Total synthesis of (+)-seimatopolide A

Article abstract of DOI:10.1002/ejoc.201200732

The first enantioselective total synthesis of a polyhydroxylated macrolide, (+)-seimatopolide A, was achieved. The key reactions, Sharpless asymmetric dihydroxylation, Yamaguchi esterification, and ring-closing metathesis, provided easy access to the target molecule from L-aspartic acid. Further, the absolute stereochemistry of the natural product has also been revised. The first total synthesis of a new macrolide, (+)-seimatopolide A, was achieved starting from the natural amino acid L-aspartic acid by using Sharpless asymmetric dihydroxylation, Yamaguchi esterification, and ring-closing metathesis reactions as key steps. The stereochemistry of the natural product was revised. Copyright

Full text of DOI:10.1002/ejoc.201200732

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201200732
Total Synthesis of (+)-Seimatopolide A
Chada Raji Reddy,*[a] Nagavaram Narsimha Rao,[a] and Motatipally Damoder Reddy[a]
Keywords: Natural products / Total synthesis / Esterification / Metathesis / Dihydroxylation
The first enantioselective total synthesis of
a
polyhy-
vided easy access to the target molecule from L-aspartic acid.
droxylated macrolide, (+)-seimatopolide A, was achieved.
The key reactions, Sharpless asymmetric dihydroxylation,
Yamaguchi esterification, and ring-closing metathesis, pro-
Further, the absolute stereochemistry of the natural product
has also been revised.
pyruvate carboxykinase (PEPCK), which suggests that
compound 1 is a possible therapeutic candidate as an anti-
diabetic drug. These structural and biological profiles com-
bined with our interest in the synthesis of polyhydroxylated
macrolides[2] prompted us to focus our attention on the to-
tal synthesis of seimatopolide A. Herein, we report the first
enantioselective total synthesis of seimatopolide A.
Introduction
In 2012, Lee and co-workers reported the isolation of
two new polyhydroxylated macrolides, seimatopolides A (1)
and B (2, Figure 1), from the ethyl acetate extract of the
fungal culture medium of Seimatosporium discosioides.[1]
The structures of these natural products were established as
10-membered macrolides containing a 9-carbon-atom side
chain and 3 hydroxy groups (for 1) or 2 hydroxy groups (for
2) based on the spectroscopic data, including 1D and 2D
NMR spectroscopy. The absolute configurations were also
established by using the modified Mosher’s method as
(3R,6R,7R,9S) for 1 and (3R,6S,9S) for 2. Further, peroxi-
some proliferator-activated receptor (PPAR) transactivation
abilities of seimatopolides A and B revealed that compound
1 is more potent (EC50 = 1.15 μm) in activating PPAR-γ
compared to 2 (EC50 = 11.05 μm). Seimatopolide A also
remarkably reduced the expression of two gluconeogenic
genes, glucose-6-phosphatase (G6Pase) and phosphoenol-
Results and Discussion
As depicted in Scheme 1, the synthesis of seimatopol-
ide A is envisioned from two precursors, alcohol 3 (C5–C18
fragment) and acid 4 (C1–C4 fragment), which could be
stitched via Yamaguchi esterification followed by ring-clos-
ing metathesis. Subsequently, both these fragments could be
obtained through common epoxide 5, derived from l-as-
partic acid. The desired 1,2-diol functionality in 3 could be
obtained through Sharpless asymmetric dihydroxylation.
Figure 1. Structures of seimatopolide A (1) and B (2).
[a] Division of Natural Products Chemistry
CSIR-Indian Institute of Chemical Technology
Hyderabad 500607, India
Fax: +91-040-27160512
E-mail: rajireddy@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200732.
Scheme 1. Retrosynthesis of seimatopolide A.
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SHORT COMMUNICATION
The synthesis of fragment 3 began with epoxide 5,
which was obtained from commercially available l-as-
partic acid in three steps by using a literature method
(Scheme 2).[3] Ring opening of 5 with 1-octynyllithium in
the presence of BF3·OEt2 in THF provided homopropar-
gylic alcohol 6 in 87% yield. Alcohol 6 was protected as
tert-butyldimethylsilyl (TBDMS) ether
7
by using
TBDMSCl/imidazole/DMAP(cat.) in DMF (92% yield).
Next, one-pot p-methoxybenzyl (PMB) deprotection and
reduction of the alkyne functionality by hydrogenation af-
forded primary alcohol 8 in 92% yield. Oxidation of
alcohol 8 with TEMPO/BAIB in CH2Cl2 followed by the
addition of the two-carbon ylide PPh3=CHCOOEt gave α,
β-unsaturated ester 9 (91% yield, Ͼ20:1dr),[4] a precursor
for dihydroxylation. The key Sharpless asymmetric dihy-
droxylation[5] of 9 was accomplished by using (DHQD)2-
PHAL/K3FeCN6/MeSO2NH2/OsO4 in tBuOH/H2O to af-
ford diol 10 in 85% yield as an inseparable diastereomeric
mixture (9:1, separated at a later stage of the synthesis).
Towards alcohol fragment 3, initially, lactonization of diol
10 followed by acetonide protection was investigated. Lac-
tonization of 10 was successful in the presence of 1 n HCl
in MeOH to give pure lactone 11. This is a natural product
isolated from Seridium unicome, which has abscisic activity
against the leaves of Chamaecyparis obtusa, inhibits the
growth of lettuce seedlings, and displays antifungal ac-
tivity against Cladosporium herbarum.[6] However, subse-
quent protection by using 2,2-DMP/CSA(cat.) failed to
give expected acetonide 12; instead, hydroxymethyl ester
13 was obtained in 78% yield. We then turned to a dif-
ferent strategy to obtain terminal olefin 3. Acetonide pro-
tection of diol 10 with 2,2-DMP/CSA(cat.) did result in
desired 14 in 93% yield. Subsequent reduction of the ester
functionality in compound 14 to the aldehyde by using
DIBAL-H followed by the addition to a one-carbon ylide
(generated from CH3PPh3+Br–, nBuLi in THF) led to ole-
fin 15 in 71% yield. Desilylation of 15 by using TBAF in
THF gave desired alcohol fragment 3 in 77% yield, and
at this stage the diastereomers formed during Sharpless
asymmetric dihydroxylation were separated by column
chromatography.
Scheme 2. Synthesis of fragment 3. Reagents and conditions: (a) 1-
Octyne, nBuLi, BF3·OEt2, THF, –78 °C, 4 h, 87%; (b) TBSCl,
imidazole, DMAP (cat.), DMF, 0 °C to r.t., 3 h, 92%; (c) H2–Pd/C
(10%), ethanol, 12 h, 92%; (d) TEMPO, BAIB,CH2Cl2, r.t., 2 h
then Ph3P=CHCO2Et, 0 °C to r.t., 3 h, 91%; (e) (DHQD)2PHAL,
K3FeCN6, K2CO3, Me2SO2NH2, OsO4, tBuOH/H2O, 0 °C, 8 h,
85%; (f) 1 n HCl, MeOH, 0 °C, 1 h, 80%; (g) 2,2-DMP, CSA (cat.),
CH2Cl2, 0 °C to r.t., 4 h, 78%; (h) 2,2-DMP, CSA (cat.), CH2Cl2,
0 °C to r.t., 4 h, 93%; (i) DIBAL-H, toluene, –78 °C, 30 min;
CH3PPh3+Br–, nBuLi, THF, 0 °C to r.t., 2 h, 71%; (j) TBAF (1 m
in THF), THF, reflux, 6 h, 77%.
Requisite acid 4 (C1–C4 fragment) was also prepared
from epoxide 5 in four steps (Scheme 3). Treatment of epox-
ide 5 with trimethylsulfonium iodide in the presence of
nBuLi as a base in THF at –20 °C afforded allyl alcohol 16
in 90% yield.[7] Protection of 16 by using TBSOTf/2,6-lut-
idine gave silyl ether 17 in 88% yield. Compound 17 was
then subjected to PMB deprotection under DDQ condi-
tions[8] (93% yield), and oxidation of resulting primary
alcohol 18 by using TEMPO/BAIB[9] in CH2Cl2/H2O pro-
vided acid 4 in 86% yield.
With both alcohol 3 and acid 4 in hand, we proceeded
to construct the macrocyclic framework (Scheme 4). The es-
terification reaction between 3 and 4 was carried out under
Yamaguchi reaction conditions (2,4,6-trichlorobenzoyl
chloride, Et3N in THF, DMAP in toluene)[10] to afford ester
Scheme 3. Synthesis of fragment 4. Reagents and conditions:
(a) Me3S+I–, nBuLi, THF, –20 °C, 2 h, 90%; (b) TBSOTf, 2,6-luti-
dine, CH2Cl2, 0 °C, 30 min, 88%; (c) DDQ, CH2Cl2/pH 7 buffer
(9:1), 0 °C, 30 min, 93%; (d) TEMPO, BAIB, CH2Cl2/H2O (1:1),
0 °C to r.t., 2 h, 86%.
Firstly, compound 19 was subjected to deprotection of
19 in 98% yield. Having precursor 19, the ring-closing me- both the acetonide and TBS groups by using 1 n HCl in
tathesis (RCM) reaction was explored. MeOH to obtain triol 20 in 80% yield. However, the RCM
2
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Total Synthesis of (+)-Seimatopolide A
opposite sign for synthetic 1 and analysis of the data of the
Mosher ester in the isolation paper[1,14] revealed that the
absolute configuration of the natural product is
(3S,6S,7S,9R). Thus, synthesized 1 is (+)-seimatopolide A,
which proved to be the enantiomer of the natural product.
Conclusions
In summary, we have described an expedient enantiose-
lective total synthesis of the polyhydroxylated macrolide
(+)-seimatopolide A (12 linear steps, 17% overall yield from
epoxide 5) and revised the absolute stereochemistry of the
natural product. Key features of the synthesis include the
synthesis of both desired fragments from a common start-
ing material, l-aspartic acid; and the successful exploitation
of Yamaguchi esterification and ring-closing metathesis re-
actions. The desired asymmetric 1,2-diol functionality was
attained by using Sharpless asymmetric dihydroxylation.
This approach demonstrates easy access to a macrolide
starting from a natural amino acid. Further, biological
evaluation of (+)-seimatopolide A and synthesis of its ana-
logues are currently under investigation.
Scheme 4. Coupling of 3 and 4 to seimatopolide A. Reagents and
conditions: (a) 4, 2,4,6-trichlorobenzoylchloride, Et3N, THF, 0 °C
to r.t., 2 h; then 3, DMAP, toluene, 0 °C, 15 min, 98%; (b) 1 n HCl,
MeOH, 0 °C, 2 h, 80%; (c) Grubbs 2nd generation catalyst (G-II,
20 mol-%), CH2Cl2, reflux, 1 h; (d) G-II (20 mol-%), CH2Cl2, re-
flux, 2 h, 78%; (e) 1 n HCl, MeOH, 0 °C, 2 h, 73%; (f) TBAF (1 m
in THF), THF, 0 °C to r.t., 2 h, 90%; (g) G-II (10 mol-%), CH2Cl2,
reflux, 1 h, 86%; (h) TFA, CH3CN, H2O, 0 °C to r.t., 3 h, 76%.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details; characterization data; comparison of the
1H NMR and 13C NMR spectroscopic data for synthetic 1 and
1
the natural product; copies of the H NMR and 13C NMR of all
compounds; and NOE, COSY, HMBC, and HSQC analysis of the
target molecule.
Acknowledgments
reaction of triol 20 with Grubbs 2nd generation catalyst (G-
II, 20 mol-%)[11] failed to provide desired 1 in pure form;
instead, an inseparable mixture of unidentified compounds
with only a very small amount of 1 was obtained
(Scheme 4, path I). Next, the RCM reaction of 19 with G-
II (20 mol-%) was carried out, and to our delight, desired
macrolide 21 was obtained in 78% yield (Ͼ20:1dr). Re-
N. N. R. and M. D. R. thank the Council of Scientific and Indus-
trial Research (CSIR), New Delhi for research fellowships.
[1] N. T. Hiep, Y.-h. Choi, N. Kim, S. S. Hong, S.-B. Hong, B. Y.
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784–788.
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1824; b) Ch. R. Reddy, D. Suman, N. N. Rao, Synlett 2012, 23,
using 1 n HCl in MeOH provided target natural product 1
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in 73% yield (Scheme 4, path II). Alternatively, the selective
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deprotection of the TBS group of compound 19 with TBAF
hedron Lett. 2009, 50, 2478–2480.
in THF to afford alcohol 22 (90% yield) followed by RCM
of 22 with G-II (10 mol-%) provided clean formation of
macrolide 23 in 86% yield (Ͼ20:1dr). Finally, hydrolysis of
the acetonide of 23 by using trifluoroacetic acid (TFA) in
CH3CN/H2O (76% yield) completed the total synthesis of
[3] a) J. A. Frick, J. B. Klassen, A. Bathe, J. M. Abramson, H. Ra-
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1994, 94, 2483–2547.
seimatopolide A (1; Scheme 4, path III).[12] The final com- [6] a) H. Toshima, A. Watanabe, H. Sato, A. Ichihara, Tetrahedron
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sis for synthetic 1 were in full agreement to those reported
for the natural product (comparison table provided in the
Supporting Information). However, the specific rotation of
synthetic 1 was observed as [α]2D5 = +30.0 (c = 0.05,
MeOH),[13] whereas for isolated compound it was reported
as [α]2D6 = –188.3 (c = 0.05, MeOH).[1] The observation of
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SHORT COMMUNICATION
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[12] The RCM reaction in path III requires a lower catalyst loading
compared to that required for path II (two steps) and provides
the same overall yield of the target molecule. Thus, there may
be an advantage in using path III even though it involves three
steps.
25
[13]
The specific rotation was also measured in pyridine: [α]D
+29.0 (c = 0.12, pyridine).
=
[14] The absolute configuration was misassigned in the isolation pa-
per; see ref.[1]
Received: May 31, 2012
Published Online: ᭿
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Total Synthesis of (+)-Seimatopolide A
Total Synthesis
The first total synthesis of a new macrolide,
(+)-seimatopolide A, was achieved starting
from the natural amino acid l-aspartic acid
by using Sharpless asymmetric dihydroxyl-
ation, Yamaguchi esterification, and ring-
closing metathesis reactions as key steps.
The stereochemistry of the natural product
was revised.
C. Raji Reddy,* N. N. Rao,
M. D. Reddy ...................................... 1–5
Total Synthesis of (+)-Seimatopolide A
Keywords: Natural products / Total syn-
thesis / Esterification / Metathesis / Dihy-
droxylation
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