Total synthesis of amphidinolactone A and its absolute configuration

Article abstract of DOI:10.1016/j.tetlet.2009.01.065

Asymmetric synthesis of amphidinolactone A, a cytotoxic macrolide from the cultured dinoflagellate Amphidinium sp., has been accomplished. Absolute configuration of amphidinolactone A was concluded to be 1 from comparison of the NMR data and [α]_D values of synthetic and natural amphidinolactone A.

Full text of DOI:10.1016/j.tetlet.2009.01.065

Tetrahedron Letters 50 (2009) 1475–1477
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Total synthesis of amphidinolactone A and its absolute configuration
*
Masahiro Hangyou, Haruaki Ishiyama, Yohei Takahashi, Takaaki Kubota, Jun’ichi Kobayashi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric synthesis of amphidinolactone A, a cytotoxic macrolide from the cultured dinoflagellate
Received 27 November 2008
Revised 8 January 2009
Accepted 13 January 2009
Available online 19 January 2009
Amphidinium sp., has been accomplished. Absolute configuration of amphidinolactone A was concluded
to be 1 from comparison of the NMR data and [
a]
values of synthetic and natural amphidinolactone A.
D
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Amphidinium sp.
Macrolide
Amphidinolactone A
Synthesis
Stereochemistry
Amphidinolactone A (1) is a cytotoxic 13-membered macrolide,
which was isolated from a symbiotic dinoflagellate Amphidinium
sp. (Y-25) separated from an Okinawan marine acoel flatworm
Amphiscolops sp.1 The relative stereochemistry of amphidinolac-
tone A (1) has been elucidated on the basis of extensive NMR
experiments.1
inseparable 5:3 diastereomeric mixture. Protection of the hydroxy
group at C-11 in 8 as benzyl ether yielded 9, which was subjected
to oxidative cleavage of terminal olefin followed by Wittig reaction
to provide a 4:1 (E:Z) mixture of ester (10). Reduction of ester 10
with DIBAL gave alcohol 11, which was oxidized with Dess–Martin
periodinane3 and then subjected to Yamamoto’s silver-catalyzed
asymmetric allylation4,5 to give a 5:3:2 mixture of 12, 13 and Z iso-
mers, respectively. At this stage, alcohols 12 and 13 were separated
by silica gel column chromatography. Removal of benzyl group in
12 followed by protection of hydroxy groups provided MOM ether,
which was treated with p-TsOHꢀH2O to afford diol 14.6 Selective
mesylation of diol 14 followed by treatment with K2CO3 in MeOH
provided the C-6–C-13 segment (15).
20
OH
OH
8
6
13
12
11
17
14
5
O
1
O
The absolute configuration at C-8 in 12 was confirmed by a
modified Mosher’s method.7 As shown in Figure 1, the values of
1
D
d [d(S-MTPA ester) ꢁ d(R-MTPA ester)] for H-6 and H-7 were po-
In order to determine the absolute stereochemistry of amphidi-
nolactone A (1), we planned an asymmetric total synthesis of
amphidinolactone A (1) as shown in Scheme 1. Amphidinolactone
A (1) could be obtained by ring-closing metathesis (RCM) of 2
through esterification of the C-1–C-5 segment (4) and the C-6–C-
20 segment (3), the latter of which was derived from epoxide 5
and acetylene 6 via alkynylation of oxirane. In this Letter, we de-
scribe the total synthesis of amphidinolactone A (1) and its abso-
lute configuration to be 1.
sitive, while the values of d for H-9, H-10, H-11, H-12 and H-13
D
were negative, suggesting that the absolute configuration at C-8
was R.
To confirm the absolute configuration at C-11 in 12, alcohol 12
was converted into 17 as follows (Scheme 3). Alcohol 12 was pro-
tected as t-butyldimethylsilyl ether (16), which was treated with
Na in liq. NH3 to provide alcohol 17.
The absolute configuration at C-11 in 17 was elucidated by a
modified Mosher’s method.7 The values of
D
d [d(S-MTPA es-
ter) ꢁ d(R-MTPA ester)] for H-6, H-7, H-8, H-9 and H-10 were neg-
ative, while the d values for H-12 and H-13 were positive,
The synthesis of the C-6–C-13 segment (15) of 1 is summarized
in Scheme 2. 2,3-Di-O-cyclohexylidene-(R)-(+)-glyceraldehyde
72 was treated with vinylmagnesium bromide to give 8 as an
D
suggesting that the absolute configuration at C-11 was S (Fig. 2).
The synthesis of the C-1–C-5 segment (4) is summarized in
Scheme 4. Commercially available alcohol 18 was treated with
PDC in DMF to provide the C-1–C-5 segment (4). Known acetylene
* Corresponding author. Tel.: +81 11 706 3239; fax: +81 11 706 4989.
E-mail address: jkobay@pharm.hokudai.ac.jp (J. Kobayashi).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.065

1476
M. Hangyou et al. / Tetrahedron Letters 50 (2009) 1475–1477
alkynylation
20
OH
OR
OH
OR
12
R
S
11
8
8
6
13
13
12
11
17
6
5
R
14
O
14
20
17
5
O
ring-closing
metathesis
1
1
O
esterification
O
2
1
OR
13
OR
13
S
S
8
8
12
12
11
11
R
R
R
20
6
6
O
R
14
OR
OR
OH
17
5
3
+
+
14
1
20
OH
17
5
O
6
4
Scheme 1. Retrosynthetic analysis of amphidinolactone A (1).
OBn
12
OH
OBn
13
O
13
13
11
11
11
13
12
12
12
c, d
b
EtO2C
O
O
a
H 11
O
O
R
10
10
10
O
O
O
O
7
8
9
10
OBn
OBn
OBn
12
13
13
11
11
13
11
R
R
R
R
HO
8
R
e
f, g
S
12
12
O
8
8
O
O
6
6
10
10
+
10
O
O
OH
OH
O
(5 : 3)
11
12
13
OBn
13
OMOM
OMOM
11
13
13
11
11
k, l
R
R
12
O
8
O
h, i, j
6
10
OH
S
8
O1H2
OMOM
8
OH
6
10
6
10
O
OMOM
12
14
15
Scheme 2. Synthesis of C-6–C-13 segment (15) of amphidinolactone A (1). Reagents and conditions: (a) CH2@CHMgBr, THF, 0 °C, 40 min,(60%); (b) BnBr, NaH, DMF, 50 °C, 1 h,
(86%); (c) OsO4, NaIO4, 2,6-lutidine, dioxane/H2O (3:1), rt, 1 h; (d) Ph3P@CHCO2Et, CH2Cl2, rt, 62 h, (10 (97%) as a 4:1 (E:Z) mixture for 2 steps); (e) DIBAL, CH2Cl2, ꢁ40 °C, 2 h,
(80%); (f) Dess–Martin periodinane, CH2Cl2, 0 °C, 30 min; (g) allyltrimethoxysilane, AgF, (R)-p-Tol-BINAP, MeOH, ꢁ20 °C, 4 h, (12 (44%) and 13 (27%) for 2 steps, respectively);
(h) Na, liq. NH3, ꢁ78 °C, 20 min, (98%); (i) MOMCl, iPr2NEt, CH2Cl2, rt, 14 h (84%); (j) p-TsOHꢀH2O, MeOH, rt, 50 min (71%); (k) MsCl, pyridine, 0 °C, 40 min and (l) K2CO3, MeOH,
rt, 30 min (73% for 2 steps).
OBn
OBn
OBn
+0.08
+0.08
+0.05
-0.02
-0.02
-0.05
13
13
+0.06R-0.10
8
12
12
6
13
11
8
12
a
-0.03
11
11
O
O
O
8
+0.01
+0.09
-0.09
6
6
O
O
O
OMTPA
OH
OTBS
12
16
Figure 1.
C-8 of alcohol 12.
D
d Values [
D
d (in ppm) = dS ꢁ dR] obtained for (S)- and (R)-MTPA esters at
OH
12
13
8
b
11
68 and the C-6–C-13 segment (15) in hand, we turned to alkynyla-
tion of oxirane under Yamaguchi condition9 (Scheme 4). Coupling
of 15 with known acetylene 6 using n-BuLi and BF3ꢀOEt2 provided
the alcohol 19. Reduction of 19 with hydrogen and Lindlar’s
catalyst followed by esterification of 4 with the alcohol using
1-ethyl-3-(dimethylaminopropyl)carbodiimide (EDC) gave ester.
O
6
O
OTBS
17
Scheme 3. Conversion of alcohol 12 into alcohol 17. Reagents and conditions: (a)
TBSCl, imidazole, DMF, rt, 12 h, (67%); (b) Na, liq. NH3, ꢁ78 °C, 10 min, (82%).

M. Hangyou et al. / Tetrahedron Letters 50 (2009) 1475–1477
1477
1
OH
a
OH
5
O
18
4
OMOM
13
OMOM
13
b
S
S
12
8
8
12
11
20
11
R
+
R
R
OH
14
6
10
O
20
6
R
OH
1
14
OMOM
OMOM
17
15
6
19
20
20
OH
R
OH
12
R
8
OH
S
11
S
11
8
6
13
13
17
R
c, d, e, f
17
6
R
12
+
14
14
5
5
O
O
1
O
O
1
20
Scheme 4. Alkynylation of C-6–C-13 segment (15) with C-14–C-20 segment (6) and ring-closing methathesis of 19. Reagents and conditions: (a) PDC, DMF, rt, 7 h, (61%); (b)
n-BuLi, BF3ꢀOEt2, THF ꢁ78 °C, 20 min (99%); (c) H2, Lindlar’s Pd-cat. quinoline, benzene, rt, 13 h; (d) 4, EDC, CH2Cl2, rt, 2 h; (e) Grubbs 1st generation catalyst CH2Cl2, 2 h and (f)
p-TsOHꢀH2O, MeOH, rt, 48 h (1 (4%) and 20 (2%) for 4 steps, respectively).
MTPAO
References and notes
+0.06
+0.07
-0.03
-0.03 -0.12
13
0.00
0.00
11 +0.06
6
+0.08
S12
O
1. Takahashi, Y.; Kubota, T.; Kobayashi, J. Heterocycles 2007, 72, 567–572.
2. Chattopadhyay, A.; Mamdapur, V. R. J. Org. Chem. 1995, 60, 585–587.
3. (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156; (b) Ireland, R. E.;
Liu, L. J. Org. Chem. 1993, 58, 2899.
-0.04
8
-0.09
-0.01
O
OTBS
4. Keck allylation13 using allyltributyltin (2 equiv) and 20 mol % catalyst prepared
from Ti(iPrO)4 and (R)-BINOL did not proceed.
Figure 2.
C-11 of alcohol 17.
D
d Values [
D
d (in ppm) = dS ꢁ dR] obtained for (S)- and (R)-MTPA esters at
5. Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.; Matsumoto, Y.;
Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701–3703.
6. Since removal of benzyl group proceeded in low yield at a later stage, the
hydroxy groups were protected as MOM ether.
7. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
8. Nakanishi, A.; Mori, K. Biosci., Biotechnol., Biochem. 2005, 69, 1007–1013.
9. Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
10. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100–110.
11. Because of unstability of synthetic intermediates from 19 to 1, the yield was
low.
The ester was subjected to RCM by using Grubbs’ first-generation
catalyst10 followed by removal of MOM groups to furnish amphidi-
nolactone A (1).11 The synthetic material 1 was spectroscopically
(IR, 1H and 13C NMR, HRMS)12 identical with natural product and
also had an optical rotation, ½a D21
ꢁ65 (c 0.033, benzene), in good
ꢂ
agreement with the literature value [lit.,1
½
a 1D9
ꢂ
ꢁ62 (c 0.065,
12. 1: colorless oil; ½a D21
ꢂ
ꢁ65 (c 0.033, benzene); IR (film) 3390 and 1720 cmꢁ1
;
benzene)]. Thus, the absolute stereochemistry of amphidinolac-
tone A (1) was established as 8R, 11S and 12R.
1H NMR (600 MHz, C6D6) d 5.66 (1H, m, H-6), 5.59 (1H, m, H-15), 5.59 (1H,
m, H-14), 5.54 (1H, ddd, J = 15.7, 7.5, 0.7 Hz, H-9), 5.46 (1H, m, H-17), 5.46
(1H, m, H-18), 5.30 (1H, ddd, J = 10.7, 9.6, 4.3 Hz, H-5), 5.24 (1H, ddd,
J = 15.7, 7.5, 0.7 Hz, H-10), 5.03 (1H, ddd, J = 8.9, 7.6, 0.7 Hz, H-12), 4.00 (1H,
m, H-8), 3.83 (1H, m, H-11), 2.88 (1H, m, H-16), 2.68 (1H, m, H-13a), 2.51
(1H, m, H-13b), 2.35 (1H, m, H-4a), 2.31 (1H, m, H-7a), 2.22 (1H, m, H-7b),
2.19 (1H, m, H-2a), 2.11 (1H, m, H-2b), 2.06 (1H, m, H-19), 1.87 (1H, m, H-
4b), 1.26 (1H, m, H-3b), 0.96 (1H, t, J = 7.5 Hz, H-20); 13C NMR (150 MHz,
Acknowledgements
We thank S. Oka and A. Tokumitsu, Center for Instrumental
Analysis, Hokkaido University, for ESIMS and FABMS measure-
ments. This work was partly supported by a from the Uehara
Memorial Foundation and Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology of Japan.
C6D6)
d 171.74, 136.68, 132.18, 131.24, 131.20, 130.74, 127.45, 125.11,
124.98, 74.00, 73.87, 72.39, 35.92, 32.07, 29.50, 26.00, 25.61, 22.96, 20.89,
14.40; ESIMS (positive) m/z 357 (M+Na)+; HRESIMS m/z 357.2036 (M+Na)+,
calcd for C20H30O4Na, 357.2042.
13. Keck, G. E.; Krishnamurthy, D.; Grier, M. C. J. Org. Chem. 1993, 58, 6543–6544.