Toward the stereoselective synthesis of C1-C23 fragment of spirastrellolide B

Article abstract of DOI:10.1016/j.tetlet.2014.05.111

A convergent synthesis of the protected C(1)-C(23) fragment 4 of the targeted natural product spirastrellolide B is described. The key step of the synthesis is cross metathesis (CM) and TBAF promoted oxa-Michael to construct tetrahydropyran moiety.

Full text of DOI:10.1016/j.tetlet.2014.05.111

Accepted Manuscript
Towards the Stereoselective Synthesis of C1-C23 Fragment of Spirastrellolide
B
Akkapalli Rajesh, Gangavaram V.M. Sharma, Krishna Damera
PII:
S0040-4039(14)00942-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.111
TETL 44702
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
8 March 2014
26 May 2014
28 May 2014
Please cite this article as: Rajesh, A., Sharma, G.V.M., Damera, K., Towards the Stereoselective Synthesis of C1-
C23 Fragment of Spirastrellolide B, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.111
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Towards the stereoselective synthesis of C1-C23
fragment of spirastrellolide B
Akkapalli Rajesh*, Gangavaram V. M. Sharma and Krishna Damera
1

Towards the Stereoselective Synthesis of C1-C23 Fragment of
Spirastrellolide B
Akkapalli Rajesh*, Gangavaram V. M. Sharma and Krishna Damera
D-211, Discovery Laboratory, Organic & Biomolecular Chemistry Division
CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
Abstract: A convergent synthesis of the protected C(1)-C(23) fragment 4 of the targeted natural
product spirastrellolide B is described. The key step of the synthesis is cross metathesis (CM)
and TBAF promoted oxa-Michael to construct tetrahydropyran moiety.
Keywords: Sharpless asymmetric epoxidation, oxa-Michael addition, cross metathesis and
hydroxylalkynylation.
Spirastrellolide A (1) and B (2) are two closely related polyketides, isolated by Anderson and co-
workers from the marine sponge Spirastrella coccinea. The structure of 1 was first disclosed in
20031a while, its structure and biological activity on the inhibition of protein phosphatase 2A
(PP2A) was reported in 2004.1b A phosphatase like PP2A has progressively been considered as a
potential tumor suppressor.2 X-ray analysis3 of a derivative of 2 revealed the complete relative
and absolute stereochemistry of the core spirastrellolide A.
Due to their unique structure and impressive biological activity, spirastrellolide B becomes target
for synthesis. The syntheses of fragments of spirastrellolide A (1) and B (2) molecules have been
reported, 4-9 although no total synthesis has yet been described.
_____________________________________________________________________________
*Corresponding author. Email: rajesh.rjsiict@gmail.com;
2

The overall plan consists of the assembly of two large fragments (3 and 4) by a
combination of Nozaki-Hiyama-Kishi reaction and lactonization. Further synthesis of C1-C23
subunit 4 carbon framework could be realized from 5 by acid catalyzed spiroketalization.
Fragment 5 could be synthesized by cross metathesis (CM) of 6 and 7. Alternatively, propargyl
alcohol 7 can be achieved by addition of acetylene 9 to the aldehyde 8 (Scheme 1).
For the construct pyran derivative of C(1)-C(10) fragment, starts with oxidation of 1,5-pentane
diol derivative 910 under Swern reaction conditions gave the aldehyde 9a, enantioselective
allylation of the resulted aldehyde using allyltri-n-butyltin,11 furnished 10, the secondary alcohol
in compound 10 was silylated using TBDPSCl and imidazole to silyl ether 11. Compound 11
was treated with K2CO3 in MeOH to furnish alcohol 12, subsequent oxidation of alcohol to
aldehyde 12a using Swern oxidation. Wittig olefination of aldehyde 12a with
(ethoxycarbonylmethylene)triphenyl phosphorane gave corresponding ester 13 in 71% yield,
which was treated with TBAF to cleave the silyl ether and cause a spontaneous oxa-Michael
addition12 with formation of 1:1 diastereomeric mixture of 14a and 14b (81%), while, 14a was
obtained in 49% yield by chromatographic separation.
3

(A)
(B)
3
7
3
7
(A)
(B)
Figure 2: NOESY spectra (600MHz, 298K, CDCl3) and energy minimized structures of (A) 14a
and (B) 14b.
The stereochemistry in 14a and 14b was established by 1H NMR (500 MHz, CDCl3) data
and assignments made with the help of TOCSY and NOESY experiments. The characteristic
nOe between C3H/C7H in 14a (Figure 2) suggested that both the protons are on the same face
while, the characteristic nOe between C3H/C7H in 14b (Figure 2) suggested that both the protons
are on the opposite face.
To achieve one of the key intermediate 6 with required stereochemistry, we have used
14a for further reactions. Reduction of ester in 14a with DIBAL-H furnished alcohol 15 (92%),
the resulted alcohol was protected as benzyl ether using benzyl bromide in the presence of NaH
gave 16 in 60% yield. To make the precursor for Sharpless asymmetric epoxidation, olefin 16
was ozonized to yield the corresponding aldehyde 16a, which on subjecting to Wittig olefination
with (ethoxycarbonylmethylene)triphenyl phosphorane in benzene at reflux afford 17 in 68%
yield, simultaneous reduction of the ethyl ester of 17 was accomplished with DIBAl-H.
Sharpless asymmetric epoxidation of 18 with (-)-DIPT furnished epoxy alcohol 19 in 96% yield.
4

The epoxide 19 was opened using triphenylphosphine in CCl4 to give chloro epoxide 19a, which
on treatment with sodium metal in ether gave allylic alcohol 6.13
The synthesis of the 7 was initiated from known compound 20.14 Accordingly,
regioselective opening of epoxide 20 with Me3Al15 in hexane at 0 °C furnished 1,2-diol 21 in
61% yield. Diol 21 on selective tosylation16 with p-TsCl in CH2Cl2 gave 21a, which, on further
reaction with K2CO3 in methanol furnished the epoxide 22 in 40% yield. Copper mediated
opening of epoxide17 with vinylmagnesium bromide in THF at -20 °C yielded corresponding
homoallylic alcohol 23 (50%), newly generated secondary alcohol was then capped with a MOM
group 24 in 86% yield. A standard desilylation of 24 using TBAF gave corresponding primary
alcohol 25, which was oxidized under Dess-Martin periodinane condition, afforded the aldehyde
8.
The required coupling partner 9 was initiated from known compound 26.18 Accordingly,
alcohol 26 on oxidation under Swern conditions gave the aldehyde 26a, which on Wittig
olefination with (ethoxycarbonylmethylene)triphenyl phosphorane in benzene furnished 27 in
5

69% yield (Scheme 5). Reduction of ethyl ester 27 with DIBAL-H furnished allyl alcohol 28,
which was subjected for Sharpless asymmetric epoxidation with (-)DIPT yielded 29 (83%). The
propargyl alcohol 30 derived from 29a was converted according to the protocol published by
Yadav19, the resulted secondary alcohol was treated with MeI in the presence of NaH furnished 9
in 80% yield.
Finally, one of the key fragment 7 was synthesized by base promoted addition of alkyne 9
to aldehyde 8, afforded diastereomeric mixture of propargylic alcohols 7 in 70% yield (Scheme
6). In a further study the target compound 5 is achieved by cross-methathesis (CM) of olefins 6
and 7 using Grubbs 2nd generation catalyst (10 mol%) in CH2Cl2 at room temperature to afford 5
in 65% yield.20 Spectroscopic analysis of 5 revealed that the newly formed C20-C21 double
bond is trans (J = 17.0 Hz).
6

In conclusion, we have established a stereoselective strategy for the synthesis of C1-C23
carbon frame work of spirastrellolide-B. Advanced stage intermediate tetrahydropyra 14a was
achieved by TBAF promoted oxa-Micheal addition, the stereochemistry of the resulted product
1
was established by H NMR data and assignments made with the help of TOCSY and NOESY
experiments. Finally, construction of olefin C20-C21 by cross metathesis (CM) to complete the
synthesis of C1-C23 fragment of Spirastrellolide B.
Acknowledgements
All the authors are thankful for financial support from MLP-0008 of CSIR, New Delhi. A.R. is
thankful to CSIR, New Delhi for the research fellowship.
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