Flexible stereo- and regioselective synthesis of myo-inositol phosphates (part 1): Via symmetrical conduritol B derivatives

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Flexible Stereo- and Regioselective Synthesis of myo-Inositol Phosphates

(Part 1): Via Symmetrical Conduritol B Derivatives

Michael A. L. Podeschwa,^[a]Oliver Plettenburg,^[a]and Hans-Josef Altenbach*^[a]

Keywords: Asymmetric synthesis / Biocatalytic resolution / Inositol phosphates / Natural products / Phosphorylation /

Protecting groups

A practical route is described for the preparation of myo-ino-

functionalization of axial and equatorial hydroxy groups al-

sitol polyphosphates. Optically pure myo-inositol derivatives lows the synthesis of symmetric inositol phosphates as well

can be prepared from p-benzoquinone in both forms by enzy- as unsymmetrical, enantiomerically pure inositol phosphates.

matic resolution of a C₂-symmetric diacetoxyconduritol B key

intermediate, followed by cis-dihydroxylation. Selective

Germany, 2005)

Introduction

pounds in both forms can easily be prepared from p-benzo-

quinone by enzymatic resolution of diacetoxyconduritol B

(3) to yield the building blocks for this procedure. Conduri-

tol B derivatives seemed to be ideal intermediates for the

synthesis of myo-inositol systems for two main reasons:

first, conduritol B systems are C₂-symmetric, which means

that cis-dihydroxylation of the double bond gives only one

diastereoisomeric product, and second, several conduritol B

systems are readily available synthetically in both enantio-

meric forms by epoxide formation and nucleophilic ring

opening. Protected myo-inositol systems 5 and ent-5, which

have pairwise differentiated (orthogonal protection) hy-

droxy groups, are obtained from C₂-symmetric conduritol B

systems 4 and ent-4 (see Scheme 1), respectively. Because of

the structural peculiarity of myo-inositol systems, the enan-

tiomeric systems 5 and ent-5 can lead to different re-

gioisomeric myo-inositol bis- and tetrakisphosphates,

namely bisphosphates d-myo-Ins(1,2)P₂[(–)-8], d-myo-

Ins(2,3)P₂[(+)-8] (it is clear that d-2,3- corresponds to

l-1,2-bisphosphate and likewise in the other cases), d-myo-

Ins(4,5)P₂[(–)-9], d-myo-Ins(5,6)P₂[(+)-9], d-myo-Ins(3,6)-

P₂[(–)-10], and d-myo-Ins(1,4)P₂[(+)-10], and tetrakisphos-

phates d-myo-Ins(1,2,4,5)P₄[(–)-11], d-myo-Ins(2,3,5,6)P₄

[(+)-11], d-myo-Ins(1,2,3,6)P₄[(+)-12], d-myo-Ins(1,2,3,4)P₄

[(–)-12], d-myo-Ins(3,4,5,6)P₄[(+)-13], and d-myo-

Ins(1,4,5,6)P₄[(–)-13].

Inositol phosphates play key functions in biological sys-

tems as single compounds^[1–3]or as part of more complex

structures, for example glycosyl phosphatidyl inositol sys-

tems^[4,5]and phosphatidylinositol phosphates.^[6]A new level

of attention has been focused on inositol phosphates, espe-

cially over the last two decades, after the discovery in 1983

that myo-inositol 1,4,5-trisphosphate [1; myo-Ins(1,4,5)P₃] is

a Ca²⁺-mobilizing second messenger.^[7,8]Since then quite a

large number of inositol phosphates, from Ins-P₁to Ins-P₆

and even more highly phosphorylated systems with pyro-

phosphate groups, have been found in nature, establishing

a complex inositol phosphate cascade in their metabolism,

although their specific role has not been elucidated in each

case. For biochemical studies the availability of inositol

phosphates of defined structure is essential, and a method

for their synthesis is urgently needed.

Key intermediates for the synthesis of myo-inositol poly-

phosphates are the corresponding hydroxy group(s) pro-

tected derivatives in enantiomerically pure form with free

hydroxy group(s) at the desired phosphorylation position.

Such protected inositol derivatives have been synthesized

by various methods, such as from achiral myo-inositol by

stereoselective protection and resolution, or from synthetic

intermediates prepared from chiral building blocks either

from the chiral pool or by de novo synthesis.^[9]

Regioselective manipulation within the cis-diol group af-

ter dihydroxylation, by selective protection of the equatorial

hydroxy group (see compound 6) or the axial group (see

compound 7), gives appropriate precursors for the synthesis

of myo-inositol mono-, tris-, and pentakisphosphates. Such

a desymmetrization increases the potential of this symmet-

rical approach significantly. In this article we will demon-

strate the utility of this approach.

In the present work a de novo strategy for the prepara-

tion of inositol derivatives is applied. Optically pure com-

[a] Institut für Organische Chemie, Bergische Universität Wupper-

tal,

Gaussstrasse 20, 42097 Wuppertal, Germany

Fax: +49-202-439-2648

E-mail: orgchem@uni-wuppertal.de

Eur. J. Org. Chem. 2005, 3101–3115

DOI: 10.1002/ejoc.200400911

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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

FULL PAPER

blocks, as their hydroxy groups are protected in an orthogo-

nal way. However, this concept is certainly not limited to

the given examples and should prove valuable for the prepa-

ration of further compounds.

It is well known that diol (+)-2 can be used for the prepa-

ration of 1,4-di-O-benzylconduritol B [(+)-14]. To this end

(+)-14 was synthesized in a one-pot procedure in 70% yield

from diol (+)-2, as reported previously.^[12]Subsequent

acetylation of the free hydroxy groups gave (+)-15 (see

Scheme 2). The diacetate (+)-3 could be converted in the

same way into the enantiomer (–)-14.

Scheme 1.

Results and Discussion

Synthesis of Symmetrical Conduritol B Building Blocks

Scheme 2. Reagents and conditions: (a) BnOH, THF, NaOBn

(70%). (b) Ac₂O, pyridine (76%). (c) THF, powdered molecular

sieves, KOH (77%). (d) THF, powdered molecular sieves, KOH

then MeOH (70%). (e) CH₂Cl₂, dibenzyl phosphate (55%).

The known diacetoxydibromocyclohex-5-enes (+)-3 and

(–)-3 [or the corresponding diols (–)- and (+)-2] were used

as the enantiomerically pure building blocks^[10,11]for the

synthesis of all the myo-inositol derivatives described. Race-

mic 3 can easily be prepared from p-benzoquinone in three

steps and 70% overall yield. Enantiopure compounds were

obtained by hydrolysis of racemic diacetate 3 with PPL (pig

pancreas lipase, type II from Sigma–Aldrich Chemie

GmbH) in Et₂O/phosphate buffer at pH = 7.0. The hydroly-

sis stops after 50% conversion of the starting material and

proceeds with excellent enantioselectivity (Ͼ99% ee) for

both the remaining diacetate (+)-3 and the resulting diol

(+)-2. The products can easily be separated on a 100-g scale

due to their different solubilities in dichloromethane.

The diphosphorylated conduritol B derivative (+)-17 was

synthesized^[11]by double allylic opening with dibenzyl

phosphate of anti-benzene dioxide (–)-16, which was syn-

thesized in one step from the enantiomeric building blocks

(Scheme 2).

These C₂-symmetric conduritol B systems are the start-

ing points for the syntheses of a number of myo-inositol

polyphosphates.

To avoid confusion, it should be mentioned that for the

synthesis of meso or racemic compounds all routes can be

carried out employing either racemic 2 or 3. Besides the

benefits of a shortened synthetic route, this facilitates puri-

Synthesis of myo-Inositol Polyphosphates from Di-O-

benzylconduritol B Derivatives

The intermediates obtained by the above-mentioned

fication by recrystallization, since the racemic intermediates routes were used for the preparation of myo-Ins(1,2)P₂

show an increased tendency to crystallize. The presented [(–)-8], myo-Ins(4,5)P₂[(–)-9], myo-Ins(1,2,4,5)P₄[(–)-11],

intermediates can be used as valuable inositol building and their enantiomers (see Scheme 3).

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myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

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Scheme 3. Reagents and conditions: (a) RuCl₃, NaIO₄, acetonitrile

(99%). (b) (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-

ylamine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (60–65%). (c) 1. Pd/

C, H₂, ethyl acetate/ethanol; 2. 0.25 n NaOH (99%). (d) Pd/C, H₂,

ethanol/water (99%).

Scheme 4. Reagents and conditions: (a) RuCl₃, NaIO₄, acetonitrile

(99%). (b) Pd/C, H₂, ethanol/water (99%). (c) Ac₂O, pyridine

(99%). (d) (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-

ylamine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (80%). (e) 1. Pd/C,

H₂, ethyl acetate/ethanol; 2. 0.25 n NaOH (99%).

Flash cis-dihydroxylation of the conduritol B derivative

(+)-15 with ruthenium trichloride and sodium metaperiod-

ate gave the protected and phosphorylated myo-inositol de-

rivative (+)-18 in high yield (see Scheme 3). In the case of

the symmetrical approach, cis-dihydroxylation of the con-

duritol B derivatives led to only one product, with a myo

configuration of the resulting inositol. The direct phosphor-

ylation of the free hydroxy groups of (+)-18 with (1,5-dihy-

As previously described, it is possible to synthesize the

tetrakisphosphate isomers myo-Ins(1,2,3,6)P₄[(+)-12]^[13,14]

and myo-Ins(3,4,5,6)P₄[(+)-13]^[11]from the precursor (+)-

17.

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

and

subsequent oxidation with m-CPBA gave (+)-19. Hydrogen-

ation of (+)-19 followed by saponification of the acetate

protecting groups furnished myo-Ins(1,2)P₂[(–)-8] in quan-

titative yield.

Differentiation within the cis-Diol Moiety for the Synthesis

of myo-Inositol Mono-, Tris-, and Pentakisphosphates

Synthesis of myo-Ins(1)P₁[(–)-30]

In the case of the synthesis of myo-Ins(4,5)P₂[(–)-9], the

precursor (+)-14 was first phosphorylated to form the pro-

tected conduritol B (+)-20, which was then cis-dihydrox-

ylated under the conditions described above. Hydrogena-

tion gave the target compound myo-Ins(4,5)P₂[(–)-9].

It should also be noted that the intermediate tetraol (+)-

22, which was obtained by flash cis-dihydroxylation of (+)-

14, is a useful intermediate for the synthesis of myo-

Ins(1,2,4,5)P₄[(–)-11], as reported earlier by our group.^[13]

Phosphorylation of (+)-22 and deprotection by Pd/C-cata-

lyzed hydrogenation gave myo-Ins(1,2,4,5)P₄[(–)-11] in 70%

yield over two steps.

For the synthesis of myo-Ins(1)P₁[(–)-30], the axial hy-

droxy group of the cis-diol moiety of (+)-18 has to be re-

gioselectively protected. Such desymmetrization yielded the

appropriate precursor for the synthesis of monophosphates.

The regioselective protection of the axial 2-OH group for

the synthesis of (–)-30 did not involve the previously re-

ported tedious, multistep method involving temporary pro-

tection of the equatorial 1-OH with dibutyltin.^[15]Instead,

the two hydroxy groups were differentiated by monofunc-

tionalization of the axial hydroxy group of (+)-18. Thus,

treatment of (+)-18 with triethyl orthoacetate under acidic

conditions in anhydrous THF resulted in the formation of

an intermediate orthoester, which was directly converted

with acetic acid into the axial acetate (+)-28 (see

Scheme 5).^[16]The regioselectivity in this reaction can be

traced back to stereoelectronic effects.^[17]

Synthesis of myo-Inositol Polyphosphates from 1,4-

Diphosphorylated Conduritol B Derivative (+)-17

The phosphorylation was performed by treatment with

cis-Dihydroxylation of (+)-17 with RuCl₃/NaIO₄and (1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine

subsequent Pd/C-catalyzed deprotection by hydrogenolysis in the presence of 1H-tetrazole and subsequent oxidation

gave myo-Ins(3,6)P₂[(–)-10] in excellent yield (see of the resulting phosphite with m-CPBA to give (+)-29. De-

Scheme 4). The enantiomer (–)-17 gives myo-Ins(1,4)P₂protection, carried out by hydrogenation followed by cleav-

[(+)-10] in a similar manner.

age of the acetate groups in aqueous NaOH, delivered the

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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

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Synthesis of myo-Ins(2)P (39), myo-Ins(2,3,6)P₃[(+)-42],

and myo-Ins(2,4,5)P₃[(–)-44] by a Forced Protecting-Group

Migration

We also tried to use 22 for the synthesis of a tribenzyl-

ated derivative. Employing racemic material, we were able

to synthesize the cyclic acetal by a simple zinc chloride cata-

lyzed reaction in benzaldehyde (see Scheme 7). The re-

sulting exo product 33 (exo-phenyl) is almost insoluble in

benzaldehyde and precipitates from the reaction mixture,

thereby driving the equilibrium to this product. The iso-

lated product is pure enough to be used in the ensuing reac-

Scheme 5. Reagents and conditions: (a) 1. MeC(OEt)₃, p-TSA; 2.

80% HOAc (99%). (b) (1,5-Dihydro-2,4,3-benzodioxaphosphepin- tions without purification; its conformation was unambigu-

3-yl)diethylamine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (60%). (c)

1. Pd/C, H₂, ethanol/water; 2. 0.25 n NaOH (99%).

ously assigned by NOE experiments on the acetylated deriv-

ative 49 (structure not illustrated; see Exp. Sect.). Reduction

of this acetal with borane–tetrahydrofuran complex in the

presence of dibutylboryl triflate,^[20]as described for other

acetals of carbohydrates, led to the tribenzylated isomers

in a ratio of 3:1, which were easily separable by column

target compound myo-Ins(1)P₁[(–)-30] in quantitative yield.

chromatography.

The optical rotation value of myo-Ins(1)P₁[(–)-30] was

found to be –2.6 (pH adjusted to 6 with NH₄OH), which

differs greatly from the previously reported value of

Billington et al.^[18](+3.55, pH = 9, as the dicyclohexyl-

ammonium salt). The main reason for this is that the op-

tical rotation is strongly dependent on the chosen pH value.

Pizer et al.^[19]have pointed out that the optical rotation of

myo-Ins(1)P₁[(–)-30] changes in sign when the pH value of

the solution is adjusted from basic (+3.4, pH adjusted to 9

with cyclohexylamine) to acidic (–9.8, pH = 2) conditions.

Our obtained values are +4.4 (pH adjusted to 9 with

NH₄OH), and –6.1 [pH = 2 (free acid)], thus confirming

the synthesis of (–)-30.

Scheme 7. Reagents and conditions: (a) benzaldehyde dimethylace-

tal, p-TSA, THF (69%). (b) 1 m BH₃in THF, 1 m Bu₂BOTf in

Synthesis of myo-Ins(1,4,5)P₃[(–)-1]

CH₂Cl₂, NEt₃(87%).

For the synthesis of myo-Ins(1,4,5)P₃[(–)-1] the tetraol

(+)-22 was monofunctionalized under the above-mentioned

conditions for the selective functionalization of an axial hy-

droxy group to give the direct precursor (–)-31 (see

Scheme 6). This easy and effective procedure allows the se-

However, when we employed the enantiomerically pure

starting material (+)-22 for acetalization under various re-

action conditions (zinc chloride in benzaldehyde, as men-

tioned above, or benzaldehyde dimethyl acetal and p-tolu-

lective protection of the single axial OH group in 22.

enesulfonic acid as catalyst), the lower tendency of the pro-

duct to crystallize prevented formation of a single reaction

product. We have frequently observed in our work with

conduritol and inositol derivatives that enantiomerically

pure materials are less likely to crystallize than the corre-

sponding racemates. Although the exo isomer (–)-33 is still

the less soluble one, its solubility is high enough to prevent

precipitation of one diastereoisomer from the reaction mix-

Scheme 6. Reagents and conditions: (a) 1. MeC(OEt)₃, p-TSA; 2.

ture so the reaction leads to a 1:1 mixture of the exo and

80% HOAc (95%). (b) (1,5-Dihydro-2,4,3-benzodioxaphosphepin-

endo isomers (–)-33 and (+)-34 (endo-phenyl). The two iso-

3-yl)diethylamine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (87%). (c)

mers can be separated by careful column chromatography,

however. The endo diastereoisomer (+)-34 was unambigu-

ously assigned by NOE experiments, where a strong cross

1. Pd/C, H₂, ethanol/water; 2. 0.25 n NaOH (98%).

Phosphorylation under the conditions described above peak between 2-H and the acetal-H can be observed.

gave (–)-32 in excellent yield. Hydrogenolysis and cleavage Reduction of the exo diastereoisomer under the above-

of the acetate group in aqueous NaOH delivered the target mentioned conditions led to formation of the 1- and 2-ben-

compound myo-Ins(1,4,5)P₃[(–)-1] by a short and highly zylated triols (–)-35 and (+)-36 in a 46:54 ratio. The endo

efficient reaction sequence.

diastereoisomer delivers the 2-benzyl product (+)-36 in 75%

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myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

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isolated yield with no detectable amounts of the 1-benzyl

product. Thus, this route, although it opens access to two

interesting enantiopure tribenzylated triol building blocks,

is not suitable for the synthesis of the desired myo-Ins(2,4,5)

P₃[(–)-44]. We therefore looked for a different strategy to

deliver a suitably protected building block in high yields.

One problem associated with the use of esters as protect-

ing groups in polyhydroxylated systems is the tendency for

intramolecular transesterification, which leads to migration

of the acyl function to a neighboring alcohol.^[21]Protecting-

group migration can be observed under mild basic or acidic

conditions. However, one might be able to exploit this usu-

ally unwanted side-reaction for synthetic purposes if the

equilibrium can be shifted to one product or the other.

In the case of the acetylated (+)-28, we hoped that we

could exploit the greater stability of an equatorial acetate

over the thermodynamically less favorable axial acetate in

(+)-28 to obtain (+)-37. Whereas there was no migration of

the axial acetate in position 2 to the equatorial position 1

on treatment of (+)-28 under mildly basic conditions with

K₂CO₃in CH₂Cl₂or under mildly acidic conditions with

acetic acid, the treatment of (+)-28 under more forcing con-

ditions with trimethylsilyl trifluoromethanesulfonate in an-

hydrous diethyl ether led to the desired product with a free

axial hydroxy group (see Scheme 8). The success of this con-

version can easily be observed by NMR spectroscopy (see

Figure 1). The signal of 2-H is strongly shifted upfield, from

δ = 5.70 ppm to δ = 4.34 ppm, while that for 1-H is shifted

downfield from δ = 3.68 ppm to δ = 4.88 ppm.

Scheme 8. Reagents and conditions: (a) TMS–OTf, CH₂Cl₂

(100%). (b) (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-

ylamine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (60%). (c) 1. Pd/C,

H₂, ethanol/water; 2. 0.25 n NaOH (98%). (d) Pd/C, H₂, ethyl ace-

tate/ethanol (99%).

As a further example of the opportunities provided by

this concept of forced protecting-group migration for the

synthesis of enantiomerically pure myo-inositol polyphos-

phates, the synthesis of myo-Ins(2,4,5)P₃(–)-44 is described

(see Scheme 9).

Scheme 9. Reagents and conditions: (a) THF, 2 n HCl (60%). (b)

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

tetrazole, CH₂Cl₂, then m-CPBA. (c) 1. Pd/C, H₂, ethanol/water; 2.

0.25 n NaOH (50%).

This useful intermediate (+)-37 was also employed in the

synthesis of more inositol-phosphates. Further conversion

Previous work led us to propose that enantiopure (–)-31

of the protecting groups, phosphorylation, and deprotec- would be an ideal starting material for the synthesis of myo-

tion yielded myo-Ins(2)P (39) and myo-Ins(2,3,6)P₃[(+)-42] Ins(2,4,5)P₃[(–)-44] if the axial acetate group could be in-

(see Scheme 8).

duced to migrate analogously. Initial attempts, in anhydrous

1

Figure 1. Comparison of the H NMR spectra of 28 (A) and 37 (B).

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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

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diethyl ether with TMS–OTf, were unsuccessful. It was

found in the end that migration does take place in tetra-

hydrofuran on addition of 2 n HCl and stirring at 80 °C for

36 h. The crude product contains, besides the product

(–)-43, the starting material (–)-31 and the de-O-acetylated

product (+)-22 in a 3:5:2 ratio. Longer reaction times re-

sulted in a higher proportion of the saponification product.

The desired compound (–)-43 was isolated by flash

chromatography in 30% yield; the starting material was also

re-isolated in 50% yield, which corresponds to a product

yield of 60% based on converted material. Phosphorylation

with (1,5-dihydro-2,4,3-benzodioxaphosphepin-3-yl)dieth-

ylamine in the presence of 1H-tetrazole, with subsequent

oxidation with m-CPBA and then deprotection, delivered

the desired product myo-Ins(2,4,5)P₃[(–)-44] in excellent

yield.

Conclusions

The present work further emphasizes the potential of

(+)- and (–)-3 as versatile building blocks in the construc-

tion of nonracemic inositol polyphosphates. The efficient,

high-yielding routes described allowed the synthesis of se-

veral myo-inositol polyphosphates in both enantiomeric

forms, namely myo-Ins(1)P [(–)-30], myo-Ins(2)P (39), myo-

Ins(1,2)P₂[(–)-8], myo-Ins(4,5)P₂[(–)-9], myo-Ins(3,6)P₂

[(–)-10], myo-Ins(1,4,5)P₃[(–)-1], myo-Ins(2,4,5)P₃[(–)-44],

myo-Ins(1,3,6)P₃[(–)-48], myo-Ins(2,3,6)P₃[(+)-42], myo-

Ins(1,2,4,5)P₄[(–)-11], myo-Ins(1,2,3,6)P₄[(+)-12], myo-

Ins(3,4,5,6)P₄[(+)-13], and myo-Ins (1,3,4,5,6)P₅(47), as

well as their enantiomers myo-Ins(3)P [(+)-30], myo-Ins-

(2,3)P₂[(+)-8], myo-Ins(5,6)P₂[(+)-9], myo-Ins(1,4)P₂[(+)-

10], myo-Ins(3,5,6)P₃[(+)-1], myo-Ins(2,5,6)P₃[(+)-44],

myo-Ins(1,3,4)P₃[(+)-48], myo-Ins(1,2,4)P₃[(–)-42], myo-

Ins(2,3,5,6)P₄[(+)-11], myo-Ins(1,2,3,4)P₄[(–)-12], and myo-

Ins(1,4,5,6)P₄[(–)-13].

Synthesis of myo-Ins(1,3,6)P₃[(–)-48] and the meso

Compound myo-Ins (1,3,4,5,6)P₅(47)

The versatile precursor (+)-17 can easily be transformed

in short reaction sequences into various other myo-inositol

polyphosphates by the methods described above. Thus,

both enantiomers of myo-Ins(1,3,6)P₃[(–)-48] and the meso

compound myo-Ins (1,3,4,5,6)P₅(47) were accessible. The

other enantiomer myo-Ins(1,3,4)P₃[(+)-48] was synthesized

analogously from (–)-24 (see Scheme 10).

Experimental Section

General Remarks: All NMR spectra were recorded with a Bruker

ARX 400 (400 MHz) spectrometer. In addition to ¹H, ¹³C, and ³¹

P

experiments, 2D COSY (¹H-¹H, ¹H-¹³C, and ¹H-³¹P) and DEPT

spectra were recorded for unequivocal correlation of the hydrogen,

carbon, and phosphorus atoms. The chemical shifts are given in

ppm relative to TMS, although in practice the solvents were taken

as internal standards. The multiplicity is given by the following

symbols: s (singlet), d (doublet), t (triplet), q (quadruplet), m (mul-

tiplet), ψt (pseudotriplet for unresolved dd), ur (unresolved) and br

(broad). Melting points (not corrected) were recorded with a Büchi

510 heating block. IR spectra were obtained in pressed KBr, and

only noteworthy absorptions (cm^–1) are listed. All optical rotations

of the myo-inositol phosphates are given after adjusting to pH = 6

with NH₄OH or as free acids. TLC analyses were carried out on

Merck (Darmstadt, Germany) aluminum-backed silica gel 60 F254

0.25 mm plates and were visualized by UV illumination at 254 nm

before being sprayed with phosphomolybdic acid (10% in MeOH)

and heated. For column chromatography, Merck silica gels 60 (40–

63 μm, flash) and 60H (dry) were used. All organic extracts were

dried with MgSO₄, filtered, and concentrated in a rotary evapora-

tor. Only distilled solvents were used. The building blocks (+)- and

(–)-2, (–)- and (+)-3, and their precursors were prepared according

to literature methods,^[10,11]as were 1,4-di-O-benzylconduritol B

(14)^[12]and 1,4-bis(di-O-benzylphospho)conduritol B (17).^[11]

Scheme 10. Reagents and conditions: (a) RuCl₃, NaIO₄, acetoni-

trile/EtOAc (98%). (b) 1. MeC(OEt)₃, p-TSA; 2. 80% HOAc

(98%). (c) (1,5-Dihydro-2,4,3-benzodioxaphosphepin-3-yl)diethyl-

amine, 1H-tetrazole, CH₂Cl₂, then m-CPBA (82%). (d) 1. Pd/C,

H₂, ethanol/water; 2. 0.25 n NaOH (92%).

Purification and Analysis of Inositol Tris- and Tetrakisphosphates

(HPLC-MDD): Inositol phosphates were purified and analyzed by

the HPLC-MDD method described previously.^[11,22]The com-

pounds were separated by anion-exchange chromatography on a

MonoQ HR10/10 column (Pharmacia). To purify inositol phos-

phates, a linear gradient of HCl was applied (0 min 0.2 mm HCl;

70 min 0.5 m HCl; flow rate 1.5 mLmin^–1). In analytical runs, pho-

tometric detection at 546 nm was achieved with a metal-dye reagent

[2 m Tris/HCl (pH = 9.1), 200 μm 4-(2-pyridylazo)resorcinol (PAR),

30 μm YCl₃, 10% (v/v) MeOH; flow rate 0.75 mLmin^–1]. In purifi-

cation steps, where on-line detection was not possible, an analogous

experiment was carried out on a microplate. In brief, a 0.2–2-μL

portion of the collected fraction was mixed with 100 μL of metal-

dye reagent, and the absorbance at 540 nm was measured.

Outlook

As mentioned above, all products are available in both

enantiomeric forms. The “symmetric concept”, based on

the use of C₂-symmetrical building blocks, allows the syn-

thesis of a wide variety of inositol phosphate isomers. How-

ever, it is based on pairwise differentiation (orthogonal pro-

tection) of the hydroxy groups, which certainly limits the

number of accessible building blocks. In the following arti-

cle in this issue we will present a scheme to overcome this

limitation and to complete this concept for the synthesis of

myo-inositol polyphosphates.

3106

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3101–3115

myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

FULL PAPER

(1S,2R,3R,4S)-2,3-Di-O-acetyl-1,4-di-O-benzylconduritol B

15]: (1S,2R,3R,4S)-1,4-Di-O-benzylconduritol B [(+)-14; 64 g,

0.20 mol] was dissolved in a cooled mixture of pyridine (250 mL) hydro-2,4,3-benzodioxaphosphepin-3-yl)diethylamine

[(+)-

4,5-Di-O-acetyl-3,6-di-O-benzyl-1,2-bis-O-(3-oxo-1,5-dihydro-3λ⁵-

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

D

-myo-inositol [(+)-19]: (1,5-Di-

(195 mg,

0.82 mmol) was added to a suspension of (+)-18 (150 mg,

and acetic anhydride (200 mL) and the solution was stirred at room

temperature for 12 h. For workup the solution was added to a mix-

ture of ice (350 g) and CH₂Cl₂(350 mL). The aqueous solution was

extracted with CH₂Cl₂(3×150 mL). The combined organic layers

were extracted with 15% aqueous HCl (3×150 mL), saturated

NaHCO₃(3×100 mL), and brine (100 mL). After evaporation of

the solvent, the resulting solid was crystallized from ethyl acetate

or ethanol to yield (+)-15 (61 g, 76%) as a colorless solid. R_f=

0.48 (cyclohexane/ethyl acetate, 3:2). [α]²_D⁰= +192.2 (c = 1.25,

0.34 mmol) and 1H-tetrazole (95 mg, 1.4 mmol) in anhydrous

dichloromethane (20 mL), and the solution was stirred at room

temperature for 12 h. The solution was then cooled to –40 °C and

an anhydrous solution of m-CPBA (690 mg, 2.8 mmol) in dichloro-

methane (10 mL, dried with Na₂SO₄) was added. The solution was

stirred at –20 °C for 30 min, then it was allowed to warm to room

temperature, and the stirring was continued for 1 h. The product

was worked up as described for (+)-29. Purification by flash

chromatography (ethyl acetate/cyclohexane, 2:1) gave (+)-19

1

CHCl₃). M.p. 116 °C. H NMR (CDCl₃): δ = 2.06 (s, 6 H, CH₃),

4.30 (AAЈXXЈ, 2 H, 1-H, 4-H), 4.54, 4.64 (2×d, AB, J = 11.81 Hz,

(160 mg, 58%) as a colorless foam. R_f= 0.07 (ethyl acetate/cyclo-

1

2×2 H, Ph-CH₂), 5.29 (AAЈXXЈ, 2 H, 2-H, 3-H), 5.82 (s, 2 H, 5- hexane, 1:1). [α]²_D⁰= +26 (c = 0.36, CHCl₃). H NMR (CDCl₃): δ

H, 6-H), 7.33 (m, 10 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.7 = 1.88, 1.99 (2×s, 2×3 H, CH₃), 3.65 (d, J = 10.2 Hz, 1 H, 3-H),

(CH₃), 71.3 (Ph-CH₂), 72.7 (C-2, C-3), 76.9 (C-1, C-4), 127.7,

127.8, 128.4 (C_arom.), 127.9 (C-5, C-6), 137.8 (C_ipso), 169.9 (C=O)

ppm. MS (EI, 70 eV): m/z (%) = 395 (2), 244 (8), 196 (6), 153 (5),

3.95 (ψt, J = 9.7 Hz, 1 H, 6-H), 4.48, 4.83 (2×d, AB, J = 11.7 Hz,

2×1 H, Ph-CH₂), 4.60, 4.83 (2×d, AB, J = 11.2 Hz, 2×1 H, Ph-

CH₂), 4.67 (ψt, J = 9.7 Hz, 1 H, 1-H), 4.95–5.60 [m, 8 H, (CH₂)₂-

111 (25), 91 (100), 43 (57) ppm. IR (KBr): ν = 3060, 3020 (m), C₆H₄], 5.10 (ψt, J = 9.7 Hz, 1 H, 5-H), 5.37 (ψt, J = 10.2 Hz, 1 H,

˜

1750, 1730 (s), 1370 (m), 1240, 1220 (s), 1050 (m), 775, 695 (m) 4-H), 5.41 (dψt, J = 10.1, J = 2.3 Hz, 1 H, 2-H), 7.18–7.39 (m,

cm^–1. C₂₄H₂₆O₆(410.5): calcd. C 70.23, H 6.38; found C 70.27, H 18 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.5, 20.7 (2×CH₃),

6.54.

68.5–69.0 [m, 2×(CH₂)₂C₆H₄], 70.9 (C-4), 72.0 (C-5), 72.1

(PhCH₂), 74.9 (d, J = 2.9 Hz, C-3), 75.0 (PhCH₂), 75.1 (dd, J =

1.9, J = 5.9 Hz, C-2), 75.9 (ψt, J = 4.8 Hz, C-1), 77.3 (d, J = 4.8 Hz,

C-6), 127.7, 127.85, 127.91, 128.3, 128.4, 128.56, 128.63, 128.7,

128.8, 128.9, 129.0, 129.1 (C_arom.), 134.6, 135.0, 135.3, 135.4, 136.9,

137.7 (C_ipso), 169.5, 170.0 (C=O) ppm. ³¹P{¹H} NMR (CDCl₃,): δ

= –0.21 (PC-2), 0.14 (PC-1) ppm. HR-MS (ESI-pos.): calcd. for

C₄₀H₄₂O₁₄P₂Na [M + Na]⁺831.1948; found 831.194

(1R,2S,3S,4R)-2,3-Di-O-acetyl-1,4-di-O-benzylconduritol B [(–)-15]:

A solution of (–)-14 was allowed to react to give (–)-15 under the

conditions described for the preparation of (+)-15. [α]²_D⁰= –194.7

(c = 1.25 in chloroform). The R_fvalue and ¹H and ¹³C NMR spec-

troscopic data are identical to those obtained for (+)-15.

4,5-Di-O-acetyl-3,6-di-O-benzyl-D-myo-inositol [(+)-18]: A solution

5,6-Di-O-acetyl-1,4-di-O-benzyl-2,3-bis-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)-D-myo-inositol [(–)-19]: A solu-

tion of (–)-18 was allowed to react to give (–)-19 under the same

conditions as those described for the preparation of (+)-19. [α]²_D⁰

= –30 (c = 0.76, CHCl₃). The R_fvalue and ¹H and ¹³C NMR

spectroscopic data are identical with those obtained for (+)-19.

of sodium metaperiodate (4.7 g, 22 mmol, 1.5 equiv.) and ruthe-

nium trichloride trihydrate (280 mg, 1 mmol) in water (60 mL) was

added to a vigorously stirred ice-cooled solution of (+)-15 (5.2 g,

12.8 mol) in acetonitrile/ethyl acetate (1:1, 350 mL). The stirring

was continued until TLC no longer showed any starting material

(approx. 10 min). After the reaction had been quenched by addition

of aqueous Na₂S₂O₃(20%, 200 mL), the aqueous layer was sepa-

rated and extracted with EtOAc (3×200 mL). The combined or-

ganic layers were washed twice with brine and concentrated under

reduced pressure to yield (+)-18 (4.9 g, 87%) as a grey solid. For

an analytical sample, the solid was purified by flash chromatog-

raphy on silica gel (cyclohexane/ethyl acetate, 3:2) to yield pure (+)-

18 as a colorless solid. R_f= 0.09 (cyclohexane/ethyl acetate, 3:2).

D-myo-Inositol 1,2-Bisphosphate [(–)-8]: Deprotection (hydro-

genolysis and deacetylation) of (+)-19 (50 mg, 60 μmol) was carried

out as described for the preparation of (–)-30 to give (–)-8 (20 mg,

100%) as a colorless, very hygroscopic foam. [α]²_D⁰= –12.1 [c = 1.2,

H₂O, pH = 1.5 (free acid)]. [α]²_D⁰= –13.9 [c = 0.8, H₂O, pH adjusted

to 6 (NH₄OH)]. Ref.^[23,24](bisphosphate isolated from myo-InsP₆;

dephosphorylation catalyzed by phytase from wheat germ or bran)

1

[α]²_D⁰= +34.7 (c = 0.9, CHCl₃). M.p. 129 °C. H NMR (CDCl₃): δ

[α]²_D⁰= –10.5 (c = 2, H₂O, sodium salt, pH = 7). Ref.^[23,24][α]²_D⁰

=

= 1.95, 1.99 (s, 2×3 H, CH₃), 2.70, 2.90 (2×s, br, 2 H, OH), 3.48

(dd, J = 2.7, J = 9.84 Hz, 1 H, 3-H), 3.58 (dd, J = 2.5, J = 9.5 Hz,

1 H, 1-H), 3.90 (ψt, J = 9.6 Hz, 1 H, 6-H), 4.21 (ψt, J = 2.9, 1 H,

2-H), 4.55, 4.66 (2×d, AB, J = 12.05 Hz, 2×1 H, Ph-CH₂), 4.69,

4.77 (2×d, AB, J = 11.6 Hz, 2×1 H, Ph-CH₂), 5.04 (ψt, J =

9.84 Hz, 1 H, 5-H), 5.44 (ψt, J = 9.84 Hz, 1 H, 4-H), 7.33 (m, 10

H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.68, 20.72 (CH₃), 69.1

(C-2), 71.7 (C-1), 71.7 (C-4), 72.8 (C-5), 72.4, 75.1 (Ph-CH₂), 77.1

(C-3), 79.3 (C-6), 127.6, 127.7, 127.8, 128.1, 128.5, 128.6 (C_arom.),

137.3, 138.1 (C_ipso), 170.03, 170.05 (C=O) ppm. MS (EI, 70 eV):

–6 (c = 4, H₂O, free acid). ¹H NMR (D₂O, free acid): δ = 3.30 (ψt,

J = 9.2 Hz, 1 H, 5-H), 3.58 (d, J = 10.2 Hz, 1 H, 3-H), 3.63 (ψt, J

= 9.4 Hz, 1 H, 4-H), 3.74 (ψt, J = 9.4 Hz, 1 H, 6-H), 4.05 (dψt, J

= 2.1, J = 8.9 Hz, 1 H, 1-H), 4.73 (d, J = 9.2 Hz, 1 H, 2-H) ppm.

¹³C NMR (D₂O, free acid): δ = 72.4 (d, J = 3.1 Hz, C-3), 73.5 (d,

J = 6.1 Hz, C-6), 74.5 (s, C-4), 76.5 (s, C-5), 77.4 (m, C-1), 79.4 (d,

J = 6.1 Hz, C-2) ppm. ³¹P{¹H} NMR (D₂O, free acid): δ = 1.11

(sh), 1.25 (PC-1, PC-2) ppm. HR-MS (ESI-neg, phosphoric acid

0.002%, Q-TOF): calcd. for C₆H₁₃O₁₂P₂[M – H]^–338.9883; found

338.9841.

m/z (%) = 353 (6), 247 (10), 91 (100), 43 (72). IR (KBr): ν = 3450

˜

(s, br), 3060, 3040 (m), 2960, 2900, 2890 (s_.), 1730 (s), 1370 (m),

1240 (s), 1060 (m), 740, 690 (m) cm^–1. C₂₄H₂₈O₈(444.5): calcd. C

64.85, H 6.35; found C 64.60, H 6.28.

D

-myo-Inositol 2,3-Bisphosphate [(+)-8]: A solution of (–)-19 was

allowed to react under the conditions described for the preparation

of (–)-8 to give (+)-8. [α]²_D⁰= +11.2 (c = 0.8, H₂O, free acid). The

¹H NMR and ¹³C NMR spectroscopic data are identical with those

obtained for (–)-8.

5,6-Di-O-acetyl-1,4-di-O-benzyl-D-myo-inositol [(–)-18]: A solution

of (–)-15 was allowed to react to give (–)-18 under the conditions

described for the preparation of (+)-18. [α]²_D⁰= –34.1 (c = 0.8 in

CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

are identical with those obtained for (+)-18.

(1S,2R,3R,4S)-1,4-Di-O-benzyl-2,3-bis-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)conduritol B [(+)-20]: (1,5-Dihy-

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

(700 mg,

Eur. J. Org. Chem. 2005, 3101–3115

www.eurjoc.org

3107

M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

FULL PAPER

1

3 mmol) was added to a suspension of (+)-14 (400 mg, 1.22 mmol)

and 1H-tetrazole (350 mg, 5 mmol) in anhydrous dichloromethane

(20 mL), and the solution was stirred at room temperature for 4 h.

The solution was then cooled to –40 °C, and an anhydrous solution

of m-CPBA (2.1 g, 9 mmol) in dichloromethane (20 mL, dried with

Na₂SO₄) was added. The solution was allowed to warm to room

temperature, and the stirring was continued for 1 h. The product

was worked up as described for (+)-29. Purification by flash

chromatography (ethyl acetate/cyclohexane, 3:1) yielded pure (+)-

20 (500 mg, 65%) as a colorless foam. R_f= 0.32 (ethyl acetate/

cyclohexane, 3:1). [α]²_D⁰= +21.5 (c = 1.2, CHCl₃). ¹H NMR

(CDCl₃): δ = 4.40 (m, AAЈXXЈ, 2 H, 1-H, 4-H), 4.71 (s, 4 H, Ph-

CH₂), 4.95–5.00 (m, AAЈXXЈ, 2 H, 2-H, 3-H), 5.02–5.25, 5.48–5.58

[m, 8 H, (CH₂)₂C₆H₄], 5.80 (s, 2 H, 5-H, 6-H), 7.17–7.46 (m, 18 H,

Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 68.3 [d, J = 7.1 Hz, (CH₂)

₂C₆H₄], 69.0 [d, J = 7.1 Hz, (CH₂)₂C₆H₄], 71.2 (Ph-CH₂), 78.0 (d,

J = 2.0 Hz, C-1, C-4), 78.4 (ψt, J = 4.6 Hz, C-2, C-3), 127.5 (C-5,

C-6), 127.8, 127.9, 128.4, 128.5, 128.6, 128.8, 128.9 (C_arom.), 135.0,

135.3, 137.7 (C_ipso) ppm. ³¹P{¹H} NMR (CDCl₃): δ = –0.12 (PC-

2, PC-3) ppm. MS (EI, 70 eV): m/z (%) = 571 (2), 477 (3), 277 (48),

201 (40.3), 200 (33), 184 (27), 119 (69), 104 (100), 102 (75), 65 (73).

and H and ¹³C NMR spectroscopic data are identical with those

obtained for (–)-21.

D-myo-Inositol 4,5-Bisphosphate [(–)-9]: Preactivated Pd/C (70 mg,

Degussa RW 10) was added to a suspension of (–)-21 (110 mg,

0.15 mmol) in ethanol/water (1:1, 40 mL), and the mixture was

stirred at room temperature under H₂for 12 h. The catalyst was

filtered off, and the filtrate was lyophilized to give (–)-9 (51 mg,

99%) as a colorless, very hygroscopic foam. [α]²_D⁰= –4.4 [c = 0.3,

H₂O, pH adjusted to 6 (NH₄OH)]. [α]²_D⁰= +7.9 [c = 1.2, H₂O, pH

= 1.4 (free acid)]. Ref.^[25][α]²_D⁰= –10 (c = 1, H₂O, tetrapotassium

salt). ¹H NMR (D₂O, free acid): δ = 3.55 (dd, J = 2.5, J = 10.2 Hz,

1 H, 1-H), 3.67 (dd, J = 2.0, J = 9.7 Hz, 1 H, 3-H), 3.74 (ψt, J =

9.7 Hz, 1 H, 6-H), 3.99 (ψq, J = 9.2 Hz, 1 H, 5-H), 3.99 (ψs, 1 H,

2-H), 4.28 (ψq, J = 9.2 Hz, 1 H, 4-H) ppm. ¹³C NMR (D₂O, free

acid): δ = 70.5 (d, J = 2.5 Hz, C-3), 70.8 (C-1), 71.7 (d, J = 2.5 Hz,

C-6), 72.1 (C-2), 78.3 (ψq, J = 3.2 Hz, C-4), 79.7 (ψq, J = 3.2 Hz,

C-5) ppm. ³¹P{¹H} NMR (D₂O, 161 MHz, free acid): δ = 1.21 (PC-

5), 1.55 (sh, PC-4) ppm. HR-MS (ESI-neg, phosphoric acid, Q-

TOF): calcd. for C₆H₁₃O₁₂P₂[M – H] 338.9842; found 338.9883.

D-myo-Inositol 5,6-Bisphosphate P₂[(+)-9]: A solution of (+)-21

was allowed to react under the conditions described for the prepa-

IR (film): ν = 3064 (m), 3029 (m), 3005 (m), 2934 (m), 2891 (m),

˜

ration of (–)-9 to give (+)-9. [α]²_D⁰= +8.1 (c = 1.0, H₂O, free acid).

1498 (m), 1455 (m), 1384 (m), 1290 (s, br), 1223 (m), 1024 (s, br),

850 (s, br), 750 (s, br), 698 (m), 624 (m) cm^–1. HR-MS (ESI-pos.):

calcd. for C₃₆H₃₆O₁₀P₂Na [M + Na] 713.168; found 713.1682.

1

The H and ¹³C NMR spectroscopic data are identical with those

obtained for (–)-9.

3,6-Di-O-benzyl-D-myo-inositol [(+)-22]: A solution of sodium

(1R,2S,3S,4R)-1,4-Di-O-benzyl-2,3-bis-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)conduritol B [(–)-20]: A solution of

(–)-14 was allowed to react to give (–)-20 under the conditions de-

scribed for the preparation of (+)-20. [α]²_D⁰= –21.3 (c = 1.55,

CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

are identical with those obtained for (+)-20.

metaperiodate (2 g, 9.5 mmol) and ruthenium trichloride trihydrate

(165 mg, 0.63 mmol) in water (15 mL) was added to a vigorously

stirred ice-cooled solution of (+)-14 (2.1 g, 6.4 mmol) in acetonitrile

(60 mL). The stirring was continued until TLC showed complete

absence of starting material (approx. 10 min). The reaction was

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

The aqueous layer was separated and extracted five times with

EtOAc (5×150 mL). The combined organic layers were washed

twice with brine and concentrated under reduced pressure to yield

(+)-22 (1.9 g, 82%) as a colorless solid. For an analytical sample,

the residue was crystallized from ethyl acetate. M.p. 170 °C (ref.^[26]

172 °C). R_f= 0.25 (ethyl acetate/cyclohexane, 1:1). [α]²_D⁰= +17.2 (c

= 1.8, MeOH). Ref.^[26][α]²_D⁰= +16 (c = 1, MeOH). ¹H NMR

(CDCl₃/[D₄]MeOH, 6:1): δ = 3.16 (dd, J = 9.7, J = 2.0 Hz, 1 H, 3-

H or 1-H), 3.31 (ψt, J = 9.4 Hz, 1 H, 4-H or 6-H), 3.38 (dd, J =

9.7, J = 2.5 Hz, 1 H, 1-H or 3-H), 3.58 (ψt, J = 9.4 Hz, 1 H, 5-H),

3.78 (ψt, J = 9.4 Hz, 1 H, 4-H or 6-H), 4.07 (ψt, J = 2.0 Hz, 1 H,

2-H), 4.61 (AB, 2 H, Ph-CH₂), 4.79 (AB, 2 H, Ph-CH₂), 7.16–7.38

(m, 10 H, Ph-H) ppm. ¹³C NMR (CDCl₃/[D₄]MeOH, 6:1): δ = 65.5

(C-2), 67.9 (C-1 or C-3), 68.3 (Ph-CH₂), 68.5 (C-5), 70.8 (C-4 or

C-6), 71.1 (Ph-CH₂), 75.5 (C-1 or C-3), 77.5 (C-4 or C-6), 127.8,

127.9, 128.0, 128.1, 128.4, 128.5 (C_arom.), 137.9, 138.7 (C_ipso) ppm.

MS (70 eV): m/z (%) = 360 (1) [M⁺], 270 (5), 269 (14) [M⁺– Bn],

108 (26), 107 (50), 92 (36), 91 (100), 79 (32). C₂₀H₂₄O₆(360.4):

calcd. C 66.65, H 6.71; found C 66.93, H 6.71.

3,6-Di-O-benzyl-4,5-bis-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxa-

phosphepin-3-yl)-D-myo-inositol [(–)-21]: A solution of sodium met-

aperiodate (89 mg, 0.41 mmol, 1.5 equiv.) and ruthenium trichlo-

ride trihydrate (30 mg, 0.1 mmol) in water (1 mL) was added to a

vigorously stirred ice-cooled solution of (+)-20 (200 mg,

0.29 mmol) in acetonitrile (5 mL). The stirring was continued until

TLC showed the complete absence of starting material (approx.

8 min). The reaction was then quenched by addition of aqueous

Na₂S₂O₃(20%, 10 mL). The aqueous layer was separated and ex-

tracted with EtOAc (3×20 mL). The combined organic layers were

washed twice with brine and concentrated under reduced pressure

to yield (–)-21 (220 mg, 99%) as a colorless foam. [α]²_D⁰= –32.0 (c

= 1.1, CHCl₃). ¹H NMR (CDCl₃): δ = 3.51 (dd, J = 2.3, J = 9.4 Hz,

1 H, 3-H), 3.61 (dd, J = 3.0, J = 9.7 Hz, 1 H, 1-H), 3.92 (ψt, J =

9.7 Hz, 1 H, 6-H), 4.17 (ψt, J = 2.6 Hz, 1 H, 2-H), 4.69 (m, AB, 2

H, Ph-CH₂), 4.72 (ψq, J = 9.0 Hz, 1 H, 5-H), 4.84 (s, 2 H, Ph-

CH₂), 4.91–5.56 [m, 8 H, 2×(CH₂)₂C₆H₄], 5.13 (m, 1 H, 4-H),

7.07–7.50 (m, 18 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 68.1 [dd,

J = 6.6, J = 10.7 Hz, (CH₂)₂C₆H₄], 68.7 (C-2), 68.8 [ψt, J = 7.6 Hz,

(CH₂)₂C₆H₄], 71.6 (C-1), 72.5, 74.8 (2×Ph-CH₂)_,77.9 (C-3), 78.4

(m, C-4), 79.3 (ψt, J = 5.7 Hz, C-5), 79.7 (C-6), 127.5–129.2

(C_arom.), 134.8, 134.9, 135.2, 135.3, 137.4, 138.4 (C_ipso) ppm.

³¹P{¹H} NMR (CDCl₃): δ = 0.36 (PC-4), 0.83 (PC-5) ppm. MS

(EI, 70 eV): m/z (%) = 322 (1), 200 (6), 192 (9), 104 (40), 91 (100).

1,4-Di-O-benzyl-D-myo-inositol [(–)-22]: A solution of (–)-14 was

allowed to react to give (–)-22 under the conditions described for

the preparation of (+)-22. [α]²_D⁰= –18.3 (c = 2, MeOH). The R_f

1

value and H and ¹³C NMR spectroscopic data are identical with

those obtained for (+)-22.

IR (KBr): ν = 3417 (m) 3055 (w), 3029 (w), 2934 (w), 2886 (w),

˜

D-myo-Inositol 1,2,4,5-Tetrakisphosphate [(–)-11]: (1,5-Dihydro-

1283 (m), 1026 (s, br), 859 (m), 734 (m) cm^–1. HR-MS (ESI-pos.):

calcd. for C₃₆H₃₈O₁₂P₂Na [M + Na]⁺747.1736; found 747.174.

2,4,3-benzodioxaphosphepin-3-yl)diethylamine (830 mg, 3.5 mmol)

was added to a suspension of (+)-22 (290 mg, 0.7 mmol) and 1H-

tetrazole (290 mg, 4.1 mmol) in anhydrous dichloromethane

(30 mL), and the solution was stirred at room temperature for 12 h.

The solution was then cooled to –40 °C, and an anhydrous solution

of m-CPBA (4.1 g, 16.6 mmol) in dichloromethane (30 mL, dried

1,4-Di-O-benzyl-5,6-bis-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxa-

phosphepin-3-yl)-D-myo-inositol [(+)-21]: A solution of (–)-20 was

allowed to react to give (+)-21 under the conditions used for the

preparation of (–)-21. [α]²_D⁰= +28.8 (c = 0.65, CHCl₃). The R_fvalue

3108

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Eur. J. Org. Chem. 2005, 3101–3115

myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

FULL PAPER

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

room temperature, and the stirring was continued for 1 h. The pro-

duct was worked up as described for (+)-29. Purification by flash

chromatography (ethyl acetate/cyclohexane, 5:1) yielded 3,6-di-O-

benzyl-1,2,4,5-tetra-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxa-

was continued until TLC showed the complete absence of starting

material (approx. 7 min). The reaction was then quenched by ad-

dition of aqueous Na₂S₂O₃(20%, 100 mL). The aqueous layer was

separated and extracted with EtOAc (3×100 mL). The combined

organic layers were washed twice with brine and concentrated un-

phosphepin-3-yl)-myo-inositol (595 mg, 78%, purity Ͼ90%) as a der reduced pressure to yield (+)-24 (1.6 g, 77%) as a colorless

colorless foam. ¹H NMR (CDCl₃): δ = 3.68 (d, J = 9.7 Hz, 1 H,

3-H), 3.97 (ψt, J = 9.9 Hz, 1 H, 6-H), 4.56 (d, AB, J = 11.2 Hz, 1

solid. R_f= 0.16 (CH₂Cl₂/MeOH, 95:5). [α]²_D⁰= +33.8 (c = 1.0,

CHCl₃). H NMR (CDCl₃): δ = 1.80 (s, 3 H, CH₃), 1.86 (s, 3 H,

1

H, Ph-CH₂), 4.66–5.20 (m, 18 H, CH₂and ring protons), 5.27–5.48 CH₃), 3.66 (dd, J = 2.4, J = 9.2 Hz, 1 H, 1-H), 4.34 (ψs, 1 H, 2-

(m, 5 H, CH₂and other ring protons), 7.06–7.50 (m, 26 H, Ph-H) H), 4.39 (dψt, J = 2.5, J = 9.3 Hz, 1 H, 3-H), 4.72 (ψq, J = 9.2 Hz,

ppm. ¹³C NMR (CDCl₃): δ = 68.1 [m, (CH₂)₂C₆H₄], 68.5 [m, (CH₂) 1 H, 6-H), 4.88–5.20 (m, 9 H, 4×Ph-CH₂, 5-H), 5.57 (ψt, J =

₂C₆H₄], 68.7–69.0 [m, (CH₂)₂C₆H₄], 72.5 (s, CH₂, PhCH₂), 74.5 (s,

9.9 Hz, 1 H, 4-H), 7.33 (m, 20 H, Ph-H) ppm. ¹³C NMR (CDCl₃):

CH), 74.6 (s, PhCH₂), (dd, J = 5.1, J = 1.6 Hz, CH), 75.8 (s, CH), δ = 20.5 (CH₃), 20.7 (CH₃), 69.9, 70.1, 71.0 (5×C, Ph-CH₂, C-5),

73.4 (m, 2×CH), 78.44 (m, CH), 127.36–129.18 (C_arom), 134.2– 70.3 (d, C-4), 70.7 (C-1), 71.9 (d, C-2), 76.0 (d, C-3), 78.8 (d, C-6),

135.3, 136.8, 137.0, 137.7 (C_ipso) ppm. ³¹P{¹H} NMR (CDCl₃): δ 128.0, 128.1, 128.57, 128.62, 128.7 (C_arom.), 135.5 (m, C_ipso), 169.7,

= –0.70, 0.11, 0.24, 1.17 ppm.

169.9 (C=O) ppm. ³¹P{¹H} NMR (CDCl₃): δ = 0.80, 0.72 ppm.

MS (EI, 70 eV): m/z (%) = 785 [M + H]⁺, 707 [M – C₆H₅], 729,

Hydrogenolysis: Preactivated Pd/C (100 mg, Degussa RW 10) in

ethanol/water (1:2, 30 mL) was added to a suspension of 3,6-di-O-

benzyl-1,2,4,5-tetra-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxa-

phosphepin-3-yl)-myo-inositol (200 mg, 0.18 mmol), as obtained

above, in ethanol (20 mL). The mixture was stirred at room tem-

perature under H₂overnight. The catalyst was filtered off, and the

filtrate was concentrated under high vacuum and then lyophilized

to give 90 mg of a colorless, very hygroscopic foam. Purification by

HPLC yielded pure (–)-11 (80 mg, purity Ͼ99%). [α]²_D⁰= –26.3 (c

= 0.7, H₂O, free acid). Ref.^[26][α]²_D⁰= –27.2 (c = 0.5, TEAB buffer

pH = 8.6). ³¹P{¹H} NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ =

1.93, 3.12, 3.58, 3.63 ppm. For more spectroscopic data see

refs.^[13,26]

454, 429, 391. IR (KBr): ν = 3410 (w), 3070 (w), 3030 (w), 2950

˜

(w), 1755 (s), 1240 (s), 1040 (s), 1020 (s), 755 m), 705 (m) cm^–1.

C₃₈H₄₂O₁₄P₂(784.7): calcd. C 58.16, H 5.40; found C 58.00, H

5.49.

5,6-Di-O-acetyl-1,4-bis-O-(di-O-benzylphospho)-D-myo-inositol [(–)-

24]: A solution of (–)-23 was allowed to react under the conditions

described for the preparation of (+)-24 to give (–)-24. [α]²_D⁰= –34.8

(c = 1.2, CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic

data are identical with those obtained for (+)-24.

4,5-Di-O-acetyl-3,6-bis-O-(di-O-benzylphospho)-1,2-bis-O-(3-oxo-

1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-

[(+)-25]:

D

-myo-inositol

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

ylamine (520 mg, 2.2 mmol) was added to a suspension of (+)-24

(1S,2R,3R,4S)-2,3-Di-O-acetyl-1,4-bis-O-(di-O-benzylphospho)con-

duritol B [(+)-23]: A solution of (1S,2R,3R,4S)-1,4-bis-O-(di-O- (250 mg, 0.32 mmol) and 1H-tetrazole (100 mg, 2.5 mmol) in anhy-

benzylphospho)conduritol B [(+)-17; 2 g, 3 mmol] in a cooled mix-

ture of pyridine and acetic anhydride (30 mL, 1:1) was stirred for

12 h at room temperature. For workup the solution was added to

a mixture of ice (300 g) and CH₂Cl₂(100 mL). The aqueous phase

was extracted five times with CH₂Cl₂(5×100 mL). The combined

drous dichloromethane (20 mL), and the solution was stirred at

room temperature for 12 h. The solution was then cooled to –40 °C,

and an anhydrous solution of m-CPBA (2.1 g, 6 mmol) in dichloro-

methane (25 mL, dried with Na₂SO₄) was added. The solution was

allowed to warm to room temperature, and the stirring was contin-

organic layers were extracted four times with 15% aqueous HCl ued for 1 h. The product was worked up as described for (+)-29.

(4×150 mL), saturated NaHCO₃(4×150 mL), and brine

(100 mL). Evaporation of the solvent yielded (+)-23 (1.8 g, 86%)

as a yellowish oil that crystallized after 1 d. R_f= 0.46 (dichloro-

methane/methanol, 95:5). [α]²_D⁰= +92.3 (c = 1.28, CHCl₃). ¹H

Purification by flash chromatography (dichloromethane/methanol,

3:1) yielded pure (+)-25 (300 mg, 80%) as a colorless foam. R_f=

0.51 (dichloromethane/methanol, 95:5). [α]²_D⁰= +2.5 (c = 1.3,

1

CHCl₃). H NMR (CDCl₃): δ = 1.83 (s, 3 H, CH₃), 1.88 (s, 3 H,

NMR (CDCl₃): δ = 1.66 (s, 6 H, CH₃), 5.03 (m, 8 H, Ph-CH₂), CH₃), 4.58 (ψt, J = 9.9 Hz, 1 H, 1-H or 3-H), 5.14 (m, 19 H, CH₂

5.12 (m, 2 H, 1-H, 4-H), 5.30 (m, 2 H, 2-H, 3-H), 5.73 (s, 2 H, 5-

H, 6-H), 7.35 (m, 20 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.4

(2×CH₃), 69.6 (m, 4×CH₂, Ph-CH₂), 71.6 (d, J = 4.9 Hz, 2×C,

C-1, C-4), 75.5 (d, J = 5.0 Hz, 2×C, C-2, C-3), 127.5–129.6 (C_arom.

and C_olef.), 135.4–135.5 (C_ipso), 169.7 (C=O) ppm. ³¹P NMR

and remaining CH-ring), 5.46 (ψt, J = 9.9 Hz, 2 H,), 7.31 (m, 28 H,

C₆H₅and C₆H₄) ppm. ¹³C NMR (CDCl₃): δ = 20.33 (CH₃), 20.34

(CH₃), 68.8 [m, Ph-CH₂and (CH₂)₂C₆H₄], 69.8 [m, Ph-CH₂and

(CH₂)₂C₆H₄], 69.5 (d, J = 3.8 Hz, C-4 or C-5), 70.0 [m, Ph-CH₂

and (CH₂)₂C₆H₄], 70.1 (m, CH), 73.0 (d, J = 2.9 Hz, C-4 or C-5),

(CDCl₃): δ = –0.35 (sext, J = 8.5 Hz) ppm. ³¹P{¹H} NMR (CDCl₃): 73.6 (m, CH), 75.2 (ψt, J = 5.3 Hz, CH), 76.9 (m, CH), 127.9–

δ = –0.35 ppm. MS (EI, 70 eV): m/z (%) = 751 [M + H]⁺, 473, 400,

129.9 (C_arom.), 134.4–135.9 (C_ipso); 169. 7, 169. 9 (C=O) ppm.

386, 212. C₃₈H₄₀O₁₂P₂(750.7): calcd. C 60.80, H 5.37; found C ³¹P{¹H} NMR (CDCl₃): δ = –0.65, –0.71 (PC-3 PC-6), –1.02, –1.74

60.85, H 5.45.

(PC-2, PC-1) ppm. MS (FAB): m/z = 1149 [M + H]⁺. C₅₄H₅₆O₂₀P₄

(1148.9): calcd. C 56.45, H 4.91; found C 56.35, H 5.00.

(1R,2S,3S,4R)-2,3-Di-O-acetyl-1,4-bis-O-(di-O-benzylphospho)con-

duritol B [(–)-23]: A solution of (–)-17 was allowed to react under

the conditions described for the preparation of (+)-23 to give (–)-

5,6-Di-O-acetyl-1,4-bis-O-(di-O-benzylphospho)-2,3-bis-O-(3-oxo-

1,5-dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-

D-myo-inositol

1

23. [α]²_D⁰= –90.4 (c = 1.28, CHCl₃). The R_fvalue and H and ¹³C

[(–)-25]: A solution of (–)-24 was allowed to react under the condi-

tions described for the preparation of (+)-25 to give (–)-25. [α]²_D⁰

= –1.7 (c = 1.3, CHCl₃). The R_fvalue and ¹H and ¹³C NMR spec-

troscopic data are identical with those obtained for (+)-25.

NMR spectroscopic data are identical with those obtained for (+)-

23.

4,5-Di-O-acetyl-3,6-bis-O-(di-O-benzylphospho)-D-myo-inositol

[(+)-24]: A solution of sodium metaperiodate (820 mg, 3.9 mmol,

1.5 equiv.) and ruthenium trichloride trihydrate (70 mg, 0.3 mmol)

in water (6 mL) was added to a vigorously stirred ice-cooled solu-

tion of (+)-23 (1.9 g, 2.6 mmol) in acetonitrile (40 mL). The stirring

D-myo-Inositol 1,2,3,6-Tetrakisphosphate [(+)-12]: Deprotection

(hydrogenolysis and deacetylation) of (+)-25 (300 mg, 0.22 mmol)

was carried out as described for the preparation of (–)-30 to give

(+)-12 (100 mg, 95%) as a colorless, very hygroscopic foam. [α]²_D⁰

=

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M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

FULL PAPER

+4.8 (c = 1.7, H₂O, free acid). Ref.^[33][α]²_D⁰= –19.9 (c = 2.6, H₂O,

pH 10, sodium salt). Ref.^[27][α]²_D⁰= +1.5 (H₂O). ¹H NMR [D₂O,

pH adjusted to 6 (ND₄OD)]: δ = 3.51 (ψt, J = 9.2 Hz, 1 H, 5-H),

thoacetate (11.2 mL, 60 mmol) were added to a solution of (+)-18

(5.0 g, 11.5 mmol) in anhydrous tetrahydrofuran (140 mL) under

argon. The mixture was stirred vigorously for 24 h. The solvent was

3.80 (ψt, J = 9.6 Hz, 1 H, 4-H), 3.98 (dψt, J = 2.1, J = 8.5 Hz, 1 then removed under reduced pressure, and the residue was dried

H, 3-H), 4.05 (dψt, J = 2.1, J = 9.5 Hz, 1 H, 1-H), 4.21 (ψq, J =

9.1 Hz, 1 H, 6-H), 4.81 (dψt, J = 10, J = 2.1 Hz, 1 H, 2-H) ppm.

under high vacuum. The residue was dissolved in aqueous acetic

acid (130 mL, 80%) and stirred at room temperature for 1 h. The

¹³C NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ = 73.6 (d, J = solvent was evaporated, and the residue was dissolved in CH₂Cl₂

6.1 Hz, C-4), 75.7 (m, C-1), 75.9 (s, C-5), 76.5 (dd, J = 5.6, J =

2.5 Hz, C-3), 77.0 (d, J = 6.1 Hz, C-2), 78.7 (ψt, J = 6.1 Hz, C-6) NaHCO₃(2×150 mL) and then with brine (50 mL). After evapora-

ppm. ³¹P{¹H} NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ = 2.06

tion of the dichloromethane, the crude product was purified by

(PC-2), 2.44 (PC-3), 2.49 (PC-1), 3.49 (PC-6) ppm. HR-MS (ESI- flash chromatography (cyclohexane/ethyl acetate, 3:2) to yield (+)-

(300 mL). The solution was washed with saturated aqueous

neg, phosphoric acid 0.002%, Q-TOF): calcd. for C₆H₁₅O₁₈P₄[M –

28 (4.8 g, 85%) as a colorless solid. R_f= 0.18 (ethyl acetate/cyclo-

hexane, 3:2). [α]²_D⁰= +52.0 (c = 1.44, CHCl₃). M.p. 55 °C. ¹H NMR

(CDCl₃): δ = 1.97, 1.99, 2.17 (s, 3×3 H, CH₃), 2.65 (br. s, 1 H,

OH), 3.52 (dd, J = 2.7, J = 9.7 Hz, 1 H, 3-H), 3.68 (dd, J = 2.7, J

= 9.7 Hz, 1 H, 1-H), 3.84 (ψt, J = 9.7 Hz, 1 H, 6-H), 4.42 and 4.68

(2×d, AB, J = 12.15 Hz, 2×1 H, Ph-CH₂), 4.72 [AB (ur), 2 H, Ph-

CH₂], 5.08 (ψt, J = 9.7 Hz, 1 H, 5-H), 5.33 (ψt, J = 9.7, 1 H, 4-

H), 5.70 (ψt, J = 2.70 Hz, 1 H, 2-H), 7.33 (m, 10 H, Ph-H) ppm.

¹³C NMR (CDCl₃): δ = 20.6, 20.7, 20.9 (CH₃), 68.9 (C-2), 70.1 (C-

1), 71.8 (C-4), 73.0 (C-5), 71.7, 75.1 (Ph-CH₂), 74.8 (C-3), 79.4 (C-

6), 127.6, 127.7, 127.8, 127.9, 128.3, 128.5 (C_arom.), 137.2, 137.9

(C_ipso), 169.9, 170.0, 170.4 (C=O) ppm. MS (EI, 70 eV): m/z (%) =

486 (3) [M⁺], 443 (2), 395 (46), 289 (67), 229 (13), 109 (50), 91

H]⁺498.9158; found 498.9209.

D-myo-Inositol 1,2,3,4-Tetrakisphosphate [(–)-12]: A solution of

(–)-25 was allowed to react under the conditions described for the

preparation of (+)-12 to give (–)-12. [α]²_D⁰= –6.6 (c = 3.95, H₂O,

1

free acid). The R_fvalue and H and ¹³C NMR spectroscopic data

are identical with those obtained for (+)-12.

D-myo-Inositol 3,6-Bisphosphate [(–)-10]: A solution of sodium met-

aperiodate (110 mg, 0.75 mmol) and ruthenium trichloride trihydr-

ate (10 mg, 0.03 mmol) in water (1.5 mL) was added to a vigorously

stirred ice-cooled solution of (+)-17 (200 mg, 0.3 mmol) in acetoni-

trile/dichloromethane (20 mL, 1:1). The stirring was continued un-

til TLC showed the complete absence of starting material (approx.

10 min). The reaction was then quenched by addition of aqueous

Na₂S₂O₃(20%, 20 mL). The aqueous layer was separated and ex-

tracted with EtOAc (3×50 mL). The combined organic layers were

washed twice with brine and concentrated under reduced pressure

to yield 3,6-bis-O-(di-O-benzylphospho)-myo-inositol bisphosphate

(210 mg, 98%) as a colorless solid. M.p. 158 °C (racemic). ¹H

(100), 43 (83.85). IR (KBr): ν = 3500 (m), 3060, 3040 (m ), 2930,

˜

.

2890 (m), 1750 (s), 1370 (m), 1230 (s), 1070 (m), 750, 700 (m) cm^–1.

C₂₆H₃₀O₉(486.5): calcd. C 64.19; H 6.22; found C 64.31, H 6.20.

2,5,6-Tri-O-acetyl-1,4-di-O-benzyl-D-myo-inositol [(–)-28]: A solu-

tion of (–)-18 was allowed to react under the conditions used for

the preparation of (+)-28 to give (–)-28. [α]²_D⁰= –53.3 (c = 1.74 in

NMR ([D₆]DMSO): δ = 3.37 (dψt, J = 9.2, J = 5.6 Hz, 1 H, 5-H), CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

3.59 (ddd, J = 2.2, J = 9.2, J = 6.6 Hz, 1 H, 4-H), 4.08 (ψs, 1 H,

2-H), 4.15 (dψt, J = 2.2, J = 9.1 Hz, 1 H, 3-H), 4.44 (ψq, J =

9.2 Hz, 1 H, 6-H), 5.20 (m, 8 H, Ph-CH₂), 5.39 (m, 4 H, OH), 7.35

(m, 20 H, Ph-H) ppm. ¹³C NMR ([D₆]DMSO): δ = 68.1–68.4 (4 C,

Ph-CH₂), 69.6 (CH), 70.9 (CH), 81.34 (CH), 71.2 (CH), 72.8 (CH),

78.4 (CH), 127.6–128.3 (C_arom.), 136.2–136.6 (C_ipso) ppm. ³¹P{¹H}

NMR ([D₆]DMSO): δ = 0.30, –0.63 ppm. Preactivated Pd/C

(50 mg, Degussa RW 10) in ethanol/water (1:2, 30 mL) was added

to a suspension of 3,6-bis-O-(di-O-benzylphospho)-myo-inositol

(130 mg, 0.2 mmol) in ethanol (15 mL). The mixture was stirred at

room temperature under H₂overnight. The catalyst was filtered

off, and the filtrate was concentrated under high vacuum and then

lyophilized to give 60 mg (95%) of a colorless, very hygroscopic

foam. [α]²_D⁰= –1.4 (c = 1.8, H₂O, free acid). Ref.^[28][α]²_D⁰= –0.12 (c

= 4, H₂O, tetracyclohexylammonium salt). ¹H NMR (D₂O, free

acid): δ = 3.40 (ψt, J = 9.4 Hz, 1 H, 5-H), 3.62 (dd, J = 3.0, J =

9.7 Hz, 1 H, 1-H), 3.71 (ψt, J = 9.7 Hz, 1 H, 4-H), 3.98 (dψt, J =

2.8, J = 9.6 Hz, 1 H, 3-H), 4.14 (ψq, J = 9.3 Hz, 1 H, 6-H), 4.16 (ψs,

1 H, 2-H) ppm. ¹³C NMR (D₂O): δ = 71.94 (d, J = 3.0 Hz, CH),

73.04 (2 C, CH), 74.79 (d, J = 2.0 Hz, CH), 78.72 (d, J = 6.1 Hz,

CH), 81.02 (d, J = 7.1 Hz, CH) ppm. ³¹P{¹H} NMR (D₂O, free

acid): δ = 1.12, 0.37 ppm. HR-MS (ESI-neg., phosphoric acid

0.002%, H₂O/acetonitrile, Q-TOF): calcd. for C₆H₁₃O₁₂P₂[M – H]^–

338.9841; found 338.9883.

are identical with those obtained for (+)-28.

2,4,5-Tri-O-acetyl-3,6-di-O-benzyl-1-O-(3-oxo-1,5-dihydro-3λ⁵-

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

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

0.7 mmol) was added to suspension of (+)-28 (300 mg,

D-myo-inositol [(+)-29]: (1,5-Di-

(180 mg,

a

0.62 mmol) and 1H-tetrazole (130 mg, 1.8 mmol) in anhydrous

dichloromethane (20 mL), and the solution was stirred at room

temperature for 12 h. The solution was then cooled to –40 °C, and

an anhydrous solution of m-CPBA (690 mg, 2.8 mmol) in dichloro-

methane (10 mL, dried with Na₂SO₄) was added. The solution was

allowed to warm to room temperature, and the stirring was contin-

ued for 1 h. The reaction mixture was diluted with dichloromethane

(50 mL) and washed consecutively with aqueous sodium sulfite

(20%, 2×50 mL), saturated NaHCO₃(3×50 mL), and then with

brine. After evaporation of the solvent, the resulting colorless foam

was purified by flash chromatography (ethyl acetate/cyclohexane,

1:1) to yield (+)-29 (250 mg, 60%) as a colorless foam. R_f= 0.20

(ethyl acetate/cyclohexane, 1:1). [α]²_D⁰= +44.9 (c = 0.78, CHCl₃).

¹H NMR (CDCl₃): δ = 1.91, 1.97, 2.20 (3×s, 3×3 H, CH₃), 3.56

(dd, J = 2.8, J = 9.9 Hz, 1 H, 3-H), 4.03 (ψt, J = 9.9 Hz, 1 H, 6-

H), 4.40 (d, AB, J = 12.2 Hz, 1 H, Ph-CH₂), 4.63 (d, AB, J =

11.2 Hz, 1 H, Ph-CH₂), 4.62 (dψt, J = 3.0, J = 9.0 Hz, 1 H, 1-H),

4.71 (d, AB, J = 12.2 Hz, 1 H, Ph-CH₂), 4.82 (d, AB, J = 12.2 Hz,

1 H, Ph-CH₂), 4.99–5.28 [m, 4 H, (CH₂)₂C₆H₄], 5.09 (ψt, J =

9.9 Hz, 1 H, 5-H), 5.30 (ψt, J = 9.9 Hz, 1 H, 4-H), 5.96 (ψt, J =

2.8 Hz, 1 H, 2-H), 7.17–7.28 (m, 14 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ = 20.5, 20.6, 20.9 (3×CH₃), 68.1 (C-2), 68.4 [ψt, J =

6.5 Hz, (CH₂)₂C₆H₄], 71.0 (C-4), 71.6 (PhCH₂), 72.2 (C-5), 74.6

(C-3), 75.2 (PhCH₂), 76.0 (d, J = 5.7 Hz, C-1), 77.9 (d, J = 5.7 Hz,

C-6), 127.7, 127.85, 127.91, 128.3, 128.4, 128.7, 128.8, 129.0, 129.1

(C_arom.), 134.97, 135.01, 137.1, 137.8 (C_ipso), 169.4, 169.6, 170.0

(C=O) ppm. ³¹P{¹H} NMR (CDCl₃): δ = 1.05 (PC-1) ppm. MS

D-myo-Inositol 1,4-Bisphosphate [(+)-10]: A solution of (–)-17 was

allowed to react to give (+)-10 under the conditions described for

the preparation of (–)-10. [α]²_D⁰= +1.6 (c = 1.3, H₂O, free acid).

Ref.^[25][α]²_D⁰= +3.6 (c = 0.5, H₂O, tetrapotassium salt). The R_f

1

value and H and ¹³C NMR spectroscopic data are identical with

those obtained for (–)-10.

2,4,5-Tri-O-acetyl-3,6-di-O-benzyl-D-myo-inositol [(+)-28]: p-Tolu-

enesulfonic acid monohydrate (0.34 g, 1.79 mmol) and triethyl or-

3110

www.eurjoc.org

Eur. J. Org. Chem. 2005, 3101–3115

myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

(EI, 70 eV): m/z (%) = 668 (2) [M⁺], 577 (2), 535 (3), 471 (6.1) [M⁺

FULL PAPER

70.2 (C-1), 71.8 (Ph-CH₂), 72.7 (C-4), 74.7 (C-5), 75.1 (Ph-CH₂),

+ H – Bn – BnO], 291 (21), 243 (30), 201 (72.9), 199 (39.4), 183 77.5 (C-3), 81.1 (C-6), 127.9, 128.0, 128.1, 128.1, 128.5 (C_arom),

(37), 136 (41), 109 (37), 104 (100), 43 (79). IR (KBr): ν = 3064 (w),

137.2, 138.4 (C_ipso), 170.6 (C=O) ppm. MS (70 eV): m/z (%) = 402

˜

3031 (w), 2934 (w), 1751 (s), 1371 (s), 1223 (s, br), 1016 (s, br), 947

(2), [M⁺], 311 (45) [M⁺– Bn], 310 (29), 205 (47), 127 (12), 109 (27),

(m), 869 (m), 753 (m), 735 (m), 698 (m) cm^–1. HR-MS (ESI-pos.): 107 (31), 99 (15), 92 (33), 91 (100), 86 (25), 81 (10), 73 (12), 65

calcd. for C₃₄H₃₇O₁₂PNa [M + Na]⁺691.192; found 691.192.

(15), 43 (88). HR-MS (ESI-pos): calcd. for C₂₂H₂₇O₇[M + H]⁺

403.1752; found 403.1756.

2,5,6-Tri-O-acetyl-1,4-di-O-benzyl-3-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)-D-myo-inositol [(–)-29]: A solu-

2-O-Acetyl-1,4-di-O-benzyl-D-myo-inositol [(+)-31]: A solution of

tion of (–)-28 was allowed to react under the conditions described

for the preparation of (+)-29 to give (–)-29. [α]²_D⁰= –49.7 (c = 0.6,

CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

are identical with those obtained for (+)-29.

(–)-22 was allowed to react to give (+)-31 under the conditions

described for the preparation of (–)-31. [α]²_D⁰= +19.8 (c = 5.5,

CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

are identical with those obtained for (–)-31.

D-myo-Inositol 1-Phosphate [(–)-30]: Pd/C (30 mg) was added to a

2-O-Acetyl-3,6-di-O-benzyl-1,4,5-tris-O-(3-oxo-1,5-dihydro-3λ⁵-

suspension of (+)-29 (50 mg, 74 μmol) in ethanol/water (1:1,

30 mL) and the mixture was stirred at room temperature under H₂

overnight. The catalyst was then filtered off and the filtrate was

concentrated under high vacuum. The residue was dissolved in ice-

cooled 0.25 m aqueous NaOH (10 mL) and stirred at 0 °C for 4 h.

The solution was neutralized by addition of ion exchanger (H⁺

form, Dowex 50-X), filtered, and the resin washed with water. The

filtrate was lyophilized to yield 20 mg (99%) as a colorless, very

hygroscopic foam. [α]²_D⁰= –6.1 [c = 1.4, H₂O, pH = 2 (free acid)].

Ref.^[19][α]²_D⁰= –9.8 (c = 3, H₂O, pH = 2), [α]²_D⁰= –2.6 [c = 1.2,

H₂O, pH adjusted to 6 (NH₄OH)], [α]²_D⁰= +4.4 [c = 1.2, H₂O, pH

adjusted to 9 (NH₄OH)]. Ref.^[19][α]²_D⁰= +3.4 [c = 3, H₂O, pH ad-

justed to 9 (cyclohexylamine)]. Ref.^[29][α]²_D⁰= +3.5 (c = 1, H₂O,

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

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

D

-myo-inositol [(–)-32]: (1,5-Dihy-

(1.13 g,

4.7 mmol) was added to a suspension of 2-O-acetyl-3,6-di-O-ben-

zyl-myo-inositol [(–)-31] (315 mg, 0.8 mmol) and 1H-tetrazole

(660 mg, 9.4 mmol) in anhydrous dichloromethane (30 mL), and

the solution was stirred at room temperature for 12 h. The solution

was then cooled to –40 °C, and an anhydrous solution of m-CPBA

(2.3 g, 9.4 mmol) in dichloromethane (20 mL, dried with Na₂SO₄)

was added. The solution was allowed to warm to room temperature

and the stirring was continued for 1 h. The reaction mixture was

diluted with dichloromethane (200 mL) and washed consecutively

with aqueous sodium sulfite (20%, 2×100 mL), saturated

NaHCO₃(3×150 mL), and then with brine. After evaporation of

the solvent, the residue was purified by flash chromatography (ethyl

acetate/cyclohexane, 5:1) to yield (–)-32 (646 mg, 87%) as a color-

1

sodium salt, pH = 9). H NMR (D₂O, free acid): δ = 3.28 (ψt, J =

8.1 Hz, 1 H, 5-H), 3.51 (dd, J = 2.8, J = 10.2 Hz, 1 H, 3-H), 3.60

(ψt, J = 9.9 Hz, 1 H, 4-H), 3.71 (ψt, J = 9.2 Hz, 1 H, 6-H), 3.95

(dψt, J = 2.8, J = 9.4 Hz, 1 H, 1-H), 4.21 (ψt, J = 2.8 Hz, 1 H, 2-

1

less foam. [α]²_D⁰= –5.3 (c = 1.8, CH₂Cl₂). H NMR (CDCl₃): δ =

2.16 (s, 3 H, CH₃), 3.69 (dd, J = 2.8, J = 9.9 Hz, 1 H, 3-H), 4.07

H) ppm. ¹³C NMR (D₂O, free acid): δ = 73.0 (s, C-3), 73.4 (s, C- (ψt, J = 9.7 Hz, 1 H, 6-H), 4.48 (d, AB, J = 11.4 Hz, 1 H, Ph-

2), 73.6 (d, J = 6.1 Hz, C-6), 74.5 (s, C-4), 76.1 (s, C-5), 78.5 (d, J

CH₂), 4.71 (m, 1 H, 1-H), 4.80–5.27 [m, 15 H, CH₂, (CH₂)₂C₆H₄,

= 5.1 Hz, C-1) ppm. ³¹P{¹H} NMR (D₂O, free acid): δ = 0.96 (PC- and other ring protons], 5.45–5.57 (m, 2 H, CH₂), 6.02 (ψt, J =

1) ppm. HR-MS (ESI-neg, phosphoric acid, Q-TOF): calcd. for

C₆H₁₂O₉P [M – H]^–259.0249; found 259.0219.

2.5 Hz, 1 H, 2-H), 7.06–7.49 (m, 22 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ = 20.7 (CH₃), 67.6 (CH), 68.0 (d, J = 6.7 Hz, CH₂OP),

68.4 (dd, J = 5.6, J = 10.0 Hz, 2×C, CH₂, CH₂OP), 68.8 (dd, J =

7.5, J = 1.5 Hz, CH₂, CH₂OP), 72.0 (Ph-CH₂), 74.8 (Ph-CH₂),

75.39 (CH), 75.43 (CH), 77.6 (t, J = 4.3 Hz, CH), 77.9 (dd, J =

6.2, J = 2.1 Hz, CH), 78.8 (m, CH), 126.9–129.8 (C_arom.), 132.2–

137.6 (C_ipso), 169.2 (C=O) ppm. ³¹P{¹H} NMR (CDCl₃): δ = 0.00,

0.79, 1.20 ppm. C₄₆H₄₇O₁₆P₃(948.8): calcd. C 58.23, H 4.99; found

C 57.92, H 4.95.

D-myo-Inositol 3-Phosphate [(+)-30]: A solution of (–)-29 was al-

lowed to react under the conditions described for the preparation

of (–)-30 to give (+)-30. [α]²_D⁰= +3.4 [c = 1.1, H₂O, pH adjusted to

6 (NH₄OH)]. [α]²_D⁰= –4.5 [c = 0.6, H₂O, pH adjusted to 9

(NH₄OH)]. Ref.^[30][α]²_D⁰= –3.5° (H₂O, sodium salt, pH = 9). The

R_fvalue and ¹H and ¹³C NMR spectroscopic data are identical

with those obtained for (–)-30.

2-O-Acetyl-1,4-di-O-benzyl-3,5,6-tris-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)-D-myo-inositol [(+)-32]: A solu-

2-O-Acetyl-3,6-di-O-benzyl-D-myo-inositol [(–)-31]: p-Toluenesul-

fonic acid monohydrate (15 mg) and triethyl orthoacetate (0.3 mL,

1.6 mmol) were added to a solution of the tetraol (+)-22 (300 mg,

0.83 mmol) in anhydrous tetrahydrofuran (20 mL) under argon and

the mixture was stirred vigorously for 24 h. The solvent was re-

moved under reduced pressure, and the residue was dried under

high vacuum. The residue was dissolved in aqueous acetic acid

(10 mL, 80%) and stirred at room temperature for 1 h. The organic

phase was evaporated, and the residue was dissolved in ethyl ace-

tate (100 mL). The organic phase was washed with saturated aque-

ous NaHCO₃(2×20 mL) and then with brine (20 mL). Evapora-

tion of the solvent yielded (–)-31 (320 mg, 95%) as a colorless solid.

tion of (+)-31 was allowed to react under the conditions described

for the preparation of (–)-32 to give (+)-32. [α]²_D⁰= +5.0 (c = 1.6,

1

CH₂Cl₂). The R_fvalue and H and ¹³C NMR spectroscopic data

are identical with those obtained for (–)-32.

D-myo-Inositol 1,4,5-Trisphosphate [(–)-1]: Deprotection (hydro-

genolysis and deacetylation) of (–)-32 (150 mg, 0.16 mmol) was car-

ried out as described for the preparation of (–)-30 to give (–)-1

(66 mg, 98%) as a colorless, very hygroscopic foam. [α]²_D⁰= –9.2 (c

= 1.4, H₂O, free acid). Ref.^[31][α]²_D⁰= –13.3 (c = 1, H₂O). Ref.^[32]

[α]²_D⁰= –10.3 (c = 1.8, H₂O, ammonium salt, pH = 6.73). ¹H NMR

[D₂O, pH adjusted to 8.0 (ND₄OD)]: δ = 3.66 (dd, J = 9.7, J =

1

[α]²_D⁰= –20.5 (c = 4.5, CHCl₃). H NMR (CDCl₃): δ = 2.13 (s, 3

H, CH₃), 2.99 (br., 1 H, OH), 2.58 (br., 1 H, OH), 3.30 (dd, J = 2.5 Hz, 1 H, 3-H), 3.87 (m, 3 H, 1-H, 6-H, 5-H), 4.12 (ψq, J =

9.9, J = 2.8 Hz, 1 H, 3-H), 3.50 (ψt, J = 9.2 Hz, 1 H, 5-H), 3.60

(dd, J = 9.7, J = 3.1 Hz, 1 H, 1-H), 3.65 (ψt, J = 8.9 Hz, 1 H, 6-

H), 3.81 (ψt, J = 9.7 Hz, 1 H, 4-H), 4.43 and 4.78 (2×d, AB, J =

8.7 Hz, 1 H, 4-H), 4.31 (ψt, J = 2.1 Hz, 1 H, 2-H) ppm. ¹³C NMR

[CDCl₃, pH adjusted to 8.0 (ND₄OD)]: δ = 72.8 (s, C-2), 73.8 (s,

C-3), 74.6 (d, J = 7.0 Hz, CH), 76.7 (d, J = 5.7 Hz, CH), 77.3 (t,

10.7 Hz, 2×1 H, Ph-CH₂), 4.80 and 5.00 (2×d, AB, J = 11.7 Hz, J = 5.4 Hz, C-4), 79.5 (t, J = 6.4 Hz, CH) ppm. ³¹P{¹H} NMR

2×1 H, Ph-CH₂), 5.70 (ψt, J = 2.5 Hz, 1 H, 2-H), 7.26–7.40 (m,

[CDCl₃, pH adjusted to 8.0 (ND₄OD)]: δ = 4.16 + 5.55 (PC-1 and

PC-5), 5.88 (PC-4) ppm. HR-MS (ESI-neg., phosphoric acid

10 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.9 (CH₃), 69.0 (C-2),

Eur. J. Org. Chem. 2005, 3101–3115

www.eurjoc.org

3111

M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

FULL PAPER

0.002%, H₂O/acetonitrile, Q-TOF): calcd. for C₆H₁₄O₁₅P₃

[M – H]^–418.9535; 418.9546.

2 or C-1), 75.7 (C-3), 77.03 (C-6), 79.2 (C-2 or C-1), 103.9 (acetal-

CH), 126.1, 127.5, 127.6, 127.7, 127.8, 128.2, 128.3, 128.35, 129.0

(C_arom.), 137.6, 137.9, 138.4 (C_ipso), 169.6, 169.9 (CO) ppm.

D-myo-Inositol 3,5,6-Trisphosphate [(+)-1]: A solution of (+)-32 was

1,3,6-Tri-O-benzyl-D-myo-inositol [(–)-35] and 2,3,6-Tri-O-benzyl-D-

allowed to react under the conditions described for the preparation

of (–)-1 to give (+)-1. [α]²_D⁰= +9.4 (c = 1.3, H₂O, free acid). The R_f

myo-inositol [(+)-36]: A solution of 1 m BH₃in THF (7 mL) was

added to a dry flask containing (–)-33 (240 mg, 0.53 mmol). The

mixture was stirred for 10 min, then a solution of 1 m Bu₂BOTf in

dichloromethane (0.5 mL) was added dropwise. The reaction mix-

ture was stirred for 2 h, then triethylamine (0.3 mL) was added to

the reaction flask, followed by careful addition of methanol until

formation of hydrogen had ceased. The mixture was co-distilled

with methanol three times and then subjected to column

chromatography (cyclohexane/ethyl acetate, 1:2) to give 114 mg

(47%) of 2,3,6-tri-O-benzyl-d-myo-inositol [(+)-36] and 98 mg

(40%) of 1,3,6-tri-O-benzyl-myo-inositol [(–)-35]. The use of (+)-34

(240 mg) gave exclusively 2,3,6-tri-O-benzyl-myo-inositol [(+)-36]

(180 mg, 75%). (–)-35: [α]²_D⁰= –11.0 (c = 1.2, CHCl₃). ¹H NMR

(CDCl₃): δ = 2.49 (br. s, 1 H, OH), 2.64 (br. s, 2 H, OH), 3.24 (dd,

J = 9.4, J = 2.8 Hz, 1 H, 3-H), 3.38 (dd, J = 9.4, J = 2.8 Hz, 1 H,

1-H), 3.42 (ψt, J = 9.4, 1 H, 5-H), 3.84 (ψt, J = 9.4, 1 H, 6-H),

3.98 (ψt, J = 9.4, 1 H, 4-H), 4.25 (ψt, J = 2.8, 1 H, 2-H), 4.68 (m,

4 H, PhCH₂), 4.81 and 4.94 (2×d, AB, J = 11.2 Hz, 2×1 H,

CH₂Ph), 7.27–7.40 (m, 15 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ =

67.0 (C-2), 71.9 (C-4), 72.2 (PhCH₂), 72.4 (PhCH₂), 74.3 (C-5),

75.4 (PhCH₂), 79.0 (C-3), 79.7 (C-1), 80.4 (C-6), 127.7, 127.8,

127.9, 127.91, 127.96, 128.4, 128.4, 128.5 (C_arom.), 137.7, 137.8,

1

value and H and ¹³C NMR spectroscopic data are identical with

those obtained for (–)-1.

exo-3,6-Di-O-benzyl-1,2-benzylidene-D-myo-inositol [(–)-33] and

endo-3,6-Di-O-benzyl-1,2-benzylidene-D-myo-inositol [(+)-34]: 3,6-

Di-O-benzyl-myo-inositol [(+)-22; 1 g] and a catalytic amount of p-

toluenesulfonic acid were suspended in 20 mL of dry tetra-

hydrofuran. Benzaldehyde dimethylacetal (0.63 mL, 1.5 equiv.) was

added and the reaction mixture was stirred overnight. The mixture

was diluted with diethyl ether, extracted with sodium hydrogencar-

bonate and brine, dried with sodium sulfate, and the solvents were

evaporated. The crude product was purified by column chromatog-

raphy (hexane/ethyl acetate) to give exo-3,6-di-O-benzyl-1,2-ben-

zylidene-myo-inositol [(–)-33; 450 mg, 36%] and endo-3,6-di-O-ben-

zyl-1,2-benzylidene-myo-inositol [(+)-34; 410 mg, 33%] along with

unconverted starting material (240 mg). (–)-33: [α]²_D⁰= –15.8 (c =

0.4, acetone). ¹H NMR ([D₆]DMSO): δ = 3.28 (m, 1 H, under

H₂O), 3.58 (m, 3 H), 4.33 (dd, J = 7.1, J = 5.1 Hz, 1 H), 4.38 (dd,

J = 5.6, J = 3.1 Hz, 1 H), 4.60 and 4.68 (2×d, AB, J = 12.2 Hz,

2×1 H, PhCH₂), 4.77 and 4.80 (2×d, AB, J = 12.0 Hz, 2×1 H,

CH₂Ph), 5.05 (d, J = 5.1 Hz, 1 H, OH), 5.07 (d, J = 4.6 Hz, 1 H,

OH), 5.99 (s, 1 H, acetal-H) 7.19–7.40 (m, 15 H, Ph-H) ppm. ¹³C

NMR ([D₆]DMSO): δ = 71.4 (CH₂), 71.9 (CH), 72.7 (CH₂), 73.5

(CH), 74.2 (CH), 78.2 (CH), 79.4 (CH), 79.7 (CH), 102.2 (acetal-

CH), 126.2-128.8 (C_arom.), 138.9, 139.1, 139.3 (C_ipso) ppm. IR

138.7 (C_ipso) ppm. IR (KBr): ν = 3404 (s), 3064 (m), 3028 (m), 2938

˜

(m), 2867 (m), 1496 (m), 1454 (s), 1370 (s), 1093 (s), 1057 (s), 740

(s), 697 (m) cm^–1. C₂₇H₃₀O₆(450.5); calcd. C 71.98, H 6.71; found

C 72.13, H 6.75. (+)-36: [α]²_D⁰= +7.2 (c = 0.9, CHCl₃). H NMR

1

(KBr): ν = 3484 (s), 3062 (m), 3030 (m), 2897 (m), 1453 (m), 1115

˜

(CDCl₃): δ = 2.35 (br. s, 1 H, OH), 2.66 (br. s, 2 H, OH), 3.30 (dd,

J = 9.7, J = 2.0 Hz, 1 H, 3-H), 3.48 (ψt, J = 9.2, 1 H, 5-H), 3.54

(d, J = 9.2 Hz, 1 H, 1-H), 3.69 (ψt, J = 9.2, 1 H, 6-H), 4.02 (ψt, J

= 9.4, 1 H, 4-H), 4.09 (ψt, J = 2.3, 1 H, 2-H), 4.60 and 4.73 (2×d,

AB, J = 11.7 Hz, 2×1 H, CH₂Ph), 4.70 and 4.90 (2×d, AB, J =

11.7 Hz, 2×1 H, CH₂Ph), 4.84 and 4.94 (2×d, AB, J = 11.2 Hz,

2×1 H, CH₂Ph), 7.25–7.42 (m, 15 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ = 70.6 (PhCH₂), 72.5 (C-1 or C-4), 72.6 (C-4 or C-1),

74.8 (PhCH₂), 74.9 (C-5), 75.0 (PhCH₂), 76.4 (C-2), 80.2 (C-3),

81.7 (C-6), 127.7, 127.8, 127.9, 128.0, 128.1, 128.4, 128.5, 128.6

(s), 1075 (s), 1039 (s), 1025 (s), 1000 (s), 734 (m), 695 (s), 631 (s)

cm^–1. C₂₇H₂₈O₆(448.5): calcd. C 72.30, H 6.29; found C 72.31, H

6.10. (+)-34: [α]²_D⁰= +8.2 (c = 0.36, acetone). ¹H NMR ([D₆]-

DMSO): δ = 3.28 (m, 1 H, under H₂O, 5-H), 3.49 (dd, J = 6.6, J

= 9.7 Hz, 1 H, 6-H), 3.64 (m, 2 H, 4-H, 3-H), 4.21 (ψt, J = 6.6 Hz,

1 H, 1-H), 4.47 (dd, J = 6.1, J = 3.05 Hz, 1 H, 2-H), 4.61–4.72 (m,

2×2 H, 2×PhCH₂), 4.99 (d, J = 5.1 Hz, 1 H, OH), 5.07 (d, J =

4.1 Hz, 1 H, OH), 5.82 (s, 1 H, acetal-H) 7.18–7.44 (m, 15 H, Ph-

H) ppm. ¹³C NMR ([D₆]DMSO): δ = 71.5 (CH₂), 72.0 (C-4), 72.3

(CH₂), 73.8 (C-5), 76.2 (C-2), 77.5 (C-3), 78.2 (C-1), 83.0 (C-6),

103.2 (acetal-CH), 126.7, 127.0, 127.2, 127.4, 127.9, 128.0, 128.1,

(C_arom.), 137.7, 138.5, 138.6 (C_ipso) ppm. IR (KBr): ν = 3437 (s),

˜

3061 (m), 3029 (m), 2951 (m), 2865 (m), 1452 (m), 1363 (s), 1114

(s), 1066 (s), 1027 (s), 756 (s), 701 (m) cm^–1. C₂₇H₃₀O₆(450.5):

calcd. C 71.98, H 6.71; found C 72.08, H 6.82.

129.1 (C_arom.), 137.6, 138.8, 139.9 (C_ipso) ppm. IR (KBr): ν = 3423

˜

(s), 3063 (m), 3031 (m), 2880 (m), 1454 (m), 1089 (s), 1066 (s), 1000

(s), 739 (m), 698 (s) cm^–1. C₂₇H₂₈O₆(448.5): calcd. C 72.30, H 6.29;

found C 72.50, H 6.16.

1,4,5-Tri-O-acetyl-3,6-di-O-benzyl-D-myo-inositol [(+)-37]: (+)-28

(500 mg, 1 mmol) and powdered molecular sieves (3 Å) (200 mg)

were dissolved/suspended (20 mL) in anhydrous diethyl ether. A

freshly prepared solution of 0.2 m trimethylsilyl triflate (0.5 mL) in

anhydrous diethyl ether (with powdered molecular sieves) was

added dropwise from a syringe. The mixture was stirred at room

temperature for 24 h, then a second, freshly prepared solution of

0.2 m trimethylsilyl triflate (0.5 mL) in anhydrous diethyl ether

(with powdered molecular sieves) was added dropwise, and stirring

was continued for another 24 h. For workup, NaHCO₃(500 mg)

was added, the reaction solution was filtered through a small glass

frit with silica gel, and the silica gel was washed with ethyl acetate.

The filtrate was concentrated under reduced pressure to give (+)-

37 (500 mg, 100%) as a colorless solid. [α]²_D⁰= +56.7 (c = 3.05,

exo-4,5-Di-O-acetyl-3,6-di-O-benzyl-1,2-benzylidene-D-myo-inositol

(49): For an unambiguous assignment of the new stereogenic center

of (–)-33, it was acetylated and the product was analyzed by NMR

spectroscopy. Thus, (–)-33 (100 mg, 0.22 mmol) was dissolved in a

cooled mixture of pyridine (7 mL) and acetic anhydride (7 mL) and

the mixture was stirred at room temperature for 12 h. Evaporation

of the solvent under high vacuum yielded 49 (120 g, 100%) as a

colorless solid. The relative configuration at the new stereogenic

center was confirmed by NOESY NMR, which showed only one

strong cross-peak between the acetal-H and 6-H. ¹H NMR

(CDCl₃): δ = 2.05, 2.06 (2×s, 2×3 H, CH₃), 3.85 (dd, J = 7.6, J =

3.0 Hz, 1 H, 3-H), 4.03 (dd, J = 9.3, J = 6.4 Hz, 1 H, 6-H), 4.67

(m, 2 H, 2-H, 1-H), 4.73 (s, 2 H, PhCH₂), 4.76, 4.89 (2×d, AB, J CHCl₃). ¹H NMR (CDCl₃): δ = 1.92, 1.98, 2.07 (3×s, 3×3 H,

= 12.0 Hz, 2×1 H, PhCH₂), 5.08 (dd, J = 9.2, J = 7.6 Hz, 1 H, 5- CH₃), 3.58 (dd, J = 2.5, J = 9.7 Hz, 1 H, 3-H), 4.14 (ψt, J = 9.9 Hz,

H), 5.70 (ψt, J = 7.6 Hz, 1 H, 4-H), 6.21 (s, 1 H, acetal-H), 7.26– 1 H, 6-H), 4.34 (ψt, J = 2.5 Hz, 1 H, 2-H), 4.53, 4.67 (2×d, AB, J

7.48 (m, 15 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.7, 20.7 = 12.2 Hz, 2×1 H, Ph-CH₂), 4.63, 4.70 (2×d, AB, J = 12.1 Hz,

(CH₃), 71.6 (C-4), 72.5 (C-5 and PhCH₂), 73.1 (PhCH₂), 73.9 (C- 2×1 H, Ph-CH₂), 4.88 (dd, J = 3.1, J = 10.2 Hz, 1 H, 1-H), 5.07

3112

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Eur. J. Org. Chem. 2005, 3101–3115

myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

FULL PAPER

(ψt, J = 9.9 Hz, 1 H, 5-H), 5.43 (ψt, J = 9.9 Hz, 1 H, 4-H), 7.2–

7.4 (m, 10 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 20.6, 20.7, 20.9

(CDCl₃/[D₄]MeOH, 6:1): δ = 20.6 (CH₃), 20.7 (2×CH₃), 68.7 (C-

6), 70.09 (C-3), 70.10 (C-2), 72.8 (C-4), 73.6 (C-5), 73.8 (C-1),

(3×CH₃), 67.4 (C-2), 71.4 (C-4), 72.6 (PhCH₂), 72.6 (C-5), 73.0 171.1, 171.3, 171.4 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 289 (2)

(C-1), 75.3 (PhCH₂), 76.8 (C-6), 77.1 (C-3), 127.5, 127.7, 127.72,

[M⁺– OH], 168 (8), 144 (11), 126 (37), 115 (62), 73 (74), 43 (100).

127.8, 128.2, 128.4, 128.6 (C_arom.), 137.0, 138.1 (C_ipso), 169.9, 170.0, IR (KBr): ν = 3426 (s, br), 2938 (w), 1731 (s), 1369 (s), 1243 (s,

˜

170.2 (C=O) ppm. MS (EI, 70 eV): m/z (%) = 443 (3), 395 (60),

289 (100), 229 (25), 169 (26), 127 (60), 109 (99), 91 (100), 43 (99).

br), 1043 (s), 919 (m), 734 (m), 710 (m) cm^–1. C₁₂H₁₈O₉(306.3):

calcd. C 47.06, H 5.92; found C 47.00, H 5.79.

IR (KBr): ν = 3461 (m), 3068, 3032 (w), 2979, 2941, 2900 (w), 1748

˜

3,5,6-Tri-O-acetyl-D-myo-inositol [(–)-40]: A solution of (–)-37 was

(s), 1367 (m), 1226 (s), 1058 (s), 1030 (s), 929 (m), 741 (m) cm^–1.

C₂₆H₃₀O₉(486.5): calcd. C 64.19, H 6.22; found C 64.31, H 6.20.

allowed to react under the conditions described for the preparation

of (+)-40 to give (–)-40. [α]²_D⁰= –10.5 (c = 0.41, acetone). The R_f

1

value and H and ¹³C NMR spectroscopic data are identical with

3,5,6-Tri-O-acetyl-1,4-di-O-benzyl-D-myo-inositol [(–)-37]: A solu-

tion of (–)-28 was allowed to react under the conditions used for

the preparation of (+)-37 to give (–)-37. [α]²_D⁰= –61.3 (c = 3.1,

CHCl₃). The R_fvalue and ¹H and ¹³C NMR spectroscopic data

are identical with those obtained for (+)-37.

those obtained for (+)-40.

1,4,5-Tri-O-acetyl-2,3,6-tris-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzo-

dioxaphosphepin-3-yl)-D-myo-inositol [(+)-41]: (1,5-Dihydro-2,4,3-

benzodioxaphosphepin-3-yl)diethylamine (300 mg, 1.2 mmol) was

added to a suspension of (+)-40 (100 mg, 0.33 mmol) and 1H-tetra-

zole (140 mg, 2 mmol) in anhydrous dichloromethane (10 mL), and

the solution was stirred at room temperature for 12 h. The solution

was then cooled to –40 °C, and an anhydrous solution of m-CPBA

(800 mg, 3.3 mmol) in dichloromethane (10 mL, dried with

Na₂SO₄) was added. The solution was allowed to warm to room

temperature, and the stirring was continued for 1 h. The product

was worked up as described for (+)-29. Purification by flash

chromatography (ethyl acetate) yielded pure (+)-41 (140 mg, 53%)

as a colorless foam. R_f= 0.20 (ethyl acetate). [α]²_D⁰= +14.2 (c =

0.4, CHCl₃). ¹H NMR (CDCl₃): δ = 2.14, 2.16, 2.24 (3×s, 3×3 H,

CH₃), 4.88 (ψtψt, J = 2.3, J = 9.9 Hz, 1 H, 3-H), 5.28 (dψt, J =

9.7, J = 2.5 Hz, 1 H, 2-H), 5.50 (ψt, J = 10.2 Hz, 1 H, 4-H), 4.94–

5.62 [m, 15 H, 3×(CH₂)₂C₆H₄, 1-H, 5-H, 6-H], 7.22–7.40 (m, 12 H,

Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 68.7–69.2 [m, 3×(CH₂)₂-

C₆H₄], 68.6, 69.3, 70.2, 73.6, 75.9, 75.9 (C-1 to C-6), 128.6–129.4

(C_arom.), 134.5, 134.6, 134.6, 134.8, 135.0, 135.5, 137.1 (C_ipso),

169.7, 170.1 (C=O) ppm. ³¹P{¹H} NMR (CDCl₃): δ = –2.06,

–0.67, –0.53 (PC-2, PC-3, PC-6) ppm. HR-MS (ESI-pos.): calcd.

for C₃₆H₃₉O₁₈P₃Na [M + Na]⁺875.124; found 875.1246.

1,4,5-Tri-O-acetyl-3,6-di-O-benzyl-2-O-(3-oxo-1,5-dihydro-3λ⁵-

2,4,3-benzodioxaphosphepin-3-yl)-D-myo-inositol

[(+)-38]:

The

alcohol (+)-37 (300 mg, 0.62 mmol) was phosphorylated as de-

scribed for the preparation of (+)-29 to give (+)-38 (250 mg, 60%)

as a colorless foam. R_f= 0.22 (ethyl acetate/cyclohexane, 1:1).

[α]²_D⁰= +40.8 (c = 0. 9, CHCl₃). ¹H NMR (CDCl₃): δ = 1.94, 2.02,

2.14 (3×s, 3×3 H, CH₃), 3.65 (dψt, J = 10.0, J = 2.4 Hz, 1 H, 3-

H), 4.00 (ψt, J = 9.7 Hz, 1 H, 6-H), 4.50, 4.63, 4.73, 4.79 (4×d,

AB, J = 11.7 Hz, 4×1 H, Ph-CH₂), 4.74–4.84 [m, 1 H, (CH₂)₂-

C₆H₄], 4.88 (dψt, J = 10.3, J = 2.3 Hz, 1 H, 1-H), 5.12 (ψt, J =

9.9 Hz, 1 H, 5-H), 5.21 [d, AB, J = 15.7 Hz, 2 H, (CH₂)₂C₆H₄],

5.28–5.36 [m, 1 H, (CH₂)₂C₆H₄], 5.28 (dψt, J = 9.5 J = 2.5 Hz, 1

H, 2-H), 5.39 (ψt, J = 10.2 Hz, 1 H, 4-H), 7.15–7.37 (m, 14 H, Ph-

H) ppm. ¹³C NMR (CDCl₃): δ = 20.6, 20.7, 20.8 (3×CH₃), 68.8

[dd, J = 6.6, J = 14.7 Hz, (CH₂)₂C₆H₄], 70.8 (C-4), 71.5 (d, J =

3.0 Hz, C-1), 72.1 (PhCH₂), 72.4 (C-5), 73.0 (d, J = 6.1 Hz, C-2),

75.0 (d, J = 3.1 Hz, C-3), 75.1 (PhCH₂), 76.5 (C-6), 127.6, 127.79,

127.82, 128.0, 128.37, 128.43, 128.6, 128.7, 128.8, 129.0, 129.1

(C_arom.), 134.6, 135.3, 136.9, 137.8 (C_ipso), 169.7, 170.0, 170.2

(C=O) ppm. ³¹P{¹H} NMR (CDCl₃): δ = 0.33 (PC-2) ppm. MS

(EI, 70 eV): m/z (%) = 668 (2) [M⁺], 471 (9), 291 (25), 243 (34), 201

3,5,6-Tri-O-acetyl-1,2,4-tris-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzo-

dioxaphosphepin-3-yl)-D-myo-inositol [(–)-41]: A solution of (–)-40

was allowed to react under the conditions described for the prepa-

ration of (+)-41 to give (–)-41. [α]²_D⁰= –18.0 (c = 0.4, CHCl₃). The

R_fvalue and ¹H and ¹³C NMR spectroscopic data are identical

with those obtained for (+)-41.

(100), 104 (97), 43 (78). IR (KBr): ν = 3075 (w), 3031 (w), 2941,

˜

2900 (w), 1748 (s), 1367 (m), 1288 (m), 1225 (s), 1058 (s), 1031 (s,

br), 854 (w), 829 (w), 735 (w), 697 (w) cm^–1. HR-MS (ESI-pos.):

calcd. for C₃₄H₃₇O₁₂PNa [M + Na]⁺691.193; found 691.192.

myo-Inositol 2-Phosphate (39): Deprotection (hydrogenolysis and

deacetylation) of (+)-38 (50 mg, 74 μmol) was carried out as de-

1

scribed for the preparation of (–)-30. H NMR (D₂O, pH = 3): δ

D-myo-Inositol 2,3,6-Trisphosphate [(+)-42]: Preactivated Pd/C

= 3.24 (ψt, J = 9.2 Hz, 1 H, 5-H), 3.53 (dd, J = 2.3, J = 9.2 Hz, 2

H, 1-H, 3-H), 3.63 (ψt, J = 9.7 Hz, 2 H, 4-H, 6-H), 4.55 (dψt, J =

2.3, J = 8.1 Hz, 1 H, 2-H) ppm. ¹³C NMR (D₂O, pH = 3): δ =

73.0 (d, J = 2.9 Hz, C-1, C-3), 74.8 (s, C-4, C-6), 76.6 (s, C-5), 80.3

(d, J = 5.7 Hz, C-2) ppm. ³¹P{¹H} NMR (D₂O, pH = 3): δ = 1.96

(PC-2) ppm. HR-MS (ESI-neg, phosphoric acid, Q-TOF): calcd.

for C₆H₁₂O₉P [M – H]^–259.0242; found 259.0219.

(100 mg, Degussa RW 10) was added to a suspension of (+)-41

(80 mg, 0.09 mmol) in ethanol/water (1:2, 30 mL) and the mixture

was stirred at room temperature under H₂for 12 h. The catalyst

was filtered off, and the filtrate was concentrated under reduced

pressure. The residue was taken up in ice-cooled 0.25 n NaOH

(10 mL) and stirred at this temperature for 5 h. The solution was

neutralized by ion exchange (H⁺form, DOWEX 50-X) and filtered;

the resin was washed with water. The filtrate was lyophilized to give

1,4,5-Tri-O-acetyl-D-myo-inositol [(+)-40]: Preactivated Pd/C

(100 mg, Degussa RW 10) was added to a suspension of (+)-37

(400 mg, 0.82 mmol) in ethyl acetate/ethanol (2:1, 20 mL) and the

mixture was stirred at room temperature under H₂for 4 h (TLC

control). The catalyst was filtered off and washed with ethyl ace-

tate/ethanol. Concentration of the filtrate under reduced pressure

gave (+)-40 (250 mg, 99%) as an oily solid. [α]²_D⁰= +13.5 (c = 0.5,

(+)-42 (40 mg, 100%) as a colorless, very hygroscopic foam. [α]²_D⁰

=

+19.6 (c = 1.2, H₂O, free acid). Ref.^[33][α]²_D⁰= –13.7 (c = 0.75, H₂O,

1

pH = 10, sodium salt). H NMR (D₂O, free acid): δ = 3.48 (ψt, J

= 9.2 Hz, 1 H, 5-H), 3.73 (d, J = 9.7 Hz, 1 H, 1-H), 3.79 (ψt, J =

9.7 Hz, 1 H, 4-H), 4.05 (ψt, J = 8.9 Hz, 1 H, 3-H), 4.19 (ψq, J =

9.2 Hz, 1 H, 6-H), 4.74 (d, J = 9.2 Hz, 1 H, 2-H) ppm. ¹³C NMR

acetone). ¹H NMR (CDCl₃/[D₄]MeOH, 6:1): δ = 2.02 (s, 6 H, (D₂O, free acid): δ = 69.8 (d, J = 3.2 Hz, C-1), 71.3 (d, J = 6.4 Hz,

2×CH₃), 2.10 (s, 3 H, CH₃), 3.64 (dd, J = 2.5, J = 10.2 Hz, 1 H,

C-4), 74.1 (d, J = 3.2 Hz, C-5), 75.1 (m, C-3), 76.9 (d, J = 6.4 Hz,

3-H), 3.96–4.04 (m, 4 H, 3×OH, 6-H), 4.08 (ψt, J = 2.8 Hz, 1 H, C-2), 78.5 (d, J = 6.4 Hz, C-6) ppm. ³¹P{¹H} NMR (D₂O, free

2-H), 4.69 (dd, J = 2.8, J = 10.4 Hz, 1 H, 1-H), 4.90 (ψt, J =

9.7 Hz, 1 H, 5-H), 5.22 (ψt, J = 9.9 Hz, 1 H, 4-H) ppm. ¹³C NMR

acid): δ = 1.08, 1.24, 1.90 (PC-2, PC-3, PC-6) ppm. HR-MS: calcd.

for C₆H₁₆O₁₅P₃[M + H]⁺420.967; found 420.9702.

Eur. J. Org. Chem. 2005, 3101–3115

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3113

M. A. L. Podeschwa, O. Plettenburg, H.-J. Altenbach

FULL PAPER

D-myo-Inositol 1,2,4-Trisphosphate [(–)-42]: A solution of (–)-41

D-myo–Inositol 2,5,6-Trisphosphate [(+)-44]: A solution of (+)-43

was allowed to react under the same conditions used for the prepa-

ration of (+)-42 to give (–)-42. [α]²_D⁰= –15.2 (c = 1.1, H₂O, free

acid). The ¹H NMR and ¹³C NMR spectroscopic data are identical

with those obtained for (+)-42.

was allowed to react under the conditions described for the prepa-

ration of (–)-44 to give (+)-44. [α]²_D⁰= +1.8 [c = 0.5, H₂O, pH

adjusted to 6 (NH₄OH)]. The ¹H NMR and ¹³C NMR spectro-

scopic data are identical with those obtained for (–)-44.

2-O-Acetyl-3,6-bis-O-(di-O-benzylphospho)-D-myo-inositol (45): Tri-

1-O-Acetyl-3,6-di-O-benzyl-D-myo–inositol [(–)-43]: 2 n HCl

ethyl orthoacetate (0.15 mL, 0.82 mmol) was added to a solution

of racemic 3,6-bis-O-(di-O-benzylphospho)-myo-inositol (250 mg,

0.36 mmol) [for the preparation, see the synthesis instructions for

(–)-10] and p-toluenesulfonic acid monohydrate (30 mg, 0.16 mmol)

in anhydrous tetrahydrofuran (50 mL). After the mixture had been

stirred vigorously for 2 d, the solvent was removed under reduced

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

was dissolved in aqueous acetic acid (15 mL, 80%) and stirred for

1.5 h at room temperature. The solvent was evaporated and the

residue was dissolved in dichloromethane (70 mL). The solution

was washed twice with saturated aqueous NaHCO₃(2×50 mL)

and then with brine (50 mL). Evaporation of the dichloromethane

gave a colorless solid (260 mg, 98%). ¹H NMR (CDCl₃/[D₄]-

MeOH): δ = 2.04 (s, 3 H, CH₃), 3.31 (m, 1 H, OH), 3.44 (ψt, J =

9.4 Hz, 1 H, 5-H or 4-H), 3.68 (dd, J = 2.5, J = 9.7 Hz, 1 H, 1-H),

3.79 (ψt, J = 9.7 Hz, 1 H, 5-H or 4-H), 4.25 (dψt, J = 2.8, J =

9.4 Hz, 1 H, 3-H), 4.39 (ψq, J = 9.2 Hz, 1 H, 6-H), 4.97–5.12 (m,

8 H, PhCH₂), 5.60 (ψt, J = 2.8 Hz, 1 H, 2-H) ppm. ¹³C NMR

(CDCl₃/[D₄]MeOH, 6:1): δ = 20.3 (CH₃), 68.6 (d, J = 3.8 Hz, CH),

69.3 (d, J = 5.2 Hz, CH₂), 69.5 (d, J = 5.7 Hz, CH₂), 69.5 (d, J =

6.7 Hz, CH₂), 69.7 (d, J = 5.6 Hz, CH₂), 71.5 (d, J = 4.8 Hz, CH),

72.0 (d, J = 1.9 Hz, CH), 72.9 (d, J = 2.9 Hz, CH), 76.2 (d, J =

6.7 Hz, CH), 81.0 (d, J = 6.87 Hz, CH), 127.5-135.5 (C_arom., C_ipso),

170.2 (CO) ppm. ³¹P{¹H} NMR (CDCl₃/[D₄]MeOH, 6:1): δ = 2.70,

3.33 ppm. HR-MS (ESI-pos.): calcd. for C₃₆H₄₁O₁₃P₂[M + H]⁺

743.2016; found 743.2022.

(0.2 mL) was added to a solution of (–)-31 (200 mg, 0.5 mmol) in

tetrahydrofuran (20 mL, HPLC grade). After the solution had been

stirred at 80 °C for 3 d, it was diluted with ethyl acetate (50 mL)

and neutralized with saturated aqueous NaHCO₃. The aqueous

layer was extracted with ethyl acetate (3×40 mL), and the com-

bined organic layers were washed with brine (25 mL). After evapo-

ration of the solvent, the resulting colorless oil was purified by flash

chromatography with silica gel (ethyl acetate/cyclohexane, 1:1) to

yield (–)-43 (60 mg, 30%) as a colorless solid. About 50% of the

starting material (–)-31 [100 mg, R_f= 0.08 (ethyl acetate/cyclohex-

ane, 1:1)] could also be re-isolated by chromatography. R_f= 0.08

1

(ethyl acetate/cyclohexane, 1:1), [α]²_D⁰= –1.9 (c = 1.3, CHCl₃). H

NMR (CDCl₃): δ = 2.08 (s, 3 H, CH₃), 3.40 (dd, J = 2.8, J =

9.4 Hz, 1 H, 3-H), 3.49 (ψt, J = 9.4 Hz, 1 H, 5-H), 3.92 (ψt, J =

9.9 Hz, 1 H, 6-H or 4-H), 3.93 (ψt, J = 9.4 Hz, 1 H, 4-H or 6-H),

4.31 (ψt, J = 2.5 Hz, 1 H, 2-H), 4.65 –4.74 (m, AB, 2 H, Ph-CH₂),

4.79 (s, AB, 2 H, Ph-CH₂), 4.85 (dd, J = 3.1, J = 10.2 Hz, 1 H, 1-

H), 7.25–7.41 (m, 10 H, Ph-H) ppm. ¹³C NMR (CDCl₃): δ = 21.2

(CH₃), 67.9 (C-2), 72.3 (C-4), 72.8 (PhCH₂), 73.6 (C-1), 74.5 (C-

5), 75.4 (PhCH₂), 78.8 (C-6), 79.4 (C-3), 127.4–128.6 (C_arom.),

137.4, 138.5 (C_ipso), 170.4 (C=O) ppm. C₂₂H₂₆O₇(402.4): calcd. C

65.66, H 6.51; found C 65.60, H 6.31.

D-myo–Inositol 2,4,5-Trisphosphate [(–)-44]: (–)-43 (30 mg,

0.075 mmol) was dissolved in anhydrous dichloromethane (10 mL),

and a solution of 1H-tetrazole (0.45 m in acetonitrile, 1 mL,

0.45 mmol) was added. (1,5-Dihydro-2,4,3-benzodioxaphosphepin-

3-yl)diethylamine (81 mg, 0.34 mmol) was then added dropwise at

ambient temperature, and the solution was stirred for 12 h. The

solution was then cooled to –40 °C, and an anhydrous solution of

m-CPBA (240 mg, 1 mmol) in dichloromethane (30 mL, dried with

Na₂SO₄) was added. The solution was allowed to warm to room

temperature, and the stirring was continued for 1 h. The product

was worked up as described for (+)-29. Purification by flash

chromatography (ethyl acetate, R_f= 0.45) yielded 1-O-acetyl-3,6-

di-O-benzyl-2,4,5-tris-O-(3-oxo-1,5-dihydro-3λ⁵-2,4,3-benzodioxa-

phosphepin-3-yl)-d-myo-inositol (40 mg) as a colorless foam. Pre-

activated Pd/C (40 mg, Degussa RW 10) ethanol/water (in 20 mL,

1:2) was added to a suspension of this compound (40 mg, 74 μmol)

in ethanol (10 mL). The mixture was stirred at room temperature

under H₂for 12 h. The catalyst was then filtered off, and the filtrate

was concentrated under reduced pressure. The residue was taken

up in ice-cooled 0.25 n NaOH (10 mL) and stirred at this tempera-

ture for 3 h. The solution was neutralized by ion exchange (H⁺

form, DOWEX 50-X) and filtered; the resin was washed with water.

The filtrate was lyophilized to give (–)-44 (15 mg, 50%) as a color-

less, very hygroscopic foam. [α]²_D⁰= –2.1 [c = 0.5, H₂O, pH adjusted

to 6 (NH₄OH)]. Ref.^[34][α]²_D⁰= –8.05 (H₂O, cyclohexylammonium

2-O-Acetyl-3,6-bis-O-(di-O-benzylphospho)-1,4,5-tris-O-(3-oxo-1,5-

dihydro-3λ⁵-2,4,3-benzodioxaphosphepin-3-yl)-

D-myo-inositol (46):

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

(380 mg, 1.6 mmol) was added to a solution of racemic 45 (250 mg,

0.34 mmol) and 1H-tetrazole (230 mg, 3.2 mmol) in anhydrous

dichloromethane (30 mL); the mixture was stirred at room tem-

perature for 12 h. After workup as described for the preparation of

(–)-32 [m-CPBA (1.5 g, 6.1 mmol) in dichloromethane (20 mL,

dried with Na₂SO₄)] and purification by flash chromatography

(dichloromethane/methanol, 95:5), pure 46 (360 mg, 82%) was iso-

lated as a colorless foam. ¹H NMR (CDCl₃): δ = 2.11 (s, 3 H,

CH₃), 4.56 (ψt, J = 8.1 Hz, 1 H, 1-H or 3-H), 4.71 (ψt, J = 8.7 Hz,

1 H, 1-H or 3-H), 4.81–5.56 (m, 23 H, 4-H, 5-H, 6-H, 10×CH₂),

6.16 (ψs, 1 H, 2-H), 7.20–7.39 (m, 32 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ = 20.6 (CH₃), 68.5 (d, J = 7.1 Hz, CH₂), 69.0 (d, J =

6.1 Hz, CH₂), 69.3 (s, CH), 69.5 (d, J = 6.1 Hz, CH₂), 69.8 (d, J =

6.1 Hz, CH₂), 70.2 (d, J = 6.1 Hz, CH₂), 73.1 (d, J = 3.8 Hz, CH),

73.4 (ψs, CH), 75.7 (m, CH), 76.7 (ψt, J = 5.3 Hz, CH), 77.2 (m,

CH), 127.9–129.0 (C_arom.), 134.8, 134.9, 135.2, 135.4, 135.4, 135.5

(C_ipso), 135.6 (d, J = 7.1 Hz, C_ipso), 135.9 (d, J = 7.1 Hz, C_ipso),

168.7 (CO) ppm. ³¹P{¹H} NMR (CDCl₃): δ = –0.74, –1.04 (PC-3

and PC-6), –0.07, –1.75, –2.19 (PC-1, PC-5, PC-4) ppm. HR-MS

(ESI-pos.): calcd. for C₆₀H₆₂O₂₂P₅[M + H]⁺1289.2421; found

1289.2450.

1

salt). H NMR [D₂O, pH adjusted to 6 (ND₄OD)]: δ = 3.55 (d, J

= 9.7 Hz, 1 H, 1-H), 3.67 (d, J = 9.7 Hz, 1 H, 3-H), 3.83 (ψt, J =

9.4 Hz, 1 H, 6-H), 3.92 (ψq, J = 9.0 Hz, 1 H, 5-H), 4.27 (ψq, J =

9.2 Hz, 1 H, 4-H), 4.55 (d, J = 7.6 Hz, 1 H, 2-H) ppm. ¹³C NMR

myo-Inositol 1,3,4,5,6-Pentakisphosphate (47): Compound 46

[D₂O, pH adjusted to 6 (ND₄OD)]: δ = 71.0 (m, C-3), 71.2 (d, J = (300 mg, 0.24 mmol) was hydrogenated [in ethanol/water, 1:1,

1.9 Hz, C-1), 72.9 (d, J = 1.9 Hz, C-6), 76.2 (d, J = 5.1 Hz, C-2), 50 mg Pd/C (Degussa RW 10)] and de-O-acetylated (10 mL 0.25 n

77.2 (m, C-4), 78.6 (m, C-5) ppm. ³¹P{¹H} NMR [D₂O, pH ad-

justed to 6 (ND₄OD)]: δ = 3.27 (PC-4), 3.58 (PC-5), 4.10 (PC-2)

ppm. For more analytical data see ref.^[33]

NaOH) as described for the preparation of (–)-30 to give 47

(132 mg, 92%) as a colorless, very hygroscopic foam. Separation

1

by HPLC assured purity Ͼ99%. H NMR [D₂O, pH adjusted to 9

3114

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myo-Inositol Phosphates via Symmetrical Conduritol B Derivatives

FULL PAPER

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(ND₄OD)]: δ = 3.39 (dψt, J = 2.7, J = 9.6 Hz, 2 H, 1-H and 3-H),

4.03 (ψq, J = 9.5 Hz, 1 H, 5-H), 4.30 (ψq, J = 9.6 Hz, 2 H, 4-H

and 6-H), 4.51 (ψt, J = 2.7, 1 H, 2-H) ppm. ¹³C NMR [D₂O, pH

adjusted to 9 (ND₄OD)]: δ = 70.9 (s), 74.3 (m), 76.2 (m), 77.7 (m)

ppm. ³¹P{¹H} NMR [D₂O, pH adjusted to 9 (ND₄OD)]: δ = 3.05,

3.84, 4.60 ppm. The other analytical data are in agreement with

those in ref.^[15a]

D-myo-Inositol 1,3,6-Trisphosphate [(–)-48]: Triethyl orthoacetate

(0.35 mL, 1.9 mmol) was added to a solution of (+)-24 (500 mg,

0.64 mmol) and p-toluenesulfonic acid monohydrate (20 mg) in an-

hydrous tetrahydrofuran (15 mL); the mixture was stirred at room

temperature for 24 h. Workup as described for the preparation of

45 yielded 2,4,5-tris-O-acetyl-3,6-bis-O-(di-O-benzylphospho)-d-

myo-inositol as a colorless foam (470 mg, 83%). ¹H NMR (CDCl₃):

δ = 1.78 (s, 6 H, CH₃), 2.11 (s, 3 H, CH₃), 3.89 (dd, J = 2.8, J =

9.9, 1 H, 1-H), 4.65 (dψt, J = 3.1, J = 9.9 Hz, 1 H, 3-H), 4.69 (ψq,

J = 9.3 Hz, 1 H, 6-H), 4.89–5.11 (m, 8 H, PhCH₂), 5.18 (ψt, J =

9.7 Hz, 1 H, 5-H), 5.41 (ψt, J = 9.9 Hz, 1 H, 4-H), 5.77 (ψt, J =

2.8 Hz, 1 H, 2-H), 7.25–7.38 (m, 20 H, Ph-H) ppm. ¹³C NMR

(CDCl₃): δ = 20.1, 20.2, 21.4 (3×CH₃), 69.5, 69.6, 69.7, 69.75,

69.81 (5×CH₂, PhCH₂), 69.8 (d, J = 2.9 Hz, C-1), 70.1 (d, J =

4.8 Hz, C-4), 70.7 (d, J = 4.8 Hz, C-5), 71.3 (d, J = 2.9 Hz, C-2),

73.6 (d, J = 5.7 Hz, C-3), 78.6 (d, J = 6.7 Hz, C-6), 127.7, 127.82,

127.85, 127.87, 128.5, 128.6, 129.7 (C_arom.), 135.1 (d, J = 2.0 Hz,

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¹³C and ³¹P NMR spectroscopic data are identical with those ob-

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We thank Dr. W. V. Turner for critical reading of the manuscript.

We are grateful to Bayer AG for supporting many aspects of this

report, especially for recording the HR-MS spectra. We thank Dr.

S. Adelt and G. Dallmann for help in the HPLC purification of

the inositol tris-, tetrakis-, and pentakisphosphates.

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Received: December 23, 2004

Eur. J. Org. Chem. 2005, 3101–3115

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3115

Article Doi

Flexible stereo- and regioselective synthesis of myo-inositol phosphates (part 1): Via symmetrical conduritol B derivatives

DOI: 10.1002/ejoc.200400911

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