Studies on the stereoselective synthesis of the marine antitumor agent eleutherobin

TETRAHEDRON

Pergamon

Tetrahedron 56 (2000) 4367±4382

Studies on the Stereoselective Synthesis of the Marine Antitumor

Agent Eleutherobin

²

Rich Carter, Kevin Hodgetts, Jeff McKenna, Philip Magnus and Stephen Wren

*

Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA

Received 9 February 2000; revised 13 April 2000; accepted 14 April 2000

AbstractÐ(1)-Carvone has been converted into the sulfone 14 which comprises the left-hand side of the cytotoxic sesquiterpene, eleutherobin

1. Julia coupling of 14 to the aldehyde 21, followed by oxidation, dissolving metal reduction and stereoselective reduction of the C8 carbonyl

group resulted in 29, which has the correct stereochemistry at C8 and C9. Further conversion of 29 into 37, and attempted intramolecular

cyclization resulted in fragmentation to the furan 39 and 38. Asymmetric epoxidation of the allylic alcohols 42 and 48 resulted in neighboring

group participation from the adjacent dimethoxy acetal and formation of the rearranged oxepane derivatives 44, 45 and 49, respectively.

Introduction

their synthesis with the notable exception of Overmans

synthesis of eunicellin.⁶

Eleutherobin 1 was isolated from the fermentation broth of

the soft, red-colored coral Eleutherobia cf. albi¯ora, found

in the Indian Ocean.¹It is a member of the eunicellans, a

class of marine diterpenes possessing the core carbon skele-

ton shown in the diterpene 1,²and is closely related to

sarcodictyin A 2,³as well as valdivone A 3 (Scheme 1).⁴

There are over thirty known members of this family of

diterpenes,⁵and apart from the recent synthetic efforts on

1 and 2 (see below), there has been relatively little work on

Eleutherobin 1 has been shown to possess cytotoxic activity

with a IC₅₀of 10.7 nM against the HCT116 human colon

carcinoma cell line and a IC₅₀of 13.7 nM against the A2780

human ovarian carcinoma cell line. Because of the interest

in the comparison of biological activity of 1 with taxol, there

has been considerable effort devoted to the total synthesis of

1. To-date there have been two reported total syntheses of 1

from the Nicolaou and Danishefsky groups, respectively,^7,8

Scheme 1.

Keywords: carvone; eleutherobin; cytotoxic.

* Corresponding author. Tel.: 11-512-471-3966; fax: 11-512-471-7839; e-mail: p.magnus@mail.utexas.edu

Present address: Department of Chemistry, University of Mississippi, University, MS 38677, USA.

²

PII: S0040-4020(00)00309-4

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R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

and also two approaches to the syntheses of 1 and 2 have

been published.^9,10

trimethylorthoformate to provide the acetal 6 as a single

diastereomer in 61% yield, together with 37% of recovered

starting material, Scheme 2.¹²While 6 proved to be resistant

to a wide variety of methenylating reagents such as tri-

phenylphosphonium methylide,¹³Lombardo's reagent (Zn/

CH₂Br₂/TiCl₄),¹⁴Zn/Cp₂ZrCl₂/CH₂Br₂,¹⁵as well as

TMSCH₂MgBr and TMSCH₂Li,¹⁶treatment of the enone

6 with Cp₂TiMe₂¹⁷in THF gave the diene 7 in 71% yield.

Hydroboration of the diene 7 using 9-BBN¹⁸in THF (0.5 M,

1.1 equiv.) gave, after oxidative work-up, the alcohol 8

(61%) as a single diastereomer. The stereochemistry of

the alcohol 8 was con®rmed by X-ray analysis of the corre-

sponding p-nitrobenzoate ester 9.

ꢀ1

Jones oxidation¹⁹of 8 gave cleanly the lactone 10. Subse-

quent O-alkyl cleavage of the lactone 10 with lithium

phenylthiolate in DMF gave 11, which was esteri®ed and

reduced to give the alcohol 12. Several oxidants were

examined for the oxidation of sul®de to sulfone, and hydro-

gen peroxide/sodium tungstate dihydrate²⁰converted 12

into 13 (89%). Finally, silylation of 13 yielded the desired

sulfone 14 in excellent yield.

The strategy we have pursued involves the conversion of

carvone 4 into a cis-disubstituted derivative 14 (Scheme 2)

that allows the construction of the sec- and tert-alcohols C8/

C7 via a Julia coupling to the left-hand fragment 21

(Scheme 3), Eq. (1).

Synthesis of Aldehyde 21

Synthesis of Sulfone 14

The requisite aldehyde 21 was synthesized in six steps in an

overall 45% yield as shown in Scheme 3.²¹Sharpless asym-

metric epoxidation of 2-methyl-2-propene-1-ol 15 followed

Hydrogenation of (1)-carvone 4,¹¹gave 5, which was

subsequently treated TiCl₄/i-Pr₂NEt at 2788C followed by

Scheme 2. (a) (Ph₃P)₃RhCl/H₂/PhH, 5 (93%). (b) TiCl₄/CH₂Cl₂, then i-Pr₂NEt followed by CH(OMe)₃, 2788C to 08C, 6 (61%) and 5 (37%). (c) Cp₂TiMe₂/

THF/re¯ux, 7 (71%). (d) 9-BBN (1.1 equiv.)/THF, 60±658C, followed by NaOH/H₂O₂, 8 (61%) and 7 (22%). Conversion of 8 into 9, 4-nitrobenzoyl chloride/

imidazole/DMAP/CH₂Cl₂, 9 (82%). (e) Jones reagent/acetone, 10 (73%). (f) LiH/PhSH/DMF/1108C, 11 (89%). (g) MeI/K₂CO₃/acetone, then DIBAL-H/

CH₂Cl₂/278 to 08C, 12 (86%). (h) Na₂WO₄.2H₂O/Aliquat^w336/H₂O₂/CH₂Cl₂, re¯ux, 13 (89%). (i) TBSCl/imidazole/DMF, 14 (96%).

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4369

Ê

Scheme 3. (a) (1)-DIPT/Ti(Oi-Pr)₄/cumene hydroperoxide/4 A molecular sieves/CH₂Cl₂/2208C, then P(OMe)₃/4-nitrobenzoyl chloride/imidazole, 16 (52%,

.98% e.e. after recrystallization). (b) PhSH/NaOH/dioxane/H₂O, 17 (96%). (c) p-TsOH/1-methoxycyclohexene/DMF, 18 (97%). (d) m-Chloroperoxybenzoic

acid/CH₂Cl₂/2208C, 19 (99%). (e) Ac₂O/NaOAc/re¯ux, 20 (94%). (f) MeOH/K₂CO₃/re¯ux, 21 (99%). (g) t-BuOH/H₂O (1:1)/AD-mix-b/08C, 23 (88%, 97%

Ê

ee). (h) p-TsOH/cyclohexanone/3 A molecular sieves/1508C, 24 (90%). (i) LiOH´H₂O/THF/H₂O (1:1)/re¯ux, 25 (92%). (j) Dess±Martin triacetoxyperiodi-

nane/CH₂Cl₂, 21 (83%).

by in situ protection gave the known epoxide 16 in 90% e.e.

The e.e. could be improved to .98% by recrystallization

from diisopropyl ether, as determined using the chiral

NMR shift reagent²²Eu(hfc)₃in benzene-d₆. The epoxide

16 was converted into the diol 17²³and protected as its

cyclohexyl ketal 18. After oxidation to the sulfoxide 19,²⁴

Pummerer rearrangement²⁵gave 20 as a 1:1.6 mixture

of diastereomers, which could be converted into the

aldehyde 21 by hydrolysis with potassium carbonate in

methanol.

ammonia reduction of the separated sulfones 26 and 27

gave the alcohols 28 and 29, respectively, which con-

clusively established the C-8 stereochemistry in the sulfone.

It is believed that the C-9 stereochemistry of the sulfone 27

is as drawn because oxidation of the mixture of sulfones 26

and 27 gave a single ketosulfone 30. Subsequent reduction

of the sulfone 30 using sodium in liquid ammonia³⁰gave the

ketone 31 in good yield. It was found that DIBAL-H

reduced the ketone 31 to preferentially give the alcohol 28

possessing the incorrect stereochemistry at C-8, while the

Selectride^wreagents favored the desired C-8 stereo-

chemistry with K-Selectride^wyielding the best results

(15:1, 29:28, 82% overall yield).

An alternative route using the more recently developed

asymmetric dihydroxylation technology was also used to

synthesize the aldehyde 21. Using the literature method 22

was converted into 23.²⁶The diol 23 was ketalized to give

24, which on treatment with LiOH/THF/water gave 25.

Oxidation of 25 with the Dess±Martin periodinane reagent²⁷

gave 21. This route is ®ve steps and proceeds in an overall

yield of 50%.

Deprotection of the silyl ether 29 followed by oxidation

using tetrapropylammonium perruthenate (TPAP)³¹gave

the lactone 32. Subsequent reduction of 32 with DIBAL-H

provided the lactol 33 as a single diastereomer. Treatment of

33 with p-TsOH in methanol gave the acetal 35 in 67%

yield, together with the methoxy acetal 34 in 23% yield.

The methoxy acetal 34 appeared to possess the a-stereo-

chemistry at C-2 (H-1,2 coupling constant of 8.7 Hz)

presumably due to the anomeric effect. The diol 34 could

be separated and re-equilibrated to provide a further

quantity of the acetal 35.

Julia Coupling of 14 and 21

Treatment of the sulfone 14 with n-BuLi (1.03 equiv.)

followed by the addition of the aldehyde 21 gave the

coupled products 26 and 27 as a 50:1 mixture at the

newly formed C-8 stereogenic center in 66% yield, Scheme

4.²⁸The major component 26 possessed the incorrect

stereochemistry at C-8 as shown by X-ray crystallographic

analysis. The same transformation could also be accom-

plished using EtMgBr²⁹(1.13 equiv.) in benzene to give

the sulfones 26 and 27 as a 10:1 mixture (26:27) at C-8 in

64% yield. The latter method was preferred because it was

found to be more reproducible.

Oxidation of the alcohol 35 using the Dess±Martin periodi-

nane gave the crystalline aldehyde 36. Treatment of the

aldehyde 36 with the ylide derived from phosphonium salt

36a³²gave the b-keto ester 37 (Z:E, 14:1). Although the

yields using the literature conditions³³were low and irre-

producible, this problem was overcome by the use of DMPU

as a co-solvent. Treatment of 37 with BF₃´Et₂O/CH₂Cl₂

produced complex reaction mixture from which we could

isolate 38 and the furan 39. It appeared that cleavage of the

C-7,8 bond was the reaction pathway under several of the

Lewis acidic conditions.

The stereochemistry of sulfone 27 was established by a

series of correlation experiments. Sodium in liquid

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R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

Scheme 4. (a) n-BuLi (1.03 equiv.)/THF/278 to 08C, then add 21, 278 to 258C, 26/27 (50:1) (66%), or EtMgBr (1.13 equiv.), PhH, re¯ux, then add 21 258C,

26/27 (10:1) (64%). (b) Na/NH₃/THF/2788C, 28 (53%). (c) Na/NH₃/THF/2788C, 29 (21%). (d) Dess±Martin triacetoxyperiodinane/CH₂Cl₂, 30 (94%). (e)

w

Na/NH₃/THF/2788C, 31 (92%). (f) K-Selectride /THF/08C, 29 (77%). (g) (i) TBAF/THF/258C, 99%; (ii) TPAP/NMO/4 A molecular sieves/CH₂Cl₂/258C, 32

Ê

(87%). (h) DIBAL-H/CH₂Cl₂/2788C. (i) p-TsOH/MeOH/258C, 35 (67% over two steps), 34 (23% over two steps). (j) p-TsOH/MeOH/258C, 35 (70%), 34

(21%). (k) Dess±Martin triacetoxyperiodinane/CH₂Cl₂, 30 (89%). (l) NaH/DMPU/36a/25 to 408C, 37 (84%) 1 E-isomer (6%). (m) BF₃´Et₂O/CH₂Cl₂, 38

(56%), 39 (18%).

Asymmetric Epoxidation of the C7±C8 Double Bond

adduct 42 in 44% yield over the two steps. Treatment of

allylic alcohol 42 with AD mix a³⁶gave a slow reaction, and

the ¹H NMR of the crude reaction mixture indicated prefer-

ential dihydroxylation at the internal C-11,12 ole®n as

shown in by the disappearance of the H-12 signal. Classical

dihydroxylation conditions³⁷(OsO₄/NMO/acetone/H₂O)

gave a complex mixture.

Suzuki and co-workers ®rst reported the coupling of alkyl

9-BBN adducts with vinyl or aryl halides using palladium

catalysis in 1986.³⁴Hydroboration of the diene 7 with

9-BBN gave the alkyl-9-BBN adduct 40, Scheme 5. Treat-

ment of the 9-BBN adduct 40 with the vinyl bromide 41

under standard Suzuki conditions [PdCl₂(dppf)₂/K₂CO₃/

DMF/THF] gave no coupling, however, the use of one of

Suzuki's alternative conditions³⁵[Pd(PPh₃)₄(3 mol%)/

NaOH (3 M in H₂O)/THF/658C/6 h] yielded the coupled

Corey and co-workers have shown that the use of an

aromatic protecting group a to the ole®n often improves

the enantioselectivity of the dihydroxylation via aryl±aryl

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4371

Ê

Scheme 5. (a) 9-BBN. (b) Pd(PPh₃)₄/41/THF/3M NaOH/658C, 42 (44%), 7 (33%). (c) (1)-DIPT/Ti(Oi-Pr)₄/TBHP/3 A molecular sieves/CH₂Cl₂/2408C, 45

Ê

(84%), 43 (10%). Whereas (2)-DIPT/Ti(Oi-Pr)₄/TBHP/3 A molecular sieves/CH₂Cl₂/2258C gave 44 (36%), 43 (64%).

or p-stacking interactions in the binding pocket of the

catalyst.²⁶It was hoped that this interaction may also be

used to improve the regioselectivity of the dihydroxylation.

Unfortunately, after protection of the primary hydroxyl

functionality as its 4-methoxybenzoyl ester, treatment

with AD mix a gave a complex mixture with substantial

over-hydroxylation as well as preferential dihydroxylation

of the internal C-11,12 ole®n as judged by ¹H NMR analysis

of the crude reaction mixture.

by X-ray crystallography (Fig. 1). Although the C-8 stereo-

chemistry is correct for the synthesis of eleutherobin, the

crucial C-7 stereochemistry is incorrect.

It is believed that the epoxide 43 is initially formed, but it is

rapidly opened in an intramolecular manner to give the

intermediate 43b which rearranges to give the O-methyl

ether 44. Recently, Gennari⁹has reported the formation of

these same epoxides from 42, and under his milder reaction

conditions they can be isolated, although further transforma-

tion into the acetals is promoted by acids.³⁹

An alternative method for oxygenation of the allylic alcohol

42 was the use of Sharpless' asymmetric allylic epoxidation

chemistry.³⁸Epoxidation of the C-7,8 ole®n using the (1)-

DIPT/Ti(Oi-Pr)₄/TBHP system would be expected to yield

the epoxide 43 with the correct absolute stereochemistry at

C-7 and C-8. Unfortunately, in order to convert the epoxide

43 into the acetal 34, the epoxide functionality must be

opened in an S_N2 process, causing an inversion of the C-8

stereochemistry. An alternative approach would involve the

use of the Z-ole®n geometry at the C-7,8 position which,

upon opening of the epoxide at C-8 with an oxygen nucleo-

phile, would yield the correct C-7 and C-8 stereochemistry.

The most direct method to obtain the correct C-7 and C-8

stereochemistry for eleutherobin was to use the opposite

Z-ole®n geometry. Construction of the appropriate Z-vinyl

halide 47 was possible using a known one step procedure.⁴⁰

Suzuki coupling between 40 and 47 under the conditions

In the event, treatment of allylic alcohol 42 with (1)-DIPT/

Ti(Oi-Pr)₄/TBHP at 2408C yielded 43 (10%) and the

rearranged adduct 45 (84%). The allylic alcohol 42 was

allowed to react with (2)-DIPT/Ti(Oi-Pr)₄/TBHP and

gave 44 (36%) along with 43b (64%). Protection of the

primary hydroxyl function as its p-nitrobenzoate ester

yielded the crystalline 46, whose structure was con®rmed

Figure 1. Chem 3D representation of 46 (±COC₆H₄NO₂) from X-ray

coordinates.

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R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

Ê

Scheme 6. (a) Pd(PPh₃)₄/47/THF/3M NaOH/658C, 48 (35%). (b) (1)-DET/Ti(Oi-Pr)₄/TBHP/3 A molecular sieves/CH₂Cl₂/2208C, 49 (63%). (c) MeCN/

Me₃SiCl/NaI at 08C, 35 (15%).

used previously [Pd(PPh₃)₄(3 mol%)/NaOH (3 M in H₂O)/

THF/658C, 6 h] gave trace amounts of the desired coupled

product 48, Scheme 6. The yield of this reaction could be

improved to 35% yield over two steps by increasing the

amount of Pd(PPh₃)₄to 15 mol%, the amount of 47 was

increased from 1 to 2.7 equiv., and the reaction time was

extended from 6 to 48 h. Treatment of the allylic alcohol 48

with [(1)-DIPT (50 mol%)/Ti(Oi-Pr)₄(40 mol%)/TBHP/

2108C)] gave largely the starting alcohol 48, and a small

amount of what appeared to be the epoxide 48a. Treatment

of the allylic alcohol 48 under modi®ed Sharpless condi-

tions [(1)-DIPT (3 equiv.)/Ti(Oi-Pr)₄(2.5 equiv.)/TBHP/

2108C)] gave the expected O-methyl ether 49 as a single

diastereomer in 50% yield. Furthermore, the use of (1)-

DET instead of (1)-DIPT and the presence of equimolar

reagents [(1)-DET (1.3 equiv.)/Ti(Oi-Pr)₄(1.0 equiv.)/

TBHP/288C] gave the optimum results with a yield of

Experimental

Melting points were taken on a Thomas±Hoover capillary

tube apparatus and are uncorrected. Infrared spectra were

recorded on a Perkin±Elmer 1600 FT-IR spectrophotometer

neat unless otherwise indicated. ¹H NMR spectra were

recorded on a General Electric QE-300 spectrometer at

300 MHz in the indicated solvent and are reported in ppm

relative to tetramethylsilane and referenced internally to the

residually protonated solvent. ¹³C NMR spectra were

recorded on a General Electric QE-300 spectrometer at

75 MHz in the solvent indicated and are reported in ppm

relative to tetramethylsilane and referenced internally to the

residually protonated solvent. Mass spectra were obtained

on a VG ZAB2E or a Finnigan TSQ70. Optical rotations

were recorded on a Perkin±Elmer 241 MC polarimeter

using a sodium lamp at 589 nm in CHCl₃with 1% ethanol.

1

63% and was shown to be a single diastereomer by H

and ¹³C NMR analysis.

Routine monitoring of reactions was performed using

Merck 60 F₂₅₄silica gel, aluminum-backed TLC plates.

PLC was performed using Merck 60 F₂₅₄silica gel, glass

supported plates. Flash column chromatography was

performed with the indicated eluents on Merck 60H F₂₅₄

silica gel.

In order to verify the C-7 and C-8 stereochemistry, con-

version of O-methyl ether 49 into the previously prepared

acetal 35 was necessary. Treatment of 49 with trimethylsilyl

iodide, generated in situ from trimethylsilyl chloride and

sodium iodide, in propene-saturated acetonitrile⁴¹gave the

acetal 35 as the major demethylated product, but in a poor

yield. Several other methods were tried in order to improve

the deprotection of the O-methyl ether 49, including

TMSSMe/ZnI₂/Bu₄NI,⁴²EtSH/BF₃´Et₂O,⁴³and BBr₃,⁴⁴but

all attempts led to extensive decomposition.

Solvents and commercial reagents were puri®ed in accord

with Perrin and Armarego⁴⁵or used without further purifca-

tion.

1-Methyl-(4S)-isopropyl-(5R)-dimethyl acetal-1-cyclo-

hexen-6-one 6. To a stirred solution of 5 (86.7 g,

0.57 mol) in CH₂Cl₂(1.6 L) was added TiCl₄(110.7 g,

64.0 mL, 0.58 mol) at 2788C over a 5 min period. After

an additional 15 min, i-Pr₂NEt (74.2 g, 100.0 mL,

0.57 mol) was added to the orange solution over 5 min.

The dark red solution was stirred an additional 1.5 h at

2788C, and CH(OMe)₃(121.2 g, 125.0 mL, 1.1 mol) was

added over 7 min. After 4 h at 2788C, the mixture was

warmed to 08C over 25 min. The dark solution was poured

into saturated aqueous NH₄Cl (1.5 L) and extracted with

The sulfone route in Scheme 4, although lengthy, provides

good stereocontrol at the crucial tertiary and secondary

(C7±C8) stereogenic centers.

During the course of this research the Nicolaou group

reported their successful syntheses of 1 and 2 that starts

with carvone and proceeds through some very similar

intermediates to ones described above,⁷and consequently,

we have not continued this approach.

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4373

CH₂Cl₂(3£800 mL). The dried (MgSO₄) extract was

concentrated in vacuo to give a yellow liquid. This reaction

was repeated on 87.3 g scale of the enone under identical

conditions. The combined crude liquids were passed quickly

through a short plug of silica gel, eluting with 20% Et₂O/

petroleum ether. The ®ltrate was concentrated in vacuo and

puri®ed in 50 mL batches of the crude liquid by chromato-

graphy over silica gel, eluting with 12±15% Et₂O/petroleum

ether, to give starting enone 5 (38.2 g, 0.25 mol, 37%)

followed by the acetal 6 (158.6 g, 0.70 mol, 61% yield) as

a pale yellow liquid. [a]²_D³119 (c2.50, CHCl₃). IR (®lm)

2958, 2833, 1678 cm²¹. ¹H NMR (CDCl₃) d 6.55±6.65 (1H,

m), 4.64 (1H, d, J7.2 Hz), 3.32 (3H, s), 3.30 (3H, s), 2.80

(1H, dd, J3.0, 7.2 Hz), 2.1±2.3 (1H, m), 1.90±2.05 (1H,

m), 1.75 (3H, d, J1.5 Hz), 1.6±1.8 (2H, m), 0.87 (3H, d,

J5.4 Hz), 0.85 (3H, d, J5.4 Hz). ¹³C NMR (CDCl₃) d

198.8, 143.1, 135.2, 103.6, 53.9, 53.1, 52.3, 40.8, 29.4, 25.9,

20.5, 15.9. HRMS (CI) calcd for C₁₃H₂₃O₃227.1672. Found

227.1643.

graphy over Florisil^w, eluting with 5±50% Et₂O/petroleum

ether followed by chromatography over silica gel eluting

with 30±50% Et₂O/petroleum ether, to give the starting

diene 7 (10.40 g, 0.05 mol, 22%) followed by the alcohol

8 (33.33 g, 0.14 mol, 61% yield) as a colorless oil.

[a]²_D³166 (c0.89, CHCl₃). IR (®lm) 3453, 2957 cm²¹

.

¹H NMR (CDCl₃) d 5.38 (1H, br s), 4.40 (1H, d, J5.0 Hz),

3.6±3.7 (3H, m), 3.47 (3H, s), 3.39 (3H, s), 2.4±2.45 (1H,

m), 1.95±2.05 (2H, m), 1.7±1.85 (2H, m), 1.69 (3H, s),

1.15±1.3 (1H, m), 0.90 (3H, d, J6.3 Hz), 0.82 (3H, d,

J6.3 Hz). ¹³C NMR (C₆D₆) d 133.6, 122.7, 106.5, 62.2,

55.1, 54.1, 42.0, 39.8, 36.6, 27.1, 24.7, 22.1, 21.2, 17.4.

HRMS (CI) calcd for C₁₄H₂₇O₃243.1960. Found

243.1951.

1-Methyl-(4R)-isopropyl-(5R)-dimethyl acetal-(6S)-[4⁰-

nitrobenzoyloxymethyl]-1-cyclohexene 9. To a stirred

solution of 8 (121 mg, 0.5 mmol) in CH₂Cl₂(3 mL) at

room temperature under an argon atmosphere was added

imidazole (38 mg, 0.55 mmol), 4-nitrobenzoyl chloride

(102 mg, 0.55 mmol) and 4-dimethylaminopyridine

(DMAP) (3 mg). After 24 h. the mixture was diluted with

CH₂Cl₂(10 mL) and washed with water (10 mL), brine

(10 mL), dried (MgSO₄), and evaporated to give a residue

which was puri®ed by ¯ash chromatography over silica gel,

eluting with 15% ether/petroleum ether, to give 9 (160 mg,

82%) as a white crystalline solid. A small sample was

recrystallized by vapor defusion from ether/petroleum

1-Methyl-(4R)-isopropyl-(5S)-dimethyl acetal-6-yl-1-cyclo-

hexene 7. To a stirred solution of titanocene dichloride

(136 g, 0.55 mol) in Et₂O (1.8 L) was added MeLi

(800 mL, 1.12 mol, 1.4 M in Et₂O) via cannula over

1.25 h at 08C in the dark. The orange±brown solution was

allowed to warm to ambient temperature. After 2 h cold

H₂O (750 mL) was added slowly to the mixture, and the

resulting suspension extracted Et₂O (3£700 mL). The

dried (MgSO₄) extract was concentrated in vacuo in the

dark and the orange solid was immediately dissolved in

THF (100 mL). The dimethyl titanocene solution was

added to a stirred solution of 6 (45.0 g, 0.20 mol) in THF

(200 mL) via cannula in the dark. An additional amount of

THF (2£25 mL) was used to rinse the dimethyl titanocene

¯ask. After heating the dark red solution at re¯ux in the dark

for 20 h, the mixture was concentrated in vacuo. The crude

slurry was dissolved in Et₂O (500 mL), and silica gel

(500 mL) was added slowly. The solid was ®ltered and

rinsed with Et₂O (1.5 L). The ®ltrate was concentrated in

vacuo and the silica gel cycle repeated twice. The dark

liquid was distilled at 112±1158C/2.5 mmHg to give 7

(31.5 g, 0.14 mol, 71% yield) as a colorless liquid.

ether. IR (Nujol) 2923, 2854, 1728 cm²¹

.

¹H NMR

(CDCl₃) d 8.15±8.3 (4H, m), 5.46 (1H, br s), 4.67 (1H,

dd, J5.1, 11.3 Hz), 4.47 (1H, dd, J5.3, 11.3 Hz), 4.36

(1H, d, J5.1 Hz), 3.36 (3H, s), 3.31 (3H, s), 2.6±2.65

(1H, m), 1.3±2.1 (8H, m), 0.89 (3H, d, J6.6 Hz), 0.82

(3H, d, J6.6 Hz). ¹³C NMR (CDCl₃) d 164.6, 150.3,

136.3, 133.0, 130.6, 130.6, 123.6, 123.5, 106.6, 66.8, 55.6,

55.1, 52.8, 40.4, 38.0, 36.2, 27.0, 24.4, 22.4, 21.2, 16.5.

HRMS (CI) calcd for C₂₁H₃₀NO₆392.2073. Found

392.2069.

(1S,5R,6R) 2-Methyl-isopropyl-8-oxabicyclo[4.3.0]non-

2-en-7-one 10. To a stirred solution of 8 (28.33 g,

0.12 mol) in acetone (600 mL) was slowly added Jones

reagent (250 mL) over 25 min. After 11 h, the mixture

was transferred to an Erlenmeyer ¯ask, diluted with H₂O

(200 mL), and quenched with i-PrOH (25 mL). Solid

NaHCO₃was added portion-wise until the effervescence

ceased. The slurry was ®ltered through Celite^wand rinsed

with acetone (4 L). The acetone was removed in vacuo and

the aqueous layer was extracted with Et₂O (4£300 mL). The

dried (MgSO₄) extract was concentrated in vacuo and puri-

®ed by chromatography over silica gel, eluting with 30%

Et₂O/petroleum ether to give 10 (16.67 g, 0.086 mol, 73%

[a]²_D³2117 (c1.27, CHCl₃). IR (®lm) 2942, 1608 cm²¹

.

¹H NMR (CDCl₃) d 5.47 (1H, br s), 5.05 (1H, s), 4.88 (1H,

s), 4.23 (1H, d, J8.4 Hz), 3.30 (3H, s), 3.28 (3H, s), 2.66

(1H, dd, J2.1, 8.4 Hz), 2.1±2.3 (2H, m), 1.78 (3H, d,

J1.2 Hz), 1.45±1.55 (1H, m), 1.30±1.45 (1H, m), 0.86

(3H, d, J3.3 Hz), 0.84 (3H, d, J3.3 Hz). ¹³C NMR

(CDCl₃) d 145.2, 135.5, 128.7, 115.9, 108.1, 58.2, 55.9,

50.3, 43.2, 31.3, 28.9, 24.9, 23.6, 22.9. HRMS (CI) calcd

for C₁₄H₂₄O₂225.1895. Found 225.1892.

1

1-Methyl-(4R)-isopropyl-(5R)-dimethyl acetal-(6S)-

hydroxymethyl-1-cyclohexene 8. A solution of 9-BBN

(515 mL, 0.26 mol, 0.5 M in THF) was added to 7

(52.32 g, 0.23 mol). After heating the stirred solution at

60±658C for 18 h, the mixture was cooled to 08C and

NaOH (150 mL, 4 M in H₂O) was added followed by the

dropwise addition of H₂O₂(150 mL, 30% in H₂O). After

30 min at 08C and 45 min at ambient temperature, the

THF was evaporated in vacuo and the aqueous layer was

extracted with Et₂O (4£300 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puri®ed by chromato-

yield) as a colorless oil. IR (®lm) 2961, 1771 cm²¹. H

NMR (CDCl₃) d 5.5±5.6 (1H, m), 4.36 (1H, dd, J7.2,

8.9 Hz), 4.15 (1H, dd, J4.4, 8.9 Hz), 2.85±2.9 (1H, m),

2.75±2.8 (1H, m), 1.9±2.15 (2H, m), 1.75±1.85 (2H, m),

1.6±1.8 (3H, m), 0.95 (3H, d, J6.4 Hz), 0.92 (3H, d,

J6.4 Hz). ¹³C NMR (CDCl₃) d 178.5, 130.0, 124.1, 70.6,

43.5, 41.3, 39.1, 36.8, 27.6, 23.6, 21.0, 19.2. HRMS (CI)

calcd for C₁₂H₁₉O₂195.1385. Found 195.1379.

1-Methyl-(4R)-isopropyl-(5R),(6S)-7-thiophenyl-8-oic-1-

cyclohexene 11. To a stirred solution of PhSH (13.1 g,

4374

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

12.2 mL, 0.12 mol) in DMF (40 mL) was added LiH

(945 mg, 0.12 mol) portion-wise. After 45 min, a solution

of 10 (16.67 g, 0.086 mol) in DMF (40 mL) was added via

cannula to the lithium thiolate solution. An additional

amount of DMF (3 mL) was used to rinse the lactone

¯ask. After heating the yellow solution at 1108C for 4 h,

the solution was cooled to 08C, poured into a HCl solution

(200 mL, 2 M in H₂O) and Et₂O (300 mL), and extracted

with Et₂O (4£300 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 5±50% Et₂O/petroleum ether,

to give 11 (23.25 g, 0.076 mol, 89% yield) as an off-white

solid. mp 69±708C. [a]_D²³147 (c0.90, CHCl₃). IR (®lm)

1.65 (2H, m), 0.88 (3H, d, J6.8 Hz), 0.81 (3H, d,

J6.8 Hz). ¹³C NMR (CDCl₃) d 136.1, 134.6, 130.1,

129.0, 126.6, 122.7, 61.6, 41.0, 39.3, 36.0, 34.2, 26.7,

24.2, 21.9, 21.0, 15.9. HRMS (CI) calcd for C₁₈H₂₆OS

290.1704. Found 290.1704.

1-Methyl-(4R)-isopropyl-(5R)-hydroxymethyl-(6S)-7-sul-

fonylphenylmethyl-1-cyclohexene 13. To a stirred solution

of 12 (18.34 g, 0.063 mol) in CH₂Cl₂(200 mL) and H₂O

(7.5 mL) was added Na₂WO₄´H₂O (1.63 g, 4.9 mmol) and

Aliquat^w336 (15 mL) followed by the dropwise addition of

H₂O₂(30 mL, 30% in H₂O). The yellow solution was heated

to re¯ux, and an additional amount of H₂O₂(70 mL, 30% in

H₂O) was added portion-wise periodically during the course

of the reaction. After 40 h the mixture was cooled to

ambient temperature, solid NaHSO₃was added portion-

wise until effervescence ceased followed by extraction

with CH₂Cl₂(3£200 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puri®ed by chromatography over

silica gel, eluting with 50% EtOAc/petroleum ether, to give

13 (18.00 g, 0.054 mol, 89%) as an off-white solid. mp 103±

1048C. [a]²_D³1136 (c1.23, CHCl₃). IR (®lm) 3525,

1

3500±2500, 2960, 1703 cm²¹. H NMR (CDCl₃) d 7.35±

7.4 (2H, m), 7.15±7.3 (3H, m), 5.40 (1H, br s), 3.22 (1H, dd,

J7.6, 13.4 Hz), 3.04 (1H, dd, J4.1, 13.4 Hz), 2.7±2.8

(1H, m), 2.45±2.55 (1H, m), 1.9±2.1 (3H, m), 1.85±1.9

(1H, m), 1.63 (3H, br s), 0.87 (3H, d, J6.5 Hz), 0.77

(3H, d, J6.5 Hz). ¹³C NMR (CDCl₃) d 180.7, 136.3,

133.9, 130.6, 128.8, 126.3, 122.3, 46.1, 40.2, 35.9, 34.9,

27.6, 23.5, 21.9, 20.8, 16.3. HRMS (CI) calcd for

C₁₈H₂₄O₂S 304.1497. Found 304.1488.

1

2959 cm²¹. H NMR (CDCl₃) d 7.9±8.0 (2H, m), 7.55±

1-Methyl-(4R)-isopropyl-(5R)-hydroxymethyl-(6S)-7-thio-

phenylmethyl-1-cyclohexene 12. To a stirred solution of

11 (23.25 g, 0.076 mol) in acetone (575 mL) was added

solid K₂CO₃(53.0 g, 0.38 mol). After 10 min, MeI

(104.9 g, 46 mL, 0.74 mol, ®ltered through a small plug of

basic alumina prior to use) was added. After 1.5 h, H₂O

(10 mL) was added, ®ltered and concentrated in vacuo.

The oil was dissolved in Et₂O (300 mL) and saturated

aqueous NaCl (300 mL) and extracted with Et₂O

(4£300 mL). The dried (MgSO₄) extract was concentrated

in vacuo to give the methyl ester derivative of 11 (24.16 g,

0.076 mol) as off-white solid which was used directly.

7.7 (3H, m), 5.34 (1H, br s), 3.88 (1H, dd, J3.9,

12.3 Hz), 3.62 (1H, dd, J10.2, 12.3 Hz), 3.45 (1H, dd,

J5.7, 15.9 Hz), 2.85±3.0 (2H, m), 1.75±2.0 (4H, m),

1.45±1.5 (3H, m), 1.25±1.4 (2H, m), 0.86 (3H, d,

J6.8 Hz), 0.81 (3H, d, J6.8 Hz). ¹³C NMR (CDCl₃) d

139.1, 134.7, 134.0, 129.4, 128.0, 123.0, 60.9, 57.4, 42.0,

35.6, 33.6, 26.5, 24.2, 21.3, 21.0, 15.2. HRMS (CI) calcd for

C₁₈H₂₇O₃S 323.1681. Found 323.1673.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsilyl-

(oxy)methyl-(6S)-7-sulfonylphenylmethyl-1-cyclohexene

14. To a stirred solution of 13 (3.00 g, 9.32 mmol) in DMF

(6 mL) was added imidazole (1.50 g, 22.0 mmol) and tert-

butyldimethylsilylchloride (1.45 g, 9.62 mmol). After 4 h,

the mixture was quenched with saturated aqueous NaCl

(50 mL) and extracted with Et₂O (3£100 mL). The dried

(Na₂SO₄) extract was concentrated in vacuo and puri®ed

by chromatography over silica gel, eluting with 20%

Et₂O/petroleum ether, to give 14 (3.915 g, 9.00 mmol,

96%) as a colorless oil. [a]²_D³152 (c1.09, CHCl₃). IR

[a]²_D³140 (c1.19, CHCl₃). IR (®lm) 2958, 1730 cm²¹

.

¹H NMR (CDCl₃) d 7.15±7.4 (5H, m), 5.39 (1H, br s), 3.70

(3H, s), 3.15 (1H, dd, J7.4, 12.4 Hz), 2.96 (1H, dd, J3.7,

12.4 Hz), 2.69 (1H, dd, J4.7, 9.9 Hz), 2.4±2.45 (1H, m),

1.9±2.0 (3H, m), 1.75±1.85 (1H, m), 1.62 (3H, br s), 0.88

(3H, d, J6.5 Hz), 0.73 (3H, d, J6.5 Hz). ¹³C NMR

(CDCl₃) d 174.3, 136.5, 134.2, 130.6, 128.8, 126.4, 122.2,

51.5, 46.1, 41.0, 35.4, 34.8, 27.5, 23.5, 22.0, 20.8, 15.9.

HRMS (CI) calcd for C₁₉H₂₆O₂S 318.1654. Found

318.1651.

1

(®lm) 2956, 2929, 2891, 2857 cm²¹. H NMR (CDCl₃) d

7.9±8.0 (2H, m), 7.5±7.65 (3H, m), 5.38 (1H, br s), 3.84

(1H, dd, J4.4, 14.5 Hz), 3.75 (1H, dd, J4.3, 10.6 Hz),

3.70 (1H, dd, J6.2, 10.6 Hz), 3.07 (1H, dd, J5.8,

14.5 Hz), 2.84 (1H, m), 1.75±2.0 (3H, m), 1.64 (3H, br s),

1.45 (2H, m), 0.86 (3H, d, J6.6 Hz), 0.85 (9H, s), 0.79

(3H, d, J6.6 Hz), 0.06 (3H, s), 0.04 (3H, s). ¹³C NMR

(CDCl₃) d 140.7, 134.5, 133.3, 129.1, 127.8, 123.2, 63.2,

57.2, 40.9, 36.9, 35.8, 27.0, 25.9, 23.9, 22.1, 20.9, 18.1,

16.9, 25.4, 25.8. HRMS (CI) calcd for C₂₄H₄₁O₃SSi

437.2546. Found 437.2540.

To a stirred solution of crude ester (24.16 g, 0.076 mol) in

CH₂Cl₂(1 L) was added DIBAL-H (170 mL, 0.17 mol,

1.0 M in CH₂Cl₂) over 1.25 h via a dropping funnel at

2788C. After an additional 30 min, the mixture was

warmed to 08C for 20 min and recooled to 2788C. The

mixture was quenched by the dropwise addition of MeOH

(30 mL) followed by the addition of a sodium tartrate solu-

tion (700 mL, 10% in H₂O). The mixture was allowed to

warm to ambient temperature and stirred for 2 h followed by

extraction with CH₂Cl₂(4£400 mL). The dried (MgSO₄)

extracted was concentrated in vacuo and puri®ed by

chromatography over silica gel, eluting with 30% Et₂O/

petroleum ether to give 12 (19.15 g, 0.066 mol, 86% over

steps steps) as a colorless oil. IR (®lm) 3418, 2959 cm²¹. ¹H

NMR (CDCl₃) d 7.20±7.45 (5H, m), 5.39 (1H, br s), 3.83

(1H, dd, J4.9, 11.8 Hz), 2.96 (1H, dd, J9.6, 11.8 Hz),

2.9±3.1 (2H, m), 2.4±2.5 (1H, m), 1.7±2.0 (4H, m), 1.6±

(2R)-Methyl, 3-[4-nitrobenzoyl(oxy)]-1,2-epoxy-propane

Ê

16. To a solution of powdered 3 A molecular sieves

(approximately 3.5 g) in CH₂Cl₂(150 mL) at 2208C was

added (1)-DIPT (1.40 g, 6.0 mmol) in CH₂Cl₂(10 mL) via

cannula followed sequentially by Ti(OPrⁱ)₄(1.42 g, 1.5 mL,

5.0 mmol) and cumene hydroperoxide (1.31 g, 36 mL,

0.20 mol). After 1 h, a solution of 2-methallyl alcohol 15

(7.20 g, 8.40 mL, 0.100 mol) in CH₂Cl₂(15 mL) was added

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4375

dropwise via cannula. After 16 h, the mixture was treated

dropwise with P(OMe)₃(18.62 g, 17.70 mL, 150 mmol),

taking care that the temperature did not rise above 2208C.

On warming to 08C, Et₃N (17.0 mL, 0.122 mmol) was

added followed by a suspension of 4-nitrobenzoyl chloride

(18.60 g, 0.10 mmol) in CH₂Cl₂(100 mL) via cannula.

After 1 h, the mixture was ®ltered through a pad of Celite^w,

the ®ltrate was washed with sequentially with a tartaric acid

solution (100 mL, 10% in H₂O), saturated aqueous NaHCO₃

(100 mL) and saturated aqueous NaCl (100 mL). The dried

(Na₂SO₄) extract was ®ltered through a small pad of silica

gel and concentrated under in vacuo (608C, 0.2 mmHg). The

oil, which solidi®ed on standing, was recrystallized (twice

from Et₂O, then i-Pr₂O) to give 16 (12.25 g, 0.053 mol,

52%, .98% e.e.) as an off-white solid. The enantiomeric

excess was determined by chiral shift analysis of the methyl

signal at 1.2 ppm using Eu(hfc)₃(7 mg of 16, 4.5 mg of

Eu(hfc)₃, 0.5 mL of C₆D₆). [a]²_D³26 (c2.98, CHCl₃).

mp 85±868C.

NaHCO₃(100 mL) and saturated aqueous NaCl (100 mL).

The dried (Na₂SO₄) extract was concentrated in vacuo to

give 63 (11.14 g, 37.90 mmol, 99%) as a colorless oil. IR

(®lm) 2935, 1042 cm²¹. ¹H NMR (CDCl₃) d 7.4±7.65 (5H,

m), 4.37 (1H, d, J8.9 Hz), 4.06 (1H, d, J8.9 Hz), 3.77

(2H, m), 2.8±3.0 (2H, m), 1.3±1.8 (10H, m). ¹³C NMR

(CDCl₃) d 144.8, 144.6, 130.8, 129.2, 123.8, 123.7, 110.8,

110.2, 78.5, 73.7, 71.8, 68.3, 68.0, 36.8, 36.4, 36.1, 35.9,

26.7, 24.94, 24.90, 24.4, 23.8, 23.6. HRMS (CI) calcd for

C₁₆H₂₂O₃S 295.1368. Found 295.1363.

1-Thiophenyl-1-acetoxy-(2S),3-propandiol

cyclohexyl

ketal 20. To a stirred solution of 19 (10.87 g, 37.0 mmol)

in Ac₂O (100 mL) was added NaOAc (20.0 g, 244 mmol)

and the mixture heated at re¯ux. After 16 h, the mixture was

cooled to ambient temperature, NaOH (100 mL, 1 M in

H₂O) was added and the mixture stirred for 1 h at ambient

temperature, followed by extraction with CH₂Cl₂

(3£200 mL). The combined extracts were washed with satu-

rated aqueous NaCl (300 mL). The dried (Na₂SO₄) extract

was concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 20% EtOAc/petroleum ether, to

give the diastereoisomeric acetates 20 (1.7:1), (11.69 g,

34.8 mmol, 94%) as a colorless oil. IR (®lm) 2933,

1-Thiophenyl-(2S),3-propandiol 17. To a solution of 16

(9.46 g, 39.90 mmol) in dioxane (37 mL) was added PhSH

(4.30 mL, 41.85 mmol) and then NaOH (21.0 mL,

42.0 mmol, 2 M in H₂O) dropwise. After 2 h at ambient

temperature, solid NaHCO₃(20 mL) was added and the

aqueous phase was extracted with CH₂Cl₂(4£100 mL).

The dried (Na₂SO₄) extract was concentrated in vacuo and

puri®ed by chromatography over silica gel, eluting with

70% EtOAc/petroleum ether, to give 17 (7.56 g,

38.2 mmol, 96%) as a colorless oil. IR (®lm) 3406,

1749 cm²^{1 1}H NMR (CDCl₃) d 7.45±7.55 (6H, m),

.

7.25±7.35 (4H, m), 6.26 (1H, s, major), 6.19 (1H, s,

minor), 4.23 (1H, d, J9.3 Hz, major), 4.02 (1H, d,

J8.8 Hz, minor), 3.79 (1H, d, J9.3 Hz, major), 3.72

(1H, d, J8.8 Hz, minor), 2.05 (3H, s, major), 2.01 (3H,

s, minor), 1.25±1.75 (20H, m), 1.45 (3H, s), 1.44 (3H, s).

¹³C NMR (CDCl₃) d 169.5, 169.2, 133.6, 132.6, 132.5,

132.3, 129.0, 128.9, 128.2, 128.0, 111.4, 111.1, 85.2, 84.8,

82.0, 81.9, 71.9, 71.0, 36.5, 36.1, 36.0, 35.8, 25.0, 23.8,

22.7, 20.9. HRMS (CI) calcd for C₁₈H₂₄O₄S 336.1395.

Found 336.1388.

1

2929 cm²¹. H NMR (CDCl₃) d 7.35±7.45 (2H, m), 7.2±

7.3 (2H, m), 7.1±7.2 (1H, m), 3.55 (1H, dd, J5.7,

11.2 Hz), 3.46 (1H, dd, J5.0, 11.2 Hz), 3.05±3.25 (4H,

m), 1.22 (3H, s). ¹³C NMR (CDCl₃) d 136.6, 129.3, 128.9,

126.1, 73.1, 68.4, 42.9, 23.3. HRMS (CI) calcd for

C₁₀H₁₄O₂S 198.0715. Found 198.0707.

1-Propanal-(2S),3-diol cyclohexyl ketal 21. To a stirred

solution of 20 (3.50 g, 10.42 mmol) in MeOH (20 mL)

was added solid K₂CO₃(0.950 g, 6.88 mmol) and the

mixture heated at re¯ux. After 5 h, the mixture was cooled

to ambient temperature, concentrated in vacuo and Et₂O

(100 mL) was added, precipitating a white solid. After

®ltration through Celite^w(Et₂O rinse), the organic phase

was concentrated in vacuo followed by puri®cation by

KuÈgelrohr distillation (oven temperature 1008C, 1 mmHg)

to give 21 (1.91 g, 10.3 mmol, 99%) as a colorless oil. IR

1-Thiophenyl-(2S),3-propandiol cyclohexyl ketal 18. To

a stirred solution of 17 (7.84 g, 39.60 mmol) in DMF

(10 mL) was added 1-methoxycyclohexene (6.00 g,

53.6 mmol) followed by p-toluene sulfonic acid (0.30 g,

1.50 mmol). After 40 h at ambient temperature, the mixture

was diluted with saturated aqueous brine (250 mL),

extracted with EtOAc (3£300 mL). The dried (Na₂SO₄)

extract was concentrated in vacuo and puri®ed by chromato-

graphy over silica gel, eluting with 20% EtOAc/petroleum

ether, to give 18 (10.68 g, 38.4 mmol, 97%) as a colorless

oil. IR (®lm) 2932 cm²¹. ¹H NMR (CDCl₃) d 7.35±7.4 (2H,

m), 7.25±7.35 (2H, m), 7.1±7.2 (1H, m), 3.99 (1H, d,

J8.6 Hz), 3.71 (1H, d, J8.6 Hz), 3.15 (2H, s), 1.50±

1.65 (8H, m), 1.39 (3H, s), 1.3±1.5 (2H, m). ¹³C NMR

(CDCl₃) d 137.0, 129.2, 128.8, 126.0, 110.4, 80.7, 72.6,

43.5, 36.7, 36.3, 25.0, 24.7, 23.9, 23.80. HRMS (CI) calcd

for C₁₆H₂₂O₂S 278.1341. Found 278.1335.

1

(®lm) 2939, 2863, 1737 cm²¹. H NMR (CDCl₃) d 9.66

(1H, s), 4.23 (1H, d, J8.9 Hz), 3.73 (1H, d, J8.9 Hz),

1.35±1.7 (10H, m), 1.35 (3H, s). ¹³C NMR (CDCl₃) d

202.3, 111.8, 84.1, 70.4, 36.3, 35.9, 24.9, 23.8, 19.4.

HRMS (CI) calcd for C₁₀H₁₇O₃185.1178. Found 185.1171.

(S)-3-4-Methoxybenzoyl(oxy)-2-methyl-1,2-propanediol

23. To a stirred solution of 1:1 t-BuOH/H₂O (48 mL) was

added AD-mix-b (6.79 g) and the biphasic mixture was

cooled to 08C. The benzoate 22 (1.00 g, 4.85 mmol) was

added and the heterogeneous slurry was stirred vigorously

at 08C for 3.5 h and left to warm to room temperature

overnight. Sodium sul®te (7.30 g) was added and stirring

continued for a further 30 min. The aqueous layer was

extracted with EtOAc (3£50 mL) and the combined extracts

were washed with brine (50 mL), dried (Na₂SO₄) and

concentrated in vacuo. Flash chromatography over silica

1-Phenylsul®nyl-(2S),3-propandiol cyclohexyl ketal 19.

To a stirred solution of 18 (10.54 g, 37.90 mmol) in

CH₂Cl₂(200 mL) at 2208C was added a solution of

m-chloroperoxybenzoic acid (7.90 g, 41.20 mmol, approxi-

mately 90%) in CH₂Cl₂(100 mL) via cannula. After 30 min,

the mixture was quenched with saturated aqueous NaHCO₃

(50 mL) and extracted with Et₂O (4£100 mL), followed by

washing of the combined extracts with saturated aqueous

4376

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

gel, eluting with EtOAc gave 23 (1.02 g, 88%, 97% ee) as a

colorless oil. H NMR (CDCl₃) d 7.94 (2H, m), 6.87 (2H,

m), 4.30 (1H, d, J11.2 Hz), 4.17 (1H, d, J11.2 Hz), 3.81

(3H, s), 3.56 (1H, d, J11.6 Hz), 3.46 (1H, d, J11.6 Hz),

3.36 (2H, br s), 1.23 (3H, s).

NH₄Cl (100 mL), extracted with EtOAc (3£100 mL). The

dried (Na₂SO₄) extract was concentrated in vacuo and

puri®ed by chromatography over silica gel, eluting with

10±30% Et₂O/petroleum ether, to give a mixture of 26

and 27 (3.56 g, 5.74 mmol, 64%) as an off-white solid.

The diastereomers 26 and 27 could be separated by PLC

of the mixture, eluting with 15% Et₂O/petroleum ether.

1

(S)-3-4-Methoxybenzoyl(oxy)-2-methyl-1,2-propanediol

cyclohexyl ketal 24. To a stirred solution of 23 (2.46 g,

10.29 mmol) in cyclohexanone (30 mL) was added

Procedure 2: To a stirred solution of 14 (1.17 g, 2.68 mmol)

in THF (9 mL) at 2788C was added n-BuLi (1.20 mL,

2.76 mmol, 2.3 M in hexanes). The mixture was immedi-

ately warmed to 08C. After 15 min, the mixture was

recooled to 2788C and a solution of 21 (0.495 g,

2.69 mmol) in THF (6 mL) was added via cannula. After

1 h, the mixture was warmed to 08C for an additional 1 h,

quenched with saturated aqueous NH₄Cl (100 mL), and

extracted with EtOAc (3£100 mL). The dried (Na₂SO₄)

extract was concentrated in vacuo and puri®ed by chromato-

graphy over silica gel, eluting with 10±30% Et₂O/petroleum

ether, to give 26 and 27 (1.10 g, 1.77 mmol, 66%) as an

off-white solid. Crystals of 26 suitable for X-ray crystallo-

graphy were obtained by recrystallization from hexanes.

Data for 26. mp 139±1408C. [a]²_D³175 (c0.44,

Ê

p-toluenesulfonic acid (192 mg, 1.02 mmol) and 3 A

molecular sieves (0.5 g). The mixture was heated at 1508C

overnight and then cooled to room temperature. Filtration,

concentration in vacuo, and ¯ash chromatography over

silica gel, eluting with EtOAc gave 24 (2.96 g, 90%) as a

1

colorless oil. IR (®lm) 2935, 2862, 1718 cm²¹. H NMR

(CDCl₃) d 7.98 (2H, m), 6.91 (2H, m), 4.20 (2H, q,

J10.9 Hz), 4.04 (1H, d, J8.6 Hz), 3.84 (3H, s), 3.75

(1H, d, J8.6 Hz), 1.72±1.51 (10H, m), 1.37 (3H, s). ¹³C

NMR (CDCl₃) d 212.1, 131.6, 113.6, 110.5, 71.3, 68.1,

55.4, 41.9, 36.4, 36.2, 27.0, 25.02, 24.96, 23.8, 23.0.

HRMS (CI) calcd for C₁₈H₂₅O₅(MH¹) 321.1702. Found

321.1694.

1

1-Propanol-(2S),3-diol cyclohexyl ketal 25. To a stirred

solution of 24 (914 mg, 2.98 mmol) in 1:1 THF/H₂O

(10 mL) was added lithium hydroxide monohydrate

(625 mg, 14.90 mmol) and the resulting solution was stirred

at re¯ux overnight. The solution was poured into brine

(10 mL) and extracted with Et₂O (2£10 mL). The combined

extracts were dried (Na₂SO₄) and concentrated in vacuo.

Flash chromatography over silica gel, eluting with EtOAc

gave 25 (510 mg, 92%) as a colorless oil. IR (®lm) 3460

(br), 2976, 2950, 2876 cm²¹. ¹H NMR (CDCl₃) d 3.94 (1H,

m), 3.70 (1H, m), 3.47 (2H, m), 1.91 (1H, br t), 1.71±1.50

(10H, m), 1.27 (3H, s). HRMS (CI) calcd for C₁₀H₁₉O₃

(MH¹) 187.1334. Found 187.1331.

CHCl₃). H NMR (CDCl₃) d 8.05±8.1 (2H, m), 7.4527.6

(3H, m), 5.48 (1H, br s), 4.72 (1H, br s), 4.29 (1H, d,

J9.4 Hz), 4.12 (1H, dd, J2.2, 10.9 Hz), 4.05 (1H, d,

J5.9 Hz), 3.91 (1H, d, J9.4 Hz), 3.83 (1H, dd, J5.9,

10.9 Hz), 3.11 (1H, d, J4.1 Hz), 3.05 (OH, m), 1.40±2.15

(16H, m), 1.35 (3H, s), 1.24 (3H, s), 0.93 (9H, s), 0.87 (3H,

d, J6.9 Hz), 0.74 (3H, d, J6.9 Hz), 0.14 (3H, s), 0.11

(3H, s). ¹³C NMR (CDCl₃) d 141.0, 134.2, 133.2, 130.4,

129.1, 128.2, 125.6, 108.7, 84.6, 75.9, 71.2, 65.7, 63.6,

42.9, 42.8, 37.4, 35.9, 35.6, 33.3, 26.5, 26.0, 25.0, 24.9,

23.9, 23.6, 23.4, 21.0, 18.7, 14.4, 25.1, 25.6. HRMS (CI)

calcd for C₃₄H₅₇O₆SSi 621.3586. Found 621.3601. Data for

1

27. H NMR (CDCl₃) d 7.85±7.95 (2H, m), 7.55±7.6 (1H,

m), 7.45±7.5 (2H, m), 5.50 (1H, br s), 4.25 (1H, br d,

J11.1 Hz), 4.11 (1H, d, J8.0 Hz), 4.06 (1H, d,

J10.3 Hz), 3.90 (1H, dd, J5.5, 11.1 Hz), 3.65±3.8 (2H,

m), 3.54 (1H, d, J8.0 Hz), 3.12 (OH, br s), 1.5±2.0 (12H,

m), 1.35±1.5 (2H, m), 0.9±1.0 (12H, m), 0.80 (3H, d,

J6.6 Hz), 0.06 (3H, s), 0.05 (3H, s).

1-Propanal-(2S),3-diol cyclohexyl ketal 21. To a solution

of 25 (21.1 mg, 113.4 mmol) in CH₂Cl₂(3.73 mL) was

added Dess±Martin triacetoxyperiodinane (69.0 mg,

161.5 mmol). After 30 min the mixture was diluted with

Et₂O (3 mL), quenched with saturated aqueous NaHCO₃

(2 mL), and Na₂S₂O₃(35 mg). After 10 min stirring the

solution became clear, and the layers were separated and

the aqueous layer extracted with Et₂O (3£3 mL). The

combined extracts were washed with brine (5 mL), dried

(Na₂SO₄) and concentrated in vacuo. Puri®cation by

chromatography over silica gel, eluting with 50% EtOAc/

hexane, gave 21 (17.3 mg, 83%) as a colorless oil.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[7-(9S)-methyl-(8R),9,10-butantriol 9,10-

cyclohexyl ketal]-1-cyclohexene 28. To a solution of 26

(90 mg, 0.15 mmol) in THF (1 mL) and NH₃(5 mL,

distilled over Na) at 2788C was added Na (30 mg,

1.30 mmol). After 10 min, the blue solution was quenched

at 2788C with solid NH₄Cl. After warming to ambient

temperature, the mixture was diluted with CH₂Cl₂and

®ltered through Celite^w(CH₂Cl₂rinse). The extract was

concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 20% Et₂O/petroleum ether, to

give 28 (38 mg, 0.08 mmol, 53%) as a colorless oil.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[(7S)-phenylsulfonyl-(9S)-methyl-(8S),9,10-

butanetriol 9,10-cyclohexyl ketal]-1-cyclohexene 26 and

1-methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

(6S)-[(7S)-phenylsulfonyl-(9S)-methyl-(8R),9,10-butan-

triol 9,10-cyclohexyl ketal]-methyl-1-cyclohexene 27.

Procedure 1: To a stirred solution of 14 (3.91 g,

8.97 mmol) in benzene (18 mL) was added EtMgBr

(3.75 mL, 10.13 mmol, 2.7 M in Et₂O) and the mixture

was heated at re¯ux. After 16 h, the solution was allowed

to cool to ambient temperature and a solution of 21 (4.95 g,

9.11 mmol) in benzene (8 mL) was added via cannula. After

2 h, the mixture was quenched with saturated aqueous

[a]²_D³1127 (c1.24, CHCl₃). IR (®lm) 3430, 2923 cm²¹

.

¹H NMR (CDCl₃) d 5.26 (1H, br s), 4.24 (1H, d, J1.7 Hz),

4.14 (1H, d, J8.7 Hz), 3.85 (1H, dd, J5.0, 11.1 Hz), 3.72

(1H, d, J8.7 Hz), 3.6±3.65 (2H, m), 2.2±2.25 (1H, m),

1.3±1.9 (20H, m), 1.23 (3H, s), 0.90 (9H, s), 0.88 (3H, d,

J6.8 Hz), 0.80 (3H, d, J6.8 Hz), 0.10 (3H, s), 0.09 (3H,

s). ¹³C NMR (CDCl₃) d 138.9, 119.3, 109.7, 82.4, 76.6,

73.3, 62.8, 41.8, 37.2, 36.7, 36.5, 36.2, 32.1, 26.6, 25.9,

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4377

25.2, 24.3, 23.9, 23.9, 22.9, 21.1, 19.3, 18.3, 15.3, 25.0,

25.4. HRMS (CI) calcd for C₂₈H₅₂O₄Si 480.3635. Found

480.3606.

temperature, the mixture was diluted with H₂O (100 mL)

and extracted with EtOAc (4£100 mL). The dried

(Na₂SO₄) extract was concentrated in vacuo and puri®ed

by chromatography over silica gel, eluting with 10%

Et₂O/petroleum ether, to give 31 (2.42 g, 5.06 mmol,

92%) as a colorless oil. [a]²_D³166 (c1.10). IR (®lm)

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[7-(9S)-methyl-(8S),9,10-butantriol 9,10-

cyclohexyl ketal]-1-cyclohexene 29. To a solution of 27

(38 mg, 0.06 mmol) in THF (1 mL) and NH₃(2 mL,

distilled over Na) at 2788C was added Na (0.020 g,

0.87 mmol). After 15 min, the blue solution was quenched

at 2788C with solid NH₄Cl. After warming to ambient

temperature, the mixture was diluted with CH₂Cl₂and

®ltered through Celite^w(CH₂Cl₂rinse). The extract was

concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 20% Et₂O/petroleum ether, to

give 29 (6.0 mg, 0.013 mmol, 21%) as a colorless oil.

1

2956, 1716 cm²¹. H NMR (CDCl₃) d 5.30 (1H, br s),

4.24 (1H, d, J8.8 Hz), 3.76 (1H, d, J8.8 Hz), 3.64 (1H,

dd, J5.8, 10.6 Hz), 3.51 (1H, dd, J8.0, 10.6 Hz), 2.9±3.0

(2H, m), 2.65 (1H, dd, J8.0, 10.4 Hz), 1.4±2.0 (16H, m),

1.39 (3H, s), 0.91 (3H, d, J5.9 Hz), 0.86 (9H, s), 0.81 (3H,

d, J5.9 Hz), 0.00 (3H, s), 20.01 (3H, s). ¹³C NMR

(CDCl₃) d 212.6, 136.9, 121.2, 111.5, 86.0, 72.0, 63.0,

40.7, 37.8, 37.5, 36.1, 35.7, 33.1, 27.0, 25.9, 25.0, 24.2,

23.8, 23.7, 22.4, 21.1, 18.2, 17.0, 25.4, 25.5. HRMS (CI)

calcd for C₂₈H₄₇O₄Si 479.3557. Found 479.3537.

[a]²_D³1548 (c0.90, CHCl₃). IR (®lm) 3566, 2934 cm²¹

.

¹H NMR (CDCl₃) d 5.32 (1H, br s), 3.90 (1H, d, J8.4 Hz),

3.75 (2H, m), 3.68 (1H, d, J8.4 Hz), 3.52 (1H, apparent t),

2.50 (1H, m), 2.44 (1H, d, J3.7 Hz), 1.3±2.0 (20H, m),

1.26 (3H, s), 0.9±1.0 (12H, m), 0.83 (3H, d, J6.7 Hz), 0.05

(6H, s). ¹³C NMR (CDCl₃) d 137.1, 120.9, 110.1, 83.5, 73.7,

71.2, 62.4, 40.5, 36.6, 36.4, 34.6, 31.5, 27.0, 26.0, 25.1,

24.2, 23.9, 22.3, 20.9, 20.5, 18.2, 17.2, 25.3, 25.4.

HRMS (CI) calcd for C₂₈H₅₂O₄Si 480.3635. Found

480.3609.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[7-(9S)-methyl-(8R),9,10-butantriol 9,10-

cyclohexyl ketal]-1-cyclohexene 28 and 1-methyl-(4R)-

isopropyl-(5R)-tert-butyldimethylsiloxymethyl-(6S)-[7-

(9S)-methyl-(8S),9,10-butantriol 9,10-cyclohexyl ketal]-

1-cyclohexene 29. To

a solution of 31 (221 mg,

0.462 mmol) in THF (1.5 mL) was added K-Selectride^w

(2.1 mL, 2.1 mmol, 1 M in THF) was added dropwise

over 5 min via syringe pump at 08C. After 1 h, the mixture

was allowed to warm to ambient temperature, and an addi-

tional amount of K-Selectride^w(1 mL, 1.0 mmol, 1 M in

THF) was added. After 7 h total reaction time, the solution

was cooled to 08C and quenched with aqueous ethanol solu-

tion (3 mL, 50% in H₂O), followed by NaOH (3 mL, 3 M in

H₂O) and H₂O₂(3 mL, 30% in H₂O). After 15 min at 08C,

the solution was diluted with H₂O (30 mL) and extracted

with Et₂O (5£30 mL). The dried (MgSO₄) extract was

concentrated in vacuo, ®ltered through a small plug of silica

gel (30% Et₂O/petroleum ether rinse) and puri®ed by

MPLC, eluting with 7% Et₂O/petroleum ether, to give the

undesired alcohol 28 (11 mg, 0.0229 mmol, 5%) as a color-

less oil followed by the desired alcohol 29 (171 mg,

0.356 mmol, 77%) as a colorless oil.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[(7S)-phenylsulfonyl-(9S)-methyl-9,10-

butandiol-8-one 9,10-cyclohexyl ketal]-1-cyclohexene 30.

To a solution of 26/27 (1.35 g, 2.18 mmol) in CH₂Cl₂

(20 mL) was added Dess±Martin periodinane (1.15 g,

2.71 mmol). After 2 h, the mixture was quenched with satu-

rated aqueous NaHCO₃(15 mL), and NaHSO₃(15 mL, 1 M

in H₂O), diluted with Et₂O (15 mL) and stirred until the

solution became clear. The layers were allowed to separate,

and the aqueous layer was extracted with Et₂O (3£50 mL).

The combined extracts were washed with saturated aqueous

NaCl (100 mL), dried (Na₂SO₄), and concentrated in vacuo.

The residue was puri®ed by chromatography over silica gel,

eluting with 20% Et₂O/petroleum ether, to give 30 (1.26 g,

2.04 mmol, 94%) as a colorless oil. [a]²_D³20.5 (c0.99,

1-Methyl-(4R)-isopropyl-(5R)-keto-(6S)-[7-(8S)-(9S)-

methyl-9,10-butanediol 9,10-cyclohexyl ketal]-8,11-

oxido-1-cyclohexene 32. To a stirred solution of 29

(1.84 g, 3.83 mmol) in THF (27 mL) was added n-Bu₄NF

(TBAF) (16 mL, 16 mmol, 1 M in THF) at ambient

temperature. After 10 min, saturated aqueous NaHCO₃

(200 mL) was added and the THF evaporated in vacuo.

The aqueous layer was extracted with Et₂O (4£200 mL),

dried (MgSO₄), concentrated in vacuo and puri®ed by

chromatography over silica gel, eluting with 50% Et₂O/

petroleum ether, to give the diol (1.40 g, 3.83 mmol, 99%)

1

CHCl₃). IR (®lm) 2938, 1719 cm²¹. H NMR (CDCl₃) d

7.5±8.0 (2H, m), 7.5±7.65 (3H, m), 5.69 (1H, d,

J1.5 Hz), 5.32 (1H, br s), 3.75±3.9 (2H, m), 3.78 (1H, d,

J9.0 Hz), 3.61 (1H, dd, J3.3, 10.8 Hz), 3.25 (1H, br s),

1.35±1.95 (21H, m), 0.93 (9H, s), 0.84 (3H, d, J6.7 Hz),

0.76 (3H, d, J6.7 Hz), 0.11 (3H, s), 0.10 (3H, s). ¹³C NMR

(CDCl₃) d 204.4, 140.0, 135.6, 133.7, 129.7, 128.6, 123.4,

112.3, 112.3, 86.6, 73.7, 68.3, 63.2, 43.6, 42.0, 36.4, 36.0,

35.7, 27.0, 26.03, 25.96, 24.9, 24.3, 24.0, 23.6, 23.5, 20.4,

18.6, 15.2, 25.1, 25.4. HRMS (CI) calcd for C₃₄H₅₅O₆SiS

619.3489. Found 619.3478.

as a viscous, colorless oil. IR (®lm) 3441, 2937, 1447 cm²¹

.

¹H NMR (CDCl₃) d 5.35 (1H, br s), 3.94 (1H, d, J8.6 Hz),

3.6±3.8 (4H, m), 2.5±2.55 (1H, m), 1.0±2.1 (20H, m), 1.28

(3H, s), 0.92 (3H, d, J6.7 Hz), 0.83 (3H, d, J6.7 Hz).

HRMS (CI) calcd for C₂₂H₃₈O₄266.2770. Found

366.2753. Used directly in the next step.

1-Methyl-(4R)-isopropyl-(5R)-tert-butyldimethylsiloxy-

methyl-(6S)-[7-(9S)-methyl-9,10-butandiol-8-one 9,10-

cyclohexyl ketal]-1-cyclohexene 31. To NH₃(250 mL,

distilled over Na) at 2788C was added Na (1.30 g,

54.20 mmol). After 30 min, a solution of 30 (3.39 g,

5.49 mmol) in THF (50 mL) was added via cannula and

stirred for a further 30 min. The mixture was quenched at

2788C by the sequential addition of isoprene (4 mL)

followed by solid NH₄Cl. After warming to ambient

To a stirred solution of the diol (1.40 g, 3.83 mmol) in

Ê

CH₂Cl₂(47 mL) with powdered 4 A molecular sieves

(approx 5 g) was added N-methylmorpholine N-oxide

(NMO) (1.76 g, 15.0 mmol) and n-Pr₄NRuO₄(TPAP)

4378

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

(50 mg, 0.14 mmol) at ambient temperature. An additional

amount of TPAP (29 mg, 0.08 mmol) was added during the

course of the reaction. After 27 h, the mixture was diluted

with Et₂O (100 mL), ®ltered through silica gel (500 mL

Et₂O rinse) and concentrated in vacuo. The residue was

puri®ed by chromatography over silica gel, eluting with

50% Et₂O/petroleum ether to give 32 (1.21 g, 3.34 mmol,

87%) as a colorless oil. [a]²_D³240 (c0.78, CHCl₃). IR

33.0, 28.3, 26.0, 24.1, 21.2, 15.9, 14.7. HRMS (CI) calcd

for C₁₆H₂₇O₃267.1960. Found 267.1967. Data for 34. IR

(®lm) 3445, 2961 cm²¹. ¹H NMR (CDCl₃) d 5.41 (1H, br s),

4.40 (1H, d, J8.7 Hz), 3.64 (1H, dd, J3.5, 11.1 Hz), 3.4±

3.6 (4H, m), 3.46 (1H, dd, J1.3, 12.0 Hz), 2.7 (OH, s),

2.4±2.6 (2H, m), 1.9±2.1 (3H, m), 1.75±1.85 (1H, m),

1.4±1.7 (8H, m), 0.90 (3H, d, J6.3 Hz), 0.87 (3H, d,

J6.3 Hz). HRMS (CI) calcd for C₁₇H₃₀O₄298.2144.

Found 298.2139.

1

(®lm) 2935, 2863, 1729 cm²¹. H NMR (CDCl₃) d 5.51

(1H, br s), 4.10 (1H, d, J9.0 Hz), 3.97 (1H, dd, J2.6,

11.7 Hz), 3.67 (1H, d, J9.0 Hz), 2.7±2.8 (1H, m), 2.5±

2.6 (1H, br s), 2.26 (1H, dt, J3.6, 14.4 Hz), 1.9±2.1 (2H,

m), 1.4±1.9 (19H, m), 0.91 (6H, d, J6.6 Hz). ¹³C NMR

(CDCl₃) d 173.7, 131.8, 125.0, 110.7, 80.6, 79.2, 69.8, 43.0,

40.3, 36.2, 35.6, 31.3, 26.6, 25.7, 25.1, 24.6, 24.1, 23.84,

23.78, 21.1, 20.7, 20.3. HRMS (CI) calcd for C₂₂H₃₄O₄

262.2457. Found 362.2445.

To a solution of 34 (339 mg, 1.14 mmol) in MeOH (5 mL)

was added p-toluene sulfonic acid (304 mg, 1.60 mmol) at

ambient temperature. After 16 h, the mixture was quenched

with solid NaHCO₃, diluted with H₂O (25 mL) and

extracted with EtOAc (4£50 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puri®ed by chromato-

graphy over silica gel, eluting with 50% Et₂O/petroleum

ether, to give 35 (213 mg, 0.801 mmol, 70%) as a colorless

oil and. Further elution with EtOAc gave starting material

34 (71 mg, 0.238 mmol, 21%).

1-Methyl-(4R)-isopropyl-(5R)-(6S)-[7-(8S)-(9S)-methyl-

9,10-butandiol 9,10-cyclohexyl ketal]-(11S)-hydroxyl-

8,11-oxido-1-cyclohexene 33. A stirred solution of 32

(1.21 g, 3.34 mmol) in CH₂Cl₂(43 mL) was cooled to

2788C and DIBAL-H (3.4 mL, 3.4 mmol, 1.0 M in

CH₂Cl₂) was added via syringe pump over 10 min. An addi-

tional amount of DIBAL-H (0.4 mL, 0.4 mmol, 1 M in

CH₂Cl₂) was added during the course of the reaction.

After 70 min, the mixture was quenched with MeOH

(0.5 mL) followed by HCl (50 mL, 2 M in H₂O), warmed

to ambient temperature and stirred for 15 min. The aqueous

layer was extracted with CH₂Cl₂(4£50 mL), dried (MgSO₄)

and concentrated in vacuo to give 33 as a colorless oil which

was .95% pure by ¹H NMR and used without further puri-

®cation. IR (®lm) 3429, 2983, 2859 cm²¹. ¹H NMR (CDCl₃)

d 5.42 (1H, br s), 4.76 (1H, dd, J5.7, 8.6 Hz), 4.01 (1H, d,

J8.7 Hz), 3.65 (1H, d, J8.7 Hz), 3.24 (1H, d,

J11.2 Hz), 2.74 (1H, d, J5.6 Hz), 2.5 (1H, br s), 2.1

(1H, br s), 1.96 (1H, d, J13.7 Hz), 1.3±1.8 (21H, m),

0.90 (3H, d, J6.3 Hz), 0.87 (3H, d, J6.3 Hz). HRMS

(CI) calcd for C₂₂H₃₆O₄364.2614. Found 364.2606.

1-Methyl-(4R)-(5R)-isopropyl(6S)-[7-(8S)-(9R)-methyl-

10-butanal]-8,9,(11R)-bis-oxido-1-cyclohexene 36. To a

solution of 34 (52.0 mg, 0.195 mmol) in CH₂Cl₂(2.5 mL)

was added Dess±Martin periodinane (120 mg, 0.283 mmol)

at ambient temperature. After 2 h the mixture was quenched

with saturated aqueous NaHCO₃(5 mL) and NaHSO₃

(5 mL, 1 M in H₂O), diluted with Et₂O (5 mL), and stirred

until the solution was clear. The layers were allowed to

separate and the aqueous layer was extracted with Et₂O

(3£20 mL). The dried (MgSO₄) extract was concentrated

in vacuo and puri®ed by chromatography over silica gel,

eluting with 30% Et₂O/petroleum ether, to give 36

(46.0 mg, 0.174 mmol, 89%) as an off-white solid.

[a]²_D³144 (c0.99, CHCl₃). IR (®lm) 2959, 1732 cm²¹

.

¹H NMR (CDCl₃) d 9.65 (1H, s), 5.80 (1H, s), 5.4±5.45 (1H,

m), 4.42 (1H, d, J5.0 Hz), 2.5±2.6 (1H, m), 2.0±2.1 (1H,

m), 1.8±2.0 (2H, m), 1.5±1.8 (7H, m), 1.40 (3H, s), 0.91

(3H, d, J6.9 Hz), 0.79 (3H, d, J6.9 Hz). ¹³C NMR

(CDCl₃) d 204.2, 135.0, 122.0, 103.9, 85.4, 77.2, 40.5,

36.0, 32.8, 28.0, 26.0, 24.1, 21.1, 14.7, 13.6. HRMS (CI)

calcd for C₁₆H₂₅O₃265.1804. Found 265.1795.

1-Methyl-(4R)-isopropyl-(5R)-(6S)-[7-(8S)-(9S)-methyl-

10-butanol]-8,9,(11R)-bis-oxido-1-cyclohexene 35 and 1-

methyl-(4R)-isopropyl-(5R)-(6S)-[7-(8S)-(9S)-methyl-

9,10-butandiol]-(11S)-methoxy-8,11-oxido-1-cyclo-

hexene 34. To a stirred solution of crude 33 (1.22 g,

3.34 mmol) in MeOH (173 mL) was added p-toluene-

sulfonic acid (2.13 g, 11.2 mmol) at ambient temperature.

After 14 h, solid NaHCO₃was added followed by saturated

aqueous NaHCO₃, and the mixture ®ltered and rinsed with

H₂O and Et₂O. The ®ltrate was concentrated in vacuo to

remove the MeOH, extracted with EtOAc (6£200 mL),

dried (MgSO₄), and concentrated in vacuo. The residue

was puri®ed by chromatography over silica gel, eluting

with 50% Et₂O/petroleum ether, to give 35 (590 mg,

2.21 mmol, 67%) as a colorless oil. Further elution with

EtOAc gave the diol 34 (225 mg, 0.76 mmol, 23%) as a

colorless oil. Data for 35. [a]²_D³211 (c1.09). IR (®lm)

1-Methyl-(4R)-isopropyl-(5R)-(6S)-[7-(8S)-(9S)-methyl-

10-Z-octen-12-on-14-oate ethyl ester]-8,9,(15R)-bis-

oxido-1-cyclohexene 37. To a solution of the phosphonium

salt (307 mg, 0.651 mmol) in THF (2 mL) and N,N⁰-

dimethylpropyleneurea (DMPU) (2 mL) was added NaH

(55 mg, 1.38 mmol, 60% in mineral oil) at ambient tempera-

ture. After 20 min, a solution of 36 (101 mg, 0.383 mmol) in

THF (1 mL) was added via cannula. An additional amount

of THF (2£0.5 mL) was added to rinse the aldehyde ¯ask.

After 50 min at ambient temperature, the solution was

heated to 408C. After 1.5 h, the mixture was allowed to

cool to ambient temperature and quenched with saturated

aqueous NH₄Cl (10 mL), extracted with Et₂O (3£20 mL),

washed with saturated aqueous NaCl (50 mL), and extracted

with Et₂O (3£50 mL). The dried (MgSO₄) extract was

concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 15±30% Et₂O/petroleum

ether, to give the desired cis isomer 37 (121 mg,

0.322 mmol, 84%) as a colorless oil followed by the

undesired trans isomer (8.0 mg, 0.213 mmol, 6%) as a

1

3448, 2926 cm²¹. H NMR (CDCl₃) d 5.61 (1H, s), 5.39

(1H, m), 4.05 (1H, d, J3.4 Hz), 3.49 (1H, d, J10.5 Hz),

3.42 (1H, d, J10.5 Hz), 2.55±2.7 (1H, m), 2.0±2.15 (2H,

m), 1.8±2.0 (2H, m), 1.5±1.8 (6H, m), 1.45 (3H, s), 0.87

(3H, d, J7.0 Hz), 0.76 (3H, d, J7.0 Hz). ¹³C NMR

(CDCl₃) d 135.5, 121.7, 102.7, 81.6, 68.8, 40.7, 36.0,

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4379

colorless oil. Data for 37. IR (®lm) 2958, 1741, 1695,

colorless liquid. IR (®lm) 2926, 1730 cm²¹

.

¹H NMR

1

1649 cm²¹. H NMR (C₆D₆) d 6.30 (1H, d, J13.1 Hz,

(C₆D₆) d 6.02 (1H, d, J2.9 Hz), 7.73 (1H, d, J2.9 Hz),

3.84 (2H, q, J7.4 Hz), 3.40 (2H, s), 1.96 (3H, s), 0.86 (3H,

t, J7.4 Hz). HRMS (CI) calcd for C₉H₁₃O₃169.0865.

Found 169.0867.

enol), 6.04 (1H, d, J12.5 Hz, ketone), 5.84 (1H, s, enol),

5.76 (1H, s, ketone), 5.61 (1H, d, J12.5 Hz, ketone), 5.3±

5.4 (1H, m), 5.21 (1H, dd, J1.9, 13.1 Hz, enol), 5.01 (1H,

s, enol), 4.87 (1H, d, J3.5 Hz, enol), 4.45 (1H, d,

J3.4 Hz, ketone), 3.91 (2H, q, J7.2 Hz), 3.18 (2H, s,

ketone), 2.5±2.7 (1H, m), 2.0±2.2 (1H, m), 1.7±2.0 (4H,

m), 1.5±1.7 (9H, m), 0.91 (3H, t, J7.3 Hz), 0.82 (3H,

apparent t), 0.6±0.7 (3H, m). ¹³C NMR (C₆D₆) d 193.7,

173.5, 169.8, 166.8, 154.6, 153.3, 136.0, 135.8, 124.5,

121.9, 120.4, 102.5, 102.1, 94.0, 83.6, 83.3, 80.7, 79.6,

61.0, 60.3, 50.8, 41.0, 40.8, 36.4, 33.4, 30.2, 28.7, 28.6,

26.2, 24.6, 24.5, 21.4, 21.3, 19.7, 18.2, 14.9, 14.1, 14.0.

HRMS (CI) calcd for C₂₂H₃₃O₅377.2328. Found

1-Methyl-(4R)-isopropyl-(5R)-dimethyl acetal-(6R)-[7-9-

methyl-9-E-butene-10-ol]-1-cyclohexene 42. A solution of

9-BBN (0.5 M in THF, 10.5 mL, 5.25 mmol) was added

dropwise to 7 (1.12 g, 5.0 mmol). After 20 h at 458C, the

mixture was allowed to cool to ambient temperature. To a

stirred solution of freshly prepared Pd(PPh₃)₄(175 mg,

0.15 mmol) and the vinyl bromide 41 (755 mg, 5.0 mmol)

in THF (3 mL) was added the borane adduct prepared above

followed by NaOH (5.0 mL, 3 M in H₂O) in the dark. The

resulting mixture was heated at 658C for 6 h, cooled to 08C

and treated with H₂O₂(1.5 mL, 30% in H₂O). After stirring

at ambient temperature for 1 h, H₂O (25 mL) was added and

the mixture was extracted with Et₂O (5£50 mL). The

combined extracts were washed with saturated aqueous

NaCl (2£50 mL). The dried (MgSO₄) extract was concen-

trated in vacuo and puri®ed by chromatography over silica

gel, eluting with 25% Et₂O/petroleum ether, to give starting

diene 7 (367 mg, 1.64 mmol, 33%) followed by 42 (651 mg,

2.20 mmol, 44%) as a yellow oil. IR (®lm) 3378,

1

377.2321. Data for trans-37. H NMR (C₆D₆) d 6.78 (1H,

apparent t, ketone/enol), 6.52 (1H, d, J15.5 Hz, ketone),

6.26 (1H, d, J15.5 Hz, enol), 5.75 (1H, s, enol), 5.72 (1H,

s, ketone), 5.37 (1H, br s), 5.17 (1H, s, enol), 3.9±4.0 (2H,

m), 3.60 (1H, d, J2.7 Hz, enol), 3.56 (1H, d, J2.7 Hz,

ketone), 3.26 (2H, s, ketone), 2.45±2.65 (1H, m), 2.0±2.1

(1H, m), 1.7±1.9 (2H, m), 1.1±1.7 (10H, m), 0.8±1.0 (3H,

m), 0.82 (3H, d, J6.8 Hz), 0.6±0.7 (3H, m). HRMS (CI)

calcd for C₂₂H₃₃O₅377.2328. Found 377.2324.

1

1-Methyl-(4R)-isopropyl-(5R)-(6S)-[7-(8S)-(9S)-methyl-

10-Z-octen-12-en-14-oate ethyl ester]-8,15-oxido-9,12-

oxido-1-cyclohexene 38. To a stirred solution of 37

(24.5 mg, 0.0652 mmol) in CH₂Cl₂(1 mL) was added

BF₃´Et₂O (3.5 mg, 3.0 mL, 0.024 mmol) at 2788C. After

1 h, the mixture was quenched with saturated aqueous

NaHCO₃(1 mL) and extracted with CH₂Cl₂(4£2 mL).

The dried (MgSO₄) extract was concentrated in vacuo and

puri®ed by PLC, eluting with 30% Et₂O/petroleum ether, to

give 38 (14 mg, 0.037 mmol, 56%) as a colorless oil. Data

2955 cm²¹. H NMR (CDCl₃) d 5.50 (1H, m), 5.29 (1H,

br s), 4.28 (1H, d, J5.8 Hz), 3.95 (2H, s), 3.31 (6H, s), 2.2±

2.25 (3H, m), 1.5±1.9 (8H, m), 1.64 (3H, s), 0.85 (3H, d,

J7.0 Hz), 0.77 (3H, d, J7.0 Hz). ¹³C NMR (CDCl₃) d

137.2, 133.7, 127.5, 121.1, 107.1, 69.3, 54.5, 54.3, 40.9,

39.2, 36.4, 28.8, 27.4, 24.5, 23.0, 21.3, 16.8, 13.8. HRMS

(CI) calcd for C₁₈H₃₃O₃297.2417. Found 297.2429.

1-Methyl-(4R)-isopropyl-(5R)-(6R)-[7-(8R)-methoxy-

(9S)-methyl-10-butanol]-(11R)-methoxy-9,11-oxido-1-

cyclohexene 45 and 1-methyl-(4R)-isopropyl-(5R)-di-

methyl acetal-(6R)-[7-(9R)-methyl-(8R),9-epoxy-10-

butanol]-1-cyclohexene 43. To a stirred solution of (1)-

diisopropyltartrate (56 mg, 0.24 mmol) in CH₂Cl₂(5 mL) at

1

for 38. IR (®lm) 3424, 2969, 2927, 1696, 1635 cm²¹. H

NMR (C₆D₆) d 7.69 (1H, d, J5.9 Hz), 6.33 (1H, dd, J1.2,

5.9 Hz), 5.73 (1H, d, J1.2 Hz), 5.27 (1H, br s), 4.48 (1H, d,

J8.3 Hz), 4.0±4.2 (2H, m), 3.30 (1H, d, J11.4 Hz), 2.32

(1H, br s), 2.16 (1H, br s), 1.9±2.1 (2H, m), 1.55±1.75 (3H),

1.48 (3H, s), 1.2±1.45 (4H, m), 1.02 (3H, t, J7.1 Hz), 0.85

(3H, d, J6.6 Hz), 0.78 (3H, d, J6.6 Hz). HRMS (CI)

calcd for C₂₂H₃₃O₅377.2328. Found 377.2319.

Ê

2408C was added powdered 3 A molecular sieves (60 mg)

followed by Ti(OPrⁱ)₄(56 mg, 0.20 mmol) and tert-butyl-

hydroperoxide (0.66 mL, 2.0 mmol, 3 M in isooctane).

After 45 min, a solution of 42 (296 mg, 1.0 mmol) in

CH₂Cl₂(1 mL) was added dropwise. After 24 h, the mixture

was allowed to warm to 08C and poured into a stirred solu-

tion of ferrous sulfate heptahydrate (1.6 g), tartaric acid

(0.5 g) and H₂O (5 mL) at 08C. After 10 min, the two phases

were separated and the aqueous layer was extracted with

Et₂O (3£10 mL). The combined extracts were poured into

a stirred, precooled solution of (08C, 1.0 mL) prepared from

NaCl (5 g) and NaOH (30 g) in H₂O (90 mL). The mixture

was stirred at 08C for 1 h, diluted with H₂O (5 mL) and the

two phases separated. The aqueous layer was extracted with

Et₂O (2£10 mL), the combined extracts washed with satu-

rated aqueous NaCl (20 mL). The dried (Na₂SO₄) extract

was concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 40% Et₂O/petroleum ether, to

give the acetal 45 (262 mg, 0.840 mmol, 84%) as a colorless

oil followed by the epoxide 43 (31 mg, 0.0993 mmol, 10%)

as a colorless oil. Data for 45. IR (®lm) 3433, 2928 cm²¹. ¹H

NMR (CDCl₃) d 5.42 (1H, br s), 5.05 (1H, s), 4.51 (1H, d,

J7.9 Hz), 3.65±3.75 (2H, m), 3.37 (3H, s), 3.34 (3H, s),

3.19 (1H, dd, J8.7, 3.7 Hz), 2.44 (OH, br s), 1.8±1.95 (5H,

5-Methyl-1-furyl-ethyl acetate 39. To a stirred solution of

38 (22 mg, 0.059 mmol) in CH₂Cl₂(1 mL) was added

BF₃´Et₂O (1.5 mg, 1.3 mL, 0.011 mmol) at 2358C. After

30 min, the mixture was allowed to warm to 2208C over

1 h followed by warming to 08C. After 1 h, the mixture was

quenched with saturated aqueous NaHCO₃(10 mL) and

extracted with CH₂Cl₂(4£15 mL). The dried (MgSO₄)

extract was concentrated in vacuo and puri®ed by PLC,

eluting with 30% Et₂O/petroleum ether, to give sequentially

39 (trace), 38 (2.6 mg, 6.9 mmol, 12%) as a colorless oil.

To a stirred solution of 37 (18.5 mg, 0.0492 mmol) in

CH₂Cl₂(1 mL) was added BF₃´Et₂O (31.2 mg, 27.0 mL,

0.220 mmol) at 2788C. After 20 min, the mixture was

warmed to 258C. After 1.25 h, the mixture was quenched

with saturated aqueous NaHCO₃(10 mL) and extracted with

CH₂Cl₂(4£15 mL). The dried (MgSO₄) extract was concen-

trated in vacuo and puri®ed by PLC, eluting with 30% Et₂O/

petroleum ether to give 39 (1.5 mg, 0.089 mmol, 18%) as a

4380

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

m), 1.73 (3H, s), 1.45±1.55 (2H, m), 1.18 (3H, s), 0.86 (3H,

d, J6.2 Hz), 0.83 (3H, d, J6.2 Hz). ¹³C NMR (CDCl₃) d

133.9, 123.6, 99.7, 79.2, 67.6, 57.9, 55.1, 45.7, 39.2, 34.1,

29.5, 27.1, 24.0, 21.6, 20.8, 20.3, 17.7. HRMS (CI) calcd for

C₁₈H₃₃O₄313.2379. Found 313.2373. Data for 43. IR (®lm)

3446, 2958 cm²¹. ¹H NMR (CDCl₃) d 5.34 (1H, br s), 4.31

(1H, d, J5.4 Hz), 3.5±3.65 (2H, m), 3.36 (3H, s), 3.34 (3H,

s), 3.24 (1H, dd, J4.5, 7.5 Hz), 2.4±2.5 (1H, m), 1.6±2.15

(6H, m), 1.68 (3H, d, J1.5 Hz), 1.45±1.6 (1H, m), 1.26

(3H, s), 0.87 (3H, d, J6.8 Hz), 0.78 (3H, d, J6.8 Hz). ¹³C

NMR (CDCl₃) d 136.5, 121.9, 107.2, 66.1, 61.5, 60.3, 55.0,

54.8, 41.5, 36.6, 35.6, 29.0, 27.2, 24.2, 22.9, 21.3, 16.3,

14.5. HRMS (CI) calcd for C₁₈H₃₃O₄313.2379. Found

313.2372.

concentrated in vacuo and puri®ed by chromatography

over silica gel, eluting with 40% Et₂O/petroleum ether, to

give the acetal 44 (38 mg, 0.12 mmol, 36%, d.s. .20:1) as a

colorless oil. Further elution gave the epoxide 43 (67 mg,

0.21 mmol, 64%, d.s. .20:1) as a colorless oil. Data for 44.

IR (®lm) 3465, 2932 cm²¹. ¹H NMR (C₆D₆) d 5.35 (1H, br

s), 4.45 (1H, d, J7.1 Hz), 3.6±3.8 (2H, m), 3.51 (1H, dd,

J3.0, 11.6 Hz), 3.09 (3H, s), 3.07 (3H, s), 2.41 (OH, br s),

2.21 (1H, t, J7.7 Hz), 2.0±2.1 (1H, m), 1.2±2.0 (8H, m),

1.08 (3H, s), 0.95±1.05 (1H, m), 0.96 (3H, d, J6.6 Hz),

0.94 (3H, d, J6.6 Hz). HRMS (CI) calcd for C₁₈H₃₃O₄

313.2379. Found 313.2388.

1-Methyl-(4R)-isopropyl-(5R)-(6R)-[7-(8S)-methoxy-(9R)-

methyl-10-[4⁰-nitrobenzoyloxy]-butane]-(11R)-methoxy-

9,11-oxido-1-cyclohexene 46. To a stirred solution of 44

(62 mg, 0.19 mmol) in CH₂Cl₂(2 mL) was added Et₃N

(25 mg, 35 mL, 0.25 mmol) followed by p-nitrobenzoyl

chloride (37 mg, 0.20 mmol). After 24 h at ambient

temperature, the mixture directly subjected to PLC, eluting

with 20% Et₂O/petroleum ether, to give 46 (78 mg,

0.17 mmol, 89%) as an off-white solid. Crystals suitable

for X-ray crystallography were obtained by recrystallization

1-Methyl-(4R)-isopropyl-(5R)-(6R)-[7-(8S)-methoxy-(9R)-

methyl-10-butanol]-(11R)-methoxy-9,11-oxido-1-cyclo-

hexene 44 and 1-methyl-(4R)-isopropyl-(5R)-dimethyl

acetal-(6R)-[7-(9R)-methyl-(8R),9-epoxy-10-butanol]-1-

cyclohexene 43. Procedure 1: To a stirred solution of (2)-

Ê

diisopropyltartrate (28 mg, 0.12 mmol) and powdered 3 A

molecular sieves (approx. 500 mg) in CH₂Cl₂(4 mL) was

added sequentially Ti(OPrⁱ)₄(28 mg, 0.10 mmol) and tert-

butylhydroperoxide (0.66 mL, 2.0 mmol, 3 M in isooctane)

at 2258C. After 45 min, a solution of 42 (296 mg,

1.00 mmol) in CH₂Cl₂(1 mL) was added via syringe.

After 24 h, the mixture was allowed to warm to 08C and

poured into a stirred solution of ferrous sulfate heptahydrate

(3.2 g), tartaric acid (1.0 g) and H₂O (10 mL) at 08C. After

10 min, the two phases were separated and the aqueous

layer was extracted with CH₂Cl₂(3£10 mL). The combined

extracts were poured into a stirred, precooled solution of

(08C, 5 mL) prepared from NaCl (5 g) and NaOH (30 g)

in H₂O (90 mL). The mixture was stirred at 08C for 1 h,

diluted with H₂O (5 mL) and the two phases separated.

The aqueous layer was extracted with Et₂O (2£10 mL),

and the combined extracts washed with saturated aqueous

NaCl (20 mL). The dried (Na₂SO₄) extract was concentrated

in vacuo and puri®ed by chromatography over silica gel,

eluting with 40% Et₂O/petroleum ether, to give the acetal

44 (220 mg, 0.705 mmol, 71%, d.s. .20:1) as a colorless oil.

1

from Et₂O. IR (®lm) 2924, 2853, 1722 cm²¹. H NMR

(C₆D₆) d 7.85 (2H, m), 7.63 (2H, m), 5.36 (1H, br s),

4.4±4.65 (3H, m), 3.20 (3H, s), 3.15±3.25 (1H, m), 3.02

(3H, s), 2.25 (1H, t, J7.7 Hz), 1.4±2.1 (11H, m), 1.24

(3H, s), 0.96 (3H, d, J6.8 Hz), 0.91 (3H, d, J6.8 Hz).

HRMS (CI) calcd for C₂₅H₃₆NO₇462.2492. Found

462.2478.

2-Methyl-3-Z-iodo-propenol 47. To a stirred solution of

CuI (2.3 g, 0.012 mol) in Et₂O (120 mL) was added

MeMgBr (100 mL, 0.30 mol, 3.0 M in Et₂O) at 2158C.

After 20 min propargyl alcohol (6.7 g, 7.0 mL, 0.12 mol)

was added via a syringe pump over 30 min at 2158C. The

mixture was allowed to warm to ambient temperature over

2 h. After 16 h at ambient temperature, the mixture was

recooled to 08C, and I₂(39 g, 0.15 mol) added. After

15 min, the mixture was warmed to ambient temperature

for 50 min, carefully quenched with HCl (300 mL, 10% in

H₂O), and extracted with Et₂O (4£300 mL). The dried

(MgSO₄) extract was concentrated in vacuo and puri®ed

by chromatography over silica gel, eluting with 50%

Et₂O/petroleum ether, to give 47 (12.2 g, 0.062 mmol,

Procedure 2: To a stirred solution of (2)-diisopropyltartrate

Ê

(14 mg, 0.060 mmol) and two scoops of powdered 4 A

molecular sieves (approximately 1 g) in CH₂Cl₂(2 mL)

were added sequentially Ti(OPrⁱ)₄(12 mg, 12 mL,

0.041 mmol) and tert-butylhydroperoxide (230 mL,1.2

mmol, 5 M in isooctane) at 2208C. After 30 min, a

precooled solution of 42 (100 mg, 0.338 mmol) in CH₂Cl₂

(0.5 mL) was added via cannula. An additional amount

CH₂Cl₂(0.5 mL) was added to rinse the alcohol ¯ask.

After 1.75 h at 2208C the mixture was allowed to warm

to 08C, and poured into a stirred solution of ferrous sulfate

heptahydrate (1.6 g), tartaric acid (0.5 g) and H₂O (5 mL) at

08C. After 10 min, the two phases were separated and the

aqueous layer was extracted with CH₂Cl₂(3£10 mL). The

combined extracts were poured into a stirred, precooled

solution of (08C, 10 mL) prepared from NaCl (5 g) and

NaOH (30 g) in H₂O (90 mL). The mixture was stirred at

08C for 1 h, diluted with H₂O (5 mL) and the two phases

separated. The aqueous layer was extracted with Et₂O

(2£10 mL), the combined extracts washed with saturated

aqueous NaCl (20 mL). The dried (Na₂SO₄) extract was

52%) as a yellow oil. IR (®lm) 3334, 2913 cm²^{1 1}H

.

NMR (CDCl₃) d 5.96 (1H, s), 4.23 (2H, s), 1.96 (3H, s),

1.59 (OH, br s). HRMS (CI) calcd for C₄H₇IO 197.9542.

Found 197.9538.

1-Methyl-(4R)-isopropyl-(5R)-dimethylacetal-(6R)-[9-

methyl-9-Z-butene-10-ol]-1-cyclohexene 48. To 7 (227

mg, 1.01 mmol) was added 9-BBN (2.4 mL, 1.2 mmol,

0.5 M in THF) and the mixture heated in a sealed tube to

508C. After 18 h, the mixture was allowed to cool to

ambient temperature, and NaOH (1.0 mL, 3 mmol, 3 M in

H₂O) was added followed by a solution of the iodide 222

(410 mg, 2.7 mmol) in THF (800 mL) via cannula. Freshly

prepared Pd(PPh₃)₄(170 mg, 0.147 mmol) was added to the

mixture, and it was heated at 658C in a sealed tube in the

dark for two days. The mixture was allowed to cool to

ambient temperature, diluted with saturated aqueous NaCl

(20 mL), and extracted with Et₂O (4£25 mL). The dried

R. Carter et al. / Tetrahedron 56 (2000) 4367±4382

4381

(MgSO₄) extract was concentrated in vacuo and puri®ed by

References

chromatography over silica gel eluting with 30% Et₂O/

petroleum ether, to give 48 (105 mg, 0.355 mmol, 35%) as

a yellow oil. IR (®lm) 3418, 2957 cm²¹. ¹H NMR (CDCl₃) d

5.3±5.4 (2H, m), 4.15 (1H, d, J5.6 Hz), 4.06 (1H, d,

J12.0 Hz), 3.95 (1H, d, J12.0 Hz), 3.37 (3H, s), 3.34

(3H, s), 2.4±2.5 (1H, m), 2.1±2.3 (2H, m), 1.5±2.1 (5H,

m), 0.86 (3H, d, J6.6 Hz), 0.77 (3H, d, J6.6 Hz).

HRMS (CI) calcd for C₁₈H₃₁O₃295.2273. Found 295.2267.

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Ê

of powdered 4 A molecular sieves (approx 500 mg) at

2208C was added Ti(OPrⁱ)₄(72.2 mg, 75 mL, 0.254

mmol) and tert-butylhydroperoxide (360 mL, 1.8 mmol,

5 M in isooctane). After 30 min, a solution of 48 (74 mg,

0.25 mmol) in CH₂Cl₂(160 mL) was added dropwise via

cannula. An additional amount of CH₂Cl₂(2£80 mL) was

added to rinse the allylic alcohol ¯ask. The mixture was then

allowed to warm to 288C. After 19 h, the mixture was

warmed to 08C poured into a stirred solution of ferrous sul-

fate heptahydrate (3.2 g), tartaric acid (1.0 g) and H₂O

(10 mL) at 08C. After 20 min, the two phases were separated

and the aqueous layer was extracted with Et₂O (4£20 mL).

The combined extracts were poured into a stirred, precooled

solution (08C) of NaCl (5 g) and NaOH (30 g) in H₂O

(100 mL), and stirred at 08C for 1.5 h. The two phases

were separated and the aqueous layer was extracted with

Et₂O (4£50 mL). The dried (MgSO₄) extract was concen-

trated in vacuo and puri®ed by chromatography over silica

gel, eluting with 40% Et₂O/petroleum ether (2±4% Et₃N) to

give the acetal 49 (49 mg, 0.16 mmol, 63%) as a colorless

oil. [a]²_D³131 (c0.97, CHCl₃). IR (®lm) 3450,

6. MacMillan, D. W. C.; Overman, L. E. J. Am. Chem. Soc. 1995,

117, 10 391.

7. Nicolaou, K. C.; Delft, F.; Ohshima, T.; Vourloumis, D.; Xu, J.;

Hosokawa, S.; Pfefferkorn, J.; Kim, S.; Li, T. Angew. Chem. Int.

Ed. Engl. 1997, 36, 2520. Nicolaou, K. C.; Xu, J.-Y.; Kim, S.;

Ohshima, T.; Hosokawa, S.; Pfefferkorn, J. J. Am. Chem. Soc.

1997, 119, 11 353. Sarcodictyins A and B, Nicolaou, K. C.; Xu,

J.-Y.; Kim, S.; Pfefferkorn, J.; Ohshima, T.; Vourloumis, D.;

Hosokawa, S. J. Am. Chem. Soc. 1998, 120, 8661. Nicolaou, K.

C.; Kim, S.; Pfefferkorn, J.; Xu, J.-Y.; Ohshima, T.; Hosokawa, S.;

Courloumis, D.; Li, T. Angew. Chem. Int. Ed. Engl. 1998, 37, 1418.

Eleutherobin and eleuthosides A and B, Nicolaou, K. C.; Ohshima,

T.; Hosokawa, S.; Delft, F. L.; Vourloumis, D.; Xu, J.-.L.;

Pfefferkorn, J.; Kim, S. J. Am. Chem. Soc. 1998, 120, 8674.

8. Chen, X.-T.; Gutteridge, C. E.; Bhattacharya, S. K.; Zhou, B.;

Pettus, T. R. R.; Hascall, T.; Danishefsky, S. J. Angew. Chem. Int.

Ed. Engl. 1998, 37, 185. Chen, X.-T.; Zhou, B.; Bhattacharya,

S. K.; Gutteridge, C. E.; Pettus, T. R. R.; Danishefsky, S. J.

Angew. Chem. Int. Ed. Engl. 1998, 37, 789. Chen, X.-T.;

Bhattacharya, S. K.; Zhou, B.; Gutteridge, C. E.; Pettus, T. R. R.;

Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 6563.

9. Ceccarelli, S.; Piarulli, U.; Gennari, C. Tetrahedron Lett. 1999,

40, 153.

1

2928 cm²¹. H NMR (C₆D₆) d 5.33 (1H, br s), 4.82 (1H,

d, J5.7 Hz), 3.91 (1H, d, J11.6 Hz), 3.76 (1H, d,

J11.6 Hz), 3.3±3.4 (1H, m), 3.22 (3H, s), 2.93 (3H, s),

2.3±2.4 (2H, m), 1.7±2.0 (5H, m), 1.63 (3H, s), 1.49 (3H,

s), 1.25±1.35 (1H, m), 0.91 (3H, d, J6.8 Hz), 0.84 (3H, d,

J6.8 Hz). ¹³C NMR (C₆D₆) d 136.8, 121.5, 103.2, 88.6,

78.5, 66.8, 57.3, 56.0, 45.2, 37.2, 36.6, 31.0, 29.9, 27.0,

25.2, 24.6, 21.9, 15.9. HRMS (CI) calcd for C₁₈H₃₂O₄

313.2379. Found 313.2376.

A solution of MeCN (0.5 mL) at 08C containing Me₃SiCl

(65 mL, 0.513 mmol) and NaI (96 mg, 0.641 mmol) was

stirred for 30 min, and propene was bubbled through the

solution for 5 min. To the mixture was added a solution of

49 (32 mg, 0.103 mmol) in MeCN (200 mL) and the result-

ing solution heated at 608C for 16 h. The solution was

cooled to room temperature and washed with saturated

aqueous NaHCO₃(1 mL), saturated aqueous Na₂S₂0₃

(1 mL), dried (Na₂SO₄) and evaporated in vacuo to give a

residue that contained approximately 15% of 35, as judged

10. Baron, A.; Caprio, V.; Mann, J. Tetrahedron Lett. 1999, 40,

9321.

1

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Article Doi

Studies on the stereoselective synthesis of the marine antitumor agent eleutherobin

DOI: 10.1016/S0040-4020(00)00309-4

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