Synthesis of the C1 – C16 fragment of bryostatin for incorporation into 20,20-fluorinated analogues

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Synthesis of the C1 – C16 fragment of bryostatin for incorporation into 20,20-

fluorinated analogues

Paul R. Mears, Eric J. Thomas

PII:

S0040-4020(20)30969-8

https://doi.org/10.1016/j.tet.2020.131743

TET 131743

DOI:

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To appear in: Tetrahedron

Received Date: 24 August 2020

Revised Date: 31 October 2020

Accepted Date: 3 November 2020

Please cite this article as: Mears PR, Thomas EJ, Synthesis of the C1 – C16 fragment of bryostatin for

incorporation into 20,20-fluorinated analogues, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131743.

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Synthesis of the C1 – C16 fragment of

bryostatin for incorporation into 20,20-

fluorinated analogues

Leave this area blank for abstract info.

Paul R. Mears and Eric J. Thomas*

The Department of Chemistry, The University of Manchester, Manchester, M13 9PL, UK

altered.

1

Tetrahedron

journal homepage: www.elsevier.com

Synthesis of the C1 – C16 fragment of bryostatin for incorporation into 20,20-

fluorinated analogues

Paul R. Mears and Eric J. Thomas^*

The Department of Chemistry, The University of Manchester, Manchester, M13 9PL, UK

This paper is dedicated to Richard J. K. Taylor in recognition of his outstanding contributions to organic chemistry

ARTICLE INFO

ABSTRACT

Article history:

Received

The stereoselective synthesis of a carboxylic acid ester corresponding to the C1-C16 fragment of

bryostatin, with 4-methoxybenzyl (PMB) protection for the 7-hydroxyl group, is reported. The

Received in revised form

Accepted

Available online

key steps included a Horner-Wadsworth-Emmons reaction between (5R)-3-[(E)-2-tri-

isopropylsilyloxyethylidene]-6-(4-methoxybenzyloxy)-5-triethylsilyloxyhexanal and dimethyl

(4S,6R,8S)-10-hydroxy-6,8-di-O-isopropylidene-4-(4-methoxybenzyloxy)-3,3-dimethyl-2-

oxodecan-1-yl phosphonate, that gave the corresponding (E)-alkene, followed by selective

cleavage of the triethylsilyl ether and cyclisation to give the required 2,6-cis-disubstituted 4-

[(Z)-tri-isopropylsilyloxyethylide]tetrahydropyran. Oxidation of the primary alcohol gave the

corresponding carboxylic acid that was converted into the required allyl ester.

Keywords:

Bryostatin

Horner-Wadsworth-Emmons

Oxy-Michael addition

Tetrahydropyran

Stereoselectivity

.

1.

Introduction

The bryostatins as represented by bryostatin 1 (1), see Figure

1, are a group of complex macrolides, that have been

comprehensively studied because of their potent biological

activities.¹In particular they exhibit novel anti-cancer activity

that, in part, is explained by their binding to the regulatory C1

domain of several Protein Kinase C (PKC) isozymes.²Several

outstanding total syntheses of bryostatins have been reported,³

including a recent synthesis on the multigram scale.^3j

Bryostatin 10 (2) lacks the C20 acyloxy substituent of most

bryostatins but retains the biological activity of the more widely

studied bryostatin 1.⁴In contrast, bryostatin 16 (3), being the

anhydro derivative of bryostatin 10 (2), lacks the hydroxyl group

at C19, and shows significantly reduced anti-cancer activity.⁵

Our work on the synthesis of bryostatins was focussed on

bryostatin 10 and culminated in a total synthesis of the macrolide

4 that corresponds to bryostatin 10 except for the presence of a

benzyloxy substituent at C7 rather than a pivoyloxy group.⁶

As well as studies on the total synthesis of bryostatins, the

synthesis of analogues for biological evaluation has been of

considerable interest. Early on during his work in this area,

Wender proposed that the binding of bryostatin to PKCs involves

the C1-carbonyl group and the C19 and C26 hydroxyl groups.⁷

The C3 hydroxyl group is important as it maintains the required

Figure 1 Structures of representative bryostatins

2

Tetrahedron

conformation of the macrocycle by forming an intramolecular

hydrogen bond. This analysis led to the synthesis of macrocyclic

analogues of bryostatins with the C17-C27 fragment of bryostatin

1 intact. This important work demonstrated that these bryologues

retained the nanomolar PKC binding but, perhaps surprisingly, it

was discovered that analogues with different C1-C16 fragments

could act as either tumour inhibitors, cf. bryostatins, or a tumour

promoters, cf. phorbol esters.^8,9

Notwithstanding the success of the synthesis of potently active

macrocyclic bryologues that had retained the C17-C27 fragment

of bryostatin 1, it was of interest to establish whether the

structure of this fragment could be varied and still retain potent

PKC binding.

Following completion of the synthesis of the macrolide 4, our

studies were redirected towards the synthesis of bryostatin

analogues with two fluorine substituents at C20, ideally the

bryologue 5, see Figure 2. Such analogues would retain all of the

structural features identified by Wender as being important for

potent PKC binding. However the incorporation of the fluorine

substituents might have several beneficial effects not least being

the inhibition of any dehydration involving the 19-hydroxy

group. Such dehydration would reduce the PKC binding and may

account for the reported loss of biological activity of bryostatins

with time. The introduction of the two fluorine substituents

would also increase the pKa of the 19-hydroxyl group by about

three pKa units, improve PKC binding, stabilize the ring-closed

form of the hemiacetal, and increase the electrophilicity of the

exocyclic double bond at C21.

Figure 3 Proposed strategy for the synthesis of intermediate 7.

the αβ-unsaturated ketone 8. Following selective removal of the

triethylsilyl group, an oxy-Michael cyclisation under reversible

conditions should lead to the required 2,6-cis-disubstituted 4-

[(Z)-tri-isopropylsilyloxyethylidene)tetrahydropyran

stereo-

selectively.^6,11Subsequent removal of the primary tert-

butyldiphenylsilyl group followed by oxidation of the primary

alcohol and esterification would deliver the required C(1)-C(16)-

fragment 7. This proposed synthesis of the C(1)-C(16) fragment

7, and the protecting group strategy, follows that used previously

during the synthesis of the bryostatin 4.¹¹However, the

compatibility of this synthesis with the protection of the 7-

hydroxyl group as its p-methoxybenzyl ether had to be

established and several steps improved. These were the primary

objectives of the work reported in this paper.

We have reported a synthesis of several compounds, e.g.

hemiacetal 6, see Figure 2, that correspond to the C17-C27

fragment of the 20,20-difluorinated bryostatin 5.¹⁰We now report

a synthesis of the C1-C16 fragment 7 that has the p-

methoxybenzyl (PMB) protecting group for the 7-hydroxyl

substituent. The PMB group should be easier to remove at a late

stage of the synthesis than the benzyl group so providing access

to bryologues with an unprotected hydroxyl group at C7 ready

for O-acylation. Ester

7 could be used, together with

intermediates prepared during the synthesis of the difluorinated

fragments 6,¹⁰to assemble the difluorinated bryologue 5 by

formation of the C16-C17 double-bond followed by

macrolactonization. With an easier late-stage cleavage of the p-

methoxybenxyl ether, intermediate 7 may also be incorporated

into a synthesis of bryostatin 10 (2).

2. Results and discussion.

The alkenol 14 is available from (R)-pantolactone 11 by

protection of the hydroxyl group as its p-methoxybenzyl ether 12,

followed by reduction using DIBAL-H and a Wittig reaction of

the resulting lactol 13, see Scheme 1.¹²After protection of the

primary alcohol 14, hydroboration - oxidation of the alkene 15

using the borane-THF complex gave the alcohol 16¹³although, in

our hands, this was accompanied by a small amount of p-

methoxybenzyl alcohol, ca. 7%, due to cleavage of the p-

methoxybenzyl ether. This mixture of alcohol 16 and p-

methoxybenzyl alcohol was oxidised using Parikh-Doering

conditions to give the required aldehyde 18 albeit contaminated

by p-methoxybenzaldehyde. Attempted separation of these by

chromatography on silica was accompanied by competing

elimination of p-methoxybenzyl alcohol from the aldehyde 18

leading to the αβ-unsaturated aldehyde 17¹³as a minor side-

product. The formation of this side-product could be minimized

by fast chromatography using a short plug of silica. This

procedure gave the required aldehyde 18 in a yield of 70%,

together with p-methoxybenzaldehyde (9%) (see Scheme 1).

The aldehyde 9 and the ketophosphonate 10 were recognised

as key intermediates for a synthesis of the target compound 7, see

Figure 3.

A Horner-Wadsworth-Emmons reaction of the

ketophosphonate 10 with the aldehyde 9 was expected to provide

The kinetic aldol reaction of the aldehyde 18 with 4-tert-

butyldiphenylsiloxybutan-2-one 19 gave the 5,7-anti-adduct 20

due to chelation control, essentially as a single diasteroisomer,¹⁴

the 5,7-anti-configuration being assigned by analogy with the

literature.^11,14Diastereoselective reduction¹¹of the hydroxyketone

Figure 2 20,20-Difluorinated bryologues 5 and fragments

3

20 gave the 1,3-anti-diol 21 that was converted into its acetonide

22 using 2,2-dimethoxypropane with toluene p-sulfonic acid as

the catalyst. The vicinal methyl carbons in acetonide 22 were

seen at δ 24.9 and 25.8 consistent with the 1,3-anti-configuration

that was assigned to the diol 21.¹⁵However, the conditions

required for the selective removal of the tert-butyldimethylsilyl

protecting group from the fully protected polyol 22 required

some optimization. The hydrogen fluoride-pyridine complex is

often used for the selective removal of tert-butyldimethylsilyl

groups in the presence of tert-butyldiphenylsilyl groups,¹⁶but for

the bis-silyl ether 22 it was found that the tert-butyldiphenylsilyl

ether was cleaved preferentially under these conditions perhaps

because of steric hindrance around the neopentylic tert-

butyldimethylsilyloxy group. Attempted selective deprotection

using protic acids such as triflic and toluene p-sulphonic acids

gave complex mixtures of products. However, trimethylsilyl

triflate at −78 ^oC gave selective cleavage of the tert-

butyldimethylsilyl ether¹⁷and, although some starting bis-silyl

ether 22 was recovered after a reaction time of 30 min., the

overall recovery of material was very high, and the required

primary alcohol 23 was obtained in a 51% yield together with

unchanged starting material 22 (48%) that was recycled.

methylphosphonate, and oxidation of the resulting hydroxy-

phosphonates 25 using the Dess-Martin periodinane. The Horner-

Wadsworth-Emmons reaction of ketophosphonate 10 with the

aldehyde 9 was carried out using barium hydroxide as the base¹¹

and gave the (E)-enone 8. The (E)-configuration was established

from the vinylic coupling constant of 15.1 Hz and no (Z)-isomer

was isolated. However, the commercial barium hydroxide

octahydrate required heating at 200 C¹⁸for the procedure to be

o

reproduceable. The product was usually used in the next step

without purification but, on a small scale, was purified for

characterisation by chromatography in a 42% isolated yield. The

triethylsilyl protecting group was removed selectively using the

hydrogen fluoride pyridine complex at ambient temperature, and

the oxy-Michael reaction of the resulting hydroxyenone 26 was

immediately carried out using a catalytic amount of potassium

tert-butoxide. After

5 min. at ambient temperature, the

cyclisation gave a modest yield of the required tetrahydrofuran

27 (12% based on the phosphonate 10) together with the isomeric

tetrahydrofuran 28 that was also isolated, see Scheme 2.

NMR was used to assign the configuration at C2' in the

tetrahydrofuran 27. Significant nOe effects were observed for the

The alcohol 23 was taken through to the ketophosphonate 10

by oxidation to the aldehyde 24, addition of lithiated dimethyl

Scheme 1 Synthesis of alcohol 22. Reagents and conditions: i,

Cl₃C.C(=NH)OPMB, camphor sulfonic acid (cat.), DCM, 0 ^oC to

rt, 16 h (56%); ii, DIBAL-H, THF, −78 ^oC to −37 ^oC, 4 h (49%);

o

iii, Ph₃PMeBr, KO^tBu, THF, 30 min rt, cool to 0 C, add 13, rt,

Scheme 2 Initial assembly of the C1-C16 fragment. Reagents and

16 h (82%); iv, ^tBuMe₂SiCl, DCM, imid., 0 ^oC to rt, 5 h (73%); v,

borane-THF, 0 C, THF, rt, 3 h; 30% aq. H₂_oO₂, NaOH, rt, 1 h

(61%); vi, SO₃.py., DMSO, DCM, Et₃N, 0 C to rt, 2 h (18,

o

conditions i, (COCl)₂, DMSO, DCM, −78 C, 20 min., add 23,

o

−78 C, 20 min., add Et₃N, −78 C, 20 min.; ii, MeP(O)(OMe)₂,

ⁿBuLi, THF, −78 C, 1 h, add 24, −78 C, 2 h; iii, Dess-Martin

periodinane, py., DCM, rt, 30 min., 25, rt, 2 h (76% from alcohol

23); iv, 10, Ba(OH)₂, THF, rt, 2 h, add 9, H₂O, rt, 16 h (42%); v,

HF.py., THF, 0 ^oC, 30 min.; vi, KO^tBu, THF, rt, 5 min (27, 12%,

28, 11%, both from phosphonate 10).

o

70%); vii, LDA, 19, THF, −78 C, 2 h, add 18, −78 C, 2.5 h

(67%); viii, LiI, LiAlH(O^tBu)₃, THF, −78 C, 4 h (96%); ix, 2,2-

o

dimethoxypropane, p-TsOH (cat.), DCM, rt, 2 h; x, TMSOTf,

DCM, −78 ^oC, 30 min (23, 51% from 21; 22, 48% from 21).

4

Tetrahedron

disubstituted

4-(methoxycarbonylmethylene)tetrahydropyran

analogous to the earlier product 28 was only a very minor

component of the product mixture and was not isolated. This

selectivity is believed to be the result of thermodynamic control

in the cyclisation rather than the kinetic control observed in the

formation of isomers 27 and 28 and is precedented in our earlier

work.^11,12aThe oxidation of the primary alcohol to the

corresponding carboxylic acid was carried out in two steps by

oxidation to the aldehyde using the Dess-Martin periodinane

followed by oxidation to the acid using the Pinnick procedure.

The carboxylic acid was then converted into the required allylic

ester 7 using allyl bromide under mildly basic conditions to give

the ester 7 in a 60% yield based on the alcohol 32.

Figure 4 Confirmation of the stereochemistry of the 2,6-cis-

disubstituted tetrahydropyran 27.

cis-orientated axial hydrogens at C2' and C6'. The vicinal diaxial

coupling between the axial hydrogens at C2' and C6' with the

axial hydrogens at C3' and C5' were also supportive of the

stereochemistry assigned to the isomer 27, see Figure 4.

3. Conclusion

In this preliminary study of the cyclisation reaction, the

isolation of mixtures of the 2,6-cis- and 2,6-trans-disubstituted

tetrahydropyrans 27 and 28 was indicative of kinetic control,

since analogous isomers have been shown to undergo

equilibration to give more of the required 2,6-cis-disubstituted

epimer under conditions of thermodynamic control.¹⁹The

isolated yield of the tetrahydropyran 27 was also unacceptably

low at this stage. However, rather than attempt to optimize this

reaction, it was decided to look at the deprotection and oxidation

of the 1-hydroxyl group before the Horner-Wadsworth-Emmons

assembly reaction since it was thought that this would avoid

selectivity issues that might subsequently arise due to the allylic

tri-isopropylsilyl protecting group.

The ester 7 has all the functionality present in the C1-C16

fragment of bryostatins. It remains to develop procedures for the

assembly of the 20,20-difluorinated bryostatin 5 so that the PKC

binding and biological activity of this and analogous compounds

can be assessed.

4. Experimental

4.1. General experimental details

Flash column chromatography was performed using Merck

silica gel (60H, 230-300 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. Mass spectra used electron impact ionisation

(EI⁺), chemical ionisation using ammonia (CI⁺), electrospray

ionisation in the positive mode (ES⁺), atmospheric pressure

chemical ionisation in the positive mode (APCI⁺) and time of

flight MS with electrospray ionisation (TOF ES⁺). Low

resolution mass spectra were recorded on a Waters SQD2 or on

an Agilent 5975C Triple axis spectrometer. High resolution mass

spectra were recorded using a Thermo Finnigan MAT95XP or on

a Waters QTOF spectrometer. Infra-red spectra were measured

using a Bruker Alpha P FTIR spectrometer on NaBr plates, either

neat or as evaporated films. Nuclear magnetic resonance spectra

were recorded using Bruker Avance 300, Bruker Ultrashield 400

Removal of the tert-butyldiphenylsilyl protecting group from

the phosphonate 10 gave the rather polar 10-

hydroxydecanylphosphonate 29 that was coupled with the

aldehyde 9 to give the (E)-enone 30, see Scheme 3 As before,

this was usually taken on in the synthesis without purification,

but, on a small scale, was isolated for characterization in a yield

of 66%. Selective removal of the triethylsilyl group gave the

dihydroxyenone 31 and cyclisation of this using potassium tert-

butoxide gave the required 2,6-cis-disubstituted tetrahydropyran

32 in an isolated yield of 45% over the three steps from the

hydroxyketophosphonate 29. It is interesting that the primary

hydroxyl group didn’t interfere with the Horner-Wadsworth-

Emmons or with the deprotection and cyclisation reactions. The

slightly longer reaction time for the cyclisation to 32 of 10

minutes resulted in a usefully stereoselective reaction in favour of

the tetrahydropyran 32 that has the 2- and 6-substituents of the

tetrahydropyran both equatorial. The corresponding 2,6-trans-

5

or Bruker Ultrashield 500 spectrometers at ca. 25 ^oC unless

otherwise stated. Coupling constants (J) are given in Hertz (Hz)

and chemical shifts are relative to tetramethylsilane. Residual

non-deuteriated solvent was used as the internal standard.

0.6H, d, J 11.0, ArHCH), 4.64 (0.4H, d, J 11.6, ArHCH), 5.36

(0.4H, t, J 3.1, 2-H), 5.46 (0.6H, dd, J 10.0, 4.3, 2-H) and 6.87-

6.93 and 7.26-7.31 (each 2H, m, ArH); δ_C(CDCl₃, 100 MHz)

19.7, 20.4, 24.0, 25.6, 30.3, 42.1, 53.4, 55.2, 72.1, 74.1, 78.7,

84.9, 91.1, 97.5, 102.9, 113.7, 113.9, 129.1, 129.2, 129.7, 130.3,

159.1 and 159.5; m/z (ES⁺) 275 (M⁺+ 23, 100%).

4.2.1 (3R)-3-(4-Methoxybenzyloxy)-4,4-dimethyltetrahydrofuran-

2-one (12)

4-Methoxybenzyl alcohol (9.8 g, 71 mmol) in ether (60 mL)

was added to a suspension of sodium hydride (60% in mineral

oil, 0.56 g, 14 mmol) in ether (75 mL) at rt and the mixture

stirred for 30 min before cooling to 0 °C. Trichloroacetonitrile

(7.8 mL, 78 mmol) was added and the reaction mixture stirred at

rt overnight then concentrated under reduced pressure. Light

petroleum (90 mL) was added, followed by methanol (0.6 mL).

The suspension was filtered through Celite^®and concentrated

under reduced pressure to give the acetimidate as a yellow-

orange oil (17.1 g, 60.5 mmol, 85%); δ_H(300 MHz, CDCl₃) 3.84

(3H, s, OCH₃), 5.30 (2H, s, CH₂), 6.94 and 7.40 (each 2H, d, J

8.8, ArH) and 8.39 (1H, s, NH).

4.2.3

(14)

(3S)-3-(4-Methoxybenzyloxy)-2,2-dimethylpent-4-en-1-ol

Solid methyltriphenylphosphonium bromide (1.91 g, 5.35

mmol) was stirred with solid potassium tert-butoxide (0.60 g, 5.3

mmol) for 30 min to ensure a homogenous mixture. THF (25

mL) was added and the bright yellow suspension was stirred for

30 min and then cooled to 0 °C before the addition of lactol 13

(0.9 g, from 1.0 g, 4.0 mmol of 12) in THF (5.0 mL). The

mixture was stirred for 16 h before addition of saturated aqueous

ammonium chloride (4 mL) and water (10 mL). The aqueous

phase was extracted with ether (3 × 10 mL) and the organic

extracts were dried (MgSO₄) and concentrated under reduced

pressure. Chromatography of the residue (ether:light petroleum

1:2) gave the title compound 14 (0.82 g, 3.3 mmol, 82% from 12)

(R)-Pantolactone (11) (5.0 g, 38 mmol) was added to the

acetimidate (14.4 g) in DCM (50 mL) and the solution cooled to

0 °C. Camphorsulfonic acid (1.16 g, 4.99 mmol) was added

portionwise and the reaction mixture was allowed to warm to rt.

The white suspension was stirred overnight before the addition of

saturated aqueous sodium bicarbonate (125 mL). The suspension

was filtered through Celite^®and the aqueous phase was extracted

with DCM (100 mL). The organic extracts were washed with

saturated aqueous sodium bicarbonate (90 mL), dried (MgSO₄)

and concentrated under reduced pressure. After trituration with

DCM, chromatography of the residue (ether:light petroleum

1:10) gave the title compound 12¹²(5.39 g, 21.6 mmol, 56%) as

white needles, R_f0.23 (ethyl acetate:light petroleum 1:4), m.p.

20

as a yellow oil, R_f0.35 (ether:light petroleum 1:1), [α]_D+32.4

(c 10.5, DCM) (Found: M⁺+ Na, 273.1469. C₁₅H₂₂O₃Na requires

M, 273.1462); ν_max/cm^-13368, 2962, 2361, 2341, 1514, 1438,

1248, 1178, 1121, 1033 and 885; δ_H(CDCl₃, 400 MHz) 0.88 (6H,

s, 2 × CH₃), 3.04 (1H, br. s, 1-OH), 3.35 and 3.51 (each 1H, d, J

11.0, 1-H), 3.61 (1H, d, J 8.3, 3-H), 3.79 (3H, s, OCH₃), 4.23 and

4,55 (each 1H, d, J 11.5, ArHCH), 5.24 (1H, ddd, J 17.2, 2.2, 0.8,

5-H), 5.36 (1H, ddd, J 10.3, 2.2, 0.8, 5-H'), 5.80 (1H, m, 4-H)

and 6.88 and 7.24 (each 2H, d, J 8.7, ArH); δ_C(CDCl₃, 100

MHz) 19.6, 22.4, 38.4, 55.0, 69.8, 71.0, 87.4, 113.7, 119.4,

129.3, 130.0, 134.9 and 159.0; m/z (ES⁺) 273 (M⁺+ 23, 80%).

20

59.7-63.1 °C; [α]_D+89.3 (c 6.45, CH₂Cl₂) (Found: M⁺+ Na,

273.1093. C₁₄H₁₈O₄Na requires M, 273.1098); ν_max/cm^-13310,

2960, 1780, 1758, 1512, 1247, 1111, 1031, 997, 984, 828 and

813; δ_H(CDCl₃, 400 MHz) 1.08 and 1.12 (each 3H, s, 4-CH₃),

3.72 (1H, s, 3-H), 3.82 (3H, s, OCH₃), 3.86 and 3.99 (each 1H, d,

J 8.7, 5-H), 4.70 and 4.96 (each 1H, d, J 11.8, ArHCH) and 6.90

and 7.31 (each 2H, d, J 8.7, ArH); δ_C(CDCl₃, 100 MHz) 19.3,

23.2, 40.3, 55.2, 72.0, 76.3, 79.9, 113.8, 129.2, 129.7, 159.4 and

175.5; m/z (ES⁺) 273 (M⁺+ 23, 100%).

4.2.4 (3S)-1-tert-Butyldimethylsilyloxy-3-(4-methoxybenzyloxy)-

2,2-dimethylpent-4-ene (15)

The alkenol 14 (2.54 g, 10.2 mmol) in DCM (4.0 mL) was

added to imidazole (1.04 g, 15.3 mmol) and tert-

butyldimethylsilyl chloride (1.53 g, 10.2 mmol) in DCM (11 mL)

at 0 °C. The mixture was allowed to warm to rt, stirred for 5 h

and added to saturated aqueous ammonium chloride (15 mL).

Brine (15 mL) was added, the aqueous phase was extracted with

DCM (2 × 15 mL). The organic extracts were dried (MgSO₄)

then concentrated under reduced pressure. Chromatography of

the residue (ether:light petroleum 1:9) gave the title compound

15 (2.69 g, 7.38 mmol, 73%) as a pale yellow oil, R_f0.64

4.2.2

(2RS,3R)-3-(4-Methoxybenzyloxy)-4,4-

dimethyltetrahydrofuran-2-ol (13)

Di-isobutylaluminium hydride (1 M in hexanes, 6.00 mL, 6.00

mmol) was added over 1 h to the protected (R)-pantolactone 12

(1.0 g, 4.0 mmol) in THF (10 mL) at −78 °C. The solution was

warmed to −37 °C over 1 h then stirred for 4 h and cooled to −78

°C before the cautious addition of methanol (3 mL). The solution

was warmed to 0 °C then added to a cooled mixture of saturated

aqueous sodium potassium tartrate (30 mL) and ether (50 mL).

Further ether (50 mL) was added and the aqueous phase was

extracted into ether (2 × 20 mL). The organic extracts were dried

(MgSO₄) and concentrated under reduced pressure to give the

lactol 13 (0.9 g), as a turbid, pale, yellow oil used without further

purification. For characterisation, chromatography (ether:light

petroleum 1:2) gave the title compound 13¹²(0.49 g, 1.9 mmol,

49%) as a mixture of diastereoisomers, R_f0.22 (ether:light

petroleum 1:1), (Found: M⁺+ Na, 275.1249. C₁₄H₂₀O₄Na

requires M, 275.1254); ν_max/cm^-12938, 2380, 2342, 1614, 1515,

1458, 1249, 1176, 1110, 1034 and 823; δ_H(CDCl₃, 400 MHz)

1.06 and 1.11 (each 3H, s, 4-CH₃), 3.42 (0.6H, d, J 8.1, 5-H),

3.45 (0.6H, d, J 4.3, 3-H), 3.51 (0.4H, d, J 3.1, 3-H), 3.63 (0.4H,

d, J 8.4, 5-H), 3.71 (0.6H, d, J 8.1, 5-H'), 3.81 (1.2H, s, OCH₃),

3.82 (0.4H, d, J 8.4, 5-H'), 3.82 (1.8H, s, OCH₃), 4.09 (0.6H, d, J

10.0, OH), 4.52 (0.4H, d, J 11.6, ArHCH), 4.56 and 4.60 (each

20

(ether:light petroleum 1:7), [α]_D+18.1 (c 6.85, CHCl₃), lit.^12b

20

[α]_D+8.2 (c 4.8, CHCl₃) (Found: M⁺+ H, 365.2508.

C₂₁H₃₇O₃Si requires M, 365.2507); ν_max/cm^-12956, 2930, 2857,

2380, 2342, 1514, 1472, 1248, 1090, 1040 and 837; δ_H(CDCl₃,

400 MHz) 0.10 (6H, s, 2 × SiCH₃), 0.90 and 0.96 (each 3H, s,

CH₃), 0.97 [9H, s, SiC(CH₃)₃], 3.36 and 3.55 (each 1H, d, J 9.2,

1-H), 3.74 (1H, d, J 7.8, 3-H), 3.84 (3H, s, OCH₃), 4.30 and 4.58

(each 1H, d, J 11.4, ArHCH), 5.31 (1H, ddd, J 17.5, 2.2, 0.8, 5-

H), 5.35 (1H, ddd, J 10.3, 2.2, 0.8, 5-H'), 5.86 (1H, m, 4-H) and

6.93 and 7.32 (each 2H, d, J 8.8, ArH); δ_C(CDCl₃, 100 MHz)

−5.6, 18.2, 20.0, 21.1, 25.9, 39.5, 55.1, 69.2, 70.2, 83.9, 113.5,

118.2, 129.0, 131.3, 135.8 and 158.8; m/z (ES⁺) 387 (M⁺+ 23,

100%).

4.2.5 (3S)-3-(4-Methoxybenzyl)oxy-5-tert-butyldimethylsilyloxy-

4,4-dimethylpentan-1-ol (16)

Borane.THF complex (1M in THF, 1.44 mL, 1.44 mmol) was

added dropwise over 30 min to the alkene 15 (0.50 g, 1.4 mmol)

in dry THF (5.3 mL) at 0 °C. The solution was warmed to rt and

stirred for 3 h under nitrogen. Aqueous sodium hydroxide (3M,

6.64 mL) was added cautiously followed by aqueous hydrogen

6

Tetrahedron

peroxide (30%, 6.64 mL) and the mixture stirred for 1 h. Water

(MgSO₄) then concentrated under reduced pressure.

Chromatography of the residue (ether:light petroleum 1:7 to 1:3)

gave the title compound 20 (0.18 g, 0.25 mmol, 67%) as a

colourless gum, R_f0.18 (ether:light petroleum 1:3); [α]_D²⁰−4.0 (c

4.00, CHCl₃) (Found: M⁺+ NH₄, 724.4432. C₄₁H₆₆NO₆Si₂

requires M, 724.4424); ν_max/cm^-13515, 2955, 2929, 2856, 1708,

1613, 1513, 1471, 1428, 1389, 1361, 1301, 1248, 1173, 1105,

1086, 938 and 836; δ_H(CDCl₃, 400 MHz) 0.04 and 0.05 (each

3H, s, SiCH₃), 0.88 (6H, s, 2 × 8-CH₃), 0.92 and 1.04 [each 9H, s,

SiC(CH₃)₃], 1.45-1.65 (2H, m, 6-H₂), 2.53-2.68 (4H, m, 2-H₂and

4-H₂), 3.17 (1H, dd, J 3.5, 1.0, 5-OH), 3.29 and 3.55 (each 1H, d,

J 9.6, 9-H), 3.75 (1H, dd, J 10.3, 2.2, 7-H), 3.79 (3H, s, OCH₃),

3.93 (2H, t, J 6.3, 1-H₂), 4.26 (1H, m, 5-H), 4.63 (2H, s, ArCH₂),

6.87 and 7.29 (each 2H, d, J 8.7, ArH), 7.36-7.47 (6 H, m, ArH)

and 7.63-7.69 (4H, m, ArH); δ_C(CDCl₃, 100 MHz) −5.5, 18.3,

19.1, 20.0, 21.8, 25.9, 26.8, 37.4, 40.4, 46.1, 50.7, 55.3, 59.4,

64.7, 69.6, 74.5, 78.8, 113.7, 127.7, 129.3, 129.7, 131.5, 133.3,

135.5, 159.0 and 211.0; m/z (ES⁺) 729 (M⁺+ 23, 100%).

(100 mL) and ether (100 mL) were added, the aqueous phase was

extracted into ether (3 × 100 mL) and the organic extracts were

washed with water (2 × 100 mL) to neutral pH. Concentration

under reduced pressure and chromatography of the residue

(ether:light petroleum 1:3) gave the title compound 16 (0.32 g,

1

0.84 mmol, 61%) containing 4-methoxybenzyl alcohol (7%, H

NMR) as a colourless oil, R_f0.07 (ether:light petroleum 1:3);

[α]_D−9.2 (c 30.4, CHCl₃), lit.¹³[α]_D−6.1 (c 1.5, DCM)

20

23

(Found: M⁺

+ Na, 405.2431. C₂₁H₃₈O₄SiNa requires M,

405.2432; ν_max/cm^-13339, 2956, 2858, 2361, 1614, 1515, 1472,

1420, 1249, 1092, 1036 and 837; δ_H(CDCl₃, 400 MHz) 0.00 (6H,

s, 2 × SiCH₃), 0.81 and 0.84 (each 3H, s, 4-CH₃), 0.86 [9H, s,

SiC(CH₃)₃], 1.65-1.72 (2H, m, 2-H₂), 1.95 (1H, br. s, 1-OH), 3.21

and 3.50 (each 1H, d, J 9.6, 5-H), 3.58 (1H, dd, J 9.1, 4.0, 3-H),

3.61-3.74 (2H, m, 1-H₂), 3.75 (3H, s, OCH₃), 4.48 and 4.57 (each

1H, d, J 10.5, ArHCH) and 6.83 and 7.23 (each 2H, d, J 8.8,

ArH); δ_C(CDCl₃, 100 MHz) −5.5, 18.3, 20.0, 21.6, 25.9, 33.0,

40.6, 55.3, 61.3, 69.6, 74.3, 80.9, 113.8, 129.4, 131.1 and 159.1;

m/z (ES⁺) 405 (M⁺+ 23, 100%).

4.2.8

(3S,5R,7S)-9-tert-Butyldimethylsilyloxy-7-(4-

methoxybenzyloxy)-1-tert-butyldiphenylsilyloxy-8,8-

4.2.6 (3S)-5-tert-Butyldimethylsilyloxy-3-(4-methoxybenzyloxy)-

4,4-dimethylpentanal (18)

dimethylnonane-3,5-diol (21)

Lithium iodide (0.22 g, 1.6 mmol) was added the ketone 20

(0.23 g, 0.32 mmol) in ether (10.4 mL) and the solution cooled to

−78 °C before the addition of LiAl(O^tBu)₃H (1M in THF, 1.61

mL, 1.61 mmol). After 4 h aqueous hydrogen chloride (10%, 25

mL) was added and the reaction mixture was diluted using ether

(50 mL) and water (50 mL). The aqueous phase was extracted

with ether (3 × 25 mL) and the organic extracts were washed

with water (50 mL) then dried (MgSO₄). After concentration

under reduced pressure, the residue was dissolved in light

petroleum:ether (1:1) and filtered through a plug of silica to

afford the title compound 21 (0.22 g, 0.31 mmol, 96%) as a pale

The alcohol 16 (0.20 g, 0.52 mmol) and triethylamine (0.47

mL, 3.4 mmol) in DCM (2.84 mL) were added dropwise to sulfur

trioxide.pyridine complex (0.27 g, 1.7 mmol) in DMSO/DCM

(1.67 mL, 3:2 v/v) at 0 °C. After warming to rt and stirring for

1.75 h, the mixture was poured into a mixture of saturated

aqueous ammonium chloride (2.5 mL) and ether (2.5 mL). Water

(5 mL) was added and the aqueous phase was extracted into ether

(3 × 5 mL). The organic extracts were washed with brine (10

mL), dried (MgSO₄) and concentrated under reduced pressure.

The residue was dissolved in light petroleum:ether (3:1) and the

solution filtered through a silica plug as quickly as possible to

afford a mixture of the title compound 18¹³(0.16 g, 0.42 mmol,

70%) and 4-methoxybenzaldehyde (9%) as a yellow oil, R_f0.41

(ether:light petroleum 1:3); ν_max/cm^-12955, 2856, 2360, 2341,

1724, 1700, 1616, 1514, 1472, 1249, 1217, 1092, 1036 and 837;

δ_H(CDCl₃, 500 MHz) 0.05 (6H, s, 2 × SiCH₃), 0.86 and 0.89

(each 3H, s, 4-CH₃), 0.91 [9H, s, SiC(CH₃)₃], 2.64 (2H, dd, J 6.0,

2.3, 2-H₂), 3.28 and 3.53 (each 1H, d, J 9.7, 5-H), 3.81 (3H, s,

OCH₃), 3.99 (1H, t, J 6.0, 3-H), 4.52 (2H, s, ArCH₂), 6.87 and

7.24 (each 2H, d, J 8.8, ArH) and 9.81 (1H, t, J 2.3, 1-H); δ_C

(CDCl₃, 100 MHz) −5.5, 18.2, 20.2, 21.4, 25.9, 40.4, 45.6, 55.2,

69.3, 73.3, 77.6, 113.7, 129.2, 130.8, 159.1 and 202.3; m/z (ES⁺)

403 (M⁺+ 23, 100%), 398 (80) and 381 (M⁺+ 1, 30). The

unsaturated aldehyde 17¹³was isolated as a side-product if the

crude product was chromatographed on silica.

20

yellow gum, R_f0.46 (ether:light petroleum 1:1), [α]_D+1.6 (c

10.0, CHCl₃) (Found: M⁺+ H, 709.4319. C₄₁H₆₅O₆Si₂requires M,

-

709.4315; ν_max/cm^-12931, 2361, 2341, 1559, 1250, 1089 and

837; δ_H(CDCl₃, 400 MHz) 0.05 and 0.06 (each 3H, s, SiCH₃),

0.89 and 0.90 (each 3H, s, 8-CH₃), 0.92 and 1.07 [each 9H, s,

SiC(CH₃)₃], 1.50-1.61 (2H, m, 2-H₂), 1.63-1.73 (2H, m, 4-H₂),

1.81-1.93 (2H, m, 6-H₂), 3.18 (1H, d, J 4.5, 5-OH), 3.31 and 3.55

(each 1H, d, J 9.6, 9-H), 3.72-3.76 (2H, m, 7-H and 3-OH), 3.78

(3H, s, OCH₃), 3.85-3.90 (2H, m, 1-H), 4.14 (1H, m, 5-H), 4.26

(1H, m, 3-H), 4.64 (2H, s, ArCH₂), 6.87 and 7.30 (each 2H, d, J

8.7, ArH), 7.38-7.48 (6H, m, ArH) and 7.66-7.71 (4H, m, ArH);

δ_C(CDCl₃, 100 MHz) −5.5, -5.4, 1.0, 15.3, 18.3, 19.0, 20.2, 20.7,

25.9, 26.8, 30.3, 38.1, 40.5, 43.3, 55.2, 63.6, 65.9, 66.4, 69.8,

70.0, 74.2, 79.4, 113.7, 127.8, 129.3, 129.9, 131.6, 132.8 and

135.5; m/z (ES⁺) 731 (M⁺+ 23, 40%) and 709 (M⁺+ 1, 100).

4.2.7

(5S,7S)-9-tert-Butyldimethylsilyloxy-5-hydroxy-7-(4-

4.2.9

(3S,5R,7S)-3,5-Di-O-isopropylidene-9-tert-

methoxybenzyl)oxy-1-tert-butyldiphenylsilyloxy-8,8-

butyldimethylsilyloxy-7-(4-methoxybenzyl)oxy-1-tert-

dimethylnonan-3-one (20)

butyldiphenylsilyloxy-8,8-dimethylnonane (22)

n-Butyllithium (1.6 M in hexanes, 0.77 mL, 1.2 mmol) was

added dropwise to di-isopropylamine (0.18 mL, 1.3 mmol) in dry

THF (2.29 mL) at −30 °C and the solution stirred at 0 °C for 5

min before cooling to −78 °C. The ketone 19 (0.33 g, 1.0 mmol)

in THF (1.46 mL) cooled to −78 °C was added and the reaction

mixture was stirred for 2 h before the addition of a cooled

solution of aldehyde 18 (0.18 g, 0.69 mmol) in THF (0.49 mL).

Toluene p-sulfonic acid monohydrate (4.6 mg, 0.24 mmol)

and 2,2-dimethoxypropane (17 mL) were added to the diol 21

(0.71 g, 1.0 mmol) in DCM (17 mL) and the reaction mixture

was stirred at rt for 2 h. Potassium carbonate (0.29 g) in water

(35 mL) was added and the solution stirred for 5 min. The

aqueous phase was extracted into DCM (3 × 50 mL) and the

organic extracts were washed with brine (200 mL), dried

(MgSO₄) and concentrated under reduced pressure to give the

title compound 22 (0.76 g, 1.0 mmol, ca. 100%) as a pale yellow

gum which was used without further purification, R_f0.93

o

The reaction mixture was stirred for 2.5 h at −78 C, then a

cooled solution of acetic acid in ether (10% v/v, 1.47 mL) was

added and the solution stirred overnight at rt. The reaction

mixture was poured into saturated aqueous sodium bicarbonate (9

mL) and ethyl acetate (20 mL) was added. The aqueous phase

was extracted into ethyl acetate (3 × 20 mL) and the organic

extracts were washed to neutral pH with water (3 × 20 mL), dried

20

(ether:light petroleum 1:1); [α]_D−10.5 (c 8.0, CHCl₃) (Found:

M⁺− C₃H₃, 709.4304. C₄₁H₆₅O₆Si₂requires M, 709.4315); ν_max

/cm^-12954, 2930, 2856, 1514, 1471, 1428, 1378, 1247, 1221,

1091, 1038 and 835; δ_H(CDCl₃, 400 MHz) 0.04 and 0.05 (each

7

3H, s, SiCH₃), 0.87 and 0.89 (each 3H, s, 8-CH₃), 0.92 and 1.05

[each 9H, s, SiC(CH₃)₃], 1.36 and 1.38 [each 3H, s, O(O)CCH₃],

1.50-1.61 (2H, m, 6-H₂), 1.63-1.68 (2H, m, 4-H₂), 1.69-1.80 (2H,

m, 2-H₂), 3.28 and 3.52 (each 1H, d, J 9.5, 9-H), 3.65 (1H, dd, J

10.1, 1.8, 7-H), 3.69 (1H, dd, J 10.1, 5.0, 1-H), 3.78 (1H, m, 1-

H'), 3.80 (3H, s, OCH₃), 4.03-4.15 (2H, m, 3-H and 5-H), 4.56

and 4.60 (each 1H, d, J 10.8, ArHCH), 6.87 and 7.27 (each 2H,

d, J 8.8, ArH), 7.35-7.46 (6H, m, ArH) and 7.64-7.70 (4H, m,

ArH); δ_C(CDCl₃, 100 MHz) −5.5, −5.4, 18.2, 19.2, 20.1, 21.8,

25.3, 25.5, 25.9, 26.7, 26.8, 34.2, 38.1, 38.9, 39.0, 40.5, 55.2,

60.0, 63.3, 69.6, 74.2, 79.0, 100.1, 113.7, 127.4, 127.6, 127.6,

128.8, 129.5, 131.6, 133.9, 134.9, 135.5, 135.5 and 158.9; m/z

(ES⁺) 709 (M⁺− 39, 40%) and 121 (100).

O(O)CCH₃], 1.40-1.70 (6H, m, 4-H₂, 6-H₂and 8-H₂), 3.62 (1H,

m, 7-H), 3.67-3.72 (2H, m, 9-H₂), 3.72 (3H, s, OCH₃), 3.93-4.08

(2H, m, 3-H and 5-H), 4.40 and 4.49 (each 1H, d, J 10.5,

ArHCH), 6.77 and 7.15 (each 2H, d, J 8.7, ArH), 7.24-7.38 (6H,

m, ArH), 7.52-7.63 (4H, m, ArH) and 9.52 (1H, s, 1-H); δ_C

(CDCl₃, 100 MHz) 17.5, 19.2, 25.2, 25.5, 26.9, 30.3, 31.0, 38.4,

38.8, 51.1, 55.3, 60.0, 63.3(2), 74.2, 79.2, 100.3, 113.7, 113.8,

127.6, 127.8, 129.0, 129.1, 129.6, 130.5, 133.9, 135.6, 159.2 and

206.1; m/z (ES⁺) 655 (M⁺+ 23, 95%) and 615 (100).

n-Butyllithium (1.6 M in hexanes, 0.58 mL, 0.93 mmol) was

added to dimethyl methylphosphonate (0.11 mL, 1.0 mmol) in

THF (1.39 mL) at −78 °C and the solution stirred for 1 h. The

aldehyde 24 (from 0.33 g, 0.52 mmol of alcohol 23) in THF (1.42

mL) was added dropwise and the solution stirrred for 2 h.

Saturated methanolic ammonium chloride (20 mL) was added

and the mixture warmed to rt then poured into a mixture of water

(30 mL) and ethyl acetate (30 mL). The aqueous phase was

extracted into ethyl acetate (4 × 20 mL) and the organic extracts

were washed with brine (100 mL), dried (MgSO₄) and

concentrated under reduced pressure to give the

hydroxydecanylphosphonate 25 as a pale yellow gum, as a

mixture of diastereoisomers, which was used without further

purification, R_f0.15 (ether) (Found: M⁺+ H, 757.3860.

C₄₁H₆₂O₉PSi requires M, 757.3896) m/z (ES⁺) 779 (M⁺+ 23,

100%).

Dess-Martin periodinane (0.44 g, 1.0 mmol) was stirred in dry

DCM (5.0 mL) and pyridine (0.77 mL, 9.5 mmol) at rt for 30

min. The hydroxydecanylphosphonate 25 (from 0.33 g, 0.52

mmol, of alcohol 23) in DCM (16 mL) was added and the

mixture stirred for 2 h then poured into saturated aqueous sodium

bicarbonate (25 mL). The organic layer was washed with

saturated aqueous sodium thiosulfate (25 mL) and the aqueous

extracts were extracted into DCM (4 × 50 mL). The organic

extracts were washed with brine (50 mL), dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

residue (ethyl acetate:light petroleum 1:10 to neat ethyl acetate)

gave the title compound 10 (0.29 g, 0.39 mmol, 76% from 23) as

4.2.10

(3S,5R,7S)-5,7-Di-O-isopropylidene-3-(4-

methoxybenzyloxy)-9-tert-butyldiphenylsilyloxy-2,2-

dimethylnonan-1-ol (23)

Trimethylsilyl triflate (0.03 mL, 0.17 mmol) was added to the

acetonide 22 (62 mg, 0.083 mmol) in DCM (0.62 mL) at −78 °C

and the solution stirred for 30 min. Methanol (0.62 mL) was

added slowly and the mixture was stirred for

5 min.

Triethylamine (0.046 mL, 0.33 mmol) was added and, after 20

min, the mixture was warmed to rt and poured into saturated

aqueous sodium bicarbonate (5 mL). Water (5 mL) and ethyl

acetate (10 mL) were added and the aqueous phase was extracted

into ethyl acetate (3 × 10 mL). The organic extracts were washed

with brine (40 mL), and the aqueous wash extracted with ether (2

× 40 mL). The organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography of the

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

material 22 (30 mg, 48%) followed by the title compound 23 (27

mg, 0.043 mmol, 51%) as a pale yellow gum, R_f0.10 (ether:light

20

petroleum 1:3), [α]_D−5.6 (c 10.0, CHCl₃) (Found: M⁺+ Na,

657.3578. C₃₈H₅₄O₆SiNa requires M, 657.3582); ν_max/cm^-12954,

2933, 2858, 1613, 1514, 1248, 1224, 1111, 1037 and 823; δ_H

(CDCl₃, 400 MHz) 0.93 and 1.01 (each 3H, s, 2-CH₃), 1.06 [9H,

s, SiC(CH₃)₃], 1.36 and 1.37 [each 3H, s, O(O)CCH₃], 1.51-1.63

(2H, m, 4-H₂), 1.64-1.70 (2H, m, 6-H₂), 1.71-1.83 (2H, m, 8-H₂),

2.93 (1H, t, J 5.7, 1-OH), 3.39 (1H, dd, J 11.1, 5.7, 1-H), 3.52

(1H, m, 1-H'), 3.56 (1H, m, 3-H), 3.71 and 3.78 (each 1H, m, 9-

H), 3.80 (3H, s, OCH₃), 3.99-4.15 (2H, m, 5-H and 7-H), 4.55

and 4.60 (each 1H, d, J 10.7, ArHCH), 6.88 and 7.27 (each 2H,

d, J 8.7, ArH), 7.36-7.47 (6H, m, ArH) and 7.65-7.71 (4H, m,

ArH); δ_C(CDCl₃, 100 MHz) 21.6, 21.9, 25.1, 25.4, 26.8, 38.2,

38.8, 38.9, 39.6, 55.3, 59.9, 63.3, 64.6, 70.4, 74.1, 82.6, 100.3,

113.8, 127.6, 129.0, 129.6, 130.6, 133.8(2), 135.5 and 159.1; m/z

(ES⁺) 657 (M⁺+ 23, 10%) and 121 (100).

20

a pale yellow gum, R_f0.60 (ethyl acetate), [α]_D−3.9 (c 5.30,

CH₂Cl₂) (Found: M⁺+ H, 755.3741. C₄₁H₆₀O₉PSi requires M,

755.3739); ν_max/cm^-12955, 2856, 1702, 1514, 1466, 1428, 1380,

1250, 1224, 1112, 1070, 1033 and 823; δ_H(CDCl₃, 400 MHz)

1.05 [9H, s, SiC(CH₃)₃], 1.18 and 1.23 (each 3H, s, 3-CH₃), 1.35

and 1.37 [each 3H, s, O(O)CCH₃], 1.48-1.56 (2H, m, 9-H₂), 1.57-

1.72 (2H, m, 7-H₂), 1.73-1.79 (2H, m, 5-H₂), 3.23 and 3.28 (each

1H, dd, J 31.4_P-H, 15.9, 1-H), 3.69 (1H, m, 4-H), 3.75-3.83 [11H,

m, 10-H₂, P(O)(OCH₃)₂, OCH₃], 3.97-4.12 (2H, m, 6-H and 8-H),

4.49 and 4.60 (each 1H, d, J 10.7, ArHCH), 6.87 and 7.23 (each

2H, d, J 8.8, ArH), 7.36-7.46 (6H, m, ArH) and 7.64-7.69 (4H,

m, ArH); δ_C(CDCl₃, 100 MHz) 19.2, 20.7, 21.0, 25.1, 25.4, 26.8,

30.3, 37.1 (d, J_C-P138.0), 38.8, 38.9, 52.8 (d, J_C-P6.5), 53.6 (d, J_C-

4.2.11 Dimethyl (4S,6R,8S)-10-tert-butyldiphenylsilyloxy-6,8-di-

O-isopropylidene-4-(4-methoxybenzyloxy)-3,3-dimethyl-2-

oxodec-1-yl phosphonate (10)

3.7), 55.3, 59.9, 63.2, 63.4, 74.5, 80.8, 113.8, 127.6(2), 128.9,

P

Dimethyl sulfoxide (0.11 mL, 1.6 mmol) in DCM (1.12 mL)

was added to oxalyl chloride (0.074 mL, 0.88 mmol) in DCM

(1.12 mL) at −78 °C and the solution stirrred for 20 min. The

alcohol 23 (0.33 g, 0.52 mmol) in DCM (1.19 mL) was added

dropwise and the solution was stirred for 20 min. Triethylamine

(0.43 mL, 3.09 mmol) was slowly added and, after 20 min, the

mixture was warmed to rt. The reaction mixture was poured into

saturated aqueous ammonium chloride (10 mL) and ether (10

mL). The aqueous phase was extracted with ether (3 × 10 mL)

and ethyl acetate (2 × 10 mL). The organic extracts were washed

with brine (60 mL), dried (MgSO₄) and concentrated under

reduced pressure to give the aldehyde 24 a pale yellow gum

which was used without further purification, R_f0.25 (ether:light

petroleum 1:6); δ_H(CDCl₃, 400 MHz) 0.95 [9H, s, SiC(CH₃)₃],

0.96 and 1.04 (each 3H, s, 2-CH₃), 1.26 and 1.27 [each 3H, s,

129.5, 129.6, 130.5, 133.9(2), 135.5, 159.1 and 207.1 (d, J_C-P

7.4); m/z (ES⁺) 777 (M⁺+ 23, 100%).

4.2.12 (2R,6E,10S,12R,14S)-16-tert-Butyldiphenylsilyloxy-1,10-bis-

(4-methoxybenzyloxy)-9,9-dimethyl-12,14-di-O-isopropylidene-2-

triethylsilyloxy-4-[(Z)-2-tri-isopropylsilyloxyethylidene]hexadec-6-

en-8-one (8)

The ketophosphonate 10 (0.12 g, 0.16 mmol) in THF (1.3 mL)

was added to a well-stirred suspension of Ba(OH)₂(29 mg, 0.17

mmol) in THF (0.73 mL) and the mixture stirred for 2 h at rt. The

aldehyde 9 (96 mg, 0.17 mmol) in THF (2.03 mL) and water (52

µL) was added and the mixture stirred for 16 h then filtered

through Celite^®with DCM (30 mL). The filtrate was washed

with saturated aqueous sodium hydrogen carbonate (30 mL) and

the aqueous phase extracted into DCM (2 × 30 mL). The organic

8

Tetrahedron

extracts were washed with brine (90 mL), dried (MgSO₄) and

[33H, m, 3 × SiCH(CH₃)₂, Si(C(CH₃)₃and 3-CH₃), 1.13 (3H, s,

3-CH₃'), 1.26 and 1.29 [each 3H, s, O(O)CCH₃], 1.35-1.54 (4H,

m, 5-H₂and 7-H₂), 1.58-1.68 (2H, m, 9-H₂), 1.74 (1H, t, J 12.6,

5'-H_ax), 1.83 (1H, t, J 12.0, 3'-H_ax), 2.14 (1H, d, J 13.4, 3'-H_eq),

2.38 (1H, d, J 13.4, 5'-H_eq), 2.50 (1H, dd, J 17.7, 6.6, 1-H), 2.93

(1H, dd, J 17.7, 5.8, 1-H'), 3.32 (1H, dd, J 10.1, 4.3, 6'-CH), 3.37

(1H, dd, J 10.1, 5.3, 6'-CH'), 3.43 (1H, m, 6'-H), 3.60 (1H, m, 10-

H), 3.66-3.75 (7H, m, 10-H' and 2 × OCH₃), 3.80 (1H, m, 2'-H),

3.86 (1H, d, J 8.3, 4-H), 3.88-4.03 (2H, m, 6-H and 8-H), 4.18

(2H, d, J 6.3, 2''-H₂), 4.38 (2H, s, ArCH₂), 4.41 and 4.48 (each

1H, d, J 10.7, ArHCH), 5.35 (1H, t, J 6.3, 1''-H), 6.74-6.81 and

7.10-7.18 (each 4H, m, ArH), 7.27- 7.37 (6H, m, ArH) and 7.55-

7.62 (4H, m, ArH); δ_C(CDCl₃, 75 MHz) 12.0, 18.0, 19.2, 20.4,

20.8, 25.2, 25.4, 26.9, 30.3, 38.9, 45.0, 52.8, 55.3, 59.4, 60.0,

63.3, 63.5, 72.8, 73.0, 74.6, 80.2, 100.3, 113.8(2), 124.5, 127.6,

128.8, 129.3, 129.6, 130.4, 130.9, 133.9, 134.8, 135.6, 159.1,

159.2, 181.3 and 212.7; m/z (ES⁺) 1102 (M⁺+ 23, 100%). A

concentrated under reduced pressure to give the enone 8 as

colourless oil that was usually used without further purification.

In this case, for characterisation, chromatography of the residue

(ethyl acetate:light petroleum 1:20 to 1:10) gave the title

compound 8 (76 mg, 0.064 mmol, 42%) as a colourless oil, R_f

20

0.60 (ethyl acetate:light petroleum 1:5), [α]_D−3.0 (c 8.0,

CHCl₃) (Found: M⁺+ H, 1193.7379. C₇₀H₁₀₉O₁₀Si₃requires M,

1193.7324); ν_max/cm^-12948, 2865, 2361, 1683, 1614, 1513,

1463, 1428, 1382, 1365, 1302, 1248, 1222, 1172, 1111, 1039,

1012, 882 and 821; δ_H(CDCl₃, 400 MHz) 0.56 (6H, q, J 7.8, 3 ×

SiCH₂CH₃), 0.92 (9H, t, J 7.8, 3 × SiCH₂CH₃), 1.01-1.07 [30H,

m, 3 × SiCH(CH₃)₂, SiC(CH₃)₃], 1.13 and 1.20 (each 3H, s, 9-

CH₃), 1.36 and 1.38 [each 3H, s, 2 × O(O)CCH₃], 1.40-1.61 (4H,

m, 11-H₂and 13-H₂), 1.65-1.77 (2H, m, 15-H₂), 2.17 (1H, dd, J

13.5, 7.3, 3-H), 2.32 (1H, dd, J 13.5, 5.3, 3-H'), 2.94 (2H, d, J

7.1, 5-H₂), 3.26-3.35 (2H, m, 1-H₂), 3.68 (1H, m, 16-H), 3.74-

3.83 (7H, m, 16-H' and 2 × OCH₃), 3.86 (1H, dd, J 7.0, 5.3, 2-H),

3.92 (1H, dd, J 6.0, 5.8, 10-H), 4.01-4.11 (2H, m, 12-H and 14-

H), 4.23 (1H, dd, J 13.1, 5.8, 2'-H), 4.29 (1H, dd, J 13.1, 6.3, 2'-

H'), 4.44 (2H, s, ArCH₂), 4.47 and 4.52 (each 1H, d, J 10.6,

ArHCH), 5.45 (1H, t, J 5.8, 1'-H), 6.59 (1H, d, J 15.1,7-H), 6.82-

6.89 (4H, m, 4 × ArH), 6.93 (1H, dt, J 15.1, 3.1, 6-H), 7.18-7.26

(4H, m, 4 × ArH), 7.35-7.45 (6H, m, ArH) and 7.63-7.69 (4H, m,

ArH); δ_C(CDCl₃, 100 MHz) 4.9, 6.9, 11.8, 12.0, 17.9, 18.0, 19.2,

20.5, 25.2, 25.5, 26.8, 38.8, 51.3, 55.2, 60.0, 60.3, 63.2, 63.3,

70.8, 72.9, 74.4, 77.2, 80.1, 100.2, 113.6, 113.7, 127.0, 127.6(2),

128.9, 129.2, 129.5, 130.1, 133.8, 134.0, 135.5(2), 144.6, 159.0,

159.1 and 203.3; m/z (ES⁺) 1211 (M⁺+ 19, 100%) and 1210 (M⁺

+ 18, 90%).

second

fraction

contained

the

2,6-trans-disubstituted

tetrahydropyran 28 (54 mg, 11%), R_f0.05 (ether:light petroleum

1:5); δ_H(CDCl₃, 400 MHz) 0.95-1.06 [33H, m, 3 × SiCH(CH₃)₂,

Si(C(CH₃)₃and 3-CH₃), 1.10 (3H, s, 3-CH₃'), 1.27 and 1.30 [each

3H, s, O(O)CCH₃], 1.35-1.53 (4H, m, 5-H₂and 7-H₂), 1.58-1.70

(2H, m, 9-H₂), 1.85 (1H, m, 5'-H), 2.01 (1H, m, 3'-H), 2.22-2.38

(2H, d, 3'-H' and 5'-H'), 2.71 (1H, dd, J 17.7, 6.6, 1-H), 2.78 (1H,

dd, J 17.7, 5.8, 1-H'), 3.34 (1H, dd, J 10.0, 4.4, 6'-CH), 3.41 (2H,

m, 6'-H and 6'-CH'), 3.56 and 3.65 (each 1H, m 10-H), 3.65 and

3.68 (each 3H, s, OCH₃), 3.75-3.85 (2H, m, 2'-H and 4-H), 3.90-

4.05 (2H, m, 6-H and 8-H), 4.10-4.22 (2H, m, 2''-H₂), 4.35-4.50

(4H, m, 2 × ArCH₂), 5.34 (1H, t, J 6.5, 1''-H), 6.74-6.80 and

7.10-7.18 (each 4H, m, ArH), 7.27- 7.38 (6H, m, ArH) and 7.55-

7.62 (4H, m, ArH); m/z (ES⁺) 1102 (M⁺+ 23, 100%).

4.2.13 (2R,6E,10S,12R,14S)-16-tert-Butyldiphenylsilyloxy-1,10-bis-

(4-methoxybenzyloxy)-9,9-dimethyl-2-hydroxy-12,14-di-O-

isopropylidene-4-[(Z)-2-tri-isopropylsilyloxyethylidene]hexadec-6-

en-8-one (26)

4.2.15

Dimethyl

(4S,6R,8S)-10-Hydroxy-6,8-di-O-

isopropylidene-4-(4-methoxybenzyloxy)-3,3-dimethyl-2-

oxododec-1-yl phosphonate (29)

Hydrogen fluoride.pyridine complex (70% HF, 0.49 mL) was

added to the enone 8 (from 0.17 mmol aldehyde 9) in THF (10.0

mL) and pyridine (0.97 mL) at 0 °C and the solution stirred for

exactly 30 min. Saturated aqueous sodium hydrogen carbonate

(40 mL) was added and the mixture was stirred at rt for 1 h.

Diethyl ether (40 mL) was added and the aqueous phase was

extracted into ether (2 × 40 mL). The organic extracts were

washed with brine (100 mL) then dried (MgSO₄) and

concentrated under reduced pressure to give the title compound

26 (0.36 g) as an oil that was used without further purification, R_f

0.17 (ethyl acetate:light petroleum 1:5).

Tetra-n-butylammonium fluoride (1 M in THF, 0.22 mmol,

0.22 mL) was added to the ketophosphonate (10) (0.14 g, 0.18

mmol) in THF (5.15 mL) at rt and the solution stirred for 16 h.

Saturated aqueous sodium hydrogen carbonate (10 mL) and ethyl

acetate (10 mL) were added and the aqueous phase was extracted

into ethyl acetate (3 × 10 mL). The organic extracts were washed

with brine (40 mL), dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue (ethyl

acetate:light petroleum 1:3 to neat ethyl acetate) gave the title

compound 29 (74 mg, 0.14 mmol, 78%) as a pale orange oil, R_f

20

0.05 (ethyl acetate), [α]_D−8.4 (c 50.0, CH₂Cl₂) (Found: M⁺+

Na, 539.2375. C₂₅H₄₁O₉PNa requires M 539.2381); ν_max/cm^-1

3429, 2984, 2938, 1703, 1612, 1514, 1465, 1379, 1246, 1224,

1173 and 1029; δ_H(CDCl₃, 400 MHz) 1.17 and 1.20 (each 3H, s,

3-CH₃), 1.25 (1H, m, 7-H), 1.37 [6H, s, 2 × O(O)CCH₃], 1.47-

1.58 (3H, m, 9-H₂and 7-H'), 1.65-1.77 (2H, m, 5-H₂), 2.56 (1H,

br. s, 10-OH), 3.21 (1H, dd, J 37.6_P-H, 15.9, 1-H), 3.26 (1H, dd, J

36.8_P-H, 15.9, 1-H'), 3.70-3.81 [12H, m, 4-H, 10-H₂, P(O)(OCH₃)₂

and OCH₃), 3.98-4.08 (2H, m, 6-H and 8-H), 4.49 and 4,58 (each

1H, d, J 10.8, ArHCH) and 6.87 and 7.23 (each 2H, d, J 8.7,

ArH); δ_C(CDCl₃, 100 MHz) 20.8, 21.0, 25.2, 25.4, 37.1 (d, J_C-P

139.0), 37.6, 38.4, 38.9, 52.8 (d, J_C-P6.5), 52.9 (d, J_C-P6.5), 53.6,

55.2, 61.0, 63.5, 66.6, 74.6, 80.7, 100.4, 113.8, 128.8, 130.4,

159.1 and 207.1 (d, J_C-P7.4); m/z (ES⁺) 539 (M⁺+ 23, 100%).

4.2.14

(4S,6R,8S)-4-(4-Methoxybenzyloxy)-10-tert-

butyldiphenylsilyloxy-1-{(2S,6R)-

isopropylsilyloxyethylidene]-6-(4-

and

-{(2R,6R)-4-[(Z)-2-tri-

methoxybenzyloxymethyl)tetrahydropyran-2-yl}-6,8-di-O-

isopropylidene-3,3-dimethyldecan-2-one (27) and (28).

Potassium tert-butoxide (1 M in THF, 0.082 mmol, 82 µL)

was added to the alcohol 26 (from 0.45 mmol of phosphonate 10)

in THF (1.90 mL) and the solution stirred for exactly 5 min at rt.

Saturated aqueous ammonium chloride (10 mL) was added

followed by ether (10 mL). The aqueous phase was extracted into

ether (2 × 10 mL) and the organic extracts were washed with

water (10 mL) and brine (10 mL) then dried (MgSO₄). After

concentration under reduced pressure, chromatography of the

residue (ether:light petroleum 1:10 to 1:5) gave the title

compound 27 (60 mg, 12%) as a colourless oil, R_f0.10

4.2.16

(2R,6E,10S,12R,14S)-16-Hydroxy-1,10-bis-(4-

methoxybenzyloxy)-9,9-dimethyl-12,14-di-O-isopropylidene-2-

triethylsilyloxy-4-[(Z)-2-tri-isopropylsilyloxyethylidene]hexadec-6-

en-8-one (30)

Phosphonate 29 (0.11 g, 0.20 mmol) in THF (1.3 mL) was

added to a well-stirred suspension of Ba(OH)₂(38 mg, 0.22

20

(ether:light petroleum 1:5), [α]_D−3.4 (c 3.5, CH₂Cl₂) (Found:

M⁺+ Na, 1101.6267. C₆₄H₉₄O₁₀Si₂Na requires M, 1101.6278;

ν_max/cm^-12941, 2864, 1705, 1613, 1514, 1463, 1379, 1364, 1248,

1172, 1111, 1037 and 823; δ_H(CDCl₃, 400 MHz) 0.93-1.06

9

mmol) in THF (0.94 mL) and the mixture stirred for 2 h at rt. The

aldehyde 9 (0.12 g, 0.22 mmol) in THF (2.7 mL) and water (0.07

mL) was added and the mixture stirred for 16 h at rt then filtered

through Celite^®using DCM (50 mL). The filtrate was washed

with saturated aqueous sodium hydrogen carbonate (30 mL) and

the aqueous washings extracted with DCM (3 × 30 mL). The

organic extracts were washed with brine (90 mL), dried (MgSO₄)

and concentrated under reduced pressure to give the enone 30 as

a yellow oil that was usually used without further purification. In

this case, chromatography of the residue (ethyl acetate:light

petroleum 1:5 with 1% NEt₃) gave the title compound 30 (0.13 g,

0.13 mmol, 66%) as a colourless oil, R_f0.29 (ethyl acetate:light

858.5547); ν_max/cm^-13437, 2939, 2864, 1703, 1613, 1513,

1464, 1380, 1366, 1247, 1224, 1172, 1096, 1060, 1036, 907 and

821; δ_H(CDCl₃, 400 MHz) 1.01-1.09 [21H, m, 3 × SiCH(CH₃)₂],

1.09 and 1.21 (each 3H, s, 3-CH₃), 1.38 [6H, s, 2 × O(O)CCH₃],

1.39-1.59 (4H, m, 5-H₂and 7-H₂), 1.66-1.76 (2H, m, 9-H₂), 1.81

(1H, t, J 12.5, 5'-H_ax), 1.91 (1H, t, J 12.5, 3'-H_ax), 2.21 (1H, d, J

13.5, 3'-H_eq), 2.45 (1H, d, J 13.5, 5'-H_eq), 2.50 (1H, br. s, 1-OH),

2.58 (1H, dd, J 17.5, 6.3, 1-H), 3.00 (1H, dd, J 17.5, 5.8, 1-H'),

3.37-3.45 (2H, m, 6'-CH₂), 3.50 (1H, m, 6'-H), 3.71-3.78 (2H, m,

10-H₂), 3.80 and 3.81 (each 3H, s, OCH₃), 3.87 (1H, m, 2'-H),

3.93 (1H, d, J 9.8, 4-H), 3.99-4.10 (2H, m, 6-H and 8-H), 4.26

(2H, d, J 6.2, 2''-H₂), 4.47 (2H, s, ArCH₂), 4.51 and 4.56 (each

1H, d, J 10.8, ArHCH), 5.42 (1H, t, J 6.2, 1''-H) and 6.87 and

7.24 (each 4H, d, J 8.6, 4 × ArH); δ_C(CDCl₃, 125 MHz) 11.9,

17.9, 20.1, 20.9, 25.2, 25.2, 31.4, 37.5, 38.4, 39.0, 41.3, 44.9,

52.7, 55.1, 55.2, 59.3, 61.0, 63.4, 66.6, 72.7, 72.8, 74.3, 74.5,

76.5, 80.1, 100.3, 113.7, 124.4, 128.7, 129.2, 130.2, 130.7, 134.6,

159.0, 159.1 and 212.5; m/z (ES⁺) 858 (M⁺+ 18, 100%).

20

petroleum 1:1), [α]_D+4.0 (c 12.0, CH₂Cl₂) (Found: M⁺+ Na,

977.5957. C₅₄H₉₀O₁₀Si₂Na requires M, 977.5965); ν_max/cm^-1

2941, 2866, 1685, 1613, 1513, 1463, 1379, 1366, 1246, 1224,

1172, 1092, 1059, 1036 and 1012; δ_H(CDCl₃, 400 MHz) 0.56

(6H, q, J 7.8, 3 × SiCH₂CH₃), 0.92 (9H, t, J 7.8, 3 × SiCH₂CH₃),

1.01-1.09 [21H, m, 3 × SiCH(CH₃)₂, 1.12 and 1.20 (each 3H, s,

9-CH₃], 1.39 [6H, s, 2 × O(O)CCH₃], 1.49-1.58 (4H, m, 11-H₂

and 13-H₂), 1.66-1.77 (2H, m, 15-H₂), 2.09 (1H, dd, J 13.9, 7.8,

3-H), 2.24 (1H, dd, J 13.9, 8.6, 3-H'), 2.43 (1H, br. s, 1-OH), 2.86

(2H, d, J 7.0, 5-H₂), 3.21 (1H, dd, J 9.7, 6.0, 1-H), 3.25 (1H, dd, J

9.7, 4.3, 1-H'), 3.65-3.70 (2H, m, 16-H₂), 3.72 and 3.73 (each 3H,

s, OCH₃), 3.79 (1H, m, 2-H), 3.83 (1H, m, 12-H), 3.92-4.04 (2H,

m, 10-H and 14-H), 4.15 (1H, dd, J 13.0, 5.6, 2'-H), 4.22 (1H, dd,

J 13.0, 6.0, 2'-H'), 4.36 and 4.43 (each 2H, s, ArCH₂), 5.37 (1H, t,

J 6.0, 1'-H), 6.50 (1H, d, J 15.1, 7-H), 6.76-6.81 (4H, m, 4 ×

ArH), 6.85 (1H, m, 6-H) and 7.10-7.18 (4H, m, 4 × ArH); δ_C

(CDCl₃, 75 MHz) 4.9, 6.9, 12.0, 18.0, 20.9, 25.3, 25.4, 36.3,

37.6, 38.5, 38.8, 40.7, 51.4, 55.3, 60.3, 61.3, 63.4, 66.9, 70.8,

72.9, 73.0, 74.0, 74.5, 80.1, 100.4, 113.7, 113.8, 126.9, 128.9(2),

129.2, 130.1, 130.4, 130.8, 134.0, 144.7, 159.1 and 203.2; m/z

(ES⁺) 978 (M⁺+ 23, 100%).

4.2.19

Prop-2-enyl

(3R,5R,7S,11S,15R)-7,16-bis-(4-

methoxybenzyloxy)-3,5-di-O-isopropylidene-11,15-epoxy-8,8-

dimethyl-13-[(Z)-2-triisopropylsilyloxyethylidene]hexadecanoate

(7)

The alcohol 32 (95 mg, 0.11 mmol) in DCM (2.0 mL) was

added to the Dess-Martin periodinane (72 mg, 0.17 mmol) in

DCM (2.6 mL) and pyridine (0.14 mL) and the solution stirred

for 1.5 h. Saturated aqueous sodium bicarbonate (10 mL) was

added followed by saturated aqueous sodium thiosulfate (10 mL)

and ether (20 mL). The aqueous phase was extracted into ether (3

× 20 mL) and the organic extracts were washed with brine (100

mL), dried (MgSO₄) and concentrated under reduced pressure to

give the corresponding aldehyde (98 mg) as a pale yellow oil, R_f

0.31 (ethyl acetate:light petroleum 3:7).

tert-Butanol (2.0 mL) and 2-methyl-2-butene (2 M in THF,

0.26 mmol, 0.13 mL) was added to this aldehyde followed by

sodium chlorite (70 mg, 0.77 mmol) and sodium dihydrogen

phosphate monohydrate (NaH₂PO₄.H₂O, 0.20 g, 1.3 mmol) in

water (1 mL). The mixture was stirred for 1 h before brine (20

mL) and ethyl acetate (20 mL) were added. The aqueous phase

was extracted into ethyl acetate (3 × 20 mL) and the organic

extracts were washed with brine (60 mL), dried (MgSO₄) and

concentrated under reduced pressure to give the corresponding

carboxylic acid (103 mg) as a yellow oil. This was taken up in

benzene and the solution concentrated under reduced pressure to

remove any water as its benzene azeotrope before use, R_f0.11

(ethyl acetate:light petroleum 30:70); m/z (ES⁺) 877 (M⁺+ 23,

100%).

N,N-Dimethylformamide (0.40 mL), sodium bicarbonate (43

mg, 0.52 mmol) and freshly distilled allyl bromide (33 µL, 0.39

mmol) were added to the carboxylic acid and the mixture heated

under reflux for 16 h. Saturated aqueous ammonium chloride (10

mL) and ether (10 mL) were added and the aqueous phase

extracted into ether (3 × 10 mL). The organic extracts were

washed with brine (40 mL), dried (MgSO₄) and concntrated

under reduced pressure. Chromatography of the residue (ethyl

acetate:light petroleum 1:20 to 1:10 with 1% NEt₃) gave the title

4.2.17

(2R,6E,10S,12R,14S)-16-Hydroxy-1,10-bis-(4-

methoxybenzyloxy)-9,9-dimethyl-2-hydroxy-12,14-di-O-

isopropylidene-4-[(Z)-2-tri-isopropylsilyloxyethylidene]hexadec-6-

en-8-one (31)

Cooled pyridine (0.92 mL) and cooled HF.pyridine complex

(70%, 0.47 mL) were added to the enone 30 (from 0.38 mmol of

phosphonate 29) in THF (9.2 mL) at 0 °C and the mixture stirred

for exactly 25 min. Saturated aqueous sodium hydrogen

carbonate (30 mL) was added and the mixture was stirred at rt for

1 h. Ether (30 mL) was added and the aqueous phase was

extracted into ether (3 × 30 mL). The organic extracts were

washed with brine (100 mL), dried (MgSO₄) and concentrated

under reduced pressure to give the diol 31 a pale yellow oil (0.32

g) that was used without purification, R_f0.15 (ethyl acetate:light

petroleum 1:1).

4.2.18 (4S,6R,8S)-10-Hydroxy-4-(4-Methoxybenzyloxy)-1-{(2S,6R)-

4-[(Z)-2-tri-isopropylsilyloxyethylidene]-6-(4-

methoxybenzyloxymethyl)tetrahydropyran-2-yl}-6,8-di-O-

isopropylidene-3,3-dimethyldecan-2-one (32)

Potassium tert-butoxide (1 M in THF, 0.09 mmol, 0.09 mL)

was added to the diol 31 (from 0.34 mmol of phosphonate 29) in

THF (2.0 mL) and the deep-red solution stirred for exactly 10

min. Saturated aqueous ammonium chloride (30 mL) and ether

(30 mL) were added and the aqueous phase extracted into ether

(3 × 30 mL). The organic extracts were washed with brine (100

mL), dried (MgSO₄) and concentrated under reduced pressure.

Chromatography of the residue (ethyl acetate:light petroleum

1:20 to 1:10 with 1% NEt₃) gave the title compound 32 (0.13 g,

0.16 mmol, 45% from phosphonate 29) as a colourless oil, R_f

compound 7 (61 mg, 0.068 mmol, 60% from alcohol 32) as a

20

colourless oil, R_f0.38 (ethyl acetate:light petroleum 3:7), [α]_D

+

+1.5 (c 8.0, CH₂Cl₂) (Found: M+ + Na, 917.5200.

C₅₁H₇₈O₁₁SiNa requires M, 917.5206); ν_max/cm^-12940, 2865,

1735, 1704, 1613, 1513, 1247 and 1062; δ_H(CDCl₃, 500 MHz)

1.00-1.10 [24H, m, 3 × SiCH(CH₃)₂and 8-CH₃], 1.21 (3H, s, 8-

CH₃), 1.36 and 1.37 [each 3H, s, O(O)CCH₃], 1.47-1.53 (2H, m,

4-H₂), 1.44-1.69 (2H, m, 6-H₂), 1.81 (1H, t, J 12.3, 14-H_ax), 1.91

(1H, t, J 12.3, 12-H_ax), 2.21 (1H, d, J 13.1, 12-H_eq), 2.41-2.49

(2H, m, 2-H and 14-H_eq), 2.51-2.60 (2H, m, 2-H' and 10-H), 3.00

20

0.29 (ethyl acetate:light petroleum 1:1), [α]_D+4.0 (c 17.0,

CH₂Cl₂) (Found: M⁺+ NH₄, 858.5560. C₄₈H₈₀NO₁₀Si requires M,

10

Tetrahedron

(1H, dd, J 17.4, 5.8, 10-H'), 3.37-3.46 (2H, m, 16-H₂), 3.50

8. (a) Wender PA, Baryza JL, Bennett CE, Bi FC, Brenner SE,

Clarke MO, Horan JC, Kan C, Lacôte E, Lippa B, Nell PG,

Turner TM, J. Am. Chem. Soc. 2002; 124: 13648; (b)

Wender PA, Loy BA, Schrier AJ. Isr. J. Chem. 2011; 51:

453; (c) Wender PA, Baryza JL, Brenner SE, DeChristopher

BA, Loy BA, Schrier AJ, Verma VA. Proc. Natl. Acad. Sci.

USA. 2011; 108: 6721.

(1H, m, 15-H), 3.80 and 3.81 (each 3H, s, OCH₃), 3.87 (1H, m,

11-H), 3.93 (1H, d, J 9.7, 7-H), 4.04 (1H, m, 5-H), 4.22-4.30

(3H, m, 3-H and 2'-H₂), 4.39 (2H, s, ArCH₂), 4.41 and 4.49 (each

1H, d, J 10.5, ArHCH), 4.60 (2H, d, J 5.7, CO₂CH₂), 5.15 (1H,

dd, J 10.3, 1.0, =HCH), 5.25 (1H, dd, J 17.3, 1.0, =HCH), 5.43

(1H, t, J 6.3, 1'-H), 5.91 (1H, ddt, J 17.3, 10.3, 5.7, CH=CH₂),

6.86 (2H, d, J 8.6, ArH), 6.87 (2H, d, J 8.8, ArH), 7.22 (2H, d, J

8.6, ArH) and 7.24 (2H, d, J 8.8, ArH); δ_C(CDCl₃, 125 MHz)

11.9, 17.9, 20.2, 20.8, 24.9, 25.0, 31.4, 38.0, 38.9, 40.6, 41.3,

44.9, 52.7, 55.1, 59.3, 63.3, 65.1, 65.8, 72.7, 72.8, 74.3, 74.5,

76.5, 80.1, 100.5, 113.6, 113.7, 118.1, 124.4, 128.7, 129.2, 130.2,

130.7, 132.0, 134.6, 159.0, 159.1, 170.4 and 212.5; m/z (ES⁺) 917

(M⁺+ 23, 100%).

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Declaration of interests

☒ The authors declare that they have no known competing financial interests or personal relationships

that could have appeared to influence the work reported in this paper.

☐The authors declare the following financial interests/personal relationships which may be considered

as potential competing interests:

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Synthesis of the C1 – C16 fragment of bryostatin for incorporation into 20,20-fluorinated analogues

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