Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2017, 19, 5732-5735
Asymmetric Synthesis of (−)-6′-β-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination Gyudong Kim,† Ji-seong Yoon,† Dnyandev B. Jarhad,† Young Sup Shin,† Mahesh S. Majik,† Varughese A. Mulamoottil,† Xiyan Hou,† Shuhao Qu,† Jiyong Park,‡ Mu-Hyun Baik,‡ and Lak Shin Jeong*,† †
Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 151-742, Korea Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon, 34141, Korea
‡
S Supporting Information *
ABSTRACT: (−)-6′-β-Fluoro-aristeromycin (2), a potent inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, has been synthesized via stereoselective electrophilic fluorination followed by a purine base build-up approach. Interestingly, purine base condensation using a cyclic sulfate resulted in a synthesis of (+)-5′-β-fluoro-isoaristeromycin (2a). Computational analysis indicates that the fluorine atom controlled the regioselectivity of the purine base substitution.
(trimethylsilyl)difluoride (TASF).5 The key fluoroazide 5 was converted to the desired product 2 using a the linear base buildup approach. However, these fluorination-containing approaches required many steps to prepare the substrates 4a and 7a for fluorination and had low overall yields. Furthermore, the opening of racemic epoxide 3 with sodium azide was not regioselective (4a:4b = 1:1) and the opening of chiral epoxide 6 was only moderately regioselective (7a:7b = 4:1).5b Thus, it was highly desirable to develop a stereoselective fluorination method with a substrate that could be efficiently prepared. In the present work, stereoselective electrophilic fluorination of the silyl enol ether 13 was employed for the synthesis of the key fluoroketone 9β, which could be elaborated to the desired (−)-2. It was also previously reported that the 6-α-fluoro epoxide derived from 3 was opened with an adenine anion, but this method showed poor regioselectivity (2:1 ratio) and low yield.5a We thought that these drawbacks might be overcome by employing a cyclic sulfate6 as a carbafuranosyl donor, because of its high electrophilicity and its capacity for regioselectivity under mild conditions. Herein, we report a stereoselective synthesis of optically pure (−)-6′-β-fluoroaristeromycin (2) via a stereocontrolled electrophilic fluorination and the regioselective synthesis of 5′-βfluoro-isoaristeromycin using cyclic sulfate chemistry, starting from D-ribose. As shown in our retrosynthetic plans (Scheme 2), our priority (route I) was to try a Mitsunobu condensation of 12a (R = H) or a direct purine base condensation of 12b (R = Tf),
(−)-Aristeromycin (1),1 isolated from Streptomyces citricolor, is a representative carbocyclic nucleoside that exists in Nature (Figure 1). This compound is a potent inhibitor of S-
Figure 1. Structures of (−)-aristeromycin (1) and its analogue 2.
adenosylhomocysteine (AdoHcy) hydrolase2 and shows potent antiviral activities against several RNA and DNA viruses. It was first synthesized as a racemate by Clayton and his co-worker,3 and its enantioselective synthesis4 has since been reported. Based on a bioisosteric rationale, racemic mixtures of 6′substituted aristeromycin analogues were also synthesized and evaluated for their inhibitory activity against AdoHcy hydrolase.5a Among these, (±)-6′-β-fluoro-aristeromycin (2) exhibited the most potent inhibitory activity against AdoHcy hydrolase. Thus, the synthesis of optically pure (−)-6′-β-fluoro-aristeromycin (2) is an interesting objective because the biological activity is generally only found in one enantiomer, the D-isomer. As illustrated in Scheme 1, previous work demonstrated that racemic (±)-25a as well as optically active (−)-25b could be synthesized via the key fluoroazide 5, which was synthesized by treating the azido alcohols 4a and 7a with triflic anhydride followed by fluorination with tris(dimethylamino)sulfur © 2017 American Chemical Society
Received: August 10, 2017 Published: October 13, 2017 5732
DOI: 10.1021/acs.orglett.7b02470 Org. Lett. 2017, 19, 5732−5735
Letter
Organic Letters
fluoroketone 9β could be prepared through a stereoselective electrophilic fluorination of silyl enol ether 13, which could be easily accessed from 8. Compound 8 could be prepared from 14 by a Michael reaction using a Gilman reagent,8 and 14 could be efficiently derived from D-ribose with our previously published procedure.9 To begin our synthesis (Scheme 3), D-ribose was converted to known 14 in five steps, according to a modified known
Scheme 1. Comparison of Previous and Present Synthesis of 2
Scheme 3. Synthesis of β-Fluoroketone 9β
procedure9 using ring-closing metathesis of 15 with Neolyst M2 followed by PDC oxidation. Michael addition of 14 with a Gilman reagent afforded known compound 88 in 70% yield. With 8, the substrate for fluorination in hand, we tried to introduce the β-fluorine at the 6-position. After many experiments, the key fluorination was achieved using the electron-rich silyl enol ether 13 with an electrophilic fluorine source such as Selectfluor or N-fluorobenzenesulfonimide (NFSI). The silyl enol ether 13 was prepared by trapping 8 with TESCl in the presence of LiHMDS. The best result for βfluorination was obtained using Selectfluor in DMF at 0 °C (Table 1, entry 4). The ratio of β-fluoroketone 9β and α-
Scheme 2. Retrosynthetic Analysis of (−)-2
Table 1. Stereoselective Electrophilic Fluorination entry
solvent
temp (°C)
time (h)
ratio (9α:9β)a
yield (%)b
1 2 3 4 5
CH3CN CH3CN CH3CN DMF DMF
−10 rt 50 0 rt
48 12 1 12 4
1:1.5 1:2 1:14 1:5.2 1:4.3
62 60 36 91 82
a
Determined by crude 1H NMR. bIsolated total yield after silica gel column chromatography.
to access (−)-2. The second synthetic plan (route II) was to condense the highly electrophilic cyclic sulfate 116,7 with a purine base. Compound 11 could be derived from 9β via the regioselective cleavage of the acetonide as a key step. The last strategy (route III) would utilize the linear purine base build-up approach from amino intermediate 10, which could easily be derived from 12a or 12b. It was envisaged that the β-
fluoroketone 9α depended on the reaction temperature and solvent, giving ratios between 1.5:1 to 14:1 (Table 1). However, reagent-controlled asymmetric fluorination using quinine or quinidine alkaloids did not give any desired product.10 Tactics other than the use of Selectfluor were 5733
DOI: 10.1021/acs.orglett.7b02470 Org. Lett. 2017, 19, 5732−5735
Letter
Organic Letters problematic. For instance, fluorination using NFSI afforded the desired β-fluoroketone 9β in low yield (15%). With the key β-fluorinated substrate 9β in hand, we turned our attention to direct SN2 base condensation, as shown in Scheme 4. Compound 9β was reduced with NaBH4 to give 12a,
dipoles (F and OR) in a developing SN2 transition state, topside steric hindrance caused by the adjacent C6−F and the bulky β-trans pseudoaxial-CH2OtBu groups impedes the attack of incoming sterically bulky and weakly nucleophilic purine bases, hindering the development of the colinear SN2 transition state needed for displacement, resulting in the SN2 reaction not proceeding.11 In contrast, the SN2 displacement of triflate 12b with NaN3 occurred readily since the azide was a linear, less bulky, and a more powerful nucleophile capable of attaining the requisite colinear SN2 transition state, which is made more favorable by the aforementioned dipole-lowering “Vicinal Triflate Effect”, which inductively reduces the adjacent permanent opposing dipoles associated with the C6−F and the C2−O groups. These findings show that Hale’s dipolelowering “Vicinal Triflate Effect” extends to carbafuranose triflates with vicinal dipolar electronegative groups. The azide obtained above was reduced with LAH to afford amine 10, which was converted to the final (−)-2 using the purine base build-up approach.5 Compound 10 was treated with 5-amino-4,6-dichloropyrimidine5 to give a base precursor, which was cyclized with CH3C(O)OCH(OEt)25 to yield 16. Treatment of 16 with tert-butanolic ammonia followed by the removal of protective groups with 67% aq trifluoroacetic acid (TFA) yielded the final product, (−)-6′-β-fluoro-aristeromycin (2). To overcome the failure of the direct SN2 purine base condensation, a cyclic sulfate was proposed as a glycosyl donor, as shown in Scheme 5. Regioselective cleavage of the
Scheme 4. Synthesis of (−)-2 Using the Purine Base Buildup Approach
Scheme 5. Synthetic Approach to (+)-2a Using Cyclic Sulfate Chemistry
which was converted to triflate 12b by treatment with triflic anhydride. 12a and 12b were condensed with 6-chloropurine or N6-Boc-adenine under the Mitsunobu conditions and direct SN2 conditions, respectively, but to our disappointment, Mitsunobu condensation of 12a gave only recovery of starting material and direct SN2 condensation of 12b resulted in the elimination product instead of giving desired condensed product 16 or 17. The failure of the SN2 displacement of the triflate 12b with purine nucleophiles can be explained by Hale’s rules for SN2 displacement of pyranoside and furanoside triflates, which emphasize the great importance of opposing α- and β-steric effects and unfavorable dipolar repulsions in developing SN2 transition states in sulfonate ester systems.11 Although 12b exhibits a favorable “Vicinal Triflate Effect”, wherein a strongly electron-withdrawing OTf lowers adjacent repulsive permanent
isopropylidene group of 12a with trimethylaluminum12 afforded diol 19. Treatment of 19 with thionyl chloride gave the cyclic sulfite, which was immediately oxidized to cyclic sulfate 11.6,7 To our surprise, condensation of 11 with 6chloropurine in the presence of NaH and 18-crown-6 produced isomeric 5′-β-fluoro-isoaristeromycin analogue 20 as a single regioisomer after acidic hydrolysis. The structural determination of 20, using 2D NMR experiments, showed that the C2position had been substituted with 6-chloropurine (see pp S66−S68 in Supporting Information (SI)). This result could be also explained by Hale’s rules.11 Nucleophilic attack at C1 5734
DOI: 10.1021/acs.orglett.7b02470 Org. Lett. 2017, 19, 5732−5735
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ACKNOWLEDGMENTS This work was supported by a grant from the Midcareer Research Program (370C-20160046) of the National Research Foundation, Korea.
would lead to greater dipolar repulsive and steric repulsive interactions in the developing SN2 transition state, but these transition state destabilizing interactions would not be observed for the same reaction at C2. As a result, the C2 displacement proceeded regioselectively. Density functional theory (DFT) calculations were utilized to elucidate the origin of the observed regioselectivity. The reaction energy profile of the SN2 attack of the nucleophile (6chloropurine anion) was computed on the C1 and C2 positions of the cyclic sulfate (see Figure 1S in SI). The nucleophilic substitution steps are rate-determining, bearing the highest energy barriers to the activation: 32.3 kcal/mol for the substitution at C1 and 29.0 kcal/mol for the substitution at C2. The substitution at the 2′-position is favored by 3.3 kcal/ mol, which is in excellent agreement with the experimental outcome where the C2 substituted product is the sole product. To explain the energy preference shown in Figure 1S, fragment analysis was also carried out. The distortion energy penalty for the cyclic sulfate substrate in the transition state for C1substitution was +6.3 kcal/mol higher in energy than that for C2-substitution, which confirmed the preference on 2′substitution (see Figure 2S in SI). Treatment of 20 with tert-butanolic ammonia followed by deprotection with 67% aqueous TFA produced the final isonucleoside (+)-2a. The final compound (−)-2 was assayed for inhibitory activity against AdoHcy hydrolase. As expected, it exhibited potent inhibitory activity (IC50 = 0.37 μM). In conclusion, enantiomerically pure (−)-6′-β-fluoro-aristeromycin (2) was synthesized from D-ribose. The β-fluoro unit was prepared by stereoselective electrophilic fluorination with a readily available silyl enol ether. Our method provides a βfluorinated sugar, which can be extensively utilized for the structure−activity relationship studies of fluorocarbocyclic nucleosides. We also developed a regioselective synthesis of (+)-5′-β-fluoro-isoaristeromycin (2a) using cyclic sulfate chemistry, whose displacement outcome was supported by DFT calculations. It is believed that all chemistry employed in this study can be extensively applied to the synthesis of fluorinated carbocyclic nucleosides.
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S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02470.
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REFERENCES
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ASSOCIATED CONTENT
Experimental procedures; copies of 1H, 13C, and NMR spectra; and DFT energy calculation (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Mu-Hyun Baik: 0000-0002-8832-8187 Lak Shin Jeong: 0000-0002-3441-707X Notes
The authors declare no competing financial interest. 5735
DOI: 10.1021/acs.orglett.7b02470 Org. Lett. 2017, 19, 5732−5735
