A short de novo synthesis of nucleoside analogs

Article abstract of DOI:10.1126/science.abb3231

Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their syntheses benefit from decades of research but are often protracted, unamenable to diversification, and reliant on a limited pool of chiral carbohydrate starting materials. We present a process for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride displacement reaction provides a functionalized nucleoside analog. The versatility of this process is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids, iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates opportunities for the preparation of diversity libraries and will support efforts in both drug discovery and development.

Full text of DOI:10.1126/science.abb3231

RESEARCH
ORGANIC CHEMISTRY
protected NAs 10 (and hence C2′-modified
NAs), providing flexibility in nucleobase sub-
stitution, and offering a direct route to C4′-
modified NAs. We expect this strategy will
become a powerful tool that will enable and
inspire drug synthesis.
A short de novo synthesis of nucleoside analogs
Michael Meanwell1, Steven M. Silverman2, Johannes Lehmann1, Bharanishashank Adluri1, Yang Wang1,
Ryan Cohen2, Louis-Charles Campeau2, Robert Britton1*
In a proposed prebiotic synthesis of DNA
(22), couplings between nucleobase-type ena-
mines 11 (Fig. 2A) and glyceraldehyde form a
nucleobase iminium ion 12 before the fura-
nose in a ribose-last approach. Our experiences
in ribose synthesis from chlorohydrins (23)
have suggested that N and Cl hemiaminals
are too unstable to serve as precursors to re-
lated nucleobase iminium ions. Thus, as a
synthetic equivalent to 12, we proposed the
fluorinated acyclic NA 13 on the basis of the
broad utility of glycosyl fluorides as sugar
donors. Control over both relative and abso-
lute stereochemistry in 13 may be possible
through an organocatalytic aldol reaction of
a dihydroxyacetone derivative (e.g., 8) (24)
and the a-fluoroaldehyde 14 (25–27). This
approach to NAs would require (i) harness-
ing the reactivity of notoriously unstable
a-fluoroaldehydes (28) coupled with the ad-
ditional challenge of a nucleobase connected
via an N and F hemiaminal (e.g., 14) and (ii)
developing an AFD reaction to form the ri-
bose ring in the last step.
To explore this process, we investigated the
a-fluorination (27) of a-pyrazolyl aldehyde 15
(Fig. 2B) and found that a combination of
L-proline and N-fluorobenzenesulfonimide
(NFSI) in dimethylformamide (DMF) (29) pro-
vided an a-fluorohydrate (table S1) as the sole
product. Although we were unable to dehy-
drate this material, direct addition of dioxa-
none 8 in acetonitrile (MeCN) afforded the
fluorohydrins 16a and 16b in good yield and
enantioselectivity (Fig. 2B, entry 2; see table S1
for full optimization details). Fluorohydrins
16a and 16b were formed as an ~1.4:1 mixture
of epimers at the pseudo-anomeric carbon (in-
dicated with an asterisk in Fig. 2B) that do not
interconvert during the reaction or isolation.
This result is consistent with a slow epimer-
ization of a-pyrazolyl-a-fluoroaldehydes that
precludes a dynamic kinetic resolution (23) or
indicates that the transition structures for the
proline catalyzed aldol reaction between dioxanone
8 and (R)- or (S)-a-pyrazolyl-a-fluoroaldehydes
are energetically similar. Nevertheless, we anti-
cipated that the cyclization event would proceed
through the formation of a transient azacarbe-
nium cation (30), which would render the fluo-
romethine configuration inconsequential. Toward
cyclization (AFD), reduction of the fluorohydrins
16a and 16b provided a mixture of 1,3-syn diols,
and subsequent reaction with the fluorophilic
Lewis acid Sc(OTf)3 afforded the NA 17 as a
singleb-anomer (entry 4). Alternatively, treatment
of the diols 18a and 18b with base (NaOH) re-
sulted in the formation of a mixture of a- and
Nucleoside analogs are commonly used in the treatment of cancer and viral infections. Their
syntheses benefit from decades of research but are often protracted, unamenable to diversification,
and reliant on a limited pool of chiral carbohydrate starting materials. We present a process
for rapidly constructing nucleoside analogs from simple achiral materials. Using only proline
catalysis, heteroaryl-substituted acetaldehydes are fluorinated and then directly engaged in
enantioselective aldol reactions in a one-pot reaction. A subsequent intramolecular fluoride
displacement reaction provides a functionalized nucleoside analog. The versatility of this process
is highlighted in multigram syntheses of D- or L-nucleoside analogs, locked nucleic acids,
iminonucleosides, and C2′- and C4′-modified nucleoside analogs. This de novo synthesis creates
opportunities for the preparation of diversity libraries and will support efforts in both drug
discovery and development.
s fundamental biomolecules, nucleosides
play key roles in diverse cellular pro-
cesses, ranging from cell signaling to
metabolism (1). Not surprisingly, syn-
thetic nucleoside analogs (NAs), which
(13). In recent years, there has also been in-
creased interest in unnaturally configured
NAs (14, 15). For example, the b-L-NA lam-
ivudine (3TC) has found widespread use in the
treatment of HIV-1 and AIDS, and several a-D-
thymidine analogs have demonstrated prom-
ise as antimalarials (16).
A
are designed to mimic their natural counter-
parts, are widely exploited in medicinal chem-
istry (2–6) and used as tool compounds in
chemical biology. NAs have been in use for
more than half a century for the treatment of
cancer (2, 5), and they represent the largest
class of small molecule antivirals (e.g., 1 to 3,
Fig. 1) (3, 4). Mechanistically, after in vivo
phosphorylation, NAs operate as toxic anti-
metabolites (4) and can inhibit enzymes that
are crucial to cancer cell growth or viral replica-
tion (e.g., DNA or RNA polymerases, ribonuc-
leotide reductases, or nucleoside phosphorylases)
(2, 4). Recently, NAs have also demonstrated
promise as epigenetic modulators, and NA in-
hibitors of DNA methyltransferase have been
approved for cancer therapy (4).
Despite intense efforts, NA synthesis still
presents many challenges (17). First, NAs are
often synthesized from naturally occurring
carbohydrates, which limits patterns of sub-
stitution and furanose stereochemistry. Sec-
ond, the addition of nucleobases to activated
ribose derivatives (the Vorbrüggen reaction)
often fails or proceeds with poor diastereo-
selectivity with C2′- or C4′-modified NAs (18, 19).
Third, modifications at C2′ often require mul-
tistep protecting group manipulations, and ef-
ficient strategies for producing C4′-modified
NAs do not exist. In fact, a recent summit of
key opinion leaders highlighted the synthesis
of noncanonical nucleosides as an “emerging
area of high potential impact” (20). Although
efforts to develop de novo NA syntheses have
aimed to address these challenges, the result-
ing processes are often lengthy and target spe-
cific, as highlighted by the 16-step process
required to produce the C4′-modified NA
MK-8591 (2) (19). As a notable example of de
novo NA synthesis, MacMillan and colleagues
have reported the synthesis of C2′-modified
NAs, including the core of sofosbuvir (1), using
a sequence that involved a Mukaiyama aldol
coupling between a ketene acetal (5) and an
a-oxyaldehyde (6) (21). In this work, we disclose
a straightforward NA synthesis that involves a
one-pot, proline-catalyzed a-fluorination and
aldol reaction (aFAR) of heteroaryl-substituted
acetaldehydes 9 followed by reduction or or-
ganometallic addition and annulative fluo-
ride displacement (AFD). This concise (two- to
three-step) process addresses several major
and longstanding challenges in NA synthe-
sis by enabling direct access to C3′- and C5′-
The discovery and development of anticancer
and antiviral NAs builds on several decades of
medicinal chemistry (5, 7, 8). In the early 1980s,
C2′ fluorination was found to improve meta-
bolic stability and influence furanose confor-
mation [PSI-6206 (9): 1] (3, 7, 10). Methylation
at C2′ and modifications to C3′ and C4′ func-
tionalization (e.g., methyl, azido, and alkynyl)
can also influence furanose conformation and
attenuate reactivity of the C3′ and C5′ alcohols
toward chain extension (MK-8591: 2) (8, 11).
Modified nucleobases can often improve NA
potency or drug-like properties, and five-
membered ring heterocycles [e.g., ribavirin
(3)] (12) have been shown to mimic structur-
ally related intermediates that are involved
in de novo purine nucleotide biosynthesis
1Department of Chemistry, Simon Fraser University, Burnaby,
BC V5A 1S6, Canada. 2Department of Process Research and
Development, Merck & Co., Inc., Rahway, NJ 07065, USA.
*Corresponding author. Email: rbritton@sfu.ca
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b-anomeric NAs that varied in composition
depending on reaction conditions (entries 5
and 6). Using an excess of NaOH (entry 6), the
b-anomer 17 was formed as the exclusive pro-
duct in excellent yield. To examine the mech-
anism of cyclization, diols 18a and 18b were
separated and their relative stereochemistry
assigned by J-based configurational analysis
and/or x-ray analysis (see supplementary mate-
rials). Subjecting the purified syn-fluorohydrin
18a to NaOH (Fig. 2C) promoted a clean cycli-
zation to the b-anomer 17 (an SN2 process).
Similarly, the anti-fluorohydrin 18b cyclized
to the a-anomer 19, again through stereo-
chemical inversion. Fortuitously, under these
same basic reaction conditions, the a- anomer
19 epimerizes to afford the more stable and
naturally configured b-anomer 17 (14, 31).
Thus, both fluorohydrin aldol products can
be transformed together into a single naturally
configured b-D-NA through this straightfor-
ward reaction sequence. It is notable that the
enantiomeric purity of 17 (entry 6) represents
an average of the enantiomeric purities of the
epimeric fluorohydrins 16.
To assess the general utility of this NA syn-
thesis, we prepared a collection of acetalde-
hyde derivatives through the alkylation of
several heterocycles with bromoacetaldehyde
diethyl acetal (20) (Fig. 3A; see supplementary
materials for details). Using either Selectfluor
or NFSI as the electrophilic fluorinating agent
(F+), aldehydes 21 underwent proline-catalyzed
aFAR with dioxanone 8 to provide fluorohydrins
22 functionalized with one of the heterocycles
uracil, thymine, triazole, deazadenine, pyrazole,
phthalimide, adenine, or 2,6-dichloropyrimidine.
In the case of the adenine-containing fluoro-
hydrin, the enantiomeric purity was lowered by
competing (nonproline) catalysis in the aFAR.
Each of the fluorohydrins was isolated as a
mixture of epimers at the fluoromethine center
that subsequently underwent a 1,3-syn selective
carbonyl reduction and cyclization promoted
by either base (Fig. 2B) or a Lewis acid (Fig. 2C),
as indicated. We found that several hetero-
cycles were compatible with this process and
that uracil-, thymine-, or adenine-substituted
acetaldehydes could be exploited in short (four-
step total) de novo syntheses of the endogenous
ribonucleosides uridine (U: 24), 5-methyluridine
(m5U: 25), and adenosine (A: 31). Generally,
the optimal Lewis acids for promoting AFD
reactions were InCl3 or Sc(OTf)3, whereas
pyrazole- and uracil-derived fluorohydrins
cyclized using NaOH. With the exception of
triazole 28, trifluoromethyluracil 29, and de-
azaadenines 32 and 33, the NAs were pro-
duced as an approximate average of the
enantiomeric purities of the precursor fluo-
rohydrins 22. Thus, most NAs examined undergo
epimerization after AFD (14), which provides a
straightforward means to convert mixtures of
epimeric aldol products into naturally config-
ured b-D-NAs. For the trifluoromethyl uracil
29 and deazaadenines 32 and 33, aFAR prod-
ucts (e.g., 22) were reduced, separated, and
treated individually with Sc(OTf)3 or InCl3 (Fig.
3C). For trifluoromethyl uracil, only the anti-
fluorohydrin underwent AFD to form 29, which
did not epimerize under the reaction conditions.
With deazaadenine, both the syn-fluorohydrin
and anti-fluorohydrin cyclized to provide the
b- and a-anomers 32 and 33, respectively, by
direct fluoride displacement.
To evaluate the practical utility of these
processes, several of the aFARs were dem-
onstrated on a >10-g scale [e.g., 25, 28, 29,
30, and 32 (Fig. 3)] and proceeded without
complication. C-linked NA 27 could be pre-
pared using this reaction sequence (HetAr =
4,6-dichloropyrimidine), which further extends
the utility of this strategy to an additional
and important class of NAs (32). In this case,
however, the major product of the aldol re-
action cyclizes to an a-D-NA and then under-
goes a second cyclization event to form the
tricycle 27. In addition to naturally config-
ured NAs, this strategy can be adapted for
the synthesis of enantiomeric (L-configured)
NAs (Fig. 3E) by using D-proline in the aFAR.
Thus, L-uridine (ent-24) and the L-configured
NA ent-28 were accessed in a straightforward
manner. Crude reaction products were gener-
ally treated with aqueous acid to remove the
acetonide protecting group, but eliminating
Fig. 1. Nucleoside analogs: objectives and obstacles. WHO, World Health Organization; e.r., enantiomeric ratio.
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this step allowed us to isolate C3′- and C5′-
protected NAs directly (e.g., 34 and 35, Fig.
3D). To demonstrate that these acetonide-
protected NAs can be further derivatized using
standard protocols, several C2′-modified NAs
were prepared, including C2′-oxo (36), C2′-
deoxy (37), C2′-3° alcohol (38), and C2′-epi
(39) (Fig. 3F).
Having ready access to a range of aFAR
products, we anticipated that the addition of
organometallic reagents (rather than hydride
reduction) would lead directly to C4′-modified
NAs. Toward this goal, we examined reactions
of fluorohydrin 41 with a range of organo-
metallic reagents under a variety of reac-
tion conditions (see supplementary materials).
Grignard reagents in CH2Cl2 proved to be most
compatible, and executing the reactions at
−78°C proved necessary because higher re-
action temperatures promoted 1,2-hydride shift
and fluoride displacement. These reactions
generally gave mixtures of tertiary alcohols
with a preference for addition to the re face
(24), and when the crude reaction mixture
was allowed to warm to room temperature,
the intermediate magnesium alkoxide 42a
underwent AFD to provide the C4′-modified
NA 43 directly. This short sequence enables
access to enantiomerically enriched C4′-
modified NAs in only three steps from simple
achiral heterocycles and bromoacetaldehyde
diethyl acetal. Alternatively, quenching the mix-
ture of magnesium alkoxides 42a and 42b
with ammonium chloride followed by a sub-
sequent Lewis acid–promoted AFD using InCl3
gave the anomeric a-D-NA 44. In this case,
the magnesium alkoxides 42a and 42b cy-
clize selectively using base or Lewis acid to
afford access to a-L– and a-D–configured NAs,
which are both unnaturally configured NAs
of contemporary interest to medicinal chem-
ists (14–16).
These results led us to examine the reac-
tion of several additional Grignard reagents
with aldol adducts containing triazole, dea-
zaadenine, thymine, pyrazole, or trifluoro-
methyluracil functions (Fig. 4A). We found
that diastereoselectivity depends on both the
Fig. 2. A short synthesis of
the pyrazolyl NA 17. (A) Ribose-
last approach in a proposed prebiotic
synthesis of nucleosides inspired
a synthetic strategy to NAs.
(B) Proline-catalyzed aFAR, followed
by reduction and AFD. (2.5x),
2.5 equivalence. (C) Mechanistic
studies of the AFD process. NFSI,
N-fluorobenzenesulfonimide;
DMF, dimethylformamide; MeCN,
acetonitrile; OTf, triflate; equiv,
equivalence; ND, not determined.
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solvent and the heterocycle, and reactions in
tetrahydrofuran (THF) generally gave mixtures
of tertiary alcohols of different composition
from those generated in CH2Cl2. The addition
of MeMgI to ketofluorohydrins substituted
with triazole gave predominantly 1,3-syn-diols
that cyclized to the naturally configured
NA 48. Thus, subtle differences in chelation
structures involving the heterocycle and/or
Fig. 3. Scope of nucleoside and
NA synthesis. (A) A simple
four-step reaction sequence
converts readily available starting
materials into enantioenriched and
naturally configured b-D-NAs.
(B) AFD to produce uracil, thymine,
pyrazolyl, and 5-pyrimidinyl
nucleosides; and NAs can be
promoted by NaOH. (C) AFD to
produce trifluoromethyl uracil,
triazolyl, phthalimidyl, deazaade-
nine, and adenosine nucleosides;
and NAs can be promoted by
the Lewis acids Sc(OTf)3 or InCl3.
(D) NAs protected at both the
C3′ and C5′ alcohol functions are
now readily available. (E) Using
D-proline to catalyze the aFAR
reaction, unnatural nucleosides
(L-enantiomers) are now readily
available. (F) Exploiting this conve-
nient process, we prepared a small
collection of C2′-modified NAs.
aTEMPO, BAIB, CH2Cl2 (92% from
34). bi) thiocarbonyldiimidazole,
THF; ii) Bu3SnH, azobisisobutyroni-
trile (55% over two steps from 35).
ci) TEMPO, BAIB, CH2Cl2; ii)
MeMgBr, THF, −78°C (80% over
d
two steps from 34). DAST, CH2Cl2
then HCl, methanol (MeOH)
(53% from 35). TEMPO, 2,2,6,6-
Tetramethylpiperidin-1-yl)oxyl;
BAIB, bis(acetoxy)iodobenzene;
THF, tetrahydrofuran; DAST,
diethylaminosulfur trifluoride;
aq, aqueous; rt, room temperature;
SI, supplementary materials;
d.r., diastereomeric ratio.
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Fig. 4. Rapid synthesis of C4′-modified and other NAs. (A to E) Diversification and large-scale production of aFAR products provide access to C4′-modified NAs,
a
c
iminonucleosides, and LNAs to support medicinal chemistry efforts. Yield from keto-fluorohydrin aldol adduct. bCombined yield of diastereomers. Product after
d
heating of crude reaction mixture to 50°C with camphorsulfonic acid (CSA) and dimethoxyacetone. Product after treatment of crude reaction mixture with aqueous
e
HCl. Starting from a single fluorohydrin 59.
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b-alkoxide function and organomagnesium
reagents play a notable stereodetermining
role in these 1,2-addition reactions. Control-
ling this aspect of the process to selectively
access b-D–configured NAs will be the sub-
ject of future studies. In this study, a col-
lection of deazaadenine-substituted NAs 43
to 47 were readily accessed as both a- and
b-anomers. In general, and as noted in Fig. 3,
base-promoted cyclizations resulted in C3′-OH–
and C5′-OH–protected NAs (e.g., 49 to 54),
whereas Lewis acid–promoted cyclizations re-
sulted in deprotection or protecting group
migration (e.g., 44 and 47). Densely function-
alized L-configured C4′-modified NAs could
be rapidly accessed from the corresponding
ketofluorohydrin aldol adducts, including NAs
substituted with methyl, cyclopropyl, aryl, and
alkynyl groups (Fig. 4). From this study, it is
clear that larger collections of C4′-modified
NAs (e.g., focused screening libraries) are now
readily available. It is worth highlighting
that each of the C4′-methyl, cyclopropyl, p-
methoxyphenyl, p-chlorophenyl, and alkynyl
NAs 43 to 54 were prepared in only three
or four steps total, which compares favorably
to contemporary syntheses.
Considering the potential for this process
to affect the large-scale production of NAs, we
examined the synthesis of the D-uridine de-
rivative 56 starting with 900 g of uracil. With-
out additional optimization, we were able to
generate ~380 g of the aldol adduct 55 (Fig.
2B), which was converted into the protected
uridine 56 in excellent yield. Oxidation of
the C2′-OH function followed by deprotection
and addition of MeMgBr in THF gave the
tertiary alcohol 57. This later compound is a
previously reported intermediate in the large-
scale production of MK-3682 (uprifosbuvir: 58)
(33), an HCV NS5B RNA polymerase inhib-
itor developed for the treatment of hepatitis C
virus (HCV).
We also briefly assessed the utility of this
process for accessing an unusual class of NAs
known as iminonucleosides, wherein the fura-
nose oxygen is replaced by a nitrogen atom. In
a single example (Fig. 4C), we observed that
reductive amination of the fluorohydrin aldol
adduct 59 (isolated as a single diastereomer,
as shown) using benzyl amine and followed
by a basic work-up led directly to the b-D–
configured iminonucleoside 60 in good yield.
To further demonstrate the advantages of
this strategy, we prepared a C4′-modified
deoxy NA (Fig. 4D). In this case, C4′-allyl ri-
bothymidine 61 was accessed through the
addition of allylmagnesium bromide to the
fluorohydrin 59 followed by base-promoted
AFD. A Barton-McCombie deoxygenation then
gave the C4′-allyl NA 62 in only six steps from
thymine.
of locked nucleic acids (LNAs) (34). These
conformationally restricted NAs demonstrate
improved stability, and their incorporation
in antisense oligonucleotides can lead to sub-
stantial increases in specificity and potency.
We evaluated the addition of alkynylmagne-
sium chloride to the thymine-containing aldol
adduct 59 and found that the reaction gave
two diastereomeric addition products 63 and
64. The major product was transformed di-
rectly into the unusual LNA 65 by simply
reacting with NaOH, which promoted both
the AFD reaction and a subsequent cyclization
between the free alcohol function and alkyne.
This four-step total synthesis is comparable
to the 23-step route reported for the analo-
gous uracil LNA 67 (35). We were also able
to generate the unusual alkyne-functionalized
LNA 68, an unreported scaffold in nucleo-
side chemistry, by simply effecting an AFD
of the 1,2-addition product 64. From here,
formation of the 2,2′-anhydrothymidine fol-
lowed by deprotection and treatment with
base in warm DMF (36) gave the LNA 68. This
scaffold is primed for further diversification
through standard click or Sonagashira cou-
pling reactions.
The demonstration of several aFARs on
scales >10 g and up to 400 g supports the
use of this strategy in the process scale pro-
duction of NAs. Several generations of medi-
cinal chemistry and total synthesis have
provided reliable templates for nucleoside
and NA synthesis; however, this study pro-
vides opportunities that should influence the
construction of diversity libraries and support
future efforts in both drug discovery and
development.
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ACKNOWLEDGMENTS
The authors thank D. McKearney (Simon Fraser University) and
J. A. Newman (Merck & Co., Inc.) for carrying out x-ray
crystallographic analyses. Funding: R.B. acknowledges support
from the Canadian Glycomics Network (Strategic Initiatives
Grant, CD-46), the Natural Sciences and Engineering Research
Council (NSERC) of Canada (Discovery Grant, RGPIN-2019-
06468), and Merck & Co., Inc. M.M. was supported by an NSERC
CGSD2 scholarship, and J.L. was supported by the Deutsche
Forschungsgemeinschaft (DFG). Author contributions: M.M.
and S.M.S. developed the methodology; M.M., S.M.S., J.L.,
B.A., and Y.W. performed the experiments; R.C. developed a
protocol for assigning stereochemistry by nuclear magnetic
resonance (NMR) spectroscopic and computational methods;
L.-C.C. and R.B. were responsible for project administration;
R.B. conceptualized the research; L.-C.C. and R.B. supervised
the execution of experiments; and R.B. wrote the original
draft. Competing interests: Simon Fraser University and
Merck & Co., Inc. have filed a patent application describing
the synthesis of nucleoside analogs via the process presented
in this manuscript—U.S. provisional patent application
no. 62/994,349. Data and materials availability: All data
are available in the manuscript or the supplementary
materials. X-ray structures are deposited at the Cambridge
Crystallographic Data Centre under reference numbers 1955427,
2008890, and 1955420.
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SUPPLEMENTARY MATERIALS
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Materials and Methods
Supplementary Text
Figs. S1 to S14
Tables S1 to S12
Liquid Chromatography Chromatograms
NMR Data
References (37–52)
MDAR Reproducibility Checklist
Finally, we aimed to exploit this facile C4′-
functionalization strategy in the preparation
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15 February 2020; accepted 5 June 2020
10.1126/science.abb3231
Meanwell et al., Science 369, 725–730 (2020)
7 August 2020
6 of 6

A short de novo synthesis of nucleoside analogs
Michael Meanwell, Steven M. Silverman, Johannes Lehmann, Bharanishashank Adluri, Yang Wang, Ryan Cohen,
Louis-Charles Campeau and Robert Britton
Science 369 (6504), 725-730.
DOI: 10.1126/science.abb3231
Short path to a complex ring
Nucleotide analogs are valuable tools and therapeutics because of their ability to interfere with processes such as
DNA synthesis, which are vital to rapidly dividing cells and replicating viruses. These molecules are challenging to
synthesize chemically. Meanwell et al. developed a ''ribose last'' synthetic strategy in which a fluorinated acyclic nucleic
acid is formed by an l- or d-proline−catalyzed aldol reaction (see the Perspective by Miller). This intermediate can then be
cyclized to yield the nucleic acid analog in one pot with control of anomeric conformation based on cyclization conditions.
Nucleotide analogs accessible by this strategy include those with modifications at C2 ′ and C4′, purines and pyrimidines,
and locked and protected products.
Science, this issue p. 725; see also p. 623
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