Highly stereoselective synthesis of new α-amino-β-hydroxy six-membered heterocyclic phosphonic acids, serine analogues

Article abstract of DOI:10.1016/j.tet.2009.07.040

The synthesis of 2-hydroxy-4-heterocyclic phosphonic acids was achieved in a six-step sequence from the appropriate ketones. Thus, 2-hydroxyheterocyclic ketone acetals were prepared and then esterified by N-Boc-l-phenylalanine, used as a chiral auxiliary. The resulting heterocyclic acetal esters gave by a one-pot reaction bicyclic ketimines. These imines underwent nucleophilic addition with phosphite to provide efficiently and stereoselectively, under kinetic control, bicyclic aminophosphonates. Cleavage of the phenylalanine moiety by oxidation followed by acidic hydrolysis of the resulting heterocyclohexylphosphonates provided the new (4-amino-3-hydroxypiperidin-4-yl)-, (4-amino-3-hydroxytetrahydro-2H-pyran-4-yl)- and (1-amino-2-hydroxycyclohexyl)phosphonic acids.

Full text of DOI:10.1016/j.tet.2009.07.040

Tetrahedron 65 (2009) 8587–8595
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Highly stereoselective synthesis of new a-amino-b-hydroxy six-membered
heterocyclic phosphonic acids, serine analogues
*
Nicolas Louaisil, Nicolas Rabasso, Antoine Fadel
ˆ
´
Laboratoire de Synthe`se Organique et Me´thodologie, CNRS, UMR 8182, Institut de Chimie Mole´culaire et des Mate´riaux d’Orsay, Bat. 420, Universite Paris-Sud 11, 91405 Orsay, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 May 2009
Received in revised form 9 July 2009
Accepted 17 July 2009
Available online 23 July 2009
The synthesis of 2-hydroxy-4-heterocyclic phosphonic acids was achieved in a six-step sequence from
the appropriate ketones. Thus, 2-hydroxyheterocyclic ketone acetals were prepared and then esterified
by N-Boc-L-phenylalanine, used as a chiral auxiliary. The resulting heterocyclic acetal esters gave by
a one-pot reaction bicyclic ketimines. These imines underwent nucleophilic addition with phosphite to
provide efficiently and stereoselectively, under kinetic control, bicyclic aminophosphonates. Cleavage of
the phenylalanine moiety by oxidation followed by acidic hydrolysis of the resulting hetero-
cyclohexylphosphonates provided the new (4-amino-3-hydroxypiperidin-4-yl)-, (4-amino-3-hydroxy-
tetrahydro-2H-pyran-4-yl)- and (1-amino-2-hydroxycyclohexyl)phosphonic acids.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Aminophosphonic acids
Heterocycles
Serine analogues
Nucleophilic addition
Piperidines
1. Introduction
Strecker reaction,20,21 or Diels–Alder cycloaddition22 in asymmetric
version. The synthesis of the heterocyclic derivatives 2a, 2b and 2c
Several
a
-aminophosphonic acids show activity, as enzyme in-
have been little studied,23 especially since the amide derivatives of
2c are useful antiarrhythmic agents.23a In contrast, 3-hydroxy-, 4-
piperidine-aminophosphonic acid 3c (antiarrhythmic analogue),
tetrahydropyran acid 3a, and tetrahydrothiopyran acid 3b phos-
phonic analogues are still unknown (Fig. 1).
hibitors, antibacterials, herbicides, or plant growth regulators.1
These acid derivatives, in which the tetrahedral phosphorus moiety
acts as a transition-state analogue of peptide bond cleavage, se-
lectively inhibit peptidases and proteinases (e.g., HIV protease,2
serine protease3). In recent years, many cyclic
a
-aminophosphonic
In continuation of our ongoing program on the synthesis of
acids have been prepared from ketones,4–11 mainly by Mannich-
cyclic aminophosphonic acids,8 we recently described a short and
type reactions using cyclohexanones.12 Very few examples of het-
efficient synthesis of new heterocyclic
a-aminophosphonic acids
erocyclic
a
-aminophosphonic acids 1a–c or the corresponding
1a–d in good yields from ketone imines 4 via aminophosphonates 5
(Scheme 1).17a We also applied the same sequence to obtain
(3-amino-piperidin-3-yl)-phosphonic acids from the correspond-
ing cyclic ketones.17b However, the synthesis of cucurbitine phos-
phonic analogues 8a–d required the use of hydrazone
intermediates 6 instead of imine to provide hydrazinophospho-
nates 7. Subsequent cleavage of N–N bonds gives aminophosphonic
acid 8a–d (cucurbitine analogue) (Scheme 1).24
phosphonates have been reported by others13–16 and by us.17 In all
theses synthetic approaches the Kabachnick–Fields reaction15a,b
was used to provide
yields.
a-aminophosphonates in moderate to good
L-Serine plays a crucial role in peptides and proteines, not only
as a hydrophilic residue but also, with the hydroxy moiety, as
a catalytic site of serine proteases.18 In this context, 1-amino-2-
hydroxycyclohexanecarboxylic acid (c6Ser) 2d (n¼1) has received
considerable attention since high rigidity is achieved in this mol-
O
OH
OH
O
OH
OH
COOH
NH2
OH
ecule by having the
a
-carbon on the amino acid incorporated into
P
NH2
P
a six-membered-ring. Only few syntheses of c6Ser 2d have been
reported in the literature. These syntheses involved Bucherer–Berg
and Strecker reactions19 in a racemic version, and intramolecular
NH2
OH
X
X
X
( )n
1a X = O
3a X = O
2a X = O, n = 1
1b X = S
3b X = S
2b X = S, n = 1
1c X = NH
1d X = CH2
3c X = NH
3d X = CH2
2c X = NR, n = 1
2d X = CH2, n = 0, 1
* Corresponding author. Tel.: þ33 1 6915 3239; fax: þ33 1 6915 6278.
E-mail address: antfadel@icmo.u-psud.fr (A. Fadel).
Figure 1. Heterocyclic a-aminocarboxylic and phosphonic acids.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.040

8588
N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
O
P
OEt
OEt
O
OH
OH
H
NBoc
Ph
P
NHR
P
NH2
NR
H+
P(OEt)3
HO2C
H
O
O
NBoc
Ph
O
O
I2, KOH
MeOH
O
X
X
X
X
OH
O
14
9a–d
4
5
1a–d
X = O, S, NR1, CH2
0 °C →rt
DCC, DMAP
0 °C →rt
X
X
69–95%
( )-10a–d
15a–d/16a–d
77–99%
OEt
OEt
O
OH
OH
NH2
O
P
a X = O
H+
P(OEt)3
NHR
N
b X = S
N NHR
pTsOH,
c X = NCbz
d X = CH2
N
H
X
X
1.8 eq
Ph
6
7
8a–d
X
X = O, S, NR1, CH2
O
11a–d/12a–d
O
then Na2CO3
90–95%
TFA
P(OEt)3
Scheme 1.
EtO
O
EtO
O
EtO
H
EtO
H
In order to expand the scope of our method,17 we decided to
prepare c6Ser phosphonic analogues 3a–d (Fig. 1) involving the
addition of phosphite to bicyclic imine intermediates 11a–d/12a–d,
as key-step. Such imines are prepared from heterocyclic ketones
9a–d via acetals 10a–d. Thus the nucleophilic addition should occur
stereoselectively, under kinetic control, to provide amino-
phosphonates 13a–d, precursors of aminophosphonic acids 3a–
d (Scheme 2).
P
P
N
N
Ph
Ph
O
X
X
O
H
O
O
H
dr 89:11 to 99:1
17a–d
13a–d
Scheme 4.
resulting keto amines 15/16 into imines 11/12, we changed several
reaction conditions depending on the nature of the heteroatom (X)
(Table 1).
O
Ph
O
Ph
O
HO
HO
kinetic
control
P
NH2
OH
H
N
O
P
EtO
EtO
N
X
Table 1
O
H
O
Preparation in a one-pot reaction of imines 11a–d/12a–d from acetals 15a–d/16a–
d produced via Scheme 4a
X
X
3a–d
X = O, S, NR, CH2
11a–d/12a–d
13a–d
Entry
Acetal 15/16 (X)
p-TsOH (equiv)
T (ꢀC)/t (h)
Imine 11/12
1
2
3
4
15a/16a (O)
15b/16b (S)
15c/16c (NCbz)
15d/16d (CH2)
1.8
1.8
2.8
1.8
20/24
20/24
20/24
20/24
11a/12a
11b/12b
11c/12c
11d/12d
O
OMe
MeO
OH
X
9a–d
X
10a–d
a
Reactions conditions: Acetals 15a–d/16a–d, p-TsOH (n equiv), acetone, 25 or
55 ꢀC, 24 h, then Na2CO3 (5 equiv).
Scheme 2. Retrosynthetic sequence for the peparation of
b-hydroxy aminophosphonic
We found that no imines 11/12 were formed directly from ac-
etals 15/16 using 0.15 or 1.2 equiv para-toluenesulfonic acid
(p-TsOH). However, complete conversion of 15a/16a, 15b/16b and
15d/16d into corresponding imines 11/12 was achieved by in-
creasing p-TsOH to 1.8 equiv and for compounds 15c/16c (X¼NCbz)
(Table 1, entries 1, 2, 4 and 3) to 2.8 equiv. The resulting crude
imines 11a–d/12a–d, obtained as a 50:50 to 35:65 mixture, were
used in the next step without further purification.
Reaction of crude imines 11a–d/12a–d (Scheme 4) with 2 equiv
of triethyl phosphite in the presence of 1 equiv of TFA in ethanol at
30 ꢀC for 17 h (method A) gave the corresponding amino-
phosphonates 13a–d in acceptable yields (46–70%) and high dia-
steroselectivity (Table 2, entries 1, 3, 5, and 6). On the other hand,
acids.
Studies on the reactivity of imine 11d under Strecker reaction
conditions were reported by Ohfune et al.20b In the presence of
a Brønsted acid the aminonitriles A and B were formed in moder-
ates selectivities, whereas with a Lewis acid a reverse selectivity
was observed (Scheme 3).
H
NC
H
NC
N
O
N
N
O
Bn
O
Bn
O
Bn
O
ref. 20b
O
H
B
H
11d/12d
A
NaCN, TFA, iPrOH
or TMSCN, ZnCl2
66 : 34
41 : 59
Table 2
Scheme 3.
Preparation of aminophosphonates 13a–d from imines 11a–d/12a–d produced via
Scheme 4a
2. Results and discussion
Entry
Imine (X)
Conditiona Phosphonate13/17
Yieldb (%) drc
1
2
3
4
5
6
7
8
9
11a/12a (O)
11a/12a (O)
11b/12b (S)
11b/12b (S)
11c/12c (NCbz)
11c/12c (NCbz)
11c/12c (NCbz)
11c/12c (NCbz)
11d/12d (CH2)
A
B
A
B
13a
13a
13b
13b/17b
13c
13c
13c
13ca
13d
60
72
46
77
49
70
71
54
62
96:4
In this paper we present an efficient strategy for the synthesis of
enantiopure 2-hydroxyheterocyclic aminophosphonic acids. For
this purpose, imine formation was carried out under mild condi-
tions. The commercially available ketones 9a–d reacted, following
known reaction,25 with iodine/potassium hydroxide in methanol at
0 ꢀC to furnish hydroxy acetals 10a–d in good yields. However, use
99:1
96:4
89:11
95:5
96:4
99:1
97:3
95:5
A
Ad
B
Ae
A
26
of potassium hydroxide/PhI(OAc)2 as the reagent gave hydroxy
a
acetals 10a–d in moderate yields. Subsequent esterification with
Reactions conditions: method A: imine (prepared from acetals 15/16 with
p-TsOH, then aq NaHCO3) reacted with P(OEt)3 (1.2 equiv), TFA (1.0 equiv) in EtOH,
30 ꢀC, 17 h; method B: imine (prepared from acetal with p-TsOH, then aq Na2CO3)
reacted with P(OEt)3 (2.0 equiv), TFA (1.0 equiv) in CH2Cl2, ꢁ78 ꢀC to rt, 6 h.
L
-N-Boc-phenylalanine 14 in the presence of 1,3-dicyclohexyl-
carbodiimide (DCC) and a catalytic amount of dimethylamino-
pyridine (DMAP, 10 mol %)27 led to diastereomeric mixtures (50:50)
of esters 15a–d/16a–d in excellent yields (Scheme 4).
In order to examine the possibility to achieve in a one-pot re-
action: deacetalization, deprotection and condensation of the
b
Overall yield calculated from acetals 15/16.
c
Ratio was determined from 31P NMR spectra of the crude mixture.
With P(OEt)3 (2 equiv).
d
e
P(OMe)3 in MeOH was used instead of P(OEt)3 in EtOH.

N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
8589
reaction with triethyl phosphite (2 equiv) in the presence of TFA
(1 equiv) in dichloromethane at ꢁ78 ꢀC for 6 h (method B), pro-
vided the aminophosphonates 13a–c in good yields (71–77%) and
excellent diastereoselectivities (Table 2, entries 2 and 7). Replacing
triethyl phosphite with trimethyl phosphite and ethanol with
methanol in method A gave the corresponding aminophosphonate
13ca in 54% yield and with the same selectivity (entry 8).
Likewise, the carbocyclic imines 11d/12d by method A furnished
the expected aminophosphonate 13d in good yield and high se-
lectivity (95:5) (entry 9). By comparison, reaction of imines 11d/12d
with cyanide anion (instead of triethyl phosphite) is reported to
give the corresponding aminonitrile analogues A/B with a lower
selectivity (66:34) (Scheme 3).20b
3c$HCl and 3d$HCl were purified by propylene oxide in ethanol, or
by Dowex$Hþ to give new (3S,4S)-3c and (3S,4S)-3d in good yields
(Scheme 5).
In order to examine the selectivity of phosphite addition to
imines 11a/12a, the reaction was performed using boron tri-
fluoridediethyletherate (BF3$OEt2) and trimethylsilyl-dimethyl-
phosphite [TMSP(O)(OMe)2] in methylene chloride at ꢁ78 ꢀC and
then quenched by adding an aq NaHCO3 solution. The resulting
aminophosphonates were composed of a mixture of diastereomers
(20a/21a, 60:40) in 51% overall yield from esters 15a/16a. The mi-
nor dimethyl phosphonate 21a, with similar NMR data than 13a,
gave the acid (3S,4S)-3a as shown above. While the major dimethyl
phosphonate 20a was separately treated by ozone in ethyl acetate
at ꢁ78 ꢀC followed by addition of dimethylsulfide to give a non-
isolated mixture of an imine/enamine 22a/23a. Subsequent acidic
hydrolysis of the crude mixture of 22a/23a provided (3R,4R)-ent-
3a, which showed the same analytical data but the opposite sign of
specific rotation of (3S,4S)-3a (Scheme 6).
The diastereoselectivity ratios were determined from their 31P
NMR spectra of crude aminophosphonate products. Attempts to
isolate the minor isomers by purification on silica gel column flash
chromatography for entries 1, 5, 6 and 8 failed. Although, the
aminophosphonates 13a–d are solids, only 13b afforded crystals
suitable for X-ray crystallographic analysis (Fig. 2).28
N
a
Ph
15a/16a
O
O
O
11a/12a
50/50
b
Ph
O
Ph
O
H
N
H
N
O
P
O
P
2
2
MeO
MeO
MeO
MeO
+
O
H
O
H
4a
4a
60 : 40
c
O
O
21a
20a
MeO
O
N
MeO
P
Ph
O
P
O
HO
HO
NH2
O
O
O
H
22a/23a
OH
H
mixture
Figure 2. X-ray diffraction analysis of compound 13b.
d
(3S,4S)-3a
(3R,4R)-ent-3a
We next examined the conversion of 13a–d into the expected
aminophosphonic acid by removal of the phenylalanine moiety.
Treatment of phosphonates 13c and 13d, with tert-butyl hypo-
chlorite at 0 ꢀC and 1,4-diazabicyclooctane (DABCO) at room tem-
perature gave the imine/enamine mixture 18c/19c and 18d/19d in
good yields, respectively. However, it gave 20a/21a only in 30%
yield with a degradation product for 13a and a sulfoxide byproduct
from 13b. To overcome this problem 13a was oxidized with ozone29
to give a mixture of 18a and 19a in excellent yield. Acidic hydrolysis
of this mixture provided the new optically pure (3S,4S)-3a in 77%
yield from 13a.
Scheme 6. Reactions conditions: (a)1.8 equiv of p-TsOH in acetone at 25 ꢀC, 15 h, then
solid Na2CO3 in CH3CN; (b) TMSP(O)(OMe)2 (2 equiv), BF3$OEt2 (1.1 equiv) in CH2Cl2,
ꢁ78 to rt, 17 h, 51% overall yield from 15a/16a; (c) O3 in EtOAc, ꢁ78 ꢀC, 10 min, then
Me2S; (d) 6 M HCl at reflux, 17 h, then propylene oxide, 58% two steps from 20a.
2.1. Absolute configuration and mechanistic discussion
The absolute configuration of the major aminophosphonate 13b
was assigned by X-ray analysis as (2S,4aR,8aS) (Fig. 2). Therefore,
aminophosphonates 13a and 13c are also assigned as (2S,4aS,8aS)
and 13d as (3S,4aS,8aS), respectively (Scheme 4, Table 2). However,
the absolute configuration of the minor isomer 17b (X¼S) is
assigned by comparison with NMR data. Examination of the 1H
NMR data of 20a and 17b showed a high field shift of 2-H com-
pared, respectively, to compounds 21a and 13b in which the proton
2-H and the phosphonate function are syn. However, the 4a-H
proton, syn to the phosphonate function, showed roughly the same
chemical shifts in 21a/20a and 13b/17b, respectively (Table 3).
Consequently, the same absolute configuration was attained for
compounds 17b and 20a, but (due to sulfur atom in 17b)30 the
configuration is described as (2S,4aS,8aR) for 17b and as
(2S,4aR,8aR) for 20a.
The crude imine/enamine mixtures 18c/19c and 18d/19d were
then treated with 6 M HCl at reflux for 15 h and the resulting crude
EtO
tBuOCl,
EtO
O
N
O
N
Ph
O
Ph
O
EtO
EtO
13c
or
DABCO
H
P
P
CH2Cl2, 0 °C
13d
X
X
O
O3
O
13a
H
H
MeOH, 0 °C
18a
19a
19c
19d
X = O
X = NCbz
X = CH2
18c
18d
1. 6 M HCl
2. EtOH,
OH
P OH
NH2
O
O
or Dowex H+
Table 3
X
OH
Comparison of chemical shifts for 21a/20a and 13b/17b
3a X = O (77% from 13a)
3c X = NH (58% from 13c)
3d X = CH2 (75% from 13d)
Proton
21a
20a
13b
17b
2-H
4a-H
4.29
4.56
4.05
4.66
4.33
4.73
4.04
4.83
Scheme 5.

8590
N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
The high stereoselectivity observed in the phosphite addition to
appropriate ketones. The chiral transfer process from the phenyl-
alanyl group, with construction of two consecutive chiral centres,
appeared very highly stereoselective. This efficient transfer of chi-
rality with the phosphite addition was better than those previously
reported for the analogue Strecker addition of cyanide anion in
carbocyclic systems.20b,32 The heterocyclic aminophosphonates
13a–d, were obtained in good yields and excellent stereoselectivity.
Finally, oxidation with tert-butyl hypochlorite or ozone followed by
subsequent hydrolysis provided aminophosphonic acids 3 in good
yields.
the iminium ion could be explained as described in Scheme 7. It is
understood that the iminium intermediates C and D are equilibrated
via an enammonium-type intermediate E (equilibrium supported by
deuterium exchange) similar to the pathway reported for the five-
and six-membered-ring system (X¼CH2).20b Furthermore, it seems
that the selectivity of aminophosphonate formation is under kinetic
and not thermodynamic control. Since the aminophosphonates 13b
and 17b separately treated under reaction conditions (TFA/P(OEt)3)
gave the recovered starting material without any epimerization. We
estimate that chair–boat conformation (iminium ion C) is favoured
by about 2.14–5.56 kcal molꢁ1 (X¼O, S, NCbz and CH2) relative to the
epimeric-4a twist boat–boat conformation (iminium ion D), based
4. Experimental section
4.1. General
on DFT calculations at the B3LYP/6-31G level. Optimized con-
*
formers of intermediates C and D were obtained by molecular me-
chanics calculations.31 Based on this analysis, the highly
diastereoselective formation of 13 results from a kinetic addition of
phosphite (rate determining-step) to the less hindred Si-face of the
iminium C (exo bicyclic attack and anti attack versus benzyl group)
conformer, yielding 13a–d as the major products and the sole
products under method B (X¼O, NCbz) (Scheme 7).
All reactions were carried out under argon with magnetic stir-
ring. Di- and triethyl phosphite were distilled at reduced pressure
and stored under argon. All other solvents and chemical com-
pounds were purified based on standard procedures. Reagent-
grade solvents were used without purification for all extractions
and work-up procedures. Rf values refer to values obtained by TLC
on 0.25 mm silica gel plates (60-F254). Flash chromatography (FC)
was performed on silica gel 60 (0.040–0.063 mm). Yields refer to
chromatographically and spectroscopically pure compounds, ex-
cept where noted. IR spectra were acquired on a FTIR and are
reported in wavenumbers (cmꢁ1) with polystyrene as a standard.
Melting points were determined on a Bu¨chi B-545 capillary melting
point apparatus and are uncorrected. 1H NMR spectra were recor-
ded on a Bruker AM250 (250 MHz) or Bruker AC360 (360 MHz)
spectrometer. Chemical shifts were recorded in parts per million
Ph
Ph
X
H
H
H
N
N
4a
O
H
O
H
O
H
favored
O
X
D
C
exo attack
H
H
Ph
N
Si-face
X
O
O
EtO
EtO
O
N
enammonium
E
O
EtO
EtO
H
from the solvent resonance (CDCl3 at 7.27 and D2O at 4.8 ppm). 13
C
P
H
P
N
Ph
Ph
NMR spectra were recorded on a Bruker AM250 (62.9 MHz) or
Bruker AC360 (90.56 MHz) spectrometer. Chemical shifts are
reported in parts per million from the solvent resonance (CDCl3 at
77.16 ppm). 31P NMR spectra were recorded on a Bruker AC250
(101.25 MHz), and chemical shifts are quoted relative to internal
X
X
O
O
O
O
H
17a–d
H
13a–d
Scheme 7. Plausible approach of phosphite to the iminium intermediates.
85% H3PO4 (
d
¼0 ppm). High-resolution mass spectra were recorded
on a Finnigan MAT 95S using the following ionization techniques:
chemical ionization (CI), electron impact (EI) and electrospray (ES).
All new compounds were determined to be >95% pure by 1H NMR
spectroscopy. Elemental analyses were performed by The Micro-
analytical Service Laboratory of CNRS at Gif/Yvette (France).
From the results shown in Scheme 6, the kinetic addition of
phosphite in the presence of Lewis acid to both iminium in-
termediates is also exo-attack favoured. The major isomer 20a
should be (2S,4aR,8aR) and formed from imine 24a, while the mi-
nor 21a should come from 25a (Scheme 8).
4.2. Synthesis of 2-hydroxy dimethyl acetals
exo/syn approach
O
O
O
Si
BF3
P
4.2.1. Benzyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (10c).
Unknown compound was prepared by using literature procedure.25
Yield 88%; colourless oil; Rf¼0.46 (EtOAc/petroleum ether: 50:50). IR
(film): nmax¼3446, 2946, 1695, 1435, 1243, 1116, 1075 cmꢁ1. 1H NMR
X
BF3
H
H
N
O
N
O
O
X
O
H
H
O
O
O
Si
P
O
endo/anti
exo/anti
(300 MHz, CDCl3, 330 K)
d
¼1.68 (ddd, J¼13.8, 2.7, 2.7 Hz, 1H, H-5),
O
24a
25a
1.85 (ddd, J¼13.8, 12.0, 4.8 Hz, 1H, H-5), 2.54 (br s, OH), 2.92 (ddd,
J¼12.0,13.2, 2.7 Hz,1H, H-6), 3.00–3.20 (m,1H, H-2), 3.19 (s, 3H, CH3),
3.21 (s, 3H, CH3), 3.72 (br s, 1H, H-3), 3.94 (br d, J¼13.2 Hz, 1H, H-6),
4.05 (dd, J¼13.2,1.2 Hz,1H, H-2), 5.10 (s, 2H, H-2, CH2benzyl), 7.14–7.38
20a
60 : 40
21a
Scheme 8. Plausible approach of nucleophile in the presence of BF3$OEt2.
(m, 5H). 13C NMR (75.5 MHz, CDCl3)
d¼27.5 (C-5), 40.7 (C-6), 47.8 (C-
2), 47.5 (CH3), 47.9 (CH3), 67.0 (CH2benzyl), 67.05 (C-3), 99.1 (C-4) [6
arom C: 127.5 (2CH), 127.6 (CH), 128.2 (2CH), 137.0 (Cq)],156.0 (COO).
ESþMS m/z: 318.1 [MþNa]þ. HRMS (ES) m/z [MþNa]þ calcd for
C15H21NO5þNa: 318.1312; found: 318.1321.
In contrast, the reported Strecker addition of cyanide anion on
carbocyclic imines 11d/12d (X¼CH2) in the presence of Lewis acid
provided the major product B by an endo/anti attack of cyanide
(Scheme 3).20b,32
4.2.2. (2S)-4,4-Dimethoxytetrahydro-2H-pyran-3-yl N-(tert-butoxy-
3. Conclusion
carbonyl)-L-phenylalaninate (15a/16a). General procedure A: A so-
lution of (S)-N-tert-butyloxycarbonylphenylalanine 14 (4.00 g,
15 mmol), and dicyclohexylcarbodiimide (DCC), (3.10 g, 15 mmol)
in dry CH2Cl2 (33 mL) was stirred at 0 ꢀC for 10 min. Then, a solution
of crude hydroxy acetal 10a (1.62 g,10 mmol) in CH2Cl2 (26 mL) and
In summary, we have developed an easy and efficient synthesis
of new
a
-amino- -hydroxyheterocyclohexylphosphonic acids 3a,
b
3c and
a
-amino-b-hydroxycyclohexylphosphonic acid 3d from the

N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
8591
dimethylaminopyridine (DMAP)27 (122 mg, 1.0 mmol) were added,
successively. The reaction mixture was allowed to warm to room
temperature with stirring for 17 h. The urea formed was filtered off,
and washed with CH2Cl2. The organic layer was diluted with water
(10 mL) and extracted with CH2Cl2 (2ꢂ200 mL) then dried, filtered
and concentrated under vacuum. The residue was purified by flash
chromatography (silica gel, eluent, EtOAc/petroleum ether, 20:80 to
40:60) to give the corresponding esters 15a/16a (3.815 g, 93% from
ketone 9a).
136.3 (Cq), 136.7 (Cq)], 154.9 (NCO), 155.7 (NCOO), 170.7 (COO).
ESþMS m/z: 565.3 [MþNa]þ. HRMS (ES) m/z [MþNa]þ calcd for
C29H38N2O8þNa: 565.2520; found: 565.2524. C29H38N2O8
(542.62): calcd C 64.19, H 7.06, N 5.16; found C 63.75, H 7.03, N
5.18.
4.3. Formation of imines 11a–d/12a–d from esters 15a–d/16a–
d, procedure B
Yield 93% (two steps); colourless oil; Rf¼0.47 (EtOAc/petroleum
ether: 30:70). IR (film): nmax¼3442, 3360, 2974, 1742 (COO), 1716
(NCO), 1497, 1367, 1173, 1072 cmꢁ1. 1H NMR (360 MHz, CDCl3) two
To a solution of esters 15a/16a (410 mg, 1 mmol) in acetone
(5 mL) was added para-toluenesulfonic acid (p-TsOH$H2O)
(350 mg, 1.8 mmol). After stirring at 25–30 ꢀC for 17 h, complete
conversion was observed. The solvent was removed and the residue
was taken with CH3CN (4 mL) then solid Na2CO3 (530 g, 5 mmol)
and MgSO4 (1.20 g, 10 mmol) were added. After stirring for 2 h at
room temperature, the mixture was filtered over CeliteÒ and the
cake washed with CH3CN (50 mL). The organic layer concentrated
gave the crude imines 11a/12a (245 mg, quant. yield), which was
used in the next step without further purification. Purification of
a sample on silica gel for spectral characterization.
isomers (15a/16a, 50:50)
d
¼1.36/1.39 (s, 9H, C(CH3)3, 15a/16a),
1.70–2.00 (m, 2H, H-5), 2.90–3.26 (m, 2H, Hbenzyl), 3.07/3.10 (s, 3H,
OCH3), 3.16/3.18 (s, 3H, OCH3), 3.40–3.54 (m, 1H, H-6), 3.60–3.74
(m, 1H, H-2), 3.74–3.90 (m, 2H, H-2 and H-6), 4.52–4.70 (m, 1H,
CH–N), 4.82/4.92 (br s, 1H, H-3), 5.01–5.18 (m, 1H, HN), 7.10–7.32
(m, 5H). 13C NMR (90.56 MHz, CDCl3) (two diastereomers 15a/16a,
50:50)
d
¼28.3 (C(CH3)3), 29.3/29.5 (C-5, 15a/16a), 37.8 (CH2benzyl),
47.6 (2CH3O), 54.4/54.5 (CH–N, 15a/16a), 64.2 (C-6), 67.1/67.4 (C-2,
15a/16a), 69.2/69.6 (C-3, 15a/16a), 79.6 (C(CH3)3), 96.9/97.0 (C-4,
15a/16a) [6 arom C: 126.9 (CH), 129.4 (2CH), 129.4/129.5 (2CH, 15a/
16a), 136.0/136.2 (Cq, 15a/16a)], 155.0 (NCO), 171.0/171.1 (COO, 15a/
16a). ESþMS m/z: 432.2 [MþNa]þ. HRMS (ES) m/z [MþNa]þ calcd
for C21H31NO7þNa: 432.1993; found: 432.1996. C21H31NO7
(409.47): calcd C 61.60, H 7.63, N 3.42; found C 61.21, H 7.54, N
3.87.
4.3.1. (2S,4aR/S)-2-Benzyl-4a,5,7,8-tetrahydropyrano[3,4-b][1,4]ox-
azin-3(2H)-one (11a/12a). Pale yellow oil; Rf¼0.20/0.34 (ether). IR
(film): nmax¼3342, 2929, 1760/1739 (COO), 1695/1683, 1496,
1075 cmꢁ1. 1H NMR (360 MHz, CDCl3) (two diastereomers, 11a/12a,
50:50)
d¼1.87 (dd, J¼10.4, 10.4 Hz, 1H, H-5, 12a), 2.30–2.70 (m, 2H,
H-8, 11a/12a), 3.10 (dd, J¼10.8, 10.8 Hz, 1H, H-5, 11a), 3.10–3.30 (m,
3H, H-7, Hbenzyl, 12a and H-4a, 11a), 3.30 (dd, JAB¼13.3 Hz, J¼4.7 Hz,
1H, Hbenzyl, 11a), 3.38–3.50 (m, 3H, Hbenzyl, 12a and H-7, Hbenzyl, 11a),
3.88 (dd, J¼10.4, 6.5,1.1 Hz,1H, H-5,12a), 3.97–4.15 (m, 3H, H-5, H-7,
11a; and H-7, 12a), 4.55–4.65 (m, 1H, H-2, 11a), 4.70 (ddd, J¼3.6, 6.5,
10.4 Hz, 1H, H-4a, 12a), 4.83 (ddd, J¼4.7, 4.7, 3.6 Hz, 1H, H-2, 12a),
7.00–7.40 (m, 5H 11a/12a). 13C NMR (90.56 MHz, CDCl3) (di-
4.2.3. (2S)-4,4-Dimethoxy-tetrahydro-2H-thiopyran-3-yl N-(tert-
butoxycarbonyl)-L-phenylalaninate (15b/16b). Prepared following
procedure A: yield 69% (two steps); colourless oil; Rf¼0.26 (ether/
petroleum ether: 30:70). IR (film): nmax¼3369, 2931, 1745 (COO),
1716 (NCO), 1497, 1369, 1243, 1172, 1060 cmꢁ1. 1H NMR (300 MHz,
CDCl3) (diastereomers 15b/16b)
d
¼1.42 (s, 9H, C(CH3)3), 1.99–2.17
astereomers 11a/12a)
d
¼36.1/37.4 (C-8, 11a/12a), 39.6/39.8
(m, 2H, H-5), 2.40–2.54 (m, 1H, H-6), 2.60–2.72 (m, 1H, H-2),
2.72–2.85 (m, 1H, H-6), 3.00–3.33 (m, 3H, H-2 and 2Hbenzyl), 3.13/
3.16 (s, 3H, OCH3, 15b/16b), 3.19/3.20 (s, 3H, OCH3, 15b/16b),
4.61–4.73 (m, 1H, CHN), 4.94–5.09 (m, 1H, HN), 5.09/5.14 (d,
J¼3.2 Hz, 1H, H-3, 15b/16b), 7.10–7.35 (m, 5H). 13C NMR
(CH2benzyl, 12a/11a), 59.0/60.3 (C-2, 12a/11a), 67.6/68.0 (C-7, 11a/
12a), 70.0/70.5 (C-5, 11a/12a), 73.6/75.8 (C-4a, 11a/12a) [arom C:
127.4/127.7 (CH, 12a/11a), 128.4/128.6 (2CH, 12a/11a), 130.4/130.6
(2CH, 11a/12a), 135.1/136.0 (Cq, 12a/11a)], 163.9/165.3 (C-8a, 12a/
11a), 166.9/168.0 (C-3, 11a/12a). ESþMS m/z 268.0 [MþNa]þ. HRMS
(ES) m/z [MþNa]þ calcd for C14H15NO3þNa: 268.0944; found:
268.0944.
(75.5 MHz, CDCl3) (diastereomers 15b/16b)
d
¼24.7 (C-6), 28.3
(C(CH3)3), 29.8/30.0 (C-2, 15b/16b), 30.3/30.5 (C-5, 15b/16b),
37.9/38.0 (CH2benzyl, 15b/16b), 47.5 (OCH3), 47.6/47.7 (OCH3, 15b/
16b), 54.4 (CHN), 68.3 (C-3), 79.8 (C(CH3)3), 97.8/97.9 (C-4, 15b/
16b) [6 arom C: 127.0 (CH), 128.5 (2CH), 129.5 (2CH), 136.0 (Cq)],
155.0 (NCO), 170.9 (COO). HRMS (ES) m/z [MþNa]þ calcd for
C21H31NO6SþNa: 448.1764; found: 448.1767. C21H31NO6S
(425.54): calcd C 59.27, H 7.34, N 3.29; found C 59.64, H 7.41, N
3.54.
4.3.2. (2S,4aR/S)-2-Benzyl-4a,5,7,8-tetrahydro-thiopyrano[3,4-
b][1,4]oxazin-3(2H)-one (11b/12b). Prepared following procedure
B: yellow oil; Rf¼0.20/0.27 (EtOAc/petroleum ether: 70:30). IR
(film): nmax¼3031, 2921, 1747, 1694, 1496, 1455, 1064 cmꢁ1. 1H NMR
(250 MHz, CDCl3) (two diastereomers 11b/12b, 35:65)
d¼0.89 (dd,
J¼11.5, 12.5 Hz, 1H, H-5, 12b), 2.40–2.80 (m, 7H, 2H-7, H-8, 12b, and
2H-5, 2H-7, 11b), 2.47 (ddd, J¼2.0, 5.0, 12.5 Hz, 1H, H-5, 12b), 2.80–
3.10 (m, 3H, H-8, 12b, and 2H-8, 11b), 3.20 (dd, JAB¼13.5 Hz,
J¼4.5 Hz, 1H, Hbenzyl, 11b), 3.27 (dd, JAB¼13.2 Hz, J¼4.5 Hz, 1H,
Hbenzyl, 12b), 3.41 (dd, JAB¼13.5 Hz, J¼4.5 Hz, 1H, Hbenzyl, 11b), 3.52
(dd, JAB¼13.2 Hz, J¼4.3 Hz, 1H, Hbenzyl, 12b), 3.45–3.62 (m, 1H, H-4a,
11b), 4.63–4.73 (m, 1H, H-2, 12b), 4.73–4.90 (m, 1H, H-2, 11b), 4.82
(ddd, J¼3.2, 5.0, 11.5 Hz, 1H, H-4a, 12b), 7.04–7.42 (m, 5H). 13C NMR
4.2.4. (2S)-1-[(Benzyloxy)carbonyl]-4,4-dimethoxypiperidin-3]-yl N-
(tert-butoxycarbonyl)-L-phenylalaninate (15c/16c). Prepared fol-
lowing procedure A: yield 77% (two steps); colourless oil; Rf¼0.72
(EtOAc/petroleum ether: 50:50). IR (film): nmax¼3438, 3348, 2976,
1747 (COO), 1714 (N-Boc), 1699 (NCO), 1497, 1435, 1367, 1163, 1115,
.
1064 cmꢁ1 1H NMR (300 MHz, CDCl3, 330 K) (two diastereomers
15c/16c, 50:50)
d
¼1.40 (s, 9H, C(CH3)3), 1.70–1.96 (m, 2H, H-5),
(62.9 MHz, CDCl3) (diastereomers 11b/12b, 35:65)
d¼28.3/29.0 (C-
2.77–3.00 (m, 2H, 2H, H-6 and Hbenzyl), 3.00–3.39 (m, 2H, H-2 and
Hbenzyl), 2.93/3.23 (s, 3H, OCH3, 15c/16c), 3.15/3.24 (s, 3H, OCH3,
15c/16c), 4.00–4.20 (m, 1H, H-6), 4.20–4.40 (m, 1H, H2), 4.40–4.62
(m, 1H, CH–N), 4.80–5.14 (m, 2H, CH2Cbz), 5.17/5.22 (s, 1H, H-3,
15c/16c), 5.25 (s, 1H, NH), 7.06–7.44 (m, 10H). 13C NMR (75.5 MHz,
7, 11b/12b), 33.9/34.1 (C-8, 11b/12b), 39.0/39.2 (CH2benzyl, 12b/11b),
39.6/40.5 (C-5, 11b/12b), 58.5/59.4 (C-2, 12b/11b), 77.2/78.9 (C-4a,
11b/12b) [6 arom C: 125.7/128.5 (CH, 11b/12b), 127.1/128.0 (2CH,
11b/12b), 129.9/130.4 (2CH, 11b/12b), 134.9/135.2 (Cq, 11b/12b)],
164.8/165.1 (C-8a, 12b/11b), 166.3/167.1 (C-3, 12b/11b). ESþMS m/z:
284.1 [MþNa]þ.
CDCl3, 330 K) (diastereomers 15c/16c)
d
¼28.3 (C(CH3)3), 28.3 (C-5),
37.9 (CH2benzyl), 40.6/40.7 (C-6, 15c/16c), 45.1/45.2 (C-2, 15c/16c),
47.65/47.7 (OCH3, 15c/16c), 47.9 (OCH3), 54.5 (CH–N), 67.3 (CH2,
Cbz), 68.5 (C-3), 79.7 (C(CH3)3), 97.88/97.95 (C-4, 15c/16c) [12 arom
C: 126.7 (CH), 127.8 (2CH), 128.0 (CH), 128.4 (2CH), 129.4 (2CH),
4.3.3. Benzyl (2S,4aR/S)-2-Benzyl-3-oxo-2,3,4a,5,7,8-hexahydro-6H-
pyrido[3,4-b][1,4]oxazine-6-carboxylate (11c/12c). Prepared follow-
ing procedure B: pale yellow foam; Rf¼0.29/0.23 (EtOAc/petroleum

8592
N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
ether, 60:40). 1H NMR (360 MHz, CDCl3) (two diastereomers 11c/
12c, 55:45)
¼1.26 (dd, J¼10.3, 11.2 Hz, 1H, H-5, 12c), 2.18–2.75 (m,
aminophosphonates 13a–d was accomplished as noted in
method A.
d
4H, 2H-8, 11c, and 2H-8, 12c), 2.75–2.96 (m, 1H, H-5, 11c), 3.00–
3.30 (m, 2H, H-7, 12c and H-4a, 11c), 3.14 (dd, JAB¼13.3 Hz,
J¼4.7 Hz, 1H, Hbenzyl, 12c), 3.29 (dd, JAB¼13.0 Hz, J¼4.3 Hz, 1H,
Hbenzyl, 11c), 3.80 (dd, JAB¼13.3 Hz, J¼4.3 Hz, 1H, Hbenzyl, 12c), 3.46
(dd, JAB¼13.0 Hz, J¼4.3 Hz, 1H, Hbenzyl, 11c), 4.00–4.50 (m, 4H, H-5,
H-7, 11c, and H-5, H-7, 12c), 4.48–4.66 (m, 1H, H-4a, 12c), 4.58
(sharp m, 1H, H-2, 11c), 4.81(dd, J¼4.7, 4.3 Hz, 1H, H-2, 12c), 5.00–
5.15 (m, 4H, CH2O, 11c, and CH2O, 12c), 6.96–7.64 (m, 20H, 10H 11c,
and 10H 12c). 13C NMR (90.56 MHz, CDCl3) (two diastereomers
4.4.3. Diethyl [(2S,4aS,8aS)-2-benzyl-3-oxo-hexahydropyrano[3,4-
b][1,4]oxazin-8a(1H)-yl]phosphonate (13a). Prepared by procedure
C, method B: yield 72% from esters 15a/16a; yellow foam; Rf¼0.59
(EtOAc); [
a]
ꢁ24 (c 1.00, CHCl3). IR (film): nmax¼3460, 2980, 1747
D
(COO), 1455, 1231, 1019, 967 cmꢁ1. 1H NMR (360 MHz, CDCl3, 330 K)
d
¼1.24 (t, J¼7.0 Hz, 3H, CH3), 1.26 (t, J¼7.2 Hz, 3H, CH3), 1.59 (dddd,
J¼3.6, 4.3, 14.0, 14.0 Hz, 1H, H-8), 2.00–2.19 (m, 2H, H-8 and NH),
2.96 (dd, J¼13.7, 7.9 Hz, 1H, Hbenzyl), 3.23 (dd, J¼13.7, 4.0 Hz, 1H,
Hbenzyl), 3.20–3.34 (m, 1H, H-5), 3.54–3.78 (m, 3H, H-5 and 2H-7),
3.96–4.15 (m, 4H, CH2OP), 4.27 (ddd, 4JPH¼3.6 Hz, J¼4.0, 7.9 Hz, 1H,
H-2), 4.53 (ddd, 4JPH¼7.4 Hz, J¼7.9, 4.7 Hz, 1H, H-4a), 7.10–7.30 (m,
11c/12c, 55:45)
d
¼35.1/36.0 (C-8, 11c/12c), 39.5/39.6 (CH2benzyl
,
11c/12c), 43.8/44.2 (C-7, 11c/12c), 47.9/48.4 (C-5, 11c/12c), 58.9/
60.1 (C-2, 12c/11c), 67.1/67.8 (OCH2, 12c/11c), 73.4/75.4 (C-4a, 11c/
12c) [12 arom C: 128.0, 128.4, 128.5, 128.6, 130.2, 130.6, 135.0 (Cq,
11c), 135.7 (Cq, 12c), 136.0 (Cq, 11c), 136.6 (Cq, 12c)], 154.6 (NCOO,
11c and 12c), 164.1/165.2 (C-8a, 12c/11c), 166.6/167.6 (C-3, 12c/
11c). HRMS (ES) m/z [MþNa]þ calcd for C22H22N2O4þNa: 401.1477;
found: 401.1482.
5H). 13C NMR (90.56 MHz, CDCl3)
d
¼16.4 (d, 3JPC¼6.1 Hz, CH3), 16.5
3
(d, JPC¼5.5 Hz, CH3), 31.6 (C-8), 38.9 (CH2benzyl), 52.1 (d,
1JPC¼151.7 Hz, C-8a), 55.3 (C-2), 61.7 (d, JPC¼6.8 Hz, C-7), 62.5 (d,
3
2JPC¼7.9 Hz, CH2OP), 63.6 (d, JPC¼7.4 Hz, CH2OP), 65.2 (d,
2
3JPC¼6.1 Hz, C-5), 72.2 (C-4a) [6 arom C: 126.9 (CH), 128.5 (2CH),
129.8 (2CH), 137.0 (Cq)], 169.8 (C-3). 31P NMR (101.25 MHz, CDCl3)
4.3.4. (3S,8aR/S)-3-Benzyl-3,5,6,7,8,8a-hexahydro-2H-1,4-benzox-
azin-2-one (11d/12d). Prepared following procedure B: colourless
oil; Rf¼0.29/0.14 (EtOAc/petroleum ether, 50:50). 1H NMR
d
¼24.11, ( ¼23.92 ppm for minor isomer obtained by method A).
d
ESþMS m/z: 406.1 [MþNa]þ. HRMS (ES) m/z [MþNa]þ calcd for
C18H26NO6PþNa: 406.1390; found: 406.1398.
(360 MHz, CDCl3) (two diastereomers 11d/12d, 50:50)
d¼0.02
(dddd, J¼12.6, 12.3, 12.3, 3.6 Hz, 1H, H-8, 12d), 1.10–1.70 (m, 6H, 2H-
6, H-8, 11d and 2H-6, H-8, 12d), 1.70–2.25 (m, 7H, 2H-7, H-5, 11d
and 2H-7, H-5, H-8, 12d), 2.48–2.70 (m, 2H, H-5, 11d and H-5, 12d),
3.17 (dd, JAB¼13.3 Hz, J¼4.3 Hz, 1H, Hbenzyl, 12d), 3.29 (dd,
JAB¼13.0 Hz, J¼4.7 Hz, 1H, Hbenzyl, 11d), 3.20–3.38 (m, 1H, H-8a,
11d), 3.39 (dd, JAB¼13.3 Hz, J¼4.3 Hz, 1H, Hbenzyl, 12d), 3.48 (dd,
JAB¼13.0 Hz, J¼3.6 Hz, 1H, Hbenzyl, 11d), 4.53–4.65 (m, 1H, H-3, 11d),
4.57 (ddd, J¼12.3, 5.9, 3.2 Hz, 2H, H-3, 11d, and H-8a, 12d), 4.76
(ddd, J¼4.5, 4.5, 3.2 Hz, 1H, H-3, 12d), 7.05–7.45 (m, 5H, 11d and
12d). 13C NMR (62.9 MHz, CDCl3) (diastereomers 11d/12d, 55:45)
4.4.4. Diethyl [(2S,4aR,8aS)-2-benzyl-3-oxo-hexahydro-thiopyrano-
[3,4-b][1,4]oxazin-8a(1H)-yl]phosphonate (13b). Prepared by pro-
cedure C, method B: yield 68% from 15b/16b; white solid, mp
132 ꢀC; Rf¼0.24 (EtOAc/petroleum ether: 60:40); [
a
]
þ1.5 (c 1.00,
D
CHCl3). IR (film): nmax¼3454, 3317, 2981, 1740 (COO), 1455, 1372,
1237, 1171, 1020, 963 cmꢁ1
.
1H NMR (250 MHz, CDCl3)
d¼1.27 (t,
J¼7.0 Hz, 3H, CH3), 1.275 (t, J¼7.0 Hz, 3H, CH3), 1.40 (br s, 1H, NH),
1.98–2.17 (m, 1H, H-8), 2.17–2.40 (m, 2H, H-5 and H-8), 2.40–2.65
(m, 2H, H-7), 2.65–2.93 (m, 1H, H-5), 3.00 (dd, J¼13.5, 8.0 Hz, 1H,
Hbenzyl), 3.21 (dd, J¼13.5, 4.0 Hz, 1H, Hbenzyl), 3.95–4.25 (m, 4H,
CH2OP), 4.23–4.38 (m, 1H, H-2), 4.73 (ddd, J¼4.0, 4.3, 8.3 Hz, 1H, H-
d
¼22.5/23.1 (C-6, 12d/11d), 25.0/25.8 (C-7, 12d/11d), 33.5/33.9 (C-8,
12d/11d), 35.5/36.0 (C-5, 12d/11d), 39.2 (CH2benzyl, 11d and 12d),
58.3/59.3 (C-3, 11d/12d), 77.2/79.0 (C-8a, 12d/11d) [6 arom C:
126.6/126.8 (CH, 11d/12d), 127.7/127.8 (2CH, 11d/12d), 129.8/130.2
(2CH, 12d/11d), 135.1/135.6 (Cq, 12d/11d)], 167.0 (C-4a, 11d and
12d), 167.6/167.7 (C-2, 11d/12d). The 1H NMR spectral data are in
accord with the literature values.32
4a), 7.20–7.40 (m, 5H). 13C NMR (62.90 MHz, CDCl3)
d
¼16.4 (d,
3JPC¼6.0 Hz, CH3), 16.5 (d, 3JPC¼5.4 Hz, CH3), 21.2 (d, 2JPC¼9.5 Hz, C-
3
8), 28.0 (d, JPC¼8.1 Hz, C-7), 34.5 (C-5), 39.7 (CH2 benzyl), 54.1 (d,
1JPC¼145.2 Hz, C-8a), 56.0 (C-2), 62.4 (d, JPC¼7.9 Hz, CH2OP), 63.5
2
2
(d, JPC¼7.5 Hz, CH2OP), 75.1 (C-4a) [6 arom C: 127.0 (CH), 128.5
(2CH), 129.9 (2CH), 137.0 (Cq)], 169.3 (C-3). 31P NMR (101.25 MHz,
CDCl3)
d
¼25.23. ESþMS m/z: 422.0 [MþNa]þ. HRMS (ES) m/z
4.4. Formation of aminophosphonates 13a–d from imines
15a–d/16a–d
[MþNa]þ calcd for C18H26NO5PSþNa: 422.1162; found: 422.1178.
C18H26NO5PS (399.44): calcd C 54.12, H 6.56, N 3.51; found C 54.02,
H 6.55, N 3.43.
4.4.1. General procedure C, method A. To a solution of crude imines
15a–d/16a–d (1.6 mmol) in absolute EtOH (4 mL/mmol of imine)
4.4.5. Data for the minor isomer (2S,4aS,8aR)-17b. Rf¼0.31 (EtOAc/
was added TFA (1.6 mmol, 123
mL). After stirring at room temper-
petroleum ether: 60:40). 1H NMR (300 MHz, CDCl3)
d
¼1.36 (t,
ature for 10 min, P(OEt)3 (1.75 mmol, 300
mL) was added. The re-
J¼7.0 Hz, 3H, CH3), 1.38 (t, J¼7.0 Hz, 3H, CH3), 1.86–2.20 (br s, 1H,
NH), 2.10–2.30 (m, 1H, H-5), 2.40–2.60 (m, 1H, H-8), 2.60–2.80 (m,
1H, H-8), 2.80–3.20 (m, 3H, 2H-7 and H-5), 3.08 (dd, JAB¼14.0 Hz,
J¼9.6 Hz, 1H, Hbenzyl), 3.52 (dd, J¼14.0, 3.6 Hz, 1H, Hbenzyl), 4.04 (dd,
J¼3.6, 9.6 Hz, 1H, H-2), 4.08–4.38 (m, 4H, CH2OP), 4.83 (ddd, J¼5.1,
5.4, 7.6 Hz, 1H, H-4a), 7.10–7.50 (m, 5H). 13C NMR (75.50 MHz,
action mixture was stirred at room temperature for 17 h, then the
volatile solvent was evaporated under vacuum. The resulting resi-
due was mixed with a satd aq NaHCO3 (3 mL) and then extracted
with EtOAc (3ꢂ20 mL). The combined organic layers were dried
over (MgSO4), filtered and then concentrated under vacuum. The
pure bicyclic aminophosphonates 13a–d were purified on silica gel
column chromatography.
CDCl3)
d
¼16.5 (d, 3JPC¼3.4 Hz, 2CH3), 21.9 (d, 2JPC¼7.2 Hz, C-8), 29.1
3
(d, JPC¼7.5 Hz, C-7), 31.9 (C-5), 39.4 (CH2benzyl), 53.5 (d,
1JPC¼152.1 Hz, C-8a), 53.9 (d, 3JPC¼3.1 Hz, C-2), 63.1 (d, 2JPC¼7.7 Hz,
2
4.4.2. General procedure C, method B. A solution of crude imines
15a–d/16a–d (1.0 mmol) in CH2Cl2 (5 mL/mmol of imine) was
CH2OP), 63.4 (d, JPC¼7.2 Hz, CH2OP), 76.1 (C-4a) [6 arom C: 127.1
(CH), 128.9 (2CH), 129.4 (2CH), 137.0 (Cq)], 169.6 (C-3). 31P NMR
added TFA (1.0 mmol, 77
m
L). After stirring for 10 min, P(OEt)3
(121.50 MHz, CDCl3)
d
¼24.90. ESþMS m/z: 422.0 [MþNa]þ.
(2.0 mmol, 345 L) was added. The reaction mixture was stirred
m
at ꢁ78 ꢀC and slowly warmed to room temperature over 6 h.
After removal of the volatile solvent under vacuum, the residue
was mixed with a satd aq NaHCO3 (2 mL) and then extracted
with EtOAc (3ꢂ20 mL). The organic layers were dried (MgSO4),
filtered and then concentrated under vacuum. Purification of
4.4.6. Benzyl [(2S,4aS,8aS)-2-Benzyl-8a-(diethoxyphosphoryl)-3-oxo-
octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate
(13c). Prepared by procedure C, method B: yield 71% from 15c/16c;
white solid; Rf¼0.14 (ether); mp 125.9 ꢀC; [
D ꢁ78.2 (c 1.00, CHCl3).
a]
IR (film): nmax¼3472, 3280, 2981,1748 (COO),1704 (NCO),1435,1229,

N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
8593
1174, 1041, 1022, 967 cmꢁ1. 1H NMR (360 MHz, CDCl3, 330 K)
d
¼1.28
0.873 mmol) in CH2Cl2 (5 mL) at ꢁ78 ꢀC. After stirring for 10 min,
(t, J¼7.0 Hz, 3H, CH3), 1.30 (t, J¼7.0 Hz, 3H, CH3), 1.34–1.50 (br s, 1H,
NH), 1.50–1.72 (m, 1H, H-8), 1.95–2.17 (m, 1H, H-8), 2.98 (dd,
JAB¼14.0 Hz, J¼8.3 Hz, 1H, Hbenzyl), 3.12 (dd, J¼13.3, 8.4 Hz, 1H,
Hbenzyl), 3.29 (dd, JAB¼14.0 Hz, J¼4.0 Hz, 1H, Hbenzyl), 3.30–3.43 (m,
1H, H-7), 3.71 (ddd, J¼4.7, 4.7, 13.3 Hz, 1H, H-7), 3.92 (ddd, J¼4.0, 1.5,
13.3 Hz, 1H, H-5), 3.98–4.17 (m, 4H, CH2OP), 4.24–4.37 (m, 1H, H-2),
TMSP(O)(OMe)2 (333 mL, 1.747 mmol) was added. The mixture was
then warmed to room temperature over 17 h, and then concen-
trated to dryness in vacuo. The residue was mixed with satd aq
NaHCO3 and extracted with EtOAc (3ꢂ30 mL). The organic layers
were dried (MgSO4), filtered, and then concentrated to give the
crude phosphonates as a mixture. Purification by flash chroma-
tography (silica gel, Et2O/CH2Cl2, 60:40) gave pure 20a (95 mg, 31%
from 15a/16a) and 21a (65 mg, 21% from 15a/16a).
4.53–4.64 (m, 1H, H-4a), 5.15 (s, 2H, CH2, Cbz), 7.10–7.47 (m,10H). 13
C
NMR (62.9 MHz, CDCl3)
d
¼16.5 (2CH3), 30.9 (C-8), 37.9 (d,
3JPC¼7.2 Hz, C-7), 38.9 (CH2benzyl), 43.6 (C-5), 52.9 (d, 1JPC¼150.7 Hz,
Data for aminophosphonate 20a: pale yellow oil; Rf¼0.29
2
2
C-8a), 55.4 (C-2), 62.6 (d, JPC¼7.8 Hz, CH2OP), 63.8 (d, JPC¼7.4 Hz,
CH2OP), 67.4 (CH2, Cbz), 72.5 (d, 2JPC¼5.2 Hz, C-4a) [12 arom C: 127.0
(CH), 128.0 (CH), 128.1 (2CH), 128.6 (4CH), 129.8 (2CH), 136.4 (Cq),
136.9 (Cq)], 154.9 (NCO), 169.7 (C-3). 31P NMR (145.78 MHz, CDCl3,
(EtOAc); [
a]
D ꢁ61.6 (c 1.00, CHCl3). IR (film): nmax¼3467, 3358, 2957,
1747 (COO), 1242, 1167, 1051, 1030 cmꢁ1. 1H NMR (250 MHz, CDCl3)
d
¼1.77 (br t, J¼5.0 Hz, 1H, NH), 1.75–2.14 (m, 2H, H-8), 3.08 (dd,
JAB¼13.7 Hz, J¼9.2 Hz, 1H, Hbenzyl), 3.47 (dd, JAB¼13.7 Hz, J¼3.7 Hz,
1H, Hbenzyl), 3.66–3.90 (m, 3H, 2H-7 and H-5), 3.81 (d, 3JPH¼2.0 Hz,
3H, CH3O), 3.85 (d, 3JPH¼2.0 Hz, 3H, CH3O), 3.94 (ddd, JAB¼11.7 Hz,
J¼3.7 Hz, 1.7 Hz, 1H, H-5), 4.05 (dddd, J¼1.2, 3.7, 3.8, 7.7 Hz, 1H, H-
2), 4.66 (ddd, J¼3.7, 4.0, 7.0 Hz, 1H, H-4a), 7.23–7.45 (m, 5H). 13C
330 K)
(minor isomer at
d
¼24.13; at 293 K two rotamers: ¼24.20 and 23.96 ppm
d
d
¼23.91 ppm). ESþMS m/z: 539.2 [MþNa]þ. HRMS
(ES) m/z [MþNa]þ calcd for C26H33N2O7PþNa: 539.1918; found:
539.1927.
NMR (62.9 MHz, CDCl3)
d
¼29.4 (C-8), 39.4 (CH2benzyl), 51.7 (d,
4.4.7. Benzyl
(2S,4aS,8aS)-2-Benzyl-8a-(dimethoxyphosphoryl)-3-
1JPC¼156.1 Hz, C-8a), 53.8 (C-2), 54.0 (d, 2JPC¼7.0 Hz, 2CH3OP), 62.1
(d, 3JPC¼4.9 Hz, C-7), 66.1 (d, 3JPC¼5.5 Hz, C-5), 74.4 (C-4a) [6 arom
C: 127.2 (CH), 129.0 (2CH), 129.5 (2CH), 137.0 (Cq)], 169.2 (C-3). 31P
oxo-octahydro-6H-pyrido[3,4-b][1,4]oxazine-6-carboxylate
(13ca). Prepared by procedure C, method A with P(OMe)3 in MeOH
instead of P(OEt)3 in EtOH: yield 54% from esters 15c/16c; white
NMR (121.25 MHz, CDCl3)
d
¼26.49. ESþMS m/z: 378.1 [MþNa]þ.
solid; Rf¼0.20 (EtOAc/petroleum ether, 80:20); mp 138.7 ꢀC; [
a
]
HRMS (ES) m/z [MþNa]þ calcd for C16H22NO6PþNa: 378.1077;
D
ꢁ44.3 (c 1.00, CHCl3). 1H NMR (360 MHz, CDCl3, 330 K)
d
¼1.43 (br s,
found: 378.1089.
1H, NH), 1.52–1.75 (m, 1H, H-8), 1.98–2.13 (m, 1H, H-8), 3.00 (dd,
JAB¼14.0 Hz, J¼7.9 Hz,1H, Hbenzyl), 3.09 (dd, J¼13.3, 8.3 Hz,1H, H-5),
3.27 (dd, JAB¼14.0 Hz, J¼4.0 Hz, 1H, Hbenzyl), 3.35 (dddd, J¼1.1, 3.2,
10.5,13.3 Hz,1H, H-7), 3.60–3.78 (m,1H, H-7), 3.71 (s, 3H, CH3), 3.74
(s, 3H, CH3), 3.90 (dd, J¼4.0, 13.3 Hz, 1H, H-5), 4.28 (ddd, J¼3.2, 4.0,
7.9 Hz, 1H, H-2), 4.56 (ddd, J¼4.0, 8.3 Hz, JP,H¼6.8 Hz, 1H, H-4a), 5.14
(sharp m, 2H, CH2, Cbz), 7.20–7.45 (m, 10H). 13C NMR (90.56, MHz,
4.4.10. Dimethyl [(2S,4aS,8aS)-2-benzyl-3-oxo-hexahydropyrano[3,4-
b][1,4]oxazin-8a(1H)-yl]phosphonate (21a). Yield 21% from 15a/16a;
white solid; Rf¼0.24 (EtOAc); mp 143.5 ꢀC; [
]D¼–26.4 (c 1.00,
a
CHCl3). IR (film): nmax¼3462, 3287, 2956, 1747 (COO), 1455, 1234,
1178, 1114, 1051 cmꢁ1
.
1H NMR (300 MHz, CDCl3)
d
¼1.46 (br t,
J¼7.2 Hz,1H, NH), 1.65 (dddd, J¼3.3, 3.7, 13.2,13.2 Hz,1H, H-8), 2.04–
2.30 (m, 1H, H-8), 3.03 (dd, JAB¼13.8 Hz, J¼7.7 Hz, 1H, Hbenzyl), 3.24
(dd, JAB¼13.8 Hz, J¼4.2 Hz, 1H, Hbenzyl), 3.16–3.35 (m, 1H, H-7), 3.55–
3.95 (m, 3H, H-7 and 2H-5), 3.73 (d, 3JPH¼0.9 Hz, 3H, CH3O), 3.76 (d,
3JPH¼0.9 Hz, 3H, CH3O), 4.29 (ddd, J¼3.5, J¼4.1, J¼7.7 Hz, 1H, H-2),
CDCl3)
d
¼30.8 (C-8), 37.7 (d, 3JPC¼7.3 Hz, C-7), 38.9 (CH2benzyl), 43.4
(C-5), 62.9 (d, 2JPC¼7.9 Hz, CH3OP), 53.1 (d, 1JPC¼151.0 Hz, C-8a), 54.1
2
(d, JPC¼6.9 Hz, CH3OP), 55.3 (C-2), 67.4 (CH2, Cbz), 72.4 (d,
2JPC¼5.2 Hz, C-4a) [12 arom C: 127.0 (CH), 128.1 (CH), 128.5 (4CH),
129.7 (4CH), 136.2 (Cq), 136.6 (Cq)], 154.7 (NCO), 169.3 (C-3). 31P
4.50–4.70 (m, 1H, H-4a), 7.14–7.48 (m, 5H). 13C NMR (75.5 MHz,
1
NMR (145.78 MHz, CDCl3, 330 K)
d
¼26.53; at 293 K two rotamers:
CDCl3)
d
¼31.8 (C-8), 39.3 (CH2benzyl), 52.4 (d, JPC¼151.4 Hz, C-8a),
d
¼26.49 and 26.71 ppm (minor isomer at
d
¼26.23 ppm). HRMS (ES)
53.0 (d, 2JPC¼7.8 Hz, CH3OP), 54.25 (d, 2JPC¼7.6 Hz, CH3OP), 55.4 (C-
m/z [MþNa]þ calcd for C24H29N2O7PþNa: 511.1610; found: 511.1616.
2), 61.7 (d, JPC¼6.9 Hz, C-7), 65.2 (d, JPC¼6.3 Hz, C-5), 72.3 (d,
2JPC¼3.2 Hz, C-4a), [6 arom C: 127.2 (CH), 128.7 (2CH), 130.0 (2CH),
3
3
4.4.8. Diethyl [(3S,4aS,8aS)-3-benzyl-2-oxo-hexahydro-2H-1,4-ben-
zoxazin-4a(5H)-yl]phosphonate (13d). Prepared by procedure C,
method A: yield 62% from 15d/16d; white solid; Rf¼0.26 (EtOAc/
136.9 (Cq)], 169.6 (C-3). 31P NMR (121.49 MHz, CDCl3)
d¼26.60.
ESþMS m/z: 378.2 [MþNa]þ. HRMS (ES) m/z [MþNa]þ calcd for
C16H22NO6PþNa: 378.1077; found: 378.1090.
petroleum ether: 50:50); mp 98.9 ꢀC, [
a
]
ꢁ35 (c 1.00, CHCl3). IR
D
(film): nmax¼3460, 3281, 2935, 1747 (COO), 1455, 1235, 1021,
4.5. Oxidation of a-aminophosphonates 13c or 13d:
procedure D, method A
963 cmꢁ1 1H NMR (360 MHz, CDCl3, 330 K)
.
d
¼1.19 (t, J¼7.2 Hz,
3H, CH3), 1.21 (t, J¼7.2 Hz, 3H, CH3), 1.23–1.34 (m, 1H, H-7), 1.34–
1.68 (m, 5H, H-5, H-7, 2H-6 and H-8), 1.70–1.95 (m, 2H, H-8 and
H-5), 2.89 (dd, J¼13.7, 8.6 Hz, 1H, Hbenzyl), 3.22 (dd, J¼13.7, 3.6 Hz,
1H, Hbenzyl), 3.90–4.10 (m, 4H, CH2O), 4.15 (dd, J¼3.6, 8.6 Hz, 1H,
To a solution of 13c or 13d (1,07 mmol) in CH2Cl2 (2 mL) was
added t-BuOCl (145 m
L, 1.28 mmol) at 0 ꢀC. After stirring the re-
action mixture at 0 ꢀC for 30 min, DABCO (290 mg, 2.56 mmol) was
added. The reaction mixture was stirred at the same temperature
for 30 min, quenched by the addition of water and extracted with
AcOEt, dried over MgSO4 and then concentrated in vacuo. The crude
mixture without separation was converted to acids 3c and 3d by
heating in 6 M aq HCl (5 mL) at reflux for 15 h. The solvent was
evaporated under reduced pressure. The residue was dissolved in
2 mL of MeOH, and then the solution was concentrated again, to
afford the crude aminophosphonic acid$xHCl, hydrochloride salt,
quantitatively. The crude hydrochloride aminophosphonic
acid$xHCl was dissolved in minimum amount of EtOH (2 mL), then
to which was added dropwise an excess of propylene oxide (3 mL)
and stirring at room temperature for 6 h. The volatile compounds
were removed by evaporation under vacuum, to give 122 mg of
aminophosphonic acid 3c and 157 mg of 3d in 58% and 75% yields,
respectively.
H-3), 4.56 (m, 1H, H-8a), 7.10–7.32 (m, 5H). 13C NMR (90.56 MHz,
3
CDCl3)
d
¼16.4 (2CH3), 19.4 (d, JPC¼6.1 Hz, C-6), 22.2 (C-7), 28.3
2
(d, JPC¼5.5 Hz, C-5), 31.6 (C-8), 38.7 (CH2 benzyl), 54.5 (d,
1JPC¼150.2 Hz, C-4a), 55.3 (C-3), 62.3 (d, JPC¼7.9 Hz, CH2O), 63.3
2
2
2
(d, JPC¼7.5 Hz, CH2O), 75.7 (d, JPC¼6.3 Hz, C-8a), [6 arom C:
126.7 (CH), 128.4 (2CH), 129.7 (2CH), 137.3 (Cq)], 171.1 (C-2). 31P
NMR (145.78 MHz, CDCl3)
d
[MþNa]þ calcd for C19H28NO5PþNa: 404.1597; found: 404.1600.
C19H28NO5P (381.40): calcd C 59.83, H 7.40, N 3.67; found C
59.94, H 7.56, N 3.66.
d
¼25.93 ppm (minor isomer at
¼25.73 ppm). ESþMS m/z: 404.1 [MþNa]þ. HRMS (ES) m/z
4.4.9. Dimethyl [(2S,4aR,8aR)-2-benzyl-3-oxo-hexahydropyrano[3,4-
b][1,4]oxazin-8a(1H)-yl]phosphonate
(20a). BF3$OEt2
(110 ml,
0.873 mmol) was added to a solution of imines 11a/12a (214 mg,

8594
N. Louaisil et al. / Tetrahedron 65 (2009) 8587–8595
4.6. Oxidation of
method B
a
-aminophosphonates 13a: procedure D,
d
¼21.47 ppm. ESþMS m/z: 198.0 [MþH]þ. HRMS (ES) m/z [MþH]þ
calcd for C5H13NO5P: 198.0526; found: 198.0531.
Ozone was bubbled through
a
solution of 13a (210 mg,
4.6.4. [(3R,4R)-4-Amino-3-hydroxy-tetrahydro-2H-pyran-4-yl]phos-
phonic acid (ent-3a). Prepared by procedure D, method B: yield 58%
from 20a; white solid; mp 232 ꢀC decomp.; Rf¼0.30 (NH3 aq/H2O/
0.550 mmol) in EtOH (30 mL) at ꢁ78 ꢀC for 15–30 min (persistent
blue colour solution). The excess of ozone was removed by argon
flow and then dimethylsulfide (2 mL) was added. The mixture 18a/
19a was warmed to room temperature, and concentrated in vacuo.
The residue without separation was hydrolyzed to acid 3a accord-
ing to method A, in 77% yield from 13a.
EtOH, 10:30:90); [
a
]
D
ꢁ18.6 (c 0.5, H2O). 1H NMR (360 MHz, D2O)
d¼2.00–2.26 (m, 2H, H-5), 3.80 (dd, J¼4.0, 12.2 Hz, 1H, H-2), 3.84–
3.93 (m, 1H, H-6), 4.00 (ddd, J¼3.6, 8.6, 12.2 Hz, 1H, H-6), 4.13 (d,
J¼12.2 Hz, 1H, H-2), 4.15 (br s, 1H, H-3). All spectral data are iden-
tical with those noted above for (3S,4S)-3a.
4.6.1. Diethyl [(4aS,8aS)-2-Benzyl-3-oxo-4a,5,7,8-tetrahydropyrano-
[3,4-b][1,4]oxazin-8a(3H)-yl]phosphonate (18a). Oxydation of 13a
using procedure D, method A, without acidic hydrolysis, gave
a mixture of three compounds. Purification of the crude mixture
(silica gel, ether/petrol ether/CH2Cl2, 65:25:10) allowed to only
isolate 18a enough pure for spectral characterization: pale yellow
oil; Rf¼0.42 (EtOAc/CH2Cl2, 50:50). 1H NMR (360 MHz, CDCl3)
4.6.5. [(3S,4S)-4-Amino-3-hydroxypiperidin-4-yl]phosphonic acid, hy-
drochloride (3c$2HCl). Prepared by procedure D, method A: yield
58% from 13c; white solid; mp 240 ꢀC decomp.; [
a]
D
þ9.5 (c 1.00,
H2O). IR (KBr): nmax¼3494, 2927, 1612, 1530, 1299, 1188, 1160,
925 cmꢁ1. 1H NMR (360 MHz, D2O)
d
¼2.05–2.34 (m, 2H, H-5), 3.33
(d, J¼13.3 Hz, 1H, H-2), 3.35 (d, J¼12.0 Hz, 1H, H-6), 3.48 (ddd, J¼4.0,
d
¼1.27 (t, J¼7.2 Hz, 3H, CH3), 1.34 (t, J¼7.2 Hz, 3H, CH3), 2.25–2.41
12.6,12.0 Hz,1H, H-6), 3.67 (d, J¼13.3 Hz,1H), 4.34 (br s,1H, H-3). 13C
(m, 2H, H-8), 3.07 (ddd, J¼10.3, J¼10.3, 1.1 Hz, 1H, H-7), 3.47 (dddd,
J¼1.8, 4.3, 10.1, 11.5 Hz, 1H, H-5), 3.82 (ddd, J¼2.5, J¼5.4, 11.5 Hz,
1H, H-5), 3.84–3.91 (m, 1H, H-7), 3.93 (dd, JAB¼13.3 Hz, J¼2.0 Hz,
1H, Hbenzyl), 4.04–4.28 (m, 5H, 1Hbenzyl and 4H, CH2OP), 4.95 (ddd,
J¼5.4, 9.0, 10.1 Hz, 1H, H-4a), 7.20–7.40 (m, 5H). 13C NMR
NMR (90.56 MHz, D2O)
d
¼23.6 (C-5), 40.4 (C-6), 46.9 (C-2), 54.7 (d,
1JPC¼138.0 Hz, C-4), 62.2 (d, 2JPC¼6.2 Hz, C-3). 31P NMR (101.25 MHz,
D2O)
d
¼10.32. HRMS (ES) m/z [MþH]þ calcd for C5H14N2O4P:
197.0686; found: 197.0692.
(90.56 MHz, CDCl3)
d
¼16.4 (CH3), 16.6 (CH3), 31.7 (C-8), 41.5
4.6.6. [(1S,2S)-1-Amino-2-hydroxycyclohexyl]phosphonic acid (3d).
Prepared by procedure D, method A: yield 75% from 13d; white
1
3
(CH2benzyl), 59.4 (d, JPC¼152.4 Hz, C-8a), 63.3 (d, JPC¼10.7 Hz, C-
2
3
5), 63.9 (d, JPC¼7.2 Hz, 2CH2OP), 64.4 (d, JPC¼8.7 Hz, C-7), 72.9
solid; mp 208 ꢀC decomp.; Rf¼0.11 (EtOAc); [
a
]
ꢁ9.4 (c 1.00, H2O).
D
(C-4a) [6 arom C: 127.3 (CH), 128.9 (2CH), 129.7 (2CH), 135.0 (Cq)],
IR (KBr): nmax¼3390, 3255, 2939,1624,1538,1163,1079, 916 cmꢁ1. 1H
154.2 (C-3), 165.7 (CO); 31P NMR (145.78 MHz, CDCl3)
d¼19.14.
NMR (250 MHz, D2O)
d
¼1.20–1.60 (m, 3H), 1.60–2.50 (m, 5H), 4.00–
HRMS (ES) m/z [MþNa]þ calcd for C18H24NO7PþNa: 404.1239;
4.16 (m, 1H, H-2). 1H NMR (360 MHz, CD3OD)
d
¼1.30–1.62 (m, 3H),
found 404.1233.
1.62–1.87 (m, 2H), 1.87–2.16 (m, 3H), 4.01 (ddd, J¼4.2, 5.0, 10.1 Hz,
1H, H-2). 13C NMR (90.56 MHz, CD3OD)
d
¼19.3 (d, 3JPC¼6.8 Hz, C-4),
4.6.2. Diethyl [(2S,4aR,8aS)-2-Benzyl-6-oxido-3-oxo-hexahydro-thio-
pyrano[3,4-b][1,4]oxazin-8a(1H)-yl]phosphonate. Byproduct obtained
from 13b by oxidation using method A without acidic hydrolysis,
and purified on silica gel for spectral characterization: yield 71%;
22.4 (C-5), 27.9 (C-6), 28.5 (C-3), 58.0 (d, 1JPC¼141.5 Hz, C-1), 68.3 (C-
2). 31P NMR (101.25 MHz, D2O)
d
d
¼14.93; in (CD3OD, 145.78 MHz)
¼14.76 ppm. HRMS (ES) m/z [MþNa]þ calcd for C6H14NO4PþNa:
218.0553; found: 218.0553.
pale yellow oil; Rf¼0.20 (MeOH/CH2Cl2: 5:95); [
CHCl3). IR (film): nmax¼3463, 3289, 2983, 1744 (COO), 1375, 1239,
1168, 1046, 966 cmꢁ1 1H NMR (250 MHz, CDCl3)
J¼7.0 Hz, 3H, CH3), 1.35 (t, J¼7.0 Hz, 3H, CH3), 1.50 (dd, J¼12.3,
12.3 Hz, 1H, H-5), 1.90 (br s, 1H, NH), 1.94–2.09 (m, 1H, H-8), 2.63–
2.82 (m, 3H, 2H-7 and H-5), 2.82–2.95 (m, 1H, H-8), 3.23 (dd,
JAB¼13.3 Hz, J¼4.3 Hz, 1H, Hbenzyl), 3.49 (dd, JAB¼13.3 Hz, J¼5.8 Hz,
1H, Hbenzyl), 4.04–4.25 (m, 4H, CH2OP), 4.44–4.54 (m, 1H, H-2),
4.99–5.09 (m, 1H, H-4a), 7.09–7.29 (m, 5H). 13C NMR (62.9 MHz,
a
]
ꢁ14.4 (c 1.00,
D
Acknowledgements
.
d
¼1.34 (t,
We thank Mr. Regis Guillot for performing X-ray crystal analysis.
Supplementary data
Experimental procedures, characterization data for new com-
pounds not reported in the experimental section, copies of 1H and
13C NMR spectra for some new compounds, X-ray data for com-
pound 13b. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.07.040.
CDCl3)
d
¼16.4 (d, 3JPC¼8.5 Hz, CH3), 16.5 (d, 3JPC¼5.3 Hz, CH3), 22.2
3
(C-8), 38.3 (d, JPC¼9.5 Hz, C-7), 39.7 (CH2benzyl), 44.4 (d,
2JPC¼7.5 Hz, C-5), 53.0 (d, 1JPC¼145.3 Hz, C-8a), 56.7 (C-2), 62.9 (d,
2JPC¼8.0 Hz, CH2OP), 63.7 (d, JPC¼7.5 Hz, CH2OP), 70.5 (C-4a) [6
2
arom C: 127.3 (CH), 128.4 (2CH), 130.4 (2CH), 136.8 (Cq)], 168.8 (C-
3). 31P NMR (101.25 MHz, CDCl3)
d
¼24.28. HRMS (ES) m/z
References and notes
[MþNa]þ calcd for C18H26NO6PSþNa: 438.1111; found: 438.1113.
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a
]
þ21.5 (c 0.50, H2O). IR (KBr): nmax¼3420, 3369,
D
3120, 2932, 1614, 1494, 1207, 1160, 1109, 1065, 916 cmꢁ1
.
1H NMR
(360 MHz, D2O)
d
¼2.00–2.26 (m, 2H, H-5), 3.80 (dd, J¼4.0, 12.2 Hz,
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2.10 (m, 1H, H-5), 3.52–3.84 (m, 4H), 3.99 (ddd, J¼5.2, 5.2, 10.5 Hz,
1H, H-3). 13C NMR (90.56 MHz, D2O)
d
¼27.4 (C-5), 55.6 (d,
1JPC¼140.5 Hz, C-4), 63.0 (C-6), 64.4 (d, 2JPC¼4.2 Hz, C-3), 67.9 (C-2).
31P NMR (101.25 MHz, D2O)
d
¼12.05, in (D2OþNaOD, 101.25 MHz)

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28. Colourless crystal of 0.220ꢂ0.180ꢂ0.035 mm3. C18H26NO5PS, M¼399.44:
monoclinic system, space group P21 (No. 4), Z¼2, with a¼6.0889(3), b¼15.8496
(8), c¼10.0715 (6) Å,
a
¼90,
b
¼95.5040 (10),
g
K
¼90.00ꢀ, V¼967.49 (9) Å3, d¼1.
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371 g cmꢁ3
,
F(000)¼424,
l
¼0.71073 Å (Mo
a
),
m
¼0.279 mmꢁ1
, 6423 re-
flections measured (ꢁ8ꢃhꢃ9, ꢁ21ꢃkꢃ24, ꢁ15ꢃlꢃ15) on a Bruker X8 diffrac-
tometer. The structure was solved and refined with SHELXL-97.33 Hydrogen
atom riding, refinement converged to R(gt)¼0.0335 for the 5860 reflections
having I>2
s
(I), and wR(gt)¼0.0775, Goodness-of-fit S¼1.026, residual electron
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density: ꢁ0.353 and 0.481 e Åꢁ3; for more details, see Supplementary data
included.34
29. Namba, K.; Shinada, T.; Teramoto, T.; Ohfune, Y. J. Am. Chem. Soc. 2000, 122,
10708–10709.
30. The numbering of the fused system and the absolute configuration are noted
following IUPAC rules, and taking into account the sulfur atom priority.
31. All calculations were performed using Spartan’ 06.
32. Shinada, T.; Kawakami, T.; Sakai, H.; Matsuda, H.; Umezawa, T.; Kawasaki, M.;
Namba, K.; Ohfune, Y. Bull. Chem. Soc. Jpn. 2006, 79, 768–774.
33. Scheldrick, G. M. SHELXL-97, Programme for Crystal Structure Refinement; Uni-
versita¨t Go¨ttingen: Go¨ttingen, 1997.
34. Crystallographic data for compound (þ)-13b have been deposited with the
Cambridge Crystallographic Data Centre as Supplementary Publication Number
CCDC 725296. Copies of the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, fax: þ44 1233 336033, E-mail:
deposit-@ccdc.cam.ac.uk.