Protecting-group directed stereoselective intramolecular nozaki-hiyamaKishi reaction: A concise and efficient total synthesis of amphidinolactone A

Article abstract of DOI:10.1002/ejoc.201000565

A convergent; total synthesis of amphidinolactone A, a cytotoxic macrolide from, the cultured dinoflagellate Amphidinium. sp., is described in 13 linear steps. The key step in the synthetic sequence involves an intramolecular NozakiHiyama-Kishi (NHK) reaction for the construction of the 13-membered lactone ring by union of two fragments derived from a single chiral epoxide. The stereochemical outcome of the NHK reaction has been supported by computational studies.

Full text of DOI:10.1002/ejoc.201000565

FULL PAPER
DOI: 10.1002/ejoc.201000565
Protecting-Group Directed Stereoselective Intramolecular Nozaki–Hiyama–
Kishi Reaction: A Concise and Efficient Total Synthesis of
Amphidinolactone A
Debendra K. Mohapatra,*[a] Pragna P. Das,[a] Manas R. Pattanayak,[a]
Gaddamanugu Gayatri,[b] G. Narahari Sastry,[b] and J. S. Yadav*[a]
Keywords: Cytotoxicity / Kinetic resolution / Olefination / Macrocycles / Lactones
A convergent total synthesis of amphidinolactone A, a cyto-
toxic macrolide from the cultured dinoflagellate Amphidin-
ium sp., is described in 13 linear steps. The key step in the
synthetic sequence involves an intramolecular Nozaki–
Hiyama–Kishi (NHK) reaction for the construction of the 13-
membered lactone ring by union of two fragments derived
from a single chiral epoxide. The stereochemical outcome of
the NHK reaction has been supported by computational
studies.
Introduction
Amphidinolactone A (1) is a cytotoxic 13-membered
macrolide isolated from a symbiotic dinoflagellate Amphidi-
nium sp. (Y-25) obtained from an Okinawa marine acoel
flatworm Amphiscolops sp.[1] The relative and absolute
stereochemistries 1 were elucidated on the basis of extensive
spectral analysis followed by a total synthesis outlined by
Kobayashi et al.[2]
The interesting biological profile as well as the structural
complexity of 1 (Figure 1) have attracted the attention of
synthetic organic chemists worldwide. In this communica-
tion, we report a convergent approach to 1 using an intra-
molecular Nozaki–Hiyama–Kishi (NHK) reaction for
macrocyclization of 2 derived from the union of 6 and 8,
both prepared from epoxide 9[3] (Scheme 1). Moreover, the
synthetic protocol should sort out all the selectivity prob-
lems faced by Kobayashi et al. during the total synthesis.
Scheme 1. Retrosynthetic analysis of amphidinolactone A (1).
Results and Discussion
Synthesis of fragment 6 started from known chiral epox-
ide 9, which was prepared by using Jacobsen’s hydrolytic
kinetic resolution protocol.[4] Epoxide 9 underwent clean
addition of the lithium acetylide prepared from the TBS-
protected alkyne following treatment with nBuLi in THF at
–78 °C in 89% yield.[5] The resulting secondary hydroxy
group was protected as its benzyl ether by treatment with
NaH and benzyl bromide at 0 °C to afford 11. Removal of
the silyl group with p-TsOH in MeOH at room temperature
followed by partial hydrogenation[6] with Lindlar’s catalyst
afforded Z-olefin derivative 12 in 86% over two steps
(Scheme 2). Oxidation of the resulting hydroxy group with
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Figure 1. Structure of amphidinolactone A (1).
[a] Organic Chemistry Division-I, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500607, India
Fax: +91-40-27160387
E-mail: mohapatra@iict.res.in
dkm_77@yahoo.com
[b] Molecular Modeling Group, Indian Institute of Chemical
Technology (CSIR),
Hyderabad 500607, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000565.
wileyonlinelibrary.com
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D. K. Mohapatra, J. S. Yadav et al.
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TEMPO[7] and BAIB followed by further Pinnick[8] oxi-
dation with NaClO2 in the presence of 2-methyl-2-butene
afforded the acid, which upon treatment with CH2N2 in
ether at 0 °C gave ester 13 in 81% yield over three steps.
Removal of the PMB group with DDQ[9] in CH2Cl2/H2O
(19:1) at room temperature gave alcohol 14, which upon
Dess–Martin periodinane oxidation[10] followed by Takai
olefination[11] afforded trans-vinyl iodide 15 as the only
product. Saponification of the ester functionality with
LiOH in THF/H2O (3:2) afforded required acid fragment 6
in 91% yield.
Scheme 3. Reagents and conditions: (a) nBuLi, BF3·OEt2, alkyne,
–78 °C, 1 h, 86%; (b) p-TsOH, MeOH, 0 °C to r.t., 1 h, 94%;
(c) TsCl, Et3N, CH2Cl2, 0 °C, 6 h, 80%; (d) NaI, acetone, reflux,
3 h, 90%; (e) TPP, CH3CN, 100 °C, 12 h, 94%; (f) nBuLi, propion-
aldehyde, –78 °C, 4 h, 83%; (g) H2, Pd/C on CaCO3, quinoline
(catalytic), benzene, r.t., 3 h, 91%.
hexyl carbodiimide (DCC)[12] and a catalytic amount of
DMAP in CH2Cl2 to afford ester 4 in 58% yield. Similarly,
coupling in the presence of EDCI[13] and DMAP in CH2Cl2
furnished ester 4 in 70% yield. However, a better result was
achieved under Yamaguchi conditions[14] to obtain ester 4
in 89% yield. It is important to note that compound 4 con-
tains all 20 carbon atoms of the target molecule (Scheme 4).
Scheme 2. Reagents and conditions: (a) nBuLi, BF3·OEt2, hexyne
derivative, –78 °C, 1 h, 89%; (b) NaH, BnBr, 0 °C to r.t., 5 h, 90%;
(c) p-TsOH, MeOH, 0 °C to r.t., 1 h, 91%; (d) H2, Pd/C on CaCO3,
quinoline, r.t., 2 h, 95%; (e) TEMPO, BAIB, CH2Cl2, r.t.; (f) 1. Na-
ClO2, NaH2PO4, tBuOH, H2O, 2-methyl-2-butene, r.t., 3 h, 85%
over two steps; 2. CH2N2, ether, 0 °C to r.t., 10 min, 96%;
(g) DDQ, CH2Cl2/H2O (9:1), r.t., 2 h, 89%; (h) DMP, CH2Cl2,
NaHCO3, r.t., 3 h, 92%; (i) CrCl2, CHI3, THF, 16 h, 82%;
(j) LiOH, THF/H2O (3:1), r.t., 3 h, 91%.
Treatment of chiral epoxide 9 with lithium acetylide fol-
lowed by cleavage of the TBS ether linkage with p-TsOH in
MeOH afforded 17 in 81% yield over two steps. The pri-
mary hydroxy group of 17 was first tosylated and then
treated with NaI in acetone to afford iodide 19. Wittig salt
20 was prepared in 94% yield by treating 19 with tri-
phenylphosphane in acetonitrile at reflux (Scheme 3). The
cis geometry at C17–C18 was then introduced by per-
forming a Wittig reaction of 20 with n-propanal in the pres-
ence of nBuLi at –78 °C to obtain 21 in 83% yield as the
only product. Partial hydrogenation using Lindlar’s catalyst
(Pd on CaCO3) in the presence of quinoline (catalytic) af-
forded alcohol 8 in 91% yield.
Scheme 4. Reagents and conditions: (a) 1. DCC, DMAP, CH2Cl2,
0 °C to r.t. 12 h, 58%; 2. EDCI, DMAP, CH2Cl2, 0 °C to r.t., 12 h,
70%; 3. 2,4,6-trichlorobenzoyl chloride, DMAP, THF, toluene, r.t.,
6 h, 89%; (b) DDQ, CH2Cl2/H2O (9:1), r.t., 3 h, 91%; (c) DMP,
CH2Cl2, r.t., 4 h; (d) CrCl2, NiCl2, DMSO/THF (3:1), r.t., 24 h,
Having acid 6 and alcohol 8 in hand, the stage was set
for the combination of the two components and the forma-
tion of the macrocycle through an intramolecular NHK re-
action. The coupling of C1–C10 fragment 6 and C11–C20
fragment 8 was initially performed by employing dicyclo- 81% over two steps.
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Total Synthesis of Amphidinolactone A
Cleavage of the PMB ether in 4 upon treatment with DDQ
afforded alcohol 22 in 90% yield. Dess–Martin periodinane
oxidation of 22 gave required aldehyde 2 in 94% yield. The
critical macrocyclization of 2 under NHK reaction condi-
tions[15] follows Felkin–Anh[16] rules in that this key step
allows macrolactonization and provides the required stereo-
chemistry of the newly formed hydroxy group (for mecha-
nism, see Figure 2). The yield and the rate of the NHK
reaction are sensitive to the reaction medium and to the
sequence of addition of the reagents. With a mixture of
DMF and THF as solvent, the starting material was con-
sumed fairly quickly (2–4 h) to give a low yield of the
macrocycle. In DMSO/THF (3:1), the macrocycle was
formed as a 2:1 mixture of inseparable diastereomeric allylic
alcohols 23 and 24 in 81% yield. However, it took about
24 h for the starting material to be completely consumed.
The diastereoselectivity of the cyclization appears to arise
from the preference of the aldehyde at C11 to adopt a con-
formation in which the metal-complexed carbonyl oxygen
atom is oriented away from the bulky benzyl group.
Scheme 5. Reagents and conditions: (a) nBuLi, BF3·OEt2, hexyne
derivative, –78 °C, 1 h, 89%; (b) TBDPSCl, imidazole, DMF, 0 °C
to r.t., 6 h, 97%; (c) p-TsOH, MeOH/CH2Cl2 (1:3), 0 °C to r.t., 1 h,
89%; (d) H2, Pd/C on CaCO3, quinoline, r.t., 2 h, 96%;
(e) TEMPO, BAIB, CH2Cl2, r.t., 3 h, 91%; (f) 1. NaClO2,
NaH2PO4, tBuOH, H2O, 2-methyl-2-butene, r.t., 3 h, 94%;
2. CH2N2, ether, 0 °C to r.t., 10 min, 95%; (g) DDQ, CH2Cl2/H2O
(9:1), r.t., 2 h, 88%; (h) DMP, CH2Cl2, r.t., 3 h, 96%; (i) CrCl2,
CHI3, THF, 16 h, 84%; (j) LiOH, THF/H2O (3:1), r.t., 3 h, 90%.
Figure 2. Diastereoselectivity in the formation of 23 as the major
product.
To desire to obtain a single isomer at this juncture forced
us to make a judicious choice of protecting groups, which
can determine and influence the facial selection of the car-
bonyl group. During our literature search, the success in the
formation of the C6–C7 bond and the installation of the
correct configuration at C7 in the total syntheses of decare-
strictine D[17a] as well as the formation of the C7–C8 bond
and the installation of the C8 stereocentre in the total syn-
thesis of aspinolide B[17b] prompted us to attach a bulky
protecting group at C8 to be employed in the intramolecu-
lar NHK coupling reaction and to verify the selectivity at
C11 during the formation of the 13-membered lactone ring.
We first tried to replace the benzyl group in 15 with the
bulky TDBPS group. Unfortunately, deprotection under
several conditions (Li/liq. NH3, Li/naphthalene, DDQ) gave
an intractable mixture of products. The synthesis of 7 com-
menced with known chiral epoxide 9 and followed the same
sequence of reactions except for the selective cleavage of the
TBDMS ether linkage in the presence of the TBDPS ether
by using p-TsOH in MeOH/CH2Cl2 (1:3) to obtain primary
alcohol 26 (Scheme 5).
Compound 7 was coupled with alcohol fragment 8 fol-
lowing Yamaguchi esterification conditions to obtain acet-
ate derivative 5 in 87% yield. Starting from 5, the same
sequence of reactions as those described in Scheme 4 af-
forded compound 31 as a single isomer. The formation of
a single isomer appears to arise from the preference of the
Scheme 6. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl
chloride, DMAP, THF, toluene, r.t., 6 h, 87%; (b) DDQ, CH2Cl2/
H2O (9:1), r.t., 3 h, 92%; (c) DMP, CH2Cl2, r.t., 4 h; (d) CrCl2,
NiCl2, DMSO, r.t., 24 h, 85% over two steps; (e) TBAF, AcOH,
aldehyde at C11 to adopt a conformation in which the THF, 0 °C to r.t., 18 h, 87%.
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D. K. Mohapatra, J. S. Yadav et al.
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metal-complexed carbonyl oxygen atom is oriented away
Figure 3 depicts the optimized structures along with the
from the highly bulky TBDPS group. Finally, cleavage of relative energies of the transition structures, intermediates
the TBDPS ether linkage with TBAF and acetic acid af- and products, which help to rationalize the experimental
forded amphidinolactone A (1) in 87% yield (Scheme 6).
observations. The relative energies of OBn-anti-TS and
To rationalize the observed experimental trends, quan- OBn-syn-TS versus those of OBn-anti-IN and OBn-syn-IN
tum chemical calculations were carried out on the anti and are 0.5 and 6.1 kcal/mol, respectively. The product stabili-
syn isomers of the OBn- and OTBDPS-substituted systems. ties of OBn-syn-Pr and OBn-anti-Pr are comparable, but
The proposed transition states (TS) corresponding to CrCl2 there is a small preference for the former by a difference of
migration, their corresponding intermediates (IN) and the 0.1 kcal/mol. Thus, considering the smaller difference in the
final products (PR) were optimized at the PM3 level by energies between the TSs, one would expect the formation
using the SPARTAN program package. Because the TSs of both anti and syn isomers. However, the larger difference
play a major role in the formation of the PRs, analysis was in the energies between the intermediates suggests the feasi-
done on the basis of the relative energies of the anti and bility of PRs in unequal ratios. These results suggest that
syn isomers of the TSs. As the variation in the experimental OBn substitution gives rise to the formation of the anti iso-
yields is mainly due to the OBn and OTBDPS groups, the mer in major quantities, which corroborates well with the
side chain attached to the ether-linked carbon was substi- observed experimental trends where anti and syn isomers
tuted with a CH3 group.
are formed in a 2:1 ratio. Further, the differences in the
Figure 3. Optimized structures of the TSs, INs and PRs along with the relative energies in kcal/mol between the syn and anti isomers.
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Total Synthesis of Amphidinolactone A
1513, 1464, 1286, 1249 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.11 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 6.80 (d, J = 8.7 Hz, 2 H,
C6H4-OMe), 4.31 (q, J = 11.5 Hz, 2 H, OCH2-Ar), 3.91 (m, 1 H,
CH-OH), 3.79 (s, 3 H, O-CH3), 3.60 (t, J = 6.2 Hz, 2 H, CH2-OAr),
3.49–3.39 (m, 2 H, CH2-OSi), 2.37–2.30 (m, 2 H, CH2-CϵC), 2.18–
2.08 (m, 2 H, CϵC-CH2), 1.65–1.55 (m, 2 H, CH2), 1.55–1.44 (m,
2 H, CH2), 1.05 [s, 9 H, SiC(CH3)3], 0.06 [s, 6 H, Si(CH3)2] ppm.
13C NMR (75 MHz, CDCl3): δ = 158.8, 130.3, 129.4, 113.4, 81.5,
76.7, 72.6, 62.01, 60.24, 55.02, 31.64, 26.7, 25.0, 24.4, 19.2, 18.4,
–4.9 ppm. MS (ESI): m/z = 429 [M + Na]+.
energies of OTBDPS-anti-TS and OTBDPS-syn-TS and
those of OTBDPS-anti-IN and OTBDPS-syn-IN are 2.1
and 5.2 kcal/mol, respectively. The difference in the product
energies between OTBDPS-syn-PR and OTBDPS-anti-PR
is 1.8 kcal/mol. The larger difference in energies between
the TSs as well as the INs suggests the exclusive formation
of the anti isomer. From these results, it can be clearly
understood that although the presence of a OBn group
yields both anti and syn PRs in an unequal ratio, the pres-
ence of a OTBDPS group results in the exclusive formation
of the anti isomer. Thus, the computational results corrobo-
rate well with the observed experimental trends.
{(8R)-8-(Benzyloxy)-9-[(4-methoxybenzyl)oxy]-5-nonynyloxy}(tert-
butyl)dimethylsilane (11): To a suspension of NaH (60% in mineral
oil, 1.7 g, 42.36 mmol) in dry THF (60 mL) was added alcohol 10
(8.6 g, 21.18 mmol) in THF (40 mL) at 0 °C under a N2 atmo-
sphere. The suspension was stirred for 1 h at room temperature.
Benzyl bromide (2.57 mL, 21.18 mmol) was added slowly to the
above reaction mixture at the same temperature. The reaction mix-
ture was stirred at room temperature for 4 h and then quenched
with water at 0 °C. The reaction mixture was extracted with EtOAc
(2ϫ100 mL). The combined organic layer was dried with anhy-
drous Na2SO4 and concentrated. Purification of the crude product
by silica gel chromatography (EtOAc/hexane, 1:19) afforded 11
(9.4 g, 90%) as a light-yellow liquid. [α]2D7 = +3.2 (c = 1.2, CHCl3).
Conclusions
In conclusion, we have accomplished the total synthesis
of amphidinolactone A (1) starting from 9 in an overall
yield of 22%.The longest linear synthetic sequence involved
13 steps. The important feature of our synthetic route is an
intramolecular NHK reaction to construct the 13-mem-
bered lactone and to control the stereochemical outcome at
C11 following esterification of two key intermediates pre-
pared by using highly concise and efficient synthetic proto-
cols.
IR (neat): ν = 3462, 2930, 2858, 2363, 1615, 1513, 1465, 1283,
˜
1249 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.44–7.33 (m, 5 H,
C6H5), 7.29 (dd, J = 4.8, 7.1 Hz, 2 H, C6H4-OMe), 6.90 (dd, J =
5.6, 8.0 Hz, 2 H, C6H4-OMe), 4.70 (ABq, J = 12.7, 20.2 Hz, 2 H,
OCH2-C6H5), 4.53 (s, 2 H, OCH2-C6H4-OMe), 3.85 (s, 3 H,
OCH3), 3.73 (m, 1 H, CH-OBn), 3.68–3.58 (m, 4 H, CH2-OAr,
CH2-OSi), 2.52–2.47 (m, 2 H, CH2-CϵC), 2.23–2.17 (m, 2 H,
CϵC-CH2), 1.66–1.52 (m, 4 H, CH2-CH2), 0.94 [s, 9 H, SiC-
(CH3)3], 0.09 [s, 6 H, Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3):
δ = 159.1, 138.5, 129.6, 129.1, 128.2, 127.7, 127.4, 113.6, 81.7, 76.9,
76.4, 73.0, 71.8, 71.3, 62.6, 55.2, 31.9, 25.9, 25.3, 21.8, 18.5,
–5.3 ppm. MS (ESI): m/z = 497 [M + H]+.
Experimental Section
General Remarks: Air- and/or moisture-sensitive reactions were
carried out in anhydrous solvents under an atmosphere of argon in
oven- or flame-dried glassware. All anhydrous solvents were dis-
tilled prior to use: THF, benzene, toluene and diethyl ether from
Na and benzophenone; CH2Cl2, quinoline and Et3N from CaH2;
MeOH and EtOH from Mg cake. Commercial reagents were used
without purification. Column chromatography was carried out on
silica gel (60–120 mesh). Infrared spectra were recorded in CHCl3/
neat (as mentioned) and are reported in wavenumber (cm–1). 1H
and 13C NMR chemical shifts are reported in ppm downfield from
tetramethylsilane (TMS), and coupling constants (J) are reported
in Hertz (Hz). The following abbreviations are used to designate
signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet,
m = multiplet, br. = broad.
(Z,8R)-8-(Benzyloxy)-9-[(4-methoxybenzyl)oxy]-5-nonen-1-ol (12):
To a stirred solution of TBS ether 11 (9.0 g, 18.14 mmol) in MeOH
(70 mL) was added p-TsOH (catalytic) at 0 °C, and the resulting
solution was stirred for 1 h at ambient temperature. The reaction
mixture was quenched with aqueous NaHCO3 (20 mL). MeOH
was removed under reduced pressure, and the residue was extracted
with EtOAc (3ϫ100 mL). The combined organic layer was washed
with brine (50 mL), dried with Na2SO4 and concentrated. Purifica-
tion of the crude product by silica gel column chromatography
(EtOAc/hexane, 1:2) furnished the desired primary alcohol (6.3 g,
91%) as a viscous colourless liquid that was immediately used for
next step. Lindlar’s catalyst (Pd/C on CaCO3) was added to a
stirred solution of the alkyne (6.2 g, 16.23 mmol) in benzene
(20 mL) followed by a catalytic amount of quinoline at room tem-
perature under a hydrogen atmosphere. The mixture was vigorously
stirred for 2 h at room temperature. After complete consumption
of the starting material (checked by TLC), the black reaction mass
was filtered through a pad of Celite, and the filtrate was concen-
trated. Purification of the crude mass by silica gel column
chromatography (EtOAc/hexane, 1:4) afforded 12 (5.9 g, 95%).
(2R)-9-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-[(4-methoxybenzyl)-
oxy]-4-nonyn-2-ol (10): A flame-dried 500-mL round-bottomed
flask was charged with TBS-protected 5-hexyne-1-ol (5.20 g,
24.74 mmol) in THF (250 mL) and cooled to –78 °C. To this solu-
tion was added nBuLi (2.5  in hexanes, 9.92 mL, 24.74 mmol)
dropwise by syringe. The resulting mixture was warmed slowly to
0 °C. During this time, the reaction mixture turned dark red in
colour. After 30 min, (S)-PMB glycidyl (9; 4.0 g, 20.62 mmol) was
slowly added, followed by BF3·OEt2 (2.85 mL, 22.68 mmol) at
–78 °C, and the mixture was stirred for an additional 30 min. The
reaction was then quenched with saturated NaHCO3, diluted with
EtOAc and warmed to room temperature. The organic layer was
extracted with EtOAc (3ϫ100 mL), and the combined organic
layer was washed with brine (100 mL), dried with Na2SO4 and con-
centrated. Purification by flash column chromatography (EtOAc/
[α]2D7 = +2.8 (c = 1.9, CHCl ). IR (neat): ν = 3474, 2928, 2857,
˜
3
2360, 1620, 1464, 1427, 1245, 1112, 1074, 940 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.36 (m, 5 H, C6H5), 7.24 (d, J = 8.3 Hz,
2 H, C6H4-OMe), 6.86 (d, J = 8.5 Hz, 2 H, C6H4-OMe), 5.49–5.40
(m, 2 H, CH=CH), 4.62 (ABq, J = 11.9, 20.0 Hz, 2 H, OCH2-
C6H5), 4.46 (s, 2 H, OCH2-C6H4-OMe), 3.79 (s, 3 H, OCH3), 3.64–
3.53 (m, 3 H, CH2-OAr, CH-OBn), 3.49 (d, J = 4.3 Hz, 2 H, CH2-
OH), 2.33 (t, J = 5.8 Hz, 2 H, CH2-CH=CH), 2.09–1.98 (m, 2 H,
hexane, 1:3) provided 10 (8.90 g, 89%) as a colourless oil. [α]2D7
–6.8 (c = 1.6, CHCl ). IR (neat): ν = 3464, 2929, 2858, 2360, 1613,
=
˜
3
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D. K. Mohapatra, J. S. Yadav et al.
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CH=CH-CH2), 1.72 (br. s, 1 H, OH), 1.57–1.46 (m, 2 H, CH2),
1.44–1.32 (m, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.0, 138.7, 132.8, 131.7, 130.3, 129.2, 128.2, 127.6, 126.0, 125.3,
113.7, 78.0, 72.9, 71.9, 71.7, 62.6, 55.2, 32.2, 29.6, 26.9, 25.6 ppm.
HRMS (ESI): calcd. for C24H32O4 [M + H]+ 385.2373; found
385.2361.
55.2, 51.4, 33.4, 31.9, 29.6, 26.6, 24.7 ppm. HRMS (ESI): calcd. for
C25H32O5 [M + Na]+ 435.2142; found 435.2125.
Methyl (Z,8R)-8-(Benzyloxy)-9-hydroxy-5-nonenoate (14): To
a
solution of PMB ether 13 (4.2 g, 10.19 mmol) in CH2Cl2 (50 mL)
and water (5 mL) at room temperature was added DDQ (3.47 g,
15.29 mmol), and the reaction mixture was stirred for 2 h at the
same temperature. The reaction was quenched with saturated
NaHCO3 (15 mL), and the organic layer was extracted with
CH2Cl2 (2ϫ50 mL). The combined organic layer was washed with
brine (50 mL), dried with anhydrous Na2SO4 and evaporated to
give a red-coloured product. Purification of the crude product by
silica gel column chromatography (EtOAc/hexane, 1:4) afforded 14
(2.64 g, 89%) as a colourless liquid. [α]2D7 = +3.2 (c = 1.6, CHCl3).
Methyl (Z,8R)-8-(Benzyloxy)-9-[(4-methoxybenzyl)oxy]-5-noneno-
ate (13): To a stirred solution of primary alcohol 12 (5.7 g,
14.84 mmol) in CH2Cl2 (80 mL) at 0 °C was added iodobenzenedi-
acetate (5.26 g, 16.32 mmol) followed by TEMPO (0.46 g,
2.96 mmol), and the mixture was stirred at ambient temperature
for 3 h. After complete consumption of the primary alcohol (moni-
tored by TLC), the reaction was quenched with a saturated solution
of sodium thiosulfate and extracted with CH2Cl2 (3ϫ70 mL). The
combined organic layer was dried with anhydrous Na2SO4 and con-
centrated. Purification of the crude aldehyde by flash chromatog-
raphy on silica gel (EtOAc/hexane, 1:9) afforded the corresponding
aldehyde (5.2 g, 92%) as a thick viscous liquid that was used imme-
diately in the next reaction. To a solution of the resulting aldehyde
(5.0 g, 13.09 mmol) in tert-butyl alcohol (45 mL) was added 2-
methyl-2-butene (2  in THF, 7 mL, 13.09 mmol) at room tempera-
ture. Sodium dihydrogenphosphate (6.12 g, 39.26 mmol) and so-
dium chlorite (1.77 g, 19.63 mmol) were dissolved in water (20 mL)
to make a clear solution, which was subsequently added to the
above-mentioned reaction mixture at 0 °C. The mixture was stirred
for another 3 h at room temperature. The reaction mixture was
extracted with EtOAc (3ϫ100 mL), and the combined organic
layer was washed with brine, dried with anhydrous Na2SO4 and
concentrated. Purification of the crude product by silica gel
chromatography (EtOAc/hexane, 3:7) afforded the corresponding
acid (5.4 g, 93%) as a colourless oil. [α]2D7 = +4.2 (c = 1.6, CHCl3).
IR (neat): ν = 3453, 2947, 2862, 1732, 1610, 1510, 1455, 1250,
˜
1095 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.26 (m, 5 H,
C6H5), 5.51–5.40 (m, 2 H, CH=CH), 4.66 (ABq, J = 11.7, 19.8 Hz,
2 H, OCH2-C6H5), 3.70–3.63 (m, 4 H, COOCH3, CH-OAr), 3.58–
3.50 (m, 2 H, CH2-OH), 2.40–2.25 (m, 4 H, CH2-CH=CH-CH2),
2.08 (dd, J = 6.9, 14.2 Hz, 2 H, CH2-COOMe), 1.69 (quint., J =
7.5 Hz, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.0,
138.2, 132.2, 131.1, 128.4, 127.7, 125.6, 79.4, 71.5, 63.9, 51.5, 33.3,
28.6, 26.6, 24.6 ppm. HRMS (ESI): calcd. for C17H24O4 [M +
Na]+ 315.1567; found 315.1581.
Methyl (5Z,8R,9E)-8-(Benzyloxy)-10-iodo-5,9-decadienoate (15): To
a stirred solution of primary alcohol 14 (2.5 g, 8.56 mmol) and so-
lid anhydrous NaHCO3 (2.0 g) in CH2Cl2 (30 mL) at 0 °C was
added Dess–Martin periodinane (4.0 g, 9.41 mmol). The resulting
reaction mixture was stirred at 0 °C for 3 h. After completion of
the reaction (monitored by TLC), the mixture was filtered through
filter paper. The filtrate was washed with saturated NaHCO3
(2ϫ20 mL). The aqueous layer was extracted with CH2Cl2
(2ϫ40 mL). The combined organic layer was dried with anhydrous
Na2SO4, and the solvent was removed. Purification of the crude
mass by flash chromatography (EtOAc/hexane, 1:5) afforded the
corresponding aldehyde (2.3 g, 92%) as a pale-yellow liquid. To a
stirred suspension of CrCl2 (5.56 g, 45.51 mmol) in THF (25 mL)
at 0 °C under a nitrogen atmosphere was added the aldehyde (2.2 g,
7.58 mmol) and CHI3 (8.85 g, 22.75 mmol) dissolved in THF
(25 mL). The reaction mixture was protected from light and stirred
at ambient temperature for 16 h. The green reaction mass was
quenched with water. The organic layer was extracted with EtOAc
(3ϫ50 mL). The combined organic extract was washed with satu-
rated aqueous Na2S2O3 (2ϫ25 mL) followed by brine (50 mL),
dried with anhydrous Na2SO4 and concentrated. Purification by
silica gel column chromatography (EtOAc/hexane, 1:19) afforded
15 (2.8 g, 82%) as a pale-yellow oil. [α]2D7 = +5.0 (c = 1.3, CHCl3).
IR (neat): ν = 3469, 2926, 2860, 1710, 1608, 1513, 1453, 1249, 1095,
˜
1
1032, 824 cm–1. H NMR (300 MHz, CDCl3): δ = 7.35–7.27 (m, 5
H, C6H5), 7.24 (d, J = 8.3 Hz, 2 H, C6H4-OMe), 6.86 (d, J =
9.2 Hz, 2 H, C6H4-OMe), 5.50–5.37 (m, 2 H, CH=CH), 4.61 (ABq,
J = 12.0, 20.1 Hz, 2 H, OCH2-C6H5), 4.46 (s, 2 H, OCH2-Ar), 3.80
(s, 3 H, OCH3), 3.60 (q, J = 5.3 Hz, 1 H, CH-OBn), 3.49 (d, J =
4.5 Hz, 2 H, CH2-OAr), 2.32 (dd, J = 5.3, 12.0 Hz, 4 H, CH2-
CH=CH-CH2), 2.07 (q, J = 7.6 Hz, 2 H, CH2-COOH), 1.67 (pent.,
J = 7.6 Hz, 2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ =
179.3, 159.1, 138.6, 131.6, 130.5, 129.2, 128.2, 127.7, 127.4, 126.3,
113.7, 77.9, 72.9, 71.8, 71.7, 55.2, 33.3, 29.6, 26.5, 24.4 ppm. MS
(ESI): m/z = 421 [M + Na]+. To a stirred solution of the above acid
(4.3 g, 10.80 mmol) in ether at 0 °C was added a freshly prepared
solution of diazomethane in diethyl ether (50 mL). The reaction
mixture was stirred for 10 min at the same temperature and then
quenched with a saturated sodium thiosulfate solution at 0 °C. Two
layers were separated, and the aqueous layer was extracted with
diethyl ether (2ϫ50 mL). The combined organic fraction was dried
with anhydrous Na2SO4, and the solvent was evaporated. Purifica-
tion of the crude product by silica gel chromatography (EtOAc/
hexane, 1:9) afforded 13 (4.3 g, 96%) as a light-yellow liquid. [α]2D7
IR (neat): ν = 2946, 2861, 1733, 1510, 1465, 1427, 1363, 1278, 1112,
˜
1075 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.32 (m, 5 H, C6H5),
6.46 (dd, J = 7.4, 14.5 Hz, 1 H, CH=CHI), 6.28 (d, J = 14.7 Hz, 1
H, CH=CHI), 5.48–5.34 (m, 2 H, CH=CH), 4.58 (ABq, J = 12.0,
36.5 Hz, 2 H, OCH2-C6H5), 3.72 (q, J = 6.8 Hz, 1 H, CH-OBn),
3.64 (s, 3 H, COOCH3), 2.40–2.21 (m, 4 H, CH2-CH=CH-CH2),
2.05 (q, J = 6.7 Hz, 2 H, CH2-COOMe), 1.66 (quint., J = 7.4 Hz,
2 H, CH2) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.1, 145.5,
138.1, 131.1, 128.4, 127.8, 125.2, 81.2, 78.6, 70.5, 51.4, 33.6, 33.1,
26.8, 24.7 ppm. MS (ESI): m/z = 415 [M + H]+.
= +5.4 (c = 1.5, CHCl ). IR (neat): ν = 2945, 2860, 1736, 1612,
˜
3
1513, 1454, 1248, 1095 cm–1. 1H NMR (300 MHz, CDCl3): δ =
7.29 (d, J = 4.3 Hz, 5 H, C6H5), 7.20 (d, J = 8.5 Hz, 2 H, C6H4-
OMe), 6.82, (d, J = 8.5 Hz, 2 H, C6H4-OMe), 5.48–5.35 (m, 2 H,
CH=CH), 4.59 (ABq, J = 11.9, 20.0 Hz, 2 H, OCH2-C6H5), 4.43
(s, 2 H, OCH2-Ar), 3.79 (s, 3 H, OCH3), 3.63 (s, 3 H, COOCH3), (5Z,8R,9E)-8-(Benzyloxy)-10-iodo-5,9-decadienoic Acid (6): To a
3.55 (dd, J = 5.5, 10.6 Hz, 1 H, CH-OBn), 3.48–3.42 (m, 2 H, CH2-
OAr), 2.33–2.21 (m, 4 H, CH2-CH=CH-CH2), 2.05 (dd, J = 7.0,
13.6 Hz, 2 H, CH2-COOMe), 1.65 (quint., J = 7.8 Hz, 2 H, CH2)
ppm. 13C NMR (75 MHz, CDCl3): δ = 174.0, 159.0, 138.7, 131.8,
130.7, 129.2, 128.2, 127.6, 127.4, 126.2, 113.7, 77.9, 72.9, 71.9, 71.7,
stirred solution of ester 15 (2.1 g, 5.07 mmol) in THF (20 mL) and
water (3 mL) was added LiOH (175 mg, 7.60 mmol), and the reac-
tion mixture stirred at room temperature for 6 h. After completion
of the reaction (monitored by TLC), the mixture was extracted with
diethyl ether, and the aqueous layer was acidified to pH 2 with
4780
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4775–4784

Total Synthesis of Amphidinolactone A
0.5  HCl. The aqueous layer was extracted with EtOAc
IR (neat): ν = 3461, 2921, 2855, 1614, 1513, 1358, 1248, 1176, 1098,
˜
(4ϫ25 mL), and the combined organic layer was washed with brine 974, 771 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J =
(20 mL), dried with anhydrous Na2SO4 and concentrated. Purifica-
tion of the crude product by silica gel column chromatography
(EtOAc/hexane, 1:2) afforded 6 (1.84 g, 91%) as a colourless oil.
8.3 Hz, 2 H, SO2-C6H4-CH3), 7.33 (d, J = 8.1 Hz, 2 H, SO2-C6H4-
CH3), 7.22 (d, J = 8.5 Hz, 2 H, C6H4-OMe), 6.84 (d, J = 8.7 Hz,
2 H, C6H4-OMe), 4.47 (s, 2 H, OCH2-Ar), 4.04 (t, J = 7.2 Hz, 2
H, CH2-OTs), 3.84 (m, 1 H, CH-OH), 3.80 (s, 3 H, OCH3), 3.50
(dd, J = 3.9, 9.4 Hz, 1 H, CH-OAr), 3.39 (dd, J = 6.6, 9.4 Hz, 1
H, CH-OAr), 2.51 (dt, J = 2.3, 6.9 Hz, 2 H, CH2-CϵC), 2.45 (s, 3
H, C6H4-CH3), 2.32 (dt, J = 2.5, 6.2 Hz, 2 H, CϵC-CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.1, 144.8, 132.7, 129.8, 129.3,
127.7, 113.6, 78.4, 76.3, 72.9, 72.4, 68.7, 67.9, 55.1, 23.6, 21.5,
19.6 ppm. HRMS (ESI): calcd. for C22H26O6S [M + Na]+ 441.1342;
found 441.1339.
(2R)-7-[1-(tert-Butyl)-1,1-dimethylsilyl]oxy-1-[(4-methoxybenzyl)-
oxy]-4-heptyn-2-ol (16): A flame-dried 100-mL two-necked round-
bottomed flask was charged with the alkyne (5.0 g, 27.2 mmol) in
THF (60 mL) and cooled to –78 °C. To this solution was added
nBuLi (2.5  in hexane, 12 mL, 29.87 mmol) slowly under a nitro-
gen atmosphere at the same temperature. After 30 min when the
solution turned light yellow, (S)-PMB-glycidol (9; 5.8 g,
29.87 mmol) in THF (30 mL) was slowly added at the same tem-
perature followed by BF3·OEt2 (4.2 g, 29.87 mmol). The reaction
mixture was stirred for an additional 30 min and then the reaction
was quenched with saturated NaHCO3 (40 mL). The organic layer
was separated, and the aqueous layer was extracted with EtOAc
(3ϫ50 mL). The combined organic layer was washed with brine
(100 mL), dried with Na2SO4 and concentrated to afford a yellow
oil. Purification of the crude product by silica gel column
chromatography (EtOAc/hexane, 1:9) afforded 16 (8.5 g, 86%) as a
(2R)-7-Iodo-1-[(4-methoxybenzyl)oxy]-4-heptyn-2-ol (19): A 100-mL
round-bottomed flask fitted with a reflux condenser was charged
with a solution of 18 (6.0 g, 14.85 mmol) in dry acetone (40 mL).
To this solution was added NaI (6.68 g, 44.55 mmol) at room tem-
perature, and the resulting reaction mixture was then heated at re-
flux for 3 h. After complete consumption of the starting material
(monitored by TLC), acetone was removed under reduced pressure
to afford a solid mass that was dissolved in H2O (50 mL). The
aqueous layer was extracted and dried with Na2SO4. The organic
colourless liquid. [α]2D7 = –11.0 (c = 1.1, CHCl ). IR (neat): ν =
˜
3
3466, 2927, 2855, 2362, 1610, 1515, 1466, 1280, 1245 cm–1. 1H layer was concentrated to give a yellow liquid, which after purifica-
NMR (300 MHz, CDCl3): δ = 7.20 (dd, J = 3.0, 11.5 Hz, 2 H,
C6H4-OMe), 6.82 (d, J = 8.3 Hz, 2 H, C6H4-OMe), 4.46 (s, 2 H,
tion by silica gel column chromatography (EtOAc/hexane, 1:9), af-
forded 19 (4.8 g, 90%) as a pale-yellow oil. [α]2D7 = –30.8 (c = 1.0,
OCH2-Ar), 3.88–3.76 (m, 4 H, OCH3, -CH-OH), 3.68–3.60 (m, 2 CHCl ). IR (neat): ν = 3442, 2919, 2859, 2357, 1612, 1513, 1461,
˜
3
H, CH2-OAr), 3.43–3.33 (m, 2 H, CH2-OSi), 2.40–2.28 (m, 4 H,
1302, 1247, 1172, 1101, 1034 cm–1. 1H NMR (300 MHz, CDCl3):
CH2-CϵC-CH2), 0.89 [s, 9 H, SiC(CH3)3], 0.05 [s, 6 H, Si(CH3)2] δ = 7.26 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 6.88 (d, J = 8.5 Hz, 2
ppm. 13C NMR (75 MHz, CDCl3): δ = 159.3, 130.0, 129.3, 113.8,
79.6, 76.8, 73.0, 72.7, 69.0, 62.1, 55.2 ppm. HRMS (ESI): calcd. for
C21H34O4Si [M + NH4]+ 396.2565; found 396.2561.
H, C6H4-OMe), 4.50 (s, 2 H, OCH2-Ar), 3.92 (m, 1 H, CH-OH),
3.80 (s, 3 H, OCH3), 3.58 (dd, J = 3.9, 9.6 Hz, 1 H, CH-OAr), 3.47
(dd, J = 6.6, 9.6 Hz, 1 H, CH-OAr), 3.17 (t, J = 7.2 Hz, 2 H, CH2-
I), 2.72 (dt, J = 2.3, 7.0 Hz, 2 H, CH2-CϵC), 2.63 (br. s, 1 H, OH),
2.39 (dt, J = 2.3, 6.2 Hz, 2 H, CϵC-CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.2, 129.8, 129.3, 113.7, 81.1, 78.0, 72.9,
72.5, 68.8, 55.2, 23.9, 23.8 ppm. HRMS (ESI): calcd. for C15H19IO3
[M + Na]+ 397.0271; found 397.0264.
(6R)-7-[(4-Methoxybenzyl)oxy]-3-heptyne-1,6-diol (17): To a stirred
solution of TBS ether 16 (8.5 g, 23.35 mmol) in MeOH (70 mL)
was added camphorsulfonic acid (catalytic) at 0 °C, and the re-
sulting solution was stirred for 1 h at ambient temperature. The
reaction mixture was quenched with aqueous NaHCO3 (25 mL),
and MeOH was removed under reduced pressure. The residue was
extracted with EtOAc (3ϫ70 mL). The combined organic layer was
dried with Na2SO4 and concentrated to obtain a yellow oil. Purifi-
cation by silica gel column chromatography (EtOAc/hexane, 1:1)
furnished 17 (5.5 g, 94%) as a colourless viscous liquid. [α]2D7 = –3.6
(6R)-6-Hydroxy-7-[(4-methoxybenzyl)oxy]-3-heptynyl(triphenyl)-
phosphonium Iodide (20): A 50-mL round-bottomed flask fitted
with a reflux condenser was charged with a solution of 19 (4.0 g,
11.11 mmol) in dry CH3CN (20 mL). To this solution was added
PPh3 (3.2 g, 12.22 mmol), and the resulting mixture was heated at
reflux for 12 h. After completion of the reaction, CH3CN was re-
moved under reduced pressure to give a white solid mass. The crude
product was purified by silica gel column chromatography
(c = 1.0, CHCl ). IR (neat): ν = 3391, 2920, 2862, 2361, 1612, 1513,
˜
3
1459, 1248, 1174, 1082, 1027 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.22 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 6.84 (d, J = 8.5 Hz, 2
H, C6H4-OMe), 4.47 (s, 2 H, OCH2-Ar), 3.87 (m, 1 H, CH-OH), (CH2Cl2/MeOH: 32:1) to furnish 20 (6.5 g, 94%) as a white semi-
3.80 (s, 3 H, OCH3), 3.63 (t, J = 5.8 Hz, 2 H, CH2-OH), 3.51 (dd, solid. [α]2D7 = +5.2 (c = 1.5, CHCl ). IR (neat): ν = 3356, 2920,
˜
3
J = 4.2, 9.4 Hz, 1 H, CH-OAr), 3.41 (dd, J = 6.6, 9.4 Hz, 1 H,
CH-OAr), 2.42–2.35 (m, 4 H, CH2-CϵC-CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 159.2, 131.7, 129.4, 113.8, 79.3, 77.8, 72.9,
72.7, 68.9, 61.0, 55.2, 23.7, 23.0 ppm. HRMS (ESI): calcd. for
C15H20O4 [M + Na]+ 287.1254; found 287.1259.
2862, 2358, 1611, 1512, 1438, 1294, 1246, 1177, 1112, 1029 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.86–7.77 (m, 8 H, ArH), 7.74–
7.67 (m, 4 H, ArH), 7.35–7.31 (m, 3 H, ArH), 7.24 (d, J = 8.7 Hz,
2 H, C6H4-OMe), 6.87 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 4.45 (s, 2
H, OCH2-Ar), 3.90–3.82 (m, 2 H, CH2-PPh3), 3.79 (s, 3 H, OCH3),
3.72 (m, 1 H, CH-OH), 3.44–3.33 (m, 2 H, CH2-OAr), 2.74 (dt, J
= 6.6, 19.5 Hz, 2 H, CH2-CϵC), 2.07–2.03 (m, 2 H, CϵC-CH2)
ppm. 13C NMR (75 MHz, CDCl3): δ = 159.1, 135.1, 133.9, 133.8,
133.5, 131.9, 130.4, 130.3, 130.0, 129.3, 128.7, 128.3, 118.3, 117.2,
113.7, 81.5, 78.2, 72.9, 72.6, 68.4, 55.3, 26.9, 23.8 ppm.
(6R)-6-Hydroxy-7-[(4-methoxybenzyl)oxy]-3-heptynyl 4-Methyl-1-
benzenesulfonate (18): To a solution of diol 17 (5.0 g, 20 mmol)
dissolved in dry CH2Cl2 (50 mL) at 0 °C was added dry Et3N
(5.4 mL, 40 mmol) followed by TosCl (3.8 g, 20 mmol) and DMAP
(catalytic). The reaction mixture was warmed to room temperature.
After completion of the reaction (monitored by TLC), the reaction
was quenched with water, and the mixture was extracted with
CH2Cl2 (2ϫ50 mL). The combined organic layer was washed with
brine (50 mL) and concentrated to give a yellow oil. Purification
by silica gel column chromatography (EtOAc/hexane, 1:4) afforded
18 (6.5 g, 80%) as a pale-yellow oil. [α]2D7 = –5.5 (c = 1.6, CHCl3).
(2R,7Z)-1-[(4-Methoxybenzyl)oxy]-7-decen-4-yn-2-ol (21): Com-
pound 20 (3.0 g, 4.82 mmol) in THF (30 mL) was stirred at room
temperature under a nitrogen atmosphere until it was dissolved
completely. To this solution was slowly added nBuLi (2.5  in hex-
ane, 4.24 mL, 10.60 mmol) at –78 °C, and the resulting solution
was warmed to 0 °C. After 1 h, the reaction mixture was again
Eur. J. Org. Chem. 2010, 4775–4784
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4781

D. K. Mohapatra, J. S. Yadav et al.
FULL PAPER
cooled to –78 °C and n-propanal (0.64 g, 10.6 mmol) was slowly
added. The mixture was stirred at the same temperature for 4 h.
After complete consumption of the starting material (monitored by
TLC), the reaction was quenched with saturated NH4Cl (30 mL)
and warmed to room temperature. The organic layer was separated,
and the aqueous layer was extracted with EtOAc (3ϫ50 mL). The
combined organic layer was washed with brine (60 mL), dried with
Na2SO4 and concentrated. Purification by silica gel column
chromatography (EtOAc/hexane, 1:12) afforded 21 (1.1 g, 83%) as
(0.65 g, 2.25 mmol) in CH2Cl2 (5 mL) at the same temperature, and
the mixture was then stirred for 12 h at room temperature. The
reaction mixture was diluted with CH2Cl2 (20 mL) and sub-
sequently washed with H2O (2ϫ20 mL) and brine (2 ϫ 20 mL).
The organic layer was dried with Na2SO4 and concentrated to give
a colourless oil. Purification by silica gel column chromatography
(EtOAc/hexane, 3:97) furnished 4 (1.1 g, 70%, based on the starting
alcohol) as a colourless liquid.
Method C: To a stirred solution of acid 6 (1.0 g, 2.5 mmol) in dry
THF (15 mL) at 0 °C was added Et3N (0.67 mL, 5 mmol) followed
by 2,4,6-trichlorobenzoyl chloride (0.6 g, 2.5 mmol). The resulting
mixture was stirred for 30 min at room temperature. THF and Et3N
were completely removed under reduced pressure to afford a semi-
solid mass that was dissolved in dry benzene (10 mL). To this re-
sulting solution was added alcohol 8 (0.65 g, 2.25 mmol) and
DMAP (2.5 mmol, 0.32 g) separately dissolved in dry benzene
(10 mL) at 0 °C, and the mixture was stirred at room temperature
for 6 h. The reaction mixture was diluted with EtOAc (20 mL) and
subsequently washed with Na2CO3 (2 ϫ 20 mL) and brine
(2ϫ20 mL). The organic layer was dried with Na2SO4 and concen-
trated to give a colourless oil. Purification by silica gel column
chromatography (EtOAc/hexane, 3:97) furnished 4 (1.34 g, 89%,
based on the starting alcohol) as a colourless liquid. [α]2D7 = +21.1
a colourless liquid. [α]2D7 = –4.8 (c = 1.0, CHCl ). IR (neat): ν =
˜
3
3434, 2923, 2851, 1607, 1513, 1463, 1251 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.20 (d, J = 8.5 Hz, 2 H, C6H4-OMe), 6.82
(d, J = 8.7 Hz, 2 H, C6H4-OMe), 5.44–5.27 (m, 2 H, CH=CH-),
4.47 (s, 2 H, OCH2-Ar), 3.85 (m, 1 H, CH-OH), 3.79 (s, 3 H,
OCH3), 3.52 (dd, J = 3.8, 9.3 Hz, 1 H, CH-OAr), 3.40 (dd, J = 6.6,
9.4 Hz, 1 H, CH-OAr), 2.88–2.82 (m, 2 H, CϵC-CH2-CH=CH),
2.42–2.32 (m, 2 H, CH2-CϵC), 2.10–2.01 (m, 2 H, CH2-CH3), 0.99
(t, J = 7.6 Hz, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.2, 133.1, 129.9, 129.3, 123.9, 113.8, 81.0, 75.3, 73.0, 72.7, 69.1,
55.2, 23.8, 20.4, 17.0, 13.9 ppm. HRMS (ESI): calcd. for C18H24O3
[M + Na]+ 311.1618; found 311.1628.
(2R,4Z,7Z)-1-[(4-Methoxybenzyl)oxy]-4,7-decadien-2-ol (8): Lind-
lar’s catalyst (Pd/C on CaCO3) was added to a stirred solution of
alkyne 21 (1.1 g, 4.01 mmol) in benzene (10 mL) followed by a cata-
lytic amount of quinoline at room temperature under a hydrogen
atmosphere. The mixture was vigorously stirred for 3 h at room
temperature. After complete consumption of the starting material
(monitored by TLC), the black reaction mass was filtered through
a pad of Celite. The filtrate was concentrated, and purification of
the crude product by silica gel column chromatography (EtOAc/
hexane, 7:93) gave 8 (1.0 g, 91%). [α]2D7 = –3.6 (c = 1.2, CHCl3). IR
(c = 1.1, CHCl ). IR (neat): ν = 2935, 2860, 2362, 1732, 1430, 1462,
˜
3
1243, 1108, 1072, 942, 822, 772, 703 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.36–7.26 (m, 5 H, C6H5), 7.23 (d, J = 8.7 Hz, 2 H,
C6H4-OMe), 6.86 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 6.48 (dd, J =
7.6, 14.5 Hz, 1 H, CH=CHI), 6.30 (d, J = 14.5 Hz, 1 H, CH=CHI),
5.50–5.22 (m, 6 H, CH=CH), 5.06 (quint., J = 6.4 Hz, 1 H, CH-
OCO-), 4.58 (d, J = 11.9 Hz, 1 H, O-CH-C6H5), 4.45 (q, J = 11.7,
19.3 Hz, 2 H, O-CH2-Ar), 4.37 (d, J = 11.9 Hz, 1 H, O-CH-C6H5),
3.79 (s, 3 H, OCH3), 3.77–3.72 (m, 1 H, CH-OAr), 3.51–3.47 (m,
2 H, CH2-OAr), 2.78 (t, J = 7 Hz, 2 H, CH=CH-CH2-CH=CH-),
2.39 (t, J = 6.6 Hz, 2 H, CH2-CH=CH), 2.35–2.25 (m, 4 H, CH2-
CH=CH), 2.10–2.00 (m, 4 H, CH2-CH=CH, CH2-COO), 1.67
(quint., J = 7.4 Hz, 2 H, CH2), 0.96 (t, J = 7.6 Hz, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 173.0, 159.2, 146.4, 138.1, 132.1,
131.3, 130.1, 129.2, 128.3, 126.7, 125.0, 123.9, 113.7, 81.1, 78.3,
72.8, 72.1, 70.5, 70.3, 55.2, 33.9, 32.8, 28.9, 26.8, 25.6, 24.9, 20.5,
14.2 ppm. MS (ESI): m/z = 690 [M + NH4]+.
(neat): ν = 3430, 2927, 1717, 1612, 1513, 1460, 1248, 1089, 1033,
˜
1
824 cm–1. H NMR (300 MHz, CDCl3): δ = 7.24 (d, J = 8.7 Hz, 2
H, C6H4-OMe), 6.86 (d, J = 8.7 Hz, 2 H, C6H4-OMe), 5.54–5.40
(m, 2 H, CH=CH), 5.40–5.22 (m, 2 H, CH=CH), 4.47 (s, 2 H,
OCH2-Ar), 3.80 (s, 4 H, CH-OH, OCH3), 3.47 (dd, J = 3.4, 9.4 Hz,
1 H, CH-OAr), 3.32 (dd, J = 1.3, 7.4 Hz, 1 H, CH-OAr), 2.79 (m,
2 H, CH=CH-CH2-CH=CH), 2.40–2.18 (m, 3 H, CH2-CH=CH,
CH-OH), 2.12–1.95 (m, 2 H, CH2-CH=CH), 0.91 (t, J = 7.5 Hz, 3
H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.3, 133.2,
130.0, 129.4, 123.9, 123.3, 113.8, 73.0, 72.7, 69.1, 55.3, 23.9, 20.4,
17.0, 14.0 ppm. MS (ESI): m/z = 308 [M + NH4]+.
(9R,12R,13R)-9,12-Dihydroxy-13-[(2Z,5Z)-2,5-octadienyl]-1-oxa-
6,10-cyclotridecadien-2-one (23) and (9R,12S,13R)-9,12-Dihydroxy-
13-[(2Z,5Z)-2,5-octadienyl]-1-oxa-6,10-cyclotridecadien-2-one (24):
To a solution of PMB ether 4 (0.6 g, 0.89 mmol) in CH2Cl2 (9 mL)
and water (0.5 mL) at room temperature was added DDQ (0.41 g,
1.78 mmol), and the mixture was stirred for 2 h at the same tem-
perature. The reaction was quenched with saturated NaHCO3
(5 mL) solution. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (2ϫ10 mL). The combined or-
ganic layer was washed with brine (20 mL), dried with anhydrous
Na2SO4 and concentrated to give the crude product. Purification
by silica gel column chromatography (EtOAc/hexane, 1:6) afforded
22 (0.45 g, 91%) as a colourless liquid. To a stirred solution of 22
(0.3 g, 0.54 mmol) and solid anhydrous NaHCO3 (0.2 g) in CH2Cl2
(10 mL) was added Dess–Martin periodinane (0.47 g, 1.08 mmol)
at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. After
complete consumption of the starting material (TLC monitored),
the reaction mixture was filtered through filter paper. The filtrate
was washed with saturated NaHCO3 (5 mL). The aqueous layer
was extracted with CH2Cl2 (2ϫ10 mL). The combined organic
layer was dried with anhydrous Na2SO4 and concentrated. The
crude mass was purified by flash chromatography (EtOAc/hexane,
1:9) to afford the aldehyde in quantitative yield, which was immedi-
(1R,3Z,6Z)-1-[(4-Methoxybenzyl)oxy]methyl-3,6-nonadienyl
(5Z,8R,9E)-8-(Benzyloxy)-10-iodo-5,9-decadienoate (4)
Method A: To a stirred solution of acid 6 (1.0 g, 2.5 mmol) in
CH2Cl2 (15 mL) at 0 °C was added Et3N (0.67 mL, 5 mmol) fol-
lowed by DCC (0.77 g, 3.75 mmol) and DMAP (2.5 mmol, 0.32 g).
The resulting mixture was stirred for 30 min. To this mixture was
slowly added a solution of alcohol 8 (0.65 g, 2.25 mmol) in CH2Cl2
(5 mL) at 0 °C, and the mixture was then stirred for 12 h at room
temperature. The white precipitate formed was filtered through a
pad of Celite and washed with CH2Cl2 (20 mL). The filtrate was
washed with H2O (2ϫ20 mL) and brine (2ϫ20 mL). The organic
layer was dried with Na2SO4 and concentrated to give a colourless
oil. Purification by silica gel column chromatography (EtOAc/hex-
ane, 3:97) furnished 4 (0.87 g, 58%, based on the starting alcohol)
as a colourless liquid.
Method B: To a stirred solution of acid 6 (1.0 g, 2.5 mmol) in
CH2Cl2 (15 mL) at 0 °C was added Et3N (0.67 mL, 5 mmol) fol-
lowed by EDCI (0.720 g, 3.75 mmol) and DMAP (2.5 mmol,
0.32 g), and the resulting reaction mixture was stirred for 30 min.
To this reaction mixture was slowly added a solution of alcohol 8
4782
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Eur. J. Org. Chem. 2010, 4775–4784

Total Synthesis of Amphidinolactone A
ately used for the next reaction. A flame-dried 50-mL round-bot-
tomed flask was charged with anhydrous CrCl2 (1.4 g, 10.8 mmol),
round-bottomed flask was added anhydrous CrCl2 (1.65 g,
12.8 mmol), NiCl2 (0.15 g, 1.28 mmol) and dry DMSO (30 mL).
NiCl2 (0.13 g, 1.08 mmol), DMSO (25 mL) and THF (8 mL), and The resulting mixture was vigorously stirred at room temperature
the resulting mixture was vigorously stirred at room temperature
for 30 min. To this reaction mixture was slowly added a solution
of the aldehyde in dry DMSO (5 mL) at the same temperature.
The reaction mixture was stirred for an additional 24 h at room
temperature. The reaction was quenched with saturated NH4Cl
for 30 min. To this reaction mixture was slowly added a solution
of aldehyde 3 in DMSO (5 mL) at the same temperature, and the
mixture was stirred for 24 h. The reaction was quenched with satu-
rated NH4Cl (20 mL) and extracted with diethyl ether (5ϫ50 mL).
The combined organic layer was washed with H2O (2ϫ50 mL) and
(15 mL) and extracted in diethyl ether (5ϫ50 mL). The combined brine (2ϫ50 mL) and concentrated. Purification by silica gel col-
organic layer was washed with H2O (2 ϫ 50 mL) and brine
(2ϫ50 mL) and concentrated. Purification by silica gel column
chromatography (EtOAc/hexane, 1:24) afforded a mixture of 23
and 24 (0.18 g, 81% over two steps) as a colourless oil. [α]2D7 = +5.5
umn chromatography (EtOAc/hexane, 1:24) afforded 31 (0.31 g,
85% over two steps) as a colourless oil. [α]2D7 = –15.2 (c = 1.2,
CHCl ). IR (neat): ν = 3429, 2940, 2858, 2359, 1732, 1427, 1454,
˜
3
1238, 1107, 1071, 944, 821, 770, 703 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 7.69–7.62 (m, 4 H, ArH), 7.45–7.32 (m, 6 H, ArH),
5.66 (q, J = 7.9 Hz, 1 H, CH=CH), 5.48 (dd, J = 7.4, 15.5 Hz, 2
(c = 1.8, CHCl ). IR (neat): ν = 3430, 2938, 2862, 2360, 1730,
˜
3
1428, 1455, 1240, 1112, 1070, 943, 821, 770, 701 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 7.37–7.30 (m, 5 H, C6H5), 5.72–5.19 (m, 8 H, CH=CH), 5.41–5.21 (m, 4 H, CH=CH), 4.88 (dd, J = 7.7,
H, CH=CH), 4.80 (m, 1 H, CH-OCO), 4.50 (ABq, J = 11.9 Hz, 2 15.7 Hz, 1 H, CH=CH), 4.66 (dt, J = 3.8, 9.1 Hz, 1 H, CH-OCO),
H, OCH2-Ar), 4.08–3.87 (m, 2 H, CH-OH, CH-OAr), 2.88–2.75 4.31 (m, 1 H, CH-OSi), 3.64 (dt, J = 2.6, 8.7 Hz, 1 H, CH-OH),
(m, 2 H, CH=CH-CH2-CH=CH), 2.60–2.44 (m, 1.5 H, CH2- 2.76 (t, J = 7.0 Hz, 2 H, CH=CH-CH2-CH=CH), 2.47 (m, 1 H,
CH=CH), 2.45–2.37 (m, 1.5 H, CH2-CH=CH), 2.37–2.20 (m, 3 H,
CH2-CH=CH), 2.14–1.97 (m, 2 H, CH2-CO), 1.98–1.84 (m, 2 H,
CH2-CH=CH), 0.97 (t, J = 7.6 Hz, 2 H, CH3), 0.88 (t, J = 7.6 Hz,
3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.4, 138.6,
135.1, 132.2, 131.9, 131.3, 130.9, 128.3, 127.6, 127.5, 126.8, 125.0,
CH2-CH=CH), 2.39–2.17 (m, 7 H, CH2-CH=CH), 2.05 (quint., J
= 7.4 Hz, 2 H, CH2-CO), 1.98–1.80 (m, 2 H, CH2), 1.08 [s, 9 H,
SiC(CH3)3], 0.96 (t, J = 7.4 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, CDCl3): δ = 172.2, 137.1, 136.1, 135.8, 134.6, 134.0,
132.6, 131.1, 130.7, 129.6, 129.4, 128.9, 127.6, 127.4, 126.9, 125.0,
124.0,79.1, 73.7, 73.5, 70.4, 70.2, 33.6, 32.3, 31.9, 29.7, 29.4, 29.0, 124.1, 73.6, 73.5, 73.2, 36.2, 32.0, 29.7, 26.9, 25.5, 25.2, 22.7, 20.5,
25.6, 22.7, 20.6,14.2, 14.1 ppm. MS (ESI): m/z = 447 [M + Na]+.
19.2, 14.2 ppm. HRMS (ESI): calcd. for C36H48O4Si [M + H]+
573.3400; found 667.3417.
tert-Butyl {(8R)-8-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-9-[(4-meth-
oxybenzyl)oxy]-5-nonynyloxy}dimethylsilane (25): To a stirred solu-
tion of alcohol 10 (8.6 g, 21.18 mmol) in dry DMF (30 mL) was
added imidazole (3.16, 46.56 mmol) followed by TBDPSCl (5.8 g,
21.18 mmol) at 0 °C under a nitrogen atmosphere. The reaction
mixture was stirred for 12 h at room temperature. The reaction was
quenched with water (100 mL) after completion (monitored by
TLC) and extracted with diethyl ether (3ϫ100 mL). The combined
organic layer was washed with brine (2 ϫ 50 mL), dried with
Na2SO4 and concentrated. Purification by silica gel column
chromatography (EtOAc/hexane, 1:99) furnished 25 (13.2 g, 97%)
(9R,12S,13R)-9,12-Dihydroxy-13-[(2Z,5Z)-2,5-octadienyl]-1-oxa-
6,10-cyclotridecadien-2-one (1): To a stirred solution of macrolide
31 (0.14 g, 0.24 mmol) in dry THF (5.0 mL) was added acetic acid
(0.2 mL) followed by TBAF (1  in THF, 1.22 mL, 1.22 mmol) at
0 °C. The resulting mixture was stirred for an additional 18 h at
room temperature. THF and acetic acid were removed under re-
duced pressure. The residue was diluted with diethyl ether (15 mL)
and washed with Na2CO3 solution (2ϫ10 mL) followed by brine
(1ϫ10 mL). The organic layer was dried with anhydrous Na2SO4
and concentrated to afford a yellowish liquid. Purification by silica
gel column chromatography (EtOAc/hexane, 2:3) furnished the fi-
nal natural product amphidinolactone A (1) as a pale yellow vis-
as a colourless liquid. [α]2D7 = –4.7 (c = 1.5, CHCl ). IR (neat): ν =
˜
3
3468, 2928, 2862, 2360, 1615, 1510, 1465, 1280, 1250 cm–1
.
1H
cous liquid (0.069 g, 87%). [α]2D7 = –58.2 (c = 0.4, C6H6). IR (KBr,
NMR (300 MHz, CDCl3): δ = 7.67–7.60 (m, 4 H, ArH), 7.40–7.26
(m, 6 H, ArH), 7.08 (d, J = 8.3 Hz, 2 H, C6H4-OMe), 6.76 (d, J =
8.5 Hz, 2 H, C6H4-OMe), 4.28 (s, 2 H, OCH2-Ar), 3.92 (m, 1 H,
CH-OSi), 3.76 (s, 3 H, OCH3), 3.55 (t, J = 5.7 Hz, 1 H, CH-OAr),
3.48 (d, J = 4.5 Hz, 1 H, CH-OAr), 3.44–3.38 (m, 2 H, CH2-OSi),
2.30 (m, 2 H, CH2-CϵC), 2.07 (m, 2 H, CϵC-CH2), 1.57–1.40 (m,
4 H, CH2-CH2), 1.02 [s, 9 H, SiC(CH3)3], 0.86 [s, 9 H, -SiC-
(CH3)3], 0.02 [s, 6 H, -Si(CH3)2] ppm. 13C NMR (75 MHz, CDCl3):
δ = 158.9, 135.8, 134.0, 130.5, 129.5, 129.0, 127.6, 127.4, 113.5,
81.7, 76.6, 72.7, 71.0, 70.5, 62.6, 55.2, 31.9, 26.9, 25.9, 25.3, 24.5,
24.3, 19.2, 18.6, –5.30 ppm. MS (ESI): m/z = 667 [M + Na]+.
1
neat): ν = 3392, 2360, 1720, 1427, 703 cm–1. H NMR (500 MHz,
˜
C6D6): δ = 5.66 (m, 1 H, CH=CH), 5.59 (t, J = 6.3 Hz, 2 H,
CH=CH), 5.54 (dd, J = 6.3, 15.8 Hz, 1 H, CH=CH), 5.49–5.34 (m,
2 H, CH=CH), 5.30 (m, 1 H, CH=CH), 5.24 (m, 1 H, CH=CH),
5.03 (m, 1 H, CH-OCO), 4.00 (m, 1 H, CH-OH), 3.83 (m, 1 H,
CH-OH), 3.51 (br. s, 1 H, OH), 2.88 (m, 2 H, CH=CH-CH2-
CH=CH), 2.68 (m, 1 H, CH=CH-CH2-CH=CH), 2.51 (m, 1 H,
CH2-CH=CH), 2.39–2.29 (m, 2 H, CH2-CH=CH), 2.20 (m, 1 H,
CH2-CH=CH), 2.19 (m, 1 H, CH2-COO), 2.11 (m, 1 H, CH2-
COO), 2.06 (m, 2 H, CH2-CH3), 1.87 (m, 2 H, CH2-CH=CH), 1.26
(m, 2 H, CH2, OH), 0.96 (t, J = 7.8 Hz, 3 H, CH3) ppm. 13C NMR
(75 MHz, C6D6): δ = 171.7, 136.3, 132.2, 131.2, 130.7, 127.6, 125.1,
124.9, 74.0, 73.8, 72.4, 35.9, 32.1, 29.5, 26.0, 25.6, 22.9, 20.9,
14.4 ppm. HRMS (ESI): calcd. for C20H30O4 [M + Na]+ 357.2041;
found 357.2034.
(9R,12S,13R)-9-[1-(tert-Butyl)-1,1-diphenylsilyl]oxy-12-hydroxy-13-
[(2Z,5Z)-2,5-octadienyl]-1-oxa-6,10-cyclotridecadien-2-one (31): To
a stirred solution of primary alcohol 30 (0.45 g, 0.64 mmol) and
solid anhydrous NaHCO3 (0.2 g) in CH2Cl2 (15 mL) at 0 °C was
added Dess–Martin periodinane (0.55 g, 1.28 mmol). The reaction
mixture was stirred at 0 °C for 3 h. After completion of reaction
(TLC monitored), the mixture was filtered through filter paper. The
filtrate was washed with saturated NaHCO3 (2 mL). The aqueous
layer was extracted with CH2Cl2 (2ϫ10 mL). The combined or-
ganic fraction was dried with anhydrous Na2SO4 and concentrated.
Purification of the crude mass by flash chromatography (EtOAc/
hexane, 1:9) afforded aldehyde 3 in quantitative yield, which was
immediately used for the next reaction. To a flame-dried 50-mL
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, spectroscopic data and scanned cop-
1
ies of the H and 13C NMR spectra for new compounds.
Acknowledgments
P. P. D., M. R. P. and G. G. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi, India, for the award of
Eur. J. Org. Chem. 2010, 4775–4784
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4783

D. K. Mohapatra, J. S. Yadav et al.
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Received: April 22, 2010
Published Online: July 1, 2010
4784
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4775–4784