Synthesis of Inducamides A and B

Article abstract of DOI:10.1021/acs.jnatprod.5b00889

The inducamides are a family of chlorinated alkaloids featuring an amide arising from union of an l-tryptophan to a rare chlorosalicylic acid unit, the production of which is linked to a chemically induced mutation in the RNA polymerase of Streptomyces sp

Full text of DOI:10.1021/acs.jnatprod.5b00889

Article
pubs.acs.org/jnp
Synthesis of Inducamides A and B
Lydia M. Scott and Jonathan Sperry*
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
S
* Supporting Information
ABSTRACT: The inducamides are a family of chlorinated alkaloids
featuring an amide arising from union of an L-tryptophan to a rare
chlorosalicylic acid unit, the production of which is linked to a
chemically induced mutation in the RNA polymerase of Streptomyces
sp. (SNC-109-M3). The synthesis of inducamides A and B has been
accomplished by the coupling of 6-hydroxy-3-chloro-2-methylbenzoic
acid with L-6-chlorotryptophan and L-tryptophan, respectively,
followed by ester hydrolysis. The spectroscopic data and optical
rotation for each synthetic sample confirm the structures of these silent secondary metabolites and their biosynthesis from L-
tryptophan.
he introduction of mutations into the ribosome or RNA
polymerase of actinomycetes can be used to activate
biosynthetic pathways that trigger the production of silent
secondary metabolites.1 A pertinent example is inducamides
A−C (1−3, Figure 1), chlorinated alkaloids recently isolated
production, and interestingly, the arene 4 is also present in the
spirotetronate antibiotic chlorothricin.4
T
An ongoing interest in the synthesis of halogenated alkaloids3
and the unique framework present in the inducamides led us to
pursue their synthesis, initially targeting inducamides A and B
(1 and 2) by the coupling of 6-hydroxy-3-chloro-2-methyl-
benzoic acid (4) with the tryptophan methyl esters 5a and 5b,
respectively, followed by ester hydrolysis (Scheme 1).
Scheme 1. Proposed Assembly of Inducamides A and B (1
and 2)
RESULTS AND DISCUSSION
■
Using a literature chlorination of a related substrate as a
guide,5,6 the chlorination of the known arene 67 with NCS
proceeded with the desired regioselectivity to give 7, confirmed
by NOE analysis and the splitting of the two aromatic protons
(J 8.9 Hz) (Scheme 2). Demethylation of 7 gave 8, which upon
ester hydrolysis delivered the desired salicylic acid 4.
Figure 1. Inducamides A−C (1−3) and 6-hydroxy-3-chloro-2-
methylbenzoic acid (4).
from the RNA polymerase (RNAP) mutant strain of
Streptomyces sp. named SNC-109-M3.2 The natural products
1−3 are assembled by the acylation of an L-tryptophan unit
with 6-hydroxy-3-chloro-2-methylbenzoic acid (4), followed by
lactonization in the case of inducamide C (3). As these natural
products are produced only by the mutant strains, it is likely
that the RNAP mutation triggers the chlorosalicylic acid
Special Issue: Special Issue in Honor of John Blunt and Murray
Munro
Received: October 5, 2015
© XXXX American Chemical Society and
American Society of Pharmacognosy
A
DOI: 10.1021/acs.jnatprod.5b00889
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
Scheme 2. Synthesis of 6-Hydroxy-3-chloro-2-methylbenzoic
Acid (4)
EXPERIMENTAL SECTION
■
Methyl 3-Chloro-6-methoxy-2-methylbenzoate (7). To a
stirred solution of methyl 2-methoxy-6-methylbenzoate (6)7 (67 mg,
0.37 mmol) in N,N,-dimethylformamide (1 mL) was added N-
chlorosuccinimide (60 mg, 0.45 mmol). After stirring for 3 days at
room temperature, the solution was diluted with ether (10 mL) and
washed with water (10 mL). The aqueous layer was then further
extracted with ether (2 × 10 mL), and the combined organic extracts
were dried (Na2SO4), filtered, and concentrated in vacuo. The crude
residue was purified by flash chromatography on silica gel eluting with
hexanes−toluene (1:9) to afford the title compound (62 mg, 0.29
mmol, 78%) as a pale yellow oil: HRMS found [M + Na]+ 237.0291,
[C10H1135ClO3 + Na]+ requires 185.0011; IR (neat) 2953, 1733, 1436,
1
1289, 1262, 1084, 662 cm−1; H NMR (400 MHz, CDCl3) δ 7.32 (1
H, d, J 8.9, ArH), 6.71 (1 H, d, J 8.9, ArH), 3.91 (3 H, s, Me), 3.80 (3
H, s, Me), 2.28 (3 H, s, Me); 13C NMR (100 MHz, CDCl3) δ 168.1
(CO), 155.0 (C), 134.1 (C), 130.7 (CH), 126.6 (C), 125.6 (C),
109.9 (CH), 56.2 (Me), 52.6 (Me), 17.3 (Me).
Methyl 3-Chloro-6-hydroxy-2-methylbenzoate (8). To a
solution of 7 (84 mg, 0.39 mmol) in dichloromethane (4 mL) was
added aluminum trichloride (209 mg, 1.57 mmol), and the resulting
solution heated to reflux for 12 h. The reaction mixture was quenched
with 1 M HCl (10 mL) and extracted with dichloromethane (3 × 10
mL). The combined organic extracts were dried (Na2SO4), filtered,
and concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel eluting with hexanes−ethyl acetate (4:1)
to afford the title compound (79 mg, 0.39 mmol, 100%) as a light
brown solid: mp 25−30 °C; HRMS found [M + Na]+ 223.0132,
[C9H935ClO3 + Na]+ requires 223.0139; IR (neat) 2954, 2925, 2854,
The synthesis of inducamide A (1) commenced with
subjecting the known 6-aminotryptophan 98 to a Sandmeyer
reaction to give 109 in 32% yield, accompanied by significant
amounts of dechlorination. Removal of both Boc groups from
10 gave 6-chlorotryptophan methyl ester 5a10,11 (Scheme 3).
Coupling of 5a with 4 gave amide 11, which upon ester
hydrolysis gave inducamide A (−)-1. Employing L-tryptophan
methyl ester 5b in the same coupling−hydrolysis sequence
delivered inducamide B (−)-2 via amide 12.12,13 The NMR
spectroscopic data of synthetic 1 and 2 were in excellent
agreement with those reported for the natural products (Table
1). The optical rotation of synthetic inducamide A (1)
correlated well with that of the natural product {[α]2D4 −12.0
(c 0.10, MeOH); lit.2 [α]D24 −18.0 (c 0.10, MeOH)}, whereas
the optical rotation of synthetic inducamide B (2) was in near
perfect agreement {[α]D22 −9.5 (c 0.10, MeOH; lit.2 [α]2D4 −10.0
(c 0.05, MeOH)}.
1
1665, 1439, 1211, 824, 679 cm−1; H NMR (400 MHz, CDCl3) δ
10.84 (1 H, s, OH), 7.40 (1 H, d, J 8.9, ArH), 6.81 (1 H, d, J 8.9,
ArH), 3.98 (3 H, s, Me), 2.59 (3 H, s, Me); 13C NMR (100 MHz,
CDCl3) δ 171.4 (CO), 160.8 (C), 137.8 (C), 135.1 (CH), 126.1
(C), 116.7 (CH), 114.3 (C), 52.6 (Me), 19.6 (Me).
3-Chloro-6-hydroxy-2-methylbenzoic Acid (4). A solution of 8
(80 mg, 0.40 mmol) in aqueous sodium hydroxide (1.4 M, 3.8 mL, 5.2
mmol) was heated to reflux for 2 h. After cooling to room
temperature, the reaction mixture was washed with ethyl acetate (10
mL), and the organic layer discarded. The remaining aqueous solution
was acidified to pH 2 with 1 M HCl and extracted with ethyl acetate (3
× 10 mL), and the combined organic extracts were dried (Na2SO4),
filtered, and concentrated in vacuo to afford the title compound (71
mg, 0.38 mmol, 95%), as a colorless solid: mp 154−157 °C; HRMS
found [M − H]− 185.0018, [C8H735ClO3 − H]− requires 185.0011; IR
In summary, the synthesis of inducamides A (−)-1 and B
(−)-2 has been achieved, confirming both the structure of these
silent secondary metabolites and their biosynthesis from L-
tryptophan. Synthetic studies toward the unusual 4-hydroxy-6-
chlorotryptophan14 present in inducamide C (and the alkaloid
itself) are in progress.
Scheme 3. Synthesis of Inducamides A (−)-1 and B (−)-2
B
DOI: 10.1021/acs.jnatprod.5b00889
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
a
Table 1. NMR Spectroscopic Data for Inducamides A (1) and B (2) in CD3OD
Inducamide A (-)-1 (R = Cl)
Inducamide B (-)-2 (R = H)
a
b
a
b
natural product
δH (J in HZ)
7.21, s
synthetic
δH (J in HZ)
7.22, s
natural product
synthetic
δH (J in HZ)
7.19, s
pos
δC
δC
δC
δH (J in HZ)
δC
2
125.7
111.9
120.5
120.2
128.2
111.5
138.3
127.6
28.3
125.71
112.0
120.5
120.3
128.3
111.5
138.4
127.7
28.3
124.6
111.1
119.3
119.7
122.3
112.2
138.0
128.8
28.4
7.19, s
124.7
111.0
119.3
119.8
122.4
112.2
138.1
128.8
28.4
3
4
7.62, d (8.5)
7.58, d (8.5)
7.63, d (7.9)
7.00, t (7.3)
7.08, t (7.3)
7.32, d (8.1)
7.62, d (7.8)
7.01, t (7.4)
7.09, t (7.4)
7.33, d (8.0)
5
6.97, dd (8.5, 1.8)
6.99, dd (8.5, 1.8)
6
7
7.31, d (1.8)
7.33, d (1.8)
8
9
10
3.43, dd (14.8, 4.6)
3.19, dd (14.8, 8.8)
4.87, dd (8.8, 4.6)
3.39, dd (14.9, 5.0)
3.22, dd (14.9, 8.5)
4.93, dd (8.5, 5.0)
3.41, dd (14.8, 5.0)
3.23, dd (14.8, 8.6)
4.93, dd (8.6, 5.0)
3.41, dd (14.9, 5.3)
3.24, dd (14.9, 8.5)
4.93, dd (8.5, 5.3)
11
13
14
15
16
17
18
19
20
21
55.0
170.3
127.5
154.3
115.5
131.2
125.6
135.2
175.4
17.1
54.8
170.3
127.6
154.4
115.5
131.2
125.70
135.3
175.1
17.1
55.1
170.3
127.6
154.4
115.5
131.2
125.6
135.2
175.5
17.0
54.8
170.3
127.6
154.4
115.5
131.2
125.7
135.3
175.2
17.0
6.66, d (8.8)
7.16, d (8.8)
6.66, d (8.7)
7.17, d (8.7)
6.66, d (8.8)
7.16, d (8.7)
6.66, d (9.0)
7.16, d (8.7)
2.07, s
2.09, s
2.06, s
2.07, s
a
b
1H and 13C NMR run at 600 and 100 MHz, respectively. 1H and 13C NMR run at 400 and 100 MHz, respectively.
1
(neat) νmax 3288, 2924, 1702, 1634, 1522, 1439, 1290, 1228, 743 cm−1;
1H NMR (400 MHz, (CD3)2SO) δ 7.26 (1 H, d, J 8.5, ArH), 6.74 (1
∼100%), as a pale green solid: H NMR (400 MHz, CD3OD) δ 7.50
(1 H, d, J 8.5, ArH), 7.40 (1 H, d, J 1.9, ArH), 7.22 (1 H, s, ArH), 7.06
(1 H, dd, J = 8.5, 1.9, ArH), 4.31−4.34 (1 H, m, CH), 3.80 (3 H, s,
Me), 3.30−3.46 (2 H, m, CH2), indole NH and NH2 not observed;
spectroscopic data consistent with the literature.11
H, d, J 8.5, ArH), 2.23 (3 H, s, Me), 2 × OH not observed; 13C NMR
(100 MHz, (CD3)2CO) δ 172.2 (C), 160.7 (C), 138.1 (C), 134.9
(CH), 126.0 (C), 117.5 (C), 117.2 (CH), 19.2 (Me).
(S)-Methyl 3-(6-Chloroindol-3-yl)-2-(3-chloro-6-hydroxy-2-
methylbenzamido)propanoate (11). To a solution of 4 (6.0 mg,
0.036 mmol) in DMF (0.2 mL) was added 1-hydroxy-7-azabenzo-
triazol (HOAt, 4.9 mg, 0.036 mmol) and EDC·HCl (10.4 mg, 0.054
mmol) at 0 °C, then warmed to room temperature. After stirring for 2
min, a solution of 5a (10.0 mg, 0.036 mmol) and triethylamine (0.01
mL, 0.072 mmol) in dichloromethane (0.2 mL) was added, and the
resulting solution stirred for 24 h at room temperature. Dichloro-
methane was added (5 mL), and the reaction mixture washed with
saturated NaHCO3 (2 × 5 mL), brine (5 mL), and water (5 mL). The
organic extract was dried (Na2SO4), filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography on
silica gel eluting with dichloromethane−ethyl acetate (19:1) to afford
the title compound (6.7 mg, 0.016 mmol, 44%), as a yellow oil: [α]D23
+18.8 (c 0.6, CHCl3); HRMS found [M + Na]+ 443.0541,
[C20H1835Cl2N2O4 + Na]+ requires 443.0536; IR (neat) νmax 3316,
Methyl N,1-Bis(tert-butoxycarbonyl)-6-chloro-L-tryptopha-
nate (10). To a solution of 98 (348 mg, 0.80 mmol) in acetonitrile
(3.3 mL) was added p-toluenesulfonic acid monohydrate (457 mg, 2.4
mmol) at 10 °C. After stirring for 10 min, a solution of sodium nitrite
(124 mg, 1.8 mmol) in water (0.55 mL) was added dropwise,
immediately followed by cuprous chloride (158 mg, 1.6 mmol) in one
portion. The reaction mixture was then stirred for 10 min at 10 °C and
warmed to room temperature. After stirring for 2 h, a further batch of
cuprous chloride (158 mg, 1.6 mmol) was added. The reaction was
stopped after stirring for a further 12 h at room temperature by
addition to an ice/water mix (30 mL). The aqueous layer was then
extracted with ethyl acetate (3 × 20 mL), and the combined organic
extracts were washed with brine (2 × 30 mL). The organic layer was
dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue
was purified by flash chromatography on silica gel eluting with
dichloromethane−ethyl acetate (19:1) to afford the title compound
(116 mg, 0.26 mmol, 32%), as pale yellow crystals: mp 80−82 °C;
1
2926, 2854, 1737, 1639, 1440, 1292, 1218, 809 cm−1; H NMR (400
{[α]D24 +40.7 (c 0.14, CHCl3), lit.10 [α]D27+41.2 (c 1.30, CHCl3)}; H
1
MHz, CDCl3) δ 9.60 (1 H, s, OH), 8.12 (1 H, br s, NH), 7.41 (1 H, d,
J 8.5, ArH), 7.35 (1 H, d, J 1.7, ArH), 7.28 (1 H, d, J 8.8, ArH), 7.06 (1
H, dd, J 8.5, 1.9, ArH), 7.00 (1 H, d, J 2.4, ArH), 6.77 (1 H, d, J 8.8,
ArH), 6.42 (1 H, d, J 7.4, CONH), 5.07−5.12 (1 H, m, CH), 3.78 (3
H, s, OMe), 3.48 (1 H, dd, J 15.0, 5.4, CH2), 3.38 (1 H, dd, J 15.0, 5.7,
CH2), 2.27 (3 H, s, Me); 13C NMR (100 MHz, CDCl3) δ 172.2 (CO),
168.9 (CO), 156.9 (C), 136.6 (C), 133.3 (C), 132.1 (CH), 128.7 (C),
126.2 (C), 126.1 (C), 123.5 (CH), 120.9 (CH), 120.3 (C), 119.5
(CH), 116.6 (CH), 111.5 (CH), 110.1 (C), 53.5 (CH), 53.0 (Me),
27.3 (CH2), 18.5 (Me).
NMR (400 MHz, CDCl3) δ 8.15 (1 H, br s, ArH), 7.38 (1 H, d, J 8.4,
ArH), 7.36 (1 H, s, ArH), 7.22 (1 H, dd, J 8.4, 1.7, ArH), 5.10 (1 H, d,
J 7.9, CONH), 4.61−4.64 (1 H, m, CH), 3.69 (3 H, s, Me), 3.12−3.26
(2 H, m, CH2), 1.67 (9 H, s, 3 × Me), 1.43 (9 H, s, 3 × Me);
spectroscopic data consistent with the literature.10
Methyl 6-Chloro-L-tryptophanate Hydrochloride (5a). A
solution of 10 (58 mg, 0.13 mmol) in 4 M HCl in dioxane (1 mL,
4.0 mmol) was stirred for 18 h at room temperature. The solution was
concentrated in vacuo to afford the title compound (38 mg, 0.13 mmol,
C
DOI: 10.1021/acs.jnatprod.5b00889
J. Nat. Prod. XXXX, XXX, XXX−XXX

Journal of Natural Products
Article
(S)-Methyl 2-(3-Chloro-6-hydroxy-2-methylbenzamido)-3-
(indol-3-yl)propanoate (12). To a suspension of 4 (100 mg, 0.50
mmol) and 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-
b]pyridinium 3-oxid hexafluorophosphate (HATU) (285 mg, 0.75
mmol) in dichloromethane (15 mL) was added N,N-diisopropylethyl-
amine (0.26 mL, 1.5 mmol). After stirring for 10 min, L-tryptophan
methyl ester (5b) (HCl salt, 127 mg, 0.49 mmol) was added in one
portion, and the resulting mixture stirred for 3 days at room
temperature. Dichloromethane was added (20 mL), and the whole
washed with 1 M HCl (20 mL), saturated NaHCO3 (20 mL), and
brine (20 mL). The organic extract was dried (Na2SO4), filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel eluting with dichloromethane−ethyl
acetate (19:1) to afford the title compound (70 mg, 0.18 mmol, 36%),
as a colorless solid: mp 70−73 °C; [α]1D7 +100.7 (c 1.0, CHCl3);
HRMS found [M + Na]+ 409.0927, [C20H1935ClN2O4 + Na]+ requires
409.0926; IR (neat) νmax 3408, 2953, 1760, 1696, 1435, 1345, 1265,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the University of Auckland for financial support.
■
DEDICATION
■
Dedicated to Professors John Blunt and Murray Munro, of the
University of Canterbury, for their pioneering work on
bioactive marine natural products.
REFERENCES
■
(1) (a) Ochi, K.; Okamoto, S.; Tozawa, Y.; Inaoka, T.; Hosaka, T.;
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1
734 cm−1; H NMR (400 MHz, (CD3)2CO) δ 9.99 (1 H, br s, OH),
7.77 (1 H, d, J 8.9, ArH), 7.55 (1 H, d, J 8.0, ArH), 7.29 (1 H, d, J 8.0,
ArH), 7.19−7.17 (2 H, m, 2 × ArH), 7.00 (1 H, t, J 7.5, ArH), 6.91 (1
H, t, J 7.5, ArH), 5.80−5.85 (1 H, dd, J 9.6, 5.7, CH), 3.56−3.75 (5 H,
m, CH2 + Me), 2.68 (3 H, s, Me), 2 × NH not observed; 13C NMR
(100 MHz, (CD3)2CO) δ 160.8 (C), 153.3 (C), 147.7 (C), 140.2 (C),
137.6 (C), 136.9 (CH), 132.5 (C), 128.5 (C), 124.8 (CH), 122.2
(CH), 119.7 (CH), 119.0 (CH), 116.7 (CH), 114.5 (C), 112.3 (CH),
111.0 (C), 56.8 (CH), 52.7 (Me), 24.8 (Me), 17.7 (CH2).
(4) (a) Keller-Schierlein, W.; Muntwyler, R.; Pache, W.; Zahner, H.
Helv. Chim. Acta 1969, 52, 127−142. (b) Jia, X. Y.; Tian, Z. H.; Shao,
L.; Qu, X. D.; Zhao, Q. F.; Tang, J.; Tang, G. L.; Liu, W. Chem. Biol.
2006, 13, 575−585.
(−)-Inducamide A (1). To a solution of 11 (5.0 mg, 0.012 mmol)
in methanol (0.5 mL) was added 1 M NaOH (0.024 mL, 0.024
mmol), and the reaction mixture stirred at room temperature for 2 h.
The methanol was removed in vacuo, and the aqueous residue diluted
with water (1 mL) and then basified to pH 9 with NaHCO3. The
resulting mixture was washed with ethyl acetate (2 mL), and the
organic phases were discarded. The aqueous layer was then acidified to
pH 2 (1 M HCl) and extracted with ethyl acetate (3 × 3 mL). The
combined organic extracts were dried (Na2SO4), filtered, and
concentrated in vacuo to afford the title compound (3.8 mg, 0.009
mmol, 78%) as a colorless oil: {[α]2D4 −12.0 (c 0.10, MeOH); lit.2 [α]2D4
−18.0 (c 0.10, MeOH)}; HRMS found [M − H]− 405.0407,
[C19H1635Cl2N2O4 − H]− requires 405.0414; IR (neat) 3318, 2925,
(5) For the chlorination of ethyl 2-hydroxy-6-methylbenzoate using
chlorine, see: Dey, S.; Mal, D. Tetrahedron 2006, 62, 9589−9602.
(6) For other approaches to compounds similar to 4, see:
(a) Muntwyler, R.; Widmer, J.; Keller-Schierlein. Helv. Chim. Acta
1970, 53, 1544−1547. (b) He, Q.-L.; Jia, X.-Y.; Tang, M.-C.; Tian, Z.-
H.; Tang, G.-L.; Liu, W. ChemBioChem 2009, 10, 813−819.
(7) Senthilmurugan, A.; Aidhen, I. S. Eur. J. Org. Chem. 2010, 2010,
555−564.
(8) Li, B. T. Y.; White, J. M.; Hutton, C. A. Aust. J. Chem. 2010, 63,
438−444.
1
2854, 1716, 1634, 1441, 1290, 805 cm−1; H and 13C NMR data see
(9) Compound 10 has been prepared by a heteroannulation process,
but we found the Sandmeyer approach employed herein gave better
overall yields; see: Shibahara, S.; Matsubara, T.; Takahashi, K.;
Ishihara, J.; Hatakeyama, S. Org. Lett. 2011, 13, 4700−4703.
(10) For the synthesis of optically active 6-chlorotryptophan
derivatives, see: (a) Sato, K.; Kozikowski, A. P. Tetrahedron Lett.
1989, 30, 4073−4076. (b) Goss, R. J. M.; Newill, P. L. A. Chem.
Commun. 2006, 4924−4925. (c) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71,
7826−7834. (d) Tanaka, M.; Hikawa, H.; Yokoyama, Y. Tetrahedron
2011, 67, 5897−5901.
Table 1.
(−)-Inducamide B (2). To a solution of 12 (70 mg, 0.18 mmol) in
methanol (6 mL) was added 1 M NaOH (0.36 mL, 0.36 mmol). After
stirring for 2 h, the solution was then basified to pH 9 with NaHCO3,
the aqueous layer washed with ethyl acetate (10 mL), and the organic
layer discarded. The aqueous layer was acidified to pH 2 with 1 M HCl
and extracted with ethyl acetate (3 × 10 mL), and the combined
organic extracts were dried (Na2SO4), filtered, and concentrated in
vacuo to afford the title compound (65 mg, 0.17 mmol, 97%), as a
colorless solid: mp 118−122 °C; {[α]2D2 −9.5 (c 0.1, MeOH); lit.2
[α]2D4 −10.0 (c 0.05, MeOH)}; HRMS found [M + Na]+ 396.0769,
[C19H1735ClN2O4 + Na]+ requires 396.0771; IR (neat) νmax 3288,
(11) Compound 5a has been previously prepared biocatalytically;
see: Oelke, A. J.; Antonietti, F.; Bertone, L.; Cranwell, P. B.; France, D.
J.; Goss, R. J. M.; Hofmann, T.; Knauer, S.; Moss, S. J.; Skelton, P. C.;
Turner, R. M.; Wuitschik, G.; Ley, S. V. Chem. - Eur. J. 2011, 17,
4183−4194.
(12) The base-mediated ester hydrolysis led exclusively to the desired
hydroxy acid, with no lactonization observed (e.g., to the seven-
membered ring present in inducamide C).
1
2924, 1702, 1634, 1522, 1439, 1290, 1228, 743 cm−1; H and 13C
NMR data see Table 1.
ASSOCIATED CONTENT
■
S
* Supporting Information
(13) The low yield for the amide coupling steps can be attributed to
the hindered nature of carboxylic acid 4.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.jnat-
prod.5b00889.
(14) 4-Hydroxy-6-chlorotryptophan is incorporated during the
biosynthesis of several nonribosomal peptides isolated from other
strains of Streptomyces sp.; see: (a) Motohashi, K.; Takagi, M.; Shin-ya,
K. J. Nat. Prod. 2010, 73, 226−228. (b) Muliandi, A.; Katsuyama, Y.;
Sone, K.; Izumikawa, M.; Moriya, T.; Hashimoto, J.; Kozone, I.;
Takagi, M.; Shin-ya, K.; Ohnishi, Y. Chem. Biol. 2014, 21, 923−934.
(c) Izumikawa, M.; Kawahara, T.; Kagaya, N.; Yamamura, H.;
Hayakawa, M.; Takagi, M.; Yoshida, M.; Doi, T.; Shin-ya, K.
Tetrahedron Lett. 2015, 56, 5333−5336.
1H and 13C NMR spectra for all novel compounds
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.sperry@auckland.ac.nz.
D
DOI: 10.1021/acs.jnatprod.5b00889
J. Nat. Prod. XXXX, XXX, XXX−XXX