One-pot synthesis of α-amino phosphonates from α-amino acids and β-amino alcohols

Article abstract of DOI:10.1016/j.tetlet.2005.09.019

The one-pot radical fragmentation-phosphorylation reaction of α-amino acids and β-amino alcohols affords α-amino phosphonates in good yields. The reaction was applied to the synthesis of potentially bioactive phosphonates.

Full text of DOI:10.1016/j.tetlet.2005.09.019

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7807–7811
One-pot synthesis of a-amino phosphonates from
a-amino acids and b-amino alcohols
*
*
´
Alicia Boto, Juan Antonio Gallardo, Rosendo Hernandez and Carlos Javier Saavedra
Instituto de Productos Naturales y Agrobiologı´a del C.S.I.C., Avda. Astrofı´sico Fco. Sa´nchez 3, 38206-La Laguna, Tenerife, Spain
Received 25 July 2005; revised 1 September 2005; accepted 6 September 2005
Available online 22 September 2005
Abstract—The one-pot radical fragmentation–phosphorylation reaction of a-amino acids and b-amino alcohols affords a-amino
phosphonates in good yields. The reaction was applied to the synthesis of potentially bioactive phosphonates.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The a-amino phosphonates are amino acid analogues,
which have elicited considerable attention due to their
interesting biological properties.1 For instance, the leu-
cine surrogate 1 (Fig. 1) is a potent inhibitor of leucine
aminopeptidase.2 The proline analogue 2 is an angioten-
sin inhibitor, useful as an antihypertensive agent.3 The
amino phosphonate 3 possesses herbicidal activity.4
Other amino phosphonates are promising antitumoural,
fungicidal, antibacterial and antiviral agents.1–4 As a
result, different synthetic methodologies to obtain these
compounds have been developed.1
We report now on a mild and efficient preparation of
these compounds from b-amino alcohols and a-amino
acid derivatives, using a sequential fragmentation–phos-
phorylation reaction (Scheme 1).
It is known that on treatment with PhI(OAc)2–I2, the
b-amino alcohol derivatives 4a (X = H,H) generate an
Scheme 1. Proposed one-pot radical fragmentation–phosphorylation
for the synthesis of a-amino phosphonates.
alkoxyl radical 5a, while the amino acids 4b (X = O)
generate a carboxyl radical 5b.5 These O-radicals were
expected to undergo a radical b-fragmentation to afford
a C-radical 6,5,6 which would be oxidized in the reaction
medium to an N-acyliminium ion 7.6 This intermediate
could be trapped by phosphorous nucleophiles, namely
dimethyl phosphonate or trialkylphosphites, to afford
Figure 1. Bioactive a-amino phosphonates.
a-amino phosphonates 8.
To explore the feasibility and scope of this reaction, sev-
Keywords: Amino acids; Amino phosphonates; Radicals; Fragmenta-
eral amino alcohol and amino acid derivatives 9–15 were
prepared in a few steps from commercial products, using
standard methodologies.
tion; Decarboxylation; Hypervalent iodine reagents.
*
Corresponding authors. Tel.: +34 922 260112; fax: +34 922 260135;
e-mail addresses: alicia@ipna.csic.es; rhernandez@ipna.csic.es
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.019

7808
A. Boto et al. / Tetrahedron Letters 46 (2005) 7807–7811
Table 1. One-pot b-fragmentation–phosphorylation reactiona
Entry
Substrate
Conditionsb
Products (%)c
1
2
3
4
5
6
7
8
9
10
9
A
B
C
D
D
D
D
D
D
D
16 (64)
16 (62)
16 (26), 17 (27)
16 (4), 17 (64)
17 (86)
18 (81)
19 (85)
20 (67)
21b (89)
22 (26)
9
9
9
10
11
12
13
14
15
a General procedure: The substrate (1 mmol) in dry dichloromethane
(15 ml) was treated with DIB (2.5 mmol) and iodine (1 mmol) and
irradiated with visible light (sunlight, or a 100 W tungsten-filament
lamp). The reaction mixture was stirred at room temperature under
nitrogen until no starting material was observed by TLC analysis
(about 3 h). Then it was cooled to 0 ꢁC and the Lewis acid (BF3ÆOEt2
or TMSOTf, 2 equiv) and the nucleophile [HP(O)(OMe)2 or
P(OMe)3, 5 equiv] were added. The reaction was allowed to reach rt
and stirred for 4 h, and afterwards it was poured into aqueous
NaHCO3–10% Na2S2O3 and extracted with CH2Cl2.
b Condition A: TMSOTf as Lewis acid and HP(O)(OMe)2 as nucleo-
phile. Condition B: BF3ÆOEt2 as Lewis acid and HP(O)(OMe)2 as
nucleophile. Condition C: TMSOTf as Lewis acid and P(OMe)3 as
nucleophile. Condition D: BF3ÆOEt2 as Lewis acid and P(OMe)3 as
nucleophile.
c Yields are given for products purified by chromatography on silica
gel.
The sequential fragmentation–phosphorylation was
studied first with substrate 9 (Table 1, entries 1–4),
which was treated with DIB–I2 and irradiated with vis-
ible light to carry out the fragmentation. Once this step
was completed, a Lewis acid (TMSOTf or BF3ÆOEt2)7
and the nucleophile [HP(O)(OMe)2 or P(OMe)3] were
added.8
When dimethyl phosphonate was used as nucleophile
(entries 1 and 2), no phosphonates were obtained, and
the 2-hydroxypyrrolidine 166g,7 was isolated instead.
This result implies that this nucleophile was not reactive
enough to trap the N-acyliminium intermediate, which
therefore reacted with water during the work-up. How-
ever, by using P(OMe)3 as nucleophile (entries 3 and 4)
the desired a-amino phosphonate 179b was obtained as
the major product.
The fragmentation of the amino acid analogue 10
(Scheme 2) was studied next (entry 5) in order to deter-
mine whether the reaction results improved by using
amino acids as substrates.10 The one-pot fragmenta-
tion–phosphorylation proceeded in good yield, afford-
ing the amino phosphonate 17. The decarboxylation–
phosphorylation of proline methyl carbamate 11
(entry 6) also proceeded in good yield, affording prod-
uct 18.
Scheme 2. Reagents and conditions: (i) DIB, I2, hm; then 0 ꢁC,
TMSOTf, HP(O)(OMe)2; (ii) DIB, I2, hm; then 0 ꢁC, BF3ÆOEt2,
HP(O)(OMe)2; (iii) DIB, I2, hm; then 0 ꢁC, TMSOTf, P(OMe)3; (iv)
DIB, I2, hm; then 0 ꢁC, BF3ÆOEt2, P(OMe)3. See Table 1 for product
yields.
When the piperazic acid derivative 12 was used as sub-
strate (entry 7), the reaction gave the desired phospho-
nate 19 in very good yield.11 The same occurred with
the fragmentation of the unnatural amino acid 13
(entry 8), which afforded the phosphonate analogue
20.12
The fragmentation of the lysine derivative 14 (entry 8)
surprisingly gave the pipecolinic acid surrogate 21b13a
in good yields. This result can be explained via an inter-
mediate 21a, formed by addition of the e-carbamate

A. Boto et al. / Tetrahedron Letters 46 (2005) 7807–7811
7809
Scheme 4. Use of precursors from the chiral pool to obtain function-
alized amino phosphonates. Reagents and conditions: (i) DIB
(2.5 mmol), I2 (1 mmol), rt, sunlight, 3 h; then 0 ꢁC, P(OMe)3 (5 equiv)
and BF3ÆOEt2 (2 equiv); 27 (40%) and 28 (26%).
Scheme 3. Use of precursors from the chiral pool to obtain function-
alized amino phosphonates. Reagents and conditions: (i) DIB
(2.5 mmol), I2 (1 mmol), rt, sunlight, 3 h; then 0 ꢁC, P(OMe)3 (5 equiv)
and BF3ÆOEt2 (2 equiv); 24 (64%) and 25 (15%).
pounds 17–22, 24, 25 and 27, 28, is currently under
study and will be reported in due course.
group to the initial N-acyliminium ion.13b On treatment
with the Lewis acid, 21a generated a cyclic acyliminium
ion, which was trapped by the phosphorous nucleophile
to afford 21b.
Acknowledgements
The fragmentation–phosphorylation of the amino acid
15 (entry 9) posed a challenge since a quaternary centre
would be formed. However, the reaction proceeded in
low yield, generating the interesting a,a-disubstituted
amino phosphonate 22.14
This work was supported by the Research Programme
´
PPQ2003-01379 of the Plan Nacional de Investigacion
´
´
´
Cientıfica, Desarrollo e Innovacion Tecnologica, Minis-
´
´
terios de Ciencia y Tecnologıa y de Educacion y Ciencia,
Spain. We also acknowledge financial support from
FEDER funds. We are especially indebted to FAES
FARMA S.A. for a contract to J.A.G. and a fellowship
to C.J.S.
The sequential decarboxylation–phosphorylation reac-
tion was also studied with substrates bearing stereogenic
centres next to the reacting centre. For instance, when
the (4R)-acetoxyproline derivative 23 (Scheme 3) was
treated with DIB–iodine and then with BF3ÆOEt2 and
P(OMe)3, the amino phosphonate 2415a,16a and its 2-epi-
mer 2515b,16b were obtained in 64% and 15% yield,
respectively (79% overall yield).
References and notes
1. Reviews about a-amino phosphonates: (a) Moonen, K.;
Laureyn, I.; Stevens, C. V. Chem. Rev. 2004, 104, 6177–
6251; (b) Aminophosphonic and Aminophosphinic Acids:
Chemistry and Biological Activity; Kukhar, V. P., Hudson,
H. R., Eds.; John Wiley: Chichester, 2000; (c) Gro¨ger, H.;
Hammer, B. Chem. Eur. J. 2000, 6, 943–948; (d) Field, S.
C. Tetrahedron 1999, 55, 12237–12273; (e) Hildebrand, R.
L. The Role of Phosphonates in Living Systems; CRC:
The carbohydrate pool can also provide a variety of pre-
cursors. For instance, the substrate 26 (Scheme 4) was
obtained in two steps from commercial 2-acetamide D-
glucopyranose.
´
Boca Raton, FL, 1982; For related b-amino phospho-
The fragmentation of the alkoxyl radical derived from
26, followed by phosphorylation with BF3ÆOEt2 and
P(OMe)3, afforded a separable 3:2 mixture of the poly-
hydroxylated products 2717a and 2817b in 66% global
yield. Since in this case the reaction proceeded via an
acyclic acyliminium ion, a low diastereoselectivity was
observed.18 However, the use of differently protected,
more rigid carbohydrate substrates, should increase
the stereocontrol.19 As shown in this example, the frag-
mentation–phosphorylation of precursors from the
chiral pool can allow the synthesis of highly functional-
ized amino phosphonates.
nates, see: (f) Palacios, F.; Alonso, C.; de los Santos, J. M.
Chem. Rev. 2005, 105, 899–931.
2. Drag, M.; Grembecka, J.; Pawelczak, M.; Kafarski, P.
Eur. J. Med. Chem. 2005, 40, 764–771.
3. Petrillo, E. W. U.S. Patent 4,186,268, 1980; Chem. Abstr.
1980, 93, 8008.
4. Moore, J. D.; Sprott, K. T.; Hanson, P. R. J. Org. Chem.
2002, 67, 8123–8129, and references cited therein.
5. For recent reviews on the generation of alkoxyl radicals
and their b-fragmentation, see: (a) Hartung, J.; Gottwald,
T.; Spehar, K. Synthesis 2002, 1469–1498; (b) Zhdankin,
V.; Stang, P. J. Chem. Rev. 2002, 102, 2523–2584; (c)
Togo, H.; Katohgi, M. Synlett 2001, 565–581; (d) Zhang,
W. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 234–245;
In summary, the one-pot fragmentation–phosphoryl-
ation reaction is a versatile and efficient pathway to
obtain many different amino phosphonates from readily
available precursors. The biological activity of com-
´
´
(e) Suarez, E.; Rodrıguez, M. S. In Radicals in Organic
Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; Vol. 2, pp 440–454; (f) McCarroll, A. J.;

7810
A. Boto et al. / Tetrahedron Letters 46 (2005) 7807–7811
Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224–2248;
(g) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271–1287; (h)
Yet, L. Tetrahedron 1999, 55, 9349–9403.
sumura, Y.; Tsubata, K. Tetrahedron Lett. 1981, 22, 3249–
3252.
1
13. (a) Compound 21b: H NMR (500 MHz) d 4.55 (1H, dd,
J = 6.3 Hz, JH,P = 17.4 Hz), 3.95 (1H, d, J = 12.8 Hz),
3.65 (3H, d, JH,P = 10.5 Hz), 3.64 (3H, d, JH,P = 10.6 Hz),
3.61 (3H, s), 3.14 (1H, ddd, J = 2.6, 13.1, 13.3 Hz), 1.96
(1H, m), 1.81 (1H, m), 1.64 (1H, m), 1.55 (2H, m), 1.29
(1H, m); 13C NMR (125.7 MHz): d 155.9 (C), 52.6 (CH3),
52.4 (CH3, d, JC,P = 6.9 Hz), 52.1 (CH3, d, JC,P = 7.1 Hz),
48.2 (CH, d, JC,P = 152.0 Hz), 41.5 (CH2), 25.0 (CH2),
24.5 (CH2), 20.0 (CH2); MS (EI, 70 eV), m/z: 251 (M+, 8),
143 (30), 142 (100); HRMS: calcd for C9H18NO5P
251.0923, found 251.0935. For a similar result, see: (b)
6. Oxidation of the C-radical to an N-acyliminium ion: (a)
´
´
Boto, A.; Hernandez, R.; de Leon, Y.; Gallardo, J. A. Eur.
J. Org. Chem. 2005, 3461; (b) Iglesias-Arteaga, M. A.;
Juaristi, E.; Gonzalez, F. J. Tetrahedron 2004, 60, 3605–
´
´
3610; (c) Boto, A.; Hernandez, R.; Montoya, A.; Suarez,
E. Tetrahedron Lett. 2004, 45, 1559–1563; (d) Iglesias-
Arteaga, M. A.; Castellanos, E.; Juaristi, E. Tetrahedron:
´
Asymmetry 2003, 14, 577–580; (e) Boto, A.; Hernandez,
´
R.; Montoya, A.; Suarez, E. Tetrahedron Lett. 2002, 43,
8269–8272; (f) Iglesias-Arteaga, M. A.; Avila-Ortiz, C. G.;
´
´
Juaristi, E. Tetrahedron Lett. 2002, 43, 5297–5300; (g)
Boto, A.; Hernandez, R.; Suarez, E. Tetrahedron Lett.
´
´
´
Boto, A.; Hernandez, R.; Leon, Y.; Suarez, E. J. Org.
1999, 40, 5945–5948.
Chem. 2001, 65, 7796–7803; (h) Boto, A.; Hernandez, R.;
Suarez, E. Tetrahedron Lett. 2000, 41, 2495–2498, and
references cited therein.
14. Compound 22: 1H NMR (500 MHz) d 4.47 (1H, br b,
NH), 3.77 (6H, d, JH,P = 10.5 Hz), 3.64 (3H, s), 2.33 (2H,
m), 1.76 (2H, dddd, J = 3.9, 4.0, 13.1, 13.3 Hz), 1.67–1.55
(2H, m), 1.49 (2H, m), 1.27 (2H, m); 13C NMR
(125.7 MHz): d 155.3 (C), 55.9 (C, d, JC,P = 160 Hz),
53.1 (2·CH3, d, JC,P = 7.2 Hz), 51.6 (CH3), 30.0 (2·CH2),
25.1 (CH2), 20.4 (CH2), 20.2 (CH2); MS (EI, 70 eV), m/z:
266 (M++H, 1), 265 (M+, 1), 234 (2), 191 (3), 156 (100);
HRMS: calcd for C10H20NO5P 265.1079, found 265.1089.
15. (a) Compound 24: 1H NMR (500 MHz, 26 ꢁC) d 5.10 (1H,
m), 4.48 (1H, m), 3.89 (1H, dd, J = 6.5, 11.5 Hz), 3.71
(3H, d, JH,P = 10.7 Hz), 3.70 (3H, d, JH,P = 10.6 Hz), 3.45
(1H, dd, J = 4.7, 11.5 Hz), 2.5–2.3 (2H, m), 2.00 (3H, s),
1.99 (3H, s); 1H NMR (400 MHz, C6D6, 26 ꢁC) d 4.80
(1H, m), 4.53 (1H, m), 3.74 (3H, d, JH,P = 10.8 Hz), 3.57
(3H, d, JH,P = 10.5 Hz), 3.33 (2H, m), 2.46 (1H, m), 1.93
(1H, m), 1.82 (3H, s), 1.68 (3H, s); 13C NMR (125.7 MHz,
26 ꢁC): d 170.5 (C), 168.9 (C), 71.8 (CH), 53.2 (CH3, d,
JC,P = 6.8 Hz), 52.6 (CH3, d, JC,P = 6.3 Hz), 52.6 (CH2),
50.7 (CH, d, JC,P = 160 Hz), 31.9 (CH2), 22.0 (CH3), 20.8
(CH3); MS (EI, 70 eV), m/z: 280 (M++H, 2), 219 (M+, 20),
110 (90), 109 (3), 68 (100); HRMS: calcd for C10H19NO6P
280.0950, found 280.0947; (b) The spectroscopic data of
compound 25 were very similar, the main differences being
observed in the 1H NMR spectrum (500 MHz, 26 ꢁC) d
5.36 (1H, m), 4.73 (1H, m), 3.83 (1H, m), 3.78 (6H, d,
JH,P = 10.3 Hz), 3.60 (1H, m), 2.61 (1H, m), 2.23 (1H, m),
2.09 (3H, m), 2.01 (3H, s).
´
´
7. For a discussion of the role of the Lewis acid in similar
´
´
reactions, see: Boto, A.; Hernandez, R.; Suarez, E. J. Org.
Chem. 2000, 64, 4930–4937, and references cited therein.
8. For examples of addition of phosphorous nucleophiles to
imines and iminium ions, see Ref. 1a and also: (a)
Kaboudin, B.; Moradi, K. Tetrahedron Lett. 2005, 46,
2989–2991; (b) Akiyama, T.; Morita, H.; Itoh, J.; Fuchibe,
K. Org. Lett. 2005, 7, 2583–2585; (c) De Risi, C.; Perrone,
D.; Dondoni, A.; Pollini, G. P.; Bertolasi, V. Eur. J. Org.
Chem. 2003, 1904–1914; (d) Stevens, C. V.; Vekemans, W.;
Moonen, K.; Rammeloo, T. Tetrahedron Lett. 2003, 44,
1619–1622, and references cited therein.
9. (a) All new compounds were characterized by H and 13
C
1
NMR, MS, HRMS, IR and elemental analysis. 2D-
COSY, HSQC and NOESY experiments were also carried
out. Selected NMR and mass spectra data are given. The
NMR spectra were recorded in CDCl3 at 70 ꢁC unless
1
otherwise stated; (b) Compound 17: H NMR (500 MHz)
d 7.51 (2H, d, J = 8.1 Hz), 7.4–7.3 (3H, m), 4.82 (1H, m),
3.77 (3H, d, JH,P = 10.5 Hz), 3.76 (3H, d, JH,P = 10.5 Hz),
3.59 (1H, ddd, J = 7.6, 7.7, 10.6 Hz), 3.47 (1H, m), 2.2–2.1
(2H, m), 1.78 (1H, m); 13C NMR (125.7 MHz): d 170.3
(C), 136.6 (C), 130.2 (CH), 128.2 (2·CH), 127.6 (2·CH),
53.0 (CH3, d, JC,P = 7.0 Hz), 52.7 (CH3, d, JC,P = 6.4 Hz),
52.2 (CH, d, JC,P = 163 Hz), 49.9 (CH2), 26.0 (CH2), 25.0
(CH2). MS (EI, 70 eV), m/z: 283 (M+, 8), 178 (4), 174 (69),
105 (100); HRMS: calcd for C13H18NO4P 283.0973, found
283.0968.
16. (a) The stereochemistry of compound 24 was determined
with a COSY experiment (400 MHz, C6D6). Thus, a
strong coupling was observed between 4-H (dH 4.80) and
3b-H (dH 1.93) and between 3b-H (dH 1.93) and 2-H (dH
4.53). In contrast, the coupling between 3a-H (dH 2.46)
and 4-H or 2-H was very weak, as expected for 2-H,3a-H
trans and 4-H,3a-H trans relationships; (b) In the case of
compound 25, the COSY experiment (500 MHz, CDCl3)
showed a strong coupling between 4-H (dH 5.36) and 3b-H
(dH 2.61). The coupling between 3a-H (dH 2.23) and 2-H
(dH 4.73) was also observe. The nucleophile was added
from the apparently more hindered face. For similar
results, see: (c) Yoda, H.; Egawa, T.; Takabe, K. Tetra-
hedron Lett. 2003, 44, 1643–1646, and references cited
therein.
10. The fragmentation of carboxyl radicals proceeds much
faster than the fragmentation of alkoxyl radicals. Thus,
Kfrag (RCOOÅ) = 1010 À1, Kfrag (PhCOOÅ) = 106 sÀ1 and
s
Kfrag (tBuOÅ) = 105 sÀ1. For a discussion on the subject,
see: Fossey, J.; Lefort, D.; Sorba, J. Free Radicals in
Organic Chemistry; Wiley: Chichester, 1995; pp 96, 148–
149, 223–225 and 295.
11. Compound 19: 1H NMR (500 MHz) d 7.35 (2H, dd,
J = 7.8, 8.1 Hz), 7.34 (2H, dd, J = 8.1, 8.0 Hz), 7.21–7.13
(6H, m), 4.70 (1H, m), 4.66 (1H, dd, J = 5.0, 16.8 Hz),
4.30 (1H, d, J = 13.5 Hz), 4.16 (1H, d, J = 12.1 Hz), 3.79
(3H, d, JH,P = 11 Hz), 3.78 (3H, d, JH,P = 11 Hz), 3.70
(1H, m), 3.40 (1H, m), 3.08 (1H, m); 13C NMR
(125.7 MHz): d 153.6 (C), 153.2 (C), 151.6 (C), 151.4
(C), 129.2 (2·CH), 129.1 (2·CH), 125.5 (CH), 125.2 (CH),
121.5 (2·CH), 121.3 (2·CH), 53.0 (CH3, d, JC,P = 7.0 Hz),
17. (a) Compound 27: 1H NMR (500 MHz, À50 ꢁC) d 7.94
(1H, s, OCHO), 6.44 (1H, d, J = 9.8 Hz, NH), 5.59 (1H,
dd, J = 7.1, 7.4 Hz, 3-H), 5.50 (1H, dd, J = 4.9, 6.4 Hz, 4-
H), 5.23 (1H, ddd, J = 5.1, 5.1, 5.3 Hz, 5-H), 4.89 (1H,
ddd, J = 2.4, 10.4 Hz, JH,P = 22.7 Hz, 2-H), 4.30 (1H, dd,
J = 4.7, 12.1 Hz, 6-Ha), 4.10 (1H, dd, J = 6.4, 11.8 Hz, 6-
Hb), 3.77 (3H, d, JH,P = 9.8 Hz, OMe), 3.75 (3H, d,
JH,P = 10.3 Hz, OMe), 2.15 (3H, s, Ac), 2.12 (3H, s, Ac),
2.10 (6H, s, 2·Ac); 13C NMR (125.7 MHz, 26 ꢁC): d 170.5
(C, CO), 170.1 (C, CO), 169.8 (C, CO), 169.6 (C, CO),
159.4 (CH, CHO), 70.1 (CH, d, JC,P = 11.5 Hz, 4-C), 69.0
52.8 (CH3, d, JC,P = 7.0 Hz), 48.5 (CH, d, JC,P
=
151.0 Hz), 43.6 (CH2), 43.0 (CH2), 41.2 (CH2); MS (EI,
70 eV), m/z: 435 (M++H, 1), 434 (M+, 1), 342 (18), 341
(99), 93 (100); HRMS: calcd for C20H23N2O7P 434.1243,
found 434.1248.
12. For very similar compounds, see: (a) Yuan, C.; Wang, G.;
Chen, S. Synthesis 1990, 522–524; (b) Shono, T.; Mat-

A. Boto et al. / Tetrahedron Letters 46 (2005) 7807–7811
7811
(CH, 5-C), 68.5 (CH, JC,P = 4 Hz, 3-C), 61.3 (CH2, 6-C),
53.9 (CH3, d, JC,P = 6.8 Hz, OMe), 53.4 (CH3, d,
JC,P = 6.4 Hz, OMe), 45.0 (CH, d, JC,P = 159 Hz, 2-C),
23.0 (CH3), 20.6 (3·CH3); MS (EI, 70 eV), m/z: 456
(M++H, 6), 57 (100); HRMS: calcd for C16H27NO12P
456.1271, found 456.1286; (b) The spectroscopic data of
compound 28 were very similar, the main differences being
observed in the 1H NMR spectrum (500 MHz, À50 ꢁC): d
8.07 (1H, s, OCHO), 7.14 (1H, br b, NH), 5.64 (1H, dd,
J = 9.9, 10.0 Hz, 3-H), 5.44 (1H, dd, J = 1.0, 8.9 Hz, 4-H),
5.28 (1H, m, 5-H), 4.77 (1H, ddd, J = 10.4, 10.5 Hz,
JH,P = 14.3 Hz, 2-H), 4.21 (1H, br d, J = 11.7 Hz, 6-Ha),
4.00 (1H, dd, J = 6.6, 12.7 Hz, 6-Hb), 3.73 (6H, d,
JH,P = 11.9 Hz, OMe), 2.14 (3H, s, Ac), 2.12 (3H, s, Ac),
2.05 (3H, s, Ac), 1.99 (3H, s, Ac).
stants at À50 ꢁC. Since at this temperature the intercon-
version between conformers is very slow, signals for each
conformer are recorded in the NMR experiment; the
intensity of the signals is related to the conformer
population. In our case, the signals of the minor confor-
mations were hardly observed. Presuming that the mini-
mum-energy conformation was the major one, the
experimental J would match the theoretical ones; The
theoretical J were calculated by using the Karplus–Altona
equation implemented in the Macromodel 7.0 program.
See: (b) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.;
Altona, C. Tetrahedron 1980, 36, 2783–2792; (c) Experi-
mental J for product 27: J2,3 = 2.4 Hz, J3,4 = 6.0 Hz, and
for compound 28: J2,3 = 10.0 Hz, J3,4 = 10.0 Hz. Calcu-
lated J for the 2R diastereomer: J2,3 = 0.3 Hz, J3,4
=
18. (a) The stereochemistry of compounds 27 and 28 was
tentatively assigned by comparing the theoretical coupling
constants calculated over the minimized structures for
both diastereomers and the experimental coupling con-
5.0 Hz, and for the 2S diastereomer: J2,3 = 8.0 Hz and
J3,4 = 4.4 Hz.
´
´
19. Boto, A.; Hernandez, R.; Suarez, E. Tetrahedron Lett.
2001, 42, 9167–9170.