Stereochemically rich pentaketides from bis(isoxazolines): A general strategy for efficient polyketide synthesis

Article abstract of DOI:10.1021/ol0490633

(Equation Presented) A strategy based on diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates has been applied to the synthesis of bis(isoxazolines) that are precursors to polyketide fragments. These intermediates ca

Full text of DOI:10.1021/ol0490633

ORGANIC
LETTERS
2004
Vol. 6, No. 14
2485-2488
Stereochemically Rich Pentaketides
from Bis(isoxazolines): A General
Strategy for Efficient Polyketide
Synthesis
Lee D. Fader and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie, ETH-Ho¨nggerberg HCI H335,
CH-8093 Zu¨rich, Switzerland
carreira@org.chem.ethz.ch
Received May 21, 2004
ABSTRACT
A strategy based on diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates has been applied to the synthesis
of bis(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols by chemoselective
reductive opening of each isoxazoline sequentially or, alternatively, both simultaneously, potentially providing access to all stereoisomers of
this carbon skeleton.
The total synthesis of polyketide natural products remains a
challenging area of modern organic chemistry that is driven
by the need to produce these compounds in sufficient
quantities for biological evaluation, chemical biology ap-
plications, and development of new medicines. Furthermore,
the structural diversity encompassed by this class of natural
products has provided a fertile arena for the development of
new synthetic methodology. For example, the last 20 years
has seen an explosion of applications of the now traditional
aldol and allylation/crotylation chemistry.1-3
We have been interested in the development of new
strategies that would provide a general and complementary
approach to polyketide construction. In this context, we
recently reported the application and development of the
nitrile oxide cycloaddition of magnesiated allylic alcohols
to furnish dipropionate fragments.4,5 In this approach, which
was pioneered by Curran throughout the 1980s,6 the ∆2-
isoxazoline serves as a masked â-hydroxy ketone that is
(2) For reviews on allylation/crotylation see: (a) Denmark, S. E.;
Almstead, N. G. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-
VCH: Weinheim, 2000; pp 299-401; (b) Chemler, S. R.; Roush, W. R. In
Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000;
pp 403-490.
(1) For recent reviews on the aldol reaction, see: (a) Palomo, C.;
Oiarbide, M.; Garcia, J. M. Chem. Eur. J. 2002, 8, 36-44. (b) Carreira, E.
M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Heidelberg, 1999; Vol. III, pp 997-
1065. (c) Heathcock, C. H. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergman: Oxford, 1991; Vol. 2, pp 133-179. (d)
Heathcock, C. H. In ComprehensiVe Organic Synthesis, Vol. 2; Trost, B.
M., Fleming, I., Eds.; Pergman: Oxford; 1991; pp 181-238. (e) Kim, B.
M.; Williams, S. F.; Masamune, S. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergman: Oxford; 1991; Vol. 2, pp 239-
275. (f) Cowden, C. J.; Paterson, I. In Organic Reactions; Paquette L. A.;
Wiley & Sons: New York, 1997; Vol. 51, pp 1-200.
(3) Other recent nonaldol approaches: (a) Smith, A. B., III; Adams, C.
M. Acc. Chem. Res. 2004, 37, 365-377. (b) Sneddon, H. F.; Gaunt, M. J.;
Ley, S. V. Org. Lett. 2003, 5, 1147-1150. (c) Hanessian, S.; Ma, J.; Wang,
W. Tetrahedron Lett. 1999, 40, 4627-4630. (d) Jung, M. E.; van den
Heuvel, A. Org. Lett. 2003, 5, 4705-4705.
(4) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2001, 40, 2082-2085.
(5) For a lead reference on Kanemasa’s work on the Mg2+-mediated
nitrile oxide cycloaddition, see: Kanemasa, S.; Nishiuchi, M.; Kamimura,
A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324-2339.
10.1021/ol0490633 CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/18/2004

Figure 1. Bis(isoxazoline) approach to polyketide construction.
revealed by reduction of the N-O bond followed by imine
hydrolysis. Advantages of this strategy include facile, dias-
tereoselective access to anti- and syn-aldol as well as methyl
ketone aldol equivalents using a single reaction protocol. Our
earlier account concluded by suggesting that use of bis-
(isoxazolines) may prove to be a viable approach to the
preparation of longer polyketide fragments. However, the
key issue of manipulating such systems (through bis-
reductive opening of a bis(isoxazoline)) was not addressed.
In this communication, we document our investigations into
the preparation and elaboration of fragments incorporating
bis(isoxazolines), and, importantly, we document the ability
to carry out their chemoselective, stepwise opening which
considerably expands access to polyketides subunits found
in natural products.
Our retrosynthetic analysis of several polyketide natural
products suggested that a diverse group of polyol building
blocks could be derived from a common class of linear
fragments incorporating bis(isoxazoline) intermediates, ir-
respective of the relative stereochemical pattern (Figure 1).
For example, bis(isoxazoline) 1 would permit access to
compounds 2 or 3, which contain syn,syn or anti,anti
stereotetrads, respectively, by simultaneous unmasking and
manipulation of both latent â-hydroxy ketones. Such a
strategy can only be employed if the relative stereochemical
relationships between pairs of 1,3-alcohols are identical, i.e.,
both syn or both anti. This constraint could be removed
provided that chemoselective unmasking and manipulation
of each â-hydroxy ketone could be attained. This would
furnish fragments 4 and 5, which possess anti,syn or syn,anti
stereotetrads. In such a scenario, the pairwise stereochemical
relationships of 1,3-diol subunits need not be identical. The
most versatile implementation of this strategy would involve
coupling of the various stereochemical permutations of
monoisoxazoline fragments through a reaction that would
not be ostensibly dependent on the stereochemical pattern
of the individual subunits. Thus, we needed to address two
key compelling issues: (1) facile coupling of isoxazoline
modules to afford bis(isoxazolines) and (2) successful
chemoselective manipulation of each isoxazoline ring.
To initiate our investigation of this approach to polyketide
construction, we prepared appropriately substituted isoxazo-
line building block partners that could be conveniently
coupled via an olefination reaction. Using our previously
described adaptation of Kanemasa’s nitrile oxide cyclo-
addition, isoxazoline 8 was prepared from readily available
oxime 6 and allylic alcohol 5 as a single diastereomer in
60% yield over four steps (Scheme 1). Similarly, sulfone
11 was prepared from chiral allylic alcohol 10 and oxime 9
as a single diasteromer in 72% yield over five steps.
Condensation of aldehyde 8 and sulfone 11 via a Kocienski-
modified Julia-Lythgoe olefination7 provided bis(isoxazo-
lines) 12a and 12b in 96% yield with an inconsequential
E/Z ratio of 30:70.8
Elaboration of bis(isoxazoline) 12a/b into protected
polyketide fragments was subsequently examined. Thus,
hydrogenation of the mixture of olefin isomers proceeded
in 97% yield (Scheme 2) to give saturated bis(isoxazoline)
(7) (a) Kocienski, P. J.; Bell, A.; Blakemore, P. R. Synlett 2000, 3, 365-
366. (b) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563-
2585.
(8) The lack of trans selectivity in this reaction was unexpected. For a
range of reaction conditions employed in an effort to improve the selectivity
of this coupling reaction, see Supporting Information.
(6) Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024-4026.
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Org. Lett., Vol. 6, No. 14, 2004

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.
Org. Lett., Vol. 6, No. 14, 2004
2487

reduction of the ketone followed by a protection step
provided acetonide 17 in 85% yield as a single diastereomer.
Finally, isoxazoline 17 was transformed to ketone 18 in 90%
yield. This ketone can be left as is or can then, in principle,
be reduced to either the corresponding 1,3-syn- or 1,3-anti-
diols at will.
Scheme 4. Synthesis of Aplyronine C22-C33 Polyola
As an additional demonstration of this strategy, we have
specifically applied this chemistry to the synthesis of 23,
which serves as a model system incorporating the stereo-
chemical pattern found in C22-C33 polyol subunit of
aplyronine A14 (Figure 2). Thus, isoxazoline building blocks
a Conditions: (a) KHMDS, THF, 75%, E/Z ) 45:55; (b) H2,
Pd-C, EtOH, 96%; (c) H2, Raney-Ni, MeOH/H2O, B(OH)3, 72%;
(d) Me4NBH(OAc)3, AcOH, MeCN; (e) (CH3)2C(OCH3)2, p-TsOH;
71%, two steps.
Figure 2. C22-C23 fragment of aplyronine A.
19 and 20 were prepared using the nitrile oxide cycloaddition
methodology and coupled in 75% yield to provide a 45:55
mixture of olefins 21a and 21b (Scheme 4). Subsequent
olefin reduction, isoxazoline ring opening, directed reduction
of the resulting ketones, and protection of the tetraol gave
bis(acetonide) 23 in 50% yield over four steps.
calolide,16 ulapualide,17 halichondramide,18 and potentially
bafilomycin,19 concanamycin,20 and formamicin21 skeletons.
Efforts to apply this strategy to such endeavors are currently
underway.
Acknowledgment. We thank the Swiss National Science
Foundation for generous support of this research. L.D.F.
thanks Natural Sciences and Engineering Research Council
of Canada for a postdoctoral fellowship.
In summary, we have shown that pentaketide fragments
are efficiently accessed from bis(isoxazoline) intermediates
prepared from aldehyde and sulfone isoxazoline coupling
partners. Since each stereocenter of fragments 15 or 18 is
set by the choice of chiral allylic alcohol and oxime
employed in the dipolar cycloaddition reaction, all 128
stereoisomers of this carbon skeleton could be accessed using
a single battery of chemical transformations. This is made
possible by the ability to manipulate an unsaturated isox-
azoline subunit within a larger fragment that contains a
saturated isoxazoline. Furthermore, the ability of unmasking
each â-hydroxy ketone separately not only facilitates instal-
lation of pendant side chains present within many polyketides
(e.g., esters, amino acids) but it also provides access to other
polyketide fragments represented by the sphinxolide,15 my-
Supporting Information Available: Detailed descrip-
tions of experimental procedures and analytical data for
compounds 6, 8, and 11-23. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0490633
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