A new method for the demetallation of tricarbonyliron diene complexes by total hydrogenation with Raney nickel. Application to a very short synthesis of (+)-[6]-gingerdiol

Article abstract of DOI:10.1016/S0040-4039(01)01263-1

Demetallation of tricarbonyliron diene complexes is rapidly achieved by treatment with freshly prepared Raney nickel. The ligands which are totally hydrogenated during the decomplexation are easily isolated in high yields, without racemization, if chiral.

Full text of DOI:10.1016/S0040-4039(01)01263-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6401–6404
A new method for the demetallation of tricarbonyliron diene
complexes by total hydrogenation with Raney nickel. Application
to a very short synthesis of (+)-[6]-gingerdiol
Michel Franck-Neumann,* Philippe Geoffroy, Paul Bissinger and Sylvie Adelaide
Laboratoire de Chimie Organique Synthe´tique, associe´ au CNRS, Institut de Chimie, Universite´ Louis Pasteur,
1, rue Blaise Pascal, F-67000 Strasbourg, France
Received 21 May 2001; accepted 12 July 2001
Abstract—Demetallation of tricarbonyliron diene complexes is rapidly achieved by treatment with freshly prepared Raney nickel.
The ligands which are totally hydrogenated during the decomplexation are easily isolated in high yields, without racemization, if
chiral. A very short and efficient synthesis of (+)-(3R,5S)-[6]-gingerdiol, based on this novel decomplexation procedure, which also
allows the synthesis of the other diastereomers/enantiomers, is described. © 2001 Elsevier Science Ltd. All rights reserved.
Tricarbonyliron complexes of four-electron organic lig-
ands are a useful class of compounds for application to
organic synthesis. By coordination to the Fe(CO)3 frag-
ment, various ligands are greatly stabilized, allowing
their use in further transformations and, more gener-
ally, the complexation results in significant changes in
the reactivity (protection, but sometimes also activa-
tion). Another important aspect in p-coordination
chemistry, is the fact that prochiral ligands give chiral
complexes and that such non racemic complexes are
relatively easy to obtain. Many reactions of organic
tricarbonyliron complexes are highly diastereoselective,
and the diastereomers obtained are, in general, easy to
separate. The stoichiometric use of such complexes
appears therefore very attractive for the synthesis of
enantiomerically pure compounds. Now, for the synthe-
sis of purely organic molecules, one of the last steps is
always a decomplexation reaction, where the metal is
cleaved from the organic fragment.
This is usually achieved by oxidation1 with liberation of
the ligand without structural changes. Another possibil-
ity is to liberate the ligand by an exchange reaction, in
general with a phosphine,2 and recently, a mild
demetallation method based on
a photolytically
induced ligand exchange, followed by oxidation with
air, was shown to be useful for the cleavage of very
reactive free ligands.3 A completely different method
H2
OR
OR
OR
Pd / C (10%)
OR
Fe(CO)3
Fe(CO)3
OBn
OBn
1 ( R = H )
2 ( R = Ac)
H2, 1 bar, EtOAc, 20°C, 16 h
H2, 10 bars, EtOH, 20°C, 16 h
93% 1 recovered
99% 2 recovered
OAc OAc
OH
Raney Ni
EtOH, 20°C
OAc
OAc
Fe(CO)3
quant.
OBn
3
2
Scheme 1.
* Corresponding author. Tel.: 33-(0)3.90.24.16.75; fax: 33-(0)3.88.60.42.48; e-mail: franckneu@chimie.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01263-1

6402
M. Franck-Neumann et al. / Tetrahedron Letters 42 (2001) 6401–6404
for cleavage of the metal is photodecomplexation, by
irradiation in acetic acid, of functionalized complexes
of four-electron ligands. In this case, the four-electron
ligand is not obtained unchanged, but is hydrogenated
to an alkene, more or less regioselectively4,5 depending
on the substituents.6 This photoreductive decomplexa-
tion, which is useful for the efficient synthesis of decon-
jugated enones and esters from dienone and dienoic
ester complexes,4 and of chiral unsaturated alcohols,5 is
particularly interesting for complexes of ligands such as
cyclobutadienes or trimethylenemethanes, where the
simple oxidative decomplexation would lead to hyper-
reactive species and unwanted secondary reactions (iso-
merizations, polymerizations, cycloadditions, etc.).
On the contrary, when freshly prepared Raney nickel
W-2, from the aluminium–nickel alloy,9 was used,
debenzylation occurred, but with decomplexation and
hydrogenation of the ligand. Finally, we found that this
result was also obtained without gaseous hydrogen,
when an excess of a freshly prepared ethanol slurry of
Raney nickel was used (ca. 10 g, 50:50 alloy for 1 g
complex). The yield was nearly quantitative after a
short period of time (ca. 1 h), with a very simple
work-up (filtration and evaporation of the solvent), and
no epimerization was observed (2“3, single
diastereomer)10 (Scheme 1).
Of course, with this decomplexation method the chemi-
cally versatile diene pattern is lost, but this can be
advantageous for the synthesis of saturated target
molecules. This is well illustrated in the following very
short and efficient synthesis of (+)-[6]-gingerdiol.
We have now found a different method for the demetal-
lation of tricarbonyliron complexes, which makes use of
freshly prepared Raney nickel, with the result that the
cleaved ligands are completely hydrogenated.
The gingerols11 and gingerdiols11b,12 are important com-
ponents of the rhizome of ginger (Zingiber officinale
Roscoe). Several asymmetric syntheses of the major
component, (+)-[6]-gingerol (one asymmetric center),
have been previously reported,13 but to our knowledge,
this is not the case for the [6]-gingerdiols (two asymmet-
ric centers), obtained only by non stereoselective reduc-
tion of natural [6]-gingerol.12 Our synthesis is based on
a highly diastereoselective crossed aldol condensation
reaction using the silyl enol ether/TiCl4 method.
During our investigations on crossed aldol condensa-
tion reactions of (3,5-heptadien-2-one) tricarbonyliron,7
we used ortho-methoxybenzyl ethers for the protection
of b-hydroxyaldehydes. Deprotection was achieved suc-
cessfully by oxidation with DDQ (without decomplexa-
tion) and acidic cleavage of the acetal formed. The
unsubstituted benzyl ethers gave equally good results
for the aldol reaction, but we were unable to achieve
deprotection by the usual hydrogenolysis, since the
benzyl group was not cleaved when complex 1 was
submitted to catalytic hydrogenation8 at atmospheric
pressure with 10% palladium on carbon. Even after
treatment for 16 h with hydrogen at 10 bars, the
corresponding diacetate 2 was quantitatively recovered,
using the same catalyst. The same was true for Raney
nickel (commercial slurry in water) as catalyst.
In three simple steps, and an overall yield of nearly
70%, (+)-[6]-gingerdiol was obtained with a high ee
from the chiral heptadienone complex (+)-4,7 via the
silyl enol ether 5 prepared in situ, and benzyl protected
dihydroconiferyl aldehyde 6.14
CHO
Me3SiO
O
1)
MeO
OBn
6
(S)
(S)
O
(S)
BnO
i
OH
Fe(CO)3
Fe(CO)3
OCH3
Fe(CO)3
2) TiCl4, CH2Cl2
-78°C
(R)
(+) - 7
95%
(isolated 86%)
and
5
(+) - 4
(S) epimer (+) - 8 (19 : 2)
OBn
OR OR
OH
(R) OH
(S)
ii
OCH3
OR
iii
(+) - 7
OCH3
Fe(CO)3
(5S)
(3R)
94%
>90%
(R)
(+) - 10 ( R = H)
(-) - 11 (R = Ac)
(-) - 9
iv
>90%
i: TMSOTf, Et3N, CH2Cl2, 0 to 20°C ii: KBH4, MeOH, 20°C
iii: Raney Ni, EtOH, 20°C iv: Ac2O, pyr, CH2Cl2, 20°C
Scheme 2.

M. Franck-Neumann et al. / Tetrahedron Letters 42 (2001) 6401–6404
6403
As in previous work with this complex,7 the aldol
reaction was highly diastereoselective (de ꢀ80%) and
the diastereomeric hydroxyketones obtained could be
easily separated by simple silica gel column chromato-
graphy ((+)-7, isolated 86%, [h]D=+138 (c 0.15, CHCl3);
(+)-8, isolated 9%). The completely stereoselective
reduction of the hydroxy ketone (+)-7 with KBH4
yielded the syn-diol (−)-9 (94%, [h]D=−6.0 (c 0.3,
CHCl3)), the reduction proceeding from the side oppo-
site to the metal, with the ‘enone’ entirely in the s-cis
conformation.7,15
Since the reduction of the ketocarbonyl group can also
be achieved with Raney nickel, the synthesis can be
shortened to two steps, by direct treatment of the
complexed hydroxyketones with Raney nickel, leading
from (+)-4 and 6 to a mixture of the gingerdiol (+)-10
(syn diol 3R,5S) and the corresponding anti diol
(3R,5R), which can be separated.12
When the aldol condensation was performed with the
lithium enolate of the complexed heptadienone (+)-4,
and not under Mukaiyama conditions, the reaction was
no longer highly stereoselective but showed the reversed
stereoselectivity ((+)-7 and (+)-8, 75%, 2:3), thus allow-
ing straightforward access to (+)-8 ([h]D=+143 (c 0.5,
CHCl3)). The other natural [6]-gingerdiol (anti diol
3S,5S) was thus also available, using the same reaction
sequence, in particular the novel demetallation and
hydrogenation reaction (reduction with KBH4: com-
plexed anti diol, 91%, [h]D=−7.0 (c 0.3, CHCl3); Raney
nickel reaction: anti 3S,5S gingerdiol, 80%, [h]D=−3.8
(c 0.13, CHCl3); lit. natural product12 [h]D=−1.2 (c 0.1,
CHCl3)). Obviously, the enantiomers of both natural
gingerdiols can be obtained in the same way, if one
starts from the enantiomeric heptadienone complex (−)-
4.
By treatment with freshly prepared Raney nickel, [6]-
gingerdiol (+)-10 was obtained as a single diastereomer
in one practical step (hydrogenolysis of the benzyl
ether, demetallation and total hydrogenation of the
diene fragment). For the purpose of simpler identifica-
tion, (+)-10 was acetylated to the triacetate (−)-11
(overall 82%, [h]D=−1.26 (c=0.4, CHCl3); lit.11b −0.8
(c 1, CHCl3); lit.12 −3.1 (c 0.3, CHCl3)) (Scheme 2).
Another very short synthesis of gingerdiol could be
achieved directly from commercially available coniferyl
aldehyde. Following acetylation, the cinnamaldehyde
derivative 12 was obtained, which underwent a crossed
aldol condensation with 5 to give primarily the ketol
(+)-13, readily isolated by simple silica gel column
chromatography (80%, [h]D=+111 (c 0.3, CHCl3)).
Diastereospecific reduction of (+)-13 with KBH4 pro-
ceeded with concomitant cleavage of the acetyl protect-
ing group16 to afford the syn-diol (−)-14 (94%,
[h]D=−6.3 (c 0.1, CHCl3)). Finally, treatment of (−)-14
with freshly prepared Raney nickel promoted both
decomplexation and hydrogenation of the diene sub-
structure and the styrenic double bond to give gingerdiol
(+)-10 (67%, [h]D=+11 (c 1, CHCl3); lit. natural
product12 +7.5 (c 1.5, CHCl3); lit. less polar reduction
product of (+)-(S)-[6]-gingerol12 +10.4 (c 1.8, CHCl3))
(Scheme 3).
A similar decomplexation with Raney nickel was
observed in model studies for the synthesis of macro-
lactin A by Donaldson and co-workers.17 However,
with the commercial aqueous slurry of Raney nickel
they used, the demetallation was very slow (stirring
over 48 h under hydrogen, 36% hydrogenated ligand
isolated).
Other decomplexation reactions by hydrogenolysis
(other main and spectator ligands and other metals) are
under investigation.
Me3SiO
OMe
AcO
12
1)
(S)
(S)
O
CHO
OH
Fe(CO)3
Fe(CO)3
2) TiCl4, CH2Cl2
(R)
-78°C
(+) -13
( isolated 62%)
and
(S) epimer
5
OCH3
OAc
9 : 1
OH OH
OH
(R)
(S)
ii
iii
OCH3
OH
(+)-13
OH
Fe(CO)3
(5S)
(3R)
94%
67%
(R)
(+) - 10
iii: Raney Ni, EtOH, 20°C
(-) - 14
ii: KBH4, MeOH, 20°C
OCH3
OH
Scheme 3.

6404
M. Franck-Neumann et al. / Tetrahedron Letters 42 (2001) 6401–6404
8. The poisoning effect of the Fe(CO)3 group on the cata-
Acknowledgements
lytic hydrogenation of CꢀC double bonds is well known.
See: (a) Weiss, E.; Hu¨bel, W. Chem. Ber. 1962, 95, 1179;
(b) Banthorpe, D. V.; Fitton, H. J. Chem. Soc., Perkin
Trans. 1 1973, 2051; (c) Barton, D. H. R.; Gunatilaka, A.
A. L.; Nakanishi, T.; Patin, H.; Widdowson, D. A.;
Worth, B. R. J. Chem. Soc., Perkin Trans. 1 1976, 821.
9. Mozingo, R. Org. Synth. 1941, 21, 15.
We are grateful to BASF and to Rhodia Organique for
gifts of Fe(CO)5 and TMSOTf.
References
10. Bissinger, P. Synthe`ses ste´re´ocontroˆle´es de de´rive´s polyhy-
droxyle´s chiraux utilisant des complexes die´niques de fer-
tricarbonyle; The`se de l’Universite´ Louis Pasteur:
Strasbourg, 1996.
11. (a) Connell, D. W.; Sutherland, M. D. Aust. J. Chem.
1969, 22, 1033; (b) Murata, T.; Shinohara, M.;
Miyamoto, M. Chem. Pharm. Bull. 1972, 20, 2291.
12. Kikuzaki, H.; Tsai, S.-M.; Nakatani, N. Phytochemistry
1992, 31, 1783.
13. (a) Enders, D.; Eichenauer, H.; Pieter, R. Chem. Ber.
1979, 112, 3703; (b) Baraldi, P. G.; Moroder, F.; Pollini,
G. P.; Simoni, D.; Barco, A.; Benetti, S. J. Chem. Soc.,
Perkin Trans. 1 1982, 2983; (c) Annunziata, R.; Cardani,
S.; Gennari, C.; Poli, G. Synthesis 1984, 702; (d)
Cinquini, M.; Cozzi, F.; Gilardi, A. J. Chem. Soc., Chem.
Commun. 1984, 551; (e) Legall, T.; Lellouche, J. P.;
Beaucourt, J. P. Tetrahedron Lett. 1989, 30, 6521; (f)
Solladie, G.; Ziani-Cherif, C. J. Org. Chem. 1993, 58,
2181; (g) Solladie, G.; Ghiatou, N. Bull. Soc. Chim. Fr.
1994, 131, 575.
1. With FeCl3, Ce(NH4)2(NO3)6, CuCl2 or Pb(OAc)4, see:
(a) Emerson, G. F.; Mahler, J. E.; Kochhar, R.; Pettit, R.
J. Org. Chem. 1964, 29, 3620; (b) Holmes, J. D.; Pettit, R.
J. Am. Chem. Soc. 1963, 85, 2531; (c) Thompson, D. J. J.
Organomet. Chem. 1976, 108, 381; (d) Brener, L.;
McKennis, J. S.; Pettit, R. Org. Synth. 1976, 55, 43. With
amine N-oxides or H2O2/NaOH, see: (e) Shvo, Y.;
Hazum, E. J. Chem. Soc., Chem. Commun. 1974, 336; (f)
Franck-Neumann, M.; Heitz, M. P.; Martina, D. Tetra-
hedron Lett. 1983, 24, 1615; cf. also: (g) Davies, S. G. J.
Organomet. Chem. 1979, 179, C5.
2. Manuel, T. A.; Stone, F. G. A. J. Am. Chem. Soc. 1960,
82, 366.
3. Kno¨lker, H. J.; Goesmann, H.; Klauss, R. Angew. Chem.
1999, 111, 727; Angew. Chem., Int. Ed. 1999, 38, 702.
4. Franck-Neumann, M.; Martina, D.; Brion, F. Angew.
Chem. 1978, 90, 736; Angew. Chem., Int. Ed. Engl. 1978,
17, 690.
5. Franck-Neumann, M.; Martina, D.; Heitz, M. P. Tetra-
hedron Lett. 1989, 30, 6679.
14. Obtained in four steps, overall yield 50%, or in five steps,
overall yield 59%,13f from the commercial ferulic acid.
15. Clinton, N. A.; Lillya, C. P. J. Am. Chem. Soc. 1970, 92,
3058.
16. Cf. Quick, J.; Crelling, J. K. J. Org. Chem. 1978, 43, 155.
17. Ba¨rmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang,
Z.; Donaldson, W. A. Tetrahedron 2000, 56, 2283.
6. A similar reductive demetallation was observed using
DBU in THF/H2O, without photochemical activation, in
the case of tricarbonyliron complexes of exo-
dimethylene-7-oxanorbornane complexes. See: Araki, S.;
Bonfantini, E.; Vogel, P. Helv. Chim. Acta 1988, 71, 1354.
7. Franck-Neumann, M.; Bissinger, P.; Geoffroy, P. Tetra-
hedron Lett. 1997, 38, 4469.
.