3822
A. Bishara et al. / Tetrahedron Letters 50 (2009) 3820–3822
38
H3C
H3C
36
26
26
O
33
34
N
H
O
CH3
21
N
Ph
N
32
H
N
21
N
H
H
O
H
O
18
18
33
13
13
N
17
17
O
H
O
N 32
N N
H C
O
3
CH3
O
CH3
Tulearin A (1)
O
+
34
30
29
29
1
1
38
CH2Cl2, r.t.
O
10
10
OH HO
OH HO
H3C
H3C
27
O
O
4
8
4
8
36
O
O
31
31
NH2
NH2
CH3
CH3
28
28
3
4
Scheme 1. Diels–Alder reaction of tulearin A (1) with N-phenyltriazolinedione.
COSY, and HSQC spectra) see Supplementary data.Crystal data:
M = 518.71, orthorhombic, space group P212121, a = 5.4308(3), b = 10.5353(6),
c = 53.487(3) Å, V = 3060.3(3) Å3, Z = 4, T = 110(2) K, Dc = 1.126 g cmꢁ3
(MoK
) = 0.076 mmꢁ1, 3152 unique reflections to 2hmax = 50.7°, 340 refined
C31H50O6,
Characteristics in the NMR spectra of both adducts were the
replacement of the C-18,20-diene system by a single trisubstituted
double bond and the appearance of the expected N-phenyl group.
The differences between 3 and 4 are in the configurations of C-
18 and C-21 as a result of cycloaddition from above or below the
plane of the molecule.12 The stereochemistry of 3 and 4, as de-
picted in Scheme 1, was deduced from NOEs around the C-17/18
bond. Namely, compound 3 exhibits NOEs between H-17 and H-
18, CH3-29, CH3-30, as well as between CH3-27 and the phenyl
H-36 (Scheme 1). While, only two NOEs between H-17 and H-18,
CH3-29 were observed in compound 4. The change in the C-17-
18 coupling constant, that is, 4 Hz and less than 1 Hz for 3 and 4,
respectively, pointed to changes in the rotamer population around
the C-17-18 bond.
Two additional tulearins obtained from the Fascaplysinopsis sp.
in very minor amounts were designated as tulearin B (5) and C
(6).13,14 Tulearin B was determined to be the 3,8-dicarbamate ana-
log of tulearin A and tulearin C (6) the 3,8,9-trihydroxy precursor of
compounds 1 and 5. Both 5 and 6 exhibited the appropriate molec-
ular peaks in the CIMS. Characteristic for 5 was the shift of the C-3
methine to dC 70.7 (d, C-3) and dH 5.10 (dd, J = 8.7, 3.2 Hz) and for 6
was the shift of methine C-8 to dC 72.3 (d, C-8) and dH 3.30 (m).14
In summary, establishment of the relative and absolute config-
urations of tulearins A–C opens the way for synthetic work toward
these biologically interesting compounds.
,
l
a
parameters, R1 = 0.049 for 2142 observations with I > 2
(wR2 = 0.132) for all unique data. CCDC 721796.
r(I), R1 = 0.088
5. Nicolaou, K. C.; Sun, Y. P.; Guduru, R.; Banerji, B.; Chen, D. Y.-K. J. Am. Chem. Soc.
2008, 130, 3633–3644. similar acidic conditions left 1 intact. A suggested
mechanism for the latter transformation under aqueous basic conditions is
depicted in Supplementary data.
6. Koepper, S.; Thiem, J. J. Carbohydr. Chem. 1987, 6, 57–85.
7. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
8. Interestingly, as with esterification with MTPA, the reactions of tulearin A (1)
with p-TsCl in pyridine, at rt for 48 h, and with (CF3CO)2O in Et3N, at rt for 24 h,
gave the 9-tosylate and the 9-trifluoroacetate in 70% and 80% yields,
respectively.
9. The similar J8,9 values for 1,1R,1S (3.9, 5.1 and 4.7 Hz, respectively) suggest that
no significant changes in the conformation around the esterification site took
place.
10. For the experimental, preparation, and NMR data, including 2D spectra, see the
Supplementary data.
11. (a) Cycloaddition product (3): colorless oil; ½a D25
ꢂ
ꢁ23 (c 0.2, CHCl3). 1H and 13C
NMR data for the substituted region (C-17)–(C-22): [dC 69.8 (d, C-17), dH 5.62
(dd, J = 11.3, 3.9 Hz); dC 58.1 (d, C-18), dH 4.51 (d, J = 3.9 Hz); dC 131.4 (s, C-19);
dC 123.9 (d, C-20), dH 5.70 (s); dC 56.7 (d, C-21), dH 4.30 (br s); dC 39.4 (t, C-22),
dH 1.74 (m)], dC 21.6 (q, C-30), dH 1.91 (s). N-phenyltriazolinedione substituent:
[dC 153.4 (s, C-32); dC 149.2 (s, C-33); dC 129.3 (s, C-34); dC 125.5 (d, C-35, 39),
dH 7.48 (d, J = 8.4 Hz); dC 129.0 (d, C-36, 38), dH 7.44 (d, J = 8.4 Hz); dC 128.0 (d,
C-37), dH 7.34 (t, J = 7.1 Hz)]. FABMS m/z 711.0 [M+H]+ (80), 733.0 [M+Na]+
(100). (b) Cycloaddition product (4): colorless oil; ½a D25
ꢂ
ꢁ19 (c 0.2, CHCl3). 1H
and 13C NMR data for the substituted region (C-17)–(C-22): [dC 69.4 (d, C-17),
dH 5.32 (d, J = 11.0 Hz); dC 56.5 (d, C-18), dH 4.78 (br s); dC 131.5 (s, C-19); dC
123.5 (d, C-20), dH 5.72 (s); dC 57.3 (d, C-21), dH 4.30 (br s); dC 36.6 (t, C-22), dH
1.90 (m), 1.23 (m)], dC 20.7 (q, C-30), dH 1.95 (s). N-phenyltriazolinedione
substituent: [dC 154.3 (s, C-32); dC 149.0 (s, C-33); dC 128.2 (s, C-34); dC 125.4
(d, C-35, 39), dH 7.54 (d, J = 8.4 Hz); dC 129.0 (d, C-36, 38), dH 7.60 (d, J = 8.4 Hz);
dC 127.9 (d, C-37), dH 7.32 (t, J = 7.1 Hz)]. FABMS m/z 711.0 [M+H]+ (15), 733.0
[M+Na]+ (100). For experimental, syntheses, and NMR data, including 2D
spectra, see the Supplementary data.
Supplementary data
Supplementary data associated with this paper can be found, in
12. From the observed NOEs between CH3-27 and H-36; and between CH3-30 and
H-17, of 3, requiring a planar rotamer and as no changes were observed with
temperature, atropoisomers were excluded.
References and notes
13. Tulearin B (5): yellow amorphous powder; ½a D26
ꢂ
ꢁ37 (c 0.13, CHCl3); IR (CHCl3)
1. Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.; Kashman, Y. Org.
Lett. 2008, 10, 153–456.
2. Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.; Kashman, Y.
Tetrahedron Lett. 2008, 49, 4355–4358.
mmax 3679, 3430, 3020, 2960, 1726, 1602, 1582 cmꢁ1
.
1H and 13C NMR data
(acetone-d6) of the segment (C-1)–(C-4): [dC 172.1 (C-1); dC 43.9 (d, C-2), dH
2.73 (qd, J = 7.2, 3.2 Hz); dC 70.7 (d, C-3), dH 5.10 (dd, J = 8.7, 3.2 Hz); dC 39.8 (t,
C-4), dH 1.70 (m), 1.29 (m); dC 11.9 (C-27), dH 1.06 (d, J = 7.2 Hz)]. HRCIMS m/z
579.4007 [M+H]+ (calcd for C32H55N2O7 579.4009).
3. Bishara, A.; Rudi, A.; Aknin, M.; Neumann, D.; Ben-Califa, N.; Kashman, Y. Org.
Lett. 2008, 10, 4307–4309.
14. Tulearin C (6): Colorless oil; ½a D18
ꢂ
ꢁ18 (c 0.24, CHCl3); IR (CHCl3) mmax 3480,
4. Cyclic carbonate of tulearin A (2): Colorless crystals (methanol); ½a D25
ꢂ
+12 (c 0.3,
3020, 1750, 1616, 1216, 1032, 926 cmꢁ1
.
1H and 13C NMR data (acetone-d6) of
CHCl3). 1H and 13C NMR data for the changed segment (C-7)–(C-10); dC 31.5 (t,
C-7), dH 1.65 (m); dC 80.7 (d, C-8), dH 4.20 (td J = 6.3, 5.3 Hz); dC 79.7 (d, C-9), dH
4.30 (tdd, J = 6.8, 5.3, 1.2 Hz); dC 32.3 (t, C-10), dH 1.95 (m), 1.67 (m); dC 154.5 (s,
C-31). FABMS m/z 519 [M+H]+ (100), 541 [M+Na]+ (45). For NMR data (1H, 13C,
the segment (C-7)–(C-10): [dC 29.3 (t, C-7), dH 1.23 (m); dC 72.3 (d, C-8), dH 3.30
(dd, J = 8.7, 3.2 Hz); dC 70.4 (d, C-9), dH 3.46 (m); dC 32.1 (m, C-10), dH 1.59 (m)].
HRCIMS m/z 493.3879 [M+H]+ (calcd for C30H52O5 493.3893).