Stereoselective synthesis of myo-, neo-, L-chiro, D-chiro, allo-, scyllo-, and epi-inositol systems via conduritols prepared from p-benzoquinone

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Stereoselective Synthesis of myo-, neo-,

L

-chiro, -chiro, allo-, scyllo-, and

D

epi-Inositol Systems via Conduritols Prepared from p-Benzoquinone

Michael Podeschwa,^[a]Oliver Plettenburg,^[a]Jochen vom Brocke,^[a]Oliver Block,^[a]

Stephan Adelt,^[b]and Hans-Josef Altenbach*^[a]

Keywords: Natural products / Asymmetric synthesis / Chiral resolution / HPIC-IPAD

A practical route is described for the flexible preparation of

enzymatic resolution of a derived conduritol B key interme-

a wide variety of inositol stereoisomers and their polyphos- diate. High-performance anion-exchange chromatography

phates. The potential of this approach is demonstrated by the

synthesis of myo-, -chiro-, -chiro-, epi-, scyllo-, allo-, and

neo-inositol systems. Optically pure compounds in either en-

antiomeric form can be prepared from p-benzoquinone via

with pulsed amperometric detection permits inositol ste-

reoisomers to be resolved and detected with high sensitivity.

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2003)

L

D

Introduction

zymes which possess remarkable features for chemoenzym-

atic preparation of defined inositol phosphate isomers. A

summary of the occurrence and possible functions of inosi-

tol stereoisomers is given in the following paragraphs.

Inositols (hexahydroxycyclohexanes) and their derivatives

are widespread in nature and have various biological func-

tions.^[1,2,3]myo-Inositol phosphates in particular represent

a large family of naturally occurring compounds which have

been intensively studied during the last two decades because

of their considerable role in cell signaling and homeost-

asis.^[4,5,6]Since cellular concentrations of myo-inositol phos-

phates are low and a fast metabolic interconversion occurs,

practical synthetic approaches to inositol phosphates are a

prerequisite to further elucidation of their biological ac-

tivity.

One important way to gain a better understanding of the

metabolism and to study structureϪactivity relationships is

the examination of specific stereoisomeric inositols (see Fig-

ure 1). For this reason there is an increasing demand for

practical and efficient synthetic methods for preparing not

only naturally occurring inositols but also diastereomers

and their analogues. Although myo-inositol systems are by

far the most abundant in living nature, several other inositol

isomers have been detected; in most cases, however, their

function remains unknown. We were attracted to the syn-

thesis of stereoisomers of myo-inositol because of our ongo-

ing study of the regiospecificity of phosphohydrolases.^[7]

Hexaphosphorylated inositol stereoisomers can serve as

tools for exploring the structural requirements for dephos-

phorylation of phytases and other phosphohydrolases, en-

Figure 1. Stereoisomeric inositols

neo-Inositol 2: This was first isolated as a by-product of

the synthesis of -chiro-inositol from 1,2:5,6-di-O-isopro-

pylidine--chiro-inositol.^[8]neo-Inositol hexakis(phosphate)

has been recognized as a constituent of soil, in which it is

often accompanied by larger amounts of myo- and scyllo-

inositol hexakis(phosphates).^[9]It has been shown that En-

tamoeba histolytica, a human intestinal parasite that causes

[a]

Institut für Organische Chemie, Bergische Universität

Wuppertal,

Gaussstrasse 20, 42097 Wuppertal, Germany

Fax: (internat.) ϩ49-(0)202-439-2648

E-mail: orgchem@uni-wuppertal.de

[b]

Institut für Biochemie, Bergische Universität Wuppertal,

Gaussstrasse 20, 42097 Wuppertal, Germany

1958

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

DOI: 10.1002/ejoc.200200572

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Inositol Systems via Conduritols Prepared from p-Benzoquinone

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amebiasis, contains high levels of several neo-inositol poly-

phosphates.^[10]-neo-Inositol-1-phosphate has been found

in micromolar concentrations in the brain, heart, testes, and

spleen of rat.^[11]The most recent stereoselective synthesis of

neo-inositol has been described by Hudlicky et al.^[12]in a

synthetic route requiring seven steps.

-chiro 5 and -chiro-Inositol 4: Derivatives of chiro-in-

ositol have recently been shown to mediate many important

biological processes. For example, -pinitol (3-O-methyl--

chiro-inositol), an active component of the traditional anti-

diabetic plant Bougainvillea spectabilis, is claimed to possess

insulin-like properties.^[13]The phosphoinositolglycans gen-

erated in rat liver in response to insulin stimulation were

reported to contain exclusively or predominantly chiro-in-

ositol.^[14]-chiro-Inositol itself has been observed in re-

duced urinary excretion of rhesus monkeys and humans

with impaired glucose tolerance, insulin resistance and type

2 diabetes mellitus.^[15]

Figure 2. Stereoisomeric conduritols

especially valuable precursors, as the cis-dihydroxylation or

epoxidation of the double bond leads to a single dia-

stereomer.

allo-Inositol 3: This has not yet been found in nature; it

was first synthesized in 1939 by Dangschat and Fischer.^[16]

Other syntheses have since been reported.^[17]

epi-Inositol 7: Shaldubina and co-workers showed that

epi-inositol, another ‘‘non-natural’’ isomer, has the ability

to modify the expression of the yeast INO1 gene encoding

Results and Discussion

We have chosen a synthetic strategy for the synthesis of

the myo-inositol-3-phosphate synthase.^[18]epi-Inositol is all chiral inositols in enantiomerically pure forms because

thus biologically active in its ability to affect the regulation the biological activities of these compounds and their phos-

of the myo-inositol biosynthetic pathway. myo-Inositol phate derivatives, especially their role in signal transduction,

phosphates, especially myo-inositol 1,4,5-trisphosphate can only be studied with enantiomerically pure phosphate

[myo-Ins(1,4,5)P₃], act as intracellular second messen- derivatives.

gers.^[19]Binding of myo-Ins(1,4,5)P₃to its endoplasmic re-

Previous work led us to believe that the known enantiom-

ticulum receptor (ERR) induces the release of calcium from erically pure diacetoxy-dibromocyclohex-5-ene (ϩ)-16 and

intracellular stores. Its closely related structure suggests that (Ϫ)-16 [or the corresponding diols (Ϫ)- and (ϩ)-17], which

epi-Ins(1,4,5)P₃49 may also have a high affinity for this re- can easily be obtained from p-benzoquinone in four steps

ceptor.

on multigram scale, would be appropriate starting materials

scyllo-Inositol 6: This has been found in animals and for the preparation of various conduritols.^[26]Our synthetic

plants,^[20]and it has been suggested that certain human dis- concept is based on the stereospecific conversion of the

eases are associated with scyllo-inositol depletion.^[21]

building blocks (ϩ)-16 and (Ϫ)-16 into suitably protected

Many syntheses of inositol isomers either start from en- enantiomerically pure conduritol derivatives, which can

antiomerically pure natural substances, particularly carbo- subsequently be transformed to inositol isomers by simple

hydrates,^[22]or involve resolution and stereospecific pro- functionalization of the double bond. Thus a single estab-

cesses starting from inexpensive myo-inositol.^[23]Some de lished enzymatic resolution can be used for the preparation

novo concepts have also been described, for instance based of a wide variety of conduritol and inositol isomers. In this

on microbial oxidation of bromobenzene^[12]or on genera- paper we describe a new synthetic methodology leading to

tion of the cyclohexene ring by ring-closing metathesis and conduritol E, conduritol C, conduritol F and conduritol B

further functionalization of the derived conduritol (5-cyclo- derivatives from enantiopure diacetate 16.

hexene-1,2,3,4-tetrol, see Figure 2) systems.^[24]Such stra-

tegies, however, often allow access to only one enantiomeric thesis of meso-compounds (1, 2, 3, 6, and 7) all routes can

series and also require tedious multistep sequences. likewise be carried out employing racemic 16 and 17,

To avoid confusion we should mention that, for the syn-

In this paper we present easy and flexible syntheses of respectively. As well as the benefits of a shortened synthetic

different inositols, with the potential to produce both en- route, this facilitates purification by recrystallization, since

antiomers in the case of chiral systems. The key intermedi- the racemic intermediates show an increased tendency to

ates of our concept are conduritol B, E, and C derivatives crystallize. We performed the synthetic sequences with en-

(see Figure 2). Conduritols and their derivatives have them- antiomerically pure starting material to provide the maxi-

selves remarkable biological properties, as they can act as mum analytical data and to use the full potential of the

inhibitors of glycosidases.^[25]Besides their pharmacological strategy for the enantiospecific synthesis of chiral deriva-

potential, they are useful precursors for the syntheses of tives. The intermediates presented can be used as valuable

inositols by stereoselective functionalization of the double inositol building blocks, as their hydroxy groups are pro-

bond. Because of their C₂-symmetry, conduritol B or E are tected in an orthogonal way. Besides the examples shown in

Eur. J. Org. Chem. 2003, 1958Ϫ1972

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M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

this article, we have used the methodology to derive other

neo- and myo-inositol phosphates, synthetic details are dis-

cussed in ref.^[27]and in ref.^[7]However, this concept is cer-

tainly not limited to the given examples and should prove

valuable for the preparation of further compounds.

Synthesis of conduritol E systems: Retrosynthetic con-

siderations showed that conduritol E derivatives should be

suitable precursors for the synthesis of neo-inositol. Treat-

ment of the diol (ϩ)-17 with DBU and CO₂(see Scheme 1)

afforded conduritol E bis-carbonate 19 in 30% yield along

with the monocarbonate (Ϫ)-18.

Scheme 1. Preparation of the monocarbonate (Ϫ)-18; reagents and

conditions: DBU, THF, CO₂, Ϫ50 °C, stirring for 2 h (Ϫ)-18: 92%,

19: 0%; stirring for 12 h (Ϫ)-18: 60%, 19: 30%

The low yield, purification problems, difficulties in sca-

ling the reaction up and the extremely low solubility of 19

made it necessary to change the protection groups to acet-

Scheme 2. Preparation of neo- 2 and -chiro-inositol 4; reagents

and conditions: (a) 1. NaOAc, AcOH (95%), 10 days, 125 °C; 2.

Ac₂O, CH₂Cl₂, DMAP (cat.). (b) (CF₃CO)₂O, H₂O₂, CH₂Cl₂,

ates. We therefore tried to find a direct conversion of the NaHCO₃. (c) Ac₂O, pyridine. (d) NaOMe, MeOH, then water/

NaOH. (e) 1. (1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)di-

diacetate (ϩ)-16 into the conduritol E (ϩ)-21, as no easy

and inexpensive large-scale conversion of (ϩ)-16 into (ϩ)-

21 has been reported yet. The first synthesis of racemic con-

duritol E from p-benzoquinone was described by Balci et

al.^[28]in 1992 and involves five steps from 17. Haines and

co-workers^[29]tried to generate 21 directly from 16 by heat-

ing it in aqueous acetic acid and potassium acetate for 24 h,

but only 1,2,4-triacetoxy-3-bromocyclohex-5-ene 20 was

isolated. The key intermediate in this reaction is an ace-

toxonium species. We thought that under appropriate con-

ditions this intermediate should lead to conduritol E deriva-

tives; namely, if the reaction were carried out in the pres-

ence of a sufficient amount of water, the diacetoxonium in-

termediate should direct the reaction towards the

Woodward product.^[30,31]We first tried this reaction under

more forcing conditions by heating in aqueous acetic acid

in the presence of silver acetate for 72 h. After acetylation

under these conditions only (ϩ)-21 could be be detected by

NMR spectroscopy. The low yield [less than 30%, which is

presumably due to oxidation of allyl alcohol by silver()]

and also the high price of silver acetate, which made this

reaction unattractive for large-scale synthesis, made us look

ethylamine, 1H-tetrazole, acetonitrile, then m-CPBA; 2. Pd/C, H₂,

ethanol/water. (f) NaOBn, BnOH/THF. (g) (CF₃CO)₂O, H₂O₂,

CH₂Cl₂, Na₂CO₃. (h) H₂SO₄, dioxane, H₂O. (i) Pd/C, H₂, ethanol/

water. (j) RuCl₃, NaIO₄, acetonitrile

Enantiopure

1,2,4-triacetoxy-3-bromocyclohex-5-ene

(ϩ)-20 was found to be an intermediate in this reaction and

could easily be isolated in 85% yield if the reaction was

stopped after three days (see Scheme 3).

Scheme 3. Preparation of conduritol F derivative (ϩ)-22; reagents

and conditions: (a) 1. NaOAc, AcOH (95%), 3 days, 110 °C;

2. Ac₂O, CH₂Cl₂, DMAP (cat.); (b) NaOBn, BnOH

Synthesis of conduritol F systems: Synthesis of the con-

for alternatives. We were delighted to find that conduritol E duritol F derivative 22 could be effected by treatment of

could be obtained from (ϩ)-16 in aqueous acetic acid and (ϩ)-20 with an excess of sodium benzylate at room tem-

sodium acetate simply by longer heating (10 days).

perature by base-induced epoxide formation and sub-

After acetylation and purification, (ϩ)-21 was obtained sequent ring opening at the allylic position (see Scheme 3).

in 70% yield as the only isomer detected by NMR spec- Chromatography of the crude reaction mixture on silica gel

troscopy. The enantiomeric purity of this conduritol E gave (ϩ)-22 as a colorless solid in 66% yield. Since cis-dihy-

tetraacetate was checked by chiral HPLC and found to be droxylation of 22 would lead predominantly to chiro-inosi-

Ͼ 99% (see Scheme 2).

tol derivatives, which are also available by the route de-

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Inositol Systems via Conduritols Prepared from p-Benzoquinone

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scribed in Scheme 2, we did not carry out this reaction. ring under acidic conditions opens selectively to form only

However, this sequence allows access to chiro-inositol de- the trans-diaxial product, the chiro-isomer (Ϫ)-32. Hydro-

rivatives bearing a different protection group pattern. This genation of the dibenzyl chiro-inositol (Ϫ)-32 gives the free

may be of interest if the synthesis of specific derivatives is chiro-inositol (Ϫ)-4 as a colorless solid.

desired.

Considering the newly developed successful synthetic

Synthesis of allo-inositol systems: The inherent C₂-sym- route to conduritol E 21, it should be possible by means of

metry of the conduritol E (ϩ)-21 makes it an ideal precur- an analogous method in the absence of water to synthesize

sor for chiral allo-inositol systems (see Scheme 4). cis-Dihy- conduritol B tetraacetate 37 in one step. We used a method

droxylation leads only to the allo-configuration, regardless reported by Stegelmeier, in which racemic diacetate 16 was

of the direction of attack by the hydroxylating reagent, and converted into conduritol B 37 by heating under reflux in

is carried out by reaction of conduritol E (ϩ)-21 with ru- acetic acid/acetic anhydride in the presence of silver acet-

thenium trichloride and NaIO₄in acetonitrile. Deprotection ate.^[34]In this reaction the acetoxonium intermediate un-

of (ϩ)-23 by treatment with a catalytic amount of sodium dergoes ring opening by attack of acetate anions exclusively

[35]

´

methoxide in methanol leads to pure allo-inositol 3 in 83% at the allylic centers to form the Prevost product. Carry-

yield on multigram scale.

ing out the reaction with enantiomerically pure (ϩ)-16 led

to the conduritol B tetraacetate 37 as the only product

(Scheme 5). The NMR spectroscopic data showed a pure

product; however, the observed optical rotation was suspect

with [α]²_D⁰ϭ Ϫ54.1 (c ϭ 1.2, CHCl₃). Trost^[36]and Ley^[37]

have reported substantially higher values for (Ϫ)-32

{[α]²_D⁰ϭ Ϫ172.8 (c ϭ 1.28, CHCl₃) and [α]²_D⁰ϭ Ϫ70 (c ϭ

0.85, CHCl₃)}. The isolated product was analyzed by chiral

HPLC (chiracell ODH, heptane/2-propanol, 95:5) and in

Scheme 4. Preparation of allo-InsP₆24; Reagents and conditions:

(a) RuCl₃, NaIO₄, acetonitrile. (b) NaOMe, MeOH. (c) 1. (1,5-di-

hydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine,

1H-tetra- accordance with the measured low optical rotation it indi-

zole, dichloromethane then m-CPBA; 2. Pd/C, H₂, ethanol/water

cated an enantiomeric excess for (Ϫ)-37 of only 24%. The

reason for this result may be that besides S_N2-attack (open-

ing in the allylic position) there is some S_NЈ-attack (1,4-

Synthesis of neo-inositol systems (see Scheme 2): Oxi- attack) which occurs for steric reason from the back side to

dation of (ϩ)-21 with trifluoroperacetic acid gave conduri- form the opposite enantiomer (ϩ)-37 and leads to partial

tol E epoxide (ϩ)-25, which could be isolated for analytical racemization.

purposes in 24% yield, besides epoxide-opening products.

More forcing conditions effected complete in situ hydroly-

sis, the neo-inositol isomer being the only product detected.

Hydrolysis of (ϩ)-26 or 27 with a catalytic amount of so-

dium methoxide in methanol was unsatisfactory because 2

precipitated along with some unsaponified material. Full

deprotection was accomplished by refluxing the resulting

precipitate in aqueous NaOH. Even in boiling water the

solubility of 2 is very low.^[32]Thus neo-inositol can easily

be purified by recrystallization from water.

Synthesis of conduritol B systems: It is well known that

diacetate (ϩ)-16 can be used for the preparation of conduri-

tol B derivative (Ϫ)-29 (see Scheme 2).^[7]The reaction is

carried out by heating (ϩ)-16 with an excess of sodium ben-

zylate in anhydrous THF. The intermediate epoxides are

opened with benzylate anion at the allylic position and form

the conduritol B derivative (Ϫ)-29 in over 80% yield.

Synthesis of myo-inositol systems: Compound (Ϫ)-29 has

served as a valuable precursor for the synthesis of myo-in-

ositol derivatives. A fast cis-dihydroxylation of (Ϫ)-29 with

RuCl₃/NaIO₄gives compound (Ϫ)-30 with myo-inositol

stereochemistry. The potential of C₂-symmetric intermedi-

ates in myo-inositol phosphate synthesis has been exploited

several times.^[7]

´

Scheme 5. Preparation of the Prevost product 37 from diacetate

(ϩ)-16; reagents and conditions: (a) AgOAc, absolute AcOH/Ac₂O,

1 day, 125 °C

Synthesis of chiro-inositol systems: Because of the C₂-

symmetry, epoxidation of the conduritol B derivative (Ϫ)-

Synthesis of scyllo-inositol systems: We were pleased to

29 gives only one product, (Ϫ)-31 (see Scheme 2). In ac- see that the regioselectivity of the epoxide opening of 31

cordance with the ‘‘FuerstϪPlattner rule’’^[33]the oxirane could be controlled by careful choice of reaction conditions

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M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

and protection groups. We observed that derivative 38 bear-

ing a cyclic isopropylidene group in the 5 and 6 position

showed inverted regioselectivity on epoxide opening, lead-

ing mainly to the scyllo isomer 39 (see Scheme 6). Upon

opening with several O-nucleophiles, for instance allyl al-

cohol or methanol, we were able to isolate the correspond-

ing inositols in good yield. After epoxide opening with allyl

alcohol followed by deprotection with acid we obtained the

pure scyllo isomer 39 in 60% yield after recrystallization. In

the case of methanol as the nucleophile, the scyllo/chiro ra-

tio was determined to be 95:5 (by GC, products detected

as acetates).

Scheme 7. Preparation of epi-inositol; Reagents and conditions:

(a) RuCl₃, NaIO₄, acetonitrile. (b) Ac₂O, pyridine. (c) Zn, Et₂O,

AcOH. (d) 1. RuCl₃, NaIO₄, acetonitrile; 2. Ac₂O, pyridine. (e)

NaOMe, MeOH

Interestingly, cis-dihydroxylation of conduritol C tetra-

acetate (Ϫ)-43 with RuCl₃/NaIO₄resulted predominantly in

epi-inositol stereochemistry. The observed high diastereo-

selectivity (80% de) may be caused by the axial acetate

group, which might be a Lewis donor for the ruthenium

complex. To avoid protecting-group movement, the product

was converted directly into the hexaacetate 44, whose dia-

stereomeric ratio was determined. Recrystallization from

ethanol led to pure 44, which was deprotected under stand-

ard conditions.

Scheme 6. Synthesis of scyllo-inositol; Reagents and conditions:

(a) 2,2-dimethoxypropane, acetone, PPTS. (b) 1. NaOAll, AllOH,

90 °C. 2. HCl. (c) 1. Pd/C, MeOH; 2. HCl, 3. Pd/C, H₂. (d) 1. (1,5-

dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine, 1H-tetra-

zole, dichloromethane, then m-CPBA; 2. Pd/C, H₂, ethanol/water

As an example of the opportunities provided by this con-

cept for the synthesis of enantiomerically pure epi-inositol

derivatives, we describe the synthesis of epi-Ins(1,4,5)P₃

(ϩ)-49 (see Scheme 8).

The regioselectivity of the epoxide opening of 38 seems

to be in contrast to the ‘‘FuerstϪPlattner Rule’’, which ap-

plies for a cyclohexene epoxide in chair conformation.^[33]It

is likely that the strain of the cyclic isoproylidene ring favors

reaction via a twist intermediate (see Figure 3), which is the

preferred conformation of 38 according to molecular

modeling with HyperChem. 5.01 (TM of Hypercube Inc;

the calculation was performed with a semiempirical AM1

method as algorithm).

Figure 3. Model of isopropylidene-protected epoxide 38 in a twist

conformation; for better view the OBn groups are replaced with R

Acidic workup of the epoxide-opening reaction left the

allylic group intact. Therefore, isomerization of the double

bond was induced by palladium on charcoal, followed by

acidic cleavage of the resulting enol ether. Finally, hydro-

genation led to the desired scyllo-inositol 6 in 85% overall

yield from 39.

Scheme 8. Preparation of epi-Ins(1,4,5)P₃(ϩ)-49; Reagents and

conditions: (a) 1. CH₃C(OEt)₃, THF, pTsOH; 2. AcOH (80%).

(b) Zn, Et₂O, AcOH, I₂. (c) (1,5-dihydro-2,4,3-benzodioxaphos-

phepin-3-yl)diethylamine, 1H-tetrazole, CH₂Cl₂then m-CPBA.

(d) 1. RuCl₃, NaIO₄, acetonitrile; 2. (1,5-dihydro-2,4,3-benzodi-

oxaphosphepin-3-yl)diethylamine, 1H-tetrazole, CH₂Cl₂then m-

CPBA. (e) 1. Pd/C, H₂, ethanol/water; 2. 0.25  NaOH

Synthesis of epi-inositol systems: A key compound for

the preparation of epi-inositol might be a conduritol C de-

The first step in the synthesis of epi-Ins(1,4,5)P₃was the

rivative. An easy preparation of this conduritol derivative monofunctionalization of the axial hydroxy group of (Ϫ)-

by the route depicted in Scheme 7 has already been de- 41. Reaction of diol (Ϫ)-41 under acidic conditions (p-tolu-

vised.^[38]

enesulfonic acid) with triethyl orthoacetate in anhydrous

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Inositol Systems via Conduritols Prepared from p-Benzoquinone

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THF resulted in the formation of an intermediate orthoes- an easy chromatographic method to determine the purity

ter, which was directly converted with acetic acid into the of inositols. Inositols are weak acids that ionize at pH 13

axial acetate (Ϫ)-45.^[39]Regioselectivity in this reaction can to 14. At these pH levels near their pK_avalues, they can be

be traced back to stereoelectronic effects.^[40]This step was separated by anion-exchange mechanisms. We employed a

followed by debromination under mild conditions to give linear gradient up to 250 m NaOH and a high-capacity

(Ϫ)-46. The introduction of the phosphate functionality column (CarboPac MA1) to resolve a mixture of the stereo-

was realized by treatment with (1,5-dihydro-2,4,3-benzo- isomers neo-, myo-, scyllo-, epi-, chiro-, and allo-inositol by

dioxaphosphepin-3-yl)diethylamine in the presence of 1H- HPIC-IPAD (high-performance ion chromatography with

tetrazole and subsequent oxidation of the resulting phos- integrated pulsed amperometric detection) (see Figure 5).

phite with m-CPBA to give (Ϫ)-47. Flash cis-dihydroxyl- Most of these compounds are epimers of myo-inositol, dif-

ation with RuCl₃/NaIO₄again furnished predominantly the fering structurally only in the orientation of one hydroxy

epi-configured product (99% yield, 80% de), which was group. Pulsed amperometric detection (PAD) is a powerful

phosphorylated under the conditions described above to detection technique for inositols (more generally carbo-

give (ϩ)-48 in 50% yield. Hydrogenation followed by cleav- hydrates) that requires, in contrast to gas chromatography,

age of the acetate groups in aqueous NaOH delivered the no sample derivatization. At high pH, the compounds are

target compound (ϩ)-49 quantitatively.

electrocatalytically oxidized at the surface of a gold elec-

It has been reported previously that epi-Ins(1,3,6)P₃[it trode by application of a positive potential, and the current

was incorrectly named epi-Ins(1,4,5)P₃in this article] has a generated is proportional to their concentration. We applied

poor affinity for the endoplasmic reticulum receptor a waveform recommended by the manufacturer (DI-

(ERR).^[41]The dramatically lower affinity to ERR found ONEX^) with integration of the recorded signal over the

for epi-Ins(1,3,6)P₃is the result of the modification of the time period of the detection potential (see Experimental

essential 6-hydroxy group (see Figure 4).^[42]Thus epi- Section). This variation of the PAD technique is called

Ins(1,4,5)P₃may have a higher activity than other ana- IPAD. The detection limit achieved for the inositol isomers

logues. With authentic epi-Ins(1,4,5)P₃(ϩ)-49 in hand this is about 50 n (corresponding to 5 pmol per substance in

hypothesis will be tested in due course.

analytical runs). As mentioned in the introduction, recent

reports indicate that, besides the major isomer myo-inositol,

other isomers can be found in many different organisms.

Their function, however, is not yet clear. The powerful ana-

lytical method described might be very useful for the direct

detection and quantification of inositol isomers and could

provide information about their distribution in different

species and habitats. It should therefore be of general inter-

est, as methods for the direct detection of free inositols have

been rarely described in the literature.^[43]

Figure 4. Structures of epi-Ins(1,4,5)P₃(ϩ)-49 analogues

Syntheses of inositol hexakis(phosphates): The introduc-

tion of six phosphate groups was achieved by treatment of

chiro-4, neo-2, scyllo-6, and allo-3 inositol with (1,5-di-

hydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine in the

presence of 1H-tetrazole in dichloromethane/acetonitrile.

After 12 h to 36 h the resulting phosphites were oxidized

with m-CPBA and purified by flash chromatography to give

the protected hexakis(phosphates) in 50% yield at most. Be-

cause of the low solubility of free inositol, especially neo-

inositol, the phosphorylation is quite difficult, so that com-

plete conversion is a problem. Changing the conditions by

varying the solvents or extending the reaction times did not

increase the yield. The subsequent Pd/C-catalyzed deprotec-

tion/hydrogenolysis gave the free inositol hexakis-

(phosphates). Alternatively, neo-inositol 2 was phosphoryl-

ated in polyphosphoric acid to give 28 in better yield. This

direct method, however, is only of minor value because of

the tedious purification necessitated by the great excess of

polyphosphoric acid. Purification of the resulting inositol

hexakis(phosphates) (Ϫ)-33, (ϩ)-33, 28, 40, and 24 by pre-

parative HPLC ensures purities suitable for biological

experiments.^[27]

Figure 5. HPIC-IPAD analysis of inositol stereoisomers; 1: neo-, 2:

myo-, 3: scyllo-, 4: epi-, 5: chiro-, 6: allo-inositol

Conclusion

We have extended the synthetic potential of the versatile

High-performance anion-exchange chromatography of building block (ϩ)- and (Ϫ)-16 to the synthesis of enanti-

inositols: In the course of our investigations we looked for omerically pure conduritol systems, namely conduritol B,

Eur. J. Org. Chem. 2003, 1958Ϫ1972

www.eurjoc.org

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1963

M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

tion was mixed with 100 µL of metal-dye reagent, and the ab-

sorbance at 540 nm was measured.

C, E, and F. With these conduritols as flexible precursors,

efficient and high-yielding stereoselective routes to myo-,

neo-, -chiro, -chiro, allo-, scyllo-, and epi-inositol deriva-

tives could be established. For further biological investi-

gation, several inositol hexakis(phosphates) and epi-

Ins(1,4,5)P₃have been synthesized.^[27]If required, all reac-

tions can be carried out on a multigram scale for both en-

antiomers of different chiral inositol systems.

The building blocks (ϩ)-17, (Ϫ)-17, (Ϫ)-16, and (ϩ)-16 and their

precursors were prepared according to literature methods.^[26]

(3aR,4S,5R,7aR)-4-Bromo-5-hydroxy-3a,4,5,7a-tetrahydro-1,3-

benzdioxol-2-one [(؊)-18] [(1R,2R,3S,4R)-3-Bromoconduritol-1,2-

carbonate C]: A portion of Na₂SO₄was added to a vigorously

stirred solution of (1R,2S,3S,4R)-2,3-dibromocyclohex-5-ene-1,4-

diol (ϩ)-17 (20.0 g, 73.8 mmol) in anhydrous THF (350 mL). At

Ϫ45 to Ϫ65 °C carbon dioxide (dried with concentrated sulfuric

acid) was continuously bubbled into the reaction mixture for 1 h.

With a syringe, diazabicycloundecene (DBU, 32 mL, 0.2 mol) was

added slowly, and the solution was stirred under continuous carbon

dioxide addition for another 2 h at Ϫ50 °C. The reaction mixture

was allowed to warm up to 0 °C and worked up by addition of 5%

aqueous HCl (400 mL) and extraction of the aqueous layer with

ethyl acetate. The organic layer was washed twice with aqueous

HCl (5%, 200 mL), then with saturated NaHCO₃, and finally with

brine. The solvent was removed under vacuum to yield 16.0 g

(0.70 mmol, 92%) of a colorless solid. [α]²_D⁰ϭ Ϫ155 (c ϭ 1.47,

MeOH). ¹H NMR (DMSO): δ ϭ 4.22 (m, 1 H, 5-H), 4.28 (dd, J ϭ

8.65, J ϭ 2.5 Hz, 1 H, 4-H), 5.24Ϫ5.31 (m, 2 H, 3a-H, 7a-H), 5.77

(dψt, J ϭ 10.2, J ϭ 3.3 Hz, 1 H, 7-H), 5.87 (d, J ϭ 6.6 Hz, 1 H,

OH), 6.06 (dd, J ϭ 10.2, J ϭ 2.1 Hz, 1 H, 6-H) ppm. ¹³C NMR

(DMSO): δ ϭ 52.07 (C-4), 65.95 (C-5), 73.16, 77.92 (C-3a, C-7a),

121.65 (C-7), 137.39 (C-6), 153.16 (CϭO) ppm. IR (KBr): ν˜ ϭ 3400

(m), 3040, 3020 (w), 2880 (m), 1770 (s), 1150, 1130 (s), 885 (s)

cm^Ϫ1. C₇H₇BrO₄(235.0): calcd. C 35.77, H 3.00; found C 35.49,

H 3.02.

Experimental Section

General: All NMR spectra were recorded on a Bruker ARX 400

(400 MHz) spectrometer. Besides ¹H, ¹³C, and ³¹P experiments, 2D

COSY- (¹H-¹H, ¹H-¹³C, and ¹H-³¹P) and DEPT spectra for the

unequivocal correlation of the hydrogen, carbon, and phosphorus

atoms were recorded. The chemical shifts are given in ppm, relative

to the solvents as internal standard. The multiplicity is given by

the following symbols: s (singlet), d (doublet), t (triplet), q (quadru-

plet), m (multiplet), ψt (pseudotriplet for unresolved dd) and br

(broad). Melting points were recorded on a Büchi 510 heating

block (not corrected). IR spectra were obtained in KBr, and only

noteworthy absorptions (cm^Ϫ1) are listed. Flash-column chroma-

tography was performed on Merck silica gel (40Ϫ63 µm). All or-

ganic extracts were dried with MgSO₄, filtered, and concentrated

on a rotary evaporator. Only distilled solvents were used.

HPIC-IPAD of Inositol Stereoisomers: Inositol analysis was per-

formed with a DX-500 ion chromatography system (DIONEX^)

consisting of a gradient pump (GP50), a chromatography oven

(LC30) with an internal valve bearing a 100 µL sample loop, a tun-

able absorbance detector (AD25), and an electrochemical detector

(ED50) connected to a gold cell equipped with a pH-Ag/AgCl ref-

erence electrode. At a constant temperature of 30 °C a CarboPac

MA1 (4 ϫ 50 mm, DIONEX^) precolumn and a CarboPac MA1

(4 ϫ 250 mm, DIONEX^) analytical column were used for the

separation presented. A linear gradient of NaOH was applied to

elute the inositol isomers (0 min, 0 m NaOH; 10 min, 250 m

NaOH; 30 min, 250 m NaOH; flow rate: 0.4 mL/min). The wave-

form had the following characteristics: 0 s, 0.05 V; 0.2 s, 0.05 V

(Start Integration); 0.4 s, 0.05 V (Stop Integration); 0.41 s, 0.75 V;

0.6 s, 0.75 V; 0.61 s, Ϫ0.15 V; 1 s, Ϫ0.15 V. The Chromeleon 6.2

software (DIONEX^) was used for data processing: The inositol

stereoisomers had the following retention times: 1: neo-

(11.07 min), 2: myo- (11.48 min), 3: scyllo- (12.83 min), 4: epi-

(15.93 min), 5: chiro- (17.48), and 6: allo-inositol (26.37 min).

1,2,3,4-Tetra-O-acetylconduritol E [(؉)-21]: (1S,2R,3R,4S)-1,4-Di-

acetoxy-2,3-dibromocyclohex-5-ene (10 g, 28 mmol) (ϩ)-16 was ad-

ded to a hot solution of potassium acetate or sodium acetate (10 g)

in acetic acid (100 mL) and water (5 mL). The mixture was stirred

for 10 days at 125 °C. The solvent was removed under reduced

pressure and the residue was dried under high vacuum. The residue

was suspended in anhydrous dichloromethane, then acetic anhy-

dride (30 mL) and DMAP (200 mg) were added. The mixture was

stirred overnight. For workup the mixture was added slowly to a

vigorously stirred aqueous solution of NaHCO₃(16 g, 0.19 mol,

100 mL water). The aqueous phase was extracted several times with

dichloromethane. The combined organic phase was washed with

saturated aqueous NaHCO₃and then with brine. After evaporation

of the solvent, the raw product (10 g, oil) was purified by flash

chromatography (cyclohexane/ethyl acetate, 3:2) to yield (ϩ)-21

(6.5 g, 70%) as a colorless oil which crystallized after 1 day. Ra-

cemic 21 was purified without flash chromatography simply by

recrystallization from EtOH to yield pure 21 (6 g, 67%) as a color-

less solid. R_fϭ 0.35 (cyclohexane/ethyl acetate, 3:2). [α]²_D⁰ϭ ϩ243

(c ϭ 1.27, CHCl₃). Ref.^[45][α]²_D⁰ϭ ϩ244 (c ϭ 1.6, CHCl₃). ¹H

NMR (CDCl₃): δ ϭ 2.04 (s, 6 H, CH₃), 2.07 (s, 6 H, CH₃), 5.44

(m, 2 H, 2-H, 3-H), 5.68 (m, 2 H, 1-H, 4-H), 5.91 (dd, J ϭ 2.8, J ϭ

1.2 Hz, 2 H, 5-H, 6-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.46 (2 ϫ

CH₃), 20.76 (2 ϫ CH₃), 66.07 (C-2, C-3), 66.57 (C-1, C-4), 128.14

(C-5, C-6), 169.90, 170.18 (CϭO) ppm. MS [EI, 70 eV, m/z (%)]:

288 (2.0), 228 (9), 210 (5), 168 (38), 43 (100), 41 (10). IR (KBr):

Deionized water for HPIC was purified by a Millipore system to a

specific resistance of 18 MΩ·cm or greater. NaOH of the highest

purity was purchased from Sigma. All eluents were sparged with

and pressurized under helium.

Purification and Analysis of Inositol Phosphates (HPLC-MDD): In-

ositol phosphates were purified and analyzed by the HPLC-MDD

method described previously.^[44,26]The compounds were separated

by anion-exchange chromatography on a MonoQ HR10/10 column

(Pharmacia). To purify inositol phosphates a linear gradient of HCl

was applied (0 min 0.2 m HCl; 70 min 0.5  HCl; flow rate

1.5 mL/min). In analytical runs photometric detection at 546 nm

was achieved with a metal-dye reagent [2  Tris/HCl (pH, 9.1), 200

µ 4-(2-pyridylazo)resorcinol (PAR), 30 µ YCl₃, 10% (v/v)

MeOH; flow rate 0.75 mL/min]. In purification steps, where on-line

detection was impossible, an analogous experiment was carried out

on a microplate. In brief, a 0.2Ϫ2-µL portion of the collected frac-

ν˜ ϭ 2960, 2900 (m), 1740 (s, br.), 1440, 1370 (s), 1210 (s) cm^Ϫ1

.

C₁₄H₁₈O₈(314.10): calcd. C 53.50, H 5.77; found C 53.65, H 6.00.

1,2,3,4-Tetra-O-acetylconduritol E [(؊)-21]: A solution of (Ϫ)-16

was allowed to react under the same conditions as described for

the preparation of (ϩ)-21 to give (Ϫ)-21. [α]²_D⁰ϭ Ϫ246 (c ϭ 1.1,

1

CHCl₃). Identical R_f, H NMR and ¹³C NMR spectroscopic data

to those of (ϩ)-21.

1964

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2003, 1958Ϫ1972

Inositol Systems via Conduritols Prepared from p-Benzoquinone

(1S,2S,3R,4S)-1,2,4-Triacetoxy-3-bromocyclohex-5-ene [(؉)-20]:

Diacetate (ϩ)-16 (10 g, 28 mmol) was added to a hot solution of

potassium acetate or sodium acetate (10 g) in acetic acid (100 mL)

and water (5 mL). The mixture was stirred for 3 days at 110 °C.

The product was worked up as described for (ϩ)-21. Purification

FULL PAPER

NaHCO₃(1.4 g, 16 mmol) in dichloromethane (35 mL). Then the

mixture was refluxed for 2 h and stirred for another 12 h at room

temperature. The reaction mixture was added slowly to a cooled

and stirred solution of saturated aqueous NaHCO₃(30 mL),

NaHCO₃(8.4 g) in brine (100 mL), and dichloromethane

by flash chromatography (cyclohexane/ethyl acetate, 3:2) yielded (200 mL). After addition of 20% aqueous Na₂S₂O₃solution

pure (ϩ)-20 (8.0 g, 85%) as a colorless oil that crystallized after

(50 mL,) the mixture was extracted four times with dichlorometh-

some days to give an oily solid. R_fϭ 0.50 (cyclohexane/ethyl acet-

ane or ethyl acetate (4 ϫ 100 mL). The combined organic layer was

1

ate, 3:2). [α]²_D⁰ϭ ϩ104 (c ϭ 1.2, CHCl₃). H NMR (CDCl₃,): δ ϭ washed with brine and then dried with MgSO₄. Evaporation of the

2.01 (s, 3 H, CH₃), 2.12 (s, 3 H, CH₃), 2.14 (s, 3 H, CH₃), 4.22 (dd,

solvent gave a yellow foam (1.2 g). The crude product was purified

J ϭ 9.2, J ϭ 2.03 Hz, 2 H, 3-H), 5.61 (m, 1 H, 1-H), 5.64 (dd, J ϭ by fractionated silica-gel filtration (first cyclohexane/ethyl acetate

10.2, J ϭ 2.0 Hz, 1 H, 6-H), 5.71 (dd, J ϭ 8.9, J ϭ 2.3 Hz, 1 H, 4- 8:2 until starting material/epoxide could not be detected by TLC,

H), 5.75 (ψt, J ϭ 1.8 Hz, 1 H, 2-H), 5.80 (dψt, J ϭ 10.2, J ϭ then ethyl acetate). The ethyl acetate fraction was evaporated to

2.3 Hz, 1 H, 5-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.47 (CH₃), 20.55

(CH₃), 20.77 (CH₃), 47.29 (C-3), 67.72 (C-1), 72.16, 72.21 (C-2, C-

yield (ϩ)-26 (900 mg, 2.7 mmol, 71%) as a colorless foam. R_fϭ

0.03 (cyclohexane/ethyl acetate, 1:1). [α]²_D⁰ϭ ϩ12.7 (c ϭ 1.1,

1

4), 126.70 (C-6), 128.36 (C-5), 169.73, 169.94, 170.04 (CϭO) ppm. CHCl₃). H NMR (CDCl₃): δ ϭ 1.99 (s, 6 H, 2 ϫ CH₃), 2.13 (s,

MS (EI, 70 eV, m/z (%)): 277, 275 (2), 195 (77), 153 (67), 110 (30), 6 H, 2 ϫ CH₃), 3.27 (br., 2 H, OH), 4.01 (s, 2 H, 1-H, 6-H), 5.20

43 (100). IR (KBr): ν˜ ϭ 3043 (w, ν[ϭCH]), 2998, 2949, 2938 (w), (s, 2 H, 3-H, 4-H), 5.62 (s, 2 H, 2-H, 5-H) ppm. ¹³C NMR (CDCl₃):

1750 (s), 1370 (m), 1224 (br. s,), 1144 (m), 1041 (s) cm^Ϫ1

.

δ ϭ 20.58 (2 ϫ CH₃), 20.70 (2 ϫ CH₃), 68.33, 68.57, 70.19 (C-1/

C₁₂H₁₅BrO₆(334.01): calcd. C 43.01, H 4.51; found C 43.05, H C-6, C-2/C-5, C-3/C-4), 170.17 (2 ϫ CϭO), 170.66 (2 ϫ CϭO)

4.58.

ppm. MS [EI, 70 eV, m/z (%)]: 271 (2), 228 (1), 210 (5), 168 (16),

157 (9), 126 (27), 115(16), 60 (18), 43 (100). C₁₄H₂₀O₁₀(348.11):

calcd. C 48.28, H 5.79; found C 48.18, H 6.00.

(1R,2R,3S,4R)-1,2,4-Triacetoxy-3-bromocyclohex-5-ene [(؊)-20]: A

solution of (Ϫ)-16 was allowed to react under the same conditions

as described for the preparation of (ϩ)-20 to give (Ϫ)-20. [α]²_D⁰

ϭ

1,2,5,6-Tetra-O-acetyl-neo-inositol [(؊)-26]: A solution of (Ϫ)-21

was allowed to react under the same conditions as described for

the preparation of (ϩ)-26 to give (Ϫ)-26. [α]²_D⁰ϭ Ϫ12.0 (c ϭ 0.95,

CHCl₃). Identical ¹H NMR and ¹³C NMR spectroscopic data to

those of (ϩ)-26.

Ϫ96 (c ϭ 0.9, CHCl₃). Identical R_f, ¹H NMR and ¹³C NMR spec-

troscopic data to those of (ϩ)-20.

(1R,2S,3S,4S)-1-O-Benzylconduritol F [(؉)-22]: Sodium (70 mg,

3 mmol) was added to anhydrous benzyl alcohol (5 mL). The mix-

ture was stirred until the sodium dissolved (3 h). This solution was

added to a solution of 1,2,4-triacetate (ϩ)-20 (500 mg, 1.5 mmol)

in anhydrous benzyl alcohol/THF (1:2). After being stirred for 12 h

at room temperature, the solution was neutralized by addition of

ion exchanger (H^ϩ, Dowex 50-X), which was filtered off and

washed with dichloromethane/methanol. The filtrate was evapo-

rated, and the remaining benzyl alcohol was removed by distil-

lation. The resulting oil (350 mg) was purified by flash chromatog-

raphy (CH₂Cl₂/methanol 90:10) to yield (ϩ)-22 (250 mg, 66%) as a

colorless solid. R_fϭ 0.57 (CH₂Cl₂/methanol, 90:10). [α]²_D⁰ϭ ϩ3.8

(c ϭ 3.15, MeOH). ¹H NMR ([D₄]MeOH): δ ϭ 3.41 (dd, J ϭ 10.2,

J ϭ 4.2 Hz, 3-H), 3.78 (dd, 1 H, J ϭ 10.2, J ഠ 7.6 Hz, 2-H), 3.87

(dψt, J ϭ 7.6, J ഠ 1.8 Hz, 1 H, 1-H), 3.98 (br. s, 3 H, OH), 4.14

(ψt, J ϭ 4.6 Hz, 1 H, 4-H), 4.65, 470 (AB, J ϭ 10.2 Hz, 2 H, Ph-

CH₂), 5.77 (m, 2 H, 5-H, 6-H), 7.2Ϫ7.4 (m, 5 H, Ph-H) ppm. ¹³C

NMR ([D₄]MeOH): δ ϭ 62.36 (C-4), 67.40, 67.44 (C-3, C-4), 67.97

(Ph-CH₂), 75.95 (C-1), 123.60, 126.39 (C-5, C-6), 123.77, 123.94,

124.39 (C_arom.), 138.45 (C_ipso) ppm. MS [EI, 70 eV, m/z (%)]: 236

(1.0) [M^ϩ], 176 (10.9), 112 (28.11), 91 (100) [Bn^ϩ]. HR-MS [CI,

(1R,2R,3R,4R,5R,6S)-1,6-Epoxy-2,3,4,5-tetra-O-acetyl-7-oxa-

bicyclo[4.1.0]heptane [(؉)-25] [(؉)-Conduritol E epoxide]: A freshly

prepared solution of trifluoroperacetic acid^[23][see synthesis of (ϩ)-

26] was added dropwise at 0 °C to a suspension of conduritol E

(ϩ)-21 (1.2 g, 3.8 mmol) and sodium carbonate (2 g, 19 mmol) in

dichloromethane (35 mL) over the course of 15 min. The mixture

was stirred for 4 h at room temperature. The product was worked

up as described for (ϩ)-26. Purification by flash chromatography

(cyclohexane/ethyl acetate, 3:2) yielded pure epoxide (300 mg, 24%)

as a colorless oil. R_fϭ 0.31 (cyclohexane/ethyl acetate, 1:1). [α]²_D⁰

ϭ

ϩ109 (c ϭ 1.4, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 2.03 (s, 3 H, CH₃),

2.04 (s, 3 H, CH₃), 2.14 (s, 6 H, 2 ϫ CH₃), 3.32 (dd, J ϭ 3.3, J ϭ

2.3 Hz, 1 H, 1-H), 3.47 (ψt, J ϭ 3.8 Hz, 1 H, 6-H), 5.28 (dd, J ϭ

9.9, J ϭ 5.3 Hz, 1 H, 4-H), 5.33 (dd, J ϭ 9.9, J ϭ 3.3 Hz, 1 H, 3-

H), 5.57 (ψt, J ϭ 4.6 Hz, 1 H, 5-H), 5.70 (ψt, J ϭ 2.3 Hz, 1 H, 2-

H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.52 (2 ϫ CH₃), 20.55 (CH₃),

20.64 (CH₃), 50.99 (C-6), 53.27 (C-1), 65.29 (C-3), 65.77 (C-4),

65.84 (C-5), 66.59 (C-2), 169.35, 169.61, 169.81, 170.19 (CϭO)

ppm. MS [EI, 70 eV, m/z (%)]: 255 (19), 212 (43), 152 (100), 43 (84),

41 (8). IR (KBr): ν˜ ϭ 2960, 2900 (w), 1740 (s), 1460, 1370 (s), 1200

(DE), iso-butane]: m/z: 237.112794 [M

C₁₃H₁₇O₄: 237.11268.

ϩ

H]^ϩcalcd. for

(s), 1060 (s) cm^Ϫ1

.

Hexa-O-acetyl-neo-inositol (27): (ϩ)-26 (1 g, 2.9 mmol) was dis-

solved in a cooled mixture of pyridine (7 mL) and acetic anhydride

(5 mL). The mixture was stirred for 12 h. Evaporation of the sol-

vent and recrystallization from ethyl acetate (7 mL) yielded pure 27

(1.0 g, 83%) as a white solid. ¹H NMR (CDCl₃): δ ϭ 1.99 (s, 12 H,

4 ϫ CH₃), 2.16 (s, 6 H, 2 ϫ CH₃), 5.34 (s, 4 H, 1-H, 3-H, 4-H, 6-

H), 5.66 (s, 2 H, 2-H, 5-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.46 (4

(1S,2R,3R,4R)-1-O-Benzyl-conduritol F [(؊)-22]: A solution of (Ϫ)-

20 was allowed to react under the same conditions as described for

the preparation of (ϩ)-22 to give (Ϫ)-22. [α]²_D⁰ϭ Ϫ4.9 (c ϭ 2.0,

1

MeOH). Identical R_f, H NMR and ¹³C NMR spectroscopic data

to those of (ϩ)-22.

2,3,4,5-Tetra-O-acetyl-neo-inositol [(؉)-26]: A solution of trifluoro-

peracetic acid^[23]was prepared by slow addition of hydrogen per- ϫ CH₃), 20.62 (2 ϫ CH₃), 67.45 (C-1, C-3, C-4, C-6), 67.99, (C-2,

oxide (1.4 mL, 85%, 42 mmol) to an ice-cooled solution of tri-

C-5), 169.5 (4 ϫ CϭO), 169.8 (2 ϫ CϭO) ppm. MS [EI, 70 eV, m/

fluoroacetic anhydride (7 mL, 50 mmol) in dichloromethane z (%)]: 373 (1), 330 (1), 270 (8), 210 (63), 168 (94), 157 (28), 126

(20 mL). The solution was stirred for 1 h at room temperature. This

solution, freshly prepared, was added dropwise at 0 °C over 15 min

(40), 115 (31), 43(100). IR (KBr): ν˜ ϭ 2984, 2962 (w), 1758 (s),

1369 (m), 1226 (s, br.), 1117 (m), 1090 (m), 1047 (m) cm^Ϫ1

.

to a suspension of conduritol E (ϩ)-21 (1.2 g, 3.8 mmol) and C₁₈H₂₄O₁₂: (432.13): calcd. C 50.00, H 5.59; found C 50.11, H 5.72.

Eur. J. Org. Chem. 2003, 1958Ϫ1972

www.eurjoc.org  2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1965

M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

neo-Inositol (2): Compound 27 (2.4 g, 5.4 mmol) was suspended in

anhydrous methanol (50 mL) under argon and cooled to 4 °C. So-

dium methoxide solution (500 µL of a 5.5  solution, 2.25 mmol)

was added dropwise over 10 min. The solution was allowed to

warm to room temperature and stirred for 12 h. The solvent was

removed, and for complete turnover the residue was dissolved in

aqueous NaOH (20 mL of a 0.25  solution) and refluxed for 2 h.

The hot solution was neutralized by addition of ion exchanger (H^ϩ,

Dowex 50-X) and filtered, and the Dowex material was washed

with boiling water. The filtrate was first concentrated under high

vacuum and then lyophilized. Recrystallization from water (50 mL)

yielded 2 (1 g, 99%) as a colorless solid. ¹H NMR (CDCl₃): δ ϭ

linear gradient of hydrochloric acid (0Ϫ1  HCl). Purification by

HPLC yielded 80 mg (31%) of neo-InsP₆28.

3,4,5,6-Tetra-O-acetyl-allo-inositol [(؉)-23]: A solution of sodium

metaperiodate (1.2 g, 5.5 mmol, 1.5 equiv.) and ruthenium trichlo-

ride trihydrate (100 mg, 0.4 mmol) in water (14 mL) was added to a

vigorously stirred, ice-cooled solution of conduritol E (ϩ)-21 (1 g,

3.2 mmol) in acetonitrile (60 mL). The stirring was continued until

TLC showed absence of the starting material (approx. 10 min). The

reaction was quenched by addition of 20% aqueous Na₂S₂O₃

(130 mL ). The aqueous layer was separated and extracted with

ethyl acetate (4 ϫ 100 mL). The combined organic layer was

washed twice with brine and concentrated under reduced pressure

to yield pure (ϩ)-23 as a colorless solid (1 g, 90%). [α]²_D⁰ϭ ϩ3.0

(c ϭ 0.78, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 2.01 (s, 6 H, 2 ϫ CH₃),

2.06 (s, 3 H, CH₃), 2.10 (s, 3 H, CH₃), 2.94 (br. s, 2 H, OH), 3.95

(dd, J ϭ 5.1, J ϭ 3.9 Hz, 1 H, 1-H or 2-H), 4.11 (ψs, 1 H, 1-H or

2-H), 5.23 (dd, J ϭ 7.3, J ϭ 3.3 Hz, 1 H), 5.41 (m, 3 H) (3-H, 4-

H, 5-H, 6-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.91 (CH₃), 20.93

(CH₃), 21.05 (2 ϫ CH₃), 67.13 (CH), 68.45 (CH), 70.23 (m, 4 ϫ

CH), 170.14, 170.21, 170.42, 170.81 (CϭO) ppm. IR (KBr): ν˜ ϭ

3467 (s, br.), 2979, 2936 (m), 1747 (s), 1375 (m), 1252 (s), 1075,

1051 (m), 933 (m) cm^Ϫ1. MS (EI, 70 eV, m/z (%)): 228 (9), 210 (4),

168 (48), 157 (28), 126 (81), 115 (58), 43 (100). C₁₄H₂₀O₁₀(348.11):

calcd. C 48.28, H 5.79; found C 48.14, H 5.95.

3.74 (s, 4 H, 1-H, 3-H, 4-H, 6-H), 4.03 (s, 2 H, 2-H, 5-H) ppm. ¹³

C

NMR (CDCl₃): δ ϭ 69.75 (C-1, C-3, C-4, C-6), 71.99, (C-2, C-5)

ppm. MS [EI, 70 eV, m/z (%)]: 144 (9), 102 (39), 73 (100). IR (KBr):

ν˜ ϭ 3422, 3342, 3197 (s, br.), 2970, 2948, 2921 (w), 1687 (w),

1632(w), 1423 (w), 1384 (w), 1281 (w), 1130 (s), 1092 (m), 1036 (s)

cm^Ϫ1. C₆H₁₂O₆: calcd. C 40.00; H 6.71; found C 39.75; H 6.61.

HR-MS: m/z: 179.0526 [M Ϫ H]^ϩcalcd. for C₆H₁₁O₆: 179.0556.

neo-Inositol Hexakis(phosphate) (28): (1,5-Dihydro-2,4,3-benzo-

dioxaphosphepin-3-yl)diethylamine (514 mg, 2.26 mmol) was ad-

ded to a suspension of neo-inositol 2 (50 mg, 0.27 mmol) and 1H-

tetrazole (315 mg, 4.5 mmol) in anhydrous dichloromethane/aceto-

nitrile (1:1, 20 mL), and the solution was stirred at 40 °C for 3 days.

For workup the solution was cooled to Ϫ40 °C, and an anhydrous

solution of m-CPBA (1.5 g, 6 mmol) in dichloromethane (15 mL,

dried with Na₂SO₄) was added. The solution was allowed to warm

to room temperature, and the stirring was continued for another

hour. The reaction mixture was diluted with dichloromethane

(150 mL) and washed consecutively with aqueous sodium bisulfite

(20%, 2 ϫ 100 mL), saturated NaHCO₃(3 ϫ 100 mL), and then

with brine. After evaporation of the solvent the resulting colorless

foam was purified by flash chromatography with silica gel (R_fϭ

0.22 (CH₂Cl₂/MeOH, 95:5) to yield hexa-O-(3-oxo-1,5-dihydro-

3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-neo-inositol (75 mg, 21%) as

1,2,5,6-Tetra-O-acetyl-allo-inositol [(؊)-23]: A solution of (Ϫ)-21

was allowed to react under the same conditions as described for

the preparation of (ϩ)-23 to give (Ϫ)-23. [α]²_D⁰ϭ Ϫ2.7 (c ϭ 1.0,

1

CHCl₃). Identical R_f, H NMR, and ¹³C NMR spectroscopic data

to those of (ϩ)-23.

allo-Inositol (3): (ϩ)-23 (800 mg, 2.3 mmol) was suspended in anhy-

drous methanol (20 mL) under argon and cooled to 4 °C. Sodium

methoxide solution (150 µL of a 5.5  solution, 0.8 mmol) was ad-

ded dropwise over 10 min. The solution was allowed to warm to

room temperature and stirred for 12 h. It was then neutralized by

ion exchanger (H^ϩ, Dowex 50-X), which was filtered off and

washed with water. The filtrate was first reduced in volume under

high vacuum, then lyophilized. Recrystallization from ethanol

(50 mL) yielded 3 (350 mg, 83%) as a colorless solid. ¹H NMR

(D₂O): δ ϭ 3.85 (s, 2 H), 3.98 (m, 4 H) ppm. ¹³C NMR (D₂O):

δ ϭ 72.70, 73.90, 74.00 ppm. MS [EI, 70 eV, m/z (%)]: 144 (1), 102

(8), 73 (100). C₆H₁₂O₁₆(340.2): calcd. C 40.00, H 6.71; found C

39.82, H 6.85. HR-MS: m/z: 179.0515 [M Ϫ H]^ϩcalcd. for

C₆H₁₁O₆: 179.0556.

1

a colorless foam. H NMR (CDCl₃): δ ϭ 5.15 (m, 4 H, 1-H, 3-H,

4-H, 6-H), 5.58 (m, 2 H, 2-H, 5-H), 5.00 Ϫ5.82 [m, 24 H, 6 ϫ

(CH₂)₂C₆H₄], 7.26Ϫ7.43 (m, 24 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ ϭ 69.19 Ϫ69.63 [m, 6 ϫ (CH₂)₂C₆H₄], 72.86 (m, C-1,

C-3, C-4, C-6), 77.06 (C-2, C-5), 128.94 Ϫ129.48 (C_arom.), 134.54,

135.63, 135.77 (C_ipso) ppm. ³¹P{¹H} NMR (CDCl₃): δ ϭ Ϫ1.48

(PC-2, PC-5), Ϫ2.39 (PC-1, PC-3, PC-4, PC-6) ppm.

Pd/C (50 mg, Degussa RW 10) was added to a suspension of hexa-

O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-neo-

inositol (50 mg, 39 µmol) in ethanol/water (1:2, 30 mL). The mix-

ture was stirred at room temperature under H₂overnight. The cata-

lyst was filtered off, and the filtrate was concentrated under high

vacuum and then lyophylized to give 28 (24 mg, 99%) as a colorless,

strongly hygroscopic foam. Purification by HPLC assured purity

Ͼ 99%. ¹H NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ ϭ 4.37 (d,

J ϭ 4.6 Hz, 4 H, 1-H, 3-H, 4-H, 6-H), 4.89 (d, J ϭ 9.2 Hz, 2 H, 2-

H, 5-H) ppm. ¹³C NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ ϭ

74.24 (C-1, C-3, C-4, C-6), 76.57 (C-2, C-5) ppm. ³¹P{¹H} NMR

[D₂O, pH adjusted to 6 (ND₄OD)]: δ ϭ 1.89 (PC-2, PC-5), 2.07

(PC-1, PC-3, PC-4, PC-6) ppm. HR-MS (MALDI-FTMS): m/z:

658.8541 [M Ϫ H]^ϩcalcd. for C₆H₁₇O₂₄P₆: 658.8527.

allo-Inositol-hexakis(phosphate) (24): (1,5-Dihydro-2,4,3-benzo-

dioxaphosphepin-3-yl)diethylamine (610 mg, 2.7 mmol) was added

to a suspension of allo-inositol 3 (66 mg, 0.37 mmol) and 1H-tetra-

zole (270 mg, 3.9 mmol) in anhydrous dichloromethane (30 mL),

and the solution was stirred at 40 °C for 1 day. The solution was

then cooled to Ϫ40 °C, and an anhydrous solution of m-CPBA

(2.3 g, 10 mmol) in dichloromethane (15 mL, dried with Na₂SO₄)

was added. The solution was allowed to warm to room tempera-

ture, and the stirring was continued for another hour. The reaction

mixture was diluted with dichloromethane (150 mL) and washed

consecutively with aqueous sodium bisulfite (20%, 2 ϫ 100 mL),

saturated NaHCO₃(3 ϫ 100 mL), and then with brine. After evap-

oration of the solvent the resulting colorless foam was purified by

flash chromatography [R_fϭ 0.15 (CH₂Cl₂/MeOH, 95:5)] to yield

hexa-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-

allo-inositol (100 mg, 30%) as a colorless foam.

Alternative Preparation: neo-Inositol 2 (70 mg, 0.38 mmol) was dis-

solved in phosphoric acid (0.22 mL) at 60 °C. Polyphosphoric acid

(4 mL) was added, and the mixture was heated to 150 °C under

vacuum for 12 h. The mixture was diluted with water and purified

on an ion exchange column (Cl^Ϫ-form, DEAE sepharose) with a

Pd/C (50 mg, Degussa RW 10) was added to a suspension of hexa-

O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-allo-

1966

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2003, 1958Ϫ1972

Inositol Systems via Conduritols Prepared from p-Benzoquinone

FULL PAPER

inositol (80 mg, 39 µmol) in ethanol/water (1:2, 30 mL). The mix-

ture was stirred at room temperature under H₂overnight. The cata-

1 H, 1-H), 3.77 (dd, J ϭ 8.2, J ϭ 1.6 Hz, 1 H, 4-H), 4.80Ϫ4.88 (m,

4 H, AB, CH₂), 7.33Ϫ7.56 (m, 10 H, Ph-H) ppm. ¹³C NMR

lyst was filtered off, and the filtrate was reduced in volume under (CDCl₃): δ ϭ 54.01 (C-2), 54.1 (C-3), 69.76 (C-5), 72.16 (CH₂Ph),

high vacuum and then lyophylized to give 24 (40 mg, 99%) as a

colorless, highly hygroscopic foam. Separation by HPLC assured

purity Ͼ 99% for the subsequent reactions. ¹H NMR [D₂O, pH

adjusted to 6 (ND₄OD)]: δ ϭ 4.42 (ψs, 2 H), 4.66 (m, 2 H, under

73.01 (CH₂Ph), 74.61 (C-6), 78.14 (C-1), 78.75 (C-4), 127.92,

127.98, 128.02, 128.55 (C_arom.), 137.62, 137.97 (C_ipso) ppm. MS [EI,

70 eV, m/z (%)]: 342 (2), 251 (18), 107 (27), 91 (100). IR (KBr): ν˜ ϭ

3300 (s, br.), 3070 Ϫ3010 (w), 2910 Ϫ2880 (w), 1470(w, br.), 1100

HDO), 4.89 (ψs, 2 H) ppm. ¹³C NMR [D₂O, pH adjusted to 6 (s) cm^Ϫ1. C₂₀H₂₂O₅(342.4): calcd. C 70.16, H 6.48; found C 69.86,

(ND₄OD)]: δ ϭ 71.13 (m), 72.30 (m), 75.40 (m) ppm. ³¹P{¹H}

NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ ϭ 1.54 (2 ϫ P), 2.02

(4 ϫ P) ppm. HR-MS (ESI-neg, phosphoric acid 0.002%, H₂O/

acetonitrile 1:1, Q-TOF): m/z: 658.8502 [M Ϫ H]^Ϫcalcd. for

C₆H₁₇O₂₄P₆: 658.8536.

H 6.52.

1,2-Anhydro-3,6-di-O-benzyl-myo-inositol [(؉)-31]: A solution of

(ϩ)-29 was allowed to react under the same conditions as described

for the preparation of (Ϫ)-31 to give (ϩ)-31. [α]²_D⁰ϭ ϩ65 (c ϭ 0.4,

CHCl₃). Identical R_f, H NMR and ¹³C NMR spectroscopic data

1

1,4-Di-O-benzylconduritol B [(؊)-29]: Sodium (23 g, 1 mol) was ad-

ded to freshly distilled, ice-cooled benzyl alcohol (705 mL) with the

temperature not exceeding 40 °C. The mixture was stirred at room

temperature until all the sodium was dissolved (3 h). This solution

was cooled to Ϫ20 °C, and a solution of 1,4-diacetoxy-2,3-di-

bromocyclohex-5-ene (ϩ)-16 (73.1 g, 0.2 mol) in absolute THF

(210 mL) was added slowly (over 40 min). The solution was stirred

for 1 h at 0 °C and stirring was continued for 12 h at room tempera-

ture to provide complete conversion. The cooled solution was di-

luted with hydrochloric acid (1 ) and later with ethyl acetate

(700 mL). The aqueous layer was separated and extracted with

ethyl acetate (3 ϫ 330 mL). The organic layer was washed with

saturated aqueous NaHCO₃and brine. The organic solution was

concentrated under reduced pressure, and the remaining benzyl al-

cohol was removed by distillation. The resulting oil (85 g) was crys-

tallized from cyclohexane to yield (Ϫ)-29 (52 g, 80%) as a colorless

solid. R_fϭ 0.55 (ethyl acetate/cyclohexane, 5:1). [α]²_D⁰ϭ Ϫ134 (c ϭ

to those of (Ϫ)-31.

2,5-Di-O-benzyl-L-chiro-inositol [(؊)-32]: 2,3-Anhydro-myo-inositol

(Ϫ)-31 (700 mg, 2.0 mmol) was added to a solution of dioxane

(14 mL), water (2 mL) and sulfuric acid (2.1 mL, 15%), and the

mixture was stirred at 80 °C for 24 h. The solution was neutralized

with NaHCO₃(ca. 1 g) and diluted with ethyl acetate (200 mL).

The organic layer was washed with brine and after evaporation of

the solvent yielded (Ϫ)-32 (570 mg, 80%) as a colorless solid.

[α]²_D⁰ϭ Ϫ53.5 (c ϭ 0.39, MeOH); ref.^[46][α]²_D⁰ϭ Ϫ35.9 (c ϭ 0.4,

1

EtOH). H NMR ([D₆]DMSO/H₂0): δ ϭ 3.40 (AAЈ, 2 H, 2-H, 5-

H), 3.50 (MMЈ, 2 H, 3-H, 4-H), 3.93 (XXЈ, 2 H, 1-H, 6-H),

4.52Ϫ4.61 (m, 2 H, CH₂), 7.21Ϫ7.37 (m, 10 H, Ph-H) ppm. ¹³C

NMR ([D₆]DMSO/H₂0): δ ϭ 68.9 (C-1/C-6), 71.3 (CH₂Ph), 72.8

(C-3/C-4), 79.1 (C-2/C-5), 127.4, 127.8, 128.3 (C_arom.), 139.6 (C_ipso

)

ppm. MS [EI, 70 eV, m/z (%)]: 360 (2), 269 (52), 107 (58), 91 (100).

IR (KBr): ν˜ ϭ 3403 (br. s, ν[OH]), 3028 (w, ν[CH_olef.]), 2932 (w,

ν[CH_ali.]), 1740 (w), 1453 (w), 1216 (w), 1099 (s), 1049 (br. s,

ν[CϪO]), 918 (w), 753 (w), 701 (m) cm^Ϫ1. C₂₀H₂₄O₆: calcd. C

66.65, H 6.71; found C 66.39, H 6.52. HR-MS (EI, (DE)): m/z:

360.15701 [M]^ϩcalcd. for C₂₀H₂₄O₆: 360.15728.

1

1.60, acetone). H NMR (CDCl₃): δ ϭ 3.20 (s, 2 H, OH), 3.78 (s,

2 H, AAЈXXЈ), 4.08 (s, 2 H, AAЈXXЈ), 4.72 (s, 4 H, Ph-CH₂), 5.74

(s, 2 H, 1-H, 2-H), 7.35 (m, 10 H, Ph-H) ppm. ¹³C NMR (CDCl₃):

δ ϭ 71.9 (Ph-CH₂), 74.7 (C-4, C-5), 79.2 (C-3, C-6), 126.9, 127.7,

127.8 (C_arom.), 128.4 (C-1, C-2), 138.2 (2 ϫ C_ipso) ppm. MS [EI,

70 eV, m/z (%)]: 326 (3.78) [M^ϩ], 266 (36.38), 235 (3.76), 189

(25.21), 176 (21.64), 112 (45.15), 91 (100). IR (KBr): ν˜ ϭ 3440 (s,

br.), 3180, 3145, 3110 (m), 2940 (m), 1630 (w), 1470 (m), 1400 (m),

1225 (m), 1075 (s) cm^Ϫ1. C₂₀H₂₂O₄(326.4): calcd. C 73.60, H 6.79;

found C 73.37, H 6.65.

2,5-Di-O-benzyl-D-chiro-inositol [(؉)-32]: A solution of (ϩ)-31 was

allowed to react under the same conditions as described for the

preparation of (Ϫ)-32 to give (ϩ)-32. [α]²_D⁰ϭ ϩ50 (c ϭ 0.26,

1

CHCl₃). Identical H NMR and ¹³C NMR spectroscopic data to

those of (Ϫ)-32.

L

-chiro-Inositol [(؊)-4]: Pd/C (40 mg) was added to a suspension

1,4-Di-O-benzyl-conduritol B [(؉)-29]: A solution of (Ϫ)-16 (or

alternatively (ϩ)-17] was allowed to react under the same con-

ditions as described for the preparation of (Ϫ)-29 to give (ϩ)-29.

[α]²_D⁰ϭ ϩ130 (c ϭ 1.6, acetone). Identical R_f, ¹H NMR and ¹³C

NMR spectroscopic data to those of (Ϫ)-29.

of (Ϫ)-32 (250 mg, 0.7 mmol) in ethanol/water (1:1, 20 mL). The

mixture was stirred at room temperature under H₂overnight. The

catalyst was filtered off, and the filtrate was reduced in volume

under high vacuum and then lyophilized to give a voluminous foam

(120 mg, 99%). Crystallization from ethanol yielded pure (Ϫ)-4

(125 mg, 99%) as a white solid. [α]²_D⁰ϭ Ϫ70 (c ϭ 0.55, H₂O). H

1

2,3-Anhydro-1,4-di-O-benzyl-myo-inositol [(؊)-31]: A freshly pre-

pared solution of trifluoroperacetic acid^[23][from trifluoroacetic an-

hydride (10.6 mL, 75 mmol) and H₂O₂(2 mL, 85%, 70 mmol) in

dichloromethane (30 mL), see synthesis of (ϩ)-26] was added drop-

wise at 0 °C over 30 min to a suspension of dibenzylconduritol B

(Ϫ)-29 (5 g, 15.3 mmol) and Na₂CO₃(4.75 g, 45 mmol) in dichloro-

methane (60 mL). After the reaction mixture had been stirred for

3 h at room temperature, aqueous saturated NaHCO₃(50 mL) and

water (20 mL) were added slowly. After addition of Na₂S₂O₃(11 g,

44 mmol), the mixture was extracted four times with dichlorometh-

ane (4 ϫ 100 mL). The combined organic layer was washed with

brine and then dried. Evaporation of the solvent gave a white solid

(4.6 g). Recrystallization from cyclohexane/ethyl acetate (3:2)

yielded pure (Ϫ)-31 (3.7 g, 71%) of a colorless solid. [α]²_D⁰ϭ Ϫ72

NMR (D₂O): δ ϭ 3.30 (s, scyllo-inositol), 3.53 (AAЈ, 2 H, 3-H, 4-

H), 3.70 (MMЈ, 2 H, 2-H, 5-H), 3.97 (XXЈ, 2 H, 1-H, 6-H) ppm.

¹³C NMR (D₂O): δ ϭ 70.6 (C-2/C-5), 71.8 (C-1/C-6), 72.9 (C-3, C-

4) ppm. MS [EI, 70 eV, m/z (%)]: 154 (4), 144 (4), 102 (22), 86 (28),

73 (100), 60 (54). IR (KBr): ν˜ ϭ 3388 (br. s, ν[OH]), 2930 (w,

ν[CH_ali.]), 1681 (s), 1433 (m), 1205 (s), 1136 (s), 1065 (s), 1023 (s),

901 (w), 837 (m), 802 (m), 724 (m), 668 (m) cm^Ϫ1. HR-MS (ESI-

neg., TOF): m/z: 179.0515 [M Ϫ H]^Ϫcalcd. for C₆H₁₁O₆: 179.0556.

D-chiro-Inositol [(؉)-5]: A solution of (ϩ)-32 was allowed to react

under the same conditions as described for the preparation of (Ϫ)-

4 to give (ϩ)-5. [α]²_D⁰ϭ ϩ57.6 (c ϭ 0.9, H₂O). Identical R_f, ¹H

NMR, and ¹³C NMR spectroscopic data to those of (Ϫ)-4.

1

(c ϭ 0.25, CHCl₃), H NMR (CDCl₃): δ ϭ 3.21 (d, J ϭ 3.6 Hz, 1

L-chiro؊Inositol Hexakis(phosphate) [(؊)-33]: (1,5-Dihydro-2,4,3-

H, 2-H), 3.35 (m, 1 H, 3-H), 3.51(dd, J ϭ 10.2, J ϭ 8.1 Hz, 1 H, benzodioxaphosphepin-3-yl)diethylamine (470 mg, 2.0 mmol) was

6-H), 3.61(dd, J ϭ 10.2, J ϭ 8.1 Hz, 1 H, 5-H), 3.74 (d, J ϭ 8.2 Hz, added to a suspension of -chiro-inositol (Ϫ)-4 (50 mg, 0.27 mmol)

Eur. J. Org. Chem. 2003, 1958Ϫ1972

www.eurjoc.org

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1967

M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

and 1H-tetrazole (226 mg, 3.2 mmol) in anhydrous dichlorometh-

ane (20 mL) and the solution was stirred at room temperature over-

night. The product was worked up as described for 28. Purification

by flash chromatography on silica gel yielded hexa-O-(3-oxo-1,5-

dihydro-3λ^5Ϫ2,4,3-benzodioxaphosphepin-3-yl)--chiro-inositol

(200 mg, 60%) as a colorless foam with a purity Ͼ80%. ¹³C NMR

MgSO₄. Concentration under reduced pressure gave a white solid

(4.5 g, 81%). R_fϭ 0.13 (ethyl acetate/cyclohexane, 1:1). [α]²_D⁰ϭ Ϫ87

(c ϭ 0.23, CHCl₃). [α]²_D⁰ϭ Ϫ76 (c ϭ 0.82, acetone). ¹H NMR

(CDCl₃/[D₄]MeOH, 6:1): δ ϭ 2.09 (s, 3 H, CH₃), 2.10 (s, 3 H,

CH₃), 3.53 (dd, J ϭ 2.8, J ϭ 9.9 Hz, 1 H, 1-H), 3.94 (ψt, 1 H, J ϭ

11.1 Hz, 5-H), 4.04 (ψt, 1 H, J ϭ 2.5 Hz, 2-H), 4.40 (ψt, 1 H, J ϭ

(CDCl₃): δ ϭ 69.03Ϫ69.74 [m, 6 ϫ (CH₂)₂C₆H₄], 73.51 (m, CH), 10.9 Hz, 4-H), 4.89 (dd, J ϭ 2.5, J ϭ 10.7 Hz, 1 H, 3-H), 5.37 (ψt,

73.81 (m, CH), 76.28 (m, CH), 128.4 Ϫ129.4 (C_arom.), 134.41, 1 H, J ϭ 10.2 Hz, 6-H) ppm. ¹³C NMR (CDCl₃/[D₄]MeOH, 6:1):

134.51, 135.33, 135.47, 135.52, 136.88 (C_ipso) ppm. ³¹P{¹H} NMR δ ϭ 20.74 (CH₃), 20.90 (CH₃), 52.78 (C-4), 53.59 (C-5), 70.52 (C-

(CDCl₃): δ ϭ Ϫ1.30, Ϫ2.05, Ϫ2.74 ppm.

2), 71.23 (C-1), 74.69 (C-3), 74.77 (C-6), 170.50, 170.99 (CϭO)

ppm. MS [EI, 70 eV, m/z (%)]: 293, 291 (2, 2), 251, 249 (8, 8), 191,

189 (24, 23), 109 (18), 43 (100). IR (KBr): ν˜ ϭ 3475 (m, br.), 2975,

Hydrogenolysis of hexa-O-(3-oxo-1,5-dihydro-3λ^5Ϫ2,4,3-benzo-

dioxaphosphepin-3-yl)--chiro-inositol was carried out as described

for 28. Separation by HPLC assured a purity Ͼ 99%. [α]²_D⁰ϭ Ϫ24.4

(c ϭ 1.17, H₂O). ¹H NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ ϭ

4.30 (AAЈ, 2 H, 3-H, 4-H), 4.36 (MMЈ, 2 H, 2-H, 5-H), under

HDO (4.65) (XXЈ, 2 H, 1-H, 6-H) ppm. ¹³C NMR [D₂O, pH ad-

justed to 6 (ND₄OD)]: δ ϭ 72.9 (m, C-1/C-6), 73.3 (m, C-2/C-5),

76.5 (m, C-3, C-4) ppm. ³¹P{¹H} NMR [D₂O, pH adjusted to 6

(ND₄OD)]: δ ϭ 1.63 (PC-1, PC-6), 1.91 (PC-2, PC-5), 2.66 (PC-

3, PC-4) ppm. HR-MS (ESI-neg, phosphoric acid 0.002%, H₂O/

acetonitrile 1:1, Q-TOF): m/z: 658.8516 [M Ϫ H]^Ϫcalcd. for

C₆H₁₇O₂₄P₆: 658.8536.

2925 (w), 1744, 1722 (s), 1372 (m), 1225 (s), 1036 (m) cm^Ϫ1

.

C₁₀H₁₄O₆Br₂: (387.92): calcd. C 30.80, H 3.62; found C 30.45, H

3.42.

5,6-Didesoxy-5,6-dibromo-1,4-di-O-acetyl-D-myo-inositol [(؉)-41]:

The (Ϫ)-enantiomer 16 was cis-dihydroxylated as described for (ϩ)-

16. [α]²_D⁰ϭ ϩ80 (c ϭ 0.22, CHCl₃). Identical ¹H NMR and ¹³C

NMR spectroscopic data to those of (Ϫ)-41.

4,5-Didesoxy-4,5-dibromo-2,3,6-tri-O-acetyl-D-myo-inositol

[(؊)-

45]: p-Toluenesulfonic acid monohydrate (150 mg, 0.8 mmol) and

triethyl orthoacetate (11.3 mL, 79 mmol) were added to a solution

of (Ϫ)-41 (4.9 g, 12.6 mmol) in anhydrous tetrahydrofuran

(140 mL) under argon. The mixture was stirred vigorously for 12 h.

The solvent was removed under reduced pressure, and the residue

was dried under high vacuum. The residue was dissolved in aque-

ous acetic acid (80 mL, 80%) and stirred for 1 h at room tempera-

ture. The organic phase was evaporated, and the residue was dis-

solved in ethyl acetate (100 mL). The organic phase was washed

with saturated aqueous NaHCO₃(2 ϫ 50 mL) and then with brine

(50 mL). Evaporation of the ethyl acetate gave a colorless, volumin-

ous foam (5.0 g, 93%). For an analytical sample the resulting foam

was purified by flash chromatography (cyclohexane/ethyl acetate,

1:1) to yield pure (Ϫ)-45. R_fϭ 0.37 (ethyl acetate/cyclohexane, 1:1).

[α]²_D⁰ϭ Ϫ85 (c ϭ 0.17, CHCl₃). ¹H NMR (CDCl₃): δ ϭ 2.08 (s,

3 H, CH₃), 2.19 (s, 3 H, CH₃), 2.21 (s, 3 H, CH₃), 3.81 (dd, J ϭ

3.0, J ϭ 9.7 Hz, 1 H, 1-H), 4.02 (ψt, 1 H, J ϭ 10.9 Hz, 5-H), 4.28

(ψt, 1 H, J ϭ 10.9 Hz, 4-H), 5.04 (dd, J ϭ 2.8, J ϭ 10.9 Hz, 1 H,

3-H), 5.37 (ψt, 1 H, J ϭ 10.2 Hz, 6-H), 5.55 (ψt, 1 H, J ϭ 2.8 Hz,

2-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.49 (CH₃), 20.77 (CH₃),

20.83 (CH₃), 51.44 (C-4), 52.44 (C-5), 69.87 (C-1), 70.87 (C-2),

72.08 (C-3), 74.49 (C-6), 169.48, 170.13, 170.72 (CϭO) ppm. MS

[EI, 70 eV, m/z (%)]: 353, 351 (3, 4), 293, 291 (48, 40), 233, 231 (13,

11), 191, 189 (18, 19), 169 (19), 109 (49), 43 (100). IR (KBr): ν˜ ϭ

3480 (m, br.), 2992, 2965, 2934 (w), 1747 (s), 1428 (m), 1377 (m),

1229 (s), 1107 (m), 1054 (m) cm^Ϫ1. HR-MS (CI, (DE), iso-butane):

m/z: 430.93377 [M ϩ H]^ϩcalcd. for C₁₂H₁₇Br₂O₇: 430.93412.

D-chiro؊Inositol Hexakis(phosphate) [(؉)-33]: The (ϩ)-enantiomer

5 was phosphitylated as described for (Ϫ)-4. Oxidation, deprotec-

tion and purification as before gave (ϩ)-33. [α]²_D⁰ϭ ϩ22 (c ϭ 0.8,

1

H₂O). Identical H NMR, ¹³C NMR and ³¹P NMR spectroscopic

data to those of (Ϫ)-33.

1,4-Di-O-benzyl-myo-inositol [(؊)-30]: A solution of sodium metap-

eriodate (2.0 g, 9.5 mmol, 1.5 equiv.) and ruthenium trichloride

trihydrate (164 mg, 0.6 mmol) in water (20 mL) was added to a

vigorously stirred, ice-cooled solution of (Ϫ)-29 (2.1 g, 6.4 mmol)

in acetonitrile (80 mL). The stirring was continued until TLC

showed absence of starting material (ca. 7 min). The reaction was

quenched by addition of 20% aqueous Na₂S₂O₃(150 mL). The

aqueous layer was separated and extracted five times with ethyl

acetate (5 ϫ 200 mL). The combined organic layer was washed

twice with brine and dried with MgSO₄. Concentration under re-

duced pressure gave a white solid (1.9 g, 82%). m.p. 170 °C (ref.^[47]

172 °C). R_fϭ 0.25 (ethyl acetate/cyclohexane, 1:1). [α]²_D⁰ϭ Ϫ18.3

1

(c ϭ 2, MeOH). H NMR (CDCl₃/[D₄]MeOH, 6:1): δ ϭ 3.16 (dd,

J ϭ 9.7, J ϭ 2.0 Hz, 1 H, 3-H or 1-H), 3.31 (ψt, 1 H, J ϭ 9.4 Hz,

4-H or 6-H), 3.38 (dd, J ϭ 9.7, J ϭ 2.5 Hz, 1 H, 1-H or 3-H), 3.58

(ψt, 1 H, J ϭ 9.4 Hz, 5-H), 3.78 (ψt, 1 H, J ϭ 9.4 Hz, 4-H or 6-

H), 4.07 (ψt, 1 H, J ϭ 2.0 Hz, 2-H), 4.61 (ψq, 2 H, AB, Ph-CH₂),

4.79 (ψdd, 2 H, AB, Ph-CH₂), 7.16Ϫ7.38 (m, 10 H, Ph-H) ppm.

¹³C NMR (CDCl₃): δ ϭ 65.51 (C-2), 67.92 (C-1 or C-3), 68.30 (Ph-

CH₂), 68.49 (C-5), 70.79 (C-4 or C-6), 71.13 (Ph-CH₂), 75.46 (C-1

or C-3), 77.46 (C-4 or C-6), 127.76, 127.93, 128.01, 128.13, 128.42,

128.48 (C_arom.), 137.90, 138.73 (C_ipso). Further analytical data is in

accordance with the literature.^[47]

(1R,2R,3S,4R)-1,2,4-Tri-O-acetylconduritol C [(؊)-46]: Zinc dust

(6.1 g, 93 mmol) and a trace of iodine were added to a solution of

(Ϫ)-45 (2.9 g, 6.7 mmol) in anhydrous diethyl ether (150 mL) and

acetic acid (6.1 mL, 99%). The mixture was refluxed for 4 h and

stirred further for 12 h at room temperature. It was then filtered

and the residue washed with diethyl ether. The organic phase was

washed once with saturated aqueous NaHCO₃and then with brine.

Evaporation of the solvent gave a colorless, pasty oil. Separation

4,5-Didesoxy-4,5-dibromo-3,6-di-O-acetyl-D-myo-inositol [(؊)-41]:

A solution of sodium metaperiodate (4.74 g, 22 mmol, 1.5 equiv.)

and ruthenium trichloride trihydrate (200 mg, 0.8 mmol) in water

(30 mL) was added to a vigorously stirred, ice-cooled solution of

(1S,2R,3R,4S)-1,4-diacetoxy-2,3-dibromocyclohex-5-ene

(5.0 g, 14.2 mmol) in acetonitrile (140 mL, HPLC-grade). The stir-

ring was continued until TLC showed absence of starting material ate/cyclohexane, 1:1). [α]²_D⁰ϭ Ϫ177 (c ϭ 0.71, CHCl₃). ¹H NMR

(ϩ)-16 by flash chromatography (cyclohexane/ethyl acetate, 1:1) yielded

pure (Ϫ)-46 (1.8 g, 82%) as a colorless solid. R_fϭ 0.25 (ethyl acet-

(ca. 10 min). The reaction was quenched by addition of 20% aque-

ous Na₂S₂O₃(100 mL). The aqueous layer was separated and ex-

tracted four times with dichloromethane (4 ϫ 100 mL). The com-

bined organic layer was washed twice with brine and dried with

(CDCl₃): δ ϭ 2.04 (s, 3 H, CH₃), 2.12 (s, 3 H, CH₃), 2.13 (s, 3 H,

CH₃), 2.65 (br. s, 1 H, OH), 3.99 (dd, J ϭ 2.0, J ϭ 7.6 Hz, 1 H, 3-

H), 5.52 (dd, J ϭ 2.0, J ϭ 7.6 Hz, 1 H, 4-H), 5.58 (m, 2 H, 1-H,

2-H), 5.65 (dψq, 1 H, J ϭ 2.0, J ϭ 10.3 Hz, 6-H), 5.79 (dψt, 1 H,

1968

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2003, 1958Ϫ1972

Inositol Systems via Conduritols Prepared from p-Benzoquinone

FULL PAPER

J ϭ 2.3, J ϭ 10.2 Hz, 5-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.70 70.13 (s, C-5), 70.35 (d, J ϭ 3.1 Hz, C-2), 70.79 (m, C-4, C-6), 74.03

(CH₃), 20.74 (CH₃), 21.02 (CH₃), 67.92 (C-2), 70.56 (C-3), 71.98 (d, J ϭ 5.1 Hz, C-1), 126.86, 127.28 128.71, 128.79, 129.10, 129.18

(C-1), 72.84 (C-4), 126.94 (C-6), 127.64 (C-5), 170.00, 170.84, (C_arom.), 134.65, 134.84 (C_ipso), 169.53, 169.78, 171.26 (CϭO) ppm.

171.49 (CϭO) ppm. MS [EI, 70 eV, m/z (%)]: 212 (2), 183 (3), 170 ³¹P{¹H} NMR (CDCl₃): δ ϭ Ϫ0.29 (PC-1) ppm.

(5), 152 (5), 141 (7), 128 (11), 110 (45), 99 (11), 43 (100). IR (KBr):

(1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine

(0.7 g, 2.9 mmol) was added to a solution of the crude product thus

ν˜ ϭ 3459 (m, br.), 2985, 2955 (w), 1743 (s), 1372 (s), 1258 (s), 1231

(s), 1032 (m) cm^Ϫ1. HR-MS (CI, (DE), iso-butane): m/z: 273.09760

obtained (575 mg, 1.2 mmol) and 1H-tetrazole (350 mg, 5 mmol)

[M ϩ H]^ϩcalcd. for C₁₂H₁₇O₇: 273.09742.

in anhydrous dichloromethane (30 mL) under argon, and the mix-

ture was stirred at room temperature for 12 h. The product was

worked up as described for (Ϫ)-47. Separation by flash chromatog-

raphy (ethyl acetate) yielded pure (ϩ)-48 (420 mg, 50%) as a color-

(1R,2R,3S,4R)-1,2,4-Tri-O-acetyl-3-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)conduritol C [(؊)-47]: (1,5-Di-

hydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine

(0.6 g,

less foam. R_fϭ 0.10 (ethyl acetate). [α]²_D⁰ϭ ϩ5.8 (c ϭ 0.28, CHCl₃).

¹H NMR (CDCl₃): δ ϭ 2.03 (s, 3 H, CH₃), 2.08 (s, 3 H, CH₃), 2.23

(s, 3 H, CH₃), 4.85 (m, 2 H, C-1, C-5), 5.04 Ϫ5.49 [m, 14 H, C-3,

C-4, 3 ϫ (CH₂)₂C₆H₄], 5.80 (ψt, 1 H, J ϭ 2.8 Hz, 2-H), 5.83 (ψt,

1 H, J ϭ 10.2 Hz, 6-H), 7.16Ϫ7.38 (m, 12 H, Ph-H) ppm. ¹³C

NMR (CDCl₃): δ ϭ 20.37 (CH₃), 20.60 (CH₃), 20.99 (CH₃), 65.66

(s, C-4), 68.11 (m, C-6), 68.32Ϫ68.95 [m, (CH₂)₂C₆H₄], 69.14 (m,

C-2), 73.22 (d, J ϭ 4.8 Hz), 73.63 (m, C-1, C-5), 75.73 (m, C-3),

128.49Ϫ129.13 (C_arom.), 134.64, 134.73, 134.85, 134.93, 135.01,

135.33 (C_ipso), 169.16, 169.66, 170.71 (CϭO) ppm. ³¹P{¹H} NMR

(CDCl₃): δ ϭ 0.27, Ϫ0.10, Ϫ1.25 ppm. HR-MS [EI, (DE)]: m/z:

852.13485 [M]^ϩcalcd. for C₃₆H₃₉O₁₈P₃: 852.13491.

2.5 mmol) was added to a solution of 1,2,4-tri-O-acetylconduri-

tol C (Ϫ)-46 (600 mg, 2.2 mmol) and 1H-tetrazole (380 mg,

5.4 mmol) in anhydrous dichloromethane (20 mL), and the solution

was stirred at room temperature for 4 h. The mixture was cooled

to Ϫ40 °C, and an anhydrous solution of m-CPBA (1.6 g,

6.5 mmol) in dichloromethane (20 mL, dried with Na₂SO₄) was ad-

ded. The solution was allowed to warm to room temperature and

stirred for another hour. The reaction mixture was diluted with

dichloromethane (50 mL) and washed consecutively with 20%

aqueous sodium bisulfite (2 ϫ 60 mL), saturated NaHCO₃(3 ϫ

70 mL), and then with brine (70 mL). After evaporation of the di-

chloromethane the resulting colorless foam was purified by flash

chromatography (cyclohexane/ethyl acetate, 2:3) to yield (Ϫ)-47

(700 mg, 70%) as a colorless foam. R_fϭ 0.20 (ethyl acetate/cyclo-

D-epi-Inositol-1,4,5-trisphosphate [(؉)-49]: Pd/C (150 mg) was ad-

ded to a suspension of (ϩ)-48 (100 mg, 0.11 mmol) in ethanol/

water (1:1, 20 mL). The mixture was stirred at room temperature

under H₂overnight. The catalyst was filtered off, and the filtrate

was concentrated under high vacuum. The residue was dissolved in

ice-cooled 0.25  aqueous NaOH (10 mL) and stirred for 4 h. The

solution was neutralized by ion exchanger (H^ϩ, Dowex 50-X) and

filtered, and then activated carbon was added. The solution was

filtered again, and the filtrate was lyophilized to give 50 mg (99%)

hexane, 3:2). [α]²_D⁰ϭ Ϫ102 (c ϭ 0.56, CHCl₃). H NMR (CDCl₃):

1

δ ϭ 2.03 (s, 3 H, CH₃), 2.13 (s, 3 H, CH₃), 2.16 (s, 3 H, CH₃), 4.88

(dψt, 1 H, J ϭ 2.2, J ϭ 8.3 Hz, 3-H), 5.07 Ϫ5.23 [m, 4 H,

(CH₂)₂C₆H₄), 5.61 Ϫ5.68 (m, 2 H, 1-H, 5-H or 6-H), 5.74 Ϫ5.84

(m, 3 H, 2-H, 4-H, 5-H or 6-H), 7.24Ϫ7.40 (m, 4 H, Ph-H). ¹³C

NMR (CDCl₃): δ ϭ 20.60 (CH₃), 20.72 (CH₃), 20.99 (CH₃), 67.67

(C-1), 68.51 [d, J ϭ 6.1 Hz, (CH₂)₂C₆H₄], 68.71 [d, J ϭ 6.1 Hz,

(CH₂)₂C₆H₄], 69.96 (d, J ϭ 4.1 Hz), 70.56 (d, J ϭ 4.1 Hz) (C-2, C-

4), 75.34 (d, J ϭ 5.1 Hz, C-3), 126.86, 127.28 (C-5, C-6), 128.74,

128.80, 129.09, 129.17 (C_arom.), 134.83, 135.00 (C_ipso), 169.60,

170.02, 170.61 (CϭO) ppm. ³¹P{¹H} NMR (CDCl₃): δ ϭ Ϫ0.1

(PC-3) ppm. MS [EI, 70 eV, m/z (%)]: 454 (1) [M^ϩ], 395 (2), 335

(4), 201 (100), 43 (100). HR-MS [EI, (DE)]: m/z: 454.10295 [M]^ϩ

calcd. for C₂₀H₂₃O₁₀P: 454.10289.

1

of a colorless foam. [α]²_D⁰ϭ ϩ7.7 (c ϭ 2.85, H₂O). H NMR [D₂O,

pH adjusted to 6 (ND₄OD)]: δ ϭ 3.75 (ψs, 1 H, 3-H), 3.85 Ϫ4.04

(m, 3 H, 1-H, 5-H, 6-H), 4.13 (ψs, 1 H, 2-H), 4.70 (d, under HDO,

J ϭ 10.7 Hz, 4-H) ppm. ³¹P{¹H} NMR [D₂O, pH adjusted to 6

(ND₄OD)]: δ ϭ 1.84, 3.05, 4.58 ppm. HR-MS (ESI-neg, phos-

phoric acid 0.002%, H₂O/acetonitrile, 1:1, Q-TOF): m/z: 418.9525

[M Ϫ H]^Ϫcalcd. for C₆H₁₄O₁₅P₃: 418.9546.

2,3,6-Tri-O-acetyl-1,4,5-tri-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzo-

4,5-Didesoxy-4,5-dibromo-1,2,3,6-tetra-O-acetyl-D-myo-inositol

dioxaphosphepin-3-yl)-

metaperiodate (450 mg, 2.1 mmol, 1.5 equiv.) and ruthenium tri-

D

-epi-inositol [(؉)-48]: A solution of sodium

[(؊)-42]: 4,5-Didesoxy-4,5-dibromo-3,6-di-O-acetyl--myo-inositol

(Ϫ)-41 (5.3 g, 13 mmol) was dissolved in a cooled mixture of pyri-

chloride trihydrate (20 mg, 0.08 mmol) in water (3 mL) was added dine (20 mL) and acetic anhydride (15 mL). The mixture was

to a vigorously stirred, ice-cooled solution of (Ϫ)-47 (600 mg, stirred for 12 h. Evaporation of the solvent gave (Ϫ)-42 (5.9 g, 99%)

1.3 mmol) in acetonitrile (30 mL, HPLC-grade). The stirring was as a white solid. For an analytical sample, recrystallization from

continued until TLC showed absence of starting material (ca.

5 min). The reaction was quenched by addition of 20% aqueous

Na₂S₂O₃(30 mL). The aqueous layer was separated and extracted

four times with ethyl acetate (4 ϫ 40 mL). The combined organic

layer was washed twice with brine and dried with MgSO₄. Concen-

tration under reduced pressure gave a white solid (660 mg, 99%,

80% de). Further purification was rendered counterproductive by

protecting-group movement. NMR spectroscopic data for 2,3,6-tri-

O-acetyl-1-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-

ethanol yielded pure (Ϫ)-42 as a white solid. R_fϭ 0.56 (ethyl acet-

ate/cyclohexane, 2:3). [α]²_D⁰ϭ Ϫ49.5 (c ϭ 0.76, CHCl₃). [α]²_D⁰

ϭ

1

Ϫ69.4 (c ϭ 1.57, CH₂Cl₂). m.p. 161.5 °C. H NMR (CDCl₃): δ ϭ

1.99, 2.08, 2.10, 2.20 (4 ϫ s, 4 ϫ 3 H, CH₃), 4.05 (ψt, 1 H, J ϭ

10.9 Hz), 4.33 (ψt, 1 H, J ϭ 11.3 Hz) (4-H, 5-H), 5.05 (dd, J ϭ 2.8,

J ϭ 10.4 Hz, 1 H), 5.16 (dd, J ϭ 2.8, J ϭ 10.9 Hz, 1 H) (1-H, 3-

H), 5.56 (ψt, 1 H, J ϭ 2.8 Hz, 2-H), 5.57 (ψt, 1 H, J ϭ 10.2 Hz, 6-

H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.38 (CH₃), 20.43 (CH₃), 20.59

(CH₃), 20.66 (CH₃), 51.26, 52.31 (C-4, C-5), 68.61, 69.36, 71.32,

3-yl)--epi-inositol. ¹H NMR (CDCl₃): δ ϭ 2.07 (s, 3 H, CH₃), 2.13 71.37 (C-1, C-2, C-3, C-6), 168.93, 169.14, 169.27, 169.72 (CϭO)

(s, 3 H, CH₃), 2.18 (s, 3 H, CH₃), 3.68 (dd, J ϭ 3.1, J ϭ 9.7 Hz, 1 ppm. MS [EI, 70 eV, m/z (%)]: 395, 393 (1.3, 1.6), 333, 335 (6.7,

H, 5-H), 4.21 (ψs, 1 H, 4-H), 4.72 (dψt, 1 H, J ϭ 3.4, J ϭ 9.7 Hz, 6.0), 293, 291 (6.6, 6.3), 233, 231 (6.5, 7.4), 169 (8.0), 109 (25.4),

1-H), 4.97 (ψt, 1 H, J ϭ 3.3 Hz, 3-H), 5.05Ϫ5.17 [m, 4 H,

43 (100). IR (KBr): ν˜ ϭ 2981, 2964 (w), 1765, 1749 (s), 1368 (m),

(CH₂)₂C₆H₄], 5.57 (ψt, 1 H, J ϭ 9.9 Hz, 6-H), 5.74 (ψt, 1 H, J ϭ 1241 (s), 1213 (s), 1056 (m) cm^Ϫ1. C₁₄H₁₈O₈Br₂(471.93): calcd. C

2.8 Hz, 2-H), 7.21 Ϫ7.38 (m, 4 H, Ph-H) ppm. ¹³C NMR (CDCl₃): 35.47, H 3.83; found C 35.60, H 3.77. HR-MS (CI, (DE), iso-

δ ϭ 20.54 (CH₃), 20.73 (CH₃), 20.93 (CH₃), 67.68 (s, C-3), 68.44

[d, J ϭ 7.1 Hz, (CH₂)₂C₆H₄], 68.71 (d, J ϭ 7.1 Hz, (CH₂)₂C₆H₄),

butane): m/z: 472.94498 [M ϩ H]^ϩcalcd. for C₁₄H₁₉Br₂O₈:

472.94468.

Eur. J. Org. Chem. 2003, 1958Ϫ1972

www.eurjoc.org

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1969

M. Podeschwa, O. Plettenburg, J. vom Brocke, O. Block, S. Adelt, H.-J. Altenbach

FULL PAPER

5,6-Didesoxy-5,6-dibromo-1,2,3,4-tetra-O-acetyl-

D

-myo-inositol 4 °C. Sodium methoxide solution (200 µL of a 5.5  solution,

[(؉)-42]: The (ϩ)-enantiomer 41 was acetylated as described for

(Ϫ)-42 to give (ϩ)-42. [α]²_D⁰ϭ ϩ52 (c ϭ 0.65, CHCl₃). Identical ¹H

NMR and ¹³C NMR spectroscopic data to those of (Ϫ)-42.

1.1 mmol) was added dropwise over 10 min. The reaction mixture

was allowed to warm to room temperature and stirred for 12 h.

The solvent was removed, and the residue was dissolved in 0.25 

aqueous NaOH (10 mL) and refluxed for 2 h. The solution was

neutralized by ion exchanger (H^ϩ, Dowex 50-X) and filtered, and

the Dowex material was washed with water. The filtrate was first

concentrated under high vacuum and then lyophilized to give 7

(170 mg, 99%) as a colorless solid. ¹H NMR (CDCl₃): δ ϭ 3.44

(dd, J ϭ 2.1, J ϭ 9.7 Hz, 2 H, 1-H, 5-H), 3.69 (ψt, 1 H, J ϭ 2.5 Hz,

3-H), 3.80 (ψt, 1 H, J ϭ 9.9 Hz, 6-H), 4.03 (ψt, 2 H, J ϭ 2.5 Hz,

2-H, 4-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 69.07 (C-3), 72.29 (C-6),

73.99 (C-1, C-5), 76.70 (C-2, C-4) ppm. MS [EI, 70 eV, m/z (%)]:

144 (2), 102 (4), 73 (100), 60 (26). IR (KBr): ν˜ ϭ 3406 (s, br.), 2920

(1R,2R,3S,4R)-1,2,3,4-Tetra-O-acetylconduritol C [(؊)-43]: Acetic

acid (10 mL) and zinc dust (10 g, 150 mmol) were added to a solu-

tion of 4,5-didesoxy-4,5-dibromo-1,2,3,6-tetra-O-acetyl--myo-in-

ositol (Ϫ)-42 (4 g, 8.3 mmol) in anhydrous diethyl ether (200 mL).

The mixture was refluxed for 12 h and then filtered, and the residue

was washed with diethyl ether. The organic phase was washed once

with saturated aqueous NaHCO₃and then with brine. Evaporation

of the solvent gave a colorless oil. Crystallization from ethanol re-

moved most of the starting material. The filtrate was concentrated

under vacuum and the resulting residue purified by flash chroma-

tography on silica gel (cyclohexane/ethyl acetate, 7:3) to yield pure

(Ϫ)-43 (1.8 g, 68%). R_fϭ 0.24 (ethyl acetate/cyclohexane, 3:7). [α]

(w), 1634 (w), 1418 (w), 1132 (w), 1064 (w), 1048 (m) cm^Ϫ1

.

C₆H₁₂O₆(180.16): calcd. C 40.00, H 6.71; found C 39.84, H 6.86.

²⁰ϭ Ϫ192 (c ϭ 0.28, CHCl₃). ref.^[48][α]²_D⁰ϭ Ϫ194 (c ϭ 3.0,

1,2-Anhydro-3,6-di-O-benzyl-4,5-di-O-isopropyl-myo-inositol (38):

2,2-Dimethoxypropane (40 mL) and pyridinium p-toluenesulfonate

(150 mg, 0.6 mmol) were added to a solution of 31 (3.0 g,

8.76 mmol) in dry acetone (12 mL). The reaction mixture was

stirred for 16 h at room temperature.To the white suspension di-

ethyl ether, 2  sodium hydroxide (8 mL) and brine (8 mL) were

added subsequently. The stirring was continued for another 30 min.

The layers were separated, and the organic layer was washed with

brine, dried with sodium sulfate, and the solvents evaporated to

dryness to yield 3.2 g (96%) of 38 as a colorless solid, which was

D

1

CHCl₃). H NMR (CDCl₃): δ ϭ 2.03, 2.04, 2.07, 2.13 (4 ϫ s, 4 ϫ

3 H, CH₃), 5.20 (dd, J ϭ 1.5, J ϭ 8.3 Hz, 1 H, 3-H), 5.62 Ϫ5.72

(m, 4 H, 1-H, 2-H, 4-H, H_olef.), 5.80 (dψt, 1 H, J ϭ 1.6, J ϭ

10.8 Hz, H_olef.) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.65 (CH₃), 20.70

(2 ϫ CH₃), 20.90 (CH₃), 67.60, 69.48, 69.78 (C-1, C-2, C-4), 70.56

(C-3), 127.07, 127.51 (C-5, C-6), 169.68, 169.87, 170.23, 170.42

(CϭO) ppm. MS [EI, 70 eV, m/z (%)]: 212 (4), 152 (51.1), 110

(100),43 (69). IR (KBr): ν˜ ϭ 3087, 3013 (w), 2956 (w), 1758 (s),

1372 (m), 1230 (s), 1044 (m) cm^Ϫ1. C₁₄H₁₈O₈(314.10): calcd. C

53.50, H 5.77; found C 53.65, H 5.69.

1

used for further conversions without purification. m.p. 104 °C. H

NMR (CDCl₃): δ ϭ 1.48 (s, 3 H, CH₃), 1.51 (s, 3 H, CH₃), 3.25 (d,

J ϭ 3.4 Hz, 1 H, 1-H), 3.39 (m, 1 H, 2-H), 3.55 (dd, J ϭ 9.9, J ϭ

8.8 Hz, 1 H, 5-H), 3.78 (dd, J ϭ 8.6, J ϭ 9.9 Hz, 1 H, 4-H), 3.98

(d, J ϭ 8.8 Hz, 1 H, 6-H), 3.98 (dd, J ϭ 2.0, J ϭ 8.6 Hz, 1 H, 3-

H), 4.75 Ϫ4.98 (m, 4 H, Ph-CH₂), 7.33 Ϫ7.49 (m, 10 H, Ph-H)

ppm. ¹³C NMR (CDCl₃): δ ϭ 27.4 (CH₃), 27.6 (CH₃), 56.8 (C-2),

56.9 (C-1), 72.3 (Ph-CH₂), 72.6 Ph-CH₂), 75.6 (C-4), 76.4 (C-6),

76.6 (C-3), 80.6 (C-5), 112.0 [C(CH₃)₂], 128.2 Ϫ129.0 (C_arom),

138.2, 138.6 (C_ipso) ppm. IR (KBr): 3080Ϫ3010 (w), 3000Ϫ2850

(m), 1490Ϫ1450 (m), 1080 (s, br.), MS [EI, 70 eV, m/z (%)]: 382 (5)

[M^ϩ], 107 (22), 91 (100) cm^Ϫ1. C₂₃H₂₆O₅(382.5): calcd. C 72.23,

H 6.85; found C 72.29, H 6.88.

(1S,2S,3R,4S)-1,2,3,4-Tetra-O-acetylconduritol C [(؉)-43]: The

(ϩ)-enantiomer 42 was debrominated as described for (Ϫ)-43 to

give (ϩ)-43. [α]²_D⁰ϭ ϩ188 (c ϭ 0.6, CHCl₃). Identical ¹H NMR

and ¹³C NMR spectroscopic data to those of (Ϫ)-43.

Hexa-O-acetyl-epi-inositol (44): A solution of sodium metaperiod-

ate (1.1 g, 5.2 mmol, 1.5 equiv.) and ruthenium trichloride trihydr-

ate (100 mg, 0.4 mmol) in water (12 mL) was added to a vigorously

stirred, ice-cooled solution of (1R,2R,3S,4R)-1,2,3,4-tetra-O-ace-

tylconduritol C (Ϫ)-43 (1.1 g, 3.4 mmol) in acetonitrile (60 mL).

The stirring was continued until TLC showed absence of starting

material (ca. 10 min). The reaction was quenched by addition of

20% aqueous Na₂S₂O₃(50 mL). The aqueous layer was separated

and extracted with ethyl acetate (4 ϫ 100 mL). The combined or-

ganic layer was washed twice with brine and concentrated under

reduced pressure. The residue was dissolved in a cooled mixture of

pyridine (20 mL) and acetic anhydride (10 mL). The mixture was

stirred for 12 h. Evaporation of the solvent under high vacuum and

recrystallization from ethanol yielded pure 44 as a white solid

1-O-Allyl-2,5-di-O-benzyl-scyllo-inositol (39): Sodium (450 mg,

20 mmol) was dissolved in allylic alcohol (5 mL). 38 (150 mg,

0.4 mmol) was added to the solution and the reaction mixture was

heated for 24 h at 90 °C. After the reaction was complete, the mix-

ture was diluted with THF and adjusted to pH 0 by addition of 4

 HCl. After stirring at room temperature, solid NaHCO₃was ad-

ded, and the aqueous layer was extracted several times with ethyl

acetate (5 ϫ 50 mL). The combined organic layer was dried and the

solvents evaporated. Recrystallization of the crude product from

hexane/ethyl acetate delivered 39 as the pure scyllo isomer (96 mg,

60%). m.p. 179 °C. ¹H NMR ([D₆]DMSO): δ ϭ 3.07 Ϫ3.39 (m,

6 H); 4.17 Ϫ4.34 (m, 2 H, O-CH₂), 4.69 Ϫ4.87 (m, 4 H, Ph-CH₂),

4.90 (d, J ϭ 4.0 Hz, 1 H, -OH), 4.96 (d, J ϭ 4.0 Hz, 1 H, -OH),

5.03 Ϫ5.22 (m, 3 H, -OH and CHϭCH₂), 5.88 Ϫ5.94 (m, 1 H,

CHϭCH₂), 7.22Ϫ7.44 (m, 10 H, Ph-H) ppm. ¹³C NMR

([D₆]DMSO): δ ϭ 73.8, 74.3, 74.4, 74.6, 74.8, 83.0 (2 C), 83.4, 116.1

(CHϭCH₂), 127.6Ϫ128.6 (C_arom), 136.9 (CHϭCH₂), 140.0, 140.3

(C_ipso) ppm. MS [EI, 70 eV m/z (%)]: 400 (2), [M^ϩ], 359 (3), 309

(100), 107 (45), 91 (100).

1

(1.1 g, 74%). H NMR (CDCl₃): δ ϭ 1.98 (s, 3 H, CH₃), 1.99 (s, 2

ϫ 3 H, CH₃), 2.02(s, 3 H, CH₃), 2.15 (s, 2 ϫ 3 H, CH₃), 5.07 (dd,

J ϭ 3.3, J ϭ 10.4 Hz, 2 H, 1-H, 5-H), 5.11 (ψt, 1 H, J ϭ 3.3 Hz,

3-H), 5.59 (ψt, 2 H, J ϭ 3.5 Hz, 2-H, 4-H), 5.69 (ψt, 1 H, J ϭ

10.7 Hz, 6-H) ppm. ¹³C NMR (CDCl₃): δ ϭ 20.31(CH₃), 20.35 (2

ϫ CH₃), 20.54 (CH₃), 20.64 (2 ϫ CH₃), 65.74 (C-3), 67.26 (C-6),

68.49 (C-2, C-4), 68.79 (C-1, C-5), 169.05 (CϭO), 169.39 (2 ϫ Cϭ

O), 169.69 (CϭO), 169.93 (2 ϫ CϭO) ppm. MS [EI, 70 eV, m/z

(%)]: 390 (2), 373 (2), 330 (2), 270 (9), 210 (80), 168 (100), 126 (50),

43 (79). IR (KBr): ν˜ ϭ 2992, 2965 (w), 1751 (s, br.), 1433 (m), 1370

(s), 1225 (s, br.), 1087 (m), 1050 (s) cm^Ϫ1. C₁₈H₁₄O₁₂(432.126777):

calcd. C 50.00, H 5.59; found C 49.89, H 5.53. HR-MS [CI (DE),

iso-butane]: m/z: 433.13490 [M ϩ H]^ϩcalcd. for C₁₈H₂₅O₁₂:

433.13460.

scyllo-Inositol (6): 39 (96 mg, 0.24 mmol) was dissolved in methanol

(10 mL). Palladium on charcoal (10%, 20 mg) was added and the

mixture was heated under reflux for 6 h. The charcoal was filtered

off and washed thoroughly with methanol, and the organic layer

epi-Inositol (7): Hexa-O-acetyl-epi-inositol 44 (400 mg, 0.9 mmol)

was suspended in anhydrous methanol under argon and cooled to

1970

 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2003, 1958Ϫ1972

Inositol Systems via Conduritols Prepared from p-Benzoquinone

FULL PAPER

S. Adelt, O. Plettenburg, G. Dallmann, F. P. Ritter, S.

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was taken to dryness. The residue was taken up in 2  HCl and

heated to 80 °C. The reaction mixture was allowed to cool to room

temperature, neutralized by addition of sodium hydroxide solution

(10 ) and extracted several times with ethyl acetate (5 ϫ 50 mL).

The combined organic layer was dried and the solvents evaporated

and the crude product was taken up in methanol/water (1:1; 5 mL).

Palladium on charcoal (10%, 20 mg) was suspended in methanol/

water (10 mL) and stirred under an atmosphere of H₂for 15 min.

The solution of the crude product in methanol was added via a

syringe, and stirring under H₂was continued for 12 h. The reaction

mixture was filtered, and the residue was washed thoroughly with

water. The filtrate was taken to dryness, and the precipitate was

recrystallized from water/methanol to yield 6 as a colorless solid

(37 mg, 85%). ¹H NMR (D₂O): δ ϭ 3.30 (s, 6 H, 1-H Ϫ 6-H) ppm.

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Acknowledgments

We thank Dr. W. V. Turner for critical reading of the manuscript.

This work was supported by the Deutsche Forschungsgemeinschaft

(Grant VO 348/3-1) and the Fonds der Chemischen Industrie. We

are grateful to the Bayer AG Company for supporting many as-

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Received October 15, 2002

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Eur. J. Org. Chem. 2003, 1958Ϫ1972

Article Doi

Stereoselective synthesis of myo-, neo-, L-chiro, D-chiro, allo-, scyllo-, and epi-inositol systems via conduritols prepared from p-benzoquinone

DOI: 10.1002/ejoc.200200572

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