A modular approach to polyketide building blocks: Cycloadditions of nitrile oxides and homoallylic alcohols

Article abstract of DOI:10.1021/ol0504953

(Chemical Equation Presented) A general approach to the diastereoselective synthesis of Δ²-isoxazolines via magnesium-mediated, hydroxyl-directed diastereoselective nitrile oxide cycloadditions of homoallylic alcohols and monoprotected homoallylic diols is disclosed. A broad spectrum of aliphatic and aromatic nitrile oxides and a variety of homoallylic alcohols participate in the cycloaddition, thus expanding the scope of polyketide building blocks that can be accessed using this strategy.

Full text of DOI:10.1021/ol0504953

ORGANIC
LETTERS
2
005
Vol. 7, No. 10
011-2014
A Modular Approach to Polyketide
Building Blocks: Cycloadditions of
Nitrile Oxides and Homoallylic Alcohols
Nina Lohse-Fraefel and Erick M. Carreira*
2
Laboratorium f u¨ r Organische Chemie, ETH H o¨ nggerberg, HCI,
H335, CH-8093 Z u¨ rich, Switzerland
carreira@org.chem.ethz.ch
Received March 8, 2005
ABSTRACT
A general approach to the diastereoselective synthesis of ∆2-isoxazolines via magnesium-mediated, hydroxyl-directed diastereoselective nitrile
oxide cycloadditions of homoallylic alcohols and monoprotected homoallylic diols is disclosed. A broad spectrum of aliphatic and aromatic
nitrile oxides and a variety of homoallylic alcohols participate in the cycloaddition, thus expanding the scope of polyketide building blocks
that can be accessed using this strategy.
The potent biological activity and stereochemical complexity
of polyketide natural products render them attractive synthetic
targets; moreover, the synthesis of useful building blocks
for polyketide construction is an important task in organic
synthesis. Although the generally employed methods ad-
and optically active allylic alcohols.4,5 The efficient nitrile
oxide cycloaddition permits the direct synthesis of a broad
spectrum of dipropionate subunits of various stereochemical
permutations, following a single reaction protocol. The utility
6
of the prepared cycloadducts as masked aldol products has
1,2
dressing this objective involve carbonyl addition reactions,
been demonstrated in the applications to the total syntheses
3
7
several alternative approaches have been disclosed.
of complex natural products and for the preparation of
8,9
We have recently reported highly regio- and diastereoselec-
tive nitrile oxide cycloadditions of aliphatic chiral nitrile oxides
stereochemically rich pentaketides. In this communication,
we document the successful extension of this methodology
to nitrile oxide cycloadditions with homoallylic alcohols (eq
1). The modular nature of the presented protocol considerably
expands the constellation of protected polyketide subunits
that can be attained from readily available starting materials.
(1) For aldol addition approaches to polyketide building blocks, see: (a)
Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982, 13, 1. (b)
Paterson, I.; Cannon, J. A. Tetrahedron Lett. 1992, 33, 797. (c) Paterson,
I. In Modern Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim,
2
000; pp 249-297. (d) Carreira, E. M. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Heidelberg, 1999; Vol. III, pp 997-1065. (e) Heathcock, C. H. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 2, pp 133-238.
(2) For the use of allylation, crotylation, and allenylmetal reagents in
polyketide synthesis, see: (a) Denmark, S. E.; Almstead, N. G. In Modern
Carbonyl Chemistry; Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; pp 299-
4
01. (b) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry;
The diastereoselective cycloaddition reaction of nitrile oxides
and allylic alcohols has been intensively studied. By contrast,
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; pp 403-490. (c) Marshall,
J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63, 817.
(
3) For recent examples, see: (a) Smith, A. B., III; Adams, C. M. Acc.
Chem. Res. 2004, 37, 365. (b) Meyer, C.; Blanchard, N.; Defosseux, M.;
Cossy, J. Acc. Chem. Res. 2003, 36, 766. (c) Lautens, M.; Paquin, J.-F.
Org. Lett. 2003, 5, 3391. (d) Misske, A. M.; Hoffmann, H. M. R. Chem.
Eur. J. 2000, 6, 3313. (e) Breit, B.; Zahn, S. K. J. Org. Chem. 2001, 66,
(4) Bode, J. W.; Fraefel, N.; Muri, D.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2001, 40, 2082.
(5) For a lead reference, see: Kanemasa, S.; Nishiuchi, M.; Kamimura,
A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324.
4
1
870. (f) Myles, D. C.; Danishefsky, S. J. Pure Appl. Chem. 1989, 61,
235.
(6) For the transformation of isoxazolines to the corresponding â-hydroxy
ketones, see: Curran, D. P. J. Am. Chem. Soc. 1982, 104, 4024.
1
0.1021/ol0504953 CCC: $30.25
© 2005 American Chemical Society
Published on Web 04/15/2005

the cycloaddition reaction of the homologue has received
scant attention. A recent study by Kociolek examin-
ed the cycloaddition of a single nitrile oxide, namely, that
derived from benzoic acid, and as disclosed below, the struc-
Table 1. Nitrile Oxide Cycloadditions with
S)-2-Methyl-3-butenol
(
10
ture was misassigned. Importantly, with respect to our inter-
est in developing this strategy as a general approach to poly-
ketide building blocks, we were interested in conducting a
broad study with nitrile oxides that would be useful for poly-
ketide construction. At the outset of the investigation there
were two clear problems that could be foreseen: (1) homo-
allylic alkoxides would be considerably less reactive than
the allylic alkoxides that have been studied, and consequently
(2) the use of aliphatic nitrile oxides would be precluded for
use in the process as these are prone to undergo dimerization
in the absence of a good olefinic coupling partner. Moreover,
in the course of such studies, we aimed to overcome the
inherent limitation of any highly diastereoselective reaction
wherein accessing the complementary diastereomers can only
be done with difficulty. Thus we wished to develop diaste-
reoselective strategies that would provide access to the
various stereochemical permutations of dipropionate subunits
Scheme 1
(Scheme 1), permitting divergent asymmetric synthesis from
a single diastereoselective cycloaddition reaction.
As shown in Table 1, a broad range of aliphatic and aroma-
tic nitrile oxides smoothly undergo cycloaddition with (S)-
2-methyl-3-butenol under conditions we have previously opti-
mized for allylic alcohols. The nitrile oxides were usually gen-
erated in situ according to standard procedures using tBuOCl
or NCS. For entries 8 and 11 in Table 1, the intermediate
hydroximinoyl chlorides were isolated and used without fur-
ther purification, and for the phosphonate-derived nitrile oxide
a
1
b
Determined by H NMR analysis of the unpurified adduct. Determined
after filtration over a short pad of silica gel. c Determined by 13C NMR
analysis of the unpurified adduct. d NCS instead of tBuOCl was used. The
e
(cf. entry 9), purification of the intermediate hydroximinoyl
f
intermediate hydroximinoyl chloride was isolated. Determined after con-
chloride by chromatography proved advantageous for obtain-
ing the corresponding cycloadduct in high yield (entry 9 vs
entry 10). Optimization studies revealed that best results were
obtained by slow addition of the hydroximinoyl solution to
the solution of alkoxides over 1-1.5 h at 0 °C. After 6 h at 0
densation with benzaldehyde. g Yield based on the hydroximinoyl chloride,
h
which was isolated in 81% yield from the corresponding oxime. 1.1 equiv
of tBuOCl was used.
room temperature over 12. The densely functionalized cyclo-
adducts were formed in 66-89% yield and anti diastereo-
selectivities (vide infra) ranging from 4:1 to 13:1.
The diastereomeric ratios were generally determined by
1H or C NMR analysis of the unpurified material unless
°
C, the reaction mixture was gradually allowed to warm to
(7) Bode, J. W.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 3611.
(8) Fader, L. D.; Carreira, E. M. Org. Lett. 2004, 6, 2485.
(9) Bode, J. W.; Carreira, E. M. Org. Lett. 2001, 3, 1587.
13
2012
Org. Lett., Vol. 7, No. 10, 2005

otherwise stated. For cycloadducts (entries 9 and 10) that
incorporate a phosphonate, the unpurified reaction product
was allowed to condense with benzaldehyde (DBU, LiCl,
MeCN) to afford the corresponding olefin, which was then
Scheme 3. Chemical Shift Correlations
1
subjected to analysis by H NMR spectrum to determine the
diastereoselectivity in the cycloaddition.
The relative stereochemistry was established by conversion
of cycloadduct 1 into known isoxazoline 4 (Scheme 2), for
Scheme 2. Synthesis of Isoxazoline 4
diastereomer. These results suggest that the prior stereo-
chemical assignment is in need of reevaluation.
The protocol developed for nitrile oxide cycloadditions
with homoallylic alcohols proved equally successful for
monoprotected homoallylic diols (Table 2), which were
which the relative stereochemistry had been previously
11
established. Isoxazoline 1, a 10:1 mixture of diastereomers,
was readily converted to the corresponding methyl ester 2
in 70% yield (3 steps). Deprotection of the silyl ether with
TBAF afforded alcohols 3a and 3b (87%), which were then
separated. Protection of the primary alcohol in 3b afforded
benzyl ether 4 in 62% yield. Isoxazoline 4 proved identical
Table 2. Nitrile Oxide Cycloadditions with Monoprotected
Homoallylic Diols
1
13
by H and C NMR in all respects to the data previously
reported for this compound, confirming the syn relationship
in this minor diastereomer and therefore an anti relationship
for the major diastereomer.1
1,12
In their studies on nitrile oxide cycloadditions with homo-
10
allylic alcohols, Kociolek and Hongfa assigned the relative
stereochemistry of the major product with the benzaldehyde
derived nitrile oxide (5) as syn (Scheme 3). They concluded
1
this from an analysis of H NMR chemical shifts and cou-
pling constants for the C
5
-H signals of the two diastereomers
5
and 6. Earlier work with related esters 7 and 8 had revealed
5
a trend with the C proton diastereomer at higher field for the
1
1
syn adduct 7 compared to that of the anti stereoisomer 8.
The conversion of primary alcohol 1 into methyl ester 2
allowed us to examine the validity of such a correlation in
structure assignment. For the cycloadducts possessing a
5
primary alcohol functionality the signal for the C isoxazoline
proton of the major anti diastereomer appeared upfield to
that of the corresponding signal for the minor syn diastere-
omer in the H NMR spectrum. When the primary alcohol
1
a
1
b
Determined by H NMR analysis of the unpurified material. Deter-
mined by 13C NMR analysis of the unpurified material.
moiety was oxidized to the corresponding methyl ester, the
5
opposite pattern was observed: the signal of the C isox-
azoline proton of the major diastereomer appeared now more
downfield than the corresponding signal of the minor
readily prepared from (Z)-butenediol via Wittig rearrange-
1
3
ment. A variety of monoprotected homoallylic diols
underwent cycloaddition with the nitrile oxide generated in
situ from oxime 9. The cycloadducts were formed in 53-
(10) Kociolek, M. G.; Hongfa, C. Tetrahedron Lett. 2003, 44, 1811.
11) Panek, J. S.; Beresis, R. T. J. Am. Chem. Soc. 1993, 115, 7898.
(
Org. Lett., Vol. 7, No. 10, 2005
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8
2
5% yield and in diastereomeric ratios ranging from 6:1 to
1:1. A positive correlation between both yield and diaste-
We have documented an alternative approach to masked
polyketide building blocks via magnesium-mediated, hy-
droxyl-directed diastereoselective nitrile oxide cycloadditions
with homoallylic alcohols and monoprotected homoallylic
diols. Through the use of monoprotected homoallylic diols,
not only anti diastereomers are accessible but the corre-
sponding syn-diastereomers as well by a simple orthogonal
protection-deprotection sequence. The method we describe
considerably expands the type of polyketide units that can
be accessed reliably through the use of nitrile-oxide cycload-
dition reactions. Further studies of these reactions are
ongoing, as well as applications in natural products synthesis,
which will be reported as results become available.
reoselectivity and the steric demand of the resident protective
group was observed. Best results were obtained with the
bulky trityl and TBDPS protective groups (entries 1 and 2).
Although the immediate cycloadducts 10 possess an anti
relationship, the corresponding syn derivatives could readily
be accessed by a simple orthogonal protection-deprotection
sequence of the primary alcohols. It is therefore possible to
secure both syn and anti diastereomers from the same set of
starting materials using the identical transformation.
(
12) The anti relationship was confirmed for two additional cycloadducts
Table 1, entries 3 and 4) via derivatization and subsequent NOE
experiments, as shown below:
(
Acknowledgment. We thank the Swiss National Science
Foundation and F. Hoffmann-LaRoche for their generous
support of our research program.
Supporting Information Available: Experimental pro-
cedures and spectral data for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(13) For the synthesis for the corresponding THP derivative, see:
Kozikowski, A. P.; Scripko, J. G. J. Am. Chem. Soc. 1984, 106, 353.
OL0504953
2014
Org. Lett., Vol. 7, No. 10, 2005