 1H, J = 11.6, 8.5,

3.1 Hz), 2.59 (ddd, 1H, J = 13.5, 7.0, 4.0 Hz), 2.35–2.10 (m,

4H), 2.07–1.96 (m, 2H), 1.90–1.81 (m, 2H), 1.57–1.40 (m,

5H), 1.21 (t, 3H, J = 7.1 Hz), 1.17–0.99 (m, 3H), 0.96 (d,

3H, J = 7.0 Hz), 0.73–0.66 (m, 1H).

Tetracycle 52b

Followed the same procedure as per cycloadduct 41, start-

ing with aldehyde 24b. Flash chromatography yielded

414 mg (82%) of 52 as a mixture of two tetracycles of

which only the one with the 14α-stereochemistry could be

isolated pure. Therefore, the crude mixture (440 mg,

0.62 mmol) was treated with a 1.0 M solution of TBAF

(2.5 mL, 2.5 mmol) in THF (1 mL). The mixture was

refluxed for 4 h before being cooled and concentrated to

dryness. The crude residue was purified by flash chromatog-

raphy (hexanes:EtOAc, 3–1:1) to give 69 mg (24%) of the

TBS-hydrolysis product 52b and 205 mg (70%) of its

stereoisomers as amorphous solids for a combined yield of

Tetracycles 49a and 49b

Aldehyde 25 underwent the same treatment as per the for-

mation of cycloadduct 41. A mixture of tetracyles 49a and

49b was isolated and purified by flash chromatography on

silica gel eluting with EtOAc and hexanes (1:3) in 84% com-

bined yield. Of this mixture, 49a and 49b could be isolated

in pure form in 12 and 7%, respectively (the reported ratio

was determined by GC from the crude mixture after charac-

terization of the pure compounds). In this particular case,

some of the precursor 13β,14β-40c (starting material) could

be isolated pure. When 13β,14β-40c was refluxed in benzene

overnight, it gave 97% of pure tetracycle 49a and 49b (same

2:1 ratio). Tetracycle 49a: mp 159.4°C. IR (cm^–1): 3499,

1

94%. Tetracycle 52b: IR (film, cm^–1): 3482, 2925, 1736. H

NMR (C₆D₆) δ: 7.25–7.07 (m, 5H), 4.43 (dd, 1H, J = 9.4,

1.9 Hz), 4.38 (s, 2H), 3.91 (dq, 1H, J = 9.5, 7.1 Hz), 3.80–

3.78 (m, 1H), 3.55–3.52 (m, 1H), 3.48 (s, 3H), 3.39 (dq, 1H,

J = 9.5, 7.1 Hz), 3.26 (dd, 1H, J = 8.0, 2.3 Hz), 2.59 (dd,

1H, J = 12.0, 7.7 Hz), 2.44–2.37 (m, 3H), 2.05–1.99 (m,

1H), 1.91–1.51 (m, 5H), 1.49–1.19 (m, 5H), 1.14 (t, 3H, J =

7.1 Hz), 0.99 (s, 3H), 0.87–0.76 (m, 1H). ¹³C NMR (C₆D₆)

δ: 172.7 (s), 139.5 (s), 130.6 (s), 128.6 (d), 128.3 (d), 127.7

(d), 126.2 (s), 101.9 (d), 76.7 (d), 74.1 (d), 71.6 (t), 69.4 (d),

63.7 (t), 50.6 (q), 49.3 (d), 43.7 (d), 42.8 (d), 40.5 (d), 39.2

(d), 37.6 (t), 36.9 (t), 30.8 (t), 29.8 (t), 26.9 (t), 21.1 (q),

1

1738, 1434. H NMR (CDCl₃) δ: 4.50 (dd, 1H, J = 9.7,

1.8 Hz), 3.84–3.77 (m, 2H), 3.65 (s, 3H), 3.47–3.39 (m, 2H),

2.67 (dd, 1H, J = 11.9, 7.2 Hz), 2.36–2.29 (m, 1H), 2.15–

2.00 (m, 4H), 1.96–1.76 (m, 3H), 1.67–1.58 (m, 3H), 1.50–

1.21 (m, 4H), 1.17 (t, 3H, J = 7.1Hz), 1.02–0.89 (m, 1H),

0.83 (d, 3H, J = 6.1 Hz). ¹³C NMR (CDCl₃) δ: 173.4 (s),

132.8 (s), 124.6 (s), 101.5 (d), 73.3 (d), 69.4 (d), 63.7 (t),

50.9 (q), 49.0 (d), 44.3 (d), 43.0 (d), 41.9 (d), 39.9 (d), 37.6

(t), 36.5 (t), 31.2 (t), 29.2 (t), 26.7 (t), 20.6 (q), 15.0 (q). LR-

MS (m/z (relative intensity)): 363 ([M⁺– H], 5), 318 (70),

301 (100). HR-MS calcd. for C₂₁H₃₁O₅: 363.2171; found:

363.2180. Anal. calcd. for C₂₁H₃₂O₅: C 69.20, H 8.85, O

15.5 (q). LR-MS (m/z (relative intensity)): 424 ([M⁺

–

EtOH], 35), 91 (100), 315 (72). HR-MS calcd. for C₂₆H₃₂O₅:

424.2250; found: 424.2248.

1

21.95; found: C 69.25, H 8.80. Tetracycle 49b: H NMR

(CDCl₃) δ: 4.95 (t, 1H, J = 7.2 Hz), 4.28–4.25 (m, 1H), 3.75

(dq, 1H, J = 9.8, 7.1 Hz), 3.66 (s, 3H), 3.46 (dq, 1H, J = 9.8,

7.1 Hz), 3.45–3.36 (m, 1H), 2.91 (t, 1H, J = 8.4 Hz), 2.49

(ddd, 1H, J = 13.6, 6.8, 4.2 Hz), 2.37–2.30 (m, 1H), 2.16–

2.05 (m, 2H), 2.02–1.77 (m, 4H), 1.69–1.58 (m, 4H), 1.56–

1.42 (m, 4H), 1.28–1.23 (m, 1H), 1.19 (t, 3H, J = 7.1 Hz),

0.92 (d, 3H, J = 7.1 Hz).

Tetracycle 54

Tetracycle 49b (42 mg, 0.116 mmol) was mixed with

imidazole (20 mg, 0.29 mmol), TBSCl (23 mg, 0.151 mmol)

in CH₂Cl₂(0.5 mL). The mixture was stirred overnight and

quenched with water. The aqueous layer was extracted with

CH₂Cl₂and the combined organic fractions were washed

with brine, dried over MgSO₄, filtered, and concentrated un-

der reduced pressure. Flash chromatography on silica gel

(hexanes:EtOAc, 6:1) of the crude product gave 54 (50 mg,

Tetracycle 51a

1

Followed the same procedure as per cycloadduct 41, start-

90%). H NMR (CDCl₃) δ: 4.93 (t, 1H, J = 7.2 Hz), 4.28–

ing with aldehyde 25. IR (cm^–1): 3499, 1738, 1434. ¹H NMR

4.25 (m, 1H), 3.76 (dq, 1H, J = 9.7, 7.1 Hz), 3.66 (s, 3H),

³Supplementary data (DUD no. 3454) may be purchased from the Depository of Unpublished Data, Document Delivery, CISTI, National Re-

search Council Canada, Ottawa, ON K1A 0S2, Canada (http://www.nrc.ca/cisti/irm/unpub_e.shtml for information on ordering electroni-

cally). CCDC 199040, 199041, 199042, and 199044 contain the supplementary data for this paper. These data can be obtained, free of

charge, via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge,

U.K.; fax +44 1223 336033; or deposit@ccdc.cam.ac.uk).

Spino et al.

107

3.45 (dq, 1H, J = 9.7, 7.1 Hz), 3.44–3.34 (m, 1H), 2.89 (t,

1H, J = 8.6 Hz), 2.43–2.27 (m, 2H), 2.18–2.07 (m, 1H),

2.05–1.82 (m, 6H), 1.70–1.55 (m, 3H), 1.51–1.44 (m, 3H),

1.20 (t, 3H, J = 7.1 Hz), 1.14–1.08 (m, 1H), 0.91 (d, 3H, J =

7.1 Hz), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). X-ray data

can be found in the supplementary material.³

6H), 3.03–2.96 (m, 2H), 2.09–1.90 (m, 3H), 1.87–1.75 (m,

1H), 1.57–1.45 (m, 2H), 1.15 (t, 3H, J = 7.1 Hz), 1.00 (s,

3H), 0.93 (d, 3H, J = 6.7 Hz), 0.80 (s, 3H). ¹³C NMR (C₆D₆)

δ: 174.4 (s), 173.3 (s), 172.1 (s), 135.7 (s), 134.2 (s), 98.4

(d), 63.2 (d), 62.4 (t), 51.7 (q), 51.5 (q), 51.2 (q), 50.9 (d),

44.5 (d), 41.0 (d), 33.0 (t), 36.8 (d), 36.1 (d), 34.4 (t), 32.3

(s), 27.2 (q), 26.8 (q), 19.4 (q), 15.4 (q). LR-MS (m/z (rela-

tive intensity)): 456 ([M + NH₄], 5), 437 ([M – 1], 30), 393

(100), 361 (70). HR-MS calcd. for C₂₃H₃₃O₈: 437.2175;

found: 437.2159.

Tetracycles 55a and 55b

Tetracycle 50b was reduced following the procedure for

the reduction of 48a. The alcohol 55a was isolated in 80%

yield (51 mg). ¹H NMR (CDCl₃) δ: 7.24 (d, 2H, J = 8.6 Hz),

6.86 (d, 2H, J = 8.6 Hz), 5.02 (t, 1H, J = 7.3 Hz), 4.55 (d,

1H, J = 11.9 Hz), 4.43–4.42 (m, 1H), 4.35 (d, 1H, J =

11.9 Hz), 3.84–3.74 (m, 1H), 3.79 (s, 3H), 3.68–3.60 (m,

2H), 3.48 (dq, 1H, J = 9.8, 7.0 Hz), 3.29 (dd, 1H, J = 11.1,

2.6 Hz), 2.36–2.31 (m, 1H), 2.17–1.89 (m, 9H), 1.76 (d, 1H

t, J = 13.8, 7.8 Hz), 1.57–1.39 (m 5H), 1.21 (t, 3H, J =

7.0 Hz), 1.09–0.98 (m, 1H), 0.95 (d, 3H, J = 7.1 Hz), 0.78–

0.72 (m, 1H). Alcohol 55a was protected, as per the protec-

tion of tetracycle 49b, which gave 55b (186 mg, 100%); mp

221.8°C. IR (cm^–1): 3007, 2929, 2856, 1612, 1513, 1249,

Conclusion

We have successfully completed an in-depth study of the

stereochemical aspect of the cycloadditions involved in the

diene-transmissive Diels–Alder strategy. The results clearly

show that the stereochemistry of both cycloadditions can be

controlled by proper positioning of susbtituents in the pre-

cursors. The study also procured useful information about

what structural features should be avoided in the

cycloaddition precursors that lead to lower selectivity. Im-

portantly, we were able to construct vinyl allene precursors

possessing the C-10 methyl group and showed that those

precursors underwent two highly stereoselective Diels–Alder

cycloadditions. We were not yet able, however, to effect the

third and last Diels–Alder reaction in those systems. Current

investigations are aimed at solving this difficulty.

1

1059, 1036. H NMR (CDCl₃) δ: 7.24 (d, 2H, J = 8.6 Hz),

6.85 (d, 2H, J = 8.6 Hz), 4.97 (t, 1H, J = 7.2 Hz), 4.54 (d,

1H, J = 11.9 Hz), 4.36 (d, 1H, J = 11.9 Hz), 4.21–4.19 (m,

1H), 3.87 (dd, 1H, J = 9.5, 4.4 Hz), 3.79 (s, 3H), 3.76 (dq,

1H, J = 9.9, 7.1 Hz), 3.58–3.56 (m, 1H), 3.48 (dq, 1H, J =

9.9, 7.1 Hz), 3.23 (t, 1H, J = 9.5 Hz), 2.25–2.20 (m, 1H),

2.12–1.88 (m, 9H), 1.66 (dt, 1H, J = 13.7, 7.3 Hz), 1.51 (bs,

3H), 1.47–1.33 (m, 2H), 1.19 (t, 3H, J = 7.1 Hz), 1.15–1.07

(m, 1H), 0.92 (d, 3H, J = 7.1 Hz), 0.87 (s, 9H), 0.01 (d, 6H,

J = 2.2 Hz). ¹³C NMR (CDCl₃) δ: 158.9 (s), 131.1 (s), 129.5

(s), 129.3 (d), 113.6 (d), 98.1 (d), 72.3 (d), 69.9 (t), 66.8 (d),

64.3 (t), 62.5 (t), 55.3 (q), 43.6 (d), 43.4 (d), 34.2 (d), 33.8

(d), 33.2 (t), 33.1 (d), 30.9 (t), 30.2 (t), 25.9 (q), 25.5 (t),

20.9 (t), 20.2 (t), 18.2 (s), 15.4 (q), 13.4 (q), –5.2 (q). LR-

MS (m/z (relative intensity)): 524 ([M⁺– C₂H₆O], 15), 74

(100), 403 (93). HR-MS calcd. for C₃₂H₄₈O₄Si: 524.3322;

found: 524.3318. X-ray data can be found in the supplemen-

tary material.³

Acknowledgements

We thank the Natural Sciences and Engineering Council

of Canada (NSERC) and the Université de Sherbrooke for fi-

nancial support.

References

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J. Am. Chem. Soc. 77, 2787 (1955).

Tetracycles 56

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tion was heated to reflux for 5 days. Methyl acrylate

(0.25 mL, 2.8 mmol) was added and reflux was continued

for 2 days. Methyl acrylate (0.25 mL, 2.8 mmol) was added

one last time and reflux was continued 1 more day and the

reaction was monitored by TLC. The solvent was evaporated

to give a yellow oil (150 mg). Flash chromatography on sil-

ica gel eluting with EtOAc and hexanes (20:80) gave 56 as a

colourless oil (82 mg, 66%) containing two separable

1

diastereomers. First isomer: H NMR (C₆D₆) δ: 4.82–4.71

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3.43–3.33 (m, 1H), 3.30 (s, 3H), 3.27 (s, 3H), 3.01–2.90 (m,

2H), 2.02–1.87 (m, 2H), 1.75–1.34 (m, 3H), 1.24 (t, 3H, J =

7.0 Hz), 1.20–0.98 (m, 1H), 0.95 (s, 3H), 0.94 (s, 3H), 0.83

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1738, 1435. ¹H NMR (C₆D₆) δ: 4.71 (m, 1H, J = 8.7,

5.4 Hz), 4.49 (dm, 1H, J = 7.3 Hz), 3.92–3.85 (m, 1H),

3.84–3.72 (m, 1H), 3.50 (s, 3H), 3.33–3.23 (m, 1H), 3.27 (s,

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108

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Article Doi

A diene-transmissive approach to the quassinoid skeleton

DOI: 10.1139/v02-196

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