The Use of Glycoside Uloses in Asymmetric Epoxidation

by

YEUNG KWAN WING

A thesis submitted to the Chemistry Division,

Graduate School, the Chinese University of Hong Kong

in partial fulfillment of the requirements

for the degree of

Master of Philosopy

(2002)

Thesis Committee:

Prof. H. F. Chow (Chairperson)

Prof. Dennis K. P. Ng

Prof. Tony K. M. Shing

Prof. T. Yamada (External Examiner)

r f 2 9 丨‘、

CONTENTS

Contents i

Acknowledgement ii

Abstract iii

Abbreviation v

1. Introduction 1

1-1 Background 1

1-2 Sharpless Epoxidation 2

1-3 Mn-Salen Complexes for Epoxidation 4

1-4 Oxaziridinium Salts 6

1-5 Dioxiranes 7

1 -6 Asymmetric Epoxidation by Dioxirane 11

2. Results and Discussion 28

2-1 C-Glycoside Ulose Catalyst derived from L-arabinose 28

2-2 Dioxirane epoxidation catalyzed by h-arabinoA-u\o^Q?> 30

3. Experimental Section 51

4. References 68

5. Appendix 74

i

Acknowledgement

I would like to express m y sincere thanks to m y supervisor, Prof. T. K. M . Shing for

his advice and guidance during the course of research and in the thesis writing.

Thanks are also given to Dr. Y. C. Leung and all the members of the T K M S research

group for their co-operation and helpful discussion on the project.

December, 2002

Yeung K w a n Wing

Department of Chemistry

The Chinese University of Hong Kong

Shatin, N e w Territories

Hong Kong

ii

Abstract

A review involving the development of chiral catalysts in asymmetric

dioxirane epoxidation from 1984 to 2002 is presented.

A series of ulose catalysts derived from L-arabinose were synthesized via

simple and effective protocols. These catalysts were used in asymmetric epoxidation

and their chiral induction capability was assessed.

C-Glycoside catalyst 146 was prepared from L-arabinose via a reaction

sequence involving acetalization, Knoevenagel condensation, Grignard reaction and

oxidation. The catalyst 146 decomposed during the epoxidation. The chemical yield

and enantioselectivity towards 炉a似-a-methylstilbene were poor (54% yield, 2 3 % ee).

Six different L-arabinoA-\AosQS (150, 152, 158, 160, 164 and 168) were

prepared in order to study their chiral induction capability in asymmetric epoxidation.

L-arahino-A-\]\o^Q^ displayed good chemical yields (73-99% yield) and

enantioselectivity (23-93% ee) in asymmetric epoxidation. Uloses 150 and 152 were

found to be efficient catalysts with high enantioselectivities for trans-disubstitutQd

and trisubstituted alkenes (for ulose 150, up to 90% ee for triphenylethylene oxide).

iii

摘要

本論文綜述了從1984年到2002年間有關手性催化劑由二環氧乙院所構成不對

稱環氧化作用的進展。

用L-阿拉伯糖作原料，應用簡單有效的合成方法，一系列的酮糖催化劑被合成

催化劑。同時，這些酮糖在不對稱環氧化中的手性誘導作用被硏究。

以L-阿拉伯糖爲原料，經用Knoevenagel縮合、Grignard反應、氧化反應，催

化劑糖苷類化合物 1 4 6被合成。但是由於化合物 1 4 6在反應中會分解而導致

化學產率及對映選擇性降低。

應用六種不的L-阿拉伯-4-酮糖來硏究它們在不對稱環氧化中的手性誘導作用。

硏究發現，L-阿拉伯-4-酮糖無論在化學產率還是對映選擇性上都表現了良好的

催化特性。在反-二取代和三取代燔烴的不對稱環氧化反應，酮糖150和152展

‘ 現了極佳的對映選擇性。

iv

Abbreviation

[a] specific rotation decomp. decomposed

°C degree Celsius dil. dilute

6 chemical shift in parts per DIPT diisopropyl tatrate

million downfield from D M A P 4-(dimethylamino)pyridine

tetramethylsilane (spectral) D M M 1,2-dimethoxymethane

A heat D M P 2,2-dimethoxypropane

ja micro- ee enantiomeric excess

Ac acetyl E D T A ethylenediaminetetra acetic

aq. aqueous acid

A I B N a,a'-azobisisobuytronitrile EI electron impact

Anal. analysis Et ethyl

anhyd. anhydrous Eu(hfc)3 Europium tris[3-

Ar aryl heptafluoroprpylhydroxyme

atm atmosphere thylene-(+)-camphorate]

bd broad doublet (spectral) F A B fast atom bombardment

Bn benzyl FT Fourier transform

bp boiling point g gram(s)

br broad (spectral) h hour(s)

brs broad singlet (spectral) H P L C high-pressure liquid

Bu butyl chromatography

Bz benzoyl Hz hertz

calcd calculated i- iso-

cat. catalytic IR infrared

config. configuration J coupling constant

cone. concentrated k kilo-

C S A camphorsulfonic acid 1 liquid

d doublet (spectral) L liter(s)

D B N 1,5 -diazabicy do [4.3.0] non- lit. literature

5-ene m multiplet (spectral),

D E T diethyl tartrate meter(s), milli-

V

m - C P B A w-chloroperbenzoic acid T B A F tetrabutylammonium

M e methyl fluoride

M e n menthyl T B H P tert-huiy\ hydroperoxide

min minute(s) T B S /er/-butyldimethylsilyl

mol mole(s) tert- tertiary

M O M methoxymethyl T E B tetraethoxybutane

m p melting point T F A trifluroacetic acid

M S molecular sieve, T H F tetrahydrofuran

mass spectrometry T L C thin layer chromatography

m/z mass to charge ratio T M B teramethoxybutane

n nano- T M S tetramethylsilane

n- normal T P A P tetrapropylammonium

N B S A/^-bromosuccinimide perruthenate

N M R nuclear magnetic resonance Ts tosyl, ；?-toluenesulfonyl

Oxone® 2KHSO5.KHSO4.K2SO4 p-TsOU ;?-toluenesulfonic acid

p- para- vie. vicinal

P C C pyridinium chlorochromate

P D C pyridinium dichromate

Ph phenyl

Piv pivaloyl

ppm parts per million

4-PPNO 4-phenyl-pyride TV-oxide

Pr propyl

q quartet

quant. quantitative

R alkyl etc.

Ra-Ni Raney-Nickel

Rf retardation factor

rt room temperature

s singlet (spectral)

sat. saturated

t triplet (spectral)

tertiary

vi

1. INTRODUCTION

1-1. Background

Epoxides are versatile building blocks which can be potential intermediates for

further chemical transformations. Asymmetric epoxidation of olefins presents a

powerful strategy for the syntheses of enantiomerically enriched epoxides.

Epoxidation is useful in the synthesis of many natural products and bioacetive

compounds such as the synthesis of (+)-disparlure 3 by Sharpless epoxidation^

(Scheme 1.1). Thus, the development of new and efficient catalysts for alkene

epoxidation is a never ending process.

Scheme 1.1 Synthesis of (+)-disparlure 3 by Sharpless epoxidation^

广 H 2 1 Ti(0;-Pr). (-)-DET ^ . > • 广

^ O H TBHP, CH2CI2 " ^ O H

1 2 3 80% yield 91% ee

The catalytic asymmetric epoxidation using metal complexes as catalysts has

been well developed and given high enantioselectivity to allylic alcohols^ and

unfunctionalized d^^-alkenes.〗 In recent years, the asymmetric epoxidation of

unfunctionalized olefins by dioxiranes derived from chiral ketones" ' ' becomes an

active area of research. Dioxiranes have been shown to be highly enantio selective for

the asymmetric epoxidation of 广r m -disubstituted and trisubstituted unfunctionalized

alkenes. However, the controlling factors for enantio selectivity are still under

1

investigation, and hence the asymmetric epoxidation catalyzed by chiral dioxiranes

still remains a challenging problem. This initiated our studies to search for efficient

catalysts to be highly enantioselective towards unfunctionalized olefins in asymmetric

epoxidation.

1-2. Sharpless Epoxidation

The best-known catalytic process is Sharpless epoxidation^ of allylic alcohols.

The. reagents of Sharpless epoxidation are all commercially available, including (+) or

(-)-diisopropyl tartrate (DIPT), titanium tetraisopropoxide, and tert-hu\y\

hydroperoxide (TBHP). Sharpless epoxidation gives high enantiomeric excess (ee)

for most allyic alcohols whatever the substrates are cis-, trans- or terminal orientation.

Also, the stereochemistry of the epoxide is controlled by the ligand, for example, L-

(+)-diisopropyl tartrate leads to the addition of oxygen atom from the bottom face to

give 5 whereas the use of D-(-)-diisopropyl tartrate affords the enantiomer ent-5

(Scheme 1.2).

Scheme 1.2

L-(+)-DIPT’ Ti(〇/-Pr)4 ^ 70-87% yield

TBHP, CH2CI2, -20。C p ^ / ^ ^ O H >90% ee

R2 丫 Ri 5

R3 H — R R

4 D-(-)-DIPT, Ti(0/-Pr)4 ^ 70-87% yield

TBHP, CH2CI2, -20X >90% ee

Ri, R2，R3 = H o「alkyi group ent-5

2

The proposed mechanism of epoxidation^ is shown in Figure 1.1. Sharpless

reported that the stereochemistry of the epoxy alcohol is based on the coordination

between the ally lie alcohol and the dimeric titanium-tartrates complex. tert-

Butylhydroperoxide (TBHP) acts as an oxygen sources and high ee of the epoxy

alcohol can be obtained. The great impact in the construction of nonracemic chiral

epoxy alcohols has been made with the introduction of catalytic systems. Many

natural products and biologically active compounds were synthesized using this

effective protocol as the key step.

Figure 1.1 Proposed mechanism of Sharpless Epoxidation

RO2C OR ROH R02C

譯 轴 R 又 ^ ^ 喊 夠 〜 u

V K 人 R r ~ ^ o人 O R

RO-^O CO2R R O ^ O CO2R

6 7

f-BuOH

‘ \

ROH

R〇2C RO2C o ^ - ^

鄉 R

OR^O C〇2R R〇入〇C02R

9 8

3

1-3. Mn-Salen complexes for Epoxidation

Jacobsen and co-workers^^ reported a chiral Mn(III)-salen complex 10

(Jacobsen's catalyst) which has been found to be a highly selective catalyst for the

asymmetric epoxidation. Jacobsen's catalyst 10 gives high ee for unfunctionalized

cz5-alkenes (Scheme 1.3). Mn(III)-salen complex-catalyzed epoxidation of simple

cw-alkenes was performed using 2-5% of catalyst 10 in CH2CI2 and different oxidants

(NaOCl, Oxone®, T B H P , m - C P B A or iodosylbenzene). The chemical yield of the

epoxide is up to 97% with enantioselectivity as high as 98% ee.

Scheme 1.3

R Ri 2-5% mol% 10, NaOCI(aq.)^ \

^ CH2CI2 V

R, Ri = H or alkyi group 叩 to 97% yield 1 up to 98% ee

d (favored)

R、、、、H c H i ^ ^ H

^ f - B u f-Bu 3'

10 b

The enantioselectivity is controlled by the structure of the chiral salen ligand.

The bulky r-butyl groups occupied at the C-3, C-3', C-5 and C-5' positions to prevent

the substrate approach to the metal-oxo center (Schemel.3, approaches a, b and c).

Thus, the substrates approach from the less sterically hindered diimine bridge

4

(approach d) to the metal-oxo center. The chiral centers at the bridge control the

enantioselectivity of the epoxide.^^ Mn-salen complexes have been applied to the

syntheses of natural products such as (-)-cramakalin^^ (13) (Scheme 1.4) and the N-

benzoyl-3-phenylisoserine^*^ (17) side chain of taxol (Scheme 1.5). The outstanding

results of Jacobsen's catalyst lead a series of salen complexes^ to be developed as

asymmetric catalysts in different types of reactions, including hydroxylation^^ by

Katsuki, aziridination】i by Burrows, hetero-Diels-Alder^^ reaction by Jacobsen and

trimethylsilylcyanation of aldehyde ^ by North.

Scheme 1.4 Synthesis of (-)-cramakalin (13)

H

N c ^ ^ ^ NaOCl(aq.), CH2CI2 ‘ NaH, D M S O n c ^ ^ ^ ^ V ^ O H

96%, 97% ee 〇 56% ‘ O 力

11 12 (S, 13

Scheme 1.5 Synthesis of A^-benzoyl-3-phenylisoserine (17)

「 , — p n rt H2 . / = \ 6 m o j % ( R R ) - 1 0、 A 匕t Lindlar Catalyst Ph^ COaEt NaOCI(aq.), CH2CI2 p / ^「。 E t

84% 4-PPNO (0.25 e q . ) … ⑷ _ 56%, 97% ee _

14 15 16

NH2〇

— ^ P h ^ ^ O H 44%f「om16

O H

17

5

1-4. Oxaziridinium Salts

Oxaziridinium salts, either used in isolated form or generated in situ from

iminium salts and Oxone®, are powerful electrophilic oxidants for olefin

epoxidation. 14 Hanquet and Lusinchi and co-workers reported a catalytic cycle

where iminium salts (e.g. 18) could be converted by Oxone® into the corresponding

oxaziridinium species 19 which could effect alkene epoxidation (Scheme 1.6). In a

preliminary investigation of the use of chiral oxaziridinium salts for asymmetric

epoxidation, a promising result of 33% ee was obtained for epoxidation of trans-

stilbene using (+)-norephedrine-derived chiral iminium salt

Scheme 1.6

BF4- , / BF4-°

18 19

O Ph ^ Ph

PK Ph

Ph

BF4-

20

Page and co-workers^^ reported the synthesis and evaluation of a range of

dihydroquinoline derivatives with various chiral groups attached to the nitrogen,

obtaining enantioselectivities up to 73% with catalysts 21 (Figure 1.2). Aggarwal^^

6

reported the novel chiral iminium salts 22 (31% ee for ra^^-stilbene oxide; 7 1 % ee

for 1 -phenylcyclohexene oxide) (Figure 1.2).

Figure 1.2

N V ^ ^ / i r ^ N -

BPh, B F ,

21 22

Yang and co-workers^^ have recently reported the asymmetric epoxidation of

olefins by chiral iminium salts, generated in situ from chiral amines and aldehydes

(Scheme 1.7). Epoxidation reactions were conducted with 20 mol% of amines and

aldehydes and the enantioselectivities could be up to 65% for trans-siiVoQnQ oxide

(amine 24 and aldehyde 30 in Scheme 1.7).

1-5. Dioxiranes

Dioximnesi9 are widely adopted as a new class of efficient oxygen-transfer

reagents, and conveniently prepared from commercially available materials.

Dioxiranes are capable of performing under mild, strictly neutral conditions, and can

be used as an environmental friendly catalyst in oxidation. They can be generated by

irradiation, by peracid, or by other methods. Sander〗。reported a photochemically

generated stable dioxirane 34 (Scheme 1.8).

7

Scheme 1.7

/ o H + 人

HA

K H S O 5 、 , 人 A- \ , 汽

\ / iminium salts \ /

八 oX.- H

oxaziridinium salts

amines aldehydes

. 2 3 H : 25 o r 28

24 ^ C H O 27 M h 30

Dioxirane 34 was the firstly isolated solid dioxirane at room temperature.

Oxidation of diazo compound 31 gave the carbonyl 0-oxide 33. Irradiation caused

the rearrangement of oxide 33 to dioxirane 34.

8

Scheme 1.8

31 32 33 34

Dioxiranes are mostly prepared from ketones and Oxone®

(2KHSO5.KHSO4.K2SO4). Dimethyldioxirane ( D M D f (37) can be used as an

oxidant in an isolated form or generated in situ from acetone^^ (Scheme 1.9). Baeyer-

Villiger23 proposed that an adduct ‘Criegee’ intermediate 36 was formed when adding

a monoperoxysulfate anion to acetone, which then underwent rearrangement to give

D M D (37).

Scheme 1.9 The formation of dimethyldioxirane (37)

HSOs"

o _ r OH ^ ^ 0 - 0

35 36 HSCV 37

D M D (37) has excellent oxidation properties, the transformations by D M D

(37) are summarized below:

i Hetero-atom oxidation:

9

D M D (37) has been used for oxidation of amines to nitro compounds in a

rapid and efficient way. Also, D M D (37) can be used to oxidize sulfur and

phosphorus compounds to their corresponding oxides (Figure 1.3).

Figure 1.3 Hetero-atom oxidation

0 - 0 乂 37

R3P ——^ R3PO R = alkyi groups

R2S ^ — — - R 2 S O

ii C — H bond insertion:i9b’25

0-atom insertions into alkane and cycloalkane C-H bonds can be performed

by D M D (37) under mild conditions. However, these reactions are highly

dependent on the properties of the substrates (Figure 1.4).

Figure 1.4 C - H bond insertion

0 - 0 OH

R，R| = alkyI groups

r ^H〇〇H ^ j R 入 R| R R' R R'

iii Epoxidation: i9b’22f

The most studied chemical transformation employing dioxiranes relates to

convert various alkenes into corresponding epoxides. As dioxiranes are inert

toward the epoxide produced, the epoxidations can be performed by D M D (37)

at low temperatures and under neutral conditions. It is highly reactive towards

10

different kinds of alkenes. More chemistry about dioxirane epoxidation will

be shown in the next chapter (Figure 1.5).

Figure 1.5 Epoxidation

R)—〈R2 又 37

R3 R4 R3 R4

R-i, R2, R3 and R4 = H or alkyI groups

1-6 Asymmetric Epoxidation by Dioxirane

Catalytic dioxirane epoxidation recently becomes a powerful strategy in

organic synthesis. The controlling factors can be shown in the catalytic cycle

(Scheme 1.10)?''

In the catalytic cycle (Scheme 1.10), addition of HSO5— to the ketone 40 gives

the 'Criegee' intermediate 42 which can be converted into dioxirane 41 or the side

product 43 via Baeyer-Villiger type reaction.〗〗 The oxygen is transferred from

dioxirane 41 to alkene 39 and epoxide 38 was formed. Moreover, self-decomposition

of dioxirane 41 back to the ketone 40 is a continuing process during the reaction.

11

Scheme 1.10 Catalytic cycle of dioxirane epoxidation

D HS〇5-Ri O R2 R5 f

R P R A / R P 、 38 \ / 40 O H Baeyer-Villiger o

y R5v^〇、。zS〇::r type reaction ^ ^ ^

I Re R5 〇

八 42 43

R3 R4 Re 、HSO4-

39 41

HSOs"-^ Ri，R2, R3, R4 = H or alkyI groups \ R5, Re = alkyI groups

、 H S〇 4 - + 〇2

R5

r 40

The pR is a very important factor for epoxidation with dioxiranes generated in

situ. At low pH, the Baeyer-Villger reaction would be predominant to form the side

product 43. The catalytic cycle will be destroyed and no epoxidation occurs. High

p U results in the rapid self-decomposition of Oxone®, thus leading to a decrease in

epoxidation efficiency. The optimal p R of the reaction should be maintained at about

7-8 during epoxidation.

Solvent systems become another important factor for the dioxirane

epoxidation. The use of organic solvents such as CH2CI2, benzene and EtiO in

dioxirane epoxidation^^^'® resulted a heterogeneous solvent system. This

heterogeneous system decreases the rate of oxygen transfer even though phase

transfer catalysts were used. A homogeneous solvent system (MeCN/HbO) was

12

reported by Yang^^^, which increased dioxirane-olefm interaction, and hence the rate

of epoxidation could be improved.

Chiral ketones are expected to be catalysts for asymmetric epoxidation. W h e n

the chiral ketone 44 was employed, a chiral dioxirane 45 could be generated. The

chiral dioxirane 45 induced asymmetry to the alkene 46 and the chiral epoxide 47 was

obtained (Figure 1.6). The first chiral ketone was developed by Curci"^^ and became

the first asymmetric epoxidation by d i o x i r a n e . T h e epoxidation used (+)-

isopinocamphone (48) and (5)-(+)-3 -phenylbutan-2-one (49) as chiral catalysts but

poor stereochemical communication between the alkene and the dioxirane

intermediate 50 and 51 was demonstrated. The alkenes can approach from either a or

b planes to the dioxiranes. Poor enantioselectivity was obtained (up to 1 2 % ee of

似-p-methylstyrene oxide) (Figure 1.7).

Figure 1.6

Rl八/R2 _ _ HSO5-

V f Y \ \ R-i, R2, R3, R4 = H or alkyl groups

R5本’ R6丰=chiral alkyl groups

八 八 * = new chiral centers

V<R2 J \ / \ HS04 R3 R4 R6

46 45

13

Figure 1.12

48 49 50 e 51

a，b = alkene approach

It is believed that electron deficient ketones are generally more reactive for

epoxidation. C u r c i ^ reported the use of commercial (+)-3-(trifluoroacetyl)-camphor

(52) and (7^)-(+)-3-methoxy-3-phenyl-4,4,4-trifluorobutan-2-one (53) to study the

asymmetric epoxidation by dioxirane. High conversions and reaction rate could be

achieved, however, the enantioselectivies were still poor (up to 2 0 % ee of trans-2-

octene oxide) (Figure 1.8).

Figure 1.8

O F X O M e

52 53

Brown4c also reported a class of 1-tetralone and 1-indanone based chiral

ketones 54 and 55 substituted at the C-2 position with a fluoro group. Although none

of these ketones provided nonracemic epoxides, the chemical yields of the epoxides

were excellent (Figure 1.9).

14

Figure 1.12

O Rs O

f V V R , 54 55

Ri = C〇2Me; C(Me)2〇H;C〇2Men R2 = Et; Me R3 = H; F

Song and co-workers' ' designed CVsymmetric chiral ketones for catalytic

asymmetric epoxidation. The chiral ketone 58 was prepared from (i^)-(+)-l,r-bi-2-

naphthol (56). Reacting (56) with 3-chloro-2-chloromethyl-1 -propene gave cyclic

ether 57. Ozonlysis of alkene 57 gave chiral ketone 58. The chiral ketone 61 was

prepared by the same procedure from {S, 1,2-diphenyl-1,2-diol (59) as shown

in Scheme 1.11. The reaction rate was slow at 0 °C so that a stoichiometric amount

of the compound 61 was used and gave a maximum of 5 9 % ee for trans-slilhQnQ

oxide.

The variation of ^symmetric chiral ketones was reported by Adam."^®

Ketones 64 and 67 were prepared from D-mannitol and {R, ie)-(+)-tartaric acid, using

a similar synthetic approach as Song's (Scheme 1.12). The best result was 80% ee of

triphenylethylene oxide using a stoichiometric amount of reagent 67.

15

Scheme 1.11

^^^、、、〇H 7 3 % ' 57%'

56 57 58

n n

^ ^ ^ ^^^

59 60 61

Reagents: a) NaH, DMF, CICH2C(=CH2)CH2CI; b) O3, CH2CI2 then PPhs

Scheme 1.12

〇 x A y 〇 H a O ^ b

D-mannito丨—— 」 I " > = t 〇

J V o J V o J v c 3

62 63 64

Ph Ph Ph Ph Ph Ph

p / > h p / S h p/\h

65 66 67

Reagents: a) N a H , D M F , CICH2C(=CH2)CH2CI; b) O3, CH2CI2 then S(CH3)2

The relationship between the stability and orientation of the a-substituent of

the chiral ketones was studied by Denmark."^^ A series of fluoro ketones 68-72 and 4-

r-butyl cyclohexanone (73) were studied for catalytic asymmetric epoxidation (Figure

16

1.10). The catalytic properties are summarized as: 72>68>71>70>69>73. The fluoro

group at equatorial position performed better catalytic properties while that at axial

position led to formation of side products via Baeyer-Villiger reaction?^ Side product

such as 74 had been isolated.

Denmark財 also used chiral tropinium salt 75 and 76 to study the catalytic

asymmetric epoxidation (Figure 1.11). The chemical yields of the epoxidation were

good (up to 85%) but the enantioselectivity was only moderate (up to 58% ee for

rra^^-stilbene oxide).

Figure 1.10

\ o 68: Ri 二 F，R2 = H, R3 = H, R4 = H 巳 69: Ri = H, R2 = F, R3 二 H，R4 = H 74 70: Ri = F，R2 二 F, R3 二 H，R4 二 H 71: Ri 二 F, R2 = H，R3 = H，R4 = F 72: Ri 二 F，R2 = H, R3 = F, R4 = H

73: Ri = H’ R2 = H, R3 = H，R4 = H

Figure 1.11

N CF3SO3- V

r 75： X = H 76:X=F

o ^ x

Armstrong and co-workers^ reported a-Fluoro-A^-ethoxycarbonyltropinone

(77) as a chiral catalyst for asymmetric epoxidation (Figure 1.12). Both the chemical

yields and ee results were good (up to 83% ee for triphenylethylene oxide).

17

Figure 1.12

C02Et

N

A d a m and co-workers'^^ reported their studies on ketones 81a and 81b. The

chiral ketones 81a and 81b were prepared from D-(-)-quinic acid and shown in

Scheme 1.13. The isopropylidene groups in ketone 81a and cyclohexylidene groups

in ketone 81b acted as steric sensors to induce chirality to epoxides. Ketone catalyst

81a gave good results rather than 81b. Ketone 81a gave good enantioselectivities

(60-85% ee) for different epoxides but the chemical yields were poor (up to 4 7 % yield

for 3 eq. of 81a used).

Scheme 1.13

O Ri 妥 O 妥 H 乂 O 2 H H ^ ^

H O、、、 C l⑶ G、、、 C U i g、、、 C X h ^ c ( 、 C X h " ^ M o

“ R i i 。 R i t。 R i t。

.. 78a. 88% 79a. 1 0 0 % 80a: 7 5 % 81a: R^ = R2 = M e 7 0 % D-quinic acid ygb： 8 5 % 79b: 1 0 0 % 80b: 4 4 % 81 b: Ri = R2 = -(CHsjg" 3 4 %

Reagents: a) 78a: D M P , p-TsOH (cat.), benzene, reflux; 78b: cyciohexanone, H 2 S O 4 (cat.)’

reflux- b) NaBH4, EtOH; c) 80a: D M P , p-TsOH (cat), benzene; 80b: cyciohexanone, p-TsOH (cat.),

toluene, reflux; d) 81a: (C〇CI)2’ D M S O then EtsN, -70 C; 81b: P C C , CH2CI2.

Great success has been achieved in catalytic asymmetric dioxirane epoxidation

by Yang and her c o - w o r k e r A series of symmetric chiral ketones 82-91 was

reported (Figure 1.13). The stereoselectivity is controlled by the steric sensors at 3-

18

and 3'- position of the chiral binaphthylene unit. Moreover, the stability of the

catalyst can be increased by the macrocyclic ester.

Figure 1.13

X (^)-82 X 二 H 〇 j

6 o (R)-83X = CH2〇CH3 \ 〇 々

帅 84X = _ < 0 ： ] ( 卿 X=CI

^ ^ (R)-85 X = (尺)-89 X = I (S)-91 X = TMS

Those series of catalysts were prepared from different synthetic approaches.

Ketone (i?)-82 was synthesized in one step from (i?)-1,1 '-binaphthyl-2,2'-dicarboxylic

acid (92)26 and 1,3-dihydroxyacetone using of 2-chloro-l-methylpyridinium iodide as

the coupling reagent (Scheme 1.14).

Scheme 1.14

n I ® 人

〇 T 〒 CI f Y ^ 〇

K A ^ ^ O H i，3_di_r=yacetone ^ ^ ^ f ^ 。 〜 •

Yir〇H 20-30% \ T i f o O ^ O ^ ^ ^ ^

92 82

Ketone 83 was prepared in a different way (Scheme 1.15). The dicarboxylic

acid 92 was converted into bisoxazoline 93, followed by undergoing orr/zo-directed

lithiation to give bishydroxymethyl compound 94. After hydrolysis and cyclization,

19

alkene 96 was formed. Oxidative cleavage^^ of 98 produced the chiral ketone 83.

The preparations of diacetal ketones 84-86 (Scheme 1.16) were similar to Scheme

1.15.

Scheme 1.15

雙 。 H 丄 把 于 丄 伊 广

o o ^ 92 93 94 O H

「 9 6 X = C〇2Me

95

f k J ^ O 厂 98 丫 = CH2

I ) = Y g

Reagents: a) 1. oxalyl chloride, 2. 2-amino-2-methyl-1-propanol, 3. SOCI2； b) 1. seoBuLi， TMEDA, 2. DMF, 3. NaBhU; c) 6N HCI; d) 1. NaOH, 2. NaH, Mel; e) NaOH, MeOH; f) CICH2C(=CH2)CH2CI，CS2CO3； g) RUCI3, Nal〇4.

Direct orr/zo-substitution of dicarboxylic acid 92 with electrophiles gave the

corresponding precursors 103-107. Subsequent cyclization and oxidative cleavage of

precursors 103-107 afforded the corresponding chiral ketones 87-91 (Scheme 1.17).

20

Scheme 1.16

• M 93 99

。 入 。 — = " " < ; 〕

34, 35 and 86

Reagents: a) 1. sec-BuLi, TMEDA, 2. DMF，3. 6N HCI; b) 1. CS2CO3, 3-chloro-2-chloromethylpropene, 2. 100: 1,2-ethanediol; 101: 1,3-propanediol 102: pinacol, benzene, p-TsOH; c) RUCI3, Nal〇4.

Scheme 1.17

T (尺)-87-89 and (S)-90-91

-(R)- or (S)-92 (R)-103X = CI (R)-104X= B「 (R)-105X= I (S)-106X = M e (S)-107X = T M S

Reagents: a) 1. sec-BuLi, TMEDA, 2. hexachloroethane for 103; 2,4,4,6-tetrabromo-2,5-cyclohexadienone for 104; 1,2-diiodoethane for 105; Mel for 106; TMSCI for 107.

Chiral ketone 88 displayed the best ee (up to 9 5 % ee for

butylstilbene oxide). Their results showed that when the size of the steric sensors

became larger (from 87 to 89), enantioselectivity firstly increased and then decreased,

21

indicating optimal results require the appropriate size of steric sensor. Their work

also provided evidence for a spiro transition state ^ during the oxygen atom transfer

from dioxirane to alkene.

Yang5d also reported another series of chiral ketones 108-112, which were

prepared from (i?)-carvone (Figure 1.14). The ee ranged from 32 to 89%.

Figure 1.14

108X = F I 109X = CI

”OX = 〇H -三 111 X = OEt

个 X 1 1 2 X : H

A fructose-derived ketone 114 was developed as an effective catalyst by

Shi6a,b,d-m (Scheme 1.18). Acetalization of D-fmctose gave the acetonide 113. P C C

oxidation of alcohol 100 gave ulose 114. Ulose 114 exhibited excellent

enantioselectivity for different rra?2 -disubstituted and trisubstituted alkenes (70-95%

ee). However, the catalytic property was poor and an excess amount of ulose 114 was

needed to give moderate yields of epoxides.

Scheme 1.18

o V o V

「。卞,/。 「。卞,/。 ^ , Acetone, HCIO4 I i PCC L L

D-Fructose = ^ ；^"^ " 。 ^ ^ ^ O 0°C, 53% O 三 UH rt, 93% O 5 u

J V o J V o

113 114

22

The study of reaction conditions ' showed that p R is an important factor for

epoxidation. The p H showed a profound effect on the substrate conversion and the

higher pR was beneficial to the catalyst efficiency. Catalytic amount of ulose 114

gave good chemical yields (70-90%) for different alkenes under basic conditions (pH

10.5).

To further probe the structural requirements for the chiral ketone catalysts, a

series of uloses 115-120 was prepared from different carbohydrates (Figure 1.15). -

Most uloses gave poor results, and this study could not give precise understanding of

all the structural requirements involved in the asymmetric epoxidation.

Figure 1.15

疫 氣 . 翻 。 V “ 兴 戈

115 116 117 118 119 120

Ulose 114 was also applied in the asymmetric epoxidation for different

alkenes,6c conjugated dienes^', enynes产，丨 2,2-disubstituted vinylsilane，enol silyl

ethers and esters ' (> 9 0 % ee) (Figure 1.16). The excellent results were obtained.

However, L-fmctose is not readily available and the preparation of the enantiomer of

114 is still a problem remains to be solved.

One drawback of ulose 114 is that it decomposes under the oxidative reaction

conditions, thus requiring relatively high catalyst loading (typically 20-30%), even at

23

the basic conditions. To reduce the catalyst loading, Shi reported a series of fructose-

derived ketone catalysts 121a-c (Figure 1.17). " The catalyst loading can be lowered

from 20-30% for ulose 114 to 1-5 m o l % for ulose 121c while the yields and ee's are

maintained (up to 9 6 % ee for raw^-stilbene oxide).

Figure 1.16

30 mol% 114, Oxone ^^

R CH3CN-H2O, pH 10 R ^ R ^

… X / T M S - ——处MS I ^ R i 力 。

R, Ri, R2 = alkyi groups

R2 R2

Figure 1.17

a" 121a R 二 Me 121b R = Bn

刚 - - ^ 121cR = f-Bu〇2CCH2

0 ”

Shi c'k also reported a series of C2 and pseudo Cj-symmetric ketone catalysts

122-137 prepared from quinic acid (Figure 1.18) to overcome the poor

enantioselectivity for terminal and cw-olefins (up to 70% ee for styrene oxide). Those

catalysts (122-137) showed that the conformation and P-substitutents could control

the enantioselectivity and catalytic properties.

24

Recently, Shi and co-workers have reported several analogue uloses 138-141

of ulose 114 (Figure 1.19)，’乂，…Those catalysts gave good ee for both cz^'-alkenes

and monosubstituted terminal alkenes (up to 9 1 % ee of c/^-P-methylstyrene oxide and

8 1 % ee of styrene oxide for 141). However, the epoxidation of 1,1-disubstituted

olefins with ulose 138-141 was rather low (up to 3 0 % ee of a-methylstyrene oxide for

141).

Figure 1.18

122 R = H Ri = M e R2 = M e 123R = C〇2Me Ri = M e R2 = Me 124R = CH2〇TBS Ri = M e R2 = Me 125 R = CH2OAC Ri = Me R2 = Me 126 R = CH2OBZ Ri = M e R2 = M e

R 127R = CH2〇TS RI = M e R2 = Me R R 128R = CH2F Ri = M e R2 = Me

d X L L /<p 129R = CMe2〇H Ri = Me R2 = M e K2 〇、、、"y"〇 1 130R = CPh2〇H Ri = M e R2 = M e

A 131R = CMe2〇Me Ri = M e R2 = Me 132R = C〇2Me Ri = Et R2 = Me 133R = CH2〇AC Ri = Et R2 = M e 134R = CMe2〇H Ri = Et R2 = M e 135R = C〇2Me Ri = M e R2 = Et 136 R = CH2OAC Ri = M e R2 = Et 137R = C M e O H R! = M e R2 = Et

Figure 1.19

〇

/ o T ^ n r

广 / 138 R = H o k X ^ 139R = Me

〇、丫 \〇 140R 二 Bn 141R = Boc

High enantioselective epoxidation of a,P-unsaturated esters using chiral

dioxiranes still remains a challenging problem. In addition to the selectivity, the low

reactivity of the ketone catalysts has been a major obstacle for achieving efficient

25

epoxidation of a,P-unsaturated esters. Shi6y reported a fructose-derived ketone 142 to

solve the problem (Figure 1.20). Ulose 142 gave the moderate yields and good ee to

the trans- and trisubstituted substrates (up to 9 6 % ee for trans-Qthyl cinnamate).

Figure 1.20

o V

r〇i" AcO、、、4O

OAc

142

The above review of asymmetric dioxirane epoxidation covers the literature

published from 1984 to April 2002. These works are summarized below:

i The chirality of the epoxides is induced by the non-bonded steric

interactions between the substrate and catalyst. Most catalysts

exhibited good ee for bulky rra^^-disubstituted alkenes.

ii During the dioxirane epoxidation, the catalysts may decompose via the

Baeyer-Villiger type reaction. Raising the pYi could suppress the

decomposition pathway.

iii Analyzing the stereochemistry of epoxides produced by chiral

dioxiranes provided evidence of the transition state (TS) during

oxygen transfer from dioxirane to alkenes. The spiro transition state ^

would be more favored reaction mode than the planar state for the

(Figure 1.21).

26

Figure 1.12

R,,!、R ^ R

〇 o ^ ” /V I \ / \ / \ / \

Z// I \ 、、、 * f • I \ 、、、

Spiro TS Planar TS

In conclusion, asymmetric dioxirane epoxidation will be a useful strategy for

the organic transformations and natural product syntheses. There is still ample room

for discovering new chiral ketone catalysts for asymmetric epoxidation.

27

2. RESULTS AND DISCUSSION

2-1. C-Glycoside Ulose Catalyst derived from L-arabinose

The objective of this project is to search for an efficient catalyst to induce

chirality with high enantiomeric excess (ee) in asymmetric epoxidation. L-Arabinose

was used as the starting material for the preparation of chiral catalysts. The

abundance of L-arabinose in the chiral pool and its commercial availability for both

enantiomers have made it the first choice for our studies. Catalyst 146 was readily

prepared from L-arabinose via a reaction sequence involving acetalization,

Knoevenagel condensation, Grignard reaction and oxidation (Scheme 2.1).

Scheme 2.1 Synthesis of the ulose 146

D M P , H+ 广 O 丫 O H acetylacetone, ^ 广 〇 Y ^ ^ 〇

> ^ " ' 。 H D M F , rt . A J ' . O H NaHC03/H20 H C f 丫 〇H 950/0 ^ T U M 9o。c’ 6 7 % ^ T ^ H

L-Arabinose 143 144

MeMgBr/Et2〇 I ^ TPAP, N M O , 3A M S ^ X ^ O ^

THF, - 7 8 ° C , 8 1 % ^ 〇H CH2CI2, rt,87%. ^ T Q H

145 146

L-Arabinose was converted into 3,4-0-isopropylidene-L-arabinopyranose 143

in one-pot using 2,2-dimethoxypropane/DMF under acidic conditions (95%).^^

Reaction of hemi-acetal with acetylacetone in alkaline medium gave p-C-glycosidic

ketone 144 in 67% yield.〗。Treatment of the ketone 144 with M e M g B r gave the diol

28

145 in 8 1 % yield. The T P A P oxidation of diol 145 afforded the hemi-acetal 146 via

an intramolecular cyclization (87%).

With the catalyst 146 in hand, w e started our study on asymmetric epoxidation.

To an acetonitrile solution (5 m L ) of r<2^5'-a-methylstilbene (0.1 mmol) and catalyst

146 (0.01 mmol) was added a N a z E D T A solution (1 m L , 4 x M ) giving a

homogeneous solution. Oxone® (1 m m o l in 3 m L 4 x lO'" M N a 2 E D T A solution) and

N a H C O s (3.1 m m o l in 3 m L H2O) were dropped concomitantly via two dropping

funnels. The use of aqueous N a z E D T A solution prevents the decomposition of

dioxiranes by trace metals^^ and the use of N a H C O s solution maintains the pYl at 7-

7.5. After removal of the solvent and the purification of the product by column

chromatography, a 5 4 % yield of the a-methylstilbene oxide was isolated and the

enantiomeric excess (ee) was 2 3 % [measured by ^H N M R spectroscopy with shift

reagent Eu(hfc)3].

The catalyst 146 could not be recovered after epoxidation (catalyst 146

disappeared on T L C and no any side product was found). This indicated that the

catalyst decomposed during epoxidation. Most research groups proposed that Baeyer-

Villiger reaction〗] had been anticipated to be the main decomposition pathway, but

only in one case were the decomposed products successfully isolated. ^ However, no

specific compounds could be isolated to support the decomposition pathway.

The catalyst 146 gave the poor catalytic activities and chiral induction. Due to

the poor results, the study of asymmetric epoxidation using C-glycoside catalyst was

29

terminated. Thus new 0-glycoside ulose catalysts had to be explored in order to

enhance the chemical yield and the ee of the asymmetric epoxidation.

2-2 Dioxirane epoxidation catalyzed by L-arabino-4-uloses

The C-glycoside catalyst 146 gave poor results for the dioxirane epoxidation.

The reason may be due to the decomposition of the catalyst during epoxidation. It

caused us to develop 0-glycoside ulose catalysts with higher stability to overcome the

decomposition.

In this chapter, L-arabino-4-u\osQS were used to study the asymmetric

epoxidation. Ulose 150 was readily prepared from L-arabinose via a reaction

sequence involving Fischer glycosidation,〗】 acetalization, ^ and oxidation (Scheme

2.2).

Scheme 2.2 Synthesis of ulose 150

n o O B n M e O ^ O M e <0、、、〇Bn

1 I BnOH，AcCI (cat.)’ rt 丄 J / \

H c / y " ' O H “ H c / V " O H H+,MeOH，reflux“ O

OH OH 76% Me〇、Y 丨

L-Arabinose 147 148

⑶ 广 丫 〇 B n / O . O B n

^ O H ’ H+’ 1 PDC’3 MS ^ o V ' " ? • 丄 P h H , reflux, 8 5 % CH2CI2, rt, 9 5 % C X ^ 。 ^ ^ ^

丫0、丫 丫 0 丫 ‘ 149 150

L-Arabinose was converted into benzyl glycoside 147 in 87% yield by Fischer

glycosidation. The anomeric effect induces the benzyl group to occupy the axial

30

position. The trans-diQO^dXondil diols in benzyl glycoside 147 was protected by

2,2,3,3-tetramethoxybutane (TMB) to afford the butane 2,3-bisacetal 148 in good

yield {16%)?^ The methoxy substituents at the bis-acetal 148 were exchanged to

isobutoxy groups by transacetalization^^ under acidic conditions and gave bis-acetal

149 in 85% yield. Pyridinium dichromate (PDC) oxidized the C-4 hydroxyl group to

the ulose 150 in 9 5 % yield. With the ulose 150 in hand, w e initiated the study of

asymmetric epoxidation. The results of the epoxidation are summarized in Table 1.

From the experimental results (Table 1), ulose 150 catalyzed the dioxirane

epoxidation under neutral conditions and gave good chemical yields (79-96%) of

epoxides and the catalysts could be recovered in 90% yield after epoxidation and the

recovered catalyst showed the identical H N M R spectrum with the original ones.

This indicated that the catalysts could overcome the problem of decomposition during

epoxidation. Besides the decomposition of the catalyst, another potential problem

associated with this type of ketone is the possible epimerizaton of the a-chiral center

due to the acidity of the proton. However, the stable trans-dQCdXin structure of ulose

150 should prevent the epimerization to occur. Ulose 150 performed better

enantioselectivity towards the trisubstituted alkenes (Table 1, entries 2, 4 & 6) than

the 似-disubstituted alkenes (Table 1, entries 1, 3, 5 & 7) and the ee is up to 86%

(Table 1, entry 4).

31

Table 1 Asymmetric epoxidation of alkenes using ulose 150 as catalyst

10 m o l % catalyst

_ 〇 x o n e / N a H C 〇 3 Ri 〇 R3

R2 R4 CH3CN/H2〇 “ rt, p H 7-7.5

Catalyst: Substrates: ph

〇 O B n P h ^ ^ P h a p h ^ P h d

" " i X o ^ P h ^ P h b P h ^ ^ ^ O A c e

^ 150 c o r f

Substrates Yield (%)' ee {%)' Config.'

1 a ^ ^ F H ^ ^

2 b 92 84 ( - ) 彻 35

3 c 80 35 ( - ) -卿 36

4 d 96 86 (+)-⑶ 36

5 e 92 72 (-)

6 f 79 67 ( - ) 彻 37，38

7 g 86 6 6 ( — 加

a All reactions were carried out at room temperature with substrate (0.1 mmol),

ketone (0.01 mmol), Oxone® (1 mmol) and N a H C O s (3.1 mmol) in CH3CN: 4 x 10'

M aqueous E D T A (5:1, v/v) for 2.5 h. b Isolated yield. 。Enantioselectivity was

determined by ^H N M R analysis of the epoxide products directly with shift reagent

Eu(hfc)3. d The absolute configurations were determined by comparing the measured

optical rotations with the reported ones.

32

The examination of possible geometries of the transition states can give better

understanding to the stereochemistry of the epoxide via dioxirane epoxidation. The

favored transition state should result from the minimum steric interaction between the

dioxirane substitutents and the substrate. The epoxidation of trans-^^iVoQnQ catalyzed

by ulose 150 was used as an example. For the dioxirane, because of the 1,3-diaxial

repulsion, the oxygen atom at the pseudo-axial position should be less reactive

(Figure 2.1). Therefore the attack of the alkenes on the dioxiranes should be from the

less hindered a-face.

The results in Table 1 provide valuable information about the reaction mode

of the epoxidation by dioxiranes. The favored spatial orientation of the alkene should

impose minimum steric interaction with the steric sensor, i.e. the aglycone x at the a-

face. Figure 2.2 shows all the possible transition states (TS) and steric interactions

between the phenyl group in the alkene and the acetal blocking group of the ulose 150.

If the reaction proceeds via a spiro mode, (5',5)-stilbene oxide is expected to form

preferentially (spiro-1 v^ spiro-2). In contrast,(尺 i^-stilbene oxide will be favored if

the reaction proceeds via a planar mode (planar-2 v^ planar-1). In the present study, it

is found that (5',5)-stilbene oxide is produced predominately, which supports the

reaction pathway proceeding through a spiro transition stateAccordingly, epoxide

configurations shown in Table 1 are consistent with the spiro TS. Therefore, the

stereochemical outcome of the reactions can be predicted with a reasonable level of

confidence based on this model.

33

Figure 1.12

y P attack

〇 y pK ^ h o y

o 如 ‘ BnO O i , B n〇 0 >

— / \ \

Ph K 厂 a attack . ,

Favored Disfavored

The results in Table 1 show that l.-arahinoA-Vi\o^Q really has the potential as

useful catalyst in asymmetric epoxidation. Owing to these outstanding results, w e

decided to modify the catalysts for better results.

34

Figure 2.2 The spiro and planar transition states for 广ra似-stilbene epoxidation

catalyzed by ulose 150.

y y

O ? Ph O o ？ 0卿 〜 0春 BnO O T BnO

Ph \ / ^ \ major <\

Ph K 〉 卜

I PK 丨

Spiro-1 Planar-1 Favored Disfavored

y y

o 杂 。 ^ ^ p r -

RnO o 1 Ph BnO O A B n 〇 • ^ O 〇\

— P h r N minor V _ p h

p / ^ 厂 卜

Spiro-2 Planar-2

Disfavored Favored

Ulose 152 had steric sensor with the same carbon chain length but different

bulkiness at the termini. The synthetic pathway of ulose 152 is shown in Scheme 2.3.

The bis-acetal 148 was converted to bis-acetal 151 by transacetalization^^ under acidic

conditions and gave bis-acetal 151 in 8 7 % yield. Oxidation of the free alcohol in bis-

acetal 151 with P D C gave ulose 152 in 9 6 % yield. Ulose 152 was used as catalysts in

asymmetric epoxidation of different alkenes. The results from ulose 152 are

summarized in Table 2.

35

Scheme 2.3 Synthesis of ulose 152

<〇、、、〇Bn O 、OBn

H+ 人 丄 一 I PDC, 3A M S

H O ^ Y '0 广 ’H H O ^ ^ T O ： ^ i ^ O M e phH, reflux, 8 7 % O ^ ^ ^ CH^Ci^, rt, 96%

M e O 丫 ‘ ^ o T ‘

148 ^ … 151 广 丫 〇 B n

yf-oY

152

The results in Table 2 show that ulose 152 gave moderate ees (34-84%) of

epoxides. Ulose 152 performed better enantioselectivity towards trisubstituted

alkenes (Table 2, entries 2 & 4) than / “似-disubstituted alkenes (Table 2, entries 1,3,

5 & 6) and the ee is up to 84% (Table 2, entry 4). Comparing to Table 1, the

experimental observations show that ulose 152 improves the ees of /r<3?w-disubstituted

alkene oxides (Table 1, entries 2 & 4; Table 2, entries 2 & 4), but the ees of the

trisubstituted alkenes decrease. This means that steric sensors of appropriate size

could induce higher enantioselectivity.

36

Table 2 Asymmetric epoxidation of alkenes using ulose 152 as catalyst

10 m o l % catalyst

fi _ O x o n e / NaHC〇3 Ri O R3

R P R A CH3CN/H2〇 “ R f \ rt，pH 7-7.5

Catalyst: Substrates:

O O B n P h l P h a e

0 々 > J < Ph j p h b I ^ P h f

I c ^ ^ ^ ^ ^ ^ ^ O B n g 152 Ph

P h ^ ^ P h d

Entry a Substrates Yield (%)' ee (%)' Config.'

1 a ^ ^ ( - ) -腳

2 b 84 80 ( - ) 调 35

3 c 61 46 ( - ) 倘 36

4 d 73 84 (+)切 36

5 e 91 75 (-)

6 f 75 71 ( - ) 彻 37，38

7 g 76 34 (-)

a All reactions were carried out at room temperature with substrate (0.1 mmol),

ketone (0.01 mmol), Oxone® (1 mmol) and N a H C O s (3.1 mmol) in CH3CN: 4 x 10"^

M aqueous E D T A (5:1, v/v) for 2.5 h. ^ Isolated yield. 。Enantio selectivity was

determined by ^H N M R analysis of the epoxide products directly with shift reagent

Eu(hfc)3. d The absolute configurations were determined by comparing the measured

optical rotations with the reported ones.

37

To further reveal the catalytic features of ulose 152, we set out to investigate

the optimum ；?H conditions for the asymmetric epoxidation. The results of the pYi

study of epoxidation are summarized in Table 3. The reaction was carried out at 0 °C

(bath temperature) with 1 m m o l of rra似-stilbene and 10 mol% of ulose 152. The

epoxidation reactions essentially stopped after 2.5 h at eachpR value studied. The p R

was monitored by apYi meter and adjusted with buffer solutions. The results in Table

3 show that the change of p R had no significant improvement on the ee of asymmetric

epoxidation (84%-89%), but on the yield (63% up to 81%) of epoxidation for 2.5 h.

The catalytic cycle of epoxidation^'^^^ of ulose 152 is shown in Scheme 2.4.

In the catalytic cycle, addition of HSO5— to the ketone 152 gives the intermediates 153

and 154 which can be converted into dioxirane 155 by the elimination of SO/—.

Since highpU favors the equilibrium towards intermediate 154, this can consequently

lead to a more efficient formation of dioxirane 155?^" (The step from 154 to 155

could be the rate-determining step.) To prove this hypothesis, the epoxidations were

proceeded at the same reaction temperature (0。C) for longer time (6 h). From the

experimental results, it shows that for a longer reaction time, the chemical yields of

epoxidation at low pR increased to those at basic conditions (the yields were among

79 to 82% throughoutpU 7-12) with the ees maintained (83-89% ee).

Comparing with the previous studies, it could be observed that the ee of the

epoxidation of trans-stilbQUQ by ulose 155 had a significant improvement from 72%

ee (Table 2, entry 1) up to 89% ee (Table 3). Indeed, the reaction conditions have

been changed to induce high ee. For comparison purpose, a p U study (pH 7-9) was

proceeded at room temperature as a control.

38

Table 3 The j^H study of the epoxidation of trans-siiVoQnQ using ulose 152 under

different conditions.

DP, 10 m o l % catalyst _

^ ^ Oxone/K2CO3 ^ 及 h

Ph C H 3 C N / H 2 O ^ Ph

Catalyst:

152

0。C (2.5 h)a 0。C (6 rt(2.5h)c

Yield (%)' ee (%)'~Yield (%)' ee ( % ) ' Y i e l d (%)' ee (%)'

' p ^ ^ ^ ^ ^ 77 ^

^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^

a Conditions a: all reactions were carried out at 0 °C (bath temperature) with

substance (0.1 mmol), ketone (0.01 mmol), Oxone® (0.5 mmol) in CHsCN-buffer,

(2.5:1, v/v) for 2.5 h. pYl was monitored by apYi meter and adjusted with buffer: i) i)

10 m L 4 X 10-4 m aqueous E D T A adjusted with 1.0 M NaHCOs； ii) H7.5-8.5,

10 m L 4 X 10-4 M aqueous E D T A adjusted with 1.0 M K O H ; iii) pU 8.5-10.5, 10 m L

0.05 M Na2B407-10H20 in4 x lO'^^M aqueous E D T A adjusted with 1.0 M KH2PO4； iv)

p H 11-12, 10 m L 0.05 M K2HPO4-O.I M N a O H , (2:1, v/v). Reaction conditions are

same as conditions a instead of 6 h for the reaction time.。Reaction conditions are

same as conditions a instead of room temperature for the reaction temperature, d

Isolated yield. ® Enantioselectivity was determined by ^H N M R analysis of the

epoxide products directly with shift reagent Eu(hfc)3.

39

Scheme 2.4 Catalytic cycle of dioxirane epoxidation

Ri 〇 R3 y y ^

R r ^ R 4 「 0 O B n , H S〇 5 -

？7 〇 V ' O n P ( A \ R2 R4 / \

156 Y

〇、、〇Bn 〇、〇 B n

. 。 • ^ ) 。 丄 - 。 , - 略 丄

155 153

154

Ri, R2,R3- R4 = H or alkyi groups

The experimental results show that not only the yield of the epoxide, but also

the ee was influenced by the reaction temperature. W h e n increasing the reaction

temperature from 0。C to room temperature at pR 1, the chemical yield of epoxide

increased from 6 3 % to 7 7 % , i.e. the rate of epoxidation increased. At the same time,

however, the ee of the epoxide decreased from 8 8 % to 80%. This means the reaction

temperature would be a major factor for inducing the enantioselectivity to the epoxide.

Based on the improvement of enantioselectivity of the epoxidation, the

catalytic properties of the uloses were studied with the new reaction conditions. To a

40

stirred solution of trans-?>Xi\hQnQ (0.1 mmol), ketone (10 mol%) and 小BU4NHSO4 (0.5

m g ) in CH3CN (10 m L ) and aqueous buffer solution (5 m L , 4 x 10—4 M aqueous

E D T A ) were added. The solution was cooled to 0 � C (bath temperature). A solution

of Oxone® (0.5 mmol) in aqueous E D T A (5 m L , 4 x 10'^ M) and a solution of

N a H C O s (3.1 mmol) in H 2 O (5 m L ) were dropped concomitantly via two dropping

funnels. The pH of the mixture was maintained at about 7-7.5 over a period of 12 h

for completing the epoxidation.

The syntheses of uloses 158 and 160 are shown in Scheme 2.5. Ulose 158

was prepared from the oxidation of alcohol 148 in 9 0 % yield. For ulose 160, the

似-diequatorial diol in benzyl glycoside 147 was protected by 2,2,3,3-

tetraethoxybutane (TEB) to afford the bis-acetal 159 in 5 0 % yield. P D C oxidation

gave ulose 160 in 8 5 % yield (Scheme 2.5). With the uloses 150, 152, 158 and 160 in

hand, w e initiated the study of asymmetric epoxidation. The results are summarized

in Table 4. Results using the original reaction conditions are also listed for

comparison.

Scheme 2.5 Synthesis of uloses 158 and 160

O y O B n 广 丫 OBn

[ ] „ PDC, 3A MS

i ^ O M e CH2Cl2,90o/o ‘ ^ ^ ^ O M e

MeO^I ''' MeO、丫 “

148 158

EtO / 八、、OBn <0、、、偷 O OBn E t O i ; K o O E t E t , 认 PDC, 3入 MS ^ ^ ^ o

H O V ' O H CH2C12,85% ^ t g 一 胞

147 159 160

41

The results from Y. C. Leung (Table 4c) proceeded at original conditions

(room temperature for 2.5 h) were reported as italic style. From the experimental

results (Table 4a-c), some information was obtained:

1. Blocking groups of different sizes at the bis-acetals induced different

enantioselectivity. The substitutents at bis-acetal with higher bulkiness were more

effective steric sensors for inducing enantioselectivity.

2. Decreasing the reaction temperature, the extents of ee of substrates increased

with different degree, i.e. no direct relationship between the temperature and the

catalysts.

3. As the bulkiness of steric sensors became larger (from methyl group to ethyl

to isobutyl to neopentyl), enantioselectivities of / raw '-disubstituted alkenes increased

(Table 4a, entries 1, 2, 5, 6, 9, 10, 13, 14; Table 4b, entries 1, 2, 5, 6, 9, 10, 13-15;

Table 4c, 1-4, 11-13), while enantioselectivities of trisubstituted alkenes first

increased and then decreased (Table 4a, entries 3, 4, 7, 8, 11, 12; Table 4b, entries 3,

4. 7, 8, 11, 12; Table 4c, 5-10). This means that steric sensors of appropriate size

could induce higher enantioselectivity. Ulose 152 performed better selectivity for

fr“似-disubstituted alkenes; ulose 150 performed better selectivity for trisubstituted

alkenes, suggesting that different types of olefins require different ketone structural

elements for enantioselectivity.

4 Benzyl rra似-hex-3-enyl ether (substrate g) is the most sensitive substrate. It

is sensitive to both the steric bulkiness of the catalysts (e.g. 30% ee for ulose 158

42

(Table 4c, entry 12) to 9 3 % ee for ulose 150 (Table 4a, entry 13)) and the reaction

temperature (from 3 4 % ee to 9 1 % ee, Table 4b, entries 13 and 14).

Table 4 Asymmetric epoxidation of alkenes using uloses 150, 152, 158 and 160 as

catalyst in two conditions.

10 mol% catalyst

_ Rs Oxone/NaHC〇3 Ri O R3

R ” CH3CN/H2O - R 仏 2 rt, pH 7-7.5 2 4

catalyst o oBn Substrates: ^ ^ ^ ^ ^ ^ P h ^ ^ ^ O A c ,

P h ^ P h b Q r ' ' f

R〇、丫 ‘ . P h ^ - . ^ c ^ ^ ^ ^ ^ ^ ^ O B n g

R = isobutyl 150 R = neopentyl 152 ^^ , O T B S R = methyl 158 Ph 〜 ^ P h ^ P h ^ ^ ^ " — ^ h R = ethyl 160

” e J ^ Catalysts SubstratesYield ee Config.'

A t I t

1 158 a ^ 42 (-H《5)34

2 160 a 95 54

3 150 a 94 64 ( - ) 调 34

4 152 a 81 72 ( - ) 彻 ' '

5 160 b M 25 (—

6 150 b 92 84 ( - ) 侧 35

7 152 b 84 80

8 150 c 80 35 ( - ) 侧 36

9 152 c 61 46 ( - ) -腳 36

10 158 d 97 M (+M》36

11 160 d 95 78 (+)-⑶ 36

43

12 150 d 96 86 (+)-⑶ 36

13 152 d 73 84

14 150 e 92 72 (-)

15 152 e 91 75 (-）

16 150 f 79 67 ( - ) -腳 37’38

17 152 f 75 71 ( - ) 调 37，38

18 158 g 73 23 (-)

19 152 g 76 34 (-)

AtO。C

20 158 a 96 47 ( - ) 倘

21 160 a 99 67

22 150 a 97 76 (-)调‘‘

23 152 a 91 83 ( - ) 倘

24 160 b 95 83 (-)调‘‘

25 150 b 93 87 ( ― 欢 5

26 152 b 84 88 ( ― 习 35

27 150 C 83 69 ( - ) 彻 36

28 152 C 90 69

.29 158 d 95 79 (+)-⑶‘‘

30 160 d 97 82 ⑴ -⑶

31 150 d 99 90 (+)-(妒

32 152 d 96 88

33 150 e 93 77 (-)

34 152 e 94 82 (-）

44

35 150 f 92 85

36 152 f 80 77 ( - ) -卿 37，38

37 158 g 97 30 (-)

38 160 g 88 56 (-)

39 150 g 92 93 (-)

40 152 g 93 91 (-)

41 150 h 85 75 ( - M S 对 a,6c

42 152 h 85 81

a Procedures are referred to the experimental section. b isolated yield,

c Enantioselectivity was determined by ^H N M R analysis of the epoxide products

directly with shift reagent Eu(hfc)3. ^ The absolute configurations were determined

by comparing the measured optical rotations with the reported ones. Results from Y.

C. Leung was reported as underline style.

Ulose 164 had blocking group of different size at the anomeric center. The

synthetic pathway of ulose 164 is shown in Scheme 2.6. Methyl glycoside 161 was

prepared from L-arabinose by Fischer glycosidation with methanol (75%).^^ trans-

Diol protection�： followed exchanging the methoxy substituents at bis-acetal to

isobutyl groups by transacetalization^^ gave 4 8 % yield of bis-acetal 163. P C C

oxidation of the C-4 hydroxy group in alcohol 163 gave the ulose 164 in 94% yield.

Ulose 164 was used to study the effect of the size of the blocking group at the

45

anomeric center on asymmetric epoxidation. The results are summarized in Table 5.

Results from uloses 150 and 152 are also listed for comparison.

Scheme 2.6 Synthesis of ulose 164

M e O . O M e 0、、、、0Me

「 0丫 O H MeOH,AcCI(ca.),rt ^ 、OMe MeO;^,OMe h+ , j ^ 、

H O ^ ^ ' ' ' 〇 H ^ ^ H c / Y " ^ ' ' '〇 H M e O H , reflux H O T ^ O M e

O H O H M e O、丫 “

L-Arabinose 161 162

O 、OMe < 0 丫、OMe

^ O H ’ H+ O H ! V ' " 0 O 丄 ,

PhH, Dean & Stark ^ ^ CH2CI2, 9 4 %

(2 steps, 4 8 % yield) I ] • I

163 164

Like uloses 150 and 152, analogue 164 also afforded good chemical yields of

epoxides (87-97% yield). However, the change of blocking groups at the anomeric

center caused no significant improvement in enantioselectivity (Table 5). This

indicated that the blocking group at C-1 is not the controlling factor for high

enantioselectivity in asymmetric epoxidation.

46

Table 5 Asymmetric epoxidation of alkenes using ulose 164 as catalyst at 0。

C

10 mo|o/o catalyst

Catalyst:

Substrates:

^^

^^

^ Ph^^〇

Ac

e

Ri

Rs

Oxone / NaHC〇

3 Ri O R3

\ J

—^

f^

‘‘ A

I '

h rvPh

f rt, p

H 7-7.5

Ph

^^

Ph

b [

『

f

R2O、

、I

^^^

Ri = Bn, R2 = isobutyl

150

^^^

c Ri 二

Bn, R2 = neopentyl

152

Ph^^^^

；;

^ Ri == Me, R2 = isobutyl

164

Ph

Ph

^P

h d

h

Entry|

1 |

2 |

3 |

4 |

5 |

6 |

7 |

8 |

9 | 10 | 11 | 12

| 13 |

14 | 15 | 16

| 17

| 18

| 19

| 20

21

| 22

| 23 丨

24

Catalysts150

152

164

150

152

164

150

152

164

150

152

164

150

152

164

150

152

164

150

152

164

150

152

164

Substrates

a a

bb

bc

cc

dd

de

ee

ff

fg

gg

hh

h

Yield (%T

97

^^

^^

%^

%^

^%

93

^^

^^

^^

^^

^^

ee (o/o)b

76

^^

^^

^^

^7

0%

^^

77

^m

^7

7^

75

UW

config.c

Bw

r (

」m

+ ^

(-)

(-

(-

)

(-)倘

“，

仗

a Isolated yield. Enantioselectivity was determined by

NMR

analysis of the epoxide products directly with shift re

agen

t Eu(hfc

)3.

^ The

absolute configurations were determined by comparing the measured optical rotations with the reported ones.

47

Ulose 168 has a steric bulk similar to that of ulose 152, but with an

electronegative O H functional group introduced. The bis-acetal 148 was converted

into bis-acetal 165 via transacetalization^^ under acidic conditions, giving bis-acetal

165 in a moderate yield (64%). Dihydroxylation"^*^ of the double bonds in bis-acetal

165 followed by glycol cleavage"^ gave dione 166 (64%). The dione 166 was

converted into tertiary alcohol 167 by adding Grignard reagent, MeMgBr/EtiO (77%

yield). Oxidation of the secondary alcohol in bis-acetal 167 with P C C gave ulose 168

in 8 6 % yield (Scheme 2.7).

Scheme 2.7 Synthesis of ulose 168

〇、、、、〇Bn O 、〇Bn

H o V ' " ? O M e 1 o H , H + , h O p ^ 丨）OsO N M O •

PhH, reflux, 64% O ^ T , ^ ^ ii) Nal04, 64%

Me〇、T '' Y"〇、、T ‘

148 165

O 、OBn 「 0 、〇Bn

H O ^ ^ Y "'0 § MeMgBr/Et20 ^ LoH PCC, 3A MS _

O ^ ? ^ ^ THF, -78°C, 77% CH^CI^, rt, 86%

〇

166 167

O 丫X)Bn

。 办 丄 。 H

168

Ulose 168 was used as a catalyst in asymmetric epoxidation of different

alkenes, and the results are summarized in Table 6. Results from uloses 150 and 152

are also listed for comparison.

48

Table 6 Asymmetric epoxidation of alkenes using ulose 168 as catalyst

P p 10 m o l % catalyst

W 3 Oxone / NaHC〇3 >

R2^R4 CH3CN/H2〇 “ p f ^ R , rt, p H 7-7.5 2 「 4

Catalysts: Substrates:

〇、〇Bn 广 O 、〇Bn 广 O 、〇Bn Ph-^^^Ph a

b

' ^ o T ' Ph

150 152 168 P h ^ - ^ ^ P h e

Entry" Catalysts Substrates~Yield (%)' ee (%)。 Config.

1 a ^ ^ ( - ) - (诚 4

2 152 a 81 72 ( - ) -腳 34

3 168 a 93 82 ( - ) 倘 34

4 150 b 92 84 ( - ) -卿 35

5 152 b 84 80

6 168 b 86 77

7 150 c 96 86 ⑴-⑶36

8 152 c 73 84 (+)-⑶

9 168 c 96 81 (+)-⑶ 36

a All reactions were carried out at room temperature with substrate (0.1 mmol),

ketone (0.01 mmol), Oxone® (1 mmol) and N a H C O s (3.1 mmol) in CH3CN: 4 x 10"^

M aqueous E D T A (5:1, v/v) for 2.5 h. ^ Isolated yield. 。Enantioselectivity was

determined by ^H N M R analysis of the epoxide products directly with shift reagent

Eu(hfc)3. d The absolute configurations were determined by comparing the measured

optical rotations with the reported ones.

49

The experimental observations (Table 6) showed that ulose 168 gave good

chemical yields and enantioselectivity to /ra '-disubstituted and trisubstituted alkenes.

Comparing to the epoxidation results of 150 and 152, the enantioselectivity of trans-

disubstituted olefins increases with the size of steric sensors of catalysts, while that of

trisubstituted alkenes decreases, therefore ulose 168 supports our previous

arrangement, different types of olefins require different ketone structural elements for

enantioselectivity. Although ulose 168 can give the outstanding epoxidation results,

the multi-steps and complicated procedures of the synthetic approach of 168 make it

not to be suitable for acting as catalyst for asymmetric epoxidation.

In conclusion, uloses 150, 152 and 164 were prepared from L-arabinose by

simple methods and they can give excellent chemical yields of dioxirane epoxidation,

good enantioselectivity for /ra^^-disubstituted and trisubstituted alkenes. Further

work is needed to design new ulose catalysts for better chiral induction in asymmetric

dioxirane epoxidation.

50

Experimental Section

General Melting points were measured with a Reichert apparatus in Celsius

degrees and are uncorrected. Optical rotations were obtained with a Perkin-Elmer

model 341 polarimeter, operating at 589 nm. Infrared (IR) spectra were recorded on a

Nicolet 205 or a Perkin-Elmer 1600 FT-IR spectrophotometer as thin films on KBr

discs. Nuclear magnetic resonance ( N M R ) spectra were measured with a Bruker

DPX300 N M R spectrometer at 300.13 M H z (^H) or at 75.47 M H z (^^C) in CDCI3

solutions, unless stated otherwise. All chemical shifts were recorded in ppm relative

to tetramethylsilane (S = 0.0). Spin-spin coupling constants (J) in H z were measured

directly from the spectra. M S and H R M S were performed at the Department of

Chemistry, The Chinese University of Hong Kong, Hong Kong, China. Carbon and

hydrogen elemental analyses were carried out by the M E D A C Ltd, Department of

Chemistry, Brunei University, Uxbridge, U.K. All reactions were monitored by

analytical thin-layer chromatography (TLC) on aluminum-precoated plates of silica

gel 60 F254 (E. Merck) and compounds were visualized with a spray of 5 % w/v

dodecamolybdophosphoric acid in EtOH and subsequent heating. E. Merck silica gel

60 (230-400 mesh) was used for all flash column chromatography. The reaction pH

was monitored by an Orion 420A pH meter with an Orion pH triode electrode. All

solvents were reagent grade unless otherwise stated. Toluene, benzene and T H F were

fleshly distilled from Na/benzophenone ketyl under nitrogen. CH2CI2 was freshly

distilled from CaHi under N2. Other reagents were purchased from commercial

suppliers and used without purification. All hexanes used are "-hexane.

51

3,4-0-Isopropylidene-p-L-arabinopyranose (143)29

To a solution of L-arabinose (10.4 g, 69.3 mmol) in D M F (lOOmL) was added 2,2-

dimethoxypropane (25 m L , 203.5 mmol) and p-TsOR (30 mg, 0.16 mmol). The

mixture was stirred at rt under nitrogen for 12 h. NEts was added and the resulting

mixture was concentrated under reduced pressure. Column chromatography of the

residue using a gradient elution of M e O H (0-10%)-CH2Cl2 afforded acetonide 143

(12.5g, 95%): m p 78—79。C; [af>103.4 (c 0.74, CHCI3) {lit.,29 m p 78—80。C and

80—81。C; [afo。+128.8 (c 0.93, H2O)}; i?/0.38 ( M e O H - C H C b , 1:9); IR (thin film)

3335 (OH) cm-i; H N M R (CDCI3) 5.20 (2H, d, J= 3.3 Hz), 4.57(1H, d, J二 7.2 Hz),

4.30-4.12 (lOH, m), 3.88-3.62 (5H, m), 3.64 (IH, t, J= 6.9 Hz), 3.49 (IH, s), 2.17(1H,

s), 1.56 (3H, s), 1.52 (9H, s), 1.37(9H, s); 'C N M R (CDCI3) ^ 110.7, 109.8, 96.7,

92.3, 78.9, 76.1, 74.9, 73.9, 73.0, 70.4, 63.7, 60.5, 28.5, 28.4, 26.6, 26.4; M S (FAB)

m/z (relative intensity) 191 ([M+H]+, 31), 173 (76), 154 (100), 137 (85), 69 (74);

H R M S (FAB) calcd for CgHnOs [M+H]+ 191.0914, found 191.0920.

P-C-glycosidic ketone 144

To a solution of acetonide 1 (190 mg, 1.0 mmol) in water (4 m L ) were added

N a H C O s (126 mg, 1.5 mmol) and acetylacetone (0.13 m L , 1.3 mmol”。After stirring

at 90 °C for 12 h, the cooled reaction mixture was extracted with EtO Ac (3x). The

combined organic extracts were dried over anhydrous MgS04, and filtered. The

filtrate was concentrated under reduced pressure. The crude residue was purified by

flash column chromatography (hexane-EtOAc, 1:2) to give ketone 144 (154 mg, 67%):

m p 54-55。C; [aj^ +76.4 (c 1.28, CHCI3)； i /0.33 (hexane-EtOAc, 1:2); IR (thin film)

1699 (C=0) cm.i; H N M R (CDCI3) d 4.24-4.18 (2H, m), 3.99 (2H, m), 3.75 (2H, dd,

J = 13.5, 2.4 Hz), 3.58-3.44 (4H, m)’ 2.20 (6H, s), 1.53 (6H, s), 1.36 (6H, s); 'C

52

N M R (CDCI3) 3 207.3, 109.7, 79.5, 74.5, 74.0, 73.5, 66.6, 45.7, 31.1, 28.2, 26.2; M S

(FAB) m/z (relative intensity) 231 ([M+H]+, 60), 215 ([M—CH3]+, 45), 43 (100); Anal.

Calcd for CuHigOs： C, 57.38; H , 7.88. Found: C, 57.26; H , 8.02.

Diol 145

To a solution of M e M g B r in EtiO (3 M , 2 m L ) in T H F (4 m L ) at —78。C was added a

solution of ketone 144 (195 mg, 0.85 mmol) in T H F (4 mL). After stirring at -78。C

for 15 min, the reaction mixture was quenched by aqueous NH4CI and was then

extracted with EtOAc (3x). The combined organic extracts were dried over

anhydrous MgSCU, and filtered. The filtrate was concentrated under reduced pressure.

The crude residue was purified by flash column chromatography (hexane-EtOAc, 1:4)

to afford diol 145 (168 mg, 81%): m p 156-158。C; [a]^ +73.1 (c 0.9, CHCI3); i^/0.30

(hexane-EtOAc, 1:4); IR (thin film) 3277 (OH) cm]; H N M R (CDCI3) S 4.28 (IH, d,

J二 13.5 Hz), 4.21 (IH, dd, J = 5.4, 2.1 Hz), 3.98 (IH, m), 3.75 (IH, dd, J = 13.5, 2.4

Hz), 3.48 (IH, dd, J = 9.6, 7.2 Hz), 3.37 (IH, dt, J = 9.0, 3.3 Hz), 2.00 (IH, dd, J =

14.7, 3.3 Hz), 1.76 (2H, dd, J= 15.0, 9.0 Hz), 1.54 (3H, s), 1.38 (3H, s), 1.28 (3H, s),

1.25 (3H, s); 13c N M R (CDCI3) b 109.8, 79.3, 74.1, 73.7, 70.3, 66.3, 44.0, 30.4, 29.2,

28.2, 26.3, 1.00; M S (CI) m/z (relative intensity) 247 ([M+H]+, 2), 231 ([M-CHs]^

10), 229 ([M—0H]+, 100); H U M S (CI) calcd for C12H22O5 [M—H]— 245.1394, found

245.2383; Anal. Calcd for C12H22O5： C, 58.52; H, 9.00. Found: C, 58.76; H, 9.28.

Hemi-acetal 146

Tetrapropylammonium perruthenate (TPAP) (11 mg, 5.6 mol%) was added to a

mixture of 4-methylmorpholine-A^-oxide ( N M O ) (119 mg, 1.01 mmol), 3 A molecular

sieve (1.8 g), alcohol 3 (131 mg, 0.53 mmol), and dry CH2CI2 (10 mL). After stirring

53

for 1.5 h at rt, the suspension was filtered through a silica gel plug and washed with

EtOAc as eluent. The filtrate was concentrated under reduced pressure to give a

crude solid. Flash column chromatography (hexane-EtOAc, 1:2) gave hemi-acetal

146 (113 mg, 87%): m p 111-112。C; [a] 0+31.8 (c 1.2, CHCI3); J^/ 0.30 (hexane-

EtOAc, 1:4); IR (thin film) 3344 (OH) cm"^; H N M R (CDCI3) 4.29 (IH, d, J二 6.9

Hz), 4.25 (IH, dd, J= 7.2, 1.8 Hz), 4.09 (IH, t, J= 6.0 Hz), 3.96 (IH, d, J= 12.9 Hz),

3.62 (IH, dd, J = 12.9, 2.1 Hz), 2.57 (IH, brs), 2.30 (2H, dd, J= 12.6, 6.6 Hz), 2.01

(2H, dd, J = 12.6, 6.3 Hz), 1,59 (3H, s), 1.56 (3H, s), 1.39 (6H, s), 1.37 (3H, s); ^^C

N M R (CDCI3) 110.1, 101.2, 83.6, 82.1,77.4, 73.1, 66.9, 44.8, 30.3, 29.3, 26.2, 25.7;

M S (CI) m/z (relative intensity) 245 ([M+H]+, 53), 229 ([M-CHs]^ 66), 228 (83), 227

(100); H R M S (CI) calcd for C12H20O5 [M—H]— 243.1237, found 243.1227.

General in situ Epoxidation Procedure at R o o m Temperature

To a stirred solution of 广ra似-stilbene (0.1 mmol), ketone (10 mol%) and n-

BU4NHSO4 (0.5 mg) in C H 3 C N (5 m L ) and aqueous buffer solution (1 m L , 4 x 10.4 M

aqueous E D T A ) were dropped concomitantly a solution of Oxone® (1 mmol) in

aqueous E D T A (3 m L , 4 x 10' M) and a solution of N a H C O s (3.1 mmol) in H2O (3

m L ) via two dropping funnels. The p R of the mixture was maintained at about 7-7.5

over a period of 2.5 h. The reaction mixture was then poured into water (10 mL),

extracted with EtiO (3x), dried with anhydrous magnesium sulfate, and filtered. The

filtrate was concentrated under reduced pressure to give a residue which was flash

column chromatographed to give the epoxide.

54

Experimental Procedure for Epoxidation at different /^H

To a stirred solution of 仏an义stilbene (0.1 mmol), ketone (10 mol%) and n-

BU4NHSO4 (5 mg) in acetonitrile (25 m L ) and aqueous buffer solution [ i) pBl, 10

m L 4 X 10-4 M aqueous E D T A adjusted with 1.0 M NaHCOs； ii)；7H7.5-8.5, 10 m L 4 x

10—4 M aqueous E D T A adjusted with 1.0 M K O H ; iii) pU 8.5-10.5, 10 m L 0.05 M

Na2B407.10H20 in 4 x lO"" M aqueous E D T A adjusted with 1.0 M KH2PO4； iv) pYi

11-12, 10 m L 0.05 M K2HPO4-O.I M N a O H , (2:1, v/v)] was added. The solution was

cooled to 0。C. Oxone® (0.5 m m o l in 4 x lO"" M aqueous E D T A ) and K2CO3 (0.58

m m o l in 10 m L H2O) were added drop wise over a period of 1.5 h. The reaction

mixture was then poured into water (10 mL), extracted with EtiO (3x), dried with

anhydrous magnesium sulfate, and filtered. After removal of the solvent from the

filtrate under reduced pressure, the residue was purified by flash column

chromatography to give the epoxide.

General in situ Epoxidation Procedure at 0

To a stirred solution of 广ra似-stilbene (0.1 mmol), ketone (10 mol%) and n-

BU4NHSO4 (0.5 mg) in C H 3 C N (10 m L ) and aqueous buffer solution (5 m L , 4 x

M aqueous E D T A ) were added. The solution was cooled to 0。C (bath temperature).

A solution of Oxone® (0.5 mmol) in aqueous E D T A (5 m L , 4 x lO'" M ) and a solution

of N a H C O s (3.1 mmol) in H2O (5 m L ) were dropped concomitantly via two dropping

funnels. The p R of the mixture was maintained at about 7-7.5 over a period of 12 h.

The reaction mixture was then poured into water (10 mL), extracted with EtiO (3x),

dried with anhydrous magnesium sulfate, and filtered. The filtrate was concentrated

under reduced pressure to give a residue and the residue was purified by flash column

chromatography to give the epoxide.

55

Benzyl p-L-Arabinopyranoside (147)3139

Acetyl chloride (7.5 m L , 109.5 mmol) was added dropwise to B n O H (130 m L , 1.3

mol) which was cooled in an ice-water bath with stirring. Then L-arabinose (25 g,

166.5 mmol) was added and the reaction temperature was raised to rt. The resulting

mixture was vigorously stirred at rt for 5 d. EtiO (500 m L ) was then added to

precipitate the benzyl glycoside that was filtered and the crude white solid washed

with EtiO (100 mL). Recrystallization from EtOH gave glycoside 147 (34.8 g, 87%)

as white crystals: m p 177—178。C; R f Q M (MeOH-CHCls, 5:1); [a]^+210.5 (c 1.2,

D M F ) {lit.,39 m p 172-173。C; [aj^ +209 (c 0.4, H2O)}; IR (thin film) 3280 (OH) c m 、

1h NMR (CD3OD) 7.61-7.48 (5H, m), 5.07 (IH, d,J= 2.3 Hz), 4.92-4.72 (2H, d, J

=12.0 Hz), 4.08-3.98 (4H, m), 3.78 (IH’ dd, J = 12.5, 2.5 Hz); " c N M R (必-DMSO)

3 138.1, 128.0, 127.3, 127.2, 98.9, 69.1, 68.7, 68.4, 68.2, 63.2. M S (EI) m/z 163

(M+-77, 14), 131 (15), 92 (100).

1,2-Bisacetal methyl ester 148

A suspension of glycoside 147 (500 mg, 2.08 mmol) in methanol (15 m L ) containing

2,2,3,3-tetramethoxybutane^^ (492 mg, 2.76 mmol), trimethyl orthoformate (0.9 m L ,

8.23 mmol) and 10-camphorsulfonic acid (49 mg, 10 mol%) was heated under reflux

for 12 h. The cooled reaction mixture was then treated with powdered N a H C O s (0.5

g) and concentrated under reduced pressure. The residue was dissolved in EtOAc and

the solution was washed with sat. N a H C O s solution. The organic layer was dried

over anhydrous MgSCU, and filtered. The filtrate was concentrated under reduced

pressure and the crude residue was purified by flash chromatography (hexane-EtOAc,

2:1) to afford bisacetal 148 as a white solid (560 mg, 76%). Recrystallization from

hexane-EtOAc gave white prisms: m p 140—141。C; [a]^ +5 (c 1.5, CHCI3); Rf 0.45

56

(hexane-EtOAc, 1:1); IR (thin film) 3469 (OH) cm-i; H N M R (CDCI3) 7.42-7.26

(5H, m), 4.95 (IH, d, J= 3.0 Hz), 4.75 (IH, d, 12.3 Hz), 4.67 (IH, d, J= 12.3 Hz),

4.19 (IH, dd, 10.5, 3.0 Hz), 4.14 (IH, dd, J = 10.5, 2.7 Hz), 3.93 (IH, m), 3.82

(IH, dd, J = 12.6, 1.2 Hz), 3.70 (IH, dd, J = 12.6, 1.5 Hz), 3.26 (3H, s), 3.22 (3H, s),

1.85 (IH, brs), 1.33 (3H, s), 1.31 (3H, s); ^C N M R (CDCI3) 5 137.6, 128.2, 127.9,

127.5, 100.2, 96.9, 69.3, 68.1, 65.8, 65.1, 63.0, 47.9, 47.8, 17.8; M S (FAB) m/z

(relative intensity) 377 ([M+Na]+, 25), 323 ([M-OCHs]^ 42), 91 (100); H R M S (FAB)

calcd for CigHieOy [M+Na]+ 377.1591, found 377.1571; Anal. Calcd for C18H26O7: Q

61.00; H , 7.39. Found: C, 60.87; H , 7.43.

1,2-Bisacetal isobutyl ester 149

To a solution of 1,2-bisacetal methyl ester 148 (228 mg, 0.64 mmol) in benzene (20

m L ) containing 2-methyl-l-propanol (190 mg, 2.56 mmol) and /?-TsOH (5 mg) was

heated under reflux with a Dean-Stark trap for 12 h. The cooled reaction mixture was

then treated with saturated N a H C O s and extracted with Et20 (3x). The combined

organic extracts were dried over anhydrous MgSOzt, and filtered. The filtrate was

concentrated under reduced pressure. The crude residue was purified by flash

chromatography (hexane-EtiO, 2:1) to afford bisacetal 149 as a syrup (240 mg, 85%):

[a]'；+13.6 (c 1.2, CHCI3)； i / 0.22 (hexane-Et^O, 2.5:1); IR (thin film) 3449 (OH)

cm.i; i H N M R (CDCI3) 7.40-7.28 (5H, m), 4.98 (IH, d, J= 2.1 Hz), 4.77 (IH, d, J =

12.3 Hz), 4.62 (IH, d, J = 12.3 Hz), 4.24 (2H, m), 3.90 (IH, d, J= 1.8 Hz), 3.81 (IH,

dd, J = 12.6, 1.5 Hz), 3.74 (IH, dd, J - 12.6，1.5 Hz), 3.25-3.15 (4H,m), 1.87-1.82

(2H, m), 1.64 (IH, brs), 1.33 (3H, s), 1.32 (3H, s), 0.95-0.92 (12H, m); ^'C N M R

(CDCI3) (5 138.0, 128.1, 127.2, 127.0, 99.8, 99.7, 97.6, 69.1, 68.2, 66.7, 65.5, 65.2,

57

63.1, 28.6, 19.6, 19.5, 18.5; M S (EI) m/z (relative intensity) 364 (M+—C4H10O, 23),

291 (10); Anal. Calcd for C24H38O7： C, 65.73; H , 8.73. Found: C, 65.68; H , 9.20.

Ulose 150

To a solution of alcohol 149 (170 mg, 0.39 mmol) in dry CH2CI2 (10 m L ) was added

slowly P D C (177 mg, 0.47 mmol) and powdered 3 A molecular sieve (0.17 g). The

mixture was stirred at rt for 12 h. The mixture was suction filtered through a pad of

silica gel and the filtrate was concentrated under reduced pressure to give a crude

syrup. Flash column chromatography (hexane-EtiO, 4:1) gave ulose 150 (161 mg,

95%) as a syrup. [a]o +12.2 (c 1.4, CHCI3)；々0.35 (EtiO-hexane, 3:7); IR (thin film)

1743, 1736 ( 0 0 ) cnfi; H N M R (CDCI3) (5 7.43-7.30 (5H, m), 5.10 (IH, d,J= 3.3

Hz), 5.00 (IH, d, J = 11.1 Hz), 4.83 (IH, d, J = 12.3 Hz), 4.75 (IH, d, J = 12.3 Hz),

4.15 (IH, d, J = 15.9 Hz), 4.09 (IH, dd, J= 11.1, 3.3 Hz), 3.90 (IH, d, J二 15.9 Hz),

3.29-3.16 (4H, m), 1.86-1.81 (2H, m), 1.40 (3H, s), 1.36 (3H, s), 0.93-0.89 (12H, m);

13c N M R (CDCI3) 200.5, 137.3, 128.3, 127.7, 127.2, 100.1, 99.5, 97.1, 70.9, 70.2,

69.9, 67.2, 67.1, 66.9, 28.6, 28.5, 19.6, 19.5, 19.4, 18.3, 18.2; M S (EI) m/z (relative

intensity) 362 (M+-C4H10O, 100), 288 (8). Anal. Calcd for C24H36O7： C, 66.03; H,

8.31. Found: C, 66.19; H, 8.38.

1,2-Bisacetal neopentyl ester 151

To a solution of 1,2-bisacetal methyl ester 148 (125 mg, 0.35 mmol) in benzene (20

m L ) containing neopentyl alcohol (239 mg, 2.7 mmol) and p-TsOR (5 mg) was

heated under reflux with a Dean-Stark trap for 12 h. The cooled reaction mixture was

then treated with saturated N a H C O s and extracted with EtiO (3x). The combined

organic extracts were dried over anhydrous MgS04, and filtered. The filtrate was

58

concentrated under reduced pressure. The crude residue was purified by flash column

chromatography (hexane-EtiO, 4:1) to afford bisacetal 151 as a white solid (141 mg,

87%): m p 1 1 2 - 1 1 3。C; [a]o-0.58 (c 1.44, CHCI3)； R/ 0.28 (hexane-Et�。，4:1); IR

(thin film) 3454 (OH) cm—i; H N M R (CDCI3) (5 7.38-7.25 (5H, m), 4.99 (IH, d, J =

2.1 Hz), 4.77 ( m , d, J = 12.3 Hz), 4.60 (IH, d, J= 12.3 Hz), 4.26 (2H, m), 3.90 (IH,

brs), 3.81 (IH, d, J = 12.6 Hz), 3.74 (IH, dd, J = 12.6, 1.5 Hz), 3.13-3.04 (4H, m),

2.48 (IH, brs), 1.34 (3H, s), 1.33 (3H, s), 0.95 (9H, s), 0.94 (9H, s); ^'C N M R (CDCI3)

d 138.5, 128.5, 127.6, 127.3, 100.3, 100.1, 98.2, 70.7, 69.5, 68.6, 65.9, 63.5, 32.1,

27.4, 18.8; M S (FAB) m/z (relative intensity) 489 ([M+Na]+, 18), 379 (34), 91 (100),

71 (76); H R M S (FAB) calcd for C26H42O7 [M+Na]+ 489.2823, found 489.2846.

Ulose 152

To a solution of alcohol 151 (56mg, 0.12 mmol) in dry CH2CI2 (10 m L ) was added

slowly P D C (55 mg, 0.15 mmol) and powdered 3 A molecular sieve (60 mg). The

mixture was stirred at rt for 12 h. The solution was suction filtered through a pad of

silica gel and the filtrate was concentrated under reduced pressure gave a crude syrup.

Flash column chromatography (hexane-EtiO, 3:1) gave ulose 152 (53 mg, 96%) as

colorless syrup: [aj^ 一5.7 (c 2.83, CHCI3);々0.28 (hexane-EtiO, 1:1); IR (thin film)

1743 ( 0 0 ) cm.i; iH N M R (CDCI3) d 7.41-7.29 (5H, m), 5.11 (IH, d, 3.0 Hz),

4.82 (IH, d, 12.3 Hz), 4.73 (IH, d, J二 12.0 Hz), 4.14 (IH, d, J 二 15.3 Hz), 4.08

(IH, dd, J二 11.1, 3.0 Hz), 3.90 (IH, d, 15.0 Hz), 3.14-3.02 (4H,m), 1.40 (3H, s),

1.36 (3H, s), 0.92 (9H, s), 0.91 (9H, s); 'C N M R (CDCI3) d 201.0, 128.7, 128.0,

127.6, 100.5, 99.9, 97.7, 71.3, 71.0, 70.9, 70.4, 67.6, 32.1, 27.3, 27.3, 18.7, 18.6; M S

(FAB) m/z (relative intensity) 487 ([M+Na]+, 2), 377 (14), 91 (100), 71 (80); H R M S

59

(FAB) calcd for C26H40O7 [M+Na]+ 487.2666, found 487.2680; Anal. Calcd for

C26H40O7： C, 67.22; H , 8.68. Found: C, 67.31; H , 8.31.

Ulose 158

To a solution of alcohol 148 (100 mg, 0.28 mmol) in dry CH2CI2 (10 m L ) was added

slowly P D C (0.18 g, 0.5 mmol), powdered 3 A molecular sieve (0.12 g). The mixture

was stirred at rt for 12 h. The mixture was suction filtered through a pad of silica gel

and the filtrate was concentrated under reduced pressure to give a crude colorless

syrup. Flash column chromatography (EtiO-hexane, 1:1) gave ulose 158 (89 mg,

90%) as a syrup: [af^ +2 (c 4.1, CHCI3); Rf 0.35 (EtOAc-hexane, 1:1); IR (thin film)

1736 (C二O) cm-i; H N M R (CDCI3) d 7.45-7.31 (5H, m), 5.09 (IH, d, J = 3.0 Hz),

4.89 (IH, d, J二 11.1 Hz), 4.81 (2H, s), 4.12 (IH, d, J = 15.0 Hz), 4.09 (IH, dd, J -

11.1, 3.3 Hz), 3.87 (IH, d, J二 15.0 Hz), 3.28 (3H, s), 3.23 (3H, s), 1.38 (3H, s), 1.35

(3H, s); 13c N M R (CDCI3) 200.5, 137.5, 129.0, 128.6, 128.5, 101.0, 100.4, 97.1,

71.5, 70.9, 70.5, 67.6, 48.9, 48.6, 18.2; M S (EI) m/z (relative intensity) 352 (M+, 2),

320 (100); Anal. Calcd for C18H24O7： C, 61.35; H, 6.86. Found: C, 61.83, H, 7.46.

1,2-Bisacetal ethyl ester 159

A suspension of glycoside 147 (500 mg, 2.1 mmol) in ethanol (30 m L ) containing

2,2,3,3-tetraethoxybutane (0.59 g, 2.5 mmol), triethyl orthoformate (1.4 m L ) and 10-

camphorsulfonic acid (10 mg) was heated under reflux for 12 h. The cooled reaction

mixture was then treated with powdered N a H C O s (ca. 0.5 g) and concentrated under

reduced pressure. The crude residue was purified by flash chromatography (hexane-

EtsO, 2:1) to afford bisacetal 159 as a white solid (398 mg, 50%). Recrystallization

from hexane-EtsO gave white prisms: m p 128—129。C; [a]D+19 (c 0.4, CHCI3)； Rf

60

0.30 (hexane-Et20, 1:1); IR (thin film) 3469 (OH) cmfi; H N M R (CDCI3) b 7.42-7.26

(5H, m), 4.97 (IH, s), 4.76 (IH, d, J = 12.6 Hz), 4.66 (IH, d, J = 12.6 Hz), 4.21 (2H,

s), 3.91 (IH, s), 3.80 (IH, d, 12.6 Hz), 3.71 (IH, d, J = 12.6 Hz), 3.53-3.46 (4H,

m)，2.55 (IH, brs), 1.35 (3H, s), 1.33 (3H, s), 1.21 (6H, q, J = 7.8 Hz); ^^C N M R

(CDCI3) 137.9, 128.1, 127.4, 100.1, 99.9, 97.3, 69.1, 68.1, 65.7, 65.2, 63.1, 55.7,

55.6, 18.6, 15.5, 15.4; M S (EI) m/z (relative intensity) 352 (M+—30, 30), 336 (M+—46,

100); Anal. Calcd for C20H30O7： C, 62.81; H, 7.91. Found: C, 63.10; H, 7.93.

Ulose 160

To a solution alcohol 159 (130 mg, 0.34 mmol) in dry CH2CI2 (15 m L ) was added

P D C (154 mg, 0.41 mmol), powdered 3 A molecular sieve (150 g). The mixture was

stirred at rt for 12 h. The mixture was suction filtered through a pad of silica gel and

the filtrate was concentrated under reduced pressure to give a crude colorless syrup.

Flash column chromatography (Et20-hexane, 1:3) gave ulose 160 (110 mg, 85%) as a

colorless syrup: [a]S +8 (c 0.7, CHCI3); Rf 0.45 (EtiO-hexane, 1:1); IR (thin film)

1736 (C二O) cnfi; H N M R (CDCI3) d 7.45-7.31 (5H, m), 5.09 (IH, d, J = 3.3 Hz),

4.96 (IH, d, 11.1 Hz), 4.81 (2H, d, 1.2 Hz), 4.13 (IH, d, J = 15.0 Hz), 4.12

(IH, dd, J = 11.1, 3.3 Hz), 3.89 (IH, d, J二 15.0 Hz), 3.58-3.47 (4H, m), 1.40 (3H, s),

1.36 (3H, s), 1.19 (6H,s); '^C N M R (CDCI3) (5 200.5, 137.2, 128.3, 127.7, 127.4,

100.3, 99.6, 96.9, 71.5, 70.9, 70.1, 69.9, 67.1, 56.1, 56.0’ 18.3, 15.4; M S (EI) m/z

(relative intensity) 352 (M+—EtOH, 100), 288 (12), 91 (91); Anal. Calcd for C20H28O7：

C, 63.14; H, 7.42. Found: C, 63.24, H, 7.68.

61

Methyl p-L-Arabinopyranoside (161)^^

Acetyl chloride (2 m L , 29.4 mol) was added dropwise to M e O H (40 m L , 0.56 mol) at

0。C with stirring. After the addition, L-arabinose (5 g, 33.3 mmol) was added

slowly and the solution was maintained at 0-5� C for 1 h. The resulting mixture was

heated under reflux for 7 h, and then cooled at 0。C overnight. The mixture was

filtered and the crude white solid was recrystallized from EtOH to give glycoside 161

(4.1 g, 75%) as white crystals: m p 168-171。C; [aj^ +241 (c 0.7, D M F ) {lit., ^ m p

169-170。C; [afo。+244 (c 1.7, H2O)}; H N M R (D2O) (5 4.77 (IH, d,J= 1.7 Hz), 3.93

(IH, m), 3.81 (IH, d, 1.7 Hz), 3.78 (2H, m), 3.59 (IH, m ) 3.35 (3H, s); ^'C N M R

(CD3OD) J 102.0, 70.8, 70.7, 70.3, 63.9, 55.8.

1,2-Bisacetal methyl ester 163

A suspension of glycoside 161 (189 g, 1.15 mmol) in methanol (20 m L ) containing

2,2,3,3-tetramethoxybutane^^ (649 mg, 3.65 mmol), trimethyl orthoformate (0.34 m L ,

3.11 mmol) and 10-camphorsulfonic acid (28 mg, 10 mol%) was heated under reflux

for 12 h. The cooled reaction mixture was then treated with powdered N a H C O s (0.5

g) and concentrated under reduced pressure. The residue was dissolved in EtOAc and

the solution was washed with sat. N a H C O s solution. The organic layer was dried

over anhydrous MgS04, and filtered. The filtrate was concentrated under reduced

pressure and the crude residue was dissolved in benzene (20 m L ) and adding with 2-

methyl-l-propanol (256 mg, 3.45 mmol) andi^-TsOH (5 mg) was heated under reflux

with a Dean-Stark trap for 12 h. The cooled reaction mixture was then treated with

saturated N a H C O s and extracted with EtiO (3x). The combined organic extracts were

dried over anhydrous MgSCU, and filtered. The filtrate was concentrated under

reduced pressure. The crude residue was purified by flash chromatography (hexane-

62

Et20, 2:1) to afford bisacetal 163 as a syrup (198 mg, 47%): [af^ —10.7 (c 0.6, CHCI3)；

Rf034 (hexane-Et20, 1:1); IR (thin film) 3434 (OH) cm—】；H N M R (CDCI3) ^ 4.40

(IH, d, 3.3 Hz), 4.20 (IH, dd, 10.5, 3.3 Hz), 4.11 (IH, dd, J二 10.5, 3.0 Hz),

3.90 (IH, d, J = 1.5 Hz), 3.79 (IH, d, J = 12.6 Hz), 3.73 (IH, dd, J = 12.6, 1.5 Hz),

3.39 (3H, s), 3.23-3.14 (4H, m), 2.53 (IH, brs), 1.92-1.79 (2H, m), 1.35 (3H, s), 1.30

(3H, s), 0.93-0.87 (12H, m); '^C N M R (CDCI3) 100.0, 99.8, 98.7, 68.1, 67.1, 66.7,

65.6, 65.2, 62.5, 55.3, 28.6, 28.5, 19.7, 19.6, 19.5, 18.6, 18.5; M S (FAB) m/z (relative

intensity) 385 ([M+Na]+, 12), 289 (32), 100 (53), 87 (60), 57 (100); H R M S (FAB)

calcd for C18H34O7 [M+Na]+ 385.2195, fo皿d 385.2200.

Ulose 164

To a solution of alcohol 163 (193 mg, 0.53 mmol) in dry CH2CI2 (10 m L ) was added

slowly P C C (171 mg, 0.80 mmol) and powdered 3 A molecular sieve (0.20 g). The

mixture was stirred at rt for 12 h. The mixture was suction filtered through a pad of

silica gel and the filtrate was concentrated under reduced pressure to give crude syrup.

Flash column chromatography (hexane-EtsO, 1.5:1) gave ulose 164 (180 mg, 94%) as

a syrup: [a]'。。—12.0 (c 0.6, CHCI3)； i^/0.38 (EtiO-hexane, 2:1); IR (thin film) 1745

(C=0) cm.i; iH N M R (CDCI3) 3 4.88 (IH, d, J = 6.6 Hz), 4.86 (IH, d, J = 7.2 Hz),

4.17 (m, d, J = 14.7 Hz), 4.09 (IH, dd, J = 10.8, 3.3 Hz), 3.93 (IH, d, J = 14.7 Hz),

3.51 (3H, s), 3.27-3.17 (4H’ m), 1.85-1.80 (2H, m), 1.38 (3H, s), 1.35 (3H, s), 0.95-

0.89 (12H, m); 'C N M R (CDCI3) (5 200.3, 100.2, 99.7, 98.2, 70.9, 70.2, 69.9, 67.3,

67.1, 66.6, 56.0, 28.5, 19.7, 19.6, 19.5, 19.4, 18.5, 18.4; M S (CI) m/z (relative

intensity) 360 (M—, 17), 198 (31), 153 (30), 143 (100); H R M S (CI) calcd for C18H32O7

M — 360.2154, fo皿d 360.2146.

63

1,2-BisacetaI ester 165

To a solution of 1,2-bisacetal methyl ester 148 (111 mg, 0.26 mmol) in benzene (30

m L ) containing 2-methyl-2-propen-1 -ol (0.1 m L , 1.2 mmol) and ;?-TsOH (5 mg) was

heated under reflux with a Dean-Stark trap for 12 h. The cooled reaction mixture was

then treated with saturated N a H C O s and extracted with EtiO (3x). The combined

organic extracts were dried over anhydrous MgS04, and filtered. The filtrate was

concentrated under reduced pressure. The crude residue was purified by flash

chromatography (hexane-Et20, 1:1) to afford bisacetal 165 as a colorless syrup (70.5

mg, 64%): [ol'D。+30.1 (c 1.73, CHCI3)； i^/0.32 (hexane-EtaO, 1:1); IR (thin film) 3477

(OH), 899 (C二C) cm-i; H N M R (CDCI3) 7.40-7.26 (5H, m), 5.09 (IH, s), 5.02 (IH,

s), 4.98 (IH, d, J二 2.4 Hz), 4.85 (IH, s), 4.81 (IH, s), 4.77 (IH, d, J = 12.3 Hz), 4.61

(IH, d, J= 12.3 Hz), 4.26 (2H, m), 3.91 (4H, m), 3.81 (IH, dd, J二 12.6, 1.5 Hz), 3.72

(IH, dd,J= 12.6, 1.5 Hz), 2.52 (IH, brs), 1.75 (3H, s), 1.74 (3H, s), 1.40 (3H, s), 1.39

(3H, s); 13c N M R (CDCI3) (5 142.2, 142.1，137.9, 128.1, 127.3, 127.1, 110.6, 110.4,

100.2, 100.1, 97.4, 69.1, 68,1, 65.8, 65.4, 63.9, 63.7, 63.1, 19.7, 18.8; M S (CI) m/z

(relative intensity) 433 ([M—H]—, 8), 293 (80), 219 (100); H R M S (CI) calcd for

C24H34O7 [M—H]— 433.2232, found 433.2226; Anal. Calcd for C24H34O7： C, 66.34; H,

7.89. Found: C, 66.31; H , 7.74.

Dione 166

To a solution of bis-acetal 165 (92 mg, 0.23 mmol), N M O (135 mg, 1.15 mmol), and

OSO4 (2 mg) in 83% aqueous acetone (5 m L ) were stirred at rt for 2 d.^ A solution of

NaI04 (150 mg, 0.70 mmol) in water (2 m L ) was added to the solution and

precipitation occurred." ^ The reaction was stirred for 5 h and was then quenched with

saturated aqueous NaiSiOs. The reaction mixture was stirred for 24 h and was

64

extracted with EtOAc (4x). The combined organic extracts were dried over

anhydrous MgS04, and filtered. The filtrate was concentrated under reduced pressure.

The crude residue was purified by flash column chromatography (hexane-EtOAc, 1:4)

to afford dione 166 as a colorless syrup (60 mg, 64%): [aj^ +11.6 (c 1.15, CHCI3)； Rf

0.31 (hexane-EtOAc, 1:4); IR (thin film) 1738, 1698 ( 0 0 ) cm"】； H N M R (CsDs) d

7.95-7.80 (5H, m), 5.58 (IH, d, J = 3.3 Hz), 5.27 (IH, d, J二 12.0 Hz), 5.06 (IH, d, J

=12.0 Hz), 4.90 (m, dd, J = 13.5, 3.3 Hz), 4.73 (IH, dd, J二 13.5, 3.0 Hz), 4.46 (IH,

s), 4.44 (3H, s), 4.30 (3H,s), 3.00 (IH, s), 2.62 (3H, s), 2.53 (3H, s), 1.93 (3H, s), 1.92

(3H, s); 13c N M R (CDCI3) d 208.2, 206.7,137.9, 128.7, 128.1, 128.0, 100.5’ 100.4,

97.4, 69.9, 68.4, 66.9, 66.5, 65.8, 63.6, 27.3, 27.2, 19.3; M S (FAB) m/z (relative

intensity) 461 ([M+Na]+, 54), 91 (100); H R M S (FAB) calcd for C22H30O9 [M+Na]+

461.1782, found 461.1768; Anal. Calcd for C22H30O9： C, 60.26; H, 6.90. Found: C,

60.39; H , 7.04.

Triol 167

To a solution of M e M g B r in Et20 (3 M, 0.3 m L ) in T H F (10 m L ) at —78。C was added

a solution of dione 166 (200 mg, 0.46 mmol) in T H F (10 mL). After stirring at 一78

oQ for 15 min, the reaction mixture was then quenched by aqueous NH4CI and was

then extracted with EtOAc (3x). The combined organic extracts were dried over

anhydrous MgS04, and filtered. The filtrate was concentrated under reduced pressure.

The crude residue was purified by flash column chromatography (MeOH-CHCls, 1:9)

to afford triol 167 as white solid (165 mg, 77%): m p 123-124。C; [a] ? +10.4 (c 0.62,

CHCI3); Rf 0.24 (hexane-EtOAc, 1:5); IR (thin film) 3402 (OH) cm—i; ^H N M R

(CDCI3) d 7.35-7.26 (5H, m), 4.97 (IH, s), 4.75 (IH, d, J = 12.0 Hz), 4.55 (IH, d, J二

12.0 Hz), 4.31 (2H, brs), 3.98 (IH, brs), 3.86 (IH, d, J = 12.6 Hz), 3.72 (IH, dd, J =

65

12.6, 1.5 Hz), 3.32-3.25 (4H, m), 1.37 (6H, s), 1.28-1.19 (12H, m); 'C N M R (CDCI3)

137.5, 128.4, 127.7, 127.5, 99.7, 97.4, 70.1, 69.9, 69.6, 68.8, 68.7, 68.2, 65.6, 65.1,

63.5, 26.5, 26.3, 26.0, 18.7, 18.6; M S (FAB) m/z (relative intensity) 493 ([M+Na]+,

30), 154 (59), 91 (77), 69 (97), 55 (100); H R M S (FAB) calcd for C24H38O9 [M+Na]+

493.2408, found 493.2414; Anal. Calcd for C24H38O9： C, 61.26; H, 8.14. Found: C,

61.02; H, 8.29.

Ulose 168

To a solution of alcohol 167 (12.4 mg, 0.03 mmol) in dry CH2CI2 (4 m L ) was added

P C C (15 mg, 0.07 mmol) and powdered 3 A molecular sieve (40 mg). The mixture

was stirred at rt for 12 h. The solution was suction filtered through a pad of silica gel

and the filtrate was concentrated under reduced pressure gave a crude syrup. Flash

column chromatography (EtOAc) gave ulose 168 (10.6 mg, 86%) as colorless syrup:

[a]'>10.8 (c 0.53, CHCI3); RfO.24 (EtOAc); IR (thin film) 3376 (OH), 1596 (C=0)

cm-i; H N M R (CDCI3) 7.40-7.29 (5H, m), 5.13 (IH, d,J=11.4 Hz), 5.10 (IH, d, J

=3.0 Hz), 4.82 (IH, d, J = 12.3 Hz), 4.70 (IH, d, J= 12.3 Hz),4.18 (IH, d, J二 14.7

Hz), 4.15 (IH, dd, J = 11.4, 3.0 Hz), 3.90 (IH, d, J = 15.0 Hz), 3.32-3.24 (4H, m),

1.47 (3H, s), 1‘39(3H, s), 1.25-1.17 (12H, m); ^^C N M R (CDCI3) b 199.8, 136.9,

128,5, 128.0, 127.6, 99.9, 99.3, 96.8, 70.7, 70.5, 69.9, 69.8, 69.0, 68.8, 67.2, 26.4,

26.3, 26.1, 25.9, 18.6, 18.5; M S (CI) m/z (relative intensity) 379 ([M—C4H902]+, 100),

307 (64), 159 (78), 91 (20); H R M S (CI) calcd for C24H38O9 [M—。4只902]+ 379.1751,

found 379.1747.

66

^H N M R analysis for enantiomeric excess of the /m«5-a-methylstilbene oxide

aa似-a-Methylstilbene oxide (8 mg) was dissolved in CDCI3 (0.6 mL), shift reagent

Eu(hfc)3 was added until ^H singlet signal at 5 3.98 was splited into two separate

signals around 5 4.30 {ratio of epoxide : Eu(hfc)3 ~ 10 : 1.4 (w/w)}

67

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73

A P P E N D I X

N M R Spectra

1h N M R and ^C N M R spectra of compound 146

1h N M R and ^C N M R spectra of compound 150

1h N M R and ^C N M R spectra of compound 152

N M R and ^C N M R spectra of compound 164

1h N M R and ^C N M R spectra of compound 168

^H N M R and ee measurement of 炉a似-a-methylstilbene oxide

74

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