Total synthesis of amphidinolide T3 using ring-closing metathesis and asymmetric dihydroxylation strategy

Article abstract of DOI:10.1055/s-0030-1259706

Total synthesis of amphidinolide T3, a 19-membered ring marine macrolide, has been accomplished using a ring-closing metathesis (RCM) and asymmetric dihydroxylation (AD) strategy. A cycloalkene having the C12=C13 double bond was assembled via RCM in 80% yield and in E/Z ratio of 76:24. The (12E)-isomer -underwent AD using 1 mol% K₂OsO₂(OH)₄ and 4 mol% (DHQD)₂AQN as the chiral catalyst at 0 C for 15 hours, furnishing the desired (12R,13R)-diol and its (12S,13S)-diastereomer in 59% and 25% yields, respectively. Selective monosilylation of (12R,13R)-diol followed by DMP oxidation and desilylation afforded amphidinolide T3 in 3.4% overall yield via a 15-step sequence. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259706

LETTER
895
Total Synthesis of Amphidinolide T3 Using Ring-Closing Metathesis and
Asymmetric Dihydroxylation Strategy
a
a,b
b
a
a,b
T
D
otal
S
ynthesis of
o
A
mphidinoli
n
de T3 gdong Wu, Huoming Li, Jian Jin, Jinlong Wu, Wei-Min Dai*
a
Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87953128; E-mail: chdai@zju.edu.cn
b
Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR,
P. R. of China
Fax +85223581594; E-mail: chdai@ust.hk
Received 9 December 2010
Dedicated to Professors Lixin Dai and Xiyan Lu
8
ring-closing metathesis (RCM) at C4–C5 followed by
hydrogenation to assemble the 19-membered ring while
Abstract: Total synthesis of amphidinolide T3, a 19-membered
ring marine macrolide, has been accomplished using a ring-closing
metathesis (RCM) and asymmetric dihydroxylation (AD) strategy.
3
b
a seco substrate possessing a dithiane-masked a-hydroxy
A cycloalkene having the C12=C13 double bond was assembled via ketone at C12/C13 was fabricated before macrolactoniza-
5
RCM in 80% yield and in E/Z ratio of 76:24. The (12E)-isomer tion. In our recently accomplished first total synthesis of
underwent AD using 1 mol% K OsO (OH) and 4 mol%
2
2
4
amphidinolide T2 (2), we used RCM to construct a 19-
membered ring cycloalkene by forming the C12=C13
double bond. It was followed by asymmetric dihydroxyla-
(
DHQD) AQN as the chiral catalyst at 0 °C for 15 hours, furnishing
2
the desired (12R,13R)-diol and its (12S,13S)-diastereomer in 59%
and 25% yields, respectively. Selective monosilylation of
9
tion (AD) as the post-RCM transformation for installa-
(
12R,13R)-diol followed by DMP oxidation and desilylation afford-
tion of the C12/C13 a-hydroxy ketone functionalities in a
ed amphidinolide T3 in 3.4% overall yield via a 15-step sequence.
4
regio- and stereoselective manner. As an extension of our
Key words: amphidinolide T3, dihydroxylation, macrocycles,
metathesis, total synthesis
4
RCM-based total syntheses of amphidinolide T2, X and
1
0
11
Y, and other macrolides, and the above mentioned
4,12
RCM–AD strategy we report here on the synthesis of
amphidinolide T3 (3) with an emphasis on effect of the
C18 alkyl side chain (n-Pr) on selective AD and mono-
silylation of the desired syn-diol intermediate.
Amphidinolide T congeners consist of five structurally
closely related 19-membered ring macrolides, which were
isolated from symbiotic marine dinoflagellate Amphidini-
1
,2
um sp. as shown in Scheme 1. Specifically, amphidino-
lide T1 (1) differs from amphidinolide T3 (3) in the
positions of the a-hydroxy ketone functionalities at C12
and C13 while amphidinolide T2 (2) possesses an extra
stereogenic center at C21 on the side chain as compared to
OH
O
1
3
O
1
Me
14
HO
O
Me
14
2
*
CH2
CH2
n-Pr
8
16
Me
Me
18
n-Pr
O
3
. Amphidinolide T4 (4) and T5 (5) are the epimers in re-
Me
Me
7
spect to the configuration of C14 methyl group and, not
O
O
surprisingly, 4 underwent base-mediated epimerization to
O
2
c
O
form 5 in the presence of K CO in MeOH. Moreover,
2
3
amphidinolide T1 (1)
amphidinolide T4 (4): 14α-Me
amphidinolide T5 (5): 14β-Me
T3 and T4 are the epimers with opposite configuration for
the C12 hydroxyl group. Amphidinolide T1–T4 were re-
ported to exhibit cytotoxicity against murine lymphoma
L1210 and human epidermoid carcinoma KB cell lines
with IC50 values of 18, 10, 7.0, and 11 mg/mL, and 35,
RCM & AD
O
Me
O
OH
HO
O
Me
10
7
12
3
2
b
1
1.5, 10, and 18 mg/mL, respectively. Among them, am-
8
O
CH2
Me
for T3
phidinolide T3 is the most potent against the examined
two cancer cell lines. Since the isolation of amphidinolide
T subgroup of macrolides in 2000–2001, total syntheses
of these macrolides have been actively pursued in many
6
Me
X
Me
+
O
esterification
Me
OH
3
–7
research laboratories. Two total syntheses of amphidin-
O
OH
18
n-Pr
1
3
3
b
5
7
olide T3 (3) have been published by Fürstner and Zhao.
amphidinolide T2 (2): X =
amphidinolide T3 (3): X = n-Pr
21 Me
A fully functionalized seco substrate with orthogonally
protected anti-diol moiety at C12/C13 was subjected to
Scheme 1 Structures of amphidinolide T1–T5 (1–5) and retrosyn-
thetic bond disconnections of amphidinolide T3 (3)
SYNLETT 2011, No. 7, pp 0895–0898
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259706; Art ID: W33110ST
Our retrosynthetic bond disconnections are illustrated in
©
Georg Thieme Verlag Stuttgart · New York
Scheme 1, providing two small fragments 6 and 7. The

8
96
D. Wu et al.
LETTER
3
d
7c
acid 6 has been synthesized by Jamison and us. In our thenium complex, afforded the 19-membered cycloalkene
synthesis, a SmI -mediated enantioselective reductive in >80% yields and in E/Z ratio of ca. 73:27. On the basis
2
coupling of the (1S,2R)-N-methylephedrine-derived cro- of our prior knowledge, we used the most reactive second-
tonate with a C1–C7 aldehyde was used to secure the cis generation initiator GII for the regioselective RCM reac-
stereochemistry at C7/C8, affording the acid 6 in >25% tion within 16. After refluxing in CH Cl for six hours in
2
2
overall yield in nine steps from a known chiral building the presence of 5 mol% GII, the cycloalkenes (E)-17 and
7
c
block. Scheme 2 depicts the synthesis of the alcohol 7 (Z)-17 were obtained in 61% and 19% yields, respective-
starting from the b-keto ester 8. The chiral b-hydroxy ly, without detection of any RCM product(s) derived from
ester 9 was prepared via asymmetric hydrogenation13 in the C16 methylene group. The ratio of (E)-17/(Z)-17 is
8
0% yield and in >99% ee. Protection of 9 as the TES 76:24, suggesting that the C18 alkyl side chain in 16 and
4
ether 10 was followed by controlled DIBAL-H reduction its bulky analogue have insignificant influence on the ste-
of the ester moiety to give the aldehyde 11a in 77% over- reochemical course of the RCM reaction.
all yield from 9. An analogous TBS-protected chiral alde-
hyde 11b was used for the synthesis of amphidinolide
3
a
5
T1 and T3. The lithium species prepared in situ from the
13
4
Me
known chiral homoallyl iodide 12 was reacted with 11a
1
4
2
,4,6-Cl3C6H2COCl
Et3N, 0 °C, 1 h
12
to furnish the alcohol 13 in 70% yield as a mixture of two
diastereomers. The latter were oxidized to the ketone 14
using DMP in 85% yield. Finally, 14 was subjected to me-
CH2
GII (5 mol%)
6
16
then 7, DMAP, r.t.
Me
CH Cl
2
2
1
8
n-Pr
(82% brsm)
O
reflux, 6 h
80%,
Me
1
4
(
thylenation using the Nysted’s reagent 15 to form the di-
ene alcohol 7, after spontaneous desilylation, in 89%
O
E/Z = 76:24)
1
5
yield.
O
1
6
Me
13
13
Me
[
(R)-BINAP]RuBr2
H2, MeOH
12
TESOTf
14
14
O
O
O
O
OH
2,6-lutidine
CH2
CH2
16
12
CH2Cl2, 0 °C
0.5 h
16
6
0 °C, 6 h
MeO
MeO
n-Pr
MeO
n-Pr
OR
Me
Me
(
80%, >99% ee)
18 n-Pr
+
18 n-Pr
Me
8
9
O
O
Me
O
O
OTES
O
DIBAL-H
O
O
n-Pr CH2Cl2, –90 °C, 1 h
77% 11a from 9)
H
(E)-17
(Z)-17
n-Pr
(
10
11a: R = TES
1b: R = TBS
see Table 1
1
t-BuLi, pentane–Et2O
OH
OH
–
–
78 °C, 0.5 h;
20 °C, 0.5 h;
13R
13S
HO
Me
HO
Me
Me
OH OTES
Me
12R
14
14
12S
I
then 11a, –78 °C, 1 h
70%)
Me
CH2
CH2
18 n-Pr
O
(
16
16
1
2
13
Me
+
Me
18
n-Pr
O
O
Me
Me
O
Me
O
OTES
DMP, NaHCO3
CH2Cl2, r.t., 2 h
15, TiCl4
O
TBSOTf, 2,6-lutidine, CH2Cl2
O
1
8
19
THF, reflux, 0.5 h
(89%)
Me
(
85%)
14
–
78 °C, 1 h (60% 20; 30% 21)
O
OH
OTBS
13R
Me
OH
BrZn
ZnBr
13R
TBSO
Me
HO
Me
Me
Zn
12R
12R
14
14
CH2
18 n-Pr
O
CH2
18 n-Pr
O
7
15
1
6
16
Me
Me
Scheme 2 Synthesis of the C13–C21 alcohol fragment 7
+
O
O
Me
Me
Our total synthesis of amphidinolide T3 (3) is illustrated
in Scheme 3. Condensation of the acid 6 with the alcohol
O
O
20
21
7
was performed under the standard esterification condi-
1
2
. DMP, NaHCO3, r.t. (95%)
. HF⋅py, MeCN, r.t. (81%)
tions to give the seco triene 16 in good yield. In our previ-
ous total synthesis of amphidinolide T2, we found the
4
N
N
Mes
Mes
first-generation ruthenium complexes incapable of pro-
moting RCM reaction in a similar substrate to 16 while all
three second-generation RCM initiators, i.e. Grubbs (GII,
Cl
GII =
Ru
3
Cl
Ph
PCy3
see Scheme 3), Hoveyda–Grubbs, and an indenylidene ru- Scheme 3 Total synthesis of amphidinolide T3 (3)
Synlett 2011, No. 7, 895–898 © Thieme Stuttgart · New York

LETTER
Total Synthesis of Amphidinolide T3
897
With the cycloalkene (E)-17 in hand, we next examined energy conformation of (E)-17 obtained using Chem3D
AD and the results are summarized in Table 1. Initially, software with the C12=C13 double bond in (E)-17 pro-
we adopted the AD conditions optimized for the total syn- jected in the same orientation as stilbene depicted in the
4
thesis of amphidinolide T2, i.e. 2.5 mol% Os and 10 AD model. Therefore, the face of C12=C13 double bond
mol% (DHQD) AQN at 0 °C for seven hours. The desired opposite to C14-Me group should be favorably attacked
2
(
12R,13R)-diol 18 was obtained in 35% isolated yield by the ligand-bound Os, affording (12R,13R)-diol 18 as
along with a tetraol in 45% yield as a mixture of several the major product.
diastereomers (entry 1, Table 1). Structure of the tetraol
+
was confirmed by HRMS (+ESI): m/z [M + Na ] calcd for
+
C H O Na : 481.3141; found: 481.3124. The results in-
2
5
46
7
dicated that the C18-n-Pr in the diols 18 and 19 exerts
‘
shielding effect’ on the C16 exo-methylene group to a
much less extent so that both diols 18 and 19 were further
dihydroxylated to form the tetraol. We reasoned that dihy-
droxylation of the C16 exo-methylene group is slower
than the 12E double bond and formation of the tetraol
would be suppressed with less Os loading. We then tried
using 1 mol% Os and 4 mol% (DHQD) AQN for the same
2
AD reaction. Indeed, after reaction for nine hours at 0 °C
both diols 18 and 19 were isolated in 46% and 15% yields,
respectively, along with 33% recovered (E)-17 (entry 2,
Table 1). By prolonging the reaction time to 15 hours at 0
ºC, (E)-17 could be completely consumed, affording 18
and 19 in 59% and 25% isolated yields, respectively (en-
try 3, Table 1). The 18/19 ratio was found to be nearly the
same during the reaction course, i.e. 75:25 after seven
hours and 70:30 after 15 hours, suggesting that the second
AD reaction on the C16 exo-methylene group in both 18
and 19 had similar rates and yet occurred to a minimal ex-
tent at low Os loading. Moreover, the C18-n-Pr side chain
in (E)-17 has less influence on diastereoselectivity of the
AD reaction as compared to a similar cycloalkene pos-
Figure 1 A Chem3D-generated low-energy conformation of (E)-17
with facial selectivity in AD (top) and an illustrative model of AD
reaction of stilbene with OsO (DHQD) AQN (bottom)
4
2
4
The remaining task en route to the target macrolide 3 was
to selectively oxidize C13-OH to assemble the a-hydroxy
ketone functionalities. This was done by first selective
monosilylation of 18 to give the C12-OTBS ether 20 in
sessing a bulky C18 alkyl side chain. The latter afforded
8
2
5:15 and 82:18 diastereoselectivity when 5 mol% and
.5 mol% of Os, respectively, with 10 mol%
4
(
DHQD) AQN were used for the AD reaction at 0 °C.
2
6
0% yield along with 30% of the C13-OTBS ether 21.
Table 1 Results of Asymmetric Dihydroxylation of (E)-17a
Entry Ligand (Os mol%) Time (h) Products [Yield (%)]
Low selectivity in monosilylation of 18 might originate
from conformational change in response to the less bulky
C18 alkyl side chain (n-Pr), resulting in exposure of C13-
OH in 18 toward the silylating agent because silylation of
C13-OH was not observed in the total synthesis of amphi-
18 (35), tetraol (45)b
1
2
(DHQD) AQN (2.5)
7
9
2
(DHQD) AQN (1)
18 (46), 19 (15), (E)-17 (33)
18 (59), 19 (25)
4
2
dinolide T2. Finally, the alcohol 20 was subjected to
DMP oxidation (95%) followed by desilylation (81%) to
furnish amphidinolide T3 (3).17 Our total synthesis fea-
tures a 15-step sequence and a 3.4% overall yield.
3
(DHQD) AQN (1)
15
2
a
AD was carried out using K OsO (OH) and (DHQD) AQN as the
2
2
4
2
chiral catalyst in the presence of K Fe(CN) (3 equiv), K CO (3
3
6
2
3
In summary, we have successfully accomplished the total
synthesis of amphidinolide T3 using our recently estab-
lished RCM–AD strategy applied for the total synthesis of
equiv), and MeSO NH (1 equiv) in t-BuOH–H O (1:1) at 0 °C. The
2
2
2
ligand/Os ratio was 4:1. Yields are for the isolated materials.
b
The tetraol was formed by full dihydroxylation as a mixture of dia-
stereomers.
4
amphidinolide T2. Although influence of different C18
alkyl side chains on the RCM reaction was not observed
in respect to both cycloalkene yields and E/Z ratios of the
newly formed endocyclic double bond we did recognize
diminished selectivity in AD reaction of the cycloalkene
Figure 1 shows a rationale for the facial selectivity of
C12=C13 double bond in AD reaction of (E)-17 with Os–
(
DHQD) AQN. The illustrative model for AD reaction of
2
(
E)-17 and monosilylation of (12R,13R)-diol 18. These
stilbene with Os–(DHQD) AQN (Figure 1, bottom) is de-
2
findings, although not comprehensive, are of general in-
rived by modifying the optimum structure for same AD
terest for studying AD in macrocycles.9
reaction with Os–(DHQD) PHAL constructed by QM/
2
9
a,16
MM methods.
On the top in Figure 1 is shown a low-
Synlett 2011, No. 7, 895–898 © Thieme Stuttgart · New York

8
98
D. Wu et al.
LETTER
Supporting Information for this article is available online at
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(
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(
4
j) Hoveyda, A. H.; Zhugralin, A. R. Nature (London) 2007,
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Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
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The Laboratory of Asymmetric Catalysis and Synthesis is esta-
blished under the Cheung Kong Scholars Program of The Ministry
of Education of China. This work is supported in part by The Natio-
nal Natural Science Foundation of China (Grant No. 20772107), the
Zhejiang University, and the Zhejiang University Education Foun-
dation.
(
Wiley-VCH: Weinheim, 2003. (m) Handbook of
Metathesis, Vol. 3; Grubbs, R. H., Ed.; Wiley-VCH:
Weinheim, 2003.
(
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References and Notes
(
10) For total synthesis of amphidinolides X and Y, see:
(
1) For reviews, see: (a) Kobayashi, J.; Tsuda, M. Nat. Prod.
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(
(
a) Chen, Y.; Jin, J.; Wu, J.; Dai, W.-M. Synlett 2006, 1177.
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2
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Q. Synlett 2008, 1737.
(
(
(
11) (a) Sun, L.; Feng, G.; Guan, Y.; Liu, Y.; Wu, J.; Dai, W.-M.
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J. Org. Chem. 2001, 66, 134. (c) Kubota, T.; Endo, T.;
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6175.
(
a) Nattrass, G. L.; Díez, E.; McLachlan, M. M.; Dixon,
D. J.; Ley, S. V. Angew. Chem. Int. Ed. 2005, 44, 580.
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Wittenberg, R.; Kirschning, A. Chem. Eur. J. 2006, 12,
719.
(
3) For total synthesis of amphidinolide T1, see: (a) Ghosh,
A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374.
(
(
b) Aïssa, C.; Riveiros, R.; Ragot, J.; Fürstner, A. J. Am.
Chem. Soc. 2003, 125, 15512. (c) Colby, E. A.; O’Brien, K.
C.; Jamison, T. F. J. Am., Chem. Soc. 2004, 126, 998.
8
(
13) (a) Genêt, J. P.; Ratovelomanana-Vidal, V.;
(
d) Colby, E. A.; O’Brien, K. C.; Jamison, T. F. J. Am.
Caño de Anderade, M. C.; Pfister, X.; Guerreiro, P.; Lenoir,
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Chem. Soc. 2005, 127, 4297. (e) Yadav, J. S.; Reddy, C. S.
Org. Lett. 2009, 11, 1705.
4) For total synthesis of amphidinolide T2, see: Li, H.; Wu, J.;
Luo, J.; Dai, W.-M. Chem. Eur. J. 2010, 16, 11530.
5) For total synthesis of amphidinolide T3, see: (a) Deng,
L.-S.; Huang, X.-P.; Zhao, G. J. Org. Chem. 2006, 71, 4625.
(
(
71, 1.
(
(
14) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313.
2
0
15) Characterization Data for Alcohol 6: colorless oil; [a]D
–
0.27 (c = 2.25, CHCl ); R 0.27 (5% EtOAc in PE). IR
(
b) Ref. 3b.
3 f
–
1
(
film): 3358 (br), 3076, 2959, 2928, 1642, 1456, 1020 cm .
(
(
6) For total synthesis of amphidinolide T4, see: (a) Fürstner,
1
H NMR (400 MHz, CDCl ): d = 5.69 (ddd, J = 17.2, 10.4,
A.; Aïssa, C.; Riveiros, R.; Ragot, J. Angew. Chem. Int. Ed.
3
7.2 Hz, 1 H), 4.95 (d, J = 17.2 Hz, 1 H), 4.92 (d, J = 10.8 Hz,
2002, 41, 4763. (b) Refs. 3b and 3d.
1
H), 4.88 (s, 1 H), 4.87 (s, 1 H), 3.71 (br s, 1 H), 2.30–2.40
7) For synthesis of fragments, see: (a) O’Brien, K. C.; Colby,
(
m, 1 H), 2.21 (dd, J = 14.0, 3.6 Hz, 1 H), 2.00–2.06 (m, 3
E. A.; Jamison, T. F. Tetrahedron 2005, 61, 6243.
H), 1.34–1.52 (m, 4 H), 1.00 (d, J = 6.4 Hz, 3 H), 0.93 (t,
(
b) Abbineni, C.; Sasmal, P. K.; Mukkanti, K.; Iqbal, J.
1
3
J = 7.0 Hz, 3 H). C NMR (100 MHz, CDCl ): d = 144.8,
Tetrahedron Lett. 2007, 48, 4259. (c) Luo, J.; Li, H.; Wu, J.;
Xing, X.; Dai, W.-M. Tetrahedron 2009, 65, 6828.
3
1
43.9, 113.9, 112.8, 68.5, 44.3, 43.3, 39.2, 35.7, 20.1, 18.9,
4.1.
1
(
d) Sasmal, P. K.; Abbineni, C.; Iqbal, J.; Mukkanti, K.
(
(
16) Norrby, P.; Rasmussen, T.; Haller, J.; Strassner, T.; Houk,
K. N. J. Am. Chem. Soc. 1999, 121, 10186.
Tetrahedron 2010, 66, 5000.
(
8) For selective reviews on RCM, see: (a) Grubbs, R. H.;
Chang, S. Tetrahedron 1998, 54, 4413. (b) Fürstner, A.
Angew. Chem. Int. Ed. 2000, 39, 3012. (c) Trnka, T. M.;
Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18. (d) Schrock,
R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42,
17) Characterization Data for Amphidinolide T3 (3):
1
colorless oil. H NMR data are identical to those of
natural amphidinolide T3 (see Figure S1 in Supporting
+
Information). HRMS (+ESI): m/z [M + Na ] calcd for
C H O Na: 445.2930; found: 445.2916.
4592. (e) Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104,
25 42
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Synlett 2011, No. 7, 895–898 © Thieme Stuttgart · New York

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