Asymmetric synthesis of phosphonic acid analogues for acylcarnitine

Article abstract of DOI:10.1016/j.tet.2005.09.126

Phosphonic acid analogues of acylcarnitine were prepared in an optically active form expecting CPT I inhibitory activities. The synthetic methodology was based on catalytic asymmetric dihydroxylation of β,γ-unsaturated phosphonates and subsequent regiosel

Full text of DOI:10.1016/j.tet.2005.09.126

Tetrahedron 62 (2006) 54–65
Asymmetric synthesis of phosphonic acid analogues
for acylcarnitine
†
Takehiro Yamagishi, Keiichi Fujii, Shiroshi Shibuya and Tsutomu Yokomatsu
*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 25 August 2005; revised 28 September 2005; accepted 29 September 2005
Available online 25 October 2005
Abstract—Phosphonic acid analogues of acylcarnitine were prepared in an optically active form expecting CPT I inhibitory activities. The
synthetic methodology was based on catalytic asymmetric dihydroxylation of b,g-unsaturated phosphonates and subsequent regioselective
amination via the cyclic sulfates.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
acylcarnitine were prepared as racemate and showed modest
activities.4a However, the structure–activity relationship of
phosphonic acid analogues for acylcarnitine including
effects of the chirality on activities has never been
investigated probably due to lack of a general method for
asymmetric synthesis of g-amino-b-acyloxyphosphonic
acid derivatives. Then, we investigated a new method for
asymmetric synthesis of g-amino-b-acyloxyphosphonates
and their transformation to phosphonic acid analogues of
acylcarnitine (Fig. 1). In this paper, we now describe full
details of our study.6
Hyperglycemia of type II diabetes is considered to be
primarily due to excess long-chain fatty acid oxidation,
which is crucial to drive gluconeogenesis at higher rates.1
Carnitine palmitoyltransferase I (CPT I) located on the outer
mitochondrial membrane plays an important role in
b-oxidation of long-chain free fatty acids, which catalyzes
a formation of acylcarnitine from carnitine and long-chain
fatty acids, then a translocase transports the fatty acids
carnitine esters across the inner mitochondrial membrane.2
CPT I inhibitors indirectly reduce gluconeogenesis by
inhibiting the b-oxidation and are hence helpful in the
treatment of type II diabetes as hypoglycemic agents.3
Recent studies demonstrated modification of the functional
groups of acylcarnitine was one access to the development
of potent CPT I inhibitors. In these studies, aminoacylcar-
nitine derivatives, in which the b-oxygen atom of
acylcarnitine was replaced with nitrogen, were discovered
as good inhibitors.4 The absolute configuration of these
molecules was found to influence their inhibitory activities;
the (R)-isomer inhibited CPT I more strongly than the
corresponding enantiomer.
2. Result and discussion
For obtaining the targeted molecules, a protected form of
chiral g-amino-b-hydroxyphosphonates would be required as
synthetic intermediates. Inspection of the literature revealed
that the key reactions used in this synthesis involved optical
resolution,7a enzymatic resolution ofg-chloro-b-hydroxypho-
sphonates,7b hydrolytic kinetic resolution of epoxyphospho-
nates with an asymmetric catalyst,7c ring-opening of
epichlorohydrin with silylphosphites,7d and diastereoselec-
tive reduction of g-amino-b-ketophosphonates.7e Although
Since phosphonic acids are known to function as a
bioisosteric group of carboxylic acids,5 modification of the
carboxylic moiety of acylcarnitine has been also examined.
To date, three kinds of phosphonic acid analogues of
Keywords: Acylcarnitine; Phosphonic acid; Asymmetric dihydroxylations;
Regioselectivity.
*
Corresponding author. Tel./fax: C81 426 76 3239;
e-mail: yokomatu@ps.toyaku.ac.jp
† Present address: Faculty of Pharmaceutical Science, Teikyo-Heisei
University, 2289 Uruido, Ichihara, Chiba 290-0193, Japan.
Figure 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.09.126

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
55
catalytic asymmetric aminohydroxylation of b,g-unsatu-
rated phosphonates developed by Sharpless et al. is an
attractive method, the chemical yields were not satisfactory
due to formation of the regioisomer of the desired amino
alcohols and diols as byproducts.7f We examined asym-
metric synthesis of g-amino-b-acyloxyphosphonic acid
derivatives by our own approach, which involved
osmium-catalyzed asymmetric dihydroxylation (AD)8 of
b,g-unsaturated phosphonates, followed by selective amin-
ation of the hydroxy group at the g-position (Scheme 1).
AD reaction of b,g-unsaturated phosphonate having a
phenyl group at the g-position with AD-mix reagents was
previously reported by us to provide diols in high ee (98%
ee).9 According to the reported protocol, AD reactions of
2a–e were performed with AD-mix-a in the presence of
MeSO2NH2 and additional K2OsO4$2H2O (0.8 mol%) in
the t-BuOH–H2O solvent system (1/1) at room tempera-
ture.10 The results are summarized in Table 1.
In the series of AD reactions of ethyl esters 2a–c with AD-
mix-a, very low enantioselectivity (10% ee) was observed
when R1 is a proton (entry 1). However, the enantioselec-
tivity was slightly increased to 35% ee when R1 is a methyl
group (entry 2). Excellent selectivity (97% ee) was observed
in the case of 2c having a 4-methoxybenzoyloxymethylene
group as R1 substituent (entry 3). In the series of AD
reactions of benzyl esters 2d,e, the reaction with 2d having a
proton as R1 substituent also proceeded in poor ee (10% ee)
as in the case of the corresponding ethyl ester 2a (entry 4).11
However, 2e having a methyl group as R1 substituent
reacted with AD-mix-a reagent to give 3e in 61% ee
(entry 5). It is worthy of note that the enantioselectivity for
2e significantly improved in comparison to that for 2b (35%
ee) and crystalline 3e could be obtained in an optically pure
form (O99% ee) through one recrystallization from AcOEt
(38% recovery).
Scheme 1.
2.1. AD reactions of b,g-unsaturated phosphonates
The requisite starting materials 2a–c were readily prepared
by Arbuzov reactions of the corresponding allyl bromide
derivatives 1a–c with triethylphosphite (Scheme 2). The
compounds having a dibenzylphosphonyl group, 2d and 2e,
were prepared from 2a and 2b, respectively, through
sequential deesterification, chlorination of the acid moiety,
followed by treatment with benzyl alcohol and pyridine.
Considering Corey’s working model of the chemical
architecture provided by the ligand of AD-mix-a, in
which the ligand–osmium complex preferred the U-shaped
conformation, the high ee of 3c was accounted for by the
4-methoxybenzoyl group participating in p-stacking inter-
actions with the methoxyquinoline ring of the catalyst.12 An
improved ee of 3e may be ascribed to the enhanced
hydrophobicity of substrate 2e compared to 2b, which
facilitated substrates to be trapped into the lipophilic cavity
of the ligand–osmium complex.13
Similar reaction of 2c using AD-mix-b instead of AD-mix-a
proceeded to give ent-3c in good selectivity (98% ee)
(Scheme 3). The reaction of 2e furnished product ent-3e in
68% ee, which could be increased to O99% ee by one
recrystallization from AcOEt (59% recovery).
The absolute stereochemistry of 3a was verified to be R
by comparison of optical rotation with that reported.14
Scheme 2.
Table 1. AD reactions of b,g-unsaturated phosphonates 2a–e with AD-mix-a
Entry
3
R1
R2
Yield (%)
ee (%)a
1
2
3
4
5
a
b
c
d
e
H
Me
Et
Et
Et
Bn
Bn
41
60
58
71
69
10
35
4-MeOC6H4CO2CH2
H
Me
97b
10
61c
a Determined by 31P NMR (121 MHz, CDCl3) analysis of the corresponding bis-MTPA esters unless stated otherwise.
b Determined by HPLC analysis on a chiral phase (DAICEL CHIRALPAK AS column).
c Determined by HPLC analysis on a chiral phase (DAICEL CHIRALPAK OD column).

56
T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
active 15 since the compound was previously prepared in
racemic form.4a
Treatment of 3a with SOCl2, followed by oxidation with
RuCl3–NaIO4 afforded cyclic sulfate 8 in 80% yield.
16
When 8 was treated with NaN3 in acetone–H2O at 50 8C, the
starting material disappeared within 3 h on TLC. Sub-
sequent treatment with 20% H2SO4 gave g-azido-b-
hydroxyphosphonate 9 with complete regioselectivity in
24% yield for two steps. Although an exact reason for the
low chemical yield remained unclear, it might be associated
with partial decomposition of the diethyl phosphonate
moiety into the corresponding aqueous phosphonic acid or
monoethyl ester in the reaction mixture. After transform-
ation to TES ether 10, catalytic hydrogenation was carried
out to give g-amino-b-silyloxyphosphonate 11. Reductive
dimethylation of 11 with formaldehyde and NaBH3CN
provided 12 in 90% yield.17 Deprotection of the silyl group,
followed by treatment with myristoyl chloride in the
presence of pyridine and DMAP afforded 13, which
underwent N-methylation with MeI to give 14. Finally, 14
was deprotected with TMSBr and MeOH to give the desired
15 in 72% yield.
Scheme 3.
The absolute configuration of 3b and 3c was determined
after conversion to 4-methoxybenzoate derivatives 5b and
5c (Scheme 4). The CD spectrum of 5b showed a positive
Cotton effect at 289 nm and a negative Cotton effect at
282 nm, which were analogous to that of methoxybenzoate
6 prepared from known b,g-dihydroxyphosphonate 4,9
showing positive and negative Cotton effects at longer
(286 nm) and shorter wavelengths (275 nm), respectively.
The CD curve of 5c (a positive Cotton effect at 284 nm and a
negative Cotton effect at 276 nm) was also similar to that of
6. Accordingly, 5b and 5c have the same absolute
stereochemistry with 6, indicating the stereochemistry of
3b and 3c was as shown in Scheme 4.
The methodology was next applied to the synthesis of
g-methyl-substituted phosphonic acid analogue 27 of
acylcarnitine from diol 3e. In this synthesis, g-selective
amination of the starting 3e is a critical step because the
corresponding cyclic sulfate 16 is prone to react with an
azide anion at both b- and g-positions. However, a
molecular modeling of 16 reveals that the b-carbon is
sterically more congested than the g-carbon owing to the
bulky dibenzyl phosphonate moiety in the most stable
conformation and regioselective ring-opening reaction
would be feasible due to the steric reason.18 Then, we
examined several representative conditions for ring-opening
reaction of 16, prepared from optically pure 3e in an
analogous manner to that for preparation of 8, with metal
azides (Table 2).
The absolute configuration of 3e was verified after
transformation to the corresponding phosphonic acid 7
through hydrogenolysis of the dibenzyl phosphonate moiety
(Scheme 5). The sign of the optical rotation of 7 was
identical with that of a sample derived from 3b.
2.2. Synthesis of phosphonic acid analogues of
acylcarnitine
With chiral b,g-dihydroxyphosphonates in hand, we next
directed our efforts toward the synthesis of phosphonic acid
analogues of acylcarnitine. In these efforts, we first chose 3a
to tackle its transformation to phosphonic acid analogue 15
of acylcarnitine through the regioselective amination via a
cyclic sulfate (Scheme 6).15 Although the optical purity of
3a is not sufficient, it will be valuable to obtain optically
Upon treatment of 16 with LiN3 in DMF at room
temperature, the starting material disappeared within 12 h
on TLC (entry 1). Quenching the reaction with 50% H2SO4
Scheme 4.
Scheme 5.

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
57
Increasing the reaction temperature up to 50 8C shortened
the reaction time from 96 to 3 h (entry 4).
The structure of 17 was deduced after conversion into
g-amino-b-ketophosphonate 22 (Scheme 7). Staudinger
reaction of TES ether 19 derived from 17 with PPh3 and
subsequent hydrolysis afforded g-amino-b-siloxyphospho-
nate 20. Tosylation of 20, followed by desilylation, and
1
oxidation with PDC gave 22. In the H NMR spectrum
(400 MHz, CDCl3) of 22, a signal ascribed to the Me group
at the g-position was observed at 1.18 ppm as a doublet (JZ
7.1 Hz) but not as a singlet corresponding to regioisomeric
product 23.
Scheme 6. Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, 0 8C;
(b) RuCl3$nH2O, NaIO4, CCl4–CH3CN–H2O, 0 8C (80%, two steps);
(c) NaN3, acetone–H2O, 50 8C; (d) 20% H2SO4, Et2O, rt (24%, two steps);
(e) TESCl, imidazole, DMF, rt (80%); (f) H2, 10% Pd–C, MeOH, rt (97%);
(g) 37% HCHO, NaBH3CN, AcOH, CH3CN, rt (90%); (h) TBAF, THF,
0 8C; (i) CH3(CH2)12COCl, pyridine, DMAP, rt (52%, two steps); (j) MeI,
acetone, rt (86%); (k) TMSBr, CH2Cl2, rt; (l) MeOH, rt (72%, two steps).
Scheme 7. Reagents and conditions: (a) TESCl, imidazole, DMF, rt (98%);
(b) PPh3, THF, rt; (c) H2O, rt (97%, two steps); (d) TsCl, Et3N, CH2Cl2, rt
(13%); (e) TBAF, THF, 0 8C; (f) PDC, CH2Cl2, rt (47%, two steps).
Compound 20 was converted into 26 in the same manner to
the case of 14 (Scheme 8). In this synthesis, deprotection of
the benzyl ester moiety of 26 was attempted through
hydrogenolysis in the presence of 10% Pd–C or 20%
Pd(OH)2–C. However, the hydrogenolysis did not work to
give 27 in reproducible yield after several trials. Then,
g-methyl-substituted phosphonic acid analogue 27 of
acylcarnitine was obtained through the TMSBr-mediated
debenzylation of 26 in 48% yield (two steps).
gave g-azide 17 and b-azide 18 with a ratio of 5:1. Although
the regioselectivity of the reaction was found to be the
desired sense as expected, the chemical yield was poor
(13%). Similar yield and ratio were observed when NaN3
was used as an azide anion (entry 2). However, when the
reaction was carried out in acetone–H2O instead of DMF at
25 8C and subsequent treatment with 20% H2SO4, both yield
(41%) and 17/18 ratio (10:1) were improved (entry 3).
Table 2. Ring-opening reactions of 16 with metal azides
Entry
Nucleophile
Solvent
Temperature (8C)
Time (h)
H2SO4 (%)
Yield (%)a
17:18b
1
2
3
4
LiN3
DMF
DMF
Acetone/H2O 2:1
Acetone/H2O 2:1
25
50
25
50
12
8
96
3
50
50
20
20
13
15
41
42
5:1
4:1
10:1
10:1
NaN3
NaN3
NaN3
a Combined yield of 17 and 18.
b Determined by 31P NMR (121 MHz, CDCl3) analysis of crude products.

58
T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
The synthesis of enantiomer ent-27 of 27 was also achieved
starting from optically pure ent-3e through the same
sequence (Scheme 9). Thus, we have obtained both
enantiomers of g-methyl substituted phosphonic acid
analogues of acylcarnitine.
3. Conclusion
In conclusion, we have developed a new method for
preparing chiral g-amino-b-acyloxyphosphonic acid deriva-
tives through AD reactions of b,g-unsaturated phosphonates
and subsequent regioselective amination via cyclic sulfates.
The method was applicable to the synthesis of optically
active phosphonic acid analogues of acylcarnitine. A study
on preparing a variety of derivatives and their CPT I
inhibitory activities is underway.
4. Experimental
4.1. General
All melting points were taken on a Yanagimoto micro-
melting point apparatus and are uncorrected. Optical
rotations were measured with a JASCO DIP-360 or P1030
digiital polarimeter. IR spectra were recorded on a JASCO
FTIR-620. Mass spectra were measured on a Finnigan TSQ-
700. Elemental analysis were recorded on an Elemental
Vavio EL. NMR spectra were obtained on Bruker DPX400
1
NMR specrometer operating at 400 MHz for H, 100 MHz
for 13C, and 162 MHz for 31P. The chemical shift data for
Scheme 8. Reagents and conditions: (a) 37% HCHO, NaBH3CN, AcOH,
CH3CN, rt (85%); (b) TBAF, THF, 0 8C; (c) CH3(CH2)12COCl, pyridine,
DMAP, rt (23%, two steps); (d) MeI, acetone, rt (33%); (e) TMSBr,
CH2Cl2, rt; (f) MeOH, rt (48%, two steps).
1
each signal on H NMR are given in units of d relative to
CHCl3 (dZ7.26) for CDCl3 solution. For 13C NMR spectra,
the chemical shifts in CDCl3 are reported relative to the
CDCl3 resonance (dZ77.0). The chemical shifts of 31P are
recorded relative to external 85% H3PO4 (dZ0) with broad-
1
band H decoupling.
4.1.1. Diethyl allylphosphonate (2a). To a stirred
suspension of 1a (12.3 g, 100 mmol) and KI (16.6 g,
100 mmol) in acetone–CH3CN 10:8 (500 mL) was added
triethyl phosphite (17.2 mL, 100 mmol). The mixture was
stirred for 12 h at room temperature and then stirred for 5 h
at 60 8C. After filtration of the mixture, the filtrate was
concentrated to give a residue, which was distilled (73–
75 8C, 5 mmHg) to give 2a (16.0 g, 90%). A colorless oil;
1H NMR (400 MHz, CDCl3) d 5.80–5.74 (1H, m), 5.23–
5.16 (2H, m), 4.13–4.04 (4H, m), 2.59 (2H, dd, JZ21.9,
7.4 Hz), 1.30 (6H, t, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 127.4 (d, JCPZ11.2 Hz), 119.7 (d, JCPZ14.4 Hz),
61.7 (d, JCPZ6.6 Hz), 31.6 (d, JCPZ139.3 Hz), 16.2 (d,
JCPZ5.9 Hz); 31P NMR (162 MHz, CDCl3) d 26.46; IR
(neat) 2983, 1255, 1027 cmK1; ESIMS m/z 179 (MHC);
HRMS (ESI) calcd for C7H16O3P: 179.0873 (MHC).
Found: 179.0840.
4.1.2. Diethyl (2E)-but-2-enylphosphonate (2b). Com-
pound 2b was prepared from 1b (13.8 g, 100 mmol) in an
analogous manner to that for preparation of 2a. Purification
of the residue by distillation (85–88 8C, 7 mmHg) gave 2b
(16.4 g, 92%). A colorless oil; 1H NMR (400 MHz, CDCl3)
d 5.64–5.58 (1H, m), 5.44–5.38 (1H, m), 4.14–4.05 (4H, m),
2.57–2.49 (2H, m), 1.71–1.64 (3H, m), 1.31 (6H, t, JZ
Scheme 9. Reagents and conditions: (a) SOCl2, Et3N, CH2Cl2, 0 8C;
(b) RuCl3$nH2O, NaIO4, CCl4–CH3CN–H2O, 0 8C (76%, two steps);
(c) NaN3, acetone–H2O, 50 8C; (d) 20% H2SO4 , Et2O, rt (44%, two steps);
(e) TESCl, imidazole, DMF, rt (97%); (f) PPh3, THF, rt; (g) H2O, rt (94%,
two steps); (h) 37% HCHO, NaBH3CN, AcOH, CH3CN, rt (96%);
(i) TBAF, THF, 0 8C; (j) CH3(CH2)12COCl, pyridine, DMAP, rt (30%, two
steps); (k) MeI, acetone, rt (30%); (l) TMSBr, CH2Cl2, rt; (m) MeOH, rt
(34%, two steps).
7.0 Hz); 13C NMR (100 MHz, CDCl3) d 130.5 (d, JCP
Z
14.6 Hz), 119.5 (d, JCPZ11.2 Hz), 61.7 (d, JCPZ6.6 Hz),
30.3 (d, JCPZ139.9 Hz), 17.9 (d, JCPZ2.2 Hz), 16.3 (d,
JCPZ6.0 Hz); 31P NMR (162 MHz, CDCl3) d 24.53; IR
(neat) 2982, 1251, 1027 cmK1; ESIMS m/z 193 (MHC);

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
59
HRMS (ESI) calcd for C8H18O3P: 193.0994 (MHC).
Found: 193.0993.
CDCl3) d 29.37; IR 2960, 1253 cmK1; ESIMS m/z 317
(MHC); HRMS (ESI) calcd for C8H22O3P: 317.1307
(MHC). Found: 317.1331.
4.1.3. (2E)-4-(Diethoxyphosphoryl)but-2-enyl 4-meth-
oxybenzoate (2c). A mixture of 1c (9.36 g, 32.8 mmol)
and triethyl phosphite (6.75 mL, 39.4 mmol) was stirred for
12 h at 160 8C. After being cooled, the mixture was
chromatographed on silica gel (hexane/EtOAcZ1:2) to
give 2c (10.2 g, 76%). A pale yellow oil; 1H NMR
(400 MHz, CDCl3) d 7.98 (2H, d, JZ8.9 Hz), 6.90 (2H, d,
JZ8.9 Hz), 5.94–5.84 (2H, m), 4.78–4.75 (2H, m), 4.19
(4H, q, JZ7.1 Hz), 3.85 (3H, s), 2.63 (2H, dd, JZ21.8,
5.8 Hz), 1.28 (6H, t, JZ7.2 Hz); 13C NMR (100 MHz,
CDCl3) d 165.9, 163.4, 131.6, 129.5 (d, JCPZ14.5 Hz),
4.2. General procedure for AD reactions of 2a–e
To a stirred suspension of AD-mix-a (5.60 g) in H2O/t-
BuOH 1:1 (32 mL) was added K2OsO4$2H2O (12 mg,
0.8 mol%) at room temperature. After the mixture was
stirred until two clear phases were observed, MeSO2NH2
(380 mg, 4.0 mmol) was added at the same temperature.
After the mixture was chilled with an ice-water bath, 2a–e
(4.0 mmol) was added slowly and this mixture was stirred
for 2 h at the same temperature and then stirring was
continued for 6 h at room temperature. Sodium sulfite
(12.0 g) was added to quench the reaction and the mixture
was stirred for 1 h at room temperature. The mixture was
extracted with EtOAc and the combined extracts were
washed with brine and dried over MgSO4. Removal of the
solvent gave a residue, which was chromatographed on
silica gel (EtOAc to CHCl3/MeOHZ20:1) to give 3a–e.
124.1 (d, JCPZ11.1 Hz), 122.4, 113.5, 64.4, 62.0 (d, JCP
Z
Z
6.7 Hz), 55.3, 30.3 (d, JCPZ139.9 Hz), 16.3 (d, JCP
5.9 Hz); 31P NMR (162 MHz, CDCl3) d 26.72; IR (neat)
2983, 1715, 1257, 1167 cmK1; ESIMS m/z 343 (MHC);
HRMS (ESI) calcd for C16H24O6P: 343.1311 (MHC).
Found: 343.1289.
4.1.4. Dibenzyl allylphosphonate (2d). To a stirred
solution of 2a (1.60 g, 10 mmol) in CH2Cl2 (20 mL) was
added TMSBr (5.3 mL, 40 mmol) at room temperature. The
mixture was stirred for 9 h at the same temperature and then
concentrated to give a residue. To an ice-cooled, stirred
solution of this residue in CH2Cl2 (20 mL) was slowly
added oxalyl chloride (3.0 mL, 35 mmol) and DMF (a few
drops). After being stirred for 6 h at room temperature, the
mixture was concentrated to give a residue. To a stirred
solution of this residue in THF (30 mL) was added benzyl
alcohol (2.3 mL, 22 mmol) and pyridine (1.8 mL, 22 mmol)
at K21 8C. After the mixture was stirred for 30 min at the
same temperature, stirring was continued for 6 h at room
temperature. The mixture was poured into saturated aqueous
KHSO4 and extracted with EtOAc. The combined extracts
were washed with brine and dried over MgSO4. Removal of
the solvent gave a residue, which was chromatographed on
silica gel (hexane/EtOAcZ10:1–1:1) to give 2d (1.10 g,
4.2.1. (2R)-Diethyl 2,3-dihydroxypropylphosphonate
(3a). Compound 3a (330 mg, 41%) was prepared from 2a
(712 mg, 4.0 mmol) with AD-mix-a. A colorless oil; [a]D30
K0.67 (c 0.55, EtOH); 1H NMR (400 MHz, CDCl3) d 4.17–
4.06 (5H, m), 3.69 (1H, ddd, JZ11.4, 3.6, 1.3 Hz), 3.53
(1H, dd, JZ11.4, 5.6 Hz), 2.09–1.90 (2H, m), 1.34 (3H, t,
JZ7.1 Hz), 1.33 (3H, t, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 67.1 (d, JCPZ4.0 Hz), 66.7 (d, JCPZ16.1 Hz),
62.0 (d, JCPZ9.4 Hz), 61.9 (d, JCPZ9.4 Hz), 29.8 (d, JCP
Z
140.3 Hz), 16.3 (d, JCPZ5.2 Hz); 31P NMR (162 MHz,
CDCl3) d 30.44; IR (neat) 3346, 1221 cmK1; ESIMS m/z
213 (MHC); HRMS (ESI) calcd for C7H8O5P: 213.0892
(MHC). Found: 213.0883.
4.2.2. (2R,3S)-Diethyl 2,3-dihydroxybutylphosphonate
(3b). Compound 3b (540 mg, 60%) was prepared from 2b
(768 mg, 4.0 mmol) with AD-mix-a. A colorless oil; [a]D26
K3.22 (c 1.1, MeOH); 1H NMR (400 MHz, CDCl3) d 4.21–
4.07 (4H, m), 3.88–3.85 (1H, m), 3.66 (1H, dt, JZ11.3,
5.4 Hz), 2.04–1.93 (2H, m), 1.34 (6H, t, JZ7.1 Hz), 1.20
(3H, d, JZ6.4 Hz); 13C NMR (100 MHz, CDCl3) d 70.6 (d,
1
37%). A pale yellow oil; H NMR (400 MHz, CDCl3) d
7.39–7.29 (10H, m), 5.83–5.71 (1H, m), 5.19–5.13 (2H, m),
5.06 (2H, dd, JZ11.9, 8.8 Hz), 4.99 (2H, dd, JZ11.9,
8.2 Hz), 2.65 (1H, ddd, JZ7.4, 1.1, 1.1 Hz), 2.60 (1H, ddd,
JZ7.4, 1.1, 1.1 Hz); 13C NMR (100 MHz, CDCl3) d 136.2
JCPZ16.7 Hz), 70.4 (d, JCPZ5.5 Hz), 62.0 (d, JCP
9.3 Hz), 30.0 (d, JCPZ140.1 Hz), 18.9, 16.3 (d, JCP
Z
Z
(d, JCPZ5.7 Hz), 128.4, 128.2, 127.8, 126.9 (d, JCP
Z
11.5 Hz), 120.1 (d, JCPZ14.5 Hz), 67.3 (d, JCPZ6.6 Hz),
31.9 (d, JCPZ139.2 Hz); 31P NMR (162 MHz, CDCl3) d
28.22; IR (neat) 1255 cmK1; ESIMS m/z 325 (MNaC);
HRMS (ESI) calcd for C17H19O3NaP: 325.0970 (MNaC).
Found: 325.0976.
5.9 Hz); 31P NMR (162 MHz, CDCl3) d 30.87; IR (neat)
3356, 1220 cmK1; ESIMS m/z 249 (MNaC); HRMS (ESI)
calcd for C8H19O5NaP: 249.0868 (MNaC). Found:
249.0864.
4.2.3. (2S,3R)-4-(Diethoxyphosphoryl)-2,3-dihydroxybu-
tyl 4-methoxybenzoate (3c). Compound 3c (840 mg, 58%)
was prepared from 2c (1.37 g, 4.0 mmol) with AD-mix-a. A
colorless oil; [a]D26 K2.14 (c 1.0, MeOH); 1H NMR
(400 MHz, CDCl3) d 7.97 (2H, d, JZ8.8 Hz), 6.87 (2H, d,
JZ8.8 Hz), 4.38 (2H, d, JZ5.8 Hz), 4.09 (4H, q, JZ
6.9 Hz), 4.05–4.00 (1H, m), 3.87–3.85 (1H, m), 3.82 (3H, s),
2.22–1.96 (2H, m), 1.29 (6H, t, JZ7.0 Hz); 13C NMR
(100 MHz, CDCl3) d 166.4, 163.5, 131.7, 122.2, 113.6, 72.4
(d, JCPZ14.9 Hz), 66.8 (d, JCPZ4.5 Hz), 65.5, 62.1 (d,
4.1.5. Dibenzyl (2E)-but-2-enylphosphonate (2e). Com-
pound 2e (46.1 g, 57%) was prepared from 2b (50.0 g,
260 mmol) in an analogous manner to that for preparation of
2a after purification by column chromatography on silica
gel (hexane/EtOAcZ10:1–1:1). A pale yellow oil; 1H NMR
(400 MHz, CDCl3) d 7.37–7.30 (10H, m), 5.58–5.51 (1H,
m), 5.41–5.34 (1H, m), 5.06 (2H, dd, JZ11.9, 8.7 Hz), 4.99
(2H, dd, JZ11.9, 8.1 Hz), 2.59–2.52 (2H, m), 1.67–1.63
(3H, m); 13C NMR (100 MHz, CDCl3) d 136.3 (d, JCP
5.9 Hz), 131.0 (d, JCPZ15.0 Hz), 128.4, 128.2, 127.8, 119.0
(d, JCPZ11.5 Hz), 67.3 (d, JCPZ6.5 Hz), 30.6 (d, JCP
139.7 Hz), 17.9 (d, JCPZ2.4 Hz); 31P NMR (162 MHz,
Z
JCPZ3.2 Hz), 55.4, 30.1 (d, JCPZ140.0 Hz), 16.3 (d, JCP
Z
Z
5.9 Hz); 31P NMR (162 MHz, CDCl3) d 29.36; IR (neat)
3356, 1713, 1258, 1168 cmK1; ESIMS m/z 399 (MNaC);

60
T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
HRMS (ESI) calcd for C16H25O8NaP: 399.1185 (MNaC).
Found: 399.1185.
(hexane/EtOAcZ1:1) to provide 5b (600 mg, 38%). A
colorless oil; [a]D26 K5.01 (c 0.9, MeOH); 1H NMR
(400 MHz, CDCl3) d 8.05–7.99 (4H, m), 6.93–6.91 (4H,
m), 5.65–5.61 (1H, m), 5.39 (1H, td, JZ3.4, 3.1 Hz), 4.06–
4.03 (4H, m), 3.86 (6H, s), 2.33–2.29 (2H, m), 1.38 (3H, t,
JZ6.4 Hz), 1.34 (6H, t, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 165.2, 165.1, 163.5, 163.4, 131.8–113.6
4.2.4. (2R)-Dibenzyl 2,3-dihydroxypropylphosphonate
(3d). Compound 3d (850 mg, 71%) was prepared from 2d
(1.10 g, 3.6 mmol) with AD-mix-a. White needles; mp 55–
1
58 8C; [a]2D5 K0.64 (c 1.0, MeOH); H NMR (400 MHz,
(aromatic), 71.2 (d, JCPZ18.7 Hz), 71.0 (d, JCP
10.4 Hz), 63.4 (d, JCPZ5.5 Hz), 55.4, 27.9 (d, JCP
Z
Z
CDCl3) d 7.39–7.28 (10H, m), 5.06 (2H, ddd, JZ11.8, 9.0,
4.4 Hz), 4.97 (2H, ddd, JZ11.8, 8.1, 3.7 Hz), 4.10–4.03
(1H, m), 3.85 (1H, b), 3.63 (1H, dd, JZ11.2, 1.7 Hz), 3.48
(1H, dd, JZ11.2, 5.7 Hz), 2.95 (1H, b), 2.07 (1H, ddd, JZ
15.4, 16.8, 8.8 Hz), 1.97 (1H, ddd, JZ15.4, 19.3, 4.0 Hz);
13C NMR (100 MHz, CDCl3) d 135.9 (d, JCPZ5.7 Hz),
128.6–127.0 (aromatic), 67.6 (d, JCPZ6.9 Hz), 67.5 (d,
142.9 Hz), 16.2, 16.1 (d, JCPZ10.1 Hz); 31P NMR
(162 MHz, CDCl3) d 26.87; IR (neat) 1715, 1258 cmK1
;
ESIMS m/z 495 (MHC); HRMS (ESI) calcd for C24H32O9P:
495.1784 (MHC). Found: 495.1786.
JCPZ6.9 Hz), 67.0 (d, JCPZ4.0 Hz), 66.7 (d, JCP
Z
4.2.9. (2S,3R)-4-(Diethoxyphosphoryl)-2,3-bis[(4-meth-
oxybenzoyl)oxy]butyl 4-methoxybenzoate (5c). Com-
pound 5c (910 mg, 70%) was prepared from 3c (730 mg,
2.0 mmol) in an analogous manner to that for preparation of
5b after purification by column chromatography on silica
gel (hexane/EtOAcZ1:1). A colorless oil; [a]2D6 K7.25 (c
1.0, MeOH); 1H NMR (400 MHz, CDCl3) d 8.01 (4H, d, JZ
8.6 Hz), 7.91 (2H, d, JZ8.8 Hz), 6.91–6.89 (4H, m), 6.85
(2H, d, JZ8.8 Hz), 5.89–5.81 (1H, m), 5.76 (1H, td, JZ4.7,
4.5 Hz), 4.56 (2H, d, JZ2.2 Hz), 4.07–4.04 (4H, m), 3.86
(3H, s), 3.85 (3H, s), 3.83 (3H, m), 2.40–2.35 (2H, m), 1.23
(6H, t, JZ7.1 Hz); 13C NMR (100 MHz, CDCl3) d 165.7,
165.1, 164.9, 163.7, 163.6, 163.4, 131.9–113.6 (aromatic),
71.8 (d, JCPZ10.0 Hz), 67.3, 62.5, 62.0, 55.4, 55.3, 28.0 (d,
JCPZ143.3 Hz), 16.2; 31P NMR (162 MHz, CDCl3) d
25.84; IR (neat) 1719. 1257 cmK1; ESIMS m/z 645
(MHC); HRMS (ESI) calcd for C32H38O12P: 645.2101
(MHC). Found: 645.2098.
17.3 Hz), 30.2 (d, JCPZ139.9 Hz); 31P NMR (162 MHz,
CDCl3) d 31.43; IR (KBr) 3374, 1216 cmK1; ESIMS m/z
359 (MNaC); HRMS (ESI) calcd for C17H21O5NaP:
359.1024 (MNaC). Found: 359.1035.
4.2.5. (2R,3S)-Dibenzyl 2,3-dihydroxybutylphosphonate
(3e). Compound 3e (2.30 g, 69%) was prepared from 2e
(3.00 g, 9.6 mmol) with AD-mix-a. One recrystallization
from EtOAc gave an optically pure 3e (870 mg, 38%).
White needles; mp 93–95 8C; [a]2D2 K7.92 (c 1.0, MeOH)
1
for a sample of O99% ee; H NMR (400 MHz, CDCl3) d
7.39–7.32 (10H, m), 5.12–4.96 (4H, m), 3.70 (1H, dq, JZ
14.9, 4.2 Hz), 3.59 (1H, dt, JZ11.3, 5.6 Hz), 2.04–1.96 (2H,
m), 1.13 (3H, d, JZ6.3 Hz); 13C NMR (100 MHz, CDCl3) d
136.0 (d, JCPZ5.3 Hz), 135.9 (d, JCPZ5.3 Hz), 128.7,
128.6, 128.5, 128.1, 128.0, 70.7 (d, JCPZ17.4 Hz), 70.4 (d,
JCPZ5.6 Hz), 67.6 (d, JCPZ6.4 Hz), 30.5 (d, JCP
Z
139.6 Hz), 18.9; 31P NMR (162 MHz, CDCl3) d 31.91; IR
(KBr) 3359, 2968, 1214 cmK1; ESIMS m/z 351 (MHC);
HRMS (ESI) calcd for C18H24O5P: 351.1361 (MHC).
Found: 351.1352.
4.2.10. (1S,2R)-3-(Diethoxyphosphoryl)-2-[(4-methoxy-
benzoyl)oxy]-1-phenylpropyl 4-methoxybenzoate (6).
Compound 6 (553 mg, 50%) was prepared from 4
(576 mg, 2.0 mmol) in an analogous manner to that for
preparation of 5b after purification by column chromatog-
raphy on silica gel (hexane/EtOAcZ1:1). A colorless oil;
[a]2D6 K9.24 (c 0.9, MeOH); 1H NMR (400 MHz, CDCl3) d
7.92 (2H, d, JZ9.1 Hz), 7.28–7.20 (5H, m), 6.80 (4H, d, JZ
8.7 Hz), 6.13 (1H, d, JZ6.7 Hz), 5.84 (1H, ddt, JZ12.9,
6.5, 6.4 Hz), 3.98–3.90 (4H, m), 3.74 (6H, s), 2.15 (1H, d,
JZ6.4 Hz), 2.10 (1H, d, JZ6.5 Hz), 1.13 (3H, t, JZ
7.1 Hz), 1.07 (3H, t, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 164.7, 163.3, 163.2, 136.3–113.4 (aromatic), 76.6
4.2.6. (2R,3S)-4-(Diethoxyphosphoryl)-2,3-dihydroxybu-
tyl 4-methoxybenzoate (ent-3c). Compound ent-3c
(670 mg, 70%) was prepared from 2c (1.37 g, 4.0 mmol)
with AD-mix-b. A colorless oil; [a]2D5 C6.01 (c 1.0,
1
MeOH). The H NMR spectrum was identical with that of
ent-3c.
4.2.7. (2S,3R)-Dibenzyl 2,3-dihydroxybutylphosphonate
(ent-3e). Compound ent-3e (24.6 g, 64%) was prepared
from 2e (34.8 g, 110 mmol) with AD-mix-b. One recrys-
tallization from EtOAc gave an optically pure ent-3e
(14.6 g, 59%). White needles; [a]2D4 C7.76 (c 1.2, MeOH)
(d, JCPZ14.1 Hz), 69.7 (d, JCPZ4.6 Hz), 61.6 (d, JCP
6.3 Hz), 55.1, 27.4 (d, JCPZ143.3 Hz), 16.0 (d, JCP
Z
Z
6.7 Hz), 15.9 (d, JCPZ6.7 Hz); 31P NMR (162 MHz,
CDCl3) d 26.18; IR (neat) 1719, 1258 cmK1; ESIMS m/z
557 (MHC); HRMS (ESI) calcd for C29H33O9P: 557.1940
(MHC). Found: 557.1927.
1
for a sample of O99% ee. The H NMR spectrum was
identical with that of ent-3e.
4.2.8. (1S,2R)-3-(Diethoxyphosphoryl)-2-[(4-methoxy-
benzoyl)oxy]-1-methylpropyl 4-methoxybenoate (5b).
To a stirred solution of 4-methoxybenzoyl chloride
(1.40 g, 8.0 mmol) in CH2Cl2 (1 mL) was sequentially
added a solution of 3b (720 mg, 3.2 mmol) in CH2Cl2
(5 mL), pyridine (0.65 mL, 8.0 mmol) and DMAP (39 mg,
0.32 mmol). After stirring for 24 h at room temperature, the
mixture was poured into saturated aqueous KHSO4 and
extracted with CHCl3. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue, which was chromatographed on silica gel
4.2.11. (2R,3S)-2,3-Dihydroxybutylphosphonic acid (7).
To a solution of 3e (350 mg, 1.0 mmol) in MeOH (20 mL)
was added 10% Pd–C (40 mg) and the mixture was stirred
for 12 h at room temperature under hydrogen atmosphere.
The catalyst was removed by filtration through a pad of
Celite, the filtrate was concentrated to give 7 (160 mg,
1
94%). Amorphous; [a]2D6 K0.23 (c 0.7, MeOH); H NMR
(400 MHz, CDCl3) d 3.90–3.81 (1H, m), 3.79–3.27 (1H, m),
2.21–1.86 (2H, m), 1.21 (3H, d, JZ6.4 Hz); 13C
NMR (100 MHz, CDCl3) d 71.4 (d, JCPZ4.4 Hz), 71.1

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
61
(d, JCPZ14.2 Hz), 31.5 (d, JCPZ137.9 Hz), 18.6; 31P NMR
5.6 Hz); 31P NMR (162 MHz, CDCl3) d 29.28; IR (neat)
3361, 2104, 1220 cmK1; ESIMS m/z 238 (MHC); HRMS
(ESI) calcd for C7H17N3O4P: 238.0957 (MHC). Found:
238.0977.
(162 MHz, CDCl3) d 28.35; IR (neat) 3336, 997 cmK1
;
ESIMS m/z 171 (MHC); HRMS (ESI) calcd for C4H12O5P:
171.0422 (MHC). Found: 171.0410.
4.2.12. (2R,3S)-2,3-Dihydroxybutylphosphonic acid (7).
To a stirred solution of 3b (226 mg, 1.0 mmol) in CH2Cl2
(2 mL) was added TMSBr (0.53 mL, 4.0 mmol) and the
mixture was stirred for 12 h at room temperature.
Concentration of the mixture gave a residue, which was
dissolved in MeOH (0.1 mL). After stirring for 2 h at room
temperature, the solution was concentrated to provide 7
(158 mg, 93%). Amorphous; [a]2D6 K1.55 (c 0.9, MeOH).
4.2.15. (2R)-Diethyl 3-azido-2-[(triethylsilyl)oxy]propyl-
phosphonate (10). To a stirred solution of 9 (2.09 g,
8.82 mmol) in DMF (30 mL) was added imidazole (1.44 g,
21.2 mmol) at 0 8C and the mixture was stirred for 15 min at
the same temperature. To the solution was added TESCl
(1.8 mL, 10.6 mmol) and the mixture was stirred for 5 h at
room temperature. The mixture was poured into saturated
aqueous NaHCO3 and extracted with EtOAc. The combined
extracts were washed with brine and dried over MgSO4.
Removal of the solvent gave a residue, which was
chromatographed on silica gel (hexane/EtOAcZ3:1) to
provide 10 (2.48 g, 80%). A colorless oil; [a]2D6 C1.79 (c
0.5, MeOH); 1H NMR (400 MHz, CDCl3) d 4.23–4.17 (1H,
m), 4.14–4.02 (4H, m), 3.49 (1H, dd, JZ12.6, 3.1 Hz), 3.29
(1H, dd, JZ12.6, 5.4 Hz), 2.19 (1H, ddd, JZ16.8, 15.6,
9.3 Hz), 1.98 (1H, ddd, JZ20.0, 15.6, 3.9 Hz), 1.33 (6H, t,
JZ7.1 Hz), 0.98 (9H, t, JZ7.9 Hz), 0.65 (6H, q, JZ
7.9 Hz); 13C NMR (100 MHz, CDCl3) d 67.5, 61.7, (d,
1
The H NMR spectrum was identical to that of 7 prepared
from 3e.
4.2.13. (4R)-Diethyl (2,2-dioxido-1,3,2-dioxathiolan-4-
yl)methylphosphonate (8). To a stirred solution of 3a
(990 mg, 5.0 mmol) in CH2Cl2 (30 mL) was added Et3N
(2.8 mL, 20 mmol) and a solution of SOCl2 (0.50 mL,
15 mmol) in CH2Cl2 (3 mL) at 0 8C and the mixture was
stirred for 1 h at the same temperature. The mixture was
poured into H2O and extracted with EtOAc. The combined
extracts were washed with brine and dried over MgSO4.
Removal of the solvent gave a residue. To a stirred solution
of this residue in CCl4–CH3CN–H2O 1:1:1.5 (50 mL) was
added NaIO4 (2.00 g, 10 mmol) and RuCl3$nH2O (52 mg)
at 0 8C and the mixture was stirred for 2 h at the same
temperature. The mixture was poured into H2O and
extracted with EtOAc. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue, which was chromatographed on silica gel
(EtOAc) to give 8 (1.09 g, 80%). A pale yellow oil; [a]D25
K0.72 (c 0.8, MeOH); 1H NMR (400 MHz, CDCl3) d 5.27–
5.18 (1H, m), 4.85 (1H, dd, JZ9.2, 6.0 Hz), 4.59 (1H, dd,
JZ9.2, 7.5 Hz), 4.15–4.07 (4H, m), 2.54 (1H, ddd, JZ20.2,
15.0, 4.9 Hz), 2.33 (1H, ddd, JZ18.4, 15.0, 9.9 Hz), 1.36
(6H, t, JZ7.3 Hz); 13C NMR (100 MHz, CDCl3) d 77.6 (d,
JCPZ3.5 Hz), 73.1 (d, JCPZ4.6 Hz), 63.6 (d, JCPZ5.8 Hz),
29.9 (d, JCPZ139.6 Hz), 16.3 (d, JCPZ6.0 Hz); 31P NMR
(162 MHz, CDCl3) d 21.55; IR (neat) 1386, 1212,
1163 cmK1; ESIMS m/z 275 (MHC); HRMS (ESI) calcd
for C7H16O7PS: 275.0354 (MHC). Found: 275.0381.
JCPZ4.6 Hz), 56.6 (d, JCPZ3.1 Hz), 32.0 (d, JCP
Z
135.9 Hz), 16.3 (d, JCPZ6.1 Hz), 6.7, 4.7; 31P NMR
(162 MHz, CDCl3) d 26.87; IR (neat) 2157, 1228 cmK1
;
ESIMS m/z 352 (MHC); HRMS (ESI) calcd for C13H31N3-
O4SiP: 352.1821 (MHC). Found: 352.1808.
4.2.16. (2R)-Diethyl 3-amino-2-[(triethylsilyl)oxy]pro-
pylphosphonate (11). A solution of 10 (100 mg,
0.28 mmol) in MeOH (5.7 mL) was stirred over 10% Pd–
C (11 mg) for 12 h at room temperature under hydrogen
atmosphere. The catalyst was removed by filtration through
a pad of Celite, the filtrate was concentrated to give a
residue, which was chromatographed on silica gel (EtOAc)
1
to provide 11 (93.2 mg, 97%). A colorless oil; H NMR
(400 MHz, CDCl3) d 4.16–4.00 (5H, m), 2.92 (1H, dd, JZ
13.3, 3.6 Hz), 2.76 (1H, dd, JZ13.3, 5.0 Hz), 2.13 (1H, ddd,
JZ17.3, 15.4, 9.1 Hz), 1.95 (1H, ddd, JZ19.9, 15.4,
4.2 Hz), 1.32 (6H, t, JZ7.1 Hz), 0.96 (9H, t, JZ7.9 Hz),
0.62 (6H, q, JZ7.9 Hz); 13C NMR (100 MHz, CDCl3) d
68.8, 61.5 (d, JCPZ4.9 Hz), 47.8 (d, JCPZ3.4 Hz), 31.7 (d,
JCPZ135.7 Hz), 16.3 (d, JCPZ6.0 Hz), 6.7, 4.8; 31P NMR
(162 MHz, CDCl3) d 28.10; IR (neat) 3416, 1237 cmK1
;
4.2.14. (2R)-Diethyl 3-azido-2-hydroxypropylphospho-
nate (9). To a stirred solution of 8 (9.73 g, 35.5 mmol) in
acetone (532 mL) was added NaN3 (6.98 g, 106.5 mmol),
followed by addition of H2O (266 mL). The mixture was
stirred for 3 h at 50 8C and concentrated to give a residue,
which was dissolved in Et2O (1.78 L). To the solution was
added 20% aqueous H2SO4 (887 mL) and the mixture was
stirred for 12 h at room temperature. The mixture was
extracted with Et2O and to the combined extracts was added
K2CO3 (1.78 g). After stirring for 30 min at room
temperature, this mixture was dried over MgSO4. Removal
of the solvent gave a residue, which was chromatographed
on silica gel (hexane/EtOAcZ3:1–1:1) to give 9 (2.02 g,
24%). A colorless oil; [a]2D5 K0.18 (c 1.0, CHCl3); 1H NMR
(400 MHz, CDCl3) d 4.22–4.07 (5H, m), 3.38 (1H, dd, JZ
12.4, 4.4 Hz), 3.34 (1H, dd, JZ12.4, 5.7 Hz), 2.11–1.93
(2H, m), 1.35 (6H, t, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 65.9 (d, JCPZ4.1 Hz), 62.5 (d, JCPZ6.5 Hz), 62.3
ESIMS m/z 326 (MHC); HRMS (ESI) calcd for C13H33-
NO4SiP: 326.1917 (MHC). Found: 326.1895.
4.2.17. (2R)-Diethyl 3-(dimethylamino)-2-[(triethylsily-
l)oxy]propylphosphonate (12). To a stirred solution of 11
(91 mg, 0.28 mmol) in CH3CN (1.4 mL) was added 37%
aqueous formaldehyde (112 mg, 1.4 mmol) and NaBH3CN
(31 mg, 0.45 mmol) and the mixture was stirred for 2 h at
room temperature. To the solution was added acetic acid to
be pHZ3.0 and stirring was continued for 45 min. After
pH was adjusted to be 9.0 with 1 M KOH, the mixture was
extracted with EtOAc. The combined extracts were washed
with brine and dried over MgSO4. Removal of the solvent
gave a residue, which was chromatographed on silica gel
(hexane/EtOAcZ2:1 to CHCl3/MeOHZ20:1) to provide
12 (88 mg, 90%). A colorless oil; 1H NMR (400 MHz,
CDCl3) d 4.16–4.04 (5H, m), 2.38–2.28 (3H, m), 2.23
(6H, s), 1.89 (1H, ddd, JZ18.3, 15.4, 6.1 Hz), 1.32 (6H, t,
(d, JCPZ6.5 Hz), 30.7 (d, JCPZ140.6 Hz), 16.3 (d, JCP
Z

62
T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
JZ7.1 Hz), 0.97 (9H, t, JZ7.9 Hz), 0.63 (6H, q, JZ
7.9 Hz); 13C NMR (100 MHz, CDCl3) d 66.6, 66.0 (d, JCP
After stirring for 12 h at room temperature, the solution was
concentrated to provide 15 (88 mg, 72%). Amorphous; [a]D26
C2.25 (c 0.5, MeOH); 1H NMR (400 MHz, CDCl3) d 5.64–
5.55 (1H, m), 3.95 (1H, dd, JZ14.4, 8.7 Hz), 3.84 (1H, d,
JZ14.4 Hz), 3.23 (9H, s), 2.41 (2H, t, JZ7.5 Hz), 2.24–
2.17 (2H, m), 1.31–1.28 (22H, m), 0.89 (3H, t, JZ6.8 Hz);
13C NMR (100 MHz, CDCl3) d 174.0, 71.4, 69.7, 65.7, 54.8,
35.1, 33.0, 31.2, 30.7, 30.6, 30.4, 30.2, 26.0, 25.5, 23.7,
14.4; 31P NMR (162 MHz, CDCl3) d 20.01; IR (neat)
970 cmK1; ESIMS m/z 408 (MHC); HRMS (ESI) calcd for
C20H43NO5P: 408.2879 (MHC). Found: 408.2913.
Z
9.6 Hz), 61.3 (d, JCPZ3.2 Hz), 61.2 (d, JCPZ3.2 Hz), 46.4,
32.2 (d, JCPZ138.5 Hz), 16.4 (d, JCPZ6.1 Hz), 16.3 (d,
JCPZ6.1 Hz), 6.8, 4.9; 31P NMR (162 MHz, CDCl3) d
29.83; IR (neat) 1238 cmK1; ESIMS m/z 354 (MHC);
HRMS (ESI) calcd for C15H37NO4SiP: 354.2230 (MHC).
Found: 354.2238.
4.2.18. (1R)-2-(Diethoxyphosphoryl)-1-[(dimethylami-
no)methyl]ethyl myristate (13). To a stirred solution of
12 (402 mg, 1.14 mmol) in THF (6 mL) was added a 1 M
THF solution of TBAF (2.3 mL, 2.3 mmol) at 0 8C and the
mixture was stirred for 2 h at the same temperature. The
mixture was concentrated to give a residue, which was
dissolved in CH2Cl2 (2.5 mL). To this solution was added a
solution of myristoyl chloride (0.63 mL, 2.3 mmol) in
CH2Cl2 (2.5 mL), pyridine (0.16 mL, 2.1 mmol) and
DMAP (14 mg, 0.11 mmol) at 0 8C and the mixture was
stirred for 3.5 h at room temperature. The mixture was
poured into H2O and extracted with CHCl3. The combined
extracts were washed with brine and dried over MgSO4.
Removal of the solvent gave a residue, which was
chromatographed on silica gel (CHCl3/MeOHZ1:0–20:1)
to provide 13 (207 mg, 52%). A colorless oil; [a]2D6 C5.19
4.2.21. Dibenzyl [(4R,5S)-5-methyl-2,2-dioxido-1,3,2-
dioxathiolan-4-yl]methylphosphonate (16). Compound
16 (850 mg, 80%) was prepared from 3e (850 mg,
2.5 mmol) in an analogous manner to that for preparation
of 8 after purification by column chromatography on silica
gel (EtOAc). A pale yellow oil; [a]2D6 K12.95 (c 1.0,
MeOH); 1H NMR (400 MHz, CDCl3) d 7.40–7.33 (10H, m),
5.10–4.95 (4H, m), 4.80 (1H, dt, JZ12.9, 6.4 Hz), 4.68 (1H,
qd, JZ7.2, 7.1 Hz), 2.42–2.17 (2H, m), 1.47 (3H, d, JZ
6.2 Hz); 13C NMR (100 MHz, CDCl3) d 135.4 (d, JCP
Z
5.1 Hz), 135.3 (d, JCPZ5.1 Hz), 128.9, 128.8, 128.3, 128.2,
83.8 (d, JCPZ9.4 Hz), 82.6, 68.2 (d, JCPZ3.1 Hz), 68.1 (d,
JCPZ3.1 Hz), 29.9 (d, JCPZ141.8 Hz), 17.4; 31P NMR
(162 MHz, CDCl3) d 23.12; IR (neat) 1383, 1260,
1211 cmK1; ESIMS m/z 413 (MHC); HRMS (ESI) calcd
for C18H22O7PS: 413.0840 (MHC). Found: 413.0824.
1
(c 0.2, MeOH); H NMR (400 MHz, CDCl3) d 5.24 (1H,
dddd, JZ12.5, 12.5, 6.2, 6.2 Hz), 4.16–4.06 (4H, m), 2.54
(1H, dd, JZ12.8, 6.0 Hz), 2.46 (1H, dd, JZ12.8, 5.5 Hz),
2.32–2.22 (9H, m), 2.07 (1H, ddd, JZ18.2, 15.5, 7.0 Hz),
1.34–1.25 (28H, m), 0.88 (3H, t, JZ6.8 Hz); 13C NMR
(100 MHz, CDCl3) d 172.9, 66.9, 62.6 (d, JCPZ9.8 Hz),
61.7 (d, JCPZ7.2 Hz), 61.6 (d, JCPZ7.2 Hz), 46.0, 34.4,
31.9, 29.6, 29.5, 29.3, 29.2, 29.1, 28.3, 24.8, 22.7, 16.4 (d,
JCPZ7.1 Hz), 14.0; 31P NMR (162 MHz, CDCl3) d 27.42;
IR (neat) 1738, 1257 cmK1; ESIMS m/z 450 (MHC);
HRMS (ESI) calcd for C23H49NO5P: 450.3348 (MHC).
Found: 450.3344.
4.2.22. (2R,3R)-Dibenzyl 3-azido-2-hydroxybutylphos-
phonate (17). Compound 17 (473 mg, 42%) was prepared
from 16 (1.20 g, 3.0 mmol) in an analogous manner to that
for preparation of 9 after purification by column chroma-
tography on silica gel (hexane/EtOAcZ3:1–1:1). A color-
less oil; [a]3D0 K17.56 (c 1.0, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.40–7.32 (10H, m), 5.11–5.05 (2H, m), 5.02–4.96
(2H, m), 3.84–3.77 (1H, m), 3.66 (3H, s), 3.48 (1H, dt, JZ
12.6, 6.3 Hz), 2.07–1.88 (2H, m), 1.18 (3H, d, JZ6.7 Hz);
13C NMR (100 MHz, CDCl3) d 135.9 (d, JCPZ5.7 Hz),
4.2.19. (2R)-3-(Diethoxyphosphoryl)-N,N,N-trimethyl-2-
(tetradecanoyloxy)propan-1-aminium iodide (14). To a
stirred solution of 13 (200 mg, 0.45 mmol) in acetone
(1.9 mL) was added iodomethane (0.03 mL, 0.37 mmol)
and the mixture was stirred for 10 h at room temperature.
The solution was concentrated to give a residue, which was
chromatographed on silica gel (CHCl3/MeOHZ1:0–10:1)
135.8 (d, JCPZ5.7 Hz), 128.7, 128.6, 128.0, 69.5 (d, JCP
Z
4.9 Hz), 67.7 (d, JCPZ6.3 Hz), 67.6 (d, JCPZ6.7 Hz), 61.4
(d, JCPZ17.3 Hz), 29.5 (d, JCPZ140.4 Hz), 14.7; 31P NMR
(162 MHz, CDCl3) d 31.56; IR (neat) 3347, 2098,
1220 cmK1; ESIMS m/z 398 (MNaC); HRMS (ESI) calcd
for C18H22N3O4NaP: 398.1246 (MNaC). Found: 398.1241.
1
to provide 14 (249 mg, 86%). A colorless oil; H NMR
(400 MHz, CDCl3) d 5.57 (1H, dddd, JZ13.8, 13.8, 7.0,
7.0 Hz), 4.38–4.34 (1H, m), 4.18–4.09 (5H, m), 3.49 (9H, s),
2.43–2.24 (4H, m), 1.34–1.23 (28H, m), 0.86 (3H, t, JZ
6.7 Hz); 13C NMR (100 MHz, CDCl3) d 172.6, 68.1 (d,
JCPZ9.9 Hz), 62.6 (d, JCPZ6.4 Hz), 62.5 (d, JCPZ6.4 Hz),
54.5, 34.1, 31.7, 29.6, 29.4, 29.2, 29.1, 29.0, 28.9, 28.2,
24.2, 22.4, 16.2 (d, JCPZ5.8 Hz), 13.9; 31P NMR
4.2.23. (2R,3R)-Dibenzyl 3-azido-2-[(triethylsilyl)oxy]-
butylphosphonate (19). Compound 19 (8.83 g, 98%) was
prepared from 17 (6.90 g, 18.4 mmol) in an analogous
manner to that for preparation of 10 after purification by
column chromatography on silica gel (hexane/EtOAcZ
2:1). A colorless oil; [a]2D7 K1.20 (c 1.0, MeOH); 1H NMR
(400 MHz, CDCl3) d 7.38–7.30 (10H, m), 5.04 (2H, dd, JZ
11.5, 9.7 Hz), 4.95 (1H, dd, JZ8.5, 3.0 Hz), 4.92 (1H, dd,
JZ8.6, 3.1 Hz), 4.12–4.05 (1H, m), 3.63 (1H, qd, JZ6.7,
2.7 Hz), 2.07–1.95 (2H, m), 1.13 (3H, d, JZ6.7 Hz), 0.98–
0.90 (9H, m), 0.60 (6H, t, JZ7.9 Hz); 13C NMR (100 MHz,
CDCl3) d 136.2 (d, JCPZ5.5 Hz), 128.6–128.1 (aromatic),
70.2, 67.4 (d, JCPZ5.7 Hz), 67.3 (d, JCPZ5.6 Hz), 60.7 (d,
JCPZ5.7 Hz), 31.5 (d, JCPZ137.3 Hz), 12.5, 6.8, 4.8; 31P
NMR (162 MHz, CDCl3) d 28.91; IR (neat) 2955, 2105,
1249 cmK1; ESIMS m/z 490 (MHC); HRMS (ESI) calcd for
C24H37N3O4SiP: 490.2291 (MHC). Found: 490.2283.
(162 MHz, CDCl3) d 23.81; IR (neat) 1741, 1241 cmK1
;
ESIMS m/z 464 (MCKI); HRMS (ESI) calcd for
C24H51NO5P: 464.3505 (MCKI). Found: 464.3471.
4.2.20. (2R)-N,N,N-Trimethyl-3-phosphono-2-(tetrade-
canoyloxy)propan-1-aminium (15). To a stirred solution
of 14 (178 mg, 0.3 mmol) in CH2Cl2 (0.6 mL) was added
TMSBr (0.06 mL, 0.48 mmol) and the mixture was stirred
for 20 h at room temperature. Concentration of the mixture
gave a residue, which was dissolved in MeOH (0.06 mL).

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
63
4.2.24. (2R,3R)-Dibenzyl 3-amino-2-[(triethylsilyl)oxy]-
butylphosphonate (20). To a stirred solution of 19 (9.00 g,
18.4 mmol) in THF (180 mL) was added triphenylpho-
sphine (5.30 g, 20 mmol) and the mixture was stirred for 2 h
at room temperature. To the solution was added H2O
(50 mL) and the mixture was stirred for 12 h at room
temperature. The mixture was extracted with CHCl3 and
then the combined extracts were washed with brine and
dried over MgSO4. Removal of the solvent gave a residue,
which was chromatographed on silica gel (EtOAc to CHCl3/
MeOHZ10:1) to provide 20 (7.84 g, 97%). A colorless oil;
[a]2D4 K1.13 (c 1.0, MeOH); 1H NMR (400 MHz, CDCl3) d
7.37–7.28 (10H, m), 5.03 (2H, dd, JZ11.8, 9.1 Hz), 4.95
(2H, dd, JZ11.8, 8.2 Hz), 4.02–3.87 (1H, m), 3.15–3.11
(1H, m), 2.06–1.97 (2H, m), 1.00 (3H, d, JZ6.6 Hz), 0.91
(9H, t, JZ7.9 Hz), 0.58 (6H, q, JZ7.9 Hz); 13C NMR
(100 MHz, CDCl3) d 136.2 (d, JCPZ5.4 Hz), 128.5–127.7
a residue, which was chromatographed on silica gel
(hexane/EtOAcZ10:1–3:1) to give 22 (27 mg, 47%). A
colorless oil; [a]D25 C11.52 (c 0.1, MeOH); 1H NMR
(400 MHz, CDCl3) d 7.71 (2H, d, JZ8.2 Hz), 7.38–7.29
(10H, m), 7.24 (2H, d, JZ8.2 Hz), 5.92 (1H, d, JZ8.2 Hz),
5.08–4.91 (4H, m), 4.02 (1H, dt, JZ15.2, 7.4 Hz), 3.45 (1H,
dd, JZ23.3, 13.7 Hz), 3.03 (1H, dd, JZ22.5, 13.7 Hz), 2.36
(3H, s), 1.18 (3H, d, JZ7.1 Hz); 13C NMR (100 MHz,
CDCl3) d 200.8 (d, JCPZ6.0 Hz), 143.6, 137.4, 135.5,
129.8–127.0 (aromatic), 68.4 (d, JCPZ6.0 Hz), 68.3 (d,
JCPZ6.0 Hz), 58.2, 39.2 (d, JCPZ128.0 Hz), 21.5, 18.0; 31
P
NMR (162 MHz, CDCl3) d 20.48; IR (neat) 3277, 1724,
1243 cmK1; ESIMS m/z 502 (MHC); HRMS (ESI) calcd for
C25H29NO6PS: 502.1453 (MHC). Found: 502.1422.
4.2.27. (2R,3R)-Dibenyl 3-(dimethylamino)-2-[(triethyl-
silyl)oxy]butylphosphonate (24). Compound 24 (830 mg,
85%) was prepared from 20 (920 mg, 2.0 mmol) in an
analogous manner to that for preparation of 12 after
purification by column chromatography on silica gel
(hexane/EtOAcZ2:1–CHCl3/MeOHZ20:1). A colorless
oil; [a]2D5 C5.26 (c 0.9, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.35–7.28 (10H, m), 5.05–4.91 (4H, m), 4.08 (1H,
dq, JZ16.3, 5.5 Hz), 2.64 (1H, dt, JZ12.2, 6.7 Hz), 2.31–
2.21 (2H, m), 2.17 (6H, s), 0.93 (3H, d, JZ2.5 Hz), 0.92
(9H, t, JZ7.9 Hz), 0.59 (6H, q, JZ7.9 Hz); 13C NMR
(100 MHz, CDCl3) d 136.5 (d, JCPZ5.9 Hz), 128.5–127.8
(aromatic), 71.6, 67.2 (d, JCPZ6.6 Hz), 67.1 (d, JCP
Z
6.6 Hz), 51.3 (d, JCPZ7.6 Hz), 30.1 (d, JCPZ138.0 Hz),
17.0, 6.8, 4.9; 31P NMR (162 MHz, CDCl3) d 30.81; IR
(neat) 3457, 1608, 1240 cmK1; ESIMS m/z 464 (MHC);
HRMS (ESI) calcd for C24H39NO4SiP: 464.2386 (MHC).
Found: 464.2382.
4.2.25. (2R,3R)-Dibenzyl 3-{[(4-methylphenyl)sulfon-
yl]amino}-2-[(triethylsilyl)oxy]butylphosphonate (21).
To a stirred solution of 20 (370 mg, 0.8 mmol) in CH2Cl2
(1 mL) was added Et3N (0.14 mL, 0.97 mmol) and a
solution of tosyl chloride (0.18 g, 0.97 mmol) in CH2Cl2
(1 mL) at 0 8C and the mixture was stirred for 12 h at room
temperature. The mixture was poured into saturated aqueous
KHSO4 and extracted with Et2O. The combined extracts
were washed with brine and dried over MgSO4. Removal of
the solvent gave a residue, which was chromatographed on
silica gel (hexane/EtOAcZ10:1) to provide 21 (60 mg,
(aromatic), 69.7, 66.9 (d, JCPZ6.3 Hz), 63.3 (d, JCP
Z
6.2 Hz), 41.6, 32.6 (d, JCPZ137.2 Hz), 8.5, 6.9, 5.1; 31P
NMR (162 MHz, CDCl3) d 30.88; IR (neat) 2956, 1240,
1120 cmK1; ESIMS m/z 492 (MHC); HRMS (ESI) calcd for
C26H43NO4SiP: 492.2699 (MHC). Found: 492.2701.
4.2.28. (1R,2R)-1-{[Bis(benzyloxy)phosphoryl]methyl}-
2-(dimethylamino)propyl myristate (25). Compound 25
(487 mg, 23%) was prepared from 24 (1.76 g, 3.6 mmol) in
an analogous manner to that for preparation of 13 after
purification by column chromatography on silica gel
(CHCl3/MeOHZ1:0–30:1). A colorless oil; [a]2D5 K0.97
1
13%). A colorless oil; [a]2D5 C29.28 (c 1.0, MeOH); H
NMR (400 MHz, CDCl3) d 7.72 (2H, d, JZ8.3 Hz), 7.38–
7.31 (10H, m), 7.22 (2H, d, JZ8.2 Hz), 5.04 (1H, dd, JZ
9.4, 5.6 Hz), 5.01 (1H, dd, JZ9.4, 5.6 Hz), 4.95 (1H, dd,
JZ8.2, 3.5 Hz), 4.92 (1H, dd, JZ8.2, 3.5 Hz), 4.79 (1H, d,
JZ8.3 Hz), 4.08–4.06 (1H, m), 3.64–3.62 (1H, m), 2.37
(3H, s), 1.97–1.90 (2H, m), 0.92 (3H, d, JZ6.6 Hz), 0.87
(9H, t, JZ7.9 Hz), 0.50 (6H, q, JZ7.9 Hz); 13C NMR
(100 MHz, CDCl3) d 143.0, 138.3, 136.1 (d, JCPZ5.5 Hz),
129.6–127.0 (aromatic), 70.2 (d, JCPZ1.8 Hz), 67.5 (d,
JCPZ6.5 Hz), 67.4 (d, JCPZ6.5 Hz), 53.2 (d, JCPZ2.7 Hz),
32.1 (d, JCPZ135.3 Hz), 21.4, 14.6, 6.8, 4.7; 31P NMR
(162 MHz, CDCl3) d 28.40; IR (neat) 3159, 1323, 1261,
1146 cmK1; ESIMS m/z 618 (MHC); HRMS (ESI) calcd for
C31H45NO6SiPS: 618.2475 (MHC). Found: 618.2507.
1
(c 0.7, MeOH); H NMR (400 MHz, CDCl3) d 7.34–7.30
(10H, m), 5.31–5.23 (1H, m), 5.06–4.91 (4H, m), 4.12 (1H,
q, JZ7.0 Hz), 2.32 (2H, t, JZ3.8 Hz), 2.22–2.08 (8H, m),
1.32–1.25 (25H, m), 0.88 (3H, t, JZ6.8 Hz); 13C NMR
(100 MHz, CDCl3) d 178.8, 172.9, 136.2, 128.7, 128.6,
128.4, 128.1, 128.0, 68.1, 67.5 (d, JCPZ6.5 Hz), 67.4 (d,
JCPZ6.5 Hz), 61.6 (d, JCPZ10.7 Hz), 60.4, 40.5, 34.4, 34.3,
31.9, 29.6, 29.5, 29.3, 29.2, 28.3, 25.0, 24.6, 22.7, 21.0,
14.1, 8.5; 31P NMR (162 MHz, CDCl3) d 29.33; IR (neat)
1736, 1249, 1115 cmK1; ESIMS m/z 588 (MHC); HRMS
(ESI) calcd for C34H55NO5P: 588.3818 (MHC). Found:
588.3826.
4.2.26. (3R)-Dibenzyl 3-{[(4-methylphenyl)sulfonyl]-
amino}-2-oxobutylphosphonate (22). To a stirred solution
of 21 (60 mg, 0.1 mmol) in THF (0.5 mL) was added a 1 M
THF solution of TBAF (0.22 mL, 0.22 mmol) at 08C and the
mixture was stirred for 2 h at the same temperature. The
mixture was poured into H2O and extracted with Et2O. The
combined extracts were washed with brine and dried over
MgSO4. Removal of the solvent gave a residue, which was
dissolved in CH2Cl2 (1 mL). To the solution was added
PDC (41 mg, 0.11 mmol) and the mixture was stirred for
12 h at room temperature. After filtration of the mixture
through a pad of Celite, the filtrate was concentrated to give
4.2.29. (2R,3R)-4-[Bis(benzyloxy)phosphoryl]-N,N,N-tri-
methyl-3-(tetradecanoyloxy)butan-2-aminium iodide
(26). Compound 26 (70 mg, 33%) was prepared from 25
(170 mg, 0.29 mmol) in an analogous manner to that for
preparation of 14 after purification by column chromato-
graphy on silica gel (CHCl3/MeOHZ1:0–10:1). A colorless
oil; [a]2D5 K5.65 (c 1.0, MeOH); 1H NMR (400 MHz,
CDCl3) d 7.40–7.31 (10H, m), 5.68 (1H, dt, JZ7.5, 7.5 Hz),
5.08–4.91 (4H, m), 3.96 (1H, q, JZ6.8 Hz), 3.08 (9H, s),
2.26 (2H, td, JZ7.6, 2.1 Hz), 2.14 (2H, dd, JZ19.4,
6.8 Hz), 1.45 (3H, d, JZ6.8 Hz), 1.27–1.23 (22H, m), 0.88

64
T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
(3H, t, JZ6.8 Hz); 13C NMR (100 MHz, CDCl3) d 172.5,
135.7, 128.8, 128.7, 128.3, 128.2, 72.0 (d, JCPZ11.2 Hz),
68.1 (d, JCPZ6.5 Hz), 67.9 (d, JCPZ6.5 Hz), 64.5, 63.2,
51.6, 34.1, 31.9, 31.0, 30.9, 29.6, 29.4, 29.3, 29.2, 29.0,
24.4, 22.6, 15.2, 14.1, 8.5; 31P NMR (162 MHz, CDCl3) d
24.34; IR (neat) 1739, 1224 cmK1; ESIMS m/z 602 (MCKI);
HRMS (ESI) calcd for C35H57NO5P: 602.3974 (MCKI).
Found: 602.4066.
3.4 mmol) in an analogous manner to that for preparation
of 12 after purification by column chromatography on silica
gel (hexane/EtOAcZ2:1–CHCl3/MeOHZ20:1). A color-
less oil; [a]2D4 K10.46 (c 1.1, MeOH). The 1H NMR
spectrum was identical with that of 24.
4.2.36. (1S,2S)-1-{[Bis(benzyloxy)phosphoryl]methyl}-2-
(dimethylamino)propyl myristate (ent-25). Compound
ent-25 (1.50 g, 30%) was prepared from ent-24 (4.12 g,
8.38 mmol) in an analogous manner to that for preparation
of 13 after purification by column chromatography on silica
gel (CHCl3/MeOHZ1:0–30:1). A colorless oil; [a]D25
C0.30 (c 0.6, MeOH). The 1H NMR spectrum was identical
with that of 25.
4.2.30. (2R,3R)-N,N,N-Trimethyl-4-phosphono-3-(tetra-
decanoyloxy)butan-2-aminium (27). Compound 27
(38 mg, 48%) was prepared from 26 (139 mg, 0.19 mmol)
in an analogous manner to that for preparation of 15.
Amorphous; [a]D25 K4.03 (c 0.7, MeOH); 1H NMR
(400 MHz, CDCl3) d 5.81 (1H, dt, JZ7.4, 7.4 Hz), 4.01–
3.96 (1H, m), 3.67 (9H, s), 2.41 (2H, t, JZ7.5 Hz), 2.22–
2.14 (2H, m), 1.58 (3H, t, JZ6.7 Hz), 1.30–1.22 (22H, m),
0.88 (3H, t, JZ4.8 Hz); 13C NMR (100 MHz, CDCl3) d:
4.2.37. (2S,3S)-4-[Bis(benzyloxy)phosphoryl]-N,N,N-tri-
methyl-3-(tetradecanoyloxy)butan-2-aminium iodide
(ent-26). Compound ent-26 (500 mg, 30%) was prepared
from ent-25 (1.50 g, 2.55 mmol) in an analogous manner to
that for preparation of 14 after purification by column
chromatography on silica gel (CHCl3/MeOHZ1:0–10:1). A
173.8, 73.7 (d, JCPZ7.3 Hz), 53.6, 35.0, 32.9 (d, JCP
6.5 Hz), 31.5, 30.7, 30.5, 30.4, 30.1, 25.5, 23.6, 14.4, 8.9;
Z
31P NMR (162 MHz, CDCl3) d 19.88; IR (neat) 1000 cmK1
;
ESIMS m/z 422 (MHC); HRMS (ESI) calcd for
colorless oil; [a]2D5 C7.58 (c 1.0, MeOH). The H NMR
1
C21H45NO5P: 422.3035 (MHC). Found: 422.3040.
spectrum was identical with that of 26.
4.2.38. (2S,3S)-N,N,N-Trimethyl-4-phosphono-3-(tetra-
decanoyloxy)butan-2-aminium (ent-27). Compound ent-
27 (276 mg, 34%) was prepared from ent-26 (487 mg,
1.15 mmol) in an analogous manner to that for preparation
4.2.31. Dibenzyl [(4S,5R)-5-methyl-2,2-dioxido-1,3,2-
dioxathiolan-4-yl]methylphosphonate (ent-16). Com-
pound ent-16 (13.0 g, 76%) was prepared from ent-3e
(14.6 g, 41.6 mmol) in an analogous manner to that for
preparation of 8 after purification by column chromato-
graphy on silica gel (hexane/EtOAcZ10:1–1:1). A pale
1
of 15. Amorphous; [a]2D6 C3.34 (c 0.5, MeOH). The H
NMR spectrum was identical with that of 27.
yellow oil; [a]2D0 C18.90 (c 1.1, MeOH). The H NMR
1
spectrum was identical with that of 16.
Acknowledgements
4.2.32. (2S,3S)-Dibenzyl 3-azido-2-hydroxybutylphos-
phonate (ent-17). Compound ent-17 (330 mg, 44%) was
prepared from ent-16 (824 mg, 2.0 mmol) in an analogous
manner to that for preparation of 9 after purification by
column chromatography on silica gel (hexane/EtOAcZ
3:1–1:1). A colorless oil; [a]2D4 C14.48 (c 1.1, MeOH). The
1H NMR spectrum was identical with that of 17.
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports,
Science, and Technology, Japan.
References and notes
4.2.33. (2S,3S)-Dibenzyl 3-azido-2-[(triethylsilyl)oxy]bu-
tylphosphonate (ent-19). Compound ent-19 (6.27 g, 97%)
was prepared from ent-17 (4.96 g, 13.2 mmol) in an
analogous manner to that for preparation of 10 after
purification by column chromatography on silica gel
(hexane/EtOAcZ2:1). A colorless oil; [a]2D4 C3.06 (c 0.7,
1. Golay, A.; Swislocki, A. L. M.; Chen, Y. D.; Reaven, G. M.
Metabolism 1987, 36, 692.
2. McGarry, J. D.; Brown, N. F. Eur. J. Biochem. 1997, 244, 1.
3. For a review, see: Giannessi, F. Drugs of the Future 2003, 28,
371.
1
MeOH). The H NMR spectrum was identical with that of
19.
4. (a) Giannessi, F.; Chiodi, P.; Marzi, M.; Minetti, P.; Pessotto,
P.; De Angelis, F.; Tassoni, E.; Conti, R.; Giorgi, F.; Mabilia,
M.; Dell’Uomo, N.; Muck, S.; Tinti, M. O.; Carminati, P.;
Arduini, A. J. Med. Chem. 2001, 44, 2383. (b) Giannessi, F.;
Pessotto, P.; Tassoni, E.; Chiodi, P.; Conti, R.; De Angelis, F.;
Dell’Uomo, N.; Catini, R.; Deias, R.; Tinti, M. A.; Carminati,
P.; Arduini, A. J. Med. Chem. 2003, 46, 303.
4.2.34. (2S,3S)-Dibenzyl 3-amino-2-[(triethylsilyl)oxy]-
butylphosphonate (ent-20). Compound ent-20 (5.80 g,
94%) was prepared from ent-19 (6.46 g, 13.2 mmol) in an
analogous manner to that for preparation of 11 after
purification by column chromatography on silica gel
(EtOAc to CHCl3/MeOHZ10:1). A colorless oil; [a]D24
C2.38 (c 1.0, MeOH). The 1H NMR spectrum was identical
with that of 20.
5. (a) Hiratake, J.; Oda, J. Biosci. Biotech. Biochem. 1997, 61,
211. (b) Kafarski, P.; Lejczak, B. In Aminophosphonic and
Aminophosphinic Acids; Kukhar, V. P., Hudson, H. R., Eds.;
Wiley, 2000.
6. Preliminary communication of this work: Yamagishi, T.; Fujii,
K.; Shibuya, S.; Yokomatsu, T. Synlett 2004, 2505.
4.2.35. (2S,3S)-Dibenyl 3-(dimethylamino)-2-[(triethyl-
silyl)oxy]butylphosphonate (ent-24). Compound ent-24
(830 mg, 96%) was prepared from ent-20 (1.50 g,
´
7. (a) Ordon˜ez, M.; Gonzalez-Morales, A.; Ruiz, C.; De la Cruz-
´
´
Cordero, R.; Fernandez-Zertuche, M. Tetrahedron:

T. Yamagishi et al. / Tetrahedron 62 (2006) 54–65
65
Asymmetry 2003, 14, 1775. (b) Mikolajczyk, M.; Luczak, J.;
Kielbasinski, P. J. Org. Chem. 2002, 67, 7872. (c)
´
Wroblewski, A. E.; Halajewska-Wosik, A. Eur. J. Org.
Chem. 2002, 2758. (d) Tadeusiak, E.; Krawiecka, B.;
´
Michalski, J. Tetrahedron Lett. 1999, 40, 1791. (e) Ordon˜ez,
´
M.; De la Cruz, R.; Fernandez-Zertuche, M.; Mun˜oz-
´
Hernandez, M.-A. Tetrahedron: Asymmetry 2002, 13, 559.
(f) Thomas, A. A.; Sharpless, K. B. J. Org. Chem. 1999, 64,
8379.
11. We also examined a similar reaction of 2d with other chiral
ligand (DHQ)2AQN, however, the enantioselectivity was not
improved (10% ee). For AD reactions using (DHQ)2AQN, see:
Becker, H.; Sharpless, K. B. Angew. Chem., Int. Ed. 1996, 35,
448.
12. (a) Corey, E. J.; Guzman-Perez, A.; Noe, M. C. J. Am. Chem.
Soc. 1995, 117, 10805. (b) Corey, E. J.; Noe, M. C.; Guzman-
Perez, A. J. Am. Chem. Soc. 1995, 117, 10817.
13. Kobayashi and co-workers observed a related AD of a-olefins
having dibenzyl phosphonate showed higher enantioselectivity
than the corresponding diethyl phosphonate. Kobayashi, Y.;
William, A. D.; Tokoro, Y. J. Org. Chem. 2001, 66, 7903.
14. (a) Baer, E.; Basu, H. Can. J. Biochem. 1969, 47, 955. (b)
8. For a review, see: Kolb, H. C.; VanNieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
9. Yokomatsu, T.; Yamagishi, T.; Sada, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1998, 54, 781.
´
Wroblewski, A. E.; Halajewska-Wosik, A. Tetrahedron:
´
Asymmetry 2000, 11, 2053. (c) Wroblewski, A. E.;
Halajewska-Wosik, A. Eur. J. Org. Chem. 2002, 2758. (d)
´
Wroblewski, A. E.; Halajewska-Wosik, A. Tetrahedron:
Asymmetry 2004, 15, 2075.
10. In general, a conversion of olefin (1 mmol) required 1.4 g of
AD-mix-a, purchased from Aldrich, which contained
0.2 mol% of K2OSO4$2H2O and 1 mol% of chiral ligand
(DHQ)2PHAL. However, an additional K2OSO4$2H2O
(0.8 mol%) was critical for AD reactions of b,g-unsaturated
phosphonates since the reaction of 2b in the absence of the
osmium salt resulted in slow reaction rates (20 h at 25 8C) and
slight decrease in both chemical yield and enantioselectivity
(54% yield, 30% ee). For examples of AD reactions using
additional osmium salt, see: (a) Hermitage, S. A.; Murphy, A.;
Nielsen, P.; Roberts, S. M. Tetrahedron 1998, 54, 13185.
(b) Ref. 8.
15. For reviews, see: (a) Lohray, B. B. Synthesis 1992, 1035. (b)
Bittman, R.; Byun, H.-S.; He, L. Tetrahedron 2000, 56, 7051.
16. Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655.
17. Borch, R. F.; Hassid, A. I. J. Org. Chem. 1972, 37, 1673.
18. The molecular modeling of 16 was carried out by the MM2
calculation, followed by the semiempirical MO calculation
(MOPAC-PM3) using the CAChe system.