Asymmetric Synthesis of (-)-6′-β-Fluoro-aristeromycin via Stereoselective Electrophilic Fluorination

Article abstract of DOI:10.1021/acs.orglett.7b02470

(-)-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.

Full text of DOI:10.1021/acs.orglett.7b02470

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
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). Computa-
tional analysis indicates that the fluorine atom controlled the
regioselectivity of the purine base substitution.
1
5
(
−)-Aristeromycin (1), isolated from Streptomyces citricolor, is
(trimethylsilyl)difluoride (TASF). The key fluoroazide 5 was
a representative carbocyclic nucleoside that exists in Nature
Figure 1). This compound is a potent inhibitor of S-
converted to the desired product 2 using a the linear base build-
up approach. However, these fluorination-containing ap-
proaches 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
(
5b
was only moderately regioselective (7a:7b = 4:1). 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
Figure 1. Structures of (−)-aristeromycin (1) and its analogue 2.
(
−)-2. It was also previously reported that the 6-α-fluoro
2
adenosylhomocysteine (AdoHcy) hydrolase and shows potent
epoxide derived from 3 was opened with an adenine anion, but
this method showed poor regioselectivity (2:1 ratio) and low
yield. We thought that these drawbacks might be overcome
by employing a cyclic sulfate as a carbafuranosyl donor,
because of its high electrophilicity and its capacity for
regioselectivity under mild conditions.
antiviral activities against several RNA and DNA viruses. It wa3s
first synthesized as a racemate by Clayton and his co-worker,
5a
4
and its enantioselective synthesis has since been reported.
6
Based on a bioisosteric rationale, racemic mixtures of 6′-
substituted aristeromycin analogues were also synthesized and
evaluated for their inhibitory activity against AdoHcy hydro-
5
a
Herein, we report a stereoselective synthesis of optically pure
−)-6′-β-fluoroaristeromycin (2) via a stereocontrolled electro-
lase.
(
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-arister-
omycin (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 (±)-2 as well as optically active (−)-2 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
philic fluorination and the regioselective synthesis of 5′-β-
fluoro-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),
5
a
5b
Received: August 10, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Comparison of Previous and Present Synthesis of
2
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
8
1
4 by a Michael reaction using a Gilman reagent, and 14 could
be efficiently derived from D-ribose with our previously
9
published procedure.
To begin our synthesis (Scheme 3), D-ribose was converted
to known 14 in five steps, according to a modified known
Scheme 3. Synthesis of β-Fluoroketone 9β
9
Scheme 2. Retrosynthetic Analysis of (−)-2
procedure using ring-closing metathesis of 15 with Neolyst
M2 followed by PDC oxidation. Michael addition of 14 with a
8
Gilman reagent afforded known compound 8 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 β-
fluorination was obtained using Selectfluor in DMF at 0 °C
(
Table 1, entry 4). The ratio of β-fluoroketone 9β and α-
Table 1. Stereoselective Electrophilic Fluorination
a
b
entry
solvent
temp (°C) time (h) ratio (9α:9β)
yield (%)
1
2
3
4
5
CH CN
−10
rt
48
12
1
1:1.5
1:2
62
60
36
91
82
3
CH CN
3
CH CN
50
0
1:14
1:5.2
1:4.3
3
DMF
DMF
12
4
rt
a
1
b
Determined by crude H NMR. Isolated total yield after silica gel
column chromatography.
to access (−)-2. The second synthetic plan (route II) was to
6
,7
condense the highly electrophilic cyclic sulfate 11 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
10
product. Tactics other than the use of Selectfluor were
B
DOI: 10.1021/acs.orglett.7b02470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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
dipoles (F and OR) in a developing S 2 transition state, top-
N
side steric hindrance caused by the adjacent C −F and the
6
bulky β-trans pseudoaxial-CH OtBu groups impedes the attack
2
our attention to direct S 2 base condensation, as shown in
of incoming sterically bulky and weakly nucleophilic purine
N
Scheme 4. Compound 9β was reduced with NaBH to give 12a,
bases, hindering the development of the colinear S 2 transition
4
N
state needed for displacement, resulting in the S 2 reaction not
N
11
Scheme 4. Synthesis of (−)-2 Using the Purine Base Build-
up Approach
proceeding. In contrast, the S 2 displacement of triflate 12b
N
with NaN occurred readily since the azide was a linear, less
bulky, and a more powerful nucleophile capable of attaining the
3
requisite colinear S 2 transition state, which is made more
N
favorable by the aforementioned dipole-lowering “Vicinal
Triflate Effect”, which inductively reduces the adjacent
permanent opposing dipoles associated with the C −F and
6
the C −O groups. These findings show that Hale’s dipole-
2
lowering “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
5
purine base build-up approach. Compound 10 was treated
5
with 5-amino-4,6-dichloropyrimidine to give a base precursor,
5
which was cyclized with CH C(O)OCH(OEt)2 to yield 16.
3
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 S 2 purine base
N
condensation, a cyclic sulfate was proposed as a glycosyl donor,
as shown in Scheme 5. Regioselective cleavage of the
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
6
N -Boc-adenine under the Mitsunobu conditions and direct
SN2 conditions, respectively, but to our disappointment,
Mitsunobu condensation of 12a gave only recovery of starting
1
2
material and direct S 2 condensation of 12b resulted in the
isopropylidene group of 12a with trimethylaluminum
N
elimination product instead of giving desired condensed
product 16 or 17.
afforded diol 19. Treatment of 19 with thionyl chloride gave
the cyclic sulfite, which was immediately oxidized to cyclic
6
,7
The failure of the S 2 displacement of the triflate 12b with
sulfate 11. To our surprise, condensation of 11 with 6-
chloropurine 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 determi-
nation of 20, using 2D NMR experiments, showed that the C2-
position had been substituted with 6-chloropurine (see pp
S66−S68 in Supporting Information (SI)). This result could be
N
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 S 2
N
11
transition states in sulfonate ester systems. Although 12b
exhibits a favorable “Vicinal Triflate Effect”, wherein a strongly
electron-withdrawing OTf lowers adjacent repulsive permanent
11
also explained by Hale’s rules. Nucleophilic attack at C
1
C
DOI: 10.1021/acs.orglett.7b02470
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
would lead to greater dipolar repulsive and steric repulsive
ACKNOWLEDGMENTS
■
interactions in the developing S 2 transition state, but these
N
This work was supported by a grant from the Midcareer
Research Program (370C-20160046) of the National Research
Foundation, Korea.
transition state destabilizing interactions would not be observed
for the same reaction at C . As a result, the C displacement
2
2
proceeded regioselectively.
Density functional theory (DFT) calculations were utilized
to elucidate the origin of the observed regioselectivity. The
REFERENCES
■
(
1) Kusaka, T.; Yamamoto, H.; Shibata, M.; Muroi, M.; Kishi, T.;
Mizuno, K. J. Antibiot. 1968, 21, 255.
reaction energy profile of the S 2 attack of the nucleophile (6-
N
chloropurine anion) was computed on the C and C positions
(2) (a) De Clercq, E.; Cools, M. Biochem. Biophys. Res. Commun.
1
2
1
985, 129, 306. (b) Marquez, V. E.; Lim, M. Med. Res. Rev. 1986, 6, 1.
c) De Clercq, E.; Bergstrom, D. E.; John, A. H.; Montgomery, J. A.
Antiviral Res. 1984, 4, 119. (d) De Clercq, E. Nat. Rev. Drug Discovery
002, 1, 13.
3) (a) Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1966, 88, 3885.
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
(
2
(
substitution at C and 29.0 kcal/mol for the substitution at
1
C . The substitution at the 2′-position is favored by 3.3 kcal/
2
(b) Shealy, Y. F.; Clayton, J. D. J. Am. Chem. Soc. 1969, 91, 3075.
(c) Shealy, Y. F.; Thorpe, M. C.; Coburn, W. C., Jr.; Clayton, J. D.
Chem. Pharm. Bull. 1980, 28, 3114.
mol, which is in excellent agreement with the experimental
outcome where the C substituted product is the sole product.
2
(4) (a) Arita, M.; Adachi, K.; Ito, Y.; Sawai, H.; Ohno, M. J. Am.
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 C1-
substitution was +6.3 kcal/mol higher in energy than that for
Chem. Soc. 1983, 105, 4049. (b) Yoshikawa, M.; Okaichi, Y.; Cha, B.
C.; Kitagawa, I. Tetrahedron 1990, 46, 7459. (c) Wolfe, M. S.; Lee, Y.;
Bartlett, W. J.; Borcherding, D. R.; Borchardt, R. T. J. Med. Chem.
1
992, 35, 1782. (d) Madhavan, G. V.; Martin, J. C. J. Org. Chem. 1986,
C -substitution, which confirmed the preference on 2′-
2
51, 1287.
substitution (see Figure 2S in SI).
(5) (a) Madhavan, G. V. B.; McGee, D. P. C.; Rydzewski, R. M.;
Boehme, R.; Martin, J. C.; Prisbe, E. J. J. Med. Chem. 1988, 31, 1798.
(b) Yin, X.-Q.; Schneller, S. W. Tetrahedron Lett. 2005, 46, 7535.
Treatment of 20 with tert-butanolic ammonia followed by
deprotection with 67% aqueous TFA produced the final iso-
nucleoside (+)-2a.
The final compound (−)-2 was assayed for inhibitory activity
against AdoHcy hydrolase. As expected, it exhibited potent
inhibitory activity (IC50 = 0.37 μM).
(6) For a review of cyclic sulfites and cyclic sulfates, see: (a) Lohray,
B. B. Synthesis 1992, 1992, 1035. (b) Lohray, B. B.; Bhushan, V. Adv.
Heterocycl. Chem. 1997, 68, 89. (c) Byun, H.-S.; He, L.; Bittman, R.
Tetrahedron 2000, 56, 7051.
(7) (a) Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
In conclusion, enantiomerically pure (−)-6′-β-fluoro-arister-
omycin (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 β-
fluorinated sugar, which can be extensively utilized for the
structure−activity relationship studies of fluorocarbocyclic
nucleosides. We also developed a regioselective synthesis of
(
b) Naik, S. D.; Chandra, G.; Sahu, P. K.; Kim, H.-R.; Qu, S.; Yoon, J.-
S.; Jeong, L. S. Org. Chem. Front. 2016, 3, 1472. (c) Lee, S.; Lee, S.;
Park, H. J.; Lee, S. K.; Kim, S. Org. Biomol. Chem. 2011, 9, 4580.
(
8) (a) Gilman, H.; Jones, R. G.; Woods, L. A. J. Org. Chem. 1952, 17,
630. (b) Song, G. Y.; Paul, V.; Choo, H.; Morrey, J.; Sidwell, R. W.;
Schinazi, R. F.; Chu, C. K. J. Med. Chem. 2001, 44, 3985.
9) (a) Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon, H. R.;
Chun, M. W.; Jung, Y. H.; Jeong, L. S. J. Org. Chem. 2001, 66, 6490.
b) Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S. Tetrahedron:
1
(
(
+)-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.
Asymmetry 2002, 13, 1189. (c) Mulamoottil, V. A.; Nayak, A.; Jeong, L.
S. Asian J. Org. Chem. 2014, 3, 748.
(
10) Shibata, N.; Suzuki, E.; Asahi, T.; Shiro, M. J. Am. Chem. Soc.
001, 123, 7001.
11) (a) Hale, K. J.; Hough, L.; Manaviazar, S.; Calabrese, A. Org.
2
(
Lett. 2014, 16, 4838. (b) Hale, K. J.; Hough, L.; Manaviazar, S.;
Calabrese, A. Org. Lett. 2015, 17, 1738.
ASSOCIATED CONTENT
■
(
12) (a) Takano, S.; Ohkawa, T.; Ogasawara, K. Tetrahedron Lett.
988, 29, 1823. (b) Lee, J. A.; Kim, H. O.; Tosh, D. K.; Moon, H. R.;
Kim, S.; Jeong, L. S. Org. Lett. 2006, 8, 5081.
*
S
Supporting Information
1
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02470.
Experimental procedures; copies of H, 13C, and 19
1
F
NMR spectra; and DFT energy calculation (PDF)
AUTHOR INFORMATION
■
*
Corresponding Author
E-mail: lakjeong@snu.ac.kr.
ORCID
Mu-Hyun Baik: 0000-0002-8832-8187
Lak Shin Jeong: 0000-0002-3441-707X
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.7b02470
Org. Lett. XXXX, XXX, XXX−XXX