Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

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Synthetic studies on the pederin family of antitumour agents.

Syntheses of mycalamide B, theopederin D and pederin

Philip Kocienski,*^aRobert Narquizian,^aPiotr Raubo,^aChristopher Smith,^aLouis J. Farrugia,^a

Kenneth Muir^aand F. Thomas Boyle^b

1

^aDepartment of Chemistry, Glasgow University, Glasgow, UK G12 8QQ

^bAstraZeneca Pharmaceuticals, Mereside, Macclesﬁeld, Cheshire, UK SK10 4TG

Received (in Cambridge, UK) 16th December 1999, Accepted 24th February 2000

Published on the Web 23rd May 2000

A general modular approach to the members of the pederin family of antitumour agents is exempliﬁed by syntheses

of mycalamide B and theopederin D as well as a formal synthesis of pederin. All three compounds are prepared from

6-lithio-2,3-dimethyl-4-phenylselenomethyl-3,4-dihydro-2H-pyran and 2-(3-chloropropyl)-3,3-dimethyl-3,4-dihydro-

2H-pyran-4-one.

in Scheme 1, all three targets are constructed from two basic

building blocks, the lithiated dihydropyran 6 and the dihydro-

pyranone 7. Furthermore, there are two common features to

all three syntheses. First, the high acid-lability of the homo-

allylic acetal resulting from the exocyclic methylene at C4 was

circumvented by introduction of this troublesome function-

Introduction

The chemical history of the pederin family began in 1919 when

Netolitzky isolated the active vesicant principle from the derm-

estid beetle Paederus fuscipes in crystalline form.^1,2An interval

of 33 years elapsed before Pavan and Bo³isolated the toxic agent

afresh from 25 million specimens (ca. 100 kg), determined its

mp and gave it the name pederin by which it is known to this

ality in latent form—a tactic which had been devised by

Matsumoto in his pioneering syntheses of pederin.²¹Secondly,

day. Structural investigations were soon launched independ-

the highly hindered and acid- and base-labile N-acyl aminal

bridge linking the two heterocyclic systems was constructed by

acylation of the lithiated dihydropyran 6 by oxalamide deriv-

atives (e.g. 9 or 10) which can be prepared from a common

ently by the Matsumoto group in Japan⁴and the Quilico group

in Italy.⁵The correct molecular formula (C₂₅H₄₅O₉N) estab-

lished by Quilico and co-workers⁵in 1961 led to a detailed

study of the chemical constitution of pederin and a structure,

intermediate 8.

devoid of stereochemical deﬁnition, was proposed in 1965.⁶

With one minor exception all the conclusions drawn from the

degradation and ¹H NMR studies of Quilico⁷and Matsumoto⁸

were later conﬁrmed by an X-ray crystallographic analysis of

pederin bis(p-bromobenzoate) which also established the

Results and discussion

Synthesis of mycalamide B

absolute and relative stereochemistry.^9,10Pederin (1) remained

unique in the realm of natural products until 1988 when routine

screening for antiviral agents identiﬁed two marine natural

products which bore a close structural resemblance to pederin.

Mycalamide A (2) was isolated from a sponge of the genus

Mycale found in the Otago harbour oﬀ New Zealand¹¹whilst

onnamide A (4) was isolated from a sponge of the genus

Theonella found in Okinawan waters.¹²The pederin family grew

to 22 members by 1993 with the isolation of mycalamide B

(3),¹³a further 11 onnamides^14,15and theopederins A–E.¹⁶

All members of the pederin family are rare, diﬃcult to isol-

ate, and comparatively frail; many of them have potent and

potentially useful activity as antiviral and antitumour agents.

Moreover, mycalamide A blocks T-cell activation in mice and is

10-fold more potent than FK-506 and 1000-fold more potent

than cyclosporin A in this model.¹⁷Total syntheses of

pederin,^18–26mycalamide A,^27–31mycalamide B^27,32,33and

onnamide A³⁴have been reported, as have signiﬁcant syntheses

of various fragments.^35–44Previous publications from our

laboratory have traced the evolution of a general approach to

the pederin family including pederin itself,²⁶mycalamide B,³²

18-O-methylmycalamide B³²and theopederin D (5D).⁴⁵Our

aim was to devise a synthesis which was robust enough to

secure suﬃcient quantities of most members of the family for

biological evaluation together with their analogues. We now

give full details of our syntheses of mycalamide B and theo-

pederin D together with substantial tactical improvements to

our previous synthesis of pederin. In the basic strategy outlined

We began with the construction of the stannane which serves as

the precursor to the key lithiated dihydropyran 6. Ethyl (S)-

lactate was transformed in three simple steps to the α,β-

unsaturated ester 13 in 71% overall yield on a 0.26 mol scale

(Scheme 2).⁴⁶A diastereoselective conjugate addition of lithium

dimethylcuprate to the ester 13 in the presence of HMPA and

TMSCl at Ϫ95 ЊC^47,48aﬀorded adduct 14 in 75% yield (dr

24:1). The ﬁnal C–C bond forming reaction in the sequence

was also highly diastereoselective. Alkylation of the potassium

enolate of the ester 14 with allyl bromide gave the third

contiguous stereogenic centre in 15 in 80% yield (dr 22:1).

Ground state conformational models have been proposed

to explain the stereoselectivity of the foregoing reactions.

Yamamoto’s model for the diastereoselective conjugate

addition of various organocopper reagents to γ-alkoxy-α,β-

unsaturated carbonyl derivatives places the best electron

donating group perpendicular to the plane of the π-system

and the OTBS group in the more sterically demanding “inside

position”.⁴⁸The clear steric discrimination between the dia-

stereotopic faces as indicated in structure 16 accounts for the

anti attack of the nucleophile giving the anti-adduct 14. Houk’s

“electrophilic rule” rationalises the diastereoselective alkylation

of enolates with adjacent stereogenic centres.⁴⁹Thus the

eclipsed conformation 17 placing the hydrogen of the stereo-

genic centre in the plane of the π-system again causes steric

discrimination between the two diastereotopic faces of the

enolate leading to alkylation as shown in structure 15. Corrob-

orating evidence for the Houk model has been presented.^50–52

DOI: 10.1039/a909898d

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This journal is © The Royal Society of Chemistry 2000

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Scheme 1

Scheme 2

Scheme 3

Routine transformations accomplished the conversion of 15

to the alcohol 20 (Scheme 3) but the Mitsunobu reaction used

to invert the conﬁguration at C-2 (mycalamide numbering) in

alcohol 20 was plagued by a competing elimination to give

alkene 22. A number of variations in carboxylic acid and azodi-

carboxylate ester eventually established that the combination of

trityl as the protecting group, p-chlorobenzoic acid as the

nucleophile, and diisopropyl azodicarboxylate as the activator

returned the ester 21 in 76% yield together with only 5% of the

elimination product 22 which was easily separated by column

chromatography—the ﬁrst in the sequence. Any minor dia-

stereoisomers were easily separated by crystallisation of the

p-chlorobenzoate 21. We have since found that p-chloro-

benzoic acid is frequently superior as the nucleophilic partner

in Mitsunobu inversions in a wide range of applications and it

is now our reagent of choice.

Oxidative cleavage of the alkene 21 (Scheme 4) followed by

acid treatment achieved simultaneous trityl deprotection and

lactonisation to give the second crystalline compound of the

series, the lactone 24. The phenylseleno group in 25 was intro-

duced by nucleophilic substitution of the butyrolactone 24.⁵³

Saponiﬁcation of the p-chlorobenzoate ester in the usual way

using hot 2 M NaOH was accompanied by an unexpected side

reaction: epimerisation at C-2. Although the extent of epimeri-

sation was small (ca. 5%), we chose to suppress it altogether by

performing the cleavage with an “ate” complex derived from

addition of BuLi to DIBAL-H.⁵⁴The resultant hydroxy acid

lactonised to give 26 in 72% yield. Conversion of lactone 26 to

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Scheme 4

the stannane 27 was accomplished by a three-step sequence

previously described in our synthesis of pederin.²⁶

Dihydropyranone 7 is a critical intermediate in our synthetic

strategy because it could, in principle, be converted to the

simple monocyclic system of pederin as well as the more com-

plex trioxadecalin ring system of the mycalamides, onnamides

and theopederins. The 3-chloropropyl side chain in 7 also satis-

ﬁed the need for an inert latent alkene which could be fashioned

into any of the side chain variations of the pederin family.

Dihydropyranone 7 harbours a single stereogenic centre at C-15

(mycalamide numbering) which was constructed eﬃciently by

two diﬀerent routes. In the ﬁrst route, the lithium enolate

prepared from ethyl isobutyrate was condensed with 4-

chlorobutanoyl chloride to give the β-keto ester 29 in 93% yield

(Scheme 5). Noyori catalytic asymmetric hydrogenation of

the β-keto ester 29 using [(R)-(ϩ)-2,2Ј-bis(diphenylphosphino)-

1,1Ј-binaphthyl]chloro(p-cymene)ruthenium chloride^55–58in-

stalled the requisite (R)-conﬁgured stereogenic centre in good

yield and high enantiomeric ratio (97:3). The reaction worked

well on a 50 mmol scale but on scaleup to 150 mmol, the reac-

tion time was variable and occasionally it failed to go to com-

pletion. Moreover, the ruthenium catalyst was expensive and

commercial supplies gave variable activity. Economy, scale, cost

and reliability led us to an alternative synthesis of β-hydroxy

ester 30 using an asymmetric directed aldol reaction mediated

by the scalemic borane 32 according to the method of

Kiyooka.^59,60Although the Kiyooka method requires stoichio-

metric amounts of the borane 32, it was easily prepared from

cheap crystalline N-tosyl valine which was recovered in pure

form after one recrystallisation in 90% yield. The directed aldol

approach gave comparable yields and enantioselectivity and its

ease of execution won our favour. To complete the synthesis,

the ring was constructed by Dieckmann cyclisation of the acet-

ate 33 to give the highly crystalline β-keto lactone 34 which

could be easily obtained enantiopure by crystallisation. Simple

O-methylation under phase transfer catalysed conditions

aﬀorded the crystalline enol ether 35. Reduction of the remain-

ing carbonyl with DIBAL-H returned the desired dihydro-

pyranone 7 in 50–52% overall yield from ethyl isobutyrate. Note

that none of the steps depicted in Scheme 5 required column

chromatography.

Scheme 5

Construction of the 1,3-dioxane ring (Scheme 6) required a

three-stage sequence of 7 steps comprising appendage of a two-

carbon unit to the dihydropyranone; two oxidations at C10 and

Scheme 6

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C12; and ﬁnally ring closure. The ﬁrst stage was accomplished

in high yield (80%) and high diastereoselectivity (dr 95:5) by

Cu()-catalysed conjugate addition of vinylmagnesium bromide

to dihydropyranone 7. Attempts to launch the second stage by

substrate controlled dihydroxylation gave poor diastereocontrol

[10(R):10(S) 2:3] so the task was accomplished using the

Sharpless asymmetric dihydroxylation.⁶¹Using 20 mg of sub-

strate, several ligand systems were screened but the diastereo-

selectivity was modest at best: AD-mix-α [10(S):10(R) 1:2],

AD-mix-β (2:1), (DHQ)₂PYR⁶²(1:3.5), (DHQD)₂PYR

(2.6:1), DHQD–PYDZ⁶³(1.3:1) and DHQ 4-methyl-2-

quinolyl ether⁶⁴(1:7.5). Best results were obtained with DHQ

9-phenanthryl ether⁶⁴which gave a 75% yield of diols with

dr > 10:1 in favour of the desired 10(R) derivative 37. The diols

were inseparable but the corresponding monopivalates were

separable by simple crystallisation from ether–hexanes to aﬀord

pure 38 in 78% yield. The remaining hydroxy group was con-

verted to its crystalline MOM ether 39 which not only served as

a protecting group, but also as an essential participant in the

ﬁnal ring construction.

Scheme 8

favourable stereochemistry was also obtained with dimethyl-

dioxirane in which hydrogen bonding is precluded.

The reduction of the C13 carbonyl which introduced the

single remaining stereogenic centre on the ring was thwarted by

poor stereoselectivity (Scheme 9). The most favourable ratio of

The second oxidation was accomplished by simple epoxid-

ation of the enol silane derivative 40 prepared from ketone 39

and TBSOTf. Two aspects of the conversion 40 to 41 are note-

worthy. First, the epoxidation was highly diastereoselective

giving virtually a single diastereoisomer with the desired stereo-

chemistry at C12 (see below). Secondly, the oxirane 41 was

surprisingly stable—e.g., it could be puriﬁed by silica gel

chromatography without detriment, though in practice, the

crude product was generally used in the next step. During

a synthesis of the trioxadecalin nucleus of mycalamide A,

Roush⁶⁵had prepared the methylene acetal in 44 (Scheme 7) by

Scheme 7

adding phosphorus pentoxide to a solution of diol 43 in

dimethoxymethane according to literature precedent. We found

that the methylene acetal could be constructed directly by

adding the oxirane 41 to a solution of phosphorus pentoxide in

dichloromethane containing a large excess of dimethoxymeth-

ane at 0 ЊC. An overall yield of 77% was obtained for the three

steps from ketone 39 to methylene acetal 42 with a diastereo-

selectivity of 15:1. However, both a lower yield (70%) and

lower diastereoselectivity (ca. 8:1) was obtained when the

phosphorus pentoxide was added to a solution of the oxirane

in a mixture of dimethoxymethane in dichloromethane. The

methylene acetal could be obtained as a single diastereoisomer

by simple crystallisation from ether–hexanes.

The very favourable stereochemistry of the epoxidation of

enol silane 40 deserves comment. We had originally expected

diﬃculty with this step because it would appear that epoxid-

ation was required from the same face of the ring as the bulky

and branched side chain at C11. However, the C11 side chain

can occupy a pseudo-equatorial position in the half chair con-

formation as shown in Scheme 8 in which it oﬀers compar-

atively little steric impediment to the approach of the oxidant

compared with the pseudo-axial 3-chloropropyl side chain at

C15. Indeed, an MM2 calculation (Chem3D) predicts that the

3-chloropropyl side chain protrudes over the ring somewhat,

thereby exacerbating its steric eﬀect, hence forcing the epoxid-

ation to take place as shown. The favourable stereochemistry

could be ascribed to tethered delivery of the m-chloroper-

benzoic acid via a hydrogen-bonded intermediate but the same

Scheme 9

45a:45b (1:2) was obtained with KBH₄and CeCl₃ؒ7H₂O in

MeOH at Ϫ90 to Ϫ20 ЊC; all other variants gave mixtures

rich in 45b. BH₃ؒTHF and LiBH(s-Bu)₃gave exclusively 45b;

Rhodium-catalysed hydrosilylation gave predominantly 45b.

Dissolving metal reduction (Na, SmI₂) gave decomposition but

Mg in MeOH gave a 1:1 mixture with competing reduction

of the chloride. Fortunately, the diastereoisomeric alcohols are

easily separable, thereby allowing a recycling process. A reason

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for the poor stereoselectivity can be gleaned from the ground

state conformation of the ketone 42: formation of the desired

stereoisomer 45a requires delivery of hydride from the more

hindered concavity of the cis-fused trioxadecalin system. This

recalcitrant reduction was the greatest obstacle to progress until

a simple, convenient and eﬀective solution to the problem was

found in the form of a modiﬁed Meerwein–Ponndorf–Verley

reduction. Thus treatment of ketone 42 at room temperature

with a reagent prepared by reaction of isopropanol with tri-

methylaluminium (3.8 equiv.) gave a mixture of 45a and 45b in

66% yield with a dr of 6:1 in favour of 45a. Starting ketone 42

was also recovered (28%) making the yield based on recovered

starting material 92%. The reversible nature of the Meerwein–

Ponndorf–Verley reduction is well known to aﬀord the thermo-

dynamic alcohol.⁶⁶Evidence that 45a is the thermodynamic

product comes from two observations. First, the dr of the reac-

tion was a function of time with the mol fraction of 45a increas-

ing with time. Secondly, subjection of the pure axial alcohol

45b to the reaction conditions led to isomerisation. Attempts

to drive the reduction to completion by removing the acetone

at elevated temperature led to diminished dr. O-Methylation of

45a gave a methyl ether 46 whose stereochemistry was assigned

based on the large coupling constant J_12,1310.4 Hz for C13H

consistent with a trans-diaxial disposition of the vicinal hydro-

gens as indicated in structure 46Ј.

The C15 side chain is the principal seat of structural vari-

ation in the pederin family and our route was designed to access

as many members of the pederin family and their analogues as

possible. The chloropropyl side chain was introduced at the

outset because it oﬀered opportunities for nucleophilic substi-

tution or elimination and thence a rich vein of transformations.

For the synthesis of mycalamide B, we required an elimination

reaction. However, neither the chloride nor iodide would elim-

inate without severe decomposition. Therefore, we were forced

to adopt a regrettable three-step sequence involving substitu-

tion by phenyl selenide anion to give phenylseleno ether 47

(Scheme 9) whence thermolysis of the corresponding selenox-

ide⁶⁷aﬀorded the desired alkene 8 in excellent overall yield

(94%) for the three-step sequence from 46.

To complete the elaboration of the C15 side chain (Scheme

10) we performed a Sharpless asymmetric dihydroxylation as

Hong and Kishi²⁷had done before us. The diastereoselectivity

was poor giving a mixture of diols (dr 3:2) which was diﬃcult

to separate, but the corresponding mono-TBS ethers were sep-

arable by chromatography and gave the desired alcohol 48a as a

crystalline solid together with its C17 epimer 48b. Both com-

pounds were converted to their respective methyl ethers 49a and

49b. As before the whole gamut of standard ligands used for the

Sharpless asymmetric dihydroxylation was surveyed in the

search for improved diastereoselectivity, but to no avail. Once

Scheme 10

again DHQ 9-phenanthryl ether⁶⁴maximised the desired dia-

stereoisomer but the highest diastereoselectivity (9:1) was

obtained with (DHQD)₂PYR⁶²with the major isomer being the

unwanted C17 epimer 49b. The stereochemistry of the desired

alcohol 49a was established by X-ray analysis of a subsequent

advanced intermediate (see below).

The last remaining task in the synthesis of the trioxadecalin

fragment entailed the introduction of the N-acyl aminal func-

tion. The acid- and base-lability of the N-acyl aminal together

with the threat of isomerisation under basic conditions

demanded a mild, and reliable route. Our optimised solution is

depicted in Scheme 11. Reductive cleavage of the pivalate ester

49a followed by oxidation of the primary alcohol 50 using the

Sharpless protocol⁶⁸gave the carboxylic acid 51 which was con-

verted to the corresponding primary amide 52 using standard

procedures. A classical Hofmann rearrangement using Ag()-

assisted rearrangement⁶⁹of the N-bromoamide derivative

occurred at room temperature with clean retention of conﬁgur-

ation to give an isocyanate intermediate which was trapped by

Scheme 11

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Fig. 1 X-Ray crystal structure of compound 9 showing the atom

numbering and 20% probability ellipsoids for non-hydrogen atoms.

2-(trimethylsilyl)ethanol to give the carbamate 53 in 79%

overall yield from the alcohol 50. Alternatively, the Hofmann

rearrangement could be induced by reaction of amide 52

with 1,1-bis(triﬂuoroacetoxy)iodobenzene^70,71but the yield was

slightly lower (73%). The Curtius rearrangement of an acyl

azide derived from acid 51 is a well-precedented route to the

carbamate 53 (see below) which we also evaluated. However,

the elevated temperatures (70 ЊC) required for the rearrange-

ment resulted in decomposition with an overall reduction in

yield to 56% at best with typical yields being more like 40%.

Attempts to reduce the temperature by employing the photo-

chemical variant of the Curtius rearrangement were rewarded

with a multiplicity of products and so the route was abandoned

in favour of the Hofmann rearrangement.

The remaining two-carbon fragment was installed by reac-

tion of carbamate 53 with methyl oxalyl chloride in the pres-

ence of DMAP⁴¹to yield the imide derivative 54. Although the

reaction required six days to go to completion, the yield of

the imide was excellent (98%). To complete the sequence, the

urethane function was expunged using TBAF buﬀered with

acetic acid to give the crystalline trioxadecalin fragment 9 in

73% yield. In the absence of acetic acid, the primary TBS group

was also partially cleaved. The structure and relative stereo-

chemistry of 9 was ﬁrmly established by X-ray crystallography

(Fig. 1).

The principal task required to complete the synthesis of

mycalamide B was the construction of the N-acyl aminal bridge

linking the two ring systems. The N-acyl aminal bridge is

responsible for the protein synthesis inhibitory activity in the

pederin family⁷²and its potency depends on precise deﬁnition

of the stereochemistry at C6, C7 and C10. We had already

invested a substantial eﬀort to achieve a method for the

construction of the N-acyl aminal bridge of pederin which

reconciled the problems of steric hindrance and acid- and base-

lability and we now hoped to reap a further dividend by deploy-

ing the same linkage strategy in our synthesis of mycalamide B.

Thus addition of the trioxadecalin fragment 9 (Scheme 12) to

a mixture of the lithiated dihydropyran 6 (2.7 equiv.) and

N,N,NЈNЈ-tetramethylethylenediamine (TMEDA) at low tem-

perature gave the adduct 55 in 41% yield. Two aspects of the

acylation require further comment. First, the method as used

here is inherently wasteful since one equivalent of lithiated

dihydropyran 6 was squandered in abstracting the amide

proton. Attempts to improve the stoichiometry by using a sacri-

ﬁcial lithium reagent (BuLi) in model systems were foiled by

rapid competing addition of the butyllithium to the oxalamide.

Secondly, the yield of the coupling was variable. Whilst the

41% yield quoted here is typical, >70% was obtained in related

systems such as theopederin which will be discussed below.

Scheme 12

The acyldihydropyran adduct 55 harboured the entire skel-

eton of mycalamide B and completion of the synthesis now

only required some functional group manipulations which

began with reduction of the keto group with LiBH(s-Bu)₃. The

crude product underwent acid-catalysed addition of MeOH to

the dihydropyran and the remaining hydroxy function was

acylated with benzoyl chloride. ¹H NMR spectroscopic analysis

of the crude reaction mixture revealed two diastereoisomeric

benzoates (dr 6:1) which were separated by chromatography to

give the pure benzoate 56 in 73% overall yield from 55. Two

stereogenic centres at C6 and C7 were created in the foregoing

transformations but the detection of only two isomers at C7

indicates that addition of MeOH had occurred with very high

diastereoselectivity. Brief thermolysis of the selenoxide derived

from oxidation of phenylseleno ether 56 installed the hyper-

sensitive methylene function at C4. Finally, hydrolysis of the

benzoate ester with lithium hydroxide followed by cleavage of

the primary TBS ether with TBAF produced mycalamide B in

78% overall yield from 56. By using identical procedures, 17-

epi-mycalamide B was prepared from 49b with comparable

overall eﬃciency. The ¹H and ¹³C NMR spectroscopic data

recorded on natural and synthetic mycalamide B together with

the data for the 17-epi diastereoisomer are summarised in Table

1. Data for the synthetic material are also given in C₆D₆owing

to the slow deterioration of the synthetic material in CDCl₃.

Theopederin D

Theopederins A–E are a family of ﬁve closely related metabol-

ites isolated from a sponge of the genus Theonella collected oﬀ

Hachijo-jima island 300 km south-east of Tokyo (Scheme 13).¹⁶

Their structures were elucidated by a combination of mass

spectrometry, infra-red spectroscopy, and NMR spectroscopy.

Their spectroscopic features were reminiscent of mycalamides

A and B and detailed COSY, HMQC and HMBC experiments

revealed that all ﬁve theopederins shared a common skeleton

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Table 1 ¹H and ¹³C NMR data for natural and synthetic mycalamide B derivatives

17-epi-Mycalamide B synthetic

(C₆D₆)

Mycalamide B natural (CDCl₃)

Mycalamide B

synthetic (CDCl₃)

δ_H(J/Hz)

Mycalamide B synthetic (C₆D₆)

Position

δ_H(J/Hz)

δ_C

δ_H(J/Hz)

δ_C

δ_H(J/Hz)

δ_C

68.0

16.5

40.3

12.1

145.0

109.4

2

4.02, dq (2.8, 6.6)

1.20, d (6.6)

2.24, dq (2.4, 6.9)

1.01, d (7.1)

69.64

17.93

41.27

4.04, dq (2.8, 6.5)

1.21, d (6.6)

2.28, dq (2.8, 7.1)

1.02, d (7.2)

—

4.86, br s

4.73, br s

2.24, dm (13.9)

2.37, d (14.0)

—

3.80, dq (1.8, 6.6)

0.81, d (6.6)

1.86, dq (1.7, 7.0)

0.92, d (7.0)

—

4.71, dd (1.8, 1.8)

4.66, dd (1.9, 1.9)

2.40, dd (1.8, 14.0)

2.60, d (14.0)

—

68.1

3.82, dq (2.6, 6.6)

0.81, d (6.6)

1.88, dq (2.6, 7.1)

0.90, d (7.1)

—

4.75–4.70, m

2.42, br d (13.9)

2.60, d (13.9)

—

2-Me

3

3-Me

4

16.5

40.4

11

144.6

109.6

12.13

—

145.10

111.02

4᎐CH₂

᎐

4.85, dd (2.0, 2.0)

4.72, dd (1.9, 1.9)

5

2.22, ddd (2.0, 2.0, 13.5) 36.43

2.36, d (13.9)

32.9

33.0

6

—

3.29, s

4.29, s

99.95

48.57

71.73

99.2

47

99.1

47.1

71.1

—

6-OMe

7

7-OH

8

NH

3.3, s

3.15, s

3.21, s

4.29, d (2.0)

3.88, d (2.1)

—

7.52, d (9.6)

5.81, dd (9.6, 9.6)

5.12, d (7.0)

4.86, d (6.7)

4.16, s

4.07 (br s)

70.7 or 70.9 4.17, s

—

171.88

—

73.90

86.49

—

4.17, s

—

171.1

—

72.9

85.1

—

171.1

—

72.8

85.0

7.54, br d (10.0)

5.79, dd (9.7, 9.7)

5.12, d (7.0)

4.84, d (6.9)

3.79, dd (6.7, 9.7)

4.21, dd (6.7, 10.4)

3.44, d (10.5)

3.55, s

7.58, d (9.8)

5.83, d (9.9)

4.56, d (7.0)

4.53, d (6.9)

3.69, dd (7.0, 10.0)

4.24, dd (7.0, 10.6)

2.94, d (10.5)

3.22, s

7.48, d (9.9)

5.94, d (9.9)

4.57, d (6.9)

4.54, d (6.9)

10

10-O-CH₂

11

12

13

13-OMe

14

14-Me_eq

14-Me_ax

15

70.94 (br) 3.79, dd (6.8, 9.6)

70.7 or 70.9 3.65, dd (7.1, 9.7)

73.9 4.23, dd (6.9, 10.2)

77.5 or 77.7 2.96, d (10.4)

70.1

73.8

77.8

60.0

40.1

21.7

12.1

75.9

31.5

74.44

79.27

61.78

41.47

23.13

4.22, dd (6.8, 10.2)

3.44, d (10.4)

3.56, s

—

0.99, s

60

3.32, s

—

0.83, s

0.77, s

3.51, d (9.3)

1.65, dd (8.2, 14.8)

1.27, ddd (2.8, 10.0, 14.6)

—

0.97, s

—

0.80, s

0.76, s

40.3

21.5

11.9

74.4

29.3

0.85, s

3.41, d (3.3, 8.3)

1.55, m

13.32 (br) 0.87, s

75.46

29.63

3.46–3.40, m

3.40, dd (5.6, 6.1)

1.59–1.55, m

3.33–3.28, m

3.03, s

3.85–3.77, m

3.74–3.68, m

2.33, br s

16

1.58–1.52, m

3.23–3.16, m

3.25, s

3.70–3.63, m

3.52–3.46, m

—

1.55, m

3.2, m

3.24, s

3.65, dd (3.3, 11.9)

3.47, dd (5.7, 11.9)

—

17

17-OMe

18

78.84

56.64

63.48

77.5 or 77.7 3.27–3.18, m

78.3

55.6

62.6

55.2

62.6

3.06, s

3.61–3.55, m

1.50, br s

18-OH

—

Nakata²⁸in order to secure the stereochemistry at the aminal

centre unambiguously. The requisite acyl azide was prepared by

cleavage of the pivalate ester in 8 (Scheme 14) using Red-Al^

followed by oxidation of the primary alcohol with pyridinium

dichromate to give a carboxylic acid. The acyl azide prepared

by reaction of the carboxylic acid with diphenylphosphoryl

azide using the conditions of Shioiri et al.,⁷⁴followed by therm-

olysis in the presence of 2-(trimethylsilyl)ethanol, gave the 2-

(trimethylsilyl)ethyl carbamate 58 in 57% overall yield from 8

for the four-step sequence.⁶⁵No epimerisation of the aminal

centre was observed. The yield of the 2-(trimethylsilyl)ethyl

carbamate 58 would probably improve with deployment of the

Hofmann rearrangement as described above for mycalamide B

but the opportunity to revisit the synthesis of theopederin D

was impossible.

Scheme 13

The six-step sequence by which carbamate 9 was converted to

the bridged adducts 61a,b was achieved by methods already

described in our mycalamide synthesis and warrants no further

comment here except that the structure of crystalline inter-

mediate 60 was secured by X-ray crystallography (Fig. 2).

Elaboration of the side chain at C15 began with Sharpless

asymmetric dihydroxylation of alkene 61a using dihydro-

quinine-9-phenanthryl ether⁶⁴as the ligand. A 1:1 mixture of

diastereoisomeric diols—one of which corresponds to mycal-

amide A—was obtained without complications from the selen-

ium atom. The lack of stereoselectivity in the dihydroxylation

was of no consequence since the diol was cleaved to an aldehyde

function with concomitant oxidation of the selenium to the

selenoxide in a single operation using sodium periodate. Brief

thermolysis of the selenoxide in reﬂuxing toluene installed the

exocyclic methylene to give aldehyde 62 in 69% overall yield

from 61a. The acid sensitivity of the homoallylic acetal

imposed signiﬁcant constraints on the subsequent chemistry.

from O1 to C15 with the variable domain being the side chain

appended to C15. The theopederins were isolated in minute

quantities and hence only very limited biological data have been

gleaned. All ﬁve theopederins are cytotoxic towards murine

P388 leukaemia cells with IC₅₀’s (see Scheme 13) in the region

of those reported for mycalamide A (0.7 0.3 ng ml^Ϫ1) and B

(3.0 1.3 ng ml^Ϫ1) in the same animal model.¹³

Progress towards the synthesis of the theopederins has been

disclosed by Fukumoto and co-workers^38,73but only one total

synthesis has been reported.⁴⁵We now give full details of our

synthesis of theopederin D (5D) and its C17 epimer in which we

simply divert the course of the mycalamide synthesis described

above at intermediate 8. As before, our principal concerns were

ﬁrst, the creation of the N-acyl aminal at C10, and then elabor-

ation of the butyrolactone side chain at C15. Introduction

of the aminal centre at C10, was performed using a Curtius

rearrangement as described by Roush,^39,65Hoﬀmann⁴³and

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2363

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Scheme 14

1

carbonate gave theopederin D (5D) by comparison of the H

and ¹³C NMR spectra (400 and 100 MHz respectively) with

published data for the natural product.¹⁶17-epi-Theopederin D

prepared by the same method from 64b was clearly distinguish-

able by ¹H NMR spectroscopy.

A formal synthesis of pederin

The ﬁrst meaningful SAR study of the mycalamides and their

derivatives conducted by Thompson and co-workers^77–80estab-

lished that 18-O-methylmycalamide B prepared from natural

mycalamide A is the most potent antitumour agent in the mycal-

amide series against a range of human tumour models. Their

work together with our own based on synthetic 18-O-methyl-

mycalamide B also established that 18-O-methylmycalamide B

and pederin are nearly equipotent⁸¹and therefore pederin rep-

resents a simpler and more readily accessible candidate for

development. We have already described a synthesis of pederin

from the metallated dihydropyran 6 and the nitrile 11 which was

expensive and impractical.²⁶The ready accessibility of dihydro-

pyranone 7 on a large scale stimulated a fresh approach to the

synthesis of nitrile 11 which is far more practical. Below we

summarise the conversion of dihydropyranone 7 to nitrile 11

which, together with our much improved synthesis of metal-

lated dihydropyran 6 reported herein, represents a new formal

total synthesis of pederin.

Fig. 2 X-Ray crystal structure of compound 60 showing the atom

numbering and 20% probability ellipsoids for non-hydrogen atoms.

Attempts to introduce a propionate fragment directly by addi-

tion of 2-ethoxycarbonylethylzinc or samarium reagents gave

complex mixtures. However, the Grignard reagent derived from

unprotected 3-chloropropan-1-ol⁷⁵underwent clean but stereo-

random addition to give a 1:1 mixture of diastereoisomeric

adducts 63 at C17. Oxidation of the mixture of 1,4-diols with

TPAP⁷⁶then gave a mixture of butyrolactones from which the

desired diastereoisomer 64a was isolated by preparative TLC.

Finally, methanolysis of the benzoate ester using potassium

Conjugate addition of trimethylsilyl cyanide to dihydro-

pyranone 3 (Scheme 15) catalysed by TMSOTf gave the nitrile

65 as a single isomer in 92% yield. Luche reduction⁸²of the

carbonyl group was diastereoselective aﬀording a quantitative

2364

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

11). The fortuitous interspersion of crystalline intermediates

and the infrequent need for chromatographic separation at the

earlier stages of the synthesis, together with the ready avail-

ability of the key intermediates 6 and 7 from cheap starting

materials, make the current approach much more eﬃcient and

practical than routes we have described previously. Good to

excellent stereoselectivity was obtained for most diastereoselec-

tive reactions but the poor diastereocontrol obtained in the

Sharpless asymmetric dihydroxylation of the terminal alkenes

8, 61a and 69 remains a general problem awaiting a general

solution. However, even this blemish is unlikely to aﬀect future

developments since analogues with C15 side chains devoid of

stereochemical deﬁnition are likely to be as active as the natural

congeners.

Experimental

General aspects

¹H and ¹³C NMR spectra were recorded in Fourier Transform

mode at the ﬁeld strength speciﬁed. All spectra were obtained in

CDCl₃or C₆D₆solution in 5 mm diameter tubes, and the chem-

ical shift in ppm is quoted relative to the residual signals of

chloroform (δ_H7.27, δ_C77.0) or C₆H₆(δ_H7.10, δ_C126.7) as the

internal standard unless otherwise speciﬁed. Multiplicities in

1

the H NMR spectra are described as: s = singlet, d = doublet,

t = triplet, q = quartet, quint. = quintet, m = multiplet and br =

broad. Coupling constants (J) are reported in Hz. Numbers

in parentheses following the chemical shift in the ¹³C NMR

spectra refer to the number of protons attached to that carbon

as revealed by the Distortionless Enhancement by Phase

Transfer (DEPT) spectral editing technique, with secondary

pulses at 90Њ and 135Њ. Signal assignments were based on COSY,

HMQC and HMBC correlations. Mycalamide numbering

was used throughout in assigning NMR signals. Low and high

resolution mass spectra were run on a JEOL MStation JMS-

700 spectrometer. Ion mass/charge (m/z) ratios are reported as

values in atomic mass units followed, in parentheses, by the

peak intensity relative to the base peak (100%). Mass spectra

1

were recorded on samples judged to be ≥95% pure by H and

¹³C NMR spectroscopy unless otherwise stated.

Numbering of all intermediates uses the mycalamide system

as shown.

Scheme 15

yield of diastereoisomeric alcohols (dr 30:1) from which the

pure desired isomer 66 could be obtained by crystallisation.

After protection of the hydroxy as its TBS ether and displace-

ment of chloride with sodium phenyl selenide, the alkene was

generated by thermolysis of a selenoxide intermediate giving

terminal alkene 69. Sharpless asymmetric dihydroxylation gave

a 3:2 mixture of diastereoisomeric diols 70a,b which were sep-

arable by column chromatography. The desired (17S)-diol 70a

was then methylated to give the crystalline nitrile 11 which was

converted to pederin as described previously.²⁶

1. Mycalamide B and 17-epi-mycalamide B

Ethyl (S)-O-(tert-butyldimethylsilyl)lactate (12)

Conclusions

The title compound 12 prepared in 99% yield (0.54 mol scale)

from ethyl (S)-lactate by the procedure of Smith, Kocienski and

Street gave [α]_D²²Ϫ30.0 (c 2.5, CHCl₃); lit. [α]_DϪ30.5 (c 2.1,

CHCl₃).⁸⁴

Our syntheses of mycalamide B, theopederin D and pederin

from two common intermediates (6 and 7) testify to the ﬂexibil-

ity of our strategy. Acylation of metallated dihydropyran 6

with oxalamides ﬁrst disclosed in 1990⁸³remains one of the

few viable and general routes for accomplishing the diﬃcult

construction of the N-acyl aminal bridge though the modest

yield remains a problem. Noteworthy tactical features include

(a) the construction of the methylene acetal 42 by a series of

reactions on the oxirane 41 triggered by a methoxymethyl

carbenium ion or its equivalent (Scheme 6); (b) the modiﬁed

Meerwein–Ponndorf–Verley reduction used to reduce ketone 42

(Scheme 9); and (c) the Hofmann rearrangement by which the

N-acyl aminal is introduced under mild conditions (Scheme

Ethyl (S)-4-(tert-butyldimethylsilyloxy)pent-2-enoate (13)

The title enoate ester 13 was prepared in 72% yield (0.175 mol

scale) by the method of Annunziata et al.⁴⁶

Ethyl (3R,4S)-4-(tert-butyldimethylsilyloxy)-3-methylpent-

anoate (14)

The title ester 14 was prepared in 75% yield (71 mmol scale) by

the method of Yamamoto et al.⁴⁸

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2365

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Ethyl (2R,3R,4S)-2-allyl-4-(tert-butyldimethylsilyloxy)-3-

methylpentanoate (15)

ether 19 (26.6 g, 51.7 mmol, 94%) as a colourless oil, [α]_D²²9.8

(c 1.0, CHCl₃); ν_maxﬁlm/cm^–12935, 1452, 829; δ_H(360 MHz,

CDCl₃): 7.50–7.15 (15H, m), 5.65 (1H, dddd, J 17.1, 10.1, 7.8,

Ester 14 (24.0 g, 91.6 mmol) was added dropwise via syringe to

a stirred solution of potassium bis(trimethylsilyl)amide (23.3 g,

80%, 93.0 mmol) in THF (350 ml) at Ϫ78 ЊC. The reaction

mixture was stirred at Ϫ78 ЊC for 30 min and then allyl bromide

(40 ml, 456 mmol) was added dropwise. The reaction mixture

was stirred at Ϫ78 ЊC for 3 h, quenched with saturated aqueous

NH₄Cl and extracted with hexanes (2 × 100 ml). The combined

organic extracts were washed with brine (100 ml), dried

(Na₂SO₄) and concentrated. The residue was puriﬁed by short

path distillation to give ester 15 (22.2 g, 73.4 mmol, 80%) as a

colourless oil: bp 84–88 ЊC at 0.5 mmHg as a 22:1 mixture of

diastereoisomers according to integration of the doublets at

δ 0.06 (minor) and 0.04 (major) as revealed in the ¹H NMR spec-

trum (CDCl₃): [α]_D²²= Ϫ2.9 (c 1.5, CHCl₃); ν_maxﬁlm/cm^–12926,

1740, 1261, 838; δ_H(360 MHz, CDCl₃): 5.74 (1H, ddt, J 17.0,

5.8, ᎐CH), 4.88 (2H, m, ᎐CH ), 3.73 (1H, quint., J 6.2, C2H),

᎐

2

3.10 (1H, dd, J 9.2, 4.8, CH_AH_BO), 2.90 (1H, dd, J 9.0, 7.6,

CH_AH_BO), 2.25 (1H, m), 2.06 (1H, m), 1.82 (2H, m), 1.09 (3H,

d, J 6.1, C2Me), 0.91 (9H, s, Bu^t), 0.72 (3H, d, J 7.1, C3Me),

0.04 (3H, s, SiMe), 0.02 (3H, s, SiMe); δ_C(90 MHz, CDCl₃):

144.7 (0, 2C), 144.7 (0), 137.9 (1), 129.0 (1, 3C), 128.8 (1, 2C),

127.9 (1, 3C), 127.8 (1, 2C), 127.0 (1, 3C), 126.9 (1, 2C), 115.6

(2), 86.6 (0), 70.6 (1), 64.6 (2), 41.0 (1), 38.8 (1), 31.8 (2), 26.1

(3, 3C), 21.0 (3), 18.2 (0), 11.2 (3), Ϫ3.8 (3), Ϫ4.7 (3); m/z

(CI, NH₃) 532 [(M ϩ NH₄)^ϩ, 7%], 243 (100). Found: (M ϩ

NH₄)^ϩ, 532.3610. C₃₄H₅₀O₂NSi requires M, 532.3611.

(2R,3R,4S)-2-Allyl-3-methyl-1-triphenylmethyloxypentan-4-ol

(20)

10.1, 7.0, ᎐CH), 5.05 (1H, ddt, J 17.1, 3.3, 1.5, ᎐CH H ), 4.99

A solution of TBS ether 19 (53.6 g, 104.0 mmol) and TBAF

trihydrate (53.0 g, 168.0 mmol) in THF (200 ml) was stirred at

reﬂux for 5 h. After cooling to rt, the mixture was poured onto

water (1 l) and extracted with Et₂O (3 × 150 ml). The combined

organic extracts were dried (Na₂SO₄) and concentrated to give

crude alcohol 20 (40.4 g, 100.9 mmol, 97%) as a colourless oil

which was immediately used in the next step. Data were

obtained by puriﬁcation of a small sample by column chrom-

atography (SiO₂, 5–10% Et₂O in hexanes); [α]_D²²ϩ12.3 (c 1.6,

CHCl₃); ν_maxﬁlm/cm^–13409, 1449, 706; δ_H(360 MHz, CDCl₃):

᎐

A

B

(1H, dddd, J 10.2, 3.0, 2.2, 1.1, ᎐CH H ), 4.12 (2H, m, OCH ),

᎐

A

B

2

3.68 (1H, dq, J 6.2, 5.4, C2H), 2.47 (1H, ddd, J 8.8, 7.6, 3.7,

C4H), 2.29 (2H, m, C5H₂), 1.89 (1H, partially resolved m, J 7.0,

5.3, C3H), 1.25 (3H, t, J 7.1, OCH₂CH₃), 1.07 (3H, d, J 6.2,

C2Me), 0.89 (3H, d, J 7.0, C3Me), 0.886 (9H, s, Bu^t), 0.043 (3H,

s, SiMe), 0.355 (3H, s, SiMe); δ_C(90 MHz, CDCl₃): 175.5 (0),

136.2 (1), 116.5 (2), 69.8 (1), 60.2 (2), 47.5 (1), 42.5 (1), 32.9 (2),

26.0 (3, 3C), 19.2 (3), 18.2 (0), 14.5 (3), 11.1 (3), Ϫ4.2 (3), Ϫ4.7

(3); m/z (CI, NH₃) 315 [(M ϩ H)^ϩ, 6%], 332 [(M ϩ NH₄)^ϩ, 1],

275 (1.5), 202 (1.2), 110 (1.2). Found: (M ϩ H)^ϩ, 315.2354.

C₁₇H₃₅O₃Si requires M, 315.2355.

7.50–7.15 (15H, m), 5.71 (1H, ddt, J 17.1, 10.1, 7.2, ᎐CH), 4.96

᎐

(1H, dm, J 17.2, ᎐CH H ), 4.91 (1H, dm, J 10.1, ᎐CH H ),

᎐

A

B

A

B

3.61 (1H, quintet, J 6.7, C2H), 3.15 (1H, dd, J 9.3, 4.8, CH_A-

H_BO), 3.00 (1H, dd, J 9.3, 7.1, CH_AH_BO), 2.30–2.28 (1H, m),

2.10–1.87 (2H, m), 1.78 (1H, dquint., J 7.1, 4.1, C3H), 1.68

(1H, br, OH), 1.11 (3H, d, J 6.2, C2 Me), 0.67 (3H, d, J 7.0,

C3Me); δ_C(90 MHz, CDCl₃): 144.4 (0, 3C), 137.9 (1), 128.8

(1, 4C), 127.8 (1, 8C), 126.9 (1, 3C), 115.8 (2), 86.7 (0), 69.6 (1),

64.3 (2), 41.1 (1), 39.4 (1), 32.0 (2), 21.0 (3), 11.6 (3); m/z (CI,

NH₃) 418 [(M ϩ NH₄)^ϩ, 0.4%], 243 (32). Found: C, 84.07; H,

8.00%. C₂₈H₃₂O₂requires C, 84.00; H, 8.00.

(2R,3R,4S)-2-Allyl-4-(tert-butyldimethylsilyloxy)-3-methyl-

pentanol (18)

A solution of DIBAL-H (neat, 28 ml, 156 mmol) was added

dropwise to a stirred solution of ester 15 (21.0 g, 66.9 mmol) in

CH₂Cl₂(30 ml) between 5 and 10 ЊC over 40 min. The reaction

mixture was stirred at Ϫ5 ЊC for 1 h. A mixture of water (4 ml)

and acetone (40 ml) was added dropwise over 45 min keeping

the temperature of the reaction mixture below 20 ЊC. The clear

solution became a white solid. Aqueous HCl (2 M, 230 ml) was

then added over 15 min. The phases were separated and the

aqueous layer was extracted with CH₂Cl₂(2 × 100 ml). The

combined extracts were dried (MgSO₄) and concentrated.

Kugelrohr distillation aﬀorded alcohol 18 (16.2 g, 59.6 mmol,

89%) as a colourless oil: bp 140–145 ЊC (bath) at 0.02 mmHg;

[α]_D²²1.1 (c 1.6, CHCl₃); ν_maxﬁlm/cm^–13374, 1261, 838; δ_H(360

(2R,3R,4R)-2-Allyl-4-(4-chlorobenzoyloxy)-3-methyl-1-

triphenylmethyloxypentane (21)

A solution of diisopropyl azodicarboxylate (16.05 ml, 81.5

mmol) in THF (10 ml) was added dropwise to a stirred solution

of alcohol 20 (18.5 g, 46.3 mmol), triphenylphosphine (21.4 g,

81.6 mmol) and p-chlorobenzoic acid (12.8 g, 81.7 mmol) in

THF (150 ml). The temperature of the reaction mixture was

maintained between Ϫ10 ЊC and 0 ЊC. The reaction mixture

was stirred for 3 h between Ϫ10 ЊC and 0 ЊC. Water (1 ml) was

added and the mixture was stirred at rt for 15 min before con-

centration. The residual oil was dissolved in Et₂O (50 ml) and

hexanes (100 ml) were added dropwise to cause formation of

white crystals. The crystals (triphenylphosphine oxide) were ﬁl-

tered oﬀ and washed with hexanes (3 × 50 ml). The ﬁltrate was

extracted with 2 M aqueous NaOH (2 × 30 ml), water (50 ml)

and brine (50 ml), dried (Na₂SO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (SiO₂,

0–4% Et₂O in hexanes) to give the p-chlorobenzoate 21 as a

colourless oil that crystallised on standing (19 g, 35 mmol, 76%)

and its C2 epimer (0.6 g, 1.1 mmol, 2.4%) and elimination

product 22 (0.9 g, 2.35 mmol, 5.1%). A sample recrystallised

from MeOH–H₂O gave mp 102–103 ЊC; [α]_D²²Ϫ25.7 (c 1.25,

CHCl₃); ν_maxﬁlm/cm^–12972, 1719, 1273, 762; δ_H(360 MHz,

CDCl₃): 7.91 (2H, dm, J 8.6), 7.50–7.35 (7H, m), 7.30–7.15

MHz, CDCl ): 5.84 (1H, dddd, J 17.1, 10.1, 7.8, 5.8, ᎐CH), 5.06

᎐

3

(1H, dm, J 17.1, ᎐CH H ), 5.01 (1H, dm, J 10.0, ᎐CH H ),

᎐

A

B

A

B

3.78 (1H, quint., J 6.2, C2H), 3.68 (1H, dd, J 11.0, 4.4, CH_A-

H_BOH), 3.49 (1H, dd, J 11.0, 6.3, CH_AH_BOH), 2.30–2.10 (1H,

m), 1.95–1.50 (4H, m), 1.16 (3H, d, J 6.2, C2Me), 0.90 (9H, s,

Bu^t), 0.85 (3H, d, J 7.0, C3Me), 0.08 (3H, s, SiMe), 0.06 (3H, s,

SiMe); δ_C(90 MHz, CDCl₃): 138.3 (1), 116.1 (2), 71.0 (1), 64.1

(2), 41.1 (1), 40.8 (1), 32.6 (2), 26.1 (3, 3C), 21.5 (3), 18.2 (0),

12.5 (3), Ϫ4.0 (3), Ϫ4.7 (3); m/z (CI, NH₃) 273 [(M ϩ H)^ϩ,

100%], 290 [(M ϩ NH₄)^ϩ, 50]. Found: (M ϩ H)^ϩ, 273.2247.

C₁₅H₃₃O₂Si requires M, 273.2250.

(2R,3R,4S)-2-Allyl-4-(tert-butyldimethylsilyloxy)-3-methyl-1-

triphenylmethyloxypentane (19)

A solution of alcohol 18 (15.0 g, 55.0 mmol), trityl chloride

(17.3 g, 62.0 mmol), triethylamine (22 ml, 157 mmol) and

DMAP (610 mg, 5.0 mmol) in CH₂Cl₂(50 ml) was stirred at

rt for 12 h, poured onto aqueous saturated NaHCO₃and

extracted with CH₂Cl₂(3 × 100 ml) and concentrated. The oily

residue was dissolved in Et₂O (100 ml) treated with hexanes

(200 ml) and washed with water (500 ml). The organic layer was

dried (Na₂SO₄) and concentrated. The residue was ﬁltered

through a pad of silica gel (5% Et₂O in hexanes) to give trityl

(10H, m), 5.63 (1H, ddt, J 17.1, 10.1, 7.0, ᎐CH), 5.09 (1H,

᎐

quint., J 6.3, C2H), 4.92 (1H, dm, J 17.1, ᎐CH H ), 4.90 (1H,

᎐

A

B

dm, J 10.1, ᎐CH H ), 3.11 (1H, 4 lines of ABX system, J 9.4,

᎐

A

B

7.2, CH_AH_BO), 3.08 (1H, 4 lines of ABX system, J 9.4, 5.7,

CH_AH_BO), 2.25–2.12 (1H, m), 2.10–1.95 (2H, m), 1.90–1.80

(1H, m), 1.32 (3H, d, J 6.3, C2Me), 0.92 (3H, d, J 7.0, C3Me);

2366

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

δ_C(90 MHz, CDCl₃): 165.2 (0), 144.4 (0, 3C), 139.3 (0), 137.1

(1), 131.1 (1, 2C), 129.9 (0, 3C), 128.9 (1, 3C), 128.8 (1, 3C),

127.9 (1, 6C), 127.0 (1, 3C), 116.3 (2), 86.7 (0), 73.8 (1), 63.6 (2),

41.0 (1), 38.1 (1), 32.2 (2), 18.7 (3), 11.1 (3); m/z (CI, NH₃) 556

[(M ϩ NH₄)^ϩ, 0.24%], 539 [(M ϩ H)^ϩ, 0.01%], 316 (4), 263 (2),

243 (100). Found: C, 77.92; H, 6.60%. C₃₅H₃₅ClO₃requires C,

77.99; H, 6.49.

extracted with Et₂O (3 × 20 ml). The combined organic extracts

were washed with aqueous NaHCO₃(2 × 10 ml), dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed

by column chromatography (SiO₂20 g, 10–40% Et₂O in hex-

anes) to give acid 25 as a yellow oil (1.05 g, 2.72 mmol, 80%);

[α]_D²²Ϫ3.5 (c 1.5, CHCl₃); ν_maxﬁlm/cm^–11719, 1595, 1281, 1100;

δ_H(360 MHz, CDCl₃): 7.97–7.90 (2H, dm, J 8.5), 7.50–7.45

(2H, m), 7.44–7.38 (2H, dm, J 8.5), 7.23–7.16 (3H, m), 5.18

(1H, quintet, J 6.2), 3.06 (1H, dd, J 5.8, 3.0, C5H_AH_B), 3.02

(1H, dd, J 5.6, 3.0, C5H_AH_B), 2.61 (1H, dd, J 11.5, 4.9, CH_AH_B-

Se), 2.48 (1H, dd, J 16.4, 8.0, CH_AH_BSe), 2.40–2.30 (1H, m,

C4H), 2.25–2.15 (1H, m, C3H), 1.28 (3H, d, J 6.3, C2 Me), 1.01

(3H, d, J 7.0, C3Me); δ_C(90 MHz, CDCl₃): 179.2 (0), 165.3 (0),

139.5 (0), 133.0 (1), 131.1 (1, 2C), 129.8 (0), 129.2 (1, 2C), 129.0

(0), 128.8 (1, 2C), 127.2 (1, 2C), 73.2 (1), 40.0 (1), 37.2 (1), 35.5

(3R,4R,5R)-5-(4-Chlorobenzoyloxy)-4-methyl-3-(triphenyl-

methoxymethyl)hexanoic acid (23)

Oxidative cleavage of the oleﬁn was accomplished by the pro-

cedure of Sharpless et al.⁶⁸NaIO₄(18.3 g, 85.7 mmol) was

added to a stirred mixture of oleﬁn 21 (11.0 g, 20.4 mmol), CCl₄

(41 ml), acetonitrile (41 ml) and water (62 ml). After 15 min

RuCl₃ؒ3H₂O (270 mg, 1.0 mmol) was added and the reaction

mixture stirred vigorously for 7 h. The mixture was poured onto

water (600 ml), the organic layer removed and the aqueous

phase extracted with CH₂Cl₂(3 × 150 ml). The combined

organic extracts were dried (MgSO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (SiO₂

200 g, 5% EtOAc in hexanes) to give acid 23 (10.8 g, 19.4 mmol,

95%) as a stable white foam, mp 55–57 ЊC; [α]_D²²Ϫ44.4 (c 0.85,

CHCl₃); ν_maxKBr/cm^–12977, 1715, 1594, 1488, 1448, 1273,

1091, 1014, 760, 707; δ_H(360 MHz, CDCl₃): 7.87 (2H, dm,

J 7.2), 7.48–7.38 (7H, m), 7.32–7.15 (10H, m), 5.09 (1H, dq,

J 6.0, 0.9, C2H), 3.24 (1H, dm, J 4.4), 3.12–3.06 (1H, dm, J 6.2),

2.48–2.35 (3H, m), 2.10–1.90 (1H, m), 1.33 (3H, d, J 6.3, C2Me),

0.94 (3H, d, J 7.0, C3Me); δ_C(90 MHz, CDCl₃): 179.5 (0),

165.1 (0), 144.1 (0, 3C), 139.4 (0), 131.1 (1, 3C), 129.2 (0), 128.8

(1, 3C), 128.8 (1, 3C), 128.8 (1, 3C), 127.9 (1, 5C), 127.1 (1, 2C),

86.9 (0), 73.2 (1), 64.3 (2), 38.4 (1), 37.9 (1), 33.8 (2), 18.4 (3),

(2), 31.5 (2), 18.5 (3), 10.8 (3); m/z (EI) 454 [(M ϩ H)^ϩ, 8%],

ؒ

298 (24), 156 (45), 139 (100), 111 (29). Found: C, 55.53; H,

5.23%. C₂₁H₂₃ClO₄Se requires C, 55.56; H, 5.07.

(4R,5R,6R)-5,6-Dimethyl-4-(phenylselanylmethyl)tetrahydro-

2H-pyran-2-one (26)

Reductive cleavage of the p-chlorobenzoate ester was accom-

plished according to the procedure of Trost et al.⁸⁵n-BuLi

(3.75 ml, 2.32 M in hexanes, 8.7 mmol) was added dropwise to a

solution of DIBAL-H (neat, 8.7 mmol, 1.55 ml) in CH₂Cl₂(16

ml) at Ϫ5 ЊC. THF (32 ml) was then added, the mixture was

cooled to Ϫ78 ЊC and a solution of the ester 25 (1.31 g, 2.9

mmol) in THF (32 ml) was added via cannula. The mixture was

allowed to warm to Ϫ20 ЊC over 5 min and stirred at Ϫ20 ЊC

for 3 h. The mixture was then treated with aqueous HCl (2 M,

35 ml, 70 mmol), and Et₂O (30 ml) and stirred vigorously for

24 h. The organic layer was removed and the aqueous phase

extracted with Et₂O (2 × 40 ml). The combined organic extracts

were dried (MgSO₄) and concentrated in vacuo. The residue was

puriﬁed by column chromatography (SiO₂40 g, 10–30% Et₂O in

hexanes) to give 26 as a clear colourless oil (619 mg, 2.08 mmol,

11.3 (3); m/z (EI) 556 [(M ϩ H)^ϩ, 0.03%], 479 (0.15), 400 (3),

ؒ

324 (7), 243 (100), 165 (46), 139 (70). Found: (M ϩ Na)^ϩ,

579.1913. C₃₄H₃₃O₅ClNa requires M 579.1914.

(R)-4-[(1R,2R)-2-(4-Chlorobenzoyloxy)-1-methylpropyl]-

dihydrofuran-2(3H)-one (24)

1

72%). H NMR and ¹³C NMR spectroscopic data agree with

the literature.⁸¹

A solution of acid 23 (10.8 g, 19.3 mmol) and toluene-p-

sulfonic acid (490 mg, 2.6 mmol) in MeOH (180 ml) was stirred

at rt for 4 h before concentration in vacuo. The residue was

puriﬁed by column chromatography (SiO₂120 g, 10–50% Et₂O

in hexanes) to give lactone 24 (4.0 g, 13.5 mmol, 71%) as a white

solid. The lactone 24 was further puriﬁed by recrystallisation

from hexanes–Et₂O to remove the minor diastereoisomers: mp

69.5–70 ЊC (hexanes–Et₂O); [α]_D²²Ϫ0.37 (c 1.9, CHCl₃); ν_maxﬁlm/

cm^–11785, 1716, 1595, 1275; δ_H(360 MHz, CDCl₃): 7.93 (2H,

dd, J 6.7, 2.0), 7.43 (2H, dd, J 6.8, 2.0), 5.17 (1H, dq J 6.5, 2.7,

C2H), 4.55 (1H, dd, J 9.0, 8.1, CH_AH_BO), 4.03 (1H, t, J 9.1,

CH_AH_BO), 2.67–2.52 (2H, m), 2.33–2.21 (1H, m), 1.90–1.80

(1H, m), 1.34 (3H, d, J 6.5, C2Me), 1.10 (3H, d, J 6.9, C3Me);

δ_C(90 MHz, CDCl₃): 176.4 (0), 165.0 (0), 139.7 (0), 130.9 (1,

2C), 128.9 (1, 2C), 128.6 (0), 72.6 (1), 72.4 (2), 41.0 (1), 38.5 (1),

33.0 (2), 16.7 (3), 13.0 (3); m/z (CI, isobutane) 297 [(M ϩ H)^ϩ,

5%], 265 (1.7), 139 (100), 111 (20), 82 (12). Found: C, 60.84; H,

5.74%. C₁₅H₁₇ClO₄requires C, 60.71; H, 5.73.

(2R,3R,4R)-2,3-Dimethyl-4-(phenylselanylmethyl)-6-trimethyl-

stannyl-3,4-dihydro-2H-pyran (27)

The conversion of lactone 26 (150 mg, 0.50 mmol) to 27 (156

mg, 0.35 mmol) was accomplished in 70% yield according to a

reported procedure.²⁶

Ethyl 6-chloro-2,2-dimethyl-3-oxohexanoate (29)

n-BuLi (2.5 M in hexanes, 120 ml, 0.3 mol) was added dropwise

to a solution of diisopropylamine (42 ml, 0.3 mol) in THF (100

ml) at 0 ЊC over 15 min. After 1 h at 0 ЊC, the mixture was

cooled to Ϫ78 ЊC whereupon a solution of ethyl isobutyrate

(40.1 ml, 0.3 mol) in THF (100 ml) was added over 30 min at

a rate suﬃcient to maintain the internal temperature below

Ϫ70 ЊC. After 1 h, a solution of 4-chlorobutanoyl chloride

(Aldrich, 33.6 ml, 0.3 mol) in THF (50 ml) was added over 20

min at a rate suﬃcient to maintain the internal temperature

below Ϫ68 ЊC. After 1 h at Ϫ78 ЊC, the reaction was quenched

by addition of saturated aqueous ammonium chloride (200 ml).

The organic phase was separated and washed successively with

H₂O (3 × 200 ml) and brine (100 ml). The organic layer was

dried over MgSO₄, concentrated in vacuo, and the residue puri-

ﬁed by short path distillation to give the title β-keto ester 29

(61.6 g, 0.28 mol, 93%) as a colourless oil: ν_maxﬁlm/cm^–11714;

δ_H(300 MHz, CDCl₃): 4.19 (2H, q, J 7, CH₂O), 3.56 (2H, t,

(3S,4R,5R)-5-(4-Chlorobenzoyloxy)-4-methyl-3-(phenylselanyl-

methyl)hexanoic acid (25)

The lactone cleavage was accomplished using sodium phenyl

selenide as described in the literature.⁵³Sodium borohydride

(350 mg, 9.25 mmol) was added portionwise to a stirred yellow

suspension of diphenyl diselenide (1.6 g, 5.15 mmol) in EtOH

(5.8 ml) causing exothermic reaction and gas evolution. Lac-

tone 24 (1.0 g, 3.37 mmol) was added to the colourless solution

of sodium phenyl selenide. The resulting mixture was stirred at

reﬂux for 10 h. After cooling to rt, the reaction mixture was

diluted with Et₂O (8 ml) and treated with aqueous HCl (2 M,

5 ml). The layers were separated, and the aqueous phase was

J 6.0, CH Cl), 2.66 (2H, t, J 6.8, CH C᎐O), 2.06 (2H, dt, J 6.6,

᎐

2

6.8, CH₂CH₂CH₂), 1.37 (6H, s, CMe₂), 1.26 (3H, t, J 7.1,

CH₃CH₂); δ_C(75 MHz, CDCl₃): 207.3 (0), 173.7 (0), 62.6 (2),

55.7 (0), 44.4 (2), 34.8 (2), 26.7 (2), 22.20 (3), 14.2 (3). Found:

(M ϩ H)^ϩ, 221.0946. C₁₀H₁₈ClO₃requires M, 221.0944.

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2367

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Ethyl (R)-6-chloro-3-hydroxy-2,2-dimethylhexanoate (30)

(R)-6-(3-Chloropropyl)-5,5-dimethyltetrahydro-2H-pyran-2,4-

dione (34)

A. By asymmetric hydrogenation. A Parr high pressure

hydrogenator was charged with a solution of the β-keto ester 29

(11.0 g, 50.0 mmol) in methanol (100 ml). Methanolic HCl

(2 M, 0.1 ml) was added followed by the addition of the [(R)-

BINAP][p-cymene]RuCl₂catalyst (Aldrich, 0.2 mol%, 93 mg).

The apparatus was evacuated and ﬁlled with hydrogen three

times and the mixture allowed to stir for three days under an

atmosphere of hydrogen at 120 psi and 40 ЊC, after which time

the mixture was concentrated in vacuo and puriﬁed by ﬁltering

the dark orange oil through a pad of silica (30 g) eluting with

hexanes–Et₂O (5:1). The hydroxy ester 30 (10.4 g, 46.7 mmol,

93%) was obtained as a pale yellow oil. The enantiomeric ratio

(97:3) was determined as described below.

n-BuLi (293 ml, 2.32 M in hexane, 610 mmol) was added to a

stirred solution of diisopropylamine (90 ml, 637 mmol) in THF

(875 ml) at 0 ЊC over 15 min. After stirring at 0 ЊC for 20 min,

the solution was cooled to Ϫ74 ЊC and a solution of the ester

acetate 33 (78.2 g, 292 mmol) in THF (125 ml) was added

dropwise over 15 min keeping the temperature of the reaction

mixture below Ϫ68 ЊC. The yellow solution was stirred at

Ϫ74 ЊC for 1.5 h before adding aqueous HCl (2 M, 750 ml). The

phases were separated and the aqueous phase was extracted

with CH₂Cl₂(3 × 240 ml). The combined organic extracts were

washed with brine (200 ml), dried (Na₂SO₄) and concentrated in

vacuo. The residue was recrystallised twice from hexanes–Et₂O

to give the β-ketolactone 34 (50 g, 228 mmol, 78%) as a white

solid: mp 103–105 ЊC; [α]_D²⁰ϩ10.8 (c 1.0, CHCl₃); ν_maxﬁlm/cm^–1

1679, 1605, 1464; δ_H(400 MHz, CDCl₃): 4.35 (1H, dd, J 10.9,

1.8, C15H), 3.69 (1H, ddd, J 11.1, 7.1, 4.8, C18H_AH_B), 3.61

(1H, ddd, J 11.1, 7.1, 5.1, C18H_AH_B), 3.61 (1H, d, J 19.0,

C12H_AH_B), 3.44 (1H, d, J 19.0, C12H_AH_B), 2.28–2.19 (1H, m,

C17H_AH_B), 1.97–1.87 (2H, m, C16H_AH_Band C17H_AH_B), 1.83–

1.72 (1H, m, C16H_AH_B), 1.21 (3H, s, C14Me), 1.12 (3H, s,

C14Me); δ_C(100 MHz, CDCl₃): 205.4 (0, C11), 167.3 (0, C13),

82.5 (1, C15), 46.9 (0, C14), 45.0 (2, C12), 44.5 (2, C18), 28.8 (2,

C17), 26.1 (2, C16), 20.5 (3, C14Me), 17.6 (3, C14Me); m/z (CI,

NH₃) 236 [(M ϩ NH₄)^ϩ, 30%], 219 [(M ϩ H)^ϩ, 25%], 112 (70),

70 (100). Found: C, 54.93; H, 6.71%. C₁₀H₁₅ClO₃requires C,

54.92; H, 6.86.

B. By directed aldol condensation. A solution of BH₃ؒTHF

complex (313 ml, 1 M in THF, 313 mmol) was added dropwise

to a stirred suspension of (S)-N-tosylvaline⁸⁶(105.3 g, 388

mmol) in CH₂Cl₂(1.85 l) under nitrogen at rt over 30 min. After

30 min, the clear solution was cooled to Ϫ70 ЊC and a solution

of 4-chlorobutanal⁸⁷(41.4 g, 388 mmol) in CH₂Cl₂(35 ml) was

added over 10 min. Silyl ketene acetal 31⁸⁸(78.9 g, 419 mmol)

was then added over 30 min maintaining the reaction temper-

ature below Ϫ65 ЊC. After 2 h at Ϫ70 ЊC a solution of NaOH

(24.5 g, 612 mmol) in 300 ml of water was added and the reac-

tion mixture was allowed to warm to rt. The phases were separ-

ated, the aqueous phase was extracted with CH₂Cl₂(2 × 100

ml) and the combined organic extracts were washed with water

(500 ml) and concentrated in vacuo. The residue was treated

with water (500 ml) and extracted with Et₂O (4 × 200 ml). The

combined organic extracts were dried (MgSO₄) and concen-

trated in vacuo to give the hydroxy ester 30 (97.7 g, 370 mmol,

95%) as a yellow oil: [α]_D²⁷18.7 (c 0.9, CHCl₃); ν_maxﬁlm/cm^–1

3490, 1718; δ_H(270 MHz, CDCl₃): 4.17 (2H, q, J 7.1, CH₂O),

3.70–3.54 (3H, m, C15H and C18H₂), 2.69 (1H, br d, J 6.4,

OH), 2.20–2.00 (1H, m, C17H), 1.85 (1H, ddq, J 14.5, 9.2, 6.2,

C17H), 1.69 (1H, dddd, J 13.5, 9.3, 6.0, 1.9, C16H_AH_B), 1.39

(1H, dddd, J 13.9, 10.8, 9.3, 4.8, C16H_AH_B), 1.28 (3H, t, J 7.1,

CH₃CH₂O), 1.22 (3H, s, C14Me), 1.18 (3H, s, C14Me); δ_C(67.5

MHz, CDCl₃): 177.8 (0), 76.1 (1), 60.9 (2), 47.1 (0), 45.2 (2),

29.8 (2), 28.9 (2), 22.5 (3), 20.5 (3), 14.3 (3); m/z (CI, NH₃) 223

[(M ϩ H)^ϩ, 100%], 205 (25), 187 (45), 116 (20). Found: C,

53.67; H, 8.29%. C₁₀H₁₉O₃Cl requires C, 53.93; H, 8.54.

(R)-6-(3-Chloropropyl)-5,6-dihydro-4-methoxy-5,5-dimethyl-

2H-pyran-2-one (35)

Potassium carbonate (4.74 g, 34.4 mmol) was added to a solu-

tion of β-ketolactone 34 (5.00 g, 22.9 mmol), 18-crown-6 (60

mg, 0.25 mmol) and dimethyl sulfate (2.6 ml, 27.5 mmol) in

CH₂Cl₂(50 ml). The reaction mixture was vigorously stirred at

rt for 20 h, ﬁltered through a pad of Celite and concentrated

in vacuo. Kugelrohr distillation (bp 245–250 ЊC (oven)/0.05

mmHg) gave enol ether 35 (5.28 g, 22.7 mmol, 99%) as a colour-

less oil which formed a white solid on cooling: mp 56–57 ЊC; [α]_D²²

Ϫ68.8 (c 1.7, CHCl₃); ν_maxﬁlm/cm^–11673, 1603; δ_H(400 MHz,

CDCl₃): 5.06 (1H, s, C12H), 4.03 (1H, dd, J 11.0, 2.2, C15H),

3.72 (3H, s, OMe), 3.70–3.53 (2H, m, C18H₂), 2.30–2.11 (1H,

m), 1.97–1.62 (3H, m), 1.13 (3H, s, C14Me), 1.10 (3H, s,

C14Me); δ_C(100 MHz, CDCl₃): 179.9 (0, C11), 166.7 (0, C13),

88.7 (1, C12), 82.9 (1, C15), 56.4 (3, OMe), 44.8 (2, C18), 38.7

(0, C14), 29.7 (2, C17), 25.8 (2, C16), 20.6 (3, C14Me), 19.0 (3,

C14Me); m/z (CI, NH₃) 233 [(M ϩ H)^ϩ, 100%], 126 (85), 112

(45), 70 (70). Found: C, 56.74; H, 7.45%. C₁₁H₁₇ClO₃requires

C, 56.77; H, 7.31.

The enantiomeric ratio (97:3) was determined by integration

of the ¹H NMR signals at δ 1.16 (major) and δ 1.11 (minor) of

the (R)-MTPA esters prepared from 30 in the usual way (270

MHz, C₆D₆, referenced to 7.16 ppm).

Ethyl (R)-3-acetoxy-6-chloro-2,2-dimethylhexanoate (33)

To a solution of the crude hydroxy ester 30 (97.7 g, 370 mmol),

triethylamine (76 ml, 550 mmol), and DMAP (233 mg, 1.9

mmol) in CH₂Cl₂(300 ml) was added acetic anhydride (49 ml,

517 mmol) dropwise. The solution was stirred overnight at rt

and then diluted with hexanes (1 l), washed with water (3 × 200

ml), and brine (100 ml), dried (Na₂SO₄) and concentrated in

vacuo. The crude product was ﬁltered through a pad of silica

gel (15 g, 10% Et₂O in hexanes), concentrated in vacuo and the

residue distilled (bp 88–96 ЊC/0.01 mmHg) to give acetate 33

(78.2 g, 0.295 mol, 76%) as a colourless oil; [α]_D²²ϩ9.4 (c 1.6,

CHCl₃); ν_maxﬁlm/cm^–11718, 1236; δ_H(270 MHz, CDCl₃): 5.24

(1H, dd, J 9.3, 3.9, C15H), 4.14 (2H, q, J 7.1, CH₂O), 3.63–3.49

(2H, m, C18H₂), 2.06 (3H, s, OAc), 1.83–1.57 (4H, m, C16H₂

and C17H₂), 1.26 (3H, t, J 7.1, CH₃CH₂O), 1.18 (6H, s,

C14Me); δ_C(67.5 MHz, CDCl₃): 175.4 (0), 170.5 (0), 76.1 (1),

60.8 (2), 46.5 (0), 44.4 (2), 29.2 (2), 27.6 (2), 21.8 (3), 20.8 (3),

20.3 (3), 14.1 (3); m/z (CI, NH₃): 223 [(M ϩ H)^ϩ, 100%], 205

(25), 187 (45), 116 (20). Found: C, 54.67; H, 7.96%. C₁₂H₂₁ClO₄

requires C, 54.44; H, 7.93.

(R)-6-(3-Chloropropyl)-5,6-dihydro-5,5-dimethyl-4H-pyran-4-

one (7)

DIBAL-H (neat, 8.7 ml, 48.6 mmol) was added dropwise to a

stirred solution of lactone 35 (10.3 g, 44.2 mmol) in CH₂Cl₂(80

ml) maintaining the temperature of the reaction mixture below

Ϫ70 ЊC. The reaction mixture was stirred at Ϫ70 ЊC for 40 min

and then poured onto aqueous HCl (2 M, 250 ml) and vigor-

ously stirred at rt for 15 min. The phases were separated and

the aqueous layer was extracted with CH₂Cl₂(2 × 30 ml). The

combined organic extracts were washed with saturated aqueous

NaHCO₃, dried (Na₂SO₄) and concentrated in vacuo. The resi-

due was distilled to give enone 7 (7.6 g, 37.4 mmol, 85%) as a

colourless oil: bp 110–112 ЊC/0.8 mmHg; [α]_D²²ϩ135.1 (c 2.2,

CHCl₃); ν_maxﬁlm/cm^–11674, 1603; δ_H(400 MHz, CDCl₃): 7.29

(1H, d, J 5.8, C11H), 5.36 (1H, d, J 5.8, C12H), 4.02 (1H, dd,

J 10.2, 2.5, C15H), 3.67–3.55 (2H, m, C18H₂), 2.20–2.05 (1H, m,

C17H_AH_B), 1.96–1.75 (3H, m, C16H₂and C17H_AH_B), 1.13 (3H,

s, C14Me), 1.04 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 198.3

2368

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

(0, C13), 161.4 (1, C11), 105.2 (1, C12), 85.7 (1, C15), 44.6 (2,

C18), 44.3 (0, C14), 28.9 (2, C17), 25.4 (2, C16), 19.6 (3,

C14Me), 17.8 (3, C14Me); m/z (CI, NH₃) 203 [(M ϩ H)^ϩ,

100%], 167 (8), 112 (45), 132 (8), 98 (7), 69 (6), 41 (4). Found:

(M ϩ H)^ϩ, 203.0840. C₁₀H₁₅ClO₂requires M, 203.0839.

HPLC analysis on Chiracel OD 2 (4.6 × 50 mm) using 2%

isopropanol in cyclohexane separated the two enantiomers of 7

(major enantiomer 13.24 min; minor enantiomer 14.63 min)

and established their ratio as >99:1.

(2H, br, OH), 2.00–1.89 (1H, m, C17H_AH_B), 1.83–1.74 (1H, m,

C17H_AH_B), 1.73–1.63 (1H, m, C16H_AH_B), 1.61–1.50 (1H, m,

C16H_AH_B), 1.27 (3H, s, C14Me), 1.01 (3H, s, C14Me); δ_C(100

MHz, CDCl₃): 212.9 (0, C13), 81.6 (1, C15), 73.6 (1, C10), 71.7

(1, C11), 63.2 (2, C9), 49.6 (0, C14), 44.5 (2, C18), 38.8 (2, C12),

28.7 (2, C17), 25.3 (2, C16), 24.2 (3, C14Me), 19.3 (3, C14Me);

m/z (CI) 248 [(M ϩ NH₄)^ϩ, 100%]. Found: C, 54.50; H, 7.74;

Cl, 13.72%. C₁₂H₂₁ClO₄requires C, 54.44; H, 7.94; Cl, 13.42.

(2S,6R)-2-[(R)-2-(tert-Butylcarbonyloxy)-1-hydroxyethyl]-6-(3-

chloropropyl)tetrahydro-5,5-dimethyl-2H-pyran-4-one (38)

(2S,6R)-6-(3-Chloropropyl)tetrahydro-5,5-dimethyl-2-vinyl-2H-

pyran-4-one (36)

To a solution of diols 37 (dr 13:1, 4.8 g, 18.2 mmol) and pyri-

dine (4.45 ml, 55.0 mmol) in CH₂Cl₂(35 ml) at 0 ЊC was added

pivaloyl chloride (4.6 ml, 37.5 mmol). The reaction mixture was

stirred at 0 ЊC for 1 h, treated with saturated aqueous NaHCO₃

and extracted with Et₂O (3 × 70 ml). The combined extracts

were washed with aqueous HCl (2 M, 50 ml), brine (70 ml),

dried (Na₂SO₄) and concentrated in vacuo. The residue was

ﬁltered through a pad of silica (50 g, 20–50% Et₂O in hex-

anes) and concentrated in vacuo. Diastereoisomerically pure

monopivalate ester 38 (11.6 g, 33.5 mmol, 78%) was obtained as

colourless needles by recrystallisation from hexanes–Et₂O: mp

69–70 ЊC; [α]_D¹⁹Ϫ2.0 (c 1.0, CHCl₃); ν_maxCCl₄/cm^–13599, 1716;

δ_H(400 MHz, CDCl₃): 4.27 (1H, dd, J 11.6, 3.6, C9H_AH_B), 4.12

(1H, dd, J 11.6, 6.4, C9H_AH_B), 3.96 (1H, dddd, J 14.8, 6.4, 5.6,

4.0, C10H), 3.92 (1H, dt, J 9.8, 5.3, C11H), 3.80 (1H, dd, J 12.0,

3.2, C15H), 3.58 (1H, ddd, J 10.9, 6.2, 1.1, C18H_AH_B), 3.55

(1H, ddd, J 10.9, 6.6, 1.6, C18H_AH_B), 2.82 (1H, dd, J 14.8, 9.6,

C12H_AH_B), 2.70–2.20 (1H, d, J 4.4, OH), 2.42 (1H, dd, J 14.8,

4.0, C12H_AH_B), 2.00–1.85 (1H, m, C17H_AH_B), 1.83–1.73 (1H,

m, C17H_AH_B), 1.73–1.61 (1H, m, C16H_AH_B), 1.60–1.50 (1H, m,

C16H_AH_B), 1.29 (3H, s, C14Me), 1.22 (9H, s, ^tBu), 1.03 (3H, s,

C14Me); δ_C(100 MHz, CDCl₃): 211.9 (0, C13), 179.1 (0, ester

To a stirred solution of enone 7 (17.6 g, 86.8 mmol) and cop-

per() iodide (1.0 g, 5.35 mmol) in THF (170 ml) at Ϫ95 ЊC was

added a solution of vinylmagnesium chloride (1.7 M in THF,

90 ml, 153 mmol) over 30 min. The reaction mixture was stirred

for 1.5 h at Ϫ90 ЊC and then allowed to warm up to Ϫ30 ЊC

over 1.5 h. Saturated aqueous NH₄Cl (300 ml) was added fol-

lowed by concentrated ammonia solution (60 ml). The resulting

mixture was stirred for 30 min at rt before being extracted with

Et₂O (3 × 80 ml). The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. The residue was puriﬁed

by Kugelrohr distillation to give vinyl ketone 36 (16.0 g, 63.3

mmol, 80%) as a colourless oil: bp 160–180 ЊC (bath) at 0.07

mmHg. The diastereoisomeric ratio was 95:5 according to

integration of the ¹H NMR spectrum signals (400 MHz,

CDCl₃) at δ 2.85 and 2.81 ppm (minor) and 2.67 and 2.55 ppm

(major) corresponding to C12H₂. The following data were

recorded on the mixture: [α]_D²⁰ϩ46.5 (c 1.1, CHCl₃); ν_max

ﬁlm/cm^–11712, 1128; δ_H(400 MHz, CDCl₃): 5.85 (1H, ddd,

J 17.2, 11.2, 4.8, C10H), 5.25 (1H, t, J 1.2, C9H_AH_B), 5.21 (1H,

dt, J 8.8, 1.2, C9H_AH_B), 4.56 (1H, qt, J 4.8, 1.6, C11H), 3.61

(1H, dd, J 10.0, 3.6, C15H), 3.55 (2H, t, J 6.4, C18H₂), 2.67

(1H, dd, J 14.4, 6.0, C12H_AH_B), 2.55 (1H, dd, J 14.4, 6.0,

C12H_AH_B), 2.02–1.92 (1H, m, C17H_AH_B), 1.81–1.70 (1H, m,

C17H_AH_B), 1.70–1.50 (2H, m, C16H₂), 1.11 (3H, s, C14Me),

1.06 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 211.5 (0, C13),

137.3 (1, C10), 117.9 (2, C9), 79.3 (1, C15), 72.6 (1, C11), 49.8

(0, C14), 45.0 (2, C18), 41.5 (2, C12), 29.3 (2, C17), 25.9 (2,

C16), 22.0 (3, C14Me), 19.4 (3, C14Me); m/z (CI) 248

[(M ϩ NH₄)^ϩ, 100%]. Found: (M ϩ H)^ϩ, 230.1071. C₁₂H₁₉ClO₂

requires M, 230.1074. Found: C, 62.48; H, 8.18%. C₁₂H₁₉ClO₂

requires C, 62.47; H, 8.24.

C᎐O), 82.1 (1, C15), 72.3 (1, C10), 71.2 (1, C11), 64.9 (2, C9),

᎐

49.7 (0, C14), 44.8 (2, C18), 39.1 (0, CMe₃), 38.6 (2, C12), 28.8

(2, C17), 27.4 (3, 3C, CMe₃), 25.4 (2, C16), 24.8 (3, C14Me),

19.5 (3, C14Me); m/z (CI) 349 [(M ϩ H)^ϩ, 20%]. Found: C,

58.71; H, 8.02; Cl, 10.37%. C₁₇H₂₉ClO₅requires C, 58.54; H,

8.32; Cl, 10.19.

(2S,6R)-2-[(R)-2-(tert-Butylcarbonyloxy)-1-(methoxymethoxy)-

ethyl]-6-(3-chloropropyl)tetrahydro-5,5-dimethyl-2H-pyran-

4-one (39)

A mixture of alcohol 38 (7.1 g, 20.0 mmol), N-ethyldiiso-

propylamine (10.8 ml, 62.0 mmol), tetabutylammonium

iodide (355 mg, 0.92 mmol), chloromethyl methyl ether

(4.7 ml, 62.0 mmol) and anhydrous toluene (55 ml) were

stirred at 90 ЊC for 2 h. The reaction mixture was cooled to

rt and treated with saturated aqueous NaHCO₃(30 ml). The

layers were separated and the aqueous layer was extracted with

Et₂O (2 × 30 ml). The combined organic extracts were washed

with brine (30 ml), dried (Na₂SO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (SiO₂50 g,

10–40% Et₂O in hexanes) to give the desired MOM ether 39

(2.63 g, 6.7 mmol, 97%) as a white solid: mp 42–43 ЊC

(hexanes–Et₂O); [α]_D²¹ϩ3.4 (c 1.4, CHCl₃); ν_maxCCl₄/cm^–11732,

1716, 1154; δ_H(400 MHz, CDCl₃): 4.69 (1H, d, J 6.9, OCH_A-

H_BO), 4.61 (1H, d, J 6.9, OCH_AH_BO), 4.29 (1H, dd, J 11.8, 4.3,

C9H_AH_B), 3.99 (1H, dd, J 11.8, 4.9, C9H_AH_B), 3.92 (1H, dt,

J 9.9, 4.6, C11H), 3.78 (1H, q, J 5.0, C10H), 3.68 (1H, dd, J 11.7,

3.2, C15H), 3.47 (2H, t, J 5.5, C18H₂), 3.30 (3H, s, OMe), 2.71

(1H, dd, J 14.8, 10.0, C12H_AH_B), 2.34 (1H, dd, J 14.7, 4.3,

C12H_AH_B), 1.90–1.80 (1H, m, C17H_AH_B), 1.74–1.62 (1H, m,

C17H_AH_B), 1.62–1.51 (1H, m, C16H_AH_B), 1.50–1.40 (1H, m,

C16H_AH_B), 1.19 (3H, s, C14Me), 1.11 (9H, s, ^tBu), 0.93 (3H, s,

C14Me); δ_C(100 MHz, CDCl₃): 211.3 (0, C13), 177.8 (0, ester

(2S,6R)-6-(3-Chloropropyl)-2-[(R)-1,2-dihydroxyethyl]tetra-

hydro-5,5-dimethyl-2H-pyran-4-one (37)

The procedure of Sharpless et al. was used.⁶⁴Oleﬁn 36 (10.0 g,

43.5 mmol) and hydroquinine 9-phenanthryl ether (Aldrich,

t

439 mg, 0.9 mmol) were stirred in BuOH (260 ml) until the

ligand dissolved completely. After cooling to rt, water (260 ml),

K₃Fe(CN)₆(43.3 g, 131.3 mmol) and K₂CO₃(18.3 g, 132.6

mmol) were added and the mixture was cooled to 0 ЊC before

addition of potassium osmate dihydrate (267 mg, 0.72 mmol).

The reaction mixture was stirred for 3 h at 0 ЊC, then treated

with saturated aqueous Na₂SO₃(400 ml) and water (100 ml).

After stirring at ambient temperature for 30 min the mixture

was extracted with CH₂Cl₂(400 ml ϩ 2 × 200 ml). The com-

bined organic extracts were dried (Na₂SO₄) and concentrated in

vacuo to give the crude diol. Filtration through silica gel (100 g,

10–40% EtOAc in Et₂O) aﬀorded diol 37 (8.63 g, 32.7 mmol,

75%) as a 13:1 mixture of diastereoisomers according to inte-

1

gration of H NMR signals (360 MHz, CDCl₃) derived from

the gem-dimethyl groups [δ 1.26 ppm (major) and 1.28 ppm

(minor)]: [α]_D¹⁹Ϫ8.0 (c 1.1, CHCl₃); ν_maxﬁlm/cm^–13412, 1712; δ_H

(400 MHz, CDCl₃): 3.94 (1H, dt, J 9.7, 4.6, C11-H), 3.81 (1H,

ddd, J 9.8, 6.2, 3.7, C10H), 3.77 (1H, dd, J 11.9, 3.5, C15H),

3.73 (1H, dd, J 11.4, 3.6, C9H_AH_B), 3.65 (1H, dd, J 11.3, 6.4,

C9H_AH_B), 3.58 (2H, t, J 6.0, C18H₂), 2.80 (1H, dd, J 14.6, 9.7,

C12H_AH_B), 2.38 (1H, dd, J 14.6, 4.3, C12H_AH_B), 2.00–1.74

C᎐O), 96.2 (2, O–CH –O), 81.5 (1, C15), 76.5 (1, C10), 70.3

᎐

2

(1, C11), 62.4 (2, C9), 55.8 (3, OMe), 49.3 (0, C14), 44.4 (2,

C18), 38.7 (2, C12), 38.6 (0, CMe₃), 28.4 (2, C17), 26.9 (3, 3C,

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2369

View Article Online

CMe₃), 24.9 (2, C16), 24.3 (3, C14Me), 19.1 (3, C14Me); m/z

(CI) 393 [(M ϩ H)^ϩ, 7%]. Found: C, 58.36; H, 8.12; Cl, 8.94%.

C₁₉H₃₃ClO₆requires C, 58.09; H, 8.41; Cl, 9.04.

(1S,5R,6R,8R)-5-(tert-Butylcarbonyloxy)methyl-8-(3-chloro-

propyl)-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decan-10-one

(42)

A mixture of crude oxirane 41 (3.5 g, ca. 92% pure, 6.17 mmol)

in CH₂Cl₂(15 ml) was added via cannula to a solution of

dimethoxymethane (30 ml) and P₂O₅(2.5 g, 8.8 mmol) in

CH₂Cl₂(15 ml) at 0 ЊC over 5 min. The cool bath was removed

and the reaction mixture was stirred at rt for 2 h whereupon the

reaction mixture was poured onto saturated aqueous NaHCO₃

(50 ml). The phases were separated and the aqueous layer was

extracted with CH₂Cl₂(3 × 100 ml). The combined extracts

were washed with brine (100 ml), dried (Na₂SO₄) and concen-

(2S,6R)-2-[(R)-2-(tert-Butylcarbonyloxy)-1-(methoxymethoxy)-

ethyl]-4-[(tert-butyldimethylsilyl)oxy]-6-(3-chloropropyl)-5,6-

dihydro-5,5-dimethyl-2H-pyran (40)

To a mixture of ketone 39 (17.5 g, 44.5 mmol) and triethyl-

amine (12.1 ml, 86.6 mmol) in CH₂Cl₂(70 ml) at 0 ЊC was added

TBSOTf (12.1 ml, 51.5 mmol) in a dropwise fashion over 5 min.

After the addition was complete the cooling bath was removed

and the reaction mixture stirred for 1.5 h at rt. Saturated aque-

ous NaHCO₃(200 ml) was added and the mixture extracted

with hexanes (3 × 50 ml). The combined extracts were dried

(Na₂SO₄) and concentrated in vacuo to give crude silyl enol

ether 56. TBSOH was removed under vacuum at 50 ЊC/1 mmHg

overnight to give the desired silyl enol ether 40 (19.2 g, 37.8

mmol, 85%) as a clear colourless oil: [α]_D¹⁷ϩ10.3 (c 1.1, CHCl₃);

ν_maxﬁlm/cm^–11732, 1664, 1154; δ_H(400 MHz, CDCl₃): 4.74

(1H, d, J 3.0, C12H), 4.72 (1H, d, J 6.8, OCH_AH_BO), 4.66 (1H,

d, J 6.8, OCH_AH_BO), 4.46 (1H, dd, J 11.9, 2.5, C9H_AH_B), 4.20

(1H, dd, J 7.8, 3.0, C11H), 4.08 (1H, dd, J 12.0, 5.7, C9H_AH_B),

3.71 (1H, ddd, J 7.9, 5.7, 2.5, C10H), 3.65–3.53 (2H, m,

C18H₂), 3.40 (1H, dd, J 10.6, 2.1, C15H), 3.37 (3H, s, OMe),

2.10–2.00 (1H, m, C17H_AH_B), 1.83–1.70 (1H, m, C17H_AH_B),

1.70–1.59 (1H, m, C16H_AH_B), 1.59–1.49 (1H, m, C16H_AH_B),

1

trated in vacuo. A H NMR spectrum of the crude product

showed a 15:1 ratio of diastereoisomers by integration of the

¹H NMR signals (360 MHz, CDCl₃) derived from gem-dimethyl

groups at δ 1.06 ppm (major) and 1.32 ppm (minor)]. The crude

product was puriﬁed by column chromatography (SiO₂45 g,

10–40% Et₂O in hexanes) to give ketone 42 (1.79 g, 4.75 mmol,

77%) as a white solid: mp 88–89 ЊC (hexanes–Et₂O); [α]_D²⁰ϩ166.6

(c 1.4, CHCl₃); ν_maxKBr/cm^–11724, 1282, 1164, 1150; δ_H(400

MHz, CDCl₃): 4.94 (1H, d, J 7.8, C12H), 4.87 (1H, d, J 6.5,

OCH_AH_BO), 4.83 (1H, d, J 6.5, OCH_AH_BO), 4.50 (1H, dd,

J 12.2, 1.6, C9H_AH_B), 4.30 (1H, dd, J 10.9, 7.8, C11H), 4.03

(1H, dd, J 12.2, 6.9, C9H_AH_B), 3.88 (1H, ddd, J 10.8, 6.9, 1.6,

C10H), 3.60 (2H, dt, J 6.8, 5.1, C18H₂), 3.56 (1H, dd, J 12.4,

4.0, C15H), 2.12–2.02 (1H, m, C17H_AH_B), 1.90–1.70 (1H, m,

t

C17H_AH_B), 1.70–1.61 (2H, m, C16H₂), 1.22 (12H, s, BuC᎐O

t

᎐

1.19 (9H, s, Bu), 1.01 (3H, s, C14Me), 0.93 (3H, s, C14Me),

and C14Me), 1.08 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 208.2

t

0.92 (9H, s, BuSi), 0.16 (3H, s, MeSi), 0.15 (3H, s, MeSi);

(0, C13), 178.3 (0, ester C᎐O), 89.8 (2, OCH O), 78.6 (1, C15),

᎐

2

δ (100 MHz, CDCl ): 178.2 (0, ester C᎐O), 156.0 (0, C13), 98.2

᎐

C

3

73.3 (1, C12), 72.6 (1, C10), 70.0 (1, C11), 62.8 (2, C9), 51.0 (0,

(1, C12), 96.4 (2, OCH₂O), 79.0 (1, C15), 77.3 (1, C10), 70.0

(1, C11), 64.2 (2, C9), 55.8 (3, OMe), 45.2 (2, C18), 38.7 (0, CMe₃

C14 or CMe₃), 45.0 (2, C18), 38.7 (0, CMe₃or C14), 29.4 (2,

C17), 27.0 (3, 3C, ^tBuC᎐O), 26.7 (2, C16), 19.0 (3, C14Me), 18.9

᎐

or C14), 38.4 (0, C14 or CMe₃), 29.6 (2, C17), 27.1 (3, 3C,

(3, C14Me); m/z (CI, NH₃) 394 [(M ϩ NH₄)^ϩ, 100%]. Found:

(M ϩ H)^ϩ, 376.1652. C₁₈H₃₀ClO₆requires M, 376.1653. Found:

C, 57.37; H, 7.64; Cl, 9.46%. C₁₈H₂₉ClO₆requires C, 57.37; H,

7.70; Cl, 9.43.

t

^tBuC᎐O), 26.2 (2, C16), 25.6 (3, 3C, BuSi), 23.0 (3, C14Me),

᎐

19.7 (3, C14Me), 18.1 (0, CSi), Ϫ4.5 (3, MeSi), Ϫ4.8 (3, MeSi);

m/z (CI, NH₃) 524 [(M ϩ NH₄)^ϩ, 40%]. Found: (M ϩ H)^ϩ,

507.2910. C₂₅H₄₈ClO₆Si requires M, 507.2909. Found: C, 59.31;

H, 9.01%. C₂₅H₄₇ClO₆Si requires C, 59.35; H, 9.23.

Reduction of ketone 42

Two procedures were used, the more selective being a modiﬁed

Meerwein–Ponndorf–Verley reduction. Thus, trimethylalumin-

ium (2.5 ml, 2.0 M in hexane, 5 mmol) was added to isoprop-

anol (50 ml). The solution was stirred for 30 min at rt before

solid ketone 42 (500 mg, 1.325 mmol) was added. The reaction

mixture was stirred for 24 h at rt, then concentrated in vacuo.

The residue was diluted with EtOAc (50 ml) and treated with

HCl (0.5 M, 25 ml). The phases were separated and the aqueous

phase was extracted with EtOAc (2 × 25 ml). The combined

organic extracts were dried (MgSO₄) and concentrated in vacuo

to give a mixture of the ketone 42, the alcohol 45a, and the

undesired alcohol 45b as a colourless oil. Separation by column

chromatography (SiO₂10 g, 30–50% Et₂O in hexanes) gave

ketone 42 (140 mg, 0.371 mmol, 28%), and a mixture of alco-

hols 45a and 45b (332 mg, 0.878 mmol, 66%, or 92% based on

recovered starting material) in the ratio 6:1 (major product is

the desired one). The alcohols were then separated by a second

column chromatography (SiO₂10 g, 10–50% Et₂O in hexanes)

to give alcohols 45a and 45b as colourless oils.

(2R,3S,4S,6R)-2-[(R)-2-(tert-Butylcarbonyloxy)-1-

(methoxymethoxy)ethyl]-4-[(tert-butyldimethylsilyl)oxy]-6-(3-

chloropropyl)-3,4-epoxytetrahydro-5,5-dimethyl-2H-pyran (41)

A solution of m-chloroperbenzoic acid (15.2 g, 57–80%) in

CH₂Cl₂(150 ml) was dried over Na₂SO₄, ﬁltered and stirred

with sodium hydrogen orthophosphate (11.2 g, 78.7 mmol) at rt

for 30 min. The mixture was then cooled to 0 ЊC and a solution

of enol ether 40 (8.58 g, 17.0 mmol) in CH₂Cl₂(56 ml) was

added dropwise over 20 min. The reaction mixture was stirred

for 40 min, treated with saturated aqueous Na₂SO₃and hexanes

(500 ml). The phases were separated and the organic layer was

extracted with aqueous NaOH (2 M, 2 × 70 ml), washed with

water (70 ml), brine (70 ml), dried (Na₂SO₄) and concentrated in

vacuo to aﬀord crude oxirane 41 (9.58 g, 18.4 mmol, ca. 100%,

single diastereoisomer) as a clear colourless oil: [α]_D²⁰ϩ10.0 (c

2.0, CHCl₃); ν_maxﬁlm/cm^–11732, 1152; δ_H(360 MHz, CDCl₃):

4.78 (1H, d, J 6.7, OCH_AH_BO), 4.74 (1H, d, J 6.7, OCH_AH_BO),

4.54 (1H, dd, J 12.0, 1.8, C9H_AH_B), 4.05 (1H, dd, J 9.9, 3.2,

C11H), 4.01 (1H, dd, J 12.0, 4.3, C9H_AH_B), 3.94 (1H, ddd,

J 9.9, 4.1, 1.6, C10H), 3.57–3.47 (2H, m, C18H₂), 3.51 (1H, d,

J 3.2, C12H), 3.43 (3H, s, OMe), 3.27 (1H, dd, J 10.3, 1.4,

C15H), 2.00–1.85 (1H, m), 1.70–1.50 (2H, m), 1.40–1.30

(1S,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-(3-

chloropropyl)-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decan-10-ol

(45a). [α]_D²⁰ϩ87.0 (c 2.0, CHCl₃); ν_maxﬁlm/cm^–13486, 1740, 1728;

δ_H(400 MHz, CDCl₃): 4.94 (1H, d, J 6.4, OCH_AH_BO), 4.80

(1H, d, J 6.8, OCH_AH_BO), 4.49 (1H, dd, J 12.0, 2.0, C9H_AH_B),

4.16 (1H, ddd, J 10.4, 6.8, 1.6, C10H), 4.06 (1H, dd, J 10.4, 6.4,

C11H), 4.03–3.94 (3H, m), 3.65–3.50 (2H, m, C18H₂), 3.26 (1H,

dd, J 10.4, 1.6, C15H), 2.24 (1H, br, OH), 2.10–1.90 (1H, m),

(1H, m), 1.22 (9H, s, ^tBuC᎐O), 1.05 (3H, s, C14Me), 0.98 (3H,

᎐

s, C14Me), 0.91 (9H, s, ^tBuSi), 0.14 (3H, s, SiMe), 0.06

(3H, s, SiMe); δ_C(90 MHz, CDCl₃): 178.5 (0), 96.3 (2), 86.6 (0),

76.0 (1), 71.7 (1), 68.9 (1), 63.6 (2), 60.4 (1), 56.2 (3), 45.3 (2),

39.1 (0), 38.9 (0), 30.1 (2), 27.4 (3, 3C), 26.9 (2), 25.8 (3,

3C), 18.7 (3), 18.0 (0), 16.8 (3), Ϫ3.1 (3), Ϫ3.4 (3); m/z (CI,

t

1.80–1.60 (2H, m), 1.50–1.37 (1H, m), 1.23 (9H, s, BuCOO),

NH₃) 540 [(M ϩ NH₄)^ϩ, 100%]. Found: (M ϩ H)^ϩ, 522.2781.

1.04 (3H, s, C14Me), 0.93 (3H, s, C14Me); δ_C(100 MHz,

ؒ

C₂₅H₄₇ClO₇Si requires M, 522.2780.

CDCl₃): 178.6 (0), 86.7 (2), 78.1 (1), 72.8 (1), 71.4 (1), 69.4 (1),

2370

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

67.4 (1), 63.8 (2), 45.4 (2), 40.8 (0), 39.0 (0), 29.7 (2), 27.3 (3,

3C), 26.3 (2), 23.1 (3), 12.6 (3); m/z (CI) 379 [(M ϩ H)^ϩ, 100%].

Found: C, 57.11; H, 8.10%. C₁₈H₃₁ClO₆requires C, 57.07; H,

8.19.

CDCl₃): 4.98 (1H, d, J 6.6, OCH_AH_BO), 4.84 (1H, d, J 6.6,

OCH_AH_BO), 4.48 (1H, dd, J 12.0, 1.6, C9H_AH_B), 4.19–4.13

(2H, m, C10H, C12H), 4.00 (1H, dd, J 12.0, 7.0, C9H_AH_B), 3.92

(1H, dd, J 10.6, 6.8, C11H), 3.63–3.50 (2H, m, C18H₂), 3.55

(3H, s, OMe), 3.42 (1H, d, J 10.3, C13H), 3.24 (1H, d, J 9.7,

C15H), 2.02–1.94 (1H, m, C17H_AH_B), 1.80–1.68 (1H, m,

(1S,5R,6R,8R,10R)-5-(tert-Butylcarbonyloxy)methyl-8-(3-

chloropropyl)-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decan-10-ol

(45b). [α]_D²²ϩ66.3 (c 0.3, CHCl₃); ν_maxﬁlm/cm^–13496, 1734; δ_H

(360 MHz, CDCl₃): 5.15 (1H, d, J 5.8, OCH_AH_BO), 4.89 (1H, d,

J 5.8, OCH_AH_BO), 4.30 (2H, apparent d, J 5.7, C9H₂), 4.21

(1H, dt, J 10.4, 5.2, C10H), 4.06 (1H, t, J 3.8), 3.75–3.62 (3H,

C17H_AH_B), 1.68–1.60 (1H, m, C16H_AH_B), 1.46–1.35 (1H, m,

t

C16H H ), 1.22 (9H, s, BuC᎐O), 1.00 (3H, s, C14Me), 0.86

᎐

A

B

(3H, s, C14Me); δ_C(100 MHz, CDCl ): 178.4 (0, ester C᎐O),

᎐

3

86.9 (2, OCH₂O), 79.2 (1, C13), 78.0 (1, C15), 73.3 (1, C10 or

C12), 71.2 (1, C12 or C10), 67.3 (1, C11), 63.7 (2, C9), 61.7

(3, OMe), 45.2 (2, C18), 41.6 (0, C14), 38.8 (0, CMe₃), 29.5

(2, C17), 27.1 (3, 3C, ^tBu), 26.1 (2, C16), 23.1 (3, C14Me), 13.4

(3, C14Me); m/z (CI) 393 [(M ϩ H)^ϩ, 100%]. Found: (M ϩ H)^ϩ,

393.2040. C₁₉H₃₄ClO₆requires M, 393.2044. Found: C, 58.19;

H, 8.41%. C₁₉H₃₃ClO₆requires C, 58.09; H, 8.41.

m), 3.59 (2H, t, J 5.5, C18H₂), 2.32 (1H, d, J 8.1, OH), 2.00–

t

1.58 (4H, m), 1.21 (9H, s, BuC᎐O), 1.13 (3H, s, C14Me), 0.96

᎐

(3H, s, C14Me); δ_C(100 MHz, CDCl₃): 178.3 (0), 89.1 (2), 78.0

(1, broad signal), 74.3 (1, broad signal), 73.1 (1), 70.2 (1), 65.4

(1), 62.3 (2), 45.1 (2), 38.9 (0), 38.5 (0), 29.3 (2), 27.2 (3, 3C),

24.0 (2), 22.6 (3), 22.2 (3, broad signal); δ_C(90 MHz, CDCl₃,

333 K): 178.1 (0), 89.1 (2), 78.0 (1), 74.3 (1), 73.1 (1), 70.3 (1),

65.7 (1), 62.6 (2), 44.9 (2), 38.9 (0), 38.4 (0), 29.5 (2), 27.2 (3,

3C), 24.1 (2), 22.7 (3), 22.1 (3); m/z (CI) 379 [(M ϩ H)^ϩ, 100%].

Found: C, 57.05; H, 8.05%. C₁₈H₃₁ClO₆requires C, 57.07; H,

8.19.

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-10-

methoxy-9,9-dimethyl-8-(3-phenylselanylpropyl)-2,4,7-

trioxabicyclo[4.4.0]decane (47)

Solid NaBH₄(610 mg, 16.1 mmol) was added in several batches

to a stirred suspension of diphenyl diselenide (2.5 g, 8.26 mmol)

in anhydrous ethanol (30 ml) to cause exothermic reaction. The

reaction mixture was stirred at rt until a clear yellow solution

was obtained. A solution of chloride 46 (4.2 g, 10.7 mmol) in

ethanol (30 ml) was then added via cannula and the resulting

mixture was heated at reﬂux for 10 min. The reaction mixture

was cooled to rt, poured onto saturated aqueous NaHCO₃(200

ml) and extracted with Et₂O (3 × 200 ml). The combined

organic extracts were washed with aqueous NaOH (2 M, 100

ml) and brine (100 ml), dried (MgSO₄) and concentrated in

vacuo. The residue was puriﬁed by column chromatography

(SiO₂, 10–40% Et₂O in hexanes) to give selenide 47 (5.25 g, 10.2

mmol, 96%) as a colourless oil: [α]_D²⁰ϩ71.3 (c 1.6, CHCl₃); ν_max

ﬁlm/cm^–11732, 1580, 1186, 1162, 1112, 1040; δ_H(400 MHz,

CDCl₃): 7.54–7.51 (2H, m), 7.31–7.23 (3H, m), 4.99 (1H, d,

J 6.6, OCH_AH_BO), 4.88 (1H, d, J 6.6, OCH_AH_BO), 4.47 (1H,

dd, J 12.0, 1.6, C9H_AH_B), 4.20–4.16 (1H, m, C10H collapsed by

C12H), 4.18 (1H, dd, J 10.3, 6.8, C12H), 4.02 (1H, dd, J 12.1,

6.9, C9H_AH_B), 3.97 (1H, dd, J 10.6, 6.8, C11H), 3.59 (3H,

s, OMe), 3.42 (1H, d, J 10.3, C13H), 3.23 (1H, dd, J 10.2,

1.4, C15H), 2.96 (2H, t, J 7.0, C18H₂), 2.00–1.90 (1H, m,

C17H_AH_B), 1.75–1.65 (1H, m, C17H_AH_B), 1.65–1.57 (1H,

m, C16H_AH_B), 1.47–1.40 (1H, m, C16H_AH_B), 1.25 (9H, s,

^tBuC᎐O), 1.00 (3H, s, C14Me), 0.87 (3H, s, C14Me); δ (100

Alcohols 45a and 45b were also generated by reduction of

ketone 42 with KBH₄in the presence of CeCl₃ؒ7H₂O. A solu-

tion of ketone 42 (1.80 g, 4.8 mmol) and CeCl₃ؒ7H₂O (2.6 g, 7.1

mmol) in anhydrous methanol (90 ml) was stirred at rt for 15

min and then cooled to 0 ЊC. Solid KBH₄(740 mg, 14.1 mmol)

was added (gas evolution!). After 1.5 h acetone (1 ml) was

added to the reaction mixture followed by saturated aqueous

NaHCO₃(50 ml). The methanol was removed in vacuo and the

aqueous phase extracted with CH₂Cl₂(3 × 50 ml). The com-

bined extracts were washed with brine (50 ml), dried (Na₂SO₄)

1

and concentrated in vacuo. H NMR spectrum of the crude

product showed a 1:2 ratio of diastereoisomers by integration

1

of H NMR signals (360 MHz, CDCl₃) derived from the gem-

dimethyl groups at δ 1.14 ppm (major) and 1.05 ppm (minor).

The undesired alcohol 45b was the major product. The crude

product was puriﬁed by column chromatography (SiO₂50 g,

30–50% Et₂O in hexanes) to give a mixture of alcohols 45a,b

(1.72 g, 4.56 mmol, 95%) as a colourless oil. The diastereo-

isomers were separated by column chromatography (SiO₂150 g,

hexanes–Et₂O 20–40%).

The undesired alcohol 45b was converted back to ketone 42

by Dess–Martin oxidation.⁸⁹Dess–Martin periodinane (2.7 g,

6.35 mmol) was added in one portion to a stirred solution of

alcohol 45b (1.6 g, 4.3 mmol) in CH₂Cl₂(20 ml). The reaction

mixture was stirred at rt for 25 min and treated with saturated

aqueous Na₂S₂O₃(25 ml) and saturated aqueous NaHCO₃(20

ml). After 1 h the phases were separated and the aqueous layer

was extracted with CH₂Cl₂(3 × 20 ml). The combined extracts

were dried (Na₂SO₄) and concentrated. The residue was puri-

ﬁed by column chromatography (SiO₂10 g, 10–30% Et₂O in

hexanes) to give ketone 42 (1.61 g, 4.3 mmol, 100%).

᎐

C

MHz, CDCl ): 178.3 (0, ester C᎐O), 132.7 (1, 2C), 130.3 (0),

᎐

3

129.0 (1, 2C), 126.7 (1), 86.9 (2, OCH₂O), 79.2 (1, C13), 78.1

(1, C15), 73.4 (1, C10 or C12), 71.2 (1, C12 or C10), 67.3 (1, C11),

63.6 (2, C9), 61.7 (3, OMe), 41.6 (0, C14 or CMe₃), 38.9 (0,

CMe₃or C14), 28.6 (2, C18), 27.9 (2, C17 or C16), 27.1 (3, 3C,

^tBu), 27.1 (2, C16 or C17), 23.2 (3, C14Me), 13.4 (3, C14Me);

m/z (EI) 514 [(M ϩ H)^ϩ, 33%], 357 (15), 243 (15), 193 (20),

ؒ

113 (25), 71 (100). Found: (M ϩ H)^ϩ, 514.1830. C₂₅H₃₈O₆Se

ؒ

requires M, 514.1835. Found: C, 58.47; H, 7.48%. C₂₅H₃₈O₆Se

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-

(3-chloropropyl)-10-methoxy-9,9-dimethyl-2,4,7-trioxabicyclo-

[4.4.0]decane (46)

requires C, 58.48; H, 7.41.

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-10-

methoxy-9,9-dimethyl-8-(prop-2-enyl)-2,4,7-trioxabicyclo-

[4.4.0]decane (8)

A solution of alcohol 45a (4.2 g, 11.0 mmol) in THF (25 ml)

was added dropwise to a stirred solution of sodium bis(tri-

methylsilyl)amide (2 M in THF, 7.3 ml, 14.5 mmol) in THF

(5 ml) at Ϫ78 ЊC. After 5 min methyl triﬂuoromethanesulfonate

(2.5 ml, 22.4 mmol) was added dropwise. The reaction mixture

was stirred at Ϫ78 ЊC for 20 min, treated with saturated aque-

ous NaHCO₃(50 ml) and extracted with Et₂O (3 × 50 ml). The

combined organic extracts were dried (MgSO₄) and concen-

trated in vacuo. The residue was puriﬁed by column chrom-

atography (SiO₂, 5–20% Et₂O in hexanes) to give methyl ether 46

(3.7 g, 9.41 mmol, 86%) as a colourless oil: [α]_D²¹ϩ54.7 (c 1.1,

CHCl₃); ν_maxﬁlm/cm^–11732, 1162, 1112, 1040; δ_H(400 MHz,

Sodium metaperiodate (3.5 g, 16.8 mmol) was added in one

portion to a stirred mixture of selenide 47 (5.20 g, 10.1 mmol),

water (60 ml) and MeOH (150 ml) at rt. The reaction mixture

was stirred for 25 min then diluted with water (50 ml) and

extracted with CH₂Cl₂(3 × 50 ml). To the combined organic

extracts was added 5 ml of triethylamine and the extracts were

dried (Na₂SO₄) and concentrated in vacuo. The residue was

dissolved in toluene (110 ml) and triethylamine (110 ml) and

heated at reﬂux for 10 min. The yellow reaction mixture was

allowed to cool to rt, poured onto saturated aqueous NaHCO₃

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2371

View Article Online

(200 ml) and extracted with CH₂Cl₂(3 × 100 ml). The combined

organic extracts were dried (Na₂SO₄) and concentrated at rt in

vacuo. The residue was dissolved in toluene (7 ml) and puriﬁed

by column chromatography (SiO₂, hexanes until the yellow band

eluted and then Et₂O–hexanes) (5–50%) to give oleﬁn 8 (3.55 g,

9.96 mmol, 98%) as a colourless oil: [α]_D²²ϩ25.9 (c 1.4, CHCl₃);

ν_maxﬁlm/cm^–11732, 1480, 1284; δ_H(400 MHz, CDCl₃): 5.84

(1H, ddt, J 18.0, 11.4, 6.8, C17H), 5.08 (1H, ddm, J 5.6, 1.2,

C18H_AH_B), 5.04 (1H, dm, J 1.2, C18H_AH_B), 4.99 (1H, d, J 6.6,

OCH_AH_BO), 4.86 (1H, d, J 6.6, OCH_AH_BO), 4.47 (1H, dd,

J 12.0, 1.9, C9H_AH_B), 4.20–4.15 (1H, m, C10H collapsed by

C12H), 4.18 (1H, dd, J 10.2, 6.8, C12H), 4.06 (1H, dd, J 12.0,

6.6, C9H_AH_B), 3.99 (1H, dd, J 10.6, 6.8, C11H), 3.57 (3H, s,

OMe), 3.44 (1H, d, J 10.2, C13H), 3.30 (1H, dd, J 10.1, 2.3,

3.79 (1H, m, C17H), 3.62 (1H, dd, J 10.0, 5.2, C18H_AH_B), 3.57

(3H, s, OMe), 3.52–3.43 (3H, m, C13H, C15H and C18H_AH_B),

3.12 (1H, br d, J 1.6, OH), 1.82 (1H, ddd, J 14.5, 3.6, 2.0,

C16H_AH_B), 1.44 (1H, ddd, J 14.5, 10.0, 8.0, C16H_AH_B), 1.23

t

(9H, s, BuC᎐O), 1.00 (3H, s, C14Me), 0.90 (3H, s, C14Me),

᎐

t

0.89 (9H, s, BuSi), 0.07 (6H, s, Me₂Si); δ_C(100 MHz, CDCl₃):

178.3 (0, ester C᎐O), 86.9 (2, OCH O), 78.92 (1, C13 or C15),

᎐

2

78.87 (1, C15 or C13), 73.1 (1, C12), 71.7 (1, C17), 71.2 (1, C10),

67.4 (1, C11), 66.4 (2, C18), 63.4 (2, C9), 61.7 (3, OMe), 41.7 (0,

C14 or CMe₃), 38.8 (0, CMe₃or C14), 32.2 (2, C16), 27.1 (3, 3C,

t

^tBu), 25.8 (3, 3C, BuSi), 23.1 (3, C14Me), 18.2 (0, CSi), 13.4

(3, C14Me), Ϫ5.4 (3, 2C, SiMe₂); m/z (CI, isobutane) 505

[(M ϩ H)^ϩ, 100%]. Found: (M ϩ H)^ϩ, 505.3193. C₂₅H₄₉O₈Si

requires M, 505.3197. Found: C, 59.29; H, 9.53%. C₂₅H₄₈O₈Si

requires C, 59.49; H, 9.59.

C15H), 2.19 (1H, dddt, J 14.4, 10.2, 7.1, 1.2, C16H_AH_B), 2.12–

t

2.03 (1H, m, C16H H ), 1.23 (9H, s, BuC᎐O), 1.02 (3H, s,

᎐

A

B

C14Me), 0.89 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 178.6 (0,

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-

{(2R)-3-[(tert-butyldimethylsilyl)oxy]-2-hydroxypropyl}-10-

ester C᎐O), 135.8 (1, C17), 116.7 (2, C18), 87.2 (2, OCH O),

᎐

2

79.3 (1, C13), 78.5 (1, C15), 73.5 (1, C12), 71.3 (1, C10), 67.3

(1, C11), 63.5 (2, C9), 61.8 (3, OMe), 41.6 (0, C14), 38.9 (0,

methoxy-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decane

(48b).

[α]_D²³ϩ75.3 (c 0.3, CHCl₃); ν_maxﬁlm/cm^–13568, 2958, 1186, 1732,

1472, 1040; δ_H(400 MHz, CDCl₃): 5.00 (1H, d, J 6.6, OCH_A-

H_BO), 4.86 (1H, d, J 6.6, OCH_AH_BO), 4.66 (1H, dd, J 12.1, 1.3,

C9H_AH_B), 4.22–4.15 (1H, m, C10H collapsed by C12H), 4.19

(1H, dd, J 10.3, 7.1, C12H), 4.03 (1H, dd, J 12.1, 6.9, C9H_AH_B),

3.95 (1H, dd, J 11.0, 7.0, C11H), 3.85–3.75 (1H, m, C17H), 3.62

(1H, dd, J 9.8, 2.4, C15H), 3.57 (3H, s, OMe), 3.57 (1H, dd,

J 9.9, 4.4, C18H_AH_B) 3.47 (1H, d, J 10.5, C13H), 3.47 (1H, dd,

t

CMe₃), 33.4 (2, C16), 27.2 (3, 3C, Bu), 23.2 (3, C14Me), 13.4

(3, C14Me); m/z (CI) 357 [(M ϩ H)^ϩ, 100%]. Found: (M ϩ H)^ϩ,

357.2277. C₁₉H₃₃O₆requires M, 357.2276. Found: C, 64.04; H,

9.19%. C₁₉H₃₂O₆requires C, 64.04; H, 9.00.

Sharpless asymmetric dihydroxylation of alkene 8

Alkene 8 (2 g, 5.61 mmol) and dihydroquinine 9-phenanthryl

ether⁶⁴(86 mg, 0.170 mmol) were stirred in ^tBuOH (40 ml) until

the crystals of ligand dissolved completely. After cooling to rt,

water (40 ml), K₃Fe(CN)₆(5.6 g, 17.1 mmol) and K₂CO₃(2.3 g,

16.7 mmol) were added and the mixture was cooled to 0 ЊC.

Potassium osmate dihydrate (60 mg, 0.16 mmol) was added and

the reaction mixture was stirred for 3 h at 0 ЊC, then treated

with saturated aqueous Na₂SO₃(70 ml) and extracted with

CH₂Cl₂(3 × 100 ml). The combined organic extracts were

washed with brine, dried (MgSO₄) and concentrated in vacuo to

give the crude diols as an inseparable mixture (1.5:1) of dia-

stereoisomers which were used immediately in the next step. The

isomeric ratio was ascertained by integration of the crude mix-

ture which revealed signals derived from one of the C9 protons

at δ 4.82 (dd, J 12.2, 1.2, minor) and 4.60 ppm (dd, J 12.1, 1.2,

minor)] in the ¹H NMR spectrum (360 MHz, CDCl₃).

J 10.0, 3.3, C18H_AH_B), 3.13 (1H, br d, J 4.0, OH), 1.45–1.33

t

(2H, m, C16H ), 1.23 (9H, s, BuC᎐O), 0.99 (3H, s, C14Me),

᎐

2

0.90 (9H, s, ^tBuSi), 0.86 (3H, s, C14Me), 0.07 (6H, s, Me₂Si); δ_C

(100 MHz, CDCl₃): 178.8 (0, COO), 86.9 (2, OCH₂O), 79.4 (1,

C13), 74.0 (1, C15), 73.6 (1, C10 or C12), 71.7 (1, C12 or C10),

67.9 (1, C17), 67.8 (2, C18), 67.3 (1, C11), 64.0 (2, C9), 61.8 (3,

OMe), 41.3 (0, C14 or CMe₃), 38.9 (0, CMe₃or C14), 32.0 (2,

t

C16), 27.1 (3, 3C, Bu), 25.9 (3, 3C, BuSi), 22.9 (3, C14Me),

18.3 (0, CSi), 13.2 (3, C14Me), Ϫ5.3 (3, 2C, SiMe₂); m/z (CI,

isobutane) 505 [(M ϩ H)^ϩ, 100%], 487 (8), 447 (10). Found:

(M ϩ H)^ϩ, 505.3193. C₂₅H₄₉O₈Si requires M, 505.3197. Found:

C, 59.58; H, 9.40%. C₂₅H₄₈O₈Si requires C, 59.49; H, 9.59.

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-{(2S)-3-

[(tert-butyldimethylsilyl)oxy]-2-methoxypropyl}-10-methoxy-

9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decane (49a)

tert-Butyldimethylsilyl chloride (1.72 g, 11.45 mmol) was

added in one portion to a stirred solution of crude mixture of

diols, triethylamine (1.6 ml, 11.0 mmol) and DMAP (70 mg,

0.58 mmol) in CH₂Cl₂(25 ml) at 0 ЊC. The reaction mixture was

stirred at 0 ЊC for 1 h and at rt for 2 h. Saturated aqueous

NaHCO₃(40 ml) was added and the resulting mixture was

extracted with CH₂Cl₂(3 × 100 ml). The combined organic

extracts were dried (MgSO₄) and concentrated in vacuo. The

residue was puriﬁed by column chromatography (SiO₂, 30–40%

Et₂O in hexanes) to give a mixture of 48a and 48b (2.7 g, 5.3

mmol, 95% from the alkene). Separation by chromatography on

silica gel (0–50% Et₂O in hexanes) gave the desired mono-

protected diol 48a (1.5 g, 3.0 mmol, 53%) which crystallised on

standing and the undesired monoprotected diol 48b (1.0 g, 2.0

mmol, 36%) as a colourless oil. TLC monitoring conditions:

50% Et₂O in hexanes (phosphomolybdic acid); R_f(8) 0.00

(black); R_f(48a) 0.43 (black), (48b) 0.31 (black).

A solution of alcohol 48a (525 mg, 1.04 mmol), 2,6-di-tert-

butyl-4-methylpyridine (700 mg, 3.36 mmol) and methyl tri-

ﬂuoromethanesulfonate (350 µl, 3.05 mmol) in toluene (3 ml)

was stirred at 70 ЊC (oil bath temperature) for 4 h and overnight

at 40 ЊC. The reaction mixture was cooled to rt and treated with

saturated aqueous NaHCO₃and extracted with Et₂O (3 × 20

ml). The combined organic extracts were washed with aqueous

HCl (2 M) and brine, then dried (Na₂SO₄) and concentrated

in vacuo. The residue was puriﬁed by column chromatography

(SiO₂, 5–25% Et₂O in hexanes) to give methyl ether 49a (412

mg, 0.794 mmol, 76%) as a colourless oil which solidiﬁed on

standing: mp 30–32 ЊC (hexanes–Et₂O); [α]_D²¹ϩ91.4 (c 0.3,

CHCl₃); ν_maxKBr/cm^–12958, 1732, 1472, 1108; δ_H(400 MHz,

CDCl₃): 5.01 (1H, d, J 6.6, OCH_AH_BO), 4.86 (1H, d, J 6.6,

OCH_AH_BO), 4.46 (1H, dd, J 10.1, 5.5, C9H_AH_B), 4.20–4.11

(3H, m, C9H_AH_B, C10H, C12H), 4.00 (1H, dd, J 10.2, 6.8,

C11H), 3.67 (2H, d, J 4.3, C18H₂), 3.57 (3H, s, OMe), 3.43 (1H,

d, J 10.3, C13H), 3.36 (3H, s, OMe), 3.35 (1H, dd, J 9.8, 1.6,

C15H), 3.29 (1H, dq, J 8.1, 4.3, C17H), 1.81 (1H, ddd, J 14.2,

8.1, 1.6, C16H_AH_B), 1.52 (1H, ddd, J 14.2, 10.1, 4.3, C16H_AH_B),

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-

{(2S)-3-[(tert-butyldimethylsilyl)oxy]-2-hydroxypropyl}-10-

methoxy-9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decane

(48a).

Mp 32–34 ЊC (hexanes–Et₂O); [α]_D²³ϩ58.0 (c 0.42, CHCl₃); ν_max

ﬁlm/cm^–13542, 2958, 1186, 1732, 1472, 1040; δ_H(400 MHz,

CDCl₃): 5.00 (1H, d, J 6.6, OCH_AH_BO), 4.86 (1H, d, J 6.6,

OCH_AH_BO), 4.54 (1H, dd, J 12.0, 1.7, C9H_AH_B), 4.22 (1H, ddd,

J 10.5, 6.4, 1.7, C10H), 4.17 (1H, dd, J 12.0, 6.8, C9H_AH_B), 4.14

(1H, dd, J 12.4, 6.4, C12H), 4.00 (1H, dd, J 10.6, 6.8, C11H),

1.23 (9H, s, ^tBuC᎐O), 1.00 (3H, s, C14Me), 0.90 (9H, s, ^tBuSi),

᎐

0.89 (3H, s, C14Me), 0.07 (6H, s, Me₂Si); δ_C(100 MHz, CDCl₃):

178.4 (0, ester C᎐O), 87.0 (2, OCH O), 79.8 (1, C17), 79.5

᎐

2

(1, C13), 76.2 (1, C15), 73.4 (1, C10 or C12), 71.4 (1, C12 or

C10), 67.3 (1, C11), 63.8 (2, C18 or C9), 63.6 (2, C9 or C18),

61.8 (3, OMe), 57.2 (3, OMe), 41.7 (0, C14 or CMe₃), 39.0

2372

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

t

(0, CMe₃or C14), 30.5 (2, C16), 27.3 (3, 3C, Bu), 26.1 (3, 3C,

(M ϩ H)^ϩ, 435.2779. C₂₁H₄₃O₇Si requires M, 435.2778. Found:

C, 58.08; H, 9.73%. C₂₁H₄₂O₇Si requires C, 58.03; H, 9.74.

^tBuSi), 23.4 (3, C14Me), 18.4 (0, CSi), 13.5 (3, C14Me), Ϫ5.2 (3,

2C, Me₂Si); m/z (CI, isobutane) 519 [(M ϩ H)^ϩ, 100%], 461 (8),

387 (10). Found: (M ϩ H)^ϩ, 519.3350. C₂₆H₅₁O₈Si requires M,

519.3353. Found: C, 60.31; H, 9.63%. C₂₆H₅₁O₈Si requires C,

60.20; H, 9.71.

17-epi-50

Reductive cleavage of pivalate ester 49b (320 mg, 0.62 mmol) by

the same procedure aﬀorded alcohol 17-epi-50 (264 mg, 0.61

mmol, 98%) as a clear colourless oil: [α]_D²²ϩ92.0 (c 1.5, CHCl₃);

ν_maxﬁlm/cm^–13466, 2930, 1470; δ_H(400 MHz, CDCl₃): 5.02

(1H, d, J 6.5, OCH_AH_BO), 4.83 (1H, d, J 6.5, OCH_AH_BO), 4.13

(1H, dd, J 10.3, 6.8, C12H), 4.05 (1H, ddd, J 10.6, 5.5, 2.5,

C10H), 3.96 (1H, dd, J 10.6, 6.9, C11H), 3.89–3.81 (1H, m,

C9H_AH_B), 3.71–3.64 (1H, m, C9H_AH_B), 3.62–3.55 (2H, m,

C18H₂), 3.53 (3H, s, OMe), 3.49 (1H, d, J 10.3, C13H), 3.43

(1H, d, J 10.4, C15H), 3.39 (3H, s, OMe), 3.37–3.30 (1H, m,

C17H), 2.54 (1H, br s, OH), 1.53–1.45 (1H, m, C16H_AH_B),

1.40–1.30 (1H, m, C16H_AH_B), 0.93 (3H, s, C14Me), 0.86 (9H, s,

^tBuSi), 0.82 (3H, s, C14Me), 0.02 (6H, s, Me₂Si); δ_C(100 MHz,

CDCl₃): 86.6 (2, OCH₂O), 79.4 (1, C15), 77.8 (1, C17), 73.9 (1,

C13), 73.5 (1, C10 or C12), 73.4 (1, C10 or C12), 67.4 (1, C11),

64.7 (2, C18), 62.8 (2, C9), 61.6 (3, OMe), 57.5 (3, OMe), 41.2

(1R,5R,6R,8R,10S)-5-(tert-Butylcarbonyloxy)methyl-8-{(2R)-

3-[(tert-butyldimethylsilyl)oxy]-2-methoxypropyl}-10-methoxy-

9,9-dimethyl-2,4,7-trioxabicyclo[4.4.0]decane (49b)

Methylation of 48b (530 mg, 1.05 mmol) by the same procedure

gave methyl ether 49b (403 mg, 0.78 mmol, 74%) as a colourless

oil: [α]_D¹⁹ϩ82.5 (c 0.8, CHCl₃); ν_maxKBr/cm^–12957, 1732, 1473,

1111; δ_H(400 MHz, CDCl₃): 5.02 (1H, d, J 6.6, OCH_AH_BO),

4.85 (1H, d, J 6.6, OCH_AH_BO), 4.36–4.30 (1H, m, C9H_AH_B),

4.23 (1H, dd, J 10.4, 7.0, C9H_AH_B,), 4.23–4.18 (1H, m collapsed

by signals at 4.23 and 4.21 ppm, C10H), 4.16 (1H, dd, J 10.2,

6.9, C12H), 3.98 (1H, dd, J 10.4, 6.9, C11H), 3.63 (1H, dd,

J 10.8, 4.6, C18H_AH_B), 3.60–3.54 (1H, m, C18H_AH_B), 3.56 (3H,

s, OMe), 3.51 (1H, dd, J 10.1, 1.0, C15H), 3.47 (1H, d, J 10.3,

C13H), 3.37 (3H, s, OMe), 3.38–3.31 (1H, m, C17H), 1.52 (1H,

t

(0, C14), 31.2 (2, C16), 25.8 (3, 3C, BuSi), 23.0 (3, C14Me),

18.2 (0, CSi), 13.1 (3, C14Me), Ϫ5.5 (3, 2C, Me₂Si); m/z (CI,

isobutane) 435 [(M ϩ H)^ϩ, 100%], 403 (12), 377 (10), 345 (4),

303 (23). Found: (M ϩ H)^ϩ, 435.2777. C₂₆H₄₃O₇Si requires M,

435.2778. Found: C, 58.12; H, 9.68%. C₂₁H₄₂O₇Si requires C,

58.03; H, 9.74.

ddd, J 14.3, 10.4, 1.4, C16H_AH_B), 1.40 (1H, ddd, J 14.4, 10.4,

t

2.3, C16H H ), 1.21 (9H, s, BuC᎐O), 0.97 (3H, s, C14Me),

᎐

A

B

0.88 (9H, s, ^tBuSi), 0.85 (3H, s, C14Me), 0.04 (6H, s, Me₂Si); δ_C

(100 MHz, CDCl ): 178.2 (0, ester C᎐O), 86.8 (2, OCH O), 79.4

᎐

3

2

(1, C13), 77.6 (1, C17), 74.0 (1, C15), 73.5 (1, C12), 71.3 (1,

C10), 67.0 (1, C11), 64.5 (2, C18), 63.6 (2, C9), 61.7 (3, OMe),

57.4 (3, OMe), 41.2 (0, C14 or CMe₃), 38.8 (0, CMe₃or C14),

31.5 (2, C16), 27.1 (3, 3C, Bu), 25.8 (3, 3C, BuSi), 23.1 (3,

C14Me), 18.2 (0, CSi), 13.3 (3, C14Me), Ϫ5.4 (3, 2C, Me₂Si);

m/z (CI, isobutane) 519 [(M ϩ H)^ϩ, 80%], 487 (60), 461 (10),

387 (10), 355 (100), 315 (15). Found: (M ϩ H)^ϩ, 519.3352.

C₂₆H₅₁O₈Si requires M, 519.3353. Found: C, 60.28; H, 9.59%.

C₂₆H₅₀O₈Si requires C, 60.20; H, 9.71.

(1R,5S,6S,8R,10S)-8-{(2S)-3-[(tert-Butyldimethylsilyl)oxy]-2-

methoxypropyl}-10-methoxy-9,9-dimethyl-5-{N-[(2-trimethyl-

silyl)ethoxycarbonyl]amino}-2,4,7-trioxabicyclo[4.4.0]decane

(53) via Curtius rearrangement

t

Sodium periodate (750 mg, 3.5 mmol) was added to a stirred

mixture of alcohol 50 (280 mg, 0.65 mmol), carbon tetra-

chloride (5 ml), acetonitrile (5 ml) and water (7.5 ml) followed

by ruthenium chloride trihydrate (11.3 mg, 0.043 mmol). The

reaction mixture was stirred at rt for 3 h and extracted with

CH₂Cl₂(3 × 10 ml). The combined organic extracts were dried

(MgSO₄) and concentrated in vacuo. The crude black-green

residue was dissolved in anhydrous toluene (2 ml) and concen-

trated in vacuo three times and then immediately used in the

next step.

(1R,5R,6R,8R,10S)-8-{(2S)-3-[(tert-Butyldimethylsilyl)oxy]-2-

methoxypropyl}-5-hydroxymethyl-10-methoxy-9,9-dimethyl-

2,4,7-trioxabicyclo[4.4.0]decane (50)

To a solution of ester 49a (415 mg, 0.800 mmol) in THF (5 ml)

at Ϫ80 ЊC was added Red-Al^(400 µl, 1.1 M in THF, 0.44

mmol) dropwise over 5 min. The cooling bath was removed and

the clear colourless reaction mixture allowed to warm to 0 ЊC

over 30 min whereupon acetone (40 µl) was added and the mix-

ture then poured onto ice cold aqueous NaOH (1 M, 1.9 ml).

Dichloromethane (2 ml) and H₂O (2 ml) were added and the

clear colourless phases were then separated and the aqueous

phase was extracted with CH₂Cl₂(3 × 30 ml). The combined

organic extracts were dried (MgSO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (SiO₂,

40% Et₂O in hexanes) to give alcohol 50 (327 mg, 0.75 mmol,

94%) as a clear colourless oil: [α]_D²¹ϩ67.4 (c 1.6, CHCl₃); ν_max

ﬁlm/cm^–13466, 2932, 1472; δ_H(400 MHz, CDCl₃): 5.02 (1H, d,

J 6.5, OCH_AH_BO), 4.85 (1H, d, J 6.5, OCH_AH_BO), 4.14 (1H,

dd, J 10.3, 6.0, C11H), 4.20–3.80 (2H, m, C10H, C12H), 3.85

(1H, br d, J 11.7, C9H_AH_B), 3.73–3.66 (1H, m, C9H_AH_B), 3.65

(1H, dd, J 10.8, 4.7, C18H_AH_B), 3.59 (1H, dd, J 10.8, 4.5,

C18H_AH_B), 3.56 (3H, s, OMe), 3.42 (1H, d, J 10.4, C13H), 3.36

(3H, s, OMe), 3.37–3.33 (1H, m, C15H), 3.28 (1H, dq, J 7.6,

4.4, C17H), 2.48 (1H, br s, OH), 1.76 (1H, ddd, J 14.4, 7.6, 1.6,

C16H_AH_B), 1.49 (1H, ddd, J 14.4, 9.6, 4.8, C16H_AH_B), 0.97

The crude acid 51 was dissolved in anhydrous toluene (3 ml)

to which freshly activated 4 Å molecular sieves (80 mg) and

anhydrous N-ethyldiisopropylamine (0.180 ml, 1.03 mmol)

were added. 2-Trimethylsilylethanol (0.73 ml, 5.1 mmol), dried

by the addition of freshly activated 4 Å molecular sieves (80

mg), and diphenylphosphoryl azide (0.18 ml, 0.83 mmol) were

then added. The mixture was plunged into an oil bath at 65 ЊC

and evolution of N₂gas was observed. After heating at 65 ЊC

for 3 h the reaction mixture was quenched by the addition of

saturated aqueous NaHCO₃(15 ml) and extracted with CH₂Cl₂

(3 × 20 ml). The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. The residue was puriﬁed

by column chromatography (SiO₂, 5–25% Et₂O in hexane) to

give carbamate 53 (205 mg, 0.364 mmol, 56%) as a pale yellow

oil: [α]_D¹⁸ϩ56.6 (c 0.73, CHCl₃); ν_max(CDCl₃)/cm^–13437, 2959,

1729, 1514, 1212; δ_H(400 MHz, CDCl₃): 5.51 (1H, br t, J 9.3,

C10H), 5.32 (1H, d, J 9.3, NH), 5.14 (1H, d, J 6.7, OCH_AH_BO),

4.85 (1H, d, J 7.0, OCH_AH_BO), 4.25–4.15 (3H, m, C12H and

OCH₂CH₂TMS), 3.80 (1H, dd, J 9.5, 6.9, C11H), 3.63 (1H, dd,

J 11.1, 3.5, C18H_AH_B), 3.56 (1H, dd, J 10.8, 4.0, C18H_AH_B),

3.56 (3H, s, OMe), 3.43 (1H, d, J 10.3, C13H), 3.32 (3H, s,

OMe), 3.29 (1H, d, J 9.5, C15H), 3.18 (1H, dq, J 7.8, 4.0,

C17H), 1.84 (1H, dd, J 13.2, 8.0, C16H_AH_B), 1.47 (1H, m,

C16H_AH_B), 1.05–0.95 (2H, m, CH₂TMS), 0.99 (3H, s, C14Me),

t

(3H, s, C14Me), 0.89 (9H, s, BuSi), 0.86 (3H, s, C14Me), 0.06

(6H, s, Me₂Si); δ_C(100 MHz, CDCl₃): 86.7 (2, OCH₂O), 79.9 (1,

C17), 79.2 (1, C13), 76.0 (1, C15), 73.3 (1, C10 or C11 or C12),

73.2 (1, C10 or C11 or C12), 68.0 (1, C10 or C12), 63.9 (2, C18),

63.4 (2, C9), 61.7 (3, OMe), 57.0 (3, OMe), 41.7 (0, C14), 30.5

(2, C16), 25.8 (3, 3C, ^tBuSi), 23.2 (3, C14Me), 18.2 (0, CSi), 13.1

(3, C14Me), Ϫ5.4 (3, 2C, Me₂Si); m/z (CI, isobutane) 435

[(M ϩ H)^ϩ, 100%], 403 (12), 377 (15), 345 (4), 303 (23). Found:

t

0.89 (9H, s, BuSi), 0.88 (3H, s, C14Me), 0.06 (6H, s, Me₂Si),

0.05 (9H, s, Me₃Si); δ_C(90 MHz, CDCl₃): 155.8 (0, O–C(O)–

NH), 86.3 (2, OCH₂O), 79.7 (1, C17), 79.6 (1, C13), 76.5 (1, C10

or C15), 76.3 (1, C10 or C15), 74.4 (1, C12), 70.3 (1, C11), 63.9

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2373

View Article Online

(2, OCH₂CH₂TMS), 62.1 (2, C18), 61.8 (3, OMe), 56.9 (3,

OMe), 41.7 (0, C14), 29.7 (2, C16), 25.9 (3, 3C, ^tBuSi), 23.3 (3,

C14Me), 18.3 (0, CSi), 17.7 (2, CH₂Si), 13.4 (3, C14Me), Ϫ1.5

(3, 3C, Me₃Si), Ϫ5.4 (3, 2C, Me₂Si); m/z (CI, isobutane) 564

[(M ϩ H)^ϩ, 20%], 536 (100), 488 (25), 372 (25). Found:

(M ϩ H)^ϩ, 564.3385. C₂₆H₅₄NO₈Si₂requires M, 564.3388.

80.5 (1, C13), 79.7 (1, C17), 77.2 (1, C15), 73.4 (1, C10), 72.7 (1,

C12), 67.0 (1, br, C11), 63.1 (2, C18), 61.6 (3, OMe), 57.1 (3,

OMe), 49.1 (0, C14), 29.9 (2, C16), 24.9 (3, 3C, ^tBuSi), 24.5 (3,

C14Me), 18.3 (0, CSi), 16.5 (3, br, C14Me), Ϫ5.317 (3, MeSi),

Ϫ5.373 (3, MeSi); m/z (CI, isobutane) 448 [(M ϩ H)^ϩ, 30%],

279 (20), 225 (100). Found: (M ϩ H)^ϩ, 448.2729. C₂₁H₄₂NO₇Si

requires M, 448.2731. Found: C, 56.40; H, 9.16; N, 3.12%.

C₂₁H₄₁O₇Si requires C, 56.35; H, 9.23; N, 3.13.

(1R,5S,6S,8R,10S)-8-{(2R-3-[(tert-Butyldimethylsilyl)oxy]-2-

methoxypropyl}-10-methoxy-9,9-dimethyl-5-{N-[(2-trimethyl-

silyl)ethoxycarbonyl]amino}-2,4,7-trioxabicyclo[4.4.0]decane

(17-epi-53)

(1R,5S,6S,8R,10S)-8-{(2S)-3-[(tert-Butyldimethylsilyl)oxy]-2-

methoxypropyl}-10-methoxy-9,9-dimethyl-5-{N-[(2-trimethyl-

silyl)ethoxycarbonyl]amino}-2,4,7-trioxabicyclo[4.4.0]decane

(53) via Hofmann rearrangement

Alcohol 17-epi-50 (258 mg, 0.59 mmol) was converted to carb-

amate 17-epi-53 (192 mg, 0.340 mmol, 57%) by the same pro-

cedure: [α]_D¹⁹ϩ65.0 (c 0.4, CHCl₃); ν_max(CDCl₃)/cm^–13322, 2953,

1729; δ_H(400 MHz, CDCl₃): 5.52 (1H, br t, J 8.5, C10H), 5.36

(1H, d, J 8.3, NH), 5.14 (1H, d, J 6.7, OCH_AH_BO), 4.85 (1H, d,

J 7.0, OCH_AH_BO), 4.24–4.17 (2H, m, C12H and OCH_AH_B-

CH₂TMS), 4.17–4.05 (1H, m, OCH_AH_BCH₂TMS), 3.80 (1H,

br t, J 8.5, C11H), 3.61–3.53 (2H, m, C18H₂), 3.56 (3H, s,

OMe), 3.51–3.40 (2H, m, C13H and C15H), 3.49 (3H, s, OMe),

3.31–3.25 (1H, m, C17H), 1.48–1.35 (2H, m, C16H₂), 0.98 (3H,

Procedure A. Trimethylsilylethanol (0.05 ml, 0.35 mmol),

silver acetate (4.1 mg, 0.025 mmol) followed by N-bromo-

succinimide (4.5 mg, 0.025 mmol) were added to a solution of

amide 52 (8.1 mg, 18.1 µmol) in N,N-dimethylformamide (1 ml)

at rt. The reaction mixture was stirred at rt for 24 h, treated with

saturated aqueous NaHCO₃(1 ml) and extracted with hexanes–

Et₂O (1:1) (3 × 3 ml). The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. The residue was then

puriﬁed by column chromatography (SiO₂, 0–30% Et₂O in

hexanes) to give carbamate 53 (8.9 mg, 15.9 µmol, 88%) as a pale

yellow oil.

t

s, C14Me), 0.98–0.93 (2H, m, CH₂TMS), 0.89 (9H, s, BuSi),

0.84 (3H, s, C14Me), 0.045 and 0.032 (15H, 2 × s, Me₂Si and

Me₃Si); δ_C(100 MHz, CDCl ): 155.9 (0, N–C᎐O), 86.1 (2,

᎐

3

OCH₂O), 79.6 (1, C13 or C15), 78.3 (1, C17), 76.3 (1, C10), 74.9

(1, C13 or C15), 74.4 (1, C12), 70.2 (1, C11), 65.2 (2, OCH₂–

CH₂TMS), 63.8 (2, C18), 61.8 (3, OMe), 58.1 (3, OMe), 41.3 (0,

C14), 31.9 (2, C16), 25.9 (3, 3C, ^tBuSi), 23.1 (3, C14-Me), 18.3

(0, CSi), 17.7 (2, CH₂TMS), 13.4 (3, C14Me), Ϫ1.6 (3, 3C,

SiMe₃), Ϫ5.4 (3, 2C, SiMe₂); m/z (FAB mode, PEG) 564

[(M ϩ H)^ϩ]. Found: (M ϩ H)^ϩ, 564.3384. C₂₆H₅₄NO₈Si₂

requires M, 564.3388.

Procedure B. Trimethylsilylethanol (0.05 ml, 0.35 mmol),

pyridine (2 µl, 24.5 µmol) followed by I,I-bis(triﬂuoroacet-

oxy)iodobenzene (Aldrich, 10.5 mg, 24.5 µmol) were added

to a solution of amide 52 (8.5 mg, 19.0 µmol) in acetonitrile

(0.1 ml) at rt. The reaction mixture was stirred at rt for 24 h,

treated with saturated aqueous NaHCO₃(2 ml) and extracted

with CH₂Cl₂(3 × 3 ml). The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. The residue was then

puriﬁed by column chromatography (SiO₂, 0–30% Et₂O in

hexanes) to give carbamate 53 (8.6 mg, 15.3 µmol, 81%) as a

pale yellow oil.

(1R,5S,6S,8R,10S)-5-Aminocarbonyl-8-{(2S)-3-[(tert-

butyldimethylsilyl)oxy]-2-methoxypropyl}-10-methoxy-9,9-

dimethyl-2,4,7-trioxabicyclo[4.4.0]decane (52)

Sodium periodate (50 mg, 0.24 mmol) was added to a stirred

mixture of alcohol 50 (21 mg, 0.048 mmol), carbon tetra-

chloride (0.3 ml), acetonitrile (0.3 ml) and a solution of

ruthenium chloride trihydrate in water (6.7 mM, 0.45 ml, 0.003

mmol). The reaction mixture was stirred at rt for 5 h and

extracted with CH₂Cl₂(3 × 3 ml). The combined organic

extracts were dried (MgSO₄) and concentrated in vacuo. The

crude black-green residue (24 mg) was immediately used in the

next step.

(1R,5S,6S,8R,10S)-8-{(2S)-3-[(tert-Butyldimethylsilyl)oxy]-2-

methoxypropyl}-10-methoxy-9,9-dimethyl-5-[N-(methoxalyl)-

amino]-2,4,7-trioxabicyclo[4.4.0]decane (9)

To a solution of DMAP (233 mg, 1.68 mmol) and methyl oxalyl

chloride (140 µl, 1.53 mmol) in CH₂Cl₂(2 ml) was added

carbamate 53 (178 mg, 0.316 mmol) and the reaction mixture

was stirred at rt for 6 d. The solution was then diluted with Et₂O

(5 ml) and quickly washed with ice-cooled ammonia solution

(0.1 M, 10 ml) and then washed quickly with ice-cooled aque-

ous HCl solution (0.1 M, 10 ml) and ﬁnally washed with satur-

ated aqueous NaHCO₃(10 ml). The organic phase was then

dried (Na₂SO₄) and concentrated in vacuo to give the fairly pure

N-Teoc amide 54 as a pale yellow oil (201 mg, 0.309 mmol,

98%) which was used crude in the next reaction. N-Teoc amide

54 was unstable towards column chromatography but a sample

isolated in low yield (34%) gave the following spectroscopic

data: [α]_D²⁰ϩ30.9 (c 1.1, CHCl₃); ν_max(ﬁlm)/cm^–12955, 2919,

2856, 1748, 1715, 1253; δ_H(400 MHz, CDCl₃): 6.12 (1H, d,

J 10.4, C10H), 5.13 (1H, d, J 6.7, OCH_AH_BO), 4.97 (1H, d,

J 6.7, OCH_AH_BO), 4.88 (1H, dd, J 10.4, 7.2, C11H), 4.39–4.36

(2H, m, OCH₂CH₂TMS), 4.32 (1H, dd, J 10.6, 7.2, C12H), 3.90

(3H, s, OMe), 3.66 (1H, dd, J 11.3, 3.3, C18H_AH_B), 3.59 (3H, s,

OMe), 3.49 (1H, dd, J 11.3, 3.3, C18H_AH_B), 3.47 (1H, d, J 10.3,

C13H), 3.31 (3H, s, OMe), 3.23 (1H, d, J 9.9, C15H), 3.14 (1H,

dq, J 9.0, 3.0, C17H), 1.90 (1H, dd, J 14.0, 10.0, C16H_AH_B),

1.41 (1H, ddd, J 14.0, 10.2, 3.1, C16H_AH_B), 1.16–1.10 (2H, m,

CH₂TMS), 0.97 (3H, s, C14Me), 0.90 (9H, s, ^tBuSi), 0.89 (3H, s,

C14Me), 0.074 (6H, s, Me₂Si), 0.070 (9H, s, Me₃Si); δ_C(90

MHz, CDCl₃): 163.0 (0), 161.1 (0), 152.3 (0), 87.5 (2, OCH₂O),

79.2 (1, C13), 78.7 (1, C17), 76.9 (1, C10), 76.3 (1, C15), 74.8

(1, C12), 67.3 (2, CH₂CH₂TMS), 66.7 (1, C11), 61.4 (2, C18),

To crude acid 51 in CH₂Cl₂(0.5 ml) was added 1-hydroxy-

benzotriazole monohydrate (6.5 mg, 0.048 mmol) followed by a

solution of 1,3-dicyclohexylcarbodiimide in CH₂Cl₂(96 mM,

0.5 ml, 0.048 mmol) at rt. The reaction mixture was stirred for

1 h and ammonia (gas) was bubbled into the reaction mixture for

15 min to yield a white precipitate. The solution was ﬁltered and

the solid was washed with CH₂Cl₂(4 ml). The combined ﬁltrate

was washed with saturated aqueous NaHCO₃(3 ml), ice cooled

HCl (0.1 M, 3 ml), aqueous NaHCO₃(3 ml), brine (3 ml), and

then dried (MgSO₄) and concentrated in vacuo. The residue was

puriﬁed by column chromatography (SiO₂5g, 70–100% Et₂O in

hexanes and then 0–50% EtOAc in Et₂O) to give the desired

amide 52 (19.3 mg, 0.043 mmol, 90%) as an oil: [α]_D²⁴ϩ35.9 (c

0.85, CHCl₃); ν_max(CDCl₃)/cm^–13332, 2929, 1697; δ_H(400

MHz, CDCl₃): 6.65 (1H, s, NH_AH_B), 5.45 (1H, s, NH_AH_B), 5.06

(1H, d, J 6.5, OCH_AH_BO), 4.91 (1H, d, J 6.5, OCH_AH_BO), 4.39

(1H, d, J 8.0, C10H), 4.24 (1H, dd, J 7.8, 5.4, C11H), 4.05 (1H,

dd, J 7.7, 5.2, C12H), 3.78 (1H, dd, J 11.1, 4.2, C18H_AH_B), 3.69

(1H, dd, J 11.1, 4.1, C18H_AH_B), 3.51 (3H, s, OMe), 3.51–3.46

(1H, m, C15H), 3.41–3.36 (1H, m, C17H), 3.37 (3H, s, OMe),

3.26 (1H, d, J 7.9, C13H), 1.85 (1H, ddd, J 14.5, 7.7, 2.4,

C16H_AH_B), 1.79–1.64 (1H, m, C16H_AH_B), 1.08 (3H, s, C14Me),

t

0.91 (3H, s, C14Me), 0.90 (9H, s, BuSi), 0.07 (6H, s, Me₂Si);

δ (100 MHz, CDCl ): 170.7 (0, H N–C᎐O), 87.4 (2, OCH O),

᎐

C

3

2

2374

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

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61.2 (3, OMe), 56.5 (3, OMe), 52.9 (3, OMe), 41.7 (0, C14), 30.0

(2, C16), 25.9 (3, 3C, ^tBuSi), 23.1 (3, C14Me), 18.3 (0, CSi), 17.3

(2, CH₂TMS), 13.1 (3, C14Me), Ϫ1.7 (3, 3C, Me₃Si), Ϫ5.40 (3,

MeSi), Ϫ5.46 (3, MeSi); m/z (CI, isobutane) 650 [(M ϩ H)^ϩ,

100%], 578 (70), 506 (50), 490 (50), 403 (70). Found: (M ϩ H)^ϩ,

650.3393. C₂₉H₅₆NO₁₁Si₂requires M, 650.3392. Found: C,

55.38; H, 9.52; N, 2.24%. C₂₉H₅₅O₁₁Si₂requires C, 55.38; H,

9.47; N, 2.48.

(0), 87.5 (2, OCH₂O), 79.1 (1, C13 or C15), 77.8 (1, C17), 77.2

(1, C10), 75.6 (1, C15 or C13), 74.8 (1, C12), 67.6 (2, CH₂CH₂-

TMS), 66.3 (1, C11), 64.5 (2, C18), 61.8 (3, OMe), 57.2 (3,

OMe), 52.9 (3, OMe), 41.5 (0, C14), 32.3 (2, C16), 25.9 (3, 3C,

^tBuSi), 23.1 (3, C14Me), 18.3 (0, CSi), 17.3 (2, CH₂TMS), 13.2

(3, C14Me), Ϫ1.6 (3, 3C, Me₃Si), Ϫ5.38 (3, MeSi), Ϫ5.40 (3,

MeSi); m/z (CI, isobutane) 650 [(M ϩ H)^ϩ, 55%], 622 (70), 578

(60), 506 (35), 474 (45), 458 (25), 403 (70), 371 (45). Found:

(M ϩ H)^ϩ, 650.3387. C₂₉H₅₆NO₁₁Si₂requires M, 650.3392.

Cleavage of N-Teoc amide 17-epi-54 by the same procedure

described above gave recovered carbamate 17-epi-53 (29 mg,

0.052 mmol, 15%) and 17-epi-9 (106 mg, 0.230 mmol, 63%) as

an oil: [α]_D²³ϩ70.6 (c 1.5, CHCl₃); ν_max(CHCl₃)/cm^–13330, 2954,

2930, 2857, 1717, 1529, 1111, 1026, 836, 777; δ_H(360 MHz,

CDCl₃): 7.56 (1H, d, J 9.1, NH), 5.73 (1H, t, J 9.4, C10H), 5.18

(1H, d, J 7.0, OCH_AH_BO), 4.87 (1H, d, J 7.0, OCH_AH_BO), 4.25

(1H, dd, J 10.3, 6.8, C12H), 3.96–3.90 (1H, m, C11H), 3.92

(3H, s, OMe), 3.60–3.52 (2H, m, C18H₂), 3.58 (3H, s, OMe),

3.52–3.46 (2H, m, C13H and C15H), 3.27 (3H, s, OMe), 3.22–

3.17 (1H, m, C17H), 1.51–1.38 (2H, m, C16H₂), 1.00 (3H, s,

A solution of TBAF (0.76 g, 2.4 mmol) and acetic acid (0.5

ml, 8.8 mmol) in CH₂Cl₂(9.5 ml) was added to the N-Teoc

amide 54 and immediate gas evolution was observed. The reac-

tion mixture was stirred for 4 min and then immediately diluted

with CH₂Cl₂(10 ml), and washed with water (3 × 10 ml). The

organic phase was dried (MgSO₄) and concentrated in vacuo.

The residue was then puriﬁed by column chromatography

(SiO₂, 50–70% Et₂O in hexanes) to give 9 (116 mg, 0.230 mmol,

73%) as a white solid: mp 136–138 ЊC (hexanes–ether); [α]_D²⁰

ϩ56.2 (c 0.8, CHCl₃); ν_max(CHCl₃)/cm^–13401, 3019, 2956, 2884,

1720; δ_H(360 MHz, CDCl₃): 7.53 (1H, d, J 9.2, NH), 5.71 (1H,

t, J 9.5, C10H), 5.16 (1H, d, J 7.0, OCH_AH_BO), 4.88 (1H, d,

J 7.0, OCH_AH_BO), 4.23 (1H, dd, J 10.1, 6.6, C12H), 3.93 (1H,

dd, J 9.5, 6.7, C11H), 3.93 (3H, s, OMe), 3.57 (1H, dd, J 10.8,

4.4, C18H_AH_B), 3.57 (3H, s, OMe), 3.52 (1H, dd, J 11.0, 4.1,

C18H_AH_B), 3.43 (1H, d, J 10.2, C13H), 3.30 (1H, dd, J 9.6, 0.9,

C15H), 3.27 (3H, s, OMe), 3.12 (1H, dq, J 8.2, 4.1, C17H), 1.82

(1H, ddd, J 14.3, 7.5, 1.4, C16H_AH_B), 1.47 (1H, ddd, J 14.5, 9.9,

t

C14Me), 0.88 (9H, s, BuSi), 0.87 (3H, s, C14Me), 0.04 (6H, s,

Me₂Si); δ_C(90 MHz, CDCl₃): 160.3 (0, C(O)), 156.4 (0, C(O)),

86.3 (2, OCH₂O), 79.5 (1, C13 or C15), 78.0 (1, C17), 75.2

(1, C13 or C15), 74.4 (1, C12), 74.1 (1, C10), 70.0 (1, C11), 64.8

(2, C18), 61.8 (3, OMe), 57.7 (3, OMe), 53.9 (3, OMe), 41.3

t

(0, C14), 31.7 (2, C16), 25.9 (3, 3C, BuSi), 23.2 (3, C14Me),

t

4.2, C16H_AH_B), 1.00 (3H, s, C14Me), 0.88 (12H, s, BuSi and

18.2 (0, C-Si), 13.5 (3, C14Me), Ϫ5.5 (3, 2C, Me₂-Si); m/z (CI,

isobutane) 506 [(M ϩ H)^ϩ, 100%], 476 (15), 474 (10), 448 (10),

391 (7). Found: (M ϩ H)^ϩ, 506.2785. C₂₃H₄₄NO₉Si requires M,

506.2785.

C14Me), 0.05 (6H, s, Me₂Si); δ_C(90 MHz, CDCl₃): 160.2 (0,

C(O)), 156.4 (0, C(O)), 86.4 (2, OCH₂O), 79.7 (1, C17), 79.4 (1,

C13), 76.7 (1, C15), 74.2 (1, C12), 74.0 (1, C10), 69.9 (1, C11),

62.7 (2, C18), 61.7 (3, OMe), 56.8 (3, OMe), 53.9 (3, OMe), 41.6

t

(0, C14), 29.7 (2, C16), 25.8 (3, 3C, BuSi), 23.3 (3, C14Me),

Formation of adduct 55

18.2 (0, CSi), 13.5 (3, C14Me), Ϫ5.5 (3, 2C, Me₂Si); m/z (CI,

isobutane) 506 [(M ϩ H)^ϩ, 100%], 474 (25), 448 (20), 444 (10),

374 (15). Found: (M ϩ H)^ϩ, 506.2782. C₂₃H₄₄NO₉Si requires

M, 506.2785. Found: C, 54.09; H, 8.29; N, 2.69%. C₂₃H₄₃NO₉Si

requires C, 54.63; H, 8.57; N, 2.77.

The structure and relative stereochemistry of 9 were con-

ﬁrmed by X-ray crystallography with Mo X-rays on a CAD4

diﬀractometer.^90,91Crystal data (9): C₂₃H₄₃NO₉Si, M = 505.67,

orthorhombic, a = 9.824(2), b = 12.368(2), c = 22.340(6) Å,

U = 2934(1) Å³, T = 293 K, space group P2₁2₁2₁, Z = 4, µ(Mo-

Kα) 0.13 mm^–1, 10536 reﬂections measured, 3588 unique

(R_int= 0.052) used in reﬁnement. R₁[2369 with I > 2σ(I)] =

0.083, wR₂(all data) = 0.27. The absolute structure could not be

determined from the X-ray data. The results for 9 reﬂect the

poor quality of the crystals. The atoms of the C15 side-chain

show large U_eqvalues and some atypical bond lengths which

suggest positional disorder.†

To a solution of stannane 27 (170 mg, 0.383 mmol) and 4 Å MS

in THF (2.5 ml) at Ϫ80 ЊC was added n-BuLi (265 µl, 1.43 M

solution in hexane, 0.370 mmol) and the bright yellow solution

stirred at Ϫ80 ЊC for 15 min. TMEDA (57 µl, 0.378 mmol) was

added and after 10 min at Ϫ80 ЊC, a solution of ester 9 (73 mg,

0.144 mmol) and 4 Å MS in THF (2.25 ml) was quickly added.

After stirring for 1 h maintaining the temperature below

Ϫ60 ЊC, the mixture was poured into brine (3 ml), and extracted

with CH₂Cl₂(2 × 5 ml). The combined extracts were dried

(Na₂SO₄) and concentrated to give a yellow oil which was puri-

ﬁed by column chromatography (SiO₂, PhMe–hexanes–EtOAc,

100:0:0, 0:95:5, 0:75:25, 0:50:50) to give (2R,3R,64R)-2,3-

dimethyl-4-phenylselanylmethyl-3,4-dihydro-2H-pyran (77 mg,

0.274 mmol, 74%) and the coupling product 55 (44 mg, 0.058

mmol, 41% based on the fragment 9) as a colourless oil: [α]_D²⁴

ϩ29.0 (c 0.9, CHCl₃); ν_max(CHCl₃)/cm^–13054, 2974, 2933, 2878,

1640, 1578, 1477, 1454, 1437, 1382, 1237, 1091, 736, 690; δ_H

(400 MHz, CDCl₃): 7.43–7.40 (2H, m), 7.20–7.10 (3H, m), 6.21

(1H, dd, J 2.4, 6.2, C6H), 4.40 (1H, dt, J 1.7, 6.2, C5H), 3.92

(1H, dq, J 1.7, 6.6, C2H), 2.78 (1H, dd, J 9.1, 11.8, CH_AH_B),

2.73 (1H, dd, J 7.2, 11.8, CH_AH_B), 2.65–2.57 (1H, m, C4H),

1.83–1.75 (1H, m, C3H), 1.14 (3H, d, J 6.6, C2 Me), 0.72 (3H,

d, 7.0, C3Me); δ_C(100 MHz, CDCl₃): 143.8 (1, C6), 132.6

(1, 2C), 130.0 (0), 129.0 (1, 2C), 126.8 (1), 101.9 (1, C5), 75.3

(1, C2), 37.0 (1, C4), 34.0 (1, C3), 31.0 (2, CH₂Se), 18.2

(3, C2Me), 5.1 (3, C3Me). Found: (M ϩ H)^ϩ, 282.0522.

C₁₄H₁₈OSe requires M, 282.0523.

17-epi-9

Acylation of carbamate 17-epi-53 (190 mg, 0.337 mmol) by the

same procedure described above gave the N-Teoc amide 17-epi-

54 in 50% yield: [α]_D²⁴ϩ74.2 (c 1.1, CHCl₃); ν_max(CDCl₃)/cm^–1

2954, 2922, 2857, 1749, 1715, 1252, 1109, 1026, 837, 775; δ_H

(400 MHz, CDCl₃): 6.13 (1H, d, J 10.4, C10H), 5.13 (1H, d,

J 6.7, OCH_AH_BO), 4.96 (1H, d, J 6.7, OCH_AH_BO), 4.89 (1H,

dd, J 10.4, 7.3, C11H), 4.40–4.35 (2H, m, OCH₂CH₂TMS), 4.32

(1H, dd, J 10.6, 7.3, C12H), 3.89 (3H, s, OMe), 3.62 (1H, dd,

J 10.8, 4.5, C18H_AH_B), 3.59 (3H, s, OMe), 3.55 (1H, dd, J 10.8,

4.4, C18H_AH_B), 3.53–3.50 (2H, m, J 10.3, C13H and C15H),

3.34 (3H, s, OMe), 3.23–3.18 (1H, m, C17H), 1.52 (1H, dd,

J 14.5, 9.4, C16H_AH_B), 1.41 (1H, ddd, J 14.6, 9.4, 2.3, C16H_A-

H_B), 1.15–1.10 (2H, m, CH₂TMS), 1.00 (3H, s, C14Me), 0.89

(9H, s, ^tBuSi), 0.85 (3H, s, C14Me), 0.073 (9H, s, Me₃Si), 0.044

(6H, s, Me₂Si); δ_C(90 MHz, CDCl₃): 162.9 (0), 161.1 (0), 152.6

Acyl dihydropyran 55: [α]_D²⁰Ϫ21.2 (c 0.5, CHCl₃); ν_max

(CHCl₃)/cm^–13319, 2928, 1671, 1106, 1023, 826; δ_H(400 MHz,

CDCl₃): 7.56 (1H, d, J 9.5, NH), 7.55–7.51 (2H, m), 7.31–7.28

(3H, m), 7.14 (1H, t, J 1.8, C5H), 5.68 (1H, t, J 9.3, C10H), 5.16

(1H, d, J 6.9, OCH_AH_BO), 4.88 (1H, d, J 6.9, OCH_AH_BO), 4.23

(1H, dd, J 6.4, 9.9, C12H), 4.09 (1H, dq, J 1.2, 6.5, C2H), 3.95

(1H, dd, J 6.5, 9.3, C11H), 3.57 (3H, s, OMe), 3.57 (1H, dd,

J 4.1, 10.9, C18H_AH_B), 3.50 (1H, dd, J 3.8, 11.0, C18H_AH_B), 3.42

(1H, d, J 10.0, C13H), 3.31 (1H, br d, J 9.3, C15H), 3.26 (3H, s,

OMe), 3.10–3.16 (1H, m, C17H), 2.98–2.94 (2H, m, CH₂Se),

† CCDC reference number 207/406. See http://ww w .rsc.org/suppdata/

p1/a9/a909898d/ for crystallographic ﬁles in .cif format.

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2375

View Article Online

2.85 (1H, dddd, J 2.5, 5.7, 8.1, 10.6, C4H), 2.07–1.99 (1H, m,

C3H), 1.83 (1H, ddd, J 1.4, 8.0, 14.1, C16H_AH_B), 1.57–1.47

(1H, m, C16H_AH_B), 1.39 (3H, d, J 6.5, C2Me), 1.01 (3H, s,

C14Me), 0.90 (3H, s, C14Me), 0.88 (9H, s, ^tBuSi), 0.82 (3H, d,

J 7.0, C3Me), 0.04 (6H, s, Me₂Si); δ_C(100 MHz, CDCl₃): 179.6

(0), 160.7 (0), 148.0 (0), 133.2 (1, 2C), 129.3 (1, 2C), 129.1 (0),

127.4 (1), 125.0 (1, C5), 86.4 (2, OCH₂O), 79.7 (1, C13 or C17),

79.4 (1, C17 or C13), 77.2 (1, C2 or C15), 76.8 (1, C15 or C2),

74.1 (1, C12), 73.8 (1, C10), 69.6 (1, C11), 62.3 (2, C18), 61.7 (3,

OMe), 56.9 (3, OMe), 41.4 (0, C14), 39.0 (1, C4), 33.1 (1, C3),

29.5 (2, C16 or CH₂Se), 29.4 (2, CH₂Se or C16), 25.9 (3, 3C,

^tBuSi), 23.5 (3, C14Me), 18.3 (0, CSi), 18.2 (3, C2 Me), 13.9

(3, C14Me), 5.9 (3, C3Me), Ϫ5.30 (3, MeSi), Ϫ5.33 (3, MeSi);

m/z (CI, isobutane) 756 [(M ϩ H)^ϩ, 30%], 698 (20), 598 (100),

540 (60). Found: (M ϩ H)^ϩ, 756.3047. C₃₆H₅₈NO₉SeSi requires

M, 756.3045.

dried (Na₂SO₄) and concentrated in vacuo, to give the crude

diastereoisomeric acetals as a colourless oil which were used

immediately in the next step.

A yellow solution of benzoyl chloride (15 µl, 0.129 mmol),

DMAP (10 mg, 0.082 mmol) and N,N-diisopropylethylamine

(80 µl, 0.459 mmol) in CH₂Cl₂(0.5 ml) and 4 Å MS was added

to a stirred solution of the crude acetals in CH₂Cl₂(1.5 ml). The

reaction mixture was stirred for 1 h at rt before MeOH (0.5 ml)

was added. After 10 min the mixture was poured into brine

(3 ml) and extracted with CH₂Cl₂(3 × 5 ml). The combined

organic extracts were dried (Na₂SO₄) and concentrated in

vacuo. The residue was puriﬁed by column chromatography on

silica gel (5 g) eluting with 50% hexanes–Et₂O in hexanes to give

26 mg (29.1 µmol, 73% over 3 steps) of a mixture of the two

diastereoisomers at C7 in the ratio 6:1 (determined by integra-

tion of signals derived from C12H [¹H NMR (400 MHz, C₆D₆):

δ 4.24 (dd, major) and 4.17 (dd, minor)]. The mixture was puri-

ﬁed by column chromatography on silica gel (5 g) eluting with

10–20% Et₂O in CH₂Cl₂to give diastereoisomer 56 (16 mg, 17.9

µmol, 45%) along with an impure mixture of 56 and its C7-

epimer (8 mg, 8.95 µmol, 23%). Data for benzoate 56: [α]_D²⁰

ϩ50.0 (c 0.55, CHCl₃); ν_max(CHCl₃)/cm^–13358, 2929, 2856,

1732, 1706, 1524, 1471, 1263, 1123, 1032, 836; δ_H(400 MHz,

C₆D₆): 8.23 (2H, ddm, J 1.6, 8.3), 7.41 (2H, ddm, J 1.6, 8.1),

7.31 (1H, d, J 9.6, NH), 7.10–6.97 and 6.95–6.85 (6H, 2 m), 5.87

(1H, s, C7H), 5.86 (1H, t, J 9.7, C10H), 4.50 (1H, d, J 7.0,

OCH_AH_BO), 4.44 (1H, d, J 7.0, OCH_AH_BO), 4.24 (1H, dd,

J 6.6, 10.2, C12H), 3.95 (1H, dd, J 2.6, 11.7, C18H_AH_B), 3.86

(1H, dd, J 2.4, 11.7, C18H_AH_B), 3.71 (1H, dd, J 6.7, 9.5, C11H),

3.49 (1H, dq, J 2.3, 6.7, C2H), 3.46 (1H, br d, J 8.8, C15H),

3.42–3.38 (1H, m, C17H), 3.32 (3H, s, OMe), 3.21 (3H, s,

OMe), 3.05 (1H, d, J 10.1, C13H), 2.85 (3H, s, OMe), 2.78 (2H,

dd, J 7.9, SeCH₂), 2.41–2.31 (1H, m, C4H), 2.20 (1H, dd, J 3.5,

8.1, C5H_AH_B), 2.09 (1H, ddd, J 0.8, 5.6, 10.6, C16H_AH_B), 1.69

(1H, t, J 13.0, C5H_AH_B), 1.66–1.57 (1H, m, C16H_AH_B), 1.52–

Formation of adduct 17-epi-55

Acylation of dihydropyran 6 (135 mg, 0.304 mmol) by the

procedure described above gave (2R,3R,4R)-3,4-dihydro-2,3-

dimethyl-4-phenylselanylmethyl-2H-pyran (66 mg, 0.235 mmol,

77%) and the coupling product 17-epi-55 (36 mg, 0.048 mmol,

39% based on the right half fragment 17-epi-9) as a colourless

oil: [α]_D²³ϩ16.0 (c 1.0, CHCl₃); ν_max(CHCl₃)/cm^–13366, 2928,

2855, 1727, 1670, 1104, 1024, 836; δ_H(400 MHz, CDCl₃): 7.63

(1H, d, J 8.7, NH), 7.52–7.45 (2H, m), 7.30–7.20 (3H, m), 7.15

(1H, t, J 1.8, C5H), 5.67 (1H, t, J 9.2, C10H), 5.14 (1H, d, J 7.0,

OCH_AH_BO), 4.85 (1H, d, J 6.9, OCH_AH_BO), 4.21 (1H, dd, J 6.5,

10.2, C12H), 4.06 (1H, dq, J 1.3, 6.5, C2H), 3.93 (1H, dd, J 6.6,

9.5, C11H), 3.54 (3H, s, OMe), 3.52–3.43 (4H, m, C18H₂,

C15H, C13H), 3.23–3.14 (1H, m, C17H), 3.19 (3H, s, OMe),

2.90–2.84 (2H, m, CH₂Se), 2.84–2.77 (1H, m, C4H), 2.10–1.92

(1H, m, C3H), 1.50–1.40 (1H, m, C16H_AH_B), 1.30–1.18 (1H, m,

C16H_AH_B), 1.34 (3H, d, J 6.5, C2Me), 0.97 (3H, s, C14Me),

t

0.84 (9H, s, BuSi), 0.83 (3H, s, C14Me), 0.73 (3H, d, J 7.0,

t

1.48 (1H, m, C3H), 0.99 (3H, s, C14Me), 0.96 (9H, s, BuSi),

C3Me), 0.00 (6H, s, Me₂Si); δ_H(400 MHz, C₆D₆): 7.49 (1H, d,

J 9.0, NH), 7.35–7.32 (2H, m), 7.16 (1H, t, J 1.9, C5H), 6.97–6.91

(3H, m), 5.81 (1H, t, J 9.5, C10H), 4.68 (1H, d, J 6.9, OCH_A-

H_BO), 4.57 (1H, d, J 6.9, OCH_AH_BO), 4.19 (1H, dd, J 6.9, 10.4,

C12H), 3.53–3.40 (5H, m), 3.38 (3H, s, OMe), 3.38–3.36 (1H,

m), 3.19 (3H, s, OMe), 2.98 (1H, J 10.4, C13H), 2.59–2.51 (2H,

m), 2.50–2.44 (1H, m), 1.61–1.53 (1H, m, C16H_AH_B), 1.48–1.40

(2H, m, C3H and C16H_AH_B), 0.95 (3H, d, J 6.7, C2Me), 0.91

0.89 (3H, s, C14Me), 0.80 (3H, d, J 6.6, C2Me), 0.77 (3H, d,

J 7.1, C3Me), 0.101 (3H, s, MeSi), 0.091 (3H, s, MeSi); δ_C(100

MHz, C₆D₆): 165.3 (0), 164.0 (0), 132.0 (1), 131.5 (1), 129.7 (0),

129.0 (0), 128.9 (1, 2C), 128.0 (1, 2C), 127.4 (1, 2C), 125.6

(1, 2C), 98.0 (0, C6), 85.2 (2, OCH₂O), 78.0 (1, C13 or

C17), 77.9 (1, C17 or C13), 75.1 (1, C15), 73.7 (1, C12), 72.9 (1,

C7 or C10), 71.4 (1, C10 or C7), 70.3 (1, C11), 69.4 (1, C2), 61.0

(2, C18), 59.9 (3, OMe), 55.1 (3, OMe), 46.7 (3, OMe), 40.4

(0, C14), 34.2 (1, C3), 33.8 (1, C4), 30.8 (2, CH₂Se), 30.0 (2, C5),

28.5 (2, C16), 24.9 (3, 3C, ^tBuSi), 22.2 (3, C14Me), 17.3 (0, CSi),

16.8 (3, C2 Me), 12.5 (3, C14Me), 3.4 (3, C3Me), Ϫ6.39 (3,

MeSi), Ϫ6.49 (3, MeSi); m/z (FAB mode) 916 [(M ϩ Na)^ϩ, 4%],

914 (2), 758 (1), 628 (1), 479 (4). Found: (M ϩ Na)^ϩ, 916.3547.

C₄₄H₆₇NO₁₁SeSiNa requires M, 916.3547.

t

(9H, s, BuSi), 0.85 (3H, s, C14Me), 0.82 (3H, s, C14Me), 0.55

(3H, d, J 7.0, C3Me), 0.004 (3H, s, MeSi), Ϫ0.003 (3H, s,

MeSi); δ_C(100 MHz, C₆D₆): 179.4 (0), 160.5 (0), 147.2 (0), 131.9

(1, 2C), 128.1 (1, 2C), 126.6 (0), 126.0 (1), 122.4 (1, C5), 84.9 (2,

OCH₂O), 77.9 (1, C13), 77.0 (1), 75.0 (1), 73.8 (1), 73.7 (1, C12),

72.7 (1, C10), 68.9 (1), 63.5 (2, C18), 60.0 (3, OMe), 56.6 (3,

OMe), 40.1 (0, C14), 37.7 (1), 32.0 (1), 31.0 (2, C16), 28.2 (2,

CH₂Se), 24.8 (3, 3C, ^tBuSi), 21.6 (3, C14Me), 17.2 (0, CSi), 16.7

(3, C2Me), 12.2 (3, C14Me), 4.5 (3, C3Me), Ϫ6.47 (3, MeSi),

Ϫ6.52 (3, MeSi); m/z (CI, isobutane) 756 [(M ϩ H)^ϩ, 20%], 598

(100), 540 (20). Found: (M ϩ H)^ϩ, 756.3049. C₃₆H₅₈NO₉SeSi

requires M, 756.3045.

17-epi-56

Acyldihydropyran 17-epi-55 (30.0 mg, 39.7 µmol) was con-

verted to 17-epi-56 (14 mg, 15.7 µmol, 40%) by the procedure

described above: [α]_D²⁰ϩ61.4 (c 0.7, CHCl₃); ν_max(CHCl₃)/cm^–1

3359, 2929, 2856, 1732, 1706, 1523, 1471, 1263, 1124, 1030, 836;

δ_H(400 MHz, C₆D₆): 8.21 (2H, ddm, J 1.5, 8.0), 7.45 (2H, ddm,

J 1.5, 8.0), 7.36 (1H, d, J 9.6, NH), 7.05–6.88 (6H, m), 5.96 (1H,

t, J 9.7, C10H), 5.91 (1H, s, C7H), 4.54 (1H, d, J 7.3, OCH_A-

H_BO), 4.52 (1H, d, J 7.5, OCH_AH_BO), 4.27 (1H, dd, J 6.9, 10.2,

C12H), 3.73 (1H, dd, J 7.0, 9.6, C11H), 3.70 (1H, dd, J 9.4,

10.0, C15H), 3.67 (1H, dd, J 4.6, 9.9, C18H_AH_B), 3.62–3.57

(1H, m, C18H_AH_B) 3.58 (3H, s, OMe), 3.51 (1H, dq, J 2.3, 6.6,

C2H), 3.51–3.43 (1H, m, C17H), 3.20 (3H, s, OMe), 3.01 (1H,

J 10.3, C13H), 2.86 (1H, dd, J 7.1, 12.0, SeCH_AH_B), 2.86 (3H, s,

OMe), 2.79 (1H, dd, J 8.6, 12.1, SeCH_AH_B), 2.44–2.35 (1H, m,

C4H), 2.26 (1H, dd, J 3.5, 13.1, C5H_AH_B), 1.77 (1H, t, J 13.0,

C5H_AH_B), 1.65 (1H, dd, J 10.2, 14.2, C16H_AH_B), 1.67–1.50

(1H, m, C3H), 1.46 (1H, br dd, J 9.3, 13.8, C16H_AH_B), 0.95

Synthesis of benzoate 56

To a solution of acyldihydropyran 55 (30.0 mg, 39.7 µmol) in

THF (2.5 ml) at Ϫ95 ЊC was added dropwise LiBH(s-Bu)₃(0.1

ml, 1.0 M solution in THF, 0.1 mmol). After 10 min at Ϫ95 ЊC

the mixture was treated with brine (1 ml) and extracted with

CH₂Cl₂(2 × 4 ml). The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. The residue was immedi-

ately dissolved in CH₂Cl₂(2 ml) and MeOH (0.2 ml). Cam-

phorsulfonic acid (3.0 mg, 0.012 mmol) was added and the

solution stirred at rt for 1.5 h. Solid K₂CO₃(25 mg, 0.18 mmol)

was added slowly during 10 min after which the mixture was

poured into saturated aqueous NaHCO₃(2 ml) and extracted

with CH₂Cl₂(3 × 5 ml). The combined organic extracts were

2376

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

t

(9H, s, BuSi), 0.92 (3H, s, C14Me), 0.88 (3H, s, C14Me), 0.81

d, J 7.0, C3Me), 0.81 (3H, d collapsed by C14Me, J 6.6, C2Me),

0.80 (3H, s, C14Me), 0.76 (3H, s, C14Me); δ_C(100 MHz,

C D ): 171.1 (0, C8), 144.6 (0, C4), 109.6 (2, ᎐CH ), 99.2 (0,

(3H, d, J 6.4, C2 Me), 0.80 (3H, d, J 7.1, C3Me), 0.063 (3H, s,

MeSi), 0.061 (3H, s, MeSi); δ_C(100 MHz, C₆D₆): 165.4 (0),

146 (0), 132.0 (1), 131.7 (1, 2C), 129.4 (0), 128.9 (1, 2C), 128.1

(1, 2C), 127.3 (1, 2C), 125.8 (1), 124.5 (1), 98.0 (0, C6), 84.9

(2, OCH₂O), 77.8 (1, C13), 76.8 (1, C17), 74.6 (1, C15), 73.8

(1, C12), 72.9 (1, C10), 71.4 (1, C7), 70.4 (1, C11), 69.5 (1, C2),

63.9 (2, C18), 60.0 (3, OMe), 56.8 (3, OMe), 46.7 (3, OMe), 40.1

(0, C14), 34.1 (1, C4), 33.8 (1, C3), 32.2 (2, C16), 30.9 (2, CH₂Se),

30.3 (2, C5), 24.9 (3, 3C, ^tBuSi), 21.9 (3, C14Me), 17.3 (0, CSi),

16.8 (3, C2 Me), 12.4 (3, C14Me), 3.3 (3, C3Me), Ϫ6.3 (3,

MeSi), Ϫ6.4 (3, MeSi); m/z (FAB mode) 916 [(M ϩ Na)^ϩ, 28%],

914 (16), 758 (6), 329 (24). Found: (M ϩ Na)^ϩ, 916.3548.

C₄₄H₆₇NO₁₁SeSiNa requires M, 916.3547.

᎐

6

2

C6), 85.1 (2, OCH₂O), 77.7 (1, C13 or C17), 77.5 (1, C17 or

C13), 74.4 (1, C15), 73.9 (1, C12), 72.9 (1, C10), 70.9 (1, C7

or C11), 70.7 (1, C11 or C7), 68.1 (1, C2), 62.6 (2, C18), 60.0

(3, C13OMe), 55.2 (3, C17OMe), 47.0 (3, C6OMe), 40.4 (1, C3),

40.3 (0, C14), 32.9 (1, C5), 29.3 (2, C16), 21.5 (3, C14Me_eq), 16.5

(3, C2Me_ax), 11.9 (3, C14Me), 11.0 (3, C3Me); m/z (FAB mode)

540 [(M ϩ Na)^ϩ, 100%], 507 (20), 486 (25), 176 (32). Found:

(M ϩ Na)^ϩ, 540.2790. C₂₅H₄₃NO₁₀Na requires M, 540.2785.

17-epi-Mycalamide B

Selenide 17-epi-56 (14 mg, 15.7 µmol) gave 17-epi-mycalamide

B (17-epi-3) (6.3 mg, 12.2 µmol, 78% over 4 steps) by the pro-

cedure described above: ν_max(CHCl₃)/cm^–13356, 2971, 2933,

1686, 1524, 1468, 1382, 1194, 1109, 1074, 1033, 959, 878, 790;

δ_H(400 MHz, C₆D₆): 7.48 (1H, d, J 9.9, NH), 5.94 (1H, t, J 9.9,

Mycalamide B (3)

Sodium periodate (30 mg, 0.14 mmol) was added in one portion

to a solution of the diastereoisomerically pure selenide 56 (10

mg, 11.2 µmol) in MeOH–H₂O–CH₂Cl₂(3:1:1, 3.5 ml). After

30 min the mixture was diluted with Et₂O (10 ml) and Et₃N (0.5

ml) and washed with H₂O (2 × 5 ml), dried (Na₂SO₄) and con-

centrated in vacuo to give the selenoxide as a colourless oil

which was dissolved in toluene (2 ml) whereupon Et₃N (2 ml,

14.3 µmol) was added. After reﬂuxing for 5 min, the reaction

mixture was poured into saturated aqueous NaHCO₃(5 ml)

and extracted with Et₂O (2 × 10 ml). The organic extracts were

dried (Na₂SO₄) and concentrated in vacuo to give a pale yellow

oil which was dissolved in MeOH (3 ml) to which was added

aqueous LiOH (0.3 ml, 1.0 M, 0.3 mmol). After 30 min at rt the

mixture was concentrated, the residue was dissolved in Et₂O

(5 ml), washed with H₂O (2 × 2 ml) and brine (2 ml), dried

(Na₂SO₄), and concentrated in vacuo to give 18-O-TBS mycal-

amide B as a yellow oil which was used immediately in the next

step.

TBAF (22 mg, 70 µmol) was added to a solution of 18-O-

TBS mycalamide B in THF (1 ml) and after 1 h at rt the reac-

tion mixture was diluted with Et₂O (5 ml) and washed with

saturated aqueous NaHCO₃(2 ml). The aqueous phase was

extracted with CH₂Cl₂(2 × 5 ml) and the combined organic

layers dried (Na₂SO₄) and concentrated in vacuo to give an oil

which was puriﬁed by column chromatography on silica gel

(1 g) eluting with hexanes–EtOAc–NEt₃(100:0:1, 75:25:1,

50:50:1, 25:75:1, 0:100:1) to give mycalamide B (3) (4.5 mg,

8.69 µmol, 78% over 4 steps): ν_max(CHCl₃)/cm^–13359, 2971,

2933, 1686, 1522, 1468, 1382, 1193, 1109, 1075, 1032, 959, 879,

789; δ_H(400 MHz, CDCl₃): 7.54 (1H, d, J 9.6, NH), 5.83 (1H,

t, J 9.6, C10H), 5.14 (1H, d, J 7.0, OCH_AH_BO), 4.88 (1H, d,

C10H), 4.75–4.70 (2H, m, ᎐CH ), 4.57 (1H, d, J 6.9, OCH -

᎐

2

A

H_BO), 4.54 (1H, d, J 6.9, OCH_AH_BO), 4.23 (1H, dd, J 6.9, 10.2,

C12H), 4.17 (2H, s, C7H and C7OH), 3.82 (1H, dq, J 2.6, 6.6,

C2H), 3.65 (1H, dd, J 7.1, 9.7, C11H), 3.61–3.55 (2H, m,

C18H₂), 3.51 (1H, d, J 9.3, C15H), 3.32 (3H, s, C13OMe),

3.27–3.18 (1H, m, C17H), 3.21 (3H, s, C6OMe), 3.06 (3H, s,

C17OMe), 2.96 (1H, d, J 10.4, C13H), 2.60 (1H, d, J 13.9,

C5H_AH_B), 2.42 (1H, br d, J 13.9, C5H_AH_B), 1.88 (1H, dq, J 2.6,

7.1, C3H), 1.65 (1H, dd, J 8.2, 14.8, C16H_AH_B), 1.50 (1H, br s,

C18OH), 1.27 (1H, ddd, J 2.8, 10.0, 14.3, C16H_AH_B), 0.90 (3H,

d, J 7.1, C3Me), 0.83 (3H, s, C14Me), 0.81 (3H, d, J 6.6, C2Me),

0.77 (3H, s, C14Me); δ_C(100 MHz, C₆D₆): 171.1 (0, C8),

145.0 (0, C4), 109.4 (2, ᎐CH ), 99.1 (0, C6), 85.0 (2, OCH O),

᎐

2

78.3 (1, C17), 77.8 (1, C13), 75.9 (1, C15), 73.8 (1, C12), 72.8

(1, C10), 71.1 (1, C7), 70.1 (1, C11), 68.0 (1, C2), 62.6 (2, C18),

60.0 (3, C13OMe), 55.6 (3, C17OMe), 47.1 (3, C6OMe), 40.3

(1, C3), 40.1 (0, C14), 33.0 (1, C5), 31.5 (2, C16), 21.7 (3,

C14Me), 16.5 (3, C2 Me), 12.1 (3, C14Me), 11.1 (3, C3Me); m/z

(FAB mode) 540 [(M ϩ Na)^ϩ, 100%], 508 (20), 486 (25). Found:

(M ϩ Na)^ϩ, 540.2789. C₂₅H₄₃NO₁₀Na requires M, 540.2785.

2. Theopederin D

(1S,5R,6R,8R,10S)-5-Hydroxymethyl-10-methoxy-9,9-

dimethyl-8-(prop-2-enyl)-2,4,7-trioxabicyclo[4,4,0]decane (57)

To a solution of ester 8 (814 mg, 2.29 mmol) in THF (10 ml) at

Ϫ70 ЊC was added Red-Al^(Aldrich, 1.55 M in PhMe and

THF, 3 ml) dropwise over 5 min. The cooling bath was removed

and the clear colourless reaction mixture was allowed to warm

up to 0 ЊC over 30 min. After such time acetone (0.4 ml) was

added. The mixture was then poured onto ice cold NaOH (2 M,

10 ml). CH₂Cl₂(20 ml) and H₂O (20 ml) were then added. The

clear colourless phases were then separated. The aqueous phase

was extracted with CH₂Cl₂(3 × 30 ml), dried (Na₂SO₄) and

concentrated. Puriﬁcation by column chromatography (SiO₂,

50–60% Et₂O in hexanes) gave the alcohol 57 (608 mg, 2.24

mmol, 98%) as a clear colourless oil: [α]_D²³ϩ102.3 (c 1.2, CHCl₃);

ν_maxﬁlm/cm^–13465, 1640, 1468, 1177, 1110; δ_H(400 MHz,

CDCl₃): 5.77 (1H, ddt, J 17.0, 10.4, 6.8, C17H), 5.07 (1H, dm,

J 5.2, C18H_AH_B), 5.03 (1H, m, C18H_AH_B), 5.01 (1H, d, J 6.4,

OCH_AH_BO), 4.82 (1H, d, J 6.4, OCH_AH_BO), 4.15 (1H, dd,

J 10.4, 6.4, C12H), 4.01 (2H, m, C11H, C10H), 3.83 (1H, ddd,

J 12.0, 6.8, 2.8 collapses to dd, J 12.0, 2.8 after D₂O shake,

CH_AH_BOH), 3.66 (1H, ddm, J 11.6, 5.6 collapses to dd, J 11.6,

5.2 after D₂O shake, CH_AH_BOH), 3.56 (3H, s, OMe), 3.43 (1H,

d, J 10.4, C13H), 3.26 (1H, dd, J 10.4, 2.0, C15H), 2.27 (1H, t,

J 6.4, OH), 2.16 (1H, dddt, J 11.3, 7.4, 2.0, 1.2, C16H_AH_B), 2.03

(1H, dddt, J 14.2, 10.3, 6.8, 0.8, C16H_AH_B), 1.00 (3H, s,

C14Me), 0.87 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 135.9 (1),

117.0 (2), 87.0 (2), 79.3 (1), 78.5 (1), 73.5 (1), 73.2 (1), 68.0 (1),

63.0 (2), 61.9 (3), 41.7 (0), 33.5 (2), 23.2 (3), 13.2 (3); m/z (CI,

J 6.7, OCH H O), 4.88 (1H, br s, ᎐CH H ), 4.75 (1H, br s,

᎐

A

B

A

B

᎐CH H ), 4.31 (1H, d, J 2.0, C7H), 4.24 (1H, dd, J 6.8, 10.2,

᎐

A

B

C12H), 4.06 (1H, dq, J 2.8, 6.5, C2H), 3.90 (1H, d, J 2.1,

C7OH), 3.81 (1H, dd, J 6.8, 9.6, C11H), 3.72–3.65 (1H, m,

C18H_AH_B), 3.58 (3H, s, OMe), 3.54–3.48 (1H, m, C18H_AH_B),

3.46 (1H, d, J 10.4, C13H), 3.48–3.42 (1H, m hidden, C15H),

3.32 (3H, s, OMe), 3.27 (3H, s, OMe), 3.25–3.18 (1H, m,

C17H), 2.39 (1H, d, J 14.0, C5H_AH_B), 2.30 (1H, dq, J 2.8, 7.1,

C3H), 2.26 (1H, dm, J 13.9, C5H_AH_B), 1.60–1.54 (2H, m,

C16H₂), 1.23 (3H, d, J 6.6, C2Me), 1.04 (3H, d, J 7.2, C3Me),

1.01 (3H, s, C14Me), 0.89 (3H, s, C14Me); δ_H(400 MHz, C₆D₆):

7.58 (1H, d, J 9.8, NH), 5.83 (1H, t, J 9.9, C10H), 4.71 (1H, t,

J 1.8, ᎐CH H ), 4.66 (1H, t, J 1.9, ᎐CH H ), 4.56 (1H, d, J 7.0,

᎐

A

B

A

B

OCH_AH_BO), 4.53 (1H, d, J 6.9, OCH_AH_BO), 4.24 (1H, dd,

J 7.0, 10.6, C12H), 4.16 (1H, s, C7H), 4.07 (1H, br s, C7OH),

3.85–3.77 (1H, m, C18H_AH_B), 3.80 (1H, dq, J 1.8, 6.6, C2H),

3.74–3.68 (1H, m, C18H_AH_B), 3.69 (1H, dd, J 7.0, 10.0, C11H),

3.40 (1H, dd, J 5.6, 6.1, C15H), 3.33–3.28 (1H, m, C17H), 3.22

(3H, s, C13OMe), 3.15 (3H, s, C6OMe), 3.03 (3H, s, C17OMe),

2.94 (1H, d, J 10.5, C13-H), 2.60 (1H, d, J 14.0, C5-H_AH_B), 2.40

(1H, dt, J 1.8, 14.0, C5H_AH_B), 2.33 (1H, br s, C18OH), 1.86

(1H, dq, J 1.7, 7.0, C3H), 1.59–1.55 (2H, m, C16H₂), 0.92 (3H,

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2377

View Article Online

isobutane) 373 [(M ϩ H)^ϩ, 50%], 231 (100). Found: (M ϩ H)^ϩ,

273.1704. C₁₄H₂₅O₅requires M, 273.1702.

(1), 77.2 (1), 75.2 (1), 67.7 (2), 67.0 (1), 62.0 (3), 53.1 (3), 41.8

(0), 33.7 (2), 23.1 (3), 17.5 (2), 13.3 (3), Ϫ1.5 (3, 3C); m/z (EI)

ϩ

487 [M^ϩ, 1%], 446 (7), 449 (8), 374 (14), 362 (35). Found: M

,

ؒ

(1S,5R,6R,8R,10S)-10-Methoxy-9,9-dimethyl-8-(prop-2-enyl)-

5-{N-[(2-trimethylsilyl)ethoxycarbonyl]amino}-2,4,7-trioxa-

bicyclo[4,4,0]decane (58)

487.2219. C₂₂H₃₇O₉NSi requires M, 487.2238.

(1S,5R,6R,8R,10S)-9,9-Dimethyl-10-methoxy-5-[N-(meth-

oxalyl)amino]-8-(prop-2-enyl)-2,4,7-trioxabicyclo[4,4,0]decane

(10)

Pyridinium dichromate (3.0 g, 7.97 mmol) was added to a mix-

ture of alcohol 57 (200 mg, 0.735 mmol) in anhydrous DMF (4

ml) and stirred at rt. After 8 h a further portion of pyridinium

dichromate (1.0 g, 2.66 mmol) was added and the mixture

stirred for a further 15 h. After such time H₂O (60 ml) was

added and the mixture extracted with EtOAc (5 × 25 ml). The

combined organic extracts were washed with brine (20 ml),

dried (Na₂SO₄) and concentrated. The residue was taken up in

toluene (2 × 5 ml) and concentrated twice to give crude acid

(290 mg) as a brown oil which was dissolved in anhydrous tolu-

ene (2 ml) to which freshly activated 4 Å molecular sieves and

anhydrous N-ethyldiisopropylamine (0.2 ml, 148 mg, 1.15

mmol) were added. 2-Trimethylsilylethanol (0.8 ml, 660 mg,

5.58 mmol), dried by the addition of freshly activated 4 Å

molecular sieves, and diphenylphosphoryl azide (0.2 ml, 255

mg, 0.93 mmol) were then added at the same time. The mixture

was plunged into an oil bath at 65 ЊC and the evolution of N₂

gas was observed over a period of 8 min. After heating at 65 ЊC

for 1 h the green reaction mixture was quenched by the addition

of saturated aqueous NaHCO₃(18 ml) and extracted with

CH₂Cl₂(3 × 25 ml). The combined organic extracts were dried

(Na₂SO₄) and concentrated. The residue was puriﬁed by col-

umn chromatography (SiO₂, 10–25% Et₂O in hexanes) to give

carbamate 58 (171 mg, 4.26 mmol, 58%) as a pale yellow oil: [α]_D²³

ϩ46.7 (c 0.09, CHCl₃); ν_maxﬁlm/cm^–11720, 1542, 1109, 1032;

δ_H(400 MHz, CDCl₃): 5.72 (1H, ddt, J 16.8, 10.0, 6.8, C17H),

5.53 (1H, t, J 9.2, C10H), 5.30 (1H, d, J 9.2, NH), 5.14 (1H, d,

J 7.2, OCH_AH_BO), 5.03 (1H, dq, J 17.2, 1.6, C18H_AH_B), 4.95

(1H, dm, J 7.2, C18H_AH_B), 4.86 (1H, d, J 7.2, OCH_AH_BO), 4.21

(3H, m, OCH₂CH₂SiMe₃and C11H), 3.80 (1H, dd, J 10.0, 6.8,

C12H), 3.57 (3H, s, OMe), 3.45 (1H, d, J 10.4, C13H), 3.31 (1H,

d, J 9.2, C15H), 2.18 (1H, ddm, J 6.8, 2.0, C16H_AH_B), 2.10–

2.00 (1H, m, C16H_AH_B), 1.01 (2H, m, CH₂SiMe₃), 1.01 (3H, s,

C14Me), 0.88 (3H, s, C14Me), 0.05 (9H, s, SiMe₃); δ_C(90 MHz,

CDCl₃): 156.1 (0), 135.9 (1), 116.3 (2), 86.7 (2), 79.6 (1), 78.6

(1), 76.5 (1), 74.9 (1), 70.8 (1), 64.1 (2), 62.0 (3), 41.9 (0), 33.6

(2), 23.3 (3), 17.8 (2), 13.5 (3), Ϫ1.3 (3, 3C); m/z (CI, isobutane)

402 [(M ϩ H)^ϩ, 70%], 374 (100). Found: (M ϩ H)^ϩ, 402.2315.

C₁₉H₃₆O₆NSi requires M, 402.2312.

TBAFؒ3H₂O (ca. 95%, 400 mg) was added to a solution of

carbamate 59 (155 mg, 0.318 mmol) in THF (6 ml) at 0 ЊC in

one portion. After 2 min the mixture was diluted with CH₂Cl₂

(40 ml) and washed with H₂O (60 ml). The aqueous phase was

extracted with CH₂Cl₂(2 × 20 ml) and the combined organic

extracts dried (Na₂SO₄) and concentrated. The residue was

puriﬁed by column chromatography (SiO₂, 50% Et₂O in hex-

anes) to give the desired amide 10 (90 mg, 0.262 mmol, 83%) as

a white solid: mp 169–170 ЊC; [α]_D²³ϩ76.2 (c 0.6, CHCl₃); ν_max

KBr/cm^–11737, 1701, 1036; δ_H(360 MHz, CDCl₃): 7.53 (1H, d,

J 9.2, NH), 5.73 (1H, t, J 9.7, C10H), 5.62 (1H, ddt, J 17.0,

10.1, 6.9, C17H), 5.15 (1H, d, J 7.0, OCH_AH_BO), 4.97 (1H, dm,

J 17.1, C18H_AH_B), 4.88 (1H, m, C18H_AH_B), 4.88 (1H, d, J 7.3,

OCH_AH_BO), 4.25 (1H, dd, J 10.3, 6.8, C12H), 3.93 (3H, s,

C(O)OCH₃), 3.90 (1H, dd, J 9.8, 6.8, C11H), 3.57 (3H, s, OMe),

3.45 (1H, d, J 10.3, C13H), 3.28 (1H, dd, J 9.9, 1.4, C15H), 2.16

(1H, ddm, J 14.0, 5.5, C16H_AH_B), 2.0 (1H, ddd, J 17.0, 5.6, 5.5,

C16H_AH_B), 1.01 (3H, s, C14Me), 0.88 (3H, s, C14Me); δ_C(90

MHz, CDCl₃): 160.3 (0), 156.5 (0), 135.7 (1), 116.5 (2), 86.9 (2),

79.5 (1), 78.9 (1), 74.8 (1), 74.3 (1), 70.6 (1), 62.0 (3), 54.0 (3),

41.9 (0), 33.4 (2), 23.2 (3), 13.6 (3); m/z (CI, isobutane) 344

[(M ϩ H)^ϩ, 100%]. Found: (M ϩ H)^ϩ, 344.1708. C₁₆H₂₆O₇N

requires M, 344.1709. Found: C, 56.08; H, 7.14; N, 4.04%.

C₁₆H₂₅NO₇requires C, 55.98; H, 7.29; N, 4.08.

(1S,5S,6S,8S,10R)-5{[(2R,3R,4R)-2,3-Dimethyl-4-phenyl-

selanylmethyl-3,4-dihydro-2H-pyran-6-yl]oxoethanamido}-

9,9-dimethyl-10-methoxy-8-(prop-2-enyl)-2,4,7-trioxabicyclo-

[4.4.0]decane (60)

A ﬂame dried 25 ml Schlenk ﬂask was charged with stannane 27

(230 mg, 0.52 mmol) in THF (3 ml) and cooled to Ϫ78 ЊC. n-

BuLi (0.61 M in hexanes, 0.84 ml, 0.52 mmol) was added drop-

wise over 10 min keeping the reaction mixture at Ϫ78 ЊC. After

15 min TMEDA (0.35 ml, 0.44 g, 3.80 mmol) was added drop-

wise to the yellow solution over 1 min. The mixture was stirred

for a further 15 min at Ϫ78 ЊC before a cold solution of ester 10

(60 mg, 0.174 mmol) in THF (2 ϩ 2 ml) was added via cannula.

The clear colourless reaction mixture was stirred for 2 h at

Ϫ78 ЊC before being quenched by the addition of saturated

aqueous NH₄Cl (6 ml) and stirred vigorously for 15 min. The

mixture was then extracted with CH₂Cl₂(3 × 20 ml) and the

combined organic extracts dried (Na₂SO₄) and concentrated.

The residue was puriﬁed by column chromatography (SiO₂, 10–

40% Et₂O in hexanes) to give the desired product 60 (80 mg,

0.135 mmol, 78%) as a white solid: mp 144–145 ЊC (hexanes–

Et₂O); [α]_D²¹Ϫ32.0 (c 0.5, CHCl₃); ν_maxKBr/cm^–11670, 1124,

1024; δ_H(400 MHz, CDCl₃): 7.56–7.48 (3H, m), 7.31–7.25 (3H,

m), 7.09 (1H, dd, J 2.0, 1.6, C5H), 5.72 (1H, t, J 9.6), 5.62 (1H,

ddt, J 17.0, 10.2, 6.8, C17H), 5.16 (1H, d, J 6.9, OCH_AH_BO),

5.55 (1H, ddm, J 17.2, 2.0, C18H_AH_B), 4.90 (1H, d, J 6.9,

OCH_AH_BO), 4.84 (1H, ddm, J 10.2, 1.6, C18H_AH_B), 4.25 (1H,

dd, J 10.3, 6.7, C12H), 4.10 (1H, dq, J 1.2, 6.4, C2H), 3.92

(1H, dd, J 9.8, 6.7, C11H), 3.58 (3H, s, C13OMe), 3.46 (1H, d,

J 10.3, C13H), 3.29 (1H, dd, J 10.0, 2.0, C15H), 2.95 (2H, m,

CH₂SePh), 2.86 (1H, m, C4H), 2.15 (1H, ddm, J 13.6, 5.5,

C16H_AH_B), 2.08–1.98 (2H, m, C16H_AH_Band C3H), 1.39 (3H,

d, J 6.5, C2Me), 1.03 (3H, s, C14Me), 0.89 (3H, s, C14Me),

0.82 (3H, d, J 7.0, C3Me); δ_C(90 MHz, CDCl₃): 179.7 (0), 160.7

(0), 148.7 (0), 135.8 (1), 133.4 (1, 2C), 129.4 (1, 2C), 129.3 (0),

127.6 (1), 124.8 (1), 116.6 (2), 86.9 (2), 79.6 (1), 78.9 (1), 76.8 (1),

74.8 (1), 74.0 (1), 70.4 (1), 62.0 (3), 41.8 (0), 39.1 (1), 33.4 (1, 2,

(1S,5R,6R,8R,10S)-10-Methoxy-9,9-dimethyl-8-(prop-2-enyl)-

5-{N-(methoxalyl)-N-[(2-trimethylsilyl)ethoxycarbonyl]amino}-

2,4,7-trioxabicyclo[4,4,0]decane (59)

To a solution of carbamate 58 (68 mg, 0.17 mmol) in CH₂Cl₂

was added DMAP (124 mg, 1.0 mmol, recrystallised from

CH₂Cl₂–Et₂O–hexanes) and methyl oxalyl chloride (90 µl, 0.98

mmol). The mixture was stirred for 91 h and concentrated. The

residue was puriﬁed by column chromatography (SiO₂, 5% Et₂O

in hexanes) to give the imide 59 (55 mg, 0.11 mmol, 66%) as

a clear colourless oil and starting carbamate 58 (6 mg, 0.15

mmol, 9%) as a clear colourless oil: [α]_D²²ϩ63.8 (c 0.8, CHCl₃);

ν_maxﬁlm/cm^–11776, 1689, 1644, 1470; δ_H(360 MHz, CDCl₃):

6.13 (1H, d, J 10.5, C10H), 5.68 (1H, ddt, J 17.0, 10.1, 6.8,

C17H), 5.11 (1H, d, J 6.7, OCH_AH_BO), 4.98 (1H, d, J 6.8,

OCH_AH_BO), 5.07 (2H, m, C18H₂), 4.86 (1H, dd, J 10.4, 7.3,

C11H), 4.35 (2H, ddd, J 8.5, 6.3, 3.7, OCH₂CH₂SiMe₃), 4.33

(1H, dd, J 10.5, 7.3, C12H), 3.90 (3H, s, C(O)OMe), 3.59 (3H,

s, OMe), 3.47 (1H, d, J 10.5, C13H), 3.29 (1H, dd, J 9.9, 2.1,

C15H), 2.15 (1H, dddt, J 13.0, 7.2, 2.2, 1.5, C16H_AH_B), 2.03

(1H, dddt, J 14.4, 10.0, 6.9, 1.2, C16H_AH_B), 1.12 (2H, ddd,

J 8.4, 6.2, 3.7, CH₂SiMe₃), 1.02 (3H, s, C14Me), 0.88 (3H, s,

C14Me), 0.07 (9H, s, SiMe₃); δ_C(90 MHz, CDCl₃): 162.9 (0),

161.3 (0), 152.5 (0), 135.7 (1), 116.6 (2), 87.8 (2), 79.5 (1), 78.9

2378

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

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2C), 29.6 (2), 23.3 (3), 18.3 (3), 13.7 (3), 6.1 (3); m/z (EI) 593

[(M ϩ H)^ϩ, 3%], 435 (10), 223 (50), 151 (52), 87 (100). Found:

C, 58.67; H, 6.58; N, 2.25%. C₂₉H₃₉NO₇Se requires C, 58.78;

H, 6.59; N, 2.36.

74.9 (1), 72.9 (1), 72.5 (1), 71.0 (1), 61.7 (3), 48.3 (3), 42.0 (0),

35.9 (1), 35.5 (1), 34.4 (2), 32.5 (2), 31.6 (2), 23.5 (3), 18.5 (3),

14.1 (3), 5.0 (3). Found: M^ϩ, 731.2575. C₃₇H₄₉NO₉Se requires

ؒ

M, 731.2576.

The structure and absolute stereochemistry of 60 was

conﬁrmed by X-ray crystallography with Mo X-rays on a

CAD4 diﬀractometer.^90,91Crystal data (60): C₂₉H₃₉NO₇Se,

M = 592.57, monoclinic, a = 8.5035(5), b = 10.0704(9), c =

17.6777(6), β = 103.768(3)Њ, U = 1470.3(2) Å³, T = 293 K, space

group P2₁, Z = 2, µ(Mo-Kα) 1.321 mm^–1, 4104 reﬂections

measured, 3402 unique (R_int= 0.023) used in reﬁnement.

R₁[2097 with I > 2σ(I)] = 0.036, wR₂(all data) = 0.077. Flack

absolute structure parameter x = Ϫ0.010(11).†

61b. Mp 74–79 ЊC; [α]_D²³ϩ17.5 (c 0.4, CHCl₃); ν_maxKBr/cm^–1

1733, 1708, 1264, 1128, 1107, 1026; δ_H(360 MHz, C₆D₆refer-

enced to 7.16 ppm): 8.32 (2H, dd, J 8.2, 1.5), 7.49–7.38 (3H, m),

7.11–6.92 (6H, m), 6.19 (1H, ddt, J 16.9, 10.2, 6.5, C17H), 6.02

(1H, t, J 9.8, C10H), 5.92 (1H, s, C7H), 5.55 (1H, dm, J 10.2,

C18H_AH_B), 5.22 (1H, ddm, J 17.0, 2.1, C18H_AH_B), 4.71 (1H, d,

J 6.9, OCH_AH_BO), 4.64 (1H, d, J 6.9, OCH_AH_BO), 4.33 (1H,

dd, J 10.4, 6.8, C12H), 3.74 (1H, dd, J 10.1, 6.8, C11H), 3.52

(1H, dq, J 2.1, 6.5, C2H), 3.31 (1H, t, J 6.0, C15H), 3.27 (6H, s,

C6OMe and C13OMe), 3.05 (1H, d, J 10.4, C13H), 2.54 (2H,

m, CH₂SePh), 2.25 (1H, m with 10 lines, C4H), 2.07 (3H, m),

1.64 (1H, t, J 13.2, C5H), 1.50 (1H, m, C3H), 0.89 (3H, s,

C14Me), 0.84 (3H, d, J 6.5, C2Me), 0.73 (3H, s, C14Me), 0.59

(3H, s, d, J 7.0, C3Me); δ_C(90 MHz, C₆D₆referenced to 128.4

ppm): 167.3 (0), 166.0 (0), 137.1 (1), 133.6 (1), 133.3 (1, 2C),

131.4 (0), 130.8 (0), 130.7 (1, 2C), 129.7 (1, 2C), 129.0 (1, 2C),

127.3 (1), 117.0 (2), 99.9 (0), 87.1 (2), 79.6 (1), 78.9 (1), 76.0 (1),

74.5 (1), 72.7 (1), 72.1 (1), 70.9 (1), 61.7 (3), 49.3 (3), 42.1 (0),

35.7 (1), 35.3 (1), 34.1 (2), 32.4 (2), 32.0 (2), 23.1 (3), 18.4 (3),

Benzoates 61a,b

L-Selectride (1 M in THF, 0.27 ml, 0.27 mmol) was added

dropwise to a solution of ketone 60 (85 mg, 0.144 mmol) in

THF (2.7 ml) at Ϫ95 ЊC over 15 min. After stirring at Ϫ95 ЊC

for 15 min the reaction was quenched by the addition of brine

(5 ml) and CH₂Cl₂(5 ml). The mixture was stirred vigorously

for a further 15 min and extracted with CH₂Cl₂(3 × 20 ml). The

combined organic extracts were dried (Na₂SO₄) and concen-

trated to give a clear colourless oil (102 mg). The residue (102

mg) was dissolved in CH₂Cl₂(4.5 ml) and MeOH (0.4 ml) to

which CSA (4 mg) was added at rt. The mixture was stirred at

rt for 40 min before K₂CO₃(16 mg) was added. The mixture

was then stirred for 30 min and poured onto saturated aqueous

NaHCO₃(6 ml). The mixture was extracted with CH₂Cl₂

(3 × 20 ml), dried (Na₂SO₄) and concentrated to give a clear

yellow oil (114 mg). The residue (114 mg) was dissolved in

CH₂Cl₂(4.5 ml) to which DMAP (34 mg, 0.29 mmol),

N-ethyldiisopropylamine (0.25 ml, 186 mg, 1.44 mmol) and

benzoyl chloride (47 µl, 0.41 mmol) were added at rt. The mix-

ture was stirred at rt for 1 h before MeOH (0.4 ml) was added.

After stirring for 10 min, brine (6 ml) was added and the mix-

ture extracted with CH₂Cl₂(3 × 20 ml). The combined organic

extracts were dried (Na₂SO₄) and concentrated to give a yellow

solid. Column chromatography (SiO₂, 50% Et₂O in hexanes)

aﬀorded the desired benzoates 61a,b (96 mg, 0.132 mmol, 91%)

13.8 (3), 4.6 (3). Found: M^ϩ, 731.2581. C₃₇H₄₉NO₉Se requires

ؒ

M, 731.2576.

Aldehyde 62

Oleﬁn 61a (50 mg, 0.0685 mmol) and hydroquinine 9-phen-

anthryl ether⁶⁴(2 mg, 0.004 mmol) were dissolved in t-BuOH

(1 ml) to which water (1 ml) was added followed by K₃FeCN₆

(45 mg, 0.14 mmol), K₂CO₃(20 mg, 0.14 mmol) and

potassium osmate dihydrate (1 mg, 0.003 mmol). After stirring

at rt for 8 h saturated aqueous Na₂SO₄(2 ml) was added. The

mixture was extracted with EtOAc (3 × 15 ml) and the com-

bined organic extracts were dried (Na₂SO₄) and concentrated to

give a clear yellow oil which was dissolved in MeOH (2 ml) to

which water (0.65 ml) and NaIO₄(100 mg, 0.047 mmol) were

added. The mixture was stirred at rt for 1 h then diluted with

CH₂Cl₂(30 ml) and washed with water (2 × 15 ml). The organic

phase was dried (Na₂SO₄) to which Et₃N (2ml) was added

before the mixture was concentrated in vacuo (12 mmHg, 18 ЊC)

to give a yellow oil. The yellow oil was dissolved in toluene

(1 ml) and Et₃N (1 ml) and heated at reﬂux for 2 min. The mix-

ture was allowed to cool to rt before saturated aqueous NaHCO₃

(8 ml) was added. The mixture was extracted with CH₂Cl₂(3 ×

20 ml), the combined organic layers dried (Na₂SO₄) and con-

centrated in vacuo. The yellow oil was puriﬁed by column chrom-

atography (SiO₂, 50% Et₂O in hexanes containing 1% Et₃N)

to give the desired aldehyde 62 (27 mg, 0.0470 mmol, 69%) as a

white powder: mp 86–87 ЊC; [α]_D²³ϩ110.3 (c 0.3, CH₂Cl₂); ν_max

KBr/cm^–11730, 1701, 1654, 1647, 1270, 1126, 1106, 1037; δ_H

(400 MHz, C₆D₆referenced to 7.16 ppm): 9.72 (1H, d, J 4.5,

C17H), 8.38 (2H, dd, J 8.0, 1.6), 7.47 (1H, d, J 9.2, NH), 7.11–

7.00 (3H, m), 5.93 (1H, s, C7H), 5.91 (1H, t, J 9.6, C10H),

1

as a white solid. H NMR spectroscopic analysis (C₆D₆, refer-

enced to 7.16 ppm) of the mixture revealed doublets at δ 4.53

(major) and 4.71 (minor) attributed to the OCH_AH_BO proton

corresponding to a 5:1 mixture of diastereoisomeric benzoates.

The diastereoisomers were separated by column chromato-

graphy (SiO₂, 5% Et₂O in CH₂Cl₂) to give the desired diastereo-

isomer 61a (66 mg, 0.090 mmol, 63%) as a white foam and

the undesired diastereoisomer 61b (10 mg, 0.0137 mmol, 10%)

as a white foam and a mixture of diastereoisomers 61a,b (20

mg, 0.027 mmol, 20%) as a white solid.

61a. Mp 72–76 ЊC; [α]_D²³ϩ103.8 (c 0.8, CHCl₃); ν_maxKBr/cm^–1

1732, 1704, 1272, 1033; δ_H(360 MHz, C₆D₆referenced to 7.16

ppm): 8.32 (2H, dd, J 8.2, 1.6), 7.47 (2H, dd, J 7.8, 1.5), 7.42

(1H, d, J 9.6, NH), 7.10–6.92 (6H, m), 6.06 (1H, ddt, J 16.5,

10.3, 6.9, C17H), 5.95 (1H, s, C7H), 5.94 (1H, t, J 9.8, C10H),

5.14 (1H, ddm, J 10.1, 0.9, C18H_AH_B), 5.06 (1H, ddm, J 17.1,

1.2, C18H_AH_B), 4.59 (1H, d, J 6.9, OCH_AH_BO), 4.53 (1H, d,

J 6.9, OCH_AH_BO), 4.32 (1H, dd, J 10.3, 6.8, C12H), 3.79 (1H,

dd, J 9.7, 6.8, C11H), 3.56 (2H, m, C15H and C2H), 3.27 (3H, s,

OMe), 3.07 (1H, d, J 10.4, C13H), 2.89 (3H, s, OMe), 2.85 (1H,

m, CH_AH_BSePh), 2.83 (1H, dd, J 14.4, 11.9, CH_AH_BSePh), 2.43

(1H, m with 10 lines, C4H), 2.29 (1H, dd, J 13.5, 3.6, C5H),

2.09 (1H, m, C16H_AH_B), 2.03 (1H, dd, J 14.4, 7.6, C16H_AH_B),

1.86 (1H, t, J 13.0, C5H), 1.55 (1H, m, C3H), 0.87 (3H, s,

C14Me), 0.85 (3H, d, J 6.7, C2Me), 0.80 (3H, d, J 6.8, C3Me),

0.79 (3H, s, C14Me); δ_C(90 MHz, C₆D₆referenced to 128.4

ppm): 166.7 (0), 166.0 (0), 137.7 (1), 133.6 (1), 133.2 (1, 2C),

131.4 (0), 130.8 (0), 130.7 (1, 2C), 129.7 (1, 2C), 129.0 (1, 2C),

127.3 (1), 116.3 (2), 99.8 (0), 87.1 (2), 79.4 (1), 78.9 (1), 75.7 (1),

4.94 (1H, d, J 1.6, ᎐CH H ), 4.85 (1H, J 1.6, ᎐CH H ), 4.59

᎐

A

B

A

B

(1H, d, J 6.8, OCH_AH_BO), 4.50 (1H, d, J 6.8, OCH_AH_BO), 4.26

(1H, dd, J 10.4, 6.8, C12H), 4.02 (1H, dd, J 10.4, 2.4, C15H),

3.81 (1H, dq, J 6.4, 2.8, C2H), 3.77 (1H, dd, J 9.6, 6.8, C11H),

3.27 (3H, s, C13OMe), 3.09 (1H, d, J 10.4, C13H), 2.91 (1H, d,

J 14.4, C5H_AH_B), 2.90 (3H, s, C6OMe), 2.81 (1H, d, J 14.4,

C5H_AH_B), 2.08 (1H, ddd, J 15.6, 10.4, 4.4, C16H_AH_B), 1.93

(1H, dq, J 7.2, 2.8, C3H), 1.82 (1H, dd, J 16.0, 2.4, C16H_AH_B),

0.99 (3H, d, J 7.2, C3Me), 0.86 (3H, d, J 6.8, C2 Me), 0.70 (3H,

s, C14Me), 0.64 (3H, s, C14Me); δ_C(100 MHz, C₆D₆referenced

to 128.4 ppm): 200.9 (1), 167.3 (0), 166.1 (0), 145.6 (0), 133.7

(1), 130.8 (1, 2C), 130.7 (0), 129.1 (1, 2C), 111.6 (2), 100.4 (0),

87.3 (2), 79.0 (1), 75.5 (1), 75.0 (1), 75.0 (1), 73.0 (1), 72.7 (1),

70.3 (1), 61.7 (3), 48.4 (3), 44.1 (2), 42.0 (1), 41.5 (0), 35.3 (2),

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2379

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23.3 (3), 18.0 (3), 13.8 (3), 12.7 (3). Found: M^ϩ, 575.2734.

Found: (M ϩ NH₄)^ϩ, 649.3339. C₃₃H₄₉N₂O₁₁requires M,

C₃₀H₄₁NO₁₀requires M, 575.2730.

649.3336.

17-epi-7-O-Benzoyltheopederin D (64b). [α]_D²¹ϩ71.3 (c 0.3,

EtOAc); δ_H(400 MHz, C₆D₆referenced to 7.16 ppm): 8.25 (2H,

m), 7.12 (1H, d, J 9.2, NH), 7.09–7.02 (3H, m), 5.94 (1H, s,

7-O-Benzoyltheopederin D (65a) and 17-epi-7-O-benzoyltheo-

pederin D (64b)

Chloromagnesium 3-chloromagesio-1-propoxide was prepared

by the method of Normant et al.⁷⁵3-Chloropropan-1-ol (0.9

ml, 8.42 ml) in THF (8.0 ml) was cooled to Ϫ20 ЊC to which

MeMgCl (3.1 M in THF, 2.72 ml, 8.42 mmol) was added drop-

wise over 3 min. After stirring at rt for 20 min Mg (314 mg, 14

mmol) and 1,2-dibromoethane (0.016 ml, 0.19 mmol) were

added. The mixture was reﬂuxed for 1 h before another portion

of 1,2-dibromoethane (0.016 ml, 0.19 mmol) was added. After

reﬂuxing for a further 2 h, a homogeneous solution was formed.

The mixture was allowed to cool to rt and the concentration

was found to be 0.30 M in THF by titration.⁹²

C7H), 5.77 (1H, t, J 9.2, C10H), 4.80 (2H, dm, J 9.7, ᎐CH ),

᎐

2

4.64 (2H, s, OCH₂O), 4.55 (1H, ddd, J 15.2, 9.2, 3.2, C17H),

4.24 (1H, dd, J 10.0, 6.8, C12H), 3.90 (1H, dd, J 9.6, 6.8,

C11H), 3.83 (1H, dq, J 6.4, 2.8, C2H), 3.51 (1H, dd, J 8.8,

0.8, C15H), 3.28 (3H, s, OMe),3.04 (3H, s, OMe), 2.99 (1H, d,

J 10.0, C13H), 2.85 (1H, bd, J 14.4, C5H_AH_B), 2.78 (1H, d,

J 14.0, C5H_AH_B), 2.27 (1H, dt, J 17.6, 9.6, C19H_AH_B), 2.04 (1H,

ddd, J 17.2, 9.2, 3.2, C19H_AH_B), 1.95 (1H, dq, J 7.2, 2.8, C3H),

1.74 (1H, dddd, J 12.8, 10.0, 6.4, 3.6, C18H_AH_B), 1.42 (1H, ddd,

J 14.4, 8.8, 1.6, C16H_AH_B), 1.30–1.10 (2H, m, C16H_AH_B)

and C18H_AH_B), 1.02 (3H, d, J 7.2, C3Me), 0.92 (3H, d, J 6.8,

C2Me), 0.79 (3H, s, C14Me), 0.78 (3H, s, C14Me); δ_C(100

MHz, C₆D₆referenced to 128.4 ppm): 176.0 (0), 167.1 (0), 166.1

(0), 146.5 (0), 133.8 (1), 130.6 (1, 2C), 130.4 (0), 129.2 (1, 2C),

111.2 (2), 100.1 (0), 87.1 (2), 79.4 (1), 78.0 (1), 76.2 (1), 75.4 (1),

75.2 (1), 73.7 (1), 71.4 (1), 70.1 (1), 61.7 (3), 48.9 (3), 42.0 (1),

41.5 (0), 36.3 (2), 35.3 (2), 29.3 (2), 29.1 (2), 23.4 (3), 18.1 (3),

To a solution of aldehyde 62 (15 mg, 0.026 mmol) in THF

(0.5 ml) at Ϫ78 ЊC was added the Grignard reagent prepared

above (0.30 M in THF, 0.17 ml, 0.052 mmol). After stirring

at Ϫ78 ЊC for 2 h the reaction was quenched at Ϫ78 ЊC by

the addition of saturated aqueous NaHCO₃(2 ml) and EtOAc

(1 ml). The mixture was stirred and allowed to warm up to rt

during a 15 min period. The mixture was extracted with EtOAc

(3 × 4 ml) and the combined organic layers were dried (Na₂SO₄)

and concentrated in vacuo. Puriﬁcation by column chromato-

graphy (SiO₂, 30% Et₂O in hexanes, neat Et₂O and 50% Et₂O

in EtOAc) aﬀorded a diastereoisomeric mixture of diols 63

(20 mg) as a white solid. The diols 63 (20 mg) were dissolved

in CH₂Cl₂(0.9 ml) and MeCN (0.1 ml) to which 4-methyl-

morpholine N-oxide (6 mg, 0.048 mmol), 4 Å molecular sieves

(16 mg) and TPAP (6 mg, 0.018 mmol) were added at rt. After

stirring for 0.5 h, Et₂O (2 ml) was added and the mixture was

concentrated in vacuo. The residue was puriﬁed by ﬁltration

through a pad of SiO₂(50% EtOAc in CH₂Cl₂) to give a dia-

stereoisomeric mixture of lactones 64a,b (14 mg, 0.022 mmol,

14.7 (3), 12.8 (3); m/z (EI) 600 [(M Ϫ OCH₃)^ϩ, 10%]. Found:

ؒ

(M ϩ NH₄)^ϩ, 649.3331. C₃₃H₄₉N₂O₁₁requires M, 649.3336.

Theopederin D (5D)

Potassium carbonate (1 mg, 0.007 mmol) was added to a solu-

tion of 7-O-benzoyltheopederin D 64a (3 mg, 0.0048 mmol)

in anhydrous MeOH (0.3 ml) at rt. The mixture was stirred for

1 h before the addition of H₂O (3 ml). The mixture was then

extracted with EtOAc (3 × 6 ml), the combined organic

extracts washed with brine (2 ml), dried (Na₂SO₄) and concen-

trated in vacuo. The residue was puriﬁed by ﬁltration through a

pad of SiO₂(50% EtOAc in hexanes) to give theopederin D 5D

(2 mg, 0.0038 mmol, 79%) as a white solid, mp 87–88 ЊC: δ_H

(400 MHz, CDCl₃referenced to 7.24 ppm) 7.51 (1H, d, J 10.3,

NH), 5.80 (1H, dd, J 9.5, 9.5, C10H), 5.11 (1H, d, J 7.0,

OCH_AH_BO), 4.86 (1H, d, J 7.0, OCH_AH_BO), 4.84 (1H, app t,

1

85%) as a clear colourless oil. H NMR spectroscopic analysis

(C₆D₆, referenced to 7.16 ppm) of the mixture revealed singlets

at δ 5.94 and 5.84 ppm attributed to the C7 proton correspon-

ding to a 1:1 mixture of diastereoisomeric lactones 64a,b. The

diastereoisomers were separated by preparative TLC. The mix-

ture was divided into six portions and each portion separated

on a 5 × 20 cm silica gel 60 F-254 plate eluting with 50% EtOAc

in hexanes containing 1% Et₃N. Two elutions were required for

full separation. The top band gave 7-O-benzoyltheopederin D

64a (6 mg, 0.0095 mmol, 37%) as a clear colourless oil and the

lower band gave 17-epi-7-O-benzoyltheopederin D 64b (4 mg,

0.0063 mmol, 24%) also as a clear colourless oil.

J 1.7, ᎐CH H ), 4.73 (1H, app t, J 1.7, ᎐CH H ), 4.42 (1H, ddd,

᎐

A

B

A

B

J 14.1, 8.2, 5.9, C17H), 4.25 (1H, d, J 3.2, C7H), 4.19 (1H,

dd, J 9.7, 6.4, C12H), 4.11 (1H, d, J 3.2, OH), 4.01 (1H, dq,

J 2.8, 6.6, C2H), 3.80 (1H, dd, J 9.2, 6.4, C11H), 3.54 (3H,

s, C13OMe), 3.42 (1H, d, J 9.5, C13H), 3.40 (1H, d, J 9.0,

C15H), 3.28 (3H, s, C6OMe), 2.55–2.48 (1H, m, C19H_AH_B),

2.46 (1H, dd, J 18.0, 10.3, C19H_AH_B), 2.41–2.35 (1H, m,

C18H_AH_B), 2.33 (1H, d, J 13.9, C5H_AH_B), 2.24 (1H, dq, J 7.1,

2.6, C3H), 2.18 (1H, d, J 14.1, C5H_AH_B), 1.97–1.87 (1H,

m, C16H_AH_B), 1.80–1.68 (1H, m, C18H_AH_B), 1.58 (1H, ddd,

J 14.3, 8.3, 1.3, C16H_AH_B), 1.18 (3H, d, J 6.6, C2Me), 1.00

(3H, s, C14Me), 0.98 (3H, d, J 7.1, C3Me), 0.86 (3H, s, C14Me);

δ_C(100 MHz, CDCl₃referenced to 77.0 ppm) 177.5 (0, C20),

7-O-Benzoyltheopederin D (64a). [α]_D²³ϩ54.0 (c 0.5, EtOAc);

δ_H(400 MHz, C₆D₆referenced to 7.16 ppm): 8.25 (2H, dd, J 8.4,

1.6), 7.27 (1H, d, J 9.6, NH), 7.11–7.00 (3H, m), 5.84 (1H, s,

C7H), 5.76 (1H, t, J 9.6, C10H), 4.80 (2H, m, ᎐CH ), 4.57 (1H,

᎐

2

172.3 (0, C8), 145.0 (0, C4), 111.0 (2, ᎐CH ), 99.8 (0, C6), 86.5

᎐

2

d, J 7.2, OCH_AH_BO), 4.60–4.50 (1H, m, C17H), 4.50 (1H, d,

J 7.2, OCH_AH_BO), 4.23 (1H, dd, J 10.4, 6.8, C12H), 3.81 (1H,

dq, J 6.4, 2.4, C2H), 3.66 (1H, dd, J 9.6, 6.8, C11H), 3.26 (3H,

s, C13OMe), 3.15 (1H, d, J 10.4, C15H), 2.93 (1H, d, J 12.4,

C13H), 2.92 (3H, s, C6OMe), 2.78 (1H, bd, J 13.6, C5H_AH_B),

2.72 (1H, d, J 14.0, C5H_AH_B), 2.50–2.35 (1H, m), 2.36 (1H, dt,

J 17.2, 9.6, C19H_AH_B), 2.18–2.08 (1H, m, C16H_AH_B), 1.90 (1H,

dq, J 2.8, 7.2, C3H), 1.92–1.82 (1H, m, C16H_AH_B), 1.13–1.15

(2H, m, C18H₂), 1.03 (3H, d, J 6.8, C3Me), 0.90 (3H, d, J 6.4,

C2Me), 0.75 (3H, s, C14Me), 0.68 (3H, s, C14Me); δ_C(100

MHz, C₆D₆referenced to 128.4 ppm): 176.4 (0), 167.4 (0), 165.8

(0), 145.3 (0), 134.0 (1), 130.5 (1, 2C), 130.2 (0), 129.3 (1, 2C),

111.9 (2), 100.1 (0), 86.9 (2), 79.1 (1), 78.4 (1), 75.5 (1), 75.3 (1),

74.5 (1), 73.4 (1), 72.4 (1), 70.3 (1), 61.7 (3), 48.8 (3), 41.8 (1),

41.6 (0), 36.0 (2), 35.0 (2), 29.2 (2), 28.6 (2), 23.2 (3), 18.0 (3),

14.7 (3), 12.6 (3); m/z (CI, isobutane) 649 [(M ϩ NH₄)^ϩ, 20%],

617 [(M ϩ NH₄Ϫ OCH₃)^ϩ, 75%], 600 [(M Ϫ OCH₃)^ϩ, 10%].

(2, OCH₂O), 79.5 (1, C13), 79.2 (1, C17), 76.0 (1, C15), 74.0

(1, C12), 73.6 (1, C10), 71.6 (1, C7), 69.5 (1, C11), 69.5 (1, C2),

61.7 (3, C13OMe), 48.5 (3, C6OMe), 41.3 (1, C3), 41.1 (0,

C14), 35.0 (2, C16), 33.3 (2, C5), 28.7 (2, C19), 28.0 (2, C18),

22.6 (3, C14Me_eq), 18.0 (3, C2 Me), 14.1 (3, C14Me_ax), 12.0

(3, C3Me).

17-epi-Theopederin D

Potassium carbonate (1 mg, 0.007 mmol) was added to a solu-

tion of 17-epi-7-O-benzoyltheopederin D 64b (2 mg, 0.0032

mmol) in anhydrous MeOH (0.3 ml) at rt. The mixture was

stirred for 1 h before the addition of H₂O (3 ml). The mixture

was then extracted with EtOAc (3 × 6 ml), the combined

organic extracts washed with brine (2 ml), dried (Na₂SO₄) and

concentrated in vacuo. The residue was puriﬁed by ﬁltration

through a pad of SiO₂(50% EtOAc in hexanes) to give 17-epi-

2380

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

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theopederin D (1 mg, 0.0019 mmol, 59%) as a white solid mp

80–82 ЊC; δ_H(400 MHz, CDCl₃referenced to 7.24 ppm): 7.41

(1H, d, J 9.4, NH), 5.83 (1H, t, J 9.2, C10H), 5.12 (1H, d, J 7.0,

OCH_AH_BO), 4.87 (1H, d, J 6.8, OCH_AH_BO), 4.87 (1H, t, J 2.0,

᎐CH H ), 4.75 (1H, t, J 1.7, ᎐CH H ), 4.48 (1H, ddd, J 12.1,

Et₂O in CH₂Cl₂) gave pure undesired alcohol epi-66 (110 mg,

0.48 mmol, 0.8%) and 12.8 g of a mixture of 66 and epi-66

which was recrystallised from hexanes–Et₂O to give pure alco-

hol 66 (10.1 g, 43.6 mmol, 77%) as white crystals: mp 71–72 ЊC;

[α]_D²⁷ϩ83.0 (c 1.0, CHCl₃); ν_max(CCl₄)/cm^–13630, 3540; δ_H(400

MHz, CDCl₃): 4.91 (1H, dd, J 5.9, 1.5, C11H), 3.75 (1H, dd,

J 11.0, 5.1, C13H), 3.67–3.53 (2H, m, C18H₂), 3.42 (1H, dd,

J 10.3, 1.5, C15H), 2.01 (1H, ddd, J 13.5, 11.7, 6.0, C12H_AH_B),

1.94 (1H, ddd, J 13.5, 4.9, 1.5, C12H_AH_B), 2.05–1.90 (1H, m,

C17H_AH_B), 1.73–1.87 (2H, m, C16H_AH_Band C17H_AH_B), 1.67

(1H, br s, C13OH), 1.60–1.48 (1H, m, C16H_AH_B), 1.02 (3H, s,

C14Me), 0.88 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 117.8 (0,

C10), 81.1 (1, C15), 71.9 (1, C13), 64.0 (1, C11), 44.9 (2, C18),

39.4 (0, C14), 32.7 (2, C12), 29.4 (2, C17), 25.7 (2, C16), 22.2 (3,

C14Me), 12.0 (3, C14Me); m/z (CI, NH₃) 249 [(M ϩ NH₄)^ϩ,

100%]. Found: C, 56.87; H, 7.70; N, 6.03; Cl, 15.35%.

C₁₁H₁₈ClNO₂requires C, 56.97; H, 7.76; N, 6.04; Cl, 15.32.

The minor isomer (2S,4S,6R)-6-(3-chloropropyl)-2-cyano-

tetrahydro-5,5-dimethyl-2H-pyran-4-ol (epi-66) was isolated as

a colourless oil: [α]_D²⁰ϩ84.2 (c 1.3, CHCl₃); ν_max(ﬁlm)/cm^–13491,

2964; δ_H(400 MHz, CDCl₃): 4.77 (1H, d, J 6.7, C11H), 3.95

(1H, dd, J 10.7, 1.2, C15H), 3.61–3.54 (3H, m, C13H and

C18H₂), 2.32–2.25 (2H, m, OH and C12H_AH_B), 2.04–1.94 (1H,

m, C17H_AH_B), 1.89–1.78 (2H, m, C17–H_AH_B), 1.70–1.61 (1H,

m, C16H_AH_B), 1.50–1.39 (1H, m, C16H_AH_B), 0.98 (3H, s,

C14Me), 0.90 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 119.4 (0,

C10), 75.1 (1, C15), 72.2 (1, C13), 60.7 (1, C11), 45.0 (2, C18),

36.9 (0, C14), 31.5 (2, C12), 29.2 (2, C17), 25.6 (2, C16), 22.7 (3,

C14Me), 19.0 (3, C14Me); m/z (CI, NH₃) 249 [(M ϩ NH₄)^ϩ,

100%]. Found: (M ϩ NH₄)^ϩ, 249.1368. C₁₁H₂₂O₂N₂Cl requires

M, 249.1370. Found: C, 56.96; H, 7.74; N, 6.01%. C₁₁H₁₈ClNO₂

requires C, 56.97; H, 7.76; N, 6.04.

᎐

A

B

A

B

9.1, 6.4, C17H), 4.26 (1H, d, J 2.4, C7H), 4.19 (1H, dd, J 9.7,

6.5, C12H), 4.05 (1H, dq, J 6.6, 2.8, C2H), 3.83 (1H, d, J 2.5,

C7OH), 3.82 (1H, dd, J 9.0, 6.5, C11H), 3.65 (1H, dd, J 9.8, 1.5,

C15H), 3.54 (3H, s, OMe), 3.44 (1H, d, J 9.7, C13H), 3.30 (3H,

s, OMe), 2.49 (2H, m, C19H₂), 2.36 (1H, d, J 13.9, C5H), 2.28

(1H, dq, J 2.7, 7.1, C3H), 2.20 (1H, m, C18H_AH_B), 2.16 (1H,

bd, J 14.1, C5H), 1.83–1.70 (2H, m, C16H_AH_Band C18H_AH_B),

1.60 (1H, dd, J 9.7, 3.0, C16H_AH_B), 1.19 (3H, d, J 6.6, C2Me),

1.02 (3H, s, C14Me), 0.99 (3H, d, J 7.1, C3Me), 0.84 (3H, s,

C14Me); δ_C(100 MHz, CDCl₃referenced to 77.0 ppm): 176.5

(0), 171.5 (0), 145.4 (0), 111.1 (2), 99.8 (0), 86.5 (2), 79.5 (1), 78.1

(1), 77.2 (1), 76.0 (1), 74.2 (1), 74.05 (1), 71.5 (1), 69.4 (1), 61.7

(3), 48.7 (3), 41.2 (1), 40.9 (0), 35.4 (2), 33.3 (2), 29.0 (2), 28.7

(2), 22.7 (3), 18.0 (3), 14.1 (3), 12.5 (3); m/z (CI, isobutane)

496 [(M Ϫ OCH₃)^ϩ, 100%]. Found: (M Ϫ OCH₃)^ϩ, 496.2516.

C₂₅H₃₈NO requires M, 496.2546.

3. Pederin

(2S,6R)-6-(3-Chloropropyl)-2-cyanotetrahydro-5,5-dimethyl-

2H-pyran-4-one (65)

Trimethylsilyl triﬂuoromethanesulfonate (110 µl, 0.6 mmol) was

added to a stirred solution of dihydropyranone 7 (4.0 g, 19.7

mmol) and trimethylsilyl cyanide (2.7 ml, 21.7 mmol) in CH₂Cl₂

(40 ml) at 0 ЊC. The reaction mixture was stirred for 1.5 h at

0 ЊC and poured onto saturated aqueous NaHCO₃(10 ml). The

phases were separated and the aqueous phase was extracted

with CH₂Cl₂(2 × 20 ml). The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. The residue was

treated with THF (10 ml) and aqueous HCl (2 M, 2 ml) and

then stirred at rt for 30 min. The reaction mixture was extracted

with CH₂Cl₂(3 × 25 ml). The combined organic extracts were

dried (MgSO₄) and concentrated in vacuo. Kugelrohr distil-

lation [bp 250 ЊC (oven)/0.05 mmHg] gave a colourless oil which

crystallised upon cooling in the refrigerator. Recrystallisation

from hexanes–Et₂O gave cyano ketone 65 (4.15 g, 18.1 mmol,

92%) as a white solid: mp 36–38 ЊC; [α]_D²⁰ϩ120.0 (c 1.0, CHCl₃);

ν_maxﬁlm/cm^–11715; δ_H(400 MHz, CDCl₃): 5.18 (1H, dd, J 8.1,

1.5, C11H), 3.79 (1H, dd, J 8.8, 3.7, C15H), 3.62 (2H, t, J 6.6,

C18H₂), 3.10 (1H, dd, J 15.5, 8.1, C12H_AH_B), 2.57 (1H, dd,

J 15.5, 2.2, C12H_AH_B), 2.12–2.01 (1H, m, C17H_AH_B), 1.93–1.82

(1H, m, C17H_AH_B), 1.77–1.70 (2H, m, C16H₂), 1.16 (3H, s,

C14Me), 1.12 (3H, s, C14Me); δ_C(100 MHz, CDCl₃): 206.4 (0,

C13), 116.7 (0, C10), 81.4 (1, C15), 64.5 (1, C11), 50.1 (0, C14),

44.7 (2, C18), 40.1 (2, C12), 29.2 (2, C17), 26.0 (2, C16), 18.9

The isomers are easily separable on TLC (CH₂Cl₂–Et₂O 9:1)

R_f(major isomer) 0.39: R_f(minor isomer) 0.47.

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-6-(3-chloropropyl)-2-

cyanotetrahydro-5,5-dimethyl-2H-pyran (67)

tert-Butyldimethylsilyl triﬂuoromethanesulfonate (3.85 ml, 16.6

mmol) was added dropwise to a stirred solution of alcohol 66

(3.5 g, 15.1 mmol) and 2,6-lutidine (3.67 ml, 18.2 mmol) in dry

CH₂Cl₂(25 ml) at 0 ЊC. The reaction mixture was stirred at 0–

5 ЊC for 2.5 h, then poured into saturated aqueous NaHCO₃

(10 ml). The phases were separated and the aqueous phase

was extracted with CH₂Cl₂(2 × 30 ml). The combined organic

extracts were washed with aqueous HCl (2 M, 70 ml) followed

by water (90 ml), dried (Na₂SO₄) and concentrated in vacuo.

The residue was puriﬁed by column chromatography (SiO₂,

10% Et₂O in hexanes) to give silyl ether 67 as a white solid (5.20

g, 15.0 mmol, >99%): mp 44–46 ЊC (hexanes–Et₂O); [α]_D²⁰ϩ60.7

(c 1.84, CHCl₃); ν_max(CCl₄)/cm^–12958, 2932, 2858, 1472, 1258,

1084, 876, 838; δ_H(400 MHz, CDCl₃): 4.87 (1H, dd, J 5.9, 1.5,

C11H), 3.67 (1H, dd, J 11.8, 5.2, C13H), 3.65–3.53 (2H, m,

C18H₂), 3.43 (1H, dd, J 10.3, 1.5, C15H), 2.08–1.91 (2H, m),

1.89–1.69 (3H, m), 1.60–1.44 (1H, m), 0.93 (3H, s, C14Me),

0.90 (9H, s, ^tBuSi), 0.85 (3H, s, C14Me), 0.09 (3H s, SiMe), 0.08

(3H, s, SiMe); δ_C(100 MHz, CDCl₃): 117.9 (0, C10), 81.2 (1,

C15), 72.5 (1, C13), 63.9 (1, C11), 44.9 (2, C18), 40.0 (0, C14),

(3, 2C, C14Me); m/z (EI): 231 (10), 229 (M^ϩ, 30), 123 (87), 70

ؒ

(100%). Found: (M^ϩ), 229.0867. C₁₁H₁₆O₂NCl requires M,

229.0870. Found: C, 57.32; H, 6.95; N, 5.96%. C₁₁H₁₆ClNO₂

requires C, 57.52; H, 7.02; N, 6.10.

(2S,4R,6R)-6-(3-Chloropropyl)-2-cyanotetrahydro-5,5-dimethyl-

2H-pyran-4-ol (66)

t

33.7 (2, C12), 29.5 (2, C17), 26.0 (2, C16), 25.9 (3, 3C, BuSi),

To a solution of ketone 65 (13 g, 56.6 mmol) and CeCl₃ؒ7H₂O

(10.4 g, 28.0 mmol) in MeOH (130 ml) at Ϫ95 ЊC was added

in one portion sodium borohydride (6.5 g, 169.7 mmol). The

reaction mixture was stirred for 1 h below Ϫ85 ЊC and was then

allowed to warm to Ϫ60 ЊC over 1 h with stirring before pour-

ing onto aqueous HCl (2 M, 150 ml) at 0 ЊC. The phases were

separated and the aqueous phase was extracted with CH₂Cl₂

(3 × 150 ml). The combined organic extracts were washed with

saturated aqueous NaHCO₃(35 ml), dried (Na₂SO₄) and con-

centrated in vacuo. The residue was ﬁltered through a pad of

SiO₂to give a 30:1 mixture of alcohols (13.0 g, >99%) as a

white solid. Puriﬁcation by column chromatography (SiO₂, 10%

22.8 (3, C14Me), 18.1 (0, CSi), 12.4 (3, C14Me), Ϫ4.0 (3, MeSi),

Ϫ4.8 (3, MeSi); m/z (CI, NH₃) 363 [(M ϩ NH₄)^ϩ, 100%].

Found: C, 58.97; H, 9.24; N, 3.99; Cl, 10.26%. C₁₇H₃₂ClNO₂Si

requires C, 58.97; H, 9.26; N, 4.04; Cl, 10.26.

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyano-6-(3-phenyl-

selanylpropyl)-5,5-dimethyltetrahydro-2H-pyran (68)

Sodium borohydride (720 mg, 18.7 mmol) was added portion-

wise to a stirred suspension of diphenyl diselenide (2.65 g, 8.46

mmol) in dry ethanol (25 ml). The exothermic reaction resulted

in a pale yellow solution to which was added chloride 67 (4.5 g,

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

2381

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13 mmol). The resulting mixture was reﬂuxed for 1 h, cooled to

rt and treated with aqueous NaOH (2 M, 40 ml) and extracted

with hexanes (3 × 20 ml). The combined organic extracts were

dried (Na₂SO₄) and concentrated in vacuo. The residue was

puriﬁed by chromatography on SiO₂eluting with toluene–

hexanes (1:1) until the yellow band passed and then hexanes–

Et₂O (85:15) to give selenide 68 (5.5 g, 91%) as a colourless oil

that crystallised on standing: mp 28–30 ЊC (hexanes–Et₂O); [α]_D²⁰

ϩ36.9 (c 1.89, CHCl₃); ν_max(CCl₄)/cm^–12958, 2932, 2858, 1595,

1472, 1258, 1084, 876, 838; δ_H(360 MHz, CDCl₃): 7.57–7.50

(2H, m), 7.35–7.20 (3H, m), 4.85 (1H, dd, J 6.0, 1.3, C11H),

3.67 (1H, dd, J 11.5, 4.6, C13H), 3.42 (1H, dd, J 10.3, 1.4,

C15H), 3.02–2.90 (2H, m, C18H₂), 1.99 (1H, ddd, J 13.6, 11.6,

6.1, C12H_AH_B), 2.00–1.88 (1H, m), 1.85–1.64 (3H, m), 1.56–

1.43 (1H, m), 0.93 (9H, s, ^tBuSi), 0.91 (3H, s, C14Me), 0.84 (3H,

s, C14Me), 0.11 and 0.10 (3H each, s, Me₂Si); δ_C(90 MHz,

CDCl₃): 132.4 (1, 2C), 130.4 (0), 129.0 (1, 2C), 126.6 (1), 117.8

(0), 81.1 (1), 72.4 (1), 63.7 (1), 39.8 (0), 33.6 (2), 28.5 (2), 27.5

(2), 27.0 (2), 25.8 (3, 3C), 22.6 (3), 17.9 (0), 12.3 (3), Ϫ4.2 (3),

Ϫ4.9 (3); m/z (CI, NH₃) 485 [(M ϩ NH₄)^ϩ, 100%], 483 (50).

Found: C, 59.29; H, 8.03; N, 2.92%. C₂₃H₃₇NO₂SeSi requires

C, 59.15; H, 7.92; N, 3.00.

umn chromatography on SiO₂(70 g, 0–1.4% MeOH in CH₂Cl₂)

to give pure diol 70a (806 mg, 2.34 mmol, 52%) and pure diol

70b (402 mg, 1.2 mmol, 26%).

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyano-6-[(2S)-

2,3-dihydroxypropyl]tetrahydro-5,5-dimethyl-2H-pyran (70a).

Mp 53–55 ЊC (hexanes–Et₂O); [α]_D²⁵ϩ50.0 (c 2.0, CHCl₃); ν_max

ﬁlm/cm^–13442, 1472, 1258, 1100, 1082, 878; δ_H(400 MHz,

CDCl₃): 4.90 (1H, dd, J 6.0, 0.9, C11H), 3.96–3.90 (1H,

m, C17H), 3.73–3.63 (3H, m (10 lines), C13H ϩ C15H ϩ

C18H_AH_B), 3.51(1H, dd, J 11.1, 6.0, C18H_AH_B), 2.00 (1H, ddd,

J 13.7, 11.6, 6.1, C12H_AH_B), 1.81 (1H, ddd, J 13.7, 4.6, 1.3,

C12H_AH_B), 1.78–1.64 (2H, m, C16H₂), 1.64–1.40 (2H, br s,

t

C17OH and C18OH), 0.91 (3H, s, C14Me), 0.89 (9H, s, Bu),

0.86 (3H, s, C14Me), 0.08 (3H, s, SiMe), 0.07 (3H, s, SiMe); δ_C

(100 MHz, CDCl₃): 117.6 (0, C10), 81.0 (1, C13 or C15 or C17),

72.2 (1, C13 or C15 or C17), 71.1 (1, C13 or C15 or C17), 65.8

(2, C18), 63.8 (1, C11), 39.8 (0, C14), 33.4 (2, C16 or C12), 32.1

t

(2, C12 or C16), 25.7 (3, 3C, BuSi), 22.6 (3, C14Me), 17.9 (0,

CSi), 12.3 (3, C14Me), Ϫ4.2 (3, MeSi), Ϫ5.0 (3, MeSi); m/z (CI,

NH₃): 361 [(M ϩ NH₄)^ϩ, 100%], 343 [(M ϩ H)^ϩ, 8], 329 (12),

96 (12). Found: (M ϩ H)^ϩ, 344.2258. C₁₇H₃₄O₄NSi requires M,

344.2257.

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyanotetrahydro-

5,5-dimethyl-6-(prop-2-enyl)-2H-pyran (69)

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyano-6-[(2R)-

2,3-dihydroxypropyl]tetrahydro-5,5-dimethyl-2H-pyran (70b).

Mp 36–38 ЊC (CHCl₃); [α]_D²⁵ϩ58.5 (c 1.0, CHCl₃); ν_maxKBr/cm^–1

3426, 1471, 1257, 1103, 1083, 881; δ_H(400 MHz, CDCl₃): 4.86

(1H, dd, J 6.0, 0.9, C11H), 3.92–3.85 (1H, m, C17H), 3.74

(1H, dd, J 10.3, 1.3, C15H), 3.70 (1H, dd, J 11.6, 4.7, C13H),

3.65 (1H, dd, J 11.1, 3.3, C18H_AH_B), 3.51(1H, dd, J 10.8, 7.2,

C18H_AH_B), 2.00 (1H, ddd, J 13.6, 11.6, 6.1, C12H_AH_B), 1.79

(1H, ddd, J 13.6, 4.6, 1.4, C12H_AH_B), 1.67 (1H, ddd, J 14.4, 8.9,

1.6, C16H_AH_B), 1.67 (1H, ddd, J 14.4, 10.3, 3.6, C16H_AH_B),

1.60–1.40 (2H, br s, C17OH and C18OH), 0.92 (3H, s, C14Me),

0.90 (9H, s, ^tBu), 0.84 (3H, s, C14Me), 0.09 (3H, s, SiMe), 0.08

(3H, s, SiMe); δ_C(100 MHz, CDCl₃): 117.7 (0, C10), 78.1 (1,

C13 or C15), 72.3 (1, C15 or C13), 69.2 (1, C17), 66.8 (2, C18),

66.8 (1, C11), 39.6 (0, C14), 33.5 (2, C16 or C12), 32.2 (2, C12

or C16), 25.7 (3, 3C, ^tBuSi), 22.5 (3C, 14Me), 17.9 (0, CSi), 12.3

(3, C14Me), Ϫ4.2 (3, MeSi), Ϫ5.0 (3, MeSi); m/z (CI, NH₃)

361 [(M ϩ NH₄)^ϩ, 100%], 343 [(M ϩ H)^ϩ, 15], 329 (25), 96

(62). Found: (M ϩ H)^ϩ, 344.2258. C₁₇H₃₄O₄NSi requires M,

344.2257.

Sodium metaperiodate (2.15 g, 10 mmol) was added in one

portion to a stirred solution of selenide 68 (3.15 g, 6.75 mmol)

in water (100 ml) and methanol (200 ml). The reaction mixture

was stirred for 30 min, extracted with CH₂Cl₂(3 × 50 ml). The

combined organic phases were dried (Na₂SO₄), triethylamine

(0.5 ml, 7.1 mmol) was added to the solution and the mixture

then concentrated under high vacuum at rt. Toluene (25 ml) was

added to the residue followed by the addition of triethylamine

(10.5 ml, 75 mmol). The reaction mixture was then reﬂuxed for

30 min. Solvent was removed in vacuo and the residue puriﬁed

by column chromatography (SiO₂, 10% toluene in hexanes) fol-

lowed by Kugelrohr distillation [bp 200 ЊC (oven)/0.05 mmHg]

to give the oleﬁn 69 (2.0 g, 6.46 mmol, 96%) as a colourless oil:

[α]_D²⁰ϩ48.6 (c 1.35, CHCl₃); ν_maxﬁlm/cm^–11644, 1472, 1258,

1162, 1104, 1082, 880, 838, 776; δ_H(400 MHz, CDCl₃): 5.84

(1H, ddt, J 16.8, 10.2, 6.8, C17H), 5.10 (1H, dq, J 16.8, 1.5,

C18H_AH_B), 5.07 (1H, dq, J 10.2, 1.5, C18H_AH_B), 4.87 (1H, dd,

J 6.0, 1.5, C11H), 3.68 (1H, dd, J 11.4, 4.6, C13H), 3.54 (1H,

dd, J 10.0, 2.5, C15H), 2.33 (1H, dddt, J 15.0, 6.2, 2.5, 1.5,

C16H_AH_B), 2.17 (1H, dddt, J 15.0, 9.8, 6.8, 1.3, C16H_AH_B),

2.00 (1H, ddd, J 13.7, 11.6, 6.0, C12H_AH_B), 1.78 (1H, ddd,

J 13.7, 4.6, 1.6, C12H_AH_B), 0.94 (3H, s, C14Me), 0.90 (9H, s,

^tBuSi), 0.86 (3H, s, C14Me), 0.09 and 0.08 (3H each, s, Me₂Si);

δ_C(90 MHz, CDCl₃): 135.7 (1, C17), 117.9 (0, C10), 116.6 (2,

C18), 81.6 (1, C15), 72.5 (1, C13), 64.0 (1, C11), 40.0 (0, C14),

Neither 70a nor 70b gave satisfactory microanalytical data.

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyano-6-[(2S)-2,3-

dimethoxypropyl]tetrahydro-5,5-dimethyl-2H-pyran (11)

NaH (310 mg, 7.7 mmol, 60% in oil) was added in one portion

to diol 71a (870 mg, 2.53 mmol), MeI (0.79 ml, 12.6 mmol) and

18-crown-6 (80 mg, 0.30 mmol) in THF (24 ml) at 0 ЊC. The ice

bath was removed and the reaction mixture was sealed and

stirred at rt for 24 h. The reaction mixture was then poured

onto saturated aqueous NH₄Cl (5 ml), extracted with CH₂Cl₂

(3 × 25 ml) and the combined organic extracts were dried

(MgSO₄) and concentrated in vacuo. The residue was puriﬁed

by column chromatography (SiO₂50 g, 20% Et₂O in hexanes) to

give the title compound 11 (860 mg, 2.31 mmol, 91%) as a white

solid: mp 47–49 ЊC (hexanes–Et₂O); lit. mp 46–48 ЊC.²⁵

t

33.8 (2, C12), 33.5 (2, C16), 25.9 (3, 3C, BuSi), 22.9 (3,

C14Me), 18.1 (0, CSi), 12.6 (3, C14Me), Ϫ4.0 (3, MeSi), Ϫ4.8

(3, MeSi); m/z (CI, NH₃) 327 [(M ϩ NH₄)^ϩ, 100%]. Found:

C, 66.15; H, 10.09; N, 4.62%. C₁₇H₃₁NO₂Si requires C, 66.02; H,

10.03; N, 4.53.

Asymmetric dihydroxylation of alkene 69

Alkene 69 (1.4 g, 4.5 mmol) and dihydroquinine 9-phenanthryl

ether⁶⁴(113 mg, 0.225 mmol) were stirred in warm t-BuOH (28

ml) until the crystals of ligand dissolved completely. After cool-

ing to rt, water (28 ml), K₃Fe(CN)₆(4.5 g, 13.5 mmol) and

K₂CO₃(1.90 g, 13.5 mmol) were added and the mixture was

cooled to 0 ЊC before addition of potassium osmate dihydrate

(89 mg, 0.225 mmol). The reaction mixture was stirred for 3 h at

0 ЊC, then treated with saturated aqueous Na₂SO₃(40 ml) and

extracted with CH₂Cl₂(80 ϩ 2 × 40 ml). The combined organic

extracts were washed with brine (30 ml), dried (MgSO₄) and

concentrated in vacuo to give the crude diols 70a,b as a 1.5:1

mixture of diastereoisomers. The residue was puriﬁed by col-

(2S,4R,6R)-4-(tert-Butyldimethylsilyloxy)-2-cyano-6-[(2R)-2,3-

dimethoxypropyl]tetrahydro-5,5-dimethyl-2H-pyran (71b)

By the same procedure described above, diol 70b (390 mg, 1.13

mmol), MeI (0.35 ml, 5.6 mmol) gave the dimethyl ether 71b

(341 mg, 0.91 mmol, 81%) as a white solid: mp 72–74 ЊC

(hexanes–Et₂O); [α]_D²¹ϩ51.0 (c 1.0, CHCl₃); ν_maxKBr/cm^–12953,

2931, 1857, 1473, 1252, 1104, 881, 839; δ_H(360 MHz, CDCl₃):

4.86 (1H, dd, J 6.1, 1.0, C11H), 3.73 (1H, dd, J 1.4, 10.0,

C15H), 3.70 (1H, dd, J 11.6, 4.7, C13H), 3.48–3.37 (3H, m,

2382

J. Chem. Soc., Perkin Trans. 1, 2000, 2357–2384

View Article Online

29 T. Nakata, H. Fukui, T. Nakagawa and H. Matsukura,

C17H, C18H₂), 3.48 (3H, s, OMe), 3.38 (3H, s, OMe), 1.99 (1H,

ddd, J 13.5, 11.6, 6.1, C12H_AH_B), 1.78 (1H, ddd, J 13.6, 4.7, 1.3,

C12H_AH_B), 1.67 (1H, ddd, J 14.4, 9.3, 1.4, C16H_AH_B), 1.49

(1H, ddd, J 14.5, 10.3, 2.2, C16H_AH_B), 0.91 (3H, s, C14Me),

0.90 (9H, s, ^tBu), 0.83 (3H, s, C14Me), 0.09 (3H, s, SiMe), 0.07

(3H, s, SiMe); δ_C(90 MHz, CDCl₃): 117.8 (0, C10), 78.1.0 (1,

C15), 76.4 (1, C17), 74.3 (2, C18), 72.4 (1, C13), 63.7 (1, C11),

59.3 (1, OMe), 58.5 (1, OMe), 39.4 (0, C14), 33.6 (2, C12), 32.2

(2, C16), 25.7 (3, 3C, ^tBuSi), 22.5 (3, C14Me), 17.9 (0, CSi), 12.3

(3, C14Me), Ϫ4.2 (3, Me–Si), Ϫ5.0 (3, MeSi); m/z (CI, iso-

butane) 372 [(M ϩ H)^ϩ, 100%], 340 (5), 314 (5), 287 (5), 240 (5),

213 (20). Found: (M ϩ H)^ϩ, 372.2573. C₁₉H₃₈O₄NSi requires M,

372.2570. Found: C, 61.56; H, 10.02; N, 3.72%. C₁₉H₃₇NO₄Si

requires C, 61.41; H, 10.04; N, 3.77.

Heterocycles, 1996, 42, 159.

30 H. Fukui, Y. Tsuchiya, K. Fujita, T. Nakagawa, H. Koshino and

T. Nakata, Bioorg. Med. Chem. Lett., 1998, 7, 2081.

31 N. S. Trotter, S. Takahashi and T. Nakata, Org. Lett., 1999, 1, 957.

32 P. J. Kocienski, R. Narquizian, P. Raubo, C. Smith and F. T. Boyle,

Synlett, 1998, 869.

33 P. Kocienski, P. Raubo, J. K. Davis, F. T. Boyle, D. E. Davies and

A. Richter, J. Chem. Soc., Perkin Trans. 1, 1996, 1797.

34 C. Y. Hong and Y. Kishi, J. Am. Chem. Soc., 1991, 113, 9693.

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62, 474.

38 M. Toyota, Y. Nishikawa and K. Fukumoto, Heterocycles, 1998, 47,

675.

39 W. R. Roush and T. G. Marron, Tetrahedron Lett., 1993, 34, 5421.

40 W. R. Roush and T. G. Marron, Tetrahedron Lett., 1995, 36, 1581.

41 W. R. Roush and L. A. Pfeifer, J. Org. Chem., 1998, 63, 2062.

42 W. R. Roush, L. A. Pfeifer and T. G. Marron, J. Org. Chem., 1998,

63, 2064.

43 R. W. Hoﬀmann and A. Schlapbach, Tetrahedron Lett., 1993, 34,

7903.

Acknowledgements

We thank the EPSRC for a post-doctoral fellowship (P. R.),

and AstraZeneca Pharmaceuticals and Glasgow University for

studentships (R. N., C. S.). We also thank James Tweedie for

technical assistance and Tony Ritchie for mass spectra. Addi-

tional ﬁnancial support was generously provided by Merck

Sharp and Dohme and Pﬁzer Central Research.

44 R. W. Hoﬀmann, S. Breitfelder and A. Schlapbach, Helv. Chim.

Acta, 1996, 79, 346.

45 P. J. Kocienski, R. Narquizian, P. Raubo, C. Smith and F. T. Boyle,

Synlett, 1998, 1432.

46 R. Annunziata, M. Cinquini, F. Cozzi, G. Dondio and L. Raimondi,

Tetrahedron, 1997, 43, 2369.

47 S. Hanessian, Y. Gai and W. Wang, Tetrahedron Lett., 1996, 37,

7473.

48 Y. Yamamoto, Y. Chouman, S. Nishii, T. Ibuka and H. Kitahara,

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Article Doi

Synthetic studies on the pederin family of antitumour agents. Syntheses of mycalamide B, theopederin D and pederin

DOI: 10.1039/a909898d

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