Elucidation of the stereostructure of the annonaceous acetogenin (+)-montecristin through total synthesis

View Article Online / Journal Homepage / Table of Contents for this issue

Elucidation of the stereostructure of the annonaceous acetogenin

(+ )-montecristin through total synthesis

Christian Harcken¤” and Reinhard Bruckner¤*

Institut fur Organische Chemie und Biochemie der Albert-L udwigs-Universitat, Albertstr. 21,

D-79104 Freiburg, Germany. E-mail: reinhard.brueckner=organik.chemie.uni-freiburg.de

Fax: ]49-761-2036100

Received (in Montpellier, France) 10th April 2000, Accepted 30th May 2000

First published as an Advance Article on the web 7th December 2000

Total syntheses of ent-5-epi-montecristin (1a) and of ([)-montecristin (1b) were accomplished. The stereocenters of

compounds 1a and 1b were established by asymmetric dihydroxylations of the trans-conÐgurated b,c-unsaturated

esters 6 (]4, up to 80% ee; Scheme 3; improved procedure with up to 94% ee: Scheme 7) and 56 (]55, 97% ee:

Scheme 9) while the stereogenic C2C bonds stem from the carbocuprations 48 ] 49 and 50 ] 51 (Scheme 9).

Treating hydroxylactones 27 (Scheme 7), 3a (Scheme 12) and 3b (Scheme 13) with PPh and DEAD, we found a

3

racemization-free dehydration giving butenolide 26 and epimerization-free dehydrations giving butenolides 2a and

2b. Relating the [a] values of synthetic 1a and 1b to the [a] value of natural (])-montecristin, the absolute

D

conÐguration of its side-chain stereocenters was determined to be R.

Annonaceous acetogenins are an ever more numerous class of

natural products isolated from Annonaceae.1 They are c-

methylbutenolides or c-methylbutyrolactones with an

unbranched C or C side-chain at C-a. This side-chain is

we also wished to determine the absolute conÐguration of its

side-chain, we had to synthesize two compounds rather than

one; as such, we chose structures 1a and 1b (Scheme 1, absol-

ute conÐgurations shown), which are the two possible dia-

stereomers of structure 1 considering its relative conÐguration.

Considering absolute conÐgurations, synthetic 1a might turn

out to be identical with (])-montecristin because the former

and the latter possess identically conÐgurated butenolide moi-

eties. Conversely, synthetic 1b might turn out to be the enantio-

mer of (])-montecristin (i.e. levorotatory montecristin) because

the former and the latter possess oppositely conÐgurated bute-

nolide moieties. Accordingly, as soon as we would have syn-

thesized both 1a and 1b we would know the complete

stereostructure of (])-montecristin. However, we could not

know beforehand whether at that point we would have also

synthesized (])-montecristin or ““onlyÏÏ ([)-montecristin.

30

32

usually oxidized, exhibiting one, two or three THF rings

and/or hydroxy, acetoxy, epoxy or carbonyl groups. The syn-

thesis of such compounds has attracted much attention recent-

ly,2 in part because of their strong anti-tumor, anti-parasitic

and insecticide activities. A few annonaceous acetogenins

contain cis-conÐgurated C2C bonds in the place of of oxygen-

ated side-chain functions, such as muridienin3,4 or chatenay-

trienin.4 These compounds are probably biogenetic precursors

of the more heavily oxygenated annonaceous acetogenins.

Given this background, the annonaceous acetogenin (])-

montecristin (1; Scheme 1) isolated in 1997 from the roots of

Annona muricata L.5 might be an intermediate en route

between the less and the more oxygenated acetogenins. Mon-

tecristin is an a,c-disubstituted butenolide with a C side-

32

chain at C-a. The constitution of montecristin was established

by NMR spectroscopy, chemical derivatization and mass

spectrometric analysis.5 It has a side-chain which contains a

glycol moiety and two cis-conÐgurated C2C bonds. The rela-

tive conÐguration of the glycol moiety was shown to be syn,

while the absolute conÐguration remained unknown. Monte-

cristin also consists of a butenolide moiety which possesses the

S-conÐguration that is common to all butenoide-containing

annonaceous acetogenins.

In recent years, we have prepared many kinds of c-chiral

butanolides and butenolides by means of SharplessÏ asym-

metric dihydroxylation6 of trans-conÐgurated b,c-unsaturated

carboxylic esters.7 However, we had not yet synthesized a c-

chiral butenolide having the substitution pattern displayed by

1. Therefore, we chose this compound (or its enantiomer) as a

synthetic target. Since, however, the stereostructure of natural

montecristin, i.e. (])-montecristin, was not known beyond

formula 1 (Scheme 1, absolute conÐguration shown), and since

¤ Previous address: Institut fur Organische Chemie der Georg-

August-Universitat, Tammannstr. 2, D-37077, Gottingen, Germany.

” Present address: Department of Chemistry and Biochemistry, Uni-

versity of Texas at Austin, Texas 78712, USA.

Scheme 1

40

New J. Chem., 2001, 25, 40È54

DOI: 10.1039/b002905j

This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2001

View Article Online

It was evident that 1a and 1b would not be distinguishable

from one another spectroscopically since their stereocenters

are 13 carbon atoms apart. However, the speciÐc rotations of

1a and 1b would be distinct and therefore suitable for com-

parison with the speciÐc rotation reported for 1.

manner by simpler iodides than compound 5 in earlier work

of ours.7che,g

Our original preparation of hydroxylactone S,S-47c,8 was

by the asymmetric dihydroxylation of the commercially avail-

able pentenoic ester 6 (Scheme 3). The enantiomeric hydroxy-

lactone R,R-4 could be accessed analogously. Unfortunately,

these preparations su†ered from low yields (O40%) and selec-

tivities (O80% ee). Since continuous extraction did not

increase these yields, we could exclude the possibility that

some 4, because of its miscibility with water, escaped our iso-

lation procedure. The low ee values were probably due to the

smallness of the methyl substituent at the C2C bond of our

dihydroxylation substrate 6. The adverse e†ect of too small

substituents was precedented.9

Results and discussion

Retrosynthesis

Our retrosynthetic analysis started by tracing back butenol-

ides 1a and 1b via the acetonides 2a and 2b to the acetonide-

containing hydroxylactones 3a and 3b, respectively (Scheme

2). The latter were thought to arise from the alkylation of the

dilithio derivatives of hydroxylactones S,S-4 and R,R-4,

respectively, with the acetonide-containing iodide 5.

Hydroxylactones S,S-4 and R,R-4 were alkylated in a similar

The retrosynthetic simpliÐcation of iodide 5 (Scheme 2) fol-

lowed two strategies (Scheme 4). By ““strategy AÏÏ, we wanted

to dihydroxylate enantioselectively the C2C bond of the ene-

diynol precursor 9 and then hydrogenate its C2C bonds cis-

selectively. Precursor 9 would originate from an alkylation of

a trans-conÐgurated alkenyl metal 7 with the alkyl halide (or

sulfonate) 8 or from a coupling between a trans-conÐgurated

alkenyl iodide 7 and an organometallic 8. By ““strategy BÏÏ,

iodide 5 would stem from a saturated precursor 10 and from

an unsaturated precursor 11 with two cis-C2C bonds. We left

open the question whether 10 should be the nucleophile and

11 the electrophile or vice versa. The glycol underlying com-

pound 10 would be synthesized by the asymmetric

dihydroxylation of an appropriate trans-oleÐn.

Synthesis of the lactone moiety

The discussion of Scheme 3 implied that the desired hydroxy-

lactones S,S-4 and R,R-4 might be reached with [95% ee7 by

modifying the b,c-unsaturated ester substrate of the dihy-

droxylation such that the small CH group at C-c would be

3

made more voluminous by introducing one or several bulky

substituents. Scheme 5 shows our vain e†orts to prepare, in

this sense, the tribromo analog 12 of the previous dihydroxyl-

ation substrate 6. Tribromoacetaldehyde (18) did not react

with the ylide derived from zwitterion 17 by various deproton-

ating agents10 to give the underlying tribromoacid 13; this

was unexpected since tribromoacetaldehyde forms an oleÐn

with Ph P2CHÈCH2O.11 Also, we could not add vinyl-

3

magnesium bromide to tribromoacetaldehyde in order to

attain alcohol 16. But 5% of this compound could at least be

obtained following a protocol for saturated aldehydes.12 This

was insufficient for advancing to the next step, which would

have been the Buechi rearrangement13 16 ] 14.

More modest size increases of the ““too small methyl groupÏÏ

of dihydroxylation substrate 6 were possibleÈnow intro-

ducing a single dummy substituent instead of three of them

(Scheme 6). We started from the known14 hydroxyester 20. It

Scheme 3 a: AD-mix a (1.4 g mmol~1), ButOHÈH O (1 : 1), 0 ¡C, 4

2

days; 40%. b: AD-mix b (1.4 g mmol~1), ButOHÈH O (1 : 1), 0 ¡C, 4

2

Scheme 2

days; 38%.

New J. Chem., 2001, 25, 40È54

41

View Article Online

Scheme 6 a: Ph S (3.0 equiv.), Bu P (4.0 equiv.), toluene, room

2 2

3

temperature, 2 h; 81%. b: NCS (1.2 equiv.), Me S (1.2 equiv.),

2

CH Cl , 0 ¡C ] room temperature, 16 h; 83%. c: AD-mix a (1.4 g

2

mmol~1), MeSO NH (1.0 equiv.), ButOHÈH O (1 : 1), 0 ¡C, 36 h;

2

63%. d: AD-mix a (1.4 g mmol~1), NaHCO (3.0 equiv.), MeSO NH

3

2

(1.0 equiv.), ButOHÈH O (1 : 1), 0 ¡C, 24 h; 19%.

2

was converted into the phenylthio-containing ester 23 by a

Mukaiyama redox condensation.15 Its asymmetric

Scheme 4

dihydroxylation gave the desired lactone 24 but the ee was

80% and thereby no better than the ee of the dihydroxylations

of Scheme 3. As an alternative, hydroxyester 20 was trans-

formed into the chlorinated ester 2216 under CoreyÏs condi-

tions.17 The dihydroxylation of chloroester 22 gave only 19%

of the corresponding lactone 25, even when working in

bicarbonate-bu†ered solution as recommended for the asym-

metric dihydroxylation of allyl halides.18 This 19% yield was

too little to pursue this approach. The only substituent tested

that improved the yield of the ester ] lactone conversion and

the enantioselectivity (92% ee instead of 78% in the case of

S,S-4) was the ButMe SiO group of ester 21.7c While 21 could

2

be carried on towards the silylated aglycone 19 of ranunculin

as reported,7c there was no straightforward way for converting

it into the desired S,S-4.

Fortunately, we then found a chemically and stereochemi-

cally improved synthesis of hydroxylactones S,S- and R,R-4

(Scheme 7). An ““improved asymmetric dihydroxylationÏÏ had

been reported for a 1,1-disubstituted oleÐn using 10 times

more ligand and osmate;19 thereby, this oleÐn could be dihy-

droxylated with 97% ee rather than with 85% ee under the

standard conditions. Following the same procedure, we dihy-

droxylated ester 6 with ees up to 86% (AD a, ]S,S-4) and

94% (AD b, ]R,R-4). However, these values were not exactly

reproducible. Rather, they oscillated between 80 and 86% in

the case of S,S-4 and between 86 and 94% in the case of R,R-

4. (This random variation explains why starting material 4 of

di†erent ee was used in the reactions of Schemes 7, 12 and 13).

The improved dihydroxylation procedure also conveniently

Scheme 5 a: (2-Carboxyethyl)triphenylphosphonium bromide (1.0

equiv.), NaH (2.0 equiv.) or KOBut (2.0 equiv.), THFÈDMSO 1 : 1,

room temperature, 20 h. b: CeCl (5 mol %), THF, room temperature,

3

1 h; 15 (1.1 equiv.), room temperature, 2 h; 0%. c: Acrolein, CBr (3

4

equiv.), SnF (1 equiv.), DMSO, room temperature, 5 min; SnF (1

2

equiv.), 5 min; 5%.

42

New J. Chem., 2001, 25, 40È54

View Article Online

Scheme

7

a: K Fe(CN) (3.0 equiv.), K CO (3.0 equiv.),

3

6

2

3

(DHQ) PHAL (10 mol %), K OsO (2.0 mol %), ButOHÈH O (1 : 1),

2

4

2

0 ¡C, 16 h; 73%. b: K Fe(CN) (3.0 equiv.), K CO (3.0 equiv.),

3

6

2

3

(DHQD) PHAL (10 mol %), K OsO (2.0 mol %), ButOHÈH O

2

4

2

(1 : 1), 0 ¡C, 16 h; 69%. c: Pri NH (2.5 equiv.), BuLi (2.5 equiv.), THF,

2

[78 ¡C, 30 min; addition of R,R-4, THF, [78 ¡C, 2 h; BuI (1.2

equiv.), THFÈDMPU (1 : 1), [45 ¡C, 20 h; 84%. d: PPh (2.0 equiv.),

3

DEAD (2.0 equiv.), THF, [20 ¡C ] room temperature, 3 h; 89%.

reduced the reaction time to one-tenth (from 5 days to 16 h)

and almost doubled the yields [from 40% S,S-4 (Scheme 3) to

73% (Scheme 7) and from 38% R,R-4 (Scheme 3) to 69%

(Scheme 7)]. In addition, we recovered the chiral ligand

almost quantitatively (up to 94% yield) by extraction into

aqueous hydrochloric acid, addition of NaOH and back-

extraction into dichloromethane.

Repeating the completely trans-selective butylation pre-

viously performed7c,d with S,S-4 (78% ee) with the newly

accessible R,R-4 (here: of 86% ee) we obtained compound

2720 (ent-5-epi-blastmycinolactole; 86% ee). Compound 27

served to probe whether dehydration giving butenolide 2621

would be possible without partial racemization. This was of

great interest since the penultimate step of our synthesis of

montecristin would be an exactly analogous dehydration

3 ] 2 (cf. Scheme 2). The problem is that butenolides such as

compounds 26 or 2 can give up their stereochemical integrity

even at room temperature when

a base as weak as

diethylamine is present.22 Thus, we were afraid that the dehy-

Scheme 8 a: Dihydro-2H-pyran (3.0 equiv.), camphor sulfonic acid

(calatytic amount), CH Cl , 0 ¡C ] room temperature, 3 h; 96%. b:

dration procedure appropriate for S,S-4Ètreatment with

2

MsCl and NEt in dichloromethane at 0 ¡C, 30 min7dÈwould

NaNH (1.1 equiv.), THF, 0 ¡C, 1 h; 1-bromododecane (1.1 equiv.),

3

2

put product stereochemistry at stake when applied to com-

DMSO, room temperature, 2.5 h; 53%. c: p-TsOH (0.4 equiv.),

MeOH, room temperature, 30 min; 99%. d: PPh (1.2 equiv.), NBS

pound 27 (or later to 3) because starting from 27 it lasted

several hours at room temperature without even then having

gone to completion. Therefore, we were glad to Ðnd that the

dehydration 27 ] 26 could be brought about by treatment

3

(1.1 equiv.), THF, [20 ¡C ] 0 ¡C, 4 h; 88%. e: PPh (1.1 equiv.),

3

imidazole (2.2 equiv.), I (1.1 equiv.), THF, 0 ¡C, 1 h; 88%. f: NEt (1.2

2

3

equiv.), Tf O (1.2 equiv.), CH Cl , 0 ¡C, 2 h; quantitative. g: BuLi (1.1

2

2 2

equiv.), THF, 0 ¡C, 30 min; addition of alkylating agent (1.0 equiv.),

THF, room temperature, 16 h; 10È32%. Dihydro-2H-pyran (3.0

equiv.), PPTS (cat.), CH Cl , 0 ¡C ] room temperature, 16 h; 84%. i:

with

2

equivalents of both triphenylphosphine and

diethylazodicarboxylate.23 The reaction proceeded in 89%

yield and conserved the optical purity (86% ee) completely.

This was reassuring as concerned the envisaged approach to

the butenolide moiety of montecristin (Scheme 2).

2

BunLi (1.2 equiv.), THF, 0 ¡C, 30 min; Non-Br (1.1 equiv.), DMSO,

room temperature, 24 h; 68%. j: TsOH (cat.), MeOH, room tem-

perature, 2 h; 84%. k: Li (6.0 equiv.), 1,2-diaminopropane, reÑux, 30

min; KOBut (4.0 equiv.), room temperature, 30 min; addition of 40,

room temperature, 1 h; 74%. l: ButMe SiCl (1.1 equiv.), imidazole (2.1

2

equiv.), CH Cl , room temperature, 1 h; 97%. m: ButPh SiCl (1.0

Synthesis of the side-chain

2

equiv.), imidazole (2.1 equiv.), CH Cl , 0 ¡C ] room temperature, 1 h;

2

99%. n: NaH (1.2 equiv.), para-methoxybenzyl chloride (1.2 equiv.),

DMFÈTHF 1 : 1, room temperature, 3 h; 96%. o: DIBAL (1.05

equiv.), hexane, room temperature, 1 h; I (1.0 equiv.). p: Zr(cp) ClH

Scheme 8 summarizes our e†orts to access iodide 5 by means

of strategy A of Scheme 4. The upper part of this scheme con-

cerns the synthesis of the diyne equivalent 35 of the diyne

2

(0.95 equiv.), THF, room temperature, 1 h.

New J. Chem., 2001, 25, 40È54

43

View Article Online

synthon 8 of Scheme 4. First, we protected24 3-butynol (28) as

the THP ether 29.25 This compound was less easy to alkylate

than the homologous THP ether 38 of propargyl alcohol.

Deprotonating compound 29 with n-BuLi in a mixture of

THF and DMSO26 and adding dodecyl bromide thereafter

led mainly to the formation of 1-dodecene and only 7% of the

alkylation product 30.27 Changing the solvent to DMPU

increased the yield of 30 to 17%. Replacing dodecyl bromide

by dodecyl triÑate gave 48% 30. A 53% yield was Ðnally

obtained in THFÈDMSO, using the cheaper dodecyl bromide

as the alkylating agent but deprotonating the substrate with

sodium amide. The resulting THP ether 30 was cleaved in

methanol through the action of TsOH (99% yield).28 The

alkynol 3129 thus obtained was converted into a series of

alkylating agents by treatment with NBSÈPPh 30 (]bromide

3

32, 88%) or PPh ÈimidazoleÈI 31 (]iodide 33, 88%) or

3

2

Tf OÈNEt 32 (]triÑate 35, quantitative yield). However,

2

3

none of them could be introduced into THP ether 29 in satis-

factory yield: the sodium acetylide of compound 29 and

bromide 32 gave the desired diyne 35 in only 4% yield33

besides ca. 50% of the elimination product 36. Similarly, the

lithium acetylide of compound 29 and iodide 33 furnished

only trace amounts of diyne 35 besides 55% of enyne 36. The

same lithium acetylide and triÑate 34 were a better com-

bination (as expected34), delivering diyne 35 as the major

product and only traces of 36. However, the yield of 35 was

10È32% and never became higher or reliable.

The lower part of Scheme 8 shows our approach to the

trans-oleÐn equivalents 45È47 of synthon 7 of Scheme 4.

Protecting24 propargyl alcohol (37) as the THP ether 38,35

alkylating the latter via its anion26 with nonyl bromide,

deprotecting28 the resulting chain-elongated THP ether 39

(]40), shifting its C3 C bond to the end of the molecule36

(]4437), and protecting the OH group led to the terminal

alkynes 41È43. DIBAL reduction/iodination of compounds 41

and 42 seemed to su†er from the sensitivity of the silyl ethers

towards the reductant. When the hydrozirconation of 41È43

started with unpromising yields of the respective addition

product 47, we stopped pursuing strategy A of Scheme 4

towards iodide 5 and began to test strategy B. As shown in

the upper part of Scheme 9, we synthesized the cis,cis-di-

enyliodide 51 as a realization of synthon 11 of Scheme 4. To

this end, dodecyl bromide (48) was converted via the corre-

sponding Gilman cuprate into a mixed cuprate (with a

hexynyl group). It was added to acetylene whereupon the

resulting cis-vinylcuprate was transmetalated with hexynyl-

lithium, giving a mixed cuprate that was hydroxyalkylated

with ethylene oxide, all as described in the pionieering study

of Alexakis et al.38 Thus we advanced in a single step and

81% yield to homoallyl alcohol 49.39 It was converted into

iodide 50 by treatment with PPh ÈimidazoleÈI .31 Com-

Scheme 9 a: Li (3.0 equiv.), Et O, 0 ¡C, 3 h; CuI (0.5 equiv.), Et O,

2

[35 ¡C, 30 min; acetylene (1.0 equiv.), [50 ¡C ] [25 ¡C, 30 min;

][30 ¡C; ethylene oxide (1.0 equiv.); hexynyl lithium (0.5 equiv.),

Et O, [15 ¡C, 3 h; 81%. b: PPh (1.1 equiv.), imidazole (2.2 equiv.),

2

3

I

(1.1 equiv.), THF, 0 ¡C ] room temperature, 30 min; 99%. c: ButLi

3

2

(2.0 equiv.), Et OÈhexane (1 : 1), [20 ¡C, 30 min; CuI (0.5 equiv.),

pound 50 was subjected to a Li/I exchange reaction with

ButLi.40 Conversion into a Gilman cuprate followed by addi-

tion to acetylene and iodiation of the resulting alkenylcopper

intermediate41 rendered the dienyliodide 51 with the desired

cis,cis-conÐguration in 66% yield. We found that the cuprate

precursor of compound 51 did not react well with iodide 5.

Quenching this cuprate as shown here and regenerating the

organolithium derivative later (Ðrst reaction of Scheme 10)

worked much better.

2

Et O, [35 ¡C, 30 min; acetylene (1.0 equiv.), [50 ¡C ] [25 ¡C, 1 h;

2

I

(1.0 equiv.), [60 ¡C ] [10 ¡C, 2 h; 66%. d: ButPh SiCl (1.0

2

equiv.), imidazole (2.0 equiv.), DMF, room temperature, 15 h; 59%. e:

(ClCO) (1.1 equiv.), DMSO (2.2 equiv.), CH Cl , [78 ¡C, 3 min;

2

2 2

addition of 53, [40 ¡C, 1 h; NEt (5.0 equiv.), [40 ¡C ] 0 ¡C, 1 h;

3

83%. f: HO CCH CO Me (1.1 equiv.), NEt (1.1 equiv.), 90 ¡C, 12 h,

2

3

66%. g: K Fe(CN) (3.0 equiv.), K CO (3.0 equiv.), (DHQ) PHAL

3

6

2

3

2

(1.0 mol %), K OsO (0.2 mol %), MeSO NH (1.0 equiv.),

2

4

2

ButOHÈH O (1 : 1), 0 ¡C, 4 days; 68%. h: LiAlH (1.0 equiv.), THF,

2

4

[78 ¡C ] room temperature, 30 min; 98%. i: 2,2-Dimethoxypropane

Next, we synthesized acetonide 59 (Scheme 9, bottom half)

(8.0 equiv.), Amberlyst 15, acetone, room temperature, 2 h. j: PPh

3

(1.0 equiv.), imidazole (2.0 equiv.), I (1.0 equiv.), THF, 0 ¡C ] room

2

as an equivalent of synthon 10 of Scheme 4. We started by

monosilylating 1,12-dodecanediol (52) with ButPh SiCl. Silyl-

temperature, 15 min; 94% for two steps.

2

ether 53 was formed in 59% yield. It was oxidized by the

method of Omura and Swern42 but at slightly higher tem-

perature ([40 ¡C ] 0 ¡C) and longer than usual times in order

to make up for the poor solubility of the substrate in cold

dichloromethane. Aldehyde 54, obtained in 83% yield, was

subjected to a deconjugating decarboxylating Knoevenagel

condensation with monomethyl malonate.43 It provided 66%

of the trans-conÐgurated b,c-unsaturated ester 56. The asym-

metric dihydroxylation of this compound7 using AD-mix a

furnished the hydroxylactone 55 in 68% yield. The enantio-

meric purity of this material was determined to be 97% ee by

1H-NMR analysis of the methoxy singlets of its R-Mosher

ester.

44

New J. Chem., 2001, 25, 40È54

View Article Online

Scheme 10 a: 51, ButLi (2.2 equiv.), Et O, [50 ¡C, 30 min; 59 (1.0

2

equiv.), THF, ]room temperature, 4 h; 64%. b: TBAF (1.2 equiv.),

THF, room temperature, 20 h; 99%. c: PPh (1.2 equiv.), imidazole

3

(2.4 equiv.), I (1.2 equiv.), THF, 0 ¡C ] room temperature, 30 min;

96%.

2

Hydroxylactone 55 was reduced with LiAlH , giving the

4

1,3,4-triol 57. After hydrolytic work-up, extraction by

dichloromethane, and evaporation of the solvent 98% of a

white solid remained, which was used without puriÐcation.

MeyerÏs selective acetalizations of the butanetriol obtained

from optically active malic acid revealed that under ther-

modynamic control acetone is preferentially taken up by the

Scheme 12 a: Pri NH (2.5 equiv.), BuLi (2.5 equiv.), THF, [78 ¡C,

2

30 min; addition of S,S-4, THF, [78 ¡C, 2 h; 5 (1.0 equiv.), THFÈ

DMPU (1 : 1), [45 ¡C, 20 h; 56%; 38% of reisolated 5. b: PPh (2.0

3

equiv.), DEAD (2.0 equiv.), THF, [20 ¡C ] room temperature, 4 h;

94%. c: HCl (4.0 equiv.), MeOHÈCH Cl (5 : 1), room temperature,

2

24 h; 88%.

1,2-diol moiety, giving a dioxolane, rather than by the 1,3-diol

moiety, which would give a 1,3-dioxane.44 Exploiting this

e†ect, triol 57, excess dimethoxypropane in acetone and

Amberlyst as a catalyst provided, after 2 h at room tem-

perature, essentially 1,3-dioxane 58. This compound was so

sensitive towards hydrolysis that we could not purify it even

by Ñash chromatography on deactivated (NEt ) silica gel.

3

However, we could use it crude and transform it by treatment

with PPh ÈimidazoleÈI 31 into iodide 59 (94% yield from

3

2

lactone 56). Thereby, the latter became accessible from 1,12-

dodecanediol (52) in seven steps (20% overall yield).

The ultimate steps to the key precursor 5 of montecristin

are shown in Scheme 10. To combine the alkyl iodide 59 with

the alkenyl iodide 51 we had the options of performing a tran-

sition metal catalyzed coupling between an alkyl metal and an

alkenyl halide or of performing a nucleophilic substitution of

an alkenyl metal at an alkyl halide. Lithiation of alkyl iodide

59 with tert-BuLi, followed by transmetalation with MgBr

2

and the addition of alkenyl iodide 51 and a catalytic amount

Scheme 11 a: HCl (4.0 equiv.), MeOHÈCH Cl (5 : 1), room tem-

2

perature, 24 h; 50%; 76% of reisolated 26.

of NiCl (PPh ) 45 gave a B1 : 1 mixture of the desired coup-

2

3 4

New J. Chem., 2001, 25, 40È54

45

View Article Online

yield). This meant that these conditions were suitable for de-

protecting butenolides 2a (Scheme 12) and 2b (Scheme 13)

without a†ecting their stereostructures.

Combining the building blocks

Reassured by the result from Scheme 11, we performed the

Ðnal steps of our syntheses in parallel experiments. We headed

for the stereoisomer 1a of montecristin as shown Scheme 12

and for its diastereomer 1b as shown in Scheme 13.

Each sequence lasted three steps. The start was deprotonat-

ing the enantiomeric b-hydroxylactones S,S-4 (here 80% ee;

Scheme 12) and R,R-4 (here 90% ee; Scheme 13) twice using

2.5 equiv. of LDA. In HMPA-containing THF the a-

alkylation of dilithiated b-hydroxy-c-lactones occurs such that

the a-substituent is oriented exclusively trans with respect to

the b-OH group.48 Conveniently, alkylating the dilithiated

hydroxylactones S,S- and R,R-4 with iodide 5 (97% ee) in 6 : 1

THFÈDMPU49 delivered also nothing but trans-alkylated

hydroxylactones, namely compounds 3a (56% yield; 90% con-

sidering that 38% 5 was recovered) and 3b (62% yield; 94%

considering that 34% 5 was recovered), respectively.

The ensuing b-eliminations followed the protocol developed

for the dehydration 27 ] 26 of Scheme 7, that is under Mitsu-

nobu conditions: 2 equiv. each of PPh and DEAD were

3

added to THF solutions of hydroxylactones 3a (Scheme 12)

and 3b (Scheme 13). The resulting mixtures were gradually

warmed from [20 ¡C to room temperature. Thereupon we

isolated 94% of butenolide 2a and 97% of butenolide 2b,

respectively. The terminating steps were the acetonide cleav-

ages. They were e†ected under the ““stereochemically benignÏÏ

conditions of Scheme 11. This led to diastereomers 1a and 1b

in yields of 88 and 83%, respectively.

As expected, the 1H-NMR, 13C-NMR and IR data of com-

pounds 1a and 1b were identical with one another and identi-

cal to those of montecristin. However, their speciÐc rotations

were distinct. They demonstrated unequivocally50 that 1a is

ent-5-epi-montecristin while 1b is the enantiomer of (])-mon-

tecristin. This statement is justiÐed even if our specimen of 1a

must have been a ca. 90 : 10 mixture with 1b and our speci-

men of 1b a ca. 95 : 5 mixture with 1a; the occurrence of these

mixtures is an inevitable consequence of the incomplete

optical purity of the building blocks S,S-4 (80% ee), R,R-4

(90% ee) and 5: (97% ee) incorporated into 1a and 1b.

In summary, we have accomplished the Ðrst total syntheses

of ent-5-epi-montecristin (1a) and ([)-montecristin (1b). In the

longest linear sequence 13 steps were needed, which gave an

overall yield of 6% (\81% per step). The side-chain conÐgu-

ration of (])-montecristin was established to be 11@R,12@R.

Scheme 13 a: Pri NH (2.5 equiv.), BuLi (2.5 equiv.), THF, [78 ¡C,

2

30 min; addition of R,R-4, THF, [78 ¡C, 2 h; 5 (1.0 equiv.), THFÈ

DMPU (1 : 1), [45 ¡C, 20 h; 62%; 34% reisolated 5. b: PPh (2.0

3

equiv.), DEAD (2.0 equiv.), THF, [20 ¡C ] room temperature, 4 h;

97%. c: HCl (4.0 equiv.), MeOHÈCH Cl (5 : 1), room temperature,

2

24 h; 83%.

ling product 61 and the b-hydride elimination productÈ

which is a vinyl-substituted dioxolaneÈof the alkyl nickel

derivative of 59. Conversely, clean CÈC bond formation

occurred when we switched polarities: lithiated the alkenyl

iodide 51, added the alkyl iodide 59, and isolated the

alkylation46 product 61 in 64% yield. Desilylation liberated

Experimental

General

All reactions were performed in oven-dried (80 ¡C) glassware

under N . THF was freshly distilled from K, Et O from Na,

the underlying alcohol 62. It reacted with PPh È

3

imidazoleÈI 31 to give the key iodide 5.

2

CH Cl , DMSO, DMPU and 1,2-diaminopropane from

2

One issue needed to be clariÐed before iodide 5 was fully

CaH . Products were puriÐed by Ñash chromatography51 on

MachereyÈNagel silica gel 40È63 lm (eluents given in

2

qualiÐed for introducing the side-chain of montecristin (1)

because the vic-glycol moiety of 1 was protected as an aceton-

ide in 5. We wondered whether we would be able to release

this acetonide at the butenolide stage 2a/2b (cf. Scheme 2)

without destroying the stereocenter C-c. We modelled the

answer to this question by e†ecting the related acetonide

cleavage 5 ] 63 with concentrated HClÈMeOHÈCH Cl 47

brackets). Yields refer to analytically pure samples. Isomer

ratios were derived from suitable 1H NMR integrals. 1H

NMR [CHCl (7.26 ppm) as internal standard in CDCl or

3

C HD (7.16 ppm) as internal standard in C D ] and 13C

6

5

6 6

NMR [CDCl (77.00 ppm) as internal standard in CDCl ]

3

were recorded on Varian VXR 200, Bruker AMX 300, and

Varian VXR 500S spectrometers. For 1H NMR spectra the

integrals were in accord with assignments; coupling constants

are in Hz. In APT 13C NMR spectra the peak orientations

were in accord with asssignments. The assignments of 1H and

2

(Scheme 11). What mattered in this context was hardly the

50% yield of diol 63 but rather that the model butenolide 26,

which was present while the acetonide was cleaved, could be

re-isolated with undiminished enantiomeric purity (86% ee; 77%

46

New J. Chem., 2001, 25, 40È54

View Article Online

13C NMR resonances refer to the IUPAC nomenclature with

primed numbers belonging to the side-chains in the order of

their appearance in the IUPAC name. Combustion analyses

were obtained by F. Hambloch, (Institute of Organic Chem-

istry, University of Gottingen) and MS by Dr. G. Remberg

(Institute of Organic Chemistry, University of Gottingen). IR

spectra were recorded on a PerkinÈElmer 1600 Series FTIR

spectrometer neat or in KBr. SpeciÐc rotations were measured

on a PerkinÈElmer polarimeter 241 at 589 nm; the underlying

to [a]25 \ [25.9 (c \ 0.4)52 Mlit.5: [a]25 \ ]25 for montec-

D

ristin (c \ 0.1, MeOH)N. 1H NMR (300 MHz): d \ 0.88 (t,

J

\ 6.8, 32@-H ), 1.25È1.38 (m, 2@-H to 9@-H , 22@-H to

32{, 31{

3

2

31@-H ), 1.41 (d, J

\ 6.7, 5-Me), 1.43È1.60 (m, 10@-H ,

2

5, 5vMe

2

13@-H ), ca. 1.82 (very br s, 2 OH), 2.02 (td, J

B

2

21{, 22{

J

B 6.5, 21@-H ), in part superimposed by 2.11 (m , 17@-

21{, 20{

2

c

H , 18@-H ), in part superimposed by 2.13Èca. 2.23 (m, 14@-

H ), in part superimposed by 2.26 (tdd, J

2

1{, 5

2

\ 7.8, 4J

\

1{, 2{ 1{, 4

5J

\ 1.7, 1@-H ), 3.38È3.47 (m, 11@-H, 12@-H), 5.00 (qdt,

2

\ 6.8, J \ 5J

5, 4

rotational values were averaged over

5

measurements

J

\ 1.8, 5-H), 5.30È5.47 (m, 15@-H,

5, 5vMe

5, 1{

(undertaken with a given solution of the respective sample).

Melting points were measured on a Dr. Tottoli apparatus

(Buchi) and are uncorrected.

16@-H, 19@-H, 20@-H), 6.98 (td, 4J

\ J \ 1.5, 4-H). 13C

4, 1{

4, 5

NMR (125.7 MHz, APT): d \ 14.00 (C-32@), 19.05 (5-Me),

22.56, 23.40, 25.02, 25.56, 27.15 (2-fold intensity), 27.24 (2-fold

intensity), 29.03, 29.15, 29.20, 29.23, 29.34, 29.40, 29.45, 29.53

(2-fold intensity), 29.56 (2-fold intensity), 29.61, 31.79, 33.36

and 33.47 (C-1@ to C-10@, C-13@, C-14@, C-17@, C-18@, C-21@ to

C-31@, 19 resonances of 23-fold total intensity for 25 C atoms),

73.86 and 74.31 (C-11@, C-12@), 77.40 (C-5), 128.85, 129.34,

129.86 and 130.36 (C-15@, C-16@, C-19@, C-20@), 134.08 (C-3),

Syntheses

(5S,11ºS,12ºS)-Z,Z-3-(10,11-Dihydroxy-15,19-

dotriacontadienyl)-5-methyl-2(5H)-furanone (ent-5-epi-

montecristin) (1a). HCl (12 M, 15 ll, 0.18 mmol, 4.0 equiv.)

was added to a solution of the acetonide 2a (27.0 mg, 0.0441

mmol) in MeOHÈCH Cl (5 : 1, 0.6 ml) and the mixture was

148.93 (C-4), 173.90 (C-2). C

11.57; found C 77.41, H 11.50.

H

O (574.9) calcd. C 77.30, H

37 66

4

2

stirred for 24 h at room temperature. Water (2 ml) was added

and the organic phase extracted with ButOMe (3 ] 10 ml).

The combined organic phases were dried over Na SO and

(5S,4/S,5/S)-Z,Z-3-{10-[5-(3,7-Eicosadienyl)-2,2-

dimethyl-1,3-dioxolan-4-yl]decyl}-5-methyl-2(5H)-furanone

(2a). A solution of the b-hydroxylactone 3a (42 mg, 0.066

2

4

the solvent was removed. The residue was puriÐed by Ñash

chromatography (2.5 cm, petroleum etherÈButOMe

2 : 1 ] fraction 13, 1 : 1 ] fraction 20, fractions 8È18) to give

the title compound (22.3 mg, 88%) as a white solid (mp 52 ¡C).

mmol) in THF (2 ml) was treated with PPh (40.8 mg, 0.132

3

mmol, 2.0 equiv.) and DEAD (40% in toluene, 68 ll, 26 mg,

0.13 mmol, 2.0 equiv.) at [20 ¡C. The reaction mixture was

warmed to room temperature within 4 h. Water (2 ml) was

added and the resulting mixture was extracted with ButOMe

[a]25 \ ]1.9 (c \ 0.4). Calculating the speciÐc rotation for

D

the 100% enantiopure product, taking into account the ees of

the di†erent building blocks (lactone S,S-4 80% ee; iodide 5

97% ee) as well as the speciÐc rotation measured for com-

(3 ] 10 ml). The organic phase was dried over MgSO and the

4

solvent was removed. From the residue the title compound

pound 1b (vide infra) leads to [a]25 \ ]4.7 (c \ 0.4)52 Mlit.5:

(38.2 mg, 94%) was isolated as a colorless oil by Ñash chroma-

D

[a]25 \ ]25 for montecristin (c \ 0.1, MeOH)N. 1H NMR

tography (2 cm, petroleum etherÈButOMe 10 : 1, fractions

D

(300 MHz): d \ 0.88 (t, J

\ 6.8, 32@-H ), 1.24È1.38 (m,

4È9). [a]25 \ [1.5 (c \ 1.4). 1H NMR (300 MHz): d \ 0.88

32{, 31{

3

D

2@-H to 9@-H , 22@-H to 31@-H ), 1.41 (d, J

\ 6.8, 5-Me),

(t, J

\ 6.8, 20Ó-H ), 1.24Èca. 1.38 (m, 2@-H to 9@-H ,

2

5, 5vMe

20`, 19`

3

2

1.44È1.60 (m, 10@-H , 13@-H ), ca. 1.94 (very br s, 2 OH), in

10Ó-H to 19Ó-H ), superimposed by 1.379 and 1.382 [2 s,

2

part superimposed by 2.02 (td, J

B J

B 6.5, 21@-

2A-(CH ) ], 1.41 (d, J

\ 6.7, 5-Me), 1.47È1.60 (m, 10@-H ,

21{, 22{

21{, 20{

3 2

5, 5vMe

B J

2

H ), 2.11 (m , 17@-H , 18@-H ), in part superimposed by 2.13È

ca. 2.23 (m, 14@-H ), in part superimposed by 2.26 (tdd,

1Ó-H ), 2.02 (td, J

B 6.6, 9Ó-H ), in part super-

2

c

2

9`, 10`

9`, 8`

2

imposed by 2.10 (m , 5Ó-H , 6Ó-H ), in part superimposed by

2

c

2

J

\ 7.8, 4J

\ 5J

\ 1.7, 1@-H ), 3.38È3.48 (m, 11@-H,

2.13Èca. 2.23 (m, 2Ó-H ), in part superimposed by 2.26 (tdd,

1{, 2{

1{, 4

1{, 5

2

1{, 5

12@-H), 5.00 (qdt, J

\ 6.6, J \ 5J

\ 1.8, 5-H),

J

\ 7.1, 4J

4.99 (qdt, J

\ 5J

\ 6.8, J \ 5J

\ 1.7, 1@-H ), 3.60 (m , 4A-H, 5A-H),

5, 5vMe

5, 4

5, 1{

1{, 2{

1{, 4

5, 5vMe

2

5, 1{

c

5.30È5.47 (m, 15@-H, 16@-H, 19@-H, 20@-H), 6.99 (td, 4J

\

\ 1.7, 5-H), 5.30È5.46

4, 1{

5, 4

J

\ 1.5, 4-H). 13C NMR (125.7 MHz, APT; slightly con-

(m, 3Ó-H, 4Ó-H, 7Ó-H, 8Ó-H), 6.98 (td, 4J

\ J \ 1.5,

4, 5

4, 1{

4, 5

taminated at d \ 29.1): d \ 14.05 (C-32@), 19.10 (5-Me), 22.61,

23.45, 25.06, 25.58, 27.19 (2-fold intensity), 27.29 (2-fold

intensity), 29.07, 29.18, 29.25, 29.28, 29.37, 29.43, 29.46, 29.49,

29.58 (2-fold intensity), 29.60, 29.61, 29.65, 31.84, 33.39 and

33.51 (C-1@ to C-10@, C-13@, C-14@, C-17@, C-18@, C-21@ to C-31@;

21 resonances of 24-fold total intensity for 25 C atoms), 73.94

and 74.39 (C-11@, C-12@), 77.42 (C-5), 128.88, 129.35, 129.99 and

130.45 (C-15@, C-16@, C-19@, C-20@), 134.16 (C-3), 148.93 (C-4),

173.93 (C-2). IR (KBr): l \ 3415, 3355, 3000, 2920, 2850, 1740,

1655, 1465, 1365, 1320, 1205, 1085, 1065, 1025, 930, 895, 720

4-H). IR (neat): l \ 2985, 2925, 2855, 1760, 1460, 1370, 1320,

1240, 1080, 1025, 950, 870, 725 cm~1. C

H

O (615.0) calcd.

40 70

4

C 78.12, H 11.47; found C 78.01, H 11.39.

(5R,4/S,5/S)-Z,Z-3-{10-[5-(3,7-Eicosadienyl)-2,2-

dimethyl-1,3-dioxolan-4-yl]decyl}-5-methyl-2(5H)-furanone

(2b). 2b was prepared as for 2a using b-hydroxylactone 3b (64

mg, 0.101 mmol) in THF (2 ml), PPh (52.9 mg, 0.202 mmol,

3

2.0 equiv.) and DEAD (40% in toluene, 102 ll, 38.6 mg, 0.202

mmol, 2.0 equiv.). From the residue of the work-up the title

compound (60.1 mg, 97%) was isolated as a colorless oil by

Ñash chromatography (2.5 cm, petroleum etherÈButOMe

cm~1. C

H

O (574.9) calcd. C 77.30, H 11.57; found C

37 66

4

77.27, H 11.33.

10 : 1, fractions 4È10). [a]25 \ [20.0 (c \ 2.25). 1H NMR

D

(5R,11ºS,12ºS)-Z,Z-3-(11,12-Dihydroxy-15,19-

(300 MHz; contains 1.2 wt.% dihydro-DEAD; quartet at

dotriacontadienyl)-5-methyl-2(5H)-furanone (ent-montecristin)

(1b). 1b was prepared as for 1a using HCl (12 M, 20 ll, 0.22

mmol, 4.0 equiv.) and acetonide 2b (33.0 mg, 0.0544 mmol).

The residue obtained after work-up was puriÐed by Ñash

chromatography (2.5 cm, petroleum etherÈButOMe

2 : 1 ] fraction 12, 1 : 1 ] fraction 20, fractions 8È19) to give

the title compound (25.8 mg, 83%) as a white solid (mp 58 ¡C,

d \ 4.99): d \ 0.88 (t, J

\ 6.8, 20Ó-H ), 1.24Èca. 1.38

20`,19`

3

(m, 2@-H to 9@-H , 10A-H to 19Ó-H ), superimposed by 1.38

2

[br s, (CH ) ], 1.41 (d, J

\ 6.8, 5-Me), 1.45È1.60 (m, 10@-

3 2

5, 5vMe

H , 1Ó-H ), 2.02 (td, J

B J

B 6.4, 9Ó-H ), in part

2

9`, 10`

9`, 8`

2

superimposed by 2.10 (m , 5Ó-H , 6Ó-H ), in part superim-

c

2

posed by 2.13Èca. 2.23 (m, 2Ó-H ), 2.26 (incompl. res. tdd,

2

J

\ 7.5, 4J

4.99 (qdt, J

\ 5J

\ 1.7, 1@-H ), 3.60 (m , 4A-H, 5A-H),

1{, 2{

1{, 4

1{, 5

2

c

lit.5: for the enantiomer 62 ¡C). [a]25 \ [24.2 (c \ 2.48). Cal-

\ 6.7, J \ 5J

\ 1.7, 5-H), 5.30È5.45

D

5, 5vMe

5, 4

5, 1{

culating the speciÐc rotation for the 100% enantiopure

(m, 3Ó-H, 4Ó-H, 7Ó-H, 8Ó-H), 6.98 (td, 4J

\ J \ 1.5,

4, 1{

4, 5

product, taking into account the ees of the di†erent building

blocks (lactone R,R-4 90% ee; iodide 5 97% ee) as well as the

speciÐc rotation measured for compound 1a (vide supra) leads

4-H). IR (neat): l \ 2980, 2925, 2855, 1760, 1460, 1370, 1320,

1240, 1080, 1025, 870, 725 cm~1. C

H

O (615.0) calcd. C

40 70

4

78.12, H 11.47; found C 78.00, H 11.29.

New J. Chem., 2001, 25, 40È54

47

View Article Online

(3S,4S,5S,4/S,5/S)-Z,Z-3-{10-[5-(3,7-Eicosadienyl)-2,2-

dimethyl-1,3-dioxolan-4-yl]-decyl}-4,5-dihydro-4-hydroxy-5-

methyl-2(3H)-furanone (3a). n-BuLi (1.90 M in hexane, 0.66

heptakis-(2,6-di-O-methyl-3-O-pentyl-b-cyclodextrin) in 80%

OV1701 (25 m), 70 kPa H , 110 ¡C isothermal; R 45.4 min,

2

T

R

of R,R enantiomer 44.3 min]. [a]25 \ [62.2 (c \ 0.73)

T

D

ml, 1.3 mmol, 2.5 equiv.) was added to a solution of i-Pr NH

Mlit.: [a]25 \ [73.7 (c \ 0.93, EtOH)N. 1H NMR (300 MHz):

2

D

(0.16 ml, 0.13 g, 1.3 mmol, 2.5 equiv.) in THF (2.5 ml) at

d \ 1.45 (d, J

\ 6.8, 1@-H ), 2.49 (br s, OH), AB signal

1{, 5

3

[78 ¡C. After 30 min a solution of the b-hydroxylactone S,S-4

(58 mg, 0.50 mmol) in THF (2.5 ml) was added. After 2 h at

[78 ¡C a solution of iodide 5 (322 mg, 0.500 mmol, 1.0 equiv.)

in THFÈDMPU (1 : 1, 2 ml) was added dropwise. The mixture

was stirred for 20 h at [45 ¡C and worked up by the addition

of HCl (2 M, 2.5 ml). After extraction with ButOMe (3 ] 20

(d \ 2.58, d \ 2.82, J \ 17.8, in addition split by J

\

A

B

AB

A, 4

1.0, J \ 5.7, 3-H ), 4.45 (br dd, J

B J B 4, 4-H),

B, 4

4.58 (qd, J

5, 1{

2

4, 3vH(B)

4, 5

\ 6.5, J \ 3.8, 5-H).

5, 4

(4R,5R)-4,5-Dihydro-4-hydroxy-5-methyl-2(3H)-furanone

(R,R-4). Method A: AD-mix b [14.0 g; containing 1,4-bis-

(dihydroquinidinyl)phthalazine (1 mol.%), K Fe(CN) (3

ml), drying over MgSO and removal of the solvents the

4

3 6

equiv.), K CO (3 equiv.), K OsO (0.2 mol.%)] and methyl

residue was separated by Ñash chromatography (3 cm, pet-

2

3

2

4

roleum etherÈButOMe 1 : 1) to give unreacted 5 (fractions 2È3,

121 mg, 38%) and the title compound (fractions 5È11, 175 mg,

56%; 90% based on recovered starting material) as colorless

trans-3-pentenoate (1.23 ml, 1.14 g, 10.0 mmol) were added to

a 1 : 1 mixture of ButOH and H O (50 ml each) at 0 ¡C. After

2

stirring for 4 days the reaction was terminated by the addition

oils. [a]25 \ [21.8 (c \ 0.78). 1H NMR (300 MHz): d \ 0.88

of aqueous Na SO solution (30 ml). After extraction with

D

2

3

(t, J

\ 6.8, 20Ó-H ), ca. 1.24Èca. 1.40 (m, 2@-H to 9@-

CH Cl (10 ] 50 ml) the organic extracts were dried over

20`, 19`

3

2

2 2

H , 10Ó-H to 19Ó-H ), superimposed by 1.379 and 1.383 [2 s,

Na SO . Removal of the solvent yielded a residue that was

2

4

2A-(CH ) ], 1.41 (d, J

\ 6.7, 5-Me), 1.43È1.63 (m, 1@-H1,

puriÐed by Ñash chromatography (3 cm, ButOMe, fractions

12È24) to give R,R-4 (441 mg, 38%). Chiral capillary gas chro-

matography revealed ee \ 80% [20% heptakis-(2,6-di-O-

methyl-3-O-pentyl-b-cyclodextrin) in 80% OV1701 (25 m), 70

kPa H , 110 ¡C isothermal; R 44.3 min, R of S,S enantiomer

3 2

5, 5vMe

10@-H , 1Ó-H ), 1.69È1.79 (m, 1@-H2), 2.02 (td, J

B

2

9`, 10`

J

B 6.5, 9Ó-H ), in part superimposed by 2.10 (m , 5Ó-

9`, 8`

2

c

H , 6Ó-H ), in part superimposed by ca. 2.13È2.26 (m, 2Ó-H ),

2

B 7.1, J \ 3.6, 3-H), 3.60

3, 4

2.54 (ddd, J

B J

3, 1{vH(1)

3, 1{vH(2)

2

45.4 min].

T

(m , 4A-H, 5A-H), 4.20 (dd, J \ 4.7, J \ 3.6, 4-H), 4.63

c

4, 5

4, 3

(qd, J

\ 6.4, J \ 4.9, 5-H), 5.30È5.46 (m, 3Ó-H, 4Ó-H,

Method B: Same as for S,S-4 using (DHQD) PHAL [\1,4-

5, 5vMe

5, 4

2

7Ó-H, 8Ó-H). IR (neat): l \ 3445, 2985, 2925, 2855, 1760, 1460,

bis(dihydroquinidinyl)phthalazine; 78.0 mg, 0.100 mmol, 10.0

1375, 1240, 1185, 1100, 1055, 995, 725 cm~1. C

H

O

mol.%]. After extraction with CH Cl (10 ] 50 ml) the

40 72

5

2 2

(633.0) calcd. C 75.90, H 11.47; found C 75.69, H 11.15.

organic phase was dried over Na SO . After removal of the

2

4

solvent R,R-4 (80 mg, 69%) was obtained from the residue by

Ñash chromatography (2.5 cm, ButOMe, fractions 6È12).

Chiral capillary gas chromatography revealed ee \ 94% [20%

heptakis-(2,6-di-O-methyl-3-O-pentyl-b-cyclodextrin) in 80%

OV1701 (25 m), 70 kPa H , 110 ¡C isothermal; R 44.3 min,

(3R,4R,5R,4/S,5/S)-Z,Z-3-{10-[5-(3,7-Eicosadienyl)-2,2-

dimethyl-1,3-dioxolan-4-yl]-decyl}-4,5-dihydro-4-hydroxy-5-

methyl-2(3H)-furanone (3b). 3b was prepared as for 3a using

b-hydroxylactone R,R-4 (58 mg, 0.50 mmol). The residue after

extraction and solvent removal was separated by Ñash chro-

matography (3 cm, petroleum etherÈButOMe 1 : 1) to give

unreacted 5 (fractions 2È3, 111 mg, 34%) and the title com-

pound (fractions 6È12, 195 mg, 62%; 94% based on recovered

2

T

R of S,S enantiomer 45.4 min].

T

(4S,5S)-Z,Z-4-(3,7-Eicosadienyl)-5-(10-iododecyl)-2,2-

dimethyl-1,3-dioxolane (5). At 0 ¡C, PPh (605 mg, 2.31 mmol,

3

1.2 equiv.), imidazole (315 mg, 4.63 mmol, 2.4 equiv.) and I

2

starting material) as colorless oils. [a]25 \ ]6.02 (c \ 0.93).

D

1H NMR (300 MHz, slightly contaminated around d \ 0.9):

(587 mg, 2.31 mmol, 1.2 equiv.) were added to a solution of

d \ 0.88 (t, J

\ 7.2, 20Ó-H ), 1.24Èca. 1.40 (m, 2@-H to

alcohol 62 (1.03 g, 1.93 mmol) in THF (20 ml). The reaction

mixture was warmed to room temperature within 30 min, fol-

lowed by the addition of water (20 ml). The organic phase was

separated and the aqueous phase extracted with ButOMe (50

20`, 19`

3

2

9@-H , 10Ó-H to 19Ó-H ), superimposed by 1.38 [br s, 2A-

2

(CH ) ], 1.41 (d, J

\ 6.4, 5-Me), 1.43È1.63 (m, 1@-H1, 10@-

3 2

5, 5vMe

H , 1Ó-H ), 1.69È1.79 (m, 1@-H2), 2.02 (td, J

B J

B

2

9`, 10` 9`,8`

6.5, 9Ó-H ), in part superimposed by 2.10 (m , 5Ó-H , 6Ó-H ),

in part superimposed by 2.13È2.26 (m, 2Ó-H ), 2.54 (ddd,

ml). The combined organic phases were dried over MgSO

and the solvent was removed. The residue was puriÐed by

2

c

2

4

2

J

B J

B 7.0, J \ 3.7, 3-H), 3.60 (m , 4A-H,

Ñash chromatography (3 cm, deactivated silica, petroleum

etherÈButOMe 100 : 1, fractions 3È9). The title compound

(1.19 g, 96%) was obtained as a colorless liquid. [a]25 \

3, 1{vH(1)

3, 1{vH(2)

3, 4

4, 5

c

5A-H), 4.20 (poorly res. dd, J \ 4.6, J \ 3.6, 4-H), 4.63

4, 3

(qd, J

\ 6.4, J \ 4.9, 5-H), 5.30-5.45 (m, 3Ó-H, 4Ó-H,

5, 5vMe

5, 4

D

7Ó-H, 8Ó-H). IR (neat): l \ 3445, 2985, 2925, 2855, 1755, 1460,

[8.29 (c \ 0.76). 1H NMR (300 MHz): d \ 0.88 (t, J

\

20{, 19{

2

1375, 1240, 1185, 1100, 1055, 995, 725 cm~1. C

H

O

7.2, 20@-H ), 1.24Èca. 1.43 (m, 10@-H to 19@-H , 2A-H to 8A-

40 72

5

3

2

(633.0) calcd. C 75.90, H 11.47; found C 75.80, H 11.31.

H ), superimposed by 1.38 [s, 2-(CH ) ], 1.45È1.60 (m, 1@-H ,

2

3 2

2

1A-H ), 1.82 (tt, J

\ J

\ 7.2, 9A-H ), 2.02 (br td,

2

9_, 10_

9_, 8_

2

(4S,5S)-4,5-Dihydro-4-hydroxy-5-methyl-2(3H)-furanone

J

B J

B 6.4, 9@-H ), in part superimposed by 2.10

9{, 10{

c

9{, 8{

2

(S,S-4). Method A: Ref. 7d. Method B: At 0 ¡C K Fe(CN)

(m , 5@-H , 6@-H ), in part superimposed by ca. 2.14È2.26 (m,

3

6

2

(987 mg, 3.00 mmol, 3.0 equiv.), K CO (414 mg, 3.00 mmol,

2@-H ), 3.19 (t, J

\ 6.9, 10A-H ), 3.60 (m , 4-H, 5-H),

2

3

2

10_, 9_

2

c

3.0 equiv.), (DHQ) PHAL [\1,4-bis(dihydroquininyl)phthala-

5.30È5.46 (m, 3@-H, 4@-H, 7@-H, 8@-H). 13C NMR (50.3 MHz,

APT): d \ 7.05 (C-10A), 14.04 (C-20@), 22.61, 23.83, 26.06,

27.19, 27.27, 28.44, 29.25, 29.29,* 29.30,* 29.38,j 29.49, 29.58,j

29.62,j 29.65,* 30.41, 31.85, 32.89, 32.92 and 33.47 (19 reso-

nances for 24 C atoms: C-1@, C-2@, C-5@, C-6@, C-9@ to C-19@,

2

zine; 78.0 mg, 0.100 mmol, 10.0 mol.%], K OsO (6.6 mg,

2

4

0.020 mmol, 2.0 mol.%) and methyl trans-3-pentenoate (123

ll, 114 mg, 1.00 mmol) were added to a 1 : 1 mixture of

ButOH and H O (5 ml each). After this mixture had been

2

stirred for 16 h the reaction was terminated by the addition of

C-1A to C-9A), 27.24 [C(CH ) ], 80.30 and 80.86 (C-4, C-5),

3 3

aqueous Na SO solution (10 ml). After extraction with

107.75 [C(CH ) ], 129.00, 129.19, 130.06 and 130.45 (C-3@,

3 3

2

3

CH Cl (10 ] 50 ml) the organic extracts were washed with

C-4@, C-7@, C-8@); * increased but not 2-fold intensity; j2-fold

2

diluted HCl. (DHQ) PHAL (74 mg, 95%) could be reisolated

from this extract after neutralization and extraction. The

intensity. IR (neat): l \ 2985, 2925, 2855, 1460, 1370, 1240,

2

1175, 1100, 1000, 875, 720 cm~1. C

H

O (644.8) calcd. C

35 65

2

organic phase was dried over Na SO . After removal of the

65.20, H 10.16, found C 64.94, H 10.13.

2

4

solvent S,S-4 (85 mg, 73%) was obtained from the residue by

Ñash chromatography (2.5 cm, ButOMe, fractions 6È12).

Chiral capillary gas chromatography revealed ee \ 86% [20%

1,1,1-Tribromo-2-hydroxy-3-butene (16). SnF (0.237 g, 3

2

mmol, 1 equiv.) was added to a mixture of CBr (2.98 g, 9

4

48

New J. Chem., 2001, 25, 40È54

View Article Online

mmol, 3 equiv.) and acrolein (0.2 ml, 3 mmol) in DMSO (12

ml) and the solution was stirred for 5 min. Another portion of

d \ 2.42 (br s, OH), AB signal (d \ 2.58, d \ 2.76, J

\

A

B

AB

17.9, split by J \ 5.6, 3-H ), AB signal (d \ 3.29, d \

B, 4

2

A

B

SnF (0.237 g, 3 mmol, 1 equiv.) was added and stirring was

3.44, J \ 13.6, split by J \ 9.5, J \ 5.3, 1@-H ), 4.45

2

AB

A, 5

B, 5

2

continued for a further 5 min. The mixture was diluted with

(ddd, J

\ 9.8, J

\ 4.9, J \ 3.4, 5-H), 4.64 (br

B 4.5, 4-H), 7.23È7.36 (m, 3 Ar-H), 7.41È

5, 1{vH(A)

5, 1{vH(B)

5, 4

CH Cl (5 ml) and HCl (2 M, 5 ml). After 30 min the organic

dd, J B J

2

4, 5

4, 3vH(B)

materials were extracted with CH Cl . The combined organic

7.46 (m, 2 Ar-H). No combustion analysis was performed.

2

layers were dried over MgSO , Ðltered and concentrated with

a rotary evaporator. The resultant crude product was puriÐed

4

(4S,5R)-5-Chloro-4,5-dihydro-4-hydroxy-2(3H)-furanone

by Ñash chromatography (pentaneÈether 8 : 2) to give the

(25). AD-mix a (1.72 g, 3.69 mmol, 3.0, equiv.), NaHCO (309

3

desired product (40 mg, 5%) as a pale yellow oil. 1H NMR

mg, 3.69 mmol, 3.0 equiv.), methanesulfoneamide (117 mg,

(300 MHz): d \ 2.98 (br s, OH), 4.54 (d, J \ 3.8, 2-H), 5.58

1.23 mmol, 1.0 equiv.) and the b,c-unsaturated ester 22 (182

2, 3

(dt, J \ 10.5, 4J

\ 1.3, 4-HZ), 5.58 (dt, J

\ 17.3,

\ 10.5,

mg, 1.23 mmol) in ButOH (1 ml) were added to a 1 : 1 mixture

cis

Zv4, 2

trans

4J

\ 1.3, 4-HE), 6.14 (ddd,

J

\ 17.0,

J

of ButOH and H O (6 ml each) at 0 ¡C. After this mixture had

Ev4, 2

3, 2

trans

cis

2

J

\ 5.2, 3-H). 13C (50.3 MHz, APT, CDCl as internal

been stirred for 24 h the reaction was terminated by the addi-

3

standard): d \ A [ A 52.96 (C-1), A ] A 84.50 (C-2), A [ A 121.84

tion of aqueous Na SO solution (2 ml) and water (10 ml).

2

3

(C-4), A ] A 132.80 (C-3).

After extraction with ButOMe (3 ] 50 ml) the organic extracts

were dried over Na SO . Removal of the solvent yielded a

2

4

Methyl E-5-chloro-3-pentenoate (2216). Hydroxyester 2014

(290 mg, 2.23 mmol) was added to a solution of NCS (356 mg,

residue that was puriÐed by Ñash chromatography (3 cm, pet-

roleum etherÈButOMe 2 : 1 ] fraction 12, 1 : 1 ] fraction 26,

fractions 13È24) to give 25 (53 mg, 19%). 1H NMR (300

MHz): d \ AB signal (d \ 2.64, d \ 2.85, J \ 17.8, split

2.68 mmol, 1.2 equiv.) and Me S (0.20 ml, 0.17 g, 2.7 mmol, 1.2

2

equiv.) in CH Cl (10 ml) at 0 ¡C. The reaction mixture was

2

A

B

AB

stirred for 16 h at room temperature. After addition of water

by J \ 1.2, J \ 5.8, 3-H ), superimposed by 2.64 (br d,

A, 4

B, 4

2

1{, 5

(10 ml) and extraction with CH Cl (3 ] 20 ml) the organic

J

\ 4.1, OH), 3.86 (d, J

\ 7.2, 1@-H ), 4.59 (td, J

\

B

2

OH, 4

2

5, 1{

4, OH

phases were dried over MgSO . After removal of the solvent

7.2, J \ 3.7, 5-H), 4.72 (br ddd, J B J

B J

4

5, 4

4, 5

4, 3vH(B)

the title compound (273 mg, 83%) was obtained by Ñash chro-

4.5, 4-H). No combustion analysis was performed.

matography (3 cm, petroleum etherÈButOMe 50 : 1 ] fraction

12, 20 : 1 ] fraction 22, fractions 13È22) as a colorless liquid.

1H NMR (300 MHz): d \ 3.13 (br d, J \ 6.7, 2-H ), 3.70 (s,

(5R)-3-Butyl-5-methyl-2(5H)-furanone (26). PPh (334 mg,

3

2, 3

2

1.28 mmol, 2.0 equiv.) and DEAD (40% in toluene, 0.58 ml,

OCH ), 4.06 (poorly res. dd, J \ 6.6, 4J \ 1.0, 5-H ),

3

5, 4

5, 3

2

0.22 g, 1.3 mmol, 2.0 equiv.) were added to a solution of the

b-hydroxylactone 27 (110 mg, 0.640 mmol; 86% ee) in THF

(10 ml) at [20 ¡C. The reaction mixture was allowed to warm

to room temperature within 3 h. Water (10 ml) was added,

followed by extraction with ButOMe (3 ] 20 ml). The organic

5.75 (dtt, J

\ 15.0, J \ 6.8, 4J \ 1.4, 3-H*), 5.90 (dt

trans

3, 2

3, 5

with shoulders, J

\ 15.4, J \ 6.8, 4-H*); * assignments

trans

4, 5

interchangeable.

Methyl E-5-(phenylthio)-3-pentenoate (23). Ph S (4.53 g,

2 2

20.8 mmol, 3.0 equiv.) and Bu P (6.89 ml, 5.60 g, 27.7 mmol,

3

phase was dried over MgSO and the solvent was removed.

4

The residue yielded the title compound (88.0 mg, 89%) as a

4.0 equiv.) were dissolved in toluene (40 ml). Hydroxyester

colorless liquid after Ñash chromatography (2.5 cm, petroleum

2014 (900 mg, 6.92 mmol) in THF (5 ml) was added after 2 h at

room temperature. After stirring overnight the solvent was

removed. The residue was puriÐed by Ñash chromatography (6

cm, petroleum ether ] fraction 10, petroleum etherÈButOMe

10 : 1 ] fraction 35, fractions 23È35). The title compound (1.24

g, 81%) was isolated as a colorless liquid. 1H NMR (300

MHz; with MeO-containing impurity at d \ 3.63): d \ 3.03

(d, J \ 3.8, 2-H ), 3.54 (dm , J B 4, 5-H ), 3.65 (s, OMe),

etherÈButOMe 4 : 1, fractions 3È6). [a]25 \ [48.3 (c \ 1.09);

D

since the starting material 27 had 86% ee, this measured spe-

ciÐc rotation corresponds to [48.3/0.86 \ [56.1 for enantio-

pure 26 Mlit.: [a]25 \ [53.7 (c not given, CHCl )N. 1H NMR

D

3

(300 MHz): d \ 0.93 (t, J

\ 7.4, 4@-H ), 1.29È1.44 (m, 3@-

4{, 3{

3

H ), superimposed by 1.41 (d, J

(m, 2@-H ), 2.28 (tdd, J

\ 6.8, 5-Me), 1.49È1.60

2

5, 5vMe

\ 7.5, 4J

\ 5J

\ 1.6, 1@-H ),

2

1{, 2{

1{, 4

5, 1{

1{, 5

2

2, 3

2

c

5, 4

2

4.99 (qdt, J

4J

\ 6.8, J \ 5J

\ 1.8, 5-H), 6.99 (td,

5.57È5.71 (m, 3-H, 4-H), 7.15È7.22 (m, 1 Ar-H), 7.24È7.36 (m, 4

Ar-H). IR (neat): l \ 3055, 3000, 2950, 1735, 1585, 1480, 1435,

1355, 1290, 1255, 1195, 1170, 1025, 970, 740, 690 cm~1. No

combustion analysis was performed.

5, 5vMe

5, 4

\ J \ 1.6, 4-H).

4, 1{

4, 5

(3R,4R,5R)-3-Butyl-4,5-dihydro-4-hydroxy-5-methyl-

2(3H)-furanone (27). BunLi (1.90 M in hexane, 2.63 ml, 5.00

(4S,5R)-4,5-Dihydro-4-hydroxy-5-[(phenylthio)methyl]-

2(3H)-furanone (24). At 0 ¡C AD-mix a [2.80 g containing 1,4-

bis(dihydroquininyl)phthalazine (1 mol%), K Fe(CN) (3

mmol, 2.5 equiv.) was added to a solution of Pri NH (0.66 ml,

2

0.51 g, 5.0 mmol, 2.5 equiv.) in THF (20 ml) at [78 ¡C. After

30 min a solution of the b-hydroxylactone R,R-4 (232 mg, 2.00

mmol, 86% ee) in THF (5 ml) was added. After stirring the

mixture for 2 h at this temperature 1-iodobutane (0.27 ml, 0.44

g, 2.4 mmol, 1.2 equiv.) in THFÈDMPU (1 : 1, 8 ml) was

added. After stirring at [45 ¡C for 20 h the mixture was

hydrolyzed with HCl (1 M, 10 ml). After extracting the

aqueous phase with ButOMe (3 ] 30 ml) the combined

3

6

equiv.), K OsO (0.2 mol%)], methanesulfoneamide (190 mg,

2

4

2.00 mmol, 1.0 equiv.) and the b,c-unsaturated ester 23 (444

mg, 2.00 mmol) in ButOH (1 ml) were added to a 1 : 1 mixture

of ButOH and H O (6 ml each). After stirring for 36 h, the

2

mixture was hydrolyzed by the addition of aqueous Na SO

2

3

solution (2 ml) and water (10 ml). After extraction with

ButOMe (3 ] 50 ml) the organic extracts were dried over

organic phases were dried over MgSO and the solvent was

4

MgSO . After removal of the solvent the residue was puriÐed

removed. Flash chromatography (3 cm, petroleum etherÈ

4

by Ñash chromatography (3 cm, petroleum etherÈButOMe

ButOMe 4 : 1 ] fraction 10, 2.5 : 1 ] fraction 26, fractions

15È23) of the residue yielded the title compound (298 mg,

84%) as a colorless oil. [a]20 \ ]58.4 (c \ 1.18) Mlit.: [a]20 \

2 : 1 ] fraction 12, 1 : 1 ] fraction 20, ButOMe ] fraction 32,

fractions 14È30). 24 (283 mg, 63%) was isolated as a colorless

oil. Chiral capillary gas chromatography of traces of the sub-

sequently obtained (Raney Ni treatment in acetoneÈEtOH, 5

D

]71 (c \ 0.5, MeOH)N; since the starting material R,R-4 had

86% ee this measured speciÐc rotation corresponds to

bar H , room temperature, 5 days), desulfurized material

[a]20 \ ]58.4/0.86 \ ]67.9 for enantiopure 27. 1H NMR

2

D

revealed ee \ 80% [20% heptakis-(2,6-di-O-methyl-3-O-

(300 MHz): d \ 0.92 (t, J

\ 7.2, 4@-H ), 1.30È1.80 (m, 1@-

4{, 3{

3

pentyl-b-cyclodextrin) in 80% OV1701 (25 m), 70 kPa H ,

H , 2@-H , 3@-H ), in part superimposed by 1.41 (d, J

\

B

2

5vMe, 5

110 ¡C isothermal; R 44.3 min, R of R,R enantiomer 43.2

6.8, 5-Me), 2.21 (m , OH), 2.55 (poorly res. ddd, J

T

c

3, 1{vH(1)

min]. 1H NMR (300 MHz; contains 1.4 wt% ButOMe):

7.8, J

\ 6.4, J \ 3.4, 3-H), 4.21 (br ddd, J

3, 1{vH(2)

3, 4

4, 5

New J. Chem., 2001, 25, 40È54

49

View Article Online

J

B J

4, OH

B 4.5, 4-H), 4.64 (qd, J

5, 5vMe

\ 6.4, J \ 4.9,

liquid. 1H NMR (300 MHz, contains traces of Ph P):

4, 3

5-H).

5, 4

3

d \ 0.88 (t, J

\ 6.6, 16-H ), 1.22È1.54 (m, 6-H to 15-H ),

16, 15

3

2

2.14 (tt, J \ 7.0, 5J \ 2.3, 5-H ), 2.71 (tt, J \ 7.3,

5, 6 5, 2 2, 1

5J \ 2.3, 2-H ), 3.41 (t, J \ 7.4, 1-H ). No combustion

2, 5 1, 2

analysis was performed.

2

1-[(2-Tetrahydropyranyl)oxy]-3-butyne (29). A mixture of

3,4-dihydro-(2H)-pyran (27.4 ml, 25.2 g, 300 mmol, 3.0 equiv.)

and 3-butyn-1-ol (9.30 ml, 8.41 g, 100 mmol) in CH Cl (100

ml) and a catalytic amount of camphor sulfonic acid was

stirred for 3 h at room temperature. Water (50 ml) was added

and the phases were separated. The aqueous phase was

extracted with ButOMe (100 ml) and the combined organic

phases were dried over MgSO . After removal of the solvent

the title compound (14.81 g, 96%) was isolated from the

2

1-Iodo-3-hexadecyne (33). A solution of alkynol 31 (1.90 g,

7.89 mmol) in THF (30 ml) at 0 ¡C was successively treated

with PPh (2.30 g, 8.78 mmol, 1.1 equiv.), imidazole (1.19 g,

3

17.6 mmol, 2.2 equiv.) and I (2.23 g, 8.78 mmol, 1.1 equiv.).

2

After 1 h NH Cl solution (10 ml) was added and the organic

phase was separated. After extraction with petroleum ether

4

(2 ] 100 ml) the combined organic phases were dried and the

solvent removed. The residue was puriÐed via Ñash chroma-

tography (4 cm, petroleum ether, fractions 3È9) to provide the

title compound (2.433 g, 88%) as a colorless liquid. 1H NMR

residue by distillation under reduced pressure (bp 74 ¡C at 20

mbar). 1H NMR (300 MHz): d \ 1.46È1.90 (m, 3@-H , 4@-H ,

2

5@-H ), 1.98 (t, 4J \ 2.7, 4-H), 2.50 (td, J \ 7.2, 4J

\

2

4, 2

2, 1

2, 4

2.7, 2-H ), ca. 3.52 (m , 6@-H1), heavily superimposed by A

2

c

(300 MHz): d \ 0.88 (t, J

\ 6.8, 16-H ), 1.24È1.54 (m,

branch of AB signal (d \ 3.57, d \ 3.83, J \ 9.8, split by

16, 15

3

A

B

AB

6-H to 15-H ), 2.13 (tt, J \ 6.8, 5J \ 2.3, 5-H ), 2.73 (tt,

J

\ 7.0, J \ 7.2, 1-H ), B branch severely superimposed

2

5, 6

5, 2

2

A, 2

B, 2

c

2

J

\ 7.4, 5J \ 2.3, 2-H ), 3.21 (t, J \ 7.4, 1-H ). IR

by ca. 3.88 (m , 6@-H2), 4.65 (dd, J

B J

\ 3.4,

2, 1

2, 5

2

1, 2

2

2{, 3{vH(1) 2{, 3{vH(2)

(neat): l \ 2925, 2850, 1465, 1435, 1250, 1170, 720 cm1. No

2@-H).

combustion analysis was performed.

1-[(2-Tetrahydropyranyl)oxy]-3-hexadecyne (30). Alkyne 29

3-Hexynyl triÑuoromethanesulfonate (34) and 1-[(2-tetra-

hydropyranyl)oxy]-3,7-eicosadiyne (35). The alkynol 31 (770

mg, 3.24 mmol) was dissolved in CH Cl (10 ml); NEt (0.54

(15.7 ml, 15.4 g, 100 mmol) was added dropwise to a suspen-

sion of NaNH (4.29 g, 111 mmol, 1.1 equiv.) in THF (50 ml)

2

at 0 ¡C. 1-Bromododecane (26.4 ml, 27.4 g, 110 mmol, 1.1

2

3

ml, 0.39 g, 3.9 mmol, 1.2 equiv.) and Tf O (0.65 ml, 1.1 g, 3.9

equiv.) and DMSO (50 ml) were added to the yellowish solu-

tion after 1 h. The reaction mixture was stirred for 2.5 h at

room temperature and hydrolyzed with water (50 ml). After

extraction of the aqueous phase with ButOMe (3 ] 200 ml)

2

mmol, 1.2 equiv.) were added at 0 ¡C. After 2 h the solvent was

removed and the residue Ðltered over a short silica column (3

cm, petroleum etherÈButOMeÈCH Cl 5 : 1 : 1). The resulting

2

crude triÑate 34 was dissolved in THF (2 ml). This solution

was added at 0 ¡C to a solution prepared from alkyne 29 (505

mg, 3.24 mmol, 1.0 equiv.) and BunLi (1.50 M in hexane, 2.37

ml, 3.56 mmol, 1.1 equiv.) in THF (8 ml; deprotonation time

30 min). After stirring at room temperature for 16 h an

the combined organic phases were dried over MgSO . After

4

removal of the solvent Ñash chromatography (8 cm, petroleum

ether ] fraction 8, petroleum etherÈButOMe 50 : 1 ] fraction

12, 20 : 1 ] fraction 20, fractions 8È18) yielded the title com-

pound (16.73 g, 53%) as a colorless liquid. 1H NMR (300

aqueous NH Cl solution (10 ml) was added. After extracting

MHz): d \ 0.88 (t, J

\ 6.8, 16-H ), 1.22È1.90 (m, 6-H to

4

16, 15

15-H , 3@-H , 4@-H , 5@-H ), 2.13 (tt, J \ 7.0, 5J \ 2.3,

5, 6 5, 2

5-H ), 2.46 (tt, J \ 7.4, 5J \ 2.5, 2-H ), AB signal (d \

2, 1 2, 5

3

2

the aqueous phase with ButOMe (3 ] 20 ml) the combined

2

organic phases were dried over MgSO . After removal of the

4

2

A

solvent Ñash chromatography (3 cm, petroleum etherÈ

3.52, d \ 3.79, J \ 9.6, split by J \ J \ 7.2, 1-H ), A

B

AB

A, 2

B, 2

2

ButOMe 50 : 1 ] fraction 10, 20 : 1 ] fraction 20, fractions

9È18) provided 35 (383 mg, 32%) as a colorless liquid. 1H

branch superimposed by ca. 3.50 (m , 6@-HA), B branch of AB

c

signal (broadened, d \ 3.89,

J

\ 11.3, split by

\ 3.4, 6@-HB), 4.65 (dd,

B

AB

NMR (300 MHz): d \ 0.88 (t, J

\ 6.8, 20-H ), 1.22È1.88

J

\ 7.9,

J

20, 19

3

6{vH(B), 5{vH(1)

B J

6{vH(B), 5{vH(2)

(m, 10-H to 19-H , 3@-H , 4@-H , 5@-H ), 2.13 (br t, J

\

B 3.4, 2@-H).

2

9, 10

2{, 3{vH(1)

2{, 3{vH(2)

7.0, 9-H ), 2.33 (br s, 5-H , 6-H ), 2.46 (t, J \ 7.2, 2-H ),

2, 1

AB signal (d \ 3.52, d \ 3.79, J \ 9.8, split by J

AB

\ 7.2, 1-H ), A branch superimposed by ca. 3.50 (m ,

2

\

A

B

A, 2

3-Hexadecyn-1-ol (31). While stirring, p-TsOH (1.56 g, 8.22

J

B, 2

2

c

mmol, 0.4 equiv.) was added to a solution of the THP ether 30

(6.62 g, 20.6 mmol) in MeOH (60 ml) at room temperature.

After 30 min water (50 ml) and ButOMe (50 ml) were added

and the phases separated. After extraction of the aqueous

phase with ButOMe (2 ] 50 ml) the combined organic phases

6@-H1), B branch of AB signals (d \ 3.88, J \ 11.2, split by

B

AB

J

\ 7.5, J

\ 3.7, 6@-H2), 4.64 (dd, J

B

B, 5{vH(1)

2{, 3{vH(2)

B, 5{vH(2)

2{, 3{vH(1)

B 3.4, 2@-H). This compound was not characterized

by combustion analysis.

were dried over MgSO . After removal of the solvent the

1-Hexadecen-3-yne (36). The title compound was obtained

instead of the desired diyne 35 in the following experiment. At

0 ¡C, BuLi (1.43 M in hexane, 5.61 ml, 8.03 mmol, 1.2 equiv.)

was added to the THP ether 29 (1.03 g, 6.69 mmol) in THF

(20 ml). After 30 min iodide 33 (2.33 g, 6.69 mmol, 1.0 equiv.)

in DMSO (50 ml) was added and the mixture was allowed to

warm to room temperature. After stirring for 12 h water (50

ml) and ButOMe (50 ml) were added. The aqueous phase was

extracted with ButOMe (2 ] 50 ml). The combined organic

4

alkynol 31 (4.90 g, 99%) was isolated as a white solid (mp

41 ¡C). 1H NMR (300 MHz): d \ 0.88 (t, J

\ 6.8, 16-H ),

16, 15

3

1.23È1.54 (m, 6-H to 15-H ), 1.81 (br s, OH), 2.16 (tt, J

\

2

5, 6

7.0, 5J \ 2.3, 5-H ), 2.43 (tt, J \ 6.1, 5J \ 2.3, 2-H ),

5, 2 2, 1 2, 5

2

3.68 (br t, J \ 6.2, 1-H ). IR (neat): l \ 3320, 2925, 2850,

1465, 1435, 1380, 1335, 1185, 1045, 720 cm~1. C

1, 2

2

H

O

16 30

(238.4) calcd. C 80.61, H 12.68; found C 80.88, H 12.45.

1-Bromo-3-hexadecyne (32). A solution of alkynol 31 (715

mg, 3.00 mmol) in THF (6 ml) at [20 ¡C was successively

phases were washed with brine and dried over MgSO . After

4

removal of the solvent the residue was puriÐed via Ñash chro-

treated with PPh (943 mg, 3.60 mmol, 1.2 equiv.) and NBS

matography (4 cm, petroleum ether, fractions 2È5) to yield

enyne 36 (1.377 g, 93%). 1H NMR (300 MHz): d \ 0.88 (t,

3

(587 mg, 3.30 mmol, 1.1 equiv.). The reaction mixture was

warmed to 0 ¡C. After 4 h NH Cl solution (10 ml) was added

J

\ 6.8, 16-H ), 1.24È1.57 (m, 6-H to 15-H ), 2.29 (td,

4

16, 15

5, 6

3

2

and the organic phase was separated. After extraction with

\ 7.2, 5J \ 1.9, 5-H ), 5.37 (dd, J \ 11.0, J \ 2.3,

5, 2

2

cis

gem

petroleum ether (2 ] 50 ml) the combined organic phases

were dried and the solvent removed. The residue was puriÐed

via Ñash chromatography (3 cm, petroleum ether, fractions

4È6) to yield the title compound (794 mg, 88%) as a colorless

1-HE), 5.54 (dd, J

\ 17.3, J \ 2.3, 1-HZ), 5.78 (ddt,

trans

gem

J

\ 17.3, J \ 10.9, 5J \ 2.1, 2-H). IR (neat): l \ 2920,

trans

cis

2, 5

2855, 1610, 1455, 1380, 1330, 970, 910, 720 cm~1. C

(220.4) calcd. C 87.19, H 12.81; found C 87.22, H 12.57.

H

16 28

50

New J. Chem., 2001, 25, 40È54

View Article Online

1-(2-Tetrahydropyranyloxy)-2-dodecyne (39). BunLi (1.90 M,

11.7 ml, 22.2 mmol, 1.2 equiv.) was added to a solution of the

alkyne 3835 (2.60 g, 18.5 mmol) in THF at 0 ¡C. After 30 min

1-bromononane (3.90 ml, 4.22 g, 20.4 mmol, 1.1. equiv.) and

DMSO (50 ml) were added. After stirring at room tem-

perature for 24 h the reaction was terminated by the addition

of water (50 ml). After extraction with ButOMe (2 ] 50 ml) the

(KBr): l \ 3285, 2920, 2850, 1470, 1060, 1030, 725 cm~1.

Z-3-Hexadecen-1-ol (4938). Li (2.07 g, 300 mmol, 3.0 equiv.)

was cut into small pieces and suspended in Et O (50 ml).

2

Within 1 h 1-bromododecane (14.0 ml, 24.9 g, 100 mmol) in

Et O (50 ml) was added dropwise at 0 ¡C to this mixture.

2

After stirring for an additional 2 h at 0 ¡C the concentration of

organic phase was dried over MgSO . After removal of the

the resulting 1-lithiododecane was determined by titration of a

hydrolyzed sample of known volume (1.0 ml) with HCl (0.1

M) using phenolphthalein as an indicator. Subsequently, the

solution of this organolithium compound (103 ml, 0.95 M,

98.0 mmol) was transferred to a suspension of CuI (9.31 g, 49.0

4

solvent Ñash chromatography (5 cm, petroleum etherÈ

ButOMe 50 : 1, fractions 12È17) of the residue yielded the title

compound (3.36 g, 68%) as a colorless liquid. 1H NMR (300

MHz): d \ 0.88 (t, J

\ 6.8, 12-H ), 1.27 and 1.33È1.73

12, 11

3

(m and m, respectively, 5-H È11-H , 4@-H , 5@-H ), 2.21 (tt,

mmol, 0.50 equiv.) in Et O (100 ml) at [35 ¡C. After 30 min

c

2

J

\ 7.2, 5J \ 2.2, 4-H ), 3.49È3.56 and 3.81È3.89 (2m, 6@-

4, 1

acetylene (2.4 l, 98 mmol, 1.0 equiv.) was introduced at

4, 5

2

H ), AB signal (d \ 4.22, d \ 4.27, J \ 15.5, split by

[50 ¡C into the dark-grey suspension. After another 30 min

of stirring at [25 ¡C a green suspension was obtained. At

[30 ¡C it was treated with previously condensed ethylene

oxide (4.9 ml, 4.3 g, 98 mmol, 1.0 equiv.) and a previously

prepared solution of hexynyllithium [from BuLi (2.05 M in

hexane, 23.9 ml, 49.0 mmol, 0.50 equiv.) and 1-hexyne (5.62 ml,

2

A

B

AB

5J \ 2.2, 5J \ 2.3, 1-H ), 4.81 (t, J

A, 4

spectrum was recorded. C

17 30

11.35; found C 76.43, H 11.15.

\ 3.4, 2@-H). No IR

B

2

2{, 3{

O (266.4) calcd. C 76.64, H

H

2

2-Dodecyn-1-ol (40). A solution of THP ether 39 (3.18 g,

10.8 mmol) and TsOH monohydrate (0.830 g, 4.36 mmol, 0.4

equiv.) in methanol (80 ml) was stirred at room temperature

for 2 h. Distribution between water and ether, drying of the

4.02 g, 49.0 mmol, 0.50 equiv.)] in Et O (100 ml). The black

2

reaction mixture was stirred for 3 h at [15 ¡C and then

hydrolyzed with HCl (6 M, 40 ml) and sat. NH Cl solution

4

etheral phase over MgSO , concentration in vacuo and Ñash

(40 ml). After removing insoluble material by Ðltration

4

chromatography (pentaneÈether 8 : 1) yielded the title com-

ButOMe (200 ml) was added, the organic phase separated and

pound (1.92 g, 84%). 1H NMR (300 MHz): d \ 0.88 (t,

the aqueous phase extracted with ButOMe (2 ] 100 ml). The

J

\ 6.7, 12-H ), 1.27È1.45 (m, 6-H È11-H ), 1.68 (br s,

organic phases were dried over MgSO and the solvent was

12, 11

3

2

4

OH), 2.21 (tt, J \ 7.2, 5J \ 2.3, 4-H ), 4.25 (t, 5J

\

removed. Flash chromatography (8 cm, petroleum etherÈ

4, 5

4, 1

2

1, 4

2.3, 1-H ). 13C NMR (50.3 MHz, APT): d \ 14.09 (C-12),

ButOMe 10 : 1 ] fraction 10, 5 : 1 ] fraction 25, fractions

7È22) of the residue provided the title compound (19.07 g,

81%) as a colorless liquid. 1H NMR (300 MHz): d \ 0.88 (t,

2

18.72, 22.66, 28.59, 28.86, 29.13, 29.27, 29.46 and 31.85 (C-4ÈC-

11), 51.38 (C-1), 78.23 and 86.61 (C-2, C-3). IR (KBr):

l \ 3175, 2955, 2945, 2850, 1470, 1400, 1135, 1025, 780, 715

J

\ 6.6, 16-H ), 1.24È1.41 (m, 6-H to 15-H ), 1.49 (br s,

16, 15

3

2

cm~1. C

H

O (182.3) calcd. C 79.06, H 12.16; found C

OH), 2.06 (td, J \ J \ 6.7, 5-H ), 2.33 (td, J

B

12 22

5, 4

B 6.6, 2-H ), 3.65 (t, J \ 6.6, 1-H ), 5.36 (br dtt,*

1, 2

\ 10.8, J \ 7.4, 4J \ 1.5, 4-H), 4.57 (br dtt,* J

3, 2 3, 5

5, 6

2

2, 1

78.81, H 12.11.

J

2, 3

cis

2

\

cis

12-(tert-Butyldiphenylsiloxy)-1-dodecyne (42). At 0 ¡C

10.8, J \ 7.5, 4J \ 1.5, 3-H); *with additional peaks of

the beginning of a transition to a higher order signal.

4, 5

4, 2

ButPh SiCl (3.47 ml, 3.67 g, 13.7 mmol, 1.0 equiv.) and imid-

2

azole (1.92 g, 28.1 mmol, 2.1 equiv.) were added to a solution

of alcohol 44 (2.43 g, 13.4 mmol) in CH Cl (50 ml). After

Z-1-Iodo-3-hexadecene (50). At 0 ¡C PPh (2.88 g, 11.0

2

3

stirring for 1 h at room temperature the mixture was hydro-

lyzed with diluted HCl (1 M, 20 ml). The aqueous phase was

extracted with ButOMe (3 ] 50 ml) and the combined organic

phases were dried. After removal of the solvent the title com-

pound (5.58 g, 99%) was obtained without the need for further

puriÐcation. 1H NMR (300 MHz): d \ 1.05 (s, SiBut), 1.22È

1.44 (m, 5-H to 10-H ), 1.46È1.60 (m, 4-H , 11-H ), 1.94 (t,

mmol, 1.1 equiv.), imidazole (1.50 g, 22.0 mmol, 2.2 equiv.) and

I

(2.79 g, 11.0 mmol, 1.1 equiv.) were added to a solution of

2

the alcohol 49 (2.40 g, 10.0 mmol) in THF (100 ml). The reac-

tion mixture was warmed to room temperature within 30 min.

Subsequently water (100 ml) was added. The organic phase

was separated and the aqueous phase extracted with ButOMe

(100 ml). The combined organic phases were dried over

2

4J \ 2.6, 1-H), 2.18 (td, J \ 7.0, 4J \ 2.7, 3-H ), 3.65

MgSO and the solvent was removed. The residue was puri-

1, 3

(t, J

3, 4

3, 1

2

4

\ 6.4, 12-H ), 7.34È7.45 (m, 6 Ar-H), 7.64È7.70 (m, 4

Ðed by Ñash chromatography (4 cm, petroleum ether, fractions

12, 11

2

Ar-H). C

H

SiO (420.7) calcd. C 79.94, H 9.58; found C

4È6). The title compound (3.48 g, 99%) was obtained as a

28 40

79.85, H 9.45.

colorless liquid. 1H NMR (300 MHz): d \ 0.88 (t, J

16, 15

6.8, 16-H ), 1.24È1.38 (m, 6-H to 15-H ), 2.02 (br td, J

\

3

2

5, 6

11-Dodecyn-1-ol (4437). Li (391 mg, 56.3 mmol, 6.0 equiv.)

was added in small pieces to 1,2-diaminopropane (40 ml).

After 10 min the deep-blue solution was heated under reÑux

until the blue color disappeared. After cooling the mixture to

room temperature KOBut (4.21 g, 37.6 mmol, 4.0 equiv.) was

added. The olive-brown suspension was stirred for 30 min and

the alkyne 40 (1.71 g, 9.39 mmol) was added. After 1 h ice

water was added and the mixture was extracted with ButOMe

(3 ] 100 ml). The combined organic phases were dried and the

solvent was removed. The isolated residue was puriÐed by

Ñash chromatography (4 cm, petroleum etherÈButOMe

3 : 1 ] fraction 8, 2 : 1 ] fraction 12, fractions 5È11). Alkynol

44 (1.266 g, 74%) was isolated as a white solid (mp 25 ¡C). 1H

NMR (300 MHz): d \ 1.24È1.45 (m, 3-H to 8-H ), 1.46È1.62

J

\ 6.9, 5-H ), 2.63 (br td, J \ J \ 7.0, 2-H ), 3.13 (t,

5, 4

1, 2

2

2, 1

\ 7.2, 1-H ), 5.31 (dtt, J \ 10.9, J \ 7.2, J \ 1.5,

cis vic allyl

2, 3

2

4-H*), 5.53 (dtt, J \ 10.6, J \ 7.5, J \ 1.5, 3-H*); *as-

cis

vic

allyl

signments interchangeable. IR (neat): l \ 3010, 2925, 2850,

1695, 1460, 1375, 1300, 1240, 1170, 970, 720 cm~1. C

H

I

16 31

(350.3) calcd. C 54.86, H 8.92; found C 54.97, H 8.99.

Z,Z-1-Iodo-1,5-octadecadiene (51). Iodide 50 (6.20 g, 17.7

mmol) was dissolved in Et OÈhexane (1 : 1, 40 ml), and at

2

[20 ¡C ButLi (1.52 M in Et O, 23.3 ml, 35.4 mmol, 2.0 equiv.)

was added. After 30 min the resulting solution was transferred

to a [35 ¡C suspension of CuI (1.68 g, 8.85 mmol, 0.5 equiv.)

in Et O (20 ml). The dark-grey suspension was stirred for

2

another 30 min at [35 ¡C. At [50 ¡C acetylene (425 ml, 17.7

2

(m, 2-H , 9-H ), 1.94 (t, 4J

\ 2.7, 12-H), 2.18 (td, J

\

mmol, 1.0 equiv.) was introduced. The mixture was allowed to

2

12, 10

10, 9

7.0, 4J

\ 2.6, 10-H ), 3.64 (t, J \ 6.8, 1-H ); the reso-

nance of the OH was not detected. 13C NMR (50.3 MHz,

APT): d \ 18.36, 25.69, 28.44, 28.70, 29.05, 29.37, 29.49 and

32.74 (C-2-C-9), 62.97 (C-1), 68.02 (C-12), 84.73 (C-11). IR

warm to [25 ¡C and stirred again for 1 h. At [60 ¡C pow-

10, 12

2

1, 2

2

dered I (4.49 g, 17.7 mmol, 1.0 equiv.) was added to the

2

greenish-black suspension. The reaction mixture was warmed

to [10 ¡C within 2 h and hydrolyzed thereafter at the same

New J. Chem., 2001, 25, 40È54

51

View Article Online

temperature with water (10 ml) and sat. NH Cl solution (10

ml). After separation from insoluble material by Ðltration the

Ðltrate was extracted with petroleum ether (100 ml). The

unsaturated ester 56 (11.1 g, 22.4 mmol) were added to a 1 : 1

4

mixture of ButOH and H O (110 ml each). This mixture was

2

stirred for 4 days. The reaction was worked up by the addition

organic phase was washed with diluted NH solution (10 ml)

of aqueous Na SO solution (100 ml). After extraction with

3

2

3

and Na S O solution (0.5 M, 10 ml). The now colorless solu-

EtOAc (3 ] 200 ml) the organic extracts were dried over

2 2

3

tion was dried and the solvent removed. Flash chromato-

graphy (6 cm, petroleum ether, fractions 4È6) yielded the title

iodide (4.41 g, 66%) as a colorless liquid. 1H NMR (300 MHz,

C D ; in CDCl the oleÐnic signals superimpose each other):

Na SO . Removal of the solvent yielded a residue that was

2

4

puriÐed by Ñash chromatography (6 cm, petroleum etherÈ

ButOMe 3 : 1 ] fraction 8, 1 : 1 ] fraction 18, 1 : 2 ] fraction

50, fractions 5È24) to yield 55 (7.56 g, 68%) as a colorless

6

3

d \ 0.92 (t, J

\ 6.4, 18-H ), 1.29È1.38 (m, 8-H to 17-H ),

liquid. [a]25 \ [17.9 (c \ 0.84). The R-Mosher ester of 55

18, 17

3

2

D

1.96È2.16 (m, 3-H , 4-H , 7-H ), AB signal (d \ 5.35, d \

revealed ee \ 97% by

d

\ 3.48 vs.

d

in the

2

A

B

MeO

5.45, J \ 10.9, A branch split by J \ 7.0, B branch split

AB vic

by J \ 7.2, 5-H, 6-H), 5.80 (td, J B J B 6.8, 2-H), 5.92

vic 2, 3 cis

(br d, J \ 7.5, 1-H). 13C NMR (50.3 MHz, APT, CDCl ):

diastereomer \ 3.54. 1H NMR (300 MHz, contains 11 wt.%

ButOMe): d \ 1.05 (s, ButSi), 1.22È1.60 (m, 2@-H to 9@-H ),

2

1.65È1.92 (m, 1@-H ), 2.11 (d, J

\ 4.5, OH), AB signal

cis

3

2

OH, 4

d \ 14.15 (C-18), 22.72, 25.65, 27.29, 29.34, 29.39, 29.60, 29.70

(3-fold intensity), 31.96 and 34.83 (C-3, C-4, C-7 to C-17),

82.56 (C-1), 127.99, 131.20 and 140.70 (C-2, C-5, C-6). IR

(neat): l \ 3005, 2925, 2850, 1610, 1460, 1285, 1240, 720

(d \ 2.54, d \ 2.78, J \ 17.7, split by J \ 5.3, 3-H ),

A

B

AB

B, 4

2

3.65 (t,

J

\ 6.6, 10@-H ), 4.35 (ddd,

J

\ 8.8,

10{, 9{

2

5, 1{vH(1)

\ 5.7, J \ 3.6, 5-H), 4.46 (ddd, J

B J

4, 5

B

5, 1{vH(2)

4, OH

5, 4

4, 3vH(B)

B 4.5, 4-H), 7.34È7.45 (m, 6 Ar-H), 7.64È7.70 (m, 4

cm~1. C

H 8.69.

H

I (376.4) calcd. C 57.44, H 8.84; found C 57.27,

Ar-H). IR (neat): l \ 3435, 3070, 2930, 2855, 1765, 1465, 1430,

1390, 1360, 1200, 1170, 1110, 1015, 825, 740, 705, 610 cm~1.

18 33

C

9.33.

H

SiO (496.8) calcd. C 72.53, H 8.96; found C 72.30, H

30 44

4

12-(tert-Butyldiphenylsiloxy)-1-dodecanol (53). At room tem-

perature imidazole (10.2 g, 150 mmol, 2.0 equiv.) and

ButPh SiCl (19.3 ml, 20.6 g, 75.0 mmol, 1.0 equiv.) were added

Methyl E-14-(tert-butyldiphenylsiloxyl)-3-tetradecenoate

2

to a solution of 1,12-dodecanediol (15.2 g, 75.0 mmol) in DMF

(56). A mixture of aldehyde 54 (15.0 g, 34.2 mmol), mono-

(150 ml). After 15 h the reaction was terminated by the addi-

tion of water (100 ml) and EtOAc (100 ml). After extraction of

the aqueous phase with EtOAc (3 ] 200 ml) the combined

organic phases were washed with water (50 ml) and dried over

methylmalonate (4.44 g, 37.6 mmol, 1.1 equiv.) and NEt (5.20

3

ml, 3.80 g, 37.6 mmol, 1.1 equiv.) was heated at 90 ¡C over-

night. After the addition of ice (100 ml), diluted HCl (2 M, 40

ml) and ButOMe (100 ml) the organic phase was separated

MgSO . After removal of the solvent the residue was puriÐed

and dried over MgSO . After removal of the solvent the

4

by Ñash chromatography (8 cm, petroleum etherÈButOMe

residue was puriÐed by Ñash chromatography (6 cm, pet-

20 : 1 ] fraction 15, 10 : 1 ] fraction 25, 5 : 1 ] fraction 40,

2 : 1 ] fraction 52, fractions 22È46) to yield the title com-

pound (19.60 g, 59%). 1H NMR (300 MHz): d \ 1.05 (s,

ButSi), 1.22È1.40 (m, 3-H to 10-H ), 1.50È1.61 (m, 2-H , 11-

roleum etherÈButOMe 50 : 1 ] fraction 7, 20 : 1 ] fraction 15,

fractions 7È13) to give the title compound (11.15 g, 66%). 1H

NMR [300 MHz; contains 6 mol.% methyl trans-14-(tert-

butyldiphenylsiloxy)-2-dodecenoate as determined from the

2

H ), 3.63 (t, J \ 6.6, 1-H ),* in part superimposed by 3.65

integral intensity of its CO Me group at d \ 3.72]: d \ 1.05

2

1, 2

2

(t, J

\ 6.4, 12-H ),* 7.34È7.44 (m, 6 Ar-H), 7.64È7.70 (m,

(s, ButSi), 1.20È1.40 (m, 6-H to 12-H ), 1.55 (tt, J

B

12, 11

2

13, 14

4 Ar-H); *assignments interchangeable. IR (neat): l \ 3340,

J

B 6.9, 13-H ), 2.02 (dt, J B J B 6.4, 5-H ), 3.03 (d,

13, 12

2

5, 4

5, 6

2

3070, 2930, 2855, 1465, 1430, 1390, 1360, 1190, 1110, 825, 740,

\ 5.3, 2-H ), 3.65 (t, J

\ 6.4, 14-H ), in part super-

2, 3

2

14, 13

2

705 cm~1. C

H

O Si (440.7) calcd. C 76.30, H 10.06; found

imposed by 3.68 (s, OMe), extreme AB signal with additional

28 40

2

C 76.39, H 9.91.

peaks indicating transition to higher order signal (d \ 5.50,

A

d \ 5.57, J \ 15.5, split by J \ 5.6,* J \ 5.6,* 3-H,

12-(tert-Butyldiphenylsiloxy)dodecanal (54). At [78 ¡C

DMSO (6.72 ml, 7.39 g, 94.8 mmol, 2.2 equiv.) was added

dropwise to a solution of oxalylic chloride (4.15 ml, 6.02 g,

47.4 mmol, 1.1 equiv.) in CH Cl (120 ml). After 3 min alcohol

B

AB

A, 2

B, 5

4-H; *assignments of coupling partners interchangeable),

7.34È7.44 (m, 6 Ar-H), 7.64È7.70 (m, 4 Ar-H). IR (neat):

l \ 3050, 2930, 2855, 1740, 1465, 1430, 1390, 1360, 1255, 1165,

2

1110, 970, 825, 740, 705, 610 cm~1.( C

H

SiO (494.8) calcd.

53 (19.0 g, 43.1 mmol) in CH Cl (10 ml) was added. After

31 46

3

2

C 75.25, H 9.37; found C 75.41, H 9.51.

stirring for 1 h at [40 ¡C NEt (29.9 ml, 21.8 g, 216 mmol, 5.0

equiv.) was added. Within 1 h the mixture was allowed to

3

(3S,4S)-14-(tert-Butyldiphenylsiloxy)-1,3,4-tetradecanetriol

(57). At [78 ¡C a solution of hydroxylactone 55 (5.67 g, 11.4

mmol) in THF (25 ml) was slowly added to a suspension of

warm to 0 ¡C and water (150 ml) was added. The organic

phase was separated, washed with HCl (2 M, 100 ml) and

NaHCO solution (10 ml) and dried over MgSO . After

3

4

LiAlH (433 mg, 11.4 mmol, 1.0 equiv.) in THF (25 ml). The

removal of the solvent the residue was puriÐed by Ñash chro-

matography (8 cm, petroleum etherÈButOMe 15 : 1, fractions

7È12) to yield the title compound (15.43 g, 83%). 1H NMR

(300 MHz, contains traces of petroleum ether): d \ 1.05 (s,

ButSi), 1.23È1.38 (m, 4-H to 10-H ), 1.55 (m , 3-H ),* in part

4

reaction mixture was warmed to room temperature and after

30 min hydrolyzed with diluted H SO (3 wt.%, 40 ml). The

2

4

mixture was extracted with EtOAc (4 ] 100 ml). The com-

bined organic extracts were thoroughly dried over Na SO .

After removal of the solvent the title compound (5.59 g, 98%)

2

4

2

c

2

superimposed by 1.63 (m , 11-H ),* 2.41 (td, J \ 7.4,

c

2

2, 3

was obtained as a colorless liquid. [a]25 \ [4.4 (c \ 0.45). 1H

J

\ 1.9, 2-H ), 3.65 (t, J

\ 6.6, 12-H ), 7.34È7.44 (m, 6

D

NMR (300 MHz): d \ 1.05 (s, But), 1.20È1.38 (m, 6-H to 12-

2

2, 1

2

12, 11

2

Ar-H), 7.64È7.70 (m, 4 Ar-H), 9.76 (t, J \ 1.9, 1-H); *as-

1, 2

H ), 1.39È1.58 (m, 5-H , 13-H ), 1.68È1.83 (m, 2-H ), ca. 2.80

signments interchangeable. IR (neat): l \ 3070, 2930, 2855,

2

(very br s, 2 ] OH), ca. 3.30 (very br s, 1 ] OH), 3.45 (m ,

1710, 1465, 1430, 1390, 1360, 1185, 1110, 825, 740, 705, 615

c

4-H), 3.65 (t, J

\ 6.6, 14-H ), superimposed by ca. 3.68

cm~1. C

H

O Si (438.7) calcd. C 76.65, H 9.65; found C

14, 13

2

28 42

2

(m , 3-H), 3.86 (m , 1-H ), 7.33È7.44 (m, 6 Ar-H), 7.64È7.70

76.51, H 9.69.

c

2

(m, 4 Ar-H). The HÈCÈO signals in the 1H NMR spectrum

were assigned as in the related compound (3S,4S)-14-(tert-

butyldimethylsiloxy)-1,3,4-tetradecanetriol in which the corre-

ponding signals are less superimposed. IR (neat): l \ 3380,

3070, 2930, 2855, 1465, 1430, 1390, 1110, 825, 740, 705 cm~1.

(4S,5S)-5-[10-(tert-Butyldiphenylsiloxy)decyl]-4,5-

dihydro-4-hydroxy-2(3H)-furanone (55). At 0 ¡C K Fe(CN)

3

6

(22.1 g, 67.3 mmol, 3.0 equiv.), K CO (9.29 g, 67.3 mmol, 3.0

2

3

equiv.), (DHQ) PHAL (174 mg, 0.224 mmol, 1.0 mol.%),

2

K OsO

(17 mg, 0.045 mmol, 0.2 mol.%), meth-

C

H

SiO (500.8) calcd. C 71.95, H 9.66; found C 71.72, H

2

4

30 48

4

anesulfoneamide (2.13 g, 22.4 mmol, 1.0 equiv.) and the

9.86.

52

New J. Chem., 2001, 25, 40È54

View Article Online

(4ºS,5ºS)-2-{5-[10-(tert-Butyldiphenylsiloxy)decyl]- 2,2-

dimethyl-1,3-dioxolan-4-yl}ethanol (58). Triol 57 (3.10 g, 6.20

mmol) was dissolved in acetone (25 ml); 2,2-dimethoxyprop-

ane (6.12 ml, 5.20 g, 50.0 mmol, 8.0 equiv.) and Amberlyst 15

ion exchange resin (120 mg) were added. After stirring the

mixture for 2 h at room temperature the resin was removed by

Ðltration and the solvent evaporated. The residue obtained

was used in the next reaction without further puriÐcation.

Ñash chromatography (2.5 cm, petroleum etherÈButOMe

100 : 1, fractions 6È14) yielded the title compound (123 mg,

64%). [a]25 \ [7.4 (c \ 0.64). 1H NMR (300 MHz): d \ 0.88

D

(t, J

\ 6.6, 20@-H ), 1.05 (s, But), 1.24È1.38 (m, 10@-H to

20{, 19{

3

2

19@-H , 2@-H to 8A-H ), 1.39 [br s, 2-(CH ) ], 1.47È1.60 (m,

3 2

B 6.3, 9@-H ), in

2

1@-H , 1A-H , 9A-H ), 2.02 (td, J

9{, 10{

part superimposed by 2.10 (m , 5@-H , 6@-H ), in part superim-

B J

2

9{, 8{

2

c

2

posed by 2.14È2.26 (m, 2@-H ), 3.61 (m , 4-H, 5-H), in part

2

c

[a]25 \ [12 (c \ 0.81). 1H NMR (500 MHz): d \ 1.05 (s,

superimposed by 3.65 (t, J

\ 6.4, 10A-H ), 5.30È5.46 (m,

D

10_, 9_

2

But), 1.24È1.38 (m, 2A-H to 8A-H ), 1.40 [s, C(Me) ], 1.45È1.59

3@-H, 4@-H, 7@-H, 8@-H), 7.34È7.46 (m, 6 Ar-H), 7.65È7.70 (m, 4

2

(m, 1@-H , 9A-H ), AB signal (d \ 1.74, d \ 1.84, J \ 14.4,

split by J

5.6,* J

OH), 3.65 (t, J

Ar-H). IR (neat): l \ 3050, 2925, 2855, 1465, 1430, 1370, 1240,

2

A

B

AB

\ 9.0, J

\ 6.6, J

\ 5.2, J

\

1110, 825, 740, 705 cm~1. C

H

SiO (773.3) calcd. C 79.21,

A, 4{

A, 1vH(1)

A, 1vH(2)

B, 1vH(1)

51 84

3

\ 5.2,* J

\ 3.2, 2-H ), 2.41 (br t, J

\ 6.5, 10A-H ), superimposed by 3.68

\ 4.7,

H 11.95; found C 79.73, H 11.94.

B, 1vH(2)

B, 4{

2

OH, 1

10_, 9_

2

5{, 4{

(probably interpretable as ddd, J

\ 8.3, J

\ 7.1,

\ 8.6,

(4ºS,5ºS)-Z,Z-10-[5-(3,7-Eicosadienyl)-2,2-dimethyl-1,3-

dioxolan-4-yl]-1-decanol (62). At room temperature silylether

61 (1.64 g, 2.12 mmol) in THF (20 ml) was treated with

5{, 1_vH(1)

J

\ 4.2, 5@-H**), 3.77 (ddd, J

\ J

5{, 1_vH(2)

4{, 2vH(B)

4{, 5{

4{, 2vH(A)

\ 3.0, 4@-H), 3.83 (br td, J B J

B 5.2, 1-H ),

1, 2

1, OH

2

7.36È7.45 (m, 6 Ar-H), 7.66È7.70 (m, 4 Ar-H); *assignments

interchangeable; **analysis of the coupling constants perfor-

med as in (4@S,5@S)-2-M5-[10-(tert-butyldimethylsiloxy)decyl]-

2,2-dimethyl-1,3-dioxolan-4-ylNethanol where the 5-H signal

Bu NF (1.0 M in THF, 2.55 ml, 2.55 mmol, 1.2 equiv.). Stir-

4

ring was continued for 20 h. After hydrolysis with water (20

ml) the aqueous phase was extracted with ButOMe (3 ] 50

ml). The organic phases were dried over MgSO and the

4

and the 10A-H signal do not coincide. IR (neat): l \ 3425,

3070, 2930, 2855, 1465, 1430, 1375, 1240, 1110, 875, 825, 740,

solvent was evaporated. Flash chromatography (3 cm, pet-

2

roleum etherÈButOMe 10 : 1 ] fraction 12, 2 : 1 ] fraction 30,

705 cm~1. C

H

SiO (540.9) calcd. C 73.28, H 9.69; found C

fractions 17È26) yielded 62 (1.133 g, 99%). [a]25 \ [9.33

33 52

4

D

73.34, H 9.98.

(c \ 1.20). 1H NMR (300 MHz, slightly contaminated around

d \ 0.9): d \ 0.88 (t, J

\ 6.5, 20A-H ), 1.24Èca. 1.38 (m,

20_, 19_

3

(4S,5S)-4-[10-(tert-Butyldiphenylsiloxy)decyl]-2,2-

10A-H to 19A-H , 3-H to 9-H ), 1.38 [s, 2@-(CH ) ], 1.45È

2

3 2

dimethyl-5-(2-iodoethyl)-1,3-dioxolane (59). At 0 ¡C PPh (1.62

1.62 (m, 2-H , 10-H , 1A-H ), 2.02 (td, J

B J

B 6.4,

3

2

9_, 10_

9_, 8_

g, 6.20 mmol, 1.0 equiv.), imidazole (843 mg, 12.4 mmol, 2.0

9A-H ), in part superimposed by 2.10 (m , 5A-H , 6A-H ), in

2

c

2

equiv.) and I (1.58 g, 6.20 mmol, 1.0 equiv.) were added to a

part superimposed by 2.13È2.26 (m, 2A-H ), 3.60 (m , 4@-H,

2

c

solution of alcohol 58 (crude product from 3.10 g of triol 57,

5@-H), in part superimposed by 3.64 (t, J \ 6.6, 1-H ), 5.30È

1, 2

2

6.20 mmol) in THF (50 ml). The reaction mixture was allowed

to warm to room temperature within 15 min. Water (100 ml)

was added, the organic phase separated and the aqueous

phase extracted with ButOMe (100 ml). The combined organic

5.46 (m, 3A-H, 4A-H, 7A-H, 8A-H). IR (neat): l \ 3360, 2925,

2855, 1460, 1375, 1240, 1170, 1090, 1060, 875, 725 cm~1.

C

H

O (534.9) calcd. C 78.59, H 12.44; found C 78.71, H

35 66

3

12.52.

phases were dried over MgSO and the solvent was removed.

4

The residue was puriÐed by Ñash chromatography (4 cm,

(11S,12S)-Z,Z-1-Iodo-15,19-dotriacontadien-11,12-diol

(63). HCl (12 M, 10 ll, 0.10 mmol, 4.0 equiv.) was added to a

solution of the acetonide 5 (30.0 mg, 0.0466 mmol) and the

butenolide 26 (40.0 mg, 0.260 mmol) in MeOHÈCH Cl (5 : 1,

deactivated silica, petroleum etherÈButOMe 50 : 1, fractions

3È10). The title compound (3.814 g, 94% over the two steps

from triol 57) was obtained as a colorless liquid. [a]25 \

D

[20.0 (c \ 1.09). 1H NMR (500 MHz): d \ 1.05 (s, But), 1.23È

2

0.6 ml) and the mixture was stirred for 24 h at room tem-

perature. Water (2 ml) was added and the organic phase

extracted with ButOMe (3 ] 10 ml). The combined organic

phases were dried over Na SO and the solvent was removed.

1.38 (m, 2@-H to 8@-H ), 1.37 and 1.39 [2 s, C(Me) ], 1.42È1.58

2

(m, 1@-H , 9@-H ), AB signal (d \ 2.03, d \ 2.08, J \ 14.3,

2

A

B

AB

split by J \ J

\ 8.3, J

\ 5.3, J

\

A, 4

A, 2_vH(A)

A, 2_vH(B)

B, 2_vH(B)

J

3.34,

\ 8.3, J \ 3.0, 1A-H ), AB signal (d \ 3.24, d \

2

4

B, 2_vH(A)

B, 4

2

A

B

The residue was puriÐed by Ñash chromatography (2.5 cm,

petroleum etherÈButOMe 10 : 1 ] fraction 12, 5 : 1 ] fraction

18, 2.5 : 1 ] fraction 34). The unconsumed butenolide 26

Mfractions 10È15, 30.6 mg, 76%; [a]25 \ [48.4 (CHCl ,

J

\ 9.6, split by

J

\ J

\ 8.0,

AB

A, 1_vH(A)

2

A, 1_vH(B)

J

\ 7.3, J

\ 5.1, 2A-H ), 3.66 (t, J

\ 6.7,

B, 1_vH(B)

B, 1_vH(A)

10{, 9{

10@-H ), completely superimposed by (m , 4-H, 5-H), 7.36È7.45

2

c

(m, 6 Ar-H), 7.66È7.70 (m, 4 Ar-H); *assignments and analysis

of coupling constants as in the 1H NMR spectrum of the

alcohol precursor 58. 13C NMR (50.3 MHz, APT): 1.87 (C-2A),

D

3

c \ 0.8)N and the title compound (fractions 28È34, 14.1 mg,

50%) were obtained as colorless liquids. 1H NMR (300 MHz):

d \ 0.88 (t, J

\ 6.8, 32-H ), 1.24Èca. 1.43 (m, 3-H to

9-H , 22-H to 31-H ), ca. 1.45È1.60 (m, 10-H , 13-H ), 1.82

19.22 [C(CH ) ], 25.76, 26.03, 29.35, 29.50 (2-fold intensity),

32, 31

3

2

3 3

29.57, 29.73, 32.58, 32.78 and 37.45 (C1@ to C-9@ C-1A), 26.87

2

(tt, J \ J \ 7.1, 2-H ), 2.02 (br td, J

2, 1 2, 3 21, 22

B J

B 6.5,

[C(CH ) ], 27.23 and 27.30 (2 ] Me), 63.98 (C-10@), 80.32 and

2

21, 20

3 3

21-H ), in part superimposed by 2.11 (m , 17-H , 18-H ), in

80.57 (C-4, C-5), 108.31 (C-2), 127.52, 129.42 and 135.52 (4

2

c

2

1, 2

part superimposed by ca. 2.14È2.25 (m, 14-H ), 3.19 (t, J

\

ortho, 4 meta and 2 para C), 134.12 (2 ipso C). IR (neat):

2

7.0, 1-H ), 3.36È3.47 (m, 11-H, 12-H), 5.30È5.47 (m, 15-H,

16-H, 19-H, 20-H). No combustion analysis was performed.

l \ 3070, 2930, 2855, 1465, 1430, 1375, 1235, 1175, 1110, 825,

2

740, 705 cm~1. C

H

SiO I (650.8) calcd. C 60.91, H 7.90;

33 51

3

found C 61.09, H 7.79.

(4S,5S)-Z,Z-4-[10-(tert-Butyldiphenylsiloxy)decyl]-5-(3,7-

eicosadienyl)-2,2-dimethyl-1,3-dioxolane (61). Vinyl iodide 51

Acknowledgements

(94.0 mg, 0.250 mmol) was dissolved in Et O (1 ml) and ButLi

We are grateful to Magali SlozsekÈPinaud [Laboratoire de

Pharmocognosie, (CNRS URA 1843 BIOCIS), Faculte de

Pharmacie, Chatenay-Malabry, France] for her participation

in the exploratory phase of this work and to the European

Union for Ðnancing her stay through a stipend of the

ERASMUS Program. Moreover, we are indebted to the

Metallgesellschaft GmbH (Langelsheim) and BASF AG

(Ludwigshafen) for donating chemicals.

2

(1.52 M in Et O, 0.36 ml, 0.55 mmol, 2.2 equiv.) was added at

2

[50 ¡C. After 30 min alkyl iodide 59 (163 mg, 0.250 mmol, 1.0

equiv.) in THF (1 ml) was added. The mixture was warmed to

room temperature and stirred for another 4 h. The reaction

was terminated by the addition of HCl (1 M, 2 ml). After

extraction with ButOMe (2 ] 20 ml) the combined organic

phases were dried over MgSO . After removal of the solvent

4

New J. Chem., 2001, 25, 40È54

53

View Article Online

23 Procedure: R. H. Bradbury and K. A. M. Walker, J. Org. Chem.,

1983, 48, 1741.

References and notes

24 Procedure: D. Savoia, E. Tagliavini, C. Trombini and A. UmaniÈ

Ronchi, J. Org. Chem., 1981, 46, 5340.

1

J. K. Rupprecht, Y.-H. Hui and J. L. McLaughlin, J. Nat. Prod.,

1990, 53, 237; X.-P. Fang, M. J. Rieser, Z. M. Gu, G. X. Zhao

and J. L. McLaughlin, Phytochem. Anal., 1993, 4, 27 and 49; A.

Cave, B. Figadere, A. Laurens and D. Cortes, Prog. Chem. Nat.

Prod., 1997, 70, 81; F. Q. Alali, X.-X. Liu and J. L. McLaughlin,

J. Nat. Prod., 1999, 62, 504.

(a) B. Figadere, Acc. Chem. Res., 1995, 28, 359; (b) U. Koert, Syn-

thesis, 1995, 115; (c) R. Hoppe and H.-D. Scharf, Synthesis, 1995,

1447; (d) G. Casiraghi, F. Zanardi, L. Battistini, G. Rassu and G.

Appendino, Chemtracts, 1998, 11, 803.

C. Gleye, A. Laurens, R. Hocquemiller, B. Figadere and A. Cave,

T etrahedron L ett., 1996, 37, 9301.

25 This compound was previously described by: E. R. H. Jones, T.

Y. Shen and M. C. Whiting, J. Chem. Soc., 1950, 230.

26 Procedure: L. Brandsma, Preparative Acetylenic Chemistry, Else-

vier, Amsterdam, 1988, pp. 42È43.

27 This compound was previously described by: A. Branner and H.

Budzikiewicz, Org. Mass. Spectrom., 1983, 18, 324.

28 Procedure: E. J. Corey, H. Niwa and J. Knolle, J. Am. Chem.

Soc., 1978, 100, 1942.

29 This compound was previously described by: R. E. Doolittle, D.

G. Patrick and R. H. Heath, J. Org. Chem., 1993, 58, 5063.

30 Method: H. Hayashi, K. Nakanishi, C. Brandon and J. Marmur,

J. Am. Chem. Soc., 1973, 95, 8749.

31 Procedure: U. Berlage, J. Schmidt, U. Petres and P. Welzel,

T etrahedron L ett., 1987, 27, 3091.

2

3

4

C. Gleye, S. Raynaud, R. Hocquemiller, A. Laurens, C. Fourneau,

L. Serani, O. Laprevote, F. Roblot, M. Leboeuf, A. Fournet, A.

R. De Arias, B. Figadere and A. Cave, Phytochemistry, 1998, 47,

749.

32 Procedure: J. Bao, W. D. Wul†, V. Dragisich, S. Wenglowsky

and R. G. Ball, J. Am. Chem. Soc., 1994, 116, 7616.

33 Alkylation of an acetylide with a homopropargyl bromide: ref.

26.

34 Alkylation of an acetylide with a homopropargyl triÑate: ref. 32.

35 This compound was described by: H. B. Henbest, E. R. H. Jones

and I. M. S.Walls, J. Chem. Soc., 1950, 3646.

36 Method: C. A. Brown and A. Yamashita, J. Am. Chem. Soc.,

1975, 97, 891; procedure: S. R. Abrams and A. C. Shaw, Org.

Synth., 1993, VIII, 146.

5

6

C. Gleye, A. Laurens, R. Hocquemiller, A. Cave, O. Laprevote

and L. Serani, J. Org. Chem., 1997, 62, 510.

Reviews: (a) R. A. Johnson and K. B. Sharpless, Asymmetric

Catalysis in Organic Synthesis, ed. I. Ojima, VCH, New York,

1993, pp. 227È272; (b) H. C. Kolb, M. S. VanNieuwenhze and K.

B. Sharpless, Chem. Rev., 1994, 94, 2483.

(a) Z.-M. Wang, X.-L. Zhang, K. B. Sharpless, S. C. Sinha, A.

SinhaÈBagchi and E. Keinan, T etrahedron L ett., 1992, 33, 6407;

(b) Y. Miyazaki, H. Hotta and F. Sato, T etrahedron L ett., 1994,

35, 4389; (c) C. Harcken and R.Bruckner, Angew. Chem., 1997,

109, 2866; Angew. Chem. Int., Ed. Engl., 1997, 36, 2750; (d) C.

Harcken, E. Rank and R. Bruckner, Chem. Eur. J., 1998, 4, 2342

(corrigendum: 2390); (e) T. Berkenbusch and R. Bruckner, T etra-

hedron, 1998, 54, 11461; ( f ) T.Berkenbusch and R. Bruckner,

T etrahedron, 1998, 54, 11471; (g) C. Harcken, T. Berkenbusch, S.

Braukmuller, A. Umland, K. Siegel, F. Gorth, F. von der Ohe

and R. Bruckner, in Current T rends in Organic Synthesis, ed. C.

Scolastico and F. Nicotra, Plenum Press, New York, 1999, pp.

153È161.

Previous preparation of compound 4: S.-Y. Chen and M. M.

Joullie, J. Org. Chem., 1984, 49, 2168. SpeciÐc rotation of 4: C. A.

M. Afonso, M. T. Barros, L. S. Godinho and C. D. Maycock,

T etrahedron, 1993, 49, 4283.

Asymmetric dihydroxylations of disubstituted oleÐns trans-MeÈ

CH2CHÈR showed 72% ee in the case of 2-butene (““unpublished

resultsÏÏ in ref. 6b, 73% ee in the case of 1-phenyl-3-penten-1-yne

(K.-S. Jeong, P. Sjo and K. B. Sharpless, T etrahedron L ett., 1992

33, 3833) and 95% ee in the cases of 1-chloro-2-butene (K. P. M.

Vanhessche, Z.-M. Wang and K. B. Sharpless, ibid, 1994, 35,

3469) or 4,4-dimethyl-2-pentene (““unpublished resultsÏÏ in ref. 6b).

7

37 This compound is known: R. Rossi and A. Carpita, T etrahedron,

1983, 39, 287.

38 A. Alexakis, G. Cahiez and J. F. Normant, T etrahedron, 1980, 36,

1961.

39 This compound was used by: M. Horiike, G. Yuan and C.-S.

Kim, Org. Mass. Spectrom., 1992, 27, 944.

40 W. F. Bailey, R. P. Gagnier and J. J. Patricia, J. Org. Chem., 1984,

49, 2098.

41 Method: A. Alexakis, G. Cahiez and J. F. Normant, J.

Organomet. Chem., 1979, 177, 293.

8

9

42 K. Omura and D. Swern, T etrahedron L ett., 1978, 1651.

43 Method: H. Yamanaka, M. Yokoyama, T. Sakamoto, T. Shi-

raishi, M. Sagi and M. Mizugaki, Heterocycles, 1983, 20, 1541.

44 A. I. Meyers and J. P. Lawson, T etrahedron L ett., 1982, 23, 4883.

45 Ni-catalyzed coupling between alkyl Grignard reagents and

alkenyl iodides: T. Hayashi, M. Konishi, Y. Kobori, M.

Kumada, T. Higuchi and K. Hirotsu, J. Am. Chem. Soc., 1984,

106, 158.

46 Method: G. Linstrumelle, T etrahedron L ett., 1974, 3809.

47 Procedure: U. Berlage, J. Schmidt, U. Petres and P. Welzel,

T etrahedron L ett., 1987, 27, 3091.

48 Method: H.-M.Shieh and G. D. Prestwich, J. Org. Chem., 1981,

46, 4319; T etrahedron L ett., 1982, 23, 4643.

49 Organic synthesis applications of DMPU: D. Seebach, Chimia,

1985, 39, 147; D. Seebach, A. K. Beck and A. Studer, Modern

Synthetic Methods 1995, ed. B. Ernst and C. Leumann, VCH,

Weinheim, 1995, pp. 1È178.

10 Method using NaH or LiHMDS: B. E. Maryano†, A. B. Reitz

and B. A. DuhlÈEmswiler, J. Am. Chem. Soc., 1985, 107, 217;

using NaH: R. Beugelmans, J. Chastanet, H. Ginsburg, L.

QuinteroÈCortes and G. Roussi, J. Org. Chem., 1985, 50, 4933;

using dimsyl-Li: S. R. Baker, D. W. Clissold and A. McKillop,

T etrahedron L ett., 1988, 29, 991; using KOBut: F. Ozaki, M.

Matsukura, Y. Kabasawa, K. Ishibashi and M. Ikemori, Chem.

Pharm. Bull., 1992, 40, 2735.

11 S. Zahr and I. Ugi, Synthesis, 1979, 266.

12 Method: T. Mukaiyama, M. Yamaguchi and J.-i. Kato, Chem.

L ett., 1981, 1505.

13 G. Buechi, M. Cushman and H. Wuest, J. Am. Chem. Soc., 1974,

96, 5563.

14 C. S. Pak, E. Lee and G. H. Lee, J. Org. Chem., 1993, 58, 1523.

15 Procedure: F. Kido, K. Yamaji, S. C. Sinha, T. Abiko and M.

Kato, T etrahedron, 1995, 51, 7697.

16 E. J. Corey, C. U. Kim and M. Takeda, T etrahedron L ett., 1972,

4339.

17 This compound was Ðrst prepared by: J. Tsuji, J. Kiji and S.

Hosaka, T etrahedron L ett., 1964, 605.

18 K. P. M. Vanhessche, Z.-M. Wang and K. B. Sharpless, T etra-

hedron L ett., 1994, 35, 3469.

19 P. Blundell, A. K. Ganguly and V. M. Girijavallabhan, Synlett,

1994, 263.

20 Earlier preparation: J. Mulzer, T. Schulze, A. Strecker and W.

Denzer, J. Org. Chem., 1988, 53, 4098.

21 Earlier preparation: J. Corbera, J. Font, M. Monsalvatje, R. M.

Ortun and F. SanchezÈFerrando, J. Org. Chem., 1988, 53, 4393.

22 P. Duret, B. Figadere, R. Hocquemiller and A. Cave, T etrahedron

L ett., 1997, 38, 8849.

50 Cf. the detailed calculations in Experimental.

51 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.

52 This value is based on the following calculation, wherein [a]25

D

lactone is not the speciÐc rotation of compound S,S-4 but the

““molar contribution of a 100% enantiopure left-hand moiety of

compound 1a to the [a]25 value of 1aÏÏ. Analogously, [[a]25

D

lactone is not the speciÐc rotation of compound R,R-4 but the

““molar contribution of a 100% enantiopure left-hand moiety of

compound 1b to the [a]25 value of 1bÏÏ. Similarly, [a]25 iodide is

D

not the speciÐc rotation of compound 5 but the ““molar contribu-

tion of a 100% enantiopure right-hand moiety of compounds 1a

or 1b to the [a]25 values of 1a or 1b, respectively. One starts from

D

the equation 0.80 ] [a]25 lactone ] 0.97 ] [a]25 iodide \ ]1.9

D

(\[a]25 obtained sample of 1a) and the equation 0.90 ] ([[a]25

D

lactone) ] 0.97 ] [a]25 iodide \ [24.2 (\[a]25 obtained

D

sample of 1b). Separation of the unknowns delivers [a]25

D

lactone \ 15.3 and [a]25 iodide \ [10.6. Inserting these values

D

into the equations 1.00 ] [a]25 lactone ] 1.00 ] [a]25 iodide \

D

[a]25 sterically pure sample of 1a and 1.00 ] ([[a]25) lactone

D

] 1.00 ] [a]25 iodide \ [a]25 sterically pure sample of 1b),

D

respectively, leads to [a]25 sterically pure sample of

D

1a \ 1.00 ] 15.3 ] 1.00 ] ([10.6) \ ]4.7 and to [a]25 sterically

D

pure sample of 1b \ 1.00 ] (]15.3) ] 1.00 ] ([10.6) \ [25.9.

54

New J. Chem., 2001, 25, 40È54

Article Doi

Elucidation of the stereostructure of the annonaceous acetogenin (+)-montecristin through total synthesis

DOI: 10.1039/b002905j

Source and publish data:

Authors:

Article abstract of DOI:10.1039/b002905j

Full text of DOI:10.1039/b002905j

Products guided by the article

R&D Labs maybe for 115093-30-6

Relevant to this article

Hot Product