Synthesis of (2S)-2-Chloro-2-fluororibolactone via Stereoselective Electrophilic Fluorination

Article abstract of DOI:10.1021/acs.joc.7b02245

A novel and efficient route for the preparation of (2S)-2-chloro-2-fluorolactone 29 is described. This approach takes advantage of a highly efficient diastereoselective electrophilic fluorination reaction (94% yield; >50:1 dr)

Full text of DOI:10.1021/acs.joc.7b02245

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Article
Synthesis of (2S)-2-Chloro-2-Fluoro-ribolactone
via Stereoselective Electrophilic Fluorination
Coralie De Schutter, Ozkan Sari, Steven J. Coats, Franck Amblard, and Raymond Felix Schinazi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02245 • Publication Date (Web): 15 Nov 2017
Downloaded from http://pubs.acs.org on November 28, 2017
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The Journal of Organic Chemistry
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Synthesis of (2S)-2-Chloro-2-Fluoro-ribolactone via Stereoselec-
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tive Electrophilic Fluorination
Coralie De Schutter,† Ozkan Sari,† Steven J. Coats,‡ Franck Amblard,† and Raymond F. Schinazi*,†
† Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics,
Emory University School of Medicine, Atlanta, USA
‡ Cocrystal Pharma, Inc., Tucker, USA
ABSTRACT:
TBSO
O
TBSO
O
O
TBSO
LiHMDS
NFSI
O
(S)
O
Cl
R
R
O
O
F
Cl
O
Cl
TBSO
F
29
A novel and efficient route for the preparation of (2S)ꢀ2ꢀchloroꢀ2ꢀfluoro lactone 29 is described. This
approach takes advantage of a highly efficient diastereoselective electrophilic fluorination reaction (94%
yield; >50:1 dr)
INTRODUCTION
Hepatitis C virus (HCV) a flavivirus that causes significant morbidity and mortality, affects at least 71
million people worldwide.1 Globally, this major public health concern is responsible for approximately
27% of liver cirrhosis and around 25% of hepatocellular carcinoma.2 Since the discovery of HCV in
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1989, several antiviral drug regimens have been developed.3 Until 2011, subcutaneous pegylated
interferon alfa and oral ribavirin were used as the main HCV treatment. Since then, the addition of
protease inhibitors (PIs) and the development of interferonꢀfree therapies considerably increased the
rates of treatment tolerability and sustained virological response. Further improvement was recently
achieved with Epclusa®, the first allꢀoral, panꢀgenotypic, single tablet regimen for chronic HCV
infection (combination of NS5B inhibitor sofosbuvir and NS5A inhibitor velpatasvir).4 Despite these
advances, new potent panꢀgenotypic nucleosides analogs that can reduce treatment duration (~12
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weeks) are needed. Recently, our group and other laboratories paid special attention to the (S)ꢀ2’ꢀchloroꢀ
2’ꢀfluoroꢀdeoxyribouridine prodrug 1 (Figure 1)5 which displays high panꢀgenotypic potency against
HCV in subgenomic 1a replicon assays (EC50 = 0.1 ꢁM).5d This prodrug was rapidly metabolized in
human hepatocytes to its active metabolite, 2’ꢀchloroꢀ2’ꢀfluoroꢀdeoxyribonucleoside 5’ꢀtriphosphate,
which inhibits the NS5B polymerase by competing with natural uridine triphosphate. With a sofosbuvir
like C2’ꢀexoꢀpuckered sugar, this prodrug also exhibited a favorable resistance and safety profile which
makes it a potential candidate for clinical development.
Figure 1. Structure of sofosbuvir and novel 2’-Cl,2’-F nucleoside analog 1.
The synthesis of this nucleoside analog is particularly challenging due to the unusual (2’S)ꢀCl,F
substitution on the sugar moiety. One of the key intermediate required for the synthesis of 1 is the
lactone 4, which can be prepared in 4 steps from 2ꢀdeoxyꢀDꢀribose (Scheme 1a).5d,6 However, the
reported synthesis is hampered by the lack of stereoselectivity of the fluorination/chlorination sequence.
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These halogenations reactions also suffer from undesired side reactions like βꢀelimination6 or over
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fluorination resulting in low yields and difficult chromatographic separations.
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Modified riboside moieties are generally prepared from natural sugars such as ribose or 2’ꢀdeoxyribose,
but also from Dꢀglyceraldehyde via Reformatsky, Wittig or aldol reactions. The later approach was
successfully used for the synthesis of several 2’ꢀmodified nucleosides such as sofosbuvir7 or
gemcitabine.8 Regarding the formation of gemꢀClꢀFꢀcarbons, there is only few examples in the literature
and most of them are synthesized via electrophilic fluorination of an αꢀchloro carbonyl compound.9
Partial stereoselectivity is usually achieved by using chiral transition metal complexes (Ni, Pd, Ti)10
with or without organocatalysts such as spiro oxazoline ligands,11 cinchona alkaloid esters,12 Nꢀ
acyloxazolidinones,13 and the Jørgensen catalyst.14 It is worth mentioning that there are only a few
examples reporting the stereoselective electrophilic chlorination of αꢀfluoro carbonyl compounds.14a
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Scheme 1. Reported synthesis and retrosynthetic approach for the preparation of (2S)-2-chloro-2-fluoro
ribolactone 4.
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Herein we report an alternative route for the preparation of the (S)ꢀ2ꢀchloroꢀ2ꢀfluoro lactone
intermediate 4 using stereoꢀselective aldolisation and fluorination reactions (Scheme 1b). This strategy
allows us to introduce directly the chlorine atom during the aldol step and therefore avoid an additional
chlorination step. Using this approach we expect the stereochemistry of the C3 hydroxyl group to be
controlled by the C4 chiral center, mostly favoring a 3,4ꢀtrans configuration. Also, according to
literature precedents, the use of (S)ꢀ4ꢀbenzyloxazolidinone (Xc) as chiral auxiliary could potentially
improve the chiral induction towards the desired (3R) configuration.15
RESULTS AND DISCUSSION
Initially, we investigated the aldolisation between ethyl chloroacetate 9 and glyceraldehyde 8 (Table 1).
Table 1. Aldol reaction optimization.
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entry Rx
Conditions
product (yield, ratio)a,b
11 (39%, 2:2:5:1)
11 (47%, 6:1:8:1)
11 (0%)
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LiHMDS, THF, ꢀ78 °C
LDA, THF, ꢀ78 °C
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TiCl4, DIPEA, CH2Cl2, ꢀ78 °C
Bu2BOTf, DIPEA, CH2Cl2, ꢀ78 °C to 0 °C
Bu2BOTf, DIPEA, CH2Cl2, ꢀ78 °C to 0 °C
TiCl4, DIPEA, CH2Cl2, ꢀ78 °C
LiHMDS, THF, ꢀ78 °C
9
11 (62%, 3:1:3:3)
12 (traces)
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12 (traces)
(2R,3R)ꢀ12 (54%, >50:1)
(2R,3R)ꢀ12 (44%, >50:1)
LDA, THF, ꢀ78 °C
aIsolated yield. bRatio determined by 1H NMR analysis.
The reaction of a lithium enolate of 9, generated by using either LiHMDS or LDA gave the aldol
product 11 in moderate yields as a mixture of the four possible diastereomers (Entries 1 and 2).16 The
yield increased to 62% when we used a boron enolate but, as mentioned earlier, no apparent
diastereoselectivity was observed (Entry 4).17 On the other hand, the use of a titanium enolate was found
to be incompatible with our reactants as only degradation was observed (entry 3).18 The lack of
selectivity of this reaction along with the possible side reactions (such as self Claisen7b or Darzens16
condensations) that could occur during the process led us to investigate an aldol reaction between Nꢀ(αꢀ
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chloroacetyl)ꢀoxazolidinone 10 and glyceraldehyde 8. Unfortunately, standard conditions with either
TiCl4 or Bu2BOTf only gave traces of the desired compound 12 with complete recovery of the starting
materials (entries 5 and 6).19 However, when the reaction was performed with a lithiated base such as
LiHMDS or LDA, only one diastereomer was obtained in 54% and 44% yield, respectively (entries 7
and 8). Despite our efforts, we were not able to improve this yield as compound 12 seems to undergo
partial retroꢀaldolisation during workꢀup.20
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Although our ultimate goal was to introduce a fluorine atom at C2, it was important to fully define the
newly set stereo centers in compound 12. Unfortunately, we were unable to assign the absolute
configuration at this stage and therefore product 12 was further converted to the lactone 15 using the
chemistry depicted in Scheme 2. Thus, compound 12 was first silylated with TBSOTf in presence of
2,6ꢀlutidine to give compound 13 in 94% yield. Our initial attempt to directly convert 13 to 15 using a
standard LiOHꢀH2O2 hydrolysis resulted in epimerization at C2.21 Therefore, the oxazolidinone was first
cleaved by careful treatment with 0.5 equivalents of sodium ethoxide at ꢀ78 °C to afford ester 14 in 91%
yield as a single diastereomer.22 Compound 14 was finally cyclized in acidic conditions followed by 5ꢀ
TBSꢀprotection to give the 2ꢀchlorolactone 15 which was identified as the (2R,3R) isomer by Xꢀray
crystallography (Figure 2).
Scheme 2. Synthesis of 2-Cl lactone 15.
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Figure 2. Crystal structure of (2R,3R)-2-chlorolactone 15 showing thermal ellipsoids at the 50% proba-
bility level.
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Fluorination of oxazolidinone derivative 13 was attempted using 1.3 equiv LiHMDS and 1.5 equiv
NFSI (Scheme 3), but unfortunately, no fluorinated product was observed under these standard
conditions.23 We hypothesized that the approach of the fluorinating reagent toward the C2 center might
be restricted by the presence of the nearby bulky oxazolidinone and therefore prevent the fluorination.
Scheme 3. Fluorination attempt on compound 13.
To confirm this hypothesis, the less hindered ethyl ester 11 was prepared from Evans’ oxazolidinone 10
through a one pot aldolisation/auxiliary cleavage sequence (Scheme 4). Thus, the aldol reaction of 10
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with glyceraldehyde 8 was performed in presence of LiHMDS and quenched by addition of ethanol at ꢀ
78 °C to provide ester 11 in 67% with an excellent stereoselectivity at C3. However, despite an
improvement in yield and simpler one pot reaction versus Table 1 entry 7, ethanol quenching led to
significant epimerization at C2 (ratio 7:3, determined by 1HꢀNMR). As the subsequent fluorination step
in our approach goes through an enolate intermediate, racemization had limited consequences and 11
was directly reacted with TBSOTf and 2,6ꢀlutidine to afford protected compound 14 almost
quantitatively.
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Scheme 4. Synthesis of compound 14.
Fluorination of the epimeric mixture 14 was attempted following the conditions described above (Table
2, entry 1). Surprisingly, the reaction afforded only a single diastereomer, which was later confirmed to
be the desired (2S)ꢀisomer. Unfortunately, the reaction was not complete after 1 h at ꢀ78 °C and gave
15% of the elimination product 18.24 Interestingly, we were able to remove the undesired olefin 18
7
a
during work up by treatment of the crude mixture with solid potassium permanganate. It is noteworthy
that warming the reaction to room temperature or increasing the reaction time affected neither the
conversion rate nor the diastereoselectivity.
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Table 2. Fluorination conditions screening.
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entry
base
NFSI
Conversion, %a S/Rꢀ17b
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5
LiHMDS, 1.3 eq
LiHMDS, 2.5 eq
1.5 eq
2.5 eq
70
>50:1
>50:1
16:1
100 (94)
100 (79)
96 (92)
100 (33)
NaHMDS, 2.5 eq 2.5 eq
KHMDS, 2.5 eq
LDA, 1.3 eq
2.5 eq
1.5 eq
10:1
>50:1
aDetermined by 1HꢀNMR, isolated yield in parenthesis. b(2S:2R) ratio determined by 1HꢀNMR or 19FꢀNMR.
Nevertheless, complete conversion was finally achieved using 2.5 equivalents of both LiHMDS and
NFSI (Table 2, entry 2) which afforded (2S)ꢀ17 in 94% yield along with approximately 5% of
elimination product 18 (ratio Z/E, 33:1). In order to investigate the role of the chelating effect of the
counterꢀion in the diastereoselectivity of this particular reaction, the fluorination of compound 14 was
attempted using NaHMDS and KHMDS (entries 3ꢀ4). Although these reactions yielded the fluorinated
product in good yields, only partial diastereoselectivity was observed (16:1 and 10:1 with NaHMDS and
KHMDS, respectively). Interestingly, fluorination in presence of a stronger base like LDA25 also gave
compound 17 as a single diastereomer, but with a low yield due to rapid elimination of the βꢀOTBS
group and formation of compound 18 (entry 5).
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The mechanism illustrated in Scheme 5 was postulated in an attempt to rationalize the stereoselectivity
of this fluorination step. Thus, the reaction performed with LiHMDS might go through a transition state
in which the lithium ion simultaneously chelates the enolate and the oxygen atom at the βꢀposition,
forming a ZimmermanꢀTraxler like sixꢀmembered ring. The loss of diastereoselectivity observed with
sodium and potassium cations could be explained by their weaker interaction with oxygen relative to
lithium,26 which might destabilize the aforementioned sixꢀmembered ring transition state. This
hypothesis is supported by the fact that LDA, another lithiated base, led to complete diastereoselectivity
as well. Additionally, this transition state allows the axial attack of the electrophilic fluorinating agent
without steric hindrance from the ethoxy moiety, leading only to the formation of the 2ꢀchloroꢀ2ꢀfluoro
isomer (2S)ꢀ17.
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Scheme 5. Proposed mechanism for the fluorination of compound 14.
As a side note, the γꢀisopropylidene group and its C4 chiral center seems to have no effect on the
diastereoselectivity since similar selectivities were observed on substrates lacking a chiral center at this
position (Table 3). αꢀChloroꢀβꢀhydroxyester derivatives 22ꢀ24 were prepared by first, aldol reaction
between ethyl chloroacetate 9 and achiral alkyl or aromatic aldehydes followed by protection with
TBSOTf.27,28 Interestingly, unlike for compound 14, treatment of substrates 22ꢀ24 with LiHMDS
resulted only in partial deprotonation and prompted us to use the stronger base, LDA, instead. Obtaining
the desired 2ꢀchloroꢀ2ꢀfluoro compounds 25ꢀ27 as single S diastereomers at the 2 position (ratio >50:1,
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24ꢀ39%) indicates that the isopropylidene moiety and its chirality at the C4ꢀcenter are not influencing
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the diastereoselectivity of the fluorination of compounds such as 14.
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Table 3. Preparation of the γꢀmodified chloroacetate derivatives 25-27.
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TBSOTf,
Bu2BOTf,
DIPEA
O
O
TBSO
R
O
TBSO
R
O
HO
O
2,6-lutidine
LDA, NFSI
+
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R
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OEt
OEt
R
OEt
OEt
CH2Cl2
0 °C, 2 h
CH2Cl2
-78 °C to 0 °C
THF
-78 °C, 1 h
F
Cl
Cl
Cl
Cl
19-21
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25-27
entry
R
Yielda (ratio anti/syn)
Yielda (ratio)
Fluorinationb
Aldolisation
Protection
1
2
3
iꢀPr
19, 88% (2.3:1)
22, 92% (2.4:1)
23, 96% (2:1)
24, 95% (1.6:1)
25, 33% (>50:1)
26, 24% (>50:1)
27, 39% (>50:1)
cyclopentyl 20, 76% (2.3:1)
Ph 21, 88% (1.8:1)
aIsolated yield; ratio determined by 1HꢀNMR. bLDA (2.5 eq), NFSI (2.5 eq).
Finally, with compound 17 in hand, the desired 2ꢀchloroꢀ2ꢀfluorolactone 29 was readily obtained by
cyclisation and 5ꢀTBSꢀprotection (Scheme 6). As our attempts to crystallize the TBSꢀlactone 29 to
determine the absolute configuration at C2 were unsuccessful, introduction of different protecting
groups at position 5 was investigated. Xꢀray crystallography of the 5ꢀparaꢀnitrobenzoylꢀprotected
lactone 30, prepared from intermediate 28 by reaction with paraꢀnitrobenzoyl chloride and
triethylamine in 1,4ꢀdioxane (Figure 3), revealed the S configuration of the C2 position.
Scheme 6. Synthesis of ribolactones 29 and 30.
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HO
TBSO
1
2
3
4
AcOH, H2O
TBSCl, imidazole
O
O
O
O
(2S)-17
Cl
Cl
ACN, 80 °C, 2 h
DMF, rt, 2 h
83% over 2 steps
TBSO
F
TBSO
TBSO
F
F
28
5
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29
p-NO2BzO
p-NO2BzCl, Et3N
O
O
Cl
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1,4-dioxane, rt, 30 min
49%
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Figure 3. Crystal structure of (2S,3R)ꢀ2ꢀCl,2ꢀFꢀlactone 30 showing thermal ellipsoids at the 50% probability
level
.
CONCLUSION
In conclusion, we developed an alternative pathway to prepare a key intermediate required for the
synthesis of the prodrug 1. The 2ꢀchloroꢀ2ꢀfluoro lactone 29 was obtained in 5 steps with an improved
40% overall yield compared to the 10% overall yield of the original 4 step synthesis. This new route
starts with an efficient oneꢀpot synthesis of 2ꢀchloro acetate 11 from 10 and takes advantage of the
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diastereoselective electrophilic fluorination of this derivative to form the (2S)ꢀCl,Fꢀstereocenter in high
yield. Further investigations are underway to determine the scope and limitations of this ligandꢀfree
diastereoselective fluorination.
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EXPERIMENTAL SECTION
General Information. NMR spectra were recorded on a Bruker Ascend™ 400 MHz Fourier transform
spectrometer at rt in CDCl3 or DMSOꢀd6 as indicated. Chemical shift are reported in parts per million
(ppm) with tetramethylsilane (TMS) as an internal standard. NMR treatment was performed with
MestReNova version 10.0.2ꢀ15465 using the following abbreviations for signal characterization: s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad signal), dd (doublet of doublets) or
heptd (heptuplet of doublet). Highꢀresolution mass spectra (HRMS) were recorded on a ThermoFisher Q
Exactive Plus orbitrap highꢀresolution mass spectrometer with electrospray ionization positive (ESI+) or
negative (ESIꢀ). Reactions were monitored by thinꢀlayer chromatography (TLC) and visualized by
ultraviolet irradiation and/or KMnO4 dip. Purifications were performed on silica gel column
chromatography (60 Å, 63ꢀ200 ꢁm, or 40ꢀ75 ꢁm) with CombiFlash® Rf 200. Anhydrous solvents were
purchased from Aldrich Chemical Company, Inc. (Milwaukee). Reagents were purchased from
commercial sources and used without further purification.
(S)-4-Benzyl-3-(2-chloroacetyl)oxazolidin-2-one (10). To a solution of (S)ꢀ4ꢀbenzylꢀ2ꢀoxazolidinone
(5 g, 28.2 mmol) in dry THF (150 mL) at ꢀ78 °C under N2 was added nꢀBuLi (2.5 M in hexanes, 13.5
mL, 33.9 mmol). The solution was stirred at ꢀ78 °C for 15 min and chloroacetyl chloride (2.47 mL, 31.0
mmol) was added in one portion. After full conversion (typically 30 min), the reaction was quenched by
addition of a saturated aqueous solution of NH4Cl and allowed to reach rt. The mixture was diluted with
EtOAc, washed with water and brine. The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude residue was purified via column chromatography on silica gel to afford a
colorless syrup (5.1 g, 71%), which crystalized over standing. Alternatively, precipitation could be
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initiated by dilution of the syrup in cold diethyl ether to afford a white solid after filtration. 1H and 13Cꢀ
NMR data matched those reported in the literature.29
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Ethyl 2-chloro-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropanoate (11). Procedure A:
Ethyl chloroacetate 9 (5.0 g, 40.8 mmol) was added to a solution of LDA (1 M in THF/hexanes, 53 mL,
53.0 mmol) in dry THF (300 mL) at ꢀ78 °C under N2. After 15 min, (R)ꢀ2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4ꢀ
carbaldehyde 8 (6.1 mL, 49.0 mmol)30 was introduced to the mixture and the reaction was stirred for an
additional hour at ꢀ78 °C. The reaction was quenched with 1 M HCl at ꢀ78 °C. The mixture was
extracted with ethyl acetate, washed with water, brine, dried over MgSO4 and concentrated in vacuo.
The crude product was purified by flash column chromatography (hexanes/EtOAc 9:1 to 8:2) to afford
compound 11 (colorless oil, 4.8 g, 47%) as a diastereomeric mixture of 4 isomers. NMR data matched
those reported in the literature.31 Procedure B: To a solution of LiHMDS (1 M in THF, 5.9 mL, 5.90
mmol) in dry THF (20 mL) at ꢀ78 °C under N2 was added dropwise via cannula a solution of 10 (1 g,
3.94 mmol) in THF (2 mL). The mixture was stirred 30 min at this temperature and a solution of (R)ꢀ
2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4ꢀcarbaldehyde 8 (736 µL, 5.90 mmol) in THF (2 mL) was added dropwise
via cannula. After 30 min, anhydrous ethanol (5 mL) was added at ꢀ78 °C and the reaction mixture was
further stirred for 15 min before addition of silica (10 g). The mixture was filtered on a silica gel pad
prior to concentration under reduced pressure. The crude residue was purified via column
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chromatography on silica gel (hexanes/EtOAc 95:5 to 70:30) to afford the desired aldol product 11 as a
mixture of 2 diastereomers in 67% yield (670 mg, 2R/2S ratio 7:3, colorless oil). HRMS (ESIꢀTOF) m/z:
[M + H]+ calcd for C10H18ClO5 253.0843, found 253.0838.
(S)-4-Benzyl-3-((2R,3R)-2-chloro-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-
hydroxypropanoyl)oxazolidin-2-one (12). To a solution of LiHMDS (1 M in THF, 1.48 mL, 1.48
mmol) in dry THF (5 mL) at ꢀ78 °C under N2 was added dropwise via cannula a solution of 10 (250 mg,
0.99 mmol) in THF (2 mL). The mixture was stirred 30 min at this temperature and a solution of (R)ꢀ
2,2ꢀdimethylꢀ1,3ꢀdioxolaneꢀ4ꢀcarbaldehyde 8 (115 µL, 1.28 mmol) in THF (2 mL) was added dropwise
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via cannula. After 30 min, the reaction was quenched at ꢀ78 °C by addition of 1 M HCl. The mixture
was rapidly diluted with EtOAc and then washed with water and brine. The organic layer was dried over
MgSO4 and filtered on a silica gel pad prior to concentration under reduced pressure. The crude residue
was purified via column chromatography on silica gel (hexanes/EtOAc 95:5 to 70:30) to afford the
desired aldol product as a single diastereoisomer in 54% yield as a white solid (205 mg). 1H NMR (400
MHz, CDCl3) δ 7.39ꢀ7.27 (m, 3H), 7.25 (d, J = 6.9 Hz, 2H), 5.77 (d, J = 6.1 Hz, 1H), 4.79ꢀ4.72 (m,
1H), 4.38ꢀ4.08 (m, 6H), 3.31 (dd, J = 13.6, 3.3 Hz, 1H), 3.27 (bs, 1H), 2.85 (dd, J = 13.5, 9.2 Hz, 1H),
1.47 (s, 3H), 1.39 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 168.5, 152.4, 134.7, 129.5, 129.1, 127.6,
109.9, 75.9, 73.7, 66.4, 65.9, 55.5, 52.7, 37.6, 26.6, 25.1; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for
C18H23ClNO6 384.1214, found 384.1201.
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(S)-4-Benzyl-3-((2R,3R)-3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-((R)-2,2-dimethyl-1,3-dioxolan-
4-yl)propanoyl)oxazolidin-2-one (13). To a solution of compound 12 (230 mg, 0.60 mmol) in dry
CH2Cl2 (6 mL) at 0 °C under N2 were sequentially added 2,6ꢀlutidine (280 µL, 2.4 mmol) and TBSOTf
(275 µL, 1.2 mmol). The mixture was stirred 1 h at 0 °C and quenched by addition of 1 M HCl (5 mL).
The mixture was extracted with CH2Cl2 (2 x 10 mL). Combined organic layers were washed with water,
brine, dried over MgSO4 and concentrated in vacuo. The crude residue was purified via column
chromatography on silica gel (hexanes/EtOAc, 95:5) to afford the desired silylated derivative 13 in 94%
yield as a white solid (281 mg). 1H NMR (400 MHz, CDCl3) δ 7.47ꢀ7.23 (m, 5H), 5.71 (d, J = 4.0 Hz,
1H), 4.78ꢀ4.70 (m, 1H), 4.54 (dd, J = 6.1, 4.0 Hz, 1H), 4.43 (dd, J = 13.4, 6.3 Hz, 1H), 4.32ꢀ4.22 (m,
1H), 4.10 (dd, J = 8.2, 6.4 Hz, 1H), 3.92 (t, J = 7.8 Hz, 1H), 3.52 (dd, J = 13.3, 2.8 Hz, 1H), 2.65 (dd, J
= 13.2, 10.6 Hz, 1H), 1.40 (s, 3H), 1.32 (s, 3H), 0.93 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 165.9,
152.9, 135.2, 129.3, 129.1, 127.5, 109.3, 74.6, 72.4, 67.1, 66.3, 62.0, 56.1, 38.0, 26.6, 25.7, 25.4, 18.1, ꢀ
4.5, ꢀ4.9; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C24H37ClNO6Si 498.2079, found 498.2075.
Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)propanoate
(14). Procedure A: To a solution of compound 13 (52 mg, 0.10 mmol) in a mixture of anhydrous EtOH
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(1.5 mL) and THF (1.5 mL) at ꢀ78 °C was added NaOEt (21 wt% in EtOH, 0.02 mL, 0.5 mmol). The
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mixture was stirred 30 min at ꢀ78 °C and quenched by addition of 1 M HCl (5 mL). After dilution with
EtOAc, the organic layer was washed with a saturated aqueous solution of NaHCO3 and brine. The
organic layer was dried over MgSO4 and concentrated in vacuo. The crude residue was purified via
column chromatography on silica gel (hexanes/EtOAc, 95:5) to afford the desired ethyl ester 14 as a
colorless oil (35 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 4.60 (d, J = 2.7 Hz, 1H), 4.34ꢀ4.28 (m, 1H),
4.25 (qd, J = 7.2, 1.1 Hz, 2H), 4.20 (dd, J = 7.2, 2.7 Hz, 1H), 4.07 (dd, J = 8.4, 6.3 Hz, 1H), 3.89 (dd, J
= 8.4, 5.4 Hz, 1H), 1.40 (s, 3H), 1.36ꢀ1.30 (m, 6H), 0.90 (s, 9H), 0.19 (s, 3H), 0.15 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ 166.8, 109.4, 75.8, 75.6, 66.6, 62.2, 61.3, 26.6, 25.7, 25.1, 18.0, 14.1, ꢀ4.3, ꢀ4.7;
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C16H32ClO5Si 367.1708, found 367.1701. Procedure B: To a
solution of compound (3R)ꢀ11 (2.32 g, 9.18 mmol) in dichloromethane (10 mL) at 0 °C was added 2,6ꢀ
lutidine (4.28 mL, 36.72 mmol) followed by TBSOTf (4.22 mL, 18.36 mmol). The reaction mixture was
stirred for 2 h then quenched with a saturated aqueous solution of NaHCO3. The crude mixture was
extracted with ethyl acetate, washed with 1 M HCl, brine, dried over MgSO4 and concentrated under
reduced pressure. Purification by flash column chromatography (hexanes/EtOAc, 95/5) afforded the two
major diastereoisomers (2R,3R)ꢀ14 and (2S,3R)ꢀ14 in 99% yield (colorless oil, 3.33 g, ratio 7:3).
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(3R,4R,5R)-4-((tert-Butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-
chlorodihydrofuran-2(3H)-one (15). To a solution of compound 14 (29 mg, 0.08 mmol) in acetonitrile
(0.2 mL) were added water (0.01 mL) and acetic acid (0.05 mL). The reaction mixture was refluxed for
1 h and coꢀevaporated with toluene under reduced pressure. The crude 2ꢀchloroꢀlactone was dissolved in
DMF (0.2 mL) and TBSCl (24 mg, 0.16 mmol) and imidazole (14 mg, 0.20 mmol) were added. The
reaction was stirred at rt for 2 h and quenched with water (5 mL). The mixture was extracted with
EtOAc/Et2O (1:1). The organic layer was washed with water (3 x 10 mL), a saturated aqueous solution
of NH4Cl (10 mL), brine (10 mL), dried over MgSO4 and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (hexanes/EtOAc, 95:5) to afford the
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protected lactone 15 as a white solid (30.7 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 4.62 (d, J = 5.4 Hz,
1H), 4.51 (dd, J = 5.6, 2.7 Hz, 1H), 4.41 (d, J = 2.5 Hz, 1H), 3.94 (dd, J = 12.0, 2.7 Hz, 1H), 3.82 (dd, J
= 12.0, 2.0 Hz, 1H), 0.93 (s, 9H), 0.90 (s, 9H), 0.17 (s, 3H), 0.14 (s, 3H), 0.10 (s, 3H), 0.09 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 171.1, 85.8, 70.4, 61.4, 55.7, 25.7, 25.6, 18.3, 18.2, ꢀ4.9, ꢀ5.1, ꢀ5.5, ꢀ5.6; mp
85ꢀ86 °C; HRMS (ESIꢀTOF) m/z: [M ꢀ H]ꢀ calcd for C17H36ClO4Si2 395.1841, found 395.1830.
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Ethyl (2S,3R)-3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-
fluoropropanoate (17). A solution of LiHMDS (1 M in THF, 0.34 mL, 0.34 mmol) was added dropwise
to a mixture of compound (3R)ꢀ14 (50 mg, 0.14 mmol) and NFSI (107 mg, 0.34 mmol) in anhydrous
THF (0.5 mL) at ꢀ78 °C. After 1 h, the reaction was quenched with a saturated aqueous solution of
NH4Cl and extracted with EtOAc. Solid potassium permanganate (300 mg) and water (0.5 mL) were
added to the organic layer (consumption of the elimination compound was monitored by TLC,
hexanes/EtOAc 9:1, Rf = 0.57). A saturated aqueous solution of Na2S2O3 (20 mL) was added to the
heterogeneous mixture and formation of a brown precipitate was observed after vigorous shaking. The
mixture was treated with 1 M HCl (10 mL). The organic layer was separated and washed with brine,
dried over MgSO4 and concentrated under reduced pressure. The crude residue was purified by flash
column chromatography (hexanes/EtOAc, 95/5) to give compound 17 as a colorless oil (49 mg, 94%,
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ratio 2S/2R >50:1). H NMR (400 MHz, CDCl3) δ 4.42ꢀ4.21 (m, 4H), 4.10ꢀ4.00 (m, 1H), 3.93 (dd, J =
8.2, 6.4 Hz, 1H), 1.41 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.33 (s, 3H), 0.93 (s, 9H), 0.20 (s, 3H), 0.17 (s,
3H); 19F NMR (377 MHz, CDCl3) δ ꢀ127.12 (d, J = 18.2 Hz); 13C NMR (101 MHz, CDCl3) δ 164.8 (d,
J = 27.6 Hz), 108.9, 104.8 (d, J = 261.4 Hz), 77.2 (d, J = 21.4 Hz), 75.3 (d, J = 4.0 Hz), 65.6 (d, J = 1.5
Hz), 63.1, 25.9, 25.8, 24.6, 18.3, 13.9, ꢀ4.0, ꢀ4.2, ꢀ4.2; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for
C16H31ClFO5Si 385.1613, found 385.1607.
Ethyl 2-chloro-3-hydroxy-4-methylpentanoate (19). To a solution of 9 (0.22 mL, 2.04 mmol) in
CH2Cl2 (20 mL) at ꢀ78 °C were added dibutylboryl trifluoromethanesulfonate (1.0 M in CH2Cl2, 4.1
mL, 4.08 mmol) and DIPEA (1 mL, 6.12 mmol). The mixture was stirred 2 h at ꢀ78 °C and isobutyralꢀ
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dehyde (0.28 mL, 3.06 mmol) was added. The reaction was stirred at this temperature for 1 h and for
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another hour at 0 °C. The mixture was quenched with a (1:1) mixture of methanol/phosphate buffer (20
mL, pH 7.2) followed by H2O2 (10 mL, 30% w/w in water) and the solution was stirred 16 h at rt. After
removal of the solvent under reduced pressure, the solution was extracted with CH2Cl2. The combined
organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The
crude compound was purified by flash column chromatography (hexanes/EtOAc, 9:1) to give compound
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19 as an anti/syn mixture (2.3:1) (colorless oil, 350 mg, 88%). H and 13CꢀNMR data matched those
reported in the literature.32 Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.30ꢀ4.22 (m, 2H), 4.20 (d, J =
7.9 Hz, 1H), 3.81 (dd, J = 8.0, 4.1 Hz, 1H), 2.72 (bs, 1H), 2.12ꢀ 2.04 (m, 1H), 1.31 (t, J = 7.2 Hz, 3H),
1.02 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C8H16ClO3
195.0788, found 195.0785.
Ethyl 2-chloro-3-cyclopentyl-3-hydroxypropanoate (20). Compound 20 was prepared following the
procedure described for 19 using cyclopentanecarboxaldehyde to give 20 as an anti/syn mixture (2.3:1)
(colorless oil, 76%). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.29ꢀ3.85 (m, 4H), 2.75 (bs, 1H),
2.26ꢀ2.14 (m, 1H), 1.94ꢀ1.35 (m, 8H), 1.32 (t, J = 7.2 Hz, 3H); Mixture: 13C NMR (101 MHz, CDCl3) δ
168.8, 168.7, 76.1, 76.0, 62.4, 62.2, 61.9, 58.7, 43.1, 41.8, 29.0, 28.9, 28.9, 27.1, 25.6, 25.4, 25.4, 25.4,
14.0, 13.9; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C10H18ClO3 221.0944, found 221.0939.
Ethyl 2-chloro-3-hydroxy-3-phenylpropanoate (21). Compound 21 was prepared following the proꢀ
cedure described for 19 using benzaldehyde to give 21 as an anti/syn mixture (1.8:1) (colorless oil,
88%). 1H and 13CꢀNMR data matched those reported in the literature.32 Major isomer: 1H NMR (400
MHz, CDCl3) δ 7.45ꢀ7.33 (m, 5H), 5.07 (dd, J = 7.7, 5.5 Hz, 1H), 4.41 (d, J = 7.5 Hz, 1H), 4.28 (q, J =
7.2 Hz, 2H), 3.07 (d, J = 5.0 Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H).
Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-4-methylpentanoate (22). Compound 22 was preꢀ
pared following conditions described for 14 (procedure B) with 19 (250 mg, 1.28 mmol), TBSOTf (0.6
mL, 2.56 mmol) and 2,6ꢀlutidine (0.6 mL, 5.12 mmol) in CH2Cl2 (6 mL) to afford 22 (colorless oil, 366
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mg, 92%) as an anti/syn mixture (2.4:1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.27ꢀ4.19 (m,
2H), 4.17 (d, J = 7.7 Hz, 1H), 4.00 (dd, J = 7.7, 3.3 Hz, 1H), 2.17 (heptd, J = 6.9, 3.2 Hz, 1H), 1.32 (t, J
= 7.1 Hz, 3H), 0.99ꢀ088 (m, 15H), 0.10ꢀ0.03 (m, 6H); Mixture: 13C NMR (101 MHz, CDCl3) δ 169.0,
168.8, 61.9, 61.8, 61.2, 58.2, 31.9, 30.3, 26.1, 26.0, 20.2, 19.5, 18.5, 18.4, 16.5, 16.0, 13.9, 13.9, ꢀ3.8, ꢀ
4.0, ꢀ4.2, ꢀ4.5; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C14H30ClO3Si 309.1653, found 309.1647.
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Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-cyclopentylpropanoate (23). Compound 23 was
prepared following conditions described for 14 (procedure B) with 20 (250 mg, 1.13 mmol), TBSOTf
(0.5 mL, 2.26 mmol) and 2,6ꢀlutidine (0.5 mL, 4.52 mmol) in CH2Cl2 (5 mL) to afford 23 (colorless oil,
364 mg, 96%) as an anti/syn mixture (2:1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 4.31ꢀ4.29 (m,
1H), 4.27ꢀ4.20 (m, 2H), 4.10ꢀ4.04 (m, 1H), 2.38ꢀ2.24 (m, 1H), 1.80ꢀ1.36 (m, 7H), 1.32 (t, J = 7.2 Hz,
3H), 1.28ꢀ1.16 (m, 1H), 0.89 (s, 9H), 0.12ꢀ0.08 (m, 6H); Mixture: 13C NMR (101 MHz, CDCl3) δ 168.7,
168.2, 62.5, 62.0, 61.9, 61.2, 43.9, 43.2, 29.7, 28.9, 28.0, 27.8, 26.0, 25.9, 25.5, 25.9, 25.2, 25.1, 18.4,
18.3, 14.0, ꢀ3.9, ꢀ4.0, ꢀ4.2, ꢀ4.3; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C16H32ClO3Si 335.1809,
found 335.1801.
Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-phenylpropanoate (24). Compound 24 was preꢀ
pared following conditions described for 14 (procedure B) with 21 (410 mg, 1.79 mmol), TBSOTf (0.82
mL, 3.58 mmol) and 2,6ꢀlutidine (0.83 mL, 7.16 mmol) in CH2Cl2 (20 mL) to afford 24 (colorless oil,
582 mg, 95%) as an anti/syn mixture (1.6:1). Major isomer: 1H NMR (400 MHz, CDCl3) δ 7.44ꢀ7.29
(m, 5H), 4.95 (d, J = 9.1 Hz, 1H), 4.33ꢀ4.25 (m, 2H), 4.23 (d, J = 9.1 Hz, 1H), 1.36 (t, J = 7.1 Hz, 3H),
0.83 (s, 9H), 0.12ꢀꢀ0.24 (m, 6H); Mixture: 13C NMR (101 MHz, CDCl3) δ 168.9, 167.9, 139.9, 139.7,
128.5, 128.2, 128.1, 127.5, 127.1, 63.7, 61.9, 61.7, 60.3, 25.6, 25.5, 18.1, 17.9, 14.0, 13.7, ꢀ4.7, ꢀ5.0, ꢀ
5.4; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C17H28ClO3Si 343.1496, found 343.1491.
Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-2-fluoro-4-methylpentanoate (25). To a solution of
diisopropylamine (0.09 mL, 0.65 mmol) in dry THF (1 mL) at ꢀ78 °C under N2 was added dropwise nꢀ
BuLi (2.5 M in hexanes, 0.26 mL, 0.65 mmol). After 10 min at ꢀ78 °C, compound 22 (100 mg, 0.32
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mmol) in dry THF (0.3 mL) was introduced dropwise to the reaction mixture. A solution of NFSI (224
mg, 0.70 mmol) in anhydrous THF (0.5 mL) was immediately, added. After 1 h at ꢀ78 °C, the reaction
was quenched with a saturated aqueous solution of NH4Cl and extracted with EtOAc. Solid potassium
permanganate (300 mg) and water (0.5 mL) were added to the organic layer (consumption of the elimiꢀ
nation product was monitored by TLC, hexanes/EtOAc 95:5, Rf = 0.54). A saturated aqueous solution of
Na2S2O3 (20 mL) was added to the heterogeneous mixture and formation of a brown precipitate was
observed after vigorous shaking. The mixture was treated with 1 M HCl (10 mL). The organic layer was
separated and washed with brine, dried over MgSO4 and concentrated under reduced pressure. The
crude residue was purified by flash column chromatography (hexanes/EtOAc 95:5 as eluent) to give
compound 25 (colorless oil, 17.3 mg, 33%). 1H NMR (400 MHz, CDCl3) δ 4.35 (q, J = 7.1 Hz, 2H),
4.04 (dd, J = 20.0, 2.2 Hz, 1H), 2.00 (heptd, J = 6.8, 2.3 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.04 (d, J =
7.0 Hz, 3H), 0.97 (s, 9H), 0.94 (dd, J = 6.8, 1.8 Hz, 3H), 0.21 (s, 3H), 0.15 (s, 3H); 19F NMR (377 MHz,
CDCl3) δ ꢀ126.02 (d, J = 20.2 Hz); 13C NMR (101 MHz, CDCl3) δ 165.5 (d, J = 27.9 Hz), 106.9 (d, J =
263.9 Hz), 80.3 (d, J = 19.2 Hz), 63.0, 30.9, 26.0, 22.1, 18.6, 16.2 (d, J = 3.6 Hz), 13.9, ꢀ4.1; HRMS
(ESIꢀTOF) m/z: [M + H]+ calcd for C14H29ClFO3Si 327.1559, found 327.1553.
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Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-3-cyclopentyl-2-fluoropropanoate (26). Compound
26 was prepared following the procedure described for 25 with 23 (50 mg, 0.15 mmol), LDA (2 M in
THF/heptane/ethylbenzene, 0.1 mL, 0.20 mmol) and NFSI (118 mg, 0.37 mmol) in THF (1.5 mL) to
afford 26 (colorless oil, 12.6 mg, 24%). 1H NMR (400 MHz, CDCl3) δ 4.34 (qd, J = 7.1, 1.1 Hz, 2H),
4.19 (dd, J = 17.8, 3.6 Hz, 1H), 2.25ꢀ2.08 (m, 1H), 1.85ꢀ1.73 (m, 1H), 1.72ꢀ1.40 (m, 7H), 1.37 (t, J =
7.1 Hz, 3H), 0.94 (s, 9H), 0.19 (d, J = 1.0 Hz, 3H), 0.14 (s, 3H); 19F NMR (377 MHz, CDCl3) δ ꢀ123.05
(d, J = 18.0 Hz); 13C NMR (101 MHz, CDCl3) δ 165.3 (d, J = 28.1 Hz), 106.8 (d, J = 261.3 Hz), 78.9 (d,
J = 20.4 Hz), 63.0, 42.3 (d, J = 1.8 Hz), 31.1, 26.5 (d, J = 2.3 Hz), 26.0, 25.3 (d, J = 16.1 Hz), 18.6,
13.9, ꢀ4.0 (d, J = 2.7 Hz), ꢀ4.1; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C16H31ClFO3Si 353.1715,
found 353.1703.
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Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-chloro-2-fluoro-3-phenylpropanoate (27). Compound 27
was prepared following the procedure described for 25 with 24 (50 mg, 0.15 mmol), LDA (2M in
THF/heptane/ethylbenzene, 0.15 mL, 0.30 mmol) and NFSI (118 mg, 0.37 mmol) in THF (1.5 mL) to
afford 30 (colorless oil, 20.4 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.45ꢀ7.39 (m, 2H), 7.37ꢀ7.31 (m,
3H), 5.17 (d, J = 17.0 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 0.91 (s, 9H), 0.14 (s,
3H), ꢀ0.10 (s, 3H); 19F NMR (377 MHz, CDCl3) δ ꢀ130.11 (d, J = 17.2 Hz); 13C NMR (101 MHz,
CDCl3) δ 164.8 (d, J = 26.9 Hz), 136.6, 128.9, 128.5, 128.5, 127.9, 106.3 (d, J = 263.0 Hz), 78.2 (d, J =
21.3 Hz), 63.0, 25.6, 18.2, 13.8, ꢀ4.9, ꢀ5.2; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C17H27ClFO3Si
361.1402, found 361.1396.
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(2S)-2-Deoxy-2-chloro-2-fluoro-3-O-(tert-butyldimethylsilyl)-5-hydroxy-D-ribonolactone (28). To a
solution of compound 9 (150 mg, 0.39 mmol) in acetonitrile (0.5 mL) were added water (0.05 mL) and
acetic acid (0.3 mL). The reaction mixture was stirred at 80 °C for 2 h and coꢀevaporated with toluene
under reduced pressure. Compound 28 was obtained in 88% yield and used in the next step without
further purification. A sample was purified for analysis by flash column chromatography
(hexanes/EtOAc, 8:2) to afford chloroꢀfluoroꢀlactone 28 as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 4.56 (dd, J = 13.2, 6.5 Hz, 1H), 4.41 (dt, J = 6.4, 3.1 Hz, 1H), 4.09 (dd, J = 13.0, 2.3 Hz, 1H), 3.83 (d,
J = 12.9 Hz, 1H), 2.02 (bs, 1H), 0.95 (s, 9H), 0.25 (s, 3H), 0.20 (s, 3H); 19F NMR (377 MHz, CDCl3) δ ꢀ
134.91 (d, J = 13.3 Hz); 13C NMR (101 MHz, CDCl3) δ 164.9 (d, J = 25.7 Hz), 102.4 (d, J = 258.3 Hz),
83.4, 74.2 (d, J = 16.3 Hz), 59.2, 25.5, 18.0, ꢀ4.3, ꢀ5.2; HRMS (ESIꢀTOF) m/z: [M ꢀ H]ꢀ calcd for
C11H19ClFO4Si 297.0725, found 297.0732.
(2S)-2-Deoxy-2-chloro-2-fluoro-3,5-di-O-(tert-butyldimethylsilyl)-D-ribonolactone (29). To a
solution of compound 28 (3.89 g, 13 mmol) in DMF (30 mL) were added imidazole (2.3 g, 52 mmol)
and TBSCl (3.9 g, 26 mmol). The mixture was stirred 2 h at 25 °C and quenched with water. The
solution was extracted with ethyl acetate/diethyl ether (1:1) and the organic layer was washed with
water (3 x 30 mL), a saturated aqueous solution of NH4Cl (30 mL), brine (30 mL), dried over MgSO4
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and concentrated under reduced pressure. The crude was purified by flash column chromatography
(hexanes/EtOAc, 95:5) to afford protected lactone 29 as a colorless oil (5.0 g, 94%). 1H NMR (400
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MHz, CDCl3) δ 4.58 (dd, J = 12.0, 5.7 Hz, 1H), 4.37ꢀ4.32 (m, 1H), 3.98 (dd, J = 12.1, 3.7 Hz, 1H), 3.84
(dd, J = 12.1, 2.9 Hz, 1H), 0.92 (s, 9H), 0.89 (s, 9H), 0.21 (s, 3H), 0.16 (s, 3H), 0.09 (s, 3H), 0.08 (s,
3H); 19F NMR (377 MHz, CDCl3) δ ꢀ134.67 (d, J = 11.9 Hz); 13C NMR (101 MHz, CDCl3) δ 165.2 (d, J
= 26.0 Hz), 102.1 (d, J = 259.6 Hz), 83.6, 74.1 (d, J = 16.0 Hz), 59.5, 25.7, 25.5, 18.2, 18.0, ꢀ4.4, ꢀ5.2, ꢀ
5.4, ꢀ5.5; HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C17H35ClFO4Si2 413.1746, found 413.1739.
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((2R,3R,4S)-3-((tert-Butyldimethylsilyl)oxy)-4-chloro-4-fluoro-5-oxotetrahydrofuran-2-yl)methyl
4-nitrobenzoate (30). To a solution of lactone 28 (140 mg, 0.47 mmol) in 1,4ꢀdioxane (2 mL) were
added paraꢀnitrobenzoyl chloride (93 mg, 0.50 mmol) and triethylamine (0.09 mL, 0.65 mmol). The
reaction mixture was stirred at rt for 45 min and quenched with 1 M HCl (10 mL). The organic layer
was washed with a saturated aqueous solution of NaHCO3, brine, dried over MgSO4 and concentrated
under reduced pressure. Purification by flash column chromatography (hexanes/EtOAc, 95:5) afforded
compound 30 (102 mg, 49%) as a white solid. A small amount was recrystallized by slow evaporation
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from pentane/Et2O for Xꢀray analysis. H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.9 Hz, 2H), 8.24 (d,
J = 8.9 Hz, 2H), 4.79 (dd, J = 12.3, 3.5 Hz, 1H), 4.75ꢀ4.69 (m, 1H), 4.62 (dd, J = 12.3, 5.9 Hz, 1H), 4.45
(dd, J = 8.4, 4.9 Hz, 1H), 0.95 (s, 9H), 0.24 (s, 3H), 0.19 (s, 3H); 19F NMR (377 MHz, CDCl3) δ ꢀ136.48
(d, J = 8.5 Hz); 13C NMR (101 MHz, CDCl3) δ 164.4 (d, J = 26.6 Hz), 164.0, 151.0, 134.2, 130.9,
123.8, 100.6 (d, J = 263.7 Hz), 81.4, 75.6 (d, J = 16.9 Hz), 62.6, 25.5, 18.1, ꢀ4.4, ꢀ5.2; mp 99ꢀ100 °C;
HRMS (ESIꢀTOF) m/z: [M + H]+ calcd for C18H24ClFNO7Si 448.0995, found 448.0984.
ASSOCIATED CONTENT
Supporting Information
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The Journal of Organic Chemistry
The Supporting Information, including 1H, 13C and 19F NMR spectra for newly synthesized compounds
and crystallography data for compound 15 and 30, is available free of charge on the ACS Publications
website.
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AUTHOR INFORMATION
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Corresponding Author
* Eꢀmail: rschina@emory.edu
ACKNOWLEDGMENT
We thank Dr. Bryan Cox for fruitful discussions. This work was supported in part by NIH Grant 5P30ꢀ
AIꢀ50409 (CFAR). Dr. Schinazi is the Chairman and a major shareholder of Cocrystal Pharma, Inc.
Emory received no funding from Cocrystal Pharma, Inc. to perform this work and vice versa.
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