6-membered P-heterocycles: Ring-condensed 1,3,2-

diheterophosphorinane 2-chalcogenides

Éva Frank* and János Wölfling

Department of Organic Chemistry, University of Szeged, Hungary

*Address correspondence to this author at the Department of

Organic Chemistry, University of Szeged, H-6722 Szeged, Dóm

tér 8., Hungary; Tel: +36-62-544275; E-mail: frank@chem.u-

szeged.hu

1

Keywords: 1,3,2-diheterophosphorinanes, stereostructures,

conformational preferences, 1H, 13C, 31P NMR studies

Abstract

Literature publications (up to the end of 2006) relating to

the synthesis, biological significance and conformational

behaviour of carbocycle- and heterocycle-condensed six-

membered tetracoordinate P(V) 1,3,2-diheterophosphorinanes are

reviewed. The replacement of carbon atoms of cyclohexane by P

and O and/or N to form 1,3,2-dioxa-, 1,3,2-oxaza- or 1,3,2-

diazaphosphorinanes introduces lone pair electrons instead of

hydrogens and changes the bond angles and bond lengths, and

can thereby lead to significantly different stereostructural

preferences of the hetero ring as compared with those of

cyclohexane. Although monocyclic 1,3,2-diheterophosphorinanes

often exist in a chair conformation in both the solid and

solution states, the existence of conformations other than a

chair can predominate in some cases for steric and

stereoelectronic reasons associated with the presence of bulky

2

groups on the P-containing ring or in polycyclic rigid

systems.

After a brief account on the most important pharmacological

and stereochemical features, involving the configuration

assignment and conformation determination of P-

diheterophosphorinanes, the present review mainly focuses on

the synthesis and stereostructural studies of carbo- and

heterocycle-condensed derivatives where the fused ring may

exert considerable effects on the conformational behaviour of

the P-hetero ring.

The bibliography includes 76 references.

1. INTRODUCTION

Monocyclic and condensed six-membered P-heterocycles have been

subjected to intense research during the past few decades [1].

3

Among them, particularly the tetracoordinate P(V) 1,3,2-

dioxaphosphorinanes and 1,3,2-oxazaphosphorinanes have

attracted considerable attention from both stereochemical and

pharmacological aspects (Figure 1) [2-7]. The main aims of

these studies were: (i) to clarify the mode of action of

second-messenger cyclic nucleotides (e.g. cAMP and cGMP), which

contain a 1,3,2-dioxaphosphorinane moiety and play important

roles in hormone action and cell communication [5, 8]; (ii) to

acquire more information on the biotransformations of the

clinically widely used antitumour agent cyclophosphamide and

its analogues, which contain a 1,3,2-oxazaphosphorinane ring,

in order to develop compounds with improved action and to

reveal certain structure-activity relationships [2, 9]; (iii)

to synthesise novel, potentially active 1,3,2-

diheterophosphorinane derivatives [10-13]; and (iv) to

investigate the unique conformational behaviour of differently

substituted six-membered P-hetero rings [1-7]. In contrast to

the 1,3,2-dioxa- and 1,3,2-oxazaphosphorinanes, the

corresponding 1,3,2-diaza analogues have been less

comprehensively studied, although their synthetic importance

increased when 1,3,2-diazaphosphinane phosphoramides proved to

4

be effective auxiliaries for the promotion of stereoselective

carbon-carbon or carbon-hydrogen bond-forming reactions [14].

Figure 1.

The recognition of a chiral bioactive compound via the active

site of a specific enzyme(s) responsible for its

biotransformation depends on the absolute configuration of one

or more asymmetric centres in the molecule, and the

conformation can also be determinative. Accordingly, the

stereochemistry is important for the bioactivities of chiral

heterophosphorinanes. Diheterophosphorinane rings display

stereostructural properties quite different from those of

cyclohexane as a consequence of the electron lone pairs on the

ring heteroatoms and the changed bond angles and lengths. In

general, both in solution and in the solid state, 1,3,2-

dioxaphosphorinanes adopt a chair conformation that is slightly

flattened at the P end, because of the relatively long PO

5

bonds. The interconversion between the two alternative chair

forms, however, is normally rapid in solution [4-7], unless

there is a conformational bias towards the population of one

or other conformer by very bulky groups on the P-ring and in

rigid polycycles. In these latter cases, one of the chair

conformers or an unusual intermediate twist [15], half-chair [16]

or boat [17] form becomes predominant and these systems can be

regarded as anancomeric [7]. The 1,3,2-oxazaphosphorinanes may

have an enhanced propensity towards twist conformations as

compared with the 1,3,2-dioxa series, although the ring N

substituent can have a significant modulating effect [18]. The

conformational preference of these heterocycles is mainly

influenced by the steric and electronic properties of the

substituents on the P, the size of the group on the ring N

atom and the P configuration [19-24]. In contrast to the

conformationally diverse 1,3,2-oxazaphosphorinane analogues,

the corresponding 1,3,2-N,N,P heterocycles are characterized

by chair or twist-chair conformations [25, 26]. Assignment of the

P configuration and detection of the predominant conformation

of the 1,3,2-diheterophosphorinanes in solution necessitate

different NMR techniques [4-7], but X-ray crystallography [27,

6

28] and ab initio calculations [29-33] are also important tools

for stereostructural analysis.

2. SYNTHETIC AND STEREOCHEMICAL ASPECTS OF

TETRACOORDINATE P(V) 1,3,2-DIHETEROPHOSPHORINANES

The synthesis and conformational behaviour of monocyclic and

some bicyclic diheterophosphorinanes (especially the 1,3,2-

dioxa and 1,3,2-oxaza derivatives) substituted at different

positions of the six-membered P-containing ring have been

thoroughly reviewed, by Bentrude and others [3-7]. Besides 2-oxo

derivatives, 2-thio- [34] and 2-seleno analogues [35] have

been reported that possess not only interesting conformational

features, but also variable pharmacological activities.

Accordingly, the in vitro and in vivo antitumour properties of

several cyclophosphamide-like molecules were evaluated in

search for 1,3,2-oxazaphosphorinanes highly cytotoxic to L1210

lymphoid leukaemia [36-38] or which act as tumour-targeted

prodrugs [12]. A number of 1,3,2-dioxaphosphorinanes have been

reported to exhibit diverse bioactivities and have different

synthetic applications, e.g. a potent calcium antagonist [39],

7

microsomal triglyceride-transfer protein inhibitors [40],

cytochrome P450 3A-activated prodrugs [41], efficient resolving

agents for the resolution of amines and amino acids [42] and

chiral auxilaries for diastereoselective condensation

reactions [43]. The most exhaustive studies, however, have

been focused on the conformational analyses of diastereomeric

1,3,2-diheterophosphorinanes. A general method for the

preparation of diheterophosphorinanes is the phosphorylation

of differently functionalized, originally chiral 1,3-diols,

1,3-aminoalcohols or 1,3-diamines with P-containing reagents.

During these ring-closures, two diastereomers differing in P

configuration can be obtained because of the stereogenic P

atom and they are usually separable. When both isomers are

available, different NMR methods can be used for the

assignment of the P configuration, and thus for the

determination of the P=O bond orientation. The following

indicators may be suitable for this purpose: (i) 31P NMR

chemical shifts [4, 7, 44, 45]; (ii) 1H chemical shifts due to

the 1,3-diaxial interactions; (iii) changes in 13C chemical

shifts arising from the shielding effect of oxygen; (iv) NOE

effects between the P substituent and ring protons; and (v) 1JP,N

8

coupling constants [46, 47]. 31P NMR spectroscopy has proved

very helpful for distinguishing between the related P-epimers.

In general, the isomer with the phosphoryl group axial absorbs

downfield of the isomer with the phosphoryl group equatorial.

Anomalous 31P chemical shifts have been reported for isomeric

phosphorinane structures [3, 4, 48], but have been left

unexplained or have been interpreted in terms of a chair to chair

[49] or a chair to twist-boat equilibration [24]. Hence, other

corroborative NMR parameters (such as characteristic 1H and 13C

NMR shifts) are needed in these cases for identification of

the diastereomers. Most electronegative substituents (e.g. Cl or

OR) prefer the axial position on P, with the important

exceptions of amino or substituted amino groups, which tend to

assume an equatorial location. The axial preference is

generally ascribed to the anomeric effect, i.e. stabilization of

n-* interactions between the lone pair electrons on the ring

heteroatom and the axial * P-X orbital [5], in combination

with reduced 1,3-syn-diaxial repulsions. Alkyl and aryl groups

usually prefer the equatorial position, the preference

increasing with the bulk of the substituent. The single

diastereomers display conformational flexibility in solution,

9

and the axial or equatorial propensity of a certain P

substituent can shift the conformational equilibrium, to some

extent, towards the conformer in which its orientation is

preferred. The specific conformational behaviour of these P-

containing rings has been handled in terms of a chair-

alternative boat or a chair-twist equilibrium, and the coupling

constants 3JH,H and 3JH,P have proved to be useful indicators of

possible dynamic processes [5-7]. A typical feature of 2-oxo-

1,3,2-diheterophosphorinanes, which exist predominantly in one

conformation in solution, is the combination of large 3JH,P

values for the protons equatorial to and hence antiperiplanar

to the P, and small 3JH,P values for the axial protons synclinal

to the P.

3. SYNTHESIS AND CONFORMATIONAL STUDY OF RING-CONDENSED

1,3,2-DIHETEROPHOSPHORINANES

3.1. 1,3,2-Diheterophosphorinanes condensed to a five-membered

carbo- or heterocyclic ring

In order to clarify the mode of action of natural second

messenger cyclic nucleoside monophosphates (1: cAMP and 2:

cGMP), the conformational behaviour of different analogous P-

10

derivatized dioxaphosphorinanes has been intensively studied

by means of NMR and crystallographic methods, which have

revealed that the six-membered cyclic phosphates, phosphonates

and phosphoramidates fused trans to a ribofuranose ring can

exist as equilibrium mixtures of chair and twist forms [3-7]

(Scheme 1). The interactions of natural cyclic nucleosides

with the active sites of the enzyme and therefore their

biological activities have been suggested to occur through the

pseudo-axial phosphoryl oxygen of the twist conformer.

Scheme 1

The same chair-twist equilibrium was observed for differently P-

substituted cyclopentane-fused model compounds, revealing that

the P configuration and the nature of the P substituent can

affect this conformational equilibrium, similarly as in the

cyclic nucleotides, decreasing or increasing the contribution

of one of the possible conformers [50]. Thus, the cis isomers (X

11

cis to H1) 3a8a and the trans isomers (X trans to H1) 9b and 10b

adopt exclusively the chair conformation, due to the axial

preferences of the OMe, OPh and Cl substituents in 3a8a and to

the equatorial tendency of NMe2 in 9b and 10b (Scheme 2). When

the OMe, OPh or Cl group (X) is situated equatorially in 3b8b,

its axial propensity drives the equilibrium toward the twist

conformer, where it can take up a pseudo-axial position. The

opposite is true for the axial NMe2 in 9a and 10a. Moreover,

the chair-twist equilibrium has been shown to be solvent-

sensitive.

Scheme 2

However, 2-oxo-1,3,2-dioxaphosphorinanes with cis-annelated to a

xylofuranose or cyclopentane ring, can adopt other

conformational states [6, 51-53] due to the less strained

12

arrangement of the fused rings [54, 55]. The P-epimeric pairs

of 5(R) and 5(S)-substituted P-OPh cyclic phosphates 1417 with

a cis-fused 1,2-O-isopropylidene--D-xylofuranose moiety, were

synthesised in two steps from 11 by applying a one-pot

hydrolysis–oxidation and Grignard reagent addition protocol

and subsequent phosphorylation of the corresponding 1,3-diol

precursors 12ac and 13ac [51] (Scheme 3). The existence of

certain conformers, or rather their dynamic equilibrium in

solution, was found to depend on the P configuration, and not

only the chair-twist, but also the chair-boat equilibrium was

observed in solution [50]. The coupling constants 3JH,H and 3JH,P

indicated the chair-twist equilibrium for the derivatives ac of

14 and 16 in solution, while in the solid state the chair

conformation was demonstrated to be more favourable by an X-

ray crystallographic study of 14a. In contrast, the strong

pseudo-axial-seeking force of the P-OPh group in 15and17 led

to a chair-boat equilibration in solution, with the exception of

15b, for which a chair-twist equilibrium was deduced. An upfield

shift of the axially oriented H1 signal of the furanose ring,

generated by the anisotropic shielding effect of the aromatic

ring, was noted as a result of the proximity of the H1 and the

13

pseudo-axial OPh group in the boat conformation of 15 and 17

[51, 52]. The contribution of the boat conformer was shown to

increase when the temperature was lowered, and this conformer

was confirmed by an X-ray analysis of 17b in the solid state.

Scheme 3

Despite the unfavourable equatorial orientation of the OPh

substituent in the chair conformer of 15, this conformation

becomes predominant when substituent R is a hydroxymethyl

group [53] (Scheme 3, 15d). The free OH function in 15d can

stabilize the chair form by intramolecular H-bonding with the

14

phosphoryl oxygen atom; as indicated by NMR and computational

calculations, this interaction can overcompensate the axial

preference of the OPh group.

Besides the previously-mentioned T, C1 and B1 forms

additional chair (C2) and distorted boat (B2) conformations have

been suggested for cyclic phosphates cis-fused to a cyclopentane

ring [56] (Scheme 4). However, on the basis of 1H NMR

measurements the existence of C2 was excluded for both P

epimers of 2-oxo- and 2-thio-1,3,2-dioxaphosphorinane

derivatives 1825, its non-occurrence being explained by the

strong steric interaction between the cis-fused phosphate and

cyclopentane rings. Accordingly, the cis phosphates (Y cis to H1)

18a23a and the trans isomers (X trans to H1) 24b and 25b were

demonstrated to populate almost exclusively the same C1

conformation as observed for 3’,5’-xylo-cAMP analogues [55]

with OMe, OPh or Cl in the preferred axial orientation in

18a23a, and with equatorial NMe2 in 24b and 25b. At the same

time, 18b23b, 24a and 25a were reported to exist as C1 B2

[55], rather than T C1 or C1 B1 equilibrium mixtures.

15

Scheme 4

However, conformation B2 can become predominant for the

epimeric pairs of D-ring-fused 1,3,2-dioxaphosphorinanes and

also for their 1,3,2-oxazaphosphorinane analogues, where the

five-membered ring D is part of a more rigid estrane

framework. In this regard, we recently reported the syntheses

and stereochemical analyses of dioxa- (2729) and

oxazaphosphorino[16,17]estrone derivatives (30a, 4650) [31,

32, 57] obtained from estrone precursors 26 [58, 59] and 27

[60] by direct ring-closures with different P reagents or via

phosphorylation of the reduced imines 4145 of 27 with

benzaldehydes 3135 (Scheme 5).

16

Scheme 5

The related epimers a and b of 2729 and 46-50 were separated

by column chromatography and their P configurations were

assigned by means of 31P, 1H and 13C NMR measurements. Analyses

of the coupling constants 3JH,H and 3JH,P and ab initio calculations

for the isomers of 2730 and 4750, supported by single-

crystal X-ray analysis for 27a, revealed that the P-

containing rings of the P-Ph and P-OPh-substituted epimers of

17

27, 28, 4650 and the only isolated isomer 30a, all exist in

a distorted boat conformation B2, both in solution and in the

solid state, regardless of the P configuration and the

substituent preferences (Scheme 6). The P substituent is

situated pseudo-axially in the a series (Y cis to H17), and

pseudo-equatorially in the b series (Y trans to H17) of

compounds. An approximately 0.6 ppm upfield shift of the H17

signal generated by the anisotropic shielding effect of the

P-Ph ring in 27a, 30a and 46a50a also supported conformation

B2. Nevertheless, the coupling pattern of 29a and the results

of stereochemical calculations suggested a T C2 equilibrium

mixture strongly shifted towards C2, flattened at the

phosphorus end, in view of the strong equatorial preference

of the N(CH2CH2Cl)2 group. The stereostructures were

demonstrated to be appreciably influenced by the rigidity of

the molecular structure, and the ordinary chair conformation

did not predominate in most cases. The angular methyl group

at C-13 may have a further steric modifying effect on the

preferred conformations.

18

Scheme 6

Besides the above-mentioned steroidal compounds 4650

containing a five-membered ring-condensed 1,3,2-

oxazaphosphorinane moiety, a further noteworthy example (54)

of this structural building block [61] can be found in the

literature with the N atom in a bridgehead position (Scheme

7). The bidentate P-ligand 54 was synthesised from

phosphinylisoxazolidine 51 by the reductive ring-opening and

subsequent ring-closure of 52 with

bis(diethylamino)phenylphosphine, followed by oxidation of the

intermediate phosphinyl-oxazaphosphorinane 53 to afford 54 as

a single diastereomer. Single-crystal X-ray analysis of 54

demonstrated that the oxazaphosphorinane ring adopted a twist

19

conformation with the P(O)Ph2 and P-Ph substituents in a cis

relationship.

Scheme 7

3.2. 1,3,2-Diheterophosphorinanes condensed to a six-membered

carbo- or heterocyclic ring

Bicyclic systems involving a dioxa- and an N-unsubstituted

oxazaphosphorinane moiety trans-fused to a cyclohexane ring were

thoroughly studied by Gorenstein et al. [23, 24, 62, 63] (Scheme

8). It was pointed out that a flexible chair-twist-boat

interconversion can occur in solution to a certain extent,

depending on the P configuration and the P-substituent

preferences. Thus, the P-OAr dioxaphosphorinane isomers 55a58a

and oxazaphosphorinane 60a adopt almost exclusively a chair

conformation in solution, with the OAr substituent in its

20

preferred axial orientation. The strong equatorial-seeking

force of the bis(2-chloroethyl)amino group in 59a, however,

strongly shifts the conformational equilibrium towards the twist-

boat form. The opposite is true for the b series of compounds;

while the NMR measurements supported the existence of the chair

conformer for 59b with an equatorial P-N(CH2CH2Cl)2 substituent,

compounds 55b58b and 60b, containing a P-OAr group, prefer to

adopt the twist-boat form due to the substituent preferences.

Depopulation of the chair conformation was found to occur to the

largest degree for 58b and 60b. Similar results were obtained

for the epimeric pairs a and b of the tetrahydropyran-fused 2-

chloro-1,3,2-dioxaphosphorinane-2-thione derivative 61 [64]

and the bicyclic cyclophosphamide analogue 62 [65]. The

coupling constants indicated that 61a and 62b are

predominantly in the chair, while 61b and 62a are in the twist-

chair conformation, with an axial or pseudo-axial Cl in 61 and

an equatorial or pseudo-equatorial bis(2-chloroethyl)amino

substituent in 62. However, single-crystal X-ray analyses

often reveal stereostructures in which the P-substituent is

situated in a disfavoured position [62, 65]. This can be

21

attributed to the small energy difference between the possible

conformers.

Scheme 8

In order to study the effect of the hetero ring N substituent

on the conformations of 2-[bis(2-chloroethyl)amino]-1,3,2-

oxazaphosphorinane 2-oxide derivatives not only trans- but also

cis-fused to cyclohexane, the N-H (69, 72) [63, 67], N-Me (70,

73) [29, 67] and N-Bn (71, 74) analogues [67] were synthesised

from the corresponding aminoalcohols (6365 and 6668) by

22

treatment with bis(2-chloroethyl)phosphoramidic dichloride in

THF (Scheme 9).

Scheme 9

As concerns the characteristic coupling constants 3JH,H and 3JH,P

of the trans-annelated derivatives 6971, the a series of

compounds (H8a cis to NR2) can presumably exist in an equilibrium

mixture of chair, twist-boat and two kinds of boat conformations

(Scheme 10). While a ca 50/50 mixture of chair/boat-1

conformation was assumed by Gorenstein et al. for 69a on the basis

of 1H and 13C measurements [63], a further detailed NMR study by

Pihlaja et al. also involving 15N NMR spectroscopy [46], on the

23

conformational behaviour of 69a and its N-substituted

derivatives 70a and 71a suggested the existence of the chair-

twist-boat equilibrium with only minor amounts of the two

alternative boat forms [46, 67]. However, conformational

optimization at the MP2 level additionally indicated the

population of the boat-1 conformer in 70a [29]. Moreover, the

nature of the N-3 substituent can affect the equilibration to

varying extents: the contribution of the twist-boat conformer

seems to decrease in the sequence methyl > benzyl > hydrogen

instead of benzyl > methyl > hydrogen, which would be feasible

considering the fact that the amount of the twist-boat

conformation depends on the size of the N substituent. The

anomalous sequence was explained by the unfavourable

interactions between the Ph group and other moieties of the

molecule in the twist form. The twist-boat conformation may be less

preferable for 71a because the benzyl group makes the electron

lone pair of the ring N less available for the nN → *

interaction with the axial P=O bond. The characteristic

couplings of the trans-fused isomers in the b series indicated

the chair conformation for 69b71b with an equatorial NR2

substituent [63, 67]. The geminal coupling between H4ax and H4eq

24

(ranging from -11.0 to -11.2) implies the equatorial

orientation of the ring N substituent in 69b71b, while in the

a epimers of 6971 the more negative values demonstrate that R1

displays some tendency to be located axially in the sequence

69a > 71a > 70a. Geometry optimizations utilizing the B3LYP

DFT method and subsequent vibrational analyses also confirmed

that the axial position of the N-3 substituent is less stable

for 69b and 70b and more favourable for 69a and 70a [29].

Scheme 10

The hetero ring of the cis-fused derivatives 7274 can exist in

two different chair conformations (O-in and O-out forms), this

situation being complicated by the possibility of boat and twist-

boat conformations for the a epimers (Scheme 11) [67]. On NMR

analysis of the a series of compounds, the O-in/O-out

25

equilibrium was found to shift towards the O-out conformation

to some extent, in the sequence methyl > benzyl > hydrogen;

the driving force was for the NR2 group to be located

equatorially, though a minor contribution of the twist-1

conformer was also suggested, especially for 74a. In contrast,

the b isomers of 7274 existed largely in the O-in chair

conformation, with NR2 in its preferred orientation.

Scheme 11

Since the substituents of the endocyclic N may exert

considerable effects on the conformation of the

diheterophosphorinane ring, cyclohexane-fused derivatives

containing the N next to the ring annelation position were

26

also examined. Thus, differently P- and N-substituted

oxazaphosphorinanes (8183, 8789, 93, 101103, 107109, 113)

[33, 68] and their diazaphosphorinane analogues (8486, 9092,

94, 104106, 110112, 114116) [14] trans- and cis-fused to

cyclohexane were synthesised from the corresponding

aminoalcohols 7577 and 9597 or diamines 7880 and 98100 with

three different P(V) reagents (Scheme 12). The yields of the

products and the epimeric ratios are listed in Table 1.

27

Scheme 12

28

Table 1. Yields and epimeric ratios of cyclohexane-condensedoxaza- and diazaphosphorinanes [33, 14]

Comp. Y R1 Yield(%)[b]

Ratio(a:b)

[c]

Comp.

Y R1 R2 Yield

(%)[b]

Ratio(a:b)

[c]

81 Ph H 47 [d] 84 Ph H H 29 67:3382b Ph Me 24 [e] 85 Ph H Me 31 36:6483 Ph Bn 33 55:45 86 Ph Me Me 25 55:4587 OPh H 62 48:52 90 OPh H H 47 50:5088 OPh Me 60 50:50 91 OPh H Me 65 49:5189 OPh Bn 58 41:59 92 OPh Me Me 44 50:5093 Mu[a] H 60 45:55 104 Ph H H 11 [d]

101a Ph H 22 [e] 105 Ph H Me 38 68:32102 Ph Me 32 18:82 106 Ph Me Me 22 13:87103 Ph Bn 53 56:44 110 OPh H H 44 52:48107 OPh H 48 73:27 111 OPh H Me 62 55:45108 OPh Me 44 49:51 112 OPh Me Me 67 50:50109 OPh Bn 41 49:51 114 Mu[a] H H 55 62:38113 Mu[a] H 65 50:50 115 Mu[a] H Me 32 43:57

116 Mu[a] Me Me 43 50:50[a]Mu = N(CH2CH2Cl)2[b]Sum of the pure isolated isomers a and b[c]Determined from the 1H NMR spectra of the crude products[d]Not given[e]Single epimerConformational analyses by NMR methods and DFT calculations

revealed that the hetero rings of the trans-fused

oxazaphosphorinanes 8183 and 93, together with the similar

diazaphosphorinanes 8486 and 94, predominantly adopt a chair

conformation, regardless of the P configuration, although in

29

93b and 94b a small proportion of non-chair conformations can be

predicted due to the equatorial preference of the N(CH2CH2Cl)2

group. A similar chair form was assumed for 87b89b and 90b92b,

whereas the conformational equilibrium was shifted towards skew

conformers such as B and T in 87a89a and 90a92a, since the

strong axial preference of the OPh substituent depopulates the

unfavourable chair conformation (Scheme 13). In the cis-fused

compounds 101106, 107112 and 113116, the hetero ring N can be

either axial (N-in) or equatorial (N-out) with the expected chair

conformation of the fused cyclohexane moiety. The axial or

equatorial preference of the P substituents can shift the N-

in/N-out equilibrium in a direction such that the substituents

can occupy their preferred positions in the chair conformation,

but both chair forms can depopulate towards more preferable skew

conformations when the P configuration is unfavourable (Scheme

13). The fragmentations of compounds 81and114 have been

thoroughly studied by means of electron ionization MS [69,

70].

30

Scheme 13

31

Synthetic and conformational studies of

tetrahydroisoquinoline-condensed oxazaphosphorinanes 125131

[71, 72] and diazaphosphorinanes 132136 [26], which are part

of a more rigid system containing their N atom in a bridgehead

position, were carried out by Fülöp et al. (Scheme 14). The

diastereomeric ratios (Table 2) and the conformational

distributions in these tricyclic systems were strongly

influenced by the substituents (R1, R2 and R3) of the starting

aminoalcohols 117119 and diamines 120-124. The fused hetero

rings in compounds 125, 127, 129 and 130136 proved to exist in

an ordinary chair (A)-twist (C) equilibrium, although one or

other of the conformers (A or B) can predominate, depending on

the P configuration and P-substituent preferences. Thus, the

equilibrium is shifted completely towards the chair conformation

A in the oxazaphosphorinanes 125b, 130b and 127b, 129b, due to

the equatorial tendency of the N(CH2CH2Cl)2 and Ph groups.

However, unusual distorted conformational states (C D) with

a planar bridgehead N were reported for both epimers of 126

and 128, with a predominance of conformer C for 126a, 126b and

128b and of conformer D for 128a, where the steric interaction

between the aromatic moiety of the connecting isoquinoline and

32

the Me-1 substituent (R2) can force the hetero ring to adopt

distorted twist conformations. Minor amounts of C and D

besides A and B were also suggested for the N-substituted

diazaphosphorinanes 133b and 134a. The existence of

conformations A and C in the solid state was also confirmed by

X-ray analysis of 125b and 126a. The bis(2-chloroethyl)amino-

substituted benzologues of 1,3,2-diazaphosphorino

isoquinolines (132-136) were found to possess anticancer

activity [73].

33

Scheme 14

34

Table 2. Yields and epimeric ratios of tetrahydroisoquinoline-condensed oxaza- and diazaphosphorinanes

Comp.

R1 R2 Z Yield (%)[b]

Ratio (a:b)[c]

Ref.

125 Me H N(CH2CH2Cl)2 35 50:50 [73]126 H Me N(CH2CH2Cl)2 32 50:50 [73]127 Me H Ph 51 50:50 [73]128 H Me Ph 35 50:50 [73]129 H H Ph 26 50:50 [72]130 H H N(CH2CH2Cl)2 34 50:50 [72]131a[a]

H H Cl 27 - [72]

Comp.

R1 R2 R3 Z Yield (%)[b]

Ratio (a:b)[d]

Ref.

132 H H H Ph 49 56:44 [26]133 H H Ph Ph 40 29:71 [26]134 H H Me Ph 40 27:73 [26]135a[a]

H Me H Ph 44 - [26]

136 Me H H Ph 25 57:43 [26][a]Single epimer[b]Sum of the pure isolated isomers a and b[c]Determined from the 31P NMR spectra of the crude products[d]Determined from the 1H NMR spectra of the crude products

A few benzene-fused dioxa-, oxaza- and diazaphosphorinanes are

also mentioned in the literature, but from pharmacological

35

rather than stereochemical aspects, though the condensed

aromatic moiety further restricts the conformational mobility

of the hetero ring. Nitrobenzocyclophosphamide analogues 137-

140 were synthesised and their antiproliferative activities

were examined on cell cultures (Scheme 15) [12, 74]. Compounds

137 and 139 with benzylic oxygen in the phosphorinane ring para

to the nitro group exhibited modestly enhanced cytotoxicity in

E. coli nitroreductase and could be suitable “lead” compounds in

the development of special gene-directed enzyme prodrugs. The

antibacterial activities of benzologues 141149 were evaluated

and found effective against Gram-positive and Gram- negative

bacteria at different concentrations [75]. The hybrid

derivatives 150 or 151, involving thiazolidine (150) or

benzothiazine (151) and a benzodiazaphosphorinanone moiety in

the same molecule can be valuable model compounds for research

into new pharmaceuticals [76].

36

Scheme 15

4. SUMMARY

37

The synthetic routes and stereostructural features of

carbo- and heterocycle-condensed tetracoordinate P(V)

diheterophosphorinanes have been discussed in detail.

The extreme sensitivity of the conformational behaviour of

the P ring to substitution in both mono- and poly-cyclic

systems makes these derivatives excellent model compounds for

investigation of the steric and electronic effects of

functional groups in different positions on the hetero ring.

Interest has recently been shifted towards fused

cycloalkane- and heterocycle-condensed derivatives, and new

questions have been raised concerning the bioactivities and

stereostructural properties of these compounds.

The results published so far are already of great value,

but further studies on different structures will be motivated

by the intention to develop new pharmacologically active

agents and to reveal additional important findings on the

stereochemistry of these ring systems.

ACKNOWLEDGEMENTS

Thanks are due to the Hungarian Scientific Research Fund (OTKA

grant TO49366) for financial support.

38

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