Optical resolution of racemic norbornene aldehydes: Kinetically controlled intramolecular haloetherification of ene acetals

Article abstract of DOI:10.1016/S0040-4039(00)00039-3

Haloetherification reaction of a diastereomeric mixture of the ene acetals 2 and 2', derived from racemic norbornene aldehydes and chiral non- racemic (S,S)-hydrobenzoin, proceeded in a kinetically controlled manner to give the optically pure aldehydes 3 along with the intact ene acetals 2'. Compounds 3 and 2' were converted to the optically pure norbornene aldehydes in both enantiomeric forms. Then a new chiral auxiliary for asymmetric desymmetrization of meso-1,2-diols was found. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00039-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1829–1832
Optical resolution of racemic norbornene aldehydes: kinetically
controlled intramolecular haloetherification of ene acetals
Hiromichi Fujioka,∗ Naoyuki Kotoku, Yasushi Nagatomi and Yasuyuki Kita ∗
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka, 565-0871, Japan
Received 6 December 1999; accepted 24 December 1999
Abstract
Haloetherification reaction of a diastereomeric mixture of the ene acetals 2 and 20, derived from racemic
norbornene aldehydes and chiral non-racemic (S,S)-hydrobenzoin, proceeded in a kinetically controlled manner
to give the optically pure aldehydes 3 along with the intact ene acetals 20. Compounds 3 and 20 were converted to
the optically pure norbornene aldehydes in both enantiomeric forms. Then a new chiral auxiliary for asymmetric
desymmetrization of meso-1,2-diols was found. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: optical resolution; kinetic control; norbornene aldehyde; intramolecular haloetherification; ene acetal;
hydrobenzoin.
Recently, we developed a new asymmetric desymmetrization method of meso-1,2-diols using optically
pure chiral non-racemic methylnorbornene aldehyde (2R)-1a as a chiral auxiliary. This method is quite
useful because it forms an efficient desymmetrization reaction cycle and works well for not only cyclic
meso-diols but also acyclic ones.1 However, in the studies we prepared (2R)-1a through asymmetric
Diels–Alder reaction using rather expensive Evans’ reagent as a key reaction.2 This preparation method
is useful to get optically pure (2R)-1a, because the product (90% de) of asymmetric Diels–Alder reaction
is recrystallized. Usually asymmetric Diels–Alder reactions are used for synthesizing optically active
norbornene derivatives, but the methods make it hard to get optically pure compounds without the
recrystallization process.3 So only the recrystallized compounds, which are very limited, are obtained
in an optically pure state and this methodology does not have generality. We present here an alternative
way of getting optically pure norbornene aldehyde derivatives by optical resolution via a kinetically
controlled intramolecular haloetherification using easily obtained chiral non-racemic (S,S)-hydrobenzoin
4 for a chiral resolving auxiliary (Scheme 1). And we found that non-volatile compound 1d became a
better auxiliary for our desymmetrization cycle; in contrast to this, 1a is volatile and its treatment needed
a lot of care.
∗
Corresponding author. E-mail: fujioka@phs.osaka-u.ac.jp (H. Fujioka), kita@phs.osaka-u.ac.jp (Y. Kita)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00039-3
tetl 16319

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Scheme 1.
First, we investigated the ability of chiral nonracemic diols, viz, (S,S)-hydrobenzoin 4, (2S,3S)-1,4-
dimethoxy-2,3-butanediol 5, (1R,2S,3R,4S)-1,7,7-trimethylbicyclo-[2,2,1]-heptane-2,3-diol 6 and diethyl
L-tartrate 7, as chiral resolving auxiliaries using racemic norbornene aldehyde 1a as a substrate (Fig. 1).
Acetalization of (2S)- and (2R)-1a with chirals 4, 5, 6 and 7 proceeded without any problem to give
corresponding diastereomixtures, 2a and 20a, in a quantitative yield. The haloetherification reaction was
carried out with NBS (0.5 equiv.) in the presence of H2O (5 equiv.) at rt. The reaction of the mixture of
2a and 20a, derived from racemic 1a, a 1:1 mixture of (2S)- and (2R)-1a, and 4, proceeded with very high
selectivity and gave the pure product 3a (44%), which was easily purified from the trace amount of the
diastereomer of 3a derived from 20a and the intact ene acetal 20a (50%, 96% de) by simple SiO2 column
chromatography separation (Scheme 2).4 Its stereochemistry was determined by conversion to the known
compound.1 On the other hand, 5–7 did not show enough ability as chiral-resolving auxiliaries (Fig. 1).
This observation clearly shows that hydrobenzoin 4 is the auxiliary of choice for optical resolution.
We rationalized these results due to the large steric repulsion in 20a between the norbornene aldehyde
skeleton and the benzene ring which is bulky and sterically fixed. That is, the haloetherification reaction
of 20a hardly proceeds and kinetic control occurred with high selectivity.
Fig. 1.
Applicability of this method to other racemic norbornene aldehydes, prepared in the usual way using
the Diels–Alder reaction of unsaturated aldehydes and cyclopentadiene, was then examined. The results
are shown in Table 1, including those for 2a and 20a for comparison. Treatment of 2a–d and 20a–d with
NBS (0.5 equiv.) afforded the pure aldehydes and the intact ene acetals with high diastereoselectivities
(Entries 1, 4 and 5). In the case of 2c and 20c, optically pure 20c was obtained (Entry 4). Slight excess
use of NBS was effective in increasing the diastereomeric excess of 20 (Entries 3 and 6).
Having successfully accomplished the kinetic control, we then focused our attention on the conversion

1831
Scheme 2.
Table 1
of 3 and 20 to the corresponding aldehydes (2S)- and (2R)-1. Although the yields of (2S)- and (2R)-1a,
and (2S)- and (2R)-1b were low because of their volatility, other non-volatile norbornene aldehydes (2S)-
and (2R)-1c, and (2S)- and (2R)-1d were obtained in sufficient yields. The transformation is shown in
Scheme 3. That is, debromoetherification of 3c and 3d with Zn/Zn(OTf)2 afforded (2S)-1c (80%) and
(2R)-1d (98%) along with chiral hydrobenzoin 4 respectively.5 Stereochemistries of the aldehydes were
determined by comparison with the authentic samples1 and these results made the stereochemistries of
the hydroxy aldehydes 3 and the ene acetals (2R)-2 clear. The conversion of the intact ene acetals 20c and
20d to the enantiomers of (2S)-1c and (2R)-1d, (2R)-1c (82%) and (2S)-1d (87%), with 4 was attained by
AcOH treatment.
Scheme 3.
Having both the enantiomers of norbornene aldehyde derivatives in hand, we examined the ability
of norbornene aldehyde (2R)-1d, which is non-volatile, as a chiral auxiliary for asymmetric desym-
metrization of meso-1,2-diols. Acetalization of (2R)-1d with meso-2,3-butanediol 8 afforded cis-ene
acetal 9 stereospecifically in quantitative yield. Intramolecular haloetherification, debromoetherification

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with Zn/Zn(OTf)2, protection of the hydroxyl group as a benzyl ether, then transacetalization using 8,
proceeded highly stereoselectively without any problem and gave the optically active 10.1 From this it
was proved that (2R)-1d is a good chiral auxiliary in the place of (2S)-1a (Scheme 4).
Scheme 4.
In conclusion, we disclosed the optical resolution method of norbornene aldehyde derivatives via
an extremely highly kinetically controlled intramolecular haloetherification and found a good chiral
auxiliary for our desymmetrization cycle. Since the method shown here could open the way to achieving
both enantiomers of the norbornene aldehydes in an optically pure state by an easy procedure, this work
will provide a useful tool for many studies using optically active norbornene aldehydes.
Acknowledgements
Financial support from Monbusho (Grant-in-Aid for Scientific Research on Priority Areas, No. 706:
Dynamic Control of Stereochemistry) and the Promotion of Science (No. 10671989) are gratefully
acknowledged.
References
1. Fujioka, H.; Nagatomi, Y.; Kitagawa, H.; Kita, Y. J. Am. Chem. Soc. 1997, 119, 12 016–12 017; Fujioka, H.; Nagatomi, Y.;
Kotoku, N.; Kitagawa, H.; Kita, Y. Tetrahedron Lett. 1998, 39, 7309–7312.
2. Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc. 1988, 110, 1238–1256.
3. Poll, T.; Hady, A. F. A.; Karge, R.; Linz, G.; Weetman, J.; Helmchen, G. Tetrahedron Lett. 1989, 30, 5595–5598; Takasu, M.;
Yamamoto, H. Synlett 1990, 194–196; Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J. Am. Chem. Soc. 1998,
120, 6920–6930, and references cited therein.
4. Experimental procedure for haloetherification: To a stirred solution of 2a and 20a (0.1 mmol) in CH3CN (1 ml) were added
H2O (5 equiv.) and NBS (0.5 equiv.) at rt under N2. After completion of the reaction (TLC check), aqueous saturated Na2S2O3
was added to the mixture. Extraction with EtOAc, the usual workup and purification by silica gel column chromatography
(hexane:EtOAc) afforded 3a and 20a.
5. Typical experimental procedure for debromoetherification: To a stirred solution of 3c (0.1 mmol) in CH3CON(CH3)2 (DMA)
(1 ml) were added Zn(OTf)2 (10 equiv.) and Zn (30 equiv.) under N2. The mixture was stirred at around 80°C. After completion
of the reaction (TLC check), the mixture was diluted with ether and filtered through a Celite pad. The filtrate was evaporated
in vacuo and purified by silica gel column chromatography (hexane:EtOAc) to afford (2S)-1c and 4.