Conformational transmission in pentacoordinated phosphorus compounds : synthesis and dynamic aspects of model compounds for nucleic acids

Conformational transmission in pentacoordinated phosphorus

compounds : synthesis and dynamic aspects of model

compounds for nucleic acids

Citation for published version (APA):

Koole, L. H. (1986). Conformational transmission in pentacoordinated phosphorus compounds : synthesis and

dynamic aspects of model compounds for nucleic acids. Technische Hogeschool Eindhoven.

https://doi.org/10.6100/IR242269

DOI:

10.6100/IR242269

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Published: 01/01/1986

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CONFORMATIONAL TRANSMISSION IN

PENTACOORDINATED PHOSPHORUS

COMPOUNDS

Synthesis and dynamic aspects of model compounds for

nucleic acids

CONFORMATIONAL TRANSMISSION IN

PENTACOORDINATED PHOSPHORUS COMPOUNDS

Synthesis and dynamic aspects of model compounds for

CONFORMATIONAL TRANSMISSIO

N

IN

PENTACOORDI

N

A TED

PHOSPHORUS COMPOUNDS

Synthesis and d

y

namic aspects of model compounds fo

r

nucleic acids

PROEFSCHRIFT

TER VERKRIJGING VAN DE GRAAD VAN DOCTOR IN DE TECHNISCHE WETENSCHAPPEN AAN DE TECHNISCHE HOGESCHOOL EINDHOVEN, OP GEZAG VAN DE RECTOR MAGNIF!CUS, PROF. DR. F. N. HOOGE, VOOR EEN COMMISSIE AANGEWEZEN DOOR HET COLLEGE VAN DEKANEN IN HET OPENBAAR TE VERDEDIGEN OP

VRIJDAG 14 FEBRUARI 1986 TE lli.OO UUR

DOOR

LE

V

INUS H

E

NDRIK KOOLE

DIT PROEFSCHRIFT IS GOEDGEKEURD DOOR

DE PROMOTOREN

PROF.DR.H.M.BUCK

EN

TABLE OF CONTENTS

1. General Intred uction. ... 9

2. Conformational Transmission in T rigonal Bipyramidal P V Compounds.

Enhanced Gauche(-) Population around the

c

₄

.

-

c

_{5. Linkage in 5'-P V} Phosphorylated Tetrahydrof urfuryl Model Systems.

3. Conformational Transmission in Four- and Five-Coordinated

Phos-phorus Compounds. Solvent Effects on the

c

₄

.

-c

₅. Conformation in 5'-Phosphorylated Model Nucleosides.

4. Conformational Transmission in 5'-P V TBP Phosphorylated Nucleo-sides. The Effect of Electrostalie _{0 5} ... H-base Attraction on the Con

-16

... 43

formation around the

c

₄

.-c

_{5. Linkage.} ... .. . . 61

5 lntramolecular Base-Backbone Association m 8-Bromo-2'

.3'-0-6.

isopropylidene Adenosine. Detection of an

o

_5.-H ... _{N3 Hydrogen Bond}

via a Long Range H5 .. N3 Spin-Spin Coupling. . . . . . . . . . .... 81

A Stabie Parallel Duplex Structure for the Hexamer d(T T T T T T) _{p p p p p}

with Phosphate Triester Linkages . 87

7. Crystal Structure and Molecular Conformation of 2'- Desoxy-3'

8. Pseudorotatien in Monocyclic Oxyphosphoranes .. 104

Summary .. 114

Samenvatting .. . 117

Curriculum vitae . 120

CHAPTER 1

GENERAL INTRODUCTION

The double helix of DNA is the most familiar symbol of the explosive advance in molecular biology that began in the 1940's. The DNA model proposed by Watson and Crick1 in 1953 had a particularly strong impact. since this structure contained within itself indications of how DNA might perform its functions of storing and transmitting genetic information. In fact. the Watson and Crick model was based on information from the work of Chargaff2 who found that the ratio's adenine (A)/thymine (T) and guanine (G)/cytosine (C) are always one. in DNAsof different composition. Moreover.

fiber X-ray diff raction photographs made by Wlikins3 revealed the basic structure of a right-handed helix.

At first sight. DNA in its double helical form seems fairly inert and inflexible. The

exterior of the structure is largely dominaled by the two interwound antiparallel

phosphate-sugar backbone strands. whereas a stacked array of the complementary bases -the variabie elements in the DNA structure and the actual carriers of the genetic code- forms the interior of the double helix. The compactness suggests that the structure is merely designed to store the genetic information. and will not easily be involved in biochemica! reactions. However. this appearance is definitely illusory. si nee the double helix is capable of reacting in many different ways with other molecules in the cell. In addition. double helical DNA structures display a pronounced conforma-tional variability. Nowadays it is known that an entire family of right-handed duplex

found under conditions of low humidity. and B-DNA which is stabie at a relatively

high water content. The A and B forms of DNA display subtile differences with

respect to the phosphate-sugar conformations. the positioning of the bases with

respect to the helix axis. and the base inclination. i.e. the tilt of the base pairs with

respect to the helix axis 4 A marked example of the structural flexibility is encountered

in sequences of alternating d( G-C) bases. Already in 1972. Po hl and Jovin 5 concluded

that a reversible salt-induced structural change which is accompanied by a circular

dichroism speetral inversion in the high-salt region. occurs for poly d( G-C). These

units are capable to undergo interconversion from the normal right-handed double helix

(B-DNA) into a left-handed structure with a peculiar zigzag backbene (Z-DNA) which

was identified for the first time by Rich and coworkers 6 Most noteworthy. Z-DNA has

a biologica! relevancy 8 lt was found that d(G-C) segmentsof the order of only 1.3%

of the total plasmid DNA may dramatically influence the overall topology of the

plasmid_7 Thus. the B into Z interconversion modulates the overall DNA supercailed

structure and could therefore be of importance in regulating DNA expression. In fact. it

was established that Z-DNA occurs in the chromosernes from Drasophila melanogas-. 9

ter.

The discovery of Z-DNA represents an important milestene in the history of DNA

structure. and has stimulated further research on the relationship between the inherent

reactivity and structural plasticity of DNA. and gene expression. This thesis is

particu-larly focused on the reactivity of the phosphate groups in the backbene strands. As

was put forward by van Lier et al. on the basis of quantumchemical model

calcula-· 10 11 h f · f d. d h h (Pv) · h

t1ons. · t e ormat10n o a pentacoor mate p osp orus structure w1t a

trigonal bipyramidal geometry will lead to a conformational change around the

c

₄

.-c

_5. bond. toward the gauche(-). (g-). rotamer in which the oxygens 0 5. (exocyclic) and

I

~booe

-o

o

"- I

_p

/ " '

0

5,~0s•

base

o,·

4' 0

\_/

L:

T

0

~b"'

0

L"

_p

I

_'

-o--'J

~Os~O_>./base

-o

··y

0

/

Figure 1. Co.nformational transmission in the backbene structure of DNA. Nucleophilic attack

of a fifth ligand {L) at phosphorus results in a P V TBP slructure. The enhanced electrostalie

repulsion beween _{0 5.} and _{0 1.} results in a conformational change around the

c

₄

.

-c

_5. bond. from

g+ toward g-.

0 1, (endocyclic) are in a trans orientation (Figure 1). The enhanced electrostalie repul -sion between 0 5. in axial location of the trigonal bipyramid and 01' is the driving

force for this conformational transmission. This concept provides a detailed dynamic

description of the B into Z structural transition of alternating d(G-C) duplexesll.12 In

the succeeding chapters of this thesis. extensive experimental support for the

confor-. I . . h b . f PV . d 13 14 Th I

mat1ona transmiSSIOn on t e as1s o structures IS presente . · e resu ts

obtained on 5'-phosphorylated tetrahydrofurfuryl systems and 5'-phosphorylated

nucleosides clearly show that an enhanced population of the g- rotamer can be realized

by (i) increasing the phosphorus coordination from piV (four coordinated phosphorus)

into P V. in such a way that 0 5. is located in the a x is of the trigonal bipyramid. or (i i)

decreasing the solvent polarity. which a lso leads to a more pronounced charge

experimental investigations have also provided detailed new insights into the impact of backbene-base association on the conformation of nucleosides and nucleotides. A very elegant example IS provided by the modi fied nucleoside 8-bromo-2' .3'-0-isopropylideneadenosine15 which shows a unique broadening of the H5 .. resonances in the proton NMR spectrum. as a consequence of a unique four-bond nitrogen-hydrogen spin-spin coupling via a distinct 0_5.-H .. _{N3 hydragen bond 16 In} addition. it was found that eliminating the backbene-base association in the hexanucleoside penlaphosphate d(T T T T T T) via alkylation of the phosphate groups. results in a parallel

right-p right-p right-p right-p right-p

handed duplex structure. which is based on thymine-thymine base pairing17 Most likelv. structures of this type can also be realized under the biologica! conditions of the livint: cell. and may therefore have a certain impact on the replicatien and/or transmis-sion of the genetic information. encoded in the ceii-DNA. For this reason. the parallel duplex as described above may also belang to the discoveries that should "serve as a stimulus in the search for other confermalions of DNA which may provide greater depth and scope in our attempts to understand the molecular biology of DNA." (Wang et aL. Nature 1979. 680. 1982).

OUTLINE OF THE THESIS

In Chapter 2. a conformation al 1H NMR study on a set of 5'-PIV and 5'-P V tetrahydrofurfuryl compounds is presented. The 5'-P V compounds show a greater preferenee for the g- rotamer around _{the C4}

.-

c

₅. bond. in comparison with their 5'-PIV counterparts. A precise conformational analysis for axial and equator ia! tetrahydrof ur-furyl is given. in spite of the fact that the P V systems display rapid pseudorotation. i.e. exchange of the tetrahydrofurfuryl group over the axial and equatorial sites in the trigonal bipyramid.

Chapter 3 deals with the conformational analysis of a set of 5'-PIV and 5'-P V

phosphorylated model nucleosides. With these systems. it is shown that a co nforma-tional change around the

c

₄

.

-

c

_{5. bond toward} g- can be realized either by increasing

the phosphorus coordination from P IV into P V or by decreasing the medium polarity. In Chapter 4. a set of 5'-PIV and 5'-P V phosphorylated nucleosides is

investi-gated. These systems show that increasing the coordination of phosphorus results in a competition between

o

₅

.-o

₁. charge repulsion (favoring gT and

o

₅ .... H-base electro-stalie attraction (leading to a preferenee for g +). For hydrogen-bond breaking solvents such as hexamethylphosphorustriamide (HMPT). it is found that the conformational transmission toward g- is predominant. The 5'-PIV and 5'-P V derivatives of the syn

nucleoside 8-bromo-2'.3'-0-isopropylideneadenosine represent examples of complete

elimination of the

o

_{5 .... H}-base association. Therefore. the conformational

transmis-sioneffect is fully operalive in these systems.

Chapter 5 describes a remarkable demonstratien of the impact of hydrogen bond

association between the backbone and the base with respect to the conformation of

8-bromo-2'.3'-0-isopropylideneadenosine. In apolar solvents. a unique four-bond spin -spin coupling between N _{3 and H5 .. is visuali}zed.

Chapter 6 presents experimental evidence for the existence of a stabie parallel

duplex DNA structure which is based on thymine-thymine base pairing. The

experi-ments were performed with the d(T p T p T p T p T p T) duplex. in which the phosphate

groups were exclusively methylated.

Chapter 7 describes the X-ray structure of 2'-desoxy-3'.5'-di-0-acetyladenosine. In this case. hydrogen bonding between the bases results in a twodimensional network. in contrast with the dimeric structure which was found in the crystal structure of

2'-desoxy-3' .5'-di-0-acetyladenosine with the preferred conformation in solution. reveals a remarkable anomaly with respect to the

c

₄

.

-c

₅. conformation.

Finally. Chapter 8 deals with pseudorotatien of monocyclic oxyphosphoranes that are stabilized via a dioxaphospholene ring. lt is shown that pseudorotatien of these systems may very well involve a diequatorial arrangement of the dioxaphospholene ring. although the well-known ring strain rule18 states that an axial-equatorial arrange -ment is strongly preferred for five-membered bidentate ligands.

REFERENCES AND NOTES

1. Watson. J.D.: Crick. F.H.C. Nature 1953. 171. 737.

2. Zamenhof. S.: Brawermann. G.: Chargaff. E. Biochim. Biophys. Acta 1952. 9. 402. 3. Wilkins. M.H.F.: Randall. J.T. Biochim. Biophys. Acta 1953. 10. 192.

4. Fora detailed description of these features see. e.g.: Saenger. W In "Principles of Nucleic Acid Structure": Springer Verlag lnc.: New Vork. 1984. and references cited therein.

5. Pohl. F.M.: Jovin. T.M. J. Mol. Biol. 1972. 67. 375.

6. Wang. A.H.-J.: Quigley. G.J.: Kolpak. F.J.: Crawford. J.L.: van Boom. J.H.: van der Marel. G.: Rich. A. Nature 1979. 282. 680.

7. (a) Razin. A.: Riggs. A.D. Science 1980. 210. 604. (b) van de Sande. J.H.: Jovin. T.M. Eur. J. Biochem. 1982. 1. 115.

8. Singleton. C.K.: Klysik. K.: Stirdivant. S.M.: Wells. R.D. Nature 1982. 299. 312. 9. Santella. R.M.: Grunberger. D: Weinstein. I.B.: Rich. A. Proc. Natl. Acad. Sci. USA 1981. 78. 1451.

10. van Lier. J.J.C.: Koole. LH.: Buck. H.M. Reel. Trav. Chim. Pays-Bas 1983. 102.

148.

11. van Lier. J.J.C.: Smits. M.T.: Buck. H.M. Eur. J. Biochem. 1983. 132.55. 12. van Lier. J.J.C. PhD Thesis. Eindhoven University of Technology. 1983. 13. Koole. L.H.: Lanters. E.J.: Buck. H.M. J. Am. Chem. Soc. 1984. 106. 5451. 14. Koole. L.H.: van Kooyk. R.J.L.: Buck. H.M. J. Am. Chem. Soc. 1985. 107. 4032. 15. lkehara. M.: Uesugi. S.: Kaneko. M. Nucl. Acid Chem. 1978. 2. 837.

16. Koole. L.H.: de Boer. H.: de Haan. J.W.: Haasnoot. C.A.G.: van Dael. P.: Buck. H.M. J. Chem. Soc. Chem. Commun .. in press.

17. Koole. L.H.: van Genderen. M.H.P.: Frankena. H .. Koeken. H.J.M.: Kanlers. J.A.: Buck. H.M. Proc. Kon. Ned. Akad. van Wetensch. (B). in press

18. Holmes. R.R. In "Pentacoordinated Phosphorus": American Chemica! Society: Washington. DC. 1980: ACS Monogr. No. 173. Vol. 1. and references cited therein.

CHAPTER 2*

Conformation al Transmission in T rigonal-Bipyramidal P V Compcunds.

ABSTRACT

Enhanced Gauche(-) Popuiatien a_{round the C 4}

,-c

₅, Lin ka ge in 5' -P V

Phosphorylated Tetrahydrofurfuryl Model Systems

A 300-MHz 1H NMR study on a number of 5'-phosphorylated (PIV) tetrahydrofurfuryl

compounds (1a.b. 3a.b. 4a.b) and their P V trigonal bipyramidal (TBP) analogues has been

per-formed. The results show a significantly greater population of the gauche(-) conformation for axially situated tetrahydrofurfuryl around the

c

₄

,

-

c

_5, bond in the 5'-PV TBP tetra hydrofur-furyls with respect to their related 5'-PIV compounds which show dominant ga uche(+) and gauche(trans) conformations. The conformation analysis of the P V compounds was hampered by pseudorotation. With model compound 6. in which both equalorial and axial sites that undergo pseudorotatien bear a tetrahydrofurfuryl group. a precise analysis was possible resulting in an excessof gauche(-) for tetrahydrofurfuryl in an axial position (31BK. 61%: 217K. 80%) The corresponding equatorial location shows a relatively small amount of gauche(-) compared

with the g<~uche(+) and gauche(trans) (31BK. 24%: 217K. 13%). The latter values are similar to the riVcounterpart 5. This conformational transmission in the

c

₄

,-c

₅, bond of tetrahydro-furfuryls agrees with quanturn chemica! calculations. lt is suggested that the enhanced charge repulsion between 0_5, and 01, in the PV TBP drives the rotation around the

c

4

,-c

5, bond.

The impact for conformational isomerizations in phosphorylated biomolecules (e.g .. DNA) is briefly mentioned.

*----

--

---Koele. LH.: Lanters. E.J.: Buck. H.M. I Am. Chem. Soc. 1984. 106. 5451-5457.

INTRODUCTION

Recent quanturn chemica! calculations1·2 on 5'-phosphorylated tetrahydrofurfuryl give cause for the condusion that increase in coordination of phosphorus from 5'-PIV to 5'-P V trigonal bipyramidal (TBP) with the tetrahydrofurfuryl group in axial position (opposite to the introduced ligand. H20. e.g.) results in a specific rotation of this group around the

c

₄

.-c

_{5, bond.} The rotamer popuiatien then changes from gauche(+). (g+) and gauche(trans). (gt) toward gauche(-). (g-). lt was suggested that the enhanced charge repulsion between the exocyclic oxygen (0_{5,) situated in the axial}

position of the 5'- P V TBP and the endocyclic oxygen ( 0_{1,) triggers} the rotatien around the

c

₄

,-c

_{5, bond}3 Experiment al evidence for the role of P V TBP structures in effectuating this specific rotatien will be presented in this chapter. A set of 5'-PIV and 5'-P V TB P tetrahydrof urfuryl and cyclopentanemethyl model compou nds ( Chart I) was synthesized and the

c

₄

,

-

c

_{5, conformations were analyzed} with 300-MHz 1 H

NMR. The results show a significantly greater popuiatien of the g- rotamer [in which

o

_{5, is located trans to}

o

_{1.) for the 5'-PV} TBP tetrahydrofurfuryl model compounds compared to their 5'-PIV counterparts. lnterestingly. substitution of 0₁, _{by C(H 2)}

gives identical

c

₄

,-c

_5, conforrnations for 5'-PIV and 5'-P V TBP in which gt

=

g- and dominant with respect to g

+

These experimental findings show a strong coherence

with the calculations that predieled an enhanced charge repulsion between 0_{5. and} 0_1,

for axial location of the tetrahydrofurfuryl group in the PV TBP. lt should be men-tioned. however. that pseudorotation. which involves ligand permulation between the axial and equatorial sites in the TBP. precludes a correct determination of the

c

₄

,

-

c

_5, conformation that corresponds to axial tetrahydrofurfuryl. A precise conformational

analysis around the

c

₄

,-c

₅, bond for axial and equatorial tetrahydrofurfuryl could be obtained from variable-temperature 300-MHz 1 H N MR measurements of the P V TB P

Chart I. Model Compounds Stuclied in This Chapter 18 1a : X=O;Y=0 1b :X=S;Y=0 2a : X= 0 ; Y = C ( H2l 3a X=0;3b : X=S 4a : X=0;4b:X=S R

0~

R Ph

I

I

Ph;;:.P-0

I

~

1c : R:Me;Y=0 1d : R:Ph;Y=O 2 b : R

=

Me ; Y

=

C ( H2) 2 c : R = Ph ; Y = C ( H 2) 3c : R=Me; 3d :R:Ph 4c :R:Me;4d R:Ph

model compound 6 (Figure 6) in which both equatorial and axial sites that undergo pseudorotation bear a tetrahydrofurfuryl group. These experimental data

unambigu-ously show the intrinsic bond properties of the equatorial <Jnd axial sites in the TBP which are reflected in specific

c

₄

,-c

_{5, conformational differences between axial} and equatorial tetrahydrofurfuryl. Axial location is found to be associated with a marked

preferenee for the g- rotamer. indicating a pronounced charge repulsion effect between

o

5, and 0 1 •. Equatorial location with excess of g + and gt rotamers closely resembles the

c

₄

,-c

_{5, conformations for 5'-PIV Extrapolating these results to} phospho-rylated biomolecules. one expects that con{ ormational transmission in nuc/eic

acids may be brought about by activation of the phosphate group through

change in coordination { rom P 1 V i nto P V T 8 P ( see a lso Results and Discussion).

C4

.

-c

5. CONFORMATIONAL ANALYSIS

In sol ut ion rapid interconversion between the three staggered rotamers g +. gt.

and g- (Figure 1) yields weighted time-averaged coupling constants _{J 4,5, and J 4,5 ...} which are related to the individual rotamers and their populations x(g +). x(g\ and

+ g

+

t gt - g

J4'5'(5") = x(g ) J4'5'(5") + x(g ).J4'5'(5")

+

x(g) J4'5'(5")

withx(g+)+x(gt)

+

x(g-)

=

1. The rotamer populations can be obtained with the help of an empirically generalized Karplus relation developed by Altona et a1.. 4 ·5 from which the coupling constants corresponding to the various rotamers can be calculated. Table I lists the calculated coupling constants and the corresponding proton-proton torsion angles.

Os· H s'' Hs

Y*C,

Y*C,•

Y*C,

H5 • Hs" 05• H5 H5.. 05 •

H •. H.· H ••

g+ g t

g-Figure L Newman projectionsof the rotamers around the

c

₄

.

-

c

_{5. bond (Y} = _{0. C(H 2))}

In addition a correct assignment of the protons Hs. and Hs .. is required. For the

S'-PIV model compounds Hs. and Hs .. can be distinguished on the basis of a

com-parisen of the

c

_{4.-CS' confermalions in la and 2a}. For 2a both assignments are equivalent. From _J4.5. = _{J4.5 ..} = 6.80 Hz it fellows that x(g+) = 0.18 and x(gt) = x(g-)

=

0.41. Values of 4.26 and S.78 Hz were found for J₄'5' and J_{4 '5" in la.} Assum-ing that 8S.

>

8s .. one arrives at x(g+)

=

0.40. x(gt)

=

0.43. and x(g-)

=

0.17. The reverse assignment yields x(g+) = 0.44. x(gt) = 0.19. and x(g-) = 0.37. These values

show that. toa good approximation. inversion of the Hs·/H 5 .. assignment has no effect

on the estimated g + population6 ·7 However. the populations of gt and g- are reversed

in both assignments. From the marked increase of x(g +) u pon substitution of

cyclo-Table I. H4

.-c

4

.

-c

5,-H 5,(S") Torsion Angles (c,i>) in the Rotamers around the

c

4

,

-

c

5, Bond and the Corresponding Calculated Coupling Constants

confor- c,i>(H4.-C4.- J4'5'• Hz c,i>(H4.-C4.- J4'S"· Hz mation

c

_{5.-H 5.).} Y=O y = C(H2)

c

5.-H5 .. ). Y=O y = C(H2)

deg deg g+ _{-60 2.8 1.9 60 1.9 0.9} t 60 3.1 4.1 ₁₈₀ 11.5 10.7 g -g 180 10.7 11.5 -60 4.1 S.O 20

pentanemethyl into tetrahydrofurfuryl it can be concluded _{that Os.-0 1.} gauche orien-tation represents an energetically more favored state than Os.-C(H 2) gauche orienta-tion8 This finding applied to the populations of gt (Os• gauche to

o

_{1.) and} g- (Os· gauche to

c

_{3.) yields x(gt)}

>

_{x(g-). or J 4'S'}

<

_{J4.S" This is consistent} with the assignment 8S'

>

8s"· Variabie temperature 300-MHz 1H NMR measurements on la revealed that a linear inverse relationship exists between the chemica! shift difference 8s· - 8S" and J_4'S'

+

J_{4'S" (vide infra)}. Similar linear correlations have been reported for anti-type nucleosides and nucleotides.9 The linear inverse relationshi p between 8S' - 8S" and J4'S'

+

J4'S" is used in this work to arrive at an unequivocal Hs./Hs .. assignment for each of the 5'-P V TBP model compounds.

RESUL TS AND DISCUSSION

In Table 11 the speetral parameters are given that were obtained from the Hs.fHs .. patterns of the S-PIV model compounds measured in acetone-_d6 at 300 MHz and

300K.

As typical examples. expansions of the Hs./Hs .. patterns of la and 2a are shown m Figure 2. Examinatien of the data in Table 11 reveals that the

c

_4.-CS' rotamer popu

-lations for s·_piV tetrahydrofurfuryl are found to be virtually unaffected by the various substituents on phosphorus. Obviously. the

c

₄

.-c

₅, conformations of these model compounds are dominated by the ga uche effect between Os· and _{0 1.8 The speetral}

parameters that were found under the same experirnental conditions for the PV TBP

model compounds are listed in Table 111. The S'-P V TBP tetrahydrofurfuryl model compounds 1c. 1d. 3c and 3d are characterized by a pronounced g- popuiatien (x(g-)

22

Table 11. J_4'S'(S") Values and the Conesponding

c

₄

.

-c

₅. Ro -tamer Populations for the 5'- piV Model Systems at 300 K compd J4'5' Hz J4'5"· Hz x(g+) x(gt) x(g-) la 4.26 5.78 0.40 0.43 0.17 lb 4.23 5.82 0.40 0.43 0.17 2a 6.80 6.80 0.18 0.41 0.41 3a 4.08 5.89 0.41 0.44 0.15 3b 4.26 5.76 0.40 0.43 0.17 4a 3.94 5.85 0.42 0.45 0.13 4b 3.84 6.00 0.41 0.47 0.12 I

I

\

Table 111. J 4'S'(S") Values and the Corresponding

c

₄

.-c

₅. Ro-tamer Populations for the 5'-PV TBP Model Systems at 300 Kil compd _{J 4'5' Hz J4'5" Hz} )((g+) )((gt) x{g-) 1c 5.45 5.61 0.33 0.35 0.32 ld 5.30 5.69 0.34 0.36 0.30 2b 6.80 6.80 0.18 0.41 0.41 2c 6.80 6.80 0.18 0.41 0.41 3c 5.24 5.57 0.32 0.35 0.33 3d 5.21 5.31 0.38 0.33 0.29 4c 4.74 5.36 0.41 0.36 0.23 4d 4.83 5.21 0.42 0.34 0.24

aThe rolamer populations are uncorrected for phosphorus pseu-dorolalion.

hand. substitution of 5'-PIV by 5'-P V for the cyclopentanemethyl model compounds leaves the c₄

.

-

c

₅. rotamer populations unaffected (compare 2a. Table 11. with 2b and 2c. Table 111). These results strongly reflect the effect of enhanced charge repulsion between 0 5. and 01' by coordination change of phosphorus from four to five. The J4.5. and _{J4.5 .. value}s listed in Table 111 are measured under rapid pseudorotatien

con-ditions. as is evidenced by the magnetic equivalence of the pseudoaxial and the pseu -doequatoriai sites in the 13

c

and 1 H NMR spectra (vide infra). lt must be expected

that the positional exchange of tetrahydrofurfuryl from an equatorial site (favored by

I I . 1· d ) 10 11 _. I . ( I f d b I

e ectron-re easmg 1gan s · to an ax1a s1te strong y pre erre y e ectron

-withdrawing ligands) 10.11 leads to enhanced charge repulsion between _{0 5,} and _{0 1 .}.

Therefore. the

c

₄

.-c

_5. conformations given in Table 111 must be regarcled as

time-averaged conformations due to equilibrated axial and equatorial locations of the

Table IV. f\IMR Parameters and

c

₄

.-c

_{5. Rotamer Popuiatiens} Obtained by Variabie Temperature 1H NMR on la and lca

la T. K _{J4'5' Hz} J4'5" Hz ~8 Hz x(g+) x(gt) x(g-) 321 4.37 5.70 13.2 0.41 0.41 0.18 310 4.31 5.74 13.7 0.40 0.42 0.18 300 4.26 5.78 14.0 0.40 0.43 0.17 276 4.16 5.86 15.2 0.40 0.44 0.16 262 4.11 5.90 16.4 0.40 0.45 0.15 249 4.02 5.96 18.3 0.40 0.46 0.14 235 3.91 6.06 19.3 0.40 0.48 0.12 221 3.80 6.15 19.8 0.40 0.49 0.11 lc 320 5.35 5.65 17.7 0.33 0.36 0.31 311 5.38 5.64 17.0 0.33 0.35 0.32 300 5.45 5.61 15.4 0.33 0.35 0.32 270 5.49 5.62 13.6 0.33 0.34 0.33 253 5.59 5.58 11.6 0.33 0.33 0.34 244 5.66 5.54 10.5 0.32 0.33 0.35 237 5.75 5.47 9.8 0.32 0.33 0.36 225 5.92 5.39 7.2 0.32 0.30 0.38

a No correction is made for pl10sphorus pseudorotatien

becomes more clear from examinatien of the rotamer populations of 4c and 4d. A decrease in g- population for 4c and 4d (x(g-)

=

0.23 and 0.24. respectively) is found in comparison with 1c. 1d. 3c. and 3d. The apparent explanation lies in the fact that axial location of the tetrahydrofurfuryl group in 4c and 4d results in an unfavorable diequatorial arrangement of one of the five- membered ring fragments. 11 In these spiro-phosphoranes the tetrahydrofurfuryl group is likely to act as the pivot 11.12 which accupies an equatorial position. More detailed information on the TBP-site specificity of the

c

_{4 .-C 5. conformation could be obtained by studying the variatien in the rotamer} populations with temperature for 1c (5'-P V TBP) in comparison with la (5'-PIV). The results are given in Table IV. Plots of ln(x(g+)/x(g-)) and ln(x(g1)jx(g-)) vs. 1/T

ln~l•l x I g- I In~ lol x I g-I LS 1.0 0.7 3.0 •.o 5.0

Figure 3. Van ·t Hoff plot of la resulting from variable-temperature measurements

of J_4.5. and J_4,5 •.

yield straight lines (r 2

=

0.997 and 0.998. respectively) for 1a (Figure 3). The enthalpy and entropy parameters that govern the equilibria g-~ g + and g-~ gt could be easily abstracted from the corresponding graphs: t.H0_{(g-.g+) 13 = -3.6 kJ mol-}1_{. t.S}0_(g-.

g+) 14 = -4.3 J mol"1 K- 1 t.H0_(g-.gt)

=

_{-4.4 kJ mol- 1 . and t.S}0_(g-.gt)

=

_{-6.8 J mol- 1}

K- 1 . Entirely different plots are found for lc (Figure 4). lt is established that lc

x I g'l I n - -I• I x I g-1

in~lo)

x lg -, 0.4 0.> -0.1 3.0

Figure 4. Van ·t Hoff plot of lc resulting from variable-temperature measurements

may be regarded as a rapid equilibrium between five stereoisomers ( Figure 5) of Wl.

i IS dominant at low temperatures The enantiomers ii and iii represent violations of

the polarity rule. which stales that the axial sites in the TBP are preferentially occu

-pied by electronegalive substituents (vide supra). Stereoisomers iv and v represent an

unf avorable diequatorial arrangement of the dioxaphospholane ring.11 lt follows that

lowering the temperature shifts the pseudorotation equilibrium of 1c toward i. thereby increasing the time-averaged axial location of the tetrahydrofurfuryl group. lt can be

Me

0~

Me Ph

I

I

Ph.;:::.P-0 I

0

_(i) Ph Me 0

I

. ---;;--- ; : : p - ph Me_E-o

I

Ph

!Y

Me ₀

I

o Ï ---.P- 0 M e X o ... 1 0 Ph (

/0

~

(iv) ~ (V) Figure 5. Stereoisomers of 1c.

derived (Appendix. part A) that the curves in Figure 4 approach straight lines with slopes -t.H0 _(g-.g+)R-1 and _-t.H0 _(g-.gt)R-1 _{on lowering the temperature}15 _A

ax ax

rough estimation of the slopes at 225 K reveals that ö H 0 _{a x (g-.g +)::::; 5.0 kJ mol- 1 and}

t. H

0 _{(g-.gt) ::::; 3.5 kJ mor 1. Th is means that axial location of the tetrahydrofurfuryl}

a x

group is associated with substantial stabilization of the g- rotamer. Thus. an inversion

of the relative stabilities is observed. i.e .. g + and gt are dominant for s·_piV. whereas

g- is highly preferred for axial location of the tetrahydrofurfuryl group within the PV

TBP. The results allow only a qualitative insight into the TBP-site specificity of the

-5 6

Figure 6. Model compounds 5 and 6. Dominant

c

_{4 ..}

c

_{5. rotamers are drawn for the} tetrahy-drofurfurylligands.

torial tetrahydrofurfuryl could nol be determined. Attempts to retard the pseudorota-tien of 1c failed. No decoalescence phenomena were observed in the 13

c

NMR spectra

recorded at 75 MHz down to 173 K. This problem was evaded by studying 6 in co

m-parison with 5 (Figure 6). The enthalpy and entropy parameters concerning the

equili-bria g-~ g+ and g-~ gt for 5 closely parallel the results for la. lt is found that t.H0_(g-.g+)

=

_{-4.0 kJ mol- 1. t.S}0_(g-.g+)

=

_{-5.3 J mol-l K-}1 _t.H0_(g-.gt)

=

_{-5.2 kJ}

mor 1. and t.S0_{(g-.gt) = -8.5 J mol-l K-l The}

c

4

.

-

c

5. rotamer populations for 6 again represent time-averaged values for axial and equatorial location of the

tetrahy-drofurfuryl groups. which indeed show an enhanced g- population with respect to 5

(Table V). However. because the three tetrahydrofurfuryl groups which show ligand

exchange are distributed over two equatorial and one axial position. one obtains

xexp(i)

=

~ xax(i) +t xeq(i). in which xax(i) and xeq(i) refer to axial and equatorial tetrahydrofurfuryl. respectively. for the rotamers i: g+ gt. and g- This means that the

thermadynamie parameters which govern the

c

₄

.

-

c

_5. conformational equilibria for

Table V. NMR Parameters and

c

₄

.

-c

_5. Rotamer Populations Obtained by Variabie Temperature 1H NMR on 5 and 6a

5

T.K

J4'5' Hz J4'5" Hz x(g+) x(gt) x(g-) 320 4.16 5.86 0.40 0.44 0.16 276 4.01 5.92 0.41 0.46 0.13 249 3.80 6.08 0.41 0.48 0.11 225 3.62 6.30 0.41 0.51 0.08 6 318 5.62 5.45 0.33 0.32 0.35 276 5.66 5.47 0.33 0.32 0.35 249 5.71 5.50 0.32 0.32 0.36 217 5.77 5.53 0.32 0.32 0.36

aNo correction is made for phosphorus pseudorotation

axial and equatorial tetrahydrofurfuryl can be determined precisely on the basis of J_4.5. and _{J 4.5 .. measurements} at four different temperatures (Appendix. part B). An itera-tive numerical procedure was employed which asks for an initia! estimation of the set of solutions. As a first approximation the 6.H0 _{and 65° values of 5 were used as} start-ing values for the equatorially located tetrahydrofurfuryl groups in 6. Concerning the axial location. starting values of 5 and 3.5 kJ mor 1 (according to lc. vide supra) were used for 6. H0 _{a x (g-.g +) and 6.H}0 _{a x (g- .gt). respectively. The results of the iterative}

process for 6 at 318. 276. 249. and 217 K are summarized in Table Vl. From the ther-modynamic parameters given in Table VI the

c

₄

.

-

c

_5, rotamer populations can be ca l-culated for axial and equatorial tetrahydrofurfuryl (Table Vil). lt is found that a

marked preferenee exists for the g- rotamer of axial tetrahydrof urf uryl. For 318 K

x (g+)

=

0.25. x (g1)

=

0.14. and x (g-)

=

0.61. and for 217 K x (g+)

=

0.14.

Table Vl. Thermodynamic Parameters of the

c

₄

.

-

c

_{5, Conformat}ional Equili-bria for Axial and Equatorial Tetrahydrofurfuryl in 6a

ax tetrahydrofurfuryl t.H0 3x(g-.g+)

=

4.7 kJ mor 1 t.S0 3x(g-.g+)

=

7.2 J mor 1 K-1 t.H0_{ax(g-.gt) = 6.1 kJ mol-}1 t.S0_{ax(g-.gt) = 6.9 J mor 1 K- 1} eq tetrahydrofurfuryl t.H0_eq(g-.g+)

=

_{-4.3 kJ mol- 1} óS0_eq(g-.g+)

=

_{-9.8 J mor 1 K-}1 t.H0_eq(g-.gt)

=

_{-4.0 kJ mor 1} t.S0_eq(g-,l)

=

_{-8.4 J mor1 K- 1} aCorrected for phosphorus pseudorotatien

x (gt)

=

0.06. and x (g-)

=

0.80. Clearly. a pronounced repulsion _{between 0 5. and}

ax ax

0 1. dominates the

c

_{4.-C 5. conformation for} axial _{tetrahydrof urf uryl. The C 4 .-C5.}

con-formation for equatorial tetrahydrofurfuryl resembles the

c

₄

.-c

_{5. conformation for}

5'-piV tetrahydrofurfuryl. For 318 K xeq(g+)

=

0.37. xeq(gt)

=

0.39. and xeq(g-)

=

0.24 and for 217 K xeq(g+) = 0.43. xeq(gt)

=

0.44. and xeq(g-)

=

0.13. For 5 (5'-PIV) at 320 K x(g+) = 0.40. x(gt

=

0.44. and x(g-)

=

0.16 and at 225 K x(g1·) = 0.41. x(g1)

Table VIl.

c

₄

,

-

c

_{5, Rotamer Popuiatien}s for Axial and Equa-torial Tetrahydrofurfuryla

ax tetrahydrofurfuryl eq tetrahydrof urfuryl

T.K

x(g+) x(gt) x(g-) x(g+) x(gt) x(g-)

318 0.25 0.14 0.61 0.37 0.39 0.24

276 0.21 0.11 0.68 0.39 0.41 0.20

249 0.18 0.09 0.73 0.41 0.42 0.17

217 0.14 0.06 0.80 0.43 0.44 0.13

=

0.49. and x(g-)

=

0.08. From the present results it is clearly established that a change in coordination from piV to PV TBP for the various tetrahydrofurfuryl

compounds is transmitted into a

c

_4,-CS' conformational change when the tetrahydro-furfuryl group is located in the axis of the TBP. On the basis of the experimental and theoretica! results. it can be speculaLed that conformational changes in DNA can also

be achieved by activation of the phosphate via a piV into PV TBP transition. This

dynamic model was employed recently to give a description of the primary step in the

cascade of internal motions for the isomerization of right-handed B DNA into

left-handed Z DNA1. 2·16

EXPERIMENTAL SECTION

Materials. All solvents and materials were reagent grade and were used as received or

purified as required. All reaelions were routinely run under an atmosphere of dry

nitro-gen.

Spectroscopy. 1 H NMR spectra were run in the FT mode on a Bruker CXP-300

spectrometer at 300.1 MHz. 32K data base. 3000-Hz SW. and S.47-s acquisition time.

Coupling constants were taken from expansions of the Hs./Hs .. patterns and

iterative-ly anaiterative-lyzed with the PAN IC program17 Chemica I shifts were related to the

CHD 2COCD3 quintet. which was set at 8 2.17. 31 P and 13

c

spectra were run at 36.4 and 22.6 MHz. respectively. on a Bruker HX-90R spectrometer with a Digilab

FT-N M R-3 pulsing accessory. Chemica! shifts are respe_{ctively related to 8S% H3 Po 4 and} Me_{4Si as} external standards.

Synthesis. (Tetrahydrofurfuryloxy)diphenylphosphine. A salution of chlorodi-phenylphosphine (100 mmol. 22.1 g) in 40 ml of anhydrous diethyl ether was added over 30 min to a stirred and cocled (0 °C) salution of tetrahydrofurfuryl alcohol (100 mmol. 10.2 g) and triethylamine (100 mmol. 10.1 g) in 60 ml of anhydrous diethyleth-er. After completion of the addition the mixture was refluxed for 2 h. The precipitated triethylamine hydrachloride was removed by filtratien and washed with 20 ml of anhy-drous diethyl ether. After remaval of the solvent the oily residue was distilled under

re-duced pressure to yield (tetrahydrofurfuryloxy)diphenylphosphine as a colorless liquid

(80 mmol. 80%). bp 154 °C (0.5 mm). 31 P NMR 8 115.5.

(Tetrahydrofurfuryloxy)diphenylphosphine Oxide (la). An acqueous 12%

hydra-gen peroxide salution (10 ml) was added dropwise to a caoled (0 °C) salution of

(tetrahydrofurfuryloxy)diphenylphosphine (17 mmol. 4.8 g) in 40 ml of acetone. The

reaction mixture was refluxed for 3 h. caoled to room temperature. and poured into 60 ml of water. The salution was extracted with diethyl ether. Evaporation of the diethyl ether layer yielded la as a colorless liquid 1H NMR 8 1.8-2.1 (4H.m._H2,;_{H3,). 3.8-3}.9 (2H.m.H 1.). 4._{0-4.1 (2H.m.H 5,). 4.2-4.3 (1H.m.H 4,). 7.5-8.1 (10H}.m.Ar H). 31 P NMR 8 35.8: 13

c

NMR 8 _{27.1 (C 2,)}. 29.1 (C3'). _{68.4 (C5,.JPOC}

=

6 Hz). _{69.5 (C 1 .)}. 78.9 (C 4,.JPOCC = 8 Hz). 130-134 (m. Ar C).

(Tetrahydrofurfuryloxy)diphenylphosphine Sulfide (1b).

s

_{8 (3} mmol. 0.77 g) was

added in smal! portions to a magnetically stirred salution of 23 mmo! (5.8 g) of ( tetrahydrof urfuryloxy) diphenylphosphine in 20 m L of dry toluene. Af ter completion of the addition the reaction mixture was refluxed for 1 h. Evaporation of the toluene

1

yielded 1b as a yellowish viseaus oil: H NMR 8 1.5-2.2 (4H.m.H₂,j_H3,). 3.8-4.0

(2H.m.H 1.). 4.0-4.2 (2H.m.H 5.). 4.3-4.4 (1H.m._H4,). 7.2-8.3 (10H.m.Ar H): 31 P NIVIR 13

8 82.3: C NMR _{8 27.2 (C 2,) 29.1 (C 3,)}. 68._{2 (C 5,.} JPOC

=

6 Hz). _{69.4 (C 1,).} 78.7 (C4'· JPOCC

=

8 Hz). 129-134 (m. Ar C).

2,2- Diphenyl-2- ( letrahydrofurfury loxy )-2,2-dihydro-4 ,5-dimethyl-1 ,3

,2-dioxa-phosphol- 4-ene ( 1c). A cocled (0

°C)

salution of (tetrahydrof urfuryloxy )- di pheny 1-phosphine (10 mmol. 2.9 g) and butanedione (10 mmol. 0.9 g) in 5 ml of anhydrous diethyl ether was stirred for 3 h. The product. which precipitated on standing at -20 °C for several days. was washed with anhydrous acetone to yield white crystals. mp 103-104 °C. Anal. Calcd _{for c 21 H2So4 P} C. 6773: H. 6.77. Found: C. 67S7: H. 6.82.

1H NMR 8 17-2.0 (4H.m._H2.jH3,). 2.0 _{(6H.s.CH 3).} 3.4-3.5 (2H.m_{.H 1},). 3.5-3.6

31 13

(2H.m.H 5.). 4.0-4.1 (1H.m._H4.). 75-8.0 (lOH.m.Ar H): P NMR 8 -24 4: C NMR 8 11.8 _{(CH 3.} Jpocc

=

9 Hz). 27.1 _{(c 2,)}. 29.8 (C3'). 68.0 (Cs·· Jpoc = 9 Hz). 69.2 (C 1,). 80._{0 (C 4,}. JPOCC

=

8 Hz). 128-134 (m. Ar & olefinic

C).

2 ,2,4,5-Tetraphenyl- 2- (tetra hydrof urf u ryloxy )-2,2-dihydro-1,3 .2-dioxa phos-phol-4-ene (ld). A cooled (0

°C)

salution of (tetrahydrofurfuryloxy)- diphenylphos

-phine (10 mmol. 2.9 g) and diphenylethanedione (10 mmol. 2.1 g) in S ml of anhy

-drous diethyl ether was stirred for 3 h. Evaporation of the solvent yielded ld as a

viscous oil. 1 H NMR 8 17-2.1 (4H.m._H2.;_H3,). 3.7-3.8 (2H.m.Hl'). 3.8-3.9

31 13

(2H.m.H 5.). 4.1-4._{2 (1H.m.H 4.)}. 7.3-8.2 (20H.m.Ar H): P f\IMR 8 -28.1: C NMR 8 27._{1 (C 2,). 29.8 (C 3.)}. 68.4 (Cs'· JPOC

=

9 Hz). 69.3 _{(C 1 .)}. 79.9 _(C4 .. JPOCC

=

6 Hz). 128-133 (m. Ar & olefinic C).

chlorodiphenylphosph ine ( 100 mmo I. 22.1 g) and cyclopentylmethanol ( 100 mmol. 10.0

g) according to the procedure that was described for the preparatien of

( tetrahydrof urf uryloxy) dipheny I phosphine The product was obtained as a colorless

liquid (74 mmol. 74

%)

bp 162 °C (OS mm). 31 P NMR 8 111.8.

(Cyclopentylmethoxy)diphenylphosphine Oxide (2a). 2a was prepared from

( cyclopentyl methoxy) d iphenylphosphine by the procedure that was described for the

preparatien of la. The product was obtained as a white crystalline powder. mp 83. S-84.S °C Anal. Calcd for

c

_{18 H21}

o

_2P C. 71.99: H. 7.0S. Found C. 71.99: H. 7.16. 1 H NMR 8 1.4-2.0 (8H.m.cyclopentane H). 2._{4 (1H.m.H 4.)}. 4.0 (2H.t.H₅.). 7.6--8.0 (10H.m.Ar H): 31 P NMR 8 33.8: 13

c

NMR 8 26.8 (Cl_'a/C3.). 30.S (C₁

.;c

₂.). 41.9 (C 4 •. JPOCC

=

6 Hz). 69.7 (Cs'· JPOC

=

6 Hz). 130-138 (m. Ar C).

2,2-Diphenyl- 2-( cyc lopentylmethoxy )-2.2- dihyd ro-4, 5-dimethyl-1 ,3 ,2-dioxa

-phosphol-4-ene (2b). A cooled (0 °C) salution of (cyclopentylme

thoxy)diphenyl-phosphine (10 mmol. 2.8 g) and butanedione (10 mmol. 0.9 g) in S ml of anhydrous

diethyl ether was stirred for 3 h. Evaporation of the solvent yielded 2b as a viseaus oil

1 _{H NMR 8 12-1.8 (8H.m.cyclopentane H). 2.0 (6H}

.s CH 3). 2.2 (1H.m._H4.). 3.S

(2H.t.Hs.) 7.4-8.0 (lOH.m.Ar H): 31 P NMR 8 -26.1: 13

c

NMR 8 11.9 _{(CH 3).} 26.9

(C_1,afC3.). 30.7 (C1'/_C2.). 41.7 (C4 .. JPOCC

=

6 Hz). 69.9 (Cs'· JPOC

=

6 Hz).

129-134 (m. Ar & olefinic C).

2,2 ,4,5- Tetra phenyl-2- ( cyclopentylmethoxy)-2,2-dihydro-1,3,2-dioxaphosphol

-4-ene (2c). A caoled (0

°

C)

salution of (cyclopenthylmethoxy)diphenylphosphine (10

mmol. 2.8 g) and diphenylethanedione (10 mmol. 2.1 g) in S ml of anhydrous diethyl

ether was stirred for 3 h. Evaporation of the solvent yielded 2c as a viscous oil: 1H NMR 8 1.3-2.0 (8H.m.cyclopentane H). 2.3 (1H._{m.H 4.)}. 3.6 (2H.t.Hs•). 7.3-8.2

31 13

(20H.m.Ar H): P NMR 8 -22.S: C NMR 8 26.9 (C_{1,a /C 3.)}. 30.S (_C1,j_{c 2,).} 42.0

(C 4,. JPOCC

=

6 Hz). 69.8 (Cs'· JPOC

=

6 Hz). 128-13S (m. Ar & olefinic C).

Tetrahydrofurfuryl Diethyl Phosphite. This compound was prepared from

chloro-diethoxy phosphine 18 ( 420 mmol. S2.3 g) and tetrahydrof u rf uryl alcohol ( 420 mmo I.

42.8 g). according to the procedure that was described for the preparation of

(tetrahydrofurfuryloxy)diphenylphosphine. The product was obtained as a colorless

liquid (230 mmol. SS%). bp 6S °C (003 mm). 31 P NMR 8 138.3.

Tetrahydrofurfuryl Diethyl Phosphate (3a). An ozone-oxygen stream was passed

through a solution of tetrahydrofurfuryl diethyl phosphite (45 mmol. 10 g) in 60 ml of

dry dichloromethane at -78 °C. until a light blue color of excess ozone was apparent 19

The reaction mixture was then sparged with dry nitrogen to remove excess ozone. The solution was warmed to room temperature over about 1 h. Evolution of singlet oxygen

proceeded smoothly. beginning at -30 °C. Evaporation of the solvent y ielded an oily

residue. which was distilled under reduced pressure to yield 3a as a colorless liquid (18

mmol. 40%) bp 79 °C (0.03 mm): 1H NMR 8 14 _{(6H.t.CH 3. JHH} = 7 Hz). 1.7-2.1

(4H.m.H 2,jH 3.). 3.8-4.0 _{(2H.m.H 1,).} 4.0-41 (2H.m.Hs,). 4.1-4.3 (SH m _H4.j_{CH 2)}:

31 13

P NMR 8 4.2: C NMR 8 17.3 (CH₃. JPOCC

=

6 Hz). 27.1 (C₂.). 29._{0 (C 3.)}. 6S.O

(CH 2. JPOC = 6 Hz). 69._{5 (C 1.)}. 70.6 (Cs·· JPOC = 6 Hz). 78.7 _{(C 4} .. JPOCC

=

8 Hz).

in small portions to a magnetically stirred salution of 69 mmol (15.3 g) tetrahydrofur-furyl diethyl phosphite in 100 ml of dry toluene. After completion of the addition the reaction mixture was refluxed for 2 h. 31 P NMR indicated the reaction to be complete. The product was purified by distillation under reduced pressure to yield 3b as a slight-ly colored liquid (31 mmol. 45%): bp 89-90 °( (0.001 mm): 1H NMR 8 _{1.S (6H.t.CH 3.} JHH

=

7 Hz). 1.7-2,_{2 (4H.m.H 2.jH 3.). 3}.8-4.0 (2H._{m.H 1.)}. 4.0-4.2 (2H.m.Hs•). 4.2-4.4 (5H.m.H 4,jCH 2): 31 P NMR 8 68.0: 13c _{NMR 8 17.0 (CH3. JPOCC}

=

8 Hz). 27.1 (C2.). 29.2 (C 3,). 65.5 (CH 2. JPOC = _{6 Hz). 69.5 (C 1 .). 71.2} (Cs•· JPOC

=

7 Hz). 78.S (C 4 •. JPOCC

=

7 Hz).

2,2- Diethoxy-2- ( tetrahydrof urf uryloxy )-2,2-dihydro-4 ,5-dimethy 1-1,3,2-dioxa-phosphol-4-ene (3c). A cocled (0 °C) salution of tetrahydrofurfuryl diethyl phos-phite (10 mmol. 2.2 g) and butanedione (10 mmol. 0.9 g) in 5 ml of anhydrous diethyl ether was stirred for 3 h. Evaporation of the solvent yielded 3c as a viscous oil: 1 H NMR 8 13 _{(6H.t.CH 3. JHH}

=

_{7 Hz). 1.7-2.1 (4H.m.H 2.jH3.). 1.9 (6H.s.CH 3).} 3.7-3.9 (2H.m.H 1.). 3.8-3.9 (2H.m.Hs•). 4.0-4.1 (4H._{m.CH 2). 4.1-4.3 (1H.m}._{H4,): 31 P NMR} 8 -45.8: 13c NMR 8 10._{9 (CH 3). 16}._{9 (CH 3}. JPOCC

=

6 Hz). 26.1 _{(C 2,).} 28.8 _(C3,). 64.1 (CH 2. JPOC = 11 Hz). 68.7 (C 1.). 69.9 (Cs, JPOC

=

11 Hz). 78.2 (C 4,. JPOCC

=

9 Hz). 129.4 (olefinic C. JPOC

=

2 Hz).

2,2- Diethoxy-2-( tetrahyd rof urf uryloxy)-2,2-dihydro-4 ,5-diphenyl-1 ,3,2- dioxa-phosphol-4-ene (3d) A cooled (0 °C) salution of tetrahydrofurf uryl diethyl phosphite (10 mmol. 2.2 g) and diphenylethanedione (10 mmol. 2.1 g) in S ml of anhydrous diethyl ether was stirred for 3 h. Evaporation of the solvent yielded 3c as a viscous oil: 1 _{H NMR 8}

1.4 (6H.t.CH 3. JHH

=

7 Hz). 1.7-2.1 (4H.m._H2.j_H3,). 3.7-4._{0 (2H.m.H 1}.).

4.0-4.1 (2H.m.Hs,). 4.1-4.3 (_{SH.m.H4.jCH 2). 7.4-8}.3 (10H.m.Ar H): 31 P NMR 8 -46.6: 13

C NMR 8 17.8 (CH 3. JPOCC

=

8 Hz). 27.1 (C 2,). 29.6 (C3,). 6S.3 (CH 2. JPOC

=

12Hz). 69.S (Cl'). 71.0 (Cs•· JPOC =11Hz). 79.S _{(C 4 .. JPOCC =11Hz). 128-137} (Ar & olefinic C).

2-(Tetrahydrofurfuryloxy)-1,3,2-dioxaphospholane. This compound was prepared

f ram 2-chloro--1.3.2-d ioxaphospholane20 ( 4 7 4 mmo I. 60.0 g) and tetrahydrof urf uryl

al-cohol (474 mmol. 48.3 g) according to the procedure that was described for the

preparatien of (tetrahyd rof urf u ryloxy) diphenylphosphine. The product was obtained as

a colorless oil (298 mmol. 63 %). bp 7S-76 °C (O.OS mm): 31 P NMR 8 138.3.

2- (Tetrahydrof urf uryloxy) -2-oxo-1 ,3 ,2-dioxapho spholane ( 4a). Th is compound

was prepared from 2-( tetrahydrof urf uryloxy )-1.3.2-dioxaphospholane according to the

procedure that was described for the preparation of 3a. The product was obtained as a

colorless oil: bp 128 °C (O.OS mm): 1H NMR 8 1.7-2.1 (4H.m._H2.;_H3.). 3.8-4.0 (2H.m.H 1.). 4.1-4.2 (3H.m.H 4,fHs,). 4.S-4.6 (4H.d._{CH 2): 31 P NMR} 8 22.2: 13c NMR 8 _{27.1 (C 2,)}. 29._{0 (C3,)}. _{68.0 (CH 2}. JPOC =2 Hz). _{69.S (C 1 .). 71}.S (Cs'· JPOC = 6

Hz). 78._{7 (c 4 •. Jpocc}

=

8Hz).

2-(Tetrahydrofurfuryloxy)-2-thioxo-1,3,2-dioxaphospholane (4b).

s

₈ (8.6 mmol. 2.2 g) was added in smal! portions to a magnetically stirred salution of 69 mmol (13.2

g) of 2-(tetrahydrofurfuryloxy)-1.3.2-dioxaphospholane in 100 ml of dry toluene. After

completion of the addition the reaction mixture was refluxed for 3 h. 31 P NMR indi-cated the reaction to be complete. The product was purified by distillation under

(0.02 mm): 1H NMR

o

1.7-2.1 (4H.m._H2,_{jH 3,). 3}.8-4.0 (2H.m._{H1,). 4.0-4}.1 (2H.m.Hs,)- 4.1-4.2 (1H.m._{H4.). 4.4-4.6 (4H}._{d CH 2)}: 31 P NMR

o

84.3: 13

c

NMR &

27.0 (C 2,). 29.2 (C 3.). 67.S (CH 2. JPOC

=

2 Hz). 69.3 (C 1.) 70.8 (Cs•· JPOC

=

8 Hz). 78.6 (C 4 •. JPOCC = 9 Hz).

2,3- Di methyl-5- ( tetrahydrof urfuryloxy )-1 ,4,6,9- tetraoxa-5-phosphaspiro

-[4.4]non-2-ene (4c) A cooled (0

°

C)

solution of 2-(tetrahydrofurfuryloxy)- 1.3.2-dioxaphospholane (10 mmol. 1.9 g) and butanedione (10 mmol. 0.9 g) in S ml of

anhydrous diethyl ether was stirred for 3 h. Evaporation of the solvent yielded 4c as a colorless viscous oil: 1 H NMR & 1.7-2.1 (4H.m._{H2.jH 3.)}. 2.4 (6H.s._{CH 3). 3.7-4}.0 (2H.m._{H5.). 3.9-4.1 (2H}._{m.H 1},). 4.0-4.2 (1H.m._{H4.). 4}.3-4.4 (4H.d.CH₂): 31 P NMR

o

-22.8: 13

c

NMR 8 11.5 (_{CH 3). 27}._{0 (C 2.)}. 29.2 (_{C3.). 61.3 (CH 2. JP}OC

=

5 Hz). 69.4 (C 1.). 70.7 (Cs'· JPOC

=

10 Hz). 79.0 (C 4,. JPOCC

=

9 Hz). 130.7 (olefinic C. JPOC

=

5 Hz).

2,3- Diphenyl- 5- ( tet rahy drof urf ury loxy) -1,4,6,9-tetraoxa-5- phosphaspiro-[4.4]non-2-ene (4d) A cooled (0

°C)

solution of 2-(tetrahydrofurfuryloxy)-1.3.2 -dioxaphospholane (10 mmol. 1.9 g) and diphenylethanedione (10 mmol. 2.1 g) in S ml of anhydrous diethyl ether was stirred for 3 h. Evaporation of the solvent yielded 4d as

a viscouc oil: 1H NMR 8 1.7-2.1 (4H.m.H₂.;_{H3.). 3.7}-4.0 (2H.m.Hs·l· 4.0-4.1 (2H._{m.H 1.). 4.1}-4.2 (_{1H.m.H 4.)}. 4.3-4._{4 (4H.d.CH 2). 7}.S-8.4 (10H.m.Ar H): 31 P NMR

& -23.2: 13

c

NMR & 27._{2 (C 2,)}. 29.4 (C₃.). 61.2 (CH_2. JPOC

=

4 Hz). 69._{S (C 1},).

70.7 (Cs'· JPOC

=

9 Hz). 79.S (C 4 •. JPOCC

=

8 Hz). 128-136 (Ar & olefinic C).

Tri(tetrahydrofurfuryl) Phosphite. A solution o_{f PCI3 (}300 mmol. 41.3 g) in 100

ml of anhydrous diethyl ether was added dropwise to a stirred and cooled (0 °C) solu-tion of tetrahydrofurfuryl alcohol (900 mmol. 91.5 g) and triethylamine (900 mmol. 90.9 g) in 150 ml of anhydrous diethyl ether. After completion of the addition the mixture was refluxed for 1 h. The precipitated triethylamine hydrachloride was re-moved by filtratien and washed with two 20-ml portions of anhydrous diethyl ether. After removal of the solvent the oily residue was distilled under reduced pressure to afford the desired product as a colorless liquid (265 mmol. 88

%).

bp 163-165 °C (0.05 mm). 31 P NMR 8 138.4.

Tri(tetrahydrofurfuryl) Phosphate (5). This compound was prepared from tri (tetrahydrof urfuryl) phosphi te according to the procedure that was described for the preparatien of 3a. The product could not be purified by distillation in vacuo. 1H 1\JMR

8 17-2.1 _{(12H.m.H 2.}j_{H3.). 3.8-4.0 (6H.m.H 1}.). 4.0-4.1 (6H.m._H5,). 4.1-4.2

31 13

(3H.m.H 4,): P NMR 8 1.2: C NMR 8 27.1 _{(C 2,)}. 29.2 _{(C 3,).} 69.5 _{(C 1 .)}. 70._{6 (C 5 •.}

JPOC

=

6 Hz). 78.7 (C 4 •. JPOCC

=

7 Hz).

2,2,2-Tri ( tetrahyd rof urfu ryl )-2,2-dihydro-4 ,S-dimethyl-1,3 ,2-dioxaphos

phol-4-ene (6). Th is compound was prepared f rom tri (tetrahydrof urf uryl) phosphite and bu

-tanedione according to the procedure that was described for the preparatien of 3c. The product was obtained as a yellowish viscous oil. 1 H NMR 8 1.7-2.1 (12H.m._{H2.;H 3.).}

31 1.9 (6H.s.CH 3). 3.7-3.9 (6H.m.Hd. 3.8-3.9 (6H._{m H5.). 4.1}-4.2 (3H.m._H4.): P NMR 8 -50.3: 13

c

NMR 8 _{10.9 (CH 3).} 26.8 _{(C 2.)}. 28.9 _{(C 3}._{). 69.0 (C 1.). 69.9 (C5 •}. JPOC

=

10Hz). 78.4 (C 4 .. JPOCC

=

9 Hz). 130.0 (olefinic C. JPOC = 2 Hz).

APPENDIX

Part A. Assuming that À is the mole fraction that corresponds to axial location of the tetrahydrofurfuryl group in lc it follows that

d In (x(j)/x(g-)) d(l/T)

where j

=

g+. gt Since i (Figure 5) is the only stereoisomer that does not represent violations of the polarity and/or strain rules. it can be concluded that À-1 with

de-creasing temperature. The first derivatives of the curves in Figure 4 then approach

Part 8. Since the three tetrahydrofurfuryl groups in 6 are divided over one axial and

two equatorial sites in the TBP it holds that xexp(i)

=

~ xax(i) +f xeq(i) where i= g

+

gt g-. The time-averaged

c

₄

.

-c

₅. conformation which is obtained under pseudoro-lation conditions is determined by eight thermadynamie parameters. Four of them

refer to axial tetrahydrofurfuryl (i1H0 _{(g-.g+). t.H}0 _{(g-.g1). t.S}0 _{(g-.g+). and}

ax ax ax

t.S0_{ax(g-.g1)) and four to equatorial tetrahydrofurfuryl (t.H}0_{eq(g-.g+). t.H}0_eq(g-.gt).

i1S0_{eq(g-.g+). and t.S}0_{eq(g-.g1)). These parameters can be substituted in the}

aforementioned equation (with i1G0

=

_t.H0 _{- T t.S}0_{) as:}

where j

=

g +. gt In this way. two independent equations in the eight unknown ther-modynamic parameters are obtained for each temperature. An iterative computer pr

gram. based on the FORTRAN subroutine by Powell. 21 was used to solve the set of

eight equations that resulted f rom the N M R measurements on 6 at 318. 276. 249. and 217 K.

REFERENCES AND NOTES

1. van Lier. J.J.C.: Koole. LH.: Buck. H.M. Reel. Trav. Chim. Pays-Bas 1983. 102.

148.

2. van Lier. J.J.C.: Smits. M.T.: Buck. H.M. Eur J. Biochem. 1983. 132. 55. 3. Buck. H.M. Reel. Trav. Chim. Pays-Bas 1980. 99. 181.

4. Haasnoot. C.A.G .. de Leeuw. F.A.A.M.: Altona. C. Tetrahedron 1980. 36. 2783.

5. In this generalized equation the standard Karplus relation is extended with a

correc-tion term which accounts for the influence of electronegalive substituents on 3 J H H: 3 JHH

=

13.22 cos 2 1J- 0.99 cos 1J

+

II0.87- 2.46 cos 2 (Çi(/J

+

19.91.6.x))J.6.xi

(/! is the proton-proton torsion angle. D.x i is the difference in electronegativity between the substituent and hydragen according to the electronegativity scale of Huggins. and Çi is a substituent orientat10n parameter.

6. Davies. D.B.: Danyluk. SS Biochemistry 1975. 14. 543. 7. Altona. C. Reel. Trav. Chim. Pays-Bas 1982. 101. 413.

8. The existence of a gauche-effect. i.e. a pronounced preferenee for gauche over trans

geometry in X-C-C-Y f ragments in which X and Y re present highly electronegalive

substituents (N. 0. Cl. F) is well-known (Wolfe. S. Acc. Chem. Res. 1972. 5. 102). In

addition it was pointed out that the conformational behavior of furanoses can be

ra-tionalized on the basis of a predominant preferenee of 0-C-C-0 bond sequences to

and references cited therein).

9. Davies. D.B. In "Progress in Nuclear Magnetic Resonance Spectroscopy": Emsley. J.W .. Feeney. J .. Sutcliffe. L.H .. Eds.: Pergamon Press Oxford. 1978: Vol 12. Part3. pp 181-184 and references cited therein.

10. Muetterties. E.L.: Mahler. W.: Schmutzler. R. lnorg. Chem. 1963. 2. 613.

11. Holrnes. R.R. In "Pentacoordinated Phosphorus": American Chemica! Society: Washington. DC. 1980: Vol I. 11. ACS Monogr No. 175. 176 and references cited therein.

12. Luckenbach. R. In "Dynamic Stereochemistry of Pentacoordinated Phosphorus

and Related Elements": Georg Thieme Verlag: Stuttgart. 1973.

13. t.H0_{(g-.g+). and t.H}0_{(g-.gt) denote the enthalpy differences H}0_{(g+) - H}0_{g-)

and H0_{(gt)- H}0_{(g-). respectively.}

14. t.S0_{(g-.g +) and t.S}0_{(g-.gt) denote the entropy differences S}0_{(g +) - S}0_{(g-) and}

S0_{(gt)- S}0_{(g-). respectively.}

15. The subscrirts "a x" and "eq" are used with reference to a x i al and equatorial tet rahydrof urf uryl. respectively.

16. Wang. A. H -J : Ouigley. G.J: Kolp;Jk. F.J.: Crawford. J.L.: van Boom. J.H.: van der Marel. G. Hich. A. Nature (London) 1979. 282. 680.

17. PAN IC program: Copyright. Bruker Speetrospin AG. Switzerland. 18. Huyser. E.S.: Dieter. J.A. J. Org Chem. 1968. 33. 4205.

19. Thompson. Q.E. J. Am. Chem. Soc. 1961. 83. 845.

20. Lucas. H J.: Mitchell. F.W: Scully. CN. J. Am. Chem. Soc. 1950. 72. 5491. 21. Powell. M.J.D. "A FORTRAN Subroutine for Solving Systems of IIJon-linear Alge-braic Equations". Harveil Report. AERE-R5947. H.M.S.O .. 1968.

CHAPTER 3*

Conformational Trilnsmisson in Four- and Five-Coordinated Phosphorus Compounds. Solvent Effects on the c₄

,-c

_{5, Conformation m 5'-Phosphorylated Model Nucleosides.}

ABSTRACT

The

c

_{4,-C5, conformation of the S'-PIV model} compounds 1 - 3 and the S'-PV TBP model compounds 4 - 6 has been determined in various solvents with 300- and SOO-MHz 1H NMR lt is found that lowering the solvent polarity results in a substantial increase of the

g-populations for the model compounds 1. 2. 4 and S (e.g .. for 1 in _{0 20}. x(g-) = 0.00: _CCI4.

x(g-) = 0.23). Th is effect can be attributed to an enhanced electrostalie repulsion between the

charge densities on OS' and the endocyclic oxygen(s) at lower solvent polarities. This condusion

is supported by the experimental finding that the 5'-PIV system 3 and the S'-PV TBP system 6.

in which the endocyclic oxygen(s) are replace_{d by C(H 2)}. do notshow a

c

₄,-CS' conformational

change when the medium polarity is changed. Furthermore. it is found that the 5'-PIV

nucleo-Lides 7 and 8. which are made soluble in apolar solvents by triesterification of the phosphorus. show also increased g- populations upon lowering the solvent polanty. The present results confirm the earlier propos al that enhanced charge repulsion between Os, and _{0 1}, in mononu-cleolides drives a rotation around the

c

₄

.-c

_5. bond toward

g-*Koole. L.H.: van Kooyk. R.J.L .. Buck. H.M. J. Am. Chem. Soc. 1985. 107. 4032-4037.