solation and Total Synthesis of Stolonines A–C, Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

.

Figure 1. Structures of stolonines A-C (1–3), 11-hydroxyascididemin (4) and cnemidine A (5) isolated from the tunicate C. stolonifera.

Table 1. NMR data for 1 in DMSO-d6 a.

Position	δC	δH (J in Hz)	gCOSY	gHMBCAD
1		12.20, br.s	2
2	138.5	8.82, d (3.0)	1	3, 3a, 7a
3	112.1
3a	126.2
4	121.3	8.22, dd (1.8, 7.2)	5	6, 7a
5	122.4	7.24, dt (1.8, 7.2)	4, 6	3a, 7
6	123.3	7.26, dt (1.8, 7.2)	5, 7	4, 7a
7	112.5	7.52, dd (1.8, 7.2)	6	3a, 5
7a	136.2
8	181.6
9	162.7
10		8.78, t (5.4)	11	9
11	35.5	3.50, dd (6.0, 6.6)	10, 12	9, 12
12	49.8	2.66, t (6.6)	11	11

a 1H NMR at 600 MHz referenced to residual DMSO solvent (δH 2.50 ppm) and 13C NMR at 150 MHz referenced to residual DMSO solvent (δC 39.52 ppm).

Stolonine A (1) was obtained as a white amorphous solid. The (−)-HRESIMS spectrum displayed a molecular ion [M−H]−at m/z 295.0390, which was consistent with the molecular formula C12H12N2O5S. The IR spectrum indicated the presence of an S=O stretching band at 1205 cm−1 [16]. A 1H NMR spectrum of 1 showed two exchangeable protons (δH 12.20 and 8.78 ppm), five aromatic protons (δH 8.82, 8.22, 7.52, 7.26 and 7.24 ppm) and two methylenes (δH 3.50 and 2.66 ppm). Further analysis of the 13C NMR and gHSQCAD spectra indicated that the molecule contained two carbonyls (δC 181.6 and 162.7 ppm), eight aromatic carbons (δC 138.5, 136.2, 126.2, 123.3, 122.4, 121.3, 112.5 and 112.1 ppm) and two methylenes (δC 49.8 and 35.5 ppm) (Table 1). J coupling constants of aromatic protons H-4 (δH 8.22, dd, 1.8, 7.2 Hz), H-5 (δH 7.24, dt, 1.8, 7.2 Hz), H-6 (δH 7.26, dt, 1.8, 7.2 Hz) and H-7 (δH 7.52, dd, 1.8, 7.2 Hz) and their COSY correlations were characteristic of a 1,2-disubstituted benzene ring (a, Figure 2). A gCOSY spectrum displayed correlations from the exchangeable proton H-1 (δH12.20, br.s) to H-2 (δH 8.82, d, 3.0 Hz) and also from H-11 (δH 3.50, dd, 6.0, 6.6 Hz) to the triplet exchangeable proton H-10 (δH 8.78, t, 5.4 Hz) and H-12 (δH 2.66, t, 6.6 Hz) facilitating the establishment of two other spin systems, –NH–CH= (b,Figure 2) and –NH–CH2–CH2– (c, Figure 2) respectively. The aromatic carbon C-3 (δC 112.1 ppm) was attached to C-2 (δC138.5 ppm) in the moiety b determined by a HMBC correlation from H-2 to C-3. A HMBC correlation from H-2 to C-7a (δC136.2 ppm) supported the linkage from a to b at C-7a (Figure 2). Both protons H-10 and H-11 in the moiety c showed HMBC correlations with a carbonyl carbon at δC 162.7 ppm suggesting the connection of this carbonyl to N-10 to form an amide bond (c, Figure 2). Two methylene signals at δH 3.50 and 2.66 ppm corresponding to carbons C-11 (δC 35.5 ppm) and C-12 (δC 49.8 ppm) as well as the relatively downfield resonance of the methylene C-12 were diagnostic of methylenes in a taurine moiety (c, Figure 2) [17,18,19].

Table 1. NMR data for 1 in DMSO-d6 a.

Figure 2. Partial structures (a, b and c) of 1 and their key HMBC correlations.

Figure 2. Partial structures (a, b and c) of 1 and their key HMBC correlations.

No HMBC correlation from any proton to the carbonyl C-8 (δC 181.6 ppm) was observed when HMBC experiments were performed and optimized with different JHC couplings. Therefore, two different isomers 1-I and 1-II were conceivable from these data (Figure 3). Detailed HMBC analysis showed that H-2 had a HMBC correlation with C-3a (δC 126.2 ppm). This suggested that 1 was favorable to 1-I since the H-2 to C-3a correlation in 1-I was a three-bond coupling while the H-2 to C-3a correlation in 1-II was a four-bond coupling (Figure 3).

Figure 3. Two possible structures 1-I and 1-II of 1 (1-I and 1-II are possible structural isomers of 1).

Figure 3. Two possible structures 1-I and 1-II of 1 (1-I and 1-II are possible structural isomers of 1).

Table 2. Comparison of experimental and calculated 13C and 1H chemical shifts for 1 in DMSO-d6.

Position	δC (Exp.)	1-I		1-II		δH (Exp.)	1-I		1-II
		δC (Calc.)	δC (Scaled)	δC (Calc.)	δC (Scaled)		δH (Calc.)	δH (Scaled)	δH (Calc.)	δH (Scaled)
2	138.5	136.9	140.3	141.3	142.8	8.82	8.74	8.61	8.84	8.67
3	112.1	111.5	112.9	111.2	110.2
3a	126.2	124.1	126.5	123.0	122.9
4	121.3	118.9	120.9	124.3	124.4	8.22	8.62	8.48	8.40	8.19
5	122.4	120.1	122.1	121.1	120.9	7.24	7.63	7.40	7.63	7.35
6	123.3	120.9	123.0	129.4	129.9	7.26	7.59	7.36	8.00	7.76
7	112.5	108.7	109.9	114.8	114.1	7.52	7.55	7.31	7.53	7.24
7a	136.2	131.9	134.9	134.4	135.3
8	181.6	176.7	183.2	172.5	176.5
9	162.7	156.8	161.7	159.4	162.4
11	35.5	37.1	32.6	36.9	29.8	3.50	3.69	3.11	3.71	3.08
12	49.8	57.2	54.4	58.4	53.1	2.66	3.55	2.95	3.57	2.93
CMAE			1.5		3.1			0.23		0.25
DP4		100.0%		0.0%			85.3%		14.7%

Stolonine A (1): white, amorphous solid; UV (MeOH) λmax (log ε) 210 (3.8), 252 (3.5) and 325 (3.3) nm; IR (film) νmax 3307, 1681, 1205, 1049 and 802 cm−1; 1H (600 MHz, DMSO-d6) and 13C (150 MHz, DMSO-d6) NMR data are summarized in Table 1; (−)-HRESIMS m/z 295.0390 [M − H]− (calcd for [C12H11N2O5S]−, 295.0394, Δ −1.4 ppm).

Mar. Drugs 2015, 13(7), 4556-4575; doi:10.3390/md13074556

Article

Isolation and Total Synthesis of Stolonines A–C, Unique Taurine Amides from the Australian Marine Tunicate Cnemidocarpa stolonifera

Trong D. Tran 1, Ngoc B. Pham 1, Merrick Ekins 2, John N. A. Hooper 1,2 and Ronald J. Quinn 1,*

1

Eskitis Institute for Drug Discovery, Griffith University, Brisbane, Queensland 4111, Australia

2

Queensland Museum, Brisbane, Queensland 4101, Australia

*

Author to whom correspondence should be addressed; Tel.: +61-7-3735-6009; Fax: +61-7-3735-6001.

http://www.mdpi.com/1660-3397/13/7/4556/htm
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