Designing Of Polymer Bound Triphenylphosphine Reagents Biology Essay

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Abstract

The spacer that connects polymer backbone with the reactive functional groups often dictates the reactivity which makes the designing of polymer-bound phosphines reagents with various spacers between the polymer backbone and the triphenylphosphine moiety very much crucial for the success of solid phase synthesis. Here, we reported the synthesis of polymer-bound triphenylphosphine with various spacers' length and its utility in intra-molecular Wittig reaction to give biologically active macromolecules.

Chemical Sciences

Designing of polymer-bound triphenylphosphine reagents and its applications in intramolecular Wittig reaction

Lalthazuala Rokhum

Department of Chemistry

North Eastern Hill University

Shillong-796022, India

Introduction

The development and designing of polymeric reagents to suites the growing demands in the field of synthesis is certainly one of the most exciting and spectacular topics in contemporary organic chemistry.1 Recent outburst in the use of polymeric reagents is mainly due to the ease of purification of the reaction mixtures.2 Unlike their soluble counterpart which requires tedious traditional purification process, solid phase synthesis involves an easy purification process i.e filtration, which can be achieved in one step. Synthesis using polymeric reagent facilitated easy automation and an excess reagent could be used to bolster a faster reactions.3 It has also been established that reactions performed in solid phase synthetic pathway are less moisture sensitive due to highly hydrophobic polymer backbone.4 The ease of recycling and reusability of the polymer5 and the simplification of handling a range of toxic or odorous materials added the advantage of using polymeric reagents.

Furthermore, this technique addresses problem of polymerization6 since polymer beads are discrete and reaction between two polymer beads are impossible. A high degree of cross-linking, a low level of functionalization, low reaction temperatures, and the development of electronic charges near the polymer backbone tend to encourage this situation, which may be regarding as mimicking the solution condition of "infinite dilution". In these circumstances intermolecular reaction of bound molecules is prevented, and such attached tends to react intramolecularly.7

For a solid-phase synthesis to be practical, several important issues need to be addressed, including the correct choice of solid support and the mode of attachment and cleavage of materials from the polymer itself.8 Efficiency in anchoring and removing an organic molecule from the polymeric resin relies on the correct choice of the linker as well as the spacer groups.9

Spacer unit may be defined as a link between the polymer backbone and the linkers (Figure 2). The spacer plays a number of roles. Basically, it acts to distance chemistry from the solid support and tailors the swelling properties of the resin materials mimicking a more "solution-like" properties and better solvent compatibility.10 Typical examples of spacers are PEG chains (as in PS-PEG based resins such as TentaGel 111 or resin 212) or alkyl chains as shown in 3. Spacers can therefore alter the cleavage properties of the linker, affecting resin swelling as well as complicating electronic effects. The extra methylene unit present in 4 compared to the classical hydroxymethylpolystyrene resin confers crucial properties such as acid stability13 although possibly sensitivity to β-elimination once loaded.

Figure 1. Polymeric reagents with different spacers' length

Ford et al.14 reported solid phase Wittig reaction using polymer-bound triphenylphosphine which employed a two steps synthetic route. Hughes also has reported the use of a polymer-supported phosphonium moiety in a solid-phase Wittig reaction.15 In another example, Westmann16 has reported the first ever one step microwave-assisted Wittig reaction using polymer-supported triphenyl phosphines with yields ranging from 25-95%.

Scheme 1. Microwave enhanced Wittig reaction

Results and discussion

Interestingly, there is no report on intramolecular Wittig reaction in solid phase. Our initial effort on Wittig reaction, with special emphasis on intramolecular version, with commercially available polymer-bound triphenylphosphine led us to conclude that the reaction was not working well. Therefore, we designed some polymer-bound triphenylphosphines with spacer between the polymer backbone and the triphenylphosphine moiety.

Macrocycles of natural origin or synthetic which show numerous biological activities are synthesized through cyclisation, out of which ring closing metathesis (RCM) approach and solution phase intramolecular Wittig reaction have found wide acceptance. But in both the cases, high dilution is required to retard the intermolecular reaction which is often accompanied by decrease in the yield of products. Hence, a solid phase reaction pathway, which restricts intermolecular reaction, could be expected to be far superior to the existing protocols. In earlier days Wittig reactions were performed mainly in solution phase which requires extremely anhydrous conditions. With the resurrection of solid phase synthesis in recent years, there has been reports where Wittig reactions was performed using polymer-bound triphenyl phosphines owing to the fact that it offers higher hydrophobicity due to the polymer backbone as compared to their soluble counterparts. Moreover, the byproduct of phosphines oxide remains attached to the polymer matrix, which simplifies the purification process.

In spite the aforementioned literature on intermolecular Wittig reaction,14-17 we did not come across any example of intramolecular Wittig reaction that can have tremendous application potential in the synthesis of macrocyclic lactones or lactams. Commonly used strategy for the synthesis of macrocyclic lactones such as intramolecular esterifications, ring closing metathesis of alkenes is prone to undergo polymerization even in very high dilution. Since intramolecular reaction between solid beads are virtually impossible, we envisaged that synthesis of macrocyclic lactone by intramolecular Wittig reaction will essentially eliminate the polymerization issues associated with aforesaid methods. In order optimize the reaction conditions; we initially carried out intermolecular Wittig reaction taking easily available aldehydes. Firstly, we have synthesized polymer-supported methyl(iodo)triphenylphosphonium salt 6 using commercially available polymer-bound triphenylphosphine and methyl iodide following standard literature protocol (Scheme 2).15 We then performed the intermolecular Wittig reaction of the salt with p-chlorobenzaldehyde using NaHMDS as base (Scheme 3).17 The reaction gave very good yield of the desired product 7.

Scheme 2. Synthesis of polymer-bound phosphonium salts

Scheme 3. Inter molecular Wittig reaction

After successfully synthesizing the olefins through the intermolecular Wittig reaction, our next obvious step was to develop an intramolecular Wittig reaction protocol as per our proposal. A model reaction scheme was adopted to evaluate and optimize intramolecular Wittig reaction to synthesize a macrocyclic lactone 10 (Scheme 4). To start with, the phenolic OH group of salicylaldehyde was acylated with commercially available 6-bromohexanoyl chloride in DMF in the presence of triethylamine (2 mmol) and DMAP (0.2 mmol) to achieve the bromo derivative 2-formylphenyl 6-bromohexanoate, 8 in quantitative yield. In the next step, we performed the intramolecular Wittig reaction which was standardized using variety of bases, solvents and reaction conditions as shown in Table 1-2.

Scheme 4. Solid phase intramolecular Wittig reaction

For the success of the Wittig reaction correct choice of base was very much crucial. In order to optimize the reaction conditions, several bases were first studied for intramolecular Wittig reaction using DMF as a solvent under room temperature (Table 1). Unfortunately, none of the bases shown in Table 1 was favorable for the said reaction. After optimization, it was observed that NaHMDS/LiHMDS only gave the desired product (<5%) in very low yield.

Table 1. Optimization of base for intramolecular Wittig reactiona

Entry

Base

Time (h)

Yield (%)b

1

NaOH

16

-

2

K2CO3

16

-

3

KOBut

12

-

4

NaHMDS

12

<5

5

LiHMDS

12

<5

6

n-BuLi

12

-

7

LDA

12

-

aReaction conditions: Phosphonium salt 9 (1.5 mmol), base (3 mmol), DMF (15 mL), 0 oC to rt

bIsolated yields

Since solvent plays pivotal role in solid phase reactions using polymeric resin, because of different swelling properties of resins in different solvents. Therefore, we tried the same reaction in other solvents using NaHMDS as base, the results of which are shown in Table 2. Here too, all the other solvents except DMF were found ineffective as a solvent for Intramolecular Wittig reaction (Table 2, Entry 4). Of course, increasing the reaction time from 12 h to 24 h doubled the yield of product (Table 2, Entry 4) while increase in reaction time from 36 h enhanced the chemical yield only slightly (Table 2, Entry 6). The formation of the product, 3,4,5,6-tetrahydro-2H-benzo[b]oxecin-2-one, 10 was confirmed by various spectroscopic techniques.

Table 2. Optimization of solvent for Wittig reactiona

Entry

Solvent

Time (h)

Yieldb

1

THF

12

-

2

DCM

12

-

3

Diethyl ether

12

-

4

DMF

24

10

5

DMSO

12

-

6

DMF

36

12

aReaction conditions: Phosphonium salt 9 (1.5 mmol), NaHMDS (3 mmol), solvent (15 mL), 0 oC to rt.n bIsolated yields.

As all the attempts to perform an intra-molecular Wittig reaction on the phosphonium salt 9, with varieties of strong base and reaction conditions, to generate the lactone (10) did not give acceptable yields, we reasoned that the closeness of the polymer backbone to that of the reaction centre must be hindering the progress of the reaction. We proposed that introduction of spacer or linker between polymer backbone and reacting phosphines might help to improve overall yield of the reaction. Therefore, we turned our attention toward synthesis of modified polymer-bound triphenylphosphine with various spacer lengths between the polymer backbone and the triphenylphosphine moiety in order to reduce the steric factor arising from the polymer-backbone for the said reaction.

As mentioned earlier, the spacer that connects polymer backbone with the reactive functional groups often dictates the reactivity.10,13 Recently, Koide18 has reported solid phase cross-metathesis, the yields of which are largely spacer lengths dependent. To study the distance-dependent solid phase Wittig reaction and with the expectation of feasible intramolecular Wittig reaction towards the synthesis of macromolecules, we proposed to synthesize a "spacer" of various chain lengths (Figure 2) between polymer back-bone and the triphenylphosphine moiety. These newly synthesized polymer-bound triphenylphosphine were first tested for its efficiency toward intermolecular Wittig reaction as compared to the commercially available polymer-bound triphenylphosphine.

Figure 2. Polymer-bound triphenylphosphines with spacer

After successfully preparing alcohol chain of various alkyl chain lengths, our next focus is to synthesize modified polymer-bound triphenylphosphine for use in the Wittig reaction. Polymer bound triphenylphosphines with varied length of spacer (13a-c) was synthesized by following Scheme 5.

Scheme 5. Synthesis of polymer-bound triphenylphosphine with spacers

For this purpose, we first allowed previously synthesized alcohol 11a to react with commercially available Merrifield resin to form an ether linkage in the polymer system. The polymer was washed successively with DMF, CH2Cl2 and ether, dried under vacuum at 100 oC for 24 h which gave 12a in 92% yield as confirmed by the weight gain of the polymer. Treatment of the brominated polymeric reagent first with n-butyllithium and then with chlorodiphenylphosphine in THF14 gave 13a (˃85% estimated yield). Likewise, 13b and 13c were also synthesized following the same procedure.

Scheme 6. Expansion of spacer using diacids.

Reaction of commercially available Wang resin with dicarboxylic acid (11d) in presence of DCC and DMAP in DMF for 24 h at room temperature afforded the coupled product (15d). This product (15d) further undergo another coupling reaction under the same reaction condition above gave resin (16d). Finally, polymer-bound triphenylphosphines 13d was obtained by treatment of the brominated polymeric reagent first with n-butyllithium and then with chlorodiphenylphosphine in THF14. 15e-f were also synthesized using this procedure.

At this stage, our next target is to perform Wittig reaction with the newly synthesized polymer-bound triphenylphosphine reagent with various spacer lengths. In order to achieve our goal, we first treated compound 13 (a-f) with methyl iodide in dry DMF at 70 oC for three days to get phosphonium salts 14 (a-f) in quantitative yield (Scheme 7).1 Wittig reaction was then performed on the pre-formed phosphonium salt 14(a-f) with p-chlorobenzaldehyde under room temperature to give 1-chloro-4-vinylbenzene17 in variable yield depending upon the types of polymer used for the reactions as shown in Table 2. Yields are compared with Wittig reaction using commercially available polymer-bound triphenylphosphine. Interestingly, there occurred a general trend that longer spacer length gave higher yield of the product as we expect.

Scheme 7. Preparation of phosphonium salts 52a-f

Scheme 8. Intermolecular Wittig reaction

Where PBWS:

Table 3. Wittig reaction of various Wittig salts and aldehydea

Entry

Wittig Salt

Yieldb

1

6

70

2

14a

80

3

14b

80

4

14c

88

5

14d

85

6

14e

86

7

14f

88

aReaction conditions: Phosphonium salt 6, 14a-f (0.10 mmol), aldehyde (0.10 mmol), NaHMDS (0.20 mmol), DMF (1 mL), 0 oC to rt, 6 h. bIsolated yields.

Some interesting observations were made about the effect of spacer length. From the above Table 3, it was concluded that polymer-bound triphenylphosphonium salt of the type 14c could be the most promising polymeric reagent of choice for the intermolecular Wittig reaction even though it gave comparable yield with respect to 14f, owing to the fact that the precursor 13c was easier to prepare than that of 13f. To start with, we took polymer-bound triphenylphosphine 13c (corresponding polymeric reagent of 14c) and allowed it to react with 8 which gave 9b. Finally, an intramolecular Wittig reaction was performed to afford 10 (Scheme 9).

Scheme 9. Intramolecular Wittig reaction

Table 4. Optimization of base for Intramolecular Wittig reactiona

Entry

Base

Time (h)

Yield (%)b

1

NaOH

8

-

2

K2CO3

8

-

3

NaHMDS

6

32

4

LiHMDS

6

21

5

n-BuLi

6

9

aReaction conditions: Phosphonium salt 9b (1.5 mmol), base (3 mmol), DMF (15 mL),

0 oC to rt. bIsolated yields.

Optimization of base was performed using DMF as a solvent under room temperature as shown in Table 4. Amongst various bases trailed, NaHMDS gave maximum yield of the desired product (Table 4, Entry 3). Hence, optimization of solvents was performed using NaHMDS as a base (Table. 5)

Table 5. Optimization of solvent and reaction time for Wittig reactiona

Entry

Solvent

Time (h)

Yield (%)b

1

THF

6

12

2

DCM

6

<5

3

Diethyl ether

6

<5

4

DMSO

6

9

5

DMF

6

32

6

DMF

3

18

7

DMF

8

32

aReaction conditions: Phosphonium salt 9b (1.5 mmol), NaHMDS (3 mmol), solvent (15 mL),

0 oC to rt. bIsolated yields.

It was observed that DMF was a solvent of choice for this reaction giving 32% yield of product in 6 h (Table 5, Entry 6). Increasing the reaction time to 8 h failed to improved the chemical yield (Table 5, Entry 8) where as decreasing the reaction time resulted in lower yield of product (Table 5, Entry 3). From the above data, it could be concluded that our newly synthesized polymer-bound triphenylphosphine with spacers gave higher yield of intramolecular Wittig reaction product 10 (Table 5, Entry 5) as compared to commercially available one (Table 2, Entry 4). Fascinated by this finding, we proposed to extend the methodology to access Phoracantholide (decan-9-olide), a compound isolated from the metasternal secretion of the eucalyptus Pliorncanflia synonyma.19 Due to its biological importance, total synthesis of Phoracantholide was achieved by various research groups round the world.20

Intramolecular Wittig reaction on solid phase: Total Synthesis of (±)-Phoracantholide

Impressed with our finding in the synthesis of small molecule, we now wanted to explore the possibility of performing intramolecular Wittig reaction using our newly synthesized polymer-bound triphenylphosphine of various spacer lengths between the polymer backbone and triphenylphosphine moiety for the synthesis of Phoracantholide, a biolologically active macromolecule (Scheme 10).

Scheme 10. Total synthesis of Phoracantholide

In conclusion, a new class of polymer-bound triphenylphosphines with spacers between polymer backbone and triphenylphosphine moiety was synthesized. For the first time ever, intramolecular Wittig reaction on solid phase using resin-bound triphenylphosphines to generate macrocycle is demonstrated, albeit yield of this method is poor. Using our protocol biologically active lactone (±)-Phoracantholide was synthesized using intramolecular Wittig reaction as a key step.

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