A symmetry-based approach to the heterobicyclic core of the zaragozic acids - Model studies in the pseudo C2-symmetric series

Article abstract of DOI:10.1002/adsc.200700122

Using a two-directional strategy, a concise synthesis of a pseudo C ₂-symmetric tetrabenzyl ether of a hexaol diketone was accomplished. Hydrogenolysis of this compound in the presence of acetic acid and subsequent peracetylation triggered a gr

Full text of DOI:10.1002/adsc.200700122

UPDATES
DOI: 10.1002/adsc.200700122
A Symmetry-Based Approach to the Heterobicyclic Core ofthe
Zaragozic Acids – Model Studies in the Pseudo C2-Symmetric
Series
Yuzhou Wang,a Sylvia Gang,a Anja Bierstedt,a Margit Gruner,a Roland Frçhlich,b
and Peter Metza,*
a
Department of Chemistry, Technische Universität Dresden, Bergstr. 66, 01069 Dresden, Germany
Fax : (+49)-351-463-33162; e-mail: peter.metz@chemie.tu-dresden.de
Organisch-Chemisches Institut, Universität Münster, Corrensstr. 40, 48149 Münster, Germany
b
Fax : (+49)-251-833-9772; e-mail: frohlic@nwz.uni-muenster.de
Received: March 5, 2007; Revised: July 30, 2007
Dedicated to Professor Roland Mayer on the occasion of his 80th birthday.
Abstract: Using a two-directional strategy, a concise
synthesis of a pseudo C2-symmetric tetrabenzyl
ether of a hexaol diketone was accomplished. Hy-
drogenolysis of this compound in the presence of
acetic acid and subsequent peracetylation triggered
a group-selective intramolecular acetalization to
We reasoned that compound A would represent a
suitably functionalized general building block for the
synthesis of naturally occurring zaragozic acids as well
as unnatural analogues. A conceptually novel symme-
try-based approach[4,5] to this heterobicyclic system is
depicted in Scheme 1. A retrosynthetic disconnection
of the acetal moiety of A leads to polyhydroxy
ketone B featuring regions with local meso and C2
symmetry. Expansion of the C2 region within B by ad-
dition of a two-carbon unit to the ester terminus en-
hances molecular complexity, however, a pseudo C2-
symmetric diketone C is attained,[6] which should be
accessible by two-directional synthesis.[7] Diketone C
might serve as a substitute for B, provided its intra-
molecular acetalization occurs chemoselectively and
with simultaneous differentiation[8] of the two diaste-
reotopic g,e-dihydroxy ketone moieties to give D. Fi-
nally, the superfluous appendage in D can be re-
give the desired 2,8-dioxabicyclo[3.2.1]octane deriv-
A
ative with correct relative and absolute configura-
tions at all stereogenic centers of the heterobicyclic
core.
Keywords: asymmetric catalysis; chemoselectivity;
cyclization; dihydroxylation; heterocycles; zaragozic
acids
The zaragozic acids/squalestatins are a family of natu- moved via a chemoselective oxidative cleavage to
rally occurring fungal metabolites isolated independ- generate building block A.
ently by three groups in 1991/1992.[1] These natural
We have recently communicated a concise synthesis
products are potent inhibitors of squalene synthase of the C2-symmetric linear model compound 2 from
and ras-farnesyl protein transferase and additionally the diethyl tartrate derivative 1.[4] Under suitable con-
display significant activities toward a wide spectrum ditions, the hexahydroxy diketone 2 cyclized with
of yeast and fungal pathogens. Moreover, zaragozic completely chemoselective participation of the g,e-hy-
acid A (squalestatin S1) protects against neuronal droxy groups to afford the 2,8-dioxabicyclo-
damage at low concentrations.[2] All zaragozic acids
have
dioxabicyclo
1 alkyl and C-6 acyl side chains (Scheme 1). Due to
ACHTREUNG
a
ACHTREUNG
their structural complexity and their biological activi- the pseudo C2-symmetric series, which eventually
ties, they have stimulated enormous synthetic efforts. gave rise to the C-4 epimer of 3 by chemoselective in-
Thus, the total syntheses of several zaragozic acids tramolecular acetalization of a linear hexahydroxy di-
have been accomplished, and many synthetic studies ketone prepared by a highly stereoselective two-direc-
toward the heterobicyclic core as well as detailed in- tional route.
vestigations on structure-activity relationships have
As one of the first efforts toward this goal, we tried
to utilize a tartrate-based approach similar to the suc-
been carried out.[1,3]
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Yuzhou Wang et al.
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cessful conversion of 1 to 2 but now commencing with
meso diethyl tartrate 4,[9,10] which was transformed
into the bis-Weinreb amide 6 by benzylation[11] fol-
lowed by a sequential DIBAL-H reduction/HWE ole-
fination[4,12] (Scheme 3). From a range of meso sub-
strates similar to 6, only this compound allowed a
double asymmetric dihydroxylation (AD),[13] whereas
the other substrates investigated either underwent an
intramolecular cyclization after the first AD or else
did not react at all.[14] While no conversion of 6 was
noted using the commercially available AD-mix-a in
the presence of methanesulfonamide, application of
the (DHQ)2PYR ligand[15] permitted a two-fold AD
reaction, however, with generation of the meso prod-
uct 7. The configuration of 7 was unambiguously es-
tablished by an X-ray diffraction analysis of the tetra-
silyl ether 8 (Figure 1).[16]
Since substrate control was clearly dominant in the
formation of 7, chances for success following a two-di-
rectional strategy starting from a meso compound[18]
with a central 1,2-diol unit appeared rather low with
the AD methodology currently available. Thus, we
turned to the construction of a C2-symmetric tetraol
incorporating a central alkyne unit, from which gener-
ation of the desired pseudo C2-symmetry was envis-
Scheme 1. Symmetry-based concept for the preparation of a
general building block (A) for zaragozic acids/squalestatins.
Scheme 3. Reagents and conditions: a) BnBr, TlOEt, MeCN,
558C, 74%; b) (i) DIBAL-H, toluene, À788C, (ii)
(EtO)2PO-CH(Na)-CON(Me)OMe, DME, À788C to room
temperature, 41%; c) 4 mol% K2OsO2(OH)4, K3[Fe(CN)6],
K2CO3, NaHCO3, MeSO2NH2, 10 mol% (DHQ)2PYR, t-
BuOH, H2O, 0 8C to room temperature; d) TBSOTf, 2,6-lu-
tidine, CH2Cl2, room temperature, 56% 8 from 6.
Scheme 2. Model study in the C2-symmetric series.
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A Symmetry-Based Approach to the Heterobicyclic Core of the Zaragozic Acids
UPDATES
control during the second AD reaction. A two-direc-
tional route to the pseudo C2-symmetric precursor 18
of a hexaol diketone according to this modified strat-
egy is depicted in Scheme 4.
2-Butyne-1,4-diol (9) was converted to the (E,E)
bis-enoate 10 in a one-pot Dess–Martin oxidation/
Wittig olefination process (Scheme 4).[19] A one-pot
double AD of 10 was not practical, since dihydroxyla-
tion of the intermediate diol 11 proved to be rather
slow, and isolation of the resultant tetraol was not
facile due to its high polarity. Thus, the dioxolane
moieties of the C2-symmetric diester 14 were estab-
lished by an iterative protocol consisting of a single
AD under modified Sharpless conditions[20] and sub-
sequent isopropylidene protection. The diastereomeri-
cally pure C2-symmetric bis-acetal 14 was isolated in
high overall yield from 10 implying a very high enan-
tiomeric purity after the two AD transformations.[21]
Figure 1. Crystal structure of meso compound 8.[16,17]
aged by semihydrogenation and subsequent syn dihy- Conversion of the ester termini of 14 to Weinreb
droxylation. The crucial idea was to use a dienyne as amides[22] using trimethylaluminum caused a compet-
the achiral AD substrate, where the central alkyne ing acetal cleavage, which required a reprotection to
would serve as a spacer that prevents both an intra- provide 15. Double alkylation of 15 to give diketone
molecular Michael addition of dihydroxylated syn- 16, partial reduction of the triple bond using the Lin-
thetic intermediates as well as an overriding substrate dlar catalyst and catalytic dihydroxylation of the re-
Scheme 4. Reagents and conditions: a) Ph3P=CHCO2-i-Pr, PhCO2H, Dess–Martin periodinane, CH2Cl2, DMSO, room tem-
perature, 62%; b) 3 mol% K2OsO2(OH)4, K3[Fe(CN)6], K2CO3, NaHCO3, MeSO2NH2, 6 mol% (DHQ)2PHAL, t-BuOH,
H2O, 0 8C, 88% 11 from 10, 79% 13 from 12; c) 2,2-dimethoxypropane, TsOH, CH2Cl2, room temperature, 80% 12 from
11, 90% 14 from 13, 60% 15 from 14; d) MeONHMe·HCl, Me3Al, CH2Cl2, 08C to room temperature; e) MeLi, THF,
À788C, 74%; f) 1 bar H2, 10 wt% Lindlar catalyst, EtOAc, room temperature; g) 5 mol% OsO4, NMO, acetone, H2O, room
temperature, 79% 18 from 16; h) TFA, CH2Cl2, H2O (10:20:1), room temperature; i) Ac2O, DMAP, pyridine, room tempera-
ture, 59% 19 from 18.
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Yuzhou Wang et al.
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Scheme 5. Reagents and conditions: a) Ph3P=CHCO2Et, PhCO2H, Dess–Martin periodinane, CH2Cl2, DMSO, room tempera-
ture, 73%; b) 5 mol% K2OsO2(OH)4, K3[Fe(CN)6], K2CO3, NaHCO3, MeSO2NH2, 10 mol% (DHQ)2PHAL, t-BuOH, H2O,
08C, 80% 21, 76% 23; c) BnBr, Ag2O, Et2O, reflux, 86% 22, 92% 24; d) MeONHMe·HCl, i-PrMgCl, THF, À208C to room
temperature, 97%; e) MeMgBr, THF, 08C, 93%; f) 1 bar H2, 20 wt% Lindlar catalyst, EtOAc, room temperature; g) (i)
1.1 equivs. OsO4, pyridine, toluene, 08C to room temperature, (ii) NaHSO3, H2O, 0 8C to room temperature, 90% 28 from
26.
sultant (Z) configured olefin 17 afforded the pseudo ing groups instead of a cyclic 1,2-diol protection for
C2-symmetric diol 18 as a hemi acetal mixture the four peripheral hydroxy groups in 18 (Scheme 5).
(Scheme 4). Treatment of 18 with trifluoroacetic acid
Tetrabenzyl ether 28 that exists as a hemiacetal
under conditions that were favorable for intramolecu- mixture was synthesized from 2-butyne-1,4-diol (9)
lar acetalizations of polyol monoketones to generate according to the strategy used for the preparation of
the heterobicyclic core of the zaragozic acids[23] only 18 (Scheme 5). During the synthetic elaboration to
led to the undesired acetal isomer 19[24] after perace- bis-Weinreb amide 25, the diethyl ester gave a signifi-
tylation. This isomer is formed by acetalization of the cantly higher overall yield compared to the diisoprop-
“upper” ketone function of the polyol derived from yl analogue. Again, an iterative AD[26]/protection pro-
18 with its d,e-diol subunit; the desired cyclization in- tocol was followed, in the course of which a silver
volving this ketone and its g,e-diol moiety was not ob- oxide-assisted[27] double benzylation proved to be
served. While the requisite C-4 epimer of 3 was not highly efficient. For conversion of diethyl ester 24 to
yet obtained, this experiment nevertheless suggested bis-Weinreb amide 25, isopropylmagnesium chlo-
that the presence of the diketone functionality in de- ride[28] was clearly superior to trimethylaluminum.
blocked 18 did not cause any special difficulties, be- Probably due to the steric shielding imparted by the
cause similar problems with competing g,e- and d,e- two allylic benzyl ethers in 27, a stoichiometric
cyclizations were also quite frequently observed amount of osmium tetroxide had to be used for the
during the acetalization of trihydroxy monoketones to final dihydroxylation step.
give the 2,8-dioxabicyclo
A
Hydrogenolytic debenzylation of 28 in ethyl acetate
followed by treatment with trifluoroacetic acid in di-
acids.[1,25]
A more facile formation of a six-membered hemi chloromethane/water at room temperature and pera-
acetal involving the d-hydroxy group was seen as a cetylation again led only to the undesired acetal 19 in
possible reason for the preferred generation of acetal high yield (Scheme 6). Similarly, a slower debenzyla-
19, since attack of the g-hydroxy group prior to hy- tion of 28 in tetrahydrofuran and subsequent treat-
drolysis of the “upper” isopropylidene acetal would ment with concentrated hydrochloric acid in tetrahy-
lead to two trans-fused five-membered rings.[3d,23b] drofuran[4] at room temperature followed by peracety-
Hence, we subsequently used acyclic (benzyl) protect- lation solely gave rise to isomer 19. Monitoring the
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A Symmetry-Based Approach to the Heterobicyclic Core of the Zaragozic Acids
UPDATES
alogues. Investigations along these lines will be re-
ported in due course.
Experimental Section
Asymmetric Dihydroxylation of20
A
solution of K2OsO2(OH)4 (63 mg, 0.17 mmol),
K3[Fe(CN)6]
10.2 mmol),
(3.36 g,
NaHCO3
10.20 mmol),
(0.86 g,
K2CO3
10.2 mmol)
(1.10 g,
and
(DHQ)2PHAL (265 mg, 0.34 mmol) in a mixture of t-BuOH
(30 mL) and water (30 mL) was stirred at room temperature
for 2 h, MeSO2NH2 (646 mg, 6.80 mmol) was added, and
stirring was continued for another 30 min. After cooling to
08C, a solution of bis-enoate 20 (750 mg, 3.40 mmol) in t-
BuOH (5 mL) and water (5 mL) was added, and the result-
ing mixture was stirred for 2 h. The reaction was quenched
by addition of sodium sulfite (5.10 g), stirring was continued
for another 30 min at room temperature, and the layers
were separated. After extraction of the aqueous layer with
diethyl ether (3”30 mL), washing of the combined organic
layers with brine, drying over magnesium sulfate and remov-
al of the solvents under vacuum, the residue was subjected
to flash chromatography on silica gel (diethyl ether/pentane,
3:1) to give diol 21 (yield: 688 mg, 80%, 86% ee) as a
yellow oil and some starting material 20 (98 mg, 13%).
21: Rf =0.32 (diethyl ether/pentane, 3:1); [a]2D7: +13.8 (c
Scheme 6. Reagents and conditions: a) 10 bar H2, 10% Pd/C,
EtOAc, room temperature; b) TFA, CH2Cl2, H2O (10:20:1),
room temperature; c) Ac2O, DMAP, pyridine, room temper-
ature, 84% 19 via steps [a), b), c)] from 28, 51% 19 via
steps [d), e), c)] from 28, 76% 29 from “fraction 1”, 73% 19
from “fraction 2”; d) 10 bar H2, 10% Pd/C, THF, room tem-
perature; e) conc. HCl, THF, room temperature; f) 20 bar
H2, 10% Pd/C, THF, room temperature, 30% “fraction 1”,
50% “fraction 2”; g) 30 bar H2, 10% Pd/C, THF, 100 equivs.
HOAc, room temperature, 75% “fraction 1”, 21% “fraction
2”; h) 0.5 equivs. conc. HCl, THF, À108C, 60% “fraction 1”,
33% “fraction 2”.
˜
1.0, CHCl3); IR (neat): n=3444 (br, OH), 2982 (w), 1713 (s,
C=O), 1620 (s), 1368 (m), 1267 (s), 1151 (s), 1026 (s), 970
1
(m), 863 (m) cmÀ1; H NMR (CDCl3, 300 MHz): d=1.23 (t,
3J=7.1 Hz, 3H), 1.27 (t, J=7.0 Hz, 3H), 2.73 (br s), 3.25
3
(br s), 4.12 (q, 3J=7.1 Hz, 2H), 4.25 (d, 3J=4.5 Hz, 1H),
debenzylation step by TLC revealed that in ethyl ace-
tate only a very polar fraction was rapidly formed,
whereas in addition to this fraction (“fraction 2”) an-
other less polar fraction (“fraction 1”) was detected
for the slower reaction in tetrahydrofuran.[29] Perace-
tylation of “fraction 1” delivered only the desired g,e-
cyclization product 29,[24] whereas peracetylation of
“fraction 2” solely gave rise to the unwanted d,e-cycli-
zation product 19. Acid-catalyzed conversion of “frac-
tion 2” into “fraction 1” proved to be possible at low
temperature and high concentration of hydrochloric
acid. Eventually, the optimum access to “fraction 1”
was achieved by directly performing the hydrogenoly-
sis of 28 in the presence of 100 equivalents of acetic
acid. Using these conditions, the tetraacetate 29 was
3
3
4.28 (mc, 2H), 4.75 (d, J=4.5 Hz, 1H), 5.04 (d, J=15.9 Hz,
1H), 6.73 (d, J=15.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
3
d=14.16 (q, intense), 60.91 (t), 62.73 (t), 64.24 (d), 73.31
(d), 82.65 (s), 94.85 (s), 123.83 (d), 131.71 (d), 165.50 (s),
171.37 (s); MS (GC/MS, 70 eV): m/z (%)=227 (1)
[M+ÀEt], 211 (4) [M+ÀOEt], 183 (3) [M+ÀCO2Et], 153
(30) [M+ÀCH(OH)CO2Et], 104 (100) [M+ ÀEtO2C-CH=
CH-CꢀC-CHO], 76 (83), 63 (29), 51 (38); anal. calcd. for
C12H16O6: C 56.24, H 6.29; found: C 56.32, H, 6.35.
Hydrogenolytic Debenzylation of28
A solution of tetrabenzyl ether 28 (100 mg, 0.16 mmol) in
dry THF (4.0 mL) was treated with acetic acid (0.9 mL,
16 mmol) and 10% Pd/C (15 mg). The reaction mixture was
isolated in 57% overall yield from the tetrabenzyl stirred for 14 h under a hydrogen pressure of 30 bar at room
temperature. After filtration through a glass filter funnel
and thorough rinsing with ethyl acetate/methanol (1:1), the
solution was washed with 0.5M aqueous NaHCO3 (20 mL).
The solvent was removed under vacuum, and the residue
was subjected to flash chromatography on silica gel (ethyl
acetate/methanol, 8:1, + 1 vol% Et3N) to give “fraction 1”
(yield: 32 mg, 75%; Rf =0.35) and “fraction 2” (yield:
9.1 mg, 21%; Rf =0.14).
ether 28.
In conclusion, we have developed a short and
highly stereoselective two-directional route to a
model for the heterobicyclic core of the zaragozic
acids featuring a group-selective intramolecular ace-
talization of a pseudo C2-symmetric hexahydroxy di-
ketone intermediate as the key step. Since a chemose-
lective oxidative removal of the superfluous two-
carbon appendage present in 29 had already been
achieved for the C-4 epimer 3,[4] this approach also
provides a good basis for a similar access to the fully
Typical Procedure for Peracetylation
A solution of “fraction 1” (36 mg, 0.14 mmol) in pyridine
substituted natural products as well as non-natural an- (3 mL) was treated with freshly dried acetic anhydride
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Yuzhou Wang et al.
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(0.56 mL, 5.54 mmol) and 4-(N,N-dimethylamino)pyridine
(17.5 mg, 0.14 mmol). After stirring the mixture at room
temperature for 1 day, it was filtered through a plug of silica
gel using diethyl ether/dichloromethane, 1:1, as eluent. Fol-
lowing removal of the solvent under vacuum, the crude
product was purified by flash chromatography on silica gel
(diethyl ether/dichloromethane, 1:9) to give the tetraacetate
29; yield: 43 mg (76%).
[3] For very recent synthetic work in the area, see: a) Y.
Hirata, S. Nakamura, N. Watanabe, O. Kataoka, T. Kur-
osaki, M. Anada, S. Kitagaki, M. Shiro, S. Hashimoto,
Chem. Eur. J. 2006, 12, 8898–8925; b) J. O. Bunte,
A. N. Cuzzupe, A. M. Daly, M. A. Rizzacasa, Angew.
Chem. 2006, 118, 6524–6528; Angew. Chem. Int. Ed.
2006, 45, 6376–6380; c) M. Tsubuki, H. Okita, T.
Honda, Heterocycles 2006, 67, 731–748; d) S. Naka-
mura, H. Sato, Y. Hirata, N. Watanabe, S. Hashimoto,
Tetrahedron 2005, 61, 11078–11106, and references
cited therein; e) E. Negishi, Z. Tan, B. Liang, T. Novak,
Proc. Natl. Acad. Sci. USA 2004, 101, 5782–5787.
[4] For prior studies in the C2-symmetric series, see: A.
Bierstedt, J. Roels, J. Zhang, Y. Wang, R. Frçhlich, P.
Metz, Tetrahedron Lett. 2003, 44, 7867–7870.
[5] For alternative symmetry-based approaches, see:
a) K. D. Freeman-Cook, R. L. Halcomb, J. Org. Chem.
2000, 65, 6153–6159; b) D. J. Wardrop, A. I. Velter,
R. E. Forslund, Org. Lett. 2001, 3, 2261–2264.
[6] The term “pseudo C2-symmetric” is used to character-
ize chains that would be C2-symmetric if they did not
contain (a) central chirotopic, non-stereogenic cen-
ter(s); see also ref.[7c].
[7] For reviews on two-directional synthesis, see: a) M. E.
Maier, S. Reuter, GIT Fachz. Lab. 1997, 41, 1108,
1110–1112; b) S. R. Magnuson, Tetrahedron 1995, 51,
2167–2213; c) C. S. Poss, S. L. Schreiber, Acc. Chem.
Res. 1994, 27, 9–17; d) M. E. Maier, Nachr. Chem.
Tech. Lab. 1993, 41, 314–316, 318, 321–322, 324–325,
328, 330.
[8] For recent examples of intramolecular desymmetriza-
tion of pseudo C2-symmetric substrates, see: E. A.
Voight, C. Rein, S. D. Burke, J. Org. Chem. 2002, 67,
8489–8499.
19: Rf =0.10 (dichloromethane/diethyl ether, 9:1); [a]2D4:
˜
+95.3 (c 0.77, CHCl3); IR (neat): n=2932 (w), 2849 (w),
1737 (s, C=O), 1215 (s), 1058 (s), 961 (m), 875 (w), 605 (s)
1
cmÀ1; H NMR (CDCl3, 500 MHz): d=1.43 (s, 3H), 1.96 (s,
3H), 2.07 (s, 3H), 2.13 (s, 3H), 2.18 (s, 3H), 2.21 (s, 3H),
3
3
4.42 (d, J=4.5 Hz, 1H), 4.58 (d, J=2.2 Hz, 1H), 5.09–5.12
(m, 2H), 5.15 (d, 3J=4.5 Hz, 1H), 5.31–5.32 (m, 2H);
13C NMR (CDCl3, 126 MHz): d=19.40 (q), 20.51 (q), 20.65
(q), 20.73 (q, intense), 27.73 (q), 68.08 (d), 68.69 (d), 73.02
(d), 76.10 (d), 77.18 (d), 77.25 (d), 108.26 (s), 169.86 (s),
169.99 (s), 170.06 (s, intense), 203.92 (s); MS (LC/MS, ESI):
+
m/z (%)=434 (100) [M+NH4 ]; anal. calcd. for C18H24O11:
C 51.92, H 5.81; found: C 51.98, H 5.84.
29: Rf =0.30 (dichloromethane/diethyl ether, 9:1); [a]2D4:
˜
+78.0 (c 0.60, CHCl3); IR (neat): n=2925 (w), 2853 (w),
1739 (s, C=O), 1213 (s), 1065 (s), 953 (m), 873 (w), 603 (s)
1
cmÀ1; H NMR (CDCl3, 500 MHz): d=1.54 (s, 3H), 2.03 (s,
3H), 2.11 (s, 3H), 2.168 (s, 3H), 2.171 (s, 3H), 2.28 (s, 3H),
4.34 (d, 3J=2.3 Hz, 1H), 4.45 (dd, 3J=2.8 Hz, 3J=5.0 Hz,
1H), 4.86 (dd, 3J=2.3 Hz, 3J=2.8 Hz, 1H), 5.11 (d, 3J=
3
2.3 Hz, 1H), 5.16 (d, J=2.3 Hz, 1H), 5.22 (d, 3J=5.0 Hz,
1H); 13C NMR (CDCl3, 126 MHz): d=20.42 (q), 20.65 (q,
intense), 20.71 (q), 22.47 (q), 27.94 (q), 65.52 (d), 70.77 (d),
76.13 (d), 77.26 (d), 80.46 (d, intense), 104.26 (s), 169.54 (s),
169.58 (s), 169.82 (s), 170.21 (s), 201.36 (s); MS (LC/MS,
+
ESI): m/z (%)=434 (100) [M+NH4 ]; anal. calcd. for
C18H24O11: C 51.92, H 5.81; found: C 52.07, H 5.84.
[9] D. H. G. Crout, V. S. B. Gaudet, K. O. Hallinan, J.
Chem. Soc.,Perkin Trans. 1 1993, 805–812.
[10] We prepared meso diethyl tartrate 4 from diethyl male-
ate in 89% yield according to the dihydroxylation pro-
tocol described for dimethyl maleate: T. K. M. Shing,
E. K. W. Tam, V. W.-F. Tai, I. H. F. Chung, Q. Jiang,
Chem. Eur. J. 1996, 2, 50–57.
[11] Thallous ethoxide has been used successfully with di-
ethyl d-tartrate: a) S. V. Taylor, L. D. Vu, T. P. Begley,
U. Schçrken, S. Grolle, G. A. Sprenger, S. Bringer-
Meyer, H. Sahm, J. Org. Chem. 1998, 63, 2375–2377;
b) H. O. Kalinowski, G. Crass, D. Seebach, Chem. Ber.
1981, 114, 477–487.
Acknowledgements
Financial support of this work by the Deutsche Forschungs-
gemeinschaft is gratefully acknowledged. Special thanks are
due to Marie-Kristin Lemke,TU Dresden,for her valuable
experimental help.
[12] a) M. Jørgensen, E. H. Iversen, A. L. Paulsen, R.
Madsen, J. Org. Chem. 2001, 66, 4630–4634; b) J. M.
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methyl ketone analogues with benzyl or isopropylidene
blocking of the diol gave rise to tetrahydrofuran deriva-
tives after a single AD reaction, whereas the bis-
methyl ketone analogue with TBS-protected diol was
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Adv. Synth. Catal. 2007, 349, 2361 – 2367

A Symmetry-Based Approach to the Heterobicyclic Core of the Zaragozic Acids
UPDATES
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[29] Both fractions, which were readily separated by flash
chromatography, contained several compounds, the
structures of which could not be rigorously elucidated.
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hemi acetals of the intermediate hexahydroxy diketone
corresponding to 28.
Adv. Synth. Catal. 2007, 349, 2361 – 2367
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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