The sequence leading from 12a/b to 15 represents a rapid,
highly convergent alternative route to complex polyketide
building blocks that is not based on aldol chemistry.
However, as outlined above, a key limitation of the approach
outlined in Scheme 2 is that the pairwise stereochemical
relationships between the 1,3-diols are not independent (i.e.,
for 15 both are anti). A significant improvement of this
strategy would be the ability to unmask each latent â-hydroxy
ketone in sequence and modify it appropriately. We have
previously noted that 3-alkenyl isoxazolines can be converted
to the corresponding â′-hydroxy R,â-unsaturated ketone by
treatment with excess SmI2 and B(OH)3 in THF.12 Moreover,
this system was shown to reduce saturated isoxazolines at a
slower rate. Our interest in selectively manipulating the
isoxazolines in 12a/b presents an opportunity to examine
whether the process would be chemoselective for a structure
incorporating two different isoxazolines, a prospect that had
remained untested in our original study.
Scheme 1. Synthesis of Bis(isoxazoline) 12a
We were delighted to observe (Scheme 3) that a modifica-
a Conditions: (a) (i) tBuOCl, 6 or 9, CH2Cl2; (ii) 7 or 10,
EtMgBr, iPrOH, CH2Cl2, 0 °C. (b) BzCl, Et3N, DMAP, CH2Cl2,
93%. (c) TBAF, THF, 93%. (d) Dess-Martin periodinane,9 CH2Cl2,
88%. (e) TBDPSCl, im, DMF, 98%. (f) AcOH, THF, H2O, 95%.
(g) PTSH, Ph3P, DEAD, THF, 99%. (h) Mo7O24(NH4)6‚4H2O,
H2O2, EtOH, 92%. (i) 11, KHMDS, THF, -78 °C, then 8, 96%.
Scheme 3. Synthesis of Ketone 18a
13. Both isoxazolines could then be converted to the
corresponding â-hydroxy ketones in 85% yield by subjection
to Curran’s conditions (H2, Ra/Ni, B(OH)3).10 Directed
reduction of both hydroxy ketones using the procedure of
Evans11 and protection of the derived tetraol provided bis-
(acetonide) 15 in 70% overall yield for the sequence
commencing with 12a/b.
Scheme 2. Synthesis of Bis(acetonide) 15a
a Conditions: (a) SmI2, THF/H2O, 55-70%; (b) Me4NBH(OAc)3,
AcOH, MeCN; (c) (CH3)2C(OCH3)2, p-TsOH; 85%, two steps; (d)
H2, Raney-Ni, MeOH/H2O, B(OH)3, 90%.
tion of our previous procedure afforded the conversion of
12a and 12b to the desired isoxazoline 16 in 55-70% yield,
with starting material 12a/b accounting for the remainder
of the mass balance (25-40%).13 With the stage set for
modification of each â-hydroxy ketone separately, directed
(9) Dess, P. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-7287.
(10) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826-5833.
(11) Evans, D. A.; Chapman, K. T. Tetrahedron Lett. 1986, 27, 5939-
5942. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem. Soc.
1988, 110, 3560-3578.
(12) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587-1590.
(13) In previous studies, we have shown that the presence of water in
the reaction mixture employed for the reductive opening of unsaturated
isoxazolines, analogous to 12a/b, leads to concomitant reduction of the
olefin; see 12. For a comparison of relative rates of reduction of
R,â-unsaturated esters, ketones, and imines by a related Sm(II) reductant,
see: Dahlen, A.; Hilmersson, G. Chem. Eur. J. 2003, 9, 1123-1128.
a Conditions: (a) H2, Pd-C, EtOH, 97%; (b) H2, Raney-Ni,
MeOH/H2O, B(OH)3, 85%; (c) Me4NBH(OAc)3, AcOH, MeCN;
(d) (CH3)2C(OCH3)2, p-TsOH; 85%, two steps.
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