Synthesis of chiral γ-amino-β-hydroxyphosphonate derivatives from unsaturated phosphonates

Article abstract of DOI:10.1055/s-2004-834792

γ-Amino-β-hydroxyphosphonates, useful intermediates for the synthesis of phosphonic acid analogues of carnitine, were prepared as their protected derivatives in an enantioselective manner from β,γ- unsaturated phosphonates through asymmetric dihydroxylati

Full text of DOI:10.1055/s-2004-834792

LETTER
2505
Synthesis of Chiral g-Amino-b-hydroxyphosphonate Derivatives from
Unsaturated Phosphonates
S
ynthesis of Ch
a
iral
g
-Amin
k
o-
b
-hydroxy
e
phosphona
h
te
D
erivative
i
s
ro Yamagishi, Keiichi Fujii, Shiroshi Shibuya, Tsutomu Yokomatsu*
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Fax +81(426)763239; E-mail: yokomatu@ps.toyaku.ac.jp
Received 31 July 2004
synthesis of g-amino-b-hydroxyphosphonates, the chemi-
cal yields are reported to be low.5f We investigated a new
synthesis of g-amino-b-hydroxyphosphonate derivatives
by our own approach, which involved osmium-catalyzed
Abstract: g-Amino-b-hydroxyphosphonates, useful intermediates
for the synthesis of phosphonic acid analogues of carnitine, were
prepared as their protected derivatives in an enantioselective man-
ner from b,g-unsaturated phosphonates through asymmetric
dihydroxylation and subsequent regioselective amination via the asymmetric dihydroxylation (AD)6 of b,g-unsaturated
cyclic sulfates.
phosphonates, followed by selective amination of the hy-
droxy group at the g-position (Scheme 1). In this paper,
we describe the preliminary results of this approach.
Key words: phosphorus, asymmetric synthesis, dihydoxylations,
sulfates, regioselectivity
+
+
NMe3
NMe3
Hyperglycemia of type II diabetes is considered to be pri-
marily 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 mem-
brane.2 CPT I inhibitors indirectly reduce gluconeogene-
sis by inhibiting the b-oxidation and are hence helpful in
the treatment of type II diabetes as hypoglycemic agents.3
Recent studies demonstrated that modification of the
functional groups of carnitine was one way to access po-
tent CPT I inhibitors. It was found that aminocarnitine de-
rivatives (where the hydroxy group of carnitine was
replaced with an amino group) were good inhibitors.4
However, to the best of our knowledge, little investigation
has been carried out on modifying the carboxylic moiety
of carnitine.4 The fact that phosphonic acids have been
utilized as one of the bioisosteric groups of carboxylic ac-
ids prompted us to investigate a synthesis of a phosphonic
acid analogue of carnitine (Figure 1). 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,5a enzymatic resolution of g-chloro-b-hydroxy-
phosphonates,5b hydrolytic kinetic resolution of epoxy-
phosphonates with an asymmetric catalyst,5c ring-opening
of epichlorohydrin with silylphosphites,5d and
diastereoselective reduction of g-amino-b-ketophos-
phonates.5e Although catalytic asymmetric aminohydro-
xylation of b,g-unsaturated phosphonates is known for the
O–
O–
R
P
OH
OH
O
OH
O
(R)-(–)-Carnitine
Phosphonic acid analogues
of (R)-(–)-Carnitine
Figure 1
OH
NH2
O
P(OX)2
O
O
R
R
P(OX)2
R
P(OX)2
HO
OTES
Scheme 1
We have previously reported AD reaction of a,b-unsatur-
ated phosphonates with AD-mix reagents, which could
provide a variety of chiral a,b-dihydroxyphosphonates.7,8
Although b,g-dihydroxyphosphonate having a phenyl
group at the g-position could be also prepared in high
enantiomeric excess (98% ee) through AD reaction of b,g-
unsaturated phosphonate,9 similar reactions using other
substrates have not been investigated. For both expanding
the scope of this protocol and obtaining various carnitine
analogues, AD reactions of b,g-unsaturated phosphonates
were examined. The requisite starting materials 2a–d
were readily prepared by Arbuzov reactions of the corre-
sponding allyl bromides 1a–d with triethylphosphite
(Scheme 2).
O
P(OEt)3
R1
Br
R1
P(OEt)2
R2
R2
(78–92%)
1a–d
2a–d
a: R1 = R2 = H; b: R1 = Me, R2 = H; c: R1 = 4-MeOC6H4CO2CH2, R2 = H
d: R1 = H, R2 = Ph
SYNLETT 2004, No. 14, pp 2505–2508
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834792; Art ID: U21704ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

2506
T. Yamagishi et al.
LETTER
Reactions of 2a–d 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
temperature according to our previous protocol.7,10 The
results are summarized in Table 1.
O
R
O
O
MeO
P(OEt)2
O
O
OMe
Table 1 AD of b,g-Unsaturated Phosphonates 2a–d with AD-mix-a
AD-mix-α
K2OsO4·2H2O
MeSO2NH2
4b: R = Me; 4c: R = 4-MeOC6H4CO2CH2; 5: R = Ph
OH
O
O
Figure 2
R1
P(OEt)2
R1
P(OEt)2
t-BuOH-H2O 1:1
2 h, 0 °C then 6 h, 25 °C
R2
2a–d
HO R2
3a–d
In general, AD reaction of hydrophobic compounds is
prone to afford good enantioselectivity due to those being
easily trapped into the lipophilic cavity of the ligand–os-
mium complex.6 We envisioned that enhancing the hydro-
phobicity of 2a,b by tuning the phosphonate moiety
would lead to improvement of the enantioselectivity. In
this context, b,g-unsaturated dibenzyl phosphonates were
next chosen as substrates for the AD reaction.13 The re-
quired starting materials 6a,b were prepared from 2a,b
through sequential deesterification, chlorination of the
acid moiety, followed by treatment with benzyl alcohol
and pyridine (Scheme 3).
Entry
3
a
b
c
R1
H
R2
H
Yield (%) ee (%)a
1
2
3
4
40
60
58
29
10
Me
H
35
4-MeOC6H4CO2CH2
H
97b
81b
d
H
Ph
a Determined by 31P NMR (121 MHz, CDCl3) analysis of the corre-
sponding bis-MTPA esters.
b Determined by HPLC analysis on a chiral phase (DAICEL
CHIRALPAK AS column).
1) TMSBr then MeOH
2) (COCl)2, DMF
O
O
AD reactions of 2a–c proceeded to give diols 3a–c in 40–
60% yield (entries 1–3), albeit with decrease in the chem-
ical yield of 3d possessing a phenyl group at the b-posi-
tion (entry 4). Low enantioselectivity was observed in
reactions of 2a and 2b having a proton and a methyl group
in the R1 moiety, respectively (entries 1 and 2). AD reac-
tion of 2c having a 4-methoxybenzoyloxy group at the d-
position proceeded with excellent enantioselectivity (97%
ee) to give 3c (entry 3).11 It is worthy of note that b,g-di-
hydroxyphosphonate 3d with a quarternary chiral center
could be obtained in good enantiomeric excess (81% ee)
by AD of 2d (entry 4). Considering Corey’s working
model of the chemical architecture provided by the ligand
of AD-mix-a, in which the ligand–osmium complex pre-
ferred the U-shaped conformation, the high enantiomeric
excess of 3c may be accounted for by the 4-methoxy-
benzoyl group participating in p-stacking interactions
with the methoxyquinoline ring of the catalyst.12
R
P(OEt)2
R
P(OBn)2
3) BnOH, pyridine
2a,b
6a,b
a: R = H (35%)
b: R = Me (57%)
Scheme 3
A reaction of 6a with AD-mix-a furnished diol 7a in 71%
yield, however, the enantioselectivity was not improved
(Scheme 4). On the other hand, employing 6b improved
the selectivity giving 7b in 48% ee in comparison to 3b
(35% ee). The product 7b was isolated as a crystal, there-
fore, optically pure 7b could be obtained through one
recrystallization from EtOAc (38% recovery).14
AD-mix-α
K2OsO4·2H2O
MeSO2NH2
OH
O
P(OBn)2
O
R
R
P(OBn)2
The absolute configuration of 3b and 3c was determined
after conversion to 4-methoxybenzoate derivatives 4b and
4c (Figure 2). The CD spectrum of 4b showed a positive
Cotton effect at 289 nm and a negative Cotton effect at
282 nm, which were analogous to that of methoxyben-
zoate 5 prepared from known b,g-dihydroxyphospho-
nates,9 showing positive and negative Cotton effects at
longer (286 nm) and shorter wavelengths (275 nm), re-
spectively. The CD curve of 4c was also similar to that of
5. Accordingly, 4b and 4c have the same absolute stere-
ochemistry with 5, indicating the stereochemistry of 3b
and 3c to be 2S,3S-configuration. The stereochemistry of
3d was estimated as depicted on the basis of the empirical
rule for AD with AD-mix-a.6
t-BuOH-H2O 1:1
2 h, 0 °C then 5 h, 25 °C
6a,b
OH
7a,b
7
yield (%)
71
ee (%)
10
48 (100)a
R
H
a
b
69
Me
a After one recrystallization from EtOAc
Scheme 4
The absolute configuration of 7b was verified after con-
version to the corresponding phosphonic acid 8 through
hydrogenolysis of the dibenzyl phosphonate moiety
(Scheme 5). The sign of the optical rotation of 8 was iden-
tical with that of a sample derived from 3b.
Synlett 2004, No. 14, 2505–2508 © Thieme Stuttgart · New York

LETTER
Synthesis of Chiral g-Amino-b-hydroxyphosphonate Derivatives
2507
OH
OH
Acknowledgment
O
O
H2, Pd-C
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
Me
OH
P(OBn)2
Me
P(OH)2
OH
7b
8
1) TMSBr
2) MeOH
3b
8
References
(1) Golay, A.; Swislocki, A. L. M.; Chen, Y. D.; Reaven, G. M.
Metabolism 1987, 36, 692.
Scheme 5
(2) McGarry, J. D.; Brown, N. F. Eur. J. Biochem. 1997, 244, 1.
(3) For a review, see: Giannessi, F. Drugs Future 2003, 28, 371.
(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.
Having achieved the preparation of chiral b,g-dihydroxy-
phosphonates, we next focused on their transformation
into g-amino-b-hydroxyphosphonate derivatives via cy-
clic sulfates (Scheme 6).15 Treatment of 7b with SOCl2,
16
followed by oxidation with RuCl3–NaIO4 afforded cy-
clic sulfate 9 in 89% yield. Ring-opening of 9 with NaN3
in acetone–H2O and subsequent treatment with 20%
H2SO4 gave a mixture of g-azide 10 and b-azide 11 in a ra-
tio of 5:1 (42% yield). Although the exact reason for the
g-selectivity has remained unclear, it might be associated
with the steric congestion at the b-position by the bulky
dibenzyl phosphonate moiety. After the mixture of 10 and
11 was converted into the TES ether, Staudinger reaction
with PPh3 and subsequent hydrolysis were performed. At
this stage, g-amino-b-siloxyphosphonate 12 in pure form
was provided in 61% yield after column chromatography
on silica gel.17,18 Compound 12 would be a useful inter-
mediate for transforming phosphonic acid analogues of
carnitine.
(5) (a) Ordóñez, M.; González-Morales, A.; Ruiz, C.; De la
Cruz-Cordero, R.; Fernández-Zertuche, M. Tetrahedron:
Asymmetry 2003, 14, 1775. (b) Mikolajczyk, M.; Luczak, J.;
Kielbasinski, P. J. Org. Chem. 2002, 67, 7872.
(c) Wróblewski, A. E.; Halajewska-Wosik, A. Eur. J. Org.
Chem. 2002, 2758. (d) Tadeusiak, E.; Krawiecka, B.;
Michalski, J. Tetrahedron Lett. 1999, 40, 1791.
(e) Ordóñez, M.; De la Cruz, R.; Fernández-Zertuche, M.;
Muñoz-Hernández, M.-A. Tetrahedron: Asymmetry 2002,
13, 559. (f) Thomas, A. A.; Sharpless, K. B. J. Org. Chem.
1999, 64, 8379.
(6) For a review, see: Kolb, H. C.; van Nieuwenhze, M. S.;
Sharpless, K. B. Chem. Rev. 1994, 94, 2483.
(7) (a) Yokomatsu, T.; Yoshida, Y.; Suemune, K.; Yamagishi,
T.; Shibuya, S. Tetrahedron: Asymmetry 1995, 6, 365.
(b) Yokomatsu, T.; Yamagishi, T.; Suemune, K.; Yoshida,
Y.; Shibuya, S. Tetrahedron 1998, 54, 767.
(8) Lohray and co-workers reported similar AD reactions
independently. See: Lohray, B. B.; Maji, D. K.; Nandanan,
E. Indian J. Chem., Sect. B 1995, 34, 1023.
O
O
O
O
OH
S
1) SOCl2, pyridine
O
Me
P(OBn)2
2) RuCl3, NaIO4
(89%, 2 steps)
OH
Me
P(O)(OBn)2
7b
9
(9) Yokomatsu, T.; Yamagishi, T.; Sada, T.; Suemune, K.;
Shibuya, S. Tetrahedron 1998, 54, 781.
OH
N3
(10) The 1.4 g of AD-mix-a, purchased from Aldrich, was used
for conversion of 1.0 mmol of the olefin, which contained
0.2 mol% of K2OsO4·2H2O and 1.0 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 AD reaction of 2b in the absence of
the osmium salt resulted in slow reaction rates (20 h at
25 °C) and slight decrease in enantioselectivity (54% yield,
30% ee).
O
1) NaN3
O
+
Me
P(OBn)2
Me
P(OBn)2
2) H2SO4
N3
OH
(42%, 2 steps)
10
11
10:11=5:1
1) TESCl,
imidazole
H2N
Me
O
(11) Compound 3c: oil; [a]D26 –2.14 (c 1.03, MeOH). 1H NMR
(400 MHz, CDCl3): d = 7.97 (2 H, d, J = 8.8 Hz), 6.87 (2 H,
d, J = 8.8 Hz), 4.38 (2 H, d, J = 5.8 Hz), 4.09 (4 H, q, J = 6.9
Hz), 4.05–4.00 (1 H, m), 3.87–3.85 (1 H, m), 3.82 (3 H, s),
2.22–1.96 (2 H, m), 1.29 (6 H, t, J = 7.0 Hz). 13C NMR (100
MHz, CDCl3): d = 166.4, 163.5, 131.7, 122.2, 113.6, 72.4 (d,
P(OBn)2
2) PPh3
3) H2O
OTES
(61%, 3 steps)
12
Scheme 6
J
PC = 14.9 Hz), 66.8 (d, JPC = 4.5 Hz), 65.5, 62.1 (d,
PC = 3.2 Hz), 55.4, 30.1 (d, JPC = 140.0 Hz), 16.3 (d,
J
In conclusion, we have developed a new method for pre-
paring a protected form of chiral g-amino-b-hydroxy-
phosphonates through AD reactions of b,g-unsaturated
phosphonates. A study on transforming optically active g-
amino-b-siloxyphosphonates into phosphonic acid ana-
logues of carnitine is under progress and will be the
subject of future reports.
JPC = 5.9 Hz). 31P NMR (162 MHz, CDCl3): d = 29.36. IR
(neat): 3356, 1713, 1258, 1168 cm–1. ESI-MS: m/z = 399
[MNa+]. HRMS: m/z calcd for C16H25O8NaP [MNa+]:
399.1185. Found: 399.1185.
(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.
Synlett 2004, No. 14, 2505–2508 © Thieme Stuttgart · New York

2508
T. Yamagishi et al.
LETTER
(13) Kobayashi and co-workers observed that a related AD of a-
olefins with dibenzyl phosphonate showed higher
t, J = 7.9 Hz), 0.58 (6 H, q, J = 7.9 Hz). 13C NMR (100 MHz,
CDCl3): d = 136.2 (d, JPC = 5.4 Hz), 128.5–127.7 (aromatic),
71.6, 67.2 (d, JPC = 6.6 Hz), 67.1 (d, JPC = 6.5 Hz), 51.3 (d,
enantioselectivity than the corresponding diethyl
phosphonate. See: Kobayashi, Y.; William, A. D.; Tokoro,
Y. J. Org. Chem. 2001, 66, 7903.
JPC = 7.6 Hz), 30.1 (d, JPC = 138.0 Hz), 17.0, 6.8, 4.9. 31
P
NMR (162 MHz, CDCl3): d = 30.81. ESI-MS: m/z = 464
[MH+]. HRMS: m/z calcd for C24H39NO4SiP [MH+]:
464.2386. Found: 464.2382.
(14) Compound 7b (for a sample of 100% ee): mp 93–95 °C;
[a]D22 –7.92 (c 1.01, CHCl3). 1H NMR (400 MHz, CDCl3):
d = 7.39–7.32 (10 H, m), 5.12–4.96 (4 H, m), 3.70 (1 H, qd,
J = 4.2, 14.9 Hz), 3.59 (1 H, td, J = 5.6, 11.3 Hz), 2.04–1.96
(2 H, m), 1.13 (3 H, d, J = 6.3 Hz). 13C NMR (100 MHz,
CDCl3): d = 136.0 (d, JPC = 5.5 Hz), 135.9 (d, JPC = 5.0 Hz),
128.7, 128.6, 128.6, 128.1, 128.0, 70.7 (d, JPC = 17.4 Hz),
70.4 (d, JPC = 5.6 Hz), 67.6 (d, JPC = 6.4 Hz), 30.5 (d,
(18) The chemical structure of 12 was determined after the
conversion into g-amino-b-ketophosphonate 13 through
tosylation, desilylation, and oxidation with PDC. In 1H the
NMR spectrum (400 MHz, CDCl3) of 13, a signal ascribed
to the Me group at the g-position was observed at d = 1.18
ppm as a doublet (J = 7.1 Hz) but not as a singlet
corresponding to regioisomeric b-amino-g-ketophosphonate
(Scheme 7).
J
PC = 139.6 Hz), 18.9. 31P NMR (162 MHz, CDCl3): d =
31.91. IR (KBr): 3359, 2968, 1214 cm–1. ESI-MS: m/z = 351
[MH+]. HRMS: m/z calcd for C18H24O5P [MH+]: 351.1361.
Found: 351.1352.
Ts–HN
O
1) TsCl, Et3N
(15) (a) Lohray, B. B. Synthesis 1992, 1035. (b) Bittman, R.;
Byun, H.-S.; He, L. Tetrahedron 2000, 56, 7051.
12
Me
P(OBn)2
2) TBAF
3) PCC
(16) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 110, 7538.
(17) Compound 12: oil. 1H NMR (400 MHz, CDCl3): d = 7.37–
7.28 (10 H, m), 5.03 (2 H, dd, J = 9.1, 11.8 Hz), 4.95 (2 H,
dd, J = 8.2, 11.8 Hz), 4.02–3.87 (1 H, m), 3.15–3.11 (1 H,
m), 2.06–1.97 (2 H, m), 1.00 (3 H, d, J = 6.6 Hz), 0.91 (9 H,
O
13
Scheme 7
Synlett 2004, No. 14, 2505–2508 © Thieme Stuttgart · New York