Total synthesis of zaragozic acid A (squalestatin S1). Synthesis of the relay compound

Article abstract of DOI:10.1021/jo961534e

Compound 2 has been prepared from the 1,6-anhydropyranohexose 3. The key process for elaborating the 1,7-dioxabicyclo[3.2.1]octane core of the zaragozic acids is addition of an organometallic reagent to lactone 6 and treatment of the resulting 1,2,3-trihydroxy-6-oxo ethylene acetal with acid. Use of the cerium(III) reagent of 4-bromo-1-butene in this process provided 7 in excellent yield, unaccompanied by the isomeric 1,6-anhydropyranose isomer. The remaining two carboxy groups of the zaragozic acid core were added by addition of the lithium enolate of 8 to formaldehyde, to obtain 9, and cerium(III)-mediated addition of vinyllithium to ketone 10. The latter addition was shown by 2D ¹H NMR experiments to provide the relative configuration found in the zaragozic acids. Similar stereoselective additions were observed with 2-furyllithium and (5-methyl-2-furyl)lithium, but the resulting adducts are resistant to ozonolysis. The synthesis of 2 completes a total synthesis of zaragozic acid A (squalestatin S1) (1).

Full text of DOI:10.1021/jo961534e

9126
J . Org. Chem. 1996, 61, 9126-9134
Tota l Syn th esis of Za r a gozic Acid A (Squ a lesta tin S1). Syn th esis
of th e Rela y Com p ou n d
Ste´phane Caron, Doris Stoermer, Anna Kathryn Mapp, and Clayton H. Heathcock*
Department of Chemistry, University of California, Berkeley, California 94720
Received August 7, 1996X
Compound 2 has been prepared from the 1,6-anhydropyranohexose 3. The key process for
elaborating the 1,7-dioxabicyclo[3.2.1]octane core of the zaragozic acids is addition of an organo-
metallic reagent to lactone 6 and treatment of the resulting 1,2,3-trihydroxy-6-oxo ethylene acetal
with acid. Use of the cerium(III) reagent of 4-bromo-1-butene in this process provided 7 in excellent
yield, unaccompanied by the isomeric 1,6-anhydropyranose isomer. The remaining two carboxy
groups of the zaragozic acid core were added by addition of the lithium enolate of 8 to formaldehyde,
to obtain 9, and cerium(III)-mediated addition of vinyllithium to ketone 10. The latter addition
1
was shown by 2D H NMR experiments to provide the relative configuration found in the zaragozic
acids. Similar stereoselective additions were observed with 2-furyllithium and (5-methyl-2-furyl)-
lithium, but the resulting adducts are resistant to ozonolysis. The synthesis of 2 completes a total
synthesis of zaragozic acid A (squalestatin S1) (1).
In the preceding article, we reported the interconver-
fication of the three hydroxy groups. The crude triacetate
is saponified by treatment with sodium methoxide in
methanol and the resulting mixture of triols treated with
acetone and p-toluenesulfonic acid to provide the 5,6-
acetonide of a hexofuranose. The hemiacetal is converted
into the desired lactone 6 by oxidation with pyridium
dichromate (PDC).7 Addition of the Grignard reagent
prepared from homoallyl bromide and magnesium leads
to elimination of the benzyloxy group â to the carbonyl.
This problem was circumvented by transmetalation to
the cerium reagent.8 Although the addition is very slow
at -78 °C, monoaddition can be accomplished by keeping
the solution at -50 °C. Above this temperature, sub-
stantial amounts of bis-addition are observed. The crude
addition product is treated with 2 N hydrochloric acid in
tetrahydrofuran to obtain the disubstituted 1,6-anhydro-
furanose 7 as the only product isolated in 74% yield.
Oxidation of alcohol 7 with trifluoroacetic anhydride and
dimethyl sulfoxide affords ketone 8 in 94% yield.
sion of the natural squalene synthase inhibitor zaragozic
acid A (squalestatin S1, 1) with the dimethyl acetal tri-
tert-butyl ester 2.1 In this article, we report the synthesis
of 2 from methyl R-D-glucopyranoside, thus completing
a total synthesis of 1.
The successful rearrangement of 6 to 7 gave us the
essential 1,6-anhydrofuranose core of the zaragozic acids,
equipped with two bridgehead substituents, one destined
to be converted into the C1 side chain and the other
representing one of the three carboxy groups. It re-
mained to add the other two one-carbon units, represent-
ing the other two carboxy groups of the zaragozic acids.
A good deal of experimentation9 eventually resulted in a
protocol wherein ketone 8 is metalated by reaction with
tert-butyllithium in THF and the resulting lithium eno-
late is treated with 1 equiv of paraformaldehyde. This
procedure gives aldol 9 in 57% yield, along with 39% of
recovered ketone 8. Attempts to achieve higher conver-
sion by using excess paraformaldehyde resulted in the
formation of diol monoformate esters, resulting from
intramolecular Tishchenko reduction.10 The imperfect
conversion is of little consequence, because 8 and 9 are
Our plan for the synthesis of 2, involving rearrange-
ment of a suitably constructed hexose to a 1,6-anhydro-
furanose, has been previously discussed, and model
studies that delineate the structural requirements and
reaction conditions for such a rearrangement have been
described.2 For the actual synthesis of intermediate 2,
we started with 1,6-anhydro-2,3-di-O-benzyl-â-D-ribohex-
opyranos-4-ulose (3), available in five steps and 48%
overall yield from methyl R-D-glucopyranoside.3 As shown
in Scheme 1, ketone 3 undergoes the Tamao reaction4 in
a highly stereoselective fashion to give diol 4, which is
quantitatively protected as the tert-butyldiphenylsilyl
ether (5).5,6 Compound 5 reacts with trifluoroacetic acid
(TFA) in acetic anhydride to give a triacetate, resulting
from the opening of the anhydropyranose and the esteri-
X Abstract published in Advance ACS Abstracts, December 1, 1996.
(1) Stoermer, D.; Caron, S.; Heathcock, C. H. J . Org. Chem. 1996,
61, 9115.
(2) Caron, S.; McDonald, A. I.; Heathcock, C. H. J . Org. Chem. 1995,
60, 2780.
(3) Caron, S.; McDonald, A. I.; Heathcock, C. H. J . Carbohydr. Res.,
in press.
(4) Tamao, K.; Ishida, N. Tetrahedron Lett. 1984, 25, 4245.
(5) Hanessian, S.; Lavalle´e, P. Can. J . Chem. 1975, 53, 2975.
(6) Preliminary studies of the subsequent acidic rearrangement
showed that the tert-butyldimethylsilyl ether is partially cleaved.
(7) Corey, E. J .; Schmidt, G. Tetrahedron Lett. 1979, 399.
(8) Imamoto, T.; Sugiura, Y.; Takiyama, N. Tetrahedron Lett. 1984,
25, 4233.
(9) For a complete account of the enolate chemistry of ketone 8,
see: Caron, S. Ph.D. Dissertation, University of California, Berkeley,
CA, 1995, pages 59-68.
(10) (a) Tishtschenko, W. Zh. Russ. Fiz.-Khim. Ova. 1906, 38, 355.
(b) Evans, D. A.; Hoveyda, A. H. J . Am. Chem. Soc. 1990, 112, 6447.
S0022-3263(96)01534-4 CCC: $12.00 © 1996 American Chemical Society

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9127
Sch em e 1a
a
Reagents and conditions: (a) (i) Me2(i-PrO)SiCH2MgCl, THF, -78 °C; (ii) H2O2, MeOH, THF, NaHCO3; (b) t-BuPh2SiCl, imidazole,
DMF; (c) TFA, Ac2O; (d) NaOMe, MeOH; (e) acetone, H+; (f) PDC, sieves, CH2Cl2; (g) CH2dCHCH2CH2CeCl2, THF, -78 °C; (h) HCl, H2O,
THF; (i) DMSO, TFAA, Et3N, CH2Cl2; (j) t-BuLi, 1 equiv of CH2O in THF; (k) t-BuMe2SiCl, imidazole, DMF.
Sch em e 2a
aldehyde at the bridgehead, the C3 proton would be a
double doublet.
Because the addition to 10 appeared to be rather
stereoselective, we sought other acyl anion equivalents
that could be added as lithium reagents. The next
species studied was 2-lithiofuran,14 which adds to 10 in
almost quantitative yield to give a single tertiary alcohol
(Scheme 3). After desilylation, the resulting triol was
treated sequentially with the Dess-Martin reagent13 to
obtain a dialdehyde that was oxidized to the diacid with
sodium chlorite.15 Treatment of the crude diacid with
O-tert-butyl-N,N′-diisopropylisourea16 provided 16 in 64%
yield. However, ozonolysis of 16 gave a rather complex
mixture of products. It was clear from the 1H NMR
spectrum of the crude product that both the terminal
vinyl group and the furan ring had been oxidized, but
we were unable to isolate a single product.
a
Reagents and conditions: (a) CH2dC(Li)OMe, THF; (b) TBAF,
To improve our change of success in the ozonolysis step,
2-methylfuran was investigated as the acyl anion equiva-
lent. It was hoped that ozonolysis of a more substituted
and more electron-rich furan would be possible. The
same reaction sequence used for 16 was repeated using
2-lithio-5-methylfuran (Scheme 3). The addition provided
alcohol 17 in 87% yield. Desilylation led to triol 18 (83%
yield), which was oxidized to the dialdehyde and thence
to di-tert-butyl ester 19 in the modest but unoptimized
yield of 30%. Upon reaction with ozone followed by
reduction of the ozonides with triphenylphosphine, a new
product was isolated in 88% yield. This material is
believed to be enol acetate 20 because of its infrared and
1H NMR spectra. The IR spectrum showed the two tert-
butyl esters at 1725 cm-1, the enol acetate carbonyl at
1759 cm-1, and the enol acetate double bond at 1626
THF; (c) (i) O3, CH2Cl2; (ii) Me2S; (d) (MeO)3CH, MeOH, PPTS;
(e) Dess-Martin reagent.
very easy to separate by chromatography on silica gel.
Silylation of the hydroxy group provided 10.
For introduction of the final carbon, we had to add
some acyl anion equivalent from the bottom face of the
carbonyl group of ketone 10. Our first candidate for a
carboxy equivalent was lithiated methyl vinyl ether.11,12
Addition proceeded smoothly to give an adduct, presum-
ably 11 (Scheme 2). Some desilylation occurred, but the
total product was desilylated by reaction with tetrabu-
tylammonium fluoride to give 12. Ozonolysis of this
material gave a product that contained an aldehyde
functionality, but clearly was not a methyl ester. Treat-
ment of this material sequentially with trimethyl ortho-
formate in methanol in the presence of pyridinium
p-toluenesulfonate and then with the Dess-Mardin
periodinane13 gave a product that was assigned structure
1
cm-1. The H NMR spectrum also showed the presence
of the enol acetate with a resonance at 7.51 ppm which
was coupled to the proton of the hemiacetal at 6.41 ppm
with a coupling constant of 7.5 Hz. Moreover, it was
determined that the product possessed three carboxylate
groups from analysis of the 13C NMR spectrum which had
resonances at 164.69, 165.53, and 167.56 ppm. Com-
pound 20 presumably arises from ozonolytic cleavage of
the C2-C3 bond of the furan ring, which provides the
1
13 on the basis of its H NMR spectrum. In particular,
a sharp, one-proton singlet with δ ) 4.72 ppm was
attributed to the proton adjacent to the aldehyde. The
aldehyde proton also appeared as a sharp singlet with δ
) 9.65 ppm. In the alternative cyclic acetal, having the
(11) Baldwin, J . E.; Ho¨fle, G. A.; Lever, O. W. J . J . Am. Chem. Soc.
1974, 96, 7125.
(12) (a) Chavdarian, C. G.; Heathcock, C. H. J . Am. Chem. Soc. 1975,
97, 3822. (b) Clark, R. D.; Heathcock, C. H. J . Org. Chem. 1976, 41,
1396.
(13) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155. (b)
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(14) Schmid, G.; Fukuyama, T.; Akasada, K.; Kishi, Y. J . Am. Chem.
Soc. 1979, 101, 259.
(15) (a) Lindgren, B. O.; Nilsson, T. Acta Chem. Scand. 1973, 27,
888. (b) Kraus, G. A.; Roth, B. J . Org. Chem. 1980, 45, 4825.
(16) Mathias, L. J . Synthesis 1979, 561.

9128 J . Org. Chem., Vol. 61, No. 26, 1996
Caron et al.
Sch em e 3a
a
Reagents and conditions: (a) 2-furyllithium, THF, -78 °C; (b) (5-methyl-2-furyl)lithium, THF, -78 °C; (c) TBAF, THF; (d) Dess-
Martin periodinane, CH2Cl2; (e) NaClO2; (f) (t-BuO)(i-PrNH)CdN(i-Pr); (g) O3, MeOH, CH2Cl2.
observed enol acetate and leaves an R,â-unsurated alde-
hyde. Isomerization of the double bond from Z to E,
followed by formation of the cyclic hemiacetal structure,
gives 20. Prolonged ozonolysis of 20 did not provide the
desired carboxylic acid, and this approach was aban-
doned.
The high level and sense of diastereoselection achieved
in this addition was somewhat surprising, as Carreirra
had reported that addition of nucleophiles to a similar
substrate leads to diastereoisomeric mixtures, usually
favoring the undesired product.19 Therefore the relative
configuration of the newly created C4 stereocenter was
verified using several NMR experiments. A combination
of 2D NMR experiments allowed the assignment of all
carbon and hydrogen atoms of the molecule. COSY20 and
HMBC21 experiments conclusively located the different
protons of the vinyl group and the two methine protons
adjacent to the benzyloxy groups. A NOESY22 experi-
ment showed a definite correlation between one of the
two benzyloxy methines and one of the vinyl hydrogens,
either Ha or Hb, which have almost the same chemical
shift. Regardless of which vinyl hydrogen correlates with
the benzyloxy methine, the relative configuration at C4
must be that desired for conversion into zaragozic acid:
It was eventually decided to use a simple vinyl group
as a synthon for the third carboxylic acid. We had
previously tried to avoid the use of an unsubstituted vinyl
group for several reasons. First, we thought the alkene
of the C1 side chain and the vinyl group at C4 would have
to be differentiated, resulting in a longer synthesis.
Second, the use of a simple vinyl group would necessitate
an additional oxidation because ozonolysis of the double
bond would leave us one oxidation state lower than
desired; this would also add an additional step to the
synthesis. However, during the course of our work we
became aware of the experience of Carreira and Dubois
in their synthesis of zaragozic acid C.17 These workers
introduced the carboxy group in question by successful
ozonolysis of a vinyl group, which had been obtained by
addition of an acetylene anion followed by partial reduc-
tion of the alkyne to the alkene. Because of the relative
difficulty we had with ozonolysis of the furyl groups, we
thought there was a good chance the two vinyl groups
would cleave at sufficiently different rates to make this
approach viable.
Because of the level of stereocontrol achieved with
lithiated vinyl ethers and furans, addition of vinyllithium
to ketone 10 was investigated first. Vinyllithium was
generated by addition of methyllithium to tetravinyl-
stannane18 and added to ketone 10. Although the reac-
tion provided the desired allylic alcohol as a single
diastereoisomer, the product could not be separated from
residual tin derivatives. Addition of vinylmagnesium
bromide was next attempted, but the reaction was
extremely slow. However, transmetalation of vinylmag-
nesium bromide to the cerium reagent prior to addition
to ketone 10 provided the desired product, which ap-
peared to be slightly unstable on silica gel. The crude
addition product was treated with tetrabutylammonium
fluoride to provide triol 21 in 88% overall yield from
ketone 10 (Scheme 4).
With the final carbon in place, all that remained was
the elaboration of the three tert-butyl esters, ozonolysis
of the C1 side chain, cleavage of the two benzyl ethers,
and formation of the dimethyl acetal. As shown in
Scheme 4, the two primary hydroxy groups of triol 21
were oxidized to dialdehyde 22. As reported by Meyer
and Schreiber, addition of a catalytic amount of water
to the solution containing triol 21 and the Dess-Martin
periodinane increased the rate of the reaction.23 Oxida-
tion to the dicarboxylic acid 22 was accomplished with
sodium chlorite,15 and this oxidation was followed by bis-
(19) Carreira, E. M.; Du Bois, J . Tetrahedron Lett. 1995, 36, 1209.
(20) (a) Aue, W. P.; Barthodi, E.; Ernst, R. R. J . Chem. Phys. 1976,
64, 2229. (b) Nagayama, K.; Kumar, A.; Wu¨thrich, K.; Ernst, R. R. J .
Magn. Reson. 1980, 40, 32.
(21) Bax, A.; Summers, M. F. J . Am. Chem. Soc. 1986, 108, 2093.
(22) Bodenhausen, G.; Kogler, H.; Ernst, R. R. J . Magn. Reson. 1984,
58, 370.
(17) Carreira, E. M.; Du Bois, J . J . Am. Chem. Soc. 1994, 116, 10825.
(18) Meyers, A. I.; Lutomski, K. A.; Laucher, D. Tetrahedron 1988,
44, 3107.
(23) Meyer, S. D.; Schreiber, S. L. J . Org. Chem. 1994, 59, 7549.

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9129
Sch em e 4a
a
Reagents and conditions: (a) CH2dCHMgBr, CeCl3; (b) TBAF, THF; (c) Dess-Martin, CH2Cl2; (d) NaClO2; (e) (t-BuO)(i-PrNH)CdN(i-
Pr); (f) (i) O3; (ii) NaBH4; (g) O3; (h) t-BuMe2SiCl, imidazole, DMF; (i) TBAF, THF; (j) Dess-Martin; (k) (MeO)3CH, MeOH, PPTS; (l) H2,
Pd(OH)2, MeOH.
esterification using O-tert-butyl-N,N′-diisopropylisourea16
to provide diester 24 in 76% overall yield from triol 21.
Monoozonolysis of the alkene of the C1 side chain of 24
was achieved by carefully adding a saturated solution of
ozone in methylene chloride. Reduction of the ozonide
with sodium borohydride afforded the desired primary
alcohol 25 in 61% yield.
synthesis of zaragozic acid A (1), since 2 has been
converted into the natural product.1
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, starting materials were
obtained from commercial suppliers and used without further
purification. Diethyl ether and THF were distilled from Na/
benzophenone ketyl. Benzene, CH2Cl2, Et3N, i-Pr2NH, t-
BuOH, and toluene were distilled from CaH2. Furan and
2-methylfuran were distilled from Na immediately prior to use.
Acetic anhydride (Ac2O) and trifluoroacetic anhydride (TFAA)
were distilled from P2O5. All reactions involving oxygen or
moisture sensitive compounds were performed under a dry N2
atmosphere. Alkyllithiums were titrated with diphenylacetic
acid24 and Grignard reagents were titrated with a 1.0 M
solution of 2-butanol in xylene using 1,10-phenanthroline as
an indicator.25 Organic extracts were dried with MgSO4 and
concentrated with a rotary evaporator under reduced pressure
(aspirator). Silica gel chromatography was carried out with
ICI SiliTech 32-63 D A silica gel according to Still’s proce-
dure.26 Thin layer chromatography (TLC) was performed with
Merck F-254 TLC plates. Melting points were measured in
open capillary tubes. 1H and 13C NMR spectra were measured
in CDCl3. IR spectra were measured as thin films on NaCl
plates unless otherwise indicated. Optical rotations were
measured at rt.
1,6-An h yd r o-2,3-d i-O-ben zyl-4-(h yd r oxym eth yl)-â-D-ga -
la ctop yr a n ose (4). To a solution of ketone 33 (9.60 g, 28.2
mmol) in THF (100 mL) at -78 °C was added [(dimethyliso-
propoxysilyl)methyl]magnesium chloride (45.0 mL of a 0.70
M solution in THF, 31.5 mmol). The solution was stirred at
-78 °C for 30 min, allowed to warm to -15 °C over 2 h, poured
into cold saturated NH4Cl (200 mL), and extracted with ether
(2 × 200 mL). The organic extracts were washed with cold
H2O (150 mL) and cold brine (150 mL), dried, filtered, and
We first attempted to complete the preparation of the
relay compound 2 without protection of the primary
hydroxy group of the C1 side chain. Allylic alcohol 25
was ozonized without incident to provide an aldehyde
that was further oxidized to a carboxylic acid. However,
conversion to the tri-tert-butyl ester 30 was complicated
by concomitant formation of the tert-butyl ether of the
primary alcohol. The solution to this problem was
obviously to protect the primary alcohol. Therefore, after
the ozonolysis of the more reactive double bond of 25,
the primary alcohol 26 was protected as a tert-butyldi-
methylsilyl ether (27) and the aldehyde was converted
to the tert-butyl ester by sodium chlorite oxidation and
esterification of the resulting acid 28 with O-tert-butyl-
N,N′-diisopropylisourea. Compound 29 was obtained in
41% yield from 25. The silyl ether was cleaved using
tetrabutylammonium fluoride to provide diol 30 in 61%
yield. The primary hydroxyl group was oxidized with the
Dess-Martin periodinane to afford an aldehyde which
was allowed to react with trimethyl orthoformate in
acidic methanol prior to hydrogenolysis of the two benzyl
protecting groups. This reaction sequence provided the
relay compound 2 in quantitative yield (Scheme 4).
The synthetic material was identical in almost all
respects to the material prepared by degradation of
zaragozic acid A/squalestatin S1 (1).1 The only difference
observed was the chemical shift of the two hydroxyl
groups at C6 and C7 in the 1H NMR spectrum. The
successful synthesis of 2 from 3 completes a total
(24) Kofron, W. G.; Baclawski, L. M. J . Org. Chem. 1976, 41, 1879.
(25) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.
(26) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.

9130 J . Org. Chem., Vol. 61, No. 26, 1996
Caron et al.
concentrated at 0 °C. The crude oil was dissolved in THF (75
mL) and MeOH (75 mL), to which NaHCO3 (2.38 g, 28.3 mmol)
and H2O2 (30% in H2O, 27 mL) were added. The suspension
was heated to reflux for 12 h and cooled to 0 °C, and Na2S2O3
(15 g) was very slowly added. MgSO4 was added, and the
mixture was filtered through a plug of Celite. The filter cake
was washed thoroughly with ether (500 mL), and the combined
filtrate was concentrated. The resulting crude oil was purified
by flash chromatography on silica gel (EtOAc/hexanes, 60/40)
to give diol 4 as a colorless oil (9.55 g, 91%). TLC: Rf 0.24
(EtOAc/hexanes, 50/50). [R]D: -69.4 (c 0.48, CHCl3). IR: 3473
mL) at -78 °C was added 3-butenylmagnesium bromide (18.0
mL of a 0.75 M solution in ether). The resulting suspension
was stirred for 30 min prior to addition of lactone 6 (2.999 g,
4.497 mmol) in THF (10 mL, 2 × 2 mL rinse) and was allowed
to warm to -50 °C over 6 h. The mixture was poured into
saturated NH4Cl (200 mL) and extracted with ether (2 × 200
mL). The organic extracts were washed with H2O (200 mL)
and brine (150 mL), dried, filtered, and concentrated. The
crude product was dissolved in THF (85 mL) and 2 N HCl (5
mL), and the solution was heated to reflux for 3 h, cooled to
rt, and poured into H2O (150 mL). The product was extracted
with ether (2 × 200 mL), and the organic extracts were washed
wtih H2O (150 mL) and brine (100 mL), dried, filtered, and
concentrated. The product was purified by chromatography
on silica gel (EtOAc/hexanes, 20/80) to provide 7 as a colorless
oil (2.221 g, 74%). TLC: Rf 0.29 (EtOAc/hexanes, 20/80). [R]D:
cm-1
.
1H NMR (500 MHz): δ 2.04 (br s, 1), 3.55 (s, 1), 3.57
(br s, 1), 3.66 (dd, 1, J ) 7.4, 5.3), 3.68 (d, 1, J ) 1.3), 3.80 (d,
1, J ) 11.5), 3.84 (d, 1, J ) 11.5), 4.19 (d, 1, J ) 7.8), 4.20 (d,
1, J ) 6.3), 4.35 (d, 1, J ) 11.5), 4.51 (d, 1, J ) 12.1), 4.56 (d,
1, J ) 11.5), 4.57 (d, 1, J ) 12.1), 5.41 (s, 1), 7.26-7.38 (m,
10). 13C NMR (100 MHz): δ 63.82, 65.59, 69.66, 72.07, 74.66,
75.33, 75.52, 100.22, 127.84, 127.93, 128.11, 128.28, 128.58,
128.67, 136.86, 137.34. Anal. Calcd for C21H24O6: C, 67.73;
H, 6.50. Found: C, 67.66; H, 6.56.
+12.6 (c 0.73, CHCl3). IR: 3493 cm-1 1H NMR (500 MHz):
.
δ 1.08 (s, 9), 1.70 (ddd, 1, J ) 14.0, 11.6, 5.2), 1.85 (ddd, 1, J
) 14.0, 11.5, 5.0), 2.04-2.22 (m, 2), 3.47 (br s, 1), 3.82 (d, 1, J
) 10.8), 3.85 (d, 1, J ) 11.1), 3.89 (d, 1, J ) 2.4), 4.04 (dd, 1,
J ) 11.3, 6.7), 4.15 (d, 1, J ) 10.8), 4.27 (dd, 1, J ) 10.6, 6.8),
4.35 (d, 1, J ) 2.5), 4.50-4.63 (m, 4), 4.89-4.98 (m, 2), 5.73-
5.81 (m, 1), 7.11-7.46 (m, 16), 7.62-7.67 (m, 4). 13C NMR
(100 MHz): δ 19.12, 26.90, 27.47, 35.61, 64.03, 64.85, 65.65,
72.44, 72.51, 82.75, 83.59, 89.12, 103.42, 114.39, 127.70,
127.79, 127.85, 127.87, 128.37, 130.01, 132.12, 135.65, 137.50,
137.70, 138.26. Anal. Calcd for C41H48O6Si: C, 74.06; H, 7.27.
Found: C, 73.99; H, 7.22.
1,6-An h yd r o-2,3-d i-O-ben zyl-4-[[(ter t-bu tyld ip h en ylsi-
lyl)oxy]m eth yl]-â-D-ga la ctop yr a n ose (5). To a solution of
diol 4 (0.682 g, 1.66 mmol) in DMF were added imidazole
(0.310 g, 4.55 mmol) and tert-butyl-diphenylsilyl chloride
(0.550 mL, 2.12 mmol). The reaction mixture was stirred at
rt overnight, poured into H2O (15 mL), and extracted with
ether (2 × 40 mL). The organic extracts were washed with
H2O (40 mL) and brine (25 mL), dried, filtered, and concen-
trated. The crude product was purified by flash chromatog-
raphy on silica gel (EtOAc/hexanes, 25/75) to give 5 as a
colorless oil (1.118 g, 100%). TLC: Rf 0.44 (EtOAc/hexanes,
1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4-[[(ter t-bu -
tyldiph en ylsilyl)oxy]m eth yl]-D-galactofu r an os-5-u lose (8).
To a solution of DMSO (2.50 mL, 35.2 mmol) in CH2Cl2 (100
mL) at -78 °C was added TFAA (2.50 mL, 17.7 mmol). The
solution was stirred for 15 min, and alcohol 7 (7.70 g, 11.6
mmol) in CH2Cl2 (10 mL, 2 × 5 mL rinse) was added. After
45 min Et3N (7.00 mL, 50.3 mmol) was added, and the solution
was allowed to warm to rt over 30 min. The mixture was
poured into H2O (200 mL), extracted with ether (2 × 200 mL),
and washed with H2O (150 mL) and brine (100 mL). The
organic extracts were dried, filtered, and concentrated, and
the crude product was purified by chromatography on silica
gel (EtOAc/hexanes, 20/80) to provide 8 as a colorless oil (7.24
g, 94%). TLC: Rf 0.52 (EtOAc/hexanes, 20/80). [R]D: -20.9
30/70). [R]D: -24.4 (c 0.34, CHCl3). IR: 3525 cm-1 1H NMR
.
(400 MHz): δ 1.07 (s, 9), 3.45 (s, 1), 3.52 (s, 1), 3.67 (dd, 1, J
) 7.3, 5.5, 3.72 (d, 1, J ) 1.1), 3.88 (d, 1, J ) 10.4), 3.99 (d, 1,
J ) 10.4), 4.30 (m, 2), 4.41 (d, 1, J ) 12.1), 4.47 (d, 1, J )
12.1), 4.48 (d, 1, J ) 11.8), 4.58 (d, 1, J ) 11.8), 5.42 (s, 1),
7.19-7.42 (m, 16), 7.69-7.76 (m, 4). 13C NMR (100 MHz): δ
19.42, 26.82, 63.85, 66.78, 70.36, 71.89, 73.29, 74.89, 75.75,
100.24, 127.64, 127.81, 127.85, 128.06, 128.45, 128.58, 128.58,
129.57, 129.61, 133.24, 133.49, 135.62, 135.74, 137.30, 137.53.
Anal. Calcd for C37H42O6Si: C, 72.76; H, 6.93. Found: C,
72.98; H, 6.77.
(c 3.2, CHCl3). IR: 1745 cm-1 1H NMR (500 MHz): δ 0.99
.
2,3-Di-O-ben zyl-4-[[(ter t-bu tyldiph en ylsilyl)oxy]m eth yl]-
5,6-O-isop r op ylid en e-D-ga la cto-1,4-la cton e (6). To a solu-
tion of alcohol 5 (14.26 g, 23.35 mmol) in Ac2O (80.0 mL) was
added TFA (4.1 mL). The solution was stirred at 68 °C for 90
min, cooled to rt, and concentrated. The crude product was
dissolved in MeOH (100 mL), and a 25 wt % solution of MeONa
in MeOH (2.0 mL) was added dropwise. The solution was
stirred at rt for 2 h, filtered through a plug of silica gel, and
washed thoroughly with EtOAc. The filtrate was concentrated
to afford a crude foam which was dissolved in acetone (300
mL) containing p-TsOH (2.21 g). The reaction mixture was
stirred for 90 min, and NaHCO3 (8.0 g) was added. The
mixture was filtered and concentrated. The crude product was
dissolved in CH2Cl2 (400 mL) with Celite (10.5 g), 4 Å
molecular sieves (15.0 g), and PDC (14.5 g). The resulting
suspension was stirred at rt for 3 h, filtered through a plug of
silica gel, and washed thoroughly with ether (500 mL). The
filtrate was concentrated and the crude product purified by
chromatography on silica gel (EtOAC/hexanes, 20/80) to
provide lactone 5 as a colorless oil (11.93 g, 77%). TLC: Rf
0.54 (EtOAc/hexanes, 30/70). [R]D: +34.5 (c 0.31, CHCl3). IR:
(s, 9), 1.89 (ddd, 1, J ) 14.0, 10.8, 5.5), 2.06 (ddd, 1, J ) 14.0,
10.7, 5.5), 2.26-2.36 (m, 2), 3.81 (d, 1, J ) 1.8), 3.84 (d, 1, J )
1.8), 3.96 (d, 1, J ) 11.2), 4.27 (d, 1, J ) 11.2), 4.29 (d, 1, J )
11.6), 4.31 (d, 1, J ) 16.6), 4.32 (d, 1, J ) 11.7), 4.44 (d, 1, J
) 16.6), 4.47 (d, 1, J ) 11.8), 4.57 (d, 1, J ) 11.8), 4.96-4.98
(m, 1), 5.02-5.06 (m, 1), 5.84-5.92 (m, 1), 7.03-7.05 (m, 2),
7.20-7.46 (m, 14), 7.66-7.72 (m, 4). 13C NMR (100 MHz): δ
19.27, 26.57, 27.26, 36.43, 61.66, 69.93, 72.54, 72.63, 85.85,
88.14, 93.16, 105.01, 114.68, 127.56, 127.64, 127.67, 127.84,
127.99, 128.02, 128.43, 128.49, 129.57, 129.62, 133.13, 133.27,
135.63, 135.74, 136.86, 137.21, 138.07, 205.77. Anal. Calcd
for C41H46O6Si: C, 74.29; H, 6.99. Found: C, 74.02; H, 7.00.
(6S)-1,6-An h ydr o-1-(bu t-3-en yl)-2,3-di-O-ben zyl-4-[[(ter t-
bu tyld ip h en ylsilyl)oxy]m eth yl]-6-(h yd r oxym eth yl)-D-ga -
la ctofu r a n os-5-u lose (9). To a solution of ketone 8 (0.855
g, 1.29 mmol) in THF (6.0 mL) at -78 °C was added
tert-butyllithium (1.00 mL of a 1.4 M solution in pentane). The
solution was stirred for 10 min, and a solution of formaldehyde
in THF27 (10 mL) was added. The resulting solution was
stirred at -78 °C for 1 h, poured into saturated NH4Cl (100
mL), and extracted with ether (2 × 100 mL). The organic
extracts were washed with H2O (100 mL) and brine (75 mL),
dried, filtered, and concentrated. The crude product was
purified by chromatography on silica gel to provide recovered
ketone 8 (0.333 g, 39%) and hydroxy ketone 9 (0.507 g, 57%)
as a colorless oil. TLC: Rf 0.47 (EtOAc/hexanes, 30/70). [R]D:
1790 cm-1 1H NMR (400 MHz): δ 0.93 (s, 9), 1.28 (s, 3), 1.33
.
(s, 3), 3.41 (d, 1, J ) 10.9), 3.78-3.96 (m, 4), 4.56 (d, 1, J )
7.9), 4.63 (d, 1, J ) 11.3), 4.72 (d, 1, J ) 11.3), 4.84 (d, 1, J )
11.7), 4.87 (d, 1, J ) 7.9), 5.13 (d, 1, J ) 11.7), 7.15 (t, 2, J )
7.6), 7.25-7.42 (m, 14), 7.57-7.65 (m, 4). 13C NMR (100
MHz): δ 18.90, 25.32, 25.88, 26.51, 62.48, 64.45, 72.51, 73.37,
75.06, 78.93, 81.05, 84.62, 109.78, 127.07, 127.92, 127.96,
128.12, 128.43, 128.55, 129.74, 129.95, 131.78, 132.23, 135.53,
135.60, 137.08, 137.53, 172.69. Anal. Calcd for C40H46O7Si:
C, 72.04; H, 6.95. Found: C, 72.34; H, 6.96.
+2.1 (c 2.1, CHCl3). IR: 3463, 1738 cm-1
.
1H NMR (500
MHz): δ 1.00 (s, 9), 1.96 (ddd, 1, J ) 14.2, 10.3, 5.6), 2.11 (ddd,
1, J ) 14.2, 10.2, 5.8), 2.30-2.39 (m, 2), 3.72 (d, 1, J ) 0.9),
3.84 (dd, 1, J ) 11.5, 4.7), 3.89 (d, 1, J ) 0.9), 3.91 (d, 1, J )
11.2), 3.96 (dd, 1, J ) 11.5, 6.0), 4.20 (d, 1, J ) 11.2), 4.26 (d,
1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4-[[(ter t-bu -
tyld ip h en ylsilyl)oxy]m eth yl]-â-D-ga la ctofu r a n ose (7). To
a suspension of dried CeCl3 (3.33 g, 13.5 mmol) in THF (45
(27) Schlosser, M.; J enny, T.; Guggisberg, Y. Synlett 1990, 704.

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9131
1, J ) 11.9), 4.32 (d, 1, J ) 11.8), 4.44 (d, 1, J ) 11.7), 4.78
(dd, 1, J ) 5.9, 4.8), 4.60 (d, 1, J ) 11.9), 4.98-5.01 (m, 1),
5.05-5.09 (m, 1), 5.86-5.93 (m, 1), 7.00-7.02 (m, 2), 7.19-
7.44 (m, 14), 7.67-7.72 (m, 4). 13C NMR (100 MHz): δ 19.16,
26.57, 27.48, 37.20, 61.55, 64.38, 72.24, 72.50, 81.12, 85.99,
88.06, 93.39, 105.78, 114.81, 127.60, 127.68, 127.73, 128.01,
128.08, 128.44, 128.53, 129.62, 129.68, 133.01, 133.07, 135.69,
purified by chromatography on silica gel (EtOAc/hexanes, 40/
60) to provide triol 15 as a colorless oil, which crystallized upon
standing (71.8 mg, 83%). TLC: Rf 0.44 (EtOAc/hexanes, 50/
50). [R]D: -7.0 (c 0.76, CHCl3). IR: 3381 cm-1 1H NMR (400
.
MHz): δ 1.91 (ddd, 1, J ) 14.1, 10.8, 5.7), 2.02 (dd, 1, J ) 8.4,
4.6), 2.08 (dd, 1, J ) 14.1, 10.5, 5.4), 2.23-2.42 (m, 2), 2.72
(dd, 1, J ) 8.9, 4.6), 3.54 (ddd, 1, J ) 12.0, 8.4, 3.3), 3.66 (dd,
1, J ) 12.6, 4.6), 3.69 (dd, 1, J ) 12.1, 4.6), 3.82 (dd, 1, J )
12.6, 8.9), 3.98 (s, 1), 4.05 (d, 1, J ) 2.7), 4.44 (d, 1, J ) 11.7),
4.49 (dd, 1, J ) 5.6, 3.3), 4.52 (d, 1, J ) 11.8), 4.62 (dd, 1, J )
11.7), 4.66 (d, 1, J ) 11.7), 4.74 (d, 1, J ) 2.7), 4.94-4.98 (m,
1), 5.03 (dd, 1, J ) 17.2, 3.4, 1.6), 5.79-5.89 (m, 1), 6.36 (dd,
1, J ) 3.3, 1.8), 6.45 (dd, 1, J ) 3.3, 0.8), 7.22-7.26 (m, 2),
7.28 (dd, 1, J ) 1.8, 0.9), 7.28-7.40 (m, 8). 13C NMR (100
MHz): δ 27.55, 35.55, 60.97, 62.04, 72.42, 72.73, 72.79, 74.86,
85.23, 86.55, 88.59, 104.87, 108.98, 110.64, 114.64, 127.78,
128.08, 128.18, 128.52, 128.59, 136.75, 137.37, 138.21, 142.55,
151.31. Anal. Calcd for C30H34O8: C, 68.95; H, 6.56. Found:
C, 68.61; H, 6.62.
135.75, 136.81, 137.07, 138.11, 205.45. Anal. Calcd for C42H48
O7Si: C, 72.80; H, 6.98. Found: C, 72.53; H, 6.96.
-
(6S)-1,6-An h ydr o-1-(bu t-3-en yl)-2,3-di-O-ben zyl-4-[[(ter t-
bu tyld ip h en ylsilyl)oxy]m eth yl]-6-[[(ter t-bu tyld im eth yl-
silyl)oxy]m eth yl]-D-ga la ctofu r a n os-5-u lose (10). To a so-
lution of hydroxy ketone 9 (2.07 g, 2.99 mmol) in DMF (15.0
mL) were added imidazole (0.500 g, 7.34 mmol) and TBSCl
(0.500 g, 2.32 mmol). The solution was stirred at rt for 45
min, poured into H2O (100 mL), and extracted with ether (2
× 150 mL). The organic extracts were washed with H2O (100
mL) and brine (100 mL), dried, filtered, and concentrated. The
crude product was purified by chromatography on silica gel
(EtOAc/hexanes, 20/80) to provide 10 as a colorless oil (2.37
g, 98%). TLC: Rf 0.62 (EtOAc/hexanes, 30.70). [R]D: -2.1 (c
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(ter t-bu toxyca r bon yl)-5-(2-fu r yl)-L-a ltr ofu r a n ose (16). To
a solution of triol 15 (30.4 mg, 58.2 µmol) in CH2Cl2 (2.0 mL)
was added the Dess-Martin reagent (95.5 mg, 0.225 mmol).
The suspension was stirred at rt overnight, poured into
saturated Na2S2O3 (10 mL), and extracted with ether (2 × 10
mL). The organic extracts were washed with saturated
NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL), dried,
filtered, and concentrated to provide 29.8 mg of dialdehyde as
a colorless oil that showed the following NMR data. 1H NMR
(500 MHz): δ 2.01 (ddd, 1, J ) 14.2, 10.6, 5.9), 2.16 (ddd, 1, J
) 14.2, 10.3, 5.3), 2.31-2.48 (m, 2), 3.68 (s, 1), 4.08 (d, 1, J )
2.1), 4.39 (d, 1, J ) 11.9), 4.65 (d, 1, J ) 11.9), 4.55 (d, 1, J )
11.7), 4.62 (d, 1, J ) 11.7), 4.93 (d, 1, J ) 2.1), 4.94 (s, 1), 5.00
(ddd, 1, J ) 10.1, 2.9, 1.3), 5.08 (ddd, 1, J ) 10.8, 3.3, 1.7),
5.83-5.93 (m, 1), 6.46 (dd, 1, J ) 3.4, 1.8), 6.48 (dd, 1, J )
3.4, 0.9), 7.19-7.41 (m, 10), 7.41 (dd, 1, J ) 1.8, 0.9), 9.21 (s,
1), 9.30 (d, 1, J ) 0.4). 13C NMR (125 MHz): δ 27.41, 35.22,
71.82, 72.20, 73.07, 79.36, 83.23, 87.89, 91.64, 105.71, 110.54,
111.16, 115.00, 127.95, 128.15, 128.25, 128.34, 128.58, 128.62,
136.46, 136.73, 137.80, 143.12, 148.27, 193.78, 196.10.
To a solution of the foregoing crude dialdehyde (41.2 mg,
80.6 µmol) in t-BuOH (2.0 mL) and 2-methyl-2-butene (0.8 mL)
was added dropwise a solution of NaH2PO4 (0.100 g, 0.724
µmol) and NaClO2 (0.100 g, 0.885 µmol) in H2O (0.50 mL). The
biphasic mixture was stirred at rt for 30 min, poured into 2 N
HCl (10 mL), and extracted with H2O (10 mL). The organic
extracts were washed with H2O (10 mL) and brine (10 mL),
dried, filtered, and concentrated. The crude diacid was dis-
solved in CH2Cl2 (2.0 mL) and i-PrNHC(O-Bu)N-i-Pr (0.300
g, 1.5 mmol), and the solution was stirred at rt for 4 h. The
reaction mixture was poured into 1 N HCl (10 mL) and
extracted with ether (2 × 10 mL). The organic extracts were
washed with brine (10 mL), dried, filtered, and concentrated.
The crude product was purified by chromatography on silica
gel (EtOAc/hexanes, 25/75) to provide diester 16 as a colorless
oil (32.4 mg, 64% from 15). TLC: Rf 0.43 (EtOAc/hexanes,
30/70). 1H NMR (500 MHz): δ 1.21 (s, 9), 1.27 (s, 9), 1.94 (ddd,
1, J ) 14.1, 11.2, 5.4), 2.12 (ddd, 1, J ) 14.1, 11.1, 5.0), 2.33-
2.38 (m, 2), 3.69 (s, 1), 4.05 (d, 1, J ) 2.1), 4.43 (d, 1, J ) 11.9),
4.50 (d, 1, J ) 11.8), 4.55 (d, 1, J ) 12.4), 4.58 (d, 1, J ) 12.3),
4.90 (d, 1, J ) 2.1), 4.95 (ddd, 1, J ) 10.2, 3.2, 1.3), 4.98 (s, 1),
5.04 (ddd, 1, J ) 17.1, 3.5, 1.6), 5.81-5.88 (m, 1), 6.39 (dd, 1,
J ) 3.2, 0.9), 6.42 (dd, 1, J ) 3.2, 1.8), 7.21-7.37 (m, 10), 7.42
(dd, 1, J ) 1.8, 0.9). 13C NMR (100 MHz): δ 27.39, 27.71,
27.76, 35.66, 72.17, 72.65, 72.72, 75.73, 81.78, 82.29, 83.20,
88.27, 91.48, 104.56, 108.85, 110.68, 114.67, 127.88, 127.91,
128.06, 128.37, 128.43, 137.18, 137.35, 138.07, 141.40, 151.76,
163.95, 165.58.
1.0, CHCl3). IR: 1738 cm-1 1H NMR (500 MHz): δ 0.05 (s,
.
3), 0.06 (s, 3), 0.89 (s, 9), 1.01 (s, 9), 1.93 (ddd, 1, J ) 13.9,
11.3, 5.1), 2.09 (ddd, 1, J ) 13.9, 11.3, 4.9), 2.31-2.37 (m, 1),
2.41-2.47 (m, 1), 3.75 (d, 1, J ) 1.1), 3.86 (d, 1, J ) 1.2), 3.89
(d, 1, J ) 11.1), 3.90 (m, 1), 4.02 (dd, 1, J ) 10.7, 7.8), 4.19 (d,
1, J ) 11.1), 4.26 (d, 1, J ) 11.8), 4.32 (d, 1, J ) 11.7), 4.45-
4.46 (m, 1), 4.46 (d, 1, J ) 11.7), 4.62 (d, 1, J ) 11.8), 4.98 (dd,
1, J ) 10.2, 1.8), 5.06 (ddd, 1, J ) 17.1, 3.3, 1.6), 5.86-5.95
(m, 1), 7.00-7.03 (m, 2), 7.19-7.45 (m, 14), 7.67-7.75 (m, 4).
13C NMR (100 MHz): δ -5.42, -5.36, 18.29, 19.30, 25.91,
26.86, 27.59, 35.83, 63.35, 65.27, 66.80, 72.40, 72.51, 73.09,
83.74, 84.07, 89.34, 103.65, 114.21, 127.62, 127.67, 127.75,
128.30, 128.34, 129.64, 129.68, 133.02, 133.18, 135.70, 135.76,
137.75, 137.79, 138.62. Anal. Calcd for C48H64O7Si2: C, 71.25;
H, 7.97. Found: C, 71.13; H, 7.96.
(6S)-1,6-An h ydr o-1-(bu t-3-en yl)-2,3-di-O-ben zyl-4-[[(ter t-
b u t yld ip h en ylsilyl)oxy]m et h yl]-5-(2-fu r yl)-6-[[(ter t-b u -
tyld im eth ylsilyl)oxy]m eth yl]-L-a ltr ofu r a n ose (14). To a
solution of ketone 10 (0.125 g, 0.155 mmol) in THF (2.0 mL)
at -78 °C was added dropwise 2-furyllithium (0.40 mL of a
0.54 M solution in THF prepared from furan and n-butyl-
lithium at -20 °C for 3 h, 0.43 mmol). The solution was stirred
at -78 °C for 1 h, poured into H2O (15 mL), and extracted
with ether (2 × 25 mL). The organic extracts were washed
1
with brine (20 mL), dried, filtered, and concentrated. The H
NMR spectrum indicated a diastereoselection of ∼10:1. The
crude product was purified by chromatography on silica gel
(EtOAc/hexanes, 20/80) to provide alcohol 14 as a colorless oil
(0.130 g, 96%). TLC: Rf 0.57 (EtOAc/hexanes, 30/70). [R]D:
-10.0 (c 1.2, CHCl3). IR: 3441 cm-1 1H NMR (500 MHz): δ
.
-0.01 (s, 3), 0.02 (s, 3), 0.84 (s, 9), 1.07 (s, 9), 1.91 (ddd, 1, J
) 13.9, 11.5, 5.3), 2.15 (ddd, 1, J ) 13.9, 11.4, 4.9), 2.30-2.36
(m, 1), 2.44-2.48 (m, 1), 3.69 (d, 1, J ) 11.8), 3.74 (dd, 1, J )
11.5, 2.7), 3.86 (dd, 1, J ) 11.5, 6.7), 3.91 (d, 1, J ) 2.7), 3.97
(d, 1, J ) 11.7), 4.10 (d, 1, J ) 11.8), 4.27 (d, 1, J ) 11.8),
4.53-4.55 (m, 1), 4.56 (d, 1, J ) 11.8), 4.63 (d, 1, J ) 2.7),
4.71 (d, 1, J ) 11.8), 4.99 (ddd, 1, J ) 9.0, 3.1, 1.9), 5.07 (ddd,
1, J ) 17.2, 3.5, 1.6), 5.64 (d, 1, J ) 1.6), 5.92-5.97 (m, 1),
6.39 (dd, 1, J ) 3.3, 1.9), 6.67 (dd, 1, J ) 3.3, 0.8), 6.87-6.89
(m, 2), 7.14-7.52 (m, 15), 7.62 (dd, 2, J ) 8.1, 1.4), 7.78 (dd, 2,
J ) 8.0, 1.4). 13C NMR (100 MHz): δ -5.13, 18.38, 19.11,
25.96, 26.75, 27.75, 36.00, 63.31, 66.05, 72.02, 72.46, 73.84,
84.83, 85.14, 88.64, 104.58, 109.07, 110.41, 114.31, 127.58,
127.65, 127.69, 127.73, 128.24, 128.32, 129.80, 129.86, 132.02,
132.32, 135.66, 135.79, 135.86, 137.47, 138.01, 138.71, 141.99,
154.84. Anal. Calcd for C52H66O8Si2: C, 71.36; H, 7.60.
Found: C, 71.39; H, 7.78.
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(h yd r oxym eth yl)-5-(2-fu r yl)-L-a ltr ofu r a n ose (15). To a
solution of silyl ether 14 (0.145 g, 0.166 mmol) in THF (2.0
mL) at -78 °C was added TBAF (0.80 mL of a 1.0 M solution
in THF, 0.80 mmol). The solution was stirred for 2 h, poured
into H2O (15 mL), and extracted with ether (2 × 20 mL). The
organic extracts were washed with H2O (15 mL) and brine (15
mL), dried, filtered, and concentrated. The crude product was
(6S)-1,6-An h ydr o-1-(bu t-3-en yl)-2,3-di-O-ben zyl-4-[[(ter t-
b u t yld ip h en ylsilyl)oxy]m et h yl]-5-(5-m et h yl-2-fu r yl)-6-
[[(ter t-b u t yld im et h ylsilyl)oxy]m et h yl]-L-a lt r ofu r a n ose
(17). To a solution of 2-methylfuran (0.20 mL, 2.2 mmol) in
THF at -78 °C was added n-butyllithium (0.78 mL of a 2.16
M solution in hexanes, 1.68 mmol). The solution was warmed
to -30 °C over 2 h, and the solution was added to a -78 °C
solution of ketone 10 (57.5 mmol, 71.2 µmol) in THF (2.0 mL).

9132 J . Org. Chem., Vol. 61, No. 26, 1996
Caron et al.
The resulting solution was stirred for 1 h, poured into H2O,
and extracted with ether (2 × 20 mL). The organic extracts
were washed with brine (20 mL), dried, filtered, and concen-
trated. Analysis of the 1H NMR spectrum of the crude product
indicated a diastereoselection of g10:1. The crude product was
purified by chromatography on silica gel (EtOAc/hexanes, 25/
75) to provide alcohol 17 as a colorless oil (55.2 mg, 87%).
TLC: Rf 0.63 (EtOAc/hexanes, 30/70). [R]D: -3.6 (c 0.88,
washed with brine (10 mL), dried, filtered, and concentrated.
The crude product was purified by chromatography on silica
gel (EtOAc/hexanes, 25/75) to provide diester 19 as a colorless
oil (10.2 mg, 30% unoptimized). TLC: Rf 0.44 (EtOAc/hexanes,
30/70). 1H NMR (500 MHz): δ 1.22 (s, 9), 1.23 (s, 9), 1.90-
1.09 (m, 2), 2.31 (s, 3), 2.32-2.45 (m, 2), 3.64 (s, 1), 4.04 (d, 1,
J ) 2.0), 4.40 (1, d, J ) 11.8), 4.48 (d, 1, J ) 11.8), 4.56 (d, 1,
J ) 12.3), 4.59 (d, 1, J ) 12.3), 4.87 (d, 1, J ) 2.1), 4.92-5.07
(m, 2), 4.94 (s, 1), 5.80-5.89 (m, 1), 6.00 (dd, 1, J ) 3.1, 1.0),
6.23 (d, 1, J ) 3.1), 7.26-7.41 (m, 10).
CHCl3). IR: 3453, 1471, 1428 cm-1 1H NMR (500 MHz): δ
.
0.02 (s, 3), 0.04 (s, 3), 0.86 (s, 9), 1.07 (s, 9), 1.90 (ddd, 1, J )
13.8, 11.6, 5.2), 2.14 (ddd, 1, J ) 13.8, 11.5, 4.8), 2.26 (s, 3),
2.28-2.47 (m, 2), 3.78 (d, 1, J ) 11.7), 3.81 (dd, 1, J ) 11.6,
2.5), 3.87 (dd, 1, J ) 11.6, 6.7), 3.90 (d, 1, J ) 2.7), 3.97 (d, 1,
J ) 11.7), 4.08 (d, 1, J ) 11.6), 4.23 (d, 1, J ) 11.6), 4.50-4.51
(m, 1), 4.55 (d, 1, J ) 11.9), 4.56 (d, 1, J ) 2.7), 4.71 (d, 1, J )
11.8), 4.99 (dd, 1, J ) 10.1, 1.4), 5.08 (dd, 1, J ) 17.1, 1.6),
5.59 (d, 1, J ) 1.3), 5.90-5.96 (m, 1), 5.98 (d, 1, J ) 2.8), 6.40
(d, 1, J ) 3.1), 6.86 (d, 2, J ) 6.9), 7.14-7.44 (m, 14), 7.64-
7.66 (m, 2), 7.77-7.79 (m, 2). 13C NMR (100 MHz): δ -5.19,
-5.09, 13.73, 18.38, 19.11, 25.96, 26.74, 27.74, 35.93, 63.50,
66.11, 72.26, 72.47, 73.70, 77.16, 104.45, 106.53, 109.80,
114.30, 125.99, 127.40, 127.58, 127.64, 127.67, 127.70, 128.24,
128.33, 129.77, 129.85, 132.04, 132.35, 135.68, 135.79, 137.51,
138.06, 138.71, 151.63, 152.57. Anal. Calcd for C53H68O8Si2:
C, 71.58; H, 7.71. Found: C, 71.29; H, 7.68.
(1S,4R-(3r,5r,6r,7â))-1-(3-Oxopr opyl)-6,7-bis(ben zyloxy)-
2,8-d ioxa bicyclo[3.2.1]octa n e 3,5-Bis(1,1-d im eth yleth yl)
Ester 4-Sp ir o 2-Hyd r oxy-4-a cetoxy-3,4-d ih yd r ofu r a n 20.
To a solution of diester 19 (5.0 mg, 7.4 µmol) in CH2Cl2 (1.0
mL) and MeOH (3.0 mL) at -78 °C was bubbled ozone for 25
min (2.0 L/min). To the resulting blue solution was added
PPh3 (20 mg), and the reaction mixture was allowed to warm
to rt over 1.5 h and concentrated. The crude product was
purified by chromatography on silica gel (EtOAC/hexanes, 50/
50) to provide hemiacetal 20 (4.6 mg, 88%) as a colorless oil.
TLC: Rf 0.45 (EtOAc/hexanes, 50/50). IR: 3455, 1759, 1725,
1626 cm-1 1H NMR (500 MHz): δ 1.37 (s, 9), 1.38 (s, 9), 2.09
.
(ddd, 1, J ) 14.6, 8.3, 6.2), 2.29-2.35 (m, 1), 2.32 (s, 3), 2.64-
2.79 (m, 2), 3.52 (brs, 1), 3.93 (d, 1, J ) 2.1), 4.31 (d, 1, J )
11.9), 4.38 (d, 1, J ) 11.9), 4.48 (d, 1, J ) 11.7), 4.59 (d, 1, J
) 4.59), 5.05 (s, 1), 5.13 (d, 1, J ) 1.9), 6.41 (d, 1, J ) 7.5),
7.19-7.33 (m, 10), 7.51 (d, 1, J ) 7.5), 9.76 (t, 1, J ) 1.4). 13C
NMR (100 MHz): δ 20.78, 27.77, 27.89, 29.03, 37.82, 72.59,
73.33, 76.68, 82.95, 83.25, 84.02, 87.85, 87.92, 91.69, 104.19,
106.40, 110.49, 127.88, 127.98, 128.03, 128.30, 128.39, 128.42,
136.85, 137.27, 142.85, 164.69, 165.53, 167.56, 201.42.
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(h ydr oxym eth yl)-5-(5-m eth yl-2-fu r yl)-L-altr ofu r an ose (18).
To a solution of 17 (54.0 mg, 60.7 µmol) in THF (2.0 mL) at 0
°C was added TBAF (0.20 mL of a 1.0 M solution, 0.20 mmol).
The solution was stirred for 90 min, poured into H2O (10 mL),
and extracted with ether (2 × 20 mL). The organic extracts
were washed with brine (20 mL), dried, filtered, and concen-
trated. The crude product was purified by chromatography
on silica gel (EtOAc/hexanes, 45/55) to provide triol 18 as a
colorless oil which crystallized upon standing (27.0 mg, 83%).
TLC: Rf 0.35 (EtOAc/hexanes, 50/50). [R]D: +0.41 (c 0.73,
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(h ydr oxym eth yl)-5-vin yl-6-L-altr ofu r an ose (21). To a slurry
of anhydrous CeCl3 (3.56 g, 14.4 mmol) in THF (30 mL, stirred
overnight at rt) at -78 °C was added vinylmagnesium bromide
(14.0 mL of a 1.0 M solution in THF). The resulting suspen-
sion was stirred for 30 min, and ketone 10 (2.33 g, 2.89 mmol)
in THF (10 mL, 2 × 4.0 mL rinse) was added. The reaction
mixture was allowed to warm to -50 °C over 3 h, poured into
1 N HCl (100 mL), and extracted with ether (2 × 200 mL).
The organic extracts were washed with H2O (100 mL) and
brine (100 mL), dried, filtered, and concentrated. Analysis of
CHCl3). IR: 3390 cm-1 1H NMR (500 MHz): δ 1.91 (ddd, 1,
.
J ) 14.1, 10.9, 5.5), 2.03-2.11 (m, 1), 2.19-2.40 (m, 2), 2.27
(s, 3), 2.83 (brs, 1), 3.61 (dd, 1, J ) 12.2, 3.2), 3.71-3.75 (m,
2), 3.84 (brd, 1), 4.03 (d, 1, J ) 2.7), 4.08 (s, 1), 4.45 (s, 2), 4.47
(dd, 1, J ) 5.8, 3.4), 4.60 (d, 1, J ) 11.8), 4.69 (d, 1, J ) 11.7),
4.70 (d, 1, J ) 2.7), 4.96 (dd, 1, J ) 10.2, 1.5), 5.04 (dd, 1, J )
17.1, 1.7), 5.80-5.88 (m, 1), 5.94 (dd, 1, J ) 3.1, 0.9), 6.32 (d,
1, J ) 3.1), 7.23-7.41 (m, 10). 13C NMR (100 MHz): δ 13.64,
27.55, 35.52, 61.01, 62.11, 72.61, 72.69, 72.86, 75.02, 85.74,
86.69, 88.72, 104.77, 106.70, 109.80, 114.61, 127.80, 127.93,
128.05, 128.19, 128.53, 128.54, 136.95, 137.47, 138.25, 149.25,
152.37. Anal. Calcd for C31H36O8: C, 69.39; H, 6.76. Found:
C, 69.38; H, 6.77.
1
the H NMR spectrum of the crude reaction mixture indicated
a diastereoselection >15:1, and the material showed the
following IR and NMR data. IR: 3465, 1472, 1429 cm-1 1H
.
NMR (500 MHz): δ 0.046 (s, 3), 0.049 (s, 3), 0.86 (s, 9), 1.04
(s, 9), 1.85 (ddd, 1, J ) 13.9, 11.4, 5.2), 2.10 (ddd, 1, J ) 13.9,
11.4, 4.7), 2.29-2.45 (m, 2), 3.79 (dd, 1, J ) 11.6, 6.7), 3.84
(dd, 1, J ) 11.6, 2.4), 3.88 (d, 1, J ) 10.8), 3.93 (d, 1, J ) 11.6),
3.99 (d, 1, J ) 2.6), 4.10 (dd, 1, J ) 6.9, 1.8), 4.23 (d, 1, J )
11.8), 4.36 (d, 1, J ) 11.8), 4.51 (d, 1, J ) 11.6), 4.71 (d, 1, J
) 11.6), 4.87 (s, 1), 4.97 (dd, 1, J ) 10.2, 1.8), 5.05 (ddd, 1, J
) 17.1, 3.3, 1.6), 5.36 (dd, 1, J ) 9.8, 2.9), 5.75 (d, 1, J ) 2.9),
5.77 (d, 1, J ) 9.8), 5.80-5.94 (m, 1), 6.92-6.94 (m, 2), 7.17-
7.45 (m, 14), 7.75 (dd, 4, J ) 7.9, 1.2). 13C NMR (100 MHz):
δ -5.10, -4.94, 18.38, 19.08, 25.96, 26.77, 27.74, 36.22, 63.11,
65.51, 71.83, 72.46, 74.86, 77.41, 84.58, 85.32, 88.44, 104.33,
114.35, 118.19, 127.50, 127.64, 127.66, 127.69, 127.73, 128.08,
129.30, 128.34, 129.75, 129.88, 132.08, 132.37, 135.69, 135.80,
136.42, 137.26, 137.84.
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(ter t-b u t oxyca r b on yl)-5-(5-m et h yl-2-fu r yl)-L-a lt r ofu r a -
n ose (19). To a solution of triol 18 (27.0 mg, 50.3 µmol) in
CH2Cl2 (1.0 mL) was added the Dess-Martin reagent (60.1
mg, 0.142 mmol). The suspension was stirred at rt overnight,
poured into saturated Na2S2O3 (15 mL), and extracted with
ether (2 × 15 mL). The organic extracts were washed with
saturated NaHCO3 (15 mL) and brine (15 mL), dried, filtered,
and concentrated to provide the dialdehyde as an oil that
showed the following IR and NMR data. 1H NMR (500 MHz):
δ 1.91-2.36 (m, 4), 2.28 (s, 3), 2.74 (s, 1), 4.06 (d, 1, J ) 2.1),
4.37 (d, 1, J ) 11.8), 4.41 (d, 1, J ) 11.8), 4.55 (d, 1, J ) 12.0),
4.63 (d, 1, J ) 11.8), 4.88 (d, 1, J ) 2.1), 4.92 (s, 1), 4.96-5.02
(m, 1), 5.04-5.08 (m, 1), 5.81-5.90 (m, 1), 6.03 (d, 1, J ) 3.0),
6.35 (d, 1, J ) 3.1), 7.16-7.39 (m, 10), 9.27 (s, 1), 9.33 (s, 1).
To the foregoing crude dialdehyde (27.0 mg, 50.3 µmol) in
t-BuOH (2.0 mL) and 2-methyl-2-butene (0.8 mL) was added
dropwise a solution of NaH2PO4 (0.100 g, 0.724 µmol) and
NaClO2 (0.100 g, 0.885 µmol) in H2O (0.50 mL). The biphasic
mixture was stirred at rt for 30 min, poured into 2 N HCl (10
mL), and extracted with H2O (10 mL). The organic extracts
were washed with H2O (10 mL) and brine (10 mL), dried,
filtered, and concentrated. The crude diacid was dissolved in
CH2Cl2 (2.0 mL) and i-PrNHC(C-t-Bu)N-i-Pr (0.100 g, 0.5
mmol), and the solution was stirred at rt overnight. The
reaction mixture was poured into 1 N HCl (10 mL) and
extracted with ether (2 × 10 mL). The organic extracts were
For removal of the silyl protecting group, the foregoing crude
product was dissolved in THF (8.0 mL), and TBAF (8.6 mL of
a 1.0 M solution in THF) was added at 0 °C. The solution
was stirred for 1 h, poured into 1 N HCl (75 mL), and extracted
with ether (2 × 150 mL). The organic extracts were washed
with brine (75 mL), dried, filtered, and concentrated. The
crude product was purified by chromatography on silica gel
(EtOAc/hexanes, 50/50) to provide triol 21 as a colorless oil
which crystallized upon standing (1.23 g, 88% from 10), mp
65-66 °C. TLC: Rf 0.29 (EtOAc/hexanes, 50/50). [R]D: -6.6
(c 0.98, CHCl3). IR: 3388 cm-1 1H NMR (500 MHz): δ 1.88
.
(ddd, 1, J ) 14.1, 10.8, 5.6), 2.06 (ddd, 1, J ) 14.1, 10.7, 5.3),
2.24-2.39 (m, 2), 3.70 (dd, 1, J ) 12.2, 3.5), 3.75 (dd, 1, J )
12.2, 5.6), 3.83 (s, 2), 4.03 (d, 1, J ) 2.6), 4.06 (dd, 1, J ) 5.6,
3.5), 4.10 (d, 1, J ) 2.6), 4.48 (d, 1, J ) 11.6), 4.58 (d, 1, J )
11.5), 4.60 (d, 1, J ) 11.6), 4.71 (d, 1, J ) 11.6), 4.96 (dd, 1, J

Total Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 61, No. 26, 1996 9133
) 10.2, 1.9), 5.02 (ddd, 1, J ) 17.1, 3.3, 1.6), 5.34 (dd, 1, J )
9.6, 3.0), 5.54-5.60 (m, 2), 5.79-5.87 (m, 1), 7.20-7.39 (m,
10). 13C NMR (100 MHz): δ 27.45, 35.71, 60.89, 61.64, 72.28,
72.80, 73.73, 75.13, 85.55, 86.11, 88.42, 104.56, 114.61, 118.98,
127.77, 127.94, 128.08, 128.26, 128.51, 128.61, 132.77, 136.55,
137.22, 138.13. Anal. Calcd for C28H34O7: C, 69.69; H, 7.10.
Found: C, 69.75; H, 7.12.
3.73-3.75 (m, 2), 3.84 (brs, 1), 4.02 (d, 1, J ) 2.0), 4.13 (d, 1,
J ) 2.0), 4.45 (d, 1, J ) 11.8), 4.53 (d, 1, J ) 12.0), 4.55 (d, 1,
J ) 12.0), 4.58 (s, 1), 4.60 (d, 1, J ) 11.8), 5.36 (dd, 1, J )
11.0, 1.7), 5.51 (ddd, 1, J ) 16.9, 1.7), 5.88 (dd, 1, J ) 16.9,
10.9), 7.21-7.35 (m, 10). 13C NMR (100 MHz): δ 26.74, 27.98,
28.08, 34.04, 62.58, 72.74, 72.83, 73.00, 76.02, 82.86, 83.00,
83.92, 91.33, 104.22, 117.21, 127.94, 128.16, 128.25, 128.38,
128.49, 133.37, 136.96, 137.06, 164.07, 166.02. Anal. Calcd
for C35H46O10: C, 67.07; H, 7.40. Found: C, 67.29; H, 7.54.
(1S-(1r,3r,4â,5r,6r,7â))-1-(3-[[(1,1-Dim eth yleth yl)silyl]-
o x y ] p r o p y l ) -4 -h y d r o x y -6 , 7 -b i s ( b e n z y l o x y ) -2 , 8 -
d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r boxylic Acid 3,4,5-
Tr is(1,1-d im eth yleth yl) Ester (29). Into a solution of allylic
alcohol 25 (72.5 mg, 116 µmol) in CH2Cl2 (10.0 mL) and MeOH
(2.0 mL) at -78 °C was passed a stream of ozone (0.8 L/min)
for 30 min. Dimethyl sulfide (2.0 mL) was added, and the
solution was stirred at rt for 1 h. The reaction mixture was
concentrated, and the resulting crude aldehyde 26 was used
without further purification. The crude product was dissolved
in DMF (0.80 mL), and imidazole (45.5 mg, 0.668 mmol) and
TBSCl (46.5 mg, 0.185 mmol) were added. The resulting
solution was stirred at rt for 30 min, poured into H2O (20 mL),
and extracted with ether (2 × 30 mL). The organic extracts
were washed with H2O (20 mL) and brine (20 mL), dried,
filtered, and concentrated to give a silyl ether (27). The crude
product was dissolved in a solution of t-BuOH (15.0 mL) and
â-isoamylene (3.0 mL) to which was added NaClO2 (0.169 g,
1.49 mmol) and NaH2PO4 (0.104 g, 0.754 mmol) in H2O (1.4
mL). The reaction mixture was stirred at rt for 8 h, poured
into pH 3 NaH2PO4/HCl (20 mL), and extracted with CH2Cl2
(2 × 30 mL). The organic extracts were dried, filtered, and
concentrated to yield a carboxylic acid (28). The crude acid
was dissolved in CH2Cl2 (5.0 mL) to which was added i-
PrNHC(O-t-Bu)N-i-Pr (0.340 g, 1.70 mmol). The reaction
mixture was stirred at rt for 18 h, filtered through Celite, and
washed thoroughly with ether. The filtrate was concentrated,
and the crude product was purified by chromatography on
silica gel (EtOAc/hexanes, 20/80) to provide triester 29 as a
colorless oil (38.8 mg, 41%). TLC: Rf 0.30 (EtOAc/hexanes,
(6S)-1,6-An h yd r o-1-(bu t-3-en yl)-2,3-d i-O-ben zyl-4,6-bis-
(ter t-bu toxyca r bon yl)-5-vin yl-L-a ltr ofu r a n ose (24). To a
solution of triol 21 (23.0 mg, 47.7 µmol) in CH2Cl2 (1.5 mL)
was added the Dess-Martin periodinane (0.100 g, 0.236
mmol), and the reaction mixture was stirred at rt overnight.
The mixture was poured into saturated Na2S2O3 (10 mL) and
extracted with ether (2 × 15 mL). The organic extracts were
washed with saturated NaHCO3 (20 mL) and brine (10 mL),
dried, filtered, and concentrated to provide dialdehyde 22 as
a colorless oil that showed the following IR and NMR data.
IR: 3458, 1740, 1596 cm-1 1H NMR (500 MHz): δ 1.97 (ddd,
.
1, J ) 14.2, 10.7, 5.7), 2.14 (ddd, 1, J ) 14.2, 10.5, 5.3), 2.29-
2.44 (m, 2), 3.53 (d, 1, J ) 1.7), 4.05 (d, 1, J ) 2.1), 4.27 (d, 1,
J ) 2.1), 4.44 (d, 1, J ) 11.8), 4.47 (s, 1), 4.48 (d, 1, J ) 12.8),
4.51 (d, 1, J ) 11.8), 4.61 (d, 1, J ) 11.6), 4.99 (ddd, 1, J )
10.2, 2.8, 1.2), 5.06 (ddd, 1, J ) 17.1, 3.3, 1.6), 5.52 (dd, 1, J )
11.1, 1.0), 5.60 (dd, 1, J ) 17.1, 1.0), 5.82-5.90 (m, 1), 5.97
(ddd, 1, J ) 17.1, 11.1, 1.6), 7.18-7.42 (m, 10), 9.40 (s, 1), 9.42
(d, 1, J ) 0.8). 13C NMR (100 MHz): δ 27.31, 35.37, 72.17,
73.10, 73.18, 79.38, 87.78, 91.25, 105.32, 114.96, 121.07,
127.93, 127.99, 128.34, 128.37, 128.62, 130.06, 136.24, 136.58,
137.72, 194.41, 196.44.
To a solution of the foregoing crude dialdehyde in t-BuOH
(1.0 mL) and 2-methyl-2-butene (0.6 mL) was added over 30
min a solution of NaClO2 (0.101 g of a 80% mixture, 18.7 mmol)
and NaH2PO4 (0.100 g, 15.2 mmol) in H2O (1.0 mL). The
reaction mixture was stirred for 30 min, poured into 1 N HCl
(10 mL), and extracted with ether (2 × 10 mL). The organic
extracts were washed with H2O (10 mL) and brine (10 mL),
dried, filtered, and concentrated. The crude product was
dissolved in CH2Cl2 (1.0 mL), and i-PrNHC(O-t-Bu)N-i-Pr
(0.104 g, 0.519 mmol) was added. The solution was stirred at
rt overnight, poured into 1 N HCl (10 mL), and extracted with
ether (2 × 10 mL). The organic extracts were washed with
H2O (10 mL) and brine (10 mL), dried, filtered, and concen-
trated. The crude product was purified by chromatography
on silica gel (EtOAc/hexanes, 25/75) to provide diester 24 as a
colorless oil (20.7 mg, 70% from 21). TLC: Rf 0.48 (EtOAc/
20/80). [R]D: +4.3 (c 0.44, CHCl3). IR: 3449, 1759, 1731 cm-1
.
1H NMR (500 MHz): δ 0.03 (s, 6), 0.88 (s, 9), 1.42 (s, 9), 1.43
(s, 9), 1.52 (s, 9), 1.73-1.90 (m, 2), 1.94-2.09 (m, 2), 3.66 (dt,
2, J ) 2.4, 6.3), 3.92 (brs, 1), 4.00 (d, t, J ) 1.6), 4.49 (d, 1, J
) 11.9), 4.50 (d, 1, J ) 11.9), 4.53 (d, 1, J ) 11.9), 4.60 (d, 1,
J ) 11.9), 4.92 (d, 1, J ) 1.5), 4.95 (s, 1), 7.26-7.34 (m, 10).
13C NMR (100 MHz): δ -5.26, 18.33, 26.01, 26.45, 27.93, 28.07,
28.17, 33.20, 63.14, 72.53, 72.73, 74.32, 75.44, 82.86, 83.12,
84.00, 84.61, 87.63, 91.17, 104.66, 127.61, 127.84, 127.88,
127.96, 128.35, 128.41, 137.46, 137.50, 165.42, 166.18, 169.02.
Anal. Calcd for C44H66O12: C, 64.84; H, 8.16. Found: C, 64.62;
H, 8.10.
hexanes, 30/70). IR: 3507, 1748 cm-1 1H NMR (500 MHz):
.
δ 1.39 (s, 9), 1.42 (s, 9), 1.91 (ddd, 1, J ) 14.1, 11.0, 5.5), 2.08
(ddd, 1, J ) 14.1, 10.8, 5.1), 2.32-2.45 (m, 2), 3.56 (d, 1, J )
1.8), 4.02 (d, 1, J ) 2.0), 4.12 (d, 1, J ) 2.0), 4.44 (d, 1, J )
11.7), 4.54 (d, 1, J ) 11.9), 4.55 (d, 1, J ) 11.7), 4.57 (s, 1),
4.61 (d, 1, J ) 11.9), 4.93-4.96 (m, 1), 5.03 (ddd, 1, J ) 17.2,
3.4, 1.6), 5.35 (dd, 1, J ) 11.0, 1.7), 5.51 (dd, 1, J ) 16.9, 1.7),
5.81-5.87 (m, 1), 5.88 (ddd, 1, J ) 16.9, 11.0, 1.8), 7.22-7.34
(m, 10). 13C NMR (100 MHz): δ 27.34, 28.00, 28.10, 35.81,
72.66, 72.78, 73.02, 75.97, 82.45, 82.88, 83.89, 88.13, 91.30,
104.19, 114.61, 117.02, 127.91, 128.11, 128.37, 128.46, 133.50,
137.01, 138.12, 164.17, 165.71. Anal. Calcd for C36H46O9: C,
69.43; H, 7.45. Found: C, 67.68; H, 7.65. Several attempts
to obtain elemental analysis on this compound provided neatly
identical results, and we were unable to eliminate what
appears to be 1 equiv of water from this viscous oil.
(1S-(1r,3r,4â,5r,6r,7â))-1-(3-Hydr oxypr opyl)-4-h ydr oxy-
6,7-bis(ben zyloxy)-2,8-d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr i-
ca r boxylic Acid 3,4,5-Tr is(1,1-d im eth yleth yl) Ester (30).
To a solution of silyl ether 29 (30.0 mg, 36.8 µmol) in THF
(0.45 mL) was added TBAF (0.300 mL of a 1.0 M solution in
THF). The solution was stirred at rt for 2.5 h, poured into
H2O (10 mL), and extracted with ether (2 × 20 mL). The
organic extracts were washed with brine (10 mL), dried,
filtered, and concentrated. The crude product was purified by
chromatography on silica gel to provide diol 30 as a colorless
oil (15.8 mg, 61%). TLC: Rf 0.16 (EtOAc/hexanes, 50/50). [R]D:
(6S)-1,6-An h yd r o-1-(3-h yd r oxybu t yl)-2,3-d i-O-b en zyl-
4,6-bis(ter t-bu toxyca r bon yl)-5-vin yl-L-a ltr ofu r a n ose (25).
To a solution of diester 24 (97.0 mg, 0.156 mmol) in CH2Cl2
(3.6 mL) and MeOH (0.4 mL) at -78 °C was added a saturated
solution of ozone in CH2Cl2 until TLC analysis showed disap-
pearance of the starting material. NaBH4 (0.100 g) was then
added in small portions, and the reaction mixture was warmed
to rt, stirred 30 min, poured into saturated NH4Cl (25 mL),
and extracted with ether (2 × 50 mL). The organic extracts
were washed with brine (20 mL), dried, filtered, and concen-
trated. The crude product was purified by chromatography
on silica gel (EtOAc/hexanes, 50/50) to afford alcohol 25 as a
colorless oil (59.2 mg, 61%). TLC: Rf 0.28 (EtOAc/hexanes,
+2.6 (c 0.38, CHCl3). IR: 3461, 1731 cm-1
.
1H NMR (500
MHz): δ 1.42 (s, 9), 1.44 (s, 9), 1.53 (s, 9), 1.80-1.86 (m, 2),
1.99-2.05 (m, 1), 2.13-2.17 (m, 1), 3.74-3.77 (m, 2), 4.00 (d,
1, J ) 1.6), 4.50-4.53 (m, 1), 4.50 (d, 1, J ) 11.8), 4.53 (d, 1,
J ) 11.8), 4.60 (d, 1, J ) 12.0), 4.92 (d, 1, J ) 1.6), 4.96 (s, 1),
7.27-7.35 (m, 10). 13C NMR (100 MHz): δ 26.50, 27.91, 28.06,
28.15, 33.09, 61.95, 72.62, 72.75, 74.16, 75.45, 83.43, 83.46,
84.00, 84.91, 88.04, 91.17, 104.55, 127.70, 127.92, 127.98,
128.01, 128.40, 128.47, 137.24, 137.33, 165.22, 166.13, 168.90.
Elemental analysis was not obtained because an insufficient
amount of material was available.
(1S-(1r,3r,4â,5r,6r,7â))-1-(3,3-Dim eth oxyp r op yl)-4,6,7-
tr ih yd r oxy-2,8-d ioxa bicyclo[3.2.1]octa n e-3,4,5-tr ica r box-
ylic Acid 3,4,5-Tr is(1,1-d im eth yleth yl) Ester (2). To so-
1
50/50). [R]D: +12.7 (c 0.44, CHCl3). IR: 3492, 1738 cm-1. H
NMR (500 MHz): δ 1.38 (s, 9), 1.41 (s, 9), 1.82-2.12 (m, 4),

9134 J . Org. Chem., Vol. 61, No. 26, 1996
Caron et al.
lution of diol 30 (9.0 mg, 13 µmol) in CH2Cl2 (2.0 mL) was
added the Dess-Martin periodinane (30.0 mg, 70.7 µmol), and
the reaction mixture was stirred at rt for 30 min after which
it was poured into saturated Na2S2O3 (10 mL) and extracted
with ether (2 × 20 mL). The organic extracts were washed
with saturated NaHCO3 (3 × 10 mL) and brine (10 mL), dried,
filtered, and concentrated to afford a crude aldehyde which
was used without further purification. The crude product was
dissolved in a solution of trimethyl orthoformate (0.50 mL) and
MeOH (0.50 mL), containing a catalytic amount of PPTS (0.5
mg). The solution was stirred at rt for 10 min, and Pd(OH)2
(38.0 mg) was added. The reaction mixture was stirred under
an atmosphere of H2 for 6 h. The black suspension was filtered
through Celite, washed thoroughly with ether, and concen-
trated. The crude product was purified by chromatography
on silica gel (EtOAc/hexanes/Et3N, 70/29/1) to afford triol 2
as a white solid (7.3 mg, 100%), mp 139-140 °C. TLC: Rf
0.18 (EtOAc/hexanes, 75/25). [R]D: +1.8 (c 0.40, CH2Cl2).
(s, 3), 3.338 (s, 3), 3.90 (s, 1), 4.09 (dd, 1, J ) 3.3, 2.1), 4.47 (t,
1, J ) 5.1), 4.95 (s, 1), 5.03 (dd, 1, J ) 4.6, 1.9). 13C NMR
(100 MHz): δ 26.47, 27.99, 28.08, 28.18, 31.05, 53.21, 74.35,
75.11, 78.92, 82.57, 83.09, 84.17, 84.94, 91.15, 104.76, 104.88,
165.92, 166.39, 168.59. Anal. Calcd for C26H44O13: C, 55.31;
H, 7.85. Found: C, 54.92; H, 7.96. This material was identical
in all respects to a sample obtained by degradation of zaragozic
acid A/squalestatin S1 (1).
Ack n ow led gm en t. We thank the National Science
Foundation for a research grant and FCAR and Pfizer
for awarding graduate fellowships to S.C.
Su p p or tin g In for m a tion Ava ila ble: Determination of the
relative configuration of 21 (1 page). This material is con-
tained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
IR: (KBr) 3493, 1739, 1734 cm-1 1H NMR (500 MHz): δ 1.44
.
(s, 9), 1.48 (s, 9), 1.58 (s, 9), 1.88-1.92 (m, 1), 1.94-2.01 (m,
2), 2.05-2.09 (m, 1), 2.42 (d, 1, J ) 4.8), 3.05-3.07 (m, 1), 3.337
J O961534E