Synthesis of the northern hemisphere of amphidinolide H2

Article abstract of DOI:10.1055/s-2006-942459

The stereoselective synthesis of the fully functionalized northern hemisphere of the marine natural product amphidinolide H2 is described. A vinylogous Mukaiyama aldol reaction and enzymatic desymmetrization of a meso compound are the key steps in the fragment synthesis. A stereoselective acetate aldol coupling and a 1,3-anti-reduction of the resulting β-hydroxy ketone complete the synthesis of the C14-C26 fragment. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942459

2590
PAPER
Synthesis of the Northern Hemisphere of Amphidinolide H2
Northern
H
em
l
ispher
e
o
of
A
mphidi
r
nolide
H
i
2
an P. Liesener, Ulrike Jannsen, Markus Kalesse*
Universität Hannover, Institut für Organische Chemie, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 15 February 2006; revised 30 March 2006
OH
O
Abstract: The stereoselective synthesis of the fully functionalized
OH
16
18
20
northern hemisphere of the marine natural product
amphidinolide H2 is described. A vinylogous Mukaiyama aldol re-
action and enzymatic desymmetrization of a meso compound are
the key steps in the fragment synthesis. A stereoselective acetate al-
dol coupling and a 1,3-anti-reduction of the resulting b-hydroxy ke-
tone complete the synthesis of the C14–C26 fragment.
HO
25
OH
6
O
1
7
O
O
Key words: natural products, aldol reaction, stereoselectivity, am-
amphidinolide H (1)
phidinolides, macrolides
R3
R2R1
16
R4
O
OH
18
20
R5
R6
The amphidinolides are a group of cytotoxic macrolides
isolated from marine dinoflagellate Amphidinium sp.,
which is symbiotic with the Okinawan flatworm Amphis-
colops sp. Since 1986, when Kobayashi et al. first report-
ed the isolation of a cytotoxic macrolide from laboratory
cultured Amphidinium sp.,1 37 macrolides have been
found by investigation of different strains to date.2 Two
further amphidinolides were isolated by Shimizu et al.
from a free swimming dinoflagellate collected at Brewers
Beach, St. Thomas, Virgin Islands, USA.3 The ring sizes
of the macrolactones range from 12 to 29 and all of them
show significant biological activity.
26
25
OH
6
1
O
7
O
O
amphidinolide H2 (2) R2 = Me, R4, R6 = OH, R1, R3, R5 = H, ∆6,7
amphidinolide H3 (3) R1 = Me, R3, R5 = OH, R2, R4, R6 = H, ∆6,7
amphidinolide H4 (4) R1 = Me, R3, R6 = OH, R2, R4, R5 = H, 6,7-dihydrom
amphidinolide H5 (5) R2 = Me, R4, R6 = OH, R1, R3, R5 = H, 6,7-dihydro
Figure 1 The amphidinolides of the H-group
Amphidinolide H (1) induces polyploid cell formation,
which is believed to be a result of cytokinesis inhibition.
It could be demonstrated that on treatment with
amphidinolide H the actin cytoskeleton was modified
whereas the microtubules remained unchanged.8
Amphidinolide H (1) was first isolated in 1991 from ex-
tracts of cultured cells of the Y-25 strain separated from
flatworm Amphiscolops breviviridis.4 The absolute con-
figuration of 1 was elucidated by X-ray diffraction analy-
sis and by the synthesis of a degradation product.5
Investigations of the strain Y-42 of the genus Amphidini-
um sp. led to the isolation of amphidinolide H2 (2) along
with three other H-type amphidinolides (Figure 1).6
The remarkable biological activity and the interesting
structural features have initiated considerable synthetic
efforts, but although several syntheses of fragments of H-
type amphidinolides and the structurally related amphidi-
nolides B and L have been published,9–15 to our knowl-
edge no total synthesis of these amphidinolides has been
accomplished so far.
The structure of 2 was determined by comparison of the
JH,H and JC,H coupling constants and NOESY correlations
with those of amphidinolide H (1). Its cytotoxicity was
tested against murine lymphoma L1210 and human epi-
dermoid KB cell lines and an IC50 value of 0.06 mg/mL
has been found for both.6
Retrosynthetic Analysis
Within these investigations, first SAR studies indicated
that an allyl epoxide unit, the S-cis-diene moiety, and the
C20 ketone are relevant for the cytotoxicity of amphidin-
olides of the H-group.6
Our retrosynthetic analysis dissects amphidinolide H2 (2)
into three fragments, allowing a convergent assembly of
the molecule (Scheme 1).
The coupling of these fragments was planned to be
achieved by a stereoselective acetate aldol coupling be-
tween C18 and C19, lactonization, and an enyne metathe-
sis between C13 and C14. Alternatively, a palladium-
catalyzed cross-coupling could also lead to the desired
Biological studies on amphidinolide H (1) revealed that it
acts as a specific and highly selective actin binder for
which the C8,C9-epoxide seems to be crucial.7,8
SYNTHESIS 2006, No. 15, pp 2590–2602
x
x.
x
x
.
2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-942459; Art ID: T02506SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2591
aldol coupling
O
O
OH
18
O
18
OH
enyne metathesis
or Pd-catalyzed
cross-coupling
OH
6
14
19
HO
13
HO
23
26
13
7
OH
OH
OH
1
OH
O
1
O
7
8
O
O
2
O
lactonization
Scheme 1 Retrosynthetic disconnection of amphidinolide H2 (2)
1,3-diene system. This has been shown by Chakraborty et They proposed the substituent at C16 to be responsible for
al.14 and Nelson et al.,12 who used a Stille and a Suzuki the observed selectivity, while in the relevant literature
coupling, respectively in their partial syntheses of 1,3-induction by a methyl group is indicated as only mod-
amphidinolide B.
erate.19
We planned to investigate the stereochemical outcome of
this aldol step with the aid of aldehyde 6, which could be
used for the subsequent enyne metathesis (Scheme 3).
Synthetic Considerations
In case the methyl ketone fragment induces the reported
stereochemistry of aldol product 11, it would produce the
undesired diastereomer in our case. In order to overrule
the potentially inherent induction chiral enolates or Lewis
acids could be employed.
The enyne metathesis has attracted considerable attention
during the past decade, which has led to a number of pub-
lications.16
Lee et al. have investigated the factors governing the re-
gioisomeric outcome of the enyne metathesis, proposing
that first the double bond would react with the catalyst.17
Depending on the ring size to be formed the exo or the
endo product can be obtained. For ring sizes between
n = 5–11 atoms the exo product is favored. Rings with
more than 11 atoms will preferably generate the exo-
methylene unit (endo product).
O
OH
O
25
OH
20
+
16
18
OH
OH
6
7
OH
18
O
planned
aldol coupling
Therefore, the desired endo-selective enyne ring closing
metathesis will in principal be applicable to amphidino-
lide H2 (2) as a large 26-membered macrolactone.18 Alter-
natively, a cross alkyne–alkene metathesis which is
known to be endo-selective could also be employed.
OH
16
20
HO
25
12
OH
OH
For the selectivities in the aldol step Chakraborty et al. re-
ported the aldol coupling between aldehyde 9 and methyl
ketone 10 in the synthesis of amphidinolide H (1), which
produced the desired product 11 selectively in 80% yield
(Scheme 2).10
Scheme 3 Planned diastereoselective aldol reaction between alde-
hyde 6 and methyl ketone 7
Synthesis of a C19–C26 Methyl Ketone
Our synthesis of the C19–C26 fragment 7 makes use of a
diastereoselective vinylogous Mukaiyama aldol reaction
(VMAR).20 A Sharpless asymmetric dihydroxylation
should be used in order to install the remaining hydroxy
groups (Scheme 4).
O
OTBS
O
TBDPSO
+
O
PMBO
O
9
10
The acetonide of L-glyceraldehyde (15) can be synthe-
sized from L-ascorbic acid in three steps.21 In order to op-
timize the vinylogous Mukaiyama aldol reaction as the
first step, various reaction conditions were employed us-
ing the acetonide of D-glyceraldehyde ent-16, which is
readily available from D-mannitol (Scheme 5). Interest-
ingly it turned out that in contrast to other aliphatic alde-
hydes, substrates with protected a-hydroxy groups could
be transformed into the desired aldol products with cata-
TBS
O
O
1) LDA, THF
TBDPSO
OPMB
2) TBSOTf, 2,6-lutidine,
CH2Cl2, 80%
TBSO
11
O
O
Scheme
2
Acetate aldol reaction in the synthesis of
amphidinolide H (1) as employed by Chakraborty et al.
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

2592
F. P. Liesener et al.
PAPER
OTBS
OH
O
OH
23
O
OH
25
O
O
TBSOTf
25
23
25
OH
MeO
OH
20
20
MeO
MeO
20
O
O
2,6-lutidine
CH2Cl2
77%
OH
OH
OH
O
O
7
ent-17
18
13
O
O
OTBS
25
OTBS
20
O
H2
TBAF
O
24
23
25
+
MeO
MeO
20
OH
O
O
Pd/C
EtOAc
96%
THF
18%
23
H
O
OH
15
O
14
19
20
Scheme 4 Retrosynthesis of methyl ketone 7
O
O
Ph
Ph
O
O
O
O
OMe
O
OMe
O
F3C
F3C
O
OTBS
20
O
OH
25
TPPB⋅H2O
MeO
MeO
25
O
+
MeO
MeO
20
O
O
i-PrOH, Et2O
61%
dr = 14:1:1
O
O
21
22
O
14
ent-17
Scheme 6 Synthesis of lactone 20 for determination of the relative
stereochemistry of ent-17
ent-16
Scheme 5 Diastereoselective vinylogous Mukaiyama aldol reaction
(VMAR)
The optimized conditions were then applied to the reac-
tion with protected L-glyceraldehyde 16 (Scheme 7). Af-
ter TES-protection of the newly generated alcohol 17,
dihydroxylation of the double bond was achieved with a
variation of AD-mix a22 providing the desired diol 24,
which was subsequently protected as the acetonide. Re-
moval of the TES group liberated the secondary alcohol
for transformation into the thiocarbonyl imidazolide de-
rivative 26.23 A tin-mediated free-radical deoxygenation24
followed by saponification provided acid 28. Subsequent-
ly, a sequence of acid activation by isobutyl chlorofor-
mate, transformation into the Weinreb amide25 and
addition of methyl magnesium chloride26 furnished meth-
yl ketone 29 in 11 steps and 16% overall yield
(Scheme 7).9
lytic concentrations of tris(pentafluorophenyl)borane
monohydrate (TPPB) as the Lewis acid.
No TBS catalysis was observed here even with only 1%
of the Lewis acid present (Table 1, entry 9). With these
optimized conditions the VMAR could be performed on
gram-scale quantities.9
In order to determine the stereochemistry of VMAR prod-
uct ent-17, lactone 20 was synthesized (Scheme 6). Sub-
sequent analysis of the coupling constants in the 1H NMR
spectrum revealed a C23–C24 syn configuration. Felkin–
Anh selectivity was proven unambiguously by transfor-
mation of ent-17 to the corresponding Mosher esters 21
and 22.33
Table 1 Vinylogous Mukaiyama Aldol Reaction (VMAR) with Protected D-Glyceraldehyde ent-16
Entry
14 (equiv)
i-PrOH (equiv) Time (min)
TPPB·H2O/eq
0.1
Temp (°C)
–78
Yield (%)
dra
1
2
3
4
5
6
7
8
9
2
1.1
1.1
1.1
1.1
1.1
0.7
0.7
0.7
0.7
180
60
30
60
60
40
40
40
40
34
75
45
65
67
62
63
75b
63c
10:1:1
14:1:1
13:1:2
15:1:1
10:1:1
14:1:2
12:1:1
13:1:1
14:1:1
2
0.1
–50
2
0.1
–50
2
0.05
–50
2
0.02
–50
1.2
1.2
1.2
1.2
0.02
–50
0.01
–50
0.01
–50 → r.t.
–50 → r.t.
0.01
a The diastereomeric ratio was determined from the 1H NMR spectra by integration of the vinylic proton at C22.
b Scale: 2.51 mmol.
c Scale: 12.5 mmol.
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2593
OsO4⋅t-BuOH
(DHQ)2PHAL, K3Fe(CN)6
K2CO3, MSNH2
TESCl
imidazole
O
OTBS
O
OH
25
O
OTES
O
TPPB⋅H2O
23
25
+
MeO
20
MeO
MeO
20
DMAP
DMF
77%
i-PrOH, Et2O
61%
dr = 14:1:1
O
O
O
O
O
14
t-BuOH–H2O
92%, dr = 19:1
17
23
16
N
1) HF⋅Py, THF–Py
95%
N
2,2-DMP
CSA
O
O
OTES
O
OH OTES
Bz2O2
S
2)
O
O
O
S
MeO
MeO
MeO
Et3SiH
78%
CH2Cl2
81%
O
N
N
O
N
N
O
O
OH
O
MeO
O
24
25
O
O
DMAP, toluene
92%
26
O
O
O
O
O
O
1) NMM, IBCF
NaOH
25
O
HO
20
O
2) MeON(Me)H⋅HCl
NMM, THF, 77%
3) MeMgCl, THF
85%
O
O
O
H2O–THF
quant.
O
O
O
O
28
27
29
Scheme 7 Synthesis of methyl ketone 29:9 (DHQ)2PHAL = bis(dihydroquinine)phthalazine; 2,2-DMP = 2,2-dimethoxypropane;
IBCF = isobutyl chloroformate
Table 2 Variation of Conditions in the Aldol Reaction
Synthesis of the Northern Hemisphere
Entry
Base, solvent
Yield (%)
Next, the stereochemical outcome of the aldol coupling
had to be investigated. For our initial orientating experi-
ments, the aldol reaction between methyl ketone ent-29
and n-hexanal (30) was studied. Surprisingly, it turned out
that the expected aldol reaction took place only in moder-
ate yields and aldol dimer 32 was produced in significant
quantities (Scheme 8; 28%). Furthermore, the diastereo-
meric mixture of the aldol product 31 was in favor of the
undesired isomer.27
31
35
13
19
35
35
35
32
28
16
13
28
28
28
1
2
3
4
5
6
LiHMDS, THF
KHMDS, THF
NaHMDS, THF
LDA, THF
LDA, HMPA, THF
Schwesinger base, THF28
Even extensive variation of the reaction conditions, such
as changing the base (Table 2, entries 1–6) did not lead to
better results. With boron aldol reaction chemistry29 no
product formation was observed, while DIP-Cl®30 led to
decomposition. Under Mukaiyama aldol reaction condi- Methyl ketone 33 could be synthesized starting from meso
tions, only a mixture of TMS-enolate and starting material compound dimethyl-3-methyl-glutarate (35). A known
could be isolated.
literature sequence of enzymatic desymmetrization using
porcine liver esterase (PLE), selective reduction of the
free acid with borane dimethylsulfide complex, and TBS
protection delivered ester 37.31 This was methylated a to
the ester group, producing 38 as a mixture of diastereo-
mers. Subsequent DIBAL-H reduction and tosylation of
the alcohol led to compound 39. Deprotection of the silyl
ether, Swern oxidation, addition of methyl magnesium
chloride, and another Swern oxidation provided ketone
41. In situ conversion to the corresponding iodide and
At this point we decided to change our initial synthetic
plan since the yields and selectivities for the envisioned
aldol reaction were by no means satisfactory for the future
elaboration of amphidinolide H2 (2).
Therefore, exchanging the functionalities in the aldol re-
action was considered; we modified our retrosynthetic
analysis so that the C14–C19 fragment 33 would react
with the C20–C26 aldehyde 34 (Scheme 9).
O
O
O
O
OH
O
O
O
OH
25
O
25
O
25
O
20'
O
25'
O
LiHMDS
+
+
20
20
20
4
O
O
O
O
O
THF
–78°C
O
4
O
O
31
30
ent-29
32
28%
35%, dr = 2:1
Scheme 8 Aldol reaction between methyl ketone ent-29 and n-hexanal (30)
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

2594
F. P. Liesener et al.
PAPER
aldol reaction
In order to elaborate the C18-stereocenter, a 1,3-anti-re-
duction with tetramethylammonium trisacetoxyborohy-
dride using a method developed by Evans, was
employed.34 The selectivity of this reaction is derived
from an intramolecular hydride transfer in the borate
formed from reagent and substrate. Protection of the less
sterically hindered alcohol was obtained using TIPSOTf.
Finally, reoxidation at C20 provided the fully functional-
ized northern hemisphere 47 of amphidinolide H2 (2).
OH
O
OH
16
14
19
HO
23
25
12
OH
OH
In summary, the C14–C26 fragment of amphidinolide H2
(2) has been synthesized, making use of a diastereoselec-
tive acetate aldol reaction and a subsequent selective 1,3-
anti-reduction. The fragment contains the necessary func-
tional groups for further synthesis of the natural product.
Esterification with a C1–C13 acid could be realized after
selective cleavage of the terminal acetonide and protec-
O
O
O
25
20
18
O
O
O
33
14
34
Scheme 9 Modified retrosynthetic analysis of the northern half of 2
elimination with DBU as base,32 afforded the desired tion of the primary alcohol. The terminal double bond at
C14–C19 fragment 33 in 11 steps with an overall yield of C14 can be used in an enyne metathesis with a suitable
17% (Scheme 10).
alkyne. Investigations towards those couplings are cur-
rently underway and should provide a convergent access
to amphidinolide H2 (2) in due course.
Aldehyde 34 was obtained in one step by DIBAL-H re-
duction of ester 27. Now the aldol reaction was performed
using LiHMDS at –78 °C. The coupling product 42 was
obtained in 50% yield and 15:1 dr in favor of the Felkin
product (Scheme 11). The configuration at C20 was as-
All reactions were carried out in dried glassware under a positive
pressure of argon, using Schlenk techniques when air-sensitive
signed by synthesizing (S)-Mosher ester 43 and (R)- compounds were employed. Commercially available materials
Mosher ester 44.33
were obtained from Aldrich, Fluka, Merck or Acros, and were used
without further purification unless otherwise noted. TPPB was pur-
1) PLE, MeOH/
pH 7 buffer
14
MeO2C
18
CO2Me
TBSCl, imidazole
DMF, 90%
LDA, MeI
95%
MeO2C
MeO2C
OTBS
OH
THF, dr = 1.8:1
2) BH3⋅SMe2
THF, 80%
36
37
35
O
1) HF⋅Py
1) DIBAL-H, THF
97% over 2 steps
1) MeMgCl, THF
89% over 2 steps
THF–Py, 94%
OTBS
OTBS
H
2) TsCl, Py
97%
2) (COCl)2, DMSO
then Et3N
2) (COCl)2, DMSO
then Et3N
CH2Cl2, 79%
38
40
39
MeO
TsO
O
TsO
TsO
CH2Cl2
O
O
NaI, DBU
19
DMF, 40%
14
41
33
Scheme 10 Synthesis of methyl ketone 33
O
O
O
O
O
OH
O
Me4NBH(OAc)3
33, LiHMDS
DIBAL-H
25
25
25
O
MeO
20
20
18
20
O
HOAc–MeCN
66%, dr = 19:1
O
O
O
toluene
74%
THF, 50%
dr = 15:1
O
O
O
O
14
34
42
27
TIPS
TIPS
OH OH
O
O
OH
O
O
O
O
TPAP, NMO
TIPSOTf
25
25
O
25
18
20
18
20
18
20
4 Å MS, CH2Cl2
28%
2,6-lutidine
CH2Cl2, quant.
O
O
O
O
O
O
O
O
14
14
14
45
47
46
Scheme 11 Synthesis of the protected northern hemisphere of amphidinolide H2 (2); TPAP = tetrapropylammonium perruthenate
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2595
chased from Acros and was handled under argon in a glovebox.
THF and Et2O were distilled from Na/benzophenone, CH2Cl2 and
Et3N were distilled from CaH2 prior to use. Flash chromatography
HRMS (EI): m/z calcd for C17H31O5Si [M – CH3]+: 343.19409;
found: 343.19522.
1
was performed using Merck silica gel 230–400 mesh. H and 13C
Ester 19
NMR spectra were recorded with a Bruker DRX 500, DPX 400,
AVANCE 400, or Jeol ECP 500 spectrometers. The residual undeu-
terated solvent peak (CDCl3 at 7.26 ppm) was used as the internal
standard. HRMS-EI measurements were performed using a VG Au-
tospec and ESI with a Waters Micromass LCT. Optical rotations
were determined with a Perkin Elmer 341 polarimeter at 23 °C at
589.3 nm (Na lamp) using a 1 mL quartz cell.
A solution of a,b-unsaturated ester 18 (94.1 mg, 262 mmol) in
EtOAc (5 mL) was stirred at r.t. Pd/C (cat.) was added and the mix-
ture was stirred under a hydrogen atmosphere (balloon pressure) for
1.5 h. The mixture was filtered through a pad of silica gel, which
was washed with EtOAc. The filtrate was concentrated in vacuo.
The crude material was purified by flash column chromatography
(hexane–EtOAc, 19:1) to provide ester 19 as a colorless oil
(90.3 mg, 251 mmol, 96%).
Tris(pentafluorophenyl)borane Monohydrate35
[a]D23 +26.1 (c 1.05, CHCl3); Rf 0.20 (hexane–EtOAc, 9:1).
To
a
solution of tris(pentafluorophenyl)borane (998 mg,
1H NMR (500 MHz, CDCl3): d = 4.01 (app q, J = 6.2 Hz, 1 H), 3.97
(dd, J = 7.6, 6.2 Hz, 1 H), 3.80 (dd, J = 7.5, 6.7 Hz, 1 H), 3.67 (dd,
J = 6.0, 2.7 Hz, 1 H), 3.66 (s, 3 H), 2.38 (ddd, J = 15.7, 9.6, 5.8 Hz,
1 H), 2.28 (ddd, J = 15.7, 9.3, 6.5 Hz, 1 H), 1.79 (dddd, J = 13.3,
9.6, 6.5, 4.9 Hz, 1 H), 1.69 (dddq, J = 9.3, 7.0, 4.7, 2.3 Hz, 1 H),
1.45 (app ddt, J = 13.3, 9.4, 5.8 Hz, 1 H), 1.38 (s, 3 H), 1.31 (s,
3 H), 0.90 (d, J = 6.9 Hz, 3 H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.06 (s,
3 H).
1.95 mmol) in pentane (60 mL) was added H2O (35 mL,
1.95 mmol) at r.t. After 2 h the solution and the precipitate were
separated; the precipitate was dried in vacuo overnight. TPPB⋅H2O
was obtained as a colorless solid (999 mg, 1.89 mmol, 97%) and
was stored under argon at –18 °C.
19F NMR (500 MHz, C6D6): d = –134.5 (m, ortho), –153.3 (m,
para), 162.4 (m, meta).
13C NMR (125 MHz, CDCl3): d = 174.1, 108.4, 76.7, 76.2, 67.0,
a,b-Unsaturated Ester ent-17
51.5, 36.4, 32.4, 28.3, 26.6, 25.9 (3 C), 25.3, 18.2, 14.0, –4.0, –4.1.
A solution of freshly distilled aldehyde ent-16 (3.13 g, 24.0 mmol)
in Et2O (75 mL) was stirred at –50 °C. TPPB⋅H2O (318 mg,
601 mmol) was added and the resulting mixture was stirred for
5 min. Then a solution of ketene acetal 14 (6.59 g, 28.8 mmol) and
i-PrOH (1.27 mL, 16.6 mmol) in Et2O (total solution volume,
30 mL) was added over 40 min. The solution was allowed to warm
to r.t. overnight. After stirring for 48 h the solution was concentrat-
ed in vacuo. The crude material was purified by flash column chro-
matography (hexane–EtOAc, 3:1 → 1:1) to provide ester ent-17 as
a colorless oil (3.51 g, 14.4 mmol, 61%, dr 14:1:1).
HRMS (EI): m/z calcd for C17H33O5Si [M – CH3]+: 345.20972;
found: 345.20855.
Lactone 20
To a stirred solution of silyl ether 19 (28.0 mg, 77.7 mmol) in THF
(1 mL) was added TBAF (1 M in THF; 0.09 mL, 0.09 mmol) at r.t.
The reaction mixture was stirred for 4 h at r.t. and subsequently
quenched with a sat. aq solution of NaHCO3 (2 mL). The aqueous
layer was extracted with MTBE (25 mL). The combined organic
layers were washed with brine (5 mL), dried over MgSO4, filtered,
and concentrated in vacuo. The crude material was purified by flash
column chromatography (hexane–EtOAc, 4:1) to provide lactone
20 as a colorless oil (3.0 mg, 14 mmol, 18%).
[a]D23 –51.5 (c 0.94, CHCl3); Rf 0.53 (hexane–EtOAc, 1:2).
1H NMR (400 MHz, CDCl3): d = 6.92 (dd, J = 15.7, 8.2 Hz, 1 H),
5.85 (dd, J = 15.7, 1.0 Hz, 1 H), 4.02 (app q, J = 5.7 Hz, 1 H), 3.96
(dd, J = 8.0, 6.3 Hz, 1 H), 3.89 (dd, J = 7.9, 6.5 Hz, 1 H), 3.72 (s,
3 H), 3.71–3.68 (m, 1 H), 2.51–2.43 (m, 1 H), 2.24 (br s, 1 H), 1.40
(s, 3 H), 1.33 (s, 3 H), 1.14 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.8, 150.3, 121.4, 109.0, 76.4,
73.5, 64.9, 51.6, 39.2, 26.6, 25.2, 14.3.
[a]D23 +42.5 (c 0.08, CHCl3); Rf 0.22 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = 4.16 (dd, J = 9.3, 2.8 Hz, 1 H),
4.16 (dd, J = 8.8, 5.8 Hz, 1 H), 4.10 (ddd, J = 9.4, 5.7, 4.0 Hz, 1 H),
4.01 (dd, J = 8.7, 4.1 Hz, 1 H), 2.56 (dd, J = 8.8, 6.1 Hz, 2 H), 2.34
(dddq, J = 7.2, 5.4, 3.3, 2.8 Hz, 1 H), 2.08 (ddt, J = 13.9, 8.7,
5.3 Hz, 1 H), 1.74 (ddt, J = 13.8, 6.0, 3.4 Hz, 1 H), 1.41 (s, 3 H),
1.36 (s, 3 H), 1.06 (d, J = 7.2 Hz, 3 H).
HRMS (ESI): m/z calcd for C12H21O5 [M + H]+: 245.1389; found:
245.1396.
13C NMR (125 MHz, CDCl3): d = 170.7, 109.7, 82.9, 73.8, 67.7,
Silyl Ether 18
27.0, 26.4 (2 C), 26.2, 25.1, 11.8.
A solution of alcohol ent-17 (93.3 mg, 383 mmol) in CH2Cl2
(5 mL) was stirred at 0 °C and 2,6-lutidine (0.11 mL, 0.96 mmol)
and TBSOTf (0.15 mL, 0.65 mmol) were added. The reaction mix-
ture was stirred for 3.5 h at r.t. and subsequently quenched with a
sat. aq solution of NaHCO3 (5 mL). The aqueous layer was extract-
ed with MTBE (30 mL). The combined organic layers were washed
with brine (5 mL), dried over MgSO4, and concentrated in vacuo.
The crude material was purified by flash column chromatography
(hexane–EtOAc, 19:1) to provide silyl ether 18 as a colorless oil
(105 mg, 292 mmol, 77%).
HRMS (EI): m/z calcd for C10H15O4 [M – CH3]+: 199.09703; found:
199.09716.
(S)-Mosher Ester 21
Et3N (32 mL, 24 mg, 0.24 mmol), DMAP (3.2 mg, 26 mmol), and
(R)-(–)-a-methoxy-a-(trifluoromethyl)phenylacetyl
chloride
(7.4 mL, 40 mmol) were added to a stirred solution of alcohol ent-
17 (6.5 mg, 26 mmol) in CH2Cl2 (0.5 mL) at r.t. After 14 h EtOAc
(20 mL) was added. The organic layer was washed with a solution
of NaHSO4 (1 M; 30 mL), NaOH (2 M; 10 mL), a sat. aq solution
of NaHCO3 (20 mL), and brine (10 mL). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo to provide
the crude (S)-Mosher ester 21 as a colorless liquid (11.0 mg,
23.9 mmol, 90%).
[a]D23 +44.3 (c 2.61, CHCl3); Rf 0.31 (hexane–EtOAc, 9:1).
1H NMR (500 MHz, CDCl3): d = 7.00 (dd, J = 15.7, 7.1 Hz, 1 H),
5.83 (dd, J = 15.8, 1.4 Hz, 1 H), 3.97 (app q, J = 6.2 Hz, 1 H), 3.93
(dd, J = 7.6, 6.3 Hz, 1 H), 3.79–3.74 (m, 2 H), 3.72 (s, 3 H), 3.64–
2.57 (m, 1 H), 1.38 (s, 3 H), 1.31 (s, 3 H), 1.09 (d, J = 6.9 Hz, 3 H),
0.87 (s, 9 H), 0.06 (s, 3 H), 0.04 (s, 3 H).
Rf 0.36 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = 7.53–7.50 (m, 2 H), 7.42–7.39 (m,
3 H), 6.84 (dd, J = 15.7, 7.2 Hz, 1 H), 5.76 (dd, J = 15.8, 1.5 Hz,
1 H), 5.27 (dd, J = 6.7, 4.1 Hz, 1 H), 4.18 (q, J = 6.5 Hz, 1 H), 3.94
13C NMR (125 MHz, CDCl3): d = 166.9, 151.7, 120.8, 108.7, 76.5,
75.8, 66.6, 51.4, 40.3, 26.6, 25.9 (3 C), 25.3, 18.2, 14.1, –4.1, –4.2.
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

2596
F. P. Liesener et al.
PAPER
(dd, J = 8.4, 6.2 Hz, 1 H), 3.73 (dd, J = 8.4, 6.3 Hz, 1 H), 3.73 (s,
3 H), 3.50 (app q, JH-F = 1.2 Hz, 3 H), 2.80 (ddquin, J = 7.0, 4.1,
1.5 Hz, 1 H), 1.39 (s, 3 H), 1.33 (s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H).
0 °C, and a,b-unsaturated ester 23 (2.86 g, 7.99 mmol) was added.
After 20 h, the reaction was quenched by the addition of Na2SO3
(12.1 g, 98.8 mmol), warmed to r.t., and stirred for 1 h. Brine
(10 mL) and EtOAc (10 mL) were added. The mixture was extract-
ed with EtOAc (175 mL), dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude material was purified by flash column
chromatography (hexane–EtOAc, 2:1) to provide diol 24 (2.89 g,
7.37 mmol, 92%, dr 19:1) as a colorless liquid.
5
13C NMR (125 MHz, CDCl3): d = 166.4, 165.8, 148.4, 131.7, 129.8,
1
128.5 (2 C), 127.4 (2 C), 123.3 (app d, J C-F = 288.9 Hz), 122.1,
109.6, 84.7 (app d, 2J C-F = 27.8 Hz), 77.5, 74.1, 66.3, 55.4 (app d,
3J C-F = 1.4 Hz), 51.6, 37.8, 26.5, 25.1, 13.3.
HRMS (EI): m/z calcd for C22H27F3O7 [M]+: 460.17090; found:
460.17147.
[a]D23 –24.2 (c 1.19, CHCl3); Rf 0.18 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 4.27 (d, J = 2.1 Hz, 1 H), 4.08 (t,
J = 6.1 Hz, 1 H), 4.03 (dd, J = 7.7, 6.4 Hz, 1 H), 3.84–3.78 (m,
3 H), 3.81 (s, 3 H), 3.16 (br s, 1 H), 2.43 (br s, 1 H), 2.03 (app dquin,
J = 6.9, 2.5 Hz, 1 H), 1.39 (s, 3 H), 1.31 (s, 3 H), 1.05 (d,
J = 7.2 Hz, 3 H), 0.96 (t, J = 8.0 Hz, 9 H), 0.61 (q, J = 7.9 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 174.0, 108.7, 77.0, 74.9, 72.6,
72.2, 66.9, 52.7, 40.5, 26.5, 25.1, 10.5, 6.8 (3 C), 5.2 (3 C).
(R)-Mosher Ester 22
To a mixture of (R)-(+)-a-methoxy-a-trifluoromethylphenylacetic
acid (10.1 mg, 43.0 mmol), DCC (17.7 mg, 86.0 mmol), and
DMAP (3.5 mg, 29 mmol) in THF (0.8 mL) was added alcohol ent-
17 (7.0 mg, 29 mmol) in THF (0.5 mL) at r.t. The reaction was di-
luted with CH2Cl2 (2 mL) after 4 d and a sat. aq solution of NaHCO3
(1 mL) was added. The layers were separated and the aqueous layer
was extracted with CH2Cl2 (6 mL). The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo to provide the
crude (R)-Mosher ester 22 as a colorless liquid (7.0 mg, 15 mmol,
53%).
HRMS (ESI): m/z calcd for C18H37O7Si [M + H]+: 393.2309; found:
393.2296.
Acetonide 25
To a stirred solution of diol 24 (2.84 g, 7.23 mmol) in CH2Cl2
(45 mL) was added 2,2-DMP (13.3 mL, 108 mmol) and CSA
(168 mg, 723 mmol) at r.t. The mixture was stirred for 3 h at ambi-
ent temperature and the reaction was quenched by the addition of a
sat. aq solution of NaHCO3 (15 mL). The layers were separated and
the aqueous layer was extracted with MTBE (60 mL). The com-
bined organic layers were washed with brine (10 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude material was
purified by flash column chromatography (hexane–EtOAc, 9:1) to
provide acetonide 25 as a colorless liquid (2.52 g, 5.82 mmol,
81%).
Rf 0.37 (hexane–EtOAc, 2:1).
1H NMR (500 MHz, CDCl3): d = 7.50–7.47 (m, 2 H), 7.42–7.39 (m,
3 H), 6.92 (dd, J = 15.8, 6.8 Hz, 1 H), 5.83 (dd, J = 15.8, 1.6 Hz,
1 H), 5.24 (dd, J = 7.5, 3.7 Hz, 1 H), 4.11 (dt, J = 7.5, 6.1 Hz, 1 H),
3.87 (dd, J = 8.5, 6.2 Hz, 1 H), 3.75 (s, 3 H), 3.68 (dd, J = 8.5,
6.2 Hz, 1 H), 3.48 (app q, JH-F = 1.2 Hz, 3 H), 2.86 (ddquin,
J = 6.8, 3.7, 1.7 Hz, 1 H), 1.35 (s, 3 H), 1.31 (s, 3 H), 1.12 (d,
J = 6.9 Hz, 3 H).
5
13C NMR (125 MHz, CDCl3): d = 166.4, 165.9, 148.9, 131.5, 129.8,
1
128.5 (2 C), 127.6 (2 C), 123.3 (app d, J C-F = 288.9 Hz), 122.1,
109.7, 84.7 (app d, 2J C-F = 28.3 Hz), 77.7, 74.0, 66.6, 55.4 (app d,
3J C-F = 1.4 Hz), 51.4, 37.7, 26.5, 25.3, 13.0.
[a]D23 –43.4 (c 1.04, CHCl3); Rf 0.24 (hexane–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): d = 4.29 (dd, J = 7.7, 2.5 Hz, 1 H),
4.23 (d, J = 7.7 Hz, 1 H), 4.15 (app dt, J = 6.7, 4.0 Hz, 1 H), 3.98
(dd, J = 7.9, 6.4 Hz, 1 H), 3.88 (t, J = 4.0 Hz, 1 H), 3.87 (dd,
J = 7.8, 6.9 Hz, 1 H), 3.76 (s, 3 H), 2.07 (ddq, J = 7.1, 3.8, 2.7 Hz,
1 H), 1.43 (s, 3 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.32 (s, 3 H), 1.00
(d, J = 7.2 Hz, 3 H), 0.95 (t, J = 7.8 Hz, 9 H), 0.61 (q, J = 7.9 Hz,
6 H).
13C NMR (100 MHz, CDCl3): d = 171.5, 111.1, 108.0, 78.0, 77.0,
76.4, 74.7, 65.4, 52.2, 39.1, 26.9, 26.5, 25.5, 25.0, 9.1, 6.9 (3 C), 5.1
(3 C).
HRMS (EI): m/z calcd for C22H27F3O7 [M]+: 460.17090; found:
460.17155.
Triethylsilyl Ether 23
Alcohol ent-17 (50.0 mg, 0.204 mmol) was dissolved in DMF
(2 mL). Imidazole (31 mg, 0.45 mmol), DMAP (cat., 0.5 mg,
0.4 mmol), and TESCl (52 mL, 0.31 mmol) were added at 0 °C. Af-
ter stirring for 6 h, the reaction mixture was quenched with H2O
(5 mL), and the aqueous layer was extracted with MTBE (15 mL).
The combined organic layers were washed with brine (5 mL), dried
over MgSO4, and concentrated in vacuo. The crude material was pu-
rified by flash column chromatography (hexane–EtOAc, 19:1) to
provide 23 as a colorless oil (57 mg, 0.16 mmol, 77%).
HRMS (ESI): m/z calcd for C21H41O7Si [M + H]+: 433.2622; found:
433.2624.
Thiocarbonyl Imidazolide 26
[a]D23 –43.3 (c 1.04, CHCl3); Rf 0.30 (hexane–EtOAc, 9:1).
To a solution of triethyl silyl ether 25 (2.27 g, 5.26 mmol) in py
(15 mL) and THF (15 mL) was added HF⋅py (ca. 7:3, 2.73 mL,
105 mmol). After stirring for 14 h at r.t., the mixture was quenched
with a sat. aq solution of NaHCO3 (40 mL), and NaHCO3 (17 g)
was added until the solution was pH 8. The aqueous layer was ex-
tracted with MTBE (100 mL). The combined organic layers were
washed with brine (10 mL), dried over MgSO4, filtered, and con-
centrated in vacuo. The crude material was purified by flash column
chromatography (hexane–EtOAc, 3:1 → 1:1) to provide the desired
secondary alcohol as a colorless liquid (1.58 g, 4.97 mmol, 95%).
1H NMR (400 MHz, CDCl3): d = 7.00 (dd, J = 15.6, 7.2 Hz, 1 H),
5.82 (dd, J = 15.8, 1.5 Hz, 1 H), 3.98–3.91 (m, 2 H), 3.81–3.74 (m,
2 H), 3.72 (s, 3 H), 2.58 (app ddquin, J = 7.9, 3.7, 1.5 Hz, 1 H), 1.37
(s, 3 H), 1.30 (s, 3 H) 1.07 (d, J = 6.9 Hz, 3 H), 0.93 (t, J = 7.8 Hz,
9 H), 0.58 (q, J = 8.0 Hz, 6 H).
13C NMR (100 MHz, CDCl3): d = 166.9, 151.7, 120.8, 108.8, 76.5,
75.9, 66.5, 51.4, 40.3, 26.6, 25.3, 13.1, 6.8 (3 C), 5.2 (3 C).
HRMS (ESI): m/z calcd for C18H35O5Si [M + H]+: 359.2254; found:
359.2242.
[a]D23 –27.6 (c 1.03, CHCl3); Rf 0.21 (hexane–EtOAc, 2:1).
Diol 24
1H NMR (400 MHz, CDCl3): d = 4.35 (d, J = 7.5 Hz, 1 H), 4.25
(dd, J = 7.5, 4.1 Hz, 1 H), 4.08 (dd, J = 7.7, 6.3 Hz, 1 H), 4.02 (ddd,
J = 7.6, 5.6, 5.4 Hz, 1 H), 3.94 (dd, J = 7.7, 4.7 Hz, 1 H), 3.78 (s,
3 H), 3.75–3.71 (m, 1 H), 2.56 (br s, 1 H), 2.21–2.14 (m, 1 H), 1.45
(s, 3 H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.33 (s, 3 H), 1.03 (d,
J = 6.9 Hz, 3 H).
To a stirred solution of (DHQ)2PHAL (622 mg, 799 mmol),
K3Fe(CN)6 (7.89 g, 24.0 mmol), and K2CO3 (3.31 g, 24.0 mmol) in
t-BuOH–H2O (70 mL, 1:1) was added OsO4 (0.08 M in t-BuOH;
2.0 mL, 0.16 mmol) and MsNH2 (2.28 g, 24.0 mmol) at r.t. The
mixture was stirred for 5 min at ambient temperature, cooled to
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2597
13C NMR (100 MHz, CDCl3): d = 171.9, 111.1, 109.0, 82.0, 76.5,
75.5, 74.9, 67.3, 52.6, 36.3, 26.8, 26.5, 25.3, 25.2, 6.7.
13C NMR (125 MHz, CDCl3): d = 175.8, 111.2, 108.9, 82.7, 76.1,
73.7, 69.7, 37.4, 32.4, 27.0, 26.8, 25.7, 25.5, 13.5.
HRMS (ESI): m/z calcd for C15H27O7 [M + H]+: 319.1757; found:
HRMS (ESI): m/z calcd for C14H24O6 [M + H]+: 289.1651; found:
319.1765.
289.1645.
A stirred solution of the secondary alcohol (1.5 g, 4.7 mmol), 1,1-
thiocarbonyldiimidazole (1.51 g, 8.47 mmol), and DMAP (172 mg,
1.41 mmol) in toluene (40 mL) was heated to 120 °C. After 21 h the
solvent was removed in vacuo. The crude material was purified by
flash column chromatography (hexane–EtOAc, 1:1) to provide 26
as a colorless liquid (1.85 g, 4.32 mmol, 92%).
Methyl Ketone 29
To a stirred solution of acid 28 (86.3 mg, 299 mmol) in THF (2 mL)
was added NMM (36 mL, 0.33 mmol) and isobutyl chloroformate
(43 mL, 0.33 mmol) at –20 °C. After 20 min NMM (43 mL,
0.39 mmol) and N,O-dimethylhydroxylamine (32.1 mg, 329 mmol)
were added. The reaction was stirred for 2 h at 0 °C then quenched
with a sat. aq solution of NaHCO3 (5 mL) and MTBE (5 mL). The
layers were separated and the aqueous layer was extracted with
MTBE (20 mL). The combined organic layers were washed with
brine (5 mL), dried over MgSO4, filtered, and concentrated in vac-
uo. The crude material was purified by flash column chromatogra-
phy (hexane–EtOAc, 2:1) to provide the desired Weinreb amide as
a colorless liquid (76.6 mg, 231 mmol, 77%).
[a]D23 –4.6 (c 0.96, CHCl3); Rf 0.21 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): d = 8.31 (s, 1 H), 7.61 (s, 1 H), 7.02
(s, 1 H), 5.91 (dd, J = 6.7, 3.1 Hz, 1 H), 4.42–4.38 (m, 1 H), 4.26–
4.24 (m, 1 H), 4.21 (d, J = 8.0 Hz, 1 H), 4.07 (dd, J = 8.8, 6.4 Hz,
1 H), 4.00 (dd, J = 8.8, 4.8 Hz, 1 H), 3.73 (s, 3 H), 2.64–2.58 (m,
1 H), 1.39 (s, 3 H), 1.34 (s, 3 H), 1.27 (s, 3 H), 1.21 (s, 3 H) 1.16 (d,
J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 184.3, 170.9, 136.8, 130.4, 118.2,
111.2, 109.9, 85.2, 79.6, 76.3, 74.0, 66.3, 52.4, 35.4, 26.6, 26.4,
24.9 (2 C), 7.4.
[a]D23 –9.1 (c 1.00, CHCl3); Rf 0.16 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 4.59–4.51 (m, 1 H), 4.40–4.32 (m,
1 H), 4.21–4.15 (m, 1 H), 4.03 (dd, J = 7.8, 6.0 Hz, 1 H), 3.74 (s,
3 H), 3.47 (app t, J = 7.5 Hz, 1 H), 3.22 (br s, 3 H), 2.03–1.94 (m,
1 H), 1.63 (ddd, J = 13.5, 9.0, 4.0 Hz, 1 H), 1.44 (s, 3 H), 1.42 (s,
3 H), 1.40–1.35 (m, 1 H), 1.37 (s, 3 H), 1.33 (s, 3 H), 1.00 (d,
J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 170.8, 110.3, 108.7, 81.9, 77.2,
74.3, 73.6, 69.8, 61.7, 37.3, 32.1, 30.9, 27.0, 26.0, 25.7, 14.4.
HRMS (ESI): m/z calcd for C16H30NO6 [M + H]+: 332.2073; found:
332.2082.
HRMS (ESI): m/z calcd for C19H29N2O7S [M + H]+: 429.1695;
found: 429.1692.
Ester 27
A
stirred solution of thiocarbonylimidazolide 26 (1.72 g,
4.02 mmol) in Et3SiH (19.3 mL, 14.0 g, 121 mmol) was heated to
reflux. Bz2O2 (5 × 195 mg, 4.02 mmol) was added in five portions
at 40 min intervals. The reaction was quenched with a sat. aq solu-
tion of NH4Cl (10 mL). The layers were separated and the aqueous
layer was extracted with MTBE (50 mL). The combined organic
layers were washed with NaHCO3 (5 mL), brine (5 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The crude material was
purified by flash column chromatography (hexane–EtOAc, 4:1) to
provide ester 27 as a colorless liquid (943 mg, 3.12 mmol, 78%).
MeMgCl (3 M in THF; 0.24 mL, 0.73 mmol) was added dropwise
to a stirred solution of the Weinreb amide (48.3 mg, 146 mmol) in
THF (3 mL) at 0 °C. After 1 h the reaction was quenched with a sat.
aq solution of NH4Cl (4 mL) and MTBE (5 mL). The layers were
separated and the aqueous layer was extracted with MTBE (20 mL).
The combined organic layers were washed with brine (5 mL), dried
over MgSO4, filtered, and carefully concentrated in vacuo (bath
temperature 35 °C). The crude material was purified by flash col-
umn chromatography (hexane–EtOAc, 9:1) to provide methyl ke-
tone 29 as a colorless liquid (35.4 mg, 124 mmol, 85%).
[a]D23 –20.4 (c 0.855, CHCl3); Rf 0.29 (hexane–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 4.27 (d, J = 7.2 Hz, 1 H), 4.19
(dddd, J = 8.9, 6.9, 5.9, 4.1 Hz, 1 H), 4.13 (dd, J = 7.0, 4.4 Hz, 1 H),
4.05 (dd, J = 7.8, 5.9 Hz, 1 H), 3.78 (s, 3 H), 3.51 (dd, J = 7.8,
7.2 Hz, 1 H), 2.11–2.01 (m, 1 H), 1.76 (ddd, J = 13.5, 9.1, 4.2 Hz,
1 H), 1.45 (s, 3 H), 1.44–1.38 (m, 1 H), 1.41 (s, 3 H), 1.40 (s, 3 H),
1.35 (s, 3 H), 1.01 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 172.0, 110.9, 108.8, 82.7, 76.6,
73.8, 69.8, 52.4, 37.5, 32.3, 27.0, 26.8, 25.8, 25.6, 13.7.
HRMS (ESI): m/z calcd for C15H27O6 [M + H]+: 303.1808; found:
303.1813.
[a]D23 +19.3 (c 1.01, CHCl3); Rf 0.33 (hexane–EtOAc, 4:1).
1H NMR (400 MHz, CDCl3): d = 4.17 (dddd, J = 8.9, 7.0, 5.9,
4.1 Hz, 1 H), 4.07 (d, J = 7.3 Hz, 1 H), 4.04 (dd, J = 8.0, 6.1 Hz,
1 H), 4.01 (dd, J = 7.3, 4.4 Hz, 1 H), 3.49 (app dd, J = 7.7, 7.3 Hz,
1 H), 2.27 (s, 3 H), 2.04–1.95 (m, 1 H), 1.72 (ddd, J = 13.7, 9.1,
4.4 Hz, 1 H), 1.44 (s, 3 H), 1.42–1.35 (m, 1 H), 1.38 (s, 3 H), 1.37
(s, 3 H), 1.33 (s, 3 H), 1.00 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 209.2, 110.2, 108.7, 83.0, 81.3,
Acid 28
73.8, 69.8, 37.6, 32.5, 27.0, 26.8, 26.5, 26.1, 25.8, 13.8.
A solution of methyl ester 27 (37.0 mg, 126 mmol) in H2O–THF
(1:1, 1.5 mL) was stirred with NaOH (12.6 mg, 314 mmol) for 2.5 h
at r.t. The reaction was quenched with H2O (5 mL), CH2Cl2 (5 mL),
and citric acid monohydrate (91.8 mg, 478 mmol). The layers were
separated and the aqueous layer was extracted with CH2Cl2
(20 mL). The combined organic layers were dried over MgSO4, fil-
tered, and concentrated in vacuo to provide acid 28 as a colorless
liquid (35.9 mg, 125 mmol, 99%).
HRMS (ESI): m/z calcd for C15H27O5 [M + H]+: 287.1858; found:
287.1857.
Ester 38
A solution of i-Pr2NH (4.6 mL, 32.7 mmol) in THF (40 mL) was
treated with n-BuLi (2.5 M solution in hexane; 13.1 mL,
32.7 mmol) at 0 °C. After stirring at this temperature for 45 min, the
mixture was cooled to –78 °C, and ester 3731 (7.09 g, 27.2 mmol)
dissolved in THF (20 mL) was added. The resulting solution was
stirred for 2 h at –78 °C, before MeI (2.0 mL, 32.7 mmol) was add-
ed. The cooling bath was removed after 20 min and stirring contin-
ued at r.t. for 1 h. The mixture was diluted with MTBE (50 mL),
washed with a solution of HCl (2 M; 40 mL), a sat. aq solution of
Na2S2O3 (40 mL), H2O (40 mL), brine (40 mL), dried over MgSO4,
and concentrated in vacuo to provide the product 38 as a colorless
[a]D23 –16.2 (c 1.02, CHCl3); Rf 0.02 (EtOAc).
1H NMR (500 MHz, CDCl3): d = 10.1 (br s, 1 H), 4.30 (d,
J = 7.0 Hz, 1 H), 4.23–4.18 (m, 1 H), 4.15 (dd, J = 6.9, 4.5 Hz,
1 H), 4.06 (dd, J = 7.9, 6.0 Hz, 1 H), 3.52 (app t, J = 7.5 Hz, 1 H),
2.12–2.05 (m, 1 H), 1.78 (ddd, J = 13.6, 9.2, 4.3 Hz, 1 H), 1.46 (s,
3 H), 1.43–1.40 (m, 1 H), 1.42 (s, 3 H), 1.40 (s, 3 H), 1.34 (s, 3 H),
1.02 (d, J = 6.8 Hz, 3 H).
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F. P. Liesener et al.
PAPER
oil, which could be used in the next reaction without further purifi-
cation (dr 1.8:1).
Rf 0.64 (hexane–EtOAc, 3:1)
Major diastereomer
Rf 0.65 (hexane–EtOAc, 3:1)
1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 8.5 Hz, 2 H), 7.35–
7.32 (m, 2 H), 3.98–3.81 (m, 2 H), 3.64–3.49 (m, 2 H), 2.44 (s, 3 H),
1.86–1.80 (m, 1 H), 1.78–1.61 (m, 1 H), 1.52–1.44 (m, 1 H), 1.30
(dddd, J = 13.2, 8.6, 7.0, 5.9 Hz, 1 H), 0.87 (s, 9 H), 0.79 (d,
J = 6.8 Hz, 3 H), 0.71 (d, J = 6.8 Hz, 3 H), 0.02 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 144.6, 133.1, 129.8, 127.9, 73.7,
61.2, 37.3, 36.5, 29.9, 25.9, 21.6, 18.2, 14.2, 11.3, –5.4 (2 C).
Major diastereomer
1H NMR (400 MHz, CDCl3): d = 3.65 (s, 3 H), 3.64–3.57 (m, 2 H),
2.41 (ddd, J = 14.0, 7.0, 5.7 Hz, 1 H), 2.03–1.96 (m, 1 H), 1.56 (dtd,
J = 13.6, 7.2, 5.0 Hz, 1 H), 1.35 (dddd, J = 13.6, 8.7, 6.7, 5.6 Hz, 1
H), 1.06 (d, J = 7.2 Hz, 3 H), 0.88 (s, 9 H), 0.86 (d, J = 6.7 Hz, 3 H),
0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 176.6, 61.3, 51.3, 44.1, 37.5,
Minor diastereomer
32.2, 25.9, 18.3, 15.8, 12.2, –5.3.
1H NMR (400 MHz, CDCl3): d = 7.78 (d, J = 8.5 Hz, 2 H), 7.35–
7.32 (m, 2 H), 3.98–3.81 (m, 2 H), 3.64–3.49 (m, 2 H), 2.44 (s, 3 H),
1.86–1.80 (m, 1 H), 1.78–1.61 (m, 1 H), 1.52–1.44 (m, 1 H), 1.21
(dddd, J = 13.1, 9.6, 7.1, 5.7 Hz, 1 H), 0.87 (s, 9 H), 0.86 (d,
J = 6.8 Hz, 3 H), 0.81 (d, J = 6.8 Hz, 3 H), 0.02 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 144.6, 133.1, 129.8, 127.8, 73.4,
61.3, 37.5, 35.7, 31.0, 25.9, 21.6, 18.3, 16.6, 13.5, –5.4 (2 C).
Minor diastereomer
1H NMR (400 MHz, CDCl3): d = 3.69–3.62 (m, 2 H), 3.65 (s, 3 H),
2.38 (ddd, J = 13.9, 7.0, 5.8 Hz, 1 H), 1.93–1.85 (m, 1 H), 1.64 (dtd,
J = 13.5, 7.3, 4.2 Hz, 1 H), 1.31 (dddd, J = 13.5, 9.2, 6.6, 5.5 Hz, 1
H), 1.11 (d, J = 7.0 Hz, 3 H), 0.89 (d, J = 7.0 Hz, 3 H), 0.88 (s, 9 H),
0.03 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 176.4, 61.1, 51.2, 44.5, 36.4,
32.8, 25.9, 18.3, 17.0, 13.9, –5.4 (2C).
HRMS (EI): m/z calcd for C20H37O4SSi [M + H]+: 401.2182; found:
401.2181.
HRMS (EI): m/z calcd for C13H27O3Si [M – CH3]+: 259.1729;
found: 259.1727.
Aldehyde 40
A solution of silyl ether 39 (8.00 g, 20.0 mmol) in THF (40 mL) and
py (11.4 mL) was treated with a solution of HF⋅py (ca. 7:3, 5.2 mL,
200 mmol) at r.t. and the resulting solution was stirred for 14 h. A
sat. aq solution of NaHCO3 (100 mL) was carefully added until the
solution was pH 7 and the mixture was extracted with MTBE
(210 mL). The combined organic layers were washed with brine
(40 mL), dried over MgSO4, and concentrated in vacuo. The crude
material was purified by flash column chromatography (hexane–
EtOAc, 1:1) to provide the desired alcohol as a colorless oil (5.40 g,
18.9 mmol, 94%).
Tosylate 39
A solution of ester 38 (7.21 g, 26.3 mmol) in THF (70 mL) was
treated at –78 °C with DIBAL-H (1.5 M solution in toluene; 44 mL,
65.7 mmol). After stirring at –78 °C for 2.5 h, a sat. aq solution of
NH4Cl (10 mL), a sat. aq solution of Rochelle salt (100 mL), and
EtOAc (50 mL) were added. The mixture was extracted with EtOAc
(180 mL). The combined organic phases were dried over MgSO4
and concentrated in vacuo. The crude material was purified by flash
column chromatography (hexane–EtOAc, 5:1) to provide the de-
sired alcohol as a colorless oil (6.31 g, 25.6 mmol, 97% over two
steps).
Rf 0.28 (hexane–EtOAc, 1:1)
Major diastereomer
Rf 0.43 (hexane–EtOAc, 3:1)
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 8.0 Hz, 2 H), 7.33 (d,
J = 8.0 Hz, 2 H), 3.90 (dd, J = 9.6, 7.2 Hz, 1 H), 3.85 (dd, J = 9.6,
6.8 Hz, 1 H), 3.68–3.51 m, 2 H), 2.43 (s, 3 H), 1.87–1.80 (m, 1 H),
1.69–1.63 (m, 2 H), 1.57–1.48 (m, 1 H), 1.36 (dddd, J = 13.5, 8.7,
7.2, 6.0 Hz, 1 H), 0.78 (d, J = 7.5 Hz, 3 H), 0.72 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 144.7, 132.9, 129.8, 127.8, 73.6,
60.8, 37.2, 36.5, 29.6, 21.6, 14.0, 11.2.
Major diastereomer
1H NMR (400 MHz, CDCl3): d = 3.67–3.58 (m, 2 H), 3.57–3.42 (m,
2 H), 1.89 (br s, 1 H), 1.78–1.69 (m, 1 H), 1.66–1.54 (m, 2 H), 1.38
(dddd, J = 13.5, 8.0, 7.0, 5.6 Hz, 1 H), 0.88 (s, 9 H), 0.83 (d,
J = 6.8 Hz, 3 H), 0.80 (d, J = 6.8 Hz, 3 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 66.7, 61.7, 39.8, 37.8, 30.1, 25.9,
18.3, 14.7, 11.8, –5.3 (2 C).
Minor diastereomer
Minor diastereomer
1H NMR (400 MHz, CDCl3): d = 7.77 (d, J = 8.0 Hz, 2 H), 7.33 (d,
J = 8.0 Hz, 2 H), 3.96 (dd, J = 9.6, 6.1 Hz, 1 H), 3.83 (dd, J = 9.6,
6.8 Hz, 1 H), 3.68–3.51 (m, 2 H), 2.43 (s, 3 H), 1.79–1.71 (m, 1 H),
1.69–1.63 (m, 2 H), 1.57–1.48 (m, 1 H), 1.26 (dddd, J = 13.5, 9.9,
7.0, 5.1 Hz, 1 H), 0.84 (d, J = 6.8 Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 144.7, 132.9, 129.8, 127.8, 73.1,
60.9, 37.4, 35.3, 30.7, 21.6, 16.5, 13.1.
1H NMR (400 MHz, CDCl3): d = 3.72–3.66 (m, 2 H), 3.57–3.42 (m,
2 H), 1.89 (br s, 1 H), 1.78–1.69 (m, 1 H), 1.66–1.54 (m, 2 H), 1.22
(dddd, J = 13.7, 8.9, 6.1, 4.8 Hz, 1 H), 0.90 (d, J = 6.8 Hz, 3 H),
0.89 (s, 9 H), 0.84 (d, J = 6.8 Hz, 3 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 66.0, 62.0, 40.3, 34.9, 30.4, 25.9,
18.3, 17.5, 12.7, –5.4 (2 C).
HRMS (EI): m/z calcd for C14H23O4S [M + H]+: 287.1317; found:
287.1314.
HRMS (ESI): m/z calcd for C13H31O2Si [M + H]+: 247.2093; found:
247.2101.
A solution of (COCl)2 (2.3 mL, 26.4 mmol) in CH2Cl2 (50 mL) was
treated at –78 °C with DMSO (2.5 mL, 35.3 mmol). After stirring
for 45 min, the primary alcohol (5.05 g, 17.6 mmol) dissolved in
CH2Cl2 (40 mL) was added. The mixture was stirred at –78 °C for
1.5 h, before it was treated with Et3N (12.3 mL, 88.2 mmol). The
solution was slowly warmed to r.t. with stirring over 1 h, then dilut-
ed with H2O (100 mL), and the mixture was extracted with MTBE
(210 mL). The combined organic layers were dried over MgSO4
and concentrated in vacuo to provide aldehyde 40 as a slightly yel-
low oil, which could be used in the next reaction without further pu-
rification.
A solution of the primary alcohol (6.31 g, 25.6 mmol) in py
(50 mL) was treated at 0 °C with TsCl (14.6 g, 76.8 mmol) dis-
solved in py (20 mL). The mixture was slowly warmed to r.t. with
stirring for 16 h, then H2O (40 mL) was added. The mixture was ex-
tracted with MTBE (150 mL). The combined organic layers were
washed with a sat. aq solution of NaHCO3 (60 mL), HCl (2 M;
60 mL), brine (60 mL), dried over MgSO4, and concentrated in vac-
uo. The crude material was purified by flash column chromatogra-
phy (hexane–EtOAc, 8:1), to provide tosylate 39 as a colorless oil
(9.95 g, 24.8 mmol, 97%).
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2599
Rf 0.22 (hexane–EtOAc, 3:1)
Rf 0.50 (hexane–EtOAc, 1:1)
Major diastereomer
Major diastereomer
1H NMR (400 MHz, CDCl3): d = 9.67 (t, J = 1.6 Hz, 1 H), 7.78 (d,
J = 8.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 3.90–3.87 (m, 2 H), 2.44
(s, 3 H), 2.39–2.12 (m, 3 H), 1.88–1.79 (m, 1 H), 0.81 (d, J = 6.5 Hz,
3 H), 0.79 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 201.7, 144.8, 132.8, 129.8, 127.8,
72.8, 48.6, 36.5, 28.1, 21.6, 14.6, 11.5.
1H NMR (400 MHz, CDCl3): d = 7.78–7.75 (m, 2 H), 7.34–7.32 (m,
2 H), 3.87 (dd, J = 9.7, 6.5 Hz, 1 H), 3.83 (dd, J = 9.7, 7.2 Hz, 1 H),
2.43 (s, 3 H), 2.41–2.20 (m, 2 H), 2.18–2.07 (m, 1 H), 2.09 (s, 3 H),
1.84–1.74 (m, 1 H), 0.79 (d, J = 6.8 Hz, 3 H), 0.73 (d, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 207.9, 144.7, 132.9, 129.8, 127.8,
73.2, 48.4, 36.4, 30.3, 29.5, 21.6, 14.7, 11.7.
Minor diastereomer
Minor diastereomer
1H NMR (400 MHz, CDCl3): d = 9.66 (t, J = 1.6 Hz, 1 H), 7.77 (d,
J = 8.5 Hz, 2 H), 7.34 (d, J = 8.5 Hz, 2 H), 3.93–3.84 (m, 2 H), 2.44
(s, 3 H), 2.39–2.12 (m, 3 H), 1.88–1.79 (m, 1 H), 0.88 (d, J = 6.5 Hz,
3 H), 0.86 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 201.9, 144.9, 132.8, 129.9, 127.8,
72.5, 47.1, 37.1, 29.0, 21.6, 17.2, 13.3.
1H NMR (400 MHz, CDCl3): d = 7.78–7.75 (m, 2 H), 7.34–7.32 (m,
2 H), 3.91 (dd, J = 9.7, 6.3 Hz, 1 H), 3.82 (dd, J = 9.7, 7.3 Hz, 1 H),
2.43 (s, 3 H), 2.41–2.20 (m, 2 H), 2.18–2.07 (m, 1 H), 2.08 (s, 3 H),
1.84–1.74 (m, 1 H), 0.84 (d, J = 7.2 Hz, 3 H), 0.81 (d, J = 6.8 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 208.1, 144.8, 132.8, 129.8, 127.8,
72.7, 47.0, 36.9, 30.3, 30.2, 21.6, 16.7, 13.5.
HRMS (ESI): m/z calcd for C16H23NO4SNa [M + Na + MeCN]+:
348.1245; found: 348.1248.
HRMS (ESI): m/z calcd for C15H23O4S [M + H]+: 299.1317; found:
Methyl Ketone 41
299.1312.
To a solution of MeMgCl (22% in THF; 30.8 mL, 88.0 mmol) in
THF (50 mL) was added a solution of aldehyde 40 (5.0 g,
17.6 mmol) in THF (40 mL) at –78 °C. The mixture was slowly
warmed to –50 °C with stirring for 3.5 h. A sat. aq solution of
NH4Cl (60 mL) was added and the reaction mixture was extracted
with MTBE (150 mL). The combined organic phases were dried
over MgSO4 and concentrated in vacuo. The crude material was pu-
rified by flash column chromatography (hexane–EtOAc, 4:1) to
provide the desired secondary alcohol as a slightly yellow oil
(4.69 g, 15.6 mmol, 89% over two steps).
Olefin 33
A solution of tosylate 41 (2.14 g, 7.17 mmol) in DMF (70 mL) was
treated at r.t. with NaI (2.69 g, 17.9 mmol) and DBU (5.4 mL,
35.9 mmol), and the resulting solution was heated to 100 °C with
stirring for 2.5 h. After cooling to r.t., the mixture was diluted with
Et2O (25 mL) and H2O (10 mL), and extracted with Et2O (90 mL),
the combined organic phases were washed with a sat. aq solution of
NaHCO3 (40 mL), HCl (2 M; 20 mL), brine (60 mL), dried over
MgSO4, and concentrated in vacuo (>550 mbar, bath temperature
30 °C). The crude material was purified by flash column chroma-
tography (pentane–Et2O, 10:1) to provide olefin 33 as a colorless
liquid (430 mg, 3.4 mmol, 40%).
Rf 0.40 (hexane–EtOAc, 1:1)
Mixture of four diastereomers
1H NMR (400 MHz, CDCl3): d = 7.80–7.77 (m, 2 H), 7.35–7.33 (m,
2 H), 4.01–3.77 (m, 3 H), 2.44 (s, 3 H), 1.93–1.59 (m, 3 H), 1.39–
1.07 (m, 5 H), 0.86–0.71 (m, 6 H).
[a]D23 +13.7 (c 0.68, CHCl3); Rf 0.54 (hexane–EtOAc, 3:1).
1H NMR (400 MHz, CDCl3): d = 4.65 (s, 2 H), 2.64 (sext,
J = 7.0 Hz, 1 H), 2.52 (dd, J = 15.9, 6.3 Hz, 1 H), 2.33 (dd, J = 15.9,
8.0 Hz, 1 H), 2.08 (s, 3 H), 1.66 (s, 3 H), 0.98 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 208.0, 148.8, 109.4, 49.3, 36.5,
30.1, 19.8, 19.4.
Major diastereomer
13C NMR (100 MHz, CDCl3): d = 144.7, 133.0, 129.8, 127.9, 73.6,
65.6, 44.0, 37.0, 29.7, 24.4, 21.6, 14.0, 11.4.
HRMS (EI): m/z calcd for C8H14O [M]+: 126.1045; found:
126.1045.
Minor diastereomer 1
13C NMR (100 MHz, CDCl3): d = 144.7, 133.0, 129.8, 127.8, 73.7,
66.0, 43.9, 35.9, 29.8, 23.6, 21.6, 14.4, 10.9.
Aldehyde 34
Minor diastereomer 2
DIBAL-H (1 M in hexane; 0.19 mL, 0.28 mmol) was added to a
stirred solution of ester 27 (70.0 mg, 232 mmol) in toluene (5 mL)
at –78 °C over 15 min. The reaction was stirred for 30 min at
–78 °C and then quenched with MeOH (0.40 mL) and an aq solu-
tion of Rochelle salt (1 M; 5 mL). The layers were separated and the
aqueous layer was extracted with MTBE (25 mL). The combined
organic layers were washed with brine (5 mL), dried over MgSO4,
filtered, and concentrated in vacuo. The crude material was purified
by flash column chromatography (hexane–EtOAc, 9:1→3:1) to
provide aldehyde 34 as a colorless liquid (46.4 mg, 170 mmol,
74%).
13C NMR (100 MHz, CDCl3): d = 144.7, 133.0, 129.8, 127.8, 72.9,
66.6, 42.1, 37.2, 31.5, 23.3, 21.6, 16.9, 13.4.
Minor diastereomer 3
13C NMR (100 MHz, CDCl3): d = 144.7, 133.0, 129.8, 127.9, 73.1,
65.5, 42.0, 37.7, 30.4, 24.6, 21.6, 16.4, 13.0.
HRMS (EI): m/z calcd for C15H25O4S [M + H]+: 301.1474; found:
301.1471.
A solution of (COCl)2 (1.9 mL, 22.22 mmol) in CH2Cl2 (40 mL)
was treated at –78 °C with DMSO (2.1 mL, 29.63 mmol). After stir-
ring for 1.5 h, the secondary alcohol (4.45 g, 14.81 mmol), dis-
solved in CH2Cl2 (35 mL), was added. The mixture was stirred at
–78 °C for 1.5 h, then treated with Et3N (10.3 mL, 74.07 mmol).
The solution was slowly warmed to r.t. with stirring over 45 min,
then diluted with H2O (50 mL), and the reaction mixture was ex-
tracted with MTBE (150 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo. Flash column chro-
matography (hexane–EtOAc, 3:1) afforded methyl ketone 41 as a
slightly yellow oil (3.48 g, 11.66 mmol, 79%).
[a]D23 +13.8 (c 0.98, CHCl3); Rf 0.28 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 9.75 (d, J = 2.0 Hz, 1 H), 4.18
(dddd, J = 9.2, 7.0, 5.8, 3.8 Hz, 1 H), 4.09 (dd, J = 7.0, 2.1 Hz, 1 H),
4.05 (dd, J = 7.9, 5.9 Hz, 1 H), 3.99 (dd, J = 6.9, 5.3 Hz, 1 H), 3.50
(dd, J = 7.8, 7.0 Hz, 1 H), 2.07–1.97 (m, 1 H), 1.73 (ddd, J = 13.6,
9.3, 4.0 Hz, 1 H), 1.48 (s, 3 H), 1.39 (s, 3 H), 1.38–1.32 (m, 1 H),
1.38 (s, 3 H), 1.34 (s, 3 H), 1.02 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 201.9, 110.9, 108.8, 82.6, 80.9,
73.6, 69.8, 37.0, 32.9, 27.0, 26.7, 25.9, 25.7, 14.4.
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

2600
F. P. Liesener et al.
PAPER
HRMS (ESI): m/z calcd for: C16H27NO5Na [M + Na + MeCN]+:
336.1785; found: 336.1787.
16 mmol) in CH2Cl2 (1 mL) at r.t. The reaction was quenched with
EtOAc (10 mL) after 4.5 h. The organic layer was washed with a so-
lution of NaHSO4 (1 M; 15 mL), NaOH (2 M; 5 mL), a sat. aq so-
lution of NaHCO3 (10 mL), brine (5 mL), dried over MgSO4,
filtered, and concentrated in vacuo to provide the crude (R)-Mosher
ester 44 as a colorless liquid (13.0 mg).
b-Hydroxy Ketone 42
LiHMDS (1 M in hexane; 0.21 mL, 0.21 mmol) was added drop-
wise to a solution of ketone 33 (22.9 mg, 182 mmol) in THF (3 mL)
at –78 °C. The mixture was stirred for 1 h and then aldehyde 34
(41.8 mg, 154 mmol) dissolved in THF (0.7 mL) was added. The
reaction was stopped after 40 min by the addition of a buffer solu-
tion at pH 7 (5 mL) and allowed to warm to r.t. The aqueous layer
was extracted with MTBE (25 mL). The organic layers were
washed with brine (5 mL), dried over MgSO4, filtered, and concen-
trated in vacuo. The crude material was purified by flash column
chromatography (hexane–EtOAc, 4:1) to provide aldol product 42
as a colorless liquid (30.3 mg, 76.0 mmol, 50%, dr 15:1).
Rf 0.49 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 7.52–7.48 (m, 2 H), 7.41–7.38 (m,
3 H), 5.51 (ddd, J = 8.0, 4.6, 3.6 Hz, 1 H), 4.70–4.68 (m, 2 H), 4.09
(dddd, J = 9.3, 6.9, 6.1, 3.3 Hz, 1 H), 4.04–3.98 (m, 2 H), 3.54 (dd,
J = 7.0, 5.3 Hz, 1 H), 3.52–3.51 (m, 3 H), 3.46 (t, J = 7.5 Hz, 1 H),
2.92 (dd, J = 17.8, 7.9 Hz, 1 H), 2.82 (dd, J = 17.8, 3.4 Hz, 1 H),
2.67 (app sext, J = 6.8 Hz, 1 H), 2.60 (dd, J = 16.2, 6.3 Hz, 1 H),
2.35 (dd, J = 15.9, 7.3 Hz, 1 H), 1.92–1.89 (m, 1 H), 1.70–1.69 (m,
3 H), 1.60 (ddd, J = 13.5, 9.2, 4.1 Hz, 1 H), 1.44–1.34 (m, 1 H),
1.39 (s, 3 H), 1.34 (s, 6 H), 1.32 (s, 3 H), 1.01 (d, J = 6.8 Hz, 3 H),
0.94 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.9, 166.0, 148.8, 132.1, 129.6,
128.4 (2 C), 127.5 (2 C), 109.7, 109.5, 108.7, 82.4, 78.5, 73.6, 72.4,
69.9, 55.5 (app q, 3JC-F = 1.5 Hz), 49.0, 42.8, 37.7, 36.4, 32.4, 27.3,
27.2, 27.0, 25.8, 20.0, 19.5, 13.7.
[a]D23 –31.5 (c 1.24, CHCl3); Rf 0.33 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 4.72–4.70 (m, 2 H), 4.19 (dddd,
J = 8.5, 7.2, 5.9, 4.5 Hz, 1 H), 4.05 (dd, J = 7.8, 5.9 Hz, 1 H), 4.01–
3.96 (m, 1 H), 3.91 (dd, J = 6.8, 4.0 Hz, 1 H), 3.68 (dd, J = 7.7,
6.9 Hz, 1 H), 3.50 (app t, J = 7.5 Hz, 1 H), 3.27 (d, J = 4.0 Hz, 1 H),
2.84 (dd, J = 17.9, 2.5 Hz, 1 H), 2.71 (app sext, J = 6.9 Hz, 1 H),
2.60 (dd, J = 17.7, 8.8 Hz, 1 H), 2.60 (dd, J = 15.9, 6.8 Hz, 1 H),
2.41 (dd, J = 15.8, 7.5 Hz, 1 H), 2.03–1.95 (m, 1 H), 1.77 (ddd,
J = 13.6, 8.7, 4.8 Hz, 1 H), 1.71 (dd, J = 1.3, 1.0 Hz, 3 H), 1.45–
1.37 (m, 1 H), 1.40 (s, 3 H), 1.37 (s, 3 H), 1.34 (s, 3 H), 1.33 (s,
3 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H).
HRMS (ESI): m/z calcd for C32H45F3O8Na [M + Na]+: 637.2964;
found: 637.2957.
anti-Diol 45
To a stirred suspension of Me4NBH(OAc)3 (106 mg, 402 mmol) in
MeCN (1.5 mL) was added AcOH (100%, 1.5 mL) at r.t. After stir-
ring for 40 min the reaction was cooled to –35 °C and a solution of
hydroxy ketone 42 (20.0 mg, 50.2 mmol) in MeCN (1 mL) and
AcOH (100%, 0.7 mL) was added. After 24 h an aq solution of
Rochelle salt (0.5 M; 4 mL) was added and the reaction was al-
lowed to warm to r.t. over 30 min. The reaction was quenched by
the addition of CH2Cl2 (10 mL) and a sat. aq solution of NaHCO3
(8 mL). The layers were separated and the aqueous layer was ex-
tracted with CH2Cl2 (20 mL). The combined organic layers were
washed with a sat. aq solution of NaHCO3 (5 mL). The aqueous
phases were re-extracted with CH2Cl2 (10 mL). The combined or-
ganic layers were dried over MgSO4, filtered, and concentrated in
vacuo. The crude material was purified by flash column chromatog-
raphy (hexane–EtOAc, 4:1) to provide anti-diol 45 as a colorless
liquid (13.3 mg, 33.2 mmol, 66%, dr 19:1).
13C NMR (100 MHz, CDCl3): d = 211.7, 148.7, 109.8, 108.9, 108.7,
83.7, 79.7, 74.1, 69.9 (2 C), 49.3, 46.0, 38.4, 36.5, 32.4, 27.4, 27.3,
27.1, 25.8, 19.9, 19.6, 13.5.
HRMS (ESI): m/z calcd for C22H38O6Na [M + Na]+: 421.2566;
found: 421.2578.
(S)-Mosher Ester 43
Et3N (18 mL, 0.13 mmol), DMAP (2.0 mg, 16 mmol), and (R)-(–)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride (12 mL,
64 mmol) were added to a stirred solution of alcohol 42 (6.4 mg,
16 mmol) in CH2Cl2 (1 mL) at r.t. The reaction was quenched with
EtOAc (10 mL) after 3.5 h and the organic layer was washed with a
solution of NaHSO4 (1 M; 15 mL), NaOH (2 M; 5 mL), a sat. aq so-
lution of NaHCO3(10 mL), and brine (5 mL). The organic layer was
dried over MgSO4, filtered, and concentrated in vacuo to provide
the crude (S)-Mosher ester 43 as a colorless liquid (12.0 mg).
[a]D23 –10.6 (c 0.83, CHCl3); Rf 0.37 (hexane–EtOAc, 1:1).
Rf 0.49 (hexane–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): d = 4.84–4.81 (m, 1 H), 4.75–4.72 (m,
1 H), 4.20 (dddd, J = 8.5, 6.9, 6.1, 4.4 Hz, 1 H), 4.09–4.02 (m, 1 H),
4.06 (dd, J = 7.9, 5.8 Hz, 1 H), 3.97 (dd, J = 6.8, 3.8 Hz, 1 H), 3.95–
3.90 (m, 1 H), 3.76 (t, J = 6.8 Hz, 1 H), 3.51 (t, J = 7.7 Hz, 1 H),
3.07 (br s, 1 H), 2.43 (br s, 1 H), 2.41–2.33 (m, 1 H), 2.04–1.93 (m,
1 H), 1.77 (ddd, J = 13.9, 9.0, 4.9 Hz, 1 H), 1.77–1.66 (m, 2 H),
1.72–1.71 (m, 3 H), 1.64–1.59 (m, 2 H), 1.44 (ddd, J = 13.7, 9.4,
4.3 Hz, 1 H), 1.40 (s, 3 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.35 (s, 3 H),
1.04 (d, J = 6.8 Hz, 3 H), 1.00 (d, J = 6.8& nbsp;Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 151.0, 110.3, 108.7 (2 C), 82.8,
80.4, 74.2, 70.6, 69.9, 69.1, 42.5, 39.4, 39.0, 37.8, 32.4, 27.5, 27.4,
27.1, 25.8, 20.0, 19.5, 13.4.
HRMS (ESI): m/z calcd for C22H40O6Na [M + Na]+: 423.2723;
found: 423.2739.
1H NMR (400 MHz, CDCl3): d = 7.55–7.51 (m, 2 H), 7.40–7.37 (m,
3 H), 5.58 (dt, J = 8.0, 3.8 Hz, 1 H), 4.68–4.64 (m, 2 H), 4.14 (dddd,
J = 9.3, 7.2, 5.7, 3.7 Hz, 1 H), 4.08 (dd, J = 7.9, 3.8 Hz, 1 H), 4.03
(dd, J = 7.9, 5.8 Hz, 1 H), 3.63 (dd, J = 7.5, 4.8 Hz, 1 H), 3.54–3.53
(m, 3 H), 3.49 (t, J = 7.5 Hz, 1 H), 2.92 (dd, J = 17.8, 8.2 Hz, 1 H),
2.70 (dd, J = 17.8, 3.4 Hz, 1 H), 2.61 (app sext, J = 6.8 Hz, 1 H),
2.53 (dd, J = 16.2, 6.3 Hz, 1 H), 2.24 (dd, J = 16.2, 6.3 Hz, 1 H),
1.98–1.90 (m, 1 H), 1.75–1.69 (m, 1 H), 1.68–1.67 (m, 3 H), 1.44–
1.37 (m, 1 H), 1.38 (s, 3 H), 1.37 (s, 3 H), 1.36 (s, 3 H), 1.34 (s,
3 H), 0.99 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 205.5, 165.7, 148.9, 132.0, 129.6,
128.3 (2 C), 127.5 (2 C), 109.6, 109.3, 108.8, 82.0, 78.4, 73.6, 72.3,
69.9, 55.4 (app q, 3JC-F = 1.2 Hz), 49.0, 42.1, 37.7, 36.3, 32.3, 27.2,
27.1, 26.9, 25.8, 20.1, 19.4, 13.7.
HRMS (ESI): m/z calcd for C32H45F3O8Na [M + Na]+: 637.2964;
Silyl Ether 46
found: 637.2957.
A solution of diol 45 (2.5 mg, 6.2 mmol) in CH2Cl2 (1 mL) was
stirred at 0 °C. 2,6-Lutidine (9.2 mL, 79 mmol) and TIPSOTf
(12.2 mL, 45.4 mmol) were added. The reaction mixture was stirred
for 3.5 h at r.t. and subsequently quenched with a sat. aq solution of
NaHCO3 (3 mL). The aqueous layer was extracted with CH2Cl2
(40 mL). The combined organic layers were washed with an aq so-
(R)-Mosher Ester 44
Et3N (18 mL, 0.13 mmol), DMAP (2.0 mg, 16 mmol), and (S)-(+)-
a-methoxy-a-trifluoromethylphenylacetyl
64 mmol) were added to a stirred solution of alcohol 42 (6.4 mg,
chloride
(12 mL,
Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York

PAPER
Northern Hemisphere of Amphidinolide H2
2601
lution of NaHSO4 (1 M; 10 mL), a sat. aq solution of NaHCO3
(5 mL), brine (5 mL), dried over MgSO4, and concentrated in vac-
uo. The crude material was purified by flash column chromatogra-
phy (hexane–EtOAc, 9:1) to provide silyl ether 46 as a colorless oil
in quantitative yield (3.5 mg, 6.2 mmol).
(3) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.;
Cornell, L.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994,
116, 2657.
(4) Kobayashi, J.; Shigemori, H.; Ishibashi, M.; Yamasu, T.;
Hirota, H.; Sasaki, T. J. Org. Chem. 1991, 56, 5221.
(5) Kobayashi, J.; Shimbo, K.; Sato, M.; Shiro, M.; Tsuda, M.
Org. Lett. 2000, 2, 2805.
(6) Kobayashi, J.; Shimbo, K.; Sato, M.; Tsuda, M. J. Org.
Chem. 2002, 67, 6585.
(7) Saito, S.-y.; Feng, J.; Kira, A.; Kobayashi, J.; Ohizumi, Y.
Biochem. Biophys. Res. Commun. 2004, 320, 961.
(8) 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.
[a]D23 –16.9 (c 0.35, CHCl3); Rf 0.26 (hexane–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): d = 4.72–4.70 (m, 1 H), 4.69–4.68 (m,
1 H), 4.21 (dddd, J = 8.5, 7.0, 6.1, 4.3 Hz, 1 H), 4.11–4.06 (m, 1 H),
4.06 (dd, J = 8.0, 6.0 Hz, 1 H), 4.00 (dd, J = 6.5, 4.4 Hz, 1 H), 3.98–
3.93 (m, 2 H), 3.65 (app t, J = 6.7 Hz, 1 H), 3.50 (t, J = 7.7 Hz,
1 H), 2.23–2.13 (m, 1 H), 2.02–1.96 (m, 1 H), 1.96 (ddd, J = 14.8,
3.7, 1.8 Hz, 1 H), 1.82 (ddd, J = 13.7, 8.7, 4.6 Hz, 1 H), 1.81–1.68
(m, 3 H), 1.66–1.65 (m, 3 H), 1.42 (ddd, J = 14.0, 9.0, 4.9 Hz, 1 H),
1.40 (s, 3 H), 1.39 (s, 3 H), 1.36 (s, 3 H), 1.35 (s, 3 H), 1.09–1.05
(m, 21 H), 1.03 (d, J = 7.2 Hz, 3 H), 1.00 (d, J = 6.8 Hz, 3 H).
(9) Amphidinolide H2: Liesener, F. P.; Kalesse, M. Synlett
2005, 2236.
13C NMR (100 MHz, CDCl3): d = 148.1, 110.8, 108.8, 108.6, 83.1,
81.7, 74.0, 70.8, 70.3, 70.0, 40.1, 38.5, 38.3, 36.3, 32.7, 27.6, 27.5,
27.1, 25.9, 20.9, 18.1 (7 C), 13.4, 12.3 (3 C).
HRMS (ESI): m/z calcd for C31H60O6SiNa [M + Na]+: 579.4057;
found: 579.4075.
(10) Amphidinolide H: Chakraborty, T. K.; Suresh, V. R.
Tetrahedron Lett. 1998, 39, 7775.
(11) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998,
39, 9109.
(12) Amphidinolide B: Gopalarathnam, A.; Nelson, S. G. Org.
Lett. 2006, 8, 7.
(13) (a) Ishiyama, H.; Takemura, T.; Tsuda, M.; Kobayashi, J. J.
Chem. Soc., Perkin Trans. 1 1999, 1163. (b) Ishiyama, H.;
Takemura, T.; Tsuda, M.; Kobayashi, J. Tetrahedron 1999,
55, 4583. (c) Cid, M. B.; Pattenden, G. Tetrahedron Lett.
2000, 41, 7373. (d) Eng, H. M.; Myles, D. C. Tetrahedron
Lett. 1999, 40, 2275. (e) Chakraborty, T. K.; Thippeswamy,
D.; Suresh, V. R.; Jayaprakash, S. Chem. Lett. 1997, 26,
563. (f) Lee, D.-H.; Lee, S.-W. Tetrahedron Lett. 1997, 38,
7909. (g) Cid, M. B.; Pattenden, G. Synlett 1998, 540.
(h) Ohi, K.; Shima, K.; Hamada, K.; Saito, Y.; Yamada, N.;
Ohba, S.; Nishiyama, S. Bull. Chem. Soc. Jpn. 1998, 71,
2433. (i) Ohi, K.; Nishiyama, S. Synlett 1999, 571. (j) Ohi,
K.; Nishiyama, S. Synlett 1999, 573. (k)Chakraborty, T. K.;
Suresh, V. R. Chem. Lett. 1997, 26, 565. (l) Zhang, W.;
Carter, R. G. Org. Lett. 2005, 7, 4209. (m) Mandal, A. K.;
Schneekloth, J. S.; Crews, C. M. Org. Lett. 2005, 7, 3645.
(n) Zhang, W.; Carter, R. G.; Yokochi, A. F. T. J. Org.
Chem. 2004, 69, 2569. (o) Lee, D.-H.; Rho, M.-D.
Tetrahedron Lett. 2000, 41, 2573. (p) Eng, H. M.; Myles, D.
C. Tetrahedron Lett. 1999, 40, 2279. (q) Lee, D.-H.; Rho,
M.-D. Bull. Korean Chem. Soc. 1998, 19, 386.
Ketone 47
A solution of silyl ether 46 (2.5 mg, 4.5 mmol) in CH2Cl2 (1 mL)
was added to MS (4 Å) and cooled to 0 °C. To this suspension NMO
(2.2 mg, 19 mmol) and after 10 min TPAP (0.2 mg, 0.6 mol) were
added. The reaction was warmed to r.t. in 20 min. After stirring for
an additional 30 min a second aliquot of NMO (2.2 mg, 19 mmol)
and TPAP (1.0 mg, 2.8 mmol) were added. After stirring for 1 h the
mixture was filtered through silica gel and washed with EtOAc
(15 mL). The organic layer was dried over MgSO4 and concentrated
in vacuo to provide 47 as a colorless oil (0.7 mg, 1.3 mmol, 28%).
[a]D23 +27.1 (c 0.07, CHCl3); Rf 0.33 (hexane–EtOAc, 9:1).
1H NMR (400 MHz, CDCl3): d = 4.68–4.67 (m, 2 H), 4.33 (app
quin, J = 6.1 Hz, 1 H), 4.17 (dddd, J = 8.7, 7.2, 5.8, 4.3 Hz, 1 H),
4.06 (d, J = 7.2 Hz, 1 H), 4.05 (dd, J = 7.9, 5.8 Hz, 1 H), 4.01 (dd,
J = 7.2, 4.1 Hz, 1 H), 3.49 (dd, J = 7.7, 7.3 Hz, 1 H), 3.00 (dd,
J = 17.1, 6.1 Hz, 1 H), 2.75 (dd, J = 17.2, 5.3 Hz, 1 H), 2.31 (app
sext, J = 6.9 Hz, 1 H), 2.04–1.95 (m, 1 H), 1.72 (ddd, J = 13.7, 9.1,
4.1 Hz, 1 H), 1.72–1.64 (m, 1 H), 1.67 (t, J = 1.2 Hz, 3 H), 1.48–
1.37 (m, 1 H), 1.45–1.32 (m, 1 H), 1.43 (s, 3 H), 1.39 (s, 3 H), 1.35
(s, 3 H), 1.34 (s, 3 H), 1.19–1.05 (m, 21 H), 1.04 (d, J = 6.8 Hz,
3 H), 0.99 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 209.4, 149.8, 109.8, 108.7 (2 C),
83.0, 81.2, 73.8, 69.9, 66.9, 46.4, 43.1, 37.7, 37.3, 32.5, 27.1, 26.8,
26.1, 25.8, 20.1, 19.0, 18.2 (6 C), 13.7, 12.7 (3 C).
HRMS (ESI): m/z calcd for C31H58O6SiNa [M + Na]+: 577.3900;
found: 577.3895.
(r) Chakraborty, T. K.; Thippeswamy, D.; Jayaprakash, S. J.
Indian Chem. Soc. 1998, 75, 741. (s) Mandal, A. K.;
Schneekloth, J. S.; Kuramochi, K.; Crews, C. M. Org. Lett.
2006, 8, 427.
(14) Chakraborty, T. K.; Thippeswamy, D. Synlett 1999, 150.
(15) Amphidinolide L: (a) Kobayashi, J.; Hatakeyama, A.;
Tsuda, M. Tetrahedron 1998, 54, 697. (b) Tsuda, M.;
Hatakeyama, A.; Kobayashi, J. J. Chem. Soc., Perkin Trans.
1 1998, 149.
Acknowledgment
(16) For reviews see: (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem. Int. Ed. 2005, 44, 4490; Angew. Chem.
2005, 117, 4564. (b) Mulzer, J.; Öhler, E. In Topics in
Organometallic Chemistry, Vol. 13; Dötz, K. H., Ed.;
Springer-Verlag: Berlin, 2004, 269. (c) Connon, S. J.;
Blechert, S. In Topics in Organometallic Chemistry, Vol. 11;
Bruneau, C.; Dixneuf, P. H., Eds.; Springer-Verlag: Berlin,
2004, 93. (d) Mori, M. In Topics in Organometallic
Chemistry, Vol. 1; Springer-Verlag: Berlin, 1998, 133.
(e) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317.
(17) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2004, 126, 15074.
(18) For an example of a ring closing enyne-metathesis of a
macrocycle, see: Layton, M. E.; Morales, C. A.; Shair, M. D.
J. Am. Chem. Soc. 2002, 124, 773.
U. J. gratefully acknowledges the Schering-Stiftung for a doctoral
fellowship.
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Synthesis 2006, No. 15, 2590–2602 © Thieme Stuttgart · New York