An expeditious entry to carbohydrate derived enynes and ene-diynes via Sonogashira coupling of halo-exo-glycals

Article abstract of DOI:10.1016/j.tetlet.2004.06.079

Sonogashira coupling of bromo or iodo-exo-glycals, readily prepared from 1-exo-methylene furanoses and pyranoses, provides an efficient entry to furanose- and pyranose-derived enyne and ene-diyne moieties found in biologically relevant structures.

Full text of DOI:10.1016/j.tetlet.2004.06.079

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6307–6310
An expeditious entry to carbohydrate derived enynes and
ene-diynes via Sonogashira coupling of halo-exo-glycals
*
*
´ ´ ´ ´
Ana M. Gomez, Ana Pedregosa, Aitor Barrio, Serafın Valverde and J. Cristobal Lopez
´ ´
Instituto de Quımica Organica General, Natural Products, C.S.I.C., Juan de la Cierva 3, 28006 Madrid, Spain
Received 30 April 2004; accepted 18 June 2004
Available online 10 July 2004
Abstract—Sonogashira coupling of bromo or iodo-exo-glycals, readily prepared from 1-exo-methylene furanoses and pyranoses,
provides an efficient entry to furanose- and pyranose-derived enyne and ene-diyne moieties found in biologically relevant structures.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Enyne is an important structural unit for biologically ac-
tive organic compounds, including anticancer antibiot-
ics,1 natural products,2 and also for new functional
materials.3 In this context, tetrahydrofuran containing
exocyclic enyne and ene-diyne moieties (e.g., 1, Fig. 1)
have been found as substructures in natural products
(2,4 3,4a 4,5 5,6 6,7) or have been synthesized to evaluate
their potential biological activities8 (7, 8). Our group
has recently been interested in the synthesis of sub-
stituted furanosidic exo-glycals (2,5-anhydro-1-deoxy-
hex-1-enitols),9,10 and in this Letter, we wish to report
(a) that Sonogashira coupling11 of carbohydrate
derived halo-exo-glycals, for example, 9, with terminal
alkynes can be successfully applied for the prepara-
tion of furanosidic and pyranosidic enynes, 10a and
10b, respectively, and (b) the preparation of furanose
and pyranose derived ene-diynes (10a,b R=„–Ph,
Scheme 1).
O
n
n= 1,2
1
O
RO
O
O
O
O
During the course of this work we have illustrated the
potential of the method with the preparation of substi-
tuted exo-glycals 17–22 from D-glucofuranose (11a,10
11b10) and D-galacto and D-glucopyranose-derived
halo-exo-glycals (12,12 1312) (See Table 1, Fig. 2).
O
O
3
2
R=
O
O
O
O
O
The coupling reactions of halo-exo-glycals 11a,b, 12,
and 13, with trimethylsilyl acetylene (14), 1-dodecyne
(15) and phenyl acetylene (16) took place smoothly to
HO
OH
5
4
Bn
O
O
O
O
O
O
R
Ph
R
Sonogashira
Coupling
RO
R
RO
6
7
8
Br, I
O
O
R= H, Bn
n
n
Figure 1. Enyne and ene-diyne derived tetrahydrofurans.
R
OR
OR
RO
RO
10
9
Keywords: exo-Glycals; Sonogashira; Enyne; Ene-diyne.
*
a n= 1; b n= 2
Corresponding authors. Tel.: +34-91-5622900; fax: +34-91-
5644853; e-mail: clopez@iqog.csic.es
Scheme 1. Synthesis of furanosidic enynes from halo-exo-glycals.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.079

´
A. M. Gomez et al. / Tetrahedron Letters 45 (2004) 6307–6310
6308
Table 1. Preparation of enynes by reaction of halo-exo-glycals 11–13 with terminal alkynes 14–16
Entry
i
Glycal
Alkyne
Product
Yield (%)
87a
Si(CH )
Si(CH3)3
(CH2)9-CH3
Ph
3 3
O
O
11a
O
14
OAc
OAc
OAc
AcO
17
O
O
(CH ) -CH
2 9
3
93a
O
ii
11a
15
AcO
18
O
O
Ph
88a
O
iii
11a
16
AcO
19
iv
v
11b
11b
11b
12
14
15
16
14
17
18
19
––
90a
96a
91a
0a
vi
viii
Si(CH3)3
BnO
BnO
BnO
O
ix
12
14
84b
OBn
20
x
12
12
16
16
––
0a
Ph
BnO
BnO
BnO
O
xi
92b
OBn
OBn
21
Si(CH3)3
BnO
BnO
BnO
O
xii
13
14
84b
22
a Et2NH, CuI (5%), Pd(PPh3)2Cl2 (10%).
b Et2NH, CuI (10%), Pd(PPh3)4 (5%).
give high yields of the corresponding substituted exo-
glycals.13,14 Several aspects of these reactions, however,
deserve further comment: (a) the use of iodo-exo-glycals,
compared with that of bromo-exo-glycals, resulted in
slightly higher yields of substituted exo-glycals (Table
1, compare entries (i)–(iii) with (iv)–(vi)); (b) furanosi-
dic halo-derivatives underwent coupling reactions
under standard Sonogashira–Hagihara conditions
(Pd(PPh3)2Cl2, Et2NH, CuI, THF);15 (c) the corre-
sponding pyranosidic iodo-derivatives, however, did
O
BnO
BnO
BnO
O
O
I
I
X
O
O
BnO
BnO
OBn
BnO
OBn
OAc
AcO
12
13
11a R= Br
11b R= I
Figure 2. Halo-exo-glycals starting materials.

´
A. M. Gomez et al. / Tetrahedron Letters 45 (2004) 6307–6310
6309
Acknowledgements
Ph
Ph
R
BnO
BnO
This research was supported with funds from the Direc-
´
1330, BQU2001-0582, and PPQ2003-00396). A.P.
thanks Janssen-Cilag for financial support. A.B. thanks
Janssen-Cilag and Consejo Superior de Investigaciones
BnO
BnO
O
I
cion General de Ensen˜anza Superior (Grants: PPQ2000-
24
O
Pd(PPh )
CuI, Et NH
OBn
2
3 4
BnO
BnO
OBn
89%
´
Cientıficas for a fellowship.
25
K2CO3
95%
22 R= Si(CH3)3
23 R= H
Ph
References and notes
Ph
1. (a) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992,
25, 497; (b) Maier, M. E. Synlett, 1995, 13; (c) Grissom, J.
W.; Gunawardena, G. U.; Klingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453.
O
O
26
O
11b
Pd(PPh )
CuI, Et NH
2
3 4
2. (a) Kusumi, T.; Ohtani, I.; Nishiyama, K.; Kakisawa, H.
Tetrahedron Lett. 1987, 28, 3981; (b) Kuhnt, D.; Anke, T.;
Besl, H.; Bross, M.; Herrmann, R.; Mocek, U.; Steffan, B.;
Steglich, W. J. Antibiot. 1990, 43, 1413; (c) Trowitsch-
Kienast, W.; Forche, E.; Wray, V.; Riechenbach, H.;
Hunsmann, G.; Ho¨fle, G. Liebigs Ann. Chem., 1992, 659;
(d) Ohta, T.; Uwai, K.; Kikuchi, R.; Nozoe, S.; Oshima,
Y.; Sasaki, K.; Yoshizaki, F. Tetrahedron 1999, 55, 12087.
3. (a) Boldi, A. M.; Anthony, J.; Gramlich, V.; Knobler, C.
B.; Boudon, C.; Gisselbrecht, J.-P.; Gross, M.; Diederich,
F. Helv. Chim. Acta 1995, 78, 779; (b) Hynd, G.; Jones, G.
B., II; Plourde, G. W., II; Wright, J. M. Tetrahedron Lett.
1999, 40, 4481; (c) Shimada, S.; Masaki, A.; Hayamizu,
K.; Matsuda, H.; Okada, S.; Nakanishi, H. Chem. Lett.
2000, 11, 1128; (d) Ciulei, S. C.; Tykwinski, R. R. Org.
Lett. 2000, 2, 3607.
4. Isolation: (a) Bohlmann, F.; Ates (Go¨ren), N.; Jakupovic,
J.; King, R. M.; Robinson, H. Phytochemistry 1982, 21,
2691; Biological studies: (b) Nakamura, Y.; Ohto, Y.;
Murakami, A.; Jiwajinda, S.; Ohigashi, H. J. Agric. Food
Chem. 1998, 46, 5031; (c) Nakamura, Y.; Murakami, A.;
Ohigashi, H. Asian Pacific J. Cancer Prev. 2000, 1, 115.
5. Ahmed, A. A.; Abou Elela, M. A. Phytochemistry 1999,
51, 551.
OAc
AcO
83%
27
Scheme 2. Synthesis of pyrano- and furanosidic ene-diynes.
not undergo any coupling reaction under the above
mentioned conditions and required the presence of
Pd(0)16,17 (Pd(PPh3)4, Et2NH, CuI, THF), rather than
Pd(II), as catalyst18 (Table 1, compare entries (viii)
and (x) with entries (ix), (xi)), (d) the coupling reactions,
which are described to take place with retention of the
configuration,19 afforded one single stereoisomeric exo-
glycal from the single starting halo-exo-glycal.
The synthesis of ene-diyne moieties was next studied. An
approach based on, the sometimes unreliable,16 sp–sp
Sonogashira coupling20 was first evaluated (Scheme 2).
Accordingly, terminal alkyne 23 (readily prepared from
enyne 22 by desilylation) was treated (Pd(PPh3)4, CuI,
Et2NH) with alkynyl iodide 2421 to yield ene-diyne 25.
In order to assure the feasibility of the synthesis of
ene-diynes we decided to investigate an alternative ap-
proach for the synthesis of furanose ene-diynes. In this
context we found that ene-diyne 27 could be obtained
in excellent yield by Sonogashira coupling of iodo-exo-
glycal 11 with diyne 26.22
6. Tan, R. X.; Jakupovic, J.; Bohlmann, F.; Jia, Z. J.;
Huneck, S. Phytochemistry 1991, 30, 583.
´
7. Dıaz, J. G.; Barba, B.; Herz, W. Phytochemistry 1994, 36,
703.
8. (a) Tam, T. F.; Spencer, R. W.; Thomas, E. M.; Copp, L.
J.; Krantz, A. J. Am. Chem. Soc. 1984, 106, 6849; (b)
Spencer, R. W.; Tam, T. F.; Thomas, E.; Robinson, V. J.;
Krantz, A. J. Am. Chem. Soc. 1986, 108, 5589.
´
´
9. Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C.
In summary, we have reported an efficient strategy for
the preparation of synthetically useful carbohydrate de-
rived ene-ynes by Sonogashira coupling of halo-exo-gly-
cals and terminal alkynes. Furanose derivatives undergo
the coupling reaction under standard Sonogashira–
Hagihara conditions whereas pyranose derivatives re-
quired the use of Pd(0) as catalyst. Finally, two conver-
gent approaches for the preparation of the ene-diyne
moiety, present in several natural products, have been
disclosed. The first approach involved Sonogashira cou-
pling of halo-exo-glycals23,24 with a terminal alkyne fol-
lowed by sp–sp Sonogashira coupling of the ensuing
enyne with a iodo-alkyne. The second, and more direct,
strategy implied direct Sonogashira coupling of a iodo-
exo-glycal with a terminal diyne. The use of these proto-
cols for the preparation of naturally occurring natural
products is underway in our laboratory and will be de-
scribed in due course.
Chem. Commun. 2002, 2022.
´
´
10. Gomez, A. M.; Danelon, G. O.; Pedregosa, A.; Valverde,
´
S.; Lopez, J. C. Chem. Commun. 2002, 2024.
11. Sonogashira, K. J. Organomet. Chem. 2002, 653, 46, and
references cited therein.
´
´
12. Gomez, A. M.; Pedregosa, A.; Valverde, S.; Lopez, J. C.
Tetrahedron Lett. 2003, 44, 6111.
13. For a recent review see: Taillefumier, C.; Chapleur, Y.
Chem. Rev. 2004, 104, 263.
14. Selected recent synthesis of substituted exo-glycals: (a)
Griffin, F. K.; Paterson, D. E.; Murphy, P. V.; Taylor, R.
J. K. Eur. J. Org. Chem., 2002, 1305; (b) Yang, W.-B.;
Yang, Y.-Y.; Gu, Y. F.; Wang, S.-H.; Chang, C.-C.; Lin,
C.-H. J. Org. Chem. 2002, 67, 3773; (c) Praly, J.-P.; Chen,
G.-R.; Gola, J.; Hetzer, G. Eur. J. Org. Chem., 2000, 2831;
(d) Xie, J.; Molina, A.; Czernecki, S. J. Carbohydr. Chem.
1999, 18, 481; (e) Lieberknecht, A.; Griesser, H.; Bravo, R.
D.; Colinas, P. A.; Grigera, R. J. Tetrahedron 1998, 54,
3159; (f) Belica, P. S.; Franck, R. W. Tetrahedron Lett.

´
A. M. Gomez et al. / Tetrahedron Letters 45 (2004) 6307–6310
6310
21
1998, 39, 8225; (g) Lakhrissi, M.; Chapleur, Y. Angew.
Chem., Int. Ed. 1996, 35, 750.
15. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467.
16. Negishi, E.-I.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
17. Alami, M.; Ferri, F.; Lisntrumelle, G. Tetrahedron Lett.
1993, 34, 6404.
18. For a recent overview on the Sonogashira reaction see:
Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
19. Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; VCH: Wein-
heim, 1998, Chapter 5, pp 206.
Enyne 18: ½aꢀD þ 23:4 (c 0.83, CHCl3), 1H NMR
(300MHz, CDCl3) d (ppm): 5.45 (s, 1H), 5.29 (d,
J=3.6Hz, 1H), 4.90 (s, 1H), 4.46 (dd, J=3.9, 7.9Hz,
1H), 4.32 (ddd, J=5.4, 6.3, 7.9Hz, 1H), 4.12 (m, 2H), 2.09
(s, 3H), 2.06 (s, 3H), 1.42 (s, 3H), 1.33 (s, 3H), 1.11 (m,
16H), 0.87 (t, 3H). 13C NMR (75MHz, CDCl3) d (ppm):
169.5, 169.3, 160.6, 109.8, 96.3, 86.0, 83.0, 75.1, 74.4, 74.3,
72.4, 67.2, 32.1, 29.8 (·2), 29.5, 29.4, 29.1, 28.9, 27.0, 25.5,
22.9, 21.1, 21.0, 20.0, 14.3. API-ES: 451.6 [M++1].
21
Enyne 19 : ½aꢀD þ 31:5 (c 0.9, CHCl3), 1H NMR (300MHz,
CDCl3) d (ppm): 7.32 (m, 5H), 5.54 (s, 1H), 5.37 (d,
J=4.0Hz, 1H), 5.17 (s, 1H), 4.58 (dd, J=4.0, 7.9Hz, 1H),
4.37 (ddd, J=5.3, 5.6, 7.8Hz, 1H), 4.18 (m, 2H), 2.12 (s,
3H), 1.47 (s, 3H), 1.37 (s, 3H). 13C NMR (75MHz,
CDCl3) d (ppm): 169.3, 169.2, 161.3, 131.4, 128.3, 128.1,
123.7, 109.8, 94.7, 85.4, 83.6, 83.3, 75.2, 74.2, 72.4, 67.0,
26.9, 25.4, 20.9, 20.8. API-ES: 401.2 [M++1], 423.3
[M++Na].
20. (a) Nielsen, M. B.; Utesch, N. F.; Moonen, N. N. P.;
Boudon, C.; Gisselbrecht, J.-P.; Concilio, S.; Piotto, S. P.;
Seiler, P.; Gunter, P.; Gross, M.; Diederich, F. Chem. Eur.
¨
J. 2002, 8, 3601; (b) Wityak, J.; Chan, J. B. Synth.
Commun. 1991, 21, 977.
21. Russo, M. V.; Sterzo, C. L.; Franceschini, P.; Biagini, G.;
Furlani, A. J. Organomet. Chem. 2001, 619, 49.
22. Diyne 26 was prepared, according to the synthetic Scheme
shown below according to: Dabdoub, M. J.; Baroni, A. C.
M.; Lenarda˜o, E. J.; Gianeti, T. R.; Hurtado, G. R.
Tetrahedron 2001, 57, 4271, Cadiot–Chodkiewicz coupling
reaction of bromo alkyne B and phenyl acetylene 16
yielded diyne C, which upon deprotection furnished
terminal alkyne 26.
21
Enyne 20: ½aꢀD þ 31:4 (c 1.0, CHCl3), 1H NMR (300MHz,
CDCl3) d (ppm): 7.41–7.25 (m, 20H), 5.24 (d, J=1.8Hz,
1H), 4.87 (d, J=11.4Hz, 1H), 4.71–4.42 (m, 7H), 4.35 (dd,
J=9.0, 1.8Hz, 1H), 4.03 (t, J=2.1Hz, 1H), 3.92 (dt,
J=6.3, 2.1Hz, 1H), 3.70 (d, J=6.3Hz, 2H), 3.62 (dd,
J=9.0, 2.1Hz, 1H), 0.16 (s, 9H); 13C NMR (75MHz,
CDCl3) d (ppm): 162.1, 138.4, 138.1, 137.9, 137.7, 128.4,
128.3, 128.2, 127.9 (·2), 127.7, 127.6, 127.5 (·2), 99.9,
98.7, 90.2, 81.6, 78.7, 76.5, 74.3, 74.1, 74.0, 73.5, 72.7,68.3,
0.0 (·3); API-ES: m/e: 633.3 [M+1]+.
Ph
OH
21
Enyne 21: ½aꢀD þ 33:9 (c 1.0, CHCl3), 1H NMR (300MHz,
OH
OH
Br2
KOH/H2O
Br
16
NaOH
CDCl3) d (ppm): 7.44–7.23 (m, 25H), 5.42 (d, J=1.5Hz,
1H), 4.89 (d, J=11.7Hz, 1H), 4.71–4.55 (m, 6H), 4.45 (d,
J=11.7Hz, 1H), 4.41 (dd, J=9.0, 1.0Hz, 1H), 4.07 (t,
J=2.0Hz, 1H), 3.99 (dt, J=6.0, 2.0Hz, 1H), 3.82–3.70 (m,
2H), 3.68 (dd, J=9.0, 2.0Hz, 1H); 13C NMR (75MHz,
CDCl3) d (ppm): 160.7, 138.3, 138.1, 138.0, 137.8, 131.4,
128.4, 128.3 (·2), 128.1 (·2), 127.9, 127.8, 127.7,
127.6 (·2), 127.5, 123.9, 93.6, 90.7, 84.4, 81.6, 78.9, 76.7,
74.3, 74.1,74.0, 73.5, 72.8, 68.8; API-ES: m/e: 659.3
[M+Na]+.
26
CuCl/NH2OH.HCl
BuNH2
Toluene
Ph
A
B
C
.
23. General procedure for the Sonogashira coupling reaction.
Method (a): To a thoroughly degassed (argon, 10min)
solution of halo-exo-glycal (0.17mmol) in Et2NH, were
added CuI (5%) and Pd(PPh3)2Cl2 (10%). The reaction
mixture was kept at room temperature with stirring for
5min. The appropriate terminal alkyne (1equiv) dissolved
in Et2NH (3mL) was then added via cannula. The reaction
was then stirred at room temperature until complete
disappearance of the starting material. The solution was
treated with H2O and extracted with ethyl acetate (EtOAc).
The organic layer was then dried (magnesium sulfate) and
evaporated to furnish a residue, which was purified by flash
chromatography using hexane–EtOAc mixtures as eluant.
Method (b): To a thoroughly degassed (argon, 10min)
solution of iodo-exo-glycal (0.1mmol) in Et2NH (4mL/
mmol) were added successively Pd(PPh3)4 (5lmol), CuI
(0.01mmol) and the corresponding alkyne (1.1equiv,
0.11mmol). The reaction was then stirred at room temper-
ature until complete disappearance of the starting material
(1–2h). The solution was diluted with ethyl acetate and
washed successively with saturated NH4Cl and brine. The
organic layer was dried (magnesium sulfate) and evapo-
rated to furnish a residue, which was purified by flash
chromatography using hexane–EtOAc mixtures as eluant.
21
Enyne 22: ½aꢀD þ 33:6 (c 1.2, CHCl3), 1H NMR (300MHz,
CDCl3) d (ppm): 7.42–7.19 (m, 20H), 5.00 (s, 1H), 4.80–
4.51 (m, 8H), 4.18 (ddd, J=9.7, 3.1, 2.4Hz, 1H), 3.91
(d, J=4.1Hz, 1H), 3.89–3.79 (m, 4H), 0.18 (s, 9H); 13C
NMR (75MHz, CDCl3) d (ppm): 159.8, 138.3, 138.0,
137.8, 137.4, 128.4, 128.3, 128.2, 127.9, 127.8, 127.7, 127.6,
127.5, 99.7, 98.7, 89.8, 83.6, 77.6 (·2), 77.5, 73.8 (·2),
73.0, 71.4, 68.4, 0.4 (·3); API-ES: m/e: 633.3 [M+1]+,
655.3 [M+Na]+.
21
Ene-diyne 25: ½aꢀD þ 3:0 (c 1.0, CHCl3), 1H NMR
(300MHz, CDCl3) d (ppm): 7.71–7.26 (m, 25H), 5.04 (d,
J=0.7Hz, 1H), 4.80–4.53 (m, 8H), 4.24–4.18 (m, 1H),
3.95–3.80 (m, 5H); 13C NMR (75MHz, CDCl3) d (ppm):
162.7, 138.3, 137.9, 137.7, 137.2, 132.3, 128.8, 128.5, 128.4,
128.3 (·2), 128.0, 127.9, 127.8 (·2), 127.7 (·2), 127.6,
127.4, 122.2, 88.5, 83.4, 81.5, 77.8, 77.7, 77.4 (·2), 77.1,
74.6, 73.8, 73.5, 73.1, 71.6, 68.1; API-ES: m/e: 683.3
[M+Na]+.
21
Ene-diyne 27: ½aꢀD þ 11:5 (c 0.6, CHCl3), 1H NMR
(300MHz, CDCl3) d (ppm): 7.42 (m, 5H), 7.32 (m, 5H),
5.50 (s, 1H, J=0.98Hz), 5.34 (dd, 1H, J=0.98Hz,
J=3.7Hz, H-3), 5.05 (s, 1H), 4.53 (dd, 1H, J=3.7,
8.5Hz), 4.34 (ddd, 1H, J=4.6, 5.4, 8.3Hz, H-5), 4.19
(dd, 1H, J=5.6, 8.9Hz), 4.13 (dd, 1H, J=4.6, 8.8Hz), 2.13
(s, 3H, Me),2.11 (s, 3H), 1.45 (s, 3H), 1.35 (s 3H). 13C
NMR (75MHz, CDCl3) d (ppm): 169.5, 169.3, 164.9,
132.6, 129.3, 128.6, 122.2, 110.0, 84.3, 83.9, 82.4, 78.9,
76.3, 75.3, 74.4, 74.1, 72.3, 67.3, 27.1, 25.5, 21.1, 20.1. API-
ES: 425.2 [M++1].
21
24. Data for selected compounds: Enyne 17: ½aꢀD þ 21:0 (c 0.15,
CHCl3), 1H NMR (200MHz, CDCl3) d (ppm): 5.48 (d,
J=1.1Hz, 1H), 5.33 (dd, J=1.1, 3.6Hz, 1H), 4.98 (s, 1H),
4.57 (dd, J=3.6, 7.6Hz, 1H), 4.36 (ddd, J=5.3, 5.8, 7.6Hz,
1H), 4.15 (m, 2H), 2.12 (s, 3H), 2.09 (s, 3H), 1.46 (s, 3H),
1.37 (s, 3H), 0.20 (s, 9H). 13C NMR (50MHz, CDCl3) d
(ppm): 169.3, 169.1, 162.5, 109.7, 98.9, 85.2, 83.2, 82.2,
75.1, 74.1, 72.3, 66.7, 26.8, 25.5, 20.9 (·2), 0.0. API-ES:
397 [M++1], 419.0 [M++Na].