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Scheme 6. Total synthesis of Eudistomin Y5 (9) and Y6 (10).
25. (a) Wolfe, J.P. Bischler-Napieralski Reaction in Name Reactions in Heterocyclic
Chemistry 2005, p 376; (b) Pal, B.; Jaisankar, P.; Giri, V. S. Synth. Commun. 2003,
33, 2339.
strates performed poorly in the microwave-assisted Bischler–Napi-
eralski and MnO2 oxidation reactions.
26. Representative
hydroxyphenylacetic acid 17 (0.94 g, 6.2 mmol), and N-hydroxybenzotriazole
(1.76 g, 13.0 mmol) were added to 250 ml round-bottomed flask, and
experimental.
Tryptamine
16
(1 g,
6.2 mmol),
4-
In every case, the 1H and 13C NMR spectra of the synthetic Eud-
istomins Y1–Y6 matched that reported for the natural products (5–
10).27 Attempts to prepare Eudistomin Y7 failed employing this
methodology, due perhaps to stereoelectronic effects and or solu-
bility issues of the polybrominated scaffold. Overall yields for the
three-step, two-pot process were low, but not unexpected based
on the electronics of the system with the carbonyl moiety at C1.
For the Bischler–Napieralski and MnO2 oxidation steps, thermal
conditions failed entirely. Only MAOS provided the desired Eudis-
tomin scaffold, but in modest to poor yields.
a
dissolved in 9:1 DMF/DIEA (50 ml). 1-Ethyl-3-(3-dimethylaminopropyl)-
carbodiimide hydrochloride (3.6 g, 18.6 mmol) was then added and the
reaction was allowed to stir overnight. Once complete the reaction was
quenched with 1 N HCl and extracted three times with DCM (100 ml). The
organic layer was dried with MgSO4, filtered, and concentrated. The crude
residue was purified by column chromatography to yield coupled product 18
(1.39 g, 4.7 mmol) in 76% yield.
Coupled product 18 (0.25 g, 0.850 mmol) was added to a 5 ml microwave vial
and dissolved in toluene (3 ml). POCl3 (0.79 ml, 8.50 mmol) was then added all
at once and the reaction vessel capped, and heated to 120 °C for 30 min. Once
complete the toluene was removed and the reaction quenched with satd
NaHCO3 and extracted three times with DCM (100 ml). The organic layer was
dried with MgSO4, filtered and concentrated to obtain 21 which was used
without further purification.
Thus, the first total synthesis of Eudistomins Y1–Y6 (5–10) has
been completed, requiring only three synthetic steps in a two-
pot process and with overall yields ranging from 6% to 25%. We
are currently evaluating 5–10 against a large panel of discrete
molecular targets in radioligand binding assays,28 and we are in
the process of initiating a diversity-oriented synthesis campaign
to synthesize libraries of unnatural analogs.29 These efforts are
underway and will be reported in due course.
Crude 21 (100 mg, 0.362 mmol), was added to a 20 ml MW vial and partially
dissolved in DCE (10 ml). MnO2 (315 mg, 3.62 mmol) was then added all at
once and the reaction vessel capped and heated to 160 °C for 60 min. Once
complete the reaction was vacuum filtered, concentrated, and purified by
preparative HPLC to obtain 5 (32.4 mg, 0.112 mmol) in 31% yield.
27. NMR (1H and 13C), Hi-RES MS data for Y1–Y6. Eudistomins Y1: 1H NMR
(400 MHz, DMSO-d6)
d 10.39 (br s, 1H), 8.51 (d, J = 5.2 Hz, 1H), 8.41 (d,
J = 5.2 Hz, 1H), 8.31 (d, J = 7.6 Hz, 1H), 8.24 (dt, J = 8.8, 2.8 Hz, 2H), 7.77 (d,
J = 8.4 Hz, 1H), 7.59 (t, J = 7.2 Hz, 1H), 7.30 (t, J = 7.2 Hz, 1H), 6.92 (dt, J = 8.8,
2.4 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) d 191.6, 161.9, 141.6, 137.3, 136.7,
135.6, 133.7, 130.8, 128.9, 128.2, 121.8, 120.1, 120.0, 118.2, 114.9, 112.9. HRMS
(Q-TOF): m/z calcd for C18H13N2O2 [M+H+]: 289.0977, found: 289.0973.
Eudistomins Y2: 1H NMR (400 MHz, DMSO-d6) d 10.42 (br s, 1H), 8.53 (d,
J = 5.2 Hz, 1H), 8.45 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 8.8 Hz, 2H), 7.72 (s, 2H), 6.91
(d, J = 8.8 Hz, 2H).). 13C NMR (150 MHz, DMSO-d6) d 191.1, 161.9, 140.2, 137.7,
137.1, 135.7, 133.7, 131.2, 129.7, 128.0, 124.4, 122.0, 118.7, 114.8, 112.0. HRMS
(Q-TOF): m/z calcd for C18H12N2O2Br [M+H+]: 367.0082, found: 367.0081.
Eudistomins Y3: 1H NMR (400 MHz, DMSO-d6) d 11.30 (s, 1H), 8.56 (m, 2H),
8.44 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.33 (m, 1H), 7.78 (d, J = 8.4 Hz,
1H), 7.60 (m, 1H), 7.30 (m, 1H), 7.12 (d, 8.4 Hz, 1H). 13C NMR (150 MHz, DMSO-
d6) d 190.2, 158.6, 141.6, 137.0, 136.7, 136.4, 135.7, 132.5, 131.0, 129.6, 128.9,
121.8, 120.1, 120.0, 118.7, 115.6, 112.9, 108.8. HRMS (Q-TOF): m/z calc for
C18H12N2O2Br [M+H+]: 367.0082; found: 367.0082.
Acknowledgments
The authors warmly thank Department of Pharmacology for
support of this research. Vanderbilt is a member of the production
phase of the MLCSN, termed the MLPCN, and houses the Vanderbilt
Specialized Chemistry Center for Accelerated Probe Development
(1U54MH084659-01).
References and notes
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Eudistomins Y4: 1H NMR (400 MHz, DMSO-d6) d 10.38 (br s, 1H), 8.51 (d,
J = 4.8 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 6.8 Hz,
2H), 7.77 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 8.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.92
(d, J = 7.2 Hz, 2H). 13C NMR (150 MHz, DMSO-d6) d 190.6, 160.1, 140.6, 137.6,
137.4, 136.7, 133.7, 136.3, 131.7, 130.0, 128.9, 124.7, 121.8, 120.1, 115.9, 114.9,
112.9, 108.4. HRMS (Q-TOF): m/z calcd for C18H11N2O2Br2 [M+H+]: 444.9817;
found: 444.9817.
Eudistomins Y5: 1H NMR (400 MHz, DMSO-d6) d 10.15 (br s, 1H), 8.53 (m, 3H),
8.43 (m, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 9.2 Hz, 1H), 7.58 (t, J = 6.8 Hz,
1H), 7.28 (t, J = 8.0 Hz, 1H). 13C NMR (150 MHz, DMSO-d6) d 190.1, 157.8, 144.7,
138.8, 136.7, 135.9, 135.4, 135.1, 132.6, 130.9, 126.6, 121.4, 120.3, 120.1, 119.8,
113.7, 112.2, 110.7. HRMS (Q-TOF): m/z calcd for C18H10N2O2NaBr2 [M+Na+]:
466.9007, found: 466.9009.
Eudistomins Y6: 1H NMR (400 MHz, DMSO-d6) d 8.62 (br s, 1H), 8.58 (d,
J = 4.8 Hz, 1H), 8.52 (m, 3H), 7.75 (m, 2H). 13C NMR (150 MHz, DMSO-d6) d
189.2, 156.0, 140.8, 137.9, 136.4, 135.8, 135.2, 131.9, 130.6, 128.9, 126.6, 125.0,
122.5, 120.9, 120.0, 115.5, 112.7, 111.4. HRMS (Q-TOF): m/z calcd for
C18H10N2O2Br3 [M+H+]: 522.8292; found: 522.8287.
28. Kennedy, J. P.; Brogan, J. T.; Lindsley, C. W. J. Nat. Prod. 2008, 71,
1783.
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3204; (b) Lewis, J. A.; Daniels, N. R.; Lindsley, C. W. Org. Lett. 2008, 10,
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