Two novel strategies for the construction of the core acetal of the zaragozic acids

Article abstract of DOI:10.1055/s-1999-2709

Novel strategies for the construction of the core 2,8- dioxabicyclo[3.2.1]octane ring system of zaragozic acids/squalestatins non- based on usual ketalisation are described.

Full text of DOI:10.1055/s-1999-2709

LETTER
697
Two Novel Strategies for the Construction of the Core Acetal of the Zaragozic
Acids
Claude Taillefumier, Mohammed Lakhrissi1, Yves Chapleur*
Groupe SUCRES, Unité Mixte 7565 CNRS-Université Henri Poincaré-Nancy 1, BP 239, F-54506 Vandoeuvre, France
Fax + 33 383 91 23 55 ; E-mail: yves.chapleur@meseb.u-nancy
Received 17 February 1999
D-glucose is a suitable material since the hydroxyls at
Abstract: Novel strategies for the construction of the core 2,8-di-
C-2 and C-3 have the absolute configuration required in
oxabicyclo[3.2.1]octane ring system of zaragozic acids/squalest-
zaragozic acids (C-6 and C-7). The aldehyde group at
C-1 is also suitable both for acetal formation and chain ex-
tension. Our retrosynthetic analysis of the core structure 1
of zaragozic acid takes into account these different fea-
tures. In our first model study the ketonic key intermediate
2 was chosen as a reasonable target. Chain extension at
C-4 and C-3 of 2 should open the way to zaragozic acids.
We planned to form the dioxabicyclic system of 2 by nu-
cleophilic displacement of a suitably oriented leaving
group (LG) as depicted on structure 3. The keto group at
C-5 in 3 should came from the C-5 of the glucose ring. A
straightforward formation of this carbonyl group without
sugar ring opening by way of laborious protection se-
quences would be the dihydroxylation of the 5,6-double
bond of the unsaturated sugar 4.
atins non-based on usual ketalisation are described.
Key words: Zaragozic acids, carbohydrate lactone, Wittig reaction,
1,4-addition
Zaragozic acids/squalestatins are newly discovered fungal
metabolites exhibiting high inhibition of squalene syn-
thase, an enzyme involved in the cholesterol biosynthe-
sis.2 Their biological properties made these compounds
interesting leads for the discovery of new cholesterol-low-
ering drugs. Some members of this family are inhibitors of
the ras farnesyl transferase and may have some interest in
relation with cancer therapy. Accordingly, it explain the
considerable body of synthetic work aimed at the total
synthesis of these compounds.3 Last but not least, these
compounds show intricate structures merely composed of
a core bicyclic system of nine carbons with six contiguous
chiral centres, three of which being quaternary. This was
sufficient to trigger synthetic efforts toward the synthesis
of this core 2,8-dioxabicyclo[3.2.1]octane structure. 2, 4
Most of the strategies for the construction of the bicyclic
structure rely on the formation of an acetal between an ap-
propriate carbonyl group (C-1) and two alcohol func-
tions.2 However, given the high number of hydroxyl
groups in the core structure, this approach is not straight-
forward because of the formation of unexpected acetals
and ring size modification by equilibration in acidic medi-
um.5 In this context we tried to devise new routes for the
formation of this acetal ring which would not be based on Scheme 1 Retrosynthetic analysis
acetal formation in acidic medium but would be formed in
basic medium or by nucleophilic attack on suitable deriv-
The synthesis began with the known crystalline dimes-
ative. We report in this paper two different and efficient
ylate 5 which is easily prepared in 4 steps from glucose.7
routes to model 2,8-dioxabicyclo[3.2.1]octane ring sys-
Selective displacement of the primary mesylate gave the
tems starting from sugars.6
crystalline iodo derivative 6 in excellent yield. Formation
of the double bond was achieved by treatment with sodi-
um hydride in DMF in 73% yield.8 Brief treatment of 7
under Shing conditions (RuCl3, NaIO4)9 gave the expected
diol 8. In our first experiment purification of this com-
pound on a silical gel column resulted in the removal of
the aglycon and formation of the 1,6-anhydro derivative 9.
Later on, this reaction was best performed by treatment of
8 with silica gel in dichloromethane in 73% overall yield.
Figure 1 Zaragozic acid A / Squalestatin S1
To our delight, treatment of 9 with DBU in THF gave the
bicyclic structure 10 in 74% yield.10, 15 It is likely that the
Synlett 1999, No. 6, 697–700 ISSN 0936-5214 © Thieme Stuttgart · New York

698
C. Taillefumier et al.
LETTER
base promotes proton abstraction of the hemiacetal and
subsequent opening of the pyranose ring. The newly
formed hemiacetal was then well positioned to displace
the mesylate group forming a five-membered ring. An ap-
proach to the core structure of zaragozic acids based on a
related nucleophilic ring opening of an epoxide appeared
while this work was in progress.4j
Scheme 3 Second retrosynthetic analysis
ton. Furthermore oxidation of the hydroxyl group gave the
corresponding ketone (not shown here) whose NMR spec-
trum showed that H-4 and H-5 appeared as two doublets
(J = 7.0 Hz). We therefore concluded that the thermody-
namically favoured 6,8-dioxabicyclo [3.2.1]octane13 was
formed rather than the expected 2,8-dioxabicyclo[3.2.1]
one. It is likely that under the basic conditions required for
the 1,4-addition, the acetate group of 19 migrates to the
primary position and that formation of the furanose ring
occurs followed by ring size modification from the 5-
fused ring to the less strained 6-membered ring.
Aempts to protect the hydroxyl group of 15 with a meth-
oxymethyl ether or benzyl ether were unsuccessful. How-
ever introduction of an allyl protecting group can be
performed in modest yield using the tin methodology.14
Lactone 15 was treated with tributyltin oxide in toluene
under azeotropic reflux to provide the intermediate stan-
nyl derivative which was alkylated with allyl bromide in
Scheme 2 Reagents: i: NaI, butanone, reflux, 90%; ii: NaH, DMF,
73%; iii: RuCl3, NaIO4, AcOEt/CH3CN/H2O, 30s; iv: SiO2, CH2Cl2
71% over 2 steps; v: DBU, THF, 74%.
In the second approach, (Scheme 3) we planned to intro- the presence of tetra-n-butylammonium bromide at 80°C.
duce a carbon chain at C-1 of the zaragozic acid core The allyl derivative 17 was formed together with a yet un-
structure early in the synthesis. Accordingly, the target identified isomer. Column chromatography gave the pure
structure should be 11 and the key compound of our mod- derivative 17 which was treated under our Wittig condi-
el studies was then 12. An ester (Z) should be suitable for tions to provide the olefin 20 in 62% (E + Z mixture). Se-
further chain elongation and this ester could suitably acti- lective hydrolysis under standard conditions proceeded in
vate the double bond of olefin 13. to promote the 1,4-ad- 90% yield to give the diol 21. Cyclisation of this diol gave
dition of hydroxyl groups. Examples of such a reaction compound 22 in 76% yield establishing the definitive
with this type of olefin to form furanic structures have route to our model core structure of zaragozic acids.15
been recently described by our group.11 Heptose 14 which
could be in turn transformed into 13 should be now a good
starting compound.
We have presented two novel strategies for the construc-
tion of the 2,8-dioxabicyclo[3.2.1]octane core of the zara-
gozic acid. These synthetic appproaches open the way to
Olefin 18 readily available from the D-glucoheptono lac- total synthesis of these compounds. However an impor-
tone derivative 16 was chosen as starting material.12 Se- tant problem to address is the introduction of the C-5 car-
lective hydrolysis of the 6,7-acetal gave diol19 which was boxylic chain at the early beginning of the synthesis.
treated with DBU in THF to promote the expected 1,4-ad- Accordingly, in the first approach, this would lead to the
dition. A single compound was obtained in 61% yield. formation and substitution of a tertiary mesylate at C-4 of
However the NMR data of this compound was in favour glucose. Probably the second approach would be more
of structure 23. The chemical shift of the two protons of fruitful. Indeed, a number of lactones like 17 having a sub-
the methylene group C-9 (d: 4.17 and 4.52) clearly indi- stituent at C-4 have been synthetized in several approach-
cated the presence of an acetate group at this carbon. On es toward zaragozic acids.3a, 3d, 3e, 4e, 4k, 4q Application of our
the other hand NOE experiments showed a close proxim- Wittig-based methodology to suitable lactones would
ity between one methyl of the isopropylidene ring and the likely open a new route to zaragozic acids synthesis. This
H-6 proton which was also coupled with the hydroxyl pro- approach is currently investigated in our group.
Synlett 1999, No. 6, 697–700 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Two Novel Strategies for the Construction of the Core Acetal of the Zaragozic Acids
699
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Scheme 4 Reagents: i: Ac2O, pyr; ii: 1) (Bu2Sn)2O, toluene, reflux;
2) AllylBr, Bu4NBr, 80°C, 48%; iii: Ph3PCH2COOMe, toluene,
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References and Notes
(1) On leave of absence from the Faculty of Sciences, University
Ibn Tofail, Kenitra (Morocco).
(2) For a comprehensive review on the isolation, biological
properties and synthesis see: Nadin, A.; Nicolaou, K. C.
Angew. Chem. Int. Ed. Engl. 1996, 35, 1623.
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+ 46.4 (c 0.7, CHCl3). IR n (cm-1): 3424, OH of hydrate; 1744,
CO. 1H NMR (400 MHz, CDCl3): d: 3.93 (d, 1H, J2,3 1.5 Hz,
H6); 4.20 (ddd, 1H, J1,2 4.5 Hz, J2,4 1.5 Hz, H7); 4.33 (d, 1H, J
= 18 Hz, H3); 4.43 (dd, 1H, J = 18 Hz, H3’); 4.47 (d, 1H, J 11.5
Hz, PhCH2); 4.52 (broad s, 1H, H5); 4.53 (d, 1H, J = 11.5 Hz,
PhCH2); 4.58 (d, 1H, J = 11.5 Hz, PhCH2); 4.67 (d, 1H, J =
11.5 Hz, PhCH2); 5.66 (d, 1H, H1). 13C NMR (250 MHz,
C6D6) d; 70.1 (C3); 71.9 (CH2Ph); 72.9 (CH2Ph) 84.1(C6);
85.3 (C7); 86.1 (C5); 97.4 (C1); 128.0-128.5 (10C Ph), 136.6,
136.9 (Cquat) 202.1 (C5); MS (EI 70 eV) m/z: 340.3 (M+°);
249.2 (M-CH2Ph), 204.1, 188.1, 105.1.
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Analytical data of compound 22: Rf 0.27 (H:A 2/1). [a]D
+ 17.1 (c 1.5, CHCl3). 1H NMR (400 MHz, CDCl3 and D2O)
d; 1.27 (s, 3H, CH3 acetonide); 1.42 (s, 3H, CH3 acetonide);
2.83 (d, 1H, Jgem = 15.4, CH2CO2Me); 2.91 (d, 1H, Jgem = 15.4,
CH2CO2Me); 3.64 (s, 3H, CO2Me); 3.68 (dd, 1H, Jgem = 12.5,
J
6,7 = 8.0 Hz, H8); 3.78 (dd, 1H, J4,5 = 5.3, J5,6, = 5.6 Hz, H6);
3.83 (dd, 1H, Jgem = 12.5, J3,8’ = 5.8 Hz, H8’); 4.02 (broad dd,
1H, Jgem = 12.4, J = 6.2 Hz, CH2=CH-CH2O); 4.16 (m, 1H,
H3); 4.26 (broad dd, 1H, Jgem = 12.4, J = 4.6 Hz, CH2=CH-
CH2O); 4.32 (d, 1H, J2,3 = 6.8, H7); 4.37 (dd, 1H, J6,7 = 6.8, J5,6
= 5.6 Hz, H6); 4.49 (dd, 1H, J4,5 = 5.3, J3,4 = 4.6 Hz, H4); 5.17
(dd, 1H, Jcis = 10.2 Hz, CH2=CH-CH2O); 5.23 (dd, 1H, Jtrans
=
17.2, Jgem = 1.5 Hz CH2=CH-CH2O); 5.82 (m, 1H, CH2=CH-
CH2O). 13C NMR (250 MHz, CDCl3) d; 25.9 and 27.7 (2C, 2
x CH3 acetonide); 39.0 (CH2CO2Me); 51.8 (CO2Me); 60.6
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(C8); 71.4 (CH2=CH-CH2O); 75.8 (C4); 77.0 (C7); 77.5 (C6);
78.6 (C3); 79.1 (C5); 105.2 and 111.7 (2C, C1 and CMe2);
118.5 (CH2=CH-CH2O); 133.3 (CH2=CH-CH2O); 168.8
(CO2Me); MS (EI 70 eV) m/z: 345.4 (M+H +), 329.3, 229.1,
169.1, 100.1. Anal. Calc. for C16H24O8: C, 55.8; H, 7.0;
Found: C, 55.31; H, 6.85.
Article Identifier:
1437-2096,E;1999,0,06,0697,0700,ftx,en;G07999ST.pdf
Synlett 1999, No. 6, 697–700 ISSN 0936-5214 © Thieme Stuttgart · New York