Synthesis of the C14-C29 segment of amphidinolide U utilizing a tandem dihydroxylation-SN2 cyclization protocol

Article abstract of DOI:10.1055/s-2008-1042931

The synthesis of the C14-C29 subunit of amphidinolide U is described. The key steps include the trans-2,5-disubstituted tetrahydrofurans via a highly diastereoselective and high yielding tandem dihydroxylation-S_N2 cyclization, Wittig reaction, and Nozaki-Hiyama-Kishi coupling reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1042931

LETTER
837
Synthesis of the C14–C29 Segment of Amphidinolide U Utilizing a Tandem
Dihydroxylation–SN2 Cyclization Protocol
Synthesis of the
C
1
e
4–C29 Seg
b
ment of
A
m
e
phidinolide
n
U
dra K. Mohapatra,* Hasibur Rahaman
Organic Chemistry Division, National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25902629; E-mail: dk.mohapatra@ncl.res.in
Received 18 November 2007
This paper is dedicated to Professor Yoshito Kishi on the occasion of his 70th birthday
to add hexenyl iodide to aldehyde 4 following Nozaki–
Hiyama–Kishi reaction (Scheme 1). The diene system
would be introduced by following a Wittig–Horner with
the phosphorane reported in our earlier communication.4b
We anticipated that the required trans-tetrahydrofuran
would be obtained on the basis of a recently reported pro-
tocol.5
Abstract: The synthesis of the C14–C29 subunit of amphidinolide
U is described. The key steps include the trans-2,5-disubstituted tet-
rahydrofurans via a highly diastereoselective and high yielding tan-
dem dihydroxylation–SN2 cyclization, Wittig reaction, and Nozaki–
Hiyama–Kishi coupling reaction.
Key words: amphidinolide U, cytotoxic, tandem dihydroxylation–
SN2 cyclization, Wittig reaction, Nozaki–Hiyama–Kishi coupling
The synthesis of segment 2 was technically more expedi-
ent, commencing with commercially available L-glutamic
acid. The preparation of (S)-5-hydroxymethyl butyrolac-
tone (6) was achieved in 60% yield over two steps follow-
ing a standard procedure.6 The primary hydroxy group
was protected as its TBS ether using TBDMSCl and Et3N
in CH2Cl2. To obtain the required a,b-unsaturated ester,
compound 7 was treated with DIBAL-H followed by a
stable two-carbon ylide in a Wittig reaction which afford-
Amphidinolides are a group of structurally unique mac-
rolides isolated to date from laboratory-cultured di-
noflagellates of the Amphidinium sp.1 Many of the
amphidinolides exhibit potent antitumor activity against
lymphoma L1210 and human carcinoma KB cells.2 De-
spite their common origin and uniformly high cytotoxicity
against various cancer cell lines, the amphidinolides pos-
sess a high degree of structural diversity incorporating
many variegated molecular scaffolds. Continuing search
for bioactive secondary metabolites resulted in the isola-
tion of a novel 20-membered macrolide, amphidinolide U
(1, Figure 1), possessing a tetrahydrofuran ring, two exo-
methylenes, three branched methyls, two ketones, two hy-
droxy groups, and a C10 linear side chain.3 The structure
of amphidinolide U (1) was elucidated by spectroscopy;
relative stereochemistry was assigned by NOESY studies
and absolute configurations were assigned on the basis of
modified Mosher’s method.
1
ed E-isomer as the only product. In the H NMR spectra
of 8, the olefinic proton appeared as a set of two doublet
of triplets at d = 5.86 (J = 1.6 and 15.7 Hz) and 6.92
(J = 6.9, 15.7 Hz) ppm, thereby confirming the trans-ste-
reochemistry. The secondary hydroxy group was then
protected as its mesylate. Now, the stage was set to carry
out the tandem dihydroxylation–SN2 cyclization reaction.
As per literature precedence, the mesylate derivative 9
was subjected to dihydroxylation with the Sharpless AD-
mix a reagent, where upon the trans,syn-tetrahydrofuran
10 was obtained with excellent diastereoselectivity
(Scheme 2).7 Barely detectable amounts of isomeric tet-
rahydrofuran could be detected in the product by HPLC
analysis or by NMR spectroscopy. Next, the inversion of
the hydroxy group was achieved via standard Mitsunobu
protocol to obtain the required chiral center and NMR ex-
periment done to assign the stereochemistry (Figure 2).8
Hydrolysis of p-nitrobenzoate with K2CO3 in ethanol
gave 12.9
As part of our program directed toward the synthesis of
tetrahydrofuran ring containing complex bioactive natural
products,4 we have demonstrated a high yielding tandem
dihydroxylation–SN2 cyclization protocol for the synthe-
sis of C14–C29 subunit of amphidinolide U (1).
In our synthetic plan, we envisaged a disconnection into
two segments 2 and 3. For the synthesis of 2, we planned
After Mitsunobu inversion, the stereochemical assign-
ment of the secondary hydroxy-bearing center was
achieved following modified Mosher’s method.10 Accord-
ingly, compound 12 was converted into its (S)- and (R)-
(MTPA) ester with a-methoxy-a-(trifluoromethyl)phenyl
acetic acid which showed positive chemical shift differ-
ences (Dd = dS – dR) for protons on C3 through C7 while
protons on C1 through C2¢ showed negative differences,
which is consistent with C2 bearing an R-configuration.
OH
H
O
O
O
H
O
HO
O
amphidinolide U (1)
Figure 1
SYNLETT 2008, No. 6, pp 0837–0840
Advanced online publication: 20.03.2008
x
x.
x
x.
2
0
0
8
Deprotection of TBS ether linkage with TBAF in THF at
room temperature afforded compound 13. The resulting
DOI: 10.1055/s-2008-1042931; Art ID: G39107ST
© Georg Thieme Verlag Stuttgart · New York

838
D. K. Mohapatra, H. Rahaman
LETTER
12
14
16
1. DIBAL-H
TBSCl
17
19
OH
O
O
CH2Cl2, –78 °C
2 h
O
Et3N, CH2Cl2
r.t., 8 h, 92%
22
10
26
O
H
O
29
H
O
H
OTBS
24
O
OH
H
6
2. Ph3P=CCO2Et
benzene, 60 °C
12 h, 78% (two steps)
6
7
1
O
34
8
2
HO
33
O
1
30
31
MsCl, Et3N
AD-mix α
CH2Cl2, 0 °C
2 h, 95%
0 °C, 48 h
87%
OMs
OH
OEt
OEt
14
16
O
OTBS
O
OTBS
HO
BnO
17
8
9
26
22
H
29
O
24
H
K2CO3
DIAD, p-NBA
Ph3P, THF
OPNB
CO2Et
OH
OBn
O
H
OTBS
O
34
H
H
OTBS
H
EtOH, r.t.
3 h, 96%
31
2
CO2Et
0 °C to r.t.
12 h, 80%
10
11
12 +
S
S
10
H
TBAF, THF
0 °C to r.t., 12 h, 95%
OH
OH
O
O
O
3
1
7
H
OTBS
H
OH
OH
H
H
HO
CO2Et
CO2Et
5
12
13
O
3
Scheme 2 Synthesis of intermediate 13
O
O
Ag2O, BnBr
OEt
OEt
BnO
O
O
O
EtOAc, r.t.
72 h, 88%
H
H
H
H
H
H
OBn
OBn
OH
OH
O
H
14
LAH, THF
13
H
OBn
0 °C, 2 h, 90%
4
IBX, DMSO
THF, r.t., 4 h
O
O
OH
H
O
H
OBn
H
OBn
OBn
OBn
5
15
Wittig salt
LDA, THF
–78 °C, 2 h
BnO
H
H
O
O
O
O
72% (2 steps)
H
H
O
OBn
OH
DIBAL-H
CH2Cl2
5
6
OEt
O
H
OBn
H
Scheme 1 Retrosynthetic analysis of amphidinolide U (1)
–78 °C, 2 h, 94%
OBn
16
OH
IBX, DMSO
THF, r.t., 2 h
O
H
OBn
H
H
H
OBn
H
H
17
O
TBSO
O
O
H
OBn
H
OEt
O
X
OBn
4
H
H
H
OPNB
I
18
CrCl2, NiCl2
DMSO, r.t.
12 h, 78% (2 steps)
Figure 2 NOE studies on 11
OH
diol was then protected as its benzyl ethers with BnBr in
the presence of Ag2O in 88% yield. Treatment of 1411 with
LAH in THF gave the primary alcohol 15 in 90% yield.
Our next concern was to introduce the densely olefinated
side chain. The Wittig–Horner phosphorane was prepared
starting from cis-buten-1,4-diol following the sequence of
reactions i) mono-PMB protection; ii) one-pot dihydroxy-
lation followed by chopping; iii) Wittig reaction; iv) PMB
deprotection using DDQ; v) conversion of allylic alcohol
into bromide; vi) phosphorane synthesis using triethyl
phosphite. The primary hydroxy group of 15 was then ox-
idized with IBX; a Wittig–Horner12 reaction with
O
H
OBn
H
OBn
2
Scheme 3 Synthesis of fragment 2 of amphidinolide U
phosphorane4b in the presence of LDA was performed to
obtain 16.13 Structure of 16 was investigated by spectro-
scopic data. For example, its 1H NMR spectrum revealed
signals (Scheme 3). Synthesis of fragment 2 of amphidin-
olide U due to olefinic protons at d = 6.02 (dd, J = 7.0,
Synlett 2008, No. 6, 837–840 © Thieme Stuttgart · New York

LETTER
Synthesis of the C14–C29 Segment of Amphidinolide U
839
(4) (a) Mohapatra, D. K.; Nayak, S.; Mohapatra, S.; Chorghade,
M. S.; Gurjar, M. K. Tetrahedron Lett. 2007, 48, 5197.
(b) Mohapatra, D. K.; Rahman, H.; Chorghade, M. S.;
Gurjar, M. K. Synlett 2007, 567. (c) Mohapatra, D. K.;
Mohapatra, S.; Gurjar, M. K. Tetrahedron Lett. 2006, 47,
5943.
(5) Marshal, J. A.; Sabatini, J. J. Org. Lett. 2005, 7, 4819.
(6) (a) Takano, S.; Kurotaki, A.; Takahashi, M.; Ogasawara, K.
Synthesis 1986, 403. (b) Vigneron, J. P.; Meric, R.;
Larcheveque, M.; Debal, A.; Lallemand, J.-Y.; Junesh, G.;
Tagatti, P.; Gallois, M. Tetrahedron 1984, 40, 3521; and
references therein. (c) Taniguchi, M.; Koga, K.; Yamada, S.
Tetrahedron 1970, 30, 3547.
15.3 Hz, 1 H), 6.56 (ddd, J = 1.1, 11.4, 15.3 Hz, 1 H), and
7.21 (d, J = 11.4 Hz, 1 H) ppm which were characteristic
of the E,E-dienoic group. Subsequent reduction of 16 with
DIBAL-H at –78 °C gave the allylic alcohol 17, which
was converted into the aldehyde derivative 4 (Scheme 3).
The Nozaki–Hiyama–Kishi coupling14 reaction between 4
and 18 was effected in the presence of CrCl2 and catalytic
amount of NiCl2 to give a 1:1 diastereomeric mixture of
our targeted segment 2.15
OH
(7) Analytical and Spectral Data of 10
O
[a]D25 –8.97 (c 1.8, CHCl3). IR (neat): 3337, 3113, 3080,
3056, 2929, 2857, 1736, 1672, 1607, 1530, 1464, 1439,
1346, 1207, 1119, 837 cm–1. 1H NMR (200 MHz, CDCl3):
d = 0.03 (s, 6 H), 0.88 (s, 9 H), 1.31 (t, J = 7.2 Hz, 3 H), 3.57
(d, J = 4.5 Hz, 2 H), 3.99–4.14 (m, 2 H), 4.18–4.35 (m, 3 H).
13C NMR (50 MHz, CDCl3–CCl4): d = –5.5, 14.0, 18.1, 25.7,
27.6, 27.8, 61.3, 65.4, 72.3, 79.8, 80.8, 172.8. Anal. Calcd
(%) for C15H30O5Si: C, 56.57; H, 9.49. Found: C, 56.38; H,
9.41.
H
H
OBn
OBn
2
OR
O
H
OBn
H
OBn
18
R = Ac, Bz, PNB, TBS, MOM, MEM
(8) Mitsunobu, O. Synthesis 1981, 1.
(9) Analytical and Spectral Data of 12
Scheme 4 Protection of 2 with different protecting groups
[a]D25 –4.63 (c 1.4, CHCl3). IR (neat): 3413, 3019, 2956,
2930, 2858, 1729, 1600, 1518, 1471, 1419, 1255, 1215,
1130, 838, 758 cm–1. 1H NMR (200 MHz, CDCl3): d = 0.04
(s, 6 H), 0.88 (s, 9 H), 1.29 (t, J = 7.2 Hz, 3 H), 1.72–2.06 (m,
4 H), 2.93 (br d, 1 H), 3.59 (d, J = 4.6 Hz, 1 H), 4.11 (m, 1
H), 4.19–4.37 (m, 4 H). 13C NMR (50 MHz, CDCl3–CCl4):
d = –5.4, –5.4, 14.2, 18.3, 25.7, 25.9, 27.9, 61.6, 65.7, 72.4,
80.4, 80.5, 172.4. Anal. Calcd (%) for C15H30O5Si: C, 56.57;
H, 9.49. Found: C, 56.42; H, 9.38.
We protected the secondary hydroxy group with different
protecting groups (Scheme 4) to generate variously pro-
tected diastereomers 19. Unfortunately, no separation of
diastereomers with different solvent systems was discern-
ible. The diastereomers could be separated by preparative
liquid chromatography and assigned the absolute stereo-
chemistry as reported for amphidinolide C.4b
(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.
In conclusion, the efficient and convergent route present-
ed here led to the first synthesis of the entire top half of the
amphidinolide U in 15 steps and 18% overall yield, offer-
ing the promise of the total synthesis of this molecule but
also other structurally similar congeners. Further work is
in progress.
(11) Analytical and Spectral Data of 14
[a]D25 +37.42 (c 0.9, CHCl3). IR (neat): 3063, 3030, 2927,
1745, 1496, 1454, 1368, 1262, 1199, 1087, 1028, 736, 697
cm–1. 1H NMR (200 MHz, CDCl3): d = 1.21 (t, J = 7.2 Hz, 3
H), 1.67 (m, 1 H), 1.81–2.04 (m, 3 H), 3.37 (d, J = 5.0 Hz, 2
H), 4.01 (d, J = 4.4 Hz, 1 H), 4.06–4.23 (m, 3 H), 4.28 (m, 1
H), 4.42 (d, J = 11.8 Hz, 1 H), 4.48 (s, 2 H), 4.64 (d, J = 11.8
Hz, 1 H), 7.16–7.30 (m, 10 H). 13C NMR (50 MHz, CDCl3–
CCl4): d = 14.3, 26.5, 28.4, 60.8, 72.7, 72.8, 73.3, 79.0, 79.7,
80.7, 127.5, 127.6, 127.7, 127.9, 128.3, 137.6, 138.4, 170.7.
Anal. Calcd (%) for C21H26O4: C, 73.66; H, 7.65. Found: C,
73.26; H, 7.61.
Acknowledgment
We are thankful to Dr. Mukund K. Gurjar for his constant support
and encouragement. H.R. thanks CSIR, New Delhi for financial as-
sistance in the form of a Senior Research Fellowship. We also thank
Dr. Ganesh Pandey, HOD, Organic Chemistry Division, for his va-
luable suggestions and support. Help from Dr. P. R. Rajmohanan
for NMR data is also well recorded.
(12) Song, F.; Fidanze, S.; Benowitz, A. B.; Kishi, Y. Org. Lett.
2002, 4, 647.
(13) Analytical and Spectral Data of 16
[a]D25 +51.43 (c 1.45, CHCl3). IR (neat): 3425, 3019, 2928,
1709, 1602, 1453, 1269, 1216, 1097, 1027, 757, 698, 668
cm–1. 1H NMR (200 MHz, CDCl3): d = 1.32 (t, J = 7.2 Hz, 3
H), 1.64–1.85 (m, 2 H), 1.91–2.07 (m, 5 H), 3.40–3.53 (m, 2
H), 3.98 (dd, J = 4.7, 6.9 Hz, 1 H), 4.09 (m, 1 H), 4.16–4.27
(m, 3 H), 4.46 (d, J = 12.1 Hz, 1 H), 4.56–4.57 (m, 2 H), 4.64
(d, J = 12.1 Hz, 1 H), 6.02 (dd, J = 7.0, 15.3 Hz, 1 H), 6.56
(ddd, J = 1.1, 11.4, 15.3 Hz, 1 H), 7.21 (d, J = 11.4 Hz, 1 H),
7.28–7.34 (m, 10 H). 13C NMR (50 MHz, CDCl3–CCl4): d =
12.7, 14.3, 12.0, 28.4, 60.5, 71.1, 72.6, 73.2, 78.7, 81.4,
127.4, 127.5, 127.5, 127.6, 127.7, 128.2, 128.2, 128.3,
137.0, 138.3, 168.1. Anal. Calcd (%) for C28H35O5: C, 74.64;
H, 7.61. Found: C, 74.82; H, 7.45.
References and Notes
(1) (a) Kobayashi, J.; Tsuda, M. Nat. Prod. Rep. 2004, 21, 77.
(b) Ishibashi, M.; Kobayashi, J. Heterocycles 1997, 44, 543.
(c) Chakraborty, T.; Das, S. Curr. Med. Chem.: Anti-Cancer
Agents 2001, 1, 131. (d) Kobayashi, J.; Ishibashi, M. In
Comprehensive Natural Products Chemistry, Vol. 8; Mori,
K., Ed.; Elsevier: Amsterdam, 1999, 415.
(2) The IC50 values as low as 0.00014 mg/mL were reported;
hence, amphidinolides exhibit potencies similar to that of
spongistatins, cf. ref. 1.
(3) Tsuda, M.; Endo, T.; Kobayashi, J. Tetrahedron 1999, 55,
14565.
Synlett 2008, No. 6, 837–840 © Thieme Stuttgart · New York

840
D. K. Mohapatra, H. Rahaman
LETTER
(14) Jin, H.; Uenishi, J.; Chirst, W. J.; Kishi, Y. J. Am. Chem. Soc.
1986, 108, 5644.
(15) Analytical and Spectral Data of 2
(m, 1 H), 4.41–4.67 (m, 5 H), 4.97 (s, 1 H), 5.15 (s, 1 H), 5.66
(dd, J = 7.7, 15.2 Hz, 1 H), 6.18 (d, J = 10.9 Hz, 1 H), 6.47
(dd, J = 10.9, 15.2 Hz, 1 H), 7.28–7.38 (m, 10 H). 13C NMR
(100 MHz, CDCl3): d = 12.4, 12.4, 14.0, 22.5, 27.0, 28.5,
30.1, 31.6, 70.6, 70.7, 72.8, 73.3, 78.7, 79.9, 81.7, 81.8, 81.9,
109.9, 110.0, 125.8, 125.9, 127.0, 127.4, 127.5, 127.7,
128.2, 128.3, 128.6, 129.5, 129.6, 138.2, 138.3, 138.4,
138.8, 140.9, 149.4, 149.4. Anal. Calcd for C32H42O4: C,
78.33; H, 8.63. Found: C, 78.12; H, 8.49.
[a]D25 +22.34 (c 0.9, CHCl3). IR (neat): 3445, 3018, 2959,
2931, 2872, 2400, 1717, 1636, 1496, 1454, 1382, 1216,
1087,1028, 927, 757, 698, 668, 625 cm–1. 1H NMR (200
MHz, CDCl3): d = 0.90 (t, J = 7.1 Hz, 3 H), 1.29–1.50 (m, 4
H), 1.67 (s, 3 H), 1.62–1.72 (m, 2 H), 1.82–2.05 (m, 4 H),
3.41–3.54 (m, 2 H), 3.88–3.94 (m, 2 H), 4.12 (m, 1 H), 4.25
Synlett 2008, No. 6, 837–840 © Thieme Stuttgart · New York