Tuning the stereoselectivity in one-pot scission/addition processes: Synthesis of azanucleotide analogues from proline derivatives

Article abstract of DOI:10.1002/ejoc.201201443

The one-pot preparation of azanucleotide analogues from proline derivatives has been achieved by a sequential radical decarboxylation/phosphorylation process. The process proceeded under mild conditions, giving high yields of the nucleotide analogues. Remarkably, the stereoselectivity of the reaction can be controlled by using different oxygen and nitrogen substituents at C-4 to give preferentially either the 2,4-cis or 2,4-trans products. In this way, the diastereomeric cis/trans ratio can be shifted from 98:2 to 15:85. Copyright

Full text of DOI:10.1002/ejoc.201201443

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201443
Tuning the Stereoselectivity in One-Pot Scission/Addition Processes: Synthesis
of Azanucleotide Analogues from Proline Derivatives
Javier Miguélez-Ramos,[a] Venkateswara Rao Batchu,[a] and Alicia Boto*[a]
Keywords: Sequential processes / Synthetic methods / Substitution effects / Nucleotides / Amino acids / Diastereoselectivity
The one-pot preparation of azanucleotide analogues from
proline derivatives has been achieved by a sequential radical
decarboxylation/phosphorylation process. The process pro-
ceeded under mild conditions, giving high yields of the nu-
cleotide analogues. Remarkably, the stereoselectivity of the
reaction can be controlled by using different oxygen and ni-
trogen substituents at C-4 to give preferentially either the
2,4-cis or 2,4-trans products. In this way, the diastereomeric
cis/trans ratio can be shifted from 98:2 to 15:85.
Introduction
The stereochemistry of bioactive products often deter-
mines their bioactivity, and thus the development of the
asymmetric synthesis of these compounds has received con-
siderable attention.[1] In the area of antimicrobial nucleo-
side analogues,[2] we have recently reported the stereoselec-
tive synthesis of N-azanucleosides from 4-hydroxyproline
derivatives by a one-pot radical scission/oxidation/addition
of nitrogen bases process (Scheme 1, conversion 1Ǟ3).[3]
In this process the intermediate acyliminium ion 2 was
stabilized by electrostatic interactions between the pseu-
doaxial OR group and the iminium ion. The nitrogen base
added mainly from the inner face[4] to avoid eclipsing inter-
actions on the formation of the product and therefore the
2,4-cis-azanucleoside 3 was preferentially formed. Com-
pounds 3 displayed antifungal activity.[3]
Scheme 1. Synthesis of N-azanucleosides giving the 2,4-cis prod-
ucts.
We are currently preparing other azanucleoside deriva-
tives in which the nitrogen base occupies different positions
on the ring,[5] and comparing their antiviral and cytostatic
properties. In addition, azanucleoside phosphonates have
been developed because it is known that the initial phos-
phorylation of many nucleoside analogues, which is neces-
sary for bioactivity, is often inefficient in vivo.[6] The C–P
bond of phosphonates is much more stable than the O–P
bond of phosphates, providing superior resistance to in vivo
degradation.[7–10] Herein we report the stereoselective con-
version of proline derivatives 4 (Scheme 2) into new nucleo-
tide analogues 5[11] in which the phosphonate group is di-
rectly attached to the ring using a sequential decarboxyl-
ation/phosphorylation[11] reaction.
Moreover, we report that by using different 4-nitrogen
substituents (instead of OR groups), it is possible to control
the stereochemical outcome of the process to preferentially
give either the 2,4-cis or 2,4-trans products (conversion
4Ǟ5-cis or 4Ǟ5-trans). This remarkable shift in stereoselec-
tivity (from cis/trans Ͼ98:2 to 15:85), achieved on variation
of the nitrogen function, could be applied not only to the
synthesis of optically pure azanucleotides, but also to the
generation of alkaloids and other bioactive pyrrolidine-con-
taining compounds.
[a] Instituto de Productos Naturales y Agrobiología CSIC,
Avda. Astrofísico Fco. Sánchez 3, 38206 La Laguna, Tenerife,
Spain
Fax: +34-922-260135
E-mail: alicia@ipna.csic.es
Homepage: www.ipna.csic.es/en/dept/spn/sfcb/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201443.
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Azanucleotide Analogues from Proline Derivatives
carbon nucleophiles.[2,3] However, the situation changed
when nitrogen functions were used as substituents at the 4-
position. The nature of the nitrogen function determined
whether the final product was the 2,4-cis- or the 2,4-trans-
aminophosphonate. This remarkable effect and its synthetic
applications are reported below.
The substrates 4a–4e (Table 1) were prepared from N-
methoxycarbonyl-l-hydroxyproline according to previously
reported methods.[14–17] They were then subjected to the
scission/phosphorylation sequence as described above.
Table 1. Conversion of proline derivatives with nitrogen functions
at C-4 into azanucleotide analogues.
Scheme 2. Tuning the stereochemical outcome of the process.
Results and Discussion
The scission/phosphorylation reaction was studied first
with hydroxyproline derivative 6 (Scheme 3), which was pre-
pared from commercial l-hydroxyproline according to re-
ported procedures.[12] Because the nitrogen base was present
in the starting compound, it was important to check that
the conditions for oxidative scission or the addition of the
phosphorus reagent did not affect it. The scission was car-
ried out with (diacetoxyiodo)benzene and iodine in CH2Cl2
at room temperature under irradiation with visible light.
Then the reaction mixture was cooled to 0 °C and the phos-
phorus nucleophile and Lewis acid were added. The best
results for the phosphorylation reaction were obtained with
P(OMe)3 and boron trifluoride. Concomitant silyl ether
cleavage took place to afford product 7 in 54% yield.[13]
[a] Yields are given for products purified by chromatography.
Although substrate 4a (X = N3) gave exclusively the cis
product 5a (84%), the benzamido derivative 4b gave mainly
the trans isomer 5b (trans/cis 6:1, 86% global yield). For
the azide derivative, 5a-cis ([α]D = –8.5), NOESY analysis
showed spatial correlations between 3-Hb (δH = 2.47–
Scheme 3. First studies on the conversion of hydroxyproline deriva-
tive 6 into azanucleotide analogue 7.
With substrate 6, which presents an OR (silyl ether 2.59 ppm) and both 4-H (δH = 3.96–4.03 ppm) and 2-H (δH
group) at C-4, only the cis isomer was detected, both in the = 4.29 ppm), whereas no interactions were observed be-
crude reaction mixture and on careful screening of all the tween 3-Ha (δH = 2.23–2.35 ppm) and 2-H or 4-H.
fractions after chromatographic purification. We have re-
ported similar results for the oxidative decarboxylation of +20), the NOESY experiment displayed strong spatial cor-
other hydroxyproline derivatives/addition of nitrogen or relations between 4-H (δH = 4.82 ppm) and 3-Hb (δH
For the major benzamide derivative 5b-trans ([α]D =
=
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847

J. Miguélez-Ramos, V. R. Batchu, A. Boto
SHORT COMMUNICATION
2.64–2.73 ppm), and between 2-H (δH = 4.43 ppm) and 3- scope of this methodology. The influence of the ring sub-
Ha (δH = 2.18–2.31 ppm). In the case of the minor benz- stituents on other scission/addition processes is currently
amide derivative, 5b-cis ([α]D = –31), weak spatial interac- being studied and will be reported in due course.
tions for 2-H (δH = 4.41 ppm)/4-H (δH = 5.05 ppm), 3-Ha
(δH = 2.26 ppm)/2-H, and 3-Ha/2-H were observed, as well
Conclusions
as strong spatial correlations between 3-Hb (δH = 2.47–
1
2.60 ppm) and both 2-H and 4-H. In addition, in the H
We have developed a methodology to synthesize new nu-
cleotide analogues in which the phosphonate group is di-
rectly attached to the ring. This strategy uses proline deriva-
tives as substrates, which undergo a sequential decarboxyl-
ation/phosphorylation reaction. Remarkably, by using dif-
ferent nitrogen substituents at the 4-position, it is possible
to control the stereochemical outcome of the process to give
preferentially either the 2,4-cis (for 4-azido groups) or the
2,4-trans products (for 4-amido, sulfonamido, or nitrogen
base substituents). Thus, the stereoselectivity can be shifted
from cis/trans Ͼ98:2 to 15:85. The 4-azido-substituted
aminophosphonate can be transformed into other cis nu-
cleotide analogues with amido or other nitrogen functions
at C-4.
NMR spectra, the coupling constants for 3-Ha (dd, J =
12.4, 13.3 Hz) and 5-Ha (d, J = 12.1 Hz) are typical of 2,4-
cis-substituted pyrrolidine derivatives.[2,3]
The decarboxylation/phosphorylation of the sulfamide
4c and the phthalimide derivatives 4d also proceeded in
good global yields (95 and 81%, respectively) to give the
trans isomers as the major products. Interestingly, their
trans/cis ratios (dr 4:1 for the sulfamides 5c and 2:1 for the
phthalimides 5d)[18] were smaller than for the benzamides
5b (dr 6:1), as commented upon below.
In the case of the thymine derivative 4e, the scission/
phosphorylation sequence afforded 5e-trans as the major re-
action product (65%, trans/cis dr 2:1).[19] For 5b–5e, the
trans and cis isomers were readily separated by chromatog-
raphy, which is valuable for the study of structure–activity
relationships.
Experimental Section
These results suggest that the acyliminium intermediate
derived from 4a is stabilized by the azide group through
stereoelectronic effects, as shown in Scheme 1, to afford the
cis product. However, in the case of the acyliminium ions
derived from 4b–4e, steric effects predominate to give the
trans products. In addition, in some cases, the NHR group
could stabilize the iminium ion by formation of a cyclic
intermediate in which one of the faces is blocked. For exam-
ple, in the case of X = NHBz (substrate 4b), a 4-oxa-2,6-
diazabicyclo[3.2.1]oct-2-ene could be generated.[20] This ef-
fect could explain why the trans/cis ratio is superior with X
= NHBz than with the bulkier X = NHSO2Ar or phthal-
imido groups.
The differences in the stereochemical outcome of the re-
action can be used to obtain either the trans- or cis-amino-
phosphonates. For example, the scission/phosphorylation of
4b (X = NHBz) provided 5b-trans/5b-cis in a ratio of 85:15.
To obtain 5b-cis as the major isomer (Scheme 3), azide 5a-
cis (Scheme 4) was generated (84%, cis/trans dr Ͼ98:2) and
then reduced and acylated to give compound 5b-cis in 68%
yield with a minor amount (12%) of the epimerized product
5b-trans. The two isomers were readily separated.
General Methods: Melting points were determined with a hot-stage
apparatus. Optical rotations were measured at the sodium line at
ambient temperature (26 °C) in CHCl3 solutions. NMR spectra
1
were determined at 500 or 400 MHz for H NMR and at 125.7 or
100 MHz for 13C NMR in the presence of TMS as internal stan-
dard unless otherwise stated. 31P NMR spectra were determined at
161.9 MHz using CDCl3 as solvent and 85% H3PO4 as the external
reference (δP = 0 ppm). Mass spectra were determined at 70 eV. IR
spectra were carried out by using chloroform solutions of the prod-
ucts in 0.2 mm cells. Merck silica gel 60 PF254 and 60 (0.063–
0.2 mm) were used for preparative thin-layer chromatography and
column chromatography, respectively. All reactions involving air-
or moisture-sensitive materials were performed under nitrogen. The
optical rotations were measured with a Perkin-Elmer 241 Plus pola-
rimeter. The NMR spectra were recorded with Bruker Avance 400
or Bruker AMX 500 spectrometers. The IR and MS/HRMS spectra
were recorded with Perkin-Elmer 1600/FTIR and VG Micromass
Zab 2F spectrometers, respectively. The elemental analyses were
performed by using a Fisons analyser (model EA 1108 CHN).
Conversion of Hydroxyproline Derivative 6 into Aminophosphonate
7: (Diacetoxyiodo)benzene (DIB; 145 mg, 0.45 mmol) and iodine
(46 mg, 0.18 mmol) were added to a solution of the acid 6 (75 mg,
0.18 mmol) in dry dichloromethane (3 mL) and the solution was
irradiated with visible light (80 W tungsten filament lamp) with
stirring at 26 °C for 3 h under nitrogen. Then the mixture was co-
oled to 0 °C and trimethyl phosphite (110 μL, 0.93 mmol) and
BF3·OEt2 (30 μL, 0.24 mmol) were added. The mixture was al-
lowed to warm to 26 °C, stirred for 3 h, and then poured into a
mixture of saturated aqueous NaHCO3 (10 mL) and 10% aqueous
NaHS2O3 (10 mL). The mixture was extracted with dichlorometh-
ane, dried with anhydrous sodium sulfate, and the solvents evapo-
rated under vacuum. Purification was carried out by flash
chromatography (CH2Cl2/MeOH, 98:2) to give the aminophos-
phonate 7 (35 mg, 54%). Only the cis isomer was detected after
carefully checking the remaining fractions.
Scheme 4. Synthesis of the 2,4-cis product 5b-cis.
Moreover, the azide group could also be reduced and
attached to fluorescent tags or converted into either natural
Compound 7: Syrup. IR (CHCl ): ν = 3391, 1683, 1467, 1433 cm–1.
˜
3
or non-natural nitrogen bases, which would expand the 1H NMR (500 MHz, CD3OD, 26 °C) a 5:1 mixture of rotamers
848
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Azanucleotide Analogues from Proline Derivatives
was observed, only the major rotamer is described: δ = 1.88 (s, 3
356 (2) [M]+, 235 (27) [M – PhCONH2]+, 126 (100) [M –
H, Me), 2.21 (br. dd, J = 14.0, 15.2 Hz, 1 H, 3-Ha), 2.38–2.50 (m, PhCONH2 – P(O)(OMe)2]+, 105 (30) [PhCO]+. HRMS: calcd. for
1 H, 3-Hb), 3.46 (dd, J = 3.7, 10.8 Hz, 1 H, 5-Ha), 3.78 [d, J(H,P) C15H21N2O6P 356.1137; found 356.1150.
= 10.6 Hz, 6 H, P(O)OMe2], 3.95 (dd, J = 5.9, 10.9 Hz, 1 H, 5-
5b-cis: Syrup. [α]D = –31 (c = 0.37, CHCl ). IR (CHCl ): ν = 3306,
˜
3
3
Hb), 4.45–4.50 (m, 1 H, 4-H), 4.55 (d, J = 17 Hz, 1 H, COCHaN),
4.53–4.59 (m, 1 H, 2-H), 4.66 (d, J = 16.8 Hz, 1 H, COCHbN),
7.33 (s, 1 H, CH=) ppm. 13C NMR (125.7 MHz, CD3OD, 26 °C),
5:1 rotamer mixture, only the major rotamer is described: δC = 12.2
(CH3), 35.7 (CH2), 50.4 (CH2), 53.5 (d, JC,P = 161 Hz, CH), 53.6
(d, JC,P = 7.2 Hz, CH3), 54.8 ( d, JC,P = 6.8 Hz, CH3), 55.5 (CH2),
71.2 (CH), 111.0 (C), 143.6 (CH), 153.0 (C), 167.0 (C), 168.1
(C) ppm. 31P NMR (161.9 MHz, CDCl3): δP = 28.6 ppm. MS (EI,
70 eV): m/z (%) = 362 (28) [M + H]+, 168 (100) [ThyCH2CO]+.
HRMS: calcd. for C13H21N3O7P 362.1117; found 362.1106.
1701, 1652 cm–1. 1H NMR (500 MHz, CDCl3, 70 °C): δ = 2.26 (dd,
J = 12.4, 13.3 Hz, 1 H, 3-Ha), 2.47–2.60 (m, 1 H, 3-Hb), 3.48 (d, J
= 12.1 Hz, 1 H, 5-Ha), 3.75 (s, 3 H, OMe), 3.77 [d, JH,P = 10.5 Hz,
3 H, P(O)OMea], 3.83 [d, JH,P = 10.6 Hz, 3 H, P(O)OMeb], 3.96
(dd, J = 7.2, 11.5 Hz, 1 H, 5-Hb), 4.41 (dd, J = 5.7, 10.1 Hz, 1 H,
2-H), 5.05 (ddd, J = 7.6, 7.9, 8.2 Hz, 1 H, 4-H), 7.40–7.50 (m, 3 H,
Ar), 7.95 (d, J = 8.0 Hz, 2 H, Ar), 8.89 (br. signal, 1 H, NH) ppm.
13C NMR (125.7 MHz, 70 °C): δC = 33.9 (CH2), 48.3 (CH), 52.6
(d, JC,P = 7.4 Hz, CH3), 52.9 (CH3), 53.7 (d, JC,P = 163 Hz, CH),
54.3 (d, JC,P = 7.4 Hz, CH3), 55.0 (CH2), 127.3 (2 CH), 128.4 (2
CH), 131.2 (CH), 134.3 (C), 155.9 (C), 166.3 (C) ppm. 31P NMR
(161.9 MHz, CDCl3): δP = 27.3 ppm. MS (EI, 70 eV): m/z (%) =
357 (Ͻ1) [M + H]+, 235 (32) [M – PhCONH2]+, 126 (85) [M –
PhCONH2 – P(O)(OMe)2]+, 105 (100) [PhCO]+. HRMS: calcd. for
C15H22N2O6P 357.1216; found 357.1227.
General Procedure for the Conversion of 4-Substituted Prolines 4
into the Aminophosphonates 5: (Diacetoxyiodo)benzene (DIB;
322 mg, 1.0 mmol) and iodine (127 mg, 0.50 mmol) were added to
a solution of the acid 4 (0.50 mmol) in dry dichloromethane
(3.5 mL) and the solution was irradiated with visible light (80 W
tungsten filament lamp) with stirring at 26 °C for 3 h under nitro-
gen. Then the mixture was cooled to 0 °C and trimethyl phosphite
(295 μL, 2.5 mmol) and BF3·OEt2 (123 μL, 1 mmol) were added.
The mixture was allowed to warm to 26 °C, stirred for 4 h, and
then extracted as described before. Purification was carried out by
column chromatography (hexanes/EtOAc) to give the aminophos-
phonates 5.
Compounds 5c-trans and 5c-cis: Obtained from acid 4c (171 mg,
0.50 mmol) according to the general procedure. After purification
by column chromatography (from EtOAc/hexanes, 80:20, to
MeOH/CH2Cl2, 5:95), compounds 5b-trans (154 mg, 76%) and 5b-
cis (39 mg, 19%) were isolated.
1
5c-trans: Syrup. IR (CHCl ): ν = 3367, 1704, 1601 cm–1. H NMR
˜
3
(500 MHz, CDCl3, 70 °C): δ = 1.96–2.10 (m, 1 H, 3-Ha), 2.35–2.45
(m, 1 H, 3-Hb), 2.44 (s, 3 H, Ar-Me), 3.41 (br. dd, J = 5.4, 11.5 Hz,
1 H, 5-Ha), 3.54 (br. dd, J = 6.7, 11.4 Hz, 1 H, 5-Hb), 3.71 (s, 3 H,
Compound 5a-cis: Obtained from acid 4a (107 mg, 0.50 mmol) ac-
cording to the general procedure. After purification by column
chromatography (EtOAc/hexanes, 80:20) compound 5a-cis
OMe), 3.73 [d, JH,P = 10.6 Hz, 3 H, P(O)OMea], 3.75 [d, JH,P
=
(117 mg, 84%) was isolated as a syrup. [α]D = –8.5 (c = 0.18,
10.5 Hz, 3 H, P(O)OMeb], 4.12 (ddddd, J = 6.1, 6.2, 6.5, 6.7,
6.7 Hz, 1 H, 4-H), 4.29 (ddd, J = 4.2, 4.7, 9.4 Hz, 1 H, 2-H), 4.77
(br. d, J = 7.1 Hz, 1 H, NH), 7.31 (d, J = 8.5 Hz, 2 H, Ar), 7.76
1
CHCl ). IR (CHCl ): ν = 2110, 1705, 1456, 1393 cm–1. H NMR
˜
3
3
(500 MHz, CDCl3, 70 °C): δ = 2.23–2.35 (m, 1 H, 3-Ha), 2.47–2.59
(m, 1 H, 3-Hb), 3.21 (dd, J = 6.4, 10.7 Hz, 1 H, 5-Ha), 3.72 (s, 3
H, OMe), 3.77 [d, JH,P = 10.5 Hz, 3 H, P(O)OMea], 3.79 [d, JH,P
(d, J = 8.5 Hz, 2 H, Ar) ppm. 13C NMR (125.7 MHz, 70 °C): δC
=
21.4 (CH3), 34.2 (CH2), 52.1 (d, JC,P = 164.2 Hz, CH), 52.2 (CH),
= 10.6 Hz, 3 H, P(O)OMeb], 3.96–4.03 (m, 1 H, 4-H), 3.98–4.05 52.4 (CH2), 52.9 (CH3), 53.0 (d, JC,P = 6.4 Hz, CH3), 53.1 (d, JC,P
(m, 1 H, 5-Hb), 4.29 (ddd, J = 5.2, 5.5, 9.8 Hz, 1 H, 2-H) ppm. 13
C
= 7.4 Hz, CH3), 127.1 (2 CH), 129.8 (2 CH), 137.6 (CH), 143.7
(C), 155.3 (C) ppm. 31P NMR (161.9 MHz, CDCl3): δP = 27.3 ppm.
MS (EI, 70 eV): m/z (%) = 406 (1) [M]+, 297 (16) [M – P(O)-
(OMe)2]+, 126 (100) [M – PhSO2NH2 – P(O)(OMe)2]+. HRMS:
calcd. for C15H23N2O7PS 406.0964; found 406.0958.
NMR (125.7 MHz, CDCl3, 70 °C): δC = 32.5 (CH2), 51.0 (CH2),
52.1 (d, JC,P = 165 Hz, CH), 52.8 (CH3), 52.8 (d, JC,P = 7.1 Hz,
CH3), 53.1 (d, JC,P = 7.2 Hz, CH3), 58.2 (CH), 155.0 (C) ppm. 31P
NMR (161.9 MHz, CDCl3): δP = 27.1 ppm. MS (EI, 70 eV): m/z
(%) = 279 (7) [M + H]+, 236 (15) [M – HN3]+, 169 (100) [M –
HP(O)(OMe)2]+. HRMS: calcd. for C8H16N4O5P 279.0858; found
279.0862.
5c-cis: Syrup. IR (CHCl ): ν = 3178, 1704, 1600 cm–1. 1H NMR
˜
3
(500 MHz, CDCl3, 70 °C): δ = 2.02 (dd, J = 12.9, 13.1 Hz, 1 H, 3-
Ha), 2.20–2.35 (m, 1 H, 3-Hb), 2.42 (s, 3 H, Ar-Me), 3.28 (br. d, J
= 12.2 Hz, 1 H, 5-Ha), 3.70 (s, 3 H, OMe), 3.75 [d, JH,P = 10.6 Hz,
3 H, P(O)OMea], 3.78 [d, JH,P = 10.6 Hz, 3 H, P(O)OMeb], 3.80
(m, 1 H, 5-Hb), 4.15 (m, 1 H, 4-H), 4.25 (br. dd, J = 6.3, 8.8 Hz, 1
H, 2-H), 7.24 (br. d, J = 11.2 Hz, 1 H, NH), 7.25–7.31 (d, J =
8.5 Hz, 2 H, Ar), 7.76 (d, J = 8.3 Hz, 2 H, Ar) ppm. 13C NMR
(125.7 MHz, 70 °C): δC = 21.3 (CH3), 33.9 (CH2), 52.3 (CH), 52.7
(d, JC,P = 7.4 Hz, CH3), 52.9 (CH3), 53.0 (d, JC,P = 163.8 Hz, CH),
53.9 (CH2), 54.1 (d, JC,P = 7.3 Hz, CH3), 127.0 (2 CH), 129.6 (2
CH), 139.1 (C), 143.0 (C), 155.3 (C) ppm. 31P NMR (161.9 MHz,
CDCl3): δP = 27.6 ppm. MS (EI, 70 eV): m/z (%) = 407 (Ͻ1) [M +
Compounds 5b-trans and 5b-cis: Obtained from acid 4b (146 mg,
0.50 mmol) according to the general procedure. After purification
by column chromatography (from EtOAc/hexanes, 80:20, to
MeOH/CH2Cl2, 5:95), compounds 5b-trans (132 mg, 74%) and 5b-
cis (21 mg, 12%) were isolated.
5b-trans: Syrup. [α]D = +20 (c = 0.47, CHCl ). IR (CHCl ): ν =
˜
3
3
3436, 1705, 1666 cm–1. 1H NMR (500 MHz, CDCl3, 70 °C): δ =
2.18–2.31 (m, 1 H, 3-Ha), 2.64–2.73 (m, 1 H, 3-Hb), 3.63 (dd, J =
5.0, 11.4 Hz, 1 H, 5-Ha), 3.72 (s, 3 H, OMe), 3.74–3.83 (m, 1 H, 5-
Hb), 3.81 [d, JH,P = 10.5 Hz, 3 H, P(O)OMea], 3.82 [d, JH,P
=
H]+, 297 (22) [M – P(O)(OMe)2]+, 126 (100) [M – PhSO2NH2
–
10.5 Hz, 3 H, P(O)OMeb], 4.43 (ddd, J = 4.5, 4.5, 9.2 Hz, 1 H, 2-
H), 4.82 (ddddd, J = 4.8, 4.9, 5.1, 6.8, 6.8 Hz, 1 H, 4-H), 6.13 (br.
signal, 1 H, NH), 7.42 (dd, J = 7.5, 7.8 Hz, 2 H, Ar), 7.50 (dd, J
= 7.4, 7.5 Hz, 1 H, Ar), 7.72 (d, J = 7.1 Hz, 2 H, Ar) ppm. 13C
NMR (125.7 MHz, 70 °C): δC = 33.5 (CH2), 49.5 (CH), 52.3 (d,
P(O)(OMe)2]+. HRMS: calcd. for C15H24N2O7PS 407.1042; found
407.1033.
Compounds 5d-trans and 5d-cis: Obtained from acid 4d (159 mg,
0.50 mmol) according to the general procedure. After purification
by column chromatography (EtOAc/hexanes, 80:20), compounds
5d-trans (103 mg, 54%) and 5d-cis (52 mg, 27%) were isolated.
JC,P = 160.0 Hz, CH), 52.4 (CH2), 52.9 (CH3), 53.0 (d, JC,P
=
7.4 Hz, CH3), 53.1 (d, JC,P = 7.4 Hz, CH3), 126.9 (2 CH), 128.6 (2
CH), 131.6 (CH), 134.3 (C), 155.6 (C), 167.4 (C) ppm. 31P NMR 5d-trans: Crystalline solid, m.p. 144–146 °C (EtOAc/hexanes). IR
(161.9 MHz, CDCl3): δP = 28.4 ppm. MS (EI, 70 eV): m/z (%) = (CHCl ): ν = 1716, 1454 cm–1. 1H NMR (500 MHz, CDCl , 70 °C):
˜
3
3
Eur. J. Org. Chem. 2013, 846–852
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
849

J. Miguélez-Ramos, V. R. Batchu, A. Boto
SHORT COMMUNICATION
δ = 2.45–2.55 (m, 1 H, 3-Ha), 2.78–2.93 (m, 1 H, 3-Hb), 3.64–3.76 (C), 162.4 (C), 168.8 (C) ppm. MS (EI, 70 eV): m/z (%) = 465 (Ͻ1)
(m, 1 H, 5-Ha), 3.75 (s, 3 H, OMe), 3.80 [d, JH,P = 10.4 Hz, 3 H,
P(O)OMea], 3.81 [d, JH,P = 10.5 Hz, 3 H, P(O)OMeb], 3.97 (dd, J
= 6.9, 10.8 Hz, 1 H, 5-Hb), 4.61 (ddd, J = 2.8, 4.1, 10.0 Hz, 1 H,
2-H), 5.19 (ddd, J = 7.4, 7.4, 7.6 Hz, 1 H, 4-H), 7.65–7.74 (m, 2 H,
Ar), 7.78–7.85 (m, 2 H, Ar) ppm. 13C NMR (125.7 MHz, CDCl3,
[M]+, 434 (Ͻ1) [M – OMe]+, 360 (Ͻ1) [M – PhCO]+, 126 (100)
[M – thymine – P(O)(OMe)2]+, 105 (46) [PhCO]+. HRMS: calcd.
for C20H24N3O8P 465.1301; found 465.1316.
Conversion of Azide 5a-cis into Benzamide 5b-cis: A solution of the
azide 5a-cis (100 mg, 0.36 mmol), 10% Pd/C (50 mg), and dioxane
(5 mL) was stirred under hydrogen (1 atm) for 18 h and then fil-
tered through Celite (elution with CH2Cl2). The filtrate was evapo-
rated under vacuum and the residue was dissolved in dry pyridine
(5 mL). Then catalytic 4-(dimethylamino)pyridine (DMAP; 10 mg)
and benzoyl chloride (45 μL, 0.38 mmol) were added. The solution
was stirred overnight (18 h). The mixture was then diluted with
dichloromethane and washed with 10% aqueous HCl, saturated
aqueous NaHCO3, and finally brine. The organic layers were dried
with sodium sulfate and concentrated under vacuum. Purification
by column chromatography (CH2Cl2/MeOH, 98:2 to 95:5) afforded
the benzamide 5b-cis (87 mg, 68%) and some epimerized product
5b-trans (16 mg, 12%).
70 °C): δC = 30.1 (CH2), 48.8 (CH), 49.1 (CH2), 53.1 (d, JC,P
=
163 Hz, CH), 52.8 (CH3), 52.9 (d, JC,P = 6.4 Hz, CH3), 53.0 (d,
JC,P = 7.4 Hz, CH3), 123.3 (2 CH), 132.0 (2 C), 134.1 (2 CH),
155.4 (C), 167.6 (2 C) ppm. 31P NMR (161.9 MHz, CDCl3): δP
=
27.7 ppm. MS (EI, 70 eV): m/z (%) = 382 (12) [M]+, 273 (61) [M –
P(O)(OMe)2]+, 126 (100) [M – phthalimide – P(O)(OMe)2]+.
HRMS: calcd. for C16H19N2O7P 382.0930; found 382.0939.
5d-cis: Crystalline solid, m.p. 132–134 °C (EtOAc/hexanes). IR
(CHCl ): ν = 3010, 1776, 1715, 1451 cm–1. 1H NMR (500 MHz,
˜
3
CDCl3, 70 °C): δ = 2.49–2.63 (m, 1 H, 3-Ha), 2.93–3.11 (m, 1 H,
3-Hb), 3.76 (s, 3 H, OMe), 3.84 [d, JH,P = 10.5 Hz, 3 H, P(O)OMea],
3.89 [d, JH,P = 10.5 Hz, 3 H, P(O)OMeb], 3.91 (dd, J = 10.8,
10.8 Hz, 1 H, 5-Ha), 4.07 (dd, J = 7.5, 10.5 Hz, 1 H, 5-Hb), 4.37
(ddd, J = 4.5, 9.0, 9.0 Hz, 1 H, 2-H), 4.56–4.64 (m, 1 H, 4-H),
7.66–7.75 (m, 2 H, Ar), 7.79–7.86 (m, 2 H, Ar) ppm. 13C NMR
(125.7 MHz, 70 °C): δC = 28.9 (CH2), 47.0 (CH2), 48.5 (CH), 51.6
(d, JC,P = 163 Hz, CH), 52.9 (CH3), 53.0 (d, JC,P = 7.4 Hz, CH3),
53.1 (d, JC,P = 6.5 Hz, CH3), 123.4 (2 CH), 132.0 (2 C), 134.2 (2
CH), 155.6 (C), 167.8 (2 C) ppm. MS (EI, 70 eV): m/z (%) = 383
(3) [M + H]+, 273 (26) [M – P(O)(OMe)2]+, 126 (100) [M – phthal-
imide – P(O)(OMe)2]+. HRMS: calcd. for C16H20N2O7P 382.0930;
found 382.0939.
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra for compounds 5a–e and 7, NOESY
experiments for 5a-cis, 5b-trans/cis, and 5c-trans/cis, 5d-trans/cis, 5e-
trans/cis, and 31P NMR spectra for compounds 7, 5a-cis, 5b-trans/
cis, 5c-trans/cis, 5d-trans, and 5e-trans.
Acknowledgments
This work was supported by the Spanish Plan Nacional de In-
vestigación Científica, Desarrollo e Innovación Tecnológica, Minis-
terio de Ciencia e Innovación (currently Economía y Competitivi-
dad; Research Program CTQ2009-07109). The authors also
acknowledge financial support from the European Funds for Re-
gional Development (FEDER). J. M. R. and V. R. B. thank the
Consejo Superior de Investigaciones Científicas (CSIC) for a JAE
Compounds 5e-trans and 5e-cis: Obtained from acid 4e (201 mg,
0.50 mmol) according to the general procedure. After purification
by column chromatography (from MeOH/CH2Cl2, 1:99, to MeOH/
CH2Cl2, 5:95), compounds 5e-trans (103 mg, 44%) and 5e-cis
(49 mg, 21%) were isolated.
1
5e-trans: Syrup. IR (CHCl ): ν = 1753, 1705, 1664, 1454 cm–1. H predoctoral fellowship and a postdoctoral contract, respectively.
˜
3
NMR (500 MHz, CDCl3, 70 °C): δ = 1.93 (s, 3 H, Thy-Me), 2.51–
2.60 (m, 2 H, 3-H2), 3.72 (s, 3 H, OMe), 3.76 [d, JH,P = 10.4 Hz, 3
H, P(O)OMea], 3.78 [d, JH,P = 10.0 Hz, 3 H, P(O)OMeb], 3.70–
demic Press, Oxford, UK, 2002; b) J. Seyden-Penne, Chiral
[1] a) G. Roos, Compendium of Chiral Auxiliary Applications, Aca-
3.83 (m, 2 H, 5-H2), 4.46–4.54 (m, 1 H, 2-H), 5.20–5.30 (m, 1 H,
4-H), 7.04 (s, 1 H, CH=), 7.48 (dd, J = 7.6, 8.2 Hz, 2 H, Ar), 7.63
(dd, J = 7.5, 7.5 Hz, 1 H, Ar), 7.88 (d, J = 8.5 Hz, 2 H, Ar) ppm.
13C NMR (125.7 MHz, 70 °C): δC = 12.3 (CH3), 31.3 (CH2), 49.3
(CH2), 52.5 (d, JC,P = 163 Hz, CH), 52.98 (d, JC,P = 6.3 Hz, CH3),
53.00 (CH3), 53.3 (d, JC,P = 7.3 Hz, CH3), 56.7 (CH), 111.8 (C),
129.1 (2 CH), 130.3 (2 C), 132.0 (C), 134.8 (CH), 136.9 (CH), 149.7
(C), 155.0 (C), 162.4 (C), 168.5 (C) ppm. 31P NMR (161.9 MHz,
CDCl3): δP = 26.2 ppm. MS (EI, 70 eV): m/z (%) = 465 (Ͻ1)
[M]+, 434 (2) [M – OMe]+, 360 (Ͻ1) [M – PhCO]+, 126 (100) [M –
thymine – P(O)(OMe)2]+, 105 (67) [PhCO]+. HRMS: calcd. for
C20H24N3O8P 465.1301; found 465.1294.
Auxiliaries and Ligands in Asymmetric Synthesis, Wiley, New
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5e-cis: Syrup. IR (CHCl ): ν = 3016, 1749, 1700, 1659 cm–1. 1H
˜
3
NMR (500 MHz, CDCl3, 70 °C): δ = 2.01 (s, 3 H, Thy-Me), 2.25–
2.35 (m, 1 H, 3-Ha), 2.73–2.85 (m, 1 H, 3-Hb), 3.42 (dd, J = 9.6,
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(d, JC,P = 165.1 Hz, CH), 51.6 (CH), 52.8 (d, JC,P = 7.2 Hz, CH3),
53.2 (CH3), 53.9 (d, JC,P = 7.3 Hz, CH3), 112.3 (C), 129.1 (2 CH),
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 846–852

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1
a) The H NMR and NOESY experiments on the sulfonamide
[9]
derivatives 5c-trans and 5c-cis were very similar to those of the
related benzamide derivatives 5b and hence the stereochemical
assignments were straightforward; b) in the case of the phthal-
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correlations 3-Hb (δH = 2.93–3.11 ppm)/2-H and 3-Hb/4-H
were observed.
For the thymine derivatives 5e, the stereochemical assignments
were confirmed by NOESY experiments. For the major isomer
5e-trans, the NOESY experiment was not significant. However,
in the case of the minor isomer 5d-cis, weak spatial interactions
2-H (δH = 4.46 ppm)/4-H (δH = 5.29 ppm), 3-Ha (δH = 2.25–
2.35 ppm)/2-H and 3-Ha/2-H and strong spatial correlations 3-
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Eur. J. Org. Chem. 2013, 846–852
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851

J. Miguélez-Ramos, V. R. Batchu, A. Boto
SHORT COMMUNICATION
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Received: October 29, 2012
Published Online: January 15, 2013
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Eur. J. Org. Chem. 2013, 846–852