Synthesis of the C19-C34 segment of amphidinolide C

Article abstract of DOI:10.1055/s-2007-967968

The synthesis of the C19-C34 segment of amphidinolide C is described. The key steps include the Mioskowski's Lewis acid catalyzed epoxide opening with the alcohol, ring-closing metathesis, Wittig reaction, and Nozaki-Hiyama-Kishi coupling reaction. Georg

Full text of DOI:10.1055/s-2007-967968

LETTER
567
Synthesis of the C19–C34 Segment of Amphidinolide C
Synthesis of the
C1
9–C34 Seg
b
ment of
A
m
e
phidinolide
n
C
dra K. Mohapatra,*a Hasibur Rahaman,a Mukund S. Chorghade,b Mukund K. Gurjara
a
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: dk.mohapatra@ncl.res.in
b
Chorghade Enterprises, 14 Carlson Circle, Natick, MA 01760, USA
Received 20 June 2006
This paper is dedicated to Prof. Yoshito Kishi on the occasion of his 70th birthday.
O
17
Abstract: The synthesis of the C19–C34 segment of amphidinolide
C is described. The key steps include the Mioskowski’s Lewis acid
O
14
21
catalyzed epoxide opening with the alcohol, ring-closing metathe-
sis, Wittig reaction, and Nozaki–Hiyama–Kishi coupling reaction.
38
37
Me
Me
19
22
OH
OH
27
31
O
H
Me
36
OH
34
Key words: amphidinolide C, cytotoxic, ring-closing metathesis,
Wittig reaction, Nozaki–Hiyama–Kishi coupling
H
H
H
5
O
1
Me
40
O
41
2
OH
O
amphidinolide C (1)
35 Me
The growing importance of amphidinolides group of
naturally occurring macrolides from the marine dino-
flagellates of the genus amphidinium has been attributed
to the potent biological activities and novel structural
features.1 The complete biological profiling of amphidin-
olides has been hampered because they are found only in
microscopic marine flatworms. The target molecule
Figure 1
for 2 has been outlined in Scheme 1 whose salient features
involved the Mioskowski’s Lewis acid catalyzed regio-
selective epoxide (8) opening with the alcohol 7 followed
by the RCM reaction to construct the tetrahydrofuran unit
amphidinolide C (1; Figure 1), isolated from the marine 5. For the installation of the side chain, two famous reac-
dinoflagellates Amphidinium sp. (strain Y–5), is a unique tions – Wittig and Nozaki–Hiyama–Kishi coupling – were
25-membered macrolide having two tetrahydrofuran rings envisaged.
decorated with vicinally located one-carbon branches.2
The synthesis of 8 began with cis-2-butene-1,4-diol (9)
The gross structure of 1 was elucidated by the 2D NMR
which was converted into 10 by employing the Sharpless
data. It is interesting to point out that amphidinolide C (1)
asymmetric epoxidation as previously described.4 The
enantiomeric purity of 10 was determined to be 83% ee by
chiral HPLC analysis (Scheme 2). The spectroscopic data
showed extremely potent in vitro cytotoxic activity
against murine lymphoma L1210 and epidermoid carci-
noma KB cells (IC50 = 0.0058 and 0.0046 mg mL–1, re-
(1H and 13C NMR) and the optical rotation of 10 were in
spectively).3 Based on these findings, it was but obvious
close agreement with the reported values {observed:
that amphidinolides make attractive targets for total syn-
[a]D25 –16.8 (c = 2.50, CH2Cl2); lit.4 [a]D25 –17.0 (c = 2.15,
thesis and therefore, we also embarked on one of their
family members amphidinolide C (1) and report herein the
synthesis of the C19–C34 segment (2).The retrosynthesis
CH2Cl2)}. Subsequent oxidation of 10 using 2-iodoxyben-
zoic acid (IBX)5 in DMSO followed by one-carbon Wittig
reaction with Ph3P=CH2 gave the vinyl epoxide 8.6
OH
O
I
+
O
O
H
H
OBn
H
H
OBn
OBn
Me
OBn
Me
2
3
4
+
OH
OPMB
O
OH
O
O
H
OBn
H
OPMB
H
OBn
H
OBn
OH
OBn
7
8
6
5
Scheme 1 Retrosynthetic analysis
SYNLETT 2007, No. 4, pp 0567–0570
0
1.
0
3.
2
0
0
7
Advanced online publication: 21.02.2007
DOI: 10.1055/s-2007-967968; Art ID: G20306ST
© Georg Thieme Verlag Stuttgart · New York

568
D. K. Mohapatra et al.
LETTER
O
a,b
O
c,d
b
a
HO
OH
HO
OPMB
+
OPMB
BnO
OPMB
O
OH
10
8
H
H
9
O
OH
OPMB
OBn
BnO
6
Scheme 2 Reagents and conditions: (a) NaH, PMBCl, DMF, 0 °C
to r.t., 78%; (b) (+)-DET, Ti(Oi-Pr)4, tert-butyl hydroperoxide
(TBHP), –30 °C, 20 h, 81%; (c) IBX, DMSO, THF, r.t., 6 h, 89%;
(d) Br–Ph3P+CH3, NaHMDS, THF, 0 °C, 4 h, 72%
7
8
d
c
BnO
OPMB
O
H
H
OPMB
O
OBn
H
H
H
The chirally pure allylic alcohol 7 was prepared by the
synthetic sequence described earlier from our laboratory.7
The spectroscopic and analytical data of 7 were in good
agreement with the reported values.
OBn
OBn
12
11
e
BnO
BnO
OPMB
O
OH
O
H
H
H
The coupling reaction between 7 and 8 was carried out in
the presence8 of catalytic amount of BF3·OEt2 to afford
the diene moiety 6 in 32% yield whereas the alcohol 7 was
recovered in 45% yield. It is noteworthy that with catalyt-
ic amount of Cu(OTf)2, the diene moiety was formed in
67% yield and the alcohol 7 was recovered in 18% yield.
In the 1H NMR spectrum of 6, characteristic signals due to
two olefinic groups were clearly observed. In addition, the
resonances due to benzylic protons of Bn and PMB
groups were located at d = 4.47 and 4.55 ppm, respective-
ly. The structure was further supported by the 13C NMR
and elemental analysis.9 The absolute stereochemistry of
the secondary hydroxyl group at C-24 was confirmed by
a-methoxy-a-trifluorophenylacetic acid (MTPA) ester
method.10 The secondary hydroxyl group of 6 was then
protected as its benzyl ether (11) by reacting with NaH
and BnBr. The ring-closing metathesis11 of 6 was carried
out using Grubbs’ second-generation catalyst in refluxing
CH2Cl2 to afford the dihydrofuran derivative 12 whose
hydrogenation was carried out in the presence of 10% Pd/
C in ethyl acetate at normal temperature and pressure, thus
affording the tetrahydrofuran derivative 13 (Scheme 3).
The removal of the PMB group with DDQ in CH2Cl2 and
water in a ratio of 19:1 gave the primary alcohol 5.12 The
OBn
13
5
Scheme 3 Reagents and conditions: (a) Cu(OTf)2, CH2Cl2, r.t., 4 h,
67%; (b) NaH, BnBr, DMF, 0 °C, 2 h, 87%; (c) Grubbs’ II catalyst,
CH2Cl2, 18 h, 79%; (d) Pd/C, H2, EtOAc, 2 h, 72%; (e) DDQ,
CH2Cl2–H2O, r.t., 4 h, 85%
structure of 5 was confirmed by the H, 13C NMR, and
1
elemental analysis.13
Our next concern was the introduction of the densely ole-
finated side chain for which the primary hydroxyl group
of 5 was oxidized with IBX and then the Wittig–Horner14
reaction with 1515 in the presence of LDA was performed
to obtain 16. Subsequent reduction of 16 with DIBAL-H
at –78 °C gave the allylic alcohol 17, which was converted
into the aldehyde derivative 3. The Nozaki–Hiyama–
Kishi coupling16 reaction between 3 and 4 was effected in
the presence of CrCl2 and catalytic amount of NiCl2 to
give a diastereomeric mixture of our target segment 2 and
2a in a 1:1 ratio (Scheme 4). To improve the selectivity,
the diastereomeric mixture was oxidized to the corre-
sponding keto compound 18 and reduced selectively with
Corey–Bakshi–Shibata (CBS) reagent. Because of the
O
BnO
BnO
b
a
OH
O
O
O
BnO
H
H
H
H
OEt
O
OBn
OBn
H
H
OBn
O
O
5
14
16
O
P
OEt
O
15
d
c
BnO
BnO
I
OH
OH
+
O
O
O
H
H
H
H
OBn
OBn
17
3
4
OH
e
BnO
BnO
+
O
O
H
H
H
H
OBn
OBn
2
2a
Scheme 4 Reagents and conditions: (a) IBX, DMSO, THF, 5 h; (b) 15, LDA, THF, –78 °C, 2 h, (65% over two steps); (c) DIBAL-H, CH2Cl2,
–78 °C, 1 h, 91%; (d) IBX, DMSO, THF, r.t., 2 h; (e) 4, CrCl2, NiCl2, DMSO, r.t., 24 h, 71% (over two steps)
Synlett 2007, No. 4, 567–570 © Thieme Stuttgart · New York

LETTER
Synthesis of the C19–C34 Segment of Amphidinolide C
569
highly conjugated system, an intractable mixture of
products was obtained (Scheme 5). Instead, the dia-
stereomers were easily separated by preparative liquid
chromatography17 and the absolute stereochemistry of
newly created secondary hydroxyl group bearing center
was assigned following a modification of Mosher’s
method. Accordingly, the faster-moving spot was con-
verted into its (R)- and (S)-MTPA esters with a-methoxy-
a-(trifluoromethyl)phenylacetic acid, which showed
negative chemical shift difference (Dd = dS – dR) for
protons on C30–C34, while protons on C19–C28 showed
positive differences, which is consistent with C29 bearing
an S configuration (Figure 2).10
References and Notes
(1) For recent reviews: (a) Kobayashi, J.; Ishibashi, M. Chem.
Rev. 1993, 93, 1753. (b) Chakraborty, T.; Das, S. Curr.
Med. Chem.: Anti-Cancer Agents 2001, 1, 131.
(c) Kobayashi, J.; Shimbo, K.; Kubota, T.; Tsuda, M. Pure.
Appl. Chem. 2003, 75, 337. (d) Kobayashi, J.; Tsuda, M.
Nat. Prod. Rep. 2004, 21, 77.
(2) Kobayashi, J.; Saski, T.; Ohizumi, Y. J. Am. Chem. Soc.
1988, 110, 490.
(3) Kobayashi, J.; Tsuda, M.; Ishibashi, M.; Shigemori, H.;
Yamasu, T.; Hirota, H.; Saski, T. J. Antibiot. 1991, 44, 1259.
(4) Trost, B. M.; Chisholm, J. D.; Wroleski, S. T.; Jung, M. J. J.
Am. Chem. Soc. 2002, 124, 12420.
(5) Frigeno, M.; Santagostino, M. Tetrahedron Lett. 1994, 35,
8011.
(6) Analytical and Spectral Data of 8: [a]25D +11.6 (c = 2.2,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 3.27–3.34 (m, 1
H), 3.42–3.66 (m, 3 H), 3.79 (s, 3 H), 4.44 (d, J = 11.5 Hz, 1
H), 4.54 (d, J = 11.5 Hz, 1 H), 5.30–5.51 (m, 2 H), 5.58–5.75
(m, 1 H), 6.86 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.6 Hz, 2 H).
13C NMR (50 MHz): d = 54.8, 55.6, 56.4, 67.2, 72.5, 113.5,
120.1, 129.0, 129.8, 131.8, 159.1. Anal. Calcd for C13H16O3:
C, 70.89; H, 7.32. Found: C, 70.70; H, 7.29.
OH
O
H
OBn
H
OBn
Me
a
2 + 2a
(7) Rama Rao, A. V.; Reddy, E. J.; Joshi, V. B.; Yadav, J. S.
Tetrahedron Lett. 1987, 28, 6497.
O
(8) Prestat, G.; Baylon, C.; Heck, M.-P.; Mioskowski, C.
Tetrahedron Lett. 2000, 41, 3829.
O
H
H
OBn
Me
b
(9) Analytical and Spectral Data of 6: [a]25D –3.74 (c = 1.1,
CHCl3). 1H NMR (200 MHz, CDCl3): d = 3.41–3.48 (m, 2
H), 3.51–3.56 (m, 2 H), 3.71–3.74 (m, 1 H), 3.79 (m, 3 H),
3.94–3.97 (m, 1 H), 4.07–4.10 (m, 1 H), 4.43 (d, J = 11.5 Hz,
1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.55 (br s, 2 H), 5.25–5.31
(m, 4 H), 5.65–5.74 (m, 2 H), 6.85 (d, J = 8.5 Hz, 2 H), 7.22–
7.34 (m, 7 H). 13C NMR (50 MHz, CDCl3): d = 55.2, 70.3,
72.9, 73.1, 73.3, 78.3, 113.7, 119.2, 119.6, 127.57, 128.4,
129.4, 130.2, 135.1, 135.6, 138.2, 159.2. Anal. Calcd for
C24H30O5: C, 72.34; H, 7.59. Found: C, 72.02; H, 7.83.
(10) (a) Ohtani, I.; Kusumi, J.; Kashman, Y.; Kakisawa, H. J. Am.
Chem. Soc. 1991, 113, 4092. (b) Yoshida, W. Y.; Bryan, P.
J.; Baker, B. J.; McClintock, J. B. J. Org. Chem. 1995, 60,
780.
OBn
18
intractable mixture of products
Scheme 5 Reagents and conditions: (a) IBX, DMSO, THF, 2 h,
75%; (b) (S)-CBS catalyst, BH3·THF, THF, –78 °C to 0 °C, 1 h
+50
34
19
O
+30
O
H
–80
OMTPA
+10
+10
Ph
–70
H
27
O
(11) (a) Blechert, S.; Schuster, M. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036. (b) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413. (c) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (d) Furstner, A. Angew. Chem. Int. Ed.
2000, 39, 3012.
–70
–110
+10
Me
41
H
Ph
Figure 2 Dd = (dS – dR) × 103 for (R)- and (S)-MTPA esters of
compound 2
(12) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885.
(13) Analytical and Spectral Data of 5: [a]25D +13.67 (c = 2.15,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 1.59–1.67 (m, 1
H), 1.69–1.76 (m, 1 H), 1.87–1.93 (m, 1 H), 1.95–2.01 (m, 1
H), 2.34 (br, 1 H), 3.37–3.44 (m, 3 H), 3.56 (dd, J = 5.1, 11.7
Hz, 1 H), 3.71 (dd, J = 4.1, 11.5 Hz, 1 H), 4.10–4.20 (m, 2
H), 4.49 (d, J = 12.4 Hz, 1 H), 4.52 (d, J = 12.4 Hz, 1 H), 4.63
(d, J = 11.8 Hz, 1 H), 4.68 (d, J = 11.8 Hz, 1 H), 7.18–7.30
(m, 10 H). 13C NMR (125 MHz, CDCl3): d = 27.9, 28.5, 62.2,
72.5, 72.7, 73.3, 78.6, 80.4, 80.8, 127.6, 127.7, 127.9, 128.4,
128.4, 138.4, 138.5. IR(neat): 3445, 3019, 2926, 2400, 1454,
1215, 1083, 928, 758, 669, 626 cm–1. Anal. Calcd for
C21H26O4: C, 73.66; H, 7.41. Found: C, 73.60; H, 7.66.
(14) Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett.
2002, 4, 647.
In conclusion, we have developed a convergent approach
for the synthesis of the segment 2 and its C29 epimer (2a)
of amphidinolide C in ten steps with 12% overall yield
following Mioskowski’s Lewis acid catalyzed regioselec-
tive epoxide opening reaction. Synthesis of C1–C18 of
amphidinolide C is in progress and will be reported in due
course.
Acknowledgment
H.R. thanks CSIR, New Delhi for financial assistance in the form
of a Senior Research Fellowship. We are thankful to Dr. P. R.
Rajmohanan for NMR data.
(15) Wittig–Horner reagent 15 was prepared starting from cis-2-
butene-1,4-diol (9) following standard reaction sequences as
given below (Scheme 6).
(16) Jin, H.; Uenishi, J.; Chirst, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644.
Synlett 2007, No. 4, 567–570 © Thieme Stuttgart · New York

570
D. K. Mohapatra et al.
LETTER
28.6, 30.1, 31.6, 70.4, 72.8, 73.3, 78.5, 79.8, 81.4, 81.9,
3. Wittig
4. DDQ
1. PMBCl
O
HO
HO
OH
PMBO
O
110.1, 116.2, 125.7, 127.4, 127.5, 127.7, 127.7, 128.2,
128.3, 129.7, 130.6, 138.3, 138.4, 138.7, 149.4. IR (neat):
3445, 3018, 2959, 2931, 2872, 2400, 1717, 1636, 1496,
1454, 1382, 1216, 1087, 1028, 927, 757, 698, 668, 625 cm–1.
Anal. Calcd for C32H42O4: C, 78.33; H, 8.63. Found: C,
78.63; H, 8.51. 2a (Slower-moving isomer): [a]25D +12.0
(c = 0.66, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 0.89 (t,
J = 7.3 Hz, 3 H), 1.28–1.36 (m, 2 H), 1.37–1.47 (m, 2 H),
1.67 (s, 3 H), 1.64–1.80 (m, 2 H), 1.82–2.06 (m, 4 H), 3.44–
3.53 (m, 2 H), 3.87 (dd, J = 5.6, 7.7 Hz, 1 H), 4.12–4.17 (m,
1 H), 4.18–4.23 (m, 1 H), 4.45 (d, J = 12.2 Hz, 1 H), 4.51 (s,
1 H), 4.54 (d, J = 12.2 Hz, 1 H), 4.59 (d, J = 12.2 Hz, 1 H),
4.65 (d, J = 12.2 Hz, 1 H), 4.97 (s, 1 H), 5.15 (s, 1 H), 5.68
(dd, J = 7.7, 15.2 Hz, 1 H), 6.17 (d, J = 11.1 Hz, 1 H), 6.47
(dd, J = 11.1, 15.2 Hz, 1 H), 7.23–7.36 (m, 10 H). 13C NMR
(100 MHz, CDCl3): d = 12.3, 13.9, 22.5, 27.7, 28.6, 30.1,
31.7, 70.4, 72.8, 73.3, 78.5, 79.9, 81.4, 81.8, 110.0, 116.2,
125.9, 127.4, 127.5, 127.7, 127.7, 128.3, 128.3, 129.7,
130.6, 138.2, 138.4, 138.7, 149.4.
2. OsO4
NaIO4
O
P
O
O
5. PBr3
OEt
O
OEt
6. (EtO)3P
Scheme 6
(17) Analytical and Spectral Data of 2 (Faster-moving isomer):
[a]25D –5.4 (c = 1.5, CH2Cl2). 1H NMR (400 MHz, CDCl3):
d = 0.90 (t, J = 7.2 Hz, 3 H), 1.27–1.36 (m, 2 H), 1.38–1.47
(m, 2 H), 1.67 (s, 3 H), 1.64–1.79 (m, 2 H), 1.85–2.07 (m, 4
H), 3.44–3.53 (m, 2 H), 3.86–3.89 (m, 1 H), 4.12–4.22 (m, 2
H), 4.51 (br s, 1 H), 4.43–4.67 (m, 4 H), 4.97 (s, 1 H), 5.14
(s, 1 H), 5.66 (dd, J = 7.8, 15.2 Hz, 1 H), 6.17 (d, J = 11.0
Hz, 1 H), 6.47 (dd, J = 11.0, 15.2 Hz, 1 H), 7.23–7.36 (m, 10
H). 13C NMR (100 MHz, CDCl3): d = 12.4, 13.9, 22.5, 27.7,
Synlett 2007, No. 4, 567–570 © Thieme Stuttgart · New York