Synthetic studies toward the total synthesis of amphidinolide H1

Article abstract of DOI:10.1055/s-2008-1032101

A convergent synthesis of the macrolide core as the immediate precursor to amphidinolide H1 is described, which features a palladium-catalyzed Stille cross-coupling, a methyl ketone diastereoselective aldol reaction, a Mitsunobu esterification, and an intramolecular ring-closing metathesis (RCM) reaction to construct the 26-membered macrocycle as key steps. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032101

728
LETTER
Synthetic Studies toward the Total Synthesis of Amphidinolide H1
S
tudies towar
d
i
the Tot
s
al Synthes
h
is of
A
mphid
e
inolide H1ng Deng, Zhixiong Ma, Gang Zhao*
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin
Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: zhaog@mail.sioc.ac.cn
Received 30 November 2007
intramolecular RCM from alkene 3, which should be
Abstract: A convergent synthesis of the macrolide core as the im-
available through an aldol addition between the aldehyde
mediate precursor to amphidinolide H1 is described, which features
4 and methyl ketone 5. Finally, a Stille coupling of com-
pounds 6 and 7 would lead to the fragment 4, and the latter
a palladium-catalyzed Stille cross-coupling, a methyl ketone diaste-
reoselective aldol reaction, a Mitsunobu esterification, and an in-
tramolecular ring-closing metathesis (RCM) reaction to construct fragment 5 could be assembled from the subunits 8 and 9
the 26-membered macrocycle as key steps.
via a Mitsunobu esterification.
Key words: amphidinolide H1, macrolide, aldol reaction, RCM re-
action, Mitsunobu reaction
The synthesis of vinyl iodide 6 could be achieved from the
known chiral alcohol 10,7g which can be easily prepared in
four steps either from commercially available methyl (R)-
3-hydroxyl-2-methylpropionate or by the Lewis acid me-
Amphidinolides are a family of structurally diverse mac-
rolides that have been isolated from marine dinoflagel-
lates of the genus Amphidinium living in symbiosis with
Okinawan acoel flatworm Amphiscolops sp.1,2 There are
some common structural features for the amphidinolides,
for example, they have one or more exo-methylene units,
a highly oxygenated and stereochemically rich macrocy-
cle ranging in size from 12 to 29 atoms. Due to their good
biological activity, structural complexity, and natural
scarcity, amphidinolides have been very attractive target
molecules for organic chemists.3,4
diated alkylation of N-propionyl-oxazolidinone with
BOMCl (Scheme 2).4a,9 After it was protected as a TBS
ether, the benzyl group of 11 was removed in the presence
of lithium and ammonia at –78 °C to provide 12 in 99%
yield. Oxidation of 12 using the Dess–Martin periodinane
followed by treatment of the corresponding aldehyde with
CBr4 and Ph3P led to the a,a-dibromoalkene 13 in 88%
yield,10 which was then converted into alkyne 14 (95%)
by using n-butyllithium. Treatment of 14 with trimethyla-
luminum and bis(cyclopentadienyl)zirconium(IV) dichlo-
ride in CH2Cl2,11 followed by iodination of the
intermediate in situ afforded E-vinyl iodide fragment 6 in
91% yield.
Amphidinolide H1 (1) and its congeners H2–H5 are a
group of 26-membered macrolides, which possess some
unique structural features such as an allyl epoxide or vic-
inally located one-carbon branches.5 More importantly, 1
exhibits extremely potent cytotoxicity against murine
lymphoma L1210 and human epidermoid carcinoma KB
cell lines (IC50 values: 0.48 ng/mL and 0.52 ng/mL, re-
spectively).6 So far, considerable efforts have been direct-
ed toward the syntheses of 1 and structurally related
amphidinolide B and G.7,8 Very recently, the Fürstner
group reported the first total syntheses of amphidinolide H
and G.4b On the other hand, we have finished the total syn-
thesis of amphidinolide T3 and formal synthesis of amphi-
dinolide T4,4a and the sythesis of segment C14–C26 of
amphidinolide H1.7g As a part of our ongoing project to
synthesize some members of the amphidinolide family,
herein, we would like to describe our studies on the total
synthesis of Amphidinolide H1 (1), and our successfully
stereoselective synthesis of its precursor 2.
As shown in Scheme 3, the synthesis of vinyl stannane
fragment 7 was started from alcohol 16, which was con-
veniently prepared via two steps by a known proce-
dure.8s,12 Alcohol 16 was treated with mesyl chloride and
triethylamine in CH2Cl2 at 0 °C, and the resulting mesy-
late was then converted into cyanide 17 in 78% yield
through a SN2 reaction with sodium cyanide. Diisobutyla-
luminum hydride (DIBAL-H) reduction of cyanide 17 and
subsequent Wittig reaction using Ph3P=CHCO2Et provid-
ed a E-olefin 18 in 70% yield in two steps. After reduction
of the unsaturated ester 18 with DIBAL-H, the resulting
alcohol was protected with TBSCl to give silyl ether 19.
Subsequent halogen–lithium exchange in the presence of
tert-butyllithium followed by quenching with n-Bu3SnCl
proceeded smoothly to afford the corresponding vinyl
stannane 20 in 76% yield. Finally, desilylation of 20 with
TBAF followed by a Sharpless epoxidation13 of the allylic
alcohol 21 gave 7 (86%) as a single isomer.
According to the synthetic strategy we reported recently
(Scheme 1),7g we envisioned that amphidinolide H1 (1)
could be achieved by deprotecting the MOM group of its
precursor, macrocycle 2, while 2 could be formed by an
With the two required components of 6 and 7 in hand, we
examined several reaction conditions for the Stille cross-
coupling between the vinyl iodide 6 and vinyl stannane
7.14 Using catalytic PdCl2(dppf) in the presence of freshly
prepared CuCl in MeCN at 60 °C (Scheme 4), a satisfying
result could be obtained with the desired conjugated diene
22 in 80% yield. Then diene 22 was subjected to Parikh–
SYNLETT 2008, No. 5, pp 0728–0732
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1032101; Art ID: W20707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Studies toward the Total Synthesis of Amphidinolide H1
729
aldol reaction
Me
OH
O
Pd-catalyzed
Stille cross-coupling
Me
OH
18
20
22
Me
14
HO
13
25
Me
Me
OH
6
1
O
Mitsunobu
esterification
7
O
RCM
O
amphidinolide H1 (1)
Me
Me
OH
O
Me
OH
O
OMOM
Me
OMOM
Me
Me
RCM
MOMO
MOMO
Me
Me
Me
OH
Me
OTBDPS
O
O
O
O
O
3
O
2
Me
O
O
OMOM
Me
Me
H
Me
MOMO
OTBDPS
O
aldol
O
Me
Me
+
5
4
O
Mitsunobu esterification
Stille coupling
MOMO
Me
Me
OTES
Me
OTBDPS
SnBu3
Me
I
8
OTBS
O
OMOM
+
Me
+
Me
6
OH
OH
O
7
9
O
Scheme 1 Retrosynthetic analysis of amphidinolide H1 (1)
Me
Me
Li, NH3(l), THF
–78 °C, 99%
TBSCl, imidazole
95%
BnO
HO
BnO
OH
OTBS
Br
10
11
Me
Me
1. DMP, NaHCO3, 84%
OTBS
Me
OTBS
Br
2. CBr4, Ph3P, 2,6-lutidine
CH2Cl2, 88%
13
Me
12
Me
I
OTBS
AlMe3, Cp2ZrCl2, CH2Cl2
then I2, –30 °C, 91%
n-BuLi, THF
OTBS
6
14
–78 °C, 95%
Scheme 2 Preparation of segment 6
Doering oxidation15 to give aldehyde 23 (75%). Wittig dehyde 4.16 It is noteworthy that the overall yield was up
methylenation of 23 with Ph3P+CH3Br– effectively fur- to 16% in fourteen steps from compound 16 to 4.
nished olefin 24 in 97% yield. Removal of TBS group in
The known ketone 8,7g which can be prepared in a large
24 with TBAF followed by oxidation of the resulting al-
cohol using DMP as an oxidant successfully led to the al-
scale from the commercially inexpensve L-glutamic acid,
was chosen as the starting material to synthesize methyl
ketone 5. After deprotection of the TES ether of 8 fol-
Synlett 2008, No. 5, 728–732 © Thieme Stuttgart · New York

730
L. Deng et al.
LETTER
O
O
Br
2 steps
ref 12
1. MsCl, Et3N, 0 °C
HO
O
N
2. NaCN, DMSO, 60 °C
78% two steps
Me
16
Bn
15
Br
Br
1. DIBAL-H, CH2Cl2, 0 °C
NC
EtO2C
2. Ph3PCHCO2Et
70% two steps
Me
17
Me
18
1. DIBAL-H, –78 °C
98%
TBSO
Br
t-BuLi, n-Bu3SnCl
Me
2. TBSCl, imidazole
99%
–78 °C, 76%
19
TBAF HO
99%
SnBu3
TBSO
SnBu3
Me
Me
20
21
Sharpless epoxidation
86%
HO
SnBu3
O
Me
7
Scheme 3 Preparation of segment 7
Me
in favor of the Felkin product was obtained when KH-
MDS was used as the base and the stereochemistry of
newly formed C18 was established by Mosher ester meth-
od.19
Me
SO3⋅py, Et3N,
DMSO, 75%
OTBS
Pd(dppf)Cl2, CuCl
60 °C, 80%
6
7
+
22
Me
With compound 3 in hand, the accomplishment of the to-
tal synthesis of amphidinolide H1 (1) was around the cor-
ner. The next crucial step would be the ring-closing
metathesis to construct the macrocycle. As we expected,
the RCM reaction mediated by Grubbs second-generation
ruthenium catalyst 26 gave the desired macrocycle with
the 6E-stereoisomer as a single product in 82% yield,20
which was easily converted into diol 221 in the presence of
Et3N·3HF and Et3N in excellent yield (97%).22 The final
work was to remove the two MOM groups of the diol 2 to
liberate the amphidinolide H1 (1). However, experiments
proved that it was quite problematic, due to existence of
allyl epoxide. Many attempts failed. Finally, target com-
pound 1 was observed by LCMS when 2 was treated with
boron trifluoride etherate and methyl sulfide under –20
°C, accompanied by considerable impurities, thus it was
difficult to get pure product of amphidinolide H1 (1).23
OH
O
Me
Me
Me
Me
OTBS
OTBS
Ph3P+MeBr–
NaHMDS
Me
Me
0 °C to r.t., 97%
H
24
O
23
O
O
Me
O
Me
H
1. TBAF, 95%
2. DMP, NaHCO3, 82%
Me
In summary, we have studied the total synthesis of amphi-
dinolide H1 via a highly flexible, concise, and convergent
strategy using the readily available and inexpensive chiral
pool. Although the final step to accomplish the total syn-
thesis was failed so far, the intermediate precursor 2 to the
macrolide 1 was synthesized successfully in 19 steps for
the longest linear sequence and with 6.1% overall yield.
The key setps include a palladium-catalyzed Stille cross-
coupling, a methyl ketone diastereoselective aldol reac-
tion, a Mitsunobu esterification, and an intramolecular
RCM to construct the 26-membered macrocycle, which is
4
O
Scheme 4 Preparation of aldehyde 4
lowed by a Mitsunobu esterification17 with acid 9,18 the
ketone 5 was obtained in 74% yield over two steps. The
next key step was an aldol coupling between aldehyde 4
and ketone 5. In contrast to earlier work on synthesis of
segment C14–C26,7g satisfying yield and selectivity were
not observed by using enolate derived from LHMDS in
THF. However, to our delight, good selectivity (dr = 7:1)
Synlett 2008, No. 5, 728–732 © Thieme Stuttgart · New York

LETTER
Studies toward the Total Synthesis of Amphidinolide H1
731
MOMO
Me
Me
OH
MOMO
Me
Me
OTES
PPTS
OTBDPS
OTPS
0 °C, 99%
O
OMOM
O
OMOM
25
8
O
OMOM
Me
Me
MOM
OTBDPS
CO2H
KHMDS, –78 °C
9
O
Me
O
O
then 4, 67%
dr = 7:1
DEAD, Ph3P, toluene
75%
5
Me
OH
O
Me
OMOM
Me
1. Grubbs' II 26
CH2Cl2, reflux, 82%
MOMO
2. Et3N.3HF,
MeCN, 97%
Me
Me
OTBDPS
O
O
O
3
Me
OH
O
Me
OMOM
Me
Mes
N
N
Mes
Ph
Cl
Cl
MOMO
Ru
Me
PCy3
Me
OH
O
O
26
O
2
Scheme 5 Completion of the synthesis of 1
Terrell, L. R.; Geng, F.; Ward, J. S. Org. Lett. 2002, 4, 2841.
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Continued studies toward these total syntheses are cur-
rently under way in our laboratory.
Acknowledgment
We are grateful to National Natural Science Foundation of China
for financial support (No. 20525208, 20532040, 20390057, and
20372072), QT program, and Shanghai Natural Science Council.
(j) Lepage, O.; Kattnig, E.; Fürstner, A. J. Am. Chem. Soc.
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(d, J = 6.6 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.89 (s, 9 H),
–0.33 (s, 6 H). 13C NMR (75 MHz, CDCl3): d = 202.4, 143.9,
140.8, 135.8, 125.9, 119.0, 115.1, 59.3, 59.2, 48.9, 45.8,
38.9, 37.8, 29.6, 19.6, 19.5, 15.0. MS (EI): m/z calcd for
C17H26O2 [M]+: 262; found: 262. HRMS (EI): m/z calcd for
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(21) Diol 2: [a]D24 –2.2 (c 0.51, CHCl3). IR (neat): 3488, 2925,
1708, 1456, 1263, 1151, 1028 cm–1. 1H NMR (500 Hz,
CDCl3): d = 6.76 (t, J = 6.9 Hz, 1 H), 5.87 (dt, J = 6.8, 15.3
Hz, 1 H), 5.56 (s, 1 H), 5.23 (dd, J = 6.9, 14.6 Hz, 1 H), 5.04
(ddd, J = 3.2, 6.0, 12.6 Hz, 1 H), 4.97 (s, 1 H), 4.81 (s, 1 H),
4.74–4.60 (m, 4 H), 4.19 (d, J = 5.2 Hz, 1 H), 4.05–3.96 (m,
1 H), 3.76 (m, 1 H), 3.70 (m, 1 H), 3.65 (m, 1 H), 3.35 (s, 6
H), 3.09 (br s, 1 H), 3.02 (dd, J = 2.1, 7.9 Hz, 1 H), 2.85 (dt,
J = 2.1, 8.6 Hz, 1 H), 2.76–2.63 (m, 2 H), 2.33–2.22 (m, 5
H), 2.16 (m, 1 H), 2.10 (dd, J = 5.1, 7.8 Hz, 1 H), 1.97–1.91
(m, 2 H), 1.83 (s, 3 H), 1.82 (m, 1 H), 1.74 (s, 3 H), 1.71–
1.65 (m, 1 H), 1.61–1.49 (m, 2 H), 1.43–1.36 (m, 1 H), 1.29–
1.21 (m, 2 H), 1.06 (d, J = 6.6 Hz, 3 H), 1.01 (d, J = 6.8 Hz,
3 H), 0.89 (d, J = 6.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 210.0, 168.4, 144.3, 142.5, 141.7, 134.2, 129.3, 128.3,
125.4, 114.7, 97.7, 97.3, 84.0, 81.2, 74.0, 66.0, 65.8, 59.1,
58.9, 56.4, 56.2, 46.8, 46.0, 41.5, 40.1, 39.2, 34.7, 31.8, 30.9,
29.8, 27.7, 19.9, 19.8, 14.7, 14.4, 12.6. ESI-MS: m/z calcd
for C36H58O10: 650; found C26H58O10Na+: 673 [M + Na]+.
ESI-HRMS: m/z calcd for C36H58O10Na+ [M + Na]+:
673.3922; found: 673.3909.
(9) White, J. D.; Kawasaki, M. J. Org. Chem. 1992, 57, 5292.
(10) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769.
(22) Giudicelli, M. B.; Pieq, D.; Veyron, B. Tetrahedron Lett.
1990, 31, 6527.
(11) (a) Yoshida, Y.; Negishi, E. J. Am. Chem. Soc. 1981, 103,
4985. (b) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl.
1993, 32, 1095.
(12) Evans, D. A.; Kim, A. S.; Metternich, R.; Novack, V. J.
J. Am. Chem. Soc. 1998, 120, 5921.
(23) When we were preparing this manuscript and trying to
deprotect the MOM group, Füstner group reported the first
example of total synthesis of the amphidinolide H1 (1), see
ref. 4b.
Synlett 2008, No. 5, 728–732 © Thieme Stuttgart · New York

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