Studies towards the total synthesis of (+)-13-deoxytedanolide: Stereoselective synthesis of C1-C9 and C9-C17 fragments

Article abstract of DOI:10.1016/j.tetlet.2015.12.101

A facile and stereoselective synthesis of C1-C9 and C9-C17 fragments of (+)-13-deoxytedanolide and studies towards the synthesis of (+)-13-deoxytedanolide was accomplished in 20 linear steps. The key transformations of fragment 6 are Sharpless asymmetric dihydroxylation and preparation of terminal olefin from primary alcohol utilising organo selenium reaction. The key transformations of fragment 7 are from Sharpless epoxidation and Crimmin's syn aldol chemistry.

Full text of DOI:10.1016/j.tetlet.2015.12.101

Accepted Manuscript
Studies towards the total synthesis of (+)-13-deoxytedanolide: stereoselective
synthesis of C1-C9 and C9-C17 fragments
Jhillu Singh Yadav, Vijaya Vardhan Chinnam, Saibal Das
PII:
S0040-4039(15)30516-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.12.101
TETL 47148
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 November 2015
7 December 2015
26 December 2015
Please cite this article as: Yadav, J.S., Chinnam, V.V., Das, S., Studies towards the total synthesis of (+)-13-
deoxytedanolide: stereoselective synthesis of C1-C9 and C9-C17 fragments, Tetrahedron Letters (2015), doi: http://
dx.doi.org/10.1016/j.tetlet.2015.12.101
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Tetrahedron Letters
journal homepage: www.els evier.com
Studies towards the total synthesis of (+)-13-deoxytedanolide: stereoselective
synthesis of C1-C9 and C9-C17 fragments
Jhillu Singh Yadav,*a Vijaya Vardhan Chinnam,a and Saibal Dasa
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical
Technology, Hyderabad 500 007, India
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile and stereoselective synthesis of C1–C9 and C9–C17 fragments of (+)-13-deoxytedanolide and
studies towards the synthesis of (+)-13-deoxytedanolide was accomplished in 20 linear steps. The key
transformations of fragment 6 are Sharpless asymmetric dihydroxylation and preperation of terminal
olefin from primary alcohol utilising organo selenium reaction. The key transformations of fragment 7
are from Sharpless epoxidation and Crimmin’s syn aldol chemistry.
Received in revised form
Accepted
Available online
2015 Elsevier Ltd. All rights reserved
.
Keywords:
(+)13–Deoxytedanolide
cytotoxic metabolite
Sharpless Asymmetric Dihydroxilation
Sharpless epoxidation
Crimmin’s syn aldol
13–Deoxytedanolide (1), a known cytotoxic metabolite isolated
from the Japanese marine sponge Mycale adharens by Fusetani
et al.1 in 1991. Tedanolide (2), parent molecule of (+)-13-
deoxytedanolide (1), was isolated from the Caribbean sponge
Tedania ignis in 1984 by Schmitz et al.2 Both show a remarkable
cytotoxicity against P388 murine leukaemia cells at pico to nano
molar ranges. Moreover, (+)-13-deoxytedanolide (1) has been
shown to have promising in vivo antitumor activity. Fusetani et
al. identified 13-deoxytedanolide (1) bound to the 60S large
ribosomal subunit of the budding yeast Saccharomyces
cerevisiae, thus inhibiting polypeptide elongation and is the first
macrolide inhibitor for the eukaryotic ribosome.3 Owing to the
combination of architectural complexity and bioactivity various
research groups have shown wide interest for the syntheses of
Tedanolides.4 Smith and Roush independently reported the two
total syntheses of (+)-13-deoxytedanolide (1) in 2003 and 2005
respectively.5
OH
O
O
OH
5
O
OPMB
7
1
O
OMe O
O
O
OBn
O
9
O
17
OH
13
O
OH
O
OMOM
OTBS
4
3
1
O
O
O
O
O
O
O
O
OBn OPMB
OTBS
HO2C
O
OBn OPMB
OBn
8
6
OMOM
5
HO
HO
OH
9
OMOM
OTBS
OH
7
O
OH
O
O
OMe O
Scheme 1. Retrosynthetic steps for vittarilide-A (1)
O
In 2011, our group reported the syntheses of two fragments of
C1–C9 and C9–C17, based on the application of Sharpless
asymmetric dihydroxylation and Crimmins’ syn aldol reaction
respectively.6 Futher to our refine our previous work in
decreasing number of steps we derived new strategy for the
synthesis of 6 and 7 fragments. In order to achieve the fragment
6 we employed Sharpless asymmetric dihydroxylation and
OH
R
O
(+)-13-deoxytedanolide (1) R=H
R=OH
2
(+)-tedanolide ( )
Figure 1. Structure of 13–deoxytedanolide (1)

fragment 7 the Sharpless epoxidation and Crimmins’ syn aldol
reactions were adopted. We further made trials to make 18
membered macrolactone core 4 from fragments 6 and 7 as a part
of the total synthesis of (+)-13-deoxytedanolide. The
retrosynthetic strategy was the fragment 6 was obtained from
lactone 8 and alcohol 7 could be derived from propanediol 9 via
Sharpless epoxidation and non–Evans’ aldol reactions.
involving Swern oxidation followed by Witting olefination
furnished the corresponding α,β- unsaturated ester 14 in 65%
yield (over three steps). The olefin was subjected to Sharpless
asymmetric dihydroxylation (SAD)10 conditions employing
potassium osmate (5 mol%) and potassium ferricyanide as a co-
oxidant in the presence of a (DHQ)2PHAL ligand (10 mol%) to
furnish the corresponding 1, 2-diol 15 in 80% yield and 92% de.
The 1,2-diol compound 15 was protected as its acetonide
followed by desilylation of silyl group of TIPS using TBAF
provided the primary alcohol 16 in 78% yield (over two steps).
Now, the conversion of alcohol to di-substituted olefin is crucial.
In previous synthesis our group only demonstrated this
conversion using NaI and DBU, but this reaction was not always
fruitful for poly hydroxy protected fragments, hence we used the
Grieco protocol conditions11 that, the alcohol was protected as
selenyl ether using 2-Nitro selenocyanate and tri n-butyl
phosphine to furnished the selenium product which was further
converted to terminal disubstituted olefin 17 with H2O2 in 60%
yield for two steps. Finally, the desired acid 6 was afforded by
base hydrolysis of ester using LiOH.H2O in THF/MeOH/H2O in
4:1:1 ratio in 82% yield.
We initiated the our work by the synthesis of fragment 6 which
was initiated with reductive opening of the lactone 86 using
LiAlH4 in dry THF to afford the triol 10 in which 1, 3-diol was
protected as PMB acetal with p–methoxybenzyl dimethyl acetal
and catalytic amount of CSA in CH2Cl2 gave the compound 11 in
85% yield.7 The primary hydroxyl group of 11 was protected as
TBS ether to furnish the compound 12 in 90% yield. The
regioselective reduction of PMB acetal to PMB ether using
DIBAL-H8 followed by silylation of primary alcohol using
TIPSOTf and DIPEA in CH2Cl2 yielded the compound 13 in
70% yield (over two steps). Selective deprotection of TBS group
in compound 13 using catalytic amount of CSA
in
MeOH/CH2Cl2 in 1:1 ratio9 followed by sequential steps
O
MeOPhCH(OMe)2,
O
O
p-TsOH.H2O (5 mol %),
LiAlH4, THF,
OH OBn O
O
0 oC to rt, 30 min,
CH2Cl2, rt, 3 h, 85%
OH OBn OH OH
OBn 90%
PMP
8
10
11
TBSCl, imidazole,
DMAP, CH2Cl2,
(i) DIBAl-H, CH2Cl2,
-78 °C to rt, 2 h
TBSO
TBSO
OTIPS
OBn O
O
0 °C to rt, 2 h, 90%
(ii) DIPEA, TIPSOTf,
CH2Cl2, 0 °C to rt, 30 min
70% (over two steps)
OBn OPMB
PMP
12
13
(DHQ)2PHAL, K2CO3,
K3[Fe(CN)]6, MeSO2NH2,
(i) CSA, MeOH/ CH2Cl2,
(1:1), -15 °C
OTIPS
EtO2C
(ii) DMP, NaHCO3,
CH2Cl2, 0 °C, to rt, 2 h
(iii) triethylphosphonoacetate,
NaH, 65% (over three steps)
K2[OsO2(OH)4], t- BuOH/H2O
(1:1), 0 °C, 24 h, 80%
OBn OPMB
14
(i) o-NO2C6H4SeCN,
n-Bu3P, 12 h
OH
O
(i) PPTS, CH2Cl2, 1 h
OTIPS
OH
EtO2C
EtO2C
(ii) TBAF, THF, 25 °C,
2 h, (78% over two steps)
(ii) H2O2, THF, 12 h,
60% (over two steps)
OH OBn OPMB
O
OBn OPMB
16
15
O
O
LiOH, THF/MeOH/H2O
rt, 3 h, 82%
EtO2C
HOOC
O
OBn OPMB
17
O
OBn OPMB
6
Scheme 2. Synthesis of acid fragment (6)

The synthesis of fragment 7 was initiated with commercially
available propane diol 9 which was subjected to sequential
reactions to give 18 (see ref:12) in 80% yield in five steps. The
oxidation of alcohol 18 using Swern oxidation condition yielded
the required aldehyde followed by Horner Wittig condition with
NaH and triethyl phosphano acetate afforded the epoxy ester 19
in 70% yield (over two steps).13 The regioselective opening of
epoxide by treating with TMA (Tri Methyl Aluminium) afforded
corresponding alcohol 2014 in 80% yield which in turn was
protected as MOM ether. It was followed by reduction of double
bond using Pd/C to furnish the corresponding ester 21 in 72%
yield (over two steps).15 Subsequently, the ester 21 was partially
reduced to aldehyde 22 by DIBAl-H which was further subjected
to the non-Evans’ syn aldol16 using 1 equiv of auxillary N-
propanoyl thiazolidinone, 1 equiv of TiCl4, 1 equiv of DIPEA
and obtained the desired syn aldol product as the major isolable
diastereomer (de
̴ 95%). The resulting secondary alcohol was
protected as TBS ether 23 in 68% yield (over two steps). Silyl
compound 23 was achieved by using reduction of the chiral
thiazolidinone. With DIBAl-H 23 afforded the required
aldehyde17 which in turn was subjected to Wittig olefination with
Ph3PCH3I and yielded the terminal olefin 24 in 66% (over two
steps). Eventually, selective deprotection of primary TBS using
CSA in MeOH/CH2Cl2 (1:1) to furnish required fragment 7 in
80% yield.
(i) (COCl)2, DMSO,
TEA, CH2Cl2, 45 min
TBSO
OH
TBSO
ref: 12
CO2Et
HO
OH
O
O
(ii) triethylphosphonoacetate,
NaH, 70% (over two steps)
9
19
18
i
(i) MOMCl, -Pr2NEt,
CH2Cl2, 0 to 25 °C, 3 h
Me3Al, CH2Cl2, H2O,
-40 °C, 1.5 h, 80%
TBSO
TBSO
CO2Et
CO2Et
(ii) H2, 10% Pd/C,
72% (over two steps)
OH
OMOM
20
21
Ph
(i)
N
S
O
S
i
TiCl4, -Pr2NEt, CH2Cl2, 0 °C
(i) DIBAl-H (1.0 equiv),
TBSO
CHO
i
(ii) TBSOTf, -Pr2NEt, CH2Cl2,
0 °C to rt, 68% (over two steps)
CH2Cl2, -78 °C,
75 min, 82%
OMOM
22
Ph
(i) DIBAl-H (2.5 equiv),
CH2Cl2, -78 °C, 75 min
TBSO
N
S
TBSO
(ii) Ph3P=CH2, NaHMDS,
THF 66% (over two steps)
OMOM
24
OTBS
MOMO
CSA,
TBSO
23
O
S
MeOH/CH2Cl2 (1:1),
HO
-15 °C, 80%.
OMOM
OTBS
7
Scheme 3. Synthesis of alcohol fragment (7)
Now two fragments in hand, our strategy was to couple the two
fragments 6 and 7 to make the lactone 4. In the process of
making of lactone, esterification of fragments 6 and 7 using
Yamaguchi condition18 yielded the corresponding ester 5 in
82% yield. The crucial reaction of coupling of two terminal
olefins in which one was the branched olefin posed a
challange. In fact, only few reports were seen for such that too
coupling was achieved when the branched olefin does not
contain substitution at α position. In 2007 Wei-Min Dai et al.
reported that achievement of RCM between tri-substituted and
di-substituted double19 bonds by addition of Grubbs’ second
generation catalyst 27 in portion wise (total amount equal to
100 mol%) in CH2Cl2 under refiux condition. They obtained
the required product and by-product in 1:1 ratio. We applied

the similar reaction conditions but we observed the formation
of by-product 25 only, which might be due to the hindrance of
stereomers and protection groups adjacent to tri-substituted
double bond.
Scheme 4. Synthesis of ester intermediate (5)
Scheme 4. Synthesis of ester intermediate (26)
Therefore, it was felt worthwhile to deprotect the silyl groups by
C. V. V thanks CSIR, New Delhi, India for fellowship. The
authors thank CSIR, New Delhi for financial support through
Project ORIGIN under 12th Five Year Plan and J. S. Y. thanks
CSIR and Department of Science and Technology (DST), New
Delhi for the award of Bhatnagar and J. C. Bose Fellowships.
desilylation of 5 and attempt the RCM reaction with the resulting
allylic alcohol 26. However, the RCM of 26 with 10 mol% of
Grubbs’ second generation catalyst 27 in CH2Cl2 in refluxing
conditions yilded no reaction and compound 26 as such with out
a trace of desired compound 4.Then we made several trails with
Hoyeda-Grubbs’ second generation catalyst 28 in different
solvent conditions like dichloro ethane and toluene under reflux
condition, however we did not observe any progress and only
starting material was recovered.
Supplementary data
1
Experimental procedures, Spectral data and Copies of H NMR,
13C NMR spectra of all compounds are available.
In conclusion, we have accomplished the highly stereoselective
synthesis of 6 and 7 fragments of (+)-13-deoxytedanolide (1) in a
concise manner using Sharpless asymmetric dihydroxylation,
Sharpless epoxidation and Crimmins’ syn aldol and esterification
under Yamaguchi conditions as key steps with an overall yield
4.2%.
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Studies towards the total synthesis of (+)-13-deoxytedanolide: stereoselective
synthesis of C1-C9 and C9-C17 fragments
Jhillu Singh Yadav,*a Vijaya Vardhan Chinnam,a and Saibal Dasa
Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India