From Oxygen to Sulfur and Back: Difluoro -H-phosphinothioates as a Turning Point in the Preparation of Difluorinated Phosphinates: Application to the Synthesis of Modified Dinucleotides

Article abstract of DOI:10.1021/acs.joc.9b00232

A simple, two-step procedure to convert α,α-difluorinated H-phosphinic acids into the corresponding H-phosphinothioates is described. The usefulness of these species is demonstrated by their transformation into difluorinated phosphinothioyl radicals and their addition onto alkenes. Additionally, sequential treatment of H-phosphinothioates by a strong base and a primary alkyl iodide constitutes an alternate route to the formation of the C-P bond. Both methods efficiently deliver difluorinated phosphinothioates. Similar reactions carried out with the fully oxygenated counterparts clearly indicate the superiority of the sulfur-based species and emphasize the crucial role played by sulfur in the construction of the second C-P bond. Oxidation easily transforms the thereby obtained phosphinothioates into the corresponding phosphinates. The whole strategy is applied to the stereoselective preparation of dinucleotide analogues featuring either a difluorophosphinothioyl or a difluorophosphinyl unit linking the two furanosyl rings.

Full text of DOI:10.1021/acs.joc.9b00232

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Article
From Oxygen to Sulfur and Back: Difluoro-H-Phosphinothioates as
a Turning Point in the Preparation of Difluorinated Phosphinates.
Application to the Synthesis of Modified Dinucleotides.
Jun Zhang, Emilie Lambert, Ze-Feng Xu, Julien Brioche, Pauline Remy, and Serge Rene Piettre
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00232 • Publication Date (Web): 04 Apr 2019
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The Journal of Organic Chemistry
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From Oxygen to Sulfur and Back: Difluoro-H-Phosphinothioates as a
Turning Point in the Preparation of Difluorinated Phosphinates. Application
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to the Synthesis of Modified Dinucleotides.
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Jun Zhang, Emilie Lambert, Ze-Feng Xu, Julien Brioche, Pauline Remy, and Serge R. Piettre*
University of Rouen, Department of Chemistry, COBRA-UMR 6014 CNRS, IRCOF, 76131–Mont Saint Aignan cedex (France)
Difluoro-H-phosphinothioate, difluorophosphinate, phosphorus radical, Michaelis-Becker, dinucleotide analogue
ABSTRACT: A simple, two-step procedure to convert ,–difluorinated–H-phosphinic acids into the corresponding H-
phosphinothioates is described. The usefulness of these species is demonstrated by their transformation into difluorinated
phosphinothioyl radicals and their addition onto alkenes. Additionally, sequential treatment of H-phosphinothioates by a
strong base and a primary alkyl iodide constitutes an alternate route to the formation of the C-P bond. Both methods efficiently
deliver difluorinated phosphinothioates. Similar reactions carried out with the fully oxygenated counterparts clearly indicate
the superiority of the sulfur-based species and emphasize the crucial role played by sulfur in the construction of the second
C-P bond. Oxydation easily transforms the thereby obtained phosphinothioates into the corresponding phosphinates. The
whole strategy is applied to the stereoselective preparation of dinucleotide analogues featuring either
difluorophosphinothioyl or a difluorophosphinyl unit linking the two furanosyl rings.
a
INTRODUCTION
stability in vivo resulting from the two hydrolytically stable
The pivotal role of phosphoric acid derivatives in the
chemistry of life has long been established. Thus esters and
anhydrides of phosphoric acid have been shown to play a
major role in such crucial processes as energy transfer or
cell signalling, and are an essential constituent of nucleic
acids, among others. Enzymes such as kinases,
phosphorylases, phosphatases and nucleases are dedicated
to the catalysis of O-P bond formation or cleavage, and the
controlled balance of their implication secure related
biochemical transformations. Disruption of these balances
may of course result in severe malfunctions and diseases;
for instance, hyperphosphorylation of tau protein has been
linked to neuronal apoptosis and may play a key role in the
carbon-phosphorus bonds.6 Previouswork from this group
led us to introduce ,-difluoro-H-phosphi phosphinic
acids 5 and demonstrate their usefulness as in-termediates
to prepare a variety of phosphorus-centered functional
_____________________________________________
development of both Alzeimer’s disease and Parkinson’s
disease.1 Hence, for decades, scientists have devoted efforts
to design and prepare potent isosters to phosphoric acid
esters. While the first phosphonates (encompassing one C-
P bond) and phosphinates (featuring two C-P bonds) were
reported more than a century ago, it is not before the early
1980s that ,-difluorophosphonates were independently
reported by Blackburn and McKenna.2 The beneficial effects
of fluorine atoms on both structural and electronic
properties of this functional group were later
demonstrated3 and, in the past three decades,
difluorophosphonic acids 1 have emerged as very close
mimics of phosphoric acid monoesters 2 (Figure 1),
resulting in the development of numerous methodologies4
and the preparation of more potent enzymatic inhibitors,
when compared to unfluorinated phosphonates.5
Figure 1. Structures of difluorophosphonic acid 1, phosphoric
acid monoesters 2, difluorophosphinic acid 3, phosphoric acid
diesters 4, difluoro-H-phosphinic acids 5 and difluoro-H-
phosphinothioic acids 6.
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groups.6g Thus, for instance, these species were shown to
add onto carbon-carbon double bonds in the presence of a
radical initiator to generate difluorinated phosphinic acids
3, isolated in good yields in the form of their methyl esters
(Scheme 1).
Diesterified phosphates in dinucleotides seemed well
suited for an application of our hereabove-mentioned
methodology.7 Indeed, the replacement of the phosphoric
Reports of difluorophosphinic acids 3, however, have
been scarce, in spite of both their putative usefulness as
close mimics of phosphoric acid diesters 4 and their
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acid diester with a difluorinated phosphinyl unit would product 10b and phosphonate 11a. The formation of such
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generate an internucleosidyl link essentially inert towards
the action of nucleases. Numerous phosphoryl linkages
have been described in literature following the reported
possi-ility of interfering with the biosynthesis of proteins at
the translational stage and the demonstration of the efficacy
of oligonucleotides in the process aiming at the regulation
of gene expression.8 The antisense strategy and, more
recently, the approach based on small interference RNAs
(siRNA) both rely on the use of natural or
side-products may be explained by a coupling reaction
between the carbon-centered radical adduct and the radical
generated by the homolytic cleavage of DLP, and through an
oxidative process on either the starting H-phosphinyl unit
or the phosphorus-centered radical, respectively. A similar
and somewhat disappointing result was obtained when
furanose 1415 was used (Scheme 2B): the crude mixture of
triethylammonium salts 10c and debenzylated side-
product 10d were acidified (aqueous KHSO4 solution) and
esterified with a freshly prepared solution of diazomethane
in diethyl ether to deliver low isolated yields (14-27%) of
the desired phosphinate 15a and debenzylated methyl
ester 15b in similar amounts (12-21%). This debenzylation
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Scheme 1. Previous work: examples of preparation of
difluorophosphinic acids 3 from H-phosphinic acids 5,
and their conversion into methyl esters.6g
process is presumably the result of
a sequential
intramolecular 1,5 hydrogen abstraction by the initial
radical adduct and an oxidative step.
The requirement for a more neutral substrate was met
through esterification of H-phosphinic acid 5a with
Meerwein’s salt: O-ethyl-H-phosphinate 8a was obtained in
quantitative yield and in a form pure enough to be used in a
subsequent reaction (1H, 19F and 31P NMR spectrometries).
O-Ethyl difluoro-H-phosphinates are, however, not very
stable on silica: a rapid filtration on a plug of silica using
petroleum ether/AcOEt (4/1) as eluent led to a 50% loss of
material. They are also of limited stability when kept in the
cold and undergo slow but significant oxidation. The
reaction of 8a as radical precursor proved much faster;
complete consumption of starting alkene occurred in 10 h
with 8a, and within 24-120 h, depending on the reaction
conditions, when using 7a. This is in line with a more
favored SOMO/HOMO interaction between the O-ethyl
phosphinyl radical derived from 8a (when compared to the
corresponding ammonium salt 7a) and alkene 9. However,
similar results were obtained: the desired adduct 12a was
produced in low isolated yield (15-27%), partly due to its
tedious separation from analogous side-products 12b and
13a (Scheme 2A).
TBPP = t-Bu-O-O-C(O)-t-Bu
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modified oligonucleotides to force the biochemical
machinery to down-regulate gene expression, and have
resulted in a number of applications.9,10,11
Applying the above methodology to more sensitive
substrates (protected furanoses), however, proved more
tedious than anticipated. As shown hereunder, the acidity of
H-phosphinic acids, the strength of the P–H bond and the
emergence of side-reactions led to poor conversions and
yields. In this paper, we show that esters of the hitherto
unreported ,-difluorinated H-phosphinothioic acids 6
constitute a new class of much more efficient synthetic tools
than their fully oxygenated counterparts for the
preparation of difluorophosphinates 3.
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Scheme 2. Radical addition reactions between 5a, 7a or
8a and alkenes 9 or 14.
A. Reaction with alkene 9 (DLP = DiLauroylPeroxide).
RESULTS AND DISCUSSION
Radical reactions.
Reacting H-phosphinic acid 5a6g,12 with protected 4-
vinylfuranosyl derivative 913 in the presence of a radical
initiator (DLP)14 only yielded intractable mixtures,
presumably the result of deleterious interactions between
the strongly acidic substrate and the acid sensitive
functional groups, and no trace of adduct 3a could be
detected in the crude reaction mixture (Scheme 2A). The
use of the less acidic triethylammonium salt 7a partly
solved the problem: the desired adduct 10a was formed in
varying amounts (isolated yields 35-49%), along with side-
B. Reaction with alkene 14 (DLP = DiLauroylPeroxide).
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the corresponding O-ethyl cyclooctyldifluoromethyl-H-
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phosphinothioate (18a) in an unoptimized 51% overall
yield (Scheme 4). All the O-ethyl difluorinated H-
phosphinothioates described in this paper were found to be
much more stable than the corresponding O-ethyl difluoro-
H-phosphinates, and could be kept for months in the cold
and under argon. They displayed a typical chemical shift
1
around 65 ppm in 31P NMR spectra with JP-H value around
2
600 Hz and JP-F value around 95 Hz (see Experimental
Section).
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Scheme 4. Transformation of H-phosphinic acid 5b into
diethyl H-phosphinothioate 18a.
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Results along the same line were obtained when ethyl H-
phoshinate 8b (similarly obtained by treatment of the
corresponding H-phosphinic acid 5b with Meerwein’s salt
and 2,6-lutidine) was reacted with model alkenes 16 or 17
(Scheme 3), thus indicating that the low yields, in the case
of substrate 8b, were not only the result of competitive
functional group interactions under the reactions
conditions. Quite clearly, the more nucleophilic -alkoxyl
radical generated by the addition of the phosphinyl radical
onto butyl vinyl ether (16) makes the chain reaction even
less efficient than with alkene 17, the result of a slower
hydrogen abstraction on H-phosphinate 8b by the radical
adduct: interaction between the HOMO of the P-H -bond
and the SOMO of the radical-adduct derived from 16 will be
less favoured than the analogous one involving the lower-
energy SOMO of the radical-adduct derived from 17.
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The efficacy of difluorinated H-phosphinothioate in the
radical based construction of the C-P bond was
demonstrated by reacting H-phosphinothioate 18a with
model alkenes 14, 16, 17 and 19 (Table 1). While H-
phosphinate 8b failed to give the desired adducts 12c and
12d in practical yields (see Scheme 3), H-phosphinothioate
18a cleanly delivered the expected products 20a-20d in
good to excellent yields. Noteworthy is the comparison
between the results depicted in Scheme 3 and entries 1 and
2 of Table 1, which illustrates the clear superiority of H-
phosphinothioate over its fully oxygenated counterpart in
the construction of the second carbon phosphorus bond.
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Scheme 3. Radical addition reaction between 8b and
model alkenes 16 and 17.
Table 1. Radical addition reaction between cylooctyl-
CF2-P(S)(OEt)H (18a) and alkenes 14, 16, 17 and 19.a
yldb
96
entry
1
alkene
product
16
20a
80c
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3
20b
17
14
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The low yields and the formation of the above side-
products are clearly indicative of too strong a P-H bond in
the phosphorus-centered radical precursors, inducing
coupling reactions or other, competitive hydrogen
abstraction. The documented higher lability of the P-H bond
in thiophosphites16, when compared to phosphites, led us to
consider the ethyl esters 18 of ,-difluoro-H-
phosphinothioic acids 6 as putatively more efficient radical
precursors to generate the second C-P bond.17
20c
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19
20d
There is no report in literature on either difluorinated
H-phosphinothioic acids 6 or their esters. Thus treatment of
a: Reaction carried out at 80 °C in the presence of 0.2 equivalent
of dilauroyl peroxide (DLP) for 5 h. b: Isolated yields as 1:1
mixtures of epimers at phosphorus. c: Diastereomeric ratio of
1.25/1 at phosphorus (see text).
H-phosphinic
acid
5b
with
triethyloxonium
tetrafluoroborate and 2,6-lutidine, followed by heating the
resultant crude O-ethyl-H-phosphinate 8b with Lawesson
reagent18, work-up and purification allowed the isolation of
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phosphonothioic acid 24 (23%)21 (Scheme 6). Screening a
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This strategy was next applied to H-phosphinic acid 5a.
Similar treatment with triethyloxonium tetrafluoroborate
and 2,6-lutidine, followed by heating the resultant crude O-
ethyl-H-phosphinate 8a with Lawesson reagent, work-up
and purification delivered the analogous H-
phosphinothioate 18b in a satisfactory 62% overall yield
(Scheme 5).
Interaction of the latter compound in the presence of
DLP with either alkenylfuranose 9 or 14 induced a much
faster transformation, the reaction being complete in 2 to 4
hours. Chromatography and elution led to the isolation of
expected adducts 20e or 20f in 71 and 77% yields,
respectively. As important is the fact that analysis indicated
this time the crude reaction mixtures to be nearly devoid of
any byproducts. Thus, the more labile P-H bond in H-
phosphinothioate
number of other basic conditions led to the identification of
powdered potassium hydroxide and triethylbenzyl
ammonium chloride (TEBAC) in methylene chloride as the
best option: in this medium, the desired phosphinothioate
20g was selectively produced and could be isolated in 89%
yield. Similar reactions with either 3-phenylpropyl
bromide, triflate or chloride under identical conditions
were found to be less efficient and yielded
difluorophosphinate 20g in 23%, 12% and less than 1%,
respectively. Especially noteworthy is the fact that, under
identical conditions, interaction between the corresponding
H-phosphinate 8c and iodide 21 delivered the analogous,
fully oxygenated counterpart 12e in only 13 % yield, thus
indicative of the reactive superiority of H-phosphinothioates.
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A
nearly identical result was obtained from the
alkylation of difluoro-H-phosphinothioate 18b with 21
under the same conditions (Scheme 7): phosphinothioate
20h could be isolated in 84% yield. We were thus delighted
that similar selectivity and efficiency were obtained when
these conditions were applied to furanosyl-3’-difluoro-H-
phosphinothioate 18b and furanosyl iodide 2522: the
desired phosphinothioate 20f was formed and isolated in
an excellent 86% yield.
18b resulted in a much faster hydrogen abstraction,
thereby significantly reducing the formation of byproducts
of the type 10b, 10d, 11a, 12b or 13a (see Scheme 2).
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Scheme 5. Preparation of H-phosphinothioate 18b and
radical addition reaction of 18b onto alkenes 9 and 14.
The preparation of dinucleotide analogue 12h was next
undertaken (Scheme 8). Fluorinated phosphinothioate 20f
was
sequen-
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Scheme 6. Michaelis-Becker reaction between H-
phosphinate 8c or H-phosphinothioate 18c with iodide
21.
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Michaelis-Becker reaction.
i: Lawesson reagent, toluene, 85°C (85%).
The established acidity of the P-H bond in H-
phosphinates and H-phosphinothioates19 led us to also
consider the formation of the second C-P bond by
conducting a nucleophilic substitution reaction under basic
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tially oxidized with m-chloroperbenzoic acid into its P=O
counterpart 12f (88%)23 and treated with acetic anhydride
in acetic acid to stereoselectively deliver phosphinate 12g
(77%). The same compound could also be obtained by
inverting this sequence of reactions, thus producing first
phosphinothioate 20i, then oxidizing 20i into 12g.
However, all attempts to introduce the two thymines on the
anomeric positions resulted in intractable mixtures.24
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conditions
(Michaelis-Becker
reaction).20
The
transformation was found to strongly depend on the
reaction conditions. Thus, for instance, interaction of a THF
solution of fluorinated H-phosphinothioate 18c (prepared
by treatment of 8c with Lawesson reagent) and 1-iodo-3-
phenylpropane 21 in the presence of potassium tert-
butanolate generated a mixture containing the desired
difluorophosphinothioate 20g (32%), the product resulting
from a competing S-alkylation process 22 (isolated as its
oxidized phosphonothioate 23 in 45% yield) and
Scheme 7. Alkylation of H-phosphinothioate 18b under
basic conditions.
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Reversal of the whole reaction sequence eventually
allowed us to isolate dinucleotide analogue 12h in good
overall yield (Scheme 8). Thus, treatment of
phosphinothioate 20f with acetic anhydride in acetic acid
led to the replacement of both acetonide units with acetate
groups and stereoselectively delivered phosphinothioate
20i, albeit in moderate yield (50%). Introduction of both
thymines under the Vorbrüggen conditions cleanly gave
dinucleotide analogue 20j (66%) with complete
diastereoselectivity. Phosphinothioate 20j smoothly
underwent the oxidative process: the desired difluorinated
phosphinate 12h was isolated in 85% yield.
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Scheme 8. Transformation of difluorophosphinothioate
20f into target compound 12h.
BSA=N,O-BistrimethylSilylAcetamide
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Stereochemical issues at phosphorus.
Ethyl H-difluorophosphinates 8, difluorophosphinates
12,
H-difluorophosphinothioates
18,
and
difluorophosphinothioates 20 are all featuring a chiral
phosphorus atom. No diastereoselectivity was of course
observed during the esterification reaction of H-phosphinic
acids 5 – including 5a featuring remote chiral centers -, and
the esters 8 were isolated as 1:1 mixtures of diastereomers.
Likewise, treatment with Lawesson reagent yielded H-
phosphinothioates
18
as 1:1 mixtures of diastereomers. Phosphonyl and
phosphinyl radicals, as well as their thio derivatives, have
all been shown to possess a pyramidal structure, and to add
onto alkenes with complete retention of configuration at
phosphorus.25 The chain reactions involving difluorinated
phosphinyl and phosphinothioyl radicals thus and
expectedly delivered 1:1 mixtures of diastereomeric
adducts 12 and 20, except in the case of (+)--pinene, which
yielded a 1.25:1 mixtures of diastereomers (12d and
20b)(based on 19F and 31P NMR spectra of the crude
reaction mixtures). At this time, the reason for this slight
diastereomeric excess is unclear and will need further
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investigation; the nature of the doubly bonded chalcogen triethylamine, diisopropylethylamine, dimethylsulfoxide,
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does not however seem to influence it, as the
diastereoselectivity was identical for 12d and 20b.
Likewise, Michaelis-Becker reactions carried out from 1:1
diastereomeric mixture of H-difluorophosphinothioates
toluene) or sodium/benzophenone (tetrahydrofuran,
ether). Unless otherwise indicated, all drying of organic
extracts were carried out over magnesium sulfate and all
chromatographic separations were performed on silica (40-
63 µm or 60-200 µm) from SdS. Thin-layer chromatography
(TLC) were carried out on Merck DC Kieselgel 60 F-254
aluminium sheets. Compounds were visualized by one or
both of the two following methods: (1) illumination with a
short wavelength UV lamp (λ = 254 nm) and/or (2) staining
with phosphomolybdic acid or KMnO4 staining solution
followed by heating. Unless otherwise stated, 1H NMR (300
MHz), 13C NMR (75 MHz), 19F NMR (282 MHz) and 31P NMR
(121 MHz) spectra were recorded in deuterated chloroform
18b
and
18c
delivered
1:1
mixtures
of
difluorophosphinothioates 20f, 20g or 20h.
With regards to the modified dinucleotides 12h,
incorporation of these analogues into modified
oligonucleotides will ultimately be followed by a full
deprotection of the fluorinated phosphinyl units;
prototropy in the resultant ,-difluorophosphinic acids
will suppress chirality at phosphorus. By comparison,
deprotection of the corresponding phosphinothioyl unit 20j
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on a Bruker Avance 300 spectrometer relative to (CH ) Si,
will generate
phosphinothioic
oligonucleotides marketed to date all feature
phosphorothioyl units in place of the phosphoryl links;
these phosphorothioyl units are present as 1:1 epimers at
phosphorus. 26
a
1:1 diastereomeric mixture of
acid. The modified antisense
3 4
CDCl , CFCl and 85% H PO , respectively. Chemical Shifts
3
3
3
4
are expressed in parts per million (ppm) and coupling
constants in Hertz (Hz). HSQC and COSY experiments were
run on the same apparatus to confirm the reported
assignments. Spin multiplicities are indicated by the
following symbols: s (singlet), d (doublet), t (triplet), m
(multiplet), br (broad signal). In the case of dinucleotide
analogues, the carbon atoms in the upper furanose are
numbered from I-1’ to I-5’, and those of the lower furanose,
from II-1’ to II-5’, while the atoms of the thymines are
numbered from 1 (trisubstituted nitrogen) to 6 (CH).
Infrared (IR) spectra were recorded on a Perkin Elmer FT-
IR Spectrum 100 spectrometer. Elemental analyses were
carried out with a Flash 2000 Organic Elemental Analyzer
(Thermo Scientific). Melting points were recorded on a
Kofler bench device and are uncorrected. Optical rotations
were measured on a Perkin-Elmer polarimeter 341. Low
resolution mass spectra using electron impact (EI, 70 eV)
and chemical ionization (CI) techniques were recorded on a
Shimadzu GCMS-QP2010 apparatus (direct introduction).
Low resolution mass spectra using electrospray (ESI) and
atmospheric pressure chemical ionization (APCI)
techniques were recorded on a Finnigan LCQ Advantage
MAX (ion trap) apparatus. High resolution mass spectra
were recorded on a LCT premier XE benchtop orthogonal
acceleration time-of-flight (oa-TOF) mass spectrometer
(Water Micromass); HRMS of chlorine containing
compounds are reported for isotope 35.
CONCLUSION
O-Ethyl ,-difluoro-H-phosphinothioates are easily
prepared in good overall yield from the corresponding H-
phosphinic acids via a two-step sequence of reactions. This
hitherto unreported class of compounds proves to be more
stable than the corresponding H-phosphinates and can be
kept in the cold and under inert atmosphere for an extended
period of time. In the presence of a radical initiator, these
species generate difluorophosphinothioyl radicals which
add onto alkenes to deliver difluorophosphinothioates in
good to high yields. The higher lability of the P-H bond in
fluorinated H-phosphinothioates, when compared to their
fully oxygenated counterparts, results in much cleaner
reactions nearly devoid of any competitive process. In
addition, treatment of difluorinated H-phosphinothioates
with a strong base is shown to provide a nucleophilic
difluorophosphinothioyl species that will generate
analogous phosphinothioates in high yields, when reacted
with
primary
iodides.
Here
again,
the
difluorophosphinothioyl anion proves to be a much more
efficient species than the corresponding phosphinyl anion.
Both these radical and ionic approaches are successfully
applied to the preparation of an analogue of dinucleotide
featuring a phosphinothioyl moiety linking positions C-3’
and C-5’ of the ribofuranosyl units. Easy oxidation of the P=S
5-O-(4-Chlorobenzoyl)-3-(H-hydroxylphosphino)-
difluoromethyl-1,2-O-isopropylidene-α-D-
xylofuranose (5a). To a stirring solution of the requisite
difluoroalkene6g (437 mg, 1.21 mmol) and NaOP(O)H2.H2O
(440 mg, 4.11 mmol) in methanol (10 mL) under argon was
added lauroyl peroxide (472 mg, 1.15 mmol). The resultant
solution was heated at 80°C for 3.5h, after which period of
time 19F NMR spectrometry analysis indicated a full
conversion. The solution was cooled down and evaporated
under reduced pressure. Water was added to the residue,
and the mixture was washed thrice with EtOAc (3x20 mL).
The organic layers were separated and the aqueous layer
was lyophilized to give a crude white solid which was
dissolved in 5% KHSO4 aq. solution (30 mL). The solution
was extracted with EtOAc (2x80 mL, then 40 mL), and the
combined organic extracts were first washed with brine (60
mL), then dried, and finally concentrated to give compound
5a 428 mg (83%) as white foam. 1H NMR δ 1.32 (s, 3H, CH3),
1.57 (s, 3H, CH3), 2.73-2.91 (m, 1H, 3-H), 4.32 (dd, 1H, 5a-H,
into
a
P=O bond makes of difluorinated H-
phosphinothioates useful synthetic tools for the
preparation of difluorinated phosphinates. Additionnally,
the difluorinated phosphinothioyl unit constitutes
a
potentially novel mimic of diesters of phosphoric acid.27
EXPERIMENTAL SECTION
General Information
All reactions were carried out using dried glassware and
magnetic stirring under an atmosphere of argon. All
reagents were obtained from commercially available
sources and used without further purification. DLP and
TBPP refer to DiLauroyl Peroxide and Tert-Butyl
PeroxyPivalate, respectively, and BSA to N,O-
BistrimethylSilylAcetamide. Anhydrous reaction solvents
were obtained by distillation over either calcium hydride
(dichloromethane,
1,2-dichloroethane,
acetonitrile,
6
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The Journal of Organic Chemistry
2J5a,5b = 12.6, 3J5a,4 = 4.8), 4.73 (d, 1H, 5b-H, 2J5b,5a = 12.6), 4.89
(t, 1H, 4-H, 3J = 4.2), 4.96 (dd, 1H, 2-H, 3J2, 1 = 3.3, 3J2, 3 = 9.9),
and 7.18 (2dm, 1H, 1JP-H = 636 and 624, P-H), 7.37 (d, 2H, J =
8.1, HBz), 7.93 (d, 2H, J = 8.1, HBz). 19F{1H} NMR δ
diastereomer A: -112.9 (dd, 1F, 2JF-F = 304.0, 2JF-P = 114.8, 3JF-
H = 21.1), -107.2 (dt, 1F, 2JF-F = 306.1, 2JF-P = 84.3, 3JF-H = 12.0);
diastereomer B: -112.4 (dt, 1F, 2JF-F = 324.3, 2JF-P = 81.8, 3JF-H
1
2
3
4
5
6
7
8
3
1
5.90 (d, 1H, 1-H, J1,2 = 3.6), 7.19 (dd, 1H, P-H, JH-P = 643.8,
3JH-F = 6.3), 7.37 (d, 2H, Bz, 3J = 8.4), 7.93 (d, 2H, Bz, 3J = 8.4).
13C{1H} NMR δ 26.2, 26.4 (CH3), 50.5 (m, C3), 64.5, 74.4, 79.1,
105.0 (C1), 113.3 (C(CH3)2), 128.0, 128.8 (2C), 131.3 (2C),
139.8 (Bz), 165.6 (C=O), (CF2 unobserved due to
multiplicity). 19F{1H} NMR δ -114.1 (dd, 1F, 2JF-F = 324.5, 2JF-
P = 101.4), -105.8 (dd, 1F, 2JF-F = 324.5, 2JF-P = 110.7). 31P{1H}
NMR δ 21.8 (dd, 2JP-F = 101.4 and 110.7).31P NMR δ 21.8 (dm,
2
2
3
= 14.1), -104.8 (dd, 1F, JF-F = 326, JF-P = 112.8, JF-H = 9.5).
31P{1H} NMR δ diastereomer A: 19.9 (dd, 2JF-P = 114.7, 84.3);
diastereomer B: 21.5 (dd, 2JF,P = 112.7, 82.3).
Ethyl (cyclooctyldifluoromethyl)phosphinate (8b).
Following the general procedure, the reaction was carried
out starting from 1.45 g (7.63 mmol) of Meerwein’s salt in
9
1JP-H
=
646.9). HRMS (ESI-TOF) m/z: Calcd for
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
C16H1735ClF2O7P (M-H)-: 425.0374; Found: 425.0373.
CH2Cl2
(50
mL),
a
solution
of
5-O-(4-Chlorobenzoyl)-3-(H-hydroxylphosphino)-
difluoromethyl-1,2-O-isopropylidene-α-D-
(cyclooctyldifluoromethyl)phosphinic acid6g (1.15 g, 5.08
mmol) in CH2Cl2 (15 mL) and 1.20 mL (10.2 mmol) of 2,6-
lutidine. The crude material (1.13 g) obtained after the
above workup was used without further purification. 1H
NMR δ 1.39 (t, 3H, J = 7.1), 1.64-1.40 (m, 10H), 1.81-1.65 (m,
2H), 1.97-1.83 (m, 2H), 2.49-2.19 (m, 1H), 4.36-4.18 (m, 2H),
xylofuranose ammonium salt (7a).6g The above
procedure was followed to give the crude white solid
obtained by lyophilization, which was dissolved in a 1.0 M
aqueous triethylammonium carbonate solution (40 mL).
The solution was extracted thrice with EtOAc (2x80 mL,
then 40 mL), and the combined organic extracts were first
dried, then concentrated to give compound 7a (558 mg,
87%) as a white foam. 1H NMR δ 1.23 (t, 9H, N(CH2CH3)3 , 3J
= 7.2), 1.23 (s, 3H, CH3), 1.47 (s, 3H, CH3), 2.63-2.80 (m, 1H,
H3), 2.97 (q, 6H, 3J = 7.2, N(CH2CH3)3), 4.15 (dd, 1H, H5a, 3J5a-
5b = 12.3, 3J5a-4 = 5.4), 4.70 (d, 1H, H5b, 3J5b-5a = 12.3), 4.78 (dd,
1H, H4, 3J4-3 = 10.2, 3J4-5a = 4.8), 5.01 (dd, 1H, H2, 3J2-1 = 3.6, 3J2,
1
3
7.08 (dd, 1H, JH-P = 579.3 and JH-Fa = 6.3). 31P{1H} NMR δ
21.7 (dd, 2JP-F1 = 128.2, 2JP-F2 = 108.7). 19F{1H} NMR δ -116.2
2
2
3
(dddd, 1F, JF2-F1 = 296.8, JF2-P = 108.7, JF2-H = 15.2 and JF2-
(P)H = 6.2), -118.5 (dddd, apparent ddd, 1F, 2JF1-F2 = 296.8, 2JF1-
P = 128.2, 3JF1-H = 21.5).
Ethyl
(4-tert-butylcyclohexyl)-difluoromethyl-H-
phosphinate (8c). Following the general procedure, ester
8c was prepared from 79 mg (0.415 mmol) of Meerwein’s
salt, 70.5 mg (0.277 mmol) of the requisite H-phosphinic
acid6g and 65 μL (0.554 mmol) of 2,6-lutidine. Obtained as a
colorless oil and as 4:1 mixture of inseparable
3 = 4.2), 5.77 (d, 1H, H1, 3J1-2 = 3.6), 7.10 (dd, 1H, P-H, 1JH-P
555.6, 3JH-F = 6.9), 7.31 (d, 2H, Bz, 3J = 8.4), 7.90 (d, 2H, Bz, 3J
=
2
2
= 8.4). 19F{1H} NMR δ -115.0 (ddd, 1F, JF-F = 299.9, JF-P
=
3
2
2
90.7, JF-H = 21.9), -111.3 (ddt, 1F, JF-F = 299.3, JF-P = 84.7,
3JF-H = 8.5). 31P{1H} NMR δ 9.1 (dt, 1JP-H = 556.5, 2JP-F = 86.3,
89.9).
diastereomers (67 mg, 85 %). 1H NMR
δ major
diastereomer: 0.84 (s, 9H, (CH3)3C), 1.01-1.04 (m, 2H), 1.25-
3
1.37 (m, 3H), 1.42 (t, 3H, JH-H = 6, CH2-CH3), 1.87-2.29 (m,
3
3
General procedure for the preparation of ethyl H-
phosphinates.
5H), 4.39 (dq, 2H, JH-P = 9, JH-H = 6, CH2-CH3), 7.09 (dt, 1H,
1JH-P = 579.1, JH-H = 2.9, H-P).19F{1H} NMR δ major
2
2
An anhydrous methylene chloride (4 mL) solution of the
requisite acid 5 (1 mmol) was added to a stirring,
anhydrous methylene chloride (16 mL) solution of
triethyloxonium tetrafluoroborate (354 mg, 0.95 mmol) at
r. t. under argon. The reaction mixture was stirred at r.t. for
2 h and 2,6-lutidine (130 μL, 1.1 mmol) was then added.
Stirring was continued for another 30 min, after which
period of time the mixture was diluted with CH2Cl2 (10 mL)
and sequentially washed twice with a 0.5 M solution of citric
acid (2x5mL) then brine (5 mL). The organic layer was dried
and filtered, and the solvents were removed under reduced
pressure to give the crude ester as a 1:1 mixture of
diastereomers pure at 95%. These compounds are
somewhat unstable intermediates and were usually
engaged without further purification in either the addition
reaction or the thionylation step. Purification can be
achieved by rapid chromatography on silica despite a
significant degradation of the H-phosphinates into the
corresponding phosphonic acid monoester via an oxidative
process.
diastereoisomer: -120.0 (dd, 1F, JF-F = 265, JF-P = 118), -
119.4 (dd, 1F, 2JF-F = 265,2JF-P = 118); minor diastereoisomer:
-112.6 (dd, 1F, 2JF-F = 299, 2JF-P = 116), -111.5 (dd, 1F, 2JF-F
=
299, JF-P = 117). 31P{1H} NMR δ major diastereoisomer:
2
21.7 (dt, 1JP-H = 578, 2JP-F = 118); minor diastereoisomer: 22.0
1
2
2
(ddd, JP-H = 577, JP-F = 117, JP-F = 116). 13C{1H} NMR δ
(major diastereomer) 16.1 (CH2-CH3), 23.9-24.8 (CH2-CH-
CF2), 26.1 (t-Bu-CH-CH2), 27.3 (3xCH3), 32.3 (CH3-C), 41.6
(td, 1JC-F = 19, 2JC-P= 14, CH-CF2), 47.3 (CH-t-Bu), 63.9 (d, 2JC-P
= 7, CH2-CH3), 121.4 (td, 1JC-F = 263, 1JC-P = 143, CF2). MS (ESI+,
CH3CN/H2O) m/z (%) found: 253.27 [M-(CH2-CH3)]-.
5,6-Dideoxy-3-O-Benzyl-1,2-O-isopropylidene-α-D-
xylofuranose (14). To a solution of oxalyl chloride (0.38
mL, 4.49 mmol) in dry CH2Cl2 (8 mL) was added a solution
of DMSO (0.33 mL, 4.65 mmol) in CH2Cl2 (1 mL) at -78 °C
under inert atmosphere. After 10 min stirring at -78 °C, a
solution of the requisite alcohol28 (1.04 g, 3.71 mmol) in
CH2Cl2 (6 mL) was added, and the reaction mixture was kept
stirring at -78 °C for 15 min. Then DIPEA (3.0 mL, 18.15
mmol) was added dropwise to the reaction and stirring was
continued at -78 °C for an additional 30 min. The mixture
was then warmed up to room temperature over 2.5 h and
quenched with a saturated NaHCO3 aqueous solution (15
mL). Extraction with EtOAc (3x30 mL). The combined
organic layers were dried, filtered, and the filtrate was
concentrated to afford the corresponding crude aldehyde.
KOtBu (20 wt% in THF, 4.2 mL, 6.95 mmol) was added to a
slurry of Ph3PCH2Br (2.76 g, 7.57 mmol) in anhydrous THF
5-O-(4-Chlorobenzoyl)-3-(H-monoethylphosphino)-
difluoromethyl-1,2-O-isopropylidene-α-D-
xylofuranose (8a). The crude ester 8a was obtained as a
1:1 mixture of diastereomers A:B, used as such. 1H NMR δ
1.13-1.20 (m, 6H, 2x0.5xCH3 and CH3-CH2-O), 1.51 and 1.63
(2s, 3H, 2x0.5xCH3), 2.79-2.86 (m, 1H, H3), 4.22-4.39 (m, 3H,
H5a and CH3-CH2), 4.69-4.33 (m, 2H, H5b and H4), 5.07 and
5.19 (2m, 1H, H2), 5.89 and 5.90 (2d, 1H, J1-2 = 3.6, H1), 7.14
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(15 mL) (the reaction mixture turned yellow immediately). corresponding phosphinic acid - 2 steps) as a colorless oil
1
2
3
4
5
6
7
8
After stirring at room temperature for 2 hours, a solution of
the crude aldehyde prepared as above in THF (6 mL) was
added dropwise, and the resultant reaction mixture was
stirred at room temperature for an additional 5.5 h.
Quenching with saturated NaHCO3 aqueous solution,
extraction with EtOAc, drying of the combined organic
layers, filtration and evaporation of the volatiles gave a
crude residue which was purified by chromatography and
eluted with cyclohexane/ethyl acetate (30:1 to 20:1
gradient) to afford compound 14 (817 mg, 80%) as a
colorless syrup. 1H NMR δ 1.36 (s, 3H, CH3), 1.62 (s, 3H, CH3),
3.51 (dd, 1H, 3J3,4 = 9.0, 3J2,3 = 4.2, H3), 4.47 (dd, 1H, 3J4,5 = 6.9,
3J4,3 = 8.7, H4), 4.56 (t, 1H, 3J = 3.9, H2), 4.62 (d, 1H, AB syst, J
= 12.3, Bn-CH2-), 4.75 (d, 1H, AB syst, J = 12.3, Bn-CH2-), 5.27
(ddd, dt apparent, 1H, 3J6a,5 = 10.2, 2J6a,6b = 1.2, 3J6a,4 = 1.2, H6a),
5.46 (ddd, dt apparent, 1H, 3J6b,5 = 17.1, 2J6b,6a = 1.2, 3J6b,4 = 1.2,
(containing about 7% of regioisomer). Major regioisomer:
1H NMR δ 1.35 (t, 3H, J = 7.1), 1.79-1.65 (m, 12H), 1.96-1.80
(m, 2H), 2.71-2.39 (m, 1H), 4.34-4.09 (m, 2H), 6.84 (ddd, 1H,
1JH-P = 579.3, 3JH-FA = 6.0, 3JH-FA’ = 3.0). 13C{1H} NMR δ 16.3 (d,
CH3, JC-P = 6.3), 24.9 (m, CH2), 25.4 (CH2), 25.7-25.4 (m,
2xCH2), 26.4 (2xCH2), 26.8 (CH2), 40.7 (ddd, apparent td,
3
2
2
CHCF2, JC-F = 18.1 and 18.1, JC-P = 15.0), 63.2 (d, OCH2CH3,
2JC-P = 7.5), (CF2 unobserved due to multiplicity). 31P{1H}
NMR δ 63.6 (dd, JP-F1 = 112.4, JP-F2 = 105.3). 19F NMR δ –
114.4 (dddd, 1F, 2JF2-F1 = 280.7, 2JF2-P = 105.3, 3JF2-H = 16.4, 3JF2-
(P)H = 6.2), –115.6 (dddd, 1F, 2JF1-F2 = 280.7, 2JF1-P = 112.4, 3JF1-H
= 19.8 and 3JF1-(P)H = 2.5). FTIR max (cm-1) 2922 (CH), 1053
(CF), 925, 893, 765 or 662 (P=S). HRMS (ESI-TOF) m/z:
Calcd for C11H21F2OPS [M.]+: 270.1019; Found 270.1007.
Minor regioisomer: 1H NMR δ (diagnostic signals only) 6.84
(ddd, apparent dt, 1H, 1JH-P = 500.8, 3JH-F1,2 = 3.0). 31P NMR δ
73.3 (s).
2
2
9
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
3
3
H6b), 5.74 (d, 1H, J1,2 = 3.6, H1), 5.78 (ddd, 1H, J5,6a = 10.2,
3J5,6b = 17.1, 3J5,4 = 3.6, H5), 7.35 (m, 5H, Ph-CH2).13C{1H} NMR
δ 26.8, 27.0, 72.5, 77.9, 79.4, 82.0, 104.0, 113.2, 119.2, 128.2,
128.3 (2C), 128.7 (2C), 135.1, 137.8. [α]20D = + 65.6 (C = 0.44,
CHCl3). Anal. Calcd. for C16H20O4: C, 69.54; H, 7.30. Found: C,
69.42; H, 7.64. MS (CI, NH3) found (M+NH4)+: 294.
5-O-(4-Chlorobenzoyl)-3-(O-ethyl-H-
phosphinothio)difluoromethyl-1,2-O-isopropylidene-
α-D-xylofuranose (18b). Lawesson reagent (206 mg, 0.49
mmol) was added to a solution of the crude H-phosphinate
8a obtained as above (430 mg, 0.95 mmol) in distilled
toluene (5.0 mL), and the resultant mixture was heated at
85 °C for 40 min. Concentration under reduced pressure
and purification of the residue by chromatography and
elution with cyclohexane/EtOAc (10:1 to 6:1 gradient)
delivered H-phosphinothioate 18b (261 mg, 58%) as a
colorless oil. For analytical purposes, a pure fraction of
3-O-Benzyl-5’8-dideoxy-8-iodo-1,2-O-isopropylidene-
α D-ribohexofuranose (25). The reaction was carried out
in the dark. To a solution of Cp2Zr(H)Cl (575mg, 2.17 mmol)
in dry methylene chloride (6 mL) under argon, was added a
solution of alkene 14 (500 mg, 1.81 mmol) in anhydrous
methylene chloride (6 mL) and the resultant mixture was
stirred until complete dissolution.29 Iodine (551 mg, 2.17
mmol) and DIPEA (291 µL, 2.17 mmol) were then
sequentially added and stirring was continued for 2
additional hours. The mixture was quenched with a 0,1 M
aqueous solution of HCl (10 mL) and the organic layer was
separated and washed three time with water. Drying of the
organic layer, filtration of the solid and removal of the
volatiles under reduced pressure left a crude residue which
was purified by chromatography and eluted with
cyclohexane/EtOAc (15:1) to deliver iodocompound 25 as
a colorless oil (592 mg, 81 %). 1H NMR δ 1.25 and 1.50 (2s,
6H, (CH3)3C), 1.79-1.92 (m, 1H, CH2CH2I), 2.07-2.20 (m, 1H,
CH2-CH2I), 3.02-3.16 (m, 2H, CH2-I), 3.32 (dd, 3JH-H = 8.9, 3JH-
H = 4.2, 1H, H3), 3.95 (td, 3JH-H = 8.7, 3JH-H = 3.3, 1H, H4), 4.41-
diastereoisomer
chromatography
A
was isolated by additional
and characterized separately.
Diastereoisomer A: 1H NMR δ 1.32 (s, 3H, CH3), 1.36 (t, 3H,
3J = 4.2, CH3CH2O-P), 1.53 (s, 3H, CH3), 2.85-3.01 (m, 1H, H3),
4.16-4.39 (m, 3H, H5a and CH3CH2O-P), 4.75-4.80 (m, 2H, H4
3
3
and H5b), 5.09 (t, 1H, H2, J2-1 = 4.5), 5.92 (d, 1H, J1-2 = 4.2,
H1), 7.41 (d, 2H, 3J = 8.4, Bz), 7.90 (dd, 1H, 1JH-P = 588.3, 3JH-F
= 11.7, P-H), 7.97 (d, 2H, 3J = 8.4, Bz). 13C{1H} NMR δ 16.2 (d,
CH3CH2O-P, 3JC-P = 6.8), 26.4, 26.7 (C(CH3)2), 48.7 (dt, C3, 2JC-P
2
2
= 21.9, JC-F = 17.4), 63.1 (d, CH3CH2O-P, JC-P = 7.6), 64.5 (d,
4
3
3
C5, JC-F = 2.3), 74.6 (t, C4, JC-F = 6.6), 78.9 (d, C2, JC-F = 9.4),
105.3 (s, C1), 113.3 (s, C(CH3)2), 121.2 (ddd, CF2, 1JC-F = 281.6,
1
1JC-F = 265.0, JC-P = 107.2), 128.2, 128.9 (2C, Bz), 131.2 (2C,
Bz), 139.7 (Bz), 165.3 (C=O). 19F{1H} NMR δ -108.9 (ddd, 1F,
3
2
3
2
4.48 (m, 2H, H2 and CH2Ph), 4.68 (d, 1H, AB JAB = 12.0,
2JF-F = 285.2, JF-P = 90.4, JF-H = 20.9), -106.9 (ddt, 1F, JF-F
=
=
CH2Ph), 5.59 (d, 3JH-H = 3.8, 1H, H1), 7.27 (m, 5H, HPh). 13C{1H}
NMR δ 0.0 (CH2-I), 26.0 and 26.2 (2xCH3), 36.3 (C5), 71.5
(CH2-Ph), 76.5 (C4), 77.3 (C2, overlap with solvent signal and
deduced from DEPT experiment), 80.4 (C3), 103.3 (C1),
112.4 (CH3-C), 127.4 (2C), 127.6, 128.0 (2C), 136.8. Anal.
Calcd. for C16H21IO4: C, 47.54; H, 5.24. Found: C, 47.63; H,
5.26. IR νmax/cm-1: 2935-2810 (C-Har), 758 (C-I).
286.1, 2JF-P = 90.6, 3JF-H = 11.6). 31P{1H} NMR δ 61.4 (t, 2JP-F
92.3). Diastereoisomer B: 19F{1H} NMR δ -110.3 (dddd, 1F,
2JF-F = 305.0, 2JF-P = 96.0, 3JF-H = 8.5, 19.8), -98.02 (ddd, 1F, 2JF-F
2
3
= 305.0, JF-P = 98.8, JF-H = 11.3). 31P{1H} NMR δ 63.2 (dd,
2JP-F
C18H2135ClF2O6PS (M-H)-: 469.0474; Found: 469.0467.
O-Ethyl (4-tert-butylcyclohexyl)-difluoromethyl-H-
= 94.9, 98.4). HRMS (ESI-TOF) m/z: Calcd for
O-Ethyl (cyclooctyldifluoromethyl)phosphinothioate
phosphinothioate (18c). To an anhydrous, stirring
toluene solution (3 mL) of compound 8c (77 mg, 0.303
mmol) was added Lawesson reagent (61 mg, 0.15 mmol)
under argon. The reaction mixture was stirred at 85 °C for
40 min and then concentrated. Purification by
chromatography and elution with cyclohexane/EtOAc
(100:1 to 40:1 gradient) gave the colorless, oily compound
18c (88 mg, 97 %) as a 4:1 mixture of trans and cis
inseparable cyclic diastereomers. 1H NMR δ (major
diastereomer) 0.82 (s, 9H, (CH3)3C), 0.93-1.30 (m, 5H), 1.34
(18a).
To
a
solution
of
ethyl
(cyclooctyldifluoromethyl)phosphinate 8b previously
obtained (1.13 g, 4.44 mmol) in toluene (45 ml) was added
Lawesson reagent (1.11 g, 2.67 mmol) and the reaction was
heated at 50 °C. The reaction was monitored by 31P NMR
analysis and after 1 h the reaction was allowed to cool down
to r. t. before being concentrated under reduced pressure.
The crude residue was purified by chromatography and
elution with petroleum ether/EtOAc (99:1 to 97:3 gradient)
to give 18a (700 mg, 51% global yield from the
3
(t, 3H, CH2-CH3 JH-H = 7.0), 1.44-2.38 (m, 5H), 4.08-4.32 (m,
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The Journal of Organic Chemistry
2H, CH2-CH3), 7.72 (ddd, 1H, 1JH-P = 588.8, JH-H = 6.3, JH-H = 2.1, (A) and 87.3 (B) (2d, C4’, 3JC-F = 16.6), 105.0 (A) and 105.2 (B)
H-P). 19F{1H} NMR-1H δ Major diastereomer: -118.0 (dd, 1F,
(2s, C1), 109.6 (B) and 109.8 (A) (2s, C1’), 112.6, 113.3 (B)
and 113.4 (A) (C(CH3)2), 128.3 (B) and 128.4 (A) (Bz), 128.9
(2C), 131.2 (2C, Bz), 139.68 (A) and 139.74 (B) (Bz), 165.35
(A) and 165.42 (B) (C=O). 19F{1H} NMR δ diastereoisomer
1
2
3
4
5
6
7
8
2
2
2
2JF-F = 277, JF-P = 96), -116.7 (dd, 1F, JF-F = 277, JF-P = 96).
Minor diastereomer: -109.8 (dd, 1F, 2JF-F = 280, 2JF-P = 104), -
108.7 (dd, 1F, 2JF-F = 280, 2JF-P = 116). 31P{1H} NMR δ Major
1
2
2
2
3
diastereomer: 60.8 (ddtm, JP-H = 588, JP-F = 98). Minor
diastereomer: 62.6 (dddm, 1JP-H = 599, 2JP-F = 101, 2JP-F = 117).
13C{1H} NMR δ 16.0 (d, 3JC-P = 7, CH2-CH3), 25.0 (d, 4JC-P = 7, t-
Bu-CH-CH2), 26.1 (CH2-CH-CF2), 27.4 (3xCH3), 32.4 (CH3-C),
41.1 (td, 1JC-F = 19, 2JC-P = 15, CH-CF2), 47.4 (CH-t-Bu), 62.9 (d,
2JC-P = 7, CH2-CH3), 122.6 (td, 1JC-F = 271, 2JC-P = 116, CF2). Anal.
Calcd. for C13H25F2OPS: C, 52.33; H, 8.45; S, 10.74. Found: C,
52.61; H, 9.10; S, 10.22. IR max/cm-1: 2957 (C-H), 2853 (P-
H), 1023 (P-O), 735 (P=S). MS (ESI+, CH3CN/H2O) m/z (%)
found: 299 [M+H]+.
Preparation of phosphinates 12a, 12d, 15a, 15b, and
phosphinothioates 20a-20f. General procedure for the
radical addition reaction. Under Ar, the requisite H-
phosphinate 8 or H-phosphinothioate 18 (1.0 equiv) was
dissolved in distilled methylene chloride (18 mL/mmol,
unless otherwise stated) and the resultant solution was
placed in a Schlenk tube and degassed by bubbling Ar for 30
min. The requisite alkene 9, 14, 16, 17 or 19 (1.5 equiv) was
then added and the solution was again degassed by
bubbling Ar for 15 min. DLP (0.21 equiv) was added and,
after degassing again for 15 min (in some cases, the solution
was finally degassed using the freeze/pump/thaw cycle
technique), the reaction mixture was heated at 80o C for 3 h
(the reaction can be monitored by 19F and 31P NMR analyses
of aliquots). The crude mixture was cooled down to r. t. and
the volatiles were evaporated under reduced pressure.
Unless otherwise stated, purification was achieved by
chromatography using PE/EA (30:1 to 15:1 gradient) as
eluent.
A: -111.1 (ddd, 1F, JF-F = 305.0, JF-P = 98.8, JF-H = 25.4), -
2
2
3
101.2 (ddd, 1F, JF-F = 305.0, JF-P = 76.2, JF-H = 11.3);
diastereoisomer B: -108.8 (ddd, 1F, 2JF-F = 310.6, 2JF-P = 81.9,
3JF-H = 22.6), -101.2 (ddd, 1F, 2JF-F = 310.6, 2JF-P = 107.3, 3JF-H
=
8.5). 31P{1H} NMR δ diastereoisomer A: 42.0 (dd, 2JF1-P = 76.5,
2JF2-P = 98.4); diastereoisomer B: 42.5 (dd, 2JF1-P = 81.4, 2JF2-P
= 106.9). Anal. Calcd. for C28H38ClF2O11P: C, 51.34; H, 5.85.
Found: C, 51.29; H, 5.82. MS (ESI, CH3CN/H2O) found:
(M+H)+, 654.9; (M+ H2O)+, 671.9.
9
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
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39
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59
60
Ethyl
(cyclooctyldifluoromethyl)((1S,5S)-2,4,4,5-
(12d).
tetramethylcyclohex-2-en-1-yl)phosphinate
Prepared from fluorophosphinate 8b (100 mg, 0.393 mmol),
(+)-α-pinene (17) (81 mg, 0.590 mmol) and DLP (31 mg,
0.079 mmol) in CH2Cl2 (6.50 mL). The crude residue was
chromatographed and eluted with petroleum ether:EtOAc
(9:3) to give 12d (55 mg, 36%) as a colorless oil (a 1.25:1
mixture of diastereoisomers (19F NMR analysis of the crude
reaction mixture). For analytical purposes, pure fractions of
each P-centered diastereoisomers were isolated by
additional chromatography and characterized separately.
Major diastereomer: 1H NMR δ 0.89 (d, 3H, J = 10.7), 0.93 (d,
3H, J = 10.7), 1.30 (t, 3H, J = 6.9), 1.90-1.39 (m, 19H), 2.18-
1.92 (m, 3H), 2.45-2.19 (m, 2H), 2.83 (br dd, 1H, J = 16.3 and
5.2), 4.15 (2 x qd, 1 x apparent quin, 2H, J = 6.9), 5.70-5.61
(br m, 1H). 13C{1H} NMR δ 16.6 (d, CH3, 3JC-P = 5.6), 19.3 (CH3),
19.9 (CH3), 24.0 (CH3), 25.3 (br s, CH2), 25.5-25.9 (m, 3xCH2),
26.3-26.6 (m, 2xCH2), 26.8 (br s, CH2), 27.4 (br s, CH2), 28.8
(d, CH2, 3JC-F = 3.0), 32.8 (CH3), 36.3 (CH), 39.2 (d, CH, 1JC-P
=
2
2
82.5), 41.8 (ddd, CHCF2, JC-F = 18.4 and 18.4, JC-P = 10.9),
5-O-(4-Chlorobenzoyl)-3-(O-ethyl-H-phosphino)-
difluoromethyl-1,2-O-isopropylidene-α-D-
62.0 (d, OCH2CH3, 2JC-P = 7.5), 127.5 (d, CH, 3JC-P = 10.7), 127.9
2
(d, C, JC-P = 9.7), (CF2 unobserved due to multiplicity).
xylofuranose (12a). Prepared from phosphinate 8a (272
mg, 0.60 mmol), alkene 9 (290 mg, 1.45 mmol), anhydrous
dichloroethane (8.0 mL) and DLP (106 mg, 0.26 mmol,
added to the mixture in 5 crops (every 1.5 h)). The reaction
mixture was stirred at 84 °C for a total time of 10 h (at this
point, 19F and 31P NMR spectra of aliquots showed full
conversion of 8a). Chromatographed and eluted with
cyclohexane/EtOAc (3:1 to 1:1 gradient) to give compound
12a (78 mg, 20% from 8a) as a white foam (a 1:1 mixture of
31P{1H} NMR δ 41.9 (dd, 2JP-F1 = 108.7, 2JP-F2 = 94.6). 19F{1H}
2
2
3
NMR δ -112.8 (ddd, 1F, JF2-F1 = 295.9, JF2-P = 94.6, JF2-H
=
=
2
2
3
17.5), -115.1 (ddd, 1F, JF1-F2 = 295.9, JF1-P = 108.7, JF1-H
19.2). FTIR (max cm-1) 2920 (CH), 1239 (P=O), 1025 (CF).
HRMS calcd for C21H38F2O2P [M+ H]+: 391.2578. Found
D
391.2575. [α]20
= + 85.2 (c = 1.0, CHCl3). Minor
diastereomer: 1H NMR δ 0.87 (d, 3H, J = 6.5), 0.89 (d, 3H, J =
6.5), 1.31 (t, 3H, J = 6.9), 1.85-1.34 (m, 16H), 2.49-1.87 (m,
8H), 2.85 (br dd, 1H, J = 18.1 and 5.2), 4.19 (2 x qd, 1 x
apparent quin, 2H, J = 7.1), 5.76-5.64 (br m, 1H). 13C{1H}
1
two diastereomers). H NMR δ 1.30 (s, 3H, CH3), 1.31-1.36
3
(m, 6H, C(CH3)2, OCH2CH3), 1.46 (s, 3H, CH3), 1.54 (B) and
1.57 (A) (2s, 3H, CH3), 1.83-2.26 (m, 4H, H5’, H6’), 2.74-2.92
(m, 1H, H3), 3.32 (A) and 3.34 (B) (2s, 3H, 1’-OCH3), 4.08-
4.42 (m, 4H, H4’, OCH2CH3, H5a), 4.50-4.52 (m, 1H, H3’), 4.59
(d, 1H, H2’, 3J2’-3’ = 6.0), 4.73-4.90 (m, 2H, 5b-H5b, 4-H4), 4.94
NMR δ 16.7 (d, OCH2CH3, JC-P= 5.6), 19.5 (CH3), 19.9 (CH3),
24.5 (CH3), 25.1 (br s, CH2), 25.8-25.4 (m, 3xCH2), 26.6-26.2
3
(m, 3xCH2), 26.8 (br s, CH2), 29.0 (d, CH2, JC-F = 2.5), 32.7
1
(CH), 35.1 (CH), 40.3 (d, CH, JC-P = 83.0), 41.8 (ddd, CHCF2,
2JC-F = 18.2 and 18.2, 2JC-P = 10.2), 62.6 (d, OCH2CH3, 2JC-P = 7.5),
3
3
2
(s, 1H, H1’), 5.00 (A) and 5.06 (B) (2t, 1H, H2, J = 4.2), 5.87
127.9 (d, CH, JC-P = 11.0), 128.1 (d, C, JC-P = 9.8), (CF2
(A) and 5.88 (B) (2d, 1H, H1, 3J1,2 = 3.3, 3.0), 7.40 (d, 2H, Bz,
3J = 8.1), 7.96 (2d, 2H, Bz, 3J = 8.7). 13C{1H} NMR δ 16.6 (B)
and 16.7 (A) (2d, OCH2CH3, 3JC-P = 6.0), 22.4 (A) and 23.2 (B)
unobserved due to multiplicity). 31P{1H} NMR δ 40.9 (dd,
2JP-F1 = 111.8, JP-F2 = 85.3). 19F{1H} NMR δ -112.3 (ddd, 1F,
2
2
3
2JF1-F2 = 293.7, JF1-P = 111.8, JF1-H = 14.7), -114.4 (ddd, 1F,
2
3
(2d, C6’, 1JC-P = 96.6, 98.2), 25.0 (C(CH3)2), 26.4 (d, C5’, 2JC-P
=
2JF2-F1 = 293.6, JF2-P = 85.3, JF2-H = 22.3). FTIR (max cm-1)
2920 (CH), 1237 (P=O), 1027 (CF). HRMS (ESI-TOF) m/z:
Calcd for C21H38F2O2P [M+H]+: 391.2578; Found 391.2568.
[α]20D = + 97.2 (c = 1.0, CHCl3).
4.5), 26.6 and 26.6, 26.7, 26.8 (C(CH3)2), 48.6-49.3 (m, C3),
55.2 (B) and 55.4 (A) (2s, 1’-OCH3), 63.1 (A) (d, P-OCH2CH3,
2JC-P = 7.6) and 63.4 (B) (dd, P-OCH2CH3, 2JC-P = 7.6, 4JC-F = 3.0),
64.4 (A) (d, C5, 4JC-F = 2.3) and 64.7 (B) (d, C5, 4JC-F = 3.8), 74.5-
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-O-
(isopropylidene)-α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinyl]-5,8-dideoxy-1,2-
3
74.7 (m, C4), 79.2 (A) (d, C2, JC-F = 7.6) and 79.3 (B) (d, C2,
3JC-F = 10.6), 83.8 (B) and 83.9 (A) (2s, C3’), 85.4 (s, C2’), 87.2
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O-(isopropylidene)-3-O-(benzyl)-α-D-ribo- 10.8), 2.75-2.93 (m, 1H, H3), 3.55-3.64 (m, 1H, H3’), 3.71 (B)
1
2
3
4
5
6
7
8
hexofuranose (15a) and 6-[[[5-O-(4-chlorobenzoyl)-3-
deoxy-1,2-O-(isopropylidene)-α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8-
and 3.74 (A) (2dd, 1H, H4’, J = 8.2, 8.1, J = 4.0), 3.86 (d, 3H,
3JH-P = 10.5, CH3O-P), 4.36 (A) and 4.38 (B) (2dd, 1H, H5a, 2J5a-
5b = 12.3, 3J5a,4 = 7.5), 4.55 (t, 1H, 2’-H, 3J = 4.5), 4.74-4.90 (m,
3
dideoxy-1,2-O-(isopropylidene)-3-hydroxyl-α-D-ribo-
hexofuranose (15b). Prepared from phosphinate 7a (200
mg, 0.38 mmol), alkene 14 (257 mg, 0.93 mmol), 1,2-
dichloroethane (6.0 mL) and DLP (315 mg, 0.77 mmol –
added in 9 crops every 1.5 h) The reaction mixture was
stirred at 86 °C for a total of 36 h. The crude residue
obtained after evaporation of the volatiles was dissolved in
distilled water (10 mL) and the solution was extracted with
EtOAc (2x4 mL). The aqueous solution was lyophilized and
a 5% aqueous solution of KHSO4 (10 mL) was added to the
residue. After 30 min of stirring, the solution was extracted
with EtOAc (3x5 mL) and the combined organic extracts
were dried. Evaporation of the solvent under reduced
pressure left a residue which was dissolved in methylene
chloride (6 mL) and a freshly prepared CH2N2 ethereal
solution (CAUTION) was added at r.t to the stirring solution
until a persistent yellowish color developed. Evaporation of
the volatiles, chromatography and elution with
cyclohexane/EtOAc (3:1 to 1:1 gradient) delivered 15a (76
mg, 27%) and 15b (33 mg, 13%) as white foams. 15a (a 1:1
mixture of two diastereoisomers A:B due to the phosphorus
chiral center) 1H NMR δ 1.30 (A) and 1.33 (B) (2s, 3H, CH3),
1.35 (s, 3H, CH3), 1.51 and 1.57 (2s, 6H, CH3), 1.71-1.89 (m,
1H, H5’a), 1.92-2.35 (m, 3H, H5’b, H6), 2.74-2.92 (m, 1H, 3-H),
2H, H5b, H4), 5.00 (B) and 5.06 (A) (2dd, 1H, H2, J2-1 = 3.9,
3J2-3 = 4.2), 5.75-5.77 (2d, 1H, H1’, 3J1’-2’ = 3.9), 5.87-5.88 (2d,
3
1H, H1, J1-2 = 3.6), 7.40-7.42 (m, 2H, Bz), 7.95-7.99 (m, 2H,
Bz). 13C{1H} NMR δ 21.2 (B) (d, C6’, 1JC-P = 96.6) and 21.8 (A)
1
2
(d, C6’, JC-P = 94.4), 24.3 (2d, C5’, JC-P = 4.5 z), 26.5, 26.55,
26.61, 26.7, 26.8 (C(CH3)2), 48.5-49.2 (m, C3), 53.5 (dd,
CH3O-P, 2JC-P = 6.8, 4JC-F = 2.3) and 53.8 (dd, CH3O-P, 2JC-P = 7.6,
4JC-F = 3.8), 64.3 (B) (d, C5, 4JC-F = 1.5) and 64.6 (A) (d, C5, 4JC-F
= 2.3), 74.4-74.6 (m, C4), 75.5 (C3’), 78.6 (C2’), 79.0-79.3 (C2),
79.5 (A) and 79.6 (B) (2d, C4’, 3JC-P = 15.1), 103.8 (C1’), 105.0
(B) and 105.1 (A) (C1), 112.6 (A) and 112.7 (B) (C(CH3)2),
113.38 (A) and 113.43 (B) (C(CH3)2), 128.2 (A) and 128.3
(B) (Bz), 128.9, (2C, Bz), 131.3 (2C, Bz), 139.68 (B) and
139.74 (A) (Ph), 165.4 (B) and 165.5 (A) (C=O). 19F{1H}
NMR δ diastereoisomer A: -111.7 (1F, ddd, 2JF-F = 307.8, 2JF-P
= 98.8, 3JF-H = 22.6), -101.6 (1F, ddd, 2JF-F = 307.8, 2JF-P = 76.2,
3JF-H = 11.3); diastereoisomer B: -109.0 (1F, ddd, 2JF-F = 310.6,
9
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
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57
58
59
60
2JF-P = 81.9, 3JF-H = 22.6), -101.1 (1F, ddd, 2JF-F = 310.6, 2JF-P
=
107.3, JF-H = 8.5). 31P{1H} NMR δ diastereoisomer A: 43.7
(dd, 2JF1-P = 98.4, 2JF2-P = 77.8); diastereoisomer B: 43.8 (dd,
2JF1-P = 106.9, 2JF2-P = 81.4). HRMS (ESI-TOF) m/z: Calcd for
C26H34Na35ClF2O11P (M+Na)+: 649.1388; found: 649.1359;
MS (ESI, CH3CN/H2O) found: (M+H)+, 626.7; (M+ H2O)+,
644.1.
3
3
3
3.39 (A) and 3.40 (B) (2dd, 1H, H2’, J3’-2’ = 4.2, J2’-1’ = 8.7),
3.84 (d, 3H, 3JH-P = 10.7, CH3O-P), 3.94-4.04 (m, 1H, H4’), 4.37
(A) and 4.38 (B) (2dd, 1H, H5a, 2J5a-5b = 12.3, 3J5a-4 = 7.5), 4.52
(A) and 4.53 (B) (2xd, 1H, AB syst, J = 11.7 and 12.0, Ph-
CH2-), 4.57 (dd, 1H, H2’, 3J2’-3’ = 4.2, 3J2’-1’ = 3.9), 4.74-4.90 (m,
3H, H5b, Ph-CH2-, H4), 4.98 (A) and 5.02 (B) (2dd, 1H, H2, 3J2-
O-Ethyl
(2-
butoxyethyl)(cyclooctyldifluoromethyl)phosphinothio
ate (20a). Following the general procedure, crude product
20a was obtained from H-fluorophosphinothioate 18a (100
mg, 0.37 mmol), alkene 16 (56 mg, 0.55 mmol) and DLP (30
mg, 0.079 mmol) in CH2Cl2 (6.00 mL). The crude residue
was chromatographed and eluted with petroleum
ether/EtOAc (98:2 to 9:1 gradient) to give 20a as a colorless
oil (130 mg, 96%). 1H NMR δ 0.91 (t, 3H, J = 7.4), 1.31 (t, 3H,
J = 6.7), 1.20-1.80 (m, 16H), 1.84-2.08 (m, 2H), 2.24-2.75 (m,
3H), 3.44 (t, 2H, J = 6.7), 3.68-3.86 (m, 2H), 4.02-4.26 (m, 2H).
13C{1H} NMR δ 14.0 (CH2CH3), 16.4 (d, OCH2CH3, 3JC-P = 5.6),
19.4 (br s, CH2), 25.6-25.1 (m, 3xCH2), 25.7 (CH2), 26.5 (CH2),
26.6 (CH2), 26.8 (CH2), 31.9 (CH2), 32.5 (d, CH2, 1JC-P = 69.7),
1 = 3.9, 3J2-3 = 4.2), 5.68 (A) and 5.69 (B) (2d, 1H, H1’, 3J1’-2’
=
3
3.9), 5.86 (2d, 1H, H1, J1-2 = 3.9), 7.29-7.42 (m, 7H, Bz, Ph-
CH2-), 7.95-8.00 (m, 2H, Bz). 13C{1H} NMR δ 21.2 (A) (d, C6’,
1JC-P = 95.9) and 22.2 (B) (d, C6’, 1JC-P = 96.6), 23.5 (B) and 23.6
(A) (2d, C5’, 2JC-P = 17.0, 17.4), 26.6, 26.6, 26.7, 26.8 (C(CH3)2),
2
48.4-49.2 (m, C3), 53.4 (d, CH3O-P, JC-P = 7.6) and 53.7 (dd,
CH3O-P, 2JC-P = 7.6, 4JC-F = 3.8), 64.4 (B) and 64.6 (A) (d, C5, 4JC-F
= 2.3, 3.2), 72.2 (s, -OCH2Ph), 74.5-74.6 (m, C4), 77.27 and
77.31 (C2’), 77.4-77.8 (C4’), 79.1 (B) and 79.2 (A) (2d, C2, 3JC-
2
2
40.0 (ddd, CHCF2, JC-F = 18.3, 18.3 and JC-P = 12.8), 62.5 (d,
2
= 9.8, 10.6), 81.0 (B) and 81.4 (A) (C3’), 104.0 (C1’), 105.0
OCH2CH3, JC-P = 7.0), 64.1 (CH2O), 71.0 (OCH2), (CF2
F
(B) and 105.1 (A) (C1), 112.9 (A) and 113.0 (B) (C(CH3)2),
113.4 (C(CH3)2), 128.2 (2C), 128.3, 128.4 (2C), 128.7 (2C),
128.9 (2C, Ph), 131.3 (2C, Bz), 137.3 (B) and 137.4 (A) (Ph),
139.67 (B) and 139.71 (A) (Ph), 165.38 (B) and 165.44 (A)
(C=O). 19F{1H} NMR δ diastereoisomer A: -111.8 (ddd, 1F,
unobserved due to multiplicity).19F{1H} NMR δ -111.6 (ddd,
1F, 2JF1-F2 = 280.1, 2JF1-P = 113.2, 3JF1-H = 15.8), -116.0 (ddd, 1F,
2JF2-F1 = 280.1, 2JF2-P = 89.4, 3JF2-H = 20.9). 31P{1H} NMR δ 90.8
(dd, 2JP-F1 = 113.2, 2JP-F2 = 89.4). FTIR (max cm-1) 2924 (CH),
1032 (CF), 798, 762 or 743 (P=S). HRMS (ESI-TOF) m/z:
Calcd for C17H34F2O2PS [M+H]+: 371.1985; Found 371.1998.
2JF-F = 307.8, 2JF-P = 98.8, 3JF-H = 22.6), -101.8 (ddd, 1F, 2JF-F
=
2
3
307.8, JF-P = 76.2, JF-H = 11.3); diastereoisomer B: -109.2
O-Ethyl
(cyclooctyldifluoromethyl)((1S,5S)-2,4,4,5-
(ddd, 1F, 2JF-F = 310.6, 2JF-P = 79.1, 3JF-H = 22.6), -101.2 (ddd,
tetramethylcyclohex-2-en-1-yl)phosphinothioate
1F JF-F = 310.6, JF-P = 107.3, JF-H = 8.5). 31P{1H} NMR δ
(20b). Prepared from H-fluorophosphinothioate 18a (90
mg, 0.33 mmol), (+)-α-pinene (68 mg, 0.50 mmol) and DLP
(30 mg, 0.079 mmol) in CH2Cl2 (5.5 mL). Chromatography
and elution of the the crude residue with petroleum
ether/EtOAc (99:1 to 98:2 gradient) led to the isolation of
20b (108 mg, 80%) as a colorless oil (a 1.25:1 mixture of
two inseparable P-centered diastereoisomers by 19F NMR
analysis of the crude reaction mixture). Major + minor
diastereomers (*refers to the minor isomer when
unambiguous assignment is possible): 1H NMR δ. 0.95-0.72
2
2
3
2
2
diastereoisomer A: 43.4 (dd, JF1-P = 98.4, JF2-P = 77.8);
2
2
diastereoisomer B: 43.6 (dd, JF1-P = 106.9, JF2-P = 81.4).
HRMS (ESI-TOF) m/z: Calcd for C33H40Na35ClF2O11P
(M+Na)+: 739.1857; Found: 739.1891; MS (ESI,
CH3CN/H2O) found: (M+ H2O)+,733.8. 15b (1:1 mixture of
two diastereoisomers A:B due to the phosphorus chiral
1
center ) H NMR δ 1.34 (s, 3H, CH3), 1.36 (s, 3H, CH3), 1.55
and 1.58 (2s, 6H, CH3), 1.81-1.99 (m, 1H, H5’a), 2.04-2.41 (m,
3H, H5’b, H6), 2.49 (B) and 2.52 (A) (2d, 1H, 3’-OH, J = 10.5,
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The Journal of Organic Chemistry
(m, 6H), 1.17-1.29 (m, 3H), 1.30-1.82 (m, 17H), 1.84-2.18 (m,
center as measured by 19F NMR analysis); chromatography
1
2
3
4
5
6
7
8
5H), 2.24-2.43 (m, 1H), 2.51-2.79 (m, 1H), 2.92-3.09 (br m,
1H), 3.97-4.24 (m, 2H), 5.60-5.72 (br m, 1H). 13C{1H} NMR
δ 16.1-16.5 (m, CH3), 19.5 (CH3), 19.9 (CH3), 20.1* (CH3),
24.4 (CH3), 25.2-26.0 (m, CH2), 26.5-27.0 (m, CH2), 28.3-29.0
(m, CH2), 32.9 (CH), 33.0* (CH), 35.2* (CH), 35.3 (CH), 40.2-
and elution with petroleum ether/EtOAc (3:2) allowed the
isolation of phosphinothioate 20d (145 mg, 69%) as a white
solid. 1H NMR δ 4.29-3.95 (m, 2H), 3.64-3.48 (m, 1H), 2.71-
2.44 (m, 1H), 2.35-2.05 (m, 1H), 2.00-1.84 (m, 4H), 1,83-
0,83 (m, 36H), 0.79 (s, 3H), 0.71-0.68 (m, 1H), 0.56 (s,
41.1 (m, CHCF2), 42.4 (d, CH, 1JC-P = 59.0), 45.9* (d, CH, 1JC-P
=
0.55x3H), 0.55 (s, 0.45x3H). 13C{1H} NMR
δ (CF2
59.0), 62.1 (d, CH2, 2JC-P = 8.0), 62.8* (d, CH2, 2JC-P = 8.0), 128.0
unobserved due to multiplicity), 74.5 (CH), 62.6 (d, CH2, 2JC-
(d, CH, 2JC-P = 7.5), 128.2 (d, CH, 2JC-P = 10.5), 128.5 (d, C, 3JC-P
= 7.0), 62.5 (d, OCH2CH3, JC-P = 7.4), 55.1-54.6 (m, CH),
2
P
3
= 9.6), 129.1* (d, C, JC-P = 7.5), (CF2 unobserved due to
45.11 (CH), 45.07 (CH), 44.4 (d, CH, 2JC-P = 5.4), 43.7 (C), 43.6-
43.3 (m, CH), 43.2 (C), 41.4-39.6 (m, CHCF2), 38.4 (CH2), 37.2
(CH2), 37.0 (CH2), 35.9 (CH), 35.8 (C), 34.0 (CH2), 33.4 (CH2),
32,7 (CH2), 32,3 (CH2), 31,9 (CH2), 30.0 (CH2), 29.8 (CH2),
29.8 (CH2), 26.8 (CH2), 26.7 (CH2), 26.5 (CH2), 25.9 (CH2),
25.8 (CH2), 25.5 (CH2), 25.3 (CH2), 25.3 (CH2), 25.1 (CH2), 21.
9
multiplicity). 31P{1H} NMR δ 94.0* (dd, 2JP-F1 = 116.0, 2JP-F2
=
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
83.8), 97.7 (dd, 2JP-F1 = 109.8, 2JP-F2 = 86.0). 19F{1H} NMR δ -
109.2* (ddd, 1F, 2JF1-F2 = 280.0, 2JF1-P = 116.0, 3JF1-H = 12.1), -
2
2
3
110.0 (ddd, 1F, JF1-F2 = 280.0, JF1-P = 109.8, JF1-H = 14.7), -
2
2
3
115.2 (ddd, 1F, JF2-F1 = 280.0, JF2-P = 86.0, JF2-H = 21.2), -
2
2
3
3
115.5* (ddd, 1F, JF2-F1 = 280.0, JF2-P = 83.8, JF2-H = 23.4).
FTIR (max cm-1) 2920 (CH), 1031 (CF), 780 or 726 (P=S).
HRMS (ESI-TOF) m/z: Calcd for C21H38F2OPS [M+H]+:
407.2349; Found 407.2346.
1 (CH2), 16.6 (d, CH3CH2OP, JC-P = 6.8), 16.5 (d, CH3CH2OP,
3JC-P = 6.8), 13.1 (CH3), 12,7 (CH3), 12.5 (2xCH3). 31P{1H}
NMR δ 96.4 (dd, 2JP-F1 = 98.0 and 2JP-F2 = 94.3), 94.2 (dd, 2JP-F1
= 107.9, 2JP-F2 = 86.0). 19F{1H} NMR δ -111,8 (ddd, 1F, 2JF1-F2
= 280.7, 2JF1-P = 107.9, 3JF1-H = 16.4), from -112.0 to -113.7 (m,
O-Ethyl
(2-((3aR,5R,6R,6aR)-6-(benzyloxy)-2,2-
dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-
1F, 2JF1-F2 = undetermined due to overlapping signals, 2JF1-P
=
=
3
2
yl)ethyl)(cyclooctyldifluoromethyl)phosphinothioate
(20c). Application of the general procedure to H-
difluorophosphinothioate 18a (100 mg, 0.370 mmol),
alkene 14 (154 mg, 0.550 mmol) and DLP (30 mg, 0.08
mmol) in CH2Cl2 (6.00 mL) furnished, after chromatography
and elution with petroleum ether/CH2Cl2/EtOAc
(50:50:0.3), compound 20c (120 mg, 59%) as a colorless oil
(a 1:1 mixture of P-centered diastereoisomers as measured
by 19F NMR analysis of the crude reaction mixture). When
TBPP (14 mg, 0.08 mmol) was used as radical initiator,
product 20c was isolated in 62% (125 mg). 1H NMR δ 1.26
and 1.27 (2t, 3H, J = 6.9), 1.33 (s, 3H), 1.57 (s, 3H), 1.37-1.79
(m, 12H), 1.85-2.36 (m, 6H), 2.45-2.69 (m, 1H), 3.42 (dd, 1H,
J = 8.9 and 4.4), 3.93-4.09 (m, 2H), 4.10-4.26 (m, 1H), 4.53
(d, 1H, AB syst, JAB = 11.7), 4.53-4.58 (m, 1H), 4.77 (d, 1H, AB
syst, JAB = 11.7), 5.69 (2d, 1H, J = 4.2), 7.25-7.39 (m, 5H).
13C{1H} NMR δ 16.6 (d, OCH2CH3, 3JC-P = 5.6), 26.7 (CH3), 26.9
98.0, JF2-H = 18.3), -113.1-(-)114.9 (m, 1F, JF2-F1
undetermined due to overlapping signals, 2JF2-P = 94.3, 3JF2-H
2
2
3
= 18.1), -115,2 (ddd, 1F, JF2-F1 = 280.7, JF2-P = 86.0, JF2-H
=
20.3). FTIR (max cm-1) 3335 (OH), 2922 (CH), 1035 (CF),
732 or 634 (P=S). HRMS (ESI-TOF) m/z: Calcd for
C31H52F2O2PS [M-H]-: 557.3399; Found 557.3393.
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-O-
(isopropylidene)-α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8-
dideoxy-1-methoxy-2,3-O-(isopropylidene)-α-D-ribo-
hexofuranose (20e). Prepared from phosphinothioate
18b (139 mg, 0.295 mmol), alkene 9 (93 mg, 0.464 mmol),
anhydrous dichloroethane (4.0 mL) and DLP (13.6 mg,
0.033 mmol). The reaction mixture was stirred at 80 °C for
2 h (19F and 31P NMR analyses showed full conversion) and
the crude residue was chromatographed and eluted with
cyclohexane/EtOAc, (15:1 to 8:1 gradient) to yield
phosphinothioate 20e as a white foam (140 mg, 71%).
Diastereoisomer A could be separated and isolated by
1
(CH3), 24.3-27.1 (m, 8xCH2), 28.2 (d, CH2, JC-P = 72.8), 28.3
(d, CH2, 1JC-P = 72.8), 41.2-41.3 (m, CHCF2), 62.6 (d, OCH2CH3,
2JC-P = 6.5), 72.2 (OCH2Ph), 77.4 (CH), 77.6 (overlap with
solvent signal and deduced from DEPT experiment / d, CH,
JC-P = 4.0), 77.8 (d, CH, JC-P = 4.3), 81.4 (CH), 81.5 (CH), 104.1
(CH), 113.0 (C), 128.1 (2xCH), 128.2 (CH), 128.7 (2xCH),
137.5 (C), (CF2 unobserved due to multiplicity). 31P{1H}
1
additional chromatography. Diastereoisomer A: H NMR δ
3
1.28 (t, 3H, CH3CH2, J = 6.9), 1.31 (s, 3H, CH3), 1.32 (s, 3H,
CH3), 1.47 (s, 3H, CH3), 1.55 (s, 3H, CH3), 1.76-1.90 (m, 1H,
H5’a), 1.97-2.16 (m, 1H, H5’a), 2.32-2.41 (m, 2H, H6’), 3.03-
3.19 (m, 1H, H3), 3.35 (s, 3H, -OCH3), 4.02-4.16 (m, 2H,
CH3CH2, H4’), 4.24-4.35 (m, 2H, CH3CH2, H5a), 4.55 (d, 1H, H3’,
3J3’-2’ = 6.0), 4.62 (d, 1H, H2’, 3J2’-3’ = 6.0), 4.71-4.76 (m, 1H, H4),
4.80 (d, 1H, H5b, 2J5b-5a = 12.3), 4.96 (s, 1H, H1’), 5.03 (dd, 1H,
H2, 3J2-1 = 3.9, 3J2-3 = 4.2), 5.88 (d, 1H, H1, 3J1-2 = 3.9), 7.40-7.43
(m, 2H, Bz), 7.96-8.00 (m, 2H, Bz). 13C{1H} NMR δ 16.4 (d,
CH3CH2O-P, 3JC-P = 6.0), 25.0, 26.6, 26.8 (C(CH3)2), 27.0 (d, C5’,
2JC-P = 3.8), 29.2 (d, C6’, 1JC-P = 76.2), 48.2 (ddd, C3, 2JC-P = 23.4,
NMR δ 93.9 (dd, 2JP-F1 = 108.5, 2JP-F2 = 88.9), 93.7 (dd, 2JP-F1
=
=
=
2
109.9, JP-F2 = 88.2). 19F{1H} NMR δ -111.3 (ddd, 1F,2JF1-F2
2
3
2
281.0, JF1-P = 109.5, JF1-H = 16.4), -112.1 (ddd, 1F, JF1-F2
281.5, 2JF1-P = 108.5, 3JF1-H = 16.7), -114.7 (ddd, apparent td,
1F, JF2-F1 = 281.0, JF2-P = 88.9, JF2-H = 19.5), -115.0 (ddd,
2
2
3
2
2
3
apparent td, 1F, JF2-F1 = 281.0, JF2-P = 88.2, JF2-H = 20.0).
FTIR (max cm-1) 2923 (CH), 1019 (CF), 732 or 698 (P=S).
HRMS (ESI-TOF) m/z: Calcd for C27H45F2NO5PS [M+NH4]+:
564.2724; Found 564.2741.
2
2JC-F = 17.4), 55.3 (s, 1’-OCH3), 63.6 (dd, -CH2O-P, JC-P = 7.6,
4JC-F = 3.0), 64.8 (d, C5, 4JC-F = 2.3), 75.0 (dd, C4, 3JC-P = 5.3, 3JC-F
= 6.8), 79.1 (d, C2, 3JC-F = 9.8), 83.9 (C3’), 85.4 (C2’), 87.1 (d, C4’,
3JC-P = 17.4), 105.2 (C1), 109.6 (C1’), 112.5, 113.3 (C(CH3)2),
127.2, 128.3, 128.9 (2C, Bz), 131.3 (2C, Bz), 139.7 (Bz),
165.4 (C=O), (CF2 unobserved due to multiplicity). 19F{1H}
O-Ethyl(cyclooctyldifluoromethyl)(((3S,10S,13S)-3-
hydroxy-10,13-dimethylhexadecahydro-1H-
cyclopenta[a]phenanthren-17-
yl)methyl)phosphinothioate (20d). The above general
procedure, when applied to H-fluorophosphinothioate 18a
(100 mg, 0.370 mmol), alkene 19 (154 mg, 0.550 mmol) and
DLP (30 mg, 0.08 mmol) in CH2Cl2 (6.00 mL), generated a
crude residue (1:1 mixture of diastereomers at phosphorus
2
NMR δ -111.9 (ddd, 1F, JF-F = 290.9, 2JF-P = 87.5, 3JF-H = 25.4),
-100.4 (ddd, 1F, 2JF-F = 288.0, 2JF-P = 81.9, 3JF-H = 8.5). 31P{1H}
NMR δ 91.2 (dd, 2JF1,P = 86.3, 2JF2,P = 81.4). [α]20D = + 21.4 (C
1
= 0.126, CHCl3). Diastereoisomer B: H NMR δ 1.30 (s, 3H,
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CH3), 1.33 (t, 3H, CH3CH2, 3J = 6.9), 1.33 (s, 3H, CH3), 1.47 (s,
Page 12 of 18
3H, CH3), 1.65-1.80 (m, 1H, H5’a), 2.04-2.40 (m, 3H, H5’b, H6),
3.13-3.25 (m, 1H, H3), 3.42 (dd, 1H, H3’, 3J3’-2’ = 4.5, 3J3’-4’ = 9.0),
4.01-4.37 (m, 4H, CH3CH2, H4’, H5a), 4.53 (d, AB syst, 1H, Ph-
CH2-, JAB = 12.0), 4.58 (dd, 1H, H2’, 3J2’-3’ = 4.2, 3J2’-1’ = 3.9), 4.76-
1
2
3
4
5
6
7
8
3H, CH3), 1.57 (s, 3H, CH3), 1.81-2.02 (m, 2H), 2.15-2.21 (m,
1H), 2.32-2.43 (m, 1H), 3.11-3.24 (m, 1H, 3-H), 3.35 (s, 3H,
1’-OCH3), 4.04-4.18 (m, 2H, CH3CH2, H4’), 4.25-4.37 (m, 2H, -
CH3CH2, H5a), 4.55 (d, 1H, H3’, 3J3’-2’ = 6.0), 4.61 (d, 1H, H2’, 3J2’-3’
= 5.7), 4.77-4.84 (m, 2H, 4-H, H5b), 4.96 (s, 1H, H1’), 4.99 (dd,
3
4.84 (m, 3H, 4-H4, H5b, PhCH2-), 4.98 (dd, 1H, H2, J2-1 = 3.6,
3J2-3 = 3.6), 5.70 (d, 1H, H1’, 3J1’-2’ = 3.6), 5.87 (d, 1H, H1, 3J1-2
=
1H, H2, 3J2-1 = 3.6, J2-3 = 3.9), 5.88 (d, 1H, H1, 3J1-2 = 3.6), 7.41
3.6), 7.26-7.36 (m, 5H, PhCH2-), 7.41 (d, 2H, Bz, 3J = 8.4), 7.99
(d, 2H, Bz, 3J = 8.4). 13C{1H} NMR δ 16.6 (d, CH3CH2O-P, 3JC-P
= 6.0), 24.5 (s, C5’), 26.8 (d, C6’, 1JC-P = 73.2), 26.6, 26.8, 26.9,
27.0 (C(CH3)2), 45.3-47.0 (m, C3), 62.9 (d, -CH2O-P, 2JC-P = 7.6),
3
(d, 2H, Bz, J = 8.7), 7.98 (d, 2H, Bz, J = 9.0). 13C{1H} NMR δ
3
16.6 (d, CH3CH2O-P, JC-P = 6.0), 25.0, 26.6, 27.0 (C(CH3)2),
27.3 (s, C5’), 27.8 (d, C6’, 1JC-P = 74.0), 46.4-47.1 (m, C3), 55.5
9
2
4
(s, 1’-OCH3), 62.9 (d, -CH2O-P, JC-P = 6.8), 64.6 (d, C5, JC-F
=
64.6 (d, C5, 4JC-F = 3.8), 72.20 (s, -OCH2Ph), 75.0 (dd, C4, 3JC-F
=
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
3.8), 75.0 (dd, C4, 3JC-F = 6.8, 3JC-P = 3.0), 78.7 (d, C2, 3JC-F = 9.8),
6.8, JC-F = 3.0), 77.3 (C2’), 78.8 (d, C2, JC-F = 9.8), 81.3 (C3’),
104.0 (C1’), 105.1 (C1), 113.0, 113.4 (C(CH3)2), 128.2 (2C),
128.3, 128.4, 128.7 (2C), 128.9 (2C), 131.3 (2C), 137.4,
139.7, 165.4 (C=O), (CF2 unobserved due to multiplicity).
19F{1H} NMR δ -113.8 (1F, ddd, 2JF-F = 290.9, 2JF-P = 79.1, 3JF-H
= 25.4), -99.8 (1F, ddd, 2JF-F = 288.0, 2JF-P = 107.3, 3JF-H = 5.6).
3
3
3
83.9 (C3’), 85.4 (C2’), 87.1 (d, C4’, JC-P = 18.1), 105.1 (C1),
109.8 (C1’), 112.6, 113.4 (C(CH3)2), 128.4, 128.9 (2C), 131.3
(2C), 139.7 (Bz), 165.4 (C=O), (CF2 unobserved due to
2
multiplicity). 19F{1H} NMR δ -113.7 (ddd, 1F, JF-F = 290.9,
2JF-P = 79.1, 3JF-H = 25.4), -99.6 (ddd, 1F, 2JF-F = 290.0.0, 2JF-P
=
2
2
107.3, 3JF-H = 5.6). 31P{1H} NMR δ 91.6 (dd, 2JF1-P = 108.1, 2JF2-P
= 77.8). Anal. Calcd. for C28H38ClF2O10PS: C, 50.11; H, 5.71; S,
4.78. Found: C, 50.82; H, 6.10; S, 4.56. MS (ESI, CH3CN/H2O)
found: (M-H+formic acid)-, 715.1. IR (NaCl), ν (cm-1): 1720
(C=O), 1271, 1096, 1019, 959, 762 (P=S).
31P{1H} NMR δ 91.9 (dd, JF1-P = 108.1, JF2-P = 79.0). Anal.
Calcd. for C34H42ClF2O10PS: C, 54.65; H, 5.67; S, 4.29. Found:
C, 54.80; H, 6.02; S, 4.17. MS (ESI, CH3CN/H2O) found:
(M+H)+, 747.07; (M+H2O)+,764.07. IR (NaCl), ν (cm-1): 1720
(C=O), 1090, 1013, 758 (P=S).
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-O-
(isopropylidene)-α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8-
General procedure for the Michaelis-Becker reaction.
To a dry methylene chloride (3 mL) slurry of powdered KOH
(56 mg, 1 mmol) and benzyl triethyl ammonium chloride
(114 mg, 0.5 mmol) under argon was added a dry CH2Cl2 (3
dideoxy-1,2-O-(isopropylidene)-3-O-(benzyl)-α-D-ribo-
hexofuranose (20f). The radical addition was carried out
according to the general procedure above, starting from
phosphinothioate 18b (172 mg, 0.36 mmol), alkene 14 (116
mg, 0.42 mmol) methylene chloride (6 mL) and DLP (31.6
mg, 0.076 mmol – added in two crops at t=0 and t=2h). The
reaction mixture was heated at 80 °C for a total of 4 hours.
Chromatography and elution with cyclohexane/EtOAc
(15:1 to 9:1 gradient) yielded difluorophosphinothioate 20f
as a white foam (201 mg, 77% - a 1:1 mixture of
diastereomers). For analytical purposes, a pure fraction of
diastereoisomer A could be isolated by additional, careful
mL) solution of the requisite phosphinate
8
or
phosphinothioate 18 (1 mmol) dropwise, followed by a dry
CH2Cl2 (3 mL) solution of the requisite iodide (1 mmol). The
stirring reaction mixture was then heated at 40 °C for 2 h.
After cooling down to r.t., the solution was quenched with a
saturated aqueous solution of ammonium chloride (15 mL).
The separated aqueous layer was extracted with CH2Cl2
(2x7 mL). The combined organic layers were washed with
brine (15 mL), dried, filtered and concentrated under
reduced pressure. Chromatography and elution with
cyclohexane/EtOAc, (15:1 to 9:1) delivered the pure
products.
chromatography
and
characterized
separately.
Diastereoisomer A. 1H NMR δ 1.26 (s, 3H, CH3), 1.28 (t, 3H,
CH3CH2, 3J = 7.2), 1.35 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.57 (s,
3H, CH3), 1.83-1.97 (m, 1H, H5’a), 2.00-2.14 (m, 1H, H5’b),
2.30-2.41 (m, 2H, H6’), 3.02-3.18 (m, 1H, H3), 3.42 (dd, 1H,
O-Ethyl (4-tert-butylcyclohexyl)difluoromethyl (3-
phenyl)propyl phosphinate (12e). Carried out on H-
phosphinate 8c (282 mg, 1 mmol) and iodide 21 (246 mg, 1
mmol). Chromatography and elution of the crude material
with cyclohexane/EtOAc, (8:2) delivered phosphinate 12e
(52 mg, 13 % yield) as a 4:1 mixture of trans and cis cyclic
diastereomers. 1H NMR δ (major diastereomer) 0.84 (s, 9H,
(CH3)3C), 1.07-1.52 (m, 8H), 1,76-2.07 (m, 9H), 2.56-2.71 (m,
2H), 4.08-4.27 (m, 2H), 7.16-7.31 (m, 5H). 19F{1H} NMR δ
3
3
H3’, J3’-2’ = 4.2, J3’-4’ = 8.7), 4.05-4.12 (m, 2H, CH3CH2, H4’),
4.20-4.35 (m, 2H, CH3CH2, H5a), 4.54 (d, AB syst, 1H, Ph-CH2-,
JAB = 11.7), 4.58 (dd, 1H, H2’, 3J2’-3’ = 4.2, 3J2’-1’ = 3.9), 4.71-4.82
3
3
(m, 3H, H4, H5b, Ph-CH2-), 4.96 (dd, 1H, H2, J2-1 = 3.6, J2-3
=
3.9), 5.69 (d, 1H, H1’, 3J1’-2’ = 3.9), 5.85 (d, 1H, H1, 3J1-2 = 3.6),
2
7.31-7.44 (m, 7H, Bz, Ph-CH2-), 7.96-8.01 (m, 2H, Bz).
major diasteromer A: -115.73 (d, 1F, JF-P = 87), -115.72 (d,
13C{1H} NMR δ 16.4 (d, CH3CH2, 3JC-P = 6.0), 24.3 (d, C5’, 2JC-P
=
=
1F, JF-P = 99). Minor diasteromer A: -108.35 (d, 1F, JF-P
2
1
2
3.8), 26.5, 26.6, 26.7, 26.8 (s, C(CH3)2), 28.5 (d, C6’, JC-P
=102), minor diasteromer B: -108.33 (d, 1F, JF-P =107).
76.2), 47.9 (ddd, C3, 2JC-F = 33.2, 2JC-F = 22.6, 2JC-P = 16.6), 63.5
(dd, CH3CH2, 2JC-P = 6.8, 4JC-F = 2.3), 64.7 (d, C5, 4JC-F = 3.8), 72.1
(s, -OCH2Ph), 74.9 (dd, C4, 3JC-F = 6.8, 3JC-F = 5.3), 77.3 (s, C2’),
79.0 (d, C2, 3JC-F = 9.8), 81.3 (s, C3’), 104.0 (s, C1’), 105.1 (s, C1),
112.9, 113.4 (s, C(CH3)2), 128.1 (2C), 128.3, 128.4, 128.7
(2C), 128.9 (2C), 131.3 (2C), 137.4, 139.7, 165.4 (C=O), (CF2
unobserved due to multiplicity). 19F{1H} NMR δ -111.9 (ddd,
1F, 2JF-F = 290.9, 2JF-P = 87.5, 3JF-H = 25.4), -100.9 (ddd, 1F, 2JF-
31P{1H} NMR δ Major diasteromer: 43.4 (dd, JP-F = 92, JP-F
1
2
=100). Minor diasteromer: 43.3 (t, JP-F = 103, 1P). 13C{1H}
1
3
NMR δ 16.6 (d, JC-P
= 8, CH2CH3), 24.6-25.3 (m,
(CH2)2CHCF2), 26.4 (CH2CH2)2CHCF2), 27.5 (CH3)3C), 31.3,
33.9, 36.5 (CH2CH2CH2Ph), 36.9 (CH3)3C), 42.2 (td, 2JC-F = 15,
2
2JC-P = 17, CHCF2), 47.4 (CH3)3CCH), 62.3 (d, JC-P = 11,
CH2CH3), 126.2, 128.5, 140.8 (CPh), (CF2 unobserved due to
multiplicity). IR max/cm-1: 2928 (C-H), 1238 (P=O), 1034 (C-
F). HRMS (ESI-TOF) m/z: Calcd for C22H36F2O2P (M+H)+:
401.2421; Found: 401.2411.
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-O-
(isopropylidene)-α-D-ribofuranos-3-
2
3
= 288.0, JF-P = 81.9, JF-H = 8.5). 31P{1H} NMR δ 91.4 (dd,
F
2JF1-P = 86.3, 2JF2-P = 81.4). [α]20D = + 66.0 (C = 0.206, CHCl3).
Diastereoisomer B. 1H NMR δ 1.33 (t, 3H, CH3CH2, 3J = 6.2),
1.35 (s, 3H, CH3), 1.42 (s, 3H, CH3), 1.57 (s, 3H, CH3), 1.58 (s,
12
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The Journal of Organic Chemistry
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8- 2.38 (m ,4H), 2.60-2.85 (m, 2H), 2.96-3.27 (m, 1H, H3), 3.97-
1
2
3
4
5
6
7
8
dideoxy-1,2-O-(isopropylidene)-3-O-(benzyl)-α-D-ribo-
hexofuranose (20f). Prepared from 0,607 mmol of H-
phosphinothioate 18b and 0,607 mmol of iodide 25.
Chromatography and elution of the crude material with
cyclohexane/EtOAc, (15:1 to 9:1 gradient) allowed the
partial separation and pure diastereomer A was obtained
first as a white foamy material, followed by a [1:4] mixture
of diastereomers A and B (389 mg, total yield: 86 %). Data
identical to those obtained with the compound obtained by
the radical addition reaction (see above).
O-Ethyl (4-tert-butylcyclohexyl)difluoromethyl (3-
phenyl)propyl phosphinothioate (20g). Carried out from
0,27 mmol of H-phosphinothioate 18c and 0,27 mmol of
iodide 21. Purified by chromatography and elution with
cyclohexane/EtOAc (15:1 to 9:1 gradient) to deliver
colorless, oily product 20g as a 4:1 mixture of trans and cis
cyclic diastereomers (96 mg, 89 %). 1H NMR δ (major
diastereomer) 0.75 (s, 9H), 1.03-1.34 (m, 9H), 1.64-2.23 (m,
8H), 2.38-3.00 (m, 2H), 3.97-4.19 (m, 2H), 7.09-7.23 (m, 5H).
4.40 (m, 3H, H5b and 12), 4.64-4.85 (m, 2H, H4 and 5a), 4.92-5.00
(m, 1H, H2), 5.83 (d, J = 3.8, 0.67×1H, H1), 5.85 (d, J = 3.8,
0.33×1H, H1), 7.17-7.29 (m, 5H, HPh), 7.41 (m, 2H, HBz), 7.99
(m, 2H, HBz). 19F NMR δ Diastereomer A, -111.6 (ddd, JF-F
=
289, JP-F = 87, JP-H = 24, 1F), -100.2 (ddd, JF-F = 289, JP-F = 80,
JP-H = 9, 1F). Diastereomer B, -113.1 (ddd, JF-F = 290, JP-F = 78,
JP-H = 26, 1F), -99.1 (ddd, JF-F = 290, JP-F = 108, JP-H = 7, 1F).
31P{1H} NMR-1H δ Diastereomer A, 91.8 (dd, JP-F = 87, JP-F
=
80). Diastereomer B, 92.0 (dd, JP-F = 108, JP-F = 78). 13C{1H}
NMR (*refers to the minor diastereomer when
unambiguous distinction is possible) δ 16.4 (d, J = 6), 16.6*
(d, J = 7), 23.0 (d, J = 4), 23.3* (d, J = 4.5), 26.6, 26.7*, 26.8,
27.0*, 30.0* (d, J = 71), 31.2 (d, J = 74), 36.6 (d, J = 17) ,46.4-
47.2* (m), 47.7-48.7 (m), 63.0* (d, J = 6.7), 63.6 (dd, J = 6.7,
2), 64.7* (d, J = 4.5, C5), 64.9 (d, J = 3, C5), 74.9-75.2 (m), 78.9*
(d, J = 9, C2), 79.2 (d, J = 10.5, C2), 105.24* (C1), 105,29 (C1),
113.2, 113.4*, 126.5, 128.5, 128.65*, 128.69, 128.73, 131.4,
139.8, 140.8*, 140.9, 165.46*, 165.52. IR, γmax/cm-1: 1723
(C=O), 1022 (C-F), 1014 (P-O), 758 (P=S). HRMS (ESI-TOF)
m/z: Calcd for C27H3235ClF2NaO6PS (M+Na)+: 611.1211;
Found: 611.1209.
9
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
19F{1H} NMR δ Major Diastereoisomer, -116.4 (dd, 1F, 2JF-F
=
282, 2JF-P = 86), -114.5 (dd, 2JF-F = 282, 2JF-P = 105, 1F). Minor
diastereoisomer, -108.4 (dd, 2JF-F = 282, 2JF-P = 90, 1F), -105.8
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-O-
(isopropylidene)-α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinyl]-5,8-dideoxy-1,2-
O-(isopropylidene)-3-O-(benzyl)-α-D-ribo-
2
2
(dd, 1F, JF-F = 282, JF-P = 107). 31P{1H} NMR δ Major
2
2
diastereoisomer, 93.3 (dd, JP-F = 105, JP-F = 86). Minor
diastereoisomer, 94.0 (dd, JP-F = 107, JP-F = 90). 13C{1H}
2
2
3
NMR δ 16.4 (d, JC-P
=
9, CH2CH3), 24.8-25.2 (m,
hexofuranose (12f). m-CPBA (140 mg, 0.81 mmol) was
added to a methylene chloride (5 mL) solution of compound
20f (121 mg, 0.16 mmol) and, after 2 hours of stirring at
room temperature, the mixture was quenched with a
saturated sodium thiosulfate solution. The separated
aqueous layer was extracted with CH2Cl2 (2x5 mL) and the
combined organic layers were sequentially washed with a
saturated bicarbonate solution, a saturated ammonium
chloride solution and brine, then dried, filtered and
concentrated under reduced pressure to generate the crude
sample. Purification by chromatography and elution with
cyclohexane/EtOAc (7:3 to 1:1 gradient) led to the isolation
of 104 mg (88 %) of 12f as a 2:1 mixture of diastereomers
(CH2)2CHCF2), 26.4 ((CH2CH2)2CHCF2), 27.4 (CH3)3C), 31.2,
34.9, 35.3 (CH2CH2CH2Ph), 35.5 ((CH3)3C), 42.1 (td, 2JC-F = 12,
2
2JC-P = 18, CHCF2), 47.4 ((CH3)3CCH), 62.2 (d, JC-P = 8,
CH2CH3), 126.2, 128.5, 140.8 (CPh), (CF2 unobserved due to
multiplicity). MS (ESI+, CH3CN/H2O) m/z (%) found: 417.15
[M+H]+. IR, ν max/cm-1: 2945 (C-H), 1028 (C-F), 735 (P=S).
HRMS (APCI-TOF) m/z: Calcd for C22H36F2OPS (M+H)+:
417.2187; Found: 417.2137.
O-Ethyl-S-(3-phenylpropyl)(4-tert-
butylcyclohexyl)difluoromethylphosphonothioate 24.
1H NMR δ (major diastereomers) 0.83 (s, 9H), 0.98 (s, 3H),
1.24-1.37 (m, 6H), 1.84 (s, 2H), 1.98-2.12 (m, 4H), 2.66-2.75
(m, 2H), 2.92-3.02 (m, 2H), 4.19-4.31 (m, 2H), 7.12-7.27 (m,
5H). 19F{1H} NMR δ Major diastereoisomers, -115.7 (dd, 2JF-
F = 293, 2JF-P = 131, 1F), -113.8 (dd, 2JF-F = 225, 2JF-P = 112, 1F).
1
A and B (colorless oil)). H NMR δ 1.27-1.35 (m, 9H), 1.50
(br s, 2H), 1.53-1.57 (m, 4H), 1.66-1.84 (m, 1H, H5’a), 1.93-
2.35 (m, 4H, PCH2, H5’b, H3), 3.34-3.41 (m, 1H, H3’), 3.91-4.05
(m, 1H, H4), 4.06-4.30 (m, 2H, CH3CH2), 4.31-4.40 (m, 1H,
H5a), 4.47-4.59 (m, 2H, H2‘ and Ph-CH2), 4.70-4.88 (m, 3H, H4,
H 5b and Ph-CH2), 4.94-5.03 (m, 1H, H2), 5.67 (m, 1H, H1’),
2
2
Minor diastereoisomers, -108.3 (dd, JF-F = 293, JF-P = 121,
1F), -105.0 (dd, JF-F = 276, JF-P = 85, 1F). 31P{1H} NMR δ
2
2
2
2
(major diastereoisomers), 41.8 (dd, JP-F = 131, JP-F = 112,
1P), minor diastereoisomer could not be detected. MS (ESI+,
CH3CN/H2O) m/z (%) found: 433.3 [M+H]+, 450.7 [M+H2O].
IR ν (cm-1): 1239 (P=O), 1023 (P-O), 703 (P-S).
3
5.84 (d, 1H, JH-H = 3.5, H1), 7.26-7.36 (m, 5H, ArH), 7.39 (d,
2H, 3JH-H = 8.5, BzH), 7.95 (d, 2H, 3JH-H = 8.4, BzH). 19F{1H} NMR
2
2
δ diastereomer A: -110.4 (dd, 1F, JF-F = 306, JF-P = 98), -
101.7 (dd, 1F, 2JF-F = 306, 2JF-P = 78); diastereomer B: -108.9
(dd, 1F, 2JF-F = 310, 2JF-P = 82), -101.1 (dd, 1F, 2JF-F = 310, 2JF-P
= 106). 31P{1H} NMR δ diastereomer A: 41.7 (dd, 2JF-P = 98,
3-Deoxy-3-
[difluoro(ethoxyphosphino(phenylpropyl)thioyl)meth
yl]-1,2-O-(isopropylidene)-5-O-(acetyl)-α-D-
2
2
2JF-P = 78); diastereomer B: 41.9 (dd, JF-P = 106, JF-P = 82).
ribofuranose (20h). Prepared from an anhydrous,
vigourously stirred, CH2Cl2 (1 mL) suspension of powdered
KOH (7 mg, 0.1 mmol), TEBAC (6 mg, 0.026 mmol), an
anhydrous CH2Cl2 (1 mL) solution of H-phosphinothioate
18b (23 mg, 0.049 mmol), and 3-phenylpropyl iodide (1 mg,
0.05 mmol), according to the general procedure above.
Chromatography and elution (cyclohexane/EtOAc, 10/1 to
4/1, v/v) delivered the colorless, oily product 20h as a [1:1]
mixture of diastereomers (24 mg, 84 %). 1H NMR δ 1.20 (s,
0.67×3H, CH3), 1.25-1.33 (m, 3H and 0.33×3H, CH2CH3 and
CH3), 1.47 (s, 0.67×3H, CH3), 1.53 (s, 0.33 ×3H, CH3), 1.81-
13C{1H} NMR (*refers to the minor diastereomer when
unambiguous distinction is possible) δ 16.6 (d, JC-P = 5),
22.4 (d, J C-P = 99), 23.4-23.8 (m), 26.57, 26.62, 26.7, 26.8,
3
1
48.2-49.5 (m), 63.1* (d, 2JC-P = 7), 63.4 (d, 2JC-P = 7), 64.5*, 64.9,
72.2, 74.5-74.8 (m), 77,3, 77.5, 77.9, 79.4-79.1 (m), 81.1*,
81.5, 104.0, 105.0*, 105.1, 112.9, 113.0*, 113.4, 128.1 (2C),
128.2, 128.37, 128.40*, 128.6 (2C), 128.9 (2C), 131.2 (2C),
137.4*, 137.5, 139.66*, 139.68, 165.37*, 165.39, (CF2
unobserved due to multiplicity). MS: ESI+ CH3CN/H2O): m/z
(%) found: 748.00 [M+H2O]+. IR ν max/cm-1: 1724
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The Journal of Organic Chemistry
Page 14 of 18
(C=O),1265 (P=O), 1014 (C-F). HRMS (ESI-TOF) m/z: Calcd
3H, 4’-H, CH3CH2O), 4.34 (B) and 4.36 (A) (2dd, 1H, 5a-H,
for C34H42Na35ClF2O11P (M+Na)+: 753.2019; Found:
753.2016.
2J5a,5b = 12.3, 12.0, 3J5a,4 = 5.7, 6.3), 4.45 (B) and 4.46 (A) (d,
1H, AB syst, J = 11.4, PhCH2), 4.62 (B) and 4.63 (A) (d, 1H,
AB syst, J = 11.4, PhCH2), 4.74 (A) and 4.82 (B) (2d, 1H, 5b-
H, 2J5b,5a = 12.3, 12.0), 4.89-4.97 (m, 1H, 4-H), 5.30 (d, 1H, 2’-
H, 3J2’,3’ = 4.5), 5.46 (B) and 5.55 (A) (2d, 1H, 2-H, 3J2,3 = 4.5),
1
2
3
4
5
6
7
8
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-di-O-acetyl-α-
D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8-
dideoxy-1,2-di-O-(acetyl)-3-O-(benzyl)-α-D-ribo-
hexofuranose (12g). A solution of compound 12f (102 mg,
3
6.07 (B) and 6.11 (A,B) (d and s, 2H, 1-H, 1’-H, J1’,2’ = 1.5),
7.28-7.44 (m, 7H, Bz, Ph-CH2), 8.00-8.04 (m, 2H, Bz). 13C{1H}
NMR δ 16.36 (B) and 16.40 (A) (d, CH3CH2, 3JC-P = 6.0), 20.8,
20.9, 21.0, 21.1, 21.17, 21.23 (CH3COO), 26.5, 27.2, 27.39
and 27.42 (C5’, C6’), 42.0-43.4 (m, C3), 63.1 (2d, CH3CH2, 2JC-P
= 6.8, 4JC-F = 5.3), 65.7-65.9 (m, C5), 73.4 (-OCH2Ph), 73.67 (B)
and 73.72 (A) (C2’), 74.9 (B) and 75.7 (A) (2d, C2, 3JC-F = 8.3,
3JC-F = 6.8), 77.4 (C4), 80.2 (C3’), 81.2 (B) and 81.3 (A) (2d, C4’,
J = 17.9, 17.6), 98.46, 98.51, 98.54, 98.56 (C1, C1’), 128.15,
128.2, 128.3, 128.4, 128.7, 128.9 (Ph), 131.2 (A) and 131.3
(B) (Bz), 137.08 (B) and 137.14 (A) (Ph), 139.88 (B) and
139.94 (A) (Ph), 165.2 (C=O), 168.8 (A), 168.9 (B), 169.06
(A), 169.11 (B), 169.6 (B), 169.7 (A), 169.9 (C=O), CF2 was
not detected. 19F{1H} NMR δ diastereoisomer B: -115.7 (ddd,
0.139 mmol) in
a
67/8/1 (v/v/v) mixture of
AcOH/Ac2O/H2SO4 (3 mL) was stirred for 15 h at room
temperature, then poured into ice-water (10 mL), and
stirred for another 1 h. The mixture was extracted with
EtOAc (2x5 mL) and the combined organic layers were
washed with water, saturated bicarbonate aqueous solution,
brine, dried, filtered and evaporated. Purification by
chromatography and elution with cyclohexane/EtOAc (8:2
to 4:1 gradient) furnished the colorless, oily phosphinate
12g as a [1.5:1] mixture of diastereoisomers A and B (101
mg, 77 %). The same compound was obtained in 92% yield
by oxidation of phosphinothioate 20i with m-CPBA, using
the procedure, work up and purification described above
9
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
2
2
3
2
1F, JF-F = 291, JF-P = 78, JF-H = 25), -102.2 (ddd, 1F, JF-F
=
1
for compound 12f. H NMR δ 1.18-1.33 (m, 3H, OCH2CH3),
294, 2JF-P = 107, 3JF-H = 6); diastereoisomer A: -111.7 (ddd, 2JF-
F = 291, 2JF-P = 102, 3JF-H = 20, 1F), -103.6 (ddd, 2JF-F = 294, 2JF-P
= 82, 3JF-H = 11, 1F). 31P{1H} NMR δ diastereoisomer A: 91.8
(dd, 2JF-P = 102, 2JF-P = 80); diastereoisomer B: 92.6 (dd, 2JF-P
1.75-1.95 (2 × br s and m, 5H), 1.95-2.17 (5 × br s and m,
11H), 3.30-3.09 (m, 1H, H3), 3.84 (d, 0.4H, J = 4.5, H3‘), 3.87
(d, 0.6H, J = 4.5, H3‘), 3.92-4.20 (m, 3H, H4 and OCH2CH3),
4.28-4.43 (m, 1H), 4.36 (d, 1H, AB syst, J = 12.3, Ph-CH2),
4.55 (d, 1H, AB syst, J = 12.3, Ph-CH2), 4.61-4.76 (m, 1H),
2
= 107, JF-P = 79). HRMS (ESI-TOF) m/z: Calcd for
C36H42Na35ClF2O15PS (M+Na)+: 857.1582; Found: 857.1549.
MS (ESI+, CH3CN/H2O) found: 833.1 [M+H]+, 852.1 [M+
H2O]+. IR ν max/cm-1: 1745 and 1728 (C=O), 1014 (C-F), 733
(P=S).
3
4.82-4.94 (m, 1H, H4), 5.23 (d, 1H, JH-H = 4.2, H2‘), 5.48 (d,
1H, 3JH-H = 4.5, H2), 6.02 (br s, 2H, H1 and H1‘), 7.13-7.39 (m,
7H, ArH, BzH), 7.93-7.98 (m, 2H, BzH).19F{1H} NMR δ
2
2
diastereoisomer B: -112.4 (dd, JF-F = 307, JF-P = 104, 1F), -
104.3 (dd, 2JF-F = 304, 2JF-P = 82, 3JF-H = 6); diastereoisomer A:
-112.1 (dd, 2JF-F = 309, 2JF-P = 85, 1F), -105.9 (dd, 2JF-F = 307,
2JF-P = 107, 3JF-H = 11, 1F). 31P{1H} NMR δ diastereoisomer A:
40.7 (dd, 2JF-P = 105, 2JF-P = 84); diastereoisomer B: 42.6 (dd,
2JF-P = 107, 2JF-P = 85). 13C{1H} NMR δ 16.6 (d, 3JC-P = 6), 16.7
6’-[[[5’-O-(4-Chlorobenzoyl)-3’-deoxy-1’-N-(1-
thymidylyl)-2’-O-(acetyl)-α-D-ribofuranos-3’-
yl]difluoromethyl]ethoxyphosphinothioyl]-5’,8’-
dideoxy-2’-O-(acetyl)-3’-O-(benzyl)-1’-N-(1-
thymidylyl)-α-D-ribo-hexofuranose (20j). To an
anhydrous 1,2-dichloroethane (3.0 ml) solution of thymine
(154 mg, 1.19 mmol) was added BSA (0.6 ml, 2.33 mmol),
and the mixture was heated at 80 °C for 1 h, after which
period of time it was cooled down to 0 °C. An anhydrous 1,2-
dichloroethane (3.0 ml) solution of compound 20i (151 mg,
0.18 mmol) and TMSOTf (74 µl, 0.40 mmol) were then
added and the resultant stirring reaction mixture was
heated to 80 °C for 2 h, cooled down to room temperature
and diluted with CH2Cl2 (5 mL). The crude solution was
sequentially washed with a saturated aqueous solution of
sodium bicarbonate (5 mL) and brine (5 mL). The organic
layer was dried, filtered and then concentrated under
reduced pressure. The residue was purified by
chromatography and eluted with CH2Cl2/MeOH (80:1 to
60:1) to give 20j as a white solid (115 mg, 66 % a 1:1
3
2
2
(d, JC-P = 6), 20.2-21.6 (m), 25.5 (d, JC-P = 3), 25.8 (d, JC-P
=
3), 43.5-44.5 (m), 63.1-63.5 (m), 65.8, 65.9, 73.4, 73.6, 75.1
75.5 (m), 77.6 (overlap with solvent signal and deduced
from DEPT experiment), 79.97, 80.05, 81.1, 81.3, 128.30,
128.33, 128.4, 128.7 (2 × C), 128.9 (2 × C), 131.1 (2 × C),
137.0, 137.1, 139.8, 139.9, 165.1, 168.7, 168.8, 169.0, 169.1,
169.4, 169.6, 169.8, (CF2 unobserved due to multiplicity).
MS (ESI+ CH3CN/H2O): m/z (%) found: 836.00 [M+H2O]+;
841.13 [M+ Na]+. IR ν max/cm-1: 1744 (C=O), 1210
(P=O)1013 (C-F). HRMS (ESI-TOF) m/z: Calcd for
C36H42Na35ClF2O15P (M+Na)+: 841.1816; Found: 841.1817.
6-[[[5-O-(4-Chlorobenzoyl)-3-deoxy-1,2-di-O-(acetyl)-
α-D-ribofuranos-3-
yl]difluoromethyl]ethoxyphosphinothioyl]-5,8-
1
dideoxy-1,2-di-O-(acetyl)-3-O-(benzyl)-α-D-ribo-
hexofuranose (20i). Acetic anhydride (0.52 mL, 5.5 mmol)
and concentrated sulfuric acid (65 µL) were sequentially
added dropwise to a stirring solution of compound 20f (288
mg, 0.38 mmol) in acetic acid (4.2 mL) at 0 °C. The above
procedure (12f12g) and work up were then followed;
purification by chromatography and elution with
cyclohexane/EtOAc (6:1 to 4:1) gave compound 20i (161
mg, 50 %) as a white foam (a 1:1 mixture of diastereomers
A and B). 1H NMR δ 1.26 (B) and 1.30 (A) (3t, 3H, CH3CH2O-
inseparable mixture of diastereomers A and B). H NMR δ
1.27 (B) and 1.28 (A) (2t, 3H, CH3CH2O-P, 3J = 7.0), 1.76 (A)
and 1.77 (B) (2s, 3H, 5-CH3), 1.91 (s, 3H, 5-CH3), 2.10, 2.11,
2.12 and 2.14 (4s, 6H, CH3COO-), 1.82-2.28 (m, 4H, 5’II-H,
6’II-H), 3.92-4.24 (m, 5H, 3’I-H, 3’II-H, 4’II-H, CH3CH2O-P),
4.43-4.61 (m, 3H, 5’I-H, -CH2-Ph), 4.74-4.90 (m, 2H, 5’I-H, 4’I-
H), 5.34 (A) and 5.40 (B) (2d, 1H, 1’I-H, 3J1’-2’ = 1.3, 2.4), 5.44
(B) and 5.49 (A) (2dd, 1H, 2’II-H, 3J2’-1’ = 3.3, 2.7, 3J2’-3’ = 5.8),
5.58 (A) and 5.60 (B) (2d, 1H, 1’II-H, 3J1’-2’ = 2.7, 3.3), 5.70 (A)
and 5.82 (B) (d and dd, 1H, 2’I-H, 3J2’-3’ = 6.0, 6.6, 3J2’-1’ = 2.4),
6.95-6.97 (m, 2H, 6-H), 7.27-7.34 (m, 5H, Ph), 7.40-7.44 (m,
2H, Bz), 8.01-8.06 (m, 2H, Bz), 9.42 (B), 9.54 (B), 9.63 (A)
3
P, J = 6.9), 1.75-2.27 (8s and m, 16H, CH3C(O)), 5’H, 6’H),
3.45-3.80 (m, 1H, 3-H), 3.92-3.96 (m, 1H, 3’-H), 4.04-4.20 (m,
14
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The Journal of Organic Chemistry
and 9.74 (A) (4s, 2H, 3-NH). 19F{1H} NMR δ diastereoisomer
137.8 (CH), 138.1 (CH), 140.1 (C), 150.0 (C), 150.1 (C), 163.7
2
2
3
1
2
3
4
5
6
7
8
A: -113.4 (ddd, 1F, JF-F = 291, JF-P = 81, JF-H = 25), -100.8
(ddd,1F, 2JF-F = 291, 2JF-P = 94, 3JF-H = 8,); diastereoisomer B: -
111.0 (ddd, 1F, 2JF-F = 292, 2JF-P = 100, 3JF-H = 23, 1F), -103.4
(C=O), 163.8 (C=O), 165.4 (C=O), 170.4 (C=O), 170.6 (C=O),
(CF2 unobserved due to multiplicity). 19F{1H} NMR δ
diastereoisomer B: -112.4 (dd, 1F, JF-F = 306.4, JP-F = 101.1, JF-
H = 22.9), -105.6 (dd, 1F, JF-F = 306.4, JP-F = 85.9, JF-H = 20.5);
diastereoisomer A: -111.8 (dd, 1F, JF-F = 307.0, JP-F = 101.1,
JF-H = 20.5), -106.5 (dd, 1F, JF-F = 307.0, JP-F = 84.5, JF-H = 15.5).
31P{1H} NMR δ diastereoisomer B: 40.2 (dd, 1P, JP-F = 101.1,
JP-F = 85.9); diastereoisomer A: 40.9 (dd, 1P, JP-F = 101.1, JP-F
= 84.5). IR ν max/cm-1: 1695 (C=O), 1265 (P=O), 1229 (C-
N), 1092 (C-F), 1015 (P-O). MS (ESI-, CH3CN/H2O) found:
921,27 [M-Et]-. Anal. Calcd. for C42H46ClF2N4O15P: C, 53.03;
H, 4.87; N, 5.89. Found: C, 53.08; H, 4.89; N, 5.92.
2
2
3
(ddd, 1F, JF-F = 291, JF-P = 82, JF-H = 11). 31P{1H} NMR δ
2
2
diastereoisomer A: 91.0 (dd, JF-P = 94, JF-P = 81);
diastereoisomer B: 91.6 (dd, JF-P = 100, JF-P = 82). 13C{1H}
2
2
NMR δ 12.3 (B), 12.4 (A), 12.5 (A), 12.6 (B) (C7I and 7II), 16.4
3
(d, JC-P = 6, CH3CH2), 20.8 (B), 20.9 (A), 21.1 (B), 21.2 (A)
(CAc), 24.3 (A) and 24.9 (B) (C5’II), 26.2 (A) and 26.7 (B) (2d,
1JC-P = 74, 74, C6’II), 43.3-44.2 (m, C3’I), 63.3 (A) and 63.4 (B)
(2d, 2JC-P = 6, 7, CH3CH2), 64.9-65.2 (m, C5’I), 73.6 (A) and 73.7
(B) CCH2Ph), 73.9 (B) and 74.1 (A) (C2’II), 75.4 (B) and 75.6 (A)
9
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
3
(2d, JC-F = 7, 7, C2’I,), 77.4 (m, C4’I), 79.1 (C3’II), 80.9 (A) and
81.0 (B) (2d, 3JC-P = 18, 17, C4’II), 91.5 (B) and 93.0 (A) (C1’II),
94.3 (B) and 95.1 (A) (C1’I), 111.4 (A), 111.5 (B), 111.6 (B),
111.7 (A) (C5), 119.8 (m, CF2), 128.2, 128.3, 128.4, 128.7,
129.0 (Ph), 131.3 (Bz), 137.18 and 137.22 (Ph, q), 138.0,
138.1, 138.2 (C6), 139.9 (A) and 140.0 (B) (Ph, q), 150.06,
150.11, 150.5 (C2), 163.8 (A), 164.01 (B), 164.04 (B), 164.4
(A) (C4), 165.4 (C6’I), 170.3 (B), 170.36 (A), 170.44 (A), 170.5
ASSOCIATED CONTENT
Supporting Information
Copy of 1H, 13C, 19F and 31P NMR spectra of the compounds
(PDF)
The Supporting Information is available free of charge on the
ACS Publications website.
(B)
(CAc).
HRMS
(ESI-TOF)
m/z:
Calcd
for
C42H4535ClF2N4O14PS (M-H)-: 965.2053; Found: 965.2057.
MS (ESI, CH3CN/H2O) found: 966.9 [M+H]+, 990.3 [M+Na]+.
IR ν max/cm-1: 1720, 1688 (C=O), 1227 (C-N), 1090 (C-F),
1014 (P-O), 759 (P=S).
AUTHOR INFORMATION
Corresponding Author
*Email: serge.piettre@univ-rouen.fr
6’-[[[5’-O-(4-Chlorobenzoyl)-3’-deoxy-1’-N-(1-
thymidylyl)-2’-O-(acetyl)-α-D-ribofuranos-3’-
Present Addresses
yl]difluoromethyl]ethoxyphosphinyl]-5’,8’-dideoxy-2’-
O-(acetyl)-3’-O-(benzyl)-1’-N-(1-thymidylyl)-α-D-ribo-
hexofuranose (12h). To a stirring solution of compound
20j (89 mg, 0.09 mmol) in dry CH2Cl2 (2 ml) at 0 °C was
added m-CPBA (59 mg, 0.24 mmol) in one crop. The mixture
was stirred for 3 h and quenched with a saturated aqueous
solution of sodium thiosulfate (5 mL). The aqueous layer
was extracted twice with CH2Cl2 (2x5 mL) and the combined
organic layers were sequentially washed with a sodium
bicarbonate saturated aqueous solution (5 mL), a saturated
aqueous solution of ammonium chloride (5 mL) and brine
(5 mL). Drying, filtration and concentration under reduced
pressure afforded a crude residue which was purified by
chromatography and eluted with CH2Cl2/MeOH (10:1) to
deliver a [1:1] mixture of diastereomers 12h (61 mg, 81 %,
white solid). For analytical purposes, a 4:1 mixture of each
P-centered diastereoisomers A:B was isolated by additional
chromatography and fully characterized. 1H NMR δ 1.31 (t,
0.8x3H, J = 7.0, A), 1.32 (t, 0.2x3H, J = 7.0, B), 1.76 (s, 0.8x3H,
A), 1.78 (s, 0.3x3H, B), 1.89 (s, 3H), 2.09 (2s, 2x0.8x3H, A),
2.11 (2s, 2x0.2x3H, B), 1.85-2.13 (m, 4H), 3.66-4.00 (m, 2H),
4.04-4.29 (m, 3H), 4.41-4.62 (m, 3H), 4.72-4.92 (m, 2H),
5.38-5.54 (m, 3H), 5,71 (0.2H, dd, min, J = 6.9 and 2.5, B),
5,79 (0.8H, dd, maj, J = 7.0 and 3.2, A), 6.87-7.00 (m, 2H, CH
thymine), 7.21-7.36 (m, 5H, ArH), 7.37-7.45 (m, 2H, ArH), 7.96-
8.06 (m, 2H, ArH), 8.81 (0.8H, A, NH), 8.84 (0.2H, B, NH), 8.92
(0.2H, B, NH), 8.96 (0.8H, A, NH). 13C{1H} NMR δ 12.5 (CH3),
12.6 (CH3), 16.8 (d, 3JC-P = 5.0, CH3), 20.9-21.1 (m, 2xC), 24.0
(br, CH2), 29.9 (br, CH2), 43.2-44.0 (m, CH), 63.5 (d, 2JC-P = 6.6,
CH2), 65.1 (CH2), 73.8 (CH2), 73.9 (CH), 75.1 (d, 3JC-F = 6.0, CH),
76.8 (m, CH, overlap with solvent signal and deduced from
DEPT experiment), 79.0 (CH), 81.2 (d, 3JC-P = 16.5, CH), 92.4
(CH), 94.8 (CH), 111.6 (C), 111,7 (C), 128.2 (C), 128.3 (CH),
128.5 (CH), 128.8 (CH), 129.1 (CH), 131.4 (CH), 137.3 (C),
†If an author’s address is different than the one given in the
affiliation line, this information may be included here.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
E. L. is indebted to the ERDF (INTERREG IVa, IS-CE Chem
4061) for a fellowship. Financial support from Région
Haute-Normandie is acknowledged.
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phosphinodifluoromethyl derivative.
(8) (a) Paterson, B. M.; Roberts, B. E; Ku, E. L. Structural Gene
Identification and Mapping by DNA-mRNA Hybrid-Arrested Cell-Free
Translation. Proc. Natl. Acad. Sci. U.S.A., 1977, 74, 4370–4374. (b)
Zamecnik, P. C; Stephenson, M. L. Inhibition of Rous Sarcoma Viral RNA
Translation by a Specific Oligodeoxyribonucleotide. Proc. Natl. Acad.
Sci. U.S.A. 1978, 75, 285-88. (c) Fire, A.; S. Xu, S.; Montgomery, K.;
Kostas, S. A.; Driver, S. E.; Mello, C. C. Potent and Specific Genetic
Interference by Double-Stranded RNA in Caenorhabditis Elegans.
Nature 1998, 391, 806-811.
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(5) See for instance: (a) Bialy, L.; Waldmann, H. Inhibitors of Protein
Tyrosine Phosphatases: Next‐Generation Drugs? Angew. Chem. Int. Ed.
2005, 44, 3814-3839. (b) Han, Y.; Belley, M.; Bayly, C. I.; Colucci, J.;
Dufresne, C.; Giroux, A.; Lau, C. K.; Leblanc, Y.; McKay, D.; Therien, M.;
Wilson, M.-C.; Skorey, K.; Chan, C.-C.; Scapin, G.; Kennedy, B. P.
(9) (a) Crooke, S. T. in Antisense Drug Technology, CRC Press 2008; (b)
Burnett, J. C.; Rossi, J. RNA-Based Therapeutics: Current Progress and
Discovery
of
[(3-Bromo-7-cyano-2-
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Future Prospects. J. Chem. Biol. 2012, 19, 60-71. (c) Wan, W. B.; Seth, P.
P. The Medicinal Chemistry of Therapeutic Oligonucleotides. J. Med.
Chem. 2016, 59, 9645-9667.
phosphorus derivatives has been shown to result in decreased pKa
values; see: Haake, P.; R. D. Cook, R. D.; Hurst, G. H. Evaluation of the
Basicity of Phosphine Oxides and Phosphine Sulfides by Measurements
of Chemical Shift in Sulfuric Acid Solutions. J. Am. Chem. Soc. 1967, 89,
2650-2654.
(20) (a) Bhattacharya, A. K.; N. K. Ray in The Chemistry of
Organophosphorus Compounds (Ed. Hartley, F. R.) Vol 2, Wiley,
Chichester, 1995, 192. (b) Savignac, P.; Iorga, B. in Modern Phosphonate
Chemistry CRC Press, Boca Raton 2003.
(10) A number of antisense drugs have been approved for marketing
by the FDA, and many others are in advanced clinical trials (II or III).
See: V. K. Sharma, V. K.; Sharma, R. K.; Singh, S. K. Antisense
Oligonucleotides: Modifications and Clinical Trials. Med. Chem.
Commun. 2014, 5, 1454-1471.
(11) (a) de Fougerolles, A.; Vornlocher, H.-P.; Maraganore, J.;
Lieberman, J. Interfering with Disease: a Progress Report on siRNA-
Based Therapeutics. Nature Rev. 2007, 6, 443-453. (b) B. L. Davidson,
B. L.; McCray, P. B. Jr. Current Prospects for RNA Interference-Based
Therapies. Nature Rev. Genet. 2011, 12, 329-340. (c) Tatiparti, K.; Sau,
S.; Kashaw, S. K.; Iyer, A. K. siRNA Delivery Strategies: A Comprehensive
Review of Recent Developments. Nanomaterials 2017, 7, 77-93. (d) See
also reference 9 (a).
(21) Phosphinothioic acid monoester 23 was not isolated and
identified on the basis of 1H, 19F and 31P NMR spectra.
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(22) Obtained by sequential hydrozirconation and iodinolysis of the
adduct; see Experimental Section.
(23) Lopin, C.; Gautier, A; Gouhier, G.; Piettre, S. R. First and Efficient
Synthesis of Phosphonodifluoromethylene Analogues of Nucleoside-3'-
phosphates: Crucial Role Played by Sulfur in Construction of the Target
Molecules. J. Am. Chem. Soc. 2002, 124, 14668-14675.
(24) (a) Niedballa, U.; Vorbrüggen, H. A General Synthesis of
Pyrimidine Nucleosides. Angew. Chem. Int. Ed. Engl. 1970, 9, 461-462.
(b) Niedballa, U.; Vorbrüggen, H. A General Synthesis of N-Glycosides. I.
Synthesis of Pyrimidine Nucleosides. J. Org. Chem. 1974, 39, 3654-
3660. (c) Niedballa, U.; Vorbrüggen, H. A General Synthesis of N-
Glycosides. II. Synthesis of 6-Methyluridines. Ibid. 1974, 39, 3660-
3663. (d) Niedballa, U.; Vorbrüggen, H. A General Synthesis of N-
(12) Acid 5a is more prone to oxidation into phosphonic acid (within
days) than its ammonium salt 7a (stable for weeks).
(13) Hanessian, S.; Huang, G.; Chenel, C.; Machaalani, R.; Loiseleur, O.
Total Synthesis of N-Malayamycin A and Related Bicyclic Purine and
Pyrimidine Nucleosides. J. Org. Chem. 2005, 70, 6721-6734.
(14) Dilauroyl peroxide (DLP) is commercially available and was
used without further purification. DLP and the commercially
unavailable Tert-Butyl PeroxyPivalate (TBPP) give essentially identical
conversions and yields in these radical reactions. For example, use of
ammonium salt 7a and TBPP generated adduct 10a which was
esterified with diazomethane to give the corresponding ester in 38%
isolated yield (35-49% with DLP).
(15) Redlich, H; Lenfers, J. B.; Kopf, J. Chiral Cyclobutanones by [2 +
2]-Cycloaddition of Dichloroketene to Carbohydrate Enol Ethers.
Angew. Chem. Int. Ed. Engl. 1989, 28, 777-778.
(16) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D. Radical
Addition Reactions of Phosphorus Hydrides: Tuning the Reactivity of
Phosphorus Hydrides, the Use of Microwaves and Horner–
Wadsworth–Emmons-Type Reactions. Eur. J. Org. Chem. 2006, 71,
1547-1554.
(17) For radical reactions involving thiophosphites, see for instance:
(a) Piettre, S. R. Simple and Efficient Synthesis of 2,2-Disubstituted-1,1-
difluoromethylene Phosphonates and phosphonothioates. Tetrahedron
Lett. 1996, 37, 2233-2236. (b) Gautier, A; Garipova, G.; Dubert, O.;
Oulyadi, H.; Piettre, S. R. Efficient and Practical Aerobic Radical
Addition of Thiophosphite to Alkenes. Tetrahedron Lett. 2001, 42,
5673-5676. (c) Jessop, C. M.; Parsons, A. F.; Routledge, A.; Irvine, D.
Et3B-Induced Radical Addition of Diphenylphosphine Oxide to
Unsaturated Compounds. Tetrahedron Lett. 2003, 44, 6169-6171.
(18) (a) Pedersen, B. S.; Scheibye, S.; Nilson, N. H.; Lawesson, S.-O.
Studies on Organophosphorus Compounds XX. Syntheses of
Thioketones. Bull. Soc. Chim. Belg. 1978, 87, 223-228. (b) Scheibye, S.;
Pedersen, B. S.; Lawesson, S.-O. Studies on Organophosphorus
Compounds XXI. The Dimer of p-Methoxyphenylthionophosphine
Sulfide as Thiation Reagent. A New Route to Thiocarboxamide. Bull. Soc.
Chim. Belg. 1978, 87, 229-238. (c) Pedersen B. S.; Scheibye, S.; Nilson,
N. H.; Clausen, K.; Lawesson, S.-O. Studies on Organophosphorus
Compounds XXII. The Dimer of p-Methoxyphenylthionophosphine
Sulfide as Thiation Reagent. A New Route to O-Substituted Thioesters
and Dithioesters. Bull. Soc. Chim. Belg. 1978, 87, 293-297. (d) Scheibye,
S.; Pedersen, B.S.; Lawesson, S.-O. Studies on Organophosphorus
Glycosides. III.
A Simple Synthesis of Pyrimidine Disaccharide
Nucleosides. Ibid. 1974, 39, 3664-3667. (e) Niedballa, U.; Vorbrüggen,
H. A General Synthesis of N-Glycosides. IV. Synthesis of Nucleosides of
Hydroxy and Mercapto N-Heterocycles. Ibid. 1974, 39, 3668-3671. (f)
Niedballa, U.; Vorbrüggen, H. A General Synthesis of N-Glycosides. V.
Synthesis of 5-Azacytidines. Ibid. 1974, 39, 3672-3674. (g) Vorbrüggen,
H.; Krolikiewicz, K.; B. Bennua, B. Nucleoside Syntheses, XXII.
Nucleoside Synthesis with Trimethylsilyl Triflate and Perchlorate as
Catalyst. Chem. Ber. 1981, 114, 1234-1255. (h) Vorbrüggen, H.; Höfle,
G. Nucleoside Syntheses, XXIII On the Mechanism of Nucleoside
Synthesis. Ibid. 1981, 114, 1256-1268.
(25) (a) Benshop, H. P., Platenburg, D. H. J. M., Meppelder, J. H., Reiff,
L. P., Boter H. L. Stereospecific reactions of optically pure menthyl
methylphosphinate. Chem. Commun. 1970, 33-34. (b) Farnham, W. B.,
Murray, R. K., Mislow, K. Stereospecific free-radical addition of menthyl
phenylphosphinate to cyclohexene: evidence for retention of
configuration at phosphorus. Chem. Commun. 1971, 146-147. (c) Reiff,
L. P.; Aaron, H. S. Stereospecific Synthesis and Reactions of Optically
Active Isopropyl Methylphosphinate. J. Am Chem. Soc. 1970, 92, 5275-
5276. (d) H. S. Jockush, S., Turro, N. J. Phosphinoyl Radicals:ꢀ Structure
and Reactivity. A Laser Flash Photolysis and Time-Resolved ESR
Investigation. J. Am Chem. Soc. 1998, 120, 11773-11777. (e) Jessop, C.
M., Parsons, A. F., Routledge, A., Irvine, D. J. Radical Addition Reactions
of Chiral Phosphorus Hydrides. Tetrahedron: Asymmetry 2003, 14,
2849-2851.
(26) For a discussion about this problem and a very recent,
innovative strategy bringing a solution, see: Knouse, K. W.; deGruyter,
J. N.; Schmidt M. A.; Zheng, B.; Vantourout, J. C.; Kingston, C.; Mercer, S.
E.; Mcdonald, I. M.; Olson, R. E.; Zhu, Z.; Hang, C.;Zhu, J.; Yuan, C.; Wang,
Q.; Park, P.; Eastgate, M. D.; Baran, P. S. Unlocking P(V) : Reagents for
Chiral Phosphorothioates Synthesis. Science 2018, 361, 1234-1238.
(27) In addition to their resistance to the action of nucleases, the P=S
bond in difluorophosphinothioates should generate an increased
cellular uptake, when compared to analogous difluorophosphinates, in
line with such differences observed between phosphorothioates and
phosphates. See reference 9a.
(28) Arzel, L.; Dubreuil, D.; Chenel, C.; Dénès, F.; Silvestre, V.; Mathé-
Allainmat, M.; Lebreton, J. Synthesis of Ribonucleosidic Dimers with an
Amide Linkage from D-Xylose . J. Org. Chem. 2016, 81, 10742-10758.
(29) Schwartz’s reagent (Cp2Zr(H)Cl) was prepared according to
literature and titrated with 2-vinylnaphthalene: Buchwald, S. L.;
Lamaire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M. Schwartz’s
Reagent. Organic Syntheses 1993, 71, 77.
Compounds
XXIII.
Synthesis
of
Salicylthioamides
and
4H-1,3,2-Benzoxaphoshorine Derivatives From the Dimer of
p-Methoxyphenylthionophosphine Sulfide and Salicylamide. Bull. Soc.
Chim. Belg. 1978, 87, 299-306. For examples of treatment of P=O bonds
with Lawesson reagent, see: (e) Piettre, S. R. Raboisson, P. Easy and
General Access to ,–Difluoromethylene Phosphonothioic Acids. A
New Class of Compounds. Tetrahedron Lett. 1996, 37, 2229-2232. (f)
Piettre, S. R. Interconversion of ,–Difluoromethylene Phosphonates
and ,–Difluoromethylene Phosphonothioates Tetrahedron Lett.
1996, 37, 4707-4710.
(19) PKa of P-H bonds in H-phosphinates have been reported to be in
the range of 17-22, depending on the substituent on the phosphorus
atom; see: Li, J. N.; Liu, L.; Fu, Y.; Guo, Q. X. What Are the pKa Values of
Organophosphorus Compounds? Tetrahedron 2006, 62, 4453-4462.
The replacement of the doubly bonded oxygen with sulfur in
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From Oxygen to Sulfur and Back: Difluoro-H-phosphinothioates as a Turning Point in the
Preparation of Difluorinated Phosphinates. Application to the Synthesis of Modified
Dinucleotides
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