Construction of the zaragozic acids core bicycle

Article abstract of DOI:10.1055/s-1998-1988

Concise synthesis of the bicyclic core of zaragozic acids has been accomplished by the utilization of (2S, 3S)-furylglycerol 7. The key features are based on the diastereoselective dihydroxylation of enone 8 followed by reduction of ketone 11 to control the stereochemistries at the C4-C6 positions of the target molecule. Addition of lithium trimethylsilylacetylide to aldehyde 20 provided propargyl alcohol 21, which was further transformed into the bicyclic core 25, a potent intermediate for the synthesis of zaragozic acids.

Full text of DOI:10.1055/s-1998-1988

December 1998
SYNLETT
1417
Construction of the Zaragozic Acids Core Bicycle
Masayoshi Tsubuki,* Hiroyuki Okita and Toshio Honda*
Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41, Shinagawa-ku, Tokyo 142-8501, Japan
FAX: 81-3-5498-5791; E-mail: honda@hoshi.ac.jp
Received 1 September 1998
Abstract: Concise synthesis of the bicyclic core of zaragozic acids has
been accomplished by the utilization of (2S, 3S)-furylglycerol 7. The
key features are based on the diastereoselective dihydroxylation of
enone
8 followed by reduction of ketone 11 to control the
stereochemistries at the C4-C6 positions of the target molecule.
Addition of lithium trimethylsilylacetylide to aldehyde 20 provided
propargyl alcohol 21, which was further transformed into the bicyclic
core 25, a potent intermediate for the synthesis of zaragozic acids.
During the screening of fungi for inhibitors of squalene synthase,
1
structurally related novel compounds, zaragozic acids
and
2
squalestatins, were isolated independently from Sporormiella
intermedia and Phoma sp. C 2932 by Merck and Glaxo groups,
respectively.(Figure 1) These natural products exhibited potent activity
against mammalian squalene synthase, a key enzyme in cholesterol
1b,2c
biosynthesis.
These compounds share a common 4,6,7-trihydroxy-
2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid core and differ at
C-1 alkyl and C-6 O-acyl side chains. The interest in both the novel
structural feature and the significant activity has provoked a large
3
number of synthetic studies and has resulted in total syntheses of
4
5
zaragozic acids A and C by 6 groups. For ongoing studies directed to
the synthesis of physiologically active natural compounds using chiral
furylcarbinols, we have been interested in the synthesis of the squalene
The basic features of our strategy towards the bicyclic core of zaragozic
acids are shown in Scheme 1. We envisaged that model core 1 could be
accessible from the highly oxygenated pyran derivative 3 via the acyclic
precursor 2 by the introduction of C1 unit, synthetically equivalent to
carboxylic acid, and the intramolecular acetalization. Compound 3
would arise from manipulation of pyranone 4, derived from chiral
6
synthase inhibitor zaragozic acid. Here we report a facile method for the
7
construction of the bicyclic core of zaragozic acids.
6
furylglycerol 5, on the basis of our previous results.
The requisite chiral pyran 15 was obtained as follows (Scheme 2).
8
Chelation-controlled addition of 2-lithiofuran derivative, prepared by
9
lithiation of 3,4-bis(methoxymethoxymethyl)furan 6, to (S)-2,3-O-
10
isopropylideneglyceraldehyde
in the presence of zinc bromide
afforded furylglycerol 7 in 82% yield with 83% diastereomeric excess.
11
Ring enlargement of 7 with N-bromosuccinimide in aqueous THF

1418
LETTERS
SYNLETT
gave lactol, whose hydroxyl group was protected as silyl ethers 8 and 9
in a ratio of 4.5 : 1, respectively. Osmylation of the major enone 8
proceeded from the opposite side with respect to the adjacent silyloxy
group to furnish the vicinal syn-diol 10 as a sole product. Acid treatment
of diol 10 in acetone resulted in cleavage of both MOM ethers followed
by acetonide formation of the corresponding tetraol to afford
triacetonide 11. Reduction of ketone 11 with NaBH occurred from the
4
less hindered equatorial side to give the desired alcohol 12 (91%)
together with its epimer 13 (9%). The stereostructure of 12 was
unambiguously determined by the X-ray crystallographic analysis of
desilylated compound 14. Alcohol 12 was further converted into lactol
15 by etherification with benzyl bromide and desilylation with
tetrabutylammonium fluoride in 89% yield (2 steps).
Employing the highly oxygenated tetrahydropyran 15, we began to
examine the diastereoselective introduction of an ethynyl moiety, a
latent carboxylic acid group, to lactol. (Scheme 3) Addition of
trimethylsilylethynylmagnesium chloride to 15 furnished adduct 16 as a
12
sole product. The observed selectivity of the Grignard reaction can be
13
understood by the δ-chelation model A as depicted in Figure 2. The
Grignard reagent would form the cyclic intermediate A and the
addition to such polyalkoxy aldehyde 20, the formation of 21 may be
attributed to the formation of the α-chelate B. (Figure 3) The
stereochemistry of 21 was proved by its transformation into the bicyclic
core 25.
nucleophilic addition could occur from the less hindered si-face. The
14
requisite epimer 17 was obtained by Dess-Martin oxidation of
propargyl alcohol 16 and reduction of the corresponding ketose with
15
NaBH in 30% yield (2 steps).
4
Figure 2
With the key intermediate 21 having the desired five contiguous chiral
centers in hand, we explored the construction of 2,8-
dioxabicyclo[3.2.1]octane ring system as follows. (Scheme 5)
Conversion of 21 into precursor 24 was achieved by successive
desilylation of the TMS group in 21, protection of the propargyl alcohol
as MOM ether 22, selective removal of the terminal acetonide group in
In order to aim at the opposite stereochemistry in the introduction of an
ethynyl moiety, we next investigated the nucleophilic addition to
aldehyde 20. (Scheme 4) Conversion of 15 into 20 was carried out by
sequential reduction of 15 with LiAlH , selective acetylation of the
4
primary hydroxyl group, silylation of the secondary hydroxyl group
with TBSOTf, alkaline hydrolysis of the acetate, and Dess-Martin
oxidation of 19 in 76% overall yield. Addition of lithium
trimethylsilylacetylide to 20 proceeded with high diastereoselectivity to
afford propargyl alcohol 21 as an almost sole product. Although it is
very difficult to explain the stereochemical outcome of the nucleophilic
16
22, acetylation of the primary hydroxyl group in 23, and Dess-Martin
oxidation of the resulting secondary alcohol in 48% overall yield.
Treatment of 24 with conc. HCl in MeOH at 50°C for 48 h brought
about removal of all the protecting groups except benzyl ether followed
by the intramolecular acetalization to produce the unstable bicyclic

December 1998
SYNLETT
1419
compounds, which without purification were acetylated to furnish the
Finlay, M. R. V. Tetrahedron Lett. 1997, 38, 4301. (n) Ito, H.;
Matsumoto, M.; Yoshizawa, T.; Tkao, K.; Kobayashi, S.
Tetrahedron Lett. 1997, 38, 9009. (o) Brogan, J. B.; Zercher, C. K.
Tetrahedron Lett. 1998, 39, 1691. (p) Kataoka, O.; Kitagaki, S.;
Watanabe, N.; Kobayashi, J.; Nakamura, E.; Shiro, M.;
Hashimoto, S. Tetrahedron Lett. 1998, 39 , 2371. (q) Mann, R. K.;
Parsons, J. G.; Rizzacasa, M. A. J.Chem. Soc., Perkin Trans. 1
1998, 1283.
requisite bicyclic core 25 and its isomeric acetal 26 in a ratio of 3 : 2,
17
respectively. The stereostructures of both compounds 25 and 26
were elucidated by NMR experiments including HMQC, HMBC,
and NOESY. Especially, the coupling constants (J =2.4Hz for 25,
6-7
J
=3.1Hz for 26) and NOE enhancements between H-3 and H-6 (17%
6-7
for both 25 and 26) provide strong evidence for the stereochemical
assignments.
(4) (a) Nicolaou, K. C.; Nadin, A.; Leresche, J. E.; Yue, E. W.;
LaGreca, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 2190. (b)
Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock, C. H. J. Org.
Chem. 1996, 61, 9126.
(5) (a) Carreira, E. M.; Du Bois, J. J. Am. Chem. Soc. 1994, 116,
10825. (b) Evans, D. A.; Barrow, J. C.; Leighton, J. L.;
Robichaud, A. J.; Sefkow, M. J. Am. Chem. Soc. 1994, 116,
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Synlett 1997, 451. (d) Armstrong, A.; Jones, L. H.; Barsanti, P.
Tetrahedron Lett. 1998, 39, 3337.
Figure 3
Thus, we have developed a concise synthetic route to the bicyclic core
of zaragozic acids employing the stereocontrolled modifications of
chiral pyranone 8, accessible from chiral furylglycerol 7.
(6) (a) Tsubuki, M.; Kanai, K.; Honda, T. J. Chem. Soc., Chem.
Comm. 1992, 1640. (b) Tsubuki, M; Kanai, K; Honda, T. Synlett
1993, 653. (c) Honda, T.; Tomitsuka, K.; Tsubuki, M. J. Org.
Chem. 1993, 58, 4274.
Ackowledgements: This research was financially supported by the
Ministry of Education, Science and Culture, Japan.
(7) A preliminary account of some of this work has been presented.
Tsubuki, M.; Tomitsuka, K.; Okita, H.; Honda, T. Symposium
Papers of 38th Symposium on the Chemistry of Natural Products;
Sendai, Japan, 1996; p 601.
References and Notes:
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2261.
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(9) Furan derivative 6 was prepared from commercially available 3,4-
bis(acetoxymethyl)furan by hydrolysis of the acetate and
etherification of the diol with MOMCl.
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(12) A similar result of Grignard reaction between ethynylmagnesium
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bromide and 2,3-O-isopropylidene-
Buchanan, J. G.; Dunn, A. D.; Edgar, A. R. J. Chem. Soc., Perkin
Trans. 1 1975, 1191.
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(15) Attempts to invert the stereochemistry of the secondary alcohol by
Mitsunobu reaction failed. NaBH reduction of the ketose gave
4
the desired alcohol 17 together with an unidentified product which
might be an overreduction product having a tetrahydropyran
skeleton.
(3) (a) Abdel-Rahman, H.; Adams, J. P.; Boyes, A. L.; Kelly, M. J.;
Mansfield, D. J.; Procopiou, P. A.; Roberts, S. M.; Slee, D. H.;
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24
(17) Data for 25: colorless oil, [α]
+15.8° (c 0.1, CHCl ); υ max
3
D
-1
3480, 3280, 1750 cm ; δ (500MHz, CDCl ) 1.91, 1.98, 2.10 and
H
3
2.17 (each 3H, each s, 4 x CH CO), 2.61 (1H, d, J=2.1Hz, -CCH),
3
4.13 and 4.30 (each 1H, each d, J=12.2Hz, CH OAc), 4.14 and
2
4.44 ( each 1H, each d, J=12.2Hz, CH OAc), 4.35 (1H, d,
2
J=2.4Hz, H-6), 4.38 and 4.50 (each 1H, each d, J=11.3Hz,
CH OAc), 4.45 and 4.68 (each 1H, each d, J=12.2Hz, CH Ph),
2
2
4.87 (1H, d, J=2.1Hz, H-3), 5.50 (1H, d, J=2.4Hz, H-7), 7.25-7.38
(5H, m, C H ); δ (125MHz, CDCl ) 20.68, 20.71, 20.87, 22.70,
6
5
C
3
60.62, 63.08, 63.57, 67.97, 70.76, 71.93, 76.58, 76.83, 78.24,
82.00, 86.70, 103.17, 127.86, 128.34, 128.67, 136.69, 168.99,
169.37, 169.57, 169.95.