Synthesis of Alkyl Citrates (-)-CJ-13,981, (-)-CJ-13,982, and (-)-L-731,120 via a Cyclobutene Diester

Article abstract of DOI:10.1021/acs.orglett.8b01665

An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (-)-CJ-13,982 (1), (-)-CJ-13,981 (2), and (-)-L-731,120 (3) via a cross-metathesis and subsequent reduction.

Full text of DOI:10.1021/acs.orglett.8b01665

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Synthesis of Alkyl Citrates (−)-CJ-13,981, (−)-CJ-13,982, and (−)-L-
31,120 via a Cyclobutene Diester
7
†
†
†
†
Liselle Atkin, Zongjia Chen, Angus Robertson, Dayna Sturgess, Jonathan M. White,
and Mark A. Rizzacasa*
School of Chemistry and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, Victoria
3
010, Australia
*
S Supporting Information
ABSTRACT: An efficient and step-economic new approach to alkyl citrate natural products from a cyclobutene diester is
presented. The key sequence involves a formal [2 + 2]-cycloaddition of a silylketene acetal with dimethylacetylene dicarboxylate
to provide the cyclobutene diester 14 with 4.5:1 stereoselectivity. Exposure of diester 14 in acidic methanol effected a
hydrolysis, intramolecular oxy-Michael reaction, and cyclobutanone methanolysis cascade to give the triester 15. Iodination and
elimination then afforded a key alkyl citrate alkene intermediate, which was converted into the natural products (−)-CJ-13,982
(
1), (−)-CJ-13,981 (2), and (−)-L-731,120 (3) via a cross-metathesis and subsequent reduction.
4
lkyl citrate natural products comprise a large family of
fungal metabolites that possess a common 2-substituted
a HRPKS, citrate synthase, and a hydrolase. Many of the alkyl
citrates possess potent activity against squalene synthase (SqS),
the enzyme responsible for the first pathway-specific step in the
A
citric acid moiety. Alkyl citrates such as CJ-13,982 (1), CJ-
1
2
6
1
3,981 (2), and L-731,120 (3) have a basic alkyl-substituted
biosynthesis of cholesterol. The most active are the zaragozic
acids or sqaulestatins, with zaragozic acid A (4) having a IC50
0.29 nM against rat SqS. Compounds 1, 2, and 3 are
somewhat less active but still reasonably potent with IC
values of 1.1, 2.8, and 0.77 μM respectively.
Alkyl citrates are challenging synthetic targets owing to their
high oxidation state and two contiguous stereocenters, and
3
5
citrate moiety, while the more complex zaragozic acid A (4)
incorporates the citrate into a highly oxidized 2,8-
dioxabicyclo[3.2.1]octane core. Indeed, it recently has been
demonstrated that L-731,120 (3) is the biosynthetic precursor
=
50
1
,2
4
to zaragozic acid A (4) (Figure 1). This suggests that the
7
stereochemistry at C12 in 3 is R as shown.
previous syntheses of both natural (−)-1 and unnatural (+)-1
and (+)-2 are summarized in Figure 2. The first syntheses of
The oxygen atoms at C2, C4, C5 C6, C7, and C11 in
zaragozic acid A (4) are derived from atmospheric oxygen by
5
an amazing sequence of C−H oxidations. Cyclization by
intramolecular ketalization then forms the bicyclic core of 4.
Perhaps even more remarkable is the fact that compound 3
itself is produced as a single enantiomer by only three enzymes,
Figure 2. Previous approaches to (+)-1 and (−)-1.
the unnatural enantiomers of CJ-13,982 and CJ-13,981 were
8
reported by Barrett and co-workers, which confirmed the
absolute stereochemistry of these compounds. This utilized an
9
aldol/alkylation sequence to construct the contiguous
asymmetric centers with good stereocontrol. We have reported
the synthesis of natural (−)-CJ-13,982 (1) which utilized an
Received: May 27, 2018
Figure 1. Examples of alkyl citrate natural products.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Rearrangement of Cyclobutene Diesters
Ireland−Claisen rearrangement as the key step to introduce
immediately treated with DMAD (10) in MeCN to afford the
cyclobutene diester 11 as a stable adduct in good yield.
Acetonitrile proved to be the best solvent for this formal [2 +
2]-cycloaddition, which presumably proceeds via the mecha-
nism shown, and it is noteworthy that this reaction proceeded
efficiently in a solvent without Lewis acid catalysis. The
cycloaddition also proceeded well in dichloromethane, but
other solvents such as THF gave no improvement. Conducting
the reaction neat was also inferior, while addition of Lewis
acids (e.g., ZrCl , TiCl , and Cu(OTf) ) mostly resulted in
the two asymmetric centers with some degree of stereocontrol
10
but in low overall yield (Figure 2). The synthesis of the
proposed stereoisomer of L-731,120 (3) has not been
reported. These approaches to simple alkyl citrates are lengthy
due multiple functional group transformations. We now report
a shorter, highly stereoselective approach to alkyl citrates from
cyclobutene diesters, which can be adapted to produce a
number of the alkyl citrate family of natural products.
The cyclobutene approach to the citrate moiety is based on
4
4
2
11,12
studies by Meisch and Wendling,
who reported that
decomposition of the silyl ketene acetal. In addition, the
cycloaddition also proceeded in the presence of hindered base
(2,6-di-tert-butyl-4-methylpyridine), which demonstrates that
traces of acid are not required for this reaction. As hoped,
treatment of cyclobutenediester with concentrated HCl in
MeOH at 55 °C caused the desired cascade of reactions to
bicyclic cyclobutene diesters of general structure 5 are
converted into cyclobutanones upon treatment with BF3·
OEt (X = O) or aq HCl (X = S) via an unprecedented
2
rearrangement involving acetal cleavage and intramolecular
oxa- or thia-Michael addition as shown in Scheme 1.
1
3
12
Subsequent acid-mediated cyclobutanone methanolysis
afford the tetrahydrofuran 12 as a single diastereoisomer in
afforded the triesters 6 with the relative configuration shown,
which maps onto the alkyl citrate moiety. Given this precedent,
we postulated that the direct rearrangement of tetrahydrofuran
cyclobutenediester 5a to tetrahydrofuran 6a might simply be
achieved by treatment of 5a with acidic methanol. This would
serve as a rapid entry into the alkyl citrate moiety with the
correct stereochemistry and oxidation level.
excellent yield. Oxidation of 12 by treatment with RuCl and
3
17
NaIO4 afforded lactone 7 as a crystalline solid, and the
stereochemistry was then confirmed by a single-crystal X-ray
structure.
Guided by this efficient route to the racemic lactone 7, we
next embarked on an enantiospecific synthesis of (−)-CJ-
18
13,982 (1) (Scheme 3). The known optically pure lactone 13
Our investigations began with the synthesis of the triester
lactone 7 as shown in Scheme 2. Cyclobutenediesters can be
Scheme 3. Synthesis of (−)-CJ-13,982
Scheme 2. Model Study
(
prepared from (S)-(+)-γ-hydroxymethyl-γ-butyrolactone) was
converted into the silyl ketene acetal, and cycloaddition with
DMAD (10) at −40 °C to rt afforded the major adduct
cyclobutene 14 in 63% yield (+ 14% minor diastereoisomer, dr
4.5:1) as a result of the approach of 10 from the least hindered
face of the ketene acetal. The isomers were separated by flash
chromatography, and the stereochemistry of the major adduct
was confirmed by its subsequent conversion into (−)-CJ-
13,982 (1). Exposure of the cyclobutene to HCl in MeOH at
55 °C induced concomitant silyl ether and acetal hydrolysis,
readily accessed via the formal [2 + 2]-cycloaddition of ketene
14
acetals with acetylenic diesters. Dimethyl acetylenedicarbox-
1
4,15
ylate (DMAD) (10) reacts with alkyl
and silyl ketene
11,12
acetals in the absence of Lewis acid and solvent
to produce
cyclobutene diesters. In our hands, the cyclobutenes produced
from TMS ketene acetals proved too labile, so we elected to
16
utilize the TBS ketene acetal. Enolization and silylation of γ-
butyrolactone 8 afforded the crude ketene acetal 9, which was
B
DOI: 10.1021/acs.orglett.8b01665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
subsequent oxy-Michael addition, and cyclobutene methanol-
ysis to afford the triester 15 as a single stereoisomer good yield.
Higher yields were obtained for smaller scale reactions (76%
for <1 g); however, for larger scales (>2g), immediate
tosylation of the crude alcohol 15 and purification gave
tosylate 16 in a better reproducible yield over the two steps.
Displacement gave a sensitive iodide, which upon immediate
zinc-mediated reductive elimination gave the key alkyl citrate
fragment 17. Cross metathesis (CM) with undecene followed
by hydrogenation afforded (−)-CJ-13,982 trimethyl ester 18.
Scheme 5. Synthesis of (−)-L-731,120
10
This compound compared well with that reported by us and
8
by Barrett (except for the sign of rotation).
8
Base hydrolysis of trimethyl ester 18 as previously described
(
excess aq NaOH, overnight) resulted in considerable
19
decomposition, presumably via a retro aldol pathway. After
some experimentation, we found that the use of 5 equiv of 1 M
aqueous NaOH in dioxane cosolvent at 80 °C for only 2 h gave
(
−)-CJ-13,982 (1) which could be purified by RP-HPLC. This
sequence constitutes the shortest enantiospecific synthesis of
this compound.
The synthesis of congener (−)-CJ-13,981 (2) is shown in
Scheme 4 and begins with alcohol 19. Silylation followed by
Scheme 4. Synthesis of (−)-CJ-13,981
In conclusion, we have achieved a new and efficient
enantiospecific synthesis of the alkyl citrates CJ-13,982 (1)
(
10 steps from (S)-(+)-γ-hydroxymethyl-γ-butyrolactone, 7%
overall) and CJ-13,981 (2) (13 steps, 12% overall) and the first
total synthesis of the zaragozic acid biosynthetic precursor L-
7
31,120 (3) (10 steps, 7% overall). Noteworthy features of this
approach include the construction of the two contiguous
asymmetric centers of the citrate by an acid-mediated
rearrangement of a cyclobutenediester with complete control
of the relative stereochemistry and no need for any functional
group manipulations to achieve the triacid oxidation level. This
allowed for the synthesis of the key alkyl citrate alkene 17
intermediate in seven steps from a commercially available
starting material (30% overall, three chromatographic
purifications). The synthesis of higher oxidized more complex
alkyl citrates using this methodology is currently under
investigation.
CM with alkene 16 and hydrogenation afforded triester 20 in
good yield. CM using the free alcohol 19 was not as efficient.
Desilylation and subsequent methylenation gave the trimethyl
ester of CJ-13,981 (22), which was also identical to that
8
reported apart from the sign of rotation. Base hydrolysis and
ASSOCIATED CONTENT
Supporting Information
RP-HPLC purification gave CJ-13,982 (2), the data for which
■
1
was identical to the natural material.
*
S
The synthesis of the zaragozic acid precursor L-731,120 (3)
is shown in Scheme 5. This began with the known (R)-alcohol
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01665.
20
2
2, secured via Evans’ alkylation, which was oxidized to the
aldehyde and Grignard addition afforded the alcohol 23 as a
mixture of diastereoisomers. Immediate subjection of this to a
Johnson−Claisen rearrangement gave ester 24 in 57% overall
yield. Reduction, oxidation, and Wittig extension provided the
diene 25 and CM with the citrate fragment 16 gave the diene
Experimental procedures and copies of NMR spectra of
all new compounds (PDF)
Accession Codes
CCDC 1837642 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
26 as an E/Z mixture. Selective reduction of the disubstituted
alkene proved challenging with many conditions (e.g., Pd−C/
21
4
H , Wilkinson’s catalyst/H , cat. RuCl /NaBH ) failing to
2
2
3
give acceptable selectivity for reduction of the disubstituted
22
alkene. Eventually, we found that modified diimide reduction
afforded (−)-L-731,120 trimethyl ester 27 along with a small
amount of over-reduced byproduct, which were separated
23
AUTHOR INFORMATION
Corresponding Author
■
using AgNO -impregnated silica gel. Base hydrolysis under
3
the conditions as described above followed by RP-HPLC
purification gave L-731,120 (3).
*E-mail: masr@unimelb.edu.au.
C
DOI: 10.1021/acs.orglett.8b01665
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(21) Babler, J. H.; White, N. A. Tetrahedron Lett. 2010, 51, 439−
4
(
(
41.
Jonathan M. White: 0000-0002-0707-6257
Mark A. Rizzacasa: 0000-0002-7297-1303
Author Contributions
22) Marsh, B. J.; Carbery, D. R. J. Org. Chem. 2009, 74, 3186−3188.
23) Williams, C. M.; Mander, L. N. Tetrahedron 2001, 57, 425−
447.
†L.A., Z.C., D.S., and A.R. contributed equally
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 Circa Pty
Ltd. for the generous gift of (S)-(+)-γ-hydroxymethyl-γ-
butyrolactone.
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DOI: 10.1021/acs.orglett.8b01665
Org. Lett. XXXX, XXX, XXX−XXX