Studies on the Synthesis of Novel Four-Membered Cyclic Oxaphosphetanes via Intramolecular Mitsunobu Reaction of Bishydroxyalkylphosphinic Acids

Article abstract of DOI:10.1055/s-0035-1560426

Studies on the synthesis of novel four-membered cyclic oxaphosphetanes from bishydroxyphosphinic acids is reported. Investigations showed that the conversion proceeds through an intramolecular Mitsunobu cyclisation of bishydroxyphosphinic acids with a mix

Full text of DOI:10.1055/s-0035-1560426

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
B. Kaboudin et al.
Letter
Synlett
Studies on the Synthesis of Novel Four-Membered Cyclic Oxapho-
sphetanes via Intramolecular Mitsunobu Reaction of Bishydroxy-
alkylphosphinic Acids
Babak Kaboudin*a
Hamideh Haghighata
Tsutomu Yokomatsub
O
O
OH
PPh3/DIAD
R
P
R
P
H
R
H
R
toluene/CH2Cl2
r.t., 6–12 h
OH
O
OH OH
up to 83% isolated yield
13 examples
a Department of Chemistry, Institute for Advanced Studies in Basic Sciences
(IASBS), Zanjan 45137-66731, Iran
dl-pair and meso
R = substituted phenyl
kaboudin@iasbs.ac.ir
b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences,
1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received: 12.01.2016
Accepted after revision: 05.02.2016
Published online: 24.03.2016
O
P
O
O
90 °C, 1 h
Ar
Ar
Ar
P
Ar
H
P
H
Ar CHO
2
+
+
OH
OH
DOI: 10.1055/s-0035-1560426; Art ID: st-2015-d0024-l
OH
OH OH
OH OH
rac-2
meso-2
Abstract Studies on the synthesis of novel four-membered cyclic oxa-
phosphetanes from bishydroxyphosphinic acids is reported. Investiga-
tions showed that the conversion proceeds through an intramolecular
Mitsunobu cyclisation of bishydroxyphosphinic acids with a mixture of
triphenylphosphine and diisopropylazodicarboxylate (DIAD) in tolu-
ene–CH2Cl2 at room temperature. The treatment of two diastereomers
of bishydroxymethylphosphinic acids (dl pair and meso) with a mixture
of triphenylphosphine and DIAD gives only one stereoisomer of the cy-
clic oxaphosphetane.
O
OH
O
PPh3/DIAD
P
Ar
P
Ar
H
Ar
H
Ar
toluene/CH2Cl2
r.t., 6 h
OH
O
OH OH
cis-3
rac-2
Scheme 1
In this paper, we wish to describe the interesting reac-
tivity of the Mitsunobu reaction of the meso isomers of
bis(hydroxymethyl)phosphinic acids 2 and the application
of these findings to the concise synthesis of four-membered
oxaphosphetanes cis-3 from a diastereomeric mixture of
bishydroxymethylphosphinic acids rac-2 and meso-2.
A diastereomeric mixture of bis(α-hydroxyphenylmeth-
yl)phosphinic acid (2a) was obtained in 82% yield (as a
56:45 ratio of diastereomers) as described in our previous
paper and diastereomerically pure meso-2a was isolated
according to the previous method (Scheme 1).5
Key words bishydroxyphosphinic acids, oxetanes, oxaphosphetane,
cyclic phosphinic acids, Mitsunobu reaction
Phosphinic acids have been utilized as bioisosteric com-
ponents for biological carboxylic acid derivatives in medici-
nal chemistry.1 3-Aminopropyl(butyl)phosphinic acid (SGS-
742), a nonselective GABAc agonist, has been developed by
replacement of the carboxylic acid moiety of GABA with a
butyl phosphinic acid.2 A cyclic phosphinic acid moiety
(phosphinic heterocycle) is also applied as a conformational
restricted analogue of SGS-742 for selective GABAc receptor
antagonists.3
In our continued interests for developing useful meth-
ods for the synthesis of phosphinic acid derivatives4 and
their cyclic analogues, we recently reported a new method
for the synthesis of bis(α-hydroxyalkyl)phosphinic acids
rac-2 and meso-2 (Scheme 1).5 We also disclosed a synthe-
sis of a new class of a cyclic four-membered phosphinic
acid derivative cis-3 via the Mitsunobu reaction of the iso-
lated racemic form rac-2 of bis(α-hydroxyalkyl)phosphinic
acids.6
The diastereomerically pure meso-2a was submitted to
representative Mitsunobu conditions. Thus, meso-2a was
treated with triphenylphosphine and diisopropylazodicar-
boxylate (DIAD) in dry toluene at room temperature. How-
ever, no products were obtained after 24 hours under these
conditions. However, when the reaction was carried out in
a mixture of dry toluene and dichloromethane (5:1), the
desired cyclization product was produced in 81% yield after
six hours at room temperature (Scheme 2).
In the 31P NMR spectrum of the cyclization product, a
1
singlet peak appeared at δ = 26.81 ppm, the H NMR spec-
trum showed a doublet at δ = 5.70 ppm (JHP = 1.6 Hz) and
the 13C NMR spectrum exhibited a doublet at δ = 97.9
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
B. Kaboudin et al.
Letter
Synlett
could be available from a diastereomeric mixture of bishy-
droxymethylphosphinic acids without separation of the
mixtures.
O
OH
O
P
P
PPh3/DIAD
H
Ph
Ph
H
Ph
toluene/CH2Cl2
r.t., 6 h
Ph
OH
O
OH OH
Accordingly, a diastereomeric mixture of bis(α-hy-
droxyarylmethyl)phosphinic acids 2, prepared from a vari-
ety of aromatic and aliphatic aldehydes by the method re-
ported previously,5 was treated with triphenylphosphine
and DIAD in toluene–CH2Cl2 at room temperature. As
shown in Table 1, oxaphosphetane derivatives cis-3 having
different aromatic substituents, were obtained as expected
in a diastereomerically pure state in 41–83% isolated yields
(Table 1, entries 1–10). However, the reaction with 2k, de-
rived from an aliphatic aldehyde, failed to give 3k (Table 1,
entry 11). The reaction with bis(α-hydroxynaphthylmeth-
yl)phosphinic acids 2l and 2m also failed to form 3l and
3m, respectively (Table 1, entries 12, 13).
meso-2a
cis-3a
Scheme 2
(JCP = 72.3 Hz). The ESI-HRMS showed a signal at m/z =
283.0497. All these signals are consistent with those of cis-
3a derived from rac-2a. These results suggested that the
Mitsunobu reaction of meso-2a produces the same product
as that from rac-2a in a highly stereoselective manner.
The stereochemistry of cis-3a thus obtained was further
confirmed after conversion into the corresponding ammo-
nium salt 4 with enantiopure 1-phenylethylamine (Scheme
3). If the obtained compound were the meso form (cis-3a)
and not the racemic form (trans-3a), a single diasteromeric
salt would be theoretically formed through the reaction
(Figure 1).
Table 1 Reaction of Diastereomeric Mixture of Bishydroxyalkyl Phos-
phinic Acids 2 with a Mixture of Triphenylphosphine and DIAD
O
OH
O
P
P
PPh3/DIAD
R
R
H
R
H
R
O
OH
O
O
toluene/CH2Cl2
r.t., 6–12 h
OH
O
Ph
Me
NH2
Ph
Me
NH3
P
P
OH OH
H
Ph
H
H
Ph
H
Ph
Ph
O
cis-3
rac-2 and meso-2
O
cis-3a (meso form)
one form of salt 4 [R,S][R]
Entry
2 R
Time (h)
Yield of cis-3 31 P NMR of cis-3
(%)a
(δ, ppm)
Scheme 3
1
2
2a Ph
6
12
12
12
8
3a 83
3b 42
3c 50
3d 41
3e 54
3f 66
3g 58
3h 60
3i 82
3j 47
3k –b
3l –b
26.81
27.22
23.27
25.90
25.11
26.03
27.20
25.73
26.53
27.17
–
2b 2-MeC6H4
2c 2-BrC6H4
2d 2-FC6H4
2e 3-BrC6H4
2f 3-FC6H4
O
OH
O
OH
P
P
H
Ph
H
Ph
Ph
H
H
Ph
3
O
O
4
trans-3a
cis-3a
5
Figure 1
6
8
7
2g 4-MeC6H4
2h 4-ClC6H4
2i 4-BrC6H4
2j 4-FC6H4
10
10
10
10
12
12
12
8
Accordingly, cis-3a was treated with (R)-1-phenylethyl-
amine to afford the ammonium salt 4 in quantitative yield
(Scheme 3). In the 31P NMR spectrum, only a single peak ap-
peared at δ = 27.30 ppm. The 1H NMR spectrum had a dou-
blet at δ = 5.66 ppm (JHP = 1.2 Hz) which corresponds with
the methane protons in the product 4. The 13C NMR spec-
trum exhibited a doublet at δ = 97.7 (JCP = 65.0 Hz) corre-
sponding to CHP and two singlets at δ = 24.5 and 50.8 ppm,
which correspond to the methyl and methine carbons of 1-
phenylethylammonium in compound 4. These data demon-
strate that compound 4 is a single diastereomer. Therefore,
we had unambiguously confirmed the stereochemical out-
come of the Mitsunobu reaction of meso-2a to be cis-3a.
In the previous paper, we synthesized four-membered
oxaphosphetanes cis-3 having a variety of aromatic substit-
uents from diastereomerically pure racemic bishy-
droxymethylphosphinic acids (rac-2). However, the above
results suggested to us that the same compounds cis-3
9
10
11
12
13
2k n-C6H13
2l α-naphthyl
2m β-naphthyl
–
3m –b
–
a Yields refer to isolated pure products.
b The reaction failed to give any product.
Formation of cis-3 from both rac-2 and meso-2 can be
explained by a plausible mechanism involving an intramo-
lecular Mitsunobu reaction as shown in Scheme 4. Triphen-
ylphosphine and DIAD quickly form the betaine intermedi-
ate A that is able to deprotonate the phosphinic acid in rac-
2. The phosphinate anion attacks the alcoholic moiety to
give an alkoxide that can react with the phosphonium ion
B, produced from the betaine A, to give trans-4 and cis-4,
respectively. The other alcoholic group of trans-4 partici-
pates in an intramolecular cyclization to give cis-3 and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
B. Kaboudin et al.
Letter
Synlett
O
O
O
P
O
O
OH
P
R
P
R
R
P
R
R
R
R
P
R
B
A
R
H
R
H
OH
OH
O
OH
O
OH OH
O
OH
OH OH
O
OH
Ph3P
rac-2
cis-3
trans-4
O
O
O
O
P
O
R
P
R
R
P
R
A
R
P
R
B
R
R
R
P
R
OH
OH
O
OH OH
OH
OH
O
OH
O
OH OH
O
X
Ph3P
OH
meso-2
cis-4
PriO2C
N-CO2Pri
PriO2C
NH-CO2Pri
N
N
PPh3
PPh3
A
B
Scheme 4
triphenylphosphine oxide with inversion of the configura-
tion. In the case of cis-4 derived from meso-2, the phosphi-
nate moiety rather than the alcoholic moiety preferably cy-
clizes to give a cyclic three-membered intermediate for ste-
ric reasons and the intermediate participates further to
form cis-3.
phonic and Aminophosphinic Acids; John Wiley & Sons: Chiches-
ter, 2000. (d) Gittens, S. A.; Bansal, G.; Zernicke, R. F.; Uludag, H.
Adv. Drug Deliv. Rev. 2005, 57, 1011. (e) Kavanagh, K. L.; Guo, K.;
Dunford, J. E.; Wu, X.; Knapp, S.; Ebetino, F. H.; Rogers, M. J.;
Russel, R. G. G.; Opermann, U. Proc. Natl. Acad. Sci. U.S.A. 2006,
103, 7829. (f) Latajka, R.; Krężel Mucha, A.; Jewgiński, M.;
Kafarski, P. J. Mol. Struct. 2008, 877, 64. (g) Cates, L. A.; Li, V.-S.
Pharm. Res. 1985, 2, 135. (h) Luckman, S. P.; Coxon, F. P.;
Ebetino, F. H.; Russell, G. G.; Rogers, M. J. J. Bone Miner. Res.
1998, 13, 1668. (i) Katoh, M.; Hiratake, J.; Kato, H.; Oda, J. Bioorg.
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Jian-Qi, L.; Peyman, A.; Ruppert, D. Tetrahedron Lett. 1992, 33,
6625.
In summary, we have developed a simple and practical
approach for the synthesis of a new class of organophos-
phorus compounds. Investigations showed that the conver-
sion proceeds through an intramolecular Mitsunobu cycli-
sation of bishydroxyphosphinic acids with a mixture of
triphenylphosphine and diisopropylazodicarboxylate in tol-
uene–CH2Cl2 at room temperature. The treatment of two
diastereomers of bishydroxymethylphosphinic acid (dl pair
and meso) with a mixture of triphenylphosphine and diiso-
propylazodicarboxylate gives only one stereoisomer of the
cyclic oxaphosphetane. The structure of the novel four-
membered cyclic oxaphosphetanes was determined by
HRMS and NMR analysis that confirmed the structure of
the cyclic phosphinic acid. Some of the major advantages of
this protocol are the simplicity of the procedure and work-
up and good yields.7
(2) (a) Chebib, M.; Johnston, G. A. R. J. Med. Chem. 2000, 43, 1427.
(b) Bormann, J. Trends Pharmacol. Sci. 2000, 21, 16.
(3) Gavande, N.; Yamamoto, I.; Salam, N. K.; Ai, T.-H.; Burden, P. M.;
Johnston, G. A. R.; Hanrahan, J. R.; Chebib, M. ACS Med. Chem.
Lett. 2011, 2, 11.
(4) (a) Kaboudin, B.; Faghihi, M. R.; Kazemi, F.; Yokomatsu, T. Chi-
rality 2015, 27, 71. (b) Kaboudin, B.; Moradi, K.; Barati, A.;
Abdollahi, H. J. Iran. Chem. Soc. 2013, 10, 763. (c) Kaboudin, B.;
Moradi, K.; Faghihi, M. R.; Mohammadi, F. J. Lumin. 2013, 139,
104. (d) Kaboudin, B.; Haghighat, H.; Alaei, S.; Yokomatsu, T.
Synlett 2012, 23, 1965. (e) Kaboudin, B.; Alaie, S.; Yokomatsu, T.
Tetrahedron: Asymmetry 2011, 22, 1813. (f) Kaboudin, B.;
Saadati, F.; Golshan, A.; Abdollahi, H.; Yokomatsu, T. J. Chem.
Eng. Data 2011, 56, 3651. (g) Kaboudin, B.; Saadati, F.;
Yokomatsu, T. Synlett 2010, 1837. (h) Kaboudin, B.; Saadati, F.
Tetrahedron Lett. 2009, 50, 1450.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council.
(5) (a) Kaboudin, B.; Haghighat, H. Tetrahedron Lett. 2005, 46, 7955.
(b) Kaboudin, B.; Haghighat, H.; Yokomatsu, T. J. Org. Chem.
2006, 71, 6604. (c) Kaboudin, B.; Haghighat, H.; Yokomatsu, T.
Tetrahedron: Asymmetry 2008, 19, 862.
Supporting Information
(6) Kaboudin, B.; Haghighat, H.; Yokomatsu, T. Synthesis 2011,
3185.
(7) General Procedure for the Preparation of Cyclic Oxaphos-
phetanes 3
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560426.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
The bishydroxyalkylphosphinic acid 2 (2 mmol), obtained
according to the method of our previously published article,5
was added to a stirred mixture of triphenylphosphine (0.805 g,
3.07 mmol) and DIAD (0.6 mL, 3.07 mmol) in a mixture of dry
toluene–CH2Cl2 (5:1, 18 mL) at 0 °C under argon, and the solu-
tion was stirred for 30 min at 0 °C. Stirring was continued for 6
h at r.t. and then MeOH (0.2 mL) was added to the reaction mix-
References and Notes
(1) (a) Queff'elec, C.; Montchamp, J.-L. Org. Biomol. Chem. 2010, 8,
267. (b) Ye, Y.; Liu, M.; Kao, J. L.-F.; Marshall, G. R. Biopolymer
2008, 89, 72. (c) Kukhar, V. P.; Hudson, H. R. In Aminophos-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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B. Kaboudin et al.
Letter
Synlett
ture. After 30 min the solvent was removed in vacuo. The
residue was purified by chromatography (CHCl3–MeOH) to give
cyclic oxaphosphetane 3 in 41–83% yield. All products gave sat-
isfactory spectroscopic data in accord with the assigned struc-
tures.
(400 MHz, DMSO-d6): δ = 5.64 (d, 2 H, JHP = 1.6 Hz), 7.21 (t, 2 H,
J = 7.6 Hz), 7.32 (t, 4 H, J = 8.0 Hz), 7.41 (d, 4 H, J = 7.6 Hz) ppm.
13C NMR (100.6 MHz, DMSO-d6): δ = 97.9 (d, JPC = 72.3 Hz),
126.6, 126.9 (d, JPC = 4.4 Hz), 128.07, 140.5 (d, JPC = 12.5 Hz)
ppm. 31P NMR (162 MHz, DMSO-d6/H3PO4): δ = 26.81 ppm.
Analytical Data for 3-Hydroxy-2,4-diphenyl-1,3-oxaphosphe-
tane 3-Oxide (cis-3a)
HRMS: m/z calcd for C
14H13O3P [MNa+]: 283.0500; found
283.0497.
White solid (83%, 0.43 g); mp ca. 320 °C (decomp.). 1H NMR
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D