Stereochemical control in radical cyclization routes to N-glycosides: Role of protecting groups and of the configuration (E versus Z) of the acceptors

TETRAHEDRON:

ASYMMETRY

Pergamon

Tetrahedron: Asymmetry 14 (2003) 2939–2959

Stereochemical control in radical cyclization routes to

N-glycosides: role of protecting groups and of the conﬁguration

(E versus Z) of the acceptors

Jong Uk Rhee, Brian I. Bliss and T. V. RajanBabu*

Department of Chemistry, 100 W. 18th Avenue, The Ohio State University, Columbus, OH 43210, USA

Received 17 July 2003; accepted 25 July 2003

Abstract—The ﬁrst radical intermediate in the thiourethane-mediated deoxygenation of an alcohol (Barton–McCombie reaction)

can participate in an exo-hex-5-enyl or exo-hept-6-enyl type radical cyclization when a suitable radical acceptor (e.g. a,b-unsatu-

rated ester, oxime ether or hydrazone) is appropriately placed. Carbohydrate-derived imidazolyl and triazolyl thioates with such

acceptors, upon addition to excess of a good hydride donor (reverse addition), undergo moderately efﬁcient cyclization reactions

to give N-heterocyclic furanosides, and, surprisingly even N-pyranosides. Depending on the acceptor, glycosides with either

C₂-carbon or C₂-amino substituents are formed. In the exo-hept-6-enyl cyclizations the (Z)-oleﬁn acceptors give excellent

stereoselectivity in the generation of the C₂stereogenic center; only altro-isomers are formed. In all cases both a- and b-glycosides

are obtained with a moderate preference for the latter.

1. Introduction

inﬂuence the stereochemistry of the annulation pro-

cess.³Since both furanosides and pyranosides of N-het-

erocycles appear to be accessible through this

unconventional route, which involves the formation of

the C₁ꢀC₂bond, we decided to study in some detail the

effect of various structural parameters of the substrate

on the course of this reaction. Thus we examined the

effects of protecting groups and of Z/E-conﬁguration

of the radical acceptors on hex-5-enyl and hept-6-enyl

radical cyclizations. Improvements in selectivity were

observed for both reactions. We ﬁnd that the stereose-

lectivity in the inherently less selective heptenyl radical

cyclization is considerably better when the (Z)-isomer

of the radical acceptor is employed. These results open

new ways of preparing C₂-substituted N-heterocyclic

pyranosides and furanosides.⁴Full details of these

investigations are described herein.

Earlier we reported that imidazole thioates derived

from a 5- or 6-hydroxy-2,3-enoate (Eqs. (1) and (2))

upon addition to a large excess of an efﬁcient hydrogen

donor, undergo cyclization to give surprisingly good

yields of imidazolyl glycosides.^1,2In both cases, not

unexpectedly, mixtures of all possible stereoisomers of

the products 2 and 4 are formed in this otherwise

efﬁcient transformation. Since major applications of

this chemistry are likely to be in the area of carbohy-

drates, we wondered whether the structural features

present in this potential class of substrates might offer

solutions to this problem. For example, the hydroxyl

groups on the tether present opportunities for incorpo-

rating cyclic acetal-type protecting groups, which,

through the resident conformational features, could

(1)

* Corresponding author. E-mail: rajanbabu.1@osu.edu

doi:10.1016/j.tetasy.2003.07.013

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J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

(2)

2. Results and discussion

Wittig reagent, O-methylhydroxylamine or N,N-

dimethylhydrazine. In the case of the a,b-unsaturated

esters 7 and 8 and the nitrile 9 the major (Z)-⁶and

minor (E)-isomers were separated by column chro-

matography and subjected to cyclization. The syn and

anti isomers of the oxime^7,810 were not separated and

the hydrazones were found to exist as a single geomet-

ric isomer by NMR spectroscopy.^9,10The correspond-

ing imidazole thioates were prepared by heating the

alcohols with thiocarbonyl bisimidazole in CH₂Cl₂or

THF (Scheme 2).

2.1. Hex-5-enyl radical cyclizations. Synthesis of pre-

cursors and cyclization studies

Starting materials for the hex-5-enyl type cyclization

studies were readily

prepared

from 4,6-O-

phenylmethylglucopyranose, 5 (Scheme 1). The alde-

hyde 6⁵formed upon periodate cleavage of 5 was not

isolated, but was converted directly into the unsatu-

rated precursors 7–12 by reaction with the appropriate

Scheme 1. Synthesis of precursors for hex-5-enyl-type cyclyzations.

Scheme 2. Cyclization of substrates 7–12 (Tables 1 and 4).

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2941

1 and 2, 3 and 4, and 6 in Table 1). However, in all

cases except for the N,N-diphenylhydrazone (entry 8) a

mixture of a- and b-glycosides is formed. The a- and

b-glycosides can be separated in most cases and the

structures have been rigorously established by spectro-

scopic methods. The position of the C₁-hydrogen gives

a reliable indication of the anomeric conﬁguration. For

the a-anomers the C₁-hydrogen appears consistently

5.80 0.10 ppm and for the b-anomer this proton

appears at 6.15 0.15 ppm. In addition, NOE studies

further conﬁrm these assignments. For example, the

following NOE’s are observed for the glycosides 15-a

and 15-b: 15-a: H₁H₃; H₁CH₂; H₂H₄; H₂imi-

dazole H; H₃CH₂; H₃H_5axial) and 15-b: (H₁H₂;

H₁H₄; H₂H₄; CH₂imidazole H; H₃CH₂; H₃

The cyclization reactions were carried out under condi-

tions optimized (see Table 4, experimental) for the

formation of the N-glycoside.¹Thus in a typical reac-

tion, 0.16 mmol of (E)-7 and 0.08 mmol of AIBN

dissolved in 3.4 mL of benzene was added in ꢀ2 h to

0.80 mmol of Ph₃SnH in 12.5 mL of benzene in an oil

bath at 90°C. The reaction was continued for another

30 min at that temperature. The reaction mixture was

cooled to room temperature and the solvent was

removed. Chromatography of the crude mixture on

silica gel using hexane/ethyl acetate solvent gave pure

product(s).

The results of cyclization of substrates 7–12 (Scheme 2)

are shown in Table 1. As we had anticipated, the use of

a cyclic acetal as a protecting group indeed results in an

improvement in the selectivity of the reaction vis-a`-vis

the acyclic precursor 1 shown in Eq. (1). The C₂-sub-

stituent in the N-glycoside is formed exclusively with a

b-orientation, irrespective of the geometry of the start-

ing oleﬁn or the [CꢁN] acceptor (Scheme 2 and entries

H_5axial).

It is known that in the Barton–McCombie reaction the

slow step is the collapse of the intermediate 22 (Scheme

3).¹¹Since the rate of intramolecular addition to an

activated acceptor is likely to be faster than this decom-

position, formation of cyclic products, especially in the

presence of a sterically demanding, H-atom donor, is

not surprising. Analysis of the transition states that

lead to the cyclic products provides a satisfactory expla-

nation for the exclusive b-orientation of the C₂-sub-

stituent. Of the two possible transition states (Scheme

4), one with the ‘chair-like’ conformation 23 that leads

to the C₂-b product is likely to be favored over the

‘boat-like’ transition state 26 that results in the C₂-a

substituent. In depicting these structures the SꢀSnR₃

has been arbitrarily chosen to occupy the quasi-axial

position at C₁based on the reasonable assumption that

CꢀS and SꢀSn bonds are signiﬁcantly longer than the

CꢀN bond, and thus the imidazolyl moiety is likely to

be sterically more demanding. Homolytic cleavage of

the CꢀS bond in 24 followed by H atom abstraction by

the resulting glycosyl radical 25 will result in the two

glycosides. Predictably, there is little difference between

H-abstraction at either a- or b-face of C₁. The only

exception is in the case of the diphenylhydrazone 12,

which gave only the a-glycoside 20-a in a low (20%)

yield. In this case an unusually high yield (62%) of a

reduced product 21 was also observed. Even though

stereoelectronic effects are known to play an important

Table 1. Cyclization of imidazole thioates from 7–12^a

Entry

Alcohol

[Furanoside] XꢀY Yield (%)

a/b

1

2

3

4

5

6

7

8

Z-7

E-7

Z-8

E-8

Z-9

[13] CHCO₂Et

[14] CHCO₂Et

[15] CHCO₂Bu^t

[16] CHCO₂Bu^t

[17] CHCN

44 (32)^b

54 (28)^b

46

40

81

1.1/1.0

0.8/1.0

0.7/1.0

0.9/1.0

1.0/0.8

1.0/0.3

a-only

(Z+E)-10 [18] NOMe

11

12

63

[19] NNMe₂

[20] NNPh₂

77

20^c

^aSee Scheme 2.

^bUsing Bu₃SnH.

^c62% 21 was also formed.

Scheme 3. Deoxygenation versus cyclization in the Barton–McCombie reaction.

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J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

Scheme 4. Origin of stereoselectivity at C₂of the N-furanoside.

role in the capture of anomeric radicals¹²by H-atom

donors and electron deﬁcient oleﬁns, the conformation

of the strained bicyclo[4.3.0]-system (e.g. 25) in the

present context makes it difﬁcult to achieve any prefer-

ential alignment of the suitable orbitals for one confor-

mation to be favored. Simple steric effects might be

responsible for the modest selectivity seen for the

hydrazones. As we will see later, this becomes an

important consideration in the formation of the a/b-

anomers of the pyranosides, where the anomeric effect

is much more discernable.

2.2. Hept-6-enyl radical cyclizations

Formation of cyclohexane derivatives via exo-hept-6-

enyl radical cyclization is 20–30 times slower than the

exo-hex-5-enyl cyclization.¹³Yet we ﬁnd that several

ribose-derived imidazole thioates undergo efﬁcient

cyclization to give 1-imidazolyl pyranosides. Prototypi-

cal substrates for the cyclization were prepared from

the

D

-ribonolactone-derived hemiacetal 27¹⁴by the

reactions shown in Scheme 5. The substrates 28–38

shown in Figure 1 were prepared using standard reac-

Scheme 5. Synthesis of substrates for hept-6-enyl cyclization studies.

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2943

Figure 1. Substrates for hept-6-enyl radical cyclizations (see Scheme 5).

tion conditions. The list also includes two triazole

derivatives 31 and 37, which were prepared to explore

the generality of this procedure for the synthesis of

other heterocyclic glycosides. The geometrical isomers

of the Wittig reaction products were separated, charac-

terized and individually subjected to cyclization reac-

tions. The results of cyclization studies are listed in

Tables 2 and 3.

tures (toluene reﬂux) (see Section 4, Tables 4 and 5).

With low concentration of Bu₃SnH a thionolactone 46S

has also been observed in some runs. In the absence of

an electron-withdrawing substituent on the oleﬁn 35

(entry 3, Table 2), the reactivity and selectivity erode

considerably giving a mixture of products including an

endo-6-heptenyl cyclization product(s) tentatively iden-

tiﬁed as 47. The products of this low yielding reaction

were not fully characterized.

2.3. Conﬁguration of the radical acceptor (oleﬁn or

=NR) and stereoselectivity in the cyclization reactions

Finally the oxime ether substrates 36 and 37 (Table 3),

which exist as mixtures of syn and anti isomers, gave

low yields of the N-heterocyclic glycosides 48–50. In

both cases the altro isomers are formed as the major

products.

Both imidazole and triazole thioates carrying activated

oleﬁn acceptors 28–35 (Fig. 1) undergo exo-hept-6-enyl

type radical cyclization to give the corresponding altro

(major) and allo (minor) N-heterocyclic glycosides.

Because of the better stereoselectivity at the C₂-posi-

tion, cyclization of substrates with the Z-enoates (28–

31) are preparatively the most useful (Table 2, entry 1).

In a typical experiment, the imidazole thioate 28 (Table

2, entry 1a) mixed with AIBN was slowly added to 5

equiv. of Ph₃SnH dissolved in benzene (0.01 M) in an

oil bath at 90°C. Concentration and puriﬁcation by

chromatography gave 68% yield of the corresponding

altro adducts 39 (a:b=1:4). The a- and b-anomers were

separated and identiﬁed by NMR spectroscopy. A sim-

ilar result, with preponderance of the the b-glycoside, is

observed with the analogous t-butyl ester 29 and the

unsaturated nitrile 30 (entries 1b and 1c). A structurally

related triazole thioate 31 also gave exclusively the

altro-glycosides 42 in 87% yield (entry 1d, Table 2). We

did not observe the formation of any of the allo-iso-

mers when the pure Z-isomers of the substrates were

used for the cyclization.

The hydrazone substrate 38 (Scheme 6) upon reaction

with triphenyltin hydride gave moderate yields of cyclic

products, of which the major isomer (56%) has been

tentatively identiﬁed as the allo-b glycoside 51. Reac-

tion of 38 with Bu₃SnH leads to no cyclization prod-

ucts, but a deoxygenation product 52 was formed in

41% yield. This further conﬁrms the crucial role of

triphenyltin hydride in these relatively slow cyclization

reactions.

The difference in the selectivities of the (Z)- and (E)-

oleﬁn acceptors (the former giving exclusively the altro-

isomer, i.e. the C₂-substituent in the b-conﬁguration) is

quite striking. This result (entries 1 and 2, Table 2) can

be rationalized on the basis of the conformations of the

putative intermediates that lead to the altro- and allo-

products (Scheme 7). Inspection of models suggests that

there is an added through-space interaction between the

carboethoxy oxygen and the C₅(radical numbering)

acetal oxygen in the transition state 53 for the forma-

tion of the allo product(s). This is absent in the transi-

tion state 54, which might explain why only altro

products are obtained from the (Z)-acceptors (entry 1,

Table 2). There is no such clear distinction between the

respective transition states leading from the (E)-oleﬁn

acceptors and a mixture of allo- and altro-products are

obtained in these cases (entry 2, Table 2).

In sharp contrast to the results described in the previ-

ous paragraph, use of the E-isomers of the Wittig

products gave a mixture of pyranosides consisting of

both altro-39–41 and allo-43–45 isomers (entries 2a–c,

Table 2), even though the major products still have the

altro-conﬁguration.¹⁵An occasional complication is

represented by entry 2a, which shows the formation of

a byproduct, 46, in 18% yield. This product is formed

especially when the reaction is done at higher tempera-

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J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

Table 2. Hept-6-enyl radical cyclization. Effect of oleﬁn geometry^a

The preponderance of the formation of the b-anomer in

the pyranoside formation (Tables 2 and 3 and Scheme

6) is highly suggestive of anomeric stabilization in the

radical intermediate involved. Unlike in the trans-

bicyclic furanoside system 25 (Scheme 4), the a-conﬁr-

mation of the glycosyl radical 55 (Scheme 8) would be

expected to provide some anomeric stabilization¹²to

the intermediates from which the b-glycosides are

formed. Note that in the altro isomers the b-glycoside

formation will also be favored by the ease of H delivery

from the a-face.

3. Summary

The ﬁrst radical intermediate in the thiourethane-medi-

ated deoxygenation of an alcohol (Barton–McCombie

reaction) can participate in an exo-hex-5-enyl or exo-

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

Table 3. Hept-6-enyl radical cyclization. Oxime substrates^a

2945

Scheme 6. Effect of the hydride on cyclization versus deoxygenation.

hept-6-enyl type radical cyclization when a suitable

radical acceptor (e.g. a,b-unsaturated ester, oxime ether

or hydrazone) is appropriately placed. Carbohydrate-

derived imidazolyl and triazolyl thiourethanes with

such acceptors, upon addition to excess of a good

hydride donor (reverse addition), undergo efﬁcient

cyclization reactions to give N-heterocyclic furanosides,

and, surprisingly even N-pyranosides. Depending on

the acceptor, glycosides with either 2-amino or C₂-car-

bon substituent are formed. In the exo-hept-6-enyl

cyclizations, the (Z)-oleﬁn acceptors give excellent

stereoselectivity in the generation of the C₂stereogenic

center. Only altro-isomers are formed. In all cases both

a- and b-glycosides are obtained. A moderate prefer-

ence for the b-anomer in the pyranoside formation may

have its origin in the anomeric stabilization of the axial

radical. N-Heterocyclic glycosides are important class

of compounds that represent the structural units of

nucleic acids and of several pharmaceutically relevant

compounds.^4a–cWe plan to apply these methods for the

synthesis of nucleosides, N-glycosyl amino acids and

unusual O- and C-glycosides.

4. Experimental

4.1. General procedures

NMR spectra were recorded on Bruker AM-250, AM-

300, DPX-400, or DPX-500 MHz instruments and

CDCl₃was used as the solvent unless otherwise men-

1

tioned. For H NMR spectra the hydrogen of CDCl₃

was used as the standard (l=7.260 ppm). The ¹³C

NMR spectra were recorded at 125 MHz, 100 MHz, 75

MHz, or 62.5 MHz and the central line of CDCl₃was

used as the standard (l=77.00 ppm). Chemical shifts

are reported in parts per million on the l scale, and Hz

is used as unit for the coupling constants. Infrared

spectra were obtained on Perkin–Elmer 1600 infrared

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J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

Preparation of substrates

4.2. (E)- and (Z)-(2R,4S,5R)-(5-hydroxy-2-phenyl-

[1,3]dioxane-4-yl)-acrylic acid ethyl ester (Z)-7 and (E)-7

To a 25 mL of ﬂame-dried three-necked round-bot-

tomed ﬂask connected to a condenser were added 78

mg (estimated as 0.310 mmol) of crude [2R,4R,5R]-5-

hydroxy-2-phenyl-[1,3]dioxane-4-carbaldehyde 6⁵and

133 mg (0.384 mmol) of (carboethoxymethylene)-

triphenylphosphorane. Freshly dried toluene (10 mL)

was added and the mixture was stirred under reﬂuxing

condition for 100 min. After the solvent was removed

under vacuum, the product as an E and Z mixture was

isolated by ﬂash column chromatography eluting with

hexane:EtOAc=3:1. The E and Z compounds were

isolated as a white solid and a colorless oil respectively

in a ratio of 1.0/1.89, and the combined isolated yield

was 90%. The same reaction was also performed in

dimethoxyethane at rt. The mixture of 78 mg (estimated

as 0.310 mmol) of crude 5(R)-hydroxy-2(R)-phenyl-1,

3-dioxane-4(R)-carboxaldehyde 6 and 221 mg (0.634

mmol) of (carboethoxymethylene)triphenylphosphorane

in 10 mL of DME was stirred under a nitrogen atmo-

sphere for 26 h, when all starting material disappeared

on TLC. After the solvent was removed in a rotary

evaporator, the crude mixture was puriﬁed by column

chromatography eluting with hexane:EtOAc=2:1. The

isolated yield was the same (90%), but the ratio of Z:E

compounds increased to 2.4:1.0.

Scheme 7. Origin of the altro-selectivity in the (Z)-acceptors

(see Table 2).

(E)-7: White solid (column chromatography, hex-

ane:EtOAc=3:1). R_f=0.33 (hexane:EtOAc=2:1). Mp:

93–95°C. [h]²_D⁰=−31.7 (c 0.71, CHCl₃). ¹H NMR

(CDCl₃, 400 MHz): l 1.30 (t, J=7.1 Hz, 3H), 2.71 (br

s, 1H), 3.67 (d, J=7.5 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H),

4.21–4.25 (m, 1H), 4.32 (d, J=5.6 Hz, 1H), 5.56 (s,

1H), 6.22 (dd, J=15.8, 1.7 Hz, 1H), 7.18 (dd, J=15.8,

4.5 Hz, 1H), 7.34–7.41 (m, 3H), 7.49–7.51 (m, 2H). ¹³C

NMR (CDCl₃, 100 MHz): l 14.2, 60.7, 65.3, 71.1, 80.4,

100.8, 122.4, 126.1, 128.3, 129.1, 137.2, 143.4, 166.5. IR

(NaCl, neat): 3476br s, 2984m, 2924m, 2862m, 1702s,

1656m, 1453m, 1394m, 1370m, 1301s, 1274m, 1224m,

1189m, 1144m, 1082s, 1026s, 979m, 918w, 850w, 757m.

Anal. calcd for C₁₅H₁₈O₅: C, 64.74; H, 6.52. Found: C,

64.22; H, 6.75.

Scheme 8. Anomeric stabilization in pyranosyl radicals.

spectrometer and are reported in reciprocal centimeters

(cm⁻¹). High-resolution mass spectra were recorded on

the Micromass QTOF electrospray mass spectrometer.

Elemental analysis was performed at the Ohio State

University. Optical rotations were measured on a

Perkin–Elmer 241 MC polarimeter with a sodium lamp

at 589 nm and 1 mm slit at concentrations expressed as

(Z)-7: Colorless oil (column chromatography, hex-

ane:EtOAc=3:1).

R_f=0.42

(hexane:EtOAc=2:1).

g/dL. All melting points were determined on

a

[h]²_D⁰=−66.1 (c 0.61, CHCl₃). ¹H NMR (CDCl₃, 400

MHz): l 1.33 (t, J=7.1 Hz, 3H), 3.62–3.73 (m, 1H),

3.83 (d, J=6.7 Hz, 2H), 4.24 (qd, J=7.1, 2.9 Hz, 2H),

4.41 (dd, J=10.3, 4.5 Hz, 1H), 5.19 (apparent td,

J=9.1, 1.4 Hz, 1H), 5.55 (s, 1H), 6.09 (dd, J=11.8, 1.2

Hz, 1H), 6.34 (dd, J=11.7, 7.8 Hz, 1H), 7.35–7.37 (m,

3H), 7.47–7.50 (m, 2H). ¹³C NMR (CDCl₃, 100 MHz):

l 14.1, 61.5, 65.6, 72.1, 78.5, 100.7, 122.4, 126.1, 128.3,

129.0, 137.3, 145.2, 168.1. IR (NaCl, neat): 3431br s,

3037w, 2982m, 2930m, 2854m, 1722s, 1694s, 1658m,

1455m, 1422m, 1386s, 1302w, 1209s, 1090s, 1207s,

871w, 827m, 755m, 699s. Anal. calcd for C₁₅H₁₈O₅: C,

64.74; H, 6.52. Found: C, 63.90; H, 6.70.

Thomas–Hoover capillary melting point apparatus and

are uncorrected. All solvents were purchased from

Fisher Co. and freshly distilled. Other chemicals were

purchased from Aldrich or Acros and were used as

received. Reactions were performed in ﬂame dried

glassware under an atmosphere of nitrogen, and moni-

tored by thin layer chromatography (TLC) using EM

Science precoated 60 F₂₅₄plates or gas chromatography

(Hewlett–Packard 5890). The GC was equipped with

HP-1 column and an FID detector connected to an HP

3396 integrator. Products were isolated by column

chromatography using 60–200 mesh silica gel.

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2947

4.3. Preparation of (E)- and (Z)-[2R,4S,5R]-3-(5-hydroxy-

2-phenyl-[1,3]dioxane-4-yl)-acrylonitrile (E)-9 and (Z)-9

2H). ¹³C NMR (CDCl₃, 100 MHz): syn-10: l 62.19, 63.99,

70.15, 78.69, 101.35, 126.13, 128.33, 129.21, 137.04,

148.70; anti-10: l 62.51, 71.11, 75.62, 77.92, 100.71,

126.10, 128.33, 129.21, 136.94, 149.95. IR (NaCl, neat):

3489br s, 2978w, 3939w, 2252s, 1462m, 1390m, 1221w,

1086m, 1041m, 908s, 733s, 650m. Anal. calcd for

C₁₂H₁₅NO₄: C, 60.75; H, 6.37; N, 5.90. Found: C, 60.87;

H, 6.62; N, 5.94.

To a 100 mL ﬂame-dried three-necked round-bottomed

ﬂask connected to a condenser were added 259 mg

(estimated as 1.24 mmol) of crude 6 and 412 mg (1.368

mmol)

of

(cyanomethylene)triphenylphosphorane.

Freshly dried toluene (40 mL) was added and the mixture

was stirred under reﬂuxing condition for 12 h. Additional

206 mg of (cyanomethylene)triphenylphosphorane was

added and the reﬂuxing was continued under a nitrogen

atmosphere for 2 h. After the solvent was removed under

vacuum, the crude mixture was puriﬁed by column

chromatography eluting with hexane:EtOAc=3:1. The

isolated (E) and (Z) compounds were yellowish brown

solids, and the E/Z ratio was 1.0/2.3 (isolated yield 93%).

4.5. Prepartion of (E)-[2R,4S,5R]-4-(N,N-dimethylhydra-

zonomethyl)-2-phenyl-[1,3]dioxane-5-ol 11

To a 100 mL ﬂame-dried three-necked round-bottomed

ﬂask connected to a condenser were added 780 mg

(estimated as 3.10 mmol) of crude 6 and 932 mg (15.5

mmol, 1.18 mL) of N,N-dimethylhydrazine with 50 mL

,

of methyl alcohol and small amount of 4 A MS. After

(Z)-9: Yellowish brown solid (column chromatography,

hexane:EtOAc=3:1). R_f=0.39 (hexane:EtOAc=1:1).

the mixture was reﬂuxed under a nitrogen atmosphere for

17.5h, andallsolventwasremovedonarotaryevaporator

to get the crude product. The crude mixture was puriﬁed

by column chromatography eluting with hex-

ane:EtOAc=6:1 to 4:1 to get 652 mg (84%) of the desired

product as the (E)-isomer.⁹(E)-11: Pale yellow solid

(column chromatography, hexane:EtOAc=6:1 to 4:1).

R_f=0.35(hexane:EtOAc=1:1). Mp:66-68°C. [h]²_D⁰=+8.3

(c 0.55, CHCl₃). ¹H NMR (CDCl₃, 400 MHz): l 2.83 (s,

6H), 3.64 (br s, 1H), 3.70 (apparent t, J=10.6 Hz, 1H),

3.98 (ddd, J=10.2, 9.1, 5.2 Hz, 1H), 4.24 (dd, J=8.9, 3.2

Hz, 1H), 4.36 (dd, J=10.8, 5.2 Hz, 1H), 5.57 (s, 1H), 6.61

(d, J=3.1 Hz, 1H), 7.31-7.42 (m, 3H), 7.48-7.57 (m, 2H).

¹³C NMR (CDCl₃, 100 MHz): l 42.41, 65.09, 70.02, 80.54,

101.24, 126.12, 128.21, 128.95, 133.64, 137.46. IR (NaCl,

neat): 3392br s, 2966m, 2862s, 2778m, 2358w, 1597m,

1457s, 1396s, 1316w, 1264m, 1220m, 1085s, 1027s, 918m,

823m, 762s, 699s. Anal. calcd for C₁₃H₁₈N₂O₃: C, 62.38;

H, 7.25; N, 11.19. Found: C, 62.17; H, 7.21; N, 11.03.

1

Mp: 98–99°C. [h]²_D⁰=−156.1 (c 0.71, CHCl₃). H NMR

(CDCl₃, 400 MHz): l 2.68 (br s, 1H), 3.60–3.65 (m, 1H),

3.69 (apparent t, J=10.2 Hz, 1H), 4.31 (dd, J=9.9, 4.2

Hz, 1H), 4.53 (apparent td, J=7.9, 0.8 Hz, 1H), 5.58 (s,

1H), 5.59 (dd, J=11.4, 1.0 Hz, 1H), 6.50 (dd, J=11.4,

7.8 Hz, 1H), 7.36–7.42 (m, 3H), 7.50–7.53 (m, 2H). ¹³C

NMR (CDCl₃, 100 MHz): l 64.99, 70.81, 80.53, 100.80,

102.62, 115.50, 126.08, 128.26, 129.18, 136.74, 148.88. IR

(NaCl, neat): 3458br s, 3068m, 2977m, 2926m, 2860s,

2225s, 1714w, 1634w, 1494w, 1455s, 1402s, 1385s, 1316w,

1295m, 1267m, 1216m, 1134s, 1086s, 1028s, 919m, 872w,

737s, 701s, 675m, 645m. Anal. calcd for C₁₃H₁₃NO₃: C,

67.52; H, 5.67; N, 6.06. Found: C, 66.77; H, 5.87; N, 5.85.

4.4. Preparation of [2R,4S,5R]-5-hydroxy-2-phenyl-

[1,3]dioxane-4-carbaldehyde O-methyl-oxime syn- and

anti-10

To a 100 mLof ﬂame-dried three-neckedround-bottomed

ﬂask connected to a condenser were added 222 mg

(estimated as 1.07 mmol) of crude 6 and 142 mg (1.60

mmol) of O-methylhydroxyl amine hydrochloride in 50

mL of methyl alcohol and 1 mL of pyridine. After the

mixture was reﬂuxed under a nitrogen atmosphere for 5.5

h, all solvent was removed on a rotary evaporator to get

the crude product. The crude mixture was puriﬁed by

column chromatography eluting with hexane:EtOAc=

4:1. The desired product (0.216 g) was obtained as a white

solid (isolated yield 91%). The isolated compound is a

syn/anti mixture in a ratio of 1.0/0.18 based on ¹H NMR

analysis (C₁syn higher ﬁeld and C₁-H higher ﬁeld anti

isomer; for several carbohydrate examples, see Ref. 7).

4.6.

Preparation

of

[2R,4S,5R]-(diphenylhydra-

zonomethyl)-2-phenyl-[1,3]dioxane-5-ol 12

To a 100 mL of ﬂame-dried one-neck round-bottomed

ﬂask were added 780 mg (estimated as 3.10 mmol) of 6

and 1.37 g (6.20 mmol) of N,N%-dimethyl hydrazine

hydrochloride with 50 mL of methyl alcohol, 552 mL of

,

pyridine (6.82 mmol), and small amount of 4 A MS. The

mixture was stirred at rt under a nitrogen atmosphere for

17.5 h. After the solvent was removed in a rotary

evaporator, the crude product was puriﬁed by column

chromatography eluting with hexane:EtOAc=7:1 to give

993 mg of the desired product as white solid (isolated yield

86%). The isolated compound was assigned as anti based

on the chemical shift and coupling constant of its

1

syn- and anti-10: White solid (syn/anti=1.0/0.18)

(column chromatography, hexane:EtOAc=4:1). R_f=

characteristic hydrogen (6.63 ppm, d, J=3.2 Hz) on H

NMR spectrum. 12: White solid (column chromatogra-

phy; hexane:EtOAc=7:1). R_f=0.27 (hexane:EtOAc=

1

0.60 (hexane:EtOAc=1:1). Mp: 105–108°C. H NMR

1

(CDCl₃, 400 MHz): syn-10: l 3.70 (apparent t, J=10.5

Hz, 1H), 3.90 (s, 3H), 3.99 (ddd, J=10.2, 9.1, 5.2 Hz, 1H),

4.25 (dd, J=8.9, 3.9 Hz, 1H), 4.38 (dd, J=10.9, 5.2 Hz,

1H), 5.54 (s, 1H), 7.23–7.42 (m, 3H), 7.47–7.52 (m, 3H);

anti-10: l 3.67 (apparent t, J=9.6 Hz, 1H), 3.80 (apparent

td, J=9.9, 5.1 Hz, 1H), 3.96 (s, 3H), 4.38 (dd, J=10.8,

5.0 Hz, 1H), 4.90 (dd, J=9.5, 5.3 Hz, 1H), 5.51 (s, 1H),

6.91 (d, J=5.3 Hz, 1H), 7.33–7.42 (m, 3H), 7.47–7.52 (m,

5:1). Mp: 119-120°C. [h]²_D⁰=+58.8 (c 0.40, CHCl₃). H

NMR(CDCl₃, 400MHz):l3.42(brs, 1H), 3.75(apparent

t, J=10.5 Hz, 1H), 4.14 (apparent td, J=10.0, 5.3 Hz,

1H), 4.35 (dd, J=8.9, 3.2 Hz, 1H), 4.43 (dd, J=10.9, 5.2

Hz, 1H), 5.56 (s, 1H), 6.63 (d, J=3.2 Hz, 1H), 7.11 (d,

J=7.4 Hz, 2H), 7.35–7.43 (m, 7H), 7.47–7.50 (m, 2H).

¹³C NMR (CDCl₃, 100 MHz): l 64.66, 70.20, 80.64,

101.43, 122.35, 124.86, 128.26, 129.91, 135.90, 137.26,

2948

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

142.95. IR (NaCl, neat): w 3453br s, 3062m, 3036m,

2973m, 2927m, 2856m, 2358w, 2248m, 1955w, 1809w,

1703w, 1591s, 1495s, 1455s, 1395s, 1298s, 1215s, 1157s,

1074s, 1027s, 910s, 750s, 733s, 699s, 648s. Anal. calcd

for C₂₃H₂₂N₂O₃: C, 73.78; H, 5.92; N, 7.48. Found: C,

72.89; H, 6.14; N, 7.42.

ane:EtOAc=2:1). Mp: 101–103°C. [h]²_D⁰=−51.0 (c 2.06,

1

CHCl₃). H NMR (CDCl₃, 400 MHz): l 1.26 (t, J=7.2

Hz, 3H), 3.92 (apparent t, J=10.3 Hz, 1H), 4.18

(apparent tt, J=7.1, 3.8 Hz, 2H), 4.67 (dd, J=10.6, 5.2

Hz, 1H), 5.58 (apparent td, J=9.8, 5.2 Hz, 1H), 5.70 (s,

1H), 5.99 (dd, J=11.7, 0.8 Hz, 1H), 6.02 (apparent t,

J=9.4 Hz, 1H), 6.20 (dd, J=11.7, 8.8 Hz, 1H), 7.03 (d,

J=0.8 Hz, 1H), 7.36–7.40 (m, 3H), 7.49–7.52 (m, 2H),

7.65 (s, 1H), 8.39 (s, 1H). ¹³C NMR (CDCl₃, 100

MHz): l 14.1, 60.8, 66.6, 73.0, 74.0, 101.2, 118.4, 124.4,

126.1, 128.3, 129.3, 130.2, 136.5, 136.9, 142.9, 165.4,

182.5. IR (NaCl, neat): 3133m, 3037w, 2982m, 2926m,

1715s, 1659m, 1532m, 1469s, 1392s, 1333s, 1295s,

1279s, 1231s, 1199s, 1126s, 1094s, 1005s, 947w, 919m,

872w, 828m, 752m, 698m. Anal. calcd for

C₁₉H₂₀N₂O₅S: C, 58.75; H, 5.19; N, 7.21. Found: C,

58.05; H, 5.37; N, 7.13.

4.7. Preparation of (E)-[2R,4S,5R]-3-[5-(imidazole-1-

carbothioyloxy)-2-phenyl-[1,3]dioxan-4-yl]-acrylic acid

ethyl ester (E)-7-im

To a ﬂame-dried 50 mL ﬂask were added 51 mg (0.183

mmol) of (E)-7, 98 mg (0.550 mmol) of 1,1%-thiocar-

bonyldiimidazole, and 7 mg of DMAP along with 20

mL of fresh distilled THF. The mixture was reﬂuxed

under a nitrogen atmosphere for 14 h, and another 200

mg of 1,1%-thiocarbonyldiimidazole was added. Reﬂux-

ing was continued for 5.5 h, but some starting material

was detected on TLC. Finally, 150 mg more of 1,1%-

thiocarbonyldiimidazole and 18 h more of reﬂuxing

were required to consume all starting material. The

solvent was removed under reduced pressure to get

deep brown oil. The mixture was puriﬁed by ﬂash

column chromatography with hexane:EtOAc=2:1, to

get 62.1 mg (89%) of desired product. (E)-7-im: Pale

4.9. Preparation of (Z)-[1R,2R,4S,5R]-imidazole-1-car-

bothioic acid O-[4-(2-cyanovinyl)-2-phenyl-[1,3]dioxane-

5-yl] ester (Z)-9-im

To a ﬂame-dried 25 mL ﬂask were added 94 mg (0.407

mmol) of (Z)-9, 217 mg (1.220 mmol) of 1,1%-thiocar-

bonyldiimidazole, and 17 mg of DMAP along with 20

mL of freshly distilled THF. The mixture was reﬂuxed

under a nitrogen atmosphere for 7 h, and another 217

mg of 1,1%-thiocarbonyldiimidazole was added. Reﬂux-

ing was continued for 5 h at which time all starting

material was consumed (TLC). The solvent was

removed under reduced pressure to give the crude

mixture, which was puriﬁed by ﬂash column chro-

matography eluting with hexane:EtOAc=4:1 to 1:1.

The desired product (97 mg) was iolated in an yield of

70%.

yellow

solid

(column

chromatography,

hex-

ane:EtOAc)=2:1. R_f=0.17 (hexane:EtOAc=2:1). Mp:

100–102°C. [h]_D²⁰=−106.7 (c 0.45, CHCl₃). ¹H NMR

(CDCl₃, 400 MHz): l 1.26 (t, J=7.1 Hz, 3H), 3.84

(apparent t, J=10.4 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H),

4.71 (dd, J=10.8, 5.3 Hz, 1H), 4.74–4.69 (m, 1H), 5.54

(apparent td, J=9.8, 5.2 Hz, 1H), 5.68 (s, 1H), 6.23

(dd, J=15.7, 1.5 Hz, 1H), 6.96 (dd, J=15.7, 4.9 Hz,

1H), 7.09 (s, 1H), 7.38–7.42 (m, 3H), 7.50–7.54 (m, 2H),

7.61 (s, 1H), 8.41 (s, 1H). ¹³C NMR (CDCl₃, 100

MHz): l 14.1, 60.8, 66.7, 73.4, 76.9, 101.2, 118.0, 124.0,

126.1, 128.4, 129.4, 130.8, 136.3, 136.7, 140.4, 165.6,

181.9. IR (NaCl, neat): 3416br s, 3128m, 3038w,

2979m, 1728s, 1713s, 1666m, 1532m, 1470s, 1392s,

1334s, 1184s, 1139s, 1097s, 1004s, 920m, 852w, 748m,

699m, 653m. Anal. calcd for C₁₉H₂₀N₂O₅S: C, 58.75; H,

5.19; N, 7.21. Found: C, 58.61; H, 5.33; N, 7.20.

(Z)-9-im: Pale yellow solid (column chromatography,

hexane:EtOAc=4:1 to 1:1). R_f=0.55 (hexane:EtOAc=

1

1:1). Mp: 136-137°C. [h]²_D⁰=−90.0 (c 0.41, CHCl₃). H

NMR (CDCl₃, 400 MHz): l 3.91 (apparent t, J=10.4

Hz, 1H), 4.70 (dd, J=10.8, 5.3 Hz, 1H), 5.10 (apparent

t, J=9.1 Hz, 1H), 5.58 (dd, J=11.0, 0.6 Hz, 1H), 5.66

(apparentarent td, J=9.8, 5.3 Hz, 1H), 5.72 (s, 1H),

6.52 (dd, J=11.1, 8.7 Hz, 1H), 7.07 (d, J=0.9 Hz, 1H),

7.38-7^.42 (m, 3H), 7.50-7.54 (m, 2H), 7.68 (apparent t,

J=1.3 Hz, 1H), 8.41 (s, 1H). ¹³C NMR (CDCl₃, 100

MHz): l 66.52, 71.92, 77.38, 101.42, 104.42, 114.85,

117.77, 126.07, 128.37, 129.53, 131.31, 135.94, 137.55,

147.03, 182.43. IR (NaCl, neat): 3143br s, 3110m,

3082m, 3039m, 2948m, 2872s, 2253m, 2223s, 1767w,

1713w, 1644w, 1534s, 1480s, 1467s, 1392s, 1330s, 1297s,

1276s, 1216s, 1131s, 1097s, 1069m, 1053m, 1006s, 971s,

910s, 871m, 834s, 759s, 735s, 702s, 653s. Anal. calcd for

C₁₇H₁₅N₃O₃S: C, 59.81; H, 4.43; N, 12.31. Found: C,

59.86; H, 4.76; N, 11.70.

4.8. Preparation of (Z)-[2R,4S,5R]-3-[5-(imidazole-1-

carbothioyloxy)-2-phenyl-[1,3]dioxan-4-yl]-acrylic acid

ethyl ester (Z)-7-im

To a 50 mL of ﬂame-dried ﬂask were added 50 mg

(0.180 mmol) of (Z)-3-(5(R)-hydroxy-2(R)-phenyl-

[1,3]dioxane-4(R)-yl)-acrylic acid ethyl ester, (Z)-7, 3.0

equiv. of 1,1%-thiocarbonyldiimidazole, and 7 mg of

DMAP along with 20 mL of THF. After reﬂuxing the

mixture for 5 h, some starting material was detected on

TLC. Another 180 mg of 1,1%-thiocarbonyldiimidazole

was added and reﬂuxing was continued for 28 h. Addi-

tional 100 mg of of 1,1%-thiocarbonyldiimidazole was

required to consume all starting material with reﬂuxing

for 10 h. After the solvent was removed on a rotary

evaporator, the product was isolated by ﬂash column

chromatography with hexane:EtOAc=3:1 to give 66.9

mg of desired product as yellow solid. The isolated

yield was 96%. (Z)-7-im: Yellow solid (column chro-

matography, hexane:EtOAc=3:1). R_f=0.33 (hex-

4.10. Preparation of [2R,4S,5R]-imidazole-1-carbothioic

acid O-[4-(methoxyiminomethyl)-2-phenyl-[1,3]dioxan-5-

yl] ester (Z)- and (E)-10-im

To a ﬂame-dried 100 mL ﬂask were added 163 mg

(0.687 mmol) of Z- and E-10, 367 mg (2.061 mmol) of

1,1%-thiocarbonyldiimidazole, and 20 mg of DMAP

along with 50 mL of freshly distilled THF. The mixture

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2949

was reﬂuxed under a nitrogen atmosphere for 8.5 h,

and another 200 mg of 1,1%-thiocarbonyldiimidazole

was added. Reﬂuxing was continued for 11 h at which

time all starting material was consumed (TLC). The

solvent was removed under reduced pressure to give

crude mixture, which was puriﬁed by ﬂash column

chromatography eluting with hexane:EtOAc=6:1. The

desired product (Z)- and (E)-10-im was isolated in 90%

(215 mg) yield as an yellow solid. The isolated com-

pound was a syn/anti mixture with a ratio of 1.0/0.13

1004s, 919m, 827w, 752m. Anal. calcd for

C₁₇H₂₀N₄O₃S: C, 56.65; H, 5.59; N, 15.54. Found: C,

56.59; H, 5.79; N, 15.19.

4.12. Preparation of [2R,4S,5R]-imidazole-1-carbothioic

acid O-[4-(diphenylhydrazonomethyl)-2-phenyl-

[1,3]dioxan-5-yl] ester 12-im

To a ﬂame dried 100 mL ﬂask were added 716 mg (2.06

mmol) of 12, 1.10 g (6.18 mmol) of 1,1%-thiocarbonyldi-

imidazole, and 80 mg of DMAP along with 60 mL of

freshly distilled THF. After the mixture was reﬂuxed

under a nitrogen atmosphere for 17.5 h, another 1.10 g

of 1,1%-thiocarbonyldiimidazole was added. After 9 h

reﬂuxing, all starting material was disappeared on TLC.

The solvent was removed under reduced pressure to

give crude mixture, which was puriﬁed by ﬂash column

chromatography eluting with hexane:EtOAc=6:1 to

4:1. The desired product 12-im was obtained as yellow

solid (833 mg) and 26 mg of the starting material was

recovered. The isolated yield is 90% (93% based on the

recovered starting material). The isolated compound is

assigned as anti based on the chemical shift and cou-

pling constant of its characteristic hydrogen (6.46 ppm,

d, J=5.7 Hz) on ¹H NMR spectrum. Yellow solid

(column chromatography; hexane:EtOAc=6:1 to 4:1).

R_f=0.29 (hexane:EtOAc=2:1). Mp: 65–67°C. [h]²_D⁰=

1

based on H NMR spectrum. Yellow solid (syn/anti=

1.0/0.13) (column chromatography, hexane:EtOAc=

1

6:1). R_f=0.41 (hexane:EtOAc=1:1). Mp: 85-88°C. H

NMR (CDCl₃, 400 MHz): syn: l 3.78 (s, 3H), 3.87

(apparent t, J=10.5 Hz, 1H), 4.68 (dd, J=9.7, 6.7 Hz,

1H), 4.75 (dd, J=10.7, 5.3 Hz, 1H), 5.66 (s, 1H), 5.69

(apparent td, J=9.9, 5.3 Hz, 1H), 7.05 (d, J=1.2 Hz,

1H), 7.37-7.41 (m, 4H), 7.49-7.52 (m, 2H), 7.61 (appar-

ent t, J=1.2 Hz, 1H), 8.31 (s, 1H); anti: l 3.82 (s, 3H),

3.90 (apparent t, J=10.2 Hz, 1H), 4.69 (dd, J=9.5, 5.0

Hz, 1H), 5.39 (dd, J=11.2, 4.4 Hz, 1H), 5.65 (s, 1H),

5.66 (apparent td, J=9.9, 5.3 Hz, 1H), 6.82 (d, J=5.3

Hz, 1H), 7.05 (d, J=1.2 Hz, 1H), 7.37-7.41 (m, 3H),

7.49-7.52 (m, 2H), 7.63 (apparent t, J=1.2 Hz, 1H),

8.31 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): syn: l

62.14, 66.80, 71.49, 76.59, 101.58, 118.14, 126.12,

128.39, 129.49, 131.07, 136.23, 136.79, 145.08, 182.60;

anti: l 62.31, 66.80, 71.01, 76.59, 101.31, 118.14,

126.12, 128.39, 129.49, 130.97, 136.23, 136.79, 145.90,

182.44. IR (NaCl, neat): 3412br s, 3129m, 3037m,

2966m, 2938m, 2870m, 1631w, 1532m, 1469s, 1393s,

1355s, 1294s, 1233s, 1103s, 1039s, 1006s, 920m, 887m,

752m, 699m, 651m. Anal. calcd for C₁₆H₁₇N₃O₄S: C,

55.32; H, 4.93; N, 12.10. Found: C, 56.03; H, 5.38; N,

11.65.

1

+26.0 (c 0.45, CHCl₃). H NMR (CDCl₃, 400 MHz): l

3.93 (apparent t, J=10.5 Hz, 1H), 4.68 (dd, J=10.7,

5.4 Hz, 1H), 4.79 (dd, J=9.5, 5.7 Hz, 1H), 5.68 (s, 1H),

5.83 (apparent td, J=9.9, 5.4 Hz, 1H), 6.46 (d, J=5.7

Hz, 1H), 6.98 (dd, J=8.6, 1.2 Hz, 4H), 7.03 (d, J=0.7

Hz, 1H), 7.15 (td, J=7.4, 1.0 Hz, 2H), 7.30–7.33 (m,

4H), 7.36–7.40 (m, 3H), 7.49–7.52 (m, 2H), 7.64 (s, 1H),

8.37 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l 66.89,

72.14, 79.33, 101.64, 117.98, 122.21, 124.82, 126.19,

128.35, 129.38, 129.74, 130.92, 131.29, 136.55, 136.80,

142.84, 182.77. IR (NaCl, neat): w 3129m, 3064m,

3038m, 2967m, 2246w, 1955w, 1767w, 1702w, 1592s,

1532w, 1495s, 1464m, 1392s, 1335s, 1300s, 1279s, 1232s,

1157m, 1098s, 1004s, 911s, 831s, 750s, 733s, 699s,

644m. Anal. calcd for C₂₇H₂₄N₄O₃S: C, 66.48; H, 4.99;

N, 11.56. Found: C, 66.48; H, 5.30; N, 10.79.

4.11. Preparation of [2R,4S,5R]-imidazole-1-carbothioic

acid O-[4-(dimethylhydrazonomethyl)-2-phenyl-

[1,3]dioxan-5-yl] ester 11-im

To a ﬂame-dried 100 mL ﬂask were added 363 mg (1.45

mmol) of 11, 775 mg (4.35 mmol) of 1,1%-thiocar-

bonyldiimidazole, and 50 mg of DMAP along with 50

mL of freshly distilled THF. After the mixture was

reﬂuxed under a nitrogen atmosphere for 3 h, all start-

ing material was consumed (TLC). The solvent was

removed under reduced pressure to give the crude

mixture, which was puriﬁed by ﬂash column chro-

matography eluting with hexane:EtOAc=3:1. The

desired product 11-im was isolated in 90% (215 mg)

yield. 11-im: Pale yellow solid (column chromatogra-

phy, hexane:EtOAc=3:1). R_f=0.28 (hexane:EtOAc=

1:1). Mp: 89-90°C. [h]²_D⁰=−92.7 (c 0.94, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz): l 2.76 (s, 6H), 3.88 (appar-

ent t, J=10.4 Hz, 1H), 4.64 (dd, J=9.7, 6.0 Hz, 1H),

4.69 (dd, J=10.6, 5.3 Hz, 1H), 5.67 (s, 1H), 6.41 (d,

J=5.9 Hz, 1H), 7.03 (d, J=0.7 Hz, 1H), 7.26 (s, 1H),

7.33-7.41 (m, 3H), 7.51-7.54 (m, 2H), 7.60 (s, 1H), 8.30

(s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l 42.17, 66.97,

72.85, 79.85, 101.60, 118.14, 126.19, 127.46, 128.28,

128.34, 129.28, 130.80, 136.77, 183.09. IR (NaCl, neat):

3431br s, 3135w, 2958w, 2859m, 2790w, 1594m, 1531w,

1466s, 1392s, 1333s, 1292s, 1279s, 1232s, 1162w, 1101s,

4.13. Preparation of (Z)-29

To a 100 mL of ﬂame-dried three-necked round-bot-

tomed ﬂask connected to a condenser were added 2.09

g (6.86 mmol) of 27¹⁴and 3.09 g (8.23 mmol) of

(carb-tert-butoxymethylene)triphenylphosphorane. Di-

methoxyethane (35 mL) was added and the mixture was

stirred at rt for 4 h and then reﬂuxed for a further 4 h.

After the solvent was removed under vacuum, E and Z

mixtures of products were isolated by ﬂash column

chromatography eluting ﬁrst with 100% hexane only

and then switching to hexane:EtOAc=95:5. E and Z

products were isolated as colorless oils in a ratio of

0.24/1.0 in a combined isolated yield of 92%.

The (Z)-oleﬁn starting material for 29 and 31: Colorless

oil (column chromatography, hexane:EtOAc=95:5).

R_f=0.38 (hexane:EtOAc=9:1). [h]²_D⁰=+69.3 (c 1.0,

2950

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

1

CHCl₃). H NMR (CDCl₃, 300 MHz): l 0.07 (s, 6H),

0.90 (s, 3H), 1.36 (s, 3H), 1.47 (s, 3H), 1.47 (s, 9H), 2.9

(br s, 1H, disappeared with D₂O), 3.59 (ddd, J=8.4,

5.4, 3.0 Hz, 1H), 3.69 (dd, J=10.2, 5.4 Hz, 1H), 3.78

(dd, J=10.2, 3.0 Hz, 1H), 4.26 (dd, J=8.4, 6.3 Hz,

1H), 5.69 (ddd, J=8.5, 6.3, 1.0 Hz, 1H), 5.89 (dd,

J=11.6, 1.0 Hz, 1H), 6.18 (dd, J=11.6, 8.6 Hz, 1 H).

¹³C NMR (CDCl₃, 75 MHz): l −5.16, −5.12, 18.6, 25.6,

28.2, 28.3, 64.6, 70.3, 74.1, 78.2, 81.4, 109.2, 124.3,

143.5, 165.9. IR (NaCl, neat): 3477m, 2854s, 2933s,

2857s, 1716s, 1652s, 1463m, 1369s, 1254s, 1159s, 1058s,

836s, 779s. Anal. calcd for C₂₀H₃₈O₆Si: C, 59.70; H,

9.45. Found: C, 59.79; H, 9.69.

2875m, 1717s, 1658m, 1472m, 1463m, 1368s, 1314m,

1256s, 1217m, 1153s, 1062m, 837s, 779m.

4.15. Preparation of alcohol precursors for 30 and 34

To a 100 mL of ﬂame-dried three-necked round-bot-

tomed ﬂask was added 378 mg (1.241 mmol) of 27, 411

mg

(1.366

mmol)

of

(cyanomethylene)-

triphenylphosphorane, and 52 mg of benzoic acid under

a nitrogen atmosphere. Freshly dried toluene (40 mL)

was introduced via a syringe, and the mixture was

reﬂuxed.

Two

more

206

mg

samples

of

(cyanomethylene)triphenylphosphorane were added

after 8 and 12 h, respectively. After the solvent was

removed in vacuo, the mixture was puriﬁed by ﬂash

column chromatography eluting with hexane:EtOAc=

10:1 to 8:1, to get 146 mg of the expected (E)-oleﬁn

(white solid), and (Z)-oleﬁn 163 mg of product (yellow

oil) along with 6 mg of a cyclized product (yellow oil).

A ﬂame-dried three-necked round-bottomed ﬂask was

ﬁtted with a double spaced condenser, and 1.00 g (2.45

mmol) of the alcohol from the previous step, 0.97 g

(4.90 mmol) of 1,1-thiocarbonyldiimidazole, and 0.1 g

of DMAP were placed under a nitrogen atmosphere.

,

Dichloroethane (dried over 4 A MS, 20 mL) was added,

and the mixture was reﬂuxed for overnight (13 h 30

min.). The reaction mixture was cooled to rt, and the

solvent was removed by rotary evaporation under

house vacuum. The deep brown oil was puriﬁed by

ﬂash column chromatography eluting with hex-

ane:EtOAc=97:3 to 95:1 mixture. Desired product

(1.031 g) and starting material (86 mg) were obtained.

The yield was 89% based on the recovered starting

material.

(E)-Oleﬁn: White solid (column chromatography, hex-

ane:EtOAc=10:1 to 8:1). R_f=0.48 (hexane:EtOAc=

4:1). Mp: 68–70°C. [h]²_D⁰=−6.0 (c 0.55, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz): l 0.07 (s, 6H), 0.89 (s, 9H),

1.34 (s, 3H), 1.45 (s, 3H), 2.16 (br s, 1H), 3.45 (ddd,

J=9.4, 5.1, 3.1 Hz, 1H), 3.64 (dd, J=10.1, 5.2 Hz, 1H),

3.78 (dd, J=10.1, 3.1 Hz, 1H), 4.13 (dd, J=9.5, 6.9 Hz,

1H), 4.80 (ddd, J=6.7, 3.8, 2.1 Hz, 1H), 5.72 (dd,

J=16.2, 2.0 Hz, 1H), 7.00 (dd, J=16.2, 3.8 Hz, 1H).

¹³C NMR (CDCl₃, 100 MHz): l −5.54, −5.41, 18.27,

24.99, 25.81, 27.38, 64.11, 69.77, 76.62, 77.19, 100.30,

109.87, 117.26, 151.19. IR (NaCl, neat): 3498br s,

2989m, 2956s, 2930s, 2850s, 2227s, 1638m, 1432m,

1463m, 1383s, 1382s, 1257s, 1217s, 1165m, 1067s, 972w,

864m, 837s, 779s. Anal. calcd for C₁₆H₂₉NO₄Si: C,

58.68; H, 8.93; N, 4.28. Found: C, 58.66; H, 8.92; N,

4.12.

(Z)-29: Pale yellow oil (column chromatography, hex-

ane:EtOAc=97:3 to 95:5). [h]²_D⁰=+88.5 (c 3.42, CHCl₃).

1

R_f=0.23 (hexane:EtOAc=9:1). H NMR (CDCl₃, 250

MHz): l −0.03 (s, 3H), 0.00 (s, 3H), 0.84 (s, 9H), 1.40

(s, 9H), 1.40 (s, 3H), 1.51 (s, 3H), 3.92–4.04 (m, 2H),

4.85 (dd J=8.1, 6.3 Hz, 1H), 5.53 (ddd J=8.1, 4.0, 2.8

Hz, 1H), 5.68 (dd, J=11.6, 1.6 Hz, 1H), 5.75 (ddd,

J=7.8, 6.4, 1.5 Hz, 1H), 6.13 (dd J=11.6, 7.8 Hz, 1H),

6.98 (s, 1H), 7.53 (s, 1H), 8.25 (s, 1 H). ¹³C NMR

(CDCl₃, 75 MHz): l −5.3, 18.3, 25.4, 25.9, 27.9, 28.2,

61.2, 74.1, 74.9, 81.3, 109.6, 118.0, 124.6, 130.7, 137.2,

142.3, 164.8, 183.3. IR (NaCl, neat): 3125w, 2980m,

2953m, 2938m, 2884m, 2857m, 1713s, 1658w, 1650m,

1531w, 1463m, 1413m, 1391s, 1371s, 1345m, 1327s,

1282s, 1245s, 1156s, 1109m, 1066s, 1022m, 986m, 957m,

876m, 833s. Anal. calcd for C₂₄H₄₀N₂O₆SSi: C, 56.22;

H, 7.87; N, 5.47; S, 6.24. Found: C, 56.42; H, 8.02; N,

5.38; S, 6.07.

(Z)-Oleﬁn: Yellow oil (column chromatography, hex-

ane:EtOAc=10:1 to 8:1). R_f=0.35 (hexane:EtOAc=

1

4:1). [h]²_D⁰=−30.4 (c 1.15, CHCl₃). H NMR (CDCl₃,

400 MHz): l 0.08 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H),

1.37 (s, 3H), 1.48 (s, 3H), 2.62 (br s, 1H), 3.54 (ddd,

J=9.2, 4.5, 3.5 Hz, 1H), 3.70 (dd, J=10.1, 4.8 Hz, 1H),

4.18 (dd, J=9.4, 6.4 Hz, 1H), 5.09 (ddd, J=8.3, 6.4, 0.9

Hz, 1H), 5.52 (dd, J=11.2, 1.0 Hz, 1H), 6.56 (dd,

J=11.2, 8.5 Hz, 1H). ¹³C NMR (CDCl₃, 100 MHz): l

−5.51, −5.41, 18.29, 25.25, 25.82, 27.68, 63.91, 69.37,

76.10, 77.45, 101.76, 110.21, 115.36, 148.94. IR (NaCl,

neat): 3498br s, 3070w, 2989m, 2885s, 2857s, 2224m,

1723w, 1631w, 1472s, 1463m, 1383s, 1372s, 1255s,

1219s, 1164s, 1096s, 1063s, 937w, 869m, 837s, 779s,

736m, 670m. HRMS (Electrospray) calcd for

C₁₆H₂₉NNaSO₄(M⁺+Na): 350.1764. Found (M⁺+Na):

350.1760. Anal. calcd for C₁₆H₂₉NO₄Si: C, 58.68; H,

8.93; N, 4.28. Found: C, 58.59; H, 9.32; N, 4.24.

4.14. The (E)-oleﬁn starting material for 33 (see Sec-

tion 4.13)

Isolated as a side product of the Wittig reaction

described earlier. Colorless oil (column chromatogra-

phy, hexane:EtOAc=95:5). R_f=0.24 (hexane:EtOAc=

1

4:1). [h]²_D⁰=−4.62 (c 1.19, CHCl₃). H NMR (CDCl₃,

400 MHz): l 0.07 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H),

1.36 (s, 3H), 1.48 (s, 3H), 1.48 (s, 9H), 3.56 (ddd,

J=9.0, 5.6, 3.1 Hz, 1H), 3.65 (dd, J=10.0, 5.6 Hz, 1H),

3.79 (dd, J=10.0, 3.1 Hz, 1H), 4.10 (dd, J=9.3, 6.6 Hz,

1H), 4.80 (apparent t, J=5.1 Hz, 1H), 6.06 (dd, J=

15.6, 1.5 Hz, 1H), 7.00 (dd, J=15.6, 5.2 Hz, 1 H). IR

(NaCl, neat): 3496m, 2979m, 2950m, 2930m, 2885m,

4.16. Preparation of 34

To a ﬂame-dried 100 mL three-necked ﬂask ﬁtted with

a condenser were added 133 mg (0.406 mmol) of the

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2951

(E)-oleﬁn from the previous experiment, 3.0 equiv. of

4.17. Preparation of starting material for 36 and 37

1,1-thiocarbonyldiimidazole (217 mg, 1.217 mmol), and

15 mg of DMAP. Freshly dried THF (40 mL) was

added to the ﬂask, and the mixture was stirred under

reﬂux condition. Another 217 mg of 1,1-thiocarbonyldi-

imidazole was added after 14 h, and reﬂuxing was

continued for 8 h. All solvents were removed under

reduced pressure to give a crude brown mixture of

products. The mixture was puriﬁed by ﬂash column

chromatography eluting hexane:EtOAc=5:1 to 2:1.

The desired product 34 was obtained as pale yellow

solid (102 mg, 88% based on recovered starting mate-

rial). In addition a mixture (46 mg) of cyclized byprod-

ucts A and B in a ratio of 0.22/1.0 (cis/trans) was also

obtained. 34: Pale yellow solid (column chromatogra-

phy, hexane:EtOAc=5:1 to 2:1) R_f=0.25 (hex-

ane:EtOAc=3:1). Mp: 51–53°C. [h]²_D⁰=−9.5 (c 0.61,

A dried 100 mL three-necked round-bottomed ﬂask

was equipped with a condenser and a magnetic stirring

bar. To the ﬂask were added 27 (305 mg, 1.00 mmol)

and 133 mg (1.50 mmol) of O-methylhydroxyl amine

hydrochloride under nitrogen. Methyl alcohol (50 mL)

and 1 mL of pyridine were added, and the mixture was

reﬂuxed under nitrogen for 5.5 h. The mixture was

taken up water, and extracted with dichloromethane.

The combined organic phase was washed with brine

and dried over MgSO₄. After the solid was ﬁltered off,

the collected organic phase was concentrated on a

rotary evaporator and puriﬁed by ﬂash column chro-

matography eluting with hexane:EtOAc=6:1. The iso-

lated product (319 mg of colorless oil) was obtained as

a syn/anti mixture in a ratio of 1.0/0.25, and the yield

was 96%.

1

CHCl₃). H NMR (CDCl₃, 400 MHz): l −0.03 (s, 3H),

0.01 (s, 3H), 0.85 (s, 9H), 1.40 (s, 3H), 1.50 (s, 3H), 3.94

(dd, J=12.0, 3.1 Hz, 1H), 4.03 (dd, J=12.0, 2.4 Hz,

1H), 4.75 (dd, J=8.6, 6.5 Hz, 1H), 4.83 (ddd, J=6.4,

4.7, 1.8 Hz, 1H), 5.39 (apparent dt, J=8.5, 2.8 Hz, 1H),

5.68 (dd, J=16.2, 1.8 Hz, 1H), 6.56 (dd, J=16.1, 4.6

Hz, 1H), 7.05 (d, J=0.7 Hz, 1H), 7.60 (s, 1H), 8.29 (s,

1H). ¹³C NMR (CDCl₃, 100 MHz): l −5.69, −5.62,

18.14, 25.09, 25.68, 27.47, 60.43, 74.85, 75.86, 80.46,

101.81, 110.22, 116.16, 117.97, 131.19, 136.40, 147.56,

182.24. IR (NaCl, neat): 3412br s, 3131m, 3332m,

2988s, 2954s, 2931s, 2884s, 2857s, 2227s, 1704m,

1639m, 1533m, 1470s, 1392s, 1324s, 1283s, 1165m,

1108s, 1054m, 1023s, 957s, 837s, 813m, 779s, 744m,

673m, 655s. Anal. calcd for C₂₀H₃₁N₃O₄SSi: C, 54.89;

H, 7.14; N, 9.60. Found: C, 54.93; H, 7.37; N, 9.45.

Alcohol precursor for imidazole thioate 36 and triazole

thioate 37: Colorless oil (syn/anti=1.0/0.25) (column

chromatography, hexane:EtOAc=6:1). R_f=0.49 (hex-

1

ane:EtOAc=4:1). H NMR (CDCl₃, 250 MHz): major

isomer, syn: l 0.05 (s, 6H), 0.87 (s, 9H), 1.32 (s, 3H),

1.43 (s, 3H), 2.62 (d, J=4.8 Hz, 1H), 3.50–3.70 (m,

3H), 3.83 (s, 3H), 4.09 (dd J=8.5, 6.4 Hz 1H), 4.72

(apparent t, J=7.4 Hz 1H), 7.16 (d, J=7.7 Hz 1 H);

minor isomer, anti: l 0.05 (s, 6H), 0.87 (s, 9H), 1.11 (s,

3H), 1.21 (s, 3H), 2.70 (d, J=3.8 Hz, 1H), 3.71–3.83

(m, 3H), 3.87 (s, 3H), 4.20 (apparent t J=6.7 Hz 1H),

5.26 (apparent t, J=6.3 Hz 1H), 6.83 (d, J=6.3 Hz 1

H). ¹³C NMR (CDCl₃, 75 MHz): major isomer, syn: l

−5.3, −5.1, 18.3, 26.0, 27.0, 28.0, 62.0, 64.3, 69.5, 75.4,

78.6, 109.9, 147.2; minor isomer, anti: l −5.6, −5.5,

18.4, 25.3, 25.7, 27.8, 62.4, 63.1, 70.7, 75.9, 82.4, 113.1,

149.1. IR (NaCl, neat): 3522br, 2987s, 2956s, 2932s,

2884s, 2875s, 2819w, 1795w, 1741w, 1629w, 1471s,

1468s, 1382s, 1255s, 1219s, 1170s, 1154s, 1117s, 1047s.

The isolated side-products were assigned the following

structures:

4.18. Preparation of 36

The reaction was performed with 215 mg (0.65 mmol)

of the corresponding alcohol prepared earlier and 345

mg (1.93 mmol) of 1,1-thiocarbonyldiimidazole in 30

mL of freshly dried THF under a nitrogen atmosphere.

The mixture was reﬂuxed in an oil bath, and another

200 mg of 1,1-thiocarbonyldiimidazole was added after

9 and 11 h, respectively. Finally, the mixture was

reﬂuxed for another 18 h. After the mixture was cooled

to rt, all solvent was removed in vaccuo. The crude

mixture was puriﬁed by ﬂash column chromatography

eluting with hexane:EtOAc=8:1 to 6:1. The desired

product was isolated as yellow oil (211 mg, 74%, 97%

based on recovered starting material) long with 51 mg

of starting material. 36: Yellow oil (column chromatog-

raphy, hexane:EtOAc=8:1 to 6:1). (syn:anti=1.0/0.3)

1

A: H NMR (CDCl₃, 400 MHz): l 0.08 (s, 6H), 0.90 (s,

3H), 1.35 (s, 3H), 1.53 (s, 3H), 3.73 (d, J=4.2 Hz, 1H),

4.11–4.21 (m, 1H), 4.44 (dd, J=6.4, 4.2 Hz, 1H), 4.70

(dd, J=6.4, 2.7 Hz, 1 H). ¹³C NMR (CDCl₃, 100

MHz): l −5.51, −5.37, 18.37, 22.30, 25.04, 25.93, 27.43,

63.84, 80.47, 82.27, 84.22, 85.65, 114.16, 116.85.

B: R_f=0.47 (hexane:EtOAc=4:1). ¹H NMR (CDCl₃,

250 MHz): l 0.05 (s, 6H), 0.89 (s, 9H), 1.35 (s, 3H),

1.50 (s, 3H), 2.65 (d, J=6.7 Hz, 1H), 3.70 (dd, J=11.0,

2.8 Hz, 1H), 3.78 (dd, J=11.0, 2.9 Hz, 1H), 4.15

(apparent t, J=2.8 Hz, 1H), 4.42 (apparent dt, J=6.7,

4.3 Hz, 1H), 4.71 (dd, J=5.9, 4.3 Hz, 1H), 4.84 (d,

J=6.1 Hz, 1 H). ¹³C NMR (CDCl₃, 100 MHz): l −5.7,

−5.6, 18.1, 18.9, 24.6, 25.8, 26.0, 65.4, 78.1, 81.3, 83.3,

84.7, 112.8, 117.6.

1

R_f=0.29 (hexane:EtOAc=4:1). H NMR (CDCl₃, 400

MHz): major syn: l 0.00 (s, 3H), 0.04 (s, 3H), 0.88 (s,

9H), 1.39 (s, 3H), 1.51 (s, 3H), 3.57 (s, 3H), 3.99 (dd,

J=11.7, 2.9 Hz, 1H), 4.12 (dd, J=11.9, 2.6 Hz, 1H),

4.76–4.81 (m, 2H), 5.49–5.58 (m, 1H), 7.04 (s, 1H), 7.27

(d, J=7.8 Hz, 1H), 7.61 (s, 1H), 8.30 (s, 1 H); minor

anti: l 0.01 (s, 3H), 0.03 (s, 3H), 0.86 (s, 9H), 1.39 (s,

2952

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

3H), 1.52 (s, 3H), 3.66 (s, 3H), 3.95–4.03 (m, 2H),

4.76–4.81 (m, 1H), 5.31 (apparent t, J=6.0 Hz, 1H),

5.49–5.56 (m, 1H), 6.80 (d, J=5.6 Hz, 1H), 7.04 (s,

1H), 7.63 (s, 1H), 8.30 (s, 1 H). ¹³C NMR (CDCl₃, 125

MHz): major syn: l −5.3, 18.4, 25.3, 25.9, 27.8, 60.7,

61.9, 74.2, 75.1, 80.6, 110.6, 118.1, 131.0, 137.0, 145.9,

182.0. IR (NaCl, neat): 3133w, 2989m, 2953m, 2935m,

2897m, 2856m, 1739w, 1626m, 1531w, 1463m, 1391s,

1344m, 1323s, 1283s, 1246s, 1229s, 1109m, 1076m,

1042s. Anal. calcd for C₁₉H₃₃N₂O₅SSi: C, 51.44; H,

7.50; N, 9.42; S, 7.23. Found: C, 51.57; H, 7.61; N,

9.23; S, 7.11.

was a syn/anti mixture in a ratio of 1.69/1.00 based on

¹H NMR spectrum. 37: Yellow oil (syn/anti=1.69/1.0)

(column chromatography, hexane:EtOAc=10:1 to 8:1).

1

R_f=0.29 (hexane:EtOAc=4:1). H NMR (CDCl₃, 400

MHz): syn (major): l 0.00 (s, 3H), 0.03 (s, 3H), 0.86 (s,

9H), 1.40 (s, 3H), 1.50 (s, 3H), 3.59 (s, 3H), 4.00 (dd,

J=11.9, 3.8 Hz, 1H), 4.14 (dd, J=11.9, 2.9 Hz, 1H),

4.76–4.83 (m, 2H), 5.61 (ddd, J=11.0, 8.1, 4.2 Hz, 1H),

7.34 (d, J=7.6 Hz, 1H), 8.05 (s, 1H), 8.92 (s, 1H); anti

(minor): l 0.00 (s, 3H), 0.01 (s, 3H), 0.84 (s, 9H), 1.38

(s, 3H), 1.50 (s, 3H), 3.70 (s, 3H), 3.98–4.02 (m, 2H),

4.71–4.78 (m, 1H), 5.32 (dd, J=6.5, 5.5 Hz, 1H),

5.59–5.63 (m, 1H), 6.88 (d, J=5.4 Hz, 1H), 8.05 (s,

1H), 8.93 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): syn

(major): l −5.60, −5.55, 18.21, 25.19, 25.73, 27.60,

61.05, 62.23, 74.16, 74.87, 81.40, 110.45, 144.43, 146.06,

153.64, 180.54; anti (minor): l −5.53, −5.35, 18.16,

24.82, 25.70, 27.21, 61.05, 62.23, 74.16, 74.87, 81.40,

109.76, 144.29, 147.27, 153.61, 180.80. IR (NaCl, neat):

3123w, 2986w, 2952s, 2934s, 2857s, 1797w, 1723w,

1516m, 1466m, 1462m, 1392s, 1378s, 1345m, 1321s,

1279s, 1254s, 1199s, 1124s, 1082s, 1046s, 965s, 942m,

837s, 814m, 779s, 660s. HRMS (Electrospray) calcd for

C₁₈H₃₂N₄NaO₅SSi (M⁺+Na): 467.1755. Found (M⁺+

Na): 467.1716.

4.19. Preparation of 31

A ﬂame-dried three-necked round-bottomed ﬂask was

ﬁtted with a double spaced condenser, and 192 mg

(0.478 mmol) of the requisite (Z)-starting alcohol (see

Section 4.13), 258 mg (1.43 mmol) of 1,1-thiocar-

bonylditriazole, and 10 mg of DMAP were placed

under a nitrogen atmosphere. Freshly distilled THF (15

mL) was added, and the mixture was reﬂuxed overnight

(12 h.). The reaction mixture was cooled to rt, and the

solvent was removed by rotary evaporation under

house vacuum. The crude product was puriﬁed by ﬂash

column chromatography eluting with hexane:EtOAc=

10:1 to 8:1 mixture. Desired product (69 mg) and

starting material (115 mg) were obtained. The isolated

yield of 31 was 28% (70% based on the recovered

starting material). 31: Colorless oil (column chromatog-

raphy, hexane:EtOAc=10:1 to 8:1). R_f=0.31 (hex-

ane:EtOAc=6:1). [h]²_D⁰=+90.6 (c 0.58, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz): l −0.02 (s, 3H), 0.00 (s, 3H),

0.83 (s, 9H), 1.39 (s, 9H), 1.40 (s, 3H), 1.51 (s, 3H), 4.00

5-exo-Hex-5-enyl radical cyclizations

4.21. Cyclization of of [(E)-7-im] under reverse addition

conditions (typical procedure for cyclization)

A ﬂame-dried three-necked 25 mL ﬂask was connected

to a condenser, and the ﬂask was charged with 276 mg

of Ph₃SnH (0.785 mmol) and 12.5 mL of benzene (dried

(A6 of ABX, J_AB=11.8 Hz, J_AX=5.1 Hz, 1H), 4.02 (B6

,

of ABX, J_AB=11.8 Hz, J_BX=2.5 Hz, 1H), 4.88 (dd,

J=7.3, 6.6 Hz, 1H), 5.63 (ddd, J=7.5, 4.5, 3.1 Hz, 1H),

5.72 (dd, J=11.6, 1.5 Hz, 1H), 5.78 (ddd, J=7.9, 6.7,

1.5 Hz, 1H), 6.19 (dd, J=11.6, 7.8 Hz, 1H), 8.02 (s,

1H), 8.85 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l

−5.56, 18.15, 25.09, 25.70, 27.56, 27.99, 61.29, 73.97,

75.04, 81.17, 82.38 (two peaks), 109.50, 124.57, 142.38,

153.61, 164.61, 180.69. IR (NaCl, neat): 2985s, 2951s,

2929s, 2860s, 1712s, 1643w, 1516w, 1472w, 1462s,

1388s, 1382s, 1321m, 1279s, 1239s, 1201s, 1157s, 1124s,

1066s, 966w, 943m, 835s, 778m, 666m, 651m. Anal.

calcd for C₂₃H₃₉N₃O₆SSi: C, 53.77; H, 7.65; N, 8.18; S,

6.24. Found: C, 54.15; H, 7.62; N, 7.33; S, 6.25.

over CaH₂and stored over 4 A MS under a nitrogen

atmosphere) under a nitrogen atmosphere. The ﬂask

was immersed into an oil bath and the oil bath temper-

ature was adjusted to be 90°C. To the ﬂask was added

a solution of 60.9 mg (0.157 mmol) of (E)-7-im, and 13

mg (0.079 mmol) of AIBN in 3.4 mL of benzene via a

syringe pump during 2 h, and the mixture was stirred

for another 0.5 h at 90°C (oil bath temperature). The

mixture was cooled to rt, and the solvent was removed

in vacuo to give crude product. The concentrated mix-

ture was puriﬁed by ﬂash column chromatography elut-

ing with hexane only to hexane:EtOAc=1:2. The

cyclized N-pyranoside 14 was obtained as white solid

(30.5 mg, 54%) in the ratio of a/b=0.8/1.0. The assign-

ment and conﬁgurations were assigned based on com-

parison of chemical shifts and coupling constants of the

4.20. Preparation of 37

t

A mixture of the requisite oxime-alcohol (Section 4.17,

131 mg), thiocarbonylditriazole (142 mg), and 10 mg of

DMAP were placed in a 50 mL of ﬂame dried three-

necked ﬂask, which was connected to a double spaced

condenser. Freshly dried THF (20 mL) was added to

the ﬂask, and the mixture was reﬂuxed under a nitrogen

atmosphere for 6 h. Another 2.0 equiv. of thiocar-

bonylditriazole was added and reﬂuxing was continued

for 16 h. All solvents were removed under reduced

pressure, and the dark brown mixture was puriﬁed by

column chromatography to give 79 mg of 37 as yellow

oil along with 50 mg of starting material. The product

corresponding Bu esters described in the next experi-

ments. 14-a: White solid (column chromatography, hex-

ane

only

to

hexane:EtOAc=1:2).

R_f=0.12

(hexane:EtOAc=1:4). [h]²_D⁰=+25.0 (c 0.62, CHCl₃).

1

Mp: 126–129°C. H NMR (CDCl₃, 400 MHz): l 1.11

(t, J=7.2 Hz, 3H), 2.60 (dd, J=15.5, 8.5 Hz, 1H), 2.84

(dd, J=15.4, 4.9 Hz, 1H), 3.15 (dddd, J=8.8, 8.3, 7.0,

4.9 Hz, 1H), 3.65 (dd, J=10.6, 8.8 Hz, 1H), 3.88–4.05

(m, 4H), 4.54 (dd, J=9.3, 3.9 Hz, 1H), 5.58 (s, 1H),

5.78 (d, J=7.0 Hz, 1H), 7.14 (s, 1H), 7.35–7.41 (m,

4H), 7.49–7.52 (m, 2H), 7.71 (s, 1H). ¹³C NMR

(CDCl₃, 100 MHz): l 13.90, 34.21, 45.28, 61.17, 70.75,

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2953

73.10, 82.78, 88.93, 102.61, 117.08, 126.22, 128.40,

129.01, 129.43, 136.16, 136.42, 170.20. IR (NaCl, neat):

3394br m, 3119m, 2982m, 1731s, 1495w, 1455w, 1428w,

1370m, 1282m, 1228m, 1165m, 1094m, 1047s, 1028s,

970s, 913m, 756s, 699s, 661m. HRMS (Electrospray)

calcd for C₁₉H₂₂N₂NaO₅(M⁺+Na): 381.1421. Found

(M⁺+Na): 381.1447. Anal. calcd for C₁₉H₂₂N₂O₅: C,

63.67; H, 6.19; N, 7.82. Found: C, 64.45; H, 6.93; N,

6.39.

ane:EtOAc=1:2). [h]²_D⁰=+34.9 (c 0.59, CHCl₃). Mp:

125–128°C. ¹H NMR (CDCl₃, 500 MHz): l 1.33 (s,

9H), 2.54 (dd, J=15.1, 8.5 Hz, 1H), 2.82 (dd, J=15.1,

4.7 Hz, 1H), 3.18 (dddd, J=8.8, 8.5, 6.9, 4.8 Hz, 1H),

3.65 (dd, J=10.4, 8.9 Hz, 1H), 3.94 (apparent t, J=

10.1 Hz, 1H), 4.00 (apparent td, J=9.8, 4.1 Hz, 1H),

4.58 (dd, J=9.5, 4.1 Hz, 1H), 5.62 (s, 1H), 5.82 (d,

J=6.9 Hz, 1H), 7.20 (s, 1H), 7.21 (s, 1H), 7.41–7.46 (m,

3H), 7.53–7.58 (m, 2H), 7.81 (s, 1H). ¹³C NMR

(CDCl₃, 100 MHz): l 27.72, 35.87, 45.26, 70.76, 72.92,

81.84, 83.04, 89.05, 102.67, 117.08, 126.25, 128.39,

129.43, 130.29, 136.43, 136.70, 169.43. IR (NaCl, neat):

3393br m, 3119m, 2983m, 2931m, 2872m, 1716m,

1396w, 1369m, 1281m, 1225w, 1150s, 1089s, 1045s,

963s, 934m, 913m, 831w, 760m, 700m. HRMS (Electro-

spray) calcd for C₂₁H₂₆N₂NaO₅(M⁺+Na): 387.1915.

Found (M⁺+Na): 387.1944.

14-b: White solid (column chromatography, hexane

only

to

hexane:EtOAc=1:2).

R_f=0.22

(hex-

ane:EtOAc=1:4). [h]²_D⁰=−84.0 (c 0.77, CHCl₃). Mp:

57–60°C. ¹H NMR (CDCl₃, 400 MHz): l 1.77 (t,

J=7.1 Hz, 3H), 1.80 (dd, J=17.8, 11.4 Hz, 1H), 2.69

(dd, J=17.8, 3.5 Hz, 1H), 3.11 (apparent tdd, J=11.4,

7.6, 3.5 Hz, 1H), 3.62 (dd, J=11.6, 9.0 Hz, 1H), 3.75

(ddd, J=9.9, 9.0, 4.0 Hz, 1H), 4.03 (apparent t, J=11.0

Hz, 1H), 4.05 (q, J=7.1 Hz, 2H), 4.63 (dd, J=9.8, 4.3

Hz, 1H), 5.62 (s, 1H), 6.29 (d, J=7.5 Hz, 1H), 6.94 (s,

1H), 7.11 (s, 1H), 7.35–7.41 (m, 3H), 7.48–7.59 (m, 2H),

7.60 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l 14.04,

31.03, 43.25, 61.11, 70.97, 73.05, 81.42, 86.95, 102.84,

117.42, 126.25, 128.42, 128.99, 129.62, 136.15, 136.42,

171.60. IR (NaCl, neat): 3388br m, 3119m, 3061m,

2983m, 2928m, 1729s, 1494m, 1478m, 1428s, 1376s,

1324m, 1228s, 1212s, 1080s, 1027s, 996s, 972s, 914m,

699s, 662m. HRMS (Electrospray) calcd for

C₁₉H₂₂N₂NaO₅(M⁺+Na): 381.1421. Found (M⁺+Na):

381.1433.

15-b: White solid (column chromatography; hexane

only

to

hexane:EtOAc=1:2).

R_f=0.29

(hex-

ane:EtOAc=1:2). [h]_D²⁰=−129.6 (c 0.46, CHCl₃). Mp:

1

59–61°C. H NMR (CDCl₃, 500 MHz): l 1.37 (s, 9H),

1.71 (dd, J=17.9, 11.5 Hz, 1H), 2.64 (dd, J=17.8, 3.3

Hz, 1H), 3.07 (apparent tdd, J=11.3, 7.5, 3.3 Hz, 1H),

3.59 (dd, J=11.7, 9.0 Hz, 1H), 3.74 (apparent td,

J=9.1, 4.4 Hz, 1H), 4.03 (apparent t, J=10.0 Hz, 1H),

4.62 (dd, J=9.8, 4.4 Hz, 1H), 5.61 (s, 1H), 6.30 (d,

J=7.5 Hz, 1H), 6.94 (s, 1H), 7.11 (s, 1H), 7.37–7.40 (m,

3H), 7.47–7.51 (m, 2H), 7.61 (s, 1H). ¹³C NMR

(CDCl₃, 100 MHz): l 27.90, 32.17, 43.26, 70.97, 73.07,

81.30, 81.15, 87.14, 102.82, 117.63, 126.25, 128.40,

129.20, 130.14, 136.16, 136.46, 170.92. IR (NaCl, neat):

4.22. Optimization of cyclization using 7 and 8

Table 4. 5-exo-trig Radical cyclization with [2R,4R,5R]-5-hydroxy-2-phenyl-[1,3]dioxane-4-carbaldehyde 6 derivatives

Entry

R

Conditions

Yield (%)

(a/b)

Radical sources (equiv.)

AIBN (equiv.)

Solvent

Temp. (°C)

1

2

3

4

(Z)-7

(E)-7

(Z)-8

(E)-8

Bu₃SnH (5.0)

Ph₃SnH (5.0)

Bu₃SnH (5.0)

Ph₃SnH (5.0)

0.5

Benzene

90

32

44

28

54

46

23

40

0.84/1.0

1.13/1.0

0.66/1.0

0.80/1.0

0.66/1.0

0.93/1.0

0.89/1.0

5

6^a

6

^aNormal addition stirred at 90°C for 3 h.

4.23. Cyclization of (Z)-8-im

3388br m, 3119m, 2978m, 2931m, 2872m, 1723s,

1494m, 1455m, 1369s, 1247m, 1227m, 1157s, 1080s,

1046s, 971s, 913m, 755s, 699s. HRMS (Electrospray)

calcd for C₂₁H₂₆N₂NaO₅(M⁺+Na): 387.1915. Found

(M⁺+Na): 387.1902. Anal. calcd for C₂₁H₂₆N₂O₅: C,

65.27; H, 6.78; N, 7.25. Found: C, 62.68; H, 6.93; N,

5.64.

The typical reverse addition procedure was used under

the following conditions: Ph₃SnH (309 mg, 0.880 mmol)

in 14 mL of benzene at 90°C, 72.8 mg (0.176 mmol) of

(Z)-8-im and 14.5 mg (0.088 mmol) of AIBN in 3.8 mL

of benzene added in 2 h 25 min, the mixture stirred for

additional 0.5 h at 90°C (oil bath temperature, column

chromatography eluting with hexane only to hex-

ane:EtOAc=1:2. The cyclized N-pyranoside was

obtained as white solid (31 mg, 46%) with the ratio of

a/b=0.7/1.0).

4.24. Cyclization of (Z)-9-im

The typical reverse addition procedure was used under

the following conditions: Ph₃SnH (295 mg, 0.841 mmol)

in 13.3 mL of benzene at 90°C, 52.7 mg (0.168 mmol)

of (Z)-9-im and 14.5 mg (0.088 mmol) of AIBN in 3.6

15-a: White solid (column chromatography, hexane

only

to

hexane:EtOAc=1:2).

R_f=0.16

(hex-

2954

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

6.06 (d, J=6.8 Hz, 1H), 7.06 (s, 1H), 7.12 (s, 1H),

7.36–7.41 (m, 3H), 7.47–7.50 (m, 2H), 7.68 (s, 1H).

¹³C NMR (CDCl₃, 100 MHz): a-anomer, l 61.36,

62.89, 69.00, 70.65, 72.38, 78.92, 87.65, 116.53,

126.24, 129.08, 129.44, 130.41, 136.05, 136.30; b-

anomer, l 53.82, 64.61, 69.41, 70.80, 71.06, 79.44,

85.94, 118.29, 126.25, 129.08, 128.37, 129.45, 136.23,

137.02. IR (NaCl, neat): 3112br m, 2940s, 2893s,

2802w, 2238w, 1701m, 1495s, 1458m, 1425w, 1379s,

1313m, 1283m, 1226s, 1058s, 1078s, 1049s, 1229s,

975s, 911s, 822w, 792w, 733s, 700s, 660s. HRMS

(Electrospray) calcd for C₁₆H₁₉N₃NaO₄(M⁺+Na):

340.1268. Found (M⁺+Na): 340.1290. Anal. calcd for

C₁₆H₁₉N₃O₄: C, 60.56; H, 6.04; N, 13.24. Found: C,

60.17; H, 6.45; N, 11.19.

mL of benzene added in 2 h 20 min, the mixture

stirred for additional 0.5 h at 90°C (oil bath tempera-

ture), column chromatography eluting with hex-

ane:EtOAc 1:1 to 1:2. The cyclized N-pyranoside was

obtained as pale yellow solid (38.5 mg, 81%) with the

ratio of a/b=1.0/0.79). The assignments are based on

comparison of chemical shifts and coupling constants

t

(especially of C₁-H) with those of Bu esters described

in the previous experiments.

a- and b-17: Pale yellow solid (a/b mixture, ratio:

1.0/0.79) (column chromatography, hexane:EtOAc 1:1

to 1:2). R_f=0.12 (EtOAc only). Mp: 126–130°C. ¹H

NMR (CDCl₃, 400 MHz): a-anomer, l 2.73 (dd, J=

17.5, 4.6 Hz, 1H), 2.88 (dd, J=17.5, 5.2 Hz, 1H),

2.96–3.06 (m, 1H), 3.75–3.81 (m, 1H), 3.95 (apparent

t, J=9.7 Hz, 1H), 4.01–4.07 (m, 1H), 4.57 (dd, J=

9.6, 4.2 Hz, 1H), 5.63 (s, 1H), 5.82 (d, J=7.2 Hz,

1H), 7.13 (s, 1H), 7.19 (s, 1H), 7.37–7.42 (m, 3H),

7.49–7.52 (m, 2H), 7.79 (s, 1H); b-anomer, l 1.91

(dd, J=17.2, 9.9 Hz, 1H), 2.51 (dd, J=17.2, 4.9 Hz,

1H), 2.96–3.06 (m, 1H), 3.68 (d, J=11.2, 9.2 Hz,

1H), 3.75–3.81 (m, 1H), 4.01–4.07 (m, 1H), 4.64 (dd,

J=9.9, 4.3 Hz, 1H), 5.64 (s, 1H), 6.17 (d, J=7.5 Hz,

1H), 7.06 (s, 1H), 7.20 (s, 1H), 7.37–7.42 (m, 3H),

7.49–7.52 (m, 2H), 7.76 (s, 1H). ¹³C NMR (CDCl₃,

100 MHz): a-anomer, l 16.15, 44.85, 70.56, 73.43,

81.15, 87.60, 102.75, 116.53, 116.60, 126.22, 128.46,

129.59, 131.13, 136.06, 136.48; b-anomer, l 14.57,

69.42, 70.07, 73.08, 81.34, 85.90, 102.84, 115.73,

117.38, 126.18, 128.44, 129.55, 130.49, 136.00, 136.21.

IR (NaCl, neat): 3115m, 2971s, 2879s, 2251m, 1698s,

1493s, 1455m, 1421m, 1380s, 1314m, 1285m, 1229s,

1168s, 1142m, 1080s, 1048s, 969s, 912s, 823w, 755s,

732s, 701s, 660s. HRMS (Electrospray) calcd for

C₁₇H₁₇N₃NaO₃(M⁺+Na): 334.1162. Found (M⁺+Na):

334.1180.

4.26. Cyclization of 11-im

The typical reverse addition procedure was used

under the following conditions: Ph₃SnH (618 mg,

1.760 mmol) in 28 mL of benzene at 90°C, 117 mg

(0.352 mmol) of 11-im and 29 mg (0.176 mmol) of

AIBN in 7.6 mL of benzene added in 4 h 35 min, the

mixture stirred for additional 0.5 h at 90°C (oil bath

temperature). The concentrated mixture was puriﬁed

by ﬂash column chromatography ﬁrst eluting with

hexane:EtOAc=1:1 and then with EtOAc with 1%

Et₃N. The ratio of the crude N-pyranosides was a/

1

b=1.0/0.3 measured by H NMR. The a-anomer was

isolated as a pure component as pale yellow solid

(57.6 mg, 54%).

19-a: Pale yellow solid (column chromatography, hex-

ane:EtOAc=1:1 100% EtOAc only with 1% of Et₃N).

R_f=0.10 (EtOAc only) or 0.67 (EtOAc:MeOH=9:1).

1

Mp: 120–123°C. H NMR (CDCl₃, 400 MHz): l 2.40

(s, 6H), 3.80–3.91 (m, 2H), 3.96 (apparent t, J=10.1

Hz, 1H), 4.06 (apparent td, J=9.7, 4.3 Hz, 1H), 4.56

(dd, J=9.6, 4.3 Hz, 1H), 5.55 (s, 1H), 5.75 (d, J=4.9

Hz, 1H), 7.11 (s, 1H), 7.18 (s, 1H), 7.35–7.42 (m,

4.25. Cyclization of (syn+anti)-10-im

The typical reverse addition procedure was used

under the following conditions: Ph₃SnH (407 mg, 1.16

mmol) in 18.3 mL of benzene at 90°C, 74 mg (0.232

mmol) of 10-im and 19 mg (0.16 mmol) of AIBN in

5 mL of benzene added in 3 h 15 min, the mixture

stirred for additional 0.5 h at 90°C (oil bath tempera-

ture), column chromatography eluting with hex-

ane:EtOAc 1:1 to 1:2. The cyclized N-pyranoside was

obtained as pale yellow solid (42.2 mg, 63%) with the

ratio of a/b=1.0/0.80).

3H), 7.47–7.50 (m, 2H), 7.75 (s, 1H); NH

laps with 3 Hs between 3.80 and 4.09. The integra-

tion of this region becomes smaller as much as 0.4 H

6 peak over-

6

with D₂O exchange. ¹³C NMR (CDCl₃, 100 MHz): l

48.26, 66.19, 70.80, 72.26, 81.71, 90.66, 102.58,

116.44, 126.22, 128.40, 129.44, 130.00, 136.04, 136.42.

IR (NaCl, neat): 3209br s, 3116s, 3039m, 2982s,

2948s, 2880s, 2857s, 2778s, 1698w, 1666w, 1494s,

1454s, 1428m, 1379s, 1313s, 1282s, 1224s, 1165s,

1078s, 1049s, 1027s, 991s, 966s, 912s, 813m, 792m,

761s, 735s, 700s, 660s. HRMS (Electrospray) calcd

for C₁₇H₂₂N₄NaO₃(M⁺+Na): 353.1584. Found (M⁺+

Na): 353.1581. Anal. calcd for C₁₇H₂₂N₄O₃: C, 61.80;

H, 6.71; N, 16.96. Found: C, 61.49; H, 6.77; N,

15.99.

a- and b-18: Pale yellow oil (a/b=1.0/0.83) (column

chromatography, hexane:EtOAc=1:1 to 1:2). R_f=0.22

(hexane:EtOAc=1:6). Mp: 96–99°C. ¹H NMR

(CDCl₃, 400 MHz): a-anomer, l 3.58 (s, 3H), 3.72–

3.81 (m, 1H), 3.91–3.97 (m, 2H), 4.00–4.11 (m, 2H),

4.55 (dd, J=9.5, 4.2 Hz, 1H), 5.57 (s, 1H), 5.86 (d,

J=5.3 Hz, 1H), 7.14 (s, 2H), 7.36–7.41 (m, 3H),

7.47–7.50 (m, 2H), 7.75 (s, 1H); b-anomer, l 3.07 (s,

3H), 3.72–3.81 (m, 1H), 3.91–3.97 (m, 2H), 4.00–4.11

(m, 2H), 4.58 (dd, J=9.8, 4.0 Hz, 1H), 5.59 (s, 1H),

4.27. Cyclization of of 12-im

The typical reverse addition procedure was used

under the following conditions: Ph₃SnH (1.06 g, 3.02

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2955

nected to a condenser, and the ﬂask was charged with

02 mg of Ph₃SnH (0.860 mmol) and 13.6 mL of ben-

mmol) in 24 mL of benzene at 90°C, 138 mg (0.302

mmol) of 12-im and 50 mg (0.302 mmol) of AIBN in

6.5 mL of benzene added in 4 h 30 min, the mixture

stirred for additional 0.5 h at 90°C (oil bath tempera-

ture). The concentrated mixture was puriﬁed by ﬂash

column chromatography eluting with hexane:EtOAc=

1:2. Only the a-anomer 20 was formed under these

conditions and it was isolated in 20% (25.7 mg) yield.

A reduced product 21 was also isolated in 62% (72.4

mg).

,

zene (dried over CaH₂and stored over 4 A MS under

a nitrogen atmosphere) under a nitrogen atmosphere.

The ﬂask was immersed into an oil bath and the oil

bath temperature was adjusted to be 90°C. To the

ﬂask was added a solution of 88 mg (0.172 mmol) of

29 and 14 mg (0.086 mmol) of AIBN in 3.7 mL of

benzene via a syringe pump during 2 h 15 min, and

the mixture was stirred for another 0.5 h at 90°C (oil

bath temperature). The mixture was cooled to rt, and

the solvent was removed in vacuo to give crude

product. The concentrated mixture was puriﬁed by

ﬂash column chromatography eluting with hex-

ane:EtOAc=3:1. The cyclized N-pyranoside 40 was

obtained as a pale yellow oil (59.0 mg, 71%) in a

ratio of 0.20:1.0 for the a- and b-anomers. 40-b

(major): Colorless oil (column chromatography, hex-

ane:EtOAc=24:1), R_f=0.63 (Hexane:EtOAc=8:1).

[h]²_D⁰=+23.5 (c 3.16, CHCl₃). ¹H NMR (CDCl₃, 300

MHz): l 0.07 (s, 3H), 0.08 (s, 3H), 0.91 (s, 9H), 1.37

(s, 3H), 1.40 (s, 9H), 1.52 (s, 3H), 2.02 (dd, J=16.8,

5.9 Hz, 1H), 2.25 (dd, J=16.8, 8.6 Hz 1H), 2.88

(dddd, J=8.6, 5.9, 3.6, 3.2 Hz, 1H), 3.66–3.69 (ddd,

J=8.4, 4.4, 2.1 Hz, 1H), 3.77 (dd, J=11.5, 4.4 Hz,

1H), 3.92 (dd, J=11.5, 2.1 Hz, 1H), 4.24–4.31 (m,

2H), 5.89 (d, J=3.2 Hz, 1H), 6.96 (s, 1H), 7.08 (s,

1H), 7.62 (s, 1 H). ¹³C NMR (CDCl₃, 75 MHz): l

−5.1, −5.0, 18.5, 26.0, 28.1, 31.8, 38.5, 62.9, 68.9,

75.4, 79.4, 81.5, 83.2, 109.9, 116.4, 129.7, 135.2,

170.7. The structure was further conﬁrmed by NOE

studies. IR (NaCl, neat): 3118br m, 3002s, 2991s,

2980s, 2930s, 2851s, 1728s, 1461m, 1369s, 1254s,

1219s, 1154s, 1064s, 1000m, 941m, 906m, 838s, 779m,

739m, 662m. Anal. calcd for C₂₄H₄₂N₂O₆Si: C, 59.72;

H, 8.77; N, 5.80. Found C, 59.51; H, 8.61; N, 5.58.

Minor product 40-a was assigned by the characteristic

anomeric proton which appears at l 5.64 (d, J=8.5

Hz, 1H).

20: Pale yellow oil (column chromatography; hexane

only

to

hexane:EtOAc=2:1).

R_f=0.34

(hex-

ane:EtOAc=1:2). [h]²_D⁰=−1.9 (c 0.43, CHCl₃). ¹H

NMR (CDCl₃, 400 MHz): l 3.95 (apparent t, J=9.8

Hz, 1H), 3.98 (apparent t, J=9.3 Hz, 1H), 4.08 (dd,

J=9.6, 4.2 Hz, 1H), 4.16 (ddd, J=9.0, 5.4, 1.7 Hz,

1H), 4.53 (s, NH6 , disappeared with D₂O), 4.55 (dd,

J=9.7,.4.4 Hz, 1H), 5.53 (s, 1H), 5.89 (d, J=5.4 Hz,

1H), 6.93 (dd, J=8.5, 0.9 Hz, 4H), 7.00 (s, 1H), 7.05

(apparent td, J=7.4, 0.8 Hz, 2H), 7.12 (s, 1H), 7.24–

7.28 (m, 4H), 7.38–7.41 (m, 3H), 7.46–7.49 (m, 2H),

7.51 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l 66.35,

69.49, 70.81, 72.35, 82.85, 89.84, 102.65, 116.78,

120.49, 123.57, 126.23 (two peaks), 128.45, 129.48,

129.99, 136.29, 148.05. IR (NaCl, neat): 3059m,

2966m, 2926m, 2359w, 2320w, 1702m, 1666w, 1589s,

1494s, 1461m, 1379m, 1313m, 1266s, 1224m, 1175m,

1078s, 1049s, 1028s, 969m, 910m, 736s, 698s. HRMS

(Electrospray) calcd (M⁺+Na): 477.1897. Found (M⁺+

Na): 477.1877.

21: Pale yellow solid (column chromatography; hex-

ane only to hexane:EtOAc=7:1). R_f=0.53 (hex-

ane:EtOAc=4:1). Mp: 74–77°C. [h]²_D⁰=−54.6 (c 0.70,

1

CHCl₃). H NMR (CDCl₃, 400 MHz): l 3.60 (appar-

ent td, J=9.6, 4.5 Hz, 1H), 3.78 (apparent t, J=9.1

Hz, 1H), 3.92 (apparent t, J=9.8 Hz, 1H), 3.95

(apparent t, J=8.0 Hz, 1H), 4.01 (dd, J=9.0, 6.0 Hz,

1H), 4.16 (dd, J=8.9, 8.1 Hz, 1H), 4.42 (br s, NH6 ),

4.51 (dd, J=9.7, 4.5 Hz, 1H), 5.48 (s, 1H), 7.05

(apparent td, J=7.3, 1.1 Hz, 2H), 7.14–7.18 (m, 4H),

7.29–7.34 (m, 4H), 7.36–7.40 (m, 3H), 7.46–7.49 (m,

2H). ¹³C NMR (CDCl₃, 100 MHz): l 59.09, 71.35,

71.75, 72.42, 84.35, 102.23, 102.57, 122.90, 126.25,

128.30, 129.17, 129.24, 136.96, 148.03. IR (NaCl,

neat): w 3271m, 3061s, 3035s, 2982s, 2880s, 2240w,

1952w, 1703w, 1588s, 1495s, 1455s, 1379s, 1311s,

1271s, 1214m, 1169s, 1079s, 1049s, 1028s, 964s, 911m,

885w, 826w, 751s, 697s. HRMS (Electrospray) calcd

(M⁺+Na): 411.1679. Found (M⁺+Na): 411.1689. Anal.

calcd for C₂₄H₂₄N₂O₃: C, 74.21; H, 6.23; N, 7.21.

Found: C, 73.38; H, 6.53; N, 8.14.

In the experiment with the corresponding (E)-

acrylic acid tert-butyl ester 33, minor amount of

allo glycosides were also obtained (see Table below).

The allo-compounds were not fully characterized, but

their characteristic anomeric hydrogen peaks were

used for the tentative assignments of the conﬁgura-

tions.

1

250 MHz H NMR

altro-a altro-b allo-a allo-b

Chemical shift (ppm)

5.67

5.88

3.2

1.00

5.93

7.1

0.08

5.28

10.3

0.10

exo-Hept-6-enyl radical cyclizations

Coupling constant (Hz) 8.4

Ratio^a

0.20

4.28. The cyclization of 29 by reverse addition (typical

procedure for cyclization)

^aThe ratio was determined by ¹H NMR after column chromatog-

raphy.

A ﬂame-dried three-necked 25 mL ﬂask was con-

2956

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

4.29. Optimization of 6-exo-hept-6-enyl radical cyclization

Table 5. 6-exo-Hept-6-enyl radical cyclizations using 28, 32, 29 and 33

Expt

R

Conditions

Yield (%)

Comments^a

altro (a/b)

R₃SnH (equiv.)

AIBN (equiv.)

Solvent

Temp. (°C)

40/44 or 39/43 46 46S allo (a/b)

1

2

3

4

5

6

7

8

29 Bu₃SnH (1.5)

29 Bu₃SnH (5.0)

29 Bu₃SnH (10.0)

29 Ph₃SnH (5.0)

29 Bu₃SnH (5.0)

29 Ph₃SnH (5.0)

33 Ph₃SnH (5.0)

28 Bu₃SnH (5.0)

32 Bu₃SnH (5.0)

00.2

0.2

0.5

1.0

0.5

Toluene

Benzene

Toluene

Benzene

Toluene

Benzene

Reﬂux

90

Reﬂux

90

33

–

34

13/87

–

40

9

37

57

54

47

62

71

3

15

61

68

59

28/72

14/86

15/85

25/75

17/83

–

14/86

14/62

20/80

21/67

9

10

11^b

12

13

14

68

Reﬂux

90

37

18

10/14

3/9

90

^aThe ratio was determined by ¹H NMR before column chromatography.

^bNormal addition: the mixture of Ph₃SnH (5.0 equiv.) and AIBN (0.5 equiv.) in benzene was added to the solution of substrate in benzene via

a syringe pump.

4.30. Cyclization of 29 at high temperature

mmol) in 11.6 mL of benzene; 60 mg (0.146 mmol) of

30 and 12 mg (0.073 mmol) of AIBN in 3.2 mL of

benzene added during 2 h 30 min, additional stirring

for 0.5 h at 90°C (oil bath temperature). Solvent for

column chromatography: hexane:EtOAc=3:1 to 1:1.

The cyclized N-pyranoside 41 was obtained as a pale

yellow oil (31.9 mg, 57%) with a ratio of altro-a/altro-

b=0.26/1.0 after column chromatography. 41: ¹H

NMR (CDCl₃, 400 MHz): 41-altro-b: l 0.07 (s, 3H),

0.08 (s, 3H), 0.90 (s, 9H), 1.41 (s, 3H), 1.54 (s, 3H), 2.06

(dd, J=17.3, 5.4 Hz, 1H), 2.38 (dd, J=17.3, 9.7 Hz,

1H), 2.69–2.79 (m, 1H), 3.73 (ddd, J=8.9, 4.3, 2.1 Hz,

1H), 3.82 (dd, J=11.6, 4.4 Hz, 1H), 3.93 (dd, J=11.6,

2.0 Hz, 1H), 4.33 (dd, J=8.9, 5.4 Hz, 1H), 4.52 (dd,

J=5.4, 3.4 Hz, 1H), 5.90 (d, J=2.9 Hz, 1H), 6.98 (s,

1H), 7.15 (s, 1H), 7.69 (s, 1H); 41-altro-a: l 0.00 (s,

6H), 0.89 (s, 9H), 1.39 (s, 3H), 1.50 (s, 3H), 2.10 (dd,

J=17.3, 4.5 Hz, 1H), 2.31 (dd, J=17.2, 9.5 Hz, 1H),

2.69–2.76 (m, 1H), 3.82 (dd, J=11.6, 4.4 Hz, 1H), 3.98

(dd, J=11.5, 2.3 Hz, 1H), 4.10 (apparent td, J=4.6, 2.3

Hz, 1H), 4.28–4.35 (m, 2H), 5.74 (d, J=10.0 Hz, 1H),

7.09 (s, 1H), 7.15 (s, 1H), 7.78 (s, 1H). ¹³C NMR

(CDCl₃, 100 MHz): 41-altro-b: l −5.35, −5.33, 14.06,

18.35, 25.80, 25.93, 29.23, 39.24, 65.58, 68.19, 74.43,

80.08, 82.29, 110.31, 115.66, 117.23, 130.18, 136.10;

41-altro-a: l −5.41, −5.36, 16.36, 18.38, 25.33, 25.83,

27.71, 40.53, 68.20, 72.23, 73.90, 75.51, 80.15, 82.01,

110.18, 116.09, 116.44, 129.06, 136.13. IR (NaCl, neat):

3115 w, 2987m, 2955s, 2991s, 2892s, 2857m, 2253w,

1700w, 1494m, 1472m, 1424w, 1384m, 1370m, 1312w,

1285w, 1253s, 1221s, 1159s, 1077s, 939w, 906w, 838s,

780s, 661m. HRMS (Electrospray) calcd for

C₂₀H₃₃N₃NaO₄Si (M⁺+Na): 430.2133. Found (M⁺+Na):

430.2116. Anal. calcd for C₂₀H₃₃N₃O₄Si: C, 58.94; H,

8.16; N, 10.31. Found: C, 58.35; H, 8.27; N, 9.94.

A ﬂame-dried three-necked 25 mL ﬂask was connected

to a condenser, and the ﬂask was charged with 157 mg

of Bu₃SnH (0.54 mmol) and 7 mL of toluene (freshly

dried over Na) under a nitrogen atmosphere. To the

ﬂask was added a solution of 185 mg (0.36 mmol) of 29

and 12 mg (0.072 mmol) of AIBN in 3.5 mL of toluene

under reﬂux conditions via a syringe pump during 2 h

20 min, and the mixture was reﬂuxed for another 3 h.

The mixture was cooled to rt, and the solvent was

removed in vacuo to give crude product. The concen-

trated mixture was puriﬁed by ﬂash column chromatog-

raphy eluting with hexane:EtOAc=5:1. The isolated

product was identiﬁed as a thiolactone, 46S (53.7 mg,

33%). 46S: (preparative TLC, hexane:EtOAc=5:1).

1

R_f=0.17 (hexane:EtOAc=4:1). H NMR (CDCl₃, 400

MHz): l 0.11 (s, 3H), 1.12 (s, 3H), 0.90 (s, 9H), 1.34 (s,

3H), 1.46 (s, 9H), 1.49 (s, 3H), 2.74 (dd, J=16.4, 3.6

Hz, 1H), 2.97 (dd, J=16.4, 8.7 Hz, 1H), 3.08 (ddd,

J=12.3, 8.7, 3.7 Hz, 1H), 3.95 (dd, J=12.1, 4.2 Hz,

1H), 4.04 (dd, J=8.9, 6.9 Hz, 1H), 4.11 (dd, J=11.9,

1.6 Hz, 1H), 4.25–4.36 (m, 2 H). ¹³C NMR (CDCl₃, 100

MHz): l −5.2, −5.3, 18.4, 24.7, 25.9, 26.9, 28.0, 37.1,

50.9, 62.0, 71.0, 74.9, 78.8, 82.6, 111.3, 170.7, 218.4. IR

(NaCl, neat): 2957m, 2930s, 2857m, 1731s, 1472m,

1368m, 1338m, 1268s, 1212m, 1152s, 1076m, 836m.

HRMS (Electrospray) calcd for C₂₁H₃₈NaO₆SSi (M⁺+

Na): 469.2056. Found (M⁺+Na): 469.2057.

4.31. Cyclization 30 or 34

The reverse addition procedure was used for this

cyclization. The amounts of regents used and the time

of reaction were as follows: Ph₃SnH (257 mg, 0.732

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2957

4.32. Cyclization of 34

(M⁺+Na): 436.2259. Anal. calcd for C₁₉H₃₅N₃O₅Si: C,

55.18; H, 8.53; N, 10.16. Found: C, 54.04; H, 8.48; N,

9.28.

The reverse addition procedure was used for this

cyclization. The amounts of reagents used and the time

of reaction were as follows: Ph₃SnH (296 mg, 0.842

mmol) in 13.3 mL of benzene; 69 mg (0.168 mmol) of

the (E)-acrylonitrile 34 and 14 mg (0.084 mmol) of

AIBN in 3.6 mL of benzene added during 2 h 40 min,

additional stirring for 0.5 h at 90°C (oil bath tempera-

ture). Solvent for column chromatography: hex-

ane:EtOAc=3:1 to 1:1. The cyclized N-pyranoside was

obtained as pale yellow oil 41 and 45 (51.0 mg, 80%) in

a ratio of altro-a/altro-b/allo-a/allo-b=0.27/1.0/0.04/

0.09 after column chromatography. The assignments of

allo isomers are based on comparison of chemical shifts

and coupling constants with those of related com-

pounds, and should be considered tentative.

1

250 MHz H NMR

altro-a altro-b allo-a allo-b

Chemical shift (ppm)

5.86

5.80

2.9

1.0

6.06

6.4

0.03

5.62

7.3

0.75

Coupling constant (Hz) 8.6

Ratio^a

0.24

^aThe ratio was determined by ¹H NMR after column chromatogra-

phy.

4.34. Cyclization of 31

The reverse addition procedure was used for this

cyclization. The amounts of regents used and the time

of reaction were as follow: Ph₃SnH (233 mg, 0.663

mmol) in 10.5 mL of benzene; 68 mg (0.113 mmol) of

31 and 11 mg (0.066 mmol) of AIBN in 2.8 mL of

benzene added during 3, additional stirring for 0.5 h at

90°C (oil bath temperature). The a/b ratio of the crude

product was 0.32/1.0. The concentrated mixture was

puriﬁed by ﬂash column chromatography eluting with

hexane:EtOAc=8:1 to 7:1. An a-altro and b-altro mix-

ture of [4-(tert-butyl-dimethylsilanoyloxymethyl)-6-imi-

dazol-1-yl-2,2-dimethyltetrahydro-[1,3]dioxolo[4,5-c]pyra

n-7-yl]-acetic acid tert-butyl ester 42 was isolated in

87% (55.5 mg) yield. 42-a: Pale yellow oil (column

chromatography, hexane:EtOAc=8:1 to 7:1). R_f=0.20

1

400 MHz H NMR

altro-a altro-b allo-a allo-b

Chemical shift (ppm)

5.74

5.90

2.9

5.95

6.9

5.34

9.6

Coupling constant (Hz) 10.0

Ratio^a

0.27

1.00

0.04

0.09

^aThe ratio was determined by ¹H NMR after column chromatogra-

phy.

4.33. Cyclization of 36

The reverse addition procedure was used for this

cyclization. The amounts of regents used and the time

of reaction were as follows: Ph₃SnH (215 mg, 0.613

mmol) in 9.7 mL of benzene; 51 mg (0.123 mmol) of the

36 and 10 mg (0.061 mmol) of AIBN in 2.6 mL of

benzene added during 2 h 10 min, additional stirring

for 0.5 h at 90°C (oil bath temperature). Solvent for

column chromatography: hexane:EtOAc=2:1 to 1:1.

After column chromatography, 39.0 mg (83%) of a

mixture of cyclized products was isolated as a yellow oil

with a ratio of altro-a/altro-b/allo-a/allo-a/allo-b=

0.24/1.0/0.03/0.75, only the structure of the major com-

pound (altro-b) has been rigorously assigned. The

conﬁgurations of other diastereomers were assigned by

the comparing the chemical shift information and cou-

pling constant with known conﬁguration (vide infra

products from 29/33 and 30/34). 48: Colorless oil

(column chromatography, hexane:EtOAc=2:1 to 1:1).

1

(hexane:EtOAc=4:1). [h]²_D⁰=+20.7 (c 0.58, CHCl₃). H

NMR (CDCl₃, 500 MHz): l 0.02 (s, 3H), 0.04 (s, 3H),

0.86 (s, 9H), 1.36 (s, 3H), 1.39 (s, 9H), 1.48 (s, 3H), 2.32

(dd, J=16.2, 4.9 Hz, 1H), 2.51 (dd, J=16.2, 5.3 Hz,

1H), 2.30 (apparent dq, J=9.6, 5.1 Hz, 1H), 3.75 (dd,

J=11.6, 5.4 Hz, 1H), 3.88 (dd, J=11.6, 2.3 Hz, 1H),

4.10 (ddd, J=7.7, 5.3, 2.3 Hz, 1H), 4.28 (apparent t,

J=7.3 Hz, 1H), 4.31 (dd, J=9.3, 7.0 Hz, 1H), 5.90 (d,

J=9.4 Hz, 1H), 7.97 (s, 1H), 8.33 (s, 1H). ¹³C NMR

(CDCl₃, 125 MHz): l −5.41, −5.36, 18.31, 25.29, 25.81,

27.46, 28.02, 35.56, 38.50, 72.05, 74.62, 74.92, 81.25,

84.41, 110.37, 136.13, 152.01, 170.33. The structure was

further conﬁrmed by NOE studies. IR (NaCl, neat):

3122w, 2985s, 2954s, 2930s, 2857s, 1725s, 1507m,

1472m, 1401m, 1431m, 1369s, 1272s, 1256s, 1214s,

1152s, 1078s, 999m, 955w, 919w, 837s, 778s, 733m.

1

R_f=0.16 (hexane:EtOAc=1:3). H NMR (CDCl₃, 400

42-b: Pale yellow oil (column chromatography, hex-

ane:EtOAc=8:1 to 7:1). R_f=0.28 (hexane:EtOAc=

4:1). [h]²_D⁰=−4.3 (c 1.25, CHCl₃). ¹H NMR (CDCl₃, 500

MHz): l 0.04 (s, 3H), 0.05 (s, 3H), 0.88 (s, 9H), 1.36 (s,

3H), 1.40 (s, 9H), 1.48 (s, 3H), 1.97 (dd, J=16.7, 7.8

Hz, 1H), 2.38 (dd, J=16.7, 7.0 Hz, 1H), 3.01 (ddd,

J=13.7, 7.1, 4.1 Hz, 1H), 3.72 (dd, J=9.1, 4.9, 1.7 Hz,

1H), 3.76 (dd, J=11.4, 5.0 Hz, 1H), 3.91 (dd, J=11.4,

1.7 Hz, 1H), 4.30 (dd, J=9.2, 6.3 Hz, 1H), 4.42 (appar-

ent t, J=6.2 Hz, 1H), 6.41 (d, J=4.0 Hz, 1H), 7.98 (s,

1H), 8.24 (s, 1H). ¹³C NMR (CDCl₃, 125 MHz): l

−5.30, 18.37, 25.43, 25.84, 27.66, 27.98, 32.73, 37.56,

63.06, 69.71, 74.40, 77.83, 81.24, 84.39, 109.47, 143.11,

152.14, 170.55. The structure was further conﬁrmed by

NOE experiments. (NaCl, neat): 3122w, 2985s, 2954s,

MHz): l 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.24 (br

s, 1H), 1.37 (s, 3H), 1.52 (s, 3H), 3.46 (s, 3H), 3.51–3.61

(m, 1H), 3.72 (ddd, J=8.5, 4.3, 1.9 Hz, 1H), 3.78 (dd,

J=11.4, 4.4 Hz, 1H), 3.90 (dd, J=11.5, 2.0 Hz, 1H),

4.31 (dd, J=8.5, 6.2 Hz, 1H), 4.46 (dd, J=6.0, 4.4 Hz,

1H), 5.80 (d, J=2.9 Hz, 1H), 7.09 (s, 1H), 7.17 (s, 1H),

7.88 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l −5.37,

−5.33, 18.39, 25.45, 25.83, 29.24, 59.89, 62.17, 63.06,

69.43, 73.05, 78.87, 81.83, 109.78, 117.69, 128.81,

136.19. IR (NaCl, neat): 3168br s, 2981m, 2952s, 2932s,

2893s, 2856s, 2250w, 2211w, 1698w, 1494m, 1472s,

1458s, 1383s, 1251s, 1219s, 1146s, 1064s, 1033s, 1004m,

938w, 911w, 837s, 779s, 733s. HRMS (Electrospray)

calcd for C₁₉H₃₅N₃NaO₅Si (M⁺+Na): 436.2238. Found

2958

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2931s, 2857s, 1739w, 2236w, 1727s, 1506m, 1472m,

1461m, 1369s, 1272s, 1255s, 1214s, 1157s, 1066s,

1022m, 956m, 939m, 910m, 875m, 837s, 814m, 779s,

734s, 678m. HRMS (Electrospray) calcd for

C₂₃H₄₁N₃NaO₆Si (M⁺+Na): 506.2657. Found (M⁺+Na):

506.2665.

for 0.5 h at 90°C (oil bath temperature). After column

chromatography (hexane:EtOAc=2:1 to 1:1), 41.2 mg

(63%) of 3-diastereomer mixture was isolated in a ratio

of altro-a/altro-b/allo-b=0.04/0.09/0/1.0. 51: Pale yel-

low oil. R_f=0.17 (hexane:EtOAc=1:3). Only allo-b

1

product was fully characterized. H NMR (CDCl₃, 500

MHz): l −0.02 (s, 3H), −0.01 (s, 3H), 0.85 (s, 9H), 1.46

(s, 3H), 1.47 (s, 3H), 2.23 (s, 6H), 3.20 (dd, J=10.4, 8.5

Hz, 1H), 3.55 (apparent t, J=9.1 Hz, 1H), 3.69 (dd,

J=10.5, 9.1 Hz, 1H), 3.72–3.78 (m, 2H), 3.86–3.91 (m,

1H), 5.18 (d, J=8.5 Hz, 1H), 7.06 (s, 1H), 7.07 (s, 1H),

7.69 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): l −5.35,

18.33, 25.80, 26.50, 26.79, 49.01, 62.89, 63.26, 74.38,

78.11, 78.28, 86.35, 111.86, 117.75, 128.82, 137.03. IR

(NaCl, neat): 2985w, 2956s, 2931s, 2856s, 2817m,

2772m, 1716w, 1679w, 4198m, 1472m, 1382m, 1472m,

1382m, 1372m, 1285m, 1248s, 1230s, 1152s, 1080s,

1056s, 963w, 906w, 838s, 780s, 732w, 661m. HRMS

(Electrospray) calcd (M⁺+Na): 449.2555. Found (M⁺+

Na): 449.2558. Anal. calcd for C₂₀H₃₈N₃O₄Si: C, 56.31;

H, 8.98; N, 13.13. Found: C, 55.66; H, 9.15; N, 11.86.

The conﬁguration of the above structure was assigned

based on comparing the chemical shift and coupling

constant with compounds of known conﬁguration pre-

pared earlier. The others are tentatively assigned based

on the following data.

4.35. The cyclization of triazole-1(R)-carbothioic acid

O-{2-(tert-butyl-dimethylsilanyloxy)-1(R)-[5-(methoxy-

iminomethyl)-2,2-dimethyl-[1,3]dioxolan-4(R)-yl]-ethyl}

ester 37

The reverse addition procedure was used for this

cyclization. The amounts of reagents used and the time

of reaction were as follow: Ph₃SnH 162 mg of Ph₃SnH

(0. 461 mmol) in 7.3 mL of benzene; 41 mg (0.092

mmol) of 37 and 7.6 mg (0.046 mmol) of AIBN in 2

mL of benzene added during 1 h 20 min, additional

stirring for 0.5 h at 90°C (oil bath temperature). The

ratio of altro-a/altro-b of the crude mixture is 0.69/1.0.

Solvent for column chromatography: hexane:EtOAc=

6:1. After column chromatography, 17.6 mg (46%) of

product was isolated as an yellow oil. The structure of

the major product was conﬁrmed by NOE experiments.

50-b: Pale yellow oil. Column chromatography; hex-

ane:EtOAc=6:1.

R_f=0.23

(hexane:EtOAc=2:1).

[h]²_D⁰=−7.4 (c 0.42, CHCl₃). ¹H NMR (CDCl₃, 500

MHz): l 0.06 (s, 3H), 0.08 (s, 3H), 0.88 (s, 9H), 1.37 (s,

3H), 1.51 (s, 3H), 3.46 (s, 3H), 3.74 (ddd, J=8.9, 4.5,

2.0 Hz, 1H), 3.77 (dd, J=11.4, 4.4 Hz, 1H), 3.81 (dd,

J=5.6, 3.4 Hz, 1H), 3.91 (dd, J=11.7, 2.0 Hz, 1H),

4.33 (dd, J=8.7, 6.7 Hz, 1H), 4.44 (apparent t, J=6.3

Hz, 1H), 6.11 (d, J=3.4 Hz, 1H), 8.01 (s, 1H), 8.51 (s,

1H). ¹³C NMR (CDCl₃, 100 MHz): l −5.33, 18.43,

25.23, 25.87, 27.58, 59.76, 62.12, 63.03, 69.82, 72.50,

77.85, 82.81, 109.83, 144.08, 151.83. IR (NaCl, neat):

3263br s, 3118w, 2985m, 2954s, 2931s, 2862s, 1752w,

1508m, 1472m, 1463m, 1382s, 1276s, 1252s, 1218s,

1134s, 1068s, 954m, 914w, 836s, 813m, 780s, 734m,

698w, 677m. HRMS (Electrospray) calcd for

C₁₈H₃₄N₄NaO₅Si (M⁺+Na): 437.2191. Found (M⁺+Na):

437.2183.

1

400 MHz H NMR

altro-a altro-b allo-a allo-b

Chemical shift (ppm)

Coupling constant (Hz) 7.4

5.64

5.86

3.0

–

5.18

8.5

Ratio^a

0.04

0.09

1.0

^aThe ratio was determined by ¹H NMR after column chromatogra-

phy.

4.37. Reaction of 38 with Bu₃SnH

A ﬂame-dried three-necked 50 mL ﬂask was connected

to a condenser, and the ﬂask was charged with 384 mg

of Bu₃SnH (1.32 mmol) and 16.4 mL of benzene (dried

,

over CaH₂and stored over 4 A MS under a nitrogen

atmosphere) under a nitrogen atmosphere. The ﬂask

was immersed into an oil bath and the oil bath temper-

ature was adjusted to be 90°C. To the ﬂask was added

a solution of 120.7 mg (0.264 mmol) of 38 and 21.7 mg

(0.132 mmol) of AIBN in 10 mL of benzene via a

syringe pump during 4 h, and the mixture was stirred

for another 0.5 h at 90°C (oil bath temperature). The

mixture was cooled to rt, and the solvent was removed

in vacuo to give crude product. The concentrated mix-

ture was puriﬁed by ﬂash column chromatography elut-

ing with hexane:EtOAc=7:1 to 2:1. After column

chromatography, 41.4 mg (41%) deoxygenated product

52 was obtained. 52: Yellow oil. Column; hex-

ane:EtOAc=7:1 to 2:1. R_f=0.56 (hexane:EtOAc=4:1).

[h]²_D⁰=+20.5 (c 0.64, CHCl₃). ¹H NMR (CDCl₃, 400

MHz): l 0.03 (s, 3H), 0.04 (s, 3H), 0.88 (s, 9H), 1.40 (s,

3H), 1.41 (s, 3H), 1.76–1.84 (m, 2H), 2.81 (s, 6H),

3.69–3.78 (m, 2H), 3.98 (ddd, J=12.3, 8.3, 3.9 Hz, 1H),

4.18 (dd, J=8.5, 6.7 Hz, 1H), 6.33 (d, J=6.5 Hz, 1 H).

¹³C NMR (CDCl₃, 100 MHz): l −5.38, −5.35, 18.3,

1

400 MHz H NMR

altro-a altro-b allo-a allo-b

Chemical shift (ppm)

Coupling constant (Hz) 8.8

5.95

6.11

3.4

5.87

2.9

Ratio^a

0.69

1.0

^aThe ratio was determined by H NMR before column chromatogra-

1

phy.

4.36. Cyclization of O-4-{[2,3-O-(1-methylethyldiene)-5-

O-[(1,1-dimethyl)ethyl dimethylsilyl]]- -ribose-N,N-

D

dimethylhydrazone}-1H-imidazole thiocarbamate 38

The reverse addition procedure was used for this

cyclization. The amounts of reagents used and the time

of reaction were as follow: Ph₃SnH (269 mg, 0. 766

mmol) in 12.1 mL of benzene; 70 mg (0.153 mmol) of

38 and 12 mg (0.077 mmol) of AIBN in 3.3 mL of

benzene added during 2 h 20 min, additional stirring

J. U. Rhee et al. / Tetrahedron: Asymmetry 14 (2003) 2939–2959

2959

25.9, 27.0, 27.2, 35.2, 42.5, 59.8, 76.0, 81.9, 108.6, 130.5.

IR (NaCl, neat): 2984m, 2953s, 2856m, 2363w, 1802w,

1694w, 1598w, 1472m, 1378m, 1252m, 1167m, 1090s,

1022m, 940s, 883m, 836s, 776m. HRMS (Electrospray)

m/z calcd for C₁₆H₃₄N₂O₃Si: 353.2236 (M⁺+Na).

Found: 353.2234.

Kahlenberg, F. J. Am. Chem. Soc. 1997, 119, 9377; (b)

Beyer, J.; Madsen, R. J. Am. Chem. Soc. 1998, 120,

12137.

5. Baker, S. R.; Clissold, D. W.; McKillop, A. Tetrahedron

Lett. 1988, 29, 991.

6. For an explanation for this unexpected stereochemical

outcome, see: Webb, T. H.; Thomasco, L. M.; Schlachter,

S. T.; Gaudino, J. J.; Wilcox, C. S. Tetrahedron Lett.

1988, 29, 6823.

Acknowledgements

7. For data on several carbohydrate derived oximes, see:

Marco-Contelles, J.; Pozuelo, C.; Martinez, L.; Martinez-

Grau, A. J. Org. Chem. 1992, 57, 2625.

8. For radical addition to oxime ethers, see: (a) Corey, E. J.;

Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821; (b) Hart, D.

J.; Seely, F. L. J. Am. Chem. Soc. 1988, 110, 1631; (c)

Bartlett, P. A.; McLaren, K. L.; Ting, P. C. J. Am. Chem.

Soc. 1988, 110, 1633; (d) Ref. 7 and others cited therein.

9. Clarke, L. F.; O’Sullivan, F.; Hegarty, A. F. J. Chem.

Soc., Perkin Trans. 2 1991, 1649.

We acknowledge the ﬁnancial support by NSF (CHE

0079948) and PRF (American Chemical Society) AC

36617-AC 1 and an Alumni Association Fellowship

from Myong Ji University (Republic of Korea) to

J.U.R.

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Article Doi

Stereochemical control in radical cyclization routes to N-glycosides: Role of protecting groups and of the configuration (E versus Z) of the acceptors

DOI: 10.1016/j.tetasy.2003.07.013

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