Total syntheses of zaragozic acids A and C by a carbonyl ylide cycloaddition strategy

Article abstract of DOI:10.1002/chem.200601212

A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regiosel

Full text of DOI:10.1002/chem.200601212

FULL PAPER
DOI: 10.1002/chem.200601212
8898
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Chem. Eur. J. 2006, 12, 8898 – 8925

FULL PAPER
Total Syntheses of Zaragozic Acids A and Cby a Carbonyl Ylide
Cycloaddition Strategy
Yuuki Hirata,[a] Seiichi Nakamura,[a] Nobuhide Watanabe,[a] Osamu Kataoka,[a]
Takahiro Kurosaki,[a] Masahiro Anada,[a] Shinji Kitagaki,[a] Motoo Shiro,[b] and
Shunichi Hashimoto*[a]
Abstract: A carbonyl ylide cycloaddi-
tion approach to the squalene synthase
inhibitors zaragozic acids A and C is
described. The carbonyl ylide precursor
8 was synthesized starting from di-tert-
butyl d-tartrate (47) via an eleven-step
sequence involving the regioselective
reduction of the mono-MPM (MPM =
4-methoxybenzyl) ether 48 with LiBH4
and the diastereoselective addition of
sodium tert-butyl diazoacetate to a-
keto ester 10. The reaction of a-diazo
ester 8 with 3-butyn-2-one (40) in the
presence of a catalytic amount of [Rh2-
sequential transformations permitted
the construction of the fully functional-
ized 2,8-dioxabicyclo[3.2.1]octane core
A
A
5. Alkene 79 derived from 5 serves as a
common precursor to zaragozic acids
A (1) and C (2), since the elongation
of the C1 alkyl side chain can be at-
tained by olefin cross-metathesis, espe-
cially under the influence of Blechertꢁs
catalyst (85).
59 as a single diastereomer. The dihy-
droxylation of enone 59 followed by
Keywords:
carbonyl ylides
·
cycloaddition · diazo compounds ·
metathesis · total synthesis
Introduction
ly, in 1994. Since then, five additional total syntheses of zar-
agozic acids,[10–14] including our first-generation synthesis,
have been reported.[15] All of these approaches utilize inter-
nal ketalization in constructing the core structure; only
Heathcock adopted a stepwise approach, wherein the full
C1 alkyl side chain was installed after the ketalization event.
The zaragozic acids/squalestatins comprise a family of poly-
ketide natural products that display inhibitory activity
against squalene synthase[1] and farnesyl-protein transfer-
ase.[2] Since their discovery in 1992 by researchers at
Merck,[2b,3] Glaxo,[4] and Tokyo Noko University/Mitsubishi
Kasei Corporation,[5] zaragozic acids/squalestatins have at-
tracted considerable attention from the synthetic community
because of interest in the unique and challenging molecular
architecture of these compounds coupled with their remark-
able biological activity. Over 30 groups have made impres-
sive contributions to the literature on the synthesis of these
molecules.[6,7] The first total syntheses of zaragozic acid C
(2) and zaragozic acid A (squalestatin S1, 1) were reported
from the Carreira[8] and Nicolaou[9] laboratories, respective-
[a] Dr. Y. Hirata, Dr. S. Nakamura, Dr. N. Watanabe, Dr. O. Kataoka,
T. Kurosaki, Dr. M. Anada, Dr. S. Kitagaki, Prof. Dr. S. Hashimoto
Faculty of Pharmaceutical Sciences, Hokkaido University
Sapporo 060-0812 (Japan)
The principal goal of our study was not simply to devise
an efficient, stereocontrolled synthesis of this family of natu-
ral products, but more importantly to develop a unified
strategy that would be applicable to the synthesis of core-
modified analogues. The key feature of our first-generation
synthesis of zaragozic acid C (2) is the simultaneous creation
of contiguous, oxygen atom-substituted quaternary stereo-
Fax : (+81)11-706-3236
E-mail: hsmt@pharm.hokudai.ac.jp
[b] Dr. M. Shiro
Rigaku Corporation, 3-9-12 Matsubara, Akishima
Tokyo 196-0003 (Japan)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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S. Hashimoto et al.
centers at C4 and C5 by a Sn(OTf)2-promoted aldol cou-
G
pling reaction between an a-keto ester and a silyl ketene
thioacetal derived from l- and d-tartaric acids, respectively;
however, the coupling incurs a stereochemical problem at
C5, despite considerable effort to resolve this issue. It also
became apparent that the strategy would not be amenable
to analogue synthesis. As a result, we felt compelled to de-
velop a second-generation synthesis of zaragozic acids
through an entirely different route.
Metallocarbenoids, generated by the decomposition of a-
diazo carbonyl compounds, form cyclic carbonyl ylides as
transient species by transannular cyclization with the adja-
cent carbonyl groups, which undergo 1,3-dipolar cycloaddi-
tion reactions with multiple bonds to provide five-mem-
bered, oxygen-containing heterocycles.[16] The utility of this
method was first demonstrated by Ibata and co-workers in
1972, wherein Cu
(acac)2 was used as a catalyst.[17] Since
U
Padwa and co-workers reported that rhodium(ii)-catalyzed
cyclization/cycloaddition reactions proceeded under much
milder conditions than was common for the classic method
with Cu
(acac)2,[18] this process has been extensively studied
U
and represents an attractive strategy for the synthesis of bio-
active compounds.[19]
An inspection of the structure of zaragozic acids revealed
the intriguing possibility of applying the tandem carbonyl
ylide formation/1,3-dipolar cycloaddition sequence to con-
struct the core structure of these molecules. In this article,
we describe the details of our carbonyl ylide cycloaddition
approach to the syntheses of zaragozic acids A (1) and C
(2).[20,21]
Scheme 1. Retrosynthetic analysis of zaragozic acids. Boc=tert-butoxy-
carbonyl; Bn=benzyl; MOM=methoxymethyl.
Preliminary model studies: The synthesis plan outlined in
Scheme 1 necessitates the use of the a-diazo ester 8 as a car-
bonyl ylide precursor. Although tandem carbonyl ylide for-
mation/1,3-dipolar cycloaddition reactions are well docu-
mented with a-diazo-b-ketoesters,[16] at the outset of our
studies, a-diazo esters with an sp3 carbon at the b-position
had never been tested as substrates for these reactions.[22] In
addition, it was suggested by Padwa and co-workers that al-
ternate pathways might compete with carbonyl ylide forma-
tion in the case where the trapping carbonyl is an ester.[23]
Thus, we felt it was prudent to perform exploratory experi-
ments using a readily accessible a-diazo ester. The a-diazo
ester 11 was chosen as a model substrate for the reaction.
The synthesis of the a-diazo ester 11 commenced with the
d-isoascorbic acid-derived alcohol 12[24] and proceeded
along the path delineated in Scheme 2. Protection of the hy-
droxyl group of 12 with 4-methoxybenzyl (MPM) trichloroa-
Results and Discussion
Retrosynthetic analysis: Our cycloaddition-based retrosyn-
thetic analysis of zaragozic acids is depicted in Scheme 1.
The structures of the zaragozic acids/squalestatins are char-
acterized by a 4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-
A
3,4,5-tricarboxylic acid core with an array of six stereogenic
centers including contiguous, oxygen atom-substituted qua-
ternary ones, and the difference between these compounds
lies in the variation in the C1 alkyl and C6 acyl side chains.
To enhance the convergency of the assemblage process, we
planned to install the full C1 alkyl side chain late in the syn-
thesis. The implementation of this strategy would allow the
incorporation of a variety of C1 alkyl side chains into a
common, fully elaborated intermediate 5. The bicyclic com-
pound 6 was envisioned to arise from the 1,3-dipolar cyclo-
addition of the cyclic carbonyl ylide 7, generated from the
a-diazo ester 8 in the presence of a rhodium(ii) catalyst,
with a suitable dipolarophile. A disconnection in the C4-C5
bond led to tert-butyl diazoacetate (9) and the a-keto ester
10, which could then be traced back to d-tartaric acid. Con-
sidering our previous findings that saponification and tert-
butyl esterification at a later stage were problematic,[12] the
carboxyl groups were protected as tert-butyl esters through-
out the synthesis.
[25]
cetimidate in the presence of Ph3CBF4 provided the MPM
ether 13 in 93% yield, which, upon exposure to 10% aque-
ous HCl in THF, afforded the diol 14 in 90% yield. Selec-
tive silylation of the primary hydroxyl group with tert-butyl-
diphenylsilyl (TBDPS) chloride was followed by condensa-
tion with the carboxylic acid 16[26] to give ester 17 in 69%
yield over two steps. Oxidative removal of the MPM group
with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)[29]
provided alcohol 18 in 99% yield, which underwent a Dess–
Martin oxidation[30] to afford the a-keto ester 19 in 97%
yield. The incorporation of the a-diazo ester functionality
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Zaragozic Acids A and C
FULL PAPER
Scheme 3. Determination of the stereochemistry at C4 of a-diazo esters
20 and 21. a) K2CO3, MeOH, 08C, 1 h; b) TMS-imidazole, CH2Cl2.
Scheme 2. Synthesis of a-diazo ester 11. a) MPMOC(NH)CCl3, Ph3CBF4,
Et2O, 0 8C, 30 min; b) 10% aq. HCl, THF, 5 h; c) TBDPSCl, imidazole,
CH2Cl2, 08C, 1 h; d) EDCI, MOMO(CH2)2CO2H (16), DMAP, CH2Cl2,
N
12 h; e) DDQ, CH2Cl2, pH 7 phosphate buffer, 24 h; f) Dess–Martin peri-
odinane, CH2Cl2, 1 h; g) LiHMDS, N2CHCO2Et, THF, ꢀ788C, 30 min; h)
HMDS, imidazole, THF, 48 h. THF=tetrahydrofuran; EDCI=1-(3-dime-
thylaminopropyl)-3-ethylcarbodiimide hydrochloride; DMAP=4-(dime-
thylamino)pyridine; HMDS=1,1,3,3-hexamethyldisilazane.
Figure 1. X-ray crystal structure of g-lactone 24, rendered in Chem3D.
For purposes of clarity, only the protons attached to the C3 stereocenter
and the oxygen atom are shown.
was accomplished by employing the Wenkert protocol,[31]
namely the addition of LiHMDS to a premixed solution of
a-keto ester 19 and ethyl diazoacetate. The readily separa-
ble diastereomers 20 and 21 thus formed were isolated in 38
and 32% yield, respectively. The stereochemical assign-
ments of isomers 20 and 21 were determined in two sets of
experiments (Scheme 3). Treatment of isomer 21 with
K2CO3 in MeOH effected transesterification, the migration
of the TBDPS group,[32] and lactone formation to give the
crystalline alcohol 24 in 68% yield, which was converted to
trimethylsilyl (TMS) ether 25 in 97% yield by silylation
with TMS-imidazole. Following the same reaction sequence,
g-lactone 27 was also obtained from isomer 20, albeit in
lower yield (48% in two steps without intervening purifica-
As stated earlier, the reaction of cyclic carbonyl ylides
without a carbonyl group within the rings was unprecedent-
ed in the literature. Thus, several types of dipolarophile can-
didates were examined so as to establish the scope of the
process. The reaction involved the addition of a-diazo ester
11 over a 5 min period to a refluxing solution of a dipolaro-
phile and 5 mol% of [Rh2(OAc)4] in benzene. When elec-
A
tron-rich alkenes such as trimethylsilyl vinyl ether, benzyl
vinyl ether and 1,2-bis(trimethylsilyloxy)ethylene were em-
ployed as dipolarophiles, all attempts to obtain cycloadducts
in even trace quantities through this reaction met with fail-
ure [Eq. (1)]. In contrast, the reaction of 11 with dimethyl
acetylenedicarboxylate (29) proceeded with complete ste-
1
tion) due to the lability of intermediate 26 to base. The H
NOE between Si
figuration of 25, whereas Si(CH3)3 exhibited a significant H
G
1
NOE interaction with Hb in lactone 27 with a 4R configura-
tion. Finally, the stereochemistry of the undesired isomer 21
was unambiguously established by X-ray crystallography of
the lactone 24, as shown in Figure 1. The preparation of
model compound 11 was completed in 92% yield by the si-
lylation of 20. The C4 isomer 22 was also prepared from 21,
in a comparative experiment.
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S. Hashimoto et al.
reocontrol to give cycloadduct 30 in 66% yield as a single
diastereomer (Table 1, entry 1). It is noteworthy that N-phe-
nylmaleimide (31) and (E)-3-hexene-2,5-dione (33) proved
Table 1. 1,3-Dipolar cycloaddition of carbonyl ylide 28 with symmetrical
dipolarophiles.
Figure 2. Stereochemical course of the 1,3-dipolar cycloaddition
Entry
1
Dipolarophile
Cycloadduct
Yield [%]
66
36, arising from a C-H insertion reaction, and even trace
amounts of cycloadduct 37 were not detected [Eq. (2)].
2[a]
68
47
3
These results suggest that the stereochemistry at C4 plays
a pivotal role in the present system, presumably because the
rhodium(ii) carbenoid generated from 22 cannot adopt the
required conformation for carbonyl ylide formation.
31
[a] The reaction was performed using 2 equiv of 31.
The cycloadduct 34 was anticipated to provide the suita-
bly functionalized core compound 38 when subjected to
Baeyer–Villiger conditions.[33] However, all attempts to
effect the desired transformation resulted in the recovery of
34 or decomposition, principally through the loss of protect-
ing groups [Eq. (3)]. Consequently, the judicious selection
to be effective dipolarophiles for the tandem reaction, pro-
viding cycloadducts 32 and 34 as single diastereomers in 68
and 47% yield, respectively, although substantial amounts
of carbonyl adduct 35 were also obtained by reaction with
33 (entries 2, 3). The stereochemical assignments for cyclo-
adducts 32 and 34 were determined by diagnostic NOE ex-
periments, as shown in Table 1, and the stereochemistry of
30 was assigned by analogy. These results reveal that the
1,3-dipolar cycloaddition occurred exclusively from the b-
face of ylide 28 to avoid non-bonding interactions with the
C4 pseudoaxial trimethylsilyloxy group. The formation of 34
is consistent with a reaction through transition state A,
wherein the activating groups in 33 are nicely accommodat-
ed in a less crowded space in 28 (Figure 2). Surprisingly,
under the foregoing conditions, the major product formed in
the reaction of the C4 isomer 22 with 29 was cyclobutane
of dipolarophiles that could result in much higher yields as
well as a completed synthesis became crucial to the success
of our scenario.
Given the lack of information in the literature regarding
the HOMO and LUMO energies for cyclic carbonyl ylides
derived from a-diazo esters, calculations were performed
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Zaragozic Acids A and C
FULL PAPER
[34]
Table 3. 1,3-Dipolar cycloaddition of carbonyl ylide 28 with unsymmetri-
cal dipolarophiles.
using the simplified dipole 39 (Table 2). As anticipated,
the interaction between LUMO (dipole) and HOMO (dipo-
larophile) is energetically favored when benzyl vinyl ether is
Table 2. HOMO and LUMO energies and coefficients for cyclic carbonyl
ylide 39 and dipolarophile candidates.
Coefficient
Energy [eV]
C5
O8
C1
Entry
1
Dipolarophile
Cycloadduct
Yield [%]
85
HOMO
LUMO
ꢀ8.27
ꢀ0.94
+0.79
+0.23
ꢀ0.14
ꢀ0.41
ꢀ0.29
+0.71
Energy [eV]
Energy separation [eV]
[b]
Dipolarophile
HOMO LUMO EI[a]
EII
benzyl vinyl ether
ꢀ9.36
+0.39
ꢀ0.93
ꢀ0.82
+0.05
+0.10
ꢀ0.34
9.21
7.34
7.45
8.32
8.37
7.93
8.42
11.02
9.80
10.24
10.72
9.70
ꢁ
MeO2C-C C-CO2Me (29) ꢀ11.96
3-hexene-2,5-dione (33)
3-butyn-2-one (40)
ꢀ10.74
ꢀ11.18
ꢀ11.66
ꢀ10.64
2
3
82
44
methyl propiolate (41)
2-chloroacrylonitrile (42)
[a] EI =[HOMO (dipole)ꢀLUMO (dipolarophile)]. [b] EII =[HOMO (di-
polarophile)ꢀLUMO (dipole)].
31
used as a dipolarophile, whereas the main interaction is the
[HOMO (dipole) ꢀ LUMO (dipolarophile)] for electron-de-
ficient alkynes and alkenes. Since carbonyl ylide 28 generat-
ed from 11 underwent 1,3-dipolar cycloaddition with elec-
tron-deficient dipolarophiles, the latter is a critical interac-
tion that drives the present reaction. In our initial experi-
ments, we employed symmetrical dipolarophiles with two
electron-withdrawing groups, not only to enhance reactivity
toward cycloaddition but also to avoid the formation of re-
gioisomers. The calculations indicate that the energy separa-
tion between HOMO (dipole) and LUMO (dipolarophile)
is extended by about 1 eV when monosubstituted, unsym-
metrical alkynes 40 and 41 are employed as dipolarophiles
instead of 29. With regard to the regioselectivity of the cy-
cloaddition, Padwa and co-workers proposed that all the re-
sults obtained could be accommodated in terms of frontier
molecular orbital (FMO) theory.[18] In our system, as the
atomic coefficient at C5 is larger than C1 in the HOMO for
ylide 39, the formation of C7-substituted regioisomers
would be anticipated in reactions with mono- or 1,1-disubsti-
tuted, electron-deficient dipolarophiles.
[a]
4
[a] The cycloadduct could not be obtained.
tuted cycloadducts 46a and 46b in a combined yield of 75%
(entry 3). Although the LUMO energy for 2-chloroacryloni-
trile (42) is lower than that for 40 or 41, cycloadducts could
not be obtained with 42 (entry 4), indicating that steric fac-
tors as well as energy separations should be taken into con-
sideration for this reaction. Of the various partners tested,
alkynes 40 and 41 were chosen as the dipolarophiles that
would most likely lead to the completed synthesis.
Synthesis of carbonyl ylide precursor 8: Encouraged by the
results of the model studies described above, we then ad-
dressed the stereoselective synthesis of a-diazo tert-butyl
ester 8. The synthesis began with the mono-protection of di-
tert-butyl d-tartrate (47)[35] with MPMBr via the stannylene
acetal,[36] affording the MPM ether 48 in 92% yield
(Scheme 4). At this point, the synthetic plan called for the
selective reduction of one of the tert-butyl esters in 48.[37]
After considerable experimentation, LiBH4 proved to be the
optimal reagent for this purpose. Thus the LiBH4 reduction
of 48 followed by aqueous workup afforded the aldehyde,
which was reduced again with LiBH4 to give 1,3-diol 50 in
Gratifyingly, monosubstituted, electron-deficient alkynes
40 and 41 could be trapped by the carbonyl ylide intermedi-
ate 28, producing cycloadducts 43 and 44 in excellent yields
with complete regio- and diastereofacial selectivity (Table 3,
entries 1 and 2). endo/exo Selectivity could not be observed
with acrylonitrile (45), affording a 3:2 mixture of C7-substi-
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S. Hashimoto et al.
Table 4. Addition of the metalated a-diazo ester to a-keto ester 10.
Entry
Base
Solvent
T
[8C]
Yield
[%]
57/58[a]
1
2
3
4
5
6
7
LiHMDS
NaHMDS
KHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
THF
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ93
ꢀ93
ꢀ93
ꢀ93
80
79
26
76
64
62
73
1.0:1
2.0:1
2.1:1
2.1:1
3.2:1
4.3:1
8.0:1
THF/PhMe 10:1
THF
Et2O/THF 20:1
PhMe/THF 20:1
CH2Cl2/THF 20:1
1
[a] The ratio was determined by 500 MHz H NMR analysis of the crude
mixture.
Scheme 4. Preparation of a-keto ester 10. a) Bu2SnO, toluene, reflux, 2 h,
then CsF, MPMBr, DMF, 10 h; b) LiBH4, THF, 4 h; c) LiBH4, THF,
ꢀ788C, 4 h; d) TBDPSCl, imidazole, CH2Cl2, 08C, 30 min; e) DHP,
PPTS, CH2Cl2, 5 h; f) DDQ, CH2Cl2, pH 7 phosphate buffer, 2 h; g)
used in this type of reaction, mixed with reagent-derived
THF proved to be optimal for this reaction, providing ad-
ducts in a 73% combined yield in a ratio of 8:1 favoring the
anti-Felkin product 57, although the reason for this is not
clear at present (entry 7). After chromatographic separation
of the diastereomers, the silylation of the desired isomer 57
produced TMS ether 8 in 94% yield [Eq. (4)], which set the
stage for the tandem carbonyl ylide formation/1,3-dipolar
cycloaddition sequence.
EDCI, MOMO(CH2)2CO2H (16), DMAP, CH2Cl2, 3 h; h) TsOH, MeOH,
G
40 min; i) Dess–Martin periodinane, CH2Cl2, 2 h. DMF=N,N-dimethyl-
formamide; DHP=3,4-dihydro-2H-pyran; PPTS=pyridinium p-toluene-
sulfonate; Ts=p-toluenesulfonyl.
72% yield, along with 2% of the 1,2-diol 51. This highly
beneficial result can be rationalized by assuming the pre-
dominant formation of a rigid, six-membered boronate in-
termediate 49 that is resistant to further reduction. Selective
silylation of the major isomer 50 with TBDPSCl was fol-
lowed by interim protection of the remaining hydroxyl
group as a tetrahydropyranyl (THP) ether and oxidative re-
moval of the MPM ether to give 54 in 88% yield in three
steps. The acylation of 54 with acid 16 followed by exposure
to TsOH in MeOH provided alcohol 56 in 74% yield in two
steps, which underwent a Dess–Martin oxidation to afford
a-keto ester 10 in 97% yield. Our effort was then directed
toward the addition of metalated tert-butyl diazoacetate to
10 to set up the oxygen atom-substituted quaternary center
at C4, which posed a serious problem of stereocontrol. As in
the case of the a-keto ester 19, the use of LiHMDS as a
base resulted in a 1:1 mixture of diastereomeric products 57
and 58, the configurations of which at C4 were established
Construction of the fully functionalized 2,8-dioxabicyclo-
AHCTREUNG
1
by comparison of the H NMR chemical shifts of C3-H to
those of a-diazo esters 20 and 21 (Table 4, entry 1). Of the
three alkaline metal bis(trimethylsilyl)amide surveyed,
NaHMDS proved the best in terms of both yield and diaste-
reoselectivity (entries 1–3). The reaction of a-keto ester 10
with 9 proceeded to completion within 5 min even at ꢀ938C
(entry 4). The solvent survey revealed that unsatisfactory
diastereoselectivities were obtained in donor solvents (en-
tries 4 and 5). The use of CH2Cl2, which is not normally
ACHTREUNG
59 as a single isomer in 72% yield (Table 5, entry 1). In this
case, the consumption of the starting diazo compound 8 was
considerably slower than that of 11, perhaps owing to steric
congestion around the reacting center. As a consequence,
minor byproducts 60–62 were isolated in 14%, 6% and 6%
yields, respectively. While the formation of alcohol 60 can
be attributed to the reaction of the rhodium carbenoid inter-
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Zaragozic Acids A and C
FULL PAPER
Table 5. 1,3-Dipolar cycloaddition of carbonyl ylide 7 generated from a-diazo ester 8.
Having established a viable
route to cycloadducts 59 and
63, efforts were next focused on
the installation of the C6,C7-
trans-diol unit. The dihydroxy-
lation of enone 59 with OsO4
proceeded from the sterically
ꢀ
less hindered face of the C6 C7
double bond, affording diol 64
in 88% yield, which underwent
selective benzylation of the hy-
droxyl group at C6 to give 65 in
95% yield (Scheme 5). The ste-
reochemistry of 65 was verified
1
by a diagnostic H NOE corre-
lation (18%) between C3-H
and C6-H. In contrast, the ben-
zylation of diol 66, obtained by
the stereoselective dihydroxyla-
tion of enoate 63, under the
same conditions resulted in the
Entry
R
RhII catalyst
Solvent
T
[8C]
t
Yield [%]
60 61 62
A
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
OMe
A
N
benzene
benzene
benzene
80
80
60
80
80
80
80
80
110
80
80
40
59
59
59
59
59
59
59
59
59
59
63
72 14
67 10
6
3
0
0
0
0
0
8
4
2
–
6
7
0
A
N
140[b]
150
40
formation
of
significant
A
N
7
71
65
6
amounts (14%) of regioisomer
68. With these results, the deci-
sion was made to carry the hy-
droxyketone 65 forward in the
synthesis of natural products.
The superfluous C7 acetyl
group in 65 was removed in a
simple two-step sequence in-
volving reduction with diisobu-
A
N
trace
13
33
trace
10
15
2
A
N
benzene
benzene
benzene
toluene
toluene
40
40
40
40
66 14
A
N
11
72
4
3
A
N
A
N
28 35
46 15
9
10
11
A
N
25
20
40
A
N
A
17
78
8
9
A
N
0
[a] The reaction time includes the addition time of 15 min. [b] The reaction time includes the addition time of
120 min.
tylaluminum
(DIBALH) and oxidative cleav-
(OAc)4].
hydride
mediate with adventitious H2O,[23] pyrazole 61 and epoxide
62 were thought to result from the direct [3+2]-cycloaddi-
tion without rhodium(ii) catalysis[38] and the oxonium ylide
formation-desilylation sequence, respectively, suggesting the
presence of some competitive pathways during the carbonyl
ylide formation process. Thus, we were poised to identify
the optimal conditions for this reaction. Although it was an-
ticipated that the decreased carbenoid concentration limited
competing side reactions, the slow addition (120 min) of a-
diazo ester 8 afforded no discernible benefits (entry 2). The
rhodium(ii)-catalyzed diazo decomposition was found to
occur at 608C, but the major product formed at this temper-
ature was alcohol 60, showing that the formation of 7 and/or
the 1,3-dipolar cycloaddition of 7 with 40 required a higher
temperature than that for the formation of the rhodium car-
benoid intermediate (entry 3). With the lone exception of
age of the 1,2-diol with [Pb
ACHTREUNG
[Rh2(OCOC3F7)4] where 59 was produced in only 11% yield
N
(entry 6), the chemical yield of cycloadduct 59 was nearly
the same for each rhodium(ii) catalyst (entries 1, 4–7). An
examination of various solvents revealed that benzene was
the optimal solvent for this transformation (entries 1, 8–10).
Under optimal conditions, the reaction of a-diazo ester 8
with methyl propiolate (41) provided cycloadduct 63 in 78%
yield (entry 11).
Scheme 5. Synthesis of ketone 70. a) OsO4, NMO, acetone, tBuOH, H2O,
3 h; b) BnBr, Ag2O, DMF, 24 h; c) DIBALH, toluene, ꢀ788C, 30 min; d)
[Pb(OAc)4], benzene, 30 min. NMO=4-methylmorpholine N-oxide.
A
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8905

S. Hashimoto et al.
At this stage, we were faced with the task of reducing the
C7 carbonyl group in a stereoselective manner. While the
reduction of ketone 70 with NaBH4 in EtOH at ꢀ458C gave
a 2.1:1 ratio of alcohols favoring the desired isomer 71
(Table 6, entry 1), the use of K-Selectride, a bulky reducing
Completion of the total synthesis of zaragozic Acid C: For
the full installation of the C1 alkyl side chain, two distinct
olefination sequences were envisaged. One involved the
Wittig reaction of aldehyde 5 with a phosphorane or, equiv-
alently, the Julia coupling of 5 and a sulfone. The second
strategy would utilize olefin
cross-metathesis. We initially
Table 6. Reduction of carbonyl group at C7.
adapted the Kocienski–Julia
olefination[42] for this task, but
the attempted coupling of 5
with sulfone 77 resulted in the
complete recovery of starting
Entry
Reagent
Additive
Solvent
T
[8C]
t
Yield
[%]
71:72[a]
materials [Eq. (5)]. We then
turned our attention to the use
of a terminal olefin cross-meta-
thesis.[43] The terminal olefin
was uneventfully incorporated
by a Wittig reaction of alde-
hyde 5 with methylene-triphe-
nylphosphorane to give 79 in
93% yield [Eq. (6)]. The cou-
pling partner, alkene 82, was
[h]
1
2
3
4
5
6
NaBH4
K-Selectride
–
–
–
–
EtOH
THF
THF
toluene
CH2Cl2
CH2Cl2
ꢀ45
0
0
ꢀ78
ꢀ78
ꢀ78
0.5
1
6
0.5
0.5
0.5
95
50
95
91
96
87
2.1:1
0:1
2.8:1
4.6:1
14.4:1
46.4:1
Zn
A
DIBALH
DIBALH
DIBALH
–
ZnCl2
[a] The ratio was determined by HPLC (Zorbax Sil, 4.6”250 mm; eluent, 9% THF in n-hexane; flow rate
1.0 mLminꢀ1).
agent, resulted in the exclusive formation of the undesired
isomer 72 (entry 2). After considerable experimentation, re-
ducing agents capable of coordination with a Lewis basic
oxygen atom such as Zn(BH4)2 or DIBALH proved to be
G
effective in preferentially providing the desired isomer 71
(entries 3–6). Finally, we found that the use of DIBALH in
CH2Cl2 at ꢀ788C gave a 14.4:1 mixture of 71 and 72
(entry 5), and the diastereoselectivity was further improved
to 46.4:1 in the presence of ZnCl2 (entry 6). It should be
noted that the selection of a benzyl protecting group for the
C6 alcohol was crucial for the maximum efficiency of these
transformations, particularly in terms of the essentially per-
fect selectivities for its installation and the C7 carbonyl re-
duction.
Scheme 6. Synthesis of functionalized core 5. a) (Boc)2O, Et3N, DMAP,
CH2Cl2, 2 h; b) Bu4NF, THF, 08C, 30 min; c) Dess–Martin periodinane,
CH2Cl2, 24 h; d) NaClO2, NaH2PO4, 2-methyl-2-butene, tBuOH, H2O,
3 h; e) iPrN=C(OtBu)NHiPr, CH2Cl2, 48 h; f) TMSCl, Et4NBr, CH2Cl2,
A
The resulting C7 alcohol was protected as the tert-butyl
carbonate in 96% yield (Scheme 6). The remaining opera-
tions necessary for the construction of the bicyclic core of
zaragozic acids involved adjustment of the oxidation state at
C3. Removal of the silicon-based protecting groups with
Bu4NF afforded diol 74 in 97% yield. The diol 74 was then
converted into a carboxylic acid by two successive oxida-
tions (Dess–Martin periodinane; NaClO2),[39] which was sub-
jected to N,N’-diisopropyl-O-tert-butylisourea[40] to provide
the tri-tert-butyl ester 75 in 96% overall yield without inter-
vening purification. With the bicyclic core successfully func-
tionalized, the deprotection of the C2’ alcohol was then re-
quired, preliminary to installing the full C1 side chain. We
found that the use of TMSBr, generated in situ from TMSCl
and Et4NBr,[41] was effective for this purpose, affording diol
76 in 75% yield without the concomitant loss of other pro-
tecting groups. The oxidation of 76 with Dess–Martin peri-
odinane provided aldehyde 5 in 93% yield and set the stage
for the elongation of the C1 side chain.
08C, 1 h, then room temperature, 20 h; g) Dess–Martin periodinane,
CH2Cl2, 30 min.
readily prepared starting from epoxide 80, an intermediate
used in our first-generation synthesis of zaragozic acid C.[44]
Treatment of 80 with dimethylsulfonium methylide accord-
ing to the Mioskowski–Falck protocol[45] efficiently installed
the desired olefin functionality, affording allyl alcohol 81,
which was acetylated to give allyl acetate 82 in 84% overall
yield [Eq. (7)].
With alkenes 79 and 82 in hand, we then proceeded to in-
vestigate the cross-metathesis reaction (Table 7). Gratifying-
ly, the reaction between alkenes 79 and 82 in the presence
of 5 mol% of the second-generation Grubbs catalyst (83) in
benzene at 708C provided the desired cross-product 87 with
exclusive E stereochemistry in 67% yield, along with dimer
89 and alkene 91 in 8 and 4% yield, respectively (entry 1).
It is apparent from this experiment that alkene 79 was the
8906
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Zaragozic Acids A and C
FULL PAPER
2 equiv coupled with the use of
20 mol% of catalyst improved
the reaction efficiency, provid-
ing 87 in 90% yield (entry 7).
The use of alkene 81 instead of
82 led to the exclusive forma-
tion of the self-metathesis prod-
uct 88 (entry 8), suggesting that
the protecting group at C4’
plays an important role in the
success of this reaction.[48]
Having accomplished the
elongation of the C1 alkyl side chain, the completion of the
total synthesis of zaragozic acid C (2) required only a few
finishing touches. These efforts began with the chemoselec-
tive hydrogenation of the allylic acetate in 87 (Scheme 7). A
survey of a range of conditions revealed that the reaction of
87 in the presence of 5% Pd/BaSO4 under a hydrogen at-
mosphere proceeded without the concomitant reductive
cleavage of the acetoxy group to produce a partially deben-
zylated mixture of hydrogenation products, which upon fur-
ther treatment with 20% Pd(OH)2/C, furnished alcohol 4 in
98% overall yield. The route to 4 constitutes a formal syn-
thesis of zaragozic acid C since it intersects the same inter-
mediate employed by Carreira and Du Bois.[8b] Thus, the
acylation of the hydroxyl group at C6 with (4E,6R)-6-
methyl-9-phenyl-4-nonenoic acid[3e] and global deprotection
first to undergo a reaction with catalyst 83. As might be ex-
pected from the sterically hindered nature of the olefinic
functionality adjacent to the
core system, the dimer 90 aris-
ing from the self-metathesis of
79 was not detected. It should
be noted that the reaction of
alkene 79 with dimer 89 did not
occur under the same condi-
tions, indicating that the prod-
ucts are the result of kinetic
control. Use of 10 mol% of 83
and 2 equiv of alkene 82 did
not increase the yield of the de-
sired product 87 (entries 1 vs 2,
3). A similar result was ob-
tained when Hoveydaꢁs catalyst
(84)[46] was used (entry 4). To
our surprise, Blechertꢁs catalyst
(85)[47] exhibited a significantly
different behavior in this reac-
tion: the reaction proceeded at
608C, affording 87 as a 8:1 E/Z
mixture of olefin isomers in
48% yield, along with dimer 89
and alkene 92 in 6 and 0.4%
yield, respectively (entry 5).
While no improvement was of-
fered only with higher catalyst
loadings (entry 6), increasing
Table 7. Olefin cross-metathesis.
Alkene
[equiv]
Ru catalyst
[mol%]
T
[8C]
Cross-coupling product
Homodimer
Yield [%][b]
Entry
A
E
Yield [%]
E:Z[a]
1[c]
2[d]
3[d]
4
82
82
82
82
82
82
82
81
1.2
1.2
2.0
1.5
1.2
1.2
2.0
2.0
83
83
83
84
85
85
85
85
5
70
70
70
70
60
60
60
80
87
87
87
87
87
87
87
86
67
60
60
62
48
46
90
0
E only
E only
E only
E only
8:1
89
89
89
89
89
89
89
88
8
10
10
4
6
9
10
10
5
5[e]
6[f]
7[f]
8
5
20
20
20
8:1
8:1[g]
–
10
88
[a] Determined by 500 MHz 1H NMR analysis unless otherwise noted. [b] Based on alkene 81 or 82.
[c] Alkene 91 was obtained in 4% yield. [d] Alkene 91 was obtained in 8% yield. [e] Alkene 92 was obtained
in 0.4% yield. [f] Alkene 92 was obtained in 1.5% yield. [g] Based on isolated yields. Mes=2,4,6-trimethylphe-
the amount of alkene 82 to nyl; Cy=cyclohexyl.
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8907

S. Hashimoto et al.
of an allylic oxygen functionality of 87, we elected, for the
manipulation at C3’, to take advantage of a radical cycliza-
tion reaction of a silyl ether that introduces a one-carbon
functional chain at the a-carbon of the allylic alcohol
double bond.[49]
Although, in principle, both stereoisomers (E)-87 and
(Z)-87 could be carried forward, it was more expedient to
work with a homogeneous material. Accordingly, the syn-
thesis commenced with (E)-87 (Scheme 8). While deacetyla-
tion at C4’ with 1.0m solution of DIBALH was accompanied
by some deprotection of the C7 Boc group, the use of a
0.1m solution dramatically improved the reaction, providing
diol 86 in 84% yield. As a prelude to the radical reaction,
diol 86 was converted to silyl ether 94 in 96% yield by treat-
ment with ClSiMe2CH2Br. With regard to the crucial cycli-
zation reaction, when silyl ether 94 was subjected to Nish-
iyama conditions,[48a] namely the addition of a solution of
Bu3SnH and 2,2’-azobisisobutyronitrile (AIBN) to a reflux-
ing benzene solution of 94, the 5-exo product 95 was pro-
duced with complete regio- and stereoselectivity, which then
Scheme 7. Completion of the total synthesis of zaragozic acid C (2). a)
H2, 5% Pd/BaSO4, AcOEt, 10 h; b) H2, 20% Pd(OH)2/C, AcOEt, 1 h.
[50]
with trifluoroacetic acid (TFA) completed the total synthesis
underwent a Tamao oxidation to give triol 96 in 85%
of zaragozic acid C (2).
yield in two steps. The stereochemical assignment of the
newly formed stereocenter was established by H NOE ex-
1
Total synthesis of zaragozic acid A: Since the route to zara-
gozic acid C (2) described above is, in principle, readily ap-
plicable to side chain congeners, we next addressed the syn-
thesis of zaragozic acid A (1). As the only difference in
carbon framework between zaragozic acids A (1) and C (2)
resides at C3’, alkene 87 was anticipated to serve as a
common intermediate for the synthesis of 1. On inspection
periments using the acetonide 97 derived from 96: the vici-
nal coupling constants (J3’,4’ =10.4 Hz and J3’,14’ax =11.4 Hz)
indicated that the 1,3-dioxane ring would adopt the chair
conformation in which both C3’-H and C4’-H are axially dis-
posed. To avoid concomitant hydrogenation of the C3’
olefin at the end of the synthesis, the benzyl protecting
group in 96 should be removed at this stage. Thus benzyl
Scheme 8. Conversion of alkene (E)-87 to zaragozic acid A (1). a) DIBALH, toluene/CH2Cl2 7:2, ꢀ788C, 1 h; b) ClSiMe2CH2Br, Et3N, DMAP, CH2Cl2,
08C, 1 h; c) Bu3SnH, AIBN, benzene, reflux, 4 h; d) 35% aq. H2O2, NaHCO3, KF, THF/MeOH 1:1, 24 h; e) TsOH, Me2C(OMe)2, 1 h; f) H2, 20%
AHCTREUNG
Pd(OH)2/C, AcOEt, 13 h; g) 2-NO2C6H4SeCN, Bu3P, THF, 30 min; h) Ac2O, DMAP, CH2Cl2, 08C, 30 min; i) 35% aq. H2O2, THF, 4 h; j) 0.2% K2CO3 in
MeOH, 1 h; k) carboxylic acid 102, DCC, DMAP, CH2Cl2, 5 h; l) TFA, CH2Cl2, 16 h. DCC=dicyclohexylcarbodiimide.
8908
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Zaragozic Acids A and C
FULL PAPER
ether 96 was subjected to hydrogenolysis with 20%
Pd(OH)2/C to afford tetraol 98 in 95% yield. The primary
alcohol in 98 was selectively transformed to the 2-nitrophen-
yl selenide under Grieco conditions[51] in preparation for the
installation of the C3’ olefin. After acetylation of the secon-
dary alcohols at C6 and C4’, the exposure of selenide 100 to
aqueous hydrogen peroxide effected an oxidative elimina-
tion to give alkene 101 in 57% yield in three steps. Alcohol
3, obtained by the selective transesterification of the C6 ace-
tate with 0.2% potassium carbonate in MeOH in 80%
yield, was identical in all respects (1H NMR, 13C NMR, IR,
[a]D) with the intermediate reported by Tomooka and co-
workers.[14] We then proceeded to complete the total synthe-
sis by acylation of the hydroxyl group at C6 with (2E,4S,6S)-
4,6-dimethyl-2-octenoic acid (102)[52] followed by global de-
protection with TFA to give the fully synthetic zaragozic
acid A (1) in 81% yield in two steps.
cological investigations is currently underway, and will be
reported in due course.[53]
Experimental Section
General: Melting points were determined on a Büchi 535 digital melting
point apparatus and were uncorrected. Optical rotations were recorded
on a JASCO P-1030 digital polarimeter. Infrared (IR) spectra were re-
corded on a JASCO FT/IR-5300 spectrophotometer and absorbance
bands are reported in wavenumbers (cmꢀ1). Proton nuclear magnetic res-
onance (1H NMR) spectra were recorded on JEOL JNM-AL400
(400 MHz) or Bruker ARX500 (500 MHz) spectrometers with tetrame-
thylsilane (dH 0.00) as an internal standard. Coupling constants (J) are re-
ported in Hertz. Abbreviations of multiplicity are as follows: s, singlet; d,
doublet; t, triplet; q, quartet; m, multiplet; br, broad. Data are presented
as follows: chemical shift, multiplicity, coupling constants, integration and
assignment. Zaragozic acid numbering is used for proton assignments of
all compounds. Carbon nuclear magnetic resonance (13C NMR) spectra
were recorded on JEOL JNM-EX270 (67.8 MHz), JEOL JNM-AL400
(100.6 MHz) or Bruker ARX500 (125.8 MHz) spectrometers with CDCl3
(dC 77.0) as an internal standard. Electron ionization (EI) mass spectra
were recorded on a JEOL JMS-FABmate spectrometer. Fast atom bom-
bardment (FAB) mass spectra were obtained on a JEOL JMS-HX110
spectrometer in the Center for Instrumental Analysis, Hokkaido Univer-
sity.
Conclusion
The stereocontrolled total syntheses of squalene synthase in-
hibitors zaragozic acids A (1) and C (2) have been achieved.
The syntheses required 37 and 30 steps (longest linear se-
quences), respectively, and produced zaragozic acid A (1) in
1.5% overall yield for an average yield of 87% per step,
and zaragozic acid C (2) in 5.7% overall yield for an aver-
age yield of 91% per step. This represents the first total syn-
theses of zaragozic acids that do not involve internal ketali-
Column chromatography was carried out on Kanto silica gel 60 N (40–
50 mm or 63–210 mm) or Merck Kieselgel 60 (40–63 mm or 63–200 mm).
Analytical thin layer chromatography (TLC) was carried out on Merck
Kieselgel 60 F254 plates. Visualization was accomplished with ultraviolet
light and anisaldehyde or phosphomolybdic acid stain, followed by heat-
ing.
Reagents and solvents were purified by standard means or used as re-
ceived unless otherwise noted. Dehydrated stabilizer free THF was pur-
chased from Kanto Chemical Co., Inc. Dichloromethane was distilled
from P2O5, and redistilled from calcium hydride prior to use. Toluene
and benzene were distilled from sodium/benzophenone prior to use.
Chlorotrimethylsilane (TMSCl) and 1,1,1,3,3,3-hexamethyldisilazane
were distilled from calcium hydride. 4 Š molecular sieves was finely
ground in mortar and heated in vacuo at 2208C for 12 h. All reactions
were conducted under an argon atmosphere unless otherwise noted.
zation in constructing the 2,8-dioxabicyclo[3.2.1]octane core
A
structure. The synthetic strategy also features the elongation
of the C1 alkyl side chain through an olefin cross-metathesis
as well as high convergency and flexibility. Our strategy
would enable the synthesis of side chain congeners from late
stage intermediates possessing a completely functionalized
2,8-dioxabicyclo[3.2.1]octane ring system.
G
Materials: 4-Methoxybenzyl trichloroacetimidate,[25a] Dess–Martin peri-
odinane,[54] (E)-3-hexene-2,5-dione (33),[55] di-tert-butyl d-tartrate (47),[35]
4-methoxybenzyl bromide,[56] tert-butyl diazoacetate (9),[57] zinc borohy-
While the carbonyl ylide cycloaddition methodology with
rhodium(ii) catalysts is rapidly becoming recognized as a
powerful means for the construction of highly substituted
oxygen-containing polycycles, a limited number of examples
of the successful application of this chemistry to the com-
plete, total synthesis of natural products, especially in opti-
cally pure form, have been reported to date.[19c,j,n,o] The pres-
ent synthesis attests to the power and vitality of the tandem
reaction sequence in natural product synthesis. It is also
noteworthy that this is the first example of the 1,3-dipolar
cycloaddition of carbonyl ylides generated from a g-acyloxy-
a-diazo ester with an sp3 carbon at the b-position. This sug-
gests, based on our molecular orbital calculations, that the
interaction between HOMO (dipole) and LUMO (dipolaro-
phile) is key to the success of the present reaction and the
observed regioselectivity can also be explained by consider-
ing the orbital coefficients of the FMO. It is also important
to note that the strategy is flexible with other types of ylides
and potentially allows for the introduction of a variety of
nonnatural heteroatomic substituents into the core structure.
The synthesis of such analogues for biological and pharma-
dride [Zn
(BH4)2],[58] N,N’-diisopropyl-O-tert-butylisourea,[40] Blechertꢁs
T
ruthenium catalyst (85),[47] 2-nitrophenyl selenocyanate[59] and (2E,4S,6S)-
4,6-dimethyl-2-octenoic acid (102)[52] were prepared according to litera-
ture procedures.
Methyl (2R,3R)-3,4-(dimethylmethylenedioxy)-2-(4-methoxybenzyl)oxy-
butanoate (13): Ph3CBF4 (94 mg, 0.284 mmol) was added to a stirred so-
lution of alcohol 12[24] (1.8 g, 9.47 mmol) and 4-methoxybenzyl trichloro-
acetimidate (4.0 g, 14.16 mmol) in Et2O (80 mL) at 08C. After stirring for
30 min, the reaction was quenched with saturated aqueous NaHCO3
(80 mL), and the mixture was extracted with AcOEt (40 mL). The organ-
ic extract was washed with brine (80 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(6.5 g), which was purified by column chromatography (silica gel 150 g,
n-hexane/AcOEt 15:1) to give MPM ether 13 (2.73 g, 93%) as a colorless
oil. [a]2D0 =+48.8 (c=2.02 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
1.32 (s, 3H; acetonide CH3), 1.40 (s, 3H; acetonide CH3), 3.75 (s, 3H;
CO2CH3), 3.79 (s, 3H; C6H4OCH3), 3.93 (d, J=6.7 Hz, 1H; C4-H), 3.95
(dd, J=4.9, 8.7 Hz, 1H; OCHH), 4.03 (dd, J=6.3, 8.7 Hz, 1H; OCHH),
4.31 (ddd, J=4.9, 6.3, 6.7 Hz, 1H; C3-H), 4.42 (d, J=11.3 Hz, 1H;
OCHAr), 4.59 (d, J=11.3 Hz, 1H; OCHAr), 6.87 (m, 2H; ArH), 7.25
(m, 2H; ArH); 13C NMR (67.8 MHz, CDCl3): d=25.3, 26.6, 52.0, 55.3,
66.4, 72.6, 75.9, 77.2, 78.8, 109.9, 113.8, 128.9, 129.8, 159.5, 171.0; IR
(film): n˜ =2990, 2953, 1748, 1613, 1586, 1514, 1458, 1439, 1373, 1302,
Chem. Eur. J. 2006, 12, 8898 – 8925
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8909

S. Hashimoto et al.
1252, 1221 cmꢀ1; HR-MS (EI): m/z: calcd for C16H22O6: 310.1416, found:
310.1414 [M +].
Methyl (2R,3R)-4-(tert-butyldiphenylsilyl)oxy-2-(4-methoxybenzyl)oxy-3-
[3-(methoxymethoxy)propionyl]oxybutanoate (17): EDCI (1.36 g,
7.11 mmol) was added to a solution of alcohol 15 (2.34 g, 4.60 mmol), car-
boxylic acid 16 (681 mg, 5.08 mmol) and DMAP (808 mg, 6.60 mmol) in
CH2Cl2 (20 mL) at 08C. After stirring at room temperature for 12 h, the
reaction was quenched with 10% aqueous HCl (50 mL), and the mixture
was extracted with AcOEt (50 mL). The organic extract was successively
washed with saturated aqueous NaHCO3 (50 mL) and brine (50 mL), and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo fur-
nished the crude product (3.2 g), which was purified by column chroma-
tography (silica gel 60 g, n-hexane/AcOEt 7:1) to give ester 17 (2.30 g,
80%) as a colorless oil. [a]2D3 =+8.36 (c=2.25 in CHCl3); 1H NMR
Methyl (2R,3R)-3,4-dihydroxy-2-(4-methoxybenzyl)oxybutanoate (14):
10% Aqueous HCl (10 mL) was added to a solution of acetonide 13
(2.09 g, 6.75 mmol) in THF (20 mL) at 08C. After stirring at room tem-
perature for 5 h, the mixture was extracted with AcOEt (2”50 mL). The
combined organic extracts were successively washed with saturated aque-
ous NaHCO3 (30 mL) and brine (30 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(2.1 g), which was purified by column chromatography (silica gel 50 g, n-
hexane/AcOEt 1:1) to give diol 14 (1.64 g, 90%) as a colorless oil. [a]D21
=
+59.6 (c=2.03 in CHCl3); 1H NMR (500 MHz, CDCl3): d=3.67 (dd, J=
4.3, 11.6 Hz, 1H; OCHH), 3.70 (dd, J=4.6, 11.6 Hz, 1H; OCHH), 3.78
(s, 3H; CO2CH3), 3.81 (s, 3H; C6H4OCH3), 3.95 (ddd, J=4.3, 4.6, 5.6 Hz,
1H; C3-H), 4.08 (d, J=5.6 Hz, 1H; C4-H), 4.40 (d, J=11.1 Hz, 1H;
OCHAr), 4.67 (d, J=11.1 Hz, 1H; OCHAr), 6.88 (m, 2H; ArH), 7.26
(m, 2H; ArH); 13C NMR (67.8 MHz, CDCl3): d=52.1, 55.2, 62.8, 71.9,
72.7, 78.9, 113.8, 128.8, 129.8, 130.1, 159.5, 171.6; IR (film): n˜ =3461,
(500 MHz, CDCl3): d=1.02 (s, 9H; SiC(CH3)3), 2.52 (t, J=6.5 Hz, 2H;
A
C1’-H2), 3.31 (s, 3H; OCH3), 3.69 (s, 3H; CO2CH3), 3.73 (t, J=6.5 Hz,
2H; C2’-H2), 3.79 (s, 3H; C6H4OCH3), 3.84 (dd, J=4.7, 11.1 Hz, 1H;
CHOTBDPS), 3.89 (dd, J=5.4, 11.1 Hz, 1H; CHOTBDPS), 4.28 (d, J=
5.6 Hz, 1H; C4-H), 4.42 (d, J=11.3 Hz, 1H; OCHAr), 4.62 (s, 2H;
OCH2O), 4.66 (d, J=11.3 Hz, 1H; OCHAr), 5.31 (ddd, J=4.7, 5.4,
5.6 Hz, 1H; C3-H), 6.83 (m, 2H; ArH), 7.24 (m, 2H; ArH), 7.35–7.41
(m, 6H; ArH), 7.62–7.65 (m, 4H; ArH); 13C NMR (125.8 MHz, CDCl3):
d=19.2, 26.7, 34.9, 52.1, 52.2, 55.2, 61.5, 62.9, 72.6, 73.9, 76.0, 96.4, 113.8,
127.6, 127.7, 129.1, 129.7, 133.0, 133.2, 135.5, 135.6, 159.4, 170.3; IR
(film): n˜ =2953, 2888, 2859, 1750, 1613, 1588, 1514, 1464, 1429, 1391,
2953, 2839, 1732, 1613, 1588, 1514, 1441, 1397, 1248, 1105, 1033 cmꢀ1
HR-MS (EI): m/z: calcd for C13H18O6: 270.1103, found: 270.1094 [M +].
Methyl (2R,3R)-4-(tert-butyldiphenysilyl)oxy-3-hydroxy-2-(4-methoxy-
;
benzyl)oxybutanoate (15): TBDPSCl (1.63 mL, 6.27 mmol) was added to
a stirred solution of diol 14 (1.54 g, 5.70 mmol) and imidazole (970 mg,
14.3 mmol) in CH2Cl2 (15 mL) at 08C. After stirring for 1 h, the reaction
was quenched by addition of H2O (15 mL), and the mixture was extract-
ed with AcOEt (30 mL). The organic extract was washed with brine
(15 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (3.6 g), which was purified by column
chromatography (silica gel 40 g, n-hexane/AcOEt 6:1) to give TBDPS
1362, 1302, 1250, 1175, 1105 cmꢀ1
; HR-MS (FAB): m/z: calcd for
C34H44O9SiNa: 647.2652, found: 647.2672 [M ++Na].
Methyl (2R,3R)-4-(tert-butyldiphenylsilyl)oxy-2-hydroxy-3-[3-(methoxy-
methoxy)propionyl]oxybutanoate (18): DDQ (1.65 g, 7.28 mmol) was
added to a stirred biphasic mixture of MPM ether 17 (1.3 g, 2.08 mmol)
in CH2Cl2 (25 mL)/pH 7 phosphate buffer (2.5 mL). After stirring for
24 h, the reaction mixture was diluted with AcOEt (30 mL) and passed
through a Celite pad. The filtrate was successively washed with saturated
aqueous NaHCO3 (40 mL) and brine (40 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(1.5 g), which was purified by column chromatography (silica gel 80 g, n-
hexane/AcOEt 3:1) to give alcohol 18 (1.04 g, 99%) as a colorless oil.
ether 15 (2.49 g, 86%) as
a
colorless oil. [a]2D7 =+12.1 (c=2.39 in
(CH3)3), 2.56
CHCl3); 1H NMR (500 MHz, CDCl3): d=1.05 (s, 9H; SiC
AHCTREUNG
(d, J=6.9 Hz, 1H; OH), 3.73 (s, 3H; CO2CH3), 3.78 (s, 3H; C6H4OCH3),
3.79 (d, J=4.4 Hz, 2H; CH2OTBDPS), 3.96 (ddt, J=6.8, 6.9, 4.4 Hz, 1H;
C3-H), 4.09 (d, J=6.8 Hz, 1H; C4-H), 4.34 (d, J=11.1 Hz, 1H;
OCHAr), 4.57 (d, J=11.1 Hz, 1H; OCHAr), 6.83 (m, 2H; ArH), 7.18
(m, 2H; ArH), 7.35–7.44 (m, 6H; ArH), 7.63–7.64 (m, 4H; ArH);
13C NMR (125.8 MHz, CDCl3): d=19.2, 26.8, 51.9, 55.2, 63.8, 72.3, 72.4,
78.3, 113.8, 127.7, 129.0, 129.7, 129.8, 132.9, 133.0, 135.5, 159.4, 171.5; IR
(film): n˜ =3493, 3071, 3048, 3000, 2953, 2890, 2858, 1748, 1613, 1588,
1514, 1464, 1429, 1393, 1250, 1113, 1036 cmꢀ1; HR-MS (FAB): m/z: calcd
for C29H36O6SiNa: 531.2179, found: 531.2195 [M ++Na].
1
[a]2D0 =ꢀ29.0 (c=2.00 in CHCl3); H NMR (500 MHz, CDCl3): d=1.04 (s,
9H; SiC(CH3)3), 2.59 (dt, J=16.2, 6.1 Hz, 1H; C1’-H), 2.60 (dt, J=16.2,
G
6.1 Hz, 1H; C1’-H), 3.32 (s, 3H; OCH3), 3.35 (d, J=6.6 Hz, 1H; OH),
3.74 (s, 3H; CO2CH3), 3.78 (t, J=6.1 Hz, 2H; C2’-H2), 3.80 (dd, J=5.7,
10.8 Hz, 1H; CHOTBDPS), 3.86 (dd, J=6.4, 10.8 Hz, 1H; CHOTBDPS),
4.49 (dd, J=3.3, 6.6 Hz, 1H; C4-H), 4.59 (s, 2H; OCH2O), 5.33 (ddd, J=
3.3, 5.7, 6.4 Hz, 1H; C3-H), 7.39–7.44 (m, 6H; ArH), 7.64–7.67 (m, 4H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=19.1, 26.6, 35.0, 52.6, 55.2, 61.4,
63.0, 70.2, 74.5, 96.4, 127.7, 129.8, 132.69, 132.72, 135.4, 135.5, 170.6,
172.2; IR (film): n˜ =3470, 2955, 2934, 2890, 2859, 1746, 1472, 1429, 1391,
1364, 1263, 1213, 1179, 1148, 1113 cmꢀ1; HR-MS (FAB): m/z: calcd for
C26H37O8Si: 505.2258, found: 505.2263 [M ++H]; elemental analysis calcd
(%) for C26H36O8Si (504.6): C 61.88, H 7.19; found: C 61.86, H 7.05.
3-(Methoxymethoxy)propionic acid (16): P2O5 (100 g, 0.70 mol) was
added in ten portions to a stirred solution of methyl 3-hydroxypropio-
nate[27] (47.3 g, 0.45 mol) in dimethoxymethane (200 mL, 2.26 mol) and
CHCl3 (200 mL) at 08C. After stirring at room temperature for 10 h, the
reaction mixture was poured into an ice-cooled, two-layer mixture of
Et2O (50 mL) and saturated aqueous Na2CO3 (600 mL), and the mixture
was extracted with AcOEt (800 mL). The organic extract was successive-
ly washed with saturated aqueous NaHCO3 (300 mL) and brine (2”
300 mL), and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (55.6 g), which was used without fur-
ther purification.
Methyl (R)-4-(tert-butyldiphenylsilyl)oxy-3-[3-(methoxymethoxy)propio-
nyl]oxy-2-oxobutanoate (19): Dess–Martin periodinane (1.43 g,
3.36 mmol) was added to
a stirred solution of alcohol 18 (1.55 g,
3.07 mmol) in CH2Cl2 (20 mL). After stirring for 1 h, the reaction mixture
was poured into an ice-cooled mixture of saturated aqueous NaHCO3
(15 mL) and 10% aqueous Na2S2O3·H2O (10 mL), and the whole was ex-
tracted with AcOEt (20 mL). The organic extract was washed with brine
(30 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (1.9 g), which was purified by column
chromatography (silica gel 30 g, n-hexane/AcOEt 3:1) to give a-keto
ester 19 (1.49 g, 97%) as a colorless oil. [a]2D0 =ꢀ14.6 (c=2.05 in CHCl3);
Lithium hydroxide monohydrate (23.1 g, 0.55 mol) was added to a stirred
solution of the crude methyl ester (55.6 g) in THF (300 mL)/H2O
(150 mL). After stirring for 2 h, THF was removed in vacuo, and the re-
sultant mixture was acidified with 10% aqueous HCl (250 mL). The mix-
ture was saturated with NaCl and extracted with AcOEt (6”400 mL).
The combined organic extracts were washed with brine (2”500 mL) and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo fur-
nished the crude product (44.1 g), which was purified by distillation to
give carboxylic acid 16 (31.4 g, 52% for two steps) as a colorless oil. B.p.
1388C (13 mmHg); 1H NMR (400 MHz, CDCl3): d=2.66 (t, J=6.1 Hz,
2H; C1’-H2), 3.37 (s, 3H; OCH3), 3.83 (t, J=6.1 Hz, 2H; C2’-H2), 4.64 (s,
2H; OCH2O); 13C NMR (100.6 MHz, CDCl3): d=34.8, 55.1, 62.8, 96.3,
177.2; IR (film): n˜ =3455, 2951, 2893, 2832, 1734, 1404, 1152, 1113,
1H NMR (400 MHz, CDCl3): d=1.00 (s, 9H; SiC
(CH3)3), 2.69 (dt, J=9.0,
C
6.4 Hz, 1H; C1’-H), 2.70 (dt, J=9.0, 6.4 Hz, 1H; C1’-H), 3.34 (s, 3H;
OCH3), 3.79 (dt, J=11.1, 6.4 Hz, 1H; C2’-H), 3.81 (dt, J=11.1, 6.4 Hz,
1H; C2’-H), 3.87 (s, 3H; CO2CH3), 3.99 (dd, J=3.8, 11.3 Hz, 1H;
CHOTBDPS), 4.32 (dd, J=4.7, 11.3 Hz, 1H; CHOTBDPS), 4.62 (s, 2H;
OCH2O), 5.83 (dd, J=3.8, 4.7 Hz, 1H; C3-H), 7.36–7.46 (m, 6H; ArH),
7.62–7.65 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=19.1, 26.5,
26.6, 34.6, 53.0, 55.2, 62.9, 63.1, 77.2, 96.5, 96.6, 127.7, 127.8, 128.0, 129.9,
130.2, 132.3, 132.5, 135.4, 135.6, 160.0, 170.5, 187.6; IR (film): n˜ =3455,
1040 cmꢀ1
; HR-MS (EI): m/z: calcd for C5H9O4: 133.0501, found:
133.0502 [M +ꢀH]; elemental analysis calcd (%) for C5H10O4 (134.1): C
44.77, H 7.51; found: C 44.44, H 7.59.
2934, 2890, 1738, 1472, 1429, 1391, 1364, 1256, 1177, 1113, 1038, 704 cmꢀ1
;
8910
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
HR-MS (FAB): m/z: calcd for C26H35O5Si: 503.2101, found: 503.2129
[M ++H].
0.438 mmol) in THF (2 mL). After stirring for 48 h, the volatile elements
were removed in vacuo. Purification of the residue (162 mg) by column
chromatography (silica gel 10 g, n-hexane/AcOEt 10:1) afforded TMS
ether 22 (129 mg, 91%) as a yellow oil. [a]2D9 =+32.8 (c=1.03 in CHCl3);
4-Ethyl 1-methyl [2R,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-(me-
thoxymethoxy)propionyl]oxyethyl]-3-diazo-2-hydroxybutanedioate (20)
and 4-ethyl 1-methyl [2S,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-
(methoxymethoxy)propionyl]oxyethyl]-3-diazo-2-hydroxybutanedioate
1H NMR (500 MHz, CDCl3): d=0.10 (s, 9H; Si
ACHTREUNG
AHCTREUNG
C1’-H2), 3.32 (s, 3H; OCH3), 3.67 (dd, J=7.7, 11.0 Hz, 1H;
CHOTBDPS), 3.68 (s, 3H; CO2CH3), 3.73 (dt, J=9.9, 6.5 Hz, 1H; C2’-
H), 3.81 (dt, J=9.9, 6.5 Hz, 1H; C2’-H), 3.96 (dd, J=4.0, 11.0 Hz, 1H;
CHOTBDPS), 4.12 (dq, J=11.3, 7.1 Hz, 1H; CO2CHHCH3), 4.13 (dq,
J=11.3, 7.1 Hz, 1H; CO2CHHCH3), 4.58 (s, 2H; OCH2O), 5.90 (dd, J=
4.0, 7.7 Hz, 1H; C3-H), 7.36–7.41 (m, 6H; ArH), 7.63–7.67 (m, 4H;
ArH); 13C NMR (125.8 MHz, CDCl3): d=1.2, 14.2, 19.1, 26.6, 35.0, 52.6,
55.2, 60.9, 62.3, 62.9, 75.2, 75.6, 96.4, 127.6, 127.7, 129.6, 129.7, 133.1,
133.2, 135.5, 135.6, 135.7, 164.2, 169.59, 169.63; IR (film): n˜ =2955, 2890,
2859, 2105, 1755, 1699, 1472, 1429, 1391, 1370, 1306, 1254, 1171,
1150 cmꢀ1; HR-MS (FAB): m/z: calcd for C33H49O10Si2: 661.2864, found:
661.2844 [M +ꢀN2+H].
(21):
A 0.35m solution of lithium bis(trimethylsilyl)amide in THF
(6.26 mL, 2.19 mmol) was added to a stirred mixture of a-keto ester 19
(1.0 g, 1.99 mmol) and ethyl diazoacetate (272 mg, 2.39 mmol) in THF
(20 mL) at ꢀ788C. After stirring for 30 min, the solution was poured into
saturated aqueous NH4Cl (20 mL), and the mixture was extracted with
AcOEt (30 mL). The organic extract was washed with brine (15 mL) and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo fur-
nished the crude product (1.3 g), which was purified by flash column
chromatography (silica gel 20 g, n-hexane/Et2O 2:1) to give a-diazo
esters 20 (467 mg, 38%) and 21 (394 mg, 32%) as yellow oils.
Data for [2R,2(1R)]-isomer 20: [a]2D7 =+17.5 (c=1.45 in CHCl3);
1H NMR (500 MHz, CDCl3): d=1.03 (s, 9H; SiC
(CH3)3), 1.24 (t, J=
A
U
7.3 Hz, 3H; CO2CH2CH3), 2.61 (dt, J=12.6, 6.2 Hz, 1H; C1’-H), 2.63 (dt,
J=12.6, 6.2 Hz, 1H; C1’-H), 3.33 (s, 3H; OCH3), 3.70 (s, 3H; CO2CH3),
3.78 (m, 2H; C2’-H2), 3.90 (dd, J=4.2, 11.2 Hz, 1H; CHOTBDPS), 3.99
(dd, J=6.0, 11.2 Hz, 1H; CHOTBDPS), 4.19 (q, J=7.3 Hz, 2H;
CO2CH2CH3), 4.58 (s, 2H; OCH2O), 5.18 (s, 1H; OH), 5.57 (dd, J=4.2,
6.0 Hz, 1H; C3-H), 7.38–7.45 (m, 6H; ArH), 7.63–7.65 (m, 4H; ArH);
13C NMR (67.8 MHz, CDCl3): d=14.3, 19.1, 26.6, 35.0, 53.5, 55.2, 61.3,
62.5, 62.8, 74.0, 74.6, 96.5, 127.8, 129.9, 132.5, 135.5, 165.8, 170.2, 171.0;
IR (film): n˜ =3463, 2934, 2890, 2859, 2105, 1750, 1699, 1589, 1470, 1429,
2-hydroxy-4-butanolide (24): K2CO3 (91 mg, 0.66 mmol) was added to a
stirred solution of alcohol 21 (101 mg, 0.164 mmol) in MeOH (1.5 mL) at
08C. After stirring for 1 h, the mixture was poured into an ice-cooled,
two-layer mixture of Et2O (5 mL) and H2O (5 mL), and the whole was
extracted with AcOEt (10 mL). The organic extract was washed with
brine (5 mL) and dried over anhydrous Na2SO4. Filtration and evapora-
tion in vacuo furnished the crude product (105 mg), which was purified
by column chromatography (silica gel 10 g, n-hexane/AcOEt 20:1) to
give lactone 24 (52.5 mg, 68%) as a yellow solid. M.p. 107–1088C (yellow
prisms from n-hexane/n-Bu2O 10:1); [a]2D2 =ꢀ55.7 (c=1.03 in CHCl3);
1308, 1111, 706 cmꢀ1
; HR-MS (FAB): m/z: calcd for C30H41O10Si:
589.2469, found: 589.2458 [M +ꢀN2+H].
1H NMR (500 MHz, CDCl3): d=1.06 (s, 9H; SiC
(CH3)3), 1.31 (t, J=
G
Data for [2S,2(1R)]-isomer 21: [a]2D5 =ꢀ21.9 (c=1.11 in CHCl3); H NMR
1
7.2 Hz, 3H; CO2CH2CH3), 3.90 (dd, J=4.0, 9.4 Hz, 1H; one of lactone
CH2), 4.03 (dd, J=4.7, 9.4 Hz, 1H; one of lactone CH2), 4.25 (dq, J=
10.7, 7.2 Hz, 1H; CO2CHHCH3), 4.29 (dq, J=10.7, 7.2 Hz, 1H;
CO2CHHCH3), 4.50 (dd, J=4.0, 4.7 Hz, 1H; C3-H), 7.41–7.48 (m, 6H;
ArH), 7.61–7.63 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=14.4,
19.1, 26.6, 61.5, 71.9, 76.0, 76.1, 76.3, 76.8, 77.2, 127.9, 128.0, 128.1, 130.38,
130.42, 131.6, 132.7, 135.5, 135.6, 166.6, 172.6; IR (CHCl3): n˜ =3021, 2114,
1790, 1686, 1472, 1427, 1395, 1373, 1327, 1181, 1152 cmꢀ1; HR-MS (FAB):
m/z: calcd for C24H29N2O6Si: 469.1795, found: 469.1778 [M ++H].
(500 MHz, CDCl3): d=1.02 (s, 9H; SiC(CH3)3), 1.23 (t, J=7.1 Hz, 3H;
G
CO2CH2CH3), 2.58 (dt, J=10.7, 6.4 Hz, 1H; C1’-H), 2.59 (dt, J=10.7,
6.4 Hz, 1H; C1’-H), 3.32 (s, 3H; OCH3), 3.75 (m, 2H; C2’-H2), 3.76 (s,
3H; CO2CH3), 3.90 (dd, J=6.1, 11.3 Hz, 1H; CHOTBDPS), 3.98 (dd, J=
4.2, 11.3 Hz, 1H; CHOTBDPS), 4.17 (dq, J=10.6, 7.1 Hz, 1H;
CO2CHHCH3), 4.20 (dq, J=10.6, 7.1 Hz, 1H; CO2CHHCH3), 4.59 (s,
2H; OCH2O), 4.85 (s, 1H; OH), 5.73 (dd, J=4.2, 6.1 Hz, 1H; C3-H),
7.37–7.45 (m, 6H; ArH), 7.63–7.66 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=14.2, 19.0, 26.6, 34.9, 53.4, 55.2, 61.2, 62.3, 62.8, 73.3, 73.9,
96.4, 127.8, 129.8, 132.4, 132.6, 135.45, 135.54, 165.1, 169.8, 171.1; IR
(film): n˜ =3466, 2934, 2890, 2859, 2106, 1752, 1699, 1472, 1429, 1393,
1370, 1307, 1113, 756 cmꢀ1; HR-MS (FAB): m/z: calcd for C30H41O10Si:
589.2469, found: 589.2463 [M +ꢀN2+H].
AHCTREUNG
0.672 mmol) was added to a stirred solution of alcohol 24 (52.5 mg,
0.112 mmol) in CH2Cl2 (1 mL). After stirring for 12 h, the mixture was
evaporated in vacuo. Purification of the residue by column chromatogra-
phy (silica gel 5 g, n-hexane/AcOEt 20:1) afforded TMS ether 25
4-Ethyl 1-methyl [2R,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-(me-
thoxymethoxy)propionyl]oxyethyl]-3-diazo-2-(trimethylsilyl)oxybutane-
dioate (11): HMDS (0.18 mL, 0.818 mmol) was added to a stirred solu-
tion of a-diazo ester 20 (119 mg, 0.193 mmol) and imidazole (28 mg,
0.408 mmol) in THF (2 mL). After stirring for 48 h, the volatile elements
were removed in vacuo. Purification of the residue (150 mg) by column
chromatography (silica gel 10 g, n-hexane/AcOEt 10:1) afforded TMS
ether 11 (122 mg, 92%) as a yellow oil. [a]2D5 =ꢀ17.1 (c=1.04 in CHCl3);
(58.7 mg, 97%) as
a
yellow oil. [a]D22 =ꢀ9.62 (c=2.94 in CHCl3);
1H NMR (500 MHz, CDCl3): d=0.17 (s, 9H; Si
(CH3)3), 1.04 (s, 9H; SiC-
A
A
1H; Hb of lactone CH2), 3.92 (dd, J=4.9, 9.2 Hz, 1H; Ha of lactone
CH2), 4.19 (dq, J=10.5, 7.0 Hz, 1H; CO2CHHCH3), 4.20 (dq, J=10.5,
7.0 Hz, 1H; CO2CHHCH3), 4.55 (dd, J=4.5, 4.9 Hz, 1H; C3-H), 7.39–
7.48 (m, 6H; ArH), 7.62–7.66 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=0.8, 14.4, 19.1, 26.6, 61.1, 71.1, 77.3, 127.9, 128.0, 130.2, 130.3,
131.8, 133.0, 135.5, 135.7, 164.9, 172.3; IR (film): n˜ =2961, 2934, 2899,
2108, 1786, 1701, 1472, 1429, 1392, 1372, 1318, 1256, 1219, 1188,
1H NMR (500 MHz, CDCl3): d=0.08 (s, 9H; Si
ACHTREUNG
ACHTREUNG
1H; C1’-H), 2.64 (dt, J=16.0, 6.5 Hz, 1H; C1’-H), 3.34 (s, 3H; OCH3),
3.62 (s, 3H; CO2CH3), 3.76–3.81 (m, 2H; C2’-H2), 3.80 (dd, J=7.6,
11.1 Hz, 1H; CHOTBDPS), 3.85 (dd, J=3.7, 11.1 Hz, 1H; CHOTBDPS),
4.16 (dq, J=10.3, 7.1 Hz, 1H; CO2CHHCH3), 4.17 (dq, J=10.3, 7.1 Hz,
1H; CO2CHHCH3), 4.59 (s, 2H; OCH2O), 5.70 (dd, J=3.7, 7.6 Hz, 1H;
C3-H), 7.38–7.42 (m, 6H; ArH), 7.63–7.67 (m, 4H; ArH); 13C NMR
(67.8 MHz, CDCl3): d=1.0, 14.4, 19.1, 26.6, 35.0, 52.8, 55.2, 61.0, 62.5,
62.8, 76.7, 77.2, 96.4, 127.7, 129.6, 129.7, 133.0, 133.2, 135.5, 135.6, 164.3,
169.2, 170.1; IR (film): n˜ =2955, 2892, 2859, 2103, 1755, 1703, 1466, 1429,
1391, 1370, 1304, 1254, 1113, 1036, 847 cmꢀ1; HR-MS (FAB): m/z: calcd
for C33H49O10Si2: 661.2864, found: 661.2885 [M +ꢀN2+H].
1115 cmꢀ1
found: 541.2195 [M ++H].
(2R,3R)-3-(tert-Butyldiphenylsilyl)oxy-2-[diazo(ethoxycarbonyl)methyl]-
; HR-MS (FAB): m/z: calcd for C27H37N2O6Si2: 541.2190,
AHCTREUNG
2-(trimethylsilyl)oxy-4-butanolide (27): K2CO3 (51 mg, 0.37 mmol) was
added to a stirred solution of alcohol 20 (52 mg, 0.084 mmol) in MeOH
(1 mL) at 08C. After stirring for 1 h, the mixture was poured into an ice-
cooled, two-layer mixture of Et2O (5 mL) and H2O (5 mL), and the
whole was extracted with AcOEt (10 mL). The organic extract was
washed with brine (5 mL) and dried over anhydrous Na2SO4. Filtration
and evaporation in vacuo furnished the crude lactone 26 (23.3 mg), which
was used without further purification.
4-Ethyl 1-methyl [2S,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-(me-
thoxymethoxy)propionyl]oxyethyl]-3-diazo-2-(trimethylsilyl)oxybutane-
dioate (22): HMDS (0.19 mL, 0.876 mmol) was added to a stirred solu-
tion of a-diazo ester 21 (127 mg, 0.206 mmol) and imidazole (30 mg,
TMS-imidazole (0.02 mL, 0.149 mmol) was added to a stirred solution of
the crude lactone 26 (23.3 mg) in CH2Cl2 (0.5 mL). After stirring for
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8911

S. Hashimoto et al.
20 h, the mixture was evaporated in vacuo. Purification of the residue by
column chromatography (silica gel 5 g, n-hexane/AcOEt 20:1) afforded
TMS ether 27 (21.8 mg, 48% for two steps) as a yellow oil. [a]1D9 =+17.0
(c=1.08 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.26 (s, 9H; Si-
5-Ethyl 4-methyl (1S,3R,4S,5R,6R,7S)-6,7-diacetyl-3-[(tert-butyldiphenyl-
silyl)oxymethyl]-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-
dioxabicyclo[3.2.1]octane-4,5-dicarboxylate (34): The tandem carbonyl
A
ylide formation/1,3-dipolar cycloaddition reaction was performed accord-
ing to the typical procedure (23 mL benzene, reflux, 1 h) employing a-
diazo ester 11 (820 mg, 1.19 mmol), (E)-3-hexene-2,5-dione (33, 400 mg,
A
N
3.96 (dq, J=10.7, 7.3 Hz, 1H; CO2CHHCH3), 3.98 (dq, J=10.7, 7.3 Hz,
1H; CO2CHHCH3), 4.04 (dd, J=6.0, 8.9 Hz, 1H; Hb of lactone CH2),
4.20 (dd, J=5.7, 8.9 Hz, 1H; Ha of lactone CH2), 4.59 (dd, J=5.7, 6.0 Hz,
1H; C3-H), 7.38–7.45 (m, 6H; ArH), 7.62–7.66 (m, 4H; ArH); 13C NMR
(67.8 MHz, CDCl3): d=0.8, 14.1, 19.3, 26.8, 61.0, 70.9, 72.7, 73.9, 77.2,
127.7, 127.9, 130.0, 130.2, 132.5, 133.0, 135.6, 135.7, 163.9, 172.1; IR
(CHCl3): n˜ =3023, 2108, 1794, 1688, 1474, 1427, 1321, 1256, 1221, 1175,
1119 cmꢀ1; HR-MS (FAB): m/z: calcd for C27H36N2O6Si2Na: 563.2010,
found: 563.1992 [M ++Na].
3.57 mmol) and bis
N
N
Purification by flash column chromatography (silica gel 80 g, n-hexane/
AcOEt 4:1) afforded cycloadduct 34 (430 mg, 47%), along with cycload-
duct 35 (284 mg, 31%, dr 4:1), as colorless oils. [a]2D5 =ꢀ20.1 (c=0.39 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.02 (s, 9H; Si
(CH3)3), 1.02 (s,
H
9H; SiC(CH3)3), 1.22 (t, J=7.1 Hz, 3H; CO2CH2CH3), 2.20 (s, 3H;
N
COCH3), 2.31 (s, 3H; COCH3), 2.40 (t, J=6.4 Hz, 2H; C1’-H2), 3.35 (s,
3H; OCH3), 3.46 (d, J=5.7 Hz, 2H; CH2OTBDPS), 3.59 (d, J=6.1 Hz,
1H; C7-H), 3.73 (s, 3H; CO2CH3), 3.76 (dt, J=10.1, 6.4 Hz, 1H; C2’-H),
3.89 (dt, J=10.1, 6.4 Hz, 1H; C2’-H), 4.12 (dq, J=9.4, 7.1 Hz, 1H;
CO2CHHCH3), 4.14 (dq, J=9.4, 7.1 Hz, 1H; CO2CHHCH3), 4.25 (t, J=
5.7 Hz, 1H; C3-H), 4.60 (d, J=6.5 Hz, 1H; one of OCH2O), 4.63 (d, J=
6.5 Hz, 1H; one of OCH2O), 5.19 (d, J=6.1 Hz, 1H; C6-H), 7.37–7.46
(m, 6H; ArH), 7.60–7.63 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3):
d=2.1, 13.6, 19.0, 26.6, 29.4, 30.6, 36.5, 52.4, 55.2, 61.6, 63.1, 63.2, 63.6,
75.7, 77.9, 88.6, 96.7, 105.2, 127.6, 129.6, 132.88, 132.93, 135.4, 167.2,
170.3, 202.3, 206.3; IR (film): n˜ =2955, 2893, 2859, 1753, 1726, 1589, 1472,
1429, 1391, 1360, 1250, 1198, 1111, 1034, 937 cmꢀ1; HR-MS (FAB): m/z:
calcd for C39H56O12Si2: 772.3310, found: 772.3278 [M +].
Typical procedure for tandem carbonyl ylide formation/1,3-dipolar cyclo-
addition reaction of a-diazo ester 11: 5-ethyl 4,6,7-trimethyl
(1S,3R,4S,5R)-3-[(tert-butyldiphenylsilyl)oxymethyl]-1-[2-(methoxyme-
thoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-dioxabicyclo
A
tetracarboxylate (30): solution of a-diazo ester 11 (15.4 mg,
A
0.022 mmol) in benzene (0.6 mL) was added dropwise over 5 min to a re-
fluxing solution of dimethyl acetylenedicarboxylate (29, 9.4 mg,
0.066 mmol) and bis
N
N
in benzene (0.8 mL), and the mixture was stirred for 25 min. After cool-
ing, the volatile elements were removed in vacuo, and the greenish resi-
due (19 mg) was purified by column chromatography (silica gel 5 g, n-
hexane/AcOEt 10:1) to give cycloadduct 30 (11.9 mg, 66%) as a colorless
oil. [a]2D3 =ꢀ42.9 (c=0.60 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
Data for 35: [a]2D2 =ꢀ52.1 (c=1.07 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=0.03 (s, 9H; Si
N
N
ꢀ0.04 (s, 9H; Si
N
N
C6-CH3), 1.31 (t, J=7.1 Hz, 3H; CO2CH2CH3), 2.30 (t, J=7.8 Hz, 2H;
C1’-H2), 2.33 (s, 3H; COCH3), 3.35 (s, 3H; OCH3), 3.52 (dd, J=5.9,
10.8 Hz, 1H; CHOTBDPS), 3.54 (dd, J=5.9, 10.8 Hz, 1H; CHOTBDPS),
3.60 (s, 3H; CO2CH3), 3.72 (dt, J=9.6, 7.8 Hz, 1H; C2’-H), 3.77 (dt, J=
9.6, 7.8 Hz, 1H; C2’-H), 4.22 (dq, J=10.3, 7.1 Hz, 1H; CO2CHHCH3),
4.26 (dq, J=10.3, 7.1 Hz, 1H; CO2CHHCH3), 4.53 (t, J=5.9 Hz, 1H; C3-
H), 4.62 (s, 2H; OCH2O), 6.48 (d, J=15.6 Hz, 1H; =CHCOCH3), 6.95
(d, J=15.6 Hz, 1H; =CH), 7.34–7.45 (m, 6H; ArH), 7.57–7.65 (m, 4H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=2.1, 13.8, 19.1, 25.8, 26.7, 28.5,
35.8, 52.6, 55.1, 62.0, 62.7, 74.4, 77.7, 84.3, 89.4, 96.5, 118.1, 126.2, 127.5,
129.6, 133.0, 133.2, 135.2, 135.4, 143.9, 165.4, 169.2, 197.9; IR (film): n˜ =
2955, 2893, 2859, 1753, 1726, 1589, 1472, 1429, 1391, 1360, 1250, 1198,
CO2CH2CH3), 2.19 (dt, J=15.0, 4.9 Hz, 1H; C1’-H), 2.41 (ddd, J=6.2,
9.2, 15.0 Hz, 1H; C1’-H), 3.28 (s, 3H; OCH3), 3.56 (s, 3H; CO2CH3), 3.63
(ddd, J=4.9, 6.2, 14.4 Hz, 1H; C2’-H), 3.66 (dd, J=5.9, 10.9 Hz, 1H;
CHOTBDPS), 3.70 (dd, J=5.9, 10.9 Hz, 1H; CHOTBDPS), 3.76 (ddd,
J=4.9, 9.2, 14.4 Hz, 1H; C2’-H), 3.82 (s, 6H; 2”CO2CH3), 4.22 (dq, J=
10.7, 7.0 Hz, 1H; CO2CHHCH3), 4.27 (dq, J=10.7, 7.0 Hz, 1H;
CO2CHHCH3), 4.41 (t, J=5.9 Hz, 1H; C3-H), 4.49 (d, J=6.6 Hz, 1H;
one of OCH2O), 4.52 (d, J=6.6 Hz, 1H; one of OCH2O), 7.36–7.41 (m,
6H; ArH), 7.62–7.66 (m, 4H; ArH); 13C NMR (125.8 MHz, CDCl3): d=
2.2, 13.8, 19.3, 26.8, 33.8, 52.1, 52.3, 55.2, 62.0, 62.2, 63.1, 78.1, 78.7, 90.0,
96.4, 109.2, 127.6, 127.7, 129.6, 133.2, 133.6, 135.6, 135.8, 138.3, 141.1,
161.4, 162.8, 165.3, 170.5; IR (film): n˜ =2953, 2890, 2859, 2774, 1732,
1651, 1589, 1435, 1372, 1252, 1200, 1113, 1036, 951 cmꢀ1; HR-MS (FAB):
m/z: calcd for C39H54O14Si2Na: 825.2950, found: 825.2941 [M ++Na].
1111, 1034, 937 cmꢀ1
; HR-MS (FAB): m/z: calcd for C39H57O12Si2:
773.3388, found: 773.3389 [M ++H].
2-Ethyl 1-methyl (1S,2S,3S,4R)-3-(tert-butyldiphenylsilyl)oxy-4-[3-(me-
thoxymethoxy)propionyl]oxy-1-(trimethylsilyl)oxycyclobutane-1,2-dicar-
boxylate (36): A solution of a-diazo ester 22 (16.8 mg, 0.024 mmol) in
benzene (0.5 mL) was added dropwise over 15 min to a refluxing solution
of dimethyl acetylenedicarboxylate (29, 10 mg, 0.072 mmol) and bis-
1-Ethyl 10-methyl (1R,2R,6S,7S,9R,10S)-9-[(tert-butyldiphenylsilyl)oxy-
methyl]-7-[2-(methoxymethoxy)ethyl]-3,5-dioxo-4-phenyl-10-(trimethylsi-
lyl)oxy-4-aza-8,11-dioxatricyclo[5.3.1.02,6]undecane-1,10-dicarboxylate
(32): The tandem carbonyl ylide formation/1,3-dipolar cycloaddition reac-
tion was performed according to the typical procedure (1.8 mL benzene,
reflux, 30 min) employing a-diazo ester 11 (45 mg, 0.065 mmol), N-phe-
A
N
(0.5 mL), and the mixture was stirred for 15 min. After cooling, the vola-
tile elements were removed in vacuo, and the greenish residue (18 mg)
was purified by column chromatography (silica gel 5 g, n-hexane/AcOEt
nylmaleimide (31, 34 mg, 0.196 mmol) and bis
A
ACHTREUNG
flash column chromatography (silica gel 10 g, n-hexane/AcOEt 6:1) to
10:1) to give cyclobutane 36 (8.8 mg, 56%) as a colorless oil. [a]D23
=
give cycloadduct 32 (37.0 mg, 68%) as a colorless oil. [a]2D2 =ꢀ37.9 (c=
+43.9 (c=0.98 in CHCl3); 1H NMR (500 MHz, C6D6): d=0.30 (s, 9H;
Si(CH3)3), 0.94 (t, J=7.1 Hz, 3H; CO2CH2CH3), 1.21 (s, 9H; SiC(CH3)3),
1
1.85 in CHCl3); H NMR (500 MHz, CDCl3): d=ꢀ0.05 (s, 9H; Si
(CH3)3),
A
ACHTREUNG
1.06 (s, 9H; SiC(CH3)3), 1.24 (t, J=7.1 Hz, 3H; CO2CH2CH3), 2.23 (ddd,
N
2.33 (ddd, J=6.3, 10.0, 16.6 Hz, 1H; C1’-H), 2.36 (ddd, J=6.3, 10.0,
16.6 Hz, 1H; C1’-H), 3.18 (s, 3H; OCH3), 3.38 (s, 3H; CO2CH3), 3.63
(ddd, J=6.3, 10.0, 12.8 Hz, 1H; C2’-H), 3.66 (ddd, J=6.3, 10.0, 12.8 Hz,
1H; C2’-H), 3.74 (d, J=8.4 Hz, 1H; C5-H), 3.86 (dq, J=10.7, 7.1 Hz,
1H; CO2CHHCH3), 3.99 (dq, J=10.7, 7.1 Hz, 1H; CO2CHHCH3), 4.45
(s, 2H; OCH2O), 5.33 (dd, J=7.0, 8.4 Hz, 1H; CHOTBDPS), 5.55 (d, J=
7.0 Hz, 1H; C3-H), 7.24–7.28 (m, 6H; ArH), 7.85–7.90 (m, 4H; ArH);
13C NMR (100.6 MHz, CDCl3): d=1.8, 14.1, 19.2, 26.8, 34.4, 52.8, 53.1,
55.2, 60.8, 62.5, 70.2, 75.2, 76.8, 96.4, 127.46, 127.48, 129.7, 133.0, 133.2,
135.6, 167.2, 170.1, 170.7; IR (film): n˜ =2957, 2893, 2861, 1746, 1589,
1471, 1429, 1391, 1370, 1341, 1296, 1250, 1227, 1152, 1111, 1071,
1036 cmꢀ1; HR-MS (FAB): m/z: calcd for C33H49O10Si2: 661.2864, found:
661.2859 [M ++H]; elemental analysis calcd (%) for C33H48O10Si2 (660.9):
C 59.97, H 7.32; found: C 59.94, H 7.28.
J=5.2, 10.2, 15.3 Hz, 1H; C1’-H), 2.39 (ddd, J=5.5, 10.4, 15.3 Hz, 1H;
C1’-H), 3.32 (s, 3H; OCH3), 3.47 (d, J=7.1 Hz, 1H; C7-H), 3.62 (d, J=
5.4 Hz, 2H; CH2OTBDPS), 3.73 (s, 3H; CO2CH3), 3.77 (ddd, J=5.2,
10.4, 15.4 Hz, 1H; C2’-H), 3.90 (ddd, J=5.5, 10.2, 15.4 Hz, 1H; C2’-H),
4.16 (t, J=5.4 Hz, 1H; C3-H), 4.18 (dq, J=10.7, 7.1 Hz, 1H;
CO2CHHCH3), 4.23 (dq, J=10.7, 7.1 Hz, 1H; CO2CHHCH3), 4.59 (s,
2H; OCH2O), 4.75 (d, J=7.1 Hz, 1H; C6-H), 7.20 (m, 2H; ArH), 7.37–
7.46 (m, 9H; ArH), 7.64–7.65 (m, 4H; ArH); 13C NMR (125.8 MHz,
CDCl3): d=2.1, 13.7, 19.2, 26.8, 35.1, 49.4, 51.8, 52.7, 55.2, 62.3, 63.0, 63.2,
76.2, 89.2, 96.6, 106.4, 126.4, 127.7, 127.8, 129.0, 129.2, 129.9, 131.4, 133.0,
133.1, 135.58, 135.64, 165.8, 170.7, 172.6, 173.1; IR (film): n˜ =2955, 2893,
2859, 1759, 1721, 1597, 1501, 1472, 1429, 1389, 1310, 1252, 1202, 1111,
1026, 912 cmꢀ1
856.3161, found: 856.3164 [M ++Na].
; HR-MS (FAB): m/z: calcd for C43H55NO12Si2Na:
8912
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
5-Ethyl 4-methyl (1S,3R,4S,5R)-7-acetyl-3-[(tert-butyldiphenylsilyl)oxy-
methyl]-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-
1113, 1038 cmꢀ1
;
HR-MS (FAB): m/z: calcd for C36H51NO10Si2Na:
736.2949, found: 736.2889 [M ++Na].
Data for (1S,3R,4S,5R,7S)-isomer 46b: [a]2D2 =+3.45 (c=0.54 in EtOH);
dioxabicyclo[3.2.1]oct-6-ene-4,5-dicarboxylate (43): The tandem carbonyl
A
1H NMR (400 MHz, CDCl3): d=0.05 (s, 9H; Si
ACHTREUNG
ylide formation/1,3-dipolar cycloaddition reaction was performed accord-
ing to the typical procedure (2 mL benzene, reflux, 15 min) employing a-
diazo ester 11 (20 mg, 0.029 mmol), 3-butyn-2-one (40, 5.9 mg,
AHCTREUNG
H2), 2.42 (dd, J=11.7, 14.8 Hz, 1H; C6-H), 3.34 (s, 3H; OCH3), 3.38 (dd,
J=5.1, 11.7 Hz, 1H; C7-H), 3.51 (dd, J=5.1, 14.8 Hz, 1H; C6-H), 3.60
(dd, J=5.7, 10.5 Hz, 1H; CHOTBDPS), 3.63 (dd, J=5.7, 10.5 Hz, 1H;
CHOTBDPS), 3.67 (dt, J=10.9, 5.0 Hz, 1H; C2’-H), 3.69 (s, 3H;
CO2CH3), 3.77 (dt, J=10.9, 5.0 Hz, 1H; C2’-H), 4.17 (dq, J=14.2, 7.1 Hz,
1H; CO2CHHCH3), 4.19 (dq, J=14.2, 7.1 Hz, 1H; CO2CHHCH3), 4.60
(d, J=6.5 Hz, 1H; one of OCH2O), 4.61 (d, J=6.5 Hz, 1H; one of
OCH2O), 4.75 (t, J=5.7 Hz, 1H; C3-H), 7.36–7.43 (m, 6H; ArH), 7.65–
7.67 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=2.4, 14.1, 19.3,
26.9, 34.9, 35.1, 36.8, 52.7, 55.5, 62.0, 62.4, 63.0, 75.9, 76.7, 87.1, 96.7,
105.1, 117.5, 127.55, 127.59, 129.5, 129.6, 132.8, 133.1, 135.4, 167.6, 170.2;
IR (film): n˜ =3073, 3050, 2955, 2892, 2859, 2249, 1755, 1464, 1429, 1393,
1319, 1113, 1030 cmꢀ1; HR-MS (FAB): m/z: calcd for C36H51NO10Si2Na:
736.2949, found: 736.2999 [M ++Na].
0.087 mmol) and bis
G
G
Purification by column chromatography (silica gel 3 g, n-hexane/AcOEt
3:1) afforded cycloadduct 43 (17.9 mg, 85%) as a colorless oil. [a]D23
=
ꢀ20.2 (c=0.62 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.09 (s, 9H;
Si
G
E
2.27 (dt, J=15.0, 4.9 Hz, 1H; C1’-H), 2.33 (s, 3H; COCH3), 2.52 (ddd,
J=6.7, 8.9, 15.0 Hz, 1H; C1’-H), 3.27 (s, 3H; OCH3), 3.61 (dd, J=5.3,
10.8 Hz, 1H; CHOTBDPS), 3.61–3.69 (m, 2H; C2’-H2), 3.65 (s, 3H;
CO2CH3), 3.69 (dd, J=6.3, 10.8 Hz, 1H; CHOTBDPS), 4.21 (dd, J=5.3,
6.3 Hz, 1H; C3-H), 4.22 (q, J=7.1 Hz, 2H; CO2CH2CH3), 4.48 (d, J=
6.4 Hz, 1H; one of CH2O), 4.50 (d, J=6.4 Hz, 1H; one of CH2O), 7.13
(s, 1H; C6-H), 7.34–7.41 (m, 6H; ArH), 7.59–7.61 (m, 4H; ArH);
13C NMR (125.8 MHz, CDCl3): d=2.4, 14.0, 19.2, 26.9, 27.9, 29.7, 33.4,
52.5, 55.1, 62.1, 62.4, 62.9, 79.5, 90.0, 96.2, 108.8, 127.6, 129.7, 133.2, 133.3,
135.6, 135.7, 141.6, 141.8, 166.3, 170.8, 194.1; IR (film): n˜ =2955, 2890,
2859, 1759, 1736, 1688, 1250, 1211, 1113, 1026 cmꢀ1; HR-MS (FAB): m/z:
calcd for C37H53O11Si2: 729.3126, found: 729.3153 [M ++H].
Di-tert-butyl
(2S,3S)-2-hydroxy-3-(4-methoxybenzyl)oxybutanedioate
(48): In a flask equipped with a Dean–Stark apparatus whose sidearm
was filled with 4 Š molecular sieves, Bu2SnO (29.0 g, 0.117 mol) was
added to a solution of di-tert-butyl d-tartrate (47, 30.0 g, 0.114 mol) in tol-
uene (300 mL), and the mixture was refluxed for 2 h. After cooling, the
solvent was evaporated in vacuo, and cesium fluoride (35.0 g, 0.228 mol)
was added to the resulting white solid. The mixture was suspended in
DMF (120 mL), and 4-methoxybenzyl bromide (21 mL, 0.148 mol) was
added. After stirring for 10 h, Et2O (200 mL) and water (100 mL) were
added at 08C, and the mixture was extracted with Et2O (2”150 mL). The
combined organic extracts were stirred vigorously with saturated aqueous
NaHCO3 (200 mL) for 2 h, during which time a white precipitate formed.
The mixture was filtered through a Celite pad, and the layers were sepa-
rated. The organic layer was washed with brine (200 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (55.7 g), which was purified by column chromatography
(silica gel 200 g, n-hexane/AcOEt 20:1) to give MPM ether 48 (40.1 g,
92%) as a colorless oil. [a]2D4 =ꢀ49.7 (c=2.17 in CHCl3); 1H NMR
5-Ethyl 4,7-dimethyl (1S,3R,4S,5R)-3-[(tert-butyldiphenylsilyl)oxymeth-
yl]-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-dioxabicyclo-
A
mation/1,3-dipolar cycloaddition reaction was performed according to the
typical procedure (1.4 mL benzene, reflux, 15 min) employing a-diazo
ester 11 (20 mg, 0.029 mmol), methyl propiolate (41, 7.3 mg, 0.087 mmol)
and bis
N
N
by column chromatography (silica gel 4 g, n-hexane/AcOEt 6:1) afforded
cycloadduct 44 (17.7 mg, 82%) as a colorless oil. [a]2D4 =ꢀ23.0 (c=0.69 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.08 (s, 9H; Si
(CH3)3), 1.03 (s,
R
9H; SiC(CH3)3), 1.27 (t, J=7.2 Hz, 3H; CO2CH2CH3), 2.29 (dt, J=14.5,
C
5.0 Hz, 1H; C1’-H), 2.53 (ddd, J=6.9, 8.7, 14.5 Hz, 1H; C1’-H), 3.28 (s,
3H; OCH3), 3.62 (dd, J=5.6, 10.7 Hz, 1H; CHOTBDPS), 3.64–3.74 (m,
2H; C2’-H2), 3.65 (s, 3H; CO2CH3), 3.70 (dd, J=5.6, 10.7 Hz, 1H;
CHOTBDPS), 3.81 (s, 3H; CO2CH3), 4.20 (q, J=7.2 Hz, 2H;
CO2CH2CH3), 4.31 (t, J=5.6 Hz, 1H; C3-H), 4.49 (d, J=6.6 Hz, 1H; one
of CH2O), 4.52 (d, J=6.6 Hz, 1H; one of CH2O), 7.29 (s, 1H; C6-H),
7.35–7.41 (m, 6H; ArH), 7.60–7.62 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=2.4, 14.0, 19.2, 26.8, 33.6, 51.9, 52.5, 55.1, 62.1, 62.4, 63.0, 77.2,
79.5, 90.0, 96.3, 108.4, 127.6, 127.8, 129.7, 133.2, 133.4, 134.8, 135.7, 143.4,
162.8, 166.1, 170.7; IR (film): n˜ =2953, 2890, 2859, 2774, 1732, 1651, 1589,
1435, 1372, 1252, 1200, 1113, 1036, 951 cmꢀ1; HR-MS (FAB): m/z: calcd
for C37H53O12Si2: 745.3076, found: 745.3062 [M ++H].
(400 MHz, CDCl3): d=1.44 (s, 9H; CO2C
A
AHCTREUNG
J=2.3 Hz, 1H; C3-H), 4.39 (d, J=10.9 Hz, 1H; OCHAr), 4.44 (dd, J=
2.3, 8.8 Hz, 1H; C4-H), 4.74 (d, J=10.9 Hz, 1H; OCHAr), 6.85 (m, 2H;
ArH), 7.24 (m, 2H; ArH); 13C NMR (67.8 MHz, CDCl3): d=27.9, 28.1,
55.2, 72.6, 78.6, 82.2, 82.8, 113.7, 129.1, 129.8, 159.4, 168.5, 170.3; IR
(film): n˜ =3499, 2978, 2936, 2839, 1746, 1613, 1588, 1514, 1460, 1395,
1370, 1155, 1098, 1034 cmꢀ1; HR-MS (EI): m/z: calcd for C20H30O7:
382.1992, found: 382.1971 [M +].
tert-Butyl (2S,3R)-2,4-dihydroxy-3-(4-methoxybenzyl)oxybutanoate (50):
A solution of ester 48 (38.0 g, 99.4 mmol) in THF (180 mL) was added to
a 1.69m solution of LiBH4 in THF (100 mL, 169 mmol) at 08C. After stir-
ring at room temperature for 4 h, the mixture was poured into 1n aque-
ous HCl (300 mL) at 08C, and the whole was extracted with AcOEt (2”
300 mL). The combined organic extracts were successively washed with
saturated aqueous NaHCO3 (300 mL) and brine (300 mL), and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude aldehyde (29.1 g), which was used without further purification.
5-Ethyl 4-methyl (1S,3R,4S,5R)-3-[(tert-butyldiphenylsilyl)oxymethyl]-7-
cyano-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-
dioxabicyclo[3.2.1]octane-4,5-dicarboxylate (46): The tandem carbonyl
U
ylide formation/1,3-dipolar cycloaddition reaction was performed accord-
ing to the typical procedure (3 mL benzene, reflux, 15 min) employing a-
diazo ester 11 (100 mg, 0.145 mmol), acrylonitrile (45, 23.1 mg,
0.435 mmol) and bis
N
N
Purification by column chromatography (silica gel 5 g, n-hexane/AcOEt
6:1) afforded cycloadducts 46a (45.9 mg, 44%) and 46b (31.6 mg, 31%)
as colorless oils.
A solution of the crude aldehyde (29.1 g) in THF (180 mL) was added to
a 1.69m solution of LiBH4 in THF (100 mL, 169 mmol) at ꢀ788C. After
stirring for 4 h, the mixture was poured into 1n aqueous HCl (300 mL)
at 08C, and the whole was extracted with AcOEt (2”300 mL). The com-
bined organic extracts were successively washed with saturated aqueous
NaHCO3 (300 mL) and brine (300 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(29.0 g), which was purified by column chromatography (silica gel 300 g,
n-hexane/AcOEt 2:1) to give 1,3-diol 50 (24.5 g, 72%) as a white solid,
along with 1,2-diol 51 (620 mg, 2%) as a white solid.
Data for (1S,3R,4S,5R,7R)-isomer 46a: [a]2D3 =ꢀ10.7 (c=0.59 in CHCl3);
1H NMR (400 MHz, CDCl3): d=0.03 (s, 9H; Si
(CH3)3), 1.03 (s, 9H; SiC-
U
A
1H; C6-H), 2.32–2.47 (m, 2H; C1’-H2), 3.19 (dd, J=5.5, 8.6 Hz, 1H; C7-
H), 3.30 (s, 3H; OCH3), 3.55–3.78 (m, 5H; C6-H, C2’-H2, CH2OTBDPS),
3.67 (s, 3H; CO2CH3), 4.08 (t, J=5.9 Hz, 1H; C3-H), 4.15–4.24 (m, 2H;
CO2CH2CH3), 4.57 (d, J=6.3 Hz, 1H; one of CH2O), 4.60 (d, J=6.3 Hz,
1H; one of CH2O), 7.37–7.47 (m, 6H; ArH), 7.61–7.64 (m, 4H; ArH);
13C NMR (100.6 MHz, CDCl3): d=2.3, 14.1, 19.3, 26.9, 35.4, 36.6, 37.0,
52.6, 55.2, 62.1, 62.2, 63.2, 75.7, 76.9, 86.9, 96.3, 105.9, 119.4, 127.5, 127.6,
129.7, 132.8, 135.39, 135.44, 167.5, 170.3; IR (CHCl3): n˜ =3021, 2957,
2934, 2892, 2861, 2249, 1759, 1732, 1464, 1429, 1393, 1373, 1316, 1285,
Data for 50: M.p. 59.7–63.68C (colorless needles from n-hexane/AcOEt
10:1); [a]2D7 =+10.6 (c=2.05 in benzene); 1H NMR (500 MHz, CDCl3):
d=1.49 (s, 9H; CO2C(CH3)3), 2.46 (brs, 1H; CH2OH), 3.20 (d, J=
A
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8913

S. Hashimoto et al.
7.5 Hz, 1H; C4-OH), 3.76–3.87 (m, 3H; C3-H, CH2OH), 3.79 (s, 3H;
C6H4OCH3), 4.22 (dd, J=1.9, 7.5 Hz, 1H; C4-H), 4.53 (d, J=11.1 Hz,
1H; OCHAr), 4.56 (d, J=11.1 Hz, 1H; OCHAr), 6.86 (m, 2H; ArH),
7.25 (m, 2H; ArH); 13C NMR (125.8 MHz, CDCl3): d=28.0, 55.2, 61.7,
71.9, 72.3, 78.9, 82.8, 113.8, 129.4, 129.9, 159.3, 171.9; IR (Nujol): n˜ =
80.1, 80.3, 81.1, 81.5, 96.4, 100.3, 113.5, 113.6, 127.6, 129.5, 129.55, 129.63,
130.5, 130.6, 133.2, 133.3, 133.5, 135.56, 135.63, 159.0, 170.3, 170.4; IR
(film): n˜ =2936, 1740, 1612, 1514, 1248, 1113, 1080, 1035 cmꢀ1; HR-MS
(FAB): m/z: calcd for C37H50O7SiNa: 657.3224, found: 657.3205 [M +
+Na].
3457, 2978, 2936, 1732, 1613, 1514, 1462, 1370, 1173, 1130, 1084 cmꢀ1
;
tert-Butyl (2S,3R)-4-(tert-butyldiphenylsilyl)oxy-3-hydroxy-2-(tetrahydro-
pyran-2-yl)oxybutanoate (54): DDQ (878 mg, 3.87 mmol) was added to a
stirred biphasic mixture of MPM ether 53 (1.17 g, 1.84 mmol) in CH2Cl2
(20 mL)/pH 7 phosphate buffer (1 mL). After stirring for 2 h, the reaction
mixture was diluted with AcOEt (30 mL) and passed through a Celite
pad. The filtrate was successively washed with saturated aqueous
NaHCO3 (40 mL) and brine (40 mL), and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (1.65 g),
which was purified by column chromatography (silica gel 50 g, n-hexane/
HR-MS (EI): m/z: calcd for C16H24O6: 312.1573, found: 312.1589 [M +];
elemental analysis calcd (%) for C16H24O6 (312.4): C 61.52, H 7.74;
found: C 61.42, H 7.80.
Data for 51: m.p. 79.5–80.58C (colorless needles from n-hexane/AcOEt
10:1); [a]2D1 =ꢀ83.7 (c=1.11 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
1.51 (s, 9H; CO2C(CH3)3), 2.33 (brs, 1H; OH), 2.84 (brs, 1H; OH), 3.64
A
(m, 1H; one of CH2OH), 3.67 (dt, J=4.2, 11.3 Hz, 1H; C4-H), 3.80 (s,
3H; C6H4OCH3), 3.90 (d, J=4.2 Hz, 1H; C3-H), 3.92 (m, 1H; one of
CH2OH), 4.38 (d, J=11.1 Hz, 1H; OCHAr), 4.73 (d, J=11.1 Hz, 1H;
OCHAr), 6.88 (m, 2H; ArH), 7.27 (m, 2H; ArH); 13C NMR (125.8 MHz,
CDCl3): d=28.1, 55.2, 63.6, 72.2, 72.4, 78.6, 82.3, 113.9, 129.0, 129.1,
130.0, 159.6, 169.7; IR (Nujol): n˜ =3443, 2924, 2855, 1744, 1611, 1517,
AcOEt 20:1) to give alcohol 54 (914 mg, 96%) as a colorless oil. [a]D24
=
ꢀ20.8 (c=2.01 in CHCl3); 1H NMR (500 MHz, CDCl3): d=1.067 (s,
4.5H; SiC
A
N
A
N
1464, 1372, 1285, 1221, 1182, 1159, 1140, 1084, 1069, 1049, 1022, 997 cmꢀ1
;
ether CH2), 1.64–1.87 (m, 3H; three of THP ether CH2), 2.41 (d, J=
6.7 Hz, 0.5H; OH), 2.51 (d, J=6.7 Hz, 0.5H; OH), 3.44–3.47 (m, 1H;
one of THP ether OCH2), 3.66 (dd, J=6.9, 10.1 Hz, 0.5H; CHOTBDPS),
3.70 (dd, J=5.9, 9.9 Hz, 0.5H; CHOTBDPS), 3.75 (dd, J=6.4, 10.1 Hz,
0.5H; CHOTBDPS), 3.76 (m, 1H; C3-H), 3.79 (dd, J=6.9, 9.9 Hz, 0.5H;
CHOTBDPS), 4.00 (m, 0.5H; one of THP ether OCH2), 4.08 (ddd, J=
2.5, 7.1, 9.1 Hz, 0.5H; one of THP ether OCH2), 4.23 (d, J=3.8 Hz,
0.5H; C4-H), 4.47 (d, J=2.7 Hz, 0.5H; C4-H), 4.74 (t, J=3.1 Hz, 0.5H;
THP ether OCHO), 4.83 (t, J=2.5 Hz, 0.5H; THP ether OCHO), 7.36–
7.43 (m, 6H; ArH), 7.65–7.69 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=18.6, 18.8, 19.2, 25.2, 25.3, 26.8, 27.9, 28.1, 30.0, 30.1, 61.8,
62.1, 63.5, 64.3, 72.7, 72.8, 73.0, 77.1, 77.2, 81.5, 81.9, 96.5, 100.2, 127.6,
127.7, 129.7, 129.8, 133.06, 133.10, 133.2, 133.4, 135.5, 135.6, 170.2, 170.4;
IR (film): n˜ =3482, 3071, 1741, 1514, 1472, 1370, 1244, 1113 cmꢀ1; HR-
MS (FAB): m/z: calcd for C29H43O6Si: 515.2829, found: 515.2802 [M +
+H]; elemental analysis calcd (%) for C29H42O6Si (514.7): C 67.54, H
8.40; found: C 67.74, H 8.26.
HR-MS (FAB): m/z: calcd for C16H25O6: 313.1651, found: 313.1642 [M +
+H]; elemental analysis calcd (%) for C16H24O6 (312.4): C 61.52, H 7.74;
found: C 61.41, H 7.69.
tert-Butyl (2S,3R)-4-(tert-butyldiphenylsilyl)oxy-2-hydroxy-3-(4-methoxy-
benzyl)oxybutanoate (52): TBDPSCl (1.2 mL, 4.62 mmol) was added to a
stirred solution of diol 50 (1.31 g, 4.20 mmol) and imidazole (715 mg,
10.5 mmol) in CH2Cl2 (20 mL) at 08C. After stirring for 30 min, the reac-
tion was quenched with H2O (20 mL), and the mixture was extracted
with AcOEt (30 mL). The organic extract was washed with brine (30 mL)
and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (2.75 g), which was purified by column chro-
matography (silica gel 30 g, n-hexane/AcOEt 10:1) to give TBDPS ether
52 (2.24 g, 97%) as a colorless oil. [a]2D2 =ꢀ11.1 (c=2.11 in CHCl3);
1H NMR (400 MHz, CDCl3): d=1.06 (s, 9H; SiC
CO2C
ACHTREUNG
ACHTREUNG
CHOTBDPS), 3.77 (s, 3H; C6H4OCH3), 3.84 (dd, J=5.8, 9.0 Hz, 1H;
CHOTBDPS), 3.85 (ddd, J=3.8, 5.8, 7.3 Hz, 1H; C3-H), 4.31 (dd, J=7.3,
8.1 Hz, 1H; C4-H), 4.35 (d, J=11.1 Hz, 1H; OCHAr), 4.44 (d, J=
11.1 Hz, 1H; OCHAr), 6.79 (m, 2H; ArH), 7.10 (m, 2H; ArH), 7.35–
7.45 (m, 6H; ArH), 7.65–7.68 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=19.1, 26.8, 28.1, 55.2, 62.4, 70.7, 72.9, 79.9, 82.3, 113.7, 127.7,
129.3, 129.7, 130.1, 133.2, 133.4, 135.6, 159.2, 172.5; IR (film): n˜ =3511,
1736, 1514, 1300, 1250, 1173, 1113 cmꢀ1; HR-MS (FAB): m/z: calcd for
C32H43O6Si: 551.2830, found: 551.2814 [M ++H].
tert-Butyl (2S,3R)-4-(tert-butyldiphenylsilyl)oxy-3-[3-(methoxymethoxy)-
propionyl]oxy-2-(tetrahydropyran-2-yl)oxybutanoate (55): EDCI (2.46 g,
12.8 mmol) was added to a solution of alcohol 54 (3.44 g, 6.69 mmol), 3-
(methoxymethoxy)propionic acid (16, 1.08 g, 8.03 mmol) and DMAP
(1.17 g, 12.05 mmol) in CH2Cl2 (60 mL) at 08C. After stirring at room
temperature for 3 h, the reaction was quenched with 10% aqueous HCl
(70 mL), and the mixture was extracted with AcOEt (100 mL). The or-
ganic extract was successively washed with saturated aqueous NaHCO3
(100 mL) and brine (100 mL), and dried over anhydrous Na2SO4. Filtra-
tion and evaporation in vacuo furnished the crude product (4.6 g), which
was purified by column chromatography (silica gel 60 g, n-hexane/AcOEt
10:1) to give 55 (3.42 g, 81%) as a colorless oil. [a]2D1 =ꢀ13.4 (c=2.81 in
tert-Butyl (2S,3R)-4-(tert-butyldiphenylsilyl)oxy-3-(4-methoxybenzyl)oxy-
2-(tetrahydropyran-2-yl)oxybutanoate (53): PPTS (196 mg, 0.78 mmol)
was added to a stirred solution of alcohol 52 (4.27 g, 7.76 mmol) and
DHP (1.4 mL, 15.5 mmol) in CH2Cl2 (50 mL). After stirring for 5 h, the
reaction was quenched with Et3N (5 mL), and the volatile elements were
removed in vacuo. Purification of the residue (6.2 g) by column chroma-
tography (silica gel 80 g, n-hexane/AcOEt 15:1) afforded THP ether 53
CHCl3); 1H NMR (500 MHz, CDCl3) d 1.05 (s, 9H; SiC
9H; CO2C(CH3)3), 1.51 (m, 2H; two of THP ether OCH2), 1.62 (m, 2H;
A
AHCTREUNG
colorless oil. [a]D24 =ꢀ17.1 (c=2.51 in EtOH);
two of THP ether OCH2), 1.72 (m, 2H; two of THP ether OCH2), 2.55–
2.59 (m, 2H; C1’-H2), 3.30 (s, 3H; OCH3), 3.40–3.45 (m, 1H; one of THP
ether OCH2), 3.75 (dt, J=7.8, 5.0 Hz, 1H; one of THP ether OCH2),
3.75–3.78 (m, 2.5H; C2’-H2, CHOTBDPS), 3.82 (dd, J=5.8, 10.4 Hz,
0.5H; CHOTBDPS), 3.90 (dd, J=6.0, 10.7 Hz, 0.5H; CHOTBDPS), 3.98
(m, 0.5H; C2’-H), 4.31 (d, J=4.4 Hz, 0.5H; C4-H), 4.53 (d, J=3.2 Hz,
0.5H; C4-H), 4.55 (s, 1H; one of OCH2O), 4.56 (s, 1H; one of OCH2O),
4.72 (t, J=3.2 Hz, 0.5H; THP ether OCHO), 4.78 (t, J=2.5 Hz, 0.5H;
THP ether OCHO), 5.34 (dt, J=4.4, 6.0 Hz, 0.5H; C3-H), 5.50 (ddd, J=
3.2, 5.8, 6.4 Hz, 0.5H; C3-H), 7.26–7.41 (m, 6H; ArH), 7.66–7.69 (m, 4H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=18.6, 18.8, 19.1, 25.2, 25.3, 26.7,
27.8, 27.9, 30.0, 30.1, 34.8, 55.1, 61.2, 61.8, 62.1, 62.9, 71.8, 73.7, 73.8, 75.9,
77.2, 81.5, 82.0, 96.4, 100.4, 127.6, 127.66, 127.69, 129.66, 129.74, 132.96,
133.01, 133.1, 133.2, 135.5, 168.8, 169.0, 170.3, 170.4; IR (film): n˜ =2935,
1748, 1471, 1429, 1392, 1370, 1282, 1256, 1113 cmꢀ1; HR-MS (FAB): m/z:
calcd for C34H51O9Si: 631.3302, found: 631.3307 [M ++H]; elemental
analysis calcd (%) for C34H50O9Si (630.8): C 64.73, H 7.99; found: C
64.80, H 7.94.
(4.67 g, 95%) as
a
1H NMR (500 MHz, CDCl3): d=1.04 (s, 4.5H; SiC
(CH3)3), 1.05 (s, 4.5H;
A
SiC
A
G
N
1.51–1.60 (m, 3H; three of THP ether CH2), 1.64–1.92 (m, 3H; three of
THP ether CH2), 3.38–3.48 (m, 1H; one of THP ether OCH2), 3.65 (dd,
J=6.1, 10.6 Hz, 0.5H; CHOTBDPS), 3.72–3.75 (m, 1H; C3-H,
CHOTBDPS), 3.75 (s, 1.5H; C6H4OCH3), 3.77 (s, 1.5H; C6H4OCH3),
3.86 (dt, J=11.2, 5.4 Hz, 0.5H; one of THP ether OCH2), 3.91 (dd, J=
6.7, 10.0 Hz, 0.5H; CHOTBDPS), 3.95 (m, 0.5H; C3-H), 3.97 (dd, J=6.7,
10.6 Hz, 0.5H; CHOTBDPS), 4.01 (dt, J=10.9, 3.0 Hz, 0.5H; one of
THP ether OCH2), 4.24 (d, J=5.0 Hz, 0.5H; C4-H), 4.47 (d, J=11.3 Hz,
0.5H; OCHAr), 4.49 (d, J=11.3 Hz, 0.5H; OCHAr), 4.50 (d, J=5.7 Hz,
0.5H; C4-H), 4.51 (d, J=11.3 Hz, 0.5H; OCHAr), 4.56 (d, J=11.3 Hz,
0.5H; OCHAr), 4.77 (t, J=3.0 Hz, 0.5H; THP ether OCHO), 4.80 (t, J=
2.7 Hz, 0.5H; THP ether OCHO), 6.76–6.79 (m, 2H; ArH), 7.13–7.18
(m, 2H; ArH), 7.35–7.42 (m, 6H; ArH), 7.63–7.67 (m, 4H; ArH);
13C NMR (67.8 MHz, CDCl3): d=18.5, 18.8, 19.10, 19.14, 25.3, 25.4, 26.8,
27.9, 28.1, 30.0, 30.1, 55.2, 61.6, 61.9, 62.4, 62.7, 73.0, 73.2, 73.4, 77.2, 77.9,
8914
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
tert-Butyl (2S,3R)-4-(tert-butyldiphenylsilyl)oxy-2-hydroxy-3-[3-(methoxy-
methoxy)propionyl]oxybutanoate (56): p-Toluenesulfonic acid monohy-
drate (94 mg, 0.49 mmol) was added to a stirred solution of THP ether 55
(6.20 g, 9.84 mmol) in MeOH (80 mL). After stirring for 40 min, H2O
(100 mL) was added, and the mixture was extracted with AcOEt (2”
300 mL). The combined organic extracts were washed with brine
(200 mL) and dried over anhydrous Na2SO4. Filtration and evaporation
in vacuo furnished the crude product (5.50 g), which was purified by
column chromatography (silica gel 100 g, n-hexane/AcOEt 6:1) to give
alcohol 56 (4.88 g, 91%) as a colorless oil. [a]2D3 =ꢀ2.61 (c=2.22 in ben-
3052, 2978, 2934, 2890, 2861, 2099, 1746, 1699, 1321, 1254, 1150, 1115,
1047 cmꢀ1; HR-MS (FAB): m/z: calcd for C35H50N2O10SiNa: 709.3132,
found: 709.3149 [M ++Na].
1
Data for [2S,2(1R)]-isomer 58: [a]2D7 =ꢀ30.2 (c=2.62 in CHCl3); H NMR
(400 MHz, CDCl3): d=1.01 (s, 9H; SiC(CH3)3), 1.43 (s, 9H; CO2C-
T
A
N
2H; C1’-H2), 3.31 (s, 3H; OCH3), 3.74 (dt, J=11.9, 6.6 Hz, 1H; C2’-H),
3.76 (dt, J=11.9, 6.6 Hz, 1H; C2’-H), 3.86 (dd, J=7.5, 11.1 Hz, 1H;
CHOTBDPS), 3.95 (dd, J=4.0, 11.1 Hz, 1H; CHOTBDPS), 4.56 (s, 2H;
OCH2O), 5.80 (dd, J=4.0, 7.5 Hz, 1H; C3-H), 7.36–7.42 (m, 6H; ArH),
7.63–7.67 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=19.1, 26.6,
27.6, 28.2, 34.8, 55.2, 62.4, 62.7, 73.5, 73.7, 82.5, 83.9, 96.4, 127.7, 128.0,
129.8, 132.7, 132.8, 135.5, 135.6, 164.5, 169.6, 169.7; IR (film): n˜ =3461,
3073, 3052, 2934, 2890, 2859, 2101, 1748, 1699, 1318, 1256, 1148, 1113,
1046 cmꢀ1; HR-MS (FAB): m/z: calcd for C35H50N2O10SiNa: 709.3132,
found: 709.3124 [M ++Na].
zene); 1H NMR (500 MHz, CDCl3): d=1.05 (s, 9H; SiC
9H; CO2C
ACHTREUNG
ACHTREUNG
1H; OH), 3.29 (s, 3H; OCH3), 3.73 (t, J=6.3 Hz, 2H; C2’-H2), 3.79 (dd,
J=6.5, 10.1 Hz, 1H; CHOTBDPS), 3.85 (dd, J=7.4, 10.1 Hz, 1H;
CHOTBDPS), 4.38 (dd, J=1.8, 7.1 Hz, 1H; C4-H), 4.55 (s, 2H;
OCH2O), 5.39 (ddd, J=1.8, 6.5, 7.4 Hz, 1H; C3-H), 7.32–7.45 (m, 6H;
ArH), 7.65–7.70 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=19.1,
26.7, 27.8, 34.8, 55.1, 61.5, 62.8, 69.5, 73.7, 83.1, 96.4, 127.7, 129.7, 133.0,
133.1, 135.5, 135.6, 170.0, 171.5; IR (film): n˜ =3499, 3073, 2934, 2888,
2859, 1742, 1285, 1256, 1179, 1113, 1044 cmꢀ1; HR-MS (EI): m/z: calcd
for C25H33O8Si: 489.1945, found: 489.1952 [M +ꢀC4H9]; elemental analy-
sis calcd (%) for C29H42O8Si (546.7): C 63.71, H 7.74; found: C 63.88, H
7.71.
Di-tert-butyl [2R,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-(methoxy-
methoxy)propionyl]oxyethyl]-3-diazo-2-(trimethylsilyl)oxybutanedioate
(8): HMDS (3.4 mL, 16.0 mmol) was added to a stirred solution of a-
diazo ester 57 (3.66 g, 5.33 mmol) and imidazole (545 mg, 8.00 mmol) in
THF (40 mL). After stirring for 48 h, the volatile elements were removed
in vacuo. Purification of the residue (4.3 g) by column chromatography
(silica gel 40 g, n-hexane/AcOEt 10:1) afforded TMS ether 8 (3.78 g,
94%) as
(500 MHz, CDCl3): d=0.10 (s, 9H; Si
1.30 (s, 9H; CO2C(CH3)3), 1.47 (s, 9H; CO2C
a
yellow oil. [a]2D6 =+9.53 (c=2.04 in CHCl3); 1H NMR
(CH3)3), 1.00 (s, 9H; SiC(CH3)3),
(CH3)3), 2.61 (dt, J=13.9,
tert-Butyl (R)-4-(tert-butyldiphenylsilyl)oxy-3-[3-(methoxymethoxy)pro-
pionyl]oxy-2-oxobutanoate (10): Dess–Martin periodinane (8.30 g,
N
ACHTREUNG
19.5 mmol) was added to
a stirred solution of alcohol 56 (8.90 g,
G
ACHTREUNG
16.2 mmol) in CH2Cl2 (160 mL). After stirring for 2 h, the reaction mix-
ture was poured into an ice-cooled saturated aqueous NaHCO3 (100 mL)
containing Na2S2O3·H2O (10 g), and the layers were separated. The or-
ganic layer was washed with brine (100 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(9.6 g), which was purified by column chromatography (silica gel 150 g,
n-hexane/AcOEt 6:1) to give a-keto ester 10 (8.60 g, 97%) as a colorless
oil. [a]2D3 =ꢀ6.57 (c=2.15 in CHCl3); 1H NMR (500 MHz, CDCl3): d=
6.8 Hz, 1H; C1’-H), 2.65 (dt, J=13.9, 6.8 Hz, 1H; C1’-H), 3.35 (s, 3H;
OCH3), 3.79 (dt, J=10.0, 6.8 Hz, 1H; C2’-H), 3.81–3.84 (m, 2H;
CH2OTBDPS), 3.82 (dt, J=10.0, 6.8 Hz, 1H; C2’-H), 4.60 (s, 2H;
OCH2O), 5.79 (dd, J=3.8, 7.3 Hz, 1H; C3-H), 7.35–7.41 (m, 6H; ArH),
7.62–7.66 (m, 4H; ArH); 13C NMR (100.6 MHz, CDCl3): d=1.4, 19.1,
26.7, 27.6, 28.3, 35.1, 55.2, 62.80, 62.84, 77.2, 77.8, 82.1, 83.1, 96.4, 127.57,
127.64, 129.5, 129.6, 133.0, 133.1, 135.4, 135.5, 163.5, 167.0, 169.8; IR
(film): n˜ =2934, 2890, 2859, 2097, 1755, 1701, 1370, 1318, 1252, 1148,
1115, 1040 cmꢀ1
; HR-MS (FAB): m/z: calcd for C38H58N2O10Si2Na:
1.01 (s, 9H; SiC
A
G
781.3528, found: 781.3518 [M ++Na].
6.2 Hz, 1H; C1’-H), 2.72 (dt, J=15.4, 6.2 Hz, 1H; C1’-H), 3.34 (s, 3H;
OCH3), 3.80 (dt, J=9.5, 6.2 Hz, 1H; C2’-H), 3.85 (dt, J=9.5, 6.2 Hz, 1H;
C2’-H), 3.98 (dd, J=2.7, 11.4 Hz, 1H; CHOTBDPS), 4.36 (dd, J=4.5,
11.4 Hz, 1H; CHOTBDPS), 4.62 (s, 2H; OCH2O), 5.81 (dd, J=2.7,
4.5 Hz, 1H; C3-H), 7.37–7.45 (m, 6H; ArH), 7.61–7.67 (m, 4H; ArH);
13C NMR (67.8 MHz, CDCl3): d=19.1, 26.5, 27.7, 34.6, 55.1, 62.8, 63.1,
77.1, 84.5, 96.4, 127.6, 127.7, 129.8, 132.3, 132.7, 135.4, 135.5, 159.0, 170.4,
188.1; IR (film): n˜ =3482, 3073, 3052, 2934, 2888, 1748, 1725, 1308, 1256,
1150, 1113, 1036 cmꢀ1; HR-MS (EI): m/z: calcd for C25H31O8Si: 487.1788,
found: 487.1759 [M +ꢀC4H9].
Typical procedure for tandem carbonyl ylide formation/1,3-dipolar cyclo-
addition reaction of a-diazo tert-butyl ester 8: di-tert-butyl
(1S,3R,4S,5R)-7-acetyl-3-[(tert-butyldiphenylsilyl)oxymethyl]-1-[2-(me-
thoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-dioxabicyclo
ACHTREUNG
ene-4,5-dicarboxylate (59): solution of a-diazo ester
A
8
2.04 mmol) in benzene (12 mL) was added dropwise over 15 min to a re-
fluxing solution of 3-butyn-2-one (40, 0.48 mL, 6.13 mmol) and bis-
A
N
and the mixture was stirred for 25 min. After cooling, the volatile ele-
ments were removed in vacuo, and the greenish residue (1.70 g) was puri-
fied by column chromatography (silica gel 40 g, n-hexane/AcOEt 10:1) to
give cycloadduct 59 (1.18 g, 72%) as a colorless oil, along with alcohol 60
(214 mg, 14%, dr 10:1), pyrazole 61 (101 mg, 6%, dr 9:1) and epoxide 62
(81 mg, 6%, dr 4.2:1) as colorless oils. [a]2D0 =ꢀ20.8 (c=1.92 in CHCl3);
Di-tert-butyl [2R,2(1R)]-2-[2-(tert-butyldiphenylsilyl)oxy-1-[3-(methoxy-
methoxy)propionyl]oxyethyl]-3-diazo-2-hydroxybutanedioate (57):
A
1.0m solution of sodium bis(trimethylsilyl)amide in THF (0.6 mL,
0.604 mmol) was added to a stirred solution of a-keto ester 10 (300 mg,
0.549 mmol) and tert-butyl diazoacetate (9, 94 mg, 0.659 mmol) in CH2Cl2
(12 mL) at ꢀ938C. After stirring for 5 min, the reaction mixture was
poured into saturated aqueous NH4Cl (10 mL), and the mixture was ex-
tracted with AcOEt (20 mL). The organic extract was washed with brine
(15 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (402 mg), which was purified by flash
column chromatography (silica gel 20 g, toluene/AcOEt 20:1) to give a-
diazo ester 57 (245 mg, 65%) as a yellow oil, along with isomer 58
(30.5 mg, 8%) as a yellow oil.
1H NMR (500 MHz, CDCl3): d=ꢀ0.05 (s, 9H; Si
ACHTREUNG
SiC
(CH3)3), 1.44 (s, 9H; CO2C
(CH3)3), 1.46 (s, 9H; CO2C
ACHTREUNG
(dt, J=14.9, 4.5 Hz, 1H; C1’-H), 2.37 (s, 3H; COCH3), 2.64 (ddd, J=6.9,
8.9, 14.9 Hz, 1H; C1’-H), 3.30 (s, 3H; OCH3), 3.50 (dd, J=1.9, 11.5 Hz,
1H; CHOTBDPS), 3.64–3.74 (m, 3H; C2’-H2, CHOTBDPS), 4.21 (dd,
J=1.9, 8.0 Hz, 1H; C3-H), 4.51 (d, J=6.4 Hz, 1H; one of OCH2O), 4.54
(d, J=6.4 Hz, 1H; one of OCH2O), 7.15 (s, 1H; C6-H), 7.34–7.40 (m,
6H; ArH), 7.60–7.70 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=
2.5, 19.2, 26.7, 27.7, 27.9, 28.1, 28.2, 33.8, 55.1, 62.7, 64.3, 78.7, 79.7, 82.9,
83.3, 89.7, 96.3, 108.7, 127.5, 127.6, 129.5, 133.2, 133.9, 135.5, 135.8, 141.5,
142.8, 165.3, 169.1, 194.1; IR (film): n˜ =2934, 2890, 2861, 1742, 1688,
Data for 57: [a]2D7 =+33.7 (c=2.14 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=1.01 (s, 9H; SiC
N
N
9H; CO2C(CH3)3), 2.65 (dt, J=12.9, 6.4 Hz, 1H; C1’-H), 2.69 (dt, J=
ACHTREUNG
1248, 1155, 1113, 1047, 1020 cmꢀ1
; HR-MS (FAB): m/z: calcd for
12.9, 6.4 Hz, 1H; C1’-H), 3.34 (s, 3H; OCH3), 3.80 (dt, J=10.4, 6.4 Hz,
1H; C2’-H), 3.82 (dd, J=2.8, 11.3 Hz, 1H; CHOTBDPS), 3.83 (dt, J=
10.4, 6.4 Hz, 1H; C2’-H), 3.99 (dd, J=7.7, 11.3 Hz, 1H; CHOTBDPS),
4.61 (s, 2H; OCH2O), 5.57 (dd, J=2.8, 7.7 Hz, 1H; C3-H), 7.36–7.44 (m,
6H; ArH), 7.63–7.66 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=
19.0, 26.6, 27.5, 28.2, 35.0, 55.2, 62.7, 62.8, 74.3, 75.1, 82.5, 84.0, 96.5,
127.7, 129.8, 132.7, 135.5, 165.2, 169.3, 170.2; IR (film): n˜ =3461, 3073,
C42H62O11Si2Na: 821.3728, found: 821.3732 [M ++Na]; elemental analysis
calcd (%) for C42H62O11Si2 (799.1): C 63.13, H 7.82; found: C 62.84, H
7.79.
Data for 60: [a]2D2 =+4.28 (c=1.21 in benzene); 1H NMR (500 MHz,
CDCl3): d=0.09 (s, 9H; Si
N
G
CO2C(CH3)3), 1.44 (s, 9H; CO2C
A
ACHTREUNG
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8915

S. Hashimoto et al.
C1’-H), 2.67 (dt, J=10.0, 6.8 Hz, 1H; C1’-H), 3.06 (d, J=8.8 Hz, 1H;
OH), 3.34 (s, 3H; OCH3), 3.81 (dt, J=9.9, 6.8 Hz, 1H; C2’-H), 3.86 (dt,
J=9.9, 6.8 Hz, 1H; C2’-H), 3.92 (dd, J=2.3, 10.8 Hz, 0.1H;
CHOTBDPS), 3.93 (dd, J=2.6, 10.8 Hz, 0.9H; CHOTBDPS), 3.99 (dd,
J=5.3, 10.8 Hz, 0.1H; CHOTBDPS), 4.00 (dd, J=9.1, 10.8 Hz, 0.9H;
CHOTBDPS), 4.26 (d, J=8.8 Hz, 1H; C5-H), 4.58 (s, 1.8H; OCH2O),
4.60 (s, 0.2H; OCH2O), 5.63 (dd, J=2.3, 5.3 Hz, 0.1H; C3-H), 5.63 (dd,
J=2.6, 9.1 Hz, 0.9H; C3-H), 7.35–7.41 (m, 6H; ArH), 7.64–7.68 (m, 4H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=2.4, 19.3, 26.7, 28.0, 28.1, 34.8,
35.4, 37.0, 55.4, 62.7, 64.5, 77.3, 77.6, 83.3, 83.5, 87.2, 96.9, 105.2, 117.7,
127.6, 127.7, 129.6, 133.2, 133.7, 135.6, 135.8, 166.7, 168.7; IR (film): n˜ =
3493, 2934, 2893, 2859, 1734, 1698, 1460, 1427, 1393, 1370, 1354, 1254,
CHOTBDPS), 3.52 (dd, J=1.7, 11.5 Hz, 1H; CHOTBDPS), 3.67–3.80
(m, 2H; C2’-H2), 3.82 (s, 3H; CO2CH3), 4.28 (dd, J=1.7, 8.1 Hz, 1H; C3-
H), 4.54 (d, J=6.5 Hz, 1H; one of OCH2O), 4.55 (d, J=6.5 Hz, 1H; one
of OCH2O), 7.32 (s, 1H; C6-H), 7.34–7.39 (m, 6H; ArH), 7.61–7.71 (m,
4H; ArH); 13C NMR (100.6 MHz, CDCl3): d=2.6, 19.4, 26.7, 27.8, 27.9,
28.0, 28.1, 33.8, 51.8, 55.2, 62.8, 64.3, 78.7, 79.6, 82.9, 83.3, 89.8, 96.4,
108.4, 127.4, 127.5, 127.7, 129.4, 133.2, 134.0, 134.3, 135.4, 135.5, 135.6,
135.8, 144.4, 162.9, 165.1, 168.9; IR (film): n˜ =2934, 2890, 2859, 1732,
1631, 1589, 1429, 1392, 1370, 1252, 1150 cmꢀ1; HR-MS (FAB): m/z: calcd
for C42H62O12Si2Na: 837.3678, found: 837.3660 [M ++Na].
Di-tert-butyl (1S,3R,4S,5R,6R,7R)-7-acetyl-3-[(tert-butyldiphenylsilyl)oxy-
methyl]-6,7-dihydroxy-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)-
1177, 1113, 1040, 947 cmꢀ1
;
HR-MS (FAB): m/z: calcd for
A
N
C38H60O11Si2Na: 771.3572, found: 771.3572 [M ++Na].
of OsO4 in tert-butyl alcohol (0.6 mL, 0.074 mmol) was added to a stirred
solution of enone 59 (510 mg, 0.639 mmol) and NMO (50% in H2O,
0.4 mL, 1.20 mmol) in acetone (4.4 mL)/H2O (0.6 mL) at 08C. After stir-
ring at room temperature for 3 h, the reaction was quenched by addition
of 10% aqueous Na2S2O3 (5 mL), and the mixture was extracted with
AcOEt (15 mL). The organic extract was washed with brine (5 mL) and
dried over anhydrous Na2SO4. Filtration and evaporation in vacuo fur-
nished the crude product (600 mg), which was purified by column chro-
matography (silica gel 20 g, n-hexane/AcOEt 4:1) to give diol 64
Data for 61: [a]2D2 =+20.5 (c=1.21 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=ꢀ0.08 (s, 0.9H; Si
8.1H; SiC(CH3)3), 1.04 (s, 0.9H; SiC
1.32 (s, 0.9H; CO2C(CH3)3), 1.50 (s, 0.9H; CO2C
CO2C(CH3)3), 2.49 (s, 3H; COCH3), 2.56 (dt, J=9.7, 6.8 Hz, 1H; C1’-H),
A
ACHTREUNG
A
N
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
2.57 (dt, J=9.7, 6.8 Hz, 1H; C1’-H), 3.29 (s, 0.3H; OCH3), 3.32 (s, 2.7H;
OCH3), 3.76 (dt, J=8.8, 6.8 Hz, 0.9H; C2’-H), 3.77 (m, 0.2H; C2’-H2),
3.78 (dt, J=8.8, 6.8 Hz, 0.9H; C2’-H), 3.84 (dd, J=9.0, 11.1 Hz, 0.9H;
CHOTBDPS), 3.89 (dd, J=8.9, 11.2 Hz, 0.1H; CHOTBDPS), 4.06 (dd,
J=1.8, 11.1 Hz, 0.9H; CHOTBDPS), 4.18 (dd, J=2.4, 11.2 Hz, 0.1H;
CHOTBDPS), 4.49 (s, 0.2H; OCH2O), 4.56 (s, 1.8H; OCH2O), 6.40 (dd,
J=1.8, 9.0 Hz, 0.9H; C3-H), 6.56 (dd, J=2.4, 8.9 Hz, 0.1H; C3-H), 7.24
(s, 0.9H; =CH), 7.26 (s, 0.1H; =CH), 7.34–7.40 (m, 6H; ArH), 7.62–7.65
(m, 4H; ArH); 13C NMR (125.8 MHz, CDCl3): d=1.3, 19.1, 26.4, 26.6,
27.6, 28.1, 35.0, 35.2, 55.1, 62.8, 63.2, 76.0, 82.5, 82.7, 83.2, 83.7, 91.7, 96.4,
112.7, 127.6, 127.7, 129.59, 129.64, 133.2, 133.3, 135.56, 135.62, 136.6,
148.4, 157.6, 165.1, 169.6, 193.6; IR (film): n˜ =2934, 2893, 2859, 1734,
1698, 1460, 1427, 1393, 1370, 1354, 1254, 1177, 1113, 1040, 947 cmꢀ1; HR-
MS (FAB): m/z: calcd for C42H62N2O11Si2Na: 849.3790, found: 849.3767
[M ++Na].
(467 mg, 88%) as
a
colorless amorphous. [a]2D1 =+9.49 (c=2.11 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=ꢀ0.10 (s, 9H; Si
ACHTREUNG
(s, 9H; SiC
A
A
ACHTREUNG
2.24 (ddd, J=6.0, 7.5, 13.9 Hz, 1H; C1’-H), 2.45 (s, 3H; COCH3), 2.54
(dt, J=13.9, 7.5 Hz, 1H; C1’-H), 3.19 (d, J=7.5 Hz, 1H; C6-OH), 3.38 (s,
3H; OCH3), 3.39 (dd, J=1.1, 11.2 Hz, 1H; CHOTBDPS), 3.54 (dd, J=
7.9, 11.2 Hz, 1H; CHOTBDPS), 3.82 (ddd, J=6.0, 7.5, 13.9 Hz, 1H; C2’-
H), 3.87 (dt, J=13.9, 7.5 Hz, 1H; C2’-H), 4.43 (dd, J=1.1, 7.9 Hz, 1H;
C3-H), 4.63 (d, J=6.4 Hz, 1H; one of OCH2O), 4.67 (d, J=6.4 Hz, 1H;
one of OCH2O), 4.91 (brs, 1H; C7-OH), 5.74 (d, J=7.5 Hz, 1H; C6-H),
7.35–7.40 (m, 6H; ArH), 7.59–7.66 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=2.4, 19.2, 25.9, 26.6, 28.0, 28.3, 33.4, 55.3, 63.3, 64.9, 73.6, 77.5,
77.7, 83.4, 83.5, 86.8, 90.9, 96.6, 106.9, 127.6, 127.7, 129.6, 133.1, 133.4,
135.4, 135.6, 165.5, 169.0, 204.1; IR (Nujol): n˜ =3347, 2728, 2361, 1742,
1462, 1377, 1306, 1250, 1206, 1155, 1038 cmꢀ1; HR-MS (FAB): m/z: calcd
for C42H64O13Si2Na: 855.3783, found: 855.3777 [M ++Na].
Data for 62: [a]2D2 =+15.8 (c=0.53 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.03 (s, 7.2H; SiC
N
G
14.4H; 2”CO2C(CH3)3), 1.46 (s, 3.6H; 2”CO2C
A
ACHTREUNG
C1’-H2), 2.66 (dt, J=9.6, 6.6 Hz, 0.8H; C1’-H), 2.68 (dt, J=9.6, 6.6 Hz,
0.8H; C1’-H), 3.33 (s, 0.6H; OCH3), 3.34 (s, 2.4H; OCH3), 3.81 (m,
1.6H; C2’-H2), 3.82 (m, 0.4H; C2’-H2), 3.97 (dd, J=7.4, 11.2 Hz, 0.2H;
CHOTBDPS), 3.98 (dd, J=3.1, 11.4 Hz, 0.8H; CHOTBDPS), 4.06 (dd,
J=5.4, 11.4 Hz, 0.8H; CHOTBDPS), 4.14 (dd, J=4.2, 11.2 Hz, 0.2H;
CHOTBDPS), 4.59 (s, 0.4H; OCH2O), 4.60 (s, 1.6H; OCH2O), 4.62 (s,
0.8H; C5-H), 4.63 (s, 0.2H; C5-H), 5.58 (dd, J=3.1, 5.4 Hz, 0.8H; C3-H),
5.83 (dd, J=4.2, 7.4 Hz, 0.2H; C3-H), 7.26–7.43 (m, 6H; ArH), 7.61–7.65
(m, 4H; ArH); 13C NMR (125.8 MHz, CDCl3): d=19.2, 19.3, 26.6, 26.65,
26.68, 27.8, 27.9, 28.0, 28.1, 29.7, 34.8, 34.9, 44.4, 55.3, 62.6, 63.0, 63.1,
63.3, 63.6, 63.8, 65.0, 72.8, 78.5, 81.5, 81.6, 83.2, 83.3, 83.4, 96.4, 104.0,
127.67, 127.68, 127.76, 127.79, 129.67, 129.72, 129.85, 129.89, 132.7, 132.8,
133.1, 133.3, 135.55, 135.59, 135.63, 163.2, 163.4, 164.1, 166.2, 169.9, 170.4,
170.5, 172.4, 196.6; IR (film): n˜ =2934, 2888, 2859, 1730, 1657, 1474, 1429,
1393, 1370, 1308, 1256, 1150, 1113, 1042, 999, 920 cmꢀ1; HR-MS (FAB):
m/z: calcd for C35H50O10SiNa: 681.3071, found: 681.3071 [M ++Na].
Di-tert-butyl (1S,3R,4S,5R,6R,7R)-7-acetyl-6-benzyloxy-3-[(tert-butyldi-
phenylsilyl)oxymethyl]-7-hydroxy-1-[2-(methoxymethoxy)ethyl]-4-(trime-
thylsilyl)oxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylate (65): Benzyl
G
bromide (1.0 mL, 7.98 mmol) was added to a stirred solution of diol 64
(1.11 g, 1.33 mmol) and Ag2O (618 mg, 2.67 mmol) in DMF (13 mL).
After stirring for 24 h in the dark, the reaction was quenched by addition
of H2O (30 mL), and the resulting mixture was stirred for another 24 h.
The whole mixture was extracted with AcOEt (3”40 mL), and the com-
bined organic extracts were washed with brine (30 mL) and dried over
anhydrous Na2SO4. Filtration and evaporation in vacuo furnished the
crude product (3.5 g), which was purified by column chromatography
(silica gel 40 g, n-hexane/AcOEt 15:1) to give benzyl ether 65 (1.17 g,
95%) as a colorless oil. [a]D =+16.4 (c=2.04 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=ꢀ0.11 (s, 9H; Si
C
(CH3)3),
G
ACHTREUNG
10.5, 13.7 Hz, 1H; C1’-H), 2.36 (s, 3H; COCH3), 2.63 (ddd, J=6.2, 10.2,
13.7 Hz, 1H; C1’-H), 3.34 (dd, J=1.7, 11.1 Hz, 1H; CHOTBDPS), 3.37
(s, 3H; OCH3), 3.49 (dd, J=7.5, 11.1 Hz, 1H; CHOTBDPS), 3.84 (m,
2H; C2’-H2), 3.95 (s, 1H; OH), 4.38 (dd, J=1.7, 7.5 Hz, 1H; C3-H), 4.46
(d, J=10.9 Hz, 1H; OCHPh), 4.63 (d, J=10.9 Hz, 1H; OCHPh), 4.64 (d,
J=6.4 Hz, 1H; one of OCH2O), 4.67 (d, J=6.4 Hz, 1H; one of OCH2O),
5.80 (s, 1H; C6-H), 7.24–7.42 (m, 9H; ArH), 7.59–7.66 (m, 6H; ArH);
13C NMR (67.8 MHz, CDCl3): d=3.0, 19.3, 25.9, 26.7, 27.5, 28.1, 28.3,
33.1, 55.2, 63.8, 65.0, 75.4, 77.3, 77.9, 81.8, 82.9, 83.4, 86.8, 89.8, 96.8,
107.1, 127.6, 127.7, 128.0, 128.41, 128.44, 128.5, 128.6, 129.7, 133.2, 133.6,
135.5, 135.6, 136.2, 165.2, 168.9, 204.4; IR (film): n˜ =3447, 2934, 2890,
2859, 1744, 1728, 1250, 1202, 1152, 1113, 1071, 1042 cmꢀ1; HR-MS (FAB):
m/z: calcd for C49H70O13Si2Na: 945.4253, found: 945.4285 [M ++Na]; ele-
mental analysis calcd (%) for C49H70O13Si2 (923.2): C 63.75, H 7.64;
found: C 63.62, H 7.74.
4,5-Di-tert-butyl 7-methyl (1S,3R,4S,5R)-3-[(tert-butyldiphenylsilyl)oxy-
methyl]-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-dioxa-
A
N
ester 8 (50 mg, 0.066 mmol) in benzene (0.6 mL) was added dropwise
over 15 min to a refluxing solution of methyl propiolate (41, 17 mg,
0.198 mmol) and bis
N
N
in benzene (0.8 mL), and the mixture was stirred for 25 min. After cool-
ing, the volatile elements were removed in vacuo, and the greenish resi-
due was purified by column chromatography (silica gel 5 g, n-hexane/
AcOEt 10:1) to give cycloadduct 63 (42 mg, 78%) as a colorless oil,
along with alcohol 60 (4.4 mg, 9%) as a colorless oil. [a]2D4 =ꢀ28.3 (c=
1
2.20 in CHCl3); H NMR (500 MHz, CDCl3): d=ꢀ0.05 (s, 9H; Si
G
1.02 (s, 9H; SiC
(CH3)3), 2.35 (dt, J=14.3, 5.0 Hz, 1H; C1’-H), 2.64 (ddd, J=7.1, 8.6,
14.3 Hz, 1H; C1’-H), 3.31 (s, 3H; OCH3), 3.33 (dd, J=8.1, 11.5 Hz, 1H;
A
A
ACHTREUNG
8916
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
4,5-Di-tert-butyl 7-methyl (1S,3R,4S,5R,6R,7S)-3-[(tert-butyldiphenylsi-
4H; ArH); 13C NMR (125.8 MHz, CDCl3): d=2.4, 19.3, 26.3, 26.7, 28.1,
28.3, 29.7, 32.8, 52.7, 55.2, 63.9, 65.3, 70.7, 75.3, 83.4, 83.5, 90.5, 92.0, 96.8,
107.6, 127.3, 127.6, 127.7, 128.0, 128.5, 129.65, 129.69, 133.1, 133.5, 135.4,
135.6, 137.0, 165.1, 168.3, 168.9; IR (film): n˜ =3544, 2932, 1740, 1589,
1456, 1393, 1370, 1113, 920, 887 cmꢀ1; HR-MS (FAB): m/z: calcd for
C49H71O14Si2: 939.4382, found: 939.4390 [M ++H].
ACHTREUNG
A
N
A
solution of OsO4 in tert-butyl alcohol (0.02 mL, 2.5 mmol) was added to a
stirred solution of enoate 63 (42 mg, 0.052 mmol) and NMO (50% in
H2O, 0.03 mL, 0.092 mmol) in acetone (1 mL)/H2O (0.1 mL) at 08C.
After stirring at room temperature for 3 h, the reaction was quenched by
addition of 10% aqueous Na2S2O3 (5 mL), and the mixture was extracted
with AcOEt (15 mL). The organic extract was washed with brine (5 mL)
and dried over anhydrous Na2SO4. Filtration and evaporation in vacuo
furnished the crude product (51 mg), which was purified by column chro-
matography (silica gel 5 g, n-hexane/AcOEt 4:1) to give diol 66 (37.1 mg,
Di-tert-butyl (1S,3R,4S,5R,6R,7S)-6-benzyloxy-3-[(tert-butyldiphenylsilyl)-
oxymethyl]-7-hydroxy-7-(1-hydroxyethyl)-1-[2-(methoxymethoxy)ethyl]
A
4-(trimethylsilyl)oxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylate (69):
AHCTREUNG
DIBALH in toluene (1.0m, 2.64 mL, 2.64 mmol) was added to a stirred
solution of ketone 65 (973 mg, 1.06 mmol) in toluene (13 mL) at ꢀ788C.
After stirring for 30 min, the reaction was quenched by addition of
MeOH (2 mL) followed by 15% aqueous potassium sodium tartrate
(10 mL). After stirring at room temperature for 10 h, the mixture was ex-
tracted with AcOEt (30 mL). The organic extract was washed with brine
(20 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (1.5 g), which was purified by column
chromatography (silica gel 30 g, n-hexane/AcOEt 7:1) to give diol 69
(972 mg, quant.) as a colorless oil. [a]2D0 =+6.89 (c=2.61 in CHCl3);
84%) as
a
colorless amorphous. [a]2D1 =+7.57 (c=1.16 in CHCl3);
1H NMR (500 MHz, CDCl3): d=ꢀ0.11 (s, 9H; Si
ACHTREUNG
SiC
G
A
ACHTREUNG
(dt, J=14.7, 6.2 Hz, 1H; C1’-H), 2.53 (dt, J=14.7, 7.3 Hz, 1H; C1’-H),
3.34 (d, J=7.7 Hz, 1H; C6-OH), 3.37 (s, 3H; OCH3), 3.44 (dd, J=1.2,
11.4 Hz, 1H; CHOTBDPS), 3.53 (dd, J=7.7, 11.4 Hz, 1H; CHOTBDPS),
3.77 (ddd, J=6.2, 7.3, 10.2 Hz, 1H; C2’-H), 3.82 (s, 3H; CO2CH3), 3.84
(ddd, J=6.2, 7.3, 10.2 Hz, 1H; C2’-H), 4.63 (d, J=6.6 Hz, 1H; one of
OCH2O), 4.67 (d, J=6.6 Hz, 1H; one of OCH2O), 4.68 (dd, J=1.2,
7.7 Hz, 1H; C3-H), 5.07 (s, 1H; C7-OH), 5.80 (d, J=7.7 Hz, 1H; C6-H),
7.35–7.39 (m, 6H; ArH), 7.61–7.67 (m, 4H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=2.4, 19.3, 26.7, 28.0, 28.3, 33.3, 53.2, 55.5, 62.9, 65.4, 75.0, 77.2,
77.7, 77.9, 82.6, 83.2, 91.3, 96.6, 107.3, 127.6, 127.7, 129.7, 133.2, 133.5,
135.4, 135.6, 165.2, 169.1, 170.7; IR (film): n˜ =3389, 3052, 2978, 2934,
2860, 1740, 1474, 1458, 1429, 1393, 1370, 1325, 1248, 1154, 1073, 1038,
1H NMR (500 MHz, CDCl3): d=ꢀ0.09 (s, 9H; Si
A
SiC
G
N
CH(OH)CH3), 1.53 (s, 9H; CO2C(CH3)3), 2.38 (d, J=7.2 Hz, 1H;
G
CHOH), 2.43 (dt, J=14.7, 7.6 Hz, 1H; C1’-H), 2.47 (dt, J=14.7, 7.6 Hz,
1H; C1’-H), 3.36 (s, 3H; OCH3), 3.42 (dd, J=0.5, 11.1 Hz, 1H;
CHOTBDPS), 3.59 (dd, J=7.7, 11.1 Hz, 1H; CHOTBDPS), 3.81 (s, 1H;
C7-OH), 3.84 (t, J=7.6 Hz, 2H; C2’-H2), 4.14 (dq, J=7.2, 6.4 Hz, 1H;
CH(OH)CH3), 4.25 (dd, J=0.5, 7.7 Hz, 1H; C3-H), 4.60 (d, J=10.5 Hz,
1H; OCHPh), 4.62 (d, J=6.4 Hz, 1H; one of OCH2O), 4.65 (d, J=
6.4 Hz, 1H; one of OCH2O), 4.77 (d, J=10.5 Hz, 1H; OCHPh), 5.05 (s,
1H; C6-H), 7.29–7.41 (m, 11H; ArH), 7.63–7.71 (m, 4H; ArH);
13C NMR (67.8 MHz, CDCl3): d=2.5, 19.2, 19.4, 26.7, 28.1, 28.2, 33.3,
55.1, 64.0, 65.2, 68.2, 75.6, 77.2, 77.9, 82.4, 82.7, 83.3, 90.2, 96.5, 108.3,
127.7, 128.1, 128.2, 128.4, 129.6, 129.7, 132.9, 133.6, 135.4, 135.7, 136.6,
166.1, 169.8; IR (CHCl3): n˜ =3490, 3073, 3017, 2982, 2957, 1746, 1725,
1589, 1427, 1393, 1370, 1325, 1252, 1144, 1111, 1069, 997 cmꢀ1; HR-MS
(FAB): m/z: calcd for C49H72O13Si2Na: 947.4409, found: 947.4460 [M +
+Na].
999 cmꢀ1
; HR-MS (FAB): m/z: calcd for C42H64O14Si2Na: 871.3732,
found: 871.3739 [M ++Na].
4,5-Di-tert-butyl 7-methyl (1S,3R,4S,5R,6R,7S)-6-benzyloxy-3-[(tert-bu-
tyldiphenylsilyl)oxymethyl]-7-hydroxy-1-[2-(methoxymethoxy)ethyl]-4-
(trimethylsilyl)oxy-2,8-dioxabicyclo[3.2.1]octane-4,5,7-tricarboxylate (67):
G
Benzyl bromide (18 mg, 0.108 mmol) was added to a stirred solution of
diol 66 (23 mg, 0.027 mmol) and Ag2O (13 mg, 0.054 mmol) in DMF
(0.5 mL). After stirring for 24 h in the dark, the reaction was quenched
by addition of H2O (5 mL), and the resulting mixture was stirred for 4 h.
The whole mixture was extracted with AcOEt (15 mL), and the organic
extract was washed with brine (5 mL) and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (46 mg),
which was purified by column chromatography (silica gel 5 g, n-hexane/
AcOEt 10:1 ! 4:1) to give benzyl ether 67 (15.9 mg, 63%) as a colorless
oil, along with isomer 68 (3.2 mg, 14%) as a colorless oil.
Di-tert-butyl (1S,3R,4S,5R,6S)-6-benzyloxy-3-[(tert-butyldiphenylsilyl)oxy-
methyl]-1-[2-(methoxymethoxy)ethyl]-7-oxo-4-(trimethylsilyl)oxy-2,8-
dioxabicyclo
N
G
1.19 mmol) was added to
a
0.995 mmol) in benzene (15 mL). After stirring for 30 min, the reaction
was quenched by addition of ethylene glycol (1 mL) and 10% aqueous
Na2S2O3 (10 mL), and the mixture was extracted with AcOEt (15 mL).
The organic extract was washed with brine (10 mL) and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (1.20 g), which was purified by column chromatography (silica
gel 30 g, n-hexane/AcOEt 15:1) to give ketone 70 (822 mg, 94%) as a
colorless oil. [a]2D2 =ꢀ69.4 (c=2.45 in CHCl3); 1H NMR (500 MHz,
Data for 67: [a]2D1 = +16.9 (c = 0.63 in CHCl3); 1H NMR (500 MHz,
CDCl3): d = ꢀ0.13 (s, 9H; SiC
C
(CH3)3), 1.34 (s,
G
ACHTREUNG
1H; C1’-H), 2.51 (dt, J=14.1, 7.9 Hz, 1H; C1’-H), 3.36 (s, 3H; OCH3),
3.37 (dd, J=1.0, 11.2 Hz, 1H; CHOTBDPS), 3.49 (dd, J=7.7, 11.2 Hz,
1H; CHOTBDPS), 3.78 (s, 3H; CO2CH3), 3.83 (t, J=7.9 Hz, 2H; C2’-
H2), 4.08 (s, 1H; C7-OH), 4.49 (dd, J=1.0, 7.7 Hz, 1H; C3-H), 4.60 (d,
J=10.9 Hz, 1H; OCHPh), 4.63 (d, J=6.5 Hz, 1H; one of OCH2O), 4.66
(d, J=6.5 Hz, 1H; one of OCH2O), 4.69 (d, J=10.9 Hz, 1H; OCHPh),
5.88 (s, 1H; C6-H), 7.31–7.40 (m, 11H; ArH), 7.60–7.66 (m, 4H; ArH);
13C NMR (100.6 MHz, CDCl3): d=2.6, 19.4, 26.7, 28.2, 28.3, 32.3, 52.9,
55.2, 63.7, 65.2, 75.6, 77.6, 77.8, 83.1, 83.4, 90.0, 96.6, 107.6, 127.5, 127.6,
128.4, 128.5, 129.6, 133.0, 133.5, 135.3, 135.6, 136.0, 168.9, 170.1; IR
(film): n˜ =3455, 2978, 2934, 2860, 1740, 1589, 1474, 1456, 1429, 1393,
1370, 1323, 1248, 1209, 1152, 1074, 1037, 999 cmꢀ1; HR-MS (FAB): m/z:
calcd for C49H71O14Si2: 939.4382, found: 939.4409 [M ++H].
CDCl3): d=ꢀ0.09 (s, 9H; Si
C
(CH3)3), 1.28 (s, 9H;
G
ACHTREUNG
1H; C1’-H), 2.29 (dt, J=14.4, 7.8 Hz, 1H; C1’-H), 3.33 (s, 3H; OCH3),
3.37 (dd, J=0.9, 11.6 Hz, 1H; CHOTBDPS), 3.57 (dd, J=7.6, 11.6 Hz,
1H; CHOTBDPS), 3.75 (dt, J=13.8, 7.8 Hz, 1H; C2’-H), 3.76 (ddd, J=
4.9, 7.8, 13.8 Hz, 1H; C2’-H), 4.09 (dd, J=0.9, 7.6 Hz, 1H; C3-H), 4.51
(brs, 1H; C6-H), 4.56 (d, J=6.5 Hz, 1H; one of OCH2O), 4.61 (d, J=
6.5 Hz, 1H; one of OCH2O), 4.73 (d, J=12.3 Hz, 1H; OCHPh), 4.84 (d,
J=12.3 Hz, 1H; OCHPh), 7.34–7.41 (m, 11H; ArH), 7.57–7.64 (m, 4H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=2.5, 19.2, 26.7, 27.7, 28.2, 32.0,
55.1, 62.2, 64.9, 72.0, 74.5, 77.2, 78.0, 79.4, 83.4, 83.5, 88.4, 96.7, 100.5,
127.6, 127.7, 128.1, 128.4, 128.6, 129.6, 132.8, 133.4, 135.4, 135.7, 136.5,
168.0, 208.5; IR (film): n˜ =3071, 2934, 2890, 2861, 1771, 1746, 1730, 1250,
1211, 1154, 1113 cmꢀ1; HR-MS (FAB): m/z: calcd for C47H66O12Si2Na:
901.3991, found: 901.3975 [M ++Na].
Data for 68: [a]2D1 =+3.88 (c=0.22 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=ꢀ0.14 (s, 9H; Si
C
(CH3)3), 1.41 (s, 9H;
G
ACHTREUNG
2.55 (d, J=12.4 Hz, 1H; C6-OH), 3.36 (s, 3H; OCH3), 3.37 (dd, J=1.0,
11.4 Hz, 1H; CHOTBDPS), 3.48 (dd, J=7.6, 11.4 Hz, 1H; CHOTBDPS),
3.76 (s, 3H; CO2CH3), 3.84 (dt, J=9.6, 6.9 Hz, 1H; C2’-H), 3.85 (dt, J=
9.6, 6.9 Hz, 1H; C2’-H), 4.37 (dd, J=1.0, 7.6 Hz, 1H; C3-H), 4.57 (d, J=
10.8 Hz, 1H; OCHPh), 4.62 (d, J=10.8 Hz, 1H; OCHPh), 4.63 (d, J=
6.4 Hz, 1H; one of OCH2O), 4.66 (d, J=6.4 Hz, 1H; one of OCH2O),
5.91 (d, J=12.4 Hz, 1H; C6-H), 7.35–7.41 (m, 11H; ArH), 7.61–7.68 (m,
Typical procedure for the reduction of ketone 70: di-tert-butyl
(1S,3R,4S,5R,6R,7R)-6-benzyloxy-3-[(tert-butyldiphenylsilyl)oxymethyl]-
7-hydroxy-1-[2-(methoxymethoxy)ethyl]-4-(trimethylsilyl)oxy-2,8-dioxa-
A
N
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8917

S. Hashimoto et al.
0.17 mL, 0.17 mmol) was added to a stirred solution of ketone 70 (50 mg,
0.057 mmol) and ZnCl2 (23 mg, 0.171 mmol) in CH2Cl2 (0.5 mL) at
ꢀ788C. After stirring for 30 min, the reaction was quenched by addition
of MeOH (0.5 mL) followed by 15% aqueous potassium sodium tartrate
(5 mL). After stirring at room temperature for 2 h, the mixture was ex-
tracted with AcOEt (15 mL). The organic extract was washed with brine
(5 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (81 mg), from which a diastereomeric
mixture of alcohol (43.7 mg, 87%) was obtained as a colorless oil after
column chromatography (silica gel 5 g, n-hexane/AcOEt 10:1). The dia-
stereomeric ratio (71/72 46.4:1) was determined by HPLC analysis
[column, Zorbax Sil, 4.6”250 mm; eluent, n-hexane/THF 10:1; flow rate,
1.0 mLminꢀ1; detection, 254 nm; tR (7R isomer 71)=22.2 min, tR (7S
isomer 72)=19.3 min]. The diastereomers were separated by flash
column chromatography (silica gel 10 g, toluene/AcOEt 40:1) to afford
alcohol 71 (42.7 mg, 85%) as a colorless oil, along with undesired isomer
72 (1.0 mg, 2%) as a colorless oil. [a]2D3 =ꢀ9.07 (c=2.15 in CHCl3);
H), 3.35 (s, 3H; OCH3), 3.42 (dd, J=0.9, 11.3 Hz, 1H; CHOTBDPS),
3.60 (dd, J=7.8, 11.3 Hz, 1H; CHOTBDPS), 3.73 (dt, J=9.4, 6.2 Hz,
1H; C2’-H), 3.84 (dt, J=9.4, 6.2 Hz, 1H; C2’-H), 4.42 (dd, J=0.9, 7.8 Hz,
1H; C3-H), 4.59 (d, J=11.8 Hz, 1H; OCHPh), 4.61 (d, J=6.4 Hz, 1H;
one of OCH2O), 4.63 (d, J=6.4 Hz, 1H; one of OCH2O), 4.74 (d, J=
11.8 Hz, 1H; OCHPh), 4.95 (brs, 1H; C7-H), 5.21 (d, J=1.6 Hz, 1H; C6-
H), 7.29–7.39 (m, 11H; ArH), 7.63–7.72 (m, 4H; ArH); 13C NMR
(67.8 MHz, CDCl3): d=2.5, 19.2, 26.6, 27.6, 27.7, 28.1, 36.4, 55.0, 62.8,
64.5, 65.7, 71.9, 77.8, 78.0, 82.2, 82.5, 82.7, 83.1, 90.5, 96.4, 103.4, 127.4,
127.5, 128.05, 128.14, 129.4, 133.0, 133.8, 135.4, 135.7, 137.4, 152.7, 159.7,
168.9; IR (film): n˜ =2934, 1748, 1688, 1589, 1456, 1429, 1393, 1370, 922,
841, 791, 741 cmꢀ1
; HR-MS (FAB): m/z: calcd for C52H76O14Si2Na:
1003.4671, found: 1003.4680 [M ++Na].
Di-tert-butyl (1S,3R,4S,5R,6R,7R)-6-benzyloxy-7-(tert-butoxycarbonyl)-
AHCTREUNG
A
ACHTREUNG
1.25 mL, 1.25 mmol) was added to a stirred solution of bis-silyl ether 73
(601 mg, 0.612 mmol) in THF (9 mL) at 08C. After stirring for 30 min,
the reaction was quenched with H2O (10 mL), and the mixture was ex-
tracted with AcOEt (20 mL). The organic extract was washed with brine
(10 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (520 mg), which was purified by
column chromatography (silica gel 10 g, n-hexane/AcOEt 1:1) to give
diol 74 (402 mg, 97%) as a colorless oil. [a]2D4 =ꢀ18.9 (c=2.01 in CHCl3);
1H NMR (500 MHz, CDCl3): d=ꢀ0.06 (s, 9H; Si
ACHTREUNG
SiC
G
(CH3)3), 1.38 (s, 9H; CO2C
ACHTREUNG
(ddd, J=3.9, 11.6, 14.5 Hz, 1H; C1’-H), 2.24 (dt, J=14.5, 3.9 Hz, 1H;
C1’-H), 3.31 (s, 3H; OCH3), 3.45 (dd, J=0.6, 11.3 Hz, 1H; CHOTBDPS),
3.70 (dd, J=8.1, 11.3 Hz, 1H; CHOTBDPS), 3.72 (dt, J=10.0, 3.9 Hz,
1H; C2’-H), 3.95–3.99 (m, 2H; C3-H, C2’-H), 4.21 (brs, 1H; C7-OH),
4.59 (d, J=12.3 Hz, 1H; OCHPh), 4.61 (d, J=6.4 Hz, 1H; one of
OCH2O), 4.63 (d, J=6.4 Hz, 1H; one of OCH2O), 4.66 (m, 1H; C7-H),
4.77 (d, J=12.3 Hz, 1H; OCHPh), 4.96 (brs, 1H; C6-H), 7.35–7.39 (m,
11H; ArH), 7.63–7.69 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=
2.6, 19.2, 21.3, 26.6, 27.7, 28.1, 36.8, 55.5, 63.2, 64.7, 71.1, 77.3, 78.6, 82.4,
82.55, 82.59, 84.9, 90.2, 96.3, 104.1, 125.2, 127.4, 127.5, 127.6, 127.7, 127.8,
128.1, 128.9, 129.47, 129.52, 133.2, 133.4, 135.4, 135.5, 137.7, 165.4, 168.8;
IR (film): n˜ =3470, 2976, 2934, 2859, 1740, 1474, 1456, 1429, 1393, 1370,
1H NMR (500 MHz, CDCl3): d=1.42 (s, 9H; CO2C
ACHTREUNG
CO2C
A
ACHTREUNG
CH2OH), 2.21 (dt, J=14.1, 6.7 Hz, 1H; C1’-H), 2.29 (dt, J=14.1, 6.7 Hz,
1H; C1’-H), 3.33 (s, 3H; OCH3), 3.63 (ddd, J=5.2, 8.2, 11.6 Hz, 1H;
CHOH), 3.70 (ddd, J=0.8, 4.3, 11.6 Hz, 1H; CHOH), 3.71 (dt, J=10.1,
6.7 Hz, 1H; C2’-H), 3.83 (dt, J=10.1, 6.7 Hz, 1H; C2’-H), 3.88 (s, 1H;
C4-OH), 4.33 (dd, J=0.8, 5.2 Hz, 1H; C3-H), 4.59 (d, J=6.3 Hz, 1H;
one of OCH2O), 4.61 (d, J=6.3 Hz, 1H; one of OCH2O), 4.63 (d, J=
11.9 Hz, 1H; OCHPh), 4.77 (d, J=11.9 Hz, 1H; OCHPh), 4.80 (brs, 1H;
C7-H), 5.29 (brs, 1H; C6-H), 7.27–7.34 (m, 5H; ArH); 13C NMR
(67.8 MHz, CDCl3): d=27.5, 27.7, 35.8, 54.9, 61.0, 62.1, 71.8, 74.2, 74.7,
82.66, 82.71, 83.1, 84.5, 90.7, 96.1, 103.2, 127.6, 128.0, 137.1, 152.3, 164.8,
169.5; IR (film): n˜ =3461, 2978, 2934, 1732, 1456, 1395, 1370, 1333, 1278,
1161, 1117 cmꢀ1; HR-MS (FAB): m/z: calcd for C33H50O14Na: 693.3098,
found: 693.3080 [M ++Na].
1329, 1250, 1152, 1011, 925 cmꢀ1
; HR-MS (FAB): m/z: calcd for
C47H68O12Si2Na: 903.4147, found: 903.4152 [M ++Na]; elemental analysis
calcd (%) for C47H68O12Si2 (881.2): C 64.06, H 7.78; found: C 63.91, H
7.75.
Data for 72: [a]2D1 =ꢀ9.50 (c=2.21 in benzene); 1H NMR (500 MHz,
CDCl3): d=ꢀ0.06 (s, 9H; Si
A
N
CO2C
G
N
C1’-H), 2.32 (dt, J=12.9, 6.9 Hz, 1H; C1’-H), 3.35 (s, 3H; OCH3), 3.36
(d, J=5.3 Hz, 1H; C7-OH), 3.41 (dd, J=0.8, 11.2 Hz, 1H; CHOTBDPS),
3.60 (dd, J=7.8, 11.2 Hz, 1H; CHOTBDPS), 3.79 (dt, J=9.4, 5.6 Hz,
1H; C2’-H), 3.84 (dt, J=9.4, 6.9 Hz, 1H; C2’-H), 4.01 (dd, J=0.8, 7.8 Hz,
1H; C3-H), 4.23 (dd, J=5.3, 6.0 Hz, 1H; C7-H), 4.62 (d, J=6.7 Hz, 1H;
one of OCH2O), 4.63 (d, J=11.4 Hz, 1H; OCHPh), 4.64 (d, J=6.7 Hz,
1H; one of OCH2O), 4.67 (d, J=11.4 Hz, 1H; OCHPh), 5.17 (d, J=
6.0 Hz, 1H; C6-H), 7.33–7.40 (m, 11H; ArH), 7.62–7.68 (m, 4H; ArH);
13C NMR (67.8 MHz, CDCl3): d=2.6, 19.2, 26.7, 27.9, 28.0, 28.2, 33.3,
55.1, 63.4, 64.7, 73.7, 75.2, 77.2, 77.8, 79.7, 82.7, 82.8, 91.3, 96.5, 108.0,
127.6, 127.7, 127.9, 128.1, 128.3, 128.4, 129.6, 133.0, 133.5, 135.4, 135.6,
136.7, 165.6, 169.4; IR (film): n˜ =3486, 2932, 2859, 1744, 1726, 1146, 1111,
Tri-tert-butyl (1S,3S,4S,5R,6R,7R)-6-benzyloxy-7-(tert-butoxycarbonyl)-
A
N
AHCTREUNG
a
0.395 mmol) in CH2Cl2 (5 mL). After stirring for 24 h, the mixture was di-
luted with AcOEt (10 mL) and poured into an ice-cooled saturated aque-
ous NaHCO3 (5 mL) containing Na2S2O3·H2O (200 mg). The layers were
separated, and the organic layer was washed with brine (3 mL) and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude product (380 mg), which was used without further purification.
1063 cmꢀ1
; HR-MS (FAB): m/z: calcd for C47H68O12Si2Na: 903.4147,
NaClO2 (175 mg, 1.19 mmol) was added to a stirred mixture of the crude
aldehyde (380 mg) and NaH2PO4 (94.0 mg, 1.19 mmol) in tert-butyl alco-
hol (5 mL)/H2O (1 mL)/2-methyl-2-butene (20 mL, 2.49 mmol) at 08C.
After stirring at room temperature for 3 h, the reaction mixture was
acidified with 10% aqueous NaHSO4 (10 mL) and extracted with AcOEt
(15 mL). The organic extract was washed with brine (8 mL) and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude product (290 mg), which was used without further purification.
found: 903.4136 [M ++Na]; elemental analysis calcd (%) for C47H68O12Si2
(881.2): C 64.06, H 7.78; found: C 63.84, H 7.85.
Di-tert-butyl
yl)oxy-3-[(tert-butyldiphenylsilyl)oxymethyl]-1-[2-(methoxymethoxy)eth-
yl]-4-(trimethylsilyl)oxy-2,8-dioxabicyclo[3.2.1]octane-4,5-dicarboxylate
(1S,3R,4S,5R,6R,7R)-6-benzyloxy-7-(tert-butoxycarbon-
ACHTREUNG
A
ACHTREUNG
(73): (Boc)2O (1.14 mL, 4.96 mmol) was added to a stirred solution of al-
cohol 71 (627 mg, 0.708 mmol), Et3N (0.38 mL, 2.83 mmol) and DMAP
(130 mg, 1.06 mmol) in CH2Cl2 (12 mL) at 08C. After stirring at room
temperature for 2 h, the reaction was quenched with 10% aqueous
K2HPO4 (10 mL), and the mixture was extracted with AcOEt (10 mL).
The organic extract was washed with brine (10 mL) and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (710 mg), which was purified by column chromatography (silica
gel 15 g, n-hexane/AcOEt 15:1) to give carbonate 73 (663 mg, 96%) as a
colorless oil. [a]2D4 =+3.51 (c=2.30 in benzene); 1H NMR (500 MHz,
N,N’-Diisopropyl-O-tert-butylisourea (0.32 mL, 1.58 mmol) was added to
a stirred solution of the crude carboxylic acid (290 mg) in CH2Cl2 (5 mL).
After stirring for 48 h, the solvent was removed in vacuo. Purification by
column chromatography (silica gel 5 g, n-hexane/AcOEt 4:1) afforded
triester 75 (279 mg, 96% for three steps) as a colorless oil. [a]2D2 =ꢀ10.4
(c=1.58 in CHCl3); 1H NMR (500 MHz, CDCl3): d=1.43 (s, 9H; CO2C-
A
G
A
AHCTREUNG
14.2, 6.7 Hz, 1H; C1’-H), 3.33 (s, 3H; OCH3), 3.79 (dt, J=10.1, 6.7 Hz,
1H; C2’-H), 3.89 (dt, J=10.1, 6.7 Hz, 1H; C2’-H), 4.02 (s, 1H; C4-OH),
4.59 (d, J=6.4 Hz, 1H; one of OCH2O), 4.61 (d, J=6.4 Hz, 1H; one of
CDCl3): d=ꢀ0.09 (s, 9H; Si
CO2C(CH3)3), 1.38 (s, 9H; CO2C
2.22 (dt, J=14.0, 6.2 Hz, 1H; C1’-H), 2.27 (dt, J=14.0, 6.2 Hz, 1H; C1’-
A
ACHTREUNG
G
G
ACHTREUNG
8918
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
OCH2O), 4.64 (d, J=11.9 Hz, 1H; OCHPh), 4.77 (s, 1H; C3-H), 4.78 (d,
J=11.9 Hz, 1H; OCHPh), 4.82 (brs, 1H; C7-H), 5.30 (d, J=0.9 Hz, 1H;
C6-H), 7.28–7.34 (m, 5H; ArH); 13C NMR (67.8 MHz, CDCl3): d=27.7,
27.9, 28.0, 36.1, 55.1, 62.5, 71.7, 73.9, 75.5, 82.6, 83.0, 83.2, 83.4, 84.9, 91.3,
96.4, 103.2, 127.8, 128.28, 128.34, 137.2, 152.4, 164.7, 165.7, 168.8; IR
(film): n˜ =3453, 2980, 2934, 1744, 1456, 1395, 1370, 1333, 1277, 1256,
1155, 1116 cmꢀ1; HR-MS (FAB): m/z: calcd for C37H56O15Na: 763.3517,
found: 763.3530 [M ++Na].
orless oil. [a]2D5 =ꢀ10.9 (c=1.32 in CHCl3); 1H NMR (500 MHz, CDCl3):
d=1.43 (s, 9H; CO2C
A
G
CO2C
N
N
H2), 4.01 (s, 1H; OH), 4.60 (d, J=12.2 Hz, 1H; OCHPh), 4.76 (d, J=
12.2 Hz, 1H; OCHPh), 4.79 (brs, 1H; C7-H), 4.81 (s, 1H; C3-H), 5.16
(dd, J=1.3, 10.0 Hz, 1H; =CHH), 5.19 (d, J=1.1 Hz, 1H; C6-H), 5.24
(dd, J=1.3, 17.0 Hz, 1H; =CHH), 5.97 (ddt, J=10.0, 17.0, 7.2 Hz, 1H;
C2’-H), 7.28–7.32 (m, 5H; ArH); 13C NMR (67.8 MHz, CDCl3): d=27.7,
27.9, 28.0, 40.4, 71.6, 74.0, 75.5, 77.2, 81.4, 82.6, 83.0, 83.2, 83.4, 84.9, 91.2,
103.8, 119.3, 127.8, 128.2, 128.3, 130.9, 137.2, 152.2, 164.7, 165.7, 168.8; IR
(film): n˜ =3451, 2980, 2934, 1744, 1456, 1370, 1277, 1256, 1157, 1117,
980 cmꢀ1; HR-MS (FAB): m/z: calcd for C36H53O13: 693.3486, found:
693.3468 [M ++H].
Tri-tert-butyl (1S,3S,4S,5R,6R,7R)-6-benzyloxy-7-(tert-butoxycarbonyl)-
A
N
carboxylate (76): TMSCl (60 mL, 0.456 mmol) was added to a stirred solu-
tion of MOM ether 75 (56 mg, 0.076 mmol) and Et4NBr (96 mg,
0.456 mmol) in CH2Cl2 (2 mL) at 08C. The reaction mixture was stirred
for 1 h and then allowed to warm to room temperature. After stirring for
20 h, the reaction was quenched with saturated aqueous NaHCO3
(10 mL), and the mixture was extracted with AcOEt (15 mL). The organ-
ic extract was washed with brine (10 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(70 mg), which was purified by column chromatography (silica gel 5 g, n-
hexane/AcOEt 3:1) to give diol 76 (40 mg, 75%) as a colorless oil.
A
5.0 mL, 7.85 mmol) was added to a stirred solution of trimethylsulfonium
iodide (1.6 g, 8.04 mmol) in THF (20 mL) at ꢀ208C. After stirring for
30 min, a solution of epoxide 80[44] (326 mg, 2.01 mmol) in THF (10 mL)
was added. After stirring for another 30 min, the reaction mixture was al-
lowed to warm to room temperature and stirred for 2 h. The reaction was
quenched with H2O (15 mL), and the mixture was extracted with AcOEt
(30 mL). The organic extract was washed with brine (15 mL) and dried
over anhydrous Na2SO4. Filtration and evaporation in vacuo furnished
the crude product (420 mg), which was purified by column chromatogra-
phy (silica gel 15 g, n-hexane/AcOEt 20:1) to give allyl alcohol 81
1
[a]2D4 =ꢀ9.35 (c=1.25 in CHCl3); H NMR (500 MHz, CDCl3): d=1.45 (s,
9H; CO2C
N
N
A
9.6, 14.8 Hz, 1H; C1’-H), 3.76 (m, 1H; C2’-H), 4.06 (brs, 1H; C4-OH),
4.18 (m, 1H; C2’-H), 4.59 (d, J=12.0 Hz, 1H; OCHPh), 4.74 (d, J=
12.0 Hz, 1H; OCHPh), 4.80 (s, 1H; C3-H), 4.81 (brs, 1H; C7-H), 5.12 (d,
J=1.4 Hz, 1H; C6-H), 7.28–7.32 (m, 5H; ArH); 13C NMR (67.8 MHz,
CDCl3): d=27.7, 27.9, 28.0, 38.0, 58.4, 71.8, 73.6, 75.7, 77.2, 82.3, 83.1,
83.5, 83.8, 83.9, 85.4, 91.1, 105.0, 128.0, 128.3, 128.4, 136.9, 152.4, 164.4,
165.8, 168.7; IR (film): n˜ =3545, 3455, 2982, 2936, 1732, 1456, 1395, 1370,
(309 mg, 87%) as
a
colorless oil. [a]D21 =+23.4 (c=0.65 in CHCl3);
1H NMR (500 MHz, CDCl3): d=0.87 (d, J=6.8 Hz, 3H; C5’-CH3), 1.49
(brs, 1H; OH), 1.91 (m, 1H; C5’-H), 2.40 (dd, J=9.0, 13.5 Hz, 1H; C6’-
H), 2.86 (dd, J=5.9, 13.5 Hz, 1H; C6’-H), 4.06 (dd, J=4.2, 5.7 Hz, 1H;
C4’-H), 5.18 (dd, J=0.8, 10.5 Hz, 1H; =CHH), 5.27 (dd, J=0.8, 17.4 Hz,
1H; =CHH), 5.75 (ddd, J=5.7, 10.5, 17.4 Hz, 1H; C3’-H), 7.17–7.29 (m,
5H; ArH); 13C NMR (67.8 MHz, CDCl3): d=13.8, 39.2, 40.6, 75.5, 77.2,
115.3, 125.8, 128.2, 129.2, 139.7, 141.0; IR (film): n˜ =3405, 3027, 2967,
1603, 1495, 1454, 1428, 1030, 993, 934 cmꢀ1; HR-MS (EI): m/z: calcd for
C12H16O: 176.1201, found: 176.1204 [M +].
1275, 1115, 984, 918 cmꢀ1; HR-MS (FAB): m/z: calcd for C35H53O14
697.3435, found: 697.3412 [M ++H].
:
Tri-tert-butyl (1S,3S,4S,5R,6R,7R)-6-benzyloxy-7-(tert-butoxycarbonyl)-
oxy-1-(formylmethyl)-4-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tri-
A
ACHTREUNG
carboxylate (5): Dess–Martin periodinane (37 mg, 0.086 mmol) was
added to a stirred solution of diol 76 (40 mg, 0.057 mmol) in CH2Cl2
(2 mL) at 08C. After stirring at room temperature for 30 min, the reac-
tion mixture was diluted with AcOEt (15 mL) and poured into an ice-
cooled saturated aqueous NaHCO3 (10 mL) containing Na2S2O3·H2O
(1.0 g). The layers were separated, and the organic layer was washed with
brine (10 mL) and dried over anhydrous Na2SO4. Filtration and evapora-
tion in vacuo furnished the crude product (39 mg), which was purified by
column chromatography (silica gel 5 g, n-hexane/AcOEt 10:1) to give al-
dehyde 5 (37 mg, 93%) as a colorless oil. [a]2D3 =ꢀ4.06 (c=1.65 in
C
CHCl3); 1H NMR (500 MHz, CDCl3): d=1.45 (s, 18H; 2”CO2C
ACHTREUNG
1.47 (s, 9H; CO2C
A
ACHTREUNG
2.3 Hz, 2H; C1’-H2), 4.11 (s, 1H; C4-OH), 4.60 (d, J=12.0 Hz, 1H;
OCHPh), 4.75 (d, J=12.0 Hz, 1H; OCHPh), 4.83 (s, 1H; C3-H), 4.86
(brs, 1H; C7-H), 5.14 (d, J=1.1 Hz, 1H; C6-H), 7.29–7.32 (m, 5H;
ArH), 9.94 (t, J=2.3 Hz, 1H; CHO); 13C NMR (67.8 MHz, CDCl3): d=
27.7, 27.9, 27.98, 28.03, 48.9, 72.1, 73.8, 75.6, 77.2, 82.1, 83.0, 83.5, 83.7,
83.9, 85.5, 91.4, 102.2, 128.0, 128.3, 128.4, 136.9, 152.2, 164.3, 165.4, 168.6,
198.7; IR (film): n˜ =3449, 2982, 2936, 1732, 1476, 1458, 1395, 1372, 1258,
1155 cmꢀ1; elemental analysis calcd (%) for C35H50O14 (694.8): C 60.51, H
7.25; found: C 60.29, H 7.37.
Tri-tert-butyl (1S,3S,4S,5R,6R,7R)-1-allyl-6-benzyloxy-7-(tert-butoxycar-
bonyl)oxy-4-hydroxy-2,8-dioxabicyclo
A
Typical procedure for the olefin cross-metathesis: tri-tert-butyl [1S,1-
(79): tBuOK (258 mg, 2.30 mmol) was added to a stirred solution of
Ph3P+CH3 Brꢀ (911 mg, 2.55 mmol) in Et2O (8.5 mL) at 08C, and the
mixture was stirred at room temperature for 30 min. The 0.27m solution
of Ph3P=CH2 in Et2O thus obtained (5.1 mL, 1.38 mmol) was added to a
solution of aldehyde 5 (354 mg, 0.510 mmol) in Et2O (5 mL). After stir-
ring for 30 min, the reaction was quenched with saturated aqueous
NH4Cl (10 mL), and the mixture was extracted with AcOEt (15 mL).
The organic extract was washed with brine (10 mL) and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (403 mg), which was purified by column chromatography (silica
gel 10 g, n-hexane/AcOEt 10:1) to give alkene 79 (328 mg, 93%) as a col-
ACHTREUNG
ACHTREUNG
AHCTREUNG
0.073 mmol) was added to a stirred solution of alkenes 79 (253 mg,
0.365 mmol) and 82 (159 mg, 0.731 mmol) in benzene (3.7 mL). After stir-
ring at 608C for 8 h, the solvent was evaporated in vacuo, and the residue
(472 mg) was purified by flash column chromatography (silica gel 10 g, n-
hexane/AcOEt 20:1
(258 mg, 80%) and (Z)-87 (32.2 mg, 10%) as colorless oils, along with
!
6:1) to give cross-coupling products (E)-87
homo-dimer 89 (14.9 mg, 10%) and alkene 92 (4.7 mg, 1.5%) as colorless
oils.
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8919

S. Hashimoto et al.
1
Data for (E)-87: [a]1D9 = ꢀ9.27 (c = 1.58 in CHCl3); H NMR (500 MHz,
18H; CO2C
A
G
CDCl3): d=0.86 (d, J=6.8 Hz, 3H; C5’-CH3), 1.42 (s, 9H; CO2C
G
H), 3.00 (dd, J=6.6, 14.1 Hz, 1H; C1’-H), 4.03 (s, 1H; OH), 4.59 (d, J=
12.1 Hz, 1H; OCHPh), 4.76 (d, J=12.1 Hz, 1H; OCHPh), 4.78 (brs, 1H;
C7-H), 4.83 (s, 1H; C3-H), 5.21 (brs, 1H; C6-H), 6.34 (ddd, J=6.6, 8.1,
15.9 Hz, 1H; C2’-H), 6.56 (d, J=15.9 Hz, 1H; =CHPh), 7.19 (m, 1H;
ArH), 7.25–7.32 (m, 7H; ArH), 7.36–7.38 (m, 2H; ArH); 13C NMR
(125.8 MHz, CDCl3): d=27.5, 27.7, 27.9, 28.1, 29.7, 40.0, 71.5, 74.1, 75.7,
81.5, 82.6, 83.0, 83.2, 83.4, 84.9, 91.5, 104.1, 122.8, 126.4, 127.1, 127.8,
128.29, 128.30, 131.0, 133.9, 137.2, 137.5, 152.2, 152.3, 164.7, 165.7, 168.8;
IR (film): n˜ =3455, 2982, 2934, 1742, 1599, 1497, 1476, 1456, 1395, 1370,
1333, 1275, 1157, 1117, 1032, 978, 905 cmꢀ1; HR-MS (FAB): m/z: calcd
for C42H56O13: 768.3721, found: 768.3734 [M +].
1.43 (s, 9H; CO2C
A
G
OCO2C(CH3)3), 2.03 (s, 3H; COCH3), 2.04 (m, 1H; C5’-H), 2.33 (dd, J=
ACHTREUNG
9.5, 13.5 Hz, 1H; C6’-H), 2.69 (dd, J=7.6, 14.8 Hz, 1H; C1’-H), 2.80 (dd,
J=6.2, 14.8 Hz, 1H; C1’-H), 2.84 (dd, J=5.0, 13.5 Hz, 1H; C6’-H), 4.02
(s, 1H; OH), 4.56 (d, J=11.9 Hz, 1H; OCHPh), 4.70 (d, J=11.9 Hz, 1H;
OCHPh), 4.80 (s, 1H; C3-H), 4.82 (brs, 1H; C7-H), 5.17 (d, J=1.5 Hz,
1H; C6-H), 5.23 (dd, J=5.2, 6.0 Hz, 1H; C4’-H), 5.72 (dd, J=6.0,
15.7 Hz, 1H; C3’-H), 5.81 (ddd, J=6.2, 7.6, 15.7 Hz, 1H; C2’-H), 7.11–
7.16 (m, 3H; ArH), 7.21–7.28 (m, 7H; ArH); 13C NMR (125.8 MHz,
CDCl3): d=14.7, 21.1, 27.7, 27.9, 27.99, 28.04, 38.3, 38.7, 39.2, 71.9, 74.1,
75.5, 77.2, 81.3, 82.9, 83.1, 83.2, 83.3, 84.9, 91.2, 103.8, 125.5, 125.7, 127.8,
128.1, 128.2, 128.3, 128.4, 129.2, 131.6, 137.2, 140.8, 152.4, 164.7, 165.7,
168.7, 170.2; IR (film): n˜ =3455, 2980, 2934, 1732, 1456, 1395, 1372, 1279,
1121, 976, 910, 843 cmꢀ1; HR-MS (FAB): m/z: calcd for C48H66O15Na:
905.4299, found: 905.4327 [M ++Na].
Tri-tert-butyl [1S,1
nylhexyl)-7-(tert-butoxycarbonyl)oxy-4,6-dihydroxy-2,8-dioxabicyclo-
[3.2.1]octane-3,4,5-tricarboxylate (4): Pd/BaSO4 (5%, 60 mg) was added
(4R,5R),3S,4S,5R,6R,7R]-1-(4-acetoxy-5-methyl-6-phe-
AHCTREUNG
to a stirred solution of allyl acetate 87 (14.0 mg, 15.9 mmol) in AcOEt
(1 mL), and the mixture was vigorously stirred under 1 atm of hydrogen
for 10 h. The catalyst was filtered through a Celite pad, and the filtrate
was evaporated in vacuo to furnish the crude product (14.1 mg), which
was used without further purification.
Data for (Z)-87: [a]2D1 =ꢀ7.22 (c=1.74 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.86 (d, J=6.7 Hz, 3H; C5’-CH3), 1.435 (s, 18H; 2”CO2C-
(CH3)3), 1.444 (s, 9H; CO2C
G
N
3H; COCH3), 2.07 (m, 1H; C5’-H), 2.29 (dd, J=10.1, 13.4 Hz, 1H; C6’-
H), 2.85–2.88 (m, 3H; C1’-H2, C6’-H), 3.99 (s, 1H; OH), 4.62 (d, J=
11.9 Hz, 1H; OCHPh), 4.78 (brs, 1H; C7-H), 4.79 (d, J=11.9 Hz, 1H;
OCHPh), 4.82 (s, 1H; C3-H), 5.09 (brs, 1H; C6-H), 5.49 (dd, J=5.6,
9.6 Hz, 1H; C4’-H), 5.59 (dd, J=9.6, 11.0 Hz, 1H; C3’-H), 5.90 (dt, J=
11.0, 7.0 Hz, 1H; C2’-H), 7.13–7.15 (m, 3H; ArH), 7.23–7.34 (m, 7H;
ArH); 13C NMR (125.8 MHz, CDCl3): d=14.6, 21.2, 27.5, 27.7, 27.9, 28.0,
28.1, 28.3, 35.0, 38.5, 39.5, 71.8, 73.3, 74.0, 75.6, 77.2, 82.2, 82.7, 82.9, 83.2,
83.4, 84.9, 91.4, 103.6, 125.8, 126.9, 127.8, 128.1, 128.2, 128.3, 128.4, 129.2,
129.3, 137.3, 140.6, 152.2, 164.7, 165.7, 168.7, 170.1; IR (film): n˜ =3455,
2978, 2932, 2856, 1738, 1603, 1456, 1395, 1370, 1333, 1254, 1157, 1117,
1030, 980, 910, 843 cmꢀ1; HR-MS (FAB): m/z: calcd for C48H66O15Na:
905.4299, found: 905.4284 [M ++Na]
Data for 89: [a]2D2 =ꢀ11.5 (c=0.16 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.87 (d, J=6.8 Hz, 6H; 2”C5’-CH3), 2.02 (m, 2H; 2”C5’-
H), 2.08 (s, 6H; 2”COCH3), 2.30 (dd, J=9.3, 13.5 Hz, 2H; 2”C6’-H),
2.79 (dd, J=5.3, 13.5 Hz, 2H; 2”C6’-H), 5.21 (ddd, J=1.6, 3.5, 4.8 Hz,
2H; 2”C4’-H), 5.65 (dd, J=1.6, 3.5 Hz, 2H; 2”C3’-H), 7.10–7.20 (m,
6H; ArH), 7.25–7.28 (m, 4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=
14.6, 21.2, 38.9, 39.3, 76.2, 77.2, 126.0, 128.3, 129.1, 129.9, 140.3, 170.1; IR
(film): n˜ =3027, 2969, 2932, 1738, 1603, 1495, 1454, 1372, 1236, 1096,
1020, 970, 910 cmꢀ1; HR-MS (EI): m/z: calcd for C26H32O4: 408.2300,
found: 408.2295 [M +].
Pd(OH)2 on carbon (20%, 10 mg) was added to a stirred solution of the
partially debenzylated mixture of hydrogenation products (crude,
14.1 mg) in AcOEt (1 mL), and the mixture was vigorously stirred under
1 atm of hydrogen for 1 h. The catalyst was filtered through a Celite pad,
and the filtrate was evaporated in vacuo. Purification of the residue
(14.1 mg) by column chromatography (silica gel 3 g, n-hexane/AcOEt
6:1) afforded diol 4 (13.5 mg, 98%) as a colorless oil. [a]2D2 =+29.7 (c=
0.95 in EtOH) [lit. [a]D =+43.3 (c=0.25 in CH2Cl2),[8b] [a]D21 =+23.8 (c=
0.59 in EtOH),[12b] [a]D27 =+25.8 (c=0.47 in CH2Cl2);[13b] 1H NMR
(500 MHz, CDCl3): d=0.84 (d, J=6.8 Hz, 3H; C5’-CH3), 1.45 (s, 9H;
CO2C
A
G
N
(s, 9H; OCO2C
AHCTREUNG
3H; C1’-H2, C5’-H), 2.05 (s, 3H; COCH3), 2.31 (dd, J=9.6, 13.5 Hz, 1H;
C6’-H), 2.76 (dd, J=5.0, 13.5 Hz, 1H; C6’-H), 2.79 (d, J=2.8 Hz, 1H;
C6-OH), 3.92 (s, 1H; C4-OH), 4.64 (d, J=2.0 Hz, 1H; C7-H), 4.72 (s,
1H; C3-H), 4.87 (dt, J=6.5, 4.0 Hz, 1H; C4’-H), 5.11 (dd, J=2.0, 2.8 Hz,
1H; C6-H), 7.12–7.18 (m, 3H; ArH), 7.24–7.27 (m, 2H; ArH); 13C NMR
(125.8 MHz, CDCl3): d=13.8, 18.9, 21.2, 27.7, 28.0, 28.05, 28.13, 30.9,
35.5, 37.9, 39.4, 74.1, 75.26, 75.29, 76.8, 76.9, 83.2, 83.8, 83.9, 85.0, 85.5,
90.7, 103.9, 125.8, 128.2, 129.1, 140.7, 153.7, 165.2, 165.8, 168.5, 170.8; IR
(film): n˜ =3461, 2932, 1732, 1603, 1456, 1370, 1277, 1155, 966, 916,
845 cmꢀ1; HR-MS (FAB): m/z: calcd for C41H63O15: 795.4167, found:
795.4190 [M ++H].
Data for 92: [a]2D1 =ꢀ16.4 (c=0.14 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.935 (d, J=6.1 Hz, 3H; CHCH3), 0.938 (d, J=7.0 Hz, 3H;
C5’-CH3), 0.96 (d, J=6.1 Hz, 3H; CHCH3), 2.12 (s, 3H; COCH3), 2.15
(m, 1H; C5’-H), 2.37 (dd, J=9.6, 13.5 Hz, 1H; C6’-H), 2.91 (dd, J=5.0,
Tri-tert-butyl
toxycarbonyl)oxy-4-hydroxy-1-(4-hydroxy-5-methyl-6-phenyl-2-hexenyl)-
2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (86): DIBALH in tolu-
[1S,1
A
AHCTREUNG
AHCTREUNG
ene (0.10m, 1.0 mL, 0.10 mmol) was added dropwise over a 30 min
period to a stirred solution of acetate (E)-87 (20 mg, 0.023 mmol) in tolu-
ene (0.4 mL)/CH2Cl2 (0.4 mL) at ꢀ788C. After stirring for 30 min, the re-
action was quenched by addition of MeOH (50 mL) followed by 15%
aqueous potassium sodium tartrate (5 mL). After stirring at room tem-
perature for 1 h, the mixture was extracted with AcOEt (15 mL). The or-
ganic extract was washed with brine (5 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(19.0 mg), which was purified by column chromatography (silica gel 3 g,
n-hexane/AcOEt 3:1) to give diol 86 (16.2 mg, 84%) as a colorless oil.
[a]2D7 =+3.93 (c=1.45 in EtOH); 1H NMR (500 MHz, CDCl3): d=0.85
13.5 Hz, 1H; C6’-H), 3.72 (heptet, J=6.1 Hz, 1H; OCH(CH3)2), 5.42 (dd,
G
J=6.0, 6.8 Hz, 1H; C4’-H), 6.19 (dd, J=6.8, 16.0 Hz, 1H; C3’-H), 7.02
(d, J=16.0 Hz, 1H; =CHAr), 7.15–7.19 (m, 4H; ArH), 7.23–7.32 (m, 4H;
ArH), 7.40 (m, 2H; ArH), 7.49 (m, 1H; ArH), 7.55 (m, 2H; ArH);
13C NMR (67.8 MHz, CDCl3): d=14.8, 21.2, 22.0, 39.0, 39.7, 75.9, 76.2,
77.2, 78.0, 123.7, 125.4, 126.0, 126.6, 127.0, 128.1, 128.3, 128.7, 129.1,
129.3, 129.4, 130.7, 131.5, 136.2, 139.3, 140.5, 153.0, 170.2; IR (film): n˜ =
3061, 3027, 2973, 2930, 1738, 1497, 1453, 1426, 1372, 1236, 1177, 1138,
1107, 1020, 974 cmꢀ1; HR-MS (EI): m/z: calcd for C29H32O3: 428.2351,
found: 428.2335 [M +].
Data for 88: [a]2D2 =+21.3 (c=1.78 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.87 (d, J=6.8 Hz, 6H; 2”C5’-CH3), 1.68 (brs, 2H; 2”OH),
1.90 (m, 2H; 2”C5’-H), 2.38 (dd, J=9.0, 13.4 Hz, 2H; 2”C6’-H), 2.85
(dd, J=5.9, 13.4 Hz, 2H; 2”C6’-H), 4.06 (m, 2H; 2”C4’-H), 5.73 (dd,
J=1.4, 3.1 Hz, 2H; 2”C3’-H), 7.16–7.20 (m, 6H; ArH), 7.24–7.28 (m,
4H; ArH); 13C NMR (67.8 MHz, CDCl3): d=14.1, 39.2, 40.9, 74.9, 125.8,
128.2, 129.1, 132.9, 140.9; IR (film): n˜ =3385, 3029, 2967, 2930, 1603,
1495, 1454, 1377, 1265, 1101, 1059, 1017, 974 cmꢀ1; HR-MS (FAB): m/z:
calcd for C22H27O2: 323.2011, found: 323.2023 [M +ꢀH].
(d, J=6.8 Hz, 3H; C5’-CH3), 1.44 (s, 27H; 3”CO2C
(CH3)3), 1.50 (s, 9H;
OCO2C(CH3)3), 1.79 (brs, 1H; C4’-OH), 1.90 (m, 1H; C5’-H), 2.37 (dd,
AHCTREUNG
J=9.1, 13.3 Hz, 1H; C6’-H), 2.72 (dd, J=6.7, 14.1 Hz, 1H; C1’-H), 2.80
(dd, J=4.9, 14.1 Hz, 1H; C1’-H), 2.87 (dd, J=5.7, 13.3 Hz, 1H; C6’-H),
4.04 (dd, J=5.1, 9.4 Hz, 1H; C4’-H), 4.06 (s, 1H; C4-OH), 4.57 (d, J=
12.0 Hz, 1H; OCHPh), 4.72 (d, J=12.0 Hz, 1H; OCHPh), 4.80 (s, 1H;
C3-H), 4.81 (brs, 1H; C7-H), 5.16 (d, J=1.4 Hz, 1H; C6-H), 5.76 (dd,
J=5.1, 15.7 Hz, 1H; C3’-H), 5.81 (ddd, J=4.9, 6.7, 15.7 Hz, 1H; C2’-H),
7.14–7.18 (m, 3H; ArH), 7.23–7.30 (m, 7H; ArH); 13C NMR (125.8 MHz,
CDCl3): d=14.1, 27.7, 27.9, 28.0, 28.1, 38.6, 39.0, 40.7, 71.8, 74.0, 75.0,
75.5, 77.2, 81.5, 82.6, 83.28, 83.34, 83.5, 85.1, 91.2, 103.8, 123.9, 125.6,
Data for 91: [a]2D2 =ꢀ18.6 (c=0.79 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=1.35 (s, 9H; CO2C
A
N
8920
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
127.9, 128.1, 128.2, 128.3, 129.3, 136.7, 137.1, 141.3, 152.3, 164.7, 165.7,
168.7; IR (film): n˜ =3455, 2980, 2934, 1742, 1495, 1456, 1395, 1370, 1256,
1154, 1117, 1030, 978 cmꢀ1; HR-MS (FAB): m/z: calcd for C46H64O14Na:
863.4194, found: 863.4186 [M ++Na].
(film): n˜ =3457, 2976, 2930, 2857, 1742, 1456, 1395, 1370, 1277, 1258,
1155, 1119, 1076 cmꢀ1
;
HR-MS (FAB): m/z: calcd for C47H68O15Na:
895.4456, found: 895.4452 [M ++Na].
Tri-tert-butyl (1S,1{2,[4S,4(2R),5R]},3S,4S,5R,6R,7R)-6-benzyloxy-7-(tert-
butoxycarbonyl)oxy-4-hydroxy-1-[2-[2,2-dimethyl-4-(1-phenylpropan-2-
yl)-1,3-dioxan-5-yl]ethyl]-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxy-
AHCTREUNG
Tri-tert-butyl [1S,1
momethyl)dimethylsilyl]oxy-5-methyl-6-phenyl-2-hexenyl]-7-(tert-butoxy-
carbonyl)oxy-4-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate
(94): (Bromomethyl)chlorodimethylsilane (11 mg, 0.06 mmol) was added
to stirred solution of diol 86 (42.1 mg, 0.05 mmol), Et3N (14 mL,
A
AHCTREUNG
G
late (97): p-Toluenesulfonic acid monohydrate (0.1 mg, 0.5 mmol) was
added to a stirred solution of triol 96 (9.0 mg, 9.2 mmol) in 2,2-dimethoxy-
propane (1.0 mL). After stirring for 1 h, the reaction was quenched with
Et3N (0.1 mL), and the volatile elements were removed in vacuo. Purifi-
cation of the residue by column chromatography (silica gel 3 g, n-hexane/
AcOEt 4:1) afforded acetonide 97 (8.0 mg, 85%) as a colorless oil.
[a]2D1 =ꢀ17.0 (c=0.40 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.89
(d, J=6.8 Hz, 3H; C5’-CH3), 1.31 (s, 3H; acetonide CH3), 1.38 (s, 3H;
a
0.10 mmol) and DMAP (0.6 mg, 5.0 mmol) in CH2Cl2 (1 mL) at 08C.
After stirring for 1 h, the reaction was quenched with saturated aqueous
NaHCO3 (5 mL), and the mixture was extracted with AcOEt (15 mL).
The organic extract was washed with brine (5 mL) and dried over anhy-
drous Na2SO4. Filtration and evaporation in vacuo furnished the crude
product (29 mg), which was purified by column chromatography (silica
gel 5 g, n-hexane/AcOEt 8:1) to give silyl ether 94 (47.4 mg, 96%) as a
colorless oil. [a]2D4 =ꢀ5.33 (c=0.92 in CHCl3); 1H NMR (500 MHz,
CDCl3): d=0.24 (s, 3H; SiCH3), 0.25 (s, 3H; SiCH3), 0.79 (d, J=6.7 Hz,
acetonide CH3), 1.43 (s, 9H; CO2C
A
A
ACHTREUNG
C2’-H), 1.80 (m, 1H; C5’-H), 1.85 (t, J=8.6 Hz, 2H; C1’-H2), 2.07 (m,
1H; C3’-H), 2.56 (dd, J=7.5, 13.5 Hz, 1H; C6’-H), 2.63 (dd, J=7.8,
13.5 Hz, 1H; C6’-H), 3.44 (dd, J=1.8, 10.4 Hz, 1H; C4’-H), 3.52 (dd, J=
11.4, 11.5 Hz, 1H; C14’-Hax), 3.82 (dd, J=5.0, 11.5 Hz, 1H; C14’-Heq),
4.02 (s, 1H; C4-OH), 4.59 (d, J=12.0 Hz, 1H; OCHPh), 4.74 (d, J=
12.0 Hz, 1H; OCHPh), 4.77 (s, 1H; C3-H), 4.81 (brs, 1H; C7-H), 5.04 (d,
J=1.1 Hz, 1H; C6-H), 7.14–7.15 (m, 3H; ArH), 7.21–7.32 (m, 7H;
ArH); 13C NMR (67.8 MHz, CDCl3): d=12.7, 19.2, 20.3, 27.7, 27.9, 27.98,
28.03, 29.6, 29.7, 32.8, 35.1, 35.3, 40.1, 64.3, 71.9, 73.87, 73.91, 75.5, 76.8,
77.2, 77.8, 82.4, 82.7, 83.2, 83.3, 83.5, 85.1, 91.2, 97.9, 103.9, 125.6, 127.9,
128.1, 128.3, 128.4, 129.3, 137.1, 141.3, 152.5, 164.7, 165.8, 168.9; IR
(CHCl3): n˜ =3021, 2928, 2855, 1728, 1464, 1281, 1221, 1017, 918, 851,
760 cmꢀ1; HR-MS (ESI): m/z: calcd for C50H72O15Na: 935.4769, found:
935.4775 [M ++Na].
3H; C5’-CH3), 1.42 (s, 18H; 2”CO2C
N
N
1.50 (s, 9H; OCO2C(CH3)3), 1.83 (m, 1H; C5’-H), 2.26 (dd, J=9.9,
ACHTREUNG
13.3 Hz, 1H; C6’-H), 2.48 (d, J=16.5 Hz, 1H; one of SiCH2Br), 2.51 (d,
J=16.5 Hz, 1H; one of SiCH2Br), 2.68 (dd, J=6.5, 14.5 Hz, 1H; C1’-H),
2.80 (dd, J=3.9, 14.5 Hz, 1H; C1’-H), 2.86 (dd, J=4.6, 13.3 Hz, 1H; C6’-
H), 3.98 (s, 1H; C4-OH), 4.08 (dd, J=4.1, 4.3 Hz, 1H; C4’-H), 4.57 (d,
J=11.9 Hz, 1H; OCHPh), 4.71 (d, J=11.9 Hz, 1H; OCHPh), 4.78 (s,
1H; C3-H), 4.83 (brs, 1H; C7-H), 5.14 (d, J=1.2 Hz, 1H; C6-H), 5.72
(ddd, J=3.9, 6.5, 16.3 Hz, 1H; C2’-H), 5.75 (dd, J=4.1, 16.3 Hz, 1H; C3’-
H), 7.13–7.15 (m, 3H; ArH), 7.22–7.28 (m, 7H; ArH); 13C NMR
(125.8 MHz, CDCl3): d=ꢀ2.5, 14.2, 17.0, 27.7, 27.9, 28.0, 28.1, 38.3, 38.8,
41.8, 72.1, 74.1, 75.5, 77.3, 81.7, 83.0, 83.2, 83.3, 84.9, 91.2, 103.8, 123.7,
125.5, 127.8, 128.0, 128.2, 128.3, 129.2, 136.0, 137.2, 141.5, 152.4, 164.8,
165.7, 168.8; IR (film): n˜ =3457, 2978, 2934, 2870, 1742, 1495, 1456, 1395,
1370, 1256, 1156, 1119, 1030, 976 cmꢀ1; HR-MS (FAB): m/z: calcd for
C49H71BrO14SiNa: 1013.3694, found: 1013.3688 [M ++Na].
Tri-tert-butyl [1S,1
oxy-4,6-dihydroxy-1-[4-hydroxy-3-(hydroxymethyl)-5-methyl-6-phenyl-
hexyl]-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (98): Pd(OH)2
A
AHCTREUNG
AHCTREUNG
on carbon (20%, 82 mg) was added to a stirred solution of benzyl ether
96 (82.0 mg, 0.094 mmol) in AcOEt (3 mL), and the mixture was vigo-
rously stirred under 1 atm of hydrogen for 13 h. The catalyst was filtered
through a Celite pad, and the filtrate was evaporated in vacuo. Purifica-
tion of the residue (80 mg) by column chromatography (silica gel 5 g, n-
hexane/AcOEt 1:1) afforded tetraol 98 (69.7 mg, 95%) as a colorless oil.
[a]2D2 =+16.6 (c=1.02 in EtOH); 1H NMR (500 MHz, CDCl3): d=0.91
Tri-tert-butyl
toxycarbonyl)oxy-4-hydroxy-1-[4-hydroxy-3-(hydroxymethyl)-5-methyl-6-
phenylhexyl]-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (96): A
[1S,1(3R,4S,5R),3S,4S,5R,6R,7R]-6-benzyloxy-7-(tert-bu-
N
R
solution of Bu3SnH (60 mg, 0.206 mmol) and AIBN (1.1 mg, 7.0 mmol) in
degassed benzene (6 mL) was added dropwise over 3 h to a refluxing so-
lution of silyl ether 94 (136 mg, 0.137 mmol) in degassed benzene (6 mL),
and the mixture was stirred for 1 h. After cooling, the mixture was evapo-
rated in vacuo to provide a crude product (201 mg), which was used with-
out further purification.
(d, J=6.7 Hz, 3H; C5’-CH3), 1.45 (s, 9H; CO2C
ACHTREUNG
CO2C(CH3)3), 1.50 (s, 9H; CO2C(CH3)3), 1.58 (s, 9H; OCO2C
N
G
ACHTREUNG
1.60–1.76 (m, 2H; C2’-H2), 1.83 (m, 1H; C5’-H), 1.89 (dt, J=9.2, 6.3 Hz,
1H; C1’-H), 1.99 (dt, J=9.2, 6.3 Hz, 1H; C1’-H), 2.06 (m, 1H; C3’-H),
2.48 (dd, J=8.7, 13.4 Hz, 1H; C6’-H), 2.74 (dd, J=6.1, 13.4 Hz, 1H; C6’-
H), 2.87 (brs, 1H; OH), 2.95 (brs, 1H; OH), 3.52 (dd, J=4.0, 7.3 Hz,
1H; C4’-H), 3.75 (dd, J=5.8, 11.3 Hz, 1H; C14’-H), 3.95 (dd, J=2.9,
11.3 Hz, 1H; C14’-H), 3.99 (s, 1H; C4-OH), 4.68 (d, J=1.9 Hz, 1H; C7-
H), 4.72 (s, 1H; C3-H), 5.13 (brs, 1H; C6-H), 7.15–7.19 (m, 3H; ArH),
7.27 (m, 2H; ArH); 13C NMR (125.8 MHz, CDCl3): d=13.3, 21.0, 27.7,
28.0, 28.1, 28.2, 32.6, 37.5, 40.4, 41.9, 63.8, 74.0, 75.1, 77.2, 77.7, 83.6, 84.0,
84.2, 85.3, 85.7, 90.8, 103.9, 125.8, 128.3, 129.2, 141.0, 153.6, 165.2, 165.8,
168.5; IR (film): n˜ =3455, 2978, 2932, 1732, 1289, 1117, 986, 845,
795 cmꢀ1; HR-MS (FAB): m/z: calcd for C40H63O15: 783.4167, found:
783.4184 [M ++H].
To a stirred mixture of the crude cyclic siloxane 95 (201 mg), NaHCO3
(12 mg, 0.143 mmol) and KF (16 mg, 0.275 mmol) in THF (3 mL)/MeOH
(3 mL) was added 35% aqueous H2O2 (44 mL, 0.45 mmol), and the mix-
ture was stirred for 24 h. The reaction mixture was poured into a two-
layer mixture of Et2O (5 mL) and 50% aqueous Na2S2O3 (10 mL). The
resulting mixture was filtered through a Celite pad, and the filtrate was
extracted with AcOEt (20 mL). The organic extract was washed with
brine (10 mL) and dried over anhydrous Na2SO4. Filtration and evapora-
tion in vacuo furnished the crude product (150 mg), which was purified
by column chromatography (silica gel 10 g, n-hexane/AcOEt 3:2) to give
triol 96 (102 mg, 85%) as
a
colorless oil. [a]2D4 =ꢀ6.09 (c=1.39 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=0.90 (d, J=6.6 Hz, 3H; C5’-
CH3), 1.44 (s, 18H; 2”CO2C
A
(CH3)3), 1.51 (s,
Tri-tert-butyl [1S,1
oxy-4,6-dihydroxy-1-[4-hydroxy-5-methyl-3-[(2-nitrophenylseleno)meth-
yl]-6-phenylhexyl]-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (99):
G
9H; OCO2C(CH3)3), 1.60 (m, 2H; C2’-H2), 1.83 (m, 1H; C5’-H), 1.93
A
ACHTREUNG
(ddd, J=5.5, 9.2, 14.5 Hz, 1H; C1’-H), 2.00 (ddd, J=5.5, 9.2, 14.5 Hz,
1H; C1’-H), 2.06 (m, 1H; C3’-H), 2.47 (dd, J=8.7, 13.4 Hz, 1H; C6’-H),
2.74 (dd, J=6.0, 13.4 Hz, 1H; C6’-H), 2.95 (brs, 2H; C4’-OH, C3’-
CH2OH), 3.52 (dd, J=3.9, 7.4 Hz, 1H; C4’-H), 3.75 (dd, J=5.8, 11.4 Hz,
1H; C14’-H), 3.97 (dd, J=2.8, 11.4 Hz, 1H; C14’-H), 4.03 (s, 1H; C4-
OH), 4.59 (d, J=11.9 Hz, 1H; OCHPh), 4.74 (d, J=11.9 Hz, 1H;
OCHPh), 4.78 (s, 1H; C3-H), 4.83 (brs, 1H; C7-H), 5.09 (d, J=1.6 Hz,
1H; C6-H), 7.15–7.18 (m, 3H; ArH), 7.23–7.32 (m, 7H; ArH); 13C NMR
(125.8 MHz, CDCl3): d=13.1, 21.0, 27.7, 27.9, 28.0, 28.1, 32.8, 37.4, 40.4,
41.9, 63.8, 72.1, 73.9, 75.3, 77.8, 82.8, 83.46, 83.54, 83.6, 85.2, 91.1, 104.2,
125.7, 127.9, 128.2, 128.4, 129.2, 137.1, 141.1, 152.6, 164.8, 165.9, 168.8; IR
Bu3P (10.7 mg, 53 mmol) was added to a stirred solution of tetraol 98
(8.0 mg, 10.2 mmol) and 2-nitrophenyl selenocyanate (12.0 mg, 53 mmol)
in THF (0.5 mL). After stirring for 30 min, the solvent was removed in
vacuo, and the yellow residue (35 mg) was purified by column chroma-
tography (silica gel 5 g, n-hexane/AcOEt 3:1) to give selenide 99 (6.1 mg,
62%) as
a
yellow oil. [a]2D2 =ꢀ10.5 (c=1.22 in CHCl3); 1H NMR
(500 MHz, CDCl3): d=0.91 (d, J=6.7 Hz, 3H; C5’-CH3), 1.45 (s, 9H;
CO2C
(s, 9H; OCO2C
3H; C1’-H2, C3’-H), 2.46 (dd, J=8.5, 13.5 Hz, 1H; C6’-H), 2.75 (dd, J=
A
(CH3)3), 1.50 (s, 9H; CO2C
G
AHCTREUNG
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8921

S. Hashimoto et al.
7.4, 13.5 Hz, 1H; C6’-H), 2.82 (d, J=3.4 Hz, 1H; C6-OH), 2.96 (dd, J=
7.1, 11.2 Hz, 1H; C14’-H), 3.23 (dd, J=4.1, 11.2 Hz, 1H; C14’-H), 3.53
(m, 1H; C4’-H), 3.96 (s, 1H; C4-OH), 4.61 (d, J=1.9 Hz, 1H; C7-H),
4.72 (s, 1H; C3-H), 5.13 (dd, J=1.9, 3.4 Hz, 1H; C6-H), 7.16–7.30 (m,
6H; ArH), 7.49 (m, 1H; ArH), 7.61 (m, 1H; ArH), 8.25 (m, 1H; ArH);
13C NMR (125.8 MHz, CDCl3): d=13.6, 23.8, 27.5, 27.7, 28.0, 28.1, 28.2,
32.1, 36.9, 40.1, 40.5, 74.0, 75.2, 76.8, 83.5, 84.0, 84.1, 85.3, 90.7, 103.9,
125.2, 126.0, 126.3, 128.4, 129.2, 129.7, 133.5, 134.4, 140.6, 147.0, 153.7,
165.1, 165.8, 168.6; IR (film): n˜ =3457, 2978, 2934, 1738, 1591, 1566, 1514,
1456, 1395, 1370, 1333, 1279, 1256, 1155, 1119, 986 cmꢀ1; HR-MS (FAB):
m/z: calcd for C46H65NO16NaSe: 990.3366, found: 990.3367 [M ++Na].
tassium carbonate in MeOH (1.0 mL) was added to diacetate 101 (34 mg,
0.04 mmol) at 08C. After stirring at room temperature for 1 h, the reac-
tion was quenched with 0.3n aqueous KH2PO4 (5 mL), and the mixture
was partitioned between AcOEt (15 mL) and brine (5 mL). The organic
layer was washed with brine (5 mL) and dried over anhydrous Na2SO4.
Filtration and evaporation in vacuo furnished the crude product (32 mg),
which was purified by column chromatography (silica gel 5 g, n-hexane/
AcOEt 4:1) to give diol 3 (26.0 mg, 80%) as a white foam. [a]2D2 =+3.86
(c=1.30 in CHCl3) [lit. [a]2D7 =+1.6 (c=0.83 in CHCl3);[14] 1H NMR
(500 MHz, CDCl3): d=0.81 (d, J=6.7 Hz, 3H; C5’-CH3), 1.45 (s, 9H;
CO2C
N
N
AHCTREUNG
Tri-tert-butyl [1S,1
methyl-3-[(2-nitrophenylseleno)methyl]-6-phenylhexyl]-7-(tert-butoxycar-
bonyl)oxy-4-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate
A
2.45 (m, 2H; C2’-H2), 2.35 (dd, J=9.4, 13.5 Hz, 1H; C6’-H), 2.72 (dd, J=
5.2, 13.5 Hz, 1H; C6’-H), 2.84 (d, J=3.5 Hz, 1H; C6-OH), 3.97 (s, 1H;
C4-OH), 4.65 (d, J=1.9 Hz, 1H; C7-H), 4.73 (s, 1H; C3-H), 4.97 (brs,
2H; C14’-H2), 5.12–5.14 (m, 2H; C6-H, C4’-H), 7.14–7.18 (m, 3H; ArH),
7.24–7.27 (m, 2H; ArH); 13C NMR (125.8 MHz, CDCl3): d=13.6, 21.1,
25.4, 27.6, 27.97, 28.04, 28.1, 29.7, 33.9, 36.6, 40.0, 74.0, 75.3, 76.8, 77.2,
79.2, 83.2, 83.8, 83.9, 85.1, 85.6, 90.8, 103.6, 111.3, 125.9, 128.3, 129.2,
140.4, 145.6, 153.6, 165.1, 165.8, 168.5, 170.2; IR (film): n˜ =3461, 2980,
2932, 1732, 1456, 1395, 1372, 1279, 1157, 1036, 990, 916, 845 cmꢀ1; HR-
MS (FAB): m/z: calcd for C42H62O15Na: 829.3986, found: 829.3979 [M +
+Na].
(100): Acetic anhydride (19 mg, 0.19 mmol) was added to a stirred solu-
tion of triol 99 (42.5 mg, 0.044 mmol) and DMAP (46 mg, 0.37 mmol) in
CH2Cl2 (1 mL) at 08C. After stirring for 30 min, the reaction was
quenched with 1n aqueous KH2PO4 (5 mL), and the mixture was extract-
ed with AcOEt (15 mL). The organic extract was washed with brine
(5 mL) and dried over anhydrous Na2SO4. Filtration and evaporation in
vacuo furnished the crude product (51 mg), which was purified by
column chromatography (silica gel 5 g, n-hexane/AcOEt 5:1) to give di-
acetate 100 (45.3 mg, 98%) as a yellow oil. [a]2D2 =ꢀ12.0 (c=1.14 in ben-
zene); 1H NMR (500 MHz, CDCl3): d=0.89 (d, J=6.7 Hz, 3H; C5’-CH3),
Tri-tert-butyl [1S,1
methyl-3-methylene-6-phenylhexyl)-7-(tert-butoxycarbonyl)oxy-6-(4,6-di-
methyl-2-octenoyl)oxy-4-hydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tri-
A
N
1.43 (s, 9H; CO2C
G
G
AHCTREUNG
OCO2C(CH3)3), 1.80–1.90 (m, 3H; C2’-H2, C5’-H), 2.01 (m, 1H; C3’-H),
ACHTREUNG
carboxylate (103): DCC (66 mg, 0.320 mmol) was added to a stirred solu-
tion of carboxylic acid 102 (55 mg, 0.320 mmol) in CH2Cl2 (1.5 mL), and
the mixture was stirred for 30 min. The solution of DCC–carboxylic acid
102 in CH2Cl2 (0.5 mL) was added to a stirred solution of diol 3 (13.7 mg,
0.017 mmol) and DMAP (31 mg, 0.256 mmol) in CH2Cl2 (2 mL). After
stirring for 5 h, the reaction was quenched with saturated aqueous
NaHCO3 (6 mL), and the mixture was extracted with Et2O/n-hexane 3:1
(15 mL). The organic extract was successively washed with saturated
aqueous NaHCO3 (5 mL) and brine (5 mL), and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(52 mg), which was purified by column chromatography (silica gel 5 g, n-
hexane/AcOEt 5:1) to give ester 103 (14.6 mg, 90%) as a colorless oil.
[a]2D2 =+29.9 (c=0.73 in CHCl3) [lit. [a]D25 =+38 (c=0.43 in CHCl3);[14]
1H NMR (500 MHz, CDCl3): d=0.80 (d, J=6.7 Hz, 3H; C5’-CH3), 0.82–
0.89 (m, 6H; C8’’-H3, C6’’-CH3), 1.02 (d, J=6.7 Hz, 3H; C4’’-CH3), 1.08–
1.14 (m, 2H; C6’’-H, C7’’-H), 1.26–1.39 (m, 3H; C5’’-H2, C7’’-H), 1.42 (s,
2.10 (s, 3H; COCH3), 2.16 (s, 3H; COCH3), 2.30 (m, 2H; C1’-H2), 2.38
(dd, J=8.5, 13.5 Hz, 1H; C6’-H), 2.69 (dd, J=6.0, 13.5 Hz, 1H; C6’-H),
2.87 (dd, J=6.0, 11.4 Hz, 1H; C14’-H), 2.96 (dd, J=5.5, 11.4 Hz, 1H;
C14’-H), 4.07 (s, 1H; OH), 4.80 (d, J=1.8 Hz, 1H; C7-H), 4.89 (s, 1H;
C3-H), 5.00 (dd, J=4.1, 7.5 Hz, 1H; C4’-H), 6.40 (d, J=1.8 Hz, 1H; C6-
H), 7.16–7.31 (m, 6H; ArH), 7.51 (m, 2H; ArH), 8.26 (m, 1H; ArH);
13C NMR (125.8 MHz, CDCl3): d=13.8, 20.7, 21.3, 24.6, 27.3, 27.6, 27.86,
27.94, 28.1, 32.1, 36.4, 38.6, 40.3, 73.9, 75.3, 76.3, 77.7, 83.2, 83.4, 83.7,
84.0, 86.2, 89.9, 103.5, 125.2, 126.0, 126.3, 128.3, 129.35, 129.39, 133.6,
134.6, 140.1, 146.9, 152.3, 164.0, 165.4, 168.4, 168.6, 170.9; IR (film): n˜ =
3453, 2980, 2934, 1746, 1591, 1566, 1516, 1456, 1372, 1333, 1279, 1155,
1119, 1038, 905 cmꢀ1; HR-MS (FAB): m/z: calcd for C50H69NO18NaSe:
1074.3577, found: 1074.3568 [M ++Na].
Tri-tert-butyl
methyl-3-methylene-6-phenylhexyl)-7-(tert-butoxycarbonyl)oxy-4-hy-
droxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (101): 35%
[1S,1
A
ACHTREUNG
9H; CO2C
A
G
A
Aqueous H2O2 (21 mL, 0.22 mmol) was added at 08C to a solution of sel-
enide 100 (45.3 mg, 0.043 mmol) in THF (1 mL), and the mixture was
stirred at room temperature for 4 h. The reaction mixture was partitioned
between AcOEt (15 mL) and saturated aqueous NaHCO3 (5 mL). The
organic layer was washed with brine (5 mL) and dried over anhydrous
Na2SO4. Filtration and evaporation in vacuo furnished the crude product
(46 mg), which was purified by column chromatography (silica gel 5 g, n-
hexane/AcOEt 5:1) to give alkene 101 (34.1 mg, 93%) as a colorless oil.
[a]2D2 =+14.2 (c=1.71 in CHCl3); 1H NMR (500 MHz, CDCl3): d=0.80
1.65 (s, 9H; OCO2C
AHCTREUNG
C1’-H2, C5’-H), 2.33 (dd, J=9.7, 13.4 Hz, 1H; C6’-H), 2.28–2.48 (m, 3H;
C2’-H2, C4’’-H), 2.74 (dd, J=4.9, 13.4 Hz, 1H; C6’-H), 4.08 (brs, 1H;
OH), 4.92 (d, J=1.7 Hz, 1H; C7-H), 4.98 (brs, 2H; C14’-H2), 4.99 (s,
1H; C3-H), 5.15 (d, J=5.1 Hz, 1H; C4’-H), 5.79 (d, J=15.7 Hz, 1H;
C2’’-H), 6.51 (d, J=1.7 Hz, 1H; C6-H), 6.91 (dd, J=8.1, 15.7 Hz, 1H;
C3’’-H), 7.15–7.18 (m, 3H; ArH), 7.24–7.27 (m, 2H; ArH); 13C NMR
(125.8 MHz, CDCl3): d=11.1, 13.6, 18.9, 19.2, 20.0, 21.1, 25.2, 27.6, 27.9,
27.96, 27.99, 28.1, 29.6, 31.6, 31.7, 32.7, 34.3, 34.7, 36.6, 40.0, 43.3, 73.8,
74.0, 75.4, 75.8, 79.5, 83.25, 83.29, 83.31, 83.5, 84.1, 86.2, 90.1, 103.5, 111.5,
118.7, 125.9, 128.2, 129.2, 140.4, 145.7, 152.1, 156.5, 163.6, 164.3, 165.6,
168.7, 170.1; IR (film): n˜ =3455, 2975, 2934, 2876, 1740, 1651, 1456, 1395,
1372, 1279, 1256, 1159, 1119, 1032, 992, 949, 912 cmꢀ1; HR-MS (FAB):
m/z: calcd for C52H78O16Na: 981.5188, found: 981.5197 [M ++Na].
(d, J=6.7 Hz, 3H; C5’-CH3), 1.46 (s, 9H; CO2C
ACHTREUNG
CO2C(CH3)3), 1.471 (s, 9H; CO2C(CH3)3), 1.63 (s, 9H; OCO2C
N
G
ACHTREUNG
2.085 (s, 3H; COCH3), 2.091 (s, 3H; COCH3), 2.11–2.14 (m, 3H; C1’-H2,
C5’-H), 2.33 (dd, J=9.7, 13.4 Hz, 1H; C6’-H), 2.40 (m, 2H; C2’-H2), 2.73
(dd, J=5.0, 13.4 Hz, 1H; C6’-H), 4.10 (s, 1H; OH), 4.87 (d, J=1.8 Hz,
1H; C7-H), 4.93 (s, 1H; C3-H), 4.98 (brs, 2H; C14’-H2), 5.14 (d, J=
5.1 Hz, 1H; C4’-H), 6.42 (d, J=1.8 Hz, 1H; C6-H), 7.15–7.28 (m, 5H;
ArH); 13C NMR (125.8 MHz, CDCl3): d=13.6, 20.7, 21.1, 25.3, 27.6,
27.86, 27.92, 28.1, 34.4, 36.6, 40.0, 73.9, 75.3, 76.2, 77.2, 79.3, 83.2, 83.3,
83.5, 84.0, 86.2, 89.9, 103.5, 111.5, 125.9, 128.2, 129.2, 140.4, 145.6, 152.3,
164.0, 165.5, 168.4, 168.6, 170.1; IR (film): n˜ =3453, 2932, 2857, 1740,
1651, 1603, 1456, 1372, 1279, 1157, 1119, 1038, 936, 905, 843 cmꢀ1; HR-
MS (FAB): m/z: calcd for C44H64O16Na: 871.4092, found: 871.4086 [M +
+Na].
Zaragozic acid A (1): Trifluoroacetic acid (2.2 mL) was added to a stirred
solution of fully protected zaragozic acid A 103 (13.9 mg, 14.5 mmol) in
CH2Cl2 (6.5 mL). After stirring for 16 h, the mixture was evaporated in
vacuo, and the crude product was concentrated from toluene (10 mL) to
remove residual trifluoroacetic acid. Trituration of the residue with petro-
leum ether provided zaragozic acid A (1, 9.0 mg, 90%) as a white film.
[a]2D2 =+33.9 (c=0.45 in MeOH) [lit. [a]2D5 =+37 (c=1.29 in MeOH),[3c,d]
[a]D20 =+10.7 (c=1.0 in CHCl3),[4a] [a]D22 =+18.3 (c=0.60 in CHCl3),[9d]
[a]D25 =+36 (c=0.28 in MeOH);[14] 1H NMR (400 MHz, CD3OD): d=
0.82–0.91 (m, 9H; C5’-CH3, C8’’-H3, C6’’-CH3), 1.02 (d, J=6.8 Hz, 3H;
C4’’-CH3), 1.06–1.15 (m, 2H; C5’’-H, C7’’-H), 1.28–1.41 (m, 3H; C5’’-H,
C6’’-H, C7’’-H), 2.02 (m, 2H; C1’-H2), 2.09 (s, 3H; COCH3), 2.23 (m,
Tri-tert-butyl
[1S,1(4S,5R),3S,4S,5R,6R,7R]-1-(4-acetoxy-5-methyl-3-
A
methylene-6-phenylhexyl)-7-(tert-butoxycarbonyl)oxy-4,6-dihydroxy-2,8-
dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylate (3): A 0.2% solution of po-
U
8922
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 8898 – 8925

Zaragozic Acids A and C
FULL PAPER
1H; C5’-H), 2.43 (dd, J=8.7, 13.4 Hz, 1H; C6’-H), 2.34–2.45 (m, 3H;
C2’-H2, C4’’-H), 2.66 (dd, J=6.1, 13.4 Hz, 1H; C6’-H), 4.03 (d, J=1.9 Hz,
1H; C7-H), 4.96 (brs, 1H; C14’-H), 5.01 (brs, 1H; C14’-H), 5.07 (d, J=
4.5 Hz, 1H; C4’-H), 5.26 (s, 1H; C3-H), 5.79 (d, J=15.8 Hz, 1H; C2’’-H),
6.30 (d, J=1.9 Hz, 1H; C6-H), 6.84 (dd, J=8.1, 15.8 Hz, 1H; C3’’-H),
7.11–7.26 (m, 5H; ArH); 13C NMR (100.6 MHz, CD3OD): d=11.6, 14.3,
19.3, 20.6, 21.0, 26.6, 30.9, 33.3, 35.1, 35.7, 37.8, 41.0, 44.5, 75.6, 76.6, 80.1,
81.1, 82.6, 91.2, 106.8, 111.5, 119.9, 126.9, 129.3, 130.1, 141.6, 147.7, 157.4,
166.5, 168.5, 170.2, 172.0, 172.5; IR (film): n˜ =3443, 2962, 2928, 1736,
1649, 1456, 1372, 1254, 1144, 1022, 841, 747, 700 cmꢀ1; HR-MS (FAB):
m/z: calcd for C35H45O14: 689.2809, found: 689.2833 [M +ꢀH].
[7] a) H. Abdel-Rahman, J. P. Adams, A. L. Boyes, M. J. Kelly, D. J.
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Acknowledgements
This research was supported in part by a Grant-in-Aid for Scientific Re-
search on Priority Areas 18032002 from the Ministry of Education, Cul-
ture, Sports, Science and Technology (MEXT). We also acknowledge the
Japan Society for the Promotion of Science (JSPS) for a graduate fellow-
ship to Y.H. We thank Ms. H. Matsumoto, A. Maeda, S. Oka, and M.
Kiuchi of the Center for Instrumental Analysis, Hokkaido University, for
technical assistance in MS and elemental analysis.
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Published online: November 15, 2006
Chem. Eur. J. 2006, 12, 8898 – 8925
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
8925