A symmetry-based formal synthesis of zaragozic acid A

Article abstract of DOI:10.1021/jo000665j

A symmetry-based strategy for the synthesis of the zaragozic acids is reported. Two enantioselective dihydroxylations were used to establish the absolute configuration of a C₂ symmetric intermediate. Noteworthy transformations include a group-selective lactonization, which accomplished an end-differentiation of a pseudo-C₂ symmetric intermediate. Late stage protecting group adjustments and oxidations accomplished a formal synthesis of zaragozic acid A.

Full text of DOI:10.1021/jo000665j

J . Org. Chem. 2000, 65, 6153-6159
6153
A Sym m etr y-Ba sed F or m a l Syn th esis of Za r a gozic Acid A
Kevin D. Freeman-Cook and Randall L. Halcomb*
Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215
halcomb@colorado.edu
Received May 1, 2000
A symmetry-based strategy for the synthesis of the zaragozic acids is reported. Two enantioselective
dihydroxylations were used to establish the absolute configuration of a C2 symmetric intermediate.
Noteworthy transformations include a group-selective lactonization, which accomplished an end-
differentiation of a pseudo-C2 symmetric intermediate. Late stage protecting group adjustments
and oxidations accomplished a formal synthesis of zaragozic acid A.
In 1992, workers at Merck described the first member
of a new class of natural products.1 This compound was
produced by a fungus found in filtrates of the J alon river
in the Zaragoza province of Spain. Nearly simultaneously
with this discovery, a group at Glaxo reported the
isolation of the same substance from a different fungus
found in a soil sample from Portugal.2 This compound,
named zaragozic acid A (1, Figure 1) by the Merck group
and squalestatin S1 by the Glaxo researchers, was the
first example of what would turn out to be an extensive
F igu r e 1. Zaragozic acid A.
eration and differentiation. It has been estimated that
the ras oncogene is mutated in approximately 20% of all
human cancers and in more than 50% of colon and
pancreatic cancers.5 Therefore, these compounds show
promise as leads for the development of anticancer
substances as well as cholesterol-lowering agents. Zara-
gozic acid has been a template for the development of
novel synthesis methods and strategies in a number of
laboratories,6,7 including ours.8 Described here is a formal
synthesis of zaragozic acid A.
family of natural products. New members of this family
have subsequently been isolated from fungal sources all
over the world.3 Throughout the past decade, compounds
in this class have received a significant amount of
attention from the scientific community, both because of
their unusual, highly functionalized structures and their
important biological activities.
One such activity is their ability to inhibit squalene
synthase, a key enzyme in the cholesterol biosynthesis
pathway4 and a desirable target for therapeutic interven-
tion for the reduction of serum cholesterol levels. In
addition, these compounds inhibit ras farnesyl protein
transferase.1c Ras is a protein that regulates cell prolif-
(5) Gibbs, J . B. Cell 1991, 65, 1.
(6) Syntheses of zaragozic acid: (a) Nicolaou, K. C.; Yue, E. W.;
Lagreca, S.; Nadin, A.; Yang, Z.; Leresche, J . E.; Tsuri, T.; Naniwa,
Y.; Dericcardis, F. Chem.-Eur. J . 1995, 1, 467. (b) Carreira, E. M.;
Dubois, J . J . Am. Chem. Soc. 1995, 117, 8106. (c) Evans, D. A.; Barrow,
J . C.; Leighton, J . L.; Robichaud, A. J .; Sefkow, M. J . Am. Chem. Soc.
1994, 116, 12111. (d) Caron, S.; Stoermer, D.; Mapp, A. K.; Heathcock,
C. H. J . Org. Chem. 1996, 61, 9126. (e) Stoermer, D.; Caron, S.;
Heathcock, C. H. J . Org. Chem. 1996, 61, 9115. (f) Sato, H.; Nakamura,
S.; Watanabe, N.; Hashimoto, S. Synlett 1997, 451. (g) Armstrong, A.;
J ones, L. H.; Barsanti, P. A. Tetrahedron Lett. 1998, 39, 3337.
(7) Selected other approaches to zaragozic acid: (a) Martin, S. F.;
Naito, S. J . Org. Chem. 1998, 63, 7592. (b) Koshimizu, H.; Baba, T.;
Yoshimitsu, T.; Nagaoka, H. Tetrahedron Lett. 1999, 40, 2777. (c)
Maezaki, N.; Gijsen, H. J . M.; Sun, L. Q.; Paquette, L. A. J . Org. Chem.
1996, 61, 6685. (d) Xu, Y. P.; J ohnson, C. R. Tetrahedron Lett. 1997,
38, 1117. (e) Paterson, I.; Fessner, K.; Finlay, M. R. V. Tetrahedron
Lett. 1997, 38, 4301. (f) Kataoka, O.; Kitagaki, S.; Watanabe, N.;
Kobayashi, J .; Nakamura, S.; Shiro, M.; Hashimoto, S. Tetrahedron
Lett. 1998, 39, 2371. (g) Hodgson, D. M.; Bailey, J . M.; Harrison, T.
Tetrahedron Lett. 1996, 37, 4623. (h) Brogan, J . B.; Zercher, C. K.
Tetrahedron Lett. 1998, 39, 1691. (i) Calter, M. A.; Sugathapala, P.
M. Tetrahedron Lett. 1998, 39, 8813. (j) Walker, L. F.; Connolly, S.;
Wills, M. Tetrahedron Lett. 1998, 39, 5273. (k) Kraus, G. A.; Maeda,
H. J . Org. Chem. 1995, 60, 2. (l) Mann, R. K.; Parsons, J . G.; Rizzacasa,
M. A. J . Chem. Soc., Perkin Trans. 1 1998, 1283. (m) Hegde, S. G.;
Myles, D. C. Tetrahedron 1997, 53, 11179. (n) Tsubuki, M.; Okita, H.;
Honda, T. Synlett 1998, 1417. (o) Ito, H.; Matsumoto, M.; Yoshizawa,
T.; Takao, K.; Kobayashi, S. Tetrahedron Lett. 1997, 38, 9009. (p)
Fraisse, P.; Hanna, I.; Lallemand, J . Y. Tetrahedron Lett. 1998, 39,
7853. (q) Tomooka, K.; Kikuchi, M.; Igawa, K.; Keong, P. H.; Nakai,
T. Tetrahedron Lett. 1999, 40, 1917. (r) Reid, A. M.; Steel, P. G. J .
Chem. Soc., Perkin Trans. 1 1998, 2795.
(1) (a) Wilson, K. E.; Burk, R. M.; Biftu, T.; Ball, R. G.; Hoogsteen,
K. J . Org. Chem. 1992, 57, 7151. (b) Dufresne, C.; Wilson, K. E.; Zink,
D. L.; Smith, J .; Bergstrom, J . D.; Kurtz, M.; Rew, D.; Nallin, M.;
J enkins, R.; Bartizal, K.; Trainor, C.; Bills, G.; Meinz, M.; Huang, L.
Y.; Onishi, J .; Milligan, J .; Mojena, M.; Pelaez, F. Tetrahedron 1992,
48, 10221. (c) Dufresne, C.; Wilson, K. E.; Singh, S. B.; Zink, D. L.;
Bergstrom, J . D.; Rew, D.; Polishook, J . D.; Meinz, M.; Huang, L. Y.;
Silverman, K. C.; Lingham, R. B.; Mojena, M.; Cascales, C.; Pelaez,
F.; Gibbs, J . B. J . Nat. Prod. 1993, 56, 1923. (d) Hensens, O. D.;
Dufresne, C.; Liesch, J . M.; Zink, D. L.; Reamer, R. A.; VanMiddles-
worth, F. Tetrahedron Lett. 1993, 34, 399. (e) Bergstrom, J . D.; Kurtz,
M. M.; Rew, D. J .; Amend, A. M.; Karkas, J . D.; Bostedor, R. G.; Bansal,
V. S.; Dufresne, C.; VanMiddlesworth, F. L.; Hensens, O. D.; Liesch,
J . M.; Zink, D. L.; Wilson, K. E.; Onishi, J .; Milligan, J . A.; Bills, G.;
Kaplan, L.; Omstead, M. N.; J enkins, R. G.; Huang, L.; Meinz, M. S.;
Quinn, L.; Burg, R. W.; Kong, Y. L.; Mochales, S.; Mojena, M.; Martin,
I.; Pelaez, F.; Diez, M. T.; Alberts, A. W. Proc. Natl. Acad. Sci. U.S.A.
1993, 90, 80.
(2) (a) Dawson, M. J .; Farthing, J . E.; Marshall, P. S.; Middleton,
R. F.; O’Neill, M. J .; Shuttleworth, A.; Stylli, C.; Tait, M.; Taylor, P.
M.; Wildman, H. G.; Buss, A. D.; Langley, D.; Hayes, M. J . Antibiot.
1992, 45, 639. (b) Sidebottom, P. J .; Highcock, R. M.; Lane, S. J .;
Procopiou, P. A.; Watson, N. S. J . Antibiot. 1992, 45, 648. (c) Baxter,
A.; Fitzgerald, B. J .; Hutson, J . L.; McCarthy, A. D.; Motteram, J . M.;
Ross, B. C.; Sapra, M.; Snowden, M. A.; Watson, N. S.; Williams, R.
J .; Wright, C. J . Biol. Chem. 1992, 267, 11705.
(3) Nadin, A.; Nicolaou, K. C. Angew. Chem., Int. Ed. Engl. 1996,
35, 1623.
(4) Lindsey, S.; Harwood: H. J . J . Biol. Chem. 1995, 270, 9083.
10.1021/jo000665j CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/18/2000

6154 J . Org. Chem., Vol. 65, No. 19, 2000
Freeman-Cook and Halcomb
Sch em e 2
Sch em e 1
The route developed in this lab was intended to exploit
both the reactivity and the synthetic potential of oxygen-
substituted radicals. It relies on the cyclization of a
radical derived from homolytic cleavage of C1-X of 5
(Scheme 1) onto a radical acceptor to construct the unique
2,8-dioxabicyclo[3.2.1]octane ring system 6. Such a strat-
egy would allow the exploitation of symmetry within the
system. Beyond this, it was anticipated that this route
for constructing the zaragozic acids would be novel and
could perhaps be broadly applicable to the construction
of a variety of bicyclic ketals.
The synthesis plan (Scheme 1) would primarily be
guided by a desire to utilize hidden symmetry within the
core structure. One benefit of the C1-C7 bond connection
(5 f 6) is that it allows an intermolecular acetal
construction. Therefore, acetal 5 (X ) H) could, in
principle, be prepared from triol 4. Examination of 4
reveals the symmetry element of interest. The central
carbons (C4 and C5) each bear a carboxylic acid and a
tertiary alcohol. Each of these carbons is flanked by a
carbon bearing a secondary alcohol, then by a group
which could be derived from a primary alcohol (CH2OP
and CO2P).
Compound 4 could potentially be derived from an
intermediate such as 3. The plan for the synthesis of
intermediates corresponding to 4 was to utilize a series
of reactions that would accomplish, among other things,
differentiation of the two primary as well as the two
secondary alcohols of 3. Since compound 3 is not truly
symmetric because the stereocenters bearing the tertiary
alcohols have different configurations, it was hypoth-
esized that a transformation such as a diastereotopic
group-selective lactonization could be employed to dif-
ferentiate the various hydroxyls. This would accomplish
the selective protection of one (or possibly two) of the
alcohols, while minimizing the use of extraneous protect-
ing groups.
hydroxyls in more advanced intermediates. Since 2 is C2
symmetric, it was anticipated that a relatively short and
efficient sequence could be used to prepare it. Further-
more, the symmetry of 2 assured that the installation of
the tertiary alcohols could be accomplished without
necessitating a face-selective reaction.
Commercially available furan diester 7 (Scheme 2) was
chosen as a starting material. The furan ring serves as
both a symmetric scaffold and as a protecting group for
the carboxylic acids and the tetrasubstituted olefin of 2.
Reduction of 7 gave diol 8, and subsequent reoxidation
by an adaptation of a published procedure9 provided
furan dialdehyde 9 in 76% yield for two steps. A Peterson
olefination produced compound 10,10 which was treated
directly with AD-mix R to afford 11 (60% yield for two
steps). The enantioselective dihydroxylation installed
four hydroxyl groups and established each of the second-
ary alcohol stereocenters in the appropriate (S) configura-
tion.11-13 Since each dihydroxylation was enantioselective
(approximately 80% enantiomeric excess, assuming the
outcome of the first reaction does not influence the
second) and two sequential dihydroxylations were per-
formed in the same synthesis operation, the tetraol 11
(9) Cook, M. J .; Forbes, E. J . Tetrahedron 1968, 24, 4501.
(10) (a) Peterson, D. J . J . Org. Chem. 1968, 33, 780. (b) Ager, D. J .
Synthesis 1984, 384. (b) For a similar application to a vinyl furan,
see: Harris, J . M.; Keranen, M. D.; O’Doherty, G. A. J . Org. Chem.
1999, 64, 2982 and references therein.
(11) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
(12) Sharpless, K. B.; Amberg, W.; Bennani, Y.; Crispino, G.;
Hartung, J .; J eong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.;
Xu, D.; Zhang, X. L. J . Org. Chem. 1992, 57, 2768. This ee was
measured as follows. Treatment of the tetraol 13 with 2 equiv of
TBDPS-Cl to protect the primary alcohols was followed by formation
of the bis-Mosher ester of the resulting bis-secondary alcohol. The bis-
Mosher ester itself was prepared using both (R)-(+)-MPTA, and (S)-
(-)-MPTA. 500 MHz 1H NMR spectroscopy was used to measure the
diastereomeric ratio of the bis-Mosher esters (see ref 13). The >100:1
The synthesis of the pseudosymmetric intermediate 3
was envisioned to proceed via the tetrasubstituted olefin
2. The installation of the tertiary hydroxyls (2 f 3) would
break the C2 symmetry and provide the basis for the
subsequent discrimination of the primary and secondary
ratio of diastereomers (corresponding to >98% ee) probably is
a
minimum value and beyond the limit of accuracy that can be expected
by this method. Additional support for this determination was provided
by measuring the ratio of diastereomers produced in the dihydroxy-
lation. An ee of 97.6% was calculated by this method. For a math-
ematical description of related ee enhancements, see ref 14.
(8) (a) Freeman-Cook, K. D.; Halcomb, R. L. Tetrahedron Lett. 1996,
37, 4883. (b) Freeman-Cook, K. D.; Halcomb, R. L. Tetrahedron Lett.
1998, 39, 8567.
(13) (a) Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165.
(b) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1972, 95, 512.

Symmetry-Based Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 65, No. 19, 2000 6155
Sch em e 3
Sch em e 4
was produced in high enantiomeric excess (>98%).14 The
tetraol 11 was then protected in a straightforward
manner as the bisacetonide 12 in 69% yield.
The furan ring of 12 was oxidized using singlet oxygen
at -20 °C (Scheme 3).15 This oxidation not only provided
one of the three carboxylic acids of zaragozic acid but also
unveiled another carboxylic acid precursor as an alde-
hyde engaged in a hemiacetal and produced the desired
(Z) tetrasubstituted olefin 13 in 74% yield (5:1 mixture
of epimers at the hemiacetal). Dihydroxylation of 13 with
OsO4 installed the two tertiary alcohol stereocenters and
provided the key intermediate 14 in 66% yield. Other
catalytic dihydroxylation conditions were examined but
were not successful. A variety of solvents, additives, and
reagent combinations too numerous to list were evalu-
ated, as were other oxidation reagents such as RuCl3. The
intermediate osmate ester appears to be resistant to
hydrolysis, so turnover is inhibited. The structure of triol
14 was confirmed by X-ray crystallography (see Support-
ing Information). Compound 14 appeared to be a 5:1
mixture of inseparable hemiacetal isomers in solution,
as measured by NMR, but a single isomer appeared to
crystallize from solution. Although the precursor 13 also
existed as a mixture of diastereomers at the hemiacetal
carbon (2:1), the dihydroxylation appeared to be quite
face-selective. Spectroscopic evidence suggests that the
product that resulted from dihydroxylation of the op-
posite face may have been produced in small quantity
(<5%). Purification of this and other minor byproducts
was difficult, however, and since these byproducts would
not be useful in the synthesis sequence, their structures
were not rigorously established. One possible interpreta-
tion of these observations is that the chirality on the side
chains, namely, the acetonide-protected secondary alco-
hols, are primarily responsible for controlling the face
selectivity of the dihydroxylation.
chosen because it could be installed under mildly basic
conditions and was expected to be resistant to acetal
formation. Treatment of 14 with hydroxylamine hydro-
chloride and pyridine smoothly produced the oxime 15
in 95% yield and liberated the carboxylic acid functional
group (Scheme 4). The carboxylic acid was then used for
the discrimination of the two secondary alcohols in a
group-selective lactonization. Removal of the acetonides
from compound 15 with PPTS in methanol produced a
polar intermediate, presumably a hexaol, which was not
isolated but was allowed to lactonize upon prolonged
exposure to the reaction conditions to provide compound
16 as the sole product. This accomplished the necessary
end differentiation in a short, efficient sequence of
reactions. The high regioselectivity and high yield of this
lactonization was not entirely expected, but a similar
lactonization exists as a precedent.6a
Reprotection of the vicinal diol as an acetonide yielded
compound 17 (68% for two steps). Subsequent protection
of the remaining primary hydroxyl as a TBS ether
afforded 18 (56% yield). All four nontertiary alcohols in
compound 18 are differentiated from each other. X-ray
crystallographic analysis of 18 confirmed the structural
assignments (see Supporting Information).
After the end differentiation was solved, attention was
focused on the completion of a formal synthesis of
zaragozic acid A. It was observed that compound 17 was
structurally similar to an intermediate in the Nicolaou
synthesis of zaragozic acid A.6a A formal synthesis was
indeed accomplished in a straightforward manner from
17 by matching the Nicolaou intermediate. This involved
simply installing the same array of protecting groups that
was employed in the Nicolaou route, removing the oxime,
and oxidizing the resulting aldehyde to the carboxylic
acid oxidation state.
Early attempts to remove the acetonide protecting
groups of 14 resulted in the formation of a product
containing a cyclic acetal. Because this compound was
too inert for chemical manipulation, a protection of the
aldehyde group of 14 was undertaken to prevent the
formation of such offending acetals. After investigation
of a variety of aldehyde protecting groups, an oxime was
Protection of 17 as a bis(tert-butyldiphenylsilyl) ether
using TBDPS-Cl and imidazole provided 19 in 57% yield
(Scheme 5). The acetonide within 19 was cleanly removed
using PPTS in methanol to generate 20 in 81% yield.
(14) Schreiber, S. L.; Schreiber, T. S.; Smith, D. B. J . Am. Chem.
Soc. 1987, 109, 1525.
(15) Ickikawa, Y.; Tsuboi, K.; Naganawa, A.; Isobe, M. Synlett 1993,
12, 907.

6156 J . Org. Chem., Vol. 65, No. 19, 2000
Freeman-Cook and Halcomb
Sch em e 7
Sch em e 5
Sch em e 6
with DCBI to afford 27 (70% yield, for two steps).17 The
spectral and chromatographic properties of 27 (1H and
13C NMR, IR, HRMS, TLC) were identical to the pub-
lished data for this compound in all respects.6a Since this
intermediate has been converted into zaragozic acid A,6a
this synthesis of 27 constitutes a formal synthesis of
zaragozic acid A.
Described here is a symmetry-based approach to the
synthesis of advanced zaragozic acid intermediates and
the subsequent end-differentiation of these compounds.
This plan has culminated in a formal synthesis of
zaragozic acid A. In addition to providing a novel entry
into the zaragozic acids, it provides the basis for a
continued exploration of a radical-based approach to the
zaragozic acid core. These pursuits are the subject of a
continuing effort in this laboratory.
Selective protection of the primary alcohol as a SEM
ether was not straightforward, and significant optimiza-
tion was needed to produce substantial quantities of 21.
After a variety of conditions and methods were examined,
it was found that this protection proceeded best when
compound 20 was stirred with SEM-Cl in the presence
of the base 2,6-di-tert-butylpyridine for 48 h at room
temperature. Compound 21 was obtained from this
transformation in 56% yield. This product was ac-
companied by a small amount of the secondary SEM
ether (11%) and the bis-SEM ether (24%). These were
easily separated by flash column chromatography. The
use of this particular base was crucial to obtaining
optimal yields and regioselectivities. Other bases such
as pyridine or tertiary amines resulted in lower regiose-
lectivities and greater quantities of the bis-SEM ether.
Exp er im en ta l Section
3,4-Divin ylfu r a n (10). Dialdehyde 9 (2.95 g, 0.023 mol) was
dissolved in Et2O (65 mL) and stirred under N2 at 0 °C for 15
min. A solution of (trimethylsilyl)methylmagnesium chloride
(50 mL, 1 M in Et2O, 0.05 mol) was added dropwise, and the
reaction mixture allowed to warm to room temperature. After
1.5 h, AcOH (50 mL) and H2O (33 mL) were added, and the
Et2O was removed by distillation. The mixture was extracted
with pentane and washed with saturated NaHCO3 and H2O.
The organic layer was dried with MgSO4, filtered, and con-
centrated under vacuum (bath temperature ) 0 °C). This gave
4.4 g of a solution of 10 in Et2O (1H NMR estimate, 0.018 mol,
80%). This solution was used directly without further purifica-
tion in the next reaction: 1H NMR (400 MHz, CDCl3) δ 7.45
(s, 1H), 6.57 (dd, J ) 10.98, 17.67 Hz, 1H), 5.50 (dd, J ) 1.61,
17.67 Hz, 1H), 5.22 (dd, J ) 1.61, 10.98 Hz, 1H).
Protection of the secondary and tertiary hydroxyls of
21 as an acetonide was accomplished with 2-methox-
ypropene and PPTS (Scheme 6). This produced not only
the desired acetonide 22 but also the regioisomer 23, in
a 1.4:1 ratio (88% yield overall). Attempts to convert the
minor compound (23) to the major (22) were unsuccessful.
The conversion of 22 to the desired zaragozic acid
intermediate was accomplished in a straightforward way
(Scheme 7). Removal of the TBDPS protecting groups
with n-Bu4NF and acetic acid provided 24 in 80% yield.
The oxime was removed by ozonolysis to produce alde-
hyde 25 (69% yield, quantitative based on recovered 24).
NaClO2 oxidation produced the carboxylic acid 26.16
Without purification, the carboxylic acid was esterified
(1′S, 1′′S)-3,4-Bis(1,2-d ih yd r oxyeth yl)fu r a n (11). AD-mix
R (5.6 g), tert-butyl alcohol (35 mL), and H2O (35 mL) were
mixed at room temperature, and the mixture was stirred for
(16) Balkrishna, S. B.; Childers, W. E.; Pinnick, H. W. Tetrahedron
Lett. 1981, 37, 2091.
(17) Mathias, L. J . Synthesis 1979, 8, 561.

Symmetry-Based Synthesis of Zaragozic Acid A
J . Org. Chem., Vol. 65, No. 19, 2000 6157
10 min at 0 °C. A solution of compound 10 (508 mg, 4.0 mmol)
in THF (2 mL) was added. K3Fe(CN)6 (4 g, 12.09 mmol) and
K2CO3 (1.67 g, 12.09 mmol) were added, and stirring was
continued at 0 °C. The reaction mixture was allowed to warm
to room temperature and stirred for 3 h. The reaction was
quenched by the addition of Na2SO3 (s) (17.9 g, 0.14 mol) and
stirred for an additional 14 h. The aqueous layer was saturated
with NaCl (s), and the mixture was extracted with EtOAc. The
organic layers were combined, dried over MgSO4, filtered, and
concentrated to give 444.9 mg (59%) of compound 11 as a white
powder. This was pure enough for direct use in the following
reaction. A small sample was further purified for characteriza-
tion by flash chromatography (SiO2, 1:6:1 hexanes/EtOAc/
MeOH, Rf ) 0.3): [R]20D +33.6° (c 1.1, CH3OH); IR (KBr) 3400
sticky, brown solid, which was purified by flash chromatog-
raphy (SiO2, 1:2 hexanes/EtOAc). This provided 14 (370 mg,
66%) as an inseparable 2:1 mixture of diastereomers at the
hemiacetal carbon: Rf ) 0.68 (SiO2, 1:2 hexanes/EtOAc); [R]20
D
-49.3° (c 0.67, CHCl3); IR (film) 3430 (br), 1782 cm-1; 1H NMR
(500 MHz, CDCl3) δ 5.63 (m, 1.5H), 5.35 (m, 0.6H), 4.62 (t, J
) 6.75 Hz, 1H), 4.57 (t, J ) 6.80 Hz, 1H), 4.52 (m, 2H), 4.39
(dd, J ) 4.57, 9.43 Hz, 1H), 4.37 (s, 0.5H), 4.34 (s, 0.5H), 4.27
(dd, J ) 6.05, 8.73 Hz, 0.6H), 4.21 (dd, J ) 6.55, 8.34 Hz, 0.6H),
4.17 (dd, J ) 6.75, 9.43 Hz, 1H), 4.08 (m, 3H), 3.60 (s, 1H),
3.27 (s, 0.6H), 3.22 (s, 1H), 3.15 (s, 0.6H), 1.48 (s, 1.7H), 1.47
(s, 1.7H), 1.46 (s, 3H), 1.44 (s, 1.7H), 1.44 (s, 1.7H), 1.43 (s,
3H), 1.42 (s, 3H), 1.36 (s, 3H); 13C NMR (100 MHz, CDCl3)
Ma jor δ 173.3, 111.0, 109.7, 97.4, 80.7, 77.2, 76.2, 74.3, 65.0,
64.1, 26.0, 25.7, 25.4, 24.6; Min or δ 112.1, 110.1, 101.4, 81.4,
77.8, 75.3, 74.0, 65.4, 64.3, 26.0, 25.8, 25.1, 24.9; MS m/z EI+
319 (M - CH3)+, CI+ 319 (M - CH3)+; HRMS (EI+) calcd for
C13H19O9 (M - CH3)+ 319.1029, found 319.1045.
1
(br), 1625 cm-1; H NMR (400 MHz, CD3OD) δ 7.44 (s, 1H),
4.71 (dd, J ) 4.66, 7.15 Hz, 1H), 3.75 (dd, J ) 4.66, 11.22 Hz,
1H), 3.68 (dd, J ) 7.25, 11.22 Hz, 1H); 13C NMR (100 MHz,
CD3OD) δ 141.7, 126.2, 68.2, 67.2; MS m/z EI+ 188 (M+), CI-
187 (M - H)-; HRMS (EI+) calcd for C8H12O5 (M+) 188.0685,
found 188.0724.
(1′S, 1′′S)-3,4-Bis(2,2-d im eth yl-(1,3)d ioxola n -4-yl)fu r a n
(12). Tetraol 11 (843.8 mg, 4.5 mmol) was dissolved in
anhydrous DMF (30 mL) and 2,2-dimethoxypropane (10 mL).
TsOH (85.4 mg, 0.45 mmol) was added, and the mixture was
stirred at room temperature for 21 h. The reaction was diluted
with EtOAc and washed with saturated NaHCO3, H2O, and
saturated NaCl. The organic layer was dried over MgSO4,
filtered, and concentrated to give a yellow syrup. Flash
chromatography (SiO2, 8:2 hexanes/EtOAc) gave 12 (827 mg,
(2R,3S,1′R,1′′R)-2,3-Bis(2,2-d im et h yl-[1,3]d ioxola n -4-
yl)-2,3-d ih yd r oxy-4-(ca r ba ld eh yd e oxim e)bu tyr ic Acid
(15). Hydroxylamine hydrochloride (75.5 mg, 1.08 mmol) was
added to a flask containing triol 14 (181.5 mg, 0.54 mmol).
The mixture was dissolved in THF (5 mL) and methanol (5
mL). Pyridine (220 µL, 2.7 mmol) was added, and the mixture
was then heated to 70 °C for 5.5 h. The solution was
concentrated under vacuum and azeotroped with toluene to
remove traces of pyridine. Flash chromatography (SiO2, 7:3
EtOAc/MeOH) provided 15 (178.5 mg, 94%): Rf ) 0.5 (SiO2,
7:3 EtOAc/MeOH); [R]20D -1.8° (c 1.1, CH3OH); IR (film) 3394
69%) as a yellow oil: Rf ) 0.3 (SiO2, 8:2 hexanes/EtOAc); [R]20
(br), 1728 cm-1 1H NMR (500 MHz, CD3OD) δ 7.24 (s, 1H,
;
D
+30.5° (c 1.2, CHCl3); IR (film) 2986, 1455 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.41 (s, 1H), 5.08 (dd, J ) 6.15, 7.64 Hz, 1H),
4.31 (dd, J ) 6.15, 8.04 Hz, 1H), 3.78 (t, J ) 7.8 Hz, 1H), 1.47
(s, 3H), 1.45 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 140.4, 123.1,
109.3, 70.4, 69.9, 26.5, 25.7; MS m/z EI+ 268 (M+), CI+ 269 (M
+ H)+, CI- 267 (M - H)-; HRMS (EI+) calcd for C14H20O5 (M+)
268.1311, found 268.1327.
CHdN), 4.70 (t, J ) 7.23 Hz, 1H), 4.56 (t, J ) 6.96, 1H), 3.88
(m, 2H), 3.82 (m, 2H), 1.35 (s, 3H, CH3), 1.32 (s, 3H), 1.30 (s,
3H), 1.27 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 150.0, 110.7,
109.1, 79.0, 77.9, 77.8, 66.3, 66.0, 26.3, 26.1, 25.8; MS m/z ESI+
350 (M + H)+, FAB+ 372 (M + Na)+, FAB- 348 (M - H)-;
HRMS (FAB-) calcd for C14H22NO9 (M - H)- 348.1295, found
348.1271.
(1′S,1′′S)-3,4-Bis(2,2-d im eth yl-[1,3]d ioxola n -4-yl)-5-h y-
d r oxy-5H-fu r a n -2-on e (13). Acetonide 12 (1.25 g, 4.7 mmol)
was dissolved in CH2Cl2 (120 mL). EtN(i-Pr)2 (1.62 mL, 9.3
mmol) and rose bengal (50 mg, 0.047 mmol) were added, and
the mixture was cooled to -20 °C. O2 (g) was bubbled through
the solution, and the mixture was irradiated with a 500 W
quartz-halogen lamp for 11 h, after which TLC indicated that
the reaction was complete. The mixture was concentrated
under vacuum. Flash chromatography (SiO2, 1:1 hexanes/
EtOAc) gave 13 (1.04 g, 74%) as a yellow oil. The product was
an inseparable mixture of diastereomers (5:1 at the hemiacetal
(2R,3S,4R,1′R)-4-(1,2-Dih yd r oxyeth yl)-3,4-d ih yd r oxy-2-
h yd r oxym et h yl-5-oxot et r a h yd r ofu r a n -3-ca r b a ld eh yd e
Oxim e (16). PPTS (129 mg, 0.51 mmol) and methanol (15 mL)
were added to a flask containing acid 15 (178.5 mg, 0.51 mmol).
This solution was stirred under N2 at 65 °C for 15 h. The
solution was concentrated, and the product was used without
purification in the subsequent reaction. A small sample of 16
was purified by flash chromatography (SiO2, 1:6:1 hexanes/
EtOAc/MeOH, Rf ) 0.3) for characterization: [R]20 +100.1°
D
1
(c 0.7, CH3OH); IR (film) 3280 (br), 1770 cm-1; H NMR (500
MHz, CD3OD) δ 7.58 (s, 1H), 4.83 (dd, J ) 2.68, 7.64 Hz, 1H),
4.08 (dd, J ) 3.87, 6.75 Hz, 1H), 3.90 (dd, J ) 2.68, 12.70 Hz,
1H), 3.82 (dd, J ) 7.64, 12.70 Hz, 1H), 3.81 (dd, J ) 3.87, 11.41
Hz, 1H), 3.74 (dd, J ) 6.75, 11.41, 1H); 13C NMR (100 MHz,
CD3OD) δ 176.5, 148.1, 85.0, 80.9, 80.3, 73.4, 62.6, 61.0; MS
m/z ESI+ 252 (M + H)+, FAB+ 252 (M + H)+, HRMS (FAB-)
calcd for C8H12NO8 (M - H)- 250.0563, found 250.0603.
(2R,3S,4R,1′R)-4-(2,2-Dim eth yl-[1,3]d ioxola n -4-yl)-3,4-
d ih yd r oxy-2-h yd r oxym et h yl-5-oxot et r a h yd r ofu r a n -3-
ca r ba ld eh yd e Oxim e (17). A mixture of 16 (ca. 128 mg, 0.51
mmol) and PPTS (129 mg, 0.51 mmol) was dissolved in 2,2-
dimethoxypropane (75.5 mL, 0.61 mmol) and DMF (6 mL). The
mixture was stirred under N2 for 5.5 h at room temperature,
concentrated under vacuum, and azeotroped with toluene to
remove traces of DMF. The product was purified by flash
chromatography (SiO2, 1:2 hexanes/EtOAc, Rf ) 0.3). This
provided 17 (101.8 mg, 68% for two steps) as well as recovered
carbon): Rf ) 0.6 (SiO2, 1:1 hexanes/EtOAc); [R]20 +63.2° (c
D
0.95, CHCl3); IR (film) 3372 (br), 1766 cm-1
;
1H NMR (500
MHz, CDCl3) Ma jor δ 6.3 (dd, J ) 1.69, 5.95 Hz, 1H), 5.53 (t,
J ) 7.64 Hz, 1H), 4.91 (m, 1H), 4.46 (dd, J ) 6.6, 8.48 Hz,
1H), 4.23 (t, J ) 7.54 Hz, 1H), 4.02 (t, J ) 7.84, 1H), 3.73 (t,
J ) 8.44, 1H), 3.54 (d, J ) 5.86, 1H), 1.56 (s, 3H), 1.51 (s, 3H),
1.46 (s, 3H), 1.44 (s, 3H); Min or δ 6.13 (d, J ) 3.67, 1H), 5.53
(m, 1H), 4.96 (m, 1H), 4.38 (dd, J ) 7.07, 8.52 Hz, 1H), 3.95
(d, J ) 3.77 Hz, 1H), 3.83 (dd, J ) 7.05, 8.63 Hz, 1H), 3.72 (t,
J ) 8.49, 1H), 1.54 (s, 3H),1.47 (s, 3H), 1.45 (s, 3H), 1.43 (s,
3H); 13C NMR (125 MHz, CDCl3) Ma jor δ 169.6, 157.1, 129.0,
110.7, 110.1, 97.0, 71.1, 71.0, 68.7, 68.3, 26.1, 25.9, 25.4, 25.4;
MS m/z EI+ 285 (M - CH3)+; HRMS (EI+) calcd for C13H17O7
(M - CH3)+ 285.0974, found 285.0948.
(3R,4S,1′R,1′′R)-3,4-Bis(2,2-d im et h yl-[1,3]d ioxola n -4-
yl)-3,4,5-tr ih yd r oxy-4,5-d ih yd r ofu r a n -2-on e (14). Olefin 13
(506.9 mg, 1.69 mmol) was dissolved in pyridine (21 mL), and
the mixture was cooled to 0 °C. A solution of OsO4 in tert-
butyl alcohol (11 mL, 0.16 M, 1.69 mmol) was added, and the
mixture was allowed to warm to room temperature and was
stirred for 24 h. The solution was cooled to 0 °C, and NaHSO3
(4.6 g, 44 mmol), pyridine (60 mL), and H2O (69 mL) were
added. This mixture was stirred for an additional 30 min at 0
°C, and for 1 h at room temperature. The solution was
extracted with CHCl3. The organic extracts were combined,
dried over MgSO4, filtered, concentrated, and azeotroped with
toluene to remove traces of pyridine. This gave 622 mg of a
16 (24 mg, 19%): [R]20 +73.4° (c 1.6, CH3OH); IR (film) 3382
D
1
(br), 1770 cm-1; H NMR (500 MHz, CD3OD) δ 7.50 (s, 1H),
4.83 (dd, J ) 3.48, 6.96 Hz, 1H), 4.41 (dd, J ) 6.42, 8.30 Hz,
1H), 4.01 (dd, J ) 6.43, 8.03 Hz, 1H), 3.90 (t, J ) 8.30 Hz,
1H), 3.82 (m, 2H), 1.40 (s, 3H), 1.36 (s, 3H); 13C NMR (100
MHz, CD3OD) δ 175.6, 147.5, 110.8, 84.8, 81.1, 79.4, 76.5, 65.7,
60.9, 26.2, 25.9; MS m/z EI+ 276 (M - CH3)+, CI+ 292 (M +
H)+, CI+ 276 (M - CH3)+; HRMS (EI+) calcd for C10H14NO8
(M - CH3)+ 276.0719, found 276.0707.
(2R,3S,4R,1′R)-2-(ter t-Bu tyld im eth ylsilyloxym eth yl)-4-
(2,2-d im eth yl-[1,3]d ioxola n -4-yl)-3,4-d ih yd r oxy-5-oxotet-

6158 J . Org. Chem., Vol. 65, No. 19, 2000
Freeman-Cook and Halcomb
r a h yd r ofu r a n -3-ca r ba ld eh yd e Oxim e (18). Imidazole (64
mg, 0.94 mmol), tert-buyldimethylsilyl chloride (73 mg, 0.48
mmol), and DMF (2 mL) were added to a flask containing
acetonide 17 (136.2 mg, 0.47 mmol). The reaction mixture was
stirred for 12 h under N2 at room temperature, concentrated
under vacuum, and azeotroped with toluene to remove traces
of DMF. The product was then purified by flash chromatog-
raphy (SiO2, 6:4 hexanes/EtOAc). This provided a small
amount of bis-silylated material (22 mg, 9%, Rf ) 0.8), desired
product 18 (105 mg, 56%, Rf ) 0.4), and unreacted starting
material 17 (26 mg, 19%): [R]20D +78.8° (c 1.0, CHCl3); IR (film)
starting to become more prominent, so the reaction was
concentrated under vacuum. Flash chromatography on silica
gel (gradient, 9:1 f 8:2 hexanes/EtOAc) gave bis-SEM ether
(11.5 mg, 24%, Rf ) 0.66, SiO2, 6:4 hexanes/EtOAc), as well
as 21 (23 mg, 56%, Rf ) 0.5, SiO2, 6:4 hexanes/EtOAc) and a
small amount of the SEM ether of the secondary alcohol (4.3
mg, 11%, Rf ) 0.45, SiO2, 6:4 hexanes/EtOAc): [R]20 +43.19°
D
(c ) 0.47, CH2Cl2); IR (film) 3390 (br), 1778 cm-1
;
1H NMR
(500 MHz, CDCl3) δ 7.93 (s, 1H), 7.62 (m, 8H), 7.40 (m, 12H),
5.34 (s, 1H), 4.70 (t, J ) 3.97 Hz, 1H), 4.61 (s, 2H), 4.31 (s,
1H), 4.27 (t, J ) 4.86 Hz, 1H), 3.98 (dd, J ) 3.97, 12.11 Hz,
1H), 3.94 (dd, J ) 4.27, 12.11 Hz, 1H), 3.87 (dd, J ) 4.44, 11.19
Hz, 1H), 3.74 (m, 1H), 3.63 (m, 2H), 1.09 (s, 9H), 1.04 (s, 9H),
0.95 (m, 2H), 0.02 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 174.3,
153.3, 135.6, 135.5, 135.4, 132.5, 130.1, 130.0, 129.9, 127.9,
127.9, 127.7, 95.6, 81.5, 80.5, 79.5, 69.2, 68.1, 65.9, 61.3, 26.9,
26.7, 19.2, 19.1, 18.0, -1.3; MS m/z ESI+ 880 (M + Na)+, ESI-
892 (M + Cl)-; HRMS (MALDI+) calcd for C46H63NO9Si3Na
(M + Na+) 880.3708, found 880.3688.
3362 (br), 1782 cm-1 1H NMR (500 MHz, CDCl3) δ 7.61 (s,
;
1H), 5.17 (s, 1H), 4.71 (t, J ) 3.75 Hz, 1H), 4.52 (dd, J ) 6.16,
8.57 Hz, 1H), 4.12 (m, 3H), 3.81 (t, J ) 8.57, 1H), 3.69 (s, 1H),
1.47 (s, 6H), 0.89 (s, 9H), 0.12 (s, 6H); 13C NMR (125 MHz,
CDCl3) δ 173.2, 147.8, 109.9, 80.4, 79.5, 78.2, 74.2, 64.4, 60.4,
25.9, 25.7, 25.6, 18.0, -5.6, -5.7; MS m/z EI+ 390 (M - CH3)+;
HRMS (EI+) calcd for C16H28NO8Si (M - CH3)+ 390.1584,
found 390.1574.
(2R,3S,4R,1′R)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-4-
(2,2-d im eth yl-[1,3]d ioxola n -4-yl)-3,4-d ih yd r oxy-5-oxotet-
r a h yd r ofu r a n -3-[(ter t-b u t yld ip h en ylsilyloxy)ca r b a ld e-
h yd e oxim e] (19). Lactone 17 (382.1 mg, 1.313 mmol) and
imidazole (357 mg, 5.25 mmol) were dissolved in anhydrous
DMF (5 mL). tert-Butyldiphenylsilyl chloride (751 µL, 2.88
mmol) was added, and the reaction mixture was stirred under
N2 at room temperature. After 16 h, the solution was concen-
trated under high vaccuum (bath temperature of 35 °C) and
azeotroped with toluene to remove residual DMF. The residue
was redissolved in EtOAc and washed sequentially with NH4-
Cl, H2O, and NaCl. The organic layer was dried with MgSO4,
filtered, and concentrated under vacuum to provide 1.41 g
crude material. Flash chromatography on silica gel (8:2
hexanes/EtOAc) provided bis-silyl ether 19 (571.6 mg, 57%)
(4R,5R,8R,9S)-8-(ter t-Bu t yld ip h en ylsilyloxym et h yl)-
9-h yd r oxy-2,2-d im eth yl-6-oxo-4-(2-tr im eth ylsilyleth oxy-
methoxymethyl)-1,3,7-trioxa-spiro[4.4]nonane-9-[(tert-butyl-
d ip h en ylsilyloxy)ca r ba ld eh yd e oxim e] (22). Triol 21 (12
mg, 0.014 mmol) and PPTS (4 mg, 0.016 mmol) were dissolved
in CH2Cl2, and the solution was stirred at room temperature
under N2. 2-Methoxypropene (10 µL, 0.10 mmol) was added,
and the reaction mixture was sealed and stirred overnight.
After 48 h the reaction was mostly complete by TLC, but a
small amount of starting material remained. After an ad-
ditional 48 h, the reaction mixture was concentrated under
vacuum. Flash chromatography on silica gel (9:1 hexanes/
EtOAc) gave 22 (6.5 mg, 52%, Rf ) 0.32) and 23 (4.5 mg, 36%,
Rf ) 0.26). Data for 22: [R]20 +54.33° (c ) 1.34, CH2Cl2); IR
D
(film) 34000 (br), 1790 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.92
(s, 1H), 7.62 (m, 9H), 7.40 (m, 9H), 7.26 (m, 2H), 5.52 (s, 1H),
4.92 (dd, J ) 3.38, 7.74 Hz, 1H), 4.66 (t, J ) 3.18 Hz, 1H),
4.64 (AB, J AB ) 6.95 Hz, ∆νAB ) 37.48 Hz, 2H), 4.13 (dd, J )
3.38, 11.32 Hz, 1H), 3.96 (d, J ) 3.18 Hz, 2H), 3.78 (dd, J )
7.74, 11.32 Hz, 1H), 3.62 (m, 2H), 1.44 (s, 3H), 1.43 (s, 3H),
1.08 (s, 9H), 1.01 (s, 9H), 0.94 (t, J ) 8.34 Hz, 2H), 0.02 (s,
9H); 13C NMR (125 MHz, CDCl3) δ 173.0, 152.1, 135.7, 135.5,
135.4, 135.4, 132.9, 132.8, 132.1, 131.6, 130.1, 130.0, 129.8,
129.8, 127.9, 127.9, 127.6, 111.1, 95.0, 84.7, 80.2, 79.5, 77.5,
65.5, 64.9, 62.3, 27.0, 26.9, 26.6, 25.1, 19.2, 19.1, 18.0, -1.4;
MS m/z ESI+ 920 (M + Na)+, ESI- 932 (M + Cl)-; HRMS
(MALDI+) calcd for C49H67NO9Si3Na (M + Na+) 920.4021,
found 920.4062.
1
as a clear oil: Rf ) 0.2 (SiO2, 8:2 hexanes/EtOAc); H NMR
(500 MHz, CDCl3) δ 7.85 (s, 1H), 7.60 (m, 8H), 7.40 (m, 12H),
4.79 (s, 1H), 4.64 (t, J ) 4.37 Hz, 1H), 4.34 (t, J ) 7.25 Hz,
1H), 3.92 (t, J ) 4.92 Hz, 2H), 3.87 (m, 2H), 3.76 (s, 1H), 1.46
(s, 3H), 1.43 (s, 3H), 1.10 (s, 9H), 1.04 (s, 9H); MS m/z ESI+
790 (M + Na)+, ESI- 802 (M + Cl)-.
(2R,3S,4R,1′R)-2-(ter t-Bu tyld ip h en ylsilyloxym eth yl)-4-
(1,2-d ih yd r oxyet h yl)-3,4-d ih yd r oxy-5-oxot et r a h yd r ofu -
r a n -3-[(ter t-bu tyld ip h en ylsilyloxy)ca r ba ld eh yd e oxim e]
(20). Acetonide 19 (380 mg, 0.50 mmol) and PPTS (186 mg,
0.74 mmol) were dissolved in methanol (25 mL), and the
reaction mixture was heated to 55 °C for 4 h. Although some
starting material remained at this point on the basis of TLC
analysis, loss of the TBDPS groups started to become competi-
tive with acetonide removal. The reaction was then cooled to
room temperature and concentrated under vacuum. Flash
chromatography on silica gel (1:1 hexanes/EtOAc) gave 20 (290
(4R,4a R,7R,7a S)-7-(ter t-Bu t yld ip h en ylsilyloxym et h -
yl)-4a-hydroxy-2,2-dimethyl-5-oxo-4-(2-trimethylsilylethoxy-
methoxymethyl)dihydrofuro[3,4-d][1,3]dioxine-7a-[(tert-butyl-
d ip h en ylsilyloxy)ca r ba ld eh yd e oxim e] (23). [R]20D -2.68°
1
mg, 81%) as a clear oil: Rf ) 0.48 (SiO2, 1:1 hexanes/EtOAc);
(c ) 0.97, CH2Cl2); IR (film) 34000 (br), 1806 cm-1; H NMR
1
[R]20 +42.94° (c 0.85, CH2Cl2); IR (film) 3400, 1775 cm-1; H
(500 MHz, CDCl3) δ 8.00 (s, 1H), 7.65 (m, 9H), 7.40 (m, 13H),
4.74 (s, 1H), 4.66 (AB, J AB ) 6.55 Hz, ∆νAB ) 9.47 Hz, 2H),
4.57 (dd, J ) 5.06, 8.64 Hz, 1H), 4.06 (d, J ) 4.96 Hz, 2H),
4.03 (t, J ) 9.43 Hz, 1H), 3.94 (t, J ) 5.06 Hz, 1H), 3.83 (dd,
J ) 5.36, 10.12 Hz, 1H), 3.61 (dd, J ) 7.54, 8.93 Hz, 2H), 1.42
(s, 3H), 1.36 (s, 3H), 1.14 (s, 9H), 1.10 (s, 9H), 0.95 (m, 2H),
0.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 170.1, 156.8, 135.6,
135.4, 135.3, 135.3, 130.3, 130.3, 130.0, 129.9, 128.0, 127.9,
127.8, 127.6, 100.2, 95.1, 83.2, 78.0, 73.6, 70.6, 65.8, 65.1, 58.8,
29.6, 26.9, 26.8, 22.7, 19.1, 19.1, 18.0, -1.4; MS m/z ESI+ 920
(M + Na)+, ESI- 932 (M + Cl)-; HRMS (MALDI+) calcd for
D
NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.65 (m, 8H), 7.40, (m,
12H), 5.34 (s, 1H), 4.71 (t, J ) 4.77 Hz, 1H), 4.16 (s, 1H), 4.02
(m, 1H), 4.00 (dd, J ) 4.77, 11.71 Hz, 1H), 3.93 (dd, J ) 4.77,
11.71 Hz, 1H), 3.68 (m, 3H), 1.10 (s, 9H), 1.08 (s, 9H); 13C NMR
(125 MHz, CDCl3) δ 174.8, 153.3, 135.6, 135.4, 135.3, 135.3,
132.4, 132.3, 132.1, 131.9, 130.1, 130.0, 130.0, 128.1, 127.9,
127.9, 127.7, 127.7, 82.4, 79.9, 79.7, 69.8, 61.1, 60.9, 26.8, 26.6,
19.0; MS m/z ESI+ 750 (M + Na)+, ESI- 762 (M + Cl)-; HRMS
(MALDI+) calcd for C40H49NO8Si2Na (M + Na+) 750.2894,
found 750.2873.
(2R,3S,4R,1′R)-2-(ter t-Bu t yld ip h en ylsilyloxym et h yl)-
3,4-d ih yd r oxy-4-[1′-h yd r oxy-2′-(2-t r im et h ylsilylet h oxy-
methoxy)ethyl]-5-oxo-tetrahydrofuran-3-[(tert-butyldiphen-
ylsilyloxy)ca r ba ld eh yd e oxim e] (21). Tetraol 20 (35.1 mg,
0.048 mmol) was dissolved in CH2Cl2 (5 mL) and was stirred
under N2. 2,6-Di-tert-butylpyridine (163 µL, 0.73 mmol) was
added, and the solution was cooled to 0 °C. A solution of
anhydrous SEM-Cl (256 µL, 0.94 M in benzene, 0.24 mmol)
was added, and the reaction was stirred under N2 for 48 h.
During this time the cooling bath was allowed to warm to room
temperature, but the reaction flask was kept in the bath. After
48 h, TLC indicated that the undesired bis-SEM ether was
C
49H67NO9Si3Na (M + Na+) 920.4021, found 920.3983.
(4R,5R,8R,9S)-9-H yd r oxy-8-h yd r oxym et h yl-2,2-d im e-
th yl-6-oxo-4-(2-tr im eth ylsilyleth oxym eth oxym eth yl)-1,3,7-
tr ioxa sp ir o[4.4]n on a n e-9-ca r ba ld eh yd e Oxim e (24). Silyl
ether 22 (33 mg, 0.037 mmol) was dissolved in anhydrous THF
(10 mL). AcOH (10.5 µL, 0.18 mmol) was added, and the
mixture was stirred at room temperature. A solution of TBAF
(75.4 µL, 1 M in THF, 0.075 mmol) was added, and the reaction
mixture stirred for 30 min at room temperature. The reaction
mixture was then concentrated under vacuum, and flash
chromatography on silica gel (1:1 hexanes/EtOAc) gave 24
(12.2 mg, 80%) as a clear oil: Rf ) 0.18 (SiO2, 6:4 hexanes/

Symmetry-Based Synthesis of Zaragozic Acid A
EtOAc); IR (film) 3400 (br), 1791 cm-1 1H NMR (500 MHz,
J . Org. Chem., Vol. 65, No. 19, 2000 6159
;
(4R,5R,8R,9S)-9-H yd r oxy-8-h yd r oxym et h yl-2,2-d im e-
th yl-6-oxo-4-(2-tr im eth ylsilyleth oxym eth oxym eth yl)-1,3,7-
tr ioxa sp ir o[4.4]n on a n e-9-ca r boxylic Acid Ben zyl Ester
(27). Crude acid 26 (7.5 mg) was dissolved in anhydrous THF
(3 mL) and stirred under N2 at room temperature. A solution
of DCBI (100 µL, 0.636 M in toluene, 0.064 mmol) was added,
and the reaction mixture was stirred at room temperature for
16 h. The reaction was then concentrated under vacuum. Flash
chromatography on silica gel (6:4 hexanes/EtOAc) provided 27
(3.7 mg, 70% for 2 steps): Rf ) 0.4 (SiO2, 6:4 hexanes/EtOAc);
[R]20D +36.47° (c 0.26, CH2Cl2); IR (film) 3400 (br), 1793, 1740
cm-1; 1H NMR (500 MHz, CDCl3) δ 7.39, (m, 5H), 5.84, (s, 1H),
5.26, (AB, J AB ) 12.11 Hz, ∆νAB ) 9.33 Hz, 2H), 5.09, (t, J )
CDCl3) δ 7.70 (s, 1H), 5.24 (s, 1H), 4.85 (t, J ) 4.37 Hz, 1H),
4.77 (m, 3H), 4.15 (m, 2H), 4.07 (dd, J ) 4.37, 11.91 Hz, 1H),
3.93 (dd, J ) 4.37, 11.91 Hz, 1H), 3.65 (m, 2H), 1.47 (s, 3H),
1.45 (s, 3H), 0.96 (m, 2H), 0.03 (s, 9H,); 13C NMR (125 MHz,
CDCl3) δ 172.9, 148.0, 111.2, 95.2, 84.8, 81.5, 78.5, 66.1, 64.1,
59.8, 27.0, 25.2, 18.0, -1.4; MS m/z ESI+ 444 (M + Na)+, ESI-
456 (M + Cl)-; HRMS (MALDI+) calcd for C17H31NO9SiNa (M
+ Na+) 444.1666, found 444.1652.
(4R,5R,8R,9S)-9-H yd r oxy-8-h yd r oxym et h yl-2,2-d im e-
th yl-6-oxo-4-(2-tr im eth ylsilyleth oxym eth oxym eth yl)-1,3,7-
tr ioxa sp ir o[4.4]n on a n e-9-ca r ba ld eh yd e (25). Oxime 24
(7.3 mg, 0.017 mmol) was dissolved in CH2Cl2 (8 mL) and
methanol (0.4 mL). NaHCO3 (15 mg) was added, and the
mixture was cooled to -78 °C and stirred for 20 min. O3 was
bubbled through the solution for 2 min (until a blue color
persisted). The solution was then kept at -78 °C for 1 h
(without stirring) and then at -70 °C overnight. After 16 h,
dimethyl sulfide (2 mL) was added, and the reaction was
warmed to room temperature. After 10 min, the mixture was
concentrated under vacuum, and flash chromatography (gradi-
ent, 6:4 f 1:2 hexanes/EtOAc) gave aldehyde 25 (5 mg, 69%,
Rf ) 0.47, SiO2, 1:1 hexanes/EtOAc) and unreacted starting
material 24 (2.2 mg, 30%): IR (film) 3434 (br), 1792, 1731
4.86 Hz, 1H), 4.89, (dd, J ) 4.96, 6.35, 1H), 4.70, (AB, J AB
)
6.75 Hz, ∆νAB ) 21.19 Hz, 2H), 4.11, (dd, J ) 6.35, 11.32 Hz,
1H), 4.07, (m, 1H), 4.02 (m, 1H), 3.93, (dd, J ) 4.96, 11.51 Hz,
1H), 3.61, (m, 2H), 1.42, (s, 3H), 1.27, (s, 3H), 0.94, (m, 2H),
0.03, (s, 9H); 13C NMR (125 MHz, CDCl3) δ 172.5, 168.9, 134.7,
129.1, 129.0, 128.9, 112.0, 95.4, 85.9, 81.4, 81.3, 77.5, 68.4, 66.3,
64.5, 60.3, 27.5, 25.8, 18.3, -1.1; MS m/z ESI+ 535 (M + Na)+,
ESI- 547 (M + Cl)-, ESI- 511 (M - H)-; HRMS (MALDI+)
calcd for C24H36O10SiNa (M + Na+) 535.1975, found 535.1978.
Ack n ow led gm en t. This research was supported by
the NIH (GM53496). R.L.H. also thanks the National
Science Foundation (Career Award), the Camille and
Henry Dreyfus Foundation (Camille Dreyfus Teacher-
Scholar Award), Pfizer (J unior Faculty Award), and
Novartis (Young Investigator Award) for support. K.D.F.-
C. acknowledges the Howard Hughes Medical Institute
for a Predoctoral Fellowship. This work was greatly
facilitated by a 500 MHz NMR spectrometer that was
purchased partly with funds from an NSF Shared
Instrumentation Grant (CHE-9523034). Bob Barkley
(University of Colorado) is thanked for obtaining mass
spectra which greatly aided structure elucidation of
synthetic intermediates. Bruce Noll (University of Colo-
rado) is thanked for the determination of all of the X-ray
crystal structures that were presented here. Prof. K. C.
Nicolaou (Scripps Research Institute) is thanked for
kindly providing information which helped to verify the
formal synthesis.
1
cm-1; H NMR (500 MHz, CDCl3) δ 9.94 (s, 1H), 5.19 (s, 1H),
5.01 (t, J ) 5.56 Hz, 1H), 4.84 (t, J ) 3.38 Hz, 1H), 4.69 (AB,
J AB ) 6.55 Hz, ∆νAB ) 6.36 Hz, 2H), 3.98 (dd, J ) 3.77, 11.91
Hz, 1H), 3.95 (m, 2H), 3.90 (dd, J ) 3.38, 11.91 Hz, 1H), 3.64
(m, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 0.96 (m, 2H), 0.04 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 197.2, 172.2, 111.4, 94.9, 85.6,
82.0, 79.4, 79.3, 66.1, 63.6, 59.3, 26.7, 25.1, 18.0, -1.4; MS m/z
ESI- 405 (M - H)-; HRMS (MALDI+) calcd for C17H31O9Si (M
+ H+) 407.1737, found 407.1743.
(4R,5R,8R,9S)-9-H yd r oxy-8-h yd r oxym et h yl-2,2-d im e-
th yl-6-oxo-4-(2-tr im eth ylsilyleth oxym eth oxym eth yl)-1,3,7-
tr ioxa sp ir o[4.4]n on a n e-9-ca r boxylic Acid (26). Aldehyde
25 (8 mg, 0.020 mmol) was dissolved in tert-butyl alcohol (1.2
mL) and H2O (0.3 mL). NaH2PO4 (12 mg, 0.087 mmol) and a
solution of 2-methyl-2-butene (83 µL, 2 M in THF, 0.17 mmol)
were added, and the reaction mixture was stirred for 5 min at
room temperature. NaClO2 (12 mg, 0.13 mmol) was added, and
the reaction mixture was stirred at room temperature. After
3 h, the reaction was quenched with H2O (2 mL), and 5 drops
of 5% HCl were added (to adjust the pH to ca. 1.5). The
aqueous layer was extracted with CHCl3, dried over MgSO4,
filtered, and concentrated under vacuum to provide 26 (12.3
mg), which was used without purification: 1H NMR (500 MHz,
CDCl3) δ 4.99 (t, J ) 3.08 Hz, 1H), 4.91 (t, J ) 2.98 Hz, 1H),
4.83 (s, 2H), 4.33 (m, 2H), 4.17 (m, 2H), 3.70 (m, 2H), 1.50 (s,
3H), 1.45 (s, 3H), 0.96 (m, 2H), 0.03 (s, 9H).
Su p p or tin g In for m a tion Ava ila ble: Complete X-ray
crystallography data for compounds 14 and 18, and photo-
copies of selected 1H and 13C NMR spectra. This information
is available free of charge via the Internet at http://pubs.acs.org.
J O000665J