Total synthesis of salicylihalamides A and B

Article abstract of DOI:10.1002/chem.200400617

The paper illustrates two efficient routes to macrolactone 19 containing a 3-(para-methoxybenzyloxy)propyl side chain at C-15. The chiral center at C-15 was introduced by a Noyori reduction of keto ester 5. The intermediate common to both routes, aldehyde 8, was prepared from keto ester 5. The subsequent chain extension utilized Evans aldol reactions. The first route leads to the alkene 14, which was used, after hydroboration, for a Suzuki cross-coupling reaction with vinyl iodide 15. The derived seco acid 18 was converted into the macrolactone 19 by a Mitsunobu lactonization by using immobilized triphenylphosphine. Alternatively, an aldol reaction of 8 with the 4-pentenoyl derivative 20 was used to prepare alkene 26. This building block led to ester 28, which could also be converted into macrolactone 19 by the classical ring-closing metathesis. After conversion of the C-15 side chain to the corresponding aldehyde, the enamide was introduced through hemiaminal formation and formal elimination of water. Separation of the double-bond isomers and removal of the silyl protecting groups provided salicylihalamides A (E)-1 and B (Z)-1.

Full text of DOI:10.1002/chem.200400617

FULL PAPER
Total Synthesis of Salicylihalamides A and B
Christian Herb, Alexander Bayer, and Martin E. Maier*[a]
Dedicated to Professor J. Mulzer on the occasion of his 60th birthday
Abstract: The paper illustrates two effi-
cient routes to macrolactone 19 con-
taining a 3-(para-methoxybenzyloxy)-
propyl side chain at C-15. The chiral
center at C-15 was introduced by a
Noyori reduction of keto ester 5. The
intermediate common to both routes,
aldehyde 8, was prepared from keto
ester 5. The subsequent chain exten-
sion utilized Evans aldol reactions. The
first route leads to the alkene 14, which
was used, after hydroboration, for a
Suzuki cross-coupling reaction with
vinyl iodide 15. The derived seco acid
18 was converted into the macrolac-
tone 19 by a Mitsunobu lactonization
by using immobilized triphenylphos-
phine. Alternatively, an aldol reaction
of 8 with the 4-pentenoyl derivative 20
was used to prepare alkene 26. This
building block led to ester 28, which
could also be converted into macrolac-
tone 19 by the classical ring-closing
metathesis. After conversion of the C-
15 side chain to the corresponding al-
dehyde, the enamide was introduced
through hemiaminal formation and
formal elimination of water. Separation
of the double-bond isomers and remov-
al of the silyl protecting groups provid-
ed salicylihalamides A (E)-1 and
(Z)-1.
B
Keywords:
lactonization
antitumor agents
metathesis
·
·
·
salicylihalamide · total synthesis
Introduction
es or antiangiogenic effects were observed. Prototypical
examples of the benzolactone enamides are salicylihalam-
ide A and apicularen A (Scheme 1). The salicylihalamides
were isolated from the sponge Haliclona sp.,[9] whereas api-
cularen A has been discovered in various myxobacteria
strains.[10]
Secondary metabolites that contain a benzolactone ring
have been known for some time. Typical examples include
zearalenone,[1] radicicol,[2] C292,[3] the pochonins,[4] and
queenslandon.[5] While the biosynthetic pathways to these
compounds are quite similar, they show a broad spectrum of
biological activity. Recently, the structural diversity of this
class of natural products was widened with the discovery of
the benzolactone enamides.[6] In addition to the benzolac-
tone part, these compounds feature an enamide side chain.
The additional enamide side chain makes these natural
products powerful antitumor compounds. Their initial bio-
logical targets seem to be mammalian vacuolar adenosine
triphosphatase (V-ATPase) enzymes.[7] Recent studies show
that salicylihalamide binds to the V0 and not the V1 sector
of the V-ATPases.[8] These membrane-bound enzymes are
responsible for controlling the pH value in vacuoles and the
cytoplasm. Depending on the cell type studied, other effects
such as phosphorylation of mitogen-activated protein kinas-
Scheme 1. Structures of two important benzolactone enamides.
Both of these natural products are unique in their own
right. Thus, the macrolactone double bond in salicylihalam-
ide A is striking since it is in an allylic position relative to
the aromatic ring. On the other hand, the unique feature of
apicularen A is the ether bridge that spans the macrolactone
ring. The challenging structural features of these natural
products combined with their novel mode of action have
stimulated a number of synthesis programs. So far, total syn-
[a] Dipl.-Chem. C. Herb, Dipl.-Chem. A. Bayer, Prof. Dr. M. E. Maier
Institut für Organische Chemie
Universität Tübingen
Auf der Morgenstelle 18, 72076 Tübingen (Germany)
Fax : (+49)7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2004, 10, 5649 – 5660
DOI: 10.1002/chem.200400617
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5649

FULL PAPER
theses for the salicylihalamides[11] and apicularen A[12] have
been described. In addition, formal total syntheses[13,14] and
synthetic studies have been published.[15]
A synthesis of salicylihalamide basically has to address
three issues. First, the building-block synthesis has to pro-
vide the three stereocenters. Then, in order to form the mac-
rolactone ring, the best one of several strategies should be
chosen. Finally, an efficient method for attachment of the
enamide side chain is required. The known syntheses of the
macrolactone ring of salicylihalamide can be summarized as
follows (Scheme 2). In several cases, a Mitsunobu esterifica-
cases where the enamide is fashioned by nucleophilic addi-
tion to a vinyl isocyanate or by cross-coupling between a
vinyl iodide and the unsaturated amide, the side chain is
two carbon atoms long. In this paper we show that macro-
lactone 19 containing a three-carbon side chain can be con-
verted into salicylihalamides A and B by reaction of the cor-
responding aldehyde with the unsaturated amide 34. Macro-
lactone 19 was reached either by the Suzuki cross-coupling/
intramolecular Mitsunobu strategy or by the intermolecular
Mitsunobu/ring-closing metathesis tactic. It turned out that
both routes are of more or less similar efficiency if one ne-
glects the provision of the aromatic building blocks.
Results
As a common precursor to both routes we used the chiral b-
alkoxyaldehyde 8. The synthesis of this aldehyde started
from the monoprotected ethylene glycol[16] 3 which was con-
verted into the iodide 4 (Scheme 3) by using a combination
Scheme 3. Synthesis of the protected hydroxy aldehyde 8. a) PPh3
(1.01 equiv), imidazole (2equiv), I 2 (1.01 equiv), THF, 08C, 1 h, 97%;
b) NaH (1.2equiv), ethyl acetoacetate, THF, nBuLi (1.2equiv), ꢀ508C,
30 min, then add iodide
4
(1 equiv), 95%; c) [RuCl2(PhH)]2
(0.003 equiv), (R)-(+)-BINAP (0.07 equiv), DMF, 908C, 20 min, then add
to 5 in EtOH, H2 (4 bar), 908C, 20 h, 82%, 95%ee; d) TBDMSOTf
(1.12 equiv), 2,6-lutidine (2.5 equiv), CH2Cl2, 0!238C, 1 h, 100%;
e) DIBAL (1.2equiv), CH 2Cl2, ꢀ788C, 2h, 83%. BINAP =2,2’-bis(di-
phenylphosphanyl)-1,1’-binaphthyl, TBDMSOTf=tert-butyldimethylsilyl-
triflate, DIBAL=diisobutylaluminum hydride.
Scheme 2. General approaches to the macrolactone core of the salicyli-
halamides. RCM=ring-closing metathesis, MOM=methoxymethyl,
TBDMS=tert-butyldimethylsilyl, PMB=para-methoxybenzyl.
tion was used to combine a benzoic acid, containing the
allyl group, with a secondary alcohol that contains all the
stereocenters and a terminal alkene. Macrocyclization of
ester B was then achieved by ring-closing metathesis. In our
group we developed two complementary routes to the core
structure of salicylihalamide A.[13b,15e] In both cases the ester
is formed by Mitsunobu reaction and the trans-alkene is cre-
ated by a Suzuki cross-coupling reaction between a vinyl
iodide F and an alkylborane, with the latter being generated
from G by a diastereoselective hydroboration. The two ap-
proaches only differ by the order of the events. In the syn-
thesis of the Rizzacasa group, the two key building blocks I
and J are combined by a Stille coupling of a vinyl stannane
with a benzyl bromide. Macrolactonization is accomplished
by intramolecular attack of an alkoxide on an acetal
ester.[13a]
of iodine and triphenylphosphine.[17] Due to the somewhat
unstable nature of 4, this compound was used immediately
in a Weiler alkylation[18] of ethyl acetoacetate to provide the
b-keto ester 5. Reduction of the keto group under Noyori
conditions[19,20] with (R)-(+)-BINAP as the chirality inducer
gave the b-hydroxyestor 6 in good yield and with good opti-
cal purity (82%, 95% ee). After protection of the secondary
alcohol moiety with TBDMSOTf/2,6-lutidine,[21] the result-
ing ester 7 was reduced with DIBAL to give the desired al-
dehyde 8.
In order to enter the Suzuki cross-coupling route, alde-
hyde 8 was subjected to an Evans aldol reaction under
Crimmins conditions[22] (1.05 equiv of TiCl4, 2.5 equiv of dia-
mine) with the propionyloxazolidinone[23] 9 (Scheme 4). This
gave the syn-aldol product 10 in good yield. Protection of
the secondary alcohol as a MOM ether was followed by re-
ductive removal of the chiral auxiliary.[24] In order to intro-
duce the terminal double bond, the primary alcohol 12 was
The length of the side chain that extends from C-15 de-
pends very much on the way the enamide is attached. In
5650
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660

Salicylihalamide Total Synthesis
5649 – 5660
standard method for forming the salicylihalamide core struc-
ture. An aldol reaction of aldehyde 8 with the pentenoyloxa-
zolidinone[27] 20 by using the proven Crimmins conditions
gave the syn-aldol product 21 (Scheme 5). In order to reach
Scheme 4. Synthesis of the macrolactone 19 by Suzuki cross-coupling and
intramolecular Mitsunobu reaction. a) TiCl4 (1.05 equiv), TMEDA
(2.5 equiv), CH2Cl2, 08C, then add aldehyde 8 (1.1 equiv), 08C, 1 h, 78%;
b) iPr2NEt (20 equiv), MeOCH2Cl (10 equiv), Bu4NI (0.1 equiv), 0!
238C, 12h, 86%; c) NaBH 4 (5 equiv), H2O/THF (1:2), 0 to 238C, 12h,
80%; d) TsCl (3 equiv), pyridine, 08C, 5 h, 100%; e) NaI (2.5 equiv),
DBU (5 equiv), glyme, reflux, 3 h, 89%; f) 9-BBN (1.5 equiv), THF, 0!
238C, 12h, then add [PdCl 2(dppf)] (0.1 equiv), vinyl iodide 15
(0.9 equiv), 3n NaOH (3 equiv), 408C, 4 h, 84%; g) TBAF (3 equiv),
THF, 0!238C, 48 h, 100%; h) THF/EtOH/H2O (4:8:8), LiOH·H2O,
(10 equiv), 708C, 3 d, 92%; i) PS-PPh3 (5 equiv), THF, 15 min, then add
DEAD (2equiv), 0 !238C, 72%. TMEDA =N,N,N’,N’-tetramethyl-1,2-
ethanediamine, Ts=tosyl=toluene-4-sulfonyl, DBU=1,8-diazabicy-
clo[5.4.0]undec-7-ene, 9-BBN=9-borabicyclo[3.3.1]nonane, dppf=1,1’-
bis(diphenylphosphanyl)ferrocene, TBAF=tetrabutylammonium fluo-
ride, PS=polystyrene, DEAD=diethylazodocarboxylate.
Scheme 5. Synthesis of the macrolactone 19 by Mitsunobu esterification
and ring-closing metathesis. a) TiCl4 (1.05 equiv), (ꢀ)-spartein
(2.5 equiv), CH2Cl2, 08C, add aldehyde 8 (1.1 equiv), 08C, 1 h, 68%;
b) iPr2NEt (20 equiv), MeOCH2Cl (10 equiv), Bu4NI (0.1 equiv), 0!
238C, 3 d, 82%; c) NaBH4 (5 equiv), H2O/THF (1:2), 0!238C, 12h,
86%; d) TsCl (3 equiv), pyridine, 08C, 12h, 95%; e) Et 3BHLi
(3.6 equiv), THF, 0!238C, 15 h, 95%; f) TBAF (3 equiv), THF, 0!
238C, 48 h, 99%; g) Ph3P (2.5 equiv), acid 27 (5 equiv), DIAD
(2.55 equiv), toluene, 238C, 3 h, 71%; h) Grubbs catalyst 29 (0.1 equiv),
toluene, 708C, 2h, 75% of ( E)-19 and 12% of (Z)-19. DIAD=diisopro-
pylazodicarboxylate.
converted into the tosylate 13. Elimination to form alkene
14 was smoothly accomplished by heating tosylate 13 in the
presence of NaI and DBU.[25] In this way, alkene 14 could be
produced in gram quantities. The methyl-bearing stereocen-
ter from the aldol reaction was intentionally destroyed to
allow for its reintroduction with the opposite stereochemis-
try by a diastereoselective hydroboration reaction.[26] The in-
termediate borane resulting from treatment of 14 with 9-
BBN was added to a solution of the vinyl iodide[13b] 15 in
THF containing aqueous NaOH and [PdCl2(dppf)]. This led
to the trans-alkene 16 in high yield. Treatment of 16 with
TBAF in THF caused cleavage of the silyl ether group. The
methyl ester moiety of 17 was cleaved with LiOH to give
rise to the seco acid 18. Based on our previous experience
with the macrolactonization of a related substrate, the Mit-
sunobu macrolactonization was run in the presence of im-
mobilized triphenylphosphine. In this way, macrolactone 19
was obtained in 72% yield from the hydroxy acid 18. We
found that the yields for the Suzuki cross-coupling and the
macrolactonization were somewhat higher with the longer
side chain, an observation that is difficult to rationalize.
While this synthesis of macrolactone 19 is quite effective,
concise, and stereoselective, we also wanted to compare it
directly to the ring-closing metathesis strategy, the quasi
the anti stereochemistry of the vicinal methyl- and hydroxy-
bearing stereocenters, the acyl group of the aldol product 21
had to be reduced to a methyl group.[11,28] Prior to this, the
secondary alcohol was protected with MOM chloride to give
22. Reductive removal of the chiral auxiliary, tosylation of
the primary alcohol group of 23, and substitution of the to-
sylate moiety of 24 with hydride by using super hydride
gave the aliphatic chain 25. After cleavage of the silyl ether
protecting group, the resulting secondary alcohol 26 was
combined with benzoic acid[11g] 27 by a Mitsunobu esterifica-
tion. The dienyl ester 28 was subjected to a ring-closing
metathesis[29] by using the second-generation Grubbs cata-
lyst[30] 29 (0.1 equiv, 1mm in toluene at 708C). This led to a
mixture of the desired E isomer (E)-19 (75%) and the Z
isomer (Z)-19 (12%). Similar ratios for the ring-closing
metathesis have been observed by other groups.[6] The two
diastereomers could be separated by flash chromatography.
From the aldehyde 8 this sequence requires eight steps
(22.8% overall yield). While the Suzuki coupling/macrolac-
tonization strategy requires nine steps, the overall yield
(26.6%) is somewhat higher.
Chem. Eur. J. 2004, 10, 5649 – 5660
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5651

M. E. Maier et al.
FULL PAPER
With two efficient routes to the key macrolactone 19 in
hand, the total synthesis of salicylihalamide was targeted.
The successful realization of this task relied on our ability to
convert an aldehyde into an enamide.[31] First, all ether
groups of 19 were cleaved by treatment with 9-iodoborobi-
cyclononane[32] (Scheme 6). The rather polar crude triol 30
Conclusion
In summary, we illustrated two efficient routes to the macro-
lactone 19 containing a 3-(para-methoxybenzyloxy)propyl
side chain at C-15. The chiral center at C-15 was introduced
by a Noyori reduction of keto ester 5. The intermediate
common to both routes, aldehyde 8, was extended by Evans
aldol reactions. The first route leads to the alkene 14, which
was used, after hydroboration, for a Suzuki cross-coupling
reaction with vinyl iodide 15. The derived seco acid 18 was
converted into macrolactone 19 by a Mitsunobu lactoniza-
tion with immobilized triphenylphosphine. Alternatively, an
aldol reaction of 8 with the 4-pentenoyl derivative 20 was
used to prepare alkene 26. From this building block, ester
28 was prepared; this could be converted into macrolactone
19 by a classical ring-closing metathesis. After conversion of
the C-15 side chain to form the corresponding aldehyde 33,
the enamide was introduced through hemiaminal formation
and formal elimination of water. With the great diversity po-
tential of the aldehyde function, a number of salicylihalam-
ide side-chain analogues should now be accessible.
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400 spectrometer; spectra
were recorded at 295 K, either in CDCl3, C6D6, or CD3OD; chemical
shifts are calibrated to the residual proton and carbon resonances of the
solvent: CDCl3 (dH=7.25, dC=77.0 ppm), C6D6 (dH=7.16, dC=
128.0 ppm), or CD3OD (dH=3.30, dC=49.0 ppm); NMR spectroscopy
peaks were assigned according to the numbering by Boyd et al.[9]. IR:
Jasco FT/IR-430 apparatus. Optical rotation: Jasco P-1020 polarimeter;
reported in degrees; [a]D (c [g/100 mL], solvent); recorded at 298 K. MS:
Finnigan Triple-Stage-Quadrupole TSQ-70 (ionizing voltage of 70 eV) or
Intectra AMD 402mass spectrometers. HRMS: Intectra AMD MAT-
711A (EI) or Bruker Daltonic APEX 2(ESI) mass spectrometers. Flash
chromatography: J. T. Baker silica gel, 43–60 mm. Thin-layer chromatog-
raphy: Macherey–Nagel Polygram Sil G/UV254 plates. All solvents used
in the reactions were distilled before use. Dry diethyl ether, tetrahydro-
furan, and toluene were distilled from sodium and benzophenone, where-
as dry dichloromethane, dimethylformamide, pyridine, and triethylamine
were distilled from CaH2. Petroleum ether with a boiling range of 40–
608C was used. Reactions were generally run under an argon atmos-
phere. All commercially available compounds were used as received,
unless stated otherwise.
Scheme 6. Synthesis of salicylihalamides A and B from the macrolactone
19. a) 9-I-9-BBN (1.9 equiv), CH2Cl2, 2 8C3 , 90 s; b) TBDMSCl,
(35 equiv), imidazole (44 equiv), DMAP (1.8 equiv), DMF, 238C, 4 d,
60% over 2steps; c) CSA (0.2equiv), CH 2Cl2/MeOH, 08C, 1.5 h, 85%;
d) TPAP (0.125 equiv), NMO (1.45 equiv), CH2Cl2, 08C, 1 h, 91%; e) di-
enamide 34 (2equiv), DIBAL (2.54 equiv), THF, 0 8C, 30 min, then add
aldehyde 33 (1 equiv), 08C, 14 h, 61% of 35 and 32% of 33; f) pyridine
(30 equiv), Ac2O (15 equiv), THF, 238C, 24 h, then reflux, 48 h, 45% of
(E)-36 and 14% of (Z)-36; g) HF·pyridine (2.2m in THF/pyridine, 5.4:1),
238C, 3 d, 75% of (E)-1, 69% of (Z)-1. DMAP=4-dimethylaminopyri-
dine, (ꢁ)-CSA=(ꢁ)-camphorsulfonic acid, TPAP=tetra-n-propylammo-
nium perruthenate, NMO=4-methylmorpholine N-oxide.
1-[(2-Iodoethoxy)methyl]-4-methoxybenzene (4): A solution of alcohol[16]
3 (8.00 g, 43.9 mmol) in THF (80 mL) was treated with PPh3 (11.63 g,
44.3 mmol) and imidazole (5.98 g, 87.8 mmol) and then cooled to 08C.
Iodine (11.25 g, 44.3 mmol) was added in 3 portions and the mixture was
stirred for 1 h while it warmed to room temperature. The solution was
transfered to a round-bottom flask containing a suspension of silica gel
(200 g) in THF (300 mL) and the solvent was removed completely in
vacuo. The residue was chromatographed over a short pad of silica gel
(elution with petroleum ether/ethyl acetate, 2:1) to provide the iodide 4
(12.43 g, 97%) as a light-yellow oil.
was completely silylated to give macrolactone 31 (60% for
2steps). A subsequent selective desilylation [33] with CSA in
a mixture of methanol and CH2Cl2 led to the primary alco-
hol 32. Oxidation of 32 to form aldehyde 33 was accomplish-
ed with TPAP.[34] The enamide side chain could be attached
by treating aldehyde 33 with the aluminum carboximidoate
derived from the amide[31] 34 and DIBAL.[35] This furnished
the hemiaminal 35 in 61% yield as a 1:1 mixture of diaster-
eomers, together with 32% recovered aldehyde. The formal
elimination of water from 35 was achieved by heating a
THF solution of 35 containing acetic anhydride and pyridine
to reflux. These conditions resulted in a separable mixture
of the E/Z-enamides (E)-36 (45%) and (Z)-36 (14%). Fi-
nally, both enamides were deprotected with HF in pyri-
dine[11d] to give the natural products salicylihalamide A
(75%) and salicylihalamide B (69%), respectively.
Ethyl 6-[(4-methoxybenzyl)oxy]-3-oxohexanoate (5): A solution of ethyl
3-oxobutanoate (3.89 mL, 4.00 g, 30.7 mmol) in THF (40 mL) was added
dropwise to a cooled (ꢀ208C) suspension of NaH (0.89 g, 36.9 mmol) in
THF (30 mL). After gas evolution had stopped, the solution was stirred
at room temperature for 30 min and then recooled to ꢀ508C. The cooled
solution was treated with n-butyllithium (15.0 mL, 37.5 mmol, 2.5m in
hexane) and stirred for a further 30 min before a solution of iodide 4 in
THF (40 mL) was added dropwise. The cooling bath was removed and
the mixture was allowed to warm to room temperature. The reaction was
then quenched by treatment with saturated aqueous NH4Cl solution. The
phases were separated and the aqueous layer extracted twice with diethyl
5652
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660

Salicylihalamide Total Synthesis
5649 – 5660
ether (50 mL). The combined organic extracts were washed with saturat-
ed aqueous NaHCO3 solution and dried over Na2SO4. After filtration
and evaporation of the solvent, the crude product was chromatographed
over silica gel to produce the b-keto ester 5 (8.59 g; 95%) as a light-
yellow oil. Rf =0.47 (petroleum ether/ethyl acetate, 2:1); 1H NMR
(400 MHz, CDCl3): d=1.27 (t, J=7.2Hz, 3H; Et C H3), 1.90 (tt, J=6.1,
7.1 Hz, 2H; H-5), 2.65 (t, J=7.1 Hz, 2H; H-4), 3.43 (s, 2H; H-2), 3.46 (t,
J=6.1 Hz, 2H; H-6), 3.80 (s, 3H; PMB CH3), 4.18 (q, J=7.2Hz, 2H; Et
CH2), 4.40 (s, 2H; PMB CH2), 6.88 (d, J=8.6 Hz, 2H; PMB H-3,5),
7.24 ppm (d, J=8.6 Hz, 2H; PMB-H-2,6); 13C NMR (100 MHz, CDCl3):
d=14.0 (Et CH3), 23.6 (C-5), 39.7 (C-4), 49.2( C-2), 55.2 (OCH3), 61.2
(Et CH2), 68.6 (C-6), 72.4 (PMB CH2), 113.7 (PMB C-3,5), 129.2 (PMB
C-2,6), 130.3 (PMB C-1), 159.1 (PMB C-4), 167.2( C-1), 202.6 ppm (C-3);
IR (film): n˜ =1033, 1097, 1248, 1303, 1514, 1715 cmꢀ1; MS (EI): m/z (%):
292 (4), 156 (13), 136 (45), 135 (73), 121 (38), 111 (72), 86 (60), 84 (100),
77 (24); HRMS (ESI): calcd for C16H22NaO5 [M+Na]+: 317.13594;
found: 317.13578.
4), 171.7 ppm (C-1); IR (film): n˜ =1038, 1096, 1173, 1204, 1249, 1302,
1362, 1464, 1472, 1514, 1613, 1737, 2856, 2930, 2954 cmꢀ1; MS (EI): m/z
(%): 347 (7), 189 (8), 149 (22), 147 (24), 121 (100), 77 (7), 75 (16), 73
(19); HRMS (ESI): calcd for C22H38NaO5Si [M+Na]+: 433.23807; found:
433.23809.
(3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]hexanal
(8): DIBAL (1.0m in hexane, 2.92 mL) was added dropwise to a stirred
solution of ester 7 (1.00 g, 2.44 mmol) in dry CH2Cl2 (25 mL) over 10 min
at ꢀ788C. After the reaction had been stirred for 2h at ꢀ788C, methanol
(0.7 mL) was added, the cooling bath was removed, and the mixture was
allowed to warm to room temperature. H2O (5 mL) was then added and
the mixture was extracted with Et2O (3”15 mL). The combined organic
layers were washed with water (10 mL) and brine (10 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The residue was purified
by flash chromatography (petroleum ether/diethyl ether, 2:1) to yield al-
dehyde 8 (0.74 g, 83%) as a pale-yellow oil. Rf =0.46 (petroleum ether/
ethyl acetate, 5:1); [a]D =ꢀ0.9 (c=1.09, CH2Cl2)1H NMR (400 MHz,
CDCl3): d=0.04, 0.05 (2”s, 3H each; Si(CH3)2), 0.86 (s, 9H; SiC(CH3)3),
1.55–1.66 (m, 4H; H-4, H-5), 2.49 (ddd, J=15.8, 5.5, 2.4 Hz, 1H; H-2a),
2.53 (ddd, J=15.8, 5.9, 2.6 Hz, 1H; H-2b), 3.43 (t, J=5.8 Hz, 2H; H-6),
3.79 (s, 3H; PMB CH3), 4.16–4.24 (m, 1H; H-3), 4.41 (s, 2H; PMB CH2),
6.86 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.24 (d, J=8.6 Hz, 2H; PMB H-
2,6), 9.79 ppm (dd, J=2.6, 2.4 Hz, 1H; H-1); 13C NMR (100 MHz,
CDCl3): d=ꢀ4.7 (Si(CH3)2), ꢀ4.5 (Si(CH3)2), 17.9 (SiC), 25.4 (C-5), 25.7
(C(CH3)3), 34.4 (C-4), 50.8 (C-2), 55.2 (PMB CH3), 67.9 (C-3), 69.8 (C-6)
72.5 (PMB CH2), 113.7 (PMB C-3,5), 129.2 (PMB C-2,6), 130.5 (PMB C-
1), 159.1 (PMB C-4), 202.2 ppm (C-1); IR (film): n˜ =1006, 1038, 1096,
1173, 1249, 1362, 1464, 1514, 1613, 1725, 2856, 2930, 2953 cmꢀ1; MS (EI):
m/z (%): 190 (5), 189 (4), 187 (7), 171 (10), 152(11), 145 (43), 135 (32),
122 (22), 121 (100), 77 (17), 75 (95), 73 (16), 71 (18); HRMS (EI): calcd
for C20H34NaO4Si [M+Na]+: 389.21186; found: 389.21205.
Ethyl (3R)-3-hydroxy-6-[(4-methoxybenzyl)oxy]hexanoate (6): Dry, de-
gassed DMF (3 mL) was added to a flask containing benzene rutheni-
um(ii) chloride dimer (43 mg, 0.09 mmol) and (R)-(+)-BINAP (116 mg,
0.19 mmol). The slurry was heated to 908C with stirring for 20 min. The
reddish brown solution was allowed to cool to room temperature and
then added through a cannula to a Parr hydrogenation bomb containing
a degassed solution of b-keto ester 5 (8.31 g, 28.2 mmol) in dry, degassed
ethanol (15 mL). The hydrogenation bomb was flushed a few times with
hydrogen and then kept under a hydrogen pressure of 4.0 bar at 908C
with vigorous shaking for 20 h. After cooling to room temperature the
dark-red solution was concentrated in vacuo and the residue was purified
by flash chromatography to provide b-hydroxy ester 6 (6.88 g, 82%, 95%
ee) as a pale-yellow oil. The enantioselectivity was determined by chiral
HPLC and was found to be 97.5:2.5 with the desired isomer favored. Rf =
0.24 (petroleum ether/ethyl acetate, 2:1); HPLC: tR (R enantiomer)=
9.1 min, tR (S enantiomer)=12.0 min on a CHIRA-GROM 4 column,
8 mm, 60”2mm (corresponds to CHIRACEL AS) with n-heptane/iPrOH
89:11, 0.1 mLminꢀ1 flow; [a]D =ꢀ8.0 (c=1.32, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=1.25 (t, J=7.2Hz, 3H; Et C H3), 1.47–1.63 (m,
2H; H-4), 1.63–1.81 (m, 2H; H-5), 2.41 (dd, J=16.2, 8.2 Hz, 1H; H-2a),
2.47 (dd, J=16.2, 4.2 Hz, 1H; H-2b), 3.29 (brs, 1H; OH), 3.47 (t, J=
6.1 Hz, 2H; H-6), 3.78 (s, 3H; PMB CH3), 4.01 (dddd, J=8.2, 8.1, 4.4,
4.2Hz, 1H; H-3), 4.15 (q, J=7.2Hz, 2H; Et C H2), 4.42(s, 2H; PMB
CH2), 6.86 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.24 ppm (d, J=8.6 Hz, 2H;
PMB H-2,6); 13C NMR (100 MHz, CDCl3): d=14.1 (Et CH3), 25.9 (C-5),
33.6 (C-4), 41.5 (C-2), 55.2 (PMB CH3), 60.5 (Et CH2), 67.7 (C-3), 69.8
(C-6) 72.5 (PMB CH2), 113.7 (PMB C-3,5), 129.2 (PMB C-2,6), 130.3
(PMB C-1), 159.1 (PMB C-4), 172.7 ppm (C-1); IR (film): n˜ =1248, 1302,
1372, 1514, 1612, 1732, 2859, 2937, 3449 cmꢀ1; MS (EI): m/z (%): 297
(10), 296 (17), 278 (22), 241 (8), 203 (9), 190 (12), 160 (11), 142 (37), 137
(88), 121 (100), 109 (19), 99 (18), 91 (9), 77 (10); HRMS (EI): calcd for
C16H24O5 [M]+: 296.1623; found: 296.1675.
(4S)-4-Benzyl-3-{(2S,3R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-
8-[(4-methoxybenzyl)oxy]-2-methyloctanoyl}-1,3-oxazolidin-2-one (10):
Titanium(iv) chloride (0.94 mL, 1.62g, 8.55 mmol) was added dropwise
to a stirred, cooled (08C) solution of (4S)-4-(benzyl)-3-propanoyl-1,3-ox-
azolidin-2-one[23] (9) (1.90 g, 8.15 mmol) in CH2Cl2 (60 mL) and the re-
sulting mixture was allowed to stir for 5 min. Subsequently, TMEDA
(3.05 mL, 2.37 g, 20.4 mmol) was added to the yellow slurry. The dark-
red enolate solution was stirred for 20 min at 08C before a solution of al-
dehyde 8 (3.28 g, 8.96 mmol) in CH2Cl2 (45 mL) was added dropwise and
the mixture was stirred for 1 h at 08C. The reaction was quenched with
half-saturated aqueous NH4Cl solution (20 mL) and allowed to warm to
room temperature. After separation of the layers, the aqueous layer was
extracted with CH2Cl2 (2”30 mL) and the combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography afforded the desired product 10 (3.81 g,
78%) as a colorless viscous oil. Rf =0.48 (petroleum ether/diethyl ether,
2:3); [a]D =+35.4 (c=1.43, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
0.06, 0.07 (2”s, 3H each; Si(CH3)2), 0.86 (s, 9H; SiC(CH3)3), 1.25 (d, J=
7.0 Hz, 3H; CH3), 1.51–1.72(m, 6H; H-6, H-4, H-7), 2.75 (dd, J=13.4,
9.6 Hz, 1H; Bn CH2), 3.25 (dd, J=13.4, 3.2Hz, 1H; Bn C H2), 3.31 (brs,
1H; OH), 3.39–3.45 (m, 2H; H-8), 3.74 (qd, J=7.0, 4.0 Hz, 1H; H-2),
3.78 (s, 3H; PMB CH3), 3.90–3.98 (m, 1H; H-5), 4.05 (ddd, J=9.2, 3.8,
3.0 Hz, 1H; H-3), 4.15 (dd, J=9.1, 3.3 Hz, 1H; H-5’a), 4.18 (dd, J=9.1,
6.8 Hz, 1H; H-5’b), 4.41 (s, 2H; PMB CH2), 4.67 (dddd, J=9.6, 6.8, 3.3,
3.2Hz, 1H; H-4’), 6.86 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.18–7.34 ppm
(m, 7H; Bn H, PMB H-2,6); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7
(Si(CH3)2), ꢀ4.2(Si( CH3)2), 11.2( CH3), 18.0 (SiC), 25.0 (C-7), 25.8
(C(CH3)3), 33.9 (C-6), 37.7 (Bn CH2), 40.4 (C-4), 42.8 (C-2), 55.2 (PMB
CH3), 55.3 (C-4’), 66.1 (C-5’), 70.1 (C-8), 70.3 (C-3), 71.6 (C-5), 72.5
(PMB CH2), 113.7 (PMB C-3,5), 127.4 (Bn C-4), 128.9 (Bn C-3,5), 129.2
(PMB C-2,6), 129.4 (Bn C-2,6), 130.6 (PMB C-1), 135.2(Bn C-1), 153.0
(C-2’), 159.1 (PMB C-4), 176.5 ppm (C-1); IR (film): n˜ =1037, 1112, 1210,
1248, 1362, 1385, 1455, 1513, 1696, 1783, 2856, 2930, 2953, 3525 cmꢀ1; MS
(EI): m/z (%): 233 (2), 142 (3), 122 (10), 121 (100), 91 (5), 57 (10);
HRMS (ESI): calcd for C33H49NNaO7Si [M+Na]+: 622.31705; found:
622.31728.
Ethyl (3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-
hexanoate (7): 2,6-Lutidine (2.11 mL, 1.94 g, 18.1 mmol) and
TBDMSOTf (2.32 mL, 2.67 g, 8.71 mmol) were added to a stirred so-
lution of b-hydroxy ester 6 (2.15 g, 7.26 mmol) in dry CH2Cl2 (35 mL) at
08C. The resulting solution was stirred for 1 h and allowed to warm to
room temperature. After adding water (70 mL), the phases were separat-
ed and the aqueous layer was extracted with Et2O (3”30 mL). The com-
bined organic layers were washed with 1n HCl (30 mL) and brine
(30 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resi-
due was purified by flash chromatography to yield the protected alcohol
7 (2.98 g, 100%) as a slightly yellow oil. Rf =0.71 (petroleum ether/ethyl
acetate, 5:1); [a]D =ꢀ10.0 (c=1.31, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=0.02, 0.04 (2”s, 3H each; Si(CH3)2), 0.85 (s, 9H; SiC(CH3)3),
1.24 (t, J=7.1 Hz, 3H; Et CH3), 1.51–1.69 (m, 4H; H-4, H-5), 2.39 (dd,
J=14.7, 5.6 Hz, 1H; H-2a), 2.44 (dd, J=14.7, 7.1 Hz, 1H; H-2b), 3.42 (t,
J=6.4 Hz, 2H; H-6), 3.79 (s, 3H; PMB CH3), 4.10 (qd, J=7.1, 2.1 Hz,
2H; Et CH2), 4.10–4.18 (m, 1H; H-3), 4.41 (s, 2H; PMB CH2), 6.86 (d,
J=8.5 Hz, 2H; PMB H-3,5), 7.24 ppm (d, J=8.5 Hz, 2H; PMB H-2,6);
13C NMR (100 MHz, CDCl3): d=ꢀ4.9 (Si(CH3)2), ꢀ4.6 (Si(CH3)2), 14.2
(Et CH3), 17.9 (SiC), 25.2 (C-5), 25.7 (C(CH3)3), 34.1 (C-4), 42.7 (C-2),
55.2(PMB CH3), 60.3 (Et CH2), 69.2( C-3), 70.0 (C-6) 72.4 (PMB CH2),
113.7 (PMB C-3,5), 129.2 (PMB C-2,6), 130.6 (PMB C-1), 159.1 (PMB C-
(4S)-4-Benzyl-3-[(2S,3R,5R)-5-{[tert-butyl(dimethyl)silyl]oxy}-8-[(4-me-
thoxybenzyl)oxy]-3-(methoxymethoxy)-2-methyloctanoyl]-1,3-oxazolidin-
2-one (11): N,N-diisopropylethylamine (2.60 mL, 1.97 g, 15.2 mmol),
chloromethylmethyl ether (0.58 mL, 0.61 g, 7.60 mmol), and TBAI
Chem. Eur. J. 2004, 10, 5649 – 5660
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5653

M. E. Maier et al.
FULL PAPER
(28 mg, 76 mmol) were added to a stirred, cooled (08C) solution of alco-
hol 10 (0.46 g, 0.76 mmol) in CH2Cl2 (15 mL). The reaction mixture was
protected from light and allowed to warm to room temperature within
12h while being stirred. The reaction mixture was treated with saturated
aqueous NaHCO3 solution (20 mL) and diluted with Et2O (30 mL). After
separation of the phases, the organic layer was washed with 1n HCl
(10 mL) and brine (6 mL), and the aqueous layer was extracted with
Et2O (2”20 mL). The combined organic extracts were dried (Na 2SO4),
filtered, and concentrated in vacuo. Flash chromatography of the residue
provided MOM ether 11 (0.42g, 86%) as a slightly yellow viscous oil.
(2”s, 3H each; Si(CH3)2), 0.82–0.87 (m, 3H; CH3), 0.84 (s, 9H;
SiC(CH3)3), 1.40–1.65 (m, 6H; H-6, H-7, H-4), 1.98–2.09 (m, 1H; H-2),
2.43 (s, 3H; Ts CH3), 3.25 (s, 3H; MOM CH3), 3.40 (t, J=6.5 Hz, 2H; H-
8), 3.63 (td, J=6.5, 2.6 Hz, 1H; H-3), 3.65–3.72(m, 1H; H-5), 3.79 (s,
3H; PMB CH3), 3.87 (dd, J=9.2, 7.5 Hz, 1H; H-1a), 4.05 (dd, J=9.2,
6.4 Hz, 1H; H-1b), 4.41 (s, 2H; PMB CH2), 4.45 (d, J=6.8 Hz, 1H;
MOM CH2), 4.50 (d, J=6.8 Hz, 1H; MOM CH2), 6.86 (d, J=8.6 Hz, 2H;
PMB H-3,5), 7.24 (d, J=8.6 Hz, 2H; PMB H-2,6), 7.32 (d, J=8.2Hz,
2H; Ts H-3,5), 7.77 ppm (d, J=8.2Hz, 2H; Ts H-2,6); 13C NMR
(100 MHz, CDCl3): d=ꢀ4.5 (Si(CH3)2), ꢀ4.4 (Si(CH3)2), 10.8 (CH3), 18.0
(SiC), 21.6 (Ts CH3), 25.3 (C-7), 25.8 (C(CH3)3), 33.5 (C-6), 36.0 (C-2),
38.5 (C-4), 55.2(PMB CH3), 55.7 (MOM CH3) 69.0 (C-5), 70.1 (C-8),
72.4 (C-1), 72.5 (PMB CH2), 75.1 (C-3), 96.2(MOM CH2), 113.7 (PMB
C-3,5), 127.9 (Ts C-2,6), 129.2 (PMB C-2,6), 129.8 (Ts C-3,5), 130.6
(PMB C-1), 133.1 (Ts C-1), 144.6 (Ts C-4), 159.1 ppm (PMB C-4); IR
(film): n˜ =969, 1038, 1097, 1178, 1189, 1249, 1363, 1464, 1513, 2855, 2929,
2952 cmꢀ1; MS (EI): m/z (%): 233 (2), 189 (6), 147 (34), 122 (10), 121
(100), 91 (6), 57 (17); HRMS (ESI): calcd for C32H52NaO8SSi [M+Na]+:
647.30444; found: 647.30360.
Rf =0.62(petroleum ether/diethyl ether, 1:)2;
[
a]D =+70.3 (c=1.22,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.02, 0.03 (2”s, 3H each;
Si(CH3)2), 0.86 (s, 9H; SiC(CH3)3), 1.21 (d, J=7.0 Hz, 3H; CH3), 1.39–
1.48 (m, 1H; H-6a), 1.53–1.78 (m, 5H; H-7a, H-6b, H-7b, H-4), 2.75 (dd,
J=13.4, 9.7 Hz, 1H; Bn CH2), 3.27 (dd, J=13.4, 3.0 Hz, 1H; Bn CH2),
3.30 (s, 3H; MOM CH3), 3.43 (t, J=6.5 Hz, 2H; H-8), 3.77 (s, 3H; PMB
CH3), 3.79–3.85 (m, 2H; H-3, H-5), 3.96 (qd, J=7.0, 4.4 Hz, 1H; H-2),
4.09–4.17 (m, 2H; H-5’), 4.41 (s, 2H; PMB CH2), 4.54 (d, J=7.1 Hz, 1H;
MOM CH2), 4.55–4.62(m, 1H; H-4’), 4.60 (d, J=7.1 Hz, 1H; MOM
CH2), 6.85 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.17–7.33 ppm (m, 7H; Bn
H-2,6, PMB H-2,6, Bn H-4, Bn H-3,5); 13C NMR (100 MHz, CDCl3): d=
ꢀ4.6 (Si(CH3)2), ꢀ4.5 (Si(CH3)2), 12.1 (CH3), 18.0 (SiC), 25.3 (C-7), 25.9
(C(CH3)3), 32.7 (C-6), 37.7 (Bn CH2), 40.7 (C-4), 41.8 (C-2), 55.2 (PMB
CH3), 55.8 (C-4’), 56.1 (MOM CH3) 66.0 (C-5’), 69.2( C-5), 70.3 (C-8),
72.3 (PMB CH2), 76.6 (C-3), 96.5 (MOM CH2), 113.7 (PMB C-3,5), 127.3
(Bn C-4), 128.9 (Bn C-3,5), 129.2 (PMB C-2,6), 129.4 (Bn C-2,6), 130.8
(PMB C-1), 135.3 (Bn C-1), 153.2( C-2’), 159.0 (PMB C-4), 174.8 ppm
(C-1); IR (film): n˜ =1035, 1100, 1210, 1249, 1382, 1455, 1513, 1782, 2855,
2930, 2953 cmꢀ1; MS (EI): m/z (%): 233 (8), 177 (4), 149 (11), 142 (16),
136 (36), 135 (56), 121 (68), 91 (22), 75 (36), 57 (100); HRMS (ESI):
calcd for C35H53NNaO8Si [M+Na]+: 666.34327; found: 666.34223.
(4R,6R)-4-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(4-methoxybenzyl)oxy]-6-
(methoxymethoxy)-7-methyloct-7-ene (14):
A mixture of tosylate 13
(1.54 g, 2.46 mmol), NaI (923 mg, 6.16 mmol), and DBU (1.86 mL, 1.88 g,
12.3 mmol) in glyme (35 mL) was refluxed with stirring for 3 h. The so-
lution was cooled to room temperature, diluted with Et2O (60 mL), and
washed with saturated aqueous NaHCO3 solution (10 mL), 1n HCl
(10 mL), and brine (10 mL). The organic layer was dried (Na2SO4), fil-
tered, and concentrated in vacuo. Filtration of the residue over a short
pad of silica gel gave pure alkene 14 (0.99 g, 89%) as a slightly yellow
oil. Rf =0.78 (petroleum ether/diethyl ether, 1:1); [a]D =+53.4 (c=1.23,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.03 (s, 6H; Si(CH3)2), 0.87 (s,
9H; SiC(CH3)3), 1.43–1.54 (m, 1H; H-3a), 1.55–1.73 (m, 4H; H-3b, H-5a,
H-2), 1.63 (s, 3H; CH3), 1.74–1.84 (m, 1H; H-5b), 3.32(s, 3H; MOM
CH3), 3.42(t, J=6.4 Hz, 2H; H-8), 3.74–3.80 (m, 1H; H-4), 3.78 (s, 3H;
PMB CH3), 4.10 (dd, J=7.7, 5.9 Hz, 1H; H-6), 4.41 (s, 2H; PMB CH2),
4.44 (d, J=6.7 Hz, 1H; MOM CH2), 4.57 (d, J=6.7 Hz, 1H; MOM CH2),
4.91 (s, 2H; H-8), 6.85 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.24 ppm (d, J=
8.6 Hz, 2H; PMB H-2,6); 13C NMR (100 MHz, CDCl3): d=ꢀ4.4
(Si(CH3)2), ꢀ4.3 (Si(CH3)2), 16.7 (CH3), 18.0 (SiC), 25.4 (C-2), 25.9
(C(CH3)3), 33.2( C-3), 41.2( C-5), 55.2(PMB CH3), 55.5 (MOM CH3)
69.2( C-4), 70.3 (C-1), 72.4 (PMB CH2), 76.9 (C-6), 93.3 (MOM CH2),
113.7 (PMB C-3,5), 114.2, (C-8), 129.1 (PMB C-2,6), 130.7 (PMB C-1),
143.8 (C-7), 159.0 ppm (PMB C-4); IR (film): n˜ =1037, 1065, 1095, 1153,
1249, 1463, 1514, 1613, 2856, 2886, 2930, 2952 cmꢀ1; MS (EI): m/z (%):
292 (3), 149 (4), 135 (7), 122 (9), 121 (100), 89 (8), 77 (10), 57 (7); HRMS
(ESI): calcd for C25H44NaO5Si [M+Na]+: 475.28502; found: 475.28523.
(2R,3R,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)oxy]-
3-(methoxymethoxy)-2-methyl-1-octanol (12): A solution of sodium boro-
hydride (0.81 g, 21.5 mmol) in water (22 mL) was added dropwise to a
cooled (08C) solution of amide 11 (2.77, 4.30 mmol) in THF (45 mL).
Stirring was continued for 12h with concomitant warming of the mixture
to room temperature. The solution was treated with saturated aqueous
NH4Cl solution (40 mL), stirred for 1 h, and transferred into a separation
funnel. After extraction with ethyl acetate (3”40 mL), the combined or-
ganic layers were dried over MgSO4, filtered, and concentrated in vacuo.
Flash chromatography of the residue provided alcohol 12 (1.63 g, 80%)
as a colorless oil. Rf =0.42(petroleum ether/ethyl acetate, 2:1); [ a]D =
ꢀ13.4 (c=1.20, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.03, 0.05 (2”
s, 3H each; Si(CH3)2), 0.80 (d, J=7.0 Hz, 3H; CH3), 0.87 (s, 9H;
SiC(CH3)3), 1.43–1.75 (m, 6H; H-6, H-7, H-4), 1.88–1.98 (m, 1H; H-2),
2.70 (brs, 1H; OH), 3.37 (s, 3H; MOM CH3), 3.42(t, J=6.4 Hz, 2H; H-
8), 3.51 (dd, J=11.0, 5.3 Hz, 1H H-1a), 3.60 (dd, J=11.0, 8.9 Hz, 1H; H-
1b), 3.71–3.77 (m, 1H; H-5), 3.77–3.84 (m, 1H; H-3), 3.79 (s, 3H; PMB
CH3), 4.41 (s, 2H; PMB CH2), 4.60 (d, J=6.6 Hz, 1H; MOM CH2), 4.62
(d, J=6.6 Hz, 1H; MOM CH2), 6.86 (d, J=8.6 Hz, 2H; PMB H-3,5),
7.24 ppm (d, J=8.6 Hz, 2H; PMB H-2,6); 13C NMR (100 MHz, CDCl3):
d=ꢀ4.4 (Si(CH3)2), ꢀ4.4 (Si(CH3)2), 10.9 (CH3), 18.0 (SiC), 25.4 (C-7),
25.9 (C(CH3)3), 33.6 (C-6), 37.7 (C-2), 38.6 (C-4), 55.2(PMB CH3), 55.9
(MOM CH3) 65.3 (C-1), 69.2( C-5), 70.2( C-8), 72.5 (PMB CH2), 76.7 (C-
3), 96.3 (MOM CH2), 113.7 (PMB C-3,5), 129.2 (PMB C-2,6), 130.6
(PMB C-1), 159.1 ppm (PMB C-4); IR (film): n˜ =1038, 1095, 1249, 1514,
2856, 2930, 2952, 3466 cmꢀ1; MS (EI): m/z (%): 349 (2), 167 (2), 149 (7),
122 (9), 121 (100), 89 (6), 77 (6), 73 (6), 59 (9), 58 (9), 43 (36); HRMS
(ESI): calcd for C25H46NaO6Si [M+Na]+: 493.29559; found: 493.29557.
Methyl 2-[(2E,5S,6R,8R)-8-{[tert-butyl(dimethyl)silyl]oxy}-11-[(4-meth-
oxybenzyl)oxy]-6-(methoxymethoxy)-5-methyl-2-undecenyl]-6-methoxy-
benzoate (16): 9-BBN (0.5m solution in THF, 2.67 mL, 1.34 mmol) was
added to olefin 14 (403 mg, 0.89 mmol) in THF (9 mL) at 08C. After
being stirred for 12h at room temperature, the solution was cooled to
08C and treated with [PdCl2(dppf)] (73 mg, 0.089 mmol), vinyl iodide[15e]
15 (266 mg, 0.80 mmol), and 3n NaOH (0.89 mL). The mixture was
heated to 408C for 4 h, cooled to room temperature, and diluted with
Et2O (20 mL) and brine (20 mL). After separation of the phases, the
aqueous layer was extracted with Et2O (3”20 mL) and the combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Pu-
rification by flash chromatography (petroleum ether/ethyl acetate, 4:1,
and CH2Cl2/acetone, 30:1) afforded coupling product 16 (444 mg, 84%)
as a light-yellow oil. Rf =0.29 (petroleum ether/ethyl acetate, 5:1); [a]D =
+15.5 (c=1.38, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.04, 0.05 (2”
s, 3H each; Si(CH3)2), 0.85–0.90 (m, 3H; CH3), 0.88 (s, 9H; SiC(CH3)3),
1.34–1.52(m, 2H; H-9a, H-7a), 1.52–1.75 (m, 4H; H-9b, H-7b, H-10),
1.75–1.85 (m, 2H; H-5, H-4a), 2.00–2.05 (m, 1H; H-4b), 3.27 (d, J=
6.1 Hz, 2H; H-1), 3.34 (s, 3H; MOM CH3), 3.41 (t, J=6.5 Hz, 2H; H-
(2R,3R,5R)-5-{[tert-Butyl(dimethyl)silyl]oxy}-8-[(4-methoxybenzyl)oxy]-
3-(methoxymethoxy)-2-methyloctyl 4-methylbenzenesulfonate (13): p-
Toluenesulfonyl chloride (1.17 g, 6.11 mmol) was added to a stirred so-
lution of alcohol 12 (0.96 g, 2.04 mmol) in pyridine (4 mL) at 08C. After
being stirred for 5 h, the reaction was quenched by addition of ice (0.5 g)
and H2O (8 mL). The mixture was diluted with Et2O (40 mL) and
washed with saturated aqueous NaHCO3 solution (7 mL), 1n HCl
(7 mL), and brine (7 mL). The organic layer was dried (Na2SO4), filtered,
and concentrated in vacuo. Filtration of the residue over a short pad of
silica gel and evaporation of the solvent gave the pure tosylate 13 (1.27 g,
100%) as a colorless oil. Rf =0.55 (petroleum ether/diethyl ether, 1:1);
ꢀ
11), 3.43–3.49 (m, 1H; H-6), 3.77 (s, 3H; PMB CH3), 3.79 (s, 3H; Ph
OCH3), 3.79–3.85 (m, 1H; H-8), 3.87 (s, 3H; CO2CH3), 4.41 (s, 2H; PMB
CH2), 4.55 (d, J=6.8 Hz, 1H; MOM CH2), 4.60 (d, J=6.8 Hz, 1H; MOM
CH2), 5.41 (dt, J=15.2, 6.4 Hz, 1H; H-3), 5.51 (dt, J=15.2, 6.1 Hz, 1H;
H-2), 6.75 (d, J=8.3 Hz, 1H; H-3’), 6.80 (d, J=7.6 Hz, 1H; H-5’), 6.85
(d, J=8.5 Hz, 2H; PMB H-3,5), 7.24 (d, J=8.5 Hz, 2H; PMB H-2,6),
7.24–7.27 ppm (m, 1H; H-4’); 13C NMR (100 MHz, CDCl3): d=ꢀ4.6
1
[a]D =+1.6 (c=1.00, CH2Cl2); H NMR (400 MHz, CDCl3): d=0.01, 0.01
5654
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660

Salicylihalamide Total Synthesis
5649 – 5660
(Si(CH3)2), ꢀ4.4 (Si(CH3)2), 14.1 (CH3), 18.0 (SiC), 25.3 (C-10), 25.8
(C(CH3)3), 32.8 (C-9), 35.6 (C-4), 36.1 (C-1), 36.4 (C-5), 37.7 (C-7), 52.0
m/z (%): 361(2), 311 (2), 187 (5), 137 (12), 122 (13), 121 (100); HRMS
(ESI): calcd for C30H42NaO8 [M+Na]+: 553.27719; found: 553.27712.
ꢀ
(CO2CH3), 55.1 (PMB CH3), 55.6 (MOM CH3) 55.7 (Ph OCH3), 69.4 (C-
(3S,5R,6S)-14-Methoxy-3-{3-[(4-methoxybenzyl)oxy]propyl}-5-(methoxy-
methoxy)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-
one (19)
8), 70.2( C-11), 72.3 (PMB CH2), 78.3 (C-6), 95.6 (MOM CH2), 108.6 (C-
3’), 113.6 (PMB C-3,5), 121.5 (C-5’), 123.3 (C-1’), 129.1 (PMB C-2,6),
129.1 (C-2), 130.3 (C-4’), 130.6 (PMB C-1), 130.7 (C-3), 139.2( C-6’),
156.3 (C-2’), 159.0 (PMB C-4), 168.5 ppm (CO2CH3); IR (film): n˜ =1038,
1071, 1109, 1249, 1470, 1513, 1734, 2855, 2931, 2952 cmꢀ1; MS (EI): m/z
(%): 293 (2), 192 (5), 181 (10), 178 (10), 176 (10), 170 (17), 168 (12), 166
(16), 150 (16), 141 (17), 137 (47), 121 (100), 97 (14), 77 (8); HRMS (ESI):
calcd for C37H58NaO8Si [M+Na]+: 681.37932; found: 681.37870.
Method A (from the hydroxy acid 18): Polymer-bound PPh3 (1.6 mmol of
P per g of resin, 365 mg, 584 mmol) was added to a cooled (08C) solution
of hydroxy acid 18 (62mg, 117 mmol) in THF (5.9 mL). After being
shaken for 15 min at room temperature, the slurry was recooled to 08C
and treated dropwise with DEAD (ꢂ40% solution in toluene, 102 mL,
41 mg, 234 mmol). Over a period of 24 h with agitation, the reaction mix-
ture was allowed to warm to room temperature. The resin was filtered
off and washed thoroughly with THF. After evaporation of the solvent,
the residue was purified by flash chromatography to give the desired lac-
tone (E)-19 (43 mg, 72%) as a colorless oil. Rf =0.75 (petroleum ether/
ethyl acetate, 1:1).
Methyl 2-[(2E,5S,6R,8R)-8-hydroxy-11-[(4-methoxybenzyl)oxy]-6-(meth-
oxymethoxy)-5-methyl-2-undecenyl]-6-methoxybenzoate (17): TBAF (1m
in THF, 1.57 mL, 1.57 mmol) was added to a solution of TBDMS ether
16 (345 mg, 0.52mmol) in THF (5.2mL) at 0 8C. After being stirred for
2days, the solution was treated with saturated aqueous NaHCO 3 solution
(10 mL) and the mixture was extracted with Et2O (3”15 mL). The com-
bined extracts were dried (Na2SO4), filtered, and concentrated. Flash
chromatography of the residue gave the desired alcohol 17 (284 mg,
100%) as a colorless oil. Rf =0.53 (diethyl ether); [a]D =+19.5 (c=1.00,
CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.85 (d, J=6.3 Hz, 3H; CH3),
1.40–1.60 (m, 4H; H-7, H-9), 1.60–1.75 (m, 2H; H-10), 1.75–2.00 (m, 4H;
H-4a, H-5, H-4b), 3.27 (d, J=6.4 Hz, 2H; H-1), 3.37 (s, 3H; MOM CH3),
3.42–3.48 (m, 2H; H-11), 3.53 (d, J=1.7 Hz, 1H; OH), 3.65–3.74 (m, 2H;
Method B (by ring-closing metathesis from the diene 28): The second-gen-
eration Grubbs catalyst 29 (13.3 mg, 15.7 mmol) was added to a solution
of diene 28 (85.0 mg, 157 mmol) in toluene (160 mL) and the light-purple
solution was heated to 708C for 2h. After completion of the reaction
(checked by 1H NMR spectroscopy), ethoxyethylene (0.41 mL, 567 mg,
7.86 mmol) was added and the solution was allowed to cool to room tem-
perature. The solvent was removed in vacuo and the residue was purified
by flash chromatography. Both isomers, E macrolactone (E)-19 (61.0 mg,
75%) and Z derivative (Z)-19 (9.8 mg, 12%), could be isolated as slightly
yellow waxes.
Compound (E)-19: [a]D =ꢀ42.3 (c=1.25, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=0.85 (d, J=6.8 Hz, 3H; CH3), 1.41 (dd, J=15.5, 9.4 Hz, 1H;
H-14a), 1.62–1.78 (m, 5H; H-11a, H-16, H-14b, H-17a), 1.82–1.90 (m,
1H; H-17b), 2.06–2.16 (m, 1H; H-12), 2.28 (brd, J=14.2Hz, 1H; H-
11b), 3.31 (brd, J=16.6 Hz, 1H; H-8a), 3.43 (s, 3H; MOM CH3), 3.47 (t,
J=6.3 Hz, 2H; H-18), 3.70 (dd, J=16.6, 9.5 Hz, 1H; H-8b), 3.74 (s, 3H;
ꢀ
H-6, H-8), 3.77 (s, 3H; PMB CH3), 3.79 (s, 3H; Ph OCH3), 3.87 (s, 3H;
CO2CH3), 4.42(s, 2H; PMB C H2), 4.60 (d, J=6.8 Hz, 1H; MOM CH2),
4.69 (d, J=6.8 Hz, 1H; MOM CH2), 5.39 (dt, J=15.2, 6.5 Hz, 1H; H-3),
5.50 (dt, J=15.2, 6.4 Hz, 1H; H-2), 6.75 (d, J=8.4 Hz, 1H; H-3’), 6.79 (d,
J=7.7 Hz, 1H; H-5’), 6.85 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.24 (d, J=
8.6 Hz, 2H; PMB H-2,6), 7.26 ppm (dd, J=8.4, 7.7 Hz, 1H; H-4’);
13C NMR (100 MHz, CDCl3): d=13.5 (CH3), 25.7 (C-10), 34.3 (C-9), 35.5
(C-5), 35.9 (C-7), 36.0 (C-4), 36.3 (C-1), 52.0 (CO2CH3), 55.1 (PMB
ꢀ
CH3), 55.7 (Ph OCH3), 55.8 (MOM CH3), 70.0 (C-11), 70.8 (C-8), 72.4
(PMB CH2), 81.0 (C-6), 95.3 (MOM CH2), 108.7 (C-3’), 113.6 (PMB
C-3,5), 121.4 (C-5’), 123.2 (C-1’), 129.1 (PMB C-2,6), 129.4 (C-2), 130.2
(C-3), 130.3 (C-4’), 130.4 (PMB C-1), 139.1 (C-6’), 156.3 (C-2’), 159.0
(PMB C-4), 168.5 ppm (CO2CH3); IR (film): n˜ =1169, 1248, 1263, 1363,
1439, 1469, 1513, 1584, 1732, 2849, 2948, 3494 cmꢀ1; MS (EI): m/z (%):
359 (2), 311 (3), 243 (3), 199 (4), 190 (5), 187 (7), 137 (11), 122 (10), 121
(100); HRMS (ESI): calcd for C31H44NaO8 [M+Na]+: 567.29284; found:
567.29316.
ꢀ
PMB CH3), 3.79 (s, 3H; Ph OCH3), 4.10–4.15 (m, 1H; H-13), 4.42(s,
2H; PMB CH2), 4.78 (d, J=6.7 Hz, 1H; MOM CH2), 4.89 (d, J=6.7 Hz,
1H; MOM CH2), 5.26–5.38 (m, 2H; H-15, H-9), 5.42–5.52 (m, 1H; H-
10), 6.74 (d, J=7.7 Hz, 1H; H-6), 6.78 (d, J=8.4 Hz, 1H; H-4), 6.86 (d,
J=8.6 Hz, 2H; PMB H-3,5), 7.24 (d, J=8.6 Hz, 2H; PMB H-2,6), 7.18–
7.23 ppm (m, 1H; H-5); 13C NMR (100 MHz, CDCl3): d=13.3 (CH3),
25.6 (C-17), 32.8 (C-16), 34.1 (C-12), 35.7 (C-14), 37.7 (C-8), 37.8 (C-11),
ꢀ
55.3 (PMB CH3), 55.3 (Ph OCH3), 55.5 (MOM CH3), 69.7 (C-18), 72.5
2-[(2E,5S,6R,8R)-8-Hydroxy-11-[(4-methoxybenzyl)oxy]-6-(methoxyme-
thoxy)-5-methyl-2-undecenyl]-6-methoxybenzoic acid (18): A solution of
methyl ester 17 (352mg, 0.65 mmol) in a mixture of THF (4 mL), ethanol
(8 mL), and H2O (8 mL) was treated with LiOH·H2O (271 mg,
6.46 mmol) and stirred at 708C for 3 days. After being allowed to cool to
room temperature, the reaction mixture was diluted with Et2O (20 mL)
and water (50 mL). The organic layer containing unreacted starting mate-
rial and side products was washed with water (10 mL), dried (Na2SO4),
and concentrated separately. The combined aqueous layers were acidified
(pHꢂ3) by addition of 1n HCl at 08C and extracted with EtOAc (3”
30 mL). The combined extracts were washed with brine (10 mL), dried
(MgSO4), filtered, and concentrated to give the desired acid 18 (317 mg,
92%) as a light-yellow oil. Rf =0.52(petroleum ether/ethyl acetate, 1:3);
[a]D =+26.5 (c=0.75, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.84 (d,
J=6.3 Hz, 3H; CH3), 1.42–1.62 (m, 4H; H-9, H-7), 1.62–1.75 (m, 2H; H-
10), 1.78–1.99 (m, 4H; H-4a, H-5, H-4b), 3.31–3.57 (m, 2H; H-1), 3.41 (s,
3H; MOM CH3), 3.43–3.57 (m, 1H; OH), 3.45 (t, J=6.6 Hz, 2H; H-11),
(PMB CH2), 74.5 (C-15), 79.4 (C-13), 97.0 (MOM CH2), 109.1 (C-4),
113.7 (PMB C-3,5), 122.7 (C-6), 124.7 (C-2), 128.6 (C-9), 129.1 (PMB C-
2,6), 129.9 (C-5), 130.8 (PMB C-1), 131.3 (C-10), 138.9 (C-7), 156.5 (C-3),
159.1 (PMB C-4), 168.5 ppm (C-1); IR (film): n˜ =1040, 1096, 1249, 1275,
1468, 1513, 1583, 1721, 2851, 2927, 2952 cmꢀ1; MS (EI): m/z (%): 480
(12), 467 (9), 315 (10), 259 (4), 245 (6), 227 (7), 203 (11), 190 (20), 134
(12), 122 (17), 121 (100), 45 (23); HRMS (ESI): calcd for C30H40NaO7
[M+Na]+: 535.26662; found: 535.26633.
Compound (Z)-19 (minor product from ring-closing metathesis): Rf =0.48
(petroleum ether/ethyl acetate, 2:1); [a]D =ꢀ4.8 (c=1.00, CH2Cl2);
1H NMR (400 MHz, CDCl3): d=0.92(d, J=6.2Hz, 3H; C H3), 1.56 (dd,
J=15.4, 9.3 Hz, 1H; H-14a), 1.65–1.80 (m, 4H; H-17, H-16), 1.83–1.90
(m, 1H; H-11a), 1.87 (dd, J=15.4, 9.7 Hz, 1H; H-14b), 2.02–2.16 (m,
2H; H-12, H-11b), 3.01 (brd, J=15.6 Hz, 1H; H-8a), 3.39 (s, 3H; MOM
CH3), 3.41–3.48 (m, 2H; H-18), 3.77–3.81 (m, 1H; H-13), 3.79 (s, 3H;
ꢀ
PMB CH3), 3.80 (s, 3H; Ph OCH3), 3.96 (br dd, J=15.6, 8.4 Hz, 1H; H-
8b), 4.39 (s, 2H; PMB CH2), 4.72(d, J=6.7 Hz, 1H; MOM CH2), 4.78
(d, J=6.7 Hz, 1H; MOM CH2), 5.30–5.40 (m, 3H; H-9, H-10, H-15), 6.80
(d, J=7.5 Hz, 1H; H-4), 6.80 (d, J=8.5 Hz, 1H; H-6), 6.85 (d, J=8.6 Hz,
2H; PMB H-3,5), 7.22 (d, J=8.6 Hz, 2H; PMB H-2,6), 7.27 ppm (dd, J=
8.5, 7.5 Hz, 1H; H-5); 13C NMR (100 MHz, CDCl3): d=13.4 (CH3), 25.7
(C-17), 32.0 (C-11), 32.1 (C-16), 32.5 (C-8), 36.3 (C-14), 36.5 (C-12), 55.2
ꢀ
3.67–3.83 (m, 2H; H-8, H-6), 3.77 (s, 3H; PMB CH3), 3.81 (s, 3H; Ph
OCH3), 4.44 (s, 2H; PMB CH2), 4.61 (d, J=6.9 Hz, 1H; MOM CH2),
4.77 (d, J=6.9 Hz, 1H; MOM CH2), 5.36–5.54 (m, 2H; H-3, H-2), 6.77
(d, J=8.3 Hz, 1H; H-3’), 6.78 (d, J=7.4 Hz, 1H; H-5’), 6.85 (d, J=
8.5 Hz, 2H; PMB H-3,5), 6.97 (brs, 1H; CO2H), 7.24 (d, J=8.5 Hz, 2H;
PMB H-2,6), 7.24–7.28 ppm (m, 1H; H-4’); 13C NMR (100 MHz, CDCl3):
d=13.8 (CH3), 25.7 (C-10), 34.0 (C-9), 35.0 (C-7), 35.0 (C-5), 36.4 (C-4),
ꢀ
(PMB CH3), 55.5 (MOM CH3), 55.9 (Ph OCH3), 69.5 (C-18), 72.4 (PMB
CH2), 74.1 (C-15), 78.0 (C-13), 97.4 (MOM CH2), 109.4 (C-4), 113.7
(PMB C-3,5), 122.7 (C-6), 123.6 (C-2), 128.7 (C-9), 129.2 (PMB C-2,6),
129.3 (C-10), 130.7 (PMB C-1), 130.7 (C-5), 140.0 (C-7), 157.1 (C-3),
159.1 (PMB C-4), 167.1 ppm (C-1); IR (film): n˜ =1038, 1096, 1264, 1469,
1513, 1729, 2852, 2929, 2953, 3002 cmꢀ1; MS (EI): m/z (%): 480 (3), 467
(3), 331 (3), 314 (4), 227 (5), 203 (9), 190 (12), 163 (11), 148 (10), 122
ꢀ
36.9 (C-1), 55.2(PMB CH3), 55.7 (MOM CH3), 55.9 (Ph OCH3), 70.0
(C-11), 71.1 (C-8), 72.4 (PMB CH2), 79.4 (C-6), 94.4 (MOM CH2), 109.1
(C-3’), 113.7 (PMB C-3,5), 122.2 (C-5’), 122.9 (C-1’), 129.4 (PMB C-2,6),
129.6 (C-2), 129.8 (C-3), 130.2(PMB C-1), 130.6 (C-4’), 139.6 (C-6’),
156.6 (C-2’), 159.1 (PMB C-4), 169.5 ppm (CO2H); IR (film): n˜ =1035,
1083, 1249, 1265, 1470, 1513, 1584, 1725, 2840, 2937, 3431 cmꢀ1; MS (EI):
Chem. Eur. J. 2004, 10, 5649 – 5660
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5655

M. E. Maier et al.
FULL PAPER
(11), 121 (100), 91 (5), 45 (6); HRMS (FAB): calcd for C30H40NaO7
(PMB C-1), 135.1 (C-4’), 135.4 (Bn C-1), 153.2( C-2), 159.0 (PMB C-4),
173.4 ppm (C-1’); IR (film): n˜ =1031, 1099, 1249, 1383, 1513, 1612, 1698,
1781, 2855, 2929, 2955 cmꢀ1; MS (EI): m/z (%): 580 (3), 460 (9), 430 (4),
386 (3), 251 (4), 190 (4), 145 (6), 135 (11), 122 (24), 121 (100), 45 (6);
HRMS (ESI): calcd for C37H55NNaO8Si [M+Na]+: 692.35892; found:
692.35871.
[M+Na]+: 535.26716; found: 535.27231.
(4S)-4-Benzyl-3-((2S)-2-{(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-1-hy-
droxy-6-[(4-methoxybenzyl)oxy]hexyl}-4-pentenoyl)-1,3-oxazolidin-2-one
(21): Titanium(iv) chloride (0.89 mL, 1.53 g, 8.07 mmol) was added drop-
wise to a stirred, cooled (08C) solution of (4S)-4-benzyl-3-(4-pentenoyl)-
1,3-oxazolidin-2-one[27] (20) (1.99 g, 7.69 mmol) in CH2Cl2 (80 mL) and
the mixture was allowed to stir for 5 min. Subsequently, (ꢀ)-sparteine
(4.42mL, 4.51 g, 19.2mmol) was added to the yellow slurry. The dark-
red enolate solution was stirred for 20 min at 08C before a solution of al-
dehyde 8 (3.10 g, 8.46 mmol) in CH2Cl2 (45 mL) was added dropwise and
the mixture was stirred for 1 h at 08C. The reaction was quenched with
half-saturated aqueous NH4Cl solution (20 mL) and allowed to warm to
room temperature. After separation of the layers, the aqueous layer was
extracted with CH2Cl2 (2”30 mL) and the combined organic layers were
dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the
residue by flash chromatography afforded the desired product 21 (3.17 g,
68%) as a colorless viscous oil. Rf =0.60 (petroleum ether/diethyl ether,
2:3); [a]D =+29.9 (c=1.00, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
0.06, 0.08 (2”s, 3H each; Si(CH3)2), 0.87 (s, 9H; SiC(CH3)3), 1.51–1.71
(m, 6H; H-4’’, H-5’’, H-2’’), 2.40–2.50 (m, 1H; H-3’a), 2.56–2.65 (m, 2H;
H-3’b, Bn CH2), 3.23–3.32 (m, 2H; Bn CH2, OH), 3.36–3.48 (m, 2H; H-
6’’), 3.78 (s, 3H; PMB CH3), 3.91–3.98 (m, 1H; H-3’’), 4.00–4.06 (m, 1H;
H-1’’), 4.06–4.16 (m, 3H; H-2’, H-5), 4.41 (s, 2H; PMB CH2), 4.66 (dddd,
J=10.1, 5.6, 3.3, 3.3 Hz, 1H; H-4), 5.02(brd, J=10.1 Hz, 1H; H-5’a),
5.09 (brd, J=17.1 Hz, 1H; H-5’b), 5.85 (dddd, J=17.1, 10.1, 7.2, 7.2 Hz,
1H; H-4’), 6.86 (d, J=8.6 Hz, 2H; PMB H-3,5), 7.17–7.33 ppm (m, 7H;
Bn H-2,6, PMB H-2,6, Bn H-4, Bn H-3,5); 13C NMR (100 MHz, CDCl3):
d=ꢀ4.7 (Si(CH3)2), ꢀ4.2(Si( CH3)2), 17.9 (SiC), 24.9 (C-5’’), 25.8
(C(CH3)3), 32.0 (C-3’), 34.1 (C-4’’), 38.0 (Bn CH2), 40.3 (C-2’’), 47.6 (C-
2’), 55.3 (PMB CH3), 55.6 (C-4), 65.9 (C-5), 70.1 (C-6’’), 70.7 (C-1’’), 72.2
(C-3’’), 72.5 (PMB CH2), 113.7 (PMB C-3,5), 117.2( C-5’), 127.3 (Bn C-4),
128.9 (Bn C-3,5), 129.2 (PMB C-2,6), 129.4 (Bn C-2,6), 130.6 (PMB C-1),
135.3 (Bn C-1), 135.4 (C-4’), 153.3 (C-2), 159.1 (PMB C-4), 174.6 ppm
(C-1’); IR (film): n˜ =1036, 1100, 1207, 1250, 1386, 1513, 1612, 1697, 1781,
2856, 2929, 2953, 3482 cmꢀ1; MS (EI): m/z (%): 259 (6), 135 (7), 122 (17),
121 (100), 83 (18), 55 (8); HRMS (ESI): calcd for C35H51NNaO7Si
[M+Na]+: 648.33270; found: 648.33237.
(2R)-2-[(1R,3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)-
oxy]-1-(methoxymethoxy)hexyl]-4-penten-1-ol (23): A solution of sodium
borohydride (395 mg, 10.4 mmol) in water (10 mL) was added dropwise
to a cooled (08C) solution of amide 22 (1.40 g, 2.09 mmol) in THF
(20 mL). Stirring was continued for 12 h while the mixture was allowed
to warm to room temperature. The solution was treated with saturated
aqueous NH4Cl solution (20 mL), stirred for 1 h, and transferred into a
separation funnel. After extraction with ethyl acetate (3”20 mL), the
combined organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. Flash chromatography of the residue provided alcohol 23
(0.89 g, 86%) as a colorless oil. Rf =0.49 (petroleum ether/ethyl acetate,
2:1); [a]D =+6.2( c=1.50, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=
0.04, 0.05 (2”s, 3H; Si(CH3)2), 0.87 (s, 9H; SiC(CH3)3), 1.39–1.49 (m,
1H; H-4’a), 1.53–1.69 (m, 4H; H-4’b, H-5’, H-2’a), 1.75 (ddd, J=14.1, 8.1,
5.4 Hz, 1H; H-2’b), 1.89–2.07 (m, 3H; H-2, H-3), 2.69 (dd, J=7.0, 4.7 Hz,
1H; OH), 3.37 (s, 3H; MOM CH3), 3.42(t, J=6.4 Hz, 2H; H-6’), 3.60
(ddd, J=11.2, 7.0, 4.3 Hz, 1H; H-1a), 3.67 (ddd, J=11.2, 7.8, 4.7 Hz, 1H;
H-1b), 3.75–3.84 (m, 2H; H-3’, H-1’), 3.79 (s, 3H; PMB CH3), 4.41 (s,
2H; PMB CH2), 4.60 (d, J=6.7 Hz, 1H; MOM CH2), 4.63 (d, J=6.7 Hz,
1H; MOM CH2), 5.00 (brd, J=10.1 Hz, 1H; H-5a), 5.04 (brd, J=
17.1 Hz, 1H; H-5b), 5.76 (dddd, J=17.1, 10.1, 6.8, 6.8 Hz, 1H; H-4), 6.86
(d, J=8.6 Hz, 2H; PMB H-3,5), 7.24 ppm (d, J=8.6 Hz, 2H; PMB H-
2,6); 13C NMR (100 MHz, CDCl3): d=ꢀ4.4 (Si(CH3)2), ꢀ4.4 (Si(CH3)2),
18.0 (SiC), 25.4 (C-5’), 25.9 (C(CH3)3), 31.5 (C-3), 33.3 (C-4’), 38.2( C-2’),
42.6 (C-2), 55.3 (PMB CH3), 56.0 (MOM CH3), 63.5 (C-1), 69.2( C-3’),
70.2( C-6’), 72.5 (PMB CH2), 76.9 (C-1’), 96.1 (MOM CH2), 113.7 (PMB
C-3,5), 116.4 (C-5), 129.2 (PMB C-2,6), 130.7 (PMB C-1), 136.8 (C-4),
159.1 ppm (PMB C-4); IR (film): n˜ =1037, 1096, 1249, 1361, 1464, 1513,
1613, 2856, 2887, 2929, 2952, 3074, 3470 cmꢀ1; MS (EI): m/z (%): 460 (2),
430 (3), 241 (5), 135 (11), 122 (10), 121 (100), 91 (3), 45 (3); HRMS
(ESI): calcd for C27H48NaO6Si [M+Na]+: 519.31124; found: 519.31153.
(2R)-2-[(1R,3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)-
oxy]-1-(methoxymethoxy)hexyl]-4-pentenyl
4-methylbenzenesulfonate
(4S)-4-Benzyl-3-{(2S)-2-[(1R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-
methoxybenzyl)oxy]-1-(methoxymethoxy)hexyl]-4-pentenoyl}-1,3-oxazoli-
din-2-one (22): N,N-diisopropylethylamine (9.63 mL, 7.27 g, 56.2 mmol),
chloromethylmethyl ether (2.14 mL, 2.26 g, 28.1 mmol), and TBAI
(104 mg, 281 mmol) were added to a stirred, cooled (08C) solution of al-
cohol 21 (1.76 g, 2.81 mmol) in CH2Cl2 (28 mL). The reaction mixture
was protected from light and stirred for 3 days at room temperature. The
reaction was quenched with saturated aqueous NaHCO3 solution
(60 mL) and the mixture was diluted with Et2O (100 mL). After separa-
tion of the phases, the organic layer was washed with 1n HCl (30 mL)
and brine (20 mL), then the aqueous layer was extracted with Et2O (2 ”
50 mL). The combined extracts were dried (Na2SO4), filtered, and con-
centrated in vacuo. Flash chromatography of the residue provided MOM
ether 22 (1.54 g, 82%) as a slightly yellow viscous oil. Rf =0.52(petrole-
um ether/ethyl acetate, 3:1); [a]D =+72.3 (c=1.50, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.03, 0.04 (2”s, 3H each; Si(CH3)2), 0.87 (s, 9H;
SiC(CH3)3), 1.37–1.48 (m, 1H; H-4’’a), 1.55–1.67 (m, 2H; H-4’’b, H-5’’a),
1.67–1.82(m, 3H; H-5’’b, H-2’’), 2.32 (ddd, J=14.1, 5.3, 5.3 Hz, 1H; H-
3’a), 2.57 (ddd, J=14.1, 8.7, 8.7 Hz, 1H; H-3’b), 2.67 (dd, J=13.3,
10.0 Hz, 1H; Bn CH2), 3.27 (dd, J=13.3, 2.8 Hz, 1H; Bn CH2), 3.33 (s,
3H; MOM CH3), 3.43 (t, J=6.4 Hz, 2H; H-6’’), 3.77 (s, 3H; PMB CH3),
3.76–3.88 (m, 2H; H-3’’, H-1’’), 4.08–4.15 (m, 2H; H-5), 4.42(ddd, J=
14.3, 9.5, 4.6 Hz, 1H; H-2’), 4.42(s, 2H; PMB C H2), 4.50 (d, J=7.1 Hz,
1H; MOM CH2), 4.59–4.68 (m, 1H; H-4), 4.65 (d, J=7.1 Hz, 1H; MOM
CH2), 5.03 (brd, J=10.2Hz, 1H; H-5’a), 5.10 (brd, J=17.1 Hz, 1H; H-
5’b), 5.81 (dddd, J=17.1, 10.2, 6.9, 6.9 Hz, 1H; H-4’), 6.86 (d, J=8.6 Hz,
2H; PMB H-3,5), 7.18–7.34 ppm (m, 7H; Bn H-2,6, PMB H-2,6, Bn H-4,
Bn H-3,5); 13C NMR (100 MHz, CDCl3): d=ꢀ4.7 (Si(CH3)2), ꢀ4.4
(Si(CH3)2), 18.0 (SiC), 25.3 (C-5’’), 25.9 (C(CH3)3), 32.4 (C-4’’), 32.6 (C-
3’), 37.8 (Bn CH2), 40.2( C-2’’), 45.7 (C-2’), 55.2(PMB CH3), 55.9 (C-4),
56.1 (MOM CH3), 65.7 (C-5), 69.1 (C-1’’), 70.2( C-6’’), 72.3 (PMB CH2),
75.9 (C-3’’), 96.1 (MOM CH2), 113.6 (PMB C-3,5), 117.1 (C-5’), 127.2
(Bn C-4), 128.8 (Bn C-3,5), 129.1 (PMB C-2,6), 129.4 (Bn C-2,6), 130.7
(24): p-Toluenesulfonyl chloride (380 mg, 1.99 mmol) was added to a stir-
red solution of alcohol 23 (330 mg, 0.66 mmol) in pyridine (1.3 mL) at
08C. After being stirred for 12h at room temperature, the reaction was
quenched by addition of ice (0.2g) and water (3 mL). The mixture was
diluted with Et2O (15 mL) and washed with saturated aqueous NaHCO3
solution (3 mL), 1n HCl (3 mL), and brine (3 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. Purification of
the residue by flash chromatography gave the pure tosylate 24 (412mg,
95%) as a colorless oil. Rf =0.46 (petroleum ether/ethyl acetate, 3:1);
[a]D =+8.6 (c=1.50, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.02(s,
3H; Si(CH3)2a), 0.02(s, 3H; Si(C H3)2b), 0.86 (s, 9H; SiC(CH3)3), 1.35–
1.45 (m, 1H; H-4’a), 1.48–1.66 (m, 5H; H-4’b, H-2’, H-5’), 1.95–2.04 (m,
1H; H-2), 2.04–2.14 (m, 2H; H-3), 2.42 (s, 3H; Ts CH3), 3.25 (s, 3H;
MOM CH3), 3.41 (t, J=6.4 Hz, 2H; H-6’), 3.63–3.70 (m, 1H; H-1’), 3.70–
3.80 (m, 1H; H-3’), 3.78 (s, 3H; PMB CH3), 4.00 (dd, J=9.4, 5.5 Hz, 1H;
H-1a), 4.08 (dd, J=9.4, 5.9 Hz, 1H; H-1b), 4.41 (s, 2H; PMB CH2), 4.48
(d, J=7.0 Hz, 1H; MOM CH2a), 4.48 (d, J=7.0 Hz, 1H; MOM CH2b),
4.94–5.00 (m, 2H; H-5), 5.59–2.70 (m, 1H; H-4), 6.86 (d, J=8.6 Hz, 2H;
PMB H-3,5), 7.24 (d, J=8.6 Hz, 2H; PMB H-2,6), 7.31 (d, J=8.2Hz,
2H; Ts H-3,5), 7.31 ppm (d, J=8.2Hz, 2H; Ts H-2,6); 13C NMR
(100 MHz, CDCl3): d=ꢀ4.5 (Si(CH3)2), 17.9 (SiC), 21.5 (Ts CH3), 25.2
(C-5’), 25.8 (C(CH3)3), 30.8 (C-3), 33.1 (C-4’), 38.4 (C-2’), 41.0 (C-2), 55.1
(PMB CH3), 55.7 (MOM CH3), 69.0 (C-3’), 69.7 (C-1), 70.0 (C-6’), 72.4
(PMB CH2), 74.7 (C-1’) 96.2(MOM CH2), 113.6 (PMB C-3,5), 117.0 (C-
5), 127.8 (Ts C-2,6), 129.1 (PMB C-2,6), 129.7 (Ts C-3,5), 130.6 (PMB C-
1), 132.9 (Ts C-1), 135.6 (C-4), 144.6 (Ts C-4), 159.0 ppm (PMB C-4); IR
(film): n˜ =1037, 1097, 1178, 1249, 1364, 1513, 2855, 2929, 2952, 3070 cmꢀ1
MS (EI): m/z (%): 411 (2), 271 (3), 241 (10), 229 (46), 195 (5), 165 (8),
145 (14), 122 (14), 121 (100), 91 (13), 75 (12); HRMS (ESI): calcd for
C34H54NaO8SSi [M+Na]+: 673.32009; found: 673.32744.
;
(4R,6R,7S)-4-{[tert-Butyl(dimethyl)silyl]oxy}-1-[(4-methoxybenzyl)oxy]-
6-(methoxymethoxy)-7-methyl-9-decene (25): Lithium triethylborohy-
5656
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660

Salicylihalamide Total Synthesis
5649 – 5660
dride (1m solution in THF, 0.55 mL, 0.55 mmol) was added dropwise to a
cooled (08C) solution of tosylate 24 (100 mg, 154 mmol) in THF (1.5 mL).
Stirring was continued for 12h while the mixture was allowed to warm to
room temperature. After recooling to 08C, the reaction was quenched by
careful addition of THF and water (1:1, 1 mL). The solution was treated
with saturated aqueous NH4Cl solution (2mL) and allowed to warm to
room temperature within 1 h while being stirring. The slurry was extract-
ed with Et2O (3”10 mL) and the combined organic layers were dried
over Na2SO4. After removal of the solvent, the residue was purified by
flash chromatography to yield methyl compound 25 (70 mg, 95%) as a
colorless oil. Rf =0.62(petroleum ether/ethyl acetate, 3:1); [ a]D =+17.4
(c=1.29, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.04, 0.05 (2”s, 3H
each; Si(CH3)2), 0.86–0.89 (m, 3H; CH3), 0.88 (s, 9H; SiC(CH3)3), 1.38–
1.47 (m, 1H; H-3a), 1.52(ddd, J=14.1, 8.2, 3.6 Hz, 1H; H-5a), 1.57–1.75
(m, 4H; H-3b, H-2, H-5b), 1.79–1.91 (m, 2H; H-7, H-8a), 2.03–2.12 (m,
1H; H-8b), 3.35 (s, 3H; MOM CH3), 3.42(t, J=6.6 Hz, 2H; H-1), 3.48
(ddd, J=8.8, 3.4, 3.4 Hz, 1H; H-6), 3.79 (s, 3H; PMB CH3), 3.80–3.86
(m, 1H; H-4), 4.42(s, 2H; PMB C H2), 4.57 (d, J=6.9 Hz, 1H; MOM
CH2), 4.61 (d, J=6.9 Hz, 1H; MOM CH2), 4.98 (brd, J=10.1 Hz, 1H; H-
10a), 5.00 (brd, J=17.0 Hz, 1H; H-10b), 5.74 (dddd, J=17.0, 10.1, 6.9,
6.9 Hz, 1H; H-9), 6.86 (d, J=8.5 Hz, 2H; PMB H-3,5), 7.25 ppm (d, J=
8.5 Hz, 2H; PMB H-2,6); 13C NMR (100 MHz, CDCl3): d=ꢀ4.5
(Si(CH3)2), ꢀ4.4 (Si(CH3)2), 14.2( CH3), 18.0 (SiC), 25.4 (C-2), 25.9
(C(CH3)3), 32.9 (C-3), 35.9 (C-7), 37.1 (C-8), 37.7 (C-5), 55.2(PMB CH3),
55.7 (MOM CH3), 69.5 (C-4), 70.3 (C-1), 72.4 (PMB CH2), 78.2( C-6),
95.7 (MOM CH2), 113.7 (PMB C-3,5), 115.8 (C-10), 129.1 (PMB C-2,6),
130.7 (PMB C-1), 137.4 (C-9), 159.0 ppm (PMB C-4); IR (film): n˜ =1039,
1097, 1249, 1512, 2856, 2889, 2930, 2953 cmꢀ1; MS (EI): m/z (%): 271 (4),
241 (3), 203 (3), 122 (13), 121 (100); HRMS (ESI): calcd for
C27H48NaO5Si [M+Na]+: 503.31632; found: 503.31641.
4.73 (d, J=6.8 Hz, 1H; MOM CH2), 4.91 (brd, J=10.1 Hz, 1H; H-7’a),
4.96 (brd, J=17.1 Hz, 1H; H-7’b), 5.05 (brd, J=17.7 Hz, 1H; H-9a), 5.05
(brd, J=11.2Hz, 1H; H-9b), 5.31–5.38 (m, 1H; H-1’), 5.74 (dddd, J=
17.1, 10.1, 7.3 Hz, 1H; H-6’), 5.94 (dddd, J=17.7, 11.2, 6.5 Hz, 1H; H-8),
6.77 (brd, J=8.4 Hz, 1H; H-5), 6.82(brd, J=7.7 Hz, 1H; H-3), 6.87 (d,
J=8.6 Hz, 2H; PMB H-3,5), 7.26 (d, J=8.6 Hz, 2H; PMB H-2,6),
7.27 ppm (dd, J=8.4, 7.7 Hz, 1H; H-4); 13C NMR (100 MHz, CDCl3): d=
13.6 (CH3), 25.3 (C-2’’), 31.8 (C-1’’), 34.7 (C-2’), 36.5 (C-4’), 37.2( C-7),
ꢀ
37.6 (C-5’), 55.2(PMB CH3), 55.5 (Ph OCH3), 55.7 (MOM CH3), 69.8
(C-3’’), 72.4 (C-1’), 72.5 (PMB CH2), 78.3 (C-3’), 97.0 (MOM CH2), 108.7
(C-5), 113.7 (PMB C-3,5), 115.8 (C-7’), 116.3 (C-9), 121.5 (C-3), 124.2 (C-
1), 129.2 (PMB C-2,6), 130.1 (C-4), 130.7 (PMB C-1), 136.4 (C-8), 137.1
ꢀ
(C-6’), 138.1 (C-2), 156.2 (C-6), 159.1 (PMB C-4), 168.0 ppm (Ph CO2);
IR (film): n˜ =1038, 1100, 1247, 1266, 1469, 1513, 1585, 1724, 2843, 2932,
3075 cmꢀ1; MS (EI): m/z (%): 495 (4), 303 (3), 203 (11), 175 (45), 121
(100); HRMS (ESI): calcd for C32H44NaO7 [M+Na]+: 563.29792; found:
563.29916.
(3S,5R,6S)-5,14-Dihydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-
hexahydro-1H-2-benzoxacyclododecin-1-one (30): 9-I-9-BBN (1m so-
lution in n-hexane, 206 mL, 206 mmol) was added to a solution of macro-
lactone 19 (55.0 mg, 107 mmol) in CH2Cl2 (2.1 mL) quickly through a sy-
ringe. After 90 s, methanol (3 mL) was added and stirring was then con-
tinued for 1 h. The solvent was removed under reduced pressure and the
residue was treated again with methanol (3 mL). This process was repeat-
ed twice whereafter the crude product could be used in the next step
without further purification. For analytical purposes, purification was per-
formed by flash chromatography to yield triol 30 (18.7 mg, 52%) as a col-
orless viscous oil. Rf =0.40 (petroleum ether/ethyl acetate, 1:5); [a]D =+
13.8 (c=0.70, CH2Cl2); 1H NMR (400 MHz, CDCl3): d=0.91 (d, J=
6.8 Hz, 3H; CH3), 1.37 (dd, J=15.0, 8.7 Hz, 1H; H-14a), 1.63–1.87 (m,
7H; H-17, C-13-OH, C-18-OH, H-16, H-11a), 1.87–1.94 (m, 1H; H-12),
1.99 (dd, J=15.0, 10.8 Hz, 1H; H-14b), 2.29–2.38 (m, 1H; H-11b), 3.38
(brd, J=16.6 Hz, 1H; H-8a), 3.64 (dd, J=8.7, 3.1 Hz, 1H; H-13), 3.70
(td, J=6.1, 1.7 Hz, 2H; H-18), 3.75 (dd, J=16.6, 5.6 Hz, 1H; H-8b),
5.04–5.15 (m, 1H; H-10), 5.47 (brd, J=15.3 Hz, 1H; H-9), 5.55 (brdt, J=
10.8, 5.3 Hz, 1H; H-15), 6.69 (dd, J=7.4, 0.9 Hz, 1H; H-6), 6.88 (dd, J=
8.3, 0.9 Hz, 1H; H-4), 7.29 ppm (dd, J=8.3, 7.4 Hz, 1H; H-5); 13C NMR
(100 MHz, CDCl3): d=13.7 (CH3), 28.0 (C-17), 32.0 (C-16), 35.8 (C-14),
37.2( C-12), 38.4 (C-11), 39.1 (C-8), 62.4 (C-18), 70.6 (C-13), 74.8 (C-15),
116.7 (C-4), 123.3 (C-2), 123.5 (C-6), 126.6 (C-10), 132.8 (C-9), 133.9 (C-
5), 142.2 (C-7), 162.4 (C-3), 171.3 ppm (C-1); IR (film): n˜ =1019, 1065,
1120, 1294, 1345, 1465, 1588, 1695, 2874, 2926, 2955, 3320 cmꢀ1; MS (EI):
m/z (%): 334 (6), 317 (7), 316 (11), 298 (15), 246 (6), 239 (6), 231 (16),
213 (18), 196 (30), 181 (37), 173 (43), 172 (100), 147 (32), 115 (28), 97
(27), 71 (42), 43 (74); HRMS (EI): calcd for C19H26O5 [M]+: 334.1780;
found: 334.1811.
(4R,6R,7S)-1-[(4-Methoxybenzyl)oxy]-6-(methoxymethoxy)-7-methyl-9-
decen-4-ol (26): TBAF (1m in THF, 0.89 mL, 0.89 mmol) was added to a
solution of TBDMS ether 25 (142mg, 295 mmol) in THF (3 mL) at 08C.
After being stirred for 15 h, the solution was treated with saturated aque-
ous NaHCO3 solution (2mL) and the mixture was extracted with Et 2O
(3”5 mL). The combined extracts were dried (Na2SO4), filtered, and con-
centrated in vacuo. Flash chromatography of the residue gave the desired
alcohol 26 (107 mg, 99%) as a colorless oil. Rf =0.36 (petroleum ether/
ethyl acetate, 2:1); [a]D =+29.1 (c=1.16, CH2Cl2); 1H NMR (400 MHz,
CDCl3): d=0.89 (d, J=6.5 Hz, 3H; CH3), 1.47–1.64 (m, 4H; H-3, H-5),
1.67–1.78 (m, 2H; H-2), 1.83–1.97 (m, 2H; H-8a, H-7), 1.99–2.06 (m, 1H;
H-8b), 3.40 (s, 3H; MOM CH3), 3.48 (td, J=6.2, 2.3 Hz, 2H; H-1), 3.53
(brs, 1H; OH), 3.72(ddd, J=9.6, 3.6, 3.6 Hz, 1H; H-6), 3.74–3.79 (m,
1H; H-4), 3.80 (s, 3H; PMB CH3), 4.44 (s, 2H; PMB CH2), 4.63 (d, J=
6.8 Hz, 1H; MOM CH2), 4.72(d, J=6.8 Hz, 1H; MOM CH2), 5.00 (brd,
J=10.4 Hz, 1H; H-10a), 5.01 (brd, J=17.0 Hz, 1H; H-10b), 5.75 (dddd,
J=17.0, 10.4, 6.8, 6.8 Hz, 1H; H-9), 6.87 (d, J=8.6 Hz, 2H; PMB H-3,5),
7.26 ppm (d, J=8.6 Hz, 2H; PMB H-2,6); 13C NMR (100 MHz, CDCl3):
d=13.5 (CH3), 25.8 (C-2), 34.4 (C-3), 35.2( C-7), 36.0 (C-5), 37.5 (C-8),
55.1 (PMB CH3), 55.9 (MOM CH3), 70.1 (C-1), 70.8 (C-4), 72.5 (PMB
CH2), 81.0 (C-6), 95.3 (MOM CH2), 113.6 (PMB C-3,5), 116.0 (C-10),
129.2 (PMB C-2,6), 130.4 (PMB C-1), 136.9 (C-9), 159.0 ppm (PMB C-4);
(3S,5R,6S)-5,14-Bis{[tert-butyl(dimethyl)silyl]oxy}-3-(3-{[tert-butyl(dime-
thyl)silyl]oxy}propyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacy-
clododecin-1-one (31): TBDMSCl (298 mg, 1.97 mmol) was added to a
stirred solution of crude triol 30, imidazole (168 mg, 2.47 mmol), and
DMAP (12.1 mg, 98.7 mmol) in dry DMF (2.2 mL). The resulting solution
was stirred at ambient temperature for 4 d, then diluted with H2O (5 mL)
and extracted with Et2O (3”10 mL). The combined extracts were washed
with 0.1n HCl (10 mL) and brine (10 mL), dried (Na2SO4), filtered, and
concentrated in vacuo. The resulting residue was purified by flash chro-
matography to give the desired ether 31 (40.1 mg, 60% from macrolac-
tone 19) as a colorless viscous oil. Rf =0.45 (petroleum ether/diethyl
ether, 20:1); [a]D =+8.7 (c=0.53, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d=0.03 (s, 6H; Si(CH3)2), 0.11 (s, 3H; Si(CH3)2), 0.15 (s, 3H; Si(CH3)2),
0.16 (s, 3H; Si(CH3)2), 0.22 (s, 3H; Si(CH3)2), 0.83 (d, J=6.6 Hz, 3H;
CH3), 0.88 (s, 9H; SiC(CH3)3), 0.91 (s, 9H; SiC(CH3)3), 0.96 (s, 9H;
SiC(CH3)3), 1.40 (dd, J=15.1, 8.9 Hz, 1H; H-14a), 1.56–1.62(m, 2H; H-
17), 1.62–1.74 (m, 4H; H-14b, H-16, H-11a), 1.76–1.84 (m, 1H; H-12),
2.25 (brd, J=12.3 Hz, 1H; H-11b), 3.31 (brd, J=16.3 Hz, 1H; H-8a),
3.55–3.69 (m, 2H; H-18), 3.66 (dd, J=16.3, 9.1 Hz, 1H; H-8b), 4.27 (dd,
J=8.9, 3.0 Hz, 1H; H-13), 5.12–5.19 (m, 1H; H-15), 5.30–5.46 (m, 2H;
H-9, H-10), 6.70 (d, J=8.3 Hz, 1H; H-4), 6.72(d, J=7.7 Hz, 1H; H-6),
7.09 ppm (dd, J=8.3, 7.7 Hz, 1H; H-5); 13C NMR (100 MHz, CDCl3): d=
ꢀ5.3 (Si(CH3)2), ꢀ4.5 (Si(CH3)2), ꢀ4.4 (Si(CH3)2), ꢀ4.4 (Si(CH3)2), ꢀ4.2
(Si(CH3)2), 13.1 (CH3), 18.0 (SiC), 18.3 (SiC), 18.4 (SiC), 25.7 (C(CH3)3),
25.9 (C(CH3)3), 26.0 (SiC(CH3)3), 28.9 (C-17), 32.3 (C-16), 36.5 (C-14),
IR (film): n˜ =1037, 1096, 1248, 1513, 1613, 2860, 2934, 3075, 3463 cmꢀ1
;
MS (EI): m/z (%): 203 (3), 185 (4), 137 (44), 122 (12), 121 (100), 84 (21),
49 (15); HRMS (ESI): calcd for C21H34NaO5 [M+Na]+: 389.22985;
found: 389.22996.
(1S,3R,4S)-1-{3-[(4-Methoxybenzyl)oxy]propyl}-3-(methoxymethoxy)-4-
methyl-6-heptenyl 2-allyl-6-methoxybenzoate (28): A solution of acid[11g]
27 (246 mg, 1.28 mmol) and DIAD (129 mL, 132mg, 654 mmol) in toluene
(3 mL) was added dropwise to a solution of alcohol 26 (94 mg, 256 mmol)
and triphenylphosphine (168 mg, 641 mmol) in toluene (3 mL). After the
mixture was stirred for 3 h at room temperature, the solvent was re-
moved and the residue was purified by flash chromatography. Ester 28
(98 mg, 71%) was isolated as a pale-yellow oil. Rf =0.62(petroleum
ether/ethyl acetate, 2:1); [a]D =+2.3 (c=1.03, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.90 (d, J=6.7 Hz, 3H; CH3), 1.63–1.70 (m, 2H;
H-2’), 1.71–1.86 (m, 5H; H-2’’, H-1’’, H-5’a), 1.88–1.98 (m, 1H; H-4’),
2.06 (brdd, J=13.4, 6.1 Hz, 1H; H-5’b), 3.37 (brd, J=6.5 Hz, 2H; H-7),
3.40 (s, 3H; MOM CH3), 3.48 (brt, J=6.2Hz, 2H; H-3’’), 3.70 (ddd, J=
ꢀ
9.0, 3.3, 3.3 Hz, 1H; H-3’’), 3.80 (s, 3H; PMB CH3), 3.80 (s, 3H; Ph
OCH3), 4.44 (s, 2H; PMB CH2), 4.70 (d, J=6.8 Hz, 1H; MOM CH2),
Chem. Eur. J. 2004, 10, 5649 – 5660
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5657

M. E. Maier et al.
FULL PAPER
37.1 (C-12), 38.0 (C-11), 38.2( C-8), 63.1 (C-18), 72.0 (C-13), 74.9 (C-15),
118.0 (C-4), 123.2 (C-6), 127.8 (C-2), 128.2 (C-9), 129.3 (C-5), 131.3 (C-
10), 138.6 (C-7), 152.7 (C-3), 168.4 ppm (C-1); IR (film): n˜ =1067, 1098,
1254, 1278, 1456, 1585, 1723, 2857, 2898, 2929, 2955 cmꢀ1; MS (EI): m/z
(%): 619 (22), 602 (7), 527 (6), 487 (24), 419 (42), 395 (11), 355 (18), 337
(20), 299 (23), 247 (22), 203 (25), 149 (59), 147 (100), 133 (74), 109 (67),
75 (80), 73 (97); HRMS (EI): calcd for C33H59O5Si3 [MꢀtBu]+:
619.36701; found: 619.36946; HRMS (FAB): calcd for C37H68O5NaSi3
[M+Na]+: 699.42723; found: 699.42184.
Bis[tert-butyl(dimethyl)silyl]-salicylihalamide-hemiaminal (35): DIBAL
(1.0m in hexane, 0.149 mL) was added dropwise to a well-stirred solution
of (2Z,4Z)-hepta-2,4-dienamide (34) (15.1 mg, 0.121 mmol) in dry THF
(1.0 mL) at 08C. After the mixture had been stirred for 30 min at 08C, a
solution of aldehyde 33 (32.9 mg, 0.0587 mmol) in dry THF (0.25 mL)
was added. The resulting solution was stirred overnight at 08C, before it
was diluted with ethyl acetate (5 mL) and quenched with buffer (pH 7,
5 mL) at 08C. After separation of the layers, the aqueous layer was ex-
tracted with ethyl acetate (4”3 mL). The combined organic layers were
washed with brine (1 mL), dried over MgSO4, filtered, and concentrated
in vacuo. Purification of the residue by flash chromatography (petroleum
ether/ethyl acetate, 4:1) gave unreacted aldehyde 33 (10.5 mg, 32%) and
35 (24.5 mg, 61%) as a mixture of diastereomers (approximately 1:1) as a
colorless oil. Rf =0.41 (petroleum ether/ethyl acetate, 4:1); 1H NMR
(400 MHz, C6D6): d=0.11, 0.12(2”s, 3H; SiC H3), 0.19 (2peaks, s, 2”
1.5H; SiCH3), 0.30 (s, 1.5H; SiCH3), 0.31 (s, 1.5H; SiCH3), 0.50 (s, 3H;
SiCH3), 0.79 (2peaks, t, J=7.6 Hz, 3H; H-25), 0.90 (d, J=6.3 Hz, 1.5H;
CH3), 0.91 (d, J=6.3 Hz, 1.5H; CH3), 1.02(p2eaks, s, ”24.5H;
C(CH3)3), 1.11 (s, 9H; C(CH3)3), 1.41–1.50 (m, 1H; H-14a), 1.58–1.85 (m,
7H; H-11a, H-16, H-17, H-14b, H-12), 1.99 (dq, J=8.6, 7.6 Hz, 2H; H-
24), 2.09–2.16 (m, 1H; H-11b), 3.22 (dd, J=16.3, 3.8 Hz, 1H; H-8a), 3.22
(dd, J=16.3, 8.1 Hz, 1H; H-8b), 3.85 (brs, 0.5H; OH), 3.97 (brs, 0.5H;
OH), 4.49–4.53 (m, 1H; H-15), 5.12(d, J=11.5 Hz, 1H; H-20), 5.36–5.41
(m, 2H; H-10, H-9), 5.43–5.51 (m, 2H; H-18, H-13), 5.51–5.59 (brm, 1H;
NH), 5.61–5.67 (m, 1H; H-23), 6.57 (d, J=7.6 Hz, 1H; H-6), 6.62(dd,
J=11.9, 11.5 Hz, 1H; H-21), 6.71 (d, J=7.9 Hz, 0.5H; H-4), 6.72(d, J=
7.9 Hz, 0.5H; H-4), 6.95 (dd, J=7.9, 7.6 Hz, 1H; H-5), 7.85–7.93 ppm (m,
1H; H-22); 13C NMR (100 MHz, C6D6): d=ꢀ4.4 (2peaks, Si CH3), ꢀ4.2
(3 peaks, SiCH3), ꢀ4.1 (SiCH3), ꢀ3.9 (SiCH3), ꢀ3.8 (SiCH3), 13.3 (CH3),
14.0 (C-25), 18.4 (2 peaks, SiC), 18.6 (2peaks, Si C), 20.8 (C-24), 26.0
(2peaks, C( CH3)3), 26.3 (2 peaks, C(CH3)3), 31.1 (C-17), 31.5 (C-16), 31.7
(C-16), 36.9 (C-14), 37.5 (C-12), 37.6 (C-12), 38.2 (C-11), 38.6 (2peaks,
C-8), 72.4 (C-15), 74.2(2peaks, C-13), 74.6 (C-18), 74.9 (C-18), 118.5 (C-
4), 118.6 (C-4), 120.1 (C-20), 123.6 (C-6), 124.8 (C-22), 128.7 (C-9), 128.8
(C-9), 128.9 (C-2), 129.5 (C-5), 131.5 (C-10), 136.3 (C-21), 136.4 (C-21),
138.9 (C-7), 141.4 (C-23), 153.3 (2 peaks, C-3), 166.9 (C-19), 168.4 ppm
(C-1); IR (film): n˜ =1006, 1029, 1067, 1117, 1225, 1265, 1361, 1381, 1457,
1501, 1581, 1593, 1628, 1663, 1724, 2857, 2897, 2930, 2956, 3317,
3421 cmꢀ1; HRMS (ESI): calcd for C38H63NNaO6Si2 [M+Na]+: 708.40861;
found: 708.40864.
(3S,5R,6S)-5,14-Bis{[tert-butyl(dimethyl)silyl]oxy}-3-(3-hydroxypropyl)-6-
methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one (32):
A
cooled (08C) solution of silyl ether 31 (50.0 mg, 73.8 mmol) in CH2Cl2
(3.0 mL) and methanol (1.0 mL) was treated with CSA (0.03m solution in
methanol, 492 mL, 14.8 mmol) with stirring. The resulting mixture was stir-
red for 1.5 h before the reaction was quenched by addition of saturated
aqueous NaHCO3 solution (5.0 mL). The slurry was extracted with Et2O
(3”10 mL) and the combined organic layers were dried (Na2SO4), fil-
tered, and concentrated in vacuo. Flash chromatography of the residue
provided recovered starting material 31 (4.9 mg, 10%) and primary alco-
hol 32 (35.2mg, 85%) as a colorless viscous oil. Rf =0.57 (petroleum
ether/ethyl acetate, 4:1); [a]D =+13.5 (c=1.00, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d=0.11 (s, 3H; Si(CH3)2), 0.15 (s, 3H; Si(CH3)2),
0.16 (s, 3H; Si(CH3)2), 0.21 (s, 3H; Si(CH3)2), 0.83 (d, J=6.7 Hz, 3H;
CH3), 0.91 (s, 9H; SiC(CH3)3), 0.95 (s, 9H; SiC(CH3)3), 1.39 (dd, J=15.2,
9.0 Hz, 1H; H-14a), 1.46 (brs, 1H; OH), 1.62–1.75 (m, 6H; H-17 H-14b,
H-11a, H-16), 1.75–1.85 (m, 1H; H-12), 2.25 (brd, J=12.9 Hz, 1H; H-
11b), 3.31 (brd, J=16.5 Hz, 1H; H-8a), 3.60–3.69 (m, 2H; H-18), 3.65
(dd, J=16.5, 9.2Hz, 1H; H-8b), 4.27 (dd, J=9.0, 3.4 Hz, 1H; H-13),
5.17–5.23 (m, 1H; H-15), 5.32(brdd, J=15.2, 9.2 Hz, 1H; H-9), 5.41
(brdd, J=15.2, 10.2 Hz, 1H; H-10), 6.71 (d, J=8.4 Hz, 1H; H-4), 6.73 (d,
J=7.9, 1H; H-6), 7.10 ppm (dd, J=8.4, 7.9 Hz, 1H; H-5); 13C NMR
(100 MHz, CDCl3): d=ꢀ4.6 (Si(CH3)2), ꢀ4.4 (Si(CH3)2), ꢀ4.4
(Si(CH3)2), ꢀ4.3 (Si(CH3)2), 13.0 (CH3), 18.0 (SiC), 18.3 (SiC), 25.7
(C(CH3)3), 25.9 (C(CH3)3), 28.4 (C-17), 32.0 (C-16), 36.3 (C-14), 37.0 (C-
12), 38.0 (C-11), 38.2( C-8), 62.7 (C-18), 72.0 (C-13), 74.6 (C-15), 118.1
(C-4), 123.3 (C-6), 127.8 (C-2), 128.3 (C-9), 129.4 (C-5), 131.3 (C-10),
138.6 (C-7), 152.6 (C-3), 168.3 ppm (C-1); MS (EI): m/z (%): 505 (38),
487 (60), 419 (19), 373 (53), 355 (98), 299 (37), 247 (58), 203 (56), 151
(54), 133 (73), 85 (38), 75 (81), 73 (100); IR (film): n˜ =1026, 1066, 1116,
1254, 1281, 1457, 1581, 1724, 2857, 2894, 2929, 2954, 3430 cmꢀ1; HRMS
(EI): calcd for C27H45O5Si2 [MꢀtBu]+: 505.28054; found: 505.28262;
HRMS (FAB): calcd for C31H54O5NaSi2 [M+Na]+: 585.354075; found:
585.34224.
Bis[tert-butyl(dimethyl)silyl]-salicylihalamide
(36):
Dry
pyridine
(0.085 mL, 1.05 mmol) and dry acetic anhydride (0.050 mL, 0.525 mmol)
were added to a stirred solution of hemiaminal 35 (24 mg, 0.035 mmol) in
dry THF (1.0 mL). The resulting mixture was stirred for 24 h at room
temperature and was then heated to reflux for 48 h. After the solution
had cooled to room temperature, it was treated with buffer (pH 7,
2.5 mL), the phases were separated, and the aqueous layer was extracted
with diethyl ether (4”1.5 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 solution (1.5 mL) and buffer
(pH 7, 1.5 mL), dried over MgSO4, filtered, and concentrated in vacuo.
Purification of the residue by rapid flash chromatography (petroleum
ether/ethyl acetate, 30:1, containing 0.2% of NEt3) gave cis-di-TBDMS-
salicylihalamide (Z)-36 (3.3 mg, 14%) and trans-di-TBDMS-salicylihal-
amide (E)-36 (10.5 mg, 45%), both as colorless oils.
3-((3S,5R,6S)-5,14-Bis{[tert-butyl(dimethyl)silyl]oxy}-6-methyl-1-oxo-
3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-3-yl)propanal (33):
A
cooled (08C) solution of primary alcohol 32 (26.5 mg, 47.0 mmol) in
CH2Cl2 (4.0 mL) was treated with NMO (8.0 mg, 68.3 mmol), molecular
sieves (4) Š, 20 mg), and TPAP (2.1 mg, 5.9 mmol) in turn. The resulting
slurry was stirred 1 h at 08C and filtered over a short pad of silica gel
(petroleum ether/ethyl acetate, 2:1) to yield aldehyde 33 (24.0 mg, 91%)
as a pale-yellow oil. Rf =0.75 (petroleum ether/ethyl acetate, 5:1); [a]D =
+12.0 (c=1.00, CH2Cl2); 1H NMR (400 MHz, C6D6): d=0.06, 0.16, 0.28,
0.46 (4”s, 3H each; Si(CH3)2), 0.87 (d, J=6.8 Hz, 3H; CH3), 0.98 (s, 9H;
SiC(CH3)3), 1.10 (s, 9H; SiC(CH3)3), 1.27 (dd, J=15.0, 9.0 Hz, 1H; H-
14a), 1.57–1.65 (m, 1H; H-11a), 1.60 (dd, J=15.0, 8.6 Hz, 1H; H-14b),
1.72–1.81 (m, 1H; H-12), 1.82–1.99 (m, 2H; H-16), 2.11 (brdt, J=14.3,
4.6 Hz, 1H; H-11b), 2.14–2.24 (m, 2H; H-17), 3.20 (dd, J=16.2, 4.0 Hz,
1H; H-8a), 3.68 (brdd, J=16.2, 8.3 Hz, 1H; H-8b), 4.45 (dd, J=8.8,
3.5 Hz, 1H; H-13), 5.32–5.42 (m, 3H; H-10, H-9, H-15), 6.56 (d, J=
7.6 Hz, 1H; H-6), 6.68 (brd, J=8.2, 1H; H-4), 6.90 (dd, J=8.2, 7.6 Hz,
1H; H-5), 9.39 ppm (brs, 1H; H-18); 13C NMR (100 MHz, C6D6): d=
ꢀ4.4 (Si(CH3)2), ꢀ4.3 (Si(CH3)2), ꢀ4.1 (Si(CH3)2), ꢀ4.0 (Si(CH3)2), 13.2
(CH3), 18.3 (SiC), 18.6 (SiC), 25.9 (C(CH3)3), 26.2 (C(CH3)3), 28.5 (C-16),
36.8 (C-14), 37.4 (C-12), 38.2 (C-11), 38.6 (C-18), 39.8 (C-17), 72.3 (C-
13), 73.4 (C-15), 118.6 (C-4), 123.7 (C-6), 128.8 (C-2), 128.8 (C-9), 129.5
(C-5), 131.4 (C-10), 138.9 (C-7), 153.3 (C-3), 168.3 (C-1), 199.4 ppm (C-
18); IR (film): n˜ =1022, 1066, 1115, 1254, 1457, 1581, 1726, 2713, 2857,
2892, 2929 cmꢀ1; MS (FAB): m/z (%): 737 (8), 683 (22), 624 (5), 584 (8),
561 (9), 543 (17), 504 (24), 411 (30), 353 (21), 287 (35), 203 (49), 136
(100); HRMS (EI): calcd for C27H43O5Si2 [MꢀtBu]+: 503.26489; found:
503.26671.
Compound (Z)-36 (minor product): Rf =0.28 (petroleum ether/ethyl ace-
tate, 20:1, with 0.2% NEt3); [a]D =ꢀ64.9 (c=0.37, CH2Cl2); 1H NMR
(400 MHz, C6D6): d=0.10, 0.15, 0.28, 0.44 (4”s, 3H each; SiCH3), 0.79 (t,
J=7.6 Hz, 3H; H-25), 0.88 (d, J=6.8 Hz, 3H; CH3), 0.97 (s, 9H;
C(CH3)3), 1.11 (s, 9H; C(CH3)3), 1.38–1.47 (m, 1H; H-14a), 1.53–1.63 (m,
1H; H-11a), 1.71–1.77 (m, 1H; H-12), 1.75–1.82 (m, 1H; H-14b), 2.02
(dq, J=8.6, 7.6 Hz, 2H; H-24), 2.03–2.07 (m, 1H; H-11b), 2.11–2.20 (m,
1H; H-16a), 2.50–2.57 (m, 1H; H-16b), 3.14 (d, J=16.4 Hz, 1H; H-8a),
3.62(dd, J=16.4, 7.1 Hz, 1H; H-8b), 4.44–4.47 (m, 1H; H-15), 4.65 (ddd,
J=8.6, 8.3, 8.3 Hz, 1H; H-17), 5.19–5.26 (m, 1H; H-9), 5.27–5.36 (m, 1H;
H-10), 5.47 (d, J=11.4 Hz, 1H; H-20), 5.56–5.63 (m, 1H; H-15), 5.57–
5.64 (m, 1H; H-23), 6.53 (d, J=7.6 Hz, 1H; H-6), 6.75 (d, J=7.9 Hz, 1H;
H-4), 6.76 (dd, J=11.9, 11.4 Hz, 1H; H-21), 6.91 (dd, J=7.9, 7.8 Hz, 1H;
H-5), 7.32–7.37 (m, 1H; H-18), 7.81–7.88 (brm, 1H; NH), 8.03 ppm (dd,
J=11.6, 11.4 Hz, 1H; H-22); 13C NMR (100 MHz, C6D6): d=ꢀ4.4
(2peaks, Si CH3), ꢀ4.1 (SiCH3), ꢀ4.0 (SiCH3), 13.2( CH3), 14.0 (C-25),
18.4 (SiC), 18.5 (SiC), 20.8 (C-24), 25.8 (C(CH3)3), 26.2 (C(CH3)3), 32.7
5658
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660

Salicylihalamide Total Synthesis
5649 – 5660
(C-16), 37.6 (C-14), 38.0 (C-12), 38.5 (C-11), 38.7 (C-8), 72.4 (C-13), 75.0
(C-15), 103.6 (C-17), 118.7 (C-4), 120.0 (C-20), 124.3 (C-6), 125.2 (C-22),
125.8 (C-18), 127.9 (C-9), 128.8 (C-2), 129.7 (C-5), 131.9 (C-10), 136.8 (C-
21), 139.5 (C-7), 141.3 (C-23), 152.7 (C-3), 163.0 (C-19), 168.1 ppm (C-1);
IR (film): n˜ =1022, 1066, 1113, 1199, 1260, 1381, 1456, 1485, 1593, 1657,
1727, 2856, 2928, 2958, 3394 cmꢀ1; HRMS (ESI): calcd for C38H61NNaO5-
Si2 [M+Na]+: 690.39805; found: 690.39870.
H-9), 5.14–5.18 (m, 1H; H-10), 5.18–5.25 (m, 1H; H-15), 5.48 (d, J=
11.3 Hz, 1H; H-20), 5.63 (brdt, J=10.8, 7.7 Hz, 1H; H-23), 6.46 (dd, J=
7.6, 3.1 Hz, 1H; H-6), 6.63 (brt, J=11.6 Hz, 1H; H-21), 6.95–6.98 (m,
2H; H-4, H-18), 7.31 (t, J=10.0 Hz, 1H; H-5), 7.63 (brd, J=9.6 Hz, 1H;
NH), 7.96 (brt, J=11.3 Hz, 1H; H-22), 11.66 ppm (brs, 1H; OH);
13C NMR (100 MHz, C6D6): d=13.8 (C-26), 14.0 (C-25), 20.8 (C-24), 31.4
(C-16), 36.1 (C-14), 38.0 (C-12), 38.4 (C-11), 39.4 (C-8), 70.9 (C-13), 76.1
(C-15), 103.2( C-17), 117.2( C-4), 119.5 (C-20), 123.7 (C-6), 124.9 (C-22),
125.4 (C-5), 126.8 (C-9), 132.8 (C-10), 134.7 (C-18), 137.4 (C-21), 141.9
(C-23), 163.0 (C-19), 172.1 ppm (C-1); IR (film): n˜ =1033, 1063, 1117,
1213, 1293, 1364, 1464, 1505, 1589, 1651, 1701, 2852, 2870, 2927, 2962,
3357 cm; HRMS (ESI): calcd for C26H33NNaO5 [M+Na]+: 462.22509;
found: 462.22524.
Compound (E)-36 (main product): Rf =0.19 (petroleum ether/ethyl ace-
tate, 20:1, with 0.2% NEt3); [a]D =ꢀ11.0 (c=1.23, CH2Cl2); 1H NMR
(400 MHz, C6D6): d=0.12, 0.17, 0.31, 0.51 (4”s, 3H each; SiCH3), 0.77 (t,
J=7.6 Hz, 3H; H-25), 0.88 (d, J=6.8 Hz, 3H; CH3), 1.04 (s, 9H;
C(CH3)3), 1.11 (s, 9H; C(CH3)3), 1.56 (ddd, J=15.1, 8.9, 8.8 Hz, 1H; H-
14a), 1.63–1.68 (m, 1H; H-11a), 1.70 (ddd, J=15.1, 8.9, 8.8 Hz, 1H; H-
14a), 1.75–1.83 (m, 1H; H-12), 1.97 (dq, J=8.8, 7.6 Hz, 2H; H-24), 2.08–
2.15 (m, 1H; H-11b), 2.41–2.53 (m, 2H; H-16), 3.22 (dd, J=16.4, 4.0 Hz,
1H; H-8a), 3.72(dd, J=16.4, 8.6 Hz, 1H; H-8b), 4.50–4.53 (m, 1H; H-
13), 4.94 (ddd, J=14.2, 7.6, 7.1 Hz, 1H; H-17), 5.00 (d, J=11.4 Hz, 1H;
H-20), 5.34–5.39 (m, 1H; H-10), 5.38–5.43 (m, 1H; H-9), 5.48–5.55 (m,
1H; H-15), 5.57–5.64 (m, 1H; H-23), 6.16 (brd, J=10.8 Hz, 1H; NH),
6.58 (d, J=7.9 Hz, 1H; H-6), 6.59 (dd, J=11.9, 11.4 Hz, 1H; H-21), 6.72
(d, J=8.1 Hz, 1H; H-4), 6.91 (dd, J=8.1, 7.9 Hz, 1H; H-5), 7.21 (dd, J=
14.2, 10.8 Hz, 1H; H-18), 7.94 ppm (dd, J=11.6, 11.4 Hz, 1H; H-22);
13C NMR (100 MHz, C6D6): d=ꢀ4.4 (SiCH3), ꢀ4.3 (SiCH3), ꢀ4.1
(SiCH3), ꢀ3.9 (SiCH3), 13.2( CH3), 14.0 (C-25), 18.4 (SiC), 18.5 (SiC),
20.8 (C-24), 25.9 (C(CH3)3), 26.3 (C(CH3)3), 36.2( C-14), 36.6 (C-16), 37.7
(C-12), 38.2 (C-11), 38.5 (C-8), 67.8 (C-13), 72.4 (C-15), 106.4 (C-17),
118.3 (C-4), 119.7 (C-20), 123.6 (C-6), 125.0 (C-22), 125.9 (C-18), 128.8
(C-9), 129.0 (C-2), 129.5 (C-5), 131.5 (C-10), 136.7 (C-21), 139.0 (C-7),
141.4 (C-23), 153.3 (C-3), 162.3 (C-19), 168.2ppm ( C-1); IR (film): n˜ =
1035, 1066, 1117, 1216, 1265, 1282, 1361, 1458, 1520, 1582, 1593, 1652,
1682, 1724, 2857, 2897, 2929, 2956, 3286 cmꢀ1; HRMS (ESI): calcd for
C38H61NNaO5Si2 [M+Na]+: 690.39805; found: 690.39866.
Acknowledgement
Financial support by the Deutsche Forschungsgemeinschaft (grant:
Ma 1012/10-1) and the Fonds der Chemischen Industrie is gratefully ac-
knowledged.
[1] a) M. Stob, R. S. Baldwin, J. Tuite, F. N. Andrews, K. G. Gillette,
Nature 1962, 196, 1318; b) W. H. Urry, H. L. Wehrmeister, E. B.
Hodge, P. H. Hidy, Tetrahedron Lett. 1966, 3109–3114; c) P. H. Hidy,
R. S. Baldwin, R. L. Greasham, C. L. Keith, J. R. McMullen, Adv.
Appl. Microbiol. 1977, 22, 59–82; d) C. Cordier, M. Gruselle, G.
Jaouen, D. W. Hughes, M. J. McGlinchey, Magn. Reson. Chem. 1990,
28, 835–845.
[2] a) R. N. Mirrington, E. Ritchie, C. W. Shoppee, W. C. Taylor, S.
Sternhell, Tetrahedron Lett. 1964, 365–370; b) K. Nozawa, S. Nakaji-
ma, J. Nat. Prod. 1979, 42, 374–377; c) W. A. Ayer, S. P. Lee, A. Tsu-
neda, Y. Hiratsuka, Can. J. Microbiol. 1980, 26, 766–773.
[3] P. SellØs, R. Lett, Tetrahedron Lett. 2002, 43, 4621–4625.
[4] V. Hellwig, A. Mayer-Bartschmid, H. Müller, G. Greif, G. Kley-
mann, W. Zitzmann, H.-V. Tichy, M. Stadler, J. Nat. Prod. 2003, 66,
829–837.
[5] Y. Hoshino, V. B. Ivanova, K. Yazawa, A. Ando, Y. Mikami, S. M.
Zaki, A.-Z. A. Karam, Y. A. Youssef, U. Gräfe, J. Antibiot. 2002, 55,
516–519.
[6] For a review, see: L. Yet, Chem. Rev. 2003, 103, 4283–4306.
[7] a) J. A. Beutler, T. C. McKee, Curr. Med. Chem. 2003, 10, 787–796;
b) M. R. Boyd, C. Farina, P. Belfiore, S. Gagliardi, J. W. Kim, Y.
Hayakawa, J. A. Beutler, T. C. McKee, B. J. Bowman, E. J. Bowman,
J. Pharmacol. Exp. Ther. 2001, 291, 114–120.
Salicylihalamide A (E)-1: Disilylated salicylihalamide (E)-36 (14.8 mg,
22.2 mmol) was treated with a solution (1.1 mL) prepared from commer-
cially available HF·pyridine (0.5 g) in pyridine (1.25 mL) and THF
(6.75 mL). After the reaction had stirred for 2d, a further portion
(0.5 mL) was added and stirring was continued for 24 h. Thereafter, the
reaction was quenched by addition of buffer (pH 7, 15 mL) and the mix-
ture was extracted with ethyl acetate (4”5 mL). The organic layers were
dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatog-
raphy of the residue yielded salicylihalamide A (E)-1 (7.3 mg, 75%) as a
colorless wax: Rf =0.44 (petroleum ether/ethyl acetate, 1:1); [a]D =ꢀ37
(c=0.14, MeOH); 1H NMR (400 MHz, CD3OD): d=0.86 (d, J=6.7 Hz,
3H; H-26), 1.02 (t, J=7.6 Hz, 3H; H-25), 1.37 (dd, J=15.4, 9.2Hz, 1H;
H-14a), 1.71–1.80 (m, 2H; H-11a, H-14b), 1.82–1.93 (m, 1H; H-12), 2.23–
2.33 (m, 3H; H-11b, H-24), 2.37–2.47 (m, 2H; H-16), 3.31–3.37 (m, 1H;
H-8a), 3.56 (dd, J=16.4, 8.1 Hz, 1H; H-8b), 4.12(dd, J=8.9, 3.3 Hz, 1H;
H-13), 5.24–5.39 (m, 3H; H-10, H-15, H-9), 5.38 (dt, J=14.3, 7.6 Hz, 1H;
H-17), 5.69 (brd, J=11.4 Hz, 1H; H-20), 5.83 (brdt, J=10.7, 7.5 Hz, 1H;
H-23), 6.65 (brd, J=7.6 Hz, 1H; H-6), 6.72(d, J=8.1 Hz, 1H; H-4), 6.81
(brd, J=14.3 Hz, 1H; H-18), 6.87 (dd, J=12.0, 11.4 Hz, 1H; H-21), 7.12
(dd, J=8.1, 7.6 Hz, 1H; H-5), 7.30 ppm (br dd, J=12.0, 10.7 Hz, 1H; H-
22); 13C NMR (100 MHz, CD3OD): d=13.5 (C-26), 14.4 (C-25), 21.5 (C-
24), 36.5 (C-14), 37.6 (C-16), 38.5 (C-12), 38.8 (C-8), 38.9 (C-11), 72.0 (C-
13), 76.0 (C-15), 110.4 (C-17), 115.3 (C-4), 120.3 (C-20), 122.4 (C-6),
123.1 (C-2), 125.3 (C-22), 126.2 (C-18), 130.7 (C-9), 131.6 (C-5), 131.7 (C-
10), 137.8 (C-21), 140.6 (C-7), 142.6 (C-23), 157.1 (C-3), 165.8 (C-19),
171.0 ppm (C-1); IR (film): n˜ =1032, 1064, 1120, 1215, 1248, 1294, 1367,
1464, 1506, 1647, 2846, 2871, 2929, 2961, 3292 cmꢀ1; HRMS (ESI): calcd
for C26H33NNaO5 [M+Na]+: 462.22509; found: 462.22513.
[8] X.-S. Xie, D. Padron, X. Liao, J. Wang, M. G. Roth, J. K. De
Brabander, J. Biol. Chem. 2004, 279, 19755–19763.
[9] K. L. Erickson, J. A. Beutler, J. H. Cardellina II, M. R. Boyd, J. Org.
Chem. 1997, 62, 8188–8192.
[10] a) B. Kunze, R. Jansen, F. Sasse, G. Hçfle, H. Reichenbach, J. Anti-
biot. 1998, 51, 1075–1080; b) R. Jansen, B. Kunze, H. Reichenbach,
G. Hçfle, Eur. J. Org. Chem. 2000, 913–919.
[11] Total syntheses of salicylihalamide: a) Y. Wu, L. Esser, J. K. De
Brabander, Angew. Chem. 2000, 112, 4478–4480; Angew. Chem. Int.
Ed. 2000, 39, 4308–4310; b) A. Fürstner, T. Dierkes, O. Thiel, G.
Blanda, Chem. Eur. J. 2001, 7, 5286–5298; c) D. Labrecque, S. Char-
ron, R. Rej, C. Blais, S. Lamothe, Tetrahedron Lett. 2001, 42, 2645–
2648; d) B. B. Snider, F. Song, Org. Lett. 2001, 3, 1817–1820;
e) A. B. Smith, III, J. Zheng, Synlett 2001, 1019–1023; f) Y. Wu, X.
Liao, R. Wang, X.-S. Xie, J. K. De Brabander, J. Am. Chem. Soc.
2002, 124, 3245–3253; g) A. B. Smith, III, J. Zheng, Tetrahedron
2002, 58, 6455–6471.
[12] Total syntheses of apicularen A: a) A. Bhattacharjee, O. R. Seguil,
J. K. De Brabander, Tetrahedron Lett. 2001, 42, 1217–1220; b) K. C.
Nicolaou, D. W. Kim, R. Baati, Angew. Chem. 2002, 114, 3853–
3856; Angew. Chem. Int. Ed. 2002, 41, 3701–3704; c) K. C. Nicolaou,
D. W. Kim, R. Baati, A. OꢁBrate, P. Giannakakou, Chem. Eur. J.
2003, 9, 6177–6191; d) Q. Su, J. S. Panek, J. Am. Chem. Soc. 2004,
126, 2425–2430; e) A. F. Petri, A. Bayer, M. E. Maier, Angew.
Chem. 2004, in print.
Salicylihalamide B (Z)-1: Compound (Z)-1 (2.0 mg, 69%) was prepared
according to the procedure described above for salicylihalamide A from
disilylated salicylihalamide B (Z)-36 (4.4 mg, 6.6 mmol) and 0.33 mL of
the HF solution: Rf =0.49 (petroleum ether/ethyl acetate, 2:1); [a]D =
1
ꢀ69 (c=0.08, MeOH); H NMR (400 MHz, C6D6): d=0.77 (t, J=7.5 Hz,
3H; H-25), 0.84 (d, J=6.8 Hz, 3H; H-26), 1.22 (dd, J=15.0, 8.6 Hz, 1H;
H-14a), 1.28–1.35 (m, 1H; OH), 1.50 (brq, J=6.5 Hz, 1H; H-12), 1.69–
1.77 (m, 1H; H-11a), 1.75 (dd, J=15.0, 10.7 Hz, 1H; H-14b), 1.83–1.91
(m, 1H; H-16a), 1.95 (quintd, J=7.4, 0.9 Hz, 2H; H-24), 2.01–2.13 (m,
2H; H-11a, H-16b), 3.23–3.29 (m, 2H; H-8a, H-13), 3.53–3.60 (m, 1H;
H-8b), 4.51 (dt, J=16.0, 8.1 Hz, 1H; H-17), 5.08 (dt, J=15.5, 6.8 Hz, 1H;
Chem. Eur. J. 2004, 10, 5649 – 5660
www.chemeurj.org
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5659

M. E. Maier et al.
FULL PAPER
[13] Formal total syntheses of salicylihalamide: a) G. A. Holloway, H. M.
Hügel, M. A. Rizzacasa, J. Org. Chem. 2003, 68, 2200–2204; b) C.
Herb, M. E. Maier, J. Org. Chem. 2003, 68, 8129–8135; c) K. Yang,
T. Haack, B. Blackman, W. E. Diederich, S. Roy, S. Pusuluri, G. I.
Georg, Org. Lett. 2003, 5, 4007–4009.
[22] M. T. Crimmins, B. W. King, E. A. Tabet, K. Chaudhary, J. Org.
Chem. 2001, 66, 894–902.
[23] J. R. Gage, D. A. Evans, Org. Synth. 1989, 68, 77–82.
[24] M. Prashad, H.-Y. Kim, Y. Lu, Y. Liu, D. Har, O. Repic, T. J. Black-
lock, P. Giannousis, J. Org. Chem. 1999, 64, 1750–1753.
[25] P. Phukan, M. Bauer, M. E. Maier, Synthesis 2003, 1324–1328.
[26] W. C. Still, J. C. Barrish, J. Am. Chem. Soc. 1983, 105, 2487–2489.
[27] M. T. Crimmins, B. W. King, W. J. Zuercher, A. L. Choy, J. Org.
Chem. 2000, 65, 8499–8509.
[28] For some other applications of this strategy, see: a) M. J. Kiefel, J.
Maddock, G. Pattenden, Tetrahedron Lett. 1992, 33, 3227–3230;
b) K. C. Nicolaou, A. D. Piscopio, P. Bertinato, T. K. Chakraborty,
N. Minowa, K. Koide, Chem. Eur. J. 1995, 1, 318–333.
[29] For some reviews, see: a) R. H. Grubbs, S. J. Miller, G. C. Fu, Acc.
Chem. Res. 1995, 28, 446–452; b) S. K. Armstrong, J. Chem. Soc.
Perkin Trans. 1 1998, 371–388; c) M. E. Maier, Angew. Chem. 2000,
112, 2153–2157; Angew. Chem. Int. Ed. 2000, 39, 2073–2077; d) L.
Yet, Chem. Rev. 2000, 100, 2963–3007; e) A. Fürstner, Angew.
Chem. 2000, 112, 3140–3172; Angew. Chem. Int. Ed. 2000, 39, 3012–
3043.
[30] T. M. Trnka, J. P. Morgan, M. S. Sanford, T. E. Wilhelm, M. Scholl,
T.-L. Choi, S. Ding, M. W. Day, R. H. Grubbs, J. Am. Chem. Soc.
2003, 125, 2546–2558.
[14] Formal total syntheses of apicularen A: a) A. Lewis, I. Stefanuti,
S. A. Swain, S. A. Smith, R. J. K. Taylor, Tetrahedron Lett. 2001, 42,
5549–5552; b) A. Lewis, I. Stefanuti, S. A. Swain, S. A. Smith,
R. J. K. Taylor, Org. Biomol. Chem. 2003, 1, 104–116; c) B. R.
Graetz, S. D. Rychnovsky, Org. Lett. 2003, 5, 3357–3360; d) F. Hilli,
J. M. White, M. A. Rizzacasa, Org. Lett. 2004, 6, 1289–1292.
[15] Synthetic studies on salicylihalamide: a) Y. Wu, O. Seguil, J. K. De
Brabander, Org. Lett. 2000, 2, 4241–4244; b) J. T. Feutrill, G. A.
Holloway, F. Hilli, H. M. Hügel, M. A. Rizzacasa, Tetrahedron Lett.
2000, 41, 8569–8572; c) A. Fürstner, O. R. Thiel, G. Blanda, Org.
Lett. 2000, 2, 3731–3734; d) G. I. Georg, Y. M. Ahn, B. Blackman, F.
Farokhi, P. T. Flaherty, C. J. Mossman, S. Roy, K. Yang, Chem.
Commun. 2001, 255–256; e) M. Bauer, M. E. Maier, Org. Lett. 2002,
4, 2205–2208.
[16] K. A. H. Chehade, K. Kiegiel, R. J. Isaacs, J. S. Pickett, K. E.
Bowers, C. A. Fierke, D. A. Andres, H. P. Spielmann, J. Am. Chem.
Soc. 2002, 124, 8206–8219.
[17] T. Tokoroyama, T. Aoto, J. Org. Chem. 1998, 63, 4151–4157.
[18] a) S. N. Huckin, L. Weiler, J. Am. Chem. Soc. 1974, 96, 1082–1087;
b) M. Kato, V. P. Kamat, A. Yoshikoshi, Synthesis 1988, 699–701;
c) C. D. Vanderwal, D. A. Vosburg, S. Weiler, E. J. Sorensen, J. Am.
Chem. Soc. 2003, 125, 5393–5407.
[31] A. Bayer, M. E. Maier, Tetrahedron 2004, 60, 6665–6677.
[32] A. Fürstner, G. Seidel, J. Org. Chem. 1997, 62, 2332–2336.
[33] K. C. Nicolaou, K. R. Reddy, G. Skokotas, F. Sato, X. Y. Xiao, C. K.
Hwang, J. Am. Chem. Soc. 1993, 115, 3558–3575.
[19] a) M. Kitamura, M. Tokunaga, T. Ohkuma, R. Noyori, Org. Synth.
1992, 71, 1–13; b) S. A. King, A. S. Thompson, A. O. King, T. R.
Verhoeven, J. Org. Chem. 1992, 57, 6689–6691; c) R. Noyori, T.
Ohkuma, Angew. Chem. 2001, 113, 41–75; Angew. Chem. Int. Ed.
2001, 40, 40–73.
[34] a) W. P. Griffith, S. V. Ley, Aldrichimica Acta 1990, 23, 13–19;
b) S. V. Ley, J. Norman, W. P. Griffith, S. P. Marsden, Synthesis 1994,
639–666.
[35] T. R. Hoye, M. Hu, J. Am. Chem. Soc. 2003, 125, 9576–9577.
[20] S. Hoppen, S. Bäurle, U. Koert, Chem. Eur. J. 2000, 6, 2382–2396.
[21] E. J. Corey, H. Cho, C. Rücker, D. J. Hua, Tetrahedron Lett. 1981,
22, 3455–3458.
Received: June 18, 2004
Published online: September 30, 2004
5660
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2004, 10, 5649 – 5660