Fragmentation of carbohydrate anomeric alkoxyl radicals: Synthesis of chiral polyhydroxylated β-iodo- and alkenylorganophosphorus(V) compounds

FULL PAPER

DOI: 10.1002/ejoc.201402387

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals: Synthesis of

Chiral Polyhydroxylated β-Iodo- and Alkenylorganophosphorus(V) Compounds

Daniel Hernández-Guerra,^[a]María S. Rodríguez,*^[a]and Ernesto Suárez*^[a]

Keywords: Synthetic methods / Carbohydrates / Radicals / Phosphorus / Cyclization

A direct approach to β-iodophosphonates and β-iodophos- conducted on carbohydrate derivatives under mild condi-

phine oxides from 2,3-dideoxy-3-phosphoryl carbohydrate

derivatives has been achieved by using the anomeric alkoxyl

radical 1,2-fragmentation protocol. The reaction has been

tions with (diacetoxyiodo)benzene and molecular iodine.

Subsequent dehydroiodination afforded the corresponding

vinylphosphonates and vinylphosphine oxides.

able to find correspond to the simplest members of the

series, almost exclusively to dialkyl vinylphosphonates or

Introduction

The chemistry of vinylphosphonates^[1]and vinylphos- diphenyl(vinyl)phosphine oxide.^[3]Studies on the synthesis

phine oxides^[2]has attracted a great deal of attention be- and chemical reactivity of β-iodoorganophosphorus(V)

cause they constitute an important group of organic rea- compounds are rare. 2-Iodoethylphosphine oxides appear

gents and useful synthetic intermediates with a wide range to be practically unknown, with only one of the simplest

of biological activities. These alkenylphosphorus com- members of the family, (2-iodoethyl)(diphenyl)phosphine

pounds are used as key starting materials in Michael ad- oxide, having been synthesized.^[4]2-Iodoethylphosphonates

dition and subsequent Horner–Wadsworth–Emmons ole- are also relatively rare compounds and the reported exam-

fination of carbonyl compounds, 1,3-cycloadditions, Diels– ples that we were able to uncover correspond almost exclu-

Alder, Stetter, metathesis reactions, and for the preparation sively to diethyl 2-iodoethylphosphonate or simple alkyl-

of phosphine ligands, among others. Of special interest is branched derivatives.

the Michael addition of amines to vinyl phosphonates and

Such compounds have been prepared by halogen or

vinyl phosphinates in the preparation of β-aminophos- OTs/I exchange under Finkelstein conditions^[5]or by

phonic or β-aminophosphinic acids as bioisosteres of β- metallo-phosphorylation of zirconocene-alkene complexes

amino carboxylic acids.^[1a,1e,1j]However, there is a paucity with chlorophosphate using iodine as electrophile.^[6]Studies

of information in the literature on radical additions to these on the chemical reactivity of these compounds have largely

electrophilic double bonds. All the examples we have been been limited to diethyl 2-iodoethylphosphonate.^[5a,5c,7]In

Scheme 1. Alkoxyl radical β-fragmentation of 2,3-dideoxy-3-phosphoryl-hexopyranoses and hexofuranoses. ARF = alkoxyl radical β-

fragmentation reaction; Z = Ph (phosphine oxides), Z = OEt (phosphonates).

[a] Síntesis de Productos Naturales, Instituto de Productos

Naturales y Agrobiología del CSIC,

the context of carbohydrate-containing phosphorus com-

pounds, a point of interest is the preparation of analogues

in which the anomeric carbon has been replaced by an atom

of phosphorus,^[8]the so-called cyclic phostones^[8o]or, more

correctly, 1-phospha sugars.^[8p]They have been accorded

some attention from synthetic chemists as a consequence of

Carretera de La Esperanza 3, 38206 La Laguna, Tenerife, Spain

E-mail: mrodriguez@ipna.csic.es

esuarez@ipna.csic.es

https://ww w .ipna.csic.es/dept/spn/sipn/

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402387.

Eur. J. Org. Chem. 2014, 5033–5055

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D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

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their potential biological activity as glycosidase inhibitors completely prevented and only 3-phosphinyl-d-gulal prod-

and anticancer agents.^[9]In previous papers from this labo- ucts 9 and 10 are obtained. The reaction of triacetyl d-

ratory, we have described the anomeric alkoxyl radical β- glucal 2 deserves a brief comment. The glucal stereochemis-

fragmentation reaction (ARF) by treatment of carbo- try previously assigned to 5 is erroneous.^[17]Based on a

hydrate free anomeric alcohols with hypervalent iodine(III) careful NMR study and comparison of spectroscopic data

in the presence of molecular iodine.^[10]This reaction per- with true glucal derivative 6, the allal stereochemistry

mits the realization of remarkable transformations in the shown in Scheme 2 is preferred. The coupling constant

carbohydrate skeleton and the preparation of imino- ³J_P,H4that is dihedral angle-dependent, can be analyzed in

sugars,^[11]1,1,1-trihaloalditols,^[12]and polyhydroxylated terms of a generalized Karplus-type equation and proved

2H-azirines,^[13]among other alditol derivatives. The ready to be diagnostic in distinguishing between these two iso-

3

accessibility of the starting material, operational simplicity, mers.^[20]The observed value of 20.9 Hz for J_Pα,H4β(calcd.

and possible further synthetic transformations of the frag- 22.1 Hz) in compound 5 is notably higher than that mea-

mentation products are noteworthy and merit further ex- sured in 6 (³J_Pβ,H4β= 9.1 Hz, calcd. 5.1 Hz).^[21]

ploitation of these results. In demonstration of such a util-

ity, we set out to develop a new method for the synthesis

of chiral vinylphosphine oxides and vinylphosphonates of

generalized structure VII (Scheme 1). We have described the

preliminary results in a short communication and now re-

port full details of this methodology and its extension to

other saccharide models.^[14]

Results and Discussion

Regioselective introduction of the C–P bond into the

carbohydrate skeleton was accomplished by using two dif-

ferent strategies. 3-Phosphinyl derivatives III were prepared

from glycals I through an anomalous Ferrier reaction,^[15]

whereas a phospha-Michael addition to readily available

hex-2-enono-1,4-lactones II was used for the synthesis of

3-phosphonylated sugars IV (Scheme 1).^[16]The required

γ-hydroxyphosphinylated V (Z = Ph) or γ-hydroxyphos-

phonylated compounds V (Z = OEt) were then obtained,

respectively, by hydration of glycals III or by reduction of

lactones IV. The 3-hydroxyphosphorus compounds V were

then submitted to the ARF reaction to give β-iodophos-

phorus compounds VI, which, by base dehydroiodination,

provided the desired vinylorganophosphorus VII.

Scheme 2. Synthesis of 3-diphenylphosphoryl-hex-1-enitol precur-

sors. [a] β-d-Gal refers to the perbenzylated moiety of β-d-galact-

ose.

The Ferrier reaction of d-glucals 1 and 2, d-galactals 7

and 8, and d-lactal 11 (Scheme 2) was achieved with chloro-

diphenylphosphine and aluminum chloride by a modifica-

tion of the procedure reported by Yamamoto et al.^[17]In

Preliminary attempts to prepare 3-phosphonylated gly-

contrast to hard O-nucleophiles, which attack almost exclu- cals by using the Ferrier rearrangement mentioned above

sively at C1,^[15]the Ferrier addition of softer N- and S- upon reaction of perbenzylated d-glucal with (EtO)₂PCl/

nucleophiles tends to lead preferentially to 3-substituted AlCl₃instead of Ph₂PCl/AlCl₃proved to be unsuccessful;

glycals under equilibrium conditions.^[18]Consequently, car- therefore, an alternative route was sought. The phospha-

ried out the reactions with the diphenylphosphenium cation Michael addition of triethyl phosphite to readily accessible

intermediate under thermodynamic control. Indeed, reflux pent-2-enono-1,4-lactones 14^[22]and 16^[23]and hex-2-en-

temperatures and prolonged reaction times afforded the ono-1,5-lactones 19^[24]and 21^[25]under the conditions de-

preponderant formation of 3-phosphinyl glycal derivatives scribed by Kofoed and Pedersen,^[26]using phenol as proton-

in moderate to good yields and, in some cases, with excel- ating agent, afforded the 3-phosphonylated γ-lactones 15,

lent regio- and stereoselectivity as shown in Scheme 2.^[19]17, and 18 and δ-lactones 20, 22, and 23 (Scheme 3). The

These conditions produced substantially different results, reaction proceeded, in all cases, with excellent diastereo-

with respect to regioisomeric composition and yield of the selectivity under steric control, with the 1,4-addition taking

Ferrier products, from those used by Yamamoto with 1, 2 place preferentially anti to the vicinal substituent at the C4

and 8 glycals, which gave principally the C1 kinetic com- position.

pounds. Especially remarkable are the cases of d-galactal

It is worthwhile to note that a mixture of isomers 17 and

derivatives 7 and 8, for which formation of C1 adducts is 18 was unexpectedly formed during the phosphorylation of

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Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

sugar stereochemistry and the β-iodo phosphine oxides 31–

36, and 38 were obtained in good yields. No products com-

ing from radical epimerization at the neighboring chiral

centers could be detected in these reactions. However, in the

fragmentation of 29, a side reaction was observed, with the

formation of iodide 36 being accompanied by a small

amount (15%) of oxidized hexono-1,5-lactone 37 (not

shown, see experimental section).

These β-iodo phosphine oxides were sufficiently stable to

be purified by silica gel chromatography and could be

stored under nitrogen in a freezer for an extended period of

time. The dehydroiodination of these compounds was effec-

tively accomplished with 1,8-diazabicyclo[5.4.0]undec-7-ene

(DBU) in benzene to afford vinylphosphine oxides 39–44 in

high yields. The reaction temperature was kept as low as

possible 9–10 °C, just above the freezing point of benzene,

to prevent hydrolysis of the formate group. In the elimi-

nation of iodides 32 and 36, partial hydrolysis of the for-

mate group occurred and small amounts of dehydroiodin-

ated alcohols 41 (12%) and 45 (13%) (not shown in Table 1,

see experimental section) were also formed. The presence in

the ¹H NMR spectra of two doublets at 6.22–6.37 (³J_P,Htrans

≈ 40 Hz) and 5.58–5.75 ppm (³J_P,Hcis≈ 20 Hz) correspond-

ing to the vinylic protons and the ³¹P NMR chemical shifts

Scheme 3. Synthesis of 3-diethoxyphosphoryl-pentono-1,4-lactone

and 3-diethoxyphosphoryl-hexono-1,5-lactone precursors.

lactone 16, presumably through acid-catalyzed enolization (29.2–33.0 ppm) are the most representative spectroscopic

of the lactone, which led to epimerization at C4 prior to the characteristics of these compounds and are in good agree-

P-addition. The stereochemistry of the newly introduced ment with those previously observed for other simpler ana-

contiguous stereocenters could not be determined unambig- logues of diphenylvinylphosphine oxides prepared by

uously at this stage by NMR spectroscopy. The complete hydrophosphination of terminal alkynes.^[31]To assess the

stereochemical characterization of both compounds by scope of this methodology on the phosphonylated series, a

Mosher analysis of the C3 alcohol obtained by hydrolysis variety of 2,3-dideoxy-pentofuranose, -hexofuranose and

of related compound 60 (Table 2) is discussed below.

-hexopyranose carbohydrates were obtained. The alcohols

Precedents for such an isomerization of 4-substituted fur- required by the ARF were prepared by diisobutylaluminum

anones are documented in the literature under mild basic hydride (DIBAL-H) mediated reduction of the carboxylate

catalytic conditions.^[27]Curiously, the phosphorylation pro- group of 3-phosphonylated γ-lactones 15, 17, and 18, and

cess under conditions similar to those of analogous lactone δ-lactones 20 and 22 (Table 2). Separation of 2-deoxy-d-

14 does not appear to be accompanied by a concurrent epi- glucose 49 and 2-deoxy-d-allose 50 derivatives was chro-

merization step at C4 (see below).

matographically accomplished at this step and the reaction

Hydration of glycals 3, 5, 6, 9, 10, and 12 by a modifica- sequence was continued with both compounds separately.

tion of the procedure of Falck et al.,^[28]was accomplished The ARF reaction proceeds analogously to the diphenyl-

by using water as nucleophile. Reaction with catalytic phosphine oxide series, and β-iodophosphonates 52–57

amounts of Ph₃P·HBr in tetrahydrofuran (THF)/H₂O were obtained in good to excellent yields. These compounds

heated to reflux gave 2,3-dideoxy-hexopyranose compounds exhibit a similar stability to those of the β-iododiphenyl-

24–30 in high yields (Table 1). The phosphoryl group phosphine oxide counterparts and can be stored at –20 °C

stereochemistry is probably better studied at this stage with for a long time and handled at room temperature without

4

the pyranose ring in a more stable C₁conformation. The any apparent deterioration. The only exceptions are iodides

3

involved vicinal coupling constants J_H,Hand J_P,Hin the 53 and 54, which were partially dehydroiodinated under sil-

major α-isomer can now be more accurately read or ex- ica gel chromatographic conditions and could not be iso-

tracted through a full-lineshape fit of the calculated spec- lated in pure form. Finally, DBU-mediated elimination of

trum.^[29]In compounds 24–30 the dihedral angle depen- iodide derivatives proceeded smoothly to give vinylphos-

3

1

dence of the J_P,Hcoupling constants is clearly observed phonates 58–62. In the H NMR spectra, two doublets at

between the atom of phosphorus and hydrogen atoms at 6.24–6.35 (³J_P,Hcis≈ 22 Hz) and 6.10–6.21 ppm (³J_P,Htrans

≈

C2 and C4.^[30]In some cases, the C3 stereochemistry was 45 Hz) corresponding to the vinylic protons and the ³¹P

confirmed by 2D NOESY and H{³¹P} NMR decoupled NMR chemical shifts (15.0–16.4 ppm) are now observed for

1

spectra. The ARF reactions were performed under the con- these vinylphosphonates.

ditions summarized in Table 1, with (diacetoxyiodo)benz-

The absolute stereochemistry at C3 of compound 60 was

ene (DIB) and iodine in CH₂Cl₂. The reaction, which pro- determined by using Mosher ester analysis (Table 2, en-

ceeded smoothly, appears to be very little affected by the try 3).^[32]The alcohol obtained after formate hydrolysis was

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Table 1. Synthesis of β-iodo- and vinyl-phosphine oxides derived from carbohydrates.

[a] Reagents and conditions per mmol of substrate: Ph₃P·HBr (0.12–0.46 mmol), H₂O (0.43 mL), THF (21.5 mL), reflux. [b] Reagents

and conditions per mmol of substrate: DIB (1.1–1.5 mmol), I₂(0.6–1.1 mmol), CH₂Cl₂(25 mL). [c] Reagents and conditions per mmol

of substrate: DBU (1.1–2.6 mmol), benzene (25 mL), 9–10 °C. [d] 12% hydrolyzed compound 41 (not shown, see experimental section)

was also obtained, the global yield of the vinylphosphine oxide was 87%. [e] For clarity, β-d-Gal refers to the perbenzylated moiety of

β-d-galactose. [f] 15% oxidized lactone 37 (not shown, see experimental section) was also obtained. [g] 13% hydrolyzed compound 45

(not shown, see experimental section) was also obtained, the global yield of the vinylphosphine oxide was 96%. [h] 32% hydrolyzed

compound 45 (not shown, see experimental section) was also obtained, the global yield of the vinylphosphine oxide was 92%.

esterified with (R)- and (S)-MPA acids to form the respec- mization of vinylphosphonate 58 (Table 2, entry 1). The op-

tive 3-O-esters. Inspection of ¹H NMR spectra revealed that tical purity of compound 58 was determined by hydrolysis

3-O-(R)-MPA ester exhibited, with respect to ¹H NMR and conversion of the resulting alcohol into the Mosher

shift of 3-O-(S)-MPA ester, upfield shift of Δδ_R,S

–0.72 ppm for H1_transand Δδ_R,S= –0.31 ppm for H1_cisand mization occurs during the phosphorylation reaction.

downfield of Δδ_R,S= 0.16 ppm for H5a and Δδ_R,SFinally, to demonstrate the preparative utility of this

=

ester, confirming by ¹H NMR analysis that no partial race-

=

0.26 ppm for H5b. Hence, the absolute configuration at C3 methodology, we performed the ARF reaction starting

was established as R and consequently a structure of d- from alcohol 26 on a 9.3 mmol scale to generate 33 (3.9 g,

erythro-pent-1-enitol was assigned to 60. This means that 7.1 mmol, 76%) and 40 (2.7 g, 6.2 mmol, 87%) (see Table 1,

compound 18 possesses a 2,3-dideoxy-3-diethoxyphosphor- entry 3). Analogously, the phosphonate series was scaled-

yl-5,6-O-isopropylidene-d-ribo-hexono-1,4-lactone struc- up by fragmentation of alcohol 49 (8.3 mmol) to afford 55

ture and that it is the inverted isomer of the enolization (4.3 g, 7.3 mmol, 88%) and 61 (3.4 g, 7.3 mmol, 100%) (see

equilibrium observed during the phosphorylation of lactone Table 2, entry 4). The synthetic versatility of these polyhy-

16. Consequently, a structure of 2,3-dideoxy-3-diethoxy droxylated phosphorus compounds has been evaluated and

phosphoryl-5,6-O-isopropylidene-d-lyxo-hexono-1,4-lact- the results are summarized in Schemes 4, 5, and 6. The for-

one (17) should be assigned to the other isomer. This equi- mation of O–C-cyclic compounds is exemplified by the for-

librium does not seem to be operative during the phosphor- mate hydrolysis of β-iodo phosphine oxide 33 and subse-

ylation of lactone 14, which would otherwise lead to race- quent silver triflate-assisted cyclization (Scheme 4). The 1,4-

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Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

Table 2. Synthesis of β-iodo- and vinyl-phosphonates derived from carbohydrates.

[a] Reagents and conditions per mmol of substrate: DIBAL (4 mmol), PhCH₃(33 mL), –78 °C. [b] Reagents and conditions per mmol of

substrate: DIB (1.1–1.5 mmol), I₂(0.6–1.1 mmol), CH₂Cl₂(25 mL). [c] Reagents and conditions per mmol of substrate: DBU (1.1–

2.6 mmol), benzene (25 mL), 9–10 °C. [d] Unstable, could not be characterized.

anhydro-2-deoxy-2-diphenylphosphoryl-d-arabinitol deriv- oxy-2-phosphoryl-alditol derivatives may be of interest for

ative 63a and its partially hydrolyzed alcohol 63b were thus the design and synthesis of new phosphorus ligands in

obtained in good overall yield. A 2D-NMR study of 63b, asymmetric catalysis.^[34]Our approach should also be appli-

in particular the HMBC correlation of H1 to C4, confirmed cable to the syntheses of 2-methylene-1-phospha-pentofur-

the presence of the five-membered furane ring and dis- anoses (3-methylene-1,2-oxaphospholanes) by O–P-cycliza-

carded the alternative pyranoid cyclization. Curiously, the tion (Scheme 4). These compounds (e.g., 65 and 66), also

three possible ³J_P,Hcoupling constants have very similar ex- known as α-methylene-γ-phostones, are functional surro-

perimental values (ca. 13–15 Hz), which appears to indicate gates of α-methylene-γ-butyrolactones. 2-Deoxy-2-methyl-

a very specific conformation for the flexible furane ring. ene-d-erythro-pentono-1,4-lactone, the C-isoster of 65 and

The conformation was studied by pseudorotational analysis 66, has been prepared.^[35]α-Methylene-γ-butyrolactone

using the experimental ³J_H,Hring coupling constants calcu- constitutes the core motif of widely encountered naturally

lated by iterative simulation.^[33]Two envelope conformers occurring compounds with a variety of biologically interest-

were obtained with phase angles (P; north- and south-type, ing properties including anticancer, antimalarial, antiviral,

P_Nand P_S, respectively) and populations, as indicated: E₂antibacterial, antifungal, anti-inflammatory activities.^[36]

(P_N= 335°, 66%) and E₁(P_S= 133°, 34%). The weighted The information on the synthesis of 3-methylene-1,2-

3

average for the coupling constants J_P,Hare in reasonable oxaphospholane derivatives is scant in the literature, and

agreement with the observed values. The 1,4-anhydro-2-de- only a methodology based on a Reformatsky-like condensa-

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D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

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tion of diethyl 1-(bromomethyl)vinylphosphonate with al- forded alcohol 64, which was subsequently submitted to in-

dehydes and ketones has been described.^[37]

tramolecular transesterification conditions employing

PPTS. The P-diastereomeric mixture of 65 (R_P) and 66 (S_P)

was separated by chromatography. The phosphorus stereo-

chemistry was tentatively assigned on the basis of the small

but significant deshielding effect of the P=O bond on all

syn related protons (e.g., 65/66 Δδ 0.2 ppm for H3β and

–0.15 ppm for H4α).^[37c,38]The value of the NMR ring cou-

pling constants (³J_P,H3, J_P,H4, and J_H3,H4) differ markedly

in both isomers. Because all of them depend on the dihedral

angle in a Karplus-type relationship, these differences are

attributable to different conformations of the ring.^[20]In-

deed, molecular mechanics models indicate that in 65 the

1,2-oxaphospholane ring preferentially adopts an envelope

E₄conformation with phase angle P = 52°, whereas 66

shows a preference for an E₃(P = 204°).^[37c,38b,39]

3

The use of these vinylphosphonates as scaffolds was ex-

emplified by the synthesis of β-aminophosphonates 67 and

69 by Michael addition of the amino acid Gly-OMe·HCl to

65 and 66 (Scheme 5). The reaction stereochemistry could

be ascribed to steric hindrance by the two vicinal ether

groups. In the reaction of 65, 1,4-conjugate addition on the

β-side of the molecule was observed to give exclusively 67 as

a single stereoisomer, whereas the sterically less demanding

substrate 66 afforded a mixture of α- and β-isomers 69. The

stereochemistry at C-2 was assigned by NOESY experi-

ments, with some of the observed interactions also confirm-

ing the phosphorus stereochemistry assigned previously for

65 and 66. In both cases, conjugate elimination of the vici-

nal benzyl ether was observed as a side reaction, leading to

the formation of 68 and 70.

Scheme 4. Synthesis of 1,4-anhydro-2-deoxy-2-diphenylphos-

phoryl-d-arabinitol and 2-methylene-phospha-1-oxo-pentofur-

anoses by intramolecular cyclization.

Finally, photoinduced addition of nBuBr to diphenyl vin-

ylphosphine oxide 40 or vinylphosphonate 61, in the pres-

ence of catalytic amounts of tri-n-butyltin chloride and an

excess of sodium cyanoborohydride, was chosen as repre-

sentative examples of the reaction of these compounds un-

der radical conditions (Scheme 6). The reactions proceeded

in moderate yield to give the addition products 71 and 72

as a diastereomeric mixture of isomers. Chromatographic

separation of the isomer pairs was possible but, as expected,

the stereochemistry of the d-ribitol and d-arabinitol epi-

mers could not be assigned by spectroscopic methods.

Scheme 5. Use of 2-methylene-phospha-1-oxo-pentofuranoses as

scaffolds. Michael addition products with glycine methyl ester.

Principal NOESY correlations shown by arrows.

Conclusions

The methodology described here for the synthesis of

polyhydroxylated 1-alkylvinylphosphonate and -phosphine

oxide chiral synthons employs a simple set of reactions, in-

expensive starting carbohydrates, and mild reaction condi-

tions. The key ARF reaction is smoothly promoted at low

temperature (10–40 °C) and demonstrated high efficiency

on a broad substrate scope and excellent compatibility with

the presence of sensitive functional groups. The fragmenta-

Scheme 6. Radical additions to vinylphosphine oxides and vinyl-

phosphonates.

The preparation of 2-methylene-1-phospha-pentofur- tion has been tested by using a wide variety of 2,3-dideoxy-

anoses 65 and 66 was accomplished starting from the vinyl- 3-phosphoryl carbohydrate derivatives in pento- and hexo-

phosphonate 61. Basic hydrolysis of the formate ester af- furanose, hexopyranose, and disaccharide structures, gen-

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Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

General Procedure for the Introduction of the 3-Diphenylphosphoryl

Group (Ferrier Reaction): To a stirred solution of AlCl₃(2 equiv.)

in CH₂Cl₂(1.8 mL), at 0 °C under nitrogen was added dropwise a

solution of Ph₂PCl (2 equiv.) in CH₂Cl₂(1.8 mL) and stirring was

continued over 1 h at room temperature. The glycal (1 equiv.) in

CH₂Cl₂(1.4 mL) was then added and stirring was continued at

reflux temperature for the specified time. The reaction mixture was

then poured into water and extracted with CH₂Cl₂. The combined

extracts were washed with brine, dried with Na₂SO₄, and concen-

trated under reduced pressure. The residue was purified by

erally giving good to excellent yields. A significant advan-

tage of this methodology is that the relative position of the

readily hydrolyzable formyl group depends only on the pyr-

anose or furanose form of the starting carbohydrate and

this may be very convenient when further transformations

are required. The pairs of threo (59 and 62) and erythro

(60 and 61) isomers of pent-1-enitols illustrate this point

(Table 2). Although the results reported in Table 1 and

Table 2 were based on milligram-scale reactions, gram-scale

reactions of selected examples also afforded the corre- chromatography (hexanes/EtOAc).

sponding products in similar yields.

1,5-Anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-

ribo-hex-1-enitol (3), (1R)-1,5-Anhydro-4,6-di-O-benzyl-2,3-dide-

oxy-1-diphenylphosphoryl- -erythro-hex-2-enitol (4α) and (1S)-1,5-

Anhydro-4,6-di-O-benzyl-2,3-dideoxy-1-diphenylphosphoryl-

D-

The ease with which these relatively complex 1-(iodo-

methyl)alkylphosphonate and -phosphine oxide intermedi-

ates can be prepared on a large scale adds significant value

to this method, because the chemical reactivity of these sys-

tems has been little studied to date.

D

-

erythro-hex-2-enitol (4β):^[17]From 3,4,6-tri-O-benzyl-d-glucal (1;

50 mg, 0.12 mmol) following the general procedure by stirring

at reflux temperature for 3 h. Chromatotron chromatography of

the reaction residue (hexanes/EtOAc, 55:45) gave 3 (30 mg,

0.059 mmol, 49 %), 4α (7.5 mg, 0.015 mmol, 12 %), and 4β

(16.5 mg, 0.032 mmol, 27%).

The synthetic usefulness and reactivity of these com-

pounds has been preliminarily assessed, and the results are

summarized in Scheme 4, Scheme 5, and Scheme 6. Exam-

ples of intramolecular O–C-cyclization and P–O-cyclization

for the preparation of 1,4-anhydro-2-deoxy-2-diphenyl-

phosphoryl-d-arabinitol 63 and 1-phospha sugars 65 and

66, respectively, are illustrated in Scheme 4. The Michael

addition of glycine to vinylphosphonates 65 and 66 and the

use of these compounds for the synthesis of β-amino

carboxylic acids are shown in Scheme 5. The activated car-

bon–carbon double bond of conjugated vinylphosphonates

and vinylphosphine oxides have also been utilized as radical

traps in intermolecular additions of alkyl radicals

(Scheme 6).

Compound 3: White oil; ¹H NMR (400 MHz, CDCl₃): δ = 3.57

2

(dddd, J_P,H= 10.1, J = 6.4, 4.7, 1.9 Hz, 1 H), 3.66 (dd, J = 10.9,

2.9 Hz, 1 H), 3.77 (dd, J = 10.9, 3.7 Hz, 1 H), 4.13 (d, J = 11.4 Hz,

3

1 H), 4.22 (ddd, J_P,H= 18.8, J = 8.2, 6.1 Hz, 1 H), 4.26 (d, J =

3

11.1 Hz, 1 H), 4.28 (ddd, J_P,H= 4.2, J = 6.1, 4.2 Hz, 1 H), 4.44

(d, J = 11.9 Hz, 1 H), 4.50 (d, J = 12.2 Hz, 1 H), 4.82 (ddd, J =

7.4, 3.2, 3.2 Hz, 1 H), 6.47 (ddd, ⁴J_P,H= 4.0, J = 5.8, 1.6 Hz, 1 H),

6.76–6.78 (m, 2 H), 7.09–7.16 (m, 3 H), 7.21–7.47 (m, 11 H), 7.76–

7.85 (m, 4 H) ppm.

4,6-Di-O-acetyl-1,5-anhydro-2,3-dideoxy-3-diphenylphosphoryl-

ribo-hex-1-enitol (5)^[15]and 4,6-Di-O-acetyl-1,5-anhydro-2,3-dide-

oxy-3-diphenylphosphoryl- -arabino-hex-1-enitol (6): From 3,4,6-

D-

D

tri-O-acetyl-d-glucal (2; 100 mg, 0.367 mmol) following the general

procedure by stirring at reflux temperature for 14 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 3:7) gave

5 (91 mg, 0.219 mmol, 60%) and 6 (15.2 mg, 0.037 mmol, 10%).

Experimental Section

Compound 5: Crystalline solid; m.p. 149–151 °C (n-hexane/EtOAc);

1

[α]_D= +308.7 (c = 1.2, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

General Methods: Melting points were determined with a hot-stage

apparatus. Optical rotations were measured at the sodium line at

ambient temperature in CHCl₃solutions. IR spectra were measured

as thin films on a NaCl plate, CHCl₃, or CCl₄solutions as stated.

NMR spectra were determined at 500 or 400 MHz for ¹H, 125.7

or 100.6 MHz for ¹³C, and 161.9 MHz for ³¹P in CDCl₃or C₆D₆

as stated. The chemical shifts are given in parts per million (ppm)

relative to TMS at δ = 0.00 ppm or to residual CDCl₃at δ =

7.26 ppm for proton spectra, relative to CDCl₃at δ = 77.00 ppm

for carbon spectra, and relative to external phosphoric acid at δ =

0.00 ppm for phosphorus spectra. ¹³C DEPT-90, -135 and 2D-

COSY, HSQC, NOESY, and HMBC experiments were performed

routinely for all new compounds. When necessary, J_P,Hcoupling

constants were determined by using ¹H{³¹P} NMR decoupled

spectra. Low- and high-resolution mass spectra were recorded by

using electron impact (EI) or electrospray (ESI⁺) and TOF analyzer

as specified. Merck silica gel 60 PF (0.063–0.2 mm) was used for

column chromatography. Circular layers of 1 mm of Merck silica

gel 60 PF₂₅₄were used on a Chromatotron for centrifugally-assisted

radial chromatography. Commercially available reagents and sol-

vents were analytical grade or were purified by standard procedures

prior to use. The spray reagents for TLC analysis were composed

of 0.5% vanillin in H₂SO₄/EtOH (4:1) or alternatively Hanessian’

stain^[40]and further heating until development of color.

2

1.14 (s, 3 H), 2.01 (s, 3 H), 3.72 (dddd, J_P,H= 5.8, J = 5.8, 5.8,

1.9 Hz, 1 H), 4.19 (ddd, ³J_P,H= 3.2, J = 5.6, 5.6 Hz, 1 H), 4.22 (dd,

J = 12.3, 1.9 Hz, 1 H), 4.40 (dd, J = 12.2, 3.7 Hz, 1 H), 5.14 (ddd,

J = 10.1, 3.8, 2.1 Hz, 1 H), 5.32 (ddd, ³J_P,H= 20.9, J = 10.1, 6.6 Hz,

4

1 H), 6.51 (ddd, J_P,H= 4.5, J = 6.1, 1.6 Hz, 1 H), 7.44–7.52 (m, 6

H), 7.71–7.76 (m, 2 H), 7.85–7.87 (m, 2 H) ppm. ¹³C NMR

1

(125.7 MHz, CDCl₃): δ = 19.4 (CH₃), 20.6 (CH₃), 35.2 (d, J_P,C

=

2

69.9 Hz, CH), 61.9 (CH₂), 66.6 (d, J_P,C= 7.4 Hz, CH), 71.8 (CH),

92.4 (d, J_P,C= 7.4 Hz, CH), 128.7 (d, J_P,C= 11.7 Hz, 2ϫ CH),

128.9 (d, J_P,C= 11.7 Hz, 2ϫ CH), 130.5 (d, J_P,C= 8.5 Hz, 2ϫ

2

3

2

4

CH), 130.7 (d, J_P,C= 8.5 Hz, 2ϫ CH), 131.5 (d, J_P,C= 2.1 Hz,

4

1

2 ϫ CH), 131.6 (d, J_P,C= 2.1 Hz, 2 ϫ CH), 132.8 (d, J_{P, C}

=

1

100.7 Hz, 2ϫ CH), 133.5 (d, J_P,C= 95.4 Hz, 2ϫ CH), 146.3 (d,

³J_P,C= 9.5 Hz, CH), 170.2 (C), 170.6 (C) ppm. ³¹P NMR

(161.9 MHz, CDCl ): δ = 25.8 (s, 1 P) ppm. IR (film): ν =

˜

3

1740 cm^–1. MS (ESI⁺): m/z (%) = 437 (100) [M + Na]⁺. HRMS

(ESI⁺): m/z calcd. for C₂₂H₂₃NaO₆P [M + Na]⁺437.11301; found

437.1136.

Compound 6: Crystalline solid; m.p. 159.7–160.8 °C (n-hexane/

EtOAc); [α]_D= –32.9 (c = 0.27, CHCl₃). ¹H NMR (500 MHz,

2

CDCl₃): δ = 1.52 (s, 3 H), 2.04 (s, 3 H), 3.59 (dddd, J_P,H= 8.7, J

= 11.0, 2.5, 2.4 Hz, 1 H), 3.95 (ddd, J = 8.8, 5.1, 2.8 Hz, 1 H), 4.16

(dd, J = 12.3, 2.8 Hz, 1 H), 4.22 (dd, J = 12.5, 5.2 Hz, 1 H), 4.59

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5039

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

(ddd, J_P,H= 8.7, J = 6.2, 2.2 Hz, 1 H), 5.53 (ddd, J_P,H= 9.1, J =

3

itol (12β), (1R)-1,5-Anhydro-6-O-benzyl-2,3-dideoxy-1-diphenyl-

phosphoryl-4-O-(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-D-

4

11.1, 9.1 Hz, 1 H), 6.48 (ddd, J_P,H= 2.9, J = 5.9, 2.9 Hz, 1 H),

7.48–7.60 (m, 6 H), 7.68–7.74 (m, 2 H), 7.81–7.87 (m, 2 H) ppm. erythro-hex-2-enitol (13α), and (1S)-1,5-Anhydro-6-O-benzyl-2,3-

¹³C NMR (125.7 MHz, CDCl₃): δ = 20.1 (CH₃), 20.7 (CH₃), 39.4

dideoxy-1-diphenylphosphoryl-4-O-(2,3,4,6-tetra-O-benzyl-β- -ga-

lactopyranosyl)- -erythro-hex-2-enitol (13β): From hexa-O-benzyl-

8.2 Hz, CH), 94.6 (d, ²J_P,C= 5.5 Hz, CH), 128.6 (d, ³J_P,C= 11.8 Hz, d-lactal (11;^[41]1.227 g, 1.45 mmol) following the general procedure

D

1

3

(d, J_P,C= 69.9 Hz, CH), 61.9 (CH₂), 63.4 (CH), 74.6 (d, J_P,C

=

D

3

1

2ϫ CH), 128.7 (d, J_P,C= 10.9 Hz, 2ϫ CH), 130.6 (d, J_P,C

=

by stirring at reflux temperature for 22 h. Silica gel column

chromatography (hexanes/EtOAc, 7:3) gave 12α (616.8 mg,

0.655 mmol, 45%), 12β (194.8 mg, 0.207 mmol, 14%), 13α (103 mg,

2

99.0 Hz, C), 131.43 (d, J_P,C= 9.1 Hz, 2ϫ CH), 131.44 (d, J_P,C

1

4

8.2 Hz, 2ϫ CH), 131.45 (d, J_P,C= 97.2 Hz, C), 131.9 (d, J_P,C

2.7 Hz, CH), 132.1 (d, ⁴J_P,C= 2.7 Hz, CH), 146.0 (d, ³J_P,C= 9.1 Hz, 0.109 mmol, 7.5%), and 13β (174 mg, 0.185 mmol, 12%) all as col-

CH), 170.0 (C), 170.7 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ

orless oils.

= 28.8 (s, 1 P) ppm. IR (film): ν = 1743 cm^–1. MS (EI, 70 eV): m/z

˜

Compound 12α: [α]_D= +246.4 (c = 0.11, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 2.64 (dd, J = 9.9, 7.8 Hz, 1 H), 3.18 (dd,

J = 9.8, 2.9 Hz, 1 H), 3.31 (ddd, J = 7.3, 5.8, 0.9 Hz, 1 H), 3.57

(%) = 415 (1) [M + H]⁺, 287 (294), 201 (100). HRMS (EI, 70 eV):

m/z calcd. for C₂₂H₂₄O₆P [M + H]⁺415.4311; found 415.4311.

C₂₂H₂₃O₆P (414.39): calcd. C 63.75, H 5.60; found C 63.60, H 5.42.

2

(dddd, J_P,H= 5.8, J = 5.8, 5.8, 1.6 Hz, 1 H), 3.61–3.65 (m, 2 H),

1,5-Anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-

D

-

3.72–3.78 (m, 2 H), 3.79 (dd, J = 2.9, 1.1 Hz, 1 H), 4.05 (dddd,

xylo-hex-1-enitol (9): From 3,4,6-tri-O-benzyl-d-galactal (7; ³J_P,H= 5.6, J = 5.6, 5.6, 2.9 Hz, 1 H), 4.16 (d, J = 11.4 Hz, 1 H),

271.4 mg, 0.652 mmol) following the general procedure by stirring

at reflux temperature for 5 h. Silica gel column chromatography of

the reaction residue (hexanes/EtOAc, 1:1) gave 9 (205 mg,

0.402 mmol, 62%) as a crystalline solid: m.p. 109.9–111.0 °C (n-

hexane/EtOAc); [α]_D= +60 (c = 0.14, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 3.27 (ddddd, ²J_P,H= 12.6, J = 4.6, 1.5, 1.5,

1.5 Hz, 1 H), 3.49 (dd, J = 10.1, 6.6 Hz, 1 H), 3.67 (dd, J = 10.1,

4.27 (d, J = 8.0 Hz, 1 H), 4.30 (d, J = 4.2 Hz, 1 H), 4.33 (d, J =

4.8 Hz, 1 H), 4.45–4.56 (m, 3 H), 4.59 (d, J = 11.9 Hz, 1 H), 4.65

(d, J = 12.2 Hz, 1 H), 4.71 (d, J = 11.9 Hz, 1 H), 4.89 (d, J =

10.3 Hz, 1 H), 5.05 (ddd, J = 9.8, 2.1, 2.1 Hz, 1 H), 6.49 (ddd, ⁴J_P,H

= 4.6, J = 6.0, 1.3 Hz, 1 H), 7.00 (m, 4 H), 7.19–7.41 (m, 27 H),

7.67 (m, 2 H), 7.83 (m, 2 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃):

1

δ = 38.1 (d, J_P,C= 69.9 Hz, CH), 68.1 (CH₂), 68.6 (CH₂), 71.4

3

6.6 Hz, 1 H), 3.95 (dddd, J_P,H= 8.6, J = 1.6, 1.6, 1.6 Hz, 1 H),

(²J_P,C= 7.8 Hz, CH), 73.0 (CH₂), 73.1 (CH), 73.2 (CH₂), 73.4

(CH₂), 74.7 (2ϫ CH), 74.9 (CH₂), 75.3 (CH₂), 78.5 (CH), 81.8

4.23 (d, J = 12.2 Hz, 1 H), 4.37 (d, J = 11.9 Hz, 1 H), 4.42 (dddd,

³J_P,H= 3.4, J = 6.4, 5.0, 1.9 Hz, 1 H), 4.45 (d, J = 12.2 Hz, 1 H),

4.47 (ddd, J = 6.4, 6.4, 1.6 Hz, 1 H), 4.49 (d, J = 12.2 Hz, 1 H),

2

(CH), 92.7 (d, J_P,C= 7.8 Hz, CH), 103.6 (CH), 127.2–128.7 (Ar,

complex), 130.6–135.2 (Ar, complex), 138.0 (C), 138.2 (C), 138.7

4

3

6.64 (ddd, J_P,H= 4.0, J = 6.2, 1.7 Hz, 1 H), 6.97 (m, 2 H), 7.25

(C), 138.8 (C), 139.1 (C), 146.5 (d, J_P,C= 9.9 Hz, CH) ppm. ³¹P

(m, 8 H), 7.51 (m, 6 H), 7.80 (m, 4 H) ppm. ¹³C NMR (125.7 MHz,

NMR (161.9 MHz, CDCl ): δ = 28.2 (s, 1 P) ppm. IR (CHCl ): ν

˜

3

1

CDCl₃): δ = 37.3 (d, J_P,C= 67.2 Hz, CH), 68.6 (CH₂), 69.1 (CH), = 1076 cm^–1. MS (ESI⁺): m/z (%) = 965 (100) [M + Na]⁺. HRMS

2

71.7 (CH₂), 72.9 (CH₂), 74.2 (CH), 92.3 (d, J_P,C= 7.3 Hz, CH),

(ESI⁺): m/z calcd. for C₅₉H₅₉NaO₉P [M + Na]⁺965.3794; found

127.4 (CH), 127.5 (2ϫ CH), 127.8 (CH), 128.1 (2ϫ CH), 128.2

(2ϫ CH), 128.3 (2ϫ CH), 128.7 (d, J_P,C= 11.8 Hz, 2ϫ CH), 75.07, H 6.19.

965.3813. C₅₉H₅₉O₉P (943.09): calcd. C 75.14, H 6.31; found C

3

1

128.9 (d, J_P,C= 10.9 Hz, 2ϫ CH), 131.0 (d, J_P,C= 98.1 Hz, C),

Compound 12β: [α]_D= –9.3 (c = 0.27, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 3.35 (m, 1 H), 3.37 (dd, J = 9.8, 3.2 Hz, 1 H), 3.41

(dd, J = 8.8, 5.1 Hz, 1 H), 3.49 (dd, J = 8.8, 7.9 Hz, 1 H), 3.61–

3.63 (m, 1 H), 3.66 (dd, J = 9.8, 7.9 Hz, 1 H), 3.79 (dd, J = 9.9,

6.2 Hz, 1 H), 3.84 (d, J = 2.5 Hz, 1 H), 4.10 (dd, J = 10.1, 6.9 Hz,

1 H), 4.27 (d, J = 7.6 Hz, 1 H), 4.29–4.32 (m, 1 H), 4.38–4.40 (m,

1 H), 4.41 (d, J = 12.0 Hz, 1 H), 4.444 (d, J = 12.0 Hz, 1 H), 4.445–

4.48 (m, 1 H), 4.49 (d, J = 12.0 Hz, 1 H), 4.58 (d, J = 11.4 Hz, 1

H), 4.62 (d, J = 12.0 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.67 (d,

J = 10.7 Hz, 1 H), 4.71 (d, J = 11.7 Hz, 1 H), 4.86 (d, J = 11.0 Hz,

2

131.2 (d, J_P,C= 9.1 Hz, 2ϫ CH), 131.3 (d, J_P,C= 9.1 Hz, 2ϫ

1

4

CH), 131.5 (d, J_P,C= 95.4 Hz, C), 131.9 (d, J_P,C= 2.7 Hz, CH),

4

3

132.0 (d, J_P,C= 2.7 Hz, CH), 137.5 (C), 138.2 (C), 146.8 (d, J_P,C

= 9.1 Hz, CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 26.5 (s, 1

P) ppm. IR (film): ν = 1095 cm^–1. MS (EI, 70 eV): m/z (%) = 511

˜

(Ͻ 1) [M + H]⁺, 311 (92), 201 (72), 91 (100). HRMS (EI, 70 eV):

m/z calcd. for C₃₂H₃₂O₄P [M + H]⁺511.2038; found 511.2047.

C₃₂H₃₁O₄P (510.57): calcd. C 75.28, H 6.12; found C 75.55, H 5.88.

4,6-Di-O-acetyl-1,5-anhydro-2,3-dideoxy-3-diphenylphosphoryl-D-

xylo-hex-1-enitol (10):^[15]From 3,4,6-tri-O-acetyl-d-galactal (8;

150 mg, 0.551 mmol) following the general procedure by stirring at

reflux temperature for 20.5 h. Chromatotron chromatography of

the reaction residue (hexanes/EtOAc, 4:6) gave 10 (207 mg,

1 H), 4.92 (d, J = 11.4 Hz, 1 H), 6.50 (ddd, J_P,H= 3.6, J = 6.2,

4

2.5 Hz, 1 H), 7.18–7.36 (m, 27 H), 7.37 (m, 4 H), 7.80–7.85 (m, 4

1

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 39.1 (d, J_{P, C}

=

68.1 Hz, CH), 67.2 (CH₂), 68.2 (CH₂), 71.6 (CH), 72.8 (CH₂), 73.03

0.498 mmol, 90%) as an oil. ¹H NMR (500 MHz, CDCl₃): δ = 2.01 (CH₂), 73.05 (CH), 73.4 (CH₂), 73.6 (CH), 74.7 (CH₂), 75.2 (CH₂),

2

3

2

(s, 3 H), 2.04 (s, 3 H), 3.33 (ddddd, J_P,H= 11.8, J = 4.8, 1.6, 1.5,

75.4 (d, J_P,C= 1.8 Hz, CH), 78.9 (CH), 82.1 (CH), 92.6 (d, J_P,C

= 6.4 Hz, CH), 103.5 (CH), 127.3–128.6 (Ar, complex), 130.8–132.4

(Ar, complex), 137.8 (C), 138.43 (C), 138.46 (C), 138.5 (C), 138.7

1.4 Hz, 1 H), 4.15 (dd, J = 11.5, 5.2 Hz, 1 H), 4.19 (dd, J = 11.5,

3

7.2 Hz, 1 H), 4.32 (dddd, J_P,H= 3.0, J = 6.3, 4.8, 1.9 Hz, 1 H),

4.81 (ddddd, ⁴J_P,H= 1.6, J = 7.2, 5.2, 1.6, 1.2 Hz, 1 H), 5.08 (dddd,

(C), 144.9 (d, J_P,C= 10.0 Hz, CH) ppm. ³¹P NMR (161.9 MHz,

3

4

³J_P,H= 7.9, J = 1.9, 1.4, 1.2 Hz, 1 H), 6.64 (ddd, J_P,H= 4.3, J = CDCl ): δ = 28.6 (s, 1 P) ppm. IR (CHCl ): ν = 1096 cm^–1. MS

˜

3

6.3, 1.5 Hz, 1 H), 7.46–7.58 (m, 6 H), 7.76–7.81 (m, 2 H), 7.93–

7.98 (m, 2 H) ppm. The data for hydrogen atoms at C1–C6 shown

here have been calculated by iterative simulation using program

DAISY as implemented in Bruker Topspin v. 2.1.

(ESI⁺): m/z (%) = 965 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd.

for C₅₉H₅₉NaO₉P [M + Na]⁺965.3794; found 965.3794.

C₅₉H₅₉O₉P (943.09): calcd. C 75.14, H 6.31; found C 74.99, H 6.17.

Compound 13α: [α]_D= +23 (c = 0.20, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 3.39–3.43 (m, 2 H), 3.49–3.56 (m, 4 H), 3.67–3.71 (m,

2 H), 3.85 (d, J = 2.8 Hz, 1 H), 4.05 (m, 1 H), 4.23 (d, J = 7.6 Hz,

1,5-Anhydro-6-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-4-O-

(2,3,4,6-tetra-O-benzyl-β-D-galactopyranosyl)-D-ribo-hex-1-enitol

(12α), 1,5-Anhydro-6-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-4- 1 H), 4.32 (d, J = 12.0 Hz, 1 H), 4.38–4.40 (m, 3 H), 4.60 (d, J =

O-(2,3,4,6-tetra-O-benzyl-β- -galactopyranosyl)- -arabino-hex-1-en- 11.7 Hz, 2 H), 4.63 (d, J = 11.0 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1

D

5040

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

H), 4.72 (d, J = 12.0 Hz, 1 H), 4.92 (d, J = 11.7 Hz, 1 H), 5.09

10 Hz, C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 26.8 (s, 1

(dddd, ²J_P,H= 11.2, J = 2.7, 2.7, 2.7 Hz, 1 H), 6.12 (dddd, J = 10.5, P) ppm. IR (CHCl ): ν = 1783, 1216 cm^–1. MS (ESI⁺): m/z (%) =

˜

3

2.4, 2.4, 2.4 Hz, 1 H), 6.20 (dddd, J = 10.4, 2.5, 2.5, 2.5 Hz, 1 H),

513 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₅H₃₅

-

7.21–7.57 (m, 31 H), 7.77 (m, 2 H), 7.99 (m, 2 H) ppm. ¹³C NMR

NaO₆PSi [M + Na]⁺513.1838; found 513.1847. C₂₅H₃₅O₆PSi

(125.7 MHz, CDCl₃): δ = 68.7 (CH₂), 68.8 (CH₂), 70.5 (CH), 73.01 (490.61): calcd. C 61.20, H 7.19; found C 61.52, H 7.30.

1

(CH₂), 73.03 (CH₂), 73.28 (d, J_P,C= 77.2 Hz, CH), 73.34 (CH),

2,3-Dideoxy-3-diethoxyphosphoryl-5,6-O-isopropylidene-

D

-lyxo-

73.46 (CH), 73.48 (CH₂), 73.59 (CH), 74.60 (CH₂), 75.1 (CH₂),

hexono-1,4-lactone (17) and 2,3-Dideoxy-3-diethoxyphosphoryl-5,6-

2

79.3 (CH), 82.2 (CH), 104.2 (CH), 122.7 (d, J_P,C= 1.8 Hz, CH),

O-isopropylidene-

D

-ribo-hexono-1,4-lactone (18): From 16^[23]

1

127.5–128.6 (Ar, complex), 130.84 (d, J_P,C= 94.5 Hz, C), 130.87

(164 mg, 0.89 mmol) following the general procedure by stirring at

100 °C for 8 h. Chromatotron chromatography of the reaction resi-

due (hexanes/EtOAc, 4:6) gave 17 (72.5 mg, 0.225 mmol, 25%) and

18 (72.5 mg, 0.225 mmol, 25%).

(d, ³J_P,C= 10.0 Hz, CH), 130.9 (d, ¹J_P,C= 94.5 Hz, C), 131.8–132.4

(Ar, complex), 137.9 (C), 138.3 (C), 138.47 (C), 138.56 (C), 138.6

(C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 28.0 (s, 1 P) ppm. IR

(CHCl ): ν = 1100 cm^–1. MS (ESI⁺): m/z (%) = 965 (100) [M +

˜

3

Compound 17: Crystalline solid; m.p. 46.3–47.1 °C (n-hexane/

EtOAc); [α]_D= –20.5 (c = 0.39, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.33 (t, J = 7.1 Hz, 3 H), 1.34 (t, J = 7.1 Hz, 3 H),

1.36 (s, 3 H), 1.37 (s, 3 H), 2.66–2.76 (m, 1 H), 2.83–2.92 (m, 2 H),

3.98 (dd, J = 8.5, 6.9 Hz, 1 H), 4.08 (dd, J = 8.4, 6.8 Hz, 1 H),

4.11–4.18 (m, 4 H), 4.22 (ddd, J = 6.9, 6.9, 1.3 Hz, 1 H), 4.66 ppm

Na]⁺. HRMS (ESI⁺): m/z calcd. for C₅₉H₅₉NaO₉P [M + Na]⁺

965.3794; found 965.3794. C₅₉H₅₉O₉P (943.09): calcd. C 75.14, H

6.31; found C 75.36, H 6.13.

Compound 13β: [α]_D= +44.7 (c = 0.19, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 3.44–3.47 (m, 2 H), 3.49–3.55 (m, 2 H),

3.58 (dd, J = 10.4. 5.4 Hz, 1 H), 3.65 (m, 1 H), 3.69 (d, J = 10.4 Hz,

1 H), 3.76 (dd, J = 9.6, 7.7 Hz, 1 H), 3.86 (d, J = 2.8 Hz, 1 H),

3.91–3.93 (m, 1 H), 4.28 (d, J = 12.0 Hz, 1 H), 4.30 (d, J = 7.6 Hz,

1 H), 4.35 (d, J = 12.0 Hz, 1 H), 4.38 (s, 2 H), 4.58 (d, J = 11.7 Hz,

1 H), 4.70 (s, 2 H), 4.78 (s, 2 H), 4.90 (d, J = 11.7 Hz, 1 H), 5.11

3

(ddd, J_P,H= 16.4, J = 4.7, 1.6 Hz, 1 H). ¹³C NMR (125.7 MHz,

3

CDCl₃): δ_C= 16.39 (d, J_P,C= 5.3 Hz, CH₃), 16.41 (d, J_{P, C}

=

2

5.7 Hz, CH₃), 25.6 (CH₃), 25.7 (CH₃), 29.5 (d, J_P,C= 5.3 Hz,

CH₂), 34.5 (d, ¹J_P,C= 151.5 Hz, CH), 62.7 (d, ²J_P,C= 7.4 Hz, CH₂),

2

3

62.8 (d, J_P,C= 7.4 Hz, CH₂), 65.4 (CH₂), 77.0 (d, J_P,C= 8.2 Hz,

2

CH), 77.1 (CH), 110.2 (C), 174.6 (d, J_P,C= 7.4 Hz, C) ppm. ³¹P

3

(br. d, J_P,H= 12.3 Hz, 1 H), 6.08 (br. d, J = 11.0 Hz, 1 H), 6.14

(br. d, J = 11.7 Hz, 1 H), 7.17–7.33 (m, 27 H), 7.41–7.45 (m, 3 H),

7.51–7.54 (m, 1 H), 7.83–7.87 (m, 2 H), 7.91–7.95 (m, 2 H) ppm.

¹³C NMR (125.7 MHz, CDCl₃): δ = 68.8 (CH₂), 69.3 (CH₂), 71.8

NMR (161.9 MHz, CDCl ): δ = 26.4 (s, 1 P) ppm. IR (CHCl ): ν

˜

3

= 2995, 1786, 1224, 1025 cm^–1. MS (ESI⁺): m/z (%) = 345 (100) [M

+ Na]⁺. HRMS (ESI⁺): m/z calcd. for C₁₃H₂₃NaO₇P [M + Na]⁺

345.1079; found 345.1081. C₁₃H₂₃O₇P (322.30): calcd. C 48.45, H

7.19; found C 48.43, H 6.99.

4

(d, J_P,C= 1.8 Hz, CH), 72.9 (CH₂), 73.0 (CH₂), 73.4 (CH), 73.5

1

(CH₂), 73.5 (CH), 74.5 (CH₂), 74.8 (d, J_P,C= 92.7 Hz, CH), 75.3

3

(CH₂), 76.8 (d, J_P,C= 7.3 Hz, CH), 79.3 (CH), 82.4 (CH), 104.6

Compound 18: Colorless oil; [α]_D= –20.0 (c = 0.4, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 1.32 (t, J = 7.2 Hz, 6 H), 1.32 (s, 3

H), 1.44 (s, 3 H), 2.65–2.90 (m, 3 H), 3.86 (dd, J = 9.1, 4.9 Hz, 1

H), 4.09 (dd, J = 9.3, 7.2 Hz, 1 H), 4.12–4.18 (m, 4 H), 4.28 (ddd,

2

(CH), 123.1 (d, J_P,C= 4.5 Hz, CH), 127.4–128.4 (Ar, complex),

3

131.3 (d, J_P,C= 9.1 Hz, CH), 131.7–132.4 (Ar, complex), 137.8

(C), 138.3 (C), 138.52 (C), 138.57 (C), 138.6 (C) ppm. ³¹P NMR

(161.9 MHz, CDCl ): δ = 28.3 (s, 1 P) ppm. IR (CHCl ): ν =

˜

3

J = 7.2, 4.8, 4.8 Hz, 1 H), 4.64 (ddd, J_P,H= 17.2, J = 4.8, 2.9 Hz,

1097 cm^–1. MS (ESI⁺): m/z (%) = 965 (100) [M + Na]⁺. HRMS

(ESI⁺): m/z calcd. for C₅₉H₅₉NaO₉P [M + Na]⁺965.3794; found

965.3794. C₅₉H₅₉O₉P (943.09): calcd. C 75.14, H 6.31; found C

75.13, H 6.15.

3

1 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 16.33 (d, J_P,C

=

3

6.4 Hz, CH₃), 16.34 (d, J_P,C= 5.6 Hz, CH₃), 24.4 (CH₃), 26.2

(CH₃), 29.0 (d, J_P,C= 5.0 Hz, CH₂), 32.2 (d, J_P,C= 150.4 Hz,

2

1

2

CH), 62.7 (d, J_P,C= 7.1 Hz, CH₂), 62.8 (d, J_P,C= 7.1 Hz, CH₂),

65.2 (CH₂), 75.9 (d, J_P,C= 10.0 Hz, CH), 79.2 (²J_P,C= 2.1 Hz,

3

General Procedure for the Introduction of the 3-Diethoxyphosphoryl

Group (phospha-Michael Addition): To a solution of the α,β-unsatu-

rated lactone (1 equiv.) in phenol (4.2 mL) was added dropwise tri-

ethyl phosphite (5 equiv.) at room temperature under nitrogen. The

mixture was stirred at 100 °C for the specified time and the solvent

was evaporated under reduced pressure. The residue was purified

by Chromatotron chromatography (hexanes/EtOAc).

CH), 110.4 (C), 174.4 ppm (d, J_P,C= 3.5 Hz, C). ³¹P NMR

3

(161.9 MHz, CDCl ): δ = 27.3 (s, 1 P) ppm. IR (CHCl ): ν = 2995,

˜

3

P

3

1784, 1216, 1026 cm^–1. MS (ESI⁺): m/z (%) = 345 (100) [M +

Na]⁺. HRMS (ESI⁺): m/z calcd. for C₁₃H₂₃NaO₇P [M + Na]⁺

345.1079; found 345.1078. C₁₃H₂₃O₇P (322.30): calcd. C 48.45, H

7.19; found C 48.34, H 6.94.

4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphosphoryl-

hexono-1,5-lactone (20β) and 4,6-Di-O-benzyl-2,3-dideoxy-3-di-

ethoxyphosphoryl- -ribo-hexono-1,5-lactone (20α): From 4,6-di-O-

D-arabino-

5-O-(tert-Butyldiphenylsilyl)-2,3-dideoxy-3-diethoxyphosphoryl-D-

ribono-1,4-lactone (15):^[26]From 5-O-(tert-butyldiphenylsilyl)-2,3-

dideoxy-d-glycero-pent-2-enono-1,4-lactone (14;^[22]130.5 mg,

0.370 mmol) following the general procedure by stirring at 100 °C

for 6 h. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 6:4) gave 15 (130.8 mg, 0.266 mmol, 72%) as a

colorless oil: [α]_D= +25.6 (c = 0.39, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.05 (s, 9 H), 1.30 (t, J = 6.9 Hz, 3 H), 1.32 (t, J =

7.3 Hz, 3 H), 2.75–3.02 (m, 3 H), 3.71 (dd, J = 11.7, 2.5 Hz, 1 H),

4.01 (dd, J = 11.7, 2.2 Hz, 1 H), 4.08–4.16 (m, 4 H), 4.73 (dddd,

³J_P,H= 15.7, J = 5.2, 2.6, 2.4 Hz, 1 H), 7.37–7.45 (m, 6 H), 7.62–

7.65 (m, 4 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 16.4 (d,

D

benzyl-2,3-dideoxy-d-erythro-hex-2-enono-1,5-lactone (19;^[24]

280 mg, 0.863 mmol) following the general procedure by stirring at

100 °C for 4.5 h. Chromatotron chromatography of the reaction

residue (hexanes/EtOAc, 4:6) gave the irresoluble mixture 20α,β

(392 mg, 0.848 mmol, β/α, 4.5:1, 98 %). ¹H NMR (400 MHz,

CDCl₃) and ¹³C NMR (100.6 MHz, CDCl₃) exhibit complex reso-

nance patterns. ³¹P NMR (161.9 MHz, CDCl₃): δ = 25.9 (s, 1 P),

27.1 (s, 1 P) ppm. IR (CCl ): ν = 2985, 1751, 1241, 1026 cm^–1. MS

˜

4

(ESI⁺): m/z (%) = 485 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd.

for C₂₄H₃₁NaO₇P [M + Na]⁺485.1705; found 485.1707.

C₂₄H₃₁O₇P (462.48): calcd. C 62.33, H 6.76; found C 62.34, H 6.67.

2

³J_P,C= 5.4 Hz, 2ϫ CH₃), 19.2 (C), 26.8 (3ϫ CH₃), 30.2 (d, J_P,C

1

2

= 4.5 Hz, CH₂), 32.9 (d, J_P,C= 151.6 Hz, CH), 62.6 (d, J_P,C

=

7.3 Hz, CH₂), 62.7 (d, ²J_P,C= 7.3 Hz, CH₂), 64.5 (d, ³J_P,C= 7.3 Hz, 4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphosphoryl-

CH₂), 79.6 (CH), 127.9 (4ϫ CH), 130.02 (CH), 130.03 (CH), 132.2 1,5-lactone (22) and 4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphos-

D-xylo-hexono-

3

(C), 132.8 (C), 135.5 (2ϫ CH), 135.7 (2ϫ CH), 174.7 (d, J_P,C

=

phoryl-

D

-lyxo-hexono-1,5-lactone (23): From 4,6-di-O-benzyl-2,3-

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5041

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

dideoxy-d-threo-hex-2-enono-1,5-lactone (21;^[25]100 mg,

3

isomer) = 1.98 (dddd, J_P,H= 9.9, J = 14.5, 2.4, 2.2 Hz, 1 H), 2.25

3

2

0.308 mmol) following the general procedure by stirring at 100 °C (dddd, J_P,H= 30.1, J = 14.7, 7.0, 4.3 Hz, 1 H), 3.24 (dddd, J_P,H

for 1.5 h. Chromatotron chromatography (hexanes/EtOAc, 4:6)

gave 22 (101.3 mg, 0.219 mmol, 71%) and 23 (12 mg, 0.026 mmol,

8.4%).

= 6.3, J = 6.3, 6.3, 2.8 Hz, 1 H), 3.62 (dd, J = 10.6, 2.4 Hz, 1 H),

3.75 (dd, J = 10.7, 2.8 Hz, 1 H), 4.09 (d, J = 11.4 Hz, 1 H), 4.15

(ddd, J_P,H= 24.6, J = 9.1, 6.0 Hz, 1 H), 4.19 (d, J = 11.4 Hz, 1

3

H), 4.43 (d, J = 12.0 Hz, 1 H), 4.53 (d, J = 12.0 Hz, 1 H), 4.60

(ddd, J = 9.1, 2.5, 2.5 Hz, 1 H), 5.12 (br. d, J = 2.8 Hz, 1 H), 6.71

(m, 2 H), 7.10–7.27 (m, 10 H), 7.47 (m, 4 H), 7.78 (m, 4 H) ppm.

¹³C NMR (125.7 MHz, CDCl₃): δ (major isomer) = 31.1 (CH₂),

Compound 22: Colorless oil; [α]_D= +21.3 (c = 0.47, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 1.32 (t, J = 7.2 Hz, 3 H), 1.33 (t, J

= 6.9 Hz, 3 H), 2.58 (dddd, ²J_P,H= 20.7, J = 8.0, 8.0, 2.7 Hz, 1 H),

2.61–2.71 (m, 1 H), 2.75–2.83 (m, 1 H), 3.70 (dd, J = 9.9, 6.5 Hz,

1 H), 3.74 (dd, J = 9.9, 5.9 Hz, 1 H), 4.08–4.18 (m, 5 H), 4.44 (d,

J = 11.7 Hz, 1 H), 4.47 (d, J = 11.4 Hz, 1 H), 4.54 (d, J = 11.9 Hz,

1 H), 4.543 (ddd, J = 6.1, 6.1, 2.1 Hz, 1 H), 4.66 (d, J = 11.9 Hz,

1 H), 7.24–7.33 (m, 10 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ

= 16.4 (2ϫ CH₃), 27.4 (CH₂), 34.7 (d, ¹J_P,C= 142.0 Hz, CH), 62.66

1

3

35.6 (d, J_P,C= 69.9 Hz, CH), 68.9 (d, J_P,C= 1.8 Hz, CH), 69.3

2

(CH₂), 72.3 (CH₂), 73.5 (CH₂), 74.6 (d, J_P,C= 6.4 Hz, CH), 90.1

3

(d, J_P,C= 2.7 Hz, CH), 127.3–129.0 (Ar, complex), 130.6–132.0

(Ar, complex), 132.5 (C), 132.8 (C), 137.2 (C), 138.0 (C) ppm. ³¹P

NMR (161.9 MHz, CDCl ): δ = 36.8 (s, 1 P) ppm. IR (CHCl ): ν

˜

3

= 3212 cm^–1. MS (EI, 70 eV): m/z (%) = 529 (2) [M + H]⁺, 511 (5),

202 (36), 91 (100). HRMS (EI, 70 eV): m/z calcd. for C₃₂H₃₄O₅P

[M + H]⁺529.2144; found 529.2130. C₃₂H₃₃O₅P (528.58): calcd. C

72.71, H 6.29; found C 72.63, H 6.11.

2

(d, J_P,C= 12.7 Hz, CH₂), 62.68 (d, J_P,C= 11.3 Hz, CH₂), 68.0

(CH₂), 70.0 (CH), 71.5 (CH₂), 73.5 (CH₂), 78.4 (CH), 127.69 (2ϫ

CH), 127.74 (CH), 127.84 (2ϫ CH), 127.95 (CH), 128.35 (2ϫ CH),

3

128.4 (2ϫ CH), 137.1 (C), 137.6 (C), 169.1 (d, J_P,C= 12.0 Hz,

C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 26.7 (s, 1 P) ppm. IR

4,6-Di-O-acetyl-2,3-dideoxy-3-diphenylphosphoryl-D-ribo-hexopyr-

(CHCl ): ν = 3009, 1747, 1241, 1026 cm^–1. MS (ESI⁺): m/z (%) =

anose (25): From 5 (90.8 mg, 0.219 mmol) in THF/H₂O containing

Ph₃P·HBr (25 mg, 0.073 mmol) following the general procedure by

heating at reflux for 8 h. Chromatotron chromatography of the re-

action residue (hexanes/EtOAc, 6:4Ǟ3:7) gave starting material 5

(20.7 mg, 0.05 mmol, 23%) and compound 25 (52 mg, 0.12 mmol,

55%, anomeric mixture, α/β, 10:1). Compound 25: crystalline solid;

m.p. (double): 174.9–175.8 °C (needles), 178.0–178.6 °C (prisms)

(n-hexane/EtOAc); [α]_D= +26.8 (c = 0.13, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ (major isomer) = 1.10 (s, 3 H), 1.96 (dddd,

³J_P,H= 10.2, J = 15.0, 1.3, 1.3 Hz, 1 H), 2.04 (s, 3 H), 2.37 (dddd,

˜

3

485 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₁NaO₇P

[M + Na]⁺485.1705; found 485.1707. C₂₄H₃₁O₇P (462.48): calcd.

C 62.33, H 6.76; found C 62.34, H 6.67.

Compound 23: Colorless oil; [α]_D= –15.0 (c = 0.12, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 1.21 (t, J = 6.9 Hz, 3 H), 1.33 (t, J

2

= 7.3 Hz, 3 H), 2.44 (dddd, J_P,H= 19.6, J = 13.2, 6.0, 1.3 Hz, 1

3

H), 2.76 (ddd, J_P,H= 2.2, J = 18.3, 6.0 Hz, 1 H), 3.05 (ddd, J_P,H

= 13.3, J = 18.3, 13.3 Hz, 1 H), 3.63 (dd, J = 9.8, 6.0 Hz, 1 H),

3.70 (dd, J = 9.5, 9.5 Hz, 1 H), 4.00–4.16 (m, 4 H), 4.39 (br. d,

³J_P,H= 7.3 Hz, 1 H), 4.47–4.50 (m, 1 H), 4.47 (d, J = 11.7 Hz, 1

H), 4.52 (d, J = 11.7 Hz, 1 H), 4.66 (d, J = 11.4 Hz, 1 H), 4.91 (d, J

= 11.0 Hz, 1 H), 7.26–7.36 (m, 10 H) ppm. ¹³C NMR (125.7 MHz,

2

³J_P,H= 32.2, J = 15.1, 7.6, 4.0 Hz, 1 H), 3.43 (dddd, J_P,H= 4.8, J

= 7.7, 6.6, 1.4 Hz, 1 H), 4.03 (dd, J = 12.2, 2.1 Hz, 1 H), 4.43 (dd,

J = 12.1, 3.8 Hz, 1 H), 4.81 (ddd, J = 10.6, 3.7, 2.1 Hz, 1 H), 5.13

3

(br. d, J = 3.4 Hz, 1 H), 5.17 (ddd, J_P,H= 25.2, J = 10.5, 6.8 Hz,

3

CDCl₃): δ = 16.3 (d, J_P,C= 5.4 Hz, CH₃), 16.5 (d, J_P,C= 5.4 Hz,

1 H), 7.51 (m, 6 H), 7.79 (m, 2 H), 7.86 (m, 2 H) ppm. ¹³C NMR

CH₃), 26.4 (d, ²J_P,C= 2.7 Hz, CH₂), 35.9 (d, ¹J_P,C= 150.8 Hz, CH),

62.2 (d, J_P,C= 6.4 Hz, CH₂), 62.4 (d, J_P,C= 6.4 Hz, CH₂), 67.8

(125.7 MHz, CDCl₃): δ (major isomer) = 19.4 (CH₃), 20.7 (CH₃),

2

1

30.9 (d, J_P,C= 1.8 Hz, CH₂), 33.7 (d, J_P,C= 69.0 Hz, CH), 62.8

4

2

(d, J_P,C= 3.6 Hz, CH₂), 69.2 (d, J_P,C= 6.4 Hz, CH), 73.7 (CH₂),

2

(CH₂), 65.4 (CH), 68.0 (d, J_P,C= 6.4 Hz, CH), 89.9 (CH), 129.0

(d, J_P,C= 11.8 Hz, 2ϫ CH), 129.1 (d, J_P,C= 10.9 Hz, 2ϫ CH),

130.3 (d, J_P,C= 2.7 Hz, 2ϫ CH), 130.4 (d, J_P,C= 4.5 Hz, 2ϫ

3

74.3 (CH₂), 81.9 (d, J_P,C= 16.3 Hz, CH), 127.4 (2ϫ CH), 127.7

3

(CH), 127.9 (2ϫ CH), 128.0 (CH), 128.3 (2ϫ CH), 128.5 (2ϫ CH),

2

3

137.3 (C), 137.8 (C), 167.9 (d, J_P,C= 19.1 Hz, C) ppm. ³¹P NMR

1

4

CH), 131.3 (d, J_P,C= 98.1 Hz, C), 131.7 (d, J_P,C= 2.7 Hz, CH),

132.10 (d, ¹J_P,C= 99.9 Hz, C), 132.13 (d, ⁴J_P,C= 2.7 Hz, CH), 170.3

(C), 170.7 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 35.5 (s, 1

(161.9 MHz, CDCl ): δ = 25.1 (s, 1 P) ppm. IR (CHCl ): ν = 3019,

˜

3

1740, 1216, 1028 cm^–1. MS (ESI⁺): m/z (%) = 485 (100) [M +

Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₁NaO₇P [M + Na]⁺

485.1705; found 485.1707. C₂₄H₃₁O₇P (462.48): calcd. C 62.33, H

6.76; found C 62.56, H 6.84.

P) ppm. IR (film): ν = 3178, 1738 cm^–1. MS (EI, 70 eV): m/z (%)

˜

= 433 (9) [M + H]⁺, 287 (24), 202 (100). HRMS (EI, 70 eV): m/z

calcd. for C₂₂H₂₆O₇P [M + H]⁺433.1416; found 433.1414.

C₂₂H₂₅O₇P (432.41): calcd. C 61.11, H 5.83; found C 61.21, H 5.74.

General Procedure for the Hydration Reaction: A stirred 0.045 m

solution of lactal (1 equiv.) in THF containing water (24 equiv.)

and Ph₃P·HBr^[28](0.12–0.46 equiv.) was heated at reflux tempera-

ture for the specified time. The reaction mixture was then poured

into a saturated aqueous solution of NaHCO₃and extracted with

CH₂Cl₂. The combined organic extracts were washed with a satu-

rated aqueous solution of NaHCO₃, dried with Na₂SO₄, and con-

centrated under reduced pressure. The residue was purified by

Chromatotron chromatography (hexanes/EtOAc).

4,6-Di-O-acetyl-2,3-dideoxy-3-diphenylphosphoryl-D-arabino-hexo-

pyranose (26): From 6 (19.5 mg, 0.047 mmol) in THF/H₂O contain-

ing Ph₃P·HBr (6.5 mg, 0.019 mmol) following the general pro-

cedure by heating at reflux for 13 h. Chromatotron chromatog-

raphy of the reaction residue (hexanes/EtOAc, 2:8) gave 26 (12 mg,

0.028 mmol, 59%, anomeric mixture, α/β, 10:1 in CDCl₃; 7:3 in

CD₃OD) as a crystalline solid: m.p. 212–213.8 °C (n-hexane/

CHCl₃); [α]_D= +27.2 (c = 0.614, CHCl₃). ¹H NMR (500 MHz,

CD₃OD): δ (major isomer) = 1.12 (s, 3 H), 1.60 (dddd, ³J_P,H= 5.7,

4,6-Di-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-D-ribo-hexopyr-

3

anose (24): From 1,5-anhydro-4,6-di-O-benzyl-2,3-dideoxy-3-di-

phenylphosphoryl-d-ribo-hex-1-enitol (3;^[17]25 mg, 0.049 mmol) in

THF/H₂O containing Ph₃P·HBr (2 mg, 5.8ϫ 10^–3mmol) following

the general procedure by heating at reflux for 1.5 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 4:6) gave

24 (23 mg, 0.044 mmol, 90%, anomeric mixture, α/β, 4.5:1) as a

J = 13.7, 3.6, 1.5 Hz, 1 H), 1.91 (dddd, J_P,H= 7.0, J = 13.7, 13.6,

2

3.1 Hz, 1 H), 1.99 (s, 3 H), 3.55 (dddd, J_P,H= 1.8, J = 13.6, 11.0,

3.6 Hz, 1 H), 3.93 (dd, J = 12.1, 2.9 Hz, 1 H), 4.05 (dd, J = 12.1,

4.7 Hz, 1 H), 4.18 (ddd, J = 9.9, 4.7, 2.9 Hz, 1 H), 5.22 (dd, J =

3.1, 1.5 Hz, 1 H), 5.36 (ddd, ³J_P,H= 8.1, J = 11.0, 9.8 Hz, 1 H), 7.53

(m, 6 H), 7.81 (m, 2 H), 7.93 (m, 2 H) ppm. ¹³C NMR (125.7 MHz,

crystalline solid: m.p. 151.7–152.7 °C (n-hexane/EtOAc); [α]_D

–141.4 (c = 0.07, CHCl₃). H NMR (500 MHz, CDCl₃): δ (major observed) = 19.8 (CH₃), 20.7 (CH₃), 30.8 (d, J_P,C= 3.2 Hz, CH₂),

=

CD₃OD): δ (major isomer; note: one of the ipso carbons is not

1

2

5042

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

1

2

34.6 (d, J_P,C= 73.1 Hz, CH), 64.2 (CH₂), 66.9 (d, J_P,C= 6.4 Hz,

3215, 1732 cm^–1. MS (EI, 70 eV): m/z (%) = 433 (2) [M + H]⁺,

415 (21), 202 (100), 201 (54). HRMS (EI, 70 eV): m/z calcd. for

C₂₂H₂₆O₇P [M + H]⁺433.1416; found 433.1409. C₂₂H₂₅O₇P

(432.41): calcd. C 61.11, H 5.83; found C 61.34, H 5.91.

3

CH), 69.4 (d, J_P,C= 9.5 Hz, CH), 90.7 (d, J_P,C= 12.7 Hz, CH),

129.9 (d, J_P,C= 12.7 Hz, 2ϫ CH), 130.1 (d, J_P,C= 12.7 Hz, 2ϫ

CH), 131.7 (d, J_P,C= 8.5 Hz, 2ϫ CH), 132.0 (d, J_P,C= 9.5 Hz,

3

2

4

2ϫ CH), 133.1 (d, J_P,C= 3.2 Hz, CH), 133.3 (d, J_P,C= 2.1 Hz,

6-O-Benzyl-2,3-dideoxy-3-diphenylphosphoryl-4-O-(2,3,4,6-tetra-O-

benzyl-β-D-galactopyranosyl)-D-ribo-hexopyranose (29): From 12α

CH), 133.7 (d, J_P,C= 98.5 Hz, C), 170.8 (C), 172.5 (C) ppm. ³¹P

1

NMR (161.9 MHz, CD₃OD): δ = 32.6 (s, 1 P), 31.8 (s, 1 P) ppm.

(240 mg, 0.254 mmol) in THF/H₂O containing Ph₃P·HBr (30 mg,

0.087 mmol) following the general procedure by heating at reflux

for 6 h. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 6:4) gave starting material 12α (34 mg,

0.036 mmol, 14%) and compound 29 (186 mg, 0.194 mmol, 76%,

isomeric mixture, α/β, 25:1): crystalline solid; m.p. 173.3–174.1 °C

(n-hexane/EtOAc); [α]_D= +71.5 (c = 0.17, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ (major isomer) = 1.23 (d, J = 6.3 Hz, 1 H),

IR (CHCl ): ν = 3330, 1741 cm^–1. MS (ESI⁺): m/z (%) = 455 (100)

˜

3

[M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₂H₂₅NaO₇P [M +

Na]⁺455.1236; found 455.1234. C₂₂H₂₅O₇P (432.41): calcd. C

61.11, H 5.83; found C 60.87, H 5.86.

4,6-Di-O-benzyl-2,3-dideoxy-3-diphenylphosphoryl-D-xylo-hexopyr-

anose (27): From 9 (75.4 mg, 0.148 mmol) in THF/H₂O containing

Ph₃P·HBr (8.1 mg, 0.024 mmol) following the general procedure by

heating at reflux for 3.75 h. Chromatotron chromatography of the

reaction residue (hexanes/EtOAc, 6:4) gave starting material 9

(5.3 mg, 0.01 mmol, 7%) and 27 (72 mg, 0.136 mmol, 92%, anom-

eric mixture, α/β, 17:1) as a colorless amorphous solid: [α]_D= –38.3

3

2

1.86 (dd, J_P,H= 10.3, J = 15.0 Hz, 1 H), 2.24 (dddd, J_P,H= 32.6,

J = 14.9, 7.5, 4.3 Hz, 1 H), 2.63 (dd, J = 8.8, 8.8 Hz, 1 H), 3.18

3

(dd, J = 9.8, 2.8 Hz, 1 H), 3.26 (ddd, J_P,H= 6.2, J = 6.2, 6.2 Hz,

1 H), 3.35 (dd, J = 6.5, 6.5 Hz, 1 H), 3.46 (d, J = 10.7 Hz, 1 H),

3.66 (d, J = 10.1 Hz, 1 H), 3.67–3.69 (m, 1 H), 3.78 (dd, J = 8.2,

8.2 Hz, 1 H), 3.82 (d, J = 2.5 Hz, 1 H), 4.03 (s, 2 H), 4.23 (d, J =

1

(c = 0.12, CHCl₃). H NMR (500 MHz, CDCl₃): δ (major isomer)

3

= 1.78 (dddd, J_P,H= 11.2, J = 14.4, 0.6, 0.0 Hz, 1 H), 2.59 (dddd,

3

³J_P,H= 32.2, J = 14.8, 7.9, 4.4 Hz, 1 H), 2.80 (dddd, J_P,H= 9.5, J

2

7.9 Hz, 1 H), 4.30 (d, J = 12.0 Hz, 1 H), 4.36 (ddd, J_P,H= 27.4, J

= 10.2, 6.3 Hz, 1 H), 4.46 (d, J = 12.0 Hz, 1 H), 4.52 (d, J =

10.1 Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1

H), 4.60 (d, J = 12.0 Hz, 1 H), 4.66 (d, J = 12.0 Hz, 1 H), 4.70 (d,

J = 12.0 Hz, 1 H), 4.93 (d, J = 10.4 Hz, 1 H), 5.10 (d, J = 3.8 Hz,

1 H), 7.05–7.44 (m, 31 H), 7.73 (m, 2 H), 7.84 (m, 2 H) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ (major isomer) = 31.4 (CH₂), 37.6

= 8.5, 1.0, 1.0 Hz, 1 H), 3.55 (dd, J = 9.3, 5.5 Hz, 1 H), 3.58–3.61

(m, 2 H), 4.32 (d, J = 12.3 Hz, 1 H), 4.35 (d, J = 12.0 Hz, 1 H),

4.46 (d, J = 12.6 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.50 (dd, J

= 8.7, 5.8 Hz, 1 H), 5.19 (d, J = 4.1 Hz, 1 H), 7.11 (m, 4 H), 7.28

(m, 6 H), 7.41 (m, 2 H), 7.49 (m, 2 H), 7.58 (m, 4 H), 7.69 (m, 2

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ (major isomer) = 25.8

1

2

1

(d, J_P,C= 68.9 Hz, CH), 68.3 (CH), 68.6 (CH₂), 68.7 (CH₂), 73.0

(d, J_P,C= 2.1 Hz, CH₂), 35.5 (d, J_P,C= 63.6 Hz, CH), 66.9 (CH),

2

(CH₂), 73.1 (CH), 73.3 (CH₂), 73.4 (CH₂), 73.7 (d, J_P,C= 5.3 Hz,

68.7 (CH₂), 69.6 (d, J_P,C= 5.3 Hz, CH), 72.6 (CH₂), 72.8 (CH₂),

CH), 74.7 (CH), 74.9 (CH₂), 75.3 (CH₂), 78.7 (CH), 81.7 (CH),

89.9 (CH), 104.0 (CH), 127.3–128.8 (Ar, complex), 130.5–133.2 (Ar,

complex), 138.0 (C), 138.2 (C), 138.6 (C), 138.7 (C), 139.0 (C) ppm.

89.7 (CH), 127.2 (2ϫ CH), 127.3 (CH), 128.0 (CH), 128.13 (2ϫ

CH), 128.15 (2ϫ CH), 128.5 (2ϫ CH), 129.01 (d, ³J_P,C= 11.7 Hz,

2ϫ CH), 129.03 (d, ¹J_P,C= 99.6 Hz, C), 129.04 (d, ³J_P,C= 11.7 Hz,

³¹P NMR (161.9 MHz, CDCl ): δ = 37.9 (s, 1 P) ppm. IR (film): ν

1

2

˜

3

2ϫ CH), 130.0 (d, J_P,C= 99.6 Hz, C), 130.8 (d, J_P,C= 8.5 Hz,

= 3226, 1099 cm^–1. MS (EI, 70 eV): m/z (%) = 961 (Ͻ 1) [M +

2ϫ CH), 131.0 (d, ²J_P,C= 8.5 Hz, 2ϫ CH), 132.3 (d, ⁴J_P,C= 2.1 Hz,

H]⁺, 421 (2), 91 (100). HRMS (EI, 70 eV): m/z calcd. for

4

CH), 132.4 (d, J_P,C= 2.1 Hz, CH), 138.0 (C), 138.3 (C) ppm. ³¹P

C

₅₉H₆₂O₁₀P [M + H]⁺961.4081; found 961.4055. C₅₉H₆₁O₁₀

P

NMR (161.9 MHz, CDCl ): δ = 35.9 (s, 1 P) ppm. IR (film): ν =

˜

3

3225 cm^–1. MS (EI, 70 eV): m/z (%) = 528 (Ͻ 1) [M]⁺, 311 (25),

(961.10): calcd. C 73.73, H 6.40; found C 73.79, H 6.34.

6-O-Benzyl-2,3-dideoxy-3-diphenylphosphoryl-4-O-(2,3,4,6-tetra-O-

-galactopyranosyl)- -arabino-hexopyranose (30): From

287 (25), 202 (81), 91 (100). HRMS (EI, 70 eV): m/z calcd. for

C₃₂H₃₃O₅P [M]⁺528.2066; found 528.2079. C₃₂H₃₃O₅P (528.58): benzyl-β-

D

calcd. C 72.71, H 6.29; found C 72.86, H 6.32.

12β (63 mg, 0.067 mmol) in THF/H₂O containing Ph₃P·HBr

(3.8 mg, 0.011 mmol) following the general procedure by heating

at reflux for 1.5 h. Chromatotron chromatography of the reaction

residue (hexanes/EtOAc, 6:4) gave starting material 12β (3.1 mg,

0.003 mmol, 5%) and compound 30 (47.6 mg, 0.049 mmol, 74%,

isomeric mixture, α/β, 1:1): crystalline solid; m.p. 153.2–154.2 °C

(n-hexane/EtOAc); [α]_D= +28.3 (c = 0.23, CHCl₃). ¹H NMR

(500 MHz, CDCl₃) and ¹³C NMR (125.7 MHz, CDCl₃) exhibit

complex resonance patterns. ³¹P NMR (161.9 MHz, CDCl₃): δ =

4,6-Di-O-acetyl-2,3-dideoxy-3-diphenylphosphoryl-D-xylo-hexopyr-

anose (28): From 10 (45.1 mg, 0.109 mmol) in THF/H₂O contain-

ing Ph₃P·HBr (16.3 mg, 0.05 mmol) following the general pro-

cedure by heating at reflux for 7.5 h. Chromatotron chromatog-

raphy of the reaction residue (hexanes/EtOAc, 4:6) gave starting

material 10 (8.2 mg, 0.02 mmol, 18%) and 28 (34.6 mg, 0.08 mmol,

73%, anomeric mixture, α/β, 25:1) as an oil: [α]_D= –19.2 (c = 0.36,

CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ (major isomer) = 1.86

31.0 (s, 1 P), 35.4 (s, 1 P) ppm. IR (CHCl ): ν = 3297, 1097 cm^–1.

˜

3

(ddddd, J_P,H= 10.7, J = 15.0, 0.8, 0.8, 0.8 Hz, 1 H), 1.91 (s, 3 H),

MS (ESI⁺): m/z (%) = 983 (100) [M + Na]⁺. HRMS (ESI⁺): m/z

calcd. for C₅₉H₆₁NaO₁₀P [M + Na]⁺983.3900; found 983.3900.

C₅₉H₆₁O₁₀P (961.10): calcd. C 73.73, H 6.40; found C 75.72, H

6.29.

3

2.11 (s, 3 H), 2.44 (dddd, J_P,H= 31.5, J = 15.0, 8.0, 4.4 Hz, 1 H),

2

3.07 (dddd, J_P,H= 11.1, J = 8.3, 1.5, 1.2 Hz, 1 H), 4.03 (dd, J =

11.3, 6.8 Hz, 1 H), 4.08 (dd, J = 11.3, 6.2 Hz, 1 H), 4.50 (ddd, J =

3

6.4, 6.4, 1.1 Hz, 1 H), 4.76 (br. d, J_P,H= 6.4 Hz, 1 H), 5.23 (dd, J

General Procedure for the β-Fragmentation Reaction: A 0.04 m solu-

tion of the alcohol (1 equiv.) in anhydrous CH₂Cl₂(25 mL) con-

taining PhI(OAc)₂(1.1–1.5 equiv.) and I₂(0.6–1.5 equiv.) under ni-

trogen was stirred for the temperature and time specified in each

case. The reaction mixture was then poured into 10 % aqueous

Na₂S₂O₃, extracted with CH₂Cl₂, dried with Na₂SO₄, and concen-

trated. The residue was purified by Chromatotron chromatography

(hexanes/EtOAc).

= 11.7, 4.0 Hz, 1 H), 7.56 (m, 6 H), 7.83 (m, 2 H), 8.02 (m, 2 H),

8.20 (d, J = 11.9 Hz, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

2

(major isomer) = 20.5 (CH₃), 20.9 (CH₃), 25.1 (d, J_P,C= 2.1 Hz,

1

CH₂), 35.4 (d, J_P,C= 63.6 Hz, CH), 62.9 (CH₂), 65.1 (CH), 65.9

2

1

(d, J_P,C= 6.4 Hz, CH), 89.6 (CH), 127.9 (d, J_P,C= 100.6 Hz, C),

3

129.0 (d, J_P,C= 12.7 Hz, 2ϫ CH), 129.1 (d, J_P,C= 11.7 Hz, 2ϫ

CH), 129.9 (d, J_P,C= 100.6 Hz, C), 130.8 (d, J_P,C= 9.5 Hz, 2ϫ

CH), 131.4 (d, J_P,C= 9.5 Hz, 2ϫ CH), 132.5 (d, J_P,C= 3.2 Hz,

1

2

4

CH), 132.8 (d, J_P,C= 2.1 Hz, CH), 170.4 (C), 170.7 (C) ppm. ³¹P 3,5-Di-O-benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-

4

NMR (161.9 MHz, CDCl ): δ = 35.8 (s, 1 P) ppm. IR (film): ν = iodo- -ribitol (31): From 24 (20.2 mg, 0.038 mmol) in CH₂Cl₂

D

˜

3

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5043

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

3

(1 mL) containing PhI(OAc)₂(13.6 mg, 0.042 mmol) and I₂

(10.7 mg, 0.042 mmol) following the general procedure by stirring

at room temperature for 2.5 h. Chromatotron chromatography of

the reaction residue (hexanes/EtOAc, 6:4) gave 31 (19.7 mg,

0.03 mmol, 79%) as an oil: [α]_D= +12.5 (c = 0.24, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 3.21 (dddd, J_P,H= 10.0, J = 9.1,

1.6, 1.6 Hz, 1 H), 3.40 (ddd, J_P,H= 13.1, J = 10.9, 2.5 Hz, 1 H),

3.58 (dd, J = 11.0, 4.1 Hz, 1 H), 3.66 (ddd, J_P,H= 5.7, J = 10.9,

⁴J_P,H= 0.9, J = 8.8, 4.4, 2.5 Hz, 1 H), 5.53 (ddd, J_P,H= 14.2, J =

8.8, 1.9 Hz, 1 H), 7.52 (m, 6 H), 7.82 (m, 4 H), 8.11 (br. s) ppm.

¹³C NMR (125.7 MHz, CDCl₃): δ = –0.7 (CH₂), 20.48 (CH₃), 20.54

1

(CH₃), 43.9 (d, J_P,C= 59.3 Hz, CH), 61.6 (CH₂), 70.0 (CH), 70.6

2

3

(d, J_P,C= 2.1 Hz, CH), 128.8 (d, J_P,C= 11.7 Hz, 2ϫ CH), 128.9

2

3

2

(d, J_P,C= 11.7 Hz, 2ϫ CH), 131.1 (d, J_P,C= 8.5 Hz, 4ϫ CH),

3

1

131.2 (d, J_P,C= 99.6 Hz, C), 131.3 (d, J_P,C= 98.6 Hz, C), 132.3

3

4

(d, ⁴J_P,C= 3.2 Hz, CH), 132.4 (d, J_P,C= 2.1 Hz, CH), 160.0 (CH),

9.0 Hz, 1 H), 3.76 (dd, J = 11.0, 2.5 Hz, 1 H), 4.31 (d, J = 12.0 Hz,

169.9 (C), 170.3 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 29.6

3

1 H), 4.35 (ddd, J_P,H= 14.7, J = 8.6, 1.6 Hz, 1 H), 4.39 (d, J =

(s, 1 P) ppm. IR (CHCl ): ν = 2993, 1736, 1231, 1167 cm^–1. MS

˜

3

10.7 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.92 (d, J = 10.7 Hz, 1

H), 5.38 (ddd, J = 8.8, 3.2, 3.2 Hz, 1 H), 7.12 (m, 2 H), 7.26 (m, 8

(ESI⁺): m/z (%) = 581 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd.

for C₂₂H₂₄INaO₇P [M + Na]⁺581.0202; found 581.0207.

H), 7.51 (m, 6 H), 7.86 (m, 4 H), 8.13 (s, 1 H) ppm. ¹³C NMR C₂₂H₂₄IO₇P (558.31): calcd. C 47.33, H 4.33; found C 46.97, H

(125.7 MHz, CDCl₃): δ = –5.8 (CH₂), 42.9 (d, ¹J_P,C= 62.5 Hz, CH), 4.65.

67.9 (CH₂), 73.0 (2 ϫ CH₂), 73.3 (d, J_P,C= 7.3 Hz, CH), 73.4

(CH), 127.4 (2ϫ CH), 127.6 (CH), 127.7 (CH), 128.1 (2ϫ CH),

2

3,5-Di-O-benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-

iodo-D-xylitol (34): From 27 (14.2 mg, 0.027 mmol) in CH₂Cl₂

3

128.2 (2ϫ CH), 128.3 (2ϫ CH), 128.9 (d, J_P,C= 11.7 Hz, 2ϫ

(0.7 mL) containing PhI(OAc)₂(9.5 mg, 0.03 mmol) and I₂(4.1 mg,

0.016 mmol) following the general procedure by stirring at reflux

temperature for 2 h. Chromatotron chromatography of the reaction

residue (hexanes/EtOAc, 6:4) gave 34 (13.5 mg, 0.021 mmol, 78%)

as a colorless oil: [α]_D= –11.9 (c = 0.18, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 3.11 (m, 2 H), 3.37 (m, 1 H), 3.70 (dd, J

= 10.9, 4.6 Hz, 1 H), 3.78 (dd, J = 10.9, 3.9 Hz, 1 H), 4.41 (m, 1

H), 4.45 (d, J = 11.7 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 4.62 (d,

J = 11.4 Hz, 1 H), 4.65 (d, J = 11.7 Hz, 1 H), 5.68 (ddd, J = 6.6,

4.4, 4.4 Hz, 1 H), 6.93 (m, 2 H), 7.20 (m, 3 H), 7.35 (m, 9 H), 7.47

(m, 2 H), 7.55 (m, 2 H), 7.66 (m, 2 H), 8.10 (s, 1 H) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = 1.4 (CH₂), 43.7 (d, ¹J_P,C= 62.9 Hz,

3

2

CH), 129.0 (d, J_P,C= 11.7 Hz, 2ϫ CH), 131.0 (d, J_P,C= 8.5 Hz,

2

2ϫ CH), 131.1 (d, J_P,C= 9.5 Hz, 2ϫ CH), 131.3 (C), 131.7 (C),

4

132.1 (d, J_P,C= 3.2 Hz, CH), 132.2 (d, J_P,C= 2.1 Hz, CH), 137.6

(C), 137.7 (C), 160.2 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ

= 34.2 (s, 1 P) ppm. IR (CHCl ): ν = 1729 cm^–1. MS (EI, 70 eV):

˜

3

m/z (%) = 655 (Ͻ 1) [M + H]⁺, 329 (51), 202 (64), 91 (100). HRMS

(EI, 70 eV): m/z calcd. for C₃₂H₃₃IO₅P [M + H]⁺655.1110; found

655.1120. C₃₂H₃₂IO₅P (654.48): calcd. C 58.73, H 4.93; found C

58.79, H 5.12.

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-

iodo-D-ribitol (32): From 25 (44.8 mg, 0.104 mmol) in CH₂Cl₂

2

(2.6 mL) containing PhI(OAc)₂(36.7 mg, 0.114 mmol) and I₂

(29 mg, 0.114 mmol) following the general procedure by stirring at

room temperature for 4.5 h under irradiation with a 80 W tungsten-

filament lamp. Chromatotron chromatography of the reaction resi-

due (hexanes/EtOAc, 1:1) gave 32 (49.4 mg, 0.088 mmol, 85%) as

CH), 68.7 (CH₂), 73.5 (CH₂), 74.9 (CH), 75.5 (CH₂), 79.3 (d, J_P,C

= 3.5 Hz, CH), 127.5 (CH), 127.87 (CH), 127.91 (2ϫ CH), 128.1

3

(2ϫ CH), 128.2 (2ϫ CH), 128.3 (d, J_P,C= 11.3 Hz, 2ϫ CH),

128.4 (2ϫ CH), 128.7 (d, ³J_P,C= 12.0 Hz, 2ϫ CH), 130.80 (d, ²J_P,C

1

4

= 9.2 Hz, 2ϫ CH), 130.84 (d, J_P,C= 96.8 Hz, C), 131.86 (d, J_P,C

an oil: [α]_D= +2.4 (c = 0.17, CHCl₃). ¹H NMR (500 MHz, CDCl₃): = 7.8 Hz, CH), 131.88 (d, J_P,C= 7.8 Hz, CH), 132.1 (d, J_P,C

=

4

2

1

δ = 1.93 (s, 3 H), 1.94 (s, 3 H), 3.15 (dd, J_P,H= 9.8, J = 9.8 Hz, 1

9.2 Hz, 2ϫ CH), 132.5 (d, J_P,C= 98.9 Hz, C), 137.4 (C), 137.5

H), 3.40 (ddd, ³J_P,H= 11.9, J = 11.9, 2.4 Hz, 1 H), 3.54 (ddd, J_P,H(C), 160.8 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 31.5 (s,

3

= 5.0, J = 11.3, 9.2 Hz, 1 H), 4.08 (dd, J = 12.6, 4.4 Hz, 1 H), 4.37

(dd, J = 12.6, 2.5 Hz, 1 H), 5.63 (ddd, J = 7.8, 4.7, 2.8 Hz, 1 H),

1 P) ppm. IR (film): ν = 1724 cm^–1. MS (EI, 70 eV): m/z (%) = 655

˜

(Ͻ 1) [M + H]⁺, 202 (60), 91 (100). HRMS (EI, 70 eV): m/z calcd.

3

5.70 (ddd, J_P,H= 14.0, J = 8.4, 1.6 Hz, 1 H), 7.50–7.60 (m, 6 H),

for C₃₂H₃₃IO₅P [M + H]⁺655.1110; found 655.1110. C₃₂H₃₂IO₅P

7.55 (m, 6 H), 7.80 (m, 2 H), 7.86 (m, 2 H), 8.12 (s, 1 H) ppm. ¹³C (654.48): calcd. C 58.73, H 4.93; found C 58.74, H 4.95.

NMR (125.7 MHz, CDCl₃): δ = –6.6 (CH₂), 20.5 (CH₃), 20.6

(CH₃), 42.4 (d, J_P,C= 60.4 Hz, CH), 61.1 (CH₂), 67.4 (CH), 70.2

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-

iodo-D-xylitol (35): From 28 (90 mg, 0.208 mmol) in CH₂Cl₂

1

2

3

(d, J_P,C= 7.4 Hz, CH), 128.9 (d, J_P,C= 11.7 Hz, 2ϫ CH), 129.1

(5.2 mL) containing PhI(OAc)₂(74 mg, 0.23 mmol) and I₂(58 mg,

0.23 mmol) following the general procedure by stirring at reflux

temperature for 2.2 h. Chromatotron chromatography of the reac-

tion residue (hexanes/EtOAc, 1:1) gave 35 (93.2 mg, 0.167 mmol,

80%) and 43 (12.1 mg, 0.028 mmol, 13%). Compound 35: colorless

3

2

(d, J_P,C= 11.7 Hz, 2ϫ CH), 130.8 (d, J_P,C= 8.5 Hz, 2ϫ CH),

130.9 (d, ¹J_P,C= 97.5 Hz, 2ϫ C), 131.0 (d, ²J_P,C= 8.5 Hz, 2ϫ CH),

4

132.2 (d, J_P,C= 2.1 Hz, CH), 132.5 (d, J_P,C= 2.1 Hz, CH), 159.4

(CH), 168.9 (C), 170.4 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ

= 33.0 (s, 1 P) ppm. IR (film): ν = 1731 cm^–1. MS (EI, 70 eV): m/z

˜

1

oil; [α]_D= –39.0 (c = 0.25, CHCl₃). H NMR (500 MHz, CDCl₃):

(%) = 559 (1) [M + H]⁺, 431 (27), 201 (100). HRMS (EI, 70 eV):

m/z calcd. for C₂₂H₂₅IO₇P [M + H]⁺559.0383; found 559.0383.

C₂₂H₂₄IO₇P (558.31): calcd. C 47.33, H 4.33; found C 47.45, H

4.31.

3

δ = 1.75 (s, 3 H), 2.06 (s, 3 H), 3.23 (ddd, J_P,H= 4.1, J = 10.1,

2

10.1 Hz, 1 H), 3.30 (dddd, J_P,H= 13.1, J = 9.8, 2.7, 2.7 Hz, 1 H),

3

3.42 (ddd, J_P,H= 12.6, J = 10.4, 2.4 Hz, 1 H), 4.34 (dd, J = 12.5,

3

4.3 Hz, 1 H), 4.37 (dd, J = 12.5, 4.6 Hz, 1 H), 5.67 (ddd, J_P,H

=

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-

15.1, J = 6.5, 3.0 Hz, 1 H), 5.77 (ddd, J = 6.6, 4.4, 4.4 Hz, 1 H),

iodo-

D

-arabinitol (33): From 26 (1.53 g, 3.54 mmol) in CH₂Cl₂

7.53 (m, 4 H), 7.59 (m, 2 H), 7.82 (m, 4 H), 8.03 (s, 1 H) ppm. ¹³C

(88 mL) containing PhI(OAc)₂(1.254 g, 3.9 mmol) and I₂(989 mg, NMR (100.6 MHz, CDCl₃): δ = –1.6 (CH₂), 20.2 (CH₃), 20.8

1

2

3.9 mmol) following the general procedure by stirring at room tem-

perature for 4 h. Column chromatography of the reaction residue

(CH₃), 43.8 (d, J_P,C= 60.8 Hz, CH), 62.0 (CH₂), 71.3 (d, J_P,C=

3

2.1 Hz, CH), 71.7 (CH), 128.7 (d, J_P,C= 12.0 Hz, 2ϫ CH), 129.1

3

1

(hexanes/EtOAc, 4:6) gave 33 (1.486 g, 2.66 mmol, 75%) as a color- (d, J_P,C= 12.0 Hz, 2ϫ CH), 130.5 (d, J_P,C= 98.9 Hz, C), 130.8

less oil: [α]_D= +63.6 (c = 1.07, CHCl₃). ¹H NMR (500 MHz,

(d, ²J_P,C= 9.2 Hz, 2ϫ CH), 131.5 (d, ¹J_P,C= 98.9 Hz, C), 131.6 (d,

2

4

CDCl₃): δ = 1.94 (s, 3 H), 1.97 (s, 3 H), 3.27 (dddd, J_P,H= 10.7,

²J_P,C= 9.2 Hz, 2ϫ CH), 132.3 (d, J_P,C= 2.8 Hz, CH), 132.5 (d,

J = 10.7, 2.2, 2.2 Hz, 1 H), 3.34 (ddd, ³J_P,H= 3.5, J = 10.7, 10.7 Hz, ⁴J_P,C= 2.1 Hz, CH), 159.7 (CH), 169.9 (C), 170.4 (C) ppm. ³¹P

3

1 H), 3.42 (ddd, J_P,H= 10.7, J = 10.7, 2.5 Hz, 1 H), 4.08 (dd, J =

12.3, 4.1 Hz, 1 H), 4.16 (dd, J = 12.3, 2.5 Hz, 1 H), 5.31 (dddd,

NMR (161.9 MHz, CDCl ): δ = 30.3 (s, 1 P) ppm. IR (CHCl ): ν

˜

3 3

= 1742, 1217 cm^–1. MS (ESI⁺): m/z (%) = 581 (100) [M + Na]⁺.

5044

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

HRMS (ESI⁺): m/z calcd. for C₂₂H₂₄INaO₇P [M + Na]⁺581.0202;

found 581.0214. C₂₂H₂₄IO₇P (558.31): calcd. C 47.33, H 4.33;

found C 47.19, H 4.32.

5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-iodo-3-

O-(2,3,4,6-tetra-O-benzyl-β- -galactopyranosyl)- -arabinitol (38):

D

From 30 (47 mg, 0.049 mmol) in CH₂Cl₂(1.2 mL) containing

PhI(OAc)₂(23.6 mg, 0.073 mmol) and I₂(18.6 mg, 0.073 mmol)

following the general procedure by stirring at reflux temperature

for 40 min. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 6:4Ǟ1:1) gave 38 (36.9 mg, 0.034 mmol, 70%) as

a yellowish oil: [α]_D= +31.4 (c = 0.35, CHCl₃). ¹H NMR

(500 MHz, CDCl₃): δ = 3.16 (br. dd, J = 19.6, 10.7 Hz, 1 H), 3.23

(dd, J = 9.8, 7.6 Hz, 1 H), 3.28 (dd, J = 9.6, 2.7 Hz, 1 H), 3.36–

3.40 (m, 2 H), 3.61–3.67 (m, 3 H), 3.73 (dd, J = 11.2, 3.9 Hz, 1 H),

3.81 (ddd, J = 12.1, 9.7, 2.8 Hz, 1 H), 3.87 (d, J = 2.5 Hz, 1 H),

4.20 (d, J = 7.6 Hz, 1 H), 4.23 (d, J = 12.0 Hz, 1 H), 4.36 (d, J =

12.0 Hz, 1 H), 4.45 (d, J = 11.7 Hz, 1 H), 4.49 (d, J = 11.0 Hz, 1

5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-iodo-3-

O-(2,3,4,6-tetra-O-benzyl-β-

6-O-Benzyl-2,3-dideoxy-3-diphenylphosphoryl-4-O-(2,3,4,6-tetra-O-

benzyl-β- -galactopyranosyl)- -ribo-hexono-1,5-lactone (37): From

D-galactopyranosyl)-D-ribitol (36) and

D

29 (343.3 mg, 0.357 mmol) in CH₂Cl₂(9.0 mL) containing

PhI(OAc)₂(172.6 mg, 0.536 mmol) and I₂(136.0 mg, 0.536 mmol)

following the general procedure by stirring at reflux temperature

for 30 min. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 6:4Ǟ1:1) gave 36 (261.5 mg, 0.241 mmol, 67%)

and 37 (51.3 mg, 0.053 mmol, 15%).

3

Compound 36: Yellowish oil; [α]_D= –5.9 (c = 0.27, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 3.29 (dd, J = 9.8, 7.6 Hz, 1 H), 3.36

(dd, J = 10.1, 2.8 Hz, 1 H), 3.38 (m, 1 H), 3.42 (dd, J = 10.9,

4.3 Hz, 1 H), 3.53 (dd, J = 8.7, 4.9 Hz, 1 H), 3.56 (d, J = 2.2 Hz,

H), 4.50 (d, J = 12.0 Hz, 1 H), 4.55 (ddd, J_P,H= 22.4, J = 9.8,

1.6 Hz, 1 H), 4.70 (s, 2 H), 4.90 (d, J = 10.7 Hz, 1 H), 5.64 (ddd,

J = 9.5, 2.8, 2.8 Hz, 1 H), 7.14–7.41 (m, 30 H), 7.45–7.48 (m, 1 H),

7.65–7.69 (m, 2 H), 7.73–7.77 (m, 2 H), 8.17 (s, 1 H) ppm. ¹³C

2

3

NMR (100.6 MHz, CDCl₃): δ = 3.7 (d, J_P,C= 2.8 Hz, CH₂), 45.9

1 H), 3.58 (ddd, J_P,H= 6.0, J = 6.0, 2.2 Hz, 1 H), 3.64 (ddd, J_P,H

= 11.0, J = 11.0, 2.8 Hz, 1 H), 3.79 (dd, J = 8.7, 4.9 Hz, 1 H), 3.84

(dd, J = 8.8, 8.8 Hz, 1 H), 3.87 (d, J = 11.7 Hz, 1 H), 3.98 (d, J =

2.5 Hz, 1 H), 4.18 (d, J = 12.0 Hz, 1 H), 4.27 (d, J = 11.4 Hz, 1

H), 4.28 (d, J = 12.0 Hz, 1 H), 4.30 (d, J = 7.6 Hz, 1 H), 4.54 (d,

J = 11.7 Hz, 1 H), 4.57 (d, J = 11.7 Hz, 1 H), 4.64 (d, J = 11.0 Hz,

(d, ¹J_P,C= 60.1 Hz, CH), 67.6 (CH₂), 67.9 (CH₂), 72.6 (CH₂), 72.79

(CH₂), 72.83 (CH), 73.56 (CH₂), 73.67 (CH), 74.1 (CH), 75.0

2

(CH₂), 75.3 (CH₂), 76.9 (d, J_P,C= 4.2 Hz, CH), 78.8 (CH), 82.2

(CH), 103.1 (CH), 127.5–128.8 (Ar, complex), 130.4–133.1 (Ar,

complex), 137.7 (C), 138.0 (C), 138.4 (C), 138.4 (C), 139.0 (C),

161.0 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 31.8 (s, 1

3

1 H), 4.67 (ddd, J_P,H= 24.3, J = 9.2, 2.2 Hz, 1 H), 4.69 (d, J =

P) ppm. IR (film): ν = 1728 cm^–1. MS (ESI⁺): m/z (%) = 1109 (100)

˜

12.0 Hz, 1 H), 4.72 (d, J = 12.0 Hz, 1 H), 5.02 (d, J = 11.0 Hz, 1

H), 5.28 (ddd, J = 9.1, 3.9, 1.9 Hz, 1 H), 7.08 (m, 2 H), 7.16–7.38

(m, 24 H), 7.47 (m, 5 H), 7.79 (m, 2 H), 7.87 (m, 2 H), 8.13 (s, 1

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 2.3 (CH₂), 46.2

(d, ¹J_P,C= 60.4 Hz, CH), 67.8 (CH₂), 68.1 (CH₂), 72.79 (2ϫ CH₂),

72.83 (CH), 73.60 (CH₂), 73.63 (CH), 74.4 (d, ³J_P,C= 4.2 Hz, CH),

[M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₅₉H₆₀INaO₁₀P [M +

Na]⁺1109.2867; found 1109.2867. C₅₉H₆₀IO₁₀P (1087.00): calcd. C

65.19, H 5.56; found C 65.06, H 5.52.

General Procedure for the Dehydroiodination Reaction: To a solu-

tion of β-iodo-phosphorus compound (1 equiv.) in anhydrous benz-

ene (25–35 mL) cooled to 9–10 °C, was added DBU (1.1–2.6 equiv.)

and the mixture was stirred at this temperature for the specified

time. The reaction mixture was then poured into a saturated aque-

ous solution of NaHSO₄and extracted with EtOAc. The combined

organic extracts were washed with brine, dried with Na₂SO₄, and

concentrated under reduced pressure. The residue was purified by

Chromatotron chromatography (hexanes/EtOAc).

2

74.8 (CH₂), 75.1 (CH₂), 77.5 (d, J_P,C= 3.5 Hz, CH), 79.1 (CH),

81.8 (CH), 105.2 (CH), 127.4–132.0 (Ar, complex), 137.7 (C), 138.0

(C), 138.3 (C), 138.4 (C), 139.1 (C), 160.8 (CH) ppm. ³¹P NMR

(161.9 MHz, CDCl ): δ = 28.7 (s, 1 P) ppm. IR (film): ν =

˜

3

1731 cm^–1. MS (ESI⁺): m/z (%) = 1109 (100) [M + Na]⁺. HRMS

(ESI⁺): m/z calcd. for C₅₉H₆₀INaO₁₀P [M + Na]⁺1109.2867; found

1109.2902. C₅₉H₆₀IO₁₀P (1087.00): calcd. C 65.19, H 5.56; found

C 65.22, H 5.57.

3,5-Di-O-benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-D-

Compound 37: Colorless oil; [α]_D= +49.6 (c = 0.23, CHCl₃). ¹H

erythro-pent-1-enitol (39): From 31 (18.1 mg, 0.028 mmol) in anhy-

drous benzene (0.9 mL) containing DBU (10.5 μL, 0.07 mmol) fol-

lowing the general procedure by stirring at 9–10 °C for 30 min.

Chromatotron chromatography of the reaction residue (hexanes/

3

NMR (500 MHz, CDCl₃): δ = 2.62 (ddd, J_P,H= 10.7, J = 17.8,

3

6.0 Hz, 1 H), 2.70 (ddd, J_P,H= 11.0, J = 17.8, 9.5 Hz, 1 H), 3.27

(dd, J = 9.8, 7.9 Hz, 1 H), 3.37 (dd, J = 9.9, 3.0 Hz, 1 H), 3.42 (dd,

J = 7.4, 5.8 Hz, 1 H), 3.49 (m, 1 H), 3.52 (dd, J = 9.1, 5.4 Hz, 1 EtOAc, 1:1) gave 39 (13.4 mg, 0.025 mmol, 89%) as a colorless oil:

1

H), 3.63 (dd, J = 10.7, 2.5 Hz, 1 H), 3.69 (m, 2 H), 3.90 (d, J =

2.8 Hz, 1 H), 4.23 (d, J = 11.0 Hz, 1 H), 4.26 (d, J = 10.7 Hz, 1

H), 4.33 (d, J = 7.6 Hz, 1 H), 4.39 (d, J = 11.4 Hz, 1 H), 4.48 (d,

[α]_D= +42.2 (c = 0.11, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

3.68 (dd, J = 11.0, 6.6 Hz, 1 H), 3.74 (dd, J = 11.0, 2.8 Hz, 1 H),

4.30 (d, J = 11.7 Hz, 1 H), 4.40 (d, J = 12.0 Hz, 1 H), 4.41 (d, J =

J = 11.7 Hz, 1 H), 4.49 (d, J = 11.4 Hz, 1 H), 4.51 (d, J = 11.7 Hz, 11.4 Hz, 1 H), 4.47 (d, J = 12.0 Hz, 1 H), 4.58 (dd, J_P,H= 8.7, J

3

1 H), 4.59 (d, J = 10.7 Hz, 1 H), 4.63 (ddd, J_P,H= 14.2, J = 4.1,

= 6.2 Hz, 1 H), 5.45 (ddd, J = 6.3, 6.3, 2.8 Hz, 1 H), 5.76 (d, J_P,H

= 19.6 Hz, 1 H), 6.37 (d, J_P,H= 41.3 Hz, 1 H), 7.09 (m, 2 H), 7.28

(m, 8 H), 7.46 (m, 4 H), 7.54 (m, 2 H), 7.69 (m, 2 H), 7.74 (m, 2

H), 7.84 (s, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 68.1

(CH₂), 72.0 (CH₂), 73.0 (CH₂), 74.3 (CH), 76.8 (d, ²J_P,C= 12.7 Hz,

CH), 127.56 (CH), 127.64 (2ϫ CH), 127.7 (CH), 127.8 (2ϫ CH),

3

4.1 Hz, 1 H), 4.69 (d, J = 12.0 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1

H), 4.93 (m, 1 H), 4.98 (d, J = 10.7 Hz, 1 H), 7.14–7.18 (m, 4 H),

7.22–7.42 (m, 27 H), 7.70 (m, 4 H) ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = 27.6 (CH₂), 35.1 (d, ¹J_P,C= 71.8 Hz, CH), 68.3 (CH₂),

2

69.1 (CH₂), 69.4 (d, J_P,C= 5.5 Hz, CH), 73.0 (CH₂), 73.2 (CH),

3

73.5 (CH₂), 73.8 (CH₂), 74.0 (CH), 75.2 (2ϫ CH₂), 78.4 (d, J_P,C

128.2 (2ϫ CH), 128.3 (2ϫ CH), 128.5 (d, J_P,C= 11.7 Hz, 2ϫ

= 7.3 Hz, CH), 78.5 (CH), 81.9 (CH), 101.3 (CH), 127.5–128.5 (Ar, CH), 128.6 (d, J_P,C= 11.7 Hz, 2ϫ CH), 130.7 (d, ¹J_P,C= 98.6 Hz,

3

2

complex), 131.57 (CH), 131.63 (CH), 137.4 (C), 137.9 (C), 138.2

2ϫ C), 131.9 (d, J_P,C= 6.4 Hz, 2ϫ CH), 132.0 (d, J_P,C= 6.4 Hz,

(C), 138.4 (C), 138.8 (C), 168.2 (d, J_P,C= 10.9 Hz, C) ppm. ³¹P 2ϫ CH), 132.07 (d, ⁴J_P,C= 3.2 Hz, CH), 132.11 (d, ⁴J_P,C= 3.2 Hz,

NMR (161.9 MHz, CDCl ): δ = 31.3 (s, 1 P) ppm. IR (film): ν =

CH), 133.2 (d, ²J_P,C= 8.5 Hz, CH₂), 137.3 (C), 137.9 (C), 142.1 (d,

3

˜

3

1736 cm^–1. MS (ESI⁺): m/z (%) = 981 (100) [M + Na]⁺. HRMS ¹J_P,C= 91.1 Hz, C), 160.6 (CH) ppm. ³¹P NMR (161.9 MHz,

(ESI⁺): m/z calcd. for C₅₉H₅₉NaO₁₀P [M + Na]⁺981.3744; found

981.3744. C₅₉H₅₉O₁₀P (959.09): calcd. C 73.89, H 6.20; found C

73.73, H 6.39.

CDCl ): δ = 33.0 (s, 1 P) ppm. IR (CHCl ): ν = 1725 cm^–1. MS

˜

3 3

(EI, 70 eV): m/z (%) = 527 (5) [M + H]⁺, 257 (82), 201 (52), 91

(100). HRMS (EI, 70 eV): m/z calcd. for C₃₂H₃₂O₅P [M + H]⁺

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5045

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

527.1987; found 527.1998. C₃₂H₃₁O₅P (526.57): calcd. C 72.99, H

5.93; found C 73.16, H 5.95.

3

3.0 Hz, 1 H), 5.70 (d, J_{P, H}= 19.9 Hz, 1 H), 6.37 (d, J_{P, H}=

41.6 Hz, 1 H), 7.02 (m, 2 H), 7.27 (m, 8 H), 7.46 (m, 2 H), 7.53

(m, 3 H), 7.61 (m, 1 H), 7.70 (m, 2 H), 7.76 (m, 2 H), 8.05 (s, 1

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 68.7 (CH₂), 71.5

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-

erythro-pent-1-enitol (40) and 3,5-Di-O-acetyl-1,2-dideoxy-2-di-

phenylphosphoryl- -erythro-pent-1-enitol (41): From 32 (37.5 mg,

D-

2

(CH₂), 72.9 (CH₂), 73.5 (CH), 75.4 (d, J_P,C= 14.8 Hz, CH), 127.6

D

(CH), 127.7 (2ϫ CH), 127.9 (CH), 128.1 (2ϫ CH), 128.3 (4ϫ CH),

0.067 mmol) in anhydrous benzene (2.3 mL) containing DBU

(11.1 μL, 0.074 mmol) following the general procedure by stirring

at 9–10 °C for 20 min. Chromatotron chromatography of the reac-

tion residue (hexanes/EtOAc, 45:55) gave 40 (21.6 mg, 0.05 mmol,

75%) and 41 (3.1 mg, 7.7ϫ 10^–3mmol, 12%).

3

128.6 (d, J_P,C= 12.7 Hz, 2ϫ CH), 128.7 (d, J_P,C= 11.7 Hz, 2ϫ

1

CH), 130.4 (d, ¹J_P,C= 101.7 Hz, C), 130.5 (d, J_P,C= 104.9 Hz, C),

2

132.0 (d, J_P,C= 10.6 Hz, 2ϫ CH), 132.1 (d, J_P,C= 10.6 Hz, 2ϫ

4

CH), 132.2 (CH₂), 132.3 (d, J_P,C= 3.2 Hz, 2ϫ CH), 137.0 (C),

137.8 (C), 141.0 (d, ¹J_P,C= 91.1 Hz, C), 160.7 (CH) ppm. ³¹P NMR

Compound 40: Colorless oil; [α]_D= +61.4 (c = 0.22, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 1.65 (s, 3 H), 2.03 (s, 3 H), 4.30 (dd,

J = 12.5, 6.2 Hz, 1 H), 4.37 (dd, J = 12.6, 2.5 Hz, 1 H), 5.61 (d,

³J_P,H= 19.2 Hz, 1 H), 5.75 (dd, ³J_P,H= 11.5, J = 6.8 Hz, 1 H), 5.87

(ddd, J = 6.5, 6.5, 2.5 Hz, 1 H), 6.22 (d, ³J_P,H= 39.4 Hz, 1 H), 7.52

(m, 6 H), 7.66 (m, 2 H), 7.75 (m, 2 H), 8.04 (s, 1 H) ppm. ¹³C NMR

(125.7 MHz, CDCl₃): δ = 20.1 (CH₃), 20.7 (CH₃), 61.6 (CH₂), 71.6

(161.9 MHz, CDCl ): δ = 29.7 (s, 1 P) ppm. IR (film): ν =

˜

3

1731 cm^–1. MS (EI, 70 eV): m/z (%) = 527 (Ͻ 1) [M + H]⁺, 257

(35), 201 (25), 91 (100). HRMS (EI, 70 eV): m/z calcd. for

C

₃₂H₃₂O₅P [M + H]⁺527.1987; found 527.1974. C₃₂H₃₁O₅P

(526.57): calcd. C 72.99, H 5.93; found C 73.03, H 5.93.

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-D-

2

3

threo-pent-1-enitol (43): From 35 (93.2 mg, 0.167 mmol) in an-

hydrous benzene (5.6 mL) containing DBU (27.5 μL, 0.184 mmol)

following the general procedure by stirring at 9–10 °C for 1 h. The

residue was purified by Chromatotron chromatography (hexanes/

EtOAc, 4:6) to give 43 (70 mg, 0.163 mmol, 97%): colorless oil;

(CH), 72.6 (d, J_P,C= 11.7 Hz, CH), 128.6 (d, J_P,C= 12.7 Hz, 2ϫ

CH), 128.7 (d, ³J_P,C= 12.7 Hz, 2ϫ CH), 130.7 (d, ¹J_P,C= 103.8 Hz,

1

2

C), 130.9 (d, J_P,C= 102.7 Hz, C), 131.7 (d, J_P,C= 9.5 Hz, 2ϫ

2

4

CH), 131.9 (d, J_P,C= 9.5 Hz, 2ϫ CH), 132.2 (d, J_P,C= 2.1 Hz,

CH), 132.3 (d, ⁴J_P,C= 3.2 Hz, CH), 134.0 (d, J_P,C= 8.5 Hz, CH₂),

2

1

139.4 (d, ¹J_P,C= 93.3 Hz, C), 159.8 (CH), 169.2 (C), 170.5 (C) ppm.

[α]_D= –42.0 (c = 0.32, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

³¹P NMR (161.9 MHz, CDCl ): δ = 29.2 (s, 1 P) ppm. IR (film): ν

1.69 (s, 3 H), 2.04 (s, 3 H), 4.21 (dd, J = 12.2, 5.8 Hz, 1 H), 4.39

˜

3

= 1731 cm^–1. MS (EI, 70 eV): m/z (%) = 431 (2) [M + H]⁺, 283

(dd, J = 12.2, 4.0 Hz, 1 H), 5.58 (d, J_P,H= 19.3 Hz, 1 H), 5.82

3

(dd, J_P,H= 11.4, J = 5.6 Hz, 1 H), 5.89 (ddd, J = 5.5, 5.5, 4.1 Hz,

(99), 257 (100), 201 (94). HRMS (EI, 70 eV): m/z calcd. for

3

C

₂₂H₂₄O₇P [M + H]⁺431.1260; found 431.1252. C₂₂H₂₃O₇P

1 H), 6.22 (dd, J_P,H= 39.3, J = 0.7 Hz, 1 H), 7.50 (m, 4 H), 7.58

(m, 2 H), 7.70 (m, 4 H), 8.07 (s, 1 H) ppm. ¹³C NMR (125.7 MHz,

(430.39): calcd. C 61.40, H 5.39; found C 61.34, H 5.57.

CDCl₃): δ = 20.1 (CH₃), 20.6 (CH₃), 62.3 (CH₂), 71.7 (CH), 73.3

(d, J_P,C= 11.7 Hz, CH), 128.62 (d, J_P,C= 11.7 Hz, 2 ϫ CH),

Compound 41: Colorless oil; [α]_D= +68.6 (c = 0.14, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 1.60 (s, 3 H), 2.07 (s, 3 H), 4.11 (dd,

2

3

1

128.64 (d, J_P,C= 12.7 Hz, 2ϫ CH), 130.78 (d, J_P,C= 104.9 Hz,

3

J = 13.0, 6.6 Hz, 1 H), 4.19 (m, 2 H), 5.53 (d, J_P,H= 19.6 Hz, 1

1

2

C), 130.83 (d, J_P,C= 104.9 Hz, C), 131.7 (d, J_P,C= 9.5 Hz, 2ϫ

H), 5.64 (dd, ³J_P,H= 13.8, J = 5.6 Hz, 1 H), 6.24 (d, ³J_P,H= 40.8 Hz,

1 H), 7.48–7.61 (m, 6 H), 7.66 (m, 2 H), 7.76 (m, 2 H) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = 20.3 (CH₃), 20.9 (CH₃), 65.1

2

4

CH), 131.9 (d, J_P,C= 9.5 Hz, 2ϫ CH), 132.2 (d, J_P,C= 2.1 Hz,

CH), 132.3 (d, ⁴J_P,C= 3.2 Hz, CH), 133.8 (d, J_P,C= 7.4 Hz, CH₂),

2

139.4 (d, ¹J_P,C= 93.3 Hz, C), 160.0 (CH), 169.4 (C), 170.2 (C) ppm.

³¹P NMR (161.9 MHz, CDCl₃): δ = 29.4 (s, 1 P) ppm. IR (CHCl₃):

2

3

(CH₂), 70.3 (CH), 76.1 (d, J_P,C= 10.0 Hz, CH), 128.7 (d, J_P,C

=

3

12.7 Hz, 2ϫ CH), 128.7 (d, J_P,C= 12.7 Hz, 2ϫ CH), 129.85 (d,

ν = 1744, 1227 cm^–1. MS (ESI⁺): m/z (%) = 453 (100), 425 (66) [M

˜

¹J_P,C= 106.2 Hz, C), 129.90 (d, ¹J_P,C= 106.2 Hz, C), 131.7 (d, ²J_P,C

+ Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₂H₂₃NaO₇P [M + Na]⁺

453.1079; found 453.1071. C₂₂H₂₃O₇P (430.39): calcd. C 61.40, H

5.39; found C 61.49, H 5.58.

2

= 10.0 Hz, 2ϫ CH), 132.1 (d, J_P,C= 10.0 Hz, 2ϫ CH), 132.4 (d,

⁴J_P,C= 2.7 Hz, CH), 132.6 (d, J_P,C= 2.7 Hz, CH), 135.0 (d, J_P,C

4

2

1

= 10.0 Hz, CH₂), 140.2 (d, J_P,C= 90.8 Hz, C), 169.5 (C), 170.9

(C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 33.3 (s, 1 P) ppm. IR

5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-3-O-

(film): ν = 3232, 1738 cm^–1. MS (EI, 70 eV): m/z (%) = 403 (14) [M

˜

(2,3,4,6-tetra-O-benzyl-β-

ol (44) and 5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-3-O-

(2,3,4,6-tetra-O-benzyl-β- -galactopyranosyl)- -erythro-pent-1-enit-

D-galactopyranosy)-D-erythro-pent-1-enit-

+ H]⁺, 300 (99), 257 (100), 201 (100). HRMS (EI, 70 eV): m/z calcd.

for C₂₁H₂₄O₆P [M + H]⁺403.1311; found 403.1311. C₂₁H₂₃O₆P

(402.38): calcd. C 62.67, H 5.76; found C 62.42, H 6.05.

D

ol (45): From 36 (38 mg, 0.035 mmol) in anhydrous benzene

(1.2 mL) containing DBU (7.85 μL, 0.052 mmol) following the ge-

neral procedure by stirring at 9–10 °C for 12 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 6:4) gave

44 (28.2 mg, 0.029 mmol, 83%) and 45 (4.2 mg, 4.5ϫ 10^–3mmol,

13%) as colorless oils.

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-D-

erythro-pent-1-enitol (40) from (33): From 33 (1.234 g, 2.21 mmol)

in anhydrous benzene (75 mL) containing DBU (0.362 mL,

2.43 mmol) following the general procedure by stirring at 9–10 °C

for 1.75 h. Column chromatography of the reaction residue (hex-

anes/EtOAc, 2:8) gave 40 (810 mg, 1.88 mmol, 85%) as a colorless

oil with properties identical to that prepared previously.

1

Compound 44: [α]_D+2.8 (c = 0.18, CHCl₃). H NMR (500 MHz,

CDCl₃): δ = 3.37–3.46 (m, 3 H), 3.54 (d, J = 7.6 Hz, 1 H), 3.56 (m,

1 H), 3.69 (d, J = 4.7 Hz, 1 H), 3.69 (d, J = 4.7 Hz, 1 H), 3.87 (d,

J = 2.8 Hz, 1 H), 4.27 (d, J = 12.0 Hz, 1 H), 4.37 (d, J = 12.0 Hz,

1 H), 4.38 (d, J = 7.6 Hz, 1 H), 4.42 (s, 2 H), 4.57 (d, J = 11.4 Hz,

3,5-Di-O-benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-D-

threo-pent-1-enitol (42): From 34 (15.3 mg, 0.023 mmol) in anhy-

drous benzene (0.8 mL) containing DBU (8.9 μL, 0.06 mmol) fol-

lowing the general procedure by stirring at 9–10 °C for 1 h. Chro-

matotron chromatography of the reaction residue (hexanes/EtOAc,

1 H), 4.64 (d, J = 11.0 Hz, 1 H), 4.68 (d, J = 11.7 Hz, 1 H), 4.72

3

(d, J = 11.7 Hz, 1 H), 4.73 (d, J = 11.0 Hz, 1 H), 4.79 (dd, J_P,H

=

6:4) gave 42 (11 mg, 0.021 mmol, 91%) as a colorless oil: [α]_D

=

9.6, J = 5.8 Hz, 1 H), 4.93 (d, J = 11.4 Hz, 1 H), 5.54 (ddd, J =

3

–27.3 (c = 0.07, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 3.56 4.8, 4.8, 4.8 Hz, 1 H), 5.59 (d, J_P,H= 20.2 Hz, 1 H), 6.32 (d, J_P,H

(dd, J = 10.6, 4.9 Hz, 1 H), 3.68 (dd, J = 10.6, 7.1 Hz, 1 H), 4.12

(d, J = 11.7 Hz, 1 H), 4.41 (s, 2 H), 4.45 (d, J = 11.7 Hz, 1 H),

4.55 (dd, J_P,H= 7.1, J = 3.0 Hz, 1 H), 5.46 (ddd, J = 7.3, 4.7,

= 40.7 Hz, 1 H), 7.19 (m, 2 H), 7.22–7.34 (m, 27 H), 7.38 (m, 1 H),

7.42 (m, 1 H), 7.67 (m, 4 H), 7.86 (s, 1 H) ppm. ¹³C NMR

(125.7 MHz, CDCl₃): δ = 67.6 (CH₂), 68.4 (CH₂), 72.7 (CH₂), 73.0

3

5046

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

(CH₂), 73.3 (CH), 73.5 (CH₂), 73.9 (CH), 74.5 (CH), 74.9 (CH₂), (dddd, J = 29.2, 13.5, 11.1, 5.2 Hz, 1 H), 2.68 (dddd, J = 15.7, 11.2,

2

75.0 (CH₂), 78.0 (d, J_P,C= 14.8 Hz, CH), 79.1 (CH), 82.1 (CH), 4.2, 2.4 Hz, 1 H), 2.83–2.93 (m, 1 H), 3.60–3.67 (m, 2 H), 3.74 (dd,

104.4 (CH), 127.4–128.5 (Ar, complex), 131.1–131.4 (Ar, complex),

J = 10.9, 4.2 Hz, 1 H), 3.91 (dd, J = 11.1, 2.1 Hz, 1 H), 4.00–4.21

(m, 8 H), 4.42 (dddd, J = 14.2, 8.6, 2.4, 2.4 Hz, 1 H), 4.54 (dddd,

J = 17.8, 4.0, 4.0, 4.0 Hz, 1 H), 5.47 (d, J = 2.9 Hz, 1 H), 5.50 (d,

J = 5.0 Hz, 1 H), 7.33–7.47 (m, 12 H), 7.64–7.72 (m, 8 H) ppm.

¹³C NMR (125.7 MHz, CDCl₃): complex resonance pattern. ³¹P

NMR (161.9 MHz, CDCl₃): δ = 30.3 (s, 1 P), 34.2 (s, 1 P) ppm. IR

2

134.0 (d, J_P,C= 8.5 Hz, CH₂), 137.8 (C), 138.0 (C), 138.4 (C),

138.6 (C), 138.8 (C), 141.0 (d, ¹J_P,C= 92.2 Hz, C), 160.8 (CH) ppm.

³¹P NMR (161.9 MHz, CDCl₃): δ = 30.5 (s, 1 P) ppm. IR (CHCl₃):

ν = 1727, 1099 cm^–1. MS (EI, 70 eV): m/z (%) = 958 (Ͻ 1) [M]⁺,

˜

555 (3), 91 (100). HRMS (EI, 70 eV): m/z calcd. for C₅₉H₅₉O₁₀P

[M]⁺958.3846; found 958.3842. C₅₉H₅₉O₁₀P (959.09): calcd. C (CHCl ): ν = 3385, 1213, 783, 746 cm^–1. MS (ESI⁺): m/z (%) = 515

˜

3

73.89, H 6.20; found C 73.80, H 6.22.

(100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₅H₃₇NaO₆PSi

[M + Na]⁺515.1995; found 515.1992. C₂₅H₃₇O₆PSi (492.62): calcd.

C 60.95, H 7.57; found C 60.86, H 7.80.

1

Compound 45: [α]_D+20.6 (c = 0.32, CHCl₃). H NMR (500 MHz,

CDCl₃): δ = 3.36 (dd, J = 9.8, 3.2 Hz, 1 H), 3.38–3.41 (m, 2 H),

3.44 (dd, J = 9.8, 7.6 Hz, 1 H), 3.53 (dd, J = 10.1, 4.1 Hz, 1 H),

3.57–3.59 (m, 1 H), 3.62 (dd, J = 10.1, 5.0 Hz, 1 H), 3.85 (d, J =

2.8 Hz, 1 H), 4.03 (ddd, J = 6.5, 4.6, 4.4 Hz, 1 H), 4.32 (d, J =

7.6 Hz, 1 H), 4.39 (d, J = 12.0 Hz, 1 H), 4.43–4.47 (m, 4 H), 4.57

(d, J = 11.0 Hz, 1 H), 4.58 (d, J = 11.0 Hz, 1 H), 4.66 (d, J =

2,3-Dideoxy-3-diethoxyphosphoryl-5,6-O-isopropylidene-D-lyxo-

hexofuranose (47): From 17 (60.5 mg, 0.188 mmol) containing a 1 m

solution of DIBAL-H (0.75 mL, 0.75 mmol) following the general

procedure by stirring at –78 °C for 2.5 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 2:8) gave

47 (37 mg, 0.114 mmol, 2:1, 61%) as a colorless oil: [α]_D= –25.4

(c = 0.67, CHCl₃). ¹H NMR (500 MHz, CDCl₃) and ³C NMR

(125.7 MHz, CDCl₃) exhibit complex resonance patterns. ³¹P

NMR (161.9 MHz, CDCl₃): δ = 29.0 (s, 1 P), 33.4 (s, 1 P) ppm. IR

(CHCl ): ν = 3399, 2992 cm^–1. MS (ESI⁺): m/z (%) = 347 (100) [M

3

11.7 Hz, 1 H), 4.69 (dd, J_P,H= 12.9, J = 6.6 Hz, 1 H), 4.70 (d, J

= 11.7 Hz, 1 H), 4.94 (d, J = 11.4 Hz, 1 H), 5.42 (d, ³J_P,H= 20.2 Hz,

3

1 H), 6.23 (d, J_P,H= 41.9 Hz, 1 H), 7.19–7.38 (m, 30 H), 7.44–

7.47 (m, 1 H), 7.63–7.68 (m, 2 H), 7.70–7.74 (m, 2 H) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = 68.5 (CH₂), 70.7 (CH₂), 72.3 (CH),

73.03 (CH₂), 73.06 (CH), 73.08 (CH₂), 73.4 (CH₂), 74.0 (CH), 74.8

˜

3

+ Na]⁺. HRMS (ESI⁺): m/z calcd. for C₁₃H₂₅NaO₇P [M + Na]⁺

347.1236; found 347.1235. C₁₃H₂₅O₇P (324.31): calcd. C 48.15, H

7.77; found C 48.10, H 7.66.

2

(CH₂), 74.9 (CH₂), 79.1 (CH), 81.1 (d, J_P,C= 10.6 Hz, CH), 82.1

1

(CH), 103.9 (CH), 127.3–128.5 (Ar, complex), 130.9 (d, J_{P, C}

=

105.9 Hz, C), 131.2 (d, ¹J_P,C= 104.9 Hz, C), 131.8–132.3 (Ar, com-

plex), 134.3 (d, ²J_P,C= 8.5 Hz, CH₂), 137.9 (C), 138.46 (C), 138.49

2,3-Dideoxy-3-diethoxyphosphoryl-5,6-O-isopropylidene-D-ribo-

hexofuranose (48): From 18 (68 mg, 0.211 mmol) containing a 1 m

solution of DIBAL-H (0.84 mL, 0.84 mmol) following the general

procedure by stirring at –78 °C for 2.5 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 2:8) gave

48 (44 mg, 0.136 mmol, 1:1, 64%) as a colorless oil: Crystalline

solid; m.p. 80.2–81.9 °C (n-hexane/EtOAc); [α]_D+18.7 (c = 0.75,

CHCl₃). ¹H NMR (500 MHz, CDCl₃) and ¹³C NMR (125.7 MHz,

CDCl₃) exhibit complex resonance patterns. ^{3 1}P NMR

(161.9 MHz, CDCl₃): δ = 29.8 (s, 1 P), 33.9 (s, 1 P) ppm. IR

(C), 138.6 (C), 138.9 (C), 141.8 (d, J_P,C= 91.1 Hz, C) ppm. ³¹P

1

NMR (161.9 MHz, CDCl ): δ = 33.9 (s, 1 P) ppm. IR (CHCl ): ν

˜

3

= 3291, 1095 cm^–1. MS (ESI⁺): m/z (%) = 953 (100) [M + Na]⁺.

HRMS (ESI⁺): m/z calcd. for C₅₈H₅₉NaO₉P [M + Na]⁺953.3794;

found 953.3794. C₅₈H₅₉O₉P (931.07): calcd. C 74.82, H 6.39; found

C 74.91, H 6.42.

5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-3-O-

(2,3,4,6-tetra-O-benzyl-β-

ol (44) and 5-O-Benzyl-1,2-dideoxy-2-diphenylphosphoryl-3-O-

(2,3,4,6-tetra-O-benzyl-β- -galactopyranosyl)- -erythro-pent-1-enit-

D-galactopyranosy)-D-erythro-pent-1-enit-

(CHCl ): ν = 3341, 2992, 1026 cm^–1. MS (ESI⁺): m/z (%) = 347

˜

3

(100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₁₃H₂₅NaO₇P [M

+ Na]⁺347.1236; found 347.1234. C₁₃H₂₅O₇P (324.31): calcd. C

48.15, H 7.77; found C 48.35, H 7.47.

D

ol (45) from 38: From 38 (25.6 mg, 0.024 mmol) in anhydrous benz-

ene (0.8 mL) containing DBU (3.9 μL, 0.026 mmol) following the

general procedure by stirring at 9–10 °C for 15 h. Chromatotron

chromatography of the reaction residue (hexanes/EtOAc, 6:4) gave

44 (13.6 mg, 0.014 mmol, 60 %) and 45 (7 mg, 7.5 ϫ10^–3mmol,

32%).

4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphosphoryl-

pyranose (49) and 4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphosphor-

yl- -ribo-hexopyranose (50): From 20 (378 mg, 0.817 mmol) con-

D-arabino-hexo-

D

taining DIBAL-H (1.0 m in toluene, 3.27 mL, 3.27 mmol) following

the general procedure by stirring at –78 °C for 1 h. The residue was

purified by column chromatography (hexanes/EtOAc, 1:1Ǟ3:7) to

give 49 (185 mg, 0.398 mmol, 1.6:1, 49 %) and 50 (17.5 mg,

0.038 mmol, 2.7:1, 4.6%) both as colorless oils.

General Procedure for the DIBAL-H Mediated Reduction of Lact-

ones: To a solution of lactone (1 equiv.) in anhydrous toluene

(33 mL), was added dropwise DIBAL-H (1 m in toluene, 4 mL,

4 equiv.) at –78 °C under nitrogen and the mixture was stirred for

the specified time. EtOH (11 mL) was added at this temperature

and the solution was allowed to warm to 0 °C. A saturated solution

of NH₄Cl was then added and the mixture was extracted with

EtOAc. The organic layer was washed with brine, dried with

Na₂SO₄, and concentrated under reduced pressure. The residue was

purified by chromatography (hexanes/EtOAc).

Compound 49: ¹H NMR (400 MHz, CDCl₃) and ¹³C NMR

(125.7 MHz, CDCl₃) exhibit complex resonance patterns. ³¹P

NMR (161.9 MHz, CDCl₃): δ = 29.9 (s, 1 P), 32.7 (s, 1 P) ppm. IR

(CCl ): ν = 3316, 2985, 1026 cm^–1. MS (ESI⁺): m/z (%) = 487 (100)

˜

4

[M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₃NaO₇P [M +

Na]⁺487.1862; found 487.1868. C₂₄H₃₃O₇P (464.50): calcd. C

62.06, H 7.16; found C 62.19, H 6.94.

5-O-(tert-Butyldiphenylsilyl)-2,3-dideoxy-3-diethoxyphosphoryl-D-

ribofuranose (46): From 15 (118 mg, 0.24 mmol) containing a 1 m

solution of DIBAL-H (0.96 mL, 0.96 mmol) at –78 °C 1.3 h. Chro-

matotron chromatography of the reaction residue (hexanes/EtOAc,

Compound 50: ¹H NMR (400 MHz, CDCl₃) and ¹³C NMR

(125.7 MHz, CDCl₃) exhibit complex resonance patterns. ³¹P

NMR (161.9 MHz, CDCl₃): δ = 28.3 (s, 1 P), 29.9 (s, 1 P) ppm. IR

1:1) gave 46 (83 mg, 0.168 mmol, α/β, 1:1, 70%) as a colorless oil:

(CHCl ): ν = 3385, 3017, 1229 cm^–1. MS (ESI⁺): m/z (%) = 487

˜

3

1

[α]_D= +18.2 (c = 0.6, CHCl₃). H NMR (400 MHz, CDCl₃): δ = (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₃NaO₇P [M

1.06 (s, 9 H), 1.09 (s, 9 H), 1.25 (t, J = 7.2 Hz, 6 H), 1.29 (t, J = + Na]⁺487.1862; found 487.1861. C₂₄H₃₃O₇P (464.50): calcd. C

7.2 Hz, 3 H), 1.35 (t, J = 7.0 Hz, 3 H), 2.13–2.24 (m, 3 H), 2.42

62.06, H 7.16; found C 61.90, H 7.19.

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5047

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

4,6-Di-O-benzyl-2,3-dideoxy-3-diethoxyphosphoryl-

1

D

-xylo-hexo- (CH₃), 26.2 (CH₃), 41.0 (d, J_P,C= 137.0 Hz, CH), 62.7–62.8 (m,

3

pyranose (51): From 22 (101.3 mg, 0.22 mmol) containing a 1 m

2ϫ CH₂), 65.6 (CH₂), 71.5 (CH), 75.3 (d, J_P,C= 8.5 Hz, CH),

solution of DIBAL-H (0.88 mL, 0.88 mmol) following the general 110.0 (C), 160.0 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ =

procedure by stirring at –78 °C. The residue was purified by Crom-

atotron chromatography (hexanes/EtOAc, 4:6), to give 51 (78.5 mg,

23.9 (s, 1 P) ppm. MS (ESI⁺): m/z (%) = 473 (100) [M + Na]⁺, 345

(31) [M + Na – HI]⁺. HRMS (ESI⁺): m/z calcd. for C₁₃H₂₄INaO₇P

[M + Na]⁺473.0202; found 473.0199; calcd. for C₁₃H₂₃NaO₇P [M

0.17 mmol, α/β, 3:1, 77%) as a colorless oil: [α]_D= –3.9 (c = 0.59,

CHCl₃). H NMR (400 MHz, CDCl₃): δ (major isomer) = 1.26 (t, + Na]⁺345.1079; found 345.1092.

1

J = 7.0 Hz, 3 H), 1.33 (t, J = 7.0 Hz, 3 H), 1.87–1.93 (m, 1 H),

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-1-

iodo- -arabinitol (55): From 49 (185 mg, 0.398 mmol) containing

2.37–2.53 (m, 2 H), 3.57 (dd, J = 9.3, 5.6 Hz, 1 H), 3.65 (dd, J =

9.3, 7.7 Hz, 1 H), 3.83 (d, J = 5.8 Hz, 1 H), 4.00–4.19 (m, 4 H),

4.37 (ddd, J = 7.5, 5.8, 1.3 Hz, 1 H), 4.44 (d, J = 12.2 Hz, 1 H),

4.50 (d, J = 12.7 Hz, 1 H), 4.58 (dd, J = 12.5, 12.5 Hz, 2 H), 5.19 (d,

J = 3.7 Hz, 1 H), 7.24–7.33 (m, 10 H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃) exhibits complex resonance pattern. ^{3 1}P NMR

(161.9 MHz, CDCl₃): δ = 28.9 (s, 1 P), 32.5 (s, 1 P) ppm. IR

D

PhI(OAc)₂(141 mg, 0.438 mmol) and I₂(111 mg, 0.438 mmol) fol-

lowing the general procedure by stirring at room temperature for

1 h. Chromatotron chromatography of the reaction residue (hex-

anes/EtOAc, 1:1) gave 55 (193.3 mg, 0.327 mmol, 82%) as an oil:

1

[α]_D= +21.0 (c = 1.03, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

1.25 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2 Hz, 3 H), 2.44 (dddd,

(CHCl ): ν = 3340, 3016, 1216, 1047 cm^–1. MS (ESI⁺): m/z (%) =

˜

3

²J_P,H= 23.8, J = 6.1, 5.0, 5.0 Hz, 1 H), 3.47 (ddd, J_P,H= 11.9, J

487 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₃NaO₇P

[M + Na]⁺487.1862; found 487.1863. C₂₄H₃₃O₇P (464.50): calcd.

C 62.06, H 7.16; found C 62.37, H 7.09.

3

= 10.4, 6.1 Hz, 1 H), 3.50 (ddd, J_P,H= 20.2, J = 10.4, 4.7 Hz, 1

H), 3.69 (dd, J = 11.4, 5.8 Hz, 1 H), 3.75 (dd, J = 10.9, 3.4 Hz, 1

3

H), 4.07–4.21 (m, 4 H), 4.26 (ddd, J_P,H= 13.4, J = 6.2, 4.5 Hz, 1

4-O-(tert-Butyldiphenylsilyl)-1,2-dideoxy-2-diethoxyphosphoryl-3-

O-formyl-1-iodo-D-erythritol (52): From 46 (81 mg, 0.164 mmol)

H), 4.43 (d, J = 12.2 Hz, 1 H), 4.50 (d, J = 11.9 Hz, 1 H), 4.64 (d,

J = 10.9 Hz, 1 H), 4.72 (d, J = 11.1 Hz, 1 H), 5.47 (ddd, J = 5.4,

5.4, 3.4 Hz, 1 H), 7.26–7.34 (m, 10 H), 8.08 (s, 1 H) ppm. ¹³C NMR

containing PhI(OAc)₂(58.2 mg, 0.18 mmol) and I₂(46 mg,

0.18 mmol) following the general procedure by stirring at room

temperature for 0.75 h under irradiation with a 80 W tungsten-fila-

ment lamp. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 1:1) gave 52 (96.4 mg, 0.155 mmol, 95%) as an

2

(100.6 MHz, CDCl₃): δ = –2.8 (d, J_P,C= 2.8 Hz, CH₂), 16.2 (d,

3

1

³J_P,C= 5.7 Hz, CH₃), 16.3 (d, J_P,C= 5.7 Hz, CH₃), 41.4 (d, J_P,C

3

= 137.0 Hz, CH), 62.3 (m, 2ϫ CH₂), 67.8 (CH₂), 73.0 (d, J_P,C

=

7.8 Hz, CH), 73.1 (CH₂), 74.0 (CH₂), 76.2 (CH), 127.58 (2ϫ CH),

127.60 (CH), 127.68 (CH), 127.72 (2 ϫ CH), 128.22 (2ϫ CH),

128.25 (2 ϫ CH), 137.6 (2 ϫ C), 160.0 (CH) ppm. ³¹P NMR

1

oil: [α]_D= –12.0 (c = 0.65, CHCl₃). H NMR (500 MHz, CDCl₃):

δ = 1.05 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H), 1.28 (t, J = 7.1 Hz, 3

3

H), 2.68 (ddd, ²J_P,H= 22.7, J = 10.4, 5.7 Hz, 1 H), 3.38 (ddd, J_P,H

(161.9 MHz, CDCl ): δ = 25.7 (s, 1 P) ppm. IR (CCl ): ν = 2981,

˜

3

4

3

1735, 1026 cm^–1. MS (ESI⁺): m/z (%) = 613 (100) [M + Na]⁺.

HRMS (ESI⁺): m/z calcd. for C₂₄H₃₂INaO₇P [M + Na]⁺613.0828;

found 613.0829. C₂₄H₃₂IO₇P (590.39): calcd. C 48.83, H 5.46;

found C 48.73, H 5.64.

= 6.3, J = 10.7, 10.7 Hz, 1 H), 3.49 (ddd, J_P,H= 21.0, J = 10.7,

4.6 Hz, 1 H), 3.91 (dd, J = 11.4, 4.7 Hz, 1 H), 3.95 (dd, J = 11.4,

3

6.3 Hz, 1 H), 4.05–4.12 (m, 4 H), 5.43 (ddd, J_P,H= 19.0, J = 5.4,

5.2 Hz, 1 H), 7.36–7.44 (m, 6 H), 7.63–7.67 (m, 4 H), 7.99 (s, 1

2

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –3.8 (d, J_{P, C}

=

3

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-1-

iodo-D-ribitol (56): From 50 (17.5 mg, 0.038 mmol) containing

3.2 Hz, CH₂), 16.28 (d, J_P,C= 5.3 Hz, CH₃), 16.33 (d, J_{P, C}

1

5.3 Hz, CH₃), 19.1 (C), 26.8 (3ϫ CH₃), 39.7 (d, J_P,C= 138.8 Hz,

CH), 62.4 (d, J_P,C= 6.4 Hz, CH₂), 62.5 (d, J_P,C= 7.4 Hz, CH₂),

62.9 (d, J_P,C= 6.4 Hz, CH₂), 73.0 (CH), 127.7 (4ϫ CH), 129.8

2

PhI(OAc)₂(13.4 mg, 0.041 mmol) and I₂(10.5 mg, 0.041 mmol)

following the general procedure by stirring at room temperature for

1 h. Chromatotron chromatography of the reaction residue (hex-

anes/EtOAc, 1:1) gave 56 (13.1 mg, 0.022 mmol, 58%) as an oil:

3

(CH), 129.9 (CH), 132.8 (2ϫ C), 135.5 (2ϫ CH), 135.6 (2ϫ CH),

160.0 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 24.3 (s, 1

1

P) ppm. IR (CHCl ): ν = 3006, 1729, 1026 cm^–1. MS (ESI⁺): m/z

[α]_D= –19.5 (c = 0.21, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

˜

3

(%) = 641 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₅H₃₆-

INaO₆PSi [M + Na]⁺641.0961; found 641.0964. C₂₅H₃₆IO₆PSi

(618.52): calcd. C 48.55, H 5.87; found C 48.58, H 5.87.

1.16 (t, J = 7.1 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 2.49 (dddd,

3

²J_P,H= 23.1, J = 11.2, 3.5, 2.2 Hz, 1 H), 3.28 (ddd, J_P,H= 5.7, J

3

= 10.9, 10.9 Hz, 1 H), 3.66 (ddd, J_P,H= 9.1, J = 10.4, 3.5 Hz, 1

H), 3.78 (dd, J = 11.0, 4.4 Hz, 1 H), 3.86 (dd, J = 11.0, 2.8 Hz, 1

1,2-Dideoxy-2-diethoxyphosphoryl-3-O-formyl-1-iodo-4,5-O-iso-

propylidene-D-lyxitol (53): From 47 (30.8 mg, 0.095 mmol) contain-

3

H), 3.89–4.09 (m, 4 H), 4.36 (ddd, J_P,H= 29.5, J = 8.5, 2.4 Hz, 1

H), 4.51 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 12.0 Hz, 1 H), 4.69 (s,

2 H), 5.54 (ddd, J = 7.8, 3.8, 3.8 Hz, 1 H), 7.27–7.33 (m, 10 H),

8.11 (s, 1 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 2.6 (CH₂),

ing PhI(OAc)₂(33.6 mg, 0.1 mmol) and I₂(26.5 mg, 0.1 mmol) fol-

lowing the general procedure by stirring at reflux temperature for

1.5 h. Chromatotron chromatography of the reaction residue (hex-

anes/EtOAc, 1:1) gave 53 (29.9 mg, 0.066 mmol, 70%) as an un-

stable oil, dehydroiodination occurs easily and therefore the com-

pound could not be fully characterized: ¹H NMR (500 MHz,

CDCl₃note: The data of hydrogens at C1–C5 shown below have

been calculated by iterative simulation using program DAISY as

implemented in Bruker Topspin v. 2.1): δ = 1.345 (s, 3 H), 1.345 (t,

J = 7.3 Hz, 3 H), 1.352 (t, J = 6.9 Hz, 3 H), 1.43 (s, 3 H), 2.54

3

16.2 (d, J_P,C= 6.4 Hz, CH₃), 16.3 (d, J_P,C= 6.4 Hz, CH₃), 43.3

1

2

(d, J_P,C= 131.4 Hz, CH), 61.9 (d, J_P,C= 6.4 Hz, CH₂), 62.2 (d,

²J_P,C= 6.4 Hz, CH₂), 68.2 (CH₂), 73.4 (CH₂), 73.7 (CH), 75.5

2

(CH₂), 77.2 (d, J_P,C= 5.5 Hz, CH), 127.8 (3ϫ CH), 127.97 (CH),

128.1 (2ϫ CH), 128.39 (2ϫ CH), 128.43 (2ϫ CH), 137.6 (C), 137.7

(C), 160.6 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 21.9 (s,

1 P) ppm. IR (CHCl ): ν = 3018, 1726, 1026 cm^–1. MS (ESI⁺): m/z

˜

3

(%) = 613 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₂-

INaO₇P [M + Na]⁺613.0828; found 613.0834. C₂₄H₃₂IO₇P

(590.39): calcd. C 48.83, H 5.46; found C 48.66, H 5.59.

2

3

(dddd, J_P,H= 23.6, J = 5.7, 5.2, 4.7 Hz, 1 H), 3.47 (ddd, J_P,H

=

3

17.2, J = 10.8, 4.7 Hz, 1 H), 3.48 (ddd, J_P,H= 14.9, J = 10.8,

5.2 Hz, 1 H), 3.77 (dd, J = 8.9, 5.5 Hz, 1 H), 4.11 (dd, J = 8.9,

6.7 Hz, 1 H), 4.14–4.20 (m, 4 H), 4.66 (ddd, J = 6.7, 5.5, 5.2 Hz, 1

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-1-

H), 5.44 (ddd, ³J_P,H= 10.5, J = 5.7, 5.2 Hz, 1 H), 8.16 (s, 1 H) ppm. iodo-

D

-xylitol (57): From 51 (76.6 mg, 0.165 mmol) containing

¹³C NMR (100.6 MHz, CDCl₃): δ = –4.1 (d, J_P,C= 3.5 Hz, CH₂), PhI(OAc)₂(58.4 mg, 0.18 mmol) and I₂(46.1 mg, 0.18 mmol) fol-

2

3

16.3 (d, J_P,C= 6.4 Hz, CH₃), 16.4 (d, J_P,C= 6.4 Hz, CH₃), 25.3

lowing the general procedure by stirring at room temperature for

5048

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

1

1.5 h. Chromatotron chromatography of the reaction residue (hex-

CH₂), 135.4 (d, J_P,C= 178.7 Hz, C), 159.7 (CH) ppm. ³¹P NMR

anes/EtOAc, 1:1), gave 57 (71.2 mg, 0.121 mmol, 73%) as an oil:

(161.9 MHz, CDCl ): δ = 15.0 (s, 1 P) ppm. IR (CHCl ): ν = 2294,

˜

3 3

1

[α]_D= +15.4 (c = 0.65, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 1729, 1025 cm^–1. MS (ESI⁺): m/z (%) = 345 (100) [M + Na]⁺.

1.07 (t, J = 7.0 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3 H), 2.30 (dddd, HRMS (ESI⁺): m/z calcd. for C₁₃H₂₃NaO₇P [M + Na]⁺345.1079;

3

²J_P,H= 21.8, J = 10.8, 3.2, 2.9 Hz, 1 H), 3.33 (ddd, J_P,H= 5.3, J

found 345.1075. C₁₃H₂₃O₇P (322.30): calcd. C 48.45, H 7.19; found

C 48.29, H 7.16.

3

= 10.7, 10.7 Hz, 1 H), 3.58 (ddd, J_P,H= 8.9, J = 10.4, 3.4 Hz, 1

H), 3.67 (dd, J = 11.3, 3.3 Hz, 1 H), 3.71 (dd, J = 11.7, 3.7 Hz, 1

H), 3.82–4.05 (m, 4 H), 4.36 (ddd, J_P,H= 30.8, J = 8.0, 2.5 Hz, 1

1,2-Dideoxy-2-diethoxyphosphoryl-3-O-formyl-4,5-O-isopropylid-

ene-D-erythro-pent-1-enitol (60): From 48 (41 mg, 0.126 mmol) con-

3

H), 4.46 (d, J = 12.2 Hz, 1 H), 4.62 (d, J = 11.9 Hz, 1 H), 4.70 (d,

J = 11.1 Hz, 1 H), 4.82 (d, J = 11.1 Hz, 1 H), 5.82 (ddd, J = 7.7,

3.7, 3.3 Hz, 1 H), 7.27–7.40 (m, 10 H), 8.13 (s, 1 H) ppm. ¹³C NMR

taining PhI(OAc)₂(45 mg, 0.14 mmol) and I₂(35.3 mg, 0.14 mmol)

following the general procedure by stirring at reflux temperature

for 1.2 h. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 1:1) gave impure 54 (37.2 mg) contaminated with

60. To a solution of this mixture in anhydrous benzene (1.1 mL)

cooled to 9–10 °C, was added DBU (12.6 μL, 0.08 mmol) and the

mixture was stirred at this temperature for 0.17 h. The reaction

mixture was then poured into a saturated aqueous solution of

NaHSO₄and extracted with EtOAc. The combined organic ex-

tracts were washed with brine, dried with Na₂SO₄, and concen-

trated under reduced pressure. The residue was purified by Chro-

matotron chromatography (hexanes/EtOAc, 4:6) to give 60 (29 mg,

0.09 mmol, two-step, 71%) as a colorless oil: [α]_D= +10.0 (c =

0.41, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.33 (t, J = 6.6 Hz,

3 H), 1.33 (s, 3 H), 1.33 (t, J = 6.6 Hz, 3 H), 1.38 (s, 3 H), 3.89

(dd, J = 8.7, 6.2 Hz, 1 H), 3.95 (dd, J = 8.5, 6.9 Hz, 1 H), 4.05–

3

(125.7 MHz, CDCl₃): δ = 2.5 (CH₂), 16.0 (d, J_P,C= 6.4 Hz, CH₃),

3

1

16.2 (d, J_P,C= 6.4 Hz, CH₃), 42.6 (d, J_P,C= 131.4 Hz, CH), 61.6

(d, ²J_P,C= 6.4 Hz, CH₂), 62.6 (d, ²J_P,C= 5.3 Hz, CH₂), 68.7 (CH₂),

73.4 (CH₂), 75.7 (CH), 76.7 (CH₂), 78.7 (d, J_P,C= 5.3 Hz, CH),

2

127.79 (CH), 127.84 (CH), 128.0 (2ϫ CH), 128.1 (2ϫ CH), 128.3

(4 ϫ CH), 137.3 (C), 137.8 (C), 160.7 (CH) ppm. ³¹P NMR

(161.9 MHz, CDCl ): δ = 21.8 (s, 1 P) ppm. IR (CHCl ): ν = 3007,

˜

3

1725, 1216, 1028 cm^–1. MS (ESI⁺): m/z (%) = 613 (100) [M +

Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₂INaO₇P [M + Na]⁺

613.0828; found 613.0815. C₂₄H₃₂IO₇P (590.39): calcd. C 48.83, H

5.46; found C 49.04, H 5.07.

4-O-(tert-Butyldiphenylsilyl)-1,2-dideoxy-2-diethoxyphosphoryl-3-

O-formyl-D-glycero-tetra-1-enitol (58): From 52 (92.4 mg,

3

4.14 (m, 4 H), 4.53 (ddd, J = 6.3, 6.3, 6.3 Hz, 1 H), 5.67 (dd, J_P,H

0.149 mmol) in anhydrous benzene (3.8 mL) containing DBU

(44.6 μL, 0.3 mmol) following the general procedure by stirring at

9–10 °C for 15 min. Chromatotron chromatography of the reaction

residue (hexanes/EtOAc, 1:1) gave 58 (69 mg, 0.140 mmol, 94%) as

a colorless oil: [α]_D= +5.0 (c = 0.54, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.04 (s, 9 H), 1.20 (t, J = 7.3 Hz, 3 H), 1.29 (t, J =

6.9 Hz, 3 H), 3.79 (dd, J = 11.4, 7.3 Hz, 1 H), 3.94 (dd, J = 11.3,

3

= 10.9, J = 4.6 Hz, 1 H), 6.10 (dd, J_P,H= 44.8, J = 1.0 Hz, 1

3

H), 6.24 (d, J_P,H= 22.4 Hz, 1 H), 8.10 (s, 1 H) ppm. ¹³C NMR

3

(100.6 MHz, CDCl₃): δ = 16.17 (d, J_P,C= 5.3 Hz, CH₃), 16.22 (d,

2

³J_P,C= 6.4 Hz, CH₃), 25.1 (CH₃), 26.3 (CH₃), 62.4 (d, J_{P, C}

=

2

5.3 Hz, CH₂), 62.5 (d, J_P,C= 5.3 Hz, CH₂), 64.6 (CH₂), 71.9 (d,

²J_P,C= 18.0 Hz, CH), 75.0 (CH), 110.0 (C), 132.8 (d, ²J_P,C= 6.4 Hz,

CH₂), 135.4 (d, J_P,C= 178.0 Hz, C), 159.4 (CH) ppm. ³¹P NMR

1

3

3.2 Hz, 1 H), 3.97–4.10 (m, 4 H), 5.68 (ddd, J_P,H= 10.0, J = 7.3,

(161.9 MHz, CDCl ): δ = 15.0 (s, 1 P) ppm. IR (CHCl ): ν = 2295,

˜

3

3.2 Hz, 1 H), 6.11 (ddd, J_P,H= 45.4, J = 1.3, 1.3 Hz, 1 H), 6.28

1731, 1024 cm^–1. MS (ESI⁺): m/z (%) = 345 (100) [M + Na]⁺.

HRMS (ESI⁺): m/z calcd. for C₁₃H₂₃NaO₇P [M + Na]⁺345.1079;

found 345.1078. C₁₃H₂₃O₇P (322.30): calcd. C 48.45, H 7.19; found

C 48.52, H 7.23.

3

(dd, J_P,H= 22.7, J = 1.3 Hz, 1 H), 7.37–7.46 (m, 6 H), 7.65–7.68

(m, 4 H), 8.10 (s, 1 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ =

3

16.07 (d, J_P,C= 3.5 Hz, CH₃), 16.14 (d, ³J_P,C= 2.8 Hz, CH₃), 19.2

2

(C), 26.7 (3ϫ CH₃), 62.1 (d, J_P,C= 6.4 Hz, CH₂), 62.3 (d, J_P,C

=

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-D-

3

2

5.7 Hz, CH₂), 64.7 (d, J_{P, C}= 2.1 Hz, CH₂), 73.1 (d, J_{P, C}

erythro-pent-1-enitol (61): From 55 (175.2 mg, 0.297 mmol) in an-

hydrous benzene (7.4 mL) containing DBU (88.6 μL, 0.59 mmol)

following the general procedure by stirring at 9–10 °C for 15 min.

Chromatotron chromatography of the reaction residue (hexanes/

EtOAc, 1:1) gave 61 (136 mg, 0.294 mmol, 99%) as a colorless oil:

18.4 Hz, CH), 127.7 (4ϫ CH), 129.72 (CH), 129.75 (CH), 132.8

2

1

(d, J_P,C= 6.4 Hz, CH₂), 133.05 (C), 133.08 (C), 135.3 (d, J_P,C

=

178.0 Hz, C), 135.50 (2ϫ CH), 135.54 (2ϫ CH), 159.8 (CH) ppm.

³¹P NMR (161.9 MHz, CDCl₃): δ = 15.6 (s, 1 P) ppm. IR (CHCl₃):

ν = 3003, 1728 cm^–1. MS (ESI⁺): m/z (%) = 513 (100) [M + Na]⁺.

˜

1

[α]_D= +27.7 (c = 0.22, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

HRMS (ESI⁺): m/z calcd. for C₂₅H₃₅NaO₆PSi [M + Na]⁺513.1838;

found 513.1837. C₂₅H₃₅O₆PSi (490.61): calcd. C 61.20, H 7.19;

found C 61.12, H 7.33.

1.31 (t, J = 7.1 Hz, 6 H), 3.74 (dd, J = 11.0, 3.2 Hz, 1 H), 3.77 (dd,

J = 11.0, 6.0 Hz, 1 H), 4.05–4.16 (m, 4 H), 4.36 (d, J = 11.7 Hz, 1

3

H), 4.39 (dd, J_P,H= 12.9, J = 6.0 Hz, 1 H), 4.45 (d, J = 12.0 Hz,

1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 11.7 Hz, 1 H), 5.44

1,2-Dideoxy-2-diethoxyphosphoryl-3-O-formyl-4,5-O-isopropylid-

ene-D-threo-pent-1-enitol (59): From 53 (13.2 mg, 0.029 mmol) in

(ddd, J = 5.9, 5.9, 3.0 Hz, 1 H), 6.18 (d, ³J_P,H= 46.0 Hz, 1 H), 6.35

3

(dd, J_P,H= 22.2, J = 1.4 Hz, 1 H), 7.25–7.35 (m, 10 H), 8.06 (s, 1

anhydrous benzene (0.73 mL) containing DBU (8.8 μL, 0.06 mmol)

following the general procedure by stirring at 9–10 °C for 0.5 h.

Chromatotron chromatography of the reaction residue (hexanes/

EtOAc, 4:6) gave 59 (8.2 mg, 0.025 mmol, 87%) as a colorless oil:

3

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 16.2 (d, J_{P, C}

=

6.4 Hz, CH₃), 16.3 (d, ³J_P,C= 6.4 Hz, CH₃), 62.2 (d, ²J_P,C= 6.4 Hz,

CH₂), 62.3 (d, J_P,C= 5.3 Hz, CH₂), 67.7 (CH₂), 71.6 (CH₂), 73.1

2

1

(CH₂), 73.4 (CH), 77.4 (d, J_P,C= 14.8 Hz, CH), 127.60 (2ϫ CH),

[α]_D= –43.7 (c = 0.46, CHCl₃). H NMR (500 MHz, CDCl₃): δ =

2

127.62 (CH), 127.81 (3ϫ CH), 128.3 (4ϫ CH), 133.6 (d, J_P,C

=

1.34 (t, J = 7.3 Hz, 6 H), 1.36 (s, 3 H), 1.45 (s, 3 H), 3.81 (dd, J =

8.8, 5.7 Hz, 1 H), 4.01 (dd, J = 8.8, 6.6 Hz, 1 H), 4.06–4.15 (m, 4

1

7.4 Hz, CH₂), 136.9 (d, J_P,C= 175.9 Hz, C), 137.4 (C), 137.9 (C),

160.4 (CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 16.4 (s, 1

3

H), 4.54 (ddd, J = 6.5, 6.5, 6.5 Hz, 1 H), 5.55 (dd, J_P,H= 14.8, J

P) ppm. IR (CHCl ): ν = 2926, 1733, 1024 cm^–1. MS (ESI⁺): m/z

3

˜

3

= 6.6 Hz, 1 H), 6.20 (d, J_P,H= 44.5 Hz, 1 H), 6.32 (dd, J_P,H

=

(%) = 485 (100) [M + Na]⁺. HRMS (ESI⁺): m/z C₂₄H₃₁NaO₇P [M

+ Na]⁺485.1705; found 485.1711. C₂₄H₃₁O₇P (462.48): calcd. C

62.33, H 6.76; found C 62.19, H 6.96.

21.8, J = 1.0 Hz, 1 H), 8.13 (s, 1 H) ppm. ¹³C NMR (100.6 MHz,

CDCl₃): δ = 16.2 (d, J_P,C= 6.3 Hz, CH₃), 16.3 (d, J_P,C= 6.3 Hz,

CH₃), 25.3 (CH₃), 26.4 (CH₃), 62.44 (d, ²J_P,C= 5.7 Hz, CH₂), 62.45

3

(d, ²J_P,C= 5.7 Hz, CH₂), 65.8 (CH₂), 73.6 (d, ²J_P,C= 15.5 Hz, CH), 3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-

D-

75.7 (d, J_P,C= 2.1 Hz, CH), 110.3 (C), 134.8 (d, J_P,C= 7.1 Hz, erythro-pent-1-enitol (61) from 56: From 56 (13 mg, 0.022 mmol) in

3

2

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5049

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

anhydrous benzene (0.55 mL) containing DBU (6.6 μL,

0.044 mmol) following the general procedure by stirring at 9–10 °C

for 0.7 h. Chromatotron chromatography of the reaction residue

(hexanes/EtOAc, 1:1) gave 61 (9.1 mg, 0.020 mmol, 90%) as a col-

orless oil with properties identical to those of the previously pre-

pared compound.

425.1129. C₂₁H₂₃O₆P (402.38): calcd. C 62.68, H 5.76; found C

62.78, H 6.00.

1

Compound 63b: [α]_D= +10 (c = 0.6, CHCl₃). H NMR (500 MHz,

2

CDCl₃): δ = 1.87 (s, 3 H), 3.21 (dddd, J_P,H= 3.7, J = 7.8, 5.6,

3.7 Hz, 1 H), 3.81 (dd, J = 12.6, 4.1 Hz, 1 H), 3.87 (dd, J = 12.3,

3

3.5 Hz, 1 H), 3.98 (ddd, J = 3.5, 3.5, 3.5 Hz, 1 H), 4.16 (ddd, J_P,H

3

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-D-

= 15.8, J = 9.5, 7.9 Hz, 1 H), 4.28 (ddd, J_P,H= 13.1, J = 9.5,

3

threo-pent-1-enitol (62): From 57 (68.2 mg, 0.116 mmol) in anhy-

drous benzene (2.9 mL) containing DBU (34.5 μL, 0.23 mmol) fol-

lowing the general procedure by stirring at 9–10 °C for 1 h. Chro-

matotron chromatography of the reaction residue (hexanes/EtOAc,

5.5 Hz, 1 H), 5.52 (ddd, J_P,H= 13.7, J = 3.5, 3.5 Hz, 1 H), 7.47–

7.60 (m, 6 H), 7.76–7.86 (m, 4 H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 20.6 (CH₃), 45.4 (d, ¹J_P,C= 72.1 Hz, CH), 62.3 (CH₂),

2

3

67.0 (CH₂), 75.3 (d, J_P,C= 3.2 Hz, CH), 86.7 (d, J_P,C= 4.2 Hz,

CH), 128.8 (d, ³J_P,C= 11.7 Hz, 2ϫ CH), 129.0 (d, ³J_P,C= 12.7 Hz,

6:4) gave 62 (48.1 mg, 0.010 mmol, 90%) as a colorless oil: [α]_D

=

–30.8 (c = 0.67, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 1.31 (t,

J = 7.1 Hz, 3 H), 1.32 (t, J = 6.9 Hz, 3 H), 3.62 (dd, J = 10.4,

5.7 Hz, 1 H), 3.65 (dd, J = 10.4, 6.3 Hz, 1 H), 4.03–4.14 (m, 4 H),

4.29 (d, J = 11.7 Hz, 1 H), 4.44 (dd, ³J_P,H= 10.7, J = 3.8 Hz, 1 H),

4.46 (br. s, 2 H), 4.60 (d, J = 11.7 Hz, 1 H), 5.43 (ddd, J = 6.0, 6.0,

2

1

2 ϫ CH), 130.8 (d, J_P,C= 9.5 Hz, 2 ϫ CH), 130.9 (d, J_{P, C}

=

2

1

100.7 Hz, C), 131.1 (d, J_P,C= 9.5 Hz, 2ϫ CH), 131.3 (d, J_P,C

3

100.7 Hz, C), 132.3 (d, J_P,C= 3.2 Hz, CH), 132.4 (d, J_{P, C}

3.2 Hz, CH), 170.0 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ =

31.3 (s, 1 P) ppm. IR (CHCl ): ν = 3687, 3602, 3342, 3007, 1742,

˜

3

3.8 Hz, 1 H), 6.21 (d, ³J_P,H= 46.4 Hz, 1 H), 6.33 (dd, J_P,H= 22.4,

1119 cm^–1. MS (ESI) m/z (%) = 383 (100) [M + Na]⁺. HRMS (ESI):

J = 1.6 Hz, 1 H), 7.25–7.33 (m, 10 H), 8.08 (s, 1 H) ppm. ¹³C NMR

m/z calcd. for C₁₉H₂₁NaO₅P [M + Na]⁺383.1024; found 383.1034.

2

(125.7 MHz, CDCl₃): δ = 16.2 (d, J_P,C= 6.4 Hz, 2ϫ CH₃), 62.0

(d, ²J_P,C= 5.3 Hz, CH₂), 62.3 (d, ²J_P,C= 6.4 Hz, CH₂), 68.2 (CH₂),

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-D-erythro-pent-

2

1-enitol (64): A solution of 61 (200 mg, 0.432 mmol) in NaOEt/

EtOH 0.01 m (3.8 mL, 0.038 mmol), was stirred at room tempera-

ture under nitrogen for 3 h. The mixture was then concentrated

under reduced pressure and the residue was purified by Chromato-

tron chromatography (hexanes/EtOAc, 40:60) to give 64 (179.2 mg,

0.412 mmol, 95 %) as a colorless oil: [α]_D= +34.0 (c = 1.05,

71.3 (CH₂), 72.4 (CH), 73.1 (CH₂), 75.9 (d, J_P,C= 15.9 Hz, CH),

127.58 (2 ϫ CH), 127.61 (CH), 127.83 (CH), 128.0 (2 ϫ CH),

2

128.27 (2ϫ CH), 128.31 (2ϫ CH), 133.0 (d, J_P,C= 6.4 Hz, CH₂),

1

136.1 (d, J_P,C= 174.8 Hz, C), 137.3 (C), 137.7 (C), 160.3

(CH) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 16.4 (s, 1 P) ppm.

IR (CHCl ): ν = 3004, 1727, 1027, 1180 cm^–1. MS (ESI⁺): m/z (%)

˜

3

1

= 485 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for

C₂₄H₃₁NaO₇P [M + Na]⁺485.1705; found 485.1713. C₂₄H₃₁O₇P

(462.48): calcd. C 62.33, H 6.76; found C 62.44, H 6.69.

CHCl₃). H NMR (500 MHz, CDCl₃): δ = 1.29 (t, J = 7.3 Hz, 3

H), 1.32 (t, J = 7.3 Hz, 3 H), 3.62 (dd, J = 9.8, 5.0 Hz, 1 H), 3.64

(dd, J = 9.8, 3.8 Hz, 1 H), 4.04 (ddd, J = 6.9, 5.0, 3.8 Hz, 1 H),

3

4.06–4.17 (m, 4 H), 4.24 (dd, J_P,H= 16.4, J = 6.9 Hz, 1 H), 4.33

3,5-Di-O-acetyl-1,4-anhydro-2-deoxy-2-diphenylphosphoryl-

arabinitol (63a) and 3-O-Acetyl-1,4-anhydro-2-deoxy-2-diphenyl-

phosphoryl- -arabinitol (63b): A solution of formate 33 (47 mg,

D-

(d, J = 11.3 Hz, 1 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.54 (d, J =

3

12.0 Hz, 1 H), 4.57 (d, J = 11.3 Hz, 1 H), 6.11 (ddd, J_P,H= 46.0,

J = 1.0, 1.0 Hz, 1 H), 6.28 (dd, ³J_P,H= 21.8, J = 1.6 Hz, 1 H), 7.24–

7.33 (m, 10 H) ppm. ¹³C NMR (100.6 MHz, CDCl₃): δ = 16.16 (d,

D

0.084 mmol) in MeOH (2.1 mL) was stirred at 46–47 °C for 26 h.

The mixture was then concentrated in vacuo. To a solution of the

residue in CH₂Cl₂(2.8 mL) was added AgOTf (25.7 mg, 0.1 mmol)

and the mixture was vigorously stirred at room temperature in the

dark under nitrogen for 1.4 h. The reaction mixture was then

poured into a saturated aqueous solution of NaHCO₃and ex-

tracted with CH₂Cl₂. The combined organic extracts were washed

with brine, dried with Na₂SO₄, and concentrated under reduced

pressure. The residue was purified by chromatotron chromatog-

raphy (hexanes/EtOAc, 1:9) to give 63a (22 mg, 0.055 mmol, 65%)

and the more polar alcohol 63b (6 mg, 0.017 mmol, 20%), which

was afterward eluted with chloroform/MeOH (95:5).

3

2

³J_P,C= 6.4 Hz, CH₃), 16.17 (d, J_P,C= 6.4 Hz, CH₃), 62.2 (d, J_P,C

2

= 6.0 Hz, CH₂), 62.3 (d, J_P,C= 6.0 Hz, CH₂), 70.6 (CH₂), 71.0

(CH₂), 72.1 (CH), 73.2 (CH₂), 80.0 (d, J_P,C= 14.8 Hz, CH), 127.4

2

(CH), 127.57 (CH), 127.61 (2ϫ CH), 127.7 (2ϫ CH), 128.2 (4ϫ

CH), 132.9 (d, ²J_P,C= 6.4 Hz, CH₂), 137.5 (d, ¹J_P,C= 173.8 Hz, C),

137.6 (C), 138.1 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 18.0

(s, 1 P) ppm. IR (CHCl ): ν = 3400, 3005, 1241, 1027, 973 cm^–1.

˜

3

MS (ESI⁺): m/z (%) = 457 (100) [M + Na]⁺. HRMS (ESI⁺): m/z

calcd. for C₂₃H₃₁NaO₆P [M + Na]⁺457.1756; found 457.1750.

C₂₃H₃₁O₆P (434.47): calcd. C 63.58, H 7.19; found C 63.74, H 7.22.

(R_P)-3,5-Di-O-benzyl-1,2-dideoxy-1-ethoxy-2-methylene-1-phospha-

Compound 63a: Crystalline solid; m.p. 133.7–135.7 °C (n-hexane/

CH₂Cl₂); [α]_D= +22.6 (c = 0.38, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.74 (s, 3 H), 2.07 (s, 3 H), 3.33 (dddd, J_P,H= 3.5, J

1-oxo-

D

-erythro-pentofuranose (65) and (S_P)-3,5-Di-O-benzyl-1,2-

-erythro-pentofur-

dideoxy-1-ethoxy-2-methylene-1-phospha-1-oxo-

D

2

anose (66): To a solution of 64 (178 mg, 0.41 mmol) in toluene

(2.0 mL), was added PPTS (205.9 mg, 0.819 mmol) and the mixture

was stirred at 100 °C under nitrogen for 29 h. The solution was

then poured into water and extracted with EtOAc. The organic

layer was dried with Na₂SO₄and concentrated under reduced pres-

sure. The residue was purified by Chromatotron chromatography

(hexanes/EtOAc, 50:50) to give 65 (25.8 mg, 0.066 mmol, 16%) and

66 (48.6 mg, 0.125 mmol, 31%) as colorless oils.

= 8.8, 8.8, 6.3 Hz, 1 H), 4.07 (ddd, J = 7.5, 4.0, 4.0 Hz, 1 H), 4.15–

4.26 (m, 2 H), 4.18 (dd, J = 12.0, 7.3 Hz, 1 H), 4.29 (dd, J = 12.0,

3

3.8 Hz, 1 H), 5.46 (ddd, J_P,H= 13.9, J = 6.3, 4.4 Hz, 1 H), 7.46–

7.59 (m, 6 H), 7.75–7.83 (m, 4 H) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = 20.2 (CH₃), 20.7 (CH₃), 44.5 (d, ¹J_P,C= 73.1 Hz, CH),

2

3

62.7 (CH₂), 66.7 (d, J_P,C= 2.1 Hz, CH₂), 74.2 (CH), 82.8 (d, J_P,C

3

= 7.4 Hz, CH), 128.6 (d, J_P,C= 12.7 Hz, 2ϫ CH), 128.9 (d, J_P,C

2

= 11.7 Hz, 2ϫ CH), 130.7 (d, J_P,C= 8.5 Hz, 2ϫ CH), 131.07 (d,

¹J_P,C= 100.7 Hz, C), 131.11 (d, J_P,C= 9.5 Hz, 2ϫ CH), 131.6 (d,

Compound 65: [α]_D= +4.5 (c = 0.64, CHCl₃). ¹H NMR (500 MHz,

2

4

¹J_P,C= 99.6 Hz, C), 132.1 (d, J_P,C= 2.1 Hz, CH), 132.3 (d, J_P,C

CDCl₃): δ = 1.30 (t, J = 7.3 Hz, 3 H), 3.62 (ddd, J_P,H= 2.2, J =

= 2.1 Hz, CH), 169.5 (C), 170.6 (C) ppm. ³¹P NMR (161.9 MHz,

11.4, 3.8 Hz, 1 H), 3.69 (dd, J = 11.4, 3.8 Hz, 1 H), 4.10–4.21 (m,

3

CDCl ): δ = 28.2 (s, 1 P) ppm. IR (CHCl ): ν = 2994, 1743,

2 H), 4.32 (dddd, J_P,H= 6.6, J = 6.6, 3.8, 3.8 Hz, 1 H), 4.50 (d, J

˜

3

1229 cm^–1. MS (ESI) m/z (%) = 425 (100) [M + Na]⁺. HRMS = 12.0 Hz, 1 H), 4.57 (d, J = 11.7 Hz, 1 H), 4.59 (d, J = 11.7 Hz,

3

(ESI): m/z calcd. for C₂₁H₂₃NaO₆P [M + Na]⁺425.1130; found 1 H), 4.61 (dddd, J_P,H= 8.2, J = 6.3, 2.2, 2.2 Hz, 1 H), 4.70 (d, J

5050

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

3

= 11.7 Hz, 1 H), 6.03 (dd, J_P,H= 46.7, J = 2.2 Hz, 1 H), 6.15 (dd,

J = 12.1 Hz, 1 H), 4.61 (d, J = 11.4 Hz, 1 H), 7.23–7.38 (m, 10 H).

³J_P,H= 21.8, J = 2.5 Hz, 1 H), 7.29–7.37 (m, 10 H) ppm. ¹³C NMR ¹H NMR (400 MHz, [D₆]acetone): δ = 1.25 (t, J = 7.1 Hz, 3 H),

(125.7 MHz, CDCl₃): δ = 16.4 (d, J_P,C= 6.4 Hz, CH₃), 63.1 (d, 2.40 (dddd, ²J_P,H= 19.9, J = 8.5, 8.5, 6.6 Hz, 1 H), 2.89 (ddd, ³J_P,H

3

²J_P,C= 6.4 Hz, CH₂), 68.5 (d, J_P,C= 3.2 Hz, CH₂), 72.5 (CH₂), = 11.8, J = 11.8, 8.6 Hz, 1 H), 3.06 (ddd, J_P,H= 24.6, J = 11.6,

3

73.4 (CH₂), 76.9 (d, ²J_P,C= 32.9 Hz, CH), 80.9 (CH), 126.6 (d, ²J_P,C6.6 Hz, 1 H), 3.41 (d, J = 17.4 Hz, 1 H), 3.43 (d, J = 17.4 Hz, 1

4

= 7.4 Hz, CH₂), 127.6 (2ϫ CH), 127.8 (CH), 127.9 (2ϫ CH), 128.1

H), 3.63 (ddd, J_P,H= 1.2, J = 11.3, 4.8 Hz, 1 H), 3.67 (s, 3 H),

3.71 (dd, J = 11.3, 3.4 Hz, 1 H), 4.10–4.27 (m, 3 H), 4.22 (dddd,

1

(CH), 128.4 (2ϫ CH), 128.5 (2ϫ CH), 136.8 (d, J_P,C= 162.1 Hz,

C), 137.2 (C), 137.6 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = ³J_P,H= 8.0, J = 7.2, 4.8, 3.2 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H),

24.7 (s, 1 P) ppm. IR (CHCl ): ν = 3008, 1259, 1227, 1036,

4.57 (d, J = 10.8 Hz, 1 H), 4.60 (d, J = 11.6 Hz, 1 H), 4.71 (d, J =

˜

3

966 cm^–1. MS (ESI⁺): m/z (%) = 411 (100) [M + Na]⁺. HRMS 11.6 Hz, 1 H), 7.27–7.39 (m, 10 H) ppm. ¹³C NMR (125.7 MHz,

(ESI⁺): m/z calcd. for C₂₁H₂₅NaO₅P [M + Na]⁺411.1337; found

411.1338. C₂₁H₂₅O₅P (388.40): calcd. C 64.94, H 6.49; found C

64.92, H 6.54.

CDCl₃): δ = 16.5 (d, ³J_P,C= 5.3 Hz, CH₃), 41.6 (d, ¹J_P,C= 119.7 Hz,

2

CH), 46.4 (d, J_P,C= 3.2 Hz, CH₂), 50.3 (CH₂), 51.8 (CH₃), 63.2

2

3

(d, J_P,C= 6.4 Hz, CH₂), 68.7 (d, J_P,C= 4.2 Hz, CH₂), 73.3 (2ϫ

2

CH₂), 78.9 (d, J_P,C= 14.8 Hz, CH), 80.5 (CH), 127.7 (2ϫ CH),

Compound 66: [α]_D= +31.7 (c = 0.18, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.33 (t, J = 7.3 Hz, 3 H), 3.54 (dd, J = 10.7, 6.0 Hz,

127.8 (CH), 127.96 (2ϫ CH), 128.05 (CH), 128.4 (2ϫ CH), 128.5

(2 ϫ CH), 137.4 (C), 137.7 (C), 172.5 (C) ppm. ³¹P NMR

4

1 H), 3.65 (ddd, J_P,H= 0.9, J = 10.7, 4.7 Hz, 1 H), 4.17 (ddd, J =

(161.9 MHz, CDCl ): δ = 39.6 (s, 1 P) ppm. IR (CHCl ): ν = 3034,

˜

3

7.3, 7.3, 7.3 Hz, 1 H), 4.18 (ddd, J = 6.9, 6.9, 6.9 Hz, 1 H), 4.42

1735, 1258, 1034, 967 cm^–1. MS (ESI⁺): m/z (%) = 500 (100) [M +

Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₄H₃₂NNaO₇P [M + Na]⁺

500.1814; found 500.1828. C₂₄H₃₂NO₇P (477.49): calcd. C 60.37,

H 6.75, N 2.93; found C 60.39, H 6.80, N 2.79.

3

(dddd, J_P,H= 17.3, J = 2.8, 1.3, 1.3 Hz, 1 H), 4.47 (m, 1 H), 4.49

(d, J = 12.0 Hz, 1 H), 4.54 (d, J = 12.0 Hz, 1 H), 4.57 (d, J =

3

12.0 Hz, 1 H), 4.64 (d, J = 11.7 Hz, 1 H), 6.04 (dd, J_P,H= 46.2, J

3

= 1.2 Hz, 1 H), 6.26 (dd, J_P,H= 20.8, J = 1.6 Hz, 1 H), 7.28–7.37

(m, 10 H) ppm. ¹H NMR (500 MHz, C₆D₆): δ = 1.03 (t, J = 6.9 Hz, Compound 68: [α]_D= –17.6 (c = 0.5, CHCl₃). ¹H NMR (500 MHz,

4

3 H), 3.35 (dd, J = 10.7, 5.7 Hz, 1 H), 3.38 (ddd, J_P,H= 0.9, J =

CDCl₃): δ = 1.30 (t, J = 7.3 Hz, 3 H), 3.46 (s, 2 H), 3.61–3.68 (m,

10.7, 4.7 Hz, 1 H), 4.01 (m, 2 H), 4.12 (d, J = 11.7 Hz, 1 H), 4.19 4 H), 3.73 (s, 3 H), 4.17 (m, 2 H), 4.58 (s, 2 H), 4.99 (s, 1 H), 6.82

3

(d, J = 12.0 Hz, 1 H), 4.26 (d, J = 12.3 Hz, 1 H), 4.27 (dddd, J_P,H

(br. d, J_P,H= 44.1 Hz, 1 H), 7.28–7.37 (m, 5 H) ppm. ¹³C NMR

3

= 17.3, J = 3.2, 1.6, 1.6 Hz, 1 H), 4.31 (d, J = 11.7 Hz, 1 H), 4.42

(dddd, J_P,H= 10.1, J = 5.7, 4.7, 3.2 Hz, 1 H), 5.53 (br. d, J_P,H

(125.7 MHz, CDCl₃): δ = 16.5 (d, J_P,C= 5.3 Hz, CH₃), 45.3 (d,

3

=

²J_P,C= 15.9 Hz, CH₂), 49.7 (CH₂), 52.0 (CH₃), 63.4 (d, J_P,C

=

3

2

45.4 Hz, 1 H), 5.98 (dd, J_P,H= 20.8, J = 1.3 Hz, 1 H), 7.05–7.20 6.4 Hz, CH₂), 71.0 (CH₂), 73.6 (CH₂), 79.0 (d, J_P,C= 10.6 Hz,

3

1

(m, 10 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 16.3 (d, J_P,CCH), 127.7 (2ϫ CH), 127.9 (CH), 128.4 (2ϫ CH), 131.6 (d, J_P,C

2

3

2

= 5.3 Hz, CH₃), 63.1 (d, J_P,C= 6.4 Hz, CH₂), 69.3 (d, J_P,C

=

= 155.8 Hz, C), 137.5 (C), 142.3 (d, J_P,C= 23.3 Hz, CH), 172.2

2

2.1 Hz, CH₂), 70.7 (CH₂), 73.6 (CH₂), 78.2 (d, J_P,C= 27.6 Hz,

(C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 38.7 (s, 1 P) ppm. IR

CH), 81.3 (d, J_P,C= 2.1 Hz, CH), 127.7 (2ϫ CH), 127.8 (CH), (CHCl ): ν = 1740, 1118, 1023, 973 cm^–1. MS (ESI⁺): m/z (%) = 392

2

˜

3

127.9 (2ϫ CH), 128.0 (CH), 128.4 (2ϫ CH), 128.5 (2ϫ CH), 129.9 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₁₇H₂₄NNaO₆P [M

2

1

(d, J_P,C= 9.5 Hz, CH₂), 135.2 (d, J_P,C= 162.1 Hz, C), 137.0 (C),

+ Na]⁺392.1239; found 392.1246.

137.5 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 26.3 (s, 1

(S_P)-2-[(2-Aza-3-methoxycarbonyl)propyl]-3,5-di-O-benzyl-1,2-dide-

P) ppm. IR (CHCl ): ν = 3442, 3012, 1260, 1094, 1010, 970 cm^–1.

˜

3

oxy-1-ethoxy-1-phospha-1-oxo-

[(2-Aza-3-methoxycarbonyl)propyl]-3,5-di-O-benzyl-1,2-dideoxy-1-

ethoxy-1-phospha-1-oxo- -arabino-pentofuranose (69β), and (S_P)-2-

[(2-Aza-3-methoxycarbonyl)propyl]-5-O-benzyl-1,2,3-trideoxy-1-

ethoxy-1-phospha-1-oxo- -glycero-pent-2-enofuranose (70): To a

D-ribo-pentofuranose (69α), (S_P)-2-

MS (ESI⁺): m/z (%) = 411 (100) [M + Na]⁺. HRMS (ESI⁺): m/z

calcd. for C₂₁H₂₅NaO₅P [M + Na]⁺411.1337; found 411.1340.

C₂₁H₂₅O₅P (388.40): calcd. C 64.94, H 6.49; found C 64.93, H 6.50.

D

(R_P)-2-[(2-Aza-3-methoxycarbonyl)propyl]-3,5-di-O-benzyl-1,2-dide-

D

oxy-1-ethoxy-1-phospha-1-oxo-

2-[(2-Aza-3-methoxycarbonyl)propyl]-5-O-benzyl-1,2,3-trideoxy-1-

ethoxy-1-phospha-1-oxo- -glycero-pent-2-enofuranose (68): To a

D

-ribo-pentofuranose (67) and (R_P)-

stirred solution of 66 (24 mg, 0.062 mmol) in CHCl₃(2.1 mL) were

added Et₃N (86 μL, 0.62 mmol) and glycine methyl ester hydro-

chloride (77.8 mg, 0.62 mmol). The reaction mixture was heated at

reflux temperature under nitrogen for 10 days. The crude mixture

was diluted with CHCl₃, washed twice with water and the aqueous

phase was extracted twice with CHCl₃. The organic layer was dried

with Na₂SO₄and concentrated under reduced pressure to provide

a yellow oil. The residue was purified by Chromatotron chromatog-

raphy (CHCl₃/MeOH, 99:1) to give 66 (4.4 mg, 0.0113 mmol,

18%), 69β (2.5 mg, 0.0052 mmol, 8%), 69α (8 mg, 0.0167 mmol,

27%), and 70 (3.8 mg, 0.0103 mmol, 17%) as colorless oils.

D

stirred solution of 65 (20 mg, 0.052 mmol) in CHCl₃(1.7 mL) were

added Et₃N (72 μL, 0.52 mmol) and glycine methyl ester hydro-

chloride (65.3 mg, 0.52 mmol). The reaction mixture was heated at

reflux temperature under nitrogen for 4 days. The crude mixture

was diluted with CHCl₃, washed twice with water and the aqueous

phase was extracted twice with CHCl₃. The organic layer was dried

with Na₂SO₄and concentrated under reduced pressure to provide

a yellow oil. The residue was purified by Chromatotron chromatog-

raphy (CHCl₃/MeOH, 97:3) to give 65 (1.5 mg, 0.004 mmol, 7%),

67 (9.4 mg, 0.02 mmol, 38%) and 68 (6 mg, 0.016 mmol, 31%) as

colorless oils.

Compound 69α: [α]_D= +20.3 (c = 0.32, CHCl₃). ¹H NMR

2

(500 MHz, CDCl₃): δ = 1.35 (t, J = 7.2 Hz, 3 H), 2.52 (dddd, J_P,H

3

= 18.9, J = 7.6, 7.6, 6.6 Hz, 1 H), 2.93 (ddd, J_P,H= 12.0, J = 9.5,

Compound 67: [α]_D= –1.4 (c = 0.59, CHCl₃). ¹H NMR (500 MHz,

7.6 Hz, 1 H), 3.05 (ddd, J_P,H= 20.2, J = 12.3, 7.9 Hz, 1 H), 3.37

3

2

CDCl₃): δ = 1.31 (t, J = 7.1 Hz, 3 H), 2.49 (dddd, J_P,H= 20.3, J (d, J = 17.7 Hz, 1 H), 3.41 (d, J = 17.7 Hz, 1 H), 3.56 (ap. d, J =

3

= 8.9, 8.9, 6.3 Hz, 1 H), 2.84 (ddd, J_P,H= 12.3, J = 12.3, 8.8 Hz, 4.8 Hz, 2 H), 3.71 (s, 3 H), 4.20 (ddd, J_P,H= 26.2, J = 6.6, 2.5 Hz,

3

1 H), 3.06 (ddd, J_P,H= 24.9, J = 11.7, 6.3 Hz, 1 H), 3.37 (d, J =

1 H), 4.24 (m, 2 H), 4.41 (dddd, J_P,H= 11.4, J = 4.7, 4.7, 2.2 Hz,

4

17.3 Hz, 1 H), 3.45 (d, J = 17.3 Hz, 1 H), 3.58 (ddd, J_P,H= 1.6, J 1 H), 4.50 (d, J = 12.1 Hz, 1 H), 4.52 (d, J = 12.0 Hz, 1 H), 4.59

= 11.3, 4.1 Hz, 1 H), 3.68 (dd, J = 11.4, 3.1 Hz, 1 H), 3.73 (s, 3 (d, J = 12.0 Hz, 1 H), 4.60 (d, J = 12.1 Hz, 1 H), 7.30 (m, 10

3

H), 4.12 (ddd, J_P,H= 2.2, J = 9.5, 7.6 Hz, 1 H), 4.18–4.27 (m, 3

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 16.6 (d, J_{P, C}

=

1

H), 4.51 (d, J = 12.0 Hz, 1 H), 4.52 (d, J = 11.4 Hz, 1 H), 4.60 (d,

5.3 Hz, CH₃), 37.2 (d, J_{P, C}= 120.8 Hz, CH), 43.1 (CH₂), 50.6

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5051

D. Hernández-Guerra, M. S. Rodríguez, E. Suárez

FULL PAPER

(CH₂), 51.8 (CH₃), 63.4 (d, J_P,C= 7.4 Hz, CH₂), 69.9 (d, J_P,C

2

3

=

5.42–5.48 (m, 1 H), 5.54 (ddd, J_P,H= 13.9, J = 7.6, 2.8 Hz, 1 H),

2.1 Hz, CH₂), 72.0 (CH₂), 73.7 (CH₂), 77.2 (d, ²J_P,C= 5.3 Hz, CH), 7.45–7.56 (m, 6 H), 7.76–7.84 (m, 4 H), 8.10 (s, 1 H) ppm. ¹³C

2

80.7 (d, J_P,C= 6.4 Hz, CH), 127.8 (2ϫ CH), 127.84 (CH), 127.9 NMR (125.7 MHz, CDCl₃): δ = 13.8 (CH₃), 20.6 (CH₃), 20.7

(2ϫ CH), 128.0 (CH), 128.5 (4ϫ CH), 137.2 (C), 137.5 (C), 172.6

(CH₃), 22.0 (CH₂), 23.8 (CH₂), 29.3 (d, J_P,C= 7.4 Hz, CH₂), 31.7

(CH₂), 39.0 (d, J_P,C= 69.9 Hz, CH), 61.9 (CH₂), 68.4 (CH), 70.6

1

(C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 44.8 (s, 1 P) ppm. IR

(CHCl ): ν = 3004, 2360, 1739, 1244, 1208, 1034, 824 cm^–1. MS (d, ³J_P,C= 8.5 Hz, CH), 128.67 (d, ³J_P,C= 11.7 Hz, 2ϫ CH), 128.72

˜

3

(ESI⁺): m/z (%) = 478 (100) [M + H]⁺. HRMS (ESI⁺): m/z calcd.

for C₂₄H₃₃NO₇P [M + H]⁺478.1995; found 478.1992. C₂₄H₃₂NO₇P

(477.49): calcd. C 60.37, H 6.75, N 2.93; found C 60.35, H 6.80, N

2.79.

(d, J_P,C= 11.7 Hz, 2ϫ CH), 131.0 (d, J_P,C= 8.5 Hz, 4ϫ CH),

3

2

4

131.8 (d, J_P,C= 2.1 Hz, CH), 131.87 (d, J_{P, C}= 2.1 Hz, CH),

1

131.90 (d, J_P,C= 97.5 Hz, C), 132.1 (d, J_P,C= 96.4 Hz, C), 159.6

(CH), 169.3 (C), 170.5 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ

= 33.1 (1 P) ppm. IR (CHCl ): ν = 2962, 1735, 1229, 1170 cm^–1.

˜

3

Compound 69β: [α]_D= +3.7 (c = 0.46, CHCl₃). ¹H NMR (400 MHz,

MS (ESI⁺): m/z (%) = 511 (100) [M + Na]⁺. HRMS (ESI⁺): m/z

calcd. for C₂₆H₃₃NaO₇P [M + Na]⁺511.1862; found 511.1873.

C₂₆H₃₃O₇P (488.52): calcd. C 63.92, H 6.81; found C 64.18, H 6.52.

2

CDCl₃): δ = 1.34 (t, J = 7.2 Hz, 3 H), 2.34 (dddd, J_P,H= 19.0, J

= 6.9, 6.9, 6.9 Hz, 1 H), 2.93 (m, 2 H), 3.36 (d, J = 17.5 Hz, 1 H),

3.40 (d, J = 17.4 Hz, 1 H), 3.62 (ddd, ⁴J_P,H= 1.0, J = 11.0, 4.7 Hz,

1 H), 3.68 (dd, J = 11.5, 3.1 Hz, 1 H), 3.71 (s, 3 H), 4.11–4.23 (m,

4 H), 4.53 (d, J = 12.1 Hz, 1 H), 4.55 (d, J = 12.0 Hz, 1 H), 4.61

1

Compound 71b: Colorless oil; [α]_D= +31.2 (c = 1.14, CHCl₃). H

NMR (500 MHz, CDCl₃): δ = 0.77 (t, J = 7.3 Hz, 3 H), 1.05–1.17

(d, J = 12.0 Hz, 1 H), 4.62 (d, J = 12.1 Hz, 1 H), 7.23–7.35 (m, 10

(m, 5 H), 1.34–1.41 (m, 1 H), 1.60–1.70 (m, 2 H), 1.83 (s, 3 H),

3

H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 16.4 (d, J_{P, C}

=

2

1.95 (s, 3 H), 2.87 (dddd, J_P,H= 12.1, J = 8.0, 4.1, 4.1 Hz, 1 H),

1

5.3 Hz, CH₃), 40.7 (d, J_P,C= 118.7 Hz, CH), 46.8 (CH₂), 50.62

4.12 (dd, J = 12.3, 5.4 Hz, 1 H), 4.25 (dd, J = 12.5, 2.4 Hz, 1 H),

2

3

(CH₂), 51.8 (CH₃), 62.7 (d, J_P,C= 7.4 Hz, CH₂), 69.4 (d, J_P,C

=

5.40 (ddd, J_P,H= 11.7, J = 8.2, 3.5 Hz, 1 H), 5.50 (dddd, J = 8.0,

2

7.4 Hz, CH₂), 72.9 (CH₂), 73.6 (CH₂), 79.3 (d, J_P,C= 12.7 Hz,

CH), 80.7 (d, J_P,C= 3.2 Hz, CH), 127.8 (CH), 127.9 (2ϫ CH),

5.5, 2.4, 0.8 Hz, 1 H), 7.44–7.53 (m, 6 H), 7.81–7.90 (m, 4 H), 8.13

2

(s, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.8 (CH₃),

128.0 (2ϫ CH), 128.1 (CH), 128.4 (2ϫ CH), 128.5 (2ϫ CH), 137.4

(C), 137.7 (C), 172.3 (C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ =

41.9 (s, 1 P) ppm. IR (CHCl ): ν = 1740, 1015 cm^–1. MS (ESI⁺):

20.50 (CH₃), 20.54 (CH₃), 22.1 (CH₂), 25.1 (CH₂), 28.0 (d, J_P,C

=

1

8.5 Hz, CH₂), 31.3 (CH₂), 39.7 (d, J_P,C= 67.8 Hz, CH), 61.9

3

˜

3

(CH₂), 69.8 (CH), 70.4 (CH), 128.6 (d, J_P,C= 11.7 Hz, 2ϫ CH),

m/z (%) = 500 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for

3

2

128.6 (d, J_P,C= 11.7 Hz, 2ϫ CH), 131.0 (d, J_P,C= 8.5 Hz, 2ϫ

C₂₄H₃₂NNaO₇P [M + Na]⁺500.1814; found 500.1826.

2

4

CH), 131.1 (d, J_P,C= 8.5 Hz, 2ϫ CH), 131.6 (d, J_P,C= 2.1 Hz,

CH), 131.7 (d, J_P,C= 2.1 Hz, CH), 132.87 (d, J_P,C= 97.5 Hz, C),

4

1

Compound 70: [α]_D= –38.6 (c = 0.66, CHCl₃). ¹H NMR (500 MHz,

CDCl₃): δ = 1.34 (t, J = 6.9 Hz, 3 H), 3.44 (s, 2 H), 3.61 (m, 2 H),

3.61 (dd, J = 5.0, 10.4 Hz, 1 H), 3.68 (dd, J = 6.0, 10.4 Hz, 1 H),

3.73 (s, 3 H), 4.13–4.19 (m, 2 H), 4.58 (d, J = 12.0 Hz, 1 H), 4.61

1

132.85 (d, J_P,C= 96.4 Hz, C), 160.2 (CH), 169.8 (C), 170.5

(C) ppm. ³¹P NMR (161.9 MHz, CDCl₃): δ = 30.7 (1 P) ppm. IR

(CHCl ): ν = 2962, 1737, 1232, 1166 cm^–1. MS (ESI⁺): m/z (%) =

˜

3

511 (100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₆H₃₃NaO₇P

[M + Na]⁺511.1862; found 511.1870. C₂₆H₃₃O₇P (488.52): calcd.

C 63.92, H 6.81; found C 64.21, H 6.93.

3

(d, J = 12.0 Hz, 1 H), 4.94 (m, 1 H), 6.80 (br. d, J_P,H= 44.5 Hz,

1 H), 7.27–7.37 (m, 5 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

3

2

= 16.5 (d, J_P,C= 5.1 Hz, CH₃), 45.5 (d, J_P,C= 15.9 Hz, CH₂),

2

49.9 (CH₂), 51.9 (CH₃), 63.2 (d, J_P,C= 6.4 Hz, CH₂), 71.6 (CH₂),

73.8 (CH₂), 79.1 (d, J_P,C= 10.6 Hz, CH), 127.8 (2ϫ CH), 127.9

3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxyphosphoryl-4-O-formyl-1-C-

2

butyl-

D

-ribitol and 3,5-Di-O-benzyl-1,2-dideoxy-2-diethoxy-

-arabinitol (72ab): A solution of

1

(CH), 128.5 (2ϫ CH), 132.1 (d, J_P,C= 154.7 Hz, C), 137.5 (C),

phosphoryl-4-O-formyl-1-C-butyl-

D

2

141.7 (d, J_P,C= 22.3 Hz, CH), 172.49 (C) ppm. ³¹P NMR

61 (40.7 mg, 0.088 mmol) in freshly distilled tBuOH (4.4 mL) con-

taining nBu₃SnCl (110 μL, 0.4 mmol), sodium cyanoborohydride

(124.4 mg, 1.98 mmol), AIBN (130 mg, 0.792 mmol), and nBuBr

(140 μL, 1.32 mmol) was deoxygenated by saturation with argon

bubbling for 10 min and irradiated through Pyrex-filtered light

using a Hanovia 450 W medium-pressure mercury vapor lamp for

5 h. The mixture was concentrated under reduced pressure and the

residue was dissolved in CH₂Cl₂and washed with water. The sol-

vent was evaporated and the residue was redissolved in MeCN and

washed with n-hexane. The diastereomers were partially separated

by careful Chromatotron chromatography (benzene/EtOAc,

9:1Ǟ6:4) of the residue to give 72a (13.2 mg, 0.025 mmol, con-

taminated with ca. 19% of 72b) and 72b (9.8 mg, 0.019 mmol) in a

50% global yield.

(161.9 MHz, CDCl ): δ = 38.4 (s, 1 P) ppm. IR (CHCl ): ν = 1740,

˜

3

1119, 1022, 971 cm^–1. MS (ESI⁺): m/z (%) = 392 (100) [M + Na]⁺.

HRMS (ESI⁺): m/z calcd. for C₁₇H₂₄NNaO₆P [M + Na]⁺392.1239;

found 392.1247.

3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphosphoryl-4-O-formyl-1-C-

butyl-

D

-ribitol and 3,5-Di-O-acetyl-1,2-dideoxy-2-diphenylphos-

-arabinitol (71ab): A solution of 40

phoryl-4-O-formyl-1-C-butyl-

D

(50 mg, 0.116 mmol) in freshly distilled tBuOH (4.2 mL) containing

nBu₃SnCl (141 μL, 0.52 mmol), sodium cyanoborohydride

(164 mg, 2.6 mmol), AIBN (171.6 mg, 1.05 mmol), and nBuBr

(187 μL, 1.74 mmol) was deoxygenated by saturation with argon

bubbling for 10 min and irradiated through Pyrex-filtered light

using a Hanovia 450 W medium-pressure mercury vapor lamp for

3.5 h. The mixture was concentrated under reduced pressure and

the residue was dissolved in CH₂Cl₂and washed with water. The

solvent was evaporated and the residue was redissolved in MeCN

and washed with n-hexane. Chromatotron chromatography (hex-

anes/EtOAc, 4:6) of the residue gave 71a (16.8 mg, 0.034 mmol)

and 71b (13.7 mg, 0.028 mmol) in a 54% global yield.

Compound 72a: Colorless oil; [α]_D= +9.7 (c = 0.6, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 0.86 (t, J = 7.1 Hz, 3 H), 1.19–1.33

(m, 4 H), 1.28 (t, J = 6.3 Hz, 3 H), 1.30 (t, J = 6.9 Hz, 3 H), 1.34–

2

1.55 (m, 2 H), 1.66–1.82 (m, 2 H), 2.01 (dddd, J_P,H= 22.7, J =

7.9, 5.0, 3.2 Hz, 1 H), 3.71 (dd, J = 11.0, 5.0 Hz, 1 H), 3.74 (dd, J

3

= 11.0, 3.2 Hz, 1 H), 4.07–4.14 (m, 4 H), 4.25 (ddd, J_P,H= 13.0,

1

Compound 71a: Colorless oil; [α]_D= +33.4 (c = 1.21, CHCl₃). H J = 7.3, 3.0 Hz, 1 H), 4.48 (d, J = 12.0 Hz, 1 H), 4.54 (d, J =

NMR (500 MHz, CDCl₃): δ = 0.74 (t, J = 6.9 Hz, 3 H), 1.04–1.11

12.3 Hz, 1 H), 4.58 (d, J = 11.3 Hz, 1 H), 4.79 (d, J = 11.3 Hz, 1

(m, 5 H), 1.27–1.32 (m, 1 H), 1.74–1.78 (m, 2 H), 1.90 (s, 3 H), H), 5.27 (ddd, J = 7.4, 4.9, 3.2 Hz, 1 H), 7.26–7.35 (m, 10 H), 8.11

2

1.96 (s, 3 H), 2.59 (dddd, J_P,H= 10.7, J = 5.6, 5.6, 2.9 Hz, 1 H),

4.06 (dd, J = 12.5, 6.1 Hz, 1 H), 4.33 (dd, J = 12.3, 2.5 Hz, 1 H),

(s, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.0 (CH₃),

3

16.36 (d, J_P,C= 6.4 Hz, CH₃), 16.42 (d, ³J_P,C= 5.3 Hz, CH₃), 22.4

5052

www.eurjoc.org

Eur. J. Org. Chem. 2014, 5033–5055

Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals

vol. 33 (Ed.: G. A. Molander), Thieme, Stuttgart, Germany,

2006, p. 701–710. Selected representative examples: b) S. Ortial,

J.-L. Montchamp, Org. Lett. 2011, 13, 3134–3147; c) A. M.

González-Nogal, P. Cuadrado, M. A. Sarmentero, Tetrahedron

2010, 66, 9610–9619; d) N. A. Chernysheva, S. V. Yas’ko, N. K.

Gusarova, B. A. Trofimov, Mendeleev Commun. 2010, 20, 20–

21; e) S. Kawaguchi, S. Nagata, A. Nomoto, M. Sonoda, A.

Ogawa, J. Org. Chem. 2008, 73, 7928–7933; f) M. Oliana, F.

King, P. N. Horton, M. B. Hursthouse, K. K. Hii, J. Org.

Chem. 2006, 71, 2472–2479.

For C-radical addition to vinylphosphonates, see: a) K.

Descroix, G. K. Wagner, Org. Biomol. Chem. 2011, 9, 1885–

1863; b) R. S. Andrews, J. J. Becker, M. R. Gagné, Angew.

Chem. Int. Ed. 2010, 49, 7274–7276; Angew. Chem. 2010, 122,

7432–7434; c) A. Dickschat, A. Studer, Org. Lett. 2010, 12,

3972–3974; d) S. Vidal, I. Bruyère, A. Malleron, C. Augé, J.-P.

Praly, Bioorg. Med. Chem. 2006, 14, 7293–7301; e) L.-B. Han,

C.-Q. Zhao, J. Org. Chem. 2005, 70, 10121–10123; f) J.-P. Praly,

A. S. Ardakani, I. Bruyère, C. Marie-Luce, B. B. Qin, Car-

bohydr. Res. 2002, 337, 1623–1632; g) H.-D. Junker, N. Phung,

W.-D. Fessner, Tetrahedron Lett. 1999, 40, 7063–7066; h) H.-

D. Junker, W.-D. Fessner, Tetrahedron Lett. 1998, 39, 269–272;

i) D. H. R. Barton, S. D. Géro, B. Quiclet-Sire, M. Samadi,

Tetrahedron 1992, 48, 1627–1636. For C-radical addition to

vinylphosphine oxide, see: j) A. Brandi, S. Cicchi, A. Goti,

K. M. Pietrusiewicz, Tetrahedron Lett. 1991, 32, 3265–3268; k)

G. E. Keck, J. H. Jeffrey Byers, A. M. Tafesh, J. Org. Chem.

1988, 53, 1127–1128.

(CH₂), 24.0 (d, J_P,C= 3.2 Hz, CH₂), 28.5 (d, J_P,C= 5.3 Hz, CH₂),

32.0 (CH₂), 38.2 (d, ¹J_P,C= 138.8 Hz, CH), 61.69 (d, ²J_P,C= 7.4 Hz,

2

CH₂), 61.73 (d, J_P,C= 7.4 Hz, CH₂), 68.3 (CH₂), 72.9 (³J_P,C

=

11.7 Hz, CH), 73.2 (CH₂), 73.8 (CH₂), 75.6 (CH), 127.56 (CH),

127.67 (2ϫ CH), 127.70 (2ϫ CH), 127.72 (CH), 128.2 (2ϫ CH),

128.4 (2ϫ CH), 137.7 (C), 138.2 (C), 160.2 (CH) ppm. ³¹P NMR

(161.9 MHz, CDCl ): δ = 32.3 (1 P) ppm. IR (CHCl ): ν = 2931,

˜

3

1726, 1179, 1053, 1029 cm^–1. MS (ESI⁺): m/z (%) = 543 (100) [M

+ Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₈H₄₁NaO₇P [M + Na]⁺

543.2488; found 543.2486. C₂₈H₄₁O₇P (520.60): calcd. C 64.60, H

7.94; found C 64.79, H 7.64.

[3]

Compound 72b: Colorless oil; [α]_D= +2.3 (c = 0.47, CHCl₃). ¹H

NMR (500 MHz, CDCl₃): δ = 0.88 (t, J = 7.1 Hz, 3 H), 1.23 (t, J

= 7.1 Hz, 6 H), 1.25–1.34 (m, 4 H), 1.38–1.44 (m, 2 H), 1.56–1.68

(m, 1 H), 1.71–1.81 (m, 1 H), 2.15 (dddd, ²J_P,H= 22.7, J = 7.3, 6.0,

3.2 Hz, 1 H), 3.76 (dd, J = 11.0, 5.0 Hz, 1 H), 3.80 (dd, J = 11.0,

2.8 Hz, 1 H), 3.96–4.08 (m, 5 H), 4.50 (d, J = 12.0 Hz, 1 H), 4.56

(d, J = 12.0 Hz, 1 H), 4.59 (d, J = 11.0 Hz, 1 H), 4.65 (d, J =

11.0 Hz, 1 H), 5.43 (ddd, J = 7.5, 4.8, 2.8 Hz, 1 H), 7.25–7.37 (m,

10 H), 8.11 (s, 1 H) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.0

(CH₃), 16.43 (d, ³J_P,C= 6.4 Hz, 2ϫ CH₃), 22.4 (CH₂), 26.8 (d, ²J_P,C

= 3.2 Hz, CH₂), 27.8 (d, ³J_P,C= 8.5 Hz, CH₂), 31.6 (CH₂), 39.4 (d,

2

¹J_P,C= 138.8 Hz, CH), 61.3 (d, J_P,C= 6.4 Hz, CH₂), 61.6 (d, J_P,C

= 6.4 Hz, CH₂), 68.4 (CH₂), 73.3 (CH₂), 73.4 (CH), 74.4 (CH₂),

77.0 (d, ²J_P,C= 3.6 Hz, CH), 127.7 (4ϫ CH), 128.1 (2ϫ CH), 128.3

(2ϫ CH), 128.4 (2ϫ CH), 137.87 (C), 137.83 (C), 160.7 (CH) ppm.

³¹P NMR (161.9 MHz, CDCl₃): δ = 30.1 (1 P) ppm. IR (CHCl₃):

[4]

[5]

V. Shvchenko, R. Engel, Heteroat. Chem. 1998, 9, 495–502.

a) K. Kiyokawa, I. Suzuki, M. Yasuda, A. Baba, Eur. J. Org.

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Masojídkvá, D. T. Keough, J. Jersey, L. W. Guddat, Bioorg.

Med. Chem. 2009, 17, 6218–6232; c) P. Balczewski, W. M.

Pietrzykowski, Tetrahedron 1997, 53, 7291–7304.

a) C. Lai, C. Xi, W. Chen, R. Hua, Tetrahedron 2006, 62, 6295–

6302; b) C. Xi, M. Ma, X. Li, Chem. Commun. 2001, 2554–

2555.

ν = 2931, 1726, 1179, 1054, 1029 cm^–1. MS (ESI⁺): m/z (%) = 543

˜

(100) [M + Na]⁺. HRMS (ESI⁺): m/z calcd. for C₂₈H₄₁NaO₇P [M

+ Na]⁺543.2488; found 543.2492. C₂₈H₄₁O₇P (520.60): calcd. C

64.60, H 7.94; found C 64.65, H 7.88.

[6]

Supporting Information (see footnote on the first page of this arti-

cle): Copies of ¹H, ¹³C, and ³¹P NMR spectra for all new com-

pounds.

[7]

[8]

H. Takahashi, S. Inagaki, N. Yoshii, F. Gao, Y. Nishihara, K.

Takagi, J. Org. Chem. 2009, 74, 2794–2797.

a) A. Ferry, G. Malik, P. Retailleau, X. Guinchard, D. Crich,

J. Org. Chem. 2013, 78, 6858–6867; b) A. Ferry, X. Guinchard,

P. Retailleau, D. Crich, J. Am. Chem. Soc. 2012, 134, 12289–

12301; c) H.-J. Cristau, J. Monbrun, J. Schleiss, D. Virieux, J.-

L. Pirat, Tetrahedron Lett. 2005, 46, 3741–3744; d) P. Bisseret,

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Acknowledgments

This work was supported by the Ministerio de Economía y Compe-

titividad (Investigation Programs, grant numbers CTQ2010-18244

and CTQ2007-67492) and by the Gobierno de Canarias (grant

numbers SolSub20081000192 and ProID20100088). D.H.-G.

thanks the Ministerio de Economía y Competitividad for a fellow-

ship.

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Received: April 10, 2014

Published Online: July 11, 2014

Eur. J. Org. Chem. 2014, 5033–5055

www.eurjoc.org

5055

Article Doi

Fragmentation of carbohydrate anomeric alkoxyl radicals: Synthesis of chiral polyhydroxylated β-iodo- and alkenylorganophosphorus(V) compounds

DOI: 10.1002/ejoc.201402387

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Article abstract of DOI:10.1002/ejoc.201402387

Full text of DOI:10.1002/ejoc.201402387

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