Synthetic approaches to the C11-C27 fragments of bryostatins

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Takeharu Haino et al.

Solvent-induced emission of organogels based on tris(phenylisoxazolyl)

benzene

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Synthetic approaches to the C11-C27 fragments of bryostatins

Anthony P. Green,^aSimon Hardy^aand Eric J. Thomas^a*

Received 00th January 20xx,

Accepted 00th January 20xx

The modified Julia reaction and acyl carbanion chemistry, especially reactions of 2-lithiated dithianes, have been

investigated for the synthesis of intermediates that are the synthetic equivalents of the C11-C27 fragments of bryostatins.

The modified Julia reaction using 2-benzothiazolylsulfones was found to be more useful for the formation of the C16-C17

double-bond than the classical Julia reaction using phenylsulfones, and bulky sulfones gave very good (E)-stereoselectivity.

The alkylation of a dithiane monoxide that corresponded to a C19-acyl carbanion using (E)-1-bromobut-2-ene was efficient

but the use of a more complex allylic bromide corresponding to the C20-C27 fragment of the bryostatins was unsuccessful,

possibly due to competing elimination reactions. This meant that the use of C19 dithianes for the synthesis of 20-

deoxybryostatins would have to involve the stepwise assembly of the C20-C27 fragment from simpler precursors.

However, lithiated C19 dithianes gave good yields of adducts with aldehydes and conditions were developed for the

stereoselective conversion of the major adducts into methoxyacetals that corresponded to the C17-C27 fragment of 20-

oxygenated bryostatins. A convergent synthesis of the C11-C27 fragment of a 20-deoxybryostatin was subsequently

achieved using a 2-benzothiazolylsulfone corresponding to the intact C17-C27 fragment.

DOI: 10.1039/x0xx00000x

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Introduction

It was soon recognised that assembly of bryostatins by

formation of the C16-C17 double-bond and C20 ester formation

The synthesis of the bryostatins, as exemplified by bryostatins 1

(1) and 10 (2), see Figure 1, is of interest because of their

biological activities and relative inaccessibility from natural

sources.^1,2Several outstanding total syntheses have been

reported³and synthetic analogues have been discovered that

have tumour suppressing bryostatin-like activity or tumour

would lead to convergent syntheses and two early total

syntheses were based on this strategy using Julia reactions to

form the alkene followed by macrolactonisation.^3a,cThis work

led to seminal syntheses, but the reaction conditions necessary

for conventional Julia reactions meant that several steps had to

be deferred until after the Julia reaction and this undermined

the convergency of these approaches. Formation of the C16-C17

double bond by ring closing metathesis (RCM) has been

investigated^6,7but has not yet proved effective for the synthesis

of naturally occurring bryostatins with the geminal methyl

groups at C18, although it can be used for analogue synthesis.

Our work has been primarily concerned with the synthesis of

bryostatins that do not have an acyloxy group at C20, e.g.

bryostatin 10 (2).⁸These 20-deoxybryostatins are a subset of

bryostatins that have not been synthesised even though they

have biological activities reminiscent of their more highly

oxygenated congeners. Our early studies were concerned with

syntheses of the C(1)-C(16) and C(17)-C(27) fragments in

anticipation of developing a convergent synthesis.^9,10However,

following our difficulties encountered in using RCM for the

synthesis of 20-deoxybryostatins,⁶a new strategy had to be

devised for their assembly. In any new approach, we intended

to use as much of the chemistry that we had already developed

as possible. Indeed, this had always been part of our philosophy.

With this consideration in mind, an alternative assembly of the

C20-deoxybryostatins predicated on an early introduction of the

16,17-double-bond,^3b,11was investigated, see Figure 2.

promoting phorbol-like activity.^4,5This work has been

significant contribution to natural product synthesis and to

cancer chemotherapy.

a

Figure 1 Representative bryostatins showing disconnections into

C1-C16 and C17-C27 fragments

^a.The School of Chemistry, The University of Manchester, Manchester M13 9PL, UK

*

Corresponding

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4613;

e-mail:

e.j.thomas@manchester.ac.uk

Electronic Supplementary Information (ESI) available: [details of any

supplementary information available should be included here]. See

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diastereoisomeric hydroxysulfones but these proved difficult to

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acetylate completely for the reductive elimination step.

Moreover, reductive elimination of the hydroxysulfones

themselves using freshly prepared samarium iodide,¹⁵gave only

low yields of the required alkene 18. Mixtures of side products

including alcohols formed by the reductive removal of the

phenylsulfonyl group were isolated from these reactions. In

contrast, a modified Julia reaction¹⁶using the crystalline

benzothiazolylsulfone 17, prepared in two steps from the

alcohol 16,¹⁷was more successful and gave a 65% yield of the

alkene 18 when lithium hexamethyldisilazide was used as the

base. However, the (E):(Z) stereoselectivity of this reaction was

capricious. Better results, up to 80:20 in favour of the (E)-

isomer, were obtained when the aldehyde was added quickly to

o

the deprotonated sulfone at −78 C, followed by rapid warming

to ambient temperature, see Scheme 1. Lithium

hexamethyldisilazide was preferred over sodium or potassium

hexamethyldilazide for these reactions. In our hands no

improvement in stereoselectivity was observed using the

analogous N-phenyltetrazolylsulfone.^3b,18

The O-silylated cyanohydrin 20 was selected as the first C19

acyl carbanion equivalent.¹⁹Thus the alkene 18 was deprotected

selectively and the resulting alcohol oxidised to the aldehyde 19

that was converted into a mixture of the epimeric O-silylated

cyanohydrins 20, see Scheme 2. However, alkylation of these

hindered cyanohydrins proved to be difficult. Good yields of the

benzylated cyanohydrin 21 were obtained using lithium di-

isopropylamide as the base if HMPA was present during the

deprotonation and alkylation steps. However, an excess of

Figure 2 An alternative approach to 20-deoxybryostatins

Intramolecular stereoselective oxy-Michael reactions of

intermediates with hydroxyl groups at C15 (bryostatin

numbering) with enones have been used to prepare C10-C16

fragments of bryostatins.⁹Enones 4 should therefore be useful

for the preparation of the advanced intermediates 3. However,

the presence of the 10,11-double-bond in the enones 4 now

provides considerable flexibility in planning their synthesis

including the option of a RCM-based sequence from the ester

derived from the C11-C27-alcohol 5 and the C1-C10-acid 6.

Intermediates that are equivalent to the acids 6 have already

been prepared.⁹We now describe studies concerned with the

synthesis of the C11-C27 ketones 5 using synthetic equivalents

of the C19 acyl carbanions 7 and allylic halides 8. During the

course of this work, intermediates were also prepared that

could be used for alternative procedures to form the 10,11-

double bond, and to access bryostatins with acyloxy groups at

C20.^12,13

Results and discussion

Syntheses and alkylation of synthetic equivalents of C19 acyl

carbanions 7

Scheme 1 Synthesis of the alkene 18 Reagents and conditions i,

imid., TESCl, DCM, 0 C to rt, 2 h (ca. 100%); ii, DDQ, DCM, aq.

o

pH 7 phosphate buffer, rt, 20 min (84%); iii, Dess-Martin

periodinane, DCM, py., rt, 3 h; iv, TBAI, NaH, PMBCl, DMF, rt, 16

Following the early syntheses of bryostatins, Julia reactions

were investigated for the synthesis of synthetic equivalents of

the acyl carbanions 7. The aldehyde 12 was prepared from the

known alcohol 9⁹by O-silylation, PMB-deprotection and

oxidation of the primary alcohol 11. However, initial studies into

the Julia reaction of this aldehyde with the phenylsulfone 15

that had been prepared from the sulfide 13¹⁴via its PMB-ether

14, see Scheme 1, were disappointing. The addition of the

deprotonated sulfone to the aldehyde gave a mixture of four

o

h (86%); v, Oxone, MeOH, THF, water, 0 C to rt, 8 h (ca. 90%);

vi, (a) 2-BTSH, Ph₃P, DIAD, THF, 0 ^oC to rt, 2.5 h (b)

o

Mo₇O₂₄(NH₄)₆.4H₂O, 30% H₂O₂, EtOH, 0 C to rt (80% from 16);

vii, (a) 15, ⁿBuLi, THF, −78 ^oC, 10 min, add 12, −78 ^oC, 10 min (ca.

60%) (b) SmI₂, HMPA, THF, rt, 1 h (15% from 12); viii, 17,

LiHMDS, −78 ^oC, 20 min, add 12, warm to rt, 1.5 h [65%, (E) : (Z)

= 80 : 20].

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Scheme 2 Alkylation of the silylated cyanohydrin 20 Reagents

and conditions i, (a) DDQ, DCM, aq. pH7 phospate buffer, rt, 20

min (b) Dess-Martin periodinane, py., DCM, rt, 1.5 h (80% from

18); ii, TBSCN, ZnI₂, DCM, rt (65%); iii, HMPA, LDA, −78 ^oC, THF, 1

h, BnBr, −78 ^oC to rt, 1 h (83%, 55:45 mixture of epimers).

Scheme 3 Synthesis and alkylation of dithiane monoxide 26

Reagents and conditions i, DDQ, aq. pH7 phosphate buffer,

DCM, rt, 30 min (ca. 100%); ii, (COCl)₂, DMSO, DCM, −78 ^oC, 1 h,

benzyl bromide was necessary and lower yields were obtained

using allylic halides. As fairly complex allylic halides 8 would be

required for a synthesis of the C11-C27 fragment 5, allylation of

the O-silylated cyanohydrin 20 was not taken any further.

1,3-Dithianes have often been used as acyl carbanion

equivalents.²⁰Indeed alkylation of hindered neopentylic

dithianes has been used for formation of the C9-C10 bond of

bryostatins.^20bThe 2-(benzothiazolylsulfonylethyl)dithiane 24

was therefore prepared from the 3-p-methoxybenzyl ether 17

by deprotection, oxidation and reaction of the resulting

aldehyde 23 with propane-1,3-dithiol. The modified Julia

reaction of this sulfone with the aldehyde 12 was found to be

more stereoselective than Julia reactions with sulfone 17, and

gave the (E)-alkene 25 together with only traces of its (Z)-

isomer, see Scheme 3. However, attempts to alkylate this 1,3-

dithiane using (E)-1-bromobut-2-ene, even using tert-

butyllithium in tetrahydrofuran containing HMPA, conditions

that had been used successfully with similar systems,^20bgave

either unchanged starting materials or complex mixtures of

products. It appeared that base-promoted elimination reactions

of the skipped diene 25 were taking place with loss of the tert-

butyldiphenylsilyloxy group under the strongly basic reaction

conditions required to deprotonate the neopentylic 1,3-

dithiane. The allylic bromide was also unstable under the basic

reaction conditions.

o

22, −78 C, 1 h, Et₃N, −78 C to rt (93%); iii, propane-1,3-dithiol,

o

BF₃.Et₂O, 0 C to rt, ca. 1 h (77%); iv, LiHMDS, tol., THF, −78 C,

20 min, add 12, warm to rt, 1.5 h (55%); v, mCPBA, DCM, 0 ^oC to

rt (78%; 1:1:9:9 mixture of diastereoisomers); vi, LDA, THF,

o

HMPA, −78 C, 1 h, (E)-CH₃CH=CHCH₂Br, −78 C, 30 min, rt, 1 h

(27, 50%; recovered 26, 40%).

It was decided to study a related system that didn’t have the

base-sensitive skipped diene. The hydroxyester 28⁹was O-

silylated and the resulting ester 29 taken through to the primary

alcohol 30 by hydroxylation and periodate cleavage of the diol

with a reductive work-up.⁹Protection of the primary alcohol as

its benzyloxymethyl derivative 31, reduction of the ester and

protection of the allylic alcohol 32 as its tri-isopropylsilyl ether

33, gave the aldehyde 35 after removal of the p-methoxybenzyl

ether and oxidation. The modified Julia reaction of this aldehyde

with sulfone 24 then gave the (E)-alkene 36 in an excellent yield,

87%, and (E)-stereoselectivity, Scheme 4.

1,3-Dithiane monoxides require less basic reaction

conditions for deprotonation than their parent 1,3-dithianes.^21-23

The dithiane 25 was therefore oxidised to the monosulfoxide 26

using m-chloroperbenzoic acid, Scheme 3. This was isolated as a

mixture of the four diastereoisomers in a 1 : 1 : 9 : 9 ratio as

determined by integration of the singlets assigned to the 1’-

methyl groups. Peaks in the δ3.2-3.5 region were assigned to

the equatorial protons at C6 in the major trans-dithiane

monoxides.²²Deprotonation could now be achieved with lithium

di-isopropylamide and preliminary studies of the alkylation of

the lithiated dithiane monoxide using an excess of (E)-1-

bromobut-2-ene gave the alkylated product 27. However, this

was still a mixture of diastereoisomers and attempts to reduce it

to the corresponding dithiane using diphosphorus

tetraiodide^21,23gave complex mixtures of products. The reasons

for the difficulties in the reduction of the dithane monoxide 27

were not clear.

Scheme 4 Synthesis of 1,3-dithiane 36 Reagents and conditions

i, imid., TESCl, DCM, rt, 2 h (82%); ii, (a) NMO, OsO₄(cat.),

^tBuOH, acetone, water, rt, 4 h (98%) (b) NaIO₄, methanol, THF, 0

o

i

^oC, 45 min, NaBH₄, 0 C, 1 h (71% from 29); iii, BOMCl, Pr₂NEt,

TBAI, THF, 0 ^oC to rt, 14 h (92%); iv, DIBAL-H, heptanes, THF, −78

^oC, 1.5 h (91%); v, TIPSCl, imid., DCM, rt, 14 h (95%); vi, DDQ, aq.

o

pH 7 phosphate buffer, DCM, 0 C to rt, 1.5 h (65%); vii, Dess-

Martin periodinane, py., DCM, rt, 45 min; viii, 24, LiHMDS, tol.,

THF, −78 ^oC, 30 min., add 35, rt, 1 h (87% from 34).

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Allowing 15 min. for the deprotonation, the direct allylation

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of the 1,3-dithiane 36 with (E)-1-bromobut-2-ene using tert-

butyllithium and HMPA gave a modest, 35%, yield of the

product 37 together with 20% of unchanged starting material

and a mixture of side-products. Deprotonation for shorter

periods gave more unchanged starting material 36 and longer

deprotonation times gave more decomposition. However,

oxidation of the dithiane 36 with careful monitoring of the

oxidation by TLC, gave an excellent yield, ca. 95%, of the

monosulfoxides 38. The stereoselectivity in favour of the trans-

sulfoxides was ca. 3:1 as indicated by NMR²²although no

attempt was made to separate the four diastereoisomers.

Alkylation of this mixture of monosulfoxide diastereoisomers at

Scheme 6 Removal of the BOM-protecting group Reagents and

conditions i, (a) NH₃, EtOH, THF, −78 ^oC, 5 min (49%) or (b)

lithium naphthalenide, THF, −20 C (71% with 2-phenylethanol);

o

ii, DDQ, pH 7 phosphate buffer, DCM, rt, 1 h (41, 43%; 36, 38%).

o

−60 C using (E)-1-bromobut-2-ene now gave a 79% yield of the

Having shown that the dithiane monoxide 38 can be used as

the synthetic equivalent of a C19 acyl carbanion, it was now

necessary to prepare an allylic halide corresponding to the C20-

C27 fragment 8. Our earlier routes to this fragment had been

based on stereoselective conjugate addition reactions of alkynyl

esters.¹⁰However, a new route was envisaged in which the

geometry of the trisubstituted double-bond would be controlled

by a ring-closing metathesis, see Scheme 7.

The indium-mediated addition of 2-benzyloxymethyl-1-

bromopropene to the aldehyde 42 gave a ca. 50 : 50 mixture of

the alcohols 43 and 44 in keeping with other reactions of this

aldehyde.¹⁰However these isomers were relatively easy to

separate and the less polar epimer was shown to have the

required (4S)-configuration by comparison of the relative ¹H

NMR chemical shifts of its (R)- and (S)-O-acetyl mandelates.²⁶

The more polar (4R)-epimer 43 was converted into the less polar

alkylated product 39 and reduction using diphosphorus

tetraiodide²³under triethylamine buffered conditions gave the

alkylated dithiane 37 (70%). This three-step conversion of

dithiane 36 into the 2,2-disubstituted dithiane 37 was

significantly more efficient than the direct alkylation and was

considered to be a viable transformation, Scheme 5.

It was decided to check that the BOM-protecting group

could be removed in the presence of a dithiane. Treatment of

the BOM-protected dithiane 36 with sodium in liquid ammonia

and ethanol, gave only a modest yield of the alcohol 40 together

with unchanged starting material. Better yields, >70%, were

obtained using lithium naphthalenide in THF although the

product 40 was contaminated with 2-phenylethanol.²⁴More

complex dithianes would have different polarities from the

simpler system 40 and should be separable from any

phenylethanol. No reaction was observed on attempted

hydrogenolysis of the BOM-protected dithiane 36 using

Perlman’s catalyst and an attempted oxidative deprotection

using DDQ gave the aldehyde 41 as a 3:1 mixture of geometrical

isomers consistent with preferred allylic oxidation,²⁵Scheme 6.

(4S)-isomer 44 by

a Mitsunobu reaction followed by

saponification of the resulting nitrobenzoate making the

required (4S)-epimer 44 available in an overall yield of ca. 75%

from the aldehyde 42. In our hands this indium-mediated

procedure was more efficient than addition of the analogous

Grignard reagent to the aldehyde.

The alcohol 44 was converted into its acrylate 45 and a ring-

closing metathesis^27,28of this ester gave the lactone 46. This

reaction introduced the required trisubstituted double bond

with complete stereochemical control. A Luche reduction of the

lactone 46 now gave the diol 47 that was protected as its bis-tri-

isopropylsilyl ether 48. Removal of the benzyl ether was carried

out using lithium naphthalenide and the resulting allylic alcohol

49 was converted into the bromide 50 using mesyl chloride and

lithium bromide, see Scheme 7.

However, attempts to alkylate the dithiane monoxide 38

using the allylic bromide 50 under the conditions that had been

successful for (E)-1-bromobut-2-ene gave complex mixtures of

products, see Scheme 8. Attempts to reduce the number of

diastereoisomeric products by reduction of the crude mixtures

did not lead to the dithiane 51, a synthetic equivalent of the

C11-C27 fragment 5. The use of higher reaction temperatures or

nucleophilic catalysts did not facilitate the allylation step. It

would appear that the alkylation of the hindered dithiane

monoxide 38 is difficult with bulky, base-sensitive, allylic halides.

Scheme 5 Alkylation of the dithiane 36 Reagents and conditions

i, ^tBuLi, HMPA, THF, −78 ^oC, 15 min, (E)-CH₃CH=CHCH₂Br, −78 ^oC,

o

30 min (37, 35%; 36, 20%); ii, mCPBA, DCM, 0 C (95%); iii, LDA,

o

HMPA, THF, −78 C to −60 C, 30 min, (E)-CH₃CH=CHCH₂Br, −78

^oC, 20 min (79%); iv, P₂I₄, Et₃N, DCM, rt, 40 min (70%).

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Reactions of lithated dithianes with aldehy d_Vie_ews _Arf_tio_clr_{e On}t_lh_ine_e

DOI: 10.1039/C7OB02127E

synthesis of the C11-C27 fragment of 20-oxygenated

bryostatins

It was decided to study the reactions of lithiated dithianes with

aldehydes before investigating the modified Julia reaction for an

approach to the C11-C27 fragment 52 of a 20-oxygenated

bryostatin, see Figure 3. The C17-C27 fragment 53 was to be

prepared using the base-promoted reaction between the simple

dithiane 54 and the C20-C27 aldehyde 55 albeit control of the

configuration at C20 was expected to be an issue. The

subsequent introduction of the benzothiazolylsulfonyl group

and modified Julia reaction would complete the synthesis.

The diol 47 was converted into the aldehyde 59 by

protection of the primary allylic alcohol as its tri-isopropylsilyl

ether 56 followed by conversion of the secondary alcohol into

the more labile triethylsilyl ether 57. These conversions were in

anticipation of selective deprotection of the secondary alcohol

later in the synthesis. The benzyl group was then removed using

lithium naphthalenide and the resulting alcohol 58 was oxidised

to give the aldehyde 59, see Scheme 9.

Deprotonation of the dithiane 60, prepared from 3-

benzyloxy-2,2-dimethylpropanal (see experimental), was

achieved using n-butyllithium, and the lithiated dithiane found

to react with the aldehyde 59 to give a ca. 2 : 1 mixture of the

epimeric alcohols 61 and 62. These were separated and then

desilylated to give the diols 63 and 64, see Scheme 9. The

configurations of the alcohols 61 and 62 and the diols 63 and 64

at C4 were confirmed by nOe studies later in the synthesis. It

transpired that the configuration at C4 of the major epimers 61

and 63 corresponded to that required at C20 in the bryostatins

although the stereoselectivity was only modest. Procedures to

improve this stereochemical control were not investigated.

Protection of the ketone at C19 in derivatives of 20-

oxygenated bryostatins as methoxyacetals is well known.³It was

therefore of interest to convert the dithianes 63 and 64 into

methoxyacetals reminiscent of the C17-C27 fragments of

bryostatins and to study the introduction of the 2-

benzothiazolylsulfonyl moiety and the modified Julia reaction.

Scheme 7 Synthesis of the allylic bromide 50 Reagents and

conditions i, BnOCH₂C(=CH₂)CH₂Br, In, THF, H₂O, rt, 45 min (43,

43%; 44, 45%); ii, (a) 4-nitrobenzoic acid, Ph₃P, DIAD, THF, 0 C

o

i

to rt, 12 h (92%) (b) K₂CO₃, MeOH, 0 C, 3 h (90%); iii, Pr₂NEt,

o

CH₂=CHC(O)Cl, DCM, 0 C, 5 h (97%); iv, Grubbs II, DCE, heat

under reflux, 26 h (80%); v, CeCl₃.7H₂O, NaBH₄, MeOH, 0 ^oC

i

o

(98%); vi, 2,6-lut., Pr₃SiOTf, DCM, 0 C to rt, 2 h (82%); vii, Li,

naph., THF, rt, 1 h, add to 48, THF, −30 ^oC (77%); viii, Et₃N, MsCl,

THF, 0 ^oC, 1 h, LiBr, THF, 0 ^oC, 1 h (93%).

Other procedures can be envisaged for the conversion of the

dithiane monoxide 38 into the C11-C27 fragment of the 20-

deoxybryostatins 51, for example by using a less complex allylic

bromide with further modification after the alkylation step.

However, as reactions of lithiated dithianes with aldehydes are

very well known, it was also of interest to see whether reactions

of lithiated C19 dithianes with aldehydes could be used to

prepare intermediates that correspond to the C11-C27

fragments of bryostatins, e.g. bryostatin 1 (1), with an acyloxy

group at C20. A synthesis of an intermediate that corresponds

to the C11-C27 fragment 51 of a 20-deoxybryostatin was

subsequently developed that did not use dithiane chemistry.

This is presented in the summary and is outlined in Scheme 14.

Scheme 8 Unsuccessful synthesis of dithiane 51

Figure 3 Proposed dithiane – aldehyde synthesis of the C11-C27

and C17-C27 intermediates 52 and 53.

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Scheme 9 Assembly of the C17-C27 fragment Reagents and

i

conditions i, Pr₃SiCl, imid., DCM, rt, 2 h (90%); ii, Et₃SiCl, imid.,

DCM, rt, 90 min (92%); iii, Li, naph., THF, rt, 1 h, add to 57, −30

^oC (81%); iv, Dess-Martin periodinane, py., rt, 1 h (95%); v, 60,

o

ⁿBuLi, THF, rt, 5 min, −78 C, add 59, −78 C, 15 min (61, 53%;

62, 26%); vi, HC(OMe)₃, MeOH, THF, PPTS, rt, 1 h (63, 92%; 64,

90%).

Treatment of the major dihydroxydithiane 63 with

mercury(II) perchlorate in methanol²⁹gave the two

methoxyacetals 65 and 66 that were epimers at the anomeric

position, in isolated yields of 37% and 25%, respectively,

Scheme 10. The corresponding transacetalisation of the minor

dithiane 64 gave a mixture of the two methoxyacetals 69 and

70, ratio ca. 1 : 3, in a combined yield of 60%, although small

samples of each were obtained on repeated chromatography.

Interestingly, oxidation of the major methoxyacetal 65 from

the major dithiane 63, gave the ketone 67 that was also

obtained by oxidation of the minor methoxyacetal 69 prepared

from the minor dithiane 64. Correspondingly the minor

methoxyacetal 66 from the major dithiane 63 gave ketone 68

that was also obtained by oxidation of the major methoxyacetal

70 from the minor dithiane 64, see Scheme 10.

Scheme 10 Preparation of C17-C27 methoxyacetals from

dithianes 63 and 64 Reagents and conditions i, Hg(ClO₄)₂.3H₂O,

THF, MeOH, 2,6-lut., −5 ^oC, 30 min (65, 37%; 66, 25%; 69 and 70,

60%, 1:3); ii, Dess-Martin periodinane, py., DCM, rt, 1 h (67, 55%

from 65, 51% from 69; 68, 63% from 66, 61% from 70).

For the major methoxyacetal obtained from the minor

dithiane, and the corresponding ketone, significant nOes were

observed between the anomeric methoxy goup and H6

consistent with these groups being cis to each other as shown in

structures 70 and 68. For the major methoxyacetal obtained

from the major dithiane, significant nOes were observed

between H3 and H6 showing that these hydrogens are cis to

each other as shown in structure 65. Moreover, for the ketone

prepared by oxidation of this methoxyacetal, a significant nOe

was observed between the methoxy group at C2 and the axial

hydrogen at C5 consistent with the structure 67, see Scheme 10.

The configurations of the epimeric dithianes 63 and 64 at C4,

the ketones 67 and 68 at C2 and the methoxyacetals 65, 66, 69

and 70 at C2 and C3 were confirmed by extensive nOe studies.

6 | J. Name., 2012, 00, 1-3

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Journal Name

The non-stereoselective acetal formation from the dithianes

ARTICLE

The methoxyacetal 73 corresponds to the C17-C27 fragment

View Article Online

DOI: 10.1039/C7OB02127E

63 and 64 was unexpected since it would appear that anomeric of a 20-oxygenated bryostatin. It remained to convert the

effects were not dominating the stereoselectivity. Attempts to benzyloxy group into a 2-benzothiazolylsulfonyl moiety ready

equilibrate the epimeric acetals 65 and 66 under acidic for assembly of the C11-C27 fragment by a modified Julia

conditions led to extensive decomposition. The major reaction. Hydrogenolysis of the benzyl ether 73 gave a mixture

methoxyacetals 65 and 70 formed in the transacetalisation of the methoxy acetal 75 and the hemiacetal 74 but the

processses had the 3-hydroxyl groups cis disposed to the hemiacetal could be converted into the methoxyacetal 75 using

anomeric methoxy groups. It may be that the acetal formation is trimethyl orthoformate and pyridinium toluene p-sulfonate.

under kinetic control and is being influenced by intramolecular However, attempts to convert the primary alcohol 75 into the

hydrogen bonding involving the 3-hydroxyl and anomeric correponding sulfide 76 using 2-mercaptobenzothiazole under

methoxy groups. However, this suggestion is only speculative.

Mitsunobu conditions were unsuccessful. The only product

Nevertheless, the formation of two methoxyacetals from isolated was the tetrahydrofuran 78. The same product 78 was

each of the dithianes would lead to complications if these also formed during attempts to convert the primary mesylate 77

products were to be taken further in the synthesis and a more into the sulfide 76 using 2-mercaptobenzothiazole. Hale’s

stereoselective acetal formation was really required. With the double Thorpe-Ingold effect^1dwould appear to be facilitating an

hydrogen bonding explanation in mind for the formation of the intramolecular

displacement

involving

the

tert-

unexpected methoxyacetal 65 as the major product from diol butyldimethylsilyloxy group at C3 leading to the cyclised product

63, it was decided to see if protection of the C4 hydroxyl group 78 after desilylation. This process competed with the required

had any effect on the stereoselectivity of the transacetalisation. S_N2 reactions of derivatives of the hindered neopentylic alcohol

The major alcohol 61 from the dithiane addition reaction was 75 with external nucleophiles, Scheme 12.

therefore protected as its tert-butyldimethylsilyl ether 71 using

It was thought that the introduction of the primary

an excess of tert-butyldimethylsilyl triflate to drive the silyation benzothiazolyl group before the conversion of the dithiane into

of this hindered alcohol to completion. Following a selective a methoxyacetal might avoid the formation of tetrahydrofuran

removal of the triethylsilyl group, the transacetalisation of the 78. However, attempts to remove the benzyl group from

resulting alcohol 72 was examined. This was found to be much dithiane 71 using Birch conditions or lithium naphthalenide led

slower than the transacetalisations of the diols 63 and 64 that to decomposition and another protecting group was required

were complete within 30 min at −30 ^oC. Indeed the for the primary alcohol. The 4-methoxybenzyloxy group was

transacetalisation of the alcohol 72 was only complete after 8 h considered an option, but it was recognised that lithiation of the

at room temperature. However, a single diastereoisomer was corresponding dithiane could be complicated by competing

isolated in an excellent yield, 88%, and was identified as the lithiation ortho to the aromatic methoxy group.³⁰Nevertheless

expected anomer 73 on the basis of significant nOes between the 4-methoxbenzyl ether 81 was prepared from the

the anomeric methoxy group and H6, see Scheme 11. Because corresponding alcohol 80³²that had been prepared from 3-tert-

of the relatively vigorous conditions required, the butyldimethylsilyloxy-2,2-dimethylpropanal

79

and

the

stereoselectivity of this transacetalisation may be due to regioselectivity of its lithiation was investigated, see Scheme 13.

thermodynamic rather than kinetic control.

Scheme 12 An unexpected cyclisation Reagents and conditions i,

Scheme 11 Stereoselective transacetalisation Reagents and

H₂, Pd/C, EtOAc, MeOH, 1 bar, 25 ^oC (75, 50%; 74, 40%); ii,

HC(OMe)₃, PPTS, MeOH, THF (74%); iii, MsCl, Et₃N, DCM, 0 C, 1

conditions: i, TBSOTf, 2,6-lut., DCM, rt, 14 h (92%); ii, HC(OMe)₃,

o

MeOH, THF, PPTS, rt, 12 h (92%); iii, Hg(ClO₄)₂.3H₂O, 0 ^oC to rt, 8

h; iv, 75, 2-BTSH, PPh₃, DIAD, rt, 3 h (79%); v, 2-BTSH, DMF, NaH,

h (88%).

0 ^oC, 20 min, add 77, 120 ^oC, 12 h (72% from 75).

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Journal Name

Summary and conclusions

View Article Online

DOI: 10.1039/C7OB02127E

The modified Julia reaction and acyl carbanion chemistry,

especially the reactions of 2-lithiated dithianes, have been

investigated for the synthesis of intermediates that are

synthetic equivalents of C11-C27 fragments of bryostatins. The

modified Julia reaction using 2-benzothiazolylsulfones was

found to be more useful for the formation of the 16,17-double-

bond than the classical Julia reaction using phenylsulfones, and

the bulky sulfone 24 gave very good (E)-stereoselectivity.

Conditions were developed for the alkylation of the neopentylic

dithiane monoxide 38 that corresponded to

a C19-acyl

carbanion, using (E)-1-bromobut-2-ene, but the use of the more

complex allylic bromide 50 was unsuccessful perhaps because of

competing elimination reactions under the basic reaction

conditions. This meant that the use of dithianes for the

synthesis of 20-deoxybryostatins would have to involve the

stepwise assembly of the C20-C27 fragment from simpler

precursors. However, dithiane 60 gave a good yield of adducts

with the aldehyde 59, and conditions were developed for the

conversion of the major adduct 61 into the methoxyacetal 73

that corresponds to the C17-C27 fragment of 20-oxygenated

bryostatins.

It would appear that the use of dithianes as acyl carbanion

equivalents was being pushed to its limits during the course of

this work. Of interest in this respect were the better yields

obtained with dithiane 36 and its monoxide 38 than those

obtained using the dithiane 25 and monoxide 26. This was

attributed to the presence of a skipped diene in the latter

compounds that made these intermediates unstable to the

strongly basic conditions used for dithiane deprotonation. The

stereoselective syntheses of C20-C27 intermediates, e.g. the

bromide 50 and the aldehyde 59 based on the use of ring-

closing metathesis to introduce the trisubstituted double-bond

via the six-membered lactone 46, were also of interest.²⁸The

kinetic and thermodynamic control observed in the conversions

of the dithianes 63, 64 and 72, into methoxyacetals was of note,

with the transacetalisation of dithiane 72 providing the required

C17-C27 fragment 73 with excellent stereoselectivity. The tert-

butyldimethylsilyloxy group at C-3 may be influencing the

stereoselectivity of this conversion. The formation of the

tetrahydrofuran 78 from the 3-tert-butyldimethylsilyl ether 75

and mesylate 77 was unexpected^1dand competed with the

required substitution reactions with external nucleophiles.

Finally the role of the solvent in influencing the regioselectivity

of lithiation of the 2-(2-p-methoxybenzyloxyethyl)dithiane 81

was useful.

Scheme 13 Introduction of the 2-benzothiazolylsulfanyl group

Reagents and conditions i, propane-1,3-dithiol, BF₃.Et₂O, DCM, 0

^oC to rt, 16 h (82%); ii, NaH, DMF, 0 ^oC, 30 min, add PMBCl, TBAI

o

n

t

(cat.), 0 C to rt, 1 h (65%); iii, 81, BuLi, BuOMe, rt, 5 min, −78

o

^oC, add 59, −78 C, 15 min (82, 34%; 83, 21%); iv, TBSOTf, 2,6-

lut., DCM, rt, 3 h (90%); v, DDQ, pH7.2 phosphate buffer, DCM,

o

rt, 30 min (81%); vi, 2-BTSH, Ph₃P, THF, DIAD, 0 C to rt, 4 h

(78%).

Deprotonation of the dithiane 81 using the conditions that

had been used previously, i.e. n-butyllithium in THF for 5 min,

followed by quenching with D₂O, showed that some

deprotonation had occurred ortho to the methoxy group as well

as at C2 of the dithiane.³⁰Using ether as the solvent, selective

dithiane deuteriation was observed but was incomplete after

allowing 5 min for the lithiation. Longer lithiation times led to

precipitation of a white solid that if taken up in D₂O gave 52%

deuterium incorporation at C-2 of the dithiane. The

precipitation of the lithiated intermediate was avoided by using

tert-butyl methyl ether as the solvent and led to >70%

deuteriation of the dithiane after lithiation for 8 min and

quenching with D₂O.

Lithiation of the dithiane 81 under these optimised

conditions followed by the addition of the aldehyde 59 gave a

mixture of the epimeric alcohols 82 and 83. The configurations

of these alcohols at C4 were assigned by comparision of their ¹H

NMR spectra with those of the analogous benzyl ethers 61 and

62. Silylation of the major epimer 82 gave the tert-

butyldimethylsilyl ether 84 that was converted into the primary

alcohol 85 by oxidative removal of the 4-methoxybenzyloxy

moiety. Finally this alcohol was converted into the

corresponding thioether 86 using 2-mercaptobenzothiazole

under Mitsunobu conditions, see Scheme 13. No side-product

analogous to the tetrahydrofuran 78 was isolated from this

reaction.

The benzothiazolylsulfide 86 would appear to be a useful

intermediate for the further elaboration of the C11-C27

fragment 52 of 20-oxygenated bryostatins. However, our prime

concern remained with the synthesis of 20-deoxybryostatins,

e.g. bryostatin 10 (2), because these bryostatins had not been

the subject of many investigations by synthetic chemists.

Therefore, rather than continue with studies of the sulfone 86, it

was decided, as our next objective, to study the use of the

modified Julia reaction using more complex substrates for the

synthesis of a 20-deoxybryostatin. Since the complexity and

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ARTICLE

steric hindrance of the substrates will affect the efficiency of (J) are given in Hertz (Hz) and chemical shifts are relative to

View Article Online

this assembly process,^3b,11it was not clear, at this stage, whether tetramethylsilane. Residual non-deuteriated solvent was used as

DOI: 10.1039/C7OB02127E

a properly convergent synthesis could be developed. In the the internal standard.

event, this work led to the first synthesis of

a 20-

deoxybryostatin and is described in full in the following paper.³³(1RS,2RS)-2-{(2E,4R)-6-[(Z)-2-tert-

During the course of these studies, the C17-C27 Butyldiphenylsilyloxyethylidene]-1,1-dimethyl-4-

benzothiazolylsulfone 87 was prepared and was found to triethylsilyloxynona-2,8-dien-1-yl}-1,3-dithiane-1-oxide (26).

undergo a modified Julia reaction with the aldehyde 35 to give An aliquot (0.85 mL_,0.12 mmol) of

a solution of m-

the (E)-alkene 88 with excellent stereoselectivity, see Scheme chloroperoxybenzoic acid (70% w/w, 83 mg, 0.34 mmol) in DCM

14. This alkene corresponds to the target C11-C27 fragment 5 of (2.5 mL) was added to the dithiane 25 (84 mg, 0.13 mmol) in

o

a 20-deoxybryostatin, see Figure 2, and could be incorporated DCM (1 mL) at 0 C and the mixture warmed to r.t. before DCM

into a total synthesis as outlined in Figure 2, although this (10 mL) and saturated aqueous sodium bisulfite (10 mL) were

option has not yet been investigated.³³

added. The aqueous layer was extracted with DCM (2 × 10 mL)

and the organic extracts were dried (MgSO₄) and concentrated

under reduced pressure. Chromatography (gradient elution

8.5:1 light petroleum:ether to ethyl acetate) gave the title

compound 26 as a viscous, colourless oil (67 mg, 78%) as four

28

diastereoisomers, ratio 9:9:1:1, R_f= 0.43 (ethyl acetate), [α]_D

+0.4 (c 15.8, CHCl₃) (Found: M⁺+ Na, 719.3412. C₃₉H₆₀O₃Na₁S₂Si₂

requires M, 719.3415); v_max/cm^-13064, 2952, 2924, 2868, 1469,

1460, 1427, 1236, 1108, 1049, 1041, 1007, 973, 912, 820 and

738; δ_H(400 MHz, CDCl₃) major epimers 0.42 (6 H, q, J 8.0, 3 ×

SiCH₂), 0.79(2) (each 4.5 H, t, J 8.0, 3 × SiCH₂CH₃), 0.97 [9 H, s,

SiC(CH₃)₃], 1.19, 1.20, 1.21, 1.23 (each 1.5 H, s, 1′-CH₃), 1.91 and

1.92 (each 0.5 H, dd, J 13.4, 6.3, 5′-H), 2.03 (1 H, dd, J 13.4, 6.9,

5′-H′), 2.06 and 2.27 (each 1 H, m, 5-H), 2.33-2.50 (2 H, m, 4-H₂),

2.57 (1 H, m, 6-H), 2.68 (2 H, d, J 6.7, 7′-H₂), 3.27 (1 H, m, 6-H′),

3.38 (1 H, s, 2-H), 4.00 (1 H, m, 4′-H), 4.17 (2 H, d, J 6.1, 2′′-H₂),

4.96 (1 H, d, J 16.8, 9′-H), 4.97 (1 H, d, J 10.4, 9′-H′), 5.23 and

5.26 (each 0.5 H, dd, J 15.7, 6.7, 3′-H), 5.41 (1 H, t, J 6.1, 1′′-H),

5.53 and 5.56 (each 0.5 H, d, J 15.7, 2′-H), 5.69 (1 H, m, 8′-H),

7.25-7.38 (6 H, m, ArH) and 7.57-7.65 (4 H, m, ArH); δ_C(100

MHz, CDCl₃) major epimers 3.7(2), 5.8, 18.1, 23.8, 24.1, 25.8,

26.7, 27.0, 28.8, 29.0, 29.4(2), 38.8, 39.7, 41.4, 54.6(2), 60.2,

71.4, 71.5, 75.3, 75.4, 115.3, 126.6, 127.0, 128.5, 130.6, 130.7,

132.9(2), 133.7, 134.0, 134.5, 134.6 and 135.4; m/z (ES⁺) 719.2

(M⁺+ 23, 100%), 714.2 (M⁺+ 1, 44) and 565.1 (13). The second

fraction was mixture of the corresponding diastereoisomeric

Scheme 14 Synthesis of a C11-C27 fragment Reagents and

conditions i, 87, LiHMDS, THF, −78 ^oC to −60 ^oC, 30 min, add 35,

−78 ^oC, 20 min, rt (53%).

Experimental

General experimental details

Flash column chromatography was performed using Merck silica

gel (60H; 40-60μ, 230-240 mesh). Light petroleum refers to the

fraction boiling between 40 and 60 °C and was redistilled.

Tetrahydrofuran was dried over sodium-benzophenone and was

distilled under nitrogen. Dichloromethane was dried over CaH₂

and was distilled. Ether refers to diethyl ether. Reactions under

non-aqueous conditions were carried out under an atmosphere

of nitrogen or argon.

dithiane-1,3-dioxides (8 mg, 10%), R_f= 0.20 (ethyl acetate),

28

[α]_D

0.0 (c 7.5, CHCl₃) (Found: M⁺

+ Na, 735.3384.

C₃₉H₆₀O₄NaS₂Si₂requires M, 735.3369); v_max/cm^-13067, 2954,

2927, 2873, 1470, 1462, 1427, 1387, 1360, 1110, 1046, 823, 739

and 702; m/z (ES⁺) 736 (M⁺+ 23, 100%), 730 (M⁺+ 18, 25) and

621 (56).

(1RS,2RS)-2-[(2E)-But-2-enyl]-2-{(2E,4R)-6-[(Z)-2-tert-

butyldiphenylsilyloxyethylidene]-1,1-dimethyl-4-

triethylsilyloxynona-2,8-dienyl}-1,3-dithiane-1-oxide (27).

Mass spectra used electron impact ionisation (EI⁺), chemical

ionisation using ammonia (CI⁺), electrospray ionisation in the

positive mode (ES⁺) and atmospheric pressure chemical

ionisation in the positive or negative mode (APCI⁺or APCI^-). Low

and high resolution mass spectra were recorded using a

Micromass Trio 200 and a Kratos Concept IS spectrometer,

respectively. Infra-red spectra were measured using a Genesis

FTIR spectrometer on NaBr plates, either neat or as evaporated

films. Nuclear magnetic resonance spectra were recorded using

Varian Unity 500 (500 MHz), Varian INOVA 400 (400 MHz) and

Varian Unity 300 (300 MHz) spectrometers. Coupling constants

Lithium di-isopropylamide (1.8

M

in THF/heptanes/

ethylbenzene, 0.061 mL, 0.11 mmol)) was added to the

dithiane-1-oxide 26 (64 mg, 0.092 mmol) in THF (0.61 mL) and

o

HMPA (43 µL, 0.18 mmol) at −78 C and the solution stirred at

−78 ^oC for 1 h. (E)-1-Bromobut-2-ene (85% w/w, 14 µL, 0.14

o

mmol) was added and the mixture was stirred at −78 C for 30

min and at rt for 1 h. Ethyl acetate (10 mL) and saturated

aqueous sodium bicarbonate (10 mL) were added and the

aqueous layer was extracted with ethyl acetate (2 × 10 mL). The

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Journal Name

organic extracts were dried (MgSO₄) and concentrated under 2-enoate as a pale yellow oil (10.6 g, 76%), as a mixture of

View Article Online

27

DOI: 10.1039/C7OB02127E

reduced pressure. Chromatography of the residue gave the title epimers, R_f= 0.10 (1:2 light petroleum:ether), [α]_D+21 (c 9.9,

compound 27 a viscous, pale yellow oil (35 mg, 50%) as a CHCl₃) (Found: M⁺+ Na, 491.2444. C₂₄H₄₀O₇NaSi requires M,

mixture of diastereoisomers (¹H NMR), R_f= 0.57 (ethyl acetate) 491.2436); v_max/cm^-13421, 2952, 2879, 1717, 1644, 1613, 1514,

(Found: M⁺

+ Na, 773.3891. C₄₃H₆₆O₃NaS₂Si₂requires M, 1458, 1434, 1248, 1197, 1179, 1148, 1096, 1037, 1008, 820 and

773.3884); v_max/cm^-12954, 2927, 2873, 1426, 1388, 1360, 1237, 743; δ_H(400 MHz, CDCl₃) 0.48 and 0.49 (each 3 H, q, J 7.9, 3 ×

1111, 1053, 1005, 973, 823, 739 and 702; δ_H(400 MHz, CDCl₃) SiCH₂), 0.82 and 0.83 (each 4.5 H, t, J 7.9, 3 × SiCH₂CH₃), 2.17-

0.41 and 0.42 (each 3 H, q, J 7.9, 3 × SiCH₂), 0.79(2) (each 4.5 H, 2.37 (2 H, m, 1′-H₂), 2.51 (0.5 H, dd, J 12.7, 8.9, 4-H), 2.78 (0.5 H,

t, J 7.9, 3 × SiCH₂CH₃), 0.97 [9 H, s, SiC(CH₃)₃], 1.13 and 1.24 dd, J 12.7, 8.1, 4-H), 2.86 (0.5 H, dd, J 12.7, 4.8, 4-H′), 3.08 (0.5

(each 3 H, s, 1′-CH₃), 1.55-1.70 (3 H, m, 4′′-H₃), 1.84-2.09 (3 H, m, H, dd, J 12.7, 3.9, 4-H′), 3.30-3.42 (3 H, m, 3′-H₂, 6-H), 3.53 (1 H,

5′-H₂, 5-H), 2.10-2.29 (2 H, m, 4-H, 5-H′), 2.35-3.06 (7 H, m, 6-H₂, m, 6-H′), 3.59 and 3.60 (each 1.5 H, s, OCH₃), 3.73 (3 H, s, OCH₃),

4-H′, 1′′-H₂, 7′-H₂), 3.99 (1 H, m, 4′-H), 4.12-4.28 (2 H, m, 2′′′-H₂), 3.83 (1 H, m, 5-H), 4.09 and 4.18 (each 0.5 H, m, 2′-H), 4.37 (1 H,

4.92-5.03 (2 H, m, 9′-H₂), 5.20 and 5.24 (each 0.5 H, dd, J 15.7, s, ArCH₂), 4.38 and 4.39 (each 0.5 H, d, J 11.6, ArHCH), 5.75 (1 H,

6.8, 3′-H), 5.40 (1 H, m, 1′′′-H), 5.44-5.84 (4 H, m, 2′-H, 2′′-H, 3′′- m, 2-H), 6.79 (2 H, d, J 8.7, ArH) and 7.15-7.20 (2 H, m, ArH); δ_C

H, 8′-H), 7.25-7.38 (6 H, m, ArH) and 7.57-7.65 (4 H, m, ArH); (100 MHz, CDCl₃) 4.8(2), 6.8(2), 15.3, 29.2, 37.0, 37.3, 43.6, 44.4,

m/z (ES⁺) 773.6 (M⁺+ 23, 100%). The starting dithiane monoxide 51.0, 55.3, 66.4, 66.5, 69.8, 70.3, 71.4, 71.7, 73.0(2), 74.5, 74.7,

26 (26 mg, 40%) was also isolated.

113.7, 119.1, 119.2, 129.4, 130.3, 157.4, 158.5, 159.1 and 166.4;

m/z (ES⁺) 491.3 (M⁺+ 23, 100%), 289.2 (14), 271.3 (15) and 145.3

Methyl

(2Z,5R)-3-prop-2-enyl-6-(4-methoxybenzyloxy)-5- (52).

triethylsilyloxyhex-2-enoate (29).

Sodium periodate (10.3 g, 48.1 mmol) was added to a

Imidazole (260 mg, 3.85 mmol) and triethylsilyl chloride (0.26 mixture of these diols (5.02 g, 10.7 mmol) in THF (140 mL),

o

mL, 1.55 mmol) were added to the hydroxyester 28 (410 mg, methanol (140 mL) and water (175 mL) at 0 C and the mixture

o

1.44 mmol) in DCM (6.8 mL) and the solution stirred for 2 h at was stirred at 0 C for 1 h. Sodium borohydride (1.21 g, 32.0

rt. Water (30 mL) and DCM (30 mL) were added and the mmol) was added with cooling to maintain the reaction

o

aqueous phase extracted with DCM (2 × 30 mL). The organic temperature < 10 C. After 1 h, brine (300 mL) was added and

extracts were dried (MgSO₄) and concentrated under reduced the mixture was allowed to warm to rt then extracted with

pressure. Chromatography of the residue (9:1 light ether (4 × 500 mL). The organic extracts were dried (MgSO₄) and

petroleum:ether) gave the title compound 29 (510 mg, 82%) as a concentrated under reduced pressure. Chromatography of the

27

colourless oil, R_f= 0.63 (1:1 light petroleum:ether), [α]_D+66 (c residue (2:1 then 1:1 light petroleum:ether) afforded the title

1.2, CHCl₃) (Found: M⁺+ Na, 457.2376. C₂₄H₃₈O₅NaSi requires M, compound 30 as a clear, colourless oil (3.55 g, 76%), R_f= 0.48

457.2381); v_max/cm^-12952, 2908, 2875, 1718, 1644, 1613, 1513, (1:2 light petroleum:ether), [α]_D²⁷+46 (c 5.4, CHCl₃) (Found: M⁺+

1248, 1192, 1180, 1143, 1099, 1035, 1004 and 742; δ_H(500 Na, 461.2331. C₂₃H₃₈O₆NaSi requires M, 461.2330); v_max/cm^-1

MHz, CDCl₃) 0.54 (6 H, q, m, 3 × SiCH₂), 0.89 (9 H, t, J 7.9, 3 × 3447, 2951, 2879, 1713, 1644, 1613, 1514, 1434, 1248, 1194,

SiCH₂CH₃), 2.58 (1 H, dd, J 12.5, 8.5, 4-H), 2.94 (1 H, dd, J 16.4, 1179, 1145, 1104, 1037, 1008 and 820; δ_H(400 MHz, CDCl₃) 0.49

6.9, 1′-H), 2.97-3.03 (2 H, m, 4-H′, 1′-H′), 3.37 (2 H, d, J 5.0, 6- (6 H, q, J 7.9, 3 × SiCH₂), 0.83 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 1.89 (1

H₂), 3.64 and 3.78 (each 3 H, s, OCH₃), 4.14 (1 H, m, 5-H), 4.44 H, br. s, 2′-OH), 2.41 (2 H, td, J 6.2, 0.9, 1′-H₂), 2.59 (1 H, dd, J

and 4.45 (each 1 H, d, J 11.6, ArHCH), 5.06 (1 H, d, J 17.0, 3′-H), 12.6, 8.5, 4-H), 2.97 (1 H, ddd, J 12.6, 4.4, 0.8, 4-H′), 3.33 (2 H, d,

5.10 (1 H, d, J 10.1, 3′-H′), 5.70 (1 H, s, 2-H), 5.74 (1 H, ddt, J J 5.0, 6-H₂), 3.60 (3 H, s, OCH₃), 3.64-3.72 (2 H, m, 2′-H₂), 3.73 (3

17.0, 10.2, 6.9, 2′-H) and 6.85 and 7.24 (each 2 H, d, J 7.1, ArH); H, s, OCH₃), 4.14 (1 H, m, 5-H), 4.38 and 4.39 (each 1 H, d, J 11.6,

δ_C(125 MHz, CDCl₃) 4.9, 6.9, 37.4, 44.2, 50.9, 55.3, 71.6, 72.9, ArHCH), 5.72 (1 H, m, 2-H) and 6.79 and 7.18 (each 2 H, d, J 8.7,

74.8, 113.6, 116.9, 118.0, 129.3, 130.5, 134.4, 159.1, 160.4 and ArH); δ_C(100 MHz, CDCl₃) 4.9, 6.8, 37.1, 43.2, 50.9, 55.2, 60.5,

166.8; m/z (ES⁺) 457 (M⁺+ 23, 100%) and 377 (14).

71.5, 72.9, 74.7, 113.7, 118.4, 129.4, 130.4, 158.6, 159.1 and

166.4; m/z (ES⁺) 461.4 (M⁺+ 23, 100%), 179.1 (43) and 145.3

(25).

Methyl (2Z,5R)-3-(2-hydroxyethyl)-6-(4-methoxybenzyloxy)-5-

triethylsilyloxyhex-2-enoate (30).

N-Methylmorpholine-N-oxide (3.79 g, 32.4 mmol) was added to

the alkene 29 (12.9 g, 29.7 mmol) in acetone (360 mL) and

water (51 mL) and the mixture stirred until homogeneous.

Osmium tetraoxide (0.60 g, 2.35 mmol) in water (35 mL) and

tert-butanol (35 mL) were added and the mixture was stirred for

4 h. Saturated aqueous sodium bisulfite (750 mL) was added

and the mixture stirred for 20 min. The aqueous layer was

extracted with ethyl acetate (5 × 500 mL) and the organic

extracts were dried (MgSO₄) and concentrated under reduced

pressure. Chromatography (4:1 then 8:1 light petroleum:ether)

Methyl

(2Z,5R)-3-(2-Benzyloxymethoxyethyl)-6-(4-

methoxybenzyloxy)-5-triethylsilyloxyhex-2-enoate (31).

Di-isopropylethylamine (10 mL, 57 mmol) was added to the

alcohol 30 (5.70 g, 13.0 mmol) in THF (29 mL) and the solution

cooled to 0 ^oC. Benzyloxymethyl chloride (approx 60% w/w, 4.50

mL, 19.4 mmol) was added and the mixture was stirred at rt for

16 h. Ether (100 mL) and saturated aqueous sodium bicarbonate

(100 mL) were added and the aqueous layer was extracted with

ether (2 × 100 mL). The organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue (10:1 to 3:1 light petroleum:ether) gave the title

compound 31 as a clear, colourless oil (6.68 g, 93%), R_f= 0.52

of

the

residue

gave

methyl

(2Z,5RS)-3-[(2R)-3-(4-

methoxybenzyloxy)-2-triethylsilyloxypropyl]-5,6-dihydroxyhex-

10 | J. Name., 2012, 00, 1-3

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ARTICLE

(2:1 light petroleum:ether), [α]_D²⁷+36 (c 20.6, CHCl₃) (Found: M⁺the title compound 33 as a clear, colourless oil (6.42 g, 98%), R_f=

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+ Na, 581.2905, C₃₁H₄₆O₇NaSi requires M, 581.2905); v_max/cm^-10.32 (5:1 light petroleum:ether), [α]_D+0.4 (c 14.0, CHCl₃)

27

DOI: 10.1039/C7OB02127E

2951, 2879, 1717, 1644, 1613, 1514, 1456, 1434, 1367, 1248, (Found: M⁺

+

NH₄, 704.4747. C₃₉H₇₀O₆NSi₂requires M,

1194, 1150, 1111, 1042, 820 and 740; δ_H(400 MHz, CDCl₃) 0.48 704.4736); v_max/cm^-12941, 2866, 1613, 1514, 1460, 1248, 1171,

(6 H, q, J 7.9, 3 × SiCH₂), 0.82 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 2.43- 1106, 1083, 1039, 1011, 884 and 739; δ_H(400 MHz, CDCl₃) 0.50

2.49 (2 H, m, 1′-H₂), 2.58 (1 H, dd, J 12.5, 8.5, 4-H), 2.95 (1 H, dd, (6 H, q, J 7.9, 3 × SiCH₂), 0.85 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 0.94-

J 12.5, 4.4, 4-H′), 3.31 (2 H, d, J 5.0, 6-H₂), 3.58 (3 H, s, OCH₃), 1.05 [21 H, m, 3 × SiCH(CH₃)₂], 2.11 (1 H, dd, J 13.6, 7.2, 3-H),

3.62-3.65 (2 H, m, 2′-H₂), 3.71 (3 H, s, OCH₃), 4.07 (1 H, m, 5-H), 2.23-2.32 (3 H, m, 3-H′, 1′-H₂), 3.24 and 3.25 (each 1 H, dd, J 9.7,

4.38 and 4.39 (each 1 H, d, J 11.7, ArHCH), 4.50 (2 H, s, PhCH₂), 5.2, 1-H), 3.61 (2 H, t, J 7.1, 2′-H₂), 3.72 (3 H, s, OCH₃), 3.81 (1 H,

4.65 (2 H, s, OCH₂O), 5.70 (1 H, m, 2-H), 6.78 and 7.18 (each 2 H, m, 2-H), 4.18 (1 H, dd, J 13.1, 5.8, 6-H), 4.22 (1 H, dd, J 13.1, 6.4,

d, J 8.7, ArH) and 7.15-7.29 (5 H, m, ArH); δ_C(100 MHz, CDCl₃) 6-H′), 4.36 and 4.37 (each 1 H, d, J 12.3, ArHCH), 4.52 (2 H, s,

4.9, 6.9, 37.2, 39.8, 50.9, 55.2, 65.6, 69.5, 71.7, 72.9, 74.8, 94.5, PhCH₂), 4.67 (2 H, s, OCH₂O), 5.37-5.43 (1 H, m, 5-H), 6.79 and

113.6, 117.7, 127.7, 127.9, 128.4, 129.3, 130.5, 137.8, 158.8, 7.17 (each 2 H, d, J 8.7, ArH) and 7.19-7.30 (5 H, m, ArH); δ_C

159.1 and 166.6; m/z (ES⁺) 581.4 (M⁺+ 23, 100%), 197.2 (13) and (100 MHz, CDCl₃) 4.9, 6.9, 12.0, 18.0, 36.4, 37.4, 55.2, 60.4, 66.8,

151.3 (18).

69.3, 70.8, 72.9, 74.0, 94.6, 113.7, 127.6, 127.9, 128.4, 129.1,

129.5, 130.5, 133.7, 138.0 and 159.1; m/z (ES⁺) 704.6 (M⁺+ 18,

(2Z,5R)-3-(2-Benzyloxymethoxyethyl)-6-(4-methoxybenzyloxy)- 100%), 662.5 (5), 214.2 (12) and 151.2 (15).

5-triethylsilyloxyhex-2-en-1-ol (32).

Di-isobutylaluminium hydride (1.0 M in heptanes, 25 mL, 25 (4Z,2R)-4-(2-Benzyloxymethoxyethyl)-2-triethylsilyloxy-6-tri-

mmol) was added to the ester 31 (6.40 g, 11.5 mmol) in toluene isopropylsilyloxyhex-4-en-1-ol (34).

(100 mL) at −78 ^oC and the mixture stirred at −78 ^oC for 45 min. An aqueous pH7 phosphate buffer (5.10 mL) was added to the

Methanol (1.5 g, 47 mmol) in toluene (20 mL) was added and PMB-ether 33 (4.88 g, 7.10 mmol) in DCM (97 mL) and the

o

the mixture stirred for 10 min then allowed to warm to 0 C. mixture cooled to 0 ^oC. Dichlorodicyanoquinone (1.71 g, 7.53

Saturated aqueous Rochelle’s salt (100 mL) was added and the mmol) was added in one portion with rapid stirring and the

mixture was allowed to warm to rt, with vigorous stirring over 1 mixture was stirred vigorously for 1 h at 0 ^oC then at 10 ^oC for 2

h. More saturated aqueous Rochelle’s salt (400 mL) and DCM h. Dichloromethane (250 mL) and saturated aqueous sodium

(400 mL) were added and the aqueous layer was extracted with bicarbonate (250 mL) were added and the aqueous layer was

DCM (2 × 400 mL). The organic extracts were dried (MgSO₄) and extracted with DCM (2 × 250 mL). The organic extracts were

concentrated under reduced pressure. Chromatography (3:1 washed with saturated aqueous sodium bisulfite (250 mL) and

then 1:1 light petroleum:ether) of the residue gave the title saturated aqueous sodium bicarbonate (250 mL), dried (MgSO₄)

compound 32 as a clear, colourless oil (5.38 g, 89%), R_f= 0.19 and concentrated under reduced pressure. The residue was

27

o

(1:1 light petroleum:ether), [α]_D+4.7 (c 1.7, CHCl₃) (Found: M⁺dissolved in methanol (150 mL) and the solution cooled to 0 C.

+ Na, 553.2957. C₃₀H₄₆O₆NaSi requires M, 553.2956); v_max/cm^-1Sodium borohydride (0.41 g, 10.8 mmol) was added to reduce

3452, 2951, 2875, 1613, 1513, 1460, 1248, 1168, 1106, 1037, the 4-methoxybenzaldehyde side-product and the mixture

o

1008, 820 and 737; δ_H(400 MHz, CDCl₃) 0.50 (6 H, q, J 7.9, 3 × stirred at 0 C for 20 min. After concentrating under reduced

SiCH₂), 0.84 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 2.23-2.38 (4 H, m, 4-H₂, pressure (to ca. 20 mL), ether (100 mL) and water (100 mL) were

1′-H₂), 2.36 (1 H, br. s, OH), 3.26 (1 H, dd, J 9.7, 5.9, 6-H), 3.33 (1 added and the aqueous layer was extracted with ether (2 × 100

H, dd, J 9.7, 4.8, 6-H′), 3.61 (2 H, t, J 6.9, 2′-H₂), 3.72 (3 H, s, mL). The organic extracts were dried (MgSO₄) and concentrated

OCH₃), 3.84 (1 H, m, 5-H), 3.92 (1 H, dd, J 12.3, 7.3, 1-H), 4.02 (1 under reduced pressure. Chromatography (10:1 then 4:1 light

H, dd, J 12.3, 7.0, 1-H′), 4.38 and 4.39 (each 1 H, d, J 10.5, petroleum:ether) of the residue gave the title compound 34 as a

ArHCH), 4.50 (2 H, s, PhCH₂), 4.66 (2 H, s, OCH₂O), 5.66 (1 H, m, clear, colourless oil (2.56 g, 64%), R_f

= 0.40 (2:1 light

27

2-H), 6.79 and 7.17 (each 2 H, d, J 8.7, ArH) and 7.18-7.29 (5 H, petroleum:ether);, [α]_D–7.1 (c 14.0, CHCl₃) (Found: M⁺+ Na,

m, ArH); δ_C(100 MHz, CDCl₃) 4.8, 6.8, 35.5, 36.7, 55.3, 58.1, 589.3715. C₃₁H₅₈O₅NaSi₂requires M, 589.3715); v_max/cm^-13468,

66.5, 69.4, 69.6, 73.1, 73.9, 94.6, 113.7, 127.7, 127.8, 128.4(2), 2944, 2867, 1463, 1383, 1241, 1166, 1109, 1058, 883 and 744;

129.4, 130.1, 137.9(2) and 159.2; m/z (ES⁺) 553.7 (M⁺+ 23, δ_H(500 MHz, CDCl₃) 0.41 (6 H, q, J 7.9, 3 × SiCH₂), 0.75 (9 H, t, J

100%), 289.2 (15), 243.2 (19), 153.3 (17) and 145.3 (36).

7.9, 3 × SiCH₂CH₃), 0.83-0.94 [21 H, m, 3 × SiCH(CH₃)₂], 2.05-2.23

(4 H, m, 3-H₂, 1’-H₂), 2.42 (1 H, m, OH), 3.21 (1 H, ddd, J 11.5,

(4Z,2R)-4-(2-Benzyloxymethoxyethyl)-1-(4-methoxybenzyloxy)- 7.4, 4.3, 1-H), 3.31 (1 H, dt, J 11.5, 5.9, 1-H′), 3.49 (2 H, t, J 6.9,

2-triethylsilyloxy-6-tri-isopropylsilyloxyhex-4-ene (33). 2′-H₂), 3.65 (1 H, m, 2-H), 4.04 and 4.06 (each 1 H, dd, J 12.5,

Imidazole (1.88 g, 27.6 mmol) was added to the alcohol 32 (5.04 6.7, 6-H), 4.39 (2 H, s, PhCH₂), 4.54 (2 H, s, OCH₂O), 5.34 (1 H, t, J

g, 9.53 mmol) in DCM (55 mL) and the mixture was cooled to 0 6.7, 5-H) and 7.05-7.17 (5 H, m, ArH); δ_C(125 MHz, CDCl₃) 4.9,

^oC before the dropwise addition of tri-isopropylsilyl chloride 6.9, 12.0, 18.0, 35.1, 37.4, 59.8, 65.3, 66.7, 69.4, 71.4, 94.6,

(2.70 mL, 12.6 mmol). The mixture was stirred at rt for 16 h and 127.7, 127.9, 128.4, 128.6, 135.3 and 137.9; m/z (ES⁺) 589.4 (M⁺

DCM (50 mL) and water (50 mL) were added. The aqueous layer + 23, 100%) and 584.3 (M⁺+ 18, 14).

was extracted with DCM (2 × 100 mL) and the organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography (9:1 light petroleum:ether) of the residue gave

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J. Name., 2013, 00, 1-3 | 11

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Organic & Biomolecular Chemistry

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ARTICLE

Journal Name

2-[(2E,6Z,4R)-6-(2-Benzyloxymethoxyethyl)-1,1-dimethyl-4-

triethylsilyloxy-8-tri-isopropylsilyloxyocta-2,6-dienyl]-1,3-

dithiane (36).

requires M, 761.4095); v_max/cm^-12944, 2865, 1464, 1425, 1386,

1366, 1238, 1166, 1105, 1051, 1042, 974 and 822; δ_H(400 MHz,

CDCl₃) major diastereoisomers 0.51 (6 H, q, J 7.9, 3 × SiCH₂),

View Article Online

DOI: 10.1039/C7OB02127E

Pyridine (0.18 ml, 2.22 mmol) and the Dess-Martin periodinane 0.86 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 0.95-1.07 [21 H, m, 3 ×

(0.167 g, 0.394 mmol) were added to the alcohol 34 (0.107 g, SiCH(CH₃)₂], 1.27, 1.28 and 1.31(2) (each 1.5 H, s, 1′-CH₃), 2.03-

0.189 mmol) in DCM (1.3 mL) and the mixture was stirred for 3 h 2.18 (2 H, m, 5-H, 5′-H), 2.19-2.36 (4 H, m, 1′′-H₂, 5-H′, 5′-H′),

at rt. Ether (10 mL) and a mixture of saturated aqueous sodium 2.41-2.53 (2 H, m, 4-H₂), 2.60 (0.5 H, td, J 13.0, 3.2, 6-H), 2.61

bicarbonate and saturated aqueous sodium bisulfite (1:1, 10 mL) (0.5 H, td, J 13.2, 3.3, 6-H), 3.23-3.32 (1 H, m, 6-H′), 3.43 (1 H, s,

were added and the aqueous layer was extracted with ether (2 2-H), 3.62 (2 H, t, J 7.1, 2′′-H₂), 4.12 (1 H, m, 4′-H), 4.16-4.27 (2

× 10 mL). The organic extracts were dried (MgSO₄) and H, m, 8′-H₂), 4.52 (2 H, s, PhCH₂), 4.68 (2 H, s, OCH₂O), 5.34-5.48

concentrated under reduced pressure to give the aldehyde 35, a (2 H, m, 3′-H, 7′-H), 5.63(2) (each 0.5 H, dd, J 15.6, 0.8, 2′-H) and

a yellow oil (0.13 g) that was used directly in the next step.

7.17-7.33 (5 H, m, ArH); δ_C(100 MHz, CDCl₃) major

Lithium hexamethyldisilazide (1.0 M in toluene, 0.20 mL) diastereoisomers 3.8, 3.9(2), 11.0, 17.0, 23.9, 24.3, 26.6, 27.1,

was added to the sulfone 24 (73 mg, 0.20 mmol) in THF (1.9 mL) 28.9(2), 29.5(2), 36.6, 39.3(2), 39.8, 54.6, 54.7, 59.5, 65.7(2),

o

at −78 C and the solution stirred for 20 min. The aldehyde 35 71.8(2), 75.3, 75.4, 93.5, 126.6, 126.8, 127.4, 128.4, 130.7,

(0.13 g, from 0.189 mmol of the alcohol 34) in THF (1.2 mL) was 130.9, 132.4, 134.0, 134.2 and 136.9; m/z (ES⁺) 761.5 (M⁺+ 23,

added rapidly and the mixture was immediately allowed to 100%), 397.6 (39), 389.6 (38) and 211.1 (21).

warm to rt. After stirring for 1 h, ether (10 mL) and saturated

aqueous sodium bicarbonate (10 mL) were added and the (1RS,2RS)-2-[(2E,6Z,4R)-6-(2-Benzyloxymethoxyethyl)-1,1-

aqueous layer extracted with ether (2 × 10 mL). The organic dimethyl-4-triethylsilyloxy-8-tri-isopropylsilyloxyocta-2,6-dien-

extracts were dried (MgSO₄) and concentrated under reduced 1-yl]-2-[(2E)-but-2-enyl]-1,3-dithiane-1-oxide (39).

pressure.

Chromatography

(100:1

then

50:1

light Lithium

di-isopropylamide

(1.8

M

in

petroleum:ether) of the residue gave the title compound 36 as a THF/heptanes/ethylbenzene, 0.13 mL, 0.23 mmol) was added

pale yellow oil (71 mg, 52%), R_f

= 0.43 (5:1 light dropwise to the dithiane-1-oxide 38 (0.146 g, 0.197 mmol) in

27

petroleum:ether), [α]_D–2.2 (c 10.6, CHCl₃) (Found: M⁺+ Na, THF (1.3 mL) and hexamethyl phosphoric triamide (70 µL, 0.39

745.4127. C₃₉H₇₀O₄NaS₂Si₂requires M, 745.4146); v_max/cm^-1mmol) at −78 C and the solution was stirred for 30 min at −78

o

2943, 2868, 1463, 1421, 1385, 1365, 1243, 1166, 1106, 1063, ^oC. (2E)-1-Bromobut-2-ene (85% w/w, 30 µL, 0.25 mmol) was

o

882 and 743; δ_H(400 MHz, CDCl₃) 0.48 (6 H, q, J 7.9, 3 × SiCH₂), added and the solution stirred at −78 C for 30 min and at rt 30

0.83 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 0.92-1.05 [21 H, m, 3 × min. Ethyl acetate (10 mL) and saturated aqueous sodium

SiCH(CH₃)₂], 1.08 and 1.10 (each 3 H, s, 1′-CH₃), 1.67 and 1.95 bicarbonate (10 mL) were added and the aqueous layer was

(each 1 H, m, 5-H), 2.09 (1 H, dd, J 13.4, 6.4, 5′-H), 2.22 (1 H, dd, extracted with ethyl acetate (2 × 10 mL). The organic extracts

J 13.4, 7.0, 5′-H′), 2.26 (2 H, t, J 7.0, 1′′-H₂), 2.70-2.80 (4 H, m, 2- were washed with brine (10 mL), dried (MgSO₄) and

H₂, 4-H₂), 3.59 (2 H, t, J 7.1, 2′′-H₂), 3.89 (1 H, s, 2-H), 4.07 (1 H, concentrated under reduced pressure. Chromatography

m, 4′-H), 4.13-4.24 (2 H, m, 8′-H₂), 4.50 (2 H, s, PhCH₂), 4.65 (2 H, (gradient elution ether to ethyl acetate) gave the title compound

s, OCH₂O), 5.30 (1 H, dd, J 15.6, 7.0, 3′-H), 5.36 (1 H, t, J 6.1, 7′- 39 as a viscous, colourless oil (0.11 g, 71%), a mixture of

29

H), 5.57 (1 H, dd, J 15.6, 0.8, 2′-H) and 7.16-7.28 (5 H, m, ArH); diastereoisomers, R_f= 0.70 (ethyl acetate), [α]_D–8.6 (c 7.4,

δ_C(100 MHz, CDCl₃) 4.9, 6.9, 12.0, 18.0, 25.0, 25.4, 26.0, 31.2, CHCl₃) (Found: M⁺+ Na, 815.4558. C₄₃H₇₆O₅NaS₂Si₂requires M,

37.6, 40.4, 40.5, 60.5, 60.8, 66.8, 69.3, 73.1, 94.6, 127.6, 127.9, 815.4565); v_max/cm^-12942, 2865, 1460, 1385, 1362, 1236, 1161,

128.4, 129.3, 130.8, 133.5, 136.9 and 138.0; m/z (ES⁺) 745.8 (M⁺1105, 1054, 1038, 971, 882 and 741; δ_H(400 MHz, CDCl₃) major

+ 23, 100%), 553.2 (10), 197.3 (17) and 151.3 (38).

diastereoisomers 0.46-0.55 (6 H, m, 3 × SiCH₂), 0.86 and 0.87

(each 4.5 H, t, J 7.9, 3 × SiCH₂CH₃), 0.96-1.08 [21 H, m, 3 ×

SiCH(CH₃)₂], 1.20(2) (each 1.5 H, s, 1′-CH₃), 1.32 (3 H, s, 1′-CH₃′),

(1RS,2RS)-2-[(2E,6Z,4R)-6-(2-Benzyloxymethoxyethyl)-1,1-

dimethyl-4-triethylsilyloxy-8-tri-isopropylsilyloxyocta-2,6-dien- 1.55-1.74 (3 H, m, 4′′-H₃), 1.95-3.08 (12 H, m, 4-H₂, 5-H₂, 6-H₂,

1-yl]-1,3-dithiane-1-oxide (38). 5′-H₂, 1′′-H₂, 1’’’-H₂), 3.62 and 3.63 (each 1 H, t, J 7.1, 2′′′-H₂),

An aliquot (1.08 mL) of a solution of m-chloroperoxybenzoic 4.12 (1 H, m, 4′-H), 4.16-4.29 (2 H, m, 8′-H₂), 4.53 (2 H, s, CH₂Ph),

acid (70% w/w, 101 mg, 0.410 mmol) in DCM (2.0 mL) was 4.68 (2 H, s, OCH₂O), 5.29-5.45 (2 H, m, 3′-H, 7′-H), 5.47-5.81 (2

added to the dithiane 36 (151 mg, 0.207 mmol) in DCM (1.7 mL) H, m, 2′′-H, 3′′-H), 5.86 (1 H, m, 2′-H) and 7.18-7.33 (5 H, m,

o

at 0 C with monitoring the consumption of starting material by ArH); m/z (ES⁺) 815.6 (M⁺+ 23, 100%), 761.5 (21), 424.4 (86) and

TLC during the addition. After warming the reaction mixture to 416.4 (36). Some unreacted starting material 38 (20 mg, 13%)

rt, DCM (10 mL) and saturated aqueous sodium bisulfite (10 mL) was also isolated.

were added the aqueous layer was extracted with DCM (2 × 10

mL). The organic extracts were dried (MgSO₄) and concentrated 2-[(2E,6Z,4R)-6-(2-Benzyloxymethoxyethyl)-1,1-dimethyl-4-

under reduced pressure. Chromatography (gradient elution triethylsilyloxy-8-tri-isopropylsilyloxyocta-2,6-dien-1-yl]-2-

ether to ethyl acetate) of the residue gave the title compound [(2E)-but-2-enyl]-1,3-dithiane (37).

38 as a mixture of diastereoisomers, ratio 3:3:1:1, as a clear, Hexamethyl phosphoric triamide (0.22 mL) was added to the

colourless oil (146 mg, 95%), R_f= 0.53 (ethyl acetate), [α]_D²⁸–2.4 dithiane 36 (0.191 g, 0.264 mmol) in THF (2.6 mL) and the

o

(c 8.5, CHCl₃) (Found: M⁺+ Na, 761.4104. C₃₉H₇₀O₅NaS₂Si₂solution cooled to −78 C. tert-Butyllithium (1.6 M in pentane,

12 | J. Name., 2012, 00, 1-3

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ARTICLE

0.26 mL, 0.42 mmol) was added and the solution was stirred for 0.06 and 0.07 (each 3 H, s, SiCH₃), 0.86-0.95 (2 H, m, CH₂Si), 0.88

View Article Online

DOI: 10.1039/C7OB02127E

15 min, before the dropwise addition of (2E)-1-bromobut-2-ene [9 H, s, SiC(CH₃)₃], 1.02-1.16 [21 H, m, 3 × SiCH(CH₃)₂], 1.09 (3 H,

(85% w/w, 0.11 mL, 9.09 mmol). The solution was stirred for 30 d, J 6.2, 9-H₃), 1.49 (1 H, ddd, J 14.1, 9.3, 2.8, 6-H), 1.57 (1 H,

o

min at −78 C, methanol (0.1 mL) was added and the solution ddd, J 14.0, 9.8, 3.8, 6-H'), 2.26 (1 H, dd, J 13.6, 4.8, 4-H), 2.33 (1

was allowed to warm to rt over 10 min. Ether (10 mL) and H, dd, J 13.6, 7.8, 4-H'), 3.54-3.66 (3 H, m, OCH₂CH₂Si, 7-H), 3.68

saturated aqueous sodium bicarbonate (10 mL) were added and (1 H, d, J 3.8, 5-OH), 3.83-3.92 (2 H, m, 5-H, 8-H), 3.96 and 4.01

the aqueous layer was extracted with ether (3 × 10 mL). The (each 1 H, d, J 11.9, 3-CH), 4.32 and 4.35 (each 1 H, dd, J 13.1,

organic extracts were dried (MgSO₄) and concentrated under 6.1, 1-H), 4.48 and 4.49 (each 1 H, d, J 11.9, PhHCH), 4.70 and

reduced pressure. Chromatography (20:1 then 10:1 light 4.73 (each 1 H, d, J 6.8, OHCHO), 5.77 (1 H, t, J 6.1, 2-H) and

petroleum:ether) of the residue gave the title compound 37 as a 7.24-7.35 (5 H, m, ArH); δ_C(100 MHz, CDCl₃) −3.3, 0.0, 13.5,

pale yellow oil (72 mg, 35%), followed by unreacted starting 19.5(2) 19.9, 27.3, 38.6, 39.0, 61.4, 67.0, 67.9, 72.0, 73.3, 76.0,

material 36 (39 mg, 20%).

81.4, 97.7, 129.0, 129.2, 129.8, 132.7, 136.0 and 139.7; mlz (ES⁺)

P₂I₄(38 mg, 0.067 mmol) was added to a foil-wrapped 770.5 (19%), 733.4 (M⁺+ 23, 100), 711.5 (M⁺+ 1, 17), 593.4 (19)

round-bottomed flask under N₂followed by DCM (1.8 mL) and and 419.2 (30).

Et₃N (40 µL, 0.29 mmol). The dithiane-1-oxide 39 (93 mg, 0.118

mmol) in DCM (1.8 mL) was added and the mixture was stirred (2E)-(5S,7R,8R)-3-Benzyloxymethyl-8-tert-

at rt for 40 min. DCM (10 mL) and saturated aqueous sodium butyldimethylsilyloxy-5-triethylsilyloxy-1-tri-isopropylsilyloxy-

bisulfite (6 mL) were added and the aqueous layer was 7-(2-trimethylsilylethoxymethoxy)non-2-ene (57).

extracted with DCM (2 × 10 mL). The organic extracts were dried Imidazole (25 mg, 0.37 mmol) and triethylsilyl chloride (0.031

(MgSO₄) and concentrated under reduced pressure. mL, 0.18 mmol) were added to the alcohol 56 (100 mg, 0.14

Chromatography (20:1 to 5:1 light petroleum:ether) of the mmol) in DCM (1.0 mL) and the solution stirred at rt for 90 min

residue gave the title compound 37 as a clear, colourless oil (64 before the addition of DCM (10 mL) and water (10 mL). The

mg, 70%), R_f= 0.50 (5:1 light petroleum:ether), [α]_D²⁹−1.6 (c 8.8, aqueous phase was extracted with DCM (2 × 10 mL) and the

CHCl₃) (Found: M⁺+ Na, 799.4619. C₄₃H₇₆O₄NaS₂Si₂requires M, organic extracts were dried (MgSO₄) and concentrated under

799.4616); v_max/cm^-12941, 2866, 1463, 1455, 1383, 1252, 1164, reduced pressure. Chromatography of the residue (40:1 light

1105, 1064, 973, 882 and 743; δ_H(400 MHz, CDCl₃) 0.51 (6 H, q, petroleum:ether) gave the title compound 57 (107 mg, 92%) as a

27

J 7.9, 3 × SiCH₂), 0.86 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 0.96-1.07 [21 colourless oil, R_f= 0.44 (19:1 light petroleum:ether); [α]_D−9.3

H, m, 3 × SiCH(CH₃)₂], 1.16 and 1.18 (each 3 H, s, 1′-CH₃), 1.58- (c 0.9, CHCl₃) (Found: M⁺+ Na, 847.5583. C₄₄H₈₈O₆Si₄Na requires

1.64 (3 H, m, 4′′-H₃), 1.71 and 1.88 (each 1 H, m, 5-H), 2.12 (1 H, M, 847.5550); v_max/cm^-12952, 2867, 1462, 1414, 1380, 1250,

dd, J 13.4, 6.1, 5′-H), 2.24 (1 H, dd, J 13.4, 7.1, 5′-H′), 2.29 (2 H, t, 1148, 1103, 1059, 1015, 882, 860 and 835; δ_H(500 MHz, CDCl₃)

J 7.2, 1′′′-H), 2.61 (2 H, dt, J 14.4, 5.0, 4-H, 6-H), 2.68 (1 H, m, 1′′- 0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 × SiCH₃) , 0.57 (6 H, q, J 7.9,

H), 2.71-2.88 (3 H, m, 4-H′, 6-H′, 1′′-H′), 3.62 (2 H, t, J 7.2, 2′′′- 3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 [9 H, s, SiC(CH₃)₃], 0.92 (9

H₂), 4.10 (1 H, m, 4′-H), 4.17-4.29 (2 H, m, 8′-H₂), 4.53 (2 H, s, H, t, J 7.9, 3 × SiCH₂CH₃), 0.93 (1 H, m, HCHSi), 1.02 (3 H, d, J 6.3,

PhCH₂), 4.68 (2 H, s, OCH₂O), 5.31 (1 H, dd, J 15.7, 7.1, 3′-H), 9-H₃), 1.04-1.14 [21 H, m, 3 × SiCH(CH₃)₂], 1.40 (1 H, ddd, J 13.7,

5.38 (1 H, t, J 6.0, 7′-H), 5.42 (1 H, m, 3′′-H), 5.62 (1 H, dtq, J 9.8, 3.2, 6-H), 1.55 (1 H, ddd, J 14.0, 8.8, 1.3, 6-H'), 2.23 (1 H, dd,

15.3, 6.8, 1.4, 2′′-H), 5.89 (1 H, d, J 15.7, 2′-H) and 7.18-7.32 (5 J 13.3, 8.2, 4-H), 2.36 (1 H, dd, J 13.5, 5.4, 4-H'), 3.43 (1 H, ddd, J

H, m, ArH); δ_C(100 MHz), 3.9, 5.9, 11.0, 17.0, 17.1, 22.6, 23.1, 11.1, 9.7, 6.0, OHCHCH₂Si), 3.53 (1 H, ddd, J 9.9, 4.4, 1.4, 7-H),

25.7, 36.6, 39.3, 39.9, 45.0, 59.5, 61.0, 65.7, 68.3, 72.3, 93.5, 3.67 (1 H, ddd, J 11.4, 9.6, 5.4, OHCHCH₂Si), 3.91 (1 H, d, J 12.3,

125.5, 126.6, 126.9, 127.4, 128.1, 128.3, 130.1, 132.5, 135.0 and 3-CH), 3.95 (1 H, m, 5-H), 3.99 (1 H, d, J 12.1, 3-CH'), 4.02 (1 H,

136.9; m/z (ES⁺) 799.5 (M⁺+ 23, 100%) and 408.5 (25).

qd, J 6.3, 4.6, 8-H), 4.34 (2 H, d, J 5.1, 1-H₂), 4.45 (2 H, s, PhCH₂),

4.66 (2 H, s, OCH₂O), 5.69 (1 H, t, J 5.1, 2-H) and 7.24-7.34 (5 H,

m, ArH); δ_C(125 MHz, CDCl₃) −3.3(2), 0.0, 6.7, 8.5, 13.5, 18.6,

19.5, 19.6, 27.3, 37.2, 39.2, 61.8, 66.6, 69.9, 70.5, 73.1, 75.7,

81.7, 97.6, 128.9, 129.2, 129.7, 132.4, 134.9 and 140.0; m/z (ES⁺)

(2E)-(5S,7R,8R)-3-Benzyloxymethyl-8-tert-

butyldimethylsilyloxy-1-tri-isopropylsilyloxy-7-(2-

trimethylsilylethoxymethoxy)non-2-en-5-ol (56).

Imidazole (59 mg, 0.87 mmol) and tri-isopropylsilyl chloride 884.0 (85%), 847.8 (M⁺+ 23, 100) and 842.9 (M⁺+ 18, 33).

(0.092 mL, 0.43 mmol) were added to the diol 47 (200 mg, 0.36

mmol) in DCM (2.5 mL) and the solution stirred at rt for 2 h. (4S,6R,7R)-7-tert-Butyldimethylsilyloxy-4-triethylsilyloxy-2-

Dichloromethane (20 mL) and saturated aqueous NaHCO₃(20 [(E)-2-tri-isopropylsilyloxyethylidene]-6-(2-

mL) were added the aqueous phase was extracted with DCM (2 trimethylsilylethoxymethoxy)octan-1-ol (58).

× 20 mL). The organic extracts were dried (MgSO₄) and Lithium (183 mg, 26.2 mmol) was added to naphthalene (5.03 g,

concentrated under reduced pressure. Chromatography of the 39.3 mmol) in THF (67 mL) and the mixture stirred vigorously at

residue (9:1 light petroleum:ether) gave the title compound 56 rt for 1 h then added dropwise to the benzyl ether 57 (3.20 g,

(231 mg, 90%) as a colourless oil, R_f= 0.16 (9:1 light 3.96 mmol) in THF (33 mL) at −30 °C until the reaction was

28

petroleum:ether), [α]_D+8.0, (c 1.1, CHCi₃) (Found: M⁺+ H, complete (TLC). Water, ether (150 mL) and saturated aqueous

711.4862. C₃₈H₇₅O₆Si₃requires M, 711.4866); v_max/cm^-13468, NaHCO₃(150 mL) were added and the aqueous phase was

2950, 2893, 2865, 1463, 1381, 1251, 1104, 1058, 1030, 883, extracted with ether (2 × 150 mL). The organic extracts were

859, 835 and 776; δ_H(400 MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], dried (MgSO₄) and concentrated under reduced pressure.

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Chromatography of the residue (9:1 light petroleum:ether) gave the aqueous phase was extracted with DCM (100 mL). The

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DOI: 10.1039/C7OB02127E

the title compound 58 (2.32 g, 81%) as a colourless oil, R_f= 0.54 organic extracts were washed with aqueous NaOH (1 M, 2 × 100

25

(3:1 light petroleum:ether), [α]_D+3.3 (c 1.1, CHCl₃) (Found: M⁺mL) and water (100 mL) then dried (MgSO₄) and concentrated

+ H, 735.5285. C₃₇H₈₃O₆Si₄requires M, 735.5261); v_max/cm^-1under reduced pressure. Chromatography of the residue (15:1

3436, 2953, 2868, 1462, 1380, 1250, 1102, 1057, 1010, 882, light petroleum:ether) gave the title compound 60 (3.7 g, 85%)

859, 835, 775 and 742; δ_H(500 MHz, CDCl₃) 0.00 [9 H, s, as a colourless oil, R_f= 0.23 (20:1 light petroleum:ether) (Found:

Si(CH₃)₃], 0.03(2) (each 3 H, s, SiCH₃), 0.62 (6 H, q, J 7.9, 3 × M⁺+ Na, 305.1013. C₁₅H₂₂OS₂Na requires M, 305.1004); v_max/cm^-

1

SiCH₂), 0.83-0.97 (2 H, m, CH₂Si), 0.86 [9 H, s, SiC(CH₃)₃], 0.95 (9

3061, 3027, 2962, 2929, 2893, 1495, 1470, 1452, 1421, 1382,

H, t, J 7.9, 3 × SiCH₂CH₃), 1.02 (3 H, d, J 6.3, 8-H₃), 1.03-1.12 [21 1364, 1275, 1099, 1028, 904, 776, 736 and 697; δ_H(400 MHz,

H, m, 3 × Si(CH(CH₃)₂], 1.43 (1 H, ddd, J 14.5, 10.1, 4.7, 5-H), 1.66 CDCl₃) 1.04 (6 H, s, 2 × CH₃), 1.74 and 2.00 (each 1 H, m, 5-H),

(1 H, ddd, J 14.3, 6.9, 1.9, 5-H'), 2.29 (1 H, dd, J 13.9, 6.0, 3-H), 2.76-2.88 (4 H, m, 4-H₂, 6-H₂), 3.31 (2 H, s, 2'-H₂), 4.25 (1 H, s, 2-

2.40 (1 H, dd, J 13.9, 5.7, 3-H'), 2.80 (1 H, t, J 6.2, OH), 3.46-3.52 H), 4.46 (2 H, s, PhCH₂) and 7.18-7.29 (5 H, m, ArH); δ_C(100

(2 H, m, OHCHCH₂Si, 6-H), 3.65 (1 H, ddd, J 11.4, 9.8, 5.7, MHz, CDCl₃) 22.9, 26.2, 31.4, 39.9, 57.8, 73.3, 76.8, 127.5, 128.3

OHCHCH₂Si), 3.94-4.02 (4 H, m, 1-H₂, 4-H, 7-H), 4.27 (1 H, dd, J and 138.8; mlz (ES⁺) 305 (M⁺+ 23, 100%).

13.2, 5.5, 2'-H), 4.31 (1 H, dd, J 13.0, 6.3, 2'-H'), 4.67 and 4.70

(each 1 H, d, J 6.9, OHCHO) and 5.69 (1 H, t, J 6.0, 1'-H); δ_C(125 (4S,7S,9R,10R)-

and

(4R,7S,9R,10R)-1-Benzyloxy-10-tert-

MHz, CDCl₃) −3.3, −3.2, 0.0, 6.5, 8.4, 13.5, 18.7, 19.5, 19.6, 27.3, butyldimethylsilyloxy-7-triethylsilyloxy-5-[(E)-2-tri-

37.1, 39.6, 61.7, 66.9, 69.5, 70.5, 71.2, 82.0, 97.3, 131.7 and isopropylsilyloxyethylidene]-2,2-dimethyl-9-(2-

137.8; mlz (ES⁺) 793.4 (68%) and 736.1 (M⁺+ 1, 100).

trimethylsilylethoxymethoxy)-3,3-(1,3-dithiopropyl)undecan-4-

ols (61) and (62).

(4S,6R,7R)-7-tert-Butyldimethylsilyloxy-4-triethylsilyloxy-2-

[(E)-2-tri-isopropylsilyloxyethylidenel-6-(2-

trimethylsilylethoxymethoxy)octanal (59).

n-Butyllithium (1.60 M in hexanes, 1.20 mL, 1.92 mmol) was

added to the dithiane 60 (617 mg, 2.18 mmol) in THF (12 mL) at

rt and the solution stirred for 5 min before cooling to −78 °C.

Pyridine (0.19 mL, 2.35 mmol) and the Dess-Martin periodinane The aldehyde 59 (1.06 g, 1.45 mmol) in THF (8.4 mL) was added

(177 mg, 0.42 mmol) were added to the alcohol 58 (150 mg, and the solution stirred at −78 °C for 15 min. Methanol (1.0 mL)

0.20 mmol) in DCM (1.45 mL) and the solution stirred for 1 h at was added and the mixture allowed to warm to rt then

rt. Ether (30 mL), saturated aqueous NaHCO₃(15 mL) and partitioned between ether (60 mL) and saturated aqueous

saturated aqueous Na₂S₂O₃(15 mL) were added and the NaHCO₃(60 mL). The aqueous phase was extracted with ether

aqueous phase was extracted with ether (2 × 20 mL). The (2 × 50 mL) and the organic extracts were dried (MgSO₄) and

organic extracts were dried (MgSO₄) and concentrated under concentrated under reduced pressure. Chromatography of the

reduced pressure. Chromatography of the residue (15:1 light residue (50:1 to 15:1 light petroleum:ether) gave the (4R)-

petroleum:ether) gave the title compound 59 (142 mg, 95%) as a epimer of the title compound 62 as a pale, yellow oil (385 mg,

21

colourless oil, R_f= 0.34 (15:1 light petroleum:ether), [α]_D−9.0 26%), R_f= 0.53 (9:1 light petroleum:ether), [α]_D−9.6 (c 0.9,

(c 1.7, CHCl₃) (Found: M⁺+ NH₄, 750.5369. C₃₇H₈₄O₆Si₄N requires CHCl₃); v_max/cm^-13375, 2949, 2863, 1460, 1376, 1247, 1099,

M, 750.5370); v_max/cm^-12953, 2869, 1693, 1463, 1379, 1250, 1056, 858, 833, 772 and 742; δ_H(400 MHz, CDCl₃) 0.00 [9 H, s,

1102, 1055, 1006, 881, 860, 835 and 776; δ_H(500 MHz, CDCl₃) Si(CH₃)₃], 0.04 (6 H, s, 2 × SiCH₃), 0.59 (6 H, q, J 7.9, 3 × SiCH₂),

0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 × SiCH₃), 0.58 (6 H, q, J 7.8, 0.85 (1 H, m, HCHSi), 0.87 [9 H, s, SiC(CH₃)₃], 0.92 (9 H, t, J 7.9, 3

3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 [9 H, s, SiC(CH₃)₃], 0.93 (1 × SiCH₂CH₃), 0.93 (1 H, m, HCHSi), 1.01-1.11 [24 H, m, 11-H₃, 3 ×

H, m, OHCHSi), 0.93 (9 H, t, J 8.0, 3 × SiCH₂CH₃), 1.02 (3 H, d, J Si(CH(CH₃)₂], 1.23 and 1.31 (each 3 H, s, 2-CH₃), 1.55 (1 H, ddd, J

6.3, 8-H₃), 1.05-1.13 [21 H, m, 3 × SiCH(CH₃)₂], 1.30 (1 H, ddd, J 14.6, 9.6, 5.3, 8-H), 1.70-1.82 (2 H, m, 8-H', SCH₂HCH), 1.87 (1 H,

14.4, 9.7, 5.0, 5-H), 1.65 (1 H, ddd, J 14.2, 7.4, 1.7, 5-H'), 2.36 m, SCH₂HCH), 2.43 (1 H, ddd, J 14.1, 6.1, 3.5, SHCH), 2.53 (1 H,

and 2.42 (each 1 H, dd, J 13.0, 6.7, 3-H), 3.44 (1 H, ddd, J 11.2, dd, J 13.6, 6.1, 6-H), 2.70 (1 H, ddd, J 13.3, 7.3, 5.5, SHCH), 2.83-

9.6, 6.0, OHCHCH₂Si), 3.51 (1 H, ddd, J 9.6, 4.4, 1.7, 6-H), 3.67 (1 2.94 (2 H, m, 6-H', SHCH), 3.01 (1 H, ddd, J 14.7, 10.5, 5.4,

H, ddd, J 11.5, 9.5, 5.3, OHCHCH₂Si), 3.84 (1 H, qd, J 6.8, 5.0, 4- SHCH), 3.41 (1 H, ddd, J 11.1, 9.6, 6.0, OHCHCH₂Si), 3.48-3.54 (2

H), 4.03 (1 H, qd, J 6.3, 4.5, 7-H), 4.60 (2 H, d, J 5.3, 2'-H₂), 4.69 H, m, 1-H, 9-H), 3.71 (1 H, ddd, J 11.4, 9.5, 5.3, OHCHCH₂Si), 3.79

and 4.71 (each 1 H, d, J 7.0, OHCHO), 6.62 (1 H, t, J 5.3, 1'-H) and (1 H, m, 7-H), 3.83 (1 H, d, J 9.3, 1-H'), 4.06 (1 H, qd, J 6.3, 4.3,

9.40 (1 H, s, 1-H); δ_C(125 MHz, CDCl₃) −3.3(2), 0.0, 6.6, 8.5, 13.4, 10-H), 4.28 (1 H, dd, J 12.6, 5.3, 2'-H), 4.39 (1 H, dd, J 12.5, 7.2,

18.5, 19.4, 19.5, 19.6, 27.3, 35.6, 37.8, 62.5, 66.7, 70.4, 70.5, 2'-H'), 4.50 and 4.51 (each 1 H, d, J 12.4, PhHCH), 4.54 (1 H, s, 4-

81.8, 97.6, 140.4, 157.6 and 195.9; mlz (ES⁺) 792.0 (44%) and H), 4.57 (1 H, br. s, OH), 4.69 (2 H, s, OCH₂O), 6.05 (1 H, m, 1'-H)

756.1 (M⁺+ 23, 100).

and 7.22-7.32 (5 H, m, ArH); δ_C(100 MHz, CDCl₃) −3.3(2), 0.0,

6.7, 8.4, 13.4, 18.5, 19.5(2), 19.6, 22.9(2), 24.3, 24.5, 27.3, 27.9,

28.4, 37.3, 48.6, 61.7, 66.5, 68.0, 70.5, 72.8, 74.8, 77.9, 78.8,

2-(2-Benzyloxy-1,1-dimethylethyl)-[1,3]dithiane (60).

Boron trifluoride diethyletherate (5.63 mL, 45.6 mmol) was 82.2, 97.7, 128.8, 128.9, 129.7, 133.5, 139.2 and 139.8; m/z (ES⁺)

added to 3-benzyloxy-2,2-dimethylpropanal (15.0 mmol) and 1075.3 (62%), 1037.9 (M⁺+ 23, 100) and 1033.9 (M⁺+ 18, 30).

1,3-propanedithiol (2.75 mL, 27.4 mmol) in DCM (180 mL) at 0 The second fraction was the (4S)-epimer of the title compound

°C and the reaction mixture stirred at rt for 16 h. 61 (784 mg, 53%) as a colourless oil, R_f= 0.49 (9:1 light

Dichloromethane (100 mL) and water (100 mL) were added and petroleum:ether), [α]_D−42.8 (c 1.3, CHCl₃); v_max/cm^-13419,

20

14 | J. Name., 2012, 00, 1-3

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2953, 2870, 1462, 1375, 1250, 1102, 1057, 835 and 775; δ_H(500 81.8, 97.8, 128.9(2), 129.8, 133.3, 139.6 and 140.4; mlz (ES⁺)

View Article Online

DOI: 10.1039/C7OB02127E

MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 × SiCH₃), 0.54- 923.9 (M⁺+ 23, 100%).

0.66 (6 H, m, 3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 [9 H, s,

SiC(CH₃)₃], 0.93 (1 H, m, HCHSi), 0.94 (9 H, t, J 8.0, 3 × SiCH₂CH₃), (4R,7S,9R,10R)-1-Benzyloxy-10-tert-butyldimethylsilyloxy-5-

1.03 (3 H, d, J 6.4, 11-H₃), 1.04-1.12 [21 H, m, 3 × SiCH(CH₃)₂] [(E)-2-tri-isopropylsilyloxyethylidene]-2,2-dimethyl-9-(2-

1.26 and 1.32 (each 3 H, s, 2-CH₃), 1.49 (1 H, ddd, J 14.2, 9.7, 4.5, trimethylsilylethoxymethoxy)-3,3-(1,3-dithiopropyl)undecane-

8-H), 1.62 (1 H, ddd, J 14.4, 7.3, 1.3, 8-H'), 1.80 and 1.90 (each 1 4,7-diol (64).

H, m, SCH₂HCH), 2.44 (1 H, ddd, J 14.1, 5.3, 3.8, SHCH), 2.57 (1 H, The same procedure using pyridinium toluene 4-sulfonate (2.0

dd, J 13.6, 6.6, 6-H), 2.66 (1 H, ddd, J 14.0, 6.7, 5.2, SHCH), 2.83 mg, 7.7 μmol) and triethylsilyl ether 62 (70 mg, 0.068 mmol) in

(1 H, dd, J 13.5, 6.5, 6-H'), 2.98-3.06 (2 H, m, 2 × SHCH), 3.42 (1 THF (0.81 mL), methanol (2.4 mL) and trimethyl orthoformate

H, ddd, J 10.9, 9.7, 6.1, OHCHCH₂Si), 3.50 (1 H, d, J 9.5, 1-H), 3.54 (0.24 mL, 2.23 mmol), after chromatography (7:1 light

(1 H, ddd, J 9.4, 4.2, 1.5, 9-H), 3.69 (1 H, ddd, J 11.4, 9.8, 5.4, petroleum:ether), gave the title compound 64 (56 mg, 90%) as a

29

OHCHCH₂Si), 3.83 (1 H, d, J 9.5, 1-H'), 3.96 (1 H, qd, J 6.6, 4.7, 7- viscous colourless oil, R_f= 0.41 (3:1 light petroleum:ether), [α]_D

H), 4.04 (1 H, qd, J 6.3, 4.5, 10-H), 4.25 (1 H, br. s, OH), 4.30 (1 H, −23.6 (c 0.6, CHCl₃) (Found: M⁺+ Na, 923.5181. C₄₆H₈₈O₇S₂Si₃Na

dd, J 12.5, 5.2, 2'-H), 4.39 (1 H, dd, J 12.5, 7.6, 2'-H'), 4.49 and requires M, 923.5171); v_max/cm^-13371, 2945, 2925, 2889, 2863,

4.52 (each 1 H, d, J 12.2, PhHCH), 4.60 (1 H, br. s, 4-H), 4.67 and 1462, 1377, 1250, 1101, 1056, 883, 858, 834 and 773; δ_H(400

4.70 (each 1 H, d, J 6.9, OHCHO), 6.21 (1 H, t, J 6.3, 1'-H) and MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.07(2) (each 3 H, s, SiCH₃),

7.23-7.33 (5 H, m, ArH); δ_C(125 MHz, CDCl₃) −3.3, 0.0, 6.7, 8.5, 0.85-0.95 (2 H, m, CH₂Si), 0.88 [9 H, s, SiC(CH₃)₃], 1.02-1.13 [21

13.5, 18.7, 19.5, 19.6, 23.2, 24.4, 24.7, 27.3, 27.8, 28.3, 37.5, H, m, 3 × SiCH(CH₃)₂], 1.10 (3 H, d, J 6.3, 11-H₃), 1.25 and 1.32

42.2, 48.5, 61.9, 66.5, 67.8, 70.6, 70.7, 72.3, 74.8, 77.9, 82.0, (each 3 H, s, 2-CH₃), 1.55 (1 H, ddd, J 13.8, 9.4, 2.5, 8-H), 1.65 (1

97.5, 128.8, 128.9, 129.7, 132.9, 139.7 and 140.4; mlz (ES⁺) H, ddd, J 14.0, 10.1, 4.0, 8-H'), 1.78-1.93 (2 H, m, SCH₂CH₂), 2.43

1037.6 (M⁺+ 23, 100%), 1032.6 (M⁺+ 18, 65) and 997.7 (43).

(1 H, d, J 14.1, 6-H), 2.49 (1 H, ddd, J 14.1, 5.8, 4.3, SHCH), 2.75

(1 H, ddd, J 13.7, 7.6, 5.8, SHCH), 2.85 (1 H, dt, J 14.4, 5.8,

SHCH), 2.93 (1 H, ddd, J 14.6, 9.6, S.8, SHCH), 3.05 (1 H, t, J 11.9,

6-H'), 3.54-3.64 (4 H, m, 1-H, 9-H, OCH₂CH₂Si), 3.71 (1 H, m, 7-H),

3.8S (1 H, d, J 9.3, 1-H'), 3.87 (1 H, pent, J 6.0, 10-H), 4.31 (2 H, d,

J 6.1, 2'-H₂), 4.50 (1 H, br. s, OH), 4.50 and 4.53 (each 1 H, d, J

(4S,7S,9R,10R)-1-Benzyloxy-10-tert-butyldimethylsilyloxy-5-

[(E)-2-tri-isopropylsilyloxyethylidene]-2,2-dimethyl-9-(2-

trimethylsilylethoxymethoxy)-3,3-(1,3-dithiopropyl)undecane-

4,7-diol (63).

Pyridinium toluene 4-sulfonate (1.2 mg, 4.7 μmol) was added to 12.1, PhHCH), 4.58 (1 H, s, 4-H), 4.71 and 4.73 (each 1 H, d, J 6.7,

the triethylsilyl ether 61 (43 mg, 0.042 mmol) in THF (0.50 mL), OHCHO), 5.48 (1 H, br. s, OH), 5.93 (1 H, br. t, J 5.8, 1'-H) and

methanol (1.45 mL) and trimethyl orthoformate (0.15 mL, 1.37 7.23-7.35 (5 H, m, ArH); δ_C(100 MHz, CDCl₃) −3.3, 0.0, 13.4,

mmol) and the solution stirred at rt for 1 h. Ether (15 mL) and 19.4, 19.5, 20.0, 23.0, 24.4(2), 27.3, 28.0, 28.8, 39.0, 39.4, 48.9,

saturated aqueous NaHCO₃(15 mL) were added and the 61.4, 67.1, 68.0, 70.0, 72.3, 74.8, 77.8, 80.6, 81.7, 97.8, 128.9(2),

aqueous phase was extracted with ether (3 × 15 mL). The 129.8, 134.4, 139.8 and 140.2; mlz (ES⁺) 923 (M⁺+ 23, 100%).

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue (7:1 light (2R,3S,6S)- and (2S,3S,6S)-2-(2-Benzyloxy-1,1-dimethylethyl)-6-

petroleum:ether) gave the title compound 63 (35 mg, 92%) as a [(2R,3R)-3-tert-butyldimethylsilyloxy-2

30

viscous colourless oil, R_f= 0.46 (3:1 light petroleum:ether), [α]_D

(trimethylsilylethoxymethoxy)butyl]-2-methoxy-4-[(E)-2-tri-

−9.1 (c 0.8, CHCl₃) (Found: M⁺+ Na, 923.5186. C₄₆H₈₈O₇S₂Si₃Na isopropylsilyloxyethylidene]tetrahydropyran-3-ols (65) and

requires M, 923.5171); v_max/cm^-13436, 2943, 2928, 2865, 1730, (66).

1463, 1379, 1250, 1102, 1058, 835 and 776; δ_H(500 MHz, CDCl₃) 2,6-Lutidine (73 μL, 0.63 mmol) and Hg(ClO₄)₂.2H₂O (96 mg, 0.23

0.00 [9 H, s, Si(CH₃)₃], 0.06(2) (each 3 H, s, SiCH₃), 0.87-0.97 (2 H, mmol) was added to the diol 63 (100 mg, 0.11 mmol) in THF (1.3

m, CH₂Si), 0.88 [9 H, s, SiC(CH₃)₃], 1.03-1.13 [21 H, m, 3 × mL) and MeOH (1.3 mL) at −5 °C and the white suspension was

SiCH(CH₃)₂] 1.08 (3 H, d, J 6.3, 11-H₃), 1.25 and 1.31 (each 3 H, s, stirred at −5 ^oC for 30 min then filtered through celite with

2-CH₃), 1.51 (1 H, ddd, J 13.9, 9.1, 2.5, 8-H), 1.58 (1 H, ddd, J copious ether washings. The organic phase was washed with

13.9, 10.1, 4.1, 5-H'), 1.81 and 1.91 (each 1 H, m, SCH₂HCH), 2.47 saturated aqueous NaHCO₃(10 mL) and the aqueous phase

(1 H, ddd, J 14.2, 5.6, 4.1, SHCH), 2.66 (1 H, dd, J 13.9, 7.6, 6-H), extracted with ether (2 × 10 mL). The organic extracts were

2.68-2.79 (2 H, m, 6-H', SHCH), 2.96 (1 H, m, SHCH), 3.03 (1 H, dried (MgSO₄) and concentrated under reduced pressure.

ddd, J 15.1, 10.7, 5.4, SHCH), 3.46 (1 H, d, J 9.8, 1-H), 3.54-3.66 Chromatography of the residue using base-washed silica (20:1

(3 H, m, 9-H, OCH₂CH₂Si), 3.72 (1 H, br. s, OH), 3.85 (1 H, d, J 9.4, to 12:1 light petroleum:ether) gave first the title compound 65

1-H'), 3.87 (1 H, quin, J 6.2, 10-H), 3.93 (1 H, m, 7-H), 4.29 (1 H, (34 mg, 37%) as

a colourless oil, R_f= 0.33 (9:1 light

dd, J 12.6, 5.7, 2'-H), 4.37 (1 H, dd, J 12.6, 6.9, 2'-H'), 4.49 and petroleum:ether), [α]_D−25.1 (c 0.7, DCM) (Found: M⁺+ Na,

4.53 (each 1 H, d, J 12.1, PhHCH), 4.59 (1 H, br. s, OH), 4.71 (1 H, 847.5334. C₄₄H₈₄O₈Si₃Na requires M, 847.5372); v_max/cm^-13382,

d, J 6.9, OHCHO), 4.72 (1 H, s, 4-H), 4.74 (1 H, d, J 6.9, OHCHO), 2952, 2893, 2866, 1463, 1381, 1250, 1201, 1096, 1057, 938,

6.14 (1 H, t, J 6.3, 1'-H) and 7.24-7.35 (5 H, m, ArH); δ_C(125 MHz, 920, 883, 860, 836, 811, 776 and 736; δ_H(400 MHz, C₆D₆) 0.00 [9

CDCl₃) −3.3, 0.0, 13.4, 19.5(3), 20.1, 23.1, 24.6, 24.7, 27.3, 28.0, H, s, Si(CH₃)₃], 0.14 and 0.18 (each 3 H, s, SiCH₃), 0.93 (1 H, ddd, J

28.5, 38.8, 40.5, 48.4, 61.6, 67.1, 68.1, 69.7, 72.2, 74.8, 77.8, 13.9, 9.8, 5.7, HCHSi), 1.00 (1 H, m, HCHSi), 1.00 [9 H, s,

SiC(CH₃)₃], 1.08-1.16 [21 H, m, 3 × Si(CH(CH₃)₂], 1.25 and 1.26

22

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(each 3 H, s, 1'-CH₃), 1.28 (3 H, d, J 6.3, 4'"-H₃), 1.57 (1 H, ddd, J + 18, 22) and 133 (17). Repeated chromatography gave small

View Article Online

DOI: 10.1039/C7OB02127E

14.2, 10.2, 2.5, 1'"-H), 2.02 (1 H, ddd, J 14.2, 9.5, 1.3, 1'"-H'), samples of each diastereoisomer: δ_H(400 MHz, C₆D₆) (2R )-

2.25-2.38 (2 H, m, 5-H₂), 3.18 (1 H, d, J 9.1, 2'-H), 3.39 (3 H, s, 2- epimer 69 0.00 [9 H, s, Si(CH₃)₃], 0.16 and 0.20 (each 3 H, s,

OCH₃), 3.49 (1 H, td, J 9.8, 6.3, OHCHCH₂Si), 3.81 (1 H, td, J 9.9, SiCH₃), 0.95 (1 H, ddd, J 14.2, 10.4, 5.7, HCHSi), 1.01 [9 H, s,

5.8, OHCHCH₂Si), 3.87 (1 H, d, J 9.1, 2'-H'), 3.99 (1 H, ddd, J 10.1, SiC(CH₃)₃], 1.04 (1 H, m, HCHSi), 1.09-1.14 [21 H, m, 3 ×

4.4, 1.5, 2'"-H), 4.12 (1 H, m, 6-H), 4.13 (1 H, d, J 6.6, OH), 4.23 (1 SiCH(CH₃)₂], 1.17 (3 H, s, 1'-CH₃), 1.30 (3 H, d, J 6.3, 4'"-H₃), 1.35

H, d, J 12.0, PhHCH), 4.29-4.40 (4 H, m, 3'"-H, PhHCH, 2"-H₂), (3 H, s, 1'-CH₃), 1.63 (1 H, ddd, J 14.1, 10.4, 1.9, l"'-H), 2.08 (1 H,

4.71 (1 H, m, 3-H), 4.75 and 4.86 (each 1 H, d, J 6.9, OHCHO), dd, J 14.1, 10.0, 1'"-H'), 2.21 and 2.44 (each 1 H, m, 5-H), 3.29 (3

6.40 (1 H, m, 1"-H), 7.05 (1 H, m, ArH) and 7.13 and 7.24 (each 2 H, s, 2-OCH₃), 3.42 and 3.50 (each 1 H, d, J 9.1, 2'-H), 3.56 (1 H,

H, m, ArH); δ_C(100 MHz, C₆D₆) −4.8, −4.7, −1.5, 12.3, 17.0, 18.2, td, J 10.1, 6.0, OHCHCH₂Si), 3.82 (1 H, ddd, J 10.7, 9.8, 5.7,

18.3, 21.4, 21.5, 26.0, 34.4, 35.9, 46.6, 50.5, 60.7, 65.5, 67.1, OHCHCH₂Si), 4.07 (1 H, ddd, J 10.2, 4.5, 1.0, 2'"-H), 4.23 (1 H, d, J

67.5, 69.1, 73.5, 76.9, 80.0, 96.7, 102.7, 123.8, 127.7(2), 128.5, 11.7, PhHCH), 4.27-4.35 (5 H, m, 3-H, 3'"-H, PhHCH, 2"-H₂), 4.72

135.5 and 138.4; mlz (ES⁺) 885 (25%), 848 (M⁺+ 23, 100), 619 (1 H, d, 12.8, OH), 4.79 (1 H, d, J 6.9, OHCHO), 4.92 (1 H, m, 6-H),

(23) and 469 (11). The second fraction was the title compound 4.92 (1 H, d, J 6.9, OHCHO), 5.91 (1 H, m, 1"-H), 7.05 (1 H, m,

23

(66) (23 mg, 25%), R_f= 0.21 (4:1 light petroleum:ether), [α]_D

ArH) and 7.12 and 7.22 (each 2 H, m, ArH); (2S)-epimer 70 0.00

−20.4 (c 1.4, DCM) (Found: M⁺+ Na, 847.5345. C₄₄H₈₄O₈Si₃Na [9 H, s, Si(CH₃)₃], 0.15 and 0.19 (each 3 H, s, SiCH₃), 0.89-1.01 (2

requires M, 847.5372); v_max/cm^-13355, 2955, 2894, 2866, 1463, H, m, CH₂Si), 1.02 [9 H, s, SiC(CH₃)₃], 1.09-1.15 [21 H, m, 3 ×

1381, 1362, 1250, 1105, 1060, 937, 920, 883, 860, 835, 811 and SiCH(CH₃)₂], 1.27 (3 H, d, J 6.3, 4'"-H₃), 1.28 and 1.31 (each 3 H,

776; δ_H(400 MHz, C₆D₆) 0.00 [9 H, s, Si(CH₃)₃], 0.17 and 0.21 s, 1'-CH₃), 1.62 (1 H, ddd, J 14.2, 10.4, 2.2, 1'"-H), 1.78 (1 H, t, J

(each 3 H, s, SiCH₃), 0.90-1.03 (2 H, m, CH₂Si), 1.03 [9 H, s, 12.6, 5-H), 2.00 (1 H, ddd, J 13.9, 10.1, 1.3, 1'"-H'), 2.62 (1 H, dd,

SiC(CH₃)₃], 1.09-1.15 [21 H, m, 3 × Si(CH(CH₃)₂], 1.19 (3 H, s, 1'- J 13.6, 2.2, 5-H'), 3.33 (1 H, d, J 9.1, 2'-H), 3.46 (3 H, s, 2-OCH₃),

CH₃), 1.28 (3 H, d, J 6.3, 4'"-H₃), 1.29 (3 H, s, 1'-CH₃), 1.64 (1 H, 3.47 (1 H, td, J 9.8, 6.6, OHCHCH₂Si), 3.65 (1 H, d, J 6.9, OH), 3.68

ddd, J 13.9, 10.4, 2.5, 1'"-H), 2.11 (1 H, ddd, J 14.1, 10.1, 1.6, 1'"- (1 H, d, J 9.0, 2'-H'), 3.82 (1 H, td, J 9.9, 5.8, OHCHCH₂Si), 3.93 (1

H'), 2.31 (1 H, dd, J 14.5, 2.8, 5-H), 2.50 (1 H, t, J 13.3, 5-H'), 3.33 H, ddd, J 10.4, 4.4, 1.3, 2'"-H), 4.04 (1 H, m, 6-H), 4.29 (1 H, d, J

(3 H, s, 2-OCH₃), 3.45-3.54 (3 H, m, 2'-H₂, OHCHCH₂Si), 3.81 (1 H, 12.0, PhHCH), 4.31-4.41 (5 H, m, 3-H, 3'"-H, PhHCH, 2"-H₂), 4.73

td, J 10.0, 5.9, OHCHCH₂Si), 4.01 (1 H, ddd, J 10.4, 4.4, 1.6, 2'"- and 4.83 (each 1 H, d, J 6.8, OHCHO), 6.26 (1 H, m, 1"-H), 7.07 (1

H), 4.22 (1 H, m, 6-H), 4.26-4.41 (5 H, m, 3'"-H, PhCH₂, 2"-H₂), H, m, ArH) and 7.16 and 7.28 (each 2 H, m, ArH).

4.39 (1 H, d, J 4.7, 3-H), 4.74 (1 H, d, J 6.9, OHCHO), 4.81 (1 H, d,

J 4.1, OH), 4.87 (1 H, d, J 6.9, OHCHO), 5.90 (1 H, t, J 6.0, 1'-H), (2R,6S)-2-(2-Benzyloxy-1,1-dimethylethyl)-6-[(2R,3R)-3-tert-

7.06 (1 H, m, ArH) and 7.15 and 7.26 (each 2 H, m, ArH); δ_C(100 butyldimethylsilyloxy-2-(2-trimethylsilylethoxymethoxy)butyl]-

MHz, C₆D₆) −3.2, −3.1, 0.0, 13.7, 18.7, 19.7, 23.7, 24.0, 27.6, 2-methoxy-4-[(E)-2-tri-isopropylsilyloxyethylidene)-5,6-

33.1, 37.3, 47.1, 52.9, 61.4, 66.8, 69.8, 71.0, 73.7, 75.0, 78.5, dihydropyran-3-one (67).

81.1, 98.1, 105.3, 126.7, 129.2, 129.5, 130.0, 138.6 and 139.3; Pyridine (13 μL, 0.161 mmol) and the Dess-Martin periodinane

m/z (ES⁺) 885 (13%), 848 (M⁺+ 23, 100), 619 (11) and 469 (13).

(11.6 mg, 0.027 mmol) were added to the alcohol 65 (11 mg,

0.013 mmol) in DCM (0.15 mL) and the solution stirred at rt for

(2R,3R,6S)- and (2S,3R,6S)-2-(2-Benzyloxy-1,1-dimethylethyl)- 1 h. Ether (10 mL), saturated aqueous Na₂S₂O₃(5 mL) and

6-[(2R,3R)-3-tert-butyldimethylsilyloxy-2

saturated aqueous NaHCO₃(5 mL) were added and the aqueous

(trimethylsilylethoxymethoxy)butyl]-2-methoxy-4-[(E)-2-tri-

phase was extracted with ether (2 × 10 mL). The organic

isopropylsilyloxyethylidene]tetrahydropyran-3-ols (69) and extracts were dried (MgSO₄) and concentrated under reduced

(70) pressure. Chromatography of the residue (12:1 light

This procedure using 2,6-lutidine (73 μL, 0.63 mmol), petroleum:ether) gave the title compound 67 (6 mg, 55%) as a

Hg(ClO₄)₂.2H₂O (96 mg, 0.23mmol) and diol 64 (100 mg, 0.11 colourless oil, R_f= 0.32 (9:1 light petroleum:ether), [α]_D²³−1.8 (c

mmol) in THF (1.3 mL) and MeOH (1.3 mL), after 0.7, DCM) (Found: M⁺+ Na, 845.5217. C₄₄H₈₂O₈Si₃Na requires M,

chromatography using base washed silica (12:1 light 845.5215); v_max/cm^-12952, 2866, 1703, 1627, 1463, 1380, 1250,

petroleum:ether), gave the title compounds 69 and 70 (55 mg, 1104, 1055, 881, 860, 835 and 776; δ_H(400 MHz, C₆D₆) 0.00 [9 H,

60%) as a colourless oil, a 1:3 mixture of diastereoisomers that s, Si(CH₃)₃], 0.16 and 0.20 (each 3 H, s, SiCH₃), 0.95 (1 H, ddd, J

were difficult to separate by TLC, R_f

= 0.17 (9:1 light 13.9, 10.0, 5.8, HCHSi), 1.01 (1 H, m, HCHSi), 1.02 [9 H, s,

petroleum:ether), [α]_D−13.7 (c 4.0, DCM) (Found: M⁺+ Na, SiC(CH₃)₃], 1.03-1.07 [21 H, m, 3 × Si(CH(CH₃)₂], 1.31 (3 H, d, J

847.5398. C₄₄H₈₄O₈Si₃Na requires M, 847.5372); v_max/cm^-13379, 6.3, 4'"-H₃), 1.35 and 1.60 (each 3 H, s, 1'-CH₃), 1.61 (1 H, ddd, J

2951, 2891, 2865, 1471, 1463, 1380, 1250, 1148, 1105, 1057, 14.2, 10.4, 2.2, 1'"-H), 2.11 (1 H, ddd, J 14.2, 9.8, 1.1, 1'"-H'),

882, 859, 835 and 775; δ_C(100 MHz, CD₂Cl₂) −3.3(2), −3.2(2), 2.22 (1 H, m, 5-H), 2.52 (1 H, dd, J 15.5, 1.9, 5-H'), 3.21 (3 H, s, 2-

0.0, 13.8(2), 18.4, 18.5, 19.6(2), 19.7(2), 19.8, 19.9, 22.9, 23.7, OCH₃), 3.50 (1 H, td, J 9.8, 6.3, OHCHCH₂Si), 3.57 and 3.76 (each

24.0, 24.5, 27.4(2), 34.4, 36.3, 36.8, 37.2, 46.7, 47.7, 52.3, 53.4, 1 H, d, J 9.0, 2'-H), 3.84 (1 H, ddd, J 10.2, 9.6, 5.8, OHCHCH₂Si),

61.6, 61.7, 66.9, 67.0, 68.8, 69.9, 70.5, 70.7, 73.8, 75.2, 75.4, 4.07 (1 H, ddd, J 10.1, 4.4, 1.3, 2'"-H), 4.18 and 4.20 (each 1 H,

76.6, 78.4(2), 81.0, 81.6, 98.0, 98.1, 104.1, 104.2, 123.4, ddd, J 15.5, 5.7, 1.9, 2"-H), 4.36-4.44 (4 H, m, 3'"-H, PhCH₂, 6-H),

129.4(2), 129.7(2), 130.1, 130.2, 130.5, 136.0, 138.0, 139.3 and 4.77 and 4.90 (each 1 H, d, J 6.9, OHCHO), 7.00 (1 H, m, l"-H),

140.0; mlz (ES⁺) 958 (11%), 927 (17), 848 (M⁺+ 23, 100), 843 (M⁺7.08 (1 H, m, ArH) and 7.17 and 7.28 (each 2 H, m, ArH); δ_C(100

24

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MHz, CD₂Cl₂) −3.4, −3.2, 0.0, 13.7, 18.4, 19.5, 19.7, 19.9, 22.3, 6.4, 4'"-H₃), 1.67 (1 H, t, J 12.2, 1'"-H), 2.09 (1 H, dd, J 13.9, 10.6,

View Article Online

DOI: 10.1039/C7OB02127E

23.2, 27.4, 35.2, 37.3, 47.9, 52.2, 62.3, 67.1, 70.5, 70.7, 74.8, 1'"-H'), 2.24 (1 H, dd, J 13.7, 3.2, 5-H), 2.32 (1 H, t, J 13.6, 5-H'),

77.6, 81.2, 98.0, 105.4, 129.0, 129.1, 129.9, 134.9, 140.6, 140.7 3.02 (1 H, br. s, OH), 3.33 (3 H, s, 2-OCH₃), 3.50 (1 H, td, J 9.6,

and 198.0; m/z (ES⁺) 883 (23%), 846 (M⁺+ 23, 100) and 830 (51). 6.6, OHCHCH₂Si), 3.71 (1 H, m, 2'-H), 3.78 (1 H, td, J 9.8, 6.1,

Using the same procedure, alcohol 69 (9 mg, 0.011 mmol) OHCHCH₂Si), 3.95-4.04 (2 H, m, 2'-H', 2'"-H), 4.17 (1 H, m, 6-H),

gave the ketone 67 (4.5 mg, 51%) as a colourless oil.

4.22-4.41 (4 H, m, 3-H, 3'"-H, 2"-H₂), 4.75 and 4.85 (each 1 H, d, J

6.8, OHCHO) and 5.73 (1 H, m, 1"-H); δ_C(100 MHz, C₆D₆) −3.4,

−3.1, 0.0, 13.7, 18.6, 19.6, 19.7, 19.9, 23.6, 23.9, 27.5, 27.6,

(2S,6S)-2-(2-Benzyloxy-1,1-dimethylethyl)-6-[(2R,3R)-3-tert-

butyldimethylsilyloxy-2-(2-trimethylsilylethoxymethoxy)butyl]- 37.2, 46.7, 53.2, 61.1, 66.9, 70.1, 70.5, 72.3, 76.9, 81.2, 98.2,

2-methoxy-4-[(E)-2-tri-isopropylsilyloxyethylidene)-5,6-

106.6, 128.7 and 137.6; mlz (ES⁺) 871.9 (M⁺+ 23, 100%). The

dihydropyran-3-one (68).

second fraction was the hemi-acetal 74 (28 mg, 40%), a viscous,

29

Using the same procedure, alcohol 66 (6 mg, 0.0073 mmol) gave colourless oil, R_f= 0.29 (4:1 light petroleum:ether), [α]_D−20.0

the title compound 68 (4 mg, 63%) as a colourless oil, R_f= 0.19 (c 2.6, CHCl₃) (Found: M⁺+ Na, 857.5602. C₄₂H₉₀O₈Si₄Na requires

(15:1 light petroleum:ether), [α]_D−41.0 (c 0.8, DCM) (Found: M, 857.5605); v_max/cm^-13366, 2955, 2930, 2894, 2864, 1463,

23

M⁺+ Na, 845.5215. C₄₄H₈₂O₈Si₃Na requires M, 845.5215); 1385, 1252, 1106, 1088, 1056, 861, 838 and 776; δ_H(400 MHz,

v

_max/cm^-12953, 2892, 2865, 1703, 1627, 1471, 1463, 1379, 1362, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.04 (3 H, s, SiCH₃), 0.07 (6 H, s, 2 ×

1250, 1101, 1058, 882, 860, 835 and 776; δ_H(400 MHz, C₆D₆) SiCH₃), 0.10 (3 H, s, SiCH₃), 0.83-0.98 (2 H, m, CH₂Si), 0.88 and

0.00 [9 H, s, Si(CH₃)₃], 0.16 and 0.20 (each 3 H, s, SiCH₃), 0.89- 0.89 [each 9 H, s, SiC(CH₃)₃], 1.01 (3 H, s, 1'-CH₃), 1.03-1.12 [21

1.02 (2 H, m, CH₂Si), 1.02 [9 H, s, SiC(CH₃)₃], 1.04-1.11 [21 H, m, H, m, 3 × SiCH(CH₃)₂], 1.10 (3 H, d, J 6.3, 4'"-H₃), 1.13 (3 H, s, 1'-

3 × SiCH(CH₃)₂], 1.31 (3 H, d, J 6.3, 4'"-H₃), 1.32 and 1.49 (each 3 CH₃'), 1.51 (1 H, ddd, J 13.5, 11.0, 2.1, 1'"-H), 1.79 (1 H, ddd, J

H, s, 1'-CH₃), 1.64 (1 H, ddd, J 14.2, 10.4, 2.5, 1'"-H), 2.08 (1 H, 13.9, 11.0, 1.4, 1'"-H'), 2.18 (2 H, m, 5-H₂), 3.24 (1 H, dd, J 10.6,

ddd, J 14.2, 9.8, 1.6, 1'"-H'), 2.27-2.39 (2 H, m, 5-H₂), 3.34 (3 H, s, 5.8, 2'-H), 3.33 (1 H, t, J 5.2, 2'-OH), 3.58 (1 H, ddd, J 11.1, 9.8,

2-OCH₃), 3.48 (1 H, td, J 9.8, 6.6, OHCHCH₂Si), 3.52 and 3.74 6.1, OHCHCH₂Si), 3.64 (1 H, ddd, J 11.4, 9.8, 6.0, OHCHCH₂Si),

(each 1 H, d, J 8.8, 2'-H), 3.78 (1 H, td, J 9.6, 5.7, OHCHCH₂Si), 3.78 (1 H, ddd, J 10.9, 5.0, 1.3, 2'"-H), 3.89 (1 H, qd, J 6.3, 5.0,

4.03 (1 H, ddd, J 10.1, 4.1, 1.6, 2'"-H), 4.09 and 4.23 (each 1 H, 3'"-H), 3.95 (1 H, m, 6-H), 4.01 (1 H, s, 3-H), 4.07 (1 H, dd, J 10.6,

dd, J 15.6, 5.0, 2''-H), 4.28 (1 H, m, 6-H), 4.32 and 4.35 (each 1 H, 4.5, 2'-H'), 4.26 (1 H, dd, J 12.6, 5.6, 2"-H), 4.31 (1 H, dd, J 12.6,

d, J 12.3, PhHCH), 4.37 (1 H, m, 3'"-H), 4.70 and 4.84 (each 1 H, 6.7, 2"-H'), 4.38 (1 H, s, 2-OH), 4.69 and 4.77 (each 1 H, d, J 7.1,

d, J 6.8, OHCHO), 7.04-7.09 (2 H, m, 1"-H, ArH) and 7.16 and OHCHO) and 5.60 (1 H, t, J 6.1, 1"-H); (100 MHz, CDCl₃) −3.3(3),

7.27 (each 2 H, m, ArH); δ_C(100 MHz, CD₂Cl₂) −5.1, −5.0, −1.8, −2.3, 0.0, 13.4, 19.2, 19.5, 19.7, 22.0, 22.8, 27.3, 27.5, 32.3,

11.9, 16.7, 17.7, 17.9, 18.0, 19.8, 20.0, 25.6, 33.8, 35.1, 45.0, 37.0, 43.6, 60.7, 67.2, 67.6, 71.1, 72.5, 78.0, 80.1, 97.8, 102.6,

52.2, 60.7, 65.2, 68.8, 69.6, 73.1, 75.5, 79.2, 96.1, 103.9, 127.2, 129.7 and 138.0; m/z (ES⁺) 858 (M⁺+ 23, 100%).

127.2, 128.1, 133.0, 139.0, 139.4 and 195.4; mlz (ES⁺) 883 (25%),

846 (M⁺+ 23, 100), 301 (11) and 229 (13).

(3aS,5S,7aS)-5-[(2R,3R)-3-tert-Butyldimethylsilyloxy-2-(2-

Using the same procedure, alcohol 70 (4 mg, 0.005 mmol) trimethylsilylethoxymethoxy)butyl]-3a-methoxy-3,3-dimethyl-

gave the ketone 68 (2.5 mg, 61 %) as a colourless oil.

7-[(E)-2-tri-isopropylsilyloxyethylidene]hexahydrofuro[3,2-

b)pyran (78).

Triethylamine (0.068 mL, 0.49 mmol) and methanesulfonyl

chloride (0.019 mL, 0.24 mmol) were added to the alcohol 75

(2S,3S,6S)-2-(2-Hydroxy-1,1-dimethylethyl)-6-[(2R,3R)-3-tert-

butyldimethylsilyloxy-2-(trimethylsilylethoxymethoxy)butyl]-3- (42 mg, 0.049 mmol) in DCM (0.50 mL) at 0 °C and the solution

tert-butyldimethylsilyloxy-2-methoxy-4-[(E)-2-tri-

isopropylsilyloxyethylidene]tetrahydropyran (75).

stirred at 0 ^oC for 1 h. Ether (10 mL) and saturated aqueous

NaHCO₃(10 mL) were added and the aqueous phase was

A solution of benzyl ether 73 (80 mg, 0.085 mmol) in ethyl extracted with ether (2 × 10 mL). The organic extracts were

acetate (1.5 mL) and methanol (1.5 mL) was pumped through dried (MgSO₄) and concentrated under reduced pressure to

the H-cube™ flow hydrogenator fitted with a 10% Pd/C catalyst afford the mesylate 77 (42 mg), R_f

cartridge (previously saturated with hydrogen gas for 10 min) at petroleum:ether), which was used without purification.

25 °C and 1 bar pressure with the full hydrogen option enabled. Sodium hydride (60% dispersion in mineral oil, 20 mg, 0.51

= 0.53 (4:1 light

The flow rate was set at 1 mL/min. After concentration of the mmol) was added to 2-mercaptobenzothiazole (85 mg, 0.51

efluent under reduced presure, chromatography of the residue mmol) in DMF (0.30 mL) at 0 °C and the suspension stirred at 0

(15:1 to 4:1 light petroleum:ether) gave the title compound 75 ^oC for 20 min then allowed to warm to rt. The mesylate 77 (42

(36 mg, 50%) as a viscous, colourless oil, R_f= 0.45 (4:1 light mg, 0.045 mmol) in DMF (0.20 mL) was added and the reaction

25

petroleum:ether), [α]_D−14.2 (c 0.7, DCM) (Found: M⁺+ Na, mixture stirred at 120 °C for 12 h. After allowing the mixture to

871.5755. C₄₃H₉₂O₈Si₄Na requires M, 871.5761); v_max/cm^-13525, cool to rt, ether (10 mL) and water (10 mL) were added and the

2955, 2934, 2892, 2864, 1463, 1381, 1251, 1100, 1056, 938, aqueous phase extracted with ether (2 × 10 mL) The organic

882, 860, 836 and 775; δ_H(400 MHz, C₆D₆) 0.00 [9 H, s, Si(CH₃)₃], extracts were washed with water (2 × 20 mL), dried (MgSO₄)

0.13, 0.15, 0.18 and 0.26 (each 3 H, s, SiCH₃), 0.89-1.04 (2 H, m, and concentrated under reduced pressure. Chromatography of

CH₂Si), 1.01 and 1.03 [each 9 H, s, SiC(CH₃)₃], 1.06-1.14 [21 H, m, the residue (12:1 light petroleum:ether) gave the title

3 × SiCH(CH₃)₂], 1.24 and 1.26 (each 3 H, s, 1'-CH₃), 1.27 (3 H, d, J compound 78 (23 mg, 72%) as a colourless oil, R_f= 0.34 (9:1,

J. Name., 2013, 00, 1-3 | 17

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ARTICLE

Journal Name

29

light petroleum:ether); [α]_D−30.2 (c 0.5, DCM) (Found: M⁺+ = 0.18 (15:1 light petroleum:ether) (Found: M⁺+ Na, 335.1113.

View Article Online

DOI: 10.1039/C7OB02127E

Na, 739.4800. C₃₇H₇₆O₇Si₃Na requires M, 739.4791); v_max/cm^-1C₁₆H₂₄O₂S₂Na requires M, 335.1110); v_max/cm 2960, 2931, 2895,

-1

2956, 2931, 2866, 1464, 1380, 1250, 1160, 1108, 1059, 996, 2855, 1612, 1585, 1512, 1465, 1247, 1172, 1096, 1036 and 820;

883, 860, 835 and 775; δ_H(400 MHz, C₆D₆), 0.00 [9 H, s, Si(CH₃)₃], δ_H(400 MHz, CDCl₃) 1.02 (6 H, s, 2 × 1'-CH₃), 1.73 and 2.00 (each

0.16 and 0.18 (each 3 H, s, SiCH₃), 0.91-1.01 (2 H, m, CH₂Si), 1.02 1 H, m, 5-H), 2.76-2.91 (4 H, m, 4-H₂, 6-H₂), 3.27 (2 H, s, 2'-H₂),

[9 H, s, SiC(CH₃)₃], 1.04-1.12 [21 H, m, 3 × SiCH(CH₃)₂], 1.12 (6 H, 3.73 (3 H, s, OCH₃), 4.24 (1 H, s, 2-H), 4.39 (2 H, s, ArCH₂) and

s, 2 × 3-CH₃), 1.28 (3 H, d, J 6.3, 4'-H₃), 1.66 (1 H, ddd, J 14.4, 6.80 and 7.20 (each 2 H, m, ArH); δ_C(100 MHz, CDCl₃) 22.9, 26.2,

10.1, 2.5, 1'-H), 2.15 (1 H, ddd, J 14.1, 9.6, 1.4, 1'-H'), 2.31 (1 H, 31.4, 39.8, 55.3, 57.8, 72.9, 76.5, 113.7, 129.1, 130.8 and 159.0;

td, J 13.6, 1.3, 6-H), 2.36 (1 H, dd, J 13.6, 3.0, 6-H'), 3.24 (3 H, s, mlz (ES⁺) 335.0 (M⁺+ 23, 100%), 330.0 (M⁺+ 18, 44) and 313.0

3a-OCH₃), 3.49 (1 H, td, J 9.8, 6.6, OHCHCH₂Si), 3.56 (1 H, d, J (M⁺+ 1, 38).

7.6, 2-H), 3.79 (1 H, ddd, J 10.2, 9.6, 5.9, OHCHCH₂Si), 3.92 (1 H,

d, J 7.4, 2-H'), 3.94 (1 H, m, 2'-H), 4.00 (1 H, m, 5-H), 4.27-4.36 (3 (4S,7S,9R,10R)-

and

(4R,7S,9R,10R)-10-tert-

H, m, 3'-H, 2"-H₂), 4.37 (1 H, s, 7a-H), 4.74 and 4.78 (each 1 H, d, Butyldimethylsilyloxy-7-triethylsilyloxy-5-[(E)-2-tri-

J 7.1, OHCHO) and 5.89 (1 H, td, J 6.1, 1.5, 1"-H); δ_C(100 MHz, isopropylsilyloxyethylidene]-2,2-dimethyl-1-(4-

C₆D₆) −4.7, −1.5, 12.2, 17.1, 18.1, 19.4, 23.1, 25.9, 30.0, 31.5, methoxybenzyloxy)-9-(2-trimethylsilylethoxymethoxy)-3,3-

35.6, 44.5, 49.3, 59.7, 65.4, 68.2, 69.3, 80.4, 81.0, 81.8, 96.6, (1,3-dithiopropyl)undecan-4-ol (82) and (83).

105.5, 130.6, 133.5; mlz (ES⁺) 775.6 (23%), 739.7 (M⁺+ 23, 100) n-Butyllithium (53 μL, 1.60 M in hexanes, 0.086 mmol) was

and 734.4 (M⁺+ 18, 13).

added to the dithiane 81 (41 mg, 0.13 mmol) in t-BuOMe (0.5

Di-isopropyl azodicarboxylate (8 μL, 0.014 mmol) was added mL) at rt and the solution stirred for 5 min before cooling to −78

to the alcohol 75 (12 mg, 0.014 mmol), PPh₃(11 mg, 0.042 °C. The aldehyde 59 (29 mg, 0.039 mmol) in t-BuOMe (0.5 mL)

mmol) and 2-mercaptobenzothiazole (7 mg, 0.042 mmol) in THF was added and the solution stirred at −78 °C for 15 min.

(0.2 mL) and the solution stirred at rt for

3 h. After Methanol (0.1 mL) was added and the mixture allowed to warm

concentration under reduced pressure, chromatography of the to rt. Ether (10 mL) and saturated aqueous NaHCO₃(10 mL)

residue (20:1 to 12:1 light petroleum:ether) gave the title were added and the aqueous phase was extracted with ether (2

compound 78 (8 mg, 79%) as a colourless oil.

× 10 mL). The organic extracts were dried MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue (50:1 to 15:1 light petroleum:ether) gave the (4R)-

2-(1,1-Dimethyl-2-hydroxyethyl)-1,3-dithiane (80).³²

Boron trifluoride diethyletherate (0.86 mL, 6.96 mmol) was epimer of the title compound 83 (8.5 mg, 21%) as a viscous

added to the aldehyde 79 (2.29 mmol) and 1,3-propanedithiol colourless oil, R_f= 0.62 (5:1 light petroleum:ether), [α]_D²⁹−4.0 (c

(0.42 mL, 4.18 mmol) in DCM (27.5 mL) at 0 °C and the solution 1.0, DCM); v_max/cm^-13380, 2946, 2863, 1612, 1513, 1462, 137,

stirred at rt for 16 h. Dichloromethane (20 mL) and water (20 1249, 1099, 1058, 882, 856, 835, 775 and 739; δ_H(400 MHz,

mL) were added and the aqueous phase extracted with DCM (20 CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 × SiCH₃), 0.60 (6 H, q,

mL). The organic extracts were washed with aqueous NaOH (1 J 7.8, 3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 [9 H, s, SiC(CH₃)₃],

M, 2 × 20 mL) and water (20 mL), dried (MgSO₄) and 0.93 (9 H, t, J 7.8, 3 × SiCH₂CH₃), 0.93 (1 H, m, HCHSi), 1.02-1.13

concentrated under reduced pressure. Chromatography of the [21 H, m, 3 × SiCH(CH₃)₂], 1.03 (3 H, d, J 6.3, 11-H₃), 1.21 and

residue (1:1 light petroleum:ether) gave the title compound 80 1.29 (each 3 H, s, 2-CH₃), 1.55 (1 H, ddd, J 14.1, 9.6, 5.0, 8-H),

(360 mg, 82%) as

a white solid, R_f= 0.38 (1:1 light 1.72 (1 H, ddd, J 13.9, 6.8, 1.3, 8-H'), 1.73-1.92 (2 H, m,

petroleum:ether), m.p. 57.2-58.8 °C (lit.³²55.3-57.4 °C); v_max/cm^-SCH₂CH₂), 2.43 (1 H, ddd, J 13.9, 5.8, 3.3, SHCH), 2.53 (1 H, dd, J

1

3337, 2967, 2938, 2901, 1466, 1411, 1363, 1273, 1194, 1037, 13.9, 6.6, 6-H), 2.70 (1 H, ddd, J 13.1, 7.0, 5.3, SHCH), 2.82-2.93

1003, 906 and 779; δ_H(400 MHz, CDCl₃) 1.01 (6 H, s, 2 × 1'-CH₃), (2 H, m, 6-H', SHCH), 3.02 (1 H, ddd, J 14.0, 10.5, 5.6, SHCH),

1.77 (1 H, m, 5-H), 2.02-2.11 (2 H, m, OH, 5-H'), 2.78-2.92 (4 H, 3.42 (1 H, ddd, J 11.1, 9.6, 6.1, OHCHCH₂Si), 3.46 (1 H, d, J 9.3, 1-

m, 4-H₂, 6-H₂), 3.47 (2 H, d, J 5.1, 2'-H₂) and 4.16 (1 H, s, 2-H); δ_CH), 3.51 (1 H, ddd, J 9.5, 4.2, 1.5, 9-H), 3.71 (1 H, ddd, J 11.4, 9.6,

(100 MHz) 22.5, 26.1, 31.4, 40.2, 57.7 and 69.9; m/z (ES⁺) 215 5.6, OHCHCH₂Si), 3.78 (3 H, s, ArOCH₃), 3.79 (1 H, m, 7-H), 3.80

(M⁺+ 23, 100%).

(1 H, d, J 9.3, 1-H'), 4.06 (1 H, qd, J 6.3, 4.3, 10-H), 4.28 (1 H, dd, J

12.6, 5.3, 2'-H), 4.39 (1 H, dd, J 12.5, 7.1, 2'-H'), 4.42 and 4.44

(each 1 H, d, J 11.7, ArHCH), 4.53 (1 H, d, J 3.5, 4-H), 4.60 (1 H,

br. s, OH), 4.69 (2 H, s, OCH₂O), 6.06 (1 H, m, 1'-H) and 6.84 and

2-[1,1-Dimethyl-2-(4-methyoxybenzyloxy)ethyl]-1,3-dithiane

(81).

Sodium hydride (60% dispersion in mineral oil, 13.5 mg, 0.34 7.23 (each 2 H, m, ArH); δ_C(100 MHz, CDCl₃) −3.3, 0.0, 6.7, 8.4,

mmol) was added to the alcohol 80 (50 mg, 0.26 mmol) in DMF 13.4, 18.5, 19.5(2), 22.9, 24.5, 27.3, 27.9, 28.4, 37.3, 41.6, 48.6,

o

(0.4 mL) at 0 °C and the mixture stirred at 0 C for 30 min. 4- 56.7, 61.7, 66.5, 68.1, 70.5, 72.7, 74.5, 77.5, 78.7, 82.2, 97.7,

Methoxybenzyl chloride (46 μL, 0.34 mmol) and TBAI (9.6 mg, 115.1, 130.5, 131.9, 133.4, 139.2 and 160.5; mlz (ES⁺) 1147.3

0.026 mmol) were added and the mixture stirred at rt for 1 h. (22%), 1068.1 (M⁺+ 23, 100) and 1063.2 (M⁺+ 18, 17). The

Ether (10 mL) and water (10 mL) were added and the aqueous seond fraction was the title compound 82 (14 mg, 34%), a

29

phase extracted with ether (2 × 10 mL). The organic extracts viscous colourless oil, R_f= 0.56 (5:1 light petroleum:ether), [α]_D

were dried (MgSO₄) and concentrated under reduced pressure. −34.6 (c 1.4, DCM); v_max/cm^-13396, 2952, 2863, 1615, 1514,

Chromatography of the residue (15:1 light petroleum:ether) 1463, 1379, 1249, 1099, 1057, 882, 858, 835, 807, 775 and 742;

gave the title compound 81 (53 mg, 65%) as a pale yellow oil, R_fδ_H(400 MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 ×

18 | J. Name., 2012, 00, 1-3

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SiCH₃), 0.56-0.64 (6 H, m, 3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 132.9, 134.1, 137.7 and 160.3; mlz (ES⁺) 1263.8 (100%), 1182.5

View Article Online

DOI: 10.1039/C7OB02127E

[9 H, s, SiC(CH₃)₃], 0.93 (1 H, m, HCHSi), 0.93 (9 H, t, J 7.8, 3 × (M⁺+ 23, 100) and 1177.5 (M⁺+ 18, 39).

SiCH₂CH₃), 1.02-1.13 [24 H, m, 11-H₃, 3 × SiCH(CH₃)₂], 1.23 and

1.30 (each 3 H, s, 2-CH₃), 1.49 (1 H, ddd, J 14.0, 9.6, 4.7, (4S,7S,9R,10R)-4,10-Bis-tert-butyldimethylsilyloxy-7-

SCH₂HCH), 1.62 (1 H, ddd, J 14.1, 7.2, 1.5, SCH₂HCH), 1.80 and triethylsilyloxy-5-[(E)-2-tri-isopropylsilyloxyethylidene]-2,2-

1.90 (each 1 H, m, 8-H), 2.43 (1 H, ddd, J 14.1, 5.8, 3.5, SHCH), dimethyl-9-(2-trimethylsilylethoxymethoxy)-3,3-(1,3-

2.57 (1 H, dd, J 13.6, 6.6, 6-H), 2.66 (1 H, ddd, J 13.9, 6.8, 5.0, dithiopropyl)undecan-1-ol (85).

SHCH), 2.82 (1 H, dd, J 13.6, 6.5, 6-H'), 2.95-3.07 (2 H, m, 2 × Dichlorodicyanoquinone (3 mg, 0.013 mmol) was added to the

SHCH), 3.39-3.46 (2 H, m, OHCHCH₂Si, 1-H), 3.54 (1 H, ddd, J 9.3, 4-methoxybenzyl ether 84 (13 mg, 0.011 mmol) in DCM (0.25

4.3, 1.8, 9-H), 3.70 (1 H, ddd, J 11.4, 9.6, 5.6, OHCHCH₂Si), 3.79 mL) and an aqueous pH 7.2 phosphate buffer (0.05 mL) and the

(3 H, s, ArOCH₃), 3.81 (1 H, d, J 9.4, 1-H'), 3.95 (1 H, qd, J 6.8, 4.8, mixture stirred for 30 min. Ether (10 mL) and saturated aqueous

7-H), 4.04 (1 H, qd, J 6.3, 4.3, 10-H), 4.29 (1 H, dd, J 12.4, 5.3, 2'- NaHCO₃(10 mL) were added and the aqueous phase was

H), 4.37 (1 H, br. s, OH), 4.39 (1 H, dd, J 12.5, 7.6, 2'-H'), 4.41 and extracted with ether (2 × 10 mL). The organic extracts were

4.45 (each 1 H, d, J 11.8, ArHCH), 4.59 (1 H, d, J 4.8, 4-H), 4.68 dried (MgSO₄) and concentrated under reduced pressure.

and 4.71 (each 1 H, d, J 6.9, OHCHO), 6.20 (1 H, t, J 6.3, 1'-H) and Chromatography of the residue (20:1 light petroleum:ether)

6.85 and 7.23 (each 2 H, m, ArH); δ_C(100 MHz, CDCl₃) −3.3, 0.0, gave the title compound 85 (9.5 mg, 81%) as a viscous colourless

29

6.7, 8.5, 13.4, 18.6, 19.5, 19.6, 23.1, 24.6, 27.3, 27.8, 28.3, 37.5, oil, R_f= 0.31 (7:1 light petroleum:ether), [α]_D−16.5 (c 0.8,

42.3, 48.4, 56.7, 61.8, 66.5, 67.8, 70.6, 72.3, 74.5, 76.2, 77.5, DCM); v_max/cm^-13438, 2952, 2925, 2866, 1470, 1464, 1377,

82.0, 97.5, 115.2, 130.5, 131.7, 132.9, 140.3 and 160.5; m/z (ES⁺) 1250, 1093, 1055, 884, 861, 836 and 775; δ_H(400 MHz, CDCl₃)

1068.2 (M⁺+ 23, 51%), 1063.2 (M⁺+ 18, 100) and 327.1 (19).

0.00 [9 H, s, Si(CH₃)₃], 0.03 (6 H, s, 2 × SiCH₃), 0.05 and 0.15

(each 3 H, s, SiCH₃), 0.55-0.66 (6 H, m, 3 × SiCH₂), 0.84 (1 H, ddd,

J 13.9, 11.1, 5.3, HCHSi), 0.87 and 0.95 [each 9 H, s, SiC(CH₃)₃],

0.93 (1 H, m, HCHSi), 0.95 (9 H, t, J 8.0, 3 × SiCH₂CH₃), 0.98 (3 H,

d, J 6.3, 11-H₃), 1.03-1.12 [21 H, m, 3 × SiCH(CH₃)₂], 1.19 and

1.21 (each 3 H, s, 2-CH₃), 1.38-1.51 (2 H, m, 8-H₂), 1.79-1.92 (2 H,

m, SCH₂CH₂), 2.38 (1 H, t, J 12.8, 6-H), 2.60-2.94 (4 H, m, 2 ×

(4S,7S,9R,10R)-4,10-Bis-tert-butyldimethylsilyloxy-7-

triethylsilyloxy-5-[(E)-2-tri-isopropylsilyloxyethylidene]-2,2-

dimethyl-1-(4-methoxybenzyloxy)-9-(2-

trimethylsilylethoxymethoxy)-3,3-(1,3-dithiopropyl)undecane

(84).

2,6-Lutidine (17 μL, 0.14 mmol) and tert-butyldimethylsilyl SCH₂), 2.99 (1 H, d, J 13.0, 6-H'), 3.08 (1 H, br. s, OH), 3.39 (1 H,

trifluoromethanesulfonate (16 μL, 0.073 mmol) were added to ddd, J 11.1, 9.6, 6.1, OHCHCH₂Si), 3.62 (1 H, ddd, J 9.6, 4.3, 2.8,

the alcohol 82 (13 mg, 0.012 mmol) in DCM (0.20 mL) and the 9-H), 3.70 (1 H, ddd, J 11.4, 9.6, 5.4, OHCHCH₂Si), 3.74 (2 H, br. s,

solution stirred at rt for 3 h. Dichloromethane (10 mL) and 1-H₂), 4.09 (1 H, m, 7-H), 4.13 (1 H, qd, J 6.3, 4.5, 10-H), 4.29 (1

saturated aqueous NaHCO₃(10 mL) were added and the H, dd, J 12.9, 5.0, 2'-H), 4.37 (1 H, dd, J 12.9, 7.1, 2'-H'), 4.56 (1

aqueous phase was extracted with DCM (2 × 10 mL). The H, s, 4-H), 4.66 and 4.69 (each 1 H, d, J 6.8, OHCHO) and 6.18 (1

organic extracts were dried (MgSO₄) and concentrated under H, m, 1'-H); δ_C(100 MHz) −3.7, −3.4, −3.3, −0.8, 0.0, 7.1, 8.6,

reduced pressure. Chromatography of the residue (55:1 light 13.7, 18.5, 19.5(3), 20.2, 23.0, 23.7, 24.5, 27.2, 27.3, 27.8, 28.3,

petroleum:ether) gave the title compound 84 (13 mg, 90%) as a 36.1, 43.2, 48.8, 62.1, 66.6, 69.0, 69.9, 71.6, 72.5, 78.3, 81.8,

viscous colourless oil, R_f= 0.50 (15:1 light petroleum:ether), 97.8, 134.5 and 137.4; mlz (ES⁺) 1141.3 (100%), 1062.2 (M⁺+ 23,

29

[α]_D−15.3 (c 1.1, DCM); v_max/cm^-12953, 2925, 2863, 1613, 71) and 492.4 (24).

1513, 1463, 1376, 1249, 1093, 1060, 885, 858, 836, 776 and

745; δ_H(400 MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.02 (3 H, s, (4S,7S,9R,10R)-1-(Benzothiazol-2-ylsulfanyl)-4,10-bis-tert-

SiCH₃), 0.04 (6 H, s, 2 × SiCH₃), 0.11 (3 H, s, SiCH₃), 0.56-0.67 (6 butyldimethylsilyloxy-7-triethylsilyloxy-5-[(E)-2-tri-

H, m, 3 × SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 and 0.93 [each 9 H, s, isopropylsilyloxyethylidene]-2,2-dimethyl-9-(2-

SiC(CH₃)₃], 0.94 (1 H, m, HCHSi), 0.95 (9 H, t, J 8.0, 3 × SiCH₂CH₃), trimethylsilylethoxymethoxy)-3,3-(1,3-dithiopropyl)undecane

0.99 (3 H, d, J 6.3, 11-H₃), 1.03-1.12 [21 H, m, 3 × SiCH(CH₃)₂], (86).

1.26 and 1.28 (each 3 H, s, 2-CH₃), 1.38-1.50 (2 H, m, SCH₂CH₂), Di-isopropyl azodicarboxylate (0.54 M in THF, 50 μL, 0.027

1.74-1.89 (2 H, m, 8-H₂), 2.36 (1 H, t, J 12.6, 6-H), 2.55-2.91 (4 H, mmol) was added to the alcohol 85 (9.5 mg, 0.009 mmol), PPh₃

m, 2 × SCH₂), 3.04 (1 H, d, J 12.6, 6-H'), 3.39 (1 H, ddd, J 11.0, (7 mg, 0.027 mmol) and 2-mercaptobenzothiazole (4.5 mg,

9.6, 6.1, OHCHCH₂Si), 3.62 (1 H, m, 9-H), 3.65 (1 H, d, J 8.8, 1-H), 0.027 mmol) in THF (0.2 mL) at 0 °C and the mixture stirred at 0

3.70 (1 H, ddd, J 11.4, 9.6, 5.5, OHCHCH₂Si), 3.79 (3 H, s, ^oC for 1 h then at rt for 3 h. Ether (10 mL) and saturated

ArOCH₃), 3.82 (1 H, d, J 8.6, 1-H'), 4.09 (1 H, m, 7-H), 4.13 (1 H, aqueous NaHCO₃(10 mL) were added and the aqueous phase

qd, J 6.3, 4.5, 10-H), 4.29 (1 H, dd, J 12.9, 5.3, 2'-H), 4.36 (1 H, was extracted with ether (2 × 10 mL). The organic extracts were

dd, J 13.0, 6.6, 2'-H'), 4.39 and 4.46 (each 1 H, d, J 11.6, ArHCH), dried (MgSO₄) and concentrated under reduced pressure.

4.56 (1 H, s, 4-H),4.66 and 4.70 (each 1 H, d, J 7.0, OHCHO), 6.14 Chromatography of the residue (70:1 light petroleum:ether)

(1 H, m, 1'-H) and 6.85 and 7.24 (each 2 H, m, ArH); δ_C(100 MHz, gave the title compound 86 (8.5 mg, 78%) as a viscous colourless

29

CDCl₃) −3.7, −3.4, −3.3, −0.7, 0.0, 7.1, 8.6, 13.4, 18.5, 19.5(2), oil, R_f= 0.22 (40:1 light petroleum:ether), [α]_D−14.2 (c 0.9,

20.2, 23.8, 23.9, 27.3, 27.8, 28.3, 36.1, 43.1, 50.4, 56.7, 62.2, DCM); v_max/cm^-12946, 2865, 1463, 1428, 1382, 1361, 1250,

66.5, 69.0, 69.9, 71.9, 74.5, 77.1, 77.9, 81.9, 97.9, 115.0, 130.1, 1145, 1096, 1058, 1017, 933, 886, 860, 835, 776, 754, 725 and

667; δ_H(400 MHz, CDCl₃) 0.00 [9 H, s, Si(CH₃)₃], 0.04 (6 H, s, 2 ×

J. Name., 2013, 00, 1-3 | 19

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Journal Name

5136; (f) P. A. Wender and D. Staveness, Org. Lett ., 2014, 16 ,

SiCH₃), 0.07 and 0.20 (each 3 H, s, SiCH₃), 0.54-0.67 (6 H, m, 3 ×

SiCH₂), 0.85 (1 H, m, HCHSi), 0.87 [9 H, s, SiC(CH₃)₃], 0.93 (1 H, m,

HCHSi), 0.93 (9 H, t, J 7.9, 3 × SiCH₂CH₃), 0.96 [9 H, s, SiC(CH₃)₃],

0.98-1.08 [24 H, m, 11-H₃, 3 × SiCH(CH₃)₂], 1.34 (6 H, s, 2 × 2-

CH₃), 1.41-1.52 (2 H, m, 8-H₂), 1.78-1.95 (2 H, m, SCH₂CH₂), 2.42

(1 H, t, J 12.5, 6-H), 2.62-2.95 (4 H, m, 2 × SCH₂), 3.05 (1 H, d, J

12.6, 6-H'), 3 .40 (1 H, td, J 10.4, 6.0, OHCHCH₂Si), 3.62 (1 H, m,

9-H), 3.72 (1 H, ddd, J 11.4, 10.1, 5.4, OHCHCH₂Si), 3.93-4.00 (2

H, m, 1-H₂), 4.10-4.17 (2 H, m, 7-H, 10-H), 4.31 (1 H, dd, J 12.9,

5.4, 2'-H), 4.36 (1 H, dd, J 12.9, 6.6, 2'-H'), 4.65 (1 H, s, 4-H), 4 .68

and 4.72 (each 1 H, d, J 6.9, OHCHO), 6.18 (1 H, m, 1'-H), 7.25

and 7.36 (each 1 H, t, J 7.6, ArH), 7. 71 (1 H, d, J 7.8, ArH) and

7.82 (1 H, d, J 7.9, ArH); δ_C(100 MHz, CDCl₃) −3.7, −3.4, −3.3,

−0.7, 0.0, 7.1, 8.6, 13.4, 18.5, 19.5, 19.6, 20.2, 23.7, 27.3, 27.6,

27.8, 28.6, 36.1, 43.1, 44.7, 50.1, 62.1, 66.6, 69.0, 69.9, 73.1,

78.1, 81.9, 97.9, 122.2, 122.9, 125.3, 127.3, 134.6, 136.6, 137.7,

154.8 and 170.2; m/z (ES⁺) 1188.6 (M⁺+ 23, 31%) and 540.7

(100).

View Article Online

5140; (g) B. A. Loy, A. B. Lesser,_DD_O._{I: 1}S₀t_.1a₀v₃e₉n_/Ce₇s_Os_B, ₀K₂₁.₂₇L_E.

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Ackowledgements

We thank the Dr. R. Dumeunier for preliminary studies of the

classical Julia reaction, Dr. Ralph Adams for help with NMR data,

and the EPSRC for a research grant and studentships (to S. H.

and A. P. G.).

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(a) R. Dumeunier, T. Gregson, S. MacCormick, H. Omori

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Notes and references

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11 In his seminal work on the synthesis of bryostatin 2, Evans

investigated both the classical Julia reaction and the use of

N-methylimidazol-2-yl sulfones, for the assembly of

fragments with the 16,17-double bond. It was found that

these reactions were very sensitive to steric hindrance

particularly in the C17 sulfones (bryostatin numbering). In

Evans’ final synthesis, the classical Julia reaction was used to

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methoxycarbonylmethylene groups. This fragment was

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assembly of the 16,17-double-bond by Julia-type processes.

12 Preliminary communication on the use of the modified Julia

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20 | J. Name., 2012, 00, 1-3

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DOI: 10.1039/C7OB02127E

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24 Formation of 2-phenylethanol can be explained by

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J. Name., 2013, 00, 1-3 | 21

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Article Doi

Synthetic approaches to the C11-C27 fragments of bryostatins

DOI: 10.1039/c7ob02127e

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