An efficient approach to 2-substituted N-tosylpiperdines: asymmetric synthesis of 2-(2-hydroxy substituted)piperidine alkaloids

Article abstract of DOI:10.1016/j.tetlet.2007.01.082

We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral α-substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinylethanol 15 and ent-15, was achieved from l- and d-aspartic acids, respectively in few steps. Piperidine 15 was converted into 2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline (R,R)-2a, (+)- and (-)-sedamine 2b, (+)- and (-)-allosedamine 2c, (+)- and (-)-sedridine 2d, (+)- and (-)-allosedridine 2e, (+)-tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted via Mitsunobu inversion in excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.01.082

Tetrahedron Letters 48 (2007) 1907–1910
An efficient approach to 2-substituted N-tosylpiperdines:
asymmetric synthesis of 2-(2-hydroxy substituted)-
piperidine alkaloids
Alakesh Bisai and Vinod K. Singh*
Department of Chemistry, Indian Institute of Technology Kanpur, Kanpur 208 016, India
Received 10 December 2006; revised 11 January 2007; accepted 18 January 2007
Available online 20 January 2007
Abstract—We have developed an efficient and a general approach to chiral 2-substituted N-tosylpiperidines starting from chiral a-
substituted-N-tosylaziridines. Using this approach, we have synthesized (+)-coniine. The synthesis of chiral N-tosyl-2-piperidinyl-
ethanol 15 and ent-15, was achieved from L- and D-aspartic acids, respectively in few steps. Piperidine 15 was converted into
2-(2-hydroxysubstituted)piperidines of type 2 in optically active form. By applying this strategy, asymmetric syntheses of halosaline
(R,R)-2a, (+)- and (ꢀ)-sedamine 2b, (+)- and (ꢀ)-allosedamine 2c, (+)- and (ꢀ)-sedridine 2d, (+)- and (ꢀ)-allosedridine 2e, (+)-
tetraponerine T-3 3a, T-4 3c, T-7 3b, and T-8 3d have been achieved in high yields. These stereoisomers can be interconverted
via Mitsunobu inversion in excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The asymmetric synthesis of 2-substituted piperidine
NR
NH
OH
OH
NR
NH
alkaloids of type 1 (Fig. 1) is a field of intense research
as these compounds display a broad range of biological
activities.1 As these alkaloids are usually available in
only trace amounts from natural sources, there is a great
need for diverse methods for their synthesis. Piperidine
is a core unit for these alkaloids, which are widespread
in Nature and occupy an important position both as
bioactive targets and useful synthetic intermediates.
(S)–2-Propylpiperdine 1a (coniine), the simplest alkaloid
in the family, is toxic to all classes of livestock and hu-
mans.2 Among others, 2-(2-hydroxy substituted)piper-
idine-based alkaloids 2, having 1,3-aminoalcohol
connectivity where N is part of the heterocycle, are
highly desirable and constitute a large family of com-
pounds having a wide range of physiological activities.
R'
R''
1a
Coniine
1
(R,R)-2a
Halosaline
2
NMe OH
Ph
NMe OH
Ph
NMe OH
Ph
NMe OH
Ph
(-)-2c
(-)-2b
(+)-2c
(+)-2b
Sedamine
Allosedamine
NH OH
NH OH
NH OH
NH OH
(-)-2d
(+)-2d
Sedridine
(+)-2e
Allosedridine
(-)-2e
H
H
R
R
N
H
N
N
H
N
Sedamine 2b and sedridine 2d are two alkaloids isolated
from Sedum acre.3 Later, these were obtained from
other species also.4 (ꢀ)-Allosedamine 2c has been iso-
lated from Lobelia inflata which is also known as Indian
tobacco,5 the crude extract of which has been used for
treatment of respiratory illnesses such as asthma, bron-
chitis, and pneumonia.6 Although several syntheses of
sedamine have been reported as a single enantiomer,7,8
(+)-3c T-4; (R = Me)
(+)-3d T-8; (R = n-Pr)
(+)-3a T-3; ( R = Me)
(+)-3b T-7; (R = n-Pr)
Figure 1. 2-Substituted piperidine alkaloids.
there are not many reports in the literature for the syn-
thesis of chiral allosedamine.8d,9,10
Both enantiomers of allosedridine 2e,11 which have
*
Corresponding author. Tel.: +91 512 2597291; fax: +91 512
memory-enhancing properties and may be effective for
2597436; e-mail: vinodks@iitk.ac.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.082

1908
A. Bisai, V. K. Singh / Tetrahedron Letters 48 (2007) 1907–1910
the treatment of Alzheimer’s disease,12 were isolated
from Sedum nudum.1 Halosaline 2a is another important
alkaloid which has received synthetic attention.13 (+)-
Tetraponerines 3 (Fig. 1) were isolated from the venom
of a New Guinean ant Tetraponera sp.14 These are toxic
alkaloids which represent the major constituents of the
contact poison. Since their isolation, several diastereose-
lective15 and enantioselective16 syntheses have been
reported in the literature.
COOH
a
COOMe
b
c
HOOC
S
S
MeOOC
HO
85%
94%
82%
NHTs OH
9
NH2
NHTs
8
OTBS
R
OTBS
d
e
N
Ts
OR
98%
NHTs
12
NHTs
13
82%
OH
10, R =H
11, R =TBS
OR
f
R
NTs
14, R =TBS
15, R = H
Initially, we were interested in developing a general
flexible approach to chiral 2-substituted piperidines 1
from chiral a-substituted-N-tosylaziridines 4 (Scheme 1),
which could be easily synthesized from naturally occur-
ring L-a-amino acids.17 The reason for using the tosylate
protecting group was that it was quite stable under
reaction conditions and could be removed easily. The
regioselective cleavage of N-tosylaziridines 4 with
allylmagnesium bromide was achieved in almost quanti-
tative yields. Alkenes 5, thus obtained, were subjected to
hydroboration using BH3ÆDMS followed by oxidative
cleavage of the borane adduct to provide 1,5-N-tosyl
aminoalcohols 6 in very good yields. Employing our
established conditions,18 N-tosyl-1,5 amino alcohols 6
were cyclized using triphenylphosphine and diisoprop-
ylazodicarboxylate (DIAD) via Mitsunobu condensa-
tion. Thus, several (S)-N-tosyl-2-alkyl piperidines 7
were synthesized in excellent yields (Scheme 1). Since
cleavage of the N-tosyl bond in 7b is already known in
the literature,19 a formal total synthesis of (S)-coniine
1a was achieved in 70% overall yield.
g
80%
Scheme 2. Asymmetric synthesis of 15. Reaction conditions:
(a) SOCl2, MeOH, 0 °C–rt, 12 h, then TsCl, Et3N, 0 °C–rt, 12 h;
(b) LiAlH4, THF, 0 °C–rt, 12 h; (c) ADDP, n-Bu3P, toluene, 0 °C–rt,
16 h, then TBSCl, Imidazole, THF, 0 °C–rt, 8 h; (d) Allylmagnesium
bromide, THF–Et2O (1:1), ꢀ78 °C–rt, 6 h; (e) BH3ÆDMS, THF,
ꢀ10 °C–rt, 8 h, then H2O2, NaOH, 0 °C–rt, 2 h; (f) DIAD, Ph3P,
THF, 0 °C–rt, 8 h; (g) TBAF, THF, rt, 6 h, 99%.
and n-Bu3P under Mitsunobu condensation reaction
conditions resulted in smooth and selective formation
of aziridine 10. Due to difficulties in removal of residual
hydrazide during the purification step, the hydroxyl
group was protected as TBS ether 11. Regioselective
ring opening of N-tosylaziridine 11 by an allyl Grignard
reagent followed by construction of the piperidine ring
using the protocol described in Scheme 1 gave (R)-14.
Desilylation was efficiently carried out using tetrabutyl-
ammonium fluoride (TBAF) to afford enantiopure
N-tosyl-2-piperidinylethanol (R)-15 (Scheme 2).
Having established an efficient route to 2-substituted-N-
tosylpiperidine 7, attention was turned toward chiral N-
tosyl-2-piperidinylethanol 15 (Scheme 2), which can be
used as a key intermediate for asymmetric syntheses of
2-(2-hydroxy substituted)piperidines of type 2 (Fig. 1).
For this purpose, it was decided to investigate the
Mitsunobu cyclization of an amino diol 9 in an attempt
to produce an aziridine functionalized with a hydroxyl
moiety. As outlined in Scheme 2, esterification of
(S)-aspartic acid in the presence of SOCl2 in MeOH,
followed by protection of the amine as the tosylate fur-
nished N-tosyldimethyl aspartate 8, which was then
reduced with LiAlH4 at rt to afford amino diol 9 in high
yield. Next, we decided to exploit the well-established
preference for three-membered ring closure over four-
membered ring closure.
N-Tosyl-2-piperdinylethanol 15 was oxidized under
Swern conditions to aldehyde (R)-16 (Scheme 3). Diaste-
reoselective addition of phenyl or alkyl Grignards gave
mixtures of syn alcohols 17 and anti alcohols 18, where
the former was the major isomer. These could easily be
separated by silica gel column chromatography. The
absolute stereochemistry was established at a later stage
after converting some of them to natural products. The
N–Ts bond of each compound was cleaved using Na and
naphthalene and the resulting amine was Cbz protected
in situ (Scheme 3).
NTs OH
R
NTs O
R
NTs
OH
R
b
a
(R)-15
+
R
R
17
16
18
(More polar)
(Less polar)
It was heartening to note that the exposure of N-tosyl-
aminodiol 9 to 1,10-(azodicarbonyl)dipiperdine (ADDP)
17a (62%)
17b (55%)
17c (58%)
17d (60%)
18a (25%)
18b (30%)
18c (28%)
18d (32%)
OH
a, R = Ph
b, R = Me
c, R = allyl
d, R = n-pentyl
Ts
c
60-92%
58-91%
N
TsHN
R
c
TsN
R
a
b
TsHN
R
c
Cbz
R
Cbz
OH
4a-e
5a-e
6a-e
7a-e
N
OH
N
R
R
a, R = Me; b, R =
n
-Pr; c, R =
i
-Pr; d, R =
s
-Bu; e, R =
i
-Bu
R
R
19a-d
20a-d
Scheme 1. An approach to 2-substituted piperidines. Reaction condi-
tions: (a) Allylmagnesium bromide, THF–Et2O (1:1), ꢀ78 °C–rt, 6 h
(95–99% yield); (b) (i) BH3ÆDMS, THF, ꢀ10 °C–rt, 8 h, (ii) H2O2,
NaOH, 0 °C–rt, 2 h (77–85% yield); (c) DIAD, Ph3P, THF, 0 °C–rt,
8 h (90–96% yield).
Scheme 3. Asymmetric synthesis of 19 and 20. Reaction conditions:
(a) (COCl)2, DMSO, Et3N, ꢀ78 °C–rt, 8 h, 95%; (b) RMgX, THF–
Et2O (1:1), ꢀ78 °C–rt, 6 h, chromatographic separation; (c) Na,
naphthalene, THF, 0 °C–rt, 2 h, then NaHCO3, CbzCl, 2 h.

A. Bisai, V. K. Singh / Tetrahedron Letters 48 (2007) 1907–1910
1909
Piperdine 19a was treated with LiAlH4 to reduce the
COOH
R
S
Cbz group to a methyl group to give (+)-sedamine 2b.
Similarly, (+)-allosedamine 2c was synthesized from
20a (Scheme 4). Since 19b–d have already been con-
verted into (+)-allosedridine 2e, (+)-tetraponerine-3
(T-3) 3a, and (+)-tetraponerine-7 (T-7) 3b, we have com-
pleted formal syntheses of these alkaloids. Similarly, the
conversions of 20b–d to (ꢀ)-sedridine 2d, (+)-tetrapon-
erine-4 (T-4) 3c, and (+)-tetraponerine-8 (T-8) 3d are
also known, we have completed formal total syntheses
of these natural products (Scheme 4).
HOOC
R
NTs OR'
N
Ts
OR'
NH2
ent-14, R' = TBS
ent-15, R' = H
a
ent-10, R' = H
ent-11, R' = TBS
b
NTs OH
NTs O
NTs
OH
+
S
S
S
R
R
ent-18a-b
(Less polar)
ent-16
ent-17a-b
(More polar)
ent-17a (62%) : ent-18a (24%)
ent-17b (56%) : ent-18b (30%)
a, R = Ph
b, R = Me
In order to synthesize the antipode of the above synthe-
sized natural products, ent-19a–b and ent-20a–b were
synthesized following the same sequence of reactions
as in Schemes 2 and 3 using D-aspartic acid (Scheme
5). Treatment of ent-19a with LiAlH4 gave (ꢀ)-sedamine
2b. Similarly, (ꢀ)-allosedamine 2c was synthesized from
ent-20a in the same way. Since ent-19b and ent-20b have
already been converted to (ꢀ)-allosedridine 2e and (+)-
sedridine 2d, we have also completed the formal synthe-
ses of these natural products.20
c
c
Cbz
Cbz
N
S
OH
N
OH
S
R
R
ent-20a-b
ent-19a-b
Scheme 5. Asymmetric synthesis of ent-19 and ent-20. Reaction con-
ditions: (a) (COCl)2, DMSO, Et3N, ꢀ78 °C–rt, 8 h, 95%; (b) RMgX,
THF–Et2O (1:1), ꢀ78 °C–rt, 6 h, chromatographic separation; (c) Na,
Napthalene, THF, 0 °C–rt, 2 h, then NaHCO3, CbzCl, 2 h, 85–90%.
As we can see from Schemes 3 and 5, addition of the
Grignard reagents to chiral aldehydes was syn selective.
This can be explained by invoking the transition state
model depicted in Figure 2. In the most stable confor-
mation of the piperidine ring, the tosyl group attached
to the ‘N’ and carboxymethylene group attached to the
C-2 position of the piperidine ring are equatorially
oriented. Addition of the Grignard reagent to 16 or
ent-16 may generate a chelated six-membered transition
static co-ordinating the Mg. In this orientation, the
aromatic ring of the tosyl group blocks the re face of
the aldehyde favoring the si face attack. In general, the
selectivity was 70:30 in favor of the syn diastereomer.
The low selectivity could be due to poor chelation as
the nitrogen lone pair is not fully accessible.
si face
O
Mg
O
N
N
S
RMgX
O
S
O
O
H
O
H
Figure 2. Diastereoselective Grignard addition.
b
NTs
OPNB
R
a
18a-d
17a-d
17a-d
18a-d
R
92-98%
85-93%
21a-d
b
NTs
OPNB
a
R
In order to show versatility in our synthesis, all the ste-
reoisomers of 2-(2-hydroxy substituted)piperidines 17,
18, and their antipodes were interconverted by Mitsun-
obu inversion (Scheme 6). In all cases, the yields were
excellent.
94-97%
84-92%
R
22a-d
b
NTs
OPNB
a
ent-18a-b
ent-17a-b
ent-17a-d
ent-18a-d
S
94-95%
86-88%
R
ent-21a-d
b
NTs
OPNB
In conclusion, we have developed an efficient and gen-
eral approach to chiral 2-substituted N-tosylpiperidines
and 2-(2-hydroxy substituted)piperidines of type 2 in
optically active form. The approach is general in the
sense that several of these compounds can be made from
a single precursor. Using the Mitsunobu inversion meth-
a
S
94-95%
86-90%
R
ent-22a-d
a, R = Ph; b, R = Me; c, R = Allyl; d, R = n-C5H11
.
Scheme 6. Interconversion of 17, 18, ent-17, and ent-18 to their
opposite diastereomers by Mitsunobu protocol. Reaction conditions:
(a) p-NO2C6H4COOH, DIAD, Ph3P, THF, 0 °C–rt, 24 h, (b) K2CO3,
MeOH, rt, 12 h.
LiAlH , THF,
4
LiAlH , THF,
4
reflux,16-20 h
reflux, 16-20 h
19a
20a
(+)-2b
(+)-2c
od, it has been shown that the stereoisomer can be inter-
converted in excellent yields.
82%
80%
Ref. 11b
Ref. 11b
19b
19c
19d
(-)-2d
(+)-3c
(+)-3d
(+)-2e
(+)-3a
(+)-3b
20b
20c
20d
Ref. 11b
Ref. 11b
Ref. 11b
Ref. 11b
Acknowledgments
V.K.S. thanks the Department of Science and Technol-
ogy, Government of India, for a research grant. A.B.
Scheme 4. Synthesis of 2-(2-hydroxy substituted)piperidine alkaloids.

1910
A. Bisai, V. K. Singh / Tetrahedron Letters 48 (2007) 1907–1910
10. For a synthesis of (+)-allosedamine, see: Kang, B.; Chang,
S. Tetrahedron 2004, 60, 7353.
thanks the Council of Scientific and Industrial Research,
New Delhi, for a senior research fellowship.
11. For asymmetric syntheses of sedridine and allosedridine,
see: (a) Davis, F. A.; Prasad, K. R.; Nolt, M. B.; Wu, Y.
Org. Lett. 2003, 5, 925; (b) Takahata, H.; Kubota, M.;
Ikota, N. J. Org. Chem. 1999, 64, 8594; (c) Louis, C.;
Hottele, C. Tetrahedron: Asymmetry 1997, 8, 109; (d)
Littler, B. J.; Gallagher, T.; Boddy, I. K.; Riordan, P. D.
Synlett 1997, 22.
12. (a) Micel, K.-H.; Sandberg, F.; Haglid, F.; Norin, T. Acta
Pharm. Suec. 1967, 4, 97; (b) Micel, K.-H.; Sandberg, F.;
Haglid, F.; Norin, T.; Chan, R. P. K.; Craig, J. C. Acta
Chem. Scand. 1969, 23, 3479.
13. For asymmetric syntheses of halosaline, see: (a) Lesma,
G.; Crippa, S.; Danieli, B.; Passarella, D.; Sacchetti, A.;
Silvani, A.; Virdis, A. Tetrahedron 2004, 60, 6437; (b)
Kochi, T.; Tang, T. P.; Ellman, J. A. J. Am. Chem. Soc.
2003, 125, 11276; (c) Stragies, R.; Blechart, S. Tetrahedron
1999, 55, 8179.
14. (a) Merlin, P.; Braekman, J. C.; Daloze, D.; Pasteels, J. M.
J. Chem. Ecol. 1988, 14, 517; (b) Braekman, J. C.; Daloze,
D.; Pasteels, J. M.; Vanhecke, P.; Declercq, J. P.; Sinnwell,
V.; Franke, W. Z. Naturforsch. 1987, 42c, 627.
References and notes
1. (a) Strunzand, G. M.; Finlay, J. A. In The Alkaloids;
Brossi, A., Ed.; Academic Press: New York, 1985; Vol. 26,
pp 89–174; For a review on the synthesis of piperdines,
see: (b) Buffat, M. G. P. Tetrahedron 2004, 60, 1701.
2. For details about coniine, see a recent review on Hemlock
alkaloids: (a) Reynolds, T. Phytochemistry 2005, 66, 1399,
and references cited therein; For the most recent paper on
asymmetric syntheses of coniine and related alkaloids, see:
(b) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2006, 128,
9646.
3. (a) Marion, L. Can. J. Res. 1945, 23B, 165; (b) Marion, L.;
Lavigne, R.; Lemay, L. Can. J. Chem. 1951, 29, 347; (c)
Franck, B. Chem. Ber. 1958, 91, 2803; (d) Franck, B.
Chem. Ber. 1960, 93, 2360; (e) Fodor, G.; Butruille, D.;
Huber, S. C.; Letourneau, F. Tetrahedron 1971, 27, 2055,
and references cited therein.
15. (a) Charette, A. B.; Matheiu, S.; Martel, J. Org. Lett.
2005, 7, 5401, and references cited therein; (b) Kim, J. T.;
Butt, J.; Gevorgyan, V. J. Org. Chem. 2004, 69, 5638; (c)
Kim, J. T.; Gevorgyan, V. Org. Lett. 2002, 4, 4697; (d)
Takahata, H.; Kubota, M.; Ikota, N. J. Org. Chem. 1999,
64, 8594; (e) Barluenga, J.; Tomas, M.; Kouznetsov, V.;
Rubio, E. J. Org. Chem. 1994, 59, 3699; (f) Merlin, P.;
Braekman, J. C.; Daloze, D. Tetrahedron 1991, 47,
3805.
4. Kim, J. H.; Hart, H. T.; Stevens, J. F. Phytochemistry
1996, 41, 1319.
5. (a) Weiland, H.; Koschara, K.; Dane, E.; Renz, J.;
Schwarze, W.; Linde, W. Liebigs Ann. Chem. 1939, 540,
103; (b) Schopf, C.; Kauffmann, T.; Berth, P.; Bundschuh,
W.; Dummer, G.; Fett, H.; Habermehl, G.; Wieters, E.;
Wust, W. Liebigs Ann. Chem. 1957, 608, 88.
6. Gershwin, M. E.; Terr, A. Clin. Rev. Allergy Immunol.
1996, 14, 241.
16. (a) Stragies, R.; Blechert, S. J. Am. Chem. Soc. 2000, 122,
9584; (b) Yue, C.; Gauthier, I.; Royer, J.; Husson, H.-P. J.
Org. Chem. 1996, 61, 4949, and references cited therein; (c)
Devijver, C.; Macours, P.; Braekman, J. C.; Daloze, D.;
Pasteels, J. M. Tetrahedron 1995, 51, 10913; (d) Yue, C.
Y.; Royer, J.; Husson, H.-P. J. Org. Chem. 1990, 55, 1140.
17. (a) Yuxin, P.; Katja, B.; Emilie, B.; Lars, H.; Fredrik, L.;
Christina, M. Eur. J. Org. Chem. 2005, 13, 2835; (b)
Argouarch, G.; Stones, G.; Gibson, C. L.; Kennedy, A.
R.; Sherrington, D. C. Org. Biomol. Chem. 2003, 1, 4408,
and references cited therein.
18. (a) Prasad, B. A. B.; Bisai, A.; Singh, V. K. Org. Lett.
2004, 6, 4829; (b) Pandey, M. K.; Bisai, A.; Pandey, A.;
Singh, V. K. Tetrahedron Lett. 2005, 46, 5039.
19. For the synthesis of (S)-N-tosyl-coniine, see: (a) Eskici,
M.; Gallagher, T. Synlett 2000, 1360; For (R)-N-tosyl-
coniine, see: (b) Kim, Y. H.; Choi, J. Y. Tetrahedron Lett.
1996, 37, 5543.
7. For a review on syntheses of sedum and related alkaloids,
see: (a) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58, 5957;
For a general account on the asymmetric synthesis of
substituted piperidines, see: (b) Bailey, P. D.; Millwood,
P. A.; Smith, P. D. Chem. Commun. 1998, 633.
8. For selected syntheses of chiral sedamine, see: (a) Yadav,
J. S.; Reddy, M. S.; Rao, P. P.; Prasad, A. R. Tetrahedron
Lett. 2006, 47, 4397; (b) Bates, R. W.; Boonsombat, J.
Org. Biomol. Chem. 2005, 3, 520; (c) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2004,
126, 3734; (d) Angoli, M.; Barilli, A.; Lesma, G.; Passa-
rella, D.; Riva, S.; Silvani, A.; Danieli, B. J. Org. Chem.
2003, 68, 9525; (e) Cossy, J.; Willis, C.; Bellosta, V.;
Bouzbouz, S. J. Org. Chem. 2002, 67, 1982, and references
cited therein.
9. For syntheses of (ꢀ)-allosedamine, see: (a) Raghavan, S.;
Rajender, A. Tetrahedron Lett. 2004, 60, 5059; (b) Felpin,
F.-X.; Lebreton, J. Tetrahedron Lett. 2002, 43, 225; (c)
Oppolzer, W.; Deerberg, J. O. Helv. Chim. Acta 1994, 77,
554.
20. Takahata, H.; Kubota, M.; Momose, T. Tetrahedron Lett.
1997, 38, 3451.