Stereocontrolled synthesis of the C21-C38 fragment of the unnatural enantiomer of the antibiotic nystatin A1.

Article abstract of DOI:10.1002/chem.200305540

The C(21)-C(38) fragment all-trans-41 of the unnatural enantiomer 1 of nystatin A(1) was prepared starting from the N-propionyl oxazolidinone 9. Aldol adduct ent-8 (ee > 96 %) derived in two steps was hydroborated with (thexyl)BH(2). Oxidative work-up and treatment with acid furnished delta-lactone 4. It contains the complete stereotetrade of the target molecule. The alpha,beta-unsaturated ester 28 was reached after another four steps. It should be a precursor for the polyene moieties of a variety of polyol,polyene macrolides. Illustrating that, the alpha,beta-unsaturated aldehyde 29 obtained from 28 and DIBAL was extended by 10 C atoms in four steps yielding the C(21)-C(38) segment 41. The latter set of transformations included the regio- and stereoselective Claisen rearrangement 32-->35.

Full text of DOI:10.1002/chem.200305540

FULL PAPER
Stereocontrolled Synthesis of the C21 C38 Fragment of the Unnatural
Enantiomer of the Antibiotic Nystatin A1
Thilo Berkenbusch[a] and Reinhard Br¸ckner*[b]
Abstract: The C21 C38 fragment all-trans-41 of the unnatural enantiomer 1 of nys-
tatin A1 was prepared starting from the N-propionyl oxazolidinone 9. Aldol adduct
ent-8 (ee > 96%) derived in two steps was hydroborated with (thexyl)BH2. Oxida-
tive work-up and treatment with acid furnished d-lactone 4. It contains the com-
plete stereotetrade of the target molecule. The a,b-unsaturated ester 28 was
reached after another four steps. It should be a precursor for the polyene moieties
of a variety of polyol,polyene macrolides. Illustrating that, the a,b-unsaturated al-
dehyde 29 obtained from 28 and DIBAL was extended by 10 C atoms in four
steps yielding the C21 C38 segment 41. The latter set of transformations included
the regio- and stereoselective Claisen rearrangement 32!35.
Keywords: aldol reaction ¥ Horner
Wadsworth Emmons reaction ¥ pol-
yol,polyene macrolides
¥
Claisen
rearrangement
synthesis
¥
stereoselective
Introduction
tericin B–albeit only slightly–while substructures 2 and 4
are identical.
Nystatin A1 and amphotericin B are drugs of choice for the
treatment of life-threatening fungal infections.[1] They are
typical representatives of more than 200 polyol,polyene
macrolides discovered so far.[2] Nystatin A1 became the first
member of this important class of antibiotics when it was
isolated from Streptomyces noursei in 1950.[3] Amphoteri-
cin B, a secondary metabolite from Streptomyces nodosus,
was discovered shortly later.[4] Its X-ray crystal structure
having been reported in 1970,[5] it stayed the only polyol,po-
lyene macrolide throughout two decades for which the com-
plete 3D structure was known (its mirror image, see 5,
Scheme 1). The stereostructure of nystatin A1 was assigned
more recently by controlled degradation and partial synthe-
ses (its mirror image, see 1, Scheme 1).[6,7] Either of these
antibiotics is a macrolactone and comprises the following
substructures: a hydrophilic polyol moiety (C1 C12), a pyra-
noside ring (C13 C19), a lipophilic polyene moiety (C20 C33),
and a small polypropionate section (C34 C38). The first and
third substructure are different in nystatin A1 versus ampho-
Several total[8,9] and partial[10] syntheses of amphotericin B
or its aglycon (™amphoteronolide B∫) have been completed
to date. Of the synthetic efforts directed towards nystatin
A1,[7b,c,11] the most advanced is Solladiÿ×s.[11d]: He and his
co-workers obtained the polyol portion (C1 C13) with the
natural configuration. We worked in this field, too, synthe-
sizing a C14 C20 building block[10g] and a C33 C38 fragment,[10c]
both with the natural configuration. In the meantime we
modified our goals–and since then have strived for ana-
logues of the mentioned antibiotics. These, hopefully, will
help understanding whether and how much stereochemistry
matters for the biological activity of such polyol,polyene an-
tibiotics. Promising analogues ought to be, among others,
the unnatural enantiomers 1 and 5 of nystatin A1 and am-
photericin B, respectively (Scheme 1). We traced them back
retrosynthetically to an a,b-unsaturated ester 3. This is a
C31 C38 building block both for 1 and 5. It was elaborated to
a type-2 C21 C38 building block (only) for 1. Ester 3 was pre-
pared from d-lactone 4, which exhibited already all stereo-
centers.
[a] Dr. T. Berkenbusch
Present address: Bayer AG
BCH-FCH-RD-LP2
Building G 8, 51368 Leverkusen (Germany)
Results and Discussion
The boron-mediated addition[12] of Evans× norephedrine-
based oxazolidinone 6[13,14] to (E)-tiglinaldehyde[15] delivered
the known[16] syn-aldol product 7 with the C34 and C35 con-
figurations of natural nystatin A1 and amphotericin B
(Scheme 2; 88%; ds >98%). The C34 and C35 configurations
[b] Prof. Dr. R. Br¸ckner
Institut f¸r Organische Chemie und Biochemie
der Albert-Ludwigs-Universit‰t
Albertstrasse 21, 79104 Freiburg (Germany)
Fax : (+49)761-203-6100
E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
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FULL PAPER
Scheme 2. a) NEt3 (1.2 equiv), nBu2BOTf (1.1 equiv), CH2Cl2, 08C, 1 h,
! ꢀ788C; (E)-2-methyl-2-butenal (1.15 equiv), ! 08C within 1 h; 08C,
1 h; phosphate buffer (pH 7), MeOH, 35% H2O2, 1 h; 88% (ds > 98:2).
b) NaOMe (1.6 equiv), MeOH, 08C, 8 min; 75%. c) Same as a); 96%
(ds > 98:2). d) tBuMe2SiOTf (1.5 equiv), 2,6-lutidine (2.2 equiv), CH2Cl2,
08C, 1.5 h; 94%. e) Same as b); 86%. f) Same as d); 99%.
with their C=C but also with their C=O bonds. Besides that,
the tert-butyldimethylsilyl ethers 11 and 12 lost their silyl
groups depending on the detailed conditions of the oxidative
work-up: 35% H2O2/10% NaOH led to partial deprotec-
tion, whereas sodium perborate[24] affected neither the silyl
Scheme 1. Unnatural enantiomers 1 of nystatin A1 and 5 of amphoteri-
cin B and retrosynthetic analysis of the boxed sections of these species.
of unnatural nystatin A1 and amphotericin B were establish-
ed analogously–in aldol adduct 10 previously not descri-
bed–from the same aldehyde and the valinol-derived oxa-
zolidinone 9 (96%; ds >98:2).[17,18] The chiral auxiliaries
were removed by methanolysis according to Seebach
et al.[19]: Treatment of 7 and 10 with NaOMe and purifica-
tion by flash chromatography on silica gel[20] provided
methyl esters 8[21] (75%) and ent-8 (86%), respectively, both
with >96% ee (along with 90 95% recovered chiral auxili-
ary). Compound 8[21] had the undesired absolute configura-
tion but was needed for assessing the enantiopurity of the
enantiomer ent-8 with the desired configuration. Hydroxyoxa-
zolidinone 10 and the identically configured b-hydroxyester
ent-8 were protected[22] as tert-butyldimethylsilyl ethers 11
(94% yield) and 12 (99% yield), respectively.
Having completed a set of four differently substituted,
albeit identically configured allyl alcohols (ent-8, 10) or allyl
silyl ethers (11, 12), we proceeded testing whether hydrobo-
ration/oxidation would lead in just one more step to the d-
lactone 4 (Scheme 3). The latter exhibits the complete ste-
reotetrade of our target molecules 2 and 3. This plan called
for anti-Markovnikov and syn-selective hydroborations with
respect to the relative orientation of the OH groups in the
dihydroxycarboxylate precursor 14 of lactone 4. Literature
precedent[23] made such stereocontrol likely. 9-BBN or
BH3¥SMe2 turned out to fail as hydroborating agents: Sub-
strates ent-8, 10, 11, and 12 were essentially inert towards 9-
BBN while they reacted with BH3¥SMe2 readily, yet not only
ꢀ
groups nor, surprisingly, the B C bond. Screening other hy-
droborating agents, the combination of (thexyl)BH2 with
[25]
the unprotected ester ent-8 proved to work nicely when
35% H2O2 combined with ™Sharpless-solution∫[26] [NaOH
(9m) and NaCl] was employed as an oxidizing mixture (!
13; Scheme 3). This apparently provided carboxylate 14. It
was never isolated but treated with concentrated HCl so
that it lactonized spontaneously. After purification by flash
chromatography on silica gel[20] we isolated d-lactone 4 in
60% yield as a single diastereomer.[27] Its stereostructure
was established by X-ray crystallography.
From this point onward we continued our synthesis on
two routes differing by the protecting group which was
about to be installed (Scheme 3). The first route proceeded
via the tBuMe2Si-containing lactol 17, the second via the
MOM-containing lactol 18. These compounds were obtained
from lactone 4 in two steps: 1) Protection of the free hy-
droxy group with tert-butyldimethylsilyl triflate[22] in the
presence of 2,6-lutidine delivered lactone 15.[28] The yield
did not exceed 72% because we could not prevent that 15
underwent about 25% elimination of tBuMe2SiOH (! ca.
25% a,b-unsaturated lactone). The ensuing reduction 15 !
17[29] with DIBAL in toluene at ꢀ788C was accomplished in
100% yield. 2) Using chloromethyl methyl ether and
H¸nig×s base[30] for protecting lactone 4 and DIBAL in tolu-
ene at low temperature for the subsequent reduction, the
MOM-protected lactol 18 of the second route resulted in
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Nystatin A1
1545 1557
ture, no more than 17% of the desired ester 21 were ob-
tained (experiments not shown in Table 1). At reflux temper-
ature in toluene, a 2 h run led to the desired product 21 in
11% yield along with 68% recovered lactol 17 (entry 1). In
contrast to that, a 24 h run went to complete conversion but
hardly improved the yield of 21 (17%; entry 2). This was be-
cause the reaction proceeded beyond that stage through tet-
rahydropyran formation by an intramolecular Michael addi-
tion. It furnished 42% 23 as a 74:26 mixture of diastereo-
mers, which were separated by flash chromatography on
silica gel[20] but remained configurationally unassigned.
This kind of over-reaction is known from Wittig reactions
of sugar lactols.[33] In a few cases,[34] the addition of a small
amount of carboxylic acid and use of tributylphosphorane
27–freshly prepared from tributylphosphonium bromide
26[35]–instead of triphenylphosphorane 25 turned out to in-
crease the yield of acyclic product (and the trans-selectivity
as well). Therefore, we added benzoic acid (20 mol%) to
our olefination mixtures and employed phosphorane 27
(entry 4) as an alternative to phosphorane 25 (entry 3).[36]
This led to the acyclic product (21) as desired and to no tet-
rahydropyran 23 at all. The yield of 21 remained neverthe-
less low: 26 and 31%, respectively. Therefore, we gave up
elaborating the TBDMS-containing lactol 17, exchanging it
for its MOM-protected analogue 18.[37] Continuing to rely
upon the beneficial effects both of added benzoic acid and
of employing the tributylphosphorane (27) we found that
the formation of the desired unsaturated ester 22 was slug-
gish at <858C in toluene and once again exhibited moder-
ate yields (23 37%; entries 5 and 6). Increasing the temper-
ature accelerated the reaction. Unfortunately, this also pro-
moted loss of the MOMO group through b-elimination:
Scheme 3. a) (Thexyl)BH2 (2.0 equiv), addition of ent-8, 08C, 30 min, !
RT, 16 h; ! 08C, NaOH (9m, 8.4 equiv), 35% H2O2 (9.2 equiv), NaCl
(1.0 equiv), 2 h, ! RT, 2 h; conc. HCl until pH ꢁ 1; 60% (ds >98:2).
b) tBuMe2SiOTf (2.6 equiv), 2,6-lutidine (1.5 equiv), CH2Cl2, 08C, 12 h;
72%. c) MOMCl (8.2 equiv), NEtiPr2 (8.7 equiv), nBu4NI (1.1 mol%),
CH2Cl2, RT, 1.5 h; 99%. d) DIBAL (2.2 equiv), toluene, ꢀ788C, 2.5 h;
99%. e) Same as d); 99%.
98% yield over both steps.[31]
1H- and 13C NMR spectroscopy
Table 1. Wittig reactions between lactols 17 and 18 and ylides 25 or 2.
revealed the siloxy-containing
lactol 17 to be a 60:40 mixture
of anomers and the MOM-con-
taining lactol 18 a 79:21 mix-
ture. There was no indication of
the presence of the respective
open-chain
hydroxyaldehyde
isomers 19 and 20 (see Table 1).
Nonetheless, the latter spe-
cies were the ones to be scav-
enged in the next step by a
Wittig olefination effecting a C2
elongation by furnishing the
a,b-unsaturated ethyl esters 21
and 22, respectively (Table 1).
While trans-selectivities were
satisfactory (>92:8) from the
beginning and regardless which
ylide or solvent we employed,
our yields stayed low for an ex-
tended period of time. Starting
with standard conditions,[32] that
is, combining substrate 17 and
ylide 25 in CH2Cl2, THF, DMF
or benzene at room tempera-
Yield [%]
Entry Reaction conditions (solvent: toluene)
17[a]
18[a]
21 22
23
24
1
2
17, 25 (3.0 equiv), 1108C, 2 h
17, 25 (2.0 equiv), 1108C, 1 d
63
11
17
26
31
23
37
55
37
46
n. a.
42[b]
3
4
5
6
7
8
9
10
17, 25 (3.0 equiv), benzoic acid (20 mol%), 1108C, 3 h
17, 27 (3.0 equiv), benzoic acid (20 mol%), 958C, 3 h
18, 27 (6.0 equiv), benzoic acid (40 mol%), 858C, 4 h
18, 27 (2.5 equiv), benzoic acid (20 mol%), 858C, 9.5 h
18, 27 (4.0 equiv), benzoic acid (30 mol%), 908C, 5 h
18, 27 (6.0 equiv), benzoic acid (40 mol%), 928C, 2.5 h
18, 27 (3.7 equiv), benzoic acid (20 mol%), 958C, 2 h
18, 27 (3.5 equiv), benzoic acid (40 mol%), 1058C, 2 h
n.a.
n.a.
54
5
<2[c]
6
<2[c]
47
<2[c]
11
12
53
[a] That is, recovered starting material. [b] 74:26 mixture of diastereomers, which was separated by flash chro-
matography.[20] [c] Very small amounts of the compound in question were detected by TLC but neither isolated
nor subjected to an exact yield determination.
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R. Br¸ckner and T. Berkenbusch
FULL PAPER
Above 1058C we isolated preponderantly the dienoic ester
24 (53%) rather than 22 (entry 10). The Ca=Cb bond of 24
was exclusively trans-configured (Ja,b =15.6 Hz), while the
Cg=Cd bond belonged to an isomeric mixture (89:11). The
best we managed doing in the tightrope act of achieving
good conversions of lactol 18 and avoiding the formation of
24 was maintaining the temperature between 90 and 958C
and working up the reaction mixture as soon as TLC indi-
cated the formation of dienoate 24. In that manner the de-
sired Wittig product 23 was obtained as a pure trans-isomer
in up to 55% isolated yield or in up to 70% yield based on
recovered lactol 18 (entries 7 and 9, respectively).
a,b-Unsaturated esters 21 (TBDMS-protected) and 22
(MOM-protected) were protected as regioisomeric
TBDMS- and MOM-containing esters 28 (84% yield) and
30 (85% yield) following standard procedures[22,30]
(Scheme 4). Both 28 and 30 are equivalents of the C31 C38
fragment 3 of our retrosynthetic analysis of ent-nystatin A1
(1) and ent-amphotericin B (5; Scheme 1). Thus, their prepa-
ration meant reaching an important subgoal. Due to the
better accessibility of 28 (59% overall yield from lactone 4)
compared to 30 (19% overall yield) we continued our syn-
thesis with the former compound.
For further elaboration of the carbon framework, we ad-
justed the oxidation state of ester 28 by DIBAL reduction
in CH2Cl2 at ꢀ788C and by oxidizing the resulting crude al-
[38]
lylic alcohol with MnO2 in CH2Cl2. This provided 89% of
the a,b-unsaturated aldehyde 29 (trans:cis >98:2). This
compound furnished the divinyl carbinol 31 (93% yield; ds
ꢂ50:50) by the addition of vinylmagnesium bromide.[39]
A
one-pot vinyl ether exchange/Claisen rearrangement proto-
col[40] was applied next. It meant refluxing a solution of com-
pound 31 and a stoichiometric amount of Hg(OAc)2 in tert-
butyl vinyl ether (70 equiv). This gave rise to the short-lived
vinyl ether 32 (1:1 diastereomeric mixture) and caused the
latter to undergo a Claisen rearrangement. Of the two allylic
C=C bonds, the rearrangement involved primarily the one
sterically least hindered. Regiocontrol was 82:18 at least, as
evidenced by the following findings:[41] First, purification by
flash chromatography on silica gel[20] gave an unanalyzed
mixture of the regioisomeric Claisen products (95% yield).
Therefrom, we obtained 78% of the pure rearrangement
product 35 by another passage through flash silica gel; the
Scheme 4. a) tBuMe2SiOTf (2.0 equiv), 2,6-lutidine (3.6 equiv), CH2Cl2,
08C, 15 h; 84%. b) MOMCl (8.3 equiv), NEtiPr2 (10 equiv), nBu4NI
(14 mol%), CH2Cl2, RT, 18 h; 85%. c) (i) DIBAL (3.1 equiv), CH2Cl2,
788C, 1.5 h; (ii) MnO2 (22 equiv), CH2Cl2, RT, 4 h; 89%. d) H2C=CH-
MgBr (2.3 equiv), THF, ꢀ788C, 70 min; 93% (ds ꢂ50:50). e) Hg(OAc)2
(1.1 equiv), tert-butyl vinyl ether (70 equiv), reflux, 9 h; 78%. f) Ph3P=
CH-CO2Me (3.1 equiv), toluene, RT, 16 h; 89% (trans:cis
> 98:2).
g) i) DIBAL (2.6 equiv), CH2Cl2, ꢀ788C, 2.5 h; ii) MnO2 (20 equiv),
CH2Cl2, RT, 14 h; 89%.
the cyclohexadiene-containing isomer 39 dominated.[43] This
outcome suggests that lithio-36 attacked the a,b-unsaturated
aldehyde 34 preferentially in a conjugate addition and in-
volved C-g rather than C-a of the phosphonate. The sur-
mised intermediate 38 displays an aldehyde enolate as well
as an ester-substituted alkene phosphonate. Proton transfer
from the latter upon the former would lead to a more stable
intermediate, equipped with an aldehyde moiety and a met-
alophosphonate. These functionalities ought to lead to prod-
uct 39 by an intramolecular HWE reaction.
32
34
trans,trans-configuration of segment C30=C31 C =C of 35
follows from the magnitude of its olefinic couplings: J30,31
32,33 =14.5 Hz. The yield of any regioisomer(s) of 35 was
ꢀ
=
J
thereby limited to 95%ꢀ78%=17%. Aldehyde 35 was
then C2-homologated in 79% yield (! a,b-unsaturated al-
dehyde 34) by a Wittig reaction[32] with PH3P=CH CO2Me
ꢀ
(35 ! 33; trans:cis >98:2), by a reduction, and an oxida-
tion.
The final steps of our synthesis of the C21 C38 fragment of
ent-nystatin A1 (1) were realized with Horner-Wadsworth-
Emmons (HWE) reactions (Scheme 5).[42] Initially, we com-
bined our most advanced intermediate, namely the C25 C38
aldehyde 34, with the lithio derivative obtained from phos-
phonate 36 (trans:cis >90:10) and LDA. Surprisingly, this
afforded a 24:76 mixture (52% yield, separable) in which
the expected trienoic ester 40 was the minor constituent and
The C-3 elongation of C25 C38 aldehyde 34 by HWE re-
agent 36 having failed, we moved the site of our retrosyn-
thetic disconnection ™westward∫ (Scheme 5). This called for
a C-5 elongation of C27 C38 aldehyde 35 by phosphonate 37
(accessible from 4-bromocrotonate[44]). Treating this reagent
90:10) first with LDA and
then with aldehyde 35, we obtained an inseparable 66:34
mixture of the all-trans-configured unsaturated ester 40 and
=
=
CCO2Me
(trans,trans:cisH CC C,transC
2
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Nystatin A1
1545 1557
its cis26,27-isomer (74% yield). Isomerization in an NMR
tube with 8 mol% of iodine in CDCl3 increased the all-
trans-content to 93:7.[45] Without purification we proceeded
to aldehyde all-trans-41 in 78% overall yield by sequential
oxidation and reduction. This compound stands for the C21
C38 fragment 2 of ent-nystatin A1 (1). Because of its carbon-
yl group, it is properly set up for appending a Cx C20 syn-
thon en route to the full structure of ent-nystatin A1.
The connectivities and stereostructures of all-trans- and
cis26,27-40 as well as all-trans-41 were established by
1
500 MHz H NMR spectroscopy (Table 2). The C22=C23 and
C24=C25 bonds were clearly trans-configured because of the
sizes of the J22,23 (15.2 15.3 Hz) and J24,25 (14.7 14.8 Hz).
Likewise, in compounds all-trans-40 and all-trans-41 we
found J26,27 =15.1 Hz. This contrasts with J26,27 =10.8 Hz in
the isomer cis26,27-40, to which we therefore attributed one
cis-configured C=C bond.
Conclusion
A stereoselective and straightforward synthesis of com-
pound all-trans-41 has been developed. It was obtained from
the N-propionyl oxazolidinone
9 in 9.8% yield over
12 steps. A key intermediate was the a,b-unsaturated ester
28. It might be used for the construction of other polyol,po-
lyene macrolides like, for example, ent-amphotericin B (5).
Efforts to elaborate all-trans-41 into unnatural nystatin A1
(1) are currently underway in our laboratory.
Experimental Section
Scheme 5. a) 36 (1.9 equiv), LDA (2.3 equiv), THF, ꢀ608C, 25 min; addi-
tion of 34, ! ꢀ308C, 2 h; 52% (21% 39, 20% of a 93:7 mixture of 39
and 40, and 11% 40). b) 37 (1.9 equiv), LDA (1.8 equiv), THF, ꢀ608C,
30 min, ! 08C during 15 min, ! ꢀ608C; addition of 35, !ꢀ608C, 1 h;
74% (trans26,27:cis26,27 =66:34). c) i) I2 (8.0 mol%), CDCl3, RT, 9 min (!
trans26,27:cis26,27 =93:7); ii) DIBAL (2.7 equiv), CH2Cl2, ꢀ78 ! ꢀ608C,
1 h; iii) MnO2 (39 equiv), CH2Cl2, RT, 1 h; 78%.
General methods: Reactions with light-sensitive compounds were per-
formed in brown glassware or in ordinary glassware wrapped in alumi-
num foil. Products were purified by flash chromatography[20] on Merck
silica gel 60 (eluent given in parentheses). Yields refer to analytically
pure samples. Isomer ratios were derived from suitable 1H NMR inte-
1
grals. H [CHCl3 (7.26 ppm) as internal standard in CDCl3] and 13C NMR
[CDCl3 (77.00 ppm) as internal standard in CDCl3]: Bruker AM 400 or
DRX 500; integrals in accord with assignments; coupling constants in Hz.
1
The assignments of H and 13C NMR resonances refer to the IUPAC no-
menclature; primed numbers belong to the side chain. Combustion analy-
1
Table 2. 500 MHz H NMR data in CDCl3 of the conjugated triene segments of esters 40 and aldehyde 41; chemical shifts in ppm, coupling constants in
Hz.
C22=C23
J22,23
C24=C25
d24-H
C26=C27
d26-H
d22-H
d23-H
J24,25
d25-H
J26,27
d27-H
all-trans-40[a]
cis26,27-40[b]
all-trans-41
5.85
5.88
6.13
15.3
15.3
15.2
7.30
7.35
7.11
6.22
6.30
6.35
14.8
14.7
14.8
6.52
6.93
6.64
6.15
6.10
6.20
15.1
10.8
15.1
5.92
5.67
[c]
[a] Sample of a 93:7 mixture of all-trans-40 and cis26,27-40. [b] Sample of a 66:34 mixture of all-trans-40 and cis26,27-40. [c] Superimposed.
1549
Chem. Eur. J. 2004, 10, 1545 1557
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R. Br¸ckner and T. Berkenbusch
FULL PAPER
ses: H. B‰hr and E. Hickl, Institut f¸r Organische Chemie und Bioche-
mie, Universit‰t Freiburg. MS: Dr. J. Wˆrth, Institut f¸r Organische
Chemie und Biochemie, Universit‰t Freiburg. IR spectra: Perkin Elmer
PARAGON 1000. Optical rotations measured with a Perkin Elmer po-
larimeter 341 at 589 nm and calculated according to the Drude equation
{[a]n˜# =(aexptl î 100)/(c î d)}; rotational values are the average of five
measurements of a in given solution of the respective sample. Melting
points: Dr. Tottoli apparatus (Fa. B¸chi), uncorrected.
an H,H-correlation spectrum; 13C NMR (125.7 MHz): d=10.43 (2’-
CH3)*, 13.03 and 13.07 (4’-CH3, C-6)*, 14.31 (4-CH3)*, 40.66 (C-2’), 54.92
(C-4), 75.53 (C-3’)**, 78.94 (C-5)**, 120.50 (C-5’)***, 125.59 and 128.73
(each 2-fold intensity, 2 ortho and 2 meta C), 128.81, 133.12 and 134.29
(ipso C, para C, C-4’), 152.59 (C-1’), 176.85 (C-2); *,** distinguishable by
a C,H-correlation spectrum; *** assigned by a C,H-correlation spectrum;
IR (film): n˜ =3605, 3530, 2985, 2925, 2865, 1780, 1690, 1455, 1365, 1345,
1235, 1195, 1150, 1120, 1090, 1070, 1030, 990, 960 cmꢀ1; elemental analysis
calcd (%) for C18H23NO4 (317.4): C 68.12, H 7.30, N 4.41; found: C 67.99,
H 7.34, N 4.24.
(3S,4R,5S,6R)-Tetrahydro-4-hydroxy-3,5,6-trimethyl-2-pyranone (4): At
ꢀ108C a solution of 2,3-dimethyl-2-butene (1.24 mL, 879 mg, 10.5 mmol,
2.0 equiv) in THF (6 mL) was added dropwise to a solution of BH3¥SMe2
(10m, 1.05 mL, 10.5 mmol, 2.0 equiv) in THF (2 mL). The addition was
completed after 25 min, and the mixture was warmed to 08C. After stir-
ring for 2 h at this temperature, the reaction mixture was treated drop-
wise with a solution of methyl ester ent-8 (921 mg, 5.35 mmol) in THF
(7 mL) within 30 min. The mixture was allowed to reach room tempera-
ture and stirred for 16 h. The reaction was terminated at 08C by careful
addition of an aqueous solution [5 mL of a solution prepared from
NaOH (30 g), NaCl (5 g) and H2O (90 mL): ca. 45 and 5.1 mmol, respec-
tively, ca. 8.4 and 1.0 equiv, respectively] and H2O2 (30% in water,
5.0 mL, 1.7 g, 49 mmol, 9.2 equiv). Stirring was continued for 2 h at 08C
and then for another 2 h at room temperature The organic phase was
separated and the aqueous phase extracted with tBuOMe (4î70 mL).
The combined organic phases were washed with water (100 mL) and
brine (100 mL). The combined aqueous phases were treated with aque-
ous conc. HCl (until the pH value was <1) and with Na2SO3 (to destroy
the excess of H2O2; peroxide test!). After a second extraction with
tBuOMe (5 î 150 mL) the combined organic phases were dried with
MgSO4. The solvent was evaporated in vacuo to afford an oily residue
which was submitted to flash chromatography (cyclohexane/EtOAc 1:1)
to afford d-lactone 4 (504 mg, 60%) as a pure diastereomer and a color-
less solid. M.p. 116 1178C; [a]2D5 =+23.1 (c=0.87 in CDCl3); 1H NMR
[500 MHz; contains contaminant-peak (s) at d=1.25]: d=1.06 (d, J5-
Me,5 =6.9, 5-Me)*, 1.32 (d, J3-Me,3 =7.5, 3-Me)*, 1.37 (d, J6-Me,6 =6.3, 6-
Me)*, 1.84 (dqd, J5,6 =10.1, J5,5-Me =6.8, J5,4 =3.4, 5-H), 2.06 (brs, OH),
2.68 (qd, J3,3-Me =7.4, J3,4 =4.0, 3-H), 3.73 (dd, J4,3 =J4,5 =3.6, 4-H), 4.47
(dq, J6,5 =9.9, J6,6-Me =6.4, 6-H); * assigned by an H,H-correlation spec-
trum; 13C NMR (125.7 MHz; peak of contaminant at d=29.68): d=12.55
(5-CH3)*, 15.82 (3-CH3)*, 19.54 (6-CH3)*, 37.22 (C-5)**, 43.44 (C-3)**,
73.32 (C-4)***, 76.64 (C-6)***, 174.11 (C-2); *,**,*** distinguishable by
a C,H-correlation spectrum; IR (CDCl3): n˜ =3460, 2980, 2940, 2855,
1730, 1600, 1460, 1385, 1360, 1240, 1205, 1100, 1045, 975, 930, 920,
910 cmꢀ1; elemental analysis calcd (%) for C8H14O3 (158.2): C 60.74, H
8.92; found: C 60.51, H 9.06.
(2S,3S,4E)-3-Hydroxy-2,4-dimethyl-4-hexenoic acid methyl ester (ent-8):
Na (554 mg, 24.1 mmol, 1.4 equiv) was dissolved in MeOH (85 mL), and
the mixture was cooled to 08C. A solution of the oxazolidinone 10
(4.633 g, 17.20 mmol) in MeOH (15 mL) was then added in one portion.
The mixture was stirred for 10 min and then poured into phosphate
buffer (pH 7, 110 mL). The solution was extracted with CH2Cl2 (4
î
200 mL), and the combined organic extracts were dried with MgSO4 and
evaporated in vacuo. The residue was submitted to flash chromatography
(cyclohexane/EtOAc 4:1) to afford methyl ester ent-8 (2.536 g, 86%) as a
colorless liquid. The chiral auxiliary could be recovered by flushing the
column with EtOAc. [a]D25 =ꢀ13.8 (c=0.84 in CDCl3); 1H NMR
(500 MHz): d=1.14 (d, J2-Me,2 =7.1, 2-Me), 1.59 (m, presumably interpret-
4
5
able as dq, J4-Me,5 ꢂ J4-Me,6 ꢂ1.0, 4-Me), 1.62 (dm, J6,5 =6.8, 6-H3), 2.30
(brs, OH), 2.69 (qd, J2,2-Me =7.1, J2,3 =5.5, 2-H), 3.68 (s, OMe), 4.26 (brd,
4
4
J
3,2 =5.4, 3-H), 5.55 (qdq, J5,6 =6.7, J5,3 ꢂ J5,4-Me ꢂ1.3, 5-H); 13C NMR
(125.7 MHz): d=11.28 (2-CH3)*, 12.24 (4-CH3)*, 12.98 (C-6)*, 42.97 (C-
2), 51.70 (OCH3), 76.97 (C-3), 121.15 (C-5), 134.66 (C-4), 176.06 (C-1);
* distinguishable by a C,H-correlation spectrum; IR (film): n˜ =2935,
2895, 2860, 1780, 1650, 1500, 1470, 1400, 1255, 1215, 1160, 1090, 1060,
970, 915, 840, 780 cmꢀ1; elemental analysis calcd (%) for C9H16O3 (172.1):
C 62.77, H 9.36; found: C 62.48, H 9.66.
(2R,3R,4E)-3-Hydroxy-2,4-dimethyl-4-hexenoic acid methyl ester (8): Na
(59 mg, 2.6 mmol, 1.6 equiv) was dissolved in MeOH (15 mL), and the
mixture was cooled to 08C. A solution of the oxazolidinone 7 (513 mg,
1.62 mmol) in MeOH (4.5 mL) was then added in one portion. The mix-
ture was stirred for 8 min and then poured into phosphate buffer (pH 7,
20 mL). The solution was extracted with CH2Cl2 (4 î 20 mL), and the
combined organic extracts were dried with MgSO4 and evaporated in
vacuo. The residue was submitted to flash chromatography (cyclohexane/
EtOAc 4:1) to afford methyl ester 8 (208 mg, 75%) as a colorless liquid.
The chiral auxiliary could be recovered by flushing the column with
EtOAc. [a]2D5 =+13.3 (c=0.47 in CDCl3); 1H NMR,13C NMR and IR
data were identical with those of ent-8.
(4S)-3-[(2S,3S,4E)-3-Hydroxy-2,4-dimethyl-4-hexenoyl]-4-isopropyl-1,3-
oxazolidin-2-one (10): Dibutylboron triflate (50 mL of a 1.0m solution in
CH2Cl2, 50 mmol, 1.1 equiv) was added dropwise at ꢀ38C within 35 min
to a solution of oxazolidinone 9 (8.149 g, 45.45 mmol) and triethylamine
(7.6 mL, 5.5 g, 55 mmol, 1.2 equiv) in CH2Cl2 (130 mL). After stirring for
1 h, the mixture was cooled to ꢀ788C, and a solution of (E)-2-methylbu-
tenal (4.8 mL, 4.2 g, 50 mmol, 1.1 equiv) in CH2Cl2 (4 mL) was added
dropwise during 85 min. The reaction mixture was allowed to reach 08C
over 1 h, stirred for 1 h at this temperature and treated with phosphate
buffer (pH 7, 45 mL) and MeOH (150 mL). Then a mixture of aqueous
H2O2 (35%, 50 mL) and MeOH (60 mL) was added dropwise taking care
that the reaction temperature was kept below 48C. After stirring for 1 h
at 08C, water (300 mL) was added, and the mixture was extracted with
tBuOMe (4 î 400 mL). The combined organic phases were washed with
semisaturated aqueous NaHCO3 (400 mL) and brine (250 mL) and dried
with MgSO4. The solvent was evaporated in vacuo to afford an oily resi-
due (15 g) which was submitted to flash chromatography (cyclohexane/
EtOAc 4:1) to afford the title compound 10 (11.756 g, 96%) as a pure di-
astereomer and a colorless oil. [a]2D5 =+59.7 (c=1.45 in CDCl3); 1H
(4R,5S)-3-[(2R,3R,4E)-3-Hydroxy-2,4-dimethyl-4-hexenoyl]-4-methyl-5-
phenyl-1,3-oxazolidin-2-one (7): Dibutylboron triflate (4.4 mL of a 1.0m
solution in CH2Cl2, 4.4 mmol, 1.1 equiv) was added dropwise at 08C
within 12 min to a solution of oxazolidinone 6 (930 mg, 3.99 mmol) and
triethylamine (0.67 mL, 49 mg, 4.8 mmol, 1.2 equiv) in CH2Cl2 (12 mL).
After stirring for 1 h, the mixture was cooled to ꢀ788C, and a solution of
(E)-2-methylbutenal (425 mL, 307 mg, 4.39 mmol, 1.1 equiv) in CH2Cl2
(2 mL) was added dropwise during 25 min. The reaction mixture was al-
lowed to reach 08C over 1 h, stirred for 1 h at this temperature and treat-
ed with phosphate buffer (pH 7, 4 mL) and MeOH (12 mL). Then a mix-
ture of aqueous H2O2 (35%, 4 mL) and MeOH (8 mL) was added drop-
wise taking care that the reaction temperature was kept below 48C.
After stirring for 1 h at 08C, water (40 mL) was added, and the mixture
was extracted with tBuOMe (5 î 60 mL). The combined organic phases
were washed with semisaturated aqueous NaHCO3 (40 mL) and brine
(40 mL) and dried with MgSO4. The solvent was evaporated in vacuo to
afford an oily residue which was submitted to flash chromatography (cy-
clohexane/EtOAc 3:1) to afford a diastereomeric mixture (33 mg, 2.6%)
and the title compound 7 (1.117 g, 88%, ref.[16] 70%) as a pure diaster-
eomer and a colorless solid. M.p. 878C, ref.[16] 86 878C; [a]D25 =+33.4
NMR (500 MHz): d=0.89 (d, J1’-Me(1),1’ =6.9, 1’-Me1), 0.92 (d, J1’-Me(2),1’
7.1, 1’-Me2), 1.18 (d, J2’’-Me,2’’ =7.1, 2’’-Me)*, 1.60 (m, 4’’-Me), 1.64 (dm,
6’’,5’’ =6.8, 6’’-H3), 2.38 (qqd, J1’,1’-Me(1) =J1’,1’-Me(2) =7.0, J1’,4 =4.0, 1’-H), 2.88
=
1
(c=1.22 in CDCl3), ref.[16] 35.5 (c=1.70 in CHCl3); H NMR (500 MHz):
J
d=0.90 (d, J4-Me,4 =6.6, 4-Me)*, 1.17 (d, J2’-Me,2’ =7.0, 2’-Me), 1.64 (m, 4’-
Me), 1.66 (dm, J6’,5’ =6.8, 6’-H3), 2.74 (d, JOH,3’ =2.8, OH), 3.99 (qd,
(brs, OH), 3.98 (qd, J2’’,2’’-Me =7.0, J2’’,3’’ =3.7, 2’’-H), AB signal (dA =4.22,
dB =4.28, JAB =8.9, in addition split by JA,4 =3.0, JB,4 =8.7, 5-H2), 4.32
4.35 (m, 3’’-H), 4.46 (ddd, J4,5-H(B) =8.3, J4,1’ =4.0, J4,5-H(A) =3.0, 4-H), 5.62
(qdq, J5’’,6’’ =6.8, J5’’,3’’ ꢂ J5’’,4’’-Me ꢂ1.4, 5’’-H); * distinguished from 1’-
Me1/1’-Me2 through the presence of a cross-peak with the 2’’-H resonance
(d=3.98) in an H,H-correlation spectrum; 13C NMR (125.7 MHz): d=
J
2’,2’-Me =7.0, J2’,3’ =3.8, 2’-H), 4.37 (brs, 3’-H), 4.77 (qd, J4,4-Me =J4,5 =6.8,
4
4
4
4
4-H), 5.63 (qdq, J5’,6’ =6.7, J5’,3’ ꢂ J5’,4’-Me ꢂ1.3, 5’-H), 5.67 (d, J5,4 =7.3,
5-H), 7.30 7.33 and 7.36 7.45 (2îm, 5 Ar-H); * distinguished from 2’-Me
through the presence of a cross-peak with the 4-H resonance (d=4.77) in
1550
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1545 1557

Nystatin A1
1545 1557
1
10.97 (2’’-CH3)*, 13.02 and 13.15 (4’’-CH3, C-6’’)*, 14.68 (1’-CH3 )*, 17.89
to flash chromatography (cyclohexane/EtOAc 15:1 ! fraction 44, 12:1
! fraction 65, 10:1 ! fraction 80) to afford the title compound 15
(96.8 mg, 72%) as colorless needles. M.p. 828C; [a]2D0 =+0.7 (c=0.41 in
CDCl3), ref.[10n] ꢀ0.88 (enantiomer, c=1.0 in CHCl3); 1H NMR
(500 MHz): d=0.06 and 0.08 (2îs, SiMe2), 0.89 (s, SiCMe3), 0.99 (d, J5-
Me,5 =6.8, 5-Me)*, 1.27 (d, J3-Me,3 =7.5, 3-Me)*, 1.35 (d, J6-Me,6 =6.5, 6-
2
(1’-CH3 )*, 28.37 (C-1’), 40.39 (C-2’’), 58.37 (C-4)**, 63.34 (C-5)**, 75.10
(C-3’’)**, 120.52 (C-5’’)***, 134.07 (C-4’’), 153.49 and 177.46 (C-1’’, C-2);
*,** distinguishable by a C,H-correlation spectrum; *** assigned by a
C,H-correlation spectrum; IR (film): n˜ =3605, 3530, 2970, 2935, 2880,
1780, 1690, 1460, 1380, 1300, 1205, 1120, 990, 930, 885, 760 cmꢀ1; m/z:
269.1627 ꢃ5 mDa [M +] confirmed by HRMS (EI, 70 eV); elemental
analysis calcd (%) for C14H23NO4 (269.3): C 62.43, H 8.61, N 5.20; found:
C 62.07, H 8.64, N 5.15.
Me)*, 1.81 (dqd, J5,6 =9.9, J5,5-Me =6.8, J5,4 =2.3, 5-H), 2.64 (qd, J3,3-Me
=
7.6, J3,4 =2.7, 3-H), 3.64 (dd, J4,3 =J4,5 =2.5, 4-H), 4.47 (dq, J6,5 =9.9, J6,6-Me
=6.4, 6-H); * signal assigned by comparison with the analogous reso-
nances and coupling constants of 4; 13C NMR (125.7 MHz; peak of con-
taminant at d=15.77): d=ꢀ4.83 and ꢀ4.50 [Si(CH3)2], 13.92 (5-CH3)*,
16.54 (3-CH3)*, 17.97 [SiC(CH3)3], 19.85 (6-CH3)*, 25.71 [3-fold intensity,
SiC(CH3)3], 36.09 (C-5)*, 44.13 (C-3)*, 74.47 (C-4)*, 77.32 (C-6)*, 174.20
(C-2); * signals assigned by comparison with the analogous resonances of
4; IR (CDCl3): n˜ =2955, 2935, 2885, 2860, 1720, 1465, 1385, 1360, 1255,
1240, 1130, 1100, 1060, 1035, 860, 840 cmꢀ1; elemental analysis calcd (%)
for C14H28O3Si (272.5): C 61.72, H 10.36; found: C 61.76, H 10.45.
(4S)-3-[(2S,3S,4E)-3-(tert-Butyldimethylsiloxy)-2,4-dimethyl-4-hexenoyl]-
4-isopropyl-1,3-oxazolidin-2-one (11): At 08C tert-butyldimethylsilyl tri-
flate (0.84 mL, 0.97 g, 3.7 mmol, 1.5 equiv) was added to a solution of al-
cohol 10 (653 mg, 2.43 mmol) and 2,6-lutidine (0.62 mL, 0.57 g, 5.3 mmol,
2.2 equiv) in CH2Cl2 (30 mL). After stirring at this temperature for 1.5 h,
the mixture was hydrolyzed with phosphate buffer (pH 7, 80 mL). The
aqueous phase was extracted with CH2Cl2 (3 î 50 mL), and the com-
bined organic phases were dried with MgSO4. The solvent was evaporat-
ed in vacuo to afford an oily residue which was submitted to flash chro-
matography (cyclohexane/EtOAc 8:1) to afford the title compound 11
(876 mg, 94%) as a colorless oil. [a]2D5 =+48.7 (c=0.62 in CHCl3); 1H
(3S,4R,5S,6R)-Tetrahydro-4-(methoxymethoxy)-3,5,6-trimethyl-2-pyra-
none (16): At 08C (chloromethyl) methyl ether (2.4 mL, 2.5 g, 32 mmol,
5.8 equiv) was added dropwise to a solution of b-hydroxy-d-lactone 4
(868 mg, 5.49 mmol) and diisopropylethylamine (5.7 mL, 4.3 g, 33 mmol,
6.1 equiv) in CH2Cl2 (20 mL). The reaction mixture was treated with tet-
rabutylammonium iodide (22.6 mg, 0.0612 mmol, 1.1 mol%) and allowed
to reach RT. After stirring at this temperature for 17.5 h, (chloromethyl)
methyl ether (1.0 mL, 1.1 g, 13 mmol, 2.4 equiv) and diisopropylethyla-
mine (2.4 mL, 1.8 g, 14 mmol, 2.6 equiv) were added (once again) and the
reaction was terminated after stirring for another 5 h by addition of aque-
ous saturated NaHCO3 (10 mL). Stirring was continued for 1 h to destroy
the excess of (chloromethyl) methyl ether. Then the aqueous phase was
extracted with CH2Cl2 (3 î 20 mL), and the combined organic phases
were dried with MgSO4. The solvent was evaporated in vacuo to afford
an oily residue which was submitted to flash chromatography (cyclohex-
ane/EtOAc 5:2) to afford the title compound 16 (1.102 g, 99%) as a col-
orless liquid. [a]2D5 =+7.2 (c=1.16 in CDCl3); 1H NMR [500 MHz; small
peak of contaminant (s) at d=1.25]: d=1.06 (d, J5-Me,5 =6.9, 5-Me)*, 1.31
(d, J3-Me,3 =7.6, 3-Me)*, 1.36 (d, J6-Me,6 =6.5, 6-Me)*, 1.90 (dqd, J5,6 =9.7,
NMR (500 MHz): d=ꢀ0.05 and 0.02 (2 î s, SiMe2), 0.87 (d, J1’-Me(1),1’
=
6.9, 1’-Me1), 0.88 (s, SiCMe3), 0.90 (d, J1’-Me(2),1’ =7.1, 1’-Me2), 1.20 (d, J2’’-
Me,2’’ =7.0, 2’’-Me), 1.54 1.58 (m, 4’’-Me, 6’’-H3), 2.36 (qqd, J1’,1’-Me(1) =J1’,1’-
Me(2) =7.0, J1’,4 =3.9, 1’-H), 4.08 (dq, J2’’,3’’ =7.8, J2’’,2’’-Me =6.8, 2’’-H), 4.14
4.20 (m, 5-H2), 4.21 (brd, J3’’,2’’ =7.8, 3’’-H), 4.31 (ddd, J4,5-H(1) =7.4, J4,5-
H(2) =J4,1’ =3.6, 4-H), 5.39 (qm, J5’’,6’’ ꢂ6, 5’’-H); 13C NMR (125.7 MHz):
d=ꢀ5.28 and ꢀ4.77 [Si(CH3)2], 11.26 and 13.00 (4’’-CH3, C-6’’)*, 13.93
1
2
(2’’-CH3)*, 14.72 (1’-CH3 )*, 17.98 (1’-CH3 )*, 18.17 [SiC(CH3)3], 25.79 [3-
fold intensity, SiC(CH3)3], 28.49 (C-1’), 42.42 (C-2’’), 58.79 (C-4)**, 63.20
(C-5)**, 79.07 (C-3’’)**, 121.54 (C-5’’)***, 136.37 (C-4’’)***, 153.65 and
175.23 (C-1’’, C-2); *,**,*** distinguishable by a C,H-correlation spec-
trum; IR (film): n˜ =3385, 2960, 2935, 2875, 2855, 1775, 1700, 1465, 1385,
1305, 1250, 1220, 1205, 1120, 1100, 1070, 1030, 990, 875, 835, 775,
700 cmꢀ1; m/z: 326.1876 ꢃ5 mDa [M +ꢀtBu] confirmed by HRMS (EI,
70 eV); elemental analysis calcd (%) for C20H37NO4Si (383.6): C 62.62, H
9.72, N 3.65; found: C 62.93, H 10.16, N 3.43.
J
5,5-Me =6.9, J5,4 =2.8, 5-H), 2.85 (qd, J3,3-Me =7.6, J3,4 =3.0, 3-H), 3.39
(2S,3S,4E)-3-(tert-Butyldimethylsiloxy)-2,4-dimethyl-4-hexenoic
acid
(OMe), 3.58 (dd, J4,3 =J4,5 =2.9, 4-H), 4.46 (dq, J6,5 =9.9, J6,6-Me =6.4, 6-H),
AB signal (dA =4.64, dB =4.72, JAB =7.1, -OCH2OMe); * signal assigned
by comparison with the analogous resonances and coupling constants of
4; 13C NMR (125.7 MHz): d=13.36 (5-CH3)*, 16.56 (3-CH3)*, 19.96 (6-
CH3)*, 35.38 (C-5)**, 40.78 (C-3)**, 55.88 (OCH3), 76.74 (C-6)***, 79.09
(C-4)***, 95.93 (OCH2OCH3), 173.88 (C-2); *,**,*** distinguishable by a
C,H-correlation spectrum; IR (film): n˜ =2980, 2940, 2890, 2825, 1735,
1460, 1385, 1355, 1300, 1235, 1150, 1095, 1040, 980, 965, 930 cmꢀ1; ele-
mental analysis calcd (%) for C10H18O4 (202.2): C 59.39, H 8.97; found: C
59.15, H 8.69.
methyl ester (12): At 08C tert-butyldimethylsilyl triflate (340 mL, 391 mg,
1.48 mmol, 1.6 equiv) was added to a solution of hydroxy ester ent-8
(160 mg, 0.930 mmol) and 2,6-lutidine (0.25 mL, 0.23 g, 2.1 mmol,
2.3 equiv) in CH2Cl2 (17 mL). After stirring at this temperature for
50 min, the mixture was allowed to reach romm temp. and after further
20 min stirring hydrolyzed with phosphate buffer (pH 7, 20 mL). The
aqueous phase was extracted with CH2Cl2 (2 î 20 mL), and the com-
bined organic phases were dried with MgSO4. The solvent was evaporat-
ed in vacuo to afford an oily residue which was submitted to flash chro-
matography (cyclohexane/EtOAc 20:1) to afford the title compound 12
(264 mg, 99%) as a colorless oil. [a]2D5 =ꢀ2.9 (c=1.25 in CHCl3); 1H
NMR (500 MHz; contains small impurity signals which might be caused
by tBuMe2SiOH): d=ꢀ0.04 and 0.02 (2 î s, SiMe2), 0.87 (s, SiCMe3),
(3S,4R,5R,6R)-4-(tert-Butyldimethylsiloxy)-3,4,5,6-tetrahydro-3,5,6-tri-
methyl-2(1H)-pyranol as an 85:15 mixture of unassigned a- and b-
anomer (17): At ꢀ788C DIBAL (2.1m in toluene, 1.7 mL, 3.6 mmol,
2.2 equiv) was added dropwise to a solution of d-lactone 15 (441.9 mg,
1.622 mmol) in toluene (12 mL). After stirring for 2.5 h, the reaction mix-
ture was poured into aqueous saturated sodium potassium tartrate
(30 mL) and stirred at RT for 1 h. The aqueous phase was extracted with
tBuOMe (3 î 20 mL), and the combined organic phases were dried with
MgSO4. The solvent was evaporated in vacuo to afford lactol 17
(441.1 mg, 99%) as a colorless oil, which could be used for the next reac-
tion without further purification. 1H NMR (500 MHz; peak of contami-
nant at d=0.92): major isomer: d=0.10 and 0.14 (2îs, SiMe2), 0.87 (d,
1.14 (d, J2-Me,2 =6.9, 2-Me), 1.54 1.58 (m, 4-Me, 6-H3), 2.63 (qd, J2,2-Me
2,3 =7.0, 2-H), 3.59 (s, OMe), 4.10 (brd, J3,2 =7.7, 3-H), 5.55 (qm, J5,6
=
J
ꢂ
6.6, 5-H); 13C NMR (125.7 MHz; contains small impurity signals which
might be caused by tBuMe2SiOH): d=ꢀ5.27 and ꢀ4.68 [Si(CH3)2], 11.11
and 12.93 (2-fold intensity, 2 resonances of 3-fold total intensity for 3C
atoms: 2-CH3, 4-CH3, C-6), 18.16 [(SiC(CH3)3], 25.77 [3-fold intensity,
SiC(CH3)3], 45.31 (C-2), 51.28 (OCH3), 79.97 (C-3), 121.38 (C-5), 136.25
(C-4), 175.20 (C-1); IR (film): n˜ =2955, 2930, 2885, 2860, 1740, 1460,
1435, 1390, 1360, 1345, 1255, 1195, 1165, 1125, 1090, 1060, 1030, 1005,
880, 835, 775 cmꢀ1; m/z: 229.1260 ꢃ5 mDa [M +ꢀtBu] confirmed by
HRMS (EI, 70 eV); elemental analysis calcd (%) for C15H30O3Si (286.5):
C 62.89, H 10.55; found: C 62.39, H 9.62.
J
J
5-Me,5 =6.9, 5-Me)*, 0.94 (s, SiCMe3), 1.02 (d, J3-Me,3 =7.3, 3-Me)*, 1.21 (d,
6-Me,6 =6.3, 6-Me)*, 1.67 (dqd, J5,6 =10.1, J5,5-Me =7.0, J5,4 =2.6, 5-H)**,
2.03 (qdd, J3,3-Me =7.3, J3,4 =2.8, J3,2 =1.0, 3-H)**, 3.71 (dd, J4,5 =4.2,***
4,3 =2.4,*** 4-H),**** 3.96 (dq, J6,5 =10.5, J6,6-Me =6.2, 6-H),**** 4.85
(brd, 2,OH =10.7, 2-H)*****, 5.47 (d, OH,2 =10.7, OH)*****;
J
(3S,4R,5R,6R)-4-(tert-Butyldimethylsiloxy)-tetrahydro-3,5,6-trimethyl-2-
pyranone (15): At 08C tert-butyldimethylsilyl triflate (0.30 mL, 0.35 mg,
1.3 mmol, 2.6 equiv) was added to a solution of b-hydroxy-d-lactone 4
(78.0 mg, 0.493 mmol) and 2,6-lutidine (86 mL, 79 mg, 0.73 mmol,
1.5 equiv) in CH2Cl2 (8 mL). After stirring at this temperature for 12 h,
the reaction mixture was hydrolyzed with phosphate buffer (pH 7,
40 mL). The aqueous phase was extracted with CH2Cl2 (3 î 40 mL), and
the combined organic phases were dried with MgSO4. The solvent was
evaporated in vacuo at 08C to afford an oily residue which was submitted
J
J
*,**,**** distinguishable by an H,H-correlation spectrum; *** inter-
changeable; ***** distinguishable by a H/D-exchange experiment with
D2O; minor isomer: d=0.04 and 0.07 (2 î s, SiMe2), 0.80 (d, J5-Me,5 =6.9,
5-Me)*, 0.90 (s, SiCMe3), 0.95 (d, J3-Me,3 =7.1, 3-Me)*, 1.18 (d, J6-Me,6 =6.3,
6-Me)*, 1.55 (m, 5-H)**, 1.88 1.94 (m, 3-H)**, 2.65 (brs, OH), 3.63 (dd,
J
4,5 =J4,3 =2.8, 4-H),*** 3.67 (dq, J6,5 =10.2, J6,6-Me =6.3, 6-H),*** 5.19 (m,
2-H); *,**,*** distinguishable by an H,H-correlation spectrum; 13C NMR
1551
Chem. Eur. J. 2004, 10, 1545 1557
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

R. Br¸ckner and T. Berkenbusch
FULL PAPER
(125.7 MHz): major isomer: d=ꢀ4.91 and ꢀ4.56 [Si(CH3)2], 14.66 (5-
CH3)*, 15.02 (3-CH3)*, 17.98 [SiC(CH3)3], 19.28 (6-CH3)*, 25.83 [3-fold
intensity, SiC(CH3)3], 36.12 (C-5)**, 39.87 (C-3)**, 64.49 (C-6)***, 76.50
(C-4)***, 96.81 (C-2); *,**,*** distinguishable by a C,H-correlation spec-
trum; minor isomer: d=ꢀ4.94 and ꢀ4.51 [Si(CH3)2], 8.88 (5-CH3)*, 13.83
(3-CH3)*, 19.39 (6-CH3)*, 36.47 (C-5)**, 41.46 (C-3)**, 72.13 (C-6)***,
76.57 (C-4)***, 93.60 (C-2); *,**,*** interchangeable; IR (film): n˜ =3690,
3605, 3465, 2955, 2935, 2870, 1775, 1715, 1605, 1460, 1385, 1260, 1110,
1030, 930, 845, 760, 710, 650 cmꢀ1; elemental analysis calcd (%) for
C14H30O3Si (274.5): C 61.26, H 11.02; found: C 61.45, H 11.12.
1150, 1080, 1040, 835, 775 cmꢀ1
; elemental analysis calcd (%) for
C18H36O4Si (344.6): C 62.74, H 10.53; found: C 63.02, H 10.66.
(2E,4R,5S,6R,7R)-7-Hydroxy-5-(methoxymethoxy)-4,6-dimethyl-2-octe-
noic acid ethyl ester (22): A solution of tributyl(ethoxycarbonylmethyl)-
phosphonium bromide (26, 5.99 g, 16.2 mmol, 6.0 equiv) in CH2Cl2
(50 mL) was washed with aqueous NaOH (1m, 2î30 mL), dried with
MgSO4 and diluted with toluene (10 mL). The CH2Cl2 was successively
evaporated in vacuo. This solution was then transferred via cannula to a
solution of lactol 18 (552 mg, 2.70 mmol) and benzoic acid (132 mg,
1.08 mmol, 40 mol%) in toluene (20 mL), which was stirred at 928C.
After stirring at this temperature for 2.5 h, the reaction mixture was
cooled to RT and purified by flash chromatography (5.0 cm, cyclohexane/
EtOAc 4:1 ! fraction 35, 3:1 ! fraction 60, 2:1 ! fraction 120) to
afford unconsumed lactol 18 (259.3 mg, 47%) and a,b-unsaturated ethyl
ester 22 (274.1 mg, 37%; 70% based on recovered starting material) as a
colorless liquid. [a]2D5 =+28.9 (c=0.94 in CDCl3); 1H NMR (500 MHz):
(3S,4R,5S,6R)-Tetrahydro-4-(methoxymethoxy)-3,5,6-trimethyl-2-pyranol
as a 79:21 mixture of unassigned a- and b-anomer (18): At ꢀ788C
DIBAL (1.5m in toluene, 0.90 mL, 1.4 mmol, 2.2 equiv) was added drop-
wise to a solution of d-lactone 16 (126.8 mg, 0.6277 mmol) in toluene
(5 mL). After stirring for 2.5 h, the reaction mixture was poured into
aqueous saturated Rochelle×s salt (20 mL) and stirred at RT for 1 h. The
aqueous phase was extracted with tBuOMe (3 î 20 mL), and the com-
bined organic phases were dried with MgSO4. The solvent was evaporat-
ed in vacuo to afford lactol 18 (127.2 mg, 99%) as a colorless oil, which
d=0.88 (d, J6-Me,6 =7.1, 6-Me)*, 1.11 (d, J4-Me,4 =6.8, 4-Me)*, 1.17 (d, J8,7
=
6.3, 8-H3)*, 1.29 (t, J2’,1’ =7.1, 2’-H3), 1.77 (qdd, J6,6-Me =J6,5 =J6,7 =7.1, 6-
4
H), 2.64 (qddd, J4,4-Me =J4,3 =7.0, J4,5 =4.1, J4,2 =1.5, 4-H), 2.78 (brs, OH),
1
3.40 (s, OMe), 3.50 (dd, J5,6 =7.2, J5,4 =4.2, 5-H), 3.84 (brdq, J7,6 =J7,8
6.5, 7-H), 4.19 (q, J1’,2’ =7.1, 1’-H2), AB signal (dA =4.62, dB =4.64, JAB
6.8, OCH2OMe), 5.85 (dd, Jtrans =15.8, 4J2,4 =1.4, 2-H), 7.01 (dd, Jtrans
=
=
=
could be used for the next reaction without further purification. H NMR
(500 MHz): major isomer: d=0.93 (d, J5-Me,5 =6.8, 5-Me)*, 1.05 (d, J3-Me,3
=7.4, 3-Me)*, 1.22 (d, J6-Me,6 =6.3, 6-Me)*, 1.73 (dqd, J5,6 =10.2, J5,5-Me
6.9, J5,4 =3.1, 5-H)**, 2.17 (qdd, J3,3-Me =7.3, J3,4 =2.8, J3,2 =1.1, 3-H)**,
3.43 (OMe), 3.61 (dd, 4,5 =4.1, 4,3 =2.7, 4-H), 3.93 (dq, 6,5 =10.5,
6,6-Me =6.2, 6-H), AB signal (dA =4.63, dB =4.78, JAB =6.9, OCH2OMe),
=
15.8, J3,4 =7.4, 3-H); * distinguishable by an H,H-correlation spectrum;
13C NMR [125.7 MHz; peaks of contaminant(s) at d=29.26 and 53.80]:
d=13.53 (4-CH3)*, 13.86 (6-CH3)*, 14.24 (C-2’)*, 20.30 (C-8)*, 39.70 (C-
4)**, 43.18 (C-6)**, 56.34 (OCH3)***, 60.29 (C-1’)***, 69.63 (C-7)****,
85.61 (C-5)****, 97.92 (OCH2OCH3), 120.97 (C-2), 151.94 (C-3), 166.58
(C-1); *,**,***,**** distinguishable by a C,H-correlation spectrum; IR
(film): n˜ =3450, 2975, 2935, 1715, 1650, 1455, 1370, 1300, 1265, 1185,
J
J
J
J
4.87 (d, J2,OH =10.5, 2-H), 5.10 (d, JOH,2 =10.5, OH)***; *,** distinguisha-
ble by an H,H-correlation spectrum; *** distinguishable by a H/D-ex-
change experiment with D2O; minor isomer: d=0.89 (d, J5-Me,5 =6.9, 5-
Me)*, 0.98 (d, J3-Me,3 =7.1, 3-Me)*, 1.20 (d, J6-Me,6 ꢂ7, 6-Me)*, 1.64 (dqd,
1150, 1095, 1035, 960, 920 cmꢀ1
; elemental analysis calcd (%) for
J
5,6 =10.1, J5,5-Me =6.9, J5,4 =3.2, 5-H)**, 2.13 (qdd, J3,3-Me =7.1, J3,2 =J3,4 =
C14H26O5 (274.4): C 61.29, H 9.55; found: C 61.01, H 9.79.
2.8, 3-H)**, 2.75 (brs, OH)***, 3.39 (OMe), 3.54 (dd, J4,3 =J4,5 =2.8, 4-H),
3.65 (dq, J6,5 =10.2, J6,6-Me =6.3, 6-H), AB signal (dA =4.60, dB =4.74,
[(3R,4R,5R,6R)-4-(tert-Butyldimethylsiloxy)-tetrahydro-3,5,6-trimethyl-
pyran-2-yl]acetic acid ethyl ester (23) as a 74:26 mixture of two unas-
signed C-2’ diastereomers, which could be separated by flash chromatog-
raphy: A refluxing solution of lactol 17 (151 mg, 0.551 mmol) and (ethox-
JAB =6.9, OCH2OMe), 5.15 (m, 2-H)****; *,** distinguishable by an
H,H-correlation spectrum; *** exchangable with D2O; **** resonates in
a H/D-exchange experiment with D2O at d=5.14 (d, J2,3 =2.4, 2-H);
13C NMR (125.7 MHz): major isomer: d=14.12 (5-CH3)*, 15.10 (3-
CH3)*, 19.32 (6-CH3)*, 35.29 (C-5)**, 37.29 (C-3)**, 56.28 (OCH3), 65.05
(C-6)***, 81.29 (C-4)***, 96.51 and 96.63 (C-2, OCH2OCH3);
*,**,*** distinguishable by a C,H-correlation spectrum; minor isomer:
d=8.92 (3-CH3)*, 13.34 (5-CH3)*, 19.48 (6-CH3)*, 35.65 (C-5)**, 37.92
(C-3)**, 55.75 (OCH3), 72.63 (C-6)***, 81.70 (C-4)***, 93.84 (C-2)****,
95.96 (OCH2OCH3)****; **,**,***,**** distinguishable by a C,H-correla-
tion spectrum; IR (film): n˜ =3425, 2970, 2935, 2905, 1715, 1650, 1455,
1380, 1330, 1280, 1215, 1155, 1100, 1040, 990, 955, 920, 895 cmꢀ1; elemen-
tal analysis calcd (%) for C10H20O4 (204.3): C 58.80, H 9.87; found: C
58.76, H 9.62.
ycarbonylmethylen)triphenylphosphorane
(25,
1.35 g,
3.88 mmol,
7.0 equiv) in toluene (15 mL) was stirred for 24 h. After cooling to RT,
the solvent was evaporated in vacuo to a volume of ca. 2 mL, and the res-
idue was submitted to flash chromatography (cyclohexane/EtOAc 5:1) to
afford a contaminated diastereomeric mixture of 23 (121 mg) and the
a,b-unsaturated ethyl ester 21 (32.1 mg, 17%) as a colorless liquid. The
mixture was resubmitted to flash chromatography (cyclohexane/EtOAc
12:1) to afford the pure major diastereomer of 23 (58.1 mg, 31%) and
the pure minor diastereomer of 23 (20.2 mg, 11%) as a colorless liquid
(each).
Major diastereomer: [a]2D5 =+15.1 (c=0.74 in CHCl3); 1H NMR
(500 MHz): d=0.04 (s, SiMe2), 0.79 (d, J5’-Me,5’ =6.9, 5’-Me)*, 0.917 (s,
SiCMe3), superimposed by 0.923 (d, J3’-Me,3’ =6.9, 3’-Me)*, 1.11 (d, J6’-
Me,6’ =6.3, 6’-CH3)*, 1.25 (t, J2’’,1’’ =7.2, 2’’-H3), 1.51 (dqd, J5’,6’ =9.8, J5’,5-
Me =7.0, J5’,4’ =2.6, 5’-H)**, 1.65 (qdd, J3’,3’-Me =7.1, J3’,2’ =J3’,4’ =2.7, 3’-
H)**, AB signal (dA =2.30, dB =2.54, JAB =14.6, in addition split by
(2E,4R,5S,6R,7R)-5-(tert-Butyldimethylsiloxy)-7-hydroxy-4,6-dimethyl-2-
octenoic acid ethyl ester (21): A solution of tributyl(ethoxycarbonylme-
thyl)phosphonium bromide (26, 389 mg, 1.05 mmol, 2.3 equiv) in CH2Cl2
(15 mL) was washed with aqueous NaOH (1m, 2 î 10 mL), dried with
MgSO4 and diluted with toluene (4 mL). The CH2Cl2 was successively
evaporated in vacuo. This solution was then transferred via cannula to a
solution of lactol 17 (126 mg, 0.459 mmol) and benzoic acid (11 mg,
0.090 mmol, 20 mol%) in toluene (8 mL), which was stirred at 958C.
After stirring at this temperature for 3 h, the reaction mixture was cooled
to RT and purified by flash chromatography (3.0 cm, cyclohexane/EtOAc
5:1) to afford the a,b-unsaturated ethyl ester 21 (48.9 mg, 31%) as a col-
JA,2’ =6.6, JB,2’ =7.8, 2-H2), 3.55 (dd, J4’,3’ =J4’,5’ =2.9, 4’-H)***, partly super-
imposed by 3.57 (dq, J6’,5’ =10.1, J6’,6’-Me =6.2, 6’-H)***, extreme AB signal
(dA =4.10, dB =4.16, JAB =10.8, in addition split by JA,2’’ =JB,2’’ =7.1, 1’’-
H2), 4.36 (ddd, J2’,2-H(B) =7.8, J2’,2-H(A) =6.7, J2’,3’ =2.3, 2’-H)***; *,** distin-
guishable by an H,H-correlation spectrum; *** 2’-H (ddd), 4’-H (dd) and
6’-H (dq) were distinguished by the differing multiplicity and by the con-
cerning coupling constants; 13C NMR (125.7 MHz; peak of contaminant
at d=68.26): d=ꢀ4.88 and ꢀ4.48 [Si(CH3)2], 10.80 (3’-CH3)*, 14.21 (C-
2’’)*, 14.40 (5’-CH3)*, 18.12 [3-fold intensity, SiC(CH3)3], 19.53 (6’-CH3)*,
25.86 [SiC(CH3)3]**, 36.81 (C-5’)**, 38.43 (C-2)**, 39.37 (C-3’)**, 60.29
(C-1’’)***, 70.47 (C-2’)***, 73.86 (C-6’)***, 75.84 (C-4’)***, 171.47 (C-1);
*,**,*** distinguishable by a C,H-correlation spectrum; IR (film): n˜ =
2960, 2930, 2900, 2860, 1740, 1460, 1380, 1330, 1285, 1270, 1255, 1180,
1115, 1075, 1035, 1005, 865, 835, 775 cmꢀ1; elemental analysis calcd (%)
for C18H36O4Si (344.6): C 62.74, H 10.53; found: C 63.07, H 11.05.
1
orless liquid. [a]2D5 =+9.9 (c=0.44 in CDCl3); H NMR (500 MHz; slight-
ly contaminated by a diastereomer): d=0.08 and 0.11 (2îs, SiMe2), 0.85
(d, J6-Me,6 =7.1, 6-Me)*, 0.92 (s, SiCMe3), 1.08 (d, J4-Me,4 =6.8, 4-Me)*, 1.14
(d, J8,7 =6.1, 8-H3)*, 1.29 (t, J2’,1’ =7.2, 2’-H3), 1.67 (dqd, J6,7 =8.2, J6,6-Me
=
4
7.0, J6,5 =5.7, 6-H), 2.57 (qddd, J4,4-Me =J4,3 =J4,5 =6.6, J4,2 =1.3, 4-H), 2.79
(brs, OH), 3.63 (dd, J5,6 =5.7, J5,4 =4.7, 5-H), 3.73 (dq, J7,6 =8.2, J7,8 =6.2,
7-H), 4.16 4.23 (m, 1’-H2), 5.82 (dd, Jtrans =15.8, 4J2,4 =1.3, 2-H), 6.97 (dd,
J
trans =15.8, J3,4 =7.9, 3-H); * distinguishable by an H,H-correlation spec-
trum; 13C NMR (125.7 MHz): d=ꢀ4.20 and ꢀ3.97 [Si(CH3)2], 14.26,
14.42 and 14.70 (4-CH3, 6-CH3, C-2’), 18.23 [SiC(CH3)3], 20.67 (C-8)*,
26.03 [3-fold intensity, SiC(CH3)3], 41.89 (C-4)**, 44.62 (C-6)**, 60.23 (C-
1’)***, 69.53 (C-7)***, 79.70 (C-5)***, 121.11 (C-2), 152.21 (C-3), 166.58
(C-1); *,**,*** distinguishable by a C,H-correlation spectrum; IR (film):
n˜ =3455, 2960, 2930, 2900, 2860, 1725, 1650, 1465, 1370, 1330, 1255, 1185,
Minor diastereomer: [a]2D5 =+15.9 (c=0.42 in CDCl3); 1H NMR
(500 MHz): d=0.05 (s, SiMe2), 0.91 (s, SiCMe3), 0.92 (d, J5’-Me,5’ =6.9, 5’-
Me)*, 1.00 (d, J3’-Me,3’ =7.1, 3’-Me)*, 1.18 (d, J6’-Me,6’ =6.6, 6’-Me)*, 1.25 (t,
J
2’’,1’’ =7.1, 2’’-H3), 1.65 (dqd, J5’,6’ =J5’,5-Me =6.8, J5’,4’ =3.7, 5’-H)**, 1.70
(qdd, J3’,3’-Me =6.9, J3’,2’ =J3’,4’ =5.5, 3’-H)**, AB signal (dA =2.67, dB =2.84,
1552
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1545 1557

Nystatin A1
1545 1557
J
AB =15.0, in addition split by JA,2’ =4.8, JB,2’ =8.9, 2-H2), 3.61 (dd, J4’,3’
5.8, J4’,5’ =3.7, 4’-H)***, 3.80 (dq, J6’,5’ =J6’,6’-Me =6.5, 6’-H)***, 3.92 (ddd,
2’,2-H(B) =8.9, 2’,2-H(A) =J2’,3’ =4.7, 2’-H)***, 4.14 (q, 1’’,2’’ =7.1, 1’’-H2);
=
mitted to flash chromatography (cyclohexane/EtOAc 13:1) to afford the
title compound 28 (55.2 mg, 84%) as a colorless oil. [a]2D5 =+14.0 (c=
1.03 in CDCl3); 1H NMR (500 MHz): d=0.046 and 0.050 (2 î s, SiMe2),
0.86 (d, J6-Me,6 =7.1, 6-Me)*, 0.88 (s, SiCMe3), 1.06 (d, J8,7 =6.2, 8-H3)*,
J
J
J
*,** distinguishable by an H,H-correlation spectrum; *** 2’-H (ddd), 4’-
H (dd) and 6’-H (dq) were distinguished by the differing multiplicity and
by the concerning coupling constants; 13C NMR (125.7 MHz): d=ꢀ4.71
and ꢀ4.45 [Si(CH3)2], 13.76 (5’-CH3)*, 14.24 (C-2’’)*, 16.15 (3’-CH3)*,
18.13 [SiC(CH3)3], 18.55 (6’-CH3)*, 25.94 [3-fold intensity, SiC(CH3)3],
38.03 (C-5’)**, 38.30 (C-3’)**, 39.01 (C-2)**, 60.25 (C-1’’)***, 69.77 (C-
6’)***, 73.21 (C-2’)***, 73.96 (C-4’)***, 172.10 (C-1); *,**,*** distinguish-
able by a C,H-correlation spectrum; IR (film): n˜ =2960, 2930, 2905, 2860,
1740, 1465, 1380, 1310, 1255, 1180, 1150, 1120, 1090, 1065, 1025, 865, 835,
775 cmꢀ1; elemental analysis calcd (%) for C18H36O4Si (344.6): C 62.74, H
10.53; found: C 60.77, H 9.58.
1.08 (d, J4-Me,4 =6.8, 4-Me)*, 1.29 (t, J2’,1’ =7.2, 2’-H3), 1.85 (qdd, J6,6-Me
6,5 =7.2, J6,7 =4.5, 6-H), 2.61 (qddd, J4,4-Me =J4,3 =6.9, J4,5 =3.7, 4J4,2 =1.4,
4-H), 3.37 (s, OMe), 3.41 (dd, J5,6 =7.7, J5,4 =3.8, 5-H), 4.05 (qd, J7,8 =6.2,
7,6 =4.6, 7-H), 4.19 (q, J1’,2’ =7.1, 1’-H2), AB signal (dA =4.55, dB =4.56,
AB =6.9, OCH2OMe), 5.83 (dd, Jtrans =15.8, 4J2,4 =1.4, 2-H), 7.03 (dd,
trans =15.8, J3,4 =7.4, 3-H); * distinguishable by an H,H-correlation spec-
=
J
J
J
J
trum; 13C NMR (125.7 MHz): d=ꢀ4.75 and ꢀ4.32 [Si(CH3)2], 10.38 (6-
CH3)*, 13.13 (4-CH3)*, 14.27 (C-2’)*, 18.04 [SiC(CH3)3], 18.52 (C-8)*,
25.87 [3-fold intensity, SiC(CH3)3], 38.77 (C-4)**, 43.15 (C-6)**, 56.09
(OCH3)***, 60.20 (C-1’)***, 68.14 (C-7)***, 83.19 (C-5)***, 97.65
(OCH2OCH3), 120.55 (C-2), 152.64 (C-3), 166.63 (C-1); *,**,*** distin-
guishable by a C,H-correlation spectrum; IR (film): n˜ =2955, 2930, 2890,
2835, 1720, 1650, 1470, 1465, 1385, 1370, 1330, 1300, 1255, 1180, 1160,
1140, 1100, 1035, 995, 965, 940, 835, 775 cmꢀ1; elemental analysis calcd
(%) for C20H40O5Si (388.6): C 61.81, H 10.37; found: C 61.86, H 10.35.
(2E,6S,7R)-7-Hydroxy-4,6-dimethyl-2,4-octadienoic acid ethyl ester as a
inseparable 89:11 mixture of two unassigned C4 C5-bond isomers (24): A
solution of tributyl(ethoxycarbonylmethyl)phosphonium bromide (26,
468 mg, 1.27 mmol, 2.6 equiv) in CH2Cl2 (15 mL) was washed with aque-
ous NaOH (1m, 2 î 15 mL), dried with MgSO4 and diluted with toluene
(3 mL). The CH2Cl2 was successively evaporated in vacuo. This solution
was then transferred via cannula to a refluxing solution of lactol 18
(99.1 mg, 0.485 mmol) and benzoic acid (10.9 mg, 0.0893 mmol,
18 mol%) in toluene (5 mL). After stirring for 2 h, the reaction mixture
was cooled to RT and purified by flash chromatography (2.5 cm, cyclo-
hexane/EtOAc 5:1) to afford the title compound 24 (54.6 mg, 53%) as a
light yellow liquid. 1H NMR (500 MHz; slightly contaminated): major
(2E,4R,5S,6S,7R)-7-(tert-Butyldimethylsiloxy)-5-(methoxymethoxy)-4,6-
dimethyl-2-octenal (29): At ꢀ788C DIBAL (1.5m in toluene, 1.8 mL,
2.7 mmol, 3.1 equiv) was added dropwise to a solution of ethyl ester 28
(340 mg, 0.875 mmol) in CH2Cl2 (20 mL). After stirring for 80 min, the
reaction mixture was poured into aqueous saturated Rochelle’s salt
(50 mL) and stirred at RT for 1 h. The aqueous phase was extracted with
CH2Cl2 (3 î 40 mL), and the combined organic phases were dried with
MgSO4. Evaporation of the solvent in vacuo gave a residue which was
dissolved in CH2Cl2 (23 mL) and treated with MnO2 (1.69 g, 19.6 mmol,
22 equiv). After 4 h stirring at RT, the reaction mixture was filtered
through a pad of Celite, and the filter cake was washed with CH2Cl2 (3î
5 mL). The filtrate and washings were evaporated in vacuo to afford a
residue which was submitted to flash chromatography (cyclohexane/
EtOAc 8:1) to afford aldehyde 29 (269 mg, 89%) as a colorless oil.
[a]2D5 =+7.0 (c=1.17 in CHCl3); 1H NMR (500 MHz): d=0.05 and 0.06
(2 î s, SiMe2), 0.857 (d, J6-Me,6 =6.9, 6-Me)*, superimposes in part 0.864
(s, SiCMe3), 1.05 (d, J8,7 =6.3, 8-H3)*, 1.11 (d, J4-Me,4 =6.8, 4-Me)*, 1.85
isomer: d=1.02 (d, J6-Me,6 =6.8, 6-Me), 1.18 (d, J8,7 =6.3, 8-H3), 1.30 (t,
J
4
2’,1’ =7.2, 2’-H3), 1.60 1.88 (m, OH), superimposed by 1.82 (d, J4-Me,5
=
1.2, 4-Me), 2.57 (dqd, J6,5 =10.0, J6,6-Me =6.5, J6,7 =6.4, 6-H), 3.67 (dq,
7,6 =J7,8 =6.2, 7-H), 4.21 (q, J1’,2’ =7.1, 1’-H2), 5.79 (brd, J5,6 =10.0, 5-H),
J
5
4
5.83 (dd, Jtrans =15.7, J2,5 =0.5, 2-H), 7.34 (dd, Jtrans =15.7, J3,5 =0.6, 3-H);
minor isomer*: d=1.31 (t, J2’,1’ =7.2, 2’-H3), 1.90 (d, 4J4-Me,5 =1.2, 4-Me),
2.76 (brdqd, J6,5 =10.3, J6,6-Me =J6,7 =6.6, 6-H), 3.64 (dq, J7,6 =J7,8 =6.2, 7-
H), 4.23 (q, J1’,2’ =7.1, 1’-H2), 5.64 (brd, J5,6 =10.0, 5-H), 5.93 (dd, Jtrans
=
15.6, 5J2,5 =0.7, 2-H), 7.71 (d, Jtrans =15.5, 3-H); * other signals are super-
imposed; 13C NMR (125.7 MHz): major isomer: d=12.57, 14.28, 16.45
and 20.53 (4-CH3, 6-CH3, C-8, C-2’), 40.87 (C-6), 60.20 (C-1’)*, 71.49 (C-
7)*, 116.44, 140.97, 143.30, 149.23 (C-2, C-3, C-4, C-5), 167.39 (C-1); * in-
terchangeable; minor isomer*: d=13.60, 17.21, 20.28 and 20.55 (4-CH3, 6-
CH3, C-8, C-2’), 39.89 (C-6), 60.33 (C-1’)**, 71.54 (C-7)**, 167.45 (C-1);
* other signals superimposed; ** interchangeable; IR (film): n˜ =3450,
2975, 2930, 2875, 1715, 1625, 1450, 1395, 1370, 1310, 1275, 1175, 1095,
1095, 1030, 985, 940, 905, 850 cmꢀ1; m/z: 212.1409 ꢃ5 mDa [M +] con-
firmed by HRMS (EI, 70 eV); elemental analysis calcd (%) for C12H20O3
(212.3): C 67.89, H 9.50; found: C 67.28, H 9.98.
(dqd, J6,5 =8.0, J6,6-Me =7.1, J6,7 =4.3, 6-H), 2.74 (qddd, J4,4-Me =J4,3 =6.8,
4
J
4,5 =3.3, J4,2 =1.5, 4-H), 3.33 (s, OMe), 3.45 (dd, J5,6 =8.1, J5,4 =3.4, 5-H),
4.02 (qd, J7,8 =6.3, J7,6 =4.4, 7-H), extreme AB signal (dA =4.54, dB =4.55,
J
AB =6.9, OCH2OMe), 6.11 (ddd, Jtrans =15.7, J2,1 =7.8, 4J2,4 =1.5, 2-H),
6.95 (dd, Jtrans =15.8, J3,4 =6.8, 3-H), 9.52 (d, J1,2 =7.7, 1-H); * distinguisha-
ble by an H,H-correlation spectrum; 13C NMR (125.7 MHz): d=ꢀ4.71
and ꢀ4.29 [Si(CH3)2], 10.70 (6-CH3)*, 12.79 (4-CH3)*, 18.04 [SiC(CH3)3],
18.65 (C-8)*, 25.86 [3-fold intensity, SiC(CH3)3], 39.19 (C-4)*, 43.21 (C-
6)*, 56.08 (OCH3)*, 68.31 (C-7)*, 83.24 (C-5)*, 97.68 (OCH2OCH3),
131.81 (C-2), 162.52 (C-3), 195.06 (C-1); * assignment by comparison
with the analogous resonance of ethyl ester 28–criterion of assignment:
D(d) ꢁ 0.5 ppm; IR (film): n˜ =2955, 2930, 2890, 2835, 1695, 1635, 1465,
1385, 1255, 1150, 1100, 1035, 965, 835, 775 cmꢀ1; m/z: 313.2199 ꢃ5 mDa
[M +ꢀOMe] confirmed by HRMS (EI, 70 eV); elemental analysis calcd
(%) for C18H36O4Si (344.6): C 62.74, H 10.53; found: C 62.93, H 10.78.
Tributyl(ethoxycarbonylmethyl)phosphonium bromide (26): At 08C, a
solution of bromoacetic acid ethyl ester (13.4 mL, 20.2 g, 121 mmol,
1.0 equiv) in toluene (20 mL) was added dropwise to a solution of tribu-
tylphosphine (30 mL, 24 g, 0.12 mol) in toluene (120 mL). The reaction
mixture was allowed to reach RT, and after 22 h the resulting precipitate
was filtered and dried in vacuo (6î10ꢀ4 mbar) at 508C for 20 h to afford
the title compound 26 (37.9 g, 86%) as a colorless solid. M.p. 968C;
1H NMR (400 MHz): d=0.98 (t, J4’,3’ =7.0, 3 î 4’-H3), 1.31 (t, J2,1 =7.2, 2-
H3), 1.48 1.64 (m, 3 î 2’-H2, 3 î 3’-H2), 2.61 (m, 3 î 1’-H2), 4.18 (d,
(2E,4R,5S,6R,7R)-5-(tert-Butyldimethylsiloxy)-7-(methoxymethoxy)-4,6-
dimethyl-2-octenoic acid ethyl ester (30): At 08C (chloromethyl) methyl
ether (0.66m in CH2Cl2, 0.70 mL, 0.46 mmol, 5.3 equiv) was added drop-
wise to a solution of alcohol 21 (30.2 mg, 0.0876 mmol) and diisopropyle-
thylamine (90 mL, 68 mg, 0.53 mmol, 6.0 equiv) in CH2Cl2 (4 mL). After
40 min stirring the reaction mixture was allowed to reach RT and stirred
for 6 h at this temperature. (Chloromethyl) methyl ether (0.66m in
CH2Cl2, 0.40 mL, 0.26 mmol, 3.0 equiv), diisopropylethylamine (60 mL,
45 mg, 0.35 mmol, 4.0 equiv) and tetrabutylammonium iodide (4.4 mg,
0.012 mmol, 14 mol%) were added, and the reaction was terminated
after stirring for another 12 h by addition of water (8 mL). Stirring was
continued for 1 h to destroy the excess of (chloromethyl) methyl ether.
Then the aqueous phase was extracted with CH2Cl2 (3î5 mL), and the
combined organic phases were dried with MgSO4. The solvent was
evaporated in vacuo to afford an oily residue which was submitted to
flash chromatography (cyclohexane/EtOAc 10:1) to afford the title com-
pound 30 (29.0 mg, 85%) as a colorless oil. [a]2D5 =+10.6 (c=0.60 in
CHCl3); 1H NMR (500 MHz): d=0.03 and 0.05 (2îs, SiMe2), 0.87 (d,
2J1’’,P =13.1, 1’’-H2), partly superimposed by 4.22 (q,
J1,2 =7.1, 1-H2).
13C NMR (100.6 MHz): d=13.38 (3-fold intensity, s, 3 î C-4’), 13.95 (s,
1
C-2), 19.56 (3-fold intensity, d, JC-1’,P =47, 3 î C-1’), 23.80 (3-fold intensi-
3
1
ty, brs, 3 î C-2’), 23.90 (d, JC-3’,P =10, 3 î C-3’), 27.55 (d, JC-1’’,P =54, C-
1’’), 62.80 (s, C-1), 165.68 (s, C=O); IR (CDCl3): n˜ =2965, 2935, 2875,
2205, 1725, 1465, 1400, 1380, 1310, 1190, 1135, 1095, 1020, 930, 925, 890,
885 cmꢀ1; elemental analysis calcd (%) for C16H34BrO2P (369.3): C 52.03,
H 9.28; found: C 52.15, H 9.41.
(2E,4R,5S,6S,7R)-7-(tert-Butyldimethylsiloxy)-5-(methoxymethoxy)-4,6-
dimethyl-2-octenoic acid ethyl ester (28): At 08C tert-butyldimethylsilyl
triflate (77 mL, 89 mg, 0.34 mmol, 2.0 equiv) was added to a solution of al-
cohol 22 (46.3 mg, 0.169 mmol) and 2,6-lutidine (70 mL, 64 mg,
0.60 mmol, 3.6 equiv) in CH2Cl2 (6 mL). After stirring at this temperature
for 15 h, the reaction mixture was hydrolyzed with aqueous saturated
NaHCO3 (10 mL). The aqueous phase was extracted with CH2Cl2 (3 î
10 mL), and the combined organic phases were dried with MgSO4. The
solvent was evaporated in vacuo to afford an oily residue which was sub-
J
J
6-Me,6 =7.1, 6-Me)*, 0.91 (s, SiCMe3), 1.06 (d, J4-Me,4 =6.8, 4-Me)*, 1.09 (d,
8,7 =6.2, 8-H3)*, 1.29 (t, J2’,1’ =7.2, 2’-H3), 1.90 (dqd, J6,5 =J6,6-Me =6.9,
1553
Chem. Eur. J. 2004, 10, 1545 1557
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

R. Br¸ckner and T. Berkenbusch
FULL PAPER
J
6,7 =5.3, 6-H), 2.55 (poorly resolved qddd, J4,4-Me =J4,3 =7.0, J4,5 =4.0,
4J4,2 =1.3, 4-H), 3.35 (s, OMe), 3.64 (dd, J5,6 =6.5, J5,4 =4.0, 5-H), 3.85 (qd,
7,8 =J7,6 =6.0, 7-H), 4.19 [m; perhaps interpretable as extreme AB signal
(dA =4.18, dB =4.20, JAB =3.2, in addition split by JA,2’ =JB,2’ =7.1, 1’-H2)],
AB signal (dA =4.60, dB =4.64, JAB =6.8, OCH2OMe), 5.80 (dd, Jtrans
J
12,12-Me =7.2, J12,13 =4.5, 12-H)*, 2.23 (brtd, J5,4 =J5,6 =7.0, 5-H2)**, 2.30
(td with small extra-peaks indicating transition to higher-order spectrum
and/or unresolved J4,2, J4,5 =J4,3 =7.0, 4-H2)**, 2.44 (brdqd, J10,9 =J10,10-
4
J
Me =6.9, J10,11 =4.2, 10-H)*, 3.29 (dd, J11,12 =7.8, J11,10 =3.9, 11-H)*, 3.37 (s,
OCH2OMe)*, 3.73 (s, CO2Me), 4.09 (qd, J13,14 =6.2, J13,12 =4.5, 13-H)*,
AB signal (dA =4.56, dB =4.59, JAB =6.6, OCH2OMe)*, 5.56 (dt with
small extra-peaks indicating transition to higher-order spectrum, Jtrans
14.5, J6,5 =7.0, 6-H)*, 5.62 (dd, Jtrans =14.5, J9,10 =7.6, 9-H)*, 5.84 (dt with
small extra-peaks indicating transition to higher-order spectrum, Jtrans
15.7, J2,4 =1.5, 2-H), 6.01 (m, 7-H, 8-H)*, 6.96 (dt, Jtrans =15.7, J3,4 =6.7, 3-
H); * assignment by comparison with the analogous resonance of alde-
hyde 35–criterion of assignment: D(d) ꢁ 0.02 ppm; ** distinguishable
by an H,H-correlation spectrum; 13C NMR (125.7 MHz)*: d= ?4.69 and
?4.32 [Si(CH3)2], 10.21 (12-CH3)*, 14.09 (10-CH3)*, 18.06 [SiC(CH3)3],
18.33 (C-14)*, 25.89 [3-fold intensity, SiC(CH3)3], 30.99 (C-5)**, 32.02 (C-
4)**, 38.85 (C-10)*, 42.98 (C-12)*, 51.40 (CO2CH3), 56.07
(OCH2OCH3)*, 68.10 (C-13)*, 84.42 (C-9)*, 97.87 (OCH2OCH3), 121.32
(C-2)***, 129.19 and 131.44 (C-7, C-8)***, 130.59 (C-6)***, 136.86 (C-
9)***, 148.60 (C-3)***, 167.02 (C-1); * assignment by comparison with
the analogous resonance of aldehyde 35–criterion of assignment: D(d)
=
15.7, 4J2,4 =1.4, 2-H), 7.00 (dd, Jtrans =15.8, J3,4 =7.6, 3-H); * distinguisha-
ble by an H,H-correlation spectrum; 13C NMR (125.7 MHz)*: d=ꢀ4.00
and ꢀ3.95 [Si(CH3)2], 10.75 (6-CH3)*, 13.69 (4-CH3)*, 14.26 or 14.28 (C-
2’)**, 16.13 (C-8)*, 18.49 [SiC(CH3)3], 26.06 [3-fold intensity, SiC(CH3)3],
39.80 (C-4)***, 42.91 (C-6)***, 55.31 (OCH3)****, 60.14 (C-1’)****,
73.38 (C-7)****, 76.24 (C-5)****, 95.00 (OCH2OCH3), 120.49 (C-2),
153.26 (C-3), 166.66 (C-1); * distinguishable by a C,H-correlation spec-
trum; ** two resonances of the same intensity, i.e., one is based on a–
albeit unknown–contaminant; ***,**** distinguishable by a C,H-corre-
lation spectrum; IR (film): n˜ =2960, 2930, 2885, 2860, 1720, 1655, 1465,
1370, 1265, 1185, 1110, 1045, 840, 780 cmꢀ1; elemental analysis calcd (%)
for C20H40O5Si (388.6): C 61.81, H 10.37; found: C 62.06, H 10.46.
=
=
4
(4E,6R,7S,8S,9R)-9-(tert-Butyldimethylsiloxy)-7-(methoxymethoxy)-6,8-
dimethyl-1,4-decadien-3-ol (31) as a 50:50 mixture of two C-3 diaster-
eomers: At ꢀ788C vinylmagnesium bromide (1.6m in Et2O, 0.50 mL,
0.8 mmol, 2.3 equiv) was added dropwise to a solution of aldehyde 29
(119.0 mg, 0.3454 mmol) in THF (10 mL). After stirring for 70 min, the
reaction was terminated by addition of MeOH (0.5 mL) in one portion
and after that aqueous semisaturated NaHCO3 (12 mL). The aqueous
phase was extracted with tBuOMe (3 î 12 mL), and the combined or-
ganic phases were dried with MgSO4. Evaporation of the solvent in
vacuo gave a residue which was submitted to flash chromatography (cy-
clohexane/EtOAc 6:1) to afford divinyl carbinol 31 (120.1 mg, 93%) as a
colorless oil. 1H NMR (500 MHz; a 50:50 mixture of two diastereom-
ers–in case of differing resonances for analogous protons the signals are
indicated with ™dia.-A∫ and ™dia.-B∫): d=0.04 and 0.05 (2 î s, SiMe2),
0.84 (d, J8-Me,8 =7.1, 8-Me)*, 0.89 (s, SiMe3), 1.02 [d, J6,6-Me =6.9, 6-Me
(dia.-A)]*, superimposed by 1.03 [d, J6-Me,6 =6.8, 6-Me (dia.-B)]*, 1.04 (d,
ꢁ
0.5 ppm; **,*** distinguishable by a C,H-correlation spectrum; IR
(film): n˜ =2955, 2930, 2890, 2855, 1730, 1660, 1460, 1440, 1380, 1315,
1270, 1255, 1200, 1170, 1140, 1100, 1035, 990, 965, 835, 775 cmꢀ1; elemen-
tal analysis calcd (%) for C25H46O5Si (454.7): C 66.03, H 10.20; found: C
66.29, H 10.31.
(2E,6E,8E,10R,11S,12S,13R)-13-(tert-Butyldimethylsiloxy)-11-(methoxy-
methoxy)-10,12-dimethyl-2,4,6-tetradecatrienal (34): At ꢀ788C DIBAL
(1.11m in toluene, 0.40 mL, 0.44 mmol, 4.1 equiv) was added dropwise to
a solution of methyl ester 33 (49.0 mg, 0.108 mmol) in CH2Cl2 (5 mL).
After stirring for 2.5 h, the reaction mixture was poured into aqueous sa-
turated Rochelle×s salt (8 mL) and stirred at RT for 1 h. The aqueous
phase was extracted with CH2Cl2 (3î10 mL), and the combined organic
phases were dried with MgSO4. Evaporation of the solvent in vacuo gave
a residue which was dissolved in CH2Cl2 (8 mL) and treated with MnO2
(190 g, 2.19 mmol, 20 equiv). After 14 h stirring at RT, the reaction mix-
ture was filtered through a pad of Celite, and the filter cake was washed
with CH2Cl2 (3î5 mL). The filtrate and washings were evaporated in
vacuo to afford a residue which was submitted to flash chromatography
(cyclohexane/EtOAc 10:1) to afford aldehyde 34 (40.6 mg, 89%) as a col-
orless oil. [a]2D5 =+12.5 (c=0.42 in CHCl3). 1H NMR (500 MHz): d=
0.036 and 0.044 (2 î s, SiMe2), 0.85 (d, J12-Me,12 =7.1, 12-Me)*, 0.88 (s,
SiCMe3), 1.03 (d, J10,10-Me =6.8, 10-Me)*, 1.05 (d, J14,13 =6.2, 14-H3)*, 1.84
(dqd, J12,11 =J12,12-Me =7.2, J12,13 =4.5, 12-H)*, 2.30 (brtd, J5,4 =J5,6 =7.2, 5-
H2)**, 2.44 (td with small extra-peaks indicating transition to higher-
J
10,9 =6.2, 10-H3)*, 1.70 (brs, OH), 1.84 (dqd, J8,7 =8.3, J8,8-Me =7.1, J8,9 =
4.3, 8-H), 2.45 (m, 6-H), 3.29 (brdd, J7,8 =8.4, J7,6 =3.4, 7-H), 3.370 [s,
OMe (dia. A)], poorly separated from 3.371 [s, OMe (dia. B)], 4.07 [qd,
J
6.3, J9,8 =4.1, 9-H (dia.-B)], AB signal [dA =4.54, dB =4.58, JAB =6.9,
OCH2OMe (dia.-A)], superimposed by AB signal [dA =4.54, dB =4.59,
9,10 =6.2, J9,8 =4.5, 9-H (dia.-A)], superimposes in part 4.09 [qd, J9,10 =
J
AB =6.8, OCH2OMe (dia.-B)], superimposed by 4.60 (brdd, J3,2 =J3,4 =
7.2, 3-H), 5.13 (dm, Jcis =10.3, 1-HE), 5.26 (ddd, Jtrans =17.2, Jgem =4J1-
H(Z),3 =1.4, 1-HZ), 5.53 (ddd, Jtrans =15.6, J4,3 =6.5, J4,6 =1.2, 4-H), 5.77 {m,
4
4
perhaps interpretable as two dd’s: 5.76 [dd, Jtrans =17.1, J5,6 =8.1, J5,3
=
1.2, 5-H (dia. A)] and 5.78 [dd, Jtrans =15.4, J5,6 =7.3, 4J5,3 =1.2, 5-H (dia.
B)]}, 5.90 (m, probably interpretable as ddd with a small extra-peak indi-
cating transition to higher-order spectrum, Jtrans =17.2, Jcis =10.4, J2,3 =5.9,
2-H); * distinguishable by an H,H-correlation spectrum; 13C NMR
(125.7 MHz, most signals with two resonances due to the existence of
two diastereomers): d=ꢀ4.67 (1.5-fold intensity), ꢀ4.36 and ꢀ4.32
[Si(CH3)2], 10.13 and 10.17 (8-CH3)*, 13.31 and 13.50 (6-CH3)*, 18.06,
18.07, 18.19 and 18.22 [C-10, SiC(CH3)3]*, 25.88 [3-fold intensity,
SiC(CH3)3], 38.12 and 38.29 (C-6)*, 42.90 and 42.96 (C-8)*, 56.02
(OCH3)*, 68.09 and 68.16 (C-9)*, 73.84 (C-3)*, 84.59 and 84.67 (C-7)*,
97.94 (OCH2OCH3), 114.84 (C-1)**, 130.19 and 130.27 (C-4)**, 136.58
and 136.77 (C-5)**, 139.61 and 139.65 (C-2)**; * assignment by compari-
son with the analogous resonance of ethyl ester 28–criterion of assign-
ment: D(d) ꢁ 1.2 ppm; ** distinguishable by a C,H-correlation spectrum;
IR (film): n˜ =3415, 2955, 2930, 2885, 2855, 1470, 1465, 1385, 1360, 1255,
1140, 1105, 1035, 990, 970, 920, 835, 800, 775 cmꢀ1; elemental analysis
calcd (%) for C20H40O4Si (372.6): C 64.47, H 10.82; found: C 64.76, H
11.00.
4
order spectrum and/or unresolved J4,2, J4,5 ꢂJ4,3 ꢂ7.0, 4-H2)**, superim-
posed by ca. 2.45 (m, 10-H)*, 3.30 (dd, J11,12 =7.8, J11,10 =4.0, 11-H)*, 3.37
(s, OMe), 4.09 (qd, J13,14 =6.2, J13,12 =4.5, 13-H)*, AB signal (dA =4.56,
dB =4.59, JAB =6.8, OCH2OMe), 5.56 (dt, Jtrans =14.3, J6,5 =7.0, 6-H)*,
5.64 (dd, Jtrans =14.5, J9,10 =7.5, 9-H)*, 6.03 (m, 7-H, 8-H)*, 6.14 (ddt,
J
trans =15.7, J2,1 =7.9, 4J2,4 =1.5, 2-H), 6.84 (dt, Jtrans =15.7, J3,4 =6.7, 3-H),
9.51 (d, J1,2 =7.8, 1-H); * assignment by comparison with the analogous
resonance of methyl ester 33–criterion of assignment: D(d) ꢁ 0.02 ppm;
** distinguishable by an H,H-correlation spectrum; 13C NMR
(125.7 MHz; contains 4 mol% of an unassigned diastereomer)*: d=
ꢀ4.69 and ꢀ4.31 [Si(CH3)2], 10.23 (12-CH3)*, 14.08 (10-CH3)*, 18.05
[SiC(CH3)3], 18.33 (C-14)*, 25.89 [3-fold intensity, SiC(CH3)3], 30.79 (C-
5)*, 32.41 (C-4)*, 38.86 (C-10)*, 42.98 (C-12)*, 56.07 (OCH2OCH3)*,
68.10 (C-13)*, 84.39 (C-11)*, 97.84 (OCH2OCH3), 129.01 and 131.81 (C-
7, C-8)**, 130.12 (C-6)**, 133.31 (C-2)**, 137.24 (C-9)**, 157.62 (C-3)**,
193.93 (C-1); * assignment by comparison with the analogous resonance
of methyl ester 33–criterion of assignment: D(d) ꢁ 0.4 ppm; ** distin-
guishable by a C,H-correlation spectrum; IR (film): n˜ =2955, 2930, 2855,
1695, 1640, 1600, 1470, 1460, 1450, 1385, 1255, 1120, 1035, 1005, 990, 970,
835, 775 cmꢀ1; elemental analysis calcd (%) for C24H44O4Si (424.7): C
67.87, H 10.44; found: C 68.15, H 10.66.
(2E,6E,8E,10R,11S,12S,13R)-13-(tert-Butyldimethylsiloxy)-11-(methoxy-
methoxy)-10,12-dimethyl-2,6,8-tetradecatrienoic acid methyl ester (33): A
solution of aldehyde 35 (91.0 mg, 0.228 mmol) and (methoxycarbonylme-
thylen)triphenylphosphorane (234 mg, 0.701 mmol, 3.1 equiv) in toluene
(3 mL) was stirred at RT for 16 h. The reaction mixture was submitted to
flash chromatography (cyclohexane/EtOAc 18:1) to afford a,b-unsaturat-
ed methyl ester 33 (92.7 mg, 89%) as a pure diastereomer and a colorless
oil. [a]2D5 =+11.9 (c=0.52 in CHCl3); 1H NMR (500 MHz): d=0.036 and
0.044 (2îs, SiMe2), 0.85 (d, J12-Me,12 =7.1, 12-Me)*, 0.88 (s, SiCMe3), 1.02
(4E,6E,8R,9S,10S,11R)-11-(tert-Butyldimethylsiloxy)-9-(methoxyme-
thoxy)-8,10-dimethyl-4,6-dodecadienal (35): A refluxing solution of divin-
yl carbinol 31 (69.6 mg, 0.187 mmol) and Hg(OAc)2 (64.1 mg,
0.201 mmol, 1.1 equiv) in tert-butyl vinyl ether (1.7 mL, 1.3 g, 13 mmol,
70 equiv) was stirred for 9 h. The reaction mixture was cooled to RT and
then submitted to flash chromatography (cyclohexane/EtOAc 7:1) to
(d, J10,10-Me =6.8, 10-Me)*, 1.05 (d, J14,13 =6.2, 14-H3)*, 1.84 (dqd, J12,11
=
1554
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 1545 1557

Nystatin A1
1545 1557
afford an unanalyzed mixture of (regio-)isomers (70.9 mg, 95%), from
which the desired rearrangement product 35 (57.8 mg, 78% based on
starting material 31) was obtained as a pure diastereomer and colorless
nance of methyl ester 33, aldehyde 34, and aldehyde 35–criterion of as-
signment: D(d) ꢁ 0.3 ppm; ** two resonances for two C-6-epimers and
assigned by a C,H-correlation spectrum; *** distinguishable by a C,H-
correlation spectrum; IR (film): n˜ =2955, 2930, 2855, 1710, 1575, 1470,
1465, 1435, 1380, 1360, 1255, 1140, 1095, 1035, 990, 965, 940, 920, 835,
805, 775, 735, 705 cmꢀ1; m/z: 506.3428 ꢃ5 mDa (C29H50O5Si [M +]) con-
firmed by HRMS (EI, 70 eV); no combustion analysis was performed.
oil by a second flash chromatography (cyclohexane/EtOAc 12:1). [a]D25
=
+13.2 (c=0.55 in CHCl3); 1H NMR (500 MHz): d=0.03 and 0.04 (s,
SiMe2), 0.85 (d, J10-Me,10 =7.1, 10-Me)*, 0.88 (s, SiCMe3), 1.02 (d, J8,8-Me
6.9, 8-Me)*, 1.04 (d, J12,11 =6.3, 12-H3)*, 1.84 (dqd, J10,9 =J10,10-Me =7.4,
10,11 =4.6, 10-H), 2.41 (brtd, J3,2 =J3,4 =6.9, 3-H2)**, superimposed by
2.45 (dqd, J8,7 =J8,8-Me =6.9, J8,9 =4.0, 8-H), 2.53 (t with a small extra-peak
indicating transition to higher-order spectrum and/or unresolved J2,1
2,3 =6.9, 2-H2)**, 3.29 (dd, J9,10 =7.7, J9,8 =4.0, 9-H), 3.37 (s, OMe), 4.08
=
J
(2E,4E,6E,10E,12E,14R,15S,16S,17R)-17-(tert-Butyldimethylsiloxy)-15-
(methoxymethoxy)-14,16-dimethyl-2,4,6,10,12-octadecapentaenoic
acid
,
methyl ester (all-trans-40) as a 66.2:33.8 or 93.4:6.6 mixture with the 6-
cis-isomer (cis26,27-40): HWE-reaction: At ꢀ608C a solution of lithium
N,N-diisopropyamide (0.29m in THF, 0.75 mL, 0.22 mmol, 1.8 equiv) in
THF (1.0 mL) was added dropwise to a solution of a 90:10 mixture of
J
(qd, J11,12 =6.2, J11,10 =4.5, 11-H), AB signal (dA =4.56, dB =4.58, JAB =6.8,
OCH2OMe), 5.57 (dt, Jtrans =14.5, J4,3 =7.0, 4-H)***, 5.63 (dd, Jtrans =14.5,
=
=
phosphonates trans,trans-37 and cisH CC C,transC CCO Me-37 (54 mg,
0.23 mmol, 1.9 equiv). After stirring at this temperature for 30 min, the
reaction mixture stirred at 08C for 15 min, then cooled to ꢀ608C and
after 50 min treated dropwise with a solution of aldehyde 35 (47.3 mg,
0.119 mmol) in THF (2.3 mL). After stirring for 7 min, the reaction mix-
ture was allowed to reach ꢀ408C and after further 1 h stirring, treated
with aqueous semisaturated ammonium chloride (5 mL). The aqueous
phase was extracted with tBuOMe (3 î 2 mL), and the combined organic
phases were dried with MgSO4. Evaporation of the solvent in vacuo gave
a residue which was submitted to flash chromatography (cyclohexane/
EtOAc 13:1 ! fraction 9, 10:1 ! fraction 30) to afford the title com-
pound 40 (44.6 mg, 74%) as 66.2:33.8 mixture of the 6-E- and 6-Z-
isomer.
2
2
J
7,8 =7.5, 7-H)***, 5.96 6.07 (m, 5-H, 6-H)***, 9.78 (t, J1,2 =1.5, 1-H);
* signal assigned by comparison with the analogous resonances and cou-
pling constants of ethyl ester 28, aldehyde 29 and ethyl ester 30; ** 2-H2
(brtd) and 3-H2 (t; unresolved J2,1) were distinguished by the differing
multiplicity and by the concerning coupling constants; *** distinguishable
by an H,H-correlation spectrum; 13C NMR (125.7 MHz): d=ꢀ4.69 and
ꢀ4.31 [Si(CH3)2], 10.23 (10-CH3)*, 14.13 (8-CH3)*, 18.06 [SiC(CH3)3],
18.35 (C-12)*, 25.12 (C-3)**, 25.89 [3-fold intensity, SiC(CH3)3], 38.87 (C-
8)*, 42.98 (C-10)*, 43.32 (C-2)**, 56.08 (OCH3)*, 68.10 (C-11)*, 84.40
(C-9)*, 97.85 (OCH2OCH3), 129.01 and 131.63 (C-5, C-6)***, 129.84 (C-
4)***, 137.18 (C-7)***, 201.88 (C-1); * assignment by comparison with
the analogous resonance of ethyl ester 28 and divinyl carbinol 31–crite-
rion of assignment: D(d) ꢁ 1.0 ppm; **,*** distinguishable by a C,H-cor-
relation spectrum; IR (film): n˜ =2955, 2930, 2890, 2855, 1730, 1600, 1470,
1465, 1445, 1410, 1385, 1360, 1255, 1140, 1100, 1035, 990, 965, 835,
775 cmꢀ1; elemental analysis calcd (%) for C22H42O4Si (398.7): C 66.28, H
10.62; found: C 66.09, H 10.89.
Isomerization with iodine: At RT a solution of a 66.2:33.8 mixture
(8.3 mg, 16 mmol) of all-trans-40 and cis26,27-40 in CDCl3 (0.5 mL) in a
NMR tube was treated with iodine (0.031m in CDCl3, 42 mL, 1.3 mmol,
8.1 mol%). After 2 min, the isomerization was completed at a 93.4:6.6-
equilibrium composition of all-trans-40 and cis26,27-40 (1H NMR,
500 MHz). The reaction mixture was used without purification for the
preparation of aldehyde 41.
all-trans-40: 1H NMR (500 MHz; sample of a 93.4:6.6 mixture of all-
trans-40 and cis26,27-40): d=0.036 and 0.045 (2 î s, SiMe2), 0.85 (d, J16-
Me,16 =7.0, 16-Me)*, 0.88 (s, SiCMe3), 1.02 (d, J14-Me,14 =6.8, 14-Me)*, 1.05
(d, J18,17 =6.2, 18-H3)*, 1.83 (dqd, J16,15 =J16,16-Me =7.2, J16,17 =4.5, 16-H)*,
2.16 2.27 [m, presumably interpretable as: d=2.19 (brtd, J9,8 =J9,10 =6.4,
6-[(3E,5E,7R,8S,9S,10R)-10-(tert-Butyldimethylsiloxy)-8-(methoxyme-
thoxy)-7,9-dimethyl-3,5-undecadienyl]-1,3-cyclohexadiene-1-carboxylic
acid methyl ester as a 50:50 mixture of two C-6-epimers (39): At ꢀ608C
a solution of a 90:10 mixture of phosphonates trans-36 and cis-36 (0.60m
in THF, 0.24 mL, 0.14 mmol, 1.9 equiv) was added dropwise to a solution
of lithium N,N-diisopropyamide (0.29m in THF, 0.60 mL, 0.17 mmol,
2.3 equiv). After stirring at this temperature for 25 min, the reaction mix-
ture was treated dropwise with a solution of aldehyde 34 (30.9 mg,
0.0728 mmol) in THF (1.6 mL), allowed to reach ꢀ308C and after 2 h
stirring, treated with aqueous semisaturated ammonium chloride (2 mL).
The aqueous phase was extracted with tBuOMe (3 î 2 mL), and the
combined organic phases were dried with MgSO4. Evaporation of the sol-
vent in vacuo gave a residue which was submitted to flash chromatogra-
phy (cyclohexane/EtOAc 15:1) to afford the title compound 39 (7.7 mg,
21%), a 92.6:7.4 mixture (7.3 mg) of 39 (pure 39: 6.8 mg, 18%) and all-
trans-40 (pure all-trans-40: 0.54 mg, 1.5%) and all-trans-40 (4.1 mg,
11%). 1H NMR (500 MHz): d=0.03 and 0.04 (2 î s, SiMe2), 0.84 (d, J9’-
Me,9’ =6.9, 9’-Me)*, 0.88 (s, SiCMe3), 1.01 (d, J7’-Me,7’ =6.9, 7’-Me)*, 1.04 (d,
9-H2)** and d=2.24 (brtd, J8,9 =J8,7 =6.3, 8-H2)**], 2.44 (dqd, J14,13
=
J
14,14-Me =7.0, J14,15 =4.0, 14-H)*, 3.29 (dd, J15,16 =7.8, J15,14 =4.0, 15-H)*,
3.367 (s, OCH2OMe)*, 3.741 (s, CO2Me), 4.09 (qd, J17,18 =6.2, J17,16 =4.5,
17-H)*, AB signal (dA =4.56, dB =4.59, JAB =6.8, OCH2OMe)*, 5.57 (dt,
J
trans =14.2, J10,9 =6.7, 10-H)*, 5.61 (dd, Jtrans =14.0, J13,14 =7.5, 13-H)*, 5.85
(d, Jtrans =15.4, 2-H), 5.92 (dt, Jtrans =15.1, J7,8 =7.2, 7-H)***, 5.97 6.05 (m,
11-H, 12-H)*, 6.15 (dd, Jtrans =15.2, J6,5 =10.7, 6-H)***, 6.22 (dd, Jtrans
=
14.8, J4,3 =11.3, 4-H)***, 6.52 (dd, Jtrans =14.8, J5,6 =10.7, 5-H)***, 7.30
(dd, Jtrans =15.3, J3,4 =11.3, 3-H); * signal assigned by comparison with the
analogous resonances and coupling constants of methyl ester 33–criteri-
on of assignment: D(d) ꢁ 0.02 ppm; **,*** distinguishable by an H,H-
correlation spectrum; 13C NMR (125.7 MHz; sample of a 93.4:6.6 mixture
of all-trans-40 and cis26,27-40): d=ꢀ4.68 and ꢀ4.32 [Si(CH3)2], 10.20 (16-
CH3)*, 14.11 (14-CH3)*, 18.06 [SiC(CH3)3], 18.32 (C-18)*, 25.89 [3-fold
intensity, SiC(CH3)3], 32.01 (C-9)**, 32.79 (C-8)**, 38.84 (C-14)*, 42.97
(C-16)*, 51.45 (CO2CH3), 56.07 (OCH2OCH3)*, 68.09 (C-17)*, 84.43 (C-
15)*, 97.85 (OCH2OCH3), 119.72 (C-2)***, 128.04 (C-4)***, 129.32 and
131.13 (C-11, C-12)***, 130.23 (C-6)***, 131.32 (C-10)***, 136.55 (C-
13)***, 139.50 (C-7)***, 141.08 (C-5)***, 144.96 (C-3)***, 167.59 (C-1);
* assignment by comparison with the analogous resonance of methyl
J
J
11’,10’ =6.3, 11’-H3)*, 1.41 1.52 (m, 1’-H2), 1.83 (dqd, J9’,8’ =J9’,9’-Me =7.1,
9’,10’ =4.5, 9’-H)*, AB signal (dA =1.99, dB =2.12, JAB =15.1, in addition
split by JA,1’-H(1)***=8.7,
JA,1’-H(2) =JA,3’***=6.8, JB,1’-H(2) =9.4****, JB,1’-
H(1) =JB,3’****=5.6, 2’-H2)**, 2.34 (ddd, Jgem =18.4, J5-H(1),4 =5.1, J5-H(1),6
=
1.9, 5-H1)**, ca. 2.36 2.46 (m, 5-H2, 7’-H)**, 2.72 (dddd, J6,1’-H(1) =J6,5-
H(2) =8.6, J6,1’-H(2) =5.6, J6,5-H(1) =1.7, 6-H), 3.28 (dd, J8’,9’ =7.9, J8’,7’ =3.9, 8’-
H)*, 3.37 (s, OCH2OMe)*, 3.75 (s, CO2Me), 4.09 (poorly resolved qd,
J
10’,11’ =6.2, J10’,9’ =4.6, 10’-H)*, AB signal (dA =4.55, dB =4.59, JA,B =6.6,
OCH2OMe)*, 5.53 5.61 (m, 3’-H, 6’-H)*, 5.96 6.06 (m, 3-H, 4-H, 4’-H,
4
5’-H), 6.99 (dd, J2,3 =4.1, J2,4 =1.3, 2-H); * signal assigned by comparison
ester 33 and aldehyde 34–criterion of assignment: D(d)
**,*** distinguishable by a C,H-correlation spectrum;
ꢁ
0.4 ppm;
with the analogous resonances and coupling constants of methyl ester 33,
aldehyde 34, and aldehyde 35–criterion of assignment: D(d)
ꢁ
1
cis26,27-40: H NMR (500 MHz; sample of a 66.2:33.8 mixture of all-trans-
0.02 ppm; ** distinguishable by an H,H-correlation spectrum; *** inter-
changeable; **** interchangeable; APT-13C NMR (125.7 MHz): d=™+∫
ꢀ4.69 and ™+∫ ꢀ4.33 [Si(CH3)2], ™+∫ 10.17 (9’-CH3)*, ™+∫ 14.11 (7’-
CH3)*, ™+∫ 18.05 [SiC(CH3)3], ™+∫ 18.28 (C-11’)*, ™+∫ 25.89 [3-fold in-
tensity, SiC(CH3)3], ™ꢀ∫ 27.32 and ™ꢀ∫ 27.34 (C-5)**, ™+∫ 29.79 (C-6)*,
™ꢀ∫ 29.90 (C-2’)***, ™ꢀ∫ 30.50 (C-1’)***, ™+∫ 38.83 (C-7’)*, ™+∫ 42.96
(C-9’)*, ™+∫ 51.56 (CO2CH3), ™+∫ 56.07 (OCH2OCH3)*, ™+∫ 68.09 (C-
10’)*, ™+∫ 84.50 (C-8’)*, ™ꢀ∫ 97.88 (OCH2OCH3), ™+∫ 123.49, ™+∫
129.59, ™+∫ 130.49, ™+∫ 131.81, ™+∫ 132.51, ™+∫ 132.53 and ™+∫
135.93 (C-2, C-3, C-4, C-3’, C-4’, C-5’, C-6’), ™ꢀ∫ 131.45 (C-1), ™ꢀ∫
167.82 (CO2CH3); * assignment by comparison with the analogous reso-
40 and cis26,27-40)*: d=2.34 (brtd,
J8,9 =J8,7 =7.6, 8-H2), 3.371 (s,
OCH2OMe), 3.747 (s, CO2Me), AB signal (dA =4.56, dB =4.59, JAB =6.7,
OCH2OMe), 5.62 (dd, Jtrans =14.3, J13,14 =7.4, 13-H)**, 5.67 (dt, Jcis =10.8,
J
7,8 =7.7, 7-H)**, 5.88 (d, Jtrans =15.7, 2-H)**, 6.10 (dd, Jcis =J6,5 =10.9, 6-
H)**, 6.30 (dd, Jtrans =14.9, J4,3 =11.4, 4-H)**, 6.83 (dd, Jtrans =14.7, J5,6
=
11.5, 5-H)**, 7.35 (dd, Jtrans =15.3, J3,4 =11.3, 3-H); * the signals of other
(not listed) protons are superimposed or isochron with all-trans-40;
** distinguishable by an H,H-correlation spectrum; 13C NMR
(125.7 MHz; sample of a 66.2:33.8 mixture of all-trans-40 and cis26,27-40)*:
d=27.94 (C-8), 32.40 (C-9), 51.48 (CO2CH3), 120.26 (C-2), 128.33 (C-6),
1555
Chem. Eur. J. 2004, 10, 1545 1557
www.chemeurj.org
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

R. Br¸ckner and T. Berkenbusch
FULL PAPER
131.22 and 131.25 (C-10, C-11, C-12), 129.90 (C-4), 135.88 (C-5), 136.62
(C-7), 144.86 (C-3), 167.49 (C-1); * resonances of other (not listed) car-
bons are superimposed/isochron by/with all-trans-40; all signals are as-
signed by a C,H-correlation spectrum;
[1] a) Autorenkollektiv in Arzneimittelneben- und -wechselwirkungen
(Ed.: H. P. T. Ammon), Wissenschaftliche Verlagsgesellschaft mbH,
Stuttgart, 2001, pp. 1456 1462; b) E. Mutschler, G. Geisslinger,
H. K. Kroemer, M. Sch‰fer-Korting, Mutschler Arzneimittelwirkun-
gen–Lehrbuch der Pharmakologie und Toxikologie, Wissenschaftli-
che Verlagsgesellschaft mbH, Stuttgart, 2001, pp. 836 839; c) F.
Marty, E. Mylonakis, Exp. Opin. Pharmacother. 2002, 3, 91 102 and
references therein.
[2] a) S. Omura, H. Tanaka in Macrolide Antibiotics: Chemistry, Biology
and Practice (Ed.: S. Omura), Academic Press, New York, 1984,
pp. 351 404; b) J. M. Beau in Recent Progress in the Chemical Syn-
thesis of Antibiotics (Eds.: G. Lukacs, M. Ohno), Springer, Berlin,
1990, pp. 132 182; c) S. D. Rychnovsky, Chem. Rev. 1995, 95, 2021
2040.
IR (film): n˜ =3020, 2955, 2855, 1710, 1620, 1465, 1435, 1380, 1360, 1310,
1255, 1140, 1120, 1100, 1040, 1005, 990, 965, 940, 925, 835, 775 cmꢀ1; ele-
mental analysis calcd (%) for C29H50O5Si (506.8): C 68.73, H 9.94; found:
C 68.81, H 10.21.
(2E,4E,6E,10E,12E,14R,15S,16S,17R)-17-(tert-Butyldimethylsiloxy)-15-
(methoxymethoxy)-14,16-dimethyl-2,4,6,10,12-octadecapentaenal
(all-
trans-41): At RT a 93.4:6.6 mixture (8.3 mg, 0.016 mmol) of the methyl
esters all-trans-40 and cis26,27-40 plus iodine (0.031m in CDCl3, 42 mL,
1.3 mmol, 8.1 mol%) in CDCl3 (0.5 mL) was treated with Na2SO3 (ca.
0.05 g) and water (20 mL). After the violet color of iodine had disap-
peared, the solution was filtered through a pipette with MgSO4, and the
filter cake was washed with CH2Cl2 (3 î 2 mL). The filtrate and washings
were evaporated in vacuo to a remaining volume of 1.5 mL, cooled to
ꢀ788C and treated with DIBAL (1.12m in toluene, 50 mL, 0.056 mmol,
3.4 equiv). After stirring for 1 h, the reaction mixture was allowed to
reach ꢀ558C and after stirring for another 30 min, quenched with aque-
ous semisaturated Rochelle×s salt (0.3 mL) and MeOH (0.2 mL). The sol-
ution was filtered through a pipette with MgSO4, and the filter cake was
washed with CH2Cl2 (3 î 2 mL). The filtrate and washings were evapo-
rated in vacuo to a remaining volume of 3 mL, treated with MnO2
(56.1 mg, 0.645 mmol, 39 equiv) and stirred at RT for 1 h. After filtration,
the solvent was evaporated in vacuo and at 08C to afford a residue which
was submitted to flash chromatography (cyclohexane/EtOAc 8:1) to
afford aldehyde 41 (6.0 mg, 78%) as a light yellow oil. [a]2D5 =+12.5 (c=
0.42 in CHCl3); [a]2D5 =+9.9 (c=0.24 in CDCl3); 1H NMR (500 MHz;
slightly contaminated)*: d=0.036 and 0.045 (2îs, SiMe2), 0.85 (d, J16-
Me,16 =7.1, 16-Me)*, 0.88 (s, SiCMe3), 1.02 (d, J14,14-Me =6.8, 14-Me)*, 1.05
(d, J18,17 =6.2, 18-H3)*, 1.83 (dqd, J16,15 =J16,16-Me =7.2, J16,17 =4.5, 16-H),
2.21 (brtd, J9,8 ꢂJ9,10 ꢂ7.0, 9-H2)**, 2.27 (brtd, J8,9 ꢂJ8,7 ꢂ7.1, 8-H2)**,
2.45 (dqd, J14,13 =J14,14-Me =6.9, J14,15 =4.1, 14-H)*, 3.29 (dd, J15,16 =7.9,
[3] Isolation: a) E. L. Hazen, R. Brown, Science 1950, 112, 423 430;
b) E. L. Hazen, R. Brown, Proc. Soc. Exp. Biol. Med. 1951, 76, 93
98.
[4] Isolation: J. Vanderputte, J. L. Wachtel, E. T. Stiller, Antibiot. Annu.
1956, 587 591.
[5] Structure: a) W. Mechlinski, C. P. Schaffner, P. Ganis, G. Avitabile,
Tetrahedron Lett. 1970, 11, 3873 3876; b) P. Ganis, G. Avitabile, W.
Mechlinski, C. P. Schaffner, J. Am. Chem. Soc. 1971, 93, 4560 4564.
[6] Elucidation of constitution: a) C. N. Chong, R. W. Rickards, Tetrahe-
dron Lett. 1971, 12, 3873 3876; b) E. Borowski, J. Zielinski, L. Fal-
kowski, T. Ziminski, J. Golik, P. Kolodziejczyk, E. Jereczek, M.
Gdulewicz, Y. Shenin, T. Kotienko, Tetrahedron Lett. 1971, 12, 685
690.
[7] Elucidation of configuration: a) J.-M. Lancelin, F. Paquet, J.-M.
Beau, Tetrahedron Lett. 1988, 29, 23, 2827 2830 (relative configura-
tion); b) K. C. Nicolaou, K. H. Ahn, Tetrahedron Lett. 1989, 30,
1217 1220 (absolute configuration by synthesis of the C1 C10 frag-
ment); c) J. Prandi, J.-M. Beau, Tetrahedron Lett. 1989, 30, 4517
4520 (absolute configuration by synthesis of a C1 C10 fragment);
d) J.-M. Lancelin, J.-M. Beau, Tetrahedron Lett. 1989, 30, 4521
4524.
[8] Total synthesis: a) K. C. Nicolaou, T. K. Chakraborty, Y. Ogawa,
R. A. Daines, N. S. Simpkins, G. T. Furst, J. Am. Chem. Soc. 1988,
110, 4660 4672; b) K. C. Nicolaou, R. A. Daines, J. Uenishi, W. S.
Li, D. P. Papahatjis, T. K. Chakraborty, J. Am. Chem. Soc. 1988, 110,
4672 4685; c) K. C. Nicolaou, R. A. Daines, T. K. Chakraborty, Y.
Ogawa, J. Am. Chem. Soc. 1988, 110, 4685 4696; d) K. C. Nicolaou,
R. A. Daines, Y. Ogawa, T. K. Chakraborty, J. Am. Chem. Soc. 1988,
110, 4696 4705.
J
15,14 =4.0, 15-H)*, 3.37 (s, OCH2OMe), 4.09 (qd, J17,18 =6.2, J17,16 =4.5,
17-H)*, AB signal (dA =4.56, dB =4.59, JAB =6.6, OCH2OMe), 5.57 (dt,
trans =14.3, J10,9 =7.1, 10-H)*, 5.62 (dd, Jtrans =14.5, J13,14 =7.8, 13-H)*,
J
5.98 6.06 (m, 7-H, 11-H*, 12-H*), 6.13 (dd, Jtrans =15.1, J2,1 =8.0, 2-H)***,
4
6.20 (brdd with unresolved J6,8, Jtrans =15.1, J6,5 =10.8, 6-H)***, 6.35 (dd,
J
trans =14.8, J4,3 =11.2, 4-H)***, 6.64 (dd, Jtrans =14.8, J5,6 =10.7, 5-H)***,
7.11 (dd, Jtrans =15.2, J3,4 =11.1, 3-H)***, 9.55 (d, J1,2 =8.0, 1-H); * signal
assigned by comparison with the analogous resonances and coupling con-
stants of methyl esters 33 and all-trans-40–criterion of assignment: D(d)
[9] Formal total syntheses: a) S. Masamune, P. Ma, H. Okumoto, J. W.
Ellingboe, J. Org. Chem. 1984, 49, 2834 2837; b) D. Boschelli, T.
Takemasa, Y. Nishitani, S. Masamune, Tetrahedron Lett. 1985, 26,
5239 5242; c) R. M. Kennedy, A. Abiko, T. Takemasa, H. Okumo-
to, S. Masamune, Tetrahedron Lett. 1985, 26, 5239 5242, and refer-
ences therein; d) G. J. McGarvey, J. M. Williams, R. N. Hiner, Y.
Matsubara, T. Oh, J. Am. Chem. Soc. 1986, 108, 4943 4952; e) G. J.
McGarvey, J. A. Mathys, K. J. Wilson, J. Org. Chem. 1996, 61, 5704
5705, and references therein.
[10] Leading references: a) G. Solladiÿ, N. Wilb, C. Bauder, Eur. J. Org.
Chem. 1999, 3021 3026; b) J. Kr¸ger, E. M. Carreira, Tetrahedron
Lett. 1998, 39, 7013 7016; c) C. Gibson, T. Buck, M. Walker, R.
Br¸ckner, Synlett 1998, 201 205; d) A. F¸rstner, J. Baumgartner,
Tetrahedron 1993, 49, 8541 8560; e) S. David, A. Malleron, New J.
Chem. 1993, 17, 505 511; f) S. Takano, Y. Shimazaki, Y. Sekiguchi,
K. Ogasawara, Chem. Lett. 1988, 2041 2044; g) R. Br¸ckner, Tetra-
hedron Lett. 1988, 29, 5747 5750; h) D. Liang, A. DeCamp Schuda,
B. Fraser-Reid, Carbohydr. Res. 1987, 229 240, and references
therein; i) M. Kinoshita, H. Takami, M. Taniguchi, T. Tamai, Bull.
Chem. Soc. Jpn. 1987, 60, 2151 2161; j) M. Kinoshita, M. Morioka,
M. Taniguchi, J. Shimizu, Bull. Chem. Soc. Jpn. 1987, 60, 4005
4014; k) S. Hanessian, S. P. Sahoo, M. Botta, Tetrahedron Lett. 1987,
28, 1143 1146; l) S. Hanessian, S. P. Sahoo, M. Botta, Tetrahedron
Lett. 1987, 28, 1147 1150; m) G. Solladiÿ, G. Demally, C. Greck,
Tetrahedron Lett. 1985, 26, 435 438; n) D. W. Brooks, R. P. Kellogg,
Tetrahedron Lett. 1982, 23, 4991 4994.
ꢁ
0.02 ppm; **,*** distinguishable by an H,H-correlation spectrum;
13C NMR (125.7 MHz; peak of contaminant at d=29.69): d=ꢀ4.68 and
ꢀ4.32 [Si(CH3)2], 10.22 (16-CH3)*, 14.10 (14-CH3)*, 18.06 [SiC(CH3)3],
18.32 (C-18)*, 25.90 [3-fold intensity, SiC(CH3)3], 31.90 (C-9)**, 32.86 (C-
8)**, 38.85 (C-14)*, 42.97 (C-16)*, 56.08 (OCH2OCH3)*, 68.09 (C-17)*,
84.44 (C-15)*, 97.85 (OCH2OCH3), 128.10 (C-4)***, 129.26 (one carbon
of the signal group C-7, C-11, C-12)***, 130.19 (C-6)***, 130.83 (C-
3)***, 131.12 (C-10)***, 131.25 (one carbon of the signal group C-7, C-
11, C-12)***, 136.69 (C-13)***, 141.38 (one carbon of the signal group C-
7, C-11, C-12)***, 142.96 (C-5)***, 152.24 (C-3)***, 193.53 (C-1); * as-
signment by comparison with the analogous resonance of methyl ester
all-trans-40–criterion of assignment: D(d) ꢁ 0.1 ppm; **,*** distinguish-
able by a C,H-correlation spectrum; IR (film): n˜ =3065, 2980, 2940, 1720,
1600, 1450, 1375, 1315, 1275, 1180, 1115, 1070, 1025, 715 cmꢀ1; MS (CI,
NH3): m/z (%): 477 (12) [M +], 445 (100) [M +ꢀHOMe]; elemental anal-
ysis calcd (%) for C28H48O4Si (476.8): C 70.54, H 10.15; found: C 72.14,
H 11.39.
Acknowledgment
We thank Witco GmbH and Wacker AG for donating chemicals. We ex-
press our gratitude to Dr. Manfred Keller (Institut f¸r Organische
Chemie und Biochemie, Universit‰t Freiburg) for measuring the NMR
spectra and for assisting in their analysis as well as for performing the X-
ray structure analysis of compound 4.
[11] a) C. Bonini, G. Righi, L. Rossi, Tetrahedron 1992, 48, 9801 9808;
b) C. Bonini, A. Giugliano, R. Racioppi, G. Righi, Tetrahedron Lett.
1556
¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Chem. Eur. J. 2004, 10, 1545 1557

Nystatin A1
1545 1557
1996, 37, 2487 2490; c) C. Schneider, M. Rehfeuter, Tetrahedron
Lett. 1998, 39, 9 12; d) G. Solladiÿ, N. Wilb, C. Bauder, J. Org.
Chem. 1999, 64, 5447 5452.
[28] Earlier preparation of compound 15: Ref. [10n].
[29] Compound 17 could be used as a crude product.
[30] Procedure: G. Stork, T. Takahashi, J. Am. Chem. Soc. 1977, 99,
1275 1276.
[12] Procedure: G. Dahmann, R. W. Hoffmann, Liebigs Ann. Chem.
1994, 837 845.
[31] Compounds 16 and 18 were previously described: Ref. [10i].
[32] B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863 927.
[33] a) F. J. L. Aparicio, F. J. L. Herrera, Carbohydr. Res. 1980, 80, C4
C7; b) C. Lievre, C. Frechou, G. Demailly, Tetrahedron Lett. 1993,
34, 5895 5898; c) C. Lievre, C. Frechou, G. Demailly, Tetrahedron
Lett. 1995, 36, 6467 6470.
[34] a) J. G. Buchanan, A. E. Edgar, M. J. Power, P. D. Teaker, Carbo-
hydr. Res. 1974, 38, C22 C24; b) E. J. Corey, G. Goto, Tetrahedron
Lett. 1980, 21, 3463 3466; c) C. Harcken, S. F. Martin, Org. Lett.
2001, 3, 3591 3593.
[13] Compound 6 was prepared according to G. R. Pettit, D. D. Burkett,
J. BarkÛczy, G. L. Breneman, W. E. Pettit, Synthesis 1996, 719 725.
[14] Leading references for asymmetrical Evans aldol reaction: a) D. A.
Evans, E. B. Sjogren, A. E. Weber, R. E. Conn, Tetrahedron Lett.
1987, 28, 39 42; b) D. A. Evans, E. B. Sjogren, J. Bartoli, R. L. Dow,
Tetrahedron Lett. 1986, 27, 4957 4960; c) D. A. Evans, A. E. Weber,
J. Am. Chem. Soc. 1986, 108, 6757 6761; d) D. A. Evans, M. M.
Morrissey, R. L. Dorow, J. Am. Chem. Soc. 1981, 103, 2127 2129.
[15] (E)-2-Methylbutenal is commercially available from ALDRICH.
[16] Compound
7
was previously described by: a) K. J. Hale, G. S.
[35] Procedure: I. H. Aspinall, P. M. Cowley, G. Mitchell, C. M. Raynor,
R. J. Stoodley, J. Chem. Soc. Perkin Trans. 1 1999, 2591 2600.
[36] We followed the procedure of ref. [34c].
[37] A unsuccessful Wittig reaction employing compound 18 is described
in ref. [10i].
Bhatia, S. Andrew Peak, S. Manaviazar, Tetrahedron Lett. 1993, 34,
5343 5346; b) J. D. White, A. T. Johnson, J. Org. Chem. 1994, 59,
3347 3358.
[17] Compound 9 was prepared according to: D. A. Evans, R. L. Dow,
T. L. Shih, J. M. Takacs, R. Zahler, J. Am. Chem. Soc. 1990, 112,
5291 5313.
[38] Procedure: E. Adler, H.-D. Becker, Acta Chem. Scand. 1961, 15,
849 852.
[18] All new compounds gave satisfactory 1H NMR and IR spectra.
Except compounds 12, 23, 39, and 41 they also gave correct combus-
tion analyses.
[39] Isomer ratios were derived from suitable 13C NMR integrals.
[40] Methods: a) P. A. Wender, T. M. Dore, Tetrahedron Lett. 1998, 39,
8589 8592 [Hg(OAc)2 (cat.), tert-butyl vinyl ether, sealed vessel,
17 bar, 2008C]; b) H. Zhang, M. Seepersaud, S. Seepersaud, D. R.
Mootoo, J. Org. Chem. 1998, 63, 2049 2052 [Hg(OAc)2 (1.0 equiv),
n-butyl vinyl ether, reflux].
[19] R. F. W. Jackson, M. A. Sutter, D. Seebach, Liebigs Ann. Chem.
1985, 2313 2327.
[20] W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923 2925.
[21] Earlier preparations of compound 8: a) M. Ono, N. Yoshida, Y.
Kokubu, E. Sato, H. Akita, Chem. Pharm. Bull. 1997, 45, 1428 1434
(racemic synthesis); b) H. Akita, H. Matskura, T. Oishi, Tetrahedron
Lett. 1986, 27, 5241 5244 (synthesis with moderate enantioselectivi-
ty: 38% < ee < 64%); ref. [16a] (enantioselective synthesis via 7).
[22] Procedure: E. J. Corey, H. Cho, C. R¸cker, D. H. Hua, Tetrahedron
Lett. 1981, 22, 3455 3458.
[23] a) D. A. Evans, J. Bartoli, T. Godel, Tetrahedron Lett. 1982, 23,
4577 4580; b) W. C. Still, J. C. Barrish, J. Am. Chem. Soc. 1983, 105,
2487 2489; c) K. N. Houk, N. G. Rondan, Y.-D. Wu, J. T. Metz,
M. N. Paddon-Row, Tetrahedron 1984, 40, 2257 2274.
[24] Method: G. W. Kalbaka, T. M. Shoup, N. M. Goudgaon, J. Org.
Chem. 1989, 54, 5930 5933.
[25] This reagent was freshly prepared from 2,3-dimethyl-2-butene and
BH3¥SMe2 in THF (E.-I. Negishi, H. C. Brown, J. Am. Chem. Soc.
1972, 94, 3567 3572).
[26] This solution is normally used for the work-up of asymmetrical
Sharpless epoxidations (Y. Gao, R. M. Hanson, J. M. Klunder, S. Y.
Ko, H. Masamune, K. B. Sharpless, J. Am. Chem. Soc. 1987, 109,
5765 5780).
[41] First Claisen rearrangement of a vinyl ether derived from a symmet-
rical divinyl carbinol: S. F. Reed, Jr., J. Org. Chem. 1965, 30, 1663
1665. First Claisen rearrangement of a vinyl ether derived from an
unsymmetrical divinyl carbinol: P. Cresson, L. Lacour, C. R. Acad.
Sci. Ser. C 1966, 262, 1157 1160.
[42] In order to obtain compound 41 we also tested Hoffmann×s alde-
hyde homologation strategy ™n+6∫ with aldehyde 34 and their (di-
oxenyl)propenyl borolane (R. W. Hoffmann, F. Sch‰fer, E. Haeber-
lin, T. Rhode, K. Kˆrber, Synthesis 2000, 2060 2068), however,
without success (T. Berkenbusch, Dissertation, Universit‰t Freiburg,
2002, pp. 134 138).
[43] For a related cyclocondensation from our laboratory giving a cyclo-
hexadiene in an attempted Horner Wadsworth Emmons olefination
see J. H¸bner, Dissertation, Universit‰t Freiburg, 2001, pp. 125 145.
[44] Compound 37 was prepared from 4-bromocrotonate in 25% overall
yield [DIBAL; MnO2; Ph3P=CHCO2Me; P(OMe)3] as a 90:10 trans,-
=
=
CCO2Me
trans:cisH CC C,transC
mixture following the procedure of
2
ref. [10i].
[45] Method: I. Ernest, A. J. Main, R. Menassÿ, Tetrahedron Lett. 1982,
23, 167 170.
[27] Earlier preparation of compound 4: Ref. [10i].
Received: September 11, 2003 [F5540]
1557
Chem. Eur. J. 2004, 10, 1545 1557
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¹ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim