Desymmetrization of hydrazinocyclohexadienes: A new approach for the synthesis of polyhydroxylated aminocyclohexanes

Article abstract of DOI:10.1021/ol900779v

Hydrazlnocyclohexadlenes, easily prepared by an ene-reactlon between commercially available azodlcarboxylate reagents and cyclohexadlene, are Interesting substrates for desymmetrlzatlon reactions. Under Sharpless asymmetric dihydroxylation conditions, the

Full text of DOI:10.1021/ol900779v

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2912-2915
Desymmetrization of
Hydrazinocyclohexadienes: A New
Approach for the Synthesis of
Polyhydroxylated Aminocyclohexanes
Gauthier Errasti,† Cyrille Kounde´,† Olivier Mirguet,‡ Thomas Lecourt,† and
Laurent Micouin*,†
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a` l’UniVersite´
Paris Descartes, Faculte´ des Sciences Pharmaceutiques et Biologiques,
4 aV de l’ObserVatoire, 75270 Paris cedex 06, France, and CEDD-Laboratoire
GlaxoSmithKline, 25-27 aVenue du Que´bec, 91951 Les Ulis, France
laurent.micouin@parisdescartes.fr
Received April 10, 2009
ABSTRACT
Hydrazinocyclohexadienes, easily prepared by an ene-reaction between commercially available azodicarboxylate reagents and cyclohexadiene,
are interesting substrates for desymmetrization reactions. Under Sharpless asymmetric dihydroxylation conditions, they can lead efficiently
to several chiral building blocks as well as advanced precursors of biologically active compounds.
Desymmetrization of cyclohexa-1,4-dienes is among the
most efficient strategies to prepare in a few synthetic
transformations a large variety of polyfunctional cyclohex-
anes in a stereoselective manner.1 The synthetic potential
of this approach is due in part to the great number of
asymmetric transformations available to convert cyclohexa-
dienes into valuable intermediates and also to the availability
of the racemic starting material. These compounds are
typically prepared by a Birch reduction or reductive alky-
lation of aromatic compounds, leading to the symmetrical
cyclohexa-1,4-dienes bearing a tertiary or quaternary prochiral
center.2 An elegant variant of this strategy based on metalated
cyclohexadienes has also been recently proposed by Studer
and co-workers.3
(2) (a) Angelaud, R.; Landais, Y. J. Org. Chem. 1996, 61, 5202. (b)
Angelaud, R.; Babot, O.; Charvat, T.; Landais, Y. J. Org. Chem. 1999, 64,
9613. (c) Landais, Y.; Zekri, E. Eur. J. Org. Chem. 2002, 4037. (d) Lebeuf,
R.; Robert, F.; Landais, Y. Org. Lett. 2005, 7, 4557. (e) Lebeuf, R.; Robert,
F.; Schenk, K.; Landais, Y. Org. Lett. 2006, 8, 4755. (f) Crich, D.;
Krishnamurthy, V. Tetrahedron 2006, 62, 6830. (g) Beniazza, R.; Dunet,
J.; Robert, F.; Schenk, K.; Landais, Y. Org. Lett. 2007, 9, 3913. (h) Butters,
M.; Elliot, M. C.; Hill-Cousins, J.; Paine, J. S.; Walker, J. K. E. Org. Lett.
2007, 9, 3635.
† University Paris Descartes, CNRS.
‡ GlaxoSmithKline.
(1) (a) Abd Rahman, N.; Landais, Y. Curr. Org. Chem. 2002, 6, 1369.
(b) Studer, A.; Schleth, F. Synlett 2005, 3033.
10.1021/ol900779v CCC: $40.75
Published on Web 05/26/2009
 2009 American Chemical Society

In our ongoing work on the use of meso hydrazines for
the stereoselective synthesis of polyfunctional amino or
hydrazinocyclopentanes,4 we were interested to access the
corresponding cyclohexanic homologues via a similar strat-
egy. In this context, hydrazinocyclohexadienes 1 seemed to
be attractive substrates (Figure 1). These compounds are
that dihydroxylated compounds 3a,b could be obtained under
Sharpless biphasic conditions, without significant aromati-
zation or oxidative cleavage. The dihydroxylation reaction
proved to be fully diastereoselective, leading to the anti
diastereomers (Table 1). Enantiomeric excesses were in the
Table 1. Asymmetric Dihydroxylation of Dienes 1a,b
Figure 1. Hydrazino- or silylated dienes for desymmetrization
studies.
R ) tBu, 3a
R ) Bn, 3b
entry
ligand
yield (%)a ee (%)b yield (%)a ee (%)c
indeed readily prepared on multigram quantities by a nearly
quantitative solvent-free ene-reaction between cyclohexadi-
ene and commercial azodicarboxylates, as first reported in
the early 1960s.5 They can be considered as nitrogenated
analogues of silylated dienes 2, known to be excellent
precursors for the synthesis of aminocyclitols since the now
classical pioneering work of Landais and co-workers in this
field.
1
2
3
4
5
6
(DHQ)2AQN
(DHQD)2AQN
(DHQ)2PYR
(DHQD)2PYR
(DHQ)2PHAL
(DHQD)2PHAL
58
62
32
45
40
69d
35
45
26
14
41
55d
44
52
40
37
44
43
35
50
24
16
41
47
a Isolated yield. b Determined by chiral HPCL analysis. c Determined
by chiral HPCL analysis hydrogenolysis and acetylation. d Reaction
conducted on a 20 g scale.
Herein, we outline the desymmetrization of substrates 1
and their subsequent transformations as a new entry to the
frequently encountered aminocyclohexanediol framework.6
Compounds 1a,b were prepared as previously reported and
were obtained as stable solids on a large (20-30 g) scale
(Scheme 1).
range of those obtained from silylated dienes 2, the best
results beeing obtained with (DHQD)2PHAL ligand and
compound 1a (entry 6).
Interestingly, enantiomerically pure hydrazinodiol 3a can
be obtained at this stage by recrystallization in toluene, thus
preventing the problems of enantiomeric purity encountered
in the silylated series. As the desymmetrization step can be
conducted on a large scale (20 g), this new route enables
the preparation of a large amount of enantiomerically pure
compound 3a.
Scheme 1. Solvent-Free Synthesis of Dienes 1a,b
The absolute configuration of compound 3a was estab-
lished by chemical correlation (Scheme 2). Thus, compound
Scheme 2
.
Determination of Absolute Configuration of 3a by
Asymmetric dihydroxylation of these substrates was then
investigated.7 Despite structural analogy between compounds
1 and 2, the stability of hydrazines 1 under oxidative
conditions was unknown.8 We were therefore pleased to see
Chemical Correlation
(3) (a) Schleth, F.; Studer, A. Angew. Chem., Int. Ed. 2004, 43, 313.
(b) Schleth, F.; Vogler, T.; Harms, K.; Studer, A. Chem.sEur. J. 2004, 10,
4171. (c) Maji, M. S.; Fro¨hlich, R.; Studer, A. Org. Lett. 2008, 10, 1847.
(4) (a) Perez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson,
H.-P.; Gougeon, S.; Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George,
P. J. Org. Chem. 2002, 67, 3522. (b) Perez Luna, A.; Bonin, M.; Micouin,
L.; Husson, H.-P. J. Am. Chem. Soc. 2002, 124, 12098. (c) Perez Luna, A.;
Cesario, M.; Bonin, M.; Micouin, L. Org. Lett. 2003, 5, 4771. (d)
Bunlaksananusorn, T.; Perez Luna, A.; Bonin, M.; Micouin, L.; Knochel,
P. Synlett 2003, 2240. (e) Alexakis, A.; Polet, D.; Bournaud, C.; Bonin,
M.; Micouin, L. Tetrahedron: Asymmetry. 2005, 16, 3672. (f) Bournaud,
C.; Lecourt, T.; Micouin, L.; Me´liet, C.; Agbossou-Niedercorn, F. Eur. J.
Org. Chem. 2008, 2298. (g) Bournaud, C.; Falciola, C.; Lecourt, T.; Rosset,
S.; Alexakis, A.; Micouin, L. Org. Lett. 2006, 8, 3581.
a Determined for enantiomerically enriched (33% ee) material. See ref
11.
3a was first quantitatively deprotected under acidic condi-
tions, and the resulting hydrochloride was submitted to an
oxidative treatment delivering the corresponding diol 5 by
Org. Lett., Vol. 11, No. 13, 2009
2913

Scheme 3
.
Synthesis of Aminocyclohexanediols 6 and 7
Scheme 5. Acces to Poly-oxygenated Phenanthridone Skeleton
Scheme 4. Synthesis of Alkaloids Precursors
a 78% based on unreacted recovered starting material. b 81% based on
unreacted recovered starting material.
four-step enantioselective synthesis of cyclohexene diol 5
from cyclohexadiene compares favorably with any other
routes reported for the preparation of this useful synthetic
intermediate. The determination of the absolute configuration
of compound 3a confirmed that dienes 1 and 2 behave
similarly under Sharpless asymmetric dihydroxylation condi-
tions, the same absolute and relative configuration being
obtained with the same ligands.
Several other simple synthetic transformations can be
carried out on compound 3a. Diastereo- and enantiomerically
pure aminocyclohexanediol 6 was for example obtained by
a Pt-catalyzed hydrogenolysis. This compound was peracety-
lated, enabling the confirmation of its anti relative config-
uration by NMR analysis.
retro-ene reaction after a simple biphasic extraction in 75%
overall yield. Although retro-ene reactions involving allylic
hydrazines are generally triggered by a base-catalyzed
elimination of substituted benzenesulfinic acid,9 we found
that generating the allylic azo intermediate under biphasic
oxidative conditions was even more straightforward.10 This
Finally, a new route to the skeleton of oxygenated alkaloids
from Amaryllidaceae was explored.12 For this purpose, a
selective hydrazine cleavage was needed, without any double
reduction or isomerization. Although numerous reductive
cleavages of hydrazines have been reported, this step proved
to be particularly difficult. We found, after extensive
investigations, that reductive TFA-promoted cleavage by
SmI2 was the most appropriate method to achieve this goal.13
This reaction was systematically accompanied by the sol-
volysis of the trifluoroacetamide moiety of tetrasubstituted
hydrazine 9, which proved to be rather unstable, leading back
(5) (a) Gillis, B. T.; Beck, P. E. J. Org. Chem. 1962, 27, 1947. (b)
Franzus, B.; Surridge, J. H. J. Org. Chem. 1962, 27, 1951. (c) Franzus, B.
J. Org. Chem. 1963, 28, 2954. For a review on ene-reactions, see: Hoffmann,
H. M. R. Angew. Chem., Int. Ed. 1969, 8, 556.
(6) For selected recent examples of diastereoselective syntheses of the
aminocyclohexanediol motif, see:(a) Aciro, C.; Davies, S. G.; Kurosawa,
W.; Roberts, P. M.; Russel, A. J.; Thomson, J. E. Org. Lett. 2009, 11, 1333.
(b) Aciro, C.; Davies, S. G.; Roberts, P. M.; Russel, A. J.; Smith, A. D.;
Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3762. (c) Aciro, C.; Davies,
S. G.; Roberts, P. M.; Russel, A. J.; Smith, A. D.; Thomson, J. E. Org.
Biomol. Chem. 2008, 6, 3751. (d) Davies, S. G.; Long, M. C.; Smith, A. D.
Chem. Commun. 2005, 36, 4536.
(7) For selected examples of diastereoselective dihydroxylation of allylic
cyclohexanic amines, see: (a) Huang, J.; Bergmeier, S. C. Tetrahedron 2008,
64, 6434. (b) Verhelst, S. H. L.; Wennekes, T.; van der Marel, G. A.;
Overkleeft, H. S.; van Boeckel, C. A. A.; van Boom, J. H. Tetrahedron
2004, 60, 2813. (c) Ko, H.; Kim, E.; Park, J. E.; Kim, D.; Kim, S. J. Org.
Chem. 2004, 69, 112. (d) Donohoe, T. J.; Blades, K.; Moore, P. R.; Waring,
M. J.; Winter, J. J. G.; Helliwell, M.; Newcombde, N. J.; Stemp, G. J.
Org. Chem. 2002, 67, 7946. (e) Jana, C. K.; Studer, A. Chem.sEur. J.
2008, 14, 6326.
(11) (a) Takano, S.; Yoshimitsu, T.; Ogasawara, K. J. Org. Chem. 1994,
59, 54. All configurational assignments are reversed in this publication;
see erratum: Takano, S.; Yoshimitsu, T.; Ogasawara, K. J. Org. Chem. 1995,
60, 1478. (b) Wang, Z.-M.; Kakiuchi, K.; Sharpless, K. B. J. Org. Chem.
1994, 59, 6895.
(12) Review: Kornienko, A.; Evidente, A. Chem. ReV. 2008, 108, 1982.
(13) (a) Ding, H.; Friestad, G. K. Org. Lett. 2004, 6, 637. (b) Fernandez,
M.; Alonso, R. Org. Lett. 2003, 5, 2461. (c) Friestad, G. K.; Marie´, J.-C.;
Suh, Y.; Qin, J. J. Org. Chem. 2006, 71, 7016. (d) Kawasaki, M.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482. (e) Poulsen, T. B.;
Alemparte, C.; Jorgensen, K. A. J. Am. Chem. Soc. 2005, 127, 11614. (f)
Giampietro, N. C.; Wolfe, J. P. J. Am. Chem. Soc. 2008, 130, 12907. (g)
Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005,
127, 9974. (h) Xu, X.; Yabuta, T.; Yuan, P.; Takemoto, Y. Synthesis 2006,
137. (i) Chowdari, N. S.; Barbas, C. F. Org. Lett. 2005, 7, 867. (j) Suri,
J. T.; Steiner, D. D.; Barbas, C. F. Org. Lett. 2005, 7, 3885.
(8) As “proaromatic substrates”, cyclohexadienes 1 could be expected
to easily aromatize under metal-catalyzed oxidative conditions, with or
without C-N bound cleavage. The use of biphasic conditions might prevent
this problem. For a review on this reactivity, see :Walton, J. C.; Studer, A.
Acc. Chem. Res. 2005, 38, 794.
(9) (a) Myers, A. G.; Movassaghi, M.; Zheng, B. J. Am. Chem. Soc.
1997, 119, 8572. (b) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007,
72, 1838, and references therein.
(10) For an early example of retro-ene triggered by oxidation of allylic
hydrazines, see: Baldwin, J. E.; Brown, J. E.; Ho¨fle, G. J. Am. Chem. Soc.
1971, 93, 788.
2914
Org. Lett., Vol. 11, No. 13, 2009

to 8 as a side product of this transformation. Nevertheless,
amide 11 could be obtained in five steps from compound
3a, in 13% overall yield.
mentary to the existing desymmetrization strategies unmask-
ing C-Si or C-C stereogenic centers from analogous
prochiral precursors. It opens a new route to polyfunction-
alized aminocyclohexanes with expanded chemical and
stereochemical diversity. Application to the synthesis of more
complex alkaloids such as lycoricidine is under investigation
and will be reported in due course.
Introduction of this piperonyl moiety14 enables the con-
struction of the polyoxygenated phenanthridone skeleton via
an intramolecular Heck cyclization. Compounds 12 and 14
were obtained using cyclization conditions reported by Beller
and co-workers, as single diastereomers, without any double
bond migration.15
Acknowledgment. G.E. thanks GlaxoSmithKline and
In conclusion, we have shown that hydrazines 1, readily
available by an almost quantitative solvent-free ene-reaction
from cyclohexadiene, are valuable precursors for desymme-
trization reactions. As an example, the use of Sharpless
asymmetric dihydroxylation enables a fast and efficient
access to several useful chiral building blocks. This approach,
based on prochiral dienes bearing a C-N bond, is comple-
CNRS for a grant.
Note Added after ASAP Publication. This article posted
ASAP on May 26, 2009 with errors in the footnotes for
Schemes 2 and 5. The final corrected version posted May
29, 2009.
Supporting Information Available: Analytical data for
all new compounds and NMR spectra of all synthesized
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) The bromopiperonyl acyl chloride was prepared in four steps from
piperonyl alcohol.
(15) For a discussion on bond migration on similar substrates during a
Pd-catalyzed cyclisation, see: Von Wangelin, A. J.; Neumann, H.; Go¨rdes,
D.; Hu¨bner, S.; Wendler, C.; Klaus, S.; Stru¨bing, D.; Spannenberg, A.; Jiao,
H.; El Firdoussi, L.; Thurow, K.; Stoll, N.; Beller, M. Synthesis 2005, 2029.
OL900779V
Org. Lett., Vol. 11, No. 13, 2009
2915