Synthesis of Carbohydrates and Derivatives from 7 ... - ACS Publications

Chapter

13

Synthesis of Carbohydrates and Derivatives from 7-Oxanorbornenes ("Naked Sugars")

Downloaded by UNIV OF GUELPH LIBRARY on May 21, 2013 | http://pubs.acs.org Publication Date: December 30, 1989 | doi: 10.1021/bk-1989-0386.ch013

Pierre Vogel, Yves Auberson, Mampuya Bimwala, Etienne de Guchteneere, Eric Vieira, and Jürgen Wagner Institut de Chimie Organique de l'Université', 2 Rue de la Barre, CH 1005 Lausanne, Switzerland

The regioselectivity of electrophilic additions of the C=C double bond in 7-oxabicyclo[2.2.1]hept-5-en-2-yl (7-oxanorborn-5-en-2-yl) derivatives depends on the nature of the substituents at C(2). The adducts so-obtained can be transformed into the corresponding 5,6-disubstituted 7-oxanorbornan-2-ones, which can be monosubstituted at C(3) stereoselectively, giving products with the same stereochemical information as hexoses. Thus, optically pure 7-oxanorborn-5-en-2-yl derivatives can be viewed as "naked sugars" Applications to the total, asymmetric syntheses of L-daunosamine, 2-deoxy-L-fucose, D- and L-allose, D- and L-talose, D- and L-ribose, Dand L-methyl 2,5-anhydroallonate, cyclohexenepolyols, (4R,5R,6R)-2-crotonyloxymethyl-4,5,6-trihydroxycyclohex-2-enone, (+)- and (-)-methyl nonactate are presented.

An increasing number of rare, natural, carbohydrate derivatives are being discovered. Some of them show interesting biological properties. Others are part of important molecules such as antibiotics or enzyme inhibitors. Because of their rarity, there is a need to develop synthetic technologies that allow one to prepare them in significant amounts. Furthermore, many unnatural carbohydrate derivatives also show interesting biological activities and thus justify the invention of new synthetic methods for their preparation. Many natural sugars (e.g., D-glactose, D-glucose) are obvious starting materials because they are inexpensive and optically pure. However, structural modification of their skeletons and/or changes in their substitution often requires many protection and deprotection steps that may lead to lengthy procedures of no practical value. Alternatively, more efficient procedures can be envisioned through total, asymmetric synthesis. The concept of "naked sugars" that is presented here is one approach towards that goal. 1

From MO Calculations to the "Naked Sugars" Methyl propynoate adds to 5,6-dimethylidenebicyclo[2.2.1]heptan-2-one (1) with c

0097-6156/89/0386-0197$12.25/0 1989 American Chemical Society

In Trends in Synthetic Carbohydrate Chemistry; Horton, D., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1989.

198

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY

relatively good "para" regioselectivity, giving the major Diels-Alder adduct 2? The results were in agreement with predictions based on FMO theory which considers the HOMO(diene) - LUMO(dienophile) orbital interaction to control the regioselectivity of the cycloaddition. The HOMO of 1 showed a significant difference in the size of the ρ atomic coefficients between those at C(5)=CH and those at C(6)=CH . Furthermore, the shape of this HOMO suggested also an important hyperconjugative interaction of n(CO) oC(l),C(2) 99 % e.e.). (+)-81 and (-)-8I were also obtained by catalytical hydrogénation of the C-C double bond in (+)-7 and (-)-7, respectively. We shall see that (+)-81 and (-)-81 can be transformed in 5 synthetic steps to (+)- and (-)-methyl nonactate, respectively. The sulfoximides 87 and 88 derived from (±)-82 were also readily separated by elution chromatography on silica gel (AR = 0.13) and afforded ketones (+)-82 and (-)-82, respectively, on thermolysis (230 °C/15 Torr). As we shall see, these compounds are starting material for the synthesis of a variety of 50

f

f

36

f


208



natural compounds including D- and L-ribose, D- and L-allose, D- and L-talose, conduritols and COTC (52).

83 (1R,2R,4R)

Ζ = CH=CH

85 (1R,2R,4S)

Ζ = CH -CH 2

2

84 (1S,2S,4S)

Ζ = CH=CH

86 (1S,2S,4R)

Ζ = CH -CH 2

2

88 (1S,2S,4S,5S,6S) Ζ = CH- CH / \ o. o

87 (1R,2R,4R,5R,6R) Ζ = CH- CH / \ Ο .0

The optical resolution of (+)- and (-)-7-oxanorborn-5-en-2-£rtd0-carboxylic acid ((+)-89 and (-)-89) has been accomplished by the use of (+)-(R)- and (-)-(S)-a-methylbenzylamine, respectively. Treatment of (-)-89 with 90 % aq. HCOOH and 35 % H 0 gave lactone 90 (66 %). LiAlH reduction followed by acetylation afforded the triacetate 91. Acetolysis of 91 (Ac 0/AcOH/H S0 , 80 °C, 20 h) gave a mixture of the fully acetylated pseudo-sugars 92 (27 %) and 93 (34 %). Triacetate 91 was also transformed into the protected validamine 94. (-)-89 was the starting material for total syntheses of (+)-pipoxide and (+)-p-senepoxide. 2

2

4

2

2

4

51

52

/6

Jb

Ο

Ο

I COOH

COOH

(+)-89

Ο

(-)-89

AcO ι

\

0

0

AcO

OAc 90

O

A

c

91

.OAc

J

^

\

A c O ^ A ^ ^ \ AcO

AcO AcO

I

OAc

OAc 92

93

NHo

94


13. V O G E L E T AL.

Synthesis from 7-Oxanorbornenes

209

The reaction of 7-oxabenzonorbornadiene 95 with (-)-diisopinocamphenylborane (96) gave the corresponding trialkylborane which, on treatment with acetaldehyde, followed by oxidation with H j O ^ a O H , afforded (+)-(lR,2S,4R)7-oxabenzonorborn-5-en-2-£jcc>-ol (97) in 80 % yield and 100 % enantiomeric purity.


53

95

96

97

Total Synthesis of D- and L-Deoxy-Sugars We present now some applications of the "naked sugars" to the total synthesis of important deoxycarbohydrates. L-Daunosamine (98 3-amino-2,3,6-trideoxy-L/yjttf-hexose) is the carbohydrate component of antitumor anthracycline antibiotics such as Adriamycin and Daunomycin. Several ingenious syntheses of 98 have been reported starting from carbohydrate and noncarbohydrate substrates. The technology described here (Scheme 2) is highly stereoselective and is amenable to large the scale preparation of 98 and of related derivatives such as 2-deoxy-L-fucose (99), the carbohydrate component of a large number of antibiotics. ' 54

55

56

57

58

lb 59

Addition of benzeneselenenyl chloride to camphanate 32 gave adduct 100 in 97 % yield. On treatment with a ten-fold excess of 30 % aqueous H2O2, 100 was oxidized to 101 (92 %). Saponification followed by treatment with formaline yielded the β,γ-unsaturated chloro ketone 102 (99 %). The (-)-camphanic acid was recovered at this stage in 85 % yield. Quantitative and stereospecific hydrogénation of the chloroalkene 102 to the chloro ketone 103 was achieved with diimide. Upon addition of a small excess of t-BuOK to a mixture of ketone 103 and methyl iodide in anhydrous THF, the monomethylated derivative 104 was obtained in 71 % yield. The 360 MHz *H-NMR spectrum confirmed the exo position of the methyl group at C(3) (no vicinal J coupling constant observed between H-C(3) and H-C(4)). Pure 104 was isolated by crystallization from CHC1 at - 20 °C. HPLC of the mother liquor allowed one to isolate 4 - 8 % of a dimethylated derivative. No trace of the eAwfo-monomethyl isomer of 104 could be detected in the reaction mixture. 60

59

3

H H

3


210


Ο

,

C N

PhSeCl

PhSe Ο

CN

(

H.O w

fit.OR*

OR*

2

Ο

R* = (lS)-camphanyl


recycling of chiral auxiliary

OR

Cl

CI 32

CN

2

100

101 KOH

ι

(-)-camphanic acid

fir

+

0

C 1

102

fir - fi& — 0

102

CI

CI

CI 103

d

105

104

ÔMe °

COOH

CI

Me

108

106

KOAc, 18-Cr-6 OMe

r

OH

Me

110

^ÔMe

^ÔMe N

3

AcO^

γ Me 109

Me 111

ι

L-daunosamine HC1

2-deoxy-L-fucose Scheme 2

Baeyer-Villiger oxidation of ketone 104 with metachloroperbenzoic (MCPBA) acid afforded lactone 105 (86 %). There was no detectable trace of the product resulting from oxygen insertion between centers C(2) and C(3). On treatment with acidic methanol, 105 was transformed into a 90:4 mixture of a- and β-acetal-acids 106 (94 %). Treatment with 2 equivalents of M e L i afforded methyl ketone 107 60

61

62


13. V O G E L E T A L .

111

Synthesis from 7- Oxanorhornenes

(63%). Bayer-Villiger oxidation of 107 yielded the desired acetate 108 (85 %) with complete retention of configuration at C(5). Attempts to obtain 108 directly from the acids 106 through oxidative decarboxylation with Pb(OAc) gave low yields of a mixture of acetates. The chloride 108 was displaced in a S 2 fashion ' with NaN (DMF, 120 °C, 12 h) to give the azide 109 (80 %). Catalytic hydrogénation of 109 gave the corresponding free amine which, on ammonolysis, afforded 110 (94.5 %), the methyl furanoside form of L-daunosamine. 110 was transformed to the hydrochloride of L-daunosamine (67 %) on heating with HC1 in aqueous tetrahydrofuran. 63

64

4

566 65

N

66

3

57g


564

CI

CI

112

E = PhSe

114

113

E = PhS

115

Hoping to improve or to shorten our total synthesis of L-daunosamine, we explored the following reactions with 112 and 113, the adducts of the racemic 7-oxanorbornene derivative 47 + 48 to PhSeCl and PhSCl, respectively. Saponification of 112 and 113, followed by treatment with formalin, afforded ketones 114 and 115, respectively. Treatment of with tributyltin hydride in toluene/benzene (ABBN 1 - 2%, 80 °C) gave the key intermediate (±)-103 in 69 % yield. Under the same conditions, 115 was reduced to (±)-103 in 40 - 45 % yield. Raney nickel reduction of 115 afforded (±)-103 in 50 % yield together with 40 % of (±)-7-oxabicyclo[2.2.1]heptan-2-one. However, we found the multistep procedure 3 2 ^ 1 0 0 ^ 1 0 1 — ^ 102 —» 103 easier to scale up. Several intermediates in our synthesis do not have to be isolated. For instance, transfomation of 32 into 102 can be carried out in the same pot in 94 % yield. The "naked sugar" 32 has been transformed into methyl 3-amino-2,3,6trideoxy-/vJC^-L-hexofuranosides (110) in 21.8 % overall yield. The synthesis required the isolation of eight synthetic intermediates. Many of these are potential starting materials for the total synthesis of other natural products. For instance we found that displacement of the chloride 108 with AcOK (0.6 equiv. 18-crown-6 ether, dimethylformamide, 110 °C) gave the diacetate 111 (35 - 40 %, a precursor of 2-deoxy-L-fucose (99). 2-Deoxy-L-fucose has been derived from other carbohydrates or by using tartaric acid as starting material. Chmielewskf reported a synthesis of 2-deoxy-DL-fucose starting with the Diels-Alder addition of 1- methoxybutadiene to tertiobutyl glyoxalate. The first total synthesis of 2- deoxy-D-fucose has been presented by Rous h and Brown. It is based on the enantioselective S harp less epoxidation of allylic alcohols. Using our " naked sugar" 38 (derived from furan and (+)-(lR)-camphanic acid) instead of 32, the method outlined in Scheme 2 realizes a second total, asymmetric synthesis of 2-deoxy-D-fucose. Similarly, D-daunosamine can be derived from 38. 67

68

69

70

71

72

73

15

76


4


212


The technology described in Scheme 2 is highly stereoselective, and the asymmetry is induced by commercially available chiral auxiliaries that are recovered at an earlier stage of the synthesis. Furthermore, it permits one to obtain the deoxysugars in both their fiiranose and pyranose form. It exploits the high stereoselectivity of the electrophilic additions of 7-oxanorborn-5-en-2-yl derivative 38 that give exclusively adducts where the electrophile (E) sits in the exo position of center C(6) and the nucleophile (X) at the endo position of center C(5) (32 + EX —> 33, see Scheme 1). This high regioselectivity was attributed to the electronwithdrawing effect and/or to the bulk of the substituents at C(2). Ketone (+)-7 (derived from 32) adds electrophilic agents onto its homoconjugated double bond with opposite regioselectivity (giving exclusively adducts 34, see Scheme 1). This was attributed to the electron-donating ability of the carbonyl group. We are exploring the application of that principle in a new approach to the total, asymmetric synthesis of D-lividosamine (116 : 2-ammo-2,3-dideoxy-D-nfo?-hexopyranose) a component of antibiotics Lividomycins A and B . Our preliminary results are presented in Scheme 3. l b

79

fir*^vv-vy ci

(+)-7

Ο

Cl

119

120 Ο

Ο OH OCOAr OSiMe tBu 2

121

Ο Q

OH

122

123

I j w OMe

>

Ο ^jjL^ C 1

COOMe OH

124

Scheme 3 Benzeneselenyl chloride added to (+)-7 and gave adduct 119 nearly quantitatively. Treatment with N-methvl-N-tertbutyldimethvlsilvltrifluoroacetamide and triethylamine (dimethylformamide, molecular sieves, 40 °C, 15 h) afforded enol ether 120 in high yield (>90 %). Oxidation with an excess of MCPBA gave 121


13.

VOGEL ET AL.

213

Synthesis front 7-Oxanorbornenes

resulting from oxidative elimination of the benzeneselenyl group and epoxidation of the enol ether. Catalytical hydrogénation of 121, followed by treatment with K C 0 in methanol furnished 122. Baeyer-Villiger oxidation of 122 with MCPBA afforded 123. Attempts to displace the chloride in 123 and in 124 (obtained by acidic methanolysis of 123) led to epimerization of the alcohol. Studies are underway in our laboratory to explore the transformation of 124 into 118 which, by analogy with our synthesis of L-daunosamine (Scheme 2), should allow one to obtain the methyl furanoside of D-lividosamine. Several syntheses of D-lividosamine and its derivatives have already been reported. They use carbohydrates ' or optically pure but-3-ene-l,2-diol as starting materials. 2

3

78 80


81

Total Synthesis of D- and L-AUose, D- and L-Talose and of D- and L-Ribose Derivatives 47

In their pioneering work, Just and co-workers have described many interesting transformations of the Diels-Alder adducts of furan to methyl nitroacrylate (77 + 77') and to dimethyl acetylenedicarboxylate (53). The mixture of racemic adducts 77 + 77' was hydroxylated into the exo-cis-diols 125 + 125', separable by crystallization. Treatment of the isopropylidene acetal obtained from 125 with diazabicyclo[5.4.0]undec-5-ene (DBU) gave a high yield of alkene 126. Ozonolysis followed by a reductive work-up with dimethylsulfide, then with NaBH , gave a mixture of epimeric triols 127. Cleavage with sodium periodate afforded 2,5-anhydro-3,4-0-isopropylidene-DL-allose (128) in 15 % yield, based on methyl 2-nitroacrylate used. The same allose derivative was obtained from adduct 53. ' 4

47

128

129

130

131


82

214

TRENDS IN SYNTHETIC CARBOHYDRATE CHEMISTRY 83

Lactol 128 has been converted into a variety of racemic C-nucleosides. The unstable aldehyde 130 was prepared from 128 by way of oxazolidine 129. Lactone 131 was also derived from 128 and used as starting material in the synthesis of racemic C-nucleosides. Adducts 77 + 77' were transformed into epoxide 132. Opening of the epoxide, followed by ozonolysis and reduction allowed one to Ε Ε 8215


84

OR 132

OAc

133

Ε = COOMe

134

135

R = tBuMe Si 2

prepare the keto-ester 133. The latter was applied in the synthesis of DL-2-epi~ showdomycin, and also of DL-2-ep/-pyrazofurin A. Similarly, adduct 77 was transformed into keto-ester 135 via acetate 134. 135 was applied in the synthesis of DL-2-deoxyshowdomycin. Inspired by the work of Just *'*'* '* and others ' ' we converted our "naked sugar" 32 into optically pure, protected methyl 2,5-anhydro-D-allonates 140, 145, the acetal 141 and lactones 131 and 146 (Scheme 4). These systems are potential precursors for the total asymmetric synthesis of C-nucleosides. ' Stereospecific cis-hydroxylation of 32 with H 0 and a catalytic amount of O s 0 gave diol 136 which was isolated in the form of the corresponding acetonide 137 (65%) using acetone, 2,2-dimethoxypropane and para-toluenesulfonic acid in the work-up. Saponification of 137 (KOH/H 0/THF), followed by treatment with formalin gave ketone 138 (92 %) and pure (-)-camphanic acid (83 %). Treatment of 138 with tBuMe SiN(Me)COCF and NEt in DMF (40 °C, 12 h) afforded the silyl enol ether 139 (85 %). Ozonolysis in MeOH/CH Cl at -70 °C, followed by reduction with NaBH (-70 °C, 1 h; then -10 °C, 30 min), acidification (pH = 3, HCl/MeOH), and treatment with diazomethane furnished 140 (65 %). Under more acidic work-up conditions and without addition of CH N , lactone 131 was isolated as the major product. Ozonolysis of 139, followed by acidic work-up (HCl/MeOH) afforded the dimethylacetal derivative 141 (65 %). Protection of diol 136 by tBuMe Si groups gave 142 which was transformed, as above, into methyl 2,5-anhydroallonate 145 (73 %) via the synthetic intennediates 143 and 144. The corresponding lactone 146 (65 %) was also derived from 144. Silyl enol ether 139 has also been transformed into D-allose, as shown in Scheme 5. The same methods can be applied to the enantiomeric enol ether derived from camphanate 38, and this allows one to prepare L-allose and its derivatives. Oxidation of 139 with MCPBA in THF (20 °C) led to the product of epoxide acidolysis 147 (69 %) which yielded 148 on heating to 200 °C for 15 min. Addition of 1.1 equiv. of MCPBA converted 148 into lactone 149 which in the presence of MeOH and K C 0 (20 °C), gave selectively diester 150. Reactions 147 20a

20

2

19

4

20c

d

85 86 87

2

2

4

2

2

3

3

2

2

4

2

2

2

88

89

90

2

3


13. VOGELETAL. 0

Synthesisfrom7-Oxanorbornenes

™

RO Ο

OR*

RO

^

32

215 0

OR*

136 R = Η

138 R,R = Me C 2

137 R,R = Me C 2

RO

Ο

I

,

142 R = tBuMe Si

143 R = tBuMe Si


2

2

139 R,R = Me C 144 R = BuMe Si 2

2

OMe

140 R,R = Me C

141

2

146

145 R = tBuMe Si 2

Scheme k

—» 148 —» 149 —» 150 were carried out in "one-pot" with an overall yield of 78 %. The methyl furanoside 151 (92 %) was obtained on acidic methanolysis of 150. Reduction of 151 with 4.2 equiv. of LiAlH (THF, 20 °C, 15 min) afforded 152 (71 %). Acidic hydrolysis (2 % H S 0 in H 0 , 100 °C, 2 h) of 152 gave D-allose. L-allose was prepared in the same manner starting with 38. In the presence of 1.1 equiv. of Br in CH C1 (-50 °C), 139 gave the a-bromoketone 153 (78 %). Baeyer-Villiger oxidation of 153 with CF C0 H (CH C1 , Na HP0 , 20 °C) afforded lactone 154 (85 %). As for reaction 148 -» 149, the oxidation was highly selective yielding exclusively the product of oxygen insertion between the bridgehead center C(l) and the carbonyl group. Methanolysis of 154 in MeOH saturated with K C 0 (20 °C, 45 min) gave 155 (95 %). The reaction implies the intermediacy of hemiacetal 156 which, in the presence of a base (K C0 ) undergoes intramolecular S 2 displacement of the bromide giving 155. This hypothesis was confirmed by the isolation of 156 when 154 was treated with MeOH at 20 °C containing a small amount of NaHC0 . 156 afforded 155 on treatment with MeOH and K C 0 . Reduction of 155 with LiAlH (THF, 20 °C) gave l,4-anhydro-2,3-0-isopropylidene-ia/i?pyranose (157) in 82 % yield (for analogous 1,4-anhydropyranoses, see reference 93). Treatment with 1 Ν HC1 (20 °C, 4 d) afforded L-talose. D-talose and its derivatives can be obtained in the same 4

91

92

2

4

2

91

2

2

2

3

2

2

2

4

2

2

3

3

N

3

2

3

4

94


3

216



156

L-talose Scheme 6


13. VOGELETAL

in

Synthesis from 7-Oxanorbornenes

manner starting with the "naked sugar" 38 derived from furan and (lR)-camphanic acid. (See Scheme 6.) The best syntheses of D-ribose (an important component of nucleic acids, polysaccharides, nucleosides, vitamins, co-enzymes and many antibiotics, etc.) use natural, optically pure starting materials. Stroh and co-workers on one hand, and Kiss and co-workers on the other hand, transformed D-glucose into D-ribose in five synthetic steps in 24 % and 18.1 % global yield, respectively. Yamada and co-workers transformed L-glutamic acid into a 2.7:1 mixture of methyl 5-0-benzyl-2,3-0-isopropylidene-p-D-n7?i?furanoside and methyl 5-

Synthesis of Carbohydrates and Derivatives from 7 ... - ACS Publications

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