Improved Access to Imidazole-phosphonic Acids: Synthesis of D-manno-Tetrahydroimidazopyridine-2-phosphonates)

Article abstract of DOI:10.1002/hlca.200490067

The D-manno-tetrahydroimidazopyridine-2-phosphonate 11 was prepared via a high-yielding Pd(PPh₃)₄-catalysed diphenylphosphonylation of the manno-iodoimidazole 12, followed by transesterification to the diethyl phosphonate 14 and deal

Full text of DOI:10.1002/hlca.200490067

Helvetica Chimica Acta Vol. 87 (2004)
719
Improved Access to Imidazole-phosphonic Acids: Synthesis of d-manno-
Tetrahydroimidazopyridine-2-phosphonates1)
by Miroslav Terinek and Andrea Vasella*
Laboratorium f¸r Organische Chemie, ETH-Hˆnggerberg, Wolfgang-Pauli Strasse 10, CH-8093 Z¸rich
The d-manno-tetrahydroimidazopyridine-2-phosphonate 11 was prepared via a high-yielding Pd(PPh3)4-
catalysed diphenylphosphonylation of the manno-iodoimidazole 12, followed by transesterification to the
diethyl phosphonate 14 and dealkylation, providing 11 in eight steps from the thionolactam 1 and in an overall
yield of 15%. Alternatively, a more highly convergent synthesis based on the HgCl2/Et3N-promoted
condensation of the thionolactam 1 with the a-aminophosphonate 24 in THF led to 11 in four steps and in
the same overall yield. In the presence of HgCl2/Et3N, the thionolactam 1 reacted at 808 with 2-methoxyethanol
to provide 66% of a 64 :36 mixture of the gluco- and manno-iminoethers 29/30. Performing the reaction at 228
yielded preferentially the gluco-isomer 29 (86%, 84 :16).
Introduction. We described the synthesis of the gluco-configured tetrahydroimi-
dazopyridine-2-phosphonate 7 (Scheme 1) [1] and its transformation into the oleyl,
phytanyl, and dolichyl imidazole-phosphonates 8 10, potential inhibitors of the
glucosyl transferase Alg10p [2]2). This enzyme is one of several glucosyl and mannosyl
transferases involved in the biosynthesis of N-glycosylated proteins [18]. For the
synthesis of the manno-configured analogue of the dolichyl ester 10, we required the
phosphonate 11. Similarly to the synthesis of 7 from 3, it should be available by
phosphonylation of the manno-iodoimidazole 12 [19]. The synthesis of 7, however, has
two shortcomings. The iodoimidazole 3 was prepared by a rather long synthesis, viz. by
a two step condensation of thionolactam 1 with aminoacetaldehyde dimethyl acetal3)
to form the imidazole 2 [20], followed by diiodination and regioselective deiodination
[21], and the diphenyl phosphonate 4 that was formed in the highest yield by Pd-
catalysed phosphonylation of 3 to 4 6 could not be hydrolysed to the phosphonate 7
[1]. We planned to address these issues in the context of the synthesis of 11, first by
elaborating a method for the dephenylation of the manno-analogue of 4, and then by
designing a shorter synthesis.
Synthesis. a) By Phosphonylation of the Iodoimidazole 12. The manno-configured
phosphonates 13 15 (Scheme 2) were prepared by Pd-catalysed cross-coupling4) of
1
)
)
Presented in part at the XXIst International Carbohydrate Symposium, Cairns, Australia, July 7 12, 2002,
Abstract Nr. PP 180.
2
Several imidazole-derived phosphonates are known. Most of them were prepared by construction of the
substituted imidazole ring [3 14]. A few cases describe a phosphonylation [1][15][16], or phosphinylation,
followed by oxidation [17] of an imidazole. Two sugar-derived imidazole-phosphonates are known [1][17].
Depending on the exact reaction conditions, this condensation provides either the pure gluco-imidazole 2,
or a mixture of 2 and the manno-isomer 17 [20].
3
4
)
)
For further examples of the Pd-catalysed coupling of heteroaryl halides with dialkyl H-phosphonates, cf.
[15][22 31].

720
Helvetica Chimica Acta Vol. 87 (2004)
Scheme 1
a) 1. Lawesson×s reagent, toluene; 2. H2NCH2CH(OMe)2, Hg(OAc)2, THF, 58; 3. TsOH ¥ H2O, toluene/H2O,
658; 75% [20]. b) 1. N-Iodosuccinimide, DMF, 808; 2. EtMgBr, THF, 08; 68 86% [21]. c) HP(O)(OR)2,
Pd(PPh3)4, Et3N, toluene, 958; 84% of 4, 62% of 5, and 31% of 6 [1].
Scheme 2
a) HP(O)(OR)2, Pd(PPh3)4, Et3N, toluene, 958; R ˆ Ph: 86% of 13; R ˆ Et: 58% of 14 and 40% of 17; R ˆ Me:
24% of 15 and 23% of 17. b) HP(O)(OSiMe3)2, Pd(PPh3)4, Et3N, toluene, 958; 65% of 16 and 4% of 17. c) KF,
18-crown-6, EtOH, reflux; 90%, or CsF, EtOH, reflux; 84%. d) KF, 18-crown-6, MeOH, reflux; 84%, or CsF,
MeOH, reflux; 88%. e) Me3SiBr, CH2Cl2. f) H2, Pd(OH)2/C, MeOH/AcOEt/H2O; (77% from 14; 83% from
15). g) Ac2O, pyridine; 96%. h) H2, Pd(OH)2/C, AcOEt/MeOH/H2O/AcOH; 82%. i) Ac2O, DMAP, pyridine;
76%.
the iodoimidazole 12 [19] with diphenyl, diethyl, and dimethyl H-phosphonate,
respectively. Like in the gluco-series [1], phosphonylation with diphenyl H-phospho-
nate (Pd(PPh3)4, Et3N) led to the highest yield and the cleanest transformation,
providing 86% of 13, while diethylphosphonylation yielded 58% of 14, and the use of

Helvetica Chimica Acta Vol. 87 (2004)
721
dimethyl H-phosphonate resulted in only 24% of 15. The formation of 14 and 15 was
accompanied by significant dehalogenation of 12 to 17 [20]. The only difference to the
phosphonylation of the gluco-imidazole 3 was the effect of the amine. 1,2,2,6,6-
Pentamethylpiperidine or EtN(i-Pr)2 increased the yield of the diethylphosphonylation
of 3, but lowered the yield of the diethylphosphonylation of 12 (from 58 to 51 and 43%,
resp.).
Phosphonylation of 12 with bis(trimethylsilyl) H-phosphonate should readily lead
to the desired phosphonic acid 16. Indeed, this phosphonylation (Pd(PPh3)4, Et3N) led
to the desired bis(trimethylsilyl) ester5) besides the dehalogenated imidazole 17.
Chromatography (RP-C18 SiO2; MeOH, H2O) provided 65% of the phosphonic acid
16. We did, however, not pursue this reaction. In addition to the high price of
bis(trimethylsilyl) H-phosphonate, scale-up proved difficult, and the separation of the
acid cumbersome.
Hydrolysis of the diphenyl phosphonate 13 failed under acidic and basic conditions
[33 38]. Hydrogenolysis of 13 in the presence of Adams× catalyst (PtO2) [39 43]
provided an inseparable mixture. However, CsF-induced transesterification [39] of 13
in boiling EtOH or MeOH gave the diethyl and dimethyl phosphonates 14 (84%) and
15 (88%), respectively. Similar results (90% of 14 and 84% of 15) were obtained when
CsF was replaced by KF and 18-crown-6 [39][44].
The diethyl and dimethyl phosphonates 14 and 15 were dealkylated with Me3SiBr
[45][46], and the resulting crude phosphonic acid 16 was debenzylated (H2, Pd(OH)2).
Treating the crude product with 3 equiv. of Et3N, followed by lyophilisation, gave 11
(78% from 14), mostly as the mono(triethylammonium) salt (1.10 equiv. of Et3N
1
according to H-NMR). Chromatography of the crude hydrogenolysis product on
DEAE-cellulose (elution with aq. triethylammonium hydrogencarbonate), followed
by lyophilisation, provided 77 and 83% of the phosphonate 11 (1.19 1.25 equiv. of
1
Et3N) from 14 and 15, respectively. According to H- and 31P-NMR spectroscopy, the
purity of 11 was not affected by chromatography on DEAE-cellulose. Acetylation of
11 (1.60 equiv. of Et3N) gave the tetraacetate 18 in 96% yield (1.62 equiv. of Et3N). We
also examined the dealkylation of the acetylated diethyl phosphonate 20 by excess
Me3SiBr. The acetate 20 was obtained from the tetrol 19, resulting from hydrogenolytic
debenzylation of 14. Unfortunately, this attempted dealkylation led to a complex
mixture, and we did not pursue this route to 18.
b) By Condensation of the Thionolactam 1 with the a-Aminophosphonate 24.
Condensation of the gluco-thionolactam 1 with the aminophosphonates 24 or 26
instead of aminoacetaldehyde dimethyl acetal6) should allow for a more convergent,
shorter synthesis of the gluco- and manno-phosphonates 7 and 11 (Scheme 3). The a-
aminophosphonate dimethyl acetals 23 and 257) were prepared similarly to the
analogous diethyl acetal corresponding to 23 (diethyl [1-(benzylamino)-2,2-diethoxy-
5
)
The iodoimidazole 12 failed to react with the bis[(tert-butyl)dimethylsilyl] H-phosphonate; only the
dehalogenated imidazole 17 (34%) was isolated. The required H-phosphonate was prepared similarly to
HP(O)(OSiMe3)2 [32] by treating phosphoric acid with (t-Bu)Me2SiCl in the presence of Et3N in 86%
yield.
6
7
)
The synthesis of imidazoles by condensation of thionolactams with aminoacetaldehyde dimethyl acetal is
well precedented [20][47 49]; the use of substituted aminoacetals is less well documented [50].
For reviews on the preparation of a-aminophosphonic acids and their derivatives, cf. [51][52].
)

722
Helvetica Chimica Acta Vol. 87 (2004)
Scheme 3
a) BnNH2, MgSO4, THF, 08 ! 228; 90%. b) HP(O)(OEt)2, Et3N, Me3SiCl, CH2Cl2, 08 ! 228; 70%.
c) HP(O)(OMe)2, Et3N, Me3SiCl, CH2Cl2, 08 ! 228; 60%. d) H2, Pd/C, EtOH; 74%. e) H2, Pd/C, MeOH;
73%. f) 1. 24, HgCl2, Et3N, mol. sieves (3 ä), THF, reflux; 2. TsOH ¥ H2O, toluene, 658; 45% of 5/14 55:45 and
11% of 27/28 75 :25. g) 1. 26, HgCl2, Et3N, mol. sieves (4 ä), THF, reflux; 2. TsOH ¥ H2O, toluene, 658; 12% of
6/15 57:43 and 22% of 27/28 71:29. h) 24, HgCl2, Et3N, mol. sieves (4 ä), 2-methoxyethanol, 808; 66% of 29/30
64:36 and 16% of 27/28 54:46. i) HgCl2, Et3N, mol. sieves (4 ä), 2-methoxyethanol, 228; 86% of 29/30 84 :16
and 7% of 27/28 65 :35. j) As i, but 808; 75% of 29/30 68 :32 and 12% of 27/28 58 :42.
ethyl]phosphonate) [53]. Treatment of glyoxal 1,1-dimethyl acetal (21) with BnNH2 in
the presence of MgSO4 yielded 90% of the imine 22. Addition of in situ generated
diethyl or dimethyl trimethylsilyl phosphite [32][54 63] provided the phosphonates 23
(70%) and 25 (60%), respectively. The debenzylated aminophosphonates 24 and 26
were obtained by hydrogenolysis (10% Pd/C) of 23 and 25, and isolated by bulb-to-
bulb distillation under reduced pressure in 74 and 73% yield, respectively.
The aminophosphonate 24 proved much less reactive than aminoacetaldehyde
dimethyl acetal (cf. [20][47]). Thus, the thionolactam 1 did not react with excess 24 up
to 908 and decomposed at 1208. Hg(OAc)2 led to partial hydrolysis and epimerisation at
C(2) (cf. [64 66]), providing a mixture of the known lactams 27 and 28. HgO
promoted the condensation of 1 and 24, as evidenced by the formation of the gluco- and
manno-configured imidazoles 5 and 14 (17%, 55 :45) upon acid treatment of the crude.

Helvetica Chimica Acta Vol. 87 (2004)
723
HgCl2 in boiling THF proved more useful, but the addition of 2 equiv. of Et3N and of
molecular sieves was required to suppress the formation of 27/28 and to provide (after
acid treatment of the crude) a 55 :45 mixture of the desired imidazoles 5 and 14 (45%),
besides 11% of 27/28 (3 :1). This mixture was readily separated by chromatography to
give 5 (25%) and 14 (20%). Not surprisingly, HgCl2-promoted condensation of the
thionolactam 1 with the dimethyl aminophosphonate 26 provided the gluco- and
manno-configured imidazoles 6 and 15 in only 12% yield.
Unexpectedly, under otherwise identical conditions, 1 reacted with 24 in 2-
methoxyethanol at 808 to provide cleanly the gluco/manno-iminoether mixture 29/308)
(64 :36), isolated in 66% yield besides 16% of 27/28 (54 :46). Separation of 29 and 30
proved difficult. While the gluco-isomer 29 was obtained pure, the manno-isomer 30
could not be completely separated from an unknown impurity. The iminoethers
decomposed partially during chromatography on SiO2, and addition of Et3N was
required to minimize their hydrolysis to the lactams 27/28. The iminoethers 29/30 (75%,
68 :32) and lactams 27/28 (12%, 58 :42) were also obtained when 1 was treated with
HgCl2/Et3N in 2-methoxyethanol at 808 in the absence of the aminophosphonate 24.
Performing the reaction at 228 led preferentially to the gluco-isomer 29 (86% of 29/30,
84 :16). Attempted debenzylation of the iminoether 29 under Birch conditions [71][72]
resulted in a complex mixture.
In conclusion, both improved routes proved useful for the synthesis of the d-
manno-tetrahydroimidazopyridine-2-phosphonate 11. The high-yielding diphenylphos-
phonylation of 12, followed by transesterification to 14 and dealkylation, provided the
phosphonate 11 in eight steps from 1 and an overall yield of 15%, while the analogous
route involving a diethylphosphonylation of 12 led to 11 in 11% over seven steps. The
more highly convergent synthesis, based on the two step condensation of 1 with 24,
provided 11 in four steps and an overall yield also of 15%. This appears to be the first
example of the formation of an imidazole by condensation of a thionolactam and an
acceptor-substituted aminoacetaldehyde acetal.
The introduction of the phosphonate group has no influence on the solution
6
conformation (7H6 and H7 2 :1; see Table 1 in Exper. Part)9) of the protected and
unprotected manno-imidazoles 11, 13 16, and 18 20 [20][73]. The 13C signals of
C(5) C(8) of 14 (Table 2 in Exper. Part) were assigned on the basis of HSQC-GRASP
spectrum; those of the other imidazoles were assigned by analogy. The C(2)ÀPbond in
1
the phosphonates 13 15 is evidenced by J(2,P) of 256.3, 246.6, and 245.8 Hz in the
13C-NMR spectra (CDCl3) of 13 15, respectively.
The imine 22 is characterised by a 13C doublet at 161.18 ppm and a weak IR band at
1676 cmÀ1 (CˆN). The formation of C(1)ÀPbond in the phosphonates 23 26 is
1
evidenced by 13C dd×s at 56.23, 51.60, 56.19, and 51.38 ppm, showing J(1,P) of 153.5,
154.4, 153.8, and 154.4 Hz, respectively (see Table 3 in Exper. Part).
8
)
Glyconolactam-derived iminoethers were mostly prepared by treatment of the lactams with Meerwein×s
salt [67 69]. For the preparation of iminoethers by HgO-promoted solvolysis of thioacetamides, see [70].
The direction of numbering of imidazopyridines (cf. 12 in Scheme 2) is opposite to that of pyranosides.
Thus, the sides above and below the plane of the imidazoles, as defined by the clockwise and
counterclockwise numbering, are interchanged relative to those defined by carbohydrate nomenclature.
9
)

724
Helvetica Chimica Acta Vol. 87 (2004)
The formation of the iminoethers 29 and 30 is confirmed by the disappearance of
the NH signal in their 1H-NMR spectra, 13C singlets at 160.89 (29) and 160.23 ppm (30),
and strong IR bands at 1675 and 1677 cmÀ1 (CˆN) of 29 and 30, respectively. The
assignment of the gluco- and manno-configuration to 29 and 30 is based on the values of
J(4,5) (7.8 and 3.7 Hz, resp.; cf. Scheme 3).
We thank Dr. B. Bernet for checking the experimental part, and the Swiss National Science Foundation and
Oxford Glycosciences Ltd., Abingdon (UK), for generous support.
Experimental Part
General. Solvents were distilled before use: THF and toluene from Na and benzophenone, CH2Cl2 from
P2O5, 2-methoxyethanol from CaH2. Reactions were carried out under Ar, unless stated otherwise. Molecular
sieves were dried at 1508/0.05 Torr for 12 h. Qual. TLC: precoated silica-gel plates (Merck silica gel 60 F254);
detection by heating with −mostain× (400 ml of 10% H2SO4 soln., 20 g of (NH4)6Mo7O24 ¥ 6 H2O, 0.4 g of
Ce(SO4)2. Flash chromatography (FC): silica gel Fluka 60 (0.04 0.063 mm), unless indicated otherwise.
Optical rotations: 1-dm cell at 258, 589 nm. UV Spectra (ca. 0.2 mm solns.): in 1-cm cell at 258 in the range of 190
to 500 nm (log e values in parenthesis). FT-IR Spectra: KBr or ca. 2% soln. in CHCl3, absorption in cmÀ1. 1H-,
13C-, and 31P-NMR spectra: chemical shifts d in ppm rel. to TMS (1H and 13C) or H3PO4 31P) as external
(
standard, and coupling constants J in Hz. FAB-MS and HR-MALDI-MS: 3-nitrobenzyl alcohol (NOBA) and
gentisic acid (ˆ2,5-dihydroxybenzoic acid (DHB)) as matrix, respectively.
Bis[(tert-butyl)dimethylsilyl] H-Phosphonate. A soln. of H3PO410) (3.0 g, 36.59 mmol) in THF (25 ml) was
treated with a soln. of (t-Bu)Me2SiCl (11.1 g, 73.64 mmol) in Et2O (120 ml) and Et3N (10 ml, 71.75 mmol),
vigorously stirred for 3 h at 758, and cooled to 228. The precipitate (Et3NCl) was filtered off and washed with
Et2O (3 Â 60 ml). The combined filtrate and washings were evaporated, and the residual oil was distilled at 0.5
Torr to give bis[(tert-butyl)dimethylsilyl] H-phosphonate (9.81 g, 86%) as a colourless liquid. Rf (AcOEt) 0.08.
B.p. (0.5 Torr) 87 898. IR (CHCl3): 3403w (br.), 3001m, 2957s, 2933s, 2887m, 2861m, 2434w, 1634w, 1472m,
1464m, 1393w, 1364w, 1263s, 1055s, 1016s, 998s, 939w, 845s, 828s. 1H-NMR (CDCl3, 300 MHz): 0.246 (s, 2 MeSi);
0.252 (s, 2 MeSi); 0.92 (s, 2 Me3CSi); 6.86 (d, 1J(H,P) ˆ 697.9, HPˆO). 13C-NMR (CDCl3, 75 MHz): À3.79 (q, 2
MeSi); À3.64 (q, 2 MeSi); 17.80 (d, 3J(C,P) ˆ 1.8, 2 Me3CSi); 25.16 (q, 2 Me3CSi). 31P-NMR (CDCl3, 121 MHz):
‡
‡
‡
À12.67. EI-MS: 309 (<1, [M À H] ), 295 (8, [M À Me] ), 253 (100, [M À t-Bu] ), 211 (14), 195 (20, [M À
‡
‡
TBDMS] ), 179 (6, [M À TBDMSO] ), 169 (8), 135 (24), 73 (53). Anal. calc. for C12H31O3Si2P(310.52):
C 46.42, H 10.06; found: C 46.24, H 9.93.
Diphenyl (5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-
a]pyridine-2-phosphonate (13). A suspension of 12 (36.7 mg, 0.054 mmol) and Pd(PPh3)4 (18.0 mg, 15.6 mmol)
in freshly distilled and degassed toluene (134 ml) was treated under Ar with Et3N (52 ml, 0.373 mmol) and
HPO(OPh)2 (51 ml, 0.265 mmol), and stirred at 958 for 15 h. The mixture was concentrated and co-evaporated
with toluene (4 Â 2 ml). The 1H-NMR spectrum of the crude showed 13, besides P(O)Ph3 and HPO(OPh)2. FC
(hexane/AcOEt 8 :2 ! 6 :4 ! 0 :1), followed by FC (CH2Cl2/i-PrOH 10 :0.05 ! 10 :0.3), gave 13 (36.5 mg,
86%). Colourless oil. Rf (hexane/AcOEt 1 :1) 0.44. [a]2D5 ˆ À35.3 (c ˆ 0.99, CHCl3). UV (CHCl3): 259 (3.15). IR
(CHCl3): 3151w, 3066w, 2926m, 2868m, 1952w, 1875w, 1812w, 1728w, 1593m, 1490s, 1455m, 1363w, 1272s, 1161s,
1
1113s, 1026s, 941s. H-NMR (CDCl3, 400 MHz): see Table 1; additionally, 3.51 (irrad. at 3.68 ! change); 3.68
(irrad. at 3.51 ! change); 3.86 (irrad. at 4.84 ! d, J ˆ 9.3); 4.11 (irrad. at 3.51 ! change); 4.26 (irrad. at 3.86 ! d,
J ꢀ 7.0); 4.36 (d, J ˆ 12.1, PhCH); 4.39 (d, J ˆ 12.1, PhCH); 4.586 (d, J ˆ 11.2, PhCH); 4.590 (d, J ˆ 12.1, PhCH);
4.60 (d, J ˆ 11.9, PhCH); 4.67 (d, J ˆ 11.9, PhCH); 4.68 (d, J ˆ 12.1, PhCH); 4.84 (irrad. at 3.86 ! s); 4.96 (d, J ˆ
11.2, PhCH); 7.05 7.36 (m, 30 arom. H). 13C-NMR (CDCl3, 100 MHz): see Table 2; additionally, 70.59, 71.91,
73.22, 74.96 (4t, 4 P hCH2); 120.93 (dd, 3J(C,P) ˆ 4.5, C(2) and C(6) of PhO); 120.95 (dd, 3J(C,P) ˆ 4.5, C(2) and
C(6) of PhO); 125.01 (br. d, 2 C(4) of 2 PhO); 127.69 128.55 (several d); 129.53 (br. d, C(3) and C(5) of PhO);
2
129.56 (br. d, C(3) and C(5) of PhO); 137.15, 137.62 (2s); 137.75 (2s); 150.46 (d, J(C,P) ˆ 7.5, C(1) of PhO);
‡
150.48 (d, 2J(C,P) ˆ 7.1, C(1) of PhO). 31P-NMR (CDCl3, 121 MHz): see Table 1. FAB-MS: 1585 (2, [2M ‡ H] ),
‡
‡
‡
793 (100, [M ‡ H] ), 685 (6, [M À BnO] ), 579 (5), 473 (5), 91 (90, C7H7 ). HR-MALDI-MS: 831.2528 (1,
10
)
Commercially available H3PO3 (99%; Aldrich 21,511-2) was co-evaporated with toluene (3 Â 20 ml) before
use.

Helvetica Chimica Acta Vol. 87 (2004)
725
Table 1. Selected 1H- and 31P-NMRChemical Shifts [ppm] and Coupling Constants [Hz] of the Protected
Imidazoles 13 16, 18, and 20 and of the Deprotected Imidazoles 11 and 19
13
14
14
15
16
18
20
11
1919
CDCl3 CDCl3
C6D6 CDCl3 CD3OD
CD3OD CDCl3
D2O D2O
CD3OD
7.94
HÀC(3)
HÀC(5)
HÀC(6)
HÀC(7)
HÀC(8)
7.86
4.11
4.26
3.86
4.84
7.80
8.00 7.81
7.91a)
4.04 4.25 3.77 4.13 4.52 4.62 4.62
7.71
7.69b)
4.35
5.59
5.41
6.39
4.30
4.50 4.62
5.9
7.64 7.80
4.16 4.05 4.15 3.95
4.28 3.91
4.07 3.86
5.13 4.82
4.04 3.90
4.29
3.87
4.84
3.58
3.73
7.5
9.3
3.1
7.2
3.1
4.24 4.28
3.46 3.86
4.85 4.82
3.28 3.57
3.44 3.72
6.5 7.2
9.7 9.3
3.1 3.1
6.5 7.2
3.1 3.1
10.0 10.3
4.29
4.15
5.17
3.73
3.81
3.1
6.4
3.1
7.2
4.4
5.71
5.50
6.37
4.40
4.67
6.7
4.01 4.23
3.85
4.80 4.90
3.89
CHÀC(5) 3.51
CH'ÀC(5) 3.68
4.21 4.05 4.15 4.17
J(5,6)
J(6,7)
J(7,8)
J(5,CH)
J(5,CH')
7.1
9.3
3.1
7.1
3.1
6.8 5.9
8.9 10.0
3.7 3.7
6.2
9.0
3.7
6.2
2.5
9.4
9.0
3.7
3.7
4.8
6.5
3.6 4.1
c
3.4
2.8
2.9
)
J(CH,CH') 10.2
10.0
10.3
À 1.37
12.2
0.04
11.2
11.22
12.6 16.2
À 1.92 14.86
11.2
13.39
P5.01 12.21
12.06 14.91
b
a) 3J(H,P) ˆ 1.9 Hz. ) 3J(H,P) ˆ 0.9 Hz. c) Not assigned.
Table 2. Selected 13C-NMRChemical Shifts [ppm] and Coupling Constants [Hz] of the Protected Imidazoles
13 16, 18, and 20 and of the Deprotected Imidazoles 11 and 19
13
14a)
14
15
16
18
20
11
1919
CDCl3 CDCl3 C6D6
CDCl3 CD3OD CD3OD CDCl3
D2O
D2O
CD3OD
b
C(2)
C(3)
C(5)
128.83 130.83 132.48 129.19
)
138.37
127.28
58.81
63.57
66.38c)
70.23
64.40c)
142.99
233.9
34.2
132.56
127.86
57.93
63.48
65.44c)
68.63
63.08c)
142.49
246.6
37.2
135.67
125.95
64.59c)
62.11
67.79c)
72.02
65.38c)
147.96
197.9
21.9
127.06
128.44
61.51
59.47
64.49c)
70.56
63.64c)
148.63
246.0
36.6
129.70
130.04
64.33
63.07
67.21c)
72.78
65.67c)
150.47
246.6
36.6
b
130.57 129.18
)
129.46 127.75
60.35
70.08
73.70
79.81
68.21
60.36
70.38
73.97
80.15
68.66
60.28
69.97
73.64
80.49
68.23
60.29
70.16
73.74
79.90
68.56
62.40
d
CH2ÀC(5)
)
C(6)
73.92c)
75.68
C(7)
C(8)
C(8a)
1J(2,P)
2J(3,P)
3J(8a,P)
70.36c)
146.06 145.99 145.85 145.91 146.70
e
256.3
39.7
23.7
246.6
37.9
22.0
242.9
)
22.0
245.8
36.6
22.0
)
e
20.8
8.5
20.8
22.6
7.3
21.4
20.7
a) Assignment based on a HSQC-GRASPspectrum. b) Hidden by the aromatic signals at 127.79 130.12 ppm.
c) Assignment may be interchanged. d) Hidden by the PhCH2 signals at 74.42 and 74.45 ppm. e) Not assigned.
‡
‡
‡
‡
[M ‡ K] , C48H45KN2O7P ; calc. 831.2601), 815.2817 (36, [M ‡ Na] , C48H45N2NaO7P ; calc. 815.2862),
‡
‡
‡
‡
793.3026 (100, [M ‡ H] , C48H46N2O7P ; calc. 793.3042), 685.2450 (18, [M À BnO] , C41H38N2O6P ; calc.
685.2467), 397.1549 (3). Anal. calc. for C48H45N2O7P(792.87): C 72.71, H 5.72, N 3.53; found: C 72.71, H 6.00,
N 3.51.
Preparation of 5 and 14. a) By Pd(PPh3)4-Catalysed Phosphonylation of 12. A suspension of 12 (900 mg,
1.31 mmol) and Pd(PPh3)4 (456 mg, 0.395 mmol) in freshly distilled and degassed toluene (3.25 ml) was treated
under Ar with Et3N (1.26 ml, 9.04 mmol) and HPO(OEt)2 (0.85 ml, 6.60 mmol), warmed to 958, stirred for 19 h,
cooled to 228, diluted with AcOEt (15 ml), and filtered through Celite (the solid was washed with 300 ml of
AcOEt). The combined yellow filtrate and washing was concentrated to 100 ml, washed with H2O (100 ml) and
brine (100 ml), dried (MgSO4), and evaporated. The 1H-NMR spectrum of the crude showed a mixture of 14/17
ca. 62 :38, P(O)Ph3, and HPO(OEt)2. FC (hexane/AcOEt/Et3N 5 :5 :0.3 ! 3 :7 :0.3 ! 0 :1:0.03) gave 17

726
Helvetica Chimica Acta Vol. 87 (2004)
(296 mg, 40%) [20] as a pale yellow oil and a mixture containing mainly 14 and P(O)Ph3 (739 mg). FC (RP-C18
silica gel, MeOH/H2O 7 :3 ! 9 :1) of this mixture gave pure 14 (534 mg, 58%).
b) By KF-Induced Transesterification of 13. A suspension of 13 (12 mg, 15.1 mmol), KF (8.9 mg,
0.153 mmol), and 18-crown-6 (2 mg, 7.57 mmol) in EtOH (0.5 ml) was refluxed for 45 min and evaporated. A
soln. of the residue in AcOEt (5 ml) was washed with H2O (3 Â 5 ml) and brine (5 ml), dried (MgSO4), and
evaporated. FC (hexane/AcOEt 1:1 ! 1:3) gave 14 (9.4 mg, 90%).
c) By CsF-Induced Transesterification of 13. A soln. of 13 (18.5 mg, 23.3 mmol) and CsF (9 mg, 59.2 mmol)
in EtOH (0.5 ml) was refluxed for 150 min. Workup and FC, as described in b, afforded 14 (12.9 mg, 80%). This
experiment was repeated on a large scale: a soln. of 13 (1.13 g, 1.43 mmol) and CsF (0.54 g, 3.55 mmol) in EtOH
(30 ml) was refluxed for 6 h. Workup and FC gave 14 (831 mg, 84%). Colourless oil.
d) By Treatment of 1 with the Aminophosphonate 24 and HgCl2. A suspension of 1 (100 mg, 0.181 mmol),
HgCl2 (71 mg, 0.262 mmol), and molecular sieves (3 ä, 100 mg) in THF (2 ml) was treated successively with 24
(90 mg, 0.373 mmol) and Et3N (50 ml, 0.359 mmol), warmed to 808, stirred for 8 h, cooled to 228, diluted with
Et2O (10 ml), and filtered over Celite (the solid was washed with 30 ml of Et2O). The combined filtrate and
washing was washed with sat. NH4Cl soln. (3 Â 20 ml). The combined aq. layers were extracted with Et2O (2 Â
25 ml). The combined org. layers were washed with H2O (40 ml) and brine (40 ml), dried (MgSO4), and
evaporated. A soln. of the residue (121 mg) in toluene (5 ml) was treated with TsOH ¥ H2O (115 mg,
0.605 mmol), stirred for 7 h at 658, cooled to 228, diluted with Et2O (50 ml), and washed with sat. NH4Cl soln.
(3 Â 20 ml). The combined aq. layers were extracted with Et2O (2 Â 20 ml). The combined org. layers were
washed with H2O (50 ml) and brine (50 ml), dried (MgSO4), and evaporated. FC (hexane/AcOEt 3 :1 ! 1:1 !
0 :1) gave 27/28 75 :25 (10.7 mg, 11%) [74][75], 5 (18.3 mg, 15%) [1], 5/14 41:59 (30.7 mg, 24%), and 14
(7.9 mg, 6%).
Data of Diethyl (5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimid-
azo[1,2-a]pyridine-2-phosphonate (14). Rf (hexane/AcOEt 1:1) 0.09. [a]2D5 ˆ À27.9 (c ˆ 1.05, CHCl3). UV
(CHCl3): 265 (2.77). IR (CHCl3): 3152w, 3065w, 2908m, 2869m, 1954w, 1812w, 1727w, 1603w, 1516m, 1453m,
1393w, 1364m, 1253s, 1100s, 1028s, 972s. 1H-NMR (CDCl3, 300 MHz): see Table 1; additionally, 1.32 (br. t, J ˆ
7.2, MeCH2O); 1.35 (br. t, J ˆ 6.9, MeCH2O); 3.58 (irrad. at 3.73 ! change); 3.73 (irrad. at 3.58 ! change); 3.87
(irrad. at 4.84 ! d, J ꢀ 9.1); 4.04 4.25 (m, irrad. at 3.58 ! change, 2 MeCH2O, HÀC(5)); 4.29 (irrad. at 3.87 !
change); 4.45 (br. s, P hCH2); 4.59 (d, J ˆ 11.2, PhCH); 4.62 (d, J ˆ 12.1, PhCH); 4.65 (d, J ˆ 12.1, PhCH); 4.68
(d, J ˆ 11.8, PhCH); 4.73 (d, J ˆ 12.1, PhCH); 4.84 (irrad. at 3.87 ! s); 4.98 (d, J ˆ 10.9, PhCH); 7.22 7.36 (m, 20
arom. H). 1H-NMR (C6D6, 300 MHz): see Table 1; additionally, 1.17 (t, J ˆ 7.2, MeCH2O); 1.19 (t, J ˆ 7.2,
MeCH2O); 3.28 (irrad. at 3.77 ! d, J ˆ 9.7); 3.44 (irrad. at 3.28 ! change, irrad. at 3.77 ! change); 3.77 (irrad. at
3.28 ! change); 4.02 (d, J ˆ 12.1, PhCH); 4.07 (d, J ˆ 12.1, PhCH); 4.15 4.35 (m, 2 MeCH2O); 4.20 (d, J ˆ 10.9,
PhCH); 4.24 (irrad. at 3.77 ! change); 4.35 (d, J ˆ 11.8, PhCH); 4.39 (d, J ˆ 11.2, PhCH); 4.80 (d, J ˆ 12.1,
PhCH); 4.85 (irrad. at 3.46 ! s); 4.86 (d, J ꢀ 12.8, PhCH); 4.89 (d, J ˆ 11.5, PhCH); 7.03 7.19 (m, 16 arom. H);
7.23 7.28 (m, 2 arom. H); 7.43 7.48 (m, 2 arom. H). 13C-NMR (CDCl3, 75 MHz): see Table 2; additionally,
16.39 (dq, 3J(C,P) ꢀ 7.3, MeCH2O); 16.45 (dq, 3J(C,P) ꢀ 6.1, MeCH2O); 62.41 (dt, 2J(C,P) ꢀ 8.6, MeCH2O);
2
62.48 (dt, J(C,P) ꢀ 7.3, MeCH2O); 70.90, 72.04, 73.35, 75.10 (4t, 4 P hCH2); 127.84 128.78 (several d); 137.57,
137.97, 138.10, 138.23 (4s). 13C-NMR (C6D6, 75 MHz): see Table 2; additionally, 16.75 (dq, 3J(C,P) ˆ 6.1, 2
MeCH2O); 62.21 (dt, 2J(C,P) ˆ 4.9, MeCH2O); 62.28 (dt, 2J(C,P) ˆ 5.5, MeCH2O); 70.95, 71.64, 73.14, 74.90 (4t,
4 P Ch H2); 127.79 129.31 (several d, incl. C(3)); 137.92, 138.50, 138.59, 138.70 (4s). 31P-NMR (CDCl3,
‡
121 MHz): see Table 1. 31P-NMR (C6D6, 121 MHz): see Table 1. FAB-MS: 1393 (3, [2M ‡ H] ), 697 (86, [M ‡
‡
‡
‡
‡
‡
H] ), 589 (5, [M À BnO] ), 377 (7), 91 (100, C7H7 ). HR-MALDI-MS: 735.2650 (2, [M ‡ K] , C40H45KN2O7P ;
‡
‡
‡
calc. 735.2601), 719.2876 (62, [M ‡ Na] , C40H45N2NaO7P ; calc. 719.2862), 697.3045 (100, [M ‡ H] ,
‡
C40H46N2O7P ; calc. 697.3043), 669.2740 (8), 645.2135 (4), 623.2344 (3), 607.2547 (2), 589.2479 (19, [M À
‡
‡
BnO] , C33H38N2O6P ; calc. 589.2467), 561.2177 (14), 533.1867 (8), 515.1754 (7). Anal. calc. for C40H45N2O7P
(696.78): C 68.95, H 6.51, N 4.02; found: C 68.76, H 6.72, N 3.97.
Preparation of 6 and 15. a) By Pd(PPh3)4-Catalysed Phosphonylation of 12. A suspension of 12 (21.7 mg,
31.6 mmol) and Pd(PPh3)4 (12.4 mg, 10.7 mmol) in freshly distilled and degassed toluene (79 ml) was treated
under Ar with Et3N (31 ml, 0.222 mmol) and HPO(OMe)2 (15 ml, 0.164 mmol), warmed to 958, and stirred for
22 h. The mixture was concentrated and co-evaporated with toluene (3 Â 5 ml). The 1H-NMR spectrum of the
crude showed a mixture 15/17 ca. 50 :50, besides P(O)Ph3 and HPO(OMe)2. FC (hexane/AcOEt 8 :2 ! 5 :5 !
3 :7 ! 1:9 ! 0 :1) gave 17 (4 mg, 23%) [20] and crude 15 as colourless oils. FC (RP-C18 silica gel, MeOH/H2O
6 :4 ! 1:0) gave pure 15 (5 mg, 24%).
b) By KF-Induced Transesterification of 13. A suspension of 13 (14 mg, 17.7 mmol), KF (10 mg,
0.172 mmol), and 18-crown-6 (2.5 mg, 9.46 mmol) in MeOH (0.5 ml) was refluxed for 90 min and evaporated.

Helvetica Chimica Acta Vol. 87 (2004)
727
A soln. of the residue in AcOEt (5 ml) was washed with H2O (3 Â 5 ml) and brine (5 ml), dried (MgSO4), and
evaporated. FC (hexane/AcOEt 1:1 ! 0 :1) gave 15 (9.9 mg, 84%).
c) By CsF-Induced Transesterification of 13. A soln. of 13 (16.5 mg, 20.8 mmol) and CsF (12 mg, 79.0 mmol)
in MeOH (0.5 ml) was refluxed for 90 min. Workup and FC, as described in b, yielded 15 (13.0 mg, 94%). This
experiment was repeated on a large scale: a soln. of 13 (490 mg, 0.618 mmol) and CsF (230 mg, 1.51 mmol) in
MeOH (15 ml) was refluxed for 17 h. Workup and FC afforded 15 (362 mg, 88%).
d) By Treatment of 1 with the Aminophosphonate 26 and HgCl2. At 228, a suspension of 1 (50 mg,
90.3 mmol), HgCl2 (35 mg, 0.129 mmol), and molecular sieves (4 ä; 50 mg) in THF (1 ml) was treated
successively with 26 (45 mg, 0.211 mmol) and Et3N (25 ml, 0.179 mmol), warmed to 808, stirred for 9 h, cooled to
228, diluted with Et2O (10 ml), and filtered over Celite (the solid was washed with 30 ml of Et2O). The filtrate
was washed with sat. NH4Cl soln. (3 Â 20 ml). The combined aq. layers were extracted with Et2O (3 Â 15 ml).
The combined org. layers were washed with H2O (30 ml) and brine (30 ml), dried (Na2SO4), and evaporated. A
soln. of the residue (74 mg) in toluene (2.5 ml) was treated with TsOH ¥ H2O (60 mg, 0.315 mmol), stirred for
12 h at 658, diluted with Et2O (40 ml), and washed with sat. NH4Cl soln. (3 Â 20 ml). The combined aq. layers
were extracted with Et2O (2 Â 20 ml). The combined org. layers were washed with H2O (50 ml) and brine
(50 ml), dried (Na2SO4), and evaporated. FC (hexane/AcOEt 3 :1 ! 1:1 ! 0 :1) gave 27/28 71:29 (10.7 mg,
22%) [74][75], 6 (3.7 mg, 6%) [1], 6/15 39:61 (1.5 mg, 2%), and 15 (2.5 mg, 4%).
Data of Dimethyl (5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimida-
zo[1,2-a]pyridine-2-phosphonate (15). Colourless oil. Rf (AcOEt) 0.18. [a]2D5 ˆ À35.7 (c ˆ 0.99, CHCl3). UV
(CHCl3): 259 (2.91). IR (CHCl3): 3151w, 3065w, 2954m, 2864m, 1954w, 1879w, 1813w, 1602w, 1516m, 1455m,
1
1363m, 1259s, 1110s, 1035s, 913w, 832m. H-NMR (CDCl3, 300 MHz): see Table 1; additionally, 3.57 (irrad. at
3
3
3.72 ! change); 3.72 (irrad. at 3.57 ! change); 3.80 (d, J(H,P) ˆ 11.2, MeO); 3.81 (d, J(H,P) ˆ 11.2, MeO);
3.86 (irrad. at 4.28 ! change, irrad. at 4.82 ! d, J ˆ 9.3); 4.13 (irrad. at 3.57 ! dd, J ˆ 3.2, 7.2, irrad. at 4.28 !
change); 4.28 (irrad. at 3.86 ! change); 4.45 (br. s, P hCH2); 4.59 (d, J ˆ 11.2, PhCH); 4.61 (d, J ˆ 12.1, PhCH);
4.64 (d, J ˆ 11.8, PhCH); 4.67 (d, J ˆ 12.1, PhCH); 4.72 (d, J ˆ 12.1, PhCH); 4.82 (irrad. at 3.86 ! s); 4.97 (d, J ˆ
10.9, PhCH); 7.21 7.36 (m, 20 arom. H). 13C-NMR (CDCl3, 75 MHz): see Table 2; additionally, 52.84 (dq,
2J(C,P) ˆ 6.1, MeO); 53.05 (dq, 2J(C,P) ˆ 6.1, MeO); 70.86, 71.93, 73.22, 74.98 (4t, 4 P hCH2); 127.61 128.57
(several d); 137.24, 137.64, 137.76, 137.90 (4s). 31P-NMR (CDCl3, 121 MHz): see Table 1. HR-MALDI-MS:
‡
‡
‡
‡
707.2287 (5, [M ‡ K] , C38H41KN2O7P ; calc. 707.2288), 691.2553 (62, [M ‡ Na] , C38H41N2NaO7P ; calc.
‡
‡
‡
‡
691.2549), 669.2725 (100, [M ‡ H] , C38H42N2O7P ; calc. 669.2729), 561.2164 (22, [M À BnO] , C31H34N2O6P ;
calc. 561.2154), 334.6364 (5). Anal. calc. for C38H41N2O7P(668.72): C 68.25, H 6.18, N 4.19; found: C 68.09,
H 6.30, N 4.25.
(5R,6R,7S,8R)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
phosphonic Acid (16). A suspension of 12 (16.6 mg, 24.2 mmol) and Pd(PPh3)4 (8.2 mg, 7.10 mmol) in freshly
distilled and degassed toluene (61 ml) was treated under Ar with Et3N (24 ml, 0.172 mmol) and HPO(OSiMe3)2
(28 ml, 0.120 mmol), warmed to 958, and stirred for 44 h. The mixture was concentrated and co-evaporated with
toluene (4 Â 5 ml). FC (RP-C18 silica gel, MeOH/H2O 6 :4 ! 1:0) gave 16 (10.1 mg, 65%) and 17 (0.6 mg, 4%)
[20].
Data of 16: White foam. Rf (RP C18, MeOH/H2O 9 :1) 0.32. IR (CHCl3): 3500 2100m (br.), 3162w,
3066m, 2961m, 2871m, 1952w, 1875w, 1812w, 1723w, 1601w, 1536w, 1497m, 1454m, 1365m, 1332w, 1261s, 1098s,
1015s, 916m, 870w. 1H-NMR (CD3OD, 300 MHz): see Table 1; additionally, 3.73 (irrad. at 3.81 ! change); 3.81
(irrad. at 3.73 ! change); 4.15 (irrad. at 4.29 ! d, J ˆ 3.1, irrad. at 5.17 ! d, J ˆ 6.2); 4.29 (irrad. at 4.15 !
change); 4.41 (d, J ˆ 12.1, PhCH); 4.45 (d, J ˆ 12.8, PhCH); 4.52 4.62 (m, irrad. at 4.29 ! change, HÀC(5));
4.53 (d, J ˆ 11.5, PhCH); 4.58 (d, J ˆ 11.8, PhCH); 4.60 (d, J ˆ 11.8, PhCH); 4.63 (d, J ˆ 11.5, PhCH); 4.76 (d, J ˆ
11.5, PhCH); 4.81 (d, J ˆ 11.8, PhCH); 5.17 (irrad. at 4.15 ! s); 7.17 7.37 (m, 18 arom. H); 7.41 7.44 (m, 2
arom. H). 13C-NMR (CD3OD, 75 MHz): see Table 2; additionally, 74.42 (3t), 74.45 (2t) (CH2ÀC(5), 4 PhCH2);
129.35 130.12 (several d); 138.57, 138.91, 138.96, 139.00 (4s); d of C(2) is hidden by signals at 129.35 130.12
‡
‡
ppm. 31P-NMR (CD3OD, 121 MHz): see Table 1. FAB-MS: 1960 (3, [3M ‡ K] ), 1944 (2, [3M ‡ Na] ), 1922 (3,
‡
‡
‡
‡
‡
[3M ‡ H] ), 1319 (2, [2M ‡ K] ), 1303 (2, [2M ‡ Na] ), 1281 (22, [2M ‡ H] ), 679 (1, [M ‡ K] ), 663 (7, [M ‡
‡
‡
‡
‡
‡
Na] ), 641 (100, [M ‡ H] ), 561 (1, [M À HPO3] ), 533 (5, [M À BnO] ), 91 (90, C7H7 ).
Deprotection of 14 and 15. a) A soln. of 14 (603 mg, 0.865 mmol) in CH2Cl2 (8.5 ml) was cooled to 08,
treated with Me3SiBr (670 ml, 5.18 mmol), stirred for 1 h, warmed to 238, and stirred for 19 h. The mixture was
concentrated and co-evaporated with toluene (4 Â 4 ml). The residue was taken up in MeOH/H2O 9 :1 (20 ml),
evaporated, and co-evaporated with toluene (2 Â 4 ml) to afford a white foam (crude 16). A soln. of crude 16
(568 mg) in MeOH/AcOEt/H2O 3 :1:1 (15 ml) was treated with 20% Pd(OH)2/C (210 mg) and hydrogenated
for 43 h at atmospheric pressure and 238. The suspension was filtered through Celite (washing with 30 ml MeOH/

728
Helvetica Chimica Acta Vol. 87 (2004)
H2O 9 :1). Evaporation gave crude 11 (280 mg), which was taken up in 2 ml of H2O and applied to a DEAE-
1
cellulose column (Cellex-D, Bio-Rad, 15 Â 1.5 cm, 0.5 0.7 bar; H-NMR detection). The column was washed
with H2O (100 ml), and 11 was eluted with a triethylammonium hydrogen carbonate buffer (pH ca. 7.4 ; 5 mm,
100 ml; 10 mm, 100 ml; 15 mm, 100 ml; 20 mm, 100 ml; 25 mm, 100 ml). The fractions containing 11 were
‡
combined and lyophilized (3Â) to give 11 (270 mg, 1.25 equiv. of Et3NH , 77%).
b) Similarly as a, a soln. of 14 (100 mg, 0.144 mmol) in CH2Cl2 (1.4 ml) was treated with Me3SiBr (110 ml,
0.851 mmol), and stirred for 15 min at 08 and for 20 h at 238. Workup gave crude 16 (77 mg), which was
dissolved in MeOH/AcOEt/H2O 3 :1:1 (1.5 ml), treated with 20% Pd(OH)2/C (65 mg), and hydrogenated for
26 h. Filtration over Celite, evaporation of the filtrate, and lyophilisation yielded crude 11 (36 mg), which was
dissolved in H2O (1 ml) and treated with Et3N (50 ml, 0.359 mmol). The soln. was evaporated and co-evaporated
with toluene (4 Â 2 ml). The residue was taken up in MeOH/H2O 1 :1 (2 ml), treated with activated charcoal,
‡
and filtered. Evaporation and lyophilisation (3Â) gave 11 (44 mg, 1.10 equiv. of Et3NH , 78%).
c) Similarly as a, a soln. of 15 (360 mg, 0.538 mmol) in CH2Cl2 (5.5 ml) was treated with Me3SiBr (420 ml,
3.25 mmol), and stirred for 15 min at 08, and for 15 h at 238. Workup gave crude 16 (365 mg), which was
dissolved in MeOH/AcOEt/H2O 3 :1:1 (8 ml), treated with 20% Pd(OH)2/C (350 mg), and hydrogenated for
36 h. Filtration over Celite and evaporation of the filtrate yielded crude 11 (199 mg). Ion-exchange
‡
chromatography and lyophilisation gave 11 (179 mg, 1.19 equiv. of Et3NH , 83%).
Data of Triethylammonium Hydrogen (5R,6R,7S,8R)-6,7,8-Trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahy-
droi midazo[1,2-a]pyridine-2-phosphonate (11). Rf (MeOH/NH3/H2O 4 :3 :1) 0.50. IR (KBr): 3394s (br.),
2975m, 2937s, 2738s, 2678s, 2492m, 1640w, 1476m, 1434m, 1398m, 1092s, 1036m, 804w. 1H-NMR (D2O, 400 MHz,
1.60 equiv. of Et3N): see Table 1; additionally, 1.23 (t, J ˆ 7.3, 1.60 (MeCH2)3NH); 3.15 (q, J ˆ 7.3, 1.60
(MeCH2)3NH); 4.04 (irrad. at 4.21 ! change); 4.07 (irrad. at 5.13 ! d, J ꢀ 9.0); 4.16 (irrad. at 4.04 ! change);
4.21 (irrad. at 4.04 ! change); 4.28 (irrad. at 4.07 ! change); 5.13 (irrad. at 4.07 ! s). 13C-NMR (D2O,
100 MHz, 1.60 equiv. of Et3N): see Table 2; additionally, 10.91 (q, 1.60 (MeCH2)3NH); 49.34 (t, 1.60
(MeCH2)3NH). 31P-NMR (D2O, 121 MHz, 1.60 equiv. of Et3N): see Table 1. ESI-MS (MeOH/H2O 1:1,
negative mode): 581 (13, [2M À 2 H ‡ Na]À), 559 (15, [2M À H]À), 375 (22), 339 (25), 325 (80), 311 (100, [M ‡
MeO]À), 297 (26, [M ‡ HO]À), 279 (63, [M À H]À), 255 (26), 213 (63).
Triethylammonium Hydrogen (5R,6R,7S,8R)-6,7,8-Triacetoxy-5-[(acetoxy)methyl]-5,6,7,8-tetrahydroimid-
‡
azo[1,2-a]pyridine-2-phosphonate (18). A suspension of 11 (50 mg, 1.60 equiv. of Et3NH , 0.113 mmol) in
distilled pyridine (1.3 ml) was treated with distilled Ac2O (390 ml, 4.13 mmol) and stirred under Ar at 238. After
2 h, the suspension changed to a clear soln., which was stirred for next 34 h, evaporated, and co-evaporated with
toluene (4 Â 2 ml). The residue was dissolved in H2O (10 ml) and washed with AcOEt (4 Â 3 ml). The aq. layer
‡
was concentrated in vacuo and lyophilised to give 18 (66.1 mg, 1.62 equiv. of Et3NH ; 96%). Rf (AcOEt/MeOH/
H2O 8 :4 :1) 0.41. IR (KBr): 3414m (br.), 2976m, 2938s, 2739m, 2678s, 2492m, 1748s, 1641w, 1517w, 1476m,
1434m, 1398m, 1372s, 1232s, 1171m, 1141m, 1070s, 950m, 924m, 849w, 805w. 1H-NMR (CD3OD, 400 MHz): see
Table 1; additionally, 1.31 (t, J ˆ 7.3, 1.62 (MeCH2)3NH); 2.03, 2.07, 2.12, 2.13 (4s, 4 AcO); 3.21 (q, J ˆ 7.3, 1.62
(MeCH2)3NH). 13C-NMR (CD3OD, 100 MHz): see Table 2; additionally, 9.22 (q, 1.62 (MeCH2)3NH); 20.50,
20.55, 20.59, 20.61 (4q, 4 Me); 47.81 (t, 1.62 (MeCH2)3NH); 171.07, 171.24, 171.36, 171.86 (4s, 4 CˆO). 31P-NMR
‡
‡
(CD3OD, 121 MHz): see Table 1. FAB-MS: 923 (2, [2M ‡ 2 Na À H3O] ), 901 (6, [2M ‡ Na À H2O] ), 897 (2,
‡
‡
‡
‡
[2M ‡ H] ), 879 (2, [2M À OH] ), 693 (6, [M À 3 H ‡ 2 Et3N ‡ 2 Na] ), 614 (9, [M À 4 H ‡ Et3N ‡ 3 Na] ), 592
‡
‡
‡
(38, [M À 3 H ‡ Et3N ‡ 2 Na] ), 550 (10, [M ‡ Et3NH] ), 535 (9, [M À 5 H ‡ 4 Na] ), 529 (10), 513 (46, [M À 4
‡
‡
‡
‡
‡
H ‡ 3 Na] ), 491 (4, [M À 3 H ‡ 2 Na] ), 487 (10, [M ‡ K] ), 471 (28, [M ‡ Na] ), 453 (36, [M ‡ Na À H2O] );
‡
‡
449 (31, [M ‡ H] ); 102 (100, Et3NH ).
Diethyl (5R,6R,7S,8R)-6,7,8-Trihydroxy-5-(hydroxymethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
phosphonate (19). A soln. of 14 (103 mg, 0.148 mmol) in AcOEt/MeOH/H2O 1:6 :1 (0.8 ml) and AcOH
(0.4 ml) was treated with 20% Pd(OH)2/C and hydrogenated for 24 h at 238 and at the atmospheric pressure.
The mixture was filtered through Celite (washing with 20 ml of MeOH). Evaporation, FC (AcOEt/i-PrOH/H2O
8 :4 :1), and lyophilization gave 19 (41 mg, 82%) as a white powder. Rf (AcOEt/i-PrOH/H2O 8 :4 :1) 0.26.
[a]2D5 ˆ À18.9 (c ˆ 0.75, MeOH). UV (MeOH): 211 (3.97), 193 (3.21). UV (H2O): 210 (3.98). IR (KBr): 3700
2000s (br.), 2987m, 2924m, 1643w, 1522m, 1476w, 1440w, 1394m, 1218s, 1163m, 1097s, 1051s, 1023s, 976m, 902w,
794m, 768m, 663m. 1H-NMR (CD3OD, 300 MHz): see Table 1; additionally, 1.31 (t, J ˆ 7.2, MeCH2O); 1.32 (t,
J ˆ 7.2, MeCH2O); 3.85 (irrad. at 4.86 ! d, J ˆ 8.7); 3.95 (irrad. at 3.89 ! change); 4.01 4.23 (m, HÀC(6), 2
MeCH2O); 4.17 (irrad. at 3.89 ! change, irrad. at 3.95 ! change); the signal of HÀC(8) is partially hidden by
the signal of HDO. 1H-NMR (D2O, 300 MHz): see Table 1; additionally, 1.15 (br. t, J ˆ 7.2, 2 MeCH2O); 3.98 (br.
q, J ꢀ 6.8, MeCH2O); 4.00 (br. q, J ꢀ 7.2, MeCH2O); 4.05 4.15 (m, HÀC(5), CH'ÀC(5)). 13C-NMR (CD3OD,
75 MHz): see Table 2; additionally, 16.56 (dq, 3J(C,P) ˆ 6.7, 2 MeCH2O); 63.90 (dt, 2J(C,P) ꢀ 5.3, MeCH2O);

Helvetica Chimica Acta Vol. 87 (2004)
729
63.93 (dt, 2J(C,P) ꢀ 5.1, MeCH2O). 13C-NMR (D2O, 75 MHz): see Table 2; additionally, 15.43 (dq, 3J(C,P) ˆ 6.1,
2 MeCH2O); 63.99 (dt, 2J(C,P) ˆ 4.9, MeCH2O); 64.05 (dt, 2J(C,P) ˆ 4.3, MeCH2O). 31P-NMR (CD3OD,
‡
121 MHz): see Table 1. 31P-NMR (D2O, 121 MHz): see Table 1. HR-MALDI-MS: 375.0730 (4, [M ‡ K] ,
‡
‡
‡
C12H21KN2O7P ; calc. 375.0723), 359.0981 (100, [M ‡ Na] , C12H21N2NaO7P ; calc. 359.0984), 337.1158 (72,
‡
‡
[M ‡ H] , C12H22N2O7P ; calc. 337.1165), 332.1834 (15), 309.0840 (7), 276.1209 (5), 210.1482 (15). Anal. calc.
for C12H21N2O7P¥ 0.5 H 2O (345.29): C 41.74, H 6.42, N 8.11; found C 42.09, H 6.79, N 8.01.
Diethyl (5R,6R,7S,8R)-6,7,8-Triacetoxy-5-[(acetoxy)methyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-
phosphonate (20). A soln. of 19 (15 mg, 44.6 mmol) and DMAP(1.2 mg, 9.82 mmol) in pyridine (0.4 ml) was
treated with Ac2O (26 ml, 0.275 mmol), stirred for 16 h, and treated with sat. NH4Cl soln. (2 ml). The mixture
was diluted with CH2Cl2 (30 ml) and washed with sat. NH4Cl soln. (3 Â 20 ml). The combined aq. layers were
extracted with CH2Cl2 (2 Â 20 ml). The combined org. extracts were washed with H2O (40 ml) and brine
(40 ml), dried (Na2SO4), evaporated, and co-evaporated with toluene (3 Â 5 ml). FC (AcOEt/Et3N 1:0.03)
yielded 20 (17.1 mg, 76%). Colourless oil. Rf (AcOEt/Et3N 1:0.03) 0.13. Rf (AcOEt) 0.10. [a]2D5 ˆ À39.6 (c ˆ
1.00, CHCl3). UV (CHCl3): 239 (2.43). IR (CHCl3): 2997m, 2931w, 2856w, 1755s, 1602w, 1516w, 1427w, 1370m,
1
1239s, 1133m, 1053s, 1028s, 974m, 953m, 916w. H-NMR (CDCl3, 300 MHz): see Table 1; additionally, 1.35 (t,
J ˆ 7.2, 2 MeCH2O); 2.05, 2.11, 2.12, 2.13 (4s, 4 AcO); 4.07 4.26 (m, 2 MeCH2O); 4.30 (irrad. at 4.56 !
change); 4.35 (irrad. at 4.56 ! change, irrad. at 5.59 ! change); 4.50 4.62 (m, Jgem ˆ 11.2, CH'ÀC(5)); 5.41
(irrad. at 5.59 ! change, irrad. at 6.39 ! d, J ˆ 8.7); 5.59 (irrad. at 5.41 ! change); 6.39 (irrad. at 5.41 ! s).
13C-NMR (CDCl3, 75 MHz): see Table 2; additionally, 16.29 (dq, 3J(C,P) ˆ 6.7, MeCH2O); 16.31 (dq, 3J(C,P) ˆ
6.7, MeCH2O); 20.52 (q, Me); 20.66 (q, 2 Me); 20.73 (q, Me); 62.59 (dt, 2J(C,P) ˆ 4.9, MeCH2O); 62.65 (dt,
2J(C,P) ˆ 4.9, MeCH2O); 169.29, 169.36, 169.49, 170.06 (4s, 4 CˆO). 31P-NMR (CDCl3, 121 MHz): see Table 1.
‡
‡
‡
HR-MALDI-MS: 543.1141 (2, [M ‡ K] , C20H29KN2O11P ; calc. 543.1146), 527.1397 (43, [M ‡ Na] ,
‡
‡
‡
C20H29N2NaO11P ; calc. 527.1406), 505.1586 (100, [M ‡ H] , C20H30N2O11P ; calc. 505.1587), 385.1158 (9),
343.1049 (9), 325.0945 (19), 252.5781 (7).
Benzyl[(2,2-dimethoxy)ethylidene]amine (22). A suspension of BnNH2 (16.95 g, 0.158 mol) and MgSO4
(19.67 g, 0.163 mol) in THF (280 ml) was cooled to 08, treated dropwise over 10 min with ca. 45% glyoxal 1,1-
dimethyl acetal in t-BuOMe (34.5 ml, 0.134 mol), stirred for 4 h at 08 and for another 12 h at 0 ! 228. The solid
was filtered off and washed with Et2O (50 ml). Evaporation of the combined filtrate and washing ( ! yellowish
oil) and distillation (micro-distillation apparatus) at 0.3 Torr gave 22 (23.45 g, 90%). Colourless liquid. Rf
(hexane/AcOEt 1:1) 0.48. B.p. (0.3 Torr) 80 848. IR (CHCl3): 3085w, 3066w, 3029w, 3012m, 2966m, 2938m,
2895m, 2836m, 1950w, 1872w, 1808w, 1744w, 1676w, 1604w, 1496w, 1453m, 1376m, 1298w, 1256w, 1169w, 1136m,
1
1099s, 1067s, 994m, 961m, 915w. H-NMR (CDCl3, 300 MHz): see Table 3; additionally, 3.41 (s, 2 MeO); 4.65
(br. s, w1/2 ꢀ 3.5, PhCH2); 7.21 7.35 (m, 5 arom. H). 13C-NMR (CDCl3, 75 MHz): see Table 3; additionally, 53.87
(q, 2 MeO); 64.43 (t, P hCH2); 127.05 (d, C(4) of Ph); 127.98 (d, C(2) and C(6) of Ph); 128.40 (d, C(3) and C(5) of
‡
Ph); 138.00 (s, C(1) of Ph). ESI-MS: 354 (9), 295 (18), 264 (8, [M ‡ MeOH ‡ K] ), 248 (88, [M ‡ MeOH ‡
‡
‡
‡
‡
‡
Na] ), 226 (85, [M ‡ MeOH ‡ H] ), 216 (28, [M ‡ Na] ), 194 (100, [M ‡ H] ), 162 (16, [M À MeO] ), 108
‡
(28), 91 (12, C7H7 ). Anal. calc. for C11H15NO2 (193.25): C 68.37, H 7.82, N 7.25; found: C 68.36, H 8.05, N 7.42.
1
Table 3. Selected H-, 13C-, and 31P-NMRChemical Shifts [ppm] and Coupling Constants [Hz] of the Imine 22
and the Amines 23 26 in CDCl3
22
23
24
25
26
HÀC(1)
HÀC(2)
J(1,2)
2J(1,P)
3J(2,P)
C(1)
7.60a)
4.74
4.4
3.11
4.54
4.4
3.23
4.51
4.7
3.14
4.57
4.4
3.28
4.53
4.7
15.3
15.6
14.9
15.6
4.7
56.23
104.56
153.5
8.6
4.1
51.60
104.09
154.4
6.1
5.0
56.19
104.42
153.8
8.5
4.1
51.38
103.94
154.4
6.1
161.18
102.96
C(2)
1J(1,P)
2J(2,P)
P
25.76
25.70
28.17
28.17
a) 4J(1,CH2) ˆ 1.6 Hz.

730
Helvetica Chimica Acta Vol. 87 (2004)
Diethyl [1-(Benzylamino)-2,2-dimethoxyethyl]phosphonate (23).
A
soln. of HPO(OEt)2 (6.70 ml,
52.0 mmol) and Et3N (8.0 ml, 57.4 mmol) in CH2Cl2 (1 l) was cooled to 08, treated dropwise within 15 min
with Me3SiCl (7.40 ml, 58.3 mmol), stirred for 15 min, treated with a soln. of 22 (10.03 g, 51.9 mmol) in CH2Cl2
(15 ml), stirred for 20 min at 08 and for 16 h at 228, and poured into H2O (500 ml). The layers were separated
and the aq. phase was extracted with CH2Cl2 (2 Â 200 ml). The combined org. layers were washed with brine
(350 ml), dried (MgSO4), and evaporated. FC (AcOEt) gave 23 (12.0 g, 70%) and 22 (0.83 g, 8%) as colourless
oils.
Data of 23: Rf (AcOEt) 0.17. IR (CHCl3): 3366w (br.), 3027w, 2994s, 2935m, 2910m, 2867w, 2837w, 2472w,
1
1950w, 1874w, 1810w, 1751w, 1603w, 1495w, 1454m, 1391w, 1369w, 1242m, 1100m, 1055s, 1028s, 966s. H-NMR
(CDCl3, 300 MHz): see Table 3; additionally, 1.315 (t, J ˆ 7.2, MeCH2O); 1.320 (t, J ˆ 7.2, MeCH2O); 1.90 2.00
(br. s, exchange with CD3OD, NH); 3.35, 3.39 (2s, 2 MeO); 3.94 (br. d, J ˆ 13.4, w1/2 ꢀ 2.1, PhCH); 4.01 (br. d,
J ˆ 13.4, w1/2 ꢀ 2.1, PhCH'); 4.01 4.21 (m, 2 MeCH2O); 7.18 7.36 (m, 5 arom. H). 13C-NMR (CDCl3, 75 MHz):
see Table 3; additionally, 16.41 (dq, 3J(C,P) ꢀ 5.7, MeCH2O); 16.47 (dq, 3J(C,P) ꢀ 5.2, MeCH2O); 52.77 (dt,
3J(C,P) ˆ 6.7, PhCH2); 55.18 (q, MeO); 55.60 (q, MeO); 61.94 (dt, 2J(C,P) ˆ 6.7, MeCH2O); 62.40 (dt, 2J(C,P) ˆ
6.7, MeCH2O); 126.92 (d, C(4) of Ph); 128.17 (d, C(2) and C(6) of Ph); 128.47 (d, C(3) and C(5) of Ph); 139.83
‡
(s, C(1) of Ph). 31P-NMR (CDCl3, 121 MHz): see Table 3. ESI-MS: 685 (3, [2M ‡ Na] ), 530 (2), 386 (2, [M ‡
‡
‡
‡
‡
‡
MeOH ‡ Na] ), 370 (11, [M ‡ K] ), 354 (100, [M ‡ Na] ), 332 (27, [M ‡ H] ), 300 (20, [M À MeO] ), 194 (2,
‡
‡
‡
[M À PO3Et2] ). HR-ESI-MS: 685.3011 (100, [2M ‡ Na] , C30H52N2NaO10P2 ; calc. 685.2995), 370.1209 (<1,
‡
‡
‡
‡
[M ‡ K] , C15H26KNO5P ; calc. 370.1186), 354.1438 (12, [M ‡ Na] , C15H26NNaO5P ; calc. 354.1446), 332.1640
‡
‡
‡
‡
(2, [M ‡ H] , C15H27NO5P ; calc. 332.1627), 300.1374 (1, [M À MeO] , C14H23NO4P ; calc. 300.1365). Anal.
calc. for C15H26NO5P(331.35): C 54.37, H 7.91, N 4.23; found: C 54.27, H 8.05, N 4.41.
Diethyl (1-Amino-2,2-dimethoxyethyl)phosphonate (24). a) At the atmospheric pressure and 228, a
suspension of 23 (77 mg, 0.232 mmol) and 20% Pd(OH)2/C (40 mg) in EtOH (1.5 ml) was stirred under H2 for
3 h. The catalyst was filtered off over Celite, and the filtrate was evaporated to give 24 (38.1 mg, 68%).
b) A soln. of 23 (60 mg, 0.181 mmol) in EtOH (1.5 ml) was treated with 10% Pd/C (30 mg) and
hydrogenated at the atmospheric pressure for 3 h. Filtration over Celite and evaporation gave 24 (36.9 mg,
84%).
c) A soln. of 23 (5.0 g, 15.1 mmol) in EtOH (100 ml) was treated with 10% Pd/C (500 mg) and
hydrogenated for 42 h at the atmospheric pressure and 228. New portions of the fresh catalyst (5 Â 500 mg) had
to be added during the reaction period. After the reaction was complete, the mixture was filtered over Celite.
Evaporation and bulb-to-bulb distillation at 0.4 Torr gave 24 (2.78 g, 76%).
d) At 228 and 6 bar, a suspension of 23 (800 mg, 2.41 mmol) and 10% Pd/C (400 mg) in EtOH (10 ml) was
hydrogenated for 2 h and filtered over Celite. Evaporation and distillation according to c gave 24 (429 mg, 74%).
Colourless oil.
Data of 24: Rf (AcOEt/MeOH 7 :1) 0.24. B.p. (0.4 Torr) 1308. IR (CHCl3): 3394w, 3026w, 2995s, 2938m,
2911m, 2837w, 2472w, 1598w (br.), 1445w, 1392w, 1369w, 1244m, 1163m, 1119m, 1055s, 1028s, 977s, 881w, 828w.
1H-NMR (CDCl3, 300 MHz): see Table 3; additionally, 1.31 (t, J ˆ 7.2, MeCH2O); 1.32 (t, J ˆ 7.2, MeCH2O);
1.43 1.64 (br. s, exchange with CD3OD, NH2); 3.42, 3.44 (2s, 2 MeO); 4.12 (br. q, J ˆ 7.2, w1/2 ˆ 3.6, MeCH2O);
4.14 (br. q, J ˆ 7.2, w1/2 ˆ 3.6, MeCH2O). 13C-NMR (CDCl3, 75 MHz): see Table 3; additionally, 16.37 (q,
MeCH2O); 16.45 (q, MeCH2O); 55.10 (q, MeO); 55.51 (q, MeO); 62.17 (dt, 2J(C,P) ˆ 6.7, MeCH2O); 62.40 (dt,
2J(C,P) ˆ 6.7, MeCH2O). 31P-NMR (CDCl3, 121 MHz): see Table 3. HR-ESI-MS: 533.2383 (13), 505.2061 (100,
‡
‡
‡
‡
[2M ‡ Na] , C16H40N2NaO10P2 ; calc. 505.2056), 483.2248 (14, [2M ‡ H] , C16H41N2O10P2 ; calc. 483.2236),
‡
‡
‡
‡
280.0726 (8, [M ‡ K] , C8H20KNO5P ; calc. 280.0716), 264.0971 (31, [M ‡ Na] , C8H20NNaO5P ; calc.
‡
‡
264.0977), 252.6343 (3), 242.1167 (3, [M ‡ H] , C8H21NO5P ; calc. 242.1157), 210.0900 (14). Anal. calc. for
C8H20NO5P(241.22): C 39.83, H 8.36, N 5.81; found: C 40.02, H 8.33, N 5.98.
Dimethyl [1-(Benzylamino)-2,2-dimethoxyethyl]phosphonate (25). A soln. of HPO(OMe)2 (0.48 ml,
5.24 mmol) and Et3N (0.80 ml, 5.74 mmol) in CH2Cl2 (100 ml) was cooled to 08, treated dropwise within 3 min
with Me3SiCl (0.74 ml, 5.83 mmol), stirred for 10 min, treated with a soln. of 22 (1.03 g, 5.33 mmol) in CH2Cl2
(5 ml), stirred for 5 min at 08 and for 3 h at 228, and poured into H2O (100 ml). The layers were separated, and
the aq. phase was extracted with CH2Cl2 (2 Â 50 ml). The combined org. layers were washed with brine (100 ml),
dried (MgSO4), and evaporated. FC (AcOEt) afforded 25 (976 mg, 60%) and 22 (103 mg, 10%) as colourless
oils.
Data of 25: Rf (AcOEt) 0.08. IR (CHCl3): 3406w (br.), 3028w, 3001m, 2957m, 2853w, 2838w, 2473w, 1950w,
1876w, 1810w, 1753w, 1603w, 1495w, 1454m, 1358w, 1242m, 1103m, 1061s, 1039s, 970w, 908w, 834w. 1H-NMR
(CDCl3, 300 MHz): see Table 3; additionally, 1.89 2.01 (br. s, exchange with CD3OD, NH); 3.36, 3.38 (2s, 2
MeO); 3.74 (d, 3J(H,P) ˆ 10.6, MeOP); 3.79 (d, 3J(H,P) ˆ 10.6, MeOP); 3.92 (br. d, J ˆ 13.4, w1/2 ꢀ 3.0 Hz,

Helvetica Chimica Acta Vol. 87 (2004)
731
PhCH); 4.00 (br. d, J ˆ 13.1, w1/2 ꢀ 3.0 Hz, PhCH); 7.19 7.35 (m, 5 arom. H). 13C-NMR (CDCl3, 75 MHz): see
Table 3; additionally, 52.74 (dq, 2J(C,P) ˆ 7.3, MeOP); 52.82 (dt, 3J(C,P) ˆ 6.7, PhCH2); 53.27 (dq, 2J(C,P) ˆ 7.3,
MeOP); 55.08 (q, MeO); 55.78 (q, MeO); 127.03 (d, C(4) of Ph); 128.25 (d, C(2) and C(6) of Ph); 128.47 (d,
C(3) and C(5) of Ph); 139.70 (s, C(1) of Ph). 31P-NMR (CDCl3, 121 MHz): see Table 3. HR-ESI-MS: 657.2688
‡
‡
‡
‡
(6), 629.2406 (100, [2M ‡ Na] , C26H44N2NaO10P2 ; calc. 629.2369), 342.0887 (1, [M ‡ K] , C13H22KNO5P ; calc.
‡
‡
‡
‡
342.0873), 326.1125 (10, [M ‡ Na] , C13H22NNaO5P ; calc. 326.1133), 304.1331 (<1, [M ‡ H] , C13H23NO5P ;
calc. 304.1314). Anal. calc. for C13H22NO5P(303.29): C 51.48, H 7.31, N 4.62; found: C 51.41, H 7.24, N 4.86.
Dimethyl (1-Amino-2,2-dimethoxyethyl)phosphonate (26). A suspension of 25 (800 mg, 2.64 mmol) and
10% Pd/C (400 mg) in MeOH (10 ml) was hydrogenated at 6 bar and 228 for 3 h, and filtered over Celite.
Evaporation and bulb-to-bulb distillation of the yellowish oil at 0.3 Torr gave 26 (409 mg, 73%) as a colourless
oil.
Data of 26: Rf (AcOEt/MeOH 7 :1) 0.24. B.p. (0.3 Torr) 1308. IR (CHCl3): 3395w, 3027w, 3001s, 2958m,
1
2853w, 2838w, 2473w, 1601w (br.), 1447m, 1364w, 1248m, 1178m, 1119m, 1062s, 1039s, 974m, 835m. H-NMR
(CDCl3, 300 MHz): see Table 3; additionally, 1.43 1.63 (br. s, exchange with CD3OD, NH2); 3.45, 3.47 (2s, 2
MeO); 3.79 (d, 3J(H,P) ˆ 10.6, MeOP); 3.80 (d, 3J(H,P) ˆ 10.6, MeOP). 13C-NMR (CDCl3, 75 MHz): see
Table 3; additionally, 52.82 (dq, 2J(C,P) ˆ 6.1, MeOP); 53.11 (dq, 2J(C,P) ˆ 6.7, MeOP); 54.99 (q, MeO); 55.58
‡
(q, MeO). 31P-NMR (CDCl3 , 121 MHz): see Table 3. HR-ESI-MS: 449.1425 (17, [2M ‡ Na] ,
‡
‡
‡
C12H32N2NaO10P2 ; calc. 449.1430), 427.1626 (1, [2M ‡ H] , C12H33N2O10P2 ; calc. 427.1610), 326.1129 (5),
‡
‡
‡
‡
236.0655 (100, [M ‡ Na] , C6H16NNaO5P ; calc. 236.0664), 182.0578 (5, [M À MeO] , C5H13NO4P ; calc.
182.0582). Anal. calc. for C6H16NO5P(213.17): C 33.81, H 7.57, N 6.57; found: C 34.00, H 7.42, N 6.62.
Preparation of 29 and 30. a) By Treatment of 1 with the Aminophosphonate 24 and HgCl2 in 2-
Methoxyethanol at 808. A suspension of 1 (50 mg, 90.3 mmol), HgCl2 (35 mg, 0.129 mmol), and molecular sieves
(4 ä; 50 mg) in 2-methoxyethanol (1 ml) was treated successively with 24 (44 mg, 0.182 mmol) and Et3N (25 ml,
0.179 mmol), heated for 5 h at 808, cooled to 228, diluted with AcOEt (5 ml), and filtered over Celite (washing
with 40 ml of AcOEt). The combined filtrate and washings were extracted with sat. NaHCO3 soln. (3 Â 20 ml)
and brine (30 ml), dried (Na2SO4), and evaporated. FC (hexane/AcOEt/Et3N 3 :1 :0.12 ! 2 :1 :0.09 !
1:1:0.06) gave 29 (19.1 mg, 36%), 29/30 42 :58 (8.3 mg, 15%), 30 containing up to 10% of an unidentified
impurity (8.3 mg, ca. 15%), and 27/28 54:46 (8.4 mg, 16%) [74][75].
b) By Treatment of 1 with HgCl2 in 2-Methoxyethanol at 228. A suspension of 1 (50 mg, 90.3 mmol), HgCl2
(35 mg, 0.129 mmol), and molecular sieves (4 ä; 50 mg) in 2-methoxyethanol (1 ml) was treated with Et3N
(25 ml, 0.179 mmol) and stirred for 14 h at 228. Workup and FC (as described in a) gave 29 (37.6 mg, 70%), 29/30
15 :85 (8.6 mg, 16%), and 27/28 65 :35 (3.4 mg, 7%) [74][75].
c) By Treatment of 1 with HgCl2 in 2-Methoxyethanol at 808. A suspension of 1 (100 mg, 0.181 mmol), HgCl2
(78 mg, 0.287 mmol), and molecular sieves (4 ä, 100 mg) in 2-methoxyethanol (2 ml) was treated with Et3N
(50 ml, 0.359 mmol) and heated for 2 h at 808. Workup and FC, as described in a, gave 29 (33.1 mg, 31%), 29/30
75:25 (28.6 mg, 27%), 30 containing up to 10% of an unidentified impurity (18.7 mg, ca. 17%), and 27/28 58:42
(11.5 mg, 12%) [74][75].
Data of (2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-[(benzyloxy)methyl]-6-[2-(methoxy)ethoxy]-2,3,4,5-tetra-
hydropyridine (29). Colourless oil. Rf (hexane/AcOEt/Et3N 2 :1:0.09) 0.48. [a]2D5 ˆ ‡95.6 (c ˆ 1.02, CHCl3). UV
(CHCl3): 259 (2.91). IR (CHCl3): 3089w, 3067w, 3032w, 3012m, 2875m, 1951w, 1875w, 1810w, 1751w, 1675s,
1604w, 1496w, 1454m, 1402w, 1360m, 1296m, 1267w, 1232m, 1126s, 1094s, 1028m, 913w, 844w. 1H-NMR (CDCl3,
300 MHz): 3.42 (s, MeO); 3.54 (dtd, J ꢀ 1.9, 3.1, 8.7, HÀC(2)); 3.67 3.79 (m, MeOCH2CH2O, CH2ÀC(2),
HÀC(3)); 3.93 (dd, J ˆ 7.8, 9.7, HÀC(4)); 4.16 (dd, J ˆ 1.9, 7.8, HÀC(5)); 4.27 4.30 (m, MeOCH2CH2O); 4.51
(d, J ˆ 12.5, PhCH); 4.54 (d, J ˆ 11.2, PhCH); 4.58 (d, J ˆ 12.5, PhCH); 4.70 (d, J ˆ 10.9, PhCH); 4.81 (d, J ˆ
11.2, PhCH); 4.83 (d, J ˆ 10.6, PhCH); 4.87 (d, J ˆ 10.6, PhCH); 5.00 (d, J ˆ 10.6, PhCH); 7.21 7.24 (m, 2 arom.
1
H); 7.25 7.38 (m, 16 arom. H); 7.39 7.43 (m, 2 arom. H). H-NMR (C6D6, 300 MHz): 3.09 (s, MeO); 3.39 (t,
J ˆ 5.3, MeOCH2CH2O); 3.64 (dtd, J ꢀ 1.9, 2.8, 8.7, irrad. at 4.09 ! td, J ˆ 2.8, 8.7, HÀC(2)); 3.79 (dd, J ˆ 2.5, 9.0,
irrad. at 3.64 ! d, J ˆ 9.0, CHÀC(2)); 3.83 (dd, J ˆ 3.1, 9.0, irrad. at 3.64 ! d, J ˆ 9.0, CH'ÀC(2)); 3.89 (t, J ꢀ 9.0,
irrad. at 3.64 ! d, J ꢀ 9.0, HÀC(3)); 3.98 (dd, J ˆ 7.2, 9.3, irrad. at 4.09 ! d, J ˆ 9.3, HÀC(4)); 4.09 (dd, J ˆ 1.9,
6.9, irrad. at 3.64 ! d, J ˆ 7.2, irrad. at 3.98 ! d, J ꢀ 1.3, HÀC(5)); 4.27 4.41 (m, irrad. at 3.39 ! change,
MeOCH2CH2O); 4.37 (d, J ˆ 12.1, PhCH); 4.44 (d, J ˆ 12.1, PhCH); 4.62 (d, J ˆ 11.5, PhCH); 4.63 (d, J ˆ 11.2,
PhCH); 4.73 (d, J ˆ 11.5, PhCH); 4.80 (d, J ˆ 11.5, PhCH); 4.93 (d, J ˆ 11.2, PhCH); 5.03 (d, J ˆ 11.2, PhCH);
7.04 7.20 (m, 12 arom. H); 7.24 7.32 (m, 6 arom. H); 7.41 7.45 (m, 2 arom. H). 13C-NMR (CDCl3, 75 MHz):
58.95 (q, MeO); 60.47 (d, C(2)); 64.65 (t, MeOCH2); 70.36, 70.74 (2t, CH2ÀC(2), CH2OÀC(6)); 73.16, 74.64,
74.74, 74.87 (4t, 4 P hCH2); 77.06, 79.05, 83.18 (3d, C(3), C(4), C(5)); 127.35 128.25 (several d); 137.87, 138.19,
138.32, 138.42 (4s); 160.89 (s, C(6)). 13C-NMR (C6D6, 75 MHz): 58.63 (q, MeO), 61.07 (d, C(2)); 65.03 (t,

732
Helvetica Chimica Acta Vol. 87 (2004)
MeOCH2); 70.92, 71.04 (2t, CH2ÀC(2), CH2OÀC(6)); 73.46, 74.49, 74.54, 74.88 (4t, 4 P hCH2); 77.58, 79.36,
83.82 (3d, C(3), C(4), C(5)); 127.57 128.52 (several d); 138.96 (s); 139.29 (2s); 139.41 (s); 161.62 (s, C(6)). HR-
‡
‡
‡
MALDI-MS: 652.2678 (1, [M ‡ K ‡ H2O] , C37H43KNO7 ; calc. 652.2676), 636.2932 (15, [M ‡ Na ‡ H2O] ,
‡
‡
‡
C37H43NNaO7 ; calc. 636.2937), 614.3110 (100, [M ‡ H ‡ H2O] , C37H44NO7 ; calc. 614.3118), 596.3015 (4, [M ‡
‡
‡
H] , C37H42NO6 ; calc. 596.3012), 560.2415 (2), 538.2584 (2), 506.2541 (10). Anal. calc. for C37H41NO6 (595.73):
C 74.60, H 6.94, N 2.35; found: C 74.65, H 6.81, N 2.52.
Data of (2R,3R,4S,5S)-3,4,5-Tris(benzyloxy)-2-[(benzyloxy)methyl]-6-[2-(methoxy)ethoxy]-2,3,4,5-tetra-
hydropyridine (30; containing up to 10% of an unidentified impurity). Colourless oil. Rf (hexane/AcOEt/Et3N
2 :1:0.09) 0.41. Rf (CH2Cl2/MeOH/Et3N 1:0.01:0.01) 0.23 (30) and 0.13 (impurity). IR (CHCl3): 3391w
(impurity), 3089w, 3066w, 3028w, 3012w, 2928w, 2861w, 1951w, 1875w, 1810w, 1706m (impurity), 1677s, 1602m,
1496w, 1455m, 1410w, 1363w, 1319w, 1265m, 1097s, 1013m, 911w, 823w. 1H-NMR (CDCl3, 300 MHz): 3.14 3.22
(m, impurity); 3.38 (s, MeO); 3.41 (s, impurity); 3.54 3.64 (m, HÀC(2), CH2ÀC(2)); 3.65 3.69 (m,
MeOCH2CH2O); 3.73 (dd, J ˆ 3.7, 9.0, HÀC(4)); 4.08 (dd, J ˆ 6.8, 9.0, HÀC(3)); 4.13 (d, J ˆ 3.7, HÀC(5));
4.17 4.22 (m, MeOCH2CH2O); 4.26 4.31 (m, impurity); 4.40 (dd, J ˆ 2.5, 5.9, impurity); 4.47 (s, impurity);
4.52 (d, J ˆ 12.1, PhCH); 4.53 (s, impurity); 4.575 (d, J ˆ 12.1, PhCH); 4.582 (d, J ˆ 12.1, PhCH); 4.59 (d, J ˆ 11.2,
PhCH); 4.63 (d, J ˆ 12.1, PhCH); 4.78 (d, J ˆ 12.1, PhCH); 4.86 (d, J ˆ 10.9, PhCH); 4.87 (d, J ˆ 12.1, PhCH);
5.24 (d, J ˆ 5.9, impurity); 7.21 7.38 (m, 18 arom. H); 7.40 7.44 (m, 2 arom. H). 13C-NMR (CDCl3, 75 MHz):
58.94 (q, MeO); 61.76 (d, C(2)); 64.60 (t, MeOCH2); 70.68, 71.48 (2t, CH2ÀC(2), CH2OÀC(6)); 71.57 (d, C(3)),
71.84 (t, P hCH2); 73.07 (t, 2 P hCH2), 74.25 (t, P hCH2), 74.42 (d, C(5)); 79.43 (d, C(4)); 127.25 128.23 (several
‡
d); 138.12, 138.14, 138.44, 138.60 (4s); 160.23 (s, C(6)). HR-MALDI-MS: 652.2684 (1, [M ‡ K ‡ H2O] ,
‡
‡
‡
C37H43KNO7 ; calc. 652.2676), 636.2931 (12, [M ‡ Na ‡ H2O] , C37H43NNaO7 ; calc. 636.2937), 614.3109 (100,
‡
‡
‡
‡
[M ‡ H ‡ H2O] , C37H44NO7 ; calc. 614.3118), 596.3013 (4, [M ‡ H] , C37H42NO6 ; calc. 596.3012), 560.2415
(3), 506.2541 (9).
REFERENCES
[1] I. Billault, A. Vasella, Helv. Chim. Acta 1999, 82, 1137.
[2] P. Burda, M. Aebi, Glycobiology 1998, 8, 455.
[3] A. I. Razumov, P. A. Gurevich, J. Gen. Chem. USSR(Engl. Transl.) 1967, 37, 1537.
[4] R. W. Ratcliffe, B. G. Christensen, Tetrahedron Lett. 1973, 14, 4645.
[5] P. A. Bartlett, J. T. Hunt, J. L. Adams, J.-C. E. Gehret, Bioorg. Chem. 1978, 7, 421.
[6] E. ÷hler, M. El-Badawi, E. Zbiral, Chem. Ber. 1984, 117, 3034.
[7] P. S. Khokhlov, B. A. Kashemirov, A. D. Mikityuk, A. L. Chimishkyan, Y. A. Strepikheev, J. Gen. Chem.
USSR(Engl. Transl.) 1984, 54, 2414.
[8] J. G. Buchanan, A. E. McCaig, R. H. Wightman, J. Chem. Soc., Perkin Trans. 1 1990, 955.
[9] M. P. Sokolov, B. I. Buzykin, T. A. Zyablikova, J. Gen. Chem. USSR(Engl. Transl.) 1990, 60, 1155.
[10] M. Schnell, M. Ramm, A. Kˆckritz, J. Prakt. Chem. 1994, 336, 29.
[11] W.-S. Huang, C.-Y. Yuan, Synthesis 1996, 511.
[12] F. I. Guseinov, K. A. Asadov, R. N. Burangulova, V. V. Moskva, Chem. Heterocycl. Compd. (N. Y.) 2001, 37,
1050.
[13] F.-Z. Hu, H.-Z. Yang, Synth. Commun. 2001, 31, 3817.
[14] P. Jimonet, G. A. Bohme, J. Bouquerel, A. Boireau, D. Damour, M. W. Debono, A. Genevois-Borella, J.-C.
¬
Hardy, P. Hubert, F. Manfre, P. Nemecek, J. Pratt, J. C. R. Randle, Y. Ribeill, J.-M. Stutzmann, M.
Vuilhorgne, S. Mignani, Bioorg. Med. Chem. Lett. 2001, 11, 127.
[15] J. Lin, C. M. Thompson, J. Heterocycl. Chem. 1994, 31, 1701.
[16] I. V. Komarov, M. Y. Kornilov, A. V. Turov, M. V. Gorichko, V. O. Popov, A. A. Tolmachev, A. J. Kirby,
Tetrahedron 1995, 51, 12417.
[17] T. Tschamber, F. Gessier, M. Neuburger, S. S. Gurcha, G. S. Besra, J. Streith, Eur. J. Org. Chem. 2003, 2792.
[18] R. D. Cummings, in −Glycoconjugates: Composition, Structure, and Function×, Eds. H. J. Allen and E. C.
Kisailus, Marcel Dekker, New York, 1992, p. 333.
[19] M. Terinek, A. Vasella, Helv. Chim. Acta 2003, 86, 3482.
[20] T. Granier, N. Panday, A. Vasella, Helv. Chim. Acta 1997, 80, 979.
[21] N. Panday, Y. Canac, A. Vasella, Helv. Chim. Acta 2000, 83, 58.
[22] T. Hirao, T. Masunaga, Y. Ohshiro, T. Agawa, Synthesis 1981, 56.
[23] T. Hirao, T. Masunaga, N. Yamada, Y. Ohshiro, T. Agawa, Bull. Chem. Soc. Jpn. 1982, 55, 909.

Helvetica Chimica Acta Vol. 87 (2004)
[24] A. A. Tolmachev, E. S. Kozlov, A. M. Pinchuk, J. Gen. Chem. USSR(Engl. Transl.) 1986, 56, 2214.
733
¬
[25] D. F. Ortwine, T. C. Malone, C. F. Bigge, J. T. Drummond, C. Humblet, G. Johnson, G. W. Pinter, J. Med.
Chem. 1992, 35, 1345.
¬
[26] P. Pechy, F. P. Rotzinger, M. K. Nazeeruddin, O. Kohle, S. M. Zakeeruddin, R. Humphry-Baker, M.
Gr‰tzel, J. Chem. Soc., Chem. Commun. 1995, 65.
[27] P. Desos, J. M. Lepagnol, P. Morain, P. Lestage, A. A. Cordi,J. Med. Chem. 1996, 39, 197.
[28] V. Penicaud, F. Odobel, B. Bujoli, Tetrahedron Lett. 1998, 39, 3689.
[29] T. Johansson, J. Stawinski, Chem. Commun. 2001, 2564.
[30] M. Sawa, T. Kiyoi, K. Kurokawa, H. Kumihara, M. Yamamoto, T. Miyasaka, Y. Ito, R. Hirayama, T. Inoue,
Y. Kirii, E. Nishiwaki, H. Ohmoto, Y. Maeda, E. Ishibushi, Y. Inoue, K. Yoshino, H. Kondo, J. Med. Chem.
2002, 45, 919.
[31] T. Johansson, J. Stawinski, Phosphorus Sulfur Silicon Relat. Elem. 2002, 177, 1779.
[32] M. Sekine, K. Okimoto, K. Yamada, T. Hata, J. Org. Chem. 1981, 46, 2097.
[33] J. A. Mikroyannidis, Phosphorus Sulfur Silicon Relat. Elem. 1982, 12, 249.
[34] C.-Y. Yuan, S.-H. Cui, Phosphorus Sulfur Silicon Relat. Elem. 1991, 55, 159.
[35] D. G. Cameron, H. R. Hudson, M. Pianka, Phosphorus Sulfur Silicon Relat. Elem. 1993, 83, 21.
[36] S. De Lombaert, K. Singh, L. Blanchard, V. F. Soliman, Bioorg. Med. Chem. Lett. 1994, 4, 899.
[37] S. De Lombaert, L. Blanchard, C. Berry, R. D. Ghai, A. J. Trapani, Bioorg. Med. Chem. Lett. 1995, 5,
151.
[38] E. M. Wallace, J. A. Moliterni, M. A. Moskal, A. D. Neubert, N. Marcopulos, L. B. Stamford, A. J. Trapani,
P. Savage, M. Chou, A. Y. Jeng, J. Med. Chem. 1998, 41, 1513.
[39] B. Lejczak, P. Kafarski, J. Szewczyk, Synthesis 1982, 412.
[40] M. M. Vaghefi, R. J. Bernacki, W. J. Hennen, R. K. Robins, J. Med. Chem. 1987, 30, 1391.
[41] A. Dessinges, A. Vasella, Carbohydr. Res. 1988, 174, 47.
[42] L. Cheng, C. A. Goodwin, M. F. Scully, V. V. Kakkar, G. Claeson, Tetrahedron Lett. 1991, 32, 7333.
[43] V. Corizzi, B. Badet, M.-A. Badet-Denisot, J. Chem. Soc., Chem. Commun. 1992, 189.
[44] J. Szewczyk, B. Lejczak, P. Kafarski, Synthesis 1982, 409.
[45] C. E. McKenna, M. T. Higa, N. H. Cheung, M.-C. McKenna, Tetrahedron Lett. 1977, 18, 155.
[46] C. E. McKenna, J. Schmidhauser, J. Chem. Soc., Chem. Commun. 1979, 739.
[47] N. Panday, M. Meyyappan, A. Vasella, Helv. Chim. Acta 2000, 83, 513.
[48] S. J. Williams, R. Hoos, S. G. Withers, J. Am. Chem. Soc. 2000, 122, 2223.
[49] A. Peer, A. Vasella, Helv. Chim. Acta 1999, 82, 1044.
¬
¬
¬
¬
¬
[50] G. Abraham, S. Solyom, E. Csuzdi, P. Berzsenyi, I. Ling, I. Tarnawa, T. Hamori, I. Pallagi, K. Horvath, F.
¬
¬
¬
¬
Andrasi, G. Kapus, L. G. Harsing Jr., I. Kiraly, M. Patthy, G. Horvath, Bioorg. Med. Chem. 2000, 8, 2127.
[51] P. Kafarski, J. Zon, in −Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity×,
Eds. V. P. Kukhar and H. R. Hudson, John Wiley & Sons Ltd., Chichester, 2000, p. 33.
[52] V. P. Kukhar, in −Aminophosphonic and Aminophosphinic Acids: Chemistry and Biological Activity×, Eds.
V. P. Kukhar and H. R. Hudson, John Wiley & Sons Ltd., Chichester, 2000, p. 127.
[53] K. Afarinkia, C. W. Rees, J. I. G. Cadogan, Tetrahedron 1990, 46, 7175.
[54] Y. P. Auberson, H. Allgeier, S. Bischoff, K. Lingenhoehl, R. Moretti, M. Schmutz,Bioorg. Med. Chem. Lett.
2002, 12, 1099.
[55] B. Boduszek, M. Soroka, Pol. J. Chem. 2002, 76, 1105.
[56] A. Bongini, R. Camerini, M. Panunzio, Tetrahedron: Asymmetry 1996, 7, 1467.
[57] X. Creary, C. C. Geiger, K. Hilton, J. Am. Chem. Soc. 1983, 105, 2851.
[58] D. A. Evans, K. M. Hurst, J. M. Takacs, J. Am. Chem. Soc. 1978, 100, 3467.
[59] G. Godin, P. Compain, G. Masson, O. R. Martin, J. Org. Chem. 2002, 67, 6960.
[60] F. Hammerschmidt, Liebigs Ann. Chem. 1991, 469.
[61] T. Johansson, A. Kers, J. Stawinski, Tetrahedron Lett. 2001, 42, 2217.
[62] Z.-H. Li, C.-F. Zhu, Y.-Z. Zhao, Phosphorus Sulfur Silicon Relat. Elem. 1994, 86, 229.
[63] E. Stanoeva, S. Varbanov, V. Alexieva, I. Sergiev, V. Vasileva, M. Rashkova, A. Georgieva, Phosphorus
Sulfur Silicon Relat. Elem. 2000, 165, 117.
[64] S. Vonhoff, A. Vasella, Synth. Commun. 1999, 29, 551.
¬
¬
¬
[65] M. Avalos, R. Babiano, P. Cintas, C. J. Duran, F. J. Higes, J. L. Jimenez, I. Lopez, J. C. Palacios, Tetrahedron
1997, 53, 14463.
[66] C. J. Aucken, F. J. Leeper, A. R. Battersby, J. Chem. Soc., Perkin Trans. 1 1997, 2099.
[67] M. K. Tong, G. Papandreou, B. Ganem, J. Am. Chem. Soc. 1990, 112, 6137.

734
Helvetica Chimica Acta Vol. 87 (2004)
[68] T. Kajimoto, K. K.-C. Liu, R. L. Pederson, Z.-Y. Zhong, Y. Ichikawa, J. A. Porco Jr., C.-H. Wong, J. Am.
Chem. Soc. 1991, 113, 6187.
[69] R. Hoos, A. B. Naughton, W. Thiel, A. Vasella, W. Weber, K. Rupitz, S. G. Withers, Helv. Chim. Acta 1993,
76, 2666.
[70] T. Y. Dol×nikova, V. A. Kozlov, A. F. Grapov, N. N. Mel×nikov, J. Gen. Chem. USSR(Engl. Transl.) 1984,
54, 76.
[71] C. M. McCloskey, Adv. Carbohydr. Chem. 1957, 12, 137.
œ
œ
[72] K. D. Philips, J. Zemlicka, J. P. Horwitz, Carbohydr. Res. 1973, 30, 281.
[73] N. Panday, A. Vasella, Synthesis 1999, 1459.
[74] R. Hoos, A. B. Naughton, A. Vasella, Helv. Chim. Acta 1993, 76, 1802.
[75] H. S. Overkleeft, J. van Wiltenburg, U. K. Pandit, Tetrahedron 1994, 50, 4215.
Received October 31, 2003