Stereoselective synthesis of a C1-C18 fragment of amphidinolides G and H

Article abstract of DOI:10.1016/j.tet.2013.02.062

A stereoselective synthesis of a C1-C18 segment of the structure of the cytotoxic macrolides amphidinolides G and H is reported. The target compound was retrosynthetically disconnected into three fragments. In the synthetic sense, connection of the fragme

Full text of DOI:10.1016/j.tet.2013.02.062

Tetrahedron 69 (2013) 3192e3196
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of a C1ꢀC18 fragment of amphidinolides
G and H
,
Jorge García-Fortanet a b, Pilar Formentín a, Santiago Díaz-Oltra a, Juan Murga a,
,
c,
*
Miguel Carda a , J. Alberto Marco
*
a
ꢀ
ꢀ
ꢀ
ꢀ
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, 12071 Castellon, Spain
b Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
c
ꢀ
Depart. de Q. Organica, Univ. de Valencia, 46100 Burjassot, Valencia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 January 2013
Received in revised form 9 February 2013
Accepted 18 February 2013
Available online 26 February 2013
A stereoselective synthesis of a C1eC18 segment of the structure of the cytotoxic macrolides amphidi-
nolides G and H is reported. The target compound was retrosynthetically disconnected into three frag-
ments. In the synthetic sense, connection of the fragments was made by means of a Stille coupling and
a JuliaeKocienski olefination. Precursors from the chiral pool were used as the starting materials.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrolides
Amphidinolides
JuliaꢀKocienski olefination
Stille coupling
OhiraꢀBestmann reaction
Alkyne silylstannation
1. Introduction
Marine microorganisms belonging to several phyla have
attracted 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, various marine microorganisms.1
Amongst these metabolites, the amphidinolides are a family of
macrolides isolated from marine dinoflagellates of the Amphidi-
nium genus that are symbiotic to Amphiscolops flatworm species.2
These macrolides have been found to display a range of pharma-
cological properties, most particularly cytotoxicity against several
tumoral cell lines. Amphidinolides G 1 and H 2 (Fig.1, now renamed
G1 and H1) have been shown to be very potent in this aspect
(IC50<1 nm), a feature which renders these compounds promising
for cancer chemotherapy. In the specific case of amphidinolide H,
its pharmacological action has been related to its ability to co-
valently bind on actin subdomain 4 with subsequent stabilization
of the actin filaments.3 In view of these pharmacological properties,
it is not surprising that the amphidinolides have attracted consid-
erable interest from the synthetic community. Indeed, many total
syntheses of various amphidinolides have already been reported.4
Fig. 1. Structures of amphidinolides G (1) and H (2).
For the reasons stated above, we have been interested in per-
forming a stereoselective synthesis of macrolides 1 and 2. Hydro-
lytic lactone ring-opening of these two isomeric lactones would
give the same open-chain hydroxy acid. Herein, we report a short
* Corresponding authors. E-mail address: alberto.marco@uv.es (J. Alberto Marco).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.062

J. García-Fortanet et al. / Tetrahedron 69 (2013) 3192e3196
3193
synthesis of a C1eC18 fragment common to these two natural
compounds.5,6
Our retrosynthetic analysis for 1, also valid for 2, is shown in
Fig. 2. Scission of the C1eO and C18eC19 bonds via lactone ring-
opening and retroaldol cleavage gives rise to compounds 3 (frag-
ment C1eC18), our present target, and 4 (fragment C19eC26), which
has previously been prepared by us.5e Further bond scissions in 3 at
C6]C7 via JuliaeKocienski olefination7 and at C13eC14 via Stille
coupling8 lead to the synthetic subtargets 5e8.
Scheme 1. Synthesis of sulfone 6. Acronyms and abbreviations: TBDPS, tert-butyldiphe-
nylsilyl; MOM, methoxymethyl; DIPEA, N,N-diisopropyl ethylamine; TBAF, tetrabuty-
lammonium fluoride; PT, 1-phenyl-1H-tetrazol-5-yl; DIAD, diisopropyl azodicarboxylate.
Scheme 2. Synthesis of iodide 7. Acronyms and abbreviations: Bn, benzyl.
aldehyde. Homologation of the latter to alkyne 19 was best per-
formed in this case with the aid of the OhiraꢀBestmann pro-
cedure.14 Desilylation of 19 gave 20, projected to be the next
member in the sequence leading to 8.
Fig. 2. Retrosynthetic disconnection of amphidinolide G (1) (for acronyms and ab-
breviations, see below).
2. Results and discussion
The synthesis of tetrazolyl sulfone 6 was performed as depicted
in Scheme 1. Conversion of 1,4-butanediol into the known primary
allylic alcohol 9 was performed in 4 steps following literature
procedures.9 Alcohol protection in 9 afforded 10, which was desi-
lylated to primary alcohol 11. The latter was then converted into 6
by means of a standard procedure via sulfide 12.
The known iodide 7 was prepared as shown in Scheme 2. The
chiral and commercially available ester 13 was first converted into
the known primary alcohol 14.5f Silylation of 14 gave 15, which was
then hydrogenolytically debenzylated to 16.10 Swern oxidation11 of
the alcohol group in 16 followed by CoreyeFuchs homologation12
of the intermediate aldehyde gave alkyne 17,13 which was then
converted into vinyl iodide 7 through the previously reported car-
bometallationeiodination sequence.6a,13
For the preparation of alcohol 8, we initially used alcohol 16 as
the starting material (Scheme 3). Mesylation of 16 and treatment of
the resulting mesylate with potassium cyanide in DMSO gave ni-
trile 18, which was subsequently reduced to the corresponding
Scheme 3. Synthesis of epoxy alcohol 8. Acronyms and abbreviations: Ms, meth-
anesulfonyl; DME, 1,2-dimethoxyethane; DIBAL, diisobutylaluminum hydride; DMSO,
dimethyl sulfoxide.

3194
J. García-Fortanet et al. / Tetrahedron 69 (2013) 3192e3196
However, we found this reaction sequence too long (12
3. Experimental
steps from the commercial ester 13) and eventually replaced it
by another more efficient one, also depicted in Scheme 3. The
new sequence is based, with some modifications, on the one
used by Cid and Pattenden15 in their route toward amphidi-
nolide B, with methyl hydrogen (R)-3-methylglutarate 21 as
the chiral starting material. Borane reduction of the carboxy
group to primary alcohol, Swern oxidation of the latter to the
aldehyde16 and OhiraeBestmann homologation provided al-
kyne 22.17 Reduction of the ester to primary alcohol afforded
alcohol 20 in only four steps from the commercially available
precursor 21.
Conversion of 20 into epoxy alcohol 23 was performed in
four steps.6a Thus, the primary alcohol group of 20 was oxidized
to the corresponding aldehyde, followed by HornerꢀWadsworthꢀ
Emmons18 olefination of the aldehyde, DIBAL reduction of the
resulting conjugated ester to an allylic alcohol and Sharpless ep-
oxidation19 of the latter. Silylation of 23 gave 24, which was then
subjected to palladium-catalyzed silylstannation20 to yield 25.
Treatment of the latter with TBAF caused both O- and C-desilylation
and gave the desired 8.
3.1. General experimental features
See Supplementary data.
3.1.1. (E)-6,13,13-Trimethyl-12,12-diphenyl-2,4,11-trioxa-12-silatetra-
dec-6-ene (10). A solution of alcohol 99 (4.42 g, 12 mmol) in dry
CH2Cl2 (60 mL) was treated at room temperature under N2 with
DIPEA (6.2 mL, 36 mmol) and MOMCl (1.82 mL, 24 mmol). The
mixture was heated at reflux for 2 h. Work-up (extraction with
CH2Cl2) followed by column chromatography on silica gel (hexanes/
EtOAc, 8:2) afforded 10 (4.85 g, 98%) as a yellowish oil: 1H NMR
d
7.80e7.75 (4H, br m), 7.50e7.40 (6H, br m), 5.52 (1H, br t,
Jw6.8 Hz), 4.68 (2H, s), 4.00 (2H, br s), 3.77 (2H, t, J¼6.2 Hz), 3.44
(3H, s), 2.25 (2H, br q, Jw7.5 Hz), 1.75 (3H, br s), 1.75e1.70 (2H, m),
1.16 (9H, s); 13C NMR
(ꢁ2), 128.1, 127.5 (ꢁ4) (CH), 95.2, 73.2, 63.3, 32.3, 24.0 (CH2), 55.1,
26.8 (ꢁ3), 13.9 (CH3); HR FABMS m/z 435.2344 (MþNaþ), calcd for
C25H36NaO3Si, 435.2331.
d
134.0 (ꢁ2), 131.9, 19.2 (C), 135.5 (ꢁ4), 129.5
The next step was the Stille coupling8 of 7 and 8, which was
performed as shown in Scheme 4. Epoxide 8 was dissolved in
dry NMP and treated with Pd2(dba)3 and Ph3As,21 followed by
addition of iodide 7 and CuTC.22 This provided the desired diene
5 in 61% yield. Oxidation of the primary alcohol function in 5
to the corresponding aldehyde in 26 was best performed by
means of IBX in DMSO.23 Good conditions for the final coupling
of 26 with sulfone 6 via JuliaeKocienski olefination were found
only after extensive experimentation. The best results were
found under the so-called Barbier conditions,7 which led to the
desired compound 3 in 75% yield as a ca. 4:1 E/Z mixture. Sep-
aration of these configurational isomers proved not feasible at
this stage. We hope that further advance in the projected syn-
thesis will permit the separation of the two isomers in a later
intermediate.
3.1.2. (E)-6-(Methoxymethoxy)-5-methylhex-4-en-1-ol (11). A solu-
tion of compound 10 (4.54 g, 11 mmol) in dry THF (70 mL) was
treated under N2 with TBAF (3.45 g, 13.2 mmol). The mixture was
stirred at room temperature for 2 h. Removal of all volatiles under
reduced pressure was followed by column chromatography of the
residue on silica gel (hexanes/Et2O, 1:1) to yield alcohol 11 (1.88 g,
99%) as a colorless oil: IR nmax 3420 (br, OH) cmꢀ1 1H NMR
; d 5.46
(1H, br t, Jw7.3 Hz), 4.62 (2H, s), 3.93 (2H, br s), 3.65 (2H, t,
J¼6.4 Hz), 3.38 (3H, s), 2.14 (2H, br q, Jw7.3 Hz), 1.67 (3H, br s), 1.65
(2H, br quint, Jw7 Hz),1.50 (1H, br s, OH); 13C NMR
d 132.4 (C), 127.8
(CH), 95.4, 73.3, 62.5, 32.4, 24.0 (CH2), 55.2, 14.0 (CH3); HR FABMS
m/z 197.1165 (MþNaþ), calcd for C9H18NaO3, 197.1153.
3.1.3. (E)-5-[(6-Methoxymethoxy-5-methylhex-4-en-1-yl)thio]-1-
phenyl-1H-tetrazole (12). A solution of alcohol 11 (1.74 g, 10 mmol)
in dry THF (125 mL) was treated at 0 ꢂC under N2 with Bu3P (5 mL,
20 mmol), 1-phenyl-1H-tetrazol-5-thiol (3.56 g, 20 mmol) and
DIAD (4.92 mL, 25 mmol). The mixture was stirred at 0 ꢂC for 1 h.
Work-up (extraction with EtOAc) and column chromatography on
silica gel (hexanes/EtOAc, 8:2) furnished sulfide 12 (2.64 g, 79%) as
a yellowish oil: 1H NMR
d 7.55e7.45 (5H, br m), 5.40 (1H, br t,
Jw7 Hz), 4.57 (2H, s), 3.89 (2H, br s), 3.35 (2H, t, J¼7.2 Hz), 3.32 (3H,
s), 2.18 (2H, br q, Jw7.2 Hz),1.88 (2H, br quint, Jw7.2 Hz),1.63 (3H, br
s); 13C NMR
d
154.2, 133.6, 133.2 (C), 130.0, 129.6 (ꢁ2), 126.1, 123.7
(ꢁ2) (CH), 95.3, 72.9, 32.7, 28.7, 26.4 (CH2), 55.1, 14.0 (CH3); HR
FABMS m/z 357.1369 (MþNaþ), calcd for C16H22N4NaO2S, 357.1361.
3.1.4. (E)-5-[(6-(Methoxymethoxy)-5-methylhex-4-en-1-yl)sulfonyl]-
1-phenyl-1H-tetrazole (6). A solution of sulfide 12 (1.67 g, 5 mmol)
in EtOH (100 mL) was treated at 0 ꢂC with (NH4)6Mo7O24$4H2O
(1.85 g, 1.5 mmol) and 30% H2O2 (5.6 mL, w50 mmol). The mixture
was stirred at room temperature for 16 h. The reaction was then
quenched by addition of aqueous Na2S2O3 (1.6 M,100 mL). Work-up
(extraction with EtOAc) and column chromatography on silica gel
(hexanes/EtOAc, 8:2) afforded sulfone 6 (1.46 g, 80%) as a colorless
Scheme 4. Synthesis of compound 3. Acronyms and abbreviations: NMP, N-methyl-
pyrrolidone; IBX, iodoxybenzoic acid; KHMDS, potassium hexamethyldisilylazide;
DMF, N,N-dimethylformamide; CuTC, copper(I) thiophene-2-carboxylate.
oil: IR nmax 1337, 1152 (SO2) cmꢀ1; 1H NMR
d 7.70e7.55 (5H, br m),
5.42 (1H, br t, Jw7.3 Hz), 4.62 (2H, s), 3.93 (2H, br s), 3.72 (2H, br t,
Jw5.5 Hz), 3.37 (3H, s), 2.28 (2H, br q, Jw7.3 Hz), 2.04 (2H, br quint,
Jw7.3 Hz), 1.67 (3H, br s); 13C NMR
d 153.4, 134.7, 133.0 (C), 131.4,
In summary, compound 3, which constitutes a C1eC18 fragment
of the structures of amphidinolides G/H, has been prepared in
a stereoselective way. Coupling of this fragment with a C19eC26
fragment previously reported by us5e will hopefully lead to the
preparation of the complete structure of these two strongly cyto-
toxic lactones.
129.7 (ꢁ2), 125.1, 124.6 (ꢁ2) (CH), 95.5, 72.8, 55.4, 25.9, 21.9 (CH2),
55.3, 14.1 (CH3); HR FABMS m/z 389.1269 (MþNaþ), calcd for
C16H22N4NaO4S, 389.1259.
3.1.5. (S)-[4-(Benzyloxy)-3-methylbutoxy](tert-butyl) diphenylsilane
(15). A solution of alcohol 145f (3.88 g, 20 mmol) in dry CH2Cl2

J. García-Fortanet et al. / Tetrahedron 69 (2013) 3192e3196
3195
(100 mL) was treated at 0 ꢂC under N2 with Et3N (4.2 mL, 30 mmol),
TPSCl (6.24 mL, 24 mmol) and DMAP (24 mg, 0.2 mmol). The
mixture was then stirred at room temperature for 3 h. Work-up
(extraction with CH2Cl2) and column chromatography on silica
gel (hexanes/EtOAc, 95:5) gave silyl ether 15 (8.13 g, 94%) as a col-
(2H, m), 2.18 (1H, ddd, J¼16.5, 6, 2.5 Hz), 2.13 (1H, ddd, J¼16.5, 6.5,
2.5 Hz), 2.00 (1H, br s, OH), 1.96 (1H, t, J¼2.5 Hz), 1.84 (1H, apparent
sextuplet, Jw6.5 Hz), 1.69 (1H, apparent sextuplet, Jw6.5 Hz), 1.48
(1H, apparent sextuplet, Jw6.5 Hz), 1.00 (3H, d, J¼6.8 Hz); 13C NMR
d
82.9 (C), 69.4, 29.1 (CH), 60.7, 38.6, 25.7 (CH2), 19.4 (CH3); HR EIMS
orless oil: [
a
]
ꢀ1.1 (c 1.35, CHCl3); 1H NMR
d
7.70e7.65 (4H, m),
m/z (rel int.) 97.0645 (MþꢀMe, 11), 91 (26), 55 (100), calcd for
C7H12OꢀMe, 97.0653.
D
7.40e7.25 (11H, br m), 4.45 (2H, s), 3.74 (2H, t, J¼6.5 Hz), 3.33 (1H,
dd, J¼9, 5.8 Hz), 3.24 (1H, dd, J¼9, 6.5 Hz), 2.00 (1H, apparent
sextuplet, Jw6.5 Hz), 1.76 (1H, apparent sextuplet, Jw6.5 Hz), 1.40
(1H, apparent sextuplet, Jw7 Hz),1.08 (9H, s), 0.93 (3H, d, J¼6.7 Hz);
3.1.9. tert-Butyl (2S,3S)-3-[(R)-2-methylpent-4-ynyl] oxiran-2-
ylmethoxy diphenylsilane (24). A solution of alcohol 236a (617 mg,
4 mmol) in dry CH2Cl2 (40 mL) was treated at room temperature
under N2 with imidazole (408 mg, 6 mmol) and TPSCl (1.25 mL,
4.8 mmol). The mixture was then stirred at room temperature for
1 h. Work-up (extraction with CH2Cl2) and column chromatography
on silica gel (hexanes/EtOAc, 95:5) gave silyl ether 24 (1.54 g, 98%)
13C NMR
d
138.8, 134.1 (ꢁ2), 19.2 (C), 135.5 (ꢁ4), 129.5 (ꢁ2), 128.3
(ꢁ2), 127.6 (ꢁ4), 127.4 (ꢁ2), 127.3, 30.3 (CH), 75.8, 72.9, 62.1, 36.6
(CH2), 26.9 (ꢁ3), 17.3 (CH3); HR FABMS m/z 455.2365 (MþNaþ),
calcd for C28H36NaO2Si, 455.2382.
3.1.6. (S)-4-(tert-Butyldiphenylsilyloxy)-2-methylbutan-1-ol (16).
Palladium hydroxide (20%, Degussa-type, 3 g) was suspended in
EtOH (250 mL) under a H2 atmosphere. After stirring at room
temperature and ambient pressure for 15 min, a solution of com-
pound 15 (6.49 g, 15 mmol) in EtOH (20 mL) was added via syringe.
The mixture was then stirred for 90 min. When the starting com-
pound was consumed (TLC monitoring), the reaction mixture was
filtered through a Celite pad. The pad was then washed with EtOAc.
The organic layers were evaporated to dryness and the residue was
subjected to column chromatography on silica gel (hexanes/EtOAc,
3:1). This provided 16 (4.52 g, 88%) as a colorless oil having the
reported physical and spectral properties.10
as a colorless oil: [
a
]
ꢀ10.8 (c 0.65, CHCl3); IR nmax 3296 (C^C)
D
cmꢀ1; 1H NMR
d
7.70e7.65 (4H, m), 7.45e7.35 (6H, m), 3.78 (2H, m),
2.91 (1H, td, J¼4.5, 2 Hz), 2.84 (1H, td, J¼6, 2 Hz), 2.24 (1H, ddd,
J¼16.5, 6, 2.5 Hz), 2.18 (1H, ddd, J¼16.5, 6.5, 2.5 Hz), 1.99 (1H, t,
J¼2.5 Hz), 1.92 (1H, m), 1.69 (1H, dt, J¼14, 6 Hz), 1.45 (1H, ddd, J¼14,
8.3, 5.5 Hz), 1.08 (3H, d, overlapped), 1.07 (9H, s); 13C NMR
d 133.3
(ꢁ2), 82.7, 19.2 (C), 135.6 (ꢁ2), 135.5 (ꢁ2), 129.8 (ꢁ2), 127.7 (ꢁ4),
64.2, 58.6, 54.9, 30.6 (CH), 69.6, 37.9, 26.1 (CH2), 26.8 (ꢁ3), 19.3
(CH3); HR FABMS m/z 393.2269 (MþHþ), calcd for C25H33O2Si,
393.2249.
3.1.10. Silylstannane 25. A solution of 24 (1.18 g, 3 mmol) in dry,
degassed DME (25 mL) was treated at room temperature under N2
with PhMe2SieSnMe3 (900 mg, w3 mmol),20c Ph3P (140 mg,
0.54 mmol), and Pd(OAc)2 (27 mg, 0.12 mmol). The mixture was
then stirred at 35 ꢂC for 7 d. After consumption of the starting
material (TLC monitoring), the mixture was evaporated under re-
duced pressure and the residue was subjected to column chroma-
tography on silica gel (hexanes/EtOAc, 98:2) to yield 25 (1.39 g, 67%)
3.1.7. (R)-tert-Butyl(3-methylhex-5-ynyloxy) diphenylsilane (19). A
solution of alcohol 16 (3.08 g, 9 mmol) in dry CH2Cl2 (40 mL) was
treated at 0 ꢂC under N2 with Et3N (2.5 mL, 18 mmol), MsCl
(1.05 mL, 13.5 mmol), and DMAP (12 mg, 0.1 mmol). The mixture
was then stirred at room temperature for 2 h. Work-up (extraction
with CH2Cl2) gave a crude mesylate, which was dissolved in dry
DMSO (45 mL) and treated under N2 at room temperature with KCN
(1.76 g, 27 mmol). The mixture was then stirred at 60 ꢂC for 4 h.
Work-up (extraction with Et2O) afforded crude nitrile 18, which
as a colorless oil: [
a
]
D ꢀ4.9 (c 0.8, CHCl3); 1H NMR
d 7.75e7.70 (4H,
m), 7.56 (2H, m), 7.50e7.35 (9H, br m), 6.50 (1H, br s), 3.80 (2H, m),
2.90 (1H, td, J¼4.5, 2 Hz), 2.85 (1H, td, J¼6, 2 Hz), 2.50 (1H, dd,
J¼12.5, 6.3 Hz), 2.30 (1H, ddd, J¼12.5, 7.5 Hz), 1.80e1.70 (2H, m),
1.36 (1H, ddd, J¼14, 8.3, 5.5 Hz), 1.10 (9H, s), 0.98 (3H, d, J¼6.5 Hz),
was used as such in the next step: IR nmax 2245 (C^N) cmꢀ1
;
1H
NMR
d
7.70e7.65 (4H, m), 7.45e7.35 (6H, m), 3.72 (2H, t, J¼6 Hz),
2.38 (1H, dd, J¼16.5, 5.4 Hz), 2.28 (1H, dd, J¼16.5, 7 Hz), 2.15 (1H,
m), 1.80e1.50 (2H, br m), 1.08 (3H, d, overlapped), 1.08 (9H, s).
A solution of 18, as obtained above, in dry hexane (50 mL) was
treated under N2 at ꢀ78 ꢂC with DIBAL (1 M solution in hexane,
12 mL,12 mmol). The mixture was then stirred at ꢀ78 ꢂC for 15 min.
Work-up (extraction with Et2O) gave an oily residue, which was
dissolved in MeOH (15 mL) and treated at room temperature under
N2 with K2CO3 (2.2 g, 16 mmol) and freshly prepared Ohir-
aeBestmann’s reagent (1.85 g, 9.6 mmol). The mixture was stirred
overnight at room temperature. Work-up (extraction with Et2O)
and column chromatography on silica gel (hexanes-Et2O, 8:2) fur-
nished alkyne 19 (2.42 g, 77% overall for the four steps from 16) as
0.40 (6H, s), 0.09 (9H, s); 13C NMR
d
167.2, 139.6, 133.3 (ꢁ2), 19.2 (C),
143.4 (ꢁ2), 135.6 (ꢁ4), 134.1 (ꢁ2), 129.8 (ꢁ2), 128.9, 127.7 (ꢁ5),
59.0, 55.0, 30.5 (CH), 64.3, 55.8, 38.5 (CH2), 26.8 (ꢁ3), 19.4, ꢀ0.06
(ꢁ2), ꢀ6.8 (ꢁ3) (CH3).
3.1.11. (2S,3S)-3-[(S)-2-(Methyl-4-(trimethylstannyl) pent-4-enyl)ox-
iran-2-yl]methanol (8). A solution of compound 25 (1.38 g, 2 mmol)
in dry DMSO (50 mL) was treated under N2 with TBAF (1 M solution
in THF, 12 mL, 12 mmol). The mixture was stirred at 80 ꢂC for 10 min
and then at room temperature for 20 min. Work-up (extraction with
Et2O) and column chromatography on silica gel (hexanes/Et2O, 1:1)
furnished alcohol 815 (415 mg, 65%) as a colorless oil: [
a
]
ꢀ21.8 (c
D
a yellowish oil: IR nmax 3300 (C^C) cmꢀ1; 1H NMR
d
7.70e7.65 (4H,
0.8, CHCl3); IR nmax 3400 (br, OH) cmꢀ1; 1H NMR
d
5.63 (1H, br s), 5.20
m), 7.45e7.35 (6H, m), 3.72 (2H, t, J¼6.4 Hz), 2.19 (1H, ddd, J¼16.5,
6, 2.5 Hz), 2.10 (1H, ddd, J¼16.5, 6.5, 2.5 Hz), 2.00e1.85 (2H, m), 1.73
(1H, apparent sextuplet, Jw6.5 Hz), 1.49 (1H, apparent sextuplet,
(1H, br d, J¼2.5 Hz), 3.91 (1H, dd, J¼12.5, 2.4 Hz), 3.63 (1H, dd, J¼12.5,
4.3 Hz), 2.98 (1H, td, J¼6, 2.2 Hz), 2.89 (1H, m), 2.34 (1H, dd, J¼13.5,
6.6 Hz), 2.18 (1H, ddd, J¼13.5, 7.7 Hz), 2.00 (1H, br s, OH),1.75 (1H, m),
1.65 (1H, m),1.30 (1H, m), 0.94 (3H, d, J¼6.5 Hz), 0.14 (9H, s); 13C NMR
Jw6.5 Hz), 1.06 (9H, s), 1.00 (3H, d, J¼6.6 Hz); 13C NMR
133.3 (ꢁ2),
d
83.2, 19.4 (C), 135.6 (ꢁ4), 129.6 (ꢁ2), 127.6 (ꢁ4), 69.2, 29.1 (CH),
62.0, 38.5, 25.7 (CH2), 26.9 (ꢁ3), 19.3 (CH3).
d 154.3 (C), 58.9, 54.6, 30.7 (CH), 126.2, 61.6, 49.0, 38.4 (CH2),
19.6, ꢀ9.5 (ꢁ3) (CH3); HR EIMS m/z (rel int.) 305.0575 (MþꢀMe, 22),
165 (100), calcd for C12H24O2SnꢀMe, 305.0558 (value calculated for
120Sn, the most abundant isotope of tin).
3.1.8. (R)-3-Methylhex-5-yn-1-ol (20). A solution of alkyne 19
(2.1 g, 6 mmol) in dry THF (40 mL) was treated under N2 with TBAF
(1.72 g, 6.6 mmol). The mixture was stirred at room temperature for
2 h. Removal of all volatiles under reduced pressure was followed
by column chromatography of the residue on silica gel (hexanes/
3.1.12. (2S,3S)-(3-[(2R,7S,E)-9-tert-Butyldiphenylsilyl-oxy-2,6,7-
trimethyl-4-methylenenon-5-enyl]oxiran-2-yl)methanol (5). A solu-
tion of epoxy alcohol 8 (383 mg, 1.2 mmol) in dry, degassed NMP
(10 mL) was treated under N2 at room temperature with Ph3As
(220 mg, 0.72 mmol) and Pd2(dba)3 (165 mg, 0.18 mmol). The
Et2O, 1:1) to yield 20 (639 mg, 95%) as a yellowish oil: [
a
]
D þ4.2 (c
0.8, CHCl3); IR nmax 3400 (br, OH), 3300 (C^C) cmꢀ1; 1H NMR
d
3.67

3196
J. García-Fortanet et al. / Tetrahedron 69 (2013) 3192e3196
reaction mixture was stirred under N2 at room temperature for
15 min. Addition first of iodoalkene 7 (600 mg, 1.25 mmol) in dry,
degassed NMP (15 mL) and then of CuTC (344 mg, 1.8 mmol) was
followed by stirring under N2 at 35 ꢂC for 40 min. Work-up (ex-
traction with Et2O) and column chromatography on silica gel
(hexanes/EtOAc, 8:2) furnished compound 5 (371 mg, 61%) as
Supplementary data
Supplementary data associated with this article (graphical NMR
spectra) can be found in the online version. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.02.062.
a yellowish oil: [
a
]
D ꢀ7.4 (c 1.24, CHCl3); IR nmax 3440 (br, OH) cmꢀ1
;
1H NMR
d
7.70e7.65 (4H, m), 7.45e7.35 (6H, m), 5.57 (1H, br s), 4.96
References and notes
(1H, br s), 4.79 (1H, br s), 3.90 (1H, br d, Jw12 Hz), 3.70e3.60 (3H,
m), 2.91 (1H, td, J¼6, 2 Hz), 2.86 (1H, m), 2.40 (1H, apparent sex-
tuplet, Jw7 Hz), 2.10 (1H, dd, J¼12.5, 6.5 Hz),1.94 (2H, br dd, Jw13.5,
8 Hz, overlapping OH signal), 1.80e1.55 (5H, br m), 1.66 (3H, s), 1.07
€
€
1. (a) Konig, G. M.; Kehraus, S.; Seibert, S. F.; Abdel-Lateff, A.; Muller, D. Chem-
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(9H, s), 1.02 (3H, d, J¼7 Hz), 0.90 (3H, d, J¼6.8 Hz); 13C NMR
d 144.3,
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142.4, 134.1 (ꢁ2), 19.2 (C), 135.5 (ꢁ4), 129.5 (ꢁ2), 127.6 (ꢁ4), 125.2,
58.9, 54.7, 39.7, 29.6 (CH), 114.5, 62.4, 61.7, 45.8, 38.4, 37.7 (CH2),
26.9 (ꢁ3), 19.7, 19.5,14.1 (CH3); HR EIMS m/z (rel int.) 506.3211 (Mþ,
3), 449 (14), 431 (19), 199 (100), calcd for C32H46O3Si, 506.3216.
3.1.13. Compound 3. A solution of alcohol 5 (355 mg, 0.7 mmol) in
dry DMSO (10 mL) was treated under N2 at room temperature with
IBX (392 mg, 1.4 mmol, 2 equiv). The reaction mixture was stirred
under N2 at 50 ꢂC for 1 h. During the work-up, extraction with Et2O
had to be repeated 8e10 times, due to the slow extraction of the
product with this solvent. Column chromatography on silica gel
(hexanes/EtOAc, 7:3) provided aldehyde 26, pure enough for use in
the next step.
3. (a) Usui, T.; Kazami, S.; Dohmae, N.; Mashimo, Y.; Kondo, H.; Tsuda, M.;
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€
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The material from the previous step and sulfone 6 (385 mg,
1.05 mmol) were dissolved under N2 in dry DMF (15 mL). The so-
lution was then cooled to ꢀ78 ꢂC and treated dropwise with
KHMDS (0.5 M in toluene, 2 mL, 1 mmol). The reaction mixture was
then stirred overnight under N2 at ꢀ78 ꢂC. Work-up (extraction
with Et2O) and column chromatography on silica gel (hexanes/
EtOAc, 8:2) afforded compound 3 (338 mg, 75% overall for the two
steps) as a yellowish oil. NMR analysis revealed that the compound
was an inseparable w80:20 mixture of E/Z stereoisomers. A small
sample could be partially concentrated in the E isomer for analytical
purposes: oil; 1H NMR (signals of the major E stereoisomer)
6. For total syntheses of members of the amphidinolide G/H family, see: (a)
€
ꢀ
Furstner, A.; Bouchez, L. C.; Morency, L.; Funel, J. A.; Liepins, V.; Poree, F. H.;
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d
7.70e7.65 (4H, m; TPS aromatic), 7.45e7.35 (6H, m; TPS aromatic),
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5.90 (1H, dt, J¼15.5, 6.5 Hz; H-6), 5.56 (1H, br s; H-14), 5.46 (1H, m;
H-3), 5.20 (1H, dd, J¼15.5, 8 Hz; H-7), 4.95 (1H, br s; C]CH2), 4.76
(1H, br s; C]CH2), 4.63 (2H, s; CH2OMe), 3.94 (2H, br s; H-1/10),
3.62 (2H, m; H-18/180), 3.38 (3H, s; OMe), 3.00 (1H, dd, J¼8, 2 Hz; H-
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1.67 (3H, s; MeC2 or MeC15), 1.64 (3H, s; MeC15 or MeC2), 1.80e1.50
(5H, br m; H-10/100/11/17/170), 1.06 (9H, s; tBu), 1.01 (3H, d,
J¼6.8 Hz; MeC11 or MeC16), 0.89 (3H, d, J¼6.8 Hz; MeC16 or MeC11);
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13C NMR (signals of the major E stereoisomer)
d 144.4, 142.3, 132.4
(ꢁ3), 19.2 (C), 135.5 (ꢁ4), 134.1, 129.5 (ꢁ2), 128.1, 127.6 (ꢁ4), 127.5,
125.3, 59.1 (ꢁ2), 39.7, 29.7 (CH), 114.4, 95.4, 73.2, 62.4, 45.9, 38.9,
37.7, 32.1, 27.2 (CH2), 55.3, 29.6, 26.9 (ꢁ3), 19.7, 19.5, 14.1 (CH3) (for
atom numbering, see Fig. 2).
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Acknowledgements
Financial support hasbeen granted to M.C. by the SpanishMinistry
of Education and Science (projects CTQ2008-02800 and CTQ2011-
27560), by the Consellería dEmpresa, Universitat i Ciencia de la
Generalitat Valenciana (projects ACOMP09/113) and by the BANCAJA-
UJI Foundation (projects P1-1B-2008-14 and PI-1B2011-37).
ꢀ