Synthesis and characterisation of 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones

Article abstract of DOI:10.1016/j.tetlet.2011.12.031

Novel 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones have been synthesised via the Mannich reaction of a phosphorinanone, a primary amine and formaldehyde. The new phosphorus-nitrogen (PN) compounds are rigid and adopt a twin-chair conformation both in solutio

Full text of DOI:10.1016/j.tetlet.2011.12.031

Tetrahedron Letters 53 (2012) 923–926
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Tetrahedron Letters
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Synthesis and characterisation of 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones
⇑
Almas I. Zayya, Raymond Vagana, Melanie R.M. Nelson, John L. Spencer
School of Chemical and Physical Sciences, Victoria University of Wellington, Kelburn, Wellington 6012, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 3-aza-7-phosphabicyclo[3.3.1]nonan-9-ones have been synthesised via the Mannich reaction of a
phosphorinanone, a primary amine and formaldehyde. The new phosphorus–nitrogen (PN) compounds
are rigid and adopt a twin-chair conformation both in solution and the solid states. The coordination
properties of the PN compounds were explored and a stable platinum complex was synthesised in which
the PN ligand was bonded through both donor atoms.
Received 16 August 2011
Revised 28 November 2011
Accepted 9 December 2011
Available online 16 December 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Bispidinones
Mannich reaction
Piperidinones
Phosphorinanones
P-Michael reaction
PN ligands
The rigid bicyclo[3.3.1]nonan-9-one framework occurs in many
polycyclic alkaloids such as sparteine (1, shown is the structure of
Replacement of one of the nitrogen atoms in bispidinone com-
pounds with a heteroatom leads to 3-aza-7-heterobicyclo[3.3.1]
nonan-9-ones. Oxygen,7 sulfur8,9 and selenium10 analogues have
been prepared by the Mannich reaction starting from the respective
4-heterocyclohexanones. These bispidinone analogues have been
used for conformational studies and were tested for potential bio-
logical activity due to their antiarrhythmic and analgesic properties.
To date, bispidinone derivatives containing both phosphorus
and nitrogen atoms are not known. Such compounds are attractive
synthetic targets as the combination of the rigid and highly preor-
ganised bicyclic backbone and the different features associated
with each donor atom are expected to provide unique properties
to the resultant phosphorus–nitrogen (PN) derivatives as chelating
ligands in transition metal complexes. Furthermore, the possibility
of substitution at the 1/5, 2/4 and 6/8 positions of the bicyclic ring
offers unique opportunities to fine-tune the steric environment
around the metal centre. Herein, we report the synthesis and spec-
troscopic and structural data of the first examples of 3-aza-7-
phosphabicyclo[3.3.1]nonan-9-ones.
a
-isosparteine) and in the synthetic bispidinone derivatives 2.
Since sparteine has known medical and chemical applications,1
the simplified bispidinones have also been extensively investigated
for potential biological activity and as bidentate ligands for transi-
tion metals.1–5
O
N
N
N
R
N
R
1
2
Bispidinones were first reported by Mannich and Mohs in 1930.6
In general, they can be easily prepared by the Mannich condensation
reaction of a ketone with acidic a-C–H protons, an aldehyde and a
primary amine in a protic solvent (Scheme 1). The reaction interme-
diate is a piperidinone which can either be isolated or condensed
further with 2 equiv of aldehyde and 1 equiv of a primary amine to
produce the diazabicyclo[3.3.1]nonan-9-one. In total, four Mannich
condensations are required to yield the final bispidinone.
The bispidinone synthetic method is not chemically viable to
prepare the analogous PN compounds as there is no equivalent
for the iminium ion, which is the reactive species in the Mannich
reaction,11,12 in phosphorus chemistry due to the weakness of
P@C bonds. Thus, a different route was developed using the phos-
phorus analogues of piperidinones, known as 4-phosphorinanones,
to obtain the new bispidinone derivatives.
The condensation of dimethyl 1,3-acetonedicarboxylate (3) with
p-dimethylaminobenzaldehyde produced the
a,b-unsaturated
carbonyl compound 4 (Scheme 2). Subsequently, the P-Michael13
reaction of 4 with bis(hydroxymethyl)phenylphosphine in pyridine
⇑
Corresponding author. Tel.: +64 4 463 5119; fax: +64 4 463 5241.
E-mail address: john.spencer@vuw.ac.nz (J.L. Spencer).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.031

924
A. I. Zayya et al. / Tetrahedron Letters 53 (2012) 923–926
R
N
O
O
2
8
O
4
6
R'
R'
RNH2, 2CH2O
RNH2, 2CH2O
R'
R'
R'
R'
N
R
N
R
Scheme 1. General synthesis of bispidinones.
under reflux yielded a complex reaction mixture containing several
phosphorinanone isomers, from which 5 was isolated as an air-sta-
ble solid.14
Ph-P orientations have been determined.15–17 The 31P NMR spec-
trum of 5 showed one resonance at À6.9 ppm.
The Mannich reaction of phosphorinanone 5 with methylamine
and 2 equiv of formaldehyde in ethanol produced the air-stable
bicyclic PN compound 6 (Scheme 2).18 The 1H NMR spectrum of
6 implied symmetrical positions for the carbomethoxy and dim-
ethylaminophenyl substituents, and for H6/8 and H2/4. The 31P
NMR spectrum showed a single resonance at À15.1 ppm, and the
IR spectrum was dominated by two carbonyl stretches at 1722
and 1744 cmÀ1 corresponding to the ketone and ester groups,
respectively.
Phosphorinanone 5 displayed characteristically simple 1H and
13C NMR spectra owing to the presence of a plane of symmetry.
The pairs of equivalent protons H3/H5 and H2/H6 appeared as dou-
blets of doublets at 3.79 and 4.24 ppm, respectively, with large
diaxial coupling constants. This indicated that the bulky carbome-
thoxy and dimethylaminophenyl groups were in equatorial posi-
tions. The orientation of the phenyl group on phosphorus could
not be determined in compound 5. However, in previous confor-
mational analysis work on six-membered phosphacycles, axial
Crystals of PN compound 6 were obtained from diethyl ether
and dichloromethane. The X-ray crystal structure shows a mirror
symmetrical chair–chair conformation with the carbomethoxy,
dimethylaminophenyl, Me and Ph substituents in equatorial sites
(Fig. 1). This observation is in agreement with the structure in
solution. The solid state crystal structure also shows that PN
compound 6 is similar to the bispidinones as the intramolecular
distance between the phosphorus and nitrogen donor atoms is
O
O
O
CHO
2
MeO
OMe
Me2N
3
86%
O
O
O
MeO
OMe
4
Me2N
NMe2
PhP(CH2OH)2
77%
O
O
O
MeO
OMe
2
6
5
3
P
Ph
Me2N
NMe2
5
2CH2O
MeNH2
45%
Me
N
O
O
O
4
6
2
8
MeO
OMe
P
Ph
Me2N
NMe2
6
Figure 1. ORTEP diagrams of PN compound 6 (30% thermal ellipsoids). Hydrogen
Scheme 2. Synthesis of 3-aza-7-phosphabicyclo[3.3.1]nonan-9-one derivative 6.
atoms omitted for clarity.

A. I. Zayya et al. / Tetrahedron Letters 53 (2012) 923–926
925
2.9 Å, which is the same as the average N–N distance in bispid-
inone compounds.1
8. The crystallographic parameters and a summary of bond dis-
tances and angles for compound 6 are also included. CCDC
838817 contains the supplementary crystallographic data for com-
pound 6. This information can be obtained free of charge via http://
www.ccdc.cam.ac.uk/conts/retrieving.html, or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ,
UK; e-mail: deposit@ccdc.cam.ac.uk.
Similarly, phosphorinanone 5 was reacted with ethylamine or
isobutylamine and formaldehyde via the Mannich reaction to yield
the new PN analogues 7 and 8. The spectroscopic data19 of 7 and 8
were very similar to 6 as they adopted a mirror symmetrical chair–
chair conformation in solution.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.031.
R
N
References and notes
O
O
O
1. Comba, P.; Kerscher, M.; Schiek, W. Prog. Inorg. Chem. 2007, 55, 613–704.
2. Jeyaraman, R.; Avila, S. Chem. Rev. 1981, 81, 149–174.
3. Black, D. S.; Deacon, G. B.; Rose, M. Tetrahedron 1995, 51, 2055–2076.
4. Gogoll, A.; Grennberg, H.; Axén, A. Organometallics 1997, 16, 1167–1178.
5. Gogoll, A.; Grennberg, H.; Axén, A. Organometallics 1998, 17, 5248–5253.
6. Mannich, C.; Mohs, P. Chem. Ber. 1930, B63, 608–612.
7. Arjunan, P.; Berlin, K. D.; Barnes, C. L.; van der Helm, D. J. Org. Chem. 1981, 46,
3196–3204.
MeO
OMe
P
Ph
Me2N
NMe2
36% yield
7
R = CH2CH3
8 R = CH2CH(CH3)2 60% yield
8. Bailey, B. R.; Berlin, K. D.; Holt, E. M.; Scherlag, B. J.; Lazzara, R.; Brachmann, J.;
van der Helm, D.; Powell, D. R.; Pantaleo, N. S.; Ruenitz, P. C. J. Med. Chem. 1984,
27, 758–767.
9. Yu, V. K.; Praliev, K. D.; Fomicheva, E. E.; Mukhasheva, R. D.; Klepikova, S. G.
Chem. Heterocycl. Compd. 2006, 42, 512–519.
10. Thompson, M. D.; Smith, G. S.; Berlin, K. D.; Holt, E. M.; Scherlag, B. J.; van der
Helm, D.; Muchmore, S. W.; Fidelis, K. A. J. Med. Chem. 1987, 30, 780–788.
11. Tramontini, M.; Angilini, L. Tetrahedron 1990, 46, 1791–1837.
12. Arend, M.; Westermann, B.; Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044–
1070.
13. Enders, D.; Saint-Dizier, A.; Lannou, M.; Lenzen, A. Eur. J. Org. Chem. 2006, 29–
49.
14. Preparation of 4-phenyl-2,6-di(carbomethoxy)-3,5-bis(p-dimethylaminophenyl)-
4-phosphacyclohexanone (5):
PN ligand 6 was reacted with [PtMe2(1,5-hexadiene)] to form the
square planar complex [PtMe2(6)] (9).20 The 31P NMR spectrum
showed a single resonance at 14.6 ppm with 195Pt satellites of
2036 Hz. The 1H NMR spectrum of 9 was simple indicating that
the coordinated PN ligand retained its plane of symmetry upon
coordination to platinum.
Compound
(0.03 cm3, 0.23 mmol) were heated under reflux for 4 h in pyridine (10 cm3)
under an inert atmosphere. After 30 min, white solid (shown to be
4 (0.10 g, 0.23 mmol) and bis(hydroxymethyl)phenylphosphine
Ar
Ar
Ph
a
MeO2C
Me
Me
paraformaldehyde) deposited in the condenser. The solvent was removed in
vacuo to give a red oil, which was taken up in EtOH and kept at 5 °C. The title
compound precipitated as an orange solid. This was filtered and recrystallised
from EtOH (0.10 g, 77%); mp 154–156.9 °C. IR (KBr) mmax 1740, 1642, 1629,
P
N
Pt
O
MeO2C
1610 cmÀ1 1H NMR d (300 MHz, CDCl3): 2.85 (s, 12H, NMe2), 3.57 (s, 6H, OMe),
;
Me
3.79 (dd, JHH = 112.8 Hz, JPH = 6.6 Hz, 2H, PCH), 4.24 (dd, JHH = 13.4 Hz,
JPH = 5.7 Hz, 2H, PCCH), 6.48 (d, JHH = 8.0 Hz, 4H, m-H), 6.92 (d, JHH = 8.0, 4H,
o-H), 7.14–7.34 (m, 5H, C6H5); 13C NMR d (75 MHz, CDCl3): 40.5 (s, NMe2), 45.4
(d, JPC = 19.2 Hz, PCH), 52.6 (s, OMe), 64.5 (m, PCCH), 112.1 (s, Ar), 120.4 (s, Ar),
125.9 (d, JPC = 34.8 Hz, Ar), 127.7 (d, JPC = 9.2 Hz, Ar), 130.0 (s, Ar), 132.4 (d,
JPC = 8.6 Hz, Ar), 133.0 (d, JPC = 6.4 Hz, Ar), 150.1 (s, Ar), 169.2 (d, JPC = 10.3 Hz,
COO), 202.7 (s, CO); 31P NMR d (121 MHz; CDCl3): À6.9; HRMS calcd for
9 (Ar = p-C6H4N (Me)2
)
C
C
31H36N2O5P [M+H]+: m/z = 547.2362; found: 547.2365; Anal. calcd for
31H35N2O5P: C, 68.1; H, 6.5; N, 5.1; P, 5.7; found: C, 68.4; H, 6.7; N, 5.2; P, 5.8.
The NMR signals for the methyl groups in 9 were differentiated as a
result of being trans to the different donor atoms: the methyl group
trans to phosphorus resonated at 1.35 ppm in the 1H NMR spec-
trum, while the methyl trans to nitrogen appeared at 1.43 ppm.
Both signals were doublets with JPH values of 7.5 Hz. The trans-ef-
fect of P and N was much more pronounced in the 13C NMR chem-
ical shifts of the methyl groups: the methyl trans to phosphorus
resonated at 11.2 ppm as a doublet (JPC = 114.6 Hz) with 195Pt satel-
lites of 727 Hz, whereas the methyl group trans to nitrogen ap-
peared at À20.9 ppm as a doublet (JPC = 3.7 Hz) with a slightly
larger 195Pt coupling constant of 787 Hz. The above NMR data con-
firm that PN ligand 6 is bonded to platinum via both donor atoms,
hence maintaining its chair–chair conformation.
In conclusion, novel phosphorus–nitrogen derivatives of the
bispidinones were synthesised by the Mannich reaction of phos-
phorinanone 5 with primary amines and formaldehyde. The new
bicyclic PN compounds adopted a rigid chair–chair conformation
both in solution and solid states. This conformation is favourable
as it presets a bidentate capability for such PN compounds to serve
as chelating ligands for transition metals.
15. Featherman, S. I.; Quin, L. D. J. Am. Chem. Soc. 1975, 97, 4349–4356.
16. Rampal, J. B.; Macdonell, G. D.; Edasery, J. P.; Berlin, K. D.; Rahman, A.; van der
Helm, D.; Pietrusiewicz, K. M. J. Org. Chem. 1981, 46, 1156–1165.
17. Doherty, R.; Haddow, M. F.; Harrison, Z. A.; Orpen, A. G.; Pringle, P. G.; Turner,
A.; Wingad, R. L. Dalton Trans. 2006, 36, 4310–4320.
18. Preparation of 1,5-di(carbomethoxy)-6,8-bis(p-dimethylaminophenyl)-3-methyl-
7-phenyl-3-aza-7-phosphabicyclo[3.3.1]nonan-9-one (6):
Phosphorinanone 5 (0.10 g, 0.18 mmol), methylamine (0.02 cm3, 0.18 mmol)
and formaldehyde (0.03 cm3, 0.36 mmol) were combined in EtOH (35 cm3).
The red reaction mixture was heated under reflux for 1 d under an inert
atmosphere. The title compound precipitated from the reaction mixture as it
cooled down to room temperature as a pale-yellow solid (0.05 g, 45%); mp
145–149 °C. IR (KBr) mmax 1744, 1722, 1709, 1646 cmÀ1 1H NMR d (300 MHz,
;
CDCl3): 2.67 (s, 3H, NMe), 2.83 (d, JHH = 11.7 Hz, 2H, CH2), 2.90 (s, 12H, NMe2),
3.57 (d, JHH = 12.6 Hz, 2H, CH2), 3.67 (s, 6H, OMe), 4.14 (d, JPH = 6.2 Hz, 2H,
PCH), 6.60 (d, JHH = 8.8 Hz, 4H, m-H), 7.09 (m, 2H, PC6H5), 7.17 (m, 3H, PC6H5),
7.30 (d, JHH = 8.5 Hz, 4H, o-H); 13C NMR d (75 MHz, CDCl3): 40.6 (s, NMe2), 44.5
(s, NMe), 47.4 (d, JPC = 19.7 Hz, PCH), 52.3 (s, OMe), 60.4 (s, CH2), 65.7 (d,
JPC = 2.8 Hz, PCHC), 112.4 (s, Ar), 125.2 (d, JPC = 17.5 Hz, Ar), 128.2 (d,
JPC = 5.3 Hz, Ar), 128.6 (s, Ar), 131.6 (d, JPC = 19.5 Hz, Ar), 132.1 (d,
JPC = 13.4 Hz, Ar), 141.2 (d, JPC = 33.1 Hz, Ar), 149.9 (s, Ar), 169.5 (d,
JPC = 3.6 Hz, COO), 205.2 (s, CO); 31P NMR d (121 MHz; CDCl3): À15.1; HRMS
calcd for C34H41N3O5P [M+H]+: m/z = 602.2784; found: 602.2785; Anal. calcd
for C34H40N3O5P: C, 67.9; H, 6.7; N, 7.0; P, 5.2; found: C, 66.8; H, 6.9; N, 6.7; P,
5.3.
19. Spectral data for compound 7:
IR (KBr) mmax 1743, 1725, 1707, 1611 cmÀ1 1H NMR d (500 MHz, CDCl3): 1.41
;
Supplementary data
(t, JHH = 7.1 Hz, 3H, NCH2CH3), 2.85 (d, JHH = 11.2 Hz, 2H, CH2), 2.90 (s, 12H,
NMe2), 2.95 (q, JHH = 7.1 Hz, 2H, NCH2CH3), 3.62 (d, JHH = 11.2 Hz, 2H, CH2), 3.68
(s, 6H, OMe), 4.14 (d, JPH = 5.6 Hz, 2H, PCH), 6.61 (d, JHH = 6.8 Hz, 4H, m-H), 7.09
(m, 2H, PC6H5), 7.16 (m, 3H, PC6H5), 7.33 (d, JHH = 7.3 Hz, 4H, o-H); 13C NMR d
The synthesis and characterisation data for compound 4 are
supplied, as well as the synthetic methods for compounds 7 and

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A. I. Zayya et al. / Tetrahedron Letters 53 (2012) 923–926
(125 MHz, CDCl3): 11.5 (s, NCH2CH3), 40.4 (s, NMe2), 46.9 (d, JPC = 20.1 Hz, calcd for C37H46N3O5P: C, 69.0; H, 7.2; N, 6.5; P, 4.8; found: C, 68.8; H, 7.3; N,
PCH), 51.1 (s, CH2), 52.0 (s, OMe), 57.5 (s, NCH2CH3), 65.6 (d, JPC = 3.3 Hz,
PCHC), 112.2 (s, Ar), 125.0 (d, JPC = 17.4 Hz, Ar), 127.9 (d, JPC = 5.1 Hz, Ar), 128.2
(s, Ar), 131.2 (d, JPC = 19.4 Hz, Ar), 131.8 (d, JPC = 13.4 Hz, Ar), 149.7 (d,
6.4; P,.5.0.
20. Preparation of [PtMe2(6)] (9):
PN ligand
6 (0.05 g, 0.08 mmol) and [PtMe2(1,5-hexadiene)] (0.02 g,
JPC = 1.7 Hz, Ar), 169.4 (d, JPC = 3.3 Hz, COO), 205.2 (s, CO); 31P NMR
(121 MHz; CDCl3): À16.2.
d
0.08 mmol) were combined in CH2Cl2 (5 cm3). The yellow mixture was
stirred at room temperature for 1 d. The solvent was evaporated in vacuo to
give the title compound as a yellow solid (0.06 g, 86%); mp 230–233 °C. IR
HRMS calcd for C35H43N3O5P [M+H]+: m/z = 616.2940; found: 616.2941; Anal.
calcd for (C35H42N3O5P)3.CDCl3: C, 64.7; H, 6.6; N, 6.4; P, 4.7; found: C, 64.3; H,
6.7; N, 6.5; P, 5.0.
(KBr) mmax 1745, 1735, 1720, 1625 cmÀ1 1H NMR d (300 MHz, C6D6): 1.35 (d,
;
JPH = 7.5 Hz, 3 H, Me trans to P), 1.43 (d, JPH = 7.5 Hz, 3 H, Me trans to N), 2.34 (s,
3 H, NMe), 2.37 (s, 12 H, NMe2), 2.94 (m, 2 H, CH2), 3.38 (s, 6 H, OMe), 4.32 (d,
JHH = 13.4 Hz, 2 H, CH2), 4.44 (d, JPH = 12.1 Hz, 2 H, PCH), 6.50 (d, JHH = 8.4 Hz, 4
H, m-H), 6.76 (m, 5H, PC6H5), 8.61 (d, JHH = 8.4 Hz, 4 H, o-H); 13C NMR d
(75 MHz, CDCl3): À20.9 (d, JPC = 3.7 Hz, JPtP = 787 Hz, Me trans to N), 11.2 (d,
JPC = 114.6 Hz, JPtP = 727 Hz, Me trans to P), 40.2 (s, NMe2), 45.1 (d, JPC = 19.1 Hz,
PCH), 52.2 (s, OMe), 57.3 (s, NMe), 64.1 (d, JPC = 2.0 Hz, CH2), 64.2 (d,
JPC = 5.3 Hz, PCHC), 111.8 (s, Ar), 120.0 (d, JPC = 2.5 Hz, Ar), 125.6 (d,
JPC = 35.1 Hz, Ar), 127.4 (d, JPC = 9.0 Hz, Ar), 129.6 (d, JPC = 1.9 Hz, Ar), 132.1
(d, JPC = 8.6 Hz, Ar), 132.7 (d, JPC = 6.2 Hz, Ar), 149.8 (d, JPC = 0.9 Hz, Ar), 167.8 (d,
JPC = 10.3 Hz, COO), 202.3 (d, JPC = 1.5 Hz, CO); 31P NMR d (121 MHz; C6D6): 14.6
(JPtP = 2036 Hz).
Spectral data for compound 8:
IR (KBr) mmax 1744, 1709, 1621, 1519 cmÀ1 1H NMR d (300 MHz, CDCl3): 1.32
;
(d, JHH = 6.4 Hz, 6H, NCH2CH(CH3)2), 2.18 (m, 1H, NCH2CH(CH3)2), 2.47 (d,
JHH = 6.8 Hz, 2H, NCH2CH(CH3)2), 2.76 (d, JHH = 12.4 Hz, 2H, CH2), 2.90 (s, 12 H,
NMe2), 3.64 (m, 2H, CH2), 3.67 (s, 6H, OMe), 4.13 (d, JPH = 5.2 Hz, 2H, PCH), 6.59
(d, JHH = 7.1 Hz, 4H, m-H), 7.08 (m, 2H, PC6H5), 7.16 (m, 3H, PC6H5), 7.30 (d,
JHH = 8.3 Hz, 4H, o-H); 13C NMR d (75 MHz, CDCl3): 22.2 (s, NCH2CH(CH3)2),
22.3 (s, NCH2CH(CH3)2), 26.4 (s, NCH2CH(CH3)2), 40.8 (s, NMe2), 47.3 (d,
JPC = 21.4 Hz, PCH), 52.2 (s, OMe), 59.7 (s, CH2), 65.6 (d, JPC = 3.9 Hz, PCHC), 67.6
(s, NCH2CH(CH3)2), 112.5 (br s, Ar), 125.4 (br s, Ar), 128.1 (d, JPC = 5.5 Hz, Ar),
128.6 (s, Ar), 131.6 (d, JPC = 19.6 Hz, Ar), 131.9 (d, JPC = 12.2 Hz, Ar), 149.8 (br s,
Ar), 169.6 (d, JPC = 3.7 Hz, COO), 205.5 (s, CO); 31P NMR d (121 MHz; CDCl3):
À16.1.
HRMS calcd for C36H45N3O5PPt [MÀH]+: m/z = 825.2745; found: 825.2761;
Anal. calcd for C36H46N3O5PPt: C, 52.3; H, 5.6; N, 5.1; found: C, 53.7; H, 5.8; N,
4.7.
HRMS calcd for C37H47N3O5P [M+H]+: m/z = 644.3253; found: 644.3257; Anal.