Synthesis and evaluation of new chiral diols based on the dicyclopentadiene skeleton

Article abstract of DOI:10.1016/S0040-4039(03)00664-6

The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo (2R)-1a alcohol. The endo (2S)-1b alcohol was obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey's general procedure respectively, afforded with high diastereoselectivity the C₂ symmetry diols (2R,2′R)-2a and (2S,2′S)-2b, with endo oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2′R)-2a and (2S,2′S)-2b was tested towards the LiAlH₄ reduction of acetophenone. The C₂ symmetry appears to play a fundamental role.

Full text of DOI:10.1016/S0040-4039(03)00664-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3517–3520
Synthesis and evaluation of new chiral diols based on the
dicyclopentadiene skeleton
Giuseppe Borsato,a Ottorino De Lucchi,b Fabrizio Fabris,b Vittorio Lucchini,a,*
Pietrogiulio Frascellaa and Alfonso Zambona
aDipartimento di Scienze Ambientali, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
bDipartimento di Chimica, Universita` Ca’ Foscari di Venezia, Dorsoduro 2137, I-30123 Venezia, Italy
Received 16 January 2003; revised 7 March 2003; accepted 7 March 2003
Abstract—The resolution by Lipase PS of rac-5 (from reduction of ketone 6, obtained from dicyclopentadiene with a new
environment-friendly synthesis) gives (2S)-5, which was further reduced to the endo (2R)-1a alcohol. The endo (2S)-1b alcohol was
obtained from camphor with a multistep synthesis. Pinacol couplings of 3a,b, carried out with Mg/Hg or Corey’s general
procedure respectively, afforded with high diastereoselectivity the C2 symmetry diols (2R,2%R)-2a and (2S,2%S)-2b, with endo
oriented OH functions. The enantiogenic power of the endo alcohol (2R)-1a and (2S)-1b and of the diols (2R,2%R)-2a and
(2S,2%S)-2b was tested towards the LiAlH4 reduction of acetophenone. The C2 symmetry appears to play a fundamental role.
© 2003 Elsevier Science Ltd. All rights reserved.
Optically active 1,2-diols are of widespread use as chiral
auxiliaries in asymmetric synthesis and a large number
of such compounds have been reported so far.1 Among
them, C2-symmetrical diols are of particular interest,
due to the numerous additional advantages of the C2
auxiliaries over the asymmetrical ones.2 In this work we
describe the synthesis of new enantiopure, C2-symmetri-
cal diols based on the endo-dicyclopentadiene skeleton,
and a preliminary evaluation of their enantiogenic
power. Actually, the 1a and 1b alcohols, with endo
oriented OH groups, are attractive substrates for the
development of chiral auxiliaries, by virtue of their
most interesting steric feature: the two faces of the
five-membered ring are strongly differentiated by the
wrapping of the bicyclo moiety, thus making the endo
face much more hindered than the exo one. This poten-
tial ability may also be shared by the enantiopure diols
2a and 2b, which in addition offer the advantage of C2
symmetry.
The synthetic approach towards chiral diols 2a and 2b
is based on the pinacol coupling of enantiopure ketones
3a and 3b, which occurs exclusively via an exo–exo
approach of the two monomers, because of the steric
hindrance exerted by the wrapping to the endo face.3
The OH groups of the diols are therefore pushed
toward the endo face of the dicyclopentadiene skeleton,
thus achieving the presumably greatest enantiodifferen-
tiating capability.
The synthesis of the enantiopure ketone 3a, is achieved
via resolution of the suitable substrate by Lipase PS
enzyme.4,5 The resolution may be performed on either
the exo alcohol 4 or on the endo alcohol 5. The exo
alcohol 4, in the racemic form, was directly obtained
from oxidation of the cyclopentadiene dimer by seleni-
* Corresponding author. Tel.: + 39-0412348619; fax: +39-0412348584;
e-mail: lucchini@unive.it
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00664-6

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G. Borsato et al. / Tetrahedron Letters 44 (2003) 3517–3520
um(IV) oxide.6 The Lipase PS resolution then gives
(2R)-4,5 which was then further oxidized to ketone
(2R)-6 with MnO2.
The ketone was then coupled in the presence of magne-
sium amalgam.3 The enantiomeric purity was also
confirmed by the coupling reaction, which afforded the
pinacol (2R,2%R)-2a as sole product (a single set of 13C
NMR signals).14 On the contrary, when rac-3a
(obtained with the same synthetic sequel, but skipping
the resolution step) was reacted under the same condi-
tions, a 1:1 mixture of the racemic dl pinacols [(2S,2%S)-
2a and (2R,2%R)-2a] and the of meso pinacol
[(2S,2%R)-2a] was obtained (two sets of 13C NMR sig-
nals).15 As already pointed out, in both cases the cou-
pling resulted from an exo–exo approach of the two
ketones, because of the steric hindrance exerted by the
wrapping to the endo face.
With the aim to avoid the use of toxic selenium(IV), we
selected the alternative synthetic sequel described in
Scheme 1. This sequel considers the direct formation of
ketone rac-6, followed by reduction to the endo alcohol
rac-5. The ketone was obtained in the past by photo-
chemical allylic oxidation of dicyclopentadiene with
singlet oxygen, followed by a multistep procedure,7
which however turned out to be unpractical for a
large-scale preparation. Therefore, we tested a new
methodology to obtain rac-6 in high yields and free
from traces of metals, namely the one-pot allylic oxida-
tion by Mihelich and Eickhoff, catalyzed by tetra-
phenylporphyrin (TPP).8 This methodology proved to
be highly effective for the synthesis of rac-6,9 that was
obtained as the sole product (after work-up the only
contaminant was highly colored TPP, that was not
The optically pure diol (2S,2%S)-2b was synthesized
starting from the known enantiopure, camphor-derived,
acid 8,16 according to the reaction sequence shown in
Scheme 2. After quantitative esterification to 9 with
methyl iodide in acetone,17 the key step for the genera-
tion of the tricyclic system is the intramolecular acyloin
condensation, which occurred in 80% yield by slow
addition (5 h) of ester 9 to a solution of lithium
naphthalenide in THF at −78°C.18 Dehydroxilation of
the a-hydroxyketone 10 with trimethylsilyl iodide in
CHCl3 afforded (2S)-3b in good yield.19
1
detected in the H NMR spectra). The two-step reduc-
tion of rac-6 afforded the endo alcohol rac-5.10 The
Lipase PS resolution of the endo alcohol gave satisfac-
tory results, with the separation of the enantiopure
(2R)-5 endo alcohol from the (2S)-5 acetate.5,11 Jones’
oxidation of the alcohol afforded the (2R)-7 ketone,12
whose enantiomeric purity was confirmed after titration
with Eu(tfc)3, monitored by NMR. The catalytic hydro-
genation of (2R)-7 gave the sought-for (2R)-3a ketone
in almost quantitative yield.13
Scheme 2. Reagents and conditions (yields): (i) CH3I, Na2CO3,
acetone, rt (94%); (ii) Li-Naph., THF, −78°C (80%); (iii)
TMSI, CHCl3 (quant.); (iv) Mg(Hg)/TiCl4, THF, −10°C
(80%).
Scheme 1. Reagents and conditions (yields): (i) O2, Ac2O, Py.,
hw, CH2Cl2, 6 h (quant.); (ii) (1) Zn(0), AcOH, (2) LiAlH4,
THF, rt (70% overall); (iii) vinyl acetate, Lipase PS, t-
BuOMe, 38°C, 7 days (48%); (iv) Jones’ oxidation (80%); (v)
H2, Pd/C, AcOEt (98%); (vi) Mg/Hg, TMSCl, THF, rt (80%).
Figure 1. Schematic representation of the steric hindrance
exerted on the reaction center by the bridgehead positions in
the complexes of diols 2a (left) and 2b (right) with LiAlH4.

G. Borsato et al. / Tetrahedron Letters 44 (2003) 3517–3520
3519
Table 1. Enantiogenic power of endo alcohols (2R)-1a and (2S)-1b and of diols (2R,2%R)-2a and (2S,2%S)-2b towards the
LiAlH4 reduction of acetophenone, in THF at −78°C
Alcohol or diol
LiAlH4:alcohol or diol ratio
Ethanol:diol ratio
Time (h)
Conversion (%)
E.e. (%)
(2R)-1a
(2S)-1b
(2R,2%R)-2a
(2R,2%R)-2a
(2S,2%S)-2b
(2S,2%S)-2b
1:3
1:3
1:1
1:1
1:1
1:1
–
–
–
1:1
–
2
2
2
6
2
2
80
60
75
27
75
60
0
5
15
30
35
17
1:1
Unexpectedly, the procedure for pinacol coupling with
magnesium amalgam is not effective for ketone 3b.
After unsuccessful investigations of alternative coupling
reagents, such as SmI2 or Li/NH3, the diol (2R,2%R)-2b
was finally obtained with a satisfactory 80% yield by
the Corey’s general procedure for the reductive cou-
pling of carbonyl compounds.20,21
other chiral diols with C2 symmetry,23 the e.e. is
increased to 30% by the participation of an equimolar
amount of ethanol. As expected, diol (2S,2%S)-2b gives
the best results: the reduction of acetophenone with
equimolar LiAlH4 gives 35% e.e. Curiously, the addic-
tion of an equimolar amount of ethanol reduces, in this
case, the e.e. to 17%, probably because of the strong
steric strain of the LiAlH4–2b–EtOH complex, which
promotes his disproportionation into less selective
species.22a
These results clearly highlight the importance of the C2
symmetry. The observed enantioselectivity is modest,
however comparable to that of other chiral C2 aliphatic
diols.24 Actually, it is not clear if the low e.e. should be
attributed to the modestly efficient steric shielding of
the norbornane units or by electronic effects, which
seems to favor aromatic chiral auxiliary over aliphatic
ones in the asymmetric reduction of ketones.22b,c In the
continuation of this research further modifications of
the norbornane structure will be evaluated, together
with alternative applications of these promising
molecules.
Finally, stereoselective reduction of (2R)-3a and (2S)-
3b by LiAlH4 gave the corresponding endo alcohols
(2R)-1a and (2S)-1b with excellent yields.
To test the enantiogenic capability of diols (2R,2%R)-2a
and (2S,2%S)-2b, the asymmetric reduction of acetophe-
none with the diol/LiAlH4 adducts was examined.22
Because of the steric repulsion between the two norbor-
nane moieties, these latter units and the hydroxy groups
in free 2a or free 2b are reciprocally gauche oriented.
However, when the diol 2a or the diol 2b combine with
LiAlH4, the CꢀO bonds should assume an almost
eclipsed conformation around the central CꢀC bond,
thus acquiring an increased rigidity and a C2 axial
symmetry, with steric shielding exerted by the norbor-
nane units at the opposing angles of a quadrant, as
represented in Figure 1. It is worth noting that the
bridgehead positions are strategically oriented towards
the reaction center, and thus affecting the asymmetric
induction. The diol 2b, which bears a methyl sub-
stituent at the bridgehead positions, is then expected to
exert a greater asymmetric induction than the unsubsti-
tuted diol 2a.
Acknowledgements
This work was cofounded by MURST (Rome) within
the national project ‘Stereoselezione in Sintesi Organ-
ica. Metodologie e Applicazioni’. We gratefully thanks
Amano Pharmaceutical for a kind donation of Lipase
PS enzyme.
Moreover, it may be wondered whether the enantio-
genic power is to be attributed to the C2 structure of
diols 2a and 2b, or it is rather already present in the
monomeric alcohol units. Actually, the hydroxyl group
in the endo alcohol (2R)-1a and (2S)-1b is positioned
inside an helically-shaped scaffold, characterized by
structural rigidity and presenting the faces of the
hydroxycyclopentane ring strongly differentiated as for
the steric shielding.
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