Total Synthesis of Myrrhine
A solution of pyridinium salt 54 (0.131 g, 0.280 mmol) in MeOH
(2 mL) was hydrogenated over Pd(OH)2/C (10.0 mg) with H2-
balloon for 8 h. After filtering off the catalyst, MeOH was
evaporated under reduced pressure, and aqueous NaOH (1 M,
0.5 mL) and H2O (1 mL) were added to the highly colored residue.
The resulting mixture was extracted with Et2O (5 × 4 mL), and
the combined organic layers were washed with saturated aqueous
NaCl (5 mL) and dried over MgSO4. After solvent removal under
reduced pressure, the crude product was purified by flash column
chromatography using NEt3 deactivated (2% in EtOAc/hexanes )
9:1) silica gel (eluent 30% EtOAc in hexanes) to afford the all-syn
tricycle 55 (30.0 mg, 44%) as an inseparable 5:1 mixture of axial
and equatorial esters.
Conclusion
We have described here a detailed study on total syntheses
of Coccinellidae defensive alkaloids featuring an intramolecular
aza-[3 + 3] annulation approach. All five members of this
family, precoccinelline, coccinelline, hippodamine, convergine,
and myrrhine, have now been prepared from the same common
intermediate derived from a stereoselective aza-annulation
reaction. A mechanistic model for the observed anti stereose-
lectivity in the annulation step based on semiempirical calcula-
tions is also described here. This work provides a de noVo
stereoselective approach toward the 2-methyl-perhydro-9b-
azaphenalene family of alkaloids.
KOH Hydrolysis of Ester 55. To a solution of esters 55
(20.8 mg, 80.0 µmol) in MeOH (1.5 mL) was added KOH (1.7 M
in H2O, 500.0 µL, 8.50 mmol). The reaction mixture was heated at
50 °C for 36 h and monitored by TLC (Al2O3). After complete
consumption of the starting material, the mixture was cooled to
room temperature, after which MeOH was evaporated under reduced
pressure and H2O (2 mL) was added. The aqueous phase was
extracted with CH2Cl2 (1 × 2 mL) to remove impurities and then
acidified with 1 M HCl until pH ) 3-4 before being saturated
with solid NaCl. The crude product was extracted with CHCl3
(6 × 5 mL), and the combined organic layers were dried over
Na2SO4. Removal of CHCl3 under reduced pressure afforded acid
56-eq (9.80 mg, 50%) as colorless solid: 1H NMR (500 MHz,
CDCl3) δ 0.96 (d, 3 H, J ) 6.0 Hz), 1.54 (qt, 1 H, J ) 13.5, 3.5
Hz), 1.63-1.91 (m, 9 H), 1.98 (brd, 1 H, J ) 13.5 Hz), 2.13-2.23
(m, 3 H), 2.30 (q, 1 H, J ) 13.0 Hz), 2.80 (t, 1 H, J ) 12.0 Hz),
2.87 (t, 1 H, J ) 12.0 Hz), 3.09 (t, 1 H, J ) 11.5 Hz), 3.25 (td, 1
H, J ) 11.5, 3.5 Hz), 11.15 (brs, 1 H).
LiI Hydrolysis of Ester 55. A solution of ester 55 (29.9 mg,
0.120 mmol) and LiI (65.0 mg, 0.490 mmol) in EtOAc (1.5 mL)
was heated at 80 °C in a sealed tube overnight shielded from light
with aluminum foil. The reaction mixture was cooled to room
temperature, the precipitate was filtered off, and the filter cake was
washed with EtOAc (1 mL) and Et2O (1 mL) and dried on high
vacuum to afford Li-carboxylate 57-ax (21.0 mg, 73%) as slightly
brown solid:26 mp > 200 °C; 1H NMR (400 MHz, CD3OD) δ 0.96
(d, 3 H, J ) 6.0 Hz), 1.25 (q, 1 H, J ) 12.0 Hz), 1.55-1.70 (m,
4 H), 1.77-2.02 (m, 10 H), 2.59 (brs, 1 H), 3.07 (tt, 1 H, J )
12.0, 2.4 Hz), 3.10-3.18 (m, 1 H), 3.21 (dd, 1 H, J ) 11.6,
2.4 Hz); 13C NMR (100 MHz, CD3OD) δ 21.6, 23.3, 24.3, 26.9,
29.3, 29.7, 33.1, 33.6, 38.9, 40.7, 64.8, 65.5, 65.8, 180.4; IR (film)
cm-1 2931s, 2871s, 2730m, 2652m, 1573s, 1425s, 1415s, 1187m,
1047m.
Synthesis of Myrrhine 10. Li-carboxylate 57-ax (11.8 mg,
50.0 µmol) was dissolved in H2O and acidified with 1% aqueous
HCl until pH ) 3-4 before being saturated with solid NaCl. The
mixture was extracted with CHCl3 (5 × 5 mL), and the combined
organic layers were dried over Na2SO4. Removal of CHCl3 under
reduced pressure afforded acid 56-ax (3.80 mg) as colorless solid:
1H NMR (500 MHz, CDCl3) δ 0.91 (d, 3 H, J ) 6.5 Hz), 1.17 (q,
1 H, J ) 11.5 Hz), 1.40-1.50 (m, 3 H), 1.53-1.60 (m, 1 H), 1.64
(brd, 1 H, J ) 14.0 Hz), 1.68-1.79 (m, 8 H), 2.06-2.09 (m, 1 H),
2.24 (t, 1 H, J ) 11.5, 2.4 Hz), 2.32 (t, 1 H, J ) 10.5 Hz), 2.44 (d,
1 H, J ) 11.0 Hz), 2.61 (brs, 1 H); 13C NMR (125 MHz, CDCl3)
δ 21.6, 23.6, 27.0, 29.4, 29.7, 33.3, 33.7, 39.2, 40.8, 46.9, 62.7,
62.9, 63.2, 176.5; mass spectrum (APCI): m/e (% relative intensity)
238 (100) M+ + H.
Experimental Section
Preparation of Pyridinium Salt 54. To a solution of tricycle
42 (0.253 g, 1.02 mmol) in CH2Cl2 (7 mL) was added a warm
solution of DDQ (0.270 g, 1.19 mmol) in CH2Cl2 (20 mL). An
immediate color change from yellow to dark brown was observed.
The reaction mixture was stirred vigorously for 1 h at room
temperature, and the formation of dark brown oil on the bottom of
the flask occurred, at which time the stirring was stopped. The
reaction mixture was cooled to 0 °C, and CH2Cl2 was carefully
decanted, leaving behind the precipitated brown oil that solidified
upon placing the flask on the high vacuum. The brown solid was
pulverized, washed with Et2O (7 mL), and dried on high vacuum
to give pyridinium salt 54 (0.414 g, 85%) as an orange solid: mp
1
) 125-130 °C (decomp); H NMR (400 MHz, CD3OD) δ 1.14
(d, 3 H, J ) 6.4 Hz), 1.55 (q, 1 H, J ) 12.4 Hz), 1.70-1.90 (m,
2 H), 2.11-2.25 (m, 2 H), 2.38-2.44 (m, 2 H), 2.49-2.59 (m, 1
H), 3.18-3.36 (m, 2 H), 3.62 (ddd, 1 H, J ) 18.8, 5.2, 2.4 Hz),
3.97 (s, 3 H), 4.54 (tt, 1 H, J ) 11.2, 4.4 Hz), 7.84 (d, 1 H, J ) 8.4
Hz), 8.66 (d, 1 H, J ) 8.4 Hz); 13C NMR (100 MHz, CD3OD) δ
17.3, 21.6, 25.17, 25.25, 30.0, 37.9, 54.1, 55.0, 64.0, 100.6, 116.4,
126.9, 129.9, 131.5, 145.5, 154.3, 159.1, 161.9, 165.1; IR (film)
cm-1 2956m, 2226s, 1734s; 1618s, 1564m, 1437s, 1278s, 1207s,
1135s, 1079s.
Hydrogenation of Pyridinium Salt 54. A solution of pyridinium
salt 54 (40.0 mg, 90.0 µmol) in glacial AcOH (2 mL) was
hydrogenated over prereduced Adams’ catalyst PtO2 (10.0 mg) in
a Parr apparatus at 60 psi of H2 overnight. After filtering off the
catalyst, AcOH was evaporated under reduced pressure, and aqueous
NaOH (1 M, 0.5 mL) and H2O (1 mL) were added to the highly
colored residue. The resulting mixture was extracted with Et2O (5
× 4 mL), and the combined organic layers were washed with
saturated aqueous NaCl (5 mL) and dried over MgSO4. After
removal of excess solvents under reduced pressure, the crude
product was purified by flash column chromatography using NEt3
deactivated (2% in EtOAc/hexanes ) 9:1) silica gel (eluent 30%
EtOAc in hexanes) to afford the all-syn tricycle 55 (13.3 mg, 63%)
as an inseparable 2:1 mixture of axial and equatorial esters. 55-ax:
Rf ) 0.29 [10% EtOAc in hexanes, neutral Al2O3]; 1H NMR
(400 MHz, CDCl3) δ 0.86 (d, 3 H, J ) 6.4 Hz), 1.00 (q, 1 H, J )
11.6 Hz), 1.17 (q, 1 H, J ) 11.6 Hz), 1.26-1.59 (m, 10 H), 1.61-
1.66 (m, 1 H), 1.71-1.79 (m, 2 H), 1.87-1.95 (m, 2 H), 2.09 (ddd,
1 H, J ) 11.6, 4.0, 2.4 Hz), 2.54 (ddt, 1 H, J ) 6.8, 4.0, 1.6 Hz),
3.66 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 22.2, 24.5, 27.0,
29.9, 31.0, 34.0, 34.2, 40.5, 42.5, 45.2, 51.2, 62.9, 63.2, 63.4, 174.3.
55-eq: Rf ) 0.29 [10% EtOAc in hexanes, neutral Al2O3]; 1H NMR
(400 MHz, CDCl3) δ 0.85 (d, 3 H, J ) 6.4 Hz), 0.89-1.06
(m, 2 H), 1.26-1.59 (m, 10 H), 1.61-1.66 (m, 1 H), 1.71-1.79
(m, 2 H), 1.87-1.95 (m, 2 H), 2.18 (td, 1 H, J ) 10.8, 2.0 Hz),
2.37 (ddd, 1 H, J ) 12.4, 10.8, 4.0 Hz), 3.67 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ 22.1, 24.2, 28.4, 30.1, 32.8, 34.3, 34.4, 40.1,
42.6, 49.9, 51.7, 61.8, 62.2, 62.9, 175.9; IR (film) cm-1 2925s,
2862s, 2793m, 2734m, 2619m, 1737s, 1445m, 1374m, 1152s;
mass spectrum (APCI): m/e (% relative intensity) 252 (100)
M+ + H.
To a suspension of above acid 56-ax (3.80 mg, 16.0 µmol) in
THF (0.5 mL) was added diisopropylethylamine (8.00 µL, 48.0
µmol), and the resulting mixture was cooled to -10 °C. i-BuOCOCl
(4.00 µL, 31.0 µmol) was then added, and the mixture was stirred
at -10 °C for 15 min before being allowed to warm to room
(26) Hydrogens R to nitrogen atom in Li-carboxylate 57-ax are deshielded
compared to these hydrogens in 55-ax likely due to the fact that 57-ax is
1
a lithum salt and its H NMR was taken in a different solvent.
J. Org. Chem, Vol. 72, No. 7, 2007 2483