Design and synthesis of helically chiral spirocyclic P3 phosphazenes and characterization of their onium salts

Article abstract of DOI:10.1055/s-0033-1340058

Helically chiral spirocyclic P3 phosphazenes were designed as a novel family of chiral organosuperbases. The newly designed chiral P3 phosphazenes were synthesized from commercially available sources in several steps and characterized by X-ray crystallographic analysis of their onium salts. The optically pure P3 phosphazenium salt was obtained by using preparative chiral stationary phase HPLC and the absolute configuration of the helical chirality was determined. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340058

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Design and Synthesis of Helically Chiral Spirocyclic P3 Phosphazenes and
Characterization of Their Onium Salts
Helically Chiral Spirocyclic P3 Phosphazenes
Masahiro Terada,*a,b Kengo Goto,a Masafumi Oishi,a Tadahiro Takeda,c Eunsang Kwon,b Azusa Kondoha
a
Department of Chemistry, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Fax +81(22)7956584; E-mail: mterada@m.tohoku.ac.jp
b
Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
c
Process Technology Research Laboratories, Daiichi Sankyo Co., Ltd., Edogawa-ku, Tokyo 134-8630, Japan
Received: 03.10.2013; Accepted: 04.10.2013
the central iminophosphorane core. The fundamental
Abstract: Helically chiral spirocyclic P3 phosphazenes were de-
structure of such a chiral P3 phosphazene 1 is depicted in
signed as a novel family of chiral organosuperbases. The newly de-
Figure 1 as the free base 1 and its conjugate acid form
signed chiral P3 phosphazenes were synthesized from
commercially available sources in several steps and characterized
[1·H]+. Herein, we report the synthesis of novel chiral P3
by X-ray crystallographic analysis of their onium salts. The optical- phosphazene organosuperbases 1 from commercially
ly pure P3 phosphazenium salt was obtained by using preparative
chiral stationary phase HPLC and the absolute configuration of the
helical chirality was determined.
available sources in several steps and isolation as well as
X-ray crystallographic analysis of their 1·HX salts. In ad-
dition, the preparation of optically pure phosphazenium
salts by using chiral stationary phase HPLC and the deter-
Key words: chirality, enantiomeric resolution, helical structure,
phosphazene, spirocycle
mination of the absolute configuration are also presented.
NR2
P
NR2
P
R1
R1
2
2
H
N
H
N
N
N
N
For more than three decades, the design and synthesis of
uncharged strong organobases has attracted much
attention1 because their unique characteristics allow de-
protonation of a wide range of weak acids and results in
the generation of weakly coordinated ‘naked-like’, and
hence highly reactive, anionic species. Schwesinger’s
phosphazenes2 and Verkade’s phosphatranes3 are repre-
sentative of phosphorus-based strong organobases. In ef-
forts to enhance the basicity of uncharged organobases,
inclusion of increasing numbers of iminophosphorane
units has afforded a series of phosphazene organosuper-
bases such as P2, P3, and P4 phosphazenes.4
N
P
N
P
NR2
NR2
2
2
R22N
R22N
P
P
N
N
N
N
N
H
R1
R1
R22N
R22N
[1⋅H]+
1
Figure 1 Fundamental structure of helically chiral spirocyclic P3
phosphazene 1 and its protonated form [1·H]+
The prominent structural feature of the newly designed P3
phosphazenes 1 is their helical chirality around the five-
membered spirocyclic system. In addition, we arranged
hydrogen bond donor and acceptor sites around the central
phosphorus atom, because the side-by-side arrangement
of the donor and acceptor sites has proven to be funda-
mental to achieving highly efficient enantioselective chi-
ral organobase catalysts such as chiral guanidines and P1
phosphazenes.5 As shown in the free base 1 (Figure 1), the
nitrogen atom of the central iminophosphorane moiety
(N=P) functions as the hydrogen bond acceptor, whereas
the N–H moiety adjacent to the central phosphorus atom
functions as the hydrogen bond donor. In line with this
molecular design, we synthesized two types of helically
chiral P3 phosphazenium salts, 1a·HI and 1b·HCl, as
shown in Figure 2.
Another significant issue in the arena of strong organobas-
es is the development of chiral variants that can be utilized
for catalytic enantioselective transformations. In this re-
gard, chiral guanidines and P1 phosphazenes have
emerged as efficient enantioselective catalysts, and signif-
icant progress has been made in the development of a
wide range of enantioselective transformations using
these chiral strong organobases.5–7 However further en-
hancement of the basicity of a chiral uncharged organo-
base, leading to a chiral organosuperbase, has remained
largely unexploited so far.8,9 The design and synthesis of
chiral organosuperbases is still a challenging topic in syn-
thetic organic chemistry because of the unique features of
uncharged organobases. We, therefore, envisaged the de-
sign and synthesis of a novel chiral organosuperbase. In
our approach to a chiral organosuperbase, we adopted a
P3 phosphazene framework, not only to gain high basicity
but also to construct a C2-symmetrical structure around
Chiral P3 phosphazenium salt 1a·HI possesses phenyl
groups on the nitrogen atoms of the hydrazine moieties
and ethylenediamine units on the terminal phosphorus at-
oms, giving four continuous spirocycles. The synthesis of
1a·HI began with treatment of N-Boc-phenylhydrazine
(2) with 2-chloro-1,3-dimethyl-1,3,2-diazaphosphorane
(3) followed by Staudinger reaction with Cbz azide to pro-
vide P1 phosphazenium 4 in 95% yield over two steps
(Scheme 1). After removal of the Cbz group under reduc-
tive conditions, the spirocyclic structure was constructed
SYNLETT 2013, 24, 2531–2534
Advanced online publication: 28.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340058; Art ID: ST-2013-D0931-C
© Georg Thieme Verlag Stuttgart · New York

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M. Terada et al.
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Me
N
N
P
N
H
H
N
Ph
Ph
N
N
N
N
Me
N
P
N
P
N
N
P
N
N
N
P
P
N
Me
N
N
H
N
N
H
Ph
Ph
Me
I
Cl
1b⋅HCl
1a⋅HI
Figure 2 Molecular structure of helically chiral spirocyclic P3 phos-
phazenium salts 1a·HI and 1b·HCl
by treating 5 with pentachlorophosphorane in the pres-
ence of the Hünig’s base. Finally, the synthesis of racemic
1a·HI was accomplished by removing the Boc group with
sodium iodide and chlorotrimethylsilane. After exchang-
ing the counter anion from iodide to tetrafluoroborate,
each enantiomer of (±)-1a·HBF4 was resolved by using
analytical HPLC equipped with a chiral stationary phase
column.10
Figure 3 ORTEP drawing of 1a·HI with probability ellipsoids
drawn at the 50% level. Although the absolute structure is depicted as
the (M)-form, the X-ray grade crystal was obtained from a racemic
mixture of 1a·HI.
to afford the diaminochlorophosphine intermediate. Sub-
sequently, addition of N-Boc-phenylhydrazine (2) fol-
lowed by Staudinger reaction with Cbz azide furnished P1
phosphazenium salt 7 in 35% yield over three steps. After
removal of the Cbz and Boc groups by sequential reduc-
tion and acid hydrolysis, respectively, the synthesis of ra-
cemic P3 phosphazenium salt 1b·HCl was accomplished
by the reaction of 9 with pentachlorophosphorane in the
presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
It is noteworthy that during the synthesis of 1b·HCl from
7, no silica gel column purification was required. In each
step, washing the crude mixture with an appropriate sol-
vent, such as hexane (for 8), acetonitrile (for 9), or acetone
(for 1b·HCl), provided effectively pure compounds.
Me
Cl
Me
N
H
i
N
N
Boc
N
P
NHCbz
NHBoc
Ph
N
+
P
N
Me
H
N
Cl
Me
2
Ph
3
4
95% from 2 (2 steps)
Me
Boc
N
Me
Cl
Ph
N
N
N
Me
N
P
N
P
N
ii
iii
N
P
NH2
N
P
N
Me
Me
N
N
N
Ph
Ph
NHBoc
Boc
Me
Cl
5
89%
H
Cl
Me
N
N
P
N
( )-6
48%
N
N
P
N
i
H
Ph
N
NHCbz
PCl3
+
N
Me
iv
N
P
N
N
P
N
Ph
NHBoc
Me
N
N
Ph
H
7
Me
I
35% from PCl3 (3 steps)
( )-1a⋅HI
2Br
NH2
NH3
Cl
N
P
N
N
20%
ii
iii
N
NH2
N
P
N
Scheme 1 Synthesis of (±)-1a·HI. Reagents and conditions: (i) (1) 3
(1.3 equiv), DIPEA (5.0 equiv), toluene, 0 °C to r.t., 2 h; (2) CbzN3
(1.3 equiv), r.t., 12 h; (ii) PdCl2 (15 mol%), Et3SiH (4.0 equiv), Et3N
(70 mol%), CH2Cl2, reflux, 2 h; (iii) PCl5 (0.48 equiv), DIPEA (4.8
equiv), CH2Cl2, 0 °C to r.t. (containing small amount of impurities);
(iv) NaI (6.0 equiv), TMSCl (6.0 equiv), MeCN, 50 °C, 48 h.
Ph
NHBoc
Ph
8
95%
9
90%
N
P
N
H
N
Ph
N
iv
N
P
N
N
P
N
As illustrated in Figure 3, the structure of 1a·HI was ver-
ified by single-crystal X-ray diffraction analysis of the ra-
cemic P3 phosphazenium salt.11 Importantly, the iodide
anion is located in close proximity to the two N-H pro-
tons, which strongly suggests the formation of hydrogen
bonds between the iodide anion and the two N-H protons.
N
N
H
Ph
Cl
( )-1b⋅HCl
45%
Scheme 2 Synthesis of (±)-1b·HCl. Reagents and conditions:
(i) (1) Et3N (2.1 equiv), pyrrolidine (2.0 equiv), toluene, 0 °C, 2 h;
(2) N-Boc-phenylhydrazine (2; 1.0 equiv), Et3N (4.0 equiv), 0 °C to
r.t., 2 h; (3) CbzN3 (1.2 equiv), r.t., 12 h; (ii) PdCl2 (15 mol%), Et3SiH
(4.0 equiv), Et3N (70 mol%), CH2Cl2, reflux, 5 h; (iii) 47% HBr (5.0
equiv), MeOH, 50 °C, 7 h; (iv) PCl5 (0.55 equiv), DBU (4.5 equiv),
CH2Cl2, –60 °C, 18 h.
We then synthesized spirocyclic 1b·HCl, having pyrro-
lidine moieties at the terminal phosphorus atoms. As
shown in Scheme 2, the synthesis of 1b·HCl was initiated
by the preparation of P1 phosphazenium salt 7. Trichloro-
phosphine was treated with two equivalents of pyrrolidine
Synlett 2013, 24, 2531–2534
© Georg Thieme Verlag Stuttgart · New York

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Helically Chiral Spirocyclic P3 Phosphazenes
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The optical resolution of racemic P3 phosphazenium salt In conclusion, we have designed and synthesized helically
(±)-1b·HCl was attempted by using preparative chiral sta- chiral spirocyclic P3 phosphazenes as a new family of chi-
tionary phase HPLC. After thorough screening of separa- ral organosuperbases. The structure of these novel P3
tion conditions by using analytical chiral stationary phase phosphazenes was successfully verified by X-ray single
HPLC, Daicel CHIRALPAK IB was found to be effective crystal analysis of their halide salts. The optical resolution
(Figure 4).12 The enantiomer of the first peak was success- of a racemic helically chiral P3 phosphazenium salt was
fully isolated by using preparative chiral stationary phase achieved by using preparative chiral stationary phase
HPLC under the optimized conditions.13 The first peak of HPLC to afford the optically pure P3 phosphazene in its
1b·HCl was found to be the (+)-form on the basis of its onium salt form. The present structural motif is potential-
specific rotation.14
ly useful as a fundamental structural class of chiral or-
ganosuperbase catalysts. Further studies are in progress to
apply the helically chiral P3 phosphazene derivatives to
catalytic enantioselective transformations.
Acknowledgment
This work was partially supported by a Grant-in-Aid for Scientific
Research on Innovative Areas ‘Advanced Molecular Transforma-
tions by Organocatalysts’ from MEXT, Japan and a Grant-in-Aid
for Scientific Research (Grant No. 24350045) from the JSPS. We
also thank Daicel CPI Company Co., Ltd. for their support in esta-
blishing conditions for chiral stationary phase HPLC analysis.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Figure 4 Chiral stationary phase HPLC analysis of (±)-1b·HCl
References and Notes
To determine the absolute configuration of optically pure
(+)-1b·HCl, we attempted single-crystal X-ray diffraction
analysis, however, an X-ray grade single crystal of (+)-
1b·HCl could not be obtained. We therefore exchanged
the counter anion from chloride to bromide. To our satis-
faction, an X-ray grade single crystal of optically pure
1b·HBr could be obtained from a mixture of acetone/hex-
ane/chloroform, and the helical chirality of 1b·HBr, de-
rived from (+)-1b·HCl, was determined to be the (P)-form
(Figure 5).15
(1) For reviews on organobase catalysis, see: (a) Palomo, C.;
Oiarbide, M.; López, R. Chem. Soc. Rev. 2009, 38, 632.
(b) Superbases for Organic Synthesis; Ishikawa, T., Ed.;
John Wiley & Sons: Chippenham, 2009.
(2) (a) Schwesinger, R.; Schlemper, H. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1167; and references therein.
(b) Schwesinger, R.; Willaredt, J.; Schlemper, H.; Keller,
M.; Schmitt, D.; Fritz, H. Chem. Ber. 1994, 127, 2435; and
references therein . (c) Schwesinger, R.; Schlemper, H.;
Hasenfratz, C.; Willaredt, J.; Dambacher, T.; Breuer, T.;
Ottaway, C.; Fletschinger, M.; Boele, J.; Fritz, H.; Putzas,
D.; Rotter, H. W.; Bordwell, F. G.; Satish, A. V.; Ji, G.-Z.;
Peters, E.-M.; Peters, K.; von Schnering, H. G.; Walz, L.
Liebigs Ann. 1996, 1055.
(3) (a) Tang, J. S.; Dopke, J.; Verkade, J. G. J. Am. Chem. Soc.
1993, 115, 5015. (b) Kisanga, P. B.; Verkade, J.;
Schwesinger, R. J. Org. Chem. 2000, 65, 5431. (c) Verkade,
J. G. Top. Curr. Chem. 2003, 223, 1; and references therein.
(4) Schwesinger, R. Chimia 1985, 39, 269.
(5) For reviews on enantioselective catalysis by using chiral
guanidines and P1 phosphazenes, see: (a) Ishikawa, T.;
Kumamoto, T. Synthesis 2006, 737. (b) Leow, D.; Tan,
C.-H. Chem. Asian J. 2009, 4, 488. (c) Sohtome, Y.;
Nagasawa, K. Synlett 2010, 1. (d) Leow, D.; Tan, C.-H.
Synlett 2010, 1589. (e) Terada, M. J. Synth. Org. Chem.,
Jpn. 2010, 68, 1159. (f) Uraguchi, D.; Ooi, T. J. Synth. Org.
Chem., Jpn. 2010, 68, 1185.
(6) For the preparation of chiral phosphatrane derivatives, see:
Ilankumaran, P.; Zhang, G.; Verkade, J. G. Heteroatom
Chem. 2000, 11, 251.
(7) For the preparation of chiral P1 phosphazene derivatives,
see: Köhn, U.; Schulz, M.; Schramm, A.; Günther, W.;
Görls, H.; Schenk, S.; Anders, E. Eur. J. Org. Chem. 2006,
4128.
Figure 5 ORTEP drawing of (P)-1b·HBr with probability ellipsoids
drawn at the 50% level. The solvent molecule (CHCl3) is omitted for
clarity. The X-ray grade crystal was obtained from optically pure
1b·HBr, which was prepared from (+)-1b·HCl through counterion
exchange.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2531–2534

2534
M. Terada et al.
CLUSTER
(8) (a) Bandar, J. S.; Lambert, T. H. J. Am. Chem. Soc. 2012,
134, 5552. (b) Bandar, J. S.; Lambert, T. H. J. Am. Chem.
Soc. 2013, 135, 11799.
(MeOH–Et2NH = 100:0.1, 1.0 mL/min, 240 nm, 40 °C): tR =
29.9 (isolated), 33.5 min. See Supporting Information (page
S18).
(9) Takeda, T.; Terada, M. J. Am. Chem. Soc. 2013, 135, 15306.
(10) The enantiomers of (±)-1a·HBF4 were resolved by using
analytical HPLC equipped with a Daicel CHIRALPAK IB
(MeOH–Et2NH = 100:0.1, 1.0 mL/min, 240 nm, 40 °C): tR =
23.3, 26.0 min. See Supporting Information (page S14).
(11) CCDC-964338 [(±)-1a·HI] contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
(13) The second peak could not be isolated in an optically pure
form because of overlap with the first peak under the
preparative chiral stationary phase HPLC conditions.
(14) Specific rotation of the first eluting enantiomer, (+)-1b·HCl:
[α]D27 +91.7 (c 0.90, CHCl3).
(15) CCDC-964339 [(±)-1b·HBr] contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre via
Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
www.ccdc.cam.ac.uk/data_request/cif.
(12) The enantiomers of (±)-1b·HCl were resolved by using
analytical HPLC equipped with a Daicel CHIRALPAK IB
Synlett 2013, 24, 2531–2534
© Georg Thieme Verlag Stuttgart · New York

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