Asymmetric synthesis of cytotoxic sponge metabolites R-strongylodiols A and B

Article abstract of DOI:10.1016/j.tetlet.2004.05.122

The asymmetric synthesis of the marine sponge natural products, R-strongylodiols A 1 and B 2 using a minimum protection strategy is described. The chirality of the natural products was introduced via the Noyori asymmetric reduction of ynones.

Full text of DOI:10.1016/j.tetlet.2004.05.122

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5645–5647
Asymmetric synthesis of cytotoxic sponge metabolites
R-strongylodiols A and B
*
*
James E. D. Kirkham, Timothy D. L. Courtney, Victor Lee and Jack E. Baldwin
Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford OX1 3TA, UK
Received 19 April 2004; revised 13 May 2004; accepted 21 May 2004
Available online 15 June 2004
Abstract—The asymmetric synthesis of the marine sponge natural products, R-strongylodiols A 1 and B 2 using a minimum
protection strategy is described. The chirality of the natural products was introduced via the Noyori asymmetric reduction of
ynones.
Ó 2004 Elsevier Ltd. All rights reserved.
Strongylodiols A 1, B 2 and C 3 are three natural
products isolated from the Okinawan marine sponge of
the genus Strongylophora by Iguchi and co-workers.
The gross structures of 1–3 were determined by a com-
bination of NMR and mass spectrometry analysis and
through the application of the modified Mosher’s
method; compounds 1–3 were found to exist as enan-
tiomeric mixtures (R/S ratio 91:9 for 1, 97:3 for 2 and
HO
HO
1
H
OH
OH
1
H
8
4:16 for 3) with the R-enantiomer as the major com-
2
ponent in each compound. The enantiomeric mixtures
of 1–3 were found to be cytotoxic towards MOTL-4,
IMR-90 and DLD-1cells. Previously Yadav and Mishra
reported the synthesis of R-2 via the b-elimination of a
chiral epoxychloride and recently Carreira and co-
workers completed the syntheses of R-1 and R-2
HO
2
H
OH
3
5
through the addition of a chiral zinc acetylide to alde-
3
hydes. We report here our effort in the asymmetric
synthesis of R-1 and 2 based on a minimum protection
strategy. Retrosynthetically we envisaged that both R-1
and 2 could be derived from the common intermediate 5.
We first investigated the synthesis of R-2 due to its
simpler structure.
HO
corresponding dianion, which was subsequently quen-
ched with 1-iodooctane to afford alcohol 6 in 54% yield.
Oxidation of alcohol 6 to aldehyde 7 was achieved in
Commercially available 9-dodecyn-1-ol 4 was subject to
4
a zipper reaction using lithium 3-aminopropanamide in
5
the presence of potassium tert-butoxide to give 11-
dodecyn-1-ol 5 in 92% yield. Alcohol 5 was treated with
8
6% yield with o-iodoxybenzoic acid (IBX) in THF/
7
DMSO. Addition of lithium trimethylsilylacetylide to
aldehyde 7 gave rac-8 in 86% yield, which was subjected
to IBX oxidation to give ynone 9 in 87% yield. Asym-
metric reduction of 9 with catalyst 10 in propan-2-ol
delivered R-8 in 90% yield. The enantiomeric excess of
R-8 was 95% as determined by F NMR analysis of
6
2
equiv of n-BuLi in DMPU /THF to generate the
8
Keywords: Sponge; Asymmetric reduction.
*
19
Corresponding authors. E-mail addresses: victor.lee@chem.ox.ac.uk;
jack.baldwin@chem.ox.ac.uk
9
its Mosher’s ester. The terminal trimethylsilyl group in
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.05.122

5646
J. E. D. Kirkham et al. / Tetrahedron Letters 45 (2004) 5645–5647
i
ii
HO
HO
HO
4
5
6
iii
86%
Me3Si
O
iv
OH
rac-8
7
iii 87%
Me3Si
Me3Si
v
H
O
OH
9
R-8
vi
HO
vii
H
H
OH
OH
R-2
11
Ts
N
Ru
Br
OH
N
1
2
H
1
0
t
Scheme 1. Reagents and conditions: (i) LiHN(CH
2
)
3
NH
2
, KO Bu, H
2
N(CH
2
)
3
NH
2
, rt, 92%; (ii) n-BuLi (2 equiv), THF, DMPU, then CH
3 2 7
(CH ) I,
54%; (iii) IBX, DMSO, THF, rt; (iv) trimethylsilylacetylene, n-BuLi, THF, 86%; (v) 10, i-PrOH, 30 °C, 90%; (vi) NH
4
F, MeOH, 91%; (vii) 12, CuCl,
NH OHÆHCl, EtNH , MeOH, 82%.
2
2
i
HO
ii
6
8
7%
O
1
3
14
iii
Me3Si
3
Me Si
ii
93%
O
OH
1
6
rac-15
iv
Me3Si
v
H
H
OH
OH
17
R-15
vi
HO
H
OH
R-1
Scheme 2. Reagents and conditions: (i) Lindlar catalyst, quinoline, H
2
, benzene, 86%; (ii) IBX, DMSO, THF, rt; (iii) trimethylsilylacetylene, n-BuLi,
OHÆHCl, EtNH , MeOH, 80%.
THF, 76%; (iv) 10, i-PrOH, 30 °C, 97%; (v) NH F, MeOH, 100%; (vi) 12, CuCl, NH
4
2
2

J. E. D. Kirkham et al. / Tetrahedron Letters 45 (2004) 5645–5647
5647
R-8 was removed by ammonium fluoride in methanol to
References and notes
10
afford 11 in 91% yield. To the best of our knowledge
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11
12
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kiewicz coupling of 11 and 2-bromopropyn-1-ol 12
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3
4
2
The synthesis of 1 commenced with the Lindlar hydro-
genation of 6 to 13 in 86% yield, which was oxidised to
13
8
7
aldehyde 14 in 87% yield by IBX in THF/DMSO.
Reaction of aldehyde 14 with lithium trimethylacetylide
delivered rac-15 in 76% yield. Oxidation of rac-15 with
IBX afforded a 93% yield of ynone 16 and subsequent
chiral reduction of 16 with catalyst 10 in propan-2-ol
8
9
gave R-15 in 97% yield with 95% ee. Removal of the
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3
10
ammonium fluoride in methanol to deliver terminal
acetylenic alcohol 17 in quantitative yield, which was
(
11
coupled with 12 to afford R-2 in 80% yield (Scheme 2).
8
The spectral data and specific rotation values of both
R-1 and R-2 are in excellent agreement with their cor-
responding literature values. In summary, we have
developed an efficient synthesis of R-1 and R-2 without
the deliberate use of protecting groups. We have also
demonstrated that the Noyori reduction of ynones 9 and
9. Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969,
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strongylodiols.
1
1
1
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14
Acknowledgements
We thank Professor Kazuo Iguchi for providing us with
the spectra of natural strongylodiols A and B.