Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular Radical Addition to Aldehyde

Article abstract of DOI:10.1021/jacs.0c06354

Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1-C11 linear chain and is decora

Full text of DOI:10.1021/jacs.0c06354

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Article
Convergent Total Synthesis of Hikizimycin Enabled
by Intermolecular Radical Addition to Aldehyde
Haruka Fujino, Takumi Fukuda, Masanori Nagatomo, and Masayuki Inoue
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c06354 • Publication Date (Web): 06 Jul 2020
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Convergent Total Synthesis of Hikizimycin Enabled by Intermolecular
Radical Addition to Aldehyde
Haruka Fujino,† Takumi Fukuda,† Masanori Nagatomo, and Masayuki Inoue*
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Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
ABSTRACT: Hikizimycin (1), which exhibits powerful anthelmintic activity, has the most densely functionalized structure among
nucleoside antibiotics. A central 4-amino-4-deoxyundecose of 1 possesses 10 contiguous stereocenters on a C1-C11 linear chain and
is decorated with a cytosine base at C1 and a 3-amino-3-deoxyglucose at C6-OH. These distinctive structural features of 1 make it
an extremely challenging target for de novo construction. Herein, we report a convergent total synthesis of 1 from four known
components: 3-azide-3-deoxyglucose derivative 4, bis-TMS-cytosine 5, D-mannose 9, and D-galactose derivative 10. We first de-
signed and devised a novel radical coupling reaction between multiply hydroxylated aldehydes and α-alkoxyacyl tellurides. The
generality and efficiency of this process was demonstrated by the coupling of 7c and 8, which were readily accessible from two
hexoses, 9 and 10, respectively. Et3B and O2 rapidly induced decarbonylative radical formation from α-alkoxyacyl telluride 8, and
intermolecular addition of the generated α-alkoxy radical to aldehyde 7c yielded 4-amino-4-deoxyundecose 6-α with installation of
the desired C5,6-stereocenters. Subsequent attachments of the cytosine with 5 and of the 3-azide-3-deoxyglucose with 4 were realized
through selective activation of the C1-acetal and selective deprotection of the C6-hydroxy group. Finally, the 3 amino and 10 hydroxy
groups were liberated in a single step to deliver the target 1. Thus, the combination of the newly developed radical-coupling and
protective-group strategies minimized the functional group manipulations, and thereby enabled the synthesis of 1 from 10 in only 17
steps. The present total synthesis demonstrates the versatility of intermolecular radical addition to aldehyde for the first time and
offers a new strategic design for multi-step target-oriented syntheses of various nucleoside antibiotics and other bioactive natural
products.
forming reactions4 and acts as a powerful anthelmintic agent
against a variety of common parasites as well as an antibiotic
agent.
INTRODUCTION
Nucleosides are endogenous compounds involved in cellular
processes essential to all living organisms, such as DNA and
RNA synthesis, cell signaling, enzyme regulation, and metabo-
lism. Diverse nucleoside analogues are also found as secondary
metabolites of microbial origin, and are collectively designated
nucleoside antibiotics.1 Whereas endogenous nucleosides com-
prise a nitrogen-containing nucleobase and a furanose, nucleo-
side antibiotics include various structural modifications on both
the nucleobase and sugar moieties, and often possess larger and
more intricate architectures. Reflecting the multiple fundamen-
tal functions of endogenous nucleosides, these antibiotics per-
turb a wide variety of cellular metabolic pathways and thereby
have a broad range of biological activities, including antibacte-
rial, antifungal, antiviral, antitumor, herbicidal, insecticidal, and
immunomodulatory properties. Evolution has optimized the
structures of these natural products for their dedicated functions,
making them promising scaffolds for the development of new
drug leads.2
The exceedingly complex chemical structure and significant
biological activity of 1 have attracted the interest of the chemi-
cal community for many decades.5 Synthetic chemists have in-
vented creative methods to approach the formidable challenges
posed by 1. Four groups, Secrist,6 Danishefsky,7 Fürstner,8 and
Inoue,9 have reported different solutions for the construction of
a protected form of hikosamine (2). None of the groups elabo-
rated the prepared hikosamines into 1, however, highlighting
the difficulties in discriminating and activating specific posi-
tions of the polyhydroxylated chain for the two glycosylations.
Schreiber and Ikemoto disclosed the only total synthesis of 1 in
1990,10 by taking advantage of a latent C2-symmetry within the
hikosamine structure and utilizing two-directional linear trans-
formations for chain extension and oxidation from L-diisopro-
pyl tartrate (3). Selective protection of the polyfunctionalized
intermediates allowed for site-selective introduction of the C1-
cytosine and C6O-kanosamine moieties to produce 1 in 27 steps.
We envisioned devising a new convergent strategy for the to-
tal synthesis of 1 because it is generally more suited for a shorter
route than the linear counterpart, which involves stepwise ma-
nipulations from a simple starting material.11 In particular, our
continued interest in developing radical-based strategies moti-
vated us to integrate a powerful radical coupling reaction into
the synthesis.12,13 Herein, we detail the development of a novel
radical-based route to hikizimycin (1) from 4 simple compo-
nents in 17 steps as the longest linear sequence. The densely
functionalized hikosamine structure was convergently built by
a newly developed radical coupling reaction between an α-
In 1971, hikizimycin (1, a.k.a. anthelmycin, Scheme 1) was
isolated from the fermentation broth of Streptomyces A-5, an
organism obtained from a soil sample collected at the Hikizi
riverside in Kanagawa, Japan.3 Degradation studies of 1 having
a molecular weight 583 identified the presence of a cytosine
base, a 3-amino-3-deoxyglucose sugar (kanosamine), and a
complex long-chain 4-amino-4-deoxyundecose sugar with 1
amino and 10 hydroxy groups (2, hikosamine). Together, these
unique structural features place 1 among the most synthetically
challenging of the nucleoside antibiotic natural products. Com-
pound 1 inhibits protein synthesis by preventing peptide-
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alkoxy radical and an aldehyde. The protective group pattern
adopting the polar reaction.16 Hence, we selected a radical re-
action instead.
of the coupled adduct enabled site- and stereoselective installa-
tions of the two appending structures, ultimately yielding 1.
The new strategy and tactics developed here should have further
applications for the total syntheses of natural products with pol-
yhydroxylated carbon chains.
Radical reactions serve as versatile methods to forge the com-
plex architectures of highly oxygenated natural products be-
cause they are compatible with diverse oxygen and nitrogen
functionalities, and are applicable to the formation of sterically
hindered C–C bonds. Even so, intermolecular radical addition
of carbon radical B to aldehyde 7 would be highly problematic.
As shown in Scheme 2A, the starting carbon radical 11 and al-
dehyde 12 are energetically favored over the generation of
alkoxyl radical 13.17 Thus, β-scission of the product 13 readily
reverses the reaction.
Scheme 1. Structure, Reactions, and Synthetic Plan of Hiki-
zimycin (1)a
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Scheme 2. (A) Calculated Energy of Radical Addition to Al-
dehyde (B) Et3B/O2-Mediated Formation and Reactions of
α-Alkoxy Radical
We previously reported an Et3B/O2-promoted radical cou-
pling using α-alkoxyacyl telluride 14 and electron-deficient
double bonds (Scheme 2B).18 The first part of this reaction in-
volves the generation of an Et radical from Et3B and O2,19 for-
mation of acyl radical C through C–Te homolysis, and decar-
bonylation to produce α-alkoxy radical D.20 Conjugate addition
of D to enone 15 and capture of the resultant radical intermedi-
ate with Et3B then gives boron enolate E and an Et radical. Pro-
tonation of E affords the two-component adduct 16. We de-
cided to exploit this reagent system for aldehyde 17 due to the
facile radical initiating and terminating roles of Et3B. Namely,
Et3B and O2 would initiate the radical process to produce α-
alkoxy radical D from 14 and then terminate the process by the
formation of borinate ester F with ejection of an Et radical. Un-
like the corresponding alkoxyl radical, the polar intermediate F
would not easily undergo the reverse β-scission reaction.21 Fi-
nally, hydrolysis of F would give alcohol 18.
aBz = benzoyl, Trt = trityl, Phth = phthaloyl, TMS = trimethylsilyl.
RESULTS AND DISCUSSION
Synthetic Plan for Hikizimycin. Hikizimycin (1) consists
of three components: kanosamine, cytosine, and hikosamine (2)
(Scheme 1). Accordingly, 1 was retrosynthetically dissected
into the known compounds 414 and 5, and the protected hikosa-
mine 6-α. The C1-anomeric position of 6-α would be activated
as an acetate for introduction of the cytosine, and its C6-alcohol
would be discriminated from other hetero functions for O-gly-
cosylation. In the synthetic direction, reactions with 4 and 5 at
the C1-acetyl acetal and C6-OH must establish the C1- and
C12-stereocenters. To secure the requisite trans-relationship of
the C1/2- and C12/13-substituents, the proximal C2- and C13-
hydroxy groups of 6-α and 4 were to be protected with the ben-
zoyl groups because of their neighboring-group participation
functions. In principle, the differentially protected hikosamine
6-α would be directly assembled by a polar coupling between
anion A and aldehyde 7, or a radical coupling between radical
B and 7.15 The potential for β-elimination of the C4-nitrogen
functionality from A and for undesired reactions of the multiple
acyl protective groups with A, however, prevented us from
These considerations led us to select α-alkoxyacyl telluride 8
as a precursor of radical B (Scheme 1). The sterically cumber-
some C4N-phthalimide group of 8 was expected to control the
trans-relationship of the C4-imide and the C5-carbon chain
upon the radical addition.22 Since we could not predict the C6-
stereoselectivity a priori, stereocontrolling effects of the protec-
tive groups (R) of 7 had to be investigated during the course of
the study (see Scheme 4 below). Compounds 7 and 8 were fur-
ther traced back to D-mannose (9) and D-galactose derivative
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(10), which together carry the 6 stereocenters of the target 1 (C2,
Scheme 3. Synthesis of Differentially Protected Aldehydes
C3, C7, C8, C9, and C10). This utilization of the original chi-
ralities of the two hexoses would greatly contribute to stream-
line the route to 1.23 Hence, our original strategy toward 1 pos-
tulated an optimally convergent route, in which three hexoses
(4, 9, and 10) and silylated cytosine 5 were to be coupled and
elaborated.
7a, 7b, and 7ca
Optimization of Intermolecular Radical Addition Condi-
tions. Our initial effort to devise the key radical coupling was
conducted as a model study using the sugar-derived α-alkoxy-
acyl telluride 1918a and 3-phenylpropanal (20) (Table 1). Me3Al
(entry 1),24 Me2Zn (entry 2),25 and Et3B (entry 3) were selected
as representative radical initiators. Consequently, Et3B was
found to be far superior to Me3Al and Me2Zn for promoting the
radical addition. When 19 and 20 (3 equiv) were treated with
Et3B (5 equiv) in CH2Cl2 under air at room temperature, the req-
uisite adduct 21 was obtained in 28% yield along with 22 (39%),
which was formed through direct hydrogen-atom abstraction
(entry 3).26 In contrast, the use of Me3Al and Me2Zn under air
only generated 2% and 4% of 21, respectively. Lowering the
temperature to -30 °C (entry 4) in the presence of Et3B increased
the yield of 21 to 40%. Thus, the presumed scenario illustrated
in Scheme 2B was realized using simple and mild reaction con-
ditions.
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aReagents and conditions: (a) EtSH, 0.5M HCl in MeOH, 25 °C; (b)
benzoyl chloride (BzCl), pyridine, 25 °C, 51% (2 steps); (c) HgCl2,
HgO, acetone, MeCN, H2O, 60 °C, 99%; (d) tert-butyldiphe-
nylchlorosilane (TBDPSCl), Et3N, molecular sieves 4A, N,N-dimethyl-
4-aminopyridine, THF, 50 °C, 79% (2 steps); (e) (+)-10-camphorsul-
fonic acid ((+)-CSA), (MeO)2CMe2, 25 °C, 70%; (f) n-Bu4NF, THF,
50 °C; (g) BzCl, pyridine, 50 °C, 100% (2 steps); (h) HgCl2, HgO,
CH2Cl2, MeCN, H2O, 25 °C, 7b: 90% from 24, 7c: 97% from 26.
TBDPS = tert-butyldiphenylsilyl.
Table 1. Investigation of Radical Initiatorsa
Scheme 4. Intermolecular Radical Addition of α-Alkoxy
Carbon Radicals to Aldehydesa
yields(%)b
entry
initiator
solvent
21
22
1
2
Me3Al
Me2Zn
Et3B
THF
4
2
10
3
39
47
CH2Cl2
CH2Cl2
CH2Cl2
3
28c
40c,e
4d
Et3B
aConditions: 19 (1 equiv), 20 (3 equiv), initiator (5 equiv), solvent
(0.1M), open air, 25 °C. bYields were calculated from 1H-NMR analy-
c
sis. dr = 1.8 : 1 (entry 3) or 2.4 : 1 (entry 4) (The stereochemistries
d
e
were not determined). Reaction was conducted at -30 °C. Isolated
yield.
In the next model study, we heightened the challenge by in-
creasing the structural complexity of the acceptor from 3-phe-
nylpropanal (20) to the right-half aldehyde 7 of the hikosamine
structure. Prior to the coupling, differentially protected tetra-
benzoyl 7a and bis-acetonide 7b/c were prepared as radical ac-
ceptors (Scheme 3). The pyranose ring of D-mannose (9) was
opened using EtSH and HCl to afford dithioacetal 23. Ben-
zoylation of the four hydroxy groups of 23, followed by hydrol-
ysis of the dithioacetal with mercury salts, gave rise to 7a. Al-
ternatively, the primary alcohol of pentaol 23 was selectively
capped with the TBDPS group and the remaining secondary al-
cohols were protected with the two acetonides by treatment with
2,2-dimethoxypropane and (+)-CSA, leading to 24.27 The pro-
tective group at the primary OH of 24 was transformed from
TBDPS to Bz via the standard 2-step procedure to generate 26.
Dithioacetals 24 and 26 were separately converted to 7b and 7c,
respectively, by HgCl2-mediated hydrolysis.
aConditions: acyltellurides 19 or 27 (1 equiv), aldehyde 7a or 7b (3
equiv), Et3B (5 equiv), CH2Cl2 (0.1M), open air, –30 °C.
Two differentially protected 7a and 7b were submitted to the
radical coupling reactions to evaluate the effects of the protec-
tive groups on the reactivity and stereoselectivity (Scheme 4).
The Et3B/O2-mediated reaction between 19 and 7a under the
optimized conditions in Table 1 indeed furnished the coupling
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adduct 28. The X-ray crystallographic structure of one of the
commercially available D-galactose derivative 10 with BzCl
and pyridine capped the equatorial C2- and C3-OHs and left the
axial C4-OH untouched to afford 31. The hydroxy group of 31
was transformed to the NPhth group of 33 via Tf2O/pyridine-
promoted triflation and subsequent C4-stereochemical inver-
sion using potassium phthalimide (32). Treatment of 33 with
Ac2O in the presence of AcOH and H2SO4 exchanged the me-
thyl and trityl groups for acetyl groups, producing a 1 : 8.3 mix-
ture of 34-α and 34-β. The following 2 steps were used to syn-
thesize pure 34-α.29 The axially-oriented chloride of 35 was in-
stalled by subjecting the C1-diastereomers to MeOCHCl2 and
ZnCl2,30 and was replaced with the equatorial C1-acetoxy group
of 34-α by the action of Hg(OAc)2.31 The primary acetoxy
group of 34-α was then chemoselectively reduced with i-
Bu2AlH, and the liberated primary alcohol of 36 was oxidized
to the corresponding carboxylic acid of 37 using PhI(OAc)2 and
catalytic AZADOL.32 The requisite radical donor 8 was deri-
vatized from 37 in one pot through formation of the activated
ester, followed by attack of an anionic phenyltelluride prepared
from (PhTe)2 and i-Bu2AlH.33
obtained isomers 28-α accentuated the hindered nature of the
newly linked bond between the tetrasubstituted and trisubsti-
tuted carbons. Despite the modest yield (36%) and low C6-ste-
reoselectivity (28-α : 28-β = 1 : 1.1), it was noteworthy that the
highly oxygenated structure with the nine consecutive asym-
metric centers was constructed in a single coupling. The yield
and C6-stereoselectivity were further improved by altering the
acceptor from 7a to 7b. Submission of 19 and 7b to Et3B and
O2 at –30 °C produced a 2.1 : 1 mixture of 29-α and 29-β in
66% yield.28 When the D-ribose-derived 2718a was applied to
the same conditions, 30-α was isolated as a sole isomer in 77%
yield. The second model study also allowed us to define the
structure of the right-half fragment as 7c for the total synthesis
of 1 (Scheme 1). The bis-acetonide moiety of 7c would control
the requisite C6α-stereocenter for 6-α, while the Bz group at
C11-OH of 7c instead of the TBDPS group of 7b would be ben-
eficial for its simultaneous removal with other nucleophile-sen-
sitive protective groups (e.g., C2/3O-Bz and C4N-Phth).
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The radical addition reactions shown in Scheme 4 introduced
the two stereocenters highlighted in pink and cyan circles. The
stereochemical outcomes are attributable to the protective
groups of both the radical donors (19/27) and acceptors (7a/b).
Et3B/O2 promotes the decarbonylative radical formation of G
and H from tellurides 19 and 27, respectively (Scheme 5). The
bond formation at the α-alkoxy position proceeds from the bot-
tom convex face of the acetonide-protected 5/5-cis-fused bicy-
cle of G and H, establishing the pink-highlighted carbon center.
Installation of the cyan-highlighted C6-stereogenic center
would be explained by the conformational preferences of the
acceptors 7a and 7b. Felkin-Ahn-type transition states 7a-α and
7a-β are energetically comparable and both accept the radical
to generate a comparable amount of 28-α and 28-β, respectively.
On the other hand, 7b-β has a severe steric interaction between
the radical and the methyl group of the 6/6-cis-fused bicycle
(highlighted in gray), and thus becomes higher in energy than
7b-α, which leads to the desired C6α-stereochemistry. Hence,
the distinct three-dimensional structure of 7b fixed by the two
acetonides is likely to reflect the selective generation of 29-α
and 30-α.
We next realized the unprecedented intermolecular radical
addition of the densely functionalized fragments 8 to 7c. A
mixture of α-alkoxyacyltelluride 8, aldehyde 7c (3 equiv), and
Et3B (5 equiv) in CH2Cl2 (0.1 M) was exposed to air at -30 °C
to deliver 6-α along with the minor C6-epimer 6-β in 65% com-
bined yield (6-α : 6-β = 2.2 : 1).34 Accordingly, the desired 6-α
with its 10 contiguous stereocenters was constructed by stere-
oselectively forging the hindered C5–C6 bond. As expected
from the model experiments in Scheme 4, the desired C6-selec-
tivity was attributable to the bis-acetonide structure of 7c. On
the other hand, the complete C5-stereoselectivity can be ration-
alized by the three-dimensional arrangement of the C4N-
phthalimide group. Et3B and O2 induce the elimination of
EtTePh and carbon monoxide from telluride 8, thereby abolish-
ing the C5-stereochemical information upon forming α-alkoxy
radical B. Pyran B can adopt the chair form Ba and the boat
form Bb as representative conformations. Although Ba has
more sterically preferred equatorial substituents than Bb, the
C1-radical of Bb is more stereoelectronically favorable than Ba.
Specifically, both Ba and Bb have secondary orbital interac-
tions between the C1-radical and the pyran oxygen lone pair,
yet only Bb has a stabilizing interaction between the singly oc-
cupied orbital and the co-planar σ*-orbital of the C4–N bond.35
As a result, Bb has a lower energy than Ba, which was further
corroborated by the DFT calculation of the stable radical con-
formation at the UM06-2x/6-31+G(d) level of theory (298 K, 1
atm) (Figure 1). The β-oriented bulky C4-NPhth of Bb only
permits an α-approach by 7c to install the correct C5α-stereo-
chemistry. Therefore, the strategically selected protective
groups contributed to the stereoselective construction of the two
tertiary carbons at C5 and C6.
Scheme 5. Rationale for the Stereochemical Outcomes
Total Synthesis of Hikizimycin. Having determined the
conditions and stereocontrolling factors for the crucial radical
coupling, we set out to prepare the radical donor 8 for the total
synthesis of hikizimycin (1) (Scheme 6). Benzoylation of the
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Scheme 6. Total Synthesis of Hikizimycina
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aReagents and conditions: (a) BzCl, pyridine, 25 °C, 58%; (b) trifluoromethanesulfonic anhydride (Tf2O), pyridine, 0 °C; (c) phthalimide potassium
salt (32), DMF, 25 °C, 82% (2 steps); (d) H2SO4, AcOH, Ac2O, CH2Cl2, 25 °C, 80% (34-α: 34-β = 1 : 8.3); (e) MeOCHCl2, ZnCl2, CH2Cl2, reflux;
(f) Hg(OAc)2, AcOH, 25 °C, 92% (2 steps); (g) i-Bu2AlH, THF, -78 °C; (h) 2-hydroxy-2-azadamantane (AZADOL), PhI(OAc)2, MeCN, pH 7 buffer,
85% (2 steps); (i) i-BuOCOCl, N-methylmorpholine (NMM), THF, 0 °C; (PhTe)2, i-Bu2AlH, THF, 25 °C, 88%; (j) Et3B, air, CH2Cl2, -30 °C, 65%
(6-α : 6-β = 2.2 : 1); (k) BnO(=NPh)CF3, trifluoromethanesulfonic acid (TfOH), molecular sieves 5A, 1,4-dioxne, reflux; (l) HS(CH2)3SH, BF3ꞏOEt2,
MeCN, 25 °C; (m) Ac2O, pyridine, 50 °C; (n) 5, trimethylsilyl trifluoromethanesulfonate (TMSOTf), PhNO2, 130 °C; i-PrOH, 25 °C; BzCl, pyridine,
25 °C, 19% (4 steps from a 2.2 : 1 mixture of 6-α and 6-β); (o) 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), CH2Cl2, 60 °C, (p) 4, TMSOTf,
CH2Cl2, 0 °C, 42: 39% (2 steps), 12-epi-42: 22% (2 steps); (q) n-BuNH2, MeOH, reflux; H2, Lindlar catalyst [(5% Pd-CaCO3, Pb(OAc)2, quinoline),
500 wt%], H2O, 25 °C, 50%. Bn = benzyl.
combination of BF3ꞏOEt2 and 1,3-propane dithiol in MeCN
without affecting the potentially reactive C1-acetal or benzyl
ether.37 The resultant tetraol was converted to the correspond-
ing pentaacetate 39 using Ac2O and pyridine. Next, introduc-
tion of the cytosine required rather forcing conditions. The
freshly prepared bis-TMS-cytosine 5 and 39 were heated to
130 °C in PhNO2 in the presence of TMSOTf to induce the for-
mation of the adduct.10,38 The C20-amine was benzoylated with
BzCl and pyridine in one pot, leading to C1α-benzoylcytosine
40 as a single isomer. Prior to the glycosylation of the kanosa-
mine sugar, C6-alcohol was released from benzyl ether 40 by
employing DDQ under anhydrous conditions to produce 41
without removing or transposing the multiple acyl groups.
TMSOTf-promoted glycosylation of 41 with the trichloroace-
timidate 439,40 in turn proceeded at 0 °C, affording C12β-kanos-
amine 42 as the major isomer (42 : 12-epi-42 = 1.8 : 1). There-
fore, the requisite C1α–N and C12β–O linkages were stereose-
lectively formed, presumably because the strategically placed
C2O- and C13O-benzoyl groups secured the trans-addition of
the incoming nucleophiles by neighboring-group participation.
Figure 1. The DFT-optimized structure of radical B (UM06-
2X/6-31G+(d), 298 K, and 1 atm).
Having prepared the protected hikosamine 6-α, the final chal-
lenging task was the stepwise attachments of the cytosine and
kanosamine moieties to this large and complex structure under
acidic conditions. To prepare for these two glycosylations, the
protective groups were manipulated in the following 3 steps.
The C6-alcohol of 6-α was protected as the acid-resistant ben-
zyl ether of 38 using N-phenyl-2,2,2-trifluoroacetimidate and
catalytic TfOH.36 Chemoselective removal of the acid-labile
acetonides of 38 was realized by application of the reagent
The last mission of the total synthesis of 1 from the protected
hikizimycin 42 necessitated detachment of the seven Bz, four
acetyl, and one phthaloyl groups, and reduction of the C14-az-
ide functionality. We developed an efficient one-pot procedure
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to attain these multiple reactions. All 12 acyl groups were sim-
Because of its excellent functional group compatibilities,
radical addition to aldehydes is particularly advantageous for
expeditious construction of densely functionalized molecules.
We hope that the described radical chemistry will provide new
insights for retrosynthetic analyses in the field of organic chem-
istry and have broad applications for the total synthesis of other
bioactive nucleoside antibiotics and natural products.
ultaneously removed by applying n-BuNH2 in refluxing MeOH
to deprotect the 10 hydroxy and 2 amino groups.41 In the same
flask, reduction of the C14-azide substituent was accomplished
chemoselectively over the unsaturated cytosine ring by hydro-
genolysis using the Lindlar catalyst in H2O.10 This protocol
gave rise to the targeted hikizimycin (1) from 42 in 50% yield.
The structural integrity of the fully synthetic 1 with its 15 ste-
reocenters was confirmed by comparing the analytical data, in-
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ASSOCIATED CONTENT
1
cluding H, 13C NMR, IR, and [α]D, with those of the natural
and reported 1.10
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.XXXXXX.
CONCLUSION
Experimental procedures, characterization data, and NMR spectra
of all newly synthesized compounds (PDF)
Crystallographic structure for 28-α (CIF)
In summary, we achieved a convergent total synthesis of
hikizimycin (1) from the three hexose and cytosine structures
(4, 5, 9, and 10). Remarkably, the exceptionally complex struc-
ture of 1 was assembled in 17 steps from 10 without any extra
carbon extension or oxygen atom introduction. The synthetic
route was realized by devising a novel radical coupling strategy
and applying a judicious protective group strategy. First, we
established the conditions for the radical coupling between α-
alkoxyacyl tellurides and aldehydes. Although intermolecular
radical addition to an aldehyde is energetically disfavored, the
reagent combination of Et3B and O2 uniquely promoted the re-
action due to its radical initiating and terminating properties.
Thus, the highly oxygenated radical acceptor 7c and donor 8
were derivatized from 9 and 10, respectively, and coupled by
the action of Et3B and air. This mild, yet powerful reaction
linked the hindered tertiary carbons and installed the desired
C5,6-stereocenters, thereby constructing the hikosamine struc-
ture 6-α with its 10 contiguous stereocenters. The cytosine and
hikosamine moieties were then attached by two TMSOTf-pro-
moted glycosylations in a C1,12-stereoselective fashion. Im-
portantly, the strategically introduced protective groups of the
polyfunctionalized intermediates controlled the stereochemical
outcomes. While the bis-acetonide and C4-NPhth structures fa-
vorably affected the C5α- and C6α-stereoselectivity of the rad-
ical addition, the proximal benzoyl groups secured the C1β- and
C12β-glycosidic linkages. Lastly, transformation of the pro-
tected hikizimycin 42 into 1 were attained in one pot by detach-
ment of the 12 protective groups and hydrogenation of the one
azide function.
AUTHOR INFORMATION
Corresponding Author
*E-mail: inoue@mol.f.u-tokyo.ac.jp
ORCID
Haruka Fujino: 0000-0002-5710-0737
Masanori Nagatomo: 0000-0001-9204-194X
Masayuki Inoue: 0000-0003-3274-551X
Author Contributions
†H.F. and T.F. contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This research was financially supported by Grants-in-Aid for
Scientific Research (S) (JP17H06110), for Scientific Research on
Innovative Areas (JP17H06452) to M.I., for Early Career Scientists
(JP19K15554), and for Scientific Research on Innovative Areas
(JP18H04384) to M.N. from JSPS. Fellowships from JSPS to H.F.
(JP17J09814) and to T.F. (JP19J21221) are gratefully acknowl-
edged.
REFERENCES
(1) (a) Isono, K. Nucleoside Antibiotics: Structure, Biological Ac-
tivity, and Biosynthesis. J. Antibiot. 1988, 41, 1711-1739. (b) Serpi,
M.; Ferrari, V.; Pertusati, F. Nucleoside Derived Antibiotics to Fight
Microbial Drug Resistance: New Utilities for an Established Class of
Drugs? J. Med. Chem. 2016, 59, 10343-10382.
(2) (a) Jordheim, L. P., Durantel, D., Zoulim, F., and Dumontet, C.
Advances in the Development of Nucleoside and Nucleotide Ana-
logues for Cancer and Viral Diseases. Nat. Rev. Drug Discov. 2013, 12,
447-464. (b) Newman, D. J.; Cragg, G. M. Natural Products as Sources
of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019.
J. Nat. Prod. 2020, 83, 770-803.
(3) (a) Hammill, R. L.; Hoehn, M. M. Anthelmycin, a New Antibi-
otic with Anthelmintic Properties. J. Antibiot. 1964, 17, 100-103. (b)
Uchida, K.; Ichikawa, T.; Shimauchi, Y.; Ishikura, T.; Ozaki, A. Hiki-
zimycin, a New Antibiotic. J. Antibiot. 1971, 24, 259-262. (c) Das, B.
C.; Defaye, J.; Uchida, K. The Structure of Hikizimycin. Part 1. Iden-
tification of 3-Amino-3-Deoxy-D-Glucose and Cytosine as Structural
Components. Carbohydr. Res. 1972, 22, 293-299. (d) Uchida, K.; Das,
B. C. Hikosamine, A Novel C11 Aminosugar Component of the Anti-
biotic Hikizimycin. Biochimie 1973, 55, 635-636. (e) Vuilhorgne, M.;
Ennifar, S.; Das, B. C. Structure Analysis of the Nucleoside Disaccha-
ride Antibiotic Anthelmycin by Carbon-13 Nuclear Magnetic
Resonance Spectroscopy. A Structural Revision of Hikizimycin and Its
Identity with Anthelmycin. J. Org. Chem. 1977, 42, 3289-3291.
(4) (a) Uchida, K.; Wolf, H. Metabolic Products of Microorganisms
133* Inhibition of Ribosomal Peptidyl Transferase by Hikizimycin, A
Nucleoside Antibiotic. J. Antibiot. 1974, 27, 783-787. (b) González,
A.; Vázquez, D.; Jiménez, A. Inhibition of Translation in Bacterial and
Eukaryotic Systems by the Antibiotic Anthelmycin (Hikizimycin). Bi-
ochim Biophys Acta. 1979, 561, 403-409.
(5) Knapp, S. Synthesis of Complex Nucleoside Antibiotics. Chem.
Rev. 1995, 95, 1859-1876.
(6) Secrist, J. A., III; Barnes, K. D. Synthesis of Methyl Peracetyl α-
Hikosaminide, The Undecose Portion of the Nucleoside Antibiotic
Hikizimycin. J. Org. Chem. 1980, 45, 4526-4528.
(7) Danishefsky, S. J.; Maring, C. J. A Stereoselective Totally Syn-
thetic Route to Methyl α-Peracetylhikosaminide. J. Am. Chem. Soc.
1989, 111, 2193-2204.
(8) Fürstner, A.; Wuchrer, M. Concise Approach to the “Higher
Sugar” Core of the Nucleoside Antibiotic Hikizimycin. Chem. Eur. J.
2006, 12, 76-89.
(9) We previously devised a radical–radical cross-coupling reaction
for the assembly of protected hikosamine. Because the reaction relied
6
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1
2
3
4
5
6
7
8
9
(b) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chemistry of
Acyl Radicals. Chem. Rev. 1999, 99, 1991-2070.
on the statistical probability of the cross-coupling of the two different
radical intermediates, the desired coupling adduct was obtained in low
yield (17%). Moreover, the protecting group pattern in the resulting
product made a further elaboration into 1 difficult. Masuda, K.; Naga-
tomo, M.; Inoue, M. Direct Assembly of Multiply Oxygenated Carbon
Chains by Decarbonylative Radical–Radical Coupling Reactions. Nat.
Chem. 2017, 9, 207-212.
(10) (a) Ikemoto, N.; Schreiber, S. L. Total Synthesis of the Anthel-
mintic Agent Hikizimycin. J. Am. Chem. Soc. 1990, 112, 9657-9659.
(b) Ikemoto, N.; Schreiber, S. L. Total synthesis of (-)-Hikizimycin
Employing the Strategy of Two-Directional Chain Synthesis. J. Am.
Chem. Soc. 1992, 114, 2524-2536.
(11) (a) Urabe, D.; Asaba, T.; Inoue, M. Convergent Strategies in
Total Syntheses of Complex Terpenoids. Chem. Rev. 2015, 115, 9207-
9231. (b) Allred, T. K.; Manoni, F.; Harran, P. G. Exploring the Bound-
aries of “Practical”: De Novo Syntheses of Complex Natural Product-
Based Drug Candidates. Chem. Rev. 2017, 117, 11994-12051.
(12) Inoue, M. Evolution of Radical-Based Convergent Strategies
for Total Syntheses of Densely Oxygenated Natural Products. Acc.
Chem. Res. 2017, 50, 460-464.
(13) For recent reviews on radical reactions in natural product syn-
thesis, see: (a) Yan, M.; Lo, J. C.; Edwards, J. T.; Baran, P. S. Radicals:
Reactive Intermediates with Translational Potential. J. Am. Chem. Soc.
2016, 138, 12692-12714. (b) Pitre, S. P.; Weires, N. A.; Overman, L.
E. Forging C(sp3)−C(sp3) Bonds with Carbon-Centered Radicals in the
Synthesis of Complex Molecules. J. Am. Chem. Soc. 2019, 141, 2800-
2813. (c) Tomanik, M.; Hsu, I. T.; Herzon, S. B. Fragment Coupling
Reactions in Total Synthesis That Form Carbon-Carbon Bonds via Car-
banionic or Free Radical Intermediates. Angew. Chem. Int. Ed. DOI:
10.1002/anie.201913645.
(21) Several groups reported related radical addition reactions using
simple substrates. Intramolecular reaction: (a) Devin, P.; Fensterbank
L.; Malacria, M. Tin-Free Radical Chemistry: Intramolecular Addition
of Alkyl Radicals to Aldehydes and Ketones. Tetrahedron Lett. 1999,
40, 5511-5514. Addition of THF radical: (b) Yoshimitsu, T.; Tsunoda,
M.; Nagaoka, H. New Method for the Synthesis of α-Substituted Tet-
rahydrofuran-2-Methanols through Diastereoselective Addition of
THF to Aldehydes Mediated by Et3B in the Presence of Air. Chem.
Commun. 1999, 1745-1746. (c) Yoshimitsu, T.; Arano, Y.; Nagaoka, H.
Radical α-C−H Hydroxyalkylation of Ethers and Acetal. J. Org. Chem.
2005, 70, 2342-2345. Application of photoredox initiated hole cataly-
sis: (d) Pitzer, L.; Sandfort, F.; Strieth-Kalthoff, F.; Glorius, F. Intermo-
lecular Radical Addition to Carbonyls Enabled by Visible Light Photo-
redox Initiated Hole Catalysis. J. Am. Chem. Soc. 2017, 139, 13652-
13655. Addition to ketoacids: (e) Xie, S.; Li, D.; Huang, H.; Zhang, F.;
Chen, Y. Intermolecular Radical Addition to Ketoacids Enabled by Bo-
ron Activation. J. Am. Chem. Soc. 2019, 141, 16237-16242.
(22) Roe, B. A.; Boojamra, C. G.; Griggs, J. L.; Bertozzi, C. R. Syn-
thesis of β-C-Glycosides of N-Acetylglucosamine via Keck Allylation
Directed by Neighboring Phthalimide Groups J. Org. Chem. 1996, 61,
6442-6445.
(23) (a) Nicolaou, K. C.; Mitchell, H. J. Adventures in Carbohydrate
Chemistry: New Synthetic Technologies, Chemical Synthesis, Molec-
ular Design, and Chemical Biology. Angew. Chem., Int. Ed. 2001, 40,
1576-1624. (b) Hanessian, S.; Giroux, S.; Merner, B. L. Design and
Strategy in Organic Synthesis. From the Chiron Approach to Catalysis.
Wiley-VCH, 2013.
(24) (a) Liu, J.-Y.; Jang, Y.-J.; Lin, W.-W.; Liu, J.-T.; Yao, C.-F.
Triethylaluminum- or Triethylborane-Induced Free Radical Reaction
of Alkyl Iodides and α,β-Unsaturated Compounds. J. Org. Chem. 2003,
68, 4030-4038. (b) Castle, S. L.; Li, F. Synthesis of the Acutumine Spi-
rocycle via a Radical−Polar Crossover Reaction. Org. Lett. 2007, 9,
4033-4036.
(25) (a) Yamada, K.; Yamamoto, Y.; Tomioka, K. Initiator-Depend-
ent Chemoselective Addition of THF Radical to Aldehyde and Al-
dimine and Its Application to a Three-Component Reaction. Org. Lett.
2003, 5, 1797-1799. (b) Akindele, T.; Yamada, K.; Tomioka, K. Dime-
thylzinc-Initiated Radical Reactions. Acc. Chem. Res. 2009, 42, 345-
355.
(26) Residual H2O functions as a reductant of a radical under these
conditions. Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros,
M. R.; Wood, J. L. Deoxygenation of Alcohols Employing Water as
the Hydrogen Atom Source. J. Am. Chem. Soc. 2005, 127, 12513-
12515.
(27) Dondoni, A.; Marra, A.; Merino, P. Installation of the Pyruvate
Unit in Glycidic Aldehydes via a Wittig Olefination-Michael Addition
Sequence Utilizing a Thiazole-Armed Carbonyl Ylide. A New Stere-
oselective Route to 3-Deoxy-2-Ulosonic Acids and the Total Synthesis
of DAH, KDN, and 4-epi-KDN. J. Am. Chem. Soc. 1994, 116, 3324-
3336.
(28) The C6-stereochmistry of 29-α was established by NMR exper-
iments, and the corresponding O-methylmandelate ester of the C6-al-
cohol was used for structural determination of 30-α. See Supporting
Information for details.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(14) Wang, A. P.; Liu, C.; Yang, S.; Zhao, Z. H.; Lei, P.S. An Effi-
cient Method to Synthesize Novel 5-O-(6’-Modified)-Mycaminose 14-
Membered Ketolides. Tetrahedron 2016, 72, 285-297.
(15) Yang, Y.; Yu, B. Recent Advances in the Chemical Synthesis
of C‑Glycosides. Chem. Rev. 2017, 117, 12281-12356.
(16) For selected examples of applications of glycosyl anions, see:
(a) Carpintero, M.; Nieto, I.; Fernández-Mayoralas, A. Stereospecific
Synthesis of α- and β-C-Glycosides from Glycosyl Sulfoxides: Scope
and Limitations. J. Org. Chem. 2001, 66, 1768-1774. (b) Miquel, N.;
Doisneau, G.; Beau, J. M. Reductive Samariation of Anomeric 2-
Pyridyl Sulfones with Catalytic Nickel: An Unexpected Improvement
in the Synthesis of 1,2-trans-Diequatorial C-Glycosyl Compounds. An-
gew. Chem. Int. Ed. 2000, 39, 4111-4114. (c) Mikkelsen, L. M.; Krintel,
S. L.; Jiménez-Barbero, J.; Skrydstrup, T. Application of the Anomeric
Samarium Route for the Convergent Synthesis of the C-Linked Trisac-
charide α-D-Man-(1→3)-[α-D-Man-(1→6)]-D-Man and the Disaccha-
rides α-D-Man-(1→3)-D-Man and α-D-Man-(1→6)-D-Man. J. Org.
Chem. 2002, 67, 6297-6308. For a review, see: (d) Somsák, L. Carban-
ionic Reactivity of the Anomeric Center in Carbohydrates. Chem. Rev.
2001, 101, 81-136.
(17) (a) Beckwith, A. L. J.; Hay, B. P. Kinetics of the Reversible β-
Scission of the Cyclopentyloxy Radical. J. Am. Chem. Soc. 1989, 111,
230-234. (b) Wilsey, S.; Dowd, P.; Houk, K. N. Effect of Alkyl Sub-
stituents and Ring Size on Alkoxy Radical Cleavage Reactions. J. Org.
Chem. 1999, 64, 8801-8811.
(18) (a) Nagatomo, M.; Kamimura, D.; Matsui, Y.; Masuda, K.; In-
oue, M. Et3B-Mediated Two- and Three-Component Coupling Reac-
tions via Radical Decarbonylation of α-Alkoxyacyl Tellurides: Single-
Step Construction of Densely Oxygenated Carboskeletons. Chem. Sci.
2015, 6, 2765-2769. (b) Matsumura, S.; Matsui, Y.; Nagatomo, M.; In-
oue, M. Stereoselective Construction of anti- and syn-1,2-Diol Struc-
tures via Decarbonylative Radical Coupling of α-Alkoxyacyl Tellu-
rides. Tetrahedron 2016, 72, 4859-4866. (c) Fujino, H.; Nagatomo, M.;
Paudel, A.; Panthee, S.; Hamamoto, H.; Sekimizu, K.; Inoue, M. Uni-
fied Total Synthesis of Polyoxin J, L, and Their Fluorinated Analogues
Based on Decarbonylative Radical Coupling Reactions. Angew. Chem.
Int. Ed. 2017, 56, 11865-11869.
(19) For a review, see: Ollivier, C.; Renaud, P. Organoboranes as a
Source of Radicals. Chem. Rev. 2001, 101, 3415-3434.
(20) For reviews of decarbonylation rates, see: (a) Fischer, H.; Paul,
H. Rate Constants for Some Prototype Radical Reactions in Liquids by
Kinetic Electron Spin Resonance. Acc. Chem. Res. 1987, 20, 200-206.
(29) Compound 34-α was selectively synthesized because we found
that the C1α-stereochemistry was more beneficial for the radical addi-
tion than the C1β-counterpart in separate model experiments. These
experiments also revealed that the superiority of the N-phthaloyl group
to the N-trifluoroacetaamide or N-2,3-dimethylmaleimide at C4. See
the Supporting Information for details.
(30) Kovác, P.; Taylor, R. B.; Glaudemans, C. P. J. General Synthe-
sis of (1→3)-β-D-Galacto Oligosaccharides and Their Methyl β-Gly-
cosides by a Stepwise or a Blockwise Approach. J. Org. Chem. 1985,
50, 5323-5333.
(31) Withers, S. G.; Percival, M. D.; Street, I. P. The Synthesis and
Hydrolysis of a Series of Deoxy- and Deoxyfluoro-α-D-“glucopyra-
nosyl” phosphates. Carbohydr. Res. 1989, 187, 43-66.
(32 ) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. 2-
Azaadamantane N-Oxyl (AZADO) and 1-Me-AZADO: ꢀ Highly
7
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Page 8 of 9
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2
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7
8
9
(39) We modified the route to the known 4 (ref 14), and prepared it
in 4 steps from a commercially available material. See Supporting In-
formation for details.
Efficient Organocatalysts for Oxidation of Alcohols. J. Am. Chem. Soc.
2006, 128, 8412-8413.
(33) Inoue, T.; Takeda, T.; Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda,
N. Synthesis of Thiol, Selenol, and Tellurol Esters from Aldehydes by
the Reaction with iBu2AlYR (Y = S, Se, Te). J. Org. Chem. 1994, 59,
5824-5827.
(34) The C6-stereochemistry of 6-α was determined by CP3 analysis
and confirmed by its derivation into 1. See Supporting Information for
details. Smith, S. G.; Goodman, J. M. Assigning the Stereochemistry
of Pairs of Diastereoisomers Using GIAO NMR Shift Calculation. J.
Org. Chem. 2009, 74, 4597-4607.
(40) (a) Schmidt, R. R.; Michel, J. Facile Synthesis of α- and β-O-
Glycosyl Imidates; Preparation of Glycosides and Disaccharides. An-
gew. Chem., Int. Ed. 1980, 19, 731-732. (b) Zhu, X.; Schmidt, R. R.
New Principles for Glycoside-Bond Formation. Angew. Chem., Int. Ed.
2009, 48, 1900-1934.
(41) Kissman, H. M.; Weiss, M. J. The Synthesis of 1-(Aminode-
oxy-β-D-Ribofuranosyl)-2-Pyrimidinones. New 3'- and 5'-Aminonu-
cleosides. J. Am. Chem. Soc. 1958, 80, 2575-2583.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(35) This orbital interaction of Bb corresponds to a quasi-homo ano-
meric effect. (a) Dupuis, J.; Giese, B.; Rüegge, D.; Fischer, H.; Korth,
H.-G.; Sustmann, R. Conformation of Glycosyl Radicals: Radical Sta-
bilization by β-CO Bonds. Angew. Chem. Int. Ed. 1984, 23, 896-898.
(b) Beckwith, A. L. J.; Duggan, P. J. The Quasi-Homo-Anomeric In-
teraction in Substituted Tetrahydropyranyl Radicals: Diastereoselectiv-
ity. Tetrahedron 1998, 54, 6919-6928. (c) Praly, J.-P. Structure of Ano-
meric Glycosyl Radicals and Their Transformations under Reductive
Conditions. Adv. Carbohydr. Chem. Biochem. 2000, 56, 65-151.
(36) (a) Yu, B.; Tao, H. Glycosyl Trifluoroacetimidates. Part 1:
Preparation and Application as New Glycosyl Donors. Tetrahedron
Lett. 2001, 42, 2405–2407. (b) Okada, Y.; Ohtsu, M.; Bando, M.;
Yamada, H. Benzyl N-Phenyl-2,2,2-Trifluoroacetimidate: A New and
Stable Reagent for O-Benzylation. Chem. Lett. 2007, 992-993.
(37) Konosu, T.; Oida, S. Enantiocontrolled Synthesis of the Anti-
fungal β-Lactam (2R, 5S)-2-(Hydroxymethyl)clavam. Chem. Pharm.
Bull. 1991, 39, 2212-2215.
Table of Contents artwork
(38) (a) Niedballa, U.; Vorbrüggen, H. A General Synthesis of Py-
rimidine Nucleosides. Angew. Chem. Int. Ed. 1970, 9, 461-462. (b)
Vorbrüggen, H.; Ruh-Polenz, C. Synthesis of Nucleosides. Org. React.
1999, 55, 1-624.
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