An efficient and practical total synthesis of aigialomycin D

Article abstract of DOI:10.1016/j.tet.2007.05.013

An efficient and practical total synthesis of aigialomycin D 1 is described. This concise synthetic route features the use of readily available starting materials with the key transformations being the formation of the macrocycle by RCM under microwave ir

Full text of DOI:10.1016/j.tet.2007.05.013

Tetrahedron 63 (2007) 7053–7058
An efficient and practical total synthesis of aigialomycin D
*
Nguyen Quang Vu, Christina L. L. Chai, Kok Peng Lim, Sze Chen Chia and Anqi Chen
Institute of Chemical and Engineering Sciences (ICES), 1, Pesek Road, Jurong Island, Singapore 627833, Singapore
Received 29 January 2007; revised 16 April 2007; accepted 3 May 2007
Available online 8 May 2007
Abstract—An efficient and practical total synthesis of aigialomycin D 1 is described. This concise synthetic route features the use of readily
available starting materials with the key transformations being the formation of the macrocycle by RCM under microwave irradiation con-
ditions to effect complete E-selectivity, and regio- and stereospecific formation of the 10,20-double bond. The synthesis of aigialomycin D is
achieved with the longest linear sequence of only 11 steps and an overall yield of 19%.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Aigialomycin D 1, which possesses potent antitumour (IC50:
3.0 mg/ml against KB cells) and anti-malarial activity (IC50:
6.6 mg/ml against Plasmodium falciparum), is a member of a
group of 14-membered resorcinylic macrolides isolated
from the marine mangrove fungus Aigialus parvus BCC
5311.1 Some kinases, in particular cyclin-dependant kinase
(CDK) and glycogen synthase kinase (GSK-3), have recently
been identified as its antitumor targets of action.2 Three
synthetic routes to aigialomycin D 1 have been reported so
far. The first total synthesis was described by Danishefsky
et al. using a novel ‘ynolide’ protocol for the formation of
the resorcinylic unit.3 Subsequently, Pan4 and Winssinger2
reported two more synthetic routes using the Sharpless
asymmetric epoxidation to introduce the 50,60-diol unit,
and either the Julia–Kocienski reaction4 or selenium/sulfur
chemistry2 to install the 10,20-double bond. In Winssinger’s
work, some aigialomycin D analogues have also been
synthesised using solid-phase synthetic strategies.2
Our synthetic route to aigialomycin D 1 (Scheme 1) was
designed in conjunction with our recent efforts in the explo-
ration of new synthetic applications of D-(ꢀ)-erythronolac-
tone as a chiral building block. Disconnection of the target
compound 1 revealed three key fragments 3–5. The aromatic
portion 3 could be easily accessed by a reported cyclodime-
5
0
0
rization of methyl acetoacetate whilst the key C2 –C7 frag-
ment 5 would be derived from D-(ꢀ)-erythronolactone
acetonide 6, thus should provide the 50,60-diol with the de-
sired configuration. The formation of the ester linkage was
to be effected by the Mitsunobu reaction6 of 3, after phenolic
group protection and saponification to its carboxylic acid,
with the commercially available R-alcohol 4, and the instal-
0
0
lation of the C2 –C7 portion to be carried out at the benzylic
position either by addition to the aldehyde 5a or acylation
with the Weinreb amide7 5b, respectively, after lithiation
Mitsunobu
O
OH
5
O
MOMO
RCM
Inview of the biological activities, the lack of analogues with
structural diversity for structure–activity relationship studies
and the potential to develop more potent lead compounds, we
have independently conceived an efficient and practical total
synthetic route to aigialomycin D 1 from readily available
starting materials. In this paper, we report an efficient, stereo-
specific and practical synthesis of aigialomycin D 1 with
a longest linear sequence of only 11 steps in 19% overall
yield.
3
O
10'
8'
5'
O
1
1'
HO
MOMO
6'
OH
2'
R
O
Addition or
Acylation
OH
O
Aigialomycin D 1
2 a R=H, OH; 2b R=O
O
O
OH
O
O
R
OMe
+
HO
O
O
+
O
6
O
HO
4
Keywords: Aigialomycin D; Macrolide; D-Erythronolactone; Ring closing
metathesis.
3
5a R=H; 5b R=N(OMe)Me
* Corresponding author. Tel.: +65 67963908; fax: +65 63166184; e-mail:
chen_anqi@ices.a-star.edu.sg
Scheme 1. Retrosynthetic analysis of aigialomycin D 1.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.05.013

7054
N. Q. Vu et al. / Tetrahedron 63 (2007) 7053–7058
at the benzylic position. The macrocyclisation would then be
achieved by a ring closing metathesis (RCM) on intermedi-
ate 2 and the 10,20-alkene to be formed by regio- and stereo-
selective dehydration of the 20-alcohol. Final global
deprotection should complete a practical and efficient syn-
thesis of aigialomycin D 1.
acetonide, presumably due to the acidic nature of methoxy-
methylamine hydrochloride. After much experiment, it was
eventually found that changing the order of reagent addition
sequences by treatment of methoxymethylamine hydrochlo-
ride with 2 equiv of isopropylmagnesium chloride followed
by addition of the ester 15 gave the desired amide 5b in 96%
yield.
Our synthesis began with methyl orcillinate 3, which was
conveniently prepared by cyclodimerization of methyl ace-
toacetate in large scales according to a reported protocol.5
To couple 3 with the alcohol 4, the phenolic groups were pro-
tected as its bis-MOM ether 7,8 which was saponified to give
the desired acid 8 after acidification. It is noteworthy that the
acid is unstable under acidic conditions and undergoes fast
deprotection of one of the MOM protecting groups. There-
fore only weak organic acids, such as acetic acid, should
be used for the acidification and the crude product should
be used after workup.
O
O
O
O
O
O
b
c
a
e
R
d
6
HO
CO2Et
CO2Et
O
OH
13 R = H, OH
14 R = O
12
O
11
O
O
O
f
N
CO2Et
O
15
5b
O
Scheme 3. Reagents and conditions: (a) DIBAL-H, CH2Cl2, ꢀ78 ꢁC then
MeOH, 92%; (b) Ph3P]CHCO2Et, PhCO2H (0.2 mol %), CH2Cl2, reflux,
E/Z¼1:2, 73%; (c) H2 (1 atm), 10% Pd/C (cat.), EtOH, 97%; (d) PCC,
+
ꢀ
Coupling of the acid 8 with the alcohol 4 under Mitsunobu
conditions proceeded smoothly, affording the desired ester
9 in 86% yield (Scheme 2). At this point, the feasibility of
coupling the ester 9 with the aldehyde 5a by a benzylic lith-
iation–addition reaction was examined. Disappointingly, re-
action of the 10-lithiated 9 with n-butyraldehyde as a model
substrate afforded only the d-lactone 10,9 apparently formed
by intramolecular lactonisation after the addition reaction
had taken place. As a result, the aldehyde addition approach
was abandoned and the acylation methodology with the
Weinreb amide 5b to be investigated.
˚
NaOAc, 4 A MS, CH2Cl2, rt, 80%; (e) Ph3P CH3Br , n-BuLi, THF,
ꢀ30 ꢁC to rt, 71%; (f) MeONHMe$HCl, i-PrMgCl, THF, ꢀ20 ꢁC to rt, 96%.
With both the ester 9 and the Weinreb amide 5b in hand,
the crucial acylation step was examined. To our delight,
lithiation of 9 at the 10-position using LDA at ꢀ78 ꢁC
followed by reacting with the Weinreb amide 5b provided
the desired ketone 2b in 82% yield. At this stage, attemp-
ted reduction of the 20-carbonyl group with sodium borohy-
dride led to the cleavage of the ester linkage and formation
of d-lactone 1613 instead of the required alcohol 2a, indi-
cating again the facile intramolecular attack of the 20-alk-
oxy anion on the ester moiety. It was envisaged that
reduction after formation of the macrocycle could avoid
this problem as the macrocyclic ring strain would prevent
the 20-alkoxy anion from approaching close enough to
attack the ester.
MOMO
OH
OMOM
CO2R
O
c
a
CO2Me
O
HO
MOMO
b
MOMO
9
3
7 R = Me
8 R = H
The macrocyclisation of 2b by RCM following a reported
protocol3 afforded the cyclised product 17 in 86% yield
but with an E/Z ratio of only 5.7:1 as was evident from its
1H NMR spectrum. As the two stereoisomers were insepara-
ble by column chromatography, alternative conditions were
sought to improve the E-selectivity in this reaction. Inspired
by reports14 that RCM under microwave (MW) irradiation
improves the yield as well as the reaction efficiency, it was
considered that RCM of 2b under MW irradiation at higher
temperature could improve the selectivity by favouring the
thermodynamically more stable E-isomer. Indeed, when
the cyclisation precursor 2b (0.005 M in CH2Cl2) was
subjected to MW irradiation with Grubbs II catalyst
(10 mol %) at 100 ꢁC for only 30 min (see Section 4.1.9),
the cyclised product 17 was obtained in 98% yield with com-
plete E-selectivity (Scheme 4), which was evident from only
one set of olefinic signals in the 1H NMR spectrum charac-
terised by a 15.0 Hz coupling constant.
Scheme 2. Reagents and conditions: (a) MOMCl, NaH, THF, rt, quant.; (b)
KOH, MeOH/H2O (1:1), reflux then HOAc, pH 6, 99%; (c) DIAD, Ph3P, 4,
THF, rt, 86%.
The synthesis of the required Weinreb amide 5b for the
acylation approach is shown in Scheme 3. The acetonide 6,
which is commercially available or readily prepared follow-
ing the literature procedures,10 was reduced using DIBAL-H
to provide the known lactol 11,10 which was converted to the
ester 15 following a modified route described for its enantio-
mer.11 Thus, treatment of 11 with ethyl(triphenylphosphor-
anylidene)acetate in the presence of a catalytic amount of
benzoic acid afforded the a,b-unsaturated ester 12 as a 1:2
mixture of E- and Z-isomers in 73% yield. Without separat-
ing the two isomers, the double bond in 12 was saturated
under catalytic hydrogenation conditions to give the alcohol
13, which was oxidized to the aldehyde 14 under the buff-
ered pyridinium chlorochromate (PCC) conditions.11 Wittig
reaction on the aldehyde 14 with methylenetriphenylphos-
phorane, generated by treatment of methyl triphenylphos-
phonium bromide with n-butyllithium, afforded the alkene
15 in 71% yield. Conversion of 15 to the Weinreb amide 5
was attempted following a general protocol developed by
Williams et al. by reacting 15 with methoxymethylamine
hydrochloride in the presence of isopropylmagnesium
chloride.12 This, however, resulted in deprotection of the
Having achieved the macrocyclization, the ketone 17 was
reduced under standard conditions with sodium borohydride
to give the desired alcohol 18 as expected, in contrast to the
result before formation of the macrocycle.13 At this point,
a formal synthesis of aigialomycin D 1 has been achieved
as the alcohol 18 has been used in Danishefsky’s synthesis
of aigialomycin D 1.3

N. Q. Vu et al. / Tetrahedron 63 (2007) 7053–7058
7055
MOMO
MOMO
4. Experimental
O
O
a
b
O
O
9
4.1. General
MOMO
MOMO
€
Melting points were measured on a Buchi B-540 capillary
O
O
O
O
1
O
melting point apparatus and are uncorrected. H/13C NMR
17
O
2b
spectra were recorded at 400/100 MHz on a Bruker Advance
400 spectrometer in CDCl3 unless otherwise stated, using
either TMS or the undeuterated solvent residual signal as
the reference. IR spectra were measured on a Bio-Rad FTS
3000MX FTIR spectrometer as liquid film or evaporated
film. Optical rotations were measured using a Jasco P-
1030 polarimeter. Elemental analyses were performed on
a EuroEA 3000 Series CHNS Analyzer. Mass spectra were
run by the electron impact (EI, 70 eV) mode on a Thermo
Finnigan MAT XP95 mass spectrometer, or by the electro
spray ionisation (ESI) or the electro spray ionization-time-
of-flight (ESI-TOF) mode on an Agilent 6210 mass spec-
trometer. Microwave reactions were carried out using a
MicroSYNTHÒ multimode microwave system (Milestone
Inc., USA) with built-in temperature and pressure sensors
and programmable control software for reaction parameters.
Solvents for moisture sensitive reactions were taken from
a Glasscontour solvent purification system under nitrogen.
Commercially available reagents were used as received
unless otherwise indicated. Flash column chromatography
purification was carried out either manually or by using a
Biotage SP1Ô purification system by gradient elution.
Scheme 4. Reagents and conditions: (a) LDA, ꢀ78 ꢁC, THF then 5b, 82%;
(b) CH2Cl2 (0.005 M), Grubbs II catalyst (10 mol %), MW irradiation,
100 ꢁC, 30 min, 98%, E only.
To install the 10,20-E-double bond, the alcohol 18 was treated
with Martin’s sulfurane dehydrating reagent15 following
a literature protocol.3 However, this led to the formation of
the desired product 19 but mixed with the decomposed sul-
furane reagent, which were not separable in our hands. As
a result, alternative dehydration conditions were examined.
After screening a number of conditions, we were delighted
to find that mesylation of the alcohol 18 followed by elimi-
nation with DBU under reflux afforded cleanly the desired
alkene 19 in 74% yield with complete regio- and E-selectiv-
ity, characterised by a 15.4 Hz coupling constant at the
newly formed 10,20-double bond. Final global deprotection
of both the MOM and the acetonide protecting groups with
aqueous hydrochloric acid in methanol3 afforded aigialomy-
cin D 1 in 91% yield (Scheme 5) with all the analytical data
in agreement with those reported.1,3,4
4.1.1. 2,4-Bis(methoxymethoxy)-6-methylbenzoic acid 8.
To a solution of bis-MOM protected methyl ester 78
(1.35 g, 5.0 mmol) in MeOH (20 mL) were added KOH
(1.40 g, 25.0 mmol) and H2O (20 mL) at room temperature.
The reaction mixture was heated at 90 ꢁC for 2 days under
argon. After cooling to room temperature, the mixture
was acidified to pH 6 with acetic acid aqueous solution
(50%; v/v, 3.9 mL, 34 mmol) and extracted with EtOAc
(3ꢂ100 mL). The combined organic phases were washed
with H2O (2ꢂ50 mL), dried (MgSO4), filtered and evapo-
rated under reduced pressure to afford the acid 8 as a colour-
MOMO
O
MOMO
O
b
a
O
c
17
O
1
MOMO
MOMO
HO
O
O
O
18
O
19
Scheme 5. Reagents and conditions: (a) NaBH4, MeOH/H2O (4:1), rt,
quant.; (b) (i) MsCl, Et3N, DMAP (10 mol %), CH2Cl2; (ii) DBU, toluene,
reflux, 74% over two steps; (c) 1 N HCl/MeOH (1:1), rt, 48 h, 91%.
1
less oil (1.27 g, 99%), which was pure as judged by its H
NMR spectrum and used immediately for the next step.
Rf (EtOAc/n-hexane, 1:1) 0.28; IR (film) 3020, 2963, 2402,
1698, 1606, 1448, 1398, 1317, 1294, 1215, 1150, 1047,
3. Conclusion
1
In conclusion, we have developed a highly efficient, practi-
cal and stereospecific total synthesis of aigialomycin D 1
with the longest linear sequence of 11 steps and an overall
yield of 19%. This synthesis features the use of D-(ꢀ)eryth-
ronolactone to introduce the 50,60-chiral diol unit, formation
of the macrocycle by RCM under microwave conditions to
achieve complete E-selectivity of the 70,80-double bond
with high yields and effective regio- and stereo-controlled
installation of 10,20-double bond from the alcohol 18 by
mesylation and elimination. This facile regio- and stereo-
controlled formation of E-styrene motif, which combines
acylation at the benzylic position, reduction and elimination,
should find use in the synthesis of other biologically active,
E-styrene motif containing phenolic macrolides such as LL-
Z1640-2,16 queenslandon17 and oximidines.18 Using the
pivotal ketone intermediate 17, a series of aigialomycin D
derivatives and analogues have been prepared and are
currently being screened for antitumor and anti-malarial
activities. The results will be disclosed in due course.
1029, 928 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.72 (s,
1H), 6.61 (s, 1H), 5.24 (s, 2H), 5.18 (s, 2H), 3.52 (s, 3H),
3.48 (s, 3H), 2.47 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 174.6, 159.5, 156.6, 141.7, 116.0, 112.1, 101.4, 95.5,
94.2, 56.7, 56.3, 21.5; MS (EI) m/z 256.1 (M+); HRMS (EI)
m/z calcd for C12H16O6 (M+) 256.0947, found 256.0953.
4.1.2. (S)-Pent-4-en-2-yl 2,4-bis(methoxymethoxy)-6-
methylbenzoate 9. To a solution of 8 (1.02 g, 4.0 mmol),
(R)-pent-4-en-2-ol 4 (0.52 g, 6.0 mmol) and triphenylphos-
phine (2.62 g, 10.0 mmol) in anhydrous THF (20 mL) was
added dropwise a solution of DIAD (1.86 g, 9.2 mmol) in
THF (5 mL) at room temperature. After stirring for 2 days
under argon, the solvent was removed under reduced pres-
sure. The residue was absorbed on silica gel (5 g), followed
by flash column chromatographic purification (SiO2, EtOAc/
n-hexane, 5–70% gradient) to afford 9 (1.12 g, 86%) as a col-
ourless oil. Rf (EtOAc/n-hexane, 1:9) 0.25; [a]2D4 +11.7 (c
0.10, CHCl3); IR (film) 2828, 2362, 1718, 1607, 1483,

7056
N. Q. Vu et al. / Tetrahedron 63 (2007) 7053–7058
1451, 1149, 1104, 1051, 1026, 994, 923, 838, 804 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 6.66 (d, 1H, J¼2.1 Hz), 6.54 (d,
1H, J¼2.1 Hz), 5.84 (tdd, 1H, J¼7.00, 10.2, 17.2 Hz), 5.24
(qt, 1H, J¼6.3, 12.6 Hz), 5.08–5.14 (m, 6H), 3.46 (s, 6H),
2.33–2.50 (m, 2H), 2.29 (s, 3H), 1.33 (d, 3H, J¼6.3 Hz);
13C NMR (100 MHz, CDCl3) d 167.5, 158.5, 155.2, 137.6,
133.8, 119.1, 117.7, 110.6, 101.1, 94.6, 94.3, 70.9, 56.1,
56.0, 40.2, 19.7, 19.5; MS (EI) m/z 324.2 (M+); HRMS
(EI) m/z calcd for C17H24O6 (M+) 324.1573, found
324.1572.
HRMS (EI) m/z calcd for C11H20O5 (MꢀCH3)+ 217.1076,
found 217.1063.
4.1.5. Ethyl 3-((4S,5S)-5-formyl-2,2-dimethyl-1,3-dioxo-
lan-4-yl)propanoate 14. To a stirred suspension of PCC
(6.22 g, 28.8 mmol), sodium acetate (0.24 g, 2.85 mmol)
˚
and 4 A molecular sieves (2.68 g) in CH2Cl2 (90 mL) was
added the hydroxyl ester 13 (2.68 g, 11.55 mmol) in
CH2Cl2 (10 mL) dropwise. The suspension was stirred at
ambient temperature for 3 h. The solvent was removed under
reduced pressure and the residue extracted with diethyl ether
(4ꢂ100 mL). The combined extracts were filtered through
a silica gel column and further eluted with diethyl ether.
Evaporation of the solvent under reduced pressure provided
the aldehyde 14 (2.13 g, 80%), which was used in the next
step. Rf (EtOAc/n-hexane, 2:1) 0.50; IR (film) 3004, 2253,
4.1.3. Ethyl 3-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)acrylate 12. To a solution of (2R,3R)-
2,3-O-isopropylidene-D-erythrose 1110 (4.74 g, 29.6 mmol)
in CH2Cl2 (150 mL) were added methyl (triphenylphosphor-
anylidene)acetate (12.5 g, 36.0 mmol) and benzoic acid
(0.10 g, 0.82 mmol). The solution was heated under reflux
for 17 h until TLC showed that the lactol 11 had been con-
sumed. The solvent was evaporated and the residue was trit-
urated with 30% ether in hexane (4ꢂ100 mL). The combined
extracts were evaporated and the residue was purified by col-
umn chromatography on silica gel by gradient elution with
ether–hexane (2:1) to give the isomeric mixture (E/Z¼1:2)
of the unsaturated ester 1210a (4.96 g, 73%) as a liquid. Z-
Isomer: Rf (EtOAc/n-hexane, 1:1) 0.43; IR (film) 3441, 2986,
;
1730, 1465, 1383, 1235 cmꢀ1 1H NMR (400 MHz,
CDCl3) d 9.67 (1H, d, J¼3.1 Hz), 4.38 (ddd, 1H, J¼3.8,
7.2, 10.8 Hz), 4.30 (dd, 1H, J¼3.1, 7.2 Hz), 4.14 (q, 2H,
J¼7.1 Hz), 2.38–2.54 (m, 2H), 1.91–1.99 (m, 1H), 1.72–
1.82 (m, 1H), 1.58 (s, 3H), 1.40 (s, 3H), 1.26 (t, 3H,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 201.9, 172.6,
110.7, 81.8, 77.4, 60.6, 30.9, 27.5, 25.3, 25.2, 14.1.
4.1.6. Ethyl 3-((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxo-
lan-4-yl)propanoate 15. To a solution of the aldehyde 14
(2.85 g, 12.39 mmol) in THF (20 mL) cooled to ꢀ30 ꢁC
was added a solution of methylenetriphenylphosphorane
(generated at ꢀ30 ꢁC by treatment of methyl(triphenyl)-
phosphonium bromide (16.8 g, 48.0 mmol) with n-butyl-
lithium (17.5 mL of 1.6 M solution in hexanes,
28.0 mmol)) in THF (150 mL) under argon. After being
stirred at ꢀ30 ꢁC for 30 min, the mixture was allowed to
warm to room temperature and stirred for a further 2 h.
The mixture was poured into diethyl ether (100 mL) and
stirred for 10 min. Evaporation of the solvents followed by
flash column chromatography (SiO2, Et2O/n-hexane 1:1)
provided the alkene 15 (2.00 g, 71%) as a colourless liquid.
Rf (EtOAc/n-hexane, 1:1) 0.61; [a]2D8 ꢀ20.6 (c 2.05, EtOH)
[lit.11 ent-15 [a]2D3 +20.6 (c 1.5, EtOH)]; IR (film) 3010,
1
2938, 1714, 1645, 1456, 1416 cmꢀ1; H NMR (400 MHz,
CDCl3) d 6.39 (dd, 1H, J¼7.0, 11.6 Hz), 5.93 (dd, 1H,
J¼1.7, 11.6 Hz), 5.60 (ddd, 1H, J¼1.7, 7.0, 7.2 Hz), 4.58
(ddd, 1H, J¼3.8, 5.1, 7.2 Hz), 4.15 (q, 2H, J¼7.1 Hz), 3.56
(dd, 1H, J¼3.8, 11.8 Hz), 3.44 (dd, 1H, J¼5.1, 11.8 Hz),
2.14 (br s, 1H), 1.50 (s, 3H), 1.38 (s, 3H), 1.27 (t, 3H,
J¼7.1 Hz); 13C NMR (100 MHz, CDCl3) d 166.0, 147.3,
121.1, 108.9, 78.8, 74.9, 61.5, 60.7, 27.4, 24.7, 14.2; E-
isomer: Rf (EtOAc/n-hexane, 1:1) 0.33; 1H NMR (400 MHz,
CDCl3) d 6.89 (dd, 1H, J¼5.6, 15.6 Hz), 6.13 (dd, 1H,
J¼1.6, 15.6 Hz), 4.81 (ddd, 1H, J¼1.6, 5.7, 7.1 Hz), 4.37
(m, 1H), 4.15 (q, 2H, J¼7.1 Hz), 3.56 (dd, 1H, J¼3.8,
11.8 Hz), 3.44 (dd, 1H, J¼5.1, 11.8 Hz), 1.89 (br s, 1H),
1.50 (s, 3H), 1.38 (s, 3H), 1.27 (t, 3H, J¼7.1 Hz); 13C
NMR (100 MHz, CDCl3) d 166.0, 142.1, 123.3, 109.7,
78.4, 62.0, 60.8, 27.8, 25.4, 14.4; MS (EI) m/z 215.1
(MꢀCH3)+; HRMS (EI) m/z calcd for C11H18O5
(MꢀCH3)+ 215.0919, found 215.0916.
2986, 2936, 1737, 1449, 1371, 1249 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 5.81 (ddd, J¼7.6, 10.3, 17.5 Hz),
5.33 (d, 1H, J¼17.5 Hz), 5.25 (d, 1H, J¼10.3 Hz), 4.53
(dd, 1H, J¼6.8, 7.6 Hz), 4.09–4.17 (m, 3H), 2.33–2.51 (m,
2H), 1.71–1.77 (m, 2H), 1.47 (s, 3H), 1.35 (s, 3H), 1.25 (t,
3H, J¼7.2 Hz); 13C NMR (100 MHz, CDCl3) d 173.3,
133.8, 118.6, 108.4, 79.5, 77.2, 60.4, 30.9, 28.1, 26.0,
25.6, 14.2; MS (EI) m/z 213.1 (MꢀCH3)+; HRMS (EI) m/z
calcd for C12H20O4 (MꢀCH3)+ 213.1118, found 213.1127.
4.1.4. Ethyl 3-((4S,5R)-5-(hydroxymethyl)-2,2-dimethyl-
1,3-dioxolan-4-yl)propanoate 13. To a solution of the un-
saturated ester 12 (7.20 g, 31.3 mmol) in ethanol (150 mL)
was added 10% Pd on charcoal (1.50 g). The black mixture
was evacuated and back-filled with hydrogen for four cycles
and then stirred under H2 (ca. 1 atm) for 2.5 h. The mixture
was diluted with ethanol (100 mL) and filtered through
a pad of CeliteÒ, and the residue was washed with ethanol
(2ꢂ30 mL). The filtrates were evaporated under reduced
pressure to give the hydroxy ester 13 as a liquid (7.04 g,
97%). Rf (EtOAc/n-hexane, 2:1) 0.42; [a]2D8 ꢀ21.4 (c 2.04,
EtOH) [lit.11 ent-13 [a]2D8 +22.5 (c 2, EtOH)]; IR (film)
3514, 2986, 2937, 1733, 1448, 1373, 1249 cmꢀ1; 1H NMR
(400 MHz, CDCl3) d 4.09–4.18 (m, 4H), 3.63 (d, 2H,
J¼4.5 Hz), 2.51 (td, 1H, J¼7.2, 14.8 Hz), 2.38 (td, 1H,
J¼7.2, 14.8 Hz), 2.14 (br s, 1H), 1.80–1.83 (m, 1H), 1.43
(s, 3H), 1.33 (s, 3H), 1.23 (t, 3H, J¼7.2 Hz); 13C NMR
(100 MHz, CDCl3) d 173.2, 108.2, 77.7, 75.9, 61.5, 60.4,
31.1, 28.0, 25.4, 24.6, 14.1; MS (EI) m/z 217.1 (MꢀCH3)+;
4.1.7. N-Methoxy-N-methyl-3-((4S,5R)-2,2-dimethyl-5-
vinyl-1,3-dioxolan-4-yl)propanamide 5b. To a slurry of
Me(MeO)NH$HCl (1.24 g, 12.73 mmol) in THF (25 mL)
was added a solution of i-PrMgCl in THF (12.73 mL of
2.0 M solution, 25.5 mmol) at ꢀ20 ꢁC under argon. The
mixture was stirred for 20 min to form a homogeneous solu-
tion to which a solution of the ester 15 (1.16 g, 5.09 mmol) in
THF (10 ml) was added dropwise via a cannula. The reaction
mixture was stirred at ꢀ20 ꢁC for 1 h before being quenched
with saturated NH4Cl aqueous solution (10 mL). Upon
warming to room temperature, the mixture was extracted
with diethyl ether (2ꢂ30 mL). The combined extracts
were washed with brine and dried (MgSO4). Evaporation

N. Q. Vu et al. / Tetrahedron 63 (2007) 7053–7058
7057
of the solvent followed by purification by flash column chro-
matography (SiO2, EtOAc/n-hexane 1:1) provided the amide
5 (1.19 g, 96%) as a colourless oil. Rf (EtOAc/n-hexane, 3:1)
0.45; [a]2D4 ꢀ27.3 (c 0.27, EtOH); IR (film) 2988, 2938,
removed under reduced pressure to afford the crude cyclisa-
tion product, which was purified by flash column chromato-
graphy (SiO2, EtOAc/n-hexane, 10–100% gradient) to give
the macrolactone 17 as a light purple oil (0.14 g, 98%). Rf
(EtOAc/n-hexane, 1:1) 0.50; [a]2D6 +41.6 (c 0.339, CHCl3);
IR (film) 2982, 1718, 1605, 1585, 1270, 1218, 1148, 1102,
2252, 1650, 1427, 1381 cmꢀ1
;
1H NMR (400 MHz,
CDCl3) d 5.83 (ddd, J¼7.6, 10.3, 17.3 Hz), 5.33 (d, 1H, J¼
17.3 Hz), 5.26 (d, 1H, J¼10.3 Hz), 4.55 (dd, 1H, J¼6.5,
7.6 Hz), 4.19 (ddd, 1H, J¼4.6, 6.5, 9.5 Hz), 3.69 (s, 3H),
3.18 (s, 3H), 2.47–2.65 (m, 2H), 1.72–1.82 (m, 2H), 1.49
(s, 3H), 1.37 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 176.0, 134.0, 118.5, 108.3, 94.4, 79.6, 77.6, 61.2, 28.5,
28.2, 25.72, 25.68; MS (EI) m/z 228.1 (MꢀCH3)+; HRMS
(EI) m/z calcd for C12H21NO4 (MꢀCH3)+ 228.1236, found
228.1228.
1
1042, 1018 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.75 (s,
1H), 6.53 (s, 1H), 5.77 (dd, 1H, J¼6.8, 15.0 Hz), 5.53 (dd,
1H, J¼9.0, 15.0 Hz), 5.33 (dd, 1H, J¼6.3, 12.4 Hz), 5.14
(s, 4H), 4.47 (dd, J¼6.4, 9.0 Hz), 4.10–4.15 (m, 1H), 3.82
(d, 1H, J¼15.2 Hz), 3.42–3.49 (m, 7H), 2.30–2.60 (m,
4H), 1.91–1.99 (m, 1H), 1.68–1.77 (m, 1H), 1.44 (s, 3H),
1.39 (d, 3H, J¼6.3 Hz), 1.33 (s, 3H); 13C NMR (100 MHz,
CDCl3) d 205.9, 167.8, 158.9, 155.9, 133.8, 132.4, 129.0,
118.7, 110.7, 108.0, 102.1, 94.5, 94.2, 82.7, 76.3, 71.6,
56.2, 56.1, 47.2, 39.3, 37.6, 28.0, 25.2, 23.7, 20.8; MS (EI)
m/z 478.2 (M+); HRMS (EI) m/z calcd for C25H34O9 (M+)
478.2203, found 478.2203.
4.1.8. (S)-Pent-4-en-2-yl 2,4-bis(methoxymethoxy)-6-(4-
((4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl)-2-oxo-
butyl)benzoate 2b. n-Butyllithium (1.56 mL of a 1.6 M
solution in hexane, 2.50 mmol) was added to diisopropyl-
amine (0.42 mL, 3.0 mmol) in THF (5 mL) at ꢀ20 ꢁC and
the solution was stirred for 10 min. The resulting LDA solu-
tion was added to the ester 9 (0.33 g, 1.00 mmol) in THF
(3 mL) at ꢀ78 ꢁC, followed by immediate addition of the
Weinreb amide 5b (0.29 g, 1.20 mmol) in THF (3 mL).
The resulting mixture was stirred for 10 min at ꢀ78 ꢁC and
then quenched by addition of aqueous NH4Cl solution
(3 mL). Upon warming to room temperature, the mixture
was extracted with EtOAc (3ꢂ50 mL) and washed with
H2O (20 mL). The combined organic phases were dried
over MgSO4, filtered and evaporated to afford the crude prod-
uct, which was purified by flash column chromatography
(SiO2, EtOAc/n-hexane, 5–100% gradient) to provide the
ketone 2b (0.42 g, 82%) as a colourless oil. Rf (EtOAc/n-
hexane, 1:1) 0.67; [a]D24 ꢀ6.5 (c 0.31, CHCl3); IR (film)
2986, 1716, 1606, 1450, 1381, 1283, 1237, 1150, 1023,
4.1.10. Macrolactone 18. To a solution of the macrolactone
17 (0.065 g, 0.14 mmol) in MeOH/H2O (v/v¼4:1, 5 mL)
was added NaBH4 (0.020 g, 0.54 mmol) portionwise at
room temperature. The reaction mixture was stirred for
30 min and quenched with saturated NH4Cl aqueous solu-
tion (3 mL). The solution was extracted with EtOAc
(3ꢂ30 mL). The combined organic phases were dried over
MgSO4, filtered and evaporated under reduced pressure to
give the macrolactone 183 as a colourless oil (0.067 g,
100%); Rf (EtOAc/n-hexane, 1:1) 0.36; [a]2D6 ꢀ26.2 (c
0.52, CHCl3); IR (film) 3489, 2934, 1718, 1604, 1583, 1449,
1399, 1379, 1269, 1216, 1147, 1040, 972, 923, 848 cmꢀ1; 1H
NMR (400 MHz, CDCl3) d 6.70 (d, 1H, J¼2.1 Hz), 6.66 (d,
1H, J¼2.1 Hz), 5.72 (dd, 1H, J¼6.8, 15.4 Hz), 5.59 (dd, 1H,
J¼9.2, 15.4 Hz), 5.35 (dd, 1H, J¼6.2, 12.5 Hz), 5.14 (s, 4H),
4.55 (dd, J¼6.2, 9.2 Hz), 4.18–4.23 (m, 1H), 3.89 (br s, 1H),
3.46 (s, 6H), 2.81 (dd, 1H, J¼4.8, 14.1 Hz), 2.71 (dd, 1H,
J¼6.1, 14.1 Hz), 2.43–2.46 (m, 2H), 1.67–1.80 (m, 4H),
1.46 (s, 3H), 1.38 (d, 3H, J¼6.2 Hz), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 168.0, 158.6, 155.4, 138.0,
132.2, 130.2, 119.3, 110.6, 107.7, 101.4, 94.5, 94.3, 79.6,
77.2, 71.5, 70.0, 56.2, 56.1, 41.1, 39.6, 31.8, 28.1, 25.3,
24.7, 21.0; MS (EI) m/z 480.2 (M+); HRMS (EI) m/z calcd
for C25H36O9 (M+) 480.2359, found 480.2358.
1
924, 830, 803 cmꢀ1; H NMR (400 MHz, CDCl3) d 6.77
(d, 1H, J¼2.1 Hz), 6.53 (d, 1H, J¼2.1 Hz), 5.73–5.89 (m,
2H), 5.07–5.32 (m, 9H), 4.49 (dd, 1H, J¼6.7, 7.2 Hz),
4.08–4.13 (m, 1H), 3.74 (d, 1H, J¼16.4 Hz), 3.67 (d, 1H,
J¼16.4 Hz), 3.47 (s, 3H), 3.46 (s, 3H), 2.51–2.68 (m, 2H),
2.31–2.48 (m, 2H), 1.65–1.71 (m, 2H), 1.45 (s, 3H), 1.33
(s, 3H), 1.30 (d, 3H, J¼6.3 Hz); 13C NMR (100 MHz,
CDCl3) d 206.4, 171.0, 170.0, 158.9, 156.2, 135.0, 134.0,
133.8, 118.4, 117.6, 111.3, 102.5, 94.7, 94.3, 79.5, 77.2,
71.1, 60.3, 56.2, 56.1, 47.9, 40.1, 38.3, 28.1, 25.5, 24.6,
21.0, 19.4, 14.1; MS (EI) m/z 506.2 (M+); HRMS (EI) m/z
calcd for C27H38O9 (M+) 506.2516, found 506.2503.
4.1.11. Macrolactone 19. To a solution of the macrolactone
18 (0.19 g, 0.39 mmol) in dry CH2Cl2 (5 mL) were added
Et3N (0.56 mL, 3.96 mmol) and DMAP (4 mg, 0.3 mol,
10 mol %) at room temperature under argon. To this mixture
was added freshly distilled methanesulfonyl chloride
(0.062 mL, 0.79 mmol) dropwise at 0 ꢁC. The reaction mix-
ture was stirred at room temperature for 5 h. The solvent was
removed under reduced pressure, and the crude mesylate
was dissolved in toluene (20 mL) with DBU (0.59 mL,
3.96 mmol) added. The mixture was heated to reflux at
120 ꢁC overnight. Toluene was removed under reduce pres-
sure and the organic material was extracted with EtOAc
(3ꢂ30 mL). The combined organic phases were washed
with water, dried over MgSO4, filtered and evaporated under
reduced pressure. The crude product was purified by flash
column chromatography (SiO2, EtOAc/n-hexane, 10–
100% gradient) to afford the macrolactone 193 as a colour-
less oil (0.14 g, 74%); Rf (EtOAc/n-hexane, 1:1) 0.48;
[a]2D2 ꢀ116.5 (c 0.13, CHCl3) [lit.3 ꢀ120 (c 0.08, CHCl3)
4.1.9. Macrolactone 17. To a solution of the ketone 2b
(0.15 g, 0.30 mmol) in anhydrous CH2Cl2 (60 mL,
0.005 M) in a 100 mL TeflonÒ vessel (supplied by the
manufacturer) was added Grubbs II catalyst (0.025 g,
0.03 mmol, 10 mol %). The vessel was immediately sealed
and secured onto the vessel holder in the reactor chamber to-
gether with a 100 mL reference vessel, which was charged
with CH2Cl2 (60 mL) and connected to the temperature
and pressure sensors. The vessels were heated to 100 ꢁC
for 30 min by programming the system, and selecting tem-
perature and reaction time as the control parameters. After
the heating was completed, the vessels were allowed to
cool to room temperature before being removed from the
reactor chamber. The mixture in the reacting vessel was
transferred to a round bottomed flask and the solvent was

7058
N. Q. Vu et al. / Tetrahedron 63 (2007) 7053–7058
and lit.4 ꢀ120 (c 1.00, CHCl3)]; IR (film) 2927, 1721, 1601,
3. (a) Geng, X.; Danishefsky, S. J. Org. Lett. 2004, 6, 413; (b)
Yang, Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
4. Lu, J.; Ma, J.; Xie, X.; Chen, B.; Shea, X.; Pan, X. Tetrahedron:
Asymmetry 2006, 17, 1066.
1
1576, 1456, 1378, 1261, 1217, 1147, 1051, 927 cmꢀ1; H
NMR (400 MHz, CDCl3) d 6.80 (d, 1H, J¼2.0 Hz), 6.68
(d, 1H, J¼2.0 Hz), 6.24 (d, 1H, J¼15.4 Hz), 6.14 (ddd,
1H, J¼4.0, 8.7, 15.4 Hz), 5.73 (ddd, 1H, J¼3.6, 9.1,
15.5 Hz), 5.59 (dd, 1H, J¼9.6, 15.5 Hz), 5.30–5.37 (m,
1H), 5.16 (s, 4H), 4.56 (dd, J¼5.4, 9.6 Hz), 4.16–4.21 (m,
1H), 3.45 (s, 6H), 2.45–2.55 (m, 2H), 2.29–2.32 (m, 1H),
2.07–2.11 (m, 1H), 1.80–1.85 (m, 1H), 1.49–1.55 (m, 1H),
1.46 (s, 3H), 1.36 (d, 3H, J¼6.2 Hz), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) d 167.4, 158.9, 155.2, 136.8,
132.3, 131.9, 129.3, 128.5, 117.9, 108.3, 104.8, 102.6,
94.6, 94.3, 80.2, 77.3, 71.6, 56.2, 56.1, 39.5, 29.0, 28.7,
28.6, 25.9, 21.2; MS (ESI) m/z 463.4 (M+H)+, 485.4
(M+Na)+; HRMS (ESI-TOF) m/z calcd for C25H34O98Na
(M+Na)+ 485.2146, found 485.2147.
ꢀ
5. Chiarello, J.; Joullie, M. M. Tetrahedron 1988, 44, 41.
6. (a) Mitsunobu, O. Synthesis 1981, 1; (b) Hughes, D. L. Org.
React. 1992, 42, 335.
7. (a) Moulin, E.; Barluenga, S.; Winssinger, N. Org. Lett. 2005,
7, 5637; (b) Moulin, E.; Zoete, V.; Barluenga, S.; Karplus,
M.; Winssinger, N. J. Am. Chem. Soc. 2005, 127, 6999.
8. Dodd, J. H.; Garigipati, R. S.; Weinreb, S. M. J. Org. Chem.
1982, 47, 4045.
9. The reaction was carried out by treatment of 9 with LDA at
ꢀ78 ꢁC followed by the addition of n-butyraldehyde.
MOMO
O
4.1.12. Aigialomycin D 1. To a solution of macrolactone 19
(0.13 g, 0.29 mmol) in MeOH (5 mL) was added HCl (1 N,
5 mL) and the mixture was stirred at room temperature for 2
days. The mixture was extracted with EtOAc (3ꢂ10 mL),
and the combined organic phases were washed with water
until neutral, dried (MgSO4), filtered and evaporated under
reduced pressure to afford the crude product, which was
purified by flash column chromatography (SiO2, EtOAc/n-
hexane, gradient 50%–100%) to afford aigialomycin D
11,3,4 as a white solid (0.089 g, 91%). Mp 85.6–87.2 ꢁC; Rf
(EtOAc) 0.52; [a]2D5 ꢀ21.9 (c 0.35, MeOH); IR (film) 3391,
O
MOMO
10
10. (a) Gypser, A.; Peterek, M.; Scharf, H.-D. J. Chem. Soc., Perkin
Trans. 1 1997, 1013; (b) Cohen, N.; Banner, B.; Lopresti, R.;
Wong, F.; Rosenberger, M.; Liu, Y.; Thom, E.; Liebman, A.
J. Am. Chem. Soc. 1983, 105, 3661.
11. Batty, D.; Crich, D. J. Chem. Soc., Perkin Trans. 1 1992, 3193.
12. Williams, J. M.; Jobson, R. B.; Yasuda, N.; Marchesini, G.;
Dolling, U.-H.; Grabowski, E. J. J. Tetrahedron Lett. 1995,
36, 5461.
1
1646, 1456, 1312, 1259, 1167, 1110, 972 cmꢀ1; H NMR
(400 MHz, CD3COCD3) d 11.67 (s, 1H), 9.23 (br s, 1H),
7.16 (d, 1H, J¼15.9 Hz), 6.53 (d, 1H, J¼2.5 Hz), 6.28 (d,
1H, J¼2.5 Hz), 6.10 (ddd, 1H, J¼5.7, 5.9, 15.9 Hz), 5.87
(dddd, 1H, J¼1.4, 7.3, 7.3, 15.6 Hz), 5.69 (dd, 1H, J¼5.1,
15.6 Hz), 5.40–5.47 (m, 1H), 4.36 (br d, J¼4.7 Hz), 3.78
(br s, 1H), 3.63–3.66 (m, 1H), 2.55 (ddd, J¼3.3, 7.4,
14.6 Hz), 2.32–2.36 (m, 2H), 2.11–2.19 (m, 1H), 1.58–1.61
(m, 1H), 1.39 (d, 3H, J¼6.4 Hz); 13C NMR (100 MHz,
CDCl3) d 172.3, 165.9, 163.3, 144.4, 135.8, 133.7, 130.8,
125.6, 108.0, 104.5, 102.7, 76.7, 73.4, 73.1, 38.1, 28.7,
28.1, 19.2; MS (ESI) m/z 333.2 (MꢀH)+; HRMS (ESI-
TOF) m/z calcd for C18H23O6 335.1489 (M+H)+, found
335.1499.
13. The reduction was carried out with sodium borohydride in
methanol/water (4:1). Formation of the d-lactone 16 was
evident by the loss of the characteristic signals of the ester
portion in 2b.
MOMO
O
O
MOMO
O
16
O
14. For examples: (a) Mayo, K. G.; Nearhoof, E. H.; Kiddle, J. J.
Org. Lett. 2002, 4, 1567; (b) Yang, C.; Murray, W. V.;
Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783; (c) Ronald,
G.; Martin, W.; Morris, J.; Sridharan, V. Tetrahedron Lett.
2003, 44, 4899; (d) Thanh, G. V.; Loupy, A. Tetrahedron
Lett. 2003, 44, 9091; (e) Garbacia, S.; Desai, B.; Lavastre,
O.; Kappe, O. C. J. Org. Chem. 2003, 68, 9136; (f) Salim,
S. S.; Bellingham, R. K.; Brown, R. C. D. Eur. J. Org. Chem.
2004, 800; (g) Appukkuttan, P.; Dehaen, W.; Van Der
Eycken, E. Org. Lett. 2005, 7, 2723; (h) Comer, E.; Organ,
M. G. J. Am. Chem. Soc. 2005, 127, 8160.
Acknowledgements
We thank the Agency for Science, Technology and Research
(A*STAR) of Singapore for funding this project, Weiqiang
Chen, Yonglin Mao (Xiamen University, China) and Manj-
ing Lin (ICES) for their contributions at early stages of
this investigation, and Prof. Brian Cox (AstraZeneca,
Macclesfield, UK) for helpful discussions.
15. (a) Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93,
4327; (b) Martin, J. C.; Franz, J. A.; Arhart, R. J. J. Am.
Chem. Soc. 1974, 96, 4604.
ꢁ
16. Selles, P.; Lett, R. Tetrahedron Lett. 2002, 43, 4621 and refer-
ences cited therein.
References and notes
17. Hoshino, Y.; Ivanova, V. B.; Yazawa, K.; Ando, A.; Mikami, Y.;
Zaki, S. M.; Karam, A. Z.; Youssef, Y. A.; Grafe, U. J. Antibiot.
2002, 55, 516.
1. Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M. J. Org. Chem.
2002, 67, 1561.
2. Barluenga, S.; Dakas, P.-Y.; Ferandin, Y.; Meijer, L.;
Winssinger, N. Angew. Chem., Int. Ed. 2006, 45, 3951.
18. Kim, J. W.; Shin-ya, K.; Furihata, K.; Hayakawa, Y.; Seto, H.
J. Org. Chem. 1999, 64, 153.