Asymmetric Synthesis of Chiral Acyclic Purine Nucleosides Containing

Letter pubs.acs.org/OrgLett

Cite This: Org. Lett. XXXX, XXX, XXX−XXX

Asymmetric Synthesis of Chiral Acyclic Purine Nucleosides Containing a Hemiaminal Ester Moiety via Three-Component Dynamic Kinetic Resolution Ming-Sheng Xie,* Yang-Guang Chen, Xiao-Xia Wu, Gui-Rong Qu, and Hai-Ming Guo* Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, China S Supporting Information *

ABSTRACT: An efficient route to construct chiral acyclic purine nucleosides containing a hemiaminal ester moiety is reported via three-component dynamic kinetic resolution of purines, aldehydes, and acid anhydrides. The procedure provides diverse chiral acyclic purine nucleoside analogues in a regioselective manner with good yields (up to 93% yield) and excellent enantioselectivities (up to 95% ee). Furthermore, the chiral (acyloxyalkyl)-5-fluorouracil could also be generated as a potential prodrug of 5-fluorouracil.

N

(HBV) activity.6 In this structure, a methyl group is linked to the side chain of adefovir. Furthermore, as for chiral acyclic nucleosides, the absolute configuration of the chiral center has proven to play a pivotal role in their relevant biological activities. The (S)-enantiomer of cidofovir demonstrates a higher antiCMV activity than the (R)-enantiomer.7 Thus, developing new methods to synthesize chiral acyclic nucleosides remains a critical scientific goal. Conventional methods to construct chiral acyclic purine nucleoside analogues are based on the nucleophilicity of the N9 moiety in purines.2 Owing to the two (N9−H and N7−H) tautomeric forms in purine, the competitive nucleophilicity of N9 or N7 may result in regioselectivity issues.8 In 2005, the Jacobsen group reported an asymmetric conjugate addition of purines to α,β-unsaturated ketones and imides catalyzed by [(Salen)Al]2O, affording chiral acyclic nucleoside analogues with excellent results (Scheme 1a).9 Later, the Hartwig group developed an asymmetric N-allylation of purines with allylic carbonates catalyzed by single-component metallacyclic iridium complexes, providing N-allylated purines in good yields, up to 96:4 N9/N7, 98:2 branched-linear ratio and 98% ee (Scheme 1b).10 In 2017, the Breit group reported an asymmetric addition of purines to terminal allenes utilizing a Rh/Josiphos catalyst. In doing so, branched allylic purines could be produced in good yields as well as high levels of regio- and enantioselectivities (Scheme 1b).11 However, the general regioselectivity issues of N9/N7 still remained. Herein, we report a new route to construct chiral acyclic purine nucleoside analogues, containing a hemiaminal ester moiety,12 in a regioselective manner via a Lewis base

ucleosides, containing sensitive N-glycosidic bonds, represent crucial building blocks of biological systems (Figure 1).1 Acyclic nucleosides, in which the D-ribose moiety of

Figure 1. Selected acyclic nucleosides with biological activities.

the nucleoside is replaced by an acyclic chain, have demonstrated significant antivirus and antitumor activities.2 Representative examples for such acyclic nucleosides are shown in Figure 1. For example, acyclovir and ganciclovir, containing N-glycosidic bonds, have been approved by the FDA for the treatment of herpes simplex virus (HSV) and cytomegalovirus (CMV), respectively.3 1-(Acyloxyalkyl)-5-fluorouracil exhibits antitumor activities due to the presence of a labile hemiaminal ester moiety that may be cleaved in vivo to generate 5-fluorouracil.4 Chiral acyclic nucleosides usually exhibit different biological activities compared with their achiral analogues. For example, Valtrex and Valcyte represent prodrugs of acyclovir and ganciclovir with improved oral bioavailabilities.5 Compared to adefovir, the chiral acyclic nucleoside tenofovir exhibits higher antihepatitis B virus © XXXX American Chemical Society

Received: January 12, 2018

A

DOI: 10.1021/acs.orglett.8b00135 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

4a was afforded in −63% ee (entry 2). After that, several chiral 4(pyrrolidino)pyridine catalysts were examined as acyl-transfer catalysts.16 In the presence of a Connon-type catalyst (S)-C3,17 adduct 4a was afforded with an increased enantioselectivity of 85% ee (entry 3). Variation on the diarylprolinol moieties of Connon-type catalysts did not lead to improved results (entries 3−5). When the hydroxyl group in (S)-C3 was protected, the ee value of 4a decreased obviously, indicating that the hydroxyl group on the prolinol moiety was essential for the chiral induction (entries 3 vs 5). Subsequently, different alkylamino groups on the pyridine unit of the catalyst were investigated, and 4-azepanyl-derived pyridine (S)-C7 was demonstrated to afford 4a in higher enantioselectivity with 88% ee (entries 3, 6, and 7). Next, auxiliary bases were evaluated (entries 7−10). When i Pr2EtN was used instead of Et3N, the ee value of 4a decreased significantly (entries 7 and 8), indicating that the deprotonation of the hemiaminal group played a pivotal role in the reaction. By using Na2CO3 as a heterogeneous base, the higher ee value of 4a was found (91% ee, entry 10). Furthermore, the ratio of reactants was examined (entries 10−12), and the use of 3 equiv of 2a and 3a resulted in improved results (entry 12). When the reaction temperature was increased from rt to 50 °C, the enantioselectivity was maintained (entries 12 and 13). Upon using 4 Å MS as an additive, the ee value of 4a reached 94% ee with 85% yield (entry 14). Using optimized reaction conditions (Table 1, entry 14), the substrate scope of the aldehydes was explored (Scheme 2). Various aliphatic aldehydes, including straight-chain 2a−e, αbranched 2f,g, β-branched 2h, and cyclic aliphatic aldehydes 2i,j were shown to be suitable for this reaction, affording adducts 4a− j in 72−88% yields and 91−95% ee. The absolute configuration of the chiral acyclic nucleoside analogue 4a was determined to be

Scheme 1. Different Routes To Construct Chiral Acyclic Purine Nucleoside Analogues

catalyzed dynamic kinetic resolution (DKR)13−15 of purines, aldehydes, and acid anhydrides (Scheme 1c). Initially, 6-chloropurine 1a, acetaldehyde 2a, and acetic anhydride 3a were selected as reactants (Table 1). When (S)benzotetramisole C1 was used as catalyst with Et3N as auxiliary base in toluene, the chiral acyclic purine nucleoside analogue 4a, containing a hemiaminal ester moiety, was obtained in 46% yield and 53% ee (entry 1). Fortunately, the reaction proceeded in a regioselective manner and only a N9 adduct could be detected. Then, (S)-homobenzotetramisole C2 was evaluated, and adduct Table 1. Optimization of Reaction Conditionsa

Scheme 2. Substrate Scope of Aldehydesa

entry

cat.

base

1a/2a/3a

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10 11 12 13d 14e

(S)-C1 (S)-C2 (S)-C3 (S)-C4 (S)-C5 (S)-C6 (S)-C7 (S)-C7 (S)-C7 (S)-C7 (S)-C7 (S)-C7 (S)-C7 (S)-C7

Et3N Et3N Et3N Et3N Et3N Et3N Et3N i Pr2EtN K2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3 Na2CO3

1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:1.1 1:1.1:3 1:3:3 1:3:3 1:3:3

46 51 67 45 45 60 62 52 59 61 69 88 87 85

53 −63 85 −42 23 87 88 46 82 91 91 91 91 94

a Unless otherwise noted, 1a (0.1 mmol), catalyst (10 mol %), and base (10 mol %) were added in a test tube. Then 3a, 2a, and toluene (2 mL) were added at rt. bIsolated yield based on 1a. cDetermined by chiral HPLC analysis. A negative ee value signified that the opposite enantiomer of 4a was formed preferentially. dAt 50 °C. e4 Å MS (60 mg) was added.

a Unless otherwise noted, 1a (0.1 mmol), 2 (0.3 mmol), 3a (0.3 mmol), (S)-C7 (10 mol %), Na2CO3 (10 mol %), 4 Å MS (60 mg) in toluene (2 mL) at rt. Isolated yields are reported. The ee values were determined by chiral HPLC analysis. b(R)-C7 was used.

B

DOI: 10.1021/acs.orglett.8b00135 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters the (S)-configuration via single-crystal X-ray diffraction analysis. In the case of pent-4-enal 2k, 2-phenylacetaldehyde 2l, and 3phenylpropanal 2m, the acyclic nucleoside analogues 4k−m were generated in 70−83% yields and 90−95% ee. In addition, when benzaldehyde 2n was used, the desired adduct 4n was obtained in 87% ee albeit with lower yield. Meanwhile, heteroaromatic aldehydes such as picolinaldehyde 2o and furan-2-carbaldehyde 2p were also demonstrated to be suitable substrates for the reaction, delivering the nucleoside analogues 4o,p in 75−78% yields and 83−89% ee. Furthermore, a chiral aldehyde was also explored. When (R)-2,3-O-isopropylideneglyceraldehyde 2q was used, two diastereoisomers 4q and 4q′ were generated in 82% total yield along with a low diastereoselectivity (2:1 dr). Thus, (R)-C7 was used instead of (S)-C7, and the corresponding adducts 4q and 4q′ were obtained with high diastereoselectivity (1:10 dr). Subsequently, different substituted purines were explored in this DKR reaction (Scheme 3). Several substituted purines with

Scheme 4. (a) Functional Group Transformations of 4a. (b) Synthesis of Chiral Acyclic Pyrimidine Nucleoside Analogues

In the case of 5-chlorouracil 6b, the N1 adduct 7b was obtained in 74% yield and 79% ee (Scheme 4b). To help understand the DKR process, several control experiments were carried out (Figure 2). The hemiaminal

Scheme 3. Substrate Scope of Purines and Anhydridesa

Figure 2. Control experiments.

could not be detected by 1H NMR of the crude mixture (Figure 2a). Therefore, we assumed that the addition of 1a to 2a was reversible and very fast. When 6-hydrogen purine 1h was evaluated in the presence of DMAP or (S)-C7, a mixture of N9 hemiaminal ester 5 and N7 hemiaminal ester 5′ was obtained (Figure 2b, entries 1−4).20 The latter finding indicated that the steric hindrance of the substituent group at C6 position of purine significantly influenced the N9/N7 regioselectivity. On the basis of previous reports on the kinetic resolution of alcohols,15b,17,21 a possible mechanism was proposed in Figure 3. First, the addition of purine 1a to aldehyde 2a generated the transient hemiaminal species, including N9 and N7 isomers (A− D). On the other hand, a chiral acylpyridinium cation was generated via (S)-C7 with acetic anhydride 3a. In the transition state Ts I, the N9-hemiaminal A was activated by the H-bonding interaction between the hydroxyl moiety present in the catalyst and the oxygen atom in the N9-hemiaminal A. Meanwhile, the methyl group in the acylated catalyst and purine moiety in the hemiaminal were far away from the bulky Ar groups to reduce repulsion interactions. With the help of an acetate counterion, the nucleophilic reactivity of hemiaminal was enhanced via deprotonation. Thus, N9 hemiaminal A attacked the acylated catalyst to afford the final N9 hemiaminal ester (S)-4a. In TS II, the repulsion between the methyl group in the acylated catalyst and the methyl group in the N9-hemiaminal B led to the slow formation of (R)-4a. As shown in TS III, a repulsion interaction between the methyl group in acylated catalyst and the 6-chloro substituent group in N7-hemiaminal C is believed to be an unfavorable factor in the formation of the N7 hemiaminal ester. In summary, we have reported an efficient route to construct chiral acyclic purine nucleosides, containing a hemiaminal ester

a

Reaction conditions: 1 (0.1 mmol), 2a (0.3 mmol), 3 (0.3 mmol), (S)-C7 (10 mol %), Na2CO3 (10 mol %), 4 Å MS (60 mg) in toluene (2 mL) at rt. Isolated yields are reported. The ee values were determined by chiral HPLC analysis.

halogen, amino, or alkyl sulfide substituents at C2 or C6 position were shown to be suitable for this reaction, affording the adducts 4r−v in 72−93% yields and 88−92% ee. In the case of 6phenylpurine 1g, the chiral acyclic purine nucleoside analogue 4w was generated in 74% ee. Meanwhile, the acylation reagents could be varied from acetic anhydride 3a to propionic anhydride 3b, butyric anhydride 3c, and isobutyric anhydride 3d with similar yields and enantioselectivities. In order to obtain diverse chiral acyclic purine nucleoside analogues, the Suzuki coupling of 4a with PhB(OH)2 was performed, and a 6-phenyl-substituted acyclic purine nucleoside analogue 4w was obtained in 80% yield and 96% ee (Scheme 4a, (i). Meanwhile, the hydrogenation of 4a provided the 6hydrogen purine derived acyclic nucleoside 5a in 87% yield (Scheme 4a, (ii). Considering that 5-fluorouracil remains one of the most widely used antitumor agents18 and 1-(acyloxyalkyl)-5fluorouracil demonstrates antitumor activities, the synthesis of chiral (acyloxyalkyl)-5-fluorouracil as a potential prodrug of 5fluorouracil was attempted.19 The reaction of Bz-protected 5fluorouracil 6a, acetaldehyde 2a, and acetic anhydride 3a was carried out and the chiral acyclic 5-fluorouracil nucleoside analogue 7a was provided in 77% yield and 71% ee (Scheme 4b). C

DOI: 10.1021/acs.orglett.8b00135 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

University of Henan Province (15IRTSTHN003), and the 111 Project (No. D17007).

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Figure 3. Proposed DKR mechanism.

moiety, via dynamic kinetic resolution of purines, aldehydes, and acid anhydrides. In the presence of 4-azepanyl-derived pyridine catalyst (S)-C7 as the acyl-transfer catalyst, a series of aldehydes, substituted purines, and acid anhydrides were shown to be suitable, affording chiral acyclic purine nucleosides in a regioselective manner with good yields (up to 93% yield) and excellent enantioselectivities (up to 95% ee). Furthermore, the chiral (acyloxyalkyl)-5-fluorouracil could also be generated as a potential prodrug of 5-fluorouracil.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00135. Experimental procedures and compound characterization data (PDF) Accession Codes

CCDC 1586362 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hai-Ming Guo: 0000-0003-0629-4524 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the NSFC (Nos. U1604283, 21778014, and 21402041), China Postdoctoral Science Foundation funded project (2016M592293), Program for Innovative Research Team in Science and Technology in D

DOI: 10.1021/acs.orglett.8b00135 Org. Lett. XXXX, XXX, XXX−XXX