Melsˇa et al.
1H), 3.66-3.57 (m, 1H), 3.28-3.22 (dd, J ) 1.5, 16.7 Hz, 1H),
2.36 (s, 3H), 2.05-1.96 (ddd, J ) 2.0, 5.8, 13.3 Hz, 1H), 1.87-
1.78 (ddd, J ) 1.2, 6.7, 13.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 180.9, 171.1, 137.8, 135.4, 133.6, 131.2, 129.5, 128.8, 128.0,
127.3, 81.3, 66.0, 54.0, 48.2, 32.3, 21.2; IR (KBr) 3027, 2983, 2918,
1763, 1620, 1448, 1171, 1026, 764, 694 cm-1; MS (EI) m/z (rel
intens) 305 (M, 43), 259 (19), 207 (100), 104 (14), 78 (20); HRMS
(ESI) m/z calcd for C20H16NO2 (M - H2 - 1) 302.1181, found
302.1195.
Conclusions
The reported 1,3-DC reaction of tulipalin A with nitrile ylides
is an example of diastereoselective 1,3-DC reaction whose
selectivity is significantly affected by CH/π interaction. This
weak attractive interaction between the lactone C(â)-H bond
and the nitrile ylide phenyl ring, which significantly modifies
the main tendency of the reaction to prefer the exo reaction
pathway due to steric reasons, is demonstrated by a remarkable
substituent effect correlating the observed diastereoselectivity
with the phenyl substituent σ values in a Hammett-like plot.
The low negative F value of the plot shows that electron donor
substituents favor formation of exo-diastereoisomers. The results
of DFT and mainly RI-MP2 computational analyses of the
structures and properties of the possible TSs support this
conclusion as well. The calculated geometries of the exo-TSs
show that the considered â-hydrogen is close enough to interact
with the nitrile ylide phenyl ring (approximately 2.9 Å).
Moreover, the mutual orientation of the lactone carbonyl and
the substituted phenyl ring of the ylide allows speculation also
about some contribution of CO/π interaction to the energy of
the endo-TSs, which would exhibit a similar effect of the
substituent. Evaluation of relative contributions of both interac-
tions to mediation of the substituent effect on reaction stereo-
selectivity is, however, difficult due to computational demands.
Our results show that the weak attractive interactions such as
CH/π and CO/π interaction should also be taken into account
among the effects capable of significantly affecting the diaste-
reoselectivity of 1,3-DC reactions. We believe that further
examples of such effects will appear soon.
Data for (5S*,6S*)-6-(4-phenylphenyl)-8-phenyl-2-oxa-7-
1
azaspiro[4.4]non-7-en-1-one (exo-5d): yield 0.293 g, 40%; H
NMR (300 MHz, CDCl3) δ 7.95-7.93 (dd, J ) 8.0, 1.9 Hz, 2H),
7.64-7.60 (m, 4H), 7.52 - 7.34 (m, 8H), 5.69 (s, 1H), 4.14-4.07
(dt, J ) 8.0, 2.0 Hz, 1H), 3.74-3.65 (m, 2H), 3.33-3.28 (dd, J )
16.7, 1.2 Hz), 2.12-2.04 (dt, J ) 13.4, 1.7 Hz, 1H), 2.12-1.84
(m, 1H); 13C NMR (75 MHz, CDCl3) δ 180.9, 171.3, 141.1, 140.7,
137.6, 133.6, 131.5, 129.0, 128.9, 128.1, 128.0, 127.7, 127.5, 127.2,
81.2, 66.2, 54.1, 48.4, 32.4; IR (KBr) 3027, 2983, 2917, 1763, 1620,
1487, 1171, 1026, 764, 694 cm-1; MS (EI) m/z (rel intens) 367
(M, 38), 322 (32), 269 (100), 165 (41), 78 (8); HRMS (ESI) m/z
calcd for C25H18NO2 (M - H2 - 1) 364.1338, found 364.1351.
Data for (5S*,6S*)-6-(4-Fluorophenyl)-8-phenyl-2-oxa-7-
azaspiro[4.4]non-7-en-1-one (exo-5e): yield 0.185 g, 27%; 1H
NMR (300 MHz, CDCl3) δ 7.89 (dd, J ) 8.1, 1.6 Hz, 2H), 7.50-
7.42 (m, 3H), 7.31-7.26 (m, 2H), 7.06 (t, J ) 8.6 Hz, 2H), 5.60
(s, 1H), 4.11-4.04 (ddd, J ) 7.8, 1.4, 1.3 Hz, 1H), 3.69-3.58 (m,
2H), 3.30-3.24 (dd, J ) 16.6, 1.1 Hz, 1H), 1.96-1.76 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 180.6, 171.4, 162.7 (d, J ) 246.7
Hz), 134.4 (d, J ) 3.2 Hz), 133.4, 131.5, 129.1 (d, J ) 8.0 Hz),
128.9, 128.0, 115.8 (d, J ) 21.6 Hz), 80.6, 66.0, 54.1, 48.3, 32.2;
IR (KBr) 3074, 2989, 2919, 2863, 1759, 1608, 1510, 1226, 1174,
1024, 850, 782, 698, 563, 542 cm-1; MS (EI) m/z (rel intens) 309
(M, 17), 263 (12), 211 (10), 107 (20); HRMS (ESI) m/z calcd for
C19H13FNO2 (M - H2 - 1) 306.0930, found 306.0929.
Experimental Section
Data for (5S*,6S*)-6-(4-bromophenyl)-8-phenyl-2-oxa-7-
azaspiro[4.4]non-7-en-1-one (exo-5f): yield 0.215 g, 29%; 1H
NMR (300 MHz, CDCl3) δ 7.92-7.88 (dd, J ) 1.4, 8.2 Hz, 2H),
7.52 (d, J ) 8.48 Hz, 2H), 7.53-7.43 (m, 3H), 7.21 (d, J ) 8.4
Hz, 2H) 5.60 (s, 1H), 4.14-4.06 (ddd, J ) 1.3, 1.5, 6.4 Hz, 1H),
3.74-3.66 (ddd, J ) 1.4, 1.7, 6.1 Hz, 1H), 3.66-3.60 (dd, J )
2.2, 14.2 Hz, 1H), 3.32-3.26 (dd, J ) 1.4, 16.7 Hz, 1H), 1.98-
1.78 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.8, 171.9, 137.9,
133.6, 132.3, 131.8, 129.5, 129.1, 128.2, 122.4, 80.7, 66.3, 54.3,
48.6, 32.3; IR (KBr) 3060, 2917, 2864, 1765, 1622, 1487, 1169,
1026, 760, 694 cm-1; MS (EI) m/z (rel intens) 305 (M), 369 (M,
16), 324 (142), 273 (100), 227 (58), 192 (93), 165 (20), 89 (59);
HRMS (ESI) m/z calcd for C19H13BrNO2 (M - H2 - 1) 366.0130,
found 366.0130.
Data for (5S*,6S*)-6-(4-Chlorophenyl)-8-phenyl-2-oxa-7-
azaspiro[4.4]non-7-en-1-one (exo-5g): yield 0.145 g, 22%; 1H
NMR (300 MHz, CDCl3) δ 7.89 (d, J ) 8.0 Hz, 2H), 7.49-7.41
(m, 3H), 7.35 (d, J ) 8.4 Hz, 2H), 7.25 (d, J ) 8.4 Hz, 2H), 5.59
(s, 1H), 4.12-4.04 (m, 1H), 3.72 - 3.64 (m, 1H), 3.63-3.57 (dd,
J ) 16.6, 2.3 Hz, 1H), 3.30-3.24 (dd, J ) 16.7, 0.9 Hz, 1H), 1.96-
1.76 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.5, 171.5, 137.1,
134.0, 133.4, 131.6, 129.0, 128.9, 128.3, 128.0, 80.6, 66.0, 54.1,
48.3, 32.1; IR (KBr) 3060, 2918, 1766, 1618, 1491, 1171, 1026,
760, 692 cm-1; MS (EI) m/z (rel intens) 324 (M - 1,17), 279 (19),
227 (100), 191 (43), 89 (51); HRMS (ESI) m/z calcd for C19H13-
ClNO2 (M - H2 - 1) 322.0635, found 322.0637.
General Procedure for Cycloaddition Reaction of Nitrile
Ylides to Tulipalin A. A solution of t-BuOK (315 mg, 2.66 mmol)
in dry THF (10 mL) was added dropwise to a mixture of tulipalin
A (200 mg, 2 mmol) and imidoyl chloride (2.66 mmol) in dry THF
(2 mL) over a period of 4 h, and the reaction mixture was stirred
overnight. After concentration on a rotary evaporator, the residue
was redissolved in methylene chloride (30 mL), washed with water
(50 mL), and dried over Na2SO4. The solvent was removed in
vacuo, and the residue was subjected to column chromatography
on silica gel using an ethyl acetate/benzene/hexane mixture (1:1:
1) as the eluent to give the exo-cycloadduct as a clear oily liquid.
Data for (5S*,6S*)-6,8-diphenyl-2-oxa-7-azaspiro[4.4]non-7-
en-1-one (exo-5a): yield 0.165 g, 29%; 1H NMR (300 MHz, CDCl3)
δ 7.91 (d, J ) 6.24 Hz, 2H), 7.50-7.43 (m, 3H), 7.37-7.30 (m,
5H), 5.63 (s, 1H), 4.09-4.01 (m, 1H), 3.67-3.57 (m, 2H), 3.26
1
(d, J ) 16.63 Hz, 1H), 2.03-1.94 (m, 1H), 1.88-1.79 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 180.8, 171.3, 138.6, 133.6, 131.4,
128.8, 128.2, 128.0, 127.5, 81.4, 66.0, 54.1, 48.3, 32.3; IR (KBr)
3029, 2985, 2914, 1765, 1620, 1344, 1178, 1022, 761, 708 cm-1
;
MS m/z (rel intens) 291 (M, 15), 246 (19), 193 (100), 165 (12), 90
(10), 89 (10); HRMS (ESI) m/z calcd for C19H14NO2 (M - H2 -
1) 288.1025, found 288.1034.
Data for (5S*,6S*)-6-(4-nitrophenyl)-8-phenyl-2-oxa-7-azaspiro-
[4.4]non-7-en-1-one (exo-5b): yield 0.246 g, 37%; 1H NMR (300
MHz, CDCl3) δ 8.24 (d, J ) 8.7 Hz, 2H), 7.90 (d, J ) 6.5 Hz,
2H), 7.53-7.45 (m, 5H), 5.73 (s, 1H), 4.18-4.10 (m, J ) 7.4 Hz,
1H), 3.84-3.77 (m, 1H), 3.62 (dd, J ) 16.6, 2.4 Hz, 1H), 3.36
(dd, J ) 16.6, 1.01 Hz, 1H), 1.90-1.75 (m, 1H).
Data for (5S*,6S*)-6-(4-methylphenyl)-8-phenyl-2-oxa-7-
azaspiro[4.4]non-7-en-1-one (exo-5c): yield 0.195 g, 32%; 1H
NMR (300 MHz, CDCl3) δ 7.92-7.90 (dd, J ) 2.0, 7.6 Hz, 2H),
7.49-7.42 (m, 3H), 7.21-7.15 (m, 4H), 5.60 (s, 1H), 4.09-4.01
(ddd, J ) 1.0, 5.7, 8.0 Hz, 1H), 3.66-3.60 (dd, J ) 2.4 16.7 Hz,
Acknowledgment. We thank the Academic Supercomputer
Center at Masaryk University for providing us with access to
the computer facilities and the Ministry of Education, Youth
and Sports of the Czech Republic for financial support (Grant
Nos. 570/2004, MSM6198959218, and LC512). We are grateful
to Jiˇr´ı Matousˇek from the National Centre for Biomolecular
Research at Masaryk University in Brno for giving us assistance
3038 J. Org. Chem., Vol. 73, No. 8, 2008