13-Step total synthesis of Dendrodolide K following iterative Bartlett-Smith iodocarbonate cyclization

Article abstract of DOI:10.1016/j.tetlet.2015.09.126

A convergent total synthesis of Dendrodolide K has been achieved starting from commercially available homoallyl alcohol 17 in 13 longest linear sequence with 18.2% overall yield. The key features of this synthesis are Bartlett-Smith iodocarbonate cyclizat

Full text of DOI:10.1016/j.tetlet.2015.09.126

Accepted Manuscript
1
3-Step total synthesis of Dendrodolide K following iterative Bartlett-Smith
iodocarbonate cyclization
Debendra K. Mohapatra, Karthik Pulluri, Srinivas Gajula, Jhillu S. Yadav
PII:
S0040-4039(15)30167-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.126
TETL 46798
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 August 2015
22 September 2015
26 September 2015
Please cite this article as: Mohapatra, D.K., Pulluri, K., Gajula, S., Yadav, J.S., 13-Step total synthesis of
Dendrodolide K following iterative Bartlett-Smith iodocarbonate cyclization, Tetrahedron Letters (2015), doi:
http://dx.doi.org/10.1016/j.tetlet.2015.09.126
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3-Step total synthesis of Dendrodolide K following
Leave this area blank for abstract info.
iterative Bartlett-Smith iodocarbonate cyclization
Debendra K. Mohapatra,* Karthik Pulluri, Srinivas Gajula, and Jhillu S. Yadav

Tetrahedron Letters
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Tetrahedron Letters
journal homepage: www.elsevier.com
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3-Step total synthesis of Dendrodolide K following iterative Bartlett-Smith
iodocarbonate cyclization
Debendra K. Mohapatra, Karthik Pulluri, Srinivas Gajula, and Jhillu S. Yadav
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convergent total synthesis of Dendrodolide K has been achieved starting from commercially
available homoallyl alcohol 17 in 13 longest linear sequence with 18.2% overall yield. The key
features of this synthesis are Bartlett–Smith iodocarbonate cyclization reaction for the
construction of 1,3-syn centers of the polyol system, Sharpless epoxidation followed by
titanocene induced deoxygenation of 2,3-epoxy alcohol to fix stereogenic center at C-3 position,
Yamaguchi esterification followed by ring-closing metathesis (RCM) reaction to form the
macrolactone.
Available online
Keywords:
Cytotoxic
Bartlett–Smith iodocarbonate cyclization
Titanocene induced deoxygenation
Yamaguchi esterification
Ring-closing metathesis.
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009 Elsevier Ltd. All rights reserved.
Naturally occurring 12-membered lactones isolated from
fungal metabolites play an important role in the biochemical
and co-workers reported the isolation of thirteen new 12-
membered macrolides Dendrodolides A-M (1-13) from
Figure 1: Structures of Dendrodolides.
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community due to their potent medicinal properties. Many
Dendrodochium sp., a fungus associated with the sea cucumber
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important 12-membered lactones such as recifeiolide,
Cladospolides, and Patulolides have phototoxic, antibacterial,
antiviral, antifungal and cytotoxic activities. Recently, Zhang
Holothuria obilis Selenka, which was collected from the South
China Sea. These were the first group of 12-membered
macrolides from the fungus of the genus Dendrodochium. The
structures of the Dendrodolides were elucidated by means of
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4
5
6
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8
—
——

Corresponding author. Tel.: +91 40 27193128; fax: +91 40 27160512. E-mail address: mohapatra@iict.res.in (D.K. Mohapatra).

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Tetrahedron Letters
detailed spectroscopic analysis and X-ray single crystal
diffraction studies. The absolute configurations were assigned
using the modified Mosher’s method, exciton-coupled circular
dichroism (ECCD), electronic solution and solid-state circular
dichroism (ECD) and X-ray analysis. In an in vitro bioassay,
Dendrodolides exhibited different levels of growth inhibitory
activity against SMMC-7721 and HCT116 Cells. The distinctive
biological activities, fascinating structural architecture, and
scarcity of natural products have attracted our attention to
develop a general synthetic strategy to prepare majority or all
thirteen Dendrodolides. We have already reported the synthesis
1
1a,b
of majority of macrolides of this group.
Herein, we report the
first stereoselective total synthesis of Dendrodolide K.
As part of our ongoing program in exploring the use of di-tert-
butyl dicarbonate (Bocanhydride, Boc O) in the area of total
2
1
0
synthesis particularly for creating 1,3-syn centers and also ring-
1
1
closing metathesis for macrolide syntheses, we demonstrated
the use of both strategies for the total synthesis of Dendrodolides
K. The retrosynthetic analysis of Dendrodolide K is depicted in
Scheme 1. The macrolactone 11 could be synthesized from bis-
Scheme 2. Synthesis of the fragment 15.
Here, the Bartlett–Smith iodocarbonate cyclization reaction was
repeated for generating the next sereogenic center of polyol system
in an iterative mode to afford epoxy alcohol 25 in 86% yield. The
secondary hydroxyl group was protected as its benzyl ether with
BnBr in the presence of NaH in THF at 0 °C to afford epoxide 26 in
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4% yield. Treatment of 26 with vinylmagnesium bromide in the
presence of a catalytic amount of copper(I) iodide at 0 °C affored
homoallyl alcohol 27 in 86% yield (Scheme 2). The resulting
hydroxyl group was then protected as its benzyl ether by using
benzyl bromide in the presence of NaH in anhydrous THF followed
by deprotection of silyl group under acidic conditions (CSA, MeOH)
afforded the required fragment 15 in 89% yield over two steps.
Next, our focus was shifted towards the synthesis of acid fragment
1
6
1
6 which was started from known epoxy alcohol 18. Conversion of
epoxy alcohol to allyl alcohol was achieved by applying
titanium(III)-mediated [(C TiCl] deoxygenation of 2,3-epoxy
Scheme 1. Retrosynthetic analysis.
H )
5 5 2
alcohol to opically pure allyl alcohol 28 in a single step with 84%
yield. The hydroxyl functionality present in 28 was protected as its
benzyl ether with benzyl bromide in presence of NaH
1
2
17
alkene 14 by utilizing ring-closing metathesis reaction. Bis-
alkene 14 would be synthesized by coupling alcohol 15 and acid
1
1
6 under Yamaguchi esterification conditions. Fragment 15 and
6 could be prepared from commercially available homoallyl
alcohol 17 and known epoxy alcohol 18, respectively.
Results and Discussion
The synthesis of alcohol fragment 15 began with the commercially
available (R)-pent-4-en-2-ol (17). Compound 17 was treated with di-
tert-butyl dicarbonate in the presence of triethylamine and 4-
(
dimethylamino)pyridine (DMAP) to form homoallylic tert-butyl
13
carbonate 19 in 92% yield. The next stereogenic center of the triol
system was achieved through Bartlett–Smith iodocarbonate
cyclization reaction. Accordingly, treatment of compound 19 with
1
4
N-iodosuccinimide (NIS) or iodine in CH CN at 0 °C produced the
3
desired iodocarbonate derivative 20 in 90% yield as the only product.
Iodocarbonate 20 was treated with K CO in MeOH that rapidly
2
3
underwent hydrolysis to give in situ epoxy alcohol and was protected
as its TBS ether with TBSCl in the presence of imidazol in CH Cl
Scheme 3. Synthesis of the fragment 16.
2
2
at 0 °C to afford epoxide 21 in 88% yield. Treatment of 21 with vinyl
magnesium bromide in the presence of a catalytic amount of
copper(I) iodide at 0 °C furnished homoallyl alcohol 22 in 87% yield
to achieve 29 in 94% yield. The PMB group was deprotected using
DDQ under standard reaction conditions to afford the primary
alcohol 30 in 92% yield. The primary alcohol 30 was converted to
acid by following a two-step sequence; oxidation of primary alcohol
1
5
(Scheme 3).
compound 22 was treated with di-tert-butyl
dicarbonate in the presence of triethylamine and 4-(dimethylamino)
pyridine to afford homoallylic tert-butyl carbonate 23 in 91% yield.
18
to aldehyde by Dess-Martin periodinane followed by further

Tetrahedron Letters
3
1
9
oxidation under Pinnick conditions to afford acid 16 in 87% yield
(e) Tsuda, M.; Mugishima, T.; Komatsu, K.; Sone, T.; Tanaka, M.;
Mikami, Y. Kobayashi, J. J. Nat. Prod. 2003, 66, 412.
over two steps (Scheme 3).
2
3
4
.
.
.
Vesonder, R. F.; Stodola, F. H.; Wickerha, L. J.; Ellis, J. J.; Rohwedde,
W. K. Can. J. Chem. 1971, 49, 2029.
With the requisite fragments in hand, the coupling reaction
between 15 and 16 was carried out to verify the output of RCM
reaction. Accordingly, alcohol 15 and acid 16 were coupled under
Yamaguchi conditions using 2,4,6-trichlorobenzoyl chloride to
furnish the required bis-alkene 14 in 92% yield. Pleasingly, 12-
membered macrolactone formation under ring closing metathesis
condition proceeded smoothly with Grubbs second generation
catalyst in high dilution (0.01M) under refluxing conditions to afford
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2
0
3
1 as a major isomer (E/Z = 9:1) in 78% yield. After formation of
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2
1
groups in one pot. Different conditions like Li/Naphthalene in
2
2
23
THF, TiCl4 in CH Cl and DDQ in aqueous CH Cl were tried.
2
2
2
2
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o
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3
2
2
2
4
1
yield (Scheme 4). The spectral and analytical data of 11 ( H NMR,
C NMR and MS) were identical to those of reported for the natural
product. The optical rotation of synthetic 11 {[α]D +16.4 (c 0.43,
CHCl )} was in good agreement with that of natural 11 {ref. [α]
1
3
8.
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D
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+
11.7 (c 0.285, CHCl )}.
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1
Scheme 4. Synthesis of the Dendrodolide K
6
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In summary, we have demonstrated an efficient and highly
stereoselective approach to accomplish Dendrodolide K starting
from commercial available homo allyl alcohol 17 following
Bartlett-Smith iodocarbonate cyclization strategy and ring-
closing metathesis reaction as key steps.
1
1
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The authors thank Council of Scientific and Industrial Research
(
CSIR), New Delhi, India, for financial support as part of XII five
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