Stereoselective synthesis of functionalized 1,3 diols through the tandem isomerization-aldolization reaction mediated by nickel catalysts

Article abstract of DOI:10.1016/j.tetlet.2006.08.125

A new approach to functionalized 1,3 diols, such as 15, is described using as the key step the tandem isomerization-aldolization reaction of allylic alcohols 1. The chiral imidazolidine group is shown to play a key role for the stereocontrol during aldoli

Full text of DOI:10.1016/j.tetlet.2006.08.125

Tetrahedron Letters 47 (2006) 7745–7748
Stereoselective synthesis of functionalized 1,3 diols
through the tandem isomerization–aldolization reaction
mediated by nickel catalysts
a
b
a,
*
´
´
Julien Petrignet, Thierry Roisnel and Rene Gree
a
`
`
Universite´ de Rennes 1, Laboratoire de Synthese et Electrosynthese Organiques, CNRS UMR 6510,
Avenue du Ge´ne´ral Leclerc, 35042 Rennes Cedex, France
bUniversite´ de Rennes 1, Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du Ge´ne´ral Leclerc, 35042 Rennes Cedex, France
Received 19 July 2006; revised 22 August 2006; accepted 25 August 2006
Available online 18 September 2006
Abstract—A new approach to functionalized 1,3 diols, such as 15, is described using as the key step the tandem isomerization–aldol-
ization reaction of allylic alcohols 1. The chiral imidazolidine group is shown to play a key role for the stereocontrol during aldol-
ization and reduction steps.
ꢀ 2006 Elsevier Ltd. All rights reserved.
The 1,3 diol structure is a basic subunit for many bio-
active compounds such as, for instance, the polypropio-
nate natural products.1 Therefore, the preparation of
this type of fragment is of much interest, especially if
functional groups are present in the appropriate posi-
tions in order to complete the total synthesis of the
target molecules. Although, various elegant alternative
approaches have also been reported, the aldol reaction
still remains the most versatile strategy toward such
1,3 diol structures.2 Our group has discovered a new
tandem isomerization–aldolization reaction starting
from allylic alcohols and mediated by various types of
Scheme 1. Retrosynthetic approach to the key intermediates A.
transition metal catalysts (Fe, Rh, Ru, Ni).3 Further-
more, detailed computational and experimental studies
have established the key role of the free enol in the
as a precursor for the aldehyde.5 Therefore, the type B
monoprotected diols could be used as key intermediates
mechanism of this reaction.4 In parallel to these mecha-
nistic studies, we were interested in developing the syn-
and they should be accessible by stereoselective reduc-
thetic uses of this reaction. As a first step toward this
tion of aldols C followed by a protection step. Finally,
the latter derivatives should be obtained from the allylic
alcohol 1 and aldehyde 2 by the tandem isomerization–
goal we have selected as targets, the protected 1,3 diol
subunits with the type A basic structure, since the alde-
hyde group is a versatile precursor for many synthetic
aldolization process.
transformations.
This approach should open to a large molecular diver-
Our retrosynthetic analysis is given in Scheme 1 indicat-
sity by changing the nature of the R group, as well as
ing that a masked and chiral equivalent of the formyl
by using all the potentialities of the formyl group. The
group, based on the imidazolidine rings, was considered
main challenges in this new strategy are the following:
*
• Is this transition metal mediated isomerization–aldol-
Corresponding author. Tel.: +33 (0)223235715; fax: +33
(0)223236978; e-mail: rene.gree@univ-rennes1.fr
ization process compatible with such a bulky and
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.125

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J. Petrignet et al. / Tetrahedron Letters 47 (2006) 7745–7748
basic imidazolidine group on the allylic alcohol
component?
• What is the effect of this chiral imidazolidine on the
diastereoselectivity of the aldol reaction, as well as
on the reduction of aldols such as C?
The purpose of this letter is to report our preliminary re-
sults in this area establishing: (i) the feasibility of this
strategy through the preparation, with a good stereose-
lectivity, of a type A intermediate (with R = Ph) and (ii)
the versatility of this compound, which can be used in
many reactions such as reduction, reductive amination,
and Wittig or Petasis type reactions.
The allylic alcohols 1 were prepared following the liter-
ature procedures.5a The known formyl imidazolidine 4
was obtained in 58% yield by condensation of aqueous
glyoxal with the chiral diamine 3. For the latter deriva-
tive, the isopropyl substituents on the nitrogen atoms
were selected since the corresponding imidazolidines
are more stable than the N-methyl analogues. Further-
more, they are known to induce higher diastereoselectiv-
ities in the reactions on a vicinal carbonyl group.5a
Addition of a vinyl Grignard on 4 afforded in 92% yield
the allylic alcohols 1 as a 4:1 mixture of stereoisomers
which could be separated by chromatography on SiO2
(Scheme 2).
Scheme 3. Tandem isomerization–aldolization.
The tandem isomerization–aldolization, with benzalde-
hyde selected as a model aldehyde, was performed start-
ing from 1 (as the 4:1 mixture of stereoisomers) and using
the most efficient catalytic system previously discovered:
NiHCl(dppe) + MgBr2.3d,4b It afforded, in 70% overall
yield, a mixture of three stereoisomeric aldol products
5–7, which could be separated by chromatography on
SiO2 (Scheme 3). Exactly the same results (both in terms
of yield and stereoselectivity) were obtained when the
reactions were performed starting from each pure stereo-
isomer of 1. This is in agreement with the results ob-
tained previously in another series of allylic alcohols
and using an iron-carbonyl derived catalyst.6 The ratios
of the three stereoisomers were the following: major syn
aldol 5 (70%), minor syn aldol 6 (15%), and anti aldol 7
(15%). The structures of these adducts were unambigu-
ously established by X-ray analysis (Fig. 1 for major al-
dol 5, and for 6 and 7 see data deposited at CCDC).7,8
Figure 1. ORTEP representation of major aldol 5.
a highly stereoselective manner, affording the corre-
sponding diols in a 9:1 ratio. The major compound 8
was isolated by crystallization and it was easily trans-
formed in good yield into the cyclic carbonate 9. In
the same way, the other aldols 6 and 7 were reduced,
with high stereoselectivities (95:5 for 6 and 85:15 in the
case of 7) and in excellent yields, to the corresponding
diols 10 and 12 and these derivatives could also be trans-
formed into the corresponding carbonates 11 and 13
(Scheme 4). The stereochemistry of these diols was first
established by extensive NMR studies of their carbon-
ates 9, 11, and 13. It was confirmed by X-ray analysis
of 8 (Fig. 2) and 10 (see data deposited at CCDC). It
is worth mentioning that during these three reductions,
the same configuration was obtained at the newly cre-
ated carbinol center for the major diastereoisomer. This
indicates that the reduction step is essentially controlled
by the bulky N-isopropyl group on the imidazolidine
and is almost completely independent from the substitu-
ents at the other stereocenters. This is in agreement with
previous literature data for 1,2 additions on formyl imi-
dazolidine 4.5
In the next step we have studied the reduction of these
aldols. The major adduct 5 was reduced by LiAlH4 in
The monoprotection of the benzylic alcohol of 8 was
easily performed, affording the first key intermediate
14 in 53% yield (Scheme 5). The protection of the second
hydroxyl group is under active study, but it appeared of
much interest to develop first the chemistry of the a-hy-
Scheme 2. Synthesis of the chiral allylic alcohols 1.

J. Petrignet et al. / Tetrahedron Letters 47 (2006) 7745–7748
7747
Scheme 5. Synthesis and reactions of the key intermediate 15.
Scheme 4. Stereoselective reduction of aldols 5–7.
Scheme 6. Further reactions of the key intermediate 15.
model reagents, it afforded the protected amino diol
21, in a completely stereoselective manner. The anti
aminoalcohol structure was attributed by analogy with
the literature data on this reaction and the NMR data
Figure 2. ORTEP representation of major diol 8.
3
of 21, with a low J value (3.2 Hz) at the aminoalcohol
unit, were also in agreement with this structure.10
droxy aldehyde derivative. In fact, under biphasic condi-
tions, the hydrolysis of 14 was rapid, affording the labile
aldehyde 15 easily characterized by NMR. On standing,
or more efficiently by stirring on humid silica gel, it was
transformed into the hydroxy ketone 16 by a classical
transformation of a-hydroxy aldehydes.9 On the other
hand, the crude aldehyde 15 reacted with the ketophos-
phorane to afford, in 64% yield, the E-enone 17. In the
same way, by reaction with N-Me hydroxylamine, the
chiral functionalized nitrone 18 was isolated in 55%
yield.
The cyclic carbonates can also be used in synthesis. Un-
der the same conditions as before, starting from 9, the
hydrolysis of the imidazolidine afforded the labile inter-
mediate aldehyde 22 which could also be used in a Wit-
tig type reaction to afford the E-enone 23 in 66% overall
yield from 9 (Scheme 7).
Several other basic transformations were performed
starting from the chiral functionalized intermediate 15
(Scheme 6). The reduction gave the monoprotected triol
19 in 81% yield, while the reductive amination afforded
the monoprotected aminodiol 20 in 67% yield. Finally,
the Petasis reaction10 was also possible starting from
15. With cinnamylboronic acid and aniline, selected as
Scheme 7. Wittig reaction of intermediate 22.

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J. Petrignet et al. / Tetrahedron Letters 47 (2006) 7745–7748
7. The scope and limitations of the reaction, starting from 1,
appear similar to those previously described for allylic
alcohols bearing a bulky substituent in allylic position
(Ref. 4b). Preliminary data (with non-optimized yields)
indicate that the reaction can be performed with (i)
substituted aromatic aldehydes such as p-fluorobenzalde-
hyde (59%) or p-methoxybenzaldehyde (35%), (ii) aliphatic
aldehydes such as propionaldehyde (70%) or isobutyral-
dehyde (47%), or (iii) heterocyclic derivatives such as the
challenging pyridine-2-carboxaldehyde (51%). The stereo-
selectivities are close to those observed with benzaldehyde
and the corresponding results will be discussed in the full
paper on this research.
In conclusion, we have demonstrated that the tandem
isomerization–aldolization reaction can be extended to
allylic alcohols bearing a chiral imidazolidine group.11
This reaction affords useful intermediates with a 1,3
functionalized diol structure. Extension of this approach
to asymmetric synthesis and use of such intermediates in
total synthesis are currently under active study in our
laboratory.
Acknowledgments
8. The stereoselectivity of the isomerization–aldolization
reaction, strongly in favor of the syn isomers, is in
agreement with previous results in these series. A tentative
explanation for the facial selectivity could be the follow-
ing: as previously observed with bulky substituents at the
carbinol center (see Ref. 4b) the isomerization could lead
first to a Z enol, such as X, possibly stabilized by hydrogen
bonding with the next imidazolidine nitrogen. Then
reaction of the aldehyde from the less hindered side could
afford aldols 5 and 7, while reaction on the other face of
the enol would give aldol 6. Of course, other transition
states are possible for these reactions and further studies
will be necessary in order to fully rationalize this facial
selectivity.
We thank the French Ministry for Education and Re-
search for a fellowship to J.P. and the CNRS for finan-
cial support. We thank Ms. S. M. Nazarin for
preliminary experiments. We thank Professor A. Alexa-
kis for very fruitful discussions.
References and notes
1. See for example: (a) O’Hagan, D. Nat. Prod. Rep. 1995,
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Int. Ed. 2000, 39, 2847–2849, and references cited therein.
2. (a) For general reviews on the aldol reactions see:
Comprehensive Organic Chemistry, Addition to C–X p
Bonds, Part 2; Heathcock, C. H., Ed.; Pergamon Press,
1991; pp 99–319; (b) Modern Aldol Reactions; Mahrwald,
R., Ed.; Wiley-VCH: Weinheim, Germany, 2004, and
references cited therein.
Ph
5
H
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11. Crystallographic data (excluding structure factors) for the
structures in this letter have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 615450, CCDC 615451,
CCDC 615452, CCDC 615453, CCDC 615454. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax: +44(0) 1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk].
´
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