Application of DAST mediated reactions in transformations of α-hydroxyphosphonates derived from O-isopropylidene-protected carbohydrate derivatives

Article abstract of DOI:10.1080/10426507.2017.1295967

Various α-hydroxyphosphonates derived from O-isopropylidene glyceraldehyde, hexofuranose and pentofuranose have been prepared to test nucleophilic fluorination reactions. The substrates have been conveniently prepared in Pudovik reactions and the stereose

Full text of DOI:10.1080/10426507.2017.1295967

Phosphorus, Sulfur, and Silicon and the Related Elements
ISSN: 1042-6507 (Print) 1563-5325 (Online) Journal homepage: http://www.tandfonline.com/loi/gpss20
Application of DAST mediated reactions in
transformations of α-hydroxyphosphonates
derived from O-isopropylidene-protected
carbohydrate derivatives
Rapp Magdalena, Mrowiec Patrycja & Koroniak Henryk
To cite this article: Rapp Magdalena, Mrowiec Patrycja & Koroniak Henryk (2017): Application
of DAST mediated reactions in transformations of α-hydroxyphosphonates derived from O-
isopropylidene-protected carbohydrate derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2017.1295967
To link to this article: http://dx.doi.org/10.1080/10426507.2017.1295967
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Date: 27 February 2017, At: 05:31

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Reaction of DAST with sugar hydroxyphosphonates
Application of DAST mediated reactions in transformations of α-hydroxyphosphonates derived
from O-isopropylidene-protected carbohydrate derivatives
Rapp Magdalena*, Mrowiec Patrycja, Koroniak Henryk
Adam Mickiewicz University, Faculty of Chemistry, Umultowska 89b, 61-614 Poznań, Poland
Corresponding author. Tel.: +48 618291818; fax: +48 618291505, E-mail address:
magdrapp@amu.edu.pl (M. Rapp)
In memoriam to Professor Harry R. Hudson
ABSTRACT
Various α-hydroxyphosphonates derived from O-isopropylidene glyceraldehyde, hexofuranose
and pentofuranose have been prepared to test nucleophilic fluorination reactions. The substrates
have been conveniently prepared in Pudovik reactions and the stereoselectivity, as well as the
configuration of the obtained carbohydrates have been described. Reactions have been
accomplished using DAST as the fluorinating reagent. Treatment of protected glycerol
phosphonate with DAST gave unusual conversions leading to fosfomycin analogue possessing
an oxirane ring. Subsequent reaction with diethylaminesulfur trifluoride (DAST) yielded
β-ketophosphonate. By contrast, stereoselective deoxyfluorination of hydroxyphosphonates
derived from an O-isopropylidenepentofuranose gave the major fluoride possessing D-glu
configuration while the reaction with di-O-isopropylidene hexofuranose derivative, has not been
successful presumably due to stereochemical properties of the substrate.
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Keywords
α-Hydroxyphosphonate, Carbohydrate, Fluorinated Phosphonate, Pudovik reaction,
Rearrangement, DAST
1. Introduction
Phosphate esters are a group of organic compounds fulfilling important functions in living
organisms such as genetic information or energy storage and transfers, as well as in signaling
pathways. For this reasons, their analogues are attractive targets in the synthesis of biologically
active compounds. One of the possibilities gave the application of phosphonate as surrogates of
naturally occurring phosphates. The replacement of the C–O–P bridge in phosphates by the C–
CH2–P in phosphonates make them more hydrolytically stable.[1] The syntheses of phosphonate
carbohydrate analogues possessing a phosphorus atom as a part of the furanose or pyranose
ring,[2] bearing an exocyclic phosphonate functionality [3] as well as carbohydrate derived
polyhydroxyphosphonates [4] have been already reported. On the other hand, an additional
introduction of one or two fluorine atoms to alkylphosphonates makes them isosteric or isopolar
2
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phosphate substitutes. Thus, α-monofluoroalkylphosphonates and α,α-difluoroalkylphosphonates
are usually more reactive, lipophilic and resistant to hydrolysis in biological environment.[5-7]
The fluorinated phosphonosugar derivatives possess attractive biological properties and were
applied as inhibitors of enzymes such as glycerol-3-phosphate dehydrogenase,[4g,4h]
glucose-6-phosphate
dehydrogenase,[3g,8]
phosphatidylinositol
phospholipase
C,[9]
transferase,[3h] among others. They were also exploited as ligands binding to lysophosphatidic
acid receptors.[4a,4e] One of the common strategy in synthesis of fluorinated phosphonates has
involved
nucleophilic
fluorination
of appropriate
α-hydroxyphosphonates
with
diethylaminesulfur trifluoride (DAST).[10] However, depending on phosphonate system, besides
the fluorination via substitution [3g, 4e, 5a,11-13] other reactions such as eliminations [5a] or
rearrangement [5a, 12] have been reported.
In our previous work we studied fluorination reaction in tertiary alcohols derived from
di-O-isopropylidenehexofuranose and 1,2-O-isopropylidenepentofuranose.[14] We found that
deoxyfluorination with DAST have been affected by the adjacent bottom–face
1,2-O-isopropylidene group oxygen atom leading mainly to one diastereoisomer. Moreover, the
inversion of configuration and allylic rearrangement have led to two chiral regioisomers in the
case of carbohydrate allylic fluorides. This particular stereocontrol prompted us to verify
fluorination of chiral hydroxyphosphonates derived from (R) -glyceraldehyde and other
O-isopropylidene protected carbohydrate systems. Herein, we present our results.
2. Results and Discussion
As the convenient starting materials carbohydrates possessing an aldehyde or ketone group have
been used. The appropriate α-hydroxyphosphonates have been obtained under the conditions of
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Pudovik
reaction.
Thus
introducing
the
phosphonate
gave
moiety
to
2,3-O-isopropylidene-(R)-glyceraldehyde
1
diethyl
(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)hydroxymetyl)phosphonate 2.[4b] Treatment of diethyl
phosphite by bases such as triethylamine TEA or NaHfollowed by addition of 1 gave a mixture
of two diastereoisomers of 2 in 71% yield (TEA, THF, RT, 21d;1:0.52 ratio) or in 23% yield
(NaH,
THF,
RT,
4d;
1:0.62
ratio),
respectively.
The
reaction
with
(R)-(+)-α-methoxy-α- (trifluoromethyl)phenylacetyl chloride [(R)-(+)-MTPA-Cl] according to
Mosher method has confirmed the configurations of new stereogenic C1 center of
α-hydroxyphosphonates 2 as 1S for the major diastereoisomer.[15] This results are in agreement
with an analogous assignment and diastereoselectivity for addition of dimethyl phosphite to
2,3-O-isopropylidene (R)-glyceraldehyde 1.[15] On the other hand the (S)-Al–
Li-bis(binaphthoxide) catalyzed addition of chiral di (1R,2S,5R)-menthyl phosphite to protected
(R)-glyceraldehyde gave better diastereoselectivity (90% d.e.).[4b]
Next, nucleophilic deoxyfluorination of 2 (1:0.52, dr) using diethylaminesulfur trifluoride
(DAST) gave compound 3 with 60% yield (Scheme 1).
Formation of one diastereoisomer of 3 has been confirmed by one signal at δP: 18.9 in 31P NMR
19
spectrum. However, the lack of the analogous signal in F NMR as well as distinctive doublets
at δH: 3.1 with JHP 30 Hz and δC: 47 (JCP 203 Hz) [16] indicated formation of oxirane 3 as a
rearrangement product. The stereochemistry ((1R,2R) of 3 has been determined in comparison of
the
spectra
to
the
literature
data.
So,
diethyl
((1S,2S)-3-(hydroxymethyl)-oxiran-2-yl)-phosphonate has been already obtained in few steps
synthesis starting from (1S,2R)-2,3-O-cyclohexylidene-1,2,3-trihydroxypropylphosphonate.[17]
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The plausible mechanism of observed, DAST mediated transformation of 2 leading to 3 is
presented in Scheme 2.
At the beginning, due to the reaction of (1S,2R) 2 with DAST, the α-hydroxyl moiety was
converted into a good leaving group with concomitant HF releasing (stage A). Next, the HF
catalyzed removal of 2,3-O-isopropylidene protecting group (stages B and C) led to the partially
protected vicinal 2,3-diol. Subsequent attack of the electron pair derived from the oxygen atom
of 2-hydroxyl group on adjacent DAST-derived leaving group followed by HF elimination and
deprotection (stage D) gave analogue of fosfomycin - compound 3. It is noteworthy, that only
one major diastereoisomer of 2 (1S,2R) underwent that DAST- mediated rearrangement while
the second diastereoisomer of 2 stayed intact in the reaction mixture. Moreover, the internal SN2
type reaction of the last step of proposed transformation has been confirmed by the 1R,2R
configuration of obtained oxiranephosphonate 3. The participation of oxygen derived from
1,2-O-isopropylidene neighboring group during DAST treatment of alcohols origin
di-O-isopropylidenehexofuranose and 1,2-O-isopropylidenepentofuranose has been observed as
well, leading to excellent diastereoselectivity of deoxyfluorinations.[14] <AQ>On the other
hand, anchimeric assistance throughout nucleophilic fluorination of aminoacids descended
α-hydroxyphosphonates yielded in formation of both diastereoisomers.[18]<AQ> Subsequent
treatment of 3 with DAST gave the non-fluorinated β-ketophosphonate 4 [19] in moderate yield
51% after isolation. (Scheme 1). Since in this particular DAST- caused rearrangement, the
presence of the protected hydroxyl group in the neighborhood of reaction centre has been
necessary, we were looking for similar transformation in other α-hydroxyphosphonate
carbohydrate
derivatives.
Thus,
Pudovik
reaction
performed
on
5
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1,2-O-isopropylidene-3-O-methyl-α-D-xylo-pentadialdo-1,4-furanose 5 [20] (HP(O)(OEt)2,
TEA, 80 C, 52h) gave a mixture of two epimeric carbohydrate 5-C-phosphonates with L-ido- 6
or D-gluco- 7 configurations (ratio 1:0.52 in crude reaction mixture) [21] with 63% yield and
1:0.25 ratio after isolation (Scheme 3).
The configuration of the new stereogenic C5 center has been confirmed by the reaction of 6/7
with (R)-(+)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride [(R)-(+)-MTPA-Cl] i.e.
Mosher reagent.[15] The phosphite (Nu) appears to have added preferentially from the less
hindered face according to Felkin-Ahn model (along the C4 - C5 bond) to give L-ido isomer 6
(5S) as the major compound (Scheme 3). However, the less favored addition from the up-side of
the ring, attributed to the steric impact of the bulky 3-O-methyl group, has been observed as
well, leading to configuration D-gluco in 7 (5R). This results are parallel to the studies reported
by Kovensky et al.[20] Thus, vinyl magnesium bromide attacks aldehyde 5 yielding
6,7-dideoxy-1,2-O-isopropylidene-3-O-methyl-
(α-D-gluco-hept-6-enofuranose)
and
(-β-L-ido-hept-6-enofuranose) with an excess of last-mentioned carbohydrate (ratio 1:1.2). Then,
the reaction of carbohydrate -derived α-hydroxyphosphonates (1:0.25) 6/7 with DAST has been
carried out yielding major 8 and a traces of 9 (ratio 1: 0.03 after isolation)(Scheme 4).
The analysis of 31P NMR spectrum indicated formation of one major product matched with
signals at δP: 16.7 (d) and at δF: -216.0 (ddd) while the minor product's signals were located at δP:
2
2
14.6 (d) and at δF: -215.8 (dddd) possessing geminal values JPF 70 Hz and JF-H5 44 Hz
confirming the formation of α-fluorophosphonate carbohydrate derivatives.[22] The
configuration at C5 in carbohydrates 8 and 9 has been verified by comparing coupling constants
3
3
values observed for fluorine and vicinal hydrogen atom H4 (gauche, J 5 Hz for 8 and anti, J
6
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14 Hz in case of 9), as well as bigger coupling constants between hydrogen atoms H5 and H4
(anti, 3J 9 Hz in case of 8). This results have supported the stereochemical assignment at C5 as
being 5R and D-gluco configuration for major fluoride 8.[16] On the same time, the carbohydrate
7 has been proved to be less reactive with DAST presumably due to steric hindrance preventing
reaction of C5 -OH group with the fluorinating reagent. Attempted prolongation of the reaction
time (in DCM) has caused the decomposition of both starting materials. Analogous reactions
carried out in others conditions (in various range of temperature or in solvents such as THF or
DMF) have not been successful.
<AQ>As others convenient to study α-hydroxyphosphonates hexofuranose derivatives have been
employed.</AQ> Thus, the TEA-catalyzed addition of diethyl phosphite to 1,2
;5,6-di-O-isopropylidene-α-D-ribo-hexofuran-3-ulose 10 [23] (TEA, neat, 45 °C, 19h) as
indicated on Felkin-Ahn model (along C3 - C4 bond) has led to C3 epimeric carbohydrates 11/12
(1:0.35 ratio after isolation, respectively) in 92% yield (Scheme 5).
The assignment of configuration of the obtained new stereogenic C3 centre of the predominant
carbohydrate 11 has been based on vicinal P-H4 couplings constants values (δH: 3.97, trans, J 29
Hz) [3k, 3i] supporting phosphite (Nu) addition from the top β-face of the furanose ring. The
more favored up-side addition to planar carbonyl bond giving rise to formation of major epimer
was frequently observed in case of the addition to C=O bond of 10.[3k,14,24] Next, reaction of
11/12 with DAST has been performed. However, despite of our efforts (different amount of
DAST, various solvents, ranges of temperature) the conversion of 11/12 with DAST failed.
Apparently, in this case nucleophilic attack or displacement by SN2 mechanism couldn't occur
due to steric impact of the bulky O-isopropylidene groups at carbon atoms C1/C2 and C5/C6. On
7
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the other hand, if reaction proceeded via SN1, a carbocation centered on the α-carbon would be
strongly destabilized by the electron-withdrawing phosphonate group.[25]
3. Experimental
General procedure for the preparation of α-hydroxyphosphonates (Pudovik reaction)
To the mixture of aldehyde or ketone (1 eq.) and diethyl phosphite (1 eq.), triethylamine (TEA,
0.2 eq.) was added and the reaction mixture was stirred at 80 °C (monitored by TLC). Then, the
solvent was evaporated and the residue was extracted with DCM and washed with a saturated
solution of NaHCO3 and brine, dried over Na2SO4, evaporated and purified by column
chromatography (EtOAc) to give products as oils. The Supplemental Materials contains sample
1H, 13C and 31P NMR of the products 2, 3, 4, 6/7, 8/9, and 11/12 (Figures S 1 – S 18).
Diethyl ((S/R)-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)phosphonate 2
Reaction of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 1 (972 mg, 7.48 mmol, 1 eq.) in
THF (30 mL) with HP(O)(OEt)2 (1.033 g, 7.48 mmol, 1 eq.) and TEA (80 mg, 0.75 mmol, 0.1
eq.) in THF (5 mL) was carried out at room temperature for 21 d, followed by extraction and
column chromatography (See: General procedure.) and gave compound 2 [4b] as two
diastereoisomers mixture (1:0.52 ratio) with a yield 71% (1.432 g).
Note: The reaction of (R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde 1 (137 mg, 1.06 mmol, 1
eq.) added to the mixture of HP(O)(OEt)2 (146 mg, 1.06 mmol, 1 eq.) and NaH (42 mg, 1.06
mmol, 1 eq.) in THF (5 mL) at room temperature for 4 d, followed by extraction and column
chromatography (See: General procedure) and gave compound 2 (66 mg) with a yield 23% as
two diastereoisomers mixture (ratio 1:0.62).
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Compound 2 (ratio 1:0.52) had: 1H NMR(300 MHz): δ 4.46 (ddd, J = 6.6, 5.2, 3.8 Hz, 1×0.52 H,
CHP(OH)), 4.40–4.35 (m, 1H, CHP(OH)), 4.24–4.04 (m, 6H+6×0.52 H, CH, CHH, OCH2CH3),
3.94 (ddd, J = 8.5, 6.8, 0.5 Hz, 1H, CHH), 3.85 (dd, J = 9.5, 5.3 Hz, 1×0.52 H, CHH) , 1.39 (s,
6×0.52 H, i–Pr), 1.37(s, 6H, i–Pr), 1.36 (t, J = 7.1Hz, 6H, OCH2CH3), 1.35 (t, J = 7.1Hz, 6×0.52
H, OCH2CH3); 31P NMR(121 MHz): δ 22.59 (s, 1P), 21.51 (s, 0.52 P).
GC–MS (Calcd for C10H21O6P: 268[M]+) found m/z = 253 [M–Me]+ , Rt 13.56/13.76 min
1.2.2. Diethyl [1,2-O-isopropylidene-3-O-methyl-α-L-ido-pentofuranose] 5-C-phosphonate 6
and diethyl [1,2-O-isopropylidene-3-O-methyl-α-D-gluco-pentofuranose] 5-C-phosphonate 7
The reaction of 1,2-O-isopropylidene-3-O-methyl-α-D-xylo-pentadialdo-1,4-furanose 5 [20]
(573 mg, 2.83 mmol), HP(O)(OEt)2 (1.04 eq. 407 mg, 2.95 mmol) and triethylamine (0.21 eq.
102 mg, 0.6 mmol) was stirred for 52 h at 80 °C, after extraction and column chromatography
(hexane : AcOEt, 3 :7 → AcOEt →AcOEt:SSE, 1:1, v:v, and gave products 6/7 (606 mg) as a
mixture (ratio 1:0.52, respectively) with a yield 63%.
1
Compound 6 had: H NMR δ 5.99 (dd, J = 3.9, 1.2 Hz, 1H, H1), 4.58 (d, J = 3.9 Hz, 1H, H2),
4.40 – 4.33 (m, 2H, H4, H5), 4.28–4.15 (m, 4H, OCH2CH3), 4.12 (d, J = 2.7 Hz, 1H, H3), 3.48
13
(s, 3H, OCH3), 1.49 (s, 3H, i–Pr), 1.37 (t, J = 7.5 Hz, 6H, OCH2CH3), 1.33 (s, 3H, i–Pr); C
NMR: δ 111.7(i–Pr), 104.6 (d, J = 2.2 Hz, C1), 86.0 (C3), 81.3(C2), 76.8 (d, J = 13.3 Hz, C4),
67.7 (d, J = 161.0 Hz, C5), 63.1 (d, J = 7.1 Hz, OCH2CH3), 62.4 (d, J = 7.1 Hz, OCH2CH3)),
57.7 (OCH3), 26.6, 26.1 (2×i–Pr), 16.4 (d, J = 5.6 Hz, 2×OCH2CH3); 31P NMR: δ 21.30 (s); GC–
MS (Calcd for C13H25O8P: 340[M]+) found m/z = 326 [M–Me+H]+, Rt 16.28 min.
Compound 7 had: 1H NMR δ 5.97 (d, J = 3.9 Hz, 1H, H1), 4.60 (d, J = 3.9 Hz, 1H, H2), 4.50 (td,
J = 5.8, 3.5 Hz, 1H, H4), 4.40 – 4.33 (m, 1H, H5), 4.28–4.15 (m, 4H, OCH2CH3), 3.91 (dd, J =
9
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3.5, 0.5 Hz, 1H, H3), 3.43 (s, 3H, OCH3), 1.50 (s, 3H, i–Pr), 1.37 (t, J = 7.4 Hz, 6H, OCH2CH3),
1.33 (s, 3H, i–Pr); 13C NMR: δ 112.0 (i–Pr), 104.8 (d, J = 2.5 Hz, C1), 85.6 (d, J = 5.5 Hz, C3),
81.6 (C2), 78.2 (d, J = 4.5 Hz, C4), 66.7 (d, J = 166.6 Hz, C5), 63.1 (d, J = 6.3 Hz, OCH2CH3),
62.7 (d, J = 6.8 Hz, OCH2CH3), 57.7 OCH3, 26.8, 26.3 (2×i–Pr), 16.4 (d, J = 6.0 Hz,
2×OCH2CH3); 31P NMR: δ 20.71 (s); GC–MS (Calcd for C13H25O8P: 340[M]+) found m/z = 326
[M–Me+H]+, Rt 16.54 min.
Diethyl (1,2;5,6-di-O-isopropylidene-a-D-allofuranose) 3-C-phosphonate 11 and diethyl
(1,2;5,6-di-O-isopropylidene-a-D-glucofuranose) 3-C-phosphonate 12
To the 1,2 ;5,6-di-O-isopropylidene-α-D-ribo-hexofuran-3-ulose 10 [23] (590 mg, 2.285 mmol, 1
eq.) HP(O)(OEt)2 (315 mg, 2.285 mmol, 1 eq.) and triethylamine (51 mg, 0.484 mmol, 0.21 eq.)
were added and the reaction mixture was stirred for 19 h at 45 °C. Then, the residue was
extracted, column chromatographed (CHCl3:MeOH; 100:2; v:v, see: General procedure 1.2.) to
give products 11/12 (833 mg) as a mixture (1:0.35 ratio, respectively) with a yield 92%.
Compound 11 had: 1H NMR δ 5.79 (d, J = 3.7 Hz, 1H, H1), 4.73 (dd, J = 8.0, 3.7 Hz, 1H, H2),
4.62 (ddd, J = 7.4, 6.3, 5.2 Hz, 1H, H5), 4.26 – 4.19 (m, 4H, OCH2CH3), 4.18 – 4.11 (m, 1H,
H6), 4.00 (dd, J = 8.7, 5.0 Hz, 1H, H6'), 3.97 (dd, J = 29.1, 7.7 Hz, 1H, H4), 3.21 (br d, J = 12.5
Hz, 1H, OH), 1.60 (s, 3H, i–Pr), 1.46 (d, J = 0.5 Hz, 3H, i–Pr), 1.39 (d, J = 0.4 Hz, 3H, i–Pr),
1.38 (s, 3H, –Pr), 1.37 (td, J = 7.1, 0.6 Hz, 3H, OCH2CH3), 1.36 (td, J = 7.1, 0.4 Hz, 3H,
OCH2CH3); 13C NMR δ 113.3 (i–Pr), 109.6(i–Pr), 104.4 (C1), 82.3 (d, J = 5.8 Hz, C2), 80.5 (d, J
= 8.7 Hz, C5), 79.0 (d, J = 168.6 Hz, C3), 73.9 (d, J = 3.7 Hz, C4), 67.0 (C6), 64.0 (d, J = 6.9
Hz, OCH2CH3), 62.9 (d, J = 7.4 Hz, OCH2CH3), 26.7 (i–Pr), 26.6 (i–Pr), 26.56 (i–Pr), 25.1(i–
10
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Pr), 16.5 (d, J = 5.5 Hz, OCH2CH3), 16.3 (d, J = 6.1 Hz, OCH2CH3); 31P NMR: δ 19.14 (s); GC–
MS (Calcd for C16H29O9P: 396 [M]+) found m/z = 381 [M–Me]+ , Rt 16.85 min.
Compound 12 had: 1H NMR δ 5.86 (d, J = 4.0 Hz, 1H, H1), 4.78 (dd, J = 10.7, 4.0 Hz, 1H, H2),
4.43 – 4.37 (m, 1H, H5), 4.33 – 4.27 (m, 4H, OCH2CH3), 4.18 – 4.11 (m, 2H, H6/6'), 3.90 (dd, J
= 8.9, 7.0 Hz, 1H, H4), 3.41 (br d, J = 13.8 Hz, 1H, OH), 1.63 (s, 3H, i–Pr), 1.45 (d, J = 0.5 Hz,
3H, i–Pr), 1.42 (d, J = 0.5 Hz, 3H, i–Pr), 1.38 (s, 3H, i–Pr), 1.38 (td, J = 7.1, 0.5 Hz, 3H,
13
OCH2CH3), 1.36 (td, J = 7.1, 0.5 Hz, 3H, OCH2CH3); C NMR: δ 114.5 (i–Pr), 109.1 (i–Pr),
105.3 (d, J = 6.0 Hz, C1), 85.0 (d, J = 12 Hz, C5), 81.0 (d, J = 6.8 Hz, C2), 79.0 (d, J = 168.6
Hz, C3), 75.8 (d, J = 4.6 Hz, C4), 66.3 (C6), 63.7 (d, J = 7.3 Hz, OCH2CH3), 63.6 (d, J = 6.9 Hz,
OCH2CH3), 27.0 (2×i–Pr), 26.5 (i–Pr), 25.3 (i–Pr), 16.5 (d, J = 5.4 Hz, OCH2CH3), 16.3 (d, J =
6.1 Hz, OCH2CH3); 31P NMR: δ 21.07 (s); GC–MS (Calcd for C16H29O9P: 396 [M]+) found m/z
= 381 [M–Me]+ , Rt 16.86 min.
General
procedure
for
the
reaction
of
α-hydroxyphosphonates
with
(R) -α-methoxy-α-trifluoromethylphenylacetic chloride (MTPA-Cl) - determination of
configuration of α-hydroxyl group with Mosher reagent.
To the solution of α-hydroxyphosphonate (1 eq.) in dry pyridine (2 mL), (R)-MTPA-Cl (1 eq.)
was added and the reaction mixture was stirred for 6 hours at room temperature. Then, solvent
was evaporated, the remaining mixture was partitioned (brine//DCM) and the separated inorganic
layer was extracted (DCM), dried (MgSO4) and evaporated to give a diastereoisomeric mixture
of products as slightly yellow oil.
11
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1.3.1.
(1R,2R)
-
and
(1S,2R)
-Diethyl
2,3-dihydroxy-2,3-O-isopropylidene-1-[(S) -2'-methoxy- 2'-(trifluoromethyl)phenylacetoxy]propy
lphosphonate (S) -MTPA-2 (R,R) and (S) - MTPA-2 (S,R)
Reaction of 2 (50 mg, 0.186 mmol) with (R)-MTPA-Cl (1.1 eq. 52 mg, 0.205 mmol) carried out
according to a general procedure (1.3) gave a 91 mg of mixture of two diastereoisomers (1:0.52
31
ratio) indicating as major compound (S) - MTPA-2 (S,R) [ P NMR: δ 15.45 (s)], while minor
diastereoisomer (S) - MTPA-2 (R,R) had 31P NMR: δ 16.53 (s).
Diethyl
phenylacetoxy]3-O-methyl-α-L-ido-pentofuranose] 5-C-phosphonate (S) -MTPA-6 (5S)
and diethyl [1,2-O-isopropylidene-5-O-[-[(S)-2'-methoxy-2'-(trifluoromethyl)
[1,2-O-isopropylidene-5-O-[-[(S)-2'
-methoxy-2'-(trifluoromethyl)
phenylacetoxy] -3-O-methyl-α-D-gluco-pentofuranose] 5-C-phosphonate (S)- MTPA-7 (5R)
Reaction of 6/7 (32 mg, 0.093 mmol) with (R)-MTPA-Cl (61 mg, 0.242 mmol, 2.6 eq) carried
out according to a general procedure (1.3) gave a 55 mg of mixture of two compounds (1:0.52
31
ratio) indicating as major compound (S) - MTPA-6 (5S) [ P NMR: δ 16.29 (s)], while minor
diastereoisomer (S) - MTPA-7 (5R) had 31P NMR: δ 17.10 (s).
General procedure for the DAST- mediated transformation of α-hydroxyphosphonates
o
To a mixture of DAST (1.5 eq. or 4 eq.) in dry DCM (6 mL) at -78 C, a solution of alcohol (1
eq.) in DCM (2 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h, and then an
additional 2 h at room temperature. Then, the reaction mixture was poured into small portions of
saturated NaHCO3 (aq). solution containing ice chips and extracted with DCM. The combined
organic layers were washed with small portions of H2O, dried (Na2SO4), filtered and evaporated
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under reduced pressure. The product was purified on a silica gel (EtOAc or EtOAc→
EtOAc/SSE, 1:1, v:v or CHCl3→ CHCl3/MeOH 85:15, v:v) to give products.
Diethyl ((2R,3R)-3-(hydroxymethyl)oxiran-2-yl)phosphonate 3
Reaction of 2 (241 mg, 0.9 mmol) with DAST (179 µL, 172 mg, 1.34 mmol, 1.5 eq) in dry DCM
(6 mL) carried out according to the general procedure gave compound 3 with a yield of 60%
1
(113 mg) and 2 (2R,3R; 66mg). Compound 3 had H NMR (300 MHz): δ 4.23-4.13 (m, 4H,
OCH2CH3), 3.99 (br d, J = 13 Hz, 1H, CHHOH), 3.74 (dd, J = 13.0, 3.4 Hz, 1H, CHHOH), 3.46
(ddt, J = 5.1, 3.4, 2.5 Hz, 1H, CHOox), 3.14 (dd, J = 30.5, 2.6 Hz, 1H, CHP), 1.36 (td, J = 7.1, 0.5
Hz, 3H, OCH2CH3), 1.35 (td, J = 7.1, 0.5 Hz, 3H, OCH2CH3);13C NMR: δ 63.2 (d, J = 6.5 Hz,
OCH2CH3), 62.9 (d, J = 6.5 Hz, OCH2CH3), 60.2 (CH2OH), 56.6 (CHOox), 47.0 (d, J = 203.1
Hz, CHP), 16.4 (2d, J = 5.7 Hz,2×OCH2CH3); 31P NMR(121 MHz): δ 18.88 (s); GC–MS (Calcd
for C7H15O5P: 210[M]+) found m/z = 211 [M+H]+ , Rt 12.98 min.
2.1.2. Diethyl (2-oxopropyl)phosphonate 4
Reaction of 3 (106 mg, 0.39 mmol) with DAST (79 µL, 96 mg, 0.59 mmol, 1.5 eq) in dry DCM
(6 mL) carried out according to a general procedure (2.1) at -84 °C, 2h, next RT 2h, gave
1
compound 4 with a yield 51% (50 mg). Compound 4 had H NMR(600 MHz) δ: 4.18-4.08 (m,
4H, OCH2CH3), 3.11 (dq, J = 22.6, 0.5 Hz, 2H, CH2P), 2.33 (t, J = 0.5 Hz, 3H, CH3), 1.35 (t, J =
7.5 Hz, 3H, OCH2CH3), 1.34 (t, J = 7.5 Hz, 3H, OCH2CH3);13C NMR: δ 199.9 (d, J = 6.1 Hz,
CO), 62.7 (d, J = 6.4 Hz, 2×OCH2CH3), 43.2 (d, J = 126.9Hz, CH2P), 31.4 (CH3),16.3 (d, J = 6.2
Hz, 2×OCH2CH3); 31P NMR(243 MHz): δ 20.3 (s); GC–MS (Calcd for C7H15O4P: 194 [M]+)
found m/z 195 [M+H]+ , Rt 10.7 min.
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Diethyl
[5-deoxy-5-fluoro-1,2-O-isopropylidene-3-O-methyl-α-D-gluco-pentofuranose]
and diethyl
5-C-phosphonate
8
[5-deoxy-5-fluoro-1,2-O-isopropylidene-3-O-methyl-α-L-ido-pentofuranose] 5-C-phosphonate 9
Reaction of 6/7 (71 mg, 0.21 mmol) with DAST (111 µL, 135 mg, 0.84 mmol, 4 eq.) in dry dry
DCM (6 mL) carried out according to the general procedure was stirred at -78 °C for 2 h, and
o
then at 45 C for 2.5 h, followed by extraction and column chromatography (CHCl3→
CHCl3/MeOH 85:15, v:v) to form compound 8/9 (ratio 1:0.1 in crude reaction mixture) with a
yield 26% (18 mg) and ratio 1: 0.03, respectively. Compound 8 had 1H NMR (600 MHz) δ 5.95
(dd, J = 3.7, 2.1 Hz, 1H, H1), 4.96 (ddd, J = 44.4, 9.5, 0.8 Hz, 1H, H5), 4.60 (dd, J = 3.7, 2.1 Hz,
1H, H2), 4.51 (dddd, J = 9.4, 8.2, 5.4, 3.1 Hz, 1H, H4), 4.29 – 4.24 (m, 4H, OCH2CH3), 3.88 (d,
J = 3.1 Hz, 1H, H3), 3.47 (s, 3H, OCH3), 1.52 (s, 3H, i–Pr), 1.38 (t, J = 7.1 Hz, 3H, OCH2CH3),
1.36 (t, J = 7.1 Hz, 3H, OCH2CH3), 1.35 (s, 3H, i–Pr); 13C NMR (151 MHz) δ 112.2 (i–Pr),
105.6 (C1), 84.2 (dd, JCF = 177.3, JCP = 169.8 Hz, C5), 83.4 (d, JCP = 9.6 Hz, C3), 81.3 (C2),
77.0 (d, JCF = 29.2 Hz, C4), 63.3 (d, J = 6.5 Hz, 2×OCH2CH3), 58.3 (OCH3), 26.9 (i–Pr), 26.3 (i–
31
Pr), 16. 5 (d, J = 5.9 Hz, OCH2CH3), 16.4 (d, J = 5.9 Hz, OCH2CH3); P NMR (243 MHz) δ:
16.72 (d, J = 70.2 Hz); 19F NMR (565 MHz) δ: –216.03 (ddd, J = 70.1, 44.2, 5.3 Hz).
Diagnostic signals for compound 9: 31P NMR (243 MHz) δ:14.62 (d, J = 69.0 Hz); 19F NMR(565
MHz) δ: –215.80 (dddd, J = 69.2, 47.3, 14.5, 3.0 Hz). GC–MS (Calcd for C13H24FO7P: 342
[M]+) found m/z = 343 [M+H]+ , Rt 15.68 min.
Conclusions
In summary, we have prepared the convenient α-hydroxyphosphonate derivatives 2, 6/7, 11/12 of
O-isopropylidene glyceraldehyde 1, pentofuranose 5 and hexofuranose 10. The stereoselective
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introductions of phosphonate moiety have been accomplished by Pudovik reactions. The
determination of resulted configurations have been achieved based on NMR spectroscopy
supported by the reactions of α-hydroxyphosphonates with Mosher reagent. Next, the
nucleophilic fluorinations with DAST have been performed. The ability of DAST to react
distinctly depended on the regio-and stereochemical properties of the substrates. Thus,
DAST -mediated reaction of O-isopropylidene glycerol phosphonate 2 gave unexpected oxirane
containing fosfomycin analogue 3. Subsequent reaction of 3 with DAST has yielded
β-ketophosphonate 4. Stereoselective deoxyfluorination of hydroxyphosphonates derived from
an O-isopropylidenepentofuranose 6/7 led to α-fluorophosphonate 8 with D-gluco configuration
contaminated by the traces of L-ido fluoride 9. Attempted fluorination of di-O-isopropylidene
hexofuranose hydroxyphosphonates 11/12 with DAST has failed, most probably due to sterical
hindrance of applied carbohydrate system or electron-withdrawing properties of phosphonate
moiety.
Acknowledgments
The research was supported by Wroclaw Research Centre EIT+ under the project
″Biotechnologies and advanced medical technologies″ – BioMed (POIG.01.01.02-02-003/08)
financed from the European Regional Development Fund (Operational Programme
Innovative Economy, 1.1.2).
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Scheme 1. i. HP(O)(OEt)2, TEA, THF (1:0.52 dr, 71%) or HP(O)(OEt)2, NaH, THF (1:0.62 dr,
23%); ii. DAST, -78 °C, 2h, next RT 2 h, work up (60%); iii. DAST, -84 °C, 2 h, next RT 2 h,
work up (51%).
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Scheme 2. The mechanism of DAST-mediated transformation of 2 yielding 3.
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Scheme 3. i. HP(O)(OEt)2, TEA, 80 °C, 52 h (1:0.25 6/7, 63% )
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Scheme 4. i. DAST, DCM, -78 °C, 0.5 h, next 45°C, 2.5 h, work up (1:0.03 8/9, 26%)
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Scheme 5. i. HP(O)(OEt)2, TEA, 45 °C, 19 h (1:0.35 dr, 92% )
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