Total Synthesis of (+)-Trachyspic Acid 19-n-Butyl Ester

Article abstract of DOI:10.1021/acs.orglett.0c00319

The first total synthesis of the alkyl citrate trachyspic acid 19-n-butyl ester (1) is described. A formal [2 + 2]-cycloaddition of the silylketene acetal derived from lactone 6 with di-n-butylacetylene dicarboxylate 7 provided the cyclobutene diester 5 w

Full text of DOI:10.1021/acs.orglett.0c00319

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Letter
Total Synthesis of (+)-Trachyspic Acid 19-n-Butyl Ester
Alex A. Rafaniello and Mark A. Rizzacasa*
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ABSTRACT: The first total synthesis of the alkyl citrate trachyspic acid 19-n-butyl ester (1) is described. A formal [2 + 2]-
cycloaddition of the silylketene acetal derived from lactone 6 with di-n-butylacetylene dicarboxylate 7 provided the cyclobutene
diester 5 with a dr >20:1. Acid-mediated rearrangement of 5 followed by lactone ring-opening and ester protecting group
manipulation eventually provided orthogonally protected aldehyde 3. A Nozaki−Hiyama−Kishi coupling between 3 and vinyl iodide
4
followed by oxidation of the resultant allylic alcohol gave enone 16, which was converted into the triester 17 (dr 6:1) by a
spirocyclization/oxidative cleavage/elimination sequence. Removal of the t-butyl esters then afforded trachyspic acid 19-n-butyl ester
1).
(
he alkyl citrate spiroacetals trachyspic acid 19-n-butyl
ester (1) and its congener trachyspic acid (2) were both
rationalize how the butyl ester would be installed solely at the
hindered C19 position as a result of simple exposure to n-
butanol solvent.
T
isolated from fungal strain RKGS-F2684 during screening for
1
6
polo-like kinase 1 (Plk1) inhibitors (Figure 1). Plk1 is often
Several total syntheses of trachyspic acid (2) have been
7
overexpressed in tumor cells, and the inhibition of this kinase
can result in the reduction of cancer cell proliferation, making
reported along with a formal synthesis, but no synthesis of
trachyspic acid 19-n-butyl ester (1) has been disclosed. A
major synthetic challenge is the selective installation of the n-
butyl ester at the more hindered C19 carboxylate position
while minimizing oxidative adjustments. We now report the
first stereoselective total synthesis of trachyspic acid 19-n-butyl
ester (1), which utilizes a cyclobutene diester approach to alkyl
2
it an attractive target for the treatment of cancer in humans.
Trachyspic acid (2) was first isolated from the fungus
Talaromyces trachyspermus during a screening program for
3
heparanase inhibitors. Compound 1 has an IC50 value of 102
μM against Plk1, whereas trachyspic acid (2) was less active
1
8
(
IC 128 μM).
50
citrates.
A retrosynthesis of 1 is shown in Scheme 1. A Nozaki−
9
Hiyama−Kishi (NHK) coupling between orthogonally
protected alkyl citrate aldehyde 3 and vinyl iodide 4 would
forge the C6−C7 bond, and an oxidation/spirocyclization/
6b,c
elimination sequence
then installs the desired spiroacetal
ring system. Aldehyde 3 could originate from the cascade
8
rearrangement of the cyclobutene diester 5 followed by
orthogonal ester protection. Cyclobutene 5 can be accessed by
Figure 1. Structures of the Trachyspic Acids.
8a,10
a formal [2 + 2]-cycloaddition
between acetylene diester 7
8a
and the silylketene acetal derived from known lactone 6,
available by silylation of commercially available (S)-(+)-γ-
hydroxymethyl-γ-butyrolactone.
The location of the butyl ester was revealed by heteronuclear
multiple bond correlation (HMBC) spectroscopy, but it was
originally suggested that 1 may be an artifact of isolation as n-
1
butanol was utilized as an extraction solvent. n-Butyl esters are
Received: January 22, 2020
uncommon in natural products, and very few microorganisms
have the capacity to produce either n-butyl esters or n-
4
butanol. However, there are examples, including those not
4b,5
isolated by n-butanol extraction. In addition, it is difficult to
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XXXX American Chemical Society
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Scheme 1. Retrosynthesis of Trachyspic Acid 19-n-Butyl
Scheme 3. Synthesis of Aldehyde 3
Ester (1)
The route began (Scheme 2) with the enolization and
silylation of lactone 6 followed by a formal [2 + 2]-
with allyl alcohol. Tosylation then gave the stable tosylate 10,
which was subjected to iodide displacement and zinc-mediated
8
elimination to afford the alkene 11. Selective base hydrolysis
Scheme 2. Attempted Synthesis of Diacid 9
of the least hindered C1 butyl ester could then be easily
achieved, and subsequent palladium-mediated removal of the
14
allyl ester gave the required diacid. Prolonged reaction times
lead to the formation of an unsaturated lactone minor
byproduct presumably as a result of intramolecular Heck-
15
16
type lactonization. Esterification with di-i-propyl-t-butyli-
sourea (DBIU) then afforded the di-t-butyl ester 12. Silylation
of the tertiary alcohol gave triester 13, and oxidative cleavage
of the alkene then gave sensitive aldehyde 3 ready for NHK
coupling.
The synthesis of vinyl iodide 4 commenced with
1
7
regioselective Markovnikov iodoboration of the known
6c
alkyne 14 with B-iodo-9-BBN followed by protodeborylation,
which gave vinyl iodide 15 in good yield (Scheme 4).
Scheme 4. Synthesis of Enone 16
8
a,10,11
cycloaddition
with di-n-butylacetylene dicarboxylate
1
2
7
to afford the cyclobutene diester 5 in good yield and
with excellent stereoselectivity via addition of the alkyne from
the least hindered face of the silylketene acetal. A HF·pyridine-
8b
mediated rearrangement of 5 then smoothly gave the bicyclic
lactone 8. A suggested mechanism for this cascade begins with
the deprotection of the silyl groups in 5 followed by selective
intramolecular oxa-Michael reaction of the secondary alcohol
into the cyclobutenone diester. Intramolecular cyclobutanone
1
3
ring-opening by the pendant primary alcohol then results in
formation of the lactone 8.
We next investigated what appeared to be a simple bis
hydrolysis of 8, which would facilitate orthogonal protection
for the eventual production of 1. A myriad of hydrolysis
conditions were trialed, all of which failed to provide the diacid
9
with acceptable selectivity. Although the hydrolysis of the
strained lactone to the mono acid was rapid, the second
hydrolysis proved difficult to control with the rates for the two
n-butyl esters being similar. This may be due to the presence of
the primary alcohol, which might facilitate the competitive
hydrolysis of the more hindered ester. In any case, an
alternative approach was required.
A successful route for orthogonal protection is depicted in
Scheme 3 and begins with the rearrangement of cyclobutene 5
followed by immediate ring-opening of the resultant lactone 8
Deprotection and immediate oxidation of the resultant primary
alcohol followed by acetal formation afforded the coupling
partner 4. The NHK reaction between 4 and aldehyde 3 was
achieved under standard conditions with the rigorous
exclusion of water to yield an allylic alcohol as a complex
mixture of diastereoisomers. This alcohol proved to be inert to
1
8
oxidation with MnO as well as Dess−Martin periodinane.
2
B
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Fortunately, Swern oxidation provided the enone 16 as an
inconsequential 1:1 mixture of diastereoisomers.
The final steps toward trachyspic acid 19-n-butyl ester (1)
are shown in Scheme 5 and mirror those utilized in the total
AUTHOR INFORMATION
■
Corresponding Author
Mark A. Rizzacasa − School of Chemistry and Bio21 Molecular
Science and Biotechnology Institute, The University of
Melbourne, Melbourne, Victoria 3010, Australia; orcid.org/
Scheme 5. Completion of the Synthesis of 1
0
000-0002-7297-1303; Email: masr@unimelb.edu.au
Author
Alex A. Rafaniello − School of Chemistry and Bio21 Molecular
Science and Biotechnology Institute, The University of
Melbourne, Melbourne, Victoria 3010, Australia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00319
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council Discovery Program
and the University of Melbourne Faculty of Science Research
Grant Support Scheme for funding. We also thank Dr.
Christian Gunawan and Tony Duncan (Circa Pty Ltd) for
the generous gift of (S)-(+)-γ-hydroxymethyl-γ-butyrolactone.
6
synthesis of trachyspic acid (2). Exposure of enone 16 to
aqueous perchloric acid induced spiroacetal formation, and
acetylation followed by ozonolysis with concomitant elimi-
nation afforded the desired di-t-butyl ester 17 as the major C6
spiroisomer after purification by high-performance liquid
6b,c
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