First Total Synthesis of Jomthonic Acid A 1

Article abstract of DOI:10.1055/s-0039-1691503

A stereoselective total synthesis of jomthonic acid A is described. The key features of the synthetic strategy are a Sharpless asymmetric epoxidation, a Gilmann reagent-induced methylation, a Mitsunobu reaction, a Yamaguchi esterification, and an O -(benzotriazol-1-yl)- N, N, N ′, N ′-tetramethyluronium tetrafluoroborate (TBTU)-mediated amide coupling. Jomthonic acid A is an architecturally rare amino acid containing a β-methylphenylalanine residue and a 4-methyl-(2 E,4 E)-hexa-2,4-dienoate moiety. It shows antidiabetic and antiatherogenic activities when tested against mouse ST-13 preadiopocytes.

Full text of DOI:10.1055/s-0039-1691503

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
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M. Dumpala et al.
Letter
Synlett
First Total Synthesis of Jomthonic Acid A1
Mohan Dumpala
Mitsunobu reaction
Yamaguchi esterification
Batthula Srinivas
Palakodety Radha Krishna*
0
0
0
0-0
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2-
3
2
8
7-3
4
7
7
O
O
H
N
D-211, Discovery Laboratory, Organic Synthesis and Process
Chemistry Division, CSIR-Indian Institute of Chemical Technolo-
gy, Hyderabad-500 007, India
O
OH
O
prkgenius@iict.res.in
Frater–Seebach reaction
Gilmann reaction
Received: 14.10.2019
Accepted after revision: 07.11.2019
Published online: 29.11.2019
In continuation of our interest in the total synthesis of
bioactive natural products,3 we have developed a conver-
gent synthesis of jomthonic acid A (1). Our retrosynthetic
analysis of 1 (Scheme 1) suggested that it might be derived
from the amido ester 2 through deprotection followed by
oxidation. Compound 2 might be prepared from 4-methyl-
hexa-2,4-dienoic acid (3) and amino ester 4 through amide
coupling.4 Compound 4 might be assembled from azide 5
and alcohol 6 under Yamaguchi conditions.5 Compound 5
might, in turn, be obtained from trans-cinnamyl alcohol (7)
by epoxidation, regioselective ring opening of the epoxide
with the Gilmann reagent, and Mitsunobu reaction fol-
lowed by oxidation. Likewise, alcohol 6 might be obtained
by Frater–Seebach alkylation of ethyl (3R)-3-hydroxybuta-
noate.6
DOI: 10.1055/s-0039-1691503; Art ID: st-2019-d0549-l
Abstract A stereoselective total synthesis of jomthonic acid A is de-
scribed. The key features of the synthetic strategy are a Sharpless asym-
metric epoxidation, a Gilmann reagent-induced methylation, a Mitsu-
nobu reaction, a Yamaguchi esterification, and an O-(benzotriazol-1-yl)-
N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU)-mediated am-
ide coupling. Jomthonic acid A is an architecturally rare amino acid con-
taining a -methylphenylalanine residue and a 4-methyl-(2E,4E)-hexa-
2,4-dienoate moiety. It shows antidiabetic and antiatherogenic activi-
ties when tested against mouse ST-13 preadiopocytes.
Key words Gilmann reaction, Mitsunobu reaction, Yamaguchi esteri-
fication, amide coupling, total synthesis, jomthonic acid A
Actinomycetes are a major source of structurally diverse
secondary metabolites that exhibit antagonism to Gram-
positive bacteria. Igarashi and co-workers recently reported
the isolation and characterization of the modified amino
acid derivative jomthonic acid A (1; Figure 1) from the cul-
ture broth of a soil-derived actinomycete of the genus
Streptomyces sp. BB47.2 Compound 1 contains four stereo-
centers and several unusual structural features, such as the
4-methyl-(2E,4E)-hexa-2,4-dienoate and -methylphenyl-
alanine fragments. Jomthonic acid A exhibits antidiabetic
and antiatherogenic activities against mouse ST-13 prea-
diopocytes and it also inhibits the differentiation of preadi-
pocytes into mature adipocytes at 2–50 M.
Our synthetic approach began with commercially avail-
able trans-cinnamyl alcohol (7; Scheme 2). This was con-
verted into the chiral epoxy alcohol 9 in 87% yield by Sharp-
less asymmetric epoxidation. Regioselective ring opening of
epoxide 9 with the Gilmann reagent gave diol 10 in 68%
yield.7 Next, selective protection of the primary hydroxy
group of 1,2-diol 10 by TBDMSCl/imidazole/Bu2SnO in
CH2Cl2 at 0 °C for two hours gave silyl ether 11 in 93% yield.
Subsequently, 11 was converted into the corresponding
azide 12 in 85% yield under Mitsunobu conditions by using
diphenyl phosphorazidate (DPPA) and DIAD in anhydrous
THF at 0 °C to room temperature.8,9 Subsequent deprotec-
tion of silyl ether 12 with TBAF in THF afforded alcohol 13
(95% yield).10 The purity of compound 13 was determined
by LC/MS analysis, and the diastereomeric excess was found
to be 98% (see Supporting Information). Compound 13, on
further oxidation with TEMPO and PhI(OAc)2 in CH2Cl2–H2O
(4:1) gave acid 5 in 93% yield.11
O
O
H
N
(R)
O
(R)
OH
(S)
(R)
O
Jomthonic Acid A (1)
Figure 1
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

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M. Dumpala et al.
Letter
Synlett
O
O
(E)
(E)
O
NH
OH
(R)
OH
O
NH
(S)
(R)
(R)
OTBDPS
3
O
O
O
O
O
1
O
OTBDPS
2
NH2
4
O
OH
OH
OTBDPS
N3
6
5
OH
O
OH
O
8
7
Scheme 1 Retrosynthetic analysis of jomthonic acid A (1)
(+)-DIPT, Ti(OiPr)4
TBHP, 4 Å MS
O
MeLi, CuI
OH
OH
OH
dry Et2O, –20 to 0 °C
10 h, 68%
OH
dry CH2Cl2, –20 to 0 °C
8 h, 87%
10
9
cinnamyl alcohol (7)
DPPA, DIAD, TPP
TBSCl, Bu2SnO
OTBDMS
OTBDMS
OH
imidazole, dry CH2Cl2
0 °C to rt, 2 h, 93%
dry THF, 0 °C to rt
2 h, 85%
N3
12
11
O
TEMPO, PhI(OAc)2
TBAF, THF
OH
OH
N3
0 °C to rt, 3 h
95%
N3
CH3CN/H2O (4:1)
0 °C to rt, 4 h, 93%
13
5
Scheme 2 Synthesis of fragment 5
In parallel, compound 6, required for the Yamaguchi es-
terification, was prepared from commercially available eth-
yl (3R)-3-hydroxybutanoate (8; Scheme 3). Frater–Seebach
alkylation of 8 gave 1,3-diol 14.6,12 Selective protection of
the primary hydroxy group of this 1,3-diol with TBDP-
SCl/imidazole/Bu2SnO in CH2Cl2 at 0 °C to room tempera-
ture gave silyl ether 6 in 93% yield.
Having both coupling partners in hand, we performed a
Yamaguchi esterification of acid 5 with silyl ether 6 to give
the azide derivative 15 in 68% yield (Scheme 4).5,13 Reduc-
tion of azide 15 with H2 (1 atm) over Pd/C gave amine 4 in
90% yield. Compound 2 was obtained in 68% yield by O-
(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetraflu-
oroborate (TBTU)-mediated coupling of amine 4 with acid
3, prepared from tiglic aldehyde by a reported procedure.4,14
Subsequently, the silyl group was removed by treatment
with HF·Py in CH3CN at 0 °C to room temperature to afford
the alcohol 16 in 85% yield.15 Finally oxidation of 16 with
TEMPO and PhI(OAc)2 in CH2Cl2–H2O (4:1) gave the target
compound 1. Spectroscopic data for this product were con-
sistent with the reported values.2
TBDPSCl
DMAP
OH
(S)
(R)
OH
OH
(R)
O
Ref. 9
OH
OTBDPS
(R)
O
imidazole
dry CH2Cl2
0 °C to t, 2 h, 93%
ethyl (R)-3-hydroxy
butanoate (8)
14
6
Scheme 3 Synthesis of fragment 6
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

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M. Dumpala et al.
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Synlett
O
O
6, 2,4,6-trichlorobenzoyl
chloride, DMAP
H2 , Pd-C
OH
O
OTBDPS
EtOAc
90%
N3
N3
CH2Cl2, 0 °C to rt
2 h, 68%
15
5
O
O
3, DIPEA, TBTU
Et3N
NH
OTBDPS
O
O
OTBDPS
NH2
dry CH2Cl2, 0 °C to rt
4 h, 68%
O
4
2
O
O
NH
NH
OH
O
OH
TEMPO, PhI(OAc)2
O
HF⋅Py
O
O
O
CH3CN/H2O (4:1)
CH3CN, 0 °C to rt
85%
0 °C to rt, 4 h , 80%
16
1
Scheme 4 Synthesis of jomthonic acid A (1)
In conclusion, the first stereoselective total synthesis of
jomthonic acid A was achieved by a convergent approach
with an 8.0% overall yield by employing a Sharpless asym-
metric epoxidation, a Gilmann reaction, a Mitsunobu azida-
tion, hydrogenation, a Yamaguchi esterification, and amide
coupling as the key steps.
(7) (a) Radha Krishna, P.; Arun Kumar, P. V.; Mallula, V. S.;
Ramakrishna, K. V. S. Tetrahedron 2013, 69, 2319. (b) Simmons,
B.; Walji, A. M.; MacMillan, D. W. C. Angew. Chem. Int. Ed. 2009,
48, 4349.
(8) (a) Shioiri, T. Diphenyl Phosphorazide (DPPA): More Than Three
Decades Later, TCI Mail No. 134. Tokyo Tokyo Chemical Industry
Co. Ltd 2007, https://www.tcichemicals.com/en/kr/support-
download/tcimail/backnumber/article/134drE.pdf
(accessed
Nov 19, 2019) (b) Thompson, A. S.; Grabowski, E. J. J. WO
1995001970, 1995. (c) Pastó, M.; Moyano, A.; Pericàs, M. A.;
Riera, A. J. Org. Chem. 1997, 62, 8425.
Acknowledgment
M.D. and B.S are grateful to the UGC, New Delhi for the financial sup-
port in the form of fellowships.
(9) {[(2S,3R)-2-Azido-3-phenylbutyl]oxy}(tert-butyl)dimethyl-
silane (12)
To a solution of compound 11 (1.7 g, 6.0 mmol) in THF (20 mL)
at 0 °C were added DIAD (2.39 mL, 12.1 mmol) and TPP (3.1 g,
12.1 mmol), and the mixture was stirred for 5 min. DPPA
(2.61 g, 9.5 mmol) was added at 0 °C, and the mixture was
allowed to warm to rt, stirred for 3 h, then warmed to 35 °C for
24 h. The mixture was then concentrated and purified by flash
column chromatography [silica gel, EtOAc–hexane (8:92)] to
give a pale-yellow oil; yield: 1.48 g (80%).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1691503.
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References and Notes
1H NMR (400 MHz, CDCl3):  = 7.33–7.26 (m, 2 H), 7.24–7.16 (m,
3 H), 3.60 (dd, J = 10.4, 3.1 Hz, 1 H), 3.4–3.40 (m, 1 H), 3.39–3.33
(m, 1 H), 2.91 (dq, J = 14.1, 7.0 Hz, 1 H). 1.35 (d, J = 7.0 Hz, 3 H),
0.88 (s, 9 H), –0.02 (s, 6 H). 13C NMR (100 MHz, CDCl3):
 = 143.5, 128.6, 127.55, 126.5, 69.2, 64.9, 40.3, 25.8, 18.4, 18.2,
–5.6. EI-ESI: m/z = 323 [M + NH4]+.
(1) Communication No. IICT/Pubs./2019/237.
(2) (a) Igarashi, Y.; Yu, L.; Ikeda, M.; Oikawa, T.; Kitani, S.; Nihira, T.;
Bayanmunkh, B.; Panbangred, W. J. Nat. Prod. 2012, 75, 986.
(b) García-Salcedo, R.; Álvarez-Álvarez, R.; Olano, C.; Cañedo, L.;
Braña, A. F.; Méndez, C.; De la Calle, F.; Salas, J. A. Mar. Drugs
2018, 16, 259. (c) Yu, L.; Oikawa, T.; Kitani, S.; Nihira, T.;
Bayanmunkh, B.; Panbangred, W.; Igarashi, Y. J. Antibiot. 2014,
67, 345.
(3) Bérdy, J. J. Antibiot. 2012, 65, 385.
(4) Markworth, C. J.; Marron, B. E.; Swain, N. A. WO 2010035166,
2010.
(10) (2S,3R)-2-Azido-3-phenylbutan-1-ol (13)
A 1.0 M solution of TBAF in THF (1.54 g, 8.85 mL, 5.9 mmol) was
added to a solution of compound 12 (1.2 g, 3.9 mmol) in anhyd
THF (10 mL) at 0 °C, and the mixture was stirred at rt for 2 h.
When the reaction was complete, the mixture was diluted with
H2O (5 mL), and the mixture was extracted with EtOAc (3 × 20
mL). The combined organic layers were washed with brine (2 x
10 mL) and dried (Na2SO4). Filtration, and evaporation of the
solvent under reduced pressure, followed by column chroma-
tography [silica gel, EtOAc–hexane (20:80)] gave a colorless
liquid; yield: 0.676 g (90%); []D25 –9.1 (c 0.7, CHCl3).
(5) Dhimitruka, I.; SantaLucia, J. Org. Lett. 2006, 8, 47.
(6) Fráter, G.; Müller, U.; Günther, W. Tetrahedron 1984, 40, 1269.
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D

D
M. Dumpala et al.
Letter
Synlett
1H NMR (400 MHz, CDCl3):  = 7.37–7.30 (m, 2 H), 7.27–7.19 (m,
3 H), 3.60–3.50 (m, 2 H), 3.46–3.37 (m, 1 H), 2.94–2.83 (m, 1 H),
1.40 (d, J = 6.9 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  = 142.8,
128.7, 127.3, 127.0, 70.3, 64.0, 41.4, 18.4. EI-ESI: m/z = 209 [M +
NH4]+.
 = 169.1, 141.4, 135.5, 129.6, 128.5, 127.7, 127.6, 127.2, 73.6,
67.6, 65.1, 41.7, 39.9, 26.8, 19.2, 17.0, 15.7, 12.3. HRMS (ESI):
m/z [M + NH4]+ calcd for C31H43N4O3Si: 547.3104; found:
547.3104.
(14) Matsumoto, A.; Sada, K.; Tashiro, K.; Miyata, M.; Tsubouchi, T.;
Tanaka, T.; Odani, T.; Nagahama, S.; Tanaka, T.; Inoue, K.;
Saragai, S.; Nakamoto, S. Angew. Chem. Int. Ed. 2002, 41, 2502.
(11) Zhao, M.; Li, J.; Song, Z.; Desmond, R.; Tschaen, D. M.;
Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 1998, 39, 5323.
(12) (a) Micoine, K.; Fürstner, A. J. Am. Chem. Soc. 2010, 132, 14064.
(b) AnkiReddy, S.; AnkiReddy, P.; Sabitha, G. Synthesis 2015, 47,
2860. (c) Gallenkamp, D.; Fürstner, A. J. Am. Chem. Soc. 2011,
133, 9232.
(15) (1R,2S)-3-Hydroxy-1,2-dimethylpropyl
(R)--Methyl-N-
[(2E,4E)-4-methylhexa-2,4-dienoyl]-L-phenylalaninate (16)
HF·pyridine (0.09 mL) was added dropwise to a stirred solution
of 2 (0.070 g, 0.1 mmol) in anhyd CH3CN (2 mL) at 0 °C, and the
mixture was stirred for 12 h. The reaction was then quenched
by adding sat. aq NaHCO3 (1 mL) and the mixture was extracted
with EtOAc (3 × 5 mL). The organic extracts were washed with
brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
The residue was purified by column chromatography [silica gel,
EtOAc–hexane (25:75)] to give a pale-yellow liquid; yield: 0.030
g (85%); []D25 +20.33 (c 0.3, CHCl3).
(13) (1R,2S)-3-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dimethyl-
propyl (2S,3R)-2-Azido-3-phenylbutanoate (15)
To a stirred solution of azide 5 (0.200 g, 0.9 mmol), alcohol 6
(0.333 g, 0.9 mmol), and Et3N (0.4 mL, 2.9 mmol) in THF (5 mL)
was added 2,4,6-trichlorobenzoyl chloride (0.2 mL, 1.1 mmol) at
rt, and the mixture was stirred for 2 h. DMAP (0.238 g, 1.6
mmol) was added at rt, and the mixture was stirred for 6 h.
When the reaction was complete, the mixture was quenched
with sat. aq NaHCO3 and washed with brine. The organic layer
was dried (Na2SO4), filtered, and concentrated in vacuo. The
residue was purified by column chromatography [silica gel,
EtOAc–hexane (20:80)] to give a colorless oil; yield: 0.349 g,
(68%); []D25 +22.0 (c 0.5, CHCl3).
1H NMR (500 MHz, CDCl3):  = 7.33–7.23 (m, 5 H), 7.23 (d,
J = 7.0 Hz, 1 H), 5.95 (q, J = 7.0 Hz, 1 H), 6.15–6.10 (m, 1 H), 5.77
(d, J = 15.2 Hz, 1 H), 4.82–4.70 (m, 2 H), 3.54 (dd, J = 7.0, 11.4 Hz,
1 H), 3.40 (dd, J = 6.7, 11.4 Hz, 1 H), 3.26–3.20 (m, 1 H), 3.13 (dq,
J = 7.4, 7.7 Hz, 1 H), 1.86–1.80 (m, 1 H), 1.80 (d, J = 7.0 Hz, 3 H),
1.76 (s, 3 H), 1.40 (d, J = 7.1 Hz, 3 H), 0.87 (d, J = 7.0 Hz, 3 H), 0.78
(d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3):  = 172.0, 166.7,
146.9, 141.2, 135.6, 133.3, 128.4, 127.9, 127.2, 116.6, 73.6, 64.2,
58.2, 43.0, 40.4, 18.1, 16.8, 14.4, 13.2, 11.8. HRMS (ESI): m/z [M
+ H]+ calcd for C22H32NO4: 374.2331; found: 374.2328.
1H NMR (500 MHz, CDCl3):  = 7.67–7.62 (m, 4 H), 7.45–7.35 (m,
6 H), 7.25–7.17 (m, 5 H), 5.02–4.95 (m, 1 H), 3.80 (dd, J = 7.2,
14.9 Hz, 1 H), 3.56–3.40 (m, 2 H), 3.28–3.20 (m, 1 H), 1.93–1.74
(m, 1 H), 1.34 (d, J = 7.0 Hz, 3 H), 1.05 (d, J = 5.1 Hz, 3 H), 1.04
(s, 9 H), 0.87 (d, J = 6.4 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
© 2019. Thieme. All rights reserved. Synlett 2019, 30, A–D