Synthesis of the salicylihalamide core structure from epichlorohydrin - Laying the foundation to macrolactone collections

Article abstract of DOI:10.1002/ejoc.200400705

Starting from (R)-epichlorohydrin, two successive carbon-carbon bond formations, one with acetylide and the other with cyanide, led to the 3′-hydroxynitrile 20. This compound was further elaborated to the enynol 29 via an Evans aldol reaction of the deriv

Full text of DOI:10.1002/ejoc.200400705

FULL PAPER
Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
– Laying the Foundation to Macrolactone Collections
Christian Herb,[a] Frank Dettner,[a] and Martin E. Maier*[a]
Keywords: Aldol reactions / Alkynes / Macrocycles / Metathesis
Starting from (R)-epichlorohydrin, two successive carbon–
carbon bond formations, one with acetylide and the other
with cyanide, led to the 3-hydroxynitrile 20. This compound
was further elaborated to the enynol 29 via an Evans aldol
reaction of the derived aldehyde 22 with the pentenoyloxazo-
lidinone 23 and conversion of the carboxyl to a methyl group
after the aldol reaction. Mitsunobu esterification of the en-
ynol 29 with the benzoic acid 5 gave rise to the ester 30 with
two double bonds and one triple bond. After protection of
the terminal triple bond with a TIPS group, the ring closing
metathesis proceeded in good yield. The macrolactone E-33
was converted into the vinyl iodide 34 and the pyridin con-
taining salicylihalamide analog 36. The described sequence,
the two-sided elongation of epichlorohydrin appears as a ge-
neral route to secondary alcohols that can be further elabo-
rated to functionalized macrolactones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Natural products still serve as sources of new drugs to a
substantial degree.[1] Among them are many macrolactones
which usually originate from the polyketide pathway. The
macrocycle secures the appropriate orientation of polar and
non-polar groups.[2] Natural products such as macrolac-
tones also represent attractive starting points or lead struc-
tures for the preparation of compound libraries that can be
used for chemical genetic studies.[3–6] Besides the macrolac-
tone core, certain side chains can also be essential for bio-
logical activity. For example, in the benzolactone enamides
it seems that the enamide side chain can form an acylimin-
ium ion that is trapped by a nucleophilic amino acid side
chain. This is most likely an important step in the reversible
inhibition of mammalian V-ATPases.[7] Inhibition of these
proton pumps eventually leads to cell death via apoptosis.
Important representatives of the benzolactone enamides are
the salicylihalamides (E-1, Z-1) and apicularen A (2) (Fig-
ure 1). In addition, other related molecules are known.[8]
The salicylihalamides were isolated from the sponge Hal-
iclona sp.,[9] whereas apicularen A was found in various
myxobacteria strains.[10]
Figure 1. Structures of two important benzolactone enamides.
synthetic studies[15] are known in the literature. Finally, the
synthesis of several simplified salicylihalamide analogs was
described by ring closing metathesis of bisolefinic ester sub-
strates.[16] In the case of the salicylihalamides, all syntheses
first construct the macrocyclic core followed by attachment
of the enamide side chain. The length and terminus of the
side chain at C15 of the salicylihalamides depends very
much on the way the enamide is established. Thus, the en-
amide was attached by nucleophilic addition to a vinyl iso-
cyanate,[11d,11f,11g] by cross-coupling between a vinyl iodide
and the unsaturated amide,[11b] or by reaction of the unsatu-
rated amide with an aldehyde function.[11c] With the enam-
ide side chain and the macrolactone core it might be specu-
The challenging structural features of these natural pro-
ducts combined with their novel mode of action have stimu-
lated a number of synthesis programs. Thus, several total
syntheses for the salicylihalamides[11] and apicularen A[12]
were published. In addition, formal total syntheses[13,14] and
[a]
Institut für Organische Chemie, Universität Tübingen
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: (internat.) +49-(0)7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
728
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400705
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Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
FULL PAPER
lated that salicylihalamide consists of two binding domains.
We reasoned that strong modifications on the C15 side
chain might generate macrolactones with new modes of bi-
ological activity. For this purpose a terminating functional
group was sought that has a high diversity potential[17] and
at the same time is chemically quite robust. Therefore we
chose a terminal alkyne function. With regard to library
generation Sonogashira couplings or 1,3-dipolar cycload-
dition reactions[18] appear ideal. Accordingly, the macrolac-
tone 3 (Figure 2) became our target as a branching plat-
form. Among the various strategies that have been used to
fashion the macrolactone core of the salicylihalam-
ides[11,13,15] the ring closing metathesis is probably the most
general one with regard to functional group tolerance and
potential for upscaling.[19] In addition, the high conver-
gence, the avoidance of hydroxy acids, and the reliability of
the reaction are advantageous. The retrosynthetic analysis,
illustrated in Figure 2 leads to optically active epichlorohyd-
rin, a compound that is easily available from the racemate
by Jacobsen resolution.[20]
Scheme 1. Synthesis of the benzoate 13 and its attempts to cyclize
it to the corresponding macrolactone; a) bromopentene (1 equiv.),
THF, Mg (1.38 equiv.), 50 °C, add to CuCN (0.04 equiv.), S-8 (0.77
equiv.), THF, –50 °C, 2 h, 100 %; b) NaOH (2 equiv.), ethylene
glycol, 0 to 23 °C, 1 h, 73 %; c) Me3SiCCH (1 equiv.), nBuLi (0.93
equiv.), THF, –78 °C, 30 min, add BF3·Et2O (1 equiv.), 30 min, add
11 (0.64 equiv.), –78 °C, 3 h, 36 %; d) 12 (1 equiv.), Ph3P (2.5
equiv.), acid 5 (5 equiv.), DIAD (2.5 equiv.), toluene, 23 °C, 3 h,
65 %. DIAD = diisopropylazodicarboxylate.
Figure 2. Retrosynthetic analysis of the propynyl-substituted
macrolactone 3 leading to epichlorohydrin as starting material; R
= alkyl, PG = non-silyl protecting group, Xc = chiral auxiliary.
Results
In order to probe the feasibility of this strategy and to
test the compatibility of the alkyne with the metathesis con-
dition, a model system was constructed (Scheme 1). Thus,
opening of (S)-epichlorohydrin (S-8) with 5-pentenylmag-
nesium bromide in the presence of copper cyanide (CuCN)
gave a quantitative yield of the chlorohydrin 10.[21] Treat-
ment of 10 with sodium hydroxide generated the terminal
epoxide 11.[22] Now a second carbon–carbon bond forma-
tion was performed with lithium trimethylsilyl acetylide[23]
in the presence of borontrifluoride–diethyl ether.[24] The re-
sulting secondary alcohol 12 was then condensed with the
benzoic acid 5 under Mitsunobu conditions[11b,25] leading
Scheme 2. Synthesis of the benzoate 16 with a TIPS-protected al-
kyne and its ring closing metathesis to the macrolactones 17; a)
K2CO3 (2 equiv.), MeOH, 23 °C, 4 h, 85 %; b) nBuLi (1.12 equiv.),
THF, –78 to –20 °C, 30 min, then add (iPr)3SiCl (1.2 equiv.),
THF, –78 to 23 °C, 15 h, 78 %; c) catalyst 14 (0.05 equiv.), toluene,
75 °C, 2 h, 99 % (E/Z = 4.21:1); d) TBAF (5 equiv.), THF, 0 to
to the dienyl ester 13. However, treatment of the ynediene 23 °C, 5 h, (100 %).
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C. Herb, F. Dettner, M. E. Maier
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13 with the second generation Grubbs catalyst 14 in toluene lithium trimethylsilylacetylide to the known chlorohy-
(0.001 m of 13 in toluene, 0.1 equiv. of 14, 70 °C, 2 h) led drin[24b,31] 19 (Scheme 3). As a second nucleophile, cyanide
to a complex mixture of compounds that was not further came to use. The best results were obtained with sodium
characterized. This was attributed to the participation of cyanide in ethanol,[32] which gave the hydroxynitrile 20 in
the triple bond.
almost quantitative yield. This substitution reaction was ac-
It was reasoned that a larger protecting group at the al- companied with the cleavage of the trimethylsilyl group.
kyne might prevent participation of the alkyne in the me- Thereafter, the secondary hydroxy group of 20 was pro-
tathesis reaction.[26–29] Accordingly, the trimethylsilyl group tected as tert-butyldimethylsilyl ether yielding the nitrile 21.
was removed by stirring the ester 13 with potassium car- A chemoselective reduction of the cyano function to the
bonate in methanol to give the alkynoate 15 (Scheme 2). In aldehyde 22 was possible with DIBAL in dichloromethane.
a rather remarkable reaction a selective deprotonation of The crude aldehyde 22 was then utilized in an Evans aldol
the terminal alkyne 15 was achieved with n-butyllithium. reaction[33–35] with the pentenoyloxazolidinone[36] 23. This
Quenching of the intermediate acetylide with triisopropylsi- gave a good yield of the syn-product 24. Continuing with
lyl chloride furnished the TIPS-protected alkyne 16 in 78 % the synthesis, the secondary hydroxy group was protected
yield. To our delight, ring closing metathesis of 16 with the with methoxymethyl chloride to give the MOM ether 25.
Grubbs catalyst[30] 14 in toluene at 70 °C gave an excellent Subsequent treatment of 25 with LiBH4 led to the primary
yield of the two macrolactones E-17 (80 %) and Z-17 (19 %) alcohol 26 and recovered (benzyl)oxazolidinone. The re-
which could be separated by chromatography. Deprotection quired methyl group was created from the hydroxymethyl
of E-17 led to macrolactone 18.
group of 26 via the tosylate 27. Substitution of the tosylate
In order to reach macrolactone 3 with this strategy, the with hydride[37] in the form of LiEt3BH provided the enyne
optically active (R)-epichlorohydrin was first opened with 28. Finally, cleavage of the silyl ether with TBAF gave rise
to the alcohol 29.
Esterification of the benzoic acid 5 with the secondary
alcohol 29 using Mitsunobu conditions provided the benzo-
ate 30 (Scheme 4). Like in the model system, the acetylene
Scheme 3. Synthesis of the enynol 29 from epichlorohydrin R-8; a)
Me3SiCCH (1 equiv.), nBuLi (0.93 equiv.), –78 °C, 30 min, then
add BF3 Et2O (1 equiv.), –78 °C, 30 min, then add R-8 (0.64
equiv.), –78 °C, 3 h, (98 %),[24b] b) NaCN (2.5 equiv.), EtOH, 23 °C,
3 d, 96 %; c) tBuMe2SiCl (1.5 equiv.), imidazole (2.5 equiv.),
DMAP (0.05 equiv.), DMF, 23 °C, 3 d, 100 %; d) DIBAL (1.2
equiv.), CH2Cl2, –78 °C, 4 h, 96 %; e) compound 23 (1 equiv.),
TiCl4 (1.05 equiv.), (–)-sparteine (2.5 equiv.), CH2Cl2, 0 °C, 20 min,
Scheme 4. Synthesis of the macrolactones E-33 and Z-33 by ring
closing metathesis of the TIPS-protected ynediene 32; a) alcohol
29 (1 equiv.), Ph3P (1.5 equiv.), acid 5 (1.05 equiv.), DEAD (1.5
add aldehyde 22 (1.27 equiv.), 0 °C, 1 h, 89 %; f) iPr2NEt (10 equiv.), toluene, 23 °C, 15 h, 69 %; b) nBuLi (1.1 equiv.), THF, –78
equiv.), MeOCH2Cl (5 equiv.), Bu4NI (0.2 equiv.), 0 to 23 °C, 24
h, 80 %; g) LiBH4 (1.3 equiv.), EtOH (1.3 equiv.), Et2O, 0 to 23 °C,
12 h, 68 %; h) pTsCl (3 equiv.), pyridine, 0 °C, 5 h, 100 %; i)
Et3BHLi (5 equiv.), THF, 0 to 23 °C, 93 %; j) TBAF (2 equiv.),
THF, 0 to 23 °C, 84 %.
to –20 °C, 30 min, then add (iPr)3SiCl (1.2 equiv.), DMAP (0.01
equiv.), THF, –78 to 23 °C, 15 h, 89 %; c) add solutions of ester 31
and complex 32 (0.15 equiv.) slowly to CH2Cl2, 23 °C, 12 h, 93 %
(E/Z = 30:1). DMAP = 4-Dimethylaminopyridine, DEAD = dieth-
ylazodicarboxylate.
730
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Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
FULL PAPER
was protected by reacting the corresponding anion, which age of the ether and acetal protecting groups with BBr3 in
was generated with n-butyllithium, with TIPSCl leading to dichloromethane furnished the macrolactone 36 with a 15-
the metathesis substrate 31. Both of the Grubbs catalysts [3-(2-pyridinyl)-2-propynyl] side chain. The biological
14 and 32 were able to induce the desired macrocyclization. evaluation on L929 mouse fibroblast cells led to the follow-
With the second generation catalyst 14 the E/Z selectivity ing IC50 values: Salicylihalamide A (E-1) 25 ng·mL–1, sal-
was moderate (E/Z = 2.2:1). Surprisingly the first genera- icylihalamide B (Z-1) 500 ng·mL–1, and analog 36 2000
tion catalyst 32 provided the macrolactones 33 in good ng·mL–1.[38] This result is of interest since 36 does not con-
chemical yield and excellent E/Z selectivity (E/Z = 30:1). tain an enamide which is required for ATPase inhibition
The increase in selectivity for the ring closing metathesis (Scheme 5).
using Grubb’s first generation catalyst has actually been ob-
served before.[8]
Conclusions
Removal of the TIPS group from the alkyne E-33 with
TBAF delivered the key compound 3. The alkyne 3 could
be converted into the vinyl iodide 34 by hydrostannylation
followed by treatment of the intermediate vinyl stannane
with iodine. Since 34 is an advanced intermediate in the
Fürstner synthesis of salicylihalamide,[11b] our route to 34
represents a new formal total synthesis of salicylihalamide
A. The utility of the macrolactone 3 as a platform for the
generation of salicylihalamide analogs was demonstrated by
its conversion to the pyridin-salicylihalamide derivative 36.
Thus, a Sonogashira coupling of alkyne 3 with 2-bromo-
pyridine provided the substituted pyridine 35. Finally, cleav-
Starting from (R)-epichlorohydrin (R-8) two carbon–car-
bon bond formations led to the 3-hydroxynitrile 20. This
compound was further elaborated to the enyne 29 via an
Evans aldol reaction of the aldehyde 22 with the (pen-
tenoyl)oxazolidinone 23 and conversion of the carboxyl to
a methyl group of the aldol product 24. Mitsunobu esterifi-
cation of the alcohol 29 with the benzoic acid 5 gave rise to
the ester 30 with two double bonds and one triple bond.
After protection of the terminal triple bond with a sterically
demanding TIPS group, the ring closing metathesis pro-
ceeded in good yield. The macrolactone E-33 was converted
into the vinyl iodide 34 and the pyridin containing salicylih-
alamide analog 36. The described sequence, the two-sided
elongation of epichlorohydrin, Mitsunobu esterification of
the secondary alcohol, ring closing metathesis to a macro-
lactone, and side chain modification could be the founda-
tion for the synthesis of macrolactone collections. Further
sophistication could be introduced by using aldol reactions
in the synthesis of the acid component.
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400, spectra were re-
corded at 295 K either in CDCl3, C6D6 or CD3OD; chemical shifts
are calibrated to the residual proton and carbon resonance of the
solvent: CDCl3 (δH = 7.25 ppm, δC = 77.0 ppm), C6D6 (δH = 7.16,
δC = 128.0 ppm) or CD3OD (δH = 3.30, δC = 49.0 ppm). IR: Jasco
FT/IR-430. Optical rotation: Jasco polarimeter P-1020, reported in
[α]D {c [g/100 mL], solvent}; recorded at 298 K. MS: Finnigan Tri-
ple-Stage-Quadrupol TSQ-70 (ionizing voltage of 70 eV) or Intec-
tra AMD 402 mass spectrometer. HRMS: Intectra AMD MAT-
711A (EI) or Bruker Daltonic APEX 2 (ESI). Flash chromatogra-
phy: J. T. Baker silica gel 43–60 µm. Thin-layer chromatography
Macherey–Nagel Polygram Sil G/UV254. All solvents used in the
reactions were distilled before use. Dry diethyl ether, tetrahydrofu-
ran, and toluene were distilled from sodium and benzophenone,
whereas dry dichloromethane, dimethylformamide, pyridine, and
triethylamine were distilled from CaH2. Petroleum ether with a
boiling range of 40–60 °C was used. Reactions were generally run
under argon. All commercially available compounds were used as
received unless stated otherwise. NMR peaks were assigned accord-
ing to IUPAC rules or the numbering by Boyd et al.[9]
Scheme 5. Synthesis of the vinyl iodide 34 and the salicylihalamide
analog 36 from the macrolactone E-33; a) TBAF (4.8 equiv.), THF,
23 °C, 5 h, 94 %; b) Bu3SnH (1.2 equiv.), AIBN (0.13 equiv.), tolu-
ene, reflux, 18 h, change solvent to Et2O, add I2 (1.2 equiv.), 0 °C,
(3S,5R,6S)-14-Methoxy-5-(methoxymethoxy)-6-methyl-3-(prop-2-
ynyl)-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one (3):
To a solution of TIPS alkyne E-33 (130 mg, 0.25 mmol) in THF
(4.8 mL) was added TBAF (1.2 mL, 1.2 mmol, 1 m in THF) at 0 °C.
After being stirred for 5 h at room temperature, the solution was
1
h, 83 % (E/Z = 3.8:1); c) bromopyridine (0.92 equiv.),
[PdCl2(PPh3)2] (0.022 equiv.), CuI (0.045 equiv.), Et3N, 23 °C, 18
h, 90 %; d) 9-I-9-BBN (4 equiv.), CH2Cl2, 23 °C, 70 s, 88 %. 9-I-9-
BBN = 9-Iodo-9-borabicyclo[3.3.1]nonane.
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C. Herb, F. Dettner, M. E. Maier
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treated with saturated aqueous NaHCO3 solution (4 mL) and the
mixture extracted with Et2O (2 × 10 mL). The combined extracts
were dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography (petroleum ether/ethyl acetate,
5:1) to provide 86 mg (94 %) of the desired alkyne 3 as a colorless
wax. Rf = 0.41 (petroleum ether/ethyl acetate, 4:1). [α]D = –49.3 (c
ture extracted with pentane (3 × 100 mL). The combined organic
extracts were washed with water (100 mL), dried with MgSO4, fil-
tered and the solvents evaporated. Distillation of the crude epoxide
11 provided a colorless liquid (5.03 g, 73 %) boiling at 27 °C
(1 mbar). Rf = 0.77 (petroleum ether/ethyl acetate, 3:1). [α]D
=
–10.1 (c = 1.50, CH Cl ). IR (film): ν = 1640, 2859, 2931, 2978,
˜
2
2
= 1.00, CH Cl ). IR (film): ν = 1274, 1468, 1727, 2930, 2959,
3075 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.36–1.48 (m, 4 H,
˜
2
2
3289 cm–1. H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.8 Hz, 3Ј-H, 2Ј-H), 1.48–1.55 (m, 2 H, 1Ј-H), 2.04 (br. dt, J = 6.5, 5.6 Hz,
1
3 H, CH3), 1.64–1.78 (m, 3 H, 14-H, 11-H), 2.04 (t, J = 2.7 Hz, 1
H, 18-H), 2.07–2.17 (m, 1 H, 12-H), 2.29 (br. d, J = 14.2 Hz, 1 H,
11-H), 2.49 (ddd, J = 16.7, 7.5, 2.7 Hz, 1 H, 16-H), 2.57 (ddd, J =
2 H, 4Ј-H), 2.43 (dd, J = 5.0, 2.7 Hz, 1 H, 1-H), 2.72 (dd, J = 5.0,
3.9 Hz, 1 H, 1-H), 2.85–2.90 (m, 1 H, 2-H), 4.92 (br. d, J = 10.2 Hz,
1 H, 6Ј-H), 4.98 (br. dd, J = 17.1, 1.5 Hz, 1 H, 6Ј-H), 5.78 (ddt, J =
16.7, 5.5, 2.7 Hz, 1 H, 16-H) 3.29 (br. d, J = 16.3 Hz, 1 H, 8-H), 17.1, 10.2, 6.5 Hz, 1 H, 5Ј-H) ppm. 13C NMR (100 MHz, CDCl3): δ
3.46 (s, 3 H, MOM-CH3), 3.68 (dd, J = 16.3, 9.6 Hz, 1 H, 8-H),
3.78 (s, 3 H, Ph-OCH3), 4.11 (br. dd, J = 8.2, 3.3 Hz, 1 H, 13-H),
= 25.4 (C-2Ј), 28.6 (C-3Ј), 32.3 (C-1Ј), 33.6 (C-4Ј), 47.0 (C-1), 52.2
(C-2), 114.5 (C-6Ј), 138.6 (C-5Ј) ppm. MS (EI): m/z (%) = 93 (49),
4.80 (d, J = 6.8 Hz, 1 H, MOM-CH2), 4.88 (d, J = 6.8 Hz, 1 H, 79 (46), 68 (47), 67 (100), 55 (55), 54 (76), 41 (52). HRMS (ESI):
MOM-CH2), 5.32 (br. dd, J = 15.3, 9.6 Hz, 1 H, 9-H), 5.39–5.51 [M + Na]+ calcd. for C8H14NaO 149.09369, found 149.09467.
(m, 2 H, 15-H, 10-H), 6.74 (d, J = 7.6 Hz, 1 H, 6-H), 6.79 (d, J =
(4S)-1-(Trimethylsilyl)dec-9-en-1-yn-4-ol (12): A cooled (–78 °C)
8.4 Hz, 1 H, 4-H), 7.22 (dd, J = 8.4, 7.6 Hz, 1 H, 5-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.3 (CH3), 25.6 (C-16), 34.4 (C-
solution of TMS-acetylene[23] (1.70 mL, 1.21 g, 12.3 mmol) in THF
(33 mL) was treated with nBuLi (4.60 mL, 11.5 mmol, 2.5 m in hex-
12), 34.5 (C-14), 37.5 (C-8), 37.6 (C-11), 55.5 (MOM-CH3), 55.7
ane) and the suspension was stirred for 30 min at that temperature.
(Ph-OCH3), 70.3 (C-18), 72.1 (C-15), 78.8 (C-13), 80.0 (C-17), 96.8
After addition of borontrifluoride–diethyl ether(1.55 mL, 1.75 g,
(MOM-CH2), 109.3 (C-4), 122.6 (C-6), 124.4 (C-2), 128.7 (C-9),
12.3 mmol) the mixture was stirred for 30 min and treated with a
130.0 (C-5), 131.2 (C-10), 138.8 (C-7) 156.7 (C-3), 167.9 (C-1) ppm.
solution of epoxide 11 (1.00 g, 7.94 mmol) in THF (8 mL) slowly.
Temperature was kept for 3 h and the reaction was quenched by
MS (EI): m/z (%) = 372 (3), 340 (10), 327 (19), 311 (21), 301 (10),
271 (10), 259 (62), 228 (26), 215 (33), 199 (36), 187 (100), 161 (38),
addition of saturated NH4Cl solution (1.6 mL). The mixture was
148 (24), 115 (30), 31 (13), 45 (48). HRMS (EI): [M]+ calcd. for
poured into saturated NH4Cl solution (50 mL) and extracted with
diethyl ether (3 × 40 mL). The combined organic extracts were
C22H28O5 372.19365, found 372.19547.
(2S)-1-Chlorooct-7-en-2-ol (10): To a suspension of magnesium
(2.36 g, 97.2 mmol) in THF (40 mL) were added a few drops of 5-
bromopent-1-ene (8.31 mL, 10.46 g, 70.2 mmol) in THF (40 mL)
and some grains of iodine to start the reaction. After warming
to 50 °C the remaining solution of the bromide was added slowly.
Formation of the Grignard reagent 9 was completed by refluxing
the mixture for 30 min. In a second flask copper(i) cyanide (0.24 g,
2.67 mmol) was suspended in THF (55 mL) and the slurry treated
with (S)-epichlorohydrin (S-8) (4.23 mL, 5.00 g, 54.0 mmol). To
this solution the Grignard solution was transferred carefully at
–50 °C and stirring was continued for 2 h while warming to room
temperature. The reaction was quenched by addition of saturated
NH4Cl solution (100 mL), stirring was continued for 15 min, and
the phases were separated. The aqueous layer was extracted with
ethyl acetate (3 × 50 mL) and the combined organic extracts were
dried with Na2SO4. After filtration and evaporation of the solvent,
the crude alcohol was purified by flash chromatography (petroleum
ether/ethyl acetate, 4:1) to provide the pure product 10 (8.74 g,
100 %) as a light yellow oil. Rf = 0.62 (petroleum ether/ethyl ace-
washed with saturated NaHCO3 solution (20 mL), brine (20 mL),
and dried with MgSO4. After filtration and evaporation of the sol-
vent the crude product was purified by flash chromatography (pe-
troleum ether/ethyl acetate, 5:1). Hydroxyalkyne 12 (6.44 g, 36 %)
was obtained as light yellow oil. Rf = 0.70 (petroleum ether/ethyl
acetate, 3:1). [α]D = +3.4 (c = 1.24, CH Cl ). IR (film): ν = 1249,
˜
2
2
2175, 2853, 2930, 3366 cm–1. 1H NMR (400 MHz, CDCl3): δ =
0.13 [s, 9 H, Si(CH3)3], 1.29–1.47 (m, 4 H, 7-H, 6-H), 1.47–1.54 (m,
2 H, 5-H), 2.00–2.07 (m, 3 H, OH, 8-H), 2.32 (dd, J = 16.8, 6.9 Hz,
1 H, 3-H), 2.43 (dd, J = 16.8, 4.7 Hz, 1 H, 3-H), 3.66–3.75 (m, 1
H, 4-H), 4.92 (br. d, J = 10.2 Hz, 1 H, 10-H), 4.98 (br. d, J = 17.2,
1.5 Hz, 1 H, 10-H), 5.78 (ddt, J = 17.2, 10.2, 6.7 Hz, 1 H, 9-H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 0.0 [Si(CH3)3], 25.0 (C-6),
28.7 (C-7), 28.8 (C-3), 33.6 (C-8), 36.0 (C-5), 69.7 (C-4), 87.5 (C-
1), 103.2 (C-2), 114.4 (C-10), 138.7 (C-9) ppm. MS (EI): m/z (%)
= 185 (8), 141 (14), 112 (43), 95 (84), 73 (100), 41 (16). HRMS
(ESI): [M + Na]+ calcd. for C13H24NaOSi 247.14886, found
247.14879.
(1R)-1-[3-(Trimethylsilyl)prop-2-ynyl]hept-6-enyl 2-Allyl-6-methoxy-
benzoate (13): To a solution of alcohol 12 (125 mg, 0.56 mmol) and
triphenylphosphane (370 mg, 1.41 mmol) in toluene (6 mL) was
added dropwise a solution of acid[11g] 5 (538 mg, 2.80 mmol) and
DIAD (278 µL, 285 mg, 1.41 mmol) in toluene (6 mL). After 3
hours of stirring at room temperature, the solvent was removed and
the residue purified by flash chromatography (petroleum ether/ethyl
acetate, 10:1). Ester 13 (146 mg, 65 %) was isolated as a pale yellow
oil. Rf = 0.58 (petroleum ether/ethyl acetate, 10:1). [α]D = +29.3 (c
tate, 3:1). [α]D = +0.2 (c = 1.30, CH Cl ). IR (film): ν = 1436, 1640,
˜
2
2
2859, 2933, 3393 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.29–1.47
(m, 4 H, 5-H, 4-H), 1.47–1.54 (m, 2 H, 3-H), 2.03 (br. dt, J = 6.6,
5.6 Hz, 2 H, 6-H), 2.44 (br. s, 1 H, OH), 3.44 (dd, J = 11.1, 7.0 Hz,
1 H, 1-H), 3.59 (dd, J = 11.1, 3.3 Hz, 1 H, 1-H), 3.72–3.80 (m, 1
H, 2-H), 4.91 (br. d, J = 10.2 Hz, 1 H, 8-H), 4.97 (br. dd, J = 17.1,
1.5 Hz, 1 H, 8-H), 5.76 (ddt, J = 17.1, 10.2, 6.6 Hz, 1 H, 7-H) ppm.
13C NMR (100 MHz, CDCl3): δ = 33.5 (C-6), 33.9 (C-3), 50.3 (C-
1), 71.3 (C-2), 114.5 (C-8), 138.6 (C-7) ppm. MS (EI): m/z (%) =
239 (10), 219 (5), 169 (100), 151 (23), 139 (15), 127 (30), 111 (100),
109 (63), 95 (54), 83 (86), 69 (36), 55 (61), 43 (61). HRMS (ESI):
[M + Na]+ calcd. for C8H15ClNaO 185.07036, found 185.06847.
= 0.95, CH Cl ). IR (film): ν = 1266, 1470, 1585, 1729, 2928 cm–1.
˜
2
2
1H NMR (400 MHz, CDCl3): δ = 0.14 [s, 9 H, Si(CH3)3], 1.37–
1.52 (m, 4 H, 4Ј-H, 3Ј-H), 1.69–1.87 (m, 2 H, 2Ј-H), 2.07 (br. dt, J
= 6.3, 6.3 Hz, 2 H, 5Ј-H), 2.58 (dd, J = 17.0, 6.9 Hz, 1 H, 1ЈЈ-H),
2.66 (dd, J = 17.0, 5.1 Hz, 1 H, 1ЈЈ-H), 3.37 (br. d, J = 6.6 Hz, 2
H, 7-H), 3.79 (s, 3 H, Ph-OCH3), 4.93 (br. d, J = 10.1 Hz, 1 H, 7Ј-
H), 5.00 (br. d, J = 17.1, 1 H, 7Ј-H), 5.05 (br. d, J = 10.4 Hz, 1 H,
9-H), 5.05 (br. d, J = 17.2 Hz, 1 H, 9-H), 5.13–5.20 (m, 1 H, 1Ј-
H), 5.80 (ddt, J = 17.1, 10.1, 6.7 Hz, 1 H, 6Ј-H), 5.86–5.97 (m, 1
(2S)-(2-Hex-5-enyl)oxirane (11): A cooled (0 °C) solution of chlo-
rooctenol 10 (8.74 g, 54.0 mmol) in ethylene glycol (60 mL) was
treated with grained sodium hydroxide (4.32 g, 108 mmol) and was
stirred for 1 hour while warming to room temperature. The reaction
was stopped by addition of ice-cold water (120 mL) and the mix-
732
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 728–739

Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
FULL PAPER
H, 8-H), 6.77 (d, J = 8.3 Hz, 1 H, 5-H), 6.82 (d, J = 7.7 Hz, 1 H, 3- (d, J = 7.7 Hz, 1 H, 3-H), 7.23 (dd, J = 8.3, 7.7 Hz, 1 H, 4-H) ppm.
H), 7.27 (dd, J = 8.3, 7.7 Hz, 1 H, 4-H) ppm. 13C NMR (100 MHz, 13C NMR (100 MHz, CDCl3): δ = 11.2 (TIPS-CH), 18.5 (TIPS-
CDCl3): δ = 0.0 [Si(CH3)3], 24.5 (C-3Ј), 25.4 (C-1Ј), 28.6 (C-4Ј), CH3), 24.4 (C-3Ј), 25.3 (C-1ЈЈ), 28.7 (C-4Ј), 32.5 (C-2Ј), 33.6 (C-
32.8 (C-2Ј), 33.6 (C-5Ј), 37.4 (C-7), 55.8 (Ph-OCH3), 70.5 (C-3ЈЈ), 5Ј), 37.3 (C-7), 55.7 (Ph-OCH3), 73.0 (C-1Ј), 83.1 (C-3ЈЈ), 103.7 (C-
73.0 (C-1Ј), 87.0 (C-3ЈЈ), 102.3 (C-2ЈЈ), 108.9 (C-5), 114.5 (C-7Ј), 2ЈЈ), 108.8 (C-5), 114.4 (C-7Ј), 116.3 (C-9), 121.6 (C-3), 123.8 (C-
116.4 (C-9), 121.6 (C-3), 123.8 (C-1), 130.3 (C-4), 136.4 (C-8), 138.3 1), 130.3 (C-4), 136.3 (C-8), 138.2 (C-2), 138.7 (C-6Ј), 156.4 (C-6),
(C-2), 138.7 (C-6Ј), 156.4 (C-6), 167.7 (Ph-CO2) ppm. MS (EI): 167.6 (Ph-CO2) ppm. MS (EI): m/z (%) = 439 (4), 306 (23), 305
m/z (%) = 399 (14), 249 (28), 192 (78), 177 (92), 175 (92), 174 (100), (100), 272 (8), 175 (42), 147 (23). HRMS (EI): [M – iPr]+ calcd. for
147 (76), 192 (50), 115 (39), 91 (26), 73 (43). HRMS (EI): [M]+
calcd. for C24H34SiO3 398.2277, found 398.2257.
C27H39SiO3 439.2668, found 439.2655.
14-Methoxy-3-[3-(triisopropylsilyl)prop-2-ynyl]-3,4,5,6,7,10-hexahy-
dro-1H-2-benzoxacyclododecin-1-one (17): Grubbs 2nd generation
catalyst 14 (54.3 mg, 64.1 µmol) was added to a solution of diene
16 (0.62 g, 1.28 mmol) in toluene (1280 mL) and the light purple
solution was heated to 75 °C for 2 h. After completion of the reac-
tion (checked by 1H NMR), ethoxyethylene (5.76 mL, 7.97 g,
110 mmol) was added and the solution cooled to room tempera-
ture. The solvent was removed in vacuo and the residue purified by
flash chromatography (petroleum ether/ethyl acetate, 10:1). The
two isomers, (E)-macrolactone (E-17, 0.46 g, 80 %) and (Z) deriv-
ative (Z-17, 0.11 g, 19 %), could be separated by HPLC as color-
?oas [jy?>less viscous oils. HPLC: tR (E isomer) = 13.3 min, tR (Z
isomer) = 16.8 min on GROM-SIL 120 column, Si NP-2, 10 µm,
250 × 20 mm with n-heptane/ethyl acetate, 90:10, flow 10 mL/min.
(1R)-1-(Prop-2-ynyl)hept-6-enyl 2-Allyl-6-methoxybenzoate (15): A
solution of TMS-alkyne 13 (1.18 g, 2.95 mmol) in methanol
(10 mL) was treated with potassium carbonate (0.82 g, 5.90 mmol)
and stirred for 4 h at room temperature. The mixture was diluted
with diethyl ether (200 mL) and washed with water (50 mL) and
saturated NH4Cl solution (50 mL). After filtration and evaporation
of the solvent the residue was purified by flash chromatography
(petroleum ether/ethyl acetate, 5:1) to provide the unprotected al-
kyne 15 (0.82 mg, 85 %) as a colorless oil. Rf = 0.56 (petroleum
ether/ethyl acetate, 5:1). [α]D = +30.4 (c = 1.40, CH2Cl2). IR (film):
ν = 1072, 1113, 1267, 1438, 1471, 1585, 1640, 1726, 2858, 2931,
˜
3296 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34–1.49 (m, 4 H,
4Ј-H, 3Ј-H), 1.71–1.81 (m, 2 H, 2Ј-H), 1.97 (t, J = 2.6 Hz, 1 H, 3ЈЈ-
H), 2.00–2.06 (m, 2 H, 5Ј-H), 2.56 (dd, J = 5.9, 2.6 Hz, 2 H, 1ЈЈ-
H), 3.35 (d, J = 6.6 Hz, 2 H, 7-H), 3.76 (s, 3 H, Ph-OCH3), 4.90
E-17 (main product): M. p. 88 °C. Rf = 0.65 (petroleum ether/ethyl
acetate, 10:1). [α]D = –28.3 (c = 1.00, CH Cl ). IR (KBr): ν = 1069,
˜
2
2
(d, J = 10.4 Hz, 1 H, 7Ј-H), 4.96 (dd, J = 17.2, 1.8 Hz, 1 H, 7Ј-H), 1117, 1256, 1275, 1470, 1726, 2864, 2941 cm–1. 1H NMR
5.01 (br. d, J = 10.4 Hz, 1 H, 9-H), 5.02 (br. d, J = 17.2 Hz, 1 H,
9-H), 5.16 (tt, J = 5.9, 5.6 Hz, 1 H, 1Ј-H), 5.76 (ddt, J = 17.2, 10.4,
6.7 Hz, 1 H, 6Ј-H), 5.83–5.95 (m, 1 H, 8-H), 6.73 (d, J = 8.3 Hz,
1H, 5-H), 6.78 (d, J = 7.8 Hz, 1H, 3-H), 7.23 (dd, J = 8.3, 7.8 Hz,
(400 MHz, CDCl3): δ = 0.94–1.16 (m, 22 H, TIPS-CH, TIPS-CH3,
13-H), 1.22–1.34 (m, 1 H, 12-H), 1.44–1.55 (m, 1 H, 12-H), 1.58–
1.70 (m, 2 H, 13-H, 11-H), 1.72–1.80 (m, 1 H, 16-H), 1.81–1.91 (m,
1 H, 16-H), 2.13–2.22 (m, 1 H, 11-H), 2.53 (dd, J = 16.4, 9.4 Hz,
1H, 4-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 23.9 (C-1ЈЈ), 24.5 1 H, 14-H), 2.83 (dd, J = 16.4, 4.1 Hz, 1 H, 14-H), 3.15 (d, J =
(C-3Ј), 28.6 (C-4Ј), 32.7 (C-2Ј), 33.6 (C-5Ј), 37.3 (C-7), 55.7 (Ph- 14.3 Hz, 1 H, 8-H), 3.72 (dd, J = 14.3, 10.3 Hz, 1 H, 8-H), 3.77 (s,
OCH3), 70.5 (C-3ЈЈ), 72.6 (C-1Ј), 79.8 (C-2ЈЈ), 108.8 (C-5), 114.5
3 H, Ph-OCH3), 5.05–5.14 (m, 1 H, 15-H), 5.24–5.34 (m, 1 H, 9-
(C-7Ј), 116.3 (C-9), 121.5 (C-3), 123.7 (C-1), 130.3 (C-4), 136.3 (C- H), 5.36–5.47 (m, 1 H, 10-H), 6.78 (d, J = 7.3 Hz, 1H, 6-H), 6.78
8), 138.3 (C-2), 138.6 (C-6Ј), 156.4 (C-6), 167.7 (Ph-CO2) ppm. MS
(d, J = 8.7 Hz, 1H, 4-H), 7.24 (dd, J = 8.7, 7.3 Hz, 1H, 5-H) ppm.
(EI): m/z (%) = 326 (4), 192 (54), 177 (100), 175 (92), 147 (34), 129 13C NMR (100 MHz, CDCl3): δ = 11.2 (TIPS-CH), 18.6 (TIPS-
(45), 115 (27), 91 (15), 77 (7). HRMS (ESI): [M + Na]+ calcd. for CH3), 19.8 (C-12), 24.4 (C-13), 25.3 (C-14), 31.3 (C-16), 32.7 (C-
C21H26NaO3 349.17742, found 349.17664.
11), 37.8 (C-8), 55.9 (Ph-OCH3), 70.6 (C-15), 82.9 (C-18), 104.0
(C-17), 109.6 (C-4), 122.4 (C-6), 124.0 (C-2), 128.9 (C-9), 130.3 (C-
5), 132.6 (C-10), 139.4 (C-7), 156.9 (C-3), 167.8 (C-1) ppm. MS
(EI): m/z (%) = 412 (34), 411 (100), 393 (8), 378 (9), 305 (33), 263
(23), 175 (31), 131 (33), 103 (51), 75 (32). HRMS (EI): [M – iPr]+
calcd. for C25H35SiO3 411.2355, found 411.2383.
(1R)-1-[3-(Triisopropylsilyl)prop-2-ynyl]hept-6-enyl 2-Allyl-6-meth-
oxybenzoate (16): To alkyne 15 (0.74 g, 2.27 mmol) in THF
(23 mL) was added at –78 °C nBuLi (1.02 mL, 2.55 mmol, 2.5 m in
hexane) dropwise and the resulting solution was stirred 30 min
while warming to –20 °C. After recooling to –78 °C the solution
was treated with TIPS chloride (0.58 mL, 0.53 g, 2.72 mmol) in
THF (13 mL) and warmed to room temperature within 15 h. The
reaction was quenched by addition of saturated NH4Cl solution
(30 mL) at 0 °C. After separation of the phases the aqueous layer
was extracted with diethyl ether (2 × 30 mL) and the combined
organic extracts were dried with Na2SO4. The solid was filtered off,
the solution was concentrated in vacuo, and the residue purified by
flash chromatography (petroleum ether/ethyl acetate, 10:1) to pro-
vide the TIPS-alkyne 16 (0.85 g, 78 %) as a colorless oil. Rf = 0.61
(petroleum ether/ethyl acetate, 10:1). [α]D = 31.8 (c = 1.30,
Z-17 (minor product): Rf = 0.61 (petroleum ether/ethyl acetate,
10:1). [α]D = –4.8 (c = 1.00, CH Cl ). IR (film): ν = 1114, 1243,
˜
2
2
1267, 1469, 1587, 1728, 2864, 2941 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 1.05 (br. s, 21 H, TIPS-CH, TIPS-CH3), 1.37–1.53 (m,
4 H, 13-H, 12-H), 1.85–2.09 (m, 3 H, 16-H, 11-H), 2.31–2.42 (m,
1 H, 11-H), 2.57–2.63 (m, 2 H, 14-H), 3.20 (br. d, J = 15.0 Hz, 1
H, 8-H), 3.51 (dd, J = 15.0, 10.2 Hz, 1 H, 8-H), 3.79 (s, 3 H, Ph-
OCH3), 5.13–5.22 (m, 1 H, 10-H), 5.29–5.36 (m, 1 H, 15-H), 5.43–
5.51 (m, 1 H, 9-H), 6.75 (d, J = 8.3 Hz, 1 H, 4-H), 6.89 (d, J =
7.7 Hz, 1 H, 6-H), 7.28 (dd, J = 8.3, 7.7 Hz, 1 H, 5-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 11.2 (TIPS-CH), 17.8 (C-12), 18.6
(TIPS-CH3), 23.6 (C-14), 24.4 (C-11), 26.3 (C-13), 28.5 (C-16), 31.6
(C-8), 55.8 (Ph-OCH3), 73.3 (C-15), 82.9 (C-18), 103.6 (C-17),
108.6 (C-4), 121.9 (C-6), 123.9 (C-2), 129.5 (C-10), 130.0 (C-9),
130.4 (C-5), 139.4 (C-7), 156.2 (C-3), 167.7 (C-1) ppm. MS (EI):
m/z (%) = 412 (30), 411 (100), 393 (4), 378 (5), 263 (12), 175 (13),
131 (19), 103 (23), 75 (12). HRMS (EI): [M – iPr]+ calcd. for
C25H35O3Si 411.23554, found 411.23212.
CH Cl ). IR (film): ν = 1071, 1113, 1267, 1438, 1470, 1585, 1729,
˜
2
2
2175, 2865, 2942 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.90–1.08
(m, 21 H, TIPS-CH, TIPS-CH3), 1.35–1.51 (m, 4 H, 4Ј-H, 3Ј-H),
1.71–1.81 (m, 1 H, 2Ј-H), 1.85–1.95 (m, 1 H, 2Ј-H), 2.04 (dt, J =
6.7, 6.5 Hz, 2 H, 5Ј-H), 2.56 (dd, J = 16.7, 7.9 Hz, 1 H, 1ЈЈ-H),
2.71 (dd, J = 16.7, 4.3 Hz, 1 H, 1ЈЈ-H), 3.33 (d, J = 6.5 Hz, 2 H,
7-H), 3.75 (s, 3 H, Ph-OCH3), 4.90 (br. d, J = 10.3 Hz, 1 H, 7Ј-H),
4.93–5.06 (m, 1 H, 7Ј-H, 9-H), 5.15 (ddt, J = 7.9, 4.3, 4.0 Hz, 1 H,
1Ј-H), 5.77 (ddt, J = 17.1, 10.3, 6.7 Hz, 1 H, 6Ј-H), 5.88 (ddt, J =
17.6, 9.5, 6.6 Hz, 1 H, 8-H), 6.73 (d, J = 8.3 Hz, 1 H, 5-H), 6.78
(3R)-14-Methoxy-3-(prop-2-ynyl)-3,4,5,6,7,10-hexahydro-1H-2-benz-
oxacyclododecin-1-one (18): To a solution of TIPS alkyne E-17
Eur. J. Org. Chem. 2005, 728–739
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
733

C. Herb, F. Dettner, M. E. Maier
FULL PAPER
(105 mg, 0.23 mmol) in THF (2.3 mL) was added TBAF (1 m in
THF, 1.15 mL, 1.15 mmol) at 0 °C. The solution was stirred at
room temperature for 5 h , then treated with saturated aqueous
NaHCO3 solution (3 mL) and the mixture extracted with Et2O (2
× 3 mL). The combined extracts were dried (Na2SO4), filtered, and
concentrated. Flash chromatography (petroleum ether/ethyl ace-
tate, 5:1) of the residue gave 80 mg (100 %) of the desired alkyne
18 as a colorless wax. Rf = 0.63 (petroleum ether/ethyl acetate, 5:1).
2.69 (dd, J = 16.6, 4.4 Hz, 1 H, 2-H), 4.04–4.12 (m, 1 H, 3-H) ppm.
13C NMR (100 MHz, CDCl3): δ = –4.9 [Si(CH3)2], –4.8 [Si-
(CH3)2], 17.9 (SiC), 25.5 (C-2), 25.6 [SiC(CH3)3], 27.2 (C-4), 67.3
(C-3), 71.7 (C-6), 79.1 (C-5), 117.4 (C-1) ppm. MS (EI): m/z (%) =
208 (6), 184 (24), 166 (100), 147 (6), 125 (13), 101 (68), 98 (23), 97
(86), 73 (34). HRMS (ESI): [M + Na]+ calcd. for C12H21NNaOSi
246.12846, found 246.12838.
(3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}hex-5-ynal (22): To a stirred
solution of the nitrile 21 (1.32 g, 4.47 mmol) in dry CH2Cl2 (45 mL)
was added DIBAL (5.36 mL, 5.36 mmol, 1.0 m in hexane) dropwise
over 10 min at –78 °C. After being stirred for 4 h at –78 °C, meth-
anol (1.3 mL) was added, the cooling bath removed, and the mix-
ture warmed to room temperature. Then water (13 mL) and diethyl
ether (45 mL) were added, the phases were separated, and the
cloudy aqueous layer extracted with diethyl ether (3 × 20 mL). The
combined organic layers were washed with water (20 mL), brine
(20 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The
crude aldehyde 22 (1.33 g, 96 %) was obtained as a pale yellow oil
and could be used without further purification in the next step. Rf
= 0.71 (petroleum ether/ethyl acetate, 5:1). [α]D = –22.8 (c = 1.19,
[α]D = –21.9 (c = 1.00, CH Cl ). IR (film): ν = 1069, 1118, 1278,
˜
2
2
1470, 1584, 1723, 2864, 2939, 3291, 3547 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.01–1.13 (m, 1 H, 13-H), 1.22–1.33 (m, 1
H, 12-H), 1.43–1.54 (m, 1 H, 12-H), 1.56–1.73 (m, 3 H, 13-H, 16-
H, 11-H), 1.78–1.88 (m, 1 H, H-16), 2.01 (t, J = 2.7 Hz, 1 H, H-
18), 2.12–2.21 (m, 1 H, H-11), 2.55–2.67 (m, 2 H, 14-H), 3.14 (d,
J = 14.2 Hz, 1 H, 8-H), 3.71 (dd, J = 14.2, 10.5 Hz, 1 H, 8-H), 3.79
(s, 1 H, Ph-OCH3), 5.07–5.14 (m, 3 H, 15-H), 5.24–5.32 (m, 1 H,
9-H), 5.35–5.45 (m, 1 H, 10-H), 6.77 (d, J = 7.0 Hz, 1 H, 6-H),
6.79 (d, J = 7.7 Hz, 1 H, 4-H), 7.23 (dd, J = 7.7, 7.0 Hz, 1 H, 5-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.7 (C-12), 23.9 (C-
14), 24.6 (C-13), 31.4 (C-16), 32.7 (C-11), 37.8 (C-8), 55.8 (Ph-
OCH3), 69.7 (C-15), 70.2 (C-18), 80.1 (C-17), 109.6 (C-4), 122.4
(C-6), 123.9 (C-2), 128.9 (C-9), 130.3 (C-5), 132.6 (C-10), 139.4 (C-
7), 156.9 (C-3), 167.9 (C-1) ppm. MS (EI): m/z (%) = 298 (15), 177
(20), 131 (91), 103 (100), 75 (89), 61 (38). HRMS (EI): [M]+ calcd.
for C19H22O3 298.1569, found 298.1557.
CH Cl ). IR (film): ν = 1107, 1256, 1728, 2857, 2929, 2953,
˜
2
2
3312 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.06 [s, 3 H, Si(CH3)2],
0.09 [s, 3 H, Si(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 2.02 (t, J =
2.7 Hz, 1 H, 6-H), 2.38 (ddd, J = 16.7, 7.4, 2.7 Hz, 1 H, 4-H), 2.44
(ddd, J = 16.7, 5.0, 2.7 Hz, 1 H, 4-H), 2.65 (ddd, J = 16.2, 7.1,
(3R)-3-Hydroxyhex-5-ynenitrile (20): To a solution of chlorohy- 2.5 Hz, 1 H, 2-H), 2.74 (ddd, J = 16.2, 4.5, 1.6 Hz, 1 H, 2-H), 4.34
drin[24b,31] 19 (5.13 g, 26.9 mmol) in ethanol (130 mL) was added (dddd, J = 7.4, 7.1, 5.0, 4.5 Hz, 1 H, 3-H), 9.80 (dd, J = 2.5, 1.6 Hz,
sodium cyanide (3.30 g, 67.3 mmol) and potassium carbonate
(3.90 g, 28.2 mmol) and the resulting suspension was stirred 3 days
at room temperature. After complete consumption (TLC control)
the mixture was diluted with petroleum ether (20 mL) and filtered
through celite. The filter cake was washed with diethyl ether
(150 mL) and the combined organic solutions were evaporated in
vacuo. Flash chromatography (petroleum ether/ethyl acetate, 3:2)
of the residue afforded the pure nitrile 20 (2.82 g, 96 %) as a color-
1 H, 1-H) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.9 [Si(CH3)2],
–4.6 [Si(CH3)2], 17.9 (SiC), 25.6 [SiC(CH3)3], 27.7 (C-4), 50.2
(C-2), 66.7 (C-3), 71.1 (C-6), 80.2 (C-5), 201.2 (C-1) ppm. MS (EI):
m/z (%) = 203 (4), 187 (19), 169 (32), 151 (16), 141 (27), 129 (36),
125 (64), 101 (100), 95 (56), 75 (70), 73 (49), 59 (25).
(4S)-3-[(2S,3R,5R)-2-Allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-3-hy-
droxy-7-octynoyl]-4-benzyl-1,3-oxazolidin-2-one (24): To a stirred,
cooled (0 °C) solution of (4S)-4-benzyl-3-pent-4-enoyl-1,3-oxazoli-
din-2-one[34] (23) (3.63 g, 14.0 mmol) in CH2Cl2 (140 mL) was
added dropwise titanium(iv) chloride (1.62 mL, 2.79 g, 14.7 mmol)
and the resulting mixture was stirred for 5 min. Subsequently, (–)-
sparteine (8.04 mL, 8.20 g, 35.0 mmol) was added to the yellow
slurry. The dark red enolate solution was stirred for 20 min at 0 °C
before a solution of aldehyde 22 (4.00 g, 17.9 mmol) in CH2Cl2
(35 mL) was added dropwise and the mixture stirred for 1 h at 0 °C.
The reaction was quenched with half-saturated NH4Cl solution
(70 mL) and allowed to reach room temperature. After separation
of the layers, the aqueous layer was extracted with CH2Cl2 (2 ×
70 mL) and the combined organic layers were dried (Na2SO4), fil-
less liquid. Rf = 0.55 (petroleum ether/ethyl acetate, 1:1). [α]D
=
–21.1 (c = 1.58, CH Cl ). IR (film): ν = 1080, 1416, 2254, 3291,
˜
2
2
1
3444 cm–1. H NMR (400 MHz, CDCl3): δ = 2.13 (t, J = 2.6 Hz,
1 H, 6-H), 2.53 (dd, J = 6.0, 2.6 Hz, 2 H, 4-H), 2.64 (dd, J = 16.7,
6.6 Hz, 1 H, 2-H), 2.70 (dd, J = 16.7, 5.1 Hz, 1 H, 2-H), 2.81 (br.
s, 1 H, OH), 4.08–4.15 (m, 1 H, 3-H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 24.7 (C-2), 26.5 (C-4), 66.0 (C-3), 72.3 (C-6), 78.5 (C-
5), 117.2 (C-1) ppm. MS (EI): m/z (%) = 130 (5), 110 (42), 93 (14),
82 (48), 70 (96), 69 (80), 68 (38), 65 (14), 42 (98), 41 (79), 40 (100),
39 (94). HRMS (EI): [M]+ calcd. for C6H7ON 109.052755, found
109.053331.
(3R)-3-{[tert-Butyl(dimethyl)silyl]oxy}hex-5-ynenitrile (21): TBDMS- tered, and concentrated in vacuo. Purification of the residue by
Cl (8.28 g, 54.8 mmol) was added to
a
stirred solution of
flash chromatography (petroleum ether/diethyl ether, 1:1) afforded
6.66 g (89 %) of the desired aldol product 24 as a colorless viscous
oil and 0.40 g (10 %) of unreacted aldehyde 22. Rf = 0.51 (petro-
leum ether/diethyl ether, 1:1). [α]D = +32.5 (c = 1.00, CH2Cl2). IR
alcohol 20 (3.98 g, 36.5 mmol), imidazole (6.21 g, 91.3 mmol), and
DMAP (224 mg, 1.83 mmol) in dry DMF (370 mL). The resulting
solution was stirred at ambient temperature for 3 days, then diluted
with water (370 mL) and extracted with diethyl ether (3 × 300 mL).
The combined extracts were washed with 0.1 n HCl (200 mL),
brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo.
Volatile side products and unreacted starting material were re-
moved by distillation at 70 °C (1 mbar) to leave the pure TBDMS
(film): ν = 1105, 1208, 1248, 1290, 1386, 1695, 1779, 2857, 2889,
˜
2929, 2951, 3308, 3521 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.10
[s, 3 H, Si(CH3)2], 0.11 [s, 3 H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3],
1.80 (ddd, J = 14.3, 8.8, 7.8 Hz, 1 H, 4Ј-H), 1.87 (ddd, J = 14.3,
4.9, 2.7 Hz, 1 H, 4Ј-H), 1.99 (t, J = 2.6 Hz, 1 H, 8Ј-H), 2.38 (d, J
ether 21 (8.13 g, 100 %) as slightly yellow oil. Rf = 0.70 (petroleum = 2.6 Hz, 1 H, 6Ј-H), 2.39 (d, J = 2.6 Hz, 1 H, 6Ј-H), 2.48 (ddd, J
ether/ethyl acetate, 5:1). [α]D = –16.2 (c = 1.32, CH2Cl2). IR (film):
˜
(400 MHz, CDCl3): δ = 0.11 [s, 3 H, Si(CH3)2], 0.13 [s, 3 H, Si-
= 14.2, 6.0, 4.8 Hz, 1 H, CH 2CH=CH2), 2.58–2.67 (m, 1 H, CH2-
CH=CH2), 2.63 (dd, J = 13.3, 10.2 Hz, 1 H, Bn-CH2), 3.19 (d, J
= 1.7 Hz, 1 H, OH), 3.28 (dd, J = 13.3, 3.1 Hz, 1 H, Bn-CH2),
ν = 1112, 1257, 1364, 1472, 2858, 2931, 2955, 3310 cm–1. 1H NMR
(CH3)2], 0.90 [s, 9 H, SiC(CH3)3], 2.06 (dd, J = 2.7, 2.6 Hz, 1 H, 4.00–4.17 (m, 5 H, 3Ј-H, 5Ј-H, 5-H, 2Ј-H), 4.64–4.71 (m, 1 H, 4-
6-H), 2.42 (ddd, J = 16.9, 7.5, 2.6 Hz, 1 H, 4-H), 2.48 (ddd, J =
16.9, 5.0, 2.7 Hz, 1 H, 4-H), 2.60 (dd, J = 16.6, 6.4 Hz, 1 H, 2-H),
H), 5.03 (br. d, J = 10.2 Hz, 1 H, CH2CH=CH ), 5.11 (br. d, J =
17.1 Hz, 1 H, CH2CH=CH 2), 5.86 (dddd, J = 17.1, 10.2, 7.6,
2
734
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 728–739

Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
FULL PAPER
6.6 Hz, 1 H, CH2CH=CH2), 7.19–7.34 (m, 5 H, Bn-H-2,6, Bn-H-4, nel. After extraction with CH2Cl2 (3 × 15 mL) the combined or-
Bn-H-3,5) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.8 [Si(CH3)2], ganic layers were washed with brine (5 mL), dried with MgSO4,
–4.4 [Si(CH3)2], 17.9 (SiC), 25.7 [SiC(CH3)3], 27.5 (C-6Ј), 31.9
filtered, and concentrated in vacuo. Flash chromatography (petro-
(CH2CH=CH2), 37.9 (Bn-CH2), 40.0 (C-4Ј), 47.4 (C-2Ј), 55.5 (C-4), leum ether/ethyl acetate, 3:2) of the residue provided alcohol 26
65.9 (C-5), 70.3 (C-5Ј), 70.5 (C-3Ј), 70.7 (C-8Ј), 80.6 (C-7Ј), 117.2 (0.91 g, 68 %) as a colorless oil. Rf = 0.64 (petroleum ether/ethyl
(CH2CH=CH2), 127.3 (Bn-C-4), 128.9 (Bn-C-3,5), 129.3 (Bn-C- acetate, 1:1). [α]D = –14.9 (c = 1.00, CH Cl ). IR (film): ν = 1036,
˜
2
2
2,6), 135.2 (CH2 CH=CH2), 135.3 (Bn-C-1), 153.2 (C-2), 174.5 (C-
1Ј) ppm. MS (EI): m/z (%) = 490 (3), 432 (5), 411 (6), 402 (9), 384
(16), 355 (14), 310 (4), 270 (15), 255 (22), 253 (20), 252 (100), 237
1100, 1151, 1256, 2857, 2888, 2929, 2954, 3467 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.04 [s, 3 H, Si(CH3)2], 0.05 [s, 3 H,
Si(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 1.77 (ddd, J = 14.3, 7.4, 6.1 Hz,
(10), 196 (13), 152 (19), 171 (29), 91 (53), 75 (42), 73 (33). HRMS 1 H, 4-H), 1.87 (ddd, J = 14.3, 6.0, 6.0 Hz, 1 H, 4-H), 1.87–1.94
(ESI): [M + Na]+ calcd. for C27H39NNaO5Si 508.24897, found
508.24921.
(m, 1 H, 2-H), 1.94–2.02 (m, 1 H, CH 2CH=CH2), 1.96 (dd, J = 2.6,
2.6 Hz, 1 H, 8-H), 2.07 (br. ddd, J = 14.2, 6.1, 6.1 Hz, 1 H, CH -
2
CH=CH2), 2.31 (ddd, J = 16.9, 5.1, 2.6 Hz, 1 H, 6-H), 2.37 (ddd,
J = 16.9, 6.0, 2.6 Hz, 1 H, 6-H), 2.71 (br. dd, J = 5.7, 5.7 Hz, 1 H,
OH), 3.36 (s, 3 H, MOM-CH3), 3.54–3.68 (m, 2 H, 1-H), 3.81–3.91
(m, 2 H, 3-H, 5-H), 4.60 (s, 2 H, MOM-CH2), 4.97 (br. d, J =
10.1 Hz, 1 H, CH2CH=CH 2), 5.02 (br. d, J = 17.1 Hz, 1 H,
CH2CH=CH 2), 5.75 (br. dddd, J = 17.1, 10.1, 7.0, 7.0 Hz, 1 H,
CH2CH=CH2) ppm. 13C NMR (100 MHz, CDCl3): δ = –4.7
[Si(CH3)2], –4.6 [Si(CH3)2], 17.9 (SiC), 25.7 [SiC(CH3)3], 27.0 (C-
6), 31.2 (CH2CH=CH2), 37.5 (C-4), 42.6 (C-2), 55.9 (MOM-CH3),
63.1 (C-1), 68.0 (C-5), 70.3 (C-8), 76.1 (C-3), 81.1 (C-7), 95.9
(MOM-CH2), 116.3 (CH2CH=CH2), 136.8 (CH2 CH=CH2) ppm.
MS (EI): m/z (%) = 267 (10), 237 (23), 199 (13), 183 (15), 169 (52),
145 (40), 131 (63), 123 (100), 105 (30), 89 (42), 75 (61), 45 (38).
HRMS (FAB): [M + Na]+ calcd. for C19H36NaO4Si 379.22807,
found 379.22608.
(4S)-3-[(2S,3R,5R)-2-Allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-3-
(methoxymethoxy)oct-7-ynoyl]-4-benzyl-1,3-oxazolidin-2-one (25):
To astirred, cooled (0 °C) solution of alcohol 24 (3.24 g,
6.67#160;mmol) in CH2Cl2 (67 mL) were added N,N-diisopropyle-
thylamine (11.4 mL, 8.64 g, 66.7 mmol), chloromethylmethyl ether
(2.55 mL, 2.68 g, 33.4 mmol) and TBAI (0.49 g, 1.33 mmol). The
reaction mixture was protected from light and allowed to reach
room temperature within 24 h whilst stirring before it was treated
with saturated aqueous NaHCO3 solution (35 mL) and the phases
were separated. After extraction of the aqueous layer with diethyl
ether (2 × 60 mL) the combined extracts were washed with 1 n
HCl (35 mL) and brine (35 mL). The combined extracts were dried
(Na2SO4), filtered, and concentrated in vacuo. Flash chromatogra-
phy (petroleum ether/ethyl acetate, 3:1) of the residue provided
MOM ether 25 as a colorless viscous oil; yield 2.81 g (80 %). Rf =
0.58 (petroleum ether/ethyl acetate, 3:1). [α]D = +76.3 (c = 1.00,
(2R,3R,5R)-2-Allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-3-(methoxy-
methoxy)oct-7-ynyl 4-Methylbenzenesulfonate (27): To a stirred
solution of alcohol 26 (0.88 g, 2.47 mmol) in pyridine (5 mL) was
added p-toluenesulfonyl chloride (1.42 g, 7.41 mmol) at 0 °C. After
being stirred for 5 h, the reaction was quenched by addition of ice
(2.5 g) and H2O (12 mL). The mixture was diluted with Et2O
(50 mL) and washed with saturated NaHCO3 solution (10 mL), 1 n
HCl (10 mL), and brine (10 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated in vacuo. Filtration (petro-
leum ether/ethyl acetate, 3:1) of the residue over a short pad of
silica gel and evaporation of the solvent gave the pure tosylate 27
as a colorless viscous oil, yield 1.26 g (100 %). Rf = 0.56 (petroleum
ether/ethyl acetate, 3:1). [α]D = –4.1 (c = 1.42, CH2Cl2). IR (film):
CH Cl ). IR (film): ν = 1025, 1101, 1208, 1251, 1384, 1698, 1781,
˜
2
2
2929, 2953 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.08 [s, 3 H,
Si(CH3)2], 0.09 [s, 3 H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3], 1.82
(ddd, J = 14.4, 8.7, 4.6 Hz, 1 H, 4Ј-H), 1.96 (t, br, J = 2.5 Hz, 1
H, 8Ј-H), 1.97 (ddd, J = 14.4, 7.8, 3.5 Hz, 1 H, 4Ј-H), 2.36 (ddd, J
= 16.7, 5.1, 2.5 Hz, 1 H, 6Ј-H), 2.36 (d, J = 14.1 Hz, 1 H, CH2-
CH=CH2), 2.45 (ddd, J = 16.7, 5.0, 2.5 Hz, 1 H, 6Ј-H), 2.59 (ddd,
J = 14.1, 8.6, 8.6 Hz, 1 H, CH 2CH=CH2), 2.67 (dd, J = 13.3,
10.0 Hz, 1 H, Bn-CH2), 3.27 (dd, J = 13.3, 3.0 Hz, 1 H, Bn-CH2),
3.35 (s, 3 H, MOM-CH3), 3.82–3.87 (m, 1 H, 3Ј-H), 3.93–4.00 (m,
1 H, 5Ј-H), 4.08–4.16 (m, 2 H, 5-H), 4.33 (ddd, J = 9.6, 4.7, 4.7 Hz,
1 H, 2Ј-H), 4.54 (d, J = 7.2 Hz, 1 H, MOM-CH2), 4.61–4.67 (m, 1
H, 4-H), 4.66 (d, J = 7.2 Hz, 1 H, MOM-CH2), 5.04 (br. d, J =
10.1 Hz, 1 H, CH2CH=CH 2), 5.12 (br. d, J = 17.1 Hz, 1 H,
CH2CH=CH 2), 5.82 (dddd, J = 17.1, 10.1, 6.9, 6.9 Hz, 1 H,
CH2CH=CH2), 7.18–7.34 (m, 5 H, Bn-H-2,6, Bn-H-4, Bn-H-3,5)
ppm. 13C NMR (100 MHz, CDCl3): δ = –4.7 [Si(CH3)2], 18.0 (SiC),
25.7 [SiC(CH3)3], 26.4 (C-6Ј), 32.5 (CH2CH=CH2), 37.8 (Bn-CH2),
39.2 (C-4Ј), 45.6 (C-2Ј), 55.8 (C-4), 56.2 (MOM-CH3), 65.7 (C-5),
67.9 (C-5Ј), 70.0 (C-8Ј), 75.4 (C-3Ј), 81.4 (C-7Ј), 95.9 (MOM-CH2),
117.1 (CH2CH=CH2), 127.2 (Bn-C-4), 128.8 (Bn-C-3,5), 129.4 (Bn-
C-2,6), 135.1 (CH2 CH=CH2), 135.3 (Bn-C-1), 153.2 (C-2), 173.3
(C-1Ј) ppm. MS (EI): m/z (%) = 472 (38), 428 (30), 410 (19), 370
(9), 296 (11), 265 (21), 258 (44), 251 (62), 235 (28), 211 (30), 190
(100), 169 (36), 159 (16), 117 (25), 91 (28), 86 (48), 84 (63), 49 (55).
HRMS (ESI): [M + Na]+ calcd. for C29H43NNaO6Si 552.27519,
found 552.27534.
ν = 1036, 1098, 1178, 1189, 1253, 1366, 2857, 2894, 2929,
˜
2953 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.03 [s, 3 H, Si(CH3)2],
0.05 [s, 3 H, Si(CH3)2], 0.85 [s, 9 H, SiC(CH3)3], 1.67 (ddd, J =
14.3, 6.9, 6.2 Hz, 1 H, 4-H), 1.85 (ddd, J = 14.3, 5.8, 5.8 Hz, 1 H,
4-H), 1.96 (t, J = 2.6 Hz, 1 H, 8-H), 1.97–2.08 (m, 2 H, 2-H, CH2-
CH=CH2), 2.10–2.20 (m, 1 H, CH CH=CH2), 2.31 (dd, J = 5.7,
2
2.6 Hz, 2 H, 6-H), 2.43 (s, 3 H, Ts-CH3), 3.27 (s, 3 H, MOM-CH3),
3.69–3.74 (m, 1 H, 3-H), 3.80–3.88 (m, 1 H, 5-H), 4.01 (dd, J =
9.4, 5.3 Hz, 1 H, 1-H), 4.08 (dd, J = 9.4, 6.1 Hz, 1 H, 1-H), 4.48
(d, J = 6.8 Hz, 1 H, MOM-CH2), 4.52 (d, J = 6.8 Hz, 1 H, MOM-
CH2), 4.95–5.02 (m, 2 H, CH2CH=CH 2), 5.67 (dddd, J = 17.1,
10.1, 7.1, 7.1 Hz, 1 H, CH2CH=CH2), 7.33 (d, J = 8.2 Hz, 2 H,
Ts-H-3,5), 7.77 (d, J = 8.2 Hz, 2 H, Ts-H-2,6) ppm. 13C NMR
(100 MHz, CDCl3): δ = –4.7 [Si(CH3)2], –4.5 [Si(CH3)2], 18.0 (SiC),
21.6 (Ts-CH3), 25.8 [SiC(CH3)3], 27.0 (C-6), 30.7 (CH2CH=CH2),
37.8 (C-4), 41.1 (C-2), 55.8 (MOM-CH3), 67.9 (C-5), 69.7 (C-1),
70.4 (C-8), 74.2 (C-3), 81.1 (C-7), 96.1 (MOM-CH2), 117.2
(CH2CH=CH2), 128.0 (Ts-C-2,6), 129.8 (Ts-C-3,5), 133.0 (Ts-C-1),
135.7 (CH2 CH=CH2), 144.7 (Ts-C-4) ppm. MS (EI): m/z (%) =
409 (8), 309 (4), 287 (5), 237 (32), 229 (100), 197 (11), 169 (24), 155
(32), 145 (50), 117 (21), 91 (62), 89 (28), 73 (22), 45 (22). HRMS
(FAB): [M + Na]+ calcd. for C26H42NaO6SSi 533.23691, found
533.23997.
(2R,3R,5R)-2-Allyl-5-{[tert-butyl(dimethyl)silyl]oxy}-3-(methoxy-
methoxy)oct-7-yn-1-ol (26): Lithium borohydride (2.45 mL,
4.91 mmol, 2 m in THF) was added dropwise to a cooled (0 °C)
solution of amide 25 (2.00 g, 3.78 mmol) and ethanol (0.29 mL,
0.23 g, 4.91 mmol) in dry diethyl ether (40 mL). Stirring was con-
tinued for 12 h with concomitant warming of the mixture to room
temperature. The solution was treated with saturated NH4Cl solu-
tion (10 mL), stirred for 1 h, and transferred into a separation fun-
Eur. J. Org. Chem. 2005, 728–739
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
735

C. Herb, F. Dettner, M. E. Maier
in toluene (13 mL) was added a solution of salicylic acid[11g]
(254 mg, 1.32 mmol) and DEAD (955 mg, 1.89 mmol, of a 40 % in
toluene) in toluene (13 mL) at room temperature. The mixture was
stirred for 15 h and the solvent was removed under reduced pres-
sure. Purification of the residue by flash chromatography (petro-
leum ether/ethyl acetate, 4:1) provided the ester 30 (350 mg, 69 %)
as a colorless oil. Rf = 0.55 (petroleum ether/ethyl acetate, 4:1).
FULL PAPER
(4S,5R,7R)-7-{[tert-Butyl(dimethyl)silyl]oxy}-5-(methoxymethoxy)-
4-methyldec-1-en-9-yne (28): A cooled (0 °C) solution of tosylate 27
(915 mg, 1.79 mmol) in THF (18 mL) was treated dropwise with
lithium triethylboronhydride (8.96 mL, 8.96 mmol, 1 m in THF).
After being stirred for 15 h and warming up to room temperature,
the reaction was quenched by careful addition of a 1:1 mixture of
THF and water (total 3 mL) at 0 °C. Saturated NH4Cl solution
(10 mL) was added and the mixture stirred 1 h. After extraction
with diethyl ether (3 × 10 mL) the combined organic extracts were
dried with Na2SO4, filtered and the solvents evaporated. Purifica-
tion of the residue by flash chromatography (petroleum ether/ethyl
5
[α]D = +39.4 (c = 1.00, CH Cl ). IR (film): ν = 1038, 1072, 1111,
˜
2
2
1245, 1267, 1471, 1585, 1730, 2932, 2962 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.87 (d, J = 6.7 Hz, 3 H, CH3), 1.71–1.85
(m, 3 H, 2Ј-H, 5Ј-H), 1.85–1.94 (m, 1 H, 4Ј-H), 1.98 (t, J = 2.7 Hz,
acetate, 3:1) provided the methyl derivative 28 (567 mg, 93 %) as a 1 H, CH2CCH), 1.99–2.06 (m, 1 H, 5Ј-H), 2.57 (ddd, J = 16.9, 4.6,
colorless oil. Rf = 0.79 (petroleum ether/ethyl acetate, 3:1). [α]D
=
2.7 Hz, 1 H, CH 2CCH), 2.65 (ddd, J = 16.9, 6.2, 2.7 Hz, 1 H, CH2-
CCH), 3.36 (s, 3 H, MOM-CH3), 3.68 (ddd, J = 9.4, 3.7, 2.9 Hz,
+18.1 (c = 1.00, CH Cl ). IR (film): ν = 1038, 1092, 1150, 1257,
˜
2
2
2857, 2887, 2930, 2957 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.06 1 H, 3Ј-H), 3.77 (s, 3 H, Ph-OCH3), 4.67 (s, 2 H, MOM-CH2), 4.87
[s, 3 H, Si(CH3)2], 0.08 [s, 3 H, Si(CH3)2], 0.88 [s, 9 H, SiC(CH3)3], (br. d, J = 10.1 Hz, 1 H, 7Ј-H), 4.92 (br. d, J = 17.0 Hz, 1 H, 7Ј-
0.88–0.90 (m, 3 H, CH3), 1.64–1.90 (m, 4 H, 5-H, 7-H, 8-H), 1.95
(t, J = 2.6 Hz, 1 H, 1-H), 2.06–2.15 (m, 1 H, 8-H), 2.33 (ddd, J =
16.7, 5.4, 2.6 Hz, 1 H, 3-H), 2.41 (ddd, J = 16.7, 5.4, 2.6 Hz, 1 H,
H), 4.98–5.04 (m, 2 H, 9-H), 5.29–5.35 (m, 1 H, 1Ј-H), 5.69 (dddd,
J = 17.0, 10.1, 7.3, 6.7 Hz, 1 H, 6Ј-H), 5.90 (dddd, J = 17.3, 9.6,
6.6, 6.6 Hz, 1 H, 8-H), 6.72 (d, J = 8.4 Hz, 1 H, 3-H), 6.77 (d, J =
7.7 Hz, 1 H, 5-H), 7.23 (dd, J = 8.4, 7.7 Hz, 1 H, 4-H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 13.6 (CH3), 24.6 (CH2CCH), 33.9
(C-2Ј), 36.5 (C-4Ј), 37.2 (C-7), 37.6 (C-5Ј), 55.5 (Ph-OCH3), 55.7
(MOM-CH3), 69.8 (CH2CCH), 70.9 (C-1Ј), 77.9 (C-3Ј), 79.6 (CH2
3-H), 3.36 (s, 3 H, MOM-CH ), 3.51 (ddd, J = 8.1, 4.0, 4.0 Hz, 1
3
H, 6-H), 3.92–3.98 (m, 1 H, 4-H), 4.58 (d, J = 6.9 Hz, 1 H, MOM-
CH2), 4.61 (d, J = 6.9 Hz, 1 H, MOM-CH2), 4.97 (br. d, J =
10.1 Hz, 1 H, 10-H), 5.01 (br. d, J = 17.1 Hz, 1 H, 10-H), 5.74
(dddd, J = 17.1, 10.1, 6.9, 6.9 Hz, 1 H, 9-H) ppm. 13C NMR CCH), 96.9 (MOM-CH2), 108.6 (C-3), 115.9 (C-7Ј), 116.3 (C-9),
(100 MHz, CDCl3): δ = –4.6 [Si(CH3)2], –4.6 [Si(CH3)2], 14.4 121.5 (C-5), 123.6 (C-1), 130.3 (C-4), 136.4 (C-8), 137.0 (C-6Ј) 138.3
(CH3), 18.1 (SiC), 25.8 [SiC(CH3)3], 26.8 (C-3), 35.8 (C-7), 36.9 (C- (C-6), 156.3 (C-2), 167.7 (Ph-CO2) ppm. MS (EI): m/z (%) = 331
8), 37.0 (C-5), 55.8 (MOM-CH3), 68.3 (C-4), 70.0 (C-1), 77.9 (C-
6), 81.5 (C-2), 95.6 (MOM-CH2), 115.9 (C-10), 137.3 (C-9) ppm.
MS (EI): m/z (%) = 240 (11), 239 (60), 203 (19), 183 (20), 157 (41),
147 (36), 119 (63), 107 (75), 105 (100), 89 (70), 73 (45), 59 (19), 45
(82). HRMS (ESI): [M + Na]+ calcd. for C19H36NaO3Si 363.23259,
found 363.23226.
(13), 237 (10), 219 (8), 187 (15), 175 (100), 174 (52), 156 (30), 129
(34), 123 (18), 115 (18), 91 (13), 84 (19), 45 (18). HRMS (FAB):
[M + Na]+ calcd. for C24H32NaO5 423.21475, found 423.21227.
(1S,3R,4S)-3-(Methoxymethoxy)-4-methyl-1-[3-(triisopropylsilyl)-
prop-2-ynyl]hept-6-enyl 2-Allyl-6-methoxybenzoate (31): To a solu-
tion of the alkyne 30 (470 mg, 1.17 mmol) in THF (12 mL) was
added at –78 °C nBuLi (516 µL, 1.29 mmol, 2.5 m in hexane) drop-
wise and the resulting solution stirred 30 min while warming up
to –20 °C. After recooling to –78 °C, the solution was treated with
TIPS-chloride (298 µL, 272 mg, 1.41 mmol) and DMAP (1.4 mg,
11 µmol) in THF (0.5 mL) and warmed to room temperature
within 15 h. The reaction was quenched by addition of saturated
NH4Cl solution (10 mL) at 0 °C. After separation of the phases the
aqueous layer was extracted with diethyl ether (2 × 15 mL) and the
combined organic extracts were dried with Na2SO4. Filtration and
evaporation led to the crude TIPS alkyne 31, which was purified by
flash chromatography (petroleum ether/diethyl ether, 3:1) yielding
581 mg (89 %) of a colorless oil. Rf = 0.41 (petroleum ether/ethyl
(4R,6R,7S)-6-(Methoxymethoxy)-7-methyldec-9-en-1-yn-4-ol (29):
To a solution of silyl ether 28 (875 mg, 2.57 mmol) in THF (20 mL)
was added TBAF (5.14 mL, 5.14 mmol, 1 m in THF) at 0 °C and
the mixture stirred for 12 h with concomitant warming to room
temperature. After addition of saturated NaHCO3 solution
(20 mL) the phases were separated and the aqueous layer was ex-
tracted with diethyl ether (2 × 20 mL). The combined organic ex-
tracts were dried (Na2SO4), filtered and concentrated in vacuo. Pu-
rification of the residue by flash chromatography (petroleum ether/
diethyl ether, 1:4) provided alcohol 29 (487 mg, 84 %) as a pale
yellow oil. Rf = 0.59 (petroleum ether/ethyl acetate, 1:1). [α]D
=
+56.6 (c = 1.00, CH Cl ). IR (film): ν = 1034, 1097, 1150, 2932,
˜
2
2
2959, 3455 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.87 (d, J =
6.5 Hz, 3 H, CH3), 1.62 (ddd, J = 14.6, 9.7, 8.7 Hz, 1 H, 5-H), 1.73
(ddd, J = 14.6, 3.3, 3.3 Hz, 1 H, 5-H), 1.83–1.96 (m, 2 H, 8-H, 7-
H), 1.97–2.04 (m, 1 H, 8-H), 2.00 (dd, J = 2.7, 2.6 Hz, 1 H, 1-H),
2.34 (ddd, J = 16.7, 6.4, 2.7 Hz, 1 H, 3-H), 2.39 (ddd, J = 16.7,
5.7, 2.6 Hz, 1 H, 3-H), 3.37 (s, 3 H, MOM-CH3), 3.45 (br. s, 1 H,
OH), 3.70 (ddd, J = 9.7, 3.8, 3.3 Hz, 1 H, 6-H), 3.85–3.93 (m, 1 H,
4-H), 4.60 (d, J = 6.8 Hz, 1 H, MOM-CH2), 4.69 (d, J = 6.9 Hz, 1
H, MOM-CH2), 4.95–5.02 (m, 2 H, 10-H), 5.71 (dddd, J = 17.0,
10.2, 6.9, 6.9 Hz, 1 H, 9-H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 13.5 (CH3), 27.0 (C-3), 34.8 (C-5), 35.2 (C-7), 37.5 (C-8), 56.0
(MOM-CH3), 69.6 (C-4), 70.3 (C-1), 80.7 (C-6), 80.9 (C-2), 95.3
(MOM-CH2), 116.1 (C-10), 136.7 (C-9) ppm. MS (EI): m/z (%) =
155 (4), 127 (10), 125 (100), 107 (13), 95 (43), 81 (19), 55 (18), 45
(61). HRMS (FAB): [M + Na]+ calcd. for C13H22NaO3 249.14667,
found 249.14613.
acetate, 5:1). [α]D = +51.3 (c = 1.00, CH Cl ). IR (film): ν = 1038,
˜
2
2
1071, 1111, 1243, 1267, 1471, 1585, 1730, 2865, 2889, 2942,
1
2959 cm–1. H NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 6.7 Hz,
3 H, CH3), 1.04 (br. s, 21 H, TIPS-CH, TIPS-CH3), 1.82 (br. ddd,
J = 13.2, 8.0, 8.0 Hz, 1 H, 5Ј-H), 1.85–1.97 (m, 3 H, 2Ј-H, 4Ј-H),
2.03 (br. ddd, J = 13.2, 5.9, 5.9 Hz, 1 H, 5Ј-H), 2.70–2.73 (m, 2 H,
CH2CCTIPS), 3.37 (br. d, J = 6.6 Hz, 2 H, 7-H), 3.39 (s, 3 H,
MOM-CH3), 3.68–3.72 (m, 1 H, 3Ј-H), 3.80 (s, 3 H, Ph-OCH3),
4.69 (s, 2 H, MOM-CH2), 4.88 (br. d, J = 10.2 Hz, 1 H, 7Ј-H), 4.93
(br. d, J = 17.1 Hz, 1 H, 7Ј-H), 5.01–5.07 (m, 2 H, 9-H), 5.30–5.38
(m, 1 H, 1Ј-H), 5.72 (dddd, J = 17.1, 10.2, 7.4, 6.7 Hz, 1 H, 6Ј-H),
5.87–5.98 (m, 1 H, 8-H), 6.76 (d, J = 8.3 Hz, 1 H, 3-H), 6.80 (d, J
= 7.7 Hz, 1 H, 5-H), 7.27 (dd, J = 8.3, 7.7 Hz, 1 H, 4-H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 11.2 (TIPS-CH), 13.5 (CH3), 18.6
(TIPS-CH3), 26.0 (CH2CCTIPS), 33.5 (C-2Ј), 36.4 (C-4Ј), 37.3 (C-
7), 37.7 (C-5Ј), 55.6 (Ph-OCH3), 55.7 (MOM-CH3), 70.1 (C-1Ј),
(1S,3R,4S)-3-(Methoxymethoxy)-4-methyl-1-(prop-2-ynyl)hept-6- 77.6 (C-3Ј), 83.4 (CH2CCTIPS), 96.8 (MOM-CH2), 103.6 (CH2
enyl 2-Allyl-6-methoxybenzoate (30): To a solution of alcohol 29
(285 mg, 1.26 mmol) and triphenylphosphane (495 mg, 1.89 mmol)
CCTIPS), 108.6 (C-3), 115.8 (C-7Ј), 116.3 (C-9), 121.5 (C-5), 123.8
(C-1), 130.3 (C-4), 136.4 (C-8), 137.0 (C-6Ј) 138.3 (C-6), 156.3 (C-
736
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 728–739

Synthesis of the Salicylihalamide Core Structure from Epichlorohydrin
FULL PAPER
2), 167.8 (Ph-CO2) ppm. MS (EI): m/z (%) = 513 (3), 451 (2), 306
(3S,5R,6S)-3-[(2E)-3-Iodoprop-2-enyl]-14-methoxy-5-(methoxymeth-
(22), 305 (100), 175 (88), 148 (21), 131 (22), 103 (18), 75 (15), 45 (8). oxy)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-
HRMS (EI): [M – iPr]+ calcd. for C30H45O5Si 513.303595, found
513.310648.
one (34): A solution of the alkyne 3 (30 mg, 0.081 mmol), Bu3SnH
(28 mg, 0.097 mmol) and AIBN (1.9 mg, 0.011 mmol) in toluene
(0.5 mL) was heated under reflux for 18 h. After cooling to room
temperature, the solvent was evaporated, Et2O (0.1 mL) was added
and the mixture was treated with I2 (25 mg, 0.097 mmol) at 0 °C.
The solution was stirred for 1 h at room temperature and then
quenched with a saturated aqueous solution of KF (1 mL). After
extraction of the aqueous layer twice with Et2O (1 mL), the com-
bined organic phases were washed with a saturated aqueous solu-
tion of Na2S2O4 (1 mL), then dried with Na2SO4, filtered, and con-
centrated in vacuo. The residue was purified by flash chromatogra-
phy (toluene/ethyl acetate, 10:1) to afford vinyl iodide E-34
(27.1 mg, 68 %) and the corresponding Z-isomer Z-34 (5.9 mg,
15 %) as colorless syrups.
(3S,5R,6S)-14-Methoxy-5-(methoxymethoxy)-6-methyl-3-[3-(triiso-
propylsilyl)prop-2-ynyl]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclo-
dodecin-1-one (33): To a flask charged with absolute CH2Cl2
(42.5 mL) was added simultaneously
a solution of [{(Cy)
3P}3Ru=CHPhCl2] (32) (33 mg, 0.04 mmol) in CH2Cl2 (7.1 mL)
and a solution of ester 31 (150 mg, 0.27 mmol) in CH2Cl2 (12 mL)
over a 4 h period via syringe pumps. After the addition was com-
plete, the solvent was evaporated and the residue purified by flash
chromatography (petroleum ether/ethyl acetate, 10:1) to give ben-
zolactone E-33 (130 mg, 91 %) and the corresponding Z-isomer
Z-33 (4.3 mg, 3 %) as colorless waxes.
E-34 (main product): Rf = 0.45 (toluene/ethyl acetate, 10:1). [α]D
= –37.5 (c = 1.00, benzene). 1H NMR (400 MHz, CDCl3): δ = 0.79
(d, J = 6.8 Hz, 3 H, CH3), 1.33 (dd, J = 15.5, 9.5 Hz, 1 H, 14-H),
1.61–1.67 (m, 2 H, 14-H, 11-H), 2.01–2.12 (m, 1 H, 12-H), 2.21–
2.28 (m, 2 H, 11-H, 16-H), 2.36–2.44 (m, 1 H, 16-H), 3.26 (br. d,
J = 16.3 Hz, 1 H, 8-H), 3.38 (s, 3 H, MOM-CH3), 3.64 (dd, J =
16.4, 9.4 Hz, 1 H, 8-H), 3.83 (s, 3 H, Ph-OCH3), 4.07 (br. dd, J =
9.2, 3.7 Hz, 1 H, 13-H), 4.73 (d, J = 6.6 Hz, 1 H, MOM-CH2), 4.82
(d, J = 6.8 Hz, 1 H, MOM-CH2), 5.22–5.31 (m, 2 H, 9-H, 15-H),
5.38–5.44 (m, 1 H, 10-H), 6.06 (d, J = 14.4 Hz, 1 H, 18-H), 6.70–
6.78 (m, 1 H, 17-H), 6.76 (d, J = 8.1 Hz, 1 H, 6-H), 6.82 (d, J =
8.6 Hz, 1 H, 4-H), 7.24 (dd, J = 7.8 Hz, 1 H, 5-H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 13.3 (CH3), 25.6 (C-16), 34.1 (C-12), 35.4
(C-14), 37.7 (C-8, C-11), 42.5 (C-16), 55.6 (MOM-CH3), 56.0 (Ph-
OCH3), 73.3 (C-15), 77.1 (C-18), 79.3 (C-13), 97.1 (MOM-CH2),
109.3 (C-4), 122.8 (C-6), 124.3 (C-2), 128.5 (C-9), 130.1 (C-5), 131.3
(C-10), 139.0 (C-7), 142.2 (C-17), 156.6 (C-3), 168.2 (C-1) ppm.
MS (EI): m/z (%) = 468 (10), 455 (30), 439 (50), 301 (15), 275 (48),
259 (100), 215 (50), 201 (54), 187 (87), 163 (43), 45 (46). HRMS
(EI): [M]+ calcd. for C22H29O5I 500.1060, found 500.1021.
E-33 (main product): Rf = 0.56 (petroleum ether/ethyl acetate, 5:1).
[α]D = –31.1 (c = 1.00, CH Cl ). IR (film): ν = 1047, 1116, 1154,
˜
2
2
1274, 1468, 1585, 1733, 2176, 2866, 2887, 2942 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.85 (d, J = 6.7 Hz, 3 H, CH3), 1.04 (br.
s, 21 H, TIPS-CH, TIPS-CH3), 1.63–1.74 (m, 1 H, 11-H), 1.75 (br.
dd, J = 15.3, 8.6 Hz, 1 H, 14-H), 1.83 (br. dd, J = 15.3, 8.4 Hz, 1
H, 14-H), 2.29 (br. d, J = 13.7 Hz, 1 H, 11-H), 2.57 (br. s, 1 H, 16-
H), 2.58 (d, J = 3.1 Hz, 1 H, 16-H) 3.28 (br. d, J = 16.3 Hz, 1 H,
8-H), 3.43 (s, 3 H, MOM-CH3), 3.68 (dd, J = 16.3, 9.5 Hz, 1 H, 8-
H), 3.78 (s, 3 H, Ph-OCH3), 4.07–4.12 (m, 1 H, 13-H), 4.76 (d, J
= 6.8 Hz, 1 H, MOM-CH2), 4.85 (d, J = 6.8 Hz, 1 H, MOM-CH2),
5.29 (br. dd, J = 15.3, 9.6 Hz, 1 H, 9-H), 5.37- 5.43 (m, 1 H, 15-
H), 5.47 (br. dd, J = 15.3, 10.9 Hz, 1 H, 10-H), 6.74 (d, J = 7.6 Hz,
1 H, 6-H), 6.78 (d, J = 8.4 Hz, 1 H, 4-H), 7.21 (dd, J = 8.4, 7.6 Hz,
1 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3): δ = 11.2 (TIPS-
CH), 13.2 (CH3), 18.5 (TIPS-CH3), 26.9 (C-16), 34.1 (C-14), 34.2
(C-12), 37.5 (C-11), 37.6 (C-8), 55.4 (MOM-CH3), 55.8 (Ph-OCH3),
72.2 (C-15), 78.7 (C-13), 83.2 (C-18), 96.7 (MOM-CH2), 103.9 (C-
17), 109.4 (C-4), 122.6 (C-6), 124.6 (C-2), 128.7 (C-9), 129.9 (C-5),
131.2 (C-10), 138.7 (C-7) 156.7 (C-3), 167.9 (C-1) ppm. MS (EI):
m/z (%) = 485 (85), 455 (54), 423 (52), 390 (13), 375 (10), 317 (43),
275 (49), 259 (61), 199 (50), 187 (100), 145 (82), 131 (51), 84 (47),
45 (75). HRMS (EI): [M]+ calcd. for C28H41SiO5 485.27231, found
485.27382.
(3S,5R,6S)-14-Methoxy-5-(methoxymethoxy)-6-methyl-3-[3-(pyri-
din-2-yl)prop-2-ynyl]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclodo-
decin-1-one (35): To a mixture of 2-bromopyridine (19.2 mg,
0.122 mmol) and the alkyne 3 (50 mg, 0.133 mmol) in triethylamine
(0.61 mL) were added [PdCl2(PPh3)2] (2.2 mg, 0.003 mmol) and
CuI (0.83 mg, 0.006 mmol). The reaction mixture was then stirred
at room temperature under nitrogen for 18 h. After removal of the
Z-33 (minor product): Rf = 0.39 (petroleum ether/ethyl acetate,
5:1). [α]D = +10.8 (c = 1.00, CH Cl ). IR (film): ν = 1037, 1111,
˜
2
2
1266, 1470, 1733, 2865, 2889, 2942 cm–1. 1H NMR (400 MHz, solvent in vacuo, the residue was purified by flash chromatography
CDCl3): δ = 0.92 (d, J = 6.1 Hz, 3 H, CH3), 1.04 (br. s, 21 H, TIPS- (petroleum ether/ethyl acetate, 4:1) to afford the substituted pyri-
CH, TIPS-CH3), 1.82–1.89 (m, 2 H, 14-H, 11-H), 2.00–2.11 (m, 3
H, 14-H, 12-H, 11-H), 2.59 (dd, J = 17.0, 4.2 Hz, 1 H, 16-H), 2.68
(dd, J = 17.0, 7.2 Hz, 1 H, 16-H) 2.99 (br. d, J = 15.9 Hz, 1 H, 8-
H), 3.38 (s, 3 H, MOM-CH3), 3.77 (br. d, J = 9.3 Hz, 1 H, 13-H),
3.81 (s, 3 H, Ph-OCH3), 3.99 (dd, J = 15.9, 8.9 Hz, 1 H, 8-H), 4.71
dine 35 (48.8 mg, 90 %) as a light yellowish wax. Rf = 0.12 (petro-
leum ether/ethyl acetate, 4:1). [α]D = –79.9 (c = 1.00, CH2Cl2). IR
(film): ν = 1116, 1274, 1428, 1466, 1583, 1727, 2929, 2954 cm–1. 1H
˜
NMR (400 MHz, CDCl3): δ = 0.87 (d, J = 6.8 Hz, 3 H, CH3),
1.66–1.82 (m, 2 H, 14-H, 11-H), 2.06–2.16 (m, 1 H, 12-H), 2.28 (d,
(d, J = 6.8 Hz, 1 H, MOM-CH2), 4.77 (d, J = 6.8 Hz, 1 H, MOM- J = 14.2 Hz, 1 H, 11-H), 2.79 (dd, J = 16.4, 6.3 Hz, 2 H, 16-H),
CH2), 5.24–5.36 (m, 2 H, 9-H, 10-H), 5.49–5.56 (m, 1 H, 15-H),
6.79 (d, J = 7.7 Hz, 1 H, 6-H), 6.80 (d, J = 8.4 Hz, 1 H, 4-H), 7.27
(dd, J = 8.4, 7.7 Hz, 1 H, 5-H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 11.2 (TIPS-CH), 13.4 (CH3), 18.6 (TIPS-CH3), 26.9 (C-16),
3.28 (d, J = 16.4 Hz, 1 H, 8-H), 3.43 (s, 3 H, MOM-CH3), 3.67
(dd, J = 16.3, 9.5 Hz, 1 H, 8-H), 3.72 (s, 3 H, Ph-OCH3), 4.12 (br.
d, J = 6.3 Hz, 1 H, 13-H), 4.80 (d, J = 6.6 Hz, MOM-CH2), 4.87
(d, J = 6.8 Hz, MOM-CH2), 5.29–5.35 (m, 1 H, 9-H), 5.42–5.55
32.0 (C-11), 32.5 (C-8), 35.0 (C-14), 36.5 (C-12), 55.5 (MOM-CH3), (m, 2 H, 15-H, 10-H), 6.72 (d, J = 7.6 Hz, 1 H, 6-H), 6.76 (d, J =
55.9 (Ph-OCH3), 71.2 (C-15), 77.3 (C-13), 83.3 (C-18), 97.3 (MOM- 8.3 Hz, 1 H, 4-H), 7.15–7.22 (m, 2 H, 5-H, 21-H), 7.38 (d, J =
CH2), 103.7 (C-17), 109.4 (C-4), 122.7 (C-6), 122.7 (C-2), 128.6 (C-
10), 129.4 (C-9), 131.0 (C-5), 140.5 (C-7) 157.3 (C-3), 166.6 (C-1)
ppm. MS (EI): m/z (%) = 499 (6), 485 (42), 455 (9), 423 (11), 315
(20), 275 (34), 260 (29), 199 (36), 187 (65), 162 (88), 161 (100), 145
7.8 Hz, 1 H, 23-H), 7.59 (td, J = 7.8, 1.8 Hz, 1 H, 22-H), 8.52 (d,
J = 4.8 Hz, 1 H, 20-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.4 (CH3), 26.5 (C-16), 34.5 (C-14), 34.8 (C-12), 37.6 (C-8, C-11),
55.5 (MOM-CH3), 55.8 (Ph-OCH3), 72.2 (C-15), 78.9 (C-13), 81.8
(79), 131 (46), 105 (39), 77 (57), 45 (78). HRMS (EI): [M]+ calcd. (C-18), 86.3 (C-17), 96.8 (MOM-CH2), 109.4 (C-4), 122.5 (C-6, C-
for C28H41SiO5 485.27231, found 485.27288.
21), 124.3 (C-2), 127.1 (C-23), 128.7 (C-9), 130 (C-5), 131.2 (C-10),
Eur. J. Org. Chem. 2005, 728–739
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
737

C. Herb, F. Dettner, M. E. Maier
FULL PAPER
Waldmann, J. Am. Chem. Soc. 2002, 124, 13171–13178; c) D.
Brohm, S. Metzger, A. Bhargava, O. Müller, F. Lieb, H. Wald-
mann, Angew. Chem. 2002, 114, 319–323; Angew. Chem. Int.
Ed. 2002, 41, 307–311. d) R. Breinbauer, I. R. Vetter, H. Wald-
mann, Angew. Chem. 2002, 114, 3002–3015; Angew. Chem. Int.
Ed. 2002, 41, 2878–2890.
X.-S. Xie, D. Padron, X. Liao, J. Wang, M. G. Roth, J. K. De
Brabander, J. Biol. Chem. 2004, 279, 19755–19763.
For a review, see:L. Yet, Chem. Rev. 2003, 103, 4283–4306.
K. L. Erickson, J. A. Beutler, J. H. Cardellina II, M. R. Boyd,
J. Org. Chem. 1997, 62, 8188–8192.
136 (C-22), 138.8 (C-7), 143.5 (C-19), 149.7 (C-20), 156.7 (C-3),
167.9 (C-1) ppm. MS (EI): m/z (%) = 449 (15), 418 (18), 404 (71),
388 (41), 244 (10), 216 (23), 187 (24), 172 (80), 144 (100), 131 (52),
117 (48), 93 (18). HRMS (EI): [M]+ calcd. for C27H31NO5
449.22020, found 449.22360.
[7]
(3S,5R,6S)-5,14-Dihydroxy-6-methyl-3-[3-(pyridin-2-yl)prop-2-yn-
yl]-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one (36): To
a stirred solution of compound 35 (45 mg, 0.1 mmol) in CH2Cl2
(2.1 mL) was quickly added 9-iodo-9-BBN (99.3 mg, 0.4 mmol) at
23 °C. After 70 s, the reaction was stopped by adding methanol
(2.1 mL) and then stirred for 1 h at room temperature. The solvent
and the formed boronic acid ester was removed under reduced pres-
sure. This procedure, addition of methanol and solvent evaporation
was repeated twice. Pure product 36 (37.7 mg, 88 %) was obtained
after flash chromatography (petroleum ether/ethyl acetate, 1:1) as
a colorless wax. Rf = 0.26 (petroleum ether/ethyl acetate, 1:1). [α]D
[8]
[9]
[10]
[11]
a) R. Jansen, B. Kunze, H. Reichenbach, G. Höfle, Eur. J. Org.
Chem. 2000, 913–919; b) B. Kunze, R. Jansen, F. Sasse, G.
Höfle, H. Reichenbach, J. Antibiot. 1998, 51, 1075–1080.
Total syntheses of salicylihalamide A: 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. Charron, R. Rej, C. Blais, S. Lamothe, Tetrahe-
dron 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; h)
C. Herb, A. Bayer, M. E. Maier, Chem. Eur. J. 2004, 10, 5649–
5660.
Total syntheses of apicularen A: a) A. Bhattacharjee, O. R. Se-
guil, 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–
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= –6.3 (c = 1.00, CH Cl ). IR (film): ν = 1116, 1247, 1292, 1465,
˜
2
2
1587, 1723, 2235, 2925, 2958, 3060, 3166, 3491 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 0.94 (d, J = 6.8 Hz, 3 H, CH3), 1.25 (s, 1
H, OH), 1.53 (dd, J = 14.9, 8.8 Hz, 1 H, 14-H), 1.80–1.88 (m, 1 H,
11-H), 1.91–1.97 (m, 1 H, 12-H), 2.19 (dd, J = 15.0, 10.7 Hz, 1 H,
14-H), 2.31–2.36 (m, 1 H, 11-H), 2.88 (dd, J = 5.7, 5.7 Hz, 2 H,
16-H), 3.43 (br. dd, J = 16.7, 3.3 Hz, 1 H, 8-H), 3.77 (br. dd, J =
16.4, 5.1 Hz, 1 H, 8-H), 3.83 (dd, J = 8.6, 3.0 Hz, 1 H, 13-H), 5.16–
5.23 (m, 1 H, 10-H), 5.50 (dt, J = 15.4, 4.6 Hz, 1 H, 9-H), 5.65 (dt,
J = 10.5, 5.7 Hz, 1 H, 15-H), 6.70 (d, J = 7.3, 1 H, 6-H), 6.88 (d,
J = 7.8 Hz, 1 H, 4-H), 7.24–7.29 (m, 2 H, 21-H, 5-H), 7.42 (d, J =
7.8 Hz, 1 H, 23-H), 7.68 (td, J = 7.8, 1.6 Hz, 1 H, 22-H), 8.56 (d,
J = 4.3 Hz, 1 H, 20-H) ppm. 13C NMR (100 MHz, CDCl3): δ =
13.6 (CH3), 26.1 (C-16), 35.7 (C-14), 37.4 (C-12), 38.3 (C-11), 38.9
(C-8), 70.4 (C-13), 72.2 (C-15), 81.9 (C-18), 86.6 (C-17), 116.5 (C-
4), 122.9 (C-6), 123.2 (C-21), 127.1 (C-10), 127.3 (C-23), 132.2 (C-
9), 133.4 (C-5), 136.7 (C-22), 141.8 (C-7), 142.8 (C-19), 149.3 (C-
20), 161.1 (C-3), 170.3 (C-1) ppm. MS (EI): m/z (%) = 391 (78),
184 (15), 173 (22), 172 (43), 144 (85), 117 (100), 115 (25), 91 (12),
55 (10) ppm. HRMS (EI): [M]+ calcd. for C24H25NO4 391.17834,
found 391.18067.
[12]
[13]
[14]
Supporting Information Available: Copies of 1H- and 13C NMR
spectra for all new compounds reported. For Supporting Infor-
mations see also the footnote on the first page of this article.
Acknowledgments
[15]
Financial support by the Deutsche Forschungsgemeinschaft (grant
Ma 1012/10–1) and the Fonds der Chemischen Industrie is grate-
fully acknowledged. We thank Dr. F. Sasse (GBF Braunschweig)
for performing cellular assays on several benzolactones from our
group.
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Received October 6, 2004
Eur. J. Org. Chem. 2005, 728–739
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