Towards the total synthesis of amphidinolide E: An enantioselective synthesis of C12-C29 fragment

Article abstract of DOI:10.1016/j.tetlet.2004.08.143

An enantioselective synthesis of the C12-C29 fragment of amphidinolide E is described. Key transformations include an intramolecular mercuriocyclization reaction, stereoselective introduction of methyl group at the C2 position, and Stille coupling for the

Full text of DOI:10.1016/j.tetlet.2004.08.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7899–7902
Towards the total synthesis of amphidinolide E: an
enantioselective synthesis of C12–C29 fragment
Mukund K. Gurjar,* Seetaram Mohapatra, Usha D. Phalgune, Vedavati G. Puranik and
Debendra K. Mohapatra
National Chemical Laboratory, Pune 411008, India
Received 19 July 2004; revised 16 August 2004; accepted 24 August 2004
Available online 11 September 2004
Abstract—An enantioselective synthesis of the C12–C29 fragment of amphidinolide E is described. Key transformations include an
intramolecular mercuriocyclization reaction, stereoselective introduction of methyl group at the C2 position, and Stille coupling for
the introduction of the diene side chain.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The family of amphidinolides was isolated from the
marine dinoflagellates Amphidinium sp.1 and character-
ized by a significant anti-tumor activity against a variety
of NCI tumor cell lines. Among them, amphidinolide E
1 has a unique feature of a 19-membered macrocyclic
structure, which was elucidated by 2D NMR data2 while
the relative stereochemistry of eight chiral centers posi-
tioned at C2, C7, C8, C13, C16, C17, C18 and C19 were
confirmed by a combination of the J-based configura-
tion method and detailed NOESY experiments. The
absolute stereochemistry of 1 was determined by the
exciton chirality method coupled with MosherÕs meth-
od.3 Because of its unique structural features, notable
biological activity, and limited availability, the amphidi-
nolide group of molecules represents attractive targets
for total synthesis. Herein, we report an enantioselective
synthesis of the C12–C29 fragment of amphidinolide E 1
starting from D-glucose.
tion was to employ the Stille coupling reaction between
the triflate 3 and the dienyl-stannane intermediate 8
(Scheme 1).
The reported4 intermediate 6 was prepared from D-glu-
cose by a modified protocol in which the Grignard reac-
tion was carried out in ether by reverse addition of
Grignard reagent at 0ꢁC to improve the diastereoselec-
tivity (9:1) in favor of 6. Compound 6 was isolated from
the reaction mixture by crystallization in 80% yield. The
oxymercuration reaction5 of 6 gave a cis–trans mixture
of tetrahydrofuran derivatives with 3:1 selectivity but
conveniently separated by flash chromatography to
obtain the pure cis-tetrahydrofuran 11. The stereochem-
istry of 11 was unambiguously determined by X-ray
crystallography (Fig. 1).6 The demercuration7 reaction
of 11 was carried out under a stream of oxygen in the
presence of NaBH4 to give 12, which was benzylated
to form 13 (Scheme 2).
Our retrosyntheticanalysis for the synthesis of the C12–
C29 fragment of amphidinolide E 1 is illustrated in
Scheme 1. The four chiral centers at C16–C19 were to
be obtained from D-glucose while the stereo-controlled
off-template construction of the tetrahydrofuran ring
was predicted by utilizing the mercuriocyclization proto-
col on the 4-alkenol derivative 6. The side-chain installa-
Our next concern was the introduction of a methyl
group at C2 for which compound 12 was heated under
reflux for a prolonged period with methanol and
Amberlyst IR120 H+ resin followed by chromatography
to give the pure b-glycosides 14. The b-glycoside 14
showed in its 1H NMR spectrum a characteristic singlet
at d 4.78, corresponding to H1. The secondary hydroxyl
group present in 14 was oxidized with IBX8 in DMSO to
give the 2-ulose derivative 15, which was subjected to
one carbon homologation with Ph3P@CH2 to produce
the olefin 16. The hydrogenation of the double bond
in the presence of 10% Pd–C gave 5 exclusively. The
Keywords: Mercuriocyclization; Stille coupling; Wittig reaction;
Hydroboration–oxidation.
*
Corresponding author. Tel.: +91 20 25893614; fax: +91 20
25882456; e-mail: gurjar@dalton.ncl.res.in
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.143

7900
M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 7899–7902
Bu3Sn
8
OBn
OBn
OBn
O
O
O
H
H
H
H
H
H
OH
OBn
OBn
OBn
OTf
BnO
BnO
BnO
4
3
2
O
O
15
14
13
11
O
OH
16
O
O
OMe
OH
HO
BnO
10
O
O
H
12
17
H
H
22
O
O
20
24
O
O
H
21
28
OBn
19
26
HO
HO
9
BnO
O
8
25
23
1
2
7
5
6
27
29
5
7
3
O
6
4
30
SnBu3
Bu3Sn
Cl
Bu3Sn
+
Amphidinolide E (1).
8
9
10
Scheme 1.
O
O
O
O
O
OH
ref. 4
HO
a
O
H
H
O
O
O
HgCl
H
H
O
O
O
O
BnO
OMe
BnO
O
H
11
7
6
H
OBn
BnO
OH
H
H
O
O
OMe
b
c
O
O
H
H
H
H
O
OR
OBn
NOE studies on 14
O
BnO
BnO
OH
14
12 R = OH
13 R = OBn
Scheme 2. Reagents and conditions: (a) HgCl2, H2O, 1h, rt, 90%; (b) (1) O2, NaBH4, DMF, 4h, rt, 81%; (2) NaH, BnBr, DMF, 3h, rt, 94%; (c)
Amberlyst IR 120, MeOH, 9h, reflux, 86%.
derived aldehyde 19 was subjected to a Grignard reac-
tion with MeMgI and oxidation with DMP to give the
1
ketone 20. The structure of 20 was confirmed by H,
13C NMR, mass, and elemental analysis.
The stannane derivative 8 was not known, so designing
its synthesis became our priority. Amongst several pro-
tocols that could be envisaged, a Pd-catalyzed C–C
bond forming approach12,13 was chosen for its simplic-
ity. Bis-ethylene distannane 9 was reacted with methallyl
chloride 10 in the presence of PdCl2(CH3CN)2 followed
1
by distillation to give 8, which was analyzed by H, 13C
NMR, mass, and elemental analysis (Scheme 4).
Compound 20 was first enolated with LDA and then
treated with N-(2-pyridyl)-triflimide14 to give rise to
the O-Tf derivative 3. It was immediately reacted with
8 by the modified Stille coupling reaction15 to afford
Figure 1. ORTEP diagram of 11.
the target fragment 2 (Scheme 5). The structure of com-
pound 2 was confirmed by its 1H, 13C NMR, mass spec-
structure of 5 was confirmed by NOESY experimental
data. In order to convert 5 into the primary hydroxyl
derivative 4 successive hydrolysis,9 Wittig reaction, ben-
zylation, and hydroboration–oxidation reactions10 were
carried out (Scheme 3). Compound 4 was oxidized using
the Dess–Martin periodinane (DMP)11 and then the
tra, and microanalysis.16
In conclusion, we have synthesized an advance C12–C29
segment of amphidinolide E 1 and further work leading
to the total synthesis of
investigation.
1 is under extensive

M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 7899–7902
7901
O
O
OMe
O
OMe
OMe
a
O
O
c
b
O
H
H
H
H
H
H
OBn
OBn
OBn
BnO
BnO
BnO
16
OH
O
14
15
H
OMe
H
O
O
O
O
H
OH
OBn
H
OMe
OBn
O
O
e
O
f
d
g
H
H
H
H
H
BnO
OBn
OBn
OBn
H
H
BnO
BnO
BnO
17
OBn
5
18
NOE studies on 5
OBn
OBn
h
O
O
O
H
BnO
H
H
H
H
H
O
OBn
O
OBn
OH
OBn
BnO
BnO
20
4
19
Scheme 3. Reagents and conditions: (a) IBX, DMSO, 3h, rt, 92%; (b) Ph3P@CH2, THF–Et2O, 4h, rt, 78%; (c) Pd–C, H2, MeOH, 20min, rt, 92%; (d)
20% AcOH, 4h, 80ꢁC, 76%; (e) (1) Ph3P@CH2, THF–Et2O, 4h, rt, 86%; (2) NaH, BnBr, DMF, 3h, rt, 93%; (f) 9-BBN, NaOH, H2O2, 5h, rt, 90%;
(g) Dess–Martin periodinane, DCM, 30min, rt, 96%; (h) (1) MeMgI, Et2O, 2h, rt, 87%; (2) Dess–Martin periodinane, DCM, 30min, rt, 95%.
Ref. 12
a
Bu3Sn
+
Bu3SnCl
Li
+
Cl
SnBu3
SnBu3
9
10
8
Scheme 4. Reagents and conditions: (a) PdCl2(CH3CN)2, methallyl chloride, THF, 5h, 50ꢁC, 84%.
OBn
OBn
O
O
a
H
b
H
H
H
+
20
OTf
OBn
OBn
SnBu3
BnO
BnO
3
8
2
Scheme 5. Reagents and conditions: (a) LDA, N-(2-pyridyl)-triflimide, DME, À78ꢁC, 3h, 81%; (b) Pd(PPh3)4, LiCl, CuCl, DMSO, 6h, 60ꢁC, 92%.
in dichloromethane. Colorless needle of approximate size
0.37 · 0.18 · 0.08mm, was used for data collection on
Bruker SMART APEX CCD diffractometer using Mo Ka
radiation with fine focus tube with 50kV and 30mA.
Crystal to detector distance 6.05cm, 512 · 512pixels/
frame, Quadrant data acquisition. Total scans = 4, total
frames = 2424, oscillation/frame À0.3ꢁ, exposure/
Acknowledgements
S.M. is thankful to CSIR, New Delhi, for provid-
ing financial assistance in the form of a research
fellowship.
frame = 20.0s/frame,
maximum
detector
swing
References and notes
angle = À30.0ꢁ, beam center = (260.2, 252.5), in plane
spot width = 1.24, SAINT integration, h range = 2.13 to
28.31ꢁ, completeness to h of 28.31ꢁ is 94.9%. SADABS
correction applied, 2(C19H25O5HgCl). 0.5 H2O,
M = 1156.88. Crystals belong to orthorhombic, space
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543–572; (b) Chakraborty, T. K.; Das, S. Curr. Med.
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6. CCDC 244671, X-ray crystal data: single crystals of the
complex were grown by slow evaporation of the solution
˚
group P21, a = 10.987(2), b = 20.206(3), c = 11.125(2)A,
V = 2414.0(6)A , Z = 2, Dc = 1.592mgmÀ3
3
˚
,
l
(Mo
Ka) = 6.511mmÀ1, T = 295(2)K, 27,288 reflections meas-
ured, 11,013 unique [I > 2r(I)], value 0.0373,
R
wR2 = 0.0865. All the data were corrected for Lorentzian,
polarization, and absorption effects. SHELX-97 (ShelxTL)
was used for structure solution and full matrix
least squares refinement on F2. Hydrogen atoms were
included in the refinement as per the riding model.
Compound crystallizes with half molecules of water
as solvent of crystallization (Sheldrick, G. M. SHELX-
97 Program for Crystal Structure Solution and
Refinement, University of Gottingen, Germany,
1997).

7902
M. K. Gurjar et al. / Tetrahedron Letters 45 (2004) 7899–7902
7. Sih, J. C.; Graber, D. R. J. Org. Chem. 1982, 47, 4919–4927.
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Chem. Soc. 1974, 96, 7765–7770.
11. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277–7287.
12. Bottaro, J. C.; Hanson, R. N.; Seitz, D. E. J. Org. Chem.
1981, 46, 5221–5222.
13. Naruse, Y.; Esaki, T.; Yamamoto, H. Tetrahedron 1988,
44, 4747–4756.
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6299–6301.
15. Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc.
1999, 121, 7600–7605.
16. Spectral data of compound 11: [a]D À29.3 (c 3.35, CHCl3);
1H NMR (500MHz, CDCl3) d 7.34–7.26 (m, 5H), 6.02 (d,
1H, J = 3.8Hz), 4.67 (d, 1H, J = 11.9Hz), 4.58 (d, 1H,
J = 3.8Hz), 4.45 (d, 1H, J = 11.9Hz), 4.34 (m, 1H), 4.18
(q, 1H, J = 7.4, 14.1Hz), 4.02 (dd, 1H, J = 3.3, 6.5Hz),
3.86 (d, 1H, J = 3.3Hz), 2.34 (dd, 1H, J = 5.3, 12.5Hz),
2.13 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H), 1.65 (m, 1H),
1.49 (s, 3H), 1.42 (m, 1H), 1.31 (s, 3H); 13C NMR
(125MHz, CDCl3) d 137.5, 128.5, 128.0, 127.9, 111.7,
105.3, 83.2, 83.0, 82.0, 78.7, 77.9, 71.8, 38.3, 35.3, 28.8,
27.0, 26.5; Anal. Calcd for C19H25O5HgCl: C, 40.07; H,
4.42. Found: C, 40.32; H, 4.78.
Spectral data of compound 5: [a]D +33.2 (c 5.6, CHCl3);1H
NMR (500MHz, CDCl3) d 7.30–7.23 (m, 10H), 4.70 (d,
1H, J = 5.4Hz), 4.56 (m, 2H), 4.51 (m, 2H), 4.08 (m, 1H),
4.04 (t, 1H, J = 3.7Hz), 3.85 (m, 1H), 3.80 (dd, 1H,
J = 2.2, 6.7Hz), 3.38 (m, 2H), 3.37 (s, 3H), 2.18 (m, 1H),
1.90–1.71 (m, 4H), 1.05 (d, 3H, J = 7.1Hz); 13C NMR
(125MHz, CDCl3) d 138.7, 138.5, 128.3, 127.8, 127.7,
127.6, 107.1, 85.6, 80.7, 80.4, 78.6, 73.4, 73.0, 72.2, 55.5,
42.1, 28.5, 27.4, 7.8; Anal. Calcd for C25H32O5: C, 72.79;
H, 7.82. Found: C, 72.52; H, 7.64.
Spectral data of compound 4: [a]D +14.6 (c 1.3, CHCl3);
1H NMR (500MHz, CDCl3) d 7.30–7.15 (m, 15H), 4.71
(m, 3H), 4.56 (m, 3H), 4.14 (m, 2H), 3.69 (m, 1H), 3.54
(dd, 1H, J = 3.2, 7.7Hz), 3.52 (m, 3H), 3.45 (dd, 1H,
J = 3.2, 7.7Hz), 2.09 (m, 1H), 1.92 (m, 3H), 1.78 (m, 3H),
1.61 (m, 1H), 1.00 (d, 3H, J = 3.9Hz); 13C NMR (50MHz,
CDCl3) d 138.6, 138.4, 128.3, 128.2, 127.8, 127.6, 127.5,
84.0, 81.0, 80.2, 77.8, 74.2, 73.3, 60.2, 34.3, 31.5, 28.5, 27.6,
18.0; Anal. Calcd for C32H40O5: C, 76.15; H, 7.98. Found:
C, 76.04; H, 7.85.
Spectral data of compound 20: [a]D À15.8 (c 0.9, CHCl3);
1H NMR (300MHz, CDCl3) d 7.36–7.25 (m, 15H), 4.71
(m, 3H), 4.55 (s, 2H), 4.43 (d, 1H, J = 11.6Hz), 4.14 (m,
2H), 3.54 (m, 3H), 3.39 (m, 1H), 2.87 (dd, 1H, J = 3.6,
16.9Hz), 2.46 (m, 1H), 2.27 (m, 1H), 1.99 (s, 3H), 1.89–
1.66 (m, 4H), 0.94 (d, 3H, J = 6.98Hz); 13C NMR
(75MHz, CDCl3) d 209.0, 138.9, 138.7, 128.3, 128.2,
128.0, 127.8, 127.6, 127.5, 127.4, 83.9, 82.0, 81.0, 77.9,
74.2, 73.4, 73.2, 46.5, 30.7, 30.3, 29.7, 28.4, 18.8; Anal.
Calcd for C33H40O5: C, 76.71; H, 7.80. Found: C, 76.41;
H, 7.52.
Spectral data of compound 13: [a]D À45.1 (c 4.4, CHCl3);
1H NMR (500MHz, CDCl3) d 7.36 (m, 10H), 5.96 (d, 1H,
J = 3.5Hz), 4.65 (d, 1H, J = 11.4Hz), 4.58 (d, 1H,
J = 3.5Hz), 4.54 (s, 2H), 4.41 (d, 1H, J = 11.4Hz), 4.12
(m, 2H), 4.06 (dd, 1H, J = 3.2, 6.9Hz), 3.85 (d, 1H,
J = 3.4Hz), 3.54 (dd, 1H, J = 4.4, 9.3Hz), 3.46 (dd, 1H,
J = 4.4, 9.3Hz), 1.94 (m, 1H), 1.81 (m, 2H), 1.50 (m, 1H),
1.45 (s, 3H), 1.30 (s, 3H); 13C NMR (125MHz, CDCl3) d
138.3, 137.1, 128.2, 128.0, 127.7, 127.5, 127.3, 127.2, 111.3,
105.31, 83.3, 82.5, 81.7, 78.3, 78.0, 73.1, 73.0, 72.4, 71.4,
28.0, 27.2, 26.7, 26.3; Anal. Calcd for C26H32O6: C, 70.88;
H, 7.32. Found: C, 71.12; H, 7.14.
Spectral data of compound 14: [a]D À38.0 (c 2.2, CHCl3);
1H NMR (500MHz, CDCl3) d 7.34–7.32 (m, 10H), 4.78 (s,
1H), 4.65 (d, 1H, J = 11.9Hz), 4.53 (br s, 2H), 4.46 (d, 1H,
J = 11.9), 4.24 (br s, 1H), 4.12 (m, 2H), 4.06 (t, 1H,
J = 6.3Hz), 3.84 (dd, 1H, J = 3.0, 6.3Hz), 3.56 (dd, 1H,
J = 4.8, 9.8Hz), 3.45 (dd, 1H, J = 4.8, 9.8Hz), 3.40 (s, 3H),
1.94 (m, 2H), 1.75 (m, 1H), 1.53 (m, 1H); 13C NMR
(125MHz, CDCl3) d 138.6, 137.8, 128.4, 128.3, 127.9,
127.8, 127.7, 127.5, 109.6, 83.8, 83.4, 79.3, 78.6, 78.4, 73.4,
72.9, 72.1, 55.7, 28.6, 27.6; Anal. Calcd for C24H30O6: C,
69.54; H, 7.29; Found: C, 69.43; H, 7.42.
1
Spectral data of compound 8: bp = 120–125ꢁC/1mm; H
NMR (200MHz, CDCl3) d 5.95 (t, 2H, J = 8.33Hz), 4.74
(m, 2H), 2.85 (s, 2H), 1.74 (s, 3H), 1.49 (m, 6H), 1.34 (m,
6H), 0.92 (m, 15H); 13C NMR (50MHz, CDCl3) d 146.7,
144.0, 129.5, 110.9, 46.9, 29.3, 27.4, 22.2, 13.7, 9.48; Anal.
Calcd for C18H36Sn: C, 58.24; H, 9.78. Found: C, 58.46;
H, 9.84.
Spectral data of compound 2: [a]D +11.2 (c 0.3, CHCl3);
1H NMR (500MHz, CDCl3) d 7.36–7.26 (m, 15H), 6.04
(d, 1H, J = 15.6Hz), 5.78 (dt, 1H, J = 6.6, 15.6Hz), 4.95
(s, 1H), 4.83 (s, 1H), 4.77 (d, 2H, J = 12.8Hz), 4.73 (s, 1H),
4.70 (d, 1H, J = 2.8Hz), 4.66 (s, 1H), 4.54 (m, 3H), 4.15
(m, 2H), 3.59 (t, 1H, J = 4.8Hz), 3.54 (dd, 1H, J = 4.8,
9.5Hz), 3.46 (m, 2H), 2.71 (d, 2H, J = 7.1Hz), 2.31 (m,
1H), 1.91 (m, 3H), 1.72 (s, 3H), 1.66 (s, 3H), 0.87 (d, 3H,
J = 7.1Hz); 13C NMR (125MHz, CDCl3) d 145.1, 144.6,
139.0, 138.9, 138.6, 133.6, 128.3, 128.2, 128.0, 127.8, 127.7,
127.6, 127.5, 127.4, 127.3, 127.2, 115.0, 110.7, 84.8, 82.0,
80.1, 77.6, 73.8, 73.7, 73.3, 73.1, 41.4, 34.4, 33.4, 28.4, 27.9,
22.4, 17.3; Anal. Calcd for C39H48O4: C, 80.65; H, 8.33.
Found: C, 80.51; H, 8.42.