Stereoselective synthesis of amphidinolide T1

Article abstract of DOI:10.1021/ol9002724

A highly stereoselective total synthesis of amphidinolide T1 is achieved using Sharpless asymmetric epoxidation, base-induced epoxide opening, radical cyclization, diastereoselective reduction followed by allylation, Evans methylation, base-induced reduct

Full text of DOI:10.1021/ol9002724

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1705-1708
Stereoselective Synthesis of
Amphidinolide T1
J. S. Yadav* and Ch. Suresh Reddy
Organic Chemistry DiVision I, Indian Institute of Chemical Technology, Hyderabad
500607, India
yadaVpub@iict.res.in
Received February 9, 2009
ABSTRACT
A highly stereoselective total synthesis of amphidinolide T1 is achieved using Sharpless asymmetric epoxidation, base-induced epoxide
opening, radical cyclization, diastereoselective reduction followed by allylation, Evans methylation, base-induced reductive elimination, umpolung
reaction, chemoselective oxidation, and regioselective macrolactonization.
Marine dinoflagellates of the genus Amphidinium have been
recognized as a source of novel secondary metabolites called
amphidinolides, a growing family of macrolides with unique
structure and interesting biological activity.1 Despite their
common origin and uniformly high toxicity against various
cancer cell lines, the amphidinolides possess a high degree
of structural diversity incorporating many variegated mo-
lecular scaffolds. Amphidinolide T1 (1) isolated from extracts
of the strain Y-56 of the dinoflagellate Amphidinium sp. is
a 19-membered macrolide possessing a trisubstituted tet-
rahydrofuran moiety, one exomethylene, three branched
methyls, one ketone, and one hydroxyl group. It showed
potent activity against murine lymphoma L1210 and human
epidermoid carcinoma KB cell lines.2 The structure of 1 was
established by detailed NMR studies, and the absolute
stereochemistry was established by modified Mosher’s
method followed by a single crystal X-ray analysis.3 Because
of its potent biological activity, low abundance, and unique
molecular architecture, amphidinolide T1 has attracted
significant attention from the synthetic community, and as
the result three total syntheses have been appeared in the
literature. The first total synthesis of amphidinolide T1 was
reported by Ghosh and co-workers in 2002,4 and later
Fu¨rstner5 and Jamison6 also reported the synthesis of this
molecule using very different strategies to effect macrocycle
formation. Additionally, Zhao et al.7 reported the synthesis
of amphidinolide T3 (1a) (Figure 1) that is structurally related
to amphidinolide T1. In continuation of our synthesis of
complex natural products, we report herein a new convergent
and stereoselective total synthesis of amphidinolide T1.
Our retrosynthetic analysis of amphidinolide T1 is shown
in Figure 1. The formation of the macrolactone was envis-
aged from a seco acid 2, which was disconnected at the
C12-C13 bond into trisubstituted tetrahydrofuran fragment
3 and homoallyl ether fragment 4. In the forward direction
(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.
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8, p 415.
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2005, 127, 4297.
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10.1021/ol9002724 CCC: $40.75
Published on Web 03/26/2009
2009 American Chemical Society

Scheme 1. Synthesis of Segment 3
Figure 1. Retrosynthetic analysis of amphidinolide T1.
Scheme 2. Synthesis of Compound 3
fragment 2 was envisaged to be obtained by an umpolung
reaction between 3 and 4;8 retrons 3 and 4 can be obtained
from 5 and 6, respectively.
The synthesis of compound 3 started from the known
mono benzylether 5, which was oxidized to the correspond-
ing aldehyde and further homologated by a two-carbon Wittig
olefination to afford R,ꢀ-unsaturated ester 7 (E-isomer) as
the sole product (83% over two steps). Compound 7 on
reduction with LiAlH4/AlCl3 afforded an allylic alcohol in
80% yield. Sharpless asymmetric epoxidation9 of the allyl
alcohol using (+)-DIPT, Ti(iPrO)4 and TBHP at -20 °C
furnished epoxy alcohol 8 in 91% yield and in 94% ee.
Subsequent reaction of 8 with PPh3 in CCl4 in the presence
of NaHCO3 (cat.) at reflux, followed by base-induced
dehydrohalogenation using the methodology developed by
us,10 gave alkynol 9 in 82% overall yield.
The alkynol 9 was reacted with ethyl vinyl ether and NBS
to afford bromo acetal, which on being subjected to radical
cyclization11 by treatment with n-Bu3SnH and AIBN in
refluxing benzene afforded lactolether 10 in 85% overall
yield for two steps. The lactolether 10 underwent diastereo-
selective reduction using NaBH4 and NiCl2·6H2O12 in
methanol to provide four diastereomers, which were sepa-
rated by column chromatography to afford the required
ethoxy tetrahydrofuran 11 and a stereoisomeric mixture of
ethoxy tetrahydrofuran 12 in a 1:1.1 ratio in 88% yield.
The mixture of isomers 12 were subjected to Jones
oxidation13 to furnish the syn- and anti-lactones 13 (2.3:1,
88% yield), which were separated readily by silica gel
column chromatography. The syn-lactone was reduced with
DIBAL-H to give lactol 14 (95% yield), which was
subsequently treated with allyltrimethylsilane using a known
procedure14 to furnish allylated product 15. Although the
yields were encouraging with lactol 14 as well as lactol ether
11, the anti:syn ration was not attractive. This prompted us
to explore a strategy recently developed by us15 to allylate
allyl/benzyl alcohols using allyl trimethyl silane in the
presence of a catalytic amount of iodine. Surprisingly,
(8) (a) Gu, R.-L.; Sih, J. Tetrahedron Lett. 1990, 31, 3283. (b) Tone,
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Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
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1990, 62, 1333.
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J. Am. Chem. Soc. 1982, 104, 5564. (b) Yadav, J. S.; Joyasawal, S.; Dutta,
S. K.; Kunwar, A. C. Tetrahedron Lett. 2007, 48, 5335.
(14) (a) Schmitt, A.; Reissig, H.-U. Synlett 1990, 40. (b) Larsen, C. H.;
Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121,
12208. (c) Schmitt, A.; Reibig, H.-U. Eur. J. Org. Chem. 2000, 3893.
(15) (a) Yadav, J. S.; Reddy, B. V. S.; Trimurtulu, N.; Mallikarjuna
Reddy, N.; Prasad, A. R. Tetrahedron Lett. 2008, 49, 2031. (b) Yadav,
J. S.; Reddy, B. V. S.; Rao, K. V.; Raj, K. S.; Rao, P. P.; Prasad, A. R.
Tetrahedron Lett. 2004, 45, 6505. (c) Yadav, J. S.; Reddy, B. V. S.; Reddy,
A. S.; Eeshwaraiah, B. Chem. Lett. 2007, 36, 1500.
(11) (a) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. J. Chem. Soc.,
Chem. Commun. 1980, 482. (b) Beckwith, A. L. J.; Lawrence, T.; Serelis,
A. K. J. Chem. Soc., Chem. Commun. 1980, 484. (c) Yadav, J. S.; Gadgil,
V. R. J. Chem. Soc., Chem. Commun. 1989, 1824.
(12) Satoh, T.; Nanba, K.; Suzuki, S. Chem. Pharm. Bull. 1971, 19 (4),
817.
1706
Org. Lett., Vol. 11, No. 8, 2009

Table 1. Improvement of Diastereoselectivity
conditions
substrate
time
yield %
anti:syn
product
(1) BF3Et2O (3 equiv), CH2Cl2, -78 °C
(2) BF3Et2O (3 equiv), CH2Cl2, -78 °C
(3) SnBr4 (2 equiv), CH2Cl2, rt
11
14
11
11
11
11
14
14
5 min
30 min
1 h
24 h
2 h
4 h
6 h
3 h
95
92
93
97
94
90
87
92
93:7
95:5
94:6
15
15
15
15
15
16
16
15
(4) I2 (1 mol %), CH2Cl2, rt
96:4
(5) I2 (5 mol %), CH2Cl2, -78 to 0 °C
(6) I2 (1.2 equiv), CH2Cl2, -78 to 0 °C
(7) I2 (1.2 equiv), CH2Cl2, -78 to 0°C
(8) l2 (5 mol %), CH2Cl2, -78 to 0 °C
>99:1
>99:1
96:4
96:4
Scheme 3
.
Synthesis of Segment 4
Scheme 4. Synthesis of Amphidinolide T1 (1)
alcohol was treated with catalytic OsO4 and stoichiometric
4-methylmorpholine N-oxide (NMO) to afford the diol which
on oxidative cleavage using NaIO4 gave aldehyde.18 Protec-
tion with 1,3-propanedithiol in presence of BF3·Et2O fur-
nished the dithiane 3 in 76% overall yield.
The journey for the synthesis of segment 4 began with
alkylation of diethylmalonate 19 with the known iodo
compound 619 followed by base-induced reductive elimina-
tion. Three different conditions were examined: (i) NaH as
base and LAH as reducing agent to afford a mixture of 20
and 21 in 4:1 ratio in 55% yield;20 (ii) n-BuLi as base and
DIBAL-H as reducing agent, which did not give the desired
product; and (iii) n-BuLi as base and AlH3 (alane) as
reducing agent to afford 20 exclusively in 60% yield (Table
2). After obtaining compound 20 as a single product,
conversion of the hydroxyl group to the corresponding bromo
functionality using TPP/CBr4 followed by allylation under
Barbier conditions21 gave a racemic homoallyl alcohol 22
treatment of lactol ether 11 with allyltrimethyl silane in the
presence of iodine (5 mol%) gave the desired product 15 in
94% yield with complete antiselectivity. It is noteworthy to
mention here that the presence of 1.2 equiv of iodine led to
allylation with concommitant debenzylation to afford 16 in
90% yield. Similarly, allylation of lactol 14 afforded the
required product 16 in a ratio of 96:4. Optimized condtions
of allylation and/or debenzylation are presented in Table 1.
The primary hydroxyl group in 16 was converted to the
carboxy group by oxidation with TEMPO and BAIB in
CH3CN and H2O.16 N-Acylation of the chiral (S)-oxazolidin-
2-one using the mixed anhydride conditions furnished 17 in
85% yield over two steps.17Diastereoselective alkylation of
the Na-enolate of 17 with MeI followed by reductive
cleavage of the chiral auxiliary afforded alcohol 18 as the
only isomer in 65% overall yield (Scheme 2). The resulting
(18) Albert, B. J.; Koide, K. Org. Lett. 2004, 06, 3655.
(19) Thompson, A. M.; Delaney, A. M.; Hamby, J. M.; Schroeder, M. C.;
Spoon, T. A.; Crean, S. M.; Hollis Showalter, H. D.; Denny, W. A. J. Med.
Chem. 2005, 48, 4628.
(20) (a) Marshall, J. A.; Cohen, N. J. Org. Chem. 1965, 30, 3475. (b)
Yadav, J. S.; Rao, E. S. Indian J. Chem. 1986, B25, 1174.
(21) Jogi, A.; Maeorg, U. Molecules 2001, 6, 964.
(16) Epp, J. B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293.
(17) Chakraborty, T. K.; Suresh, V. R. Tetrahedron Lett. 1998, 39, 7775.
Org. Lett., Vol. 11, No. 8, 2009
1707

Table 2. Optimization of Reductive Elimination
conditions
product ratio 20:21
yield %
55
(1) NaH, 19, 5 h, NaH, 6 h, LiAIH4, THF, reflux, 6 h
80:20
(2) n-BuLi, 19, 2 h, n-BuLi, 15 min, DIBAL-H, THF, 0 °C to rt,
5 h
no desired product
(3) n-BuLi, 19, 2 h, n-BuLi, 15 min, LiAIH4/AlCl3, THF, reflux,
5 h
>98
60
in 68% yield over two steps. Enzymatic kinetic resolution
of 22 using lipase PS-C ‘Amano’ II afforded (R)-homoallylic
acetate 24 (35% with 98% ee).22 The unrequired isomer 23
was converted to the required isomer following an oxidation,
reduction, and enzymatic resolution sequence. Deacetylation
of 24 was achieved by treatment with NaOMe, and protection
of the resulting hydroxyl group as its TBS ether gave 25 in
87% yield over two steps.
The exposure of the resulting acid 30 to HF·Py complex
gave the seco acid 2 in 93% yield. Now, the stage was set
to carry out the most crucial macrocyclization reaction under
modified Yamaguchi conditions.25,7 As expected, the seco
acid 2 following modified Yamaguchi conditions afforded
amphidinolide T1 (1) in 70% yield. The spectral (1H and
13C NMR) and analytical data were in good agreement with
the data reported for natural product.3a
Treatment of compound 25 with Li/naphthalene23 afforded
the primary hydroxyl compound, which on subsequent
oxidation with TEMPO/BAIB gave 26 in 91% yield (two
steps). Similar to compound 16a, compound 26 was con-
verted to alcohol 28 in three steps.17 Oxidation of 28 with
Dess-Martin periodinane in CH2Cl2 afforded aldehyde 4 in
95% yield.
With the successful synthesis of the two fragments 3 and
4, we proceeded to assemble both the segments. Dithiane 3
was treated with n-BuLi in THF (under Sih’s conditions)8
at -100 °C, and to it was added dropwise the precooled
solution of aldehyde (- 100 °C) 4 to afford a stereoisomeric
mixture (4:1) mainly consisting of Cram adduct (syn) 29 in
80% yield.8 The required major syn isomer was separated
easily by silica gel column chromatography. Selective
oxidation of the primary hydroxy group in 29 in presence
of a secondary hydroxyl with TEMPO/BAIB afforded keto
acid 30 in 70% yield by in situ deprotection of thio ketal.24
In summary, we have accomplished a highly convergent
and stereoselective synthesis of amphidinolide T1. The
stereocenters of substituted tetrahydrofuran moiety were
obtained by Sharpless asymmetric epoxidation, diastereose-
lective reduction of the exocyclic double bond, and allylation
on the five-membered ring oxa-carbenium ion using our own
developed methodology. The C13 and C18 stereocenters
were obtained by enzymatic kinetic resolution and umpolung
reaction.
Acknowledgment. C.S.R. thanks CSIR-New Delhi for the
award of research fellowships. We are also thankful to Prof.
J. Kobayashi for providing natural product spectra.
Supporting Information Available: Spectroscopic and
analytical data and expeimental details. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) (a) Sing, S.; Kumar, S.; Chimni, S. S. Tetrahedron: Asymmetry
2002, 13, 2679. (b) Kamal, A.; Sandbhor, M.; Venkata Ramana, K.
Tetrahedron: Asymmetry 2002, 13, 815.
OL9002724
(23) Liu, H-J.; Yip, J.; Shia, K-S. Tetrahedron Lett. 1997, 13, 2253.
(24) Van den Bos, L. J.; Litjens, R. E. J. N.; Van den Berg, R. J. B. H.
N.; Overkleeft, H. S.; Vander Marel, G. A. Org. Lett. 2005, 07, 2007.
(25) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989
.
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Org. Lett., Vol. 11, No. 8, 2009