Stereoselective synthesis of a C19-C26 fragment of amphidinolides G and H

Article abstract of DOI:10.1016/j.tetasy.2006.10.024

A short, stereoselective synthesis of the C₁₉-C₂₆ segment of the structure of the cytotoxic macrolides amphidinolides G and H is reported. A precursor from the chiral pool has been used as the starting material.

Full text of DOI:10.1016/j.tetasy.2006.10.024

Tetrahedron: Asymmetry 17 (2006) 2938–2942
Stereoselective synthesis of a C19–C26 fragment of
amphidinolides G and H
b
a,
a
b
*
´
Pilar Formentın, Juan Murga, Miguel Carda and J. Alberto Marco
aDepart. de Q. Inorga´nica y Orga´nica, Univ. Jaume I, 12071 Castello´n, Spain
bDepart. de Q. Orga´nica, Univ. de Valencia, 46100 Burjassot, Valencia, Spain
Received 9 October 2006; accepted 20 October 2006
Available online 15 November 2006
Abstract—A short, stereoselective synthesis of the C19–C26 segment of the structure of the cytotoxic macrolides amphidinolides G and H
is reported. A precursor from the chiral pool has been used as the starting material.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(Fig. 1). Hydrolytic lactone ring-opening of these two
isomeric macrolides would give the same open-chain hy-
droxy acid. Herein, we report a short synthesis of a C19–
C26 fragment common to the two natural compounds.12
This fragment corresponds to compound 1, which contains
four out of the nine sp3 stereocenters of both amphidino-
lides. Our retrosynthetic analysis for 1 is shown in Scheme
Marine microorganisms belonging to several phyla have at-
tracted the attention of natural product chemists because
of their role as the actual producers of many bioactive
metabolites, initially found in, and deemed specific to, var-
ious marine macroorganisms.1 Amongst these metabolites,
the amphidinolides are a family of macrolides isolated from
marine dinoflagellates of the Amphidinium genus that are
symbiotic to Amphiscolops flatworm species.2 These macro-
lides have been found to display a range of pharmacologi-
cal properties, most particularly cytotoxicity against
several tumoral cell lines. Amphidinolides B, G, H, and
N have been shown to be very potent in this aspect
(IC50 < 1 nm), a feature which renders them promising
for cancer chemotherapy. In the case of amphidinolide
H, its pharmacological action has been related to its ability
to covalently bind on actin subdomain 4 with subsequent
stabilization of the actin filaments.3
OH
O
OH
19
HO
OH
26
1
O
O
O
Amphidinolide G
OH
O
2. Results and discussion
OH
In view of the aforementioned pharmacological properties,
it is not surprising that the amphidinolides have attracted
considerable interest from the synthetic community. In
fact, total syntheses of amphidinolides A,4 J,5 K,6 P,7,8
T,9 W,10 and X11 have already been reported. We have re-
cently started a research project aimed at the stereoselective
synthesis of the highly potent amphidinolides G and H
HO
OH
O
O
O
Amphidinolide H
*
Corresponding author. Tel.: +34 964 728174; fax: +34 964 728214;
e-mail: jmurga@qio.uji.es
Figure 1. Proposed structures of amphidinolides G and H.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.024

P. Forment´ın et al. / Tetrahedron: Asymmetry 17 (2006) 2938–2942
2939
O
R´
O
O
R
EtO2C
OH
b
19
O
OR
OTBDPS
O
O
O
O
HO
OH
OH
OTES
4
5
R = H
6
7
R = Me R´ = H
R = H R´ = Me
a
c
d
R = TBDPS
26
TBDPSO
TBDPSO
HO
Target fragment
OH
2
1
e
EtO2C
EtO2C
OTBDPS
OTBDPS
OH
OH
OH
OR
8
2
EtO2C
O
O
O
O
OH
O
O
HO
f
HO
EtO2C
OH
OH
4
OTBDPS
3
OTBDPS
g
OTBDPS
EtO2C
OH
Scheme 1. Retrosynthetic analysis of the target C19–C26 compound 1.
9
R = H
10 R = TES
1 and relies on a starting material from the chiral pool, the
known lactone 4.
h
O
O
Scheme 2 depicts the actual synthetic sequence which led to
1. Compound 7, a silylated derivative of lactone 3 (Scheme
1) was obtained with an improved yield by means of a mod-
ified procedure. Thus, lactone 4, prepared as described from
D-glutamic acid,13,14 was first silylated15 to 5 and then meth-
ylated via the lithium enolate.13,16 This gave lactone 613 in
80% yield as the major component of a 92:8 mixture with
its diastereomer 7. The mixture was enolized again and
kinetically protonated at a low temperature with a sterically
hindered proton donor.17,18 In this way, a 96:4 mixture of 7
(major) and 6 was obtained. DIBAL reduction of 7 gave an
aldehyde, which was immediately subjected to Wittig
olefination. The resulting E-ester 2 was then submitted to
a Sharpless asymmetric dihydroxylation,19 which provided
trihydroxy ester 8 as a single stereoisomer. Protection of
the vicinal diol as an acetonide, followed by silylation of
the remaining free alcohol, furnished compound 10, with
all the stereogenic centers already in place. Hydrolysis of
the ethyl ester group was performed under mild condi-
tions,20 due to the potential base sensitivity of the silyl
groups. The resulting acid was then converted into the Wein-
reb amide 11.21 Finally, treatment of the latter with methyl-
magnesium bromide provided the desired methyl ketone 1.22
i
O
O
OTBDPS
OTBDPS
OTES
Me(OMe)NOC
OTES
O
1
11
Scheme 2. Reagents and conditions: (a) Ref. 15; (b) LDA, THF, ꢀ78 ꢁC,
40 min, then MeI, ꢀ78 ꢁC, 2 h, then TBDPSCl, NEt3, ꢀ78 ꢁC, 30 min,
80% overall (dr 92:8); (c) LDA, THF, ꢀ78 ꢁC, 40 min, then 2,6-di-tert-
butylphenol, ꢀ78 ꢁC, 1 h, then TBDPSCl, NEt3, ꢀ78 ꢁC, 30 min (dr 96:4),
followed by chromatographic separation, 67% overall; (d) DIBAL,
CH2Cl2, ꢀ78 ꢁC, 30 min, then Ph3P@CHCO2Et, toluene, 80 ꢁC, 16 h
(E/Z, 93:7), followed by chromatographic separation, 85%; (e) AD-mix-a,
MeSO2NH2, aq tert-BuOH, 0 ꢁC, 18 h, 95%; (f) 2,2-dimethoxypropane,
˚
CSA, 3 A MS, acetone, rt, 18 h, 76%; (g) TESOTf, 2,6-lutidine, CH2Cl2,
rt, 1 h, 97%; (h) Me3SiOK, THF, rt, 1 h, then MeNH(OMe)HCl, NMM,
EDAC, CH2Cl2, rt, 18 h, 89% overall; (i) MeMgBr, THF, 0 ꢁC, 1 h, 81%.
Abbreviations and acronyms: TBDPS, tert-butyldiphenylsilyl; CSA,
camphorsulfonic acid; TES, triethylsilyl; EDAC, N-(3-dimethylaminoprop-
yl)-N0-ethylcarbodiimide hydrochloride; NMM, N-methylmorpholine.
NMR and the triplet centered at 77.00 ppm for 13C
NMR data). The multiplicities of the 13C NMR signals
were determined with the DEPT pulse sequence. Mass
spectra were run by the electron impact (EIMS, 70 eV) or
with the fast atom bombardment mode (FABMS,
m-nitrobenzyl alcohol matrix) on a VG AutoSpec mass
spectrometer. IR data are only given for compounds with
relevant functions (OH, C@O) and were recorded as oily
films on NaCl plates (oils) or as KBr pellets (solids).
Optical rotations were measured at 25 ꢁC. Reactions which
required an inert atmosphere were carried out under N2
with flame-dried glassware. Et2O and THF were freshly
distilled from sodium-benzophenone ketyl. Dichloro-
methane was freshly distilled from CaH2. Commercially
available reagents were used as received. Unless detailed
otherwise, ‘work-up’ means pouring the reaction mixture
into 5% aq NaHCO3 (if the reaction was carried out in
an acidic medium) or into satd aq NH4Cl (if it was carried
out in a basic medium), extraction with the indicated
solvent, then washing again the organic layer with brine,
drying over anhydrous Na2SO4 or MgSO4 and elimination
3. Conclusions
A short, stereoselective synthesis of the C19–C26 fragment
of the cytotoxic macrolides amphidinolides G and H has
been achieved. Studies toward the total synthesis of both
natural lactones are underway.
4. Experimental
4.1. General
NMR spectra were measured at 500 MHz in CDCl3 solu-
tion at 25 ꢁC. The signals of the deuterated solvent (CDCl3)
1
were taken as the reference (the singlet at d 7.25 for H

2940
P. Forment´ın et al. / Tetrahedron: Asymmetry 17 (2006) 2938–2942
of the solvent in vacuo. When the solutions were filtered
through a Celite pad, the pad was additionally washed with
the same solvent, and the washing liquids were incorpo-
rated to the main organic layer. The material obtained
was then chromatographed on a silica gel column (60–
200 lm) with the indicated eluent.
mers. Careful column chromatography of the residue on sil-
ica gel (hexanes–EtOAc, 80:20) provided E-2 (936 mg, 85%).
Oil, [a]D = ꢀ14.0 (c 0.9, CHCl3); IR mmax (cmꢀ1) 3490 (br,
OH), 1716 (C@O); dH (500 MHz, CDCl3): 7.70–7.65 (4H,
m), 7.50–7.40 (6H, m), 6.90 (1H, dd, J = 15.7, 7.5 Hz),
5.74 (1H, dd, J = 15.7, 1.1 Hz), 4.19 (2H, q, J = 7.0 Hz),
3.78 (1H, m), 3.67 (1H, dd, J = 10.0, 3.5 Hz), 3.49 (1H,
dd, J = 10.0, 7.2 Hz), 2.49 (1H, sext, J = 7.0 Hz), 2.45
(OH, d, J = 4.0 Hz), 1.60 (1H, m), 1.33 (1H, m), 1.30 (3H,
t, J = 7.0 Hz), 1.08 (9H, s), 1.05 (3H, d, J = 6.5 Hz); dC
(125 MHz, CDCl3): d 166.8, 133.1 (·2), 19.3 (C), 154.1,
135.5 (·4), 129.9 (·2), 127.8 (·4), 119.5, 69.5, 32.8 (CH),
68.0, 60.2, 38.7 (CH2), 26.9 (·3), 18.9, 14.3 (CH3). HR-
EIMS m/z (%) = 383.1642 (M+ꢀt-Bu, 2), 337 (16), 199
(100). Calcd for C26H36O4Si–t-Bu, 383.1678. Anal. Calcd
for C26H36O4Si: C, 70.87; H, 8.23. Found, C, 70.92; H, 8.19.
4.2. (3S,5R)-5-(tert-Butyldiphenylsilyloxymethyl)-3-methyl-
dihydrofuran-2(3H)-one, 6
Lactone 5 (2.13 g, 6 mmol) was dissolved in dry THF
(120 mL) and treated at ꢀ78 ꢁC under N2 with LDA
(9.0 mL of a 2 M solution in THF, 18 mmol). The reaction
mixture was then stirred for 40 min at ꢀ78 ꢁC, followed by
the addition of MeI (2.25 mL, 36 mmol). After stirring at
ꢀ78 ꢁC for 2 h, Et3N (530 lL, 3.8 mmol), and TBDPSCl
(780 lL, 3.0 mmol) were added and the stirring was contin-
ued for 30 min at ꢀ78 ꢁC. Work-up (extraction with
EtOAc) and column chromatography on silica gel (hex-
anes–Et2O, 95:5) yielded 613 (1.77 g, 80%) as a 92:8 mixture
with 7, which was used as such in the next step.
4.5. (2R,3S,4R,6R)-7-(tert-Butyldiphenylsilyloxy)-2,3,6-tri-
hydroxy-4-methylheptanoic acid ethyl ester, 8
Ethyl ester 2 (881 mg, 2 mmol) was dissolved in a mixture
of tert-BuOH (10 mL) and water (10 mL). AD-mix-a
(8.4 g) and MeSO2NH2 (570 mg, 6 mmol) were then added
at 0 ꢁC. The reaction mixture was then stirred for 18 h at
the same temperature. After this time, Na2SO3 (3 g) was
added, with subsequent stirring for 45 min. Work-up
(extraction with CH2Cl2) and column chromatography on
silica gel (hexanes–EtOAc, 40:60) furnished trihydroxy
ester 8 (902 mg, 95%). Oil, [a]D = +9.1 (c 1.5, CHCl3); IR
mmax (cmꢀ1) 3440 (br, OH), 1738 (C@O); dH (500 MHz,
CDCl3): 7.70–7.65 (4H, m), 7.45–7.35 (6H, m), 4.26 (3H,
m), 3.82 (1H, m), 3.69 (1H, m), 3.63 (1H, dd, J = 10.0,
3.8 Hz), 3.51 (1H, dd, J = 10.0, 7.3 Hz), 3.40 (OH, br s),
3.00 (OH, br s), 2.90 (OH, br s), 2.04 (1H, br heptuplet,
J = 7.0 Hz), 1.63 (1H, ddd, J = 14.5, 10.3, 5.0 Hz), 1.30
(3H, t, J = 7.0 Hz), 1.23 (1H, ddd, J = 14.5, 8.5, 2.3 Hz),
1.08 (9H, s), 1.05 (3H, d, J = 7.0 Hz); dC (125 MHz,
CDCl3): 173.8, 133.2 (·2), 133.1 (·2), 19.2 (C), 135.5
(·4), 129.8 (·2), 127.7 (·2), 76.1, 71.3, 70.4, 34.0 (CH),
68.5, 61.9, 36.1, (CH2), 26.9 (·3), 16.1, 14.1 (CH3). HR
FABMS m/z 497.2341 [M+Na+], calcd for C26H38O6SiNa,
497.2335. Anal. Calcd for C26H38O6Si: C, 65.79; H, 8.07.
Found, C, 65.74; H, 7.98.
4.3. (3R,5R)-5-(tert-Butyldiphenylsilyloxymethyl)-3-meth-
yldihydrofuran-2(3H)-one, 7
The 6/7 lactone mixture from above (1.47 g, 4 mmol) was
dissolved in dry THF (80 mL) and treated at ꢀ78 ꢁC under
N2 with LDA (6.0 mL of a 2 M solution in THF, 12 mmol).
The reaction mixture was then stirred for 40 min at ꢀ78 ꢁC,
followed by addition of 2,6-di-tert-butylphenol (4.95 g, ca.
24 mmol). After stirring at ꢀ78 ꢁC for 1 h, Et3N (350 lL,
2.5 mmol) and TBDPSCl (520 lL, 2.0 mmol) were added
and stirring was continued for 30 min at ꢀ78 ꢁC. Work-
up (extraction with EtOAc) and column chromatography
on silica gel (hexanes–Et2O, 95:5) afforded pure 7
(985 mg, 67%). Solid, mp 85–86 ꢁC, [a]D = ꢀ13.4 (c 1.1,
CHCl3); IR mmax (cmꢀ1) 1767 (C@O); dH (500 MHz,
CDCl3): 7.70–7.65 (4H, m), 7.50–7.40 (6H, m), 4.47 (1H,
m), 3.87 (1H, dd, J = 11.5, 3.5 Hz), 3.75 (1H, dd,
J = 11.5, 3.5 Hz), 2.68 (1H, m), 2.39 (1H, m), 1.85 (1H,
m), 1.30 (3H, d, J = 7.0 Hz), 1.06 (9H, s); dC (125 MHz,
CDCl3): 179.4, 133.1, 132.9, 19.2 (C), 135.6 (·2), 135.5
(·2), 129.8 (·2), 127.8 (·4), 78.1, 32.1 (CH), 64.7, 35.4
(CH2), 26.8 (·3), 15.4 (CH3). HR FABMS m/z 369.1911
[M+H+], calcd for C22H29O3Si, 369.1886. Anal. Calcd for
C22H28O3Si: C, 71.83; H, 8.39. Found: C, 71.84; H, 8.35.
4.6. (4R,5S)-5-[(2R,4R)-5-(tert-Butyldiphenylsilyloxy)-4-
hydroxypent-2-yl]-2,2-dimethyl-1,3-dioxolane-4-carboxylic
acid ethyl ester, 9
4.4. (4R,6R)-7-(tert-Butyldiphenylsilyloxy)-6-hydroxy-4-
methylhept-2E-enoic acid ethyl ester, 2
Trihydroxy ester 8 (712 mg, 1.5 mmol) was dissolved in a
mixture of acetone (15 mL) and 2,2-DMP (4 mL) and trea-
˚
Lactone 7 (920 mg, 2.5 mmol) was dissolved in dry CH2Cl2
(15 mL) and treated at ꢀ78 ꢁC under N2 with DIBAL
(2.75 mL of a 1 M solution in hexane, 2.75 mmol). The reac-
tion mixture was then stirred for 30 min at ꢀ78 ꢁC. After
this time, MeOH was added (2 mL), with subsequent stir-
ring for 1 h. Work-up (extraction with AcOEt) and solvent
removal in vacuo provided a crude lactol that was employed
as such in the following step. It was dissolved in dry toluene
(15 mL) and treated with Ph3P@CHCOOEt (1.22 g,
3.5 mmol). The reaction mixture was then stirred for 16 h
at 80 ꢁC. Solvent removal under reduced pressure provided
a crude oil containing a 93:7 mixture of the E/Z stereoiso-
ted with camphorsulfonic acid (23 mg, 0.1 mmol) and 3 A
MS (500 mg). The reaction mixture was then stirred for
18 h and filtered through a pad of Celite. Removal of all
volatiles in vacuo and column chromatography of the res-
idue on silica gel (hexanes–EtOAc, 70:30) provided alcohol
9 (587 mg, 76%). Oil, [a]D = ꢀ2.0 (c 1.7, CHCl3); IR mmax
(cmꢀ1) 3530 (br, OH), 1753 (C@O); dH (500 MHz, CDCl3):
7.70–7.65 (4H, m), 7.45–7.35 (6H, m), 4.30–4.20 (3H, m),
4.13 (1H, dd, J = 7.0, 4.8 Hz), 3.85 (1H, m), 3.67 (1H,
dd, J = 10.0, 3.5 Hz), 3.52 (1H, dd, J = 10.0, 7.3 Hz),
2.50 (OH, d, J = 3.5 Hz), 2.16 (1H, m), 1.58 (1H, ddd,
J = 14.0, 10.0, 3.8 Hz), 1.45 (3H, s), 1.43 (3H, s), 1.28

P. Forment´ın et al. / Tetrahedron: Asymmetry 17 (2006) 2938–2942
2941
(3H, t, J = 7.0 Hz), 1.23 (1H, m), 1.10 (9H, s), 1.01 (3H, d,
J = 7.0 Hz); dC (125 MHz, CDCl3): 171.5, 133.2 (·2),
110.8, 19.2 (C), 135.5 (·4), 129.8 (·2), 127.7 (·2), 83.1,
76.8, 69.4, 31.7 (CH), 68.6, 61.2, 36.2, (CH2), 26.9 (·4),
25.6, 14.1, 13.8 (CH3). HR EIMS m/z (% rel. int.)
499.2522 (M+ꢀMe, 1), 453 (10), 399 (30), 325 (80), 241
(73), 199 (100). Calcd for C29H42O6Si–Me, 499.2516. Anal.
Calcd for C29H42O6Si: C, 67.67; H, 8.22. Found, C, 67.60;
H, 8.14.
4.7 Hz), 3.43 (1H, dd, J = 10.0, 7.0 Hz), 3.21 (3H, br s),
1.99 (1H, m), 1.58 (1H, ddd, J = 14.0, 10.5, 2.5 Hz), 1.47
(6H, s), 1.37 (1H, ddd, J = 14.0, 9.2, 2.5 Hz), 1.05 (9H,
s), 1.01 (3H, d, J = 6.8 Hz), 0.88 (9H, t, J = 8 Hz), 0.50
(6H, q, J = 8 Hz); dC (125 MHz, CDCl3): 176.0 (br),
133.7, 133.6, 110.5, 19.2 (C), 135.6 (·4), 129.6 (·2), 127.7
(·4), 82.7, 74.7 (br), 70.6, 31.6 (CH), 68.4, 38.3, 5.0 (·3)
(CH2), 61.6 (br), 32.4 (br), 27.3, 26.9 (·3), 26.2, 15.0, 6.9
(·3) (CH3). HR FABMS m/z 644.3835 [M+H+], calcd
for C35H58NO6Si2, 644.3803. Anal. Calcd for C35H57NO6-
Si2, C, 65.28; H, 8.92. Found, C, 65.18; H, 8.87.
4.7. (4R,5S)-5-[(2R,4R)-5-(tert-Butyldiphenylsilyloxy)-4-
(triethylsilyloxy)pent-2-yl]-2,2-dimethyl-1,3-dioxolane-4-
carboxylic acid ethyl ester, 10
4.9. 1-{5-[(2R,4R)-5-(tert-Butyldiphenylsilyloxy)-4-(triethyl-
silyloxy)pent-2-yl]-(4R,5S)-2,2-dimethyl-[1,3]dioxolan-4-yl}-
ethanone, 1
Ester 9 (515 mg, 1.0 mmol) was dissolved under N2 in dry
CH2Cl2 (10 mL) and treated sequentially with 2,6-lutidine
(175 lL, 1.5 mmol) and TESOTf (270 lL, 1.2 mmol). The
reaction mixture was then stirred for 1 h at room tempera-
ture and worked up (extraction with CH2Cl2). Column
chromatography on silica gel (hexane–EtOAc, 80:20) gave
ester 10 (610 mg, 97%). Oil, [a]D = +7.1 (c 1.6, CHCl3); IR
Amide 11 (322 mg, 0.5 mmol) was dissolved under N2 at
0 ꢁC in dry THF (5 mL) and treated with MeMgBr
(500 lL of a 3 M solution in Et2O, 1.5 mmol). The reaction
mixture was then stirred for 1 h at 0 ꢁC and worked up
(extraction with AcOEt). Column chromatography on
silica gel (hexane–EtOAc, 95:5) provided ketone 1 (242
mg, 81%). Oil, [a]D = +17.7 (c 0.8, CHCl3); IR mmax
(cmꢀ1) 1720 (C@O); HR FABMS m/z 599.3586 [M+H+],
calcd for C34H55O5Si2, 599.3588. Anal. Calcd for C34H54-
O5Si2: C, 68.18; H, 9.09. Found, C, 68.07; H, 8.99. For
NMR data see Ref. 22.
m
max (cmꢀ1) 1758 (C@O); dH (500 MHz, CDCl3): 7.70–7.65
(4H, m), 7.45–7.35 (6H, m), 4.30 (1H, d, J = 6.7 Hz), 4.30–
4.20 (2H, m), 4.10 (1H, dd, J = 6.5, 5.5 Hz), 3.80 (1H, m),
3.62 (1H, dd, J = 10.0, 5.0 Hz), 3.48 (1H, dd, J = 10.0,
7.0 Hz), 2.04 (1H, m), 1.64 (1H, ddd, J = 13.5, 10.3,
3.0 Hz), 1.55 (1H, ddd, J = 13.5, 8.8, 3.3 Hz), 1.48 (3H,
s), 1.46 (3H, s), 1.29 (3H, t, J = 7.0 Hz), 1.08 (9H, s),
1.03 (3H, d, J = 7.0 Hz), 0.90 (9H, t, J = 8 Hz), 0.52 (6H,
q, J = 8 Hz); dC (125 MHz, CDCl3): 171.6, 133.6 (·4),
110.9, 19.2 (C), 135.5 (·4), 129.6 (·2), 127.6 (·4), 83.7,
77.1, 70.6, 31.7 (CH), 68.2, 61.2, 38.4, 5.0 (·3) (CH2),
27.1, 26.9 (·3), 25.8, 14.3, 14.1, 6.8 (·3), (CH3). HR EIMS
m/z (% rel. int.) 613.3429 (M+ꢀMe, 10), 571 (13), 313
(100), 183 (86), 169 (84), 135 (70). Calcd for
C35H56O6Si2–Me, 613.3380. Anal. Calcd for C35H56O6Si2:
C, 66.83; H, 8.97. Found, C, 66.75; H, 8.84.
Acknowledgements
Financial support has been granted by the Spanish Minis-
try of Education and Science (Projects CTQ2005-06688-
´
C02-01/02), and by the Consellerıa d’Empresa, Universitat
i Ciencia de la Generalitat Valenciana (Projects GV05/52,
ACOMP06/006 and ACOMP06/008). P.F. and J.M. thank
the Spanish Ministry of Education and Science for a Juan
´
de la Cierva and a Ramon y Cajal contract, respectively.
4.8. (4R,5S)-5-[(2R,4R)-5-(tert-Butyldiphenylsilyloxy)-4-
(triethylsilyloxy)pent-2-yl]-2,2-dimethyl-1,3-dioxolane-4-
carboxylic acid N-methoxy-N-methylamide, 11
References
Ethyl ester 10 (503 mg, 0.8 mmol) was dissolved in dry
THF (30 mL). Then, TMSOK (1.54 g, 12 mmol) was
added, with subsequent stirring for 1 h. A solution of satu-
rated aqueous citric acid was then added, and the stirring
continued for 20 min at room temperature. After this time,
work-up (extraction with EtOAc) and evaporation under
reduced pressure provided a crude oily acid that was used
directly in the next step.
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borty, T. K.; Das, S. Curr. Med. Chem. 2001, 1, 131–149; (e)
Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure Appl.
Chem. 2003, 75, 337–342; (f) Kobayashi, J.; Tsuda, M. Nat.
Prod. Rep. 2004, 21, 77–93; (g) Kobayashi, J.; Tsuda, M.
Phytochem. Rev. 2004, 3, 267–274; (h) Kang, E. J.; Lee, E.
Chem. Rev. 2005, 105, 4348–4378.
3. Usui, T.; Kazami, S.; Dohmae, N.; Mashimo, Y.; Kondo, H.;
Tsuda, M.; Terasaki, A. G.; Ohashi, K.; Kobayashi, J.;
Osada, H. Chem. Biol. 2004, 11, 1269–1277.
4. (a) Trost, B. M.; Wrobleski, S. T.; Chisholm, J. D.;
Harrington, P. E.; Jung, M. J. Am. Chem. Soc. 2005, 127,
13589–13597; (b) Trost, B. M.; Harrington, P. E.; Chisholm,
J. D.; Wrobleski, S. T. J. Am. Chem. Soc. 2005, 127, 13598–
13610.
The crude compound from above was dissolved under N2
in dry CH2Cl2 (30 mL) and treated sequentially at 0 ꢁC
with NMM (264 lL, 2.4 mmol), EDAC (460 mg,
2.4 mmol) and Me(MeO)NHÆHCl (234 mg, 2.4 mmol).
The reaction mixture was stirred for 18 h at room temper-
ature. Work-up (extraction with CH2Cl2) and column
chromatography on silica gel (hexane–AcOEt, 90:10)
yielded 11 (458 mg, 89%). Oil, [a]D = +13.2 (c 1.1, CHCl3);
IR mmax (cmꢀ1) 1674 (C@O); dH (500 MHz, CDCl3): 7.70–
7.65 (4H, m), 7.45–7.35 (6H, m), 4.58 (1H, br s), 4.32 (1H,
m), 3.76 (1H, m), 3.72 (3H, s), 3.58 (1H, dd, J = 10.0,

2942
P. Forment´ın et al. / Tetrahedron: Asymmetry 17 (2006) 2938–2942
5. Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998, 120,
16. Partial desilylation takes place during lithium enolate meth-
ylation. Thus, resilylation of the reaction mixture in situ gives
rise to improved yields in 6.
17. See also: Martin, S. F.; Dwyer, M. P.; Hartmann, B.; Knight,
K. S. J. Org. Chem. 2000, 65, 1305–1318.
18. Resilylation in situ of the reaction mixture gives rise to
improved yields of 7.
19. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
11198–11199.
6. Williams, D. R.; Meyer, K. G. J. Am. Chem. Soc. 2001, 123,
765–766.
7. Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am.
Chem. Soc. 2005, 127, 17921–17937.
8. The nonnatural antipode of amphidinolide P has also been
obtained: (a) Williams, D. R.; Myers, B. J.; Mi, L. Org. Lett.
2000, 2, 945–948; (b) Chakraborty, T. K.; Das, S. Tetrahe-
dron Lett. 2001, 42, 3387–3390.
9. For a review on syntheses of members of the amphidinolide T
group, see: Colby, E. A.; Jamison, T. F. Org. Biomol. Chem.
2005, 3, 2675–2684.
´
Chem. Rev. 1994, 94, 2483–2547; (b) Marko, I. E.; Svendsen,
J. S. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 2000;
Vol. II, Chapter 20.
20. Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25,
5831–5834.
10. Ghosh, A. K.; Gong, G. J. Org. Chem. 2006, 71, 1085–1093.
11. Lepage, O.; Kattnig, E.; Furstner, A. J. Am. Chem. Soc. 2004,
21. Collier, P. N.; Campbell, A. D.; Patel, I.; Raynham, T.-M.;
Taylor, R. J. K. J. Org. Chem. 2002, 67, 1802–1815.
22. None of the intermediates en route towards 1 nor compound
1 itself were crystalline. Therefore, X-ray analyses aimed at
configurational confirmation could not be performed. How-
ever, the key asymmetric transformation used here (Sharpless
dihydroxylation) is a well-known process with a safely
predictable stereochemical outcome. We are thus confident
that the structure of synthetic intermediate 1 is that depicted
in Scheme 2. Furthermore, a comparison of 1H/13C NMR
chemical shift and coupling constant values within a similar
fragment A12b (see table below, the atom numbering of
Scheme 1 is also used for A, coupling constant values are
given in parentheses) gives support to our structural assign-
ment (the observed differences can be accounted for with the
different protecting groups at one end of the carbon chain).
¨
126, 15970–15971.
12. Similar fragments of amphidinolide H and of the closely
related amphidinolide H2 have been prepared using other
methodologies: (a) Chakraborty, T. K.; Suresh, V. R.
Tetrahedron Lett. 1998, 39, 7775–7778; (b) Liesener, F. P.;
Kalesse, M. Synlett 2005, 2236–2238; (c) Liesener, F. P.;
Jannsen, U.; Kalesse, M. Synthesis 2006, 2590–2602.
13. Herdeis, C.; Lutsch, K. Tetrahedron: Asymmetry 1993, 4,
¨
121–131 (corr., Tetrahedron: Asymmetry, 1993, 4, 151).
14. (a) Gringore, O. H.; Rouessac, F. P. Org. Synth. Coll. Vol.
VII 1990, 99–102; (b) Herdeis, C. Synthesis 1986, 232–233.
15. (a) Hanessian, S.; Murray, P. J. Tetrahedron 1987, 43, 5055–
5072; (b) Beach, J. W.; Kim, H. O.; Jeong, L. S.; Nampalli, S.;
Islam, Q.; Ahn, S. K.; Babu, J. R.; Chu, C. K. J. Org. Chem.
1992, 57, 3887–3894.
O
O
26
O
O
19
O
A
Atom
1
A12b
2.27 s, 3H
4.07 d (7.3)
4.01 dd (7.3, 4.4)
2.04–1.95 m
1.72 ddd (13.7, 9.1, 4.4)
1.42–1.35 m
4.17 dddd (8.9, 7, 5.9, 4.1)
4.04 dd (8, 6.1)
3.49 dd (7.7, 7.3)
1.00 d (6.8)
Atom
1
A12b
H-19
H-21
H-22
H-23
H-24
H-240
H-25
H-26
H-260
MeC23
2.25 s, 3H
4.11 d (7)
3.98 dd (7, 5.5)
1.95 m
1.58 ddd (13.5, 10, 3)
1.48 m
C-19
C-20
C-21
C-22
C-23
C-24
C-25
C-26
27.0
208.8
83.4
82.2
31.8
38.5
70.6
68.2
14.4
110.2
26.5
26.3
6.8 (CH3)
5.0 (CH2)
135.7 (CH)
133.7 (C)
133.6 (C)
129.6 (CH)
127.7 (CH)
26.9 (CH3)
19.2 (C)
27.0
209.2
83.0
81.3
32.5
37.6
73.8
69.8
13.8
110.2
26.5
26.1
—
3.75 m
3.59 dd (10, 5)
3.44 dd (10, 7)
1.00 d, 3H (6.6)
MeC23
Me2C (acetal)
Me2C (acetal)
TES
1.45 s, 3H
1.39 s, 3H
0.88 t, 9H (8)
0.50 q, 6H (8)
1.44 s (3H)
1.38 s (3H)
—
TES
TBDPS
—
TBDPS
7.70–7.65, 4H, m
7.45–7.35, 6H, br m
1.05 s, 9H
—
—
—