reduction of the cyanide moiety and closure onto the ortho
ester functionality would provide the A-ring lactam 4.
Examination of this strategy began with a model system
constructed from commercially available o-iodobenzoic acid
5 as shown in Scheme 2. Treatment of acid 5 with oxalyl
countercation was minimal. Cyclizations with sodium cya-
nide (entry 1) gave consistently higher yields than those
conducted with potassium cyanide (entry 2). The reaction
time could be significantly reduced by use of the noncoor-
dinating tetrabutylammonium cation (entry 3).
With the successful demonstration of the tandem cyanide
conjugate addition-Dieckmann cyclization to form inter-
mediate 3, we next examined the selective reduction of the
resultant aromatic cyano group in the presence of the ortho
ester functionality as shown in Scheme 3. Protection of the
Scheme 2a
Scheme 3a
a (a) (COCl)2, catalytic DMF, THF/PhH, 0 °C; CH2N2, Et2O, 0
°C (79%); (b) AgOBz, NEt3, MeOH, 0 °C (86%); (c) 8, PdCl2(PPh3)2,
CuI, NEt3, MeCN, 0 °C to rt; TsOH, MeOH (85%).
a (a) NaH, TIPSCl, DMF (quantitative); (b) CoCl2, NaBH4,
MeOH/THF (71%).
chloride in the presence of catalytic DMF,4 followed by
treatment with diazomethane,5 afforded diazoketone 6. Wolff
rearrangement was effected with silver benzoate6 in the
presence of triethylamine in methanol to afford homologated
ester 7. Sonogashira coupling7 with alkynyl ortho ester 88
under standard conditions followed by unraveling of the ortho
ester functionality gave cyclization substrate 2. The key
cyclization reaction was then examined with various sources
of cyanide as summarized in Table 1.
phenolic group as its TIPS ether was followed by selective
cyanide reduction with the combination of cobalt chloride
and sodium borohydride in methanol-THF solvent.9 The
resultant amine group spontaneously cyclized on the ortho
ester group to afford lactam 9 in 71% yield over the two
steps.
Confident that the model system was complete, our
attention turned to application in a system that would be
appropriate for the total synthesis of lactonamycin. A
convenient starting point was the known naphthalene system
1010 as shown in Scheme 4. Regioselective bromination with
pyridinium bromide perbromide11 gave alcohol 11. The
Table 1. Tandem Cyanide Addition-Dieckmann Condensation
entry
MCN
time (h)
yield (%)
Scheme 4a
1
2
3
NaCN
KCN
Bu4NCN
5
7
3.5
88
80
86
Reactions were initially conducted in DMF, though it was
found that DMSO gave superior conversions. All reactions
were run at room temperature. The effect of changing the
(1) Matsumoto, N.; Tsuchida, T.; Maruyama, M.; Sawa, R.; Kinoshita,
N.; Homma, Y.; Takahashi, Y.; Iinuma, H.; Naganawa, H.; Sawa, T.;
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1999, 52, 269. (b) Matsumoto, N.; Tsuchida, T.; Nakamura, H.; Sawa, R.;
Takahashi, Y.; Naganawa, H.; Iinuma, H.; Sawa, T.; Takeuchi, T. J. Antibiot.
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Danishefsky, S. J. Org. Lett. 2001, 3, 2899.
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(5) Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P. D. J. Am. Chem.
Soc. 1988, 110, 2894.
(6) Newman, M. S.; Beal, P. F. J. Am. Chem. Soc. 1950, 72, 5163.
(7) Sakamoto, T.; Shiga, A.; Yasuhara, A.; Uchiyama, D.; Kondo, Y.;
Yamanaka, H. Synthesis 1992, 746.
a (a) PyrH+Br3-, THF, 0 °C (99%); (b) NaH, MeI, DMF (84%);
(c) n-BuLi, THF; I2, -78 °C (91%); (d) HBr, HOAc, 50 °C (65-
79%); (e) KCN, EtOH-H2O, reflux (82%); (f) TfOH, MeOH, reflux
(86%); (g) 8, PdCl2(PPh3)2, CuI, NEt3, MeCN, 0 °C to rt; TsOH,
MeOH (97%).
(8) Stetter, H.; Uerdingen, W. Synthesis 1973, 207.
1404
Org. Lett., Vol. 4, No. 8, 2002