A synthetic approach toward taxol analogs: Studies on the construction of the CD ring

Tetrahedron 60 (2004) 9179–9197

A synthetic approach toward taxol analogs: studies on the

construction of the CD ring

*

Tony K. M. Shing, Chi M. Lee and Ho Y. Lo

Department of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, China

Received 29 April 2004; revised 23 July 2004; accepted 23 July 2004

Available online 27 August 2004

Abstract—Tricycle 6, containing the CD ring of taxol, is constructed from (S)-(C)-carvone in 21 steps involving a Diels–Alder reaction

with isoprene, a Baeyer–Villiger oxidation, an Oppenaurer oxidation and Meerwein–Ponndorf–Verley reduction, a stereospeciﬁc Grignard

addition, and an intramolecular S_N2 reaction as the key steps.

1. Introduction

of taxol by total synthesis is unlikely to be economical.

Fortunately, the supply problem of taxol has been

adequately alleviated via semisynthesis from the naturally

occurring 10-deacetylbaccatin III (3),¹⁴a renewable

resource readily extractable in relatively high yield from

the needles of the European Yew Taxus baccata. On the

other hand, syntheses of structural analogs which might

exhibit similar or improved biological activity has been an

area of intense research.^2,15

Paclitaxel (taxol^w)¹(1), the ﬁrst member of a new group of

anticancer drugs termed taxanes,²is a naturally occurring

tetracyclic diterpenoid isolated³from the stem bark of

Paciﬁc Yew Taxus brevifolia. Taxol is recommended, in

combination with cis-platin, for the treatment of primary

ovarian cancer where standard platinum-containing therapy

has failed, of metastatic breast cancer where anthracycline-

containing thereapy has been unsuccessful or is inappropri-

ate, and of nonsmall cell lung cancer when surgery and

radiation therapy inappropriate.⁴The outstanding cytotoxic

activity of taxol is believed to arise from its unique function

as a mitotic inhibitor, hindering cell replication by

preventing microtubules from depolymerization back to

tubulin.²Docetaxel (taxotere^w)⁵(2), a synthetic analog⁶of

taxol (1), is recommended for use in advanced or metastatic

breast cancer where adjutant cytotoxic chemotherapy

(anthracycline or alkylation agent) has failed and in

advanced nonsmall cell lung cancer where ﬁrst line

chemotherapy has failed.⁴Docetaxel (2) is twice as active

as taxol (1) with regard to promoting the assembly and

stability of microtubules.⁷Initially, the natural scarcity of

taxol, the inefﬁcient methods available for its isolation and

its complex, strained framework attracted considerable

attention from synthetic chemists. To date, 6 total syntheses

of taxol have been published.^8–13The shortest route is that

reported by Wender et al.¹¹starting from (1R)-(C)-

verbenone and involving 37 steps in an overall yield of

about 0.37%. Consequently, an industrial-scale production

In our quest for the discovery of a structurally simpliﬁed,

synthetically accessible taxol analog which possesses a

comparable biological proﬁle, we started a project to

investigate a facile and ﬂexible construction of the CD

ring of taxol. The oxetane D ring is indispensable for

Keywords: Taxol analog; Diels–Alder reaction; Reduction.

* Corresponding author. Tel.: C85226096344; fax: C85226035057;

e-mail: tonyshing@cuhk.edu.hk

doi:10.1016/j.tet.2004.07.094

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T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

anti-cancer properties.¹⁶Our preliminary experiments have

shown that the EtAlCl₂catalyzed Diels–Alder reaction

between (R)-(K)-carvone and isoprene occurred prepon-

derantly in an anti orientation with respect to the

isopropylene group to give decalin 4 (Scheme 1).¹⁷Such a

decalin system 4, containing a stereo-deﬁned angular

methyl group at C-9, would be a valuable synthetic

precursor for the taxane C ring system. Regioselective

dihydroxylation at the endocyclic double bond of the

cycloadduct 4 followed by acetonation gave a crystalline

acetonide 5, the structure and stereochemistry of which

were conﬁrmed by an X-ray crystallographic analysis.¹⁷

Hence the stereochemical outcome of the Diels–Alder

reaction was established and to obtain the correct absolute

conﬁguration at the angular methyl group, (S)-carvone had

to be employed in our synthesis. This paper describes in

detail our effort in the stereocontrolled construction of the

CD ring with functionalities suitable for elaboration into

taxol analogs.¹⁸

2. Results and discussion

2.1. Initial synthetic plan

Scheme 2.

yield. The ratio of 10 to 11 was determined as 11.6:1 by

GC-MS. This mixture which could not be separated by ﬂash

column chromatography on silica gel was directly put to the

next step. Protection of the carbonyl group in octalones 10

Retrosynthetic analysis of tricycle 6 containing a function-

alized CD ring is shown in Scheme 2. We envisaged that

the oxetane ring could be readily installed from the ring

closure reaction between the hydroxyl groups at C-5 and C-

11 in triol 7. This triol could simply be obtained from

dihydroxylation of the double bond in allylic alcohol 8

which would be transformed from ketone 9 via an aldol

condensation with formaldehyde. The ketone 9 should be

readily accessible from cycloadduct 10 through functional

group manipulations. Finally intermolecular Diels–Alder

reaction of S-(C)-carvone with isoprene should provide

cycloadduct 10.

2.2. Synthesis of ketone 9

The synthesis of the suitably protected ketone 9 is shown in

Scheme 3. The intermolecular Diels–Alder reaction of S-(C)-

carvone with isoprene using EtAlCl₂as catalyst at room

temperature afforded a mixture of major anti- and minor

syn-cycloadducts, 10 and 11 respectively, in 92% combined

Scheme 3. Reaction conditions: (a) isoprene, EtAlCl₂, toluene (92%); (b)

ethylene glycol, p-TsOH, PhH, reﬂux (89%); (c) OsO₄, NMO, acetone–

H₂O (4:1) then NaIO₄(74%); (d) mCPBA, CH₂Cl₂, rt (93%); (e) DMP,

p-TsOH, CH₂Cl₂(92%); (f) (i) K₂CO₃, MeOH; (ii) PCC, CH₂Cl₂(90%).

Scheme 1. Reaction conditions: (a) EtAlCl₂, rt, 48 h (100%); (b) OsO₄

(cat.), NMO, rt, 24 h (80%); (c) acetone, p-TsOH, reﬂux, 5 h (70%).

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9181

and 11 with ethylene glycol gave acetal 12 together with its

diastereomer in 89% yield, which could not be fractionated

on column chromatography either. Stereoselective dihy-

droxylation of the acetal 12 with a catalytic amount of

osmium tetraoxide and N-methylmorpholine-N-oxide¹⁹

furnished a tetraol in which the more reactive (containing

a primary alcohol) exocyclic diol was selectively cleaved

with 1 equiv of sodium metaperiodate,²⁰and methyl ketone

13 could be isolated enantiopure in 74% overall yield from

acetal 12. Attack of OsO₄was expected to occur at the less

hindered convex face (b-face) of the bicyclic skeleton 12 to

give, exclusively, the endocyclic b-diol as indicated in

ketone 13.

Installing an oxygen functionality at C-5 was effected with

Baeyer–Villiger oxidation²¹of methyl ketone 13 using

meta-chloroperbenzoic acid to give acetate 14 in 93% yield.

At this point, protection of the free diol unit was necessary

since manipulation of both alcohols would not be carried out

in the present synthetic adventure. Thus, standard acidic

acetonation of the diol moiety in 14 furnished acetonide 15

in 92% yield. Removal of the acetyl blocking group in

acetate 15 with basic methanol followed by PCC oxidation

of the liberated alcohol gave the desired ketone 9 in 90%

overall yield.

Scheme 4. Reaction conditions: (a) LDA, K78 8C gaseous HCHO,

K30 8C; (b) CeCl₃, NaBH₄, MeOH, 0 8C (35%) (18:19Z1:2).

as a singlet whereas that in 23 resonated as a doublet. Since

enol ether 22 was the major product, deprotonation must

have taken place at C-6 preponderantly. The regioselectivity

of the deprotonation could be explained in terms of the

interaction between the lithium ion and the oxygen atom of

the cyclic acetal moiety. Hence, the methylene protons (H-

6) closer to the cyclic acetal would be preferentially

abstracted by LDA.

2.3. Attempted aldol condensation of ketone 9

Since the D ring is situated across C-4 and C-5,

homologation at C-4 was our next mission and the keto

group in 9 should be assisting the elaboration. Initially, the

obvious aldol condensation with formaldehyde,²²following

a regioselective deprotonation at C-4 of ketone 9, was

attempted in the hope to obtain enone 16. Under kinetically

controlled conditions, deprotonation of ketone 9 was

speculated to take place at C-4 since the cyclic acetal

blocking group should impose steric hinderance around C-6.

Unfortunately, this step was found to be problematic. Our

results (vide infra) indicated that standard strong base LDA

reacted with ketone 9 to generate an enolate which attacked

formaldehyde to yield enone 17 rather than the desired

enone 16 (Scheme 4).

The setback with LDA was addressed with other bases and

we turned to sodium N-hexamethyldisilazane (NaHMDS)

ﬁrst. However, only silyl enol ether 22 was produced in 50%

yield when ketone 9 was treated with NaHMDS and

TBSOTf. Since strong bases could not generate the desired

C-4,5 enolate, weaker bases such as postassium carbonate,

potassium tert-butoxide and sodium hydroxide were

investigated. However, reactions with these bases afforded

a stable enone 24 as the sole product, obtainable in high

yields (Scheme 6). Again, deprotonation took place at C-6

rather than at C-4 to form an enolate which immediately

caused b-elimination-opening of the cyclic acetal. Since all

The enone 17 was found to be unstable at ambient

conditions and a subsequent reduction was carried out in

order to provide a stable compound. Thus Luche’s

reduction²³of enone 17 immediately after the aldol

condensation gave a mixture of diasteromeric allylic

alcohols 18 and 19 in a respective ratio of 1:2. Since

NMR spectral analysis could not conﬁdently conﬁrm the

position of the methylene group inserted, two additional

experiments were performed. As shown in Scheme 5, enone

17 was reduced with sodium borohyride in the absence of

cerium chloride to give saturated alcohol 20 and its

diastereomer 21 in 23% overall yield from 9. An X-ray

crystallographic analysis (CCDC-185889) of a single

crystal from alcohol 20 conﬁrmed its structure which

proved that the aldol condensation had occurred at C-6. On

the other hand, treatment of ketone 9 with LDA followed by

trapping the resultant enolate with TBSOTf furnished silyl

enol ethers 22 and 23 in a ratio of 2:1 and in a combined

yield of 48%. Their structures were readily differentiated by

¹H NMR spectroscopy as the oleﬁnic proton in 22 appeared

Scheme 5. Reaction conditions: (a) NaBH₄, MeOH, 0 8C (23%); (b) LDA,

K78 8C, TBSOTf (48%) (22:23Z2:1); (c) NaHMDS, K78 8C, TBSOTf

(50%) 22 only.

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T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

Scheme 7.

approach, the hydroxyl at C-5 would act as a nucleophile

rather than a leaving group, which is different from the

8-13

strategy reported

in the 6 total syntheses.

2.5. Synthesis of a highly functionalized precursor 33

Scheme 6. Reaction conditions: (a) Et₃N, TBSOTf, K78 8C (88%); (b)

NaOH, K₂CO₃or BuOK, THF 0 8C (83%); (c) Eschensomer’s salt, Et₃N,

CH₂Cl₂, rt; (d) CeCl₃, NaBH₄, MeOH, 0 8C (40% from 9).

The new approach started with silyl enol ether 23 which was

hydroxylated using Oxone^wand acetone²⁸to give

4-hydroxy ketone 28 in 73% yield (Scheme 8). A 1-carbon

homologation was required on C-4 and we planned to

interconvert the ketone and hydroxy functionality between

C-4 and C-5 so that the keto group at C-4 would be

amenable for such elaboration.

metal bases could not furnish the desired enolate in good

yields, organic bases might be suitable candidates to prevent

the chelation effect of the cyclic acetal. Toward this end,

ketone 9 was treated with Et₃N and TBSOTf²⁴at K78 8C

and we were delighted to learn that the desired silyl enol

ether 23 could be obtained pure in 88% yield as the sole

product (Scheme 6). With the regio-correct masked enolate

23 in hand, reaction with formaldehyde or S-trioxane under

the Mukaiyama conditions²⁵should provide an aldol

adduct. Unfortunately, after tremendous experimentations,

the Mukaiyama reaction of 23 under various conditions

(Lewis acids, solvents and temperatures) were all

unsuccessful.

This was accomplished by an intramolecular redox reaction:

Oppenaurer oxidation and Meerwein–Ponndorf–Verley

reduction²⁹of 4-hydroxy ketone 28 using Al(OiPr)₃as

catalyst afforded 5-hydroxy ketone 27 in 79% yield. We

believed that the transformation was thermodynamically

controlled as the 1,3-diaxial interaction between the OH-4

and the angular methyl group was alleviated from 28 (Fig. 1).

To our knowledge, this is the ﬁrst example of a direct

interconversion between hydroxy and ketone groups

intramolecularly in the presence of Al(OiPr)₃. It was

reported that at least 1 equiv of Al(OiPr)₃was required in

An alternative approach towards the addition of a methylene

unit at the a-position of a carbonyl group could in principle

be achieved with Eschenmoser’s salt.²⁶Ketone 9, in the

absence of base, gave no reaction with the Eschenmoser’s

salt in reﬂuxing CH₂Cl₂or THF. With the addition of

Et₃N,²⁷the a-methylenation did occur but was unbearably

sluggish in THF. Interestingly, the reaction proceeded at a

moderate rate in CH₂Cl₂. However, both C-4 and C-6 were

aminomethylated and elimination occurred concommitantly

to give an enone which was unstable upon isolation. Its

stable derivative, amenable for characterization, was

obtained by Luche’s reduction²³of the carbonyl group,

giving dialkenyl alcohol 25 in 40% overall yield. However,

careful control of the reaction conditions could not afford

the desired enone 16. On the other hand, silyl enol ether 23

was inert towards Eschenmoser’s salt. Since diene alcohol

25 could not contribute to the synthesis of the CD ring of

taxol, this approach of direct functionalization of C-4 was

therefore abandoned and an alternative avenue had to be

pursued.

2.4. Revised synthetic plan

The retrosynthesis of a new approach is summarized in

Scheme 7. Oxetane 6 would be constructed form triol 26 in

which the functionalities at C-4 could be installed by

inserting a hydroxymethyl group to a-hydroxy ketone 27.

The ketone 27 would be derived from silyl enol ether 23 via

a series of functional group manipulations. In this new

Scheme 8. Reaction conditions: (a) buffer, oxone, acetone, CH₃CN (73%);

(b) Al(OiPr)₃toluene (79%); (c) imidazol, DMAP, TBSCl, CH₂Cl₂(93%);

(d) see Table 1.

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9183

Figure 1. Proposed mechanism for the transformation of 28 into 27. The cyclic acetal is not shown for clarity reason.

intermolecular reactions.²⁹In our intramolecular case, the

optimized yield was obtained with 0.5 equiv of Al(OiPr)₃

and the yield decreased dramatically with more than this

amount. An X-ray crystallographic analysis (CCDC-

185888) of a single crystal of 27 conﬁrmed its structure

and stereochemistry. Subsequent protection of the

5-hydroxy ketone 27 with TBSCl led to silyl ether ketone

29 in 93% yield. At this point, insertion of a hydroxymethyl

group to the C-4 carbonyl group by nucleophilic addition

became feasible. From a list of nucleophiles, TMSCN³⁰

should be a good choice since the nitrile moiety could be

reduced to an aldehyde functionality by a number of

reducing agents. Thus ketone 29 reacted with TMSCN at

room temperature in the presence of 1.5 equiv (optimized)

of AlCl₃to give exclusively hydroxynitrile 30 in 66% yield

whose stereochemistry at C-4 was conﬁrmed undesirable by

an X-ray crystallographic analysis (CCDC-185890). Inter-

estingly, running the experiment at K35 8C afforded the

desirable hydroxynitrile 31 and silyl ether nitrile 32 in 83%

combined yield with a ratio of 3:1, respectively. These

results revealed that at room temperature i.e. under

thermodynamically controlled conditions, the bulkier nitrile

group preferred to occupy the equatorial position and

evaded the 1,3 diaxial interaction with the axial angular

methyl group. On the other hand, under kinetically

controlled conditions at K35 8C, the cyanide preferred to

attack from the less hindered b-face due to the steric

demand imposed by the cis-ring conformation. The yield of

silyl ether nitrile 32 increased with the amount of AlCl₃used

and the best yield of 32 was achieved with 5 equiv of AlCl₃

(Table 1). It was clear that the hydroxy group of nitrile 31

could only be trimethylsilylated under forcing conditions.

or Super hydride)^31aor basic hydrolysis conditions^31bcould

not reduce the nitrile group in 31 or 32 to an aldehyde or

hydrolysed to the corresponding acid. For a-hydroxy nitrile

31, the basic conditions caused retro-cyanohydrin formation

to occur, affording the silyl ether ketone 29 in quantitative

yield. The vicinity of the tertiary nitrile group might be

sterically hindered by the angular methyl and the adjacent

TBS group. This route was therefore abandoned and a

Grignard reagent served as a hydroxymethyl equivalent was

investigated. It has been well-known that Grignard reagent

can attack a carbonyl group stereospeciﬁcally.³²Vinyl

magnesium bromide was chosen because the alkene moiety

could be easily transformed into an aldehyde via a

dihydroxylation-glycol cleavage protocol. However,

a-silyl ether ketone 29 did not react the Grignard reagent

attributable to the bulkiness of the TBS group. A

straightforward method to alleviate this problem was to

replace the TBS ether group with the less bulky TMS ether.

Hence, transient protection of the free alcohol in 5-hydroxy

ketone 27 as a TMS ether was followed by the addition of

vinyl magnesium bromide, giving the corresponding allylic

alcohol that was hydrolyzed with dilute HCl to give diol 33

in 90% overall yield (Scheme 9). It is noteworthy that the

Grignard addition was stereospeciﬁc and only one stereo-

isomer was isolated in quantitative yield. The stereochem-

istry of the tertiary alcohol in diol 33 was conﬁrmed

desirable by an X-ray crystallographic analysis (CCDC-

185891).

The onward steps were the selective protection of the

secondary alcohol at C-5 followed by acetylation of the

steric demanding tertiary hydroxy group at C-4. Thus,

selective benzylation of the secondary alcohol in 33

afforded benzyl ether 34 in 86% yield without incident.

To provide a variant for acetylation, selective silylation was

also performed to furnish silyl ether 35 in 90% yield. To our

regret, we could not acetylate the tertiary alcohol in 34 or 35

under various conditions and only unidentiﬁed decompo-

sition products were isolated. Other research group³³also

encountered difﬁculty in carrying out acetylation in

structurally similar systems. It was observed that the

decomposition pattern of silyl ether 35 and benzyl ether

34 under various acetylation conditions were similar so only

silyl ether 35 was selected for further studies. The reason for

The next step was the reduction of the nitrile group. To our

disappointment, a number of reducing agents (DIBAL, LAH

Table 1. Reactions of ketone 29 with TMSCN promoted by AlCl₃

Conditions

Isolated yield (%)

66

Product ratio 30:31:32

TMSCN, 1.5 equiv

AlCl₃, rt, 10 min

TMSCN, 1.5 equiv

AlCl₃, K35 8C, 2 h

TMSCN, 5 equiv

AlCl₃, K35 8C, 2 h

1:0:0

83

80

1:3:0

2:1:5

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Scheme 10. Reaction conditions: (a) NaH, BnBr, THF, reﬂux (86%); (b)

OsO₄, NMO, acetone–H₂O (4:1), then NaIO₄(78%); (c) 10% Pd/C, EtOH,

H₂(78%); (d) NaBH₄, MeOH, 0 8C (80%); (e) (i) Et₃N, MsCl, CH₂Cl₂,

0 8C; (ii) NaH, THF, reﬂux (92%); (f) (i) Et₃N, MsCl, CH₂Cl₂, 0 8C; (ii)

DBU, toluene, reﬂux (92%).

Scheme 9. Reaction conditions: (a) (i) Et₃N, TMSCl, CH₂Cl₂; (ii)

vinylMgBr, THF, K78 8C; (iii) 1 M HCl (90%); (b) NaH, BnBr, THF,

50 8C (86%); (c) imidazole, DMAP, TBSCl, CH₂Cl₂(90%); (d) OsO₄,

NMO, then NaIO₄CH₂Cl₂:H₂O (8:1) (78%); (e) Pyr, DMAP, Ac₂O, reﬂux

(35%).

epoxide 42 could not be induced to undergo rearrangement

to the desired oxetane 41.³⁵In principle, the rearrangement

would occur if the C-5 hydroxyl and the leaving alkoxy

group were arranged in an anti-periplanar fashion. How-

ever, it appeared that such alignment was not possible due to

the ring strain of the C-ring. The formation of epoxide 42 as

the sole product hinted at the importance of protecting the

tertiary alcohol before the displacement reaction.

the unsuccessful acetylation was attributed to steric

hindrance. We therefore postponed the acetylation stage

until a less bulky aldehyde was installed from oxidative

cleavage of the double bond. Accordingly, we transformed

silyl ether 35 into TBS aldehyde 36 by the conventional

dihydroxylation-glycol cleavage protocol³⁴in 78% yield.

Acetylation of the tertiary alcohol in 36 under various

conditions was then examined. Only the classical method

(Ac₂O and DMAP in reﬂuxing pyridine) gave the desirable

acetate aldehyde 37 in 35% yield accompanied by a number

of unidentiﬁed side-products. The low yielding acetylation

probably resulted from the steric factor and discouraged us

to further investigate this route. Acetylation of the tertiary

alcohol was scheduled to occur until the D-ring had been

assembled.

At this stage, we were tempted to make use of the

trimethylorthroacetate³⁶chemistry to construct the oxetane

ring 6 (Scheme 11). Orthoester 43 would be assembled from

the corresponding diol and it might serve the purpose of

acetylation and oxetane formation since the C-5 hydroxyl

could attack the orthoester to provide the oxetane and the

C-4 acetate concomitantly.

As shown in Scheme 10, benzylation of the diol 33 in THF

at reﬂux gave dibenzyl ether 38 in 86% yield. Dihydroxyla-

tion of the double bond in 38 followed by oxidative

cleavage of the resulting diol afforded dibenzyl aldehyde 39

in 78% overall yield. Catalytic hydrogenolysis of dibenzyl

ether 39 gave aldehyde diol 40 (78% yield) which under-

went hydride reduction to generate triol 26 in 80% yield. To

continue with our synthetic avenue, we allowed the tertiary

hydroxyl unprotected in a hope that it would not participate

in the intramolecular displacement during the oxetane ring

formation. Thus selective mesylation of the primary alcohol

in 26 gave the corresponding mesylate which would be

attacked by the secondary C-5 alcohol to form oxetane 41 or

by the tertiary alcohol at C-4 to produce epoxide 42.

Unluckily, the results indicated that the formation of the

epoxide 42 was thermodynamically more stable. Even at

prolonged reﬂux or with an excess amount of NaH or DBU,

Scheme 11.

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9185

As shown in Scheme 12, the aldehyde moiety in 36 was

reduced to give diol 44 in 79% yield. Trimethylorthoacetate

reacted with diol 44 in the presence of a stiochiometric

amount of p-TsOH to give orthoester 45. A catalytic amount

of p-TsOH did not cause the reaction to take place. To our

surprise, orthoester 45 was unstable even in the reaction

mixture and the 5-membered ring readily hydrolyzed to

form tertiary acetate 46. Furthermore, another reaction was

then involved which interfered with the isolation of the

tertiary acetate 46. Partial migration of the acetyl group

from the tertiary position to the primary position took place

readily in the reaction mixture to give a mixture of the

tertiary acetate 46 and primary acetate 47. The life time of

the tertiary acetate 46 was too short for synthetic

manipulation as facile rearrangement of tertiary acetate 46

to primary acetate 47 occurred quickly in weakly basic

conditions (Et₃N/CH₂Cl₂). It was also found that 46 could

be converted into 47 completely in silica gel so that the

primary acetate 47 could be formed in 81% overall yield

from diol 44. Despite failure to obtain the desirable

orthoester 45, the acetate 47 could be a good candidate for

a facile conversion into a CD ring precursor, i.e. oxirane 48.

Indeed, the TBS group in silyl ether 47 was smoothly erased

with TBAF and the liberated C-5 hydroxyl was esteriﬁed

with MsCl to give a mesylate. Intramolecular S_N2

displacement promoted by DBU in reﬂuxing toluene

followed by methanolysis of the acetate ester furnished

epoxide 48 in 57% overall yield from silyl ether 47.

The next hurdle to overcome was the isomerization of the

oxirane moiety in 48 to an oxetane. Ideally, the freely

rotating primary hydroxyl group in 48 should attack the

epoxide at the less hindered C-5 in an anti-periplanar

fashion to give oxetane 41. However, attempts to isomerize

the epoxide in 48 to the oxetane under different conditions

failed. Bases such as CsCO₃or K₂CO₃in reﬂuxing DMF or

DBU in reﬂuxing toluene gave no observable reactions.

t

Reactions with BuOK, NaH and LDA gave unidentiﬁed

side-products. At this stage, we considered the possibility to

invert the C-5 stereocenter in diol 33 with a bromide so that

the C-11 primary hydroxyl, accessible from a dihydroxyla-

tion-glycol cleavage-reduction sequence, could displace the

Scheme 12. Reaction conditions: (a) NaBH₄, MeOH, 0 8C (79%); (b) trimethylorthoacetate, p-TsOH, CH₂Cl₂, then SiO₂(81%); (c) TBAF, THF; (d) Et₃N,

MsCl, 0 8C; (e) DBU, toluene, reﬂux; (f) K₂CO₃, MeOh (57% from 47); (g) Et₃N, MsCl, 0 8C (85%); (h) LiBr, CH₃CN (74%); or Bu₄NBr, PhH, reﬂux (40%);

(i) (i) OsO₄, NMO, then NaIO₄; (ii) NaBH₄, MeOH, 0 8C (72%).

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bromide to give oxetane 41. Thus, selective mesylation of

diol 33 gave monomesylate 49 and unfortunately, bromide

ion generated by LiBr in CH₃CN or Bu₄NBr in benzene

could not displace the mesylate group. Instead, the basic

character of these reagents induced the tertiary hydroxyl to

attack the mesylate group to form epoxide 50 in 74% and

40% yield, respectively. It was interesting to ﬁnd that

epoxide 50 could be transformed into oxirane 48 by a

dihydroxylation-glycol cleavage-reduction sequence in

72% overall yield (Scheme 12).

benzyl ether in oxetane 53 with 10% palladium-on-charcoal

in ethanol afforded alcohol 41 in 93% yield without

incident. Finally, acetylation of the tertiary hydroxyl

group was successfully achieved with Ac₂O and DMAP in

reﬂuxing pyridine to give the CD ring of taxol 6 in 56%

yield. Thus the tricycle 6 was constructed from (S)-(C)-

carvone in 21 steps with an overall yield of 4%.

n

In summary, we have presented a facile and stereocontrolled

synthetic avenue for the construction of the functionalized

CD ring in taxol. It is noteworthy that the BC ring in tricycle

6 or 41 is cis-fused and these tricycles may be versatile

precursors for the preparation of taxol analogs with cis-

fused BC rings and would provide excellent opportunities

for structure-activity studies. The research in this direction

is in progress.

2.6. Synthesis of the CD ring of taxol 6

The above results indicated that the tertiary alcohol had to

be blocked before oxetane formation could be realized.

After considering all the synthetic intermediates, we

envisaged that retaining the tertiary benzyl group in

dibenzyl ether 39 would be a good candidate for a successful

venture.

3. Experimental

3.1. General

Thus, catalytic and selective hydrogenolysis of the second-

ary benzyl group over the tertiary counterpart in dibenzyl

ether 39 was investigated. After considerable efforts, it was

observed that the choice of solvent could affect the rate and

regioselectivity of the hydrogenolysis in our system. Only

5% palladium-on-charcoal in ethyl acetate could accom-

plish the task whereas the reaction in ethanol or THF

showed very little selectivity. Under carefully controlled

and monitored conditions, selective deprotection of the

secondary benzyl group in 39 afforded, at best, aldehyde 51

in 70% yield, accompanied by the over-reduced diol 40 in

19% yield as shown in Scheme 13. Obviously, the

selectivity was attributable to the less hindered secondary

benzyl group. Subsequent reduction of the aldehyde in 51

with sodium borohydride in methanol furnished diol 52 in a

quantitative yield. Selective mesylation of the primary C-11

hydroxyl group with MsCl and 2,4,6-collidine³⁷at 0 8C

gave a mesylate intermediate that was followed by an

intramolecular S_N2 displacement³⁸to give oxetane 53 for

the ﬁrst time in 83% yield. Hydrogenolysis of the tertiary

Melting points are reported in Celsius degrees and are

uncorrected. Optical rotations were measured at 589 nm.

GC-MS studies were performed on a GC with fused silica

capillaries column and a GC/MS system with ion trap

detector (ITD), injector temperature (250 8C), transfer line

temperature (250 8C), oven temperature raised from 80 to

180 8C in a rate of 5 8C per min, EIMS by 70 eV electron

beam. IR spectra were recorded on FT-IR spectrometer as a

thin ﬁlm or on a KBr disk. NMR spectra were measured at

300.13 MHz (¹H) or at 75.47 MHz (¹³C) in CDCl₃

solutions, unless stated otherwise. All chemical shifts

were recorded in ppm relative to tetramethylsilane (dZ

0.0). Spin–spin coupling constants (J) were measured

directly from the spectra. MS and HRMS were performed

at the Department of Chemistry, The Chinese University of

Hong Kong, Hong Kong, China. Carbon and hydrogen

elemental analyses were carried out by MEDAC Ltd,

Department of Chemistry, Brunel University, Uxbridge,

U.K. All reactions were monitored by analytical TLC on

aluminum precoated with silica gel 60F₂₅₄(E. Merck) and

compounds were visualized with a spray of 5% w/v

dodecamolybdophosphoric acid in EtOH and subsequent

heating. E. Merck silica gel 60 (230–400 mesh) was used for

ﬂash column chromatography. All solvents were reagent

grade unless otherwise stated. Toluene, benzene, and THF

were freshly distilled from Na/benzophenone ketyl under

nitrogen. CH₂Cl₂was freshly distilled from CaH₂under N₂.

Diisopropylamine was freshly distilled from Na under N₂.

Other reagents were purchased from commercial suppliers

and used without puriﬁcation. All hexanes used are

n-hexane.

3.1.1. Octalone 10 and 11. A molar solution of EtAlCl₂in

hexane (1.5 mL, 1.5 mmol) was added to a solution of S-(C)-

carvone (751 mg, 5.0 mmol) in dry toluene (20 mL). The

solution was stirred at room temperature under N₂for

20 min for complexation. Isoprene (2.0 mL, 15.0 mmol)

was added and the resulting solution was stirred at room

temperature under N₂for 28 h. Ice water was added to the

reaction mixture which was extracted with Et₂O (3!). The

combined organic extracts were dried (MgSO₄), ﬁltered and

Scheme 13. Reaction conditions: (a) 5% Pd/C, ethyl acetate, H₂(70% for

51, 19% for 40); (b) NaBH₄, MeOH, 0 8C (100%); (c) (i) 2,4,6-collidine,

MsCl, 0 8C; (ii) NaH, THF, reﬂux (83%); (d) 10% Pd/C, EtOH, H₂(93%);

(e) Pyr, DMAP, Ac₂O (56%).

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9187

concentrated. The residue was fractionated by column

chromatography (hexanes–Et₂O, 30:1) to give a mixture of

octalones 10 and 11 as colorless oils (1.02 g, 92%, the ratio

of 10:11 was determined by GC-MS to be 11.6:1):

[a]²_D⁰ZC3.7 (c 0.27, CHCl₃); R_f0.63 (hexanes–Et₂O,

10:1); IR (thin ﬁlm) 2926, 1703, 1637, 896 cm^K1; ¹H NMR

d 1.15 (s, 3H), 1.62 (s, 3H), 1.73 (s, 3H), 4.69 (brs, 1H), 4.81

(brs, 1H), 5.30 (brs, 1H); ¹³C NMR d 21.9, 23.5 24.2, 30.8,

32.8, 33.4, 38.1, 41.6, 41.9, 47.5, 111.7, 118.5, 131.8, 147.9,

215.6; MS (EI) m/z (relative intensity) 218 (M^C, 16.9), 91

(100). Anal. calcd for C₁₅H₂₂O: C, 82.52; H, 10.16. Found:

C, 82.38; H, 10.10.

(hexanes–EtOAc, 1:2) gave acetate 14 as a white solid

(7.56 g, 93%): mp 179–180 8C; [a]²_D⁰ZK15.1(c 0.37,

CHCl₃); R_f0.53 (EtOAc); IR (thin ﬁlm) 3461, 2966,

1732, cm^K1; ¹H NMR d 1.13 (s, 3H), 1.24 (s, 3H), 2.02 (S,

3H), 3.73 (dd, JZ5.4, 11.1 Hz, 1H), 3.92 (m, 4H), 4.96 (m,

1H); ¹³C NMR d 21.4, 26.7, 27.4, 31.6, 36.2, 36.3, 37.8,

40.5, 41.6, 63.9, 64.6, 68.9, 71.4, 72.3, 112.9, 170.4; MS

(EI) m/z (relative intensity) 314 (M^C, 4), 271 (7), 255 (100),

236 (41). Anal. calcd for C₁₆H₂₆O₆: C, 61.13; H, 8.34.

Found: C, 61.42; H, 8.41.

3.1.5. Acetonide 15. To a stirred solution of acetate 14

(14.4 g, 45.9 mmol) in dry CH₂Cl₂(350 mL) was added 2,2-

dimethoxypropane (20 mL, 161 mmol) and a catalytic

amount of p-TsOH (10 mg). The reaction mixture was

stirred for 24 h at room temperature under N₂and was then

diluted with Et₂O. The organic phase was washed with

saturated NaHCO₃, dried (MgSO₄) and ﬁltered. Concen-

tration of the ﬁltrate gave a residue that was fractionated by

column chromatography (hexanes–Et₂O, 2:1) to afford the

acetonide 15 as a colorless oil (15.1 g, 92%): [a]²_D⁰ZC21.9

(c 1.5, CHCl₃); R_f0.56 (hexanes–Et₂O, 1:2); IR (thin ﬁlm)

3.1.2. Acetal 12. The aforedescribed mixture of octalones

10 and 11 (20.0 g, 0.092 mol), ethylene glycol (39.7 g,

0.64 mol) and p-TsOH (10 mg) were dissolved in benzene

(350 mL) and the resulting solution was heated at reﬂux for

12 h with continuous azeotropic removal of water by means

of a Dean–Stark trap. The cooled mixture was then washed

with aqueous NaHCO₃, saturated brine, dried over MgSO₄

and ﬁltered. The ﬁltrate was concentrated in vacuo and the

residue was fractionated by column chromatography

(hexanes–Et₂O, 30:1) to give acetal 12 as a colorless oil

(21.5 g, 89%): [a]_D²⁰ZC5.8 (c 0.2, CHCl₃); R_f0.68

(hexanes–Et₂O, 10:1); IR (thin ﬁlm) 2923, 2879, 1644,

1

2980, 1736 cm^K1; H NMR d 1.28 (s, 3H), 1.29 (s, 3H),

1.36 (s, 3H,), 1.45 (s, 3H), 1.84 (dd, JZ6.3, 12.3 Hz, 1H),

1.91 (d, JZ3.3 Hz, 1H), 1.96 (brs, 1H), 2.01 (s, 3H), 2.18

(m, 1H), 3.87 (m, 2H), 3.96 (m, 1H), 4.04 (m, 2H), 4.91 (m,

1H); ¹³C NMR d 21.3, 25.9, 26.3, 27.4, 27.6, 30.0, 32.7,

34.2, 34.9, 38.9, 39.8, 63.4, 65.1, 69.2, 79.8, 80.5, 106.6,

113.0, 170.3; MS (FAB) m/z (relative intensity) 354 ([M]^C,

5), 339 ([MKCH₃]^C, 25), 295 (100); HRMS (FAB) calcd

for C₁₉H₃₁O₆[MCH] 355.2120, found 355.2118.

1

886 cm^K1; H NMR d 0.84 (s, 3H), 1.60 (s, 3H), 1.66 (s,

3H), 3.89 (brs, 4H), 4.70 (brs, 2H), 5.32 (brs, 1H); ¹³C NMR

d 17.9, 20.8, 23.7, 30.0, 33.8, 33.9, 35.2, 37.6, 39.8, 41.6,

64.9, 65.1, 108.5, 113.3, 117.8, 130.4, 149.5; MS (EI) m/z

(relative intensity) 262 (M^C, 17), 91 (100); HRMS (EI)

calcd for C₁₇H₂₆O₂[M] 262.1927, found 262.1917.

3.1.3. Methyl ketone 13. A solution of acetal 12 (11.26 g,

43 mmol), NMO, (29 g, 215 mmol), and OsO₄(50 mg) in

83% aqueous acetone (700 mL) was stirred at room

temperature for 9 d. A solution of NaIO₄(13.8 g,

64.5 mmol) in water (20 mL) was added at room tempera-

ture and precipitation occurred. The reaction mixture was

stirred for 1 h and was then quenched with saturated

aqueous Na₂S₂O₃. The resulting mixture was stirred for 24 h

and was extracted with EtOAc (4!). The combined extracts

were dried (MgSO₄) and ﬁltered. Concentration of the

ﬁltrate under vacuum followed by ﬂash column chroma-

tography (hexanes–EtOAc, 1:1) afforded methyl ketone

13 as a white solid (9.5 g, 74%): mp 170–171 8C;

[a]²_D⁰ZC2.9 (c 0.3, CHCl₃); R_f0.43 (EtOAc); IR (thin

3.1.6. Ketone 9. Deprotection of the acetyl group in

acetonide 15 was effected by adding K₂CO₃(29.4 g,

213 mmol) to a solution of 15 (15.1 g, 42.7 mmol) in

MeOH (350 mL). The reaction mixture was stirred for 4 h at

room temperature and then concentrated in vacuo. The

residue was dissolved in Et₂O and H₂O, followed by

acidiﬁcation with 4 N aq. HCl until neutral. The solution

was extracted with CH₂Cl₂(3!) and the combined organic

extracts were washed with brine, dried (MgSO₄) and

ﬁltered. Concentration of the ﬁltrate gave a white solid

residue which was directly subjected to the next step.

To a stirred solution of the white residue in dry CH₂Cl₂

˚

(400 mL) was added a mixture of 3 A molecular sieves

1

ﬁlm) 3479, 2966, 1703, 1042 cm^K1; H NMR d 1.07 (s,

3H), 1.24 (s, 3H), 1.39 (d, JZ9.9 Hz, 1H), 1.662 (m,

2H), 2.11 (s, 3H), 2.71 (m, 1H), 3.75 (dd, JZ5.7,

14.2 Hz, 1H), 3.91 (brs, 4H); ¹³C NMR d 26.4, 27.2,

27.8, 28.3, 32.1, 36.4, 37.7, 40.1, 41.4, 44.8, 63.8, 64.3,

71.3, 71.9, 112.5, 211.3; MS (FAB) m/z (relative

intensity) 299 ([MCH]^C, 4), 281 (3), 255 (100).

Anal. calcd for C₁₆H₂₆O₅: C, 64.41; H, 8.78. Found:

C, 64.36; H, 8.93.

(70 g) and PCC (46 g, 213 mmol). The reaction mixture was

stirred for 3 h at room temperature under N₂and then

ﬁltered through a pad of Celite and silica gel. The residue

was eluted with Et₂O. Concentration of the ﬁltrate followed

by ﬂash column chromatography (hexanes–Et₂O, 1:1) gave

ketone 9 as a white solid (153 mg, 90%): mp 69–70 8C;

[a]²_D⁰ZC40.5 (c 0.4, CHCl₃); R_f0.53 (hexanes–Et₂O, 1:2);

1

IR (thin ﬁlm) 2976, 1720 cm^K1; H NMR d 1.27 (s, 3H),

1.30 (s, 3H), 1.34 (s, 3H), 1.43 (s, 3H), 1.61–1.70 (m, 2H),

1.77 (d, JZ4.2 Hz, 1H), 1.84 (dd, JZ3.3, 15.3, 1H), 2.12–

2.20 (m, 2H), 2.45 (bd, JZ16.2 Hz, 1H), 2.61 (dd, JZ7.5,

15.0 Hz, 2H), 3.93 (m, 4H), 4.13 (t, JZ3.6 Hz, 1H); ¹³C

NMR d 25.9, 26.2, 27.5, 27.6, 30.0, 34.3, 39.3, 41.1, 44.0,

46.4, 64.3, 64.9, 79.4, 79.7, 106.8, 113.6, 208.5; MS (FAB)

m/z (relative intensity) 311 ([MCH]^C, 3), 149 (100);

HRMS (FAB) calcd for C₁₇H₂₇O₅[MCH] 311.1858, found

3.1.4. Acetate 14. m-Chloroperbenzoic acid (9.1 g,

52 mmol) was added to a stirred solution of methyl ketone

13 (7.84 g, 26 mmol) in CH₂Cl₂(150 mL). The solution was

stirred at room temperature for 72 h. The milky solution was

cooled with an ice bath and the precipitated m-chloroben-

zoic acid was removed by ﬁltration. The ﬁltrate was

concentrated and upon puriﬁcation by ﬂash chromatography

9188

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

311.1854. Anal. calcd for C₁₇H₂₆O₅: C, 65.78; H, 8.44.

Found: C, 65.89; H, 8.61.

over a period of 15 min. The reaction mixture was stirred for

30 min and was then quenched with saturated NH₄Cl. The

aqueous phase was extracted with CH₂Cl₂(3!) and the

combined organic extracts were washed with brine, dried

(MgSO₄) and ﬁltered. Concentration of the ﬁltrate followed

by column chromatography (hexanes–Et₂O, 1:1) gave

alcohol 20 as a white solid (24 mg, 23%). A single crystal

for X-ray crystallography was obtained from hexanes–Et₂O,

10:1.

3.1.7. Allylic alcohols 18 and 19. To a stirred solution of

diisopropylamine (0.23 mL, 1.61 mmol) in dry THF (4 mL)

was added a 1.6 M solution of n-butyllithium in n-hexane

(1.0 mL, 1.61 mmol) under N₂at K78 8C. The reaction

mixture was stirred for 15 min and a solution of ketone 9

(100 mg, 0.323 mmol) in dry THF (4 mL) was then added

dropwise. The reaction mixture was stirred for 30 min at

K78 8C, warmed to K30 8C and an excess amount of

HCHO (1 g) was added over a period of 20 min. The

reaction was quenched with saturated NH₄Cl and extracted

with CH₂Cl₂(3!). The combined organic extracts were

washed with brine, dried (MgSO₄) and ﬁltered. Concen-

tration of the ﬁltrate followed by puriﬁcation with a short

silica gel column chromatography (hexanes–Et₂O 2:1) gave

the enone 17 which was used in the next reaction

immediately.

Data for alcohol 20: mp 151–152 8C; [a]²_D⁰Z31.9 (c 0.3,

CHCl₃); R_f0.32 (hexanes–Et₂O 1:2); IR (thin ﬁlm) 3514,

1

2936, 1210 cm^K1; H NMR d 1.27 (s, 3H), 1.30 (s, 3H),

1.34 (s, 3H), 1.43 (s, 3H), 1.65 (m, 2H), 1.77 (d, JZ4.2 Hz,

1H), 1.84 (dd, JZ3.3, 15.3 Hz, 1H), 2.18 (m, 2H), 2.45 (bd,

JZ16.2 Hz, 1H), 2.61 (dd, JZ7.5, 15.0 Hz, 2H), 3.93 (m,

4H), 4.13 (t, JZ3.6 Hz, 1H); ¹³C NMR d 11.8, 19.5, 26.4,

28.2, 29.6, 33.6, 36.1, 38.2, 42.2, 67.1, 67.6, 71.7, 78.9,

106.9, 116.4; MS (EI) m/z (relative intensity) 326 ([M]^C, 7),

311 ([MKCH₃]^C, 17), 251 (26), 205 (100); HRMS (EI)

calcd for C₁₈H₃₀O₅[M] 326.2088, found 326.2083.

To a stirred solution of the enone 17 and CeCl₃$7H₂O

(91 mg, 0.24 mmol) in MeOH (8 mL) was added NaBH₄

(23 mg, 0.61 mmol) in small batches over a period of

15 min at 0 8C. The reaction mixture was stirred for an

additional 30 min and was then quenched with saturated

NH₄Cl. The aqueous phase was extracted with CH₂Cl₂(3!)

and the combined organic extracts were washed with brine,

dried (MgSO₄) and ﬁltered. Concentration of the ﬁltrate

followed by ﬂash column chromatography (hexanes–Et₂O,

10:1) afforded the b-hydroxy alkene 18 as a colorless oil

(12 mg, 11%) and the a-hydroxy alkene 19 as a white solid

(26 mg, 24%).

3.1.9. Silyl enol ether 22. To a stirred solution of

diisopropylamine (0.1 mL, 0.73 mmol) in dry THF (4 mL)

was added a 1.6 M solution of n-butyllithium in n-hexane

(0.45 mL, 0.73 mmol) under N₂at K78 8C. The reaction

mixture was stirred for 15 min and a solution of the ketone 9

(45 mg, 0.15 mmol) in dry THF (4 mL) was added dropwise.

After 30 min, t-butyldimethylsilyl triﬂuoromethanesulfonate

(0.1 mL, 0.44 mmol) was added and the reaction mixture

was stirred for 20 min at K78 8C. The reaction was

quenched with saturated NH₄Cl and extracted with

CH₂Cl₂(3!). The combined organic extracts were dried

(MgSO₄) and ﬁltered. Concentration of the ﬁltrate under

vacuum followed by fractionation of the residue by column

chromatography (hexanes–Et₂O, 10:1) gave the silyl enol

ether 22 as a white solid (20 mg, 32%) and the silyl enol

ether 23 as a colorless oil (10 mg, 16%).

Data for 18. [a]_D²⁰ZC47.8 (c 1.6, CHCl₃); R_f0.40

(hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3420, 2930, 1072 cm^K1

;

¹H NMR (CD₃OD) d 1.13 (s, 3H), 1.26 (s, 3H), 1.33 (s, 3H),

1.39 (s, 3H), 1.59 (dd, JZ3.6, 15.3 Hz, 1H), 1.67 (m, 2H),

2.01 (m, 3H), 3.75 (m, 2H), 3.89 (m, 1H), 3.99 (m, 1H), 4.11

(t, JZ3 Hz, 1H), 4.27 (m, 1H), 5.04 (t, JZ1.8 Hz, 1H), 5.18

(t, JZ2.1 Hz, 1H); ¹³C NMR (CD₃OD) d 24.1, 24.4, 25.8,

28.9, 33.0, 37.1, 39.2, 39.5, 63.2, 63.3, 66.1, 79.3, 79.9,

104.8, 105.9, 112.3, 147.5; MS (FAB) m/z (relative

intensity) 324 ([M]^C, 32), 307 (52), 249 ([MKC₂H₄O₂–

CH₃]^C, 100); HRMS (FAB) calcd for C₁₈H₂₉O₅[MCH]

325.2015, found 325.2023.

Data for 22: mp 62–63 8C; [a]²_D⁰ZK31.5 (c 1.0, CHCl₃); R_f

0.53 (hexanes–Et₂O, 3:1); IR (thin ﬁlm) 3743, 2959, 1368,

1

1220, 1087, 847 cm^K1; H NMR d 0.13 (s, 3H), 0.14 (s,

3H), 0.89 (s, 9H), 1.07 (s, 3H), 1.26 (s, 3H), 1.43 (s, 3H),

1.71 (m, 2H), 1.99 (m, 2H), 2.11 (dd, JZ7.8, 14.7 Hz, 1H),

2.48 (ddd, JZ1.8, 6.3, 17.8 Hz, 1H), 3.84 (m, 4H), 4.03 (t,

JZ7.8 Hz, 1H), 4.75 (d, JZ1.8 Hz, 1H); ¹³C NMR d K4.5,

K4.2, 17.9, 25.6, 25.8, 28.3, 29.5, 29.8, 33.1, 35.2, 36.9,

39.5, 40.6, 63.5, 64.4, 79.3, 80.9, 104.1, 107.7, 111.4, 152.5;

MS (FAB) m/z (relative intensity) 425 ([MCH]^C, 100), 367

([MKC(CH₃)]^C, 80), 305 (57); HRMS (FAB) calcd for

C₂₃H₄₁O₅Si [MCH] 425.2718, found 425.2726.

Data for 19: mp 124–125 8C; [a]²_D⁰ZK14.9 (c 1.7, CHCl₃);

R_f0.36 (hexanes–Et₂O 1:2); IR (thin ﬁlm) 3497, 2979,

1066 cm^K1; ¹H NMR (CD₃OD) d 1.23 (s, 3H), 1.28 (s, 3H),

1.36 (s, 3H), 1.41 (s, 3H), 1.53 (m, 2H), 1.73 (m, 1H), 1.79

(d, JZ3 Hz), 1.92 (m, 1H), 2.08 (bd, JZ10.8 Hz), 3.85 (m,

4H), 3.99 (t, JZ3 Hz, 1H), 4.21 (m, 1H), 5.10 (t, JZ2.1 Hz,

1H), 5.20 (t, JZ2.1 Hz, 1H); ¹³C NMR (CD₃OD) d 24.6,

26.5, 26.6, 27.8, 35.7, 37.8, 39.5 63.1, 64.6, 68.4, 76.9, 78.1,

105.0, 106.1, 117.5, 147.5; MS (FAB) m/z (relative

intensity) 324 ([M]^C, 9), 249 ([MKC₂H₄O₂–CH₃]^C,

100), 187 (64); HRMS (FAB) calcd for C₁₈H₂₉O₅[MCH]

325.2015, found 325.2000. Anal. calcd for C₁₈H₂₈O₅: C,

66.64; H, 8.70. Found: C, 66.90; H, 8.82.

3.1.10. Silyl enol ether 23. Triethylamine (0.23 mL,

1.61 mmol) and TBDMSOTf (0.19 mL, 0.81 mmol) were

added to a stirred solution of ketone 9 (100 mg, 0.32 mmol)

in dry CH₂Cl₂(8 mL) under N₂at K78 8C. The reaction

was stirred for 30 min K78 8C and quenched with saturated

NH₄Cl. The aqueous phase was extracted with Et₂O (3!)

and the combined organic layers were dried (MgSO₄), and

ﬁltered. The ﬁltrate was concentrated under vacuum and the

residue was fractionated by ﬂash column chromatography

(hexanes–Et₂O, 6:1) to give silyl enol ether 23 as a colorless

oil (120 mg, 88%): [a]²_D⁰ZC31.3 (c 0.8, CHCl₃); R_f0.63

3.1.8. Alcohol 20. Enone 17 was prepared as above. To a

stirred solution of the enone 17 in MeOH (15 mL) at 0 8C

was added NaBH₄(61 mg, 1.61 mmol) in small batches

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9189

(hexanes–Et₂O, 3:1); IR (thin ﬁlm) 2954, 1203, 1086,

841 cm^K1; ¹H NMR d 0.109 (s, 3H), 0.123 (s, 3H), 0.90 (s,

9H), 1.24 (s, 3H), 1.29 (s, 3H), 1.35 (s, 3H), 1.47 (s, 3H),

1.64 (t, JZ12.6 Hz, 2H), 1.73 (d, JZ2.7 Hz, 2H), 2.06 (d,

JZ16.5 Hz, 1H), 2.32 (m, 2H), 3.97 (m, 4H), 4.11 (t, JZ

3 Hz, 1H), 4.70 (dd, JZ1.5, 4.5 Hz, 1H); ¹³C NMR d K4.6,

K4.3, 17.9, 25.5, 25.6, 27.2, 27.3, 28.3, 36.1, 26.4, 37.4,

39.5, 64.2, 65.1, 76.5, 76.9, 77.4, 79.8, 79.9, 106.6, 107.4,

112.7, 145.6; MS (FAB) m/z (relative intensity) 425 ([MC

H]^C, 25), 365 ([MCH-C₂H₄O₂]^C, 100), 305 (90); HRMS

(FAB) calcd for C₂₃H₄₁O₅Si [MCH] 425.2718, found

425.2710. Anal. calcd for C₂₃H₄₀O₅Si: C, 65.05; H, 9.49.

Found: C, 65.33; H, 9.67.

5.06 (d, JZ6 Hz, 2H), 5.19 (brs, 1H); ¹³C NMR d 25.7,

26.1, 27.3, 27.4, 28.8, 39.8, 41.2, 44.2, 64.2, 64.4, 70.4,

79.8, 80.3, 106.3, 106.7, 106.9, 112.7, 146.2, 151.1; MS

(FAB) m/z (relative intensity) 336 ([MCH]^C, 15), 261

([MKC₂H₄O₂–CH₃]^C, 42), 207 (100); HRMS (FAB) calcd

for C₁₉H₂₈O₅[M] calcd 336.1931, found 336.1943.

3.1.13. 4-Hydroxy ketone 28. Buffer solution [4!10^K4M

aqueous Na₂(EDTA)] (2 mL), acetone (0.1 mL, excess),

Oxone (215 mg, 0.35 mmol) and NaHCO₃(61 mg, 1 mmol)

were sequentially introduced to a solution of silyl enol ether

23 (30 mg, 0.07 mmol) in CH₃CN (10 mL). The solution

was stirred at room temperature for 4 h after which the

reaction mixture was diluted with water and extracted with

EtOAc (3!). The combined organic layers were dried

(MgSO₄), ﬁltered and the ﬁltrate was concentrated in vacuo.

Flash column chromatography (hexanes–Et₂O, 2:1) of the

residue gave 4-hydroxy ketone 28 as a colorless oil (16 mg,

73%): [a]²_D⁰ZC82.8 (c 0.6, CHCl₃); R_f0.42 (hexanes–

Et₂O, 1:2); IR (thin ﬁlm) 3477, 2977, 1718, 1102 cm^K1; ¹H

NMR d 1.21 (s, 3H), 1.36 (s, 3H), 1.37 (s, 3H), 1.44 (s, 3H),

1.84 (m, 2H), 2.06 (m, 2H), 2.64 (dd, JZ18.3, 42.9 Hz, 2H),

3.37 (d, JZ4.2 Hz, 1H), 3.91 (m, 3H), 4.16 (m, 3H); ¹³C

NMR d 26.0, 26.6, 27.6, 28.4, 28.9, 39.8, 40.2, 44.6, 45.3,

65.3, 65.6, 77.6, 107.4, 113.1, 209.9; MS (FAB) m/z

(relative intensity) 327 ([MCH]^C, 26), 269 (30), 144 (100);

HRMS (FAB) calcd for C₁₇H₂₇O₆[MCH] 327.1805, found

327.1814. Anal. calcd for C₁₇H₂₆O₆: C, 62.56; H, 8.03.

Found: C, 62.33; H, 7.96.

3.1.11. Enone 24. The experimental procedures for NaOH,

^tBuOK and K₂CO₃were the same so that only the typical

one was described. To a stirred solution of ketone 9 (40 mg,

t

0.13 mmol) in THF (4 mL) at 0 8C was added BuOK

(22 mg, 0.19 mmol). The reaction was warmed to room

temperature slowly and stirred for 1 h. The reaction was

quenched with NH₄Cl and the aqueous phase was extracted

with EtOAc (3!). The combined organic layers were dried

over MgSO₄and ﬁltered. Concentration of the ﬁltrate

followed by ﬂash column chromatography (hexanes–

EtOAc, 1:3) allowed the isolation of enone 24 as a white

solid (33 mg, 83%): mp 110–111 8C; [a]²_D⁰ZC92.3 (c 0.6,

CHCl₃); R_f0.57 (CHCl₃M–MeOH, 10:1); IR (thin ﬁlm)

1

3743, 3430, 1648, 1208 cm^K1; H NMR d 1.264 (s, 3H),

1.350 (s, 3H), 1.40 (d, JZ8.1 Hz, 2H), 1.470 (s, 3H), 1.475

(s, 3H), 1.63 (m, 1H), 1.89 (s, 1H), 2.10 (dd, JZ1.8,

16.5 Hz, 1H), 2.19 (dd, JZ3.6, 15.9 Hz, 1H), 2.37 (m, 2H),

2.72 (dd, JZ6.3, 16.5 Hz, 1H), 3.89 (m, 4H), 4.07 (t, JZ

3 Hz, 1H), 5.24 (s, 1H); ¹³C NMR d 25.3, 26.7, 26.9, 27.08,

33.2, 33.6. 37.5, 39.6, 39.6, 60.5, 69.7, 79.0, 79.7, 100.4,

107.0, 180.4, 198.7; MS (FAB) m/z (relative intensity) 310

([M]^C, 20), 309 (100), 252 (17); HRMS (FAB) calcd for

C₁₇H₂₇O₅[MCH] 311.1858, found 311.1842. Anal. calcd

for C₁₇H₂₆O₅: C, 65.78; H, 8.44. Found: C, 65.81; H, 8.62.

3.1.14. 5-Hydroxy ketone 27. Al(OiPr)₃(10 mg,

0.05 mmol) was added to a stirred solution of 4-hydroxy

ketone 28 (33 mg, 0.1 mmol) in dry toluene (2 mL) under

N₂. The mixture was stirred at room temperature for 1 h,

then was quenched with saturated NH₄Cl solution, and

extracted with EtOAc (3!). The organic layers were

combined, dried over anhydrous MgSO₄, ﬁltered and the

ﬁltrate was concentrated under vacuum. The residue was

fractionated by column chromatography (hexanes–EtOAc,

3:1 to 1:1) to furnish 5-hydroxy ketone 27 as a white solid

(15 mg, 79%) and recover starting material 28 (14 mg). A

single crystal for X-ray crystallography was obtained from

hexanes–Et₂O, 10:1.

3.1.12. Diene alcohol 25. Et₃N (0.045 mL, 0.32 mmol) was

added to a stirred solution of ketone 9 (50 mg, 0.16 mmol)

in dry CH₂Cl₂(4 mL) at room temperature under N₂. The

reaction mixture was stirred for 15 min and Eschensomer’s

salt (89 mg, 0.49 mmol) was added to the reaction mixture

which was stirred for 96 h. The reaction was quenched with

NH₄Cl and extracted with Et₂O (3!). The combined

organic layers were dried (MgSO₄), ﬁltered and the ﬁltrate

was concentrated under vacuum. The residue was directly

subjected to the next step. NaBH₄(30 mg, 0.98 mmol) was

added to a stirred solution of the residue and CeCl₃$7H₂O

(120 mg, 0.31 mmol) in MeOH (5 mL) at 0 8C. The reaction

mixture was stirred for 30 min and then quenched with

saturated NH₄Cl. The aqueous phase was extracted with

Et₂O (3!). The combined extracts were dried (MgSO₄),

ﬁltered and the ﬁltrate was concentrated in vacuo. The

residue was fractionated by ﬂash column chromatography

(hexanes–Et₂O, 2:1) to furnish diene alcohol 25 as a

colorless oil (22 mg, 40%): [a]²_D⁰ZC46.7 (c 0.9, CHCl₃);

R_f0.63 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3490, 2932,

Data for 5-hydroxy ketone27: mp 107–108 8C; [a]²_D⁰ZC82.8

(c 0.6, CHCl₃); R_f0.47 (hexanes–Et₂O, 1:2); IR (thin ﬁlm)

3742, 2975, 1708, 1080 cm^K1; ¹H NMR d 1.26 (s, 3H), 1.33

(s, 3H), 1.36 (s, 3H), 1.51 (s, 3H), 1.68 (dd, JZ3.3, 15.3 Hz,

1H), 1.94 (m, 3H), 2.34 (dd, JZ6.9, 12.9 Hz, 1H), 2.87 (dd,

JZ2.4, 13.8 Hz, 1H), 3.49 (d, JZ3.3 Hz, 1H), 3.93 (m, 5H),

4.38 (ddd, JZ3.3, 6.9, 12.6 Hz, 1H); ¹³C NMR d 25.3, 27.0,

27.2, 27.4, 28.2, 29.7, 36.8, 37.7, 41.9, 49.9, 63.8, 65.7,

71.1, 79.0, 79.2, 107.1, 111.6, 213.2; MS (FAB) m/z

(relative intensity) 327 ([MCH]^C, 11), 311 ([MCH-OH]^C,

10), 269 (8), 115 (100); HRMS (FAB) calcd for C₁₇H₂₇O₆

[MCH] 327.1805, found 327.1804. Anal. calcd for

C₁₇H₂₆O₆: C, 62.56; H, 8.03. Found: C, 62.29; H, 8.03.

3.1.15. Silyl ether ketone 29. Imidazol (25 mg,

0.368 mmol), dimethylaminopyridine (1 mg) and tert-

butyldimethylsilyl chloride (27 mg, 0.184 mmol) were

added to a solution of 5-hydroxy ketone 27 (12 mg,

0.037 mmol) in CH₂Cl₂(3 mL) at room temperature under

1

1080 cm^K1; H NMR d 1.07 (s, 3H), 1.31 (s, 3H), 1.38 (s,

3H), 1.51 (s, 3H), 1.69 (dd, JZ3.6, 15.6 Hz, 1H), 1.88 (bd,

JZ15.6 Hz, 1H), 2.07 (m, 2H), 2.75 (dd, JZ2.1, 13.8 Hz,

1H), 3.94 (m, 4H), 4.13 (t, JZ3 Hz, 1H), 4.84 (brs, 2H),

9190

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

N₂. The solution was stirred for 3 h and quenched with

saturated NH₄Cl. The aqueous phase was extracted with

Et₂O (2!) and the combined organic layers were dried over

MgSO₄. After ﬁltration and concentration of the ﬁltrate

under vacuum, the residue was subjected to ﬂash column

chromatography (hexanes–Et₂O, 4:1) to give silyl ether

ketone 29 as a white solid (15 mg, 93%): mp 98–99 8C;

[a]²_D⁰Z11.7 (c 0.4, CHCl₃); R_f0.78 (hexanes–Et₂O, 3:1); IR

(thin ﬁlm) 2933, 1721, 1116 cm^K1; ¹H NMR d 0.02 (s, 3H),

0.14 (s, 3H), 0.89 (s, 9H), 1.26 (s, 3H), 1.31 (s, 3H), 1.34 (s,

3H), 1.49 (s, 3H), 1.65 (dd, JZ3.3, 15.3 Hz, 1H), 1.92 (m,

3H), 2.09 (d, JZ2.1 Hz, 1H), 2.12 (s, 1H), 2.74 (dd, JZ2.4,

13.8 Hz, 1H), 4.04 (m, 5H), 4.43 (dd, JZ8.7, 10.5 Hz, 1H);

¹³C NMR d K5.7, K4.7, 25.4, 25.6, 25.7, 27.1, 27.2, 28.2,

37.8, 41.5, 50.8, 63.8, 65.6, 72.7, 79.1, 79.3, 107.1, 112.1,

210.9; MS (FAB) m/z (relative intensity) 440 ([M]^$C, 2),

426 ([MCH-CH]₃)^C, 16), 382 (100), 325 ([MK

C(CH)₃Si]^C, 32), 263 (34); HRMS (FAB) calcd for

C₂₃H₄₁O₆[MCH] 441.2667, found 441.2679.

R_f0.20 (hexanes–Et₂O, 3:1); IR (thin ﬁlm) 3340, 2930,

1

2357, 1107 cm^K1; H NMR d 0.12 (s, 6H), 0.93 (s, 9H),

1.31 (s, 3H), 1.36 (s, 3H), 1.52 (s, 3H), 1.59 (s, 3H), 1.65 (d.

JZ3.3 Hz, 1H), 1.83 (dd, JZ4.2, 13.5 Hz, 1H), 1.96 (m,

2H), 2.09 (m, 1H), 2.66 (dd, JZ2.1, 13.5 Hz, 1H), 3.24 (s,

1H), 3.76 (dd, JZ4.2, 12.0 Hz, 1H), 3.96 (m, 4H), 4.09 (t,

JZ3 Hz, 1H); ¹³C NMR d K4.7, K4.4, 18.5, 25.9, 26.3,

27.8, 28.2, 31.5, 32.7, 36.4, 41.5, 43.6, 64.3, 66.1, 72.1,

74.6, 79.6, 80.8, 107.7, 113.1, 122.6; MS (FAB) m/z

(relative intensity) 468 ([MCH]^C, !1), 442 ([MCH-

CN]^C, 20), 382 ([MKSiC(CH₃)₃]^C, 18), 229 (100); HRMS

(FAB) calcd for C₂₄H₄₂NO₆Si [MCH] 468.2776, found

468.2792.

3.1.18. TMS nitrile 32. Trimethylsilyl cyanide (14 mL,

0.1 mmol) was added to a solution of a-silyl ether ketone 29

(9 mg, 0.02 mmol) in dry toluene (3 mL) under N₂at

K35 8C. The solution was stirred for 5 min and AlCl₃

(11 mg, 0.08 mmol) was added intermittently throughout

20 min. The mixture was led to stir for further 2 h at K35 8C

and then quenched with saturated NaHCO₃. The mixture

was extracted with Et₂O (3!). The combined extracts were

dried (MgSO₄) and ﬁltered. The ﬁltrate was concentrated in

vacuo and the residue was separated by ﬂash column

chromatography (hexanes–Et₂O, 9:1 to 5:1) to provide TMS

nitrile 32 as a white solid (5 mg, 47%), a-hydroxy nitrile 31

(1 mg, 11%) and b-hydroxy nitrile 30 (2 mg, 22%).

3.1.16. b-Hydroxy nitrile 30. AlCl₃(5 mg, 0.035 mmol)

and trimethylsilyl cyanide (9 mL, 0.069 mmol) were added

to a solution of silyl ether ketone 29 (10 mg, 0.023 mmol) in

dry toluene (2 mL) under N₂. The solution was stirred for

5 min at room temperature and quenched with saturated

NaHCO₃. The solution was extracted with Et₂O (3!). The

combined organic layers were dried (MgSO₄), ﬁltered and

the ﬁltrate concentrated. The oil residue was puriﬁed by

ﬂash column chromatography (hexanes–Et₂O, 5:1) to give

b-hydroxy nitrile 30 as a white solid (7 mg, 66%). A single

crystal for X-ray crystallography was obtained from

hexanes–Et₂O, 10:1.

Data for TMS nitrile 32: mp 136–137 8C; [a]²_D⁰ZC6.4 (c

0.2, CHCl₃); R_f0.44 (hexanes–Et₂O, 2:1); IR (thin ﬁlm)

3734, 1517, 1127 cm^K1; ¹H NMR d 0.064 (s, 3H), 0.081 (s,

3H), 0.29 (s, 6H), 0.91 (s, 9H), 1.26 (s, 3H), 1.38 (s, 3H),

1.50 (s, 3H), 1.59 (s, 3H), 1.76 (dd, JZ4.2, 13.8 Hz, 1H),

1.90 (m, 2H), 2.09 (m, 1H), 2.51 (dd, JZ2.1, 13.5 Hz, 1H),

3.68 (dd, JZ3.9, 12.0 Hz, 1H), 3.93 (m, 4H), 4.10 (t, JZ

3 Hz, 1H); ¹³C NMR d K5.07, K4.13, 1.47, 25.2, 25.8,

27.2, 27.6, 27.7, 31.2, 33.0, 35.9, 41.0, 45.6, 63.7, 65.3,

71.9, 75.2, 78.9, 80.3, 107.0, 112.4, 121.8; MS (FAB) m/z

(relative intensity) 540 ([MCH]^C, 11), 514 ([MCH-CN]^C,

25), 482 (18), 319 (100); HRMS (FAB) calcd for

C₂₇H₅₀NO₆Si₂[MCH] 540.3171, found 540.3150. Anal.

calcd for C₂₇H₄₉NO₆Si₂: C, 60.07; H, 9.15; N, 2.59. Found:

C, 60.07; H, 8.96; N, 2.45.

Data for b-hydroxy nitrile 30: mp 192–193 8C;

[a]²_D⁰ZC11.2 (c 1.3, CHCl₃); R_f0.28 (hexanes–Et₂O,

3:1); IR (thin ﬁlm) 3445, 2927, 1078, 779 cm^K1; ¹H NMR d

0.14 (s, 3H), 0.19 (s, 3H), 0.93 (s, 9H), 1.33 (s, 3H), 1.37 (s,

3H), 1.44 (s, 3H), 1.53 (s, 3H), 1.63 (m, 1H), 1.71 (m, 1H),

1.90 (m, 2H), 2.01 (m, 1H), 2.51 (dd, JZ2.1, 14.1 Hz, 1H),

3.44 (brs, 1H), 3.96 (m, 5H), 4.10 (t, JZ3 Hz, 1H); ¹³C

NMR d K4.8, K4.5, 25.4, 25.7, 27.1, 27.2, 28.1, 29.7, 30.6,

33.0, 37.3, 39.1, 41.9, 63.7, 65.4, 71.3, 76.9, 79.2, 80.2,

107.2, 112.6, 120.6; MS (FAB) m/z (relative intensity) 452

([MKCH₃]^C, 35), 383 ([MCH-SiC(CH₃)₃]^C, 100); HRMS

(EI) calcd for C₂₃H₃₈NO₆Si [MKCH₃] 452.2463, found

452.2463.

3.1.19. Diol 33. Et₃N (0.38 mL, 2.76 mmol), DMAP (3 mg)

and TMS chloride (0.17 mL, 1.38 mmol) were added to a

solution of 5-hydroxy ketone 27 (180 mg, 0.55 mmol) in

CH₂Cl₂(8 mL). The mixture was stirred for 20 min at room

temperature under N₂. The reaction mixture was quenched

with saturated NH₄Cl and ﬁltered through a short pad of

silica gel which was eluted with Et₂O. The ﬁltrate was

removed under vacuum and the residue was put to the next

step.

3.1.17. a-Hydroxy nitrile 31. Trimethylsilyl cyanide

(56 mL, 0.42 mmol) was added to a solution of a-silyl

ether ketone 29 (37 mg, 0.084 mmol) in dry toluene (6 mL)

at K35 8C under N₂. The solution was stirred for 5 min and

AlCl₃(20 mg, 0.151 mmol) was introduced intermittently

throughout 2 h. The mixture was stirred for a further 0.5 h

and quenched with saturated NaHCO₃and extracted with

Et₂O (3!). The combined organic layers were dried

(MgSO₄), ﬁltered and the ﬁltrate was concentrated. The

residue was puriﬁed by ﬂash column chromatography

(hexanes–Et₂O, 6:1) to give the starting ketone 29 (6 mg),

a-hydroxy nitrile 31 as a colorless oil (20 mg, 61% based on

starting ketone consumed) and b-hydroxy nitrile 30 as a

white solid (7 mg, 22%).

To a vigorously stirred suspension of magnesium powder

(200 mg, 8.3 mmol) in dry THF (6 mL) under N₂at

K78 8C, was added dropwise vinyl bromide (2 mL, excess)

by means of condensation with a cold ﬁnger containing dry

ice and acetone. The suspension was stirred at room

temperature and 1,2-dibromomethane (5 mL) was added as

an initiator. When the solution started to boil, it was allowed

to stir for further 30 min. The crude product from the

previous step was dissolved in dry THF (4 mL) and the

Data for a-hydroxy nitrile 31. [a]²_D⁰ZK5.6 (c 0.25, CHCl₃);

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9191

solution was injected into the suspension at K78 8C. The

reaction was complete within 10 min and saturated NH₄Cl

was added. The resulting mixture was extracted with Et₂O

(3!) and the combined organic layers were dried, ﬁltered

and the ﬁltrate was concentrated under reduced pressure.

The residue was redissolved in THF (4 mL) and 1 M HCl

(1 mL) was added to the mixture. The reaction mixture was

stirred for 30 min at room temperature and saturated

NaHCO₃was added for neutralization. The aqueous phase

was extracted with EtOAc (3!). The combined extracts

were dried (MgSO₄), ﬁltered and the ﬁltrate concentrated.

Flash chromatography of the residue (hexanes–Et₂O, 2:1)

provided diol 33 as a white solid (175 mg, 90%). A single

crystal for X-ray crystallography was obtained from

hexanes–Et₂O, 10:1.

[a]²_D⁰ZC2.01 (c 0.85, CHCl₃); R_f0.45 (hexanes–Et₂O,

2:1); IR (thin ﬁlm) 3460, 2953, 1108 cm^K1; ¹H NMR d 0.04

(s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.33 (s, 3H), 1.36 (s, 3H),

1.46 (s, 3H), 1.48 (s, 3H), 1.64 (d, JZ3.6 Hz, 1H) 1.95 (m,

4H), 2.22 (dd, JZ2.1, 13.5 Hz, 1H), 3.31 (brs, 1H), 3.88 (m,

5H), 4.12 (t, JZ2.7 Hz, 1H), 5.14 (d, JZ10.8 Hz, 1H), 5.43

(d, JZ16.2 Hz, 1H), 6.23 (dd, JZ11.1, 17.1 Hz, 1H); ¹³C

NMR d K4.8, K4.7, 25.6, 25.7, 17.1, 27.9, 28.5, 30.6, 34.0,

37.3, 39.6, 43.4, 63.9, 64.9, 73.6, 74.4, 79.4, 80.1, 106.8,

113.7, 114.4, 144.1; MS (FAB) m/z (relative intensity) 491

([MCNa]^C, 18), 451 ([MKOH]^C, 65), 229 (100); HRMS

(FAB) calcd for C₂₅H₄₄O₆SiNa [MCNa] 491.2799, found

491.2762. Anal. calcd for C₂₅H₄₄O₆Si: C, 64.06; H, 9.46.

Found: C, 64.18; H, 9.49.

3.1.22. TBS aldehyde 36. NMO (50 mg, 0.41 mmol) and

OsO₄(2 mg) were introduced into a stirring mixture of silyl

ether 35 (48 mg, 0.01 mmol) in acetone–H₂O (4:1) (5 mL)

at room temperature. The reaction mixture was stirred for

100 h and quenched with saturated aqueous Na₂S₂O₃and

stirred for a further 24 h. The resulting mixture was

extracted with Et₂O (3!), dried (MgSO₄), ﬁltered and the

ﬁltrate was concentrated in vacuo. The crude product was

dissolved in CH₂Cl₂–H₂O (8:1) (4 mL) and sodium

metaperiodate (157 mg, 0.72 mmol) was added. The

mixture was stirred at room temperature for 48 h followed

by quenching with saturated Na₂S₂O₃and was stirred for a

further 2 h. The aqueous phase was extracted with Et₂O

(3!), dried (MgSO₄) and ﬁltered. The organic solvents

were evaporated from the ﬁltrate under vacuum and the

residue was fractionated by ﬂash column chromatography

(hexanes–Et₂O, 3:1) to furnish TBS aldehyde 36 as a white

solid (38 mg, 78%): mp 108–109 8C; [a]²_D⁰ZC2.8 (c 0.3,

CHCl₃); R_f0.75 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3437,

Data for diol 33: mp 150–151 8C; [a]²_D⁰ZC24.1 (c 0.3,

CHCl₃); R_f0.22 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3442,

1

2982, 1372, 1075 cm^K1; H NMR d 1.36 (s, 9H), 1.46 (s,

3H), 1.96 (m, 6H), 2.28 (m, 2H), 2.61 (m, 1H), 4.91 (m, 5H),

4.12 (t, JZ3.0 Hz, 1H), 5.30 (d, JZ10.8 Hz, 1H), 5.51 (d,

JZ16.5 Hz, 1H), 6.47 (m, 1H); ¹³C NMR d 25.5, 27.1, 29.1,

30.9, 34.0, 34.5, 40.7, 44.9, 63.7, 65.1, 71.7, 75.2, 79.2,

80.6, 106.1, 113.2, 116.0, 143.1; HRMS (FAB) calcd for

C₁₉H₃₁O₆[MCH] 355.2115, found 355.2112. Anal. calcd

for C₁₉H₃₀O₆: C, 64.39; H, 8.53. Found: C, 64.68; H, 8.67.

3.1.20. Benzyl ether 34. A solution of the diol 33 (15 mg,

0.041 mol) in dry THF (2mL) was slowly added to a stirring

suspension of 60% NaH (17 mg, 0.042 mmol) in dry THF

(2 mL) under N₂at 0 8C. The mixture was subsequently

stirred at room temperature for 15 min and then 0 8C for

1 min. BnBr (6.2 mL, 0.05 mmol) was added to the mixture

and the resulting mixture was stirred at 50 8C for 12 h.

Saturated NH₄Cl was added and the mixture was extracted

with Et₂O (3!), dried (MgSO₄), ﬁltered and the ﬁltrate was

concentrated. The crude product was puriﬁed by column

chromatography (hexanes–Et₂O, 6:1) to give benzyl ether

34 as a colorless oil (16 mg, 86%): [a]²_D⁰ZC1.8 (c 0.35,

CHCl₃); R_f0.58 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3595,

1

2933, 1721, 1094 cm^K1; H NMR d 0.02 (s, 3H), 0.04 (s,

3H), 0.83 (s, 9H), 1.32 (s, 3H), 1.34 (s, 3H), 1.36 (s, 3H),

1.39 (s, 3H), 1.99 (m, 4H), 2.10 (dd, JZ11.7, 13.8 Hz, 1H),

3.47 (s, 1H), 3.99 (m, 5H), 4.09 (t, JZ3 Hz, 1H), 10.09 (s,

1H); ¹³C NMR d K4.9, K4.8, 17.9, 25.5, 25.6, 25.8, 27.1,

27.3, 28.2, 29.1, 30.7, 34.0, 35.9, 37.9, 40.2, 42.7, 63.8,

65.4, 65.6, 71.9, 79.1, 79.6, 80.2, 106.9, 112.6, 203.7; MS

(EI) m/z (relative intensity) 470 ([M]^C, 4), 441 ([MK

CHO]^C, 35), 425 ([MK3CH₃]^C, 98), 384 (100); HRMS

(EI) calcd for C₂₄H₄₂O₇Si [M] 470.2694, found 470.2695.

1

2982, 1075 cm^K1; H NMR d 1.33 (s, 3H), 1.36 (s, 3H),

1.39 (s, 3H), 1.45 (s, 3H), 1.59 (dd, JZ3.3, 15 Hz, 1H), 1.93

(m, 5H), 2.24 (dd, JZ2.4, 13.8 Hz, 1H), 3.05 (brs, 1H), 3.59

(dd, JZ5.7, 8.4 Hz, 1H), 3.94 (m, 4H), 4.11 (t, JZ3 Hz,

1H), 5.19 (d, JZ10.8 Hz, 1H), 5.50 (dd, JZ1.2, 17.4 Hz,

1H), 6.42 (dd, JZ11.1, 17.4 Hz, 1H); ¹³C NMR d 25.6,

27.2, 27.8, 28.6, 30.8, 32.9, 33.9, 40.1, 44.9, 63.7, 65.0,

72.2, 74.2, 79.4, 80.3, 80.7, 106.8, 113.5, 114.9, 127.6,

128.3, 138.7, 144.0; MS (EI) m/z (relative intensity) 444

([M]^C, 1), 429 ([MKCH₃]^C, 13), 353 ([MKOBn]^C, 8),

309 ([MKOBn-OH-vinyl]^C, 81), 263 (100); HRMS (EI)

calcd for C₂₆H₃₆O₆[M] 444.2506, found 444.2494.

3.1.23. Acetate aldehyde 37. Acetic anhydride (0.1 mL,

excess) and DMAP (1 mg) were added to a stirring mixture

of tertiary alcohol 36 (10 mg, 0.021 mmol) in pyridine

(2 mL) under N₂. It was heated under reﬂux for 100 h and

quenched with saturated NH₄Cl. The aqueous phase was

extracted with Et₂O (3!) and the combined extracts were

dried (MgSO₄) and ﬁltered. The ﬁltrate was concentrated

under vacuum and the crude residue was subjected to

column chromatography (hexanes–EtOAc, 6:1) to give

starting material 36 (2 mg) and acetate aldehyde 37 as a

colorless oil (3 mg, 35% based on consumed starting

material): [a]²_D⁰ZC8.9 (c 0.9, CHCl₃); R_f0.57 (hexanes–

Et₂O 2:1); IR (thin ﬁlm) 2953, 1765, 1200 cm^K1; ¹H NMR d

0.07 (s, 3H), 0.12 (s, 3H), 0.87 (s, 9H), 1.29 (s, 3H), 1.34 (s,

3H), 1.48 (s, 3H), 1.54 (s, 3H), 1.68 (m, 2H), 1.98 (m, 2H),

2.14 (s, 3H), 2.99 (dd, JZ1.8, 13.5 Hz, 1H), 3.94 (m, 4H),

4.09 (t, JZ3 Hz, 1H), 4.21 (dd, JZ4.5, 12.3 Hz, 1H), 9.67

(s, 1H); ¹³C NMR d K5.4, K5.0, 25.4, 27.1, 27.3, 29.1,

3.1.21. Silyl ether 35. Imidazol (46 mg, 0.68 mmol),

DMAP (2 mg) and TBDMSCl (51 mg, 0.339 mmol) were

added to a mixture of diol 33 (40 mg, 0.113 mmol) in

CH₂Cl₂(6 mL) at room temperature under N₂. The mixture

was stirred for 96 h and quenched with saturated NH₄Cl,

extracted with Et₂O (3!). The organic layers were

combined, dried (MgSO₄) and ﬁltered. Removal of the

solvent in vacuo gave the residue which was fractionated by

column chromatography (hexanes–Et₂O, 7:1) to give silyl

ether 35 as a white solid (48 mg, 90%): mp 84–85 8C;

9192

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

29.2, 29.7, 31.2, 35.4, 36.9, 40.9, 43.5, 63.8, 65.5, 69.4,

78.8, 80.1, 90.2, 106.9, 112.2, 163.5, 192.6; MS (FAB) m/z

(relative intensity) 513 ([MCH]^C, 2), 441 ([MCH–

C(CH₃)₃–CH₃]^C, 24), 425 (30), 399 (26), 383 (100);

HRMS (FAB) calcd for C₂₆H₄₅O₈Si [MCH] 513.2878,

found 513.2850.

11.7, 84.3 Hz, 2H), 7.29 (m, 10H), 10.16 (s, 1H); ¹³C NMR

d 25.6, 26.9, 27.2, 28.9, 30.9, 32.7, 33.9, 34.6, 40.7, 63.4,

65.1, 65.3, 74.3, 79.5, 80.7, 82.2, 107.3, 112.2, 127.3, 127.4,

127.6, 127.7, 128.3, 138.5, 138.9, 200.4; MS (FAB) m/z

(relative intensity) 537 ([MCH]^C, 24), 391 (99), 373 (41),

307 ([MK2 OBn-CH₃]^C, 100); HRMS (FAB) calcd for

C₃₂H₄₁O₇[MCH] 537.2847, found 537.2862.

3.1.24. Dibenzyl ether 38. A solution of the diol 33 (93 mg,

0.263 mmol) in dry THF (3 mL) was slowly added to a

stirring suspension of 60% NaH (44 mg, 1.05 mmol) in dry

THF (4 mL) under N₂which had been cooled for 5 min at

0 8C. The mixture was kept to stir at room temperature for

15 min and then 0 8C for 1 min. BnBr (0.1 mL, 0.79 mmol)

was added to the mixture and the resulting solution was

heated under reﬂux for 12 h. The reaction was quenched

with saturated NH₄Cl and extracted with Et₂O (3!). The

combined organic extracts were dried (MgSO₄), ﬁltered and

the ﬁltrate was concentrated under vacuum. The residue was

subjected to ﬂash chromatography (hexanes–Et₂O, 5:1) to

furnish dibenzyl ether 38 as a white solid (121 mg, 86%):

mp 91–92 8C; [a]_D²⁰ZC6.5 (c 0.9, CHCl₃); R_f0.31

(hexanes–Et₂O, 4:1); IR (thin ﬁlm) 3741, 2981, 1457,

3.1.26. Aldehyde diol 40. 10% Palladium-on-charcoal

(10 mg) was suspended in EtOH (2 mL). The mixture was

degassed and reﬁlled with hydrogen three times and then

stirred for 10 min. A solution of the dibenzyl aldehyde 39

(32 mg, 0.059 mmol) in EtOH (2 mL) was added and the

degas process was repeated and the mixture was stirred for

30 min under H₂atmosphere (ballon). The resulting mixture

was ﬁltered and the ﬁltrate was concentrated under vacuum.

The residue was passed through a short pad of silica gel

(hexanes–Et₂O, 1:1) to give aldehyde diol 40 as a white

solid (17 mg, 78%): mp 188–189 8C; [a]²_D⁰Z9.8 (c 0.3,

CHCl₃); R_f0.29 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3442,

2979, 1709, 1070 cm^K1; ¹H NMR (CD₃OD) d 1.13 (s, 3H),

1.21 (s, 3H), 1.24 (s, 3H), 1.33 (s, 3H), 1.47 (m, 3H), 1.89

(m, 3H), 2.06 (m, 1H), 2.16 (dd, JZ2.1, 13.2 Hz), 3.85 (m,

5H), 4.03 (t, JZ3 Hz, 1H), 9.85 (d, JZ0.9 Hz, 1H); ¹³C

NMR d 23.7, 25.4, 25.7, 26.8, 29.9, 32.2, 33.5, 39.8, 40.6,

62.8, 64.5, 69.4, 72.2, 78.6, 79.7, 106.1, 111.7, 202.7; MS

(EI) m/z (relative intensity) 341 ([MKCH₃]^C, 5), 427

([MKCHO]^C, 7), 205 (13), 122 (89), 105 (100); HRMS

(EI) calcd for C₁₇H₂₅O₇[MKCH₃] 341.1595, found

341.1599. Anal. calcd for C₁₈H₂₈O₇: C, 60.66; H, 7.92.

Found: C, 60.39; H, 7.86.

1

1076 cm^K1; H NMR d 1.32 (s, 6H), 1.40 (s, 3H), 1.57 (s,

3H), 1.80 (m, 3H), 1.99 (dd, JZ2.4, 12.6 Hz, 1H), 2.72 (d,

JZ11.7 Hz, 1H), 3.85 (m, 5H), 4.12 (t, JZ3 Hz, 1H), 4.35

(dd, JZ11.4, 33.3 Hz, 2H), 4.72 (dd, JZ11.7, 82.8 Hz, 2H),

5.62 (m, 2H), 6.31 (dd, JZ11.4, 18.3 Hz, 1H), 7.27 (m,

10H); ¹³C NMR d 25.4, 27.3, 29.9, 31.4, 33.4, 33.9, 39.1,

41.3, 63.3, 63.5, 65.2, 73.7, 79.3, 79.5, 80.7, 81.0, 106.7,

112.9, 120.3, 126.7, 127.1, 127.4, 127.6, 128.1, 128.2,

135.9, 139.5, 139.9; MS (FAB) m/z (relative intensity) 535

([MCH]^C, 7), 427 ([MKOBn]^C, 78), 369 (36), 307 (100);

HRMS (FAB) calcd for C₃₃H₄₃O₆[MCH] 535.3054, found

535.3055. Anal. calcd for C₃₃H₄₂O₆: C, 74.13; H, 7.92.

Found: C, 74.22; H, 7.96.

3.1.27. Triol 26. To a stirred solution of the aldehyde diol

40 (16 mg, 0.045 mmol) in MeOH (3 mL) at 0 8C was added

NaBH₄(5 mg, 0.13 mmol). The reaction mixture was stirred

for 30 min and quenched with saturated NH₄Cl. The

aqueous phase was extracted with CH₂Cl₂(3!) and the

combined organic extracts were dried over anhydrous

MgSO₄and ﬁltered. Concentration of the ﬁltrate followed

by column chromatography (hexanes–EtOAc, 1:2) gave the

triol 26 as a colorless oil (13 mg, 80%): [a]²_D⁰ZC14.5 (c

0.25, CHCl₃); R_f0.33 (CHCl₃–MeOH, 15:1); IR (thin ﬁlm)

3418, 2976, 1071 cm^K1; ¹H NMR (CD₃OD) d 1.29 (s, 3H),

1.33 (s, 3H), 1.34 (s, 3H), 1.47 (s, 3H), 1.54 (m, 2H), 1.80

(m, 2H), 1.92 (dd, JZ2.1, 14.1 Hz, 1H), 1.74 (m, 2H), 2.02

(bd, JZ12.9 Hz, 1H), 2.38 (dd, JZ1.8, 13.2 Hz, 1H), 3.62

(d, JZ11.7 Hz, 1H), 3.94 (m, 6H), 4.09 (t, JZ3 Hz, 1H);

¹³C NMR (CD₃OD) d 24.9, 26.4, 26.9, 28.1, 29.8, 31.8,

33.9, 35.2, 39.8, 40.8, 63.7, 65.3, 65.9, 72.2, 74.9, 79.6,

81.1, 107.2, 113.2; MS (EI) m/z (relative intensity) 343

([MKCH₃]^C, 2); HRMS (EI) calcd for C₁₇H₂₇O₇[MK

CH₃] 343.1751, found 343.1756.

3.1.25. Dibenzyl aldehyde 39. NMO (53 mg, 0.45 mmol)

and OsO₄(2 mg) were introduced into a stirring solution of

dibenzyl ether 38 (120 mg, 0.23 mmol) in acetone–H₂O

(4:1) (4 mL) at room temperature. The reaction was stirred

for 96 h followed by quenched with saturated aqueous

Na₂S₂O₃. The mixture was stirred for a further 24 h and

extracted with Et₂O (3!). The combined extracts were

dried (MgSO₄) and ﬁltered. The ﬁltrate was concentrated in

vacuo and the residue was puriﬁed by ﬂash column

chromatography (hexanes–Et₂O, 5:1 then 1:1) to give the

starting dibenzyl ether 38 (20 mg) and a mixture of

diasteromeric diols as a colorless oil (90 mg, 88%). The

diols were dissolved in acetone–H₂O (5:1, 4 mL) and

sodium metaperiodate (105 mg, 0.48 mmol) was added. The

mixture was stirred at room temperature for 48 h and

quenched with saturated Na₂S₂O₃and stirred for a further

2 h. The aqueous phase was extracted with Et₂O (3!). The

combined extracts were dried (MgSO₄) and ﬁltered. The

ﬁltrate was concentrated under vacuum and the residue was

fractionated by column chromatography (hexanes–Et₂O,

3:1) to provide dibenzyl aldehyde 39 as a colorless oil

(76 mg, 89%): [a]_D²⁰ZC11.4 (c 0.4, CHCl₃); R_f0.69

3.1.28. Epoxide 42. DMAP (13 mg, 0.11 mmol) was added

to a stirred solution of triol 41 (13 mg, 0.036 mmol) in dry

CH₂Cl₂(3 mL) under N₂at 0 8C. The mixture was stirred

for 15 min and MsCl (3 mL, mmol) was introduced and

stirred at 0 8C for 12 h. The resulting solution was quenched

with saturated NH₄Cl and the aqueous phase was extracted

with EtOAc (3!). The combined organic layers were dried

(MgSO₄), ﬁltered and the ﬁltrate was concentrated. The

crude product was dissolved in THF (1 mL) and the

resulting solution was added to a stirred suspension of

(hexanes–Et₂O, 1:2); IR (thin ﬁlm) 2982, 1719, 1079 cm^K1

;

¹H NMR d 1.14 (s, 3H), 1.32 (s, 3H), 1.39 (s, 3H), 1.63 (s,

3H), 1.65 (m, 2H), 1.82 (t, JZ12.9 Hz, 1H), 1.97 (m, 2H),

2.95 (dd, JZ6.6, 8.7 Hz, 1H), 3.88 (m, 5H), 4.12 (t, JZ

3 Hz, 1H), 4.39 (dd, JZ11.7, 91.5 Hz, 2H), 4.79 (dd, JZ

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9193

60% NaH (10 mg, 0.176 mmol) in THF (2 mL) under N₂.

The mixture was heated under reﬂux for 5 h and saturated

NH₄Cl was added which was followed by extraction with

Et₂O (3!). The organic layers were combined, dried

(MgSO₄), ﬁltered and the ﬁltrate was concentrated. Flash

column chromatography of the residual oil (hexanes–Et₂O,

1:1 then CHCl₃–MeOH, 10:1) gave epoxide 42 as a

colorless oil (7 mg, 92%) and recovered some unreacted

triol 26 (5 mg).

1.46 (s, 3H), 1.50 (s, 3H), 1.83 (m, 3H), 1.98 (dd, JZ6,

14.1 Hz, 1H), 2.08 (s, 3H), 2.29 (dd, JZ2.1, 13.5 Hz, 1H),

3.18 (brs, 1H), 3.92 (m, 5H), 4.12 (t, JZ3 Hz, 1H), 4.31 (dd,

JZ12, 13.8 Hz, 2H); ¹³C NMR d K5.0, K4.9, 21.1, 25.5,

25.7, 27.0, 27.8, 28.2, 31.0, 34.5, 36.7, 38.8, 39.6, 63.9,

64.9, 67.9, 71.3, 73.7, 79.1, 80.1, 106.8, 113.4, 171.3; MS

(FAB) m/z (relative intensity) 515 ([MCH]^C, 5), 437

([MKOAc-H₂O]^C, 45), 397 (40), 229 (100); HRMS (FAB)

calcd for C₂₆H₄₇O₈Si [MCH] 515.3035, found 515.3030.

Anal. calcd for C₂₆H₄₆O₈Si: C, 60.67; H, 9.01. Found: C,

60.73; H, 9.03.

Data for epoxide 42. [a]²_D⁰ZK8.3 (c 0.3, CHCl₃); R_f0.42

(hexanes–Et₂O 1:2); IR (thin ﬁlm) 3448, 2976, 1372,

1

1077 cm^K1; H NMR d 1.32 (s, 3H), 1.33 (s, 3H), 1.35 (s,

3.1.31. Epoxide 48. A molar solution TBAF in THF

(0.04 mL, 0.04 mmol) was added to a stirred solution of the

acetate 47 (16 mg, 0.031 mmol) in THF (2 mL) under N₂.

After 30 min, the reaction mixture was ﬁltered through a

pad of silica gel and eluted with Et₂O. Concentration of the

ﬁltrate gave a crude oil which was put to the next step. Et₃N

(0.1 mL, 0.77 mmol) was added to a stirred solution of the

crude oil in CH₂Cl₂(3 mL) at 0 8C. MsCl (10 mL,

0.12 mmol) was then added to the mixture which was

stirred for 30 min at 0 8C. The reaction mixture was

quenched with saturated NH₄Cl and extracted with Et₂O

(3!). The organic layers were combined, dried (MgSO₄),

and ﬁltered. A residue was obtained upon concentration of

the ﬁltrate under reduced pressure. The residue was then

dissolved in toluene (2.5 mL) and DBU (12 mL, 0.08 mmol)

was introduced into the solution that was heated under

reﬂux for 30 min. The reaction mixture was quenched with

saturated NH₄Cl and extracted with Et₂O (3!). The

combined extracts were dried (MgSO₄), ﬁltered and the

ﬁltrate was concentrated in vacuo. The residue was

dissolved in MeOH (2 mL) and K₂CO₃(6 mg,

0.043 mmol) was added. The reaction mixture was stirred

at room temperature for 1 h and saturated NH₄Cl was added

for neutralization. The mixture was extracted with CH₂Cl₂

(3!), dried (MgSO₄), ﬁltered and the ﬁltrate was

concentrated. Puriﬁcation of the residue by column

chromatography (hexanes–EtOAc, 1:2) gave epoxide 48

as a white solid (6 mg, 57%): mp 159–160 8C; [a]²_D⁰ZK2.3

(c 0.5, CHCl₃); R_f0.28 (hexanes–Et₂O 1:2); IR (thin ﬁlm)

3H), 1.40 (s, 3H), 1.79 (m, 4H), 1.97 (dd, JZ3.3, 15.6 Hz,

1H), 2.07 (dd, JZ4.8, 12.9 Hz, 1H), 2.54 (d, JZ5.1 Hz,

1H), 3.23 (d, JZ5.1 Hz, 1H), 3.93 (m, 3H), 4.07 (m, 3H);

¹³C NMR d 25.6, 26.7, 27.3, 27.4, 29.5, 34.9, 35.9, 41.5,

41.7, 52.1, 61.7, 63.6, 63.9, 65.4, 79.5, 79.9, 106.7, 112.8;

MS (FAB) m/z (relative intensity) 341 ([MCH]^C, 75), 283

([MKC(CH₃)₂–OHCH]^C, 100), 265 (45); HRMS (FAB)

calcd for C₁₈H₂₉O₆[MCH] 341.1958, found 341.1953.

3.1.29. Diol 44. To a stirred solution of the silyl ether 36

(20 mg, 0.043 mmol) in MeOH (2 mL) at 0 8C was added

with NaBH₄(4 mg, 0.11 mmol) slowly. The reaction

mixture was stirred for 30 min and quenched with saturated

NH₄Cl. The aqueous phase was extracted with CH₂Cl₂(3!)

and the combined organic extracts were dried over

anhydrous MgSO₄and ﬁltered. Concentration of the ﬁltrate

in vacuo followed by ﬂash column chromatography

(hexanes–Et₂O, 4:1) gave diol 44 as a colorless oil

(16 mg, 79%): [a]_D²⁰ZC4.7 (c 1.0, CHCl₃); R_f0.42

(hexanes–Et₂O, 1:1); IR (thin ﬁlm) 3407, 2954, 1455,

1074 cm^K1; ¹H NMR d 0.092 (s, 3H), 0.12 (s, 3H), 0.89 (s,

9H), 1.31 (s, 3H), 1.33 (s, 3H), 1.35 (s, 3H), 1.47 (s, 3H),

1.56 (dd, JZ3.6, 15 Hz, 1H), 1.95 (m, 4H), 2.09 (dd, JZ2.1,

11.4 Hz, 1H), 2.97 (dd, JZ2.7, 9.6 Hz, 1H), 2.29 (t, JZ

10.5 Hz, 1H), 3.95 (m, 5H), 4.09 (t, JZ3 Hz, 1H), 4.31 (dd,

JZ2.7, 11.4 Hz, 1H); ¹³C NMR d K4.9, K4.8, 17.9, 25.5,

25.7, 27.1, 27.5, 28.7, 31.1, 33.8, 36.5, 40.2, 42.8, 63.8,

65.2, 68.8, 72.9, 75.3, 79.1, 80.3, 106.8, 113.2; MS (FAB)

m/z (relative intensity) 473 ([MCH]^C, 50), 455 ([MCH-

H₂O]^C, 45), 423 ([MKOTBDMS KH₂O]^C, 100), 229

(97); HRMS (FAB) calcd for C₂₄H₄₅O₇Si [MCH]

473.2929, found 473.2920. Anal. calcd for C₂₄H₄₄O₇Si: C,

60.98; H, 9.38. Found: C, 61.20; H, 9.50.

1

3460, 2923, 1072 cm^K1; H NMR d 1.25 (s, 3H), 1.31 (s,

3H), 1.36 (s, 3H), 1.47 (s, 3H), 1.54 (dd, JZ2.1, 14.4 Hz,

1H), 1.69 (m, 3H), 2.02 (dd, JZ2.1, 15.6 Hz, 1H), 2.16 (m,

2H), 3.39 (s, 1H), 3.62 (dd, JZ12.3, 19.2 Hz, 2H), 3.81 (m,

2H), 4.03 (m, 2H), 4.11 (t, JZ3 Hz, 1H); ¹³C NMR d 25.3,

26.5, 27.2, 27.8, 29.6, 35.6, 36.1, 36.9, 55.5, 59.5, 62.2,

63.7, 65.6, 79.6, 79.8, 106.7, 112.2; MS (EI) m/z (relative

intensity) 340 ([M]^C, 11), 325 ([MKCH₃]^C, 18), 309 (16),

98 (100); HRMS (EI) calcd for C₁₈H₂₈O₆[M]^C340.1880,

found 340.1877. Anal. calcd for C₁₈H₂₈O₆Si: C, 63.51; H,

8.29. Found: C, 63.30; H, 8.25.

3.1.30. Acetate 47. Trimethylorthoacetate (0.25 mL,

1.8 mmol) and p-TsOH (12 mg, 0.06 mmol) were added to

a solution of diol 44 (30 mg, 0.06 mmol) in dry CH₂Cl₂

(4 mL) at room temperature under N₂. The mixture was

allowed to stir for 5 h and made neutral by adding a few

drops of Et₃N which was followed by concentration of the

volatiles under vacuum. The residue was redissolved in

CH₂Cl₂(4 mL) and SiO₂(200 mg) was added. The mixture

was stirred at room temperature for 2 h and the SiO₂was

ﬁltered. The ﬁltrate was concentrated under vacuum and the

crude product was subjected to ﬂash column chromato-

graphy (hexanes–EtOAc, 6:1) to provide the acetate 47 as a

white solid (25 mg, 81%): mp 114–115 8C; [a]²_D⁰ZK1.6

(c 1.0, CHCl₃); R_f0.31 (hexanes–EtOAc, 4:1); IR (thin ﬁlm)

Another approach towards the epoxide 48 started with a

dihydroxylation-glycol cleavage-reduction sequence from

alkene epoxide 50. NMO (23 mg, 0.19 mmol) and OsO₄

(2 mg) were introduced into a stirring solution of alkene

epoxide 50 (22 mg, 0.065 mmol) in acetone–H₂O (4:1)

(3 mL) at room temperature. After 48 h, the mixture was

quenched with saturated Na₂S₂O₃and stirred for a further

24 h. The resulting solution was extracted with Et₂O (3!),

dried (MgSO₄) and ﬁltered. Concentration of the ﬁltrate in

vacuo provided the residue which was dissolved in CH₂Cl₂–

1

3482, 2952, 1739, 1248, 1082 cm^K1; H NMR d 0.065 (s,

3H), 0.067 (s, 3H), 0.88 (s, 9H), 1.33 (s, 3H), 1.37 (s, 3H),

9194

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

H₂O (7:1) (3 mL) and sodium metaperiodate (25 mg,

0.12 mmol) was added. The reaction mixture was stirred

at room temperature for 2 h, quenched with saturated

aqueous Na₂S₂O₃and stirred for a further 2 h. The resulting

mixture was extracted with Et₂O (3!), dried (MgSO₄) and

ﬁltered. The ﬁltrate was concentrated under vaccum and a

crude oil was obtained. Methanol (3 mL) was added to the

crude which was stirred for 15 min at 0 8C. NaBH₄(4 mg,

0.1 mmol) was slowly added to the reaction mixture which

was subsequently stirred for 30 min. Saturated NH₄Cl was

added to quench the reaction and the resulting mixture was

extracted with CH₂Cl₂(3!), dried (MgSO₄) and ﬁltered.

Concentration of the ﬁltrate followed by ﬂash column

chromatography as mentioned above gave the epoxide 48

(16 mg, 72%).

1.2, 10.5 Hz, 1H), 5.40 (dd, JZ1.2, 17.4 Hz, 1H), 5.62 (dd,

JZ10.5, 17.1 Hz, 1H); ¹³C NMR d 25.3, 26.6, 27.2, 27.3,

27.9, 29.9, 35.5, 36.7, 36.9, 59.0, 61.3, 63.7, 65.6, 79.7,

79.9, 102.7, 106.6, 111.9, 116.4, 139.2; MS (FAB) m/z

(relative intensity) 337 ([MCH]^C, 24), 277 ([MCH-

C₂H₄O₂]^C, 20), 185 (90), 93 (100); HRMS (FAB) calcd

for C₁₉H₂₉O₅[MCH] 337.2010, found 337.1989.

3.1.34. Alcohol 51. 5% Palladium-on-charcoal (40 mg) was

suspended in EtOAc (5 mL) and the mixture was degassed

and then ﬁlled with hydrogen gas three times and was stirred

for 10 min. A solution of the aldehyde 39 (80 mg,

0.15 mmol) in EtOAc (4 mL) was added and the mixture

was continuously monitored by TLC so that the starting

material was estimated to be about 80% consumed. The

resulting mixture was ﬁltered through ﬁlter paper and the

ﬁltrate was concentrated in vacuo. The residue was puriﬁed

by ﬂash column chromatography (hexanes–Et₂O, 3:1 to 1:3)

to afford the starting aldehyde 39 (7 mg), alcohol 51 as a

colorless oil (43 mg, 70%) and the aldehyde diol 40 (9 mg,

19%).

3.1.32. Mesylate 49. Et₃N (0.1 mL, 0.77 mmol) was added

to a stirred solution of diol 33 (40 mg, 0.11 mmol) in

CH₂Cl₂(4 mL) at 0 8C. It was kept stirring for 15 min and

MsCl (9 mL, 0.12 mmol) was added to the mixture which

was stirred for 3 h. The reaction mixture was quenched with

saturated NH₄Cl and extracted with Et₂O (3!). The

combined organic layers were dried (MgSO₄) and ﬁltered.

Evaporation of the solvent in vacuo followed by puriﬁcation

of the residue by column chromatography (hexanes–Et₂O,

2:1) gave mesylate 49 as a colorless oil (34 mg, 85% based

on starting material 33 consumed) and recovered the starting

material (6 mg).

Data for alcohol 51. [a]²_D⁰ZC9.4 (c 0.25, CHCl₃); R_f0.42

(hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3737, 2981, 1715,

1

1074 cm^K1; H NMR d 1.15 (s, 3H), 1.34 (s, 3H), 1.39 (s,

3H), 1.60 (s, 3H), 1.98 (m, 4H), 2.63 (brs, 1H), 2.91 (dd, JZ

3.3, 11.4 Hz, 1H), 3.98 (m, 5H), 4.13 (t, JZ3 Hz, 1H), 4.44

(dd, JZ11.4, 82.8 Hz, 2H), 7.34 (m, 5H), 10.03 (s, 1H); ¹³C

NMR d 25.5, 26.9, 27.2, 28.8, 30.9, 32.4, 33.7, 34.9, 41.1,

63.5, 65.4, 65.6, 70.1, 79.4, 80.5, 80.6, 107.2, 111.9, 127.7,

127.9, 128.4, 137.9, 200.2; MS (FAB) m/z (relative

intensity) 447 ([MCH]^C, 14), 417 ([MKCHO]^C, 36),

309 (95), 281 (92); HRMS (FAB) calcd for C₂₅H₃₅O₇[MC

H] 447.2377, found 447.2344.

Data for mesylate 49. [a]²_D⁰ZC2.3 (c 1.0, CHCl₃); R_f0.32

(hexanes–Et₂O 1:2); IR (thin ﬁlm) 3505, 2987, 1349,

1

1172 cm^K1; H NMR d 1.32 (s, 3H), 1.33 (s, 3H), 1.36 (s,

3H), 1.46 (s, 3H), 1.59 (m, 2H), 1.91 (dd, JZ2.4, 15 Hz,

1H), 2.02 (dd, JZ1.8, 14.1 Hz, 1H), 2.19 (m, 2H), 2.31 (dd,

JZ1.8, 13.5 Hz, 1H), 3.04 (s, 3H), 3.89 (m, 2H), 4.01 (m,

2H), 4.10 (t, JZ3 Hz, 1H), 4.67 (dd, JZ6.0, 9.9 Hz, 1H),

5.28 (d, JZ10.8 Hz, 1H), 5.53 (dd, JZ17.4 Hz, 1H), 6.42

(dd, JZ10.8, 17.4 Hz, 1H); ¹³C NMR d 25.4, 27.1, 27.5,

28.6, 30.8, 32.7, 34.2, 38.1, 40.3, 46.0, 63.8, 65.2, 73.3,

79.1, 80.4, 83.2, 106.9, 112.5, 116.3, 142.3; MS (EI) m/z

(relative intensity) 417 ([MKCH₃]^C, 50), 321 ([MKCH₃–

SO₂CH₃–OH]^C, 100); HRMS (EI) calcd for C₁₉H₂₇O₈S

[MKCH₃] 417.1578, found 417.1581.

3.1.35. Diol 52. To a stirred solution of the alcohol 51

(8 mg, 0.017 mmol) in MeOH (4 mL) at 0 8C was added

with NaBH₄(5 mg, 0.13 mmol) in small batches over a

period of 5 min. The reaction mixture was stirred for 30 min

and quenched with saturated NH₄Cl. The aqueous phase

was extracted with CH₂Cl₂(3!) and the combined organic

extracts were dried over anhydrous MgSO₄and ﬁltered.

Concentration of the ﬁltrate followed by ﬂash column

chromatography (hexanes–Et₂O, 1:1) afforded diol 52 as a

colorless oil (8 mg, 100%): [a]²_D⁰ZC10.6 (c 0.45, CHCl₃);

3.1.33. Epoxide 50. LiBr (66 mg, 0.76 mmol) was added to

a mixture of mesylate 49 (33 mg, 0.076 mmol) in dry

CH₃CN (5 mL) at room temperature under N₂. The resulting

mixture was stirred at room temperature for 12 h and

saturated NH₄Cl was added. The aqueous phase was

extracted with Et₂O (3!) and the combined organic layers

were dried (MgSO₄) and ﬁltered. The solvent was removed

in vacuo and puriﬁcation of the crude product was

accomplished by ﬂash column chromatography (hexanes–

Et₂O, 2:1) to afford epoxide 50 as a white solid (15 mg, 74%

based on starting material 49 consumed) and recover the

starting material (7 mg).

R_f0.35 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3313, 1378 cm^K1

;

¹H NMR d 1.31 (s, 3H), 1.32 (s, 3H), 1.37 (s, 3H), 1.51 (s,

3H), 1.89 (m, 5H), 2.24 (m, 1H), 3.06 (brs, 1H), 3.22 (brd,

JZ5.4 Hz, 1H), 3.92 (m, 6H), 4.09 (brs, 1H), 4.46 (d, JZ

12.6 Hz, 1H), 4.61 (dd, JZ9.9, 52.5 Hz, 2H), 7.36 (m, 5H);

¹³C NMR d 25.4, 27.0, 29.2, 31.6, 33.5, 34.5, 39.9, 40.8,

63.5, 65.3, 73.3, 79.1, 79.3, 80.7, 106.9, 112.6, 127.5, 128.3,

128.4, 138.6; MS (EI) m/z (relative intensity) 417 ([MK

CH₂OH]^C, 88), 359 ([MKCH₂OH–C(CH₃)₂–OHCH]^C,

100); HRMS (EI) calcd for C₂₄H₃₃O₆[MKCH₂OH] calcd

417.2272, found 417.2270.

Data for expoxide 50: mp 62–63 8C; [a]²_D⁰ZC17.7 (c 0.5,

CHCl₃); R_f0.56 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 2978,

3.1.36. Oxetane 53. 2,4,6-Collidine (0.32 mol, 2.49 mol)

was added to a stirred solution of the diol 52 (140 mg,

0.313 mmol) in dry CH₂Cl₂(6 mL) at 0 8C under N₂. After

15 min, MsCl (0.028 mL, 0.36 mmol) was added to the

reaction mixture which was kept stirring at 0 8C for 48 h.

The mixture was quenched with NH₄Cl and extracted with

1

1204, 1066, 673 cm^K1; H NMR d 1.28 (s, 3H), 1.31 (s,

3H), 1.37 (s, 3H), 1.51 (s, 3H), 1.67 (m, 3H), 2.11 (m, 2H),

2.51 (dd, JZ3.6, 11.7 Hz, 1H), 3.11 (t, JZ1.8 Hz, 1H), 3.80

(m, 2H), 4.03 (m, 2H), 4.13 (t, JZ3 Hz, 1H), 5.19 (dd, JZ

T. K. M. Shing et al. / Tetrahedron 60 (2004) 9179–9197

9195

Et₂O (3!). The combined organic extracts were dried

(MgSO₄) and ﬁltered. Concentration of the ﬁltrate gave a

crude oil which was put to the next step.

6 as a white solid (10 mg, 56% based on starting material 41

consumed) and unreacted alcohol 41 (3 mg).

Data for acetate 6: mp 131–132 8C; [a]²_D⁰ZC6.1 (c 0.25,

CHCl₃); R_f0.50 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 3742,

The crude oil was added to a suspension of NaH (24 mg,

0.62 mmol) in dry THF (5mL) and the resulting mixture was

heated under reﬂux for 4 h under N₂. The reaction was

quenched with NH₄Cl and the aqueous phase was extracted

with Et₂O (3!). The combined organic extracts were dried

(MgSO₄), ﬁltered and the ﬁltrate was concentrated in vacuo.

The residue was fractionated by ﬂash column chromato-

graphy (hexanes–Et₂O, 2:1 to 1:2) to give pure oxetane 53

as a white solid (70 mg, 83%) and the starting diol 52

(52 mg).

1

2934, 1697, 1077 cm^K1; H NMR d 1.27 (s, 3H), 1.35 (s,

3H), 1.50 (s, 3H), 1.63 (s, 3H), 1.73 (m, 2H), 2.13 (s, 3H),

2.19 (m, 1H), 2.29 (dd, JZ9, 14.7 Hz, 1H), 2.75 (dd, JZ2.7,

13.5 Hz, 1H), 3.86 (m, 1H), 3.99 (m, 3H), 4.11 (t, JZ3 Hz,

1H), 4.76 (dd, JZ8.4, 10.8 Hz, 2H), 4.82 (dd, JZ5.1,

9.3 Hz, 1H); ¹³C NMR d 21.3, 25.5, 26.9, 27.2, 27.3, 29.7,

30.7, 34.7, 36.5, 38.6, 40.9, 64.3, 64.9, 78.9, 79.8, 80.5,

82.0, 84.5, 107.0, 112.3, 169.8; MS (FAB) m/z (relative

intensity) 383 ([MCH]^C, 5), 307 ([MKC₂H₄O₂–CH₃]^C,

100); HRMS (FAB) calcd for C₂₀H₃₁O₇[MCH] 383.2064,

found 383.2060. Anal. calcd for C₂₀H₃₀O₆: C, 62.81; H,

7.91. Found: C, 62.86; H, 8.00.

Data for oxetane 53: mp 173–174 8C; [a]²_D⁰ZC16.4 (c 0.65,

CHCl₃); R_f0.56 (hexanes–Et₂O, 1:2); IR (thin ﬁlm) 2880,

1

1516, 1078 cm^K1; H NMR d 1.29 (s, 3H), 1.36 (s, 3H),

1.48 (s, 3H), 1.57 (s, 3H), 1.74 (dd, JZ3.3, 15.0 Hz, 1H),

1.84 (dd, JZ2.4, 15.3 Hz, 1H), 1.96 (dd, JZ3.6, 14.7 Hz,

1H), 2.18 (m, 2H), 2.38 (dd, JZ3.6, 11.4 Hz, 1H), 3.94 (m,

4H), 4.11 (t, JZ3 Hz, 1H), 4.54 (d, JZ7.2 Hz, 1H), 4.66 (s,

2H), 4.77 (d, JZ7.2 Hz, 1H), 4.96 (m, 1H); ¹³C NMR d

25.6, 26.9, 27.3, 27.6, 30.6, 34.5, 35.0, 38.8, 42.7, 64.4,

64.7, 65.9, 78.6, 79.1, 79.6, 79.8, 83.8, 106.7, 112.3, 127.1,

127.3, 128.3, 138.9; MS (FAB) m/z (relative intensity) 431

([MCH]^C, 6), 323 ([MKOBn]^C, 100), 309 (37), 265 (47);

HRMS (FAB) calcd for C₂₅H₃₅O₆[MCH] 431.2428, found

431.2430. Anal. calcd for C₂₅H₃₄O₆: C, 69.74; H, 7.96.

Found: C, 69.68; H, 8.04.

Acknowledgements

Financial support from CUHK Direct Grant (account no.

2060203) is gratefully acknowledged.

References and notes

1. Taxol^wis the registered trademark of Bristol-Myers Squibb

Company for Paclitaxel.

3.1.37. Alcohol 41. 10% Palladium-on-charcoal (10 mg)

was suspended in EtOH (3 mL). The mixture was degassed

and then ﬁlled with hydrogen gas three times and was stirred

for 10 min at room temperature. A solution of the oxetane

52 (27 mg, 0.063 mmol) in EtOH (2 mL) was added and the

resulting mixture was stirred for 30 min under hydrogen

(balloon). The mixture was ﬁltered and the ﬁltrate was

concentrated under vacuum. The residue was eluted through

a short pad of silica gel (hexanes–Et₂O, 2:1) to give alcohol

41 as a colorless oil (20 mg, 93%): [a]²_D⁰ZK25.2 (c 0.7,

CHCl₃); R_f0.30 (hexanes–Et₂O, 1:2); IR (thin ﬁlm)

2. (a) Kingston, D. G. I. Chem. Commun. 2001, 867. (b) Taxane

Anticancer Agents: Basic Science and Current Status; Georg,

G. I.; Chen T. T.; Ojima, I.; Vyas, D. M. Eds.; ACS

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Suffness, M., Ed.; CRC Press: New York, 1995. (d) The

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Farina, V., Ed.; Elsevier: New York, 1995. (e) Chemotherapy

With Paclitaxel and Platinum Compounds: Current Status and

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1

1378 cm^K1; H NMR d 1.35 (s, 3H), 1.38 (s, 3H), 1.28 (s,

3H), 1.53 (s, 3H), 1.77 (d, JZ3 Hz, 2H), 1.95 (dd, JZ5.4,

14.4 Hz, 1H), 2.09 (m, 2H), 2.34 (dd, JZ5.4, 9.3 Hz, 1H),

2.55 (brs, 1H), 3.94 (m, 4H), 4.10 (t, JZ3 Hz, 1H), 4.43 (dd,

JZ6.3, 5.25 Hz, 2H), 4.74 (dd, JZ6, 8.7 Hz, 1H); ¹³C NMR

d 25.9, 26.5, 27.3, 27.5, 28.9, 32.8, 34.3, 38.1, 43.6, 64.6,

64.9, 72.5, 78.8, 78.9, 84.1, 88.3, 106.8, 113.3; MS (FAB)

m/z (relative intensity) 341 ([MCH]^C, 3), 307 (70), 289

(24), 154 (100); HRMS (FAB) calcd for C₁₈H₂₉O₆[MCH]

341.1958, found 341.1916.

3.1.38. Acetate 6. Acetic anhydride (0.1 mL, excess) and

DMAP (2 mg) were added to a stirring solution of the

alcohol 41 (19 mg, 0.056 mmol) in pyridine (5 mL). The

resulting mixture was heated under reﬂux for 9 h and

quenched with saturated NH₄Cl. The aqueous phase was

extracted with Et₂O (3!). The combined organic layers

were dried (MgSO₄) and ﬁltered. Concentration of the

ﬁltrate gave a crude oil which was puriﬁed by ﬂash

chromatography (hexanes–Et₂O, 2:1 to 1:2) to give acetate

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Article Doi

A synthetic approach toward taxol analogs: Studies on the construction of the CD ring

DOI: 10.1016/j.tet.2004.07.094

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