Synthetic Studies toward Sarain A. Formation of the Western Macrocyclic Ring

Abstract

Starting with the tricyclic core 2b, annulation to form the 13-membered western ring of sarain A has been achieved to afford the macrocycle 30a by initial construction of the sterically congested quaternary center at C-3, followed by elaboration of the C-3 side-chain and ring-closing olefin metathesis. Also included is a parallel conversion of tricycle 2c to macrocycle 30b containing a functionalized side-chain at N-1 suitable for attachment of the eastern macrocyclic ring.

A General Strategy for the Synthesis of Vincamajine-Related Indole Alkaloids: Stereocontrolled Total Synthesis of (+)-Dehydrovoachalotine, (−)-Vincamajinine, and (−)-11-Methoxy-17-epivincamajine as Well as the Related Quebrachidine Diol, Vincamajine Diol, and Vincarinol1

“…The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue that resulted was purified by preparative TLC on silica gel (CHCl 3/MeOH ) 9:1) to provide 45 (21.6 mg, 90%): [R]D ) +24.8 (c 1.75, MeOH); FTIR 3372, 2915, 1618, 1489, 1459, 1262, 1227, 1077 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.53 (m, 1 H), 1.67 (d, J ) 6.8 Hz, 3 H), 1.75 (d, J ) 11.9 Hz, 1H), 2.18 (dd, J ) 11.9, 4.5 Hz, 1 H), 2.65 (s, 3 H), 2.81 (d, J ) 4.2 Hz, 1 H), 2.93 (m, 2 H), 3.42 (d, J ) 6.7 Hz, 1 H), 3.44 (m, 1 H), 3.54 (m, 1 H), 3.57 (t, J ) 2.2 Hz, 1 H), 3.63 (d, J ) 10.2 Hz, 1 H), 3.74 (dd, J ) 9.7, 5.1 Hz, 1 H), 3.82 (s, 3 H), 4.07 (s, 1 H), 5.37 (q, J ) 6.8 Hz, 1 H), 6.32 (d, J ) 2.1 Hz, 1 H), 6.40 (dd, J ) 8.0, 2.2 Hz, 1 H), 7.01 (d, J ) 8.0 Hz, 1 H); 13 C NMR (75.5 MHz, CDCl3) δ 13.0, 22.6, 28 Preparation of Na-Boc-vellosimine (47). To a solution of vellosimine 46 (100 mg, 0.34 mmol) and Boc2O (100 mg, 0.47 mmol) in dry CH3CN (1 mL) was added DMAP (5 mg).…”

“…The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated under reduced pressure. The residue that resulted was purified by preparative TLC on silica gel (CHCl 3/MeOH ) 9:1) to provide authentic diol 53 as a pale yellow powder (4.2 mg, 82%): [R]D ) +60.6 (c 0.165, MeOH); FTIR 3326, 2922, 1608, 1456 cm -1 ; 1 H NMR (300 MHz, CDCl3) δ 1.53 (dd, J ) 9.9, 4.1 Hz, 1 H), 1.71 (d, J ) 6.8 Hz, 3 H), 1.75 (m, 1 H), 2.48 (m, 1 H), 2.53 (d, J ) 7.0 Hz, 1 H), 2.74 (d, J ) 4.6 Hz, 1 H), 3.01 (d, J ) 4.7 Hz, 1 H), 3.46 (m, 2 H), 3.55 (m, 1 H), 3.67 (m, 2 H), 3.92 (d, J ) 5.0 Hz, 1 H), 4.30 (s, 1 H), 5.41 (q, J ) 6.8 Hz, 1 H), 6.83 (m, 2 H), 7.16 (m, 2 H); 13 C NMR (75.5 MHz, CDCl3) δ 12.9, 21.9, 28 (20 mL), and cold 10% aq NH4OH was added to bring the pH to 8. The organic layer was diluted with CH2-Cl2 (20 mL), washed with brine (2 × 20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure.…”

Construction of an Advanced Tetracyclic Intermediate for Total Synthesis of the Marine Alkaloid Sarain A

“…More recently, the Overman group has devised a novel approach for the enantioselective synthesis of the sarain core. Moreover, Cha has published a nice strategy for construction of the tricyclic core of the sarains via a key 3-oxidopyridinium betaine/cyclopentadiene cycloaddition. In 2005, biogenetically patterned studies leading to the sarain core were reported by Marazano and co-workers .…”

Total Synthesis of (−)‐Sarain A

“…Significant progress towards sarain A ( 1 ) has been registered by Weinreb,6 Heathcock,7 Cha,8 and Marazano,9 in addition to us 10. Although successful preparations of the diazatricycloundecane core and the saturated macrocycle of 1 have been described,7d, 6c, 8b,c assembly of the highly functionalized 14‐membered ring has been reported only in a simple model system 11. Likewise, chemistry associated with the introduction of the proximal tertiary amine and aldehyde groups has not been described.…”

“…Subsequent conversion of tetracyclic aldehyde 9 into diene 10 allows the saturated macrocycle to be formed by ring‐closing metathesis followed by hydrogenation 6c. 8b, 14 Using this synthetic sequence, tetracyclic diamine diol 11 was prepared on a multigram scale.…”