2718 J . Org. Chem., Vol. 63, No. 8, 1998
Notes
of K+ with a nontemplating cation (Table 6, entries 4 and
5) provided only a small amount of macrocycle 2, along
with bicyclic lactone 4e and other degradation products.
To determine whether the polydentate coordinating
ability of the substrates 3a and 3e is necessary for
successful cyclization, trichloroethyl 17-hydroxyhepta-
decanoate (6) was prepared19and subjected to several
lactonization attempts. In all cases, NMR analysis of the
crude reaction mixtures showed only starting material
after heating for extended periods (eq 5). These experi-
ments indicate that the trichloroethyl ester group is not
sufficiently activated to under go an intra- or intermo-
lecular transesterification reaction under these condi-
tions.
spectra were recorded at 75 MHz. Where indicated, distortion-
less enhancement by polarization transfer (DEPT) was used to
assign carbon resonances as CH3, CH2, CH, or C. Chemical
shifts are reported in ppm relative to Me4Si (δ 0.00). Elemental
analyses were performed by Desert Analytics Laboratories
(Phoenix, AZ).
Gen er a l P r oced u r e for Ma cr ola cton iza tion . To a solu-
tion of acyclic trimer alcohol 3 in THF (0.002 M) was added the
alkali metal salt (10 equiv). The reaction flask was flushed with
N2 and capped, and the mixture was stirred at the indicated
temperature. The progress of the reaction was followed by TLC
analysis until the starting material was consumed. The mixture
was filtered and the solid washed with ether or CH2Cl2 and
concentrated. The crude reaction mixture was purified by silica
gel chromatography.
Ma cr olid e 1: Rf 0.45 (5% MeOH in CH2Cl2); 1H NMR (CD3-
OD, 250 MHz, 85 °C) δ 6.08 (ddd, 3H, J ) 10.3, 5.7, 2.4 Hz),
5.71 (br d, 3H, J ) 10.1 Hz), 5.35-5.29 (m, 3H), 4.55-4.52 (m,
3H), 4.41 (d, 3H, J ) 3.4 Hz), 3.66-3.55 (m, 3H), 3.40 (dd, 3H,
J ) 14.5, 2.9 Hz), 2.58-2.48 (m, 3H), 1.42 (s, 27H), 1.05 (d, 9H,
J ) 7.0 Hz); 13C NMR (CD3OD, 75 MHz) δ 171.1 (C), 158.4 (C),
134.0 (CH), 124.6 (CH), 80.6 (C), 77.8 (CH), 77.5 (CH), 75.4 (CH),
39.0 (CH2), 33.3(CH), 28.8(CH3 × 3), 15.3(CH3); IR (thin film)
3408 (br), 2976, 1741, 1709, 1506, 1367, 1286, 1170 cm-1; MS
(FAB) m/e (relative intensity, assignment) 982.3 (60, M + Cs+),
888.4 (90, M + K+), 872.4 (75, M + Na+), 850.4 (10, M + H+),
750.4 (100, M + H+ - C4H8 - CO2), 694.3 (30, M + H+ - 2C4H8
Su m m a r y a n d Con clu sion
We have described macrolactone formation from a
hydroxy ester utilizing the templating effect of alkali
metal cations to facilitate an intramolecular transesteri-
fication reaction. In most cases, the rate-limiting step
of a transesterification is the addition of the alcohol or
alkoxide fragment to the carbonyl carbon, followed by fast
breakdown of the resulting tetrahedral intermediate.17
The data presented herein suggest that the conversions
of 3a to 1 and 3e to 2 are M+-templated cyclizations
wherein the collapse of the tetrahedral intermediate is
the slow step.20 With the proximity of the hydroxyl and
ester moieties enforced and the associated entropic costs
paid by the template effect, the formation of the tetra-
hedral intermediate would be facilitated for all substrates
3a -d . The rate of the productive collapse of this
intermediate would be dependent upon the departing
alkoxide nucleofuge, thus the superiority of the trichlo-
roethyl esters. Macrolactonization of ester 3e was suc-
cessful with a catalytic amount of KOAc and was
inhibited by the addition of cis-dicyclohexano-18-crown-
6. Unfunctionalized hydroxy trichloroethyl ester 6,
incapable of being templated, was completely inert to the
cyclization conditions. All of these observations are
consistent with a templated cyclization mechanism.
- CO2); [R]22 +218.0 (c)3.9, CH2Cl2).
D
Bicyclic la cton e 4a (R1 ) CH2NHBoc, R2 ) Me): mp 110-
1
112 °C; Rf 0.26 (25% EtOAc in hexanes); H NMR (CDCl3, 300
MHz) δ 5.89 (br d, 1H, J ) 10.3 Hz), 5.72 (ddd, 1H, J ) 10.3,
3.7, 2.6 Hz), 5.00-4.95 (m, 1H), 4.72 (ddd, 1H, J ) 8.1, 4.0, 4.0
Hz), 4.43 (d, 1H, J ) 5.9 Hz), 4.35-4.33 (m, 1H), 3.58-3.49 (m,
1H), 2.97-2.82 (m, 2H), 1.40 (s, 9H), 1.04 (d, 3H, J ) 7.7 Hz);
13C NMR (CDCl3, 75 MHz) δ 166.5 (C), 155.8 (C), 134.6 (CH),
120.9 (CH), 81.5 (CH), 80.0 (C), 73.6 (CH), 66.3 (CH), 41.3 (CH2),
32.7 (CH), 28.3 (CH3), 15.2 (CH3); IR (thin film) 3256 (br), 2978,
1745, 1711, 1514, 1367, 1229, 1170 cm-1; MS (FAB) m/e (relative
intensity, assignment) 306.2 (100, M + Na+), 250.1 (40, M +
Na+ - C4H8), 228.2 (45, M + H+ - C4H8); [R]22 +70.6 (c ) 0.6,
D
CH2Cl2).
1
Ma cr olid e 2: mp 80-87 °C; Rf 0.25 (2% MeOH/CH2Cl2); H
NMR (300 MHz, CDCl3) δ 6.02-5.94 (m, 1H), 5.58-5.51 (m, 1H),
4.60-4.52 (m, 2H), 4.25 (dd, J ) 10.7, 3.7 Hz, 1H), 3.95 (dd,
J ) 12.1, 9.2 Hz, 1H), 2.47-2.20 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 170.8 (C), 127.0 (CH), 124.8 (CH), 73.6 (CH), 72.5 (CH),
66.6 (CH2), 27.7 (CH2); IR (neat) 2947, 1734, 1298, 1184, 1099,
727 cm-1; MS (FAB) m/e 420.1 (M + H+), 443.1 (M + Na+), 460.1
(M+K+); [R]20 +181° (c ) 1.53, CHCl3). Anal. Calcd for
D
C21H24O9: C, 60.00; H, 5.75. Found: C, 59.48; H, 5.95.
Exp er im en ta l Section
Ack n ow led gm en t. This research was supported by
NIH Grant No. GM 28321 (S.D.B.), NIH Chemistry/
Biology Interface Training Grant GM 08505 (C.J .O.),
and NIH Postdoctoral Fellowship GM 17009-01A1
(T.S.M.). The University of Wisconsin NMR facility
receives financial support from NSF (CHE-9208463) and
NIH (1S10 RR0 8389-D1).
Gen er a l Meth od s. Unless otherwise noted, all reagents
were purchased from commercial suppliers and used without
further purification. Tetrahydrofuran (THF) and benzene were
distilled from sodium/benzophenone immediately prior to use.
Methylene chloride (CH2Cl2) was distilled from CaH2 im-
mediately prior to use. Silica gel chromatography was performed
according to the method of Still.21 Proton nuclear magnetic
resonance (1H NMR) spectra were recorded at 300 MHz.
Chemical shifts are reported in parts per million (ppm, δ)
relative to Me4Si (δ 0.00), and coupling constants (J ) are reported
in hertz (Hz). Carbon-13 nuclear magnetic resonance (13C NMR)
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra of compounds 1, 2, 3a , 3e, and 4e; details of the
syntheses of ester derivatives 3b-d (Table 3); and details of
competition experiment between 3a and 3b are presented (18
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
(19) Richard, M. A.; Deutch, J .; Whitesides, G. M. J . Am. Chem.
Soc. 1978, 100, 6613-6625.
(20) For an example of transesterification where the second mecha-
nistic step, also dependent upon the pKa of the departing group, is
rate-limiting; see: Breslow, R.; Chung, S. Tetrahedron Lett. 1990, 31,
631-634.
(21) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
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