Stereocontrolled coupling between aldehydes and conjugated alkenals mediated by TiIII/H2O

Article abstract of DOI:10.1021/ol0620390

In the presence of water, titanocene(III) complexes promote a stereoselective C-C bond-forming reaction that provides γ-lactols by radical coupling between aldehydes and conjugated alkenals. The method is useful for both intermolecular reactions and cyclizations. The relative stereochemistry of the products can be predicted with confidence with the aid of model Ti-coordinated intermediates. The procedure can be carried out enantioselectively using chiral titanocene catalysts.

Full text of DOI:10.1021/ol0620390

ORGANIC
LETTERS
2006
Vol. 8, No. 24
5433-5436
Stereocontrolled Coupling between
Aldehydes and Conjugated Alkenals
Mediated by TiIII/H2O
Rosa E. Este´vez,† Juan L. Oller-Lo´pez,† Rafael Robles,†
Concepcio´n R. Melgarejo,† Andreas Gansauer,‡ Juan M. Cuerva,*,† and
1
J. Enrique Oltra*,†
Department of Organic Chemistry, Faculty of Sciences, UniVersity of Granada,
E-18071 Granada, Spain, and Kekule´ Institut fu¨r Organische Chemie und Biochemie
der UniVersita¨t Bonn, Gerhard Domagk Strasse 1, D-53121 Bonn, Germany
joltra@ugr.es; jmcuerVa@ugr.es
Received August 18, 2006
ABSTRACT
In the presence of water, titanocene(III) complexes promote a stereoselective C−C bond-forming reaction that provides γ-lactols by radical
coupling between aldehydes and conjugated alkenals. The method is useful for both intermolecular reactions and cyclizations. The relative
stereochemistry of the products can be predicted with confidence with the aid of model Ti-coordinated intermediates. The procedure can be
carried out enantioselectively using chiral titanocene catalysts.
The Michael-type addition of nucleophilic reagents to R,â-
unsaturated carbonyl systems is one of the most powerful
C-C bond-forming reactions in organic synthesis.1 Although
aldehydes have electrophilic properties and their addition to
Michael-acceptor groups might seem counterintuitive, ketyl
radical anions can behave as nucleophilic radicals, thus encour-
aging the umpolung of aldehydes and facilitating their 1,4-
addition to R,â-unsaturated carbonyl derivatives. In fact, SmI2-
induced ketyl radicals have been demonstrated to mediate
radical additions of aldehydes and ketones to R,â-unsaturated
esters and nitriles.2 Nevertheless, radical coupling between
aldehydes and conjugated alkenals has remained virtually unex-
plored to date.3 Here, we report that this novel, selective C-C
bond-forming reaction can be promoted by bis(cyclopenta-
dienyl)titanium(III) chloride4 in the presence of water. More-
over, the commercially available enantiomerically pure Brint-
zinger complex5 can catalyze the process enantioselectively.
In recent years, Cp2TiCl has become a useful reagent in
organic synthesis.6 Thus, it is known that under anhydrous
conditions Cp2TiCl promotes and catalyzes the pinacol
coupling of aromatic and R,â-unsaturated aldehydes.7 Treat-
ing an aromatic aldehyde with Cp2TiCl in the presence of
(3) There are a few examples of the SmI2-mediated intramolecular
addition of aldehydes to conjugated alkenones: (a) Sato, A.; Masuda, T.;
Arimoto, H.; Uemura, D. Org. Biomol. Chem. 2005, 3, 2231-2233. (b)
Nguyen, T. C.; Lee, D. Tetrahedron Lett. 2002, 43, 4033-4036. We have
also found two reports dealing with the electrohydrodimerization of R,â-
unsaturated aldehydes: (c) Barba, F.; de la Fuente, J. L.; Galakhov, M.
Tetrahedron, 1997, 53, 5831-5838. (d) Johnston, J. C.; Faulkner, J. D.;
Mandell, L.; Day, R. A., Jr. J. Org. Chem. 1976, 41, 2611-2614.
(4) Bis(cyclopentadienyl)titanium(III) chloride generated in situ by
stirring commercial Cp2TiCl2 with Zn dust in anhydrous THF exists as an
equilibrium mixture of the monomer Cp2TiCl and the dinuclear species
(Cp2TiCl)2; see: Enemærke, R. J.; Larsen, J.; Skrydstrup, T.; Daasbjerg,
K. J. Am. Chem. Soc. 2004, 126, 7853-7864. For the sake of clarity, we
represent this complex herein as Cp2TiCl.
† University of Granada.
‡ Kekule´ Institut fu¨r Organische Chemie und Biochemie der Universita¨t
Bonn.
(1) (a) Carruthers, W.; Coldham, I. Modern Methods of Organic
Synthesis, 4th ed.; Cambridge University Press: Cambridge, 2004; pp 19-
27. (b) Smith, M. B. Organic Synthesis, 2nd ed.; McGraw-Hill: Boston,
2002; pp 794-798.
(2) For a review, see: Molander, G. A. In Radicals in Organic Synthesis;
Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinheim: 2001; Vol. 1, pp
165-174.
(5) Brintzinger’s complexes dichloro[(R,R)-ethylenebis-(4,5,6,7-tetrahy-
dro-1-indenyl)]-titanium(IV) and its enantiomer can be bought from
commercial sources or prepared by the resolution of (rac)-ethylenebis-
(tetrahydroindenyl)-titanium derivatives; see: Chin, B.; Buchwald, S. L. J.
Org. Chem. 1996, 61, 5650-5651.
10.1021/ol0620390 CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/26/2006

water, on the other hand, gives a mixture of reduction and
pinacol coupling products.8 When we treated R,â-unsaturated
geranial (1) with Cp2TiCl (1 equiv) in the presence of water
(100 equiv), however, instead of the expected reduction and
pinacol coupling products we obtained an 86% yield of
4R*,5S* γ-lactol 2 (5:1 mixture of C-2 epimers) (Scheme
1).9 The structure and stereochemistry of 2 were established
Figure 1.
viability of this method for the straightforward, selective
synthesis of substituted γ-lactols and, consequently, γ-lac-
Scheme 1. TiIII/H2O-Promoted Homocoupling of Geranial
Table 1. Cp2TiCl/H2O-Promoted Cross-Couplings between
Aldehydes (6, 7) and Conjugated Alkenals (1, 4, 8, 9)11
on the basis of spectroscopic techniques, including NOE
experiments, and confirmed by oxidation to γ-lactone 3.
This TiIII/H2O-promoted reaction was much more regi-
oselective than the electrochemical reduction of geranial,3d
in which stereoisomeric mixtures of 2 (head-to-tail) and
pinacol (head-to-head) coupling products were obtained.
Moreover, the TiIII/H2O-promoted process proceeded not only
regioselectively but also stereoselectively. Thus, the reaction
of the geranial isomer neral (4) under the same conditions
resulted in the formation of 4R*,5R* γ-lactol 5 (5:1 mixture
of C-2 epimers) (Scheme 2).10
Scheme 2. TiIII/H2O-Promoted Homocoupling of Neral
a s.m. ) starting material. b Roughly 1:1 mixture of C-2 epimers.
c Roughly 5:1 mixture of C-2 epimers.
The selectivity observed for the homocouplings of geranial
and neral prompted us to explore TiIII/H2O-induced cross-
couplings between aldehydes 6 and 7 and the conjugated
alkenals 1, 4, 8, and 9. The results (Table 1) confirm the
tones.11 Both classes of compounds constitute very wide-
spread motifs among natural terpenoids with biological
activity.12
(7) (a) Enemærke, R. J.; Larsen, J.; Hjøllund, G. T.; Skrydstrup, T.;
Daasbjerg, K. Organometallics 2005, 24, 1252-1262. (b) Dunlap, M. S.;
Nicholas, K. M. J. Organomet. Chem. 2001, 630, 125-131. (c) Gansa¨uer,
A.; Bauer, D. J. Org. Chem. 1998, 63, 2070-2071. (d) Gansa¨uer, A. Chem.
Commun. 1997, 457-458. (e) Handa, Y.; Inanaga, J. Tetrahedron Lett. 1987,
28, 5717-5718.
(6) For pioneering work, see: (a) RajanBabu, T. V.; Nugent, W. A. J.
Am. Chem. Soc. 1994, 116, 986-997. For recent reviews, see: (b) Cuerva,
J. M.; Justicia, J.; Oller-Lo´pez, J. L.; Oltra, J. E. Top. Curr. Chem. 2006,
264, 63-91. (c) Gansa¨uer, A.; Lauterbach, T.; Narayan, S. Angew. Chem.,
Int. Ed. 2003, 42, 5556-5573.
5434
Org. Lett., Vol. 8, No. 24, 2006

In fact the cross-coupling processes proceeded with ratios
of about 9:1 in favor of 4R*,5S* isomers (products 10, 13,
15, and 18) when utilizing E-conjugated alkenals 1 or 8.
Similar ratios in favor of the 4R*,5R* isomers 14 and 19
were obtained with (Z)-alkenal 4. Gratifyingly, the combined
γ-lactol yields ranged from an acceptable 62% for producsts
14 + 13, obtained from the coupling between 6 and 4, to an
excellent 97% yield for products 18 + 19, obtained from
the coupling between 7 and 1.13
In contrast to the lack of stereoselection shown by the
electrohydrodimerization,3c,d the TiIII/H2O-induced couplings
proved to be both stereoselective and stereospecific pro-
cesses. This stereochemistry highlights the crucial role played
by titanium during the coupling process, probably via
substrate coordination. Bearing this idea in mind, the
mechanism depicted in Scheme 3 may well account for the
homocoupling of benzaldehyde.7b In the presence of water,
however, titanium presumably coordinates with H2O to give
aqua-complex 21 (Scheme 3a).14 After coordination (by
ligand exchange) between 21 and a conjugated alkenal such
as 1 or 4, the inner-sphere single-electron transfer from TiIII
would give a titanoxy-allyl-type radical such as 22 (Scheme
3b). In this titanoxy derivative the TiIV atom has only 16 e-
in the valence shell and therefore could coordinate again with
the oxygen atom of an aldehyde, such as 6, to give an
intermediate such as 23. This intermediate shows the suitable
spatial arrangement to facilitate the required overlap between
the π-orbitals of the carbonyl group and the delocalized
allylic radical (Scheme 3c). Thus the crucial coupling step
from 23 to 24 might be viewed as a 7-endo-dig cyclization
favored by Baldwin’s rules.15 Moreover, the stereoselective
formation of 13 from the (E)-alkenal 1 and 14 from the (Z)-
alkenal 4 strongly suggests a notable retention of the original
alkene configuration in the delocalized allyl-type radicals 22
and 23. Subsequently, a second reduction of TiIV to TiIII by
the excess of Zn used would facilitate the formation of 25,
which would finally hydrolyze to 26 (presumably with the
formation of a stable oxygenated titanium species), thus
accounting for the formation of the corresponding γ-lactol
13 or 14.
Scheme 3. Proposed Mechanism for the Cp2TiCl/
H2O-Promoted Cross-Coupling between 6 and 1 or 4
From a mechanistic point of view, the Ti-mediated
coupling between a delocalized allyl-type radical and a
carbonyl group such as that depicted in Scheme 3 would be
conceptually different from the SmI2-promoted coupling
between ketyl radicals and conjugated carbonyl derivatives.2
Nevertheless, there has been a recent report suggesting an
allyl-type radical addition to carbonyl compounds for the
SmI2-promoted coupling of R,â-unsaturated esters and
amides to N-acyl oxazolidinones,16 which lends support to
our mechanistic proposal.
Among naturally occurring bioactive terpenoids there are
numerous substances containing a fused γ-lactol or γ-lactone
ring with a stereodefined interannular junction in their
molecule.12 Within this context we deemed that the intramo-
lecular version of the TiIII/H2O-based reaction could provide
a novel cyclization procedure that might considerably
facilitate the synthesis of these often scarce natural products.
To confirm this hypothesis we chose as target molecules the
C-3 epimeric, trans-fused menthane lactones 27, which are
components of Italo Mitcham black peppermint oil (Mentha
piperita) and have interesting olfactory properties.17 On the
basis of the anticipated cyclic intermediate 28 (adapted from
main regio- and stereochemical features observed for the
cross-coupling between an aldehyde (represented by 6) and
each of the two stereoisomeric conjugated alkenals (1 and
4).
It has been suggested that under anhydrous conditions
dimer 20 is mainly responsible for the stereoselective pinacol
(14) Cuerva, J. M.; Campan˜a, A. G.; Justicia, J.; Rosales, A.; Oller-
Lo´pez, J. L.; Robles, R.; Ca´rdenas, D.; Bun˜uel, E.; Oltra, J. E. Angew.
Chem., Int. Ed. 2006, 45, 5522-5526.
(8) Oller-Lo´pez, J. L.; Campan˜a, A. G.; Cuerva, J. M.; Oltra, J. E.
Synthesis 2005, 2619-2622.
(9) Lactol 2 was accompanied by a trace of its 4R*,5R* stereoisomer.
(10) Lactol 5 was accompanied by a minor amount (9%) of the pinacol
coupling product (dl/meso, 3/2) and a trace of its 4R*,5S* stereoisomer.
(11) We utilized NOE studies as well as oxidation to the corresponding
γ-lactones to confirm the stereochemistry of γ-lactols described in Table
1. For experimental details see Supporting Information.
(12) Connolly, J. D.; Hill, R. A. Dictionary of Terpenoids; Chapman &
Hall: London, 1991.
(15) In contrast, the pinacol-type coupling (head-to-head) would cor-
respond to a 5-endo-dig cyclization disfavored by Baldwin’s rules, thus
explaining the regioselectivity toward head-to-tail coupling products
observed. For Baldwin’s rules, see: (a) Clayden, J.; Greeves, N.; Warren,
S.; Wothers, P. Organic Chemistry; Oxford University Press: Oxford, 2001;
pp 1140-1144. (b) Baldwin, J. E.; Lusch, M. J. Tetrahedron 1982, 38,
2939-2947. (c) Baldwin, J. E. Chem. Commun. 1976, 734-736. (d)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. Chem. Commun. 1976, 736-738.
(13) γ-Lactols 10-19 were accompanied by minor quantities (roughly
10%) of decanol or 3-phenylpropanol, presumably derived from the slow
TiIII/H2O-promoted reduction of the excess (1 equiv) of 6 or 7 employed
for these syntheses.
(16) Hansen, A. M.; Lindsay, K. B.; Antharjanam, P. K. S.; Karaffa, J.;
Daasbjerg, K.; Flowers, R. A., II; Skrydstrup, T. J. Am. Chem. Soc. 2006,
128, 9616-9617.
Org. Lett., Vol. 8, No. 24, 2006
5435

23), we anticipated that 27 might easily be synthesized from
the (E)-alkenal 29 (Scheme 4).
enantioselective version of our method. In this way we
treated a mixture of 7 and 9 with a substoichiometric quantity
of Cp2TiCl2 (0.2 equiv), Zn (8 equiv), H2O (10 equiv), and
2,4,6-collidine hydrochloride (3 equiv), a titanocene-
regenerating agent that can be recovered after the reaction
by simple acid-base extraction.21 In this way we obtained
an excellent 95% yield of 17, thus confirming the viability
of the catalytic procedure. Moreover, when we employed
commercial dichloro[(R,R)-ethylenebis(4,5,6,7-tetrahydro-1-
indenyl)]-titanium(IV) (0.2 equiv) as precatalyst5 we obtained
a 49% yield of (+)-17 ([R]25D ) + 8.47) with roughly 33%
ee.22 This ee is similar to that observed for Barbier-type
reactions catalyzed by this chiral complex23 and despite its
moderate value demonstrates that the method can be adapted
for asymmetric catalysis.
In summary, we describe here a novel, stereoselective,
C-C bond-forming method that provides γ-lactols by radical
coupling between aldehydes and conjugated alkenals medi-
ated by TiIII complexes in the presence of water. The reaction
occurs at room temperature under mild conditions, fits the
principle of atom economy, and is useful for both intermo-
lecular reactions and cyclizations, and the relative stereo-
chemistry of the products can be predicted with confidence
with the aid of model intermediates such as 23 and 28.
Moreover, the procedure can be carried out enantioselectively
using chiral titanocene catalysts. At the moment we are
searching for new chiral titanocene catalysts to improve the
ee values of this reaction.
Scheme 4. Retrosynthesis of 27 Based on the Anticipated
Intermediate 28
Therefore, we prepared dialdehyde 2918 from commercial
citronellal and treated it with Cp2TiCl (1 equiv) and water
(100 equiv) for 6 h (Scheme 5).
Scheme 5. TiIII/H2O-Promoted Synthesis of trans-Fused
Menthane Lactones 27
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia for financial support (project CTQ2005-
08402/BQU) and our English colleague Dr. J. Trout for
revising our English text.
As predicted by the analysis of model 28, we obtained a
mixture of trans-fused γ-lactols (58% yield),19 the PCC
oxidation of which provided menthane lactones 27a and 27b
at a ratio of about 3/1.20 These lactones showed 1H and 13
C
Supporting Information Available: Detailed experi-
mental procedures and spectroscopic data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
NMR spectra matching those of the corresponding natural
products.17
Asymmetric catalysis plays a leading role in organic
synthesis. Therefore we decided to attempt a catalytic and
OL0620390
(17) Gaudin, J. M. Tetrahedron 2000, 56, 4769-4776 and refernces
therein.
(18) Dawson, G. W.; Pickett, J. A.; Smiley, D. W. M. Bioorg. Med.
Chem. 1996, 4, 351-361.
(19) Twenty-five percent dialdehyde 29 was recovered unchanged.
(20) Besides 27a and 27b, a trace of a third trans-fused menthane lactone,
the 3R*,3aR*,6R*,7aS* diastereomer, was detected. GC-MS analysis
indicated that these three lactones constituted more than a 96% of the
mixture.
(21) Gansa¨uer, A.; Bluhm, H.; Pierobon, M. J. Am. Chem. Soc. 1998,
120, 12849-12859.
(22) Enantiomeric excess (ee) was determined on the acetyl derivative
of (+)-17 with the aid of chiral lanthanide NMR shift reagents; see:
Sweeting, L. M.; Crans, D. C.; Whitesides, G. M. J. Org. Chem. 1987, 52,
2273-2276.
(23) Rosales, A.; Oller-Lo´pez, J. L.; Justicia, J.; Gansa¨uer, A.; Oltra, J.
E.; Cuerva, J. M. Chem. Commun. 2004, 2628-2629.
5436
Org. Lett., Vol. 8, No. 24, 2006