Formal synthesis of Abyssomicin C

Article abstract of DOI:10.1016/j.tet.2006.01.106

An alternative strategy towards Abyssomicin C (1) is described. The key ene-diene intermediate is synthesized via a Kishi type coupling of an E/Z mixture of triene-iodide 7 and a suitably functionalized derivative of 2,4-dimethylglutaric acid. A final in

Full text of DOI:10.1016/j.tet.2006.01.106

Tetrahedron 62 (2006) 5272–5279
Formal synthesis of Abyssomicin C
Elias A. Couladouros,a,b, Emmanuel A. Bouzasa,b and Alexandros D. Magosa,b
*
aChemistry Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 118 55, Greece
bLaboratory of Natural Products Synthesis and Bioorganic Chemistry, NCSR ‘‘DEMOKRITOS’’, 153 10 Ag. Paraskevi Attikis,
PO Box 60228, Athens, Greece
Received 22 December 2005; revised 5 January 2006; accepted 8 January 2006
Available online 29 March 2006
Abstract—An alternative strategy towards Abyssomicin C (1) is described. The key ene-diene intermediate is synthesized via a Kishi type
coupling of an E/Z mixture of triene-iodide 7 and a suitably functionalized derivative of 2,4-dimethylglutaric acid. A final in situ isomeriza-
tion/intramolecular Diels–Alder cyclization resulted in the formation of the known intermediate 3 as a single isomer in high yield. Further
heating of 3 using excess of iodine, afforded iodo-derivative 23, having the entire carbon skeleton of Abyssomicin D.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction and retrosynthetic analysis
and it is highly potent against resistant Staphylococcus
aureus strains (methicillin-resistant MIC¼4 mg mLꢀ1; van-
comycin-resistant MIC¼13 mg mLꢀ1).2 Efficient chemical
routes for the preparation of Abyssomicin C, as well as of re-
lated analogues, will have to be invented in order to facilitate
possible pharmaceutical application of the new architecture.
Not surprisingly many synthetic chemistry groups have al-
ready been alerted3–5 and one year after its discovery an el-
egant total synthesis has been released by Sorensen et al.6
Antibiotics with high potency against pathogenic antibiotic-
resistant bacterial strains will be of value in the clinic. Abys-
somicin C (1, Fig. 1) recently discovered by Sussmuth et al.,1
¨
is a serious candidate since it possess an unprecedent com-
plicated structure and an impressive biological profile.
Abyssomicin C, inhibits the biosynthesis of p-amino-benz-
oic acid2 (a pathway existing in bacteria but not in humans)
OR
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
HO
RO
[4+2]
Diels-Alder
O
O
R=CH3
epoxide opening
1: Abyssomicin C
O
2
OH
3
OCH3
OCH3
O
OCH3
O
O
O
OR
O
O
3
or
or
O
OR
O
O
O
O
4
7
5
6
O
O
+
+
I
O
AcO
9
Takai
8
coupling
OMe
O
10
O
O
+
12
O
O
O
11
13
I
[M]
OMe
Figure 1. Retrosynthetic analysis towards a biomimetic route to Abyssomicin C.
* Corresponding author. Tel.: +30210 529 4245; fax: +30210 677 7849; e-mail: ecoula@chem.demokritos.gr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.01.106

E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
5273
Aspiring to meet the challenge of constructing this impres-
sive architecture, we focused our attention on synthetic strat-
egies resembling a plausible biomimetic route as much as
possible (Fig. 1). Thus, assuming that an intramolecular ep-
oxide opening is possible, 1 can be disconnected to spirote-
tronate precursor 2, which may be formed from 3 upon
selective epoxidation and deprotection. The cyclohexenyl
moiety of 3 called for an ene-diene precursor, is suitably de-
signed to yield an intramolecular Diels–Alder cyclization.
Although an in situ enolization of the terminal methyl ketone
and concomitant stereoselective Diels–Alder seemed precar-
ious, linear polyketidic triene 4, was considered as a possible
biomimetic retron of 3. On the other hand, the alternative bi-
cyclic precursor 6, bearing an electron deficient exocyclic
double bond and a hemiketalic connection between the
adjacent a-methyl-carbonyls, is ideally preorganized for an
efficient [4+2] cyclization. However, 6 features two new ster-
eocenters and as a consequence, its synthesis can be antici-
pated to be lengthy. Thus, 5 was targeted as a more realistic
compromise. Indeed, while our work was in progress, Soren-
sen et al.6 and Snider and Zou5 did prove independently that
5 may be transformed smoothly and in high yield to cyclized
intermediate 3. Moreover, the former succeeded in convert-
ing 3 to Abyssomicin C, following the depicted sequence. We
report herein an alternative synthesis of key intermediate 3.
meric ratio of the crystallization mother liquor (which was
enriched in the dl-form) could be reversed upon equilibra-
tion by heating with a mild base, thus raising the reported
yield from 30 to 65%. The optically pure alcohol 17 was
then prepared within two steps11 and Swern oxidation12 of
the latter furnished aldehyde 8, which was taken forward
to the next step without further purification.
The remaining coupling partner, vinyl-iodide 7 was prepared
from commercially available sorbaldehyde 10,y in good yield
(Table 1). However, under all conditions tried (Takai9 or
Evans13,14 conditions for E selectivity or Stork’s15 conditions
for Z selectivity), the obtained stereoselectivity was very
poor. Moreover, all efforts to isomerize16,17 resulted in 1:1
E/Z mixtures, indicating the presence of an equilibrium.18
Nonetheless, since possible double bond in situ isomeriza-
tion during the IMDA reaction would result in a very short
scheme, we opted to continue our efforts employing vinyl-
iodide 7asamixtureofisomers(approximately2:1E/Zratio).
Table 1. Synthesis of vinyl-iodide 7
10
Entry Reagents/conditions Solvents
7
I
O
E/Z
Yield (%)
CrCI2, CHI3, 0 ꢁC
CrCI2, CHI3, 0 ꢁC
Ph3P+(Iꢀ)CH2I,
NaHMDS, ꢀ78 ꢁC
THF
2/1
85
75
Since the central core of 5 resembles reported meso-2,4-
dimethylglutaric acid, the readily available aldehyde 8 was
chosen to be the building block, as well as the chirality
source. The tetronate moiety could be attached by a direct
alkylation of 8 with anion of 9.7 Finally, the triene part
was planned to be mounted after transformation of the termi-
nal acetate to aldehyde, followed by a Kishi type coupling8
with vinyl-iodide 7, derived via a Takai olefination9 of com-
mercial hexadienal 10.
1
2
3
THF/dioxane 6/1 2/1
THF
1.2/1 87
The assembly of intermediate 5 commenced with coupling
between aldehyde 8 and tetronate 9 (Scheme 2). After
some experimentation, alcohol 18 was synthesized in rela-
tively high yield along with partial recover of the starting ma-
terials. Alcohol 18 was formed as a diastereomeric mixture in
1:1 ratio, however oxidation of this stereocenter at a subse-
quent step would alleviate this problem. Thus, oxidation of
the allylic alcohol with IBX,19 enzymatic cleavage20 of the
acetate and subsequent oxidation of the resulting primary al-
cohol furnished keto-aldehyde 19. Deacylation of all tetro-
nate derivatives under alkaline conditions resulted usually
in very low yields. We found that Novozyme 435 was quite
efficient in this case. Though the chemical yields of these se-
quence were good, the stability of all intermediates upon
chromatographic manipulations and storage was low. In ad-
dition, any further attempt to introduce the triene moiety (us-
ing CrCl2 or the lithium anion of the respective triene) led
only to immediate polymerization of aldehyde 19. Thus, al-
cohol 18 was protected as the corresponding p-methoxy ben-
zyl ether, anticipating that upon treatment with DDQ the
allylic alcohol would be concomitantly transformed to the re-
quired ketone. Since Novozyme 435 reacted very slowly on
this substrate, alcohol 20a was prepared using Amano Lipase
AK. It should be noted that all PMB-protected intermediates
were by far more stable than the respective keto derivatives.
In addition, Swern oxidation of 20a and subsequent coupling
2. Synthesis of key intermediate 3
The key starting material, meso-2,4-dimethylglutaric anhy-
dride 12, was prepared on a multi-gram scale from diethyl-
methyl malonate and methyl methacrylate within three steps
adopting two related syntheses10 (Scheme 1). meso-Isomer
12, selectively crystallizes out of the derived mixture of dl-
and meso-forms. We were pleased to observe that the iso-
O
a
ref. 10
+
OMe
EtO2C
CO2Et
14
15
+
O
O
O
O
O
O
(dl-)-16
(meso-)-12
b
c
d
12
8
AcO
OH
ref. 11
17
Scheme 1. Reagents and conditions: (a) i. Na, EtOH, rt, ii. HCl, AcOH,
105 ꢁC, iii. Ac2O, reflux, and iv. recrystallization (30% of 12, three steps);
(b) i. Et3N, THF, reflux and ii. recrystallization, 52%; (c) i. LAH, THF, 0 ꢁC
and ii. AcOCH]CH2, Amano lipase AK, THF, 0 ꢁC (58%, two steps); (d)
(COCl)2, DMSO, DCM, Et3N, 95%.
y
Commercial sorbaldehyde contains up to 10% of the Z isomer. As it has
been already reported by Snider5 the wrong isomer remains unreacted
in the final cyclization step. For clarity reasons this isomer is not depicted
in the schemes or mentioned in the text.

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E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
O
AcO
OH
O
O
a
b-d
8
+
9
O
O
MeO
MeO
O
18
19
e,f
X
HO
OR
HO
O
HO
OR
O
O
g,h
MeO
MeO
O
O
O
MeO
O
21a R = PMB
21b R = TBS
20a R = PMB
20b R = TBS
k or l
i
HO
O
O
O
n
MeO
I
O
OH
O
ref. 6
23
j
m
MeO
5
3
1
O
22
Scheme 2. Reagents and conditions: (a) 9 (3 equiv), LDA, THF, ꢀ100 ꢁC, then 8, 45–58%, (20% recover of 8, 50% recover of 9); (b) IBX, DMSO, 78%; (c)
Novozyme 435, toluene/phosphate buffer, 52% (16% recover); (d) IBX, DMSO, 70%; (e) PMBO(C]NH)CCl3, cyclohexane/DCM, cat. CSA, 98% or TBS-Cl,
imid., DMF, 85%; (f) Lipase AK, acetonitrile/phosphate buffer, 81% for R¼PMB, 15% for R¼TBS (recover 70%) or guanidine hydrochloride, EtOH/4 N
NaOH, 78% for R¼TBS; (g) IBX, DMSO, 88%; (h) 7, CrCl2, NiCl2, THF/DMSO, 40% (recover 47%) for R¼PMB, 50% (recover 30%) for R¼TBS; (i)
DDQ, DCM/H2O, 20% for R¼PMB; (j) Dess–Martin, DCM, 95%; (k) for R¼PMB: i. MnO2, Et2O, 90%. ii. DDQ, DCM/NaHCO3aq, 35%. iii. Dess–Martin,
DCM, 95%; (l) for R¼TBS: i. TBAF, THF, 83%. ii. IBX, DMSO, 85%; (m) toluene, cat. I2, 100 ꢁC, 3 h, 75%, (n) toluene, excess I2, 100 ꢁC, 3 h, 87%.
of the resulted aldehyde with vinyl-iodide 7, under Kishi con-
ditions, successfully lead to the targeted linear analogue of
Abyssomicins 21a. At this point we attempted an one pot, di-
rect transformation of alcohol 21a to di-keto-ene-diene 5 by
a PMB deprotection and subsequent double oxidation of both
allylic alcohols using DDQ.21 Unfortunately, this reaction
was messy and only keto-alcohol 22 could be isolated in
low yield (5–30%). The latter was oxidized to diketone 5.5
Alternatively, 5 could be derived from 21a following a three
steps protocol (MnO2 oxidation, DDQ deprotection and
Dess–Martin periodinate oxidation),22 yet in low overall
yield (20%).
D carbon skeleton in a similar manner that Snider observed
for a sulfide analogue.5
3. Conclusion
In conclusion we have presented herein an efficient and
straightforward synthesis of a key advanced intermediate to-
wards 1. We are currently working towards a scaled up syn-
thesis of Abyssomicin C as well as of related derivatives in
order to explore their antibacterial activities.
In order to improve the total yield towards 6, the previous se-
quence was repeated using t-BuMe2Si instead of PMB for the
protection of the hydroxyl group. This time, saponification of
the acetate moiety was performed by employing guanidine
under buffered conditions, since both of the previously
used enzymes reacted very slowly. Alcohol 21b, upon desily-
lation with TBAF and subsequent double oxidation of the re-
sulting diol using IBX, afforded the targeted precursor 5 in
very good yield. It should be pointed out that the aforemen-
tioned diol is a mixture of two diasteromeric centers and pos-
sesses the E/Z double bond stereochemistry originating from
the used vinyl-iodide (total eight isomers). However, the de-
rived diketone 5 was only a mixture of the E/Z isomers and, to
4. Experimental
4.1. General techniques
All reactions were carried out under anhydrous conditions
and an argon atmosphere using dry, freshly distilled solvents,
unless otherwise noted. Tetrahydrofuran (THF) was distilled
from sodium/benzophenone, dichloromethane (DCM) from
CaH2, and toluene from sodium. Yields refer to chromato-
graphically and spetroscopically (1H NMR) homogeneous
materials, unless otherwise stated. All reagents were pur-
chased at highest commercial quality and used without fur-
ther purification, unless otherwise stated. All reactions
were monitored by thin-layer chromatography (TLC) carried
out on 0.25 mm Merck silica gel plates (60 F254) using UV
light as visualizing agent and ethanolic phosphomolybdic
acid or p-anisaldehyde solution and heat as developing
agents. Merck silica gel (60, particle size 0.040–0.063 mm)
was used for flash column chromatography. NMR spectra
ꢁ
our delight, this mixture upon heating at 100 C in toluene
with a catalytic amount of I2, was smoothly converted in
high yield to the cyclized advanced intermediate of Abysso-
micin C, 3, as a single isomer. Interestingly, by adding excess
of I2 and heating for additional 3 h, iodo-derivative 23 was
isolated as the only product, giving rise to the Abyssomicin

E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
5275
were recorded on Bruker Avance DRX-500 or AC-250 in-
struments. The following abbreviations were used to explain
NMR signal multiplicities: br s ¼ broad singlet, br d ¼ broad
doublet, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, dd ¼ doublet of doublets, ddd ¼ doublet of
doublets of doublets, dt ¼ doublet of triplets. IR spectra
were recorded on a Perkin–Elmer 1600 series FTIR or Nico-
let Magna system 550 FTIR instruments. Optical rotations
were recorded on a Perkin–Elmer 241 polarimeter. High-
resolution mass spectra (HRMS) were recorded on a VG
ZAB-ZSE mass spectrometer under fast atom bombardment
(FAB) conditions and matrix-assisted (MALDI-FTMS) mass
spectra were recorded on a PerSeptive Biosystems Voyager
IonSpect mass spectrometer.
starting materials: aldehyde 8 (188 mg, 1.09 mmol; 20%)
and 4-methoxy-5-methylene-2(5H)-furanone,
9 (1.0 g,
7.93 mmol). Rf¼0.22 (Hexane/AcOEt 8:2); 1H NMR
ꢁ
(500 MHz, CDCl3, 25 C): d 5.07 (s, 4H, ]CH2), 4.46 (d,
3J(H,H)¼7.5 Hz, 1H, CHOH), 4.40 (d, 3J(H,H)¼8.6 Hz,
3
1H, CHOH), 4.12 (s, 6H, OCH3), 3.96 (dd, J(H,H)¼4.6,
10.3 Hz, 1H, AcOCH2), 3.92–3.79 (m, 3H, AcOCH2),
3.41–3.09 (br s, 2H, OH), 2.03 (s, 3H, AcO), 1.99 (s, 3H,
AcO), 1.99–1.90 (m, 2H, CH3CHCHOH), 1.89–1.79 (m,
2H, AcOCH2CHCH3), 1.42–1.13 (m, 4H, CHCH2CH),
1.05 (d, 3J(H,H)¼6.3 Hz, 3H, CH3), 0.97 (d, 3J(H,H)¼
6.9 Hz, 3H, CH3), 0.93 (d, 3J(H,H)¼6.3 Hz, 3H, CH3),
0.85 (d, 3J(H,H)¼6.9 Hz, 3H, CH3) ppm; 13C NMR
ꢁ
(125.8 MHz, CDCl3, 25 C): d 171.7, 171.6, 169.9, 162.1,
149.7, 107.4, 107.3, 93.9, 71.6, 70.9, 69.6, 69.1, 68.5, 68.3,
60.9, 37.9, 37.7, 37.6, 37.5, 33.4, 31.8, 30.6, 30.5, 30.4,
30.0, 21.3, 21.1, 19.1, 18.8, 17.6, 16.3 ppm; FTIR (neat):
nmax 3492, 2964, 2933, 2877, 1767, 1736, 1669, 1624,
4.1.1. meso-2,4-Dimethylglutaric anhydride 12. To a
solution of dl-2,4-dimethylglutaric anhydride (52.0 g,
0.366 mol) in THF (270 mL) was added triethylamine
(255 mL, 1.83 mol) under argon. The reaction mixture was
heated under reflux for 60 h and the solvents were removed
under reduced pressure. The residue was distilled under
high vacuum using air-cooled condenser to afford a colorless
solid. This material was dissolved in AcOEt (50 mL) and the
solutionwas allowed to stand at room temperature for 12 h, in
1460, 1392, 1281, 1245, 1156, 1036, 979, 878, 784 cmꢀ1
;
HRMS (ESI) calculated for C15H22O6 ([M+Na]+): m/z
321.1308, found 321.1309.
4.1.4. Aldehyde 19. To a solution of alcohol 18 (247 mg,
0.828 mmol) in DMSO (1.6 mL) was added IBX (463 mg,
1.654 mmol) at room temperature under an argon atmo-
sphere. After stirring for 2 h the reaction was quenched
with water (5 mL) and AcOEt (5 mL). The iodosocarboxylic
acid, which precipitated as a white amorphous solid, was re-
moved by filtration through Celite. The filtrate was extracted
with AcOEt (2ꢂ10 mL) and the combined organic layers
were washed with saturated NaHCO3aq (10 mL) and brine
(10 mL), dried over anhydrous Na2SO4 and concentrated un-
der reduced pressure. The crude mixture was subjected to
flash chromatography (silica gel, Hexane/AcOEt 8:2) to af-
ford the respective ketone (191 mg, 0.646 mmol; 78%) as
yellow oil. Rf¼0.44 (Hexane/AcOEt 8:2); [a]2D.5 ꢀ5ꢁ (c 7.2
ꢁ
the freezer for 6 h and at ꢀ20 C for 2 h. The colorless solid
was recrystallized from AcOEt (25 mL), to give meso-2,4-di-
methylglutaric anhydride (27 g, 52%) as a colorless solid.
23
ꢁ
ꢁ
Mp 90.5–91.9 C (lit. 91.4–92.8 C).
4.1.2. Aldehyde 8. To a stirred solution of oxalyl chlorꢁide
(1.53 mL, 0.018 mol) in dry DCM (20 mL) at ꢀ78 C,
DMSO (2.90 mL, 0.038 mol) was added drop-wise under
an argon atmosphere. After 30 min, a solution of alcohol
17 (2.0 g, 0.014 mol) in dry DCM (20 mL) was added to
ꢁ
the reaction mixture. After 30 min of stirring at ꢀ78 C,
Et3N (13.8 mL, 0.10 mol) was added and the reaction was
stirred for 1 h at ambient temperature. The reaction mixture
was quenched with saturated NH4Claq solution (30 mL) and
extracted with DCM (30 mL). The combined organic ex-
tracts were washed with water (30 mL) and brine (30 mL),
dried over anhydrous Na2SO4, filtered and concentrated un-
der reduced pressure. The crude aldehyde, 8, was used in the
next step without further purification.
1
ꢁ
in CHCl3); H NMR (500 MHz, CDCl3, 25 C): d 5.27 (d,
2J(H,H)¼2.9 Hz, 1H, ]CH2), 5.22 (d, 2J(H,H)¼2.9 Hz,
3
1H, ]CH2), 4.11 (s, 3H, OCH3), 3.95 (dd, J(H,H)¼5.7,
3
10.9 Hz, 1H, AcOCH2), 3.89 (dd, J(H,H)¼6.3, 10.9 Hz,
1H, AcOCH2), 3.72 (dd, 3J(H,H)¼6.9, 13.8 Hz, 1H,
CHCO), 2.06 (s, 3H, AcO), 1.95–1.77 (m, 1H, CH2CHCH2),
1.32–1.22 (m, 2H, CHCH2CH), 1.15 (d, J(H,H)¼7.5 Hz,
3
3H, CH3), 0.97 (d, J(H,H)¼6.9 Hz, 3H, CH3) ppm; 13C
3
ꢁ
4.1.3. Alcohol 18. To a stirred solution of 4-methoxy-5-
methylene-2(5H)-furanone, 9, (2.07 g, 16.4 mmol) in THF
NMR (62.8 MHz, CDCl3, 25 C): d 200.5, 171.2, 168.8,
166.2, 148.9, 104.7, 95.8, 69.0, 62.8, 41.8, 36.5, 30.5, 29.7,
17.5, 17.4 ppm; FTIR (neat): nmax 2964, 2934, 2876, 2855,
1772, 1738, 1684, 1666, 1592, 1456, 1390, 1366, 1287,
1241, 1155, 1040, 994, 882, 793, 738 cmꢀ1; HRMS (ESI)
calculated for C15H20O6 ([M+Na]+): m/z 319.1152, found
319.1152.
ꢁ
(235 mL), at (ꢀ100 C) under an argon atmosphere was
ꢁ
added, via cannula, a cooled (ꢀ100 C) LDA solution [pre-
pared from i-Pr2NH (2.7 mL, 19.05 mmol) and n-BuLi
(1.6 Min Hexane; 10.3ꢁmL, 16.53 mmol)in THF (83 mL) af-
ter stirring for 1 h at 0 C] over a period of 2 min. After stir-
ring for 6 min, a solution of the crude aldehyde 8 (943 mg,
5.48 mmol) in THF (46 mL) was added, over a period ꢁof
Novozyme 435 (Candida Antarctica lipase immobilized on
a macroporous acrylic resin, Novo Nordisk; 441 mg) was
added in a well-stirred solution of the previous ketone
(245 mg, 0.827 mmol), in toluene (6 mL) and sodium phos-
phate buffer (pH 6.2; 6 mL, 0.1 M), at room temperature. Af-
ter 48 h (TLC indicated no further conversion) the reaction
mixture was filtered and the retained enzyme was washed
with AcOEt (20 mL) and water (20 mL). The organic layer
was separated and the aqueous layer of the filtrate was ex-
tracted with AcOEt (2ꢂ20 mL) and the combined organic
layers were dried over anhydrous Na2SO4, filtered and
ꢁ
2 min via cannula. After being stirred at ꢀ100 C ꢀ90 C
for 15 min, the reaction was quenched with saturated
NH4Claq (50 mL) and then allowed to warm at room temper-
ature. The mixture was extracted with ethyl acetate
(2ꢂ40 mL) and the combined organic layers were washed
with brine (50 mL), dried over anhydrous Na2SO4 and con-
centrated under vacuum. The crude mixture was subjected
to flash chromatography (SiO2, Hexane/AcOEt 8:2 to 7:3)
to afford alcohol 18 (mixture of two diastereoisomers, ratio
1:1; 948 mg, 3.18 mmol; 58%) as a yellow oil, and recovered

5276
E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
concentrated under reduced pressure. The residue was sub-
jected to column chromatography (SiO2, Hexane/AcOEt
8:2–7:3) to afford the respective alcohol (110 mg,
0.433 mmol; 52%) as yellow oil, along with recovered start-
ing material (40 mg, 0.157 mmol; 16%). Rf¼0.28 (Hexane/
3.90–3.81 (m, 2H, CH2OAc), 3.79 (s, 6H, Ar-OCH3), 3.76–
3.71 (m, 1H, CHHOAc), 2.03–1.95 (m, 8H, CHCHOPMB,
OAc), 1.90–1.75 (m, 2H, CHCH2OAc), 1.33–1.22 (m, 2H,
CHCH2CH), 1.08 (d, 3J(H,H)¼6.6 Hz, 3H, CH3), 1.04–
0.99 (m, 2H, CHCH2CH), 0.97 (d, J¼6.6 Hz, 3H, CH3),
0.92 (d, J¼6.8 Hz, 3H, CH3), 0.83 (d, J¼6.8 Hz, 3H, CH3);
1
ꢁ
AcOEt 7:3); H NMR (500 MHz, Acetone-d6, 25 C):
13
5.30 (d, 2J(H,H)¼2.9 Hz, 1H, ]CH2), 5.27 (d,
C NMR (125.8 MHz, CDCl3, 25 C): d 171.1, 169.6,
169.5, 163.6, 159.3, 149.8, 129.7, 129.5, 129.4, 128.2,
113.8, 110.3, 104.8, 92.6, 92.5, 77.5, 76.8, 71.2, 71.15,
68.7, 68.0, 61.7, 55.4, 55.2, 38.4, 37.3, 36.9, 36.6, 34.9,
30.4, 29.9, 20.8, 20.7, 18.6, 18.3, 17.2, 16.6; HRMS (ESI)
calculated for C23H30O7 ([M+Na]+): m/z 441.1882, found
441.1883.
ꢁ
d
2J(H,H)¼2.9 Hz, 1H, ]CH2), 4.14 (s, 3H, OCH3), 3.70–
3.60 (m, 1H, CHCO), 3.46–3.40 (m, 1H, CH2OH), 3.35–
3.29 (m, 1H, CH2OH), 1.97–1.88 (m, 1H, HOCH2CH),
1.71–1.61 (m, 1H, CHCH2CH), 1.19–1.04 (m, 1H,
3
CHCH2CH), 1.14 (d, J(H,H)¼6.9 Hz, 3H, CH3), 0.94 (d,
3J(H,H)¼6.9 Hz, 3H, CH3) ppm; 13C NMR (125.8 MHz,
ꢁ
68.4, 64.3, 43.6, 38.4, 35.5, 18.8, 18.5 ppm.
CDCl3, 25 C): d 202.2, 170.1, 167.9, 150.9, 130.1, 96.7,
Amano Lipase AK (Pseudomonas fluorescens, Aldrich;
1.05 g) was added in a well-stirred solution of the previous
PMB–ether (950 mg, 2.27 mmol) in acetonitrile (12.6 mL)
and sodium phosphate buffer (pH 6.2; 50.5 mL; 0.1 M), at
room temperature. The reaction was completed after 12 h
(TLC), was filtered through Celite and the retained enzyme
was washed with AcOEt (50 mL) and water (30 mL). The
aqueous layer of the filtrates was extracted with AcOEt
(2ꢂ30 mL) and the combined organic layers were washed
with saturated NaHCO3aq (30 mL), brine (30 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was filtered through a silica pad
(SiO2, Hexane/AcOEt 7:3) to afford alcohol 20a (mixture
of two diastereoisomers, ratio 1:1; 692 mg, 1.838 mmol;
81%) as yellow oil. Rf¼0.25 (Hexane/AcOEt 7:3); 1H
To a solution of the previous alcohol (37 mg, 0.146 mmol) in
DMSO (1 mL) was added IBX (160 mg, 0.571 mmol) at
room temperature under an argon atmosphere. After stirring
for 2 h the reaction was quenched with water (3 mL) and
AcOEt (3 mL). The iodosocarboxylic acid, which precipi-
tated as a white amorphous solid, was removed by filtration
through Celite. The filtrate was extracted with AcOEt
(2ꢂ5 mL) and the combined organic layers were washed
with saturated NaHCO3aq (5 mL) and brine (5 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The crude mixture was subjected to flash chroma-
tography (SiO2, Hexane/AcOEt 8:2) to afford the aldehyde
19 (26 mg, 0.102 mmol; 70%) as colorless oil. Rf¼0.37
1
(Hexane/AcOEt 7:3); [a]2D.5 +31ꢁ (c 0.15 in CHCl3); H
NMR (500 MHz, CDCl3, 25 C): d 7.29–7.18 (m, 4H,
ꢁ
3
ꢁ
NMR (500 MHz, CDCl3, 25 C): d 9.62 (s, 1H, CHO),
ArH), 6.86 (d, J(H,H)¼8.0 Hz, 4H, ArH), 5.10–5.04 (m,
2
2
5.30 (d, J(H,H)¼2.9 Hz, 1H, ]CH2), 5.24 (d, J(H,H)¼
2.9 Hz, 1H, ]CH2), 4.13 (s, 3H, OCH3), 3.77–3.65 (m,
1H, CH2CHCO), 2.48–2.37 (m, 1H, CHCHO), 2.34–2.24
(m, 1H, CHCH2CH), 1.35–1.25 (m, 1H, CHCH2CH), 1.18
4H, ]CH2), 4.54–4.44 (m, 2H, OCH2Ar), 4.33–4.26 (m,
2H, OCH2Ar), 4.14 (s, 6H, OCH3), 4.14–4.10 (m, 1H,
CHOPMB), 3.80–3.86 (m, 1H, CHOPMB), 3.80 (s, 6H,
Ar-OCH3), 3.50–3.43 (m, 2H, CH2OH), 3.42–3.36 (m,
2H, CH2OH), 2.16–1.97 (m, 2H, CHCHOPMB), 1.87–1.72
(m, 2H, CHCH2OH), 1.71–1.49 (m, 2H, CHCH2CH),
3
3
(d, J(H,H)¼7.5 Hz, 3H, CH3), 1.15 (d, J(H,H)¼6.9 Hz,
13
ꢁ
3H, CH3) ppm; C NMR (125.8 MHz, CDCl3, 25 C):
d 204.4, 199.9, 148.8, 141.8, 133.3, 127.9, 96.1, 62.9, 44.4,
41.9, 32.9, 17.9, 13.9 ppm; FTIR (neat): nmax 2962, 2924,
2875, 2852, 1769, 1726, 1686, 1667, 1585, 1455, 1390,
3
1.36–1.19 (m, 2H, CHCH2CH), 1.09 (d, J(H,H)¼6.6 Hz,
3
3H, CH3), 0.96 (d, J(H,H)¼6.5 Hz, 3H, CH3), 0.93 (d,
3J(H,H)¼6.7 Hz, 3H, CH3), 0.85 (d, J(H,H)¼6.9 Hz, 3H,
3
1286, 996, 738 cmꢀ1
.
CH3) ppm;
C NMR (125.8 MHz, CDCl3, 25 C):
13
ꢁ
d 169.6, 163.9, 159.3, 149.8, 146.2, 139.1, 129.7, 129.6,
113.9, 113.8, 92.7, 92.6, 71.3, 71.1, 67.6, 66.9, 61.7, 59.6,
55.3, 38.4, 37.5, 36.6, 36.4, 32.8, 31.2, 29.7, 18.4, 18.1,
17.3, 17.2 ppm; HRMS (ESI) calculated for C21H28O6
([M+Na]+): m/z 399.1778, found 399.1779.
4.1.5. Alcohol 20a. A solutionofp-methoxybenzyltrichloro-
acetimidate (2.06 g, 7.29 mmol) in cyclohexane (3.9 mL)
was added to a solution of alcohol 18 (726 mg, 2.43 mmol)
in DCM (1.9 mL) under an argon atmosphere. The resulting
ꢁ
mixture was cooled to 0 C and treated with (ꢃ)-camphor-
sulfonic acid (120 mg, 0.504 mmol). The reaction mixture
was warmed to room temperature and stirred for 7 h, slowly
developing a white precipitate. The suspension was filtered
and washed with CCl4 (2ꢂ15 mL). The filtrate was washed
with saturated NaHCO3aq (15 mL) and brine (15 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography
(SiO2, Hexane/AcOEt 9:1) to afford the PMB-ether (mixture
of two diastereoisomers, ratio 1:1; 1.0 g, 2.39 mmol; 98%) as
colorless oil. Rf¼0.40 (Hexanes/AcOEt 8:2); 1H NMR
4.1.6. Alcohol 20b. To a solution of alcohol 18 (200 mg,
0.670 mmol) in DMF (0.1 mL) was added imidazole
(91 mg, 1.34 mmol), TBDMS-Cl (152 mg, 1.00 mmol) and
DMAP (8.18 mmol, 0.067 mmol) at room temperature under
argon an atmosphere. After being stirred for 12 h the reaction
was quenched with MeOH (0.5 mL) and saturated NH4Claq
(10 mL). The mixture was extracted with AcOEt (15 mL)
and organic layer was washed with brine (10 mL), dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography
(SiO2, Hexane/AcOEt 95:5) to afford the corresponding silyl
ether (mixture of two diastereoisomers, ratio 1:1; 235 mg,
0.569 mmol; 85%) as colorless oil. Rf¼0.65 (Hexanes/
ꢁ
(500 MHz, CDCl3, 25 C): d 7.25–7.17 (m, 4H, ArH), 6.86
(d, 3J(H,H)¼8.5 Hz, 4H, ArH), 5.10–5.03 (m, 4H, ]CH2),
4.48 (d, 2J(H,H)¼11.3 Hz, 1H, OCHHAr), 4.45 (d, 2J(H,H)¼
2
1
ꢁ
11.3 Hz, 1H, OCHHAr), 4.28 (d, J(H,H)¼11.3 Hz, 2H,
AcOEt 9:1); H NMR (500 MHz, CDCl3, 25 C): d 5.08–
5.02 (m, 4H, ]CH2), 4.31–4.26 (m, 2H, CHOTBS), 4.26
(s, 3H, OCH3), 4.25 (s, 3H, OCH3), 3.98 (dd,
OCH2Ar), 4.14 (s, 6H, OCH3), 4.11–4.05 (m, 2H,
CHOPMB), 3.96 (dd, 3J(H,H)¼4.9, 10.8 Hz, 1H, CHHOAc),

E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
5277
2J(H,H)¼3.9 Hz, 3J(H,H)¼10.8 Hz, 1H, CHHOAc), 3.91
(m, 3H, CH2OAc), 2.03 (s, 3H, Ac), 1.99 (s, 3H, Ac), 1.96–
1.78 (m, 4H, CHCH3), 1.28–1.17 (m, 2H, CHCH2CH),
1.06 (d, 3J(H,H)¼6.5 Hz, 3H, CH3), 0.99 (d, 3J(H,H)¼
6.4 Hz, 3H, CH3), 0.98–0.90 (m, 2H, CHCH2CH), 0.93 (d,
3J(H,H)¼6.8 Hz, 3H, CH3), 0.88 (s, 18H, TBS), 0.81 (d,
3J(H,H)¼6.8 Hz, 3H, CH3), 0.09 (s, 6H, TBS), ꢀ0.04 (s,
3.225 mmol) at room temperature under argon an atmosphere.
After stirring for 2 h the reaction was quenched with water
(5 mL) and AcOEt (5 mL). The iodosocarboxylic acid, which
precipitated as a white amorphous solid, was removed by fil-
tration through Celite. The filtrate was extracted with AcOEt
(2ꢂ10 mL) and the combined organic layers were washed
with saturated NaHCO3aq (15 mL) and brine (15 mL), dried
over anhydrous Na2SO4 and concentrated under vacuum.
The crude mixture was subjected to flash chromatography
(SiO2, Hexane/AcOEt 8:2) to afford the corresponding alde-
hyde (mixture of two diastereoisomers, ratio 1:1; 334 mg,
0.892 mmol; 88%) as yellow oil. Rf¼0.40 (Hexane/AcOEt
13
ꢁ
6H, TBS) ppm; C NMR (62.9 MHz, CDCl3, 25 C):
d 202.9, 171.3, 169.7, 162.9, 149.9, 107.4, 92.6, 92.6, 71.2,
70.9, 68.3, 67.6, 61.8, 39.4, 39.3, 38.0, 36.1, 30.1, 29.7,
25.8, 20.9, 20.8, 18.9, 18.6, 17.9, 17.4, 15.9, 3.6, 3.1 ppm.
1
3
ꢁ
To a solution of the previous acetyl ester (155 mg,
0.375 mmol) in EtOH (1.5 mL) was added guanidine (1 M
in EtOH; 0.48 mmol) [prepared from guanidine hydrochor-
ide (525 mg, 5.50 mmol) and NaOH (4 N; 1.3 mL) in EtOH
7:3); H NMR (500 MHz, CDCl3, 25 C): d 9.53(d, J(H,H)¼
2.3 Hz, 1H, CHO), 9.52 (d, 3J(H,H)¼2.3 Hz, 1H, CHO), 7.22
(d, 3J(H,H)¼8.6 Hz, 2H, ArH), 7.21 (d, 3J(H,H)¼8.6 Hz, 2H,
ArH), 6.87 (d, 3J(H,H)¼8.6 Hz, 2H, ArH), 6.86 (d,
2
(3.93 mL)] at 0 C and stirred for 1.5 h. The reaction mix-
3J(H,H)¼8.6 Hz, 2H, ArH), 5.12 (d, J(H,H)¼2.4 Hz, 1H,
ꢁ
2
ture was quenched with saturated NH4Claq (10 mL) and ex-
tracted with AcOEt (2ꢂ10 mL). The combined organic
layers were washed with brine (10 mL), dried over anhy-
drous Na2SO4 and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2,
Hexane/AcOEt 8:2) to afford alcohol 20b (mixture of two
diastereoisomers, ratio 1:1; 109 mg, 0.293 mmol; 78%)
as yellow oil. Rf¼0.45 (Hexane/AcOEt 7:3); 1H NMR
]CH2), 5.09 (d, J(H,H)¼2.4 Hz, 1H, ]CH2), 5.08–5.05
3
(m, 2H, ]CH2), 4.48 (d, J(H,H)¼11.5 Hz, 1H, OCH2Ar),
4.47 (d, 3J(H,H)¼11.5 Hz, 1H, OCH2Ar), 4.28 (d,
3J(H,H)¼11.5 Hz, 2H, OCH2Ar), 4.19 (s, 3H, OCH3), 4.15
3
(s, 3H, OCH3), 4.12 (d, J(H,H)¼6.9 Hz, 1H, CHOPMB),
4.10 (d, 3J(H,H)¼6.9 Hz, 1H, CHOPMB), 3.81 (s, 3H,
Ar-OCH3), 3.80 (s, 3H, Ar-OCH3), 2.56–2.57 (m, 1H,
CHCHO), 2.47–2.38 (m, 1H, CHCHO), 2.31–2.24 (m, 1H,
CHCH2CH), 2.04–1.93 (m, 2H, CHCHOPMB), 1.70–1.61
(m, 1H, CHCH2CH), 1.20–1.09 (m, 2H, CHCH2CH), 1.11
ꢁ
(500 MHz, CDCl3, 25 C): d 5.08–5.02 (m, 4H, ]CH2),
4.39–4.23 (m, 2H, CHOTBS), 4.27 (s, 3H, OCH3), 4.26
(s, 3H, OCH3), 3.59–3.51 (m, 1H, CH2OH), 3.51–3.44
(m, 1H, CH2OH), 3.44–3.28 (m, 2H, CH2OH), 2.06–1.86
(m, 2H, CHCH3), 1.88–1.66 (m, 2H, CHCH3), 1.25–1.16
3
3
(d, J(H,H)¼6.9 Hz, 3H, CH3), 1.07 (d, J(H,H)¼7.5 Hz,
3
3H, CH3), 1.05 (d, J(H,H)¼6.9 Hz, 3H, CH3), 0.82 (d,
3J(H,H)¼6.9 Hz, 3H, CH3) ppm; 13C NMR (125.8 MHz,
3
ꢁ
(m, 2H, CHCH2CH), 1.06 (d, J(H,H)¼6.5 Hz, 3H, CH3),
CDCl3, 25 C): d 205.6, 205.0, 170.4, 170.1, 164.2, 159.8,
3
1.05–0.95 (m, 2H, CHCH2CH), 0.98 (d, J(H,H)¼6.4 Hz,
150.3, 150.2, 130.1, 130.0, 128.7, 114.3, 114.2, 93.3, 93.2,
77.1, 71.7, 71.5, 62.3, 62.2, 55.7, 44.7, 44.1, 38.0, 37.8,
35.9, 34.2, 30.1, 17.2, 16.9, 15.3, 15.1 ppm.
3
3H, CH3), 0.92 (d, J(H,H)¼6.7 Hz, 3H, CH3), 0.83 (d,
3J(H,H)¼6.8 Hz, 3H, CH3), 0.1 (s, 3H, TBS), 0.09 (s, 3H,
TBS), ꢀ0.04 (s, 6H, TBS) ppm.
A solution of the previous aldehyde (230 mg, 0.614 mmol)
and freshly prepared vinyl-iodide 7 (338 mg, 1.53 mmol)
in THF/DMSO (5.4 mL/2.4 mL) was treated under an argon
atmosphere with CrCl2 (798 mg, 6.148 mmol) and NiCl2
(11.5 mg, 0.082 mmol) (thoroughly premixed and flame-
dried in vacuo). After stirring for 12 h at room temperature,
the reaction mixture was diluted with water (20 mL) and ex-
tracted with Et2O (3ꢂ20 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by flash chromatography
(SiO2, Hexanes/AcOEt/Et3N 8:2:0.1) to afford alcohol 21a
(mixture of four diastereoisomers; 115 mg, 0.246 mmol;
40%) as colorless oil, along with recovered aldehyde
(108 mg, 0.288 mmol; 47%). Rf¼0.55 (Hexanes/AcOEt
4.1.7. Triene-iodide 7. Anhydrous CrCl2 (1.9 g, 0.015 mol)
was suspended in THF (25 mL) under an argon atmosphere.
A solution of 2,4-hexadienal, 10 (0.3 mL, 2.72 mmol) and
iodoform (1.5 g, 3.81 mmol) in THF (13.6 mL) was added
ꢁ
drop-wise to the suspension at 0 C via cannula. After stir-
ꢁ
ring at 0 C for 1 h the reaction was completed (TLC), the
mixture was filtered through Celite and washed with Et2O
(50 mL). The combined filtrates were washed with water
(30 mL) and brine (30 mL). The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The
residue was subjected to flash chromatography (Al2O3, Hex-
ane) to afford the iodide, 7 (510 mg, 2.31 mmol; 85%, mix-
ture of isomers E/Z 2:1) as a yellow solid. Rf¼0.82
1
1
ꢁ
ꢁ
(Hexane); H NMR (500 MHz, CDCl3, 25 C): d 7.51–
7:3); H NMR (500 MHz, CDCl3, 25 C): d 7.25–7.18 (m,
32H, ArH), 6.90–6.83 (m, 32H, ArH), 6.59–6.41 (m, 3H),
6.41–5.89 (m, 60H), 5.89–5.44 (m, 30H), 5.44–5.26 (m,
3H), 5.16–4.97 (m, 32H, C]CH2), 4.57–4.40 (m, 18H),
4.39–4.24 (m, 18H), 4.24–3.92 (m, 75H), 3.92–3.70 (m,
49H), 2.18–1.97 (m, 16H), 1.97–1.81 (m, 10H), 1.81–1.74
(m, 36H), 1.74–1.53 (m, 10H), 1.52–1.17 (m, 32H), 1.17–
1.04 (m, 24H), 1.04–0.73 (m, 80H); FTIR (neat): nmax
3514, 3058, 3018, 2964, 2928, 2873, 2853, 1769, 1669,
1622, 1513, 1462, 1383, 1282, 1251, 1175, 1078, 1035,
3
7.41 (m, 1H), 7.18–7.06 (m, 1H), 7.02 (dd, J(H,H)¼14.3,
3
14.3 Hz, 1H), 6.83–6.74 (m, 1H), 6.71 (dd, J(H,H)¼10.0,
3
10.0 Hz, 1H), 6.57–6.48 (m, 1H), 6.44 (dd, J(H,H)¼14.9,
14.9 Hz, 1H), 6.38–6.08 (m, 7H), 6.08–5.95 (m, 4H), 5.93–
5.76 (m, 3H), 5.75–5.60 (m, 3H), 1.79 (d, 3J(H,H)¼6.8 Hz,
3
3H, CH3), 1.76 (d, J(H,H)¼7.0 Hz, 3H, CH3), 1.83–1.75
(m, 6H, CH3) ppm; 13C NMR (125.8 MHz, CDCl3, 25 C):
ꢁ
d 145.4, 138.4, 137.3, 133.8, 132.8, 132.3, 132.0, 131.7,
131.5, 130.9, 129.8, 129.6, 129.5, 129.2, 128.7, 128.6,
128.3, 127.5, 81.9, 81.2, 78.4, 77.5, 29.7, 18.5 ppm.
1002, 977, 824, 740, 707 cmꢀ1
.
4.1.8. Alcohol 21a. To a solution of alcohol 20a (380 mg,
1.011 mmol) in DMSO (7.2 mL) was added IBX (1.38 g,
4.1.9. Alcohol 21b. To a solution of alcohol 20b (86 mg,
0.231 mmol) in DMSO (1.8 mL) was added IBX (130 mg,

5278
E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
0.462 mmol) at room temperature under an argon atmo-
sphere. After stirring for 1.5 h the reaction was quenched
with water (5 mL) and AcOEt (5 mL). The iodosocarboxylic
acid, which precipitated as a white amorphous solid, was re-
moved by filtration through Celite. The filtrate was extracted
with AcOEt (2ꢂ10 mL) and the combined organic layers
were washed with saturated NaHCO3aq (15 mL) and brine
(15 mL), dried over anhydrous Na2SO4 and concentrated un-
der vacuum. The crude mixture was filtered through a small
pad of SiO2 (Hexane/AcOEt 8:2) to afford the corresponding
aldehyde (73 mg) as yellow oil, which was subjected to the
next step without further purification.
The reaction mixturewas filtered through a short pad of silica
gel and washed with Hexanes/AcOEt/Et3N (7:3:0.1; 20 mL).
The filtrate was concentrated under reduced pressure and the
residue was purified by flash chromatography (SiO2, Hexane/
AcOEt/Et3N 8:2:0.1) to afford 22 (mixture of two diastereo-
isomers; 23 mg, 35%) as colorless oil. Rf¼0.35 (Hexanes/
1
ꢁ
AcOEt 7:3); H NMR (500 MHz, CDCl3, 25 C): d
7.40–7.27 (m, 3H), 7.00–6.89 (m, 5H), 6.89–6.80 (m, 2H),
6.73–6.64 (m, 2H), 6.64–6.52 (m, 4H), 6.39–6.25 (m, 8H),
6.25–6.09 (m, 16H), 6.05–5.90 (m, 4H), 5.86–5.72
(m, 4H), 5.08 (br s, 16H), 4.32–4.03 (m, 4H), 4.14 (br s,
24H), 3.82–3.76 (m, 1H), 3.68–3.60 (m, 1H), 3.47–3.37
(m, 2H), 2.97–2.80 (m, 8H), 1.92–1.80 (m, 24H), 1.80–
1.71 (m, 8H), 1.45–1.38 (m, 8H), 1.29–1.23 (m, 8H), 1.17–
1.08 (m, 24H), 1.04–0.95 (m, 24H); HRMS (ESI) calculated
for C20H26O5 ([M+Na]+): m/z 369.1672, found 369.1673.
A solution of the aldehyde (73 mg, 0.197 mmol) and freshly
prepared vinyl-iodide 7 (107 mg, 0.486 mmol) in THF/
DMSO (1.73 mL/0.72 mL) was treated under an argon at-
mosphere with CrCl2 (264 mg, 2.034 mmol) and NiCl2
(11 mg, 0.0071 mmol) (thoroughly premixed and flame-
dried in vacuo). After stirring for 12 h at room temperature,
the reaction mixture was diluted with water (15 mL) and ex-
tracted with Et2O (3ꢂ10 mL). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated under
vacuum. The residue was purified by flash chromatography
(SiO2, Hexanes/AcOEt/Et3N 85:15:0.1) to afford 21b (mix-
ture of four diastereoisomers; 45 mg, 0.098 mmol; 50%)
as colorless oil, along with recovered aldehyde (22 mg,
0.059 mmol; 30%). Rf¼0.55 (Hexanes/AcOEt 7:3).
4.1.11. Alcohol 22. (One pot oxidation-deprotection of 21a.)
A solution of the crude trienone (90 mg, 0.193 mmol) in
DCM/0.5% NaHCO3aq (9:1; 6.4 mL) was treated with
ꢁ
DDQ (131.4 mg, 0.579 mmol) at 0 C for 2.5 h. The reac-
tion mixture was filtered through a short pad of silica gel
and washed with Hexanes/AcOEt/Et3N (7:3:0.1; 20 mL).
The filtrate was concentrated under reduced pressure and
the residue was purified by flash chromatography (SiO2,
Hexane/AcOEt/Et3N 8:2:0.1) to afford alcohol 22 (16 mg,
25%) as colorless oil.
4.1.10. Alcohol 22. To a solution of alcohol 21a (95 mg,
0.203 mmol) in Et2O (8.6 mL) was added activated MnO2
(1.51 g) and the mixture was stirred at room temperature
for 3 h (TLC indicated the end of the reaction). The solution
was filtrated through Celite, to remove MnO2 and concen-
trated under reduced pressure to provide the corresponding
trienone (82 mg, 0.180 mmol; 90%) as yellow oil, which
was subjected to the next step without further purification.
Rf¼0.40 (Hexane/AcOEt 8:2); 1H NMR (500 MHz, CDCl3,
4.1.12. Diketone 5 from 22. A solution of alcohol 22 (20 mg,
0.058 mmol) in DCM (1.3 mL) was treated with Dess–Mar-
tin periodinate (30 mg, 0.071 mmol) at ambient temperature
for 1 h. The reaction was quenched with saturated Na2S2O3
and stirred for 30 min. The mixture was separated and the
aqueous layer was extracted with DCM (2ꢂ10 mL). The
combined organic layers were washed with brine (10 mL),
dried over anhydrous Na2SO4 and concentrated under re-
duced pressure. The residue was purified by flash chromato-
graphy (SiO2, Hexanes/AcOEt/Et3N 8:2:0.1) to afford 5 as
colorless oil (mixture of E/Z isomers; 19 mg, 95%).
Rf¼0.32 (Hexanes/AcOEt 7:3); [a]2D.5 ꢀ20.1ꢁ (c 0.2 in
ꢁ
25 C): d 7.78–7.68 (m, 8H), 7.57–7.49 (m, 8H), 7.44–7.31
(m, 6H), 7.27–7.13 (m, 22H), 6.86 (dd, 3J(H,H)¼8.9,
9.9 Hz, 16H), 6.60–6.49 (m, 6H), 6.25–6.07 (m, 8H), 6.01–
5.89 (m, 4H), 5.81–5.73 (m, 2H), 5.09 (d, 2J(H,H)¼2.5 Hz,
4H), 5.07 (d, 2J(H,H)¼2.2 Hz, 4H), 5.05–5.02 (m, 8H),
4.46 (d, 3J(H,H)¼10.9 Hz, 4H), 4.44 (d, 3J(H,H)¼11.2 Hz,
1
ꢁ
CHCl3); H NMR (500 MHz, CDCl3, 25 C): d 7.26 (dd,
3J(H,H)¼10.7, 15.0 Hz, 1H), 6.59 (dd, 3J(H,H)¼10.8,
14.8 Hz, 1H), 6.28–6.09 (m, 3H), 6.01–5.89 (m, 1H), 5.27
3
2
2
4H), 4.33–4.29 (m, 1H), 4.28 (d, J(H,H)¼10.5 Hz, 4H),
(br d, J(H,H)¼2.7 Hz, 1H), 5.21 (br d, J(H,H)¼2.7 Hz,
4.26 (d, 3J(H,H)¼11.4 Hz, 4H), 4.21–4.16 (m, 1H), 4.16 (s,
6H), 4.16 (s, 6H), 4.12 (s, 6H), 4.12 (s, 6H), 4.10–4.03 (m,
6H), 3.80 (s, 12H), 3.79 (s, 12H), 2.94–2.79 (m, 6H), 2.35–
2.25 (m, 2H), 1.93–1.77 (m, 4H), 1.84 (d, 3J(H,H)¼6.9 Hz,
24H), 1.77–1.57 (m, 10H), 1.50–1.32 (m, 6H), 1.21–1.10
1H), 4.12 (s, 3H), 3.71–3.59 (m, 1H), 2.81 (ddq, J(H,H)¼
3
6.9, 6.9, 6.9 Hz, 1H), 2.27–2.16 (m, 1H), 1.84 (br d,
J¼6.0 Hz, 3H), 1.37–1.25 (m, 1H), 1.15 (d, 3J(H,H)¼7.1 Hz,
3H), 1.13 (d, 3J(H,H)¼7.0 Hz, 3H); (ZEE, partial) 7.32 (dd,
3J(H,H)¼11.4, 15.0 Hz, 1H), 6.94 (dd, 3J(H,H)¼12.3,
15.1 Hz, 1H), 6.38–6.28 (m, 1H), 5.81–5.73 (m, 1H), 1.87
3
3
(m, 2H), 1.11 (d, J(H,H)¼6.9 Hz, 9H), 1.05 (d, J(H,H)¼
3
3
6.9 Hz, 9H), 1.02 (d, J(H,H)¼6.4 Hz, 3H), 0.99–0.82 (m,
(br d, J(H,H)¼7.2 Hz, 3H); HRMS (ESI) calculated for
14H), 0.79 (d, 3J(H,H)¼6.9 Hz, 9H) ppm; 13C NMR
C20H24O5 ([M+H]+): m/z 337.1515, found 337.1518.
ꢁ
(125.8 MHz, CDCl3, 25 C): d 143.5, 143.2, 142.7, 142.5,
136.0, 135.9, 131.8, 131.7, 131.3, 130.0, 129.9, 129.4,
129.3, 128.8, 128.6, 128.5, 127.5, 127.2, 114.2, 93.1, 92.9,
71.7, 71.5, 67.9, 66.0, 62.3, 62.2, 55.7, 42.9, 42.1, 40.3,
38.5, 38.3, 38.1, 36.4, 31.0, 30.9, 30.1, 19.6, 19.1, 19.0,
18.8, 17.6, 16.9, 14.1 ppm; HRMS (ESI) calculated for
C28H34O6 ([M+Na]+): m/z 489.2245, found 489.2244.
4.1.13. Diketone 5 from 21b. To a solution of silyl ether 21b
(32 mg, 0.069 mmol) in THF (0.23 mL) was added TBAF
(0.21 mL of 1 M solution in THF, 0.207 mmol) at 0 C. After
5 min the ice bath was removed, the reaction mixture was
stirred for additional 1 h at ambient temperature (TLC indi-
cated the end of the reaction). The reaction mixture was ex-
tracted with AcOEt (2ꢂ5 mL). The combined organic
layers were washed with saturated NH4Claq (5 mL) and brine
(3 mL), dried over anhydrous Na2SO4 and concentrated
under vacuum. The crude mixture was subjected to flash
ꢁ
A solution of the previous p-methoxy benzyl ether (82 mg,
0.180 mmol) in DCM/0.5% NaHCO3aq (9:1; 5.8 mL) was
ꢁ
treated with DDQ (120 mg, 0.528 mmol) at 0 C for 2.5 h.

E. A. Couladouros et al. / Tetrahedron 62 (2006) 5272–5279
5279
chromatography (SiO2, Hexane/AcOEt 1:1) to afford the
corresponding diol (mixture of diastereoisomers; 20 mg,
References and notes
0.057 mmol; 83%) as colorless oil. Rf¼0.45 (Hexanes/
1. Bister, B.; Bischoff, D.; Strobele, M.; Riedlinger, J.; Reicke,
¨
1
ꢁ
AcOEt 1:1); H NMR (500 MHz, CDCl3, 25 C): d 6.60–
6.46 (m, 1H), 6.38–5.95 (m, 31H), 5.83–5.50 (m, 15H),
5.49–5.28 (m, 1H), 5.18–4.98 (m, 16H), 4.62–4.28 (m,
10H), 4.20–3.92 (m, 30H), 3.65–3.48 (m, 2H), 3.45–3.26
(m, 4H), 2.22–1.84 (m, 12H), 1.84–1.64 (m, 26H), 1.58–
1.47 (m, 2H), 1.45–1.35 (m, 2H), 1.33–1.14 (m, 8H), 1.12–
0.76 (m, 48H).
A.; Wolter, F.; Bull, A. T.; Zahner, H.; Fiedler, H.-P.; Sussmuth,
¨
¨
R. D. Angew. Chem., Int. Ed. 2004, 43, 2574–2576.
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2004, 57, 271–279.
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To a solution of the previous diol (18 mg, 0.052 mmol) in
DMSO (0.4 mL) was added IBX (44 mg, 0.156 mmol) at
room temperature under an argon atmosphere. After stirring
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(2ꢂ5 mL) and the combined organic layers were washed
with saturated NaHCO3aq (4 mL) and brine (3 mL), dried
over anhydrous Na2SO4 and concentrated under vacuum.
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oil (mixture of E/Z isomers; 15 mg, 0.044 mmol 85%).
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iodine under an argon atmosphere. After 3 h (TLC indicated
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duced pressure and the residue was subjected to flash chro-
matography (SiO2, Hexanes/AcOEt 8:2) to afford 3 (4 mg,
0.011 mmol, 75%). as colorless oil. Rf¼0.45 (Hexanes/
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1
ꢁ
AcOEt 8:2); H NMR (500 MHz, CDCl3, 25 C): d 6.48
(dd, 3J(H,H)¼6.8, 16.8 Hz, 1H, CH]), 6.25 (dd,
3
4J(H,H)¼1.2 Hz, J(H,H)¼16.8 Hz, 1H, CH]), 5.86 (dt,
3
3J(H,H)¼3.1, 9.9 Hz, 1H, CH]), 5.67 (dt, J(H,H)¼2.4,
´
16. Torrado, A.; Iglesias, B.; Lopez, S.; Lera, A. R. Tetrahedron
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]CHCHCH]), 3.16–3.08 (m, 1H, CHCH3), 3.00–2.90
(m, 1H, COCHCH3), 2.69–2.59 (m, 1H, CHCH3), 2.40
(dd, 2J(H,H)¼14.4 Hz, 3J(H,H)¼7.9 Hz, 1H, CHHCHCH3),
1.88 (ddd, 3J(H,H)¼4.2, 5.9 Hz, 2J(H,H)¼15.2 Hz, 1H,
CHCHHCH), 1.82 (dd, 3J(H,H)¼4.6 Hz, 2J(H,H)¼14.4 Hz,
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3
3J(H,H)¼6.8 Hz, 3H, CH3), 1.19 (d, J(H,H)¼6.8 Hz, 3H,
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21. DDQ deprotection was attempted under various conditions:
CH3), 1.15 (d, 3J(H,H)¼7.3 Hz, 3H, CH3).
Acknowledgments
ꢁ
ꢁ
Financial support co-funded by the General Secretariat for
Research and Technology of the Hellenic Ministry of Devel-
opment and the European Community is acknowledged
along with the scholarship provided to A.D. Magos by the
Institute of Physical Chemistry of N.C.S.R. ‘‘Demokritos’’.
We would also like to thank Dr. E. Pitsinos and Dr. A.
Strongilos for their valuable discussions and comments as
well as Professor A. Giannis for kindly offering his MS
facilities.
(i) DCM/H2O, 0 C; (ii) DCM/NaHCO3aq, 0 C; (iii) DCM/
ꢁ
phosphate buffer (pH¼7.2), 0 C; see: Murakami, N.;
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