Pyranoside alkene templates for the synthesis of CIS-2,5-disubstituted tetrahydrofuran subunits of the acetogenins

Journal of Carbohydrate Chemistry

ISSN: 0732-8303 (Print) 1532-2327 (Online) Journal homepage: http://www.tandfonline.com/loi/lcar20

PYRANOSIDE ALKENE TEMPLATES FOR

THE SYNTHESIS OF CIS-2,5-DISUBSTITUTED

TETRAHYDROFURAN SUBUNITS OF THE

ACETOGENINS

Huiping Zhang , Darrin Dabideen , Galyna Pushchinska & David R. Mootoo

To cite this article: Huiping Zhang , Darrin Dabideen , Galyna Pushchinska & David R.

Mootoo (2002) PYRANOSIDE ALKENE TEMPLATES FOR THE SYNTHESIS OF CIS-2,5-

DISUBSTITUTED TETRAHYDROFURAN SUBUNITS OF THE ACETOGENINS, Journal of

Carbohydrate Chemistry, 21:5, 411-430

To link to this article: http://dx.doi.org/10.1081/CAR-120014903

Published online: 21 Aug 2006.

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Date: 04 August 2017, At: 09:29

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JOURNAL OF CARBOHYDRATE CHEMISTRY

Vol. 21, No. 5, pp. 411–430, 2002

PYRANOSIDE ALKENE TEMPLATES FOR THE

SYNTHESIS OF CIS-2,5-DISUBSTITUTED

TETRAHYDROFURAN SUBUNITS

OF THE ACETOGENINS

Huiping Zhang, Darrin Dabideen, Galyna Pushchinska,

*

and David R. Mootoo

Department of Chemistry, Hunter College,

695 Park Avenue, New York, New York 10021, USA

ABSTRACT

The iodoetherification reaction of t-butyl and trityl glycosides of C6

allylated-2,3-dideoxy-^D-erythro- and D-threo-pyranosides was examined as

part of a model study aimed at the synthesis of the 2,5-disubstituted

tetrahydrofuran subunits found in the acetogenin group of natural products. In

general, the t-butyl glycosides gave moderate, and the trityl derivatives,

excellent stereoselectivity for the cis THF product.

Key Words: 2,5-disubstituted tetrahydrofuran; Iodoetherification;

Acetogenins

INTRODUCTION

The broad spectrum pharmacological activity of the tetrahydrofuran (THF)

containing acetogenins^[1–4]has resulted in considerable interest in their synthesis.^[5–18]

We have reported that C6 allylated pyranosides (e.g., 1) are practical templates for cis-

2,5-disubstituted THF motifs (e.g., 2) found in the acetogenins^[19–22](Scheme 1). The

*

Corresponding author. Fax: + 1-212-772-5332; E-mail: dmootoo@hunter.cuny.edu

411

DOI: 10.1081/CAR-120014903

0732-8303 (Print); 1532-2327 (Online)

www.dekker.com

Copyright D 2002 by Marcel Dekker, Inc.

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ZHANG ET AL.

Scheme 1. Iodoetherification of C6 allylated pyranosides.

key reaction in this methodology is an iodoetherification involving the ring oxygen of

the pyranoside on the pendant alkene. It was found that the structure of the aglycone

substituent affected the cis/trans selectivity, with optimal results being obtained for

trityl glycosides. Herein, we describe the details of this investigation.

This methodology derives from the well known electrophilic etherification of 4-

hydroxyalkenes.^[23,24]This reaction has been widely used for rapid entry into a variety of

complex THF frameworks. However, a drawback is the uncertainty of the stereochemical

outcome in highly substituted systems. We speculated that it should be possible to

control stereoselectivity by performing the reaction on conformationally restrained

templates. Saccharide alkenes are attractive because of their easy availability and the

highly functionalized nature of the reaction products. Early experiments indicated that a

variety of allylated furanosides and pyranosides were converted to iodo-THF-aldehydes

in high yield, but with a variable degree of THF stereoselectivity.^[25]Our working

mechanistic model (Scheme 2) presumes initial reaction of the saccharide alkene 3 with

iodonium ion to generate diastereomeric iodonium ions or charge transfer complexes

4c/t, which are attacked by the ring oxygen to give THF-oxonium ions 5c/t.^[26–30]

Fragmentation of 5c/t leads to oxocarbenium ions 6c/t, which in the presence of water,

leads to aldehydes 7c/t. We surmised that variation of the size of the aglycone should

alter the stereoselectivity and in order to test this hypothesis, evaluated substrates that

could be used as precursors for the THF containing acetogenins.

Scheme 2. Proposed mechanism for iodoetherification of C6 allylated pyranosides.

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PYRANOSIDE ALKENE TEMPLATES

RESULTS AND DISCUSSION

Alkene Synthesis and Iodoetherification Reactions

413

The iodoetherification reactions of 2,3-dideoxy-^D-8-enopyranosides of erythro or

threo configuration (corresponding to the stereochemical motifs in the acetogenins),

with terminal, E or Z alkenes, were examined. The reactions of a set of erythro-

terminal alkene templates containing different aglycones were first investigated in

order to identify any general trends between aglycone structure and THF stereo-

selectivity. Pyranoside alkenes 8–11 (R =OMe, OEt, O-t-Bu, O-TFE) were obtained by

treatment of the corresponding 6-O-tosylate precursor with allylmagnesium brom-

ide.^[22](Scheme 3). The tosylates were prepared via a straightforward sequence of

reactions on the 2,3-eno-pyranoside derived from the Ferrier reaction of tri-O-acetyl-^D-

glucal and the requisite alcohol.^[31,32]The trityl glycoside mixture 13 was prepared as

an inseparable mixture of anomers (ca. a/b =3/7). This material was obtained by acid

hydrolysis of the t-butyl derivative 10, followed by silver triflate mediated tritylation

of the resulting lactol 12.

Iodoetherification reactions were performed in wet dichloromethane with iodo-

nium dicollidine perchlorate (IDCP).^[33]The cis and trans THF products were separated

by chromatography^[34]and their stereochemistry assigned by analysis of the ¹³C NMR

(vide infra). There was a noticeable increase in the level of cis selectivity as the size of

the aglycone was increased. Highest selectivity was obtained with the a/b mixture of

trityl glycosides 13. The iodotherification of lactol 12 was also examined in order to

Scheme 3. Iodoetherification of terminal alkenes.

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ZHANG ET AL.

address the possibility that the THF product from 13 might be arising through 12 as a

result of initial hydrolysis of the labile trityl group. The lack of any selectivity observed

for 12 indicates that the intermediate formation of 12 was not a major factor in the

iodoetherification of 13. It is also of interest to note that increasing the electro-

negativity of the aglycone (cf. 11) decreased reactivity, but had no noticeable effect on

stereoselectivity.

The reactions of the t-butyl and trityl glycosides 15 and 16 in the threo series

were next examined, in order to determine whether the apparent cis-directing effect of

bulky aglycones is affected by changing the configuration at the C4 position of the

pyranoside template. Compound 15 was obtained by Mitsonobu inversion at the C4

position of a precursor in the erythro series.^[22]Indeed, a similar trend was observed,

the mixture of trityl glycosides 16 showing an appreciable increase in the level of cis

stereoselectivity over the t-butyl derivative 15.

The effect of alkene substitution was next assessed by evaluating the reactions of

Z and E disubstituted alkenes of t-butyl- and trityl-2,3-dideoxypyranosides in the

erythro and threo series. The t-butyl-Z-alkenes 18 and 20 were obtained from the

Wittig reaction of butylidenetriphenylphosphorane and the aldehydes derived from the

ozonolysis of terminal alkenes 10 and 15, respectively (Scheme 4). The corresponding

E isomers 22 and 24 were obtained from the Z derivatives 18 and 20 through the

Vedejs isomerization protocol.^[35]The isomer purity of the Z and E compounds was

determined to be greater than 95% as judged from NMR. The stereochemistry of the Z

and E alkenes was established by comparison of the ¹³C chemical shifts. The allylic

carbons for the Z isomer resonate upfield relative to those of the E isomer (e.g. 18: d

31.8 and 33.9; 22: d 33.8 and 35.6).^[36,37]

The trityl glycoside mixtures 19, 21, 23 and 25 were prepared from the respective

t-butyl precursors as described earlier. Treatment of alkenes 18–25 under the standard

iodoetherification conditions led to similar results as observed for the terminal alkenes,

with the t-butyl systems showing low to moderate cis selectivity, and the trityl cases

giving appreciably higher selectivity ranging from 6:1 to greater than 20:1 (Scheme 5).

Scheme 4. Synthesis of Z- and E-alkenes.

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Scheme 5. Iodoetherification Z- and E-alkenes.

Stereochemical Assignment

In the absence of any helpful NOE data, the stereochemistry of the THF products

was deduced by comparison of the ¹³C resonances of the methylene carbons of the

THF ring for corresponding pairs of cis and trans isomers. These carbons were

assigned through HSQC experiments and by comparison with data for related

THFs.^[38,39]We had previously shown for pairs of primary iodo-THFs analogous to

14c/t, that the methylene carbons in the trans isomer are downfield relative to those of

the cis derivative.^[25]This assignment was confirmed by conversion of the isomers to

known THFs. We have also observed this trend for secondary iodo THFs related to

26c/t–29c/t.^[40–42]In these cases, stereochemistry was independantly assigned on the

basis of NOE data and conversion to known compounds. This correlation between

chemical shift and stereochemistry appears to be general for other classes of 2,5-

disubstituted THFs.^[38,39]Additional support for our stereochemical assignments came

from the correlation of the so assigned primary and secondary iodides 14t and 26t

through a central THF derivative 30t (Scheme 6). Iodide 26t was transformed to 30t

via Bu₃SnH reduction of the derived alcohol. For comparison of NMR data, 30c was

obtained in a similar fashion from 24c. Compound 14t was converted to 30t via a three

step sequence involving NaBH₄reduction of the aldehyde, radical allylation of the

iodide and hydrogenation of the resulting alkene. The relative configuration at the

iodidinated carbon was inferred from the established anti addition in the haloether-

ification of alkenes.

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Scheme 6. Stereochemical correlations for more substituted THFs.

Our tentative transition state model for the high cis stereoselectivity that is

observed for both a- and b-trityl pyranosides, assumes that the pyranose ring adopts a

chair-like conformation^[43]with a preferred pseudoequatorial (vs.pseudoaxial) approach

of the iodonium ion onto the ring oxygen (Figure 1). A half-chair like orientation is

assumed for the five atoms of the forming THF ring.^[29,30]Two diastereomeric

structures of types A and B corresponding to an ‘‘alkene up’’ or ‘‘alkene down’’

orientation, are possible. The relative stabilities of A and B are also likely to be highly

dependent on the conformation with respect to the aglyconic bond. An interesting

speculation is that the reactive conformation for both a and b glycosides is a rotamer

which is stabilized by the exo-anomeric effect,^[44]e.g., A-a/B-a, and A-b/B-b. These

rotamers are also expected to make the major contribution to the basicity of the ring

oxygen.^[45–47]For both anomers transition state B places the iodinated branch of the

THF closer to the aglycone substitutent, and this leads to an appreciable destabilizing

interaction for sterically demanding aglycones such as trityl, resulting in a preference

for A, and consequently the cis THF.

It is also possible that the results obtained with the trityl glycosides represent a

higher degree of kinetic control. It is likely, due to steric crowding, that the bulky

aglycone induces an increased rate of fragmentation of the THF-oxonium ions 5c and

5t to THF products (relative to their equilbration). Alternatively, it is conceivable that

the THF oxonium ion intermediate 5 could be more rapidly transformed to the THF-

aldehyde 7 via a mechanism involving formation of an incipient trityl cation.

EXPERIMENTAL

Thin-layer chromatography (TLC) was performed on aluminum sheets precoated

with silica gel 60 (HF-254, E. Merck) to a thickness of 0.25 mm. Flash column

chromatography (FCC) was performed using Kieselgel 60 (230–400 mesh, E. Merck)

and employed a stepwise solvent polarity gradient, correlated with TLC mobility.

1

Unless otherwise stated, H and ¹³C NMR spectra were recorded at 300 and 75.5 MHz

respectively. Assignments for selected nuclei were determined from ¹HCOSY and

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417

Figure 1. Model for stereochemistry of THF formation.

HSQC experiments, and by spectral correlation for analogous compounds (Tables 1–4).

Elemental analysis were performed by Schwarzkopf Microanalysis Laboratory. High

resolution mass spectroscopy (HRMS) was carried out at the mass spectrometry facility

of the University of Illinois at Urbana-Champaign. The general procedure for pre-

paration of the C6-allylated monosaccharides from tri-O-acetyl-^D-glucal, and the syn-

thesis of 15, has been previously described.^[22]

Terminal Alkenes

Methyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-^D-erythro-non-8-enopyranoside

1

(8). R_f=0.20 (5% EtOAc:petroleum ether); H NMR (CDCl₃) d 1.40–2.40 (m, 8H),

3.20 (m, 1H), 3.40 (s, 3H), 3.62 (t, J=7.2 Hz, 1H), 4.50–4.80 (m, 3H), 5.06 (m, 2H),

5.92 (m, 1H), 7.40 (m, 5H).

Ethyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-^D-erythro-non-8-enopyranoside (9).

R_f=0.20 (5% EtOAc:petroleum ether); ¹H NMR (CDCl₃) d 1.25 (t, J= 7.2Hz, 3H), 1.40–

2.40 (m, 8H), 3.20 (m, 1H), 3.45 (m, 1H), 3.74 (m, 2H), 4.58 (ABq, Dd =0.19 ppm, J=12

Hz, 2H)), 4.80 (d, J= 2.5 Hz, 1H), 5.06 (m, 2H), 5.90 (m, 1H), 7.40 (m, 5H).

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-^D-erythro-non-8-enopyranoside

(10). R_f=0.40 (5% EtOAc:petroleum ether); [a]²⁵140° (c 2.6, EtOH); IR (neat)

D

1640, 910, 735 cm ^{À 1}; H NMR (C₆D₆) d 1.15 (s, 9H), 1.45–2.60 (m, 8H), 3.07 (ddd,

1

J= 4.6, 9.4, 11.6 Hz, 1H), 4.05 (dt, J=1.9, 9.0 Hz, 1H), 4.36 (ABq, Dd =0.28 ppm, 2H,

J= 11.5 Hz), 5.02 (bs, 1H), 5.06 (m, 2H), 5.84 (m, 1H), 7.00–7.30 (m, 5H); ¹³C NMR

(C₆D₆) d 25.0, 28.9, 31.2, 32.2, 33.4, 71.1, 71.9, 74.5, 78.7, 91.5, 115.3, 128.7, 128.8,

128.9, 140.5.

Anal. Calcd for C₂₀H₃₀O₃: C, 75.43; H, 9.50. Found: C, 75.56; H, 9.29.

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Table 2. Selected ¹³C NMR Data for t-Butyl and Trityl Pyranoside Alkenes

Pyranoside Alkene

C1

CMe₃/CPh₃

CH₂Ph, C4, C5^a

t-Butyl-terminal-erythro 10

Trityl-terminal-erythro 13a

Trityl-terminal-erythro 13b

t-Butyl-terminal-threo 15

Trityl-terminal-threo 16a

Trityl-terminal-threo 16b

t-Butyl-Z-erythro 18

Trityl-Z-erythro 19a

Trityl-Z-erythro 19b

t-Butyl-Z-threo 20

91.5

93.1

98.1

91.8

93.8

98.7

91.2

92.9

98.1

91.8

94.0

99.0

91.1

93.2

98.1

91.9

94.0

99.0

74.5

88.6

88.8

74.0

88.3

88.8

74.2

88.2

88.5

74.0

88.8

89.0

73.8

88.6

88.8

73.9

88.9

89.0

71.1, 71.9, 78.7

71.3, 73.1, 78.4

71.4, 77.4, 78.5

70.5, 71.3, 74.2

71.4, 72.0, 73.8

71.6, 73.1, 78.0

71.1, 72.1, 78.7

71.1, 73.2, 78.2

71.1, 77.2, 78.7

70.7, 71.2, 73.9

71.5, 72.5, 73.9

71.7, 73.1, 78.5

71.0, 71.8, 78.7

71.3, 73.1, 78.5

71.4, 77.5, 78.6

70.6, 71.2, 74.2

71.5, 72.2, 73.6

71.6, 73.1, 78.3

Trityl-Z-threo 21a

Trityl-Z-threo 21b

t-Butyl-E-erythro 22

Trityl-E-erythro 23a

Trityl-E-erythro 23b

t-Butyl-E-threo 24

Trityl-E-threo 25a

^aAssignments for CH₂Ph, C4, C5 may be interchanged.

1

Table 3. Selected H NMR Data for THF-Iodides

THF-Iodide

H1

H4, H5, H8, H9^a

14c

9.40 (s)

3.62 (m, 2H), 3.32 (q, 6.2, 1H), 2.88 (dd, 5.1, 9.9, 1H),

2.82 (dd, 6.2, 9.9. 1H)

14t

9.36 (bs)

3.82 (m, 1H), 3.74 (m, 1H), 3.30 (m, 1H),

2.89 (dd, 4.8, 9.9, 1H), 2.83 (dd, 6.6, 9.0, 1H)

3.65 (m, 2H), 3.10 (m, 1H), 2.80 (m, 2H)

3.85 (m, 1H), 3.72 (m, 1H), 3.05 (m, 1H), 2.80 (m, 2H)

3.88 (m, 1H), 3.68 (m, 1H), 3.46 (q, 6.2, 1H),

3.32 (m, 1H)

17c

17t

26c

9.33 (s)

9.40 (bs)

26t

9.37 (bs)

3.95 (m, 1H), 3.92 (m, 1H), 3.55 (m, 1H),

3.36 (dt, 4.8, 7.7, 1H)

27c

27t

28c

9.35 (s)

9.41 (bs)

3.84 (m, 1H), 3.72 (m, 1H), 3.32 (m, 2H)

3.98 (m, 1H), 3.60 (m, 1H), 3.30 (m, 1H), 3.09 (m, 1H)

4.04 (q, 5.7, 1H), 3.72 (q, 5.3, 1H), 3.55 (q, 6.6, 1H),

3.34 (q, 5.5, 1H),

28t

29c

9.38 (s)

9.32 (s)

4.03 (m, 1H), 3.90 (m, 1H), 3.67 (m, 1H), 3.33 (m, 1H)

3.99 (m, 1H), 3.74 (q, 7.5, 1H), 3.58 (q, 7.5, 1H),

3.15 (m, 1H)

29t

9.32 (s)

3.95 (m, 2H), 3.71 (m, 1H), 3.05 (m, 1H)

^aAssignments for H4, H5, H8, H9 may be interchanged.

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Table 4. Selected ¹³C NMR Data for THF-Iodides

THF-Iodide

C1

C4, C5, C8^a

PhCH₂

C9

C6, C7

14c

14t

17c

17t

26c

26t

27c

27t

28c

28t

29c

29t

200.7

200.9

200.7

200.9

200.5

200.3

200.8

200.6

83.0, 79.9, 79.2

82.8, 80.0, 79.0

84.1, 80.9, 79.3

84.1, 80.9, 79.2

82.9, 82.3, 79.8

83.2, 83.0, 80.0

83.9, 82.9, 81.0

83.6, 83.2, 81.0

83.3, 82.9, 80.1

83.1 (2C), 80.1

84.1, 83.3, 80.9

83.6, 83.3, 81.2

73.4

73.5

73.4

73.2

73.4

73.7

73.4

73.2

73.4

73.6

73.4

10.6

11.5

10.9

11.2

42.5

43.5

43.0

43.2

42.9

44.4

43.1

44.1

27.3, 31.9

28.0, 33.1

28.2, 31.5

29.2, 33.9

27.8, 31.2

28.0, 32.3

28.5, 31.0

29.3, 32.0

27.3, 32.5

27.9, 33.8

28.0, 32.2

29.1, 33.8

^aAssignments for C4, C5 and C8 may be interchanged.

Trifluoroethyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-D-erythro-non-8-enopyra-

1

noside (11). R_f=0.40 (5% EtOAc:petroleum ether); IR (neat) 1641 cm ^{À 1}; H NMR

(CDCl₃) d 1.65 (m, 1H), 1.90 (m, 2H), 2.05–2.50 (m, 5H), 3.30 (dt, J= 5.5, 11.0 Hz

1H), 3.78 (dt, J =2.7, 9.0 Hz, 1H), 4.0 (m, 2H), 4.70 (ABq, Dd =0.20 ppm, J= 12.0 Hz,

2H), 4.97 (bs, 1H), 5.15 (m, 2H), 5.98 (m, 1H), 7.50 (m, 5H). ¹³C NMR (CDCl₃) d

23.6, 28.7, 29.7, 31.2, 63.8 (q, J_CCF=34.4 Hz), 70.7, 71.8, 76.8, 96.7, 114.7, 124.3

(q, J_CF= 280 Hz), 127.8, 127.9, 128.5, 138.4, 138.7.

Anal. Calcd for C₁₈H₂₃O₃F₃: C, 63.04; H, 7.02. Found: C, 62.78; H, 6.70.

4-O-Benzyl-2,3,6,7,8,9-hexadeoxy-a/b-^D-erythro-non-8-enopyranose (12). To a

solution of 10 (100 mg, 0.31 mmol) in THF (3 mL) was added 0.5N HCl (1 mL). The

solution was stirred for 5 h at rt, then neutralized with NaHCO₃, and concentrated in

vacuo. FCC gave a mixture of pyranose anomers 12 (77 mg, 94%): R_f=0.30 (10%

1

EtOAc:petroleum ether); H NMR (CDCl₃) d 1.40–2.30 (m, 8H), 2.95 (bs, ca. 0.5H,

OH), 3.16 (m, 1H), 3.35 (m, ca. 0.5H), 3.60 (bs, ca. 0.5H, OH), 3.88 (m, ca. 0.5H),

4.48 (m, 1H), 4.62 (m, 1H), 4.78 (m, ca. 0.5H, H1 b-anomer), 5.00 (m, 2H), 5.20 (bs,

ca. 0.5H, H1 a-anomer), 5.90 (m, 1H), 7.15–7.40 (m, 5H); ¹³C NMR (CDCl₃) d 23.5,

27.7, 29.5, 29.8, 31.5, 31.6, 32.1, 70.8, 71.3, 76.6, 78.1, 91.0 (C1 a-anomer), 96.1 (C1

b-anomer), 114.6, 127.7, 127.8, 128.5, 138.7, 138.9.

Trityl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a/b-^D-erythro-non-8-enopyranoside

(13). Lactol 12 (50 mg, 0.19 mmol), anhydrous 2,4,6-collidine (0.7 mmol) and freshly

activated 4 A molecular sieves in dry CH₂Cl₂(2 mL) was stirred for 15 min at rt. Trityl

chloride (167 mg, 0.60 mmol) and silver trifluoromethane sulfonate (154 mg, 0.6

mmol) were then added. The solution was stirred for 10 min., then poured into 10%

aqueous Na₂S₂O₃and extracted with ether. The organic phase was dried (Na₂SO₄), and

concentrated in vacuo. FCC of the residue provided 11 as a mixture of a/b anomers (73

mg, 76%, a/b ca. 3/7): R_f= 0.40 (5% EtOAc:petroleum ether); ¹H NMR (C₆D₆) d

1.46–2.20 (m, 8H), 3.02 (m, ca. 1.7H), 4.18 (b t, J= 10 Hz, ca. 0.3H), 4.25 (ABq,

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Dd =0.20 ppm, J =11 Hz, ca. 1.7H), 4.36 (ABq, Dd= 0.24 ppm, J= 11 Hz, ca. 0.6H),

4.45 (dd. J =1.8, 8.9 Hz, ca. 0.7H, H1 b-anomer), 5.00–5.18 (m, 2.H), 5.25 (bs, ca.

0.3H, H1 a-anomer), 5.86 (m, 1H), 7.04–7.80 (m, 20H); ¹³C NMR (C₆D₆), b anomer:

d 28.7, 30.2, 31.9, 32.7, 71.4, 77.4, 78.5, 88.8, 98.1 (C1), 114.7, 127.0–130.0 (several

lines buried under C₆D₆triplet), 139.7, 140.0, 145.9. Selected signals for a anomer: d

71.3, 73.1, 78.4, 88.6, 93.1 (C1); HRMS(CI-CH₄) calcd for C₃₅H₃₇O₃(M + H) 505.2743,

found 505.2741.

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9-hexadeoxy-a-^D-threo-non-8-enopyranoside

(15).^[22]R_f=0.40 (5% EtOAc:petroleum ether); IR (neat) 1651 cm ^{À 1 1}H NMR

;

(C₆D₆) d 1.21 (s, 9H), 1.50–2.30 (m, 8H), 3.10 (bs, 1H), 3.95 (m, 1H), 4.30 (ABq,

Dd =0.30 ppm, J= 12 Hz, 2H), 5.04 (m, 2H), 5.14 (bs, 1H), 5.82 (m, 1H), 7.25–7.40

(m, 5H); ¹³C NMR (C₆D₆) d 21.9, 26.9, 29.5, 31.1, 32.1, 70.5, 71.3, 74.0, 74.2, 91.8,

114.9, 127.9, 128.1, 128.6, 128.8, 139.7.

Anal. Calcd for C₂₀H₃₀O₃: C, 75.43; H, 9.50. Found: C, 75.04; H, 9.62.

Trityl 4-O-benzyl-2,3-dideoxy-a/b-^D-threo-non-8-enopyranoside (16) t-Butyl

pyranoside 15 was subjected to the two-step hydrolysis-tritylation sequence that was

used for 13. An inseparable mixture of a/b trityl pyranosides 16 (65%, ca. ratio 1:1)

1

was obtained: R_f= 0.40 (5% EtOAc:petroleum ether); H NMR (C₆D₆) d 1.15–2.25 (m,

8H), 2.78 (bs, ca. 0.5H), 2.86 (m, ca. 0.5H), 3.18 (bs, ca. 0.5H), 4.03 (m, ca. 0.5H),

4.13 (m, 1H), 4.48 (m, 1H), 4.56 (dd, J=1.9, 9.3 Hz, ca. 0.5H, H1 b-anomer), 5.08 (m,

2H), 5.35 (bs, ca. 0.5H, H1 a-anomer), 5.82 (m, 1H), 7.05–7.75 (m, 20H); ¹³C

NMR(C₆D₆), b anomer: d 26.6, 27.7, 30.7, 31.8, 71.6, 73.1, 78.0, 88.8, 98.7 (C1),

114.7, 127.0–130.0 (several lines buried under C₆D₆triplet), 139.8, 146.1; a anomer: d

22.4, 26.2, 30.6, 31.6, 71.4, 72.0, 73.8, 88.3, 93.8 (C1), 114.7, 127.0–130.0 (several

lines buried under C₆D₆triplet), 139.7, 140.0, 146.1; HRMS(CI-CH₄) calcd for

C₃₅H₃₇O₃(M +H) 505.2743, found 505.2762.

Z and E Alkenes

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a-^D-erythro-dodeca-8Z-

enopyranoside (18). Z-alkene 18 (49%) was prepared from terminal alkene 10,

according to the general procedure described for Z-alkene 20 (see later). R_f=0.40 (5%

1

EtOAc:petroleum ether); H NMR (C₆D₆) d 0.92 (t, J=7.4 Hz, 3H), 1.25 (s, 9H), 1.30–

2.60 (m, 12H), 3.18 (dt, J= 4.0, 9.0 Hz, 1H), 4.17 (bt, J= 9.1 Hz, 1H), 4.45 (ABq,

Dd =0.27 ppm, J= 11.Hz, 2H), 5.08 (bs, 1H), 5.52 (m, 1H), 5.68 (m, 1H), 7.00–7.40

(m, 5H); ¹³C NMR (C₆D₆) d 14.4, 23.7, 24.5, 24.8, 29.4, 30.2, 31.8, 33.9, 71.1, 72.1,

74.2, 78.7, 91.2, 127.0–130.0 (several lines buried under C₆D₆triplet), 130.2, 131.2,

140.2; MS (ES) m/z 378.3 (M + NH₄).

Trityl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a/b-^D-erythro-dodeca-8Z-

enopyranoside (19). t-Butyl pyranoside 18 was subjected to the two-step hydrolysis-

tritylation sequence that was used for 13. An inseparable mixture of a/b trityl

pyranosides 19 (68%, ca ratio 2:3) was obtained: R_f= 0.40 (5% EtOAc:petroleum

1

ether); H NMR (C₆D₆) d 0.90, 0.92 (overlapping t, J=7.0 Hz, 3H), 1.25–2.20 (m,

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ZHANG ET AL.

12H), 3.00 (m, ca. 1.6H), 4.16 (dt, J= 2.0, 10.0 Hz, ca. 0.4H), 4.18 (ABq, Dd= 0.19

ppm, J =11.Hz, ca. 1.2H), 4.36 (ABq, Dd =0.24 ppm, J= 11.Hz, ca. 0.8H), 4.36 (dd,

J=2.1, 9.1 Hz, ca. 0.6H, H1 b-anomer), 5.18 (bs, ca. 0.4H, H1 a-anomer), 5.44 (m,

2H), 7.03–7.69 (m, 5H); ¹³C NMR (C₆D₆), b anomer: d 14.4, 23.6, 23.9, 28.5, 30.0,

31.7, 33.3, 71.1, 77.2, 78.7, 88.5, 98.1, 127.0–132.0 (several lines overlapped by

C₆D₆triplet), 139.5, 146.2; selected signals for a anomer: d 71.1, 73.2, 78.2, 88.2,

92.9 (C1).

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a-^D-threo-dodeca-8Z-

enopyranoside (20). The terminal alkene 15 (555 mg, 1.66 mmol) was dissolved in

5/1 CH₂Cl₂/MeOH (10 mL) and cooled to À 78°C. Ozone was bubbled through the

solution and the reaction was monitored by TLC. Upon complete disappearence of the

starting material, the solution was purged with argon and warmed to rt. MeOH (50 mL)

and triphenylphosphine (652 mg, 2.49 mmol) were then added and stirring continued

for 1 h. The solvent was removed under reduced pressure and the residue was purified

by FCC to provide the aldehyde derivative (447 mg, 80%): R_f= 0.40 (10%

EtOAc:petroleum ether); [a]²³_D= + 128° (c 0.38, CH₂Cl₂); IR (neat) 2943, 1715

1

cm ^{À 1}; H NMR (CDCl₃) d 1.26 (s, 9H), 1.85 (m, 3H), 2.12 (m, 2H), 2.40 (m, 1H),

2.60 (t, J= 6.1 Hz, 2H), 3.30 (m, 1H), 3.72 (dt, J =2.6, 9.1 Hz, 1H), 3.95 (m, 2H), 4.67

(ABq, Dd = 58.2 Hz, J= 11.7 Hz, 2H), 4.91 (s, 1H), 7.46 (m, 5H), 9.84 (s, 1H); ¹³C

NMR (CDCl₆) d 21.5, 24.9, 26.5, 29.51, 40.9, 70.0, 71.3, 73.5, 74.5, 91.9, 126.0–128.0

(several lines overlapped by C₆D₆triplet), 139.1, 203.2.

Sodium bis(trimethylsilyl) amide (4.69 mmol, 4.69 mL of 1M solution in hexane)

was added to a suspension of n-butyl triphenylphosphonium bromide (1.87 g, 4.69

mmol) in dry toluene (30 mL) at rt under an argon atmosphere. The yellow-orange

suspension were stirred for 1 h at rt then cooled to À 78°C. At that time, an anhydrous

solution of the aldehyde from the previous step (500 mg, 1.56 mmol), in toluene (15 mL)

was added dropwise to the solution of the ylide. The reaction was stirred at À 78°C for

15 min, warmed to rt and diluted with ether. The mixture was filtered through Celite and

the filtrate was concentrated in vacuo. The residue was purified by FCC to afford the Z-

1

alkene 20. (376 mg, 67%): R_f= 0.40 (5% EtOAc:petroleum ether); H NMR (C₆D₆) d

0.92 (t, J=7.3Hz, 3H), 1.35–2.50 (m, 12H), 1.27 (s, 9H), 3.21 (bs, 1H), 4.07 (bt, J =9.1

Hz, 1H), 4.36 (ABq, Dd =0.29 ppm, J= 11.9 Hz, 2H), 5.21 (s, 1H), 5.50 (m, 1H), 5.60

(m, 1H), 7.10–7.50 (m, 5H); ¹³C NMR (C₆D₆) d 14.3, 21.8, 23.6, 24.5, 26.8, 29.4, 30.1,

32.8, 70.7, 71.2, 73.9, 74.0, 91.8, 127.9, 128.8, 130.3, 130.8, 140.1.

Trityl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a/b-^D-threo-dodeca-8Z-eno-

pyranoside (21). t-Butyl pyranoside 20 was subjected to the two-step hydrolysis-

tritylation sequence that was used for 13. An inseparable mixture of a/b trityl

pyranosides 21 (80%, ca. ratio 3:7) was obtained: R_f=0.40 (5% EtOAc:petroleum

1

ether); H NMR (C₆D₆) d 0.88, 0.90 (overlapping t, J =7.2 Hz, 3H), 1.24–2.30 (m,

12H), 2.75 (bs, ca. 0.7H), 2.82 (t, J= 5.6 Hz, ca. 0.7H), 3.16 (bs, ca. 0.3H), 4.00 (t,

J=6.5 Hz, ca. 0.3H), 4.08 (m, 1H), 4.36 (m, 1H), 4.42 (dd, J= 1.9, 9.5 Hz, ca. 0.7H, H1

b-anomer), 5.28 (bs, ca. 0.3H, H1 a-anomer), 5.41 (m, 2H), 7.10–7.80 (m, 20H); ¹³C

NMR (C₆D₆), b anomer: d 14.7, 23.9, 24.7, 26.6, 27.8, 30.3, 32,7, 71.7, 73.1, 78.5,

89.0, 99.0, 127.0–132.0 (several lines overlapped by C₆D₆triplet), 139.5, 146.1;

selected signals for a anomer: d 71.5, 72.5, 73.9, 88.8, 94.0 (C1).

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PYRANOSIDE ALKENE TEMPLATES

423

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a-D-erythro-dodeca-8E-

enopyranoside (22). E-alkene 22 (68%) was prepared from Z alkene 18, according

to the procedure described for E-alkene 24 (see later). R_f=0.40 (5% EtOAc:petroleum

1

ether); H NMR (C₆D₆) d 0.92 (t, J= 7.2Hz, 3H), 1.24 (S, 9H), 1.24–2.60 (m, 12H),

3.15 (dt, J= 5.0, 10.0 Hz, 1H), 4.13 (bt, J =10.0Hz, 1H), 4.45 (ABq, Dd= 0.28 ppm,

J= 11.0 Hz), 5.10 (bs, 1H), 5.62 (m,2H), 7.00–7.40 (m, 5H); ¹³C NMR(C₆D₆) d 14.3,

23.6, 24.7, 25.2, 29.5, 31.8, 33.8, 35.6, 71.0, 71.8, 73.8, 78.7, 91.1, 127.0–130.0

(several lines buried under C₆D₆triplet), 130.6, 131.6, 140.0; MS (ES) m/z 378.4

(M +NH₄).

Trityl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a/b-^D-erythro-dodeca-8E-

enopyranoside (23). t-Butyl pyranoside 22 was subjected to the two-step hydrolysis-

tritylation sequence that was used for 13. An inseparable mixture of a/b trityl

pyranosides 23 (63%, ca. ratio 2:3) was obtained: R_f= 0.40 (5% EtOAc:petroleum

1

ether); H NMR (C₆D₆) d 0.90, 0.92 (overlapping t, J=7.0 Hz, 3H), 1.25–2.20 (m,

12H), 3.00 (m, ca. 1.6H), 4.16 (dt, J=2.0, 10.0 Hz, ca. 0.4H), 4.18 (ABq, Dd =0.19

ppm, J=11.Hz, ca. 1.2H), 4.36 (ABq, Dd= 0.24 ppm, J =11.Hz, ca. 0.8H), 4.36 (dd,

J= 2.1, 9.1 Hz, ca. 0.6H, H1 b-anomer), 5.18 (bs, ca. 0.4H, H1 a-anomer), 5.44 (m,

2H), 7.03–7.69 (m, 5H); ¹³C NMR (C₆D₆), b anomer: d 14.3, 23.6, 28.7, 29.1, 31.9,

33.6, 35.6, 71.4, 77.5, 78.6, 88.8, 98.1, 127.0–132.0 (several lines overlapped by C₆D₆

triplet), 139.8, 145.9; selected signals for a-anomer: d 71.3, 73.1, 78.5, 88.6, 93.2 (C1);

MS (ES) m/z 569.3 (M + Na).

Tert-Butyl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a-^D-threo-dodeca-8E-

enopyranoside (24). MCPBA (345 mg, ~50% w/w, 1.0 mmol) was suspended in a

mixture of 4M NaH₂PO₄/Na₂HPO₄buffer (18 mL) and CH₂Cl₂(12 mL). The

suspension was added to a solution of Z-alkene 20 (130 mg, 0.36 mmol) in CH₂Cl₂(5

mL). The reaction was stirred at rt for 1 h. The organic layer was separated, washed

with saturated aqueous solutions of NaHCO₃and Na₂S₂O₃, and brine. The combined

organic phase was dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue

was purified by FCC to afford a mixture of epoxide derivatives (120 mg, 92%):

R_f=0.20 (5% EtOAc:petroleum ether); ¹H NMR (C₆D₆) d 0.83 (t, J=7.0 Hz, 3H),

1.20 (s, 9H), 1.28–2.18(m, 12H), 2.67–2.83 (m, 2H), 3.09, 3.15 (both bs, 1H), 3.91

(m, ca. 0.5H), 4.04 (t, J=5.8 Hz, ca. 0.5H), 4.13–4.41 (m, 2H), 5.14 (bs, 1H), 7.26

(m, 5H).

A 0.5 M stock solution of Ph₂PLi was prepared by the addition of a hexane

solution of n-butyllithium to a solution of Ph₂PH in dry THF at rt. under an argon

atmosphere, followed by stirring for 1 h. An aliquot of the red solution of Ph₂PLi (2.5

mL, 1.25 mmol) was added to a solution of the above epoxide mixture (110 mg, 0.24

mmol) in dry THF (3 mL) at rt under an argon atmosphere, and stirring continued for 2

h. At that time freshly distilled MeI (0.15 mL, 2.4 mmol) was added. The mixture was

stirred for an additional 1 h, and n-butyllithium (ca. 0.1 mL of a 1.6 M solution), was

added until the red color persisted. The mixture was then diluted with ether, filtered

through Celite and concentrated in vacuo. FCC of the residue gave E-alkene 24 (78.4

1

mg, 91%): R_f=0.40 (5% EtOAc:petroleum ether); H NMR (C₆D₆) d 0.94 (t, J=7.4

Hz, 3H), 1.35–2.60 (m, 12H), 1.28 (s, 9H), 3.22 (bs, 1H), 4.05 (bt, J= 9.0 Hz, 1H),

4.35 (ABq, Dd =0.29 ppm, J=11.9 Hz, 2H), 5.21 (bs, 1H), 5.56 (m,2H), 7.15–7.45 (m,

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ZHANG ET AL.

5H); ¹³C NMR (C₆D₆) d 14.2, 21.8, 23.5, 26.8, 29.4, 29.8, 32.8, 35.2, 70.6, 71.2, 73.9,

74.2, 91.9, 127.9, 128.9, 130.8, 131.4, 140.1.

Trityl 4-O-benzyl-2,3,6,7,8,9,10,11,12-nonadeoxy-a/b-^D-threo-dodeca-8E-eno-

pyranoside (25). t-Butyl pyranoside 24 was subjected to the two-step hydrolysis-

tritylation sequence that was used for 13. An inseparable mixture of a/b trityl pyrano-

1

sides 25 (78%, ca. ratio 3:7) was obtained: R_f=0.40 (5% EtOAc:petroleum ether; H

NMR (C₆D₆) d 0.88, 0.90 (overlapping t, J=7.2 Hz, 3H), 1.24–2.30 (m, 12H), 2.75

(bs, ca. 0.7H), 2.82 (t, J=5.6 Hz, ca. 0.7H), 3.16 (bs, ca. 0.3H), 4.00 (t, J= 6.5 Hz, ca.

0.3H), 4.08 (m, 1H), 4.36 (m, 1H), 4.42 (dd, J= 1.9, 9.5 Hz, ca. 0.7H, H1 b-anomer),

5.28 (bs, ca. 0.3H, H1 a-anomer), 5.41 (m, 2H), 7.10–7.80 (m, 20H); ¹³C NMR

(C₆D₆), b anomer: d 14.5, 23.8, 26.6, 27.9, 29.9, 32.7, 35.8, 71.6, 73.1, 78.3, 89.0, 99.0,

93.6, 99.0, 103.4, 126.0–133.0 (several lines overlapped by C₆D₆triplet), 139.0, 146.4;

selected signals for a anomer: d 71.5, 72.2, 73.6, 88.9, 94.0 (C1); HRMS(EI) calcd for

C₃₈H₄₁O₃(M-H) 545.3056, found 545.3064.

General Procedure for Iodoetherification Reactions

To a stirred solution of the alkene in CH₂Cl₂(10 mL/mmol of alkene) and water

(1% volume of CH₂Cl₂), was added iodonium dicollidine perchlorate (IDCP, 1.2 mmol/

mmol of the alkene). The reaction mixture was stirred at rt for 10 min. The solution

was then quenched with 10% aqueous Na₂S₂O₃solution, and extracted with diethyl

ether. The combined organic extract was dried (Na₂SO₄) and concentrated in vacuo.

The residue was purified by FCC.

THF Aldehydes from Terminal Alkenes

1

cis-THF aldehyde (14c). R_f=0.22 (5% EtOAc:toluene); H NMR(C₆D₆) d 1.37

(m, 1H) 1.53 (m, 2H), 1.70 (m, 3H), 2.10 (m, 2H), 2.82 (dd, J =6.2, 9.9 Hz, 1H), 2.88

(dd, J= 5.1, 9.9 Hz, 1H), 3.32 (apparent q, J= 6.2 Hz, 1H), 3.62 (m, 2H), 4.47 (m, ABq,

Dd =0.12 ppm, J =11.7 Hz, 2H), 7.05–7.40 (m, 5H), 9.40 (s, 1H); ¹³C NMR (C₆D₆) d

10.6, 24.8, 27.3, 31.9, 40.3, 73.4, 79.2, 79.9, 83.0, 128.0–129.0 (several lines buried

under C₆D₆triplet), 139.6, 200.7; HRMS(CI-CH₄) calcd for C₁₆H₂₂IO₃(M + H)

389.0614, found 389.0610.

1

trans-THF aldehyde (14t). R_f= 0.26 (5% EtOAc:toluene); H NMR(C₆D₆) d 1.28

(m, 1H) 1.50–1.80 (m, 5H), 2.10 (m, 2H), 2.83 (dd, J= 6.6, 9.0 Hz, 1H), 2.89 (dd, J =4.8,

9.9 Hz, 1H), 3.30 (m, 1H), 3.74 (m, 1H), 3.82 (m, 1H), 4.47 (m, ABq, Dd =0.13 ppm,

J=11.7 Hz, 2H), 7.05–7.50 (m, 5H), 9.36 (bs, 1H); ¹³C NMR(C₆D₆) d 11.5, 24.7, 28.0,

33.1, 40.5, 73.4, 79.0, 80.0, 82.8, 128.0–129.0 (several lines buried under C₆D₆triplet),

139.7, 200.7; HRMS(FAB) calcd for C₁₆H₂₂IO₃(M +H) 389.0614, found 389.0613.

cis-THF aldehyde (17c). R_f= 0.30 (5% EtOAc:toluene); ¹H NMR (C₆D₆) d

1.20–1.60 (m, 6H), 2.10 (m, 2H), 2.80 (m, 2H), 3.10 (m, 1H), 3.65 (m, 2H), 4.58

(ABq, Dd = 0.15 ppm, J =11.6 Hz, 2H), 7.05–7.40 (m, 5H), 9.33 (s, 1H); ¹³C NMR

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PYRANOSIDE ALKENE TEMPLATES

425

(C₆D₆) d 10.9, 24.6, 28.2, 31.5, 40.6, 73.5, 79.3, 80.9, 84.1, 128.0–129.0 (several lines

buried under C₆D₆triplet), 138.4, 200.9; HRMS(CI-CH₄) calcd for C₁₆H₂₂IO₃(M +H)

389.0614, found 389.0606.

trans-THF aldehyde (17t). R_f= 0.35 (5% EtOAc:toluene); ¹H NMR(C₆D₆) d

1.10–1.60 (m, 6H), 2.06 (m, 2H), 2.80 (m, 2H), 3.05 (m, 1H), 3.72 (m, 1H), 3.85 (m,

1H), 4.55 (ABq, Dd =0.13 ppm, J= 11.6Hz, 2H), 7.05–7.40 (m, 5H), 9.33 (s, 1H); ¹³C

NMR (C₆D₆) d 11.2, 24.2, 29.2, 33.9, 40.6, 73.4, 79.2, 80.9, 84.1, 128.0–129.0 (several

lines buried under C₆D₆triplet), 138.4, 200.9.

THF Aldehydes from Z Alkenes

1

cis-THF aldehyde (26c). R_f=0.20 (5% EtOAc:toluene); H NMR (C₆D₆) d 0.80

(t, J =7.1 Hz, 3H), 1.20–1.91 (m, 10H), 2.16 (m, 2H), 3.32 (m, 1H), 3.46 (q, J =6.2 Hz,

1H), 3.68 (m, 1H), 3.68 (m, 1H), 3.88 (m, 1H), 4.55 (ABq, Dd = 0.15 ppm, J =11.7 Hz,

2H), 7.05–7.50 (m, 5H), 9.40 (bs, 1H); ¹³C NMR (C₆D₆) d 13.8, 23.8, 24.9, 27.8, 31.2,

39.6, 40.3, 42.5, 73.2, 79.8, 82.3, 82.9, 128.0–129.0 (several lines buried under C₆D₆

triplet), 139.7, 200.9; HRMS(FAB) calcd for C₁₉H₂₈IO₃(M + H) 431.1083, found

431.1084.

trans-THF aldehyde (26t). R_f= 0.25 (5% EtOAc:toluene); ¹H NMR (C₆D₆) d

0.82 (t, J= 7.1 Hz, 3H), 1.20–1.90 (m, 10H), 2.15 (m, 2H), 3.36 (dt, J =4.8, 7.7 Hz,

1H), 3.55 (m, 1H), 3.92 (m, 1H), 3.95 (m, 1H), 4.53 (ABq, Dd = 0.14 ppm, J =11.7 Hz,

2H), 7.05–7.45 (m, 5H), 9.37 (bs, 1H); ¹³C NMR (C₆D₆) d 13.9, 23.9, 24.8, 28.0, 32.3,

39.3, 40.6, 43.5, 73.4, 80.0, 83.0, 83.2, 128.0–129.0 (several lines buried under C₆D₆

triplet), 139.8, 200.7; HRMS(FAB) calcd for C₁₉H₂₈IO₃(M + H) 431.1083, found

431.1084.

1

cis-THF aldehyde (27c). R_f=0.50 (5% EtOAc:toluene); H NMR (C₆D₆) d 0.77

(t, J= 7.1 Hz, 3H), 1.25–1.85 (m, 10H), 2.12 (m, 2H), 3.32 (m, 2H), 3.72 (m, 1H), 3.84

(m, 1H), 4.75 (ABq, Dd =0.37 ppm, J=11.7 Hz, 2H), 7.10–7.45 (m, 5H), 9.35 (s, 1H);

¹³C NMR (C₆D₆,) d 13.8, 23.6, 24.8, 28.5, 31.0, 39.6, 40.7, 43.0, 73.7, 81.0, 82.9, 83.9,

128.0–129.0 (several lines buried under C₆D₆, triplet), 139.5, 200.9; HRMS(CI-CH₄)

calcd for C₁₉H₂₈IO₃(M + H) 431.1083, found 431.1064.

trans-THF aldehyde (27t). R_f= 0.55 (5% EtOAc:toluene); ¹H NMR (C₆D₆) d 0.77

(t, J= 7.1 Hz, 3H), 1.22–1.85 (m, 10H), 2.12 (m, 2H), 3.09 (m, 1H), 3.30 (m, 1H), 3.60

(m, 1H), 3.98 (m, 1H), 4.65 (ABq, Dd =0.16 ppm, J=11.6 Hz, 2H), 7.10–7.40 (m, 5H),

9.35 (s, 1H); ¹³C NMR (C₆D₆) d 13.8, 23.7, 24.2, 29.3, 32.0, 39.2, 40.6, 43.2, 73.4,

81.0, 83.2, 83.6, 128.0–129.0 (several lines buried under C₆D₆, triplet), 139.5, 200.9.

THF Aldehydes from E Alkenes

1

cis-THF aldehyde (28c). R_f=0.20 (5% EtOAc:toluene); H NMR (C₆D₆) d 0.82

(t, J =7.0 Hz, 3H), 1.20–1.80 (m, 10H₁), 2.15 (m, 2H), 3.34 (q, J =5.5 Hz, 1H), 3.55 (q,

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J=6.6 Hz, 1H), 3.72 (q, J =5.3 Hz, 1H), 4.04 (q, J= 5.7 Hz, 1H), 4.50 (ABq, Dd =0.14

ppm, J =11.7 Hz, 2H), 7.05–7.45 (m, 5H), 9.41 (bs, 1H); ¹³C NMR (C₆D₆) d 13.9,

23.5, 24.7, 27.3, 32.5, 39.5, 40.2, 42.9, 73.2, 80.1, 82.9, 83.3, 128.0–129.0 (several

lines buried under C₆D₆triplet), 139.7, 200.5; HRMS(FAB) calcd for C₁₉H₂₈IO₃

(M +H) 431.1083, found 431.1088.

trans-THF aldehyde (28t). R_f= 0.25 (5% EtOAc:toluene); ¹H NMR (C₆D₆) d

0.84 (t, J=7.0 Hz, 3H), 1.20–1.90 (m, 10H), 2.10 (m, 2H), 3.33 (m, 1H), 3.67 (m, 1H),

3.90 (m, 1H), 4.03 (m, 1H), 4.49 (ABq, Dd = 0.14 ppm, J =11.7 Hz, 2H), 7.00–7.40

(m, 5H), 9.38 (s, 1H); ¹³C NMR (C₆D₆) d 13.9, 23.5, 24.7, 27.9, 33.8, 39.3, 40.5, 44.4,

73.4, 80.1, 83.1 (2 carbons), 128.0–129.0 (several lines buried under C₆D₆triplet),

139.7, 200.3; HRMS(FAB) calcd for C₁₉H₂₈IO₃(M + H) 431.1083, found 431.1088.

1

cis-THF aldehyde (29c). R_f=0.50 (5% EtOAc:toluene); H NMR (C₆D₆) d 0.80

(t, J= 7.1 Hz, 3H), 1.30–1.73 (m, 10H), 2.06 (m, 2H), 3.15 (m, 1H), 3.58 (q, J= 7.5 Hz,

1H), 3.74 (q, J=7.5 Hz, 1H), 3.99 (m, 1H, H₉), 4.60 (ABq, Dd =0.25 ppm, J=11.7 Hz,

2H), 7.05–7.40 (m, 5H), 9.32 (s, 1H); ¹³C NMR (C₆D₆) d 13.8, 23.2, 24.6, 28.0, 32.2,

39.3, 40.6, 43.1, 73.6, 80.9, 83.3, 84.1, 128.0–129.0 (several lines buried under C₆D₆

triplet), 138.7, 200.8; HRMS(CI-CH₄) calcd for C₁₉H₂₈IO₃(M +H) 431.1083, found

431.1068.

1

trans-THF aldehyde (29t). R_f= 0.55 (5%EtOAc:toluene); H NMR (C₆D₆) d 0.80

(t, J=7.2 Hz, 3H), 1.30–1.80 (m, 10H), 2.06 (m, 2H), 3.05 (m, 1H), 3.71 (m, 1H), 3.95

(m, 2H), 4.52 (ABq, Dd= 0.26 ppm, J= 11.6 Hz, 2H), 7.05–7.40 (m, 5H), 9.32 (s, 1H);

¹³C NMR (C₆D₆) d 13.9, 23.4, 24.3, 29.1, 33.8, 39.5, 40.7, 44.1, 73.4, 81.2, 83.3, 83.6,

128.0–129.0 (several lines buried under C₆D₆triplet), 140.0, 200.6; MS(CI): m/z 448

(M +NH₄) for C₁₉H₂₇O₃I.

THF (30t), (from THF-iodide (14t)). The aldehyde 14t (500 mg, 1.29 mmol) was

dissolved in EtOH (20 mL) and treated with NaBH₄(60 mg, 1.6 mmol) at rt for 30

min. 10% HCl in MeOH was then added to the reaction mixture until the pH was 8.

The volatiles were removed under reduced pressure. FCC of the residue afforded the

derived alcohol (370 mg, 74%): R_f: 0.28 (30% EtOAc:petroleum ether); ¹H NMR

(CDCl₃) d 1.40–1.90 (m, 6H), 2.00 (m, 2H), 2.20 (m, 1H), 3.25 (m, 2H), 3.52 (m, 3H),

4.06 (m, 1H), 4.17 (m, 1H), 4.70 (ABq, Dd = 0.17 ppm, J= 11.0 Hz, 2H), 7.20–7.50 (m,

5H). A solution of the product from the previuos step (370 mg, 0.95 mmol),

allyltributyltin (0.60 mL, 1.94 mmol) and AIBN (23 mg, 0.14 mmol) in benzene (5

mL) was purged with argon. The reaction mixture was then heated at reflux, under

argon, for 18 h. The solvent was removed, and the residue dissolved in ether and stirred

with a saturated, aqueous solution of KF for 0.5 h. The aqueous layer was extracted

with ether and the organic extract dried (Na₂SO₄), and concentrated under reduced

pressure. FCC of the residue provided the allylated derivative (65 mg, 23%): R_f: 0.60

1

(30% EtOAc:petroleum ether, double development); H NMR (C₆D₆) d 1.10–1.90 (m,

11H), 2.10 (m, 2H), 3.25 (m, 2H), 3.40 (m, 1H), 3.80 (m, 2H), 4.53 (ABq, Dd =0.17

ppm, J=11.5 Hz, 2H), 4.94 (m, 2H), 4.74 (m, 1H), 7.00–7.40 (m, 5H).

A mixture of the alkene from the previous step (35 mg, 0.12 mmol, 10% w Pd/C

(5 mg) in EtOAc (5 mL) was stirred for 6 h under hydrogen (balloon). The suspension

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427

was filtered through a short plug of Celite and concentrated in vacuo. FCC of the

1

residue provided 30t (25 mg, 71%): R_f=0.30 (30% EtOAc:petroleum ether); H NMR

(CDCl₃) d 0.92 (t, J=7.0 Hz, 3H), 1.20–2.20 (m, 14H), 2.28 (m, 1H), 3.60 (m, 3H),

3.95 (m, 1H), 4.06 (m, 1H), 4.68 (ABq, Dd =0.14 ppm, J=11.0 Hz, 2H), 7.20-0-7.45

(m, 5H); ¹³C NMR (CDCl₃) d 14.3, 23.1, 27.7, 28.4, 28.7, 29.2, 32.5, 35.9, 63.2, 73.2,

79.8, 81.2, 81.4, 127.6, 128.0, 128.4, 139.2; HRMS(FAB) calcd for C₁₉H₃₁O₃(M +H)

307.2273, found 307.2274.

THF (30t), (from THF-iodide (26t). The aldehyde 26t (50 mg, 0.12 mmol) was

treated with NaBH₄according to the procedure described in the previous experiment.

FCC of the crude product provided the derived alcohol (50 mg, 96%): R_f=0.20 (5%

1

EtOAc:toluene); H NMR (C₆D₆) d 0.75 (t, J =7.2 Hz, 3H), 1.15–1.90 (m, 13H), 3.26

(m, 2H), 3.52 (m, 1H), 3.79 (m, 1H), 3.94 (m, 1H), 4.52 (ABq, Dd= 0.14 ppm, J=11.8

Hz, 2H), 7.00–7.40 (m, 5H).

A mixture of the above material (10 mg, 0.023 mmol), AIBN (5 mg, 0.03 mmol),

Bu₃SnH (0.02 mL, 0.07 mmol) in toluene (5 mL) was purged with argon. The reaction

mixture was then heated at reflux, under argon, for 3 h. Removal of the solvent under

reduced pressure and FCC of the residue afforded 26t (4 mg, 84 %), which was

identical (TLC, NMR) with the material derived from 14t.

THF (30c), (from THF-iodide (26c)). The aldehyde 26c was transformed to THF

30c following the procedure that was used for the conversion of 26t to 30t. For 30c:

1

R_f=0.30 (30% EtOAc:petroleum ether); H NMR (CDCl₃) d 0.92 (t, J= 7.0 Hz, 3H),

1.25–2.10 (m, 15H), 3.52 (m, 1H), 3.62 (m, 2H), 3.80 (m, 1H), 3.91 (m, 1H), 4.66

(ABq, Dd = 0.16 ppm, J=11.0 Hz, 2H), 7.20–7.45 (m, 5H); ¹³C NMR (CDCl₃) d 14.3,

23.1, 27.1, 28.5, 28.8, 29.2, 31.6, 36.0, 63.3, 73.1, 80.1, 80.8, 81.8, 127.6, 128.0, 128.4,

139.2; HRMS(FAB) calcd for C₁₉H₃₁O₃(M +H) 307.2273, found 307.2274.

ACKNOWLEDGMENTS

Support was provided by NIGMS MBRS SCORE grant 5 SO6 GM60654-02 to

Hunter College. "Research Centers in Minority Institutions" award RR-03037 from the

National Center for Research Resources of the NIH, which supports the infrastructure

(and instrumentation) of the Chemistry Department at Hunter, is also acknowledged.

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Received October 23, 2001

Accepted May 29, 2002

Article Doi

Pyranoside alkene templates for the synthesis of CIS-2,5-disubstituted tetrahydrofuran subunits of the acetogenins

DOI: 10.1081/CAR-120014903

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Article abstract of DOI:10.1081/CAR-120014903

Full text of DOI:10.1081/CAR-120014903

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