Application of the conformational transmission effect for the assignment of diastereotopic proton resonances

(1)

Application of the conformational transmission effect for the

assignment of diastereotopic proton resonances

Citation for published version (APA):

Genderen, van, M. H. P., & Buck, H. M. (1987). Application of the conformational transmission effect for the assignment of diastereotopic proton resonances. Magnetic Resonance in Chemistry, 25(10), 872-878. https://doi.org/10.1002/mrc.1260251009

DOI:

10.1002/mrc.1260251009

Document status and date: Published: 01/01/1987 Document Version:

Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication:

• A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website.

• The final author version and the galley proof are versions of the publication after peer review.

• The final published version features the final layout of the paper including the volume, issue and page numbers.

Link to publication

General rights

Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain

• You may freely distribute the URL identifying the publication in the public portal.

If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement:

www.tue.nl/taverne Take down policy

If you believe that this document breaches copyright please contact us at: openaccess@tue.nl

providing details and we will investigate your claim.

(2)

Application of the Conformational Transmission

Effect for the Assignment

of

Diastereotopic Proton Resonances

Marcel H. P. van Genderen* and Henk M. Buck

Department of Organic Chemistry, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands

A new method is presented for the assignment of the NMR resonances of the diastereotopic protons in tetrahydrofur- fury1 and pyrrolidinylmethyl groups, based on the conformational transmission effect. This effect describes the conformational changes produced by an increase of coordination from four to five of a phosphorus, silicon or germanium atom attached to the tetrahydrofurfuryl or pyrrolidinylmethyl moieties. The 'H NMR conformational analysis of these cyclic four- and five-coordinated compounds yields two possible results, based on two assignments of the diastereotopic proton resonances. Comparison with the conformations of the analogous four- and five- coordinated systems with acyclic 2-methoxyethyl and dimethylaminoethyl groups (which lack diastereotopic protons) directly shows which assignment is correct, since a similar conformational transmission occurs in both the cyclic and the acyclic compounds.

KEY WORDS Conformational transmission Diastereotopic proton assignment NMR conformational analysis

INTRODUCTION

High-resolution NMR techniques have proved to be an invaluable tool in studying molecular conformations in solution. In particular, the vicinal coupling constants in 'H NMR spectra provide detailed structural informa- tion, since their magnitude is related to the conformation around the central bond, as was first postulated by Karplus.' The coupling constants in each staggered rotamer can be calculated with the Karplus equation, and the rotameric contributions to the experimental coupling constants can be determined. An essential

requirement for this technique is the correct assignment of all proton resonances in the spectrum. This is usually a straightforward procedure, but difficulties are encoun- tered for diastereotopic protons since they have only small chemical shift differences. This situation arises, for example, in the conformational analysis of nucleotide systems, where the assignment of H-5' and H-5" is crucial for discrimination between the g' and g- rotamers around the C-4'-C-5' bond (see Fig. 1) on the basis of the proton-proton coupling constants J(4'5') and

J(4'5"). An incorrect assignment will result in approxi-

mately reversed populations for g' and g-. The correct identification of H-5' and H-5" in the NMR spectrum is also essential for the conformational analysis of the 0-5'-C-5' bond, based on the phosphorus-proton coupling constants J( P,H-5') and J(P,H-5") (see below).

For nucleotide-like systems, various methods have been used to arrive at a correct H-5'/H-5" assignment. The most exact method is the stereospecific replacement of one of the diastereotopic protons by deuterium, which can be achieved by enzymatic reactions using a deuterium source. Inspection of the 'H N M R spectrum * Author to whom correspondence should be addressed.

0749- 158 1/87/ 100872-07$05.00 @ 1987 by John Wiley & Sons, Ltd.

will then directly show the correct assignment. However, this procedure is elaborate and time consuming. It has been applied by Ritchie and Perlin' to adenosine, by Gerlt and Youngblood3 to tetrahydrofurfuryl alcohol and, more recently, by Meulendijks et aL4 to phos- pholipid model systems. For DNA systems, Remin and Shugar' derived an assignment by taking into account the specific shielding effects on H-5' and H-5" due to the 3'-phosphate group. This was confirmed by the work of Davies and Rabczenko.6 The fact that the gauche effect7 favours the g' conformation over the g- conformation in nucleotide systems has been used by Altona,' who derived an assignment from variable temperature studies on several di- and tri-nucleotides. On raising the temperature, the conformational preference shifts from the dominant gt rotamer mostly toward the g', and less toward the g- rotamer. In a similar way, Koole et aL9 compared tetrahydrofurfuryl and cyclopentanemethyl dimethyl phosphates, and assigned H-5' and H-5" to account for the presence of the gauche effect in the former systems. Koole et al." also observed that lower solvent polarities, which enhance 0-5'-0-4' charge repulsions, lead to the expected larger g- populations (with 0-5' and 0-4' trans) only for one assignment in an adenosine model system.

9' 9 -

Figure 1. Left: structure of a nucleotide fragment with the

diastereotopic protons H-5' and H - 5 . Right: Newman projections

of the staggered rotarners around the C - 4 - C - 5 bond.

Received 6 April 1987 Accepted 7 June 1987

(3)

PROTON RESONANCE ASSIGNMENT WITH CONFORMATIONAL TRANSMISSION 873 All these techniques yielded the same assignment,

which is generally used in conformational studies of this type, viz. H-5' resonates downfield from H-5" or 6,,>

&,.

I n this paper we present a new method for assigning the resonances of these types of diastereotopic protons, which is based on conformational transmission.

M e

3 4

CONFORMATIONAL TRANSMISSION

M e

The conformational transmission effect describes the conformational change in a phosphorylated molecule that occurs when the phosphorus atom raises its coordination from four (PI") to five (P").'," The resulting trigonal bipyramidal (TBP) structure has a higher electron density on the axial ligands, and the enhanced electrostatic repulsions cause changes in the conformational preferences. A clear example is found in l and 2,

0 M e O . - _ // Me*/'\ 0 0 [OM,

c

OMe 5 6

c;r'

M e

where it could be ascertained that the tetrahydrofurfuryl group in the axis of the TBP of 2 has a dominant g- population [x(g-) = 0.68 in acetone-d,], with 0-4' and 0 - 5 ' trans, while the equatorial tetrahydrofurfuryls [x(g-) = 0.201 and the tetrahydrofurfuryls in 1 [x(g-)'= 0.131 prefer the g+ and g' rotamers.'

In this analysis, the standard assignment was used for the protons H-5'/H-5" (see above). For P" compounds pseudorotation occurs,12 which results in a fast inter- change of axial and equatorial groups. Therefore, the C-4'-C-5' conformation that is obtained directly from the spectrum is an average of the axial and equatorial conformations, which causes conformational transmission to be seen in an obscured way. However, on comparing the average conformations of the tetrahy- drofurfuryl PIv and P" compounds 3 and 4 it is still obvious that the g- population increases on raising the phosphorus coordination' (see Table 1). Conforma- tional transmission has also been found on going from PIv to Pv in the acyclic 2-methoxyethyl compounds 5 and 611 (see Table l), which have the P-0-C-C-0 fragment in common with the tetrahydrofurfuryl compounds.

Comparing the populations in 3, 4 and 5, 6, we can

conclude that the standard assignment for the diastereotopic H-5'/ H-5" protons has indeed been correct, since the reverse assignment would have led to an increase of the g' population instead of the g- population on going from 3 (PI") to 4 (P"). This process of comparing conformational transmission in symmetric acyclic and asymmetric cyclic compounds to arrive at an H-

5'/ H-5" assignment is applied here to several other com-

pounds.

C-4'-C-5' CONFORMATIONAL ANALYSIS The conformational analyses of the C-4'-C-5' bond are based on the modified Karplus relationship as developed by Haasnoot et aL13

J ( H H ) = PI cos2

4 +

P2 cos

4 +

P3

+I

~ x i [ p 4 + ~5 c0s2 ( t i +

+

P ~ I A X ~ I ) I

I

with

Axi = Ax: - P 7 1

Ax:

In this equation,

4

is the proton-proton torsion angle, Axi is the Huggins ele~tronegativity'~ relative to hydrogen, corrected for P-substituents, and .$ is a substituent orientation parameter. Values of Pl- P, are listed for both cyclic and acyclic systems in Table 2.

j

Table 1. C-4'-C-5' rotamer populations for 3-6 in acetone-%

30 4' 5 b 6b

x(gf) 0.41 0.32 0.43 0.36

x(g7 0.44 0.35 0.43 0.36

x(g-) 0.15 0.33 0.14 0.28

a Data taken from Ref. 9.

Data taken from Ref. 1 1 .

Table 2. Values of the parameters in

the Karplus equation

Parameter Cyclica Acyclicb

p, 13.22 13.89 p2 -0.99 -0.98 p3 0 0 p4 0.87 1.02 P6 19.9 14.9 p5 -2.46 -3.40 p7 0 0.24

a Three non-hydrogen substituents. Two non-hydrogen substituents.

(4)

H 4’ H4”

9 + 9‘ 9 -

Figure 2. Newman projections of the staggered rotamers around the C-4-C-5‘ bond in the acyclic systems.

As can be seen, for cyclic systems the influence of

p-substituents is absent, since P 7 = 0 . The values of J(4‘5’) and J(4’5”) can be calculated in each staggered rotamer (see Fig. l), and population densities are obtained from the equations:

J(4’5’( 5”)) = x(g’)J(4’5’( 5 y ’

+

x(g‘)J(4‘5’( 5”))9‘

+

x (g-)J( 4’5 ’) ( 5”) g-

x(g’)

+

x(g‘)

+

x(g-) = 1

with the normalization equation

Of course, the two possible H-5’/H-5” assignments lead to two possible solutions for the conformational equilibria. In the acyclic compounds the conformational analysis is simplified by the absence of diastereotopic protons, and only one coupling constant J(4’5’) is found. Since the H-4’ and H-4” protons are identical, as well as H-5‘ and H-5”, the rotamers g+ and g‘ are symmetry- related (see Fig. 2), and their populations are always equal in acyclic systems.

RESULTS AND DISCUSSION

2 4 1-Methy1pyrrolidinyl)methyl PIv and Pv compounds

The four- and five-coordinated phosphorus compounds

7 and 8 are derived from the amino acid L-proline. The reduced and methylated form of L-proline, 2-( l-methylpyrrolidinyl)methanol, has been used to prepare highly efficient phosphine ligands for catalytic asymmetric

reaction^,'^

and has served as a building block in asym-

metric alkaloid synthesis.16 Compounds 7 and 8 are similar to the tetrahydrofurfuryl systems 3 and 4, with the endocyclic oxygen 0-4’ replaced by N(CHJ.

In the acyclic systems 9 and 10, it has been shown that conformational transmission is present (see Tables 3 and 4) owing to an increased 0 - N electrostatic repul- sion.” We have now synthesized the corresponding cyclic systems, and determined their C-4’-C-5’ conformations for the two possible H-5’/H-5” assignments (Tables 3 and 4). The results clearly show that S,.< 6,. is the

Table 3. Calculated C-4’- C-5’ coupling constants (Hz) for 7-10 g + g‘ 9 Cyclic 7, 8: J ( 4 5 ) 2.36 3.76 10.96 J (4’5) 1.58 10.96 4.53 Acyclic 9, 10: J ( 4 5 ) 4.69 4.69 7.66

Table 4. Measured C-4’-C-5’ coupling constants (Hz) and C- 4‘-C-5’ rotamer populations for 7-10 in acetone-d,

s,. < %,, ss> 4, 7 8 7 8 9a 10’ J(4’5’) 4.85 5.09 6.05 6.6: 4.60 6.20 J ( 4 5 ) 6.05 6.62 4.85 5.09 x(g’) 0.39 0.31 0.38 0.30 0.31 0.24 x(g‘) 0.24 0.23 0.38 0.46 0.31 0.24 x(g-) 0.37 0.46 0.24 0.24 0.38 0.52

a Data taken from Ref. 11.

0 M e O - . - // M e O ‘ 0 4 p

c

N M e 2 9 M e I

(&

8 M e 0 ‘NMe, 10

correct assignment, since only then is the conformational transmission (i.e. an enhanced g- population) observed. Note that this assignment differs from that found for tetrahydrofurfuryl systems, so rep1:tcement of 0 by N(CH3) already changes the shift sequence.

Conformational analysis of the 0-5’-C-5‘ bond The assignment S,,< 8,” which we have now obtained can be used for a detailed conformational analysis of the 0-5’-C-5’

( p )

bond in the Prv compounds 7 and 9, using the vicinal coupling constants between phosphorus and H-5’/H-5”. The values of J(P,H-5’) and J(P,H-5”) in the staggered rotamers

p’,

p-

and

p‘

(see Fig. 3) can be calculated with a Karplus relationship proposed by Lankhorst et ~ 1 . ; ’ ~

J ( P H ) = ~ ~ . ~ c o s ~ + ~ . ~ cos ++1.6

where C$ is the torsion angle P-O-5‘-C-5’-C-4’. With

these theoretical values (see Table 5 ) , one can derive

H 5‘

P

P’

P‘

Figure 3. Newman projections of the staggered rotamers around the 0 - 5 - C - 5 bond in 7 and 9.

(5)

PROTON RESONANCE ASSIGNMENT WITH CONFORMATIONAL TRANSMISSION 875

Table 5. Calculated phosphorus-proton coupling constants (Hz) in 7 and 9

P' 0- 0'

J(P,H-5) 2.4 23.0 2.4

J( P,H-5) 23.0 2.4 2.4

the 0-5'-C-5' population densities from the following set of equations:

J(P,H-5') = 2.4x(~')+23.Ox(P-)+2.4x(Pt)

J(P,H-5") = 23.0x(p')+2.4x(p-) +2.4x(p') x ( p + ) + x ( p - ) + x ( p ' ) = 1

From the experimental data in Table 6 it is obvious that in the acyclic compound 9, where the values of J ( P,H-5') and J(P,H-5") are necessarily equal, the

p'

rotamer is dominant, while

p'

and

p-

have equal populations. In the cyclic system 7 the conformational equilibrium is also dominated by

P',

but now it is found that the

p'

and

p

rotamers have different population densities. The correct assignment of the diastereotopic protons H-5'/H-5'' is now essential to discriminate

P'

and

p -

properly.

Tetrahydrofurfuryl Si'" and Si" compounds

The four- and five-coordinated silicon systems 11-14 are a different type of compound, where an S i t N transannular interaction creates a TBP structure in the silatranes 12 and 14. [For a review of silatrane (2,8,9-

trioxa-5-aza-l-silatricyclo[3.3.3.01~5]undecane) structure Me3Si - 05' 5 v _to...

t

i

o/si-o

I

0 11 12 13 14

Table 6. Measured phosphorus-proton coupling constants (Hz) and 0-

5'-C-5' rotamer populations 7 9 J(P,H-5') 7.21 7.96 J ( P,H -5") 6.71 7.96 X ( P + ) 0.23 0.27 4 P - I 0.25 0.27 X ( P 7 0.52 0.46

Table 7. Calculated C-4'-C-5' coupling constants (Hz) for 11-14 g + g' 9 - Cyclic 11, 12: J ( 4 5 ) 2.84 3.07 10.68 J ( 4 5 ) 0.90 10.68 5.01 J(45') 4.05 4.05 7.50 Acyclic 13, 14:

and chemistry, see Ref. 18.1 These latter systems are of considerable interest, since they are biologically active with a broad spectrum of action."

A conformational transmission effect has been estab-

lished in the acyclic systems" (see Tables 7 and 8), which is due to the transfer of electron density from the nitrogen lone pair via silicon to 0-5'. The conformational transmission appears to be stronger than in the phosphorylated tetrahydrofurfuryl systems, but it must be taken into account that in the silatranes 0-5' is always located in an axial position, while in the Pv systems pseudorotation distributes 0-5' over the equatorial and axial locations. Comparison with an axially located tetrahydrofurfuryl group [x(g-) = 0.68 (see above)] shows that the conformational transmission effect is actually smaller than in the corresponding phosphorus compounds. This is due to the fact that the bond between silicon and nitrogen is only a partial one (estimated to be one quarter of a silicon-nitrogen single bondz1).

It should be noted that four-coordinated systems with four Si-0 bonds are, in principle, better for comparison with the silatranes. This was accomplished for 13 by studying 15, which was found to have an identical C- 4'-C-5' conformation to 13. However, in the cyclic case

we were unable to obtain 16 in a pure form, and we therefore used the trimethylsilyl systems, as no difference in C-4'-C-5' conformation is expected.

15 16

For the cyclic systems 11 and 12, conformational analysis shows that only the assignment S5,

<

S5", or H-5' upfield from H-S', is consistent with the conformational transmission behaviour (see Tables 7 and 8). Here, also, a reverse assignment is found compared to the phos-

phorylated tetrahydrofurfuryl compounds.

Table 8. Measured C-4'-C-5' coupling constants (Hz) and C- 4'-C-5' rotamer populations for 11-14 in acetone-d,

i&, < 85,, - 11 12 J(45') 5.05 6.95 J ( 4 ' 5 ) 5.08 4.81 x ( g + ) 0.41 0.20 x ( g ' ) 0.31 0.18 x ( g - ) 0.28 0.52

a Data taken from Ref. 20.

4. > i&... I 1 12 13 1 4" 5.08 4.81 5.08 6.02 5.05 6.95 0.41 0.23 0.35 0.22 0.31 0.52 0.35 0.22 0.28 0.25 0.30 0.56

(6)

hydrofurfury1 Ge’” and Ge” compounds

’our- and five-coordinated germanium compounds D are related to the above-mentioned silicon sys-

. For the five-coordinated germatranes, it is known

L x-ray crystal structures that they also possess a

structure with a TBP geometry around ger- ium.22 The properties of these systems, however, :not b e e n studied in great detail. The data that we here represent, to our knowledge, the first confor- ional study of germatranes in solution.

17 18

0

[OM,

19 20

since the Huggins electronegativities of germanium

d silicon are equal,14 the calculated coupling constants Table 7 can also be applied here. In the acyclic system and 20 the C-4‘-C-5’ conformational analysis clearly jicates conformational transmission (see Table 9). is is direct evidence that the Ge+N transannular eraction, which was found in the solid state, is also esent in solution. The change in the population of the rotamer is similar to that found in the silicon systems

-.

Table 8). This indicates that the transfer of electron nsity to 0-5’ due to the transannular interaction is .tually unchanged by substitution of silicon by ger- Inium. From the conformational analysis of the cyclic stems 17 and 18, and comparison with the acyclic mpounds, it is obvious that here, also, the correct signment must be 6,,< (see Table 9).

DNCLUSION

ie results presented here show that the conformational insmission effect can be a useful tool for identifying

I NMR resonances of diastereotopic protons. We were

Ile to obtain an assignment for phosphorylated tetrahy- ,ofurfuryl and pyrrolidinylmethyl systems, and for lylated and germanylated tetrahydrofurfuryl com- Iunds. For the DNA-like phosphorylated tetrahy- &xfuryl the assignment is in accordance with earlier udies (see above), but for the other three species a verse assignment is found. These results show the

Table 9. Measured C-4’-C-5’ coupling constants (Hz) and C-

4‘-C-5’ rotamer populations for 17-20 in acetone-d,

s,. > 4.. 17 18 17 18 19 20 S,.< 6,. J(45‘) 4.88 7.05 4.88 4.78 4.96 6.00 J ( 4 ’ 5 ) 4.88 4.78 4.88 7.05 x(g+) 0.43 0.28 0.43 0.23 0.37 0.21 x(g‘) 0.32 0.18 0.32 0.54 0.37 0.21 x(g-) 0.25 0.54 0.25 0.23 0.26 0.58

necessity for carefully checking the diastereotopic proton assignments in new types of compounds. The method described here can be of assistance in this process.

EXPERIMENTAL Spectroscopy

‘H NMR spectra were recorded at 300.1 MHz in the FT mode on a Bruker CXP-300 spectrometer equipped with an Aspect-2000 computer. Usually, 32K data points and a 1.5 kHz spectral window were used, resulting in an accuracy for line positions of 0.05 Hz. Samples were dissolved in acetone-d, (unless indicated otherwise) at a concentration of ca 5 mg ml-’ in 5 mm NMR tubes, and measured at 300 K. Chemical shifts are related to tetramethylsilane ( 6 = 0). ,‘P NMR spectra were run at 36.4 MHz on a Bruker HX-90R spectrometer with 85% H,P04 as external reference (6 = 0).

Synthesis

THF was carefully dried with lithium aluminium hydride, distilled and stored over 4 8, molecular sieves. Diethyl ether was dried over sodium metal. Benzene and toluene were dried over 4

A

molecular sieves. The syn- theses of 3 and 4 are described in Ref. 9, those of 5, 6,

9 and 10 in Ref. 11 and those of 14 and 15 in Ref. 20.

Dimethyl 2 4 1-methylpyrrolidiny1)methyl phosphite

2-Pyrrolidinemethanol, obtained by reduction of L-

p r ~ l i n e , ’ ~ was methylatedZ4 to form 2-( l-methylpyrrolidinyl)methanol, which was reacted with di- methoxychlorophosphine.” Distillation in Z~UCUO yiel-

ded the product in 40% yield: b.p. 42-46 “C/0.03 mmHg. ‘H NMR (CDCl,): 61.5-1.8 (4H, m, H-2’/H-3’), 1.9-2.2 (2H, m, H-l’), 2.3 (3H, s, NCH,), 2.8-3.1 ( l H , m, H-4’), 3.6-3.8 (2H, m, H-5’/H-5”). ,‘P NMR (CDC1,): 6145.1.

Dimethyl 2 4 1-methylpyrrolidiny1)methyl phosphate (7)

This compound was prepared by the reaction of dimethyl 2-( 1-methylpyrrolidiny1)methyl phosphite with ozone, according to the procedure described in Ref. 11. ‘H NMR: 61.8 (4H, m, H-2’/H-3’). 2.0 (2H, m, H-l’), 2.6 (3H, s, NCH3), 3.0 ( l H , m, H-4’), 3.7 (6H, d , OCH,), 4.1 (2H, m, H-5’/H-5”). ,‘P NMR: 66.6.

(7)

PROTON RESONANCE ASSIGNMENT WITH CONFORMATIONAL TRANSMISSION 877

2,2-Dimethoxy-2-[2-( l-methylpyrrolidinyl)methyl]-4,5-

dimethyl-1,3,2-dioxaphosphol-4-ene (8)

This compound was prepared by addition of a few drops of butanedione to dimethyl 2-( l-methylpyr- rolidiny1)methyl phosphite at 0 “C in an NMR sample tube. After ca 30 min, ,‘P NMR showed the formation of 8 to be complete. ‘H NMR: 61.8 (4H, m, H-2’/H-3’), 2.0 (2H, m, H-l’), 2.4 (6H, s, CH3 dioxaphospholene ring), 2.5 (3H, s, NCH,), 3.3 ( l H , m, H-47, 3.7 (6H, d, OCH3), 3.8-4.0 (2H, m, H-5’/H-5“). 31P NMR: 6-44.1.

(2-Methoxyethoxy)trimethylsilane (13)”

T o a stirred solution of 7.6g (0.1 mol) of 2- methoxyethanol and 7.9 g (0.1 mol) of pyridine in 30 ml of diethyl ether were added dropwise 10.9g (0.1 mol) of trimethylsilyl chloride and the mixture was stirred for 4 h. The pyridinium hydrochloride was removed by filtration and the filtrate was concentrated. Distillation yielded pure 13: b.p. 119-120°C. ‘H NMR: 60.2 (12H, s, SiCH,), 3.4 (3H, s, OCH3), 3.5 (2H, m, H-4‘/H-4”), 3.8 (2H, m, H-5’/H-5”).

(Tetrahydrofurfury1oxy)trimethylsilane (1 1)

This compound was prepared from tetrahydrofurfuryl alcohol (10.2 g, 0.1 mol) and trimethylsilyl chloride (10.9 g, 0.1 mol) according to the procedure described

for (2-methoxyethoxy)trimethylsilane. B.p. 58- 59 “C/9 mmHg. ‘H NMR: 6 0.2 (12H, s, SiCH,), 1.7-1.9 (4H, m, H-2‘/H-3’), 2.9 (2H, m, H-5’/H-Sr’), 3.0 ( l H , m, H-49, 3.1 (2H, m, H-1‘). l-Tetrahydrofurfuryloxy-2,8,9-trioxa-5-aza- 1- si1atricyc1o[3.3.3.0’’5$ndecane (12)

This compound was prepared from tetrahydrofurfuryl alcohol (5.1 g, 0.05 mol), tetraethoxysilane (10.42 g, 0.05 mol) and triethanolamine (7.46 g, 0.05 mol) according to the procedure described in Ref. 26. ‘H NMR: 61.8 (4H, m, H-2’/H-3’), 2.9 (6H, t, NCH2), 3.4 ( l H , (3H, m, H-4‘/H-lr).

d d , H-5’), 3.6 ( l H , dd, H-5’7, 3.7 (6H, t, OCHZ), 3.8

Tetra(2-methoxyethoxy)germane (19)

Through a mixture of 5 g (23 mmol) of germanium tetra- chloride and 9.65 g (127 mmol) of 2-methoxyethanol in

50ml of dry benzene was passed 5 g (0.29mol) of ammonia. The ammonium chloride was removed by filtration, and the filtrate was concentrated. Distillation

in vacuo yielded 7.39g (85’/0) of pure 19: b.p. 128 “C/0.4 mmHg. ‘H NMR: 63.32 (12H, s, OCH,), 3.49 (8H, t, H-4’/H-4”), 3.98 (8H, t, H-5’/H-5”).

Tetra(tetrahydrofurfury1oxy)germane (17)

This compound was prepared from germanium tetra- chloride (1.06 g, 5 mmol) and tetrahydrofurfuryl alcohol (2.01 g, 20 mmol) in toluene, according to the procedure described for 19. The crude product was pure enough to allow conformational analysis. ‘H NMR: 61.5-1.9 (16H, m, H-2’/H-3’), 3.5 (8H, d, H-5’/H-5”), 3.6-3.9 (12H, m, H-4’/H-lf).

1-(2-Met hoxyethoxy)-2,8,9-trioxa-5-aza-l-

germatricyclo[3.3.3.0’~5]undecane (20)

Tetra(2-methoxyethoxy)germane (5.52 g, 15 mmol) and

triethanolamine (2.20 g, 15 mmol) were heated in 50 ml of benzene and the azeotrope of 2-methoxyethanol and benzene was removed during 3 h. After cooling, 20 pre- cipitated as a white solid. Filtration and drying under a stream of nitrogen yielded 1.13 g (26%). ‘H NMR: 62.95 (6H, t, NCH2), 3.28 (3H, s, OCH3), 3.38 (2H, t, H-4’/H-4”), 3.73 (6H, t, OCH2), 3.81 (2H, t, H-5’/H-S’).

1-Tetrahydrofurfuryloxy-2,8,9-trioxa-5-aza- 1-

germatricyclo[3.3.3.01~~lundecane (18)

A mixture of tetrametho~ygermane~’ (3.06 g, 16 mmol), triethanolamine (2.32 g, 16 mmol) and tetrahydrofur- fury1 alcohol (1.59 g, 16 mmol) in 50 ml of toluene was heated, and methanol was removed by distillation during 3 h. After cooling, 18 precipitated as a white solid. Filtra- tion and drying yielded 2.78 g (54%). ‘H NMR: 61.7-1.9 (4H, m, H-2’/H-3’), 2.96 (6H, t, NCH2), 3.50 ( l H , dd, H-5’), 3.60 ( l H , m, H-4’), 3.62 (6H, t, OCH2), 3.76 ( l H , dd, H-5’9, 3.8-3.9 (2H, m, H-1’).

Acknowledgement

This research has been supported in part by the Netherlands Founda- tion for Chemical Research (SON) with financial aid from the Nether- lands Organization for the Advancement of Pure Research (ZWO). The help of R. van der Vecht and J. Kingma in the synthesis of 7 and 8 is gratefully acknowledged. Likewise, the assistance of M. Mayer and E. van Nunen in the synthesis of 17-20 is greatly appreciated.

REFERENCES 1. M. Karplus. J. Chem. Phys. 30. 11 (1959).

2. R. G. S. Ritchie and A. S. Perlin, Carbohydr. Res. 55, 121 3 J. A. Gerlt and A. V. Youngblood. J. Am. Chem. SOC. 102, 7433

4. G. H. W. M. Meulendijks, W. van Es, J. W. de Haan and H. M.

5. M. Rernin and D. Shugar, Biochem. Biophys. Res. Commun. 48,

(1 977).

( 1980).

Buck, €or. J. Biochem. 157, 421 (1986). 636 (1972).

6. D. B. Davies and A. Rabczenko, J. Chem. SOC., Perkin Trans. 2

1703 (1 975).

7. (a) S. Wolfe, Acc. Chem. Res. 5, 102 (1972); (b) A. J. Kirby, The

Anomeric Effect and Related Stereoelectronic Effects at Oxy- gen. Springer-Verlag, Berlin (1983).

8. C. Altona, Recl. Trav. Chim. Pays Bas 101, 413 (1982).

9. L. H. Koole, E. J. Lanters and H. M. Buck, J. Am. Chem. SOC.

(8)

10. L. H. Koole, R. J. L. van Kooyk and H. M. Buck, J. Am. Cbern.

SOC. 107, 4032 (1985).

1 1 . M. H. P. van Genderen, B. C. C. M. olde Scheper, L. H. Koole, L. H. van de Ven and H. M. Buck, Phosphorus Sulfur in press (1 987).

12. R. Luckenbach, Dynamic Stereochemistry of Pentacoordinated

Phosphorus and Related Elements, pp. 3-5. Georg Thierne Stuttgart (1973).

13. C. A. G. Haasnoot, F. A. A. M. de Leeuw and C. Altona, Tetra-

hedron 36, 2783 (1 980).

14. M. J. Huggins, J. Am. Cbern. SOC. 75, 4123 (1953).

15. T. Hayashi, M. Konishi, M. Fukushirna, K. Kanehira, T. Hioki and 16. C. G. Chavdarian and E. B. Saunders, US Pat. 4321 387 A (1982); 17. P. P. Lankhorst, C. A. G. Haasnoot, C. Erkelens and C. Altona,

M. Kurnada. J. Org. Cbern. 48, 2195 (1983).

Cbern. Abstr. 99, 22575d (1982).

J. Biornol. Struct. Dyns. 1, 1387 (1984).

18. M. G. Voronkov. V. M. Dyakov and S . V. Kirpichenko, J. 19. M. G. Voronkov, Top. Curr. Cbern. 84, 77 (1979).

20. M. H. P. van Genderen and H. M. Buck, Recl. Trav. Cbim. Pays

Bas 106. 449 (1987).

21. V. F. Sidorkin, V. A. Pestunovich, V. A. Shagun and M. G. Voronkov, Dokl. Akad, Nauk SSSR, Ser. Kbim. 223, 386 (1977). 22. L. 0. Atovrnyan, Ya. Ya. Bleidelis, A. A. Kernrne and R. P.

Shibaeva, Zb. Strukt. Kbirn. 11, 318 (1970).

23. D. Enclers and H. Eichenhauer, Cbem. Ber. 112, 2933 (1979). 24. Houben Weyl. Metboden der Organiscben Cbernie, Vol. 11-1,

25. A. E. Pierce, Silylation of Organic Compounds, Chapt. 1 . Pierce 26. M. G. Voronkov and G. I. Zelchan, Kbirn. Geterotsikl. Soedin. 1, 27. D. C. Bradley, L. J. Kay and W. Wardlaw, J. Cbern. SOC. 4916

Organornet. Cbem. 233, 1 (1983).

p. 650. Georg Thierne, Stuttgart (1957). Chemical, Rockford, IL (1968). 210 (1965).