RuO4-mediated oxidative polycyclization of linear polyenes. A new approach to the synthesis of the bis-THF diol core of antitumour cis-cis adjacent bis-THF annonaceous acetogenins

Tetrahedron 62 (2006) 10989–11007

RuO₄-mediated oxidative polycyclization of linear polyenes.

A new approach to the synthesis of the bis-THF diol core of

antitumour cis–cis adjacent bis-THF annonaceous acetogenins

a

Vincenzo Piccialli,^a,Teresa Caserta, Lucia Caruso,

*

Luigi Gomez-Paloma^band Giuseppe Bifulco^b

^aDipartimento di Chimica Organica e Biochimica, Universitaꢀ degli Studi di Napoli ‘Federico II’, Via Cynthia 4, 80126 Napoli, Italy

^bDipartimento di Scienze Farmaceutiche, Universitaꢀ di Salerno, Via Ponte Don Melillo, 84084 Fisciano (Salerno), Italy

Received 25 November 2005; revised 27 July 2006; accepted 10 August 2006

Available online 18 September 2006

Abstract—The RuO₄-catalyzed oxidative polycyclization of some selected linear polyenes, possessing a repetitive 1,5-diene structural motif,

has been investigated. The all-trans triene (E,E,E)-acetic acid henicosa-2,6,10-trienyl ester gave the expected bis-tetrahydrofuranyl diol prod-

uct possessing a threo-cis-threo-cis-threo relative conﬁguration, along with a mixture of the corresponding bis-THF ketols. These compounds

can be seen as useful intermediates in the synthesis of the bis-THF diol core of adjacent bis-THF antitumour acetogenins possessing a threo-

cis-threo-cis-erythro relative conﬁguration, such as rolliniastatiin-1, membranacin, rollimembrin and membrarollin. Oxidation of the related

all-trans tetraene (E,E,E,E)-acetic acid pentacosa-2,6,10,14-tetraenyl ester stops at the second cyclization step giving a mixture of a threo-cis-

threo-cis-threo bis-THF diol and the corresponding ketol products. Oxidation of the triene (E,Z,E)-acetic acid 12-acetoxy-dodeca-2,6,10-

trienyl ester stops at the monocyclization level failing to give bis-cyclized products, as previously observed for the related isoprenoid triene

(E,Z)-farnesyl acetate. This result conﬁrms the difﬁculty of closing a second THF ring when the central double bond of the triene possesses

a cis conﬁguration. Based on the collected results, a plausible model is proposed that both explains the observed cis/trans stereoselectivity for

each ring-closing step in these processes, and rationalize the stereochemical course of the previously studied polycyclization of the isoprenoid

polyenes (E,E)-farnesyl acetate, geranylgeranyl acetate and squalene.

1. Introduction

OH

O

24

15

4

O

Annonaceous acetogenins (ACGs) are a group of secondary

metabolites isolated from plants of the family Annonaceae

many of which exhibit high cytotoxic and impressive anti-

tumour activities.¹The biological effect of these substances

are attributed to the inhibition of mammalian mitochondrial

NADH-ubiquinone oxidoreductase (complex I), a mem-

brane-bound protein of the mitochondrial electron transport

system,²and to the inhibition of an ubiquinone-linked

NADH oxidase expressed in the plasma membrane of can-

cerous cells but only transiently expressed in the membranes

of ‘normal’ cells.³These mechanisms result in ATP depriva-

tion leading to apoptosis (programmed cell death) in the high

energy demanding malignant cells.⁴

O

OH

Bis-THF diol core

Figure 1. Structural features of some representative adjacent bis-THFACGs

with high antitumour activity. Conﬁguration of the bis-THF diol core

(from C₂₄to C₁₅): asimicin threo–trans–threo–trans–threo; bullatacin

erythro–trans–threo–trans–threo; trilobacin threo–cis–erythro–trans–

threo; rolliniastatin-1 erythro–cis–threo–cis–threo.

A common feature shared by the ACGs possessing the high-

est anticancer activity is the presence of a bis-THF diol

portion: two adjacent THF rings each one ﬂanked by a

hydroxyl-bearing methine group (Fig. 1). This subgroup is

very abundant amounting to more than 40% of all known

metabolites of this type. Representative examples of this

type of ACGs are asimicin, bullatacin, trilobacin and rolli-

niastatin-1, only differing in the conﬁguration of the bis-

THF diol core (Fig. 1); all these substances have shown

an in vitro antitumour potency 10⁸times higher than that

exhibited by adriamycin.⁵

From a structural point of view, they are mostly made up of

a mono- or bis-THF core ﬂanked by two long alkyl chains,

one of which ending with an a,b-unsaturated g-lactone ring,

usually carrying hydroxyl groups along their length (Fig. 1).

Keywords: RuO₄; Oxidative polycyclization; Linear polyenes; cis–cis

Adjacent bis-THF annonaceous acetogenins.

The selectivity shown towards diverse human tumour cell

lines,¹including those that exhibit multidrug resistance

* Corresponding author. Tel.: +39 81 674111; fax: +39 81 674393; e-mail:

vinpicci@unina.it

doi:10.1016/j.tet.2006.08.038

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V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

(MDR),⁶as well as their ability to only modestly affect the

normal human cells growth,⁶has prompted many research

groups to undertake the total synthesis of these substances

or to search for suitable analogues to be tested in SAR

studies.⁷

collected for all the previously studied OP, it was also ex-

pected that this product would possess an all-threo arrange-

ment (Scheme 2). In this paper we report on our studies

towards this goal.

threo

Only few adjacent bis-THF ACGs have been isolated that

possess an erythro–cis–threo–cis–threo relative conﬁg-

uration, for example, rolliniastatin-1, rollimembrin, mem-

brarollin, membranacin; however, they are among the most

effective substances of this type. Compared to other annona-

ceous acetogenins, which are popular targets for total synthe-

sis, there has been limited synthetic activity towards these

substances possibly due to the challenges posed by the

erythro–cis–threo–cis–threo relative conﬁguration of their

bis-THF diol portion.

R'

R

R'

RuO₄

O

cis

O

cis

R

Oxidative

bis-cyclization

OH

Scheme 2. Expected bis-THF diol product from the RuO₄-catalyzed

bis-cyclization of an all-trans 1,5,9-triene.

2. Results and discussion

In order to probe the above hypothesis, (E,E,E)-acetic acid

henicosa-2,6,10-trienyl ester (7) was synthesized as de-

scribed in the literature for the C₂₁alcohol analogue,¹⁰start-

ing from undecanal (Scheme 3). Cyclization of triene 7

would have allowed to access a threo–cis–threo–cis–threo

bis-THF diol product possessing a C₁₀saturated alkyl chain

(Scheme 2: R¼C₁₀H₂₁; R⁰¼CH₂OAc) characterizing rolli-

niastatin-1-type ACGs.

Recently, we have discovered a novel oxidative polycycliza-

tion (OP) process involving catalytic amounts of RuO₄that

allows to obtain, in a single step, all-threo adjacently linked

poly-tetrahydrofuran diol (poly-THF diol) compounds start-

ing from isoprenoid polyenes characterized by a repetitive

1,5-diene structural motif such as (E,E)-farnesyl acetate

[(E,E)-FA], geranylgeranyl acetate (GGA) and squalene

(Scheme 1).⁸

In particular, Grignard reaction of undecanal with vinylmag-

nesium bromide followed by ortho ester Claisen–Johnson

rearrangement of the obtained allylic alcohol allowed elon-

gation of a four-carbon fragment and concomitant stereo-

selective formation of the ﬁrst trans double bond to give

monounsaturated ester 4. Conversion of 4 to the double

unsaturated ester 5 was accomplished in four steps: transfor-

mation of 4 to the corresponding aldehyde (LAH reduction

followed by PCC oxidation) followed by the two-step

sequence used for the conversion of undecanal into 4.

Then, conversion of 5 into the corresponding aldehyde, as

above seen for 4, followed by Wittig–Horner oleﬁnation with

triethyl phosphonoacetate gave the all-trans triple unsatu-

rated ester 6. Dibal-H reduction of this one followed by

acetylation yielded the required triene 7.

We reasoned that this process could be usefully employed

for the synthesis of the bis-THF diol core of the aforemen-

tioned cis–cis adjacent bis-THFACGs provided that it could

work well for the OP of linear 1,5,9-trienes as well. In par-

ticular, based on the stereochemical course of the ﬁrst two

ring-forming steps in the OP of the above-cited isoprenoid

polyenes (a cis–cis bis-THF sequence is obtained in all

cases; see Scheme 1),⁸as well as the cis-stereoselectivity

of the THF-forming step in the RuO₄-mediated oxidative

monocyclization of linear 1,5-dienes,⁹it was expected that

a cis,cis adjacent bis-THF diol product would have been ob-

tained from an all-trans 1,5,9-triene. In addition, according

to the mechanistic hypothesis previously formulated for

these cyclizations (syn addition of oxygen across each

double bond), substantiated by stereochemical evidence

OAc

[from (E,E)- FA]

O

cis

O

cis

OH

H

OH

OAc

1

n

OAc

n=1 (E,E)-Farnesyl acetate [(E,E)]-FA

(from GGA)

n=2 Geranylgeranyl acetate (GGA)

O

OH

H

trans

HO

cis

2

O

cis

O

OH

H

trans trans

H

trans

HO

cis

Squalene

3

Scheme 1. Summary of the RuO₄-catalyzed polycyclization of some isoprenoid polyenes. Reagents and conditions: (E,E)-FA: RuO₂$2H₂O (20 mol %), NaIO₄

(4 equiv), CH₃CN–EtOAc–H₂O (3:3:1), 0 ^ꢀC, 30 min. GGA and squalene: as for (E,E)-FA but NaIO₄5 equiv and 8 equiv, respectively.

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

10991

O

c-e

a-b

CO₂Et

H

H₂₁C₁₀

63% (2 steps)

H₂₁C₁₀

35% (4 steps)

5

4

f-g

56% (3 steps)

CO₂Et

OAc

h-i

69% (2 steps)

H₂₁C₁₀

7

6

Scheme 3. Synthesis of (E,E,E)-acetic acid henicosa-2,6,10-trienyl ester (7). Reagents and conditions: (a) vinylmagnesium bromide, THF, 0 ^ꢀC; (b) triethyl

orthoacetate, propyonic acid (2%), xylene, reﬂux; (c) LiAlH₄, Et₂O, 0 ^ꢀC/rt; (d) PCC, Celite, CH₂Cl₂, rt; (e) same as for sequence a–b; (f) same as for

sequence c–d; (g) (EtO)₂P(O)CH₂CO₂Et, NaH, THF, ꢁ78 ^ꢀC/rt; (h) DIBAL-H, THF, ꢁ78 ^ꢀC; (i) Ac₂O-py, rt.

Oxidation of 7 under the standard conditions previously set

up for (E,E)-FA^8a(Scheme 4), followed by HPLC separation

of the reaction mixture, gave diol 8 as the main bis-THF prod-

uct (24%) along with the corresponding isomeric bis-THF

ketols 9 and 10 (together 23%). The overall 47% yield is not

too far from that obtained for (E,E)-FA (56%) in the same

conditions;^8athe slightly less yield probably reﬂects the efﬁ-

ciency of the ﬁrst THF-closing step, in agreement with the

difference in the yields previously observed for the monocyc-

lizations of alkylsubstituted 1,5-dienes, such as geranyl ace-

tate,^9b,9cand linear 1,5-dienes,¹¹with RuO₄. The structural

relationship among the three bicyclic products 8–10 was proven

by oxidation of 8to a mixture of 9 and 10 with TPAP_(cat.)/NMO.

In an attempt to further increase the yield of the process the

effect of ruthenium dioxide and periodate amounts was eval-

uated (Scheme 5). The increase of the amount of RuO₄, up to

one equivalent, had no signiﬁcant effect on the overall yield

of the process and the HPLC proﬁle of the bis-cyclization

products. On the other hand, as observed for the oxidation

of isoprenoid analogues,⁸reduction of the amount of the

co-oxidant (from 4 to 2.5 equiv) depresses the second cycli-

zation step, in accord with the hypothesis that oxidation at

ruthenium is indispensable for the process to go ahead, as

shown in Scheme 5. In fact, in these conditions mono-THF

oleﬁn 11 was obtained as the main reaction product (18%)

along with the corresponding ketols (overall 9%), as an in-

separable mixture while bis-THF diol 8 was only obtained

in a 3% amount. Lower yields in the THF-containing mate-

rial is probably to be attributed to the further RuO₄oxidation

of the mono-THF compounds at their oleﬁn function.

In order to establish the relative conﬁguration of 8 a detailed

2D-NMR analysis of this compound was accomplished. In

particular, a resonance speciﬁc assignment was achieved

using two-dimensional COSY, TOCSY, ¹H–¹³C HSQC and

¹H–¹³C HMBC NMR experiments. Subsequently, to assess

the stereo-relationship around the bis-THF portion, 2D-

ROESY experiments were carried out for 8 both in CDCl₃

and DMSO-d₆. In agreement with our expectations, and pre-

vious results obtained with related molecules, the experi-

ment performed in CDCl₃evidenced correlations between

the resonances at d 4.02 (H-3) and d 3.94 (H-6), and between

those at d 3.91 (H-7) and d 3.81 (H-10) that suggested a cis

arrangement for both the proton pairs H-3/H-6 and H-7/H-10

and, therefore, acis–cis sequence for the two contiguous THF

rings. Conﬁrmatory evidences arose from a high-quality 2D-

ROESY spectrum performed in DMSO-d₆, which showed

the same correlation peaks observed in the ROESY spectrum

of 8 recorded in CDCl₃.

Deﬁnitive conﬁrmation for the expected all-threo arrange-

ment for compound 8 was provided by simple chemical

transformations strictly similar to those previously carried

out on isoprenoid analogues (Scheme 6). In particular, cis-

stereoselective monocyclization of 7 with OsO_4(cat.)/NMO/

CSA¹²afforded a mixture of diastereomeric mono-THF

tetrols 12, derived from THF-diol formation and further di-

hydroxylation of the D²double bond, that resulted identical

to the dihydroxylation products of 11 with OsO_4(cat.)/NMO.

This secured a threo–cis–threo arrangement for compound

11 and, therefore, this conﬁguration could be inferred for

the bis-THF diol 8 as well. The remaining C2/C3 threo rela-

tionship in 8 was secured by the different spectral and chro-

matographic (HPLC) properties exhibited by the two C2/C3

H₂₁C₁₀

OAc

OH

11

OH¹⁰

2

+

7

3

6

O

8 (24%)

.

RuO₂2H₂O (20% mol)

OAc

OH

+

NaIO₄(4 eq.)

H₂₁C₁₀

CH₃CN/EtOAc/H₂O

(3:3:1), 0°C, 30 min.

O

H₂₁C₁₀

O

9 (14%)

7

OAc

H₂₁C₁₀

OH

O

10 (9%)

Scheme 4. RuO₄-mediated oxidative bis-cyclization of (E,E,E)-acetic acid henicosa-2,6,10-trienyl ester (7).

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V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

R

first

cyclization

R

O

Ru

R

O

OAc

OH

O

Ru

7 R=C₁₀H₂₁

Ru=O

O

Ln

NaIO₄(2.5 eq.)

(Hydrolysis)

NaIO₄(4 eq.)

(Ru oxidation)

OAc

OH

second

cyclization

R

O

OH

O

OH

OAc

O

Ru

OAc

OH

8

O

Ln

11

Mono-THF olefin

Scheme 5. Proposed mechanism for the bis-cyclization and partial cyclization of triene 7.

erythro

threo threo

OAc

H₂₁C₁₀

OAc

11

6

OsO_4(cat.)/NMO/CSA

OH¹⁰

7

O

cis

OH

H₂₁C₁₀

7

12 (two diastereomers)

OsO_4(cat.)/NMO

erythro

Acetone-H₂O (5:1)

H₂₁C₁₀

OAc

2

MCPBA(2eq.)/CSA_(cat.)

CH₂Cl₂

3

O

13

O

OH

cis

H₂₁C₁₀

OH

+

O

OH

erythro

OAc

H₂₁C₁₀

11

OAc

2

O

OH

trans

14

Scheme 6. Demonstration of the all-threo arrangement of compound 8.

erythro bis-THF diol isomers of 8 (13 and 14, Scheme 6),

synthesized by treatment of mono-THF oleﬁn 11 with

MCPBA (2 equiv)/CSA_(cat.)in CH₂Cl₂(one-step epoxida-

tion/acid-catalyzed THF formation), and compound 8 itself.

a synthetic manoeuvre generally easy to carry out through

well-known chemistry, needs to be accomplished to ﬁx the

C-23/C-24 erythro relationship that characterizes rolliniasta-

tin-1-type ACGs.^14,15On the other hand, adjustment of the

oxidation state and generation of the proper conﬁguration

at the C-2 or C-11 centres in both ketols 9 and 10 can allow

the synthetic use of these materials as well, either in the

synthesis of the above-cited substances or of their C-15

unnatural epimers. In fact, production of a complete library

of adjacent bis-THF acetogenins, and evaluation of their

biological properties, appears an important synthetic goal

towards which some research groups are currently address-

ing their efforts.¹⁶

In summary, our approach to a bis-THF diol fragment suit-

able for further synthetic elaboration along the route to

cis–cis ACGs features the formation of all six chiral centres

(ﬁve when ketols are formed) of the bis-THF diol portion in

a single, stereoselective, step. The starting all-trans triene,

(E,E,E)-acetic acid henicosa-2,6,10-trienyl ester, is obtained

following an easy-to-carry-out procedure based on an itera-

tive reaction sequence that makes use of many inexpensive

reagents (the starting aldehyde, PCC, Ac₂O, triethyl ortho-

acetate). The starting triene is achiral and formation of all

chiral centres is deferred to a ﬁnal single reaction, a ruthe-

nium-catalyzed oxidative bis-cyclization where the true ox-

idant is sodium periodate, a product commercially available

at low price. Only seven different reactions are involved into

the synthesis of the starting triene and yields are overall good

when considering the cost of the reagents employed. In ad-

dition, the right-hand part of our bis-THF diol fragment is

functionalized in such a way to allow attachment of the re-

maining, g-lactone-containing, portion following, for exam-

ple, a rather short reaction sequence similar to that recently

employed by Brown et al. in the synthesis of membrana-

cin.¹³Only the inversion of conﬁguration at C-24 (Fig. 1),

It seems also worth mentioning that bis-THF diol 8

possesses the same relative conﬁguration as that found in

squamocin-N,¹⁷the sole known ACG with a threo–cis–

threo–cis–threo conﬁguration of the bis-THF diol portion,

whose synthesis has not yet been accomplished (Fig. 2).

Having ascertained the ability of the RuO_2(cat.)/NaIO₄

oxidizing system to induce the bis-cyclization of the all-

trans triene 7, we were interested in probing whether the

related all-trans tetraene (E,E,E,E)-acetic acid pentacosa-

2,6,10,14-tetraenyl ester (16, Scheme 7) could also be

tris-cyclized in the same conditions, as it happens for the

isoprenoid tetraene GGA (Scheme 1). This compound was

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

10993

O

9

O

9

O

OH

Squamocin N

11

9

OAc

O

OH

8

R

O

11

n

9

O

OH

n=4, R=OH Rollimembrin

n=4, R=H Membrarollin

n=5, R=OH Rolliniastatin-1

n=5, R=H Membranacin

Figure 2. Bis-THF diol 8 can be further elaborated for the synthesis of some cis–cis adjacent bis-THF ACGs.

synthesized as depicted in Scheme 7 starting from (E,E)-

nonadeca-4,8-dienal, an intermediate of the synthesis of

triene 7, through the same chemistry employed for the syn-

thesis of the latter, and then subjected to RuO₄oxidation

(Scheme 8). According to the mechanism hypothesized for

the process (Scheme 5) and precedents from the oxidation

of GGA, the presence of one more double bond in 16,

a 5 equiv amount of co-oxidant (one more equivalent com-

pared to 7) was expected to be required.

(Scheme 8). The order of abundance for these products is

the same observed for compounds 8–10 obtained from the

oxidation of triene 7: bis-THF diol 17 was the main oxida-

tion product (21%) followed by ketol 18 (16%), with the

keto group next to the C₁₀alkyl chain, and ketol 19 (5%).

The structural relationship among compounds 17–19 was

once again proven by oxidation of 17 to a mixture of 18

and 19 with TPAP/NMO.

Compounds 17–19 were subjected to the same set of 2D-

NMR experiments performed for 8. In particular, inspection

of the ROESY spectrum of 17 revealed a strong correlation

peak between resonances at d 3.83 and 3.89 that, due to the

pseudo-symmetry of the molecule around its bis-THF diol

Unexpectedly, contrary to what happens for GGA,^8ano tris-

THF product was obtained from the oxidation of 16. The

process stopped at the bis-cyclization level giving the three

related bis-THF compounds 17–19 in an overall 42% yield

CO₂Et

CHO

a-b

H₂₁C₁₀

53% (2 steps)

H₂₁C₁₀

15

c-g

14% (5 steps)

OAc

H₂₁C₁₀

16

Scheme 7. Synthesis of (E,E,E,E)-acetic acid pentacosa-2,6,10,14-tetraenyl ester 16. Reagents and conditions: (a) vinylmagnesium bromide, THF, 0 ^ꢀC;

(b) triethyl orthoacetate, propyonic acid (2%), xylene, reﬂux; (c) LiAlH₄, Et₂O, 0 ^ꢀC/rt; (d) PCC, Celite, CH₂Cl₂, rt; (e) (EtO)₂P(O)CH₂CO₂Et, NaH,

THF, ꢁ78 ^ꢀC/rt; (f) DIBAL-H, THF, ꢁ78 ^ꢀC; (g) Ac₂O-py, rt.

H₂₁C₁₀

15

11

10

6

+

14

7

O

OH

OAc

OH

1

17 (21%)

H₂₁C₁₀

.

RuO₂2H₂O (20% mol)

+

OAc

O

NaIO₄(5 eq.)

OH

O

OAc

H₂₁C₁₀

CH₃CN/EtOAc/H₂O

(3:3:1), 0°C, 30 min.

18 (16%)

16

H₂₁C₁₀

O

OAc

OH

19 (5%)

Scheme 8. RuO₄-mediated oxidative bis-cyclization of (E,E,E,E)-acetic acid pentacosa-2,6,10,14-tetraenyl ester 16.

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V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

portion, accounted for the H-7/H-14 and H-10/H-11 proton

pairs, respectively. This observation preliminarily suggested

a cis–cis arrangement of the two adjacent rings. The unam-

biguous conﬁrmation of this arrangement came from the

analysis of ROESY spectra of ketols 18 and 19. In particular,

a strong ROE correlation peak between resonances at d 4.38

(H-14) and d 3.95 (H-11) suggested the cis relationship of

this proton pair in 18. The cis relationship between protons

H-14 and H-11 was also settled in 19 due to the presence

of a cross peak between resonances at d 3.83 (H-14) and

d 3.92 (H-11). Finally, the cis arrangement of protons H-7

and H-10 in 19 was established thanks to the correlation be-

tween resonances at d 4.37 (H-7) and d 3.94 (H-10) observed

in its ROESY spectrum. Therefore, based on all previous

stereochemical evidence for bis-THF diol 8, isoprenoid

poly-THF diols 1–3 and the hypothesized mechanism

(Scheme 5), an all-threo cis–cis relative conﬁguration was

assumed for compounds 17–19.

an easily accessible model triene with the central cis double

bond. In particular, we wanted to ascertain whether the

change in the conﬁguration of the central double bond from

trans (as is in triene 7) to cis would have affected the cycliza-

tion process as had happened for the related isoprenoid triene

(E,Z)-FA,^8bfor which the oxidative process stops at the

monocyclization level, contrary to what happened for its iso-

mer (E,E)-FA that gives a bis-cyclized product (Scheme 1).

The required compound 21 was synthesized by acetylation

of diester 20 in turn obtained starting from commercially

available 1,5-cyclooctadiene, following a reported proce-

dure (Scheme 9)¹⁸and subjected to oxidation with the usual

conditions (Scheme 10). HPLC separation of the reaction

mixture afforded the structurally related lactone 22 and

lactol 23, in a disappointingly overall 15% yield along

with a mixture of THF tetrols 24 (12%) as the main products.

All these compounds can be seen to originate from the fur-

ther attack of the oxidant at the double bond of the initially

formed monocyclized product (THF-oleﬁn 26, Scheme 11)

indicating that the process stops at the ﬁrst cyclization step,

in line with the previously observed reactivity of (E,Z)-FA.

No further detailed studies were carried out to ascertain

the identity of the remaining material required for mass bal-

ance. However, ¹H NMR analysis of some partially puriﬁed

(HPLC) side products indicated that they could derive from

oxidation of the double bond of the initially formed mono-

THF oleﬁn 26, followed by its further evolution.

An increasing of RuO₄up to 50% seems not to affect this

process as well, while increasing of the co-oxidant only pro-

duces the formation of some more polar products tentatively

identiﬁed as the dihydroxylation products of initially formed

17–19 at their D²double bond. It cannot be excluded that

a further increasing of yields of 17–19 could be obtained

by employing a minor (4 equiv) amount of co-oxidant (the

amount usually used for the bis-cyclization of trienes).

This should prevent the residual double bond being further

attacked by the oxidant with consequent yield improvement.

However, for the time being these conditions were not

further explored.

Therefore, we could conclude that the presence of a cis dou-

ble bond, immediately following a trans one in the polyenic

chain (at least when the latter occupies the D¹position), rep-

resents an obstacle for a further cyclization step to take

place, irrespective of the fact that the substrate be isoprenoid,

such as (E,Z)-FA, or linear, such as compound 21.

Finally, we probed our oxidative process on (E,Z,E)-acetic

acid 12-acetoxy-dodeca-2,6,10-trienyl ester (21, Scheme 9),

a

EtO₂C

CO₂Et

In one case, the oxidation of 21 gave, besides compounds

22–24, the expected bis-cyclized product 25 (Fig. 3), though

in a very low yield (ca. 1%). Unfortunately, we were unable

to reproduce this result. Referring to this experiment, it is

important to say that careful HPLC and NMR analyses

showed that compound 25 was the sole bis-THF product

obtained. Accurate 2D-NMR analyses, ES-MS spectra, and

symmetry considerations pointed to the bis-THF diol struc-

ture 25 for this compound. In particular, the proton spectrum

recorded in CDCl₃included, as expected, two acetate signals

at 2.087 and 2.093 ppm and 10 distinct resonances for pro-

tons geminal to oxygen height of which spanning between

20

b-c

71% (2 steps)

AcO

OAc

21

Scheme 9. Synthesis of (E,Z,E)-acetic acid 12-acetoxy-dodeca-2,6,10-tri-

enyl ester (21). Reagents and conditions: (a) O₃, CHCl₂, ꢁ78 ^ꢀC then

PPh₃, 1 h, thenPh₃PCHCO₂Et; (b)DIBAL-H, THF, ꢁ78 ^ꢀC;(c) Ac₂O–py, rt.

.

RuO₂H₂O (20% mol.)

NaIO₄(4 eq.)

AcO

O

+

AcO

OAc

O

CH₃CN/EtOAc/H₂O

(3:3:1), 0°C, 10 min.

OH

21

22 (13%)

OH

AcO

OH

+

O

cis

O

OH

OAc

OH

23 (2%)

24 (12%, two diastereomers)

Scheme 10. RuO₄-mediated oxidative cyclization of triene 21.

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

10995

.

RuO₂H₂O (20% mol.)

NaIO₄(2 eq.)

AcO

21

+

O

cis

O

cis

O

CH₃CN/EtOAc/H₂O

(3:3:1), O°C, 30 min.

OH

OAc

27 (11%)

26 (25%)

Scheme 11. Partial oxidative cyclization of triene 21.

AcO

nevertheless, formation of bis-THF 25 has mechanistic rele-

vance as will be explained in the next section.

OAc

OH

7

11

3

6

O

OH

H

Stopping oxidation of 21 at the ﬁrst ring-closing step may

have synthetic value, provided that the ﬁrst-formed mono-

THF product does not undergo overoxidation. We reasoned

that the use of a lesser amount of periodate (2 equiv) could

induce the formation of the ﬁrst THF ring preventing

the successive oxidation of the remaining oleﬁn function.

Under these conditions, a mixture of mono-THF oleﬁn

compounds 26 and 27 in a 36% overall yield along with a

35% of unreacted triene (Scheme 11). This process is

unoptimized but further improvements appear to be feasi-

ble by suitably tuning the co-oxidant amount and reaction

times.

In CDCl₃

In DMSO-d6

ROE correlation

25

Figure 3. Signiﬁcant ROE correlations for bis-THF 25.

3.95 and 4.30 ppm (2ꢂCH₂OAc and four THF protons) and

two in the range 3.62–3.73 attributable to the two CH–OH

protons. 2D-ROESY experiments carried out both in

CDCl₃and DMSO-d₆showed strong ROE correlation peaks

between resonances for the proton pairs H-3/H-6, H-7/H-11

and H-7/OH-11 as shown in Figure 3. This, in conjunction

with the absence of a correlation between the H-7 and H-

10 protons, were clear evidence for the cis–trans relative

conﬁguration of the THF pair. On the other hand, symmetry

considerations excluded the structures with threo–trans–

erythro–trans–threo and threo–cis–erythro–cis–threo conﬁg-

uration, incompatible with the observed NMR characteristics

of 25. The presence of a cis-THF is also in line with the struc-

ture of all the related compounds 22–24, derived from the

oxidation of 21, where the THF ring from the ﬁrst cycliza-

tion invariably possesses a cis conﬁguration.

It is interesting to note that, due to the type of functional-

isation at both termini, mono-cyclized products 26 and 27

lend themselves to further synthetic manipulations. In

particular, the threo–cis–erythro stereochemical relation-

ship around the mono-THF portion suggests their use for

the synthesis of acetogenins of the type trilobin and triloba-

cin (Fig. 4) by using, for example, previously reported

chemistry.^5a

Finally, the structural relationship among compounds 23–25

was proven as shown in Scheme 12, through simple chemi-

cal transformations involving OsO₄chemistry.

The above results indicate that, at the present level of optimi-

zation, the oxidation of 21, can hardly have synthetic value;

R

R'

AcO

O

See ref. 5a

O

⁹OH

3

O

cis

5

OH

O

OH

OAc

OH

26

R=OH, R'=H Trilobin

R=H, R'=OH, Trilobacin

Figure 4.

1.OsO₄-TMEDA, CH₂Cl₂

2. CH₂Cl₂/AcOH (2:1)

AcO

O

OH

25

OsO₄(1 eq.)

Acetone-H₂O (5:1), 15 min.

then NMO (2 eq.), 10 min.

OH

AcO

OAc

21

OsO₄(1.3 eq.),

THF-H₂O (4:1), 5 min.

then NaIO₄(5 equiv.), 2.5 h

AcO

OH

AcO

OH

O

OH

O

OH

OAc

OH

23

24 (ca. 1:1 mixture

of two diastereomers)

Scheme 12. Chemical correlation of compounds 23–25.

10996

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

2.1. An explanation for the diastereoselectivity observed

in the OP of polyenes with a repetitive 1,5-diene motif

The cis selectivity observed for the ﬁrst cyclization step

could be explained as shown in Figure 5. We cannot know

the oxidation state of ruthenium during each cyclization

step; however, the oxidation states +6 or +8 appear to be

the most plausible.²⁰Assuming an octahedral geometry for

ruthenium²¹in the ﬁrst-formed Ru(VI) diester 28 and

a chair-like conformation of the molecule in the transition

state for the cyclization step,¹⁹a [3+2] cycloaddition,²¹the

correct positioning of the double bond involved in the

THF closure, close to an O]Ru–O portion, can only occur

in the stereochemical arrangement 29. Though this arrange-

ment suffers for steric repulsions of the pseudoaxially dis-

posed C-2 carbon (numeration relative to the isoprenoid

substrate), this appears not to hamper the cyclization event

also in isoprenoid polyenes (R¼Me). On the other hand,

arrangement 31, similar to 29, can also exist where the

C(2)O–Ru bond underwent hydrolytic cleavage (see 30)

and the free C(2)–OH group is still coordinated to ruthe-

nium, that also would lead to a cis-THF.

The following points, emerged, both in the present and in our

previous related studies on the OP of isoprenoid polyenes,⁸

which need to be explained.

(a) Why in all the studied cases (isoprenoid or linear poly-

enes) the ﬁrst two THF rings are invariably obtained

with a cis selectivity;

(b) Why a cis double bond immediately following a trans

one, as in (E,Z,E)-acetic acid 12-acetoxy-dodeca-

2,6,10-trienyl ester 21 and in (E,Z)-FA, prevents the

second cyclization step to take place;

(c) Why for the all-trans tetraene (E,E,E,E)-acetic acid

pentacosa-2,6,10,14-tetraenyl ester 16 the polycycliza-

tion stops at the bis-THF level contrary to what happens

for the isoprenoid analogue GGA that gives a tris-THF

product.

2.2. Model for the cis-selective ﬁrst cyclization

It is to be noted that the ruthenium ester species 30 could, in

principle, also lead to a trans-THF via arrangement 32.

In fact, this species is strictly similar to the perrhenate ester

involved into the trans-diastereoselective cyclization of

bishomoallylic alcohols promoted by rhenium (VII) oxo-

species. In this case, the steric control model formulated by

McDonald^10b,19c(Fig. 6) could be invoked, with the molecule

We will now try to give a plausible explanation of the above

points taking into account previously developed models for

the rhenium(VII)-mediated oxidative cyclization of hydroxy-

polyenes¹⁹as well as reported oxidative chemistry for related

metal oxo-species.⁹

Pseudoaxial

R'

R

O

2

L

Bond

R

H

R'

Ru

R'

control

H

R

O

Ru

O

OH

O

H

HO

R

L

28 R=Me or H;

L

cis

R'=C₁₀H₂₁

L=Solvent

R

cis-THF

29

Hydrolysis of the

C(2)O-Ru bond;

oxidation at Ru?

trans

R

R'

H

C(2)OH not

coordinated

to ruthenium

R

Steric

control

R

2

R'

O

OH

O

H

HO

R'

O

H

R

2

OH

O

R

HO

H

HO

O

Ru

O

H

L

trans-THF

L'

L

Pseudoequatorial

30 L=Solv.

L'=Solv. or =O

32

C(2)OH coordinated

to ruthenium

R

R'

HO

O

L

2

HO

O

Chelation

control

H

Ru

cis-THF

O

cis

R

31 L=Solv. or =O

Figure 5. Chelation versus steric control in the ﬁrst cyclization step of RuO₄-mediated OP process.

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

10997

In conclusion, the ﬁrst cyclization step of the RuO₄-involv-

ing process appears to be under chelation control, if species

31 is involved, or under bond control (C(2)O–Ru bond), if

species 28 is involved. On the other hand, when formation

of a trans-THF is observed, as in related RuO₄-mediated

monocyclization of polyenes,^8aa steric control should be

operative via an intermediate of the type 32.

Pseudoaxial

R_Z

trans

H

^HR_L

R_E

O

R_E

R_L

O

R_Z

O

Re

O

H

Re

H

L

O

R_S

cis

R_S

L

Pseudoequatorial

L

disfavoured

[

] cycloaddition

3+2

favoured

2.3. Model for the cis-selective second cyclization

R_E

R_Z

R_E

R_Z

R_L

As for the second cyclization step, once again it can be spec-

ulated that the C(2)O–Ru bond could either be unbroken or

already cleaved. The observed cis-selectivity for this step

would be explained by either arrangements 35 (C(2)O–Ru

intact) or 36 (C(2)O–Ru cleaved) (Fig. 8). As far as arrange-

ment 35 is concerned, the C(2)O–Ru bond imposes the

closure of a cis-THF ring, irrespective of the fact that the

O

OH

H

OH

R_S

H

R_S

trans-THF

cis-THF

Figure 6. Steric control model for a trans-diastereoselective cyclization of

bishomoallylic alcohols promoted by rhenium (VII) oxo-species.^19c

preferably adopting an arrangement with the bulk group

(RR⁰CHOH) at C-3 pseudoequatorially disposed in the chair-

like transition state 32. That an equilibrium 28/30/32 could

exist is substantiated by the formation of minor amounts of

trans-THF products both in the RuO₄-mediated monocycli-

zation of 1,5-dienes⁹and the partial oxidative cyclization

of (E,E)-FA with the same reagent.^8aIt is also interesting to

note here that strictly related monocyclizations processes of

1,5-dienes in the presence of OsO₄,²²MnO₄^{ꢁ 23}and RuO^ꢁ₄²⁴

evidently proceed through an intermediate such as 28/29

since the formation of trans-THF products has never been ob-

served for these processes a fact that render the involvement

of the open ester form 30, in these cases, not plausible.

C-2 Oxygen bonded to ruthenium

R

2

R'

O

Closure of a

cis-THF

L

R

O

2

Ru

L

6

R

R'

HO

O

cis

O

OH

H

(Bond control)

H

R

H

R

O

cis

Pseudoaxial

R

35 L=Solv. or =O

C-2 Oxygen not bonded to ruthenium

R

R'

OH

L

R'

OH

O

2

Pseudoequatorial

L'

The above model is also in accordance with the stereochem-

ical course of the strictly related oxidative cyclization pro-

cesses promoted by Cr(VI) oxo-species (Fig. 7, top).²⁵In

particular, the monocyclization of 1,2-dihydroxyalkenes to

cis-THF’s can be explained through the formation of a chro-

mium monoester such as 33 where the coordination of the

C-2 OH group to the metal forces the molecule to adopt a

spatial arrangement analogous to 31, thus ensuring the clo-

sure of a cis-THF ring.^10bIt is to be said, however, that the

involvement of a cyclic diester species of the type 28/29 can-

not be ruled out in this process as well, owing to the bidentate

character of the dihydroxyalkene. Conversely, the same au-

thors reported that the cyclization of a monodentate hydrox-

ydiene such as 34 with PCC^25dgives a trans-THF product

(Fig. 7, bottom). In this case, due to the absence of a coordi-

nating OH group, the path depicted for rhenium (VII) in

Figure 6 (steric control, trans-selectivity) would be followed.

2

OH

O

L'

OH

O

Ru

L

R

6

O

L

6

R

H

O

Pseudoaxial

R

Non-chelated structure

(37 L=Solv; L'=Solv or =O)

Chelated structure

(36 L=Solv or =O)

Closure of a

trans-THF

Closure of a

cis-THF

X

(Steric control)

(Chelation control)

R

R'

HO

2

R'

HO

O

OH

R H

R

trans

H

R H

R

H

cis

Figure 8. Chelation versus steric control in the second cyclization step of

RuO₄-mediated OP process.

L_n

HO

2

OAc

H

Cr

H

OH

CrO₃

O

or PCC

OAc

H

OH OH

HO

AcO

cis-THF

33

i-Pr

PCC

O

OH

H

34

trans-THF

Figure 7. McDonald’s model for the cis-selective monocyclization of the 6,7-dihydroxyalkene from geranyl acetate (top) and trans-selectivity for a monodentate

hydroxydiene (bottom).

10998

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

ﬁrst-formed THF ring be or not coordinated to the metal,

though this seems possible as molecular models of 35

show. In fact, in this case, the alignment of the alkene for

the reaction to take place is incompatible with the closure

of a trans-THF. In the case the C(2)O–Ru bond be broken,

to explain the closure of the cis-THF, one should assume

that the chelated structure 36 (THF coordinated to Ru), where

the angular carbon (C-6) of the coordinated THF is posi-

tioned in a sterically demanding pseudoaxial position, should

be energetically preferred over the non-chelated structure 37,

where the THF ring is pseudoequatorial, since the latter

would lead to a trans-THF (not observed) in accord with

the steric control model (Fig. 5). This is just what hypothe-

sized by Sinha et al. to explain the observed cis selectivity

in the second cyclization step of 4,8-dien-1-ols with

CF₃CO₂ReO₃when a trans–threo substructure is formed in

the ﬁrst cyclization step.^19b

where the B THF is pushed away from the metal, and hence

non-coordinated to it, due to its pseudoequatorial disposition.

This arrangement is, however, compatible with the coordina-

tion of both the ATHF and the C(2)OH group to ruthenium.

Therefore, the trans-selectivity for the third cyclization step

both in squalene and GGA appears to be under steric control

though a chelation stabilization of the involved arrangement

could also exist.

2.5. Model for the trans-selective fourth and ﬁfth

cyclizations in the OP of squalene

The trans-selectivity for the fourth ring-closing step in squa-

lene can be explained through the steric control model

(arrangement 40, Fig. 10). In fact, the trans conﬁguration of

the third (C) THF ring pushes the metal away from both B

and C rings; nor the A ring (not shown) appears to be able

to reach a distance suitable for coordination. This is true

for the ﬁfth cyclization step as well. On the other hand, an

arrangement with C ring chelated to the metal (not shown),

that would lead to the closure of a cis-THF, would be possi-

ble but disfavoured by steric interactions such as those

observed in the third cyclization (Fig. 9), though less severe

due to the lack of the angular methyl on C THF. Therefore,

the formation of the ﬁrst trans-THF (the C-THF) in the

growing poly-THF chain appears to impose a trans-selectiv-

ity to all the successive cyclization steps in an all-trans iso-

prenoid polyene such as squalene. Further experimental

support to this deduction should be given by studying, for

example, the oxidative cyclization of analogues of squalene

with more than six isoprene units.

On the other hand, it is also to be said that arrangement 36

could be further stabilized by the coordination of the C-2

hydroxyl group to ruthenium as seen for structure 31

(Fig. 5). Therefore, the observed cis selectivity for the sec-

ond cyclization step would be explained, as seen in the ﬁrst

cyclization step, by a chelation control or by a bond control

depending on whether the species 35 or 36 is involved.

2.4. Model for the trans-selective third cyclization in

GGA and squalene

Let us refer now to the third cyclization step in GGA and

squalene, both proceeding with a trans-selectivity (Scheme

1). A chelated structure 38, stabilised by coordination of

both A and B THF rings, appears in principle possible, as

models show, that would impose a cis-selective cyclization.

However, a very disfavoured transition state, suffering

severestericrepulsions, would be required fora correctalign-

ment of the alkene to take place. In particular, the methyl-

carrying carbon (C-10) of the B THF ring is pseudoaxially

disposed and, in addition, the R⁰group and the methyl at

C-10 would be very close in the space during the cycloaddi-

tion step. On the other hand, alternative arrangements where

the C(2)O is still bonded to ruthenium, or coordinated to it,

and one or both the A/B rings coordinated as well (not

shown), are also possible but overall these would substan-

tially ﬁx the reacting portions in a reciprocal position as in

38 and the THF closure would suffer similar steric repul-

sions. A much more favourable spatial arrangement, 39,

leading to a trans-THF, is shown in the right side of Figure 9,

2.6. Explaining the failure of the second cyclization in

the (E,Z)-FA and (E,Z,E)-acetic acid 12-acetoxy-dodeca-

2,6,10-trienyl ester (21), and formation of bis-THF 25

To explain the failure of the second cyclization step in both

(E,Z)-FA and (E,Z,E)-acetic acid 12-acetoxy-dodeca-2,6,10-

trienyl ester (21) the same type of reasoning above seen for

the second cyclization step of all-E polyenes can be applied;

that is after the formation of the ﬁrst THF, the molecule

adopts a spatial arrangement of the type 35/36 (Fig. 8) where

the C(2)–O oxygen is in some way linked to the metal (che-

lated or bonded) (Fig. 11, left). In fact, if so, the erythro

relationship arising from the syn addition of two oxygens to

the cis double bond during the ﬁrst cyclization would impose

a sterically disfavoured endo transition state, leading to a cis-

THF, for the second cyclization step to take place. On the

other hand, this chelated arrangement is incompatible with

the closure of a trans-THF since the alignment of the alkene

cannot take place at all. As Sinha et al.^19bpointed out refer-

ring to the second cyclization step of the strictly related

4,8-dien-1-ols, the presence of this erythro relationship

2

A

OH

A

O

L

Ru

OH

R'

H₃C

6

O

OH

O

O^R

Ru

H

O

H

HO

B

O

B

R'

L'

O

10

HO

Pseudoaxial

H₃C

trans

H

Ru

Near in

the space

R

H

O

Pseudoequatorial

39 L=Solv. or =O

B

L

O

40 L= Solv.

L'= Solv. or =O

38 L=Solv. or =O

C

H

Squalene: R=H; R'=CH₃

GGA: R=CH₃; R'=H

trans

Pseudoequatorial

Figure 9. Left: possible chelated structure for the third cyclization step in

squalene, leading to a cis-THF; the part of the molecule joining the two THF

is omitted for sake of clarity. Right: arrangement leading to a trans-THF.

Figure 10. Arrangement explaining the trans-selective fourth cyclization in

squalene; only B and C THF’s and the cyclizing portion are shown.

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

10999

OAc

Ref 9b

O

OAc

H

HO

(E,Z)-FA

very low

yield

OAc

OH

AcO

OAc

O

HO

25

C-2 Oxygen not linked

C-2 Oxygen bonded or

coordinated to ruthenium

to ruthenium (non-chelated arrangement)

Coordination

or bond

L'

R''

OH

CH₂OAc

L'

HO

H

Ru

L

H

O

L

R

O

2

L

CH₂OAc

₂R'

Ru

O

H

R'

O

H

O

H

Disfavoured endo

transition state

trans

Erythro

H

Erythro

R'

21: L=Solv.; L'=Solv. or =O

(E,Z)-FA: R=R'=CH₃; R''=CH₂OAc

21: R=R''=CH₂OAc; R'=H

L=Solv. or =O

Figure 11. Model explaining the failure of the second cyclization in the (E,Z)-FA and 21, and formation of cis–trans bis-THF 25.

would render the non-chelated structure, energetically more

favourable leading to a trans-THF through a steric control.

In our case, however, this non-chelated structure cannot

form at all due to the C(2)O vinculum. This explanation

well agrees with, and is a further support of, the model above

proposed for the cis selectivity of the second cyclization

step of an all E polyene. On the other hand, formation of

the cis–trans bis-THF 25 can be explained assuming that

the molecule could assume, in a little extent, an arrangement

(Fig. 11, right) where both the THF and C(2)–O are not

linked to the metal so that a steric control is operative, that

leads to a trans-THF in the second cyclization step, accord-

ing to the Sinha’s hypothesis.^19b

based on steric or chelation control models. However, fur-

ther studies need to be accomplished both to support the

above models, by using suitable substrates and theoretical

calculations, and to employ the chemistry developed in the

present study for the synthesis of selected annonaceous

acetogenin targets. In particular, the unique feature of the

RuO₄-mediated OP of inducing the formation of the ﬁrst

two THF rings in the poly-THF product with cis selectivity

renders the process useful for the synthesis of ACGs such

as rollinistatin-1 and rollimembrin, two of the most active

ACGs known, both possessing a threo–cis–threo–cis–

erythro relative conﬁguration, and/or their non-natural ana-

logues. Further studies in this ﬁeld are currently ongoing.

2.7. Model explaining the failure of the third cyclization

in the all-trans tetraene (E,E,E,E)-acetic acid

pentacosa-2,6,10,14-tetraenyl ester (16)

4. Experimental

4.1. General methods

Finally we have to explain why the OP of the all-trans tetra-

ene 16 (Scheme 8) stops at the bis-THF level. A tentative

explanation can be given by referring to the reasoning devel-

oped for the third cyclization of GGA and squalene (Fig. 9).

The absence of methyl groups in 16 along the polyenic chain

could render the chelated structure of the type 38 (Fig. 9,

left) more stable, a fact that would preclude the further cycli-

zation since this arrangement, only compatible with the for-

mation of a cis-THF, would however require a disfavoured

transition state, as pointed out above for GGA and squalene.

All reagents and anhydrous solvents were purchased

(Aldrich and Fluka) at the highest commercial quality and

used without further puriﬁcation. Where necessary, ﬂame-

dried and argon-charged glassware was used. Reactions

were monitored by thin-layer chromatography carried out

on precoated silica gel plates (Merck 60, F₂₅₄, 0.25 mm

thick). Merck silica gel (Kieselgel 40, particle size 0.063–

0.200 mm) was used for column chromatography. Na₂SO₄

was used as drying agent in all the extractive work-up. HPLC

separations were carried out on a Varian 2510 apparatus

equipped with a Waters R403 dual cell differential refrac-

tometer using phenomenex 250ꢂ10 mm and 250ꢂ4.6 mm

(both 5 mm) columns. NMR experiments were performed on

Bruker DRX-600, Bruker WM 400, Varian 300, and Gemini

200 spectrometers in CDCl₃unless otherwise mentioned.

All the 2D-NMR spectra were acquired at 600 MHz in the

phase-sensitive mode with the transmitter set at the solvent

resonance and TPPI (time proportional phase increment)

usedtoachievefrequencydiscriminationintheu₁dimension.

3. Conclusion

In conclusion, the OP of some linear polyenes with the

RuO₂(cat.)/NaIO₄oxidizing system has been studied and its

ability to induce the oxidative bis-cyclization of two all-trans

linear polyenes has been established. A plausible explana-

tion of the observed stereoselectivity of each ring-closing

step, either in linear or isoprenoid polyenes, has been given

11000

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

Standard pulse sequence and phase cycling were used

for DQF-COSY, 2D-TOCSY, HSQC, 2D-HSQC-TOCSY,

HMBC, 2D-INEPT-INADEQUATE, 2D-INEDAQUATE

and ROESY spectra. The NMR data were processed on a

Silicon Graphic Indigo2 Workstation using UXNMR soft-

ware. Proton chemical shifts were referenced to the residual

CHCl₃signal (7.26 ppm); ¹³C NMR chemical shifts were

referenced to the solvent (77.0 ppm). Abbreviations for sig-

nal coupling are as follows: s, singlet; d, doublet; t, triplet;

q, quartet; m, multiplet. J values are givenin Hertz. IR spectra

were collected on a Jasco FT-IR-430 spectrometer. ESI mass

spectrometric analyses were recorded on a Waters Micro-

mass ZQ mass spectrometer equipped with an electrospray

source used in the positive mode. HRMS spectra were

recorded on a Voyager DE-PRO mass spectrometer using

MALDI-TOF ionization.

Celite (9.7 g, 0.42 g/mmol) and PCC (10.4 g, 48.3 mmol)

were added to a solution of the crude alcohol (5.2 g,

23.0 mmol) in CH₂Cl₂(100 mL) and the mixture was stirred

for 1.5 h. Filtration on a short pad of silica gel gave (E)-

pentadec-4-enal (4.38 g, 85%)^5b,28as an oil. ¹H NMR:

(200 MHz) d 9.76 (1H, t, J¼1.6, CHO), 5.43 (2H, m, oleﬁnic

protons), 2.47 (2H, q, J¼7.2), 2.33 (2H, m), 1.96 (2H, br q,

6.2), 1.38–1.17 (16H, br s), 0.88 (3H, t, J¼7.2, Me). ¹³C

NMR: (50 MHz) d 201.8, 131.8, 127.5, 43.4, 32.3, 31.7,

29.5 (2C), 29.4, 29.3, 29.2, 29.0, 25.0, 22.5, 13.9.

Vinylmagnesium bromide (1 M in THF, 23.5 mL,

23.5 mmol) was added to a solution of the above crude alde-

hyde (4.38 g, 19.5 mmol) in dry THF (10 mL) at 0 ^ꢀC.

Work-up with saturated aqueous NH₄Cl and ether, as

reported above for the preparation of ester 4, gave allyl alco-

hol (E)-heptadeca-1,6-dien-3-ol^5b(3.71 g, 76%) as an oil

that was used in the next step without further puriﬁcation.

¹H NMR: (200 MHz) d 5.87 (1H, ddd, J¼17.0, 10.8, 6.4,

H-2), 5.43 (2H, m, H-6, H-7), 5.22 (1H, br d, J¼17.2,

H_a-1), 5.10 (1H, br d, J¼10.8, H_b-1) 4.12 (1H, q, J¼6.0,

H-3), 2.08 (2H, m) 1.96 (2H, m), 1.59 (2H, m), 1.40–1.10

(16H, br s), 0.87 (3H, t, J¼7.2, Me). ¹³C NMR: (50 MHz)

d 141.1, 130.8, 129.3, 114.0, 72.2, 36.6, 32.4, 31.8, 29.5

(3C), 29.4, 29.2, 29.1, 28.3, 22.5, 13.9.

4.1.1. Synthesis of (2E,6E,10E)-acetic acid henicosa-

2,6,10-trienyl ester (7).

4.1.1.1. (E)-Pentadec-4-enoic acid ethyl ester 4. To a

solution of undecylic aldehyde (7.0 g, 41.1 mmol) in dry

THF (5 mL), at 0 ^ꢀC, was added vinylmagnesium bromide

(1 M in THF, 49.3 mL, 49.3 mmol) and the mixture was

stirred for 30 min. Then, a saturated NH₄Cl solution (20 mL)

was added and the mixture stirred for 10 min. The phases

were separated and the aqueous phase was extracted with

ether (3ꢂ20 mL). The combined ether layer was dried and

concentrated to yield tridec-1-en-3-ol²⁶(8.0 g, 98%) as an

oil that was used without further puriﬁcation in the next

A solution of the crude allyl alcohol (3.71 g, 14.7 mmol),

triethyl orthoacetate (2.1 equiv, 30.9 mmol, 5.7 mL) and

propionic acid (2%, 0.3 mmol, 22 mL) in xylene (10 mL)

was reﬂuxed for 2 h. Removal of the solvent followed by

puriﬁcation by column chromatography (petroleum ether/

petroleum ether–ethyl ether, 95:5) afforded 2.84 g (60%) of

(E,E)-nonadeca-4,8-dienoic acid ethyl ester 5^5bas an oil.

1

step of the synthesis. H NMR: (200 MHz) d 5.87 (1H,

ddd, J¼17.2, 10.8, 6.6, H-2), 5.21 (1H, dt, J¼17.2, 1.4,

H_a-1), 5.09 (1H, dt, J¼10.8, 1.4, H_b-1), 4.09 (2H, q,

J¼6.4, H-3), 1.86 (2H, m), 1.52 (2H, m), 1.25 (14H, br s),

0.87 (3H, t, J¼7.2, Me).

Compound 5: IR (neat): n_max1738 cm^ꢁ1. ¹H NMR: (CDCl₃)

d 5.50–5.30 (4H, m, oleﬁnic protons), 4.12 (2H, q, J¼7.2,

CO₂CH₂CH₃), 2.37–2.23 (4H, m), 2.08–1.87 (6H, m),

1.38–1.18 (16H, br s), 1.22 (3H, t, J¼7.2, CO₂CH₂CH₃),

0.87 (3H, t, J¼7.2, Me). ¹³C NMR: (50 MHz) d 172.5,

130.8, 130.5, 129.2, 128.1, 59.7, 34.1, 32.4, 31.7, 29.5,

29.4, 29.2, 29.0, 27.7, 22.5, 14.0, 13.8.

A solution of the crude allyl alcohol (8.0 g, 40.3 mmol),

triethyl orthoacetate (2.1 equiv, 84.6 mmol, 15.5 mL) and

propionic acid (2%, 80 mmol, 82 mL) in xylene (15 mL)

was reﬂuxed for 4 h. Removal of the solvent followed by

puriﬁcation by column chromatography (petroleum ether/

petroleum ether–ethyl ether, 9:1) afforded 6.81 g (63%) of

(E)-pentadec-4-enoic acid ethyl ester²⁷4 as an oil.

4.1.1.3. (E,E,E)-Henicosa-2,6,10-trienoic acid ethyl

ester 6. Ester 5 (2.84 g, 8.8 mmol) in dry ethyl ether (20 mL)

was reduced with LiAlH₄(702 mg, 18.5 mmol) as reported

for ester 4 to give 2.15 g (87%) of (E,E)-nonadeca-4,8-

dien-1-ol as an oil that was subjected to the next step without

further puriﬁcation. A 200 mg amount of this material

was subjected to a further HPLC puriﬁcation on an RP-18

column (MeOH–H₂O, 97:3) to obtain a pure sample for spec-

Compound 4: IR (neat): n_max1738 cm^{ꢁ1 1}H NMR:

.

(300 MHz) d 5.42 (2H, m, oleﬁnic protons), 4.11 (2H, q,

J¼7.5, CO₂CH₂CH₃), 2.33 (4H, m), 1.95 (2H, m), 1.23

(3H, t, J¼7.2, CO₂CH₂CH₃), 1.25 (16H, m), 0.87 (3H, t,

J¼7.2, Me).

4.1.1.2. Nonadeca-4,8-dienoic acid ethyl ester 5. LiAlH₄

(2.03 g, 53.3 mmol) was slowly added to a solution of ester

4 (6.81 g, 25.4 mmol) in dry ether (70 mL) at 0 ^ꢀC. The mix-

ture was allowed to warm to room temperature over 1 h, then

wet ether was added (10 mL) followed by dropwise addition

of water (10 mL). The phases were separated and the aque-

ous phase was extracted with ether (3ꢂ20 mL). The com-

bined ether layer was dried and concentrated to give 5.2 g

(90%) of (E)-pentadec-4-en-1-ol^5bas an oil that was taken

to the next step without further puriﬁcation. ¹H NMR:

(300 MHz) d 5.41 (2H, m, oleﬁnic protons), 3.65 (2H, q,

J¼5.4, H₂-1), 2.07 (2H, q, J¼7.4), 1.96 (2H, q, J¼6.6),

1.63 (2H, m), 1.39–1.20 (16H, m and br s), 0.87 (3H, t,

J¼7.2, Me).

1

tral characterization. IR (neat): n_max3339 cm^ꢁ1. H NMR:

(200 MHz) d 5.30–5.45 (4H, m, oleﬁnic protons), 3.62

(2H, t, J¼7.3, H₂-1), 2.10–1.90 (8H, m), 1.61 (2H, quintet,

J¼7.0), 1.38–1.15 (16H, br s), 0.87 (3H, t, J¼7.2, Me).

¹³C NMR: (50 MHz) d 130.7, 130.3, 129.6, 129.4, 62.1,

32.6, 32.5, 32.3, 31.8, 29.5, 29.4, 29.2, 29.1, 28.8, 22.6, 14.0.

A solution of the crude alcohol (2.15 g, 7.6 mmol) in CH₂Cl₂

was oxidized with PCC (3.45 g, 16.0 mmol) and Celite

(3.2 g) as reported for the synthesis of ester 5 giving 1.79 g

(85%) of (E,E)-nonadeca-4,8-dienal, as an oil, that was

used in the next step. IR (neat): n_max1728 cm^ꢁ1. ¹H NMR:

(200 MHz) d 9.76 (1H, t, J¼1.6, CHO), 5.50–5.32 (4H, m,

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

11001

oleﬁnic protons), 2.48 (2H, br t, J¼7.3, H-2), 2.34 (2H, br q,

J¼6.4, H-3), 2.07–1.88 (6H, m), 1.37–1.17 (16H, br s), 0.88

(3H, t, J¼6.7, Me). ¹³C NMR: (50 MHz) d 201.1, 131.0,

130.6, 129.1, 127.8, 43.2, 32.34, 32.27, 31.7, 29.46, 29.41,

29.3, 29.2, 29.0, 24.9, 22.4, 13.8. MS m/z 317 (89, M+K)⁺,

301 (28, M+Na)⁺. HRMS: calcd for C₁₉H₃₄ONa 301.2499,

found 301.2506.

m, oleﬁnic protons), 4.50 (2H, d, J¼6.4, CH₂OAc), 2.14–

1.89 (overall 13H, m overlapped with the 3H-singlet acetate

at 2.05), 1.33–1.19 (16H, m), 0.87 (3H, t, J¼6.9, Me).

¹³C NMR: (100 MHz) d 170.8, 135.9, 130.8, 130.5, 129.5,

129.3, 124.0, 65.2, 32.6, 32.2, 31.9, 29.6, 29.3, 29.1,

22.6, 20.9, 14.1. MS m/z 387 (55, M+K)⁺, 371 (77,

M+Na)⁺. HRMS: calcd for C₂₃H₄₀O₂Na 371.2916, found

371.2923.

To a mixture of NaH (60% in mineral oil, 113.6 mg,

2.84 mmol) in dry THF (5 mL) triethyl phosphonoacetate

(563 mL, 2.84 mmol) was added dropwise at room tempera-

ture and the mixture stirred for 1 h. To the light orange solu-

tion was dropwise added a solution of the aldehyde (790 mg,

2.84 mmol), obtained as above, in dry THF (2 mL), within

a 20 min period. After 1.5 h the mixture was extracted

with ether (3ꢂ10 mL) and the organic phase dried and con-

centrated. Puriﬁcation by column chromatography (gradient

from 2% to 10% ethyl ether in hexanes) afforded 740 mg

(75%) of pure (E,E,E)-henicosa-2,6,10-trienoic acid ethyl

ester 6 as an oil.

4.1.2. Oxidation of triene 7 with RuO_4(cat.)/NaIO₄. To a

solution of triene 7 (50 mg, 0.14 mmol) in the biphasic

mixture EtOAc–CH₃CN–H₂O (3:3:1) (17.5 mL) were added

in sequence NaIO₄(4 equiv, 118 mg, 0.55 mmol) and

RuO₂$2H₂O (20 mol %, 3.6 mg) under vigorous stirring

at 0 ^ꢀC. TLC monitoring (hexane–EtOAc, 3:7) indicated

that the reaction to be completed after 30 min. The process

was quenched by the addition of excess of a saturated

Na₂S₂O₃$5H₂O solution (2 mL) until the yellowish mixture

turned to black (RuO₂precipitation). Then the mixture was

ﬁltered and extracted with EtOAc (3ꢂ10 mL), and the com-

bined organic phase was dried and evaporated to give 60 mg

of an oil. HPLC separation (hexane–EtOAc, 3:7, ﬂow

2.5 mL/min) afforded bis-THF diol 8 (12.5 mg, 24%,

t_R¼15.3 min), ketol 10 (4.5 mg, 8.5%, t_R¼9.2 min) and 9

(7.5 mg, 14%, t_R¼11.7 min) as oils.

4.1.2.1. Acetic acid 2-hydroxy-2-[5⁰-(1-hydroxy-un-

decyl)-octahydro-[2,2⁰]bifuranyl-5-yl]-ethyl ester 8. IR

(neat): n_max3419, 1742 cm^ꢁ1. ¹H NMR (600 MHz, attribu-

tions by 2D-NMR): d 4.17, 4.14 (1H each, AB system further

coupled, J_AB¼11.5, J_AX¼7.0, J_BX¼4.8, H₂-1), 4.02, 3.94,

3.91, 3.81 (1H each, m’s, H-3, H-6, H-7, H-10, respectively),

3.70 (1H, dt, J¼7.0, 4.8, H-2), 3.43 (1H, dt, J¼7.8, 4.7,

H-11), 2.09 (3H, s, acetate), 2.01, 1.97 (1H each, m’s,

H₂-4), 1.96 (2H, m, H₂-5) 1.96, 1.88 (1H each, m’s, H₂-8),

1.96, 1.81 (1H each, m’s, H₂-9), 1.45 (2H, m, H₂-12), 1.27

(16H, br s, H₂-13/H₂-20), 0.88 (3H, t, J¼6.8, H₃-21).

¹H NMR (DMSO-d₆, 600 MHz, attributions by 2D-NMR):

d 4.88, 4.26 (1H each, d’s, J¼6.3 and 6.1, respectively,

2ꢂOH), 3.99, 3.96 (1H each, AB system further coupled,

J_AB¼11.1, J_AX¼6.9, J_BX¼4.8, H₂-1), 3.83 (1H, m, H-3),

3.73 (2H, m, H-6 and H-7), 3.68 (1H, q, J¼6.0, H-10),

3.58 (1H, ddd, J¼6.9, 6.3, 4.8, H-2), 3.28 (1H, m, H-11),

2.09 (3H, s, acetate), 1.80, 1.72 (1H each, m’s, H₂-4),

1.73, 1.62 (1H each, m’s, H₂-9), 1.21-1.31 (2H, m, H₂-12),

1.26 (16H, br s, H₂-13/H₂-20), 0.86 (3H, t, J¼6.8, H₃-21).

¹³C NMR (150 MHz, attributions by 2D-NMR): d 171.1

(carbonyl), 83.2 (CH-10), 81.4 (CH-6), 81.2 (CH-7), 79.6

(CH-3), 74.1 (CH-11), 72.2 (CH-2), 66.5 (CH₂-1) 34.6

(CH₂-12), 29.9 (8ꢂCH₂, C-13/C-20) 28.6 (CH₂-9), 28.4

(CH₂-8, CH₂-5), 28.3 (CH₂-4), 21.2 (CH₃acetate), 14.3

(CH₃-21).

1

Compound 6: IR (neat): n_max1725, 1655 cm^ꢁ1. H NMR:

(200 MHz) d 6.95 (1H, dt, J¼15.6, 6.4, H-3), 5.81 (1H, dt,

J¼15.6, 1.6, H-2), 5.47–5.37 (4H, m, oleﬁnic protons),

4.18 (2H, q, J¼7.0, CO₂CH₂CH₃), 2.27–1.94 (10H, overlap-

ped m’s), 1.28 (3H, t, J¼7.2, CO₂CH₂CH₃), 1.27 (16H, br s),

0.87 (3H, t, J¼7.2, Me). ¹³C NMR: (100 MHz) d 166.6,

148.5, 131.1, 130.8, 129.4, 128.6, 121.5, 60.0, 32.6, 32.5,

32.22, 32.18, 31.9, 30.9, 29.6, 29.5, 29.3, 29.1, 22.6, 14.2,

14.0. MS m/z 387 (56, M+K)⁺, 371 (80, M+Na)⁺. HRMS:

calcd for C₂₃H₄₀O₂Na 371.2916, found 371.2910.

4.1.1.4. (E,E,E)-Acetic acid henicosa-2,6,10-trienyl

ester 7. To a solution of the ester 6 (740 mg, 2.1 mmol) in

dry THF (3 mL) was added dropwise DIBAL-H (1 M in

THF, 6.4 mL, 6.4 mmol) at ꢁ78 ^ꢀC. The mixture was stirred

at this temperature for 1 h and then quenched by dropwise

addition of a saturated NH₄Cl solution (3 mL). The phases

were separated and the aqueous phase was extracted with

ether (3ꢂ5 mL). The combined ether layer was dried and

concentrated to give 610 mg (94%) of crude (E,E,E)-

henicosa-2,6,10-trien-1-ol. IR (neat): n_max3393 cm^ꢁ1

.

¹H NMR: (200 MHz) d 5.66 (2H, m, oleﬁnic protons),

5.40 (4H, m, oleﬁnic protons), 4.08 (2H, d, J¼4.4, H₂-1),

3.65 (1H, t, J¼6.8, OH), 2.18–1.90 (10H, m), 1.40–1.10

(16H, m), 0.87 (3H, t, J¼7.2, Me). ¹³C NMR: (150 MHz)

d 132.8, 131.1, 130.8, 130.5, 129.5 (2C), 129.2, 63.8, 32.7,

32.6, 32.4, 32.3, 32.1, 29.6 (2C), 29.5, 29.3, 29.2, 28.9,

22.7, 14.1. MS m/z 345 (45, M+K)⁺, 329 (75, M+Na)⁺.

HRMS: calcd for C₂₁H₃₈ONa 329.2811, found 329.2830.

Acetic anhydride (3 mL) and pyridine (3 mL) were added to

610 mg (2.0 mmol) of the above alcohol and the solution

was left at room temperature overnight. Then, the mixture

was partitioned between EtOAc and HCl 0.1 M, and the

organic layer was washed with a saturated NaHCO₃solution

and water, dried (Na₂SO₄), ﬁltered and concentrated. HPLC

puriﬁcation (hexane–EtOAc, 98:2, ﬂow 2.5 mL/min) gave

505 mg (73%) of pure triene 7 (t_R¼15.0 min) as an oil.

¹³C NMR (DMSO-d₆, 150 MHz, attributions by 2D-NMR):

d 171.1 (carbonyl), 83.0 (CH-10), 81.7 (CH-6, CH-7), 79.7

(CH-3), 72.8 (CH-11), 70.7 (CH-2), 66.6 (CH₂-1) 33.5

(CH₂-12), 29.9, 29.8 (8ꢂCH₂, C-13/C-20), 28.3 (CH₂-5,

CH₂-8), 27.6 (CH₂-9), 27.4 (CH₂-4), 21.1 (CH₃acetate),

14.6 (CH₃-21). MS m/z 453 (100, M+K)⁺, 437 (17,

M+Na)⁺. MS m/z 453 (100, M+K)⁺, 437 (27, M+Na)⁺.

HRMS: calcd for C₂₃H₄₂O₆Na 437.2868, found 437.2874.

1

Compound 7: IR (neat): n_max1738, 1229 cm^ꢁ1. H NMR:

(200 MHz) d 5.78 (1H, dt, J¼15.5, 6.0, oleﬁnic proton),

5.56 (1H, dt, J¼15.5, 6.6, oleﬁnic proton), 5.45–5.34 (4H,

11002

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

4.1.2.2. Acetic acid 2-hydroxy-2-(5⁰-undecanoyl-octa-

with saturated aqueous sodium thiosulfate (1 mL) and

NaHCO₃(1 mL) solutions and the biphasic solution was

extracted with CHCl₃(3ꢂ10 mL), then the organic phase

was dried and evaporated. The oily residue was puriﬁed by

column chromatography (gradient from CHCl₃to CHCl₃–

MeOH, 98:2) to give in the ﬁrst-eluted fractions (eluent

CHCl₃) a brown oil (10 mg) tentatively identiﬁed as the

osmate ester corresponding to tetrols 12 and then tetrols

12 (2 mg, 10%) as an oil. Compound 12: ¹H NMR

(200 MHz): d 4.30–4.05 (2H, m), 3.93–3.77 (2H, m), 3.77–

3.56 (2H, m), 3.56–3.35 (2H, m), 2.10 (3H, s, acetate), 1.25

(16H, br s), 0.87 (t, J¼6.6, Me). MS m/z 471 (62, M+K)⁺,

455 (100, M+Na)⁺. HRMS: calcd for C₂₃H₄₄O₇Na

455.2973, found 455.2966.

hydro-[2,2⁰]bifuranyl-5-yl)-ethyl ester 9. IR (neat): n_max

1

3444, 1734, 1716 cm^ꢁ1. H NMR (600 MHz, attributions

by 2D-NMR): d 4.40 (1H, dd, J¼8.7, 6.0, H-10), 4.15 (2H,

d, J¼6.0, H₂-1), 4.07–3.89 (3H, m, H-3, H-6, H-7), 3.69

(1H, br q, J¼6.0, H-2), 2.50 (2H, dt, J¼7.2, 2.1, H₂-12),

2.09 (3H, s, acetate), 1.37–1.18 (16H, br s, H₂-13/H₂-20),

0.88 (3H, t, J¼6.9, H₃-21). ¹³C NMR (150 MHz, attributions

by 2D-NMR): d 211.6 (C-11), 170.6 (carbonyl acetate), 82.7

(CH-7), 80.9 (CH-6), 80.8 (CH-10), 80.1 (CH-3), 71.9 (CH-

2), 66.7 (CH₂-1), 33.6 (CH₂-12), 29.4 (CH₂-13/CH₂-20),

27.5, 28.3 (CH₂-4, CH₂-5, CH₂-8, CH₂-9), 20.9 (CH₃ace-

tate), 13.9 (CH₃-21). MS m/z 451 (100, M+K)⁺, 435 (78,

M+Na)⁺, 413 (16, M+H)⁺. HRMS: calcd for C₂₃H₄₀O₆Na

435.2712, found 435.2719.

4.1.4.1. Dihydroxylation of 11 to 12. To a solution of 11

(5 mg, 0.012 mmol) in acetone–water (5:1, 600 mL) was

added OsO₄(0.3 mg, 10%) and NMO (32 mg, 0.24 mmol)

and the mixture stirred at room temperature for 1 h. The

reaction was quenched by the addition of a saturated solution

of sodium thiosulfate (0.5 mL) and NaHCO₃(0.5 mL) and

the whole was extracted with CHCl₃(3ꢂ3 mL). The organic

phase was dried and evaporated and the residue puriﬁed by

preparative TLC (CHCl₃–CH₃OH, 9:1, R_f¼0.31) to give

4.3 mg (80%) of tetrols 12.

4.1.2.3. Acetic acid 2-[5⁰-(1-hydroxy-undecyl)-octahy-

dro-[2,2⁰]bifuranyl-5-yl]-2-oxo-ethyl ester 10. IR (neat):

1

n_max3400, 1734, 1716 cm^ꢁ1. H NMR (600 MHz, attribu-

tions by 2D-NMR): d 5.16, 4.91 (1H each, AB system,

J_AB¼17.7, H₂-1), 4.48 (1H, dd, J¼7.6, 6.4, H-3), 3.98 (1H,

br q, J¼6.8, H-6), 3.92 (1H, br q, J¼6.8, H-7), 3.81 (1H, br

q, J¼6.4, H-10), 3.43 (1H, m, H-11), 2.18 (3H, s, acetate),

2.05–1.85 (H₂-4, H₂-5, H₂-8, H₂-9), 1.45 (2H, m, H₂-12),

1.27 (16H, br s, H₂-13/H₂-20), 0.88 (3H, t, J¼6.9, H₃-21).

¹³C NMR (150 MHz, attributions by 2D-NMR): d 204.9

(C-2), 170.2 (carbonyl acetate), 83.2 (CH-3), 82.8 (CH-10),

82.7 (CH-6), 80.9 (CH-7), 74.1 (CH-11), 66.5 (CH₂-1) 33.6

(CH₂-12), 29.9 (CH₂-13/CH₂-20), 27.5, 29.0 (CH₂-4, CH₂-5,

CH₂-8, CH₂-9), 20.2 (CH₃acetate), 14.0 (CH₃-21). MS

m/z 451 (83, M+K)⁺, 435 (63, M+Na)⁺, 413 (18, M+H)⁺.

HRMS: calcd for C₂₃H₄₀O₆Na 435.2712, found 435.2705.

4.1.5. Synthesis of acetic acid 2-hydroxy-2-[5⁰-(1-hy-

droxy-undecyl)-octahydro-[2,2⁰]bifuranyl-5-yl]-ethyl

esters 13 and 14. To a solution of 11 (5.0 mg, 0.012 mmol)

in CH₂Cl₂(1 mL) was added MCPBA (4.4 mg, 0.026 mmol)

at 0 ^ꢀC and the mixture was stirred at the same temperature

for 1.5 h. Then, CSA (0.6 mg, 0.0026 mmol) was added and

the solution was stirred for further 45 min. The reaction was

quenched with a saturated aqueous NaHCO₃solution (1 mL)

and extracted with EtOAc (3ꢂ5 mL). The organic phase was

dried and evaporated. The residue was puriﬁed by HPLC

(hexane–EtOAc, 1:1) to give the two diastereomeric bis-

THF diols 13 and 14 as oils. Major isomer (t_R¼23 min,

1.6 mg, 30%); minor isomer (t_R¼24.5 min, 1.4 mg, 26%).

4.1.2.4. Acetic acid 6-hydroxy-6-[5-(1-hydroxy-undecyl)-

tetrahydro-furan-2-yl]-hex-2-enyl ester 11. IR (neat): n_max

1

3412, 1741, 1235 cm^ꢁ1. H NMR (200 MHz): d 5.80 (1H,

dt, J¼15.7, 6.6, oleﬁnic proton), 5.59 (1H, dt, J¼15.7, 5.9,

oleﬁnic proton), 4.51 (2H, d, J¼6.4, H₂-1), 3.82 (2H, m,

H-7, H-10), 3.42 (2H, m, H-6, H-11), 2.05 (3H, s, acetate),

1.42–1.18 (br s, H₂-13/H₂-20), 0.87 (3H, t, J¼6.3, H₃-21).

MS m/z 437 (65, M+K)⁺, 421 (87, M+Na)⁺. HRMS: calcd

for C₂₃H₄₂O₅Na 421.2919, found 421.2926.

1

Major isomer. IR (neat): n_max3440, 1742, 1240 cm^ꢁ1. H

NMR (500 MHz): d 4.22, 4.05 (1H each, AB system further

coupled, J¼11.5, 3.0 and 11.5, 7.2, respectively, CH₂OAc),

4.02–3.92 (3H, m, 3ꢂCH–O), 3.88 (2H, m, CH–O), 3.37

(1H, dt, J¼7.5, 4.9, H-11), 2.10 (3H, s, acetate), 1.25 (br s,

overlapped with other signals), 0.88 (3H, t, J¼6.7, H₃-21).

MS m/z 453 (90, M+K)⁺, 437 (53, M+Na)⁺. HRMS: calcd

for C₂₃H₄₂O₆Na 437.2868, found 437.2875.

4.1.3. Oxidation of bis-THF diol 9 with TPAP/NMO. To a

solution of 8 (4.0 mg, 0.01 mmol) in CH₂Cl₂(400 mL) were

sequentially added N-methylmorpholine N-oxide monohy-

˚

drate (NMO) (2.0 mg, 1.5 equiv), powdered 4 A molecular

sieves (5 mg) and TPAP (10 mol %, 0.4 mg) under stirring

at room temperature. After 1 h the mixture was concen-

trated, ﬁltered on silica gel (CHCl₃–CH₃OH, 9:1) to give

1

Minor isomer. IR (neat): n_max3450, 1742, 1240 cm^ꢁ1. H

1

3.5 mg of a crude material. H NMR analysis revealed the

NMR (500 MHz): d 4.15 (1H, m), 4.05 (2H, m), 3.97 (1H,

br ddd, J¼7.2, 7.2, 3.3), 3.89 (2H, m), 3.83 (1H, q,

J¼6.2), 3.41 (1H, ddd, J¼7.4, 5.1, 5.1), 2.09 (3H, s, acetate),

1.25 (br s, overlapped with other signals), 0.88 (3H, t, J¼7.0,

H₃-21). MS m/z 453 (88, M+K)⁺, 437 (64, M+Na)⁺. HRMS:

calcd for C₂₃H₄₂O₆Na 437.2868, found 437.2861.

presence of a mixture of ketols 9 and 10 (together ca.

50%) in a ca. 2:1 ratio along with a 20–25% amount of a

product tentatively identiﬁed as the corresponding diketone

(d 5.10, 4.90, AB system, J¼17.7).

4.1.4. Synthesis of acetic acid 2,3,6-trihydroxy-6-[5-(1-

hydroxy-undecyl)-tetrahydro-furan-2-yl]-hexyl esters

12. A solution of triene 7 (15.6 mg, 0.046 mmol) in CH₂Cl₂

(4 mL) was treated with NMO (50 mg, 0.37 mmol) and

CSA (127.2 mg, 0.55 mmol) followed by osmium tetroxide

(1.2 mg, 0.0046 mmol, 10%) and the solution was stirred at

room temperature for 1.5 h. The reaction was quenched

4.1.6. Synthesis of (E,E,E,E)-acetic acid pentacosa-

2,6,10,14-tetraenyl ester (16).

4.1.6.1. (E,E,E)-Tricosa-4,8,12-trienoic acid ethyl ester

15. (E,E)-Nonadeca-4,8-dienal (2.8 g, 10.07 mmol) in dry

THF (5 mL), at 0 ^ꢀC, was reacted with vinylmagnesium

bromide (1 M in THF, 11 mL, 11 mmol) as reported above

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

11003

for undecylic aldehyde (see synthesis of 4) and worked-up in

the same manner to give (E,E,E)-heneicosa-1,6,10-trien-

3-ol (2.8 g, 91%) as an oil that was used without further

puriﬁcation in the next step of the synthesis. IR (neat):

The crude aldehyde obtained as above (1.80 g, 5.42 mmol)

dissolved in dry THF (2 mL) was added to a solution of tri-

ethyl phosphonoacetate (1.07 mL, 5.42 mmol) in dry THF

(3 mL), previously mixed with NaH (60% in mineral oil,

216 mg, 5.42 mmol), as described for the synthesis of ester

6, to give 1.66 g of crude (E,E,E,E)-pentacosa-2,6,10,14-

tetraenoic acid ethyl ester as an oil. Puriﬁcation of a 50 mg

amount of this material by HPLC (hexane–EtOAc, 98:2,

ﬂow: 2.5 mL/min) afforded a pure sample (25 mg, 38%,

t_R¼14.6 min) for spectral characterization. IR (neat): n_max

¹H NMR (300 MHz): d 6.95 (1H, dt, J¼15.8, 6.7, H-3),

5.81 (1H, dt, J¼15.8, 1.2, H-2), 5.50–5.30 (6H, m, oleﬁnic

protons), 4.18 (2H, q, J¼7.4, CO₂CH₂CH₃), 2.31–2.19

(2H, m), 2.19–2.09 (2H, m), 2.09–1.90 (10H, overlapped

m’s), 1.38–116 (19H, br s partly overlapped with a triplet

(J¼7.6) attributable to CO₂CH₂CH₃), 0.88 (3H, t, J¼7.0,

Me). ¹³C NMR (50 MHz): d 166.6, 148.5, 131.1, 130.7,

130.2, 129.7, 129.6, 128.6, 121.5, 60.0, 32.7, 32.57, 32.55,

32.52, 32.2, 31.9, 30.9, 29.6, 29.5, 29.3, 29.1, 22.6, 14.0.

MS m/z 441 (90, M+K)⁺, 425 (65, M+Na)⁺. HRMS: calcd

for C₂₇H₄₆O₂Na 425.3384, found 425.3378.

1

n_max3361 cm^ꢁ1. H NMR (200 MHz): d 5.81 (1H, ddd,

J¼17.2, 10.5, 6.4, H-2), 5.54–5.25 (4H, m, H-6, H-7,

H-10, H-11), 5.17 (1H, br d, J¼17.2, H_a-1), 5.04 (1H, br d,

J¼10.5, H_b-1), 4.06 (1H, q, J¼6.2, H-3), 2.17–1.84 (8H,

m), 1.70–1.45 (2H, m), 1.40–1.13 (16H, m), 0.86 (3H, t,

J¼6.7, Me). ¹³C NMR (50 MHz): d 141.1, 130.6, 130.4,

129.7, 129.4, 114.3, 72.4, 36.6, 32.63, 32.60, 32.5, 31.8,

29.6, 29.5, 29.3, 29.1, 28.4, 22.6, 14.0. MS m/z 345 (40,

M+K)⁺, 329 (83, M+Na)⁺. HRMS: calcd for C₂₁H₃₈ONa

329.2811, found 399.2800.

1724 cm^ꢁ1

.

UV l_max(MeOH)¼208 nm (3¼25,300).

A solution of crude allyl alcohol (2.8 g, 9.1 mmol), triethyl

orthoacetate (2.1 equiv, 19.2 mmol, 3.5 mL) and propionic

acid (2%, 0.18 mmol, 19 mL) in xylene (3.5 mL) was

reﬂuxed for 4 h. Removal of the solvent followed by puriﬁ-

cation by column chromatography (petroleum ether/petro-

leum ether–ethyl ether, 9:1) afforded 1.77 g (53%) of

(E,E,E)-tricosa-4,8,12-trienoic acid ethyl ester 15 as an oil.

Compound 15: IR (neat): n_max1738 cm^ꢁ1

.

¹H NMR

The remaining crude ester (1.60 g, 4.23 mmol) dissolved in

dry THF (12 mL) was reduced with DIBAL-H (1 M in THF,

12.7 mL, 12.7 mmol) at ꢁ78 ^ꢀC as described for triene 7 to

give 1.26 g of an oily product. HPLC puriﬁcation (hexane–

ethyl acetate, 7:3) gave 410 mg (24% respect to ester 15;

four steps) of (E,E,E,E)-pentacosa-2,6,10,14-tetraen-1-ol

(200 MHz): d 5.49–5.26 (6H, m, oleﬁnic protons), 4.12

(2H, q, J¼6.7, CO₂CH₂CH₃), 2.42–2.21 (2H, m), 2.15–

1.86 (12H, m), 1.41–1.15 (19H, br s including the

CO₂CH₂CH₃signal), 0.88 (3H, t, J¼6.5, Me). ¹³C NMR

(50 MHz): d 172.7, 130.9, 130.5, 130.0, 129.6, 129.4,

128.2, 59.9, 34.2, 32.5, 32.43, 32.38, 31.8, 29.5, 29.4,

29.2, 29.0, 27.8, 22.5, 14.0, 13.9. MS m/z 415 (54, M+K)⁺,

399 (85, M+Na)⁺. HRMS: calcd for C₂₅H₄₄O₂Na

399.3228, found 399.3223.

1

as an oil. IR (neat): n_max3348 cm^ꢁ1. H NMR (200 MHz):

d 5.67 (2H, m, oleﬁnic protons), 5.40 (6H, m, oleﬁnic pro-

tons), 4.08 (2H, d, J¼4.4, H₂-1), 2.15–1.87 (14H, over-

lapped m’s), 1.35–1.5 (16H, br s), 0.87 (3H, t, J¼7.2, Me).

¹³C NMR (100 MHz): d 132.7, 130.7, 130.4, 130.1, 129.9,

129.6, 129.5, 129.2, 63.8, 32.65, 32.62, 32.5, 32.2, 32.1,

31.9, 29.6, 29.5, 29.3, 29.1, 22.6, 14.0. MS m/z 399 (80,

M+K)⁺, 383 (43, M+Na)⁺. HRMS: calcd for C₂₅H₄₄ONa

383.3279, found 383.3277.

4.1.6.2. (E,E,E,E)-Acetic acid pentacosa-2,6,10,14-

tetraenyl ester 16. Ester 15 (1.77 g, 4.7 mmol) was reduced

with LiAlH₄(178 mg, 4.7 mmol) in dry ethyl ether (15 mL)

following the same procedure employed for the synthesis

of ester 5 to give 1.74 g of crude (E,E,E)-tricosa-4,8,12-

trien-1-ol as an oil that was used without further puriﬁcation

Acetylation of the above alcohol (410 mg, 1.14 mmol) with

Ac₂O–pyridine (1:1, 1 mL), as described for the synthesis of

triene 7, gave 495 mg of tetraene 16. Accurate H NMR

in the next step of the synthesis. IR (neat): n_max3347 cm^ꢁ1

.

¹H NMR (200 MHz): d 5.50–5.24 (6H, m, oleﬁnic protons),

3.57 (2H, t, J¼7.0, H₂-1), 2.13–1.87 (12H, m), 1.57 (2H,

quintet, J¼7.0), 1.30 1.17 (16H, br s), 0.85 (3H, t, J¼6.7,

Me). ¹³C NMR (50 MHz): d 130.6, 130.4, 130.1, 129.8,

129.6, 129.5, 62.1, 32.64, 32.61, 32.56, 32.5, 32.3, 31.8,

29.6, 29.4, 29.3, 29.1, 28.8, 22.6, 14.0. MS m/z 373 (70,

M+K)⁺, 399 (45, M+Na)⁺. HRMS: calcd for C₂₃H₄₂ONa

357.3123, found 357.3140.

1

analysis revealed it to be still contaminated by other minor

products exhibiting very similar chromatographic (HPLC

direct-phase) mobility. Pure 16, an oil, could be obtained

after reverse-phase (MeOH) HPLC (250 mg, 55%).

1

Compound 16: IR (neat): n_max1738, 1229 cm^ꢁ1. H NMR

(400 MHz): d 5.78 (1H, dt, J¼15.4, 6.2, oleﬁnic proton),

5.58 (1H, dt, J¼15.4, 6.4, oleﬁnic proton), 5.35–5.45 (6H,

m, oleﬁnic protons), 4.51 (2H, d, J¼6.4, H₂-1), 2.13–1.95

(17H, overlapped m’s including a 3H singlet at 2.06 ppm

due to the acetate methyl), 1.40–1.20 (16H, br s), 0.90

(3H, t, J¼7.2, Me). ¹³C NMR (100 MHz): d 170.7, 135.8,

130.7, 130.5, 130.1, 129.8, 129.6, 129.3, 124.1, 65.1,

32.67, 32.65, 32.61, 32.5, 32.2, 31.9, 29.6, 29.5, 29.3,

29.1, 22.6, 20.9, 14.0. MS m/z 441 (33, M+K)⁺, 425 (62,

M+Na)⁺. HRMS: calcd for C₂₇H₄₆O₂Na 425.3384, found

425.3377.

A solution of the crude alcohol (1.74 g, 5.2 mmol) in CH₂Cl₂

(23 mL) was oxidised with PCC (2.25 g, 10.4 mmol) and

Celite (2.2 g) as reported for the synthesis of ester 5 to give

1.8 g of (E,E,E)-tricosa-4,8,12-trienal, as an oil, that was

used in the next step. IR (neat): n_max1729 cm^ꢁ1. H NMR

1

(200 MHz): d 9.76 (1H, t, J¼1.6, CHO), 5.53–5.22 (6H,

m, oleﬁnic protons), 2.52–2.32 (2H, m), 2.39–2.24 (2H,

m), 2.09–1.88 (10H, overlapped m’s), 1.42–1.15 (16H, br

s), 0.87 (3H, t, J¼7.2, Me). ¹³C NMR (50 MHz): d 201.9,

131.2, 130.6, 130.1, 129.55, 129.47, 127.9, 43.4, 32.6,

32.5, 32.3, 31.8, 29.5, 29.4, 29.2, 29.0, 25.1, 22.6, 14.0.

MS m/z ꢁ371 (45, M+K)⁺, 355 (90, M+Na)⁺. HRMS: calcd

for C₂₃H₄₀ONa 355.2967, found 355.2961.

4.1.7. Oxidation of tetraene 16 with RuO_4(cat.)/NaIO₄.

Tetraene 16 was oxidised as reported above for triene 7.

In particular, to a solution of tetraene 16 (27.3 mg,

11004

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

0.068 mmol) in the biphasic mixture EtOAc–CH₃CN–H₂O

(3:3:1) (10.5 mL) were added in sequence NaIO₄(5 equiv,

75 mg) and RuO₂$2H₂O (20 mol %, 1.7 mg) under vigorous

stirring at 0 ^ꢀC. After 20 min a saturated Na₂S₂O₃$5H₂O

solution (2 mL) was added and, after a further 10 min stir-

ring, the mixture was ﬁltered and extracted with EtOAc

(3ꢂ10 mL). The combined organic phase was dried and

evaporated to give 35 mg of an oily product. HPLC separa-

tion (hexane–EtOAc, 3:7, ﬂow 2.5 mL/min) afforded bis-

THF diol 17 (6.2 mg, 21%, t_R¼13 min), bis-THF ketol 18

(4.8 mg, 16%, t_R¼9.6 min) and bis-THF ketol 19 (1.1 mg,

5%, t_R¼9.2 min) as oils.

4.1.7.1. Acetic acid 6-hydroxy-6-[5⁰-(1-hydroxy-un-

decyl)-octahydro-[2,2⁰]bifuranyl-5-yl]-hex-2-enyl ester 17.

IR (neat): n_max3414, 1737 cm^ꢁ1. ¹H NMR (600 MHz, attribu-

tions by 2D-NMR): d 5.73 (1H, dt, J¼15.2, 6.5, H-3), 5.59

(1H, dt, J¼15.2, 6.5, H-2), 4.50 (2H, d, J¼6.5, H₂-1), 3.89

(2H, m, H-10 and H-11), 3.83 (2H, m, H-7 and H-14), 3.40

(1H, m, H-6), 3.39 (1H, m, H-15), 2.28, 2.15 (1H each, m’s,

H₂-4), 2.06 (3H, s, acetate), 1.94, 1.81 (4H each, m’s, H₂-8,

H₂-9, H₂-12, H₂-13), 1.55, 1.53 (1H each, m’s, H₂-5), 1.45

(2H, m, H₂-16), 1.26 (16H, br s, H₂-17/H₂-24), 0.87 (3H, t,

J¼6.8, H₃-25).

H₂-1), 4.37 (1H, dd, J¼8.5, 6.0, H-7), 3.94 (1H, m, H-10),

3.92 (1H, m, H-11), 3.83 (1H, m, H-14), 3.37 (1H, br q,

J¼7.2, H-15), 2.69 (1H, dt, J¼7.2, 2.0, H₂-5), 2.33 (2H,

br q, J¼7.4, H₂-4), 2.15, 1.98 (1H each, m’s, H₂-8), 2.05

(3H, s, acetate), 1.92, 1.76 (3H each, m’s, H₂-9, H₂-12,

H₂-13), 1.26 (16H, br s, H₂-17/H₂-24), 0.87 (3H, t, J¼6.8,

H₃-25).

¹³C NMR (150 MHz, attributions by 2D-NMR): d 213.0

(C-6), 171.6 (carbonyl acetate), 134.5 (CH-3), 124.1

(CH-2), 84.2 (CH-7), 83.1 (CH-10, CH-14), 81.6 (CH-11),

74.2 (CH-15), 65.2 (CH₂-1), 38.1 (CH₂-5), 29.8 (CH₂-17/

CH₂-24), 28.8 (CH₂-8), 28.5 (CH₂-9, CH₂-12, CH₂-13),

25.7 (CH₂-4), 21.0 (CH₃acetate), 14.2 (CH₃-25). MS m/z

505 (60, M+K)⁺, 489 (82, M+Na)⁺. HRMS: calcd for

C₂₇H₄₆O₆Na 489.3180, found 489.3187.

4.1.8. Oxidation of bis-THF diol 17 with TPAP/NMO. To

a solution of 17 (5.0 mg, 0.01 mmol) in CH₂Cl₂(400 mL)

were sequentially added NMO (2.0 mg, 1.5 equiv), pow-

˚

dered 4 A molecular sieves (5 mg) and TPAP (10 mol %,

0.4 mg) under stirring at room temperature. After 1 h, the

mixture was concentrated, ﬁltered on silica gel (CHCl₃–

CH₃OH, 9:1) to give 4.5 mg of a crude material whose

¹H NMR analysis revealed the presence of a mixture of

ketols 18 and 19 in a ca. 1:1 ratio.

¹³C NMR (150 MHz, attributions by 2D-NMR): d 171.4

(carbonyl), 136.2 (CH-3), 124.1 (CH-2), 83.1 (CH-7, CH-

14), 81.3 (CH-10, CH-11); 74.1 (CH-15), 73.4 (CH-6),

65.3 (CH₂-1), 34.5 (CH₂-16), 33.9 (CH₂-5), 29.7 (CH₂-17/

CH₂-24), 28.5 (CH₂-4, CH₂-8, CH₂-9, CH₂-12, CH₂-13),

21.1 (acetate), 14.0 (CH₃-25). MS m/z 507 (47, M+K)⁺,

491 (75, M+Na)⁺. HRMS: calcd for C₂₇H₄₈O₆Na

491.3336, found 491.3343.

4.1.9. Synthesis of (E,Z,E)-acetic acid 12-acetoxy-dodeca-

2,6,10-trienyl ester (21). Ozone was bubbled through a solu-

tion of 12 g (110 mmol) of 1,5-cyclooctadiene (COD) in

120 mL of CH₂Cl₂at ꢁ78 ^ꢀC as reported in Ref. 18. Then

PPh₃(5.82 g, 22 mmol) was added and the bath removed.

After 1 h Ph₃P]CHCO₂Et (25 g, 71.8 mmol) was added

and the mixture kept at room temperature for 16 h. Then

the solvent was evaporated to give a white solid to which

was added petroleum ether (40–70). Filtration under vacuum

afforded a yellowish oil that was chromatographed on silica

gel. The fraction eluted with petroleum ether–ethyl ether

(85:15) gave 4.42 g (14.3%) of pure (E,Z,E)-dodeca-

2,6,10-trienedioic acid diethyl ester 20 as an oil.¹⁸

4.1.7.2. Acetic acid 6-hydroxy-6-(5⁰-undecanoyl-octa-

hydro-[2,2⁰]bifuranyl-5-yl)-hex-2-enyl ester 18. IR (neat):

1

n_max3414, 1734, 1716 cm^ꢁ1. H NMR (600 MHz, attribu-

tions by 2D-NMR): d 5.77 (1H, dt, J¼15.4, 6.5, H-3), 5.62

(1H, dt, J¼15.4, 6.7, H-2), 4.50 (2H, d, J¼6.7, H₂-1), 4.38

(1H, dd, J¼8.3, 5.8, H-14), 3.95 (2H, m, H-10 and H-11),

3.83 (1H, dt, J¼7.5, 5.6, H-7), 3.40 (1H, m, H-6), 2.57

(2H, dt, J¼7.2, 2.6, H₂-16), 2.30, 2.19 (1H each, m’s,

H₂-4), 2.16, 1.96 (1H each, m’s, H₂-13), 2.07 (3H, s, acetate),

2.03, 1.71 (1H each, m’s, H₂-12), 1.96, 1.81 (1H each, m’s,

H₂-9), 1.95, 1.77 (1H each, m’s, H₂-8), 1.56, 1.54 (1H

each, m’s, H₂-5), 1.27 (16H, br s, H₂-17/H₂-24), 0.88 (3H,

t, J¼6.8, H₃-25).

1

Compound 20: IR (neat): n_max1720, 1655 cm^ꢁ1. H NMR

(300 MHz): d 6.94 (1H, dt, J¼15.6, 6.6, H-3), 5.83 (1H, d,

J¼15.6, H-2), 5.40 (1H, br t, J¼4.2, H-6), 4.18 (2H, q,

J¼6.9, CO₂CH₂CH₃), 2.30–2.10 (4H, m, 2ꢂCH₂), 1.28

(3H, t, J¼7.2, Me). ¹³C NMR (75 MHz): d 165.9, 147.7,

128.8, 121.4, 59.6, 31.5, 25.4, 13.8. MS m/z 319 (55,

M+K)⁺, 303 (90, M+Na)⁺.

¹³C NMR (150 MHz, attributions by 2D-NMR): d 211.0

(C-15), 171.6 (carbonyl acetate), 136.3 (CH-3), 124.1

(CH-2), 83.4 (CH-14), 82.9 (CH-7), 82.7 (CH-11),

81.1 (CH-10), 73.4 (CH-6), 65.3 (CH₂-1), 39.2 (CH₂-16),

33.5 (CH₂-5), 29.8 (CH₂-17/CH₂-24), 29.1 (CH₂-13),

28.8 (CH₂-4), 28.2 (CH₂-8), 28.1 (CH₂-9), 27.9 (CH₂-12),

21.1 (CH₃acetate), 14.2 (CH₃-25). MS m/z 505 (45,

M+K)⁺, 489 (71, M+Na)⁺. HRMS: calcd for C₂₇H₄₆O₆Na

489.3180, found 489.3172.

To a solution of diester 20 (1.64 g, 5.86 mmol) in dry THF

(10 mL) was dropwise added DIBAL-H (1 M in toluene,

25.8 mL, 25.8 mmol) at ꢁ78 ^ꢀC. The mixture was stirred

at this temperature for 1 h and then a saturated NH₄Cl

solution (5 mL) was dropwise added. The mixture was ex-

tracted with EtOAc (4ꢂ20 mL). The combined organic

layer was dried and concentrated to give 1.12 g (98%) of

(E,Z,E)-dodeca-2,6,10-triene-1,12 diol as an oil. IR (neat):

n_max3330 cm^{ꢁ1 1}H NMR (200 MHz): d 5.63 (2H, m,

.

4.1.7.3. Acetic acid 6-[5⁰-(1-hydroxy-undecyl)-octa-

oleﬁnic protons), 5.35 (1H, br t, J¼3.8, oleﬁnic proton),

4.03 (2H, d, J¼3.8, oleﬁnic proton, H₂-1), 2.20–2.00

(4H, br s, 2ꢂCH₂).¹⁸¹³C NMR (50 MHz): d 132.0,

129.3, 63.2, 32.0, 26.7. MS m/z 235 (70, M+K)⁺, 219 (86,

M+Na)⁺.

hydro-[2,2⁰]bifuranyl-5-yl]-6-oxo-hex-2-enyl ester 19. IR

1

(neat): n_max3444, 1739, 1716 cm^ꢁ1. H NMR (600 MHz,

attributions by 2D-NMR): d 5.76 (1H, dt, J¼15.3, 6.8,

H-3), 5.59 (1H, dt, J¼15.3, 6.5, H-2), 4.48 (2H, d, J¼6.5,

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

11005

To 1.12 g (5.7 mmol) of the above diol were added Ac₂O and

pyridine (1:1, 5 mL) and the mixture was kept overnight at

room temperature. Usual work-up followed by HPLC puriﬁ-

cation (4:6 hexane–EtOAc) afforded 1.16 g (73%) of pure

triene diacetate 21 as an oil.

2ꢂH-2), 2.22–1.78 (overall 11H, multiplet overlapped with

a 3H singlet at 2.09 ppm for the acetate methyl). ¹³C NMR

(150 MHz, attributions by 2D-NMR): d 170.8 (carbonyl),

81.5, 81.0 (CH-1, CH-4, CH-5), 78.9 (CH-8), 72.0 (CH-9),

66.1 (CH-10), 29.0, 27.5 (CH₂-2, CH₂-3, CH₂-6, CH₂-7),

20.9 (CH₃acetate). MS m/z 299 (56, M+K)⁺, 283 (78,

M+Na)⁺. HRMS: calcd for C₁₂H₂₀O₆Na 283.1152, found

283.1160.

4.1.9.1. (E,Z,E)-Acetic acid 12-acetoxy-dodeca-2,6,10-

trienyl ester 21. IR (neat): n_max1738, 1234 cm^ꢁ1. ¹H NMR

(300 MHz): d 5.84–5.65 (1H, m, oleﬁnic proton), 5.57 (1H,

dt, J¼15.3, 6.0, oleﬁnic proton), 5.42–5.28 (1H, br s, oleﬁnic

proton), 4.48 (2H, d, J¼6.3, H₂-1), 2.10, 2.03 (overall 7H, br

s and s, 2ꢂCH₂and methyl acetate). ¹³C NMR (75 MHz):

d 170.8, 135.7, 129.3, 124.2, 65.1, 32.2, 26.6, 21.00. MS

m/z 319 (43, M+K)⁺, 303 (91, M+Na)⁺. HRMS: calcd for

C₁₆H₂₄O₄Na 303.1566, found 303.1573.

4.1.10.3. Acetic acid 6-[5-(2-acetoxy-1-hydroxy-ethyl)-

tetrahydro-furan-2-yl]-2,3,6-trihydroxy-hexyl ester 24.

IR (neat): n_max3390, 1733 cm^ꢁ1; ¹H NMR (selected values,

200 MHz): d 4.30–4.10 (4H, m, 2ꢂCH₂OAc), 4.10–3.84

(2H, br m, 2ꢂH-THF), 3.84–3.55 (4H, br m, H-2, H-3,

H-6, H-11), 2.10, 2.09 (3H each, s’s, 2ꢂOAc), 2.10–1.40

(8H, m, 4ꢂCH₂). MS m/z 403 (100, M+K)⁺, 387 (78,

M+Na)⁺, 365 (30, M+H)⁺. MS m/z 403 (88, M+K)⁺, 387

(43, M+Na)⁺. HRMS: calcd for C₁₆H₂₈O₉Na 387.1623,

found 387.1617.

4.1.10. Oxidation of triene 21 with RuO_4(cat.)/NaIO₄. Tri-

ene 21 was oxidised as reported above for triene 7. In partic-

ular, to a solution of 21 (45 mg, 0.16 mmol) in the biphasic

mixture EtOAc–CH₃CN–H₂O (3:3:1) (21 mL) were added

in sequence NaIO₄(4 equiv, 137.5 mg) and RuO₂$2H₂O

(20%, 4.2 mg) under vigorous stirring at 0 ^ꢀC. After 30 min,

the process was complete (disappearance of the starting prod-

uct). A saturated Na₂S₂O₃$5H₂O solution (2 mL) was added

and stirring continued for further 10 min. Then the mixture

was ﬁltered and extracted with EtOAc (3ꢂ10 mL) and the

combined organic phase was dried and evaporated to give

30 mg of an oily product. HPLC separation (hexane–EtOAc,

2:8, ﬂow 2.5 mL/min) afforded mono-THF lactone 22

(5.4 mg, 13%), the corresponding lactol (ca. 1:1 mixture of

epimers) 23 (0.8 mg, 2%) and a mixture of diastereomeric

tetrols 24 (6.9 mg, 12%).

4.1.10.4. Acetic acid2-[5⁰-(2-acetoxy-1-hydroxy-ethyl)-

octahydro-[2,2⁰]bifuranyl-5-yl]-2-hydroxy-ethyl ester 25.

IR (neat): n_max3422, 1739 cm^ꢁ1. ¹H NMR (600 MHz, attri-

butions by 2D-NMR): d 4.28 (1H, A part of an AB system

further coupled, J¼11.3, 7.7, C(1)H_aHOAc), 4.23 (1H,

ddd, J¼9.3, 6.0, 4.0, H-7), 4.17, 4.12 (1H each, AB system

further coupled, J¼11.7, 4.1 and 11.7, 6.8, respectively,

C(12)H₂OAc), 4.09, 4.07, 4.05 (overall 3H, overlapped

m’s, C(1) HH_bOAc, H-3, H-6, respectively), 4.00 (1H, dt,

J¼8.5, 5.6, H-10), 3.73 (1H, q, J¼5.0, H-11), 3.67 (1H, q,

J¼4.1, H-2), 2.093 (3H, s, acetate), 2.087 (3H, s, acetate),

1.85–2.05 (8H, overlapped m’s, H₂-4, H₂-5, H₂-8, H₂-9).

¹³C NMR (150 MHz, attributions by 2D-NMR): d 171.1

(acetate carbonyl linked to C-12), 170.8 (acetate carbonyl

linked to C-1), 82.0 (CH-6), 81.3 (CH-7), 80.4 (CH-10),

79.2 (CH-3), 72.6 (CH-2), 72.0 (CH-11), 65.9 (CH₂-1),

65.7 (CH₂-12), 28.3, 27.5 (CH₂-4, CH₂-5, CH₂-8, CH₂-9),

21.3 (acetate methyl linked to C-1), 21.2 (acetate methyl

linked to C-12). MS m/z 385 (89, M+K)⁺, 369 (71,

M+Na)⁺. HRMS: calcd for C₁₆H₂₆O₈Na 369.1518, found

369.1526.

When the reaction was conducted in the same conditions

using a 2.0 equiv amount of NaIO₄(21: 30 mg; NaIO₄:

45.8 mg; solvent amount 12 mL) a partial cyclization was

observed as previously seen for triene 7. In particular, the

starting triene was recovered in a 35% yield while mono-

THF diol 26 and mono-THF ketone 27 were obtained in

25% and 11% yields, respectively, after HPLC (EtOAc–

hexane, 75:25, ﬂow 2.5 mL/min; 26: t_R¼17.0 min; 27:

t_R¼12.5 min).

4.1.10.5. Acetic acid 6-[5-(2-acetoxy-1-hydroxy-ethyl)-

tetrahydro-furan-2-yl]-6-hydroxy-hex-2-enyl ester 26.

IR (neat): n_max3419, 1739 cm^ꢁ1. ¹H NMR (600 MHz, attri-

butions by 2D-NMR): d 5.78 (1H, dt, J¼15.6, 6.8, H-3), 5.61

(1H, dt, J¼15.6, 6.5, H-2), 4.52 (2H, d, J¼6.5, C(1)H₂OAc),

4.19, 4.16 (1H each, AB system further coupled, J¼11.7, 6.8

and 11.7, 4.1, respectively, CH₂(12)-OAc), 4.01 (1H, m, H-

10), 3.92 (1H, dt, J¼7.2, 2.8, H-7), 3.88 (1H, m, H-6), 3.74

(1H, m, H-11), 2.30, 2.16 (1H, each, m’s, H₂-4), 2.09, 2.06

(3H each, s’s, acetates), 2.05–1.85 (4H, m’s, H₂-8, H₂-9),

1.48 (2H, m, H₂-5). ¹³C NMR (150 MHz, attributions by

2D-NMR): d 171.6 (2ꢂcarbonyl), 135.2 (CH-3), 124.6

(CH-2), 83.2 (CH-7), 78.7 (CH-10), 72.0 (CH-11), 71.9

(CH-6), 66.3 (CH₂-12), 65.0 (CH₂-1), 32.0 (CH₂-5), 28.7

(CH₂-4), 28.2 (CH₂-8, CH₂-9), 21.0 (2ꢂCH₃acetates).

MS¼m/z 369 (40, [M+K]⁺), 353 (81, [M+Na]⁺). HRMS:

calcd for C₁₆H₂₆O₇Na 353.1569, found 353.1577.

4.1.10.1. Acetic acid 2-hydroxy-2-(5⁰-oxo-octahydro-

[2,2⁰]bifuranyl-5-yl)-ethyl ester 22. IR (neat): n_max3430,

1

1772, 1733 cm^ꢁ1; H NMR (300 MHz): d 4.49 (1H, br q,

J¼ꢁ5.5, H-7), 4.15 (2H, d, J¼6.0, H₂-1), 4.02 (1H, br q,

J¼5.5, H-3 or H-6), 3.97 (1H, br q, J¼6.0, H-6 or H-3),

3.74 (1H, br q, J¼5.5, H-2), 2.54 (2H, m), 2.32 (2H, m),

2.13–1.95 (overall 5H, multiplet overlapped to a 3H singlet

at 2.10 ppm for the acetate methyl), 1.95–1.82 (2H, m).

¹³C NMR (75 MHz): d 176.7, 171.1, 80.9, 80.4, 79.8, 71.8,

66.1, 28.1, 27.3, 27.2, 24.0, 20.9. MS m/z 297 (60, M+K)⁺,

281 (100, M+Na)⁺. MS m/z 297 (36, M+K)⁺, 281 (77,

M+Na)⁺. HRMS: calcd for C₁₂H₁₈O₆Na 281.0996, found

281.0989.

4.1.10.2. Acetic acid 2-hydroxy-2-(5⁰-hydroxy-octa-

hydro-[2,2⁰]bifuranyl-5-yl)-ethyl esters 23. IR (neat):

1

n_max3396, 1733 cm^ꢁ1; H NMR (300 MHz): d 5.50, 5.59

(1H each, br s’s, 2ꢂH-10), 4.41, 4.25 (1H each, m’s, 2ꢂH-

7), 4.20–4.08 (5H, overlapped m’s, 2ꢂH₂-1 and 1ꢂCHO-

THF), 4.08–3.96 (3H, m, 3ꢂCHO-THF), 3.66 (2H, m,

4.1.10.6. Acetic acid 6-[5-(2-acetoxy-1-hydroxy-ethyl)-

tetrahydro-furan-2-yl]-6-oxo-hex-2-enyl ester 27. IR

(neat): n_max3403, 1733, 1716 cm^{ꢁ1 1}H NMR (600 MHz,

11006

V. Piccialli et al. / Tetrahedron 62 (2006) 10989–11007

attributions by 2D-NMR): d 5.76 (1H, dt, J¼20.5, 6.8, H-3),

5.62 (1H, dt, J¼20.5, 6.8, H-2), 4.56 (1H, dd, J¼8.7, 3.9,

H-7), 4.55 (2H, d, J¼6.0, C(1)H₂OAc), 4.24 (2H, m,

C(12)H₂OAc) 4.18 (1H, m, H-10), 3.74 (1H, m, H-11),

2.61, 2.53 (1H each, m’s, H₂-5), 2.37, 2.41 (1H each, m’s,

H₂-4), 2.09, 2.06 (3H each, s’s, acetates), 2.05–1.85 (4H,

overlapped m’s, H₂-8, H₂-9). ¹³C NMR (150 MHz, attribu-

tions by 2D-NMR): d 211.4 (C-6), 171.6, 171.0 (2ꢂacetate

carbonyls), 133.5 (CH-3), 125.2 (CH-2), 82.6 (CH-7), 80.4

(CH-10), 70.2 (CH-11), 65.1 (CH₂-12), 64.9 (CH₂-1), 38.2

(CH₂-5), 29.0, 27.5 (CH₂-8, CH₂-9), 25.5 (CH₂-4), 21.0,

20.9 (2ꢂacetate methyls). MS m/z 367 (31, M+K)⁺, 351

(93, M+Na)⁺. HRMS: calcd for C₁₆H₂₄O₇Na 351.1413,

found 351.1406.

10 min stirring, was extracted with EtOAc (3ꢂ3 mL). The

organic phase was dried and evaporated to give 2.4 mg of

a crude product that was further puriﬁed by HPLC (hexane–

EtOAc, 2:8, ﬂow 2.5 mL/min). 1.4 mg (90%) of a pure prod-

uct was obtained that showed to be identical to the mixture of

lactols 23.

Acknowledgements

We are grateful to MURST, Italy (PRIN 2003), for ﬁnancial

support in favour of this investigation and to the ‘Centro di

ꢀ

Metodologie Chimico-Fisiche dell’Universita di Napoli

‘Federico II’ ’ for NMR and MS facilities. L. Caruso wishes

to thank CINMPIS for a grant in favour of this investigation.

We wish also to thank Professor Francesco Ruffo, Depart-

4.1.11. Synthesis of mono-THF oleﬁn 26 from triene 21.

To a solution of 19.5 mg (0.070 mmol) of triene 21 in

CH₂Cl₂(500 mL) were added TMEDA (1 equiv, 10.5 mL)

and OsO₄(1 equiv, 17.7 mg) under stirring at rt. Immediate

TLC analysis (CHCl₃–MeOH, 9:1) revealed the formation

of two coloured spots (R_f¼0.2 and 0.4), likely attributable

to the two possible osmate ester, along with a minor amount

of unreacted triene. The mixture was taken to dryness after

some 2 h and subjected to two successive HPLC runs

(CHCl₃–MeOH, 9:1 then 95:5). The material eluted after

9 min (6.5 mg) in the second solvent mixture was identiﬁed

as the osmate ester at one of the terminal double bonds.

Starting triene (4.2 mg, 22%) was recovered as well.

ꢀ

ment of Chemistry, Universita di Napoli ‘Federico II’,

for helpful discussions on the coordination chemistry of

ruthenium.

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1

appears to be very clean, as noticed by H NMR analysis of

the crude reaction mixture.

Article Doi

RuO4-mediated oxidative polycyclization of linear polyenes. A new approach to the synthesis of the bis-THF diol core of antitumour cis-cis adjacent bis-THF annonaceous acetogenins

DOI: 10.1016/j.tet.2006.08.038

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