Taber and Joerger
44.7, 39.0, 37.8, 34.6, 33.2, 32.1, 32.0, 29.0, 28.8, d 136.5, 75.0,
53.3, 52.4, 52.0, 50.5, 47.5, 43.4, 36.4, 36.0, 30.1, 28.3, 12.8, 11.2;
IR (cm-1) 2967, 2921, 1739, 999; MS m/z (%) 451 (M + Na, 100),
243 (6); HRMS calcd for C27H40O4Na (M + Na) 451.2824, obsd
451.2815; [R]D +22 (c 0.36, CH2Cl2).
product 1. In the event, through a range of bases and solvents,
we were not able to detect 1 in the crude reaction mixtures.
Rather, the product appeared to be predominantly the cyclo-
heptenone 15. We are investigating alternative strategies for the
preparation of 1.
Preparation of Bis-18,18′-desmethyl Ritterazine N 4. In
the course of our investigations, we prepared (Scheme 4) the
dimerized pyrazine 17. Diaxial opening of 13 with sodium azide
delivered the alcohol 16. The ketone from the oxidation of 16
was not stable, so we submitted it directly to dimerization
conditions,7 to give 17.
We were pleased to observe that ozonolysis followed by brief
exposure to base led to clean aldol condensation, to deliver bis-
18,18′-desmethyl ritterazine N 4 as a single diastereomer.8 As
an interim step in our investigations, we submitted the synthetic
4 for analysis in the NIH 60-cell screen. In fact, 4 did show
(Table 1) modest differential activity across the several cell lines.
It would be interesting to compare these data to those for
ritterazine N 1 itself. Unfortunately, that substance is not
currently available.
Azido Alcohol 16. In a sealable tube were combined epoxide
13 (20.0 mg, 46.6 µmol), sodium azide (33 mg, 500 µmol), and a
methanol/water solution (8:1, 1 mL). The tube was sealed and
heated. After 5 h at 102 °C, the reaction mixture was cooled, then
partitioned between EtOAc, and sequentially, water and brine. The
organic extract was dried (Na2SO4) and concentrated. The residue
was chromatographed to give the azido alcohol 16 as a colorless
1
oil (19.6 mg, 89%). TLC Rf (MTBE/PE ) 40:60) 0.46; H NMR
δ 0.87 (d, J ) 6.7 Hz, 3H), 1.03 (s, 3H), 1.15 (s, 3H), 1.19-1.44
(m, 7H) includes 1.33 (s, 3H), 1.47-2.14 (m, 17H), 2.20-2.28
(m, 1H), 2.72 (m, 1H), 3.77 (m, 1H), 3.92 (m, 1H), 4.38 (m, 1H),
5.05-5.13 (m, 2H), 5.65 (m, 1H); 13C NMR δ u 219.5, 117.7,
115.3, 81.7, 44.7, 37.8, 36.8, 36.7, 33.2, 32.3, 32.1, 31.6, 28.5, d
136.4, 75.1, 68.4, 61.3, 54.3, 52.0, 47.6, 43.5, 38.7, 35.4, 30.1, 28.3,
12.3, 11.2; IR (cm-1) 3439 (br), 2923, 2102, 1734, 1000; MS m/z
(%) 494 (M + Na, 100); HRMS calcd for C27H41N3O4Na (M +
Na) 494.2995, obsd 494.2985; [R]D -35 (c 0.70, CH2Cl2).
Pyrazine 17. To a solution of azido alcohol 16 (14.0 mg, 39.7
µmol) in CH2Cl2 (1 mL) was added Dess-Martin periodinane (85
mg, 200 µmol) at rt. After 2 h at rt, a 2 mL mixture of saturated
aqueous NaHCO3, saturated aqueous Na2S2O3, and water (1:1:1)
was added to the reaction mixture. The resulting mixture was stirred
for an additional 5 min, then was partitioned between MTBE and
brine. The organic extract was dried (Na2SO4) and concentrated to
crude azido ketone. A solution of NaTeH (approximatively 0.25
M) was prepared by heating powdered tellurium (510 mg, 4 mmol)
and NaBH4 (378 mg, 10 mmol) to 75 °C in ethanol (16 mL) for
1 h. A 0.033 M solution of NaTeH was prepared by adding 4 mL
of the 0.25 M solution to 26.3 mL of ethanol thoroughly degassed
with N2. To the crude azido ketone was added 2 mL (66 µmol) of
the freshly prepared 0.033 M solution of NaTeH, and the resulting
suspension was stirred for 1 h at rt under N2, then overnight at rt
under O2. The mixture was partitioned between CH2Cl2 and brine.
The organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give the pyrazine 17 as a white
solid (3.4 mg, 27%). Mp 244-246 °C dec; TLC Rf (MTBE/PE )
Conclusion
We are pleased that we were able to prepare practical
quantities of both the enantiomerically pure ketones 8 and 12,
and the triflate 10, and that we were able to alkylate the ketone
12 with the triflate 10. The capability to dispense scrupulously
dry KH in paraffin in micromole quantities was critical for the
success of this alkylation. For the first time, this makes
derivatives such as 4, having the full ring framework of the
6-6-5-5 ritterazines, available for further evaluation.
Experimental Section
Alkylated Ketone 13. To ketone 12 (234 mg, 1.06 mmol),
azeotropically dried with toluene, was added KH (128 mg of 50%
w/w mixture of KH/paraffin, 1.59 mmol of KH)7 and THF (8 mL).
After 1 h at rt, the triflate 10 (190 mg, 0.530 mmol) in THF (8
mL) was added. After 30 min at rt, the reaction mixture was
partitioned between EtOAc and saturated aqueous NH4Cl. The
organic extract was dried (Na2SO4) and concentrated. To the residue
were added CDCl3 (8 mL) and 3 drops of 0.1 M aqueous HCl.
The mixture was stirred for 1.5 h, then partitioned between EtOAc,
and, sequentially, saturated aqueous NaHCO3 and brine. The organic
extract was dried (Na2SO4) and concentrated. The residue was
chromatographed to give the alkylated product 13 as a colorless
oil (20.0 mg, 9% yield based on starting triflate, 24% yield based
on recovered ketone), recovered ketone 12 (82%), and the spiro
alcohol (43%). 13: TLC Rf (MTBE/PE ) 20:80) 0.36; 1H NMR δ
0.80 (s, 3H), 0.86 (d, J ) 6.7 Hz, 3H), 1.10-1.36 (m, 8H) includes
{1.14 (s, 3H), 1.31 (s, 3H)}, 1.42-2.12 (m, 18H), 2.23 (dd, J )
16.8, 4.9 Hz, 1H), 2.73 (m, 1H), 3.10 (dd, J ) 5.8, 4.1 Hz, 1H),
3.17-3.21 (m, 1H), 4.37 (m, 1H), 5.03-5.13 (m, 2H), 5.65 (dt, J
) 16.9, 9.8 Hz, 1H); 13C NMR δ ꢀ9 u 219.7, 117.6, 115.2, 81.6,
1
50:50) 0.46; H NMR δ 0.83 (s, 6H), 0.87 (d, J ) 6.7 Hz, 6H),
1.14 (s, 6H), 1.23-1.51 (m, 10H) includes 1.33 (s, 6H), 1.64-2.25
(m, 28H), 2.31 (dd, J ) 16.4, J ) 6.5 Hz, 2H), 2.58 (dd, J ) 17.7,
12.3 Hz, 2H), 2.66-2.93 (m, 8H), 4.42 (m, 2H), 5.06-5.15 (m,
4H), 5.70 (m, 2H); 13C NMR δ u 219.4, 148.5, 148.4, 117.8, 115.3,
81.6, 46.1, 44.6, 37.8, 36.4, 35.3, 33.1, 32.0, 31.7, 29.1, d 136.2,
74.9, 53.2, 52.0, 47.7, 43.5, 41.9, 36.0, 30.1, 28.3, 11.7, 11.2; IR
(cm-1) 2967, 2924, 1739, 1002; MS m/z (%) 872 (M + Na), 447
(29), 399 (63); HRMS calcd for C54H76N2O6Na (M + Na) 871.5601,
obsd 871.5596; [R]D +16 (c 0.17, CH2Cl2); UV (MTBE) λmax 289
(ꢀ 11600).
Bis-18,18′-desmethylritterazine N 4. To bisalkene 14 (3.4 mg,
4.0 µmol) was added 0.1 mg of Sudan-III and 2 mL of CH2Cl2,
and ozone was passed through the solution at -78 °C until the
color turned from red to yellow. Excess ozone was removed by
bubbling nitrogen through the solution. PPh3 (10 mg, 40 µmol)
was added, the solution was warmed to rt, and the solvent was
evaporated. To the residue was added 2 mL of the upper phase
from a mixture of {THF (3 volumes) + ethanol (3 volumes) + 10
wt % aqueous NaOH (1 volume)}. The mixture was stirred at rt
for 1.5 h, then partitioned between EtOAc, and sequentially, half-
saturated aqueous NH4Cl and brine. The organic extract was dried
(Na2SO4) and concentrated. The residue was chromatographed to
give the desmethylritterazine N 4 as a colorless oil (3.3 mg, 97%).
(5) Taber, D. F.; Liang, J. J. Org. Chem. 2007, 72, 4313.
(6) For the advantages of KH in paraffin, see: Taber, D. F.; Nelson, C. G. J.
Org. Chem. 2006, 71, 8973.
(7) (a) Suzuki, H.; Kawaguchi, T.; Takaoka, K. Bull. Chem. Soc. Jpn. 1986,
59, 665. (b) Jeong, J. U.; Sutton, S. C.; Kim, S.; Fuchs, P. L. J. Am. Chem. Soc.
1995, 117, 10157.
(8) We have not yet had sufficient material for X-ray analysis of the synthetic
4. The structure is assigned on the basis of aldol addition to the more open face
of the cyclopentanone, to give the diastereomer of the secondary alcohol that
can hydrogen bond to the ketone.
1
TLC Rf (EtOAc) 0.45; H NMR δ 0.99 (s, 6H), 1.10 (d, J ) 6.7
Hz, 6H), 1.18 (s, 6H), 1.22-1.38 (m, 8H) includes 1.34 (s, 6H),
1.38-1.52 (m, 2H), 1.52-1.63 (m, 2H), 1.66-2.17 (m, 26H),
2.42-2.70 (m, 6H), 2.86 (dd, J ) 18.0, 5.5 Hz, 2H), 2.96 (d, J )
(9) 13C multiplicities were determined with the aid of a JVERT pulse
sequence, differentiating the signals for methyl and methine carbons as “d” from
methylene and quaternary carbons as “u”.
4158 J. Org. Chem. Vol. 73, No. 11, 2008