Expanding stereochemical and skeletal diversity using petasis reactions and 1,3-dipolar cycloadditions

Article abstract of DOI:10.1021/ol102266j

A short and modular synthetic pathway using intramolecular 1,3-dipolar cycloaddition reactions and yielding functionalized isoxazoles, isoxazolines, and isoxazolidines is described. The change in shape of previous compounds and those in this study is quan

Full text of DOI:10.1021/ol102266j

ORGANIC
LETTERS
2010
Vol. 12, No. 22
5230-5233
Expanding Stereochemical and Skeletal
Diversity Using Petasis Reactions and
1,3-Dipolar Cycloadditions
Giovanni Muncipinto,† Taner Kaya,‡ J. Anthony Wilson,‡ Naoya Kumagai,§
Paul A. Clemons,‡ and Stuart L. Schreiber*,‡
Howard Hughes Medical Institute, Broad Institute of HarVard and MIT, 7 Cambridge
Center, Cambridge, Massachusetts 02142, United States, and Department of Chemistry and
Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138, United States
stuart_schreiber@harVard.edu
Received September 21, 2010
ABSTRACT
A short and modular synthetic pathway using intramolecular 1,3-dipolar cycloaddition reactions and yielding functionalized isoxazoles,
isoxazolines, and isoxazolidines is described. The change in shape of previous compounds and those in this study is quantified and compared
using principal moment-of-inertia shape analysis.
Small-molecule synthesis is enabling the testing of hypoth-
eses concerning the structural properties that enable suc-
cessful outcomes in probe and drug discovery. For example,
diversity-oriented synthesis was used recently to illuminate
roles for stereogenic elements and sp3 hybridization in the
outcome of binding assays using a large panel of diverse
proteins. Small molecules having these features showed
increased specificity and hit frequency relative to those
lacking these features.1
synthesized and densely functionalized amino alcohols. The
pathway yields functionalized isoxazoles, isoxazolines, and
isoxazolidines. As in a previous study,3 we used the Petasis
three-component, boronic acid based Mannich reaction4 in the
couple phase, where lactols and boronic acids are joined with
high anti-selectivity. By using different functional groups
incorporated in the build phase, we were able to perform
intramolecular “pairing” reactions yielding novel skeletons
(Figure 1). Using computational analyses, we demonstrate
quantitatively how the new pathway expands the scope of the
previous study and of screening candidates in general.
The Petasis reaction of (S)-lactol 2 (from L-phenyllactic
acid), amino acetal 3 (from L-phenylalaninol), and 4-meth-
oxyphenylboronic acid under ambient conditions in CH2Cl2
afforded the anti-diastereomer 4 with dr 94:6 in 79% yield.
The N-selective alkylation of 4 with propargyl bromide 5
Here, we report a short and modular synthetic pathway using
the “build/couple/pair” strategy2 with allylic alcohol rearrange-
ments and intramolecular 1,3-dipolar cycloadditions of readily
† Harvard University.
‡ Broad Institute of Harvard and MIT.
§ Current address: Graduate School of Pharmaceutical Sciences, The
University of Tokyo.
(1) Clemons, P. A.; Bodycombe, N. E.; Carrinski, H. A.; Wilson, J. A.;
Shamji, A. F.; Wagner, B. K.; Koehler, A. N.; Schreiber, S. L. Proc. Natl.
Acad. Sci. U.S.A. Published ahead of print October 18, 2010. DOI:, 10.1073/
pnas.1012741107.
(3) Kumagai, N.; Muncipinto, G.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3635–3638.
(4) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119,
445–446. (b) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1998, 120,
11798–11799.
(2) (a) Nielsen, T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008,
47, 48–56. (b) Schreiber, S. L. Nature 2009, 457, 153–154.
10.1021/ol102266j  2010 American Chemical Society
Published on Web 10/26/2010

86% yield, whereas the cis allylic alcohol 7 was obtained
using hydrogenation with Lindlar’s catalyst6 in 90% yield.
An Eschenmoser-Claisen rearrangement7 of 6 using N,N-
dimethylacetamide dimethyl acetal gave amide 8 in 82%
yield as single diastereomer. Compound 6 underwent an
Overman rearrangement rapidly at room temperature8 af-
fording allylic trichloroacetamide 9 as a single diastereomer
with complete transfer of chirality. The reaction was
performed in CH2Cl2 with trichloroacetonitrile and DBU as
base in slight excess.
Although not yet explored, the removal of the trichloro-
acetyl group should provide a versatile primary amino
function. Palladium(II)-catalyzed rearrangement of allylic
acetate9 6 furnished 10 as a single diastereomer in 78% yield.
The allylic alcohol 6 was isomerized in the presence of
[PdCl2(MeCN)2] (10 mol %) in CH2Cl2 at room temperature
overnight. All rearrangements proceeded with excellent
stereoselectivity, yielding (E)-alkenes, and with complete
transfer of chirality. Unfortunately, the same success was
not achieved with the cis allylic alcohol 7. Only the
Eschenmoser-Claisen rearrangement proceeded successfully,
giving the amide 11 in 92% yield as a single diastereomer.9b
We next studied intramolecular nitrile oxide (INOC) and
nitrone (INC) cycloadditions using 1c and 6-11 (Scheme
3).10,11 Nitrile oxides were generated in situ using N-
bromosuccinimide, catalytic pyridine, triethylamine,12 and
oximes derived from aldehyde derivatives of 1c and 6-11
with hydroxylamine hydrochloride (65-79%). While stan-
dard acidic hydrolysis of the acetal failed, microwave-assisted
conditions using catalytic pyridinium p-toluenesulfonate
succeeded, generating the corresponding aldehydes of 1c and
6-11.13
Figure 1. Comparison of previous and current study.
using microwave radiation afforded the template 1a in 86%
yield (Scheme 1). Standard conditions for the N-alkylation
Scheme 1. Three-Component Petasis Reaction and N-Alkylation
resulted in a poor yield or decomposition of propargyl
bromide.
We next explored allylic alcohol rearrangements with the
templates 6 and 7 (Scheme 2). Acetylation of 1a and selective
Intramolecular cycloadditions of the corresponding nitrile
oxides of these aldehydes bearing alkene or alkyne groups
provided bicyclic compounds 12-16 (oxime formation;
N-bromosuccinimide, catalytic pyridine and triethylamine in
CH2Cl2 at -78 °C; 55-75% yield). Compounds 14 and 16
were obtained as single diastereomers, whereas 13 and 15
were obtained as easily separable diastereomixtures. The
Scheme 2. Allylic Alcohol Rearrangement Reactions
(6) Lindlar, H.; Dubuis, R. Org. Synth. 1966, 46, 89–92.
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Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901–2910. (c) Overman,
L. E. Acc. Chem. Res. 1980, 13, 218–224. (d) Nishikawa, T.; Asai, M.;
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NY, 1984; Vol. 2, pp 368-372.
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6335. (b) Padwa, A. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.;
Wiley: New York, NY, 1984; Vol. 2, pp 279-304.
deprotection of tert-butyldiphenylsilyl ether of 1b afforded
1c in 93% yield over two steps. Compound 1c was then
subjected to stereoselective reductions of its alkyne moiety.
(12) (a) Grundmann, C.; Richter, R. J. Org. Chem. 1968, 33, 476–478.
For a comprehensive study of nitrile oxide in 1,3-dipolar cycloaddition,
see: (b) Caramella, P.; Grunanger, P. 1,3-Dipolar Cycloaddtion Chemistry;
Padwa, A., Ed.; Wiley: New York, NY, 1984; Vol. 1, pp 291-392. (c)
Torssell, K. B. G. Nitrile Oxides, Nitrones, Nitronates in Organic Synthesis;
VCH: New York, NY, 1988; pp 55-74.
5
The trans allylic alcohol 6 was obtained using LiAlH4 in
(5) (a) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem.
Soc. 1967, 89, 4245–4247. (b) Grant, B.; Djerassi, C. J. Org. Chem. 1974,
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Org. Lett., Vol. 12, No. 22, 2010
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isoxazoline during the workup. Except for 18, all isoxazo-
lidines were obtained as stereomerically pure substances. The
stereochemistry of the isoxazolidine rings was assigned using
1H NMR, COSY, and differential NOE and by comparing
data from with similar compounds (Table 1).18,19
Scheme 3
.
Intramolecular Nitrile Oxide and Nitrone
Cycloaddition Reactionsa
Table 1. NOE, J, and Φ Values for Compounds 18-21
NOEa
Jb
NOEa
Jb
NOEa
compd H3/H7 H3/H7 Φ H3/H7 H2/H3 H2/H3 Φ H2/H3 H7/H8
18
18′
19
20
21
4.05
5.18
4.26
4.32
6.75
7.5
8.5
5.0
9.0
5.5
15°
0°
38°
0°
2.50
6.30
2.25
2.15
2.30
0
100°
0°
115°
100°
120°
2.47
0
4.52
4.89
0
8.5
1.5
0
35°
2.0
a NOE values in %. b J values in Hz.
a 13, 18 R ) CH2CONMe2; 14, 19 R ) NHCOCCl3; 15, 20 R ) OAc.
Reagents and conditions: (a′) Ac2O, DMAP, py, rt; (a) MW, pyridinium
p-toluensulfonate (PPTS) (30 mol %), acetone, 10 min at 80 °C, 15 min at
100 °C; (b) N-hydroxylamine hydrochloride, NaHCO3, dry MeOH, rt; (b′)
N-methylhydroxylamine hydrochloride, NaHCO3, dry toluene, rt to 80 °C;
(c) Et3N, py (cat.), NBS, dry CH2Cl2, -78 °C. [a] Single diastereomer. [b]
14, 19, and 20 single diastereomers; 13 dr 4:1, 15 dr 1.5:1, 18 dr 1:1.
As illustrated in the proposed transition states (Figure 2),
the approach of the allylic group to the nitrone from the re
stereochemistry was assigned by differential NOE spectros-
copy and by comparing data from with similar compounds.14
Unfortunately, the acetal hydrolysis was not as successful
with the scaffolds 6 and 7 due to decomposition in the acetal
hydrolysis step, but the final isoxazolines, albeit in poor yield,
were obtained (see Supporting Information).
When the unsubstituted hydroxylamine was replaced by
N-methyl hydroxylamine hydrochloride with heating at 80
°C in toluene,15 the presumed (Z)-nitrones16 yielded isox-
azolidines 17-21 in 47-50% yield over 3 steps. Intramo-
lecular nitrone cycloadditions of 6 and 7 proceeded in poor
yield due to problems with the acetal hydrolysis. Moreover,
when the alkyne group in 1c was allowed to react with the
nitrone under identical conditions, the expected isoxazoline
was not isolated. Only 17 was obtained in appreciable yield
(50%) over 3 steps.17 Water reacted with the unstable
Figure 2. Nitrone group is attacked from (a) re side and (b) si side
for 18-20; (c) re side and (d) si side for 21.
side having a minor steric interaction between nitrone oxygen
and hydrogen at position 2 is more favorable than an attack
from the si side having a major steric interaction between
oxygen and benzyl group.20 The trans-orientation at positions
2 and 3 and cis-orientation at positions 3, 7, and 8 were
assigned for 18-20 from coupling constants and NOE
measurements. This conformation benefits from the favorable
quasi-equatorial positions of the substituents at position 2
(14) Noguchi, M.; Tsukimoto, A.; Kadowaki, A.; Hikata, J.; Kakehi,
A. Tetrahedron Lett. 2007, 48, 3539–3542.
(15) (a) Chou, S. P.; Yu, Y. Tetrahedron Lett. 1997, 38, 4803–4806.
(b) Aurich, H. G.; Geiger, M.; Gentes, C.; Harms, K.; Koster, H.
Tetrahedron 1998, 54, 3181–3196. (c) Baskaran, S.; Aurich, H. G.;
Biesemeier, F.; Harms, K. J. Chem. Soc., Perkin Trans. 1 1998, 3717–
3724. (d) Hems, W. P.; Tan, C.; Stork, T.; Feeder, N.; Holmes, A. B.
Tetrahedron Lett. 1999, 40, 1393–1396. (e) Broggini, G.; La Rosa, C.; Pilati,
T.; Terraneo, A.; Zecchi, G. Tetrahedron 2001, 57, 8323–8332. (f) Kalita,
P. K.; Baruah, B.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 7779–7782.
(16) (a) Tufariello, J. J. 1,3-Dipolar Cycloaddtion Chemistry; Padwa,
A., Ed.; Wiley: New York, NY, 1984; Vol. 2, pp 83-168. (b) Torssell,
K. B. G. Nitrile Oxides, Nitrones, Nitronates in Organic Synthesis; VCH:
New York, NY, 1988; pp 75-93. (c) Annunziata, R.; Cinquini, M.; Cozzi,
F.; Raimondi, L. Tetrahedron Lett. 1988, 29, 2881–2884.
(18) (a) Oppolzer, W.; Keller, K. Tetrahedron Lett. 1970, 11, 1117–
1120. (b) Gotoh, M.; Mizui, T.; Sun, B.; Hirayama, K.; Noguchi, M.
J. Chem. Soc., Perkin Trans. 1 1995, 1857–1862. (c) Tanaka, M.; Hikata,
J.; Yamamoto, H.; Noguchi, M. Heterocycles 2001, 55, 223–226. (d)
Chatterjee, A.; Bhattacharya, P. K. J. Org. Chem. 2005, 71, 345–348. (e)
Shing, T. K. M.; Wong, A. W. F.; Ikeno, T.; Yamada, T. J. Org. Chem.
2006, 71, 3253–3263
(19) Hess, M.; Meier, H.; Zeeh, B. Spektroskopische Methoden in der
Organischen Chemie; Georg Thieme Verlag: Stuttgart, 1991; p 105
.
.
(20) (a) Aurich, H. G.; Koster, H. Tetrahedron 1995, 51, 6285–6292.
(b) Kametani, T. J. Chem. Soc., Perkin Trans. 1 1989, 2215–2221.
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5232
Org. Lett., Vol. 12, No. 22, 2010

and 8 that are quasi-axial in the si side attack. For 21, the
two possible transition states show how the asymmetric
induction by the intramolecular cycloaddition is primarily
controlled by the stereogenic center next to the nitrone.
We performed a computational analysis of the molecular
shape space spanned by the library described here (LIB1)
and one described in our previous study (LIB2).3 We
calculated normalized principal moment-of-inertia (PMI)
ratios,21 which allow chemists to quantify molecular shapes
in terms of intuitive geometric ideas of shape. Ratios of each
of the two lower magnitude PMIs (Ismall, Imedium) to the highest
magnitude PMI (Ilarge) were plotted as characteristic coor-
dinates (Ismall/Ilarge, Imedium/Ilarge) of normalized PMI ratios for
minimum-energy conformers of each compound (Figure 3).
and spread in PMI space using a Kolomorgov-Smirnov (KS)
test.22 To understand this difference in terms of shape, we
tested whether one library was significantly closer to the rod,
disk, or sphere vertices of PMI space than the other. We
also used the disk and sphere canonical shapes as reference
points for our recently reported R shape-based descriptor.23
Differences in R shape-based distances to the sphere shape
were significant (p ) 1.16 × 10-4), whereas those relative
to the flat shape were not. In PMI space, we found that
differences between libraries relative to the sphere shape were
significant (p ) 5.86 × 10-4). Both results indicate that LIB1
molecules tend more toward a spherical shape than do LIB2
molecules. Future studies of these libraries might entail more
detailed examination of the relative roles of building blocks,
skeletons, and stereochemistry on changes in shape.24
We started this research with the hypothesis that densely
substituted and skeletally diverse small molecules will
facilitate successful outcomes in probe and drug discovery.
This new DOS pathway should enable the further testing of
this hypothesis following probe-development efforts. PMI
shape analysis quantifies the differences between the two
libraries and demonstrates how simple synthetic variations
in functional groups, incorporated in the “build phase”, can
yield significant changes in molecular shape.
Acknowledgment. The NIGMS-sponsored Center of
Excellence in Chemical Methodology and Library Devel-
opment (P50-GM069721) enabled this research. G.M.
thanks Yikai Wang currently at the Department of
Chemistry and Chemical Biology (Harvard University),
Drs. Michele Melchiorre currently at the Institute of the
Organic Synthesis and Photoreactivity of CNR, Daniela
Pizzirani currently at the Italian Institute of Technology
(IIT), Manuela Rodriquez currently at the Department of
Pharmacological Sciences (University of Salerno), Qiu
Wang currently at the Broad Institute, and Masaaki Hirano
currently at Astellas Pharma Inc. for helpful discussions.
S.L.S. is an investigator with the Howard Hughes Medical
Institute.
Figure 3. Change in molecular shape introduced by new DOS
library and PMI space comparison of LIB1 (this study) vs LIB2
(ref 3). (A) PMI space coverage for both libraries LIB1 (blue) and
LIB2 (red). (B) Distance distributions for LIB1 (blue) vs LIB2 (red)
relative to the canonical sphere; conceptual depiction of distances
for two arbitrary data sets (inset). Point densities in binned PMI
space for LIB2 (C) vs LIB1 (D).
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Points in PMI plots occupy a triangle defined by the
vertices (0,1), (0.5,0.5), and (1,1) and corresponding to the
canonical shapes of rod, disk, and sphere, respectively. To
quantify the change in shape of LIB2 (42 structures) relative
to LIB1 (31 structures), we calculated distances for members
of both libraries from the geometric center of LIB2. These
two populations of distances differed significantly in location
OL102266J
(22) Sheshkin, D. J. Handbook of Parametric and Nonparametric
Statistical Procedures, 2nd ed.; Chapman & Hall/CRC: New York, 2004.
(23) Wilson, J. A.; Bender, A.; Kaya, T.; Clemons, P. A. J. Chem. Inf.
Model. 2009, 49, 2231–2241.
(21) Sauer, W. H.; Schwarz, M. K. J. Chem. Inf. Comput. Sci. 2003,
43, 987–1003.
(24) Pizzirani, D.; Kaya, T.; Clemons, P. A.; Schreiber, S. L. Org. Lett.
2010, 12, 2822–2825.
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