hydroesterification, this method of converting homoallylic
alcohols into δ-lactones compares quite favorably to com-
monly employed olefin metathesis/reduction sequences.
The major byproduct of the hydroesterification reaction
(18% yield) was γ-lactone 15, arising through the interme-
diacy of branched ester 13. The formation of 15 contrasts
with Chang’s observation of nearly exclusive linear product
formation from nonfunctionalized alkenes when branching
is present at the allylic position. We propose that the
branched isomer forms through a competitive hydroxyl-
directed pathway that proceeds through intermediate 16
(Figure 2). Compelling precedent for a coordinating group
Scheme 3 a
a Reagents and conditions: (a) 11, Ru3(CO)12, 135 °C, then
HOAc, THF, H2O, rt, 68%. (b) LDA, THF, -78 °C, then Mel,
HMPA, 72% at 72% conversion. (c) 11, Ru3(CO)12, 135 °C, 80%.
(d) (1S,2S)-pseudoephedrine, NaH, THF, 0 °C, 83%. (e) LDA, LiCl,
THF, -78 °C, then Mel, -78 to 0 °C, 91%. (f) Bu4NF, THF, then
p-TsOH, 79%.
material throughput. To improve the methylation selectivity,
we converted pyridylmethyl ester formed from the hydroes-
terification of 17b to pseudoephedrine amide 20 through a
variant of Myers’ aminolysis conditions13 (pseudoephedrine,
NaH, THF). In accord with Myers’ studies, alkylating the
lithium enolate of 20 (LDA, LiCl, THF) with MeI provided
21. Removal of the silyl group of 21 followed in the same
flask by acid-mediated lactonization provided 18 in 79%
yield.
Figure 2.
causing a regiochemical reversal in hydrometalation reactions
has been provided through the Evans group’s studies12 on
metal-catalyzed hydroborations.
To exclude the possibility that the unexpected regioisomer
forms from a transesterification reaction between 10 and 11
followed by intramolecular hydroesterification, we subjected
the formate ester of 10 to hydroesterification conditions. This
reaction, although slower than the parent transformation,
provided the linear isomer exclusively, consistent with
suppressing the coordinative addition.
To avoid regioselectivity problems, we subjected silyl ether
17a (prepared in 94% yield by exposing 10 to TESCl and
imidazole) to hydroesterification. While the intermediate
pyridylmethyl ester, formed exclusively as the linear isomer,
could be purified and isolated, we found that stirring the
crude reaction mixture in HOAc, THF, and water at room
temperature effected silyl ether cleavage and lactonization
to form 14 in 68% yield. While requiring one additional step
relative to the one-pot lactone synthesis, the increase in
efficiency should prove to be useful for homoallylic alcohols
that are difficult to access.
Coupling of 8 and 18 (Scheme 4) was achieved with
Cohen’s method. Thus, deprotonation of the hydroxyl group
of 8 with n-BuLi followed by reductive lithiation of the
sulfide with lithium di-tert-butylbiphenylide (LDBB)14 pro-
vided a dianion that underwent transmetalation with anhy-
drous CeCl3.15 Addition of 18 to the resulting alkylcerium
reagent afforded, following an acidic workup, spiroketal 22
in 60% yield. This reaction, however, proved to be somewhat
capricious due to technical difficulties associated with
preparing the alkylcerium reagent. An exploration of alternate
reagents for effecting the transmetalation reaction showed
that MgBr2, prepared in situ from 1,2-dibromoethane and
Mg metal, promoted spiroketal formation in 56% yield and
with greater reproducibility than the alkylcerium addition.
The PMP group was removed selectively using ceric am-
monium nitrate in wet acetonitrile,16 yielding 23 in 79%
yield. Alcohol 23 is well-suited for subsequent elaboration
of the C1-C15 portion of integramycin. Significant overlap
Unfortunately, treatment of the enolate of 14 with MeI
proceeded with no stereocontrol, providing lactones 18 and
19 in a 1:1 ratio. Although 19 could be epimerized to 18,
the efficiency of the process was insufficient for large-scale
1
in the H NMR spectra of the spiroketals precluded their
(13) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) Myers, A. G.;
Yang, B. H.; Chen, H.; Gleason, J. L. J. Am. Chem. Soc. 1994, 116, 9361.
(14) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152.
(15) Takeda, N.; Imamoto, T. Org. Synth. 1998, 76, 228.
(16) Fukuyama, T.; Laud, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291.
(12) (a) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc.
1992, 114, 6671. (b) Evans, D. A.; Fu, G. C.; Anderson, B. A. J. Am. Chem.
Soc. 1992, 114, 6679.
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