A new and concise synthetic route to an enantiopure (+)-conduritol-E derivative from diethyl L-tartrate

Article abstract of DOI:10.1016/S0957-4166(99)00517-0

(+)-(1R,2R,3S,6S)-3,6-Di-O-methyl conduritol-E was efficiently synthesized in enantiomerically pure form starting from diethyl L-tartrate in 33% total yield using a ring-closing olefin metathesis reaction as one of the key steps. (C) 1999 Elsevier Science

Full text of DOI:10.1016/S0957-4166(99)00517-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4473–4475
A new and concise synthetic route to an enantiopure
(+)-conduritol-E derivative from diethyl L-tartrate
Woo-Wha Lee and Sukbok Chang ∗
Department of Chemistry, Ewha Womans University, Seoul 120-750, South Korea
Received 18 October 1999; accepted 11 November 1999
Abstract
(+)-(1R,2R,3S,6S)-3,6-Di-O-methyl conduritol-E was efficiently synthesized in enantiomerically pure form
starting from diethyl L-tartrate in 33% total yield using a ring-closing olefin metathesis reaction as one of the
key steps. © 1999 Published by Elsevier Science Ltd. All rights reserved.
A series of conduritols such as conduritol-E 1 and their derivatives are a prominent class of biologically
active compounds.1 Several of these cyclitols have been shown to inhibit the action of glycosidases.2
Moreover, they serve as versatile building blocks for the synthesis of compounds of biological signif-
icance such as inositols and their analogs. This has stimulated considerable efforts toward the synthesis of
this class of compounds with high enantiomeric excess.3 Optically active conduritol-E 1 or its derivatives,
one of the six possible diastereomers of 5-cyclohexene-1,2,3,4-tetraols, have been prepared either from
meso-benzene-derived dienediols or from inositol derivatives already equipped with all the necessary
stereogenic centers.4 However, successes in these synthetic approaches critically rely either on the
reliability of kinetic resolution to provide the required stereogenic centers or on the efficiency of tedious
protection/deprotection sequences. This report describes a short and concise strategy for the synthesis of
an enantiomerically pure conduritol-E derivative using ring-closing olefin metathesis as one of the key
steps.
As outlined in Scheme 1, a brief analysis of the structure of conduritol-E 1 indicated that the
cycloolefinic skeleton could be accessible by ring-closing olefin metathesis of a symmetric dialkenyl
precursor 2 (or in its protected form). The required dienyl tetraol 2 was envisioned to be readily prepared
by a stereoselective bis-addition of a vinyl nucleophile onto 2,3-dihydroxy butanedialdehyde (or its
equivalent) which in turn could be derived from the enantiomerically pure tartrate ester 3. The realization
of this approach is shown in Scheme 2.5 It has been known that partial reduction of the two ester groups in
4 with DIBAL-H at low temperature provides a corresponding dialuminate which in turn, as an aldehyde
equivalent, reacts under Wittig conditions to afford diolefinic compounds in good yields.6 We anticipated
∗
Corresponding author.
0957-4166/99/$ - see front matter © 1999 Published by Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00517-0
tetasy 3152

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W.-W. Lee, S. Chang / Tetrahedron: Asymmetry 10 (1999) 4473–4475
that an addition product could be obtained with a marginal facial selectivity by the treatment of the
dialdehyde equivalent with nucleophiles such as a Grignard reagent.
Scheme 1.
Partial reduction of diethyl (2R,3R)-2,3-O-isopropylidenetartrate 4 was performed by the action of
2.1 equiv. of DIBAL-H at −78°C. The dialdehyde equivalent generated was unstable and thus was
treated in situ with vinylmagnesium bromide at low temperature to afford the bis-allyl alcohol 5 and
its diastereomers as a mixture in 65–75% combined yields. We were pleased to observe that the
(bis)syn-product 5 was produced with predominance over the other diastereomers in a ratio of 77:23
1
(5:other three diastereomers) based on the H NMR integration of the crude reaction mixture.7 In
the addition reaction, several attempts were made to achieve better selectivity such as use of different
solvent systems, addition of vinyllithium instead of vinylmagnesium bromide, or use of some additives
(MgBr2 or ZnCl2). The resultant selectivities, however, were less satisfactory. The value of coupling
constants (JH3–H4=JH5–H6=4.4 Hz) of 5 separated by column chromatography on silica gel confirmed a
cis relationship for the two pairs of protons (H3/H4 and H5/H6).8 This is the first example, to the best of
our knowledge, of a stereoselective bis-addition of a nucleophile to a dialdehyde equivalent derived from
a tartrate moiety.9
Scheme 2. Reagents and conditions. (a) (i) DIBAL-H (2.1 equiv.)/toluene, −78°C, 2.5 h,( ii) CH2_CHMgBr (3.0 equiv.), −78°C
to rt (54% in two steps); (b) NaH (3.0 equiv.)/CH3I (4.0 equiv.)/DMF (94%); (c) 10% HCl/MeOH (99%); (d) Ac2O/Et3N/DMAP
(92%); (e) 9 (12 mol%)/CH2Cl2, 45°C, 18 h (73%); (f) K2CO3/MeOH (99%)
Although ring-closing olefin metathesis (RCM) has recently proven to be a very powerful tool for
the synthesis of carbocycles and heterocycles,10 direct cyclization of the dienyl compound 5 was
unsuccessful using the Grubbs’ Ru–benzylidene complex Cl2(PCy3)2Ru_CHPh (9) as the catalyst.11
Treatment of 5 with the catalyst 9 produced the corresponding fused cyclic diol in less than 5% yield
under a variety of reaction conditions. Low reactivity exhibited by the dienyl compound 5 for RCM
was not unexpected considering that the substrate is conformationally restrained for ring closure and the
nearby free hydroxyl group may deactivate the catalyst by coordination. The trans-acetonide protecting
group in 5 would force the two ethylenic appendages in a trans orientation to each other and this
unfavorable conformation of 5 may contribute in part to the lack of reactivity of this diolefinic compound
to the metathesis reaction.12 This led us to protect the allylic hydroxyl group of 5 and subsequent

W.-W. Lee, S. Chang / Tetrahedron: Asymmetry 10 (1999) 4473–4475
4475
conversion of the cyclic trans-acetonide of 5 to a different acyclic protecting group. The three successive
protection/deprotection steps (5–8) proceeded with high efficiency (86% yield over three steps). RCM
of the fully protected dienyl compound 8 was effected in refluxing CH2Cl2. The cyclohexenyl product
10 was isolated in 73% yield using 12 mol% of the catalyst 9, which was fed to the reaction mixture
in three portions over 18 h. Deacetylation of 10 provided 3,6-di-O-methyl conduritol-E 11 in an almost
quantitative yield. Its analytical data were completely identical to those reported in the literature4c and
its enantiomeric excess was determined to be >99.7%.13
In conclusion, an enantiomerically pure conduritol-E derivative 11 was efficiently synthesized in 33%
total yield from a cheap and accessible starting chiral compound through a series of routine organic
reactions and eventual RCM process that is currently prevailing.
Acknowledgements
This research was supported by the Center for Molecular Design and Synthesis (CMDS) at KAIST and
by the Ewha Womans University. The authors would like to thank Jooyoung Noh and Young-Ok Kim for
the preliminary experiments.
References
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7. (Bis)syn-product 5: 1H NMR (250 MHz, CDCl3) δ 5.99–5.92 (m, 2H), 5.42–5.27 (m, 4H), 4.19 (br s, 2H), 3.90 (dd, J=4.4,
1.5 Hz, 2H), 1.55 (br s, 2H), 1.41 (s, 6H); 13C NMR (CDCl3) δ 137.2, 117.5, 109.9, 82.4, 74.3, 27.5; IR (CH2Cl2) cm−1
3368 (broad), 2989, 2891, 1645, 1429, 1166, 996, 930; HRMS (CI) calcd for C11H19O4 [M+H]+ 215.1284, found 215.1286;
[α]2D5=−23.6 (c 1.0, CH2Cl2). (Bis)anti-isomer of 5: 1H NMR (250 MHz, CDCl3) δ 5.95–5.87 (m, 2H), 5.40–5.25 (m, 4H),
4.31 (dd, J=14.2, 6.3 Hz, 2H), 4.03 (m, 2H), 2.88 (bs, 2H), 1.44 (s, 6H).
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9. For some examples on stereoselective addition of various nucleophiles to mono-aldehyde derived from tartrate ester, see:
(a) Majewski, M.; Shao, J.; Nelson, K.; Nowak, P.; Irvine, N. M. Tetrahedron Lett. 1998, 39, 6787. (b) Chattopadhyay, A.;
Dhotare, B. Tetrahedron: Asymmetry 1998, 9, 2715.
10. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
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D. L.; Strehler, C.; Eustache, J. Tetrahedron Lett. 1999, 40, 853. (b) Ovaa, H.; Codee, J. D. C.; Lastdrager, B.; Overkleeft,
H. S.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 1999, 40, 5063. (d) Kapferer, P.; Sarabia, F.; Vasella, A. Helv.
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1996, 505. (c) Hammer, K.; Undheim, K. Tetrahedron 1997, 53, 5925.
13. [α]2D5=+233.40 (c 1.00, CHCl3) [lit.4c [α]D27=−234.04, the enantiomer of 11 (c 1.00, CHCl3)].