Synthesis of the C1-C12 fragment of amphidinolide T1

Article abstract of DOI:10.1016/j.tetlet.2007.04.069

A synthesis of the C1-C12 fragment of amphidinolide T1 utilising Evans' aldol, oxy-Michael and cross metathesis reactions as the key steps is described.

Full text of DOI:10.1016/j.tetlet.2007.04.069

Tetrahedron Letters 48 (2007) 4259–4262
Synthesis of the C1–C12 fragment of amphidinolide T1I
Chandrasekhar Abbineni,a,b Pradip K. Sasmal,a,* K. Mukkantib and Javed Iqbala,*
aDiscovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, AP, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500 072, AP, India
Received 23 February 2007; revised 4 April 2007; accepted 12 April 2007
Available online 20 April 2007
Abstract—A synthesis of the C1–C12 fragment of amphidinolide T1 utilising Evans’ aldol, oxy-Michael and cross metathesis reac-
tions as the key steps is described.
Ó 2007 Elsevier Ltd. All rights reserved.
Amphidinolides are a rapidly growing class of cytotoxic
macrolides isolated from the marine dinoflagellates
Amphidinium sp.,1 and have shown significant antitu-
mour properties against a variety of NCI tumour cell
lines. Amphidinolides 1 are extremely scarce, and as a
result, biological studies have been limited. Amphidino-
lide T1 (1a) (Fig. 1) is a 19-membered macrolide possess-
interest in this synthesis to provide SARs of this class
of molecules.
For the total synthesis4 of 1a, we envisioned retrosyn-
thetically an intramolecular McMurry coupling on
intermediate 2 (Scheme 1) to construct the C12–C13
bond keeping in mind that suitable manipulation of
the McMurry product might also give amphidinolide
T3 (1b) and amphidinolide T4 (1c) as they are the
constitutional isomers of 1a, displaying a reversal of
the hydroxyl ketone pattern (ketone at C13 and hydr-
oxyl group at C12). Intermediate 2, in turn, could be
obtained from 3. Compound 3 could be obtained
by coupling fragments 4 and 5. Herein, we report a
ing
a
trisubstituted tetrahydrofuran moiety, an
a-hydroxy ketone, an exocyclic methylene group and a
homoallylic ester linkage and has shown potent activity
against murine lymphoma L1210 as well as human epi-
dermoid carcinoma KB cell lines.2 The structure of 1a
was initially established by NMR studies followed by
X-ray analysis by Kobayashi and co-workers.3 The sig-
nificant clinical potential and unique structural architec-
ture of amphidinolides have stimulated considerable
CHO
OHC
OH
O
McMurry Coupling
10
O
1
12
12
O
OH
O
O
O
7
O
O
O
O
O
18
1
1
2
Amphidinolide T1 (1a)
12
12S
R
: Amphidinolide T3 (1b)
TBSO
O
: Amphidinolide T4 (1c)
OTBS
OTBS
OTBS
Figure 1.
O
Esterification
+
O
OH
Keywords: Amphidinolide; Evans’ aldol; Oxy-Michael; Cross
metathesis.
q DRL Publication No. 526A.
O
O
HO
*
Corresponding authors. Tel.: +91 40 2304 5439; fax: +91 40 2304 5438
(P.K.S.); e-mail addresses: sasmalpk@yahoo.co.in; javediqbaldrf@
hotmail.com
5
4
3
Scheme 1.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.069

4260
C. Abbineni et al. / Tetrahedron Letters 48 (2007) 4259–4262
facile synthesis of the C1–C12 fragment (5) of amphidi-
nolide T1.
the desilylated product which on in situ oxy-Michael
reaction8 gave the tri-substituted furan moiety 11 as a
1:1 diastereomeric mixture of 2,5-trans/cis isomers.
Our synthesis commenced with the Crimmins modified
Evans’ strategy5 involving condensation of 3-butenal6
with (R)-4-benzyl-N-propionyloxazolidinone 6, to give
the syn aldol adduct 7 in 92% yield as a single diastereo-
mer, as confirmed by NMR spectroscopy (Scheme 2).
The hydroxyl group was protected as its TBS ether
and the chiral auxiliary was reductively removed7 with
NaBH4 to give the corresponding alcohol which was
converted to its tosyl derivative 8 in 66% overall yield.
The tosyl group was converted to a cyanide which was
reduced with DIBAL-H, and the aldehyde thus obtained
was homologated with carbethoxymethylene triphenyl-
phosphorane to afford the a,b-unsaturated ester 9 in
71% overall yield. Treatment of 9 with TBAF led to
At this juncture it was crucial to utilise conditions which
forced higher trans selectivity in the oxy-Michael pro-
cess. Towards this purpose compound 9 was desilylated
with 3 N HCl in THF at room temperature to furnish
alcohol 10 in 94% yield. The use of acidic conditions
did not give any cyclised oxy-Michael product. Next,
alcohol 10 was subjected to oxy-Michael reaction under
various conditions some of which are summarised in
Table 1. It was observed that in most of cases, poor
selectivity was obtained irrespective of using different
bases in different solvents at various temperature,9
whereas in the case of NaOEt in EtOH at ꢀ15 °C (entry
3) compound 11 was obtained with 3.5:1 selectivity in
favour of the trans isomer.10 When alcohol 10 was
treated with NaOMe in MeOH at ꢀ15 °C (entry 6), a
slightly better selectivity of 4.5:1 was observed with con-
comitant transesterification to produce compound 12 in
95% isolated yield. Selectivity of 4:1 in favour of the
trans isomer was also obtained using Triton B in MeOH
(entry 7).
O
O
O
OH
O
a
O
e ,f, g
i
N
O
N
7
Bn
6
Bn
b, c, d
When compound 10 was treated with a palladium
reagent in toluene, there was no oxy-Michael product,
but instead compound 13 was obtained in 50% yield.
The E configuration of 13 was confirmed by the fact that
a NOE was observed between the ester group and the
C-3 methylene group, whereas no significant NOE was
detected between the latter and the exocyclic olefinic
proton in 13. Comparison of the chemical shift at d
5.29 of the exocyclic olefinic proton within compound
13 with those of related compounds11 also indepen-
dently confirmed the E configuration of 13.
OTBS
OTBS
EtO2C
EtO2C
TsO
9
8
h
CO2R
OH
O
H3C
11: R = Et
12: R = Me
10
Scheme 2. Reagents and conditions: (a) TiCl4, (ꢀ)-sparteine, 3-
butenal, dry CH2Cl2, 0 °C, 30 min, 92%; (b) TBSOTf, DEIA, dry
CH2Cl2, 0 °C, 2 h, 90%; (c) NaBH4, THF/H2O, 0 °C to rt, 40 h, 80%;
(d) TsCl, Et3N, DMAP, CH2Cl2, 0 °C to rt, 16 h, 92%; (e) NaCN, dry
DMF, rt, 4 d, 88%; (f) DIBAL-H, dry CH2Cl2, ꢀ78 °C, 5 h, 90%; (g)
Ph3P@CHCO2Et, C6H6, reflux, 16 h, 90%; (h) 3 N HCl, THF, rt, 16 h,
94%; (i) NaOMe, MeOH, ꢀ15 °C, 24 h, 95%.
Generally, this class of 2-alkylidenetetrahydrofurans are
obtained from the corresponding b-keto esters.12
Although, in the literature, palladium mediated intra-
molecular alkoxy-carbonylation13 of hydroxy alkenes
has been addressed, in our case, only the a,b-unsatu-
rated olefin was engaged in the reaction leaving the
Table 1. Stereochemical outcome of oxy-Michael reactions of compound 10 under different conditions
Entry
Reaction conditionsa
trans:cisb
Yieldc (%)
1d
2
3
4
5
6
7
8
TBAF (1.1 equiv), THF, rt, 1 h
1:1
1:1
3.5:1
3:1
2:1
4.5:1
4:1
82
90
95
88
92
95e
KOtBu (1.1 equiv), THF, ꢀ15 °C, 2 h
NaOEt (1.1 equiv), EtOH, ꢀ15 °C, 24 h
DBU (1.1 equiv), EtOH, 0 °C, 24 h
NaOEt (1.1 equiv), Ph3P (1.1 equiv), EtOH, ꢀ15 °C, 24 h
NaOMe (1.1 equiv), MeOH, ꢀ15 °C, 24 h
Triton B (1.1 equiv), MeOH, ꢀ15 °C, 24 h
BF3ÆOEt2, CHCl3, rt, 12 h
90e
f
—
9
10
NaHMDS (1.1 equiv), ether, ꢀ20 °C, 2 h
1:1
—
83
50 (13)g
Pd(PPh3)4 (0.5 equiv), toluene, rt, 48 h
a 1.0 mmol of compound 10 was used.
b trans/cis ratio was measured by 1H NMR spectroscopy.
c Isolated yield.
d Compound 9 was used as starting material.
e Compound 12 was obtained by transesterification.
f Complex reaction mixture was obtained.
g Recovered 10, 40%.

C. Abbineni et al. / Tetrahedron Letters 48 (2007) 4259–4262
4261
OH
OH
Pd
Pd(PPh3)4
H
CO2Me
NOE
H3C
10
E
R
a
O
b
O
A
H3C
R = allyl, E = CO2Et
H
12-trans
14
Pd
E
H
H
Me
H
Me
Pd
E
O
OH
16
CH3
H
H
O
R
OTBS
H
H
O
R
H
(staggered)
H
B
C
H
c, d
O
H3C
E
H
5
Pd
H
15
H
Me
Me
E
Pd
O
R
O
R
H
(staggered)
Scheme 4. Reagents and conditions: (a) LiAlH4, dry THF, 0 °C to rt,
20 min, 70%; (b) TBSCl, imidazole, dry DMF, rt, 1 h, 90%, (c) Grubbs’
2nd generation cat, DCM, reflux, 16 h; (d) 10% Pd/C, EtOAc, 1 h, 50%
(over two steps).
H
D
E
H
Pd
E
H
Me
Me
H
H
Pd
(eclipsed)
E
The crude material of this metathesis reaction was sub-
jected to hydrogenation using 10% Pd/C in ethyl acetate
and gratifyingly, we obtained desired compound 5 in
50% yield over the two steps.17
H
H
O
R
O
R
H
H
H
H
D'
E'
EtO2C
H
In conclusion, we have achieved a synthesis of the
C1–C12 fragment of amphidinolide T1 utilising Evans’
aldol, oxy-Michael and cross metathesis reactions as
key steps. Currently, we are proceeding towards the
total synthesis of this molecule. During these studies
we have observed a palladium mediated oxidative oxy-
Michael reaction which could be a useful protocol for
the synthesis of various furan and pyran derivatives.
Further studies are required to understand this process
better. Optimisation of this reaction is currently under-
way and will be published in due course.
NOE
CO2Et
H
H
O
O
H3C
H3C
13
13-Z
Scheme 3.
terminal olefin untouched. The formation of compound
13 from 10 can be considered as an oxidative oxy-Mi-
chael reaction suitable for further exploration for appli-
cation in synthetic organic chemistry. Mechanistically, it
can be postulated that initially a palladium alkene p-
complex A is formed (Scheme 3). Intramolecular attack
by the hydroxyl group to the olefin could produce inter-
mediates B–E; B and C are kinetically controlled inter-
mediates whereas D and E are the thermodynamically
stable intermediates with minimised dipolar and steric
interactions. Intramolecular b-hydride elimination via
a four-membered cyclic transition state through the
eclipsed conformations D0 and E0 would generate com-
pound 13. It is also possible that intermediates B and
C might initially produce compound 13-Z (Scheme 3),
which in the process of isolation and purification is con-
verted into the thermodynamically more stable com-
pound 13.14
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd. for the sup-
port and encouragement. Help from the analytical
department in the form of spectral data is also
appreciated.
References and notes
1. For a review on the isolation of the amphidinolides, see:
Kobayashi, J. In Comprehensive Natural Products Chem-
istry; Mori, K., Ed.; Elsevier: New York, 1999; Vol. 8, p
619.
2. Tsuda, M.; Endo, T.; Kobayashi, J. J. Org. Chem. 2001,
66, 134.
3. (a) Kobayashi, J.; Kubota, T.; Tsuda, M.; Endo, T. J.
Org. Chem. 2000, 65, 1349; (b) Kubota, T.; Endo, T.;
Tsuda, M.; Shiro, M.; Kobayashi, J. Tetrahedron 2001, 57,
6175.
The two diastereomers of compound 12 were separated
by preparative HPLC. Accordingly, the ester group
within 12-trans (Scheme 4) was reduced with LiAlH4
in ether to give alcohol 14. The hydroxyl group was
protected as its TBS ether and the resulting olefinic
compound 15 was subjected to a cross metathesis15
reaction with 1616 using the second generation Grubbs’
catalyst in dichloromethane under refluxing conditions.
4. For total syntheses of amphidinolide T1, see: (a) Ghosh,
A. K.; Liu, C. J. Am. Chem. Soc. 2003, 125, 2374; (b)
Aissa, C.; Riveiros, R.; Ragot, J.; Furstner, A. J. Am.
¨

4262
C. Abbineni et al. / Tetrahedron Letters 48 (2007) 4259–4262
Chem. Soc. 2003, 125, 15512; (c) Colby, E. A.; O’Brien, K.
C.; Jamison, T. F. J. Am. Chem. Soc. 2005, 127, 4297.
5. (a) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F.
J. Am. Chem. Soc. 1991, 113, 1047; (b) Crimmins, M. T.;
King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org. Chem.
2001, 66, 894, and references cited therein.
see: (a) Batmangherlich, S.; Davidson, A. H. Tetrahedron
Lett. 1983, 24, 2889; (b) Piotti, M. E.; Alper, H.
J. Org. Chem. 1997, 62, 8484; (c) Langer, P.; Eckardt, T.
Angew. Chem., Int. Ed. 2000, 39, 4343; (d) Langer, P.;
Krummel, T. Chem. Eur. J. 2001, 7, 1720; (e) Pound, M.
K.; Davies, D. L.; Pilkington, M.; de Pina Vaz Sousa, M.
M.; Wallis, J. D. Tetrahedron Lett. 2002, 43, 1915; (f) Ref.
11c.
6. Crimmins, M. T.; Kirincich, S. J.; Wells, A. J.; Choy, A. L.
Synth. Commun. 1998, 28, 3675.
7. Prashad, M.; Kim, H.-Y.; Lu, Y.; Liu, Y.; Har, D.; Repic,
O.; Blacklock, T. J.; Giannousis, P. J.Org. Chem. 1999, 64,
1750.
8. For recent examples of the oxy-Michael reaction, see: (a)
Honda, T.; Ishikawa, F. J. Org. Chem. 1999, 64, 5542; (b)
Kubota, T.; Tsuda, M.; Kobayashi, J. Org. Lett. 2001, 3,
1363; (c) Kigoshi, H.; Kita, M.; Ogawa, S.; Itoh, M.;
Uemura, D. Org. Lett. 2003, 5, 957.
9. Base mediated epimerisation based on a ring-opening/
ring-closure mechanism cannot be ruled out, see: Freifeld,
I.; Holtz, E.; Dahmann, G.; Langer, P. Eur. J. Org. Chem.
2006, 3251.
10. The stereochemistry was determined by NOE experiments.
11. (a) Al-Tel, T. H.; Voelter, W. J. Chem. Soc., Chem.
Commun. 1995, 239; (b) Langer, P.; Armbrust, H.;
Eckardt, T.; Magull, J. Chem. Eur. J. 2002, 8, 1443, and
references cited therein; (c) Bellur, E.; Bottcher, D.;
Bornscheuer, U.; Langer, P. Tetrahedron: Asymmetry
2006, 17, 892, and references cited therein.
12. For some recent examples, see: (a) Bellur, E.; Langer, P. J.
Org. Chem. 2005, 70, 3819; (b) Tang, E.; Huang, X.; Xu,
W.-M. Tetrahedron 2004, 60, 9963; (c) Langer, P.; Frei-
feld, I.; Holtz, E. Synlett 2000, 4, 501.
13. (a) White, J. D.; Kranemann, C. L.; Kuntiyong, P. Org.
Lett. 2001, 3, 4003; (b) Semmelhack, M. F.; Kim, C.;
Zhang, N.; Bodurow, C.; Sanner, M.; Dobler, W.; Meier,
M. Pure Appl. Chem. 1990, 62, 2035.
15. Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R.
H. J. Am. Chem. Soc. 2003, 125, 11360.
16. Riley, R. G.; Silverstein, R. M. Tetrahedron 1974, 30,
1171.
17. Compound characterisation data for 12-trans: 1H NMR
(CDCl3, 400 MHz): d 5.86–5.76 (m, 1H), 5.13–5.03 (m,
2H), 4.52–4.45 (m, 1H), 3.98–3.94 (m, 1H), 3.68 (s, 3H),
2.63 (dd, J = 15.2, 6.8 Hz, 1H), 2.43 (dd, J = 15.2, 6.2 Hz,
1H), 2.34–2.26 (m, 2H), 2.20–2.13 (m, 1H), 1.90–1.78 (m,
2H), 0.95 (d, J = 7.4 Hz, 3H); 13C NMR (CDCl3,
50 MHz): d 171.6, 135.2, 116.5, 80.8, 73.2, 51.6, 41.3,
39.7, 35.7, 34.9, 13.9; CIMS: m/z 199 (M+1). Compound
13: 1H NMR (CDCl3, 400 MHz): d 5.86–5.77 (m, 1H),
5.29 (t, J = 1.5 Hz, 1H), 5.19–5.11 (m, 2H), 4.37–4.32 (m,
1H), 4.12 (q, J = 7.2 Hz, 2H), 3.11 (ddd, J = 18.0, 7.6,
2.0 Hz, 1H), 2.99 (ddd, J = 18.0, 4.0, 1.6 Hz, 1H), 2.52–
2.31 (m, 2H), 2.34–2.25 (m, 1H), 1.26 (t, J = 7.2 Hz, 3H),
0.97 (d, J = 7.3, 3H); 13C NMR (CDCl3, 50 MHz): d
175.5, 168.8, 133.7, 117.7, 90.1, 85.2, 59.2, 38.8, 34.2, 33.8,
14.5, 13.6; ESMS: m/z 233 (M+23), HRMS m/z 233.1156,
1
calcd for C12H18O3Na 233.1154. Compound 5: H NMR
(CDCl3, 400 MHz): d 4.17–4.09 (m, 1H), 3.85–3.78 (m,
1H), 3.74–3.66 (m, 2H), 2.51–2.41 (m, 1H), 2.26–2.14 (m,
1H), 1.87–1.58 (m, 4H), 1.50–1.27 (m, 8H), 1.18 (d,
J = 7.0 Hz, 3H), 0.89 (s, 9H), 0.89 (d, J = 7.0 Hz, 3H),
0.05 (s, 6H); 13C NMR (CDCl3, 50 MHz): d 181.8, 80.8,
73.7, 60.7, 40.2, 39.9, 39.2, 35.9, 33.5, 30.2, 27.4, 26.7, 26.0,
18.3, 16.8, 14.1, ꢀ5.3; ESMS: m/z 395 (M+23); HRMS
m/z 395.2594, calcd for C20H40O4SiNa 395.2589.
14. Isomerisation of
Z to E configuration of 2-alkyl-
idenetetrahydrofurans is well documented in literature,