A facile synthesis of azetidin-2-ylphosphonic acid and its 1-alkyl derivatives

Article abstract of DOI:10.1135/cccc20010507

Treatment of racemic diisopropyl [1,3-bis(mesyloxy)propyl]phosphonate with allyl-, benzyl-, 2-hydroxyethy]-, or propylamine gave the corresponding diisopropyl [(3-(alkylamino)-1-(mesyloxy)propyl]phosphonates. Heating of their toluene solution with aqueous

Full text of DOI:10.1135/cccc20010507

Azetidin-2-ylphosphonic Acid
507
A FACILE SYNTHESIS OF AZETIDIN-2-YLPHOSPHONIC ACID
AND ITS 1-ALKYL DERIVATIVES
1,
Miroslav OTMAR *, Lucie POLÁKOVÁ, Milena MASOJÍDKOVÁ
2
and Antonín HOLÝ
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,
1
Flemingovo nám. 2, 166 10 Prague 6, Czech Republic; e-mail: otmar@uochb.cas.cz,
2
holy@uochb.cas.cz
Received October 5, 2000
Accepted March 29, 2001
Treatm en t of racem ic diisopropyl [1,3-bis(m esyloxy)propyl]ph osph on ate with allyl-, ben zyl-,
2-h ydroxyeth yl-, or propylam in e gave th e correspon din g diisopropyl [(3-(alkylam in o)-
1-(m esyloxy)propyl]ph osph on ates. Heatin g of th eir toluen e solution with aqueous potas-
sium carbon ate effected a cyclization to diisopropyl (1-alkylazetidin -2-yl)ph osph on ates. In
th e 1-ben zyl- an d [1-(2-h ydroxyeth yl)azetidin -2-yl]ph osph on ate, th e isopropyl ester groups
were rem oved by treatm en t with brom otrim eth ylsilan e wh ich gave 1-ben zyl- an d
[1-(2-h ydroxyeth yl)azetidin -2-yl]ph osph on ic acid. Followin g h ydrogen olysis of th e ben zyl
group afforded azetidin -2-ylph osph on ic acid.
Keywords: Ph osph on ates; Ph osph on opeptides; Azetidin es; Am in oph osph on ates; Am in o acids
an alogs; Cyclization s; Hydrolysis.
(α-Am in oalkyl)ph osph on ic acids h ave been frequen tly em ployed as attrac-
tive m im ics of am in o acids in biological system s; several of th em are poten t
an tibiotics, en zym e in h ibitors (in cludin g HIV protease), ligan ds for excit-
atory am in o acid receptors, pesticides, in secticides, an d h erbicides1–5. Nu-
m erous biologically active ph osph on ate an alogues of prolin e h ave been
described, am on g th em , aziridin -2-yl-, pyrrolidin -2-yl-, an d piperidin -2-yl-
ph osph on ic acid6,7. Paradoxically, th ere is n ot an y ph osph on ate coun ter-
part to L-azetidin e-2-carboxylic acid8, wh ich is a poten t prolin e an tagon ist
in biological system s. We foun d on ly on e related com poun d in th e litera-
ture: dim eth yl (1-tosylazetidin -2-yl)ph osph on ate9 wh ich was prepared (for
a differen t purpose) by reaction of 2-(acetoxy)-1-tosylazetidin e with
trim eth yl ph osph ite. Th is prom pted us to attem pt th e syn th esis of
azetidin -2-ylph osph on ic acid an d its derivatives10.
Collect. Czech. Chem. Commun. (Vol. 66) (2001)
doi: 10.1135/cccc20010507

508
Otmar, Poláková, Masojídková, Holý:
RESULTS AND DISCUSSION
For a con struction of th e azetidin e rin g bearin g ph osph on ate fun ction in
position 2, we selected th e curren t m eth odology wh ich em ploys rin g-
closure of 1,3-dim esylates (1,3-ditosylates, 1,3-dih alides) with prim ary
am in es11. Th e required bifun ction al syn th on (h avin g dialkylph osph on yl
group in gem in al position with respect to on e of th e m esylates) can be ob-
tain ed by addition of a dialkyl ph osph ite to carbon yl group (Pudovik reac-
tion 12
) of th e suitably protected 3-h ydroxyaldeh yde, followed by
deprotection an d subsequen t tran sform ation of th e form ed 1,3-dih ydroxy
derivative to its dim esylate. Diisopropyl ph osph ite was selected for th e
Pudovik reaction , because th e resultin g isopropyl diesters are stable en ough
in a boilin g aqueous potassium carbon ate–toluen e m ixture used for th e
azetidin e rin g-closure an d th eir bulkin ess prom oted th e cyclization .
Treatm en t of 3-(ben zyloxy)propan al13 (1) with diisopropyl ph osph ite an d
trieth ylam in e afforded diisopropyl [3-(ben zyloxy)-1-h ydroxypropyl]-
ph osph on ate (2; Sch em e 1). Ben zyl group was th en rem oved by h ydrogen a-
tion an d th e form ed diol 3 was con verted to dim esylate 4. Th e reaction of
OR2
OMs
O
O
(i)
(iv)
R1O
P
RNH
P
BnO
O
Oi-Pr
Oi-Pr
i-PrO
i-PrO
1
5a-5d
2 R1 = Bn, R2 = H
3 R1 = R2 = H
4 R1 = R2 = Ms
(ii)
(iii)
(v)
5-7
a
R
allyl
R
R
N
b
benzyl
N
(vi), (ii) (for 7e)
c
2-hydroxyethyl
propyl
O
O
P
HO OH
P
d
i-PrO Oi-Pr
7
6a-6d
e
H
7b,7c,7e
(i) HP(O)(Oi-Pr)2, Et3N; (ii) H2/Pd; (iii) MsCl, pyridine–CH2Cl2 (1 : 1); (iv) RNH2,1,2-dimethoxyethane;
(v) K2CO3, toluene–water (1 : 1), reflux; (vi) Me3SiBr, CH3CN
SCHEME 1
th is in term ediate with allyl-, ben zyl-, 2-h ydroxyeth yl-, or propylam in e at
room tem perature gave th e correspon din g diisopropyl [3-(alkylam in o)-
1-(m esyloxy)propyl]ph osph on ates (5a–5d ) in h igh yields. Heatin g of th eir
toluen e solution with aqueous potassium carbon ate resulted in
a
cyclization to th e diisopropyl (1-alkylazetidin -2-yl)ph osph on ates (6a–6d ).
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Azetidin-2-ylphosphonic Acid
509
Th is sh ows th at th e closure of 1,3-dim esylates to azetidin e rin g is n ot af-
fected by th e presen ce of diisopropylph osph on yl group in gem in al position
to on e of th e m esylates. 1-Ben zyl 6b an d 1-(2-h ydroxyeth yl) derivative 6c
were subsequen tly con verted to th e free acids 7b an d 7c by treatm en t with
brom otrim eth ylsilan e. No sign s of a cleavage of th e azetidin e rin g durin g
deprotection were observed. Azetidin -2-ylph osph on ic acid (7e) was fin ally
obtain ed by h ydrogen ation of th e com poun d 7b.
Structure of th e azetidin es 6a–6d , 7b, 7c, an d 7e was un equivocally
proved by NMR spectra. Form ation of th e azetidin e rin g from acyclic
[3-(alkylam in o)-1-(m esyloxy)propyl]ph osph on ates 5a–5d h as a sign ifican t
in fluen ce on ch em ical sh ifts of in dividual h ydrogen , carbon , as well as
ph osph orus atom s. Replacem en t of th e electron -with drawin g m esyloxy
group with am in o fun ction results in an upfield sh ift of α-H from 4.9–5.0
to 3.3–3.5 ppm an d α-C from 74–75 to 60–61 ppm . β-Carbon (position 2 is
precursors 5 correspon din g to position 3 in azetidin es 6) sh ifts from 27–31
to 19 ppm , wh ich is a value ch aracteristic for 3-C of azetidin es. Th e
rin g-closure is accom pan ied by a decrease in electron den sity at th e (origi-
n ally secon dary) am in o group. Th is causes a lowfield sh ift of γ-carbon s
from 44 to 53 ppm . Th e decreased distan ce between γ-carbon an d ph osph o-
rus resulted in an in crease in th e couplin g con stan t from 11–12 to 23–25 Hz.
At 1′-C, a sim ilar lowfield sh ift from 50–53 to 61–62 was observed. Appear-
an ce of spin couplin g between 1′-C an d ph osph orus in dicates a decrease in
th eir distan ce on th e azetidin e rin g-closure. In 31P NMR spectra, th e closure
of azetidin e rin g is m an ifested by a lowfield sh ift from 16–17 to 22–23 ppm .
Rem oval of isopropyl ester groups is m an ifested by an in crease of all proton
ch em ical sh ift values by 0.4–1.0 ppm an d by a decrease of J(2-C,P) value by
about 40 Hz.
Th e MS (EI) spectra of azetidin es 6a–6d are ch aracterized by th e presen ce
of th e m ost in ten sive peak M – 165 (100%), wh ich is due to th e loss of th e
fragm en t P(O)(Oi-Pr)2. Surprisin gly en ough , th e sam e peak dom in ates in
MS (EI) spectra (con trary to FAB) of th eir precursors 5a an d 5d . In th e
ben zyl derivative 5b an d in th e h ydroxy derivative 5c, its in ten sity is 19
an d 30%, respectively. Th is suggests th at th e electron im pact effected
cyclization of th e precursors 5a–5d to azetidin es 6a–6d wh ich are furth er
fragm en ted (see above). MS (FAB) spectra of free acids 7b, 7c, an d 7e are
ch aracterized by very in ten sive peak M – 81 (60–100%) wh ich represen ts a
loss of P(O)(OH)2 fragm en t. MS (FAB) spectrum of azetidin -2-ylph osph on ic
acid (7e) sh ows, in addition to th e m olecular peak 138 (100%, M + H),
peaks with m ultiples of th e m olecular weigh t m/z: 275 (42%, 2 M + H), 412
(7%, 3 M + H), an d 549 (4%, 4 M + H). In com poun d 7c, besides of th e m o-
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510
Otmar, Poláková, Masojídková, Holý:
lecular peak 182 (61%, M + H), a peak of a dim er 363 (24%, 2 M + H) is
m an ifested in th e spectrum . It sh ows a stron g ability of th ese com poun ds
to self-association by h ydrogen -bon din g.
In con clusion , th e described m eth od represen ts a con ven ien t syn th etic
approach to azetidin -2-ylph osph on ic acid an d its 1-alkyl derivatives.
EXPERIMENTAL
Gen eral
Meltin g poin ts were determ in ed on a Kofler block an d are un corrected. An alytical TLC was
perform ed on silica gel pre-coated alum in ium plates with fluorescen t in dicator (Merck 5554,
60 F254). Visualization was effected (i) by UV ligh t (254 n m ), (ii) by sprayin g with
4-(4-n itrobezyl)pyridin e (1% solution in eth an ol), a sh ort h eatin g to 300–400 °C followed by
exposition to gaseous am m on ia), or (iii) by sprayin g with n in h ydrin e (1% solution in eth a-
n ol) an d a sh ort h eatin g to 300–400 °C. Colum n ch rom atograph y was carried out on silica
gel (Sigm a S-0507, 40–63 µm ). Gas ch rom atograph y (GC) was carried out on an HP 5890 in -
strum en t (Hewlett–Packard) with flam e ion ization detector. For purity assays, an HP-Ultra 2
colum n with a tem perature gradien t of 8 °C/m in (80–300 °C) was used; in jection tem pera-
ture 250 °C, detector tem perature 300 °C. Mass spectra were m easured on a ZAB-EQ (VG An -
alytical) spectrom eter, usin g th e EI (electron en ergy 70 eV), FAB (ion isation with Xe,
acceleratin g voltage 8 kV, th ioglycerol–glycerol 3 : 1 m ixture or bis(2-h ydroxyeth yl)
disulfide were used as m atrixes). 1H NMR spectra were recorded at 500 MHz on a Varian
UNITY 500 in strum en t in DMSO-d6 (referen ced to th e solven t sign al δ 2.50 ppm ) or in deu-
terium oxide with 3-(trim eth ylsilyl)propan e-1-sulfon ate as an in tern al stan dard. 13C NMR
APT spectra were recorded at 127.5 MHz on a Varian UNITY 500 in strum en t in DMSO-d6
(referen ced to th e solven t sign al δ 39.70) or in deuterium oxide with dioxan e as an extern al
referen ce (δ 66.86). 31P NMR spectra were taken at 80.98 MHz on a Varian UNITY 200 in -
strum en t in DMSO-d6 or in D2O with th e use of ph osph oric acid as an extern al stan dard.
Ch em ical sh ifts are given in ppm (δ-scale), couplin g con stan ts (J) in Hz. IR spectra were
obtain ed on an FT IR Bruker IFS 88 spectrom eter in ch loroform at approxim ately 3% con -
cen tration .
Diisopropyl [3-(Ben zyloxy)-1-h ydroxypropyl]ph osph on ate (2)
Diisopropyl ph osph ite (15 m l, 90 m m ol) an d trieth ylam in e (13 m l, 90 m m ol) were added to
3-(ben zyloxy)propan al13 (1; 1.5 g, 90 m m ol) an d th e reaction m ixture was left to stan d at
room tem perature overn igh t. Trieth ylam in e was evaporated in vacuo, th e residue was taken
in to eth yl acetate, wash ed with brin e, dried over an h ydrous m agn esium sulfate, an d evapo-
rated. Ch rom atograph y on a silica gel colum n with ch loroform gave 2 (16.8 g, 62%) as a
colourless oil. MS (FAB): 331 (83%, M + H), 289 (12%, M – i-Pr + 2 H), 247 (44%, M – 2 i-Pr
+ 3 H), 139 (37%), 91 (100%, Bn ). 1H NMR (500 MHz, DMSO-d6): 7.25–7.38 m , 5 H (arom .);
5.44 t, J = 6.6 (OH); 4.45 s, 2 H (OCH2Ph ); 4.59 m , 2 H (P-OCH); 3.79 dtd, 1 H, J = 9.5, 6.6,
6.6, 3.9 (1-H); 3.52–3.60 m , 2 H (3-H); 1.91 m , 1 H (2a-H); 1.70 m , 1 H (2b-H); 1.245 d, 3 H,
J = 6.3 (CH3); 1.24 d, 3 H, J = 6.3 (CH3); 1.23 d, 6 H, J = 6.3 (CH3). 13C NMR (127.5 MHz,
DMSO-d6): 138.82 (arom .); 128.43, 2 C (arom .); 127.59, 2 C (arom .); 127.54 (arom .); 72.09
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

Azetidin-2-ylphosphonic Acid
511
(CH2-Ph ); 70.03 d, J = 7.8 (CH-O-P); 69.81 d, J = 7.8 (CH-O-P); 65.93 d, J = 14.65 (3-C);
63.60 d, J = 168.0 (1-C); 31.91 d, J = 2.9 (2-C); 24.10 d, J = 3.9 (CH3); 24.04 d, J = 3.9 (CH3);
23.92 d, J = 3.9 (CH3); 23.89 d, J = 3.9 (CH3). For C16H27O5P (330.4) calculated: 58.18% C,
8.24% H, 9.38% P; foun d: 58.21% C, 8.01% H, 9.51% P.
Diisopropyl (1,3-Dih ydroxypropyl)ph osph on ate (3)
To a solution of com poun d 2 (5 g, 15 m m ol) in eth yl acetate (1 l), palladium (10 wt.%) on
activated carbon was added un der argon an d th e reaction m ixture was h ydrogen ated un der
20 kPa overpressure for 8 h . Th e catalyst was rem oved by filtration over Celite, th e filtrate
was evaporated an d applied on to a silica gel colum n . Elution with ch loroform gave com -
poun d 3 (3.4 g, 93%) as a colourless th ick oil. MS (FAB): 241 (92%, M + H), 199 (23%, M –
i-Pr + 2 H), 157 (100%, M - 2 i-Pr + 3 H). 1H NMR (500 MHz, DMSO-d6): 5.29 br t, 1 H, J =
6.8, 6.6 (1-OH); 4.58 dsept, 1 H, J = 7.6, 6.1 (POCH); 4.56 dsept, 1 H, J = 7.6, 6.1 (POCH);
4.46 t, 1 H, J = 5.4, 5.1 (3-OH); 3.77 dtd, 1 H, J = 10.3, 6.6, 6.6, 2.9 (1-H); 3.46–3.56 m , 2 H
(3-H); 1.70–1.78 m , 1 H, J = 13.7, 8.8, 6.6, 6.6, 2.9 (2a-H); 1.55–1.63 m , 1 H, J = 13.7, 10.3,
9.8, 5.4, 4.6 (2b-H); 1.24 d, 3 H, J = 6.1 (CH3); 1.23 d, 3 H, J = 6.1 (CH3). 13C NMR
(127.5 MHz, DMSO-d6): 69.96 d, J = 6.8 (P-OCH); 69.73 d, J = 6.8 (P-OCH); 63.59 d, J =
167.0 (1-C); 57.05 d, J = 14.65 (3-C); 34.80 d, J = 2.0 (C-2); 24.15 d, J = 4.9 (CH3); 24.09 d,
J = 4.9 (CH3); 23.95 d, J = 3.9 (CH3); 23.93 d, J = 3.9 (CH3). For C9H21O5P (240.2) calculated:
45.00% C, 8.81% H, 12.89% P; foun d: 44.89% C, 8.69% H, 13.05% P.
Diisopropyl [1,3-Bis(m esyloxy)propyl]ph osph on ate (4)
Com poun d 3 (3.5 g, 14.6 m m ol) was co-evaporated with pyridin e, dissolved in a dich loro-
m eth an e–pyridin e 1 : 1 m ixture (100 m l), an d cooled to 0 °C. Th en m esyl ch loride (2.5 m l,
32 m m ol) was added an d th e m ixture was kept at room tem perature for 4 h . Th e m ixture
was cooled to 0 °C, excess water was added, reaction m ixture was taken in to eth yl acetate,
wash ed with aqueous sodium h ydrogen carbon ate an d brin e, dried with an h ydrous m agn e-
sium sulfate an d evaporated. Ch rom atograph y on a silica gel colum n with ch loroform gave
th e product 4 (4.8 g, 83%) as a colourless th ick oil. MS (FAB): 397 (20%, M + H), 355 (12%,
M – i-Pr + 2 H), 313 (100%, M – 2 i-Pr + 3 H), 217 (96%, M - 2 i-Pr – MsO + 2 H). 1H NMR
(500 MHz, DMSO-d6): 4.93 td, 1 H, J = 9.3, 9.3, 4.2 (1-H); 4.71 m , 2 H (P-OCH); 4.37 dt, J =
10.7, 5.0, 5.0 (3a-H); 4.27 ddd, J = 10.7, 8.0, 5.6 (3b-H); 3.32 s, 3 H (Ms); 3.19 s, 3 H (Ms);
2.26 m , 1 H (2a-H); 2.15 m , 1 H (2b-H); 1.31 d, 3 H, J = 6.1 (CH3); 1.30 d, 6 H (CH3);
1.295 d, 3 H (CH3). 13C NMR (127.5 MHz, DMSO-d6): 72.40 d, J = 170.9 (1-C); 72.24 d, J =
6.8 (P-OCH); 72.21 d, J = 6.8 (P-OCH); 65.93 d, J = 12.7 (3-C); 38.71 (Ms); 36.91 (Ms); 30.28
(2-C); 23.97 d, J = 3.9 (CH3); 23.88 d, J = 3.9 (CH3); 23.74 d, J = 4.9 (CH3); 23.65 d, J = 4.9
(CH3). 31P NMR (88.98 MHz, DMSO-d6): 15.99 s. For C11H25O9PS2 (396.4) calculated:
33.33% C, 6.36% H, 7.81% P; foun d: 33.50% C, 6.48% H, 7.64% P.
Diisopropyl [3-(Alkylam in o)-1-(m esyloxy)propyl]ph osph on ates (5a–5d ).
Gen eral Procedure
Com poun d 4 (790 m g, 2 m m ol) was dissolved in 1,2-dim eth oxyeth an e (4 m l), a prim ary
am in e (5 m m ol) was added, an d th e reaction m ixture was kept at room tem perature over-
n igh t. Th e solven t was evaporated an d th e residue was applied on to a silica gel colum n . Re-
peated ch rom atograph y with a gradien t of 0–2 vol.% m eth an ol in ch loroform followed by
Collect. Czech. Chem. Commun. (Vol. 66) (2001)

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Otmar, Poláková, Masojídková, Holý:
precipitation from a m ixture of 0–25% eth yl acetate in petroleum eth er afforded th e title
com poun ds 5a–5d as th ick colourless oils in 70–85% yield as free bases. Traces of th e corre-
spon din g azetidin es 6a–6d (with h igh er RF th an com poun ds 5a–5d ) were detectable on TLC.
Free bases 5b an d 5c were furth er con verted to h ydroch lorides: th ey were dissolved in 1
M
m eth an olic HCl (2 m l) an d evaporated to dryn ess. Crystallization from petroleum
eth er–eth yl acetate (3 : 1) gave h ydroch loride of com poun d 5b as wh ite crystals. Hydroch lo-
ride of 5c was obtain ed by precipitation from petroleum eth er–eth yl acetate (5 : 1) as a
colourless th ick oil. (Treatm en t of com poun d 5a an d 5d with HCl did n ot afford crystallin e
h ydroch lorides.)
Diisopropyl [3-(allylamino)-1-(mesyloxy)propyl]phosphonate (5a). Yield 88%, th ick colourless
oil. MS (FAB): 358 (100%, M + H), 274 (40%, M + H – CH2=CHCH2NHCH2CH2). MS (EI):
357 (7%, M), 273 (6%, M – CH2=CHCH2NHCH2CH2), 96 (100%, 1-allylazetidin -2-yl), 70
(27%, CH2=CHCH2NHCH2), 41 (48%, allyl). HRMS (EI): for C13H28NO6PS calculated
357.1375, foun d 357.1355. 1H NMR (500 MHz, DMSO-d6): 5.82 ddt, 1 H, J = 17.3, 10.3, 5.9,
5.9 (2′-H); 5.15 dq, 1 H, J = 17.3, 1.7, 1.7, 1.5 (3′a-H, trans); 5.04 dq, 1 H, J = 10.3, 1.7, 1.5,
1.5 (3′b-H, cis); 4.93 td, 1 H, J = 8.8, 8.8, 3.9 (1-H); 4.68 m , 2 H (P-OCH); 3.14 dq, 2 H, J =
5.9, 1.5, 1.5, 1.5 (1′-H); 3.265 s, 3 H (Ms); 3.00 br, 1 H (NH); 2.67 ddd, 1 H, J = 12.0, 7.8, 4.9
(3a-H); 2.59 dt, 1 H, J = 12.0, 7.6, 7.6 (3b-H); 1.95 m , 1 H (2a-H); 1.84 m , 1 H (2b-H); 1.29 d,
3 H, J = 6.1 (CH3); 1.285 d, 6 H, J = 6.1 CH3); 1.28 d, 3 H, J = 6.1 (CH3). 13C NMR
(127.5 MHz, DMSO-d6): 137.25 (2′-C); 115.68 (3′-C); 74.54 d, J = 169.9 (1-C); 71.69 d, J = 6.8
(P-OCH); 51.385 (1′-C); 43.96 d, J = 10.7 (3-C); 38.70 (Ms); 30.35 (2-C); 23.96 d, J = 3.9
(CH3); 23.91 d, J = 3.9 (CH3); 23.76 d, J = 4.9 (CH3); 23.67 d, J = 4.9 (CH3). 31P NMR
(88.98 MHz, DMSO-d6): 16.99 s. For C13H28NO6PS (357.4) calculated: 43.69% C, 7.90% H,
3.92% N, 8.67% P; foun d: 44.01% C, 8.11% H, 3.75% N, 8.39% P.
Diisopropyl [3-(benzylamino)-1-(mesyloxy)propyl]phosphonate hydrochloride (5b ·HCl). Yield
83%, wh ite crystals; m .p. 138–139 °C. MS (FAB): 408 (100%, M + H, free base), 324 (30%),
91 (76%, Bn ). HRMS (FAB): for C17H31NO6PS (M + H) calculated 408.1610, foun d 408.1676.
MS (EI): 407 (1.4%, M), 146 (18%, 1-ben zylazetidin -2-yl), 136 (30%), 120 (16%, Bn NHCH2),
106 (54%, Bn NH), 91 (100%, Bn ). 1H NMR (500 MHz, DMSO-d6): 7.32 m , 4 H (arom .);
7.21 m , 1 H (arom .); 5.00 td, 1 H, J = 9.5, 9.5, 3.9 (1-H); 4.68 m , 2 H (P-OCH); 3.67 s, 2 H
(1′-H); 3.27 s, 3 H (Ms); 2.70 ddd, 1 H, J = 12.0, 7.3, 4.9 (3a-H); 2.62 dt, 1 H, J = 12.0, 7.6,
7.6 (3b-H); 2.40 br, 2 H (NH +2); 2.00 m , 1 H (2a-H); 1.90 m , 1 H (2b-H); 1.29 d, 3 H, J = 6.1
(CH3); 1.285 d, 6 H, J = 6.1 (CH3); 1.28 d, 3 H, J = 6.1 (CH3). 13C NMR (127.5 MHz,
DMSO-d6): 140.965 (arom .); 128.03, 2 C (arom .); 127.20, 2 C (arom .); 126.62 (arom .);
74.65 d, J = 168.95 (1-C); 71.67 d, J = 6.8 (P-OCH); 71.65 d, J = 6.8 (P-OCH); 52.97 (1′-C);
44.16 d, J = 11.7 (3-C); 38.72 (Ms); 30.59 (2-C); 23.95 d, J = 3.9 (CH3); 23.89 d, J = 3.9 (CH3);
23.75 d, J = 4.9 (CH3); 23.66 d, J = 4.9 (CH3). 31P NMR (88.98 MHz, DMSO-d6): 15.75 s. For
C
17H31ClNO6PS (443.9) calculated: 46.00% C, 7.04% H, 7.99% Cl, 3.16% N, 6.98% P; foun d:
46.01% C, 7.13 % H, 7.94% Cl, 3.25% N, 7.09% P.
Diisopropyl {3-[(2-hydroxyethyl)amino]-1-(mesyloxy)propyl}phosphonate hydrochloride (5c·HCl).
Yield 80%, th ick colourless oil. MS (FAB): 362 (76%, M + H, free base), 278 (23%), 57
(100%). HRMS (FAB): for C12H29NO7PS (M + H) calculated 362.1402, foun d 362.1345. MS
(EI): 343 (6%, M – H2O), 330 (28%, M – CH2OH), 288 (21%), 260 (12%), 246 (100%, 6c –
H2O – H), 150 (27%, HP(O)(Oi-Pr)2 – Me), 100 (30%, 1-h ydroxyazetidin -2-yl), 43 (55%, i-Pr).
1H NMR (500 MHz, DMSO-d6): 9.20 br, 2 H (NH +2); 5.30 t, 1 H, J = 5.1 (OH); 5.04 ddd, 1 H,
J = 10. 3, 8.3, 4.6 (1-H); 4.69 m , 2 H (P-OCH); 3.66 br q, 2 H, J = 5.2 [+AcOD: t, 2 H, J = 5.2]
(2′-H); 3.32 s, 3 H (Ms); 3.06 m , 2 H (3-H); 2.99 br t, 2 H, J = 5.2 (1′-H); 2.30 m , 1 H (2a-H);
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2.20 m , 1 H (2b-H); 1.30 d, 6 H, J = 6.1 (CH3); 1.295 d, 6 H, J = 6.1 (CH3). 13C NMR
(127.5 MHz, DMSO-d6): 73.63 d, J = 170.9 (1-C); 72.65 d, J = 6.8 (P-OCH); 72.62 d, J = 6.8
(P-OCH); 56.75 (2′-C); 49.53 (1′-C); 43.71 d, J = 11.7 (3-C); 38.84 (Ms); 27.03 (2-C); 24.20 d,
J = 2.9 (CH3); 24.13 d, J = 2.9 (CH3); 24.02 d, J = 4.9 (CH3); 23.90 d, J = 4.9 (CH3). 31P NMR
(88.98 MHz, DMSO-d6): 15.77 s. For C12H29ClNO7PS (397.9) calculated: 36.23% C, 7.35% H,
8.91% Cl, 3.52% N, 7.79% P; foun d: 36.46% C, 7.19% H, 9.14% Cl, 3.25% N, 7.74% P.
Diisopropyl [1-(mesyloxy)-3-(propylamino)propyl]phosphonate (5d ). Yield 82%, th ick colourless
oil. MS (FAB): 360 (100%, M + H), 276 (26%). HRMS (FAB): for C13H30NO6PS (M + H) calcu-
lated 360.1610, foun d 360.1656. MS (EI): 360 (10%, M + H), 330 (12%, M – Et), 246 (34%),
98 (100%, 1-propylazetidin -2-yl), 72 (31%, PrNHCH2), 43 (37%, Pr). 1H NMR (500 MHz,
DMSO-d6): 4.93 ddd, 1 H, J = 9.2, 8.6, 3.9 (1-H); 4.67 m , 2 H (P-OCH); 3.265 s, 3 H (Ms);
2.66 ddd, 1 H, J = 11.7, 7.3, 4.9 (3a-H); 2.58 dt, 1 H, J = 11.7, 7.6, 7.6 (3b-H); 2.46 dt, 1 H,
J = 11.2, 7.1, 7.1 (1′a-H); 2.41 dt, 1 H, J = 11.2, 7.1, 7.1 (1′b-H); 2.10 br, 1 H (NH); 1.93 m , 1 H
(2a-H); 1.82 m , 1 H (2b-H); 1.39 sext, 2 H, J = 7.3 (2′-H); 1.29 d, 3 H, J = 6.1 (CH3); 1.285 d,
6 H, J = 6.1 (CH3); 1.28 d, 3 H, J = 6.1 (CH3); 0.86 t, 3 H, J = 7.3 (3′-C). 13C NMR (127.5 MHz,
DMSO-d6): 73.83 d, J = 169.1 (1-C); 71.72 d, J = 6.8 (P-OCH); 71.70 d, J = 6.8 (P-OCH); 50.92
(1′-C); 44.53 d, J = 11.7 (3-C); 38.69 (Ms); 30.23 (2-C); 23.99 d, J = 3.9 (CH3); 23.93 d, J = 3.9
(CH3); 23.78 d, J = 4.9 (CH3); 23.70 d, J = 4.9 (CH3); 11.86 (3′-C). 31P NMR (88.98 MHz,
DMSO-d6): 15.75 s. For C13H30NO6PS (359.4) calculated: 43.44% C, 8.41% H, 3.90% N,
8.62% P; foun d: 43.41% C, 8.22% H, 4.02% N, 8.49% P.
Diisopropyl (1-Alkylazetidin -2-yl)ph osph on ates (6a–6d ). Gen eral Procedure
To a solution of com poun d 4 (3.2 g, 8 m m ol) in toluen e (50 m l), a prim ary am in e
(9 m m ol), water (16 m l), an d potassium carbon ate (3.3 g, 24 m m ol) were added an d th e re-
action m ixture was refluxed for 8 h . Th e reaction m ixture was taken in to eth yl acetate,
wash ed with brin e, dried with an h ydrous m agn esium sulfate, an d evaporated. Repeated
ch rom atograph y on a silica gel colum n usin g toluen e–eth yl acetate or ch loroform –m eth an ol
solven t system s followed by precipitation from petroleum eth er–eth yl acetate (0–5 vol.%)
gave azetidin es 6a–6d (free bases) as th ick colourless oils. Treatm en t with HCl did n ot afford
crystallin e h ydroch lorides.
Diisopropyl (1-allylazetidin-2-yl)phosphonate 6a. Yield 62%, th ick colourless oil. MS (EI): 261
(11%, M), 96 [100%, M – P(O)(Oi-Pr)2 ], 41 (44%, allyl). HRMS (EI): for C12H24NO3P calcu-
lated 261.1494, foun d 261.1484. GC reten tion tim e: 22.94 m in . 1H NMR (500 MHz,
DMSO-d6): 5.71 dddd, 1 H, J = 17.3, 10.0, 7.1, 4.6 (2′-H); 5.13 br dq, 1 H, J = 17.3, 2.0, 1.7,
1.7 (3′a-H, trans); 5.06 br d, 1 H, J = 10.0, 2.0, 1.0 (3′b-H, cis); 4.62 d sept, 1 H, J = 7.6, 6.1
(P-OCH); 4.59 d sept, 1 H, J = 7.6, 6.1 (P-OCH); 3.43 td, 1 H, J = 8.0, 8.0, 6.8 (2-H); 3.30 ddt,
1 H, J = 13.7, 4.6, 1.7, 1.7 (1′a-H); 3.30 m , 1 H (4a-H, covered); 2.90 td, 1 H, J = 8.5, 8.5, 7.3
(4b-H); 2.84 brdd, 1 H, J = 13.7, 7.1, ≈1, ≈1 (1′b-H); 2.19 d quin t, 1 H, J = 10.7, 9.0, 9.0, 9.0,
9.0 (3a-H); 2.06 m , 1 H (3b-H); 1.28 d, 3 H, J = 6.1 (CH3); 1.25 d, 3 H, J = 6.1 (CH3); 1.24 d,
3 H, J = 6.1 (CH3); 1.22 d, 3 H, J = 6.1 (CH3). 13C NMR (127.5 MHz, DMSO-d6): 134.60
(2′-C); 116.97 (3′-C); 69.82 d, J = 6.9 (P-OCH); 69.52 d, J = 6.9 (P-OCH); 60.77 d, J = 2.9
(1′-C); 60.02 d, J = 171.9 (2-C); 53.15 d, J = 23.4 (4-C); 24.17 d, J = 2.9 (CH3); 24.01 d, 2 C,
J = 3.9 (CH3); 23.92 d, J = 4.9 (CH3); 18.77 d, J = 5.9 (3-C). 31P NMR (88.98 MHz, DMSO-d6):
22.58 s.
Diisopropyl (1-benzylazetidin-2-yl)phosphonate 6b. Yield 58%, th ick colourless oil. MS (EI):
311 (7%, M), 146 [100%, M – P(O)(Oi-Pr)2 ], 91 (85%, Bn ). HRMS (EI): for C16H26NO3P cal-
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culated 311.1650, foun d 311.1664. 1H NMR (500 MHz, DMSO-d6): 7.31 m , 2 H (arom .); 7.23,
3 H (arom .); 4.69 d sept, 1 H, J = 7.6, 6.1 (P-OCH); 4.63 d sept, 1 H, J = 7.6, 6.1 (P-OCH);
3.90 d, 1 H, J = 13.2 (1′a-H); 3.54 td, 1 H, J = 8.5, 8.5, 6.4 (2-H); 3.35 d, 1 H, J = 13.2 (1′b-H);
3.15 m , 1 H (4a-H); 2.91 td, 1 H, J = 8.6, 8.6, 7.1 (4b-H); 2.20 sept, 1 H, J = 9.0 (3a-H);
2.06 m , 1 H (3b-H); 1.32 d, 3 H, J = 6.1 (CH3); 1.28 d, 3 H, J = 6.1 (CH3); 1.26 d, 3 H, J = 6.1
(CH3); 1.24 d, 3 H, J = 6.1 (CH3). 13C NMR (127.5 MHz, DMSO-d6): 137.99 (arom .); 128.43,
2 C (arom .); 128.34, 2 C (arom .); 127.08 (arom .); 70.32 d, J = 5.8 (P-OCH); 69.83 d, J = 6.8
(P-OCH); 61.91 d, J = 3.9 (1′-C); 60.11 d, J = 171.9 (2-C); 53.16, J = 25.4 (4-C); 24.21 d, J =
3.9 (CH3); 24.08 d, J = 4.9 (CH3); 24.01 d, J = 3.9 (CH3); 23.93 d, J = 4.9 (CH3); 18.85 d, J =
5.8 (3-C). 31P NMR (88.98 MHz, DMSO-d6): 22.33 s. For C16H26NO3P (311.4) calculated:
61.72% C, 8.42% H, 4.50% N, 9.95% P; foun d: 61.59% C, 8.31% H, 4.28% N, 10.16% P.
Diisopropyl [1-(2-hydroxyethyl)azetidin-2-yl]phosphonate 6c. Yield 66%, th ick colourless oil.
MS (EI): 266 (0.5%,
M + H), 265 (0.2%, M), 234 (73%, M – CH2OH), 150 [21%,
HP(O)(Oi-Pr)2 – Me], 100 [100%, M – P(O)(Oi-Pr)2]. HRMS (EI): for C11H25NO4P calculated
266.1521, foun d 266.1540; for C11H24NO4P calculated 265.1443, foun d 265.1409. GC reten -
tion tim e: 25.35 m in . IR (CHCl3): 3 362 m (OH, assoc.), 3 005 s,sh , 2 983 s, 2 936 m , 2 873 m ,
2 850 m , 1 387 m , 1 376 m , 1 170 m ,sh , 1 142 m , 1 016 s,sh , 999 vs, 981 s,sh . 1H NMR
(500 MHz, DMSO-d6): 4.64 d sept, 1 H, J = 7.6, 6.1 (P-OCH); 4.57 d sept, 1 H, J = 7.6, 6.1
(P-OCH); 4.45 br, 1 H (OH); 3.42 td, 1 H, J = 8.5, 8.3, 7.1 (4a-H); 3.39–3.29 m , 3 H (2-H an d
2′-H); 3.00 td, 1 H, J = 8.8, 8.8, 7.1 (4b-H); 2.66 dt, 1 H, J = 11.9, 6.1, 6.1 (1′a-H); 2.38 dt, J =
11.9, 6.1, 6.1 (1′b-H); 2.18 br sept, 1 H, J = 9.0 (3a-H); 2.07 dqd, 1 H, J = 10.5, 8.1, 8.1, 8.1,
2.7 (3b-H); 1.30 d, 3 H, J = 6.1 (CH3); 1.26 d, 3 H, J = 6.1 (CH3); 1.23 d, 3 H, J = 6.1 (CH3);
1.22 d, 3 H, J = 6.1 (CH3). 13C NMR (127.5 MHz, DMSO-d6): 70.40 d, J = 5.9 (P-OCH);
69.79 d, J = 7.8 (P-OCH); 61.17 d, J = 3.9 (1′-C); 60.90 d, J = 171.9 (2-C); 59.50 (2′-C);
54.48 d, J = 24.4 (4-C); 24.18 d, J = 2.9 (CH3); 24.01 d, J = 4.9 (CH3); 23.90 d, J = 4.9 (CH3);
23.97 d, J = 3.9 (CH3); 19.19 d, J = 5.9 (3-C). 31P NMR (88.98 MHz, DMSO-d6): 22.91 s.
Diisopropyl (1-propylazetidin-2-yl)phosphonate 6d . Yield 48%, th ick colourless oil. MS (FAB):
264 (80%, M + H), 98 [100%, M – P(O)(Oi-Pr)2]. HRMS (FAB): for C12H26NO3P (M + H) calcu-
lated 264.1729, foun d 264.1673. MS (EI): 263 (3.9%, M), 98 [100%, M – P(O)(Oi-Pr)2]. GC re-
ten tion tim e 23.09 m in . 1H NMR (500 MHz, DMSO-d6): 4.62 d sept, 1 H, J = 7.6, 6.2
(P-OCH); 4.57 d sept, 1 H, J = 7.6, 6.2 (P-OCH); 3.32 m , 2 H (2-H an d 4a-H); 2.85 td, 1 H, J =
8.6, 8.6, 7.1 (4b-H); 2.56 dt, 1 H, J = 11.2, 7.8, 7.8 (1′a-H); 2.21 dt, 1 H, J = 11.2, 5.5, 5.5
(1′b-H); 2.15 m , 1 H (3a-H); 2.04 m , 1 H (3b-H); 1.29 d, 3 H, J = 6.2 (CH3); 1.25 d, 3 H, J =
6.2 (CH3); 1.25 m , 2 H (2′-H); 1.235 d, 3 H, J = 6.2 (CH3); 1.22 d, 3 H, J = 6.2 (CH3); 0.81 t,
3 H, J = 7.3 (3′-H). 13C NMR (127.5 MHz, DMSO-d6): 70.15 d, J = 5.9 (P-OCH); 69.63 d, J =
6.8 (P-OCH); 60.87 d, J = 172.9 (2-C); 60.65 br, J ≈ 3.0 (1′-C); 53.40 d, J = 24.4 (4-C);
24.18 d, J = 3.9 (CH3); 24.01 d, J = 4.9 (CH3); 23.97 d, J = 3.9 (CH3); 23.86 d, J = 4.9 (CH3);
20.14 (2′-C); 18.70 d, J = 5.9 (3-C); 11.79 (3′-C). 31P NMR (88.98 MHz, DMSO-d6): 22.56 s.
(1-Alkylazetidin -2-yl)ph osph on ic acids 7. Gen eral Procedure
Diisopropyl ester 6 (2 m m ol) was dissolved in aceton itrile (10 m l), brom otrim eth ylsilan e
(2.6 m l, 20 m m ol) was added, an d th e reaction m ixture was kept at room tem perature over-
n igh t. Th e solven t was evaporated, th e residue was dissolved in water (10 m l), alkalified
with am m on ia, an d applied on a Dowex 1X2 (100–200 m esh , 50 m l) colum n in acetate cy-
cle. Elution was perform ed with a gradien t 0–0.3 M acetic acid. Fraction s were an alyzed
by TLC in 1-propan ol–am m on ia–water 30 : 10 : 3; detection by sprayin g with n in h ydrin e
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an d h eatin g. Appropriate fraction s were collected, evaporated, an d co-evaporated with an
eth an ol–toluen e (1 : 1) m ixture. Crystallization of th e residue from eth er–m eth an ol 3 : 1
gave products 7 as wh ite crystals.
(1-Benzylazetidin-2-yl)phosphonic acid (7b). Yield 70%, wh ite crystals; m .p. 152–155 °C. MS
(FAB): 228 (55%, M + H), 146 [65%, M – P(O)(OH)2], 132 (31%), 91 (100%, Bn ). HRMS
(FAB): for C10H15NO3P (M + H) calculated 228.0790, foun d 228.0762. 1H NMR (500 MHz,
DMSO-d6): 9.00 br, 2 H (P-OH); 7.59 m , 2 H (arom .); 7.36 m , 3 H (arom .); 4.34 d, 1 H, J =
13.1 (1′a-H); 4.20 d, 1 H, J = 13.1 (1′b-H); 4.14 br q, 1 H, J = 8.5, 8.5, 7.8 (2-H); 3.75 br q,
1 H, J = 8.9, 8.9, 8.9 (4a-H); 3.66 m , 1 H (4b-H); 2.43 m , 2 H (3-H). 13C NMR (127.5 MHz,
DMSO-d6): 130.985 (arom .); 130.96 (arom .); 129.05 (arom .); 128.70, 2 C (arom .); 64.05 d,
J = 137.7 (2-C); 57.72 br s (1′-C); 50.01 d, J = 8.7 (4-C); 19.23 br, J ≈ 3 (3-C). 31P NMR
(88.98 MHz, DMSO-d6): 7.34 s.
[1-(2-Hydroxyethyl)azetidin-2-yl]phosphonic acid (7c). Yield 63%, very h ygroscopic wh ite
crystals. MS (FAB): 363 (24%, 2 M + H), 182 (61%, M + H), 100 [100%, M – P(O)(OH)2], 57
(18%, azetidin ), 56 (22%, azetidin – H). HRMS (FAB): for C5H13NO4P (M + H) calculated
182.0582, foun d 182.0600. 1H NMR (500 MHz, DMSO-d6): 8.50 br, 3 H (P-OH an d 2′-OH);
4.27 td, 1 H, J = 8.8, 8.8, 7.6 (2-H); 4.00 m , 1 H (4a-H); 3.92 q, 1 H, J = 9.4, 9.4, 9.4 (4b-H);
3.67 t, 2 H, J = 4.6, 4.6 (2′-H); 3.21 m , 2 H (1′-H); 2.43 m , 2 H (3-H). 13C NMR (127.5 MHz,
DMSO-d6): 64.33 d, J = 139.2 (2-C); 58.01 br (1′-C); 56.54 (2′-C); 52.69 d, J = 8.3 (4-C);
19.25 d, J = 3.0 (3-C). 31P NMR (88.98 MHz, DMSO-d6): 7.66 s.
Azetidin -2-ylph osph on ic Acid (7e)
A solution of com poun d 7b (1 m m ol, 230 m g) in m eth an ol (20 m l) was acidified with 1 M HCl
in m eth an ol (1 m l) an d palladium on activated carbon (10 wt.%, 50 m g) was added un der
argon . Th e reaction m ixture was h ydrogen ated un der sligh t overpressure overn igh t. Th e cat-
alyst was filtered off over cellite an d th e filtrate was evaporated. Th e residue was purified as
described above in gen eral procedure. Yield 110 m g (80%), wh ite crystals; m .p. 261–263 °C.
MS (FAB): 549 (4%, 4 M + H), 412 (7%, 3 M + H), 275 (42%, 2 M + H), 138 (100%, M + H),
57 (33%, azetidin ), 56 [60%, M – P(O)(OH)2]. HRMS (FAB): for C3H9NO3P (M + H) calculated
138.0320, foun d 138.0354. 1H NMR (500 MHz, D2O): 4.51 dt, 1 H, J = 9.6, 8.0, 8.0 (2-H);
4.14 dt, 1 H, J = 12.2, 7.8, 7.8 (4a-H); 4.04 m , 1 H (4b-H); 2.53–2.71 m , 2 H (3-C). 13C NMR
(127.5 MHz, D2O): 55.72 d, J = 141.6 (2-C); 47.00 d, J = 6.3 (4-C); 22.30 d, J = 3.9 (3-C).
31P NMR (88.98 MHz, D2O): 10.75 s.
This study was made as a part of research project No. Z4055905 of the Institute. Financial support
was provided by the Grant Agency of the Czech Republic (grant No. 203/96/K001) and by Gilead Sci-
ences (Foster City, U.S.A.). The authors thank the staff of the Laboratories of Mass Spectroscopy
(Dr K. Ubik, Head), IR Spectroscopy (Dr P. Fiedler, Head), Elemental Analysis (Dr L. Válková, Head),
and Dr J. Günterová (GLC) of this Institute for measurement of spectra and analyses. An excellent
technical assistance of Ms Y. Černá is gratefully acknowledged.
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