Synthesis of vinylic iodides for incorporation into the C17-C27 fragment of bryostatins

Accepted Manuscript

Thomas Gregson, Eric J. Thomas

PII:

S0040-4020(17)30438-6

10.1016/j.tet.2017.04.048

TET 28649

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To appear in: Tetrahedron

Received Date: 15 February 2017

Revised Date: 7 April 2017

Accepted Date: 20 April 2017

Please cite this article as: Gregson T, Thomas EJ, Synthesis of vinylic iodides for incorporation into the

C17-C27 fragment of bryostatins, Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.048.

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Synthesis of vinylic iodides for incorporation

into the C17-C27 fragment of bryostatins

Leave this area blank for abstract info.

Thomas Gregson and Eric J. Thomas

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

1

ACCEPTED MANUSCRIPT

Tetrahedron

journal homepage: www.elsevier.com

Synthesis of vinylic iodides for incorporation into the C17-C27 fragment of

bryostatins

Thomas Gregson^a, Eric J. Thomas^a

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

ARTICLE INFO

ABSTRACT

Vinylic iodides were identified as useful intermediates for the synthesis of the C17-C27 fragment of

the bryostatins with control of the geometry of the exocyclic methoxycarbonylmethylene group.

Following literature precedent, the Piers (E)-stereoselective addition of tributyltin hydride to an

alkynoate followed by ester reduction and tin-iodine exchange gave vinylic iodides that could be used

to form the C20-C21 bond of the bryostatins. Chelation controlled addition of lithiated 3-

silyloxypropynes to 2-alkoxyaldehydes followed by reductive iodination was used to prepare vinylic

iodides that could be used in the complementary assembly of the C21-C22 bond of the bryostatins.

Initial studies of the synthesis of intermediates for metathesis studies using metal catalysed reactions

of a vinylic iodide for C21-C22 bond formation were complicated by cyclisation reactions.

Article history:

Received

Received in revised form

Accepted

Available online

Keywords:

Stereoselective synthesis

Conjugate addition

Vinylic iodides

.

Chelation control

Tin-iodine exchange

1. Introduction

The bryostatins, e.g. bryostatin 1 (1),¹are an important group

of natural products with an impressive array of biological

activities including potentially useful anticancer behaviour.

However, they are difficult to produce from natural sources and

so have been studied extensively by synthetic organic chemists.²

To date several outstanding total syntheses have been completed³

and macrocyclic analogues have been prepared that show both

the anticancer activity of the bryostatins and the tumour

promoting activity of phorbol.^4,5

It was recognised that approaches to the bryostatins based on a

late-stage assembly from C1-C16 and C17-C27 fragments could

lead to a convergent synthesis. Indeed the early total syntheses

were based on this strategy and used Julia reactions to assemble

the core structure by formation of the 16,17-double-bond.^3a-cThe

formation of this double-bond by ring-closing metathesis (RCM)

has also been considered albeit with mixed success.⁶

Intermediates that are equivalent to the C17-C27 keto-esters 2

and 3 could be useful for Julia and RCM based approaches to

bryostatins, see Figure 1. These trisubstituted alkenes should be

available from the (E)- and (Z)-vinylic iodides 4 and 5. Indeed in

their landmark syntheses, Masumune and Yamamura used

vinylic iodides related to 4 and 5.^3a,cA vinylic iodide 4 was also

used in an alternative synthesis of the C17-C27 fragment.⁷We

now describe our syntheses of (E)- and (Z)-vinylic iodides 4 and

5 that may be useful for the synthesis of bryostatins.

Figure 1 Vinylic iodides for the synthesis of bryostatins

2. Results and discussion

(E)-Vinylic iodides 4 were readily available from the alkynyl

ester 6 that had been prepared in eight steps from (R)-

pantolactone during studies of the synthesis of the C17-C27

fragment of the 20-deoxybryostatins.⁸Following the literature

———

Corresponding author. Tel.: 00 44 (0)161 275 4613; e-mail: e.j.thomas@manchester.ac.uk

2

Tetrahedron

ACCEPTED MANUSCRIPT

precedent,⁷the addition of tributyltin lithium to the ester 6

according to the procedure of Piers⁹gave the (E)-alkenoate 7

with excellent stereoselectivity. Following reduction using di-

isobutylaluminium hydride and protection of the ensuing alcohol

8 as its tert-butyldimethylsilyl ether 9, tin-iodine exchange gave

the vinylic iodide 11. However, attempts to remove the

triethylsilyl group selectively were accompanied by partial loss

of the allylic tert-butyldimethylsilyl protecting group and gave

mixtures of the alcohol 12 and diol 13 with diol 13 being the

dominant product with longer reaction conditions (see Scheme

1). The lability of tert-butyldimethylsilyl ethers of allylic

alcohols relative to triethylsilyl ethers of secondary alcohols was

also characteristic of more advanced bryostatin intermediates.¹⁰

Figure 2 Proposed reductive iodination of alkynols 17

The tert-butyldiphenylsilyl ether 10 of alcohol 8 was prepared

and tin-iodine exchange gave the vinyl iodide 14. The

triethylsilyl ether could also be removed selectively from the

fully silylated stannane 10 to give the seondary alcohol 15 (see

Scheme 1). This on tin-iodine exchange gave the hydroxyvinylic

iodide 16. This was also available in an 85% yield by the

selective silylation of the diol 13.

Scheme 2 Synthesis of the alkynol 21 Reagents and conditions i,

(a) MeONHMe.HCl, benzene, Me₃Al, 0 ^oC to rt, 2 h, add 18, rt, 1

h (b) TBSCl, imid., DCM, DMAP (cat.), TBAI (cat.), rt, 1 h (19,

30%; recovered 18, 48%); ii, DIBAL-H, DCM, −78 ^oC, 2 h

(45%); iii, nBuLi, 3-tert-butyldimethylsilyloxypropyne, THF, 0

^oC, 30 min, cool to −78 ^oC, add 20, 1.75 h (21, 42%; 22, 17%).

The configuration at C-4 of the major syn-alkyne 21 does not

correspond to that in the required alkynols 17. This was not

surprising since it is consistent with both chelation¹³and Felkin-

Anh¹⁴control. However, the selectivity was not as high as

expected and so it was decided to use an oxidation – reduction

sequence to access intermediates 17 with the required

configuration at C-4 from alkynes analogous to 21 and 22

available from (R)-pantolactone. The ring opening of (R)-O-

benzylpantolactone 18 using the Weinreb amide had also been

capricious and a better synthesis of the aldehyde was required.

Lactol 23¹⁵was available by reduction of PMB-protected (R)-

pantolactone, and was converted into the silyloxypentene 25 via a

Wittig reaction and O-silyation. Hydroxylation appeared to give

a single diastereoisomer 26 that was assigned the anti-

configuration by analogy with the literature,¹⁶and oxidative

cleavage gave aldehyde 27. As expected, addition of lithiated

Scheme 1 Synthesis of vinylic iodides analogous to 4 Reagents

and conditions i, nBuLi, Bu₆Sn₂, THF, 0 ^oC, 25 min, add to

o

CuBr.DMS, THF, −50 C, 25 min, add 6 and MeOH, THF, −78

o

^oC, 4 h (78%); ii, DIBAL-H, THF, −78 C to rt, 3 h (86%); iii,

tert-butyldiphenylsilyloxypropyne to this aldehyde gave

a

mixture of the syn- and anti-alcohols, syn:anti = 75 : 25, and this

mixture was oxidised to give the ketone 28, see Scheme 3.

TBSCl, imid., DCM, rt, 16 h (78% from 6); iv, TBDPSCl, imid.,

DCM, rt, 16 h (90% from 6): v, NIS, DCM, rt, 1.5 h (11, 96%;

14, 96%; 16, 95%); vi, HF, MeCN, rt, 1.5 h (12, 25%; 13, 50%);

vii, HF, MeCN, rt, 4.5 h (13, 72%); viii, dil. HF, MeCN, rt, 2 h

(71%).

The reduction of this ketone was investigated with chelation

control expected to give the required 4,5-anti-alcohol 30, the

minor alcohol in the mixture of alcohols obtained from aldehyde

27. Reduction using di-isobutyaluminium hydride and sodium

borohydride in the presence of cerium(III) chloride gave more of

the 4,5-syn-alcohol 29, in ratios of 68 : 32 and 86 : 14,

respectively. However, zinc borohydride¹⁷was usefully selective

in favour of the chelation controlled product 30, 29 : 30 = 14 : 86,

and the use of the chiral reducing agent (R)-methylCBS/BMS¹⁸

led to stereoselectivity, 80 : 20 in favour of the required 4,5-anti-

epimer 30. The configurations shown for the alcohols 29 and 30

were assigned by comparison of their ¹H NMR spectra with those

of analogous alkynols, vide infra, and by analogy with the

selectivity for formation of the syn-adducts 21 and 29 in addition

to aldehydes 20 and 27.

Approaches to the (Z)-vinylic iodides 5 were based on the

stereoselective reductive iodination¹¹of alkyn-1-ols 17, see

Figure 2. The ring opening of the benzyl ether 18 of (R)-

pantolactone using the Weinreb reagent followed by immediate

O-silylation gave the amide 19 but only in modest yields due to

recovery of the lactone 18. After reduction, addition of lithiated

3-tert-butyldimethylsilyloxypropyne to the resulting aldehyde 20

gave a mixture of the syn- and anti-alcohols 21 and 22 with

stereoselectivity in favour of the syn-isomer 21, ratio ca. 70 : 30

(see Scheme 2). The configuration shown was assigned to the

major product 21 on the basis of the relative shifts of its (R)- and

(S)-O-acetylmandelates.¹²

3

ACCEPTED MANUSCRIPT

Scheme 3 Synthesis of the 4,5-anti-hept-2-yn-4-ol 30 Reagents

and conditions i, Ph₃MePBr, KO^tBu, rt, 30 min, THF, rt, 1 h, 23,

o

0 C to rt, 3.5 h (75%); ii, TBSCl, imid., DMAP (cat.), TBAI

(cat.), rt, 1 h (63%); iii, NMO, OsO₄(cat.), acetone, water,

^tBuOH, rt, 18 h (59%); iv, NaIO₄, THF, water, rt, 30 min (ca.

o

99%); v, (a) nBuLi, tert-butyldiphenylsilyloxypropyne, 0 C, 30

o

min, 27, −78 C to 0 C, 2 h (84%; 29 : 30 = 75 : 25) (b) Dess-

Martin periodinane, DCM, rt, 45 min (ca. 99%); vi, (a) NaBH₄,

CeCl₃.6H₂O, MeOH, rt, 1.5 h (85%, 29 : 30 = 86 : 14) (b)

o

ZnBH₄, ether, −30 C to 0 C, 3 h (86%, 29 : 30 = 14 : 86) (c)

o

(R)-2-methyl-CBS oxazaborolidine, tol., BH₃.Me₂S, −30 C to

−15 ^oC, 2 h (75%, 29 : 30 = 20 : 80); vii, TBSCl, imid., DCM, rt,

Scheme 4 Synthesis of the vinylic iodide 43 Reagents and

18 h (96%).

o

conditions i, activated Zn, 1-bromo-3-methylbut-2-ene, 32, 0 C,

4 h (53% plus 6% of its syn-epimer); ii, NaH, DMF, 0 ^oC to rt, 30

The anti-alcohol 30 was protected as its tert-

butyldimethylsilyl ether 31 but attempts to remove the less

hindered tert-butyldiphenylsilyl group selectively were

complicated by loss of both tert-butyldimethylsilyl groups to give

the corresponding triol.

o

min, PMBCl, 0 C to rt, 1 h (98%); iii, aq. AcOH, 48 C, 2 h

o

(86%); iv, NaIO₄, methanol, water, 0 C to rt, 1.25 h (ca. 99%);

v, ethynylmagnesium bromide, THF, −78 C, 2 h, rt, 2 h (37,

o

29%; 38, 21%); vi, nBuLi, 3-triethylsilyloxypropyne, 0 C, 1 h,

36, −78 ^oC, 2.5 h (39, 74%, 40, 4%); vii, TBSOTf, 2,6-lut.,

At this point, it was decided to prepare α-alkoxyaldehydes

that were pseudo-enantiomers of aldehydes 20 and 27 so that

chelation control of the addition of alkynes would give the

required configuration at C-4 directly. As (S)-pantolactone is less

readily available than its (R)-enantiomer it was necessary to vary

the synthesis and use a different starting material. It was also

decided to target alkynols 17 (Y = CH₂) suitable for use in RCM

based approaches to bryostatins.

DCM, 0 ^oC, 1 h (92%); viii, KF, methanol, THF, 0 ^oC, 2 h (77%);

o

ix, Red-Al, tol., ether, 0 C, 1 h, rt, 3 h, iodine flakes, −78 C to

−10 ^oC, 1 h (43, 69%; 44, 14%).

Initial studies of the reductive iodination of the alkynol 42 led

to mixtures of the required vinylic iodide 43 and the disubstituted

alkene 44. After optimisation, the use of Red-Al in ether with the

addition of iodine at a low temperature gave 65-70% yields of the

iodide 43 together with typically 20% of the alkene 44 (see

Scheme 4). This synthesis had given the vinylic iodide 43 in

eight steps from (R)-glyceraldehyde in an overall yield of 14.5%.

The zinc mediated Barbier reaction of (R)-glyceraldehyde 32

with isoprenyl bromide gave predominantly the anti-adduct 33

and this was protected as its PMB-ether 34. The anti-

configuration assigned to the major adduct 33 is well

precedented¹⁹and was confirmed using (R)- and (S)-O-acetyl

mandelates.¹²Following hydrolysis of the acetonide, periodate

cleavage of the diol 35 gave the (S)-aldehyde 36. The addition of

ethynylmagnesium bromide to this aldehyde proceeded with only

modest stereoselectivity in favour of the syn-addduct 37 (see

Scheme 4) but the addition of lithiated 3-triethylsilyloxypropyne

was much more stereoselective and gave the syn-adduct 39 as the

dominant product, 39 : 40 = 92 : 8. The configurations of these

products were established by comparison of their ¹H NMR

spectra with those of analogous products prepared earlier with the

chemical shifts of the diastereotopic benzylic hydrogens being

diagnostic. The syn-isomers were also always the less polar. The

syn-alcohol 39 was then protected as its tert-butyldimethylsilyl

ether 41 and the triethylsilyl group removed using potassium

fluoride in THF-methanol. Under these conditions only traces of

the diol formed by competing cleavage of the tert-

butyldimethylsilyl group were observed.

The vinylic iodides 12-14, 16 and 43 correspond to the vinylic

iodides 4 and 5 and are suitable intermediates for incorporation

into syntheses of bryostatins. To check possible reaction

conditions, some metal catalysed reactions of the iodide 43 were

briefly studied.

To provide substrates for these coupling reactions, aldehyde

45⁸was converted into the alkyne 47 via the dibromide 46.

Addition of tributyltin hydride under free radical conditions to

the alkyne gave the vinyl stannane 48 (see Scheme 5). However,

attempts to couple the alkyne 47 or the stannane 48 with the

vinylic iodide 43 were unsuccessful as Heck cyclisations

dominated instead. The methylenecyclopentane 49 was the

dominant product from the attempted Sonogashira reaction with

the alkyne 47 and the aldehyde 50 together with traces of the

alcohol 49 were formed during the attempted Stille reaction with

the stannane 48. An attempted NHK reaction with benzaldehyde

also gave a cyclised product, the methylenecyclopentane 51 (see

Scheme 6).

4

Tetrahedron

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

ACCEPTED MANUSCRIPT

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

positive mode (ES⁺). Low and high resolution mass spectra were

recorded using Micromass Trio 200 and Kratos Concept IS

spectrometers, respectively. For organostannanes., molecular ion

peaks corresponding to the ¹²⁰Sn isotope are given. 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. Spectra are at 300 Mz (¹H) and at 75

Mz (¹³C) in deuteriated chloroform unless otherwise indicated.

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. All products were

isolated as pale yellow or colourless oils.

Scheme 5 Synthesis of substrates for test Stille and Sonogashira

reactions Reagents and conditions i, CBr₄, Ph₃P, py., DCM, 0 ^oC,

20 min, 45, rt, 40 min (74%); ii, nBuLi, −78 ^oC, 15 min, 0 ^oC, 15

min (87%); iii, Bu₃SnH, AIBN (cat.), tol., 120 ^oC, 4 h [68%; (E) :

(Z) = 9 : 1].

4.2 Experimental procedures

4.2.1 Methyl (2E,5R,7R,8R)-8-tert-butyldiphenylsilyloxy-3-

tributylstannyl-5-triethylsilyloxy-7-(2-

trimethylsilylethoxymethoxy)non-2-enoate (7). n-Butyllithium

(1.6 M in hexanes, 5.00 mL, 8.0 mmol) was added to hexa-n-

butylditin (4.00 mL, 8.0 mmol) in THF (2.6 mL) at 0 ^oC. After 25

min, this solution was transferred to a suspension of CuBr.DMS

o

(1.64 g, 8.0 mmol) in THF (4.9 mL) at −50 C and this mixture

was stirred for 25 min before cooling to −78 ^oC. The ester 6 (1.10

g, 1.58 mmol) and anhydrous MeOH (109 µl, 2.7 mmol) in THF

(1.6 mL) were added and, after 4 h at −78 ^oC, MeOH (2 mL) was

added. The mixture allowed to warm to rt then diluted with ether

and filtered through celite with ether washings. The filtrate was

partitioned between water and ether. The aqueous layer was

extracted with ether and the organic extracts were washed with

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

Chromatography (1:1:98 ether:Et₃N:light petroleum) of the

residue gave the title compound 7 (1.22 g, 78%), R_f= 0.70 (1:9,

Scheme 6 Palladium(0) catalysed reactions of the iodide 43

Reagents and conditions i, 47, Pd(PPh₃)₄, CuI, Et₃N, rt, 2 h, CuI,

rt, 18 h (80%); ii, 48, Pd(PPh₃)₄, DMF, 80 ^oC, 17 h (50, 30%; 49,

3%); iii, CrCl₂, NiCl₂, 43, PhCHO, DMF, rt, 2 h (62%).

23

ether:light petroleum); [α]_D−17.6 (c 0.5, CHCl₃); ν_max/cm^-1

The structures shown were assigned to the products 49 – 51 in

Scheme 6 using spectroscopic data. The configuration of the

secondary methyl substituent in the methylenecyclopentane 51

was established from nOe studies, see experimental.

2955, 2926, 2877, 1721, 1590, 1461, 1427, 1377, 1248, 1167,

1106, 1054, 860, 834; δ 0.05 [9H, s, Si(CH₃)₃], 0.60 (1H, ddd, J

13.8, 11.5, 5.2, CHHSi), 0.68 (6H, q, J 7.6, 3

ddd, J 13.8, 11.5, 5.2, CHHSi), 0.88-1.14 (9H, m, 9-H₃, 3

SnCH₂), 0.93 (9H, t, J 7.3, 3 CH₃), 1.01 (9H, t, J 7.6, 3

SiCH₂CH₃), 1.10 [9H, s, SiC(CH₃)₃], 1.28-1.42 (6H, m, 3

1.43-1.62 (7H, m, 3 CH₂, 6-H), 1.83 (1H, ddd, J 13.8, 9.7, 1.4,

6-H ), 3.01 (1H, ddd, J 12.1, 5.1, 1.4, 4-H), 3.28 (1H, ddd, J 11.6,

9.6, 5.9, CHHCH₂Si), 3.45 (1H, dd, J 12.1, 9.3, 4-H ), 3.51 (1H,

× SiCH₂), 0.78 (1H,

×

3. Summary and conclusions

×

CH₂),

Several vinylic iodides that could be useful for the synthesis

of the C17-C27 fragment of bryostatins have been synthesized.

Of some interest is the stereocontrol found for the addition of

metalated alkynes to aldehydes, the use of the reductive

iodination of alkynols and the application of the Piers conjugated

addition of tributyltin hydride to conjugated alkynoates.

Although the initial studies of the palladium(0) promoted

reactions of the vinylic iodide 43 led to intramolecular Heck

products, this reaction would not be a problem with iodides that

didn't have the terminal double bond. In addition other

procedures could be envisaged to incorporate these iodides into

further synthetic studies.

×

′

ddd, J 11.8, 9.4, 5.2, CHHCH₂Si), 3.75 (3H, s, OCH₃), 3.81 (1H,

ddd, J 10.9, 4.3, 1.6, 7-H), 4.09 (1H, m, 5-H), 4.18 (1H, dq, J 6.1,

4.4, 8-H), 4.54 and 4.60 (each 1H, d, J 6.8, OCHHO), 6.06 (1H,

s, 2-H), 7.36-7.47 (6H, m, ArH), 7.69-7.75 (4H, m, ArH); δ_C

−1.3, 5.9, 7.4, 10.5, 13.9, 16.9, 18.1, 19.5, 27.3, 27.7, 29.2, 35.6,

44.3, 51.1, 65.0, 69.4, 69.9, 79.7, 96.4, 127.6, 127.8, 129.6,

129.8, 129.9, 134.3, 135.2, 136.1, 136.2, 164.8, 169.2; m/z (ES⁺)

1013 (M⁺+ 23, 100%).

4.2.2

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

4. Experimental

tributylstannyl-5-triethylsilyloxy-7-(2-

trimethylsilylethoxymethoxy)non-2-en-1-ol

(8).

Di-

4.1. General experimental details

isobutylaluminium hydride (1M in hexanes, 6.15 mL, 6.15

mmol) was added to the ester 7 (2.03 g, 2.05 mmol) in THF (8

mL) at −78 ^oC and the solution stirred for 1 h at −78 ^oC and for 3

h at rt. After cooling to 0 ^oC, ether and saturated aqueous sodium

potassium tartrate were added and the mixture was stirred

vigorously for 1 h. The aqueous layer was extracted with ether

and the organic extracts were washed with brine, dried (MgSO₄)

and concentrated under reduced pressure to give the alcohol 8

(1.97 g) used directly in the next reaction. Chromatography

Flash column chromatography was performed using Merck

silica gel 60. Light petroleum refers to the fraction boiling

between 40 and 60 °C and was redistilled before use.

Tetrahydrofuran was dried over sodium-benzophenone and

distilled under nitrogen prior to use. Dichloromethane was dried

over CaH₂and distilled before use. Ether refers to diethyl ether.

Reactions under non-aqueous conditions were carried out under

an atmosphere of nitrogen or argon.

5

(1:1:98 then 10:1:89, ether:Et₃N:light petroleum) of a sample

12.1, 9.6, 5.3, CHHCH₂Si), 3.66-3.73 (1H, m, 7-H), 3.73-3.81

ACCEPTED MANUSCRIPT

gave the title compound 8 (86%), R_f= 0.18 (1:9, ether:light

(1H, m, 5-H), 4.13 (1H, dq, J 4.7, 6.2, 8-H), 4.38-4.46 (3H, m, 1-

H₂, OHCHO) 4.52 (1H, d, J 6.8, OHCHO), 5.84 (1H, t, J 5.7, 2-

H), 7.25-7.46 (12H, m, ArH), 7.62-7.78 (8H, m, ArH); δ_C−1.2,

4.1, 5.2, 10.1, 14.4, 18.2, 18.4, 19.2, 27.2, 27.3, 27.5, 29.2, 36.5,

41.9, 61.1, 65.5, 67.8, 70.5, 79.4, 96.4, 127.7, 128.0, 129.7,

129.9, 134.0, 134.2, 134.7, 135.8, 135.9, 136.1, 142.7, 143.1; m/z

(ES⁺) 1143 (28%), 364 (50), 332 ( 100).

20

petroleum); [α]_D−7.3 (c 1.2, CHCl₃); ν_max/cm^-13449, 2955,

2927, 1725, 1659, 1462, 1425, 1378, 1247, 1105, 1058, 1032,

859, 834; δ_H−0.04 [9H, s, Si(CH₃)₃], 0.55-0.71 (1H, m, CHHSi),

0.66 (6H, q, J 7.6, 3

CHHSi), 0.87-1.04 (27H, m, 3

9-H₃), 1.10 [9H, s, SiC(CH₃)₃], 1.28-1.43 (6H, m, 3

1.57 (7H, m, 3

2.16 (1H, dd, J 7.2, 4.6, OH), 2.47 (1H, dd, J 13.6, 7.7, 4-H),

2.73 (1H, dd, J 13.6, 6.3, 4-H ), 3.30 (1H, ddd, J 11.6, 9.8, 5.9,

× SiCH₂), 0.80 (1H, ddd, J 13.7, 11.7, 5.7,

×

CH_3,3

×

CH₂Sn, 3

×

SiCH₂CH₃,

×

CH₂), 1.46-

×

CH₂, 6-H), 1.80 (1H, ddd, J 13.6, 7.6, 1.6, 6-H′),

4.2.5

(2E,5R,7R,8R)-1-tert-Butyldimethylsilyloxy-8-tert-

butyldiphenylsilyloxy-3-iodo-5-triethylsilyloxy-7-(2-

′

trimethylsilylethoxymethoxy)non-2-ene (11). The stannane 9 (920

mg, 0.85 mmol) in DCM (9.8 mL) was added to a suspension of

N-iodosuccinimide (287 mg, 1.27 mmol) in DCM (5.9 mL) at rt

and the mixture stirred for 1.5 h. After concentration under

reduced pressure, chromatography (2:1:97, ether:Et₃N:light

petroleum) of the residue gave the title compound 11 (746 mg,

96%), R_f= 0.45 (6% ether in light petroleum); ν_max/cm^-12955,

2930, 2879, 2858, 1466, 1426, 1377, 1256, 1105, 835, 777, 740;

CHHCH₂Si), 3.51 (1H, ddd, J 11.8, 9.5, 5.3, CHHCH₂Si), 3.70

(1H, ddd, J 10.0, 4.1, 2.1, 7-H), 3.89-3.96 (1H, m, 5-H), 4.07-

4.23 (2H, m, 1-H, 8-H), 4.36 (1H, ddd, J 12.7, 6.9, 4.6, 1-H′),

4.51 and 4.58 (each 1H, d, J 6.8, OHCHO), 5.95 (1H, t, J 6.3, 2-

H), 7.36-7.48 (6H, m, ArH), 7.68-7.75 (4H, m, ArH); δ_C−1.3,

5.7, 7.3, 10.0, 14.0, 16.8, 18.1, 19.5, 27.3, 27.8, 29.4, 35.5, 42.7,

46.4, 59.4, 65.2, 69.9, 79.9, 96.0, 127.7, 127.8, 129.8, 129.9,

134.2, 134.9, 136.1, 142.1, 144.4; m/z (ES⁺) 1064 (73%), 984

(100), 962 (40).

δ_H−0.02 (6H, s, 2

J 7.9, 3 SiCH₂), 0.77-0.91 (2H, m, SiCH₂), 0.94 (3H, d, J 5.9,

9-H₃), 0.94 [9H, s, SiC(CH₃)₃], 1.01 (9H, t, J 7.9, 3 SiCH₂CH₃),

1.11 [9H, s, SiC(CH₃)₃], 1.61 (1H, ddd, J 14.1, 10.0, 5.2, 6-H),

1.89 (1H, ddd, J 14.1, 7.1, 1.7, 6-H ), 2.67 (2H, d, J 6.1, 4-H₂),

× SiCH₃), 0.12 [9H, s, Si(CH₃)₃], 0.68 (6H, q,

×

4.2.3

(2E,5R,7R,8R)-1-tert-Butyldimethylsilyloxy-8-tert-

×

butyldiphenylsilyloxy-3-tributylstannyl-5-triethylsilyloxy-7-(2-

trimethylsilylethoxymethoxy)non-2-ene (9). Alcohol 8 (1.09 g,

1.13 mmol) in DCM (2 mL) was added to tert-butyldimethylsilyl

chloride (205 mg, 1.36 mmol) and imidazole (184 mg, 2.71

′

3.41 (1H, ddd, J 11.5, 9.6, 5.9, CHHCH₂Si), 3.54 (1H, ddd, J

11.7, 9.6, 5.4, CHHCH₂Si), 3.65 (1H, ddd, J 10.0, 4.2, 1.4, 7-H),

4.03-4.18 (2H, m, 5-H, 8-H), 4.22 (2H, t, J 6.3, 1-H₂), 4.54 and

4.60 (each 1H, d, J 6.8, OHCHO) 6.41 (1H, t, J 6.3, 2-H), 7.36-

7.49 (6H, m, ArH), 7.69-7.76 (4H, m, ArH); δ_C−4.9, −1.2, 5.6,

7.3, 16.9, 18.2, 19.5, 26.2, 27.3, 35.9, 48.6, 61.6, 65.5, 69.8, 70.1,

79.8, 96.0, 100.5, 127.7, 127.9, 128.6, 129.8, 129.9, 134.2, 134.8,

136.1, 136.1, 143.3; m/z (ES⁺) 973 (25%), 935 (M⁺+ 23, 100%);

HRMS (ES⁺): MNa⁺, found 935.3789. C₄₃H₇₇O₅Si₄INa requires

935.3785.

o

mmol) in DCM (2 mL) at 0 C and the mixture was stirred at rt

for 16 h. Saturated aqueous ammonium chloride was added and

the mixture partitioned between water and DCM. The aqueous

layer was extracted with DCM and the organic extracts were

dried MgSO₄) and concentrated under reduced pressure.

Chromatography (1:1:98, ether:Et₃N:light petroleum) of the

residue gave the title compound 9 (949 mg, 78% from 6), R_f=

20

0.58 (6% ether in light petroleum); [α]_D+1.5 (c 1.3, CHCl₃);

ν_max/cm^-12956, 2928, 2859, 1738, 1657, 1464, 1425, 1378, 1255,

4.2.6

(2E,5R,7R,8R)-1-tert-Butyldimethylsilyloxy-8-tert-

1104, 1058, 1036, 834, 776, 739; δ_H−0.05 (6H, s, 2

0.11 [9H, s, Si(CH₃)₃], 0.58 (1H, ddd, J 14.2, 11.8, 5.0, CHHSi),

0.65 (6H, q, J 8.2, 3 SiCH₂), 0.77 (1H, ddd, J 14.0, 12.0, 5.6,

CHHSi) 0.84-1.04 (6H, m, 3 CH₂Sn), 0.92 (9H, t, J 7.5, 3

CH₃), 0.95 (3H, d, J 6.3, 9-H₃), 0.96 [9H, s, SiC(CH₃)₃], 1.01

(9H, t, J 8.2, 3 SiCH₂CH₃), 1.10 [9H, s, SiC(CH₃)₃], 1.27-1.47

(7H, m, 3 CH₂, 6-H), 1.44-1.69 (7H, m, 3 CH₂, 6-H ), 2.47-

× SiCH₃),

butyldiphenylsilyloxy-3-iodo-7-(2-

trimethylsilylethoxymethoxy)non-2-en-5-ol

(12)

and

×

(2E,5R,7R,8R)-8-tert-butyldiphenylsilyloxy-3-iodo-7-(2-

×

trimethylsilylethoxymethoxy)non-2-ene-1,5-diol (13). Hydrogen

fluoride (1% in MeCN, 1 mL) was added to the triethylsilyl ether

11 (90 mg, 99 µmol) in THF (0.5 mL) in a Teflon container at rt

and the mixture stirred for 1.5 h. Saturated aqueous sodium

hydrogen carbonate was added and the mixture partitioned

between water and EtOAc. The aqueous layer was extracted with

EtOAc and the organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography (2:8 then

4:6 ether:light petroleum) of the residue gave the title compound

12 (20 mg, 25%), R_f= 0.81 (1:1, ether:light petroleum); ν_max/cm^-1

3464, 2954, 2929, 2893, 2858, 1467, 1632, 1427, 1376, 1255,

×

′

2.60 (2H, m, 4-H₂), 3.26 (1H, ddd, J 9.5, 5.7, 3.6, CHHCH₂Si),

3.51 (1H, ddd, J 9.1, 6.6, 4.2, CHHCH₂Si), 3.74-3.81 (1H, m, 7-

H), 3.87-3.93 (1H, m, 5-H), 4.20 (1H, dq, J 6.2, 4.4, 8-H), 4.37

and 4.41 (each 1H, dd, J 13.8, 5.5, 1-H), 4.51 and 4.59 (each 1H,

d, J 6.8, OHCHO), 5.77 (1H, t, J 5.4, 2-H), 7.36-7.48 (6H, m,

ArH), 7.68-7.75 (4H, m, ArH); δ_C−4.7, −1.3, 1.3, 5.8, 7.4, 10.0,

14.0, 16.8, 18.1, 19.5, 26.3, 27.3, 27.8, 29.4, 35.1, 43.8, 61.1,

65.0, 69.3, 69.8, 79.8, 96.4, 127.6, 127.8, 129.7, 129.8, 134.3,

135.1, 136.1, 136.2, 140.3, 143.7; m/z (ES⁺) 1100 (M⁺+ 23, 4%),

239 (100).

1106, 1058, 1031, 836, 800; δ_H0.04 (6H, s, 2

× SiCH₃), 0.12

[9H, s, Si(CH₃)₃], 0.82-1.14 (2H, m, CH₂Si), 0.94 [9H, s,

SiC(CH₃)₃], 1.04 (3H, d, J 6.3, 9-H₃), 1.11 [9H, s, SiC(CH₃)₃],

4.2.4

(2E,5R,7R,8R)-1,8-Bis-tert-butyldiphenylsilyloxy-3-

1.54-1.66 (1H, m, 6-H), 1.72 (1H, ddd, J 13.6, 10.0, 3.3, 6-H

2.49 (1H, dd, J 14.2, 4.1, 4-H), 2.78 (1H, dd, J 14.4, 8.2, 4-H

′

),

tributylstannyl-5-triethylsilyloxy-7-(2-

trimethylsilylethoxymethoxy)non-2-ene (10). Following the

procedure outlined for the preparation of silyl ether 9, imidazole

(335 mg, 4.92 mmol), tert-butyldiphenylsilyl chloride (640 µl,

2.46 mmol) and alcohol 8 (1.97 g), after chromatography (1:1:98,

ether:Et₃N:light petroleum), gave the title compound 10 (2.22 g,

90% from 6), R_f= 0.79 (1:9, ether:light petroleum); ν_max/cm^-1

2954, 2926, 2857, 1462, 1426, 1376, 1250, 1106, 1059; δ_H−0.06

3.28 (1H, br. s, OH), 3.51 (1H, ddd, J 11.1, 9.5, 5.9, CHHCH₂Si),

3.66-3.76 (2H, m, CHHCH₂Si, 7-H), 3.97 (1H, dq, J 6.5, 5.6, 8-

H), 4.02-4.13 (1H, m, 5-H), 4.23 (2H, d, J 6.4, 1-H₂), 4.52 and

4.58 (each 1H, d, J 6.9, OHCHO), 6.50 (1H, t, J 6.3, 2-H), 7.38-

7.48 (6H, m, ArH), 7.68-7.76 (4H, m, ArH); δ_C−4.9, −1.1, 1.3,

18.0, 18.3, 19.5, 26.2, 27.3, 36.3, 47.4, 61.4, 66.3, 66.8, 71.0,

79.7, 96.3, 101.1, 127.8, 127.9, 129.9, 130.0, 134.6, 136.1, 136.2,

143.4. The second fraction was the title compound 13 (34 mg,

50%), R_f= 0.31 (1:1, ether:light petroleum); δ_H0.06 [9H, s,

Si(CH₃)₃], 0.85-1.03 (2H, m, CH₂Si), 1.05 (3H, d, J 6.3, 9-H₃),

1.10 [9H, s, SiC(CH₃)₃], 1.60 (1H, ddd, J 14.4, 10.2, 2.9, 6-H),

[9H, s, Si(CH₃)₃], 0.54 (6H, q, J 8.2, 3

m, CHHSi), 0.76 (1H, ddd, J 13.6, 11.5, 5.8, CHHSi) 0.86-1.12

[45H, m, 3 SiCH₂CH₃, 3 CH₃, 3 SnCH₂, 2 SiC(CH₃)₃, 9-

H₃], 1.21-1.64 (14H, m, 6 CH₂, 6-H₂), 2.30-2.40 (2H, m, 4-H₂),

3.24 (1H, ddd, J 11.3, 9.7, 6.0, CHHCH₂Si), 3.48 (1H, ddd, J

× SiCH₂), 0.54-0.68 (1H,

×

1.76 (1H, ddd, J 13.9, 10.4, 4.2, 6-H′), 2.42 (1H, dd, J 14.6, 2.1,

6

Tetrahedron

ACCEPTED MANUSCRIPT

4-H), 3.06 (1H, dd, J 14.5, 9.7, 4-H

′

), 3.50 (1H, ddd, J 10.8,

stirring for 1 h and chromatography (1:19, ether:light petroleum)

9.6, 6.1, CHHCH₂Si), 3.57-3.65 (1H, m, 7-H), 3.70-3.82 (2H, m,

CHHCH₂Si, 1-H), 3.92 (1H, dq, J 6.2, 5.6, 8-H), 4.04 (1H, tt, J

10.2, 2.2, 5-H), 4.19-4.23 (1H, m, 1-H′), 4.46 and 4.58 (each 1H,

d, J 6.9, OHCHO), 6.79 (1H, t, J 7.7, 2-H), 7.37-7.53 (6H, m,

ArH), 7.68-7.77 (4H, m, ArH); δ_C−1.1, 18.2, 19.5, 27.3, 30.0,

36.7, 47.1, 59.0, 64.7, 66.9, 71.3, 80.2, 96.6, 105.4, 127.9, 128.0,

130.0, 130.2, 133.8, 134.4, 136.1, 136.2, 142.7.

gave the title compound 16 (133 mg, 95%), R_f= 0.73 (4:6,

ether:light petroleum); ν_max/cm^-13377, 2954, 2928, 2857, 1664,

1613, 1514, 1462, 1427, 1377, 1302, 1249, 1175, 1151, 1109,

1057, 1038, 858, 838, 824, 797, 739; δ_H0.03 [9H, s, Si(CH₃)₃]

0.79-1.04 (2H, m, CH₂Si), 0.99 (3H, d, J 6.1, 9-H₃), 1.08 [18H, s,

2

×

SiC(CH₃)₃], 1.44-1.64 (2H, m, 6-H₂), 2.28 (1H, dd, J 14.5,

4.7, 4-H), 2.53 (1H, dd, J 14.4, 8.0, 4-H ), 3.14 (1H, br. s, OH),

′

3.49 (1H, ddd, J 11.1, 9.7, 5.9, CHHCH₂Si), 3.59-3.73 (2H, m,

CHHCH₂Si, 7-H), 3.93 (1H, quin, J 5.9, 8-H), 3.95-4.05 (1H, m,

5-H), 4.23 (2H, d, J 6.6, 1-H₂), 4.49 and 4.56 (each 1H, d, J 6.9,

OHCHO), 6.54 (1H, t, J 6.7, 2-H), 7.38-7.48 (12H, m, ArH),

7.68-7.76 (8H, m, ArH); δ_C−1.1, 18.1, 18.3, 19.4, 19.5, 27.0,

27.3, 36.2, 47.1, 62.1, 66.3, 66.8, 71.1, 79.7, 96.3, 101.5, 127.8,

127.9, 128.0, 128.6, 129.9, 130.0, 133.6, 133.9, 134.6, 135.9,

136.1, 136.2, 142.9.

The same procedure using the triethylsilyl ether 11 (365 mg,

0.40 mmol) in THF (1 mL) and hydrogen fluoride (1% in MeCN,

4 mL), after stirring for 4.5 h and chromatography (4:6 ether:light

petroleum) gave the diol 13 (197 mg, 72%).

4.2.7

(2E,5R,7R,8R)-1,8-Bis-tert-butyldiphenylsilyloxy-3-

iodo-5-triethylsilyloxy-7-(2-trimethylsilylethoxymethoxy)non-2-

ene (14). Following the procedure outlined for the preparation of

iodide 11, N-iodosuccinimide (105 mg, 0.46 mmol) in DCM (4

mL) and the stannane 10 (325 mg, 0.27 mmol) in DCM (9.8 mL),

after chromatography (2:1:97, ether:Et₃N:light petroleum) gave

the title compound 14 (271 mg, 96%), R_f= 0.69 (2:8, ether:light

petroleum); ν_max/cm^-12956, 2930, 2854, 1613, 1512, 1460, 1423,

1379, 1299, 1243, 1173, 1178, 1110, 1060, 1039, 857, 836, 797;

δ_H−0.03 [9H, s, Si(CH₃)₃], 0.49-0.71 (1H, m, CHHSi), 0.59 (6H,

Imidazole (14 mg, 206 µmol) then tert-butyldiphenylsilyl

chloride (19 µl, 73 µmol) were added to the diol 13 (50 mg, 73

µmol) in DCM (1 mL) at rt and the mixture stirred for 25 min.

Saturated aqueous ammonium chloride was added and the

mixture was partitioned between water and DCM. The aqueous

layer was extracted with DCM and the organic extracts were

dried (MgSO₄) and concentrated under reduced pressure.

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

the title compound 16 (55 mg, 85%).

q, J 8.0, 3

6.3, 9-H₃), 0.94 (9H, t, J 7.9, 3

×

SiCH₂), 0.76-0.99 (1H, m, CHHSi), 0.94 (3H, d, J

SiCH₂CH₃), 1.07 and 1.08 [each

×

9H, s, SiC(CH₃)₃], 1.44-1.60 and 1.73-1.82 (each 1H, m, 6-H),

2.46 (2H, d, J 5.9, 4-H₂), 3.34-3.60 (3H, m, CH₂CH₂Si, 7-H),

3.95-4.01 (1H, m, 5-H), 4.07-4.12 (1H, m, 8-H), 4.21 and 4.22

(each 1H, dd, J 10.5, 6.3, 1-H), 4.49 and 4.56 (each 1H, d, J 6.8,

OHCHO), 6.46 (1H, t, J 6.3, 2-H), 7.35-7.47 (12H, m, ArH),

7.66-7.74 (8H, m, ArH); δ_C−1.0, 4.1, 5.2, 18.3, 18.4, 19.5, 19.6,

27.3, 27.6, 36.1, 47.4, 62.3, 66.1, 67.0, 79.8, 96.5, 101.7, 127.8,

127.9, 128.2, 128.7, 129.9, 130.0, 133.5, 133.7, 134.8, 135.9,

136.3, 136.4, 143.2; m/z (ES⁺) 1075 (M⁺+ 39, 5%), 1059 (M⁺+

23, 10), 738 (100).

4.2.10

(2R)-2-Benzyloxy-4-tert-butyldimethylsilyloxy-N-

methoxy-N,3,3-trimethylbutanamide (19). Trimethylaluminium

(2 M in hexanes, 2.09 mL, 4.18 mmol) was added to N,O-

dimethylhydroxylamine.hydrochloride (408 mg, 4.18 mmol) in

benzene (6 mL) at 0 C and the mixture was stirred at rt for 2 h.

After cooling to 0 C, the lactone 18 (460 mg, 2.09 mmol) in

o

benzene (4 mL) was added and the mixture was stirred at rt for 1

h. After cooling to 0 C, saturated aqueous sodium hydrogen

o

carbonate was added with stirring and, after 10 min at rt, the

mixture was diluted with EtOAc and filtered through celite with

EtOAc washings. The filtrates were washed with brine then dried

(MgSO₄) and concentrated under reduced pressure to give (2R)-

2-benzyloxy-4-hydroxy-N-methoxy-N,3,3-trimethylbutanamide

as an oil mixed with ca. 15% pantolactone; δ_H1.02 and 1.06

(each 3H, s, 3-CH₃), 3.16 (1H, m, OH), 3.28 (3H, s, OCH₃), 3.42

(1H, dd, J 11.4, 8.1, 4-H), 3.61 (3H, s, NCH₃), 3.68 (1H, dd, J

4.2.8

(2E,5R,7R,8R)-1,8-Bis-tert-butyldiphenylsilyloxy-3-

tributylstannyl-7-(2-trimethylsilylethoxymethoxy)non-2-en-5-ol

(15). Hydrogen fluoride (1% in MeCN, 8 mL) was added to the

triethylsilyl ether 10 (1.00 g, 0.83 mmol) in THF (4 mL) at rt and

the mixture stirred for 2 h. Saturated aqueous sodium hydrogen

carbonate was added and the mixture was partitioned between

water and ether. The aqueous layer was extracted with ether and

the organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography (3:1:96, ether:Et₃N:light

petroleum) of the residue gave the title compound 15 (639 mg,

11.4, 4.3, 4-H′), 4.36 (1H, s, 2-H), 4.38 and 4.69 (each 1H, d, J

12.0, PhHCH), 7.28-7.44 (5H, m, ArH).

This amide was azeotroped with benzene, dissolved with

DCM (7 mL) and imidazole (449 mg, 6.60 mmol), tert-

butyldimethylsilyl chloride (299 mg, 1.98 mmol), DMAP (cat.)

and TBAI (cat.) were added. After stirring for 1 h, saturated

aqueous ammonium chloride was added and the mixture

partitioned between water and DCM. The aqueous layer was

extracted with DCM and the organic extracts were dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (1:19 then 1:9, ether:light petroleum) of the

residue gave recovered lactone 18 (220 mg, 48%) and the title

compound 19 (160 mg, 30%), R_f= 0.65 (1:1, ether:light

20

71%), R_f= 0.41 (1:9, ether:light petroleum); [α]_D−8.1 (c 4.0,

CHCl₃); ν_max/cm^-13463, 3070, 2955, 2927, 2858, 1590, 1465,

1427, 1376, 1251, 1108, 1056, 859, 832, 772, 740; δ_H0.00 [9H,

s, Si(CH₃)₃], 0.71-1.05 (20H, m, 3

H₃), 1.08 [18H, s, 2 SiC(CH₃)₃], 1.29-1.58 (14H, m, 6

H₂), 2.26 (1H, dd, J 13.3, 5.6, 4-H), 2.36 (1H, dd, J 13.4, 7.7, 4-

), 3.00 (1H, d, J 3.5, OH), 3.39-3.54 (2H, m, CH₂CH₂Si), 3.60-

×

CH₃, 3

×

SnCH₂, SiCH₂, 9-

×

CH₂, 6-

H′

3.73 (2H, m, 5-H, 7-H), 3.96 (1H, dq, J 6.1, 5.3, 8-H), 4.32 and

4.41 (each 1H, dd, J 13.2, 5.7, 1-H), 4.48 and 4.50 (each 1H, d, J

6.4, OHCHO), 5.91 (1H, t, J 5.6, 2-H), 7.37-7.50 (12H, m, ArH),

7.69-7.77 (8H, m, ArH); δ_C−1.2, 10.2, 14.0, 17.8, 18.2, 19.4,

27.1, 27.3, 27.7, 29.4, 36.5, 41.9, 61.1, 65.5, 67.8, 70.9, 79.4,

96.0, 127.7, 127.9, 129.8, 129.9, 134.0, 134.2, 134.7, 135.9,

136.1, 136.2, 142.5, 142.8; m/z (ES⁺) 1145 (75%), 1110 (M⁺+

23, 75), 451 (100).

petroleum); [α]_D+ 36.0 (c 2.8, CHCl₃); ν_max/cm^-12955, 2931,

2901, 2857, 1673, 1471, 1391, 1254, 1092, 1000, 854, 837, 776,

738; δ_H0.00 (6H, s, 2

and 0.94 (each 3H, s, 3-CH₃), 3.10 (1H, d, J 9.5, 4-H), 3.16 (3H,

s, OCH₃), 3.45 (3H, s, NCH₃), 3.68 (1H, d, J 9.5, 4-H ), 4.37 and

20

× SiCH₃), 0.85 [9H, s, SiC(CH₃)₃], 0.87

′

4.57 (each 1H, d, J 12.0, PhHCH), 4.59 (1H, s, 2-H), 7.18-7.34

(5H, m, ArH); δ_C−5.3, −5.2, 18.5, 19.3, 21.6, 26.1, 32.3, 40.9,

61.1, 69.1, 72.2, 76.1, 127.7, 127.8, 128.5, 128.7, 173.3; m/z

(CI⁺) 396 (M⁺+ 1,100%); HRMS (CI⁺): MH⁺, found 396.2567.

C₂₁H₃₈NO₄Si requires 396.2570.

4.2.9

(2E,5R,7R,8R)-1,8-Bis-tert-butyldiphenylsilyloxy)-3-

(16).

iodo-7-(2-trimethylsilylethoxymethoxy)non-2-en-5-ol

Following the procedure outlined for the preparation of the

iodide 11, N-iodosuccinimide (50 mg, 0.23 mmol) in DCM (1.2

mL) and stannane 15 (165 mg, 0.15 mmol) in DCM (2 mL), after

7

4.2.11

(2R)-2-Benzyloxy-4-tert-butyldimethylsilyloxy-3,3-

petroleum) of the residue gave the (R)-O-acetylmandelate of the

ACCEPTED MANUSCRIPT

dimethylbutanal (20). Di-isobutylaluminium hydride (1 M in

hexanes, 2.93 mL, 2.93 mmol) was added to the amide 19 (389

mg, 0.98 mmol) in DCM (12 mL) at −78 C and the mixture

alcohol 21 (95 mg, 86%), R_f= 0.38 (2:8, ether:light petroleum);

ν_max/cm^-12954, 2932, 2891, 2858, 1754, 1466, 1370, 1254, 1230,

1087, 1052, 934, 840, 778, 738; δ_H0.00, 0.03, 0.13 and 0.14

(each 3H, s, SiCH₃), 0.65 and 0.76 (each 3H, s, 6-CH₃), 0.91 and

0.93 [each 9H, s, SiC(CH₃)₃], 2.18 (3H, s, CH₃CO), 3.09 and

3.42 (each 1H, d, J 9.5, 7-H), 3.71 (1H, d, J 3.5, 5-H), 4.36 (2H,

d, J 1.6, 1-H₂), 4.54 and 4.86 (each 1H, d, J 11.4, PhHCH), 5.70

o

stirred at −78 C for 2 h. Methanol (0.8 mL) was added and the

reaction mixture allowed to warm to rt before diluting with ether

and pouring into a flask containing saturated Rochelle’s salt

solution. The mixture was stirred for 1 h and the aqueous layer

was extracted with ether. The organic extracts were dried

(MgSO₄) and concentrated under reduced pressure to give the

aldehyde 20 (343 mg, ca. 100%) used in the next reaction.

Chromatography (1:19, ether:light petroleum) of a sample gave

the title compound 20 (45%), R_f= 0.74 (1:9, ether:light

petroleum); ν_max/cm^-12955, 2929, 2857, 1730, 1472, 1363, 1252,

1096, 838, 776; δ_H0.01 and 0.03 (each 3H, s, SiCH₃), 0.86 [9H,

(1H, dt, J 3.8, 1.8, 4-H), 6.08 (1H, s, 2′-H), 7.26-7.35 (8H, m,

ArH), 7.44-7.50 (2H, m, ArH); δ_C−5.4, −5.3, −5.0, −4.9, 18.5,

20.1, 21.0, 21.9, 26.0, 26.2, 40.4, 52.0, 65.3, 70.2, 74.7, 75.0,

77.5, 81.7, 82.9, 85.9, 127.4, 128.3, 128.4, 128.9, 129.5, 133.8,

139.3, 168.0, 170.2; m/z (ES⁺) 742 (100%), 705 (M⁺+ 23,

100%), 383 (57%); HRMS (CI⁺): MNa⁺, found 705.3618.

C₃₈H₅₈O₇Si₂Na requires 705.3613).

s, SiC(CH₃)₃], 0.94 (6H, s, 2

3.48 (1H, d, J 2.7, 2-H), 3.50 (1H, d, J 9.4, 4-H

×

3-CH₃), 3.33 (1H, d, J 9.6, 4-H),

), 4.44 and 4.64

Following the same procedure, dicyclohexyl carbodi-imide

(130 mg, 0.632 mmol), (S)-O-acetylmandelic acid (66 mg, 0.316

mmol), DMAP (cat.) and the syn-alcohol 21 (50 mg, 99 µmol),

after chromatography (8% ether in light petroleum), gave the (S)-

O-acetylmandelate of the alcohol 21 (53 mg, 77%), R_f= 0.38

(2:8, ether:light petroleum); ν_max/cm^-12952, 2930, 2894, 2857,

1753, 1702, 1466, 1369, 1252, 1229, 1088, 838, 776, 733; δ_H

0.00, 0.02, 0.03 and 0.05 (each 3H, s, SiCH₃), 0.84 and 0.90

[each 9H, s, SiC(CH₃)₃], 0.94 and 0.96 (each 3H, s, 6-CH₃), 2.18

(3H, s, CH₃CO), 3.19 and 3.55 (each 1H, d, J 9.5, 7-H), 3.76 (1H,

d, J 3.4, 5-H), 4.18 (2H, d, J 1.6, 1-H₂), 4.64 and 4.97 (each 1H,

′

(each 1H, d, J 11.7, PhHCH), 7.24-7.35 (5H, m, ArH), 9.75 (1H,

d J 3.0, 1-H); δ_C−5.3(2), 18.5, 21.0, 22.0, 26.1, 41.6, 68.3, 73.3,

88.3, 128.1(2), 128.6, 138.0, 204.7; m/z (CI⁺) 354 (M⁺+ 18,

14%), 337 (M⁺+ 1, 60), 108 (80), 91 (100); HRMS (CI⁺): MH⁺,

found 337.2204. C₁₉H₃₃O₃Si requires 337.2199).

4.2.12 (4R,5R)- and (4S,5R)-5-Benzyloxy-1,7-bis-tert-

butyldimethylsilyloxy-6,6-dimethylhept-2-yn-4-ols (21) and (22).

n-Butyllithium (1.6 M in hexanes, 0.86 mL, 1.38 mmol) was

added to 3-tert-butyldimethylsilyloxypropyne (250 mg, 1.6

o

mmol) in THF (8 mL) at 0 C and the mixture stirred for 30 min

d, J 11.3, PhHCH), 5.64-5.72 (1H, m, 4-H), 5.97 (1H, s, 2′-H),

o

at 0 C then cooled to −78 C. Aldehyde 20 (323 mg, ca. 0.9

mmol) was added in THF (2 mL) and the mixture stirred at −78

^oC for 100 min. Saturated aqueous ammonium chloride was

added, and the mixture allowed to warm to rt then partitioned

between water and ether. The aqueous layer was extracted with

ether and the organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography (3% ether

in light petroleum) of the residue gave title compound 21 (205

mg, 42 %), R_f= 0.41 (2:8, ether:light petroleum); [α]_D²⁴−18.5 (c

4.8, CHCl₃); ν_max/cm^-13506, 2954, 2930, 2886, 2857, 1471,

1390, 1362, 1254, 1125, 1086, 1006, 837, 776, 729; δ_H0.00,

7.27-7.38 (8H, m, ArH), 7.45-7.50 (2H, m, ArH); m/z (ES⁺) 742

(61%), 705 (M⁺+ 23, 100); HRMS (CI⁺): MNa⁺, found

705.3609. C₃₈H₅₈O₇Si₂Na requires 705.3613).

4.2.13 (3S)-3-(4-Methoxybenzyloxy)-2,2-dimethylpent-4-en-1-

ol (24).¹⁵Methyltriphenylphosphonium bromide (8.50 g, 23.8

mmol) was azeotroped in toluene and dried overnight under a

high vacuum. Potassium tert-butoxide (2.67 g, 23.8 mmol) was

added and the solids stirred vigorously together for 30 min under

a flow of nitrogen. Tetrahydrofuran (150 mL) was added and the

o

mixture stirred for 1 h at rt before cooling to 0 C. The lactol 23

(4.00 g, 15.9 mmol) in THF (150 mL) was added and the mixture

allowed to warm to rt then stirred for 3.5 h. Water was added and

the mixture partitioned between water and ether. The aqueous

layer was extracted with ether and the organic extracts were dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (3:17 then 1:3, ether:light petroleum) of the

residue gave the title compound 24¹⁵(2.97 g, 75%), R_f= 0.21

(3:7, ether:light petroleum); [α]_D²⁰+ 40 (c 2.2, CHCl₃); ν_max/cm^-1

3425, 2959, 2930, 2871, 2836, 1613, 1513, 1465, 1301, 1275,

0.01, 0.06 and 0.07 (each 3H, s, SiCH₃), 0.84-0.90 [24H, m, 2

×

SiC(CH₃)₃, 2 6-CH₃], 3.33 and 3.40 (each 1H, d, J 9.8, 7-H),

×

3.42 (1H, d, J 7.7, 5-H), 3.59 (1H, s, OH), 4.32 (2H, d, J 1.6, 1-

H₂), 4.55 (1H, br. d, J 7.7, 4-H), 4.67 and 5.02 (each 1H, d, J

11.0, PhHCH), 7.20-7.38 (5H, m, ArH); δ_C−5.3, −5.2, −4.9(2),

18.5, 18.6, 21.2, 22.8, 26.1, 26.2, 40.7, 52.1, 60.6, 69.5, 75.8,

83.1, 85.2, 86.7, 127.9, 128.1, 128.6, 138.8; m/z (CI⁺) 524 (M⁺+

18, 42%), 507 (M⁺+ 1, 100); HRMS (CI⁺): MH⁺, found

507.3333. C₂₈H₅₁O₄Si₂requires 507.3326). The second fraction

was the title compound 22 (78 mg, 17%), R_f= 0.34 (2:8,

1174, 1110, 1036, 821; δ_H0.91 (6H, s, 2

× 2-CH₃), 2.89 (1H, t, J

5.9, OH), 3.58 and 3.55 (each 1H, dd, J 11.0, 5.8, 1-H), 3.64 (1H,

d, J 8.2, 3-H), 3.85 (3H, s, OCH₃), 4.27 and 4.59 (each 1H, d, J

11.4, ArHCH), 5.28 (1H, dd, J 17.3, 0.7, 5-H), 5.41 (1H, dd, J

24

ether:light petroleum); [α]_D+2.8 (c 4.3, CHCl₃); ν_max/cm^-1

3441, 2954, 2930, 2886, 2857, 1471, 1390, 1362, 1255, 1087,

1029, 1006, 838, 777, 732; δ_H0.00 (6H, s, 2

× SiCH₃), 0.02 and

10.3, 0.7, 5-H′), 5.80-5.90 (1H, m, 4-H), 6.92 and 7.28 (each 2H,

0.03 (each 3H, s, SiCH₃), 0.82 and 0.85 [each 9H, s, SiC(CH₃)₃],

0.90 and 0.97 (each 3H, s, 6-CH₃), 3.34 and 3.42 (each 1H, d, J

10.1, 7-H), 3.55 (1H, d, J 6.2, 5-H), 4.39 (2H, d, J 1.7, 1-H₂),

4.63-4.69 (2H, m, 4-H, PhHCH), 4.96 (1H, d, J 11.3, PhHCH),

7.29-7.46 (5H, m, ArH); δ_C−5.3(2), −4.9, 18.5, 18.6, 21.6, 22.6,

26.1(2), 40.7, 52.1, 63.7, 70.1, 75.4, 84.6, 85.0, 86.6, 127.7,

128.0, 128.5, 139.1; m/z (ES⁺) 566 (83%), 529 (M⁺+ 23, 100);

HRMS (CI⁺): MH⁺, found 507.3324. C₂₈H₅₁O₄Si₂requires

507.3326).

d, J 8.7, ArH); δ_C19.7, 22.5, 38.4, 55.2, 69.9, 71.3, 87.7, 113.8,

119.5, 129.4, 130.1, 134.9, 159.1; m/z (EI⁺) 250 (M⁺, 4%), 194

(18), 137 (20), 121 (100); HRMS (CI⁺): MH⁺, found 251.1644.

C₁₅H₂₃O₃requires 251.1648.

Alternatively, n-butyllithium (1.6 M in hexanes, 1.18 mL,

1.89

mmol)

was

added

to

a

suspension

of

methyltriphenylphosphonium bromide (867 mg, 2.43 mmol) in

o

THF (3 mL) at −78 ^oC and the mixture stirred at 0 C for 30 min

o

before cooling to −78 C. The lactol 23 (228 mg, 0.90 mmol) in

Dicyclohexyl carbodi-imide (130 mg, 0.632 mmol), (R)-O-

acetylmandelic acid (66 mg, 0.316 mmol) and DMAP (cat.) were

added to the syn-alcohol 21 (80 mg, 0.158 mmol) in THF (2 mL)

THF (3 mL) was added and the mixture allowed to warm to rt

then stirred for 18 h. Saturated aqueous ammonium chloride was

added and the mixture partitioned between water and DCM. The

aqueous layer was extracted with DCM and the organic extracts

o

at 0 C and the solution stirred for 18 h. After concentration

under reduced pressure, chromatography (8% ether in light

8

Tetrahedron

were dried (MgSO₄) and concentrated under reduced pressure.

0.97 (6H, s, 2 × 3-CH₃), 3.36 (1H, d, J 9.5, 4-H), 3.48-3.55 (2H,

ACCEPTED MANUSCRIPT

Chromatography (1:3, ether:light petroleum) of the residue gave

m, 4-H′, 2-H), 3.85 (3H, s, OCH₃), 4.43 and 4.61 (each 1H, d, J

the title compound 24 (135 mg, 60%).

11.4, ArHCH), 6.92 and 7.30 (each 2H, d, J 8.7, ArH), 9.73 (1H,

d, J 3.0, 1-H); δ_C−5.7(2), 18.1, 20.7, 21.6, 25.7, 41.2, 55.1, 67.9,

72.6, 87.5, 113.7, 129.5, 129.7, 159.3, 204.3; m/z (CI⁺) 384 (M⁺+

18, 13%), 367 (M⁺+ 1, 9), 247 (35), 231 (62), 217 (30), 121

(100); HRMS (ES⁺): MH⁺, found 367.2302. C₂₀H₃₅O₄Si requires

367.2299.

4.2.14

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

methoxybenzyloxy)-2,2-dimethylpent-4-ene (25). Imidazole (2.12

g, 31.2 mmol), tert-butyldimethylsilyl chloride (2.36 mL, 15.6

mmol), DMAP (cat.) and TBAI (cat.) were added to the alcohol

24 (2.60 g, 10.4 mmol) in DCM (80 mL) at rt and the mixture

stirred for 1 h. Saturated aqueous ammonium chloride was added

and the mixture partitioned between water and DCM. The

aqueous layer was extracted with DCM and the organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography (1:19, ether:light petroleum) of the residue

gave the title compound 25 (2.40 g, 63%), R_f= 0.79 (3:7,

4.2.17

(5R)-5-(4-Methoxybenzyloxy)-1-tert-

butyldiphenylsilyloxy-7-tert-butyldimethylsilyloxy-6,6-

dimethylhept-2-yn-4-one (28). n-Butyllithium (1.6 M in hexanes,

2.15

mL,

3.44

mmol)

was

added

to

3-tert-

butyldiphenylsilyloxyprop-2-yne (1.09 g, 3.69 mmol) in THF at

o

0 C and the mixture stirred at 0 C for 30 min before cooling to

−78 ^oC. The aldehyde 27 (448 mg, 1.32 mml) in THF was added

dropwise and the mixture was allowed to warm to 0 ^oC and

stirred for 2 h. Saturated aqueous ammonium chloride was added

and the mixture partitioned between water and ether. The

aqueous layer was extracted with ether and the organic extracts

were dried (MgSO₄) and concentrated under reduced pressure.

Chromatography (1:19 then 1:9, ether:light petroleum) of the

residue gave a mixture of the syn- and anti-alcohols 29 and 30,

20

ether:light petroleum); [α]_D+ 8.2 (c 4.8, CHCl₃); ν_max/cm^-1

2955, 2930, 2857, 1613, 1513, 1471, 1248, 1172, 1091, 1040,

851, 837, 775; δ_H0.00 (6H, s, 2

× SiCH₃), 0.80 and 0.86 (each

3H, s, 2-CH₃), 0.88 [9H, s, SiC(CH₃)₃], 3.26 and 3.45 (each 1H,

d, J 9.2, 1-H), 3.65 (1H, d, J 8.0, 3-H), 3.69 (3H, s, OCH₃), 4.21

and 4.49 (each 1H, d, J 11.4, ArHCH), 5.19 (1H, dd, J 17.1, 2.1,

5-H), 5.26 (1H, dd, J 10.4, 2.1, 5-H′), 5.70-5.84 (1H, m, 4-H),

6.85 and 7.24 (each 2H, d, J 8.7, ArH); δ_C−5.6, 18.2, 19.9, 21.0,

25.8, 39.5, 55.2, 69.1, 70.1, 83.9, 113.5, 118.1, 129.0, 131.3,

135.8, 158.8; m/z (CI⁺) 365 (M⁺+ 1, 10%), 243 (10), 138 (19),

121 (100); HRMS (CI⁺): MH⁺, found 365.2512. C₂₁H₃₇O₃Si

requires 365.2513.

1

ratio 75:25, (using the PhCH₂peaks in the H NMR) (737 mg,

84%). A sample of the less polar, major, syn-alcohol 29 was

isolated for characterisation; ν_max/cm^-13445, 2951, 2927, 2893,

2852, 1614, 1590, 1513, 1468, 1364, 1249, 1102, 1038, 836, 776,

740; δ_H0.00 (6H, s, 2

× SiCH₃), 0.85 [15H, s, SiC(CH₃)₃, 2 × 6-

4.2.15

(2RS,3R)-3-(4-Methoxybenzyloxy)-5-tert-

CH₃], 0.98 [9H, s, SiC(CH₃)₃], 3.32-3.42 (3H, m, 5-H, 7-H₂),

3.50 (1H, s, OH), 3.73 (3H, s, OCH₃), 4.31 (2H, d, J 1.6, 1-H₂),

4.49 (1H, dt, J 7.9, 1.6, 4-H), 4.55 and 4.90 (each 1H, d, J 10.7,

ArHCH), 6.78 and 7.22 (each 2H, d, J 8.8, ArH), 7.27-7.38 (6H,

m, ArH), 7.61-7.67 (4H, m, ArH); δ_C−5.5, 18.2, 19.1, 21.0, 22.4,

25.8, 26.6, 40.3, 52.7, 55.2, 60.2, 69.1, 74.6, 82.3, 84.7, 86.7,

113.6, 127.6, 129.5, 129.7, 130.3, 133.0, 135.5, 159.1; m/z (CI⁺)

661 (M⁺+ 1, 52%), 121 (100); HRMS (CI⁺): MH⁺, found

661.3753. C₃₉H₅O₅Si₂requires 661.3755.

butyldimethylsilyloxy-4,4-dimethylpentane-1,2-diol (26). N-

Methylmorpholine N-oxide (127 mg, 1.08 mmol) and then a

single crystal of osmium tetraoxide were added to the alkene 25

(200 mg, 0.54 mmol) in acetone (5 mL), water (2.5 mL) and tert-

butanol (5 mL) and the mixture was stirred for 18 h at rt.

Saturated aqueous sodium sulfite was added and the mixture

partitioned between EtOAc and water. The aqueous layer was

extracted with EtOAc and the organic extracts were dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (3:7 then 1:1, ether:light petroleum) of the

residue gave the recovered alkene 25 (53 mg, 27%) and the title

compound 26 (129 mg, 59%) that appeared by ¹H and ¹³C NMR

to be essentially a single diastereoisomer, R_f= 0.14 (1:1,

ether:light petroleum); ν_max/cm^-13397, 2955, 2930, 2857, 1613,

The Dess-Martin periodinane (630 mg, 1.68 mmol) was added

to this mixture of diols (737 mg, 1.12 mmol) in DCM (17 mL) at

rt and the mixture stirred for 45 min. Aqueous sodium hydroxide

(1.3 M) was added and the mixture partitioned between water and

DCM. The aqueous layer was extracted with DCM and the

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure to afford the title compound 28 (730 mg, ca.

1515, 1469, 1250, 1095, 1039, 838, 776; δ_H0.00 (6H, s, 2

×

SiCH₃), 0.83 [9H, s, SiC(CH₃)₃], 0.86 and 0.91 (each 3H, s, 4-

CH₃), 1.52 (1H, s, 2-OH), 2.31 (1H, br. s, 1-OH), 3.20-3.30 (1H,

m, 2-H), 3.35 and 3.44 (each 1H, d, J 10.3, 5-H), 3.62-3.79 (5H,

m, 1-H₂, OCH₃), 4.18-4.28 (1H, m, 3-H), 4.44 and 4.55 (each 1H,

d, J 10.5, ArHCH), 6.79 and 7.18 (each 2H, d, J 8.5, ArH); δ_C

−5.6, 18.2, 19.7, 23.2, 25.7, 40.5, 55.2, 64.3, 70.4, 71.4, 75.3,

86.0, 113.8, 129.2, 130.6, 159.1; m/z (CI⁺) 399 (M⁺+ 1, 13%),

279 (10), 138 (40), 121 (100); HRMS (CI⁺): MH⁺, found

399.2566. C₂₁H₃₉O₅Si requires 399.2567.

20

99%), R_f= 0.74 (2:8, ether:light petroleum); [α]_D+2.9 (c 2.8,

CHCl₃); ν_max/cm^-13071, 3050, 2954, 2931, 2857, 2213, 1672,

1613, 1588, 1514, 1471, 1428, 1391, 1368, 1302, 1249, 1174,

1104, 1038, 1008, 838, 777, 740; δ_H0.00 and 0.01 (each 3H, s,

Si(CH₃), 0.87 [9H, s, SiC(CH₃)₃], 0.92 and 0.94 (each 3H, s, 2

×

6-CH₃), 1.05 [9H, s, SiC(CH₃)₃], 3.19 and 3.54 (each 1H, d, J

9.3, 7-H), 3.77 (3H, s, OCH₃), 3.82 (1H, s, 5-H), 4.28 (1H, d, J

11.0, ArHCH), 4.45 (2H, s, 1-H₂), 4.56 (1H, d, J 11.0, ArHCH),

6.81 and 7.24 (2H, d, J 8.6, ArH), 7.34-7.45 (6H, m, ArH), 7.65-

7.72 (4H, m, ArH); δ_C−5.6, 18.2, 19.1, 19.8, 21.4, 25.8, 26.5,

40.3, 52.5, 55.1, 68.8, 72.6, 84.6, 87.5, 92.5, 113.6, 127.8, 129.5,

129.9, 132.4, 135.5, 159.1, 190.6; m/z (CI⁺) 660 (10%), 403 (20),

377 (17), 196 (15), 154 (16), 137 (34), 121 (100); HRMS (CI⁺):

MH⁺, found 659.3540. C₃₉H₅₅O₅Si₂requires 659.3589.

4.2.16

(2R)-4-tert-Butyldimethylsilyloxy-2-(4-

methoxybenzyloxy)-3,3-dimethylbutanal (27). Sodium periodate

(738 mg, 3.45 mmol) was added to the diol 26 (460 mg, 1.15

mmol) in THF (6 mL), water (8 mL) and MeOH (6 mL) at rt and

the mixture stirred at rt for 30 min. Saturated aqueous sodium

sulfite was added and the mixture partitioned between water and

ether. The aqueous layer was extracted with ether and the organic

extracts were washed with aqueous sodium sulfite, dried

(MgSO₄) and concentrated under reduced pressure to afford the

title compound 27 (423 mg, ca. 99%), R_f= 0.54 (2:8, ether:light

4.2.18

(4S,5R)-5-(4-Methoxybenzyloxy)-7-tert-

butyldimethylsilyloxy-1-tert-butyldiphenylsilyloxy-6,6-dimethyl-

hept-2-yn-4-ol (30). (R)-2-Methyl-CBS oxazaborolidine (1 M in

toluene, 0.40 mL, 0.40 mmol) was added to the ynone 28 (257

mg, 0.40 mmol) in THF (5 mL) at rt. The mixture was stirred for

10 min then cooled to −30 ^oC and borane dimethyl sulfide (0.114

mL, 1.20 mmol) was added over 5 min. The mixture was stirred

petroleum); [α]_D+25.5 (c 1.2, CHCl₃); ν_max/cm^-12955, 2930,

2857, 1729, 1613, 1514, 1470, 1250, 1173, 1093, 1037, 838, 776;

δ_H0.06 and 0.07 (each 3H, s, SiCH₃), 0.92 [9H, s, SiC(CH₃)₃],

20

9

o

at −30 C for 1 h then at −15 C for 1 h. Saturated aqueous

ammonium chloride was added then the mixture was partitioned

between water and ether. The aqueous layer was extracted with

ether and the organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (1:19, 1:9 then 1:4, ether:light petroleum) of the

residue gave a mixture of diastereoisomers 29 and 30 (192 mg,

75%), 29 : 30 = 20:80. A sample of the more polar title

compound 30 was isolated for characterisation, [α]_D²⁰+1.9 (c 1.7,

CHCl₃); ν_max/cm^-13441, 3071, 2953, 2929, 2895, 2857, 1657,

1613, 1588, 1513, 1468, 1366, 1249, 1102, 1083, 1038, 1009,

7.34 (each 2H, d, J 8.7, ArH), 7.36-7.46 (6H, m, ArH), 7.72-

ACCEPTED MANUSCRIPT

7.77 (4H, m, ArH); δ_C−5.2, −5.1, −4.7, −3.8, 18.4, 18.6, 19.5,

20.9, 22.3, 26.2(2), 26.9, 40.1, 53.2, 55.5, 65.6, 70.3, 74.5, 84.5,

85.5, 86.1, 113.7, 128.0, 128.5, 129.6, 129.2, 130.0, 132.3, 133.5,

135.1, 135.9, 159.1; m/z (CI⁺) 792 (M⁺+ 18, 12%), 437 (6), 274

(33), 217 (100), 196 (35), 137 (35), 121 (94); HRMS (CI⁺):

+

MNH₄, found 792.4885. C₄₅H₇₄NO₅Si₃requires 792.4875.

4.2.20 (1S)-2,2-Dimethyl-1-[(4R)-2,2-dimethyl-1,3-dioxolan-

4-yl]but-3-en-1-ol (33). Zinc was activated by stirring with

aqueous hydrogen chloride (5%) for 10 min and washing with

water until neutral. This zinc was then washed with ethanol and

ether before drying under a high vacuum for 4 h. 1-Bromo-3-

methylbut-2-ene (7.3 mL, 47.5 mmol) and the aldehyde 32 (4.98

g, 38.2 mmol) in THF (45 mL) were added to a rapidly stirred

suspension of this activated zinc (4.10 g, 76 mmol) in THF (45

mL) at 0 ^oC and the mixture stirred for 1 h. Water was added and

the mixture was filtered through celite with extensive DCM

washings. The aqueous layer was extracted with DCM and the

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography (3:7, ether:light petroleum) of

the residue gave the title compound 33 (5.6 g, 76%) together

with its syn-epimer, ratio 85:15 (¹H NMR). Further

chromatography (5% ether in light petroleum) gave the syn-

epimer, (1R)-2,2-dimethyl-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-

yl)but-3-en-1-ol (423 mg, 6%), R_f= 0.50 (4:6, ether:light

836, 776, 739; δ_H0.00 (6H, s, 2

× SiCH₃), 0.84 [9H, s,

SiC(CH₃)₃], 0.87 and 0.93 (each 3H, s, 6-CH₃), 0.98 [9H, s,

SiC(CH₃)₃], 3.30-3.45 (4H, m, 7-H₂, OH, 5-H), 3.72 (3H, s,

OCH₃), 4.30 (2H, d, J 1.6, 1-H₂), 4.43-4.50 (2H, m, ArHCH, 4-

H), 4.74 (1H, d, J 10.8, ArHCH), 6.77 and 7.22 (each 2H, d, J

8.5, ArH), 7.25-7.38 (6H, m, ArH), 7.61-7.67 (4H, m, ArH); δ_C

−5.2, 18.5, 19.4, 21.7, 22.5, 26.1, 26.9, 40.7, 53.1, 55.5, 63.7,

70.1, 75.0, 84.3, 85.5, 86.2, 114.0, 128.0, 129.7, 130.0, 131.3,

133.4, 135.9, 159.3; m/z (CI⁺) 661 (M⁺+ 1, 5%), 643 (8%), 274

(40), 217 (82), 196 (43), 137 (75), 121 (100); HRMS (EI⁺): MH⁺,

found 661.3754. C₃₉H₅₇O₅Si₂requires 661.3755).

Cerium trichloride hexahydrate (33 mg, 0.09 mmol) was

added to the ketone 28 (30 mg, 0.045 mmol) in MeOH (1 mL) at

rt. Sodium borohydride (4 mg, 0.09 mmol) was added and the

mixture stirred at rt for 1.5 h. Aqueous hydrogen chloride (2%)

was the added until the mixture was neutral. After partitioning

between water and ether, the aqueous layer was extracted with

ether and the organic extracts were dried (MgSO₄) and

concentrated under reduced pressure to give a mixture of the

epimeric alcohols 29 and 30, ratio 29:30 = 86:14 (28 mg, 85%).

petroleum); [α]_D+1.5 (c 3.1, CHCl₃); ν_max/cm^-13544, 2984,

2935, 2879, 1638, 1465, 1376, 1251, 1217, 1155, 1064, 1006,

915, 857; δ_H1.07 and 1.08 (each 3H, s, 2-CH₃), 1.38 and 1.43

20

(each 3H, s, 2

4.0, 1-H), 3.73 (1H, t, J 8.0, 5

), 4.16 (1H, ddd, J 8.0, 6.5, 4.0, 4

1.0, 4-H), 5.75 (1H, dd, J 11.1, 1.0, 4-H

′

-CH₃), 2.49 (1H, d, J 7.0, OH), 3.22 (1H, dd, J 7.0,

-H), 4.00 (1H, dd, J 8.0, 6.5, 5

-H), 5.60 (1H, dd, J 17.1,

), 5.95 (1H, dd, J 17.1,

′

′-

H′

′

Zinc chloride (2.5 g) was fused under pressure then a

suspension in ether (40 mL) was heated under reflux for 1 h.

After allowing to cool to rt, the supernatant was added to a

suspension of sodium borohydride (700 mg, 18.4 mmol) in dry

ether (20 mL) and the mixture stirred for 2 d. This solution of

zinc borohydride (0.3 M, 1 mL) was added to the ketone 28 (35

11.1, 3-H); δ_C21.8, 24.9, 25.9, 26.6, 39.6, 41.2, 68.0, 75.2, 107.7,

113.2, 145.0; m/z (CI⁺) 218 (M⁺+ 18, 100%), 201 (M⁺+ 1, 85);

HRMS (ES⁺): MH⁺, found 201.1488. C₁₁H₂₁O₃requires

201.1485. After a mixed fraction (1.12 g), the title compound 33

(4.03 g, 53%) was eluted (1:1 ether:light petroleum), R_f= 0.44

(4:6, ether:light petroleum); [α]_D²⁰+32.1 (c 1.7, CHCl₃); ν_max/cm^-

o

mg, 0.05 mmol) in dry ether (0.5 mL) at −30 C and the mixture

1

3486, 2984, 2932, 2876, 1636, 1465, 1374, 1252, 1217, 1158,

1058, 917, 856; δ_H1.09 and 1.10 (each 3H, s, 2-CH₃), 1.37 and

stirred for 2 h. A further portion of zinc borohydride (1 mL) was

added and the reaction stirred at 0 ^oC. After 1 h, aqueous

hydrogen (2%) was added until the mixture was neutral. After

partitioning between water and ether, the aqueous layer was

extracted with ether and the organic extracts were dried (MgSO₄)

and concentrated under reduced pressure to give a mixture of the

epimeric alcohols 29 and 30, ratio 29:30 = 14:86 (30 mg, 86%).

1.43 (each 3H, s, 2

3.1, 1-H), 3.83-3.91 (2H, m, 5

-H), 5.06 (1H, dd, J 17.4, 1.3, 4-H), 5.08 (1H, dd, J 11.0, 1.3, 4-

′

-CH₃), 2.03 (1H, d, J 2.9, OH), 3.65 (1H, t, J

′

-H₂), 4.18 (1H, ddd, J 7.7, 6.4, 3.3,

4

′

H′), 5.92 (1H, dd, J 17.4, 11.0, 3-H); δ_C23.5, 24.3, 25.7, 26.7,

40.3, 64.9, 76.7, 107.9, 113.3, 144.7; m/z (CI⁺) 218 (M⁺+ 18,

78%), 201 (M⁺+ 1, 100); HRMS (ES⁺): MH⁺, found 201.1484.

C₁₁H₂₁O₃requires 201.1485.

4.2.19

(4S,5R)-5-(4-Methoxybenzyloxy)-4,7-bis-tert-

butyldimethylsilyloxy-1-tert-butyldiphenylsilyloxy-6,6-

(R)-(O)-Acetylmandelic acid (69 mg, 0.29 mmol), DMAP

(cat.) and dicyclohexyl carbodi-imide (91 mg, 0.44 mmol) in

THF (1 mL) were added to the alcohol 33 (42 mg, 0.21 mmol) in

THF (1.5 mL) at 0 ^oC and the mixture stirred at rt for 18 h. After

concentration under reduced pressure, chromatography of the

residue gave the (R)-O-acetylmandelate of the alcohol 33 (54 mg,

69%), R_f= 0.16 (3:17, ether:light petroleum), [α]_D²⁰−30.5 (c 1.2,

CHCl₃); δ_H0.72 and 0.87 (each 3H, s, 2-CH₃), 1.35 and 1.41

dimethylhept-2-yne (31). Imidazole (55 mg, 0.81 mmol) and tert-

butyldimethylsilyl chloride (81 mg, 0.54 mmol) were added to

the alcohol 30 (182 mg, 0.27 mmol) in DCM (1 mL) at rt and the

solution stirred for 18 h. Saturated aqueous ammonium chloride

was added and the mixture was partitioned between water and

DCM. The aqueous layer was extracted with DCM, and the

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography (1:19, ether:light petroleum)

of the residue gave the title compound 31 (200 mg, 96%), R_f=

(each 3H, s, 2

H), 3.96 (1H, t, J 8.3, 5

d, J 17.4, 4-H), 4.89 (1H, d, J 10.8, 4-H

′

-CH₃), 2.25 (3H, s, CH₃CO), 3.81 (1H, t, J 8.2, 5

-H ), 4.18-4.28 (1H, m, 4 -H), 4.81 (1H,

), 5.09 (1H, d, J 4.1, 1-

′-

′

20

0.33 (1:19, ether:light petroleum); [α]_D+18.4 (c 3.7, CHCl₃);

′

ν_max/cm^-13071, 2954, 2930, 2894, 2857, 1613, 1588, 1514, 1471,

1428, 1390, 1361, 1301, 1250, 1106, 1087, 1006, 838, 777, 740;

δ_H0.05, 0.06, 0.18 and 0.22 (each 3H, s, SiCH₃), 0.94-1.00 [24H,

H), 5.61 (1H, dd, J 17.5, 10.8, 3-H), 6.01 (1H, s, 2′′-H), 7.40-7.56

(5H, m, ArH); δ_C21.0, 23.5, 23.7, 25.6, 26.5, 40.3, 65.6, 74.6,

75.0, 79.8, 108.8, 113.6, 128.0, 128.9, 129.5, 134.2, 143.1, 168.4,

170.3; m/z (CI⁺) 394 (M⁺+ 18, 100%), 377 (M⁺+ 1, 33); HRMS

(ES⁺): MH⁺, found 377.1963. C₂₁H₂₉O₆requires 377.1959.

m, 2

× SiC(CH₃)₃, 2 × 6-CH₃], 1.08 [9H, s, SiC(CH₃)₃], 3.25 and

3.53 (each 1H, d, J 9.5, 7-H), 3.56 (1H, d, J 2.9, 5-H), 3.82 (3H,

s, OCH₃), 4.38 (2H, d, J 1.5, 1-H₂), 4.53 (1H, d, J 11.0, ArHCH),

4.70-4.80 (1H, m, 4-H), 4.99 (1H, d, J 11.0, ArHCH), 6.84 and

10

Tetrahedron

Following the same procedure, (S)-(O)-acetylmandelic acid

The organic extracts were dried (MgSO₄) and concentrated under

ACCEPTED MANUSCRIPT

gave the (S)-O-acetylmandelate of the alcohol 33 (51 mg, 65%),

R_f= 0.16 (3:17, ether:light petroleum); [α]_D²⁰+59 (c 1.0, CHCl₃);

δ_H0.92, 1.07, 1.13 and 1.22 (each 3H, s, CH₃), 2.24 (3H, s,

CH₃CO), 3.34 (1H, t, J 7.9, 5

4.11 (1H, ddd, J 7.8, 6.3, 4.3, 4

H), 5.90 (1H, dd, J 17.8, 10.8, 3-H), 5.97 (1H, s, 2′′-H), 7.40-7.56

(5H, m, ArH); δ_C20.7, 23.9, 25.0, 25.9, 26.3, 34.7, 66.2, 74.3,

75.6, 86.7, 109.5, 114.3, 127.6, 129.2, 129.8, 134.9, 144.2, 168.9,

171.1; m/z (CI⁺) 394 (M⁺+ 18, 100%), 377 (M⁺+ 1, 31), 319

(28); HRMS (ES⁺): MH⁺, found 377.1963. C₂₁H₂₉O₆requires

377.1959.

reduced pressure to give the title compound 36 (530 mg, ca.

20

99%), R_f= 0.62 (4:6, ether:light petroleum); [α]_D−57.6 (c 2.2,

CHCl₃); ν_max/cm^-12963, 2930, 2867, 1729, 1612, 1513, 1464,

1370, 1302, 1248, 1175, 1083, 1035, 921, 822; δ_H1.09 and 1.10

(each 3H, s, 3-CH₃), 3.36 (1H, d, J 3.3, 2-H), 3.82 (3H, s, OCH₃),

4.39 and 4.60 (1H, d, J 11.5, ArHCH), 5.03 (1H, d, J 17.5, 5-H),

′

-H), 3.54 (1H, dd, J 7.9, 6.3, 5

′-H′),

′

-H), 5.05-5.13 (3H, m, 4-H₂, 1-

5.06 (1H, d, J 10.8, 5-H′), 5.96 (1H, dd, J 17.6, 11.0, 4-H), 6.88

and 7.26 (each 2H, d, J 8.5, ArH), 9.60 (1H, d, J 2.9, 1-H); δ_C

23.4, 23.5, 40.9, 55.4, 72.8, 89.1, 113.4, 113.9, 129.6, 129.8,

143.3, 159.6, 204.4; m/z (CI) 266 (M⁺+ 18, 21%), 138 (25), 121

(100); HRMS (EI⁺): M⁺, found 248.1411. C₁₅H₂₀O₃requires

248.1407.

4.2.21 (4R)-4-[(1S)-1-(4-Methoxybenzyloxy)-2,2-dimethylbut-

3-enyl]-2,2-dimethyl-1,3-dioxolane (34). The alcohol 33 (627

mg, 3.13 mmol) in DMF (3 mL) was added to a suspension of

sodium hydride (60% in mineral oil, 258 mg, 6.46 mmol) in

4.2.24 (3S,4S)- and (3R,4S)-4-(4-Methoxybenzyloxy)-5,5-

dimethylhept-6-en-1-yn-3-ols (37) and (38). The aldehyde 36 (60

mg, 0.24 mmol) in ether (1 mL) was added to ethynylmagnesium

bromide (0.5 M in THF, 960 µl, 0.48 mmol) at −78 C and the

solution stirred at −78 C for 2 h. The mixture was allowed to

o

DMF (7 mL) at 0 C and the mixture allowed to warm to rt and

stirred for 30 min. After cooling to 0 ^oC, 4-methoxybenzyl

chloride (875 µl, 6.46 mmol) was added and, after 10 min, the

mixture was allowed to warm to rt and was stirred for 1 h.

Saturated aqueous ammonium chloride was added and the

mixture was partitioned between water and ether. The aqueous

layer was extracted with ether and the organic extracts were dried

(Na₂SO₄) and concentrated under reduced pressure.

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

the title compound 34 (978 mg, 98%), R_f= 0.44 (2:8, ether:light

o

warm to 0 C over 1 h and was stirred for a further 30 min, then

warmed to rt, and stirred for 2 h. Saturated aqueous ammonium

chloride was added and the mixture partitioned between water

and ether. The aqueous layer was extracted with ether and the

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography of the residue gave recovered

aldehyde 36 (30 mg, 50%) followed by the title compound 37 (19

20

mg, 29%), R_f= 0.30 (2:8, ether:light petroleum); [α]_D+8.5 (c

petroleum); [α]_D+21 (c 4.1, CHCl₃); ν_max/cm^-12983, 2935,

2906, 1613, 1514, 1463, 1374, 1248, 1215, 1172, 1062, 1041,

1.1, CHCl₃); ν_max/cm^-13486, 3291, 2961, 2930, 1612, 1514,

1465, 1377, 1303, 1248, 1174, 1079, 1037, 919, 826; δ_H1.06

20

915, 859, 823; δ_H1.01 and 1.07 (each 3H, s, 2

1.45 (each 3H, s, 2-CH₃), 3.56 (1H, d, J 1.5, 1 -H), 3.82 (3H, s,

OCH₃), 3.89 (1H, t, J 7.2, 5-H), 4.00 (1H, t, J 7.8, 5-H ), 4.27

(1H, td, J 7.8, 1.5, 4-H), 4.55 and 4.85 (each 1H, d, J 10.8,

ArHCH), 4.96-5.04 (2H, m, 4 -H₂), 5.92 (1H, dd, J 17.7, 10.5, 3

′

-CH₃), 1.36 and

(6H, s, 2 × 5-CH₃), 2.47 (1H, s, 1-H), 2.96 (1H, br. d, J 8.5, OH),

3.43 (1H, s, 4-H), 3.81 (3H, s, OCH₃), 4.43 (1H, br. d, J 8.5, 3-

H), 4.68 and 4.92 (each 1H, d, J 9.5, ArHCH), 5.04 (1H, d, J

′

16.0, 7-H), 5.05 (1H, d, J 11.5, 7-H′), 5.85 (1H, dd, J 17.5, 11.0,

′

-

6-H), 6.89 and 7.32 (each 2H, d, J 8.5, ArH); δ_C22.3, 25.1, 42.2,

55.6, 60.2, 72.8, 75.9, 86.2, 87.2, 113.4, 114.1, 130.1, 130.2,

145.0, 159.7; m/z (CI⁺) 292 (M⁺+ 18, 8%), 138 (17), 121 (100);

H), 6.89 and 7.31 (each 2H, d, J 8.7, ArH); δ_C23.6, 24.9, 25.3,

26.7, 41.2, 55.5, 64.9, 75.6, 77.4, 85.4, 107.6, 112.4, 113.9,

129.5, 131.4, 145.3, 159.2; m/z (CI⁺) 338 (M⁺+ 18, 33%), 155

+

HRMS (ES⁺): MNH₄, found 292.1900. C₁₇H₂₆NO₃requires

+

(24), 138 (83), 121 (100); HRMS (ES⁺): MNH₄, found

292.1907. The second product was the title compound 38 (14 mg,

20

338.2325. C₁₉H₃₂NO₄requires 338.2326).

21%), R_f= 0.22 (2:8, ether:light petroleum); [α]_D−7.3 (c 0.6,

CHCl₃); ν_max/cm^-13434, 3302, 2955, 2930, 1723, 1612, 1513,

1462, 1383, 1299, 1247, 1173, 1103, 1035, 918, 827; δ_H1.14

4.2.22

(2R,3S)-3-(4-Methoxybenzyloxy)-4,4-dimethylhex-5-

ene-1,2-diol (35). The dioxolane 34 (3.20 g, 10 mmol) was

(6H, s, 2

× 5-CH₃), 1.98 (1H, br. d, J 6.2, OH), 2.56 (1H, d, J 2.0,

dissolved in aqueous acetic acid (70%, 28 mL) and the solution

1-H), 3.34 (1H, d, J 3.8, 4-H), 3.83 (3H, s, OCH₃), 4.49-4.55

(1H, m, 3-H), 4.69 and 4.81 (each 1H, d, J 11.2, ArHCH), 5.05

(1H, d, J 10.7, 7-H), 5.08 (1H, d, J 17.5, 7-H′), 6.00 (1H, dd, J

o

was warmed to 48 C and stirred for 2 h. After concentration

under reduced pressure, the residue was taken up in EtOAc and

solid NaHCO₃and MgSO₄were added. The slurry was stirred

vigorously, then filtered and concentrated under reduced

pressure. Chromatography (7:3 then 8:2, ether:light petroleum) of

the residue gave the title compound 35 (2.48 g, 86%), R_f= 0.35-

17.5, 10.7, 6-H), 6.91 and 7.35 (each 2H, d, J 8.6, ArH); δ_C22.3,

25.5, 41.7, 55.5, 64.6, 75.3, 77.5, 83.6, 88.3, 112.8, 114.1, 129.8,

131.0, 145.7, 159.5; m/z (CI⁺) 292 (M⁺+ 18, 2%), 138 (7), 121

+

(100); HRMS (ES⁺): MNH₄, found 292.1904. C₁₇H₂₆NO₃

20

0.15 (1:1, ether:light petroleum); [α]_D+23.5 (c 5.1, CHCl₃);

requires 292.1907.

ν_max/cm^-13405, 2961, 2936, 2878, 1613, 1514, 1464, 1302, 1248,

1175, 1071, 1037, 916, 821; δ_H1.12 and 1.13 (each 3H, s, 4-

CH₃), 2.31 and 2.45 (each 1H, br. s, OH), 3.39 (1H, d, J 4.0, 3-

H), 3.75-3.79 (3H, m, 1-H₂, 2-H), 3.81 (3H, s, OCH₃), 4.62 and

4.64 (each 1H, d, J 10.6, ArHCH), 5.02-5.12 (2H, m, 6-H₂), 6.04

(1H, dd, J 18.0, 9.5, 5-H), 6.89 and 7.28 (each 2H, d, J 8.0, ArH);

δ_C22.9, 25.5, 41.9, 55.5, 64.2, 72.7, 76.1, 88.7, 112.7, 114.1,

129.7, 130.7, 145.8, 159.6; m/z (CI⁺) 298 (M⁺+ 18, 32%), 218

(27), 155 (32), 138 (100), 121 (93); HRMS (EI⁺): M⁺, found

280.1673. C₁₆H₂₄O₄requires 280.1674.

4.2.25 (4S,5S)- and (4R,5S)-5-(4-Methoxybenzyloxy)-6,6-

dimethyl-1-triethylsilyloxyoct-7-en-2-yn-4-ols (39) and (40). n-

Butyllithium (1.6 M in hexanes, 4.6 mL, 7.34 mmol) was added

to 3-triethylsilyloxypropyne (1.31 g, 7.71 mmol) in THF (8 mL)

o

at 0 C and the solution stirred for 1 h. After cooling to −78 C,

the aldehyde 36 (910 mg, 3.67 mmol) in THF (4.2 mL) was

o

added over 10 min and the solution stirred for 2.5 h at −78 C.

Saturated aqueous ammonium chloride was added and the

mixture was allowed to warm to rt then partitioned between

water and ether. The aqueous layer was extracted with ether and

the organic extracts were dried (MgSO₄) and concentrated under

reduced pressure to give the title compounds as a mixture of

diastereoisomers, 39:40 = 92:8 (¹H NMR). Chromatography (1:9,

ether:light petroleum with 1% Et₃N) of the mixture gave

recovered aldehyde 36 (88 mg, 10%) followed by the title

compound 39 (1.13 g, 74%), R_f= 0.45 (3:7, ether:light

4.2.23 (2S)-2-(4-Methoxybenzyloxy)-3,3-dimethylpent-4-enal

(36). Sodium periodate (916 mg, 4.28 mmol) was added to the

diol 35 (600 mg, 2.14 mmol) in MeOH (14 mL) and water (7

o

mL) at 0 C and the mixture was allowed to warm to rt and

stirred for 1 h 10 min. The mixture was partitioned between

water and DCM and the aqueous layer was extracted with DCM.

11

20

petroleum); [α]_D+16.3 (c 0.6, CHCl₃); ν_max/cm^-13507, 2956,

1H, d, J 11.3, ArHCH), 5.01 (1H, d, J 10.8, 8-H), 5.03 (1H, d,

ACCEPTED MANUSCRIPT

2913, 2878, 1613, 1514, 1463, 1372, 1245, 1123, 1082, 1040,

J 17.5, 8-H′), 6.09 (1H, dd, J 17.5, 10.7, 7-H), 6.92 and 7.36

1009, 807, 726; δ_H0.66 (6H, q, J 8.0, 3

×

SiCH₂), 0.99 (9H, t, J

(each 2H, d, J 8.6, ArH); δ_C−4.4, −4.1, 18.5, 24.0, 25.4, 26.2,

42.0, 51.6, 55.5, 63.9, 74.9, 84.6, 87.8, 88.2, 111.6, 113.8, 129.3,

131.5, 146.4, 159.1; m/z (CI⁺) 436 (M⁺+ 18, 3%), 154 (32), 138

7.9, 3 SiCH₂CH₃), 1.07 (6H, s, 2 6-CH₃), 2.92 (1H, d, J 8.5,

×

OH), 3.43 (1H, d, J 1.5, 5-H), 3.83 (3H, s, OCH₃), 4.37 (2H, d, J

1.4, 1-H₂), 4.49 (1H, dq, J 8.3, 1.5, 4-H), 4.68 and 4.92 (1H, d, J

10.6, ArHCH), 5.00-5.10 (2H, m, 8-H₂), 5.87 (1H, dd, J 17.9,

10.5, 7-H), 6.90 and 7.3 (each 2H, d, J 8.5, ArH); δ_C4.7, 7.0,

22.3, 25.0, 42.1, 51.7, 55.5, 60.4, 75.7, 83.1, 86.8, 87.2, 113.2,

114.0, 130.1, 130.3, 145.1, 159.7; m/z (CI⁺) 436 (M⁺+ 18, 81%),

+

(45), 121 (100); HRMS (CI⁺): MNH₄, found 436.2892.

C₂₄H₄₂NO₄Si requires 436.2883. The second product was

(4S,5S)-5-(4-methoxybenzyloxy)-6,6-dimethyloct-7-en-2-yne-

1,4-diol (24 mg, 3%), R_f= 0.10 (1:1, ether:light petroleum);

20

[α]_D+24.5 (c 1.3, CHCl₃); ν_max/cm^-13401, 2960, 2928, 2876,

138 (30), 121 (100); HRMS (CI⁺): MNH₄, found 436.2889.

1613, 1586, 1514, 1302, 1249, 1174, 1119, 1034, 916, 822; δ_H

1.11 and 1.12 (each 3H, s, 6-CH₃), 1.81 (1H, br. s, 1-OH), 3.03

(1H, d, J 8.3, 4-OH), 3.46 (1H, d, J 1.9, 5-H), 3.86 (3H, s,

OCH₃), 4.34 (2H, br. s, 1-H₂), 4.52 (1H, dt, J 8.2, 1.8, 4-H), 4.73

and 4.92 (each 1H, d, J 10.5, ArHCH), 5.09 (1H, d, J 17.5, 8-H),

+

C₂₄H₄₂NO₄Si requires 436.2883. The second product was the title

compound 40 (66 mg, 4%), R_f= 0.36 (3:7, ether:light petroleum);

20

[α]_D−3.2 (c 2.7, CHCl₃); ν_max/cm^-13446, 3409, 2955, 2915,

2878, 1613, 1513, 1463, 1369, 1302, 1246, 1082, 1037, 1008,

812, 740; δ_H0.61 (6H, q, J 7.9, 3

×

SiCH₂), 0.93 (9H, t, J 7.9, 3

×

5.10 (1H, d, J 10.5, 8-H′), 5.91 (1H, dd, J 17.5, 10.5, 7-H), 6.94

CH₃), 1.09 and 1.10 (each 3H, s, 6-CH₃), 1.91 (1H, d, J 5.8, OH),

3.28 (1H, d, J 3.8, 5-H), 3.78 (3H, s, OCH₃), 4.31 (2H, s, 1-H₂),

4.47-4.55 (1H, m, 4-H), 4.61 and 4.75 (each 1H, d, J 11.0,

and 7.37 (each 2H, d, J 8.7, ArH); δ_C22.4, 25.0, 42.1, 51.4, 55.5,

60.4, 75.9, 82.9, 87.3, 87.8, 113.3, 114.1, 128.9, 130.1, 144.9,

159.7; m/z (CI⁺) 322 (M⁺+ 18, 20%), 138 (22), 121 (100); HRMS

+

ArHCH), 4.99 (1H, d, J 10.8, 8-H), 5.02 (1H, d, J 17.5, 8-H

′

),

(CI⁺): MNH₄, found 322.2019. C₁₈H₂₈NO₄requires 322.2018.

5.96 (1H, dd, J 17.5, 10.8, 7-H), 6.85 and 7.29 (each 2H, d, J 8.5,

ArH); δ_C4.7, 7.0, 22.6, 25.4, 41.7, 51.8, 55.5, 64.8, 75.3, 84.3,

85.5, 88.5, 112.5, 114.0, 129.7, 131.2, 145.9, 159.4; m/z (CI⁺)

4.2.28 (2Z)-(4R,5S)-4-tert-Butyldimethylsilyloxy-3-iodo-5-(4-

methoxybenzyloxy)-6,6-dimethylocta-2,7-dien-1-ol (43) and (2E)-

(4S,5S)-4-tert-butyldimethylsilyloxy-5-(4-methoxybenzyloxy)-6,6-

dimethylocta-2,7-dien-1-ol (44). The alkynol 42 (546 mg, 1.31

mmol) in ether (5.4 mL) was added to Red-Al^TM(65% in toluene,

+

436 (M⁺+ 18, 29%), 138 (42), 121 (100); HRMS (CI⁺): MNH₄,

found 436.2892. C₂₄H₄₂NO₄Si requires 436.2883.

o

4.2.26

(4S,5S)-4-tert-Butyldimethylsilyloxy-5-(4-

783 µl, 2.61 mmol) in ether (10.9 mL) at 0 C and the mixture

methoxybenzyloxy)-6,6-dimethyl-1-triethylsilyloxyoct-7-en-2-yne

(41). 2,6-Lutidine (907 µl, 7.8 mmol) and tert-butyldimethylsilyl

triflate (894 µl, 3.9 mmol) were added to the alcohol 39 (1.08 g,

2.6 mmol) in DCM (26 mL) at 0 ^oC and the solution stirred for 1

h. Water was added and the aqueous layer was extracted with

DCM. The organic extracts were washed with brine, dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (1% ether, 1% Et₃N in light petroleum) of the

residue gave the title compound 41 (1.27 g, 92%), R_f= 0.64 (1:9,

ether:light petroleum); ν_max/cm^-12955, 2933, 2880, 1613, 1513,

1464, 1249, 1125, 1083, 1008, 838, 778, 741; δ_H0.09 and 0.16

stirred for 1 h at 0 ^oC. The mixture was allowed to warm to rt and

o

was stirred for 3 h before cooling to −78 C. Crushed iodine

flakes (663 mg, 2.61 mmol) were added in one portion and the

reaction mixture was allowed to warm slowly to −10 ^oC over 1 h.

An aqueous solution of Rochelle’s salt was added and the

mixture was allowed to warm to rt then ether was added. The

mixture was stirred vigorously for 30 min then extracted with

ether. The organic extracts were washed with saturated aqueous

sodium thiosulfate and the washings extracted with ether. The

organic extracts were dried (MgSO₄) and concentrated under

reduced pressure. Chromatography (1:9, 2:8, then 3:7, ether:light

petroleum with 1% Et₃N) of the residue gave the title compound

(each 3H, s, SiCH₃), 0.66 (6H, q, J 8.0, 3

× SiCH₂), 0.93 [9H, s,

20

SiC(CH₃)₃], 1.00 (9H, t, J 8.0, 3 SiCH₂CH₃), 1.09 and 1.13

×

43 (489 mg, 69%), R_f= 0.37 (4:6, ether:light petroleum); [α]_D

(each 3H, s, 6-CH₃), 3.26 (1H, d, J 4.7, 5-H), 3.83 (3H, s, OCH₃),

4.34 (2H, s, 1-H₂), 4.56-4.48 (2H, m, 4-H, ArHCH), 4.93 (1H, d,

J 11.2, ArHCH), 4.99 (1H, d, J 10.6, 8-H), 5.00 (1H, d, J 17.5, 8-

+8.0 (c 0.8, CHCl₃); ν_max/cm^-13411, 2952, 2859, 1613, 1513,

1464, 1249, 1109, 1075, 1042, 838; δ_H0.06 (6H, s, 2

× SiCH₃),

0.95 [9H, s, SiC(CH₃)₃], 1.10 and 1.13 (each 3H, s, 6-CH₃), 1.49

(1H, br. t, OH), 3.35 (1H, d, J 5.8, 5-H), 3.85 (3H, s, OCH₃), 4.00

(1H, d, J 5.7, 4-H), 4.20-4.24 (2H, m, 1-H₂), 4.56 and 4.83 (1H,

d, J 11.3, ArHCH), 4.96 (1H, dd, J 17.6, 1.2, 8-H), 4.99 (1H, dd,

H′), 6.04 (1H, dd, J 17.5, 10.7, 7-H), 6.89 and 7.32 (each 2H, d, J

8.4, ArH); δ_C−4.5, −4.1, 4.7, 7.0, 18.5, 23.9, 25.3, 26.1, 41.9,

51.7, 55.5, 63.7, 74.7, 84.8, 86.6, 88.2, 111.5, 113.7, 129.3,

131.7, 146.2, 159.0; m/z (CI⁺) 550 (M⁺+ 18, 35%), 532 (M⁺, 12),

121 (100); HRMS (CI⁺): M⁺, found 532.3398. C₃₀H₅₂O₄Si₂

requires 532.3399.

J 10.8, 1.2, 8-H′), 6.05 (1H, dd, J 17.3, 11.1, 7-H), 6.24 (1H, t, J

5.6, 2-H), 6.91 and 7.33 (each 2H, d, J 8.7, ArH); δ_C−4.0, −3.6,

18.4, 23.6, 25.9, 26.3, 42.2, 55.5, 67.1, 75.5, 79.8, 86.1, 111.6,

113.7, 115.5, 128.8, 131.8, 136.4, 146.1, 159.0; m/z (CI⁺) 564

(M⁺+ 18, 3%), 154 (48), 138 (100), 121 (75); HRMS (CI⁺):

4.2.27

(4S,5S)-4-tert-Butyldimethylsilyloxy-5-(4-

(42).

methoxybenzyloxy)-6,6-dimethyloct-7-en-2-yn-1-ol

+

MNH₄, found 564.2012. C₂₄H₄₃NO₄SiI requires 564.2006. The

Potassium fluoride (2.15 g, 37.0 mmol) was added to the

triethylsilyl ether 41 (1.27 g, 2.38 mmol) in THF (8.5 mL) and

MeOH (34 mL) at 0 ^oC and the mixture stirred for 2 h. Saturated

aqueous sodium hydrogen carbonate was added and the mixture

partitioned between water and ether. The aqueous layer was

extracted with ether and the organic extracts were dried (MgSO₄)

and concentrated under reduced pressure. Chromatography (3:7,

ether:light petroleum) of the residue gave recovered silyl ether 41

(113 mg, 9%) followed by the title compound 42 (767 mg, 77%),

R_f= 0.50 (1:1, ether:light petroleum); [α]_D²⁰+4.0 (c 1.6, CHCl₃);

ν_max/cm^-13411, 2955, 2932, 2859, 1613, 1514, 1467, 1353, 1249,

1093, 1036, 839, 778; δ_H0.11 and 0.18 (each 3H, s, SiCH₃), 0.85

[9H, s, SiC(CH₃)₃], 1.14 and 1.16 (each 3H, s, 6-CH₃), 1.64 (1H,

br. s, OH), 3.28 (1H, d, J 5.3, 5-H), 3.85 (3H, s, OCH₃), 4.37-

4.41 (2H, m, 1-H₂), 4.52 (1H, d, J 5.2, 4-H), 4.58 and 4.91 (each

second product was the title compound 44 (79 mg, 14%), R_f=

20

0.24 (4:6, ether:light petroleum); [α]_D−10.2 (c 1.1, CHCl₃);

ν_max/cm^-13410, 2954, 2930, 2859, 1688, 1612, 1212, 1513, 1465,

1361, 1301, 1251, 1173, 1080, 1039, 835, 777; δ_H0.04 and 0.07

(each 3H, s, SiCH₃), 0.94 [9H, s, SiC(CH₃)₃] 1.11 and 1.13 (each

3H, s, 6-CH₃), 3.13 (1H, d, J 4.8, 5-H), 3.85 (3H, s, OCH₃), 4.15

(2H, d, J 4.8, 1-H₂), 4.36 (1H, t, J 5.2, 4-H), 4.54 and 4.73 (1H,

d, J 11.1, ArHCH), 4.94 (1H, d, J 10.5, 8-H), 4.95 (1H, d, J 17.8,

8-H′), 5.76 (1H, dt, J 15.6, 5.1, 2-H), 5.86 (1H, dd, J 15.8, 5.7, 3-

H), 6.06 (1H, dd, J 18.0, 10.4, 7-H), 6.92 and 7.33 (each 2H, d, J

8.6, ArH; δ_C−4.3, −4.0, 18.4, 25.0, 25.2, 26.2, 42.2, 55.5, 63.6,

74.4, 74.6, 89.3, 110.7, 113.9, 128.6, 129.2, 131.5, 134.0, 147.3,

159.2; m/z (CI⁺) 438 (M⁺+ 18, 7%), 154 (33), 138 (100), 121

12

Tetrahedron

+

(83); HRMS (CI⁺): MNH₄, found 438.3026. C₂H₄₄NO₄Si

10.4, 14.0, 18.4, 18.5, 26.2, 27.6, 29.4, 38.5, 65.3, 69.8, 82.1,

ACCEPTED MANUSCRIPT

4

requires 438.3040.

95.6, 130.5, 146.4; m/z (ES⁺) 672 (M⁺+ 23, 100%).

4.2.29

(4R,5R)-5-tert-Butyldimethylsilyloxy-4-(2-

4.2.31

(1S,2S)-2-tert-Butyldimethylsilyloxy-5,5-dimethyl-3-

trimethylsilylethoxymethoxy)-hex-1-yne (47). Pyridine (674 µl,

8.2 mmol) and then carbon tetrabromide (5.44 g, 16.4 mmol)

were added to a suspension of triphenylphosphine (8.59 g, 32.8

[(Z)-2-hydroxyethylidene]-1-(4-methoxybenzyloxy)-4-

methylidenecyclopentane (49). The vinylic iodide 43 (100 mg,

0.18 mmol) in Et₃N (0.5 mL) was added to a suspension of

P(Ph₃)₄(13 mg, 11 µmol) and CuI (1.1 mg, 6 µmol) in Et₃N (0.5

mL) at rt. After stirring for 10 min, the alkyne 47 (72 mg, 0.20

mmol) in Et₃N (0.5 mL) was added. After stirring for 2 h, CuI

(3.3 mg, 18 µmol) was added and the mixture stirred for 18 h at

rt. Saturated aqueous ammonium chloride was added and the

mixture partitioned between water and DCM. The aqueous layer

was extracted with DCM and the organic extracts were dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (10:1:89 ether:Et₃N:light petroleum then

30:1:69 ether:Et₃N:petrol) of the residue gave the title compound

49 (60 mg, 80%), R_f= 0.22 (3:7, ether:light petroleum); ν_max/cm^-1

3447, 2955, 2927, 2857, 1614, 1514, 1466, 1357, 1249, 1070,

o

mmol) in DCM (60 mL) at 0 C and the mixture was stirred

vigorously for 20 min. The aldehyde 45 (2.33 g, 6.44 mmol) in

DCM (8 mL) was added and the mixture allowed to warm to rt

then stirred for 40 min. Saturated aqueous sodium hydrogen

carbonate (8 mL) was added and the mixture was partitioned

between water and DCM. The aqueous layer was extracted with

DCM and the organic extracts were dried (MgSO₄) and

concentrated under reduced pressure. Chromatography (2% ether

in light petroleum) of the residue gave recovered aldehyde 45

(300 mg, 13%) and the dibromoalkene 46 (2.47 g, 74%), R_f=

0.76 (1:9, ether:light petroleum); ν_max/cm^-12953, 2930, 2890,

2859, 1467, 1374, 1252, 1104, 1034, 834, 776; δ_H0.05 [9H, s,

Si(CH₃)₃], 0.08 and 0.09 (each 3H, s, SiCH₃), 0.91 [9H, s,

SiC(CH₃)₃], 0.82-1.02 (2H, m, CH₂Si), 1.13 (3H, d, J 6.3, 6-H₃),

2.24 (1H, ddd, J 15.5, 8.5, 7.2, 3-H), 2.44 (1H, ddd, J 15.5, 6.9,

1038, 836, 777; δ_H0.17 (6H, s, 2

SiC(CH₃)₃], 1.11 and 1.13 (each 3H, s, 5-CH₃), 3.36 (1H, d, J

8.0, 1-H), 3.85 (3H, s, OCH₃), 4.33-4.58 (3H, m, 2 -H₂, 2-H),

4.62 and 4.72 (each 1H, d, J 11.3, ArHCH), 5.00 and 5.16 (each

1H, s, 4-CH), 5.82 (1H, ddd, J 7.0, 4.9, 2.2, 1 -H), 6.91 and 7.32

× SiCH₃), 1.00 [9H, s,

′

3.9, 3-H′), 3.51-3.72 (3H, m, OCH₂CH₂Si, 4-H), 3.91 (1H, qd, J

6.4, 4.6, 5-H), 4.68 and 4.74 (each 1H, d, 7.1, OHCHO), 6.56

(1H, t, J 7.0, 2-H); δ_C−4.5, −4.4, −1.1, 18.1, 18.3, 18.4, 26.1,

33.7, 65.7, 69.6, 80.2, 89.5, 95.3, 136.6. m/z (ES⁺) 539 (100%).

′

(each 2H, d, J 8.7, ArH); δ_C−5.3, −5.1, 18.3, 21.2, 21.4, 26.0,

55.9, 60.0, 73.7, 81.0, 103.1, 114.5, 127.4, 128.1, 129.8, 142.1,

160.4; m/z (CI⁺) 437 (M⁺+ 28, 15%), 306 (42), 271 (80), 121

(70).

n-Butyllithium (1.6 M in hexanes, 6.3 mL, 10.1 mmol) was

added to the dibromoalkene 46 (2.40 g, 4.6 mmol) in THF (35

mL) at −78 ^oC and the solution stirred for 15 min, then allowed to

4.2.32 (3S,4S)-3-tert-Butyldimethylsilyloxy-2-formylmethyl-4-

(4-methoxybenzyloxy)-1,5,5-trimethylcyclopentene

0

^oC and stirred for a further 15 min. Saturated aqueous

(50).

ammonium chloride was added and the mixture allowed to warm

to rt then partitioned between brine and ether. The aqueous layer

was extracted with ether and the organic extracts were dried

(MgSO₄) and concentrated under reduced pressure.

Chromatography (2% ether in light petroleum) of the residue

gave the title compound 47 (1.43 g, 87%), R_f= 0.32 (4% ether in

Pd(PPh₃)₄(26 mg, 23 µmol) and the stannane 48 (298 mg, 0.46

mmol) were added to the vinylic iodide 43 (150 mg, 0.27 mmol)

in DMF (2 mL) and the flask was covered in foil before being

o

heated at 80 C for 17 h. The mixture was allowed to cool to rt

then diluted with water and ether. The aqueous layer was

extracted with ether and the organic extracts were washed with

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

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

recovered iodide 43 (8 mg, 5%) and the title compound 50 (35

20

light petroleum); [α]_D−14.1 (c 2.3, CHCl₃); ν_max/cm^-13314,

2954, 2930, 2890, 2859, 1467, 1379, 1252, 1106, 1056, 1035,

835, 776; δ_H0.04 [9H, s, Si(CH₃)₃], 0.09 (6H, s, 2

× SiCH₃) 0.91

20

[9H, s, SiC(CH₃)₃], 0.83-0.99 (2H, m, CH₂Si), 1.14 (3H, d, J 6.3,

6-H₃), 1.96 (1H, t, J 2.6, 1-H), 2.36 (1H, ddd, J 16.9, 7.3, 2.6, 3-

H), 2.58 (1H, ddd, J 16.9, 4.6, 2.7, 3-H′), 3.58-3.76 (3H, m,

OCH₂CH₂Si, 4-H), 4.03 (1H, dq, J 6.3, 4.7, 5-H), 4.77 and 4.84

(each 1H, d, J 7.1, OHCHO); δ_C−4.6, −4.3, −1.2, 18.3, 18.4,

18.5, 20.0, 26.1, 65.5, 69.1, 69.5, 80.0, 82.3, 95.4; m/z (ES⁺) 381

(M⁺+ 23, 100%); HRMS (ES⁺): MNa⁺, found 381.2255.

C₁₈H₃₈O₃Si₂Na requires 381.2252.

mg, 30%), R_f= 0.57 (3:7, ether:light petroleum), [α]_D+38.3 (c

2.3, CHCl₃); ν_max/cm^-12956, 2930, 2857, 1725, 1613, 1514,

1464, 1386, 1360, 1301, 1249, 1174, 1145, 1064, 868, 837, 777;

δ_H0.08 and 0.12 (each 3H, s, SiCH₃), 0.91 [9H, s, SiC(CH₃)₃],

1.05 and 1.16 (each 3H, s, 5-CH₃), 1.57 (3H, s, 1-CH₃), 3.02 and

3.16 (each 1H, dd, J 16.5, 2.0, 2-CH), 3.60 (1H, d, J 5.4, 4-H),

3.83 (3H, s, OCH₃), 4.56 (1H, d, J 10.7, ArHCH), 4.56-4.60 (1H,

m, 3-H), 4.67 (1H, d, J 10.7, ArHCH), 6.90 and 7.32 (each 2H, d,

J 8.6, ArH), 9.55 (1H, t, J 2.2, CHO); δ_C−4.4, −4.0, 10.3, 18.2,

21.3, 26.1, 26.9, 41.3, 47.2, 55.4, 73.5, 82.0, 95.1, 113.8, 125.5,

129.5, 130.9, 145.5, 159.3, 199.9; m/z (CI⁺) 436 (M⁺+ 18, 4%),

4.2.30

(1E,4R,5R)-5-tert-Butyldimethylsilyloxy-1-

tributylstannyl-4-(2-trimethylsilylethoxymethoxy)hex-1-ene (48).

The alkyne 47 (239 mg, 0.67 mmol) in toluene (5 mL) was added

to tributyltin hydride (215 µl, 0.80 mmol) and AIBN (17 mg,

0.10 mmol) in toluene (6 mL) and the solution heated under

reflux for 4 h. After cooling to rt and concentration under

reduced pressure, chromatography (1% ether and 1% Et₃N in

light petroleum) of the residue gave the title compound 48 (298

mg, 68%), together with its (Z)-isomer, 9:1 (¹H NMR), R_f= 0.16

(1:9, ether:light petroleum); ν_max/cm^-12955, 2927, 2857, 1463,

1378, 1251, 1106, 1053, 858, 835, 775; δ_H0.06 [9H, s, Si(CH₃)₃],

+

304 (96), 287 (94), 243 (35), 121 (100); HRMS (ES⁺): MNH₄,

found 436.2879. C₂₄H₄₂NO₄Si requires 436.2878. A small

amount of the alcohol 49 (4 mg, 3%) was also isolated.

4.2.33 (1S,2S,4R)-2-tert-Butyldimethylsilyloxy-5,5-dimethyl-

3-[(Z)-2-hydroxyethylidene]-1-(4-methoxybenzyloxy)-4-

methylcyclopentane (51). Anhydrous chromium(II) chloride (78

mg, 0.6 mmol) and anhydrous nickel(II) chloride (7.3 mg, 0.06

mmol) were added to vinylic iodide 43 (100 mg, 0.18 mmol) and

benzaldehyde (23 µl, 0.23 mmol) in DMF (2 mL) at rt and the

mixture was stirred at rt for 2 h. Saturated aqueous ammonium

chloride was added and the mixture was partitioned between

water and EtOAc. The aqueous layer was extracted with EtOAc

and the organic extracts were dried (MgSO₄) and concentrated

under reduced pressure. Chromatography of the residue (2:8 then

3:7, ether:light petroleum) gave the title compound 51 (47 mg,

0.10 (6H, s, 2

SiCH₂), 0.93 [9H, s, SiC(CH₃)₃], 1.15 (3H, d, J 6.3, 6-H₃), 1.28-

1.42 and 1.47-1.59 (each 6H, m, 3 CH₂), 2.20-2.34 and 2.53-

× SiCH₃), 0.87-1.00 [17H, m, 3 × CH₃, 3 × SnCH₂,

×

2.60 (each 1H, m, 3-H), 3.52 (1H, m, 4-H), 3.57-3.76 (2H, m,

OCH₂CH₂Si), 3.96 (1H, dq, J 6.3, 4.8, 5-H), 4.75 (2H, s,

OCH₂O), 6.01-6.06 (2H, m, 1-H, 2-H); δ_C−4.5, −4.3, −1.2, 9.7,

13

62%), R_f= 0.23 (4:6, ether:light petroleum); ν_max/cm^-13413,

Delang, L.; Leyssen, P.; Wender, P. A. J. Nat. Prod. 2016,

ACCEPTED MANUSCRIPT

79, 675; (i) Staveness D.; Abdelnabi, R.; Near, K. E.;

Nakagawa, Y.; Neyts, J.; Delang, L.; Leyssen, P.; Wender, P.

2954, 2932, 2859, 1613, 1513, 1466, 1362, 1249, 1149, 1090,

1035, 838, 777; δ_H0.13 (6H, s, 2 SiCH₃), 0.89 (3H, s, 5-CH₃),

0.96 [9H, s, SiC(CH₃)₃], 0.97 (3H, s, 5-CH₃), 1.02 (3H, d, J 7.3,

4-CH₃), 1.42 (1H, br. s, OH), 2.40 (1H, q, J 7.4, 4-H), 3.24 (1H,

d, J 8.1, 1-H), 3.82 (3H, s, OCH₃), 4.23 (2H, d, J 6.7, 2 -H₂), 4.44

(1H, dt, J 8.0, 2.2, 2-H), 4.56 and 4.68 (each 1H, d, J 11.2,

ArHCH), 5.61 (1H, tt, J 6.8, 2.4, 1 -H), 6.88 and 7.29 (each 2H,

×

A. J. Nat. Prod. 2016, 79, 680.

′

5

(a) Keck, G. E.; Li, W.; Kraft, M. B.; Kedei, N.; Lewin, N. E.;

Blumberg, P. M. Org. Lett. 2009, 11, 2277; (b) Keck, G. E.;

Poudel, Y. B.; Rudra, A.; Stephens, J. C.; Kedei, N.; Lewin, N.

E.; Peach, M. L.; Blumberg, P. M. Angew. Chem. Int. Ed. 2010,

49, 4580; (c) Keck, G. E.; Poudel, Y. B.; Rudra, A.; Stephens, J.

C.; Kedei, N.; Lewin, N. E.; Blumberg, P. M. Bioorg. Med.

Chem. Lett. 2012, 22, 4084; (d) Kraft, M. B.; Poudel, Y. B.;

Kedei, N.; Lewin, N. E.; Peach, M. L.; Blumberg, P. M.; Keck,

G. E. J. Am. Chem. Soc. 2014, 136, 13202; (e) Kedei, N.; Kraft,

M. B.; Keck, G. E.; Herald, C. L.; Melody, N.; Pettit, G. R.;

Blumberg, P. M. J. Nat. Prod. 2015, 78, 896; (f) Andrews, I. P.;

Ketcham, J. M.; Blumberg, P. M.; Kedei, N.; Lewin, N. E.;

Peach, M. L.; Krische, M. J. J. Am. Chem. Soc. 2014, 136,

13209.

′

d, J 8.7, ArH) (irradiation of 4-H gave a significant nOe

enhancement of 1-H); δ_C−4.3, −4.1, 15.7, 18.3, 18.4, 26.2, 28.6,

40.0, 42.6, 55.5, 59.9, 73.8, 78.1, 91.8, 113.8, 122.9, 129.4,

131.4, 148.4, 159.2; m/z (CI⁺) 438 (M⁺+ 18, 29%), 306 (33), 271

+

(67), 121 (100); HRMS (ES⁺): MNH₄, found 438.3035.

C₂₄H₄₄NO₄Si requires 438.3034.

Acknowledgments

6

(a) Ball, M.; Bradshaw, B.; Dumeunier, R.; Gregson, T. J.;

We thank the EPSRC for a studentship (to T. G.).

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Article Doi

Synthesis of vinylic iodides for incorporation into the C17-C27 fragment of bryostatins

DOI: 10.1016/j.tet.2017.04.048

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